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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 79




    DICHLORVOS










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

    First draft prepared by Dr. J. Sekizawa
    (National Institute of Hygienic Sciences, Japan)
    and Dr. M. Eto (Kyushu University, Japan) with
    the assistance of Dr. J. Miyamoto and
    Dr. M. Matsuo (Sumitomo Chemical Company)

    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


         The International Programme on Chemical Safety (IPCS) is a
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        ISBN 92 4 154279 9 

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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR DICHLORVOS

 1. SUMMARY AND RECOMMENDATIONS 

    1.1. General               
    1.2. Environmental transport, distribution, and transformation     
    1.3. Environmental levels and human exposure   
    1.4. Kinetics and metabolism   
    1.5. Effects on organisms in the environment   
    1.6. Effects on experimental animals and  in vitro test systems 
    1.7. Effects on man        

 2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS  

    2.1. Identity              
    2.2. Physical and chemical properties  
    2.3. Conversion factors    
    2.4. Analytical methods    
          2.4.1. Sampling methods  
                  2.4.1.1   Food and feed   
                  2.4.1.2   Blood   
                  2.4.1.3   Air 
          2.4.2. Analytical methods    
                  2.4.2.1   Analysis of technical and formulated 
                            dichlorvos products 
                  2.4.2.2   Determination of dichlorvos residues    
                  2.4.2.3   Confirmatory tests  
                  2.4.2.4   Food    
                  2.4.2.5   Blood   
                  2.4.2.6   Air 
                  2.4.2.7   Soil and water  

 3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE             

    3.1. Natural occurrence    
    3.2. Man-made sources  
          3.2.1. Production levels and processes   
                  3.2.1.1   Worldwide production figures    
                  3.2.1.2   Manufacturing process   
          3.2.2. Uses          
          3.2.3. Accidental release    

 4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION       

    4.1. Transport and distribution between media  
    4.2. Biotransformation 
          4.2.1. Abiotic degradation   
          4.2.2. Biodegradation    
          4.2.3. Bioaccumulation and biomagnification  
    4.3. Ultimate fate following use   

 5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE 

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

 6. KINETICS AND METABOLISM 

    6.1. Absorption            
          6.1.1. Human studies 
    6.2. Distribution          
          6.2.1. Studies on experimental animals   
                  6.2.1.1   Oral    
                  6.2.1.2   Inhalation  
                  6.2.1.3   Intraperitoneal 
                  6.2.1.4   Intravenous 
    6.3. Metabolic transformation  
          6.3.1. Metabolites   
    6.4. Elimination and excretion in expired air, faeces, and urine   
          6.4.1. Human studies 
          6.4.2. Studies on experimental animals   
                  6.4.2.1   Oral    
                  6.4.2.2   Parenteral  
    6.5. Retention and turnover    
          6.5.1. Biological half-life  
          6.5.2. Body burden   
          6.5.3. Indicator media   

 7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT 

    7.1. Microorganisms        
          7.1.1. Algae and plankton    
          7.1.2. Fungi         
          7.1.3. Bacteria      
    7.2. Aquatic organisms 
          7.2.1. Fish          
                  7.2.1.1   Acute toxicity  
                  7.2.1.2   Short-term toxicity 
          7.2.2. Invertebrates 
    7.3. Terrestrial organisms 
          7.3.1. Birds         
                  7.3.1.1   Acute oral toxicity 
                  7.3.1.2   Short-term toxicity 
                  7.3.1.3   Field experience    
          7.3.2. Invertebrates 
          7.3.3. Honey bees    
          7.3.4. Miscellaneous 

 8. EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS     

    8.1. Single exposures  
          8.1.1. Domestic animals  
          8.1.2. Potentiation  

    8.2. Short-term exposures  
          8.2.1. Oral          
                  8.2.1.1   Mouse   
                  8.2.1.2   Rat 
                  8.2.1.3   Rabbit  
                  8.2.1.4   Cat 
                  8.2.1.5   Dog 
                  8.2.1.6   Pig 
                  8.2.1.7   Cow 
          8.2.2. Dermal        
                  8.2.2.1   Rat 
                  8.2.2.2   Livestock   
          8.2.3. Inhalation    
                  8.2.3.1   Experimental animals    
                  8.2.3.2   Domestic animals    
          8.2.4. Studies on ChE activity   
    8.3. Skin and eye irritation; sensitization    
    8.4. Long-term exposure    
          8.4.1. Oral          
                  8.4.1.1   Rat 
                  8.4.1.2   Dog 
          8.4.2. Inhalation    
                  8.4.2.1   Rat 
    8.5. Reproduction, embryotoxicity, and teratogenicity      
          8.5.1. Reproduction  
                  8.5.1.1   Effects on testes   
                  8.5.1.2   Effect on estrous cycle 
                  8.5.1.3   Domestic animals    
          8.5.2. Embryotoxicity and teratogenicity 
                  8.5.2.1   Oral    
                  8.5.2.2   Inhalation  
                  8.5.2.3   Intraperitoneal 
          8.5.3. Résumé of reproduction, embryotoxicity, and 
                  teratogenicity studies    
    8.6. Mutagenicity and related end-points   
          8.6.1. Methylating reactivity    
                  8.6.1.1    In vitro studies    
                  8.6.1.2    In vivo studies 
                  8.6.1.3   Discussion of methylating reactivity    
          8.6.2. Mutagenicity  
                  8.6.2.1    In vitro studies    
                  8.6.2.2    In vivo studies 
    8.7. Carcinogenicity       
          8.7.1. Oral          
                  8.7.1.1   Mouse   
                  8.7.1.2   Rat 
          8.7.2. Inhalation    
                  8.7.2.1   Rat 
          8.7.3. Appraisal of carcinogenicity  
    8.8. Mechanisms of toxicity; mode of action    
    8.9. Neurotoxicity         
          8.9.1. Delayed neurotoxicity 
          8.9.2. Mechanism of neurotoxicity    
    8.10. Other studies         
          8.10.1. Immunosuppressive action  

    8.11. Factors modifying toxicity; toxicity of metabolites       
          8.11.1. Factors modifying toxicity    
          8.11.2. Toxicity of metabolites   
                  8.11.2.1  Acute toxicity  
                  8.11.2.2  Short-term exposures    
                  8.11.2.3  Long-term exposure  
                  8.11.2.4  Mutagenicity    
                  8.11.2.5  Metabolism  

 9. EFFECTS ON MAN              

    9.1. General population exposure   
          9.1.1. Acute toxicity    
                  9.1.1.1   Poisoning incidents 
          9.1.2. Effects of short- and long-term exposure      
                  9.1.2.1   Studies on volunteers   
                  9.1.2.2   Hospitalized patients
    9.2. Occupational exposure 
          9.2.1. Acute toxicity    
                  9.2.1.1   Poisoning incidents 
          9.2.2. Effects of short- and long-term exposure  
                  9.2.2.1   Pesticide operators and factory workers
                  9.2.2.2   Mixed exposure  

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

    10.1. Evaluation of human health risks  
    10.2. Evaluation of effects on the environment  
    10.3. Conclusions           

11. RECOMMENDATIONS     

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES    

REFERENCES              

WHO TASK GROUP ON DICHLORVOS

 Members
Dr L. Albert, Environmental Pollution Programme, National Institute of
   Biological Resource Research, Veracruz, Mexico
Dr E. Budd, Office of Pesticide Programs, US  Environmental  Protection
   Agency, Washington DC, USA
Mr T.P. Bwititi, Ministry of Health, Causeway, Harare, Zimbabwe
Dr S.  Deema,  Ministry  of  Agriculture  and  Cooperatives,  Bangkok,
   Thailand
Dr I. Desi, Department of Hygiene and Epidemiology,  Szeged  University
   Medical School, Szeged, Hungary
Dr A.K.H.  El  Sebae,  Pesticides  Division,  Faculty  of Agriculture,
   Alexandria University, Alexandria, Egypt
Dr R. Goulding, Keats  House, Guy's Hospital,  London, United  Kingdom
   (Chairman)
Dr J.  Jeyaratnam, National  University  of Singapore,  Department  of
   Social  Medicine and Public  Health, Faculty of  Medicine, National
   University Hospital, Singapore  (Vice-Chairman)
Dr Y.  Osman,  Occupational  Health  Department,  Ministry  of Health,
   Khartoum, Sudan
Dr A.  Takanaka,  Division  of  Pharmacology,  National  Institute  of
   Hygienic Sciences, Tokyo, Japan

 Observers
Dr N. Punja, European Chemical Industry, Ecology and Toxicology Centre
   (ECETOC), Brussels, Belgium
Ms J.  Shaw,  International   Group  of  National   Associations   of
   Manufacturers of Agrochemical Products (GIFAP), Brussels, Belgium

 Secretariat
Dr M. Gilbert, International Register of Potentially  Toxic  Chemicals,
United Nations Environment Programme, Geneva, Switzerland
Dr K.W. Jager, International Programme on Chemical Safety, World Health
   Organization, Geneva, Switzerland  (Secretary)
Dr T. Ng, Office of Occupational Health, World Health
   Organization, Geneva, Switzerland
Dr G. Quélennec, Pesticides Development and Safe Use Unit, World Health
   Organization, Geneva, Switzerland
Dr R.C.  Tincknell,  Beaconsfield,  Buckinghamshire,  United  Kingdom
    (Temporary Adviser)
Dr G.J. Van Esch,  Bilthoven, Netherlands  (Temporary   Adviser)   (Co-
   Rapporteur)
Dr E.A.H. Van Heemstra-Lequin, Laren, Netherlands  (Temporary  Adviser)
   (Co-Rapporteur)

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.  988400 - 985850).

ENVIRONMENTAL HEALTH CRITERIA FOR DICHLORVOS

    A  WHO Task Group on  Environmental Health Criteria for  Dichlorvos
met in Geneva from 1 to 5 December 1986.  Dr M. Mercier, Manager, IPCS,
opened the meeting and welcomed the participants on behalf of the heads
of  the  three  IPCS co-sponsoring  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 dichlorvos.

    The  drafts  of  the  document  were  prepared   by   DR E.A.H. VAN
HEEMSTRA-LEQUIN and DR G.J. VAN ESCH of the Netherlands.

    Draft summaries of Japanese studies on dichlorvos were prepared and
finalized  by DR  M. ETO  (Kyushu University),  and DR J. MIYAMOTO  and
DR M. MATSUO (Sumitomo Chemical Co., Ltd), with the assistance  of  the
staff   of  the  NATIONAL   INSTITUTE  OF  HYGIENIC   SCIENCES,  Tokyo,
Japan and DR I. YAMAMOTO (Tokyo University of Agriculture).

    The  proprietary data mentioned in the document were made available
to  the Central Unit of the IPCS by Temana International Ltd, Richmond,
United Kingdom for evaluation by the Task Group.

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


                               *  *  *


    The  proprietary  information  contained in  this  document  cannot
replace documentation for registration purposes, because the latter has
to  be closely linked to  the source, the manufacturing  route, and the
purity/impurities of the substance to be registered.  The  data  should
be   used  in  accordance  with  paragraphs  82-84  and  recommendation
paragraph 90 of the 2nd FAO Government Consultation (FAO, 1982).


                               *  *  *


    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 Collaborating Centre for Environmental Health Effects.  The
United  Kingdom  Department of  Health  and Social  Security generously
supported the cost of printing.

1.  SUMMARY AND RECOMMENDATIONS

1.1  General

    Dichlorvos,  an organophosphate, is a  direct-acting cholinesterase
(ChE)a inhibitor.    Since 1961, it has  been commercially manufactured
and used throughout the world as a contact and stomach insecticide.  It
is used to protect stored products and crops (mainly  in  greenhouses),
and to control internal and external parasites in  livestock  (granules
of impregnated resin) and insects in houses, buildings,  aircraft,  and
outdoor areas (as aerosols, liquid sprays, or  impregnated  cellulosic,
ceramic,  or  resin  strips).   The  present  worldwide  production  of
dichlorvos is about 4 million kg per year.

    The  purity of the technical grade product is at least 97%, and the
type  of  impurities  depends on  the  manufacturing  process.  In  the
presence  of moisture, dichlorvos breaks  down to form acidic  products
that are eventually mineralized.  Technical dichlorvos may  be  stabil-
ized,  which  improves the  storage stability, but  it is not  normally
necessary  to stabilize  high purity  products.  In  the  past,  2 - 4%
epichlorohydrin  has been used for this purpose.  Dichlorvos is soluble
in   water   and  miscible  with  most  organic  solvents  and  aerosol
propellants.  The vapour pressure of dichlorvos is relatively high (1.6
Pa at 20 °C).

    Methods  for sampling and analysing  dichlorvos in food, feed,  and
the environment and for determining the inhibition of ChE  activity  in
blood, red blood cells, plasma, and brain are described.

1.2  Environmental Transport, Distribution, and Transformation

    Dichlorvos is not directly applied to soil, but is added  to  water
to  control  invertebrate  fish parasites  encountered during intensive
fish  farming.  It breaks down  rapidly in humid air,  water, and soil,
both by abiotic and biotic processes, whereas on wooden surfaces it may
persist for a longer time (39% remaining after 33 days).   It  degrades
mainly  to dichloro-ethanol, dichloroacetaldehyde (DCA), dichloroacetic
acid,  dimethylphosphate,  dimethylphosphoric  acid, and  other  water-
soluble compounds, which are eventually mineralized.

    Dichlorvos is rapidly lost from leaf surfaces by volatilization and
hydrolysis.

    Accidental  spillage of dichlorvos may have acute hazardous effects
on man and the environment.  However, long-term effects  are  unlikely,
in  view  of  the volatility  and  instability  in humid  environments.
Bioaccumulation or biomagnification do not occur.

------------------------------------------------------------------------
a   Cholinesterase is the enzyme which breaks down acetylcholine (ACh),
    the transmitter at cholinergic nerve synapses.

1.3  Environmental Levels and Human Exposure

    The  indoor air  dichlorvos  concentrations  resulting from  house-
hold  and public health use  depend on the method  of application, tem-
perature, and humidity.  For example, one impregnated resin  strip  per
30 m3   results in concentrations of the order of 0.1 - 0.3 mg/m3   the
first  week (the latter  only in special  circumstances),  subsequently
decreasing to 0.02 mg/m3 or less over the next few weeks.

    Dichlorvos residues in food commodities are generally low  and  are
readily  destroyed during processing.  The  metabolite DCA may also  be
present  in  detectable  amounts.   Total-diet  studies  in  the United
Kingdom  and the USA have confirmed that no, or very little, dichlorvos
is found in prepared meals.

    Exposure of the general population via food and drinking-water as a
result of agricultural or post-harvest use of dichlorvos is negligible.
However,  household  and public  health use do  give rise to  exposure,
principally through inhalation and dermal absorption.

    Similar   routes   of   exposure   occur   in   professional   pest
control   with  dichlorvos.   In  warehouses,    mushroom  houses,  and
greenhouses, the concentrations of dichlorvos in the air are in general
below 1 mg/m3   when the recommended application rates are used, but in
certain circumstances they may rise considerably above this level.

1.4  Kinetics and Metabolism

    Dichlorvos is readily absorbed via all routes of  exposure.   After
oral administration, it is metabolized in the liver before  it  reaches
the systemic circulation.

    One  hour after the oral administration of 32P-dichlorvos,  maximum
concentrations  of  radioactivity  are  found  in  the  kidneys, liver,
stomach,  and intestines.   In bone,  the increase  is slower,  due  to
inorganic phosphate entering the phosphate pool of the organism.

    Pigs administered a single oral dose of 14C-labelled  dichlorvos as
a   slow-release   polyvinyl   chloride   (PVC)   formulation,   showed
radioactivity  in  all tissues,  the highest level  being in the  liver
after  2  days,  and the lowest being in the brain.  Pregnant sows were
fed vinyl-1-14C-dichlorvos   or 36Cl-dichlorvos  in PVC pellets at 4 mg
dichlorvos/kg  body  weight  per  day  during  the  last third  of  the
gestation  period.   Although  the tissues  of  the  sows  and  piglets
contained 14C   or 36Cl   ranging  from  0.3  to  18 mg/kg  tissue,  no
radioactivity   was   associated   with  dichlorvos   or   its  primary
metabolites.

    Up  to  70%  of the dichlorvos inhaled by pigs is taken up into the
body.   When rats and mice inhaled dichlorvos (90 mg/m3 for  4 h), none
or  very little (up to  0.2 mg/kg) was found  in blood, liver,  testes,
lung,  or brain.  The highest  concentrations (up to 2.4 mg/kg  tissue)
were  found  in  kidneys  and  adipose  tissue.    Dichlorvos   rapidly
disappeared from the kidneys with a half-life of approximately 14 min.

    Dichlorvos  is metabolized  mainly in  the liver  via  2  enzymatic
pathways: one, producing desmethyldichlorvos, is glutathione dependent,
while   the  other,  resulting   in  dimethyl-phosphate  and   DCA,  is
glutathione  independent.   The  metabolism of  dichlorvos  in  various
species,   including  man,  is   rapid  and  uses   similar   pathways.
Differences  between species relate  to the rate  of metabolism  rather
than to a difference of metabolites.

    The  major route of metabolism  of the vinyl portion  of dichlorvos
leads  to (a) dichloroethanol glucuronide and (b)  hippuric acid, urea,
carbon  dioxide, and other  endogenous chemicals, such  as glycine  and
serine, which give rise to high levels of radioactivity in the tissues.
No  evidence of  the accumulation  of dichlorvos  or potentially  toxic
metabolites has been found.

    The  major route for  the elimination of  the phosphorus-containing
moiety is via the urine, with expired air being a less important route.
However,  the vinyl moiety is mainly eliminated in the expired air, and
less  so  in  the  urine.   In  cows,  elimination is  roughly  equally
distributed between urine and faeces.

1.5  Effects on Organisms in the Environment

    The  effect of dichlorvos on microorganisms is variable and species
dependent.   Certain  microorganisms  have the  ability  to  metabolize
dichlorvos   but  the  pesticide  may  interfere  with  the  endogenous
oxidative metabolism of the organism.  In certain organisms  it  causes
growth  inhibition,  while in  others it has  no influence or  may even
stimulate  growth.   Dichlorvos  has  little  or  no  toxic  effect  on
microorganisms degrading organic matter in sewage.  The  above  effects
have been seen over the wide dose range of 0.1 - 100 mg/litre.

    The  acute toxicity of dichlorvos for both freshwater and estuarine
species of fish is moderate to high (96-h LC50 values  range  from  0.2
to  approximately  10 mg/litre).  Brain  and  liver ChE  inhibition  in
certain  fish was  found at  dose levels  of 0.25 - 1.25 mg/litre,  but
recovery  of ChE activity took  place when they were  returned to clean
water.

    Invertebrates  are  more  sensitive to  dichlorvos.   Levels  above
0.05 µg/litre   may have deleterious  effects.  Dichlorvos also  has  a
high  oral toxicity for birds.    The LD50 values  are in  the range of
5 - 40 mg/kg  body weight.  In short-term dietary studies, the compound
was slightly to moderately toxic for birds.  Brain ChE  inhibition  was
seen  at 50 mg/kg diet or more and at 500 mg/kg diet, half of the birds
died.   There  have been  instances when chickens  and ducks have  died
after  accidental access to dichlorvos-contaminated  feed and drinking-
water.

    Dichlorvos  is highly  toxic for  honey bees.   The  LD50 by   oral
administration  is  0.29 µg/g  bee,  and  after topical  application is
0.65 µg/g bee.

1.6  Effects on Experimental Animals and  In Vitro Test Systems

    Dichlorvos is moderately to highly toxic when administered in single
doses  to a variety  of animal species  by several routes.   It directly
inhibits acetylcholinesterase (AChE)  activity in the nervous system and
in other tissues.  Maximum inhibition generally occurs within  1 h,  and
is followed by rapid recovery.  The oral LD50 for  the rat  is  30 - 110
mg/kg   body  weight,  depending  on   the  solvent  used.  The   hazard
classification  of  dichlorvos  by  WHO  (1986a)  is  based on  an  oral
LD50 for   the rat of 56  mg/kg body weight.  The  signs of intoxication
are   typical   of   organophosphorus   poisoning,   i.e.,   salivation,
lachrymation,  diarrhoea, tremors, and terminal  convulsions, with death
occurring  from  respiratory failure.   The  signs of  intoxication  are
usually  apparent shortly  after dosing,  and, at  lethal  doses,  death
occurs within 1 h.  Survivors recover completely within 24 h.

    Potentiation   is  slight  when   dichlorvos  is  given   orally  in
combination  with  other  organophosphates,  but  in  combination   with
malathion it is marked.

    In  short-term  toxicity studies  on the mouse,  rat, dog, pig,  and
monkey, inhibition of plasma, red blood cell, and brain ChE are the most
important  signs of toxicity.  After oral administration,  approximately
0.5  mg/kg body  weight (range,  0.3 - 0.7 mg/kg)  did not  produce  ChE
inhibition.   In  a 2-year  study on dogs,  ChE inhibition was  noted at
3.2 mg/kg body weight or more.

    Flea collar dermatitis has been described in dogs and  cats  wearing
dichlorvos-impregnated  PVC flea collars.   This was a  primary irritant
contact dermatitis which may have been caused by dichlorvos.

    Many  short-term inhalation studies on different animal species have
been carried out.  Air concentrations in the range of 0.2 - 1 mg/m3   do
not  affect ChE activity significantly.   Other effects, such as  growth
inhibition  and increase  in liver  weight have  been reported  at  dose
levels at least 10 - 20 times higher.

    It is possible to produce clinical neuropathy in hens, but the doses
of dichlorvos required are far in excess of the LD50.    The effects are
associated  with high  inhibition of  neurotoxic esterase  (NTE) in  the
brain  and spinal cord.  In the rat, however, neuropathic changes in the
white  matter of the brain  have been reported following  repeated daily
oral application of an LD50 dose.

    Immune  suppression has been  reported in rabbits.   At present,  no
evaluation  as to  the relevance  for human  beings can  be given;  more
attention to this aspect is needed.

    In  a  long-term  study, rats fed dichlorvos in the diet for 2 years
showed  no signs of intoxication.  Hepatocellular fatty vacuolization of
the  liver and ChE inhibition  were significant at the  two highest dose
levels (2.5 and 12.5 mg/kg body weight).

    In   a  carefully  conducted   long-term  inhalation study  on  rats
with whole body exposure (23 h/day, for 2 years), results  were  compar-
able   with  those  seen in   the oral  study. No  effects were seen  at
0.05 mg/m3;   inhibition of ChE activity took place at 0.48  mg/m3    or
more.

    In  several reproduction studies on  rats and domestic animals,  no
effects were seen on reproduction, and there was no  embryotoxicity  at
dose  levels  that did  not cause maternal  toxicity.  At toxic  doses,
dichlorvos may cause reversible disturbances of spermatogenesis in mice
and  rats.  It was  not teratogenic in  several studies carried  out on
rats and rabbits.

    Dichlorvos is an alkylating agent and binds  in  vitro to  bacterial
and  mammalian nucleic acids.  It is mutagenic in a number of microbial
systems,  but there is no  evidence of mutagenicity in  intact mammals,
where it is rapidly degraded by esterases in blood and other tissues.

    Dichlorvos  carcinogenicity  has  been investigated  in  mice (oral
studies)  and rats (oral and inhalation studies).  The dose levels used
in  2-year  oral  studies were  up  to  800 mg/litre drinking-water  or
600 mg/kg  diet for  mice, and  up to  280 mg/litre  drinking-water  or
234 mg/kg  diet  for  rats.  In  a  rat  inhalation  study,  dichlorvos
concentrations  in air of up to 4.7 mg/m3 were  tested for 2 years.  No
statistically significant increase in tumour incidence was  found.   In
two  recent carcinogenicity studies  on mice and  rats, dichlorvos  was
administered  by intubation at dose levels between 10 and 40 mg/kg body
weight (mice) and 4 and 8 mg/kg body weight (rat)  for up to  2  years.
Only  preliminary  information has  been  provided.  The  evidence  for
carcinogenicity  in these new studies is difficult to interpret at this
time.  Only when complete and final reports become available will it be
possible  to draw  more definitive  conclusions (in  this context,  see
footnote section 8.7.3).

    From acute and short-term studies, it is clear that the metabolites
of  dichlorvos are all less  toxic than the parent  compound.  Only DCA
was positive in a few mutagenicity tests.

1.7  Effects on Man

    A  fatal  case of  dichlorvos poisoning has  been described in  the
general population: despite correct treatment, a suicide succeeded with
approximately 400 mg dichlorvos/kg body weight.  In  another  poisoning
case,  a  woman  ingested  about  100 mg  dichlorvos/kg  and  survived,
following  intensive  care  for 14  days.   Two  workers who  had  skin
exposure to a concentrated dichlorvos formulation, and failed  to  wash
it off, died of poisoning.

    There  have  been two  clinical  reports describing  four  patients
suffering  from  severe poisoning  from  dichlorvos, taken  orally, who
survived  after treatment and  who showed delayed  neurotoxic  effects.
Thus  although the possibility of neuropathy in man cannot be excluded,
it is likely to occur only after almost lethal oral doses.

    Since the 1960s, field studies in malaria control have been carried
out  and the interiors of  aircraft have been sprayed  with dichlorvos.
Exposure  to concentrations in the air of up to 0.5 mg/m3 were  without
clinical  effects, and no, or  only insignificant, inhibition of  blood
ChE activity was noted.

    When dichlorvos was administered orally to human volunteers (single
or  repeated  doses of  a  slow-release PVC  formulation),  significant
inhibition  of red blood  cell ChE activity  was found at  4 mg/kg body
weight  or more.  At 1 mg/kg  body weight or more,  plasma ChE activity
was    significantly   inhibited.    Daily    oral   doses   of    2 mg
dichlorvos/person for 28 days reduced plasma ChE activity by  30%,  but
red cell ChE activity was unaffected.

    Human volunteers who were exposed to dichlorvos by inhalation for a
certain period per day for a number of consecutive days or weeks showed
ChE  inhibition at  a concentration  of 1 mg/m3 or   more, but  not  at
0.5 mg/m3.     These results were  confirmed in studies  with pesticide
operators who came into contact with dichlorvos.

    Hospitalized   patients   showed   similar   results   after   oral
administration or exposure by inhalation.  Sick adults and children and
healthy  pregnant  women  and babies  in  hospital  wards treated  with
dichlorvos  strips   (1 strip/30  or  40 m3)     displayed  normal  ChE
activity.   Only  subjects  exposed 24 h/day  to  concentrations  above
0.1 mg/m3 or   patients  with  liver insufficiency  showed  a  moderate
decrease in plasma ChE activity.

    No  significant effects on  plasma or red  blood cell ChE  activity
were  observed  in  people  exposed  to  the  recommended rate  of  one
dichlorvos strip per 30 m3 in  their homes over a period of  6  months,
even  when the  strips were  replaced at  shorter intervals  than  that
normally recommended.  The maximum average concentration in the air was
approximately 0.1 mg/m3.

    In  factory  workers  exposed to  an  average  of 0.7  mg/m3 for  8
months,  significant  inhibition  of plasma  and  red  blood  cell  ChE
activity was found.

    Cases of dermatitis and skin sensitization due to  dichlorvos  have
been  described in  workers handling  and spraying  different types  of
pesticides.   In  addition cross-sensitization  with certain pesticides
has been seen.

2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

2.1  Identity

 Primary constituent 

Chemical structure:              O
                                ||
                         Cl2C=CHOP(OCH3)2

Chemical formula:        C4H7Cl2O4P

Chemical names:          2,2-dichloroethenyl dimethylphosphate (CAS);
                         2,2-dichlorovinyl dimethylphosphate (IUPAC)

Common synonyms:         Bayer-19149,     DDVF,    DDVP,    ENT-20738,
                         OMS-14, SD 1750, C-177

CAS registry number:     62-73-7

 Technical product

Common trade names:      Dedevap, Nogos, Nuvan, Phosvit, Vaponaa

Purity:                  should not be less than 97% (WHO, 1985)

Impurities:              depend  on the manufacturing process (section
                         3.2.1.2)

Additives:               In   the  presence  of  traces  of  moisture,
                         dichlorvos  slowly breaks down to form acidic
                         products  that catalyse further decomposition
                         of   the  compound.   In  the   past,  2 - 4%
                         epichlorohydrin  was  added to  stabilize the
                         technical  grade  product  (Melnikov,  1971).
                         Other  stabilizers  may  now be  used in some
                         products,  but improved technology and purity
                         has   largely   eliminated   the   need   for
                         stabilizers.


2.2  Physical and Chemical Properties

    Dichlorvos is a colourless to amber liquid with an aromatic odour.

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

----------------------------------------------------------------------------
a   The  Shell trademark Vapona was formerly used exclusively for dichlorvos
    and dichlorvos-containing formulations. More recently,  this  trademark
    has been  used  more  widely to  include  formulations  containing other
    active ingredients.


Table 1.  Some physical and chemical properties of dichlorvosa
-----------------------------------------------------------------------------
   Relative molecular mass           221

   Boiling point                     35 °C at 6.7 Pa (0.05 mmHg);
                                     74 °C at 133 Pa (1 mmHg)b

   Vapour pressure (20 °C)           1.6 Pa (1.2 x 10-2 mmHg)

   Density (25 °C)                   1.415

   Refractive index                  ND25 = 1.4523

   Solubility                        about 10 g/litre water at 20 °C; 2 -
                                     3  g/kg kerosene; miscible with most
                                     organic solvents and aerosol propel-
                                     lants

   Stability                         dichlorvos is stable to heat but is
                                     hydrolysed by water; a saturated
                                     aqueous solution at room temperature
                                     is converted to dimethylphosphate and
                                     dichloroacetaldehyde at a rate of
                                     about 3% per day, more rapidly in
                                     alkali

   Corrosivity                       corrosive to iron and mild steel

   Log  n-octanol/water partition     1.47c
     coefficient
-----------------------------------------------------------------------------
a   From: Worthing & Walker (1983).
b   From: Melnikov (1971).
c   From: Bowman & Sans (1983).

2.3  Conversion Factors

    1 ppm = 10 mg/m3 at 25 °C and 101 kPa (760 mmHg);

    1 mg/m3 = 0.1 ppm

2.4  Analytical Methods

    The  various analytical methods are  summarized in Tables 2,  3, 4,
and 5.


Table 2.  Analytical methods for dichlorvos residues in food and biological
media recommended by the Codex Working Group on Methods of Analysis
---------------------------------------------------------------------------------------------------------
Sample      Extraction          Clean-up        Detection and     Recovery  Limit of         Reference   
                                                quantification              detection                    
---------------------------------------------------------------------------------------------------------
grain       methanol                            gas-liquid                   0.02 mg/kg      Anon. (1973)
                                                chromatography                                           
                                                with thermionic                                          
                                                phosphorus                                               
                                                detector or                                              
                                                flame                                                    
                                                photometric                                              
                                                phosphorus                                               
                                                detector                                                 
                                                                                                         
cereal      petroleum ether/    Florisil        gas chromato-     70 - 80%   0.0025 mg/kg    Mestres et al.
products    ethyl ether         column          graphy with                                  (1979b)       
                                                flame photo-                                               
                                                metric detector                                            
                                                or thermionic                                              
                                                ionization                                                 
                                                detector                                                   
                                                                                                           
cereals     hexane              activated       gas chromato-     72 - 83%   0.01 ng         Aoki et al.   
            hexane/aceto-       charcoal        graphy with                  (sensitivity)   (1975)        
            nitrile benzene     column          flame photo-                                               
                                extraction      metric                                                     
                                acetone/        detection                                                  
                                hexane                                                                     
                                                                                                           
crops       dichloromethane     steam           gas-liquid        80 - 100%  0.01 mg/kg      Elgar et al.  
            or ethylacetate     distil-         chromato-                                    (1970)        
                                lation          graphy with                                                
                                                flame photo-                                                   
                                                metric                                                     
                                                detector,                                                  
                                                thermionic                                                 
                                                ionization                                                 
                                                detector, or                                               
                                                electron                                                   
                                                capture                                                    
                                                detector                                                   


Table 2 (contd.)
---------------------------------------------------------------------------------------------------------
Sample      Extraction          Clean-up        Detection and     Recovery  Limit of         Reference   
                                                quantification              detection                    
---------------------------------------------------------------------------------------------------------
                                                                                                           
            ethylacetate/       Florisil        gas chromato-       80%      0.002 - 0.05    Mestres et al.
            dichloromethane     column          graphy with                  mg/kg           (1979a)       
                                                flame photo-                                               
                                                metric detector                                            
                                                                                                           
fruit and   acetonitrile        extraction      gas-liquid        approxi-                   Anon. (1977)  
vegetables                      with            chromato-         mately 90%                               
                                chloroform;     graphy with       (at 0.5                                  
                                residue         flame photo-      mg/kg)                                   
                                in acetone      metric detector                                            
                                                or thermionic                                              
                                                ionization                                                 
                                                detector                                                   
                                                               
onions      acetonitrile        amberlite       gas chromato-        82%                     Iwata et al.      
            benzene             XAD-8           graphy with                                  (1981)        
                                column          flame photo-                                               
                                benzene/        metric                                                     
                                dichloro-       detection                                                  
                                methane                                                                    
                                                                                                           
                                                                                                           
                                                                                                           
            chloroform,         HCl and         gas-liquid        approxi-   0.01 mg/kg      Krause & Kirch-
            methanol            Celite          chromatography    mately 90%                 hoff (1970)    
                                                with thermionic   (at 0.05 -                                
                                                ionization        0.5 mg/kg)                                
                                                detector                                                    
                                                                                                            
                                                                                                            
            acetone and part-   double          gas-liquid        90% (at                    Luke et al.    
            ition with petro-   concentration   chromatography    0.1 mg/kg)                 (1981)         
            leum ether and      with            with flame                                                  
            dichloromethane     petroleum       photometric                                
                                ether           detector                                                    
                                                                                                            


Table 2 (contd.)
---------------------------------------------------------------------------------------------------------
Sample      Extraction          Clean-up        Detection and     Recovery  Limit of         Reference   
                                                quantification              detection                    
---------------------------------------------------------------------------------------------------------
                                                                                                            
eggplant    water/methanol                      gas chromato-        95%     0.004 mg        Nakamura &  
fruit       ether/petroleum                     graphy with                                  Shiba (1980)
            ether                               flame photo-                                                
                                                metric                                                      
                                                detection                                                   
                                                                                                            
plants      methanol            ether/          gas-liquid        95 - 100%  0.1 mg/kg       Dräger (1968)  
                                petroleum       chromatography                                              
                                ether           with phosphorus                                             
                                                detector                                                    
                                                                                                               
            acetonitrile        liquid-liquid   thin-layer                 indo-    bromo-   Mendoza &         
                or              partitioning    chromatography             phenyl-  indoxyl- Shields (1971)    
            dichloromethane     none            enzymatic assay            acetate  acetate                    
                or                              using: bee head             5 ng       -                       
            methanol/chloro-    none            extract, pig                5 ng    1 ng                       
            form                                liver extract,              5 ng    0.1 ng                  
                                                beef liver                                                     
                                                extract                                                        
                                                                                                               
            acetone or          column          thin-layer                   1 - 2 ng        Ambrus et al.     
            dichloromethane     chromato-       chromatography                               (1981)            
                                graphy          enzymatic      
                                                assay (horse                                                   
                                                serum)                                                         
                                                                                                               
                                without         thin-layer                   100 ng                            
                                clean-up        chromatography                                                 
                                                silver nitrate                                                 
                                                + UV                                                           
                                                                                                               
                                                gas-liquid        55 - 80%   0.1 - 1 ng                        
                                                chromatography               0.01 - 0.05 ng                    
                                                with thermionic              typical limit                     
                                                ionization                   of detection  
                                                detector or                  0.005 - 0.02                      
                                                electron                     mg/kg                             
                                                capture                                                        
                                                detector                                                       

                                                               
Table 2 (contd.)
---------------------------------------------------------------------------------------------------------
Sample      Extraction          Clean-up        Detection and     Recovery  Limit of         Reference   
                                                quantification              detection                    
---------------------------------------------------------------------------------------------------------
                                                               
vegetable   acetone; dichloro-  sweep co-       gas chromato-     75 - 100%                  Eichner (1978)
and animal  methane or aceto-   distillation    graphy with       (at 0.03 -                               
food,       nitrile; dichloro-                  thermionic        0.5 mg/kg)                               
tobacco     methane                             phosphorus     
                                                detector       
                                                               
whole meal  cereal: methanol;   depending       gas-liquid                                   Abbott et al.
            fats: hexane and    on type         chromatography                               (1970)       
            others:             of sample       with thermionic
            acetonitrile                        phosphorus     
                                                detector,      
                                                caesium bromide
                                                tips           
                                                               
            homogenized         silica gel      gas chromato-     97 - 100%  0.005 mg/kg     Dale et al.
            sample, ethyl       column;         graphy with                  (sensitivity)   (1973)     
            acetate-hexane      elution         flame          
            and HCl             with acetone/   photometric    
                                hexane          detector       
                                                               
animal      dichloromethane     steam           gas-liquid        80 - 100%  0.01 mg/kg      Elgar et al.
tissues     or ethylacetate     distil-         chromatography                               (1970)      
                                lation          with flame     
                                                photometric    
                                                detector,      
                                                thermionic     
                                                ionization     
                                                detector, or   
                                                electron       
                                                capture        
                                                detector       

Table 2 (contd.)
---------------------------------------------------------------------------------------------------------
Sample      Extraction          Clean-up        Detection and     Recovery  Limit of         Reference   
                                                quantification              detection                    
---------------------------------------------------------------------------------------------------------
                                                               
milk        methanol            acetonitrile    gas chromato-     80 - 90%   0.01 mg/kg      Dräger (1968)
                                and ether/      graphy with       (at 0.01 -                              
                                petroleum       phosphorus        0.1 mg/kg)                              
                                ether           detector       
                                                               
                                                               
            acetonitrile        dichloro-       gas-liquid                                   Abbott et al.
                                methane;        chromatography                               (1970)       
                                methane;        with thermionic
                                residue         phosphorus     
                                dissolved       detector,      
                                in acetone      caesium bromide
                                                tips           
                                            

Table 3.  Other analytical methods for dichlorvos residues in food and biological media
---------------------------------------------------------------------------------------------------------
Sample         Extraction     Clean-up          Detection and          Recovery  Limit of      Reference
                                                quantification                   detection
---------------------------------------------------------------------------------------------------------
agricultural   ethyl          none except for   gas-liquid chromato-             food, crops:  Anon. 
crops, animal  acetate        oil extracts      graphy with phosphorus           0.02 mg/kg    (1972)
tissues,                                        detector
beverages,
food

fruit,         hexane/        aluminium         thin-layer chromato-                           Wood & 
vegetables     acetone        oxide column      graphy; nitrobenzyl-                           Kanagasa- 
                                                pyridine/triaza un-                            bapathy
                                                decamethylene diamine                          (1983)

organs/        ethanol        none              thin-layer chromato-             0.2 ng        Ackerman 
tissues;                                        graphy enzymatic                               et al.
contents of    none or        none              assay (beef liver)                             (1969)
stomach,       chloroform
intestines;
urine

milk,          dichloro-      silica gel        gas chromatography       95%     0.003 mg/kg   Ivey & 
               methane        column, mixed     with flame photo-                              Claborn
                              solvents          metric detector                                (1969)

fat,           hexane                                                    80%     0.002 mg/kg   Ivey & 
chicken,                                                                                       Claborn
skin                                                                                           (1969)

muscle,        acetonitrile   silica gel                                 80%     0.002 mg/kg   Ivey & 
eggs                          column                                                           Claborn
                                                                                               (1969)
animal         depending on   only for fat      gas-liquid chromato-             0.05 - 0.1    Schultz 
tissuesa       sample         tissues           graphy with phosphorus           mg/kg         et al.
and fluids                                      detector                                       (1971)

milk                          silica gel col-   polarography             85%     0.15 mg/kg    Davidek 
                              umn; alkaline                                                    et al. 
                              condensation                                                     (1976)
                              with  o -phenyl-
                              enediamine
---------------------------------------------------------------------------------------------------------
a   Methods for analysing residues of four metabolites of dichlorvos are also given.

Table 4.  Analytical methods for determining the dichlorvos concentration and ChE activity in blood
---------------------------------------------------------------------------------------------------------
Sample          Extraction       Clean-up    Detection and       Recovery  Limit of   Reference
                                             quantification                detection
---------------------------------------------------------------------------------------------------------
Dichlorvos concentrations
blood           acetonitrile                 gas chromatography    86%                Ivey & Claborn
                hexane                       with flame photo-                        (1969)
                                             metric detector

blood/serum     chloroform         none      thin-layer chromato-                     Ackerman et al.
                                             graphy enzymatic                         (1969)
                                             assay (beef liver)    

blooda          water/ethanol      none      gas-liquid chromato-                     Schultz et al.
                extracted with               graphy with phosphorus                   (1971);
                ethyl acetate                detector                                 Anon. (1972)

ChE activity
blood                                        electrometric method                     Michel (1949)
(plasma and                                  for ChE activity,
red cell)                                    release of acetic
                                             acid from ACh; pH change

whole blood     ACh-perchlorate              tintometric method                       Edson (1958)
ChE             and bromothymol blue                                    

whole blood     dithiobis-nitro-             colorimetry at                           Voss & Sachsse
and plasma      benzoic acid (DTNB)          420 nm                                   (1970)
ChE             + acetylthiocholine
                (animal blood) or
                propionyl thiocholine 
                (human blood);
                eserine salicylate
                (esterase inhibitor)

whole blood     DTNB + acetylthio-           spectrophotometry                        Ellman et al.
and erythro-    choline iodide               at 412 nm                                (1961); Anderson
cyte ChE                                                                              et al. (1978)

whole blood     dithiodipyridine             spectrophotometry                        Augustinsson et
and erythro-    (DTPD) + propionyl           at 324 nm                                al. (1978)
cyte ChE        thiocholine; esterase
                inhibitor
---------------------------------------------------------------------------------------------------------
a   Methods for analysing concentrations of four metabolites of dichlorvos are also given.

Table 5.  Analytical methods for the determination of dichlorvos in air, soil, and water
---------------------------------------------------------------------------------------------------------
Sample       Extraction      Clean-up        Detection and           Recovery  Limit of      Reference
                                             quantification                    detection
---------------------------------------------------------------------------------------------------------
Air
glass tubes containing:      
water                                        electrometric pH                                Elgar & Steer
                                             method                                          (1972)

ethyl        none                            gas-liquid chromato-              0.01 mg/m3    Anon. (1972)
acetate                                      graphy with phosphorus
                                             detector

potassium    elution with                    gas chromatography         80%                  Bryant & 
nitrate      hexane                          with flame photo-                               Minett      
                                             metric detector                                 (1978)

XAD-2 (per-  desorption with                 gas chromatography                0.2 µg        NIOSH 
sonal samp-  toluene                         with flame photo-                               (1979);
ling)                                        metric phosphorus                               Gunderson 
                                             detector                                        (1981)

Soil
soil         acetone         column          thin-layer chromato-              1 - 2 ng      Ambrus 
                             chromatography  graphy enzymatic                                et al.
                                             assay (horse serum)                             (1981)

soil                         without clean-  thin-layer chromato-              100 ng        Ambrus 
                             up              graphy; silver                                  et al.
                                             nitrate + UV                                    (1981)

soil         ether/acetone                   flame photometric         91%     5 µg          Goto 
             (7:3)                           detector-gas                                    (1977)
             petroleum ether                 chromatography

Water
water        dichloro-       column          thin-layer chromato-              1 - 2 ng      Ambrus 
             methane         chromato-       graphy enzymatic                                et al.
                             graphy          assay (horse serum)                             (1981)


Table 5 (contd.)
-------------------------------------------------------------------------------------------------------------------------
Sample       Extraction      Clean-up        Detection and           Recovery  Limit of      Reference
                                             quantification                    detection
-------------------------------------------------------------------------------------------------------------------------

                             without clean-  thin-layer chromato-              100 ng
                             up              graphy; silver
                                             nitrate + UV

                                             gas-liquid chromato-    55 - 70%  0.01 - 0.05 ng;
                                             graphy with electron
                                             capture detector or
                                             thermionic ionization             0.1 - 1 ng
                                             detector                          typical limit of
                                                                               detection 0.0001
                                                                               mg/kg
-------------------------------------------------------------------------------------------------------------------------
2.4.1  Sampling methods

2.4.1.1  Food and feed

    The  "Codex Recommended Method of Sampling for the Determination of
Pesticide  Residues" (Codex Alimentarius Commission, 1979; GIFAP, 1982)
describes  sampling rates and  acceptance criteria in  relation to  the
analytical  sample  and  the  Codex  maximum  residue   limits   (Codex
Alimentarius Commission, 1983).

2.4.1.2  Blood

    Where samples cannot be determined immediately, e.g., samples taken
in  the field, they must be frozen in order to prevent the reactivation
of  inhibited plasma ChE or erythrocyte AChE.  When freezing facilities
are  limited, or where  samples must be  transported and/or stored  for
several  days, samples  of whole  blood are  applied to  filter  paper.
These  samples  can  be stored at room temperature for at least 2 weeks
and  in  a  refrigerator for  more  than  6 weeks  without reducing the
efficiency  of elution  from the  filter paper  (Eriksson &  Fayersson,
1980).

2.4.1.3  Air

    Methods  of sampling air for pesticides have been reviewed by Miles
et al. (1970), Van Dijk & Visweswariah (1975), Lewis (1976), and Thomas
& Nishioka (1985).

    Miles et al. (1970) compared the widely-used techniques and came to
the  conclusion that, although each method has certain advantages, none
are ideal.  Packed adsorption columns are very efficient  for  trapping
vapours,  but recovery of  the sample is  frequently difficult.   Glass
fibre filters or cellulose filter pads permit the collection  of  large
volumes  of air  in short  periods of  time, but  their efficiency  for
vapours  is low, and unknown losses of aerosol samples occur.  Membrane
filters are good for liquid aerosols and vapours, but the sampling rate
is  slow.  However, Tessari & Spencer (1971) considered collection on a
moist  nylon net to be the best sampling method for aerosol and vapour-
phase pesticides.  Freeze-out traps are of limited value in field work.
Impingers seem to offer a compromise; they can be operated at  quite  a
fast  flow rate, they  are efficient for  collection of aerosols,  and,
with correct solvent selection, they collect vapours efficiently.

    Heuser  & Scudamore (1966) used dry potassium nitrate in an adsorp-
tion tube and were able to measure less than 1 µg/m3     of  dichlorvos
in air.

    When  Miles et al.  (1970) used two  Greenburg-Smith-type impingers
containing  water, they trapped up to 97% of dichlorvos.  However, when
ethylacetate  was used instead of water, more than 95% of the available
dichlorvos was collected in the first impinger (Anon., 1972).

    For  personal  sampling  of  dichlorvos  in  the  work environment,
Gunderson (1981) collected air samples from the worker's breathing zone
in  glass tubes  packed with  XAD-2 (a  styrene-divinyl benzene  cross-
linked porous polymer) as sorbent.  A calibrated personal sampling pump
drew air through the filter.

2.4.2  Analytical methods

2.4.2.1  Analysis of technical and formulated dichlorvos products

    Dichlorvos  products can be analysed  by gas-liquid chromatography,
infrared  spectrometry (Oba & Kawabata,  1962), or by reaction  with an
excess  of iodine  which is  estimated by  titration  (CIPAC  Handbook,
1980).   A colorimetric method  to estimate dichlorvos  in formulations
was  described  by Mitsui  et al. (1963)  and improved by  Ogata et al.
(1975).    Formulated   dichlorvos   can  be   analysed  by  gas-liquid
chromatography after extraction or dilution with chloroform,  or  after
partitioning of the dichlorvos into acetonitrile (Anon., 1972).  Heuser
&  Scudamore  (1975)  described  a  method  to  assess  the  output  of
dichlorvos  slow-release strips for insect  control.  A method for  the
analysis  of  dichlorvos  in  technical  and  formulated  products  was
reported in WHO (1985).

    Qualitative  methods  to identify  dichlorvos  or to  separate  and
estimate  it in the presence  of other organophosphorus compounds  were
described by Sera et al. (1959) and Yamashita (1961).

2.4.2.2  Determination of dichlorvos residues

    The main methods for determining dichlorvos are:

    (a)  thin-layer chromatography (TLC);

    (b)  enzyme-inhibition detection, coupled with TLC;

    (c)  gas  chromatography (GC) with electron  capture detector (ECD)
         (specificity is poor);

    (d)  GC with flame photometric detector (FPD) (the most widely-used
         method for the determination of organophosphorus compounds);

    (e)  GC  with thermionic alkaline flame  ionization detector (TID),
         which  is  more sensitive  to phosphorous-containing compounds
         than the FPD, but is less stable (Lewis, 1976).

    Mendoza  (1974)  reviewed  the  applications  of  the   TLC-enzyme-
inhibition  technique  for  pesticide residues  and metabolite analyses
involving determination and confirmation of pesticides.

    IUPAC's  Commission  on  Pesticide  Chemistry  examined  simplified
analytical   methods  for  screening   pesticide  residues  and   their
metabolites in food and environmental samples (Batora et al., 1981).

    The Codex Committee on Pesticide Residues lists recommended methods
for the analysis of dichlorvos (FAO/WHO, 1986).

2.4.2.3  Confirmatory tests

    Confirmation  of the identity of the residue by an independent test
is  an essential part of good laboratory practice.  The ultimate choice
of  a confirmatory test  depends on the  technique used in  the initial
determination  and  on  the  available  instrumentation  and  necessary
expertise.  Details of various confirmatory tests have  been  published
(Mendoza  & Shields, 1971; Shalik  et al., 1971; Mestres  et al., 1977;
Cochrane, 1979).

2.4.2.4  Food

    The  Working Group on Methods of Analysis of the Codex Committee on
Pesticide  Residues has produced guidelines on good analytical practice
in  residue analysis  and Recommendations  of Methods  of Analysis  for
Pesticide   Residues   (Codex  Alimentarius   Commission,  1983).   The
recommended methods are mostly multiresidue ones and are  suitable  for
analysing  as many pesticide product combinations as possible up to the
Codex maximum residue limits.  The methods are summarized  in  Table 2.
Other methods for residue analysis are given in Table 3.

2.4.2.5  Blood

    Methods  for analysing dichlorvos concentrations in blood are given
in  Table 4.  The determination of  the four metabolites of  dichlorvos
was described by Schultz et al. (1971).

    The  most frequently used  method for determining  ChE activity  in
blood  is that of Ellman et al. (1961), subsequently modified by Voss &
Sachsse  (1970) and Augustinsson et al. (1978).  An improvement of this
spectrophotometric  method for determining ChE activity in erythrocytes
and  tissue homogenates was described  by Anderson et al.  (1978).  The
method  of Ellman et al. (1961) has been developed by WHO (1970) into a
field kit for the determination of blood ChE activity.

2.4.2.6  Air

    A  review of the analysis of airborne pesticides has been published
by  Lewis (1976).  Methods for determining dichlorvos concentrations in
air are given in Table 5.

2.4.2.7  Soil and water

    Methods are summarized in Table 5.


3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

3.1  Natural Occurrence

    Dichlorvos does not occur as a natural product.

3.2  Man-Made Sources

3.2.1  Production levels and processes

3.2.1.1  Worldwide production figures

    Dichlorvos  has been manufactured  commercially since 1961  in many
countries.  Worldwide production figures for 1984 are given in Table 6.

    Table 6.  The worldwide production of dichlorvos in 1984
----------------------------------------------------------------------------
    Country                          Production in tonnes
----------------------------------------------------------------------------
    Eastern Europe                             220

    Japan                                     1100

    Latin America                              400

    Middle East                               1200
    (including India and Pakistan)

    South-East Asia                            500

    USA                                        500

    Western Europe                             300

                                      Total   4220
-----------------------------------------------------------------------------

    Of  this total production, 60% is used in plant protection, 30% for
public hygiene and vector control, and 10% to protect  stored  products
(GIFAP, personal communication, 1986).

3.2.1.2  Manufacturing processes

    Dichlorvos  can  be  manufactured  by  the  dehydrochlorination  of
trichlorphon  (chlorophos)  through the  action  of caustic  alkalis in
aqueous solution at 40 - 50 °C.

       O                           O
      ||                          || 
(CH3O)2PCH(OH)CCl3 + KOH -> (CH3O)2POCH=CCl2 + KCl + H2O

    The yield of dichlorvos in this process does not exceed 60%.

    Another   process  is  the  reaction  of  chloral  with  trimethyl-
phosphite:
                                 O
                                ||
    (CH3O)3P + CCl3CHO -> (CH3O)2POCH=CCl2 + CH3Cl

Using  this method, dichlorvos  of 92 - 93% purity  can be produced  by
either a batch or a continuous process (Melnikov, 1971).

3.2.2  Uses

    Dichlorvos is a contact and stomach insecticide with  fumigant  and
penetrant action.  It is used for the protection of stored products and
crops  (mainly greenhouse crops), and  for the control of  internal and
external parasites in livestock and insects in buildings, aircraft, and
outdoor areas.

    As  a household and public health insecticide with fumigant action,
dichlorvos  has widespread use in the form of aerosol or liquid sprays,
or  as  impregnated cellulosic,  ceramic,  or resin  strips, especially
against  flies and mosquitos.   For the control  of fleas and  ticks on
livestock  and domestic animals  (pets), impregnated resin  collars are
used.   A  granular  form of an impregnated resin strip is in use as an
anthelmintic in domestic animals.

    The  various  formulations  include  emulsifiable  and  oil-soluble
concentrates,    ready-for-use   liquids,   aerosols,   granules,   and
impregnated  strips.   Formulations  containing mixtures  of dichlorvos
with   other   insecticides,   such  as   pyrethrins/piperonylbutoxide,
tetramethrin,   allethrins,   chlorpyriphos,  diazinon,   propoxur,  or
fenitrothion, are also on the market.

3.2.3  Accidental release

    Accidental  spillages of dichlorvos  could cause acute  effects  in
water (e.g., mortality of aquatic species), but long-term  effects  are
unlikely   in  view  of  its   volatility  and  instability  in   humid
environments.

4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

4.1  Transport and Distribution Between Media

    Dichlorvos  is not generally used for direct application on soil or
to  water.  However,  in intensive  fish farming,  dichlorvos is  added
directly to water.  Any residues in soil resulting from  the  treatment
of  crops will  be small  and short-lived,  due to  volatilization  and
degradation.  Therefore, contamination of ground water or surface water
is unlikely to occur in normal practice.  In air, dichlorvos is rapidly
degraded, the rate depending on the humidity of the air.

4.2  Biotransformation

4.2.1  Abiotic degradation

    In  water, dichlorvos hydrolyses  into dimethylphosphoric acid  and
DCA.

    The  photochemical  degradation  rate constant  at  environmentally
important  wavelengths  (around  300 nm)  was  265 x  10-7/s     at   a
concentration of 0.67 µg  dichlorvos/cm2 of  glass plate, and the half-
life was 7 h (Chen et al., 1984).

    The relative persistence of dichlorvos on concrete, glass, and wood
was  investigated in the laboratory.  The fastest loss occurred when it
was applied to concrete; after 1 h, only 0.7% of the applied amount was
present.   This  rapid  loss  was  almost  certainly  due  to  alkaline
decomposition.   The disappearance rate on glass was less rapid, with a
recovery  of  1%  dichlorvos  3  days  after  application.   On   wood,
dichlorvos  showed the greatest persistence; 65% and 39% of the applied
dichlorvos still remained after one and 33 days, respectively (Hussey &
Hughes, 1964).

    When houses were treated for pest control with a total of 230-330 g
dichlorvos  as  aerosol  and  4 - 50 g  as  emulsion  spray,  the  mean
dichlorvos residue on the surface was 24 µg/100 cm2 at   the end of the
first day, and fell to 6 µg/100 cm2 by   the end of 5 days (Das et al.,
1983).

4.2.2  Biodegradation

    Two  ponds  containing  9200 and  25 000 µg   plankton/litre water,
respectively,  were  treated  with  dichlorvos  by  spraying  under the
surface  of the  water.  The  initial dichlorvos  concentration in  the
water   was   325 µg/litre   and  the  half-lives  were  34  and  24 h,
respectively (Grahl, 1979).

    The  biodegradation  of  dichlorvos  in  soil  was  tested  in  the
laboratory  using moist loam.   The percentages of  the applied  amount
(200 mg/kg soil) remaining in the soil after 1, 2, and 3 days were 93%,
62%,  and 37%, respectively.   Concentrations of free  DCA in the  soil
were 9%, 7%, and 4%, respectively (Hussey & Hughes, 1964).

    In  studies  on  the fate  of  dichlorvos  in soil,  it  was  shown
that  Bacillus  cereus grown  on  a nutrient  medium  containing 1000 mg
dichlorvos/litre  could use this compound  as a sole carbon  source but
not  as a sole phosphorus source.  When soil columns were perfused with
an  aqueous solution containing 1000 mg dichlorvos/litre, the metabolic
activity of  B. cereus  accounted for 30% of the loss of dichlorvos from
the system over a 10-day period (Lamoreaux & Newland, 1978).

    Dichlorvos in concentrations ranging from 0.1 to  100 mg/litre  had
little  or no toxicity, as  measured by the oxygen  depletion caused by
microorganisms   degrading  organic  matter  in   sewage  (Lieberman  &
Alexander, 1981, 1983).

    Dichlorvos  was converted to dichloroethanol,  dichloroacetic acid,
and  ethyldichloroacetate by a microbial enrichment derived from sewage
containing,   principally,   two   species  of  Pseudomonas   and    one
of  Bacillus.  The compounds were not formed in the absence of microbial
cells.   Inorganic phosphate  was also  generated in  the  presence  of
microorganisms, and dimethylphosphate was produced in the  presence  or
absence of microbial cells (Lieberman & Alexander, 1981, 1983).

     Pseudomonas  melophthora,  the  bacterial  symbiont  of  the  apple
maggot  (Rhagoletis  pomonella), degraded  dichlorvos mainly into water-
soluble  metabolites, using esterases  (Boush & Matsumura,  1967).   In
addition, a strain of  Trichoderma viride, a  fungus isolated from soil,
has  the ability to  degrade dichlorvos to  water-soluble  metabolites,
probably through an oxidative pathway (Matsumura & Boush, 1968).

    Dichlorvos is rapidly lost from leaf surfaces by volatilization and
by hydrolysis, the half-life under laboratory conditions being  of  the
order of a few hours.  A small percentage of the  dichlorvos  deposited
appears  to penetrate into the  waxy layers of plant  tissues, where it
persists  longer  and  undergoes  hydrolysis  to  DCA  (FAO/WHO, 1968a,
1971a).

4.2.3  Bioaccumulation and biomagnification

    Due  to the transient nature  of dichlorvos, no bioaccumulation  or
biomagnification   occur  in  soil,  water,   plants,  vertebrates,  or
invertebrates.

4.3  Ultimate Fate Following Use

    Direct application of dichlorvos on crops or animals will result in
residues   disappearing  rapidly  by  volatilization   and  hydrolysis.
Airborne  dichlorvos arising from fogging,  spraying, or volatilization
from   impregnated   strips  is   hydrolysed   in  the   atmosphere  to
dimethylphosphate  and DCA.  Losses  occur through ventilation  and  by
absorption  and  hydrolysis on  surfaces.   Depending on  the material,
dichlorvos  may be absorbed and diffuse into the material, or it may be
hydrolysed on the surface.

5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

5.1  Environmental Levels

    The occurrence of dichlorvos residues in the environment  does  not
necessarily originate from the use of dichlorvos.  It can also occur as
a  conversion  product of  trichlorphon  (Miyamoto, 1959)  and butonate
(Dedek et al., 1979).

5.1.1  Air

    Examples  of indoor air concentrations resulting from the household
and  public  health use  of dichlorvos are  given in Table 7.   The air
concentration  varies according to  the method of  application (strips,
spray cans, or fogging), the temperature, and humidity (Gillett et al.,
1972).   Using strips (one strip per 30 m3),   the concentration in the
first  week  is  in  the  range  0.1 - 0.3 mg/m3,    depending  on  the
ventilation.   During succeeding weeks, the  concentration decreases to
about  0.04 mg/m3 and  after 3  months to 0.01 mg/m3 (Elgar   &  Steer,
1972).

5.1.2  Food

    Data on residues in food commodities resulting from pre-  or  post-
harvest  treatment and  from use  on animals  have been  summarized  by
FAO/WHO  (1967a, 1968a, 1971a, 1975a).  Maximum residue limits, varying
from   0.02  to  5 mg/kg,  have   been  recommended  for  a   range  of
commodities.

    Frank  et al. (1983)  analysed 260 bovine  and porcine fat  samples
collected  in the period 1973-81 in Ontario.  Only one sample contained
a trace of dichlorvos.

    Dichlorvos  residues  present  in  food  commodities  are   readily
destroyed during processing, e.g., washing, cooking.  Hence, the chance
that  dichlorvos will occur  in prepared meals  is very low.   This was
confirmed by Abbott et al. (1970) in a total-diet study in  the  United
Kingdom,  in which no residues  of dichlorvos were detected  in the 462
sub-samples analysed.

    In total-diet studies (including infant and toddler diets)  carried
out  from  1964  to 1979  by the  US Food  and Drug  Administration, no
dichlorvos was found (Johnson et al., 1981a,b; Podrebarac, 1984).

    Food  samples, meals, and unwrapped ready-to-eat foodstuffs exposed
under  practical  conditions to  dichlorvos  generated by  resin strips
showed  mean residues of less than 0.05 mg/kg, with a range of < 0.01 -
0.1 mg/kg  (Elgar  et  al., 1972a,b;  Collins  &  de Vries,  1973).  No
residues of DCA (< 0.03 mg/kg; limit of detection) were detected in the
ready-to-eat  foodstuffs  (Elgar et  al.,  1972b).  Food  and beverages
exposed to experimental air concentrations of 0.04 - 0.58  mg/m3    for
30  min contained dichlorvos  residues of 0.005 - 0.5 mg/kg,  with  the
exception  of margarine which contained  up to 1.6 mg/kg (Dale  et al.,
1973).


Table 7.  Indoor air concentrations of dichlorvos following various applications
---------------------------------------------------------------------------------------------------------
Location       Application      Dosea    Temper-  RHb  Ventilation  Time after  Concentration  Reference
                                          ature   (%)               application   (mg/m3)
                                          (°C)
---------------------------------------------------------------------------------------------------------
food shops     resin strip      1 strip/                 normal     first week    0.03         Elgar et al.
                                30 m3                               4 weeks       0.02         (1972b)

houses         resin strip      1 strip/  18-35  20-60   normal     first week    0.06 - 0.17  Leary et al.
                                30 m3                               2 - 3 weeks   0.01         (1974); Elgar
                                                                                               & Steer (1972);
                                                                                               Collins & de
                                                                                               Vries (1973)

hospital       resin strip      1 strip/  20-27  35-70   varied     several days  0.10 - 0.28  Cavagna et al.
wards                           30 m3                               20 - 30 days  0.02         (1969)

hospital       strips of paper  0.2 ml       -     -     2 h        3 days        0.06         Schulze (1979)
wards          drenched in 50%  ai/m3
               dichlorvos sol-  0.2 ml      17     -     2 h        66 h          0.1 - 0.3
               ution hanging    ai/m3
               in the room for  0.2 ml      17           2 h        90 h          0.3
               24 - 36 h        ai/m3
                                0.8 ml      30   high    2 h        3 h           3.7
                                ai/m3                               46 h          0.6

houses         0.5% solution    225 or      26   47-60   none       0             0.4          Neuwirth & White
               according to     1200 ml                             8 h           0.2          (1961)
               typical pest                                         24 h          < 0.1
               control practice

bathroom       0.5% solution    25 ml       26    60     none       0             1.1          Neuwirth & White
(sealed)       wall spray                                           4 h           0.3          (1961)
                                                                    24 h          < 0.1

Table 7 (contd.)
----------------------------------------------------------------------------------------------------------------------------------
Location       Application      Dosea    Temper-  RHb  Ventilation  Time after  Concentration  Reference
                                          ature   (%)               application   (mg/m3)
                                          (°C)
----------------------------------------------------------------------------------------------------------------------------------
living room    spray cans       2.3 mg    20-22          30 min     0             0.24         Sagner &
(experimental)                  ai/m3                    1 h        0             0.13         Schöndube (1982)

               fogging          240 mg    20-22          none       1 h           37           Sagner &
                                ai/m3                    none       24 h          5.5          Schöndube (1982)
                                                         1 h        1 h           2.5
                                                         120 h      1 h           < 0.2

apartments     0.5% solution    190 mg    26      82                0 - 2 h       0.5          Gold et al.
                                ai/m2                               2 - 24 h      0.2          (1984)
---------------------------------------------------------------------------------------------------------
a  ai = active ingredient.
b  RH = relative humidity.
5.2  General Population Exposure

    Exposure of the general population to dichlorvos via air, water, or
food,  as  a  result  of  its  agricultural  or  post-harvest  use,  is
negligible.    However,  the  household  and  public  health   use   of
dichlorvos  is a source of exposure.  The dichlorvos slow-release resin
strip  leads to exposure principally  through inhalation from the  air,
but  dermal absorption by contact  with surfaces and oral  ingestion of
exposed food may also occur.  Professional pest control with dichlorvos
in buildings results in the same routes of exposure but to lower levels
and for a shorter period (section 5.1).

    Other sources of exposure are the use of household sprays  and  pet
collars.

    The increased use of organophosphorus insecticide on lawns and turf
within parks and recreational areas presents a risk to human beings and
animals.   They may be potentially exposed to toxic levels of residues,
although most product labels recommend that pets and children  be  kept
off  treated turf  until the  spray has  dried.  To  safeguard  against
potential  hazards,  safe  levels  of  dislodgeable  residue  have been
estimated  so that safe reentry intervals or reentry precautions can be
established.  In California, the estimated safe level  of  dislodgeable
foliar dichlorvos residue is 0.06 µg/cm2.

    In  studies carried out by  Goh et al. (1986a,b),  the dislodgeable
foliar  dichlorvos residue level immediately  after application dropped
rapidly  during the first 2 - 6 h, and after 24 - 48 h, the residue was
undetectable.

5.3.  Occupational Exposure During Manufacture, Formulation, or Use

5.3.1  Air

    Employees  in a vaporizer  production plant and  adjoining  packing
rooms  were exposed, on average, to 0.7 mg/m3 air.   The highest single
value recorded was 3 mg/m3 (Menz et al., 1974).

    When  air  was  analysed by  Wright  &  Leidy (1980)  in office and
insecticide   storage  rooms in   commercial  pest  control   buildings
and   in vehicles,  the concentrations  of  dichlorvos  did not  exceed
0.001 mg/m3  air.

    Gillenwater   et  al.  (1971)  measured  maximum  values  of  2.4 -
7  mg/m3    of  dichlorvos  in  a  large  warehouse during  weekly  6-h
application   periods.   The  amounts   of  dichlorvos  dispersed   per
application   ranged  from  25   to  59 mg/m3 and   the   average   air
concentration after 8 applications was 4 mg/m3.

    When  the  floors  of a  mushroom  house  were treated  with  a 10%
solution  of a 50%  (w/v) dichlorvos emulsion  (2 g dichlorvos/m3   of
house  volume),  air concentrations of  dichlorvos   were   well below   
1 mg/m3.  The   air   concentrations  of   DCA  were  approximately  1  
mg/m3, decreasing over 14 days to 0.3 mg/m3   (Hussey & Hughes, 1964).

    During  thermal  fogging  by swingfog  of  6  greenhouses  (0.2  ml
dichlorvos/m3),   the workplace concentration was 7 - 24 mg/m3   (mean:
16   mg/m3).      Spraying    of    12   glass    and   plastic  green-
houses    resulted   in   workplace  concentrations   between  0.7  and
2.7   mg/m3 (mean:1.3   mg/m3).     Field   application   by   spraying
resulted   in  air  concentrations   of  0.01 -  0.26  mg/m3   (mean  :
0.08 mg/m3)  (Wagner & Hoyer, 1975, 1976).

    In a tobacco-drying unit used for mushroom  production,  dichlorvos
was sprayed at 8 ml aia/100   m3,   and the unit was kept closed for 24
h.   Air concentrations decreased from 3.3 mg/m3 to  0.006 mg/m3 in  24
h.   Treatment of the unit with paper strips drenched in 50% dichlorvos
formulation (40 ml/100 m3)   resulted in air concentrations of 0.38 and
0.024  mg/m3,    3 and  24 h,  respectively, after  treatment (Grübner,
1972).

    Immediately  after spraying plants in greenhouses with a 0.2 - 0.3%
dichlorvos  solution, the air concentration was 1.2 mg/m3,   decreasing
to  0.01  mg/m3 24   h  later.   When  the  plants were  "shaken",  air
concentrations increased by 10 - 26% (Zotov et al., 1977).

    The  air  levels  of dichlorvos in a room of a residence were moni-
tored  during and after treatment  with a pressurized home-fogger  con-
tainer.   The study was performed to determine if the prescribed 30 min
aeration  period was sufficient to  allow safe re-entry into  a home or
room.  The air levels were below the industrial  workplace  permissible
exposure level (PEL) of 1 mg/m3,   recommended by US OSHA, at  the  end
of the aeration period.  The dichlorvos dissipated quite  slowly  after
that.   Without ventilation, it took 18 h to reach an acceptable level.
Because there is concern that infants and elderly or  diseased  persons
occupying  rooms  almost  24 h/day,  7  days  per week,  might  be more
susceptible,  the acceptable level  for homes has  been established  at
1/40  of  the  PEL.  Consequently,  rooms  treated  with this  type  of
application  device and ventilated  after treatment should  not be  re-
entered for 10 h (Maddy et al., 1981a).

    Dichlorvos  is  used to  control  Phorid flies  in mushroom-growing
houses.   After its use in one of these houses in Ventura County in the
USA in 1981, some workers complained of headaches and nausea  upon  re-
entry  after 30 min of ventilation.  Monitoring of the mushroom houses,
after  the same treatment, revealed air concentrations of less than 0.1
mg/m3 (0.01   ppm).   Swab  samples  of  exposed  horizontal   surfaces
revealed a maximum of 0.026 µg/cm2 (Maddy et al., 1981b).


-----------------------------------------------------------------------
a   ai = active ingredient.

6.  KINETICS AND METABOLISM

6.1  Absorption

    Dichlorvos  is readily absorbed via all routes of exposure.  In the
rat, dichlorvos taken orally is absorbed by the gastrointestinal tract,
transported  via  the hepatic  portal venous system  to the liver,  and
detoxified before it reaches the systemic circulation (Gaines  et  al.,
1966; Laws, 1966).

    Air  exhaled by anaesthetized  and tracheotomized pigs  exposed  by
inhalation  to dichlorvos for  up to 6 h  revealed that, at  dichlorvos
concentrations  of 0.1 - 2 mg/m3,   the  pigs retained 15 - 70%  of the
inhaled dichlorvos (Kirkland, 1971).

    The  percutaneous absorption of undiluted  dichlorvos and solutions
of  dichlorvos applied (under  a glass cover  slip) to rabbit  skin was
calculated  from the slope of  the whole blood ChE  activity inhibition
curve.   Water  and  acetone  solutions  did  not  increase absorption,
whereas   xylene  and  dimethylsulfoxide  (DMSO)   enhanced  absorption
(Shellenberger  et al., 1965;  Shellenberger, 1980).  The  results  are
summarized in Table 8.

Table 8.  Effect of solvent on whole blood ChE activities and absorption
ratesa after percutaneous application of dichlorvos to rabbit skin
-----------------------------------------------------------------------------
   Solvent             ChE inhibition      Time after         Absorption
                             (%)          application    (mg/min per cm2)
-----------------------------------------------------------------------------
   0.5 ml undiluted          30              2 h              3.8
    dichlorvos

   +0.5 ml acetone           45              2 h              4.08

   +0.5 ml water             45              2 h              4.29

   +0.5 ml xylene           100             40 min           11.96

   +0.5 ml DMSO             100             35 min           16.08
-----------------------------------------------------------------------------
a  Calculated from the slope of the enzyme inhibition curve.

6.1.1  Human studies

    Dichlorvos was undetectable (less than 0.1 mg/litre) in  the  blood
of  two men immediately  after exposure, one  to air concentrations  of
0.25  mg  dichlorvos/m3 for  10 h and one to 0.7 mg dichlorvos/m3   for
20 h (Blair et al., 1975).

6.2  Distribution

6.2.1  Studies on experimental animals

6.2.1.1  Oral

    32P-Dichlorvos    administered orally to rats  at a single dose  of
10 mg/kg  body weight  was found  to be  readily absorbed,  distributed
among  the tissues, hydrolysed, and rapidly metabolized.  Radioactivity
was detected in the blood 15 min after administration, and  the  amount
slowly decreased over subsequent days.  The concentrations  of 32P   in
kidneys, liver, stomach, and intestines reached their maximum 1 h after
dosing,  and  decreased  within  1  day.   The  concentration  in  bone
increased  slowly with  time due  to the 32P   entering  the  inorganic
phosphate  pool of the organism.  No sex differences were found (Casida
et al., 1962).

    When  1 mg  of 14C-methyldichlorvos    was administered  orally  to
rats,  the  gut,  skin, and  carcass  contained  0.7%, 1.6%,  and 5.2%,
respectively,  of the administered  radioactivity, 4 days  after dosing
(Hutson  & Hoadley, 1972b).  In  an earlier study on  rats dosed orally
with   1 mg  vinyl-1-14C-dichlorvos,    the  gut,   skin,  and  carcass
contained  1.7%, 7.5%, and 14%, respectively, of the 14C,  4 days after
dosing (Hutson et al., 1971a,b).

    Twenty-four hours after the administration of a single oral dose of
0.2 mg  vinyl-1-14C-dichlorvos   to mice, 26 - 34% of the radioactivity
was  found in the carcass  (Hutson & Hoadley, 1972a).   Syrian hamsters
dosed with vinyl-1-14C-dichlorvos   retained similar percentages in the
gut, skin, and carcass as did rats (Hutson & Hoadley, 1972a).

    Fetuses  from  rabbits  treated  with  daily  oral  doses  of  5 mg
dichlorvos/kg  body  weight  for 25  days  of  gestation were  found to
contain no dichlorvos (Majewski et al., 1979).

    In  studies by Potter et  al. (1973a), nine pigs  received a single
oral    dose    of   vinyl-1-14C-dichlorvos      (approximately   40 mg
dichlorvos/kg   feed)    formulated   as  slow-release   PVC   pellets.
Sacrifices  after  2,  7, and  14  days  showed that  all  the  tissues
contained 14C.    The  highest  level of  radioactivity,  expressed  as
dichlorvos  equivalent,  was  found  in  liver  tissue  after  2   days
(33 mg/kg)  and the  lowest in  brain tissue  (2.5 mg/kg).  In  another
study,     pregnant   sows   were   fed    vinyl-1-14C-dichlorvos    or
36Cl-dichlorvos    in PVC pellets at 4 mg dichlorvos/kg body weight per
day for the last third of the sow's gestation period.  After farrowing,
the  sows and piglets, nursing from their own mothers, were kept for 21
days  before  being sacrificed.   The tissues of  the sows and  piglets
contained 14C  and 36Cl  residues ranging from 0.3 to  18 mg/kg  tissue
equivalents.   In  neither study,  were  residues of  dichlorvos,  DCA,
desmethyldichlorvos,  dichloroacetic acid, or dichloroethanol  found in
the tissues (Potter et al., 1973a,b).

    No dichlorvos was found in muscle (fat) tissue of  rabbits  treated
with daily oral doses of 5 mg dichlorvos/kg body weight for 2 weeks and
sacrificed  at intervals up  to 48 h after  the last dose  (Majewski et
al., 1979).

6.2.1.2 Inhalation

    When  groups  of 3  rats and mice  were exposed by  inhalation to a
concentration of 90 mg dichlorvos/m3 air  for 4 h, the  rats  exhibited
mild   signs   of  intoxication   (lethargy,  pupillary  constriction).
Concentrations  of dichlorvos were  very low or  undetectable in  blood
(< 0.2 mg/kg),  liver, testes, lung, and brain (< 0.1 mg/kg), while the
kidneys  and fat contained  the highest concentrations  (up to 2.4  and
0.4 mg/kg tissue, respectively).  In rats, the values for  the  trachea
were  higher  than those  for the lungs,  indicating perhaps that  some
dichlorvos is trapped in the trachea.  When rats were exposed  for  4 h
to  10 mg/m3 air,   only  the kidneys  of  the  male animals  contained
measurable  or detectable dichlorvos concentrations (0.08 mg/kg).  Mice
gave  different  results from  rats,  having higher  concentrations  of
dichlorvos in fat, lung, and testes, and much lower  concentrations  in
the kidneys.  Exposure of male rats to 0.5 or 0.05 mg/m3 for   14  days
did  not result in detectable residues (< 0.001 mg/kg) of dichlorvos in
blood,  liver, kidneys, renal  fat, or lung  tissue.  However, in  male
rats  exposed to approximately  50 mg dichlorvos/m3,   dichlorvos  (1.7
mg/kg)   was found in the  kidneys after 2 and  4 h exposure time.   On
removal  of the rats from  the test atmosphere, the  dichlorvos rapidly
disappeared from the kidneys, with a half-life of 13.5 min.   The  rate
of disappearance of dichlorvos in the blood was too rapid  to  measure;
it could not be detected 15 min after exposure (Blair et al., 1975).

    Short-term   inhalation   trials   in  anaesthesized   pigs did not
show   the  presence  of intact  dichlorvos  or  desmethyldichlorvos in
blood   or   lung   tissues.   Even  in  the  2-  to  4-h  trials,  the
degradation  proceeded  to the  stage  where only  methylphosphates and
phosphoric  acid could be detected (Loeffler et al., 1971).  When young
swine were exposed for 24 h to an atmosphere containing about  0.15  mg
vinyl-1-14C-dichlorvos/m3,     the 14C  content varied widely among the
different  tissues,  but none  contained  dichlorvos (Loeffler  et al.,
1976).

6.2.1.3  Intraperitoneal

    Nordgren  et  al. (1978)  showed that within  1 min after a  single
intraperitoneal injection of 10 mg dichlorvos/kg body weight  to  mice,
dichlorvos was detectable in the brain, but its concentration decreased
within a few minutes.

    Mice  and rats treated repeatedly by intraperitoneal injection with
10 or 4 mg 32P-dichlorvos/kg  body weight showed hydrolysis products in
the  tissues  within 2 h  (Casida et al.,  1962).  When male  rats were
injected intraperitoneally with vinyl-1-14C-dichlorvos,   the mean 24-h
retention  percentages  of  administered radioactivity  were:  gut, 4%;
skin, 7%; and carcass, 23% (Hutson et al., 1971b).  No  differences  in
the  amount or distribution of  radioactivity in the tissues  of female
rats  given either a single oral or intraperitoneal dose of 4 mg vinyl-
1-14C-dichlorvos/kg body weight were reported (Casida et al., 1962).

6.2.1.4  Intravenous

    The dichlorvos concentrations in the kidneys of three male rats, 10
and  30 min after a single intravenous injection, showed a considerable
decrease, suggesting rapid metabolism of dichlorvos.  As was  the  case
after  oral administration,  dichlorvos could  not be  detected in  the
kidneys of female rats (Blair et al., 1975).

6.3  Metabolic Transformation

    Early  in vitro and  in vivo studies indicated that detoxification of
dichlorvos  occurs in the liver (Casida et al., 1962; Hodgson & Casida,
1962;  Gaines et al., 1966;  Laws, 1966).   In vitro studies  have shown
that  rat liver degrades dichlorvos by two main enzymatic pathways, one
being  glutathione dependent and producing desmethyldichlorvos, and the
other  being glutathione independent and resulting in dimethylphosphate
and    DCA.   The  degradation   of  desmethyldichlorvos  to   DCA  and
monomethylphosphate  was  also  found  to  be  glutathione  independent
(Dicowsky  &  Morello, 1971).   Sakai  & Matsumura  (1971) demonstrated
the  in vitro degradation of dichlorvos by human brain esterases.

    Hodges  & Casida (1962) have found that dichlorvos is hydrolysed by
the soluble and mitochondrial fractions of the rat liver but not by the
microsomes.   DCA is reduced in the presence of NADH to dichloroethanol
and possibly to dichloroacetate.

    The   rapidity  of   dichlorvos  metabolism  has  been demonstrated
in  in  vitro studies   using  fresh liver  tissue.   Ten minutes  after
mixing  1 mg dichlorvos with  1 g of liver  tissue, 50% dichlorvos  was
recovered; after 123 min, only 0.4% remained (Majewski et  al.,  1979).
However,  it is  not only  liver tissue  that  metabolizes  dichlorvos.
32P-Dichlorvos    was  metabolized  in the  presence  of  blood and  of
adrenal, kidney, lung, and spleen tissues, mainly to dimethylphosphate.
Desmethyldichlorvos,  monomethylphosphate, and inorganic phosphate were
also found (Hodgson & Casida, 1962; Loeffler et al., 1971).

    The  identification of dichlorvos  metabolites has been  undertaken
in  in  vivo studies  of mice  (Casida et al.,  1962; Hutson &  Hoadley,
1972a,b), rats (Casida et al., 1962; Bull & Ridgeway, 1969;  Hutson  et
al.,  1971b;  Hutson  & Hoadley,  1972b),  Syrian  hamsters  (Hutson  &
Hoadley,  1972a), pigs (Loeffler et al., 1971, 1976; Page et al., 1972;
Potter et al., 1973a,b), goats (Casida et al., 1962), cows  (Casida  et
al., 1962), and human beings (Hutson & Hoadley, 1972a), after different
routes  of administration using radiolabelled  dichlorvos.  In general,
the  metabolism  of dichlorvos  in the various  species is similar  and
rapid.   Differences  between  species  are  related  to  the  rate  of
metabolite formation rather than to the nature of the metabolites.

    In  the  mouse,  O- desmethylation  is  a  more  important  route of
dichlorvos detoxification than it is in the rat (Table 9), as indicated
by  the  larger  amounts  of  radioactivity  excreted  in the  mice  as
desmethyldichlorvos.

Table 9.  Isotope dilution analysis of urine from mammals treated orally 
with vinyl-1-14C-dichlorvosa
-----------------------------------------------------------------------------
  Metabolite             Proportion of administered radioactivity as
  measured                           urinary metabolite (%)            
                         rat           mouse         hamster      man
----------------------------------------------------------------------------
  hippuric acid          1.7            0.6          1.0          0.4
  desmethyldichlorvos    2.2           18.5          -b           0.15
  urea (isolated as      0.6            0.6          -b           0.1
  the nitrate salt)
-----------------------------------------------------------------------------
a   From: Hutson & Hoadley (1972a).
b   Not measured.

    Desmethyldichlorvos  arises  from  the  hydrolysis  of  the  methyl
oxygen-phosphate  bond  and  is  further  degraded  into   DCA,   mono-
methylphosphate,  and dimethylphosphate (Casida et al., 1962; Hodgson &
Casida, 1962; Bradway et al., 1977).   S- methyl-glutathione  is  formed
along  with desmethyldichlorvos, and  is degraded to  methylmercapturic
acid and excreted in the urine (Hutson & Hoadley, 1972b).

    The  two  major routes  of metabolism of  the vinyl portion  of the
dichlorvos molecule lead to: (a) dichloroethanol glucuronide,  and  (b)
hippuric  acid, urea, carbon dioxide, and other endogenous biochemicals
which  give  rise  to high levels of radioactivity in the tissues for a
few  days  after  dosing with  vinyl-1-14C-dichlorvos.    Both pathways
have  been shown  to occur  in man,  owing to  the  presence  of  these
compounds  in  the  urine (Hutson  &  Hoadley,  1972a).  In  laboratory
animals most of the observed radioactivity in carcasses and tissues was
present  as  glycine,  serine,  and  other  normal   body   components,
indicating that the vinyl carbon atoms of dichlorvos enter the 2-carbon
metabolic  pool (Hutson  et al.,  1971b; Page  et al.,  1971; Hutson  &
Hoadley, 1972b; Loeffler et al., 1976).  No evidence of accumulation of
dichlorvos or potentially toxic metabolites was found.  A scheme of the
metabolites of dichlorvos in mammals is given in Fig. 1.

6.3.1  Metabolites

    When 32P-dimethylphosphate     (500 mg/kg    body    weight)    was
administered   orally  to  a  male  rat  almost  the  entire  dose  was
eliminated.     The    urine   contained    about   50%   unmetabolized
dimethylphosphate.   On  the   other  hand,   a rat  orally dosed  with
32P-desmethyldichlorvos     (500 mg/kg   body weight)  eliminated about
14%  of the dose  via urine in  90 h, 86% of  the  radioactivity  being
phosphoric   acid  and  14%  unchanged   desmethyldichlorvos.  The very
high  proportion of radioactivity in  the bone was indicative  of rapid
degradation to phosphoric acid (Casida et al., 1962).

    Following    the   intraperitoneal  injection  of   1-14C-DCA    or
1-14C-dichloroethanol    to female rats,  32% of the  radioactivity was
expired as carbon dioxide within 24 h (Casida et al., 1962).

FIGURE 1A

FIGURE 1B

6.4  Elimination and Excretion in Expired Air, Faeces, and Urine

6.4.1  Human studies

    Eight   hours  after  a  human   male  consumed  5 mg   of vinyl-1-
14C-dichlorvos    in orange juice,  27% of the  radioactivity had  been
eliminated  as 14C-carbon  dioxide.  Approximately 8% had been excreted
by  the urine within  one day following  dosing.  Urinary excretion  of
radioactivity  decreased gradually  and by  day 9  none was  detectable
(Hutson & Hoadley, 1972a).

    The  concentration  of  dimethylphosphate  in  the  urine  of three
pesticide control operators spraying houses with dichlorvos ranged from
0.32 to 1.4 µg at the end of the day's work (Das et al., 1983).

6.4.2  Studies on experimental animals

6.4.2.1  Oral

    Dosing   rats  orally  with 32P-dichlorvos   (0.1 -  80 mg/kg  body
weight)   resulted  in  a recovery  of  60 -  70% of  the  administered
radioactivity in the urine and approximately 10% in the faeces  over  a
6-day period following dosing (Casida et al., 1962).

    After  the oral administration  of methyl-14C-dichlorvos   to  rats
(1 mg)  and mice (0.5 mg),  the excretion of  radioactivity was  rapid.
The   major  route  of   elimination  after  4   days  was  the   urine
(approximately  60%),  followed  by  expired  air  (approximately  16%)
(Hutson & Hoadley, 1972b).

    Rats  given  an oral  dose  of vinyl-1-14C-dichlorvos    (1 mg  per
animal)   eliminated 10 - 20% of the 14C   in the urine, 3 - 5%  in the
faeces,  and approximately 40%  as expired carbon  dioxide over 4  days
following dosing (Hutson et al., 1971a,b).

    A  comparison between the excretion by rat, mouse, hamster, and man
24 h  after  oral  dosing  with  vinyl-1-14C-dichlorvos    is  given in
Table 10 (Hutson & Hoadley, 1972a).

    A    cow    treated   orally    with    20  mg/kg    body    weight
32P-dichlorvos   eliminated 40% of the radioactivity in the  urine  and
50%  in  the faeces.   In the milk,  the level of  organosoluble radio-
activity was significantly above background only within the first  2  h
(Casida et al., 1962).

Table 10. Comparison of percentages of radioactivity excreted by males
24 h after oral ingestion of vinyl-1-14C-dichlorvosa
-----------------------------------------------------------------------------
  Excretion route      Rat (3)     Mouse (1)    Hamster (2)      Man (1)
-----------------------------------------------------------------------------
  urine                 9.8         27.4          14.7           7.6

  faeces                1.5          3.2           2.9             -

  carbon dioxide       28.8         23.1          33.5      27 (8 h only)
-----------------------------------------------------------------------------
a   Number of animals are given in parentheses.

6.4.2.2  Parenteral

    The elimination of a single intraperitoneal injection  of  vinyl-1-
14C-dichlorvos    (4 mg/kg body weight) from female rats was similar to
the  elimination after oral dosing.  A goat treated subcutaneously with
1.5 mg 32P-dichlorvos/kg  body weight excreted 79% of the radioactivity
in the urine and 11% in the faeces.  Two cows received  an  intravenous
or  a subcutaneous injection with  1 mg 32P-dichlorvos/kg  body weight.

Of the radioactivity which was recovered, 70 - 80% was in the urine and
approximately 14% in the faeces (Casida et al., 1962).

6.5  Retention and Turnover

6.5.1  Biological half-life

    In studies by Blair et al. (1975), the metabolism of dichlorvos was
found to be so rapid that the biological half-life in blood  could  not
be determined.  No intact dichlorvos could be demonstrated in the blood
or  tissues  of  animals  exposed  by  routes  other  than   parenteral
injection.  Only after exposure for 4 h to an atmospheric concentration
of 90 mg dichlorvos/m3 could  dichlorvos be detected in most tissues of
the rat and mouse.  Following exposure at 50 mg/m3,   for 2 or 4 h, the
half-life in the rat kidney was 13.5 min.

    The  intraperitoneal injection of  10 mg dichlorvos/kg  body weight
into  mice increased the accumulation of ACh in the brain and caused an
inhibition   of  ChE  activity.   Symptoms  of  toxicity  were  clearly
recognizable after 15 min, and they disappeared almost completely after
60  min.   The ChE  activity and ACh  levels reached their  minimum and
maximum,  respectively,  at  15  min.   The  maximum  concentration  of
dichlorvos  in  the  brain  was  reached  after  1  min  and  decreased
thereafter, rapidly reaching the baseline level after 3  min  (Nordgren
et al., 1978).

6.5.2  Body burden

    There  is  no  evidence  for  the  storage  of  dichlorvos  or  its
metabolites  in the tissues of animals.  Small fractions of the carbon,
phosphorus,  and chlorine derived from  dichlorvos are retained in  the
body for several days because their turnover rate is the same  as  that
for identical materials from other origins.

6.5.3  Indicator media

    The  determination  of  dichloroethanol in  urine  as  a  means  of
monitoring   the   exposure  of  human  beings  to  dichlorvos  is  not
sufficiently  sensitive to detect  levels arising from  vapour exposure
through  normal  use.   However, it  could  serve  as the  basis  for a
specific detection method for the accidental ingestion of  high  levels
(Hutson  &  Hoadley,  1972a).   Two  other  methods  can be  used:  (a)
determination  of  the  blood ChE  activity;  or  (b) determination  of
dimethylphosphate  in urine  by a  rather complicated  method (Blair  &
Roderick,  1976).  Neither method  is specific when  exposure to  other
organophosphate  or  carbamate compounds,  or  to compounds  that  also
metabolize to dimethylphosphate, may have occurred.

7.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

7.1  Microorganisms

    Lal  (1982) reviewed the  accumulation, metabolism, and  effects of
organophosphorus insecticides on microorganisms.

    Microorganisms   undoubtedly   have   the  ability   to  metabolize
organophosphorus insecticides; however, there are still large  gaps  in
our  knowledge.   It also  seems  clear that  chemical,  photochemical,
physical,  and  biological  factors  may  influence  the  metabolism of
dichlorvos by microorganisms.

7.1.1  Algae and plankton

    The  dose of  dichlorvos producing  50% growth  inhibition  of  the
unicellular  alga  Euglena  gracilis has  been  quoted  as  3.5 mg/litre
(Butler, 1977).

    Treating   eutrophic   carp   ponds  with   0.325 mg/litre   killed
 Cladocera (predominantly  Bosmina and  Daphnia species)    and  decreased
 Copepoda (mainly  Cyclops ).    This was offset by increased development
of   Rotatoria    (mainly   Polyarthra   and   Brachionus   species)   and
phytoplankton  (mainly  Scenedesmus   and  Pediastrum   species), so that
the total plankton biomass changed only slightly (Grahl et al., 1981).

7.1.2  Fungi

    Dichlorvos (in the range 10 - 80 mg/litre) has been found to affect
citric  acid fermentation in  Aspergillus  niger grown in an  artificial
medium.   Inhibition of  the fermentation  was marked  only at  40  and
80 mg/litre  (Rahmatullah et al., 1978; Ali et al., 1979c).  It appears
from the decreased uptake of inorganic phosphorus that  dichlorvos  may
have  an interfering action on  oxidative metabolism in  A. niger.   The
potential    for   inhibiting   citrinin    production   by  Penicillium
 citrinum was investigated.  Dichlorvos inhibited citrinin production by
76%  at  100 µg/litre  and  by 48% at  10 µg/litre  (Draughon &  Ayres,
1978).   The effect of dichlorvos on the survival time and the membrane
potential  of the slime  mould  Physarum polycephalum was studied  in  a
laboratory test system.  The threshold value for both these effects was
found to be 300 mg/litre for technical dichlorvos and  30 mg/litre  for
the pure chemical (Terayama  et al., 1978).

    The  influence  of  dichlorvos on  17  soil  fungi,  cultivated  in
artificial  medium, was  tested.  Dose  levels of  0, 10,  30, 60,  and
120 mg/kg  were used during a test period of 21 days, and the effect on
the  growth  and morphology  of the fungi  was studied.  In  general, a
growth  depression  was found,  but its extent  depended on the  fungal
strain.  Occasionally growth was either unaffected or  even  stimulated
(Jakubowska & Nowak, 1973).

7.1.3  Bacteria

    Dichlorvos  has been found not  to influence the overall  metabolic
processes of  Escherichia coli and  Enterobacter aerogenes at doses up to
250 mg/litre  (Grahl  et  al., 1980)  and  was  not toxic  for a sewage
isolate  at  up to  10 mg/litre (Rosenberg et  al., 1979).  In  poultry
effluent  slurry,  concentrations  of  100  and  1000 mg/litre  did not
significantly  reduce coliform populations, but  10 000 mg/litre caused
almost  complete death.  Therefore, residues of dichlorvos used for fly
control in layer houses can significantly reduce the  enteric  coliform
populations that are essential to the conversion of organic nitrogen to
inorganic  nitrogen  in  poultry  waste  effluent  (Ballington  et al.,
1978).

    In  studies  by Lieberman  &  Alexander (1981),  dichlorvos  (0.1 -
100 mg/litre)  had little or  no toxicity for  microorganisms degrading
organic   matter  in  sewage,  as  measured  by  respiratory  activity,
degradation, and nitrification.

    Incubation  of  dichlorvos  with  inocula  of  ruminal  bacteria or
ciliated  protozoa under anaerobic conditions  suggests that dichlorvos
is  not  utilized by  the organisms for  growth, nor does  it stimulate
endogenous  gas production.  However,  it does, in  certain  instances,
affect volatile fatty acid production (Williams, 1977).

    The  growth  of  Bacillus  thuringiens var  th. was not  inhibited by
dichlorvos (Dougherty  et al., 1971).

7.2  Aquatic Organisms

    Reviews of the acute and chronic effects of pesticides  on  aquatic
organisms  have been made by  Brungs et al. (1977),  Livingston (1977),
and Kenaga (1979).

    The toxicity of a chemical for aquatic organisms is  influenced  by
many factors such as the stage of development of the organism  and  the
composition,  pH, oxygen content, and  hardness of the water.   In this
short review, these factors are not discussed in detail.

7.2.1  Fish

7.2.1.1  Acute toxicity

    The  acute toxicity of dichlorvos for both freshwater and estuarine
species of fish is moderate to high.  The available data are summarized
in Table 11.

    Variations in water hardness from 44 to 162 mg/litre and in pH from
6 to 9 did not alter the toxicity of dichlorvos for cutthroat  or  lake
trout (Johnson & Finley, 1980).

    In  studies  by  Yamane et al. (1974), young carp were exposed to a
concentration  of  25 mg dichlorvos/litre  water  for 45 min.   The ChE
activity  (histochemically determined) of  many tissues, including  the
stratum  griseum periventriculare, sarcolemma, and liver, was inhibited
or totally lost.


Table 11.  Acute toxicity of dichlorvos for fish
----------------------------------------------------------------------------------------------------
   Species                    Mass or       Temperature    96-h LC50      Reference
                              length            (°C)       (mg/litre)
----------------------------------------------------------------------------------------------------
Freshwater

    Clarias batrachus          26 - 31 g           -           8.9         Verma et al. (1983)

   Carp                       8 mm             20 - 23        0.34        Verma et al. (1981d)
    (Cyprinus carpio)          6 g              23             20a         Yamane et al. (1974)

   Mosquito fish              0.2 g              17           5.3         Johnson & Finley (1980)
    (Gambusia affinis) 

   Blue gill                  1.5 g              18           0.9         Johnson & Finley (1980)
    (Lepomis macrochirus) 

   African catfish            6 - 10 g           18           0.5         Verma et al. (1980, 1981a)
    (Mystus vittatus)

    Ophiopcephalus punctatus   40 - 55 g          18           2.3         Verma et al. (1981a)

   Fathead minnow             0.7 g              17           12          Johnson & Finley (1980)
    (Pimephales promelas)

   Harlequin fish             -                  20           7.8b        Alabaster (1969)
    (Rasbora heteromorpha)

   Singii                     5 - 10 g           18           6.6         Verma et al. 
    (Saccobranchus fossilis)                                               (1982a)

   Cutthroat trout            2.5 g              12           0.2         Johnson & 
    (Salmo clarki)                                                         Finley (1980)

   Lake trout                 0.3 g              12           0.2         Johnson & 
    (Salvelinus namaycush)                                                 Finley (1980)

    Tilapia mossambica         3 - 10 cm          29        1.4 - 1.9      Rath & Misra 
                                                                          (1979a)
----------------------------------------------------------------------------------------------------


    Table 11.  (contd).
----------------------------------------------------------------------------------------------------
   Species                    Mass or       Temperature    96-h LC50      Reference
                              length            (°C)       (mg/litre)
----------------------------------------------------------------------------------------------------

Estuarine

   American eel               0.14 g             20           1.8         Eisler (1970)
    (Anguilla rostrata)

   Mummichog                  1.7 g              20           2.7         Eisler (1970)
    (Fundulus heteroclitus)

   Striped killifish          0.92 g             20           2.3         Eisler (1970)
    (Fundulus majalis)

   Atlantic silverside        0.8 g              20           1.3         Eisler (1970)
    (Menidia menidia)

   Striped mullet             1 - 6 g            20           0.23        Eisler (1970)
    (Mugil cephalus)

   Northern puffer            100 g              20           2.3         Eisler (1970)
    (Sphaeroidus maculatus)

   Bluehead                   5.4 g              20           1.4         Eisler (1970)
    (Thalassoma bifasciatum)
----------------------------------------------------------------------------------------------------
a   24-h LC50.
b   48-h LC50.
7.2.1.2  Short-term toxicity

    Sublethal  concentrations  of  dichlorvos (0.5 - 1 mg/litre)   have
been found to decrease the respiratory rates  of  Tilapia  mossambica (3
different  age groups)  exposed  for up to  3 weeks.  When  the exposed
fish  were transferred  to fresh  water, the  rate did  not  completely
return  to  its pre-exposure  value (Rath &  Misra, 1979b).  Liver  and
brain  ChE activity showed considerable  inhibition when a group  of  T.
 mossambica was  exposed to dichlorvos (0.25 - 1.25 mg/litre  water) for
periods  of up to 4  weeks.  At 7-day intervals,  fish were studied  or
transferred  to  clean  water.  The  degree  of  enzyme inhibition  was
related to the dichlorvos concentration and length of exposure.  In all
age  groups of  fish, brain  tissue exhibited  a higher  degree of  ChE
inhibition  than liver.  Small fish were more susceptible to dichlorvos
with respect to AChE activity.  When the fish were transferred to clean
water,  most of the  fish recovered their  AChE activity, the  recovery
being  greater  in  liver  than  in  brain.   Small  fish  exhibited  a
comparatively  high level  of recovery.   The degree  of  recovery  was
inversely related to the length of exposure (Rath & Misra, 1981).

    Melanin dispersion in  T. mossambica exposed to 1 mg/litre water for
15  days was stimulated indirectly  by the inhibition of  ChE activity.
The original colour was regained within 96 h after transfer of the fish
to clean water (Rath & Misra, 1980).

    Exposure  of  Mystus  vittatus (collected  in the  environment)   to
sublethal  concentrations of dichlorvos (0.045 or 0.09 mg/litre) for 30
days  caused dose-related increases  in serum glutamic-oxaloacetic  and
glutamic-pyruvic  transaminase levels (Verma et  al., 1981b), increases
in  alkaline  phosphatase, acid  phosphatase, and glucose-6-phosphatase
levels  in serum (Verma et al., 1984), decreases in the levels of these
enzymes in liver, kidneys, and gills (Verma et al., 1981c), an increase
in  glucose levels in blood,  and a decrease in  liver glycogen.  Blood
lactate and muscle glycogen were unaffected (Verma et al.,  1983).   At
0.09 mg/litre,  blood clotting time,  mean corpuscular haemoglobin  and
mean corpuscular haemoglobin concentration decreased, and the number of
leukocytes increased.  Other haematological parameters did not show any
abnormalities  (Verma  et  al., 1982b).   From  these  results,  a  no-
observed-adverse-effect concentration of 0.03 mg/litre was derived.

    In  studies by Verma &  Tonk (1984),  Heteropneustes (Saccobranchus)
 fossilis was  exposed to dichlorvos for  30 days at a  concentration of
0.44   mg/litre.   Respiration,  haematological  parameters,   and  the
activities  of two enzymes (one  of them AChE)  in  liver, kidneys, and
gills  were  determined.  The  respiration  rate decreased,  and  blood
concentrations  of  sodium  and  chloride  ions  and  glucose increased
significantly,  whereas the cholesterol  level and clotting  time  were
decreased.  A significant reduction in the AChE activity of  the  three
tissues was found.

    Vadhva & Hasan (1986) studied the effect of dichlorvos (at 0, 3, 6,
and   9   mg/litre  water)  on   various  lipid  fractions  and   lipid
peroxidation   in   the   central  nervous   system   of  Heteropneustes
 fossilis.   After  one  week's  exposure,  the  results  indicated that
dichlorvos  caused dose-related increases in total lipids, cholesterol-
esterified fatty acid, and lipid peroxidation in various regions of the
brain  and  spinal  cord but  a  consistent  decrease in  the  level of
phospholipids in these regions of the central nervous system.

    Exposure   of  Clarias  batrachus to  0.5 - 2.2 mg  dichlorvos/litre
and  Saccobranchus  fossilis to 0.4 - 1.6 mg/litre for 30 days was found
to  increase blood glucose and  decrease liver glycogen, whereas  blood
lactate and muscle glycogen were normal (Verma et al., 1983).

    The   estimated   "maximum   acceptable   toxicant   concentration"
(MATC)a for   the larvae of  Cyprinus carpio was  0.016 - 0.020 mg/litre
based on a 60-day study (Verma et al., 1981d).

7.2.2  Invertebrates

    The   acute  toxicity  of   dichlorvos  for  aquatic   insects  and
crustaceans is extremely high (Table 12).  As might be expected from an
organophosphorus  insecticide,  aquatic  invertebrates are  about three
orders of magnitude more susceptible to dichlorvos than are  fish,  and
freshwater crustaceans are particularly sensitive.

    A study was carried out to determine the influence of a  number  of
pesticides on the "hatchability" of  Artemia salina dry eggs.  No effect
was  found at 10 mg dichlorvos/litre in the aqueous system (Kuwabara et
al., 1980).

    When  prawns  (Macrobrachium lamarrei) were exposed to dichlorvos at
concentrations of 0.31 or 0.62 mg/litre for 96 h, a decrease in hepatic
glycogen and an increase in the blood glucose level were found (Omkar &
Shukla,   1984).    Possibly,   the  phosphorylase   activity   of  the
hepatopancreas  and muscle  increased due  to the  inhibition  of  AChE
activity   and   the   consequent  accumulation   of  acetylcholine  at
neurosynaptic  junctions.  The latter resulted  in an induction of  the
secretion of the sinus gland, which enhanced glycogenolysis.

7.3  Terrestrial Organisms

7.3.1  Birds

7.3.1.1  Acute oral toxicity

    Dichlorvos  has a  high oral  toxicity for  birds (Table 13).   The
signs of intoxication are typical of organophosphorus poisoning, namely
salivation,  lachrymation,  tremors,  and terminal  convulsions.   They
usually appear shortly after dosing, and, at lethal doses, death occurs
within  1 h.  Survivors appear to recover completely 24 h after dosing.
Various  internal  haemorrhages were  found  at autopsy  in  sacrificed
survivors  of treated pheasants and  Mallard ducks (Tucker &  Crabtree,
1970).
-----------------------------------------------------------------------
a   Maximum concentration at which no effect was seen.


Table 12.  Acute toxicity of dichlorvos for non-target aquatic insects and Crustacea
-------------------------------------------------------------------------------------------------------
   Species                     Temperature     48-h LC50      96-h LC50      Reference
                                   (°C)        (µg/litre)     (µg/litre)
-------------------------------------------------------------------------------------------------------
Insects (stone flies)

    Pteronarcys californica          15             -              0.1        Johnson & Finley (1980)

Crustacea (fresh water)

   Water flea                       15            0.07             -         Johnson & Finley (1980)
    (Daphnia pulex)

   Water flea                       21            0.28             -         Johnson & Finley (1980)
    (Simocephalus serrulatus)

   Amphipod                         21             -              0.5        Johnson & Finley (1980)
    (Gammarus lacustris)

Crustacea (estuarine)

   Sand shrimp                      -             12              4          Eisler (1969)
    (Crangon septemspinosa)

   Grass shrimp                     -            300             15          Eisler (1969)
    (Palaemonetes vulgaris)

   Hermit crab                      -             52             45          Eisler (1969)
    (Pagurus longicarpus)
-------------------------------------------------------------------------------------------------------

Table 13.  Acute oral LD50 values for birds
------------------------------------------------------------------------------------------------------------------------
 Species                            Age              Vehicle                   LD50            Reference
                                                                         (mg/kg body weight)
------------------------------------------------------------------------------------------------------------------------
 Red-winged blackbird                                propylene glycol          13.3             Schafer & Brunton (1979)
    (Agelaius phoenicius) (male)

 Mallard duck                       5 - 7 months     capsule                    7.8             Tucker & Crabtree (1970)
    (Anas platyrhynchos) (male)

 Common pigeon                                       propylene glycol          24               Schafer & Brunton (1979)
    (Columba livia)

 Quaila                                              propylene glycol          24               Schafer & Brunton (1979)
    (Coturnix coturnix) (female)

 Domestic fowl                      21 days          aqueous suspension         6.5             Naidu et al. (1978)
   (Gallus domesticus) (male)       6 - 8 months     aqueous suspension        30               Dmitriev & Kozhemyakin
                                                                                                (1975)

 House sparrow                                       propylene glycol          17.8             Schafer & Brunton (1979)
    (Passer domesticus)

 Ring-necked pheasant               3 months         capsule                   11               Tucker & Crabtree (1970)
    (Phasianus colchicus) (male)

 Common grackle                                      propylene glycol          13.3             Schafer & Brunton (1979)
    (Quiscalus quiscula)

 Starling                           adult            propylene glycol          12               Schafer (1972)
    (Sturnus vulgaris)               -                propylene glycol          42.1             Schafer & Brunton (1979)
------------------------------------------------------------------------------------------------------------------------
a   Hattori et al. (1974) carried out studies on Japanese quail and found
    LD50 values of 22 and 26 respectively, for male and female 
    (no details available).
7.3.1.2  Short-term toxicity

    In  short-term dietary  studies, dichlorvos  has been  found to  be
slightly to moderately toxic for birds (Table 14).

    In  the study with 7-day-old male chicks, there was weight loss and
50%  mortality at 500 mg/kg  diet.  Marked, dose-related  inhibition of
brain  ChE  activity occurred  at 50, 100,  and 500 mg/kg diet,  but no
effects were noted at a level of 10 mg/kg diet (Naidu et al., 1978).

    Canaries,  Indian finches, and budgerigars, continuously exposed to
dichlorvos  vapour (0.14 mg/m3)   for  5 days, did  not show any  overt
signs  of  intoxication, but  a reduction in  ChE levels in  plasma and
brain  was  observed  in canaries  and  Indian  finches (Brown  et al.,
1968).

7.3.1.3  Field experience

    Caution  has  been advised  in the use  and handling of  dichlorvos
where birds might be exposed (Whitehead, 1971).  The necessity for this
warning  can be  illustrated by  the following  cases.  Adult  mallards
feeding  near  horse  mangers containing  dichlorvos-treated  feed were
found  dead  within a  short time.  At  necropsy, excessive amounts  of
mucus covering the mucosa of the proventriculus and scattered petechiae
along medial edges of liver lobes were observed.  The small  and  large
intestines  were markedly  extended, and  crystals were  noted  in  the
gizzard.   Brain ChE activity was inhibited by 75 - 80% (Ludke & Locke,
1976).  Domestic fowl, which had accidental access to the faeces  of  a
horse  dosed with dichlorvos pellets,  picked out the pellets  and more
than  30  birds  died  during  the next  24  h (Lloyd,  1973).   A mass
poisoning  occurred in chickens  following consumption of  accidentally
contaminated  drinking-water  (Egyed  & Bendheim,  1977).  English game
bantams   died  after  consuming   wheat  contaminated  with   300   mg
dichlorvos/kg wheat (Reece, 1982).

7.3.2  Invertebrates

    Dichlorvos was toxic for silkworm larvae when for 4 h they were fed
mulberry  leaves previously sprayed  with dilute dichlorvos  emulsions.
Spray  concentrations giving  50% mortality  ranged from  1.56 to  6.25
mg/litre (Aratake & Kayamura, 1973).

    No  adverse effects were observed  on the hatchability and  general
condition  of first  instar silkworm  larvae hatched  in the  following
generation  when 5th instar larvae were fed mulberry leaves pre-treated
with 3 mg dichlorvos/kg of leaf (Yamanoi, 1980).


Table 14.  Dietary LD50 values for birds
-------------------------------------------------------------------------------------
Species                     Age      Duration       LD50      Reference
                           (days)   of feeding   (mg/kg diet)
                                      (days)
-------------------------------------------------------------------------------------
Mallard duck                 16         8a         5000       Hill et al. (1975)
  (Anas platyrhynchos)         5         8a         1310       Hill et al. (1975)

Japanese quail               14         8a          300       Hill et al. (1975)
  (Coturnix japonica) 
Domestic fowl                 7        28           500       Naidu et al. (1978)
  (Gallus domesticus) (male)

Ring-necked pheasant         10         8a          570       Hill et al. (1975)
  (Phasianus colchicus) 
-------------------------------------------------------------------------------------
a   The median lethal dietary dose (LD50) during an 8-day test including 
    5 days of treated diet followed by 3 days of untreated diet.
7.3.3  Honey bees

    Dichlorvos is highly toxic for honey bees.  Atkins et  al.   (1973)
found  in laboratory studies an LD50 of  0.495 µg/bee  in 48 h (topical
application  of dust; 26.7 °C;  relative humidity 65%).   Beran  (1979)
obtained an oral LD50 of  0.29 µg/g  body weight and an LD50   (topical
application) value of 0.65 µg/g  body weight.  This high  toxicity  has
led  dichlorvos to be classified in the most toxic category for bees in
Austria and the USA.

    When honeycombs were exposed to dichlorvos vapour  from  dichlorvos
resin  strips for 4 months, the combs absorbed the insecticide and were
toxic  to  bees  for approximately  one  month  after exposure  ceased.
Contamination  of  the  bees appeared  to  be  by fumigant  rather than
contact action (Clinch, 1970).

7.3.4  Miscellaneous

    Dichlorvos   was  highly toxic  for  the predatory  mite  Amblyseius
 longispinosus in  contact trials.  Residual toxicity disappeared within
6  days, the  susceptibility being  the same  as  that  of  Phytoseiulus
 persimilis (Shinkaji & Adachi, 1978).

8.  EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

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

8.1  Single Exposures

    Dichlorvos  is  moderately to  highly  toxic when  administered  in
single  doses  by  various  routes  to  a  variety  of  animal  species
(Table 15).   It  is  less toxic via the dermal and oral routes than by
parenteral  routes.  The signs of  intoxication by all exposure  routes
are   typical   of   organophosphorus  poisoning,   i.e.,   salivation,
lacrimation,  diarrhoea, tremors, and terminal  convulsions, with death
occurring  from  respiratory  failure.  In  addition, lethargy, ataxia,
hypersensitivity to noise, splayed gait, and paresis may  be  observed.
The  signs  are usually  apparent shortly after  dosing and, at  lethal
doses, death occurs within 1 h.  Survivors appear to recover completely
24 h after dosing.

    The  acute  inhalational  LC50 values   for  mice  and   rats   are
summarized in Table 16.  The apparent differences in the LC50s   may be
the  result  of  the type of exposure of the animal (whole body or head
only), whether the studies were carried out with dichlorvos  vapour  or
atomized particles of spray (with or without vehicle),  or  differences
in  the purity of the  dichlorvos.  Moreover, since dichlorvos  adheres
strongly  to  surfaces  including  glass,  the  out-going  air  has   a
significantly  lower concentration of  dichlorvos than the  air  coming
into the chamber, if the system is not yet equilibrated.

    No  macroscopic abnormalities were observed in mice or rats 2 weeks
after a single exposure (MacDonald, 1982).

8.1.1  Domestic animals

    When  cattle and sheep  were treated orally  with a single  dose of
dichlorvos, 10 mg/kg body weight was toxic for calves and 25 mg/kg body
weight  for  sheep.   For the latter a dose of 10 mg/kg body weight was
without effects (Radeleff & Woodard, 1957).

8.1.2  Potentiation

    Potentiation   studies   on   male   rats   indicated   that   oral
administration  of dichlorvos with 22  other organophosphate pesticides
resulted in no (or very little) potentiation, while administration with
malathion  showed  a marked  potentiation  (Narcisse, 1967;  Kimmerle &
Lorke, 1968).  However, Cohen & Ehrich (1976) found that  the  anti-ChE
action  of 800 mg malathion/kg body weight (injected intraperitoneally)
was  not potentiated by  pre-treatment (18 h previously)  with 30 mg/kg
dichlorvos,  nor did malathion  pre-treatment potentiate the  action of
dichlorvos.


Table 15.  The acute toxicity (LD50) of dichlorvos for experimental animals
---------------------------------------------------------------------------------------------------------
Species            Route             Purity     Vehicle                LD50     Reference
                                                                     (mg/kg)
---------------------------------------------------------------------------------------------------------
Mouse (male)       oral              unknown    Eryfor EL or other   68 - 90    Vrbovsky et al. (1959);
                                                solvents                        Ueda et al. (1960)

Mouse              oral                80%      unknown                 87      Sasinovich (1968, 1970)

Mouse              oral                97%      aqueous polysor-    133 - 139a  Haley et al. (1975)
                                                bate 80

Mouse (male)       oral                98%      corn oil               140      Isshiki et al. (1983)

Mouse              oral              unknown    aqueous             124 - 275a  Yamashita (1960, 1962);
                                                                                Holmstedt et al. (1978)

Mouse (male)       subcutaneous      unknown    propylene glycol     13 - 33    Ueda et al. (1960);
                                                and other solvents              Jaques (1964)

Mouse              subcutaneous      unknown    aqueous              20 - 26    Yamashita (1960, 1962);
                                                                                Holmstedt et al. (1978)

Mouse (male)       dermal            unknown    different solvents  206 & 395b  Ueda et al. (1960)

Mouse              intraperitoneal   technical  corn oil                28      Vrbovsky et al. (1959);
                                                                                Casida et al. (1962)

Mouse              intraperitoneal   unknown    aqueous              28 - 41a   Holmstedt et al. (1978)

Mouse              intravenous       unknown    aqueous               8 - 10    Holmstedt et al. (1978)

Rat                oral              90 - 99%   peanut oil and       56 - 96a   Durham et al. (1957);
                                                other solvents                  Narcisse (1967); Gaines
                                                                                (1969)

Rat (male)         oral              unknown    Eryfor EL and        46 - 110   Vrbovsky et al. (1959);
                                                other solvents                  Ueda et al. (1960)

Rat                oral                80%      unknown                 65      Sasinovich (1968, 1970)

Rat                oral              unknown    aqueous                 30      Holmstedt et al. (1978)
---------------------------------------------------------------------------------------------------------

Table 15.  (contd).
---------------------------------------------------------------------------------------------------------
Species            Route             Purity     Vehicle                LD50     Reference
                                                                     (mg/kg)
---------------------------------------------------------------------------------------------------------
Rat                dermal            unknown    xylene               75 - 107a  Durham et al. (1957);
                                                                                Gaines (1969)

Rat                dermal              80%      unknown                113      Sasinovich (1968, 1970)

Rat                subcutaneous        95%      dimethylsulfoxide       72      Brown & Stevenson
                                                                                (1962)

Rat (male)         intraperitoneal   unknown    Eryfor EL               18      Vrbovsky et al. (1959)

Guinea-pig         subcutaneous        95%      undiluted               28      Brown & Stevenson
                                                                                (1962)

Syrian hamster     intraperitoneal      -       suspension in           30      Dzwonkowska & Hübner
                                                water                           (1986)

Rabbit             oral                93%      unknown                12.5     Desi et al. (1978)

Rabbit             oral                80%      unknown                22.5     Sasinovich (1968, 1970)

Rabbit             dermal              80%      unknown                205      Sasinovich (1968, 1970)

Cat                oral                80%      unknown                 28      Sasinovich (1968, 1970)

Dog                oral                         in capsule          100 - 316   Kodama (1960)

Swine (40- to 60-  oral              technical  in capsule             157      Stanton et al. (1979)
day-old)

Domestic fowl      oral              technical  in capsule              15      Sherman & Ross (1961)
 (chicken)
---------------------------------------------------------------------------------------------------------
a   The LD50s are often slightly different in males and females.  Furthermore, it is clear that the 
    purity of the dichlorvos tested and the vehicle used has an influence on the toxicity.
b   The two values were obtained using two different solvents.

Table 16.  Inhalational LC50 values for dichlorvos
---------------------------------------------------------------------------------------------------------
Species          Purity         Type of         Duration    LC50 (mg/m3)      Reference
                                exposure
---------------------------------------------------------------------------------------------------------
Mouse              80%          vapour             4 h          13            Sasinovich (1968, 1970)
                                whole body

Mouse              98%          vapour             4 h       > 218            MacDonald (1982)
                                head only

Mouse (male)     unknown; in    vapour             4 h         310            Ueda et al. (1960)
                 solvent Ca     whole body

Rat (male)       unknown        unknown, but       1 h         455            Kimmerle & Lorke (1968)
                                uptake by in-
                                halation only

Rat (male)         84.1%        whole body         1 h         140            Sakama & Nishimura
                 polyethylene                                                 (1977)
                 glycol

Rat (male)       unknown        unknown, but       4 h         340            Kimmerle & Lorke (1968)
                                uptake by in-
                                halation only

Rat                80%(?)       vapour             4 h          15            Sasinovich (1968, 1970)
                                whole body

Rat                98%          vapour             4 h       > 198            MacDonald (1982)
                                head only
---------------------------------------------------------------------------------------------------------
a   Solvent C = 0.5% Sorpol 2020 water solution.
     In   vitro studies  using  human  erythrocytes  and  plasma  as ChE
sources,  with  ACh as  substrate,  indicated no  potentiationa    when
dichlorvos  was  tested  in  combination  with  carbaryl,  crotoxyphos,
phosphamidon,  malathion,  malaoxon,  mevinphos,  parathion,  paraoxon,
physostigmine, and trichlorphon (Carter & Maddux, 1968, 1974).

8.2  Short-term Exposures

8.2.1  Oral

8.2.1.1  Mouse

    A  10-week (range-finding) toxicity study was carried out on B6C3F1
mice given 0, 25, 50, 100, 200, or 400 mg dichlorvos/  litre  drinking-
water.   Each group consisted  of 12 males  and 12 females,  except the
control  group (10 males  and 10 females).   Growth and mortality  were
comparable with controls.  In a second study, groups of 10 males and 10
females  received 400, 1600, 3200, 5000, or 10 000 mg dichlorvos/litre.
The  animals given the two highest doses died within 2 weeks, while the
1600  and 3200 mg  groups showed  slight and  clear growth  depression,
respectively, after 10 weeks (Konishi et al., 1981).

8.2.1.2  Rat

    For  15  weeks,  groups of 15 male and 15 female Charles River rats
were  fed diets containing  0, 0.1, 1,  10, 100, or  1000 mg dichlorvos
(93%)/kg  diet,  which  were freshly  prepared  once  each  week.   The
stability  of  dichlorvos  in  the  diets  was  not  reported  but,  in
accordance  with the 2-year oral  rat study (section 8.4.1),  it may be
assumed that the average concentration of dichlorvos in each  diet  was
approximately  47% of the  amount that had  been added.  There  were no
deaths  or signs of intoxication.   Only the rats fed  the highest dose
exhibited  decreased growth rates  at the beginning  of the study.   At
termination,  no  differences  were  observed  in  haematology,   serum
protein, urinalysis, or gross or histopathological examination.  In the
highest  dose  group,  marked inhibition  of  ChE  activity in  plasma,
erythrocytes,  and  brain  was noted.   In  the  100 mg/kg group,  only
erythrocyte ChE inhibition was observed, and the 10 mg/kg group did not
show any ChE inhibition (Witherup et al., 1964).

    Daily doses of 3.5 or 7 mg dichlorvos (purity not  stated)/kg  body
weight  administered intragastrically to rats  for 4 months and  0.7 or
1.4 mg/kg  for  12  months  caused  no  deaths.   There were  signs  of
intoxication in the 7 mg group, and decreases in food  consumption  and
body weight gain and increases in a number of organ weights  were  seen
in  all the groups except the lowest dose group.  Inhibition of plasma,
erythrocyte, and brain ChE activity was observed in all  groups  except
those  given 0.7 mg/kg body weight.   The inhibition was time  and dose
dependent (Sasinovich, 1970).

-----------------------------------------------------------------------
a   Potentiation  is the phenomenon that results in the combined effect
    of exposure to two or more chemical substances being  greater  than
    the  sum of the  effects that would  be produced by  each substance
    separately, as the result of synergistic action.

    In  a (range-finding) toxicity study,  groups of F-344 rats  (10 of
each sex)  were administered 0, 5, 10, 20, 40, or 80 mg/kg body weight,
dissolved  in 10 ml of  drinking-water.  During the  study six  animals
died,  five  of which  were in the  two highest doses  groups (Enomoto,
1981).

    Dichlorvos  administered orally to  rats at a  concentration of  70
mg/kg   body  weight  inhibited  not   only  ChE,  but  also   alkaline
phosphatase,   lactate   dehydrogenase,  and   glutamate  dehydrogenase
competitively.    It   increased   the  activity   of  glutamic-pyruvic
transaminase,  but leucine aminopeptidase  was not affected  (Ellinger,
1985).

    Ellinger  et al. (1985) also studied the influence of dichlorvos on
haematological parameters in acute and short-term toxicity studies.  In
the acute study 70 mg dichlorvos/kg body weight and in  the  short-term
study 30 mg/kg body weight were administered for 12  weeks.   Decreases
in   haemoglobin,   haematocrit,   and  mean   corpuscular  haemoglobin
concentration were found.

    Seven  rat  mothers  were  administered  different  dose  levels of
dichlorvos  (1 g or 10 g/litre  distilled water) by  stomach tube,  and
their  litters  (1 - 12 days  old) were nursed  for about 21  days, and
weaned  after  35  days of age.  Although doses of 10 and 20 mg/kg body
weight did not cause any symptoms of intoxication, the  mothers  showed
significant  inhibition  of  erythrocyte  ChE  activity.   Plasma   ChE
activity  was  affected  to a  lesser  extent.   Dose levels  of 30 and
40 mg/kg body weight caused severe inhibition of erythrocyte  ChE,  and
severe  cholinergic  symptoms were  seen.   The symptoms  occurred 10 -
20 min  after dichlorvos administration and  continued for 30 - 90 min,
when recovery took place (Tracy et al., 1960).

    When pregnant rats were given oral doses of 1 or 5 mg dichlorvos in
oil/kg  body weight during  days 14 - 21 of  pregnancy, the plasma  ChE
activity of the mothers was markedly inhibited, but that of  the  young
(up  to 56 days old)  resembled the activity in the control.  Brain ChE
activity  did not  show any  significant inhibition  (Zalewska et  al.,
1977).

8.2.1.3  Rabbit

    The progeny of rabbits, treated orally with 6 mg dichlorvos/kg body
weight per day for the last 10 days of pregnancy showed a  decrease  in
brain  ChE activity and an  increase in plasma ChE  activity throughout
days 1 - 16 of life (Maslinska & Zalewska, 1978).

8.2.1.4  Cat

    "Flea  collar  dermatitis"  has been  described  in  cats and  dogs
wearing dichlorvos-impregnated PVC flea collars.  In most  cases,  flea
collar  dermatitis  is  a  primary  irritant  contact   dermatitis   to
dichlorvos.  The  symptoms  may  consist  of  mild   local   irritation
(localized  erythema and itching), severe local irritation varying from
erythematous  alopecia  to  erosions, ulceration,  oedema, and purulent

discharges  with crusting  or, in  the most  severe cases,  generalized
dermatitis  with  secondary  pyoderma  and  systemic  illness  (Muller,
1970).

    Two trials with six and five cats, respectively, were  carried  out
to   study   the  occurrence   of   contact  dermatitis   and  systemic
intoxication.   The  cats  received  either  a  placebo  collar  or   a
dichlorvos collar.  Two cats received two dichlorvos collars  each  and
each cat was observed for 21 days.  In a third trial, four groups of 25
cats  were  used to  study hepatotoxicity.  The  cats of the  different
groups  were treated as  follows.  Group 1:   placebo collar; Group  2:
placebo  collar and intraperitoneal treatment with carbon tetrachloride
(CCl4)    7 days later; Group 3: dichlorvos collar; Group 4: dichlorvos
collar  and  intraperitoneal injection  of  CCl4 7  days  later.  Serum
glutamic pyruvic transaminase and ChE activity was estimated on  day  9
of  exposure.  In a fourth  study, 24 cats were  fitted with a  placebo
collar   to  test  the  effect  of  PVC  in  relation  to  the  contact
dermatitis.   PVC  did  not have  an  effect.   No clear  effect of the
CCl4-induced    hepatic dystrophy on  the detoxification of  dichlorvos
was found.

    The  predominant systemic abnormalities  recorded in these  studies
were  bone-marrow  depression,  ataxia, demyelination,  and depression.
Red  cell and plasma ChE activity was severely depressed.  Furthermore,
contact  dermatitis  was  seen  in  animals  with  dichlorvos  collars.
Ambient  temperature  and  relative humidity  may  have  had  a  marked
influence  on these effects, especially in the case of high temperature
and low humidity (Bell et al., 1975).

    A  90-day study on 90  mongrel cats was carried  out to verify  the
results  of Bell et al. (1975) by using a larger number of animals over
a  longer period.  There were three groups of 30 cats; one group with a
PVC  collar (without dichlorvos), one group with one dichlorvos collar,
and the third group with three dichlorvos collars.  In this  study,  in
which  all relevant  parameters were  studied, no  confirmation of  the
abnormalities described by Bell et al. (1975)  were found,  even  under
conditions of high temperature and low humidity.  The only  effect  was
contact  dermatitis, but, in this study, this was also found in the PVC
collars (Allen et al., 1978).

8.2.1.5  Dog

    Groups  of three male and three female dogs received equivalents of
approximately 0, 0.3, 1, 1.5, or 3 mg dichlorvos (93% in olive  oil  by
gelatin capsule)/kg body weight, daily, for 90 days.  No  effects  were
observed  on  mortality,  growth,  liver  and  kidney  function,  organ
weights,  haematology, or at  gross and histopathological  examination.
In the two highest dose groups, the dogs showed  excitement,  increased
activity,  and  aggression.   Plasma  and  erythrocyte  ChE  activities
(measured  initially and at  intervals of approximately  2 weeks)  were
normal  in the lowest dose group (0.3 mg/kg body weight) but reduced in
the other dose groups.  Brain ChE activity at termination  was  reduced
only in the highest dose group (Hine, 1962).

8.2.1.6  Pig

    Young  swine (35  days old)  were fed  a PVC-resin  formulation  of
dichlorvos (10%) in dosages equivalent to 1, 4, and 16 mg dichlorvos/kg
body weight per day in the feed (divided over two daily doses)  for  30
days.   Body  weight  gain,  blood  cell  counts,  packed-cell volumes,
haemoglobin concentrations, plasma glucose, plasma fatty acids, hepatic
and   muscle  glycogen  concentrations,  plasma   and  skeletal  muscle
concentrations  of electrolytes, and plasma and pancreatic insulin were
all comparable with those of control swine fed a blank PVC formulation.
Plasma and erythrocyte ChE activities were significantly  inhibited  in
the 4 and 16 mg/kg groups only (Stanton et al., 1979).

8.2.1.7  Cow

    Two  cows with suckling  calves fed 200  mg dichlorvos/kg grain  in
their rations showed normal ChE activity in the erythrocytes.  However,
severe  inhibition  of  ChE  activity  was  found  at  500 mg/kg   feed
(equivalent  to 4.5 mg/kg body weight),  and a single dose  of 27 mg/kg
body  weight caused cholinergic  collapse, followed by  rapid recovery.
The  ChE  values in  the calves remained  normal throughout the  78-day
test.    Milk  from  these  two   cows  contained  less  than   0.08 mg
dichlorvos/litre (Tracy et al., 1960).

8.2.2  Dermal

8.2.2.1  Rat

    In  studies  by  Dikshith et  al.  (1976),  groups of  48 male rats
received   daily  topical  applications   of  21.4 mg/kg  body   weight
dichlorvos  (96%) in ethanol (control animals received ethanol alone) 5
days per week for 90 days.  At intervals of 7, 15, 30, 45, 60,  and  90
days,  eight  test  rats  and  two  control  rats were  sacrificed  for
histopathological  examination of  the skin  and testes.   None of  the
animals  showed  signs  of  intoxication,  but  ChE  activity  was  not
measured.   The  skin showed  no  irritation, and  no histopathological
changes were seen in the testes or skin.

8.2.2.2  Livestock

    Spray  and  dip  studies have  shown  that  a concentration  of  1%
dichlorvos is not toxic for cattle (no further details  are  available)
(Radeleff & Woodard, 1957).

    The  effect of applying  different suspensions (different  solvents
with and without an emulsifier) of dichlorvos to the skin of  cows  has
been studied.  The dose level was 5 mg/kg body weight, increasing after
7  days  to  10 mg/kg.  Dichlorvos  at  5 mg/kg  body weight  caused  a
significant decrease in ChE activity in blood serum.  The  higher  dose
level  additionally produced symptoms  of intoxication.  No  dichlorvos
residues were found in milk (Majewski et al., 1978).

    Two  heifers were washed daily with either a 1% aqueous solution or
emulsion  of dichlorvos  or a  10% suspension  of dichlorvos  in  water
(daily  application of 1.8 g dichlorvos  for 21 days).  Two  additional
heifers  were  used  as  controls.   The  ChE  activity levels  of  the
erythrocytes remained at the lower limits of normal variation (Tracy et
al., 1960).

8.2.3  Inhalation

8.2.3.1  Experimental animals

    In  a report  by Sasinovich  (1968), groups  of rats  were  exposed
(whole body)  daily  for  4 h  to  average   dichlorvos  concentrations
of   0.11   or   1.1 mg/m3 for    4   months,   to  5.2   mg/m3 for   2
months,  or to  8.2 mg/m3   for 45 days.  The highest dose caused signs
of    intoxication;   two  of   the  eight  rats   died.   Exposure  to
5.2 mg/m3 or   more resulted in marked  inhibition of ChE activity  and
disturbance    of   the   blood-sugar   curve.    In   the   0.11   and
1.1 mg/m3 groups, no significant effects were observed.

    Mice, rats, and guinea-pigs, exposed 23 h per day for  28  consecu-
tive  days to actual dichlorvos concentrations of 0.03 mg/m3,   did not
show gross pathological changes at the end of the study.  Inhibition of
plasma and brain ChE activity occurred in male mice,  male  guinea-pigs
(plasma only), and female rats (brain only) after a 5-day  exposure  to
0.14 - 0.15 mg/m3 dichlorvos (Brown et al., 1968).

    Guinea-pigs  (P strain) exposed for  7 h per day for  5 consecutive
days  to an actual concentration of 90 - 120 mg/m3 dichlorvos  suffered
no  visible  effects  to  their  health.   Rats  (CFE) and  mice  (CF1)
similarly   exposed  to  50 mg/m3 were    not  visibly  affected.    At
concentrations  above  50 mg/m3,    the  mice  became  distressed   and
prolonged  exposure to 80 mg/m3 was  frequently lethal.  Rats were less
severely affected (Stevenson & Blair, 1969).

    In studies by Vashkov et al. (1966), 100 mice, 50 rats, 22 rabbits,
and  13 cats were exposed to a mixture containing dichlorvos, kerosene,
xylene,  and  freons  during  a  single  2-h  exposure or for  2 h  per
day   for   40  days.   Three  concentrations,  16.5,  45,  and  160 mg
dichlorvos/m3,    were tested (the  median gravimetric diameter  of the
aerosol  particles was  about 5 µm).    The overall  condition  of  the
animals  remained  normal,  and no  effects  on  body weight,  clinical
chemical  blood analyses, blood ChE  activity, or respiration rate,  or
pathological changes were observed.  Rabbits developed transient miosis
which disappeared at the end of the exposure period.

    Mice  (20), guinea-pigs (6), sheep  (7), calves (39), and  a heifer
were  exposed to  an increasing  dichlorvos concentration  in  the  air
generated  by  dichlorvos  strips (20%).   The  number  of  strips  was
increased each week for 6 weeks, reaching 80 strips per  140 m3,    and
was  then  reduced  over the  next  6  weeks.  During  exposure  to the
recommended   number  of  strips,  the dichlorvos concentration  in the
air   was   0.09 - 0.14 mg/m3.      The   highest   concentration   was
2.1 mg/m3 when   the number  of strips  was 16  times  the  recommended

number.   No mortality or signs of intoxication were observed, and mice
bore  normal litters during the study.  The serum ChE activities of the
calves  and  of those  handling the animals  were within normal  values
(Henriksson et al., 1971).

    When  10  rabbits, 8  cats, and 10  dogs (males and  females)  were
continuously exposed for 8 weeks to dichlorvos concentrations of 0.05 -
0.3 mg/m3 generated  from impregnated PVC-resin strips, no effects were
found   on  general  health,  behaviour,  plasma  and  erythrocyte  ChE
activities,  or electroencephalographic patterns  in the brain  of  the
animals (Walker et al., 1972).

    In  studies by Coulston & Griffin (1977), four male and four female
Rhesus  monkeys were continuously  exposed to dichlorvos  vapour at  an
average  actual concentration of 0.05 mg/m3 for  3 months.  The control
group  consisted of four males and one female.  No adverse effects were
observed  in  appearance,  behaviour, or  haematological  and  clinical
chemical  determinations.  Plasma ChE  activity was slightly  inhibited
(up  to 28% inhibition), whilst  the greatest erythrocyte ChE  activity
inhibition  was 36%.  No changes in nerve maximum conduction velocities
or  muscle-evoked action  potentials were  induced by  the exposure  to
dichlorvos.

8.2.3.2  Domestic animals

    Five  horses, exposed continuously to  dichlorvos for 22 days  in a
closed  barn that was  treated daily with  17 mg dichlorvos/m3,    dis-
played  mild  inhibition  of erythrocyte  ChE  activity  after 7  days,
followed by recovery at 11 - 22 days.  However, plasma ChE activity was
not  changed.  The concentration  in the barn  varied between 0.24  and
1.48 mg/m3 (Tracy et al., 1960).

    The influence on ChE activity in cattle exposed to  an  impregnated
plastic strip containing 20% of dichlorvos has been studied.  Red blood
cell ChE activity was measured during the 85 days of exposure,  and  on
the  9th  day  an average inhibition of about 35% was found.  After the
37th  day the inhibition in ChE activity gradually declined to 20%.  No
clinical signs were observed (Horvath et al., 1968),

8.2.4  Studies on ChE activity

    Groups  of  10 young  female Sherman rats  were fed for  90 days on
diets containing 0, 5, 20, 50, 200, 500, or 1000 mg dichlorvos (90%)/kg
diet (equivalent to 0, 0.4, 1.5, 3.5, 14.2, 35.7, and  69.9 mg/kg  body
weight, respectively).  Data on the stability of dichlorvos in the diet
were  not reported.   No clinical  signs of  intoxication  were  noted.
Blood samples were taken from two rats of each group for  ChE  activity
determination  on day  3, 11,   60, and  90.  In  all  test  groups,  a
decrease in plasma ChE activity was observed during the first  4  days,
gradually  returning to normal, except in the rats receiving 14.2 mg/kg
body weight or more.  At doses above 3.5 mg/kg body weight, erythrocyte
ChE  activities were decreased  throughout the test,  but at  3.5 mg/kg
body  weight, this was  only so for  the first 30  days of  the  study.
Lower dose levels produced comparable results to those of  the  control
group (Durham et al., 1957).

    Thirty-two  Rhesus monkeys were treated with 20% pelleted PVC-resin
formulations  of dichlorvos at  dosages ranging from  5 to 80 mg/kg  of
formulation (equivalent to 1 - 16 mg dichlorvos/kg body  weight)  daily
or  8 and 20 mg/kg of  formulation twice daily for  10 - 21 consecutive
days.   None of  the monkeys  developed overt  signs  of  intoxication,
though  they ate less food and had soft faeces.  Plasma and erythrocyte
ChE  activities were reduced by  approximately 80% in all  animals, and
remained   inhibited  until  completion   of  treatment.   Plasma   ChE
activities returned to normal within approximately 3 weeks, whereas the
erythrocyte  ChE  activities required  50 - 60 days  to return to  pre-
treatment values (Hass et al., 1972).

    When  groups of five  male and five  female guinea-pigs (P  strain)
were  given  daily  applications of  0,  25,  50, or  100 mg dichlorvos
(94%)/kg  body  weight on  the shorn skin  for 8 days,  all the animals
survived.  A significant dose-dependent inhibition of both  plasma  and
erythrocyte  ChE activities occurred in  all test groups.  Recovery  of
plasma  ChE  activities  was  complete  within  one  week of  the  last
exposure,  and that of erythrocyte  ChE activities was complete  within
one  week in the  females and 2  weeks in the  males (Brown &  Roberts,
1966).

    Three  Cynomolgus monkeys were treated  daily with dermal doses  of
50,  75, and 100 mg/kg body weight technical dichlorvos in xylene for 5
days  per week  until the  animals died  (after 8,  10,  and  4  doses,
respectively).   Symptoms  of  intoxication appeared  in  all  monkeys,
beginning  10 - 20 min  after administration  of the  first dose.   The
erythrocyte  ChE  activity  decreased  rapidly  and  remained  severely
inhibited  for  the period  of the study,  while plasma ChE  activities
fluctuated throughout the study (Durham et al., 1957).

    When  male and  female mice,  rats, and  guinea-pigs  were  exposed
continuously   by  inhalation  for   5  consecutive  days   to   actual
concentrations  of  0, 0.14 - 0.15,  or 1.1 - 1.3 mg/m3 dichlorvos,  no
overt  signs  of  intoxication were  observed.   In  the high  exposure
groups, plasma, erythrocyte, and brain ChE activities were inhibited in
all  three  species.  Plasma  ChE was the  most sensitive in  all three
species,  with up to  70% inhibition in  the female mice.  The greatest
inhibition of brain ChE activity (30%) was found in mice (Brown et al.,
1968).

    The  effects of dichlorvos vapour  inhalation on AChE activity  was
investigated  in the rat.  Exposure to dichlorvos concentrations of 0.8
and 1.8 mg/m3 for  3 days reduced AChE activity in the bronchial tissue
(50 - 60%  of control) but  did not produce  any changes in  blood AChE
activity.  However, at 4.3 mg/m3,   blood AChE activity  also  declined
(38%  of  control).  In  histochemical  preparations, staining  of  the
bronchial  glands and smooth  muscles revealed reduced  enzyme activity
even at the lowest dose (0.2 mg/m3)   tested.  At  this  concentration,
no inhibition of bronchial homogenate ChE was observed (Schmidt et al.,
1975,  1979).  The  significance of  bronchial ChE  inhibition  is  not
clear.

    Male mice were continuously exposed to actual concentrations  of  0
or  0.03 mg dichlorvos/m3 for  28  consecutive days.  Weekly  assays of
ChE  activities showed that brain  ChE activity was slightly  inhibited
(less  than  20%)  on the 28th day only, but plasma and erythrocyte ChE
activities were not significantly inhibited (Brown et al., 1968).

    Rabbits    exposed   to   an   average    concentration   of   1 mg
dichlorvos/m3   (0.8 - 1.3 mg/m3)   for 4 h per day for 4 months showed
up to 30% inhibition of serum and erythrocyte ChE activities during the
study.   However,  cats  similarly  exposed  did  not  show significant
inhibition (Sasinovich, 1968).

    Rats  and monkeys were exposed for 2 weeks in an inhalation chamber
sprayed  once  with  an  emulsion  of  dichlorvos.   The  initial   air
concentration was 6 mg dichlorvos/m3,   decreasing over a few  days  to
about  0.1 - 0.2 mg/m3.     No signs  of intoxication  were seen.   The
plasma  and erythrocyte  ChE activities  of the  monkeys  decreased  to
approximately 50% of pre-exposure levels, but rapid recovery took place
after  cessation of exposure.   Comparable results were  obtained  when
rats  and  monkeys  were continuously  exposed for  up to  7 days  to a
maximum air concentration of 2.2 mg/m3.    However, continuous exposure
for  4 days to 0.27 mg/m3 did   not produce any effect  on ChE activity
(Durham et al., 1957).

    Groups of two monkeys were exposed to dichlorvos vapour 2 h per day
for  4 consecutive  days.  With  concentrations up  to 0.7 mg/m3,    no
change  in plasma or  erythrocyte ChE activity  was noted, while  1.2 -
3.3 mg/m3 caused  a slight decrease in plasma ChE activity,  and  7.5 -
18 mg/m3 (mean:   13 mg/m3)    resulted  in  miosis  and  a  pronounced
inhibition  (40 - 70%) of plasma and erythrocyte ChE activities (Witter
et al., 1961).

    Groups  of  10 chickens  were exposed to  dichlorvos vapour from  a
varying number of strips (20% dichlorvos) continually or intermittently
for 3 weeks.  Exposure to a single strip in a room of  33 m3    (either
interrupted or for 16 h every day)  produced no significant  effect  on
plasma  or brain ChE activity.  Exposure to more than one strip (2 - 5)
resulted  in  up  to  50%  inhibition  of  plasma  ChE   activity   and
approximately 40% inhibition of brain ChE activity.  Dichlorvos aerosol
sprays  (0.7% dichlorvos) showed  that daily excessive  spraying for  6
seconds, 8 times per day, for 5 days, did not produce  significant  ChE
inhibition.  However, a significant decrease in plasma ChE activity was
found when the study lasted for 21 days (Rauws & van Logten, 1973).

    Three  studies were  carried out  to determine  the effect  on  the
laying  performance of hens given  dichlorvos in the feed  for 4 weeks.
Plasma   AChE  levels  were  reduced  by  70%  at  20,  30,  or  40  mg
dichlorvos/kg  diet, although  there was  no clear  influence  on  food
consumption,  egg  production, egg  weight,  or hatchability  at  these
doses.   At 80 mg/kg diet,  a decrease in food  consumption and in  egg
production was seen, the latter being a consequence, possibly,  of  the
former (Pym et al., 1984).

8.3  Skin and Eye Irritation; Sensitization

    In the skin sensitization assay procedure of  Stevens  (flank/flank
technique), 1% dichlorvos in olive oil produced no visible  effects  in
male albino guinea-pigs.  Negative results were also obtained when five
components  of  formulated dichlorvos/  PVC  products were  assayed for
their skin sensitization potential (Kodama, 1968).

    A primary skin irritation test on dichlorvos was performed by using
male  New Zealand white rabbits.  Irritation observed on the skin after
the application of 5 - 20% water solutions of dichlorvos was relatively
severe compared with that caused by other organophosphorus insecticides
(Arimatsu et al., 1977).

    In order to study the allergenicity of dichlorvos,  the  guinea-pig
maximization   test  was  used.   Threshold  limit  values  of  primary
irritancy tested on the skin of guinea-pigs (Hartley strain) were 2% or
more.  In the maximization test, 0.05 and 0.5% were used.   With  0.5%,
35%   of  the  animals  showed   slight  or  discrete  erythema.    The
allergenicity rating as determined by the Kligman test was moderate. In
combination  with methidathion, dichlorvos showed  a stronger reaction,
indicating cross-sensitization (Fujita, 1985).

8.4  Long-term Exposure

8.4.1  Oral

8.4.1.1  Rat

    In studies by Witherup et al. (1967, 1971), groups of 40  male  and
40   female   weanling  CD  rats  were  fed  diets  containing  nominal
concentrations  of 0, 0.1,  1, 10, 100,  or 500 mg dichlorvos  (93%)/kg
diet  for 2 years.  Five  males and five females  from each group  were
sacrificed  after 6, 12,  and 18 months,  and analysis of  diet samples
showed a considerable loss of dichlorvos.  This was associated  with  a
gradual  increase in DCA  concentration which ranged  in the  different
groups   from   0.014  to   28.6 mg/kg   diet.   The   average   actual
concentrations of dichlorvos in each diet were 0, 0.047,  0.467,  4.67,
46.7, and 234 mg/kg diet (equivalent to approximately 0, 0.0025, 0.025,
0.25,  2.5,  and  12.5 mg/kg body  weight).   There  were no  signs  of
intoxication,  and no effects were  seen on behaviour, mortality  rate,
food   consumption,  weight  gain,   organ  weights,  haematology,   or
urinalysis.   Plasma  and  erythrocyte ChE  activities  were  decreased
throughout  the study  in the  two highest  dose groups  compared  with
controls,  but  brain ChE  activity was decreased  in the highest  dose
group   only.   Histological  examination  of   major  organs  revealed
hepatocellular fatty vacuolization in the group with 234 mg/kg  and  in
some  of the animals with 46.7 mg/kg diet.  No effect was seen on serum
total proteins or albumin:globulin ratio, or on  hexobarbital  sleeping
time.   It can be  concluded that the  actual average concentration  of
4.7 mg/kg diet (equivalent to approximately 0.25 mg/kg body weight) was
without  significant effect  on any  of the  measured parameters.   The
tumour incidence was comparable with that of the control group.

8.4.1.2  Dog

    Groups  of three male and  three female beagle dogs  were fed diets
containing 0, 0.1, 1, 10, 100, or 500 mg dichlorvos (93%)/kg diet for 2
years,  the average actual concentrations being 0, 0.09, 0.32, 3.2, 32,
and  256 mg dichlorvos/kg diet  (equivalent to 0,  0.002, 0.008,  0.08,
0.8,  and 6.4 mg/kg body weight).  The average DCA concentration in the
diets  with 10, 100, and 500 mg dichlorvos/kg diet was 0.6, 6.4, and 20
mg/kg diet.  No effects were seen on general appearance, survival, food
consumption,   weight  gain,  haematology,  or   urinalysis.   However,
erythrocyte ChE was inhibited at dose levels of 3.2 mg/kg diet or more,
and plasma ChE activity was inhibited at the two highest  dose  levels.
Recovery to control values took place at the end of the feeding period.
Brain  ChE  activity,  measured at the end of the study, was similar to
that of the controls, and liver weights were increased in both sexes in
the  256 mg/kg diet group.   Histological examination of  major  organs
revealed  slight dose-related alterations in  the hepatic cells of  one
female in the 3.2 mg/kg diet group, and greater alterations  at  higher
doses.   No differences were seen in serum alkaline phosphatase, trans-
aminase  activities, total serum proteins,  or albumin:globulin ratios.
The  actual  average concentration  of  0.32 mg/kg diet  (equivalent to
0.008 mg/kg  body weight)  was without  effect (Jolley  et  al.,  1967;
Witherup et al., 1971).

8.4.2  Inhalation

8.4.2.1  Rat

    When   groups  of  50 male  and  50  female weanling  CFE rats were
exposed   for 23 h per day  to air concentrations of  0, 0.05, 0.5,  or
5 mg  dichlorvos (97%)/m3 air  (actual  concentrations: 0, 0.05,  0.48,
and  4.7 mg/m3)    for 2 years,  body  weight  gain was  reduced in the
two  highest  dose  groups.  After  2  years  of exposure,  plasma  and
erythrocyte  ChE  activities  were  significantly  reduced  in  the two
highest dose groups, but in the case of brain ChE activity, only in the
highest  group. No  effects attributable  to dichlorvos  were  seen  on
appearance, food consumption, haematological or blood chemistry values,
or   organ  weights,  or   upon  gross  or   microscopic   examination.
Ultrastructural  examinations of bronchi and alveoli of rats exposed to
0 or 5 mg/m3 showed no differences between the two groups.

    In  connection  with  a  reported  correlation  between  brain  ACh
concentration  and the inhibition of brain ChE activity following acute
exposure  to  organophosphorus compounds,  the  brain tissue  of  three
female  rats per group was examined for ACh and choline concentrations.
The dose level of 0.05 mg dichlorvos/m3 was  without effect on  any  of
the  measured parameters (Blair et al., 1976).  It should be noted that
in this study the rats were not only exposed by inhalation but also via
their   food,  drinking-water,  and  by  grooming.   This  resulted  in
additional oral ingestion of dichlorvos (Stevenson & Blair, 1977).

8.5  Reproduction, Embryotoxicity, and Teratogenicity

8.5.1  Reproduction

    In  a 3-generation reproduction study, weanling CD rats (six groups
of 30 animals) were fed dichlorvos (93%) at nominal  concentrations  of
0, 0.1, 1, 10, 100, or 500 mg/kg diet, prepared freshly each week.  The
stability  of  dichlorvos  in  the  diets  was  not  reported  but,  in
accordance  with the 2-year  oral rat study  (section 8.4.1.1), it  was
assumed  that the average concentration of dichlorvos was approximately
47%  of the  nominal concentrations  (equivalent to  0, 0.0025,  0.025,
0.25,  2.5, and  12.5 mg/kg body  weight).  No  effects  on  fertility,
number  and size of litters, body weight, or viability of the pups were
found.   Gross and histopathological examination of 7-day-old pups from
F1a and   F2a litters  did not  reveal any abnormalities  (Witherup  et
al., 1965, 1971).

    Oral  treatment of rats with 5.6 mg/kg body weight and rabbits with
6 mg/kg  body weight  during the  last trimester  of pregnancy  had  no
effect  on  offspring weight  and  development.  However,  the cerebral
cortices  from  the 1-day-old  rabbits were less  mature than those  of
control  rabbits, probably due  to maternal toxicity  (Dambska et  al.,
1978, 1979).

    Dambska & Maslinska (1982) observed impairment of  the  development
of the brain of rabbits dosed orally with 9 mg/kg body weight  per  day
from days 5 to 16 of life, the period of myelination.

8.5.1.1  Effects on testes

    In studies by Krause & Homolo (1972, 1974), three groups of 14 male
NMRI/Han mice received either a single oral dose of 40 mg dichlorvos/kg
body weight, daily oral doses of 10 mg dichlorvos (in olive oil)/kg for
18  consecutive days, or daily  oral doses of 0.5 ml  olive oil for  18
days,  respectively.  On days 9,  18, 27, 36, 54,  and 63, two  animals
from each group were killed and their testes  examined  histologically.
Severe  disturbances  of spermatogenesis  were  observed in  both  test
groups;  damaged seminiferous tubules were also seen and the supporting
Sertoli  cells were damaged.  In addition, there was an increase in the
number  and hypertrophy of the  Leydig cells.  No explanation  could be
offered for these effects.

    A similar study was carried out on three groups of 16 male juvenile
Wistar  rats.  The  rats received  either 20 mg  dichlorvos  (in  olive
oil)/kg body weight on days 4 and 5, 10 mg dichlorvos (in olive oil)/kg
daily from days 4 to 23, or 0.1 ml olive oil daily from days 4 to 23 of
life.   On  days  6, 12, 18, 26, 34, and 50 of life, two rats from each
group were sacrificed.  Histological examination of the  testes  showed
slight  reduction in the number  of the spermatogenic cells  and Leydig
cells.   It was  assumed that  a reduction  in  testosterone  synthesis
resulted  in damage to the  spermatogenic cells.  All the  changes were
reversed by the 50th day (Krause et al., 1976; Xing-Shu, 1983).

    In  order  to  examine the  cause  of  the observed  effect  on the
spermatogenic  and  Leydig  cells, the  study  was  repeated  with,  in
addition,  measurement of testosterone levels in serum and testes.  The
testosterone concentrations in the testes, and leutinizing hormone (LH)
and follicle stimulating hormone (FSH)  levels in serum were similar in
the presence or absence of dichlorvos (Krause, 1977).  However, the use
of  adult  rats  and a  different  dosing  regimen prevented  a  strict
comparison with the earlier study by Krause et al.  (1976).

    In  studies by Fujita et  al. (1977), 55 male  Wistar rats (aged  5
months)  were orally administered dichlorvos at levels of 5 or 10 mg/kg
body  weight  every  other day for 8 weeks.  The rats were divided into
five  groups,  and  one group of rats was killed every 4 weeks to study
the  changes  in  several organs,  including  the  testes.   About  200
individual seminiferous tubules were examined in each rat.   No  change
was seen in body weight gain or testes weight.  The score values of the
seminal cellular system decreased after 4 - 8 weeks of  treatment,  but
were restored 8 weeks after the end of treatment.

8.5.1.2  Effect on estrous cycle

    Timmons  et al. (1975) reported  studies on female rats  which were
exposed  to an atmosphere  containing 2.4 mg  dichlorvos/m3   generated
from  a dichlorvos  strip placed  on top  of each  cage.  Exposure  was
continuous from the birth of the first litter until the  estrous  cycle
began again.  Controls were housed in a separate room.   A  significant
mean  delay of 10 days in the onset of the estrous cycle, compared with
that  of controls,  was observed.   However, the  significance  of  the
results was complicated by different housing conditions.

8.5.1.3  Domestic animals

    In  studies by Bazer et al. (1969), sows were fed dichlorvos (9% in
resin pellets) at the level of 800 mg per animal per day  beginning  21
days  before breeding and continuing through gestation.  No significant
differences  in the  numbers born  alive or  dead, the  litter  weight,
number weaned, or individual weaning weights were observed.

    In a further study, dichlorvos was added to the rations of pregnant
sows  at the level of  0 or 800 mg per  animal per day.  Resin  pellets
containing 9% dichlorvos were fed either from 3 weeks  before  breeding
and  throughout gestation, or  from 18 to  56 days before  parturition.
Data  were  collected  from a  total  of  681 dams,  representing eight
replicates  over a period  of 2 years.   The dichlorvos-treated  groups
scored  consistently  higher  for individual  farrowing weights, litter
farrowing  weights,  number  weaned, individual  weaning  weights,  and
litter  weaning weights, and less  consistently, for the percentage  of
live births (Batte et al., 1969).

    When  dichlorvos (as a  PVC-resin formulation) was  administered to
sows  in  doses  ranging from 4 to 13 mg/kg body weight per day for the
last  21 - 30 days of gestation, the average farrowing interval for the
live-born  piglets was  shorter in  treated than  in  control  animals.
There  was  also a  dose-related increase in  the mean birth  weight of
live-born piglets from the dichlorvos-treated sows, while the incidence
of still births was lower than in controls (Bunding et al., 1972).

    In studies by Collins et al. (1971), male and female swine were fed
for  up to 3 years  on diets containing a  PVC-resin formulation at  0,
200,  250,  288,  400, or 500 mg dichlorvos/kg diet, and for at least 6
months  prior to initial breeding.  Two generations were raised, and no
effects  were observed on number or size of litters, survival or growth
rate of offspring, urinalysis, haematology, hepatic and renal function,
physical  structure, or calcium and  phosphorus content of the  femoral
bone, or in appearance during gross and microscopic examination.  Organ
weights  were  normal  except in  the  case  of the  liver,  which  was
generally  increased.  Whole blood ChE activity was inhibited and brain
ChE  activity  was  slightly  reduced,  but  no  clinical  evidence  of
neurophysiological impairment was observed.

    In  studies reported by Stanton  et al. (1979), pregnant  sows were
given PVC-resin formulations of dichlorvos (10%) in the diet at a daily
dose of 0, 5, or 25 mg dichlorvos/kg body weight (divided  between  two
doses  per day) during  the last one-third  of pregnancy (or  30 days).
Only  about 50% of the total dichlorvos was released from this resin in
the  gastrointestinal tract.  All pigs were born alive, and their birth
weight  was  similar to  that of control  animals.  In the  group given
25 mg/kg  body  weight,  plasma  and  erythrocyte  ChE  activities were
markedly  inhibited (80 and 90%, respectively)  in the sows, but not in
the  newborn pigs.  No changes in the packed cell volume or haemoglobin
concentration of the sows or their piglets were observed.

    In a limited test reported by Darrow (1973), dichlorvos-impregnated
collars  did not have any  adverse effects on pregnant  female goats or
later  on  their  newborn young.   Also,  blood  ChE activity  was  not
inhibited  in  either  the nannies or the kids over a period of several
weeks.  The acceptance of treated kids by the mothers was normal.

    A  pregnant non-lactating Holstein-Friesian  cow was fed  a nominal
concentration  of 6.2 mg dichlorvos/kg body weight per day in the daily
ration  from days 152 to 286 of pregnancy.  A normal calf was delivered
(Macklin & Ribelin, 1971).

    A herd of 54 dairy cows (two-thirds carrying calves) was accidently
sprayed with dichlorvos, resulting in a dosage of  50 mg  dichlorvos/kg
body  weight.  All the animals showed symptoms of intoxication and some
had  convulsions.  However, they all recovered within a few hours, with
no  abortions or other adverse effects except a temporary diminution in
milk production (Knapp & Graden, 1964).

    When  three pregnant sows were fed 8.5 mg dichlorvos/kg body weight
per day (as PVC-resin formulation) from days 41 to 70 of pregnancy, the
blood  ChE  activity  of  the  sows  was  markedly  inhibited,  but  no
demonstrable  teratogenic  effects  or functional  abnormalities in the
piglets were found (Wrathall et al., 1980).

8.5.2  Embryotoxicity and teratogenicity

8.5.2.1  Oral

    In  studies by  Schwetz et  al. (1979),  CF1 mice  and New  Zealand
rabbits  were given maximum tolerated doses of dichlorvos (96%) in corn
oil by gavage, at levels of 60 and 5 mg/kg body  weight,  respectively,

from  days 6 to 15 and days 6 to 18 of gestation, respectively.  Except
for  an increased  number of  resorptions in  rabbits,  no  significant
effect was observed on the mean number of live fetuses per  litter,  or
on fetal body measurements.  There were no gross visceral  or  skeletal
alterations.  In mice, no abnormalities were found.

    Carson  (1969)  reported  studies on  a  total  of 168  New Zealand
rabbits,  divided into 10 groups containing 15 - 26 animals.  One group
received lactose capsules, three groups different PVC-placebo capsules,
and   three  groups   PVC  capsules   containing  18,   54,  or   93 mg
dichlorvos/animal.  These capsules were provided twice daily,  so  that
the  equivalent  daily  intake was  12,  36,  or 62 mg/kg  body weight,
respectively.   The rabbits  received 12  or 36  mg dichlorvos/kg  body
weight on days 6 - 18 of gestation, or 62 mg/kg body weight on days 6 -
11 of gestation.  Fetuses were obtained by Caesarian section.  Maternal
mortality  was  increased  in the  highest  dichlorvos  group, and  the
incidences  of  in utero and  neonatal toxicity were also increased (but
not  significantly) in  the 62 mg  group, compared  with those  in  the
control  groups.  The fetal mortality was not clearly indicative of any
marked  toxic effects other than  those involving the dam,  since whole
litters   were  not  involved.   Extensive  skeletal  and  soft  tissue
examinations were carried out on all viable neonates,  but  no  adverse
effects on bone formation, articulation, or degree of ossification were
found in the dichlorvos groups.  No teratogenic effects were observed.

    When   pregnant  rabbits  were   given  oral  doses   of  PVC-resin
formulations  during the critical days of organogenesis, doses of 34 mg
dichlorvos/kg  body  weight  or  more  were  found  to  cause  maternal
toxicity.  With doses of 12 mg/kg body weight or less,  no  significant
effect  on nidation,  in utero survival, or neonatal survival was found.
No  evidence of teratogenic changes was observed on gross, visceral, or
skeletal examination of the fetuses (Vogin et al., 1971).

    The  effect of  dichlorvos on  embryonal and  fetal development  in
thyroparathyroidectomized,  thyroxine-treated,  and  euthyroid  control
rats  has  been  investigated.  On  days  8 - 15  of  gestation,  25 mg
dichlorvos/kg body weight per day was administered orally  to  pregnant
Charles River rats, and a slight decrease in fetal weight in all groups
was observed.  No gross, visceral, or skeletal anomalies of the fetuses
were  found  as  a result  of  dichlorvos  administration to  rats with
altered thryoid status (Baksi, 1978).

8.5.2.2  Inhalation

    In  studies  by Thorpe  et al. (1972),  rats of E  strain and Dutch
rabbits  were  exposed  (23 h per  day,  7  days per  week)  throughout
pregnancy  to  nominal  concentrations of  0,  0.25,  1.25, or  6.25 mg
dichlorvos/m3.     In   an  additional  study,  groups  of  20 pregnant
rabbits   were  exposed  to  nominal   concentrations  of  2  or   4 mg
dichlorvos/m3.     Maternal deaths occurred  in the rabbits  exposed to
2 mg/m3 or  more, and ChE activities in plasma, erythrocytes, and brain
were  markedly inhibited  in both  species exposed  to 1.25 mg/m3    or
more.   There was no  indication of any  dichlorvos-related teratogenic
effects.

    When CF1 mice and New Zealand rabbits were exposed to dichlorvos at
an average actual concentration of 4 mg/m3 for  7 h per day  from  days
6 to  15  and  from  days  6  to  18  of  gestation,  respectively,  no
significant effect on the mean number of live fetuses per  litter,  the
incidence or distribution of resorptions, or on fetal body measurements
was noted.  No gross, visceral, or skeletal alterations  were  observed
(Schwetz et al., 1979).

8.5.2.3  Intraperitoneal

    Kimbrough & Gaines (1968) reported a study on female  Sherman  rats
given a single intraperitoneal injection of 0 or 15 mg  dichlorvos  (in
peanut  oil)/kg body weight on  day 11 of pregnancy.   The treated dams
showed  toxic  signs  and weight  loss.   On  day 20,  the fetuses were
removed.   There was  no adverse  effect on  litter size,  resorptions,
number  of dead fetuses per litter, or average weight of fetuses, but 3
out of 41 fetuses had omphaloceles.  This latter finding, observed at a
maternally  toxic dose, is not  in agreement with the  other teratology
studies or the 3-generation reproduction study.

8.5.3  Résumé of reproduction, embryotoxicity, and teratogenicity studies

    A 3-generation study on rats, fed dichlorvos at dose levels  of  up
to  500 mg/kg diet, did not  show any effects on  fertility, number and
size of litters, body weight, or viability of the pups.

    In  studies  on mice  and rats, high  dose levels of  dichlorvos (a
single  dose of 40 mg/kg body weight or multiple doses of 5 or 10 mg/kg
body weight)  induced disturbances in spermatogenesis, characterized by
damage to the seminiferous tubules and Sertoli cells and by hypertrophy
and  increase  in  the number of Leydig cells.  It was assumed, but not
confirmed,  that testosterone synthesis was partially inhibited.  After
dichlorvos  treatment  ceased, recovery  was  complete within  about  2
months.

    A  number of reproduction studies on domestic animals, mainly sows,
have  been carried out.  Levels  of 500 mg/kg diet for  3 years had  no
effect on fertility.  Inhibition of ChE activity in the sows,  but  not
in  the  newborn  pigs,  was  induced  by  25 mg/kg  body  weight.   No
teratogenic effects were seen.

    Teratogenicity  studies  on  rats and  rabbits, orally administered
62 mg/kg   body   weight   during  gestation,   revealed   symptoms  of
intoxication and significant inhibition of ChE in the  parent  rabbits.
Except for an increased number of resorptions, no significant effect on
the mean number of live fetuses per litter or evidence of a teratogenic
effect was noted during gross, visceral, or skeletal examination.

    There  were  no  teratogenic  effects  after  rats  inhaled 6.25 mg
dichlorvos/m3 during  gestation, though maternal deaths occurred.  Mice
and  rabbits exposed to  4 mg/m3 on  days 6 - 18  of gestation did  not
show any effects.

8.6  Mutagenicity and Related End-Points

8.6.1  Methylating reactivity

    In  a quantitative colour  test for alkylating  agents,  dichlorvos
gave  a positive response, whereas the metabolites desmethyldichlorvos,
dimethylphosphate,  dichloroethanol,  DCA, and  dichloroacetic acid all
gave negative results (Bedford & Robinson, 1972).

8.6.1.1   In vitro studies

    Lawley et al. (1974) have shown that methylation by  dichlorvos  of
DNA  and  RNA,  using  either   isolated   nucleic   acids,  Escherichia
 coli   cells, or  human  tumour  HeLa  cells, broadly resembled that by
methylmethanesulfonate      (MMS)    rather    than    methylation   by
 N-methyl- N-nitrosourea.       In  E.  coli cells,  3-methyladenine,  the
principal minor product in methylated DNA apart  from  7-methylguanine,
was  not  detected, whereas  it was present  when pre-isolated DNA  was
methylated.   The overall extent of  methylation achieved in cells  was
small.   Specific  excision  of  3-methyladenine  was  indicated  in  E.
 coli cells (Lawley et al., 1974).

    Labelled 7-methylguanine was present in both DNA and  RNA  isolated
from  E.  coli exposed to 3H-dichlorvos.   The methylating capability of
dichlorvos  was less, by  a factor of  10 - 100, than that  of strongly
genotoxic   methylating   compounds   (Wennerberg  &   Löfroth,  1974).
Alkylation by dichlorvos of calf thymus DNA, resulting in the formation
of  N-7-methylguanine, was reported by Löfroth (1970).

    Shooter  (1975) has applied the test for chain breaks in RNA to the
interaction  of dichlorvos with bacteriophage R17.    Breaks in the RNA
chain  result from the  hydrolysis of phosphotriesters  and are thus  a
measure of the extent of O-alkylation and of the  SN1-type    mechanism
of the reaction.  The results so far suggest that the existence  of  O-
alkylation,   as   shown   by  degradation   following  phosphotriester
formation,   does   correlate   with   mutagenicity.    Incubation   of
bacteriophage  R17 with  0 - 100 mmol dichlorvos/litre for 90 h did not
result  in  methylation  of the  phosphate  group  of the  RNA  to  any
significant extent.

8.6.1.2   In vivo studies

    Reviews of the literature on alkylating agents including dichlorvos
have  been  made  by Bedford & Robinson (1972), Lohs et al. (1976), and
Hemminki (1983).

    In studies in which mice  were  given   intraperitoneal  injections
of  methyl-14C-dichlorvos   (1.9 µmol/kg   body  weight),   the  degree
of  alkylation  of  guanine- N-7   in  DNA  isolated  from soft  tissues
amounted  to  8 x  10-13 mol   methyl/g  DNA.   From  this, a  rate  of
clearance  of  approximately  1.4 min was  estimated  (Segerbäck, 1981;
Segerbäck  & Ehrenberg, 1981).  DNA and RNA from the total soft tissues
of  male CFE rats  exposed to atmospheres  containing 0.064 mg  methyl-
14C-dichlorvos/m3 for     12 h did not show methylation of the N-7 atom

of  guanine moieties.  The  exposure period constituted  a  significant
fraction of the half-life of the 7-methylguanine moieties in  DNA.   It
was  concluded that dichlorvos  does not pose  a methylating hazard  to
mammalian DNA  in vivo (Wooder et al., 1977; Wooder & Wright, 1981).

    The  excretion  of   labelled   7-methyl  guanine  in   the   urine
by   NMRI  mice  and R  rats injected  intraperitoneally  with  methyl-
14C-dichlorvos,    or exposed by  inhalation for 2 h  (mice only),  was
reported  by  Löfroth  & Wennerberg  (1974)  and  Wennerberg &  Löfroth
(1974).    In  rat  urine,   labelled  3-methyladenine  and   1-methyl-
nicotinamide   were  also  detected   (Löfroth  &  Wennerberg,   1974).
According  to the authors,  these results demonstrate  the  dichlorvos-
induced methylation of guanine and adenine moieties in  nucleic  acids.
However,  the administration of  radiolabelled adenine and  guanine  to
otherwise  untreated rats gave rise  to the excretion of  radiolabelled
methylated  purines  in  the  urine.   Therefore,  the   detection   of
radiolabelled  purines,  per  se, in the  urine  of animals  exposed  to
methyl-labelled  methylating agents, does  not constitute evidence  for
the  methylation of the purine moieties of nucleosides or nucleic acids
by  methylating agents (Wooder et al., 1978).  Moreover, the results of
metabolic   studies  have  demonstrated  the  existence  of  a  natural
biosynthetic pathway whereby the methyl carbon atoms of dichlorvos can,
with  partial  retention  of  hydrogen,  become  incorporated  into the
heterocyclic  rings and the  methyl groups of  urinary  7-methylguanine
after entering 1-C pools,  in vivo.   The results of preliminary studies
suggest  the  existence  of a  similar  pathway  for the  production of
urinary 3-methyladenine (Wright et al., 1979).

    Wooder & Creedy (1979) described a study on rats which investigated
the  DNA-damaging potential of dichlorvos when administered as a single
intraperitoneal  dose.  Alkaline sucrose gradient profiles of rat liver
DNA  showed  that  whereas MMS  (a  positive  control) shifted  the DNA
profile,  dichlorvos  at  10 mg/kg  body  weight  (the   maximum   dose
consistent with survival)  had no effect.

8.6.1.3  Discussion of methylating reactivity

    Many alkylation tests and  in vivo and  in vitro mutagenicity studies
have been carried out with dichlorvos.  It has been  demonstrated  that
dichlorvos  has alkylating properties, and has been suggested from some
studies  that the  in vivo alkylating potential of dichlorvos is similar
to  that of some  known mutagens.  However,  this concern is  misplaced
since  alternative  reactions were  not  considered (WHO,  1986b).  The
phosphorus  atom is markedly more electron-deficient and susceptible to
attack by nucleophiles than the alkyl carbon atom.  Analysis by Bedford
& Robinson (1972) of the data of Löfroth et al. (1969)   revealed  that
the proposed rates of alkylation by potent nucleophiles  were  probably
combined   rates   of   phosphorylation  and   alkylation,   and   that
phosphorylation  was the totally dominant  reaction in the case  of the
hydroxide  ion.   The  comparison  with  known  mutagens  is  therefore
inappropriate.   Two  factors  detract further  from  the toxicological
significance  of the alkylation studies.   The first is that  mammalian
tissues (plasma, liver, etc.)  contain active A-esterase enzymes, which
catalyse the phosphorylation of water by the  organophosphorus  esters.

Viewed  inversely,  these A-esterases  catalyse  the hydrolysis  of the
organophosphorus esters, thereby rapidly reducing circulating levels of
hazardous material.  Secondly, the comparative rate of reaction of most
of  these esters with AChE is many orders of magnitude greater than the
rate  of alkylation by the  typical nucleophile 4-nitrobenzyl-pyridine:
for  dichlorvos,  the  ratio of  rates  was  1 x 107 in  favour  of the
inhibitory  phosphorylation  of AChE  (Aldridge  & Johnson,  1977).  It
follows that, at low exposure levels,  in vivo phosphorylation  of  AChE
and  other esterases  will be  the dominant  reaction, with  negligible
uncatalysed alkylation of nucleic acid.  Indeed, no such alkylation has
been detected in sensitive  in vivo studies designed to check this point
(Wooder et al., 1977).

8.6.2.  Mutagenicity

    Reviews  of the  existing literature  have been  published by  Wild
(1975),  Fishbein  (1976, 1981,  1982),  Leonard (1976),  IARC  (1979),
Sternberg (1979), Ramel et al. (1980), Lafontaine et al.  (1981), Ramel
(1981), and Wildemauwe et al. (1983).

8.6.2.1   In vitro studies

    (a)   Microorganisms

    Numerous  mutagenicity  studies using  bacteria  and fungi  as test
organisms  have been carried out  (Table 17).  In most of  the studies,
only  one  dichlorvos  concentration, often  a  high  one, was  tested,
sometimes   resulting   in  low  survival  of  the  test  organism.   A
dose-response  relationship was established  in the few  tests where  a
range of concentrations was used.  The results indicate that dichlorvos
induces base substitutions in bacteria and mitotic gene  conversion  in
yeast.   The alkylating properties  of dichlorvos (section  8.6.1)  are
most  probably  the  cause  of  the  mutagenic  action.  This  was  the
conclusion  of  Bridges et  al.  (1973) from  tests using both  MMS and
dichlorvos  with  E. coli strains   deficient at four  different  repair
loci.

    In  Aspergillus  nidulans, dichlorvos has been found to induce point
mutations  to 8-azaguanine resistance and  a high frequency of  mitotic
crossing-over  and non-disjunction (Aulicino  et al., 1976;  Bignami et
al.,  1976,  1977;  Morpurgo et  al.,  1979).   No  mutagenic  activity
using  A.  nidulans was  found  after incubating   Nicotiana   alata cell
cultures  with  dichlorvos  for  21  days  (simulating  in   vitro plant
metabolism).  This confirms the rapid metabolism of dichlorvos (Benigni
et al., 1979).

    The  mutagenicity  of dichlorvos  has  been extensively  studied in
Japan,  (Kawachi  et  al.,  1980).   Dichlorvos  induced  gene mutation
in  Salmonella  typhimurium TA100  as well  as  E.  coli strains   in the
absence of rat-liver S9 mix.

    Dichlorvos   (0.5 - 2 mg/ml)   causes   random   strand   breakage,
repairable  by DNA polymerase  I, in  E. coli pol  A as detected  by the
alkaline  sucrose sedimentation method.   When pol+ bacteria  and  high
concentrations  of  dichlorvos  (0.2 - 0.4%) were  used, an all-or-none
breakdown  of DNA molecules to fragments of very low relative molecular
mass  occurred  which  correlated well  with  lethality.   It has  been
suggested that the major DNA damage resulting from dichlorvos treatment
arises  indirectly through alkylation  of other cellular  constituents,
this   leading  to  uncontrolled  nuclease  attack  on  DNA.   However,
discontinuities  in  newly-synthesized  DNA and  mutagenesis  following
dichlorvos  treatment presumably result  from direct alkylation  of DNA
(Bridges   et  al.,  1973;  Green  et  al.,  1973,  1974a,b).   In  the
standard  E.  coli DNA  polymerase-deficient  assay  system,  dichlorvos
(6.4 mmol/litre) gave a positive result (Rosenkranz, 1973; Rosenkranz &
Leifer,  1980).  In measuring mutation to tryphophan independence in  E.
 coli strain  WP2, it was found that 5 mg dichlorvos/litre was mutagenic
in this test system (Green et al., 1976).  Griffin & Hall  (1978)  have
found  that dichlorvos (1 mg/ml) causes breaks in colicinogenic plasmid
E1  DNA  from  E.   coli.   In  a  rec-type  repair  test   with  Proteus
 mirabilis strains   PG 713  (rec-hcr-)      and  PG 273   (wild  type),
dichlorvos (10 or 40 µmol  per plate) induced  base-pair  substitutions
and  other DNA damage.  In  the same test, desmethyldichlorvos,  at the
same concentrations, gave negative results (Adler et al.,  1976;  Braun
et al., 1982).

    (b)   Mammalian cells

    In  cultured  V79  Chinese  hamster  cells,  no  induction  of   8-
azaguanine-resistant  mutations after treatment with up to 1 mmol/litre
dichlorvos  (Wild,  1975),  or  of  ouabain-resistant  mutations  after
treatment  with 1.25 - 5 mmol/litre dichlorvos, was  found (Aquilina et
al., 1984).

    DNA strand breakage in cultured V79 Chinese hamster cells caused by
up  to  0.2%  v/v dichlorvos has been reported by Green et al. (1974a).
Dichlorvos  (1 µl)   decreased  the sedimentation  coefficient  of calf
thymus  DNA upon thermal denaturation, indicating a decrease in the DNA
molecular   size  (Rosenkranz  &  Rosenkranz,   1972).   Incubation  of
dichlorvos  (45  mmol/litre)  with  calf thymus DNA  did not result  in
changes   in  thermal  melting  curves   or  DNA  fractionation  on   a
hydroxyapatite  column.   However, changes  were  observed by  means of
differential   pulse  polarography,  indicating   that  single-stranded
segments  and  thermolabile  regions were  formed  in  the  DNA.   This
behaviour could perhaps be a consequence of guanine alkylation followed
by  depurination and chain cutting at elevated temperatures (Olinski et
al., 1980).

    The  resistance of methylated DNA  in Chinese hamster ovary  cells,
labelled    with 14C-thymidine    and   methyl-3H-1-methionine,      to
micrococcal  nuclease  digestion  was  abolished  when  the  cells were
treated  with  dichlorvos (10 mmol/litre)  for  3 h.  No  effects  were
observed  on kinetics of total DNA digestion.  These results indicate a
conformational  change  in chromatin  induced  by dichlorvos  (Nishio &
Uyeki, 1982).


Table 17.  Mutagenicity tests on microorganisms
---------------------------------------------------------------------------------------------------------
Organism/strain         Dose               Type of test      Metabolic   Result        Reference
                                                             activation
---------------------------------------------------------------------------------------------------------
 Bacillus subtilis
  H17 rec+              0.02 ml of         plate                none      -            Shirasu et al.       
  M45 rec-              10% solution       plate                none      +            (1976)

 Citrobacter freundii
  425                   0.1%               fluctuation          none      weak +       Voogd et al. (1972)
                        0.05%                                   none      -

 Enterobacter aerogenes
  6                     0.1%               fluctuation          none      weak +       Voogd et al. (1972)

 Escherichia coli
  B                     5 - 25 mmol/litre  liquid induc-        none      weak +       Wild (1973)
                        1- to 10-h         tion strepto-                  (dose-       
                        exposure           mycin-resistant                and exposure-
                                           mutants                        time related)

  B/r WP2               22.6 mmol/litre    plate reversion      none      +            Moriya et al. 
                                                               S9 mix     +            (1978)
                                                             L-cysteine   +

  CM 561, 571, 611      5 µl               plate reversion      none      -            Hanna & Dyer 
                                                                                       (1975)
  K12HfrH               0.1%               fluctuation          none      weak +       Voogd et al. 
                                                                                       (1972)
  K12(5-MT)             3.3 x 10-4         plate                none      +            Mohn (1973)
                        mol/litre

  WP2                   micro drop         plate                none      -            Dean (1972a)
                        analytical and
                        technical grade,
                        aqueous solution

Table 17.  (contd).
---------------------------------------------------------------------------------------------------------
Organism/strain         Dose               Type of test      Metabolic   Result        Reference
                                                             activation
---------------------------------------------------------------------------------------------------------
 Escherichia coli (contd).
  WP2 try-              approximately      plate                none      +            Ashwood-Smith et  
                        20 mm2 dichlor-                                                al. (1972)
                        vos strip

  WP2 try-              20 - 25 µl of      spot                 none      +            Nagy et al. (1975)
  hcr- and hcr+         50% emulsifiable   back mutation
                        concentrate

                        0.1 ml of a 5%     plate reversion      none      +            Shirasu et al. 
                        solution                                                       (1976)

  WP2 hcr               unknown (up to     plate reversion      none      +            Moriya et al. 
                        5000 µg/plate)                                                 (1983)

  WP2 uvrA,             ca 5 µl            plate reversion      none      +            Hanna & Dyer 
  WP 67                                                                                (1975)

 Klebsiella pneumoniae   0.1%; 0.05%        fluctuation          none      weak +       Voogd et al. 
                                                                                       (1972)
 Neurospora crassa
  ad-3                  exposed to air     plate                none      -            Michalek & 
                        containing                                                     Brockman (1969)
                        dichlorvos
                        (strip)

 Pseudomonas aeruginosa
  PAO 38                0.08 mol/litre     liquid reversion     none      +            Dyer & Hanna 
                                                                                       (1973)
 Saccharomyces cerevisiae
  D4 (ade2 and          4 mg/ml            plate mitotic        none      +            Dean et al. 
  trp5)                 2 mg/ml            gene conversion                             (1972)

  D4 (ade2 and          19 mmol            liquid mitotic       none      +            Fahrig (1973, 
  trp5)                                    gene conversion                             1974)

Table 17.  (contd).
---------------------------------------------------------------------------------------------------------
Organism/strain         Dose               Type of test      Metabolic   Result        Reference
                                                             activation
---------------------------------------------------------------------------------------------------------
 Salmonella typhimurium
  64-320                0.05%; 0.1%        suspension           none      +            Voogd et al. (1972)

  TA 98                 20 or 40 mmol      plate             S9 male mice -            Braun et al. (1982)

                        up to 5000 µg      plate reversion      none      -            Moriya et al. (1983)

  TA 100                20 or 40 mmol      plate             S9 male mice (+)          Braun et al. (1982)
                                                                          low survival
                        up to 5000 µg      plate reversion      none      +            Moriya et al. (1983)

  TA 1530               5 µl               plate                none      +            Hanna & Dyer (1975)

  TA 1535               5 µl               plate                none      +            Hanna & Dyer (1975)

                        0.1 ml of a 5%     plate                none      +            Shirasu et al. (1976)
                        solution

                        0.1 ml of a 5%     plate                none      +            Moriya et al. (1978)
                        solution                               S9 mix     -
                                                             L-cysteine   -

                        2800 µg            plate (spot)      S9 male rat  -            Carere et al. 
                                                                                       (1976, 1978a,b)

                        1.5 mg/ml          liquid               none      +            Carere et al. 
                                                                                       (1978a,b)
                        20 or 40 mmol      plate             S9 male mice -            Braun et al. (1982)

  TA 1536, 1537,        0.1 ml of a 5%     plate                none      -            Shirasu et al. 
  1538                  solution                                                       (1976)

  TA 1536, 1537,        2800 µg            plate (spot)      S9 male rat  -            Carere et al. 
  1538                                                                                 (1976, 1978a,b)

                        20 or 40 µg        plate             S9 male mice -            Braun et al. 
                                                                                       (1982)
                        up to 5000 µg      plate             none         -            Moriya et al. 
                                                                                       (1983)

Table 17.  (contd).
---------------------------------------------------------------------------------------------------------
Organism/strain         Dose               Type of test      Metabolic   Result        Reference
                                                             activation
---------------------------------------------------------------------------------------------------------
 Salmonella typhimurium (contd).
  his C117              0.03 mol           liquid            none         +            Dyer & Hanna (1973)

  LT2 his C117,         5 µl               plate             none         -            Hanna & Dyer (1975)
  his G 46

 Schizosaccharomyces pombe
  ade6                  1.5 - 14 mmol      plate             +            +            Gilot-Delhalle et 
                                                                                       al. (1983)

 Serratia marcescens
  Hy alpha 13,          25 mg/ml           plate (spot)      none        alpha 13 +    Dean (1972a)
  alpha 21                                                               alpha 21 -   

                        50, 100 mg/ml      plate (spot)      none         +            Dean (1972a)
                        saturated          plate (spot)      none         +            Dean (1972a)
                        aqueous solution

 Streptomyces coelicolor
  A 3(2) his Al         5600 µg            spot              none         +            Carere et al. 
                                                                                       (1976, 1978a,b)
---------------------------------------------------------------------------------------------------------
    Dichlorvos  (0.03  and 0.1 mmol/litre)  has  been found  to  induce
sister  chromatid exchanges (SCEs) in cultures of Chinese hamster ovary
cells  (Nishio & Uyeki, 1981).   On the other hand,  in Chinese hamster
V79  cells  (clone  number  15),  SCEs  were  not induced  by  0.1 mmol
dichlorvos/litre,  but only by  0.2 and 0.5 mmol/litre  solutions.  The
number  of polyploid cells was  increased at both 0.1  and 5 mmol/litre
(Tezuka et al., 1980).

    Dichlorvos  has been tested in two independent laboratories for its
ability to increase the transformation of Syrian hamster  embryo  cells
by  simian  adenovirus  SA7.     Pre-treatment  of  hamster  cells with
dichlorvos at concentrations of 0.05 up to 0.45 mmol/litre  produced  a
significant  enhancement of SA7   transformation at 0.11 mmol/litre and
higher (Hatch et al., 1986).

    The  mouse peripheral blood lymphocyte (PB) culture system has also
been  used to test for  SCE induction.  Male B6C3F1  mice were injected
intraperitoneally with 5, 15, 25, or 35 mg dichlorvos/kg  body  weight,
but  there was no  change in the  baseline SCE frequency  (Kligerman et
al., 1985).

    Dichlorvos  (6.5 - 650 mmol/litre) has  been found to  induce dose-
dependent unscheduled DNA synthesis in the human  epithelial-like  cell
line EUE (Benigni & Dogliotti, 1980a,b; Aquilina et al.,  1984).   Both
scheduled  and unscheduled DNA  synthesis of human  lymphocytes  showed
dose-related inhibition by dichlorvos (5 -500 mg/litre), as measured by
3H-thymidine uptake (Perocco & Fini, 1980).

    Dichlorvos  (0.0001 - 0.1 mmol/litre) does not induce DNA repair in
human kidney T-cells.  This was shown by a lack  of  dichlorvos-induced
3H-thymidine   incorporation into T-cells in the G1- or G2-phase of the
cell cycle.  No induction of single-strand breaks in the T-cell DNA, as
measured by alkaline sucrose gradients, was found  following  treatment
for 1, 2, or 4 h with 0.0001 - 1 mmol dichlorvos/litre (Bootsma et al.,
1971).

    No  clear effect on the  frequency of SCEs in  human lymphocytes or
human  fetal lung fibroblasts was  found after exposure to  2.5 - 10 mg
dichlorvos/litre for 72 h (Nicholas et al., 1978).

    In studies by Dean (1972b), human blood samples were  treated  with
dichlorvos (0.0001 - 1 mmol/litre) for 1, 2, 4, and 20 h,  after  which
the  lymphocytes were stimulated to  divide using phyto-haemagglutinin.
The  toxic  effect  of  1 mmol  dichlorvos/litre  was  indicated  by  a
decreased  mitotic index.  Mitotic  cells were analysed  for chromosome
aberrations, but the number of dicentrics in  dichlorvos-treated  cells
was  no different from that  found in untreated cells  (Bootsma et al.,
1971).   When  dichlorvos  (1 - 40  mg/litre)  was  added  at  specific
intervals to cultures of human lymphocytes, cytotoxicity was  found  at
5 mg/litre  or more, but no  chromosome aberrations (chromatid gaps  or
breaks) were detected (Dean, 1972b).

    Negative results in cultured human lymphocytes were  also  reported
by Fahrig (1974) and Wild (1975).

8.6.2.2   In vivo studies

    (a)   Drosophila melanogaster

    Negative  results were obtained in  the standard Muller-5 test  for
sex-linked  lethal mutations and in the induced crossing-over test with
the  approximate LD50 concentration  (0.035% dichlorvos)  (Jayasuriya &
Ratnayake,  1973).   Similarly,  0.0006 - 0.6  µmol   dichlorvos   gave
negative results in the standard Muller-5 test (Sobels & Todd, 1979).

    In  studies  by  Hanna  &  Dyer  (1975),  a Drosophila melanogaster
population    was   continuously   exposed  to   gradually   increasing
concentrations  of  dichlorvos  (because of  development  of  increased
resistance)  in the food medium  (up to 0.75 mg/kg food)   for about 18
months.   At  the  end of  this  period,  an increased  accumulation of
mutations was observed.

    Gupta   &   Singh   (1974)   reported   studies   where   female  D.
 melanogaster flies were kept on food with 1 - 50 mg  dichlorvos  (Nuvan
100  EC)/kg.  No eggs were  laid at 10 mg/kg or  more, and at  1 mg/kg,
survival of the eggs was 45% of that of the controls.   Salivary  gland
chromosome  abnormalities  were  observed  in  fully-grown  larvae  fed
1 mg/kg.   However,  Kramers &  Knaap (1978), using  the same route  of
administration, found no induction of sex-linked recessive  lethals  by
dichlorvos (0.009, 0.048, and 0.09 mg/kg food).

    (b)   Host-mediated assays

    Dichlorvos was not mutagenic in host-mediated assays in  NMRI  mice
using:

    (i)     S.   typhimurium (G46  his-)   and  Serratia  marcescens (a 21
           leu-)     after   an   intraperitoneal  injection   of  25 mg
           dichlorvos/kg body weight (Buselmaier et al., 1972, 1973);

    (ii)    S.   typhimurium (64-320) after an  oral dose of  0.2 mg  per
           animal  (equivalent to 8 -  10 mg/kg body weight)   (Voogd et
           al., 1972); or

    (iii)   Saccharomyces   cerevisae (D4  ade2 and  trp5 loci)  after an
           oral dose of 50 or 100 mg/kg body weight (or  after  exposure
           of  CF1 mice for 5 h to 60 or 90 mg dichlorvos/m3)   (Dean et
           al., 1972).
           Although  dichlorvos  was  mutagenic  to  S.  cerevisae in    in
            vitro studies, these  in vivo studies proved to be negative.

    (c)   Dominant lethal assays

    Negative  results  were  reported in  a  test  for dominant  lethal
mutations  in ICR/Ha  mice (expressed  as an  increase in  early  fetal
deaths  or,  indirectly, by  pre-implantation  losses), after  a single
intraperitoneal  injection of  13 or  16.5 mg/kg body  weight  or  five
consecutive daily oral doses of 5 or 10 mg/kg body weight.   The  total

mating  period was 8 weeks (Epstein et al., 1972).  The same result was
obtained after exposure of male CF1 mice to 30 or 55 mg/m3 for  16 h or
to  2.1  or  5.8 mg/m3 for  23 h  daily  for  4 weeks  (Dean  & Thorpe,
1972b).

    A  statistically  significant increase  in  the frequency  of  pre-
implantation  losses in mice  (Q strain) in the  second week and  fifth
week  of  mating  has been  observed  after  a  single  intraperitoneal
injection  of 10 mg/kg body weight  (Degraeve et al., 1980;  Moutschen-
Dahmen et al., 1981).

    In  studies by Degraeve  et al. (1982,  1984a), male Q strain  mice
received  drinking-water  with  2 mg  dichlorvos/litre  (equivalent  to
0.32 mg/kg  body  weight per  day) 5 days  per week, for  7 consecutive
weeks.  At the end of this period, the males were mated for 1 week with
untreated  virgin females, and the pregnant females were killed 14 days
after  the  start  of pregnancy.   No  dominant  lethal mutations  were
induced.  The same result was obtained when female CF1 mice were either
given single oral doses of 0, 25, or 50 mg dichlorvos/kg body weight or
continuously   exposed  to  atmospheres   containing  0,  2,   or  8 mg
dichlorvos/m3 from   weaning until 11 weeks  of age.  They were  either
mated  at the end of the dosing or inhalation period or at intervals of
5, 10, and 15 days thereafter (Dean & Blair, 1976).

    (d)   Chromosome abnormalities

    Male   Q strain  mice  receiving  drinking-water   containing  2 mg
dichlorvos/litre  (equivalent to 0.32 mg/kg  body weight), 5  days  per
week  for 7 weeks, did not show chromosome damage in bone marrow cells,
spermatogonia, or primary spermatocytes (Moutschen-Dahmen et al., 1981;
Degraeve  et  al., 1982,  1984a); neither did  mice of the  same strain
given  a  single intraperitoneal  injection  with 10 mg/kg  body weight
(Moutschen-Dahmen et al., 1981; Degraeve et al., 1984b).

    In  a  micronucleus  test,  Swiss  mice  were  given  daily  intra-
peritoneal  injections of dichlorvos (0.0075 - 0.015 mg/kg  body weight
per day) for 2 days and killed 6 h after the last dose.   No  induction
of aberrations in the structure or number of chromosomes in bone marrow
cells was observed (Paik & Lee, 1977).

    CF1     mice    exposed    to    concentrations    of    64 - 72 mg
dichlorvos/m3   for 16 h or to 5 mg/m3 per  day, 23 h per day,  for  21
days,  did  not  show  chromosome  abnormalities  in  bone  marrow   or
spermatocytes.   Similar results for  Chinese hamsters exposed  by  the
inhalation route to 28 -36 mg/m3 for  16 h (males only), or by a single
oral  dose of  15 mg/kg body  weight (males)  or 10 mg/kg  body  weight
(females), have been reported (Dean & Thorpe, 1972a).

    Dichlorvos  has  been  tested for  its  ability  to induce  in  vivo
chromosomal   aberrations in Syrian  hamsters bone marrow  cells.  Four
dose  levels  (3,  6,  15,  and  30  mg/kg  body  weight)  were   given
intraperitoneally.   Statistically significant increases in  the number
of  cells  with  aberrant chromosomes  (mainly  breaks  and gaps)  were
observed (Dzwonkowska & Hübner, 1986).

8.7.  Carcinogenicity

8.7.1.  Oral

8.7.1.1  Mouse

    Carcinogenicity studies were carried out on two groups of  50  male
and 50 female B6C3F1 mice fed 1000 and 2000 mg dichlorvos (94%) in corn
oil/kg diet for 80 weeks.  Due to severe signs of  intoxication,  doses
were  lowered  after  2 weeks to 300 and 600 mg/kg for the remaining 78
weeks.   Samples  of  the  diets  analysed  during  the  study   showed
dichlorvos  contents within 5% of the intended concentrations.  Matched
controls  consisted  of  10  mice  of  each  sex; the  pooled  controls
consisted  of  100 male  and 80 female  mice.  All surviving  mice were
killed  at 92 - 94 weeks.  Hair loss and rough hair coats were noted in
many  treated animals, particularly  in the male  groups, beginning  at
week  20 and persisting throughout the study.  The average body weights
of  the high-dose mice of  both sexes were slightly  decreased compared
with  controls.  The low-dose female group showed the poorest survival;
74%  of  the  animals lived  to  90  weeks.  There  was  no significant
increase  in the  incidence of  tumours attributable  to dichlorvos  in
either  sex, i.e., dichlorvos was  not demonstrated to be  carcinogenic
(NCI, 1977; Weisburger, 1982).

    In  other  studies,  groups of 50 male and 50 female B6C3F1 mice, 6
weeks  of  age,  were  given  drinking-water  with  0, 400,  or  800 mg
dichlorvos/litre  ad libitum.  The drinking-water solutions were renewed
daily.   All surviving animals  were killed during  week 102.  A  dose-
dependent  inhibition of body  weight increase was  observed throughout
the study in both sexes at both dichlorvos concentrations.   There  was
no  adverse effect on mortality.   The survival rates at  week 102 were
62%,  66%, and 84% in  males (in controls, low-,  and high-dose groups,
respectively),  and 66%, 50%,  and 80% in  females.  The  corresponding
figures  for tumour incidence were 22.4%, 39.1%, and 23.4% in males and
29.3%,  16.2%, and 9.1% in  females.  The main tumours  that were found
were  lung  adenomas  and tumours  in  the  liver, spleen,  thymus, and
salivary gland.  These tumours occurred in all three groups.  There was
no  statistically significant difference in the incidence of tumours at
any site in any group (Konishi et al., 1981).

    Preliminary  results are available from a recently completed 2-year
mouse carcinogenicity study using dichlorvos.  Groups of 50 male and 50
female  B6C3Fl mice were  given dichlorvos (dissolved  in corn oil)  by
oral gavage daily for 2 years.  Dose levels for male mice were  0,  10,
or 20 mg/kg body weight per day and for female mice 0, 20, or 40 mg/kg.
There were no statistically significant differences in  survival  rates
between  the  treated and  control male mice,  and the same  applied to
female  mice.  A statistically significant increase in the incidence of
forestomach  squamous cell papillomas was  observed in the female  mice
receiving 40 mg/kg per day.  Two forestomach squamous  cell  carcinomas
were also seen in this group, but none were observed in the controls or
the  20  mg/kg group.   Considerably  fewer forestomach  squamous  cell
papillomas were observed in male mice.  Nevertheless, a non-significant
increase  was observed in the  20 mg/kg per day  group.  No forestomach

squamous  cell carcinomas were  noted in any  male group.   Forestomach
hyperplasia  occurred relatively frequently in both control and treated
male and female mice, the incidence being similar in all  groups  (NTP,
1987).

8.7.1.2  Rat

    In studies reported by NCI (1977) and Weisburger (1982), two groups
each of 50 male and 50 female Osborne-Mendel rats were fed  either  150
or 1000 mg dichlorvos (94%) in corn oil/kg diet for 80 weeks.   Due  to
the  severe signs of intoxication,  the 1000 mg/kg dose was  reduced to
300 mg/kg  diet after 3  weeks for the  remaining 77 weeks.   The diets
were stored under conditions designed to minimize loss  of  dichlorvos,
and the animals received fresh diets daily.  Matched controls comprised
10 rats of each sex; the pooled controls consisted of 60 rats  of  each
sex.  The surviving rats were killed after 110 weeks.  The average body
weights  of  the  rats receiving  the  high  dose level  were  slightly
decreased compared with controls.  There was no significant increase in
the  incidence  and  type  of  tumours in  either  sex as  a  result of
dichlorvos treatment.

    Enomoto  et al. (1981) carried out studies on groups of 50 male and
50  female  Fisher  344 rats,  6  weeks  of age,  given  drinking-water
(renewed  daily)  containing  0,  140,  or  280 mg  dichlorvos/litre  ad
 libitum.    All surviving animals were killed in week 108 (104 weeks of
exposure  followed by a  4-week recovery).  Slight  inhibition of  body
weight increase was observed in males in the high-dose group, but there
was  no influence on  mortality.  The survival  rates in week  108 were
82%,  75%,  and  75%  in  males  and  86%,  71%,  and  82%  in females,
respectively,  in  control, low-dose,  and  high-dose groups.   A great
number  of organs and tissues were selected for microscopy.  The organs
and  tissues of all animals which died or which were killed in moribund
conditions  were  microscopically examined,  as  were all  tumours  and
macroscopical  lesions.  A number of  animals with no specific  changes
were  also examined.  The overall tumour incidences were 100%, 96%, and
98%  in  males  and 37%,  31%,  and  33% in  females,  respectively, in
control,   low-dose,   and   high-dose  groups.    High  incidences  of
interstitial  cell tumours of  the testes in  males (49/51, 41/48,  and
47/48,  respectively) were observed  in all three  groups.  Mononuclear
cell  leukaemia  was  found in  all  groups  at 4 - 12%.   There was no
statistically significant difference in tumour incidence at any site in
any group.

    Preliminary  results are available from a recently completed 2-year
rat  carcinogenicity study using dichlorvos.   Dichlorvos, dissolved in
corn oil, was administered each day by oral gavage to groups of 50 male
and  50 female Fischer 344 rats at dose levels of 0, 4, or 8 mg/kg body
weight per day.  Though survival rates were slightly decreased  in  the
treated  male and female groups compared with those of their respective
controls  groups, the differences  were not statistically  significant.
However,  a statistically-significant and dose-related  increase in the
incidence of pancreatic adenomas was observed in the male rats fed 4 or
8  mg/kg.  In female  rats fed 8  mg/kg, a non-significant  increase in
pancreatic   adenomas  was  observed.   There  was  a  relatively  high

incidence of pancreatic hyperplasia and atrophy in all groups  of  male
rats,  including the  controls, and  a lower  incidence in  all  female
groups.   A statistically significant (but  not dose-related) increased
incidence  of mononuclear leukaemia was observed in the male rats fed 4
or  8 mg/kg.  A  similar incidence was  observed in all  female groups,
including  the control  group.  Since  this is  a common  and  variable
systemic  lesion in Fischer-344 rats, the toxicological significance of
this  finding is uncertain.  It  is possible that its  incidence in the
male  control  group  was unusually  low.   An  increased incidence  of
mammary  gland fibroadenomas  (not dose  related) was  observed in  the
treated  female  rats,  but  these  were  not  considered  to   be   of
toxicological  concern.   In  addition, mammary  gland  hyperplasia was
frequently observed in all control and treated female groups at similar
incidences (NTP, 1986).

    As  reported in  section 8.4.1.1,  Witherup (1967,  1971) found  no
increase in tumour incidence following dichlorvos treatment of rats.

8.7.2.  Inhalation

8.7.2.1  Rat

    In the studies by Blair et al. (1976) described in section 8.4.2.1,
no dose-related increase in tumour incidence was found.

8.7.3.  Appraisal of carcinogenicity

    The  majority  of the  mouse and rat  studies using dichlorvos  are
considered to be negative regarding carcinogenic potential (Witherup et
al., 1967, 1971; Blair et al., 1976;  NCI, 1977;  Enomoto et al., 1981;
Konishi  et  al.,  1981;   Weisburger,  1982).   However,   preliminary
information from two recent studies on the mouse and rat, respectively,
has provided equivocal evidence of carcinogenicity (NTP, 1986)a.



------------------------------------------------------------------------
a   The NTP Peer Review Panel reviewed these studies and came to the
    following conclusions:

  "Under  the  conditions  of  these 2-year gavage  studies, there was  some
  evidence of carcinogenic activity of dichlorvos for male F344/N  rats,  as
  shown  by increased incidences  of adenomas of  the exocrine pancreas  and
  mononuclear cell leukemia.  There was equivocal evidence  of  carcinogenic
  activity  of dichlorvos  for female  F344/N rats,  as shown  by  increased
  incidence  of  adenomas  of  the  exocrine  pancreas  and  mammary   gland
  fibroadenomas.   There  was  some  evidence  of  carcinogenic  activity of
  dichlorvos for male B6C3F1 mice and clear evidence for female B6C3F1 mice,
  as shown by increased incidences of forestomach squamous cell  papillomas"
  (NTP, 1988).

    The increased incidence of forestomach tumours in the  mouse  study
is likely to be related to the route of administration  (oral  gavage),
which  has been  shown in  other mouse  studies to  induce  forestomach
tumours  due to repeated and  direct irritation of the  gastric mucosa.
If  so, ingestion of  food by human  beings could not  result  in  such
direct effects on the stomach wall.  Furthermore, human beings  do  not
possess  a stomach wall comparable  with the forestomach of  the mouse,
except perhaps for the oesophagus.  However, the transient  passage  of
food  through the oesophagus would  probably not allow sufficient  time
for the carcinogenic event to occur.

    Similarly,  the pancreatic adenomas observed  in the NTP rat  study
may  be related to the corn oil used in the study.  Evidence from other
rat  studies in which corn oil was used as a vehicle suggests that this
is  a possibility.  On the other hand, it does not explain why a higher
incidence  of pancreatic tumours  was observed in  the treated  animals
compared   with  the  controls.    Although  increased  incidences   of
mononuclear  leukaemia  were  observed  in  treated  male   rats,   the
incidence in the control group of this common and variable  tumour  may
have  been low.  The evidence  for carcinogenicity in these  two recent
studies  is difficult to interpret at present.  When complete and final
reports  of these studies become available, more definitive conclusions
may be drawn.

8.8.  Mechanisms of Toxicity; Mode of Action

    A  full description  of the  mechanism of  action can  be found  in
Environmental  Health  Criteria  63: Organophosphorus  Insecticides - A
General Introduction (WHO, 1986b).

    Dichlorvos  directly inhibits AChE  activity in the  nervous system
and other tissues. This reaction takes place in three steps:

    (a)  reversible binding of dichlorvos to the enzyme;

    (b)  reaction  with  the  enzyme to  form  a dimethylphospho-enzyme
         derivative, with the loss of DCA; and

    (c)  "aging"  of  the  phospho-enzyme  compound  to  a  more stable
         methylphospho-enzyme derivative.

Reaction  (a) is  rapid, but  reversible.  Reaction (b) is  also rapid,
but   the  phosphorylated   enzyme  can   be  returned   to its  native
state  spontaneously only by hydrolysis at very slow rates or by agents
such  as  N-methyl   2-pyridinium  aldoxime  (2-PAM)  at  higher  rates.
Reaction  (c) is comparatively slow (t´ =   about 2.5 h at 37 °C and pH
7.4),  but the product has  the same stability as  that of erythrocytes
(t´ = about 120 days) (Gillett et al., 1972).

    Death due to poisoning is caused by excessive  cholinergic  effects
such  as  bronchospasms,  hypersecretion  from  cholinergic  innervated
glands   (especially  critical  in  lungs  and  bronchi),  and  cardiac
disturbances caused by vagotonus and anoxia.  Convulsions and paralysis
in  skeletal  musculature  are  caused  by  brain  anoxia  as  well  as
cholinergic effects within the central nervous system.

     In  vivo studies on the inhibition of ChE activity resulting from a
single  oral  or  parenteral  dose  of  dichlorvos,  at  various   time
intervals,  after dosing are summarized  in Table 18.  In general,  the
maximum  inhibition occurred  within 1 h,  and was  followed  by  rapid
recovery.   Dogs seemed to  be more sensitive  than rats, and  showed a
slower recovery.

    Dichlorvos,  when  infused intravenously  (into  the ear  vein)  of
adult male rabbits, produced dose- and time-related inhibition of whole
blood  ChE  activity  during  infusion.   Spontaneous  but   incomplete
recovery  to 60 - 80%  of the  normal  activity  occurred  within  60 -
90 min  of infusion (Shellenberger et al., 1965; Gough & Shellenberger,
1970, 1977-78; Shellenberger, 1980).

    In  a study on the  influence of temperature on  ChE activity, rats
were  injected  intraperitoneally  with  a  single  dose   of   6.25 mg
dichlorvos  (95%)/kg  and kept  at either 28 °C  or 5 °C.  The  maximum
inhibition  of whole blood  ChE activity (40%)   occurred after 0.5  h.
The  animals at 5 °C  showed less inhibition  and a faster  recovery of
whole  blood ChE activity  than those at  28 °C (Chattopadhyay et  al.,
1982).

8.9.  Neurotoxicity

8.9.1.  Delayed neurotoxicity

    A   detailed   description   of   the   neurotoxic   potential   of
organophosphorus  compounds  can  be  found  in  Environmental   Health
Criteria  63:  Organophosphorus  Insecticides -  A General Introduction
(WHO, 1986b).

    Several studies have shown that dichlorvos does not produce delayed
neurotoxicity  in pre-medicated hens, whether it is administered orally
or  subcutaneously  (Durham  et al.,  1956;  Aldridge  & Barnes,  1966;
Johnson, 1969, 1975a,b, 1978, 1981; Aldridge & Johnson, 1971;  Lotti  &
Johnson,  1978).   The inhibition  of  brain neurotoxic  esterase (NTE)
without  signs of ataxia has  been observed (Aldridge &  Johnson, 1971;
Johnson, 1978).

    Caroldi  &  Lotti  (1981) reported  mild  signs  of ataxia  in pre-
medicated  hens  2  weeks after  a  single  massive  subcutaneous  dose
(100 mg/kg  body weight)  and severe  inhibition of  NTE in  peripheral
nerve, spinal cord, and brain.  However, Johnson (1978) did not observe
ataxia  in pre-medicated  hens given  the same  dose in  the same  way.
These  hens  showed  severe  inhibition  of  brain  NTE  but  far  less
inhibition  of spinal cord NTE.  It appears that ataxia arises from the
inhibition of spinal cord NTE.  When the dose was repeated  1 - 3  days
after the first dose, spinal cord NTE inhibition increased and the hens
became ataxic.

    White  leghorn  hens  have been  used  in  a 90-day  study  on  the
neurotoxic  potential  of  dichlorvos  (99.9%)  after  dermal  or  oral
administration.   For  oral  administration,  a  10 - 20%  solution  of
dichlorvos  in corn oil in gelatin capsules was used whereas, dermally,
1 - 20% emulsifiable concentrates in technical grade xylene (containing

2% Triton X-100) were used.  Dichlorvos at doses greater than  1  mg/kg
body  weight per  day (dermal)  or 6 mg/kg  (oral) led  to  cholinergic
symptoms including salivation, convulsions, and death after 2 - 3 days.
With  oral  doses  of 3 - 6 mg/kg  no  ataxia  or death  was  observed.
Dermally, dichlorvos was very toxic for hens.  Dose levels of about 1.7
and 3.3 mg/kg for an average period of 37 days caused ataxia and death.
An  average dermal dose level of 0.65 mg/kg body weight for 90 days did
not  induce  ataxia or  death.   Typical symptoms  of organophosphorus-
ester-induced delayed neurotoxicity (OPIDN)  were not observed (Francis
et al., 1985).

    In  summary, it is possible to produce clinical neuropathy in hens,
but  the  doses  required are far in excess of the LD50.    The effects
are  associated with severe inhibition of NTE in brain and spinal cord,
measured shortly after dosing (Johnson, 1981).

8.9.2.  Mechanism of neurotoxicity

    Male  rats  given  a  lethal  intraperitoneal  injection  of  40 mg
dichlorvos/kg  body weight did  not show electrocortical  disturbances.
Deaths resulted from respiratory failure (Hyde et al., 1978).

    In  studies by Desi  (1983), adult CFY  rats were given  daily oral
doses  ranging from 1.25 to 4 mg dichlorvos/kg body weight mixed in the
diet  for 3 months.  Plasma, erythrocyte, and brain ChE activities were
comparable  with those  of control  rats.  Increased  EEG activity  and
enhanced central excitability were found in the male rats only.

    No  changes  in reflex  motor unit potential  activity or in  nerve
conduction velocity were noted in dogs 7 days after single  oral  doses
of 30, 59.5, or 148 mg dichlorvos/kg body weight.  However, erythrocyte
ChE  activity was inhibited at all doses, and the highest dose produced
signs of intoxication (Hazelwood et al., 1979).

    A  single  oral dose  of 40 mg dichlorvos/kg  or repeated doses  of
1.6 mg/kg  body weight per day did not cause histological abnormalities
in the brain of adult Wistar rats.  Repeated administration of  50%  of
the LD50 (i.e.,  40 mg/kg body weight per day for 10 - 21 days), caused
myelin  pallor and  micro-vacuolation of  the white  matter.  It  seems
likely that primary degeneration of axons and secondary  myelin  sheath
abnormalities  caused the spongy  tissue loosening observed  under  the
electron microscope (Zelman, 1977; Zelman & Majdecki, 1979).

    In studies by Ali et al. (1979a) and Hasan et al. (1979), male rats
were  given 3 mg dichlorvos/kg per  day intraperitoneally for 10  days.
Following  perfusion-fixation, sections of  cerebellum and spinal  cord
were studied with the electron microscope.  An abnormal increase in the
number   of   mitochondria  in  the  spinal  cord  was  found.   Myelin
degeneration  was detected in the  spinal cord and myelin  figures were
occasionally noted within oedematous dendrite profiles.


Table 18.  Time-related ChE activity in animals after administration of a single dose of dichlorvos
---------------------------------------------------------------------------------------------------------
Species/sex   Route           Dose (mg/kg   Time      Cholinesterase activity (%)    Reference
                              body weight)            plasma  erythrocyte   brain
---------------------------------------------------------------------------------------------------------
Mouse (male)  intraperitoneal    30        15 min                             37     Cohen & Ehrich 
                                            2 h                               40     (1976)
                                            5 h                               69
                                           18 h                               92
                                                                 
Mouse (male)  intraperitoneal    10        15 min                             30     Nordgren et al. 
                                           60 min                             50     (1978)
                                            2 h                               80

Rat (male)    oral               50        15 min       30        20        10-15    Modak et al.  
                                            3 h         30        65                 (1975)
                                           24 h         60        75        60-70

Rat (male)    oral               40         1 h                               30     Teichert et al.  
                                                                                     (1976)

Rat (male)    oral               40         5 min                             55     Pachecka et al.  
                                           15 min                             20     (1977)
                                            2 h                               30
                                           24 h                               75
                                           48 h                              100

Rat (male)    intravenous        2.5       30 min       40                    15     Reiner & Plestina
                                           90 min       60                    35     (1979)
                                            3 h         90                    55
                                           12 h        100                    80
                                           48 h                               90

Dog (beagle)  oral               50         2 h         32        63                 Ward & Glicksberg
(sex not                                   24 h         63        74                 (1971)
specified)                                  5 days      92        78
                                           21 days     100        92

Dog           oral               22         1 h         12        17                 Snow & Watson 
(greyhounds                                 3 h         24        34                 (1973)
and crossbred)                             24 h         70        65
                                           72 h         95        65
---------------------------------------------------------------------------------------------------------
    Another    study   of   dichlorvos   neurotoxicity   involved   the
investigation  of lipid peroxidation.  This entails the direct reaction
between  oxygen and lipids to form free-radical intermediates and semi-
stable  peroxides.  Major cellular  components, such as  membranes  and
subcellular  organelles, are damaged by  these free radicals.  Hasan  &
Ali  (1980)  found  a dose-dependent  increase  in  the rate  of  lipid
peroxidation  in  various  regions  of  the  brain  of  the  rat  after
intraperitoneal administration of dichlorvos (at concentrations ranging
from 0.6 to 3 mg/kg body weight, daily) for 10 days.  Also,  there  was
an increased incidence of lipofuscin-like pigment in the Purkinje cells
of the cerebellar cortex.

    Maslinska et al. (1984) found that dichlorvos (dose levels  of  4 -
8  mg/kg body  weight for  10 days)  affected the  phospholipid-protein
balance in the brain of rabbits.  The animals were exposed  during  the
postnatal  "critical" life period, which constitutes a turning point in
the development of the brain.  At this time, the neurons  have  already
undergone    considerable    arborization,    and    myelination    and
vascularization are expanding rapidly.  In addition, the overall oxygen
consumption is reaching its steepest rate of increase.  In  the  myelin
sheaths  under  formation,  several phospholipids  are  deposited.  The
authors   found  changes  in   the  phospholipid-protein  ratio   which
correlated  well with the  observed delay in  myelin sheath  formation.
Ultrastructural  changes  in  certain  subcellular  organelles  may  be
connected  with the change in  this ratio, since it  is crucial to  the
structural and functional properties of the membranes and enzymes bound
to them.

    Dambska et al. (1984) have studied the influence of  dichlorvos  on
blood  vessel walls, the perivascular area, and the permeability of the
blood-brain  barrier in young rabbits.  The young animals received 9 mg
dichlorvos/kg  body weight for 16 days starting on the 6th day of life.
There  was  a  decrease  in  ChE  activity  in brain  capillary  walls.
Electron  microscopic  studies  showed  lesions  of  the   perivascular
astrocytes  and  changes  in  the  endothelial  cells.   However, these
lesions  did  not  disturb  the  blood-brain  barrier   mechanism   for
horseradish peroxidase particles.

    Studies  on the central cholinergic  system have revealed that  the
inhibition  of brain  ChE activity  and its  subsequent  recovery  were
uniform in all brain regions studied in orally dosed  (50 mg/kg)  rats.
ACh  concentrations were  increased in  brain areas  within  15 min  of
treatment.  A biphasic effect was observed on choline metabolism in the
brain.  The cortex was more cholinergic than the striatum in  terms  of
percentage  increase  in ACh  and choline (Modak  et al., 1975).   In a
similar study on rats, either receiving a single oral  dose  (40 mg/kg)
or repeated oral doses (4 mg/kg), the activity of whole  brain  choline
acetyltransferase  and the contents of  ACh and choline in  whole brain
were  not altered, though  brain ChE activity  was markedly  inhibited.
However,  in  the  cerebral  hemispheres,  and  especially  the  corpus
striatum,  the  ACh  level  was  considerably  increased,   without   a
concomitant change in choline (Teichert et al., 1976).

    Kobayashi  et al. (1980,  1986) investigated the  concentration  of
total,  free, labile-bound and  stable-bound ACh in  the brain of  rats
given single or multiple subcutaneous injections of  dichlorvos  (0.2 -
4 mg/kg  body weight).   The results  suggest that  alterations in  the
mobilization and storage of ACh in the central cholinergic  nerves  may
be induced.  The time course for ACh accumulation was measured  in  rat
brain regions after intravenous treatment with 15 mg dichlorvos/kg body
weight (Stavinoha et al., 1976). The striatum had the highest  rate  of
accumulation  and the cerebellum  the lowest.  The  calculated turnover
time  for  the  different regions  of  the  brain was  between  0.9 and
5.6 min.

    In studies by Ali & Hasan (1977) and Ali et al. (1979b, 1980), rats
were given intraperitoneally 3 mg dichlorvos/kg body weight per day for
10  or 15 days.  The concentrations of dopamine, norepinephrine, and 5-
hydroxytryptamine  (5-HT)   were  significantly decreased  in different
parts  of the brain, and 5-HT was significantly increased in the spinal
cord.

    A  single dose or short-term (12 weeks) treatment of rats with high
concentrations  of  dichlorvos,  which produced  brain  ChE inhibition,
resulted  in decreased norepinephrine levels in the brain (Brzezinski &
Wysocka-Paruszewska,  1980).  From these studies, it was suggested that
the  metabolism  of  catecholamines  and  5-HT  may  be  disturbed   by
dichlorvos.

8.10.  Other Studies

    Many  studies in different organ systems have been carried out.  In
most  of  these studies,  the route of  administration was the  oral or
intraperitoneal route.  Single or repeated dosing was used, mainly with
high  dose levels, in  mice and rats.   The influence on  brain enzymes
(other  than  brain  ChE), liver  enzymes  such  as  ChE  (inhibition),
microsomal  cytochrome  P-450  activity  (decrease),  drug-metabolizing
enzyme  activity,  and  UDP-glucuronyl transferase  (no influence), and
many other enzyme systems were studied.

    Furthermore, the influence of dichlorvos on adrenal steroidogenesis
has been investigated (Civen et al., 1980).

8.10.1.  Immunosuppressive action

    A dose-related suppression of the humoral immune  response  induced
by  S.  typhimurium was  observed  in rabbits  orally administered 0.3 -
2.5 mg  dichlorvos (93%)/kg body weight in capsules, 5 times a week for
6 weeks (Desi et al., 1978).

    In  a comparable study on rabbits, the cellular immune response was
estimated  using  the tuberculin  skin test.  The  skin redness in  the
tuberculin test and the serum antibody titres of treated animals showed
a dose-dependent decrease compared with those of controls (Desi et al.,
1980).

8.11.  Factors Modifying Toxicity; Toxicity of Metabolites

8.11.1.  Factors modifying toxicity

    In  studies on the  effect of diet  on the toxicity  of dichlorvos,
young male rats were kept for 30 days on the following synthetic diets:
high  protein (HPD), low  protein (LPD), high  fat (HFD), and  standard
(SD).   Growth rates were normal  except for a slightly  decreased body
weight gain in the HFD group.  The composition of the diet,  per se, did
not  significantly affect plasma and erythrocyte ChE activity 24 h or 5
days  after  dosing.   A  single  intraperitoneal  injection  of  50 mg
dichlorvos/kg  body weight  led to  higher mortality  in LPD  rats  (as
expected  with a  protein-deficient diet)  and lower  mortality in  HPD
rats, compared with SD animals (Purshottam & Kaveeshwar, 1979).

    In a further study, growing male rats were kept on an HFD   or  HPD
for  30 days.  At the end of this period, a single intraperitoneal dose
of  dichlorvos (20 or 30 mg/kg body weight)  was administered.  Results
showed that diets,  per se, did not affect initial plasma or erythrocyte
ChE  activity, nor did the  HPD or HFD diets  protect against mortality
from dichlorvos.  In the case of the HPD, the spontaneous  recovery  of
ChE  activity was reduced in the plasma and erythrocytes of dichlorvos-
treated  rats.  However, with an  HFD, this recovery was  significantly
increased (Purshottam & Srivastava, 1984).

    Costa & Murphy (1984) studied the interaction between acetaminophen
(which,  like dichlorvos, is detoxified by glutathione transferase) and
dichlorvos (10 mg/kg body weight)  in mice.  Acetaminophen  (600  mg/kg
body  weight)  pre-treatment  did not  have  any  affect on  dichlorvos
toxicity.   On  the  other  hand,  intraperitoneal  pre-treatment  with
diethylmaleate  (1 ml/kg body weight)  increased the acute toxicity  of
dichlorvos.

8.11.2.  Toxicity of metabolites

8.11.2.1  Acute toxicity

    The  toxicity of metabolites of dichlorvos in female mice, injected
intraperitoneally,  is  considerably  less  than  that  of   dichlorvos
(Table 19).

    Mice   (male  and  female) survived  a  single  exposure of  130 mg
DCA/m3 for 5 - 7 h (Stevenson & Blair, 1969).

8.11.2.2  Short-term exposures

    Groups  of  20  male and 20 female rats were exposed for 30 days to
actual  concentrations of 0 or  0.5 - 1 mg DCA/m3.    Half the  animals
were then killed promptly and the remainder on day 35.  After  30  days
of  exposure, the male rats showed a slight decrease in body weight and
food  intake, and  a slight  increase in  absolute and  relative  liver
weight.   There  were  no such changes in the rats left for 5 more days
unexposed  to DCA.  Histological  examination of the  lungs of  exposed
males  and females revealed  a higher incidence  of minor  inflammatory

changes  than in controls.  No  other changes attributable to  DCA were
found  in general health,  behaviour, haematology, clinical  chemistry,
organ  weights, gross pathology,  or histopathology.  A  similar  study
using groups of 10 male and 10 female rats and actual concentrations of
0  or approximately 2 mg/m3 DCA  revealed no abnormalities attributable
to DCA (Wilson & Dix, 1973).

Table 19.  Intraperitoneal LD50 values of metabolites of dichlorvos in
female micea
-----------------------------------------------------------------------------
   Compound                   Vehicle            LD50 (mg/kg body weight)
-----------------------------------------------------------------------------
   desmethyldichlorvos,       water                        1500
    sodium salt

   dichloroacetyaldehyde      corn oil                      440
   (DCA)

   dichloroethanol            corn oil                      890

   dichloroacetic acid        corn oil or water             250

   sodium dichloroacetate     water                        3000

   methyl and dimethyl        water                        1500
    phosphoric acid mixture

   sodium methyl- and         water                        3000
    dimethylphosphate
    mixture
-----------------------------------------------------------------------------
a   From: Casida et al. (1962).

8.11.2.3  Long-term exposure

    No  long-term  tests  have  been  carried  out  with DCA  as  such.
However,  in the 2-year oral  studies on rats and  dogs with dichlorvos
(section  8.4.1), the degradation product  DCA was present in  the test
diets  in increasing  amounts, so  that possible  effects of  DCA  were
included in the results of these studies.

8.11.2.4  Mutagenicity

    DCA  appears  to  be  mutagenic  in  the  Salmonella test   using  S.
 typhimurium TA100.   The mutagenicity decreased  in the presence  of  a
microsomal  activation system.  Part of  the decrease was dependent  on
the  presence  of  the  co-factors  NADP  and  glucose-6-phosphate.  No
evidence  for  mutagenicity  with 2,2-dichloroethanol  was  obtained in
this  S. typhimurium strain (Löfroth, 1978).

    In a dominant lethal assay, a single intraperitoneal  injection  of
176  mg DCA/kg in male mice (AB Jena-Halle strain)  produced a decrease
in the number of total implants and live fetuses in the first  3  weeks
of  the test, and  an increase in  post-implantation losses.  The  same
test  was  repeated  with a  strain  of  mice (DBA)  less  sensitive to
mutagenic  effects.   The  same effects  were  found,  but to  a lesser
extent, and mainly in the fourth week (Fischer et al., 1977).

8.11.2.5  Metabolism

    When 32P-dimethylphosphate   (500 mg/kg in water)  was administered
orally   to   a   male   rat,   the   autopsy  (90 h  after  treatment)
indicated   that  almost  the entire  dose had  been  eliminated.   The
urine,  containing only unmetabolized dimethylphosphate,  accounted for
about  half  of  the radioactivity.   The  tissues  were almost  devoid
of 32P-containing material (Casida et al., 1962).

    A   rat,  orally dosed  with  500 mg/kg 32P-desmethyldichlorvos  in
water,   excreted  about  14%   of  the  dose   in  the urine  in 90 h.
The  tissue distribution  of 32P  was  similar to  that which  followed
32P-dichlorvos     administration.    The   very  high   proportion  of
radioactivity  in  the  bone was  indicative  of  rapid degradation  to
phosphoric acid (Casida et al., 1962).

9.  EFFECTS ON MAN

9.1.  General Population Exposure

9.1.1.  Acute toxicity

9.1.1.1  Poisoning incidents

    A   56-year-old  woman  ingested  an  estimated  amount  of  100 mg
dichlorvos/kg body weight and survived, following intensive care for 14
days  (Watanabe et al.,  1976).  However, a  suicide with a  dichlorvos
dose  of about 400 mg/kg  succeeded in spite  of treatment (Shinoda  et
al., 1972).

    A 35-year-old female patient accidently ingested 60 g fluid Divipan
(dichlorvos concentration not reported).  She was comatose for one week
and  recovered slowly.  Clinical and  electrophysiological examinations
(no details reported) showed a pure motor form of neuropathy, according
to the authors (Vasilescu & Florescu, 1980).

    Two cases of poisoning with dichlorvos taken orally in unspecified,
but  high, quantities have  been reported.  The  patients first  showed
signs   of   severe   anti-ChE  poisoning.    After  recovery,  delayed
neurotoxicity  developed.   They  showed a  severe  axonal degeneration
neuropathy.   One  of them  recovered within 12  months (Wadia et  al.,
1985).

    Reeves  et al. (1981) reported six cases, over an 8-year period, of
bone-marrow  failure (pancytopenia) in children  shortly after exposure
to  dichlorvos and propoxur.   Van Raalte &  Jansen (1981) doubted  the
causal relationship between dichlorvos and bone-marrow failure  in  the
children,  because the disease  has not been  observed in workers  with
high exposure, or in the general population.  In addition, haematotoxic
effects have not been observed in experimental animals.

9.1.2.  Effects of short- and long-term exposure

    In the 1960s, field studies were carried out in  several  countries
to  test dichlorvos as  a residual insecticide  for malaria control  in
houses.   Numerous residents of  all ages and  conditions were  exposed
without any adverse effects attributable to dichlorvos  being  reported
(Escudié  & Sales,  1963; Funckes  et al.,  1963; Gratz  et al.,  1963;
Quarterman et al., 1963; Foll et al., 1965).  In two field studies, the
plasma and erythrocyte ChE activities were measured in adults and young
children.   No abnormalities were  found, though air  concentrations of
dichlorvos  in the treated houses  rose to 0.8 mg/m3 (Funckes  et  al.,
1963; Gratz et al., 1963).

    In a report by Gold et al. (1984), 20 single-family residences were
treated  with a  0.5% solution  of dichlorvos  (at an  average rate  of
0.189  g/m2)   to control  the cockroach  Blattella   germanica L.   The
average  air  concentration  for the  first  2  h after  treatment  was
548 µg/m3 and   for the next 2 h was 183 µg/m3.     Pesticide operators

and  the residents of treated structures were monitored for evidence of
dichlorvos  exposure,  using  exposure  pads,  air  samples,  serum and
erythrocyte  ChE  tests,  and urinalyses.   There  was  no evidence  of
dichlorvos  or dichloroacetic acid  in urine.  There  were slight,  but
statistically  significant, changes in the  mean serum ChE activity  of
some of the residents of treated structures, but the  mean  erythrocyte
ChE was unchanged.

    Passengers in an aircraft provided with an automatic insect-control
system,  which  released  0.15 - 0.30 mg dichlorvos/m3 for   periods of
about  30 min,  did not  show any signs  of discomfort (Jensen  et al.,
1965).   Tests have  shown that  man can  withstand daily  exposure  to
concentrations  of 0.5 mg/m3 without  clinical effects, and with only a
slight  depression of  blood ChE  activity (Hayes,  1961).   Three  men
exposed  to approximately the same  level during 24 tests  did not show
any change in blood ChE activity (Schoof et al., 1961).

    A  case of chronic obstructive  bronchitis ascribed to exposure  to
dichlorvos  was described by Barthel  (1983). However, it could  not be
excluded  that other components of  the unknown formulation could  have
been the cause.  ChE determinations were not performed.

9.1.2.1  Studies on volunteers

    Single  oral doses (1 - 32 mg/kg  body weight) of  dichlorvos in  a
slow-release  PVC  formulation  administered  to  107  male  volunteers
produced  measurable  reductions in  erythrocyte  ChE activity  at dose
levels  above 4 mg/kg, with a  maximum reduction of 46%  at the highest
dose.   Plasma  ChE  activity was  affected  at  lower doses,  with 50%
reduction at 1 mg/kg and about 80% at 6 mg/kg or more.   Repeated  oral
doses of 1 - 16 mg/kg body weight per day were given to  38  volunteers
for  up to 3 weeks.  The plasma ChE activity was maximally depressed at
all dose levels, and the erythrocyte ChE activity depression  was  dose
related and significant at 2 mg/kg or more.  Blood cell  count,  urine,
liver  function, prothrombin  time, and  blood urea  nitrogen were  all
normal (Hine & Slomka, 1968, 1970; Slomka & Hine, 1981).

    In studies by Rider et al. (1968), dichlorvos was given  to  groups
of five men at daily oral doses of 1, 1.5, 2, or 2.5 mg per  man.   The
plasma  ChE activity of the  2.5 mg group was reduced  by 30% after  20
days  of treatment.  Administration of  2 mg for 28 days  resulted in a
reduction  of 30% 2 days after the last dose.  Erythrocyte ChE activity
was  not significantly affected in  either group (Rider et  al., 1967).
Daily oral doses of 1.5 mg per man given to 10 volunteers for  60  days
caused  a  significant  reduction  (approximately  40%)  in  plasma ChE
activity,   which   returned   to   normal   levels   when   dichlorvos
administration was discontinued.

    Boyer et al. (1977) reported studies on two groups of six men (21 -
45  years  of  age) who received 0.9 mg of dichlorvos three times a day
for 21 days.  One group received the dichlorvos in a gelatin salad, the
other  in  a pre-meal  capsule filled with  cottonseed oil.  Two  other
groups   of  six  men   received  placebo  treatment.    No  consistent

cholinomimetic signs or symptoms were observed, nor was erythrocyte ChE
inhibited.  However, plasma ChE was significantly depressed  within  20
days,  although the extent depended  on the method by  which dichlorvos
was  administered.  Recovery was comparable  in both groups, the  half-
life for the regeneration of plasma ChE being 13.7 days.

    Volunteers  did not show  inhibition of plasma  or erythrocyte  ChE
activity either when handling a dichlorvos strip for 30 min each day or
after  having  a  piece of the strip applied to the arm for 30 min each
day for 5 consecutive days (Zavon & Kindel, 1966).

    The wearing of dichlorvos-impregnated garments by babies  for  48 -
84  h  did  not produce  changes  in  either plasma  or erythrocyte ChE
activity over a period of 5 days (Cavagna et al., 1969).

    In  studies on  eight volunteers,  carried out  in an  aircraft  at
operational   cabin  altitude  (2400 m),   no  changes  in   plasma  or
erythrocyte  ChE activity, dark  adaptation, or bronchiolar  resistance
were observed.  Dichlorvos concentration in the air ranged from 0.73 to
1.18 mg/m3 during exposures of 45 min (Smith et al., 1972).

    Hunter   (1970a)  reported  studies   on 26 men  (21 - 57 years  of
age)   and 6 women (19 - 25 years of age) who were exposed in a chamber
for  2-7´ h  to  actual  dichlorvos  concentrations  of   approximately
1 mg/m3.     Food and drink  were served in  the chamber.  No  clinical
signs  were observed, and no effects on haematology, urinalysis, kidney
function, EEG, ECG, respiratory activities, or erythrocyte ChE activity
were  found.  Plasma ChE activities  were markedly inhibited only  when
the exposure lasted over 6 - 7 h (Hunter, 1970a).

    In  studies by Hunter  (1969, 1970b), seven  men (25 - 56 years  of
age)  were  exposed  (head  and  neck)  to  dichlorvos  vapour  (actual
concentrations  of  1 - 52 mg/m3),    and  6  men  were  exposed  (head
exposure  only) to 7 - 50 mg/m3,   for periods from 10 min to 4 h.  The
maximum dose level was 52 mg/m3 (for  65 min), and the  maximum  period
was  240 min (at 13 mg/m3).   Symptoms  were confined to irritation  of
the  throat, some rhinorrhoea, and substernal discomfort at the highest
concentrations.   No effects  on the  pupil or  on visual  acuity  were
recorded.  Erythrocyte ChE activity was depressed in only  one  person.
However,  there was  a direct  relationship between  the  reduction  in
plasma ChE activity and the dichlorvos dose (concentration x time).  No
changes  were found in  either kidney or  pulmonary function or  in the
overall metabolic rate.

    When three men were exposed to dichlorvos (actual concentrations of
0.3 - 0.9   mg/m3 (mean,   0.5 mg/m3)    or  0.9 - 3.5  mg/m3    (mean,
2.1 mg/m3)    for 1 or 2 h per day for 4 consecutive days,  plasma  ChE
alone  decreased slightly in  the men exposed  for 2 h  per day to  the
higher concentration (Witter et al., 1961).

    A  group  of  15 men (23 - 61 years of age) was exposed for up to 6
half-hour intervals per night for 14 days (total of 39 doses) to actual
dichlorvos  concentrations ranging from 0.14 to 0.33 mg/m3.    No clear
changes  in plasma ChE  activity or other  parameters such as  reaction
time, airway resistance, or vision were found.  The same  results  were

obtained when a similar group was exposed to actual  concentrations  of
0.1 - 0.6  mg/m3 for  intervals of 8 - 10  h, 4 nights per  week for 11
weeks (Rasmussen et al., 1963).

    No  significant effect on  plasma or erythrocyte  ChE activity  was
observed  in  14  persons  exposed  at  the  recommended  rate  of  one
dichlorvos strip per 30 m3 in  their homes over a period of  6  months.
The  strips  were  replaced at  much  shorter  intervals than  normally
recommended.  The air concentration 40 days after the  installation  of
the fourth strip was approximately 0.09 mg/m3 (Zavon & Kindel, 1966).

    In  three home studies involving 26 families, conducted in Arizona,
USA,  no  deleterious effects  on health or  plasma or erythrocyte  ChE
activity  were observed in the  residents exposed to dichlorvos  strips
all  over the  house (8 - 10  strips) for  over a  year.  Even  monthly
replacement  of the  strips resulted  in only  a slight  inhibition  of
plasma  ChE  activity.  The  maximum  air concentrations  of dichlorvos
averaged 0.13 mg/m3 (Leary et al., 1971, 1974).

9.1.2.2  Hospitalized patients

    In a report by Pena Chavarra et al. (1969), a single oral dose of 6
or  12 mg dichlorvos/kg body weight  was administered in the  form of a
slow-release  granular resin formulation  as an anthelminthicum  to 108
hospitalized  adult patients, many of these debilitated and with severe
anaemia.  Plasma ChE activity was markedly reduced, in some patients by
76 - 100%.   However, erythrocyte ChE activity was much less inhibited.
No  symptoms  of  intoxication were  observed,  except  for brief  mild
headaches  in  a  few patients,  and  there  were no  abnormalities  in
haematological studies or in hepatic and renal function tests.

    In  studies by Cervoni  et al. (1969),  single doses of  dichlorvos
(PVC-resin  formulations) were administered orally 2 h before breakfast
to 705 adults found to be harbouring infections of  Trichuris, hookworm,
or  Ascaris.   Six  or  12 mg  dichlorvos/kg  body  weight  resulted  in
infection  cure  rates of  approximately  70 - 100%.  According  to the
authors,  minimum to modest plasma  ChE depression and zero  to minimum
erythrocyte ChE depression occurred at both dose levels.   No  clinical
symptoms  or alterations in haematology or in liver and kidney function
were observed.

    Sick adults and children and healthy pregnant women and  babies  in
hospital  wards  treated with  dichlorvos strips (one  strip per 30  or
40 m3)    had normal erythrocyte ChE activities.  Only subjects exposed
for  24 h per  day to  dichlorvos concentrations  above 0.1 mg/m3    or
patients  with liver insufficiency showed  even a moderate decrease  in
plasma  ChE activity (Cavagna et  al., 1969, 1970; Cavagna  & Vigliani,
1970).

9.2.  Occupational Exposure

9.2.1.  Acute toxicity

9.2.1.1  Poisoning incidents

    A number of fatal and non-fatal poisoning cases have been described
after  concentrated formulations of  dichlorvos splashed onto  parts of
the  body.   Two  workers who  failed  to  wash it  off  promptly  died
consequently.  However, in those cases  where the spilled solution  was
washed off immediately, the victims showed symptoms of intoxication but
recovered after treatment.  A serious non-fatal case occurred  after  a
spillage  of  120  ml  of  a 3%  formulation  that was  not  washed off
immediately.  After 1´ h, the victim developed slurred  speech,  became
drowsy, and collapsed.  He recovered completely after treatment (Hayes,
1963, 1982).

    A pest-control operator became contaminated with a 1%  solution  of
dichlorvos  in mineral spirit after  using a leaking knapsack  sprayer.
The  man changed his overalls and completed his day's work.  He noticed
weakness,  dizziness, and difficulty in  breathing.  Contact dermatitis
developed  on  the  back skin.  After the fourth day, his blood ChE was
36%  of  normal,  but there  were  no  signs of  systemic  illness.  He
recovered  without medication, and the ChE activity increased to 72% of
normal within one month.  The acute dermatitis was probably  caused  by
the solvent (Bisby & Simpson, 1975).

    A  driver of a  truck transporting a  5% commercial formulation  of
dichlorvos   (15%   petroleum   distillate  and   80%  trichloroethane)
developed   persistent  contact  dermatitis  for   2  months  following
accidental   skin  contact.   In  addition,   the  patient  experienced
headache, mild rhinorrhoea, burning of the tongue, and a  bitter  taste
in  his  mouth.   Initial blood ChE levels were in the low normal range
returning to the high normal range within 2 weeks.  Patch tests with 1%
and  0.1% dichlorvos in  petroleum distillate were  negative  (Mathias,
1983).  In view of the symptoms and the slight ChE inhibition, it seems
likely that trichloroethane caused the dermatitis.

    Cronce  &  Alden  (1968) described  four  people  who handled  dogs
wearing  anti-flea  dog  collars containing  9 - 10% dichlorvos.  Acute
primary  contact  dermatitis was  described.   Closed patch  tests with
0.25, 0.5, and 1% dichlorvos in distilled water and in mineral oil were
positive  in  all  four people.  General  experience  with the  collars
indicates  that  only  a few  people  are  susceptible to  this kind of
irritation (Hayes, 1982).

9.2.2.  Effects of short- and long-term exposure

9.2.2.1  Pesticide operators and factory workers

    The effect on sprayers of dichlorvos fume, used inside  a  building
for  cockroach control, was  examined.  When 0.3 - 0.6%  dichlorvos oil
spray  was used at the rate of 6 ml/m2 by  the sprayers (7 - 9 people),
inhibition  of ChE activity in  the subjects was 15%,  and conjunctival
injections  or sore throats were observed in some sprayers after either

18  min or 4 h of spraying operation. To examine the effect of elevated
dichlorvos  vapour pressure at  higher temperatures, four  men  sprayed
0.6%  oil  spray  for 2  h  at  the room  temperature  of  25 °C.   The
inhibition  of plasma and  erythrocyte ChE activities  was 22% and  7%,
respectively.   In another study, 11  sprayers used 0.6% oil  spray for
6 h of actual work time at 20 °C without rest.  Two of them  showed  an
inhibition  of plasma ChE activity of 38% while the others did not show
significant  inhibition  of erythrocyte  ChE.   It was  concluded  that
conjunctival  injections  and sore  throats  were attributable  to  the
kerosene solvent used and that the 38% depression in ChE  activity  was
probably  due to long hours of continuous work.  Therefore, the overall
effect  on  ChE  activity was not considered to be severe (Ueda et al.,
1959, 1960).

    Twelve  fogging machine  operators did  not show  any reduction  in
plasma or erythrocyte ChE activity when applying 4% dichlorvos aerosols
in  tobacco warehouses for 16 h per week, over a period of 2 - 4 months
(Witter, 1960).

    Sixteen  men replacing old dichlorvos dispensers and installing new
units  in houses  in Haiti,  5 days  per week  for 3  weeks,  showed  a
decrease  of up to 60% in plasma ChE activity.  No signs or symptoms of
intoxication  were  observed.  Air  concentrations  ranged from  0.3 to
2.1 mg/m3 (Stein et al., 1966).

    The blood ChE activity of sprayers, exposed during  insect  control
in  grain stores to  air concentrations of  1.9 - 3 mg/m3   dichlorvos,
was reduced to 19 - 23% (Sasinovich, 1970).

    In  a  report by  Das et al.  (1983), each of  13 pesticide-control
operators  carried out urban  pest-control for one  day in four  houses
using  230 - 330 g dichlorvos as  aerosol and 40 - 50 g  dichlorvos  as
emulsion  spray.  At the  end of the  day's work, an  operator  had  an
average dichlorvos residue of 0.8 mg/m2 on  the back, 0.4 mg/m2 on  the
chest,  and 11 mg/m2 on  the respirator  filter.  Dimethylphosphate was
detected  in the urine, but  blood and urine analyses,  including serum
ChE levels, did not reveal any other changes in clinical parameters.

    In  the  course  of  either  the  production  or  processing  of  a
dichlorvos-releasing product, 11 male and 2 female factory workers were
exposed to an average dichlorvos concentration of 0.7 mg/m3    (highest
value  3 mg/m3)    on  each working  day  for  a period  of  8  months.
Inhibition  of  plasma  ChE activity was noted within a few days of the
start  of  exposure,  while  inhibition  of  erythrocyte  ChE  activity
developed much more slowly.  The maximum plasma ChE activities recorded
were  40% lower than  the pre-exposure levels,  but 60% lower  than the
post-exposure   levels.   Erythrocyte  ChE  activity   was  reduced  by
approximately  35% compared with  pre- and post-exposure  levels.   One
month  after  exposure  had ceased,  plasma  ChE  and  erythrocyte  ChE
activities  were found to have returned to normal physiological levels.
The  other haematological investigations  and the medical  examinations
did not reveal any changes attributable to dichlorvos exposure (Menz et
al., 1974).

9.2.2.2  Mixed exposure

    A  number  of  articles  have  described  the  symptoms  found   in
individual workers or groups of workers exposed for a number  of  years
to  different types of pesticides, including dichlorvos.  In general, a
slight-to-moderate  decrease  in  ChE activity  occurred.  Furthermore,
several  complaints and symptoms  were noticed, but  no clear  clinical
poisoning cases occurred.  These case studies are, however,  of  little
relevance  for  the  evaluation of  dichlorvos  because  of  the  mixed
exposure to different pesticides (Bellin & Chow, 1974; Fournier et al.,
1976;  Gupta et al., 1979;  Ullmann et al., 1979;  Hayes et al.,  1980;
Hayes, 1982).

    From  1975  to  1977, 88  patients  with  pesticide dermatitis,  15
suffering  from photo-dermatitis, were  studied. Patch tests  using  29
different  pesticides of different categories were carried out, but did
not lead to an identification of the responsible pesticides.  Eight out
of 52 patients (15.4%) reacted positively to a photopatch  (Horiuchi  &
Ando, 1978; Horiuchi et al., 1978).

    Stoermer (1985) described a case of contact dermatitis in  a  woman
who  had  worked  as a  pest controller  for 3  months and  had sprayed
dichlorvos  and propoxur.   She was  treated and  recovered within  one
week.

    A  field survey of tea growers was made in the Chiran area of Japan
in 1982.  Out of 84 tea growers examined (21 men and 63 women), 5 women
had  contact dermatitis from  agricultural work.  Dichlorvos  was among
the  insecticides, fungicides, and herbicides used.  Patch tests showed
relatively  high rates of  positive reactions with  dichlorvos (27%  of
women  and 5%  of men).   Also, cross-sensitization  was found  between
methidathion and dichlorvos (Fujita, 1985).

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

10.1.  Evaluation of Human Health Risks

    Since  1961, dichlorvos, an organophosphate with anti-ChE activity,
has been used worldwide as a contact and stomach insecticide to control
insects  on  crops  and domestic  animals.   It  is  also  used  as  an
insecticide  in houses and  other buildings and  for insect control  in
aircraft.

    Dichlorvos is readily absorbed by the body of mammals  through  all
routes  of exposure, and is  readily metabolized in the  liver.  Within
1 h  of oral administration, dichlorvos is found in the liver, kidneys,
and other organs of experimental animals.  It is rapidly eliminated via
the kidneys, with a half-life of 14 min.

    The  metabolism of dichlorvos  in various species,  including human
beings,  follows similar pathways.  Differences  between species relate
only to the  rate of metabolism, but this is always rapid.

    Dichlorvos  is moderately  to highly  toxic for  mammals (the  oral
LD50 for  the rat is 30 - 110 mg/kg body weight).   The  classification
of dichlorvos by WHO (1986a) is based on an oral LD50 for  the  rat  of
56  mg/kg body  weight.  Signs  of intoxication  usually occur  shortly
after  exposure  and  are  typical  of  an  organophosphorus pesticide.
Inhibition  of ChE activity is  a sensitive criterion of  exposure.  In
short-term  toxicity studies on mammals, it was shown that ChE activity
was  not  decreased  at oral  dose  levels  below about  0.5 mg/kg body
weight.   In long-term studies on rats at oral dose levels of 2.5 mg/kg
body weight or more, hepatocellular fatty vacuolization was  seen.   At
0.25 mg/kg body weight, no ChE inhibition was found, nor were there any
other effects.

    Reproduction  and teratogenicity studies using a wide range of dose
levels (6.25 - 500 mg/kg body weight) were negative.  Dichlorvos showed
alkylating properties in  in vitro but not in  in  vivo studies.  Many  in
 vitro mutagenicity studies with bacteria and yeast were positive, while
the  in   vivo studies  were  mainly   negative.   From  the   available
mutagenicity  studies,  it is  unlikely  that dichlorvos  constitutes a
mutagenic hazard for man.  Carcinogenicity studies on mice and rats fed
dichlorvos  (dose levels of up  to 234 mg/kg diet)  were negative.  Two
recent carcinogenicity studies have been carried out on mice  and  rats
in which dichlorvos was administered by intubation for up to 2 years at
dose levels of 10 - 40 mg/kg body weight (mice) and 4 or 8  mg/kg  body
weight  (rats).  Only preliminary  information has been  provided.  The
evidence  for carcinogenicity  in these  new studies  is  difficult  to
interpret  at this time.  Only  when complete and final  reports become
available  will it be  possible to draw  more definite conclusions  (in
this context, see section 8.7.3).

    From  work on  hens, the  suspicion of  delayed neurotoxicity  from
dichlorvos  has neither been established nor totally refuted.  However,
there have been two clinical reports on four patients suffering intense
poisoning  from dichlorvos taken orally who survived with treatment and
who  then  displayed  neurotoxic  effects.   Thus,  the  possibility of
delayed neurotoxicity in man cannot be entirely discounted, but  it  is
likely to occur only with excessive oral doses.

    Human  volunteers who were given single or repeated oral doses of 2
mg/kg  body weight or more showed significant inhibition of erythrocyte
ChE activity.  At 1 mg/kg body weight, no such inhibition was found.

    The  application of  dichlorvos to  crops and  animals  results  in
residues that rapidly disappear by volatilization and  hydrolysis.   In
general, residues of dichlorvos and the breakdown product DCA  in  food
commodities are low and will be further reduced during processing.  The
exposure  of the general population to dichlorvos by food and drinking-
water is negligible, as is confirmed in total-diet studies.

    In   short-term   inhalation  studies   on  mammals,  1   or  2  mg
dichlorvos/m3 did not inhibit ChE activity.

    In  a 2-year, 23 h/day,  whole-body inhalation study on  rats, 0.48
mg/m3 caused   inhibition of plasma and erythrocyte activity, but brain
AChE activity was not inhibited and there were no clinical  signs.   An
unquantified,  but  considerable,  extra exposure,  resulting  from the
grooming  of contaminated fur and  contamination of food and  drinking-
water,  had contributed to this effect.  The no-observed-adverse-effect
level was 0.05 mg/m3.  There was no evidence of carcinogenicity.

    In a 6- to 7-h exposure of human volunteers to  approximately  1 mg
dichlorvos/m3,     only  plasma  ChE   activity  was  inhibited.    The
erythrocyte  AChE activity,  taken to  be representative  of  the  AChE
activity in the nervous tissue, was unaffected.

    Residents exposed for over one year to an average air concentration
of  0.1 mg/m3 arising  from slow-release strips showed no inhibition of
plasma  or  erythrocyte  ChE activity  and  no  deleterious effects  on
health.

    The  main  exposure  of  the  general  population  is  by  inhaling
dichlorvos  when used indoors to  control insects. The recommended  use
(one slow-release strip/ 30 m3)   will give concentrations in  the  air
of  up to 0.1 - 0.3 mg/m3 in  the first few days, decreasing thereafter
to  below 0.1 mg/m3.    The  air concentration depends on  temperature,
humidity, and ventilation.

    As long as approved slow-release strips are used according  to  the
label instructions, no health hazard can be expected for man.  However,
special  care may need  to be taken  with young children  and  sick  or
elderly  people who are especially vulnerable when continuously exposed
(24  h per day)  in poorly ventilated  rooms.  Other methods  of indoor
application  should  be  equally safe  if  the  label instructions  are
followed.

    There  is some indication that dichlorvos may induce dermatitis and
cross-sensitization  in  people  handling various  types  of pesticides
including dichlorvos.

    In  occupational  conditions,  the  main  route  of   exposure   to
organophosphorus pesticides is usually the dermal route.  In  the  case
of dichlorvos, with its high vapour pressure, exposure by inhalation is
also  important.   In  these occupational  situations,  the  dichlorvos
concentrations in the air are generally below 1 mg/m3 but,  in  certain
circumstances,  they  may rise  considerably  above this  level.   This
stresses the need for adequate protective measures to be  taken  during
occupational exposure and regular monitoring of ChE activity.

10.2.  Evaluation of Effects on the Environment

    The  presence  of  dichlorvos in  the  environment  as a  result of
accidental  losses or direct application  on soil or in  water will not
lead   to  long-term  effects  because   of  its  fast  breakdown   and
evaporation.   Furthermore, it is converted  to a number of  compounds,
such  as  dichloroacetic  acid, by  microorganisms.   Certain  bacteria
species can use dichlorvos as a sole carbon source, while others cannot
and  are  inhibited  in their  growth.   Therefore,  its  influence  on
microorganisms is complex.

    Dichlorvos is moderately to highly toxic (range, 0.2 - 10 mg/litre)
for  freshwater and estuarine  species of fish  and invertebrates.   In
certain  fish, concentrations of 0.25 -  1.25 mg/litre cause inhibition
of  brain  and  liver ChE  activity.   Concentrations  of as  little as
0.05 mg/litre   may   have   deleterious   effects,   particularly   in
invertebrates.   Dichlorvos has  a high  toxicity for  birds and  bees.
Caution  is advised in the  use and handling of  dichlorvos where these
species might be exposed.

    No   bioaccumulation   occurs   in  the   different   environmental
compartments and organisms.

10.3.  Conclusions

1.  Exposure  of the  general population  to dichlorvos  via  food  and
drinking-water is negligible and does not constitute a health hazard.

2.  The  in-house use of  dichlorvos as an  insecticide in the  form of
sprays   or  slow-release  strips  (at  recommended  levels)  does  not
constitute  a short- or  long-term hazard for  the general  population.
However,  continuous  (24 h  per day)  exposure  of young children  and
diseased or elderly people in non-ventilated or poorly ventilated rooms
should be avoided.

3.  In  spite of their toxicity, dichlorvos and its formulations do not
contribute  an undue hazard  to those occupationally  exposed, provided
that adequate ventilation and skin protection are used.

4.  Except under conditions of gross spillage, the recommended  use  of
dichlorvos  as an insecticide does not constitute an acute or long-term
hazard for aquatic or terrestrial organisms, although there may  be  an
acute hazard for birds and bees.

11.  RECOMMENDATIONS

1.  Continuous  (24 h/day) exposure of  young children and diseased  or
elderly  people to dichlorvos  in non-ventilated or  poorly  ventilated
rooms should be avoided.

2.  As dichlorvos from different sources may vary in purity and type of
impurities, attention should be paid to its composition.   This  should
conform  to FAO and WHO specifications (FAO, 1977;  WHO, 1985).  In the
case  of formulations, potential hazards  of other components, such  as
solvents and stabilizers, should also be considered.

12.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    Dichlorvos  was evaluated by the Joint FAO/WHO Meeting on Pesticide
Residues  (JMPR)  in  1965, 1966,  1967,  1969,  1970, 1974,  and  1977
(FAO/WHO,   1965a,b,  1967a,b,  1968a,b,  1970a,b,   1971a,b,  1975a,b,
1978a,b).   In 1966, the  JMPR established an  Acceptable Daily  Intake
(ADI)  for human beings of  0 - 0.004 mg/kg body weight, which  remains
unchanged.

    The  Pesticide Development and  Safe Use Unit,  Division of  Vector
Biology  and  Control,  WHO,  has  classified  technical  dichlorvos as
"highly  hazardous" (Class IB)   (Plestina, 1984; WHO,  1986a) and  has
produced a safety sheet on dichlorvos (No.  75.2) (WHO/FAO, 1975-86).

    Specifications  for dichlorvos use  in public health  and in  plant
protection   have   been  published  by  WHO  (1985)  and  FAO  (1977),
respectively.

    In  1979, the International  Agency for Research  on Cancer  (IARC)
came to the following conclusions in considering the carcinogenicity of
dichlorvos:

    (a)  dichlorvos   was  tested  in  different   animal  species  via
         different  routes; no conclusive  evaluation on the  basis  of
         these studies could be made;

    (b   dichlorvos is an alkylating agent and binds to  bacterial  and
         mammalian nucleic acids;

    (c)  it is a mutagen in a number of microbial systems, but there is
         no  evidence of its  mutagenicity in mammals,  in which it  is
         rapidly degraded.

    In the evaluation by IARC, it was stated that "the  available  data
do not allow an evaluation of the carcinogenicity of dichlorvos  to  be
made".

    In  its series "Scientific Reviews of Soviet Literature on Toxicity
and  Hazards of Chemicals",  the International Register  of Potentially
Toxic Chemicals has published a volume on dichlorvos (IRPTC, 1984).

REFERENCES

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    See Also:
       Toxicological Abbreviations
       Dichlorvos (HSG 18, 1988)
       Dichlorvos (ICSC)
       Dichlorvos (PDS)
       Dichlorvos (FAO Meeting Report PL/1965/10/1)
       Dichlorvos (FAO/PL:CP/15)
       Dichlorvos (FAO/PL:1967/M/11/1)
       Dichlorvos (FAO/PL:1969/M/17/1)
       Dichlorvos (AGP:1970/M/12/1)
       Dichlorvos (WHO Pesticide Residues Series 4)
       Dichlorvos (Pesticide residues in food: 1977 evaluations)
       Dichlorvos (Pesticide residues in food: 1993 evaluations Part II Toxicology)
       Dichlorvos (IARC Summary & Evaluation, Volume 53, 1991)