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    Published under the joint sponsorship of
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    and the World Health Organization

    World Health Orgnization
    Geneva, 1988

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    1.1. General
    1.2. Properties, uses, and analytical methods
    1.3. Sources, environmental transport, and distribution
    1.4. Environmental levels and human exposure 
    1.5. Kinetics and metabolism 
    1.6. Effects on organisms in the environment 
    1.7. Effects on experimental animals and in vitro test systems 
    1.8. Effects on man


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


    3.1. Natural occurrence
    3.2. Man-made sources


    4.1. Transport and distribution between media
         4.1.1. Soil 
         Persistence and volatilization
         Lateral movement
    4.2. Biotransformation 
         4.2.1. Microbial degradation
         4.2.2. Photodegradation 



    6.1. Absorption, distribution, and excretion 
    6.2. Metabolic transformation
         6.2.1. Mammals
         6.2.2. Plants 


    7.1. Microorganisms
    7.2. Aquatic organisms 
    7.3. Terrestrial organisms 
         7.3.1. Birds
         7.3.2. Honey bees 


    8.1. Single exposures
    8.2. Short- and long-term exposure 
         8.2.1. Experimental animals 
         8.2.2. Domestic animals 
    8.3. Skin and eye irritation; sensitization
    8.4. Reproduction, embryotoxicity, and teratogenicity
         8.4.1. Reproduction 
         8.4.2. Teratogenicity 
    8.5. Mutagenicity and related end-points 
    8.6. Carcinogenicity 


    9.1. Occupational exposure 







Dr U.G. Ahlborg, Unit of Toxicology, National Institute of
    Environmental Medicine, Stockholm, Sweden (Vice-Chairman)
Dr R.C. Dougherty, Department of Chemistry, Florida State
    University, Tallahassee, Florida, USA
Dr H.H. Dieter, Federal Health Office, Institute for Water,
    Soil and Air Hygiene, Berlin (West)
Dr A.H. El Sabae, Pesticide Division, Faculty of Agriculture,
    University of Alexandria, Alexandria, Egypta
Dr A. Furtado Rahde, Ministry of Public Health, Porto Alegre,
    Brazil (Chairman)
Dr S. Gupta, Department of Zoology, Faculty of Basic Sciences,
    Punjab Agricultural University, Ludhiana, Punjab, Indiaa
Dr L.V. Martson, All Union Scientific Research Institute of the
    Hygiene   and   Toxicology  of   Pesticides,  Polymers,  and
    Plastics, Kiev, USSRa
Dr U.G. Oleru, Department of Community Health, College of Med-
    icine, University of Lagos, Lagos, Nigeria
Dr Shou-Zheng Xue, Toxicology Programme, School of Public
    Health, Shanghai Medical University, Shanghai, China


Dr R.F. Hertel, Fraunhöfer Institute for Toxicology and Aerosol
    Research, Hanover, Federal Republic of Germany
Dr E. Kramer (European Chemical Industry Ecology and Toxico-
    logy Centre), Dynamit Nobel AG, Cologne, Federal Republic of
Mr G. Ozanne (European Chemical Industry Ecology and Toxico-
    logy  Centre),  Rhone  Poulenc  DSE/TOX,  Neuilly-sur-Seine,
Mr V. Quarg, Federal Ministry for Environment, Nature Con-
    servation  and  Nuclear  Safety, Bonn,  Federal  Republic of
Dr U. Schlottmann, Chemical Safety, Federal Ministry for
    Environment,  Nature Conservation and Nuclear  Safety, Bonn,
    Federal Republic of Germany
Dr M. Sonneborn, Federal Health Office, Berlin (West)
Dr W. Stöber, Fraunhöfer Institute for Toxicology and Aerosol
    Research, Hanover, Federal Republic of Germany
Dr D. Streelman (International Group of National Associations
    of   Agrochemical  Manufacturers),  Agricultural   Chemicals
    Registration   and   Regulatory   Affairs,  Rohm   &   Haas,
    Philadelphia, Pennsylvania, USA

a   Invited but unable to attend.


Mrs B. Bender, International Register for Potentially Toxic
    Chemicals, Geneva, Switzerland
Dr A. Gilman, Industrial Chemicals and Product Safety Section,
    Health  Protection Branch, Department of National Health and
    Welfare,   Tunney's   Pasture,   Ottawa,   Ontario,   Canada
    (Temporary Adviser)
Dr L. Ivanova-Chemishanska, Institute of Hygiene and Occupa-
    tional  Health, Medical Academy, Sofia,  Bulgaria (Temporary
Dr K.W. Jager, International Programme on Chemical Safety,
    World Health Organization, Geneva, Switzerland (Secretary)
Dr E. Johnson, Unit of Analytical Epidemiology, International
    Agency for Research on Cancer, Lyons, France
Dr G. Rosner, Fraunhöfer Institute for Toxicology and Aerosol
    Research,  Hanover,  Federal Republic  of Germany (Temporary
Dr G.J. Van Esch, Bilthoven, Netherlands (Temporary Adviser)


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


    A  WHO  Task  Group  on  Environmental  Health  Criteria for
Thiocarbamate  Pesticides  met  at the  Fraunhöfer Institute for
Toxicology  and Aerosol Research,  Hanover, Federal Republic  of
Germany from 20 to 24 October, 1986.  Professor W. Stöber opened
the  meeting and  welcomed the  members on  behalf of  the  host
Institute,  and Dr U. Schlottmann spoke on behalf of the Federal
Government,  who sponsored the meeting.  Dr K.W. Jager addressed
the meeting on behalf of the three  co-sponsoring  organizations
of the IPCS (UNEP/ILO/WHO).  The Task Group reviewed and revised
the draft criteria document and summarized the health  risks  of
exposure to thiocarbamate pesticides.

    The  drafts of this document were prepared by DR L. IVANOVA-
CHEMISHANSKA,  Institute  of  Hygiene and  Occupational  Health,
Sofia,   Bulgaria,   and  Dr   G.J.   VAN  ESCH   of  Bilthoven,

    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.


    The  thiocarbamates included in  this review are  those that
are  mainly used in agriculture and form part of the large group
of  synthetic organic pesticides  that have been  developed  and
produced  on  a broad  scale in the  last 30 -  40 years.  Thio-
carbamate  derivatives with pesticidal properties were developed
during and after World War II.
    In this introductory document, an attempt has been  made  to
summarize  the  available data  on  the thiocarbamates  used  as
pesticides  in order to indicate  their impact on man,  animals,
plants, and the environment.  The review is not intended  to  be
complete, and more details about certain aspects can be found in
the JMPR and IARC publications.

    It  should be noted that  the design of a  number of studies
cited  in  this document,  especially  the earlier  studies,  is


1.1  General

    Thiocarbamates  are  mainly  used in  agriculture as insect-
icides,  herbicides,  and  fungicides.  Additional  uses  are as
biocides for industrial or other commercial applications, and in
household  products.  Some are used for vector control in public
    The general formula of thiocarbamates is:

                              O     R2
                              ||    /

where  R1  is an  alkyl group attached  to the sulfur  giving  S -
thiocarbamates   or to the oxygen  giving O-thiocarbamates.   R2
and R3 represent either two alkyl groups, or one alkyl  and  one
cyclic or hexamethylene group.

    A whole range of thiocarbamates is known, but it is  out  of
the  scope of this  publication to give  all the information  on
every compound.  The intention is to cover the different aspects
of  thiocarbamates as a  group, making use  of publications  and
reports available on the compounds that are most used  and  best
known.    Data  on  carbamates  and   dithiocarbamates  are  not
included,  because these compounds  have been covered  in  other
Environmental Health Criteria documents.

1.2  Properties, Uses, and Analytical Methods

    Thiocarbamates  are  liquids  or  solids  with  low  melting
points.    They   are   volatile  compounds,   and  their  water
solubilities cover a wide range.  Some thiocarbamates are stable
in  an  acidic  aqueous  medium.   The  sequential  oxidation of
thiocarbamates  to  thiocarbamate  sulfoxide  and  thiocarbamate
sulfone decreases the hydrolytic stability.

    Some   physical  and  chemical  data   (chemical  structure,
relative  molecular mass, vapour pressure, and water solubility)
of individual substances are given in  Annex I.

    Analytical  methods for the determination  of thiocarbamates
are  outlined in the document and further details, together with
physical  and chemical data, can  be found in the  WHO Technical
Report Series and the IRPTC data profiles.

1.3  Sources, Environmental Transport, and Distribution

    Because  of  their insecticidal,  herbicidal, and fungicidal
properties,  thiocarbamates  have  a  wide  range  of  uses  and
applications  throughout the world  and, thus, are  produced  in
great quantities.

    Thiocarbamates  are  volatile  and will  therefore evaporate
from soil.  Leaching and lateral movement in soil may take place
because   of  their  water  solubility.   Some  photodegradation

    Factors  that influence the biodegradation of thiocarbamates
in   soil   include   volatility,  soil   type,  soil  moisture,
adsorption,  pH, temperature, and photodegradation, all of which
make it unlikely that long-term contamination of the  soil  will

    Soil   microorganisms   contribute   significantly  to   the
disappearance  of  thiocarbamates  from  the  soil.   In  micro-
organisms and plants, thiocarbamates undergo hydrolysis followed
by  transthiolation  and  sulfoxidation to  form  carbon dioxide
(CO2) and compounds that enter the metabolic pool.

1.4  Environmental Levels and Human Exposure

    Information  on  the environmental  impact of thiocarbamates
with  respect  to  persistence and  bioaccumulation in different
species  and  food  chains is  limited.   On  the basis  of  the
available information, it is likely that most of these compounds
are rapidly degraded.

    Estimates  of  the exposure  of  the general  population  to
thiocarbamates are not available.

1.5  Kinetics and Metabolism

    As  a general rule,  thiocarbamates can be  absorbed by  the
organism via the skin, mucous membranes, and the respiratory and
gastrointestinal  tracts.   They  are eliminated  quite rapidly,
mainly via expired air and urine.

    Two   major   pathways   exist   for   the   metabolism   of
thiocarbamates  in  mammals.   One  is  via  sulfoxidation   and
conjugation  with glutathione.  The conjugation  product is then
cleaved  to a  cysteine derivative,  which is  metabolized to  a
mercapturic acid compound.  The second route is oxidation of the
sulfur to a sulfoxide, which is then oxidized to a  sulfone,  or
hydroxylation  to  compounds  that enter  the  carbon  metabolic

    In plants, thiocarbamates are rapidly metabolized in typical
oxidation reactions, e.g., thiol sulfur oxidation to the corres-
ponding  sulfoxides, reactive intermediates that  are capable of
reacting  with sulfhydryl groups  (as in glutathione,  cysteine)
to  form conjugates.  On hydrolysis, mercaptans, carbon dioxide,
and alkylamines may be formed.

    While  thiocarbamates  and  their metabolic  products can be
found in certain organs, such as liver and kidneys, accumulation
does not take place because of their rapid metabolism.

1.6  Effects on Organisms in the Environment

    Soil   microorganisms   are   capable   of   metabolizing
thiocarbamates.   From  the  limited information  available,  it
seems  that the thiocarbamates and their break-down products can
affect  enzyme  activities,  respiration, and  nitrification, at
dose levels of the order of 10 mg/kg dry soil or more.

    The acute and long-term toxicities of thiocarbamates must be
considered for each compound, some being more toxic than others.
The acute toxicity of thiocarbamates for fish is of the order of
5 - 25 mg/litre of water.

    Thiocarbamates present little or no risk for birds and honey

1.7  Effects on Experimental Animals and In Vitro Test Systems

    The acute oral and dermal toxicities of  thiocarbamates  are
generally  low.  Only limited information  concerning inhalation
toxicity is available.

    Some thiocarbamates, e.g., molinate, have an effect on sperm
morphology  and,  consequently,  on reproduction.   However,  no
teratogenic   effects  have  been  observed.    The  results  of
mutagenicity  studies  showed  that  thiocarbamates   containing
dichloroallyl  groups  were highly  mutagenic.  Negative results
were obtained with other thiocarbamates.

    Adequate  studies  on the  carcinogenicity of thiocarbamates
are not available.

1.8  Effects on Man

    Data  concerning the effects  of thiocarbamates on  man  are
scarce.   However,  cases  of irritation  and sensitization have
been observed among agricultural workers.


2.1  Identity

    Thiocarbamates  are the semi-sulfur analogues  of carbamates
characterized by the presence of:


They exist as salts or esters of carbamic acids.  In the esters,
the  alkyl  substituent is  either  attached to  the  oxygen ( O-
thiocarbamates) or to the sulfur ( S- thiocarbamates).

    The  thiocarbamate  herbicides  belong to  the  group  of  S -
thiocarbamate esters and have the general formula of:

                                O     R2
                                ||    /

where R1 is an alkyl group attached to the sulfur, and R2 and R3
represent  either 2 alkyl groups, or one alkyl and one cyclic or
hexamethylene group.

    The  type of pesticidal activity and the chemical structures
of  the principle  thiocarbamates are  listed in  Table 1.   CAS
numbers,  chemical  names,  common  names,  molecular  formulae,
relative  molecular  mass,  and selected  chemical  and physical
properties are summarized in Annex I.

    For further information on physical and chemical properties,
other sources, such as the JMPR evaluations (Annex  II),  should
be consulted.

2.2  Physical and Chemical Properties

    At  room temperature, thiocarbamates  are liquids or  solids
with  a  low  melting  point.  As  they  are usually  N,N -dialkyl
substituted  and have a sulfur atom in place of oxygen, they are
less  polar  than methylcarbamates  and  are miscible  with most
organic solvents.

    All thiocarbamate herbicides are volatile.  Pebulate has the
highest  vapour   pressure,   followed   by  S -ethyldipropylthio-
carbamate  (EPTC),  cycloate, molinate,  butylate, diallate, and
triallate (IARC, 1976; Worthing & Walker, 1983).

    Thiocarbamates  such as EPTC, pebulate, or diallate are very
stable at pH 2 or 10.  Their sulfoxide and  sulfone  derivatives
are  also  stable  at pH 2, but much less so at pH 10 (Casida et
al., 1974).

Table 1.  Chemical structures and type of pesticidal activity of the
principal thiocarbamates
Type of          Chemical structure        Common or other name
                       ||                  cartap


                       O     R2            butylate, cycloate,
                       ||   /              diallate, EPTC,
                  R1-S-C-N                 ethiolate, molinate,
                            \             pebulate, thioben-
                             R3            carb, triallate

                       O     R2
                       ||   /

    The  presence of a double  bond in the chloroallyl  group of
diallate  and triallate might  increase, compared with  that  of
other thiocarbamates, the possible range of reactions, e.g., the
introduction  of  hydroxyl groups  on  the two-carbon  atoms  or
methylation and methoxylation (Schuphan & Ebing, 1977).

2.3  Analytical Methods

    Analysis  for  pesticide  residues consists  of sampling the
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.  Care should be taken to ensure
that  samples are truly  representative, and that  the pesticide
residues to be measured are not degraded or the  sample  further
contaminated  during  handling  and storage.   Many  methods  of
detection  are available,  and the  one chosen  depends  on  the
physical  and chemical properties of the pesticide as well as on
the equipment available.

    A   detailed  review  of  all  aspects  of  such  analytical
procedures  is beyond the  scope of this  document.  However,  a
brief summary of some of the procedures is given below.

    A  variety of techniques has been used for the determination
of thiocarbamate herbicide residues.  Hughes & Freed (1961) used
gas-liquid  chromatography (GLC)  for the  measurement of minute

amounts  of EPTC in crops.   This method is also  being used for
the  determination of other  thiocarbamates.  Another method  in
use  is a colorimetric procedure  based on the determination  of
the   amine   after   hydrolysis  of   the   thiocarbamate  with
concentrated sulfuric acid (Batchelder & Patchett, 1960).

    Other methods are available for the determination of EPTC: a
specific  method based on gas  chromatography (GC) and a  method
based  on  Kjeldahl  nitrogen  determination.   The  recommended
method  is GC when EPTC is determined with reference to a sample
of  known composition (Patchett  et al., 1964).   EPTC  residues
have  also  been determined  by  radiotracer techniques  (Fang &
Theisen, 1959), by GC (Hughes & Freed, 1961), and by colorimetry
(Batchelder  & Patchett, 1960).  The  GC method has mainly  been
used in the analysis of soil samples, but the method can also be
used  in the analysis  of some crops.   For routine crop  sample
analyses, the colorimetric method is preferred, because  of  its
proved  reliability and  the low  background values  for a  wide
range  of  sample types.   If the equipment  is available, a  GC
method involving a microcoulometric detector for sulfur  can  be


3.1  Natural Occurrence

    Cartap is a commercial insecticide developed from a zoogenic
substance,  nereistoxin, which was found by Nitta in the body of
the    marine   segmented   worm  Lumbrineris    (Lumbriconereis)
 heterepoda,   and isolated in  1934 (Okaichi &  Hashimoto, 1962;
Sakai, 1969).  The chemical structure of these two compounds are
as follows:

               CH2-S-CO-NH2                         CH2-S
              /                                    /
    (CH3)2N-CH                           (CH3)2N-CH     |
              \                                   \
               CH2-S-CO-NH2                         CH2-S

              cartap                          nereistoxin

3.2  Man-Made Sources

    Thiocarbamates  are widely used throughout the world and are
produced   in  great  quantities,   mainly  as  herbicides   and


    Like all pesticides, thiocarbamates can reach the  soil  via
many  routes,  ranging from  direct  application to  drift  from
foliage   treatment.    Generally,   these  compounds   are  not
persistent and undergo various types of degradation.

4.1  Transport and Distribution Between Media

4.1.1  Soil  Persistence and volatilization

    Several  factors are known  to determine the  persistence of
herbicides  in soil.  These  include uptake and  degradation  by
soil  microorganisms,  pH,  temperature, loss  through  physical
processes  (volatilization,  leaching),  and  chemical   changes
(photodecomposition,  chemical reaction).  Volatilization  is an
important mechanism in the loss of thiocarbamate herbicides from
soil  (Anderson & Domsch,  1980).  The loss  of EPTC is  greater
from  moist  soils  than  from  dry.   Loss  through evaporation
correlates  significantly  with  the amount  of  organic  matter
present   in  the  soil,   the  clay  content,   and   leaching.
Consequently, these factors affect the herbicidal activity (Gray
& Weierich, 1968; Fang, 1975).

    The  persistence of thiocarbamates in soil, expressed as the
approximate  half-life in moist soil, is given in Table 2 (Gray,

    Fang (1975) reported that, during the first 15 min following
spraying   on   the  soil  surface,  20%  of  the  applied  EPTC
disappeared from dry soil, 27% from moist soil, and 44% from wet
soil.   The losses were 23%, 49%, and 69%, respectively, after 1
day  and  44%,  68%,  and  90%,  respectively,  after  6   days.
Incorporation  to a depth of 5 - 7.5 cm prevented severe loss of
EPTC from soil.

    Cycloate  was  the least  volatile  of 5  herbicides tested,
followed  by molinate, pebulate, vernolate, and EPTC in order of
increasing  volatility.  Increasing the temperature  from 1.7 °C
to  37.7 °C  caused an  increase in the  loss of vernolate  from
moist and wet soils.  The effect was more pronounced as the soil
moisture content increased (Fang, 1975).

Table 2.  Persistence of thiocarbamate herbicides in moist soil 
under simulated summer growing conditions
Herbicide      Half-life in moist    Half-life in Regina heavy
               loam soil (21 -       clay (25 °C) (weeks)a
               32 °C) (weeks)a
EPTC                1                      4 - 5

Vernolate           1 - 2                  2 - 3

Pebulate            2                      2 - 3

Butylate            3                      -

Molinate            3                      -

Cycloate            3 - 4                  -

Diallate            > 4                   5 - 6

Triallate           -                      10 - 12
a   From: Stauffer Chemicals SA (1978).  Leaching

    Quantitative  leaching tests conducted in soils contained in
glass   columns  showed  that  thiocarbamate   herbicides  leach
downwards  in  direct  relation  to  their  water  solubilities.
Molinate  leached  to  the  greatest  depth  followed  by  EPTC,
vernolate,   pebulate,  cycloate,  and  butylate  in  decreasing
order.  Molinate and EPTC leached downwards to a depth of 22.5 -
37.5 cm in sandy soil when incorporated in the upper 7.5  cm  of
soil  at  11.2 kg/ha  and leached with  20 cm of  water, but the
other  compounds stayed near  the top 7.5 -  15 cm of  soil when
leached with 20 cm of water.  Leaching depth also  decreased  as
the  organic matter content of the soil increased.  In peat soil
(containing  35%  organic  matter), none  of  the  thiocarbamate
herbicides leached out of the treated zone.  The  leaching  data
indicated  that, in most soils, the thiocarbamates stayed in the
upper 7.5 - 15 cm of soil.  Under most conditions, the compounds
would disappear through microbial action before they could reach
the  deeper layers of soil  by leaching (Gray &  Weierich, 1968;
Gray, 1971).  Lateral movement

    The  lateral  movement  of  thiocarbamates  was  studied  by
placing  the compounds on filter paper discs, placed in the soil
together  with  weed  seeds.  Using  ryegrass  or  oats as  test
species, EPTC, vernolate, and pebulate moved laterally to form a
circle  of  weed  control  about  10 -  12.5  cm  in   diameter.
Molinate,  cycloate,  and butylate  gave  smaller zones  of weed
control.  The thiocarbamates also moved laterally more than most
other  commercial herbicides as shown  by their effect on  grass

weeds.   However, the  size of  the zone  depended on  both  the
activity of the herbicide and the species tested.  When  a  disc
containing EPTC was placed 7.5 cm deep in the soil, no  zone  of
weed   control  was  detected.   The  data  indicated  that  the
thiocarbamates  moved  outwards  spherically when  applied  to a
concentrated  spot in  the soil.   Because of  this property  of
lateral diffusion, thiocarbamates, applied by injection, have an
effective herbicide action (Gray, 1971).

4.2  Biotransformation

4.2.1  Microbial degradation

    Soil   microorganisms   contribute   significantly  to   the
disappearance   of   thiocarbamate  herbicides   from  the  soil
(Kaufman, 1967).  However, the mechanism involved has  not  been
established,  though it has been postulated that these compounds
could   undergo  hydrolysis  at  the  ester  linkage,  with  the
formation of a mercaptan and a secondary amine.   The  mercaptan
could  then be converted into an alcohol by transthiolation, and
further  oxidized to an  acid, prior to  entering the  metabolic
pool.  This mechanism has been proposed for the  degradation  of
EPTC  and  pebulate in  plants and animals  (Fang et al.,  1964;
Kaufman, 1967) (Fig. 1).

    Such    a   mechanism,   i.e.,   hydrolysis    followed   by
transthiolation,  could explain results observed  in persistence
and  degradation  studies on  diallate,  carried out  by Kaufman
(1967).  In two separate studies, a bioassay analysis of treated
soil  indicated a partial loss  of phytotoxicity, followed by  a
temporary  increase  in,  and  a  subsequent  complete  loss of,
phytotoxicity.    Hydrolysis  of  the  diallate  ester  linkage,
followed by transthiolation of the allylic group,  would  result
in  the  formation  of 2,3-dichloroallyl  alcohol.  However, the
results of unpublished studies indicate a more  complex  pathway
involving   oxidative   dealkylation  of   the  amine  (Stauffer
Chemicals SA, 1981).

    Persistence  tests in distilled water and tap water in clear
glass  containers showed very slow degradation of thiocarbamates
by  hydrolysis  over a  period of months.   However, in pans  of
water  containing soil, microbes,  and growing plants,  molinate
and  several  other  thiocarbamates disappeared  rapidly  within
several weeks (Gray, 1971).

4.2.2  Photodegradation

    Little   has  been  reported  on   the  photodegradation  of
thiocarbamates.   Casida et al.  (1975) exposed EPTC,  butylate,
cycloate, molinate, vernolate, and pebulate to sunlight on thin-
layer-chromatographic  (TLC)  plates.   After 16 h,  none of the
original  compounds could be recovered, but trace amounts of the
corresponding sulfoxides of EPTC and pebulate were found.


    Minimum effects are to be expected on compounds in the solid
state,  because  of poor  light  penetration (DeMarco  &  Hayes,

    DeMarco & Hayes (1979) studied the photodegradation of EPTC,
pebulate,  and  cycloate.  The  products  identified  for   each
herbicide   were  the  corresponding   formamide,  dialkylamine,
mercaptan,   and  disulfide,  indicating   a  similar  mode   of
degradation.   Fig. 2 shows a possible  photodegradation pathway
suggested by DeMarco & Hayes (1979).

    Absorption  of light causes the breakage of the carbonyl C-S
bond producing two radicals. These can combine with protons from
the solvent giving the formamide and mercaptan.   The  formamide
is  further  degraded  by  ultraviolet  radiation  (UVR)  to the
dialkylamine  by the elimination of  carbon monoxide.  Collision
of  two mercaptan  radicals would  lead to  the formation  of  a
disulfide.   Because the sulfur-sulfur bond is quite susceptible

to  photolysis, continued  exposure to  UVR would  result  in  a
return   to  separate  mercaptan  radicals,   and  the  possible
reformation  of the disulfide.   Changes in the  availability of
protons  could  influence  the concentrations  of  mercaptan and
disulfide formed (DeMarco & Hayes, 1979).



    Data  on this subject were  not available to the  Task Group
with  the exception of some occupational exposure data mentioned
in section 9.


6.1  Absorption, Distribution, and Excretion

    Thiocarbamates  in the form of an aerosol enter the organism
mainly via the respiratory tract.  Absorption through  the  skin
and  mucous membranes also occurs  during occupational exposure,
and through the digestive tract.
    In  metabolic  studies  on rats,  administered  14C-labelled
pebulate orally at 0.16 - 1.95 mg/animal (average weight 235 g),
the radioactivity was rapidly eliminated.  An average of 51% was
excreted  in the first 24 h and 80% after 3 days.  Approximately
55%  of  the radioactivity  was found in  expired air as  carbon
dioxide (CO2), while 23% was found in the urine and only  5%  in
the  faeces.  Small amounts were detected in organs and tissues,
the  highest levels being found in the liver, lungs, and kidneys
(Fang et al., 1964).

    In  a comparable study  on rats, using  labelled EPTC  (dose
levels  of 0.6 - 103  mg/animal),  increasing the dose led  to a
relative  decrease in 14CO2 output with a corresponding increase
in  the  urinary  excretion of  radioactivity.  Generally, 14CO2
elimination was complete within 15 h at lower dose  levels,  but
took approximately 35 h at higher doses (Ong & Fang, 1970).

    Approximately  97% of an oral  dose administered to rats  at
72 mg  molinate/kg body weight  was excreted within  48 h.   The
major  routes of  elimination were  the urine  (88%) and  faeces
(11%);  less than 1% was  excreted as carbon dioxide  (CO2).  No
differences  were  found between  males  and females.   With the
exception  of  blood, tissue  residues  decreased over  a  7-day
period from an average of 13.8% to 3.7% (DeBaun et al., 1978a).

6.2  Metabolic Transformation

6.2.1    Mammals

    One of the two major metabolic pathways  for  thiocarbamates
in  mammals  is  sulfoxidation,  followed  by  conjugation  with
glutathione  (GSH) by GSH  S -transferase.   The  GSH conjugate is
then cleaved to the cysteine derivative, which  is  subsequently
acetylated   and   excreted   as  S -carbamoyl-mercapturic    acid
(Hubbell & Casida, 1977; Chen & Casida, 1978).   This  metabolic
pathway is shown in Fig. 3.

    Sulfoxidation  of  thiocarbamates  such as  EPTC,  molinate,
pebulate,  and vernolate undoubtedly represents a detoxification
mechanism  in mammals, the sulfoxides generally being less toxic
than the parent compounds.  The lower toxicity of the sulfoxides
is  probably  attributable  to the  high  rate  of cleavage  and
elimination as glutathione conjugates (Casida et al., 1975).


    The  other  mechanism  is  oxidation  of  the  thiocarbamate
molecule.  Metabolism of EPTC by a mouse liver  microsome  NADPH
system  involves  oxidative attack  at  the following  sites  in
decreasing  order of importance: sulfur, alpha-carbon   of the ethyl
group, alpha-carbon   of the propyl  group, ß-carbon  of the  propyl
group,  y-carbon  of the propyl group, and ß-carbon  of the ethyl

    The   metabolites  hydroxylated  at  the   carbons alpha to  the
nitrogen  and sulfur decompose at  physiological pH, yielding  S -
ethyl  N -propylthiocarbamate    in  the  case of  the former, and
carbonylsulfide and acetaldehyde from the latter, compound.  The
sulfoxide  is further oxidized  to the sulfone.   The  carbonyl-
sulfide  undergoes further metabolism  to carbon dioxide  (CO2).
These findings indicate the major involvement of  the  sulfoxide
intermediate and also suggest that hydroxylation is an important
mechanism  for thiocarbamate cleavage  (De Matteis &  Seawright,
1973; Dalvi et al., 1974, 1975; Chen & Casida, 1978).

    In  mice,  urea was  identified as one  of the many  urinary
metabolites.   Since  urea, amino  acids,  and small  amounts of
propanethiol  and  propanol  were  found  in  the   urine,   the
thiolcarbamate  molecule  is  probably hydrolysed  at  the ester
linkage  to form n-propyl  mercaptan, which is then converted to
propanol  by a transthiolation  (Fig. 1).  The propanol  may  be
oxidized  to a C-3 acid and/or further broken down to a C-2 unit
before  entering the metabolic pool.   Incorporation into tissue
constituents, such as protein and amino acids, may  occur  (Fang
et al., 1964; Ong & Fang, 1970).

    The   available  metabolic  pathways  in   rats  differ  for
thiocarbamates  with n-alkyl   substituents as  opposed to those
with  branched  alkyl or  cyclic  substituents on  the nitrogen.
Thus,  the  yield  of  mercapturic  acids  and  the  number   of
metabolites  are greater with  the former than  with the  latter
(Hubbell  &  Casida,  1977).   Sulfoxides  can  be  detected  as
transient metabolites in the liver of mice injected  with  EPTC,
molinate, or pebulate, but not with butylate or cycloate (Casida
et  al., 1975).   However, as  cycloate and  butylate  are  also
oxidized   to   sulfoxide,  the   appropriate  mercapturic  acid
derivatives  can be  detected in  the urine  (Hubbell &  Casida,

    Metabolic  studies of [ring-14C]  molinate in the  rat  were
carried  out  by  DeBaun  et  al.  (1978b).   Unchanged molinate
accounts  for only 0.1% of the urinary 14C after an oral dose of
72  mg labelled molinate/kg  body weight.  The  major  metabolic
pathway involves sulfoxidation and conjugation with glutathione,
giving  rise to a mercapturic acid derivative that accounted for
35%  of the urinary 14C.   Ring hydroxylation to give  3- and 4-
hydroxymolinate    conjugated   as O-glucuronides    represented
approximately 26%.  Hydroxylation in the 2 position of the ring,
and subsequent ring cleavage, occurred only to a  minor  extent.
Hexamethyleneimine  (14.6%)  and 3-  and 4-hydroxyhexamethylene-
imine (10.3%) were the major metabolites, presumably  formed  by
hydrolysis  of  sulfoxidized  molinate and  its  hydroxy deriva-

6.2.2    Plants

    The  results  of  investigations with  carbonyl 14C-labelled
materials  showed  that  thiocarbamate herbicides  are initially
metabolized  in  plants  by  the  typical  oxidation   reactions
observed  for other carbamate  esters (Hubbell &  Casida,  1977;
Carringer et al., 1978; Chen & Casida, 1978), i.e., thiol sulfur
oxidation  to the corresponding  sulfoxide.  The sulfoxide  is a
reactive intermediate and is capable of reacting with sulfhydryl
groups  (e.g., in glutathione  (GSH) or cysteine),  to give  the
carbamylated  derivative  (Horvath  & Pulay,  1980).   These two
conjugates  were among the  principal metabolites isolated  from
the  plants.   The  metabolism of  thiocarbamate  herbicides  in
plants   to  the  respective   sulfoxides  is  of   considerable
theoretical  importance, since the sulfoxides are believed to be
responsible  for the herbicidal  activity of the  thiocarbamates
(Casida  et al., 1974).   Furthermore, the reaction  between GSH
and   the   thiocarbamate   sulfoxide  appears   to   result  in
detoxification  in  plants.  Antidotes  such as  N,N -diallyl-2,2-
dichloroacetamide,   which   protect   plants  from   injury  by
thiocarbamate  herbicides, also increase  the levels of  GSH and
GSH  S -transferase in the plant (Lay & Casida, 1976).

    Current  knowledge of the  metabolism of thiocarbamates  and
their  mode of action is rather limited. It can be summarized as
follows.   Thiocarbamates are readily absorbed by plants, but do
not  remain as  residues very  long.  It  is generally  believed
that,  upon  hydrolysis, thiocarbamates  yield mercaptan, carbon
dioxide  (CO2),  and dialkylamine:  a  further cleavage  of  the
sulfur  atom from the mercaptan  is possible.  Thus, the  sulfur
atom  can  be  subsequently incorporated  into sulfur-containing
amino  acids.  The other part of the molecule will become carbon
dioxide  (CO2)  or  will  be  incorporated  into  natural  plant


7.1  Microorganisms

    Endo  et al. (1982) studied  the influence of cartap  on the
enzyme  activities, respiration, and nitrification  of the soil.
Soil was treated with cartap-HCl to give a  final  concentration
of  10, 100,  or 1000 mg/kg  (dry soil  weight).   The  findings
suggested  that nitrifying organisms  were affected by  100  and
1000 mg cartap, but with 10 mg, no effects on enzyme activities,
respiration,  or  nitrification were  found  in soil  kept under
upland or flooded conditions.

7.2  Aquatic Organisms

    Data  concerning the toxicity of  thiocarbamates for aquatic
organisms are rather scarce.  Acute toxicity data for  fish  are
given   in  Table  3,  while  those  for  a  number  of  aquatic
invertebrates are summarized in Table 4.

7.3  Terrestrial Organisms

7.3.1    Birds

    The  results  of  a number  of  toxicity  studies on  birds,
lasting from 5 days to 2 months, are summarized in Table 5.  The
results  are expressed as  LD50 in the  diet or as  no-observed-
adverse-effect levels.  In the species tested, the  toxicity  of
thiocarbamates was low.

7.3.2    Honey bees

    The  toxicity  (expressed as  the  LD50) of  EPTC, molinate,
cycloate,  butylate, pebulate, and  vernolate for the  honey bee
is > 11 µg/bee.   From these results, it can be  concluded  that
these  compounds  are relatively  non-toxic  for the  honey  bee
(Stauffer Chemicals SA, 1978).
Table 3.  Acute toxicity of thiocarbamates for fish
Organism           Compound    Weight of   Temperature    96-h LC50      Comments
                                fish (g)      (°C)        (mg/litre)

Rainbow trout       vernolate      -             -            9.6
( Salmo gairdneri)  

Bluegill ( Lepomis   vernolate      -             -            8.4

Mosquitofish        vernolate      -             -           14.5        Vernam 6Ea
( Gambusia affinis)

Rainbow trout       vernolate     1.3            12           4.3b
( Salmo gairdneri)                                         (3.9 - 4.7)

Table 3.  (contd.)
Organism           Compound    Weight of   Temperature    96-h LC50      Comments
                                fish (g)      (°C)        (mg/litre)

Bluegill ( Lepomis   vernolate     1.2            24           2.5b
 macrochirus)                                              (1.7 - 3.7)

Rainbow trout       EPTC           -             -            19
( Salmo gairdneri)

Bluegill ( Lepomis   EPTC           -             -            27

Cutthroat trout     EPTC          1.0            10           17b
                                                           (15 - 19)

Lake trout          EPTC          0.9            10          16.2b
                                                           (14.8 - 17. 7)

Rainbow trout       molinate       -             -            1.3
( Salmo gairdneri)

Bluegill ( Lepomis   molinate       -             -           29

Channel catfish     molinate       -             -         > 3          no mortalityc
( Ictalurus punc-

Carp ( Cyprinus      molinate      -              -         > 2          no mortalityd

Bluegill ( Lepomis   molinate      -              -         > 1          no mortalitye

Rainbow trout       cycloate      -              -          4.5
( Salmo gairdneri)

Bluegill ( Lepomis   cycloate      -              -          5.6

Mosquitofish        cycloate      -              -         10            Ro-Neet 6Ef
( Gambusia affinis)

Rainbow trout       butylate      -              -          4.2
( Salmo gairdneri)

Bluegill ( Lepomis   butylate      -              -          6.9

Mosquitofish        butylate      -              -          8.5          Sutan 6Eg
( Gambusia affinis)

Table 3 (contd).
Organism           Compound    Weight of   Temperature    96-h LC50      Comments
                                fish (g)      (°C)        (mg/litre)

Rainbow trout       pebulate      -              -          7.4
( Salmo gairdneri)

Bluegill ( Lepomis   pebulate      -              -          7.4

Mosquitofish        pebulate      -              -         10            Tillam 6Eh
( Gambusia affinis)

Rainbow trout       diallate      -              -          7.9
( Salmo gairdneri)

Bluegill ( Lepomis   diallate      -              -          5.9

Rainbow trout       triallate     -              -          1.2
( Salmo gairdneri)

Bluegill ( Lepomis   triallate     -              -          1.3

a   Vernam 6E: herbicide formulation (vernolate).
b   From: Johnson & Finley (1980).  Other data from: Stauffer Chemicals SA (1978) 
    and Worthing & Walker (1983).
c   After 11 days.
d   After 21 days.
e   After 35 days.
f   Ro-Neet 6E: herbicide formulation (cycloate).
g   Sutan 6E: herbicide formulation (butylate).
h   Tillam 6E: herbicide formulation (pebulate).
Table 4.  Acute toxicity of thiocarbamates for aquatic invertebratesa
   Organism         Compound    Stage     Temperature    96-h LC50
                                             (°C)        (mg/litre)

 Asellus communis    EPTC        mature        15             23b
(isopod)                                                   (15 - 36)

 Gammarus fasciatus  EPTC        mature        15             66b

 Cypridopsis         vernolate   mature        21            0.25b,c
                                                         (0.15 - 0.42)

 Asellus communis    vernolate   mature        15            0.23c
(isopod)                                                 (0.16 - 0.33)

 Gammarus fasciatus  vernolate   mature        15              14
(shrimp)                                                  (9.6 - 20)

 Palaemonetes sp.    vernolate   juvenile      2.1           0.53c
(shrimp)                                                 (0.14 - 2.0)

a   From: Johnson & Finley (1980).
b   48-h EC50.
c   Tested in hard water (272 mg CaCO3/litre).

Table 5.  Toxicity of thiocarbamates for birdsa
Product   Species                Protocol              Dose (mg/kg diet)   Results
                                                       (mg/kg diet)
--------  --------------- ---------------------------- -----------------   --------------------------- 

EPTC      bobwhite quail  7-day dietary administration  1000 - 32 000       LD50 in diet: 20 000;
                          of technical EPTC                                 no-observed-adverse-effect
                                                                            level > 1800

Molinate  mallard duck    5-day dietary administration  1000 - 32 000       LD50 in diet: 13 000

Cycloate  bobwhite quail  7-day dietary administration  1800 - 56 000       LD50 in diet: 56 000
                          of Ro-Neet 6Eb

Butylate  bobwhite quail  7-day dietary administration  1800 - 56 000       LD50 > 56 000

Pebulate  bobwhite quail  7-day dietary administration  1000 - 18 000       LD50 in diet: 8400
                          of technical pebulate

Pebulate  bobwhite quail  7-day dietary administration  1000 - 24 000       LD50 in diet; 9500
                          of Tillam 6Eb

Vernolate bobwhite quail  7-day dietary administration  1800 - 24 000       LD50 in diet: 12 000
                          of technical vernolate

a   From: Stauffer Chemicals SA (1978).
b   Herbicide formulation.


    Yin-Tak  Woo  (1983)  has  reviewed  the  structure-activity
relationships for the different types of thiocarbamates.

8.1  Single Exposures

    Data  concerning  the  acute toxicity  of thiocarbamates are
summarized  in Table 6.   Very few results  on acute  inhalatory
toxicity are available.

    The acute oral and dermal toxicities of  thiocarbamates  are
relatively   low.   The  most   toxic  representatives  of   the
thiocarbamates  are molinate and diallate.  The toxicity of EPTC
for  various animal species varies significantly.  The cat seems
to  be the most  sensitive animal species.   It should be  noted
that this may also be true for other thiocarbamates, but data on
the cat are lacking.

    When  animals  are administered  high  oral dose  levels  of
thiocarbamates,   signs  such  as  anorexia,  squinting,  hyper-
salivation,   lachrymation,  piloerection,  laboured  breathing,
ataxia,  hypothermia,  incoordination, depression,  pareses, and
muscular  fibrillation may be observed, and convulsions followed
by death may occur (Akulov et al., 1972; IARC, 1976).

    Lethal  doses  of diallate  given  to rats  and  guinea-pigs
caused  restlessness within the first  2 h, followed by lack  of
coordination.  Animals died from respiratory paralysis.  Autopsy
revealed  vascular dilatation in  the cerebrum, cerebellum,  and
abdominal  viscera, meningeal haemorrhages, and enlarged adrenal
glands (Doloshitsky, 1969).

    In rabbits, a single oral dose of triallate (450 - 500 mg/kg
body  weight)  decreased acetylcholinesterase (AChE) activity in
some  parts of the  brain and in  red blood cells.   The maximum
levels  of inhibition were less than 20% in the brain and 42% in
the red blood cells (Zhavoronkov et al., 1974).

8.2  Short- and Long-Term Exposure

8.2.1   Experimental animals

    Doloshitsky  (1969)  carried  out  studies  on  albino  rats
receiving  dose levels of  0.5 - 200 mg diallate/kg  body weight
for  periods of up to 8 months.  Dose levels of 20 mg/kg or more
resulted  in a clear  increase in mortality.   At 50 mg/kg  body
weight, 73% of the animals died within 8 months.

Table 6.  Acute toxicity of thiocarbamates for experimental animals 
Compound     Animal                  Dose                Reference 
                              (mg/kg body weight)   
                               Oral       Dermal 
Butylate     rat (male)        3500          -          Worthing & Walker 
             rat (female)      3970          -          Worthing & Walker 
             rabbit                       > 2000        Hubbell & Casida 
Diallate     rat               395                      Worthing & Walker 
             rat               1000                     Doloshitsky 
             rabbit                     2000 - 2500     Worthing & Walker 
             dog               510                      Worthing & Walker 
Triallate    rat               1471                     Rappoport & Pest-
                                                        ova (1973) 
             rat            1675 - 2165                 Worthing & Walker 
             rabbit                         8200        Worthing & Walker 
Pebulate     rat               1120                     Worthing & Walker 
             rabbit                         4640        Worthing & Walker 
Vernolate    rat               1780                     Stauffer Chemicals 
                                                        SA (1978) 
Molinate     rat (male)         369                     Worthing & Walker 
             rat (female)       450                     Worthing & Walker 
             rabbit                       > 4640        Worthing & Walker 
Cycloate     mouse             2285                     Rebrin & Alexan-
                                                        drova (1971) 
             rat               2710                     Worthing & Walker 
             rabbit                       > 4640        Worthing & Walker 
EPTC         rat               1630        3200         Hubbell & Casida 

    Worthing  &   Walker  (1983) summarized  short-term toxicity
tests  of a number  of thiocarbamates.  Rats  were  administered
400 mg diallate/kg diet for 90 days.  Weight loss, irritability,
hyperactivity, and mild cardiac changes, but no deaths, occurred
at  1200 mg/kg diet, the  highest dose level tested.   In beagle
dogs, adverse effects were observed at 600 mg/kg body weight per
day,  but  not at  125 mg/kg body  weight per day.   In a 2-year
feeding   trial,  no  adverse  effects  were  observed  in  rats
receiving   200  mg  triallate/kg  diet  or  in  dogs  receiving
15 mg/kg, daily.  Cycloate did not induce toxicity  symptoms  in
dogs  administered 240 mg/kg daily for 90 days, and butylate was
well  tolerated  by rats  and dogs at  a dose level  of 40 mg/kg
daily for 90 days.

    Rats fed 147 mg triallate/kg body weight in the  diet  (one-
tenth  of the LD50), for  1, 2, or 3  months, showed congestion,
perivascular   oedema,   chromatolysis,  and   proliferation  of
adventitial  cells in the  brain.  Local fatty  degeneration and
dystrophy in the liver and kidneys were also observed (Rappoport
& Pestova, 1973).

8.2.2    Domestic animals

    Sheep  administered daily oral doses of diallate at 10 mg/kg
body  weight  for  19 weeks,  25 mg/kg  for  20 -  24 weeks, and
50 mg/kg for 25 and 26 weeks became ill only when the  dose  was
increased  to  50  mg/kg body  weight.  Cholinesterase  activity
remained  normal.  It seems  that 10 mg diallate/kg  body weight
did not cause any toxic effects (Palmer et al., 1972).

    Single   oral  doses  of  300 mg   triallate/kg  and  720 mg
triallate/kg  body  weight  to  sheep  and  pigs,  respectively,
decreased RNA and DNA levels in the leukocytes and increased the
concentration of free nucleotides (Verkhovskiy et al., 1973).

8.3  Skin and Eye Irritation; Sensitization

    Worthing  &  Walker  (1983)  summarized  the  skin  and  eye
irritation potential of a number of thiocarbamates.  Butylate is
a mild irritant to the skin and non-irritating to eyes; cycloate
is  non-irritating to eyes; diallate  is a moderate irritant  to
the  skin  and  eyes; molinate  is  non-irritating  to skin  and
moderately  irritating  to  eyes; and  triallate  is  moderately
irritating to skin and slightly to eyes.  These  compounds  were
all tested on the skin and eyes of rabbits.

8.4  Reproduction, Embryotoxicity, and Teratogenicity

8.4.1    Reproduction

    Daily administration of 3.6 mg molinate/kg body weight for 2
months  to 7- to 8-week-old rats caused gonadal and spermatozoal
changes.   When intact females  were mated with  treated  males,
resorption,  impaired  fetal  development, and  increased lethal
effects  in  offspring  were seen.   Unlike  molinate,  pebulate
administered to male rats at 11.25 mg/kg body weight, daily, for

2  months, did not  induce any gonadotoxic  effects (Voytenko  &
Medved, 1973).

8.4.2    Teratogenicity

    Pregnant  CF1 mice, Sprague Dawley rats, and golden hamsters
were  given cartap hydrochloride  orally on days  8 - 13  (mice,
hamsters) or days 9 - 15 (rats) of gestation at dose  levels  of
50 - 100 mg/kg body weight for mice and rats and  2 -  100 mg/kg
body weight for hamsters.  Mice receiving 50 mg and 100 mg, rats
receiving  50 mg,  and hamsters  receiving  2, 10,  and 50 mg/kg
tolerated  administration of cartap, except  that maternal death
occurred  in  rats  at  50 mg/kg  body  weight.   No significant
increases  in fetal abnormalities were found.  Treatment of rats
and  hamsters with 100 mg/kg  body weight resulted  in  maternal
death  and  retarded growth.   However,  the rates  of embryonal
resorption and gross malformations were comparable with those in
the   controls.   Cartap  did   not  induce  any   fetotoxic  or
teratogenic effects in this study (Mizutani et al., 1971).

8.5  Mutagenicity and Related End-Points

    Diallate  and  triallate were  mutagenic  in the  Ames test,
with  Salmonella  typhimurium strains  TA 100 and  TA 1535 (base-
pair  substitution mutants), but only  in the presence of  liver
microsomal   preparation,  indicating  the  need   for  chemical
activation.  No effects were seen with strains TA 98 and TA 1538
(frameshift  mutants) (Sikka &  Florczyk, 1978).  The  mutagenic
activity  of these compounds seems to be related to the presence
of  the chloroallyl group  in the molecule,  which is, in  fact,
very  similar  to  the  known  carcinogen  and   mutagen   vinyl

    Cartap  was tested  in vivo for cytogenic effects on the bone
marrow  cells  of CF1  mice and Wistar  rats.  The compound  was
administered at levels of 10, 100, or 150 mg/kg body  weight  to
adult  male  rats,  in either  a  single  dose or  daily  for  5
successive days. Cartap was also administered to 3-week-old rats
at  an oral dose of  200 mg/kg body weight or  intraperitoneally
(ip)  at a dose of  30 mg/kg body weight.  No  chromosomal aber-
rations were found.  No mutagenic effects were seen in male mice
using  the dominant lethal test after a single, or 5 successive,
oral doses of 100 mg/kg body weight (Kikuchi et al., 1976).

    Murnik   (1976)   showed   that   butylate   and   vernolate
significantly  increased the level of  apparent dominant lethals
in  Drosophila melanogaster, probably because of toxicity, since
genetic   assays  did  not  clearly  indicate  an  induction  of
chromosomal  breakage or loss.   An increased frequency  of sex-
linked recessive lethals was found.

8.6  Carcinogenicity

    Increased  tumour  incidence  was  observed  in  mice  given
diallate orally at 125 mg/kg body weight per day, from  the  7th
day  of  life,  for 4 weeks, and 560 mg/kg diet for a further 73
weeks (Innes et al., 1969).

9.1  Occupational Exposure

    Data  concerning the effects  of thiocarbamates on  man  are
scarce.   When  soil  was treated  with  Eptam  by aircraft  and
tractor,  the air levels  of the herbicide  in the working  zone
ranged  from 8.1 to 210  mg/m3.  Some workers reported  headache
and nausea, especially following exposure to 135 -210 mg EPTC/m3
(Medved  & Ivanova, 1971) and  also following brief exposure  to
diallate.  Skin irritation was also found.


    The Joint FAO/WHO Meeting on Pesticide Residues  (JMPR)  and
the  International  Agency for  Research  on Cancer  (IARC) have
evaluated  the  toxicity  and  carcinogenicity  data  of  a  few
thiocarbamates.  These are referred to in Annex II.

    This   Annex   also   gives  the   WHO   recommended  hazard
classification.   As indicated, WHO/FAO Data  Sheets, IRPTC Data
Profiles,  and IRPTC  Legal Files  are not  available for  these


[Triallate  poisoning of animals.]  Veterinariya, 10: 105-106 (in

ALDRIDGE,  W.N. & MAGOS, L.  (1978)   Carbamates, thiocarbamates,
dithiocarbamates, Luxembourg,   Commission   of   the   European
Communities (Report No. V/F/1/78/75 EN).

ANDERSON,  J.P.E. & DOMSCH,  K.H.  (1980)  Relationship  between
herbicide  concentration and the rates  of enzymatic degradation
of   14C-diallate  and  14C-triallate  in  soil.  Arch.  environ.
Contam. Toxicol., 9(3): 259-268.

BATCHELDER, G.H. & PATCHETT, G.G.  (1960)  A colorimetric method
for  the determination of EPTC  residues in crops and  soils.  J.
agric. food Chem., 8(3): 214-216.

CARRINGER, R.D., RIECK, C.E., & BUSH, L.P.   (1978)   Metabolism
of EPTC in corn ( Zea mays).  Weed Sci., 26(2): 157-160.

CASIDA,  J.E., GRAY, R.A.,  & TILLES, H.   (1974)  Thiocarbamate
sulfoxides:  potent,  selective,  and biodegradable  herbicides.
 Science, 184: 573-574.

CASIDA,  J.E., KIMMEL, E.C.,  OHKAWA, H., &  OHKAWA, R.   (1975)
Sulfoxidation  of  thiocarbamate  herbicides and  metabolism  of
thiocarbamate  sulfoxides  in  living  mice  and  liver   enzyme
systems.  Pestic. Biochem. Physiol., 5: 1-11.

CHEN,  Y.S.  &  CASIDA, J.E.   (1978)   Thiocarbamate  herbicide
metabolism:  microsomal  oxygenase metabolism  of EPTC involving
mono-  and dioxygenation at the sulfur and hydroxylation at each
alkyl carbon.  J. agric. food Chem., 26: 263-267.

DALVI, R.R., POORE, R.E., & NEAL, R.A.  (1974)  Studies  of  the
metabolism  of  carbon  disulfide by  rat liver microsomes.  Life
Sci., 14: 1785-1796.

DALVI, R.R., HUNTER, A.L., & NEAL, R.A.   (1975)   Toxicological
implications  of the mixed-function oxidase catalyzed metabolism
of carbon disulfide.  Chem.-biol. Interact., 10: 349-361.

DEBAUN,  J.R., BOVA, D.L., FINLEY,  K.A., & MENN, J.J.   (1978a)
Metabolism of [ring-14C]Ordram (molinate) in the rat. I. Balance
and  tissue  residue  study.  J. agric.  food Chem., 26(5): 1096-

DEBAUN,  J.R., BOVA,  D.L., TSENG,  C.K., &  MEN, J.J.   (1978b)
Metabolism  of  [ring-14C]Ordram  (molinate)  in  the  rat.  II.
Urinary  metabolite identification.  J. agric. food Chem., 26(5):

DEMARCO,  A.C. & HAYES, E.R.  (1979)  Photodegradation of thiol-
carbamate herbicides.  Chemosphere, 5: 321-326.

DE MATTEIS, F. & SEAWRIGHT, A.A.  (1973)   Oxidative  metabolism
of  carbon disulfide  by the  rat: effects  of treatments  which
modify  the  liver  toxicity  of  carbon  disulfide.  Chem.-biol.
Interact., 7: 375-388.

DOLOSHITSKY, S.L.  (1969)  Hygienic standardization of herbicide
Avadex containing chlorine in water.  Hyg. Sanit., 34: 21-25.

ENDO, T., KUSAKA, T., TAN, N., & SAKAI, M.  (1982)   Effects  of
the  insecticide cartap hydrochloride on soil enzyme activities,
respiration, and nitrification.  J. Pestic. Sci., 7: 101-110.

FANG, S.C.  (1975)  Thiocarbamates. In: Kearney, P.C. & Kaufman,
D.D.,   ed.  Herbicides,  chemistry,  degradation,  and  mode  of
action, New York, Marcel Dekker, Vol. 1, pp. 323-348.

FANG,  S.C. & THEISEN, P.   (1959)  An isotopic study  of ethyl-
 N,N -di-n-propylthiolcarbamate      (EPTC-S35) residue in various
crops.  J. agric. food Chem., 7(11): 770-771.

FANG,  S.C., GEORGE, M.,  & FREED, V.H.   (1964)  Metabolism  of
herbicides:  the  metabolism  of  S -propyl-1-14C-n-butylethyl-
thiocarbamate (tillam 14C) in rats.  J. agric. food Chem., 12(1):

FAO/WHO  (1977a)   Pesticide residues in food. Report of the 1976
Joint  Meeting of the FAO Panel of Experts on Pesticide Residues
and  the  Environment  and the  WHO  Expert  Group on  Pesticide
Residues, Geneva,   World  Health  Organization  (FAO  Food  and
Nutrition  Series  No. 9;  FAO  Plant Production  and Protection
Series No. 8; WHO Technical Report Series No. 612).

FAO/WHO  (1977b)   1976 Evaluations of some pesticide residues in
food, Geneva, World Health Organization (AGP 1977/M/14).

FAO/WHO   (1979)   Pesticide residues in food. Report of the 1978
Joint  Meeting of the FAO Panel of Experts on Pesticide Residues
in  Food  and  the  Environment  and  the  WHO Expert  Group  on
Pesticide  Residues, Rome, Food and Agriculture  Organization of
the  United Nations (FAO  Plant Production and  Protection Paper

GRAY,  R.A.  (1971)  Behaviour, persistence,  and degradation of
carbamate  and thiocarbamate herbicides in  the environment. In:
 Proceedings  of the California Weed Control Conference, pp. 128-

GRAY,   R.A.  &  WEIERICH,   A.J.   (1968)   Leaching   of  five
thiocarbamate herbicides in soils.  Weed Sci., 16(1): 77-79.

HORVATH,  L. & PULAY, A.  (1980)  Metabolism of EPTC in germina-
ting  corn:  sulfone  as the  true carbamoylating agent.  Pestic.
Biochem. Physiol., 14: 265-270.

HUBBELL,  J.P. &  CASIDA, J.E.   (1977)  Metabolic  fate of  the
 N,N -dialkylcarbamoyl    moiety  of  thiocarbamate herbicides  in
rats and corn.  J. agric. food Chem., 25(2): 404-413.

HUGHES,  R.E., Jr &  FREED, V.H.  (1961)   The determination  of
ethyl  N,N -di-n-propylthiolcarbamate     (EPTC)  in  soil by  gas
chromatography.  J. agric. food Chem., 9(5): 381-382.

IARC  (1976)  Diallate. In:  Some carbamates, thiocarbamates, and
carazides, Lyons,  International Agency for Research  on Cancer,
pp. 69-75  (Monographs on the Evaluation of Carcinogenic Risk of
Chemicals to Man, Vol. 12).

H.L.,  GART, J.J., KLEIN, M., MITCHELL, I., & PETERS, J.  (1969)
Bioassay  of  pesticides  and industrial  chemicals  for  tumor-
igenicity in mice: a preliminary note.  J. Natl Cancer Inst., 42:

IRPTC   (1983)    IRPTC  legal file  1983, Geneva,  International
Register   for  Potentially  Toxic  Chemicals,   United  Nations
Environment Programme.

JOHNSON, W.W. & FINLEY, M.T.  (1980)   Handbook of acute toxicity
of  chemicals to fish and  aquatic invertebrates, Washington DC,
US Department of Interior, Fish and Wildlife Service.

KAUFMAN,  D.D.  (1967)  Degradation  of carbamate herbicides  in
soil.  J. agric. food Chem., 15: 582-591.

KIKUCHI,   Y.,  HITOTSUMACHI,  S.,  &   YAMAMOTO,  K.I.   (1976)
[Mutagenicity tests on cartap hydrochloride. In vivo cytogenetic
and  dominant lethal tests in mammals.]  J. Takeda Res. Lab., 35:
257-263 (in Japanese).

LAY,  M.M. & CASIDA,  J.E.  (1976)  Dichloroacetamide  antidotes
enhance thiocarbamate sulfoxide detoxification by elevating corn
root    glutathione   content   and   glutathione  S -transferase
activity.  Pestic. Biochem. Physiol., 6: 442-456.

MEDVED, I. & IVANOVA, Z.V.  (1971)  [Hygienic  establishment  of
working  conditions  during  Eptam application  in agriculture.]
 Gig. i Sanit., 2: 29-32 (in Russian).

J.,  AMANO, T., &  KAZIWARA, K.  (1971)   Teratogenesis  studies
with       1,3-bis(carbamoylthio)-2-( N,N -dimethylamino)propane
hydrochloride  in the mouse,  rat, and hamster.  J.  Takeda  Res.
Lab., 30: 776-785.

MURNIK,  M.R.   (1976)  Mutagenicity  of widely-used herbicides.
 Genetics, 83: S54 (abstract).

OKAICHI,  T. & HASHIMOTO, Y.   (1962)  The  structure of  nereis
toxin.  Agric. biol. Chem., 26: 224-227.

ONG, V.Y. & FANG, S.C.  (1970)  In vivo metabolism  of  ethyl-1-
14C- N,N -di-n-propylthiol      carbamate in rats.  Toxicol.  appl.
Pharmacol., 17: 418-425.

C.E.   (1972)  Chronic toxicosis of sheep from organic herbicide
diallate.  Am. J. vet. Res., 33: 543-546.

PATCHETT, G.C., BATCHELDER, G.H., & MENN, J.J.   (1964)   Eptam.
In:  Zweig,  G.,  ed.  Analytical methods   for pesticides: plant
growth   regulations  and  food  additives, New   York,  London,
Academic Press, Vol. 4, pp. 117-123.

RAPPOPORT,  M.B. & PESTOVA, A.G.  (1973)  [Biological effects of
diisopropyltrichloroallylthiocarbamate.]  Vrach.  Delo, 10:  138-
141 (in Russian).

REBRIN,  V.G.  &  ALEXANDROVA,  L.G.   (1971)   [Toxico-hygienic
characteristics  of the new herbicide Ro-Neet.]  Vrach. Delo, 12:
118-121 (in Russian).

SAKAI, M.  (1969)   The chemistry and action of cartap, pp. 15-19
Tokyo,   Japan  Plant  Protection  Society  (Japanese  Pesticide
Information No. 6).

SCHUPHAN, I. & EBING, I.  (1977)  [Metabolism  of  thiocarbamate
herbicides.  I. Chemical conversion  of the herbicide  di-allate
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SIKKA,  H.C.  &  FLORCZYK,  P.   (1978)   Mutagenic  activity of
thiocarbamate  herbicides  in  Salmonella typhimurium.   J. agric.
food Chem., 26: 146-148.

STAUFFER  CHEMICALS  SA   (1978)   Product  safety and toxicology
review.  Behaviour of thiocarbamates in the environment, Geneva,
Stauffer Chemicals SA (Report No. Tox-05-78-01).

STAUFFER  CHEMICALS  SA   (1981)   Product  safety and toxicology
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[Changes   in   blood   of  animals   poisoned   by  triallate.]
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VETTORAZZI, G. & VAN DEN HURK, G.W. (1984)   Pesticides reference
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VOYTENKO,  G.A.  &  MEDVED,  I.L.   (1973)   [Effect   of   some
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Annex I.  Names and structures of selected thiocarbamates
Common    Trade/  Chemical structure          CAS chemical name/   Molecular    Relative Vapour  Water
name      other                               CAS registry number  formula      molec-   pres-   solu-
          name                                                                  ular     sure    bility
                                                                                mass     (25 °C) (25 °C)

butylate  Sutan   [(CH3)2CHCH2]2NCOSCH2CH3    carbamothioic acid,  C11H23NOS    217.41   170 mPa 46
                                              bis(2-methyl-propyl)-,                             mg/
                                               S -ethyl ester                                     litrea,b

cartap    Padan        O                      carbamothioic acid,  C7H15N3O2S   205
                       ||                      S,S'-[2-(dimethyl-
                  (H2N-C-SCH2)2-CH-N(CH3)2    amino)-1,3 propane-
                                              diyll ester

cycloate  Ro-Neet            O                carbamothioic acid,  C11H21NOS    215.39   830 mPa 75
          Eurex       ___    ||               ethyl(cyclo-hexyl)-,                               mg/
                     /   \-N-C-SC2H5           S -ethyl ester                                     litrea,b
                     \   / |                  (1134-23-2)

diallate  Avadex                              carbamothioic acid,  C10H17Cl2NOS 270.24   20 mPa  14
          DATC                 O              bis(1-methyl-ethyl)-,                              mg/
                               ||              S -(2,3-dichloro-2-                                litreb
                  [(CH3)2CH]2N-C-SCH2-C-CHC1  propenyl) ester
                                      |       (2303-16-4

EPTC      Eptam                               carbamothioic acid,  C9H19NOS     189.35   4.5 Pa  370
          Eradicane            O              bis(1-methyl-ethyl)-,                              mg/
          R-1608               ||              S -ethyl ester                                     litrea
                  [(CH3)2CH]2N-C-SC2H5        (759-94-4)
ethiolate Prefox          O                   carbamothioic acid,  C7H15NOS     161.29
                          ||                  diethyl-,  S -ethyl
                  (C2H5)N-C-SC2H5             ester

Annex I (contd).
Common    Trade/  Chemical structure          CAS chemical name/   Molecular    Relative Vapour  Water
name      other                               CAS registry number  formula      molec-   pres-   solu-
          name                                                                  ular     sure    bility
                                                                                 mass     (25 °C) (25 °C)

molinate  Ordram  CH2CH2CH2   O               1H-azepine-1-carbo   C9H17NOS     187.33   746 mPa 880
          Yalan   |        \ ||              thioic acid, hexa-                                 mg/
                  |         N-C-SC2H5         hydro-,  S -ethyl                                   litrea,b
                  |        /                  ester      
                  CH2CH2CH2                   (2212-67-1)

pebulate  Tillam        O                     carbamothioic acid,  C10H21NOS    203.38   4.7 Pa  60
          PEBC          ||                    butylethyl-,                                       mg/
                  C2H5-N-C-SC3H7               S -propyl ester                                    litrea,b
                       |                      (1114-71-2)

prothio-  Dynone                              carbamothioic acid,  C8H18N2OS    226.8    1.9 uPa
carb                             O            [3-(dimethyl-amino)-
                                 ||           propyl]-,  S -ethyl
                  (CH3)2N-C3H7NH-C-SC2H5      ester

triallate Avadex BW            O              carbamothioic acid,  C10H14Cl3NOS 304.68   16 mPa  4 
          Far-Go               ||             bis(1-methyl-ethyl)-,                              mg/
                  [(CH3)2CH]2N-C-S-CH2C-CCl2   S -(2,3,3-trichloro-                               litreb
                                      |       2-propenyl) ester
                                      Cl      (2303-17-5)

vernolate R-1607           O                  carbamothioic acid,  C10H21NOS    203.38   1.39 Pa 107 
          Vernam           ||                 dipropyl-, S -propyl                                mg/
                  (C3H7)2N-C-SC3H7            ester                                              litre

a   At 20 °C.
b   From: Worthing & Walker (1983).

Annex II, Table 1. Thiocarbamates: JMPR reviews, ADIs, Evaluation by IARC, 
Classification by Hazard, FAO/WHO Data Sheets, IRPTC Data profile and 
Legal filea
Compound   Year of  ADIb     Evaluation by  IARCd        Availability    WHO recom-    FAO/WHO Data
           JMPR     (mg/kg   JMPRc:         Evaluation   of IRPTCe:      mended clas-  sheets on
           meeting  body     Published in:  of carcino-  Data     Legal  sification    pesticidesf
                    weight)  FAO/WHO        genicity     profile  fileg  of pesticides
                                                                         by hazardh
Butylate                                                                  0
Cartap     1978     0-0.1    1979                                         II
           1976     0-0.5    1977b          
Cycloate                                                                  III
Diallate                                    1976                          II
EPTC                                                                      II
Molinate                                                                  II
Pebulate                                                                  II
Prothiocarb                                                               III
Triallate                                                                 III
Vernolate                                                                 II

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, Lyons, France.
e   IRPTC = International Register for Potentially Toxic Chemicals (UNEP, Geneva).
f   WHO/FAO Data Sheets on Pesticides with number and year of appearance.
g   From: IRPTC (1983).
h   From: WHO (1986).
    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 a 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.
    The classification relates to the technical material and not to the formulated product.

Annex II, Table 2. WHO recommended hazard classification for 
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

    See Also:
       Toxicological Abbreviations