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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY


    ENVIRONMENTAL HEALTH CRITERIA 64





    CARBAMATE PESTICIDES: A GENERAL INTRODUCTION







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

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

    World Health Orgnization
    Geneva, 1986


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        ISBN 92 4 154264 0  

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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR CARBAMATE PESTICIDES:  A GENERAL
INTRODUCTION

1. SUMMARY AND RECOMMENDATIONS

    1.1. Summary
         1.1.1. General
         1.1.2. Properties, uses, and analytical methods
         1.1.3. Sources, environmental transport and distribution
         1.1.4. Environmental levels and exposures
         1.1.5. Effects on organisms in the environment
         1.1.6. Kinetics and metabolism
         1.1.7. Mechanism of toxicity
         1.1.8. Effects on experimental animals and  in vitro 
                test systems
         1.1.9. Mutagenicity and related end-points
         1.1.10. Carcinogenicity
         1.1.11. Effects on man
         1.1.12. Previous evaluations by international bodies
    1.2. Recommendations

2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

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

3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1. Natural occurrence
    3.2. Man-made sources
         3.2.1. Production levels, processes, and uses

4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    4.1. Transport and distribution between media
         4.1.1. Air
         4.1.2. Water
         4.1.3. Soil
         4.1.4. Vegetation and wildlife
         4.1.5. Entry into the food chain
    4.2. Biotransformation
         4.2.1. Microbial degradation
         4.2.2. Photodegradation
         4.2.3. Photodecomposition in the aquatic environment

5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1. Exposure of the general population
         5.1.1. Food and drinking-water

6. METABOLISM AND MODE OF ACTION

    6.1. Mode of action
         6.1.1. Neuropathy target esterase

    6.2. Metabolism
         6.2.1. Absorption
         6.2.2. Distribution
         6.2.3. Metabolic transformation
                6.2.3.1  Biotransformation mechanisms
                6.2.3.2  Oxidation
                6.2.3.3  Hydrolysis
                6.3.2.4  Conjugation
                6.2.3.5  Examples of biotransformation
                         of carbamates
    6.3. Elimination and excretion in expired air, faeces, and 
         urine 
         6.3.1. Man
         6.3.2. Laboratory animals
    6.4. Metabolism in plants

7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT

    7.1. Microorganisms
    7.2. Aquatic Organisms
         7.2.1. Field studies
    7.3. Terrestrial Organisms
         7.3.1. Effects on soil fauna
         7.3.2. Wildlife
         7.3.3. Bees
    7.4. Earthworm and mite populations

8. EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

    8.1. Single exposures
         8.1.1. Oral
         8.1.2. Dermal
         8.1.3. Inhalation
    8.2. Short- and long-term exposures
         8.2.1. Oral
                8.2.1.1  Further information on short-
                         and long-term toxicity
         8.2.2. Dermal
    8.3. Skin and eye irritation; sensitization
         8.3.1. Skin irritation
         8.3.2. Eye irritation
         8.3.3. Skin sensitization
    8.4. Inhalation
    8.5. Reproduction, embryotoxicity, and teratogenicity
         8.5.1. Reproduction
         8.5.2. Endocrine system
         8.5.3. Embryotoxicity and teratogenicity
    8.6. Mutagenicity and related end-points
    8.7. Carcinogenicity
         8.7.1. General
    8.8. Special studies

9. EFFECTS ON MAN

    9.1. General population exposure
         9.1.1. Acute toxicity: poisoning incidents

         9.1.2. Effects of short- and long-term exposure
         9.1.3. Controlled human studies
    9.2. Occupational exposure
         9.2.1. Acute toxicity: poisoning incidents
         9.2.2. Effects of short- and long-term exposure
         9.2.3. Epidemiological studies
    9.3. Signs and symptoms of acute intoxication by carbamates
         9.3.1. Biochemical methods for measurement of effects
    9.4. Treatment of acute poisoning by carbamate insecticides
         9.4.1. Minimizing the absorption
         9.4.2. General supportive treatment
         9.4.3. Specific pharmacological treatment
                9.4.3.1  Atropine
                9.4.3.2  Oxime reactivators
                9.4.3.3  Diazepam

10. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

REFERENCES

ANNEX I    NAMES AND STRUCTURES AND SOME PHYSICAL AND CHEMICAL 
           PROPERTIES OF CARBAMATE PESTICIDES 

ANNEX II   SUMMARY OF THE SHORT- AND LONG-TERM TOXICITY STUDIES 
           THAT WERE USED TO ESTABLISH THE ACCEPTABLE DAILY INTAKES 
           FOR HUMAN BEINGS FOR CARBAMATE COMPOUNDS 

ANNEX III  CARBAMATES: JMPR REVIEWS, ACCEPTABLE DAILY INTAKES, 
           EVALUATION BY IARC, CLASSIFICATION BY HAZARD, FAO/WHO 
           DATA SHEETS, IRPTC DATA PROFILE AND LEGAL FILE 

ANNEX IV   ABBREVIATIONS

WHO TASK GROUP ON CARBAMATE PESTICIDES

 Members

Dr D. Ecobichon, Department of Pharmacology and Therapeutics,
   McGill University, Montreal, Quebec, Canada

Dr A.H. El-Sebae, Department of Pesticide Chemistry, Faculty
   of Agriculture, University of Alexandria, Alexandria, Egypt

Dr L. Ivanova-Chemishanska, Institute of Hygiene and Occupational 
   Health, Medical Academy, Sofia, Bulgaria  (Vice-Chairman)

Dr M.K. Johnson, Toxicology Unit, Medical Research Council
   Laboratories, Carshalton, Surrey, United Kingdom

Dr S.K. Kashyap, National Institute of Occupational Health,
   Ahmedabad, India

Dr M. Lotti, Institute of Occupational Health, Padua, Italy

Dr L. Martson, All-Union Scientific Research Institute of the
   Hygiene and Toxicology of Pesticides, Polymers, and
   Plastics (VNIIGINTOX), Kiev, USSRa

Dr U.G. Oleru, College of Medicine, University of Lagos,
   Lagos, Nigeria.

Dr W.O. Phoon, Department of Social Medicine and Public
    Health, National University of Singapore, Outram Hill,
    Republic of Singapore  (Chairman)

Dr A.F. Rahde, Ministry of Public Health, Porto Alegre, Brazil

Dr E. Reiner, Institute for Medical Research and Occupational
   Health, Zagreb, Yugoslavia

Dr J. Sekizawa, National Institute of Hygienic Sciences,
   Tokyo, Japan

 Observers

Mr R.J. Lacoste, International Group of National Associations
   of Pesticide Manufacturers (GIFAP), Brussels, Belgium

 Secretariat

Mrs B. Bender, United Nations Environment Programme,
    International Register of Potentially Toxic Chemicals,
    Geneva, Switzerland

Dr J.R.P. Cabral, Unit of Mechanisms of Carcinogenesis,
   International Agency for Research on Cancer, Lyons, France

---------------------------------------------------------------------------
a Invited, but unable to attend.

 Secretariat (contd.)

Dr K.W. Jager, International Programme on Chemical Safety,
   World Health Organization, Geneva, Switzerland  (Secretary)

Dr G.J. Van Esch, Bilthoven, The Netherlands  (Temporary
    Adviser) (Rapporteur)

Dr C. Xintaras, Office of Occupational Health, World Health
   Organization, Geneva, Switzerland

NOTE TO READERS OF THE CRITERIA DOCUMENTS

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


                        *    *    *


    Detailed data profiles and legal files for most of the 
carbamate pesticides 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 CARBAMATE PESTICIDES

    A WHO Task Group on Environmental Health Criteria for Carbamate 
Pesticides met in Geneva from 30 September to 4 October 1985.  Dr 
K.W. Jager opened the meeting on behalf of the Director-General.  
The Task Group reviewed and finalized the draft criteria document. 

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


                          * * *


    Partial financial support for the publication of this criteria 
document was kindly provided by the United States Department of 
Health and Human Services, through a contract from the National 
Institute of Environmental Health Sciences, Research Triangle Park, 
North Carolina, USA - a WHO 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.  Summary

1.1.1.  General

    The carbamates discussed in this publication are those mainly 
used in agriculture, as insecticides, fungicides, herbicides, 
nematocides, or sprout inhibitors.  In addition, they are used as 
biocides for industrial or other applications and in household 
products.  A potential use is in public health vector control.  
Thus, these chemicals are part of the large group of synthetic 
pesticides that have been developed, produced, and used on a large 
scale in the last 40 years. 

    The general formula of the carbamates is:

                         O 
                         ||
                  R1NH - C - OR2

where R1 and R2 are alkyl or aryl groups.

    More than 50 carbamates are known, and it is clear that it is 
not within the scope of this introduction to include all the 
information about each compound.  However, all the different 
aspects of the different classes of carbamates are touched on, 
making use of available publications and reports of studies and 
using well known carbamates, such as carbaryl, benomyl, and a few 
others, as examples. 

    Thiocarbamates and dithiocarbamates have not been included, 
because these groups of compounds have a different mode of action 
and will be dealt with in a separate publication. 

1.1.2.  Properties, uses, and analytical methods

    Three classes of carbamate pesticides are known.  The carbamate 
ester derivatives, used as insecticides (and nematocides), are 
generally stable and have a low vapour pressure and low water 
solubility.  The carbamate herbicides (and sprout inhibitors) have 
the general structure R1NHC(O)OR2, in which R1 and R2 are aromatic 
and/or aliphatic moieties.  Carbamate fungicides contain a 
benzimidazole group. 

    The only physical or chemical properties given in this 
publication are the relative molecular mass, vapour pressure, and 
water solubility. 

    Analytical methods for a number of important carbamates have 
been tabulated. 

1.1.3.  Sources, environmental transport and distribution

    The synthesis and commercialization of the carbamate pesticides 
has been in progress since the 1950s.  The benzimidazole fungicides 
were introduced on the market in about 1970. 

    In general, the vapour pressure of the carbamates is low; 
nevertheless, they will evaporate or sublimate slowly at normal 
temperature, which may lead to volatilization of carbamates from 
water and soil.  However, distribution via air will be a minor 
factor.  The aqueous environment will be an important route of 
transport for highly-soluble carbamates. The light absorption 
characteristics of carbamates contribute to their rapid 
decomposition (by photodegradation or photodecomposition) under 
aqueous conditions.  Thus, the hazards of long-term contamination 
with carbamates seem small.  Carbamate insecticides are mainly 
applied on the plants, and can reach the soil, while carbamate 
nematocides and herbicides are applied directly to the soil.  
Several factors influence the biodegradation of carbamates in soil, 
such as volatility, soil type, soil moisture, adsorption, pH, 
temperature, and photodecomposition.  Because the different 
carbamates have different properties, it is clear that each should 
be evaluated on its own merits, and no extrapolation of results can 
be made from one carbamate to another.  One carbamate may be easily 
decomposed, while another may be strongly adsorbed on soil.  Some 
leach out easily and may reach groundwater.  In these processes, 
the soil type and water solubility are of great importance.  
Furthermore, it should be recognized that this not only concerns 
the parent compound but also the breakdown products or metabolites. 

    Environmental conditions that favour the growth and activity of 
microorganisms also favour the degradation of carbamates.  The 
first step in the metabolic degradation of carbamates in soil is 
hydrolysis.  The hydrolysis products will be further metabolized in 
the soil-plant system. 

    Plants can metabolize carbamates in which arylhydroxylation and 
conjugation, or hydrolytic breakdown are the main routes of 
detoxification.  The results of a number of studies suggest that 
carbamates are exclusively distributed via the apoplastic system in 
plants. 

    Carbamates are metabolized by microorganisms, plants, and 
animals or broken down in water and soil. 

1.1.4.  Environmental levels and exposures

    From the available data, it appears that bioaccumulation in the 
different species and different food chains will only take place to 
a slight extent.  Certain carbamates may reach groundwater and as a 
consequence may find their way into drinking-water.  The few 
studies available indicate that exposure of the general population 
is low.  However, this should be confirmed by market-basket and/or 
total-diet studies. 

1.1.5.  Effects on organisms in the environment

    Soil microorganisms are capable of metabolizing (hydrolysing) 
carbamates and can easily adapt themselves to metabolize the 
different types of carbamates.  Nevertheless, carbamates and their 
metabolites can, at high dose levels, affect the microflora and 
cause changes that may be of importance in soil productivity.  

Although carbamates are not very stable under aquatic conditions, 
and will not persist long in this environment, some bioaccumulate 
in fish, mainly because the metabolism is slow in fish.  Other 
carbamates are metabolized rapidly and no accumulation occurs.  
Some carbamates are highly toxic for invertebrates and fish, others 
much less so.  In certain cases, the use of toxic carbamates may 
cause a significant reduction in non-target organisms. Carbamates 
are toxic for worms and other organisms living in the soil.  
Although a great reduction in the earthworm population may occur 
when applying carbamates to the soil, numbers will return to 
normal, because of the rather rapid breakdown of these compounds. 

    In general, the toxicity of carbamates for wildlife is low, but 
exceptions exist.  This means that, in order to judge the impact of 
carbamates on the organisms in the environment, the information on 
the individual carbamates should be referred to.  As a rule, birds 
are not very sensitive to carbamates while bees are extremely 
sensitive. 

1.1.6.  Kinetics and metabolism

    The metabolic fate of carbamates is basically the same in 
plants, insects, and mammals.  Carbamates are usually easily 
absorbed through the skin, mucous membranes, and respiratory and 
gastrointestinal tracts, but there are exceptions. Generally, the 
metabolites are less toxic than the parent compounds.  However, in 
certain cases, the metabolites are just as toxic or even more toxic 
than the parent carbamate. In most mammals, the metabolites are 
mainly excreted rather rapidly in the urine.  The dog seems to be 
different in this respect.  Accumulation takes place in certain 
cases, but is of minor importance because of the rapid metabolism. 

    The first step in the metabolism of carbamates is hydrolysis to 
carbamic acid, which decomposes to carbon dioxide (CO2) and the 
corresponding amine. 

    The mechanism of hydrolysis is different for  N -methyl and 
 N -dimethyl derivatives.  The  N -methyl carbamates pass through an 
isocyanate intermediate, whereas in the hydrolysis of  N -
dimethylcarbamates, an addition product with a hydroxyl ion is 
formed yielding the alcohol and  N -dimethyl substituted acid.  The 
rate of hydrolysis by esterases is faster in mammals than in plants 
and insects. 

    Apart from hydrolysis, oxidation also takes place including: 
hydroxylation of the aromatic ring,  O -dealkylation,  N -methyl 
hydroxylation,  N -dealkylation, oxidation of aliphatic side chains, 
and sulfoxidation to the corresponding sulfone. Oxidation is 
associated with the mixed-function oxidase (MFO) enzymes.  
Conjugation leads to the formation of  O - and  N -glucuronides, 
sulfates, and mercapturic acid derivatives in mammals.  Glycosides 
and phosphates are conjugation products more common in plants. 

    The metabolism of a number of carbamates is discussed in the 
text. 

    Little information is available on the distribution of 
carbamates in the various organs and tissues in mammals following 
exposure by inhalation or the oral route.  The organs in which 
residues have been reported are the liver, kidneys, brain, fat, and 
muscle.  The half-life in the rat is of the order of 3 - 8 h.  From 
the limited data available, it seems that the excretion of 
carbamates via urine is also rapid in man, and that the metabolic 
pathways in man are the same as those in the rat. 

1.1.7.  Mechanism of toxicity

    Carbamates are effective insecticides by virtue of their 
ability to inhibit acetylcholinesterase (AChE) (EC 3.1.1.7) in the 
nervous system.  They can also inhibit other esterases. 

    The carbamylation of the enzyme is unstable, and the 
regeneration of AChE is relatively rapid compared with that from a 
phosphorylated enzyme.  Thus, carbamate pesticides are less 
dangerous with regard to human exposure than organophosphorus 
pesticides.  The ratio between the dose required to produce death 
and the dose required to produce minimum symptoms of poisoning is 
substantially larger for carbamate compounds than for 
organophosphorus compounds. 

    Because of their chemical structure, carbamates do not cause 
delayed neuropathy. 

1.1.8.  Effects on experimental animals and  in vitro test systems

    The acute toxicity of the different carbamates ranges from 
highly toxic to only slightly toxic or practically non-toxic. The 
LD50 for the rat ranges from less than 1 mg/kg to over 5000 mg/kg 
body weight.  For certain methyl carbamates, the LD50 is 20 or more 
times the corresponding ED50.  This means that, in general, an 
early indication of poisoning can be obtained before a lethal dose 
is absorbed. 

    A dose-effect relationship exists between the dose, the 
severity of symptoms, and the degree of cholinesterase (ChE) 
inhibition.  Because most carbamates have a low volatility, 
inhalation studies are mainly carried out using a dust or mist.  In 
these studies, the toxicity is highly dependent on the size of the 
particles or droplets and, therefore, difficult to evaluate. 

    The acute dermal toxicity of carbamates is generally low to 
moderate; an exception is aldicarb, which is highly toxic. It 
should be noted that data are available for only a limited number 
of substances. 

    Carbamates produce slight to moderate skin and eye irritation, 
depending on the vehicle used, duration of contact, and on whether 
the substance is applied to the abraided or intact skin.  From the 
available data, it cannot be excluded that some of the carbamates 
will have a slight to moderate sensitization potential. 

    Short- and long-term toxicity studies have been carried out.  
Some carbamates are very toxic and others are less toxic in long-
term studies.  From these studies, it is evident that, apart from 
the anticholinesterase activity, the following changes can be 
found: an influence on the haemopoietic system, an influence on the 
functioning of, and, at higher dosages, degeneration of, the liver 
and kidneys, and degeneration of testes.  These abnormalities in 
the different organ systems depend on the animal strain and on the 
chemical structure of the carbamate.  A clear influence on the 
nervous system, functional as well as histological, was found, 
particularly in non-laboratory animals such as pigs. 

    For many years, long-term toxicity data on carbamates have been 
evaluated by the FAO/WHO Joint Meeting on Pesticide Residues 
(JMPR), and a number of ADIs for carbamates have been established.  
In Annex II and III, the no-observed-adverse-effect levels and the 
ADIs are summarized. 

    A considerable number of reproduction and teratogenicity 
studies have been carried out with different carbamates and various 
animal species.  Different types of abnormalities were found, i.e., 
increase in mortality, disturbance of the endocrine system, and 
effects on the hypophysis and its gonadotrophic function.  These 
effects were mainly seen at high dose levels.  Generally, the fetal 
effects included an increase in mortality, decreased weight gain in 
the first weeks after birth, and induction of early embryonic 
death. All these effects can be summarized as embryotoxic effects. 
Certain carbamates also induce teratogenic effects, mainly at high 
dose levels applied by stomach tube.  When the same dose level was 
administered with the diet, no effects were seen. 

1.1.9.  Mutagenicity and related end-points

    The well-known carbamates have been tested for their mutagenic 
activity in different test systems.  Some induce mutagenic effects, 
others are negative.  In general, the methyl carbamates are 
negative in mammalian tests, while compounds such as carbendazim, 
benomyl, and the 2 thiophanate derivatives showed a positive effect 
with very high dose levels in certain systems.  The benzimidazole 
moiety may act as a base analogue for DNA and as a spindle poison.  
They are antimitotic agents and cause mitotic arrest, mitotic 
delay, and a low incidence of chromosome damage.  Sometimes, the 
results are contradictory or cannot be reproduced, but positive 
results for point mutation and chromosome aberrations are well 
documented.  These benzimidazole derivatives can be considered as 
weak mutagenic compounds. 

1.1.10.  Carcinogenicity

    Ethyl carbamate (urethane) is a well-known carcinogen, and it 
seems that its chemical structure is optimal for such an effect.  
Any change in the molecule seems to decrease the carcinogenic 
potency, particularly when the ethyl group is replaced by larger 
side chains.  Alkyl groups on the nitrogen also reduce this 
activity. 

    However, no clear indications of carcinogenic effects have been 
found in the available long-term carcinogenicity studies with 
different carbamates. 

    The carcinogenicity studies with benzimidazole derivatives 
showed either positive or equivocal results.  Added to the fact 
that certain mutagenicity studies also give positive results, it 
cannot be excluded that these compounds may have carcinogenic or 
promotor properties.  It should be kept in mind that the dose 
levels in most tests were of the order of 50 and 500 mg/kg body 
weight. 

    Carbamate pesticides may be converted to  N -nitroso compounds.  
This was demonstrated in a great number of  in vivo nitrosation 
studies in which high levels of the carbamates were administered to 
animals in combination with high levels of nitrite.  These  N -
nitroso compounds have to be considered as mutagenic and 
carcinogenic.  However, the amount of nitroso compounds that can be 
expected to result from dietary intake of carbamate pesticide 
residues is negligible in comparison with nitroso-precursors that 
occur naturally in food and drinking-water. 

1.1.11.  Effects on man

    Health hazards for man occur mainly from occupational over-
exposure to carbamate insecticides resulting in poisoning 
characterized by cholinergic symptoms caused by inhibition of the 
enzyme AChE.  Various cases of intoxication have been described.  
Most of them were spraymen applying insecticides inside houses in 
the tropics to control mosquito vectors of malaria, or plant 
protection workers.  The main routes of exposure are inhalation and 
skin. 

    From controlled human studies, it is clear that poisoning 
symptoms can be seen a few minutes after exposure, and can last for 
a few hours.  Thereafter, recovery starts and within hours, the 
symptoms disappear, and the ChE activity in erythrocytes and plasma 
returns to normal, because the carbamate is rather rapidly 
metabolized and the metabolites excreted.  The appearance of these 
metabolites in the urine may be used for biological monitoring.  
Apart from the symptoms indicative of ChE poisoning, other signs 
and symptoms induced by certain carbamates have been described, 
such as skin and eye irritation, hyperpigmentation, and influence 
on the function of testes (slight increase of sperm abnormalities).  
These signs and symptoms were found in a few studies and should be 
confirmed before it can be stated that they were induced by 
carbamates.  Epidemiological studies with persons primarily exposed 
to carbamates are not available. 

1.1.12.  Previous evaluations by international bodies

    Previous evaluations of individual carbamates by the Joint 
FAO/WHO Meeting on Pesticide Residues (JMPR) and the International 
Agency for Research on Cancer (IARC) are summarized in Annex III.  
The WHO recommended classification of pesticides by hazard is 
included, and the availability is indicated of WHO/FAO Data Sheets 
and the IRPTC data profile and legal file on the substance. 

1.2.  Recommendations

1.  More up-to-date information is necessary on the world-wide 
production and uses of the different carbamates. 

2.  Except for the well-known carbamates, such as carbaryl, 
benomyl, and carbendazim, more information is required on 
environmental pathways, concentrations, and distribution. 

3.  More information is necessary on the occurrence and fate of the 
carbamates in surface water, soil, and groundwater, and their 
impact on plants, invertebrates, and mammals. 

4.  Further studies are necessary on the occurrence of carbamates 
in the different food chains (bioaccumulation), and in food and 
drinking-water (market-basket or total-diet studies), in order to 
estimate the daily exposure of the human population. 

5.  More information is needed, for certain carbamates, on the 
acute and long-term toxicity in aquatic and terrestrial organisms. 

6.  In general, data on the mode of action and metabolism are 
available; however, more knowledge is needed on the distribution of 
the carbamates in organs and tissues in mammals. 

7.  For many carbamates, information concerning long-term toxicity, 
mutagenicity, carcinogenicity, reproduction, and teratogenicity is 
still needed.  This is the reason why acceptable daily intakes have 
not been established for two-thirds of the carbamates. 

8.  Apart from a number of studies on human volunteers and a number 
of accidents with well-known carbamates, information on the effects 
of human exposure to carbamates is missing.  There are no 
epidemiological studies.  More information should be collected to 
evaluate the health risk in cases of human exposure to carbamates.  
In particular, more information is needed to elucidate the 
mechanisms of the effects of benzimidazole carbamates on the 
testes. 

9.  More data are needed on the use of oximes in the therapy of 
poisoning, especially in light of the fact that there are 
unconfirmed reports that oximes might potentiate carbamate 
toxicity. 

10.  Further work should be done to develop more adequate 
analytical methods (i.e., faster procedures and simpler equipment) 
to determine carbamate residues in biological material (urine, 
blood, and food). 

11.  Information is required concerning the changes in toxicity due 
to impurities that can arise in pesticides as a consequence of 
different manufacturing processes, formulating practices, and 
improper storage. 

12.  Users should be encouraged to be aware of the necessity to 
establish safe re-entry periods according to local conditions. 

    Recommendations for further work have also been described in 
previous monographs on carbamates published in the WHO Pesticide 
Residues Series and in the FAO Plant Production and Protection 
Papers, as a result of the Joint FAO/WHO Meetings on Pesticide 
Residues (JMPR). 

2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

2.1  Identity

    Carbamates are  N -substituted esters of carbamic acid. Their 
general formula is: 

                           O
                           ||
                    R1NH - C - OR2

where R2 is an aromatic or aliphatic moiety.  Three main classes of 
carbamate pesticides are known: 

    (a)  carbamate insecticides; R1 is a methyl group;

    (b)  carbamate herbicides; R1 is an aromatic moiety; and

    (c)  carbamate fungicides; R1 is a benzimidazole moiety.

2.2  Physical and Chemical Properties

    In general, simple esters or  N -substituted derivatives of 
carbamic acid are unstable compounds, especially under alkaline 
conditions.  Decomposition takes place, and the parent alcohol, 
phenol, ammonia, amine, and carbon dioxide are formed. 

    The salts and esters of substituted carbamic acid are more 
stable than carbamic acid.  This enhanced stability is the basis 
for the synthesis of many derivatives that are biologically active 
pesticides. 

    Carbamate ester derivatives are crystalline solids of low 
vapour pressure with variable, but usually low, water solubility.  
They are moderately soluble in solvents such as benzene, toluene, 
xylene, chloroform, dichloromethane, and 1,2-dichloroethane.  In 
general, they are poorly soluble in nonpolar organic solvents such 
as petroleum hydrocarbons but highly soluble in polar organic 
solvents such as methanol, ethanol, acetone, dimethylformamide, 
etc. 

    The carbamate derivatives with herbicidal action (such as 
pyrolan and dimetilan) are substantially more stable to alkaline 
hydrolysis than the methyl carbamate derivatives (carbaryl and 
propoxur), which have an insecticidal action.  For example, the 
half-life of carbaryl is 15 min at pH 10 compared with 10 days at 
pH 7.  However, pyrolan and dimetilan do not hydrolyse in the pH 
range of 4 - 10 (Aly & El Dib, 1972). Instability with alkali is of 
use for decontamination and clean-up.  Vassilieff & Ecobichon 
(1982) showed that, in acid fresh water, which is characteristic of 
the lakes and streams in heavily forested Canada, aminocarb would 
be rather stable and would persist long enough to be bioaccumulated 
by various trophic levels of food chains. 

    The carbamate fungicides carbendazim, benomyl, and thiophanates 
are related.  Carbendazim and benomyl are derivatives of 

benzimidazole.  Carbendazim is slowly hydrolysed by alkali to 2-
aminobenzimidazole, but it is stable as acid-forming water-soluble 
salts (Sypesteijn et al., 1977).  Benomyl breaks down to methyl 2-
benzimidazole carbamate (MBC) in water. Benomyl is rather unstable 
in common solvents (White et al., 1973; Chiba & Doornbos, 1974). 

    The names, chemical structure, and pesticidal activity of the 
principal carbamates are presented in Table 1, and the CAS number, 
chemical name, common names, molecular formula, relative molecular 
mass, and selected chemical and physical properties are summarized 
in Annex I.  It should be noted that it is not within the scope of 
this general introduction to describe all the physical and chemical 
properties of each pesticide in detail. 

2.3  Analytical Methods

    Analysis for pesticide residues consists of sampling the 
contaminated environmental material or matrix, extracting the 
pesticide residue, removing interfering substances from the 
extract, and identifying and quantifying the pesticide contaminant.  
The manner in which the matrix material is sampled, stored, and 
handled can affect the results; samples should be truly 
representative, and their handling and storage must not further 
contaminate or degrade the contaminant to be measured.  Many 
detection methods are available, and the one chosen depends on the 
physical and chemical properties of the contaminant as well as on 
the equipment available. 

    A detailed review of all the analytical procedures to determine 
carbamates in the different matrices is beyond the scope of this 
document.  However, for better understanding of the validity of the 
data, a brief summary of some of the analytical procedures for 
different carbamates is included in Table 2. 

    Enzymatic methods to determine erythrocyte- and plasma-ChE 
activity are used as monitors of exposure and systemic absorption 
of organophosphorus compounds and carbamate pesticides. In the case 
of carbamates, the inhibition may not be easily detected because of 
the rapid reversibility of the carbamate-enzyme inhibition 
reaction. 

    Conditions and time of storage must be carefully controlled 
before measurement of activity.  Methods must be chosen that allow 
a short time for hydrolysis of the substrate (Ellman et al., 1961; 
Voss & Schuler, 1967; Wilhelm & Reiner, 1973; Wilhelm et al., 1973; 
Reiner et al., 1974; Abd-Elroaf et al., 1977; Izmirova, 1980). 

    A colorimetric screening method has been described, to estimate 
Unden(R), carbofuran, and carbaryl in the air of the manufacturing 
and formulating plants, as well as in washings from body surfaces, 
hands, and other contaminated surfaces (Izmirova, 1980; Izmirova & 
Izmirov, unpublished report, 1985)a. 

---------------------------------------------------------------------------
a   Pharmatest-cholinesterase reactive papers for determination 
     of cholinesterase activity (ChEA) of serum or plasma.


Table 1.  Relationship of chemical structure and pesticidal activity of carbamates
---------------------------------------------------------------------------------------------------------
Pesticidal          Chemical structure        Common or other names
activity
---------------------------------------------------------------------------------------------------------
Insecticide                O                  aldoxycarb, allyxycarb, aminocarb, BPMC, bendiocarb,
                           ||                 bufencarb, butacarb, carbanolate, carbaryl, carbofuran,
                    CH3-NH-C-O-aryl           cloethocarb, dimetilan, dioxacarb, ethiofencarb, forme-
                                              tanate, hoppcide, isoprocarb, trimethacarb, MPMC,
                                              methiocarb, metolcarb, mexacarbate, pirimicarb,
                                              promacyl, promecarb, propoxur, MTMC, XMC, xylylcarb

                           O                  aldicarb, methomyl, oxamyl, thiofanox, thiodicarb
                           ||
                    CH3-NH-C-O- N-alkyl

Herbicide                   O                 asulam, barban, carbetamide, chlorbufam, desmedipham,
                            ||                phenmedipham, swep
                    aryl-NH-C-O-alkyl

                             O                dichlormate, karbutilate, terbucarb
                             ||
                    alkyl-NH-C-O-aryl

Herbicide                   O                 propham, chlorpropham
and sprout                  ||
inhibitors          aryl-NH-C-O-alkyl

Fungicide                   O                 benomyl, carbendazim, thiophanate-methyl,
                            ||                thiophanate-ethyl
                    aryl-NH-C-O-alkyl
---------------------------------------------------------------------------------------------------------

Table 2.  Analytical methods for carbamate pesticide residues
---------------------------------------------------------------------------------------------------------
Chemical     Sample type    Extraction and clean-up         Method of      Detectionb  Reference
                                                            detectiona    limit
---------------------------------------------------------------------------------------------------------
aldicarb     cotton seed,   acetone-water-peracetic acid    GLC/SFPD       0.01 mg/kg   Romine (1973)
             fruit/         extraction evaporation,
             vegetables     absorption on Florisil column,
                            elution with acetone-ether
                            

asulam       crops          acetone extraction, absorption  colorimetry    0.05 mg/kg   Brockelsby &
                            on Florisil column, elution,                                Muggleton (1973)
                            reaction with chromophore

benomyl      soils, fruit/  acidic methanol extraction and  HPLC/UV        0.05 mg/kg   Bleidner et al.
             vegetables,    ethyl acetate extraction,                                   (1978)
             tissues        conversion to carbendazim

             soils          acetone-ammonium chloride       UV                          Austin & Briggs
                            extraction and solvent                                      (1976)
                            partition

             soils, fruit/  review of methods including                    0.05 -       Baker & Hoodless
             vegetables,    those for carbendazim and                      3.0 mg/kg    (1974)
             tissues        thiophanate-methyl

carbendazim  water          reverse phase and adsorption    HPLC, variable              Austin et al.
                            systems                         wavelength                  (1976)
                                                            UV-detector

carbaryl     urine          acid hydrolysis, benzene        GLC/ECD        0.02         Shafik et al.
                            extraction, reaction with                      mg/litre     (1971)
                            chloroacetic anhydride,
                            absorption on silica gel column
                            and elution with benzene-hexane

carbaryl     plant tissue   extraction, hydrolysis, and     colorimetry    0.1 mg/kg    Stansbury &
                            reaction with chromophore                                   Miskus (1964)
---------------------------------------------------------------------------------------------------------

Table 2.  (contd.)
---------------------------------------------------------------------------------------------------------
Chemical     Sample type    Extraction and clean-up         Method of      Detectionb  Reference
                                                            detectiona    limit
---------------------------------------------------------------------------------------------------------
methiocarb   fruit and      acetone extraction of           GLC/SFPD       0.01 mg/kg   Bowman & Beroza
             vegetables     carbamates and free phenols,                                (1969)
                            partition on silica gel column,
                            hydrolysis of conjugated phenols

methomyl                    ethyl acetate extraction,       GLC/SFPD       0.02 mg/kg   Leitch & Pease
                            hexane extraction, chloroform                               (1973)
                            solution, hydrolysis and ethyl
                            acetate extraction

phenmedipham plant          hydrolysis, distillation-       colorimetry    0.05 mg/kg   Kossmann & Jenny
             tissues        extraction, and reaction                                    (1973)
                            with chromophore

propoxur     plant and      acetone-chloroform extraction,  GLC/ECD        0.1 mg/kg    Anderson (1973)
             animal         absorption on Florisil column,
             tissues        chloro form elution, solution
             milk           in benzene, and reaction with                  0.01 mg/kg
                            trichloroacetyl chloride

thiofanox    soil           acetone extraction, oxidation   GLC/SFPD                    Chin et al.
                            with hydrogen peroxide,                                     (1975)
                            absorption on Florisil column
                            and elution with chloroform
                            and diethyl ether, solution
                            benzene
---------------------------------------------------------------------------------------------------------
a  GLC  = gas-liquid chromatography.
    ECD  = electron-capture detector.
    SFPD = sulfur (sensitive) flame photometric detector.
    HPLC = high-performance liquid chromatography.
    UV   = ultraviolet.
b  Limit of detection is the sensitivity of the method; however, each method may not be able to measure 
    all the contaminants originally present in the sample, i.e., the recovery rates for spiked 
    samples < 100%.

3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

3.1  Natural Occurrence

    Methyl carbamates are related to a naturally-occurring 
carbamate alkaloid, physostigmine, isolated from the calabar bean 
 (Physostigma venenosum) in 1864. 

    Physostigmine (or eserine) has a pronounced cholinergic action 
(Still & Herrett, 1975). 
 
3.2  Man-Made Sources 

    Carbamate pesticides have been produced and in commercial use 
since the 1950s. 

    Benomyl and carbendazim, belonging to the benzimidazole group 
of fungicides, came on the market around 1970. 

3.2.1  Production levels, processes, and uses

    The carbamates included in this review are those mainly used in 
agriculture.  They are some of the many synthetic organic 
pesticides that have been produced on a large scale. Additional 
uses are as biocides for industrial or other commercial 
applications and in household products; a potential use is in 
public health vector control. 

    Global consumption of the carbamate insecticides and herbicides 
over the period 1974-82 is summarized in Table 3. The data are not 
complete but give an estimate of the magnitude of the consumption 
and distribution of the compounds throughout the world.  The 
reported global consumption is between 20 000 and 35 000 
tonnes/year.  The herbicidal carbamates, an integral part of 
industrialized agriculture, are used mainly in North and Central 
America, and Europe, with little reported use in Africa, Asia, and 
South America. However, in the period mentioned, carbamate 
insecticides were substantially used in Asia (FAO, 1985). 

Table 3.  Global consumption of carbamate insecticides 
(in 100 kg)a
-----------------------------------------------------------
Region              1974-76     1981      1982      1983
-----------------------------------------------------------
 Africa
  Sierra Leone      25
  Sudan             1590
  Zimbabwe                      4837

 North/Central America
  Bermuda
  Canada            7911
  Cuba              7333
  El Salvador       507
  Mexico            25 367      21 630    21 380    17 210
  Montserrat                    2         2
  USA                           125 000   115 000

 South America
  Argentina                     2960      2700
  Guyana                                  36
  Suriname                      369
  Uruguay           63          74        70        179

 Asia
  Brunei                        7         12        29
  Cyprus            20          124       21
  Hong Kong         100         125       64        102
  India             33 447      32 160    23 730
  Israel            1333        2160      2580      2270
  Japan                         27 770
  Jordan                        2000      16 745
  Korea Republic    7618        19 270    17 716
  Kuwait            2
  Oman                          134       6         16
  Pakistan          298         3511      1136
  Saudi Arabia      63
  Turkey                        635       666

 Europe
  Austria           213         184       153       86
  Czechoslovakia    1490        569       712
  Denmark           60                    307       440
  Finland           7
  Greece            8767
  Hungary           5854        1539      3396      11 650
  Italy             28 014      28 284    23 041
  Norway                        5         5         10
  Poland            12 353      3325      4365      4977
  Portugal          512         216       200
  Sweden                        94        130
  Switzerland       133         140       120
-----------------------------------------------------------
a  From: FAO (1985).

4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

4.1  Transport and Distribution Between Media

4.1.1  Air

    In general, the vapour pressure of carbamates is rather low.  
Some of them may sublimate slowly at room temperature, and this may 
also explain their loss from soil surfaces (Gray, 1971). 

4.1.2  Water

    The aqueous environment is an important factor in transport.  
Carbamates may enter surface water from industrial wastes, 
accidental spillage, and dumping.  However, the hazard of this is 
limited by their rapid decomposition under aqueous conditions.  
Thus, while long-term contamination by this type of compound is 
unlikely, adverse effects on aquatic animals may result from direct 
addition or from run-off shortly after application. 

4.1.3  Soil

    Reviews of the action of herbicidal carbamates in the soil have 
been made by Gray (1971) and Ashton & Crafts (1973). 

    Herbicidal carbamates are often applied directly to the soil, 
whereas insecticidal carbamates, generally applied to plants, reach 
the soil either directly or indirectly.  Several factors are 
involved in the degradation of carbamates in the soil.  These 
include volatility, leaching, soil moisture, absorption, pH, 
temperature, photodecomposition, microbial degradation, and soil 
type (Ogle & Warren, 1954). 

    Different soil types possess different binding capabilities.  
In general, carbamate insecticides are not very persistent in the 
soil.  However, the fungicide carbendazim is very persistent, with 
a half-life of about one year. 

    Because of the many factors involved and the fact that many 
carbamates have different properties, it is clear that results with 
one soil type and one carbamate cannot be extrapolated to others. 

    In general, the water solubility of carbamates is rather low 
and may explain the relative immobility of the carbamate herbicides 
in the soil with regard to leaching and diffusion. When applied to 
the soil, some chloropropham (CIPC) can be lost by vaporization or 
sublimation, but otherwise it is tightly adsorbed to certain soils 
(Ogle & Warren, 1954).  It was found by De Rose (1951) that 
chloropropham (CIPC) persisted in the soil about twice as long as 
propham (IPC). The disappearance of propham from the soil took 
about 24 days, while chloropropham persisted at least 48 days.  
Water can displace the carbamates from adsorption sites and cause 
them to be lost by volatilization (Parochetti & Warren, 1966). 

    The degradation of the carbamate herbicides in the environment 
is summarized in Fig. 1, using chloropropham as a representative 
example of the group. 

FIGURE 1

    Soil run-off and leaching characteristics of benomyl and its 
metabolites were studied in the greenhouse and laboratory using 
14C-labelled materials on soil and turf plots and on soil thin-
layer chromatographic plates (Rhodes & Long, 1974). The studies 
showed that benomyl and its metabolites are immobile in soil and do 
not leach or move from the site of application. 

    The first step in the metabolic degradation of these carbamates 
in soil is hydrolysis (Sonawane & Knowles, 1971). Simple esters are 
hydrolysed to the parent (unstable) acid and alcohol.  The general 
reaction of carbamates and the breakdown of carbamates in soils are 
described in detail in the review of Still & Herrett (1975).  
Chloropropham, barban, and swep are hydrolysed to their respective 
anilines (Still & Herrett, 1975). In alkaline soil, phenmedipharm 
converts hydrolytically to methyl-3-hydroxyphenyl-carbamate, which 
in turn hydrolyses to 3-aminophenol (Sonawane & Knowles, 1971).  
The substituted anilines that are formed are further metabolized by 
oxidation processes (Kaufman & Blake, 1973; Still & Herrett, 1975). 

    Methomyl and oxamyl degrade rapidly with carbon dioxide as the 
end product (Harvey & Pease, 1973; Harvey & Han, 1978b). 

    In soils, the predominant metabolic pathway is cleavage of the 
carbamate bond to yield the alcohol and amino moieties, which may 
be further metabolized by the soil-plant system. 

    Williams et al. (1976a,b) found that the degradation of 
carbofuran in British Columbia was slower than expected. Soils 

showed rather high residues of this compound (up to approximately 4 
mg/kg soil), and there was some evidence of build-up where 
treatments were repeated for two successive years.  While 
carbofuran has a half-life of up to 50 weeks in neutral or acid 
soils, it degrades rapidly in alkaline soils. 

4.1.4  Vegetation and wildlife

    Plant metabolism of carbanilate herbicides has been shown to 
involve aryl hydroxylation and conjugation besides hydro-lytic 
breakdown.  Consequently, they are readily transformed from 
lyophilic compounds to hydrophylic metabolites, which contain the 
intact carbamoyl group.  These polar products are not translocated 
but remain in the plant at the site of formation.  All available 
data indicate that the hydroxylated carbamate metabolites are 
detoxification products (Still & Herrett, 1975).  In studies on 
chloropropham in oat shoots, Still & Rusness (1977) found that the 
phenolic metabolites were converted to an  S -cysteinyl conjugate, 
i.e.,  S -cysteinyl-hydroxychloropropham. 

    A large number of studies on the absorption and translocation 
of carbamate herbicides have been carried out to study the fate of 
these compounds in plants.  The results suggest that plant leaf 
surfaces are a barrier to the absorption of carbamates.  Roots, 
however, absorb the herbicides to a much greater extent, and the 
carbamate moves to all plant parts.  Thus, it is suggested that 
carbamates are exclusively distributed via the apoplastic system.  
The carrier that is used plays an important role in these 
absorption studies. 

    Many studies are available concerning the actual entry of 
carbamates into the plant, their hydrolysis, aromatic ring 
hydroxylation, hydrolytic breakdown, and oxidation of aliphatic 
groups.  Other types of metabolic reactions in different plant 
species following different methods of application have also been 
described (Baldwin et al., 1954; Abdel-Wahab et al., 1966; 
Prendeville et al., 1968; Knowles & Sonawane, 1972; Still & 
Mansager, 1972, 1973a,b, 1975; Wiedmann et al., 1976; Guardigli et 
al., 1977). 

    For the metabolic pathway in wildlife, see sections 6 and 7. 

4.1.5  Entry into the food chain

    Carbamates are metabolized or broken down in soil, plants, and 
animals.  The questions of the environmental impact and the 
significance of the metabolites with respect to persistence and 
bioaccumulation in certain species and in the food chain have still 
to be answered.  For the moment, it appears that most, if not all, 
of the known carbamate metabolites are biodegraded rapidly and are 
less toxic for the environment than the parent molecules (Still & 
Herrett, 1975). 

4.2  Biotransformation

4.2.1  Microbial degradation

    The carbamates are readily degraded by soil microorganisms in 
most soils (Gray, 1971).  Environmental conditions that favour the 
growth and activity of microorganisms also favour degradation (Ogle 
& Warren, 1954).  The residual herbicidal activity of both barban 
and propham persists longer in sterile soil than in non-sterile 
soil. 

    Kaufman & Kearney (1965) and Kaufman & Blake (1973) isolated 
(by soil-enrichment techniques) and identified a soil microorganism 
capable of degrading carbamates such as chloropropham.  They 
suggested that hydrolysis was a major degradation pathway in soils. 
Each of the soil microorganisms demonstrated a different range of 
substrate specificity, but all were capable of degrading and 
dehalogenating a variety of pesticides (production of 3-
chloroaniline and subsequent liberation of free chloride ion). 

    These studies illustrated the tremendous adaptability of the 
soil microbial populations in altering the persistence and 
character of the different foreign compounds.  Studies carried out 
by Clark & Wright (1970) confirmed that cultures of  Arthrobacter 
sp. and  Achromobacter sp. were able to convert phenyl carbamates 
to the corresponding aniline compounds. 

    Suzuki & Takeda (1976) studied the metabolism of dimetilan in 
 Aspergillus niger van Tieghem.  Together with hydrolysis, 
oxidation of the alkyl side chain appeared the most important 
modification (detoxification) process.  Williams et al. (1976b) 
found that carbofuran was rapidly degraded in soils containing high 
levels of actinomycetes. 
 
4.2.2  Photodegradation

     N -methyl carbamates absorb radiation available in the solar 
region (lambda = 300 nm) and hence, would be expected to undergo 
photo-oxidation as well as metabolic degradation. Addison et al. 
(1974) studied the fate of various  N -methyl carbamates when 
solutions were sprayed on bean foliage and exposed to sunlight or 
artificial light (lambda = 254 nm).  It is not entirely clear 
whether the products they observed resulted solely from a 
photochemical reaction or from absorption followed by enzymatic 
attack (Addison et al., 1973, 1974). 

4.2.3  Photodecomposition in the aquatic environment

    Carbamate insecticides in water are subject to photo-
decomposition under the effects of ultraviolet radiation (UVR).  
The pH of the aqueous medium was found to be an important factor in 
relationship to the rates of photolysis of carbaryl and propoxur, 
which were slow at low pH values and tended to increase with 
increaseing pH value.  However, the decomposition of, for instance, 
dimetilan, was not affected by the pH of the irradiated medium.  
The primary effect of the UVR appears to be cleavage of the ester 

bond resulting in the production of the phenol or heterocyclic enol 
of the carbamate esters tested.  The hydrolysis products produced 
were further photodecomposed to other unidentified degradation 
products. Carbaryl produced 5 degradation products, one of which 
was identified as 1-naphthol.  It is assumed that, apart from the 
cleavage of the ester bond, changes at other positions in the 
molecule are produced by UVR.  However, the intact carbamate ester 
group is retained, and consequently the ChE-inhibiting activity 
(Crosby et al., 1965; Crosby 1969; Aly & El Dib, 1972). 

    Similar results were reported for the irradiation products of 
other carbamate esters such as aminocarb, mexacarbate, and a number 
of analogues (Eberle & Gunther, 1965; Abdel-Wahab F & Casida, 
1967). 

    When the half-life for photodecomposition was studied in a 
number of carbamate insecticides, the results suggested that the 
light absorption characteristics of the insecticide influenced the 
extent of its photodecomposition by a specific light source.  
However, the extent of photodecomposition was not the same under 
different conditions of irradiation (presence of solvents) and 
wave-length (Crosby et al., 1965; Eberle & Gunther, 1965). 

    Thus, it seems reasonable to suggest that photodecomposition 
may account for some loss of carbamate insecticides in clear 
surface waters exposed to sunlight for a long period. However, 
photolysis may be a minor factor in the decomposition of these 
compounds in highly-turbid waters, where the penetration of light 
will be greatly reduced (Aly & El-Dib, 1971, 1972). 

5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

5.1  Exposure of the General Population

5.1.1  Food and drinking-water

    From a market-basket study conducted during 1977-80 by the 
Finnish National Board of Trade and Consumer Interests, it became 
apparent that the residues of benomyl in food had increased.  
During the period 1974-76, the average benomyl intake was about 0.2 
mg/person per year from both domestic and imported foods.  During 
the period 1977-80, average intake was 9 mg/year.  A later more 
accurate study showed an intake of 14 mg/person per year (Finnish 
National Board of Health, 1982). 

    Contamination of groundwater and drinking-water sources by 
aldicarb, a carbamate that is used as an insecticide and as a 
nematocide, was reported from the USA in 1979 and 1980-81; levels 
even higher than 0.075 mg/litre were found (Rothschild et al., 
1982; Zaki et al., 1982).  In the Federal Republic of Germany, 
detectable amounts of up to 0.001 mg aldicarb/litre were found in a 
few samples of drinking-water (Federal Republic of Germany, 
personal communication, 1985)a. 











---------------------------------------------------------------------------
a  Letter to the IPCS from the Ministry of the Interior of
    the Federal Republic of Germany, Bonn, Federal Republic of
    Germany, 28 May, 1985.

6.  METABOLISM AND MODE OF ACTION

    Most carbamates are active inhibitors of AChE and they do not 
require metabolic activation.  However, some carbamates, such as 
the benzimidazole carbamates, do not have anticholinesterase 
activity.  Carbamates undergo metabolism, and the metabolites are 
generally less toxic than the parent compound;  some exceptions 
will be discussed later.  The metabolism of carbamates is basically 
the same in mammals, insects, and plants, and the toxic effects of 
carbamates are similar in mammals and insects.  Carbamates do not 
accumulate in the mammalian body, but are rapidly excreted, mainly 
via the urine. 

6.1  Mode of Action

    Carbamates are effective insecticides by virtue of their 
ability to inhibit AChE in the nervous system.  AChE catalyses the 
hydrolysis of the neurotransmitter acetylcholine (ACh) to choline 
and acetic acid. 

    ACh is the synaptic mediator of nerve impulses in the nervous 
system of mammals and insects: 

    (a)  as a neurotransmitter in the brain of mammals, and in
         the central nervous system of insects;

    (b)  as a pre-ganglionic neurotransmitter in the autonomic
         nervous system of mammals;

    (c)  in post-ganglionic nerve endings of the autonomic
         nervous system; and

    (d) at the neuromuscular junction of skeletal muscle.

    Carbamates, like organophosphates, can inhibit esterases that 
have serine in their catalytic centre; these are called serine-
esterases or beta-esterases.  Although the inhibition of serine-
esterases other than AChE is not significant for the toxicity of 
the compounds, it may have significance for the potentiation of 
toxicity of other compounds after long-term low-level exposure 
(Sakai & Matsumura, 1968, 1971; Aldridge & Magos, 1978). 

    To understand the mechanism of toxicity, it is necessary to 
examine the events that take place at the neuromuscular junction.  
When a muscle is innervated, as shown in Fig. 2, a nerve impulse 
moving down a neuron reaches the nerve ending where ACh, which is 
stored in vesicles at the nerve endings, is released into the 
junction.  Within 2 - 3 ms, ACh impinges on the receptor side of 
the muscle. 

FIGURE 2

    AChE then hydrolytically converts the ACh into choline and 
acetic acid, which results in a decrease in the concentration of 
ACh and cessation of muscle contraction.  When AChE is inhibited by 
a carbamate ester, it can no longer hydrolyse the ACh.  Thus, the 
ACh concentration remains high in the junction giving rise to 
continuous stimulation of the muscle which, in turn, leads to 
exhaustion and tetany. 

    Thus, inhibition of AChE by carbamate esters, causes toxic 
effects in animals and human beings that result in a variety of 
poisoning symptoms and eventually culminate in respiratory failure 
and death. 

    The mechanism of inhibition of AChE by a carbamate ester can be 
formulated as follows (Reiner & Aldridge, 1967; Aldridge & Reiner, 
1972): 

          O                            O
          ||         k1               ||
AChE + RO-C-NHCH3 '=========' [AChE x RO-C-NHCH3] (enzyme-carbamate
                     k-1       |                  complex)
                                |   kc
                               \/ 
                                O
                     kr        ||
AChE + CH3NH2 + CO2 <------ AChE-C-NHCH3 + RO-
                     H2O
                               (carbamylated enzyme)

where:  k1 =   second order rate constant for formation of
                complex;
        k-1 =   first order rate constant for breakdown of
                complex to starting materials;
        kc =   first order rate constant for carbamylation of
                the enzyme;
        kr =   first order rate constant for hydrolysis of the
                carbamylated enzyme.

The site for carbamylation of the enzyme is the hydroxyl moiety of 
the serine amino acid.  The rate of regeneration of the 

carbamylated enzyme to AChE (kr) is relatively rapid compared with 
that of an enzyme that has been inhibited (phosphorylated) by an 
organophosphorus pesticide (Reiner & Aldridge, 1967; Reiner, 1971).  
Thus, human exposure to the carbamate pesticides is less dangerous 
than exposure to organophosphorus pesticides, because the ratio 
between the dose required to produce mortality and the dose 
required to produce minimum poisoning symptoms is, in general, 
substantially larger for carbamate compounds than for 
organophosphorus compounds (Goldberg et al., 1963; Vandekar, 1965; 
Vandekar et al., 1971).  An individual experiencing symptoms of 
poisoning from a carbamate is more likely to recover on termination 
of exposure and with appropriate medical treatment than an 
individual poisoned by an organophosphorus compound. 

    The spontaneous reactivation of various carbamylated ChEs 
expressed as half-life, at pH 7.0 - 7.4 and 25 C ranged between 2 
and 240 min for AChE and between 2 and 17 min for serum-ChE.  This 
instability of the carbamylated enzyme affects the determination of 
the inhibitory power of carbamates, the recovery after poisoning, 
and the determination of inhibition of blood-ChEs (Reiner, 1971). 

6.1.1  Neuropathy target esterase

    This esterase, formerly known as neurotoxic esterase (NTE), is 
the target for the initiation of delayed neuropathy caused by some 
organophosphorus esters.  Both organophosphorylation of NTE and a 
subsequent "aging" reaction of the inhibited enzyme are required to 
initiate neuropathy.  Certain  N -aryl carbamates can also inhibit 
NTE, but the chemistry of such carbamates is such  that no "aging" 
reaction is possible. These carbamate inhibitors do not initiate 
delayed neuropathy  in vivo but can actually prevent the neuropathic 
effects of a challenge dose of an organophosphate given while the 
tissue NTE is carbamylated (Johnson, 1970).  No delayed neuropathic 
effects have been observed in tests on carbamate pesticides 
according to protocols that detect neuropathic organophosphates, 
and this agrees with the mechanism described above. 
 
6.2  Metabolism 

    The metabolic fate of carbamates is basically the same in
plants, insects, and mammals.

    Carbamates can penetrate the skin, mucous membranes, 
respiratory tract, and gastrointestinal tract of mammals. 

6.2.1  Absorption

     In vivo studies have shown that carbamates are almost 
completely absorbed during normal transit through the gastro-
intestinal tract. 

    According to absorption studies on rats, the dermal absorption 
of radioactive labelled benomyl is slow.  After absorption, rapid 
metabolism and elimination via urine took place.  After 1 h, small 
amounts of the major metabolites of benomyl, 5-hydroxy-2-
benzimidazole carbamate (5-HBC), and methyl 2-benzimidazole 

carbamate (MBC), could be detected in urine, confirming the rapid 
metabolism of benomyl.  No radioactivity was found in any body 
tissues sampled 24 h after application (FAO/WHO, 1985a). 

6.2.2  Distribution

    Ahdaya et al. (1981) studied the absorption and distribution of 
carbamates.  They found that, in mice, all carbamates  were rapidly 
distributed to the tissues and organs. The half-life values of 
penetration ranged from 8 to 17 min for carbamates. 

    No residues of benomyl or its degradation products were 
detected (level of sensitivity 0.02 mg/kg) in eggs from chickens 
fed 5 mg benomyl/kg diet.  Only 5-HBC (0.03 - 0.06 mg/kg) was found 
in eggs from chickens fed 25 mg benomyl/kg for four weeks.  No 
residues of benomyl or MBC were found in milk (< 0.02 mg/litre) 
from dairy cows fed benomyl for 32 days at dietary levels of 0, 2, 
10, and 50 mg/kg.  At the highest dietary level, the combined 
residue of 5-HBC plus 5-hydroxy-2-benzimidazole carbamate (4-HBC) 
in the milk was approximately 0.1 mg/litre.  These metabolic 
studies appear to indicate that benomyl and its metabolites do not 
accumulate in animal tissues or animal products (Gardiner et al., 
1974; FAO/WHO, 1985a). 

    A rat was administered a diet containing 2500 mg non-labelled 
benomyl/kg.  Twelve days later, the animal received an intragastric 
intubation of 2-14C-benomyl (7.7 mg).  Urine and faeces were 
collected, and organs were analysed for radioactivity.  The 
elimination was rather rapid and mainly via the urine.  After 72 h, 
0.2% of the administered dose was found in the liver, while < 0.01% 
was present in all the other organs and the carcass.  The same 
results were found when a rat was administered 2-14C-MBC 
(Gardiner et al., 1974) 

    A male beagle dog fed a diet containing non-labelled benomyl at 
2500 mg/kg, and administered 30.8 mg 2-14C-benomyl by capsule 7 
days later, showed a completely different excretion pattern.  After 
3 days, residues were found only in the liver (0.31% of the 
administered dose); the levels in the other organs were < 0.01% 
(Gardiner et al., 1974). 

    Rats administered an oral dose of 14C-labelled propham or 
chloropropham (labelled in the chain or in the ring), showed 
radioactivity in all tissues, with the highest concentration in 
the kidneys.  The average biological half-life of 14C from both 
compounds in most organs was short, ranging from 3 to 8 h.  
However, in brain, fat, and muscle, the half-life was about twice 
this value (Fang et al., 1974). 
 
6.2.3  Metabolic transformation 

6.2.3.1  Biotransformation mechanisms

    Carbamate pesticides are transformed metabolically by a variety 
of chemical reactions into more water-soluble molecules with 
increased polar properties.  The initial step, usually oxidative in 
nature, introduces a functional hydroxyl group that serves as a 
site for secondary conjugative reactions to yield products that 

can be excreted via the urine and/or faeces.  In some cases, the 
oxygenated metabolites, such as 5-hydroxypropoxur and 5-hydroxy-
carbaryl, are known to be toxic and to possess anticholinesterase 
activity (Fig. 3) (Oonnithan & Casida, 1968; Black et al., 1973).  
This undoubtedly contributes to the overall toxicity of the parent 
compound (Black et al., 1973). 

6.2.3.2  Oxidation

    The principal route of metabolism of insecticidal carbamate 
esters is oxidative and is generally associated with the mixed-
function oxidase (MFO) enzymes, which are present in several 
tissues.   Examples of the sites of oxidative attack on a 
hypothetical methyl carbamate are given in Fig. 4. 

    Depending on the functional groups in the molecule, a variety 
of reactions catalysed by these enzymes may occur (Fukuto, 1972), 
as shown in Fig. 4.  Typical oxidative reactions include: (a) 
hydroxylation of aromatic rings, or epoxidation; (b)  O -
dealkylation; (c)  N -methyl hydroxylation; (d)  N -dealkylation; (e) 
hydroxylation and subsequent oxidation of aliphatic side chains; 
and (f) thioether oxidation to sulfoxides and sulfones. 

    Because of the variety of different groups present in carbamate 
insecticides, the metabolism of these compounds is often complex.  
Carbaryl, for example, is a relatively simple compound, yet it is 
metabolized to at least 15 different compounds in mammals through a 
variety of oxidative and hydrolytic reactions (Leeling & Casida, 
1966).  A study showed that, as well as the organic solvent-soluble 
unconjugated metabolites, the urine from carbaryl-treated rabbits 
contained at least 4 or 5 other water-soluble metabolites.  These 
are probably conjugates of the hydroxylated products of carbaryl, 
i.e., glucuronides or sulfates. 

FIGURE 3

FIGURE 4

6.2.3.3  Hydrolysis

    Carbamates are hydrolysed either spontaneously or by esterases 
(Aldridge & Reiner, 1972), yielding, as final products, an amine, 
carbon dioxide (CO2), and an alcohol or phenol: 

   R1HN-C(O)OR2 + H2O ---> R1NH2 + CO2 + R2OH

    The mechanism of hydrolysis is different for  N -methyl and 
 N -dimethyl carbamates. 

    In general, the rates of hydrolysis of carbamates by esterases 
are faster in mammals than in plants and insects, though there are 
exceptions.  The differences in enzymatic rates of hydrolysis 
depend on the structure of the carbamate and on the particular 
esterase. 

    Hydrolysis of the carbamates is catalysed by a group of enzymes 
known as A-esterases or arylesterases (EC 3.1.1.2). It has been 
established that enzymatic hydrolysis occurs both  in vitro and  in 
 vivo, but, to date, it has not been determined to what extent the 
 in vivo hydrolysis contributes to the detoxification of the 
chemical. 

    The hydrolytic activity of plasma-albumin has also been 
indicated (Augustinsson & Casida 1959; Casida & Augustinsson, 1959; 
Reiner & Skrinjaric-Spoljar, 1968). 

6.2.3.4  Conjugation

    The conversion to conjugated compounds of the hydroxy products 
produced by the drug-metabolizing enzyme systems is an important 
reaction that leads to the formation of water-soluble compounds 
such as  O - and  N -glucuronides, sulfates, and mercapturic acid, 
which can be eliminated via the urine or faeces. 

6.2.3.5  Examples of biotransformation of carbamates

    A few examples of the biotransformation of carbamates are given 
in Fig. 5. 

    Aldicarb is unusual in that it does not contain an aromatic 
ring, and it is also a carbamate ester of an oxime. Knaak et al. 
(1966) studied its metabolism in rats.  The metabolic reactions of 
aldicarb are similar to the oxidative and hydrolytic pathways found 
in the thioether-containing organophosphorous esters.  The 
thioether moiety is rapidly oxidized to the oxime-sulfoxide; the 
oxime-sulfoxide is oxidized much more slowly to the oxime-sulfone.  
A large number of metabolites resulting from the hydrolysis of the 
carbamate moiety of the oxidative metabolites of aldicarb have been 
identified. 

FIGURE 5A

FIGURE 5B

    The oxime-sulfoxide was found to be the major hydrolytic 
metabolite in plants and insects.  Other research workers recovered 
the nitrile sulfoxide, in greater quantities, both compounds 
arising from cleavage of the carbamate moiety of aldicarb sulfoxide 
(Metcalf et al., 1966; Fukuto, 1972). 

    Propham and chlorpropham have been studied in a number of 
animal species.  Both compounds are rather rapidly metabolized.  
The major metabolites recovered from the animals were 4-
hydroxypropham and 4-hydroxychloropropham, respectively. Both were 
excreted as the sulfate and/or glucuronide. Depending on the animal 
species, hydroxylation of propham also occurred in the 2- and 3-
position, and even 3,4-dihydroxypropham was identified.  Oxidation 
of the 1-carbon of the isopropyl moiety of chlorpropham resulted in 
the formation of the monohydroxy product, which was converted to 
the 1,3-hydroxy and 1-carboxy derivative.  Hydrolysis of 
chloropropham also occurred to a significant extent, since the 
other major metabolites found were conjugates of 3-chloro-4-
hydroxy- and 5-chloro-2-hydroxy-acetanilide.  Chlorpropham is more 
susceptible to hydrolytic degradation than propham, or, conversely, 
propham is more susceptible to oxidative degradation than 
chlorpropham (Bobik et al., 1972; Paulson et al., 1973; Fang et 
al., 1974). 

    Phenmedipham and desmedipham were hydrolysed mainly into 
methyl- N or ethyl- N -(3 hydroxyphenyl) carbamates.  Both compounds 
were subsequently hydrolysed to 3-aminophenol. Furthermore, the 
aminophenol was  N -acetylated, and the phenolic hydroxyl moiety was 
conjugated with the sulfate or glucuronide (Sonawane & Knowles, 
1972). 

    Carbaryl is rapidly hydroxylated or hydrolysed and thereafter 
conjugated and eliminated from a number of animal species, 
principally in the urine as glucuronides or sulfates. Depending on 
the animal species, at least 8 water-soluble metabolites were 
found.  Dorough & Casida (1964) and Fukuto (1972) studied the 
biotransformation of carbaryl in animals. It was found that 
hydroxylation took place, and the following metabolites were 
identified: 1-naphthyl  N -hydroxymethylcarbamate (and as a result 
of ring hydroxylation) 4-hydroxy-1-naphthyl- N -methylcarbamate, 
5-hydroxy-1-naphthyl- N -methyl-carbamate, and 5,6-dihydroxy-1-
naphthylmethylcarbamate. 

    Certain metabolites appeared to be the hydrolytic products of 
carbamates with modified ring structures, such as 1-hydroxy-5,6-
dihydro-naphthalene and 1-naphthol.  The latter compound is found 
in the urine as 1-naphthyl glucuronide and/or 1-naphthyl sulfate.  
Sullivan et al. (1972) identified one of these metabolites, 5,6-
dihydroxy carbaryl glucuronide, in the urine of rats.  Most 
metabolites of carbaryl are eliminated in a similar pattern in 
human beings, rats, guinea-pigs, and sheep, but in a different way 
in dogs (FAO/WHO, 1968b). 

    The metabolism of benomyl has been studied in the mouse, rat, 
rabbit, dog, sheep, and cow and is qualitatively the same in all 
animal species studied. 

    The basic route of benomyl metabolism involves hydroxylation 
to 5-hydroxy-2-benzimidazolecarbamate (5-HBC).  This is the main 
metabolite and conjugates (glucuronides or sulfates) of the 
compound are usually eliminated via the urine, bile, and faeces 
(Douch, 1973; Gardiner et al., 1974).  In contrast, dogs treated 
orally with 14C-benomyl eliminated only 16% of the radioactivity in 
the urine and 83% in the faeces.  The principal metabolites in the 
faeces were carbendazim and 5-hydroxycarbendazim.  In addition, 4-
hydroxycarbendazim was identified as a metabolite in the urine, 
faeces, and milk of a cow treated with benomyl (Fig. 6). 

FIGURE 6

    Heybroek et al. (1984) studied the metabolism of [ring-14C] 
asulam in the rat.  Most of the radioactivity (61 -74%) 
administered orally or intravenously was excreted in the urine in 
24 h as unchanged asulam, 8 - 14% as  N 4-acetylasulam, and up to 
2.5% as  N 4-acetylsulfanilamide.  Small amounts of radioactivity 
were found in faeces. 

    These examples illustrate the different metabolic pathways of 
biotransformation.  For more details, readers should refer to 
Fukuto (1972) who has reviewed the metabolism of carbaryl, 
mexacarbamate, aminocarb, formetanate, aldicarb, methiocarb, 

carbofuran, MPMC, trimethacarb carbanolate, propoxur, and 
dimetilan.  Harvey & Han (1978a) have described the metabolism of 
oxamyl and Harvey et al. (1973), of methomyl in the rat. The 
metabolism of pirimicarb was extensively described in FAO/WHO 
(1977b).  Furthermore, information on the metabolism is provided in 
the handbooks on carbamates, and the different monographs of the 
Joint FAO/WHO Meetings on Pesticide Residues. 
 
6.3  Elimination and Excretion in Expired Air, Faeces, and Urine 

6.3.1  Man

    In a study on human volunteers, 2 men were dosed orally with 
carbaryl in gelatin capsules at 2.0 mg/kg body weight. 
Chromatographic analyses of a 4-h urine sample revealed 1-naphthyl 
glucuronide (15%), 1-naphthyl sulfate (8%), and 4-(methylcarbamoyl-
oxy)-1-naphthyl glucuronide (4%).  In addition, 1-naphthyl 
methylimidocarbonate  O -glucuronide was identified by fluorometry 
(FAO/WHO, 1968b).  During the first 8 h, the urinary excretion of 
these metabolites constituted 12 - 15% of the carbaryl 
administered.  Small amounts of urinary metabolites were detected 
by fluorometric analysis on the second day, but not afterwards 
(Knaak et al., 1968).  In another study, 1-naphthyl glucuronide, 1-
naphthyl sulfate, and other unidentified metabolites were found in 
24-h urine samples from men exposed to carbaryl dust during a 
packaging operation in a factory (details not available) (Knaak et 
al., 1965). 

    The determination of 1-naphthol or its sulfate or glucuronide 
in the urine of persons occupationally exposed to carbaryl is one 
method of biological monitoring for this exposure (FAO/WHO, 1982b). 

    Dawson et al. (1964) investigated the metabolism and excretion 
of propoxur in 3 male volunteers orally administered a dose of 50 
mg.  Within 8 - 10 h, 27% of the propoxur appeared in the urine as 
its metabolite 2-isopropoxyphenol, indicating that propoxur is 
rapidly absorbed and hydrolysed in human beings. 

    The absorption and fate of benomyl in animals following oral 
administration of the compound varies with species. According to a 
study that involved one rat and one dog administered 2-14C-benomyl 
by stomach tube, the rat eliminated about 86% of a single dose via 
the urine and 13% via faeces. The dog eliminated only 16% of a 
similar benomyl dose via the urine, while almost 83% was detected 
in faeces.  No data are available concerning the possible roles of 
the enterohepatic circulation and biliary excretion of benomyl or 
its metabolites (Gardiner et al., 1974). 

6.3.2  Laboratory animals

    In animals, oxidation of carbamates often, but not always, 
results in detoxification.  Oxidative metabolism generally leads to 
products of greater polarity and water solubility, and these can be 
more readily eliminated through the urine and faeces than the 
parent compound. 

    In the rat, benomyl is mainly excreted via the urine (78.9% of 
the given dose) as 5-HBC conjugates.  In the dog, 99% of the dose 
administered was eliminated within 72 h.  The major route of 
elimination was via the faeces in which benomyl and/or MBC and 5-
HBC were detected.  On the basis of studies on the rat, dog, dairy 
cow, and chicken, neither benomyl nor its metabolites tend to 
accumulate in animal tissues (Gardiner et al., 1974). 

    According to FAO/WHO (1974b), feeding of 14C- or 35S-labelled 
thiophanate-methyl to rats, mice, and dogs resulted in 80 - 100% 
recovery of the label in the faeces and urine within 96 h.  
Unmetabolized thiophanate-methyl has been reported to be the major 
component of faecal elimination.  The minor part consisted of 4-
hydroxy-thiophanate-methyl, dimethyl-4,4- O -phenylenebisallophanate.  
MBC and 5-hydroxy-MBC were also detected. 

    Following application of carbendazim to rats and mice by 
intragastric intubation, almost all metabolites in the urine were 
conjugated as sulfate esters.  5-HBC was released as the only 
metabolite extractable from water.  A higher proportion of polar 
compounds was found in the urine of mice than in that of rats.  
Polarity was caused by the phenolic hydroxyl group (FAO/WHO, 
1985a). 

    The excretion of 14C-labelled propham and chlorpropham was 
investigated in female rats after a single oral dose.  The average 
3-day urinary excretion of radioactivity was between 56 and 85%, 
depending on the position of labelling: viz chain or ring 
labelling.  With chain 14C-chlorpropham, an average of 35% of the 
administered radioactivity appeared in the respired air, compared 
with only 5% for chain 14C-propham (Fang et al., 1974). 
 
6.4  Metabolism in Plants 

    Studies on the metabolism and fate of carbamate pesticides in 
plants are of great importance for assessing the human hazards from 
the consumption of fruit and vegetables containing residues of the 
applied pesticides and metabolites. 

    Generally, the metabolism of carbamates in plants follows 
another route of detoxification.  The hydroxylated carbamates 
produced by enzymes are conjugated either with amino acids (for 
instance cysteine) or as glycosides and phosphates, which are 
stored as terminal metabolites (Still & Rusness, 1977; Aldridge & 
Magos, 1978). 

    The toxicological properties of plant conjugates in mammals or 
other animals are not generally known. Insecticidal methyl 
carbamate esters are vulnerable to hydrolytic cleavage, which 
results in detoxified products. Detoxification of carbamate esters 
in plants by hydrolysis occurs to a lesser extent than 
detoxification by oxidative metabolism; nevertheless, hydrolytic 
cleavage of the ester moiety is a significant detoxification 
mechanism.  For instance, in sugar beets treated with desmedipham, 
the major metabolites were ethyl-3-hydroxy phenyl carbamate and 3-
aminophenol (Knowles & Sonawane, 1972).  Carbetamide is hydrolysed 

to aniline (Guardigli et al., 1977).  Aromatic ring hydroxylation 
appears to be the predominant metabolic reaction that carbamate 
herbicides undergo in plants.  The major metabolites isolated from 
soybean plants, after uptake of chlorpropham, were glucoside 
conjugates of 2-hydroxy- and 4-hydroxypropham.  Similar results 
were obtained with propham (Still & Mansager, 1973a,b, 1975). 

    There is evidence that the ring hydroxylation varies with the 
plant species.  In other carbamates, for instance in the case of 
barban, ring hydroxylation did not appear to take place, and polar 
metabolites were produced, which were hydrolysed into 
chloroanilines (Still & Mansager, 1972). 

    Furthermore, oxidation of aliphatic groups takes place in 
carbamate herbicides (Wiedmann et al., 1976).  Still & Herrett 
(1975) demonstrated  N -methyl hydroxylation for dichlormate, a 
metabolite that is either conjugated or loses the hydroxymethyl 
moiety to produce  N -demethylated dichlormate. 

    Thiophanate-methyl is mainly metabolized into carbendazim (MBC) 
and, to a less extent, into 2-aminobenzimidazole (2AB). A few other 
metabolites have also been found (FAO/WHO, 1974b). 

    The metabolic pathway for carbaryl in plants is identical, 
whether the compound is injected into the stem or applied to the 
leaf surface.  After entering the plant, carbaryl undergoes 
biotransformation to its primary metabolites, which are similar to 
the ones formed in animals.  These hydroxylated metabolites, which 
are less toxic than carbaryl itself, are conjugated by plants to 
form water-soluble glycosides.  Injection of carbaryl into the 
bean plant produced water-soluble metabolites attributable to 
hydroxylation of the ring or  N -methyl group followed by 
conjugation, mainly as glycosides (Kuhr, 1968; FAO/WHO, 1970b; 
Fukuto, 1972). 

    The metabolism of aldicarb in plants is the same as that in 
mammals.  In the cotton plant, the thioether moiety is rapidly 
oxidized to the sulfoxide, and the latter is slowly transformed to 
the sulfone.  The sulfoxide is rather stable and can be present in 
cotton plants, even as long as 2 months after treatment.  The total 
metabolites present can be as high as 80% (Kuhr, 1968).  Because of 
their persistence in plants, and their even higher anticholinesterase 
activity compared with aldicarb itself, the sulfoxide and sulfone 
should be taken into account when considering residue tolerances. 

    The major metabolite isolated from bean plants, 28 days after 
treatment with carbofuran, was a conjugate of 3-hydroxy-carbofuran, 
which remained in the aqueous phase after extraction with an 
organic solvent.  The conjugate represented 55% of the total 14C-
labelled residues present in the plant.  3-Hydroxy-carbofuran is 
highly toxic for mammals (LD50 in the rat 7 mg/kg body weight).  
The conjugate may also be toxic, particularly taking into account 
the acid conditions of the mammalian stomach under which the 
conjugate will be hydrolysed (FAO/WHO, 1977b, 1980b). 

    Harvey et al. (1978) studied the metabolism of oxamyl in plants 
(tobacco, alfalfa, peanuts, potatoes, apples, oranges, and 
tomatoes).  The major route of degradation involved hydrolysis to 
the corresponding oximino compound, which in turn became conjugated 
with glucose.  Further metabolism resulted in the loss of one of 
the  N' -methyl groups and/or addition of other glucose units to the 
sugar moiety of the original conjugate.  Total breakdown into 
normal natural products has been demonstrated. 

    In a study by Harvey & Reiser (1973), methomyl rapidly degraded 
to carbon dioxide and acetonitrile, which volatilized from the 
plant tissues.  The half-life for methomyl was of the order of 3 - 
6 days.  The remainder of the compound had been reincorporated into 
natural plant components. 

    The metabolic pathways for a number of carbamate pesticides are 
described in more detail in Fukuto (1972). 

7.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

7.1  Microorganisms

    As described in section 4.2.1, soil microorganisms are capable 
of hydrolysing carbamates.  Furthermore, it seems that 
microorganisms can easily adapt themselves to metabolize the 
different types of carbamates (Aly & El-Dib, 1972).  Nevertheless, 
carbamates and their metabolites can affect the microflora and 
cause changes that may have an important impact on the maintenance 
of the soil productivity (Filip, 1974). 

7.2  Aquatic Organisms

    In general, carbamates are not very stable under aquatic 
conditions (section 4).  The solubility in water differs 
considerably for the different carbamates (Annex I).  Furthermore, 
photodecomposition takes place and microorganisms are able to 
degrade these compounds.  By these processes, the carbamate is 
broken down (oxidation, hydrolysis) into other compounds.  Some 
will be less toxic, others even more toxic than the parent 
compound.  Carbaryl will be hydrolysed into 1-naphthol, which is 
just as toxic (Armstrong & Millemann, 1974a).  It seems unlikely 
that most of the carbamates will persist long in the environment, 
but there are exceptions, such as dimetilan and carbendazim. 

    Many data are available on the acute toxicity of the carbamates 
in several fresh- and salt-water fish and other organisms, some of 
which are listed in Tables 4 and 5. 

    When carbamates are deliberately added to an aquatic system, 
caution is necessary since, with high concentrations, a number of 
species are at risk.  For example, while applications of carbaryl 
of 0.93 kg/ha were effective in controlling the ghost shrimp 
 (Callianassa californiensis), an oyster pest, they also caused a 
reduction in the population of juvenile clams (Armstrong & 
Millemann, 1974a). 

    In a similar study (Armstrong & Millemann, 1974b), carbaryl 
and its hydrolytic product, 1-naphthol, were examined for other 
effects on the mussel  (Mytilus edulis).  An age dependence was 
noted; the most sensitive stage (appearance of the first polar body 
shortly after fertilization) had EC50s of 5.3 and 5.2 mg/litre for 
carbaryl and 1-naphthol, respectively. Effects of the compounds 
on development were characterized by disjunction of blastomeres and 
asynchronous and unaligned cleavages.  Carbaryl, at a single dose 
of 0.1 mg/litre, also disrupted normal schooling behaviour in 
juvenile  Menidia medidia; the disruptive effects were attributed 
to the 1-naphthol rather than to the parent carbamate. These 
effects were reversed within 3 days of placing the fish in clean 
water (Weis & Weis, 1974).  Hansen (1969) studied the capacity of 
sheepshead minnows  (Cyprinodon variegatus) to avoid carbaryl.  The 
fish did not avoid carbaryl in concentrations of 0.1 - 10 mg/litre 
water. 


Table 4.  Acute aquatic toxicity (LC50 in mg/litre)a
----------------------------------------------------------------------------------------------------
Compound      Type of      Name of organism                    Stage or      Temp-    Concentration
              organism                                         weight (g)    erature  (mg/litre)
                                                                             (C)     (after 96 h)
----------------------------------------------------------------------------------------------------
Aldicarb      fish         Rainbow trout  (Salmo gairdneri)    0.5           12       0.56
              fish         Bluegill  (Lepomis machrochirus)    1.3           24       0.05

Aminocarb     fish         Rainbow trout  (Salmo gairdneri)    1.5           12       13.5b
              fish         Bluegill  (Lepomis machrochirus)    2.0           20       3.1b
              crustacea    Daphnia  (Daphnia magna)            first instar  21       0.01 - 0.1c
                                                                                      (48-h EC50)
              fish         Rainbow trout  (Salmo gairdneri)    1.5           10       0.13c
              fish         Bluegill  (Lepomis machrochirus)    0.6           20       0.1c
              insect       Midge  (Chironomus plumosus)        fourth instar 20       0.27c

Benomyl       fish         Rainbow trout  (Salmo gairdneri)    1.2           12       0.17d
              fish         Bluegill  (Lepomis machrochirus)    0.9           22       0.85d
              fish         Rainbow trout  (Salmo gairdneri)    1.0           12       0.31e
              fish         Bluegill  (Lepomis machrochirus)    0.6           22       1.2e

Benomyl       fish         Rainbow trout  (Salmo gairdneri)    0.2           12       0.37f
metabolite
MBC

Bufencarb     crustacea    Scud  (Gammarus fasciatus)          mature        15       0.001
              fish         Goldfish  (Carassius auratus)       1.0           18       0.29

Carbaryl      fish         Rainbow trout  (Salmo gairdneri)    1.5           12       1.95d
              fish         Bluegill  (Lepomis machrochirus)    1.2           18       6.76d
              crustacea    Daphnia  (Daphnia pulex)            first instar  16       0.0064d
                                                                                      (48-h EC50)
              crustacea    Scud  (Gammarus fasciatus)          mature        21       0.026d
----------------------------------------------------------------------------------------------------


    Table 4.  (contd.)
----------------------------------------------------------------------------------------------------
Compound      Type of      Name of organism                    Stage or      Temp-    Concentration
              organism                                         weight (g)    erature  (mg/litre)
                                                                             (C)     (after 96 h)
----------------------------------------------------------------------------------------------------

Carbofuran    fish         Rainbow trout  (Salmo gairdneri)    1.5           12       0.38d
              fish         Bluegill  (Lepomis machrochirus)    0.8           18       0.24e

Dichlormate   fish         Rainbow trout  (Salmo gairdneri)    0.8           12       4.9

Methiocarb    fish         Rainbow trout  (Salmo gairdneri)    1.3           12       0.80
              fish         Bluegill  (Lepomis machrochirus)    1.0           24       0.21

Methomyl      fish         Rainbow trout  (Salmo gairdneri)    1.1           12       1.60b
              fish         Bluegill  (Lepomis machrochirus)    0.9           20       1.05b
              crustacea    Daphnia  (Daphina magna)            first instar  21       0.009b
                                                                                      (48-h EC50)

Mexacarbate   fish         Rainbow trout  (Salmo gairdneri)    1.0           11       12.0g
              fish         Bluegill  (Lepomis machrochirus)    0.7           12       22.9g
              crustacea    Daphina  (Daphina pulex)            first instar  15       0.010g
                                                                                      (48-h EC50)
              crustacea    Scud  (Gammarus fasciatus)          mature        -        0.04g

Trimethacarb  fish         Rainbow trout  (Salmo gairdneri)    1.2           12       1.0
              fish         Bluegill  (Lepomis machrochirus)    0.9           18       11.6
----------------------------------------------------------------------------------------------------
a  From: Johnson & Finley (1980).
b  Technical material, 95 - 98%.
c  Liquid formulation, 17%.
d  Technical material, 99%.
e  Wettable powder, 50%.
f  Methyl-2-benzimidazole (MBC), 99%.
g  Technical material, 90 - 95%.

 Note:  It should be recognized that the LC50 and EC50 values only give an indication of the
        toxicity and that the toxicity for these organisms may be appreciably changed by variations
        in temperature, pH, oxygen content, and water hardness. A 10-fold increase in the toxicity
        may be found.  Also, the life stage of the organisms is an important factor in estimating
        the toxicity of the compound.

Table 5.  Acute toxicity of carbamate pesticides for some aquatic organisms
------------------------------------------------------------------------------------------------
Pesticidea              TLMs for organisms at indicated time (mg/litre)    Reference
              Carp       Goldifsh    Killifish     Guppy        Water flea
               (Cyprinus   (Carassius ( Fundulus    ( Lebistes    ( Daphnia      
               carpio     auratus)   sp)            reticulatus  pulex   
              Linn)                               Peters)      Leydig)
              48 h       48 h        48 h          48 h         3 h
------------------------------------------------------------------------------------------------
Benomyl       7.5        12          11 (wettable  -            14           Yoshida & Nishiuchi
                                     powder)                                 (1972)

BPMC          16         10 ~ 40     1.7           5.0          0.32         Yoshida & Nishiuchi
                                                                             (1972); Nishiuchi
                                                                             (1974)

Carbaryl      13         10 ~ 40     2.8           2.8          0.05         Yoshida & Nishiuchi
                                                                             (1972)

Carbendazim   > 40       -             40            -            > 40        Yoshida & Nishiuchi
                                                                             (1976)

CPMC          10 ~ 40    10 ~ 40     5.6           7.0          0.1 ~ 0.5    Yoshida & Nishiuchi
                                     (emulsifiable                           (1972); Nishiuchi
                                     concentrate)                            (1974)

Isoprocarb    10 ~ 40    10 ~ 40     5.9           3.0          0.30         Yoshida & Nishiuchi
                                                                             (1972); Nishiuchi
                                                                             (1974)

Mecarbam      0.70       0.68        0.35          0.055        0.03         Yoshida & Nishiuchi
                                                   granule                   (1972); Nishiuchi
                                                                             (1974)

Methomyl      2.8        2.7         0.87          1.0          0.045        Yoshida & Nishiuchi
                                                                             (1972); Nishiuchi
                                                                             (1974)
------------------------------------------------------------------------------------------------

Table 5.  (contd.)
------------------------------------------------------------------------------------------------
Pesticidea              TLMs for organisms at indicated time (mg/litre)     Reference
              Carp       Goldifsh    Killifish     Guppy        Water flea
               (Cyprinus   (Carassius ( Fundulus    ( Lebistes    ( Daphnia      
               carpio     auratus)   sp)            reticulatus  pulex   
              Linn)                               Peters)      Leydig)
              48 h       48 h        48 h          48 h         3 h
------------------------------------------------------------------------------------------------
MPMC          10 ~ 40    10 ~ 40     12            7.3          0.07         Yoshida & Nishiuchi
                                                                             (1972); Nishiuchi
                                                                             (1974)

MTMC          10 ~ 40    10 ~ 40     27            13           0.35         Yoshida & Nishiuchi
                                                                             (1972); Nishiuchi
                                                                             (1974)

Pirimicarb    > 40       -            40            -            0.048       Yoshida & Nishiuchi
                                                                             (1976)

Promecarb     2.7        -           3.3           -            0.020        Yoshida & Nishiuchi
                                                                             (1976)

Terbam        0.92       -           2.2           -            0.025        Yoshida & Nishiuchi
                                                                             (1976)
                                                                             
Thiophanate   > 40       > 40        > 40          -             > 40            Yoshida & Nishiuchi
                                                                             (1972)

Thiophanate   11         > 40        11 (wettable  -            > 40        Yoshida & Nishiuchi
-methyl                              powder)                                 (1972)

XMC           > 40       > 40        33            25           0.055        Yoshida & Nishiuchi
                                                                             (1972); Nishiuchi
                                                                             (1974)
------------------------------------------------------------------------------------------------
a  BPMC = 1-sec-butylphenylmethyl carbamate
    CPMC = 1-chlorophenylmethyl carbamate
    MPMC =  3,4-xylylmethyl carbamate
    MTMC = 4-tolylmethyl carbamate
    Terbam = 4-tert-butylphenylmethyl carbamate
    XMC = 3,5-xylylmethyl carbamate

 Note:  Test methods are officially recognized methods based on the Notification of the 
       Ministry of Agriculture, Forestry, and Fisheries of Japan.
    Carbamates can have adverse effects on algae.  Stadnyk et al. 
(1971) reported that carbaryl at a concentration of 0.1 mg/litre 
caused an increase in cell numbers and in the biomass of the green 
algae  Scenedesmus quadricaudata. 

    Motsuage fish  (Motsugo pseudoras bora parva) were reported to 
accumulate carbaryl and BPMC during a 30-day exposure to a 
concentration of 0.6 - 1.2 mg/litre.  Carbaryl uptake was greatest.  
However, this compound underwent more rapid metabolism and 
excretion than BPMC.  Metabolism of BPMC was slow and introduced 
permanent spinal curvature of the backbone in about 30% of the fish 
exposed, an effect seen with the organophosphorus insecticide 
diazinon (Kanazawa, 1975). 

    A residue study indicated that over a 28-day period at the 
highest exposure level of 0.75 mg methomyl/litre, no accumulation 
of the carbamate took place.  During the entire exposure period, 
the values ranged from 0.36 to 0.45 mg/kg. After a 3-day withdrawal 
period, no methomyl (< 0.02 mg/kg) was detected in the fish 
(Kaplan & Sherman, 1977). 

    The results summarized in Table 4 are representative of the 
toxicity of the different carbamates for fish and invertebrate 
species.  In general, the LC50s of carbamates for different fish 
species range from approximately 0.1 to 10 mg/litre.  Invertebrates 
are usually more sensitive.  The EC50 values for  Daphnids and 
other species are mainly below 0.1 mg/litre.  Some carbamates seem 
to be very toxic (< 0.01 mg/litre) for these invertebrates. 

7.2.1  Field studies

    Little information is available concerning the fate and 
persistence of carbamates in the aquatic environment.  The presence 
of these carbamates in surface waters may have an effect on water 
organisms. 

    Quraishi (1972) studied the persistence of aldicarb. Field 
water treated in the laboratory at 100 mg aldicarb/litre resulted 
in residues of aldicarb and its metabolites of 0.4 mg/litre after 
11 months.  Water was stored at 16 - 20 C and exposed for 
approximately 507 h to sunlight. 

    Data concerning the fate of aminocarb have been reviewed by 
Vassilieff & Ecobichon (1982).  A half-life of 28.5 days in pond 
water was found under normal environmental conditions. The 
principal metabolite appeared to be the phenol, though the 
methylamino and formylamino analogues were also observed. 

    Harvey & Pease (1973) found that, under field conditions in 
Delaware, Florida, and North Carolina, methomyl broke down almost 
completely within 1 month; most of it was lost from the soil by 
volatilization, presumably as carbon dioxide.  Small amounts 
extracted from the soil consisted of methomyl,  S -methyl  N -
hydroxythioacetimidate, and some polar compounds.  A run-off study, 
under farm conditions, showed that the compound did not move into 
untreated areas with run-off water. 

7.3  Terrestrial Organisms

7.3.1  Effects on soil fauna

    Thiophanate-methyl and carbendazim have been shown to be 
equally as toxic through contact as benomyl.  Earthworms  (Lumbricus 
 terrestris) immersed for 1 min in a 0.6% aqueous suspension of 
these compounds died in 14 days.  Worms in pots containing soil 
drenched at a rate of 0.78 g/m2 died within 18 days (Wright & 
Stringer, 1973). 

7.3.2  Wildlife

    The LD50 of benomyl for mallard ducks and quail is > 5000 
mg/kg body weight.  The cumulative toxicity of formetanate (7 days) 
is approximately 6800 mg/kg body weight for ducks, and > 4640 mg/kg 
body weight for quail and for pheasant (Aldridge & Magos, 1978). 

    Lethal and sub-lethal doses of aldicarb, methiocarb, oxamyl, 
pirimicarb, and thiofanox administered to Japanese quail produced 
significant inhibition of plasma- and brain-ChE and influenced the 
activity of other enzymes, such as alpha-naphthyl acetate esterase, 
glutamate dehydrogenase, and glutamate oxaloacetic transaminase.  
With sub-lethal dose levels, plasma-ChE activity recovered within a 
few days (Westlake et al., 1981). 

    An 8-day dietary LC50 for the Peking duck was 1890 mg/kg
feed; for bobwhite quail, the dietary LC50 was 3680 mg/kg feed
(Kaplan & Sherman, 1977).

    Bobwhites  (Colinus virginianus) were provided diets containing 
sublethal levels of carbaryl (237 or 1235 mg/kg), for 7 days, or 
carbofuran (26 mg/kg), for 14 days.  Food intake, body weight, and 
the locomotor activity of adult bobwhites were normal.  
Administration of a diet containing 131 mg carbofuran/kg resulted 
in reductions in food intake, body weight, and locomotor activity 
(Robel et al., 1982). 

7.3.3  Bees

    An undesirable effect caused by the use of carbamate 
insecticides has been the mortality of honey bees, a species that 
exhibits a high sensitivity to these compounds.  Because of the 
agricultural and ecological importance of bees, thorough 
comparative toxicity studies have been carried out on a large 
number of compounds to identify those with the widest margin of 
safety (Atkins et al., 1973). 

    Abdel-Aal & Fahmy (1977) compared the effects of aldicarb, 
methomyl,  N -desmethylmethomyl, carbaryl, and carbofuran on the 
honey bee  (Apis mellifera) and found that all of the compounds 
were extremely toxic. 

7.4  Earthworm and Mite Populations

    Studies by Stringer & Wright (1973) and Wright & Stringer 
(1973) showed that earthworm populations in apple orchard plots 

sprayed with either benomyl or thiophanate-methyl were reduced.  In 
particular,  Lumbricus terrestris, an important species in the 
ecology of the apple orchard, was virtually eliminated.  Captive 
worms would not feed on leaf material that had been sprayed at 1.75 
g/cm2 with benomyl, methyl benzimidazol-2-yl carbamate (MBC), or 
thiophanate-methyl, and feeding was significantly reduced at a 
level of 0.87 g/cm2. All the worms were killed following contact 
with benomyl as an aqueous suspension or soil drench (7.75 kg/ha). 

    It was suggested by the authors that the toxicity of benomyl 
might be due to the anticholinesterase activity of the carbamate 
moiety.  Effects such as lethargic movements, muscular paralysis, 
and death support this supposition. 

    The spraying of benomyl and thiophanate-methyl in orchards 
reduced the number and biomass of all earthworm species combined 
and also of each individual species (Stringer & Lyons, 1974).  It 
was observed that over 90% reduction in earthworm populations 
occurred in pastures treated with benomyl.  It was suggested that 
these changes were reversible, and that the populations of 
earthworms would return to normal a few years after the termination 
of the treatment (Tomlin & Gore, 1974). 

    The carbamate insecticide most commonly used in the soil is 
carbaryl; it is used mainly in woodlands and orchards where the 
formation and fertility of the soil are important. 

    Stegeman & LeRoy (1964) applied carbaryl at 1.3, 11.2, and 56 
kg ai/ha to a red pine plantation and mixed hardwood stands, and, 
though the lowest dose did not have any effects on mite and 
Collembola populations, the other 2 dose levels considerably 
decreased the numbers of mites and Collembolla. Populations began 
to recover after 2 months, but Collembola were more sensitive and 
recovered more slowly.  There seems to be little likelihood of 
long-term effects of carbaryl on mite populations (Edwards & 
Thompson, 1973). 

8.  EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

8.1  Single Exposures

    Short- and long-term toxicity studies with carbamates have been 
carried out for a period of 20 - 30 years.  It is clear that the 
production of these carbamates has improved during this period and 
that, consequently, purer products have become available.  The use 
of less pure substances in earlier toxicity studies could explain 
the conflicting results between these and later studies. 

8.1.1.  Oral

    Acute oral and dermal toxicity data on animals, for most of the 
carbamate pesticides, are given in Table 6.  The WHO Recommended 
Classification of Pesticides by Hazard is also cited.  This 
classification is based primarily on the acute oral and dermal 
toxicity of the technical material for the rat (WHO, 1984).  The 
oral LD50s range from less than 1 mg/kg body weight for the highly-
toxic aldicarb to over 5000 mg/kg body weight for the non-
insecticidal carbamates such as phenmedipham, carbendazim, propham, 
and benomyl. 

    A dose-effect relationship is generally noticed between the 
administered dose, the severity of effects, and the amount of ChE 
inhibition.  A correlation also exists between the duration of 
symptoms and the  in vivo persistence of the compound. 

    In general, the toxicological effects produced by carbaryl are 
typical of those produced by methyl carbamates.  The effects of 
carbaryl on a number of different animal species were studied by 
Carpenter et al. (1961).  Rats given a single oral dose of 560 
mg/kg body weight showed 42% and 30% inhibition of erythrocyte- and 
brain-ChE, respectively, within 1/2 h of treatment; only about 5% 
inhibition of plasma-ChE was observed.  All ChE levels were almost 
normal after 24 h.  In studies on rats administered single oral 
doses ranging from 5 to 50 mg/kg body weight, a decrease in ChE 
activity occurred within 5 min.  Recovery was quite rapid 
(Krechniak & Foss, 1982). 

    In 4 dogs, marginal inhibition of erythrocyte-ChE activity was 
seen after treatment with a single oral dose of 375 mg carbaryl/kg 
body weight.  After 30 min, signs of poisoning were observed 
including salivation, lachrymation, constriction of pupils, 
urination, defaecation, increase in respiratory rate, muscular 
twitching, tremors, and mild convulsions.  The animals appeared to 
have completely recovered the following day.  These signs of 
poisoning are classic of overstimulation of the parasympathetic 
nervous system (Carpenter et al., 1961). 

    Vassilieff & Ecobichon (1983) studied the influence of a single 
dose of 25 mg aminocarb/kg body weight on the activity of 
erythrocyte- and brain-AChE, plasma-ChE, and hepatic 
carboxylesterases in rats.  Significant inhibition of all the 
esterases was observed, 30 min or more after the administration of 
aminocarb.  This severe, but transient, inhibition of the tissue 
esterases had recovered after 24 h. 


Table 6.  Acute oral and dermal toxicity data for a number of 
carbamate pesticides 
---------------------------------------------------------------------
Carbamate            LD50 (mg/kg body weight)a      WHO Recommended
               oral                dermal            Classification 
                                                     of Pesticides 
                                                     by Hazardb
---------------------------------------------------------------------
aldicarb       0.9                 > 10.0 (rabbit)   IA

aldoxycarb     26.8                700 - 1400        -

allyxycarb     90 - 99             500               -

aminocarb      30 - 40             275               IB

asulam         > 4000              > 1200            -

barban         1376 - 1429         > 1600            -
                                   > 20 000 (rabbit)

BPMC           623 - 657           > 5000            -

bendiocarb     40 - 156            566 - 600         II

benomyl        > 10 000            > 10 000 (rabbit)  0
               > 1000 (dog)

bufencarb      87                  680 (rabbit)      -

butacarb       NA                  NA                -

carbanolate    NA                  NA                -

carbaryl       approximately       > 4000            II
               500 - 600           > 2000 (rabbit)

carbendazim    > 15 000            > 2000           0
               > 2500 (dog)        > 10 000 (rabbit)
               > 10 000 (quail)

carbetamide    10 000              > 2000            -
               1250 (mouse)        > 500 (rabbit)
               1000 (dog)

carbofuran     6 - 14              3400c (rabbit)    IB
               15 - 19 (dog)

chlorbufam     2500                NA                -

chlorpropham   5000 - 8000         10 200d          O
               5000 (rabbit)       2000 (dog)

cloethocarb    35.4                4000              -
---------------------------------------------------------------------

Table 6.  (contd.)
---------------------------------------------------------------------
Carbamate            LD50 (mg/kg body weight)a      WHO Recommended
               oral                dermal            Classification 
                                                     of Pesticides 
                                                     by Hazardb
---------------------------------------------------------------------
desmedipham    > 10 250            2000 - 10 000     -
                                   2025e (rabbit)

dimetilan      64                  > 2000            -
               60 - 65 (mouse)

dichlormate    NA                  NA

dioxacarb      72                  approximately     -
                                   3000 1950         
                                   (rabbit)

ethiofencarb   411 - 499           > 1150            II
               224 - 256 (mouse)
               155 (quail)

formetanate    21, 18 (mouse)      > 5600
               19 (dog)            > 10 200 (rabbit)

hoppicide      NA                  NA                -

isoprocarb     403 - 485           > 500
               487 - 512 (mouse)
               ca 500 (rabbit)

karbutilate    3000                > 15 400          -

methiocarb     100                 350 - 400         II
               40 (guinea-pig)

methomyl       17 - 24             > 5000 (rabbit)   IB
               28 (hen)

metolcarb      498 - 580           > 2000            -

mexacarbate    15 - 63             > 500             -

MPMC           380                 > 1500 (mouse)    -

MTMC           268 (mouse)         6000              -

oxamyl         5.4                 710 (rabbit)      IB
               4.2 (quail)

phenmedipham   > 8000              > 4000            -
               > 4000 (dog)
               > 3000 (chicken)
---------------------------------------------------------------------

Table 6.  (contd.)
---------------------------------------------------------------------
Carbamate            LD50 (mg/kg body weight)a      WHO Recommended
               oral                dermal            Classification  
                                                     of Pesticides  
                                                     by Hazardb
---------------------------------------------------------------------
pirimicarb     147 (101 - 210)     > 500 (rabbit)    II
               107 (mouse)
               100 - 200 (dog)
               25 -  50 (poultry)

promacyl       1220                > 4000            -
               2000 - 4000 (mouse)
               4000 - 8000 (hen)

promecarb      61 - 90             > 1000            -
                                   > 1000 (rabbit)

propham        9000                6800f (rabbit)    O
               3000 (mouse)

propoxur       80 - 191            1000 - 2400       II
               100 - 109 (mouse)
               40 (guinea-pig)

swep           NA                  NA                -

terbucarb      NA                  NA                -

thiodicarb     NA                  NA                -

thiofanox      8.5                 39 (rabbit)       IB
               43 (quail)

thiophanate    > 15 000            > 15 000          -
-ethyl

thiophanate    6640 - 7500         > 10 000          O
-methyl

trimethacarb   NA                  NA                -

xylylcarb      325 - 375           > 1000            -

XMC            542                 -                 -
               445 (rabbit)
---------------------------------------------------------------------
a  Data given for rats, unless otherwise stated.
b  From: WHO (1984). See this reference for classification of
    organophosphates not mentioned in this annex.
     The hazard referred to in this Classification is the acute risk for
     health (that is, the risk of single or multiple exposures over a
     relatively short period of time) that might be encountered
     accidentally by any person handling the product in accordance with the
     directions for handling by the manufacturer or in accordance with the

Table 6 (contd.)

     rules laid down for storage and transportation by competent
     international bodies.

    Classification relates to the technical material, and not to the
    formulated product:
    Class IA = Extremely hazardous. Class III = Slightly hazardous.
    Class IB = Highly hazardous.    Class O = unlikely to present
    Class II = Moderately hazardous.      acute hazard in normal use.
c  With 75% water-dispersible powder.
d  With 50% emulsifiable concentrate formulation.
e  With 16% formulation.
f  With 25% emulsifiable concentrate formulation.
NA = Not available.
 Note: References are the reports of the different WHO/FAO Joint
      meetings on pesticides residues (Annex III), Kaplan & Sherman
      (1977), and Worthing & Walker (1983).

8.1.2  Dermal

    Acute dermal toxicity values for most carbamates are mainly 
above 500 mg/kg body weight with the exception of, for instance, 
aldicarb, which is highly toxic. 

8.1.3  Inhalation

    Exposure to carbaryl (50% wettable powder, average particle 
size, 15 m) at a mean concentration of 390 mg/m3 (range 344 - 722 
mg/m3), for 4 h, produced nasal and ocular irritation in 6 guinea-
pigs.  When another group of guinea-pigs inhaled a mean of 230 mg 
carbaryl/m3 (average particle size, 5 m), for 4 h, no clear 
effects were observed.  Single exposures of dogs ranging from 2 to 
5 h to a concentration of 75 mg carbaryl/m3 (average particle size, 
5 m) caused clinical signs of ChE inhibition (Carpenter et al., 
1961).  Cats exposed to 80 mg carbaryl/m3 for 6 h showed 
salivation, excitation, respiratory difficulties, and 39 - 55% 
inhibition of ChE activity in the serum and 53 - 71% in the 
erythrocytes. A single exposure to a level of 20 mg/m3 for 6 h did 
not induce signs of intoxication, but serum- and erythrocyte-ChE 
activities were slightly inhibited (Yakim, 1967). 

8.2  Short- and Long-Term Exposures

    A number of short-term studies have been carried out with 
different carbamates and a variety of laboratory animal species.  
In the context of this introduction, it is not possible to mention 
all the reports available.  Details on the short- and long-term 
toxicities of the individual carbamates will be provided in future 
Environmental Health Criteria. Most carbamates have been discussed 
by the Joint FAO/WHO Meetings on Pesticide Residues and monographs 
have been published (see reference list).  Furthermore, the 
International Agency for Research on Cancer has published a 
monograph in which a number of carbamates have been evaluated 
(IARC, 1976). 

    In the context of this introduction, a number of examples are 
given to illustrate dose-response relationships and/or target 
organs or tissues for a number of carbamates. 

8.2.1  Oral

    Short-term tests on rats or dogs exposed to repeated oral doses 
of carbamate insecticides or fungicides (such as carbaryl, 
propoxur, formetanate, carbofuran, and benomyl), revealed 
inhibition of plasma (serum)-, erythrocyte-, and brain-ChE 
(Carpenter et al., 1961; Ivanova-Chemishanska & Antov, 1976; 
Krechniak & Foss, 1982). 

    (a)   Pirimcarb

    In a study on 4 dogs (2 males and 2 females) treated with 25 or 
50 mg pirimicarb/kg body weight per day, for 110 weeks, 2 of the 
animals developed anaemia.  Haemoglobin content was decreased, 
methaemoglobin was present, and the reticulocyte percentage was 
significantly elevated.  Levels of unconjugated bilirubin in serum 
were increased.  The 2 other animals were unaffected.  There was 
some indication that pirimicarb was able to induce the production 
of immune IgG antibodies (Jackson et al., 1977). 

    (b)   Carbaryl

    Kidney alterations, such as cytoplasmic vacuolization, were 
observed in the proximal tubules in short-term studies on monkeys 
and rats adminstered carbaryl at dose levels of up to 600 or 300 
mg/kg body weight, respectively (Coulston, 1967; cited in FAO/WHO, 
1970b). 

    Two pigs from one litter were fed a ration containing carbaryl 
at the rate of 150 mg/kg body weight for 72 and 83 days, 
respectively.  Three pigs in the same litter were fed 150 mg/kg 
body weight for 4 weeks and, thereafter, 300 mg/kg body weight, the 
total feeding period being 46 or 85 days. Two other pigs were 
maintained on the basal ration, as controls.  The clinical syndrome 
of chronic intoxication was characterized by progressive 
myasthenia, incoordination, ataxia, tremors, and chronic muscular 
contractions terminating in paralysis and death.  The lesions were 
confined to the central nervous system and skeletal muscle.  
Moderate to severe oedema of the myelinated tracts of the 
cerebellum, brain stem, and upper spinal cord was associated with 
vascular degenerative changes, consistent with a vasogenic oedema 
(Smalley et al., 1969).  Spontaneous recovery from the effects of 
sub-lethal doses occurred in about 8 h, indicating the ready 
reversibility of the carbaryl-enzyme reaction (Carpenter et al., 
1961). 

    Carbaryl was administered to dogs at dose levels of 0, 0.45, 
1.8, or 7.2 mg/kg body weight per day, for 5 days/week, for one 
year.  Cloudy swelling of the proximal convoluted and loop tubules 
of the kidneys was found in the group given 7.2 mg/kg body weight. 
There were no abnormalities in the composition of the blood, and no 
ChE inhibition was found. It should be noted that the dose levels 
tested were low (Carpenter et al., 1961). 

    In a long-term (2-year) toxicity study on CF-N rats, levels of 
0, 50, 100, 200, or 400 mg carbaryl/kg diet (equivalent to 0, 2.5, 
5, 10, or 20 mg/kg body weight) were tested.  The highest dose 
level produced cloudy swelling in the tubules of the kidneys 
(Carpenter et al., 1961). 

    (c)   Carbendazim

    Groups of ChR-CD male rats (6/dose) were intubated with 200, 
3400, or 5000 mg carbendazim/kg body weight per day, 5 times per 
week, for 2 weeks.  In all groups, the absolute and relative 
weights of the kidneys were lower, and adverse effects on the 
testes and reduction or absence of sperm in the epididymides were 
found (FAO/WHO, 1985a). 

    (d)   Benomyl

    In a 2-year toxicity study, Charles River rats were 
administered dietary levels of benomyl of 0, 100, 500, or 2500 
mg/kg (equivalent to 0, 5, 25, or 125 mg/kg body weight). No 
increase in mortality and no other compound-related effects on 
haematology, urinalysis, organ weight, or histology were found 
(Haskell Laboratories, 1969 cited in FAO/WHO, 1985a). 

    In another 2-year study, dogs were administered diets 
containing 0, 100, 500, or 2500 mg benomyl/kg (equivalent to 0, 
2.5, 12.5, and 62.5 mg/kg body weight).  Liver cirrhosis, bile duct 
proliferation, and testicular degeneration were found at the 
highest dose level; however, 100 and 500 mg/kg diet did not show 
any clear effects (Haskell Laboratories, 1970 cited in FAO/WHO, 
1985a). 

    (e)   Thiophanate-methyl

    An oral toxicity study in which thiophanate-methyl at dose 
levels of 0, 2, 10, 50, or 250 mg/kg body weight (in capsules) was 
administered to beagle dogs (8 or 10 animals per group) was 
conducted for 24 months.  Retardation of growth was seen in both 
sexes in the 250 mg/kg group.  Both male and female dogs in the 50 
and 250 mg groups showed a significant and dose-related increase in 
the weight of the thyroid.  However, there were no changes in the 
serum-protein-bound iodine (PBI) levels and no histological 
differences in the thyroid were found between the control group and 
the 2 highest dose groups. No other abnormalities were observed 
(Hashimoto & Fukuda, 1972 cited in FAO/WHO, 1974b). 

    (f)   Methomyl

    Groups of rats were given diets containing 0, 10, 50, 125 
(increased to 500), or 250 mg methomyl/kg for 90 days.  Weight gain 
in animals administered 250 and 500 mg/kg was slightly suppressed.  
No clear changes in the different parameters including plasma- and 
erythrocyte-ChE activity were found (Kaplan & Sherman, 1977). 

    The same authors carried out studies over 90 days and 2 years 
on beagle dogs.  Dietary levels of 0, 50, 100, and 400 mg 

methomyl/kg did not result in any nutritional, clinical, 
haematological, urinary, biochemical, or pathological changes.  In 
the 2-year feeding study, histopathological alterations were seen 
in kidneys and spleen of animals receiving 400 and 1000 mg 
methomyl/kg diet.  Histopathological changes were seen in the liver 
and bone marrow in animals administered 1000 mg/kg diet (Kaplan & 
Sherman, 1977). 

    The above-mentioned studies give some indication that 
carbamates may have different mechanisms of action on target organs 
that are related to substituents other than the carbamate ester 
moiety (such as the imidazole moiety). 

    Apart from the effects on ChE activity, effects have been found 
on the liver, kidneys, thyroid, and testes and also on the 
activities of other enzyme systems such as ATPase, Gl-6-ase, LDH, 
GPT, Alk-Pase, etc. (Haskell Laboratories, 1968 cited in FAO/WHO, 
1985a; Ivanova-Chemishankska & Antov, 1976). 

8.2.1.1  Further information on short- and long-term toxicity

    It is not the purpose of this introductory document to provide 
all the available data on long-term toxicity. However, these long-
term studies are important for the establishment of the no-
observed-adverse-effect level and consequently the Acceptable Daily 
Intake (ADI) for man.  Thus, it is necessary to indicate the 
studies that were considered adequate and used by the different 
FAO/WHO Joint Meetings on Pesticide Residues.  The International 
Agency for Research on Cancer has also evaluated long-term/
carcinogenicity studies of a number of carbamates.  The results of 
these international evaluations are summarized in Annex II and III. 

    From these Annexes, it is clear that aldicarb is the most toxic 
of the carbamates considered; the established ADI for this compound 
is 0.001 mg/kg body weight. 

    The ADIs for the other carbamates may vary from 0.01 to 0.1 
mg/kg body weight.  These quantities are equivalent to a daily 
intake for man (60 kg body weight) of approximately 0.6 - 6 mg. 

8.2.2  Dermal

    (a)   Pirimicarb

    Daily dermal applications of 500 mg pirimicarb/kg body weight 
to the skin of rabbits for 24 h over a 14-day period did not 
produce any signs of intoxication (FAO/WHO, 1977b). 

    (b)   Methomyl

    Methomyl applied to the intact skin of rabbits at a repeated 
rate of 200 mg/kg per day caused mild signs of intoxication such as 
nasal discharge, wheezing, and transient diarrhoea.  All animals 
survived 15 applications.  However, when applied on the abraided 
skin, much more serious systemic signs were seen, such as nasal 
discharge, salivation, tremors, poor coordination, and abdominal 
hypertonia; a few animals died (Kaplan & Sherman, 1977). 

    (c)   Carbaryl

    Application of carbaryl at 500 mg/kg body weight to the skin of 
6 rabbits resulted in 39% inhibition of serum-ChE activity and 36% 
inhibition of red cell-ChE activity during the first 24 h following 
treatment.  ChE activity returned to initial levels in 72 h (Yakim, 
1967). 
 
8.3  Skin and Eye Irritation; Sensitization 

8.3.1  Skin irritation

    Rabbits exposed to a single dermal application of carbaryl at a 
concentration of 100 g/litre in acetone did not show any skin 
irritation (Carpenter et al., 1961). 

8.3.2  Eye irritation

    Undiluted carbaryl or solutions of different concentrations 
were applied to the eyes of rabbits.  Technical carbaryl applied in 
excess as a 100 g/litre suspension in propylene glycol produced 
mild injury.  A 25% aqueous suspension of a microfine material did 
not cause any injuries; 50 mg of the dust caused only traces of 
corneal necrosis (Carpenter et al., 1961). 

8.3.3  Skin sensitization

    (a)   Carbaryl

    Groups of albino guinea-pigs were given 8 intracutaneous 
injections (3 per week) of 0.1 ml of a 0.1% dispersion of carbaryl 
in 3.3% propylene glycol.  After a 3-week incubation period, 
followed by a challenge dose, no clear sensitization reaction was 
noticed (Carpenter et al., 1961). 

    (b)   Benomyl and thiophanate-methyl

    It has been shown that benomyl and thiophanate-methyl can cause 
slight reversible skin irritation and weak sensitization in guinea-
pigs (FAO/WHO, 1974, 1985a). 

8.4  Inhalation

    (a)   Carbaryl

    The inhalation toxicity of carbamates for mammals has not been 
widely studied. 

    The effects of acute inhalation exposure to carbaryl dust have 
been examined in rats (10 mg/m3), guinea-pigs (390 mg/m3), and dogs 
(75 mg/m3) (Carpenter et al., 1961) (section 8.1.3).  No treatment-
associated, gross or microscopic lesions were seen in guinea-pigs 
and dogs, even though the exposure was sufficient to cause ChE 
inhibition.  Haemorrhagic areas in the lung were seen in guinea-
pigs at the highest level tested (390 mg/m3). 

    Four cats exposed to carbaryl in air at 63 mg/m3 for 6 h per 
day for 1 month developed signs of cholinergic stimulation during 
the first 2 h of exposure each day.  Periodic salivation was noted.  
One cat died with marked signs of poisoning on day 20.  There was 
already a significant decrease in serum- and erythrocyte-ChE 
activity after the first exposure.  Exposure to 40 mg/m3 for 6 h 
per day for 2 months was reported to impair conditioned reflexes in 
cats.  On certain days, the ChE activity dropped to below 50% of 
pre-exposure values. Exposure to concentrations of 16 mg/m3, for 6 
h per day, for 4 months did not result in any signs of toxicity 
(Yakim, 1967).  Carpenter et al. (1961) did not find any increase in 
mortality or "grossly-visible injury" when rats were exposed to a 
mean concentration of 10 mg/m3 (range 5 - 20 mg/m3), for 7 h per 
day, 5 days/week, over 90 days. 

    (b)   Propoxur

    Male and female rats were exposed to propoxur aerosols at
average concentrations of 0, 5.7, 10.7, or 31.7 mg/m3, for 6 h 
daily, 5 days/week, over a period of 12 weeks.  Depression of 
plasma-, erythrocyte-, and brain-ChE activity was observed at the 
highest dose level (Kimmerle & Iyatomi, 1976). 

8.5  Reproduction, Embryotoxicity, and Teratogenicity

    A considerable number of reproduction and teratogenicity 
studies have been carried out on different carbamates in several 
animal species.  A number of these will be used to show the state 
of the art giving the well-known carbamates, such as carbaryl, 
benomyl, carbendazim, and thiophanate-methyl, as examples. 

    For more details concerning different carbamates, the reader is 
referred to the reports of the Joint FAO/WHO Meetings on Pesticide 
Residues and, in the future, to the Environmental Health Criteria 
Documents on the individual carbamates. 

8.5.1  Reproduction

    (a)   Methomyl

    A 3-generation reproduction study with methomyl was carried out 
on rats.  Dose levels of 0, 50, or 100 mg/kg diet were administered 
for 3 months.  There was no evidence from the different indices of 
reproduction, lactation, and weanling body weights to suggest that 
methomyl affected reproduction or lactation performance in the 
litters of three generations (Kaplan & Sherman, 1977). 

    (b)   Benomyl

    The effects of benomyl on the gonads and reproductive function 
were studied in a 3-generation study on rats. Pronounced effects, 
such as a decrease in fertility and decreased activities of a 
number of enzymes in the testes were found in rats treated orally 
with 1000 mg/kg body weight (the only dose level tested), 5 
days/week, for 4 months.  Besides the effects mentioned, a 
decreased gestation index was also found, which may indicate early 

embryonic death due to the induction of a dominant lethal gene in 
the sperm cells.  An increase in mortality and decreased viablility 
and fertility were found in the F1 - F3 generations (not exposed to 
the carbamate) (Ivanova-Chemishanska & Antov, 1980; Ivanova-
Chemishanska et al., 1980).  In a second 3-generation rat 
reproduction study with benomyl, no differences in reproduction or 
lactation were observed among control and test groups of animals at 
the highest dietary level of 2500 mg/kg diet.  No pathological 
changes were found in tissues from weanling pups of the F3b litter 
(Sherman et al., 1975). 

    (c)   Carbendazim

    From 3 multigeneration reproduction studies on rats, in which 
carbendazim was tested at dose levels of up to 10 000 mg/kg diet, 
no apparent adverse effects on reproduction were found at levels of 
up to 2000 mg/kg diet.  A reduction in average litter weights was 
observed at dietary levels of 5000 and 10 000 mg/kg (FAO/WHO, 
1985a). 

    (d)   Carbaryl

    In 3-generation rat studies, carbaryl added to the diet to 
provide daily doses of up to 10 mg/kg body weight, did not result 
in any statistically-significant dose-related effects on fertility, 
gestation, viability of pups, or lactation (Weil et al., 1972). 

    In other studies by Weil et al. (1972, 1973), groups of rats 
received carbaryl in the diet at daily doses of 0, 3, 7, 25, or 100 
mg/kg body weight by intubation, for 5 days/week, or 0 or 100 mg/kg 
body weight per day in the diet.  Significant effects were found 
on reproduction (mortality and reduced fertility) in the group 
receiving 100 mg/kg. A group receiving 200 mg/kg diet did not show 
any effects. 

    The influence of carbaryl at dose levels of 2 or 5 mg/kg body 
weight on the reproductive function of rats was studied by 
Shtenberg & Otovan (1971).  Both dose levels produced adverse 
effects on the testes and ovaries (atrophic, dystrophic and 
necrotic changes) and changed the gonadotropic function of the 
hypophysis.  The changes observed increased progressively over the 
generations.  The fecundity of test females fell, the number of 
still-born offspring increased, and there was a high death rate 
among young animals. 

    Carbaryl was fed at dietary levels of 0, 2000, 5000, or 10 000 
mg/kg feed to Osborne-Mendel (10 males and 10 females) rats for 3 
generations.  At the highest dose level, fertility was impaired and 
no litters were produced from the second mating of the second 
generation.  Marked effects from birth to day 4 were manifested as 
seen in the survival index.  Dose-related decreases in average 
litter size, number of live-born progeny, number of survivors to 
day 4, and number weaned were observed. 


    In a comparative study on gerbils, dietary levels of 0, (40 
animals) 2000, 4000, 6000 (each 30 animals), and 10 000 mg 
carbaryl/kg (18 animals) were tested for 3 generations.  No litters 
were produced from the second mating of the third generation, at 
the highest dose level.  Gerbils appeared to be more sensitive than 
rats since significant decreases were found consistently at lower 
dietary levels, but the effects were not clearly dose-related.  
Effects in both species at 2000 mg/kg diet were still marginal but 
significant (Collins et al., 1971). 

    (e)   Thiophanate-methyl

    Thiophanate-methyl was tested in a 3-generation reproduction 
study on rats at dose levels of 0, 40, 160, or 640 mg/kg diet.  The 
highest dose level affected growth, but no effects of the compound 
on reproduction parameters were apparent (FAO/WHO, 1974b). 

    (f)   Carbofuran

    A 3-generation reproduction study was conducted on rats (8 
males and 16 females per group), with dietary levels of 0, 1, 10, 
or 100 mg carbofuran/kg diet.  The highest dose level resulted in 
decreased weight gain in the parents and a marked reduction in 
survival of the young.  Lower levels did not have any effects.  
Follow-up studies with lower dose levels showed that 20 mg/kg diet 
induced adverse effects on reproduction variables, noted after the 
first generation (McCarthy et al., 1971; FAO/WHO, 1977b, 1981b). 

8.5.2  Endocrine system

    (a)   Carbaryl

    Short-term studies on male and female rats were carried out to 
study the functioning of the reproductive system under the 
influence of carbaryl.  The dose levels ranged from 2 to 300 mg 
carbaryl/kg body weight and were administered over periods of 3 - 
12 months; in one study, 4 generations were bred.  Different 
criteria were studied, such as reduction of sperm motility, 
duration of sperm survival, inhibition of spermatogenesis and 
ogenesis, estrous cycle, induction of degeneration of the germinal 
epithelium, and the activities of different enzymes in the testes 
and ovaries.  Shtenberg & Rybakova (1968) found marked functional 
and morphological changes in the endocrine organs of rats 
administered carbaryl at daily doses of 7, 14, or 70 mg/kg body 
weight for up to 12 months.  It was considered by the authors that 
the effects of carbaryl on the testes and ovaries might be 
explained by the observed increase in hypophyseal gonadotropic 
function.  A direct effect on the testes and ovaries cannot be 
excluded. 

    Orlova & Zhalbe (1968) studied the effects of carbaryl on white 
rats.  Dose levels of 2.5 or 5 mg/kg body weight were administered.  
Disturbances in the enzymatic activity in the testes and ovaries, 
inhibition of spermatogenesis and ogenesis, and decreased 
fertility were observed in the P generation, and a decrease in 
viability, in the F1 generation. 

    Shtenberg & Otovan (1971) studied this effect of carbaryl in 
more detail in a 4-generation study.  The dose levels studied were 
0, 2, and 5 mg/kg body weight, and were applied for 6 months in 
each generation.  The disturbances in the function of the testes 
and ovaries described above were found at both 2 and 5 mg/kg 
(Vashakidze, 1965, 1967; Shtenberg & Rybakova, 1968; Shtenberg & 
Otovan, 1971; Shtenberg et al., 1973).  However, the studies 
reporting adverse effects on spermatogenesis in male rats were not 
confirmed in studies on mice with carbaryl by Dikshith et al. 
(1976) or in reproductive performance studies on rats. 

  (b)   Benomyl

    A study on the short-term toxicity of benomyl carried out by 
Torchinsky et al. (1976) showed that the testis of Wistar rats was 
the organ most affected.  When administered over a 12-month period, 
a dose of 62.5 mg/kg body weight showed borderline effects; 12.5 
mg/kg body weight did not show an effect.  A recent study on 
Sprague Dawley rats receiving 10 daily treatments of 0, 200, or 400 
mg benomyl/kg body weight, by gavage, showed a significant decrease 
in the total epididymal sperm counts and sperm concentrations in 
the vas deferens at both levels.  At the higher dose level, slight 
to severe hypospermatocytogenesis and generalized 
hypospermatogenesis were observed (Carter & Laskey, 1982; FAO/WHO, 
1985a). Pastushenko (1983) studied the gonadotoxic effects of 
benomyl in rats exposed to dose levels of 0.5, 1.2, 5.0, or 12.4 
mg/m3 air.  The 2 highest dose levels showed dose-related changes 
in the gonads, i.e., disturbances of the morphological and 
functional states.  At 1.2 mg/m3, only morphological changes were 
observed.  No effects were found with 0.5 mg/m3. 

    (c)   Carbendazim

    When Sprague Dawley rats were fed diets containing 0, 2000, 
4000, or 8000 mg carbendazim/kg diet for 28 days, degeneration of 
testicular tissue was observed at 4000 and 8000 mg/kg diet.  
Spermatogenesis and ogenesis were affected at these feeding 
levels.  Changes were also found in the organ weights relative to 
body or heart weight, changes in the liver being observed at 2000 
mg/kg diet (FAO/WHO, 1974b). 

    No effects on testicular weights and morphology were found in a 
study on groups of ChR-CD rats fed carbendazim in the diet for 90 
days at dose levels of 0, 100, 500, or 2500 mg/kg (FAO/WHO, 1985a). 

8.5.3  Embryotoxicity and teratogencity

    A number of carbamate esters have been tested for 
teratogenicity with the chicken embryo bioassay (Marliac, 1964; 
Ghadiri & Greenwood, 1966; Khera, 1966; Ghadiri et al., 1967; 
Rybakova, 1968; Olefir & Vinogradova, 1968; Proctor et al., 1976; 
Moscioni et al., 1977).  However, this test is not considered of 
relevance in testing for teratogenicity, and the results will not 
be discussed in this document. 

    (a)   Propoxur

    Roszkowski (1982) studied the effects of propoxur on 
intrauterine development and on the state of ossification of rat 
fetuses.  An embryotoxic effect was found at a dose of 20% of the 
LD50, administered on days 7 - 19 of the gestation period; 11.9% of 
anomalies occurred in the fetuses of treated animals compared with 
6.3% in the controls.  Decreased weight was also found in the 
fetuses.  Ossification was disturbed, but this was not related to 
the period of gestation during which the substance was 
administered.  A decrease in the concentrations of calcium and 
magnesium was found in the serum of mothers whose fetuses had shown 
bone anomalies. 

    (b)   Benomyl

    In a teratogenicity study, pregnant ChR-CD rats were fed a diet 
containing 0, 100, 500, 2500, or 5000 mg benomyl/kg from day 6 to 
day 15 of gestation; no effects were found on the outcome of 
pregnancy or embryonal development (Sherman et al., 1975).  
Hazleton Laboratories (1968) cited in FAO/WHO (1985a) reported 
similar negative results for rabbits, at dose levels up to 500 mg 
benomyl/kg diet administered on days 8 - 16 of gestation. 

    Torchinsky (1973) studied the influence of carbaryl (106 mg/kg 
body weight, daily, from day 1 to day 20 of pregnancy) and benomyl 
(single dose of 145 or 250 mg/kg body weight on day 12 of 
pregnancy) in relation to the protein content of the diet.  The 
animals were kept on diets containing 5, 10, 19, or 35% of protein 
either for one month prior to mating and during the entire 
pregnancy or only during pregnancy. The teratogenic and embryotoxic 
actions of benomyl and carbaryl did not differ in groups where the 
females received diets containing 5, 10, or 19% protein from the 
beginning of pregnancy.  An increased post-implantational lethality 
for the embryos was noted in females kept on a diet with 5% protein 
from one month before conception.  When these animals were exposed 
to carbaryl, the weight of 20-day-old fetuses declined 
considerably, yet the severity of the teratogenic action of benomyl 
did not increase under these conditions.  The teratogenic action of 
benomyl and the embryotoxic action of carbaryl were less severe in 
animals fed diets containing 10% of protein from one month before 
conception than in the groups kept on diets containing 19 or 35% 
protein. The results of a few other studies have indicated that 
benomyl causes embryotoxic and teratogenic effects in both rats and 
mice when administered orally (by gavage) at dose levels at 62.5 
mg/kg body weight (rat) and 100 mg/kg body weight (mouse) or more.  
At lower dose levels (31.2 mg for the rat and 50 mg/kg for the 
mouse), no teratogenic effects were observed.  A broad spectrum of 
malformations such as exencephaly, hydrocephaly, and 
meningocephaly, and disturbance of the CNS were found (Ruzicska et 
al., 1975; Petrova-Vergieva, 1979; Kavlock et al., 1982). 

    (c)   Carbaryl

    A number of teratogenicity studies carried out with carbaryl 
gave contradictory results.  Weil et al. (1972) administered up to 

500 mg carbaryl/kg body weight to rats.  No teratogenic effects or 
effects on fertility or gestation were seen at this high dose 
level; however, the mean body weight gain of the females during 
pregnancy was decreased.  Many pups died before weaning. No effects 
were found with administration of carbaryl at 100 mg/kg body weight 
(Weil et al., 1972). 

    Oral administration of carbaryl to pregnant rabbits and 
hamsters at doses of up to 250 mg/kg body weight, by intubation, 
did not cause any teratogenic effects or dose-related fetal 
mortality (Weil et al., 1973). 

    Dougherty et al. (1975), cited in FAO/WHO (1974b), did not 
observe any teratogenic effects in monkeys given doses of carbaryl 
of 0, 0.2, 2, or 20 mg/kg body weight from day 18 to day 40 of 
gestation.  This study indicated that even the highest dose level 
did not induce a reproductive hazard. 

    Vashakidze (1965, 1967) found reduced reproduction and abnormal 
fetal changes with intubated dose levels of 100 mg/kg body weight 
and higher.  A level of 50 mg/kg produced negative results.  
Carbaryl, administered to guinea-pigs orally during organogenesis 
(10 consecutive days between days 11 and 20 of gestation) at 300 
mg/kg body weight, induced increased maternal and fetal mortality 
and offspring with axial skeletal defects, such as cervical 
vertebrae fusion.  No abnormal fetal changes were produced in 
hamsters at the sub-lethal levels of 125 and 250 mg/kg body weight.  
In rabbits, levels ranging from 50 to 200 mg/kg body weight did not 
produce any effects on mortality or morbidity, and no abnormal 
fetal changes were seen (Robens, 1969). 

    Smalley et al. (1968) conducted studies on pregnant beagle dogs 
fed a diet containing 0, 3.125, 6.25, 12.5, 25, or 50 mg 
carbaryl/kg body weight from mating to the termination of weaning.  
Effects observed included a number of animals with dystocia 
(difficult births) due to atonic uterine musculature, an apparent 
contraceptive effect at the highest dose level, and teratogenic 
effects (different types of severe defects) at all but the lowest 
dose level. 

    The effects of carbaryl on rat reproduction and guinea-pig 
teratology were compared by Weil et al. (1973). A 3-generation 
reproduction study on rats included groups receiving carbaryl at 
maximum daily doses of 200 mg/kg diet.  Other groups concurrently 
received daily oral intubation doses as high as 100 mg/kg body 
weight.  In the guinea-pig teratology study, maximum levels of 300 
mg/kg diet or 200 mg/kg body weight (intubation) were given.  The 
concurrent administration of carbaryl by daily oral administration 
or by dietary inclusion did not result in either teratological or 
mutagenic effects in the rat or teratological effects in the 
guinea-pig, at the maximum dosage levels.  However, the groups 
receiving maximum levels orally showed severe toxic effects in both 
studies compared with little or no effect with oral administration 
of 25 mg/kg in rats and 100 mg/kg in guinea-pigs. 

    The authors concluded that the severe effects found in rats by 
Shtenberg & Otovan (1971) following repeated oral intubation of 
carbaryl at 2 mg/kg body weight could not be confirmed, even at the 
maximum oral intubation level of 100 mg/kg body weight. 

    (d)   Methomyl

    When rabbits were fed dietary levels of 0, 50, or 100 mg 
methomyl/kg on days 8 - 16 of gestation, no skeletal or visceral 
abnormalities were seen in the fetuses (Kaplan & Sherman, 1977). 

    (e)   Carbofuran

    Teratogenicity studies have been carried out on albino rats and 
albino rabbits with carbofuran.  In rats, dose levels of 0, 0.1, 
0.3, or 1.0 mg/kg body weight were administered throughout 
gestation (days 6 - 15 of pregnancy) and, in rabbits, levels of 0, 
0.2, 0.6, or 2.0 mg carbofuran/kg body weight were administered 
from day 6 to day 18 of gestation. In both animal species, the 
highest dose level showed clear signs of poisoning.  However, 
pregnancy, viability, fetal body weights, and all the other 
examinations did not show any effects.  All the progeny were 
normal.  No teratogenic effects were seen in rats or rabbits 
(McCarthy et al., 1971; FAO/WHO, 1981b). 

    (f)   Carbendazim

    Carbendazim has been shown to be embryotoxic at dose levels of 
approximately 19 mg/kg body weight or more.  This effect was not 
seen at 10 mg/kg body weight (Delatour & Richard, 1976). 

8.6  Mutagenicity and Related End-Points

    There is little evidence, if any, to suggest that methyl 
carbamate compounds are mutagenic.  An evaluation of the mutagenic 
potential of carbaryl, methomyl, propoxur, carbofuran, and 
pirimicarb, using a variety of microorganisms as indicator strains, 
including strains of  Salmonella typhimurium, Escherichia coli, 
 Saccharomyces cerevisiae, and  Bacillus subtilus, produced 
negative results.  These studies showed that carbamate compounds 
have little potential for presumptive gene mutations in higher 
animals. 

    Anderson et al. (1972) examined barban, chloropropham, propham, 
and swep for their ability to induce point mutations in 8 
histidine-requiring strains of  S. typhimurium. None showed induced 
mutations.  This study was carried out in the absence of any 
metabolic system. 

    The chemical structure of benomyl probably enables it to act 
both as a base analogue for DNA (benzimidazole ring incorporates 
into nucleic acids instead of guanine) and as a spindle poison 
(carbamate groups) (Seiler, 1975, 1976b; FAO/WHO, 1985a).  The 
binding of benomyl to microtubular proteins disturbs the mitotic 
spindle, thus causing malsegregation of chromosomes during the 
mitotic anaphase (Morris, 1980, cited by Finnish National Board of 

Health Toxicology Group, 1982).  The results of several studies 
suggest that benomyl is a strong antimitotic agent which, even in 
low concentrations, induces non-disjunction of single chromosomes 
leading to aneuploidy (FAO/WHO, 1985a). 

    The induction of low-frequency forward mutations by carbendazim 
in  S. typhimurium strain LT-2 was reported by Seiler (1972).  
Reversions reported to occur in  S. typhimurium strains His G46 and 
TA 1530 were attributed to base-substitution mutations caused by 
carbendazim. 

    Another study was made with the WP2 uvrA repair-deficient 
strain of  E. coli and the TA 1535 repair-deficient strain of 
 S. typhimurium.  Mutagenic activity was detected for benomyl in the 
former, but not in the latter or in TA 1538 (Kappas et al., 1976).  
No effects were found in the CM-611 strain of  E. coli, deficient 
in either the excision repair pathway or the lex A+-dependent 
misrepair pathway.  In studies carried out recently, benomyl was 
negative in all  S. typhimurium strains used, even though, in some 
of the repeats, significant increases in the number of revertants 
were observed in TA 1535 strain.  Carbendazim was clearly mutagenic 
in the TA 98 strain with metabolic activation (S-9 mix) and 
slightly mutagenic in the TA 1535, TA 1537, and TA 100 strains.  A 
positive result for carbendazim in the TA 1537 strain was observed, 
also without metabolic activation (Haskell Laboratories, cited by 
the Finnish National Board of Health, 1982; FAO/WHO, 1985a). 

    There is evidence that carbendazim and related compounds are 
antimitotic agents and cause mitotic arrest, mitotic delay, and a 
low incidence of chromosome damage in SPF Wistar rats and mammalian 
cell lines.  The mutagenic effects of carbendazim in bacteria are 
probably due to base substitutions, resulting from the 
incorporation of small quantities of benzimidazole into nucleic 
acids.  The effects on mammalian cells  in vivo and  in vitro 
indicate that carbendazim causes chromosome damage, which may 
result from this type of mutagenic activity, but the effects on 
mitosis suggest that, in higher organisms, the main genetic effect 
is to cause non-disjunction (Styles & Garner, 1974). 

    An abnormal number of micronucleated erythrocytes have been 
observed in the bone marrow of mice treated orally with carbendazim 
at 100 mg or more/kg body weight.  No effects were seen at 50 
mg/kg.  Benomyl at 1000 mg/kg body weight produced a slight 
increase in micronucleated erythrocytes. 

    Carbendazim did not induce chromosome breakage in Chinese 
hamster bone-marrow cells at oral doses as high as 1000 mg/kg body 
weight (Seiler, 1976a).  It was concluded that carbendazim is not 
a chromosome-breaking agent, and its micronucleic action is 
attributable to antimitotic activity caused by inhibition of 
spindle formation or spindle function. 

    An evaluation of the mutagenic properties of benomyl has been 
completed and reported by the US Environmental Protection Agency 
Pesticide Genotoxicology Program.  Benomyl increased the mutation 
frequency in a concentration-related manner in L 51784 mouse 

lymphoma cells and induced sister chromatid exchange in Chinese 
hamster ovary (CHO) cells.  Benomyl was also positive at all dose 
levels tested in the  in vivo micronucleus test with mice.  The 
results of the spot test conducted on mice support the idea that 
carbendazim (oral application of 100 - 300 mg/kg body weight to the 
mother on the 10th day following conception) may be mutagenic in 
mammalian cells due to a direct action on DNA (Fahrig & Seiler, 
1979). 

    A dominant lethal study to evaluate the potential mutagenic 
effects in the reproductive cycle of the male mouse was conducted 
with propoxur at dose levels of 0, 2.5, or 5 mg/kg body weight.  
For a period of 6 weeks, 3 virgin females were exposed to each male 
at weekly intervals and reproduction indices recorded.  The 
administration of propoxur proved to have a transient effect on the 
reproductive capability of the males but there was no sign of early 
resorption indicating a mutagenic effect (FAO/WHO, 1974b). 

    DNA-repair tests (with both isolated rat and mouse hepatocytes) 
were conducted using benomyl and carbendazim.  All tests showed 
negative results for the induction of DNA repair (Haskell 
Laboratories, 1981a,b cited in FAO/WHO, 1985a). 

    The Finnish National Board of Health (1982) summarized the 
mutagenicity data on benomyl, carbendazim, and thiophanate-methyl 
(Table 7) and concluded that the results were sometimes 
contradictory.  However, positive mutagenicity results from point 
mutation tests and chromosome aberration tests are well documented, 
especially in higher organisms, and it can be concluded that 
carbendazim fungicides should be considered as weak mutagenic 
compounds. 

    Without going into detail, it is known that a large number of  N 
-nitroso derivatives of methyl carbamates are potent mutagens.  The 
 N -nitroso derivatives of aldicarb, propoxur, carbofuran, 
trimethacarb, and methomyl caused numerous single-strand breaks in 
normal human skin cells.  The data suggested that human cellular 
DNA  in vivo was irreversibly altered resulting in numerous alkali-
sensitive bonds (Blevins et al., 1977). 

    A similar result was obtained with  N -nitroso carbaryl. This 
compound showed strong mutagenic activity in 2 bacterial systems, 
 E. coli and  Haemophilus influenzae. Using  S. typhimurium, N -
nitroso carbaryl acted as a potent base-pair substition mutagen and 
showed a relatively mild frameshift activity.  The parent compound, 
carbaryl, gave negative results (Regan et al., 1976; FAO/WHO, 
1982b). 

    Uchiyama et al. (1975) tested the nitroso derivatives of BPMC, 
propoxur, hoppcide, isoprocarb, MPMC, and MTMC, in the back 
mutation test with  E. coli B/r WP2 try- and in the rec-assay 
method with  B. subtilus strains.  The  N -nitroso derivatives of 
all these  N -methylcarbamates showed potent mutagenic activity. 


Table 7.  A summary of the mutagenicity data on benomyl, carbendazim (MBC), and 
thiophanate-methyl
----------------------------------------------------------------------------------------
Point mutations                                           Genetic change                
                               Chromosomal aberrations          Non-disjunction
----------------------------------------------------------------------------------------
 Positive results  +           +                                +

 Salmonella typhimurium        rat fetus
(Seiler, 1972)                 (Ruzicska et al., 1975)

 Salmonella typhimurium        rat bone marrow                  rat bone marrow
(Haskell Laboratories, 1982    (Styles & Garner, 1974)          (Styles & Garner, 1974)
cited in FAO/WHO, 1985a)
                                                                mouse bone marrow
                                                                (Seiler, 1976a)

 Escherichia coli                                                Aspergillus nidulans
(Kappas et al., 1976)                                           (Kappas et al., 1974;
                                                                Bignami et al., 1977)

 Fusarium oxysporum
(Dassenoy & Meyer, 1973)

Mouse/spot-test                Chinese hamster ovary (SCE)
(Fahrig & Seiler, 1979)        (SRI International, 1980,
                               cited in FAO/WHO, 1985a)

                               micronucleus  in vivo /mouse
                               (SRI International, 1980,
                               cited in FAO/WHO, 1985a)

 Negative results  -           -                                -

 Streptomyces coelicolor       rat bone marrow                  dominant lethal/rat
(Carere et al., 1978)          (Ruzicska et al., 1975)          (Sherman et al., 1975)

 Salmonella typhimurium        Chinese hamster bone marrow      dominant lethal/mice
(Fiscor et al., 1978)          (Seiler, 1976a)                  (Makita et al., 1973)
(Carere et al., 1978)

 Salmonella typhimurium        lymphocyte culture-cytotoxicity
(Haskell Laboratories, 1981;   obs.
cited in FAO/WHO, 1985a)       (Lamb et al., 1980)

 Aspergillus nidulans          benomyl-workers
(Bignami et al., 1977)         (Ruzicska et al., 1975)

 Drosophila /recessive lethal   hepatocyte culture/DNA-repair
- sterility obs.               rat, mouse
(Lamb & Lilly, 1980)           (Haskell Laboratories, 1981,
                               cited in FAO/WHO, 1985a)

                               human lymphocyte culture
                               (Gupta & Legator, 1975,
                               cited in FAO/WHO, 1985a)
----------------------------------------------------------------------------------------
From: The Finnish National Board of Health (1982) FAO/WHO (1985a).

8.7  Carcinogenicity

8.7.1  General

    The mechanism of the carcinogenic action of ethylcarbamate 
(urethane) has not yet been established, but its structure seems to 
be optimal.  All changes seem to reduce activity, particularly when 
the ethyl group is replaced with larger side chains.  The addition 
of alkyl groups to the nitrogen also reduces activity (Mirvish, 
1968).  It is not so clear why urethane is carcinogenic, whether it 
is the proximal toxin or whether it has to be converted to an 
active metabolite.  The low carcinogenic potential of esters of  N -
substituted carbamic acids is possible. 

    In 1976, a Working Group of the International Agency for 
Research on Cancer (IARC, 1976) reviewed the available data on a 
number of carbamate pesticides included carbaryl, propham, 
chloropropham, and mexacarbate. 

    Carbaryl was tested in a number of carcinogenicity tests some 
of which were not relevant or were of inadequate design. The rat 
study (40 per group), in which carbaryl was administered at dose 
levels of 0, 50, 100, 200, or 400 mg/kg diet for 2 years, did not 
give any indication of an increase in tumour incidence (Carpenter 
et al., 1961; Innes et al., 1969; Andrianova & Alekseev, 1970; 
IARC, 1976). 

    Groups of 48 male and 48 female CD-1 mice were given 0, 100, or 
400 mg carbaryl/kg diet.  After 80 weeks, the tumour incidence 
between the groups was similar (Mellon Institute, 1963 cited in 
FAO/WHO, 1965b). 

    Mexacarbate was administered orally to 2 strains of mice. The 
design of this study was inadequate (only a small number of 
animals), but an increased incidence of lung adenomas was shown in 
both strains, together with a slight increase in liver tumours in a 
number of males of one strain.  According to IARC (1976), it was 
not possible to make an evaluation of the carcinogenicity of 
mexacarbate on the basis of this study by Innes et al. (1969). 

    Propham and chlorpropham were administered via the oral route 
in a number of carcinogenicity tests on mice, rats, and hamsters.  
One or both compounds were also tested on mice and/or rats via the 
subcutaneous, intraperitoneal, or intrapleural route.  The design 
of some of these studies was inadequate.  Propham and chloropropham 
were tested for initiation properties, because the ethyl carbamates 
are related to the well-known carcinogen ethylcarbamate (urethane), 
which is an initiator of skin tumours.  There was no evidence that 
propham and/or chloropropham were carcinogenic after oral, 
subcutaneous, intraperitoneal, and intrapleural application.  
However, these two compounds acted as weak initiators in the two-
stage carcinogenicity studies on mice.  A second study by the same 
authors did not confirm the results (Van Esch et al., 1958; 
FAO/WHO, 1965b; Innes et al., 1969; Van Esch & Kroes, 1972; IARC, 
1976). 

    Long-term studies on rats did not provide any evidence of 
carcinogenic activity when propoxur was fed in the diet for 2 years 
at levels of 0, 250, 750, 2000, or 6000 mg/kg diet. Increased liver 
weight was found at the highest dose level (6000 mg/kg) in males 
and in the three highest dose levels in females. This liver change 
was not reflected in liver function tests, clinical chemical 
examinations, or histological changes (FAO/WHO, 1974b).  Similarly, 
long-term and 2-year studies on rats, dogs, mice given carbofuran 
or pirimicarb did not indicate any carcinogenic potential.  The 
dose levels tested were 175 mg/kg diet for rats and 1.8 mg/kg body 
weight for dogs for pirimicarb, 100 mg/kg diet for rats, and 500 
mg/kg diet for mice (24 months in mice) for carbofuran (FAO/WHO, 
1977b, 1981b). On the basis of a variety of test protocols, these 
carbamate compounds did not show any significant carcinogenic 
potential. 

    Benomyl was tested for carcinogenicity in CD-1 mice, at dose 
levels of 0, 500, 1500, or 5000 mg/kg diet (approximately 
equivalent to 0, 50, 150, or 500 mg/kg body weight).  A significant 
dose-dependent increase in the incidence of primary hepatocellular 
adenomas and carcinomas in female mice was seen.  Furthermore, 
histopathological changes occurred in a number of organs (Haskell 
Laboratories, 1981 cited in FAO/WHO, 1985a). 

    Low dose levels of thiophanate-methyl (0 - 640 mg/kg diet, 
equivalent to approximately 0 - 64 mg/kg body weight) were tested 
for carcinogenicity in ICR-SCL mice.  This study showed that 
ingestion of 640 mg thiophanate-methyl in the diet by a mouse 
strain susceptible to various tumours did not affect carcinogenic 
activity.  In another study on rats, dose levels of 0, 10, 40, 160, 
or 640 mg/kg diet did not have any apparent effects on the 
occurrence of tumours; the only significant effects appeared to be 
decreased growth at the highest dose levels (Hashimoto & Fukuda, 
1972, cited in FAO/WHO, 1974b). 

    The influence on the testes of ChR-CD rats of carbendazim 
administered at dose levels of 0 - 10 000 mg/kg diet was studied 
over a period of 2 years.  However, the incidence of testicular 
changes was so high in the two control groups that no opinion could 
be given on the possible influence of carbendazim on the testes 
(Haskell Laboratories, 1977 cited in FAO/WHO, 1985a). 

    Carbendazim at dose levels of 0, 150, 300, or 1000 mg/kg diet 
(this dose level was increased to 2000 mg/kg at week 4 and to 5000 
mg/kg at week 8 for the remainder of the study) was administered to 
SPF-Swiss mice.  The duration of the study was 80 weeks.  At the 
highest dose level, neoplastic nodules were found in the livers of 
female mice.  In males, there was an increased incidence of 
hepatoblastomas (CIVO/TNO, 1976 cited in FAO/WHO, 1985a). 

    A 2-year feeding study on CD-1 mice was conducted using 
carbendazim at dose levels of 0, 500, 1500, or 7500 mg/kg diet 
(only females completed the 2-year period, the 7500 mg/kg level for 
males was decreased to 3750 mg/kg after the first 15 months of the 
study and the final sacrifice of this group was antedated by 7 
months).  A significant increase in hepato-cellular carcinomas 

occurred at 1500 mg and 7500 mg/kg in female mice and at 1500 mg/kg 
in male mice (at the highest dose level for males, there were too 
few survivors to judge the effects) (Haskell Laboratories, 1982; 
FAO/WHO, 1985a). 

    Other studies demonstrated that carbamates in the presence of 
nitrite could be converted to  N -nitroso derivatives, which may be 
(partly) responsible for the "carcinogenic activity of the 
carbamates". 

    Studies in which carbendazim was administered to Swiss mice, 
twice, at 250 mg/kg body weight, intragastrically, weekly, in 
combination with 5000 mg sodium nitrite/litre drinking-water caused 
a slight increase in the incidence of lymphosarcomas (Brzsnyi & 
Csik, 1975; Brzsnyi & Pinter, 1977). 

    The results of an  in vitro study of Beraud et al. (1979) 
(IARC, 1976) suggested that nitrosocarbaryl could be produced in 
rat gastric juice from carbaryl. 

    The proposal that carbamate pesticides may be converted to  N -
nitroso compounds under the acid conditions of the stomach is based 
on the results of  in vivo nitrosation studies with secondary 
amines and other compounds in the presence of nitrite (originating, 
for instance, from certain vegetables and present in saliva) 
(Tannenbaum et al., 1974).  Elespuru & Lijinsky (1973), Eisenbrand 
et al. (1974, 1975a,b), Elespuru et al. (1974), Ungerer et al. 
(1974), Quarles & Tennant (1975), Lijinsky & Taylor (1976), and 
Oliver (1981) have shown that certain pesticides, such as carbaryl 
and dithiocarbamates, can be nitrosated  in vivo. 

    As pointed out by IARC (1976), the extrapolation of findings in 
experimental animals to man is complicated by many factors.  It is 
relatively easy to show that  N -nitroso derivatives can be formed 
and that these are mutagenic and/or carcinogenic. However, the 
crucial information is the quantity produced in man under the 
prevailing conditions.  The concentration of both reactants, 
differences in pH, the influence of competing reactions, and the 
presence of accelerators and inhibitors are all important.  In 
addition to these difficulties in defining potential human 
exposure, the susceptibility of man has to be compared with that of 
experimental animals.  General considerations on  N -nitrosatable 
pesticides are described in IARC (1983). 
 
8.8.  Special Studies

    Adequate characterization of the neurobehavioral effects of 
carbamates is still incomplete or not available.  In general, when 
given in single doses the ChE-inhibiting carbamates decrease 
activity and schedule-controlled behaviour, interfere with 
avoidance and escape performance, and decrease the amplitude of a 
variety of electrophysiological measures.  The possible 
interference with learning and memory by the carbamates has been of 
interest because of the hypothesized role of the cholinergic system 
in these functions.  However, the evidence that these compounds 
interfere with learning and memory is equivocal (Miller, 1982). 

    Carbamates interfere with shock-motivated behaviour including 
discrete-trial and one-way avoidances as well as shock-induced 
suppression.  Furthermore, these compounds decrease responsiveness 
to shock (Sideroff & Santolucito, 1972). 

    The effects of the ChE-inhibiting carbamates have been 
evaluated in man.  However, these studies have been mainly 
concerned with correlating ChE inhibition and overt symptoms. It is 
assumed that, if the clinical indicators (such as ChE levels) are 
normal after pesticide exposure, or if symptoms associated with 
cholinergic overstimulation are absent, then no risk is involved 
(Miller, 1982). 

9.  EFFECTS ON MAN

    The health hazards from overexposure to carbamate insecticides 
occur primarily as a result of the inhibition of the enzyme ChE.  
ChE inhibition leads to the accumulation of endogenous ACh and 
other choline esters in the organism.  This produces signs and 
symptoms as specified in section 9.3. 

9.1  General Population Exposure

9.1.1  Acute toxicity: poisoning incidents

    Carbamate pesticides have occasionally been used in cases of 
suicide.  Fatal poisonings have occurred with carbaryl, propoxur, 
and mexacarbate.  Farago (1969) described a case involving a 39-
year-old man who drank 1/2 litre of carbaryl. He entered the 
hospital 1 1/2 h later and received gastric lavage, but developed 
serious respiratory depression.  His condition improved somewhat 
after 4 injections of atropine at 1/2-h intervals.  Three hours 
after the carbaryl ingestion, 250 mg of 2-PAM intravenous was 
administered.  His lung condition rapidly worsened and he died.  
Administration of 2-PAM is contraindicated for cases of carbaryl 
poisoning, as it may increase toxicity rather than reactivate the 
inhibited enzyme and, in this case, it was concluded that the fatal 
outcome, though unavoidable, was hastened by 2-PAM administration. 

    Reich & Welke (1966) reported a fatal case of mexacarbate 
poisoning involving a 17-year-old nursery employee who ingested 
approximately 55 g mexacarbate in the form of a 22% formulation.  
The young man, found unconscious, had pinpoint pupils and an 
irregular heartbeat.  Emergency procedures at the hospital briefly 
restored regular heart rhythm, but brachycardia developed later 
with recurrent heart failure. The patient died about 4 - 4 1/2 h 
after the ingestion of the mexacarbate. 

    Two severe cases of propoxur poisoning following ingestion of 
150 - 200 ml of commercial Baygon formulation were described by 
Bomirska & Winiarska (1972).  One individual responded to treatment 
and recovered but the other died after failing to respond to 
treatment with atropine and 2-PAM and toxogonin given 
intravenously.  A normal ChE suggested spontaneous reactivation of 
this enzyme. 

9.1.2  Effects of short- and long-term exposure

    Propoxur was tested for its effectiveness in controlling the 
mosquito vectors of malaria in Iran.  The insecticide was sprayed 
inside houses in a 300 km2 area in which 11 000 people lived in 33 
villages.  Sixty-nine out of the 11 000 inhabitants complained of 
mild cholinergic symptoms, when they entered their houses during 
the spraying, contrary to instructions.  The symptoms were 
headache, nausea, sweating, and vomiting.  The symptoms subsided in 
2 - 3 h.  Similar experiences were reported in other villages 
sprayed with propoxur or with carbaryl (Vandekar et al., 1968). 


9.1.3  Controlled human studies

    Human volunteers tolerated single oral doses of aqueous 
solutions of aldicarb at doses of 0.025, 0.05, or 0.1 mg/kg body 
weight, with only mild depression of whole blood-ChE in all cases.  
Only the persons receiving 0.1 mg/kg presented symptoms of acute 
cholinergic stress (i.e., nausea, sweating, pinpoint pupils, 
salivation) (FAO/WHO, 1982b). 

    Groups of male volunteers (5 or 6 per group) were administered 
daily doses of 0.06 and 0.13 mg carbaryl/kg body weight, orally, 
for 6 weeks.  No subjective or objective changes were observed, 
except a slight reversible decrease in the ability of the kidneys 
to reabsorb aminoacids in the group at the highest dose level 
(Wills et al., 1968). 

    Thirty-eight urban volunteers were monitored for carbaryl 
exposure during the summer.  All volunteers were involved in the 
application of carbaryl incidental to their employment or leisure 
activities.  Exposure of clothing, skin, with and without gloves, 
were measured.  The maximum dermal exposure recorded was 2.86 mg/kg 
per h, the maximum air concentration was 0.28 mg/m3.  Only a small 
mean decrease in serum- and erythrocyte-AChE activity was found 
(Gold et al., 1982). Comparable results were obtained by Leavitt et 
al. (1982) in a study on 2 groups of professional pesticide spray 
operators with higher dermal exposure, spraying trees with 
carbaryl. 

    A 42-year-old male volunteer took a single oral dose of 135 mg 
propoxur (1.5 mg/kg body weight) about 2 h after breakfast.  
Plasma- and erythrocyte-ChE activities were determined every 15 min 
for the first 2 h after ingestion and then every hour thereafter.  
Pulse and blood pressure were recorded.  A rapid drop in 
erythrocyte-ChE activity was observed, reaching the lowest level of 
27% of normal within 20 min.  ChE activity gradually recovered, 
reaching normal levels about 2 h after ingestion.  Plasma-ChE 
activity was not affected.  In another study (single dose of 0.36 
mg/kg body weight), the lowest erythrocyte-ChE activity occurred 
within 10 min together with short-lasting stomach discomfort, 
blurred vision, nausea, and facial perspiration.  Twenty min after 
ingestion, the volunteer's pulse rate and blood pressure were 
increased.  Pronounced nausea accompanied by repeated vomiting and 
profuse sweating occurred until approximately 45 min after the 
ingestion of propoxur.  From then on, poisoning symptoms 
diminished, blood pressure and pulse returned to pre-ingestion 
values.  The disappearance within about 2 h of the poisoning 
symptoms was in line with the return of normal erythrocyte-ChE 
activity.  Forty-five percent of the ingested dose of propoxur was 
excreted as the metabolite, 2-(1-methylethyl)phenol, within 24 h of 
ingestion (Vandekar et al., 1971; FAO/WHO, 1974b). 

    In another study, 5 doses of propoxur, at 0.15 or 0.20 mg/kg 
body weight, were administered to volunteers at 1/2-h intervals.  
In this study, a symptomless depression of erythrocyte-ChE to 60% 
of normal was observed over the course of the dosing.  The enzyme 
activity recovered to normal levels soon after termination of the 

dosing.  From the above studies, it was concluded by the authors 
that an oral dose of 0.36 mg propoxur/kg body weight may be 
sufficient to induce initial cholinergic symptoms, while larger 
doses may be tolerated without symptoms if the administration is 
gradually (divided doses) (Vandekar et al., 1971). 

9.2  Occupational Exposure

9.2.1  Acute toxicity: poisoning incidents

    Tobin (1970) reported 3 cases of persons poisoned with 
carbofuran.  Two were formulation plant employees, preparing 10% 
granules and the third was an entomologist who began to feel 
uncomfortable while weighing a 50% water-dispersible powder 
formulation.  The 2 formulators developed similar symptoms 
indicative of carbamate poisoning: profuse sweating, weakness, 
blurred vision, and nausea.  Both were taken to their respective 
physicians about 3 h after the onset of symptoms.  One physician 
administered atropine; the other, noting the regression of the 
symptoms, did not administer atropine.  The patient who received 
the atropine (0.02 g im) was fully recovered in 30 min.  The 
untreated patient recovered over the course of 2 - 3 h.  The third 
case, the entomologist experienced mild discomfort that regressed 
without atropine administration in 4 - 6 h. 

    Richardson & Batteese (1973) described the case of a spray-
plane co-pilot overexposed to mexacarbate during an spraying 
operation.  The cause of the overexposure was a pin-hole leak in a 
high pressure pump line, which emitted a fine aerosol of the 
mexacarbate formulation into the fuselage.  The co-pilot developed 
the classical signs of ChE poisoning.  Toxic symptoms progressed to 
paralysis of the extremities before he could be treated.  In 
hospital, atropine sulfate was immediately administered 
intravenously followed by a second injection subcutaneously 40 min 
later.  The symptoms subsided quickly.  ChE activity in blood drawn 
after the first atropine injection was severely depressed, but 
returned to normal after 3 days. 

    Minor and transient cholinergic symptoms were experienced by 
spraymen applying propoxur formulations inside houses for testing 
this insecticide against mosquito vectors of malaria in villages in 
El Salvador (Quinby & Babione, 1966) and Iran (Vandekar et al., 
1968; Montazemi, 1969).  A pronounced fall in blood-ChE activity 
during the work and a distinct recovery after exposure ceased was 
established as a daily pattern of activity of this enzyme, 
erythrocyte-ChE being more sensitive to propoxur than plasma-ChE.  
No cumulative inhibition of ChE during the 6-week exposure was 
seen.  The investigators noted that the exposed spraymen and a few 
inhabitants recovered rapidly when removed from the source of 
exposure and when treated with atropine. 

    Vandekar et al. (1968) commented that most spraymen who became 
poisoned had heavy skin contamination, and had not cleaned their 
skin sufficiently after spraying.  The inhabitants entered the 
house while it was being sprayed.  Moreover, it was noted that 
respirators did not offer protection against intoxication under 

these circumstances and that dermal absorption accounted for most 
of the absorbed dose. 

    No adverse health effects due to carbaryl exposure (except for 
one case of skin rash) were observed in a study conducted by the 
WHO Insecticide Testing Unit in Southern Nigeria.  Ten men (out of 
105 sprayers) spraying over a single 6-h period and 95 villagers 
who resided in the sprayed houses, were examined.  The sprayers 
wore overalls, hats, and rubber boots during the entire 6 h of 
spraying, but wore masks for the first hour only.  Plasma-ChE 
activity as well as urinary metabolites of carbaryl were determined 
before and after spraying.  A slight (average 5%) reduction in 
plasma-ChE activity was reported for all 10 sprayers, the day after 
the carbaryl application.  Inhabitants of sprayed houses showed no 
inhibition of plasma-ChE activity, 1 week after the spraying. A 
slight increase in 1-naphthol was found in the urine of the 
sprayers only on the sixth day after the exposure (Vandekar, 1965). 

    In a study on 19 agricultural workers in the USSR, whole blood-
ChE activity was measured before and after 4 to 6-h exposures to 
airborne carbaryl for 3 - 4 days.  Significant ChE inhibition was 
found in men exposed to a mean airborne carbaryl concentration of 
up to 4 mg/m3.  No objective signs of ill health were observed.  No 
changes were measured at 0.7 mg/m3 (Yakim, 1967). 

    A case of acute intoxication of a woman with a total dose of 60 
mg carbofuran was described by Izmirova et al. (1981). Slight ChE 
inhibition was found, but within 72 h the patient recovered 
completely. 

    The above reports identify systemic ChE poisoning as the major 
hazard associated with occupational exposure to carbamate 
pesticides.  However, other publications indicate that certain of 
these compounds can also irritate the exterior membranes of the 
body.  Tobin (1970) described 2 cases of field workers that 
illustrate direct effects on the eye, (irritation and blurred 
vision) during carbofuran spraying operations.  These 2 persons did 
not developed symptoms of systemic poisoning. 

    Vandekar (1965) reported skin rash in a sprayman accidentally 
splashed with a carbaryl formulation.  Although carbamate compounds 
have not generally been implicated as the cause of dermatitis or 
allergic skin reactions, Vandekar (1965) suggested that certain 
individuals could develop this after unusually heavy exposure. 

9.2.2  Effects of short- and long-term exposure

    Little is known about the short- and long-term effects of 
occupational exposure to carbamate pesticides.  The few reports 
that discuss this aspect do not implicate long-term exposure to the 
carbamate compounds as a cause of human disease.  Vandekar et al. 
(1968) did not observe any evidence of cumulative toxicity among 
spraymen applying propoxur formulations during a 6-week operation.  
No long-term biochemical changes were reported among New Jersey 
farmers and spraymen compared with a minimally exposed control 
group.  It was noted that significantly higher incidences of 

hearing and eye problems, chronic cough, dizziness, headaches, and 
hypertension occurred in the occupationally exposed group. 
However, the various pesticides to which this group was exposed 
were not tabulated (Kwalick, 1971). 

    Chromosome studies on the blood cultures of 20 workers engaged 
in the production of benomyl did not reveal any increased frequency 
of structural chromosome aberrations (Ruzicska et al., 1975). 

    In a survey of occupationally acquired disease in workers at a 
pesticide plant, 11 out of 102 workers had been hospitalized for 
illness related to chemical exposure. The commonest cause of 
hospitalization was intoxication with the ChE inhibitor methomyl.  
On clinical evaluation, 5 out of 11 packaging workers, with the 
highest exposure to methomyl had experienced blurred vision or 
pupillary constriction (Morse & Baker, 1979). 

9.2.3  Epidemiological studies

    Epidemiological studies on persons occupationally exposed 
exclusively (or at least primarily) to carbamate pesticides are not 
available.  Such studies are needed before the long-term effects of 
this class of pesticides on human beings can be adequately 
evaluated. 

9.3  Signs and Symptoms of Acute Intoxication by Carbamates

    The clinical picture of carbamates intoxication results from 
accumulation of ACh at nerve endings.  Extensive description of 
the syndrome is given in several major references (Namba et al., 
1971; Kagan, 1977; Taylor, 1980).  The signs and symptoms can be 
categorized into the following 3 groups: 

    (a)  Muscarinic manifestations

     -  increased bronchial secretion, excessive sweating,
        salivation, and lachrymation;

     -  pinpoint pupils, bronchoconstriction, abdominal
        cramps (vomiting and diarrhoea); and

     -  bradycardia.

    (b)  Nicotinic manifestations

     -  fasciculation of fine muscles (in severe cases, 
        diaphragm and respiratory muscles also involved); and

     -  tachycardia.

    (c)  Central nervous system manifestations

     -  headache, dizziness, anxiety, mental confusion, 
        convulsions, and coma; and

     -  depression of respiratory centre.

    All these signs and symptoms can occur in different 
combinations and can vary in onset and sequence, depending on the 
chemical, dose, and route of exposure.  The duration of symptoms is 
usually shorter than that observed in organophosphorus poisoning.  
Mild poisoning might include muscarinic and nicotinic signs only.  
Severe cases always show central nervous system involvement; the 
clinical picture is dominated by the respiratory failure sometimes 
leading to pulmonary oedema due to the combination of the above-
mentioned symptoms. 

    Clinical diagnosis is relatively easy and is based on:

    (a)  medical history and circumstances of exposure;

    (b)  presence of several of the above-mentioned symptoms,
         in particular, bronchoconstriction and pinpoint
         pupils not reactive to light; pulse rate is not of
         diagnostic value, because the AChE effects on the
         heart reflect the complex innervation of this organ;
         on the other hand, since changes in the conduction
         and excitability of the heart might be
         life-threatening, monitoring should be performed.

    (c)  confirmation of diagnosis is made by measurement of
         AChE in RBC or plasma-pseudoChE (dibucaine number
         also, to rule out genetic deficiencies).  In view of
         the rapid reversibility, particular care should be
         taken to use analytical procedures that include
         immediate analysis and a careful control of sample
         dilutions (section 2.3).  Chemical analysis of body
         fluids (gastric lavage, blood, urine) should be
         performed for the identification of the chemical(s).

9.3.1  Biochemical methods for measurement of effects

    AChE present in human erythrocytes is the same as the enzymes 
present in the target synapses.  Measurements of AChE in RBC is 
therefore taken to mirror the effects in the target organs.  
However, it must be borne in mind that this assumption is only 
correct when the carbamate has equal access to blood and the 
synapses, and that AChE inhibition by carbamates is reversible. 

    In the case of acute poisoning, a high inhibition of RBC-AChE 
is pathognomonic, but, in the follow-up of the intoxication, it 
might not be correlated with the severity of symptoms.  However, 
monitoring of pre- and post-exposure levels of AChE in RBC gives a 
good measure of the effect of an exposure (Kaloyanova, 1976).  In 
cases when the pre-exposure AChE level is not known (as in 
accidental poisoning), reference can be made to a mean population 
AChE activity. Blood-plasma contains a related enzyme called ChE or 
pseudo-ChE, which contributes to the whole blood enzymatic 
activity; the extent of the contribution of plasma-ChE will depend 
on which substrate was used and at what concentration.  PseudoChE 
has no known physiological function, but can be inhibited 
selectively by some carbamates without causing a toxic response. 

    The sensitivities of AChE and pseudoChE to inhibitors differ so 
that measurements of the ability of whole blood samples to 
hydrolyse the usual analytical substrates give only an approximate 
estimate of the activity of the erythrocyte-AChE.  However, under 
many field conditions, procedures using whole blood are more 
practical than those using separated erythrocytes. 
 
9.4  Treatment of Acute Poisoning by Carbamate Insecticides 

    All cases of carbamate poisoning should be dealt with as an 
emergency and the patient should be hospitalized as quickly as 
possible. 

    Extensive descriptions of the treatment of poisoning by 
anticholinesterase agents are given in several major references 
(Kagan, 1977; Taylor, 1980; Plestina, 1984). 

    The treatment is based on:

    (a)  minimizing the absorption;

    (b)  general supportive treatment; and

    (c)  specific pharmacological treatment.

9.4.1  Minimizing the absorption

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

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

9.4.2  General supportive treatment

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

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

9.4.3  Specific pharmacological treatment

9.4.3.1  Atropine

    Atropine should be given, beginning with 2 mg iv repeated at 15 
to 30-min intervals.  The dose and the frequency of atropine 
treatment varies from case to case, but should maintain the 
patient fully atropinized (dilated pupils, dry mouth, skin 
flushing, etc.). 

9.4.3.2  Oxime reactivators

    There is no rational basis for using these drugs. Furthermore, 
some unconfirmed reports suggest an increased toxicity of 
carbamates when oximes have been administered. 

9.4.3.3  Diazepam

    Diazepam should be included in the therapy of all but the 
mildest cases.  Besides relieving anxiety it appears to counteract 
some aspects of CNS-derived symptoms that are not affected by 
atropine.  Doses of 10 mg sc or iv are appropriate and may be 
repeated as required. 

    Other centrally acting drugs and drugs that may depress 
respiration are not usually recommended in the absence of 
artificial respiration procedures. 

10.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    For more than 20 years, the Joint FAO/WHO Meetings on Pesticide 
Residues (JMPR) and the International Agency for Research on Cancer 
(IARC) have been evaluating the toxicity and carcinogenicity data 
on the different carbamates.  As part of the JMPR meeting, the FAO 
deals with the use and application of these pesticides and 
proposes residue limits.  Data and conclusions of the meetings were 
initially published in the WHO Technical Report Series but, since 
1977, they have been published regularly in the FAO Plant 
Production and Protection Papers. 

    It is not possible to review completely the results of the 
discussions on the approximately 50 carbamates mentioned in these 
documents.  However, Annex III contains a list of the JMPR meetings 
in which carbamates have been evaluated together with appropriate 
references.  Other information available in Annex III indicates 
whether IARC evaluations and WHO/FAO Data Sheets are available, and 
whether an IRPTC data profile and legal file exist. 

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carbanilate by soybean plants.  Pestic. Biochem. Physiol., 3: 
289-299.

STILL, G.G. & MANSAGER, E.R.  (1975)  Alfalfa metabolism of 
propham.  Pestic. Biochem. Physiol., 5: 515-522.

STILL, G.G. & RUSNESS, D.G.  (1977)   S -cysteinyl-hydroxychlor- 
propham: formation of the  S -cysteinyl conjugate of isopropyl- 
3'-chloro-4'-hydroxy-carbanilate in oat  (Avena savita L). 
 Pestic. Biochem. Physiol., 7: 210-219.

STRINGER, A. & WRIGHT, M.A.  (1973)  The effect of benomyl and 
some related compounds on  Lumbricus terrestris and other 
earthworms.  Pestic. Sci., 4: 165-170.

STYLES, J.A. & GARNER, R.  (1974)  Benzimidazole carbamate 
methylester evaluation of its effect  in vivo and  in vitro. 
 Mutat. Res., 26:: 177-187.

SULLIVAN, L.J., ELDRIDGE, J.M., KNAAK, J.B., & TALLANT, M.J.  
(1972)  5,6-dihydro-5,6-dihydroxycarbaryl glucuronide as a 
significant metabolite of carbaryl in the rat.  J. agric. food 
 Chem., 20(5): 980-985.

SUZUKI, T. & TAKEDA, M.  (1976)  Microbial metabolism of 
 N -methylcarbamate insecticide I. Metabolism of  O -sec- 
butylphenyl  N -methylcarbamate by  Aspergillus niger van 
Tieghem.  Chem. Pharm. Bull., 24(9): 1967-1975.

SYPESTEYN, A.K., DEKHUYZEN, H.M., & VONK, J.W.  (1977)  
Biological conversion of fungicides in plants and 
microorganisms,  In: Siegel, M.R. & Sisler, H.D., ed. 
 Antifungal compounds, New York, Marcel Dekker, Vol. 2, 
pp. 91-147.

TANNENBAUM, S.R., INSKEY, A.J., WEISMAN, M., & BISHOP, W.  
(1974)  Nitrite in human. Its possible relationship to 
nitrosamine formation.  J. Natl Cancer Inst., 53: 79-84.

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

TOBIN, J.S.  (1970)  Carbofuran a new carbamate insecticide. 
 J. occup. Med., 12: 16-19.

TOMLIN, A.D. & GORE, F.L.  (1974)  Effects of six insecticides 
and a fungicide on the numbers of biomass of earthworms in 
pasture.  Bull. environ. Contam. Toxicol., 12(4): 487-492.

TORCHINSKY, A.M.  (1973)  [Significance of diets with 
different protein content in manifestations of teratogenic and 
embryotoxic action of some pesticides.]  Vopr. Pitan., 3: 76-80 
(in Russian).

TORCHINSKY, A.M., ORLOVA, N.V., SMIRNOVA, E.V., & MAKAROVA, 
L.F.  (1976)  [Data for toxico-hygienic characteristics of the 
pesticide Benlate of carbamate group.]  Gig. i Sanit., 2: 35-39 
(in Russian, with English summary).

UCHIYAMA, M., TAKEDA, M., SUZUKI, T., & YOSHIKAWA, K.  (1975)  
Mutagenicity of nitroso derivatives of  N -methylcarbamate 
insecticides in microbiological method.  Bull. environ. Contam. 
 Toxicol., 14: 389-394.

UNGERER, O., EISENBRAND, G., & PREUSSMANN, R.  (1974)  [The 
reaction of nitrite with pesticides.]  Z. Krebsforsch., 81: 
217-224 (in German, with English summary).

VANDEKAR, M.  (1965)  Observations on toxicity of carbaryl, 
folithion, and 3-isopropylphenyl- N -methylcarbamate in a 
village-scale trial in Southern Nigeria.  Bull. World Health 
 Org., 33: 107-115.

VANDEKAR, M., HEDAYAT, S., PLESTINA, R., & AHMADY, G.  (1968)  
A study of the safety of  O -isopropoxyphenyl methylcarbamate in 
an operational field-trial in Iran.  Bull. World Health Org., 
38: 609-623.

VANDEKAR, M., PLESTINA, R., & WILHELM, K.  (1971)  Toxicity of 
carbamates for mammals.  Bull. World Health Org., 44: 241-249.

VAN ESCH, G.J. & KROES, R.  (1972)  Long-term toxicity studies 
of chlorpropham and propham in mice and hamsters.  Food Cosmet. 
 Toxicol., 10: 373-381.

VAN ESCH, G.J., VAN GENDEREN, H., & VINK, H.H.  (1958)  The 
production of skin tumours in mice by oral treatment with 
urethane, isopropyl- N -phenylcarbamate, or isopropyl- N -chloro- 
phenyl carbamate in combination with skin painting with croton 
oil and Tween 60.  Br. J. Cancer, 12: 355-362.

VASHAKIDZE, V.I.  (1965)  [Some questions of the harmful 
action of sevin on the reproductive function of experimental 
animals.]  Soobshch. Akad. Nauk Gruz. SSR, 39: 471-478 (in 
Russian).

VASHAKIDZE, V.I.  (1967)  [Mechanism of action of pesticides 
(granosana, sevin, donoc) on the reproductive cycle of 
experimental animal.]  Soobshch. Akad. Nauk Gruz. SSR, 48: 
219-224 (in Russian).

VASSILIEFF, I. & ECOBICHON, D.J.  (1982)  Stability of 
Matacil(R) in aqueous media as measured by changes in 
anticholinesterase potency.  Bull. environ. Contam. Toxicol., 
29: 366-370.

VASSILIEFF, I. & ECOBICHON, D.J.  (1983)  Acute toxicity of 
aminocarb in male rats and inhibition of tissue esterases. 
 Bull. environ. Contam. Toxicol., 31: 326-330.

VETTORAZZI, G.  (1979)   International regulatory aspects for 
 pesticide chemicals. Vol. 1. Toxicity profiles, Boca Raton, 
Florida, CRC Press, Inc., 232 p..

VETTORAZZI, G. & VAN DEN HURK, G.W.  (1984)   Pesticide 
 reference index, JMPR 1961-84, Geneva, World Health 
Organization (Unpublished report).

VOSS, G. & SCHULER, J.  (1967)  A fast and simple procedure 
for routine determination of plasma ChE activity.  Bull. 
 environ. Contam. Toxicol., 2(6): 357-363.

WHO  (1984)   The WHO recommended classification of pesticides 
 by hazard. Guidelines to classification 1984-85, Geneva, World 
Health Organization (Unpublished report VBC/84.2).

WHO/FAO  (1984)   Data sheets on pesticides, Geneva, World 
Health Organization.

WEIL, C.S., WOODSIDE, M.D., CARPENTER, C.P., & SMYTH, H.F., 
Jr  (1972)  Current studies of tests of carbaryl for 
reproductive and teratogenic effects.  Toxicol. appl. 
 Pharmacol., 21: 390-404.

WEIL, C.S., WOODSIDE, M.D., BERNARD, J.B., CONDRA, N.I., KING, 
J.M., & CARPENTER, C.P.,  (1973)  Comparative effect of 
carbaryl on rat reproduction and guinea-pig teratology when 
fed either in the diet or by stomach intubation.  Toxicol. 
 appl. Pharmacol., 26: 621-638.

WEIS, P. & WEIS, J.S.  (1974)  Schooling behaviour of  Menidia 
 menidia in the presence of insecticide Sevin (carbaryl).  Mar. 
 Biol., 28: 261-263.

WESTLAKE, G.E., BUNYAN, P.J., MARTIN, A.D., STANLEY, P.I., & 
STEED, L.C.  (1981)  Carbamate poisoning. Effect of selected 
carbamate pesticides on plasma enzymes and brain esterases of 
Japanese quail  (Coturnix coturnix japonica).  J. agric. food 
 Chem., 29(4): 779-785.

WHITE, E.R., BOSE, E.A., OGAWA, J.M., MANJI, B.T., & KILGORA, 
W.W.  (1973)  Thermal and base-catalysed hydrolysis products 
of the systemic fungicide benomyl.  J. agric. food Chem., 21: 
616-618.

WIEDMANN, J.L.M., ECKE, G.G., & STILL, G.G.  (1976)  Synthesis 
and isolation of 1-hydroxy-2-propyl-3-chloro-carbanilate from 
soybean plants treated with isopropyl-3-chlorocarbanilate  J. 
 agric. food Chem., 24: 588-592.

WILHELM, K. & REINER, E.  (1973)  Effect of sample storage on 
human blood cholinesterase activity after inhibition by 
carbamates.  Bull. World Health Org., 48: 235-238.

WILHELM, K., VANDEKAR, M., & REINER, E.  (1973)  Comparison of 
methods of measuring cholinesterase inhibition by carbamates. 
 Bull. World Health Org., 48: 41-44.

WILLIAMS, I.H., BROWN, M.J., & WHITEHEAD, P.  (1976a)  
Persistence of carbofuran residues in some British Columbia 
soils.  Bull. environ. Contam. Toxicol., 15(2): 242-243.

WILLIAMS, I.H., PEPIN, H.S., & BROWN, M.J.  (1976b) 
Degradation of carbofuran by soil microorganisms.  Bull. 
 environ. Contam. Toxicol., 15(2): 244-249.

WILLS, J.H., JAMESON, E. & COULSTON, F.  (1968)  Effects of 
oral doses of carbaryl on man.  Clin. Toxicol., 1(3): 265-271.

WORTHING, C.R. & WALKER, S.B.  (1983)   The pesticide manual: a 
 world compendium, 7th ed., London, British Crop Protection 
Council.

WRIGHT, M.A. & STRINGER, A.  (1973)  The toxicity of 
thiabendazole, benomyl, methyl-benzimidazol-2-yl-carbamate, 
and thiophanate-methyl to the earthworm  Lumbricus terrestris. 
 Pestic. Sci., 4: 431-432.

WYROBEK, A.J., WATCHMAKER, G., GORDON, L., WONG, K., MOORE, 
D.I., & WHORTON  (1981)  Sperm shape abnormalities in carbaryl 
exposed employees.  Environ. Health Perspect., 40: 255-265.

YAKIM, V.S.  (1967)  [Data for substantiating the maximum 
permissible concentration of sevine in the air of working 
zones.]  Gig. i Sanit., 32: 29-33 (in Russian).

YOSHIDA, K. & NISHIUCHI, Y.  (1972)  [Toxicity of pesticides 
to some water organisms.]  Bull. agric. Chem. Inspect. Stn. 
 (Japan), 12: 122-128 (in Japanese).

YOSHIDA, K. & NISHIUCHI, Y. (1976)  [Toxicity of pesticides to 
some aquatic animals.]  Bull. agric. Chem. Inspect. Stn. 
 (Japan),. 6: 65-69 (in Japanese).

ZAKI, M.H., MORAN, D., & HARRIS, D.  (1982)  Pesticides in 
groundwater: the aldicarb story in Suffolk Country, New York. 
 Am. J. public Health, 72(12): 1391-1395.

Annex I.  Names and structures and some physical and chemical properties of carbamate pesticides 
--------------------------------------------------------------------------------------------
Common name  Trade/other   CAS chemical name/    Molecular   Relative   Vapour    Water 
             name          CAS registry number   formula     molecular  pressure  solubility
                                                             mass       (25 C)   (25 C)
--------------------------------------------------------------------------------------------
aldicarb     Temik         propanal, 2-methyl-   C7H14N2O2S  190.29     13 mPa    0.6%
                           2-(methylthio)-,
                            O -[(methylamino)
                           carbonyl]oxime
                           (116-06-3)

Chemical Structure

aldoxycarb   Standak       2-methyl-2-(methyl-   C7H14N2O4S  222.3      12 mPa    0.9%      
                           sulfonyl)-propanal                                               
                            O -[(methylamino)-                                               
                           carbonyl]oxime                                                   
                           (1646-88-4)                                                      

CHEMICAL STRUCTURE 2

allyxycarb   Hydrol        phenol, 4-(di-2-pro-  C16H22N2O2 274.4                         
             APC           phenylamino)-3,5-                                                
                           dimethyl, methyl                                                 
                           carbamate                                                        
                           (6392-46-7)                                                      

Chemical Structure
--------------------------------------------------------------------------------------------
                                                                                                                     

                                                                                                                     
Annex I.  (contd.)                                                                                                   
--------------------------------------------------------------------------------------------
Common name  Trade/other   CAS chemical name/    Molecular   Relative   Vapour    Water   
             name          CAS registry number   formula     molecular  pressure  solubility
                                                             mass       (25 C)   (25 C)  
--------------------------------------------------------------------------------------------
aminocarb    Matacil       phenol, 4-(dimethyl-  C11H16N2O2 208.29     non-      slightly  
                           amino)-3-methyl-,                            volatile            
                           methyl carbamate                                                 
                           (2032-59-9)                                                      

CHEMICAL STRUCTURE 4
                                              
asulam       Asulox        carbamic acid,        C8H10N2O4S  230.26     -         0.5%      
             Asilan        [(4,-aminophenyl)-                                               
                           sulfonyl], methyl                                                
                           ester                                                            
                           (3337-71-1)                                                      

CHEMICAL STRUCTURE 5

barban       CBN           carbamic acid,        C11H9Cl2NO2 258.11     50 Pa    0.0011%   
             Carbyne       3-chlorophenyl-,                                                 
             Chlorinat     4-chloro-2-butynyl                                               
                           ester                                                            
                           (101-27-9)                                                       

CHEMICAL STRUCTURE 6
--------------------------------------------------------------------------------------------
                                                                                                                     

                                                                                                                     
Annex I.  (contd.)                                                                                                   
--------------------------------------------------------------------------------------------
Common name  Trade/other   CAS chemical name/    Molecular   Relative   Vapour    Water   
             name          CAS registry number   formula     molecular  pressure  solubility
                                                             mass       (25 C)   (25 C)  
--------------------------------------------------------------------------------------------
BPMC         Bay-Bassa     phenol, 2-(1-methyl-  C12H17NO2  207.3      48 mPab  0.061%c  
             Baycarb       propyl)-,methyl                                                  
             Sumibas       carbamate                                                        
                           (3766-81-2)                                                      

CHEMICAL STRUCTURE 7

bendiocarb   Ficam         1,3-benzodioxol-      C11H13NO4  223.25     660 Pa   0.004%    
             Garvox        4-yl, 2,2-dimethyl,                                              
             Multimet      methyl carbamate                                                 
             Tattoo        (22781-23-3)                                                     
             Seedox              

Chemical Structure
                                                                                                                     
benomyl      Arilate       carbamic acid,[1-     C14H18N4O3 290.36     non-      ~0.0002%  
             Benlate       [(butylamino)-                               volatile            
             Tersan        carbonyl]-1H-                                                    
                           benzimidazole-2-yl]-,                                            
                           methyl ester                                                     
                           (17804-35-2)                                                     
                                                                                                     
Chemical Structure
--------------------------------------------------------------------------------------------
                                                                                                                     

                                                                                                                     
Annex I.  (contd.)                                                                                                   
--------------------------------------------------------------------------------------------
Common name  Trade/other   CAS chemical name/    Molecular   Relative   Vapour    Water   
             name          CAS registry number   formula     molecular  pressure  solubility
                                                             mass       (25 C)   (25 C)  
--------------------------------------------------------------------------------------------
bufencarb    Bux           mixture of phenol,    C13H19NO2  221.33     4.0 mPac < 0.005%  
             Metalkamate   3-(1-methylbutyl)-                                               
                           phenyl)-, and                                                    
                           3-(1-ethylpropyl-                                                
                           phenyl)-, methyl                                                 
                           carbamates                                                       
                           (8065-36-9)                                                      

Chemical Structure

butacarb                   phenol, 3,5-bis       C16H25NO2  263                           
                           (1,1-dimethylethyl)-,                                            
                           methyl carbamate                                                 
                           (2655-19-8)                                                      

Chemical Structure
                                   
carbanolate  Banol         phenol, 2-chloro-4,   C10H12ClNO2 213.68                        
             SOK           5-dimethyl-, methyl                                              
                           carbamate                                                        
                           (671-04-5)                                                       

Chemical Structure
--------------------------------------------------------------------------------------------
                                                                                                                     

                                                                                                                     
Annex I.  (contd.)                                                                                                   
--------------------------------------------------------------------------------------------
Common name  Trade/other   CAS chemical name/    Molecular   Relative   Vapour    Water   
             name          CAS registry number   formula     molecular  pressure  solubility
                                                             mass       (25 C)   (25 C)  
--------------------------------------------------------------------------------------------
carbaryl     Sevin         1-naphthalenol        C12H11NO2  201.24     < 665     0.012%c  
             (Sevkul)      methyl carbamate                             mPaf               
             (Carbicide)   (63-25-2)                                                        

Chemical Structure
                           
carbendazim  Bavistin      carbamic acid,        C9H9N3O2   191.18     < 100     0.0028%c 
             BCM/MBC       -1H-benzimidazole-                           nPab     (pH 4.8)  
             Derosal       2-yl-, methyl ester                                              
                           (10605-21-7)

Chemical Structure
                          
carbetamide  Legurame      propanamide,  N -ethyl C12H16N2O3 236.30     negligible 0.35%b 
             Carbetamex    -2-[[(phenyl-amino)                          at 20C             
                           carbonyl]oxy]-, (R)-                                             
                           (16118-49-3)                                                     

Chemical Structure
--------------------------------------------------------------------------------------------
                                                                                                                     

                                                                                                                     
Annex I.  (contd.)                                                                                                   
--------------------------------------------------------------------------------------------
Common name  Trade/other   CAS chemical name/    Molecular   Relative   Vapour    Water   
             name          CAS registry number   formula     molecular  pressure  solubility
                                                             mass       (25 C)   (25 C)  
--------------------------------------------------------------------------------------------
carbofuran   Furadan       7-benzofuranol,       C12H15NO3  221.28     2.7 mPag 0.07%     
             Yaltox        2,3-dihydro-2,2-                                                 
             Curater       dimethyl-,                                                       
                           methyl carbamate                                                 
                           (1563-66-2)                                                      

Chemical Structure
                           
chlorbufam   -             1-methylprop-2ynyl-   C11H10ClNO2 223.7      2.1 mPab 0.054%b   
                           3-chlorocarbanilate                                              

Chemical Structure
                           
cloethocarb  -             2-(2-chloro-1-a      C11H14ClNO4 259.7      -         0.13%b   
                           methoxyethoxy)-                                                  
                           phenylmethyl                                                     
                           carbamate                                                        

Chemical Structure
--------------------------------------------------------------------------------------------


                                                                                                                     
Annex I.  (contd.)                                                                                                   
--------------------------------------------------------------------------------------------
Common name  Trade/other   CAS chemical name/    Molecular   Relative   Vapour    Water   
             name          CAS registry number   formula     molecular  pressure  solubility
                                                             mass       (25 C)   (25 C)  
--------------------------------------------------------------------------------------------
chlorpropham Elbanil       carbamic acid,        C10H12ClNO2 213.68     -         0.009%    
             Furloe        3-chlorophenyl-,                                                 
             Prevenol      1-methylethyl ester                                              
             Chloro IPC    (101-21-3)                                                       
             (CIPC)                                                                                           

Chemical Structure

desmedipham  Betanex       carbamic acid, [3-    C16H16N2O4 300.34                        
                           [[(phenylamino)-                                                 
                           carbonyl]oxy]phenyl]-,                                           
                           ethyl ester                                                      
                           (13684-56-6)                                                     

Chemical Structure

dimetilan    Snip          carbamic acid,        C10H16N4O3 240.3                readily   
                           dimethyl-,                                                       
                           1-[(dimethylamino)                                               
                           carbonyl]-5-methyl-                                                     
                           1H-pyrazol-3-yl ester                                               
                           (644-64-4)                                                       

Chemical Structure
--------------------------------------------------------------------------------------------


                                                                                                                     
Annex I.  (contd.)                                                                                                   
--------------------------------------------------------------------------------------------
Common name  Trade/other   CAS chemical name/    Molecular   Relative   Vapour    Water   
             name          CAS registry number   formula     molecular  pressure  solubility
                                                             mass       (25 C)   (25 C)  
--------------------------------------------------------------------------------------------
dichlormate                benzenemethanol,      C9H9Cl2NO2 199                  0.017%    
                           2,3-dichloro-,                                                   
                           methyl carbamate                                                 
                           (62046-37-1)                                                     
                             
Chemical Structure
                                                                                                                     
dioxacarb    Famid         phenol, 2-(1,3-di-    C11H13NO4  223.25     40 Pac  0.6%c    
             Elecron       oxolan-2-yl)-,                                                   
                           methyl carbamate                                                 
                           (6988-21-2)                                                      
                                                                                               
Chemical Structure

ethiofencarb Croneton      phenol, 2-[(ethyl-    C11H15NO2S  225.33     13 mPac  0.182%b  
                           thio)methyl]-,                                                   
                           methyl carbamate                                                 
                           (29973-13-5)                                                     

Chemical Structure
--------------------------------------------------------------------------------------------
                                                                                                                     

                                                                                                                     
Annex I.  (contd.)                                                                                                   
--------------------------------------------------------------------------------------------
Common name  Trade/other   CAS chemical name/    Molecular   Relative   Vapour    Water   
             name          CAS registry number   formula     molecular  pressure  solubility
                                                             mass       (25 C)   (25 C)  
--------------------------------------------------------------------------------------------
etrofol      hopcide       phenol, 2-chloro-,    C8H8ClNO2  185.62     -                   
             CPMC          methyl carbamate                                                 
                           (3942-54-9)                                                      

Chemical Structure

formetanate  Dicarzol      methanimidamide,      C11H15N3O2 257.75     27 Pa    0.63%     
             Carzol         N,N -dimethyl- N' -                                               
                           [3-[[(methylamino)                                               
                           carbonyl]oxy]-                                                   
                           phenyl]-                                                         
                           (22259-30-9)                                                     

Chemical Structure
                                                                                                                     
isoprocarb   Etrofolan     phenol, 2-(1-methyl-  C11H15NO2  193.27     -         insoluble 
             Carbamat IPM  ethyl)methyl                                                     
             Hytox         carbamate                                                        
             Mipcin        (2631-40-5)                                                      
             MIPC                                                                                     

Chemical Structure
--------------------------------------------------------------------------------------------
                                                                                                                     

                                                                                                                     
Annex I.  (contd.)                                                                                                   
--------------------------------------------------------------------------------------------
Common name  Trade/other   CAS chemical name/    Molecular   Relative   Vapour    Water   
             name          CAS registry number   formula     molecular  pressure  solubility
                                                             mass       (25 C)   (25 C)  
--------------------------------------------------------------------------------------------
karbutilate  Tandex        carbamic acid,        C14H21N3O3 279.38     6.0 nPab 0.033%b  
                           (1,1-dimethylethyl)-,                                            
                           3-[[(dimethylamino)                                              
                           carbonyl]-amino]                                                 
                           phenyl ester                                                     
                           (4849-23-5)                                                      

Chemical Structure
                                                                                                                     
MPMC         Meobal        phenol, 3,4-di-       C10H13NO2  179.24                        
                           methyl-,                                                         
                           methyl carbamate                                                 
                           (2425-10-7)                                                      

Chemical Structure
                           
methiocarb   Draza         phenol, 3,5-di-       C11H15NO2S  225.33     15 mPah  0.003%b  
             Mesurol       methyl-4-(methyl-                                                
                           thio)-, methyl                                                   
                           carbamate                                                        
                           (2032-65-7)                                                      

Chemical Structure
--------------------------------------------------------------------------------------------
                                                                                                                     

                                                                                                                     
Annex I.  (contd.)                                                                                                   
--------------------------------------------------------------------------------------------
Common name  Trade/other   CAS chemical name/    Molecular   Relative   Vapour    Water   
             name          CAS registry number   formula     molecular  pressure  solubility
                                                             mass       (25 C)   (25 C)  
--------------------------------------------------------------------------------------------
methomyl     Lannate       ethanimidothioic      C5H10N2O2S  162.23               5.8%      
             Methavin      acid,  N -[[(methyl-                                              
                           amino)carbonyl]oxy]-,                                            
                           methyl ester                                                     
                           (16752-77-5)                                                     

Chemical Structure
                          
metolcarb    -              m -tolyl methyla     C9H11NO2   165.2      145 mPab 0.26%c   
                           carbamate                                                        

Chemical Structure

mexacarbate  Zectran       phenol, 4-dimethyl-   C12H18N2O2 222.32                        
                           amino)-3,5-dimethyl-,                                            
                           methyl carbamate                                                 
                           (ester)                                                          
                           (315-18-4)                                                       

Chemical Structure
--------------------------------------------------------------------------------------------
                                                                                                                     

                                                                                                                     
Annex I.  (contd.)                                                                                                   
--------------------------------------------------------------------------------------------
Common name  Trade/other   CAS chemical name/    Molecular   Relative   Vapour    Water   
             name          CAS registry number   formula     molecular  pressure  solubility
                                                             mass       (25 C)   (25 C)  
--------------------------------------------------------------------------------------------
oxamyl       Vydate        ethanimidothioic      C7H13N3O3S  219.29     31 mPa    28.0%     
                           acid, 2-(dimethyl-                                               
                           amino)- N -[[(methyl-                                             
                           amino)carbonyl]-oxy]-                                            
                           2-oxo-, methyl ester                                             
                           (23135-22-0)                                                     

Chemical Structure
                                                                                                                     
phenmedipham Betanal       carbamic acid,        C16H16N2O4 300.34     -         .0.0005%  
                           (3-methylphenyl)-,                                               
                           3-[(methoxycarbonyl)                                             
                           amino]phenyl ester                                               
                           (13684-63-4)                                                     

Chemical Structure

pirimicarb   Aphox         carbamic acid,        C11H18N4O2 238.33     4.0 mPac 0.27%     
             Fernos        dimethyl-, 2-(di-                                                
             Pirimor       methylamino)-5,                                                  
             Rapid         6-dimethyl-4-pyrimi-                                             
                           dinyl ester                                                      
                           (23103-98-2)                                                     

Chemical Structure
--------------------------------------------------------------------------------------------
                                                                                                                     

                                                                                                                     
Annex I.  (contd.)                                                                                                   
--------------------------------------------------------------------------------------------
Common name  Trade/other   CAS chemical name/    Molecular   Relative   Vapour    Water   
             name          CAS registry number   formula     molecular  pressure  solubility
                                                             mass       (25 C)   (25 C)  
--------------------------------------------------------------------------------------------
                                                                                                                     
promacyl     Promicide     5-methyl- m -cumenyla C16H23NO3  277.4      400 Pai  slightly  
                           butyryl(methyl)                                                  
                           carbamate                                                        

Chemical Structure
                           
promecarb    Carbamult     phenol, 3-methyl-5-   C12H17NO2  207.3                0.0092%   
             Minacide      (1-methylethyl)-,                                                
                           methyl carbamate                                                 
                           (2631-37-0)                                                      

Chemical Structure
                           
propham      Banhoe        carbamic acid,        C10H13NO2  179.24     -          0.025%   
             Tuberit       phenyl-, 1-methyl-                                               
             IPC           ethyl ester                                                      
                           (122-42-9)                                                       

Chemical Structure
--------------------------------------------------------------------------------------------
                                                                                                                     

                                                                                                                     
Annex I.  (contd.)                                                                                                   
--------------------------------------------------------------------------------------------
Common name  Trade/other   CAS chemical name/    Molecular   Relative   Vapour    Water   
             name          CAS registry number   formula     molecular  pressure  solubility
                                                             mass       (25 C)   (25 C)  
--------------------------------------------------------------------------------------------
propoxur     Baygon        phenol, 2-(1-methyl   C11H15NO3  209.27     6.5 x     0.2%   
             Blattanex     ethoxy)-, methyl                             10-6               
             Sendran       carbamate                                    mm Hg               
             Suncide       (114-26-1)                                   (20 C)             
             Unden                                                                                     
             Tendex                                                                                                  
             Arprocarb                                                                                               

Chemical Structure
                                                                                                                     
swep                       carbamic acid, 3,4-   C8H7Cl2NO2 220.06                        
                           dichlorophenyl-,                                                 
                           methyl ester                                                     
                           (1918-18-9)                                                      

Chemical Structure
                                                                                                                     
terbucarb    Azac          2,6-di-ter-butyl-     C17H27NO2  277.4                0.0067%   
             Azar           p -tolyl methyl                                                  
                           carbamate                                                        
                                                                                                                     
thiodicarb   Larvin        ethanimidothioic      C10H18N4O4S3 354.3                         
                           acid,  N,N' -[thiobis                                             
                           (methylimino)-                                                   
                           carbonyloxy]                                                     
                           bis-dimethyl-ester                                               
                           (59669-26-0)                                                     
--------------------------------------------------------------------------------------------
                                                                                            

                                                                                            
Annex I.  (contd.)                                                                          
--------------------------------------------------------------------------------------------
Common name  Trade/other   CAS chemical name/    Molecular   Relative   Vapour    Water   
             name          CAS registry number   formula     molecular  pressure  solubility
                                                             mass       (25 C)   (25 C)  
--------------------------------------------------------------------------------------------
thiofanox    Dacamox       2-butanone, 3,3-di-   C9H18N2O2S  218.35     22.6 mPa  0.52%d   
                           methyl-l-(methyl-                                                
                           amino)-,  O -[(methyl-                                            
                           amino)- carbonyl]oxime                                           
                           (39196-18-4)                                                     

Chemical Structure

thiophanate  Topsin        carbamic acid,        C14H18N4O4S2 370.48    -         insoluble 
  ethyl      Cercobin      [1,2-phenylenebis                                                
             Enovit        (iminocarbonothioyl)]                                            
                           bis-, diethyl ester                                              
                           (23564-06-9)                                                     

Chemical Structure
--------------------------------------------------------------------------------------------
                                                                                            

                                                                                            
Annex I.  (contd.)                                                                          
--------------------------------------------------------------------------------------------
Common name  Trade/other   CAS chemical name/    Molecular   Relative   Vapour    Water   
             name          CAS registry number   formula     molecular  pressure  solubility
                                                             mass       (25 C)   (25 C)  
--------------------------------------------------------------------------------------------
                          
thiophanate  Topsin-M      carbamic acid,        C12H14N4O4S2 342.42    -         slightly  
  methyl     Cercobin-M    [1,2-phenylenebis-                                               
             Enovit-M      iminocarbonothioyl)]                                             
             Fungo         bis-, dimethyl ester                                             
             Mildothane    (23564-05-8)                                                     

Chemical Structure
                                                                                            
trimethacarb Broot         4:1 mixture of        C11H15NO2  193.24                        
             Landrin       phenol, 3,4,5-tri-                                               
                           methyl-, methyl-                                                 
                           carbamate and phenol,                                            
                           2,3,5-trimethyl-                                                 
                           methyl carbamate                                                 
                           (2686-99-9 and                                                   
                           2655-15-4)                               

MTMC         Tsumacide     carbamic acid,        C9H11NO2   165.21                        
                           methyl-, 3-methyl-                                               
                           phenyl ester                                                     
                           (1129-41-5)                                                      

Chemical Structure
--------------------------------------------------------------------------------------------
                                                                                            

                                                                                            
Annex I.  (contd.)                                                                          
--------------------------------------------------------------------------------------------
Common name  Trade/other   CAS chemical name/    Molecular   Relative   Vapour    Water   
             name          CAS registry number   formula     molecular  pressure  solubility
                                                             mass       (25 C)   (25 C)  
--------------------------------------------------------------------------------------------
xylylcarb    -             3,4-xylylmethyla     C10H13NO2  179.2      70 mPab  0.058%b  
                           carbamate                                                        

Chemical Structure
                          
XMC          Macbal        3,5 xylylmethyla                                                
             Cosban        carbamate             C10H13NO2  179.2                insoluble 
--------------------------------------------------------------------------------------------
a  IUPAC name.                                                                                       
b  At 20 C.                                                                                         
c  At 30 C.                                                                                         
d  At 22 C.                                                                                         
e  From: Worthing & Walker (1983) (given in the reference list of the main document).                
f  At 26 C.                                                                         
g  At 33 C.                                                                         
h  At 60 C.                                                                         
i  At 149 C.                                                                        


Annex II.  Summary of the short- and long-term toxicity studies that were used to establish 
the acceptable daily intakes for human beings for carbamate compounds
---------------------------------------------------------------------------------------------------------
Carbamate       Duration      No-observed-adverse-effect level in ratsa      Reference
                of test       mg/kg diet          mg/kg body weight
---------------------------------------------------------------------------------------------------------
Aldicarb        2 years       2.5                 0.125                       FAO/WHO (1983b)
                                                  0.25 (dog)

Aminocarb       2 years       100                                             FAO/WHO (1980b)


Bendiocarb                                        0.38
                                                  0.25 (dog)                  FAO/WHO (1985a)

Benomyl         2 years       2500                125                         FAO/WHO (1983b,
                                                  30 (based on teratology)    1985a)

Carbaryl        2 years       200                 10                          FAO/WHO (1985a)
                6 weeks                           0.06 (man)
                80 weeks      400 (mice)          60 (mice)
                1 year                            1.8 (dog)

Carbendazim     2 years       500                 25                          FAO/WHO (1986b)
                2 years       100 (dog)           2.5

Carbofuran      2 years       20                  1.0                         FAO/WHO (1981b)
                2 years       20 (mice)           2.5

Chloropropham   2 years       2000                                            FAO/WHO (1965b)
---------------------------------------------------------------------------------------------------------

Annex II.  (contd.)
---------------------------------------------------------------------------------------------------------
Carbamate       Duration      No-observed-adverse-effect level in ratsa      Reference
                of test       mg/kg diet          mg/kg body weight
---------------------------------------------------------------------------------------------------------
Ethiofencarb    90 days       500                 10                          FAO/WHO (1983b)
                              1000 (dog)          25

Methiocarb      1 year        25                  1.3                         FAO/WHO (1985a)
                              5 (dog)             0.125

Methomyl        22 months     100                 5                           FAO/WHO (1978b)

Oxamyl          14 days       100 (dog)           2.5                         FAO/WHO (1985a)

Pirimicarb      2 years       175                 9                           FAO/WHO (1983b)
                2 years                           1.8 (dog)
                17 weeks                          2 (monkey)

Propoxur        2 years       250                 12.5                        FAO/WHO (1983b)
                2 years                           (dogs)

Thiophanate     2 years       160                 8                           FAO/WHO (1976b, 1978b)
-methyl         2 years                           50 (dog)
                2 years       160                 23 (mice)
---------------------------------------------------------------------------------------------------------
a  Data given for rats, unless otherwise stated.
    References are to reports of WHO/FAO Joint Meeting on Pesticide Residues. Vettorazzi (1979) gives a 
    summary of these reports up to and including 1977.

 Note: The references to Annex II are given in the reference list of the main document.

Annex III.  Carbamates: JMPR reviews, ADIs, Evaluation by IARC, Classification by Hazard,
FAO/WHO Data Sheets, IRPTC Data Profile and Legal Filea
---------------------------------------------------------------------------------------------------------
Compound    Year of  ADIb        Evaluation  IARCd       Availability    WHO recom-    FAO/WHO Data
            JMPR     (mg/kg body  by JMPRc:   Evaluation   of IRPTCe:     mended clas-  Sheets on
            meeting  weight)      Published   of Carcino-  Data     Legal  sification    Pesticidesh
                                  in:         genicity     Profile  filef of pesticides
                                  FAO/WHO                                  by hazardg
---------------------------------------------------------------------------------------------------------
Aldicarb    1982     0-0.005      1983b                    +        +      IA            No. 53 (1982)
                                  1983a
            1979     0-0.001      1980b
                                  1980a

Aminocarb   1979     no ADI       1980b                                    IB
                                  1980a
            1978     no ADI       1979b
                                  1979a
            1984     0-0.004      1985b

Bendiocarb  1982     0-0.002      1983b                    +       +       II            No. 52 (1982)
                     (temporary)                                                         (rev. 1)

Benomyl     1983     0.02         1984                     -       +                     No. 87 (in
                                  1985a                                    0             (preparation)
            1978     no ADI       1979a
            1975     no ADI       1976a
                                  1976a
            1973     no ADI       1974a
                                  1974b
---------------------------------------------------------------------------------------------------------

Annex III.  (contd.)
---------------------------------------------------------------------------------------------------------
Compound    Year of  ADIb        Evaluation  IARCd       Availability    WHO recom-    FAO/WHO Data
            JMPR     (mg/kg body  by JMPRc:   Evaluation   of IRPTCe:     mended clas-  Sheets on
            meeting  weight)      Published   of Carcino-  Data     Legal  sification    Pesticidesh
                                  in:         genicity     Profile  filef of pesticides
                                  FAO/WHO                                  by hazardg
---------------------------------------------------------------------------------------------------------
Carbaryl    1984i   0-0.01       1985b
            1979i   0-0.01       1980b                    +        +      II            No. 3 (1978)
                                  1980a                                                  (rev. 1)
            1977i   0-0.01       1978b
                                  1978a
            1976i   0-0.01       1977b       Vol. 12,
                                              page 37
                                  1977a
            1975i   0-0.01       1976b
                                  1976a
            1973     0-0.01       1974b
                                  1974a
            1971i   0-0.01       1972a
                     (temporary)
            1970i   0-0.01       1971b
                     (temporary)
                                  1971a
            1969     0-0.01       1970b
                     (temporary)
                                  1970a
            1968i   0-0.02       1969b
                                  1969a
            1967     0-0.02       1968b
                                  1968a
            1966     0-0.02       1967b
                                  1967a
            1965     0-0.02       1965b
                                  1965a
            1963     0-0.02       1964
---------------------------------------------------------------------------------------------------------

Annex III.  (contd.)
---------------------------------------------------------------------------------------------------------
Compound    Year of  ADIb        Evaluation  IARCd       Availability    WHO recom-    FAO/WHO Data
            JMPR     (mg/kg body  by JMPRc:   Evaluation   of IRPTCe:     mended clas-  Sheets on
            meeting  weight)      Published   of Carcino-  Data     Legal  sification    Pesticidesh
                                  in:         genicity     Profile  filef of pesticides
                                  FAO/WHO                                  by hazardg
---------------------------------------------------------------------------------------------------------
Carbendazim 1985     0-0.01       1986b
            1983     0-0.01       1984                                     0             No. 89 (in
                                  1985a                                                  (preparation)
            1978     no ADI       1979a
                                  1979b
            1977     no ADI       1978a
                                  1978b
            1976     no ADI       1977a
                                  1977b
            1973     no ADI       1974a
                                  1974b

Carbofuran  1982     0-0.01       1983a                    +        +      IB
            1980     0-0.01       1981b
                                  1981a
            1979     0-0.003      1980b
                     (temporary)
                                  1980a
            1976     0-0.003      1977b
                     (temporary)
                                  1977a

Chlor-      1965     no ADI       1965b       Vol. 12,                     0
propham                                       page 55
                                  1965a
            1963     no ADI       1964
---------------------------------------------------------------------------------------------------------

Annex III.  (contd.)
---------------------------------------------------------------------------------------------------------
Compound    Year of  ADIb        Evaluation  IARCd       Availability    WHO recom-    FAO/WHO Data
            JMPR     (mg/kg body  by JMPRc:   Evaluation   of IRPTCe:     mended clas-  Sheets on
            meeting  weight)      Published   of Carcino-  Data     Legal  sification    Pesticidesh
                                  in:         genicity     Profile  filef of pesticides
                                  FAO/WHO                                  by hazardg
---------------------------------------------------------------------------------------------------------
Ethio-      1983i   0-0.1        1984a                                    II
fencarb     1982     0-0.1        1983b
                                  1983a
            1981i   0-0.1        1982b
                     (temporary)
                                  1982a
            1980i   0-0.1        1981b
                     (temporary)
                                  1981a
            1978i   0-0.1        1979b
                     (temporary)
                                  1979a
            1977     0-0.1        1978b
                     (temporary)

Methiocarb  1985     0-0.001      1986b
            1984     0-0.001      1985b                                    II
            1983     0.001        1984
                                  1985a
            1981     0-0.001      1982b
                                  1982a
                                                                                         
Methomyl    1978     no ADI       1979b                    +        +      IB            No. 55 (1983)
                                  1979a
            1977i   no ADI       1978b
                                  1978a
            1976i   no ADI       1977b
                                  1977a
            1975i   no ADI       1976b
                                  1976a

Mexacarbate                                   Vol. 12,
                                              page 237
---------------------------------------------------------------------------------------------------------

Annex III.  (contd.)
---------------------------------------------------------------------------------------------------------
Compound    Year of  ADIb        Evaluation  IARCd       Availability    WHO recom-    FAO/WHO Data
            JMPR     (mg/kg body  by JMPRc:   Evaluation   of IRPTCe:     mended clas-  Sheets on
            meeting  weight)      Published   of Carcino-  Data     Legal  sification    Pesticidesh
                                  in:         genicity     Profile  filef of pesticides
                                  FAO/WHO                                  by hazardg
---------------------------------------------------------------------------------------------------------
Oxamyl      1985     0-0.03       1986b
            1984     0-0.03       1985b                                                  
            1983i   0-0.01       1984                     +        +      IB            No. 54 (1983)
                     (temporary)
            1980     0-0.01       1981b
                     (temporary)
                                  1981a
                     0-0.0014

Pirimicarb  1982     0-0.02       1983b                    +        +      II
                                  1983a
            1981i   0-0.01       1982b
                     (temporary)
                                  1982a
            1979i   0-0.01       1980b
                     (temporary)
                                  1980a
            1978     0-0.01       1979b
                     (temporary)
                                  1979a
            1976     0-0.004      1977b
                     (temporary)
                                  1977a

Propham     1965     no ADI       1965a       Vol. 12      +        +      0
                                  1965b       Page 189
            1963     no ADI       1964a
                                                                                         
Propoxur    1983     0-0.02       1984                     +        +      II            No. 25 (1976)
            1981i   0-0.02       1982b
                                  1982a
            1978i   0-0.02       1979a
            1977i   0-0.02       1978a
            1973     0-0.02       1974b
                                  1974a
---------------------------------------------------------------------------------------------------------

Annex III.  (contd.)
---------------------------------------------------------------------------------------------------------
Compound    Year of  ADIb        Evaluation  IARCd       Availability    WHO recom-    FAO/WHO Data
            JMPR     (mg/kg body  by JMPRc:   Evaluation   of IRPTCe:     mended clas-  Sheets on
            meeting  weight)      Published   of Carcino-  Data     Legal  sification    Pesticidesh
                                  in:         genicity     Profile  filef of pesticides
                                  FAO/WHO                                  by hazardg
---------------------------------------------------------------------------------------------------------
Thiodicarb  1985     0-0.1        1986b
                     (temporary)

Thiofanox   1978i   no ADI       1979a                                    IB

Thio-       1978i   0-0.08       1979a                             +      0
phanate-    1977     0-0.08       1978b
methyl                            1978a
            1975     0-0.08       1976b
                                  1976a
            1973     0-0.08       1974b
                                  1974a
---------------------------------------------------------------------------------------------------------
a  Adapted from: Vettorazzi & van den Hurk (1984).
b  ADI = acceptable daily intake.
c  JMPR = Joint Meeting on Pesticide Residues (FAO/WHO).
d  IARC = International Agency for Research on Cancer (WHO, Lyons, France).
e  IRPTC = International Register of Potentially Toxic Chemicals (UNEP, Geneva).
f  From: IRPTC (1983).
g  From: WHO (1984a). See this reference for classification of organophosphates not mentioned in this 
    annex. 

Annex III (contd.)

 The hazard referred to in this Classification is the acute risk for health (that is, the risk of 
 single or multiple exposures over a relatively short period of time) that might be encountered 
 accidentally by any person handling the product in accordance with the directions for handling by the 
 manufacturer or in accordance with the rules laid down for storage and transportation by competent 
 international bodies. Classification relates to the technical material, and not to the formulated 
 product: 
-----------------------------------------------------------------------------------
Class                                   LD50 for the rat (mg/kg body weight)
                                        Oral                    Dermal            
                               Solids      Liquids         Solids       Liquids
-----------------------------------------------------------------------------------
1A     Extremely hazardous     5 or less   20 or less      10 or less   40 or less
1B     Highly hazardous        5 - 50      20 - 200        10 - 100     40 - 400
II     Moderately hazardous    50 - 500    200 - 2000      100 - 1000   400 - 4000
III    Slightly hazardous      over 500    over 2000       over 1000    Over 4000
O      Unlikely to present
       acute hazard in normal use
-----------------------------------------------------------------------------------
h  WHO/FAO Data Sheets on Pesticides with number and year of appearance.
i  No toxicological evaluation - residues only.
 N.B. References to Annex II are listed in the reference list of the main document.

Annex IV. Abbreviations

2-AB         2-aminobenzimidazole

ACh          acetylcholine

AChE         acetylcholinesterase

ACTH         adrenocorticotropic hormone

ADI          acceptable daily intake 

ChE          cholinesterase

CNS          central nervous system

EEG          electroencephalogram

EMG          electromyogram

FAO          Food and Agriculture Organization of the United 
             Nations 

4-HBC        4-hydroxy-2-benzimidazole carbamate

5-HBC        5-hydroxy-2-benzimidazole carbamate

IARC         International Agency for Research on Cancer

im           intramuscular

IPCS         International Programme on Chemical Safety (World 
             Health Organization) 

IRPTC        International Register of Potentially Toxic Chemicals 
             (United Nations Environment Programme) 

iv           intravenous

JMPR         Joint Meeting of the FAO Panel of Experts on Pesticide 
             Residues in Food and the Environment and a WHO Expert 
             Group on Pesticide Residues

MFO          mixed-function oxidase

MLD          minimum lethal dose

MRL          maximum residue limit

NTE          neuropathy target esterase (formerly neurotoxic 
             esterase) 

PBI          protein-bound iodine

pseudoChE    pseudocholinesterase

RBC          red blood cells

sc           subcutaneous

UVR          ultraviolet radiation






    See Also:
       Toxicological Abbreviations