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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY


    ENVIRONMENTAL HEALTH CRITERIA 78




    DITHIOCARBAMATE PESTICIDES, 
    ETHYLENETHIOUREA AND PROPYLENETHIOUREA:
    A GENERAL INTRODUCTION






    This report contains the collective views of an international group of
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    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, 1988


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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR DITHIOCARBAMATE PESTICIDES, 
ETHYLENETHIOUREA (ETU), AND PROPYLENETHIOUREA (PTU) - A GENERAL 
INTRODUCTION 

A.  DITHIOCARBAMATE PESTICIDES: A GENERAL INTRODUCTION

B.  ETHYLENETHIOUREA (ETU) AND PROPYLENETHIOUREA (PTU) 

PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES  

REFERENCES  

ANNEX I   NAMES AND STRUCTURES OF SELECTED DITHIOCARBAMATES

ANNEX II  NAMES AND STRUCTURES OF DEGRADATION PRODUCTS OF 
          ETHYLENE BISDITHIOCARBAMATES 

ANNEX III DITHIOCARBAMATES AND ETU: JMPR REVIEWS, ADIs, EVALUATION 
          BY IARC, CLASSIFICATION BY HAZARD, FAO/WHO DATA SHEETS, 
          IRPTC DATA PROFILE AND LEGAL FILE  

WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR DITHIOCARBAMATE 
PESTICIDES, ETHYLENETHIOUREA (ETU), AND PROPYLENETHIOUREA (PTU)

 Members

Dr U.G. Ahlborg, Unit of Toxicology, National Institute of 
    Environmental Medicine, Stockholm, Sweden  (Vice-Chairman) 

Dr H.H. Dieter, Federal Health Office, Institute for Water, Soil 
    and Air Hygiene, Berlin (West) 

Dr R.C. Dougherty, Department of Chemistry, Florida State 
    University, Tallahassee, Florida, USA 

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 Medicine, 
    University of Lagos, Lagos, Nigeria 

Dr Shou-Zheng Xue, Toxicology Programme, School of Public Health, 
    Shanghai Medical University, Shanghai, China 

 Observers

Dr R.F. Hertel, Fraunhöfer Institute for Toxicology and Aerosol 
    Research, Hanover, Federal Republic of Germany 

Dr E. Kramer (European Chemical Industry Ecology and Toxicology   
    Centre), Dynamit Nobel A.G., Cologne, Federal Republic of 
    Germany 

Mr G. Ozanne (European Chemical Industry Ecology and Toxicology 
    Centre), Rhone Poulenc DSE/TOX, Neuilly-sur-Seine, France 

Mr V. Quarg, Federal Ministry for Environment, Nature Conservation 
    and Nuclear Safety, Bonn, Federal Republic of Germany 

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)

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

 Observers (contd.)

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 

 Secretariat

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 Occupational 
    Health, Medical Academy, Sofia, Bulgaria  (Temporary Adviser) 

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 
     Adviser) 

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

NOTE TO READERS OF THE CRITERIA DOCUMENTS

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

ENVIRONMENTAL  HEALTH  CRITERIA FOR  DITHIOCARBAMATE PESTICIDES,
ETHYLENETHIOUREA (ETU), AND PROPYLENETHIOUREA (PTU)

    A WHO Task Group on Environmental Health Criteria for 
Dithiocarbamate Pesticides, Ethylenethiourea, and Propylene-
thiourea 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. Dr U. Schlottmann 
spoke on behalf of the Federal Government, which 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 dithiocarbamate 
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, Bilthoven, the Netherlands. 

    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. 

ABBREVIATIONS

ADI        acceptable daily intake

BSP        sulfobromophthalein

DDC        diethyldithiocarbamate

DIDTa      5,6-dihydro-3 H-imidazo(2,1- C)-1,2,4-dithiazole-3-thione

EBDC       ethylene bisdithiocarbamate

EDA        ethylenediamine

EDI        ethylene diisothiocyanate

ETD        ethylene bisthiuram disulfide

ETU        ethylenethiourea

EU         ethyleneurea

ip         intraperitoneal

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 

MIT        methylisothiocyanate

NDDC       sodium diethyldithiocarbamate

NDMA       nitrosodimethylamine

NDMC       sodium dimethyldithiocarbamate
    
PBI        protein-bound iodine

PTU        propylenethiourea

SGPT       serum glutamic-pyruvic transaminase

T3         triiodothyronine

T4         thyroxine

TSH        thyroid-stimulating hormone

----------------------------------------------------------------------
a   In  some older  studies, DIDT  is referred  to as  ethylene-
    thiuram  monosulfide (ETM).  However,  in 1974 the  chemical
    that had been referred to as ETM was shown to be DIDT, and
    so the latter term has been used throughout this document.

PART A 
DITHIOCARBAMATE PESTICIDES: A GENERAL INTRODUCTION

CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR DITHIOCARBAMATE PESTICIDES: A 
GENERAL INTRODUCTION 

INTRODUCTION

1.  SUMMARY

    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.  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  Water
         4.1.2  Soil
    4.2  Biotransformation
         4.2.1  Microbial degradation
         4.2.2  Photodegradation

5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Food
    5.2  Monitoring and market basket studies

6.  KINETICS AND METABOLISM

    6.1  Absorption, distribution, and excretion
    6.2  Metabolic transformation
         6.2.1  Mammals
    6.3  Metabolism in plants
    6.4  Decomposition in water and soil
    6.5  Metabolism in microorganisms

7.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

    7.1  Microorganisms
    7.2  Aquatic organisms
         7.2.1  Acute toxicity
         7.2.2  Short- and long-term toxicity and reproduction studies
                7.2.2.1  Fish
                7.2.2.2  Invertebrates
         7.2.3  Bioconcentration (bioaccumulation)

8.  EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

    8.1  Single exposures
    8.2  Short- and long-term exposures
         8.2.1  Oral exposure
                8.2.1.1  Rat
                8.2.1.2  Dog
                8.2.1.3  Bird
         8.2.2  Inhalation exposure
                8.2.2.1  Rat
    8.3  Skin and eye irritation; sensitization
    8.4  Reproduction, embryotoxicity, and teratogenicity
         8.4.1  Reproduction
                8.4.1.1  Rat
                8.4.1.2  Bird
         8.4.2  Teratogenicity
                8.4.2.1  Rat
                8.4.2.2  Mouse
         8.4.3  Embryotoxicity
    8.5  Mutagenicity and related end-points
    8.6  Carcinogenicity
         8.6.1  Mouse
         8.6.2  Rat
         8.6.3  Dog
         8.6.4  Dithiocarbamates in combination with nitrite
    8.7  Mechanisms of toxicity; mode of action
         8.7.1  Thyroid
         8.7.2  Interaction of dithiocarbamates and alcohol
         8.7.3  Neurotoxicity
         8.7.4  Dithiocarbamates in combination with metals
         8.7.5  Miscellaneous reactions

9.  EFFECTS ON MAN

    9.1  Occupational exposure
         9.1.1  Acute toxicity - poisoning incidents
         9.1.2  Case reports, short-term and epidemiological studies
                9.1.2.1  Dermal
                9.1.2.2  Exposure via different routes

INTRODUCTION

    The  dithiocarbamates 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  large scale  in  the  last 40 -  50 years.  The 
development  of  dithiocarbamate  derivatives  with   pesticidal 
properties  occurred  during and  after  the Second  World  War. 
However,  a  few  compounds, such  as  thiram  and  ziram,  were 
introduced in the 1930s. 

    The  world-wide  consumption of  dithiocarbamates is between 
25 000  and 35 000 metric tonnes per year.  Dithiocarbamates are 
used  as fungicides, being effective against a broad spectrum of 
fungi and plant diseases caused by fungi.  In industry, they are 
used as slimicides in water-cooling systems, in sugar, pulp, and 
paper  manufacturing,  and  as  vulcanization  accelerators  and 
antioxidants  in rubber.  Because of their chelating properties, 
they  are also used as scavengers in waste-water treatment.  The 
herbicidal   compounds,   which   are  an   integral   part   of 
industrialized agriculture, are used mostly in North and Central 
America,  and Europe, with  little use reported  in Asia,  South 
America, and Africa. 

    In this introductory document, an attempt has been  made  to
summarize  the available data  on the dithiocarbamates  used  as
pesticides, in order to indicate their impact on  man,  animals,
plants, and the environment.  This overview is not complete, nor
is it intended to be.  More details on certain aspects are given
in  the JMPR  and IARC  (International Agency  for  Research  on
Cancer)  reports, which have  already been published.   It  also
should  be recognized that the design of a number of the studies
cited, especially the older ones, is inadequate.

1.  SUMMARY

1.1.  General

    Dithiocarbamates  are mainly used in agriculture as insecti-
cides,  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
health.

    The  general formula of dithiocarbamates is characterized by
the presence of:

                       R1  S
                        \  ||
                         N-C-S-R3
                        /
                       R2

Depending  on the types of  monoamines used in the  synthesis of
these  compounds,  mono- or  dialkyldithiocarbamates are formed.
Reactions  with diamines result in the formation of two terminal
dithiocarbamate  groups linked by an alkylene (ethylene) bridge.
Both alkyl and ethylene dithiocarbamates form salts with metals,
and both can be oxidized to the corresponding disulfides.

    More  than 15 dithiocarbamates  are known.  However,  it  is
beyond the scope of this publication to give  complete  informa-
tion  on each compound.  The intention is to cover the different
aspects  of  dithiocarbamates,  making use  of  publications and
reports available on the compounds that are most used  and  best
known.   Data  on  the  carbamates  or  thiocarbamates  are  not
included,   because  these  compounds   have  been  covered   in
Environmental  Health Criteria 64: Carbamate  Pesticides and 76:
Thiocarbamate Pesticides (WHO, 1986b; WHO, 1988)

1.2.  Properties, Uses, and Analytical Methods

    Dithiocarbamates with hydrophylic groups form water-soluble,
heavy-metal  complexes, while some of  the dithiocarbamate metal
complexes  used as fungicides are insoluble in water but soluble
in non-polar solvents.  Alkylene bisdithiocarbamates (containing
two  donor  CS2  groups),  which  form  polymeric  chelates, are
insoluble in both water and non-polar solvents.

    The  heavy-metal  salts  of ethylene  bisdithiocarbamic acid
may  polymerize.   Dithiocarbamates may  decompose under certain
circumstances  into  a  number  of  compounds,  such  as sulfur,
5,  6-dihydro-3 H-imidazol   [2,1-C]-1, 2, 4-dithiazole-3-thione,
ethylenethiourea  (ETU),  and  ethylenediamine  (EDA).   ETU  is
fairly stable, has a high water solubility, and is of particular
importance because of its specific toxicity.  For  this  reason,
toxicological information on this compound is included  in  this
review.

    Physical  and  chemical  data for  individual substances are
tabulated  in the document,  and analytical methods  for dithio-
carbamates   are  described.   Further  details  for  individual
dithiocarbamates appear in the WHO Technical Report  Series  and
the IRPTC data profiles.

1.3.  Sources, Environmental Transport and Distribution

    Most  dithiocarbamates were developed during and after World
War  II.   However,  a few  compounds  (ziram  and thiram)  were
introduced  around 1931.  Dithiocarbamates, with  their insecti-
cidal,  herbicidal, and fungicidal properties, have a wide range
of applications and are produced in great  quantities.   Because
of  their  high  biological activity,  dithiocarbamates are also
used in medicine, the rubber industry, and in the  treatment  of
chronic alcoholism.

    Alkyl dithiocarbamates are stable in an alkaline medium.  By
splitting  off carbon disulfide and hydrogen sulfide, as well as
by  oxidative degradation, a number of break-down products, such
as ETU, are formed in soil and water.  The rate  of  degradation
depends on a number of factors, including pH and type of cation.
Ethylene  bisdithiocarbamates (EBDCs) are generally  unstable in
the  presence of moisture,  oxygen, or biological  systems,  and
decompose rapidly in water.

    The mobility of EBDCs in soil varies considerably, depending
on  their individual water  solubilities and the  type of  soil.
ETU is water-soluble and mobile.  It is taken up by plant roots,
is  translocated,  and  metabolized, forming  ethyleneurea (EU),
other   2-imidazole   derivatives,   and  various   unidentified
metabolites.  In addition, ETU is readily photooxidized to EU in
the presence of photosensitizers.  Residues of EBDCs and ETU are
found in and/or on crops treated with EBDCs.  The residue levels
change during storage, processing, and cooking due  to  environ-
mental factors.  During these processes, the parent compound may
be converted to ETU.

1.4.  Environmental Levels and Human Exposure

    Information  on the environmental impact of dithiocarbamates
with respect to persistence and bioaccumulation in the 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 in the presence of oxygen, moisture, etc.,
to  form  a number  of compounds, some  of which, e.g.,  ETU and
propylenethiourea (PTU), are toxicologically important.

    When  certain crops, such as spinach, carrots, and potatoes,
are  treated with EBDCs, high  levels of ETU can  be found after
cooking. In general, however, the ETU levels are below 0.1 mg/kg
product.

    Human exposure to EBDCs was calculated for the population of
the  USA  on  the basis  of  estimated  consumption  of  dietary

residues  of ETU in treated crops.  Upper limit (worst case) and
lower  limit (lowest  case) estimates  of exposure  to ETU  were
3.65 µg/kg and 0.24 µg/kg body weight per day, respectively.

    An estimate made for the Canadian population on the basis of
results  of  available  market-basket surveys  would  be  around
1 µg/kg body weight per day.

1.5.  Kinetics and Metabolism

    As a general rule, dithiocarbamates can be absorbed  by  the
organism via the skin, mucous membranes, and the respiratory and
gastrointestinal  tracts.  Whereas dithiocarbamates are absorbed
rapidly   from   the  gastrointestinal   tract,  metal-complexed
alkylene  bisdithiocarbamates are absorbed poorly  both from the
gastrointestinal tract and through the skin.

    Dialkyldithiocarbamates   and  EBDCs  are   metabolized  via
different   mechanisms.   The  metabolism   of  the  former   is
straightforward, dialkylthiocarbamic acid being formed as a free
acid  or as  S-glucuronide  conjugate.  Other  metabolic products
include  carbon  disulfide,  formaldehyde, sulfate,  and dialkyl
amine.

    The metabolic decomposition of EBDCs in mammals  is  complex
and  results in the  formation of carbon  disulfide, EDA, a  few
ethylene  bisthiuram  disulfides,  hydrogen  sulfide,   ethylene
bisthiocyanate, and ETU.  The latter is further broken  down  to
moieties  that are incorporated  into compounds such  as  oxalic
acid,  glycine, urea, and  lactose.  Dithiocarbamates and  their
metabolic  products are  found in  certain organs,  such as  the
liver,   kidneys,  and,  especially,  the   thyroid  gland,  but
accumulation of these compounds does not take place  because  of
their rapid metabolism.

    After  treating plants with dithiocarbamates, a large number
of   metabolites  are  found,   including  ETU,  EU,   imidazole
derivatives,  diisothiocyanates, diamines, disulfides, and other
metabolites, that are still unknown.

1.6.  Effects on Organisms in the Environment

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

    Dithiocarbamates  have an LC50 of  less than 1 mg/litre  for
invertebrates  (Daphnia) and  between 1 and 4  mg/litre for algae
 (Chlorella).    The acute toxicity of  dithiocarbamates for fish
is  rather high.  In general,  the acute LC50 of  dialkyldithio-
carbamates for fish is less than 1 mg/litre, and that  of  EBDCs
is in the range 1 - 8 mg/litre water.  The sac fry and early fry

stages of the rainbow trout have a higher sensitivity than other
early life stages, and embryotoxic and teratogenic  effects  are
induced  by certain dithiocarbamates.   However, bioaccumulation
is low (bioconcentration factor < 100).  The toxicity of ETU and
EU  for  fish,  Daphnia,  Chlorella, and two  bacteria species is
very low, of the order of g/litre.

    Several   dithiocarbamates  were  shown  to  intervene  with
testicular  development and function  and to cause  nerve  fibre
degeneration in domestic fowl.

    Information  on the influence  of dithiocarbamates on  honey
bees is lacking.

1.7.  Effects on Experimental Animals and  In Vitro Test Systems

    The  acute  oral  and  dermal  toxicities  of  the different
dithiocarbamates are generally low.  Most compounds have  a  low
volatility,  and only limited information  concerning inhalation
toxicity  is  available.   Local irritation  of  the respiratory
tract  occurs when dithiocarbamates  are inhaled as  dust, which
can also induce eye and dermal irritation. Some dithiocarbamates
are sensitizing agents.  ETU also has a low acute oral toxicity.

    Many short- and long-term toxicity studies have been carried
out  on  different  dithiocarbamates.   In  rats,  some  dithio-
carbamates  tested  at  high dose  levels induced dose-dependent
adverse effects on the reproduction and endocrine structures and
functions,  thus  reducing reproductive  capacity.  Some dithio-
carbamates also showed effects on reproduction in birds.

    In teratogenicity studies on mice and rats, dithiocarbamates
induced an increase in resorption sites and somatic and skeletal
malformations  (cleft  palate,  hydrocephaly, and  other abnorm-
alities).   The dose levels needed to produce these effects were
usually  higher than 200  mg/kg body weight  in rats, and  above
100 mg/kg body weight in mice.

    In  general,  the  results  of  mutagenicity  studies   with
dithiocarbamates have been negative.

    From the available long-term carcinogenicity studies on mice
and rats, there is no clear indication of a carcinogenic effect.
Some  of the dithiocarbamates have shown a goitrogenic effect at
high dose levels.

    There  is  evidence  that certain  dithiocarbamates  may  be
converted  in   vivo  to  N-nitroso    derivatives,   which    are
considered  to be both mutagenic and carcinogenic.  However, the
levels  of nitroso compounds that can be expected to result from
the  dietary  intake  of dithiocarbamate  pesticide residues are
negligible  compared with those of the nitroso precursors, which
occur naturally in food and drinking-water.

    In rats, high levels of dithiocarbamates produce an increase
in thyroid weight, a reduction in colloid in  follicles,  hyper-
plasia,   and  nodular  goitre.   These  distinct  morphological
changes are in agreement with an increase in thyroid-stimulating
hormone  (TSH).  Hypophyseal stimulation  of the thyroid  is the
consequence   of  a  decreased  blood  level  of  thyroxin,  the
synthesis  of  which  is  inhibited  by  dithiocarbamates.   The
thyroid  hyperplasia  induced  by  dithiocarbamates  is  largely
reversible on cessation of exposure.

    Another  intriguing phenomenon is  the induction of  alcohol
intolerance   by   most  of   the  alkyldithiocarbamates.   This
phenomenon has been studied in rats and produced in man.  It has
even  led to the use  of disulfiram in the  treatment of chronic
alcoholism.

    At  dose levels above 50 mg/kg body weight, dithiocarbamates
produce neurotoxic effects in rats and rabbits, characterized by
ataxia  and paralysis of  the hind legs,  and demyelination  and
degeneration  of  peripheral  nerves.  In  birds,  paralysis and
muscular and peripheral nerve atrophy have also been observed.

    Dithiocarbamates  have  been  reported to  cause a redistri-
bution of heavy metals, e.g., lead and cadmium, in  organs  such
as   the  brain.   Furthermore,   because  of  their   chelating
properties,  these dithiocarbamates may  have an effect  on  the
function of enzymes containing metals, such as zinc and copper.

1.8.  Effects on Man

    Regular  contact with dithiocarbamates can  cause functional
changes  in the nervous and hepatobiliary systems.  Skin contact
with dithiocarbamates may induce contact dermatitis, and some of
these  compounds will induce sensitization.  Alcohol intolerance
can  be  induced by  certain  dithiocarbamates, as  indicated in
section 1.7.

    There are indications that the mean incidence of chromosomal
aberrations  in lymphocytes is  increased in workers  exposed to
certain  dithiocarbamates.   Epidemiological studies  on workers
exposed  to dithiocarbamates or ETU did not show any increase in
the  incidence of thyroid  tumours.  However, only  a relatively
small number of workers was involved.

2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

2.1.  Identity

    Dithiocarbamates  are the disulfur analogues  of carbamates,
and they are characterized by the presence of:

                              S
                          \   ||
                            N-C-S-
                           /

    Secondary  monoamines,  e.g.,  dimethyl or  diethyl  amines,
react with carbon disulfide to give dialkyldithiocarbamates:

                                           S
                                           ||
                R2NH + CS2 + NaOH ---- R2N-C-S-

    Reaction   with  monoalkylamines  gives   the  corresponding
monoalkyldithiocarbamates.   The  reaction  of carbon  disulfide
with  diamines (for instance,  EDA) gives two  terminal  dithio-
carbamate groups linked by an alkylene bridge:

                                             S
                                             ||
                                      CH2-NH-C-S-
        (CH2NH2)2 + CS2 + NaOH ----> |
                                      CH2-NH-C-S-
                                             ||
                                             S

    Both  alkyl  and  ethylene dithiocarbamates  form salts with
metals and both can be oxidized to the corresponding disulfides.
EBDCs can form polymers, especially in the presence  of  certain
ubiquitous metallic ions (Engst & Schnaak, 1974).

    The  chemical  structures  and pesticidal  activity  of  the
principal  dithiocarbamates are listed in Table 1.  CAS registry
numbers,  chemical  names,  common  names,  molecular  formulae,
relative  molecular masses, and  selected chemical and  physical
properties are summarized in Annex I.  Further  information  can
be obtained from the JMPR evaluations (Annex III).

2.2.  Physical and Chemical Properties

    Dithiocarbamates  with hydrophylic groups,  such as OH-  and
COOH,   form  water-soluble  heavy  metal  complexes.   However,
dithiocarbamate  metal  complexes  used as  fungicides  are  all
insoluble  in  water,  though  they  are  soluble  in  non-polar
solvents.   Alkylene  bisdithiocarbamates  containing two  donor

CS2-  groups, which form  polymeric chelates, are  insoluble  in
both water and non-polar solvents.

        R1                          R1               R1
          \                           \            /
            N-C-S-Metal                 N-C-S-S-C-N
          /   ||                      /   ||    || \
        R2    S                     R2    S     S    R2

   Dithiocarbamate                    Thiuram disulfide

          S
          ||
   CH2-NH-C-S                       R1             R1
   |         \                         \         /
   |           Metal                    N-C-S-C-N
   |         /                        /   ||  || \
   CH2-NH-C-S                       R2    S   S    R2
          ||
          S

      EBDC                           Thiuram monosulfide

                   [-CH2-CH2NH-C-S-C-NH-]x
                               ||  ||
                               S   S

                            Polymer


Table 1.  Relationship of chemical structure and pesticidal activity 
of dithiocarbamates
--------------------------------------------------------------------
Pesticidal           Chemical structure     Common or other name
activity
--------------------------------------------------------------------
Herbicides                     S            sulfallatea
                               ||
                     dialkyl-N-C-S-alkyl

Fungicides and/         S                   ferbam, mancozeb,
or insecticides         ||                  maneb, metam-sodiumb,
                     >N-C-S-Metal           metiram, nabam, 
                                            propineb, zineb, 
                                            ziram
--------------------------------------------------------------------
a   Pre-emergence herbicide.
b   Soil fungicide, nematocide, and herbicide.

    Dithiocarbamates  are  unstable  in  acidic  conditions  and
readily  convert to  the amine  and carbon  disulfide (Ludwig  &
Thorn,  1962;  Thorn & Ludwig, 1962).  The  heavy metal salts of
ethylene  bisdithiocarbamic  acid,  i.e., maneb  and  zineb, may
polymerize, the extent of polymerization depending on the method
of preparation.

    ETU  may be formed  during the manufacture  of  dithiocarba-
mates.  Bontoyan & Looker (1973) studied the initial ETU content
of  various EBDC products  and the amount  found after  storage.
Lyman  & Lacoste (1974) found that the average ETU content of 76
lots  of mancozeb manufactured  at six different  locations  was
0.07%.  No significant ETU build-up was observed  during  normal
spray tank residence times.

2.3.  Analytical Methods

    Residue  analysis  consists  of sampling  the  environmental
material  or matrix, extracting the  pesticide residue, removing
interfering  substances  from  the extract,  and identifying and
quantifying  the  pesticide residue.   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
residue being measured.

    The  dithiocarbamates,  thiuram  disulfides  included,   are
conveniently determined on the basis of their  decomposition  by
mineral  acids to the amine and carbon disulfide.  The amount of
either  of  these hydrolysis  products  can be  determined,  the
carbon  disulfide  being  commonly  measured  iodometrically  or
colorimetrically.   This  decomposition  method is  adaptable to
micro-determinations  for  the  assay of  pesticide  residues on
crops  or to  the macro-methods,  which are  used  to  determine
concentrations  of ingredients in pesticide formulations (Clarke
et al., 1951).

    A polarographic method has been used to estimate residues of
maneb  and  zineb  (detection  limit,  0.5 mg/kg  product)   and
ethylene  bisthiuram  monosulfide  (detection limit,  0.02 mg/kg
product) (Engst & Schnaak, 1969a,b,c, 1970b).

    A  number of procedures  for the quantification  of  dithio-
carbamates  are  based  on high-pressure  liquid chromatography.
The limits of detection in water solutions for zineb, ziram, and
thiram are 0.05, 0.01, and 0.01 mg/kg, respectively (IARC, 1976;
Gustafsson & Thompson, 1981; Kirkbright & Mullins, 1984; Tetsumi
et al., 1985).

    For  further  details  of analytical  methods for individual
dithiocarbamates,  see Conkin & Gleason (1964), Fishbein (1975),
Ashworth et al. (1980), and Worthing & Walker (1983).

3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

3.1.  Natural Occurrence

    No data are available.

3.2.  Man-Made Sources

    The  development  of  mono- and  dithiocarbamate derivatives
with pesticidal properties occurred during and after  World  War
II.  However, a few compounds were introduced earlier, including
ziram in 1930 and thiram in 1931.

    Dithiocarbamates   were   developed   as   practical   field
fungicides in the United Kingdom in about 1936.   The  compounds
were  already being explored  as fungicides and  insecticides in
the  USA, where  the classic  Tisdale and  Williams  patent  was
issued  in  1934.   This covered  the  use  of compounds  of the
formula  X(Y)NCS2Z (where X is hydrogen or alkyl, Y is hydrogen,
alkyl,  or  aryl,  and Z  is  metallic  in nature)  and  thiuram
sulfides as bactericides and fungicides (Thorn & Ludwig, 1962).

3.2.1.  Production levels, processes, and uses

    Dithiocarbamates  have  also  been used  to  control various
dermatophytes   (Kligman  &  Rosensweig,  1948).   For  example,
tetramethylthiuram  disulfide, incorporated in various soaps and
lotions, has been used since 1942 for the treatment  of  scabies
and other parasitic diseases of the skin in veterinary and human
medicine   (Schultheiss,  1957).   Dithiocarbamates   also  have
considerable biocidal activity against a number of protozoa.

    An  interesting development was the  discovery of disulfiram
as a treatment for chronic alcoholism (Hald &  Jacobsen,  1948).
Other  important  applications  of dithiocarbamates  are  in the
field  of  rubber  chemistry as  antioxidants  and  accelerators
(Thorn & Ludwig, 1962).

    Annual  production and use figures  for a number of  dithio-
carbamates  in various  parts of  the world  are given  in  IARC
(1976); consumption figures are listed in Table 2.

Table 2.  Consumption of dithiocarbamate pesticides 
(in 100 kg)a
-----------------------------------------------------------
Area                            Dithiocarbamates          
                         1974-76   1981     1982     1983
-----------------------------------------------------------
Africa

   Egypt                 30
   Zimbabwe                        795

North/Central America

   Canada                10 977
   Mexico                4531      38 350   34 000   33 050
   USA                             60 000   50 000

South America

   Argentina                       4890     8370
   Uruguay               1454      822      1114     1668

Asia

   Brunei                          3        2        2
   Cyprus                701       2242     1538
   India                 16 193    14 650   17 130
   Israel                4177      3110     3370     3580
   Jordan                          27 500   28 748
   Korea Republic        5027      18 380   18 233
   Kuwait                6
   Oman                            115      62       120
   Pakistan              24        370      881
   Turkey                5906      8901     9346

Europe

   Austria               2751      2334     2322     2207
   Czechoslovakia        6927      8678     6501
   Denmark               2187               11 485   13 747
   Finland               504
   Greece                12 763
   Hungary               37 347    29 476   31 932   43 415
   Italy                 145 697   121 808  97 238
   Malta                           350
   Norway                438       383      372      285
   Poland                4007      11 386   14 102   12 517
   Portugal              8114      8358     7592
   Sweden                3283      3800     4380
-----------------------------------------------------------
a   From: FAO (1985).

4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    Dithiocarbamates,  like all pesticides,  can reach the  soil
through  many routes, ranging  from direct application  to drift
from  foliage  treatment.   Generally, these  compounds  are not
persistent and undergo different types of degradation.

4.1.  Transport and Distribution Between Media

    In  alkaline medium, alkyl dithiocarbamates  are stable, but
EBDCs  are not.   EBDCs are  also unstable  in the  presence  of
moisture  and  oxygen  as well  as  in  biological systems.   By
splitting  off carbon disulfide and hydrogen sulfide, as well as
by oxidative degradation, a great number of  secondary  products
are formed, amongst them, ETU (Aldridge & Magos, 1978).

    The rates of alkyl dithiocarbamates decomposition depends on
pH (Turner & Corden, 1963) and the cation present. The  rate  of
decomposition,  and  the  production  of  carbon  disulfide   is
decreased by cations in the following order: Na+ > Zn2+ > Fe3+ >
Cu2+.

    The  release of carbon disulfide from EBDCs is influenced by
the  chemical nature of  the hydrolysing medium.   It is low  in
acetic  acid and nearly 100% in sulfuric acid (Aldridge & Magos,
1978);  it  also  depends on  the  temperature  (Clarke et  al.,
1951).

    Decomposition  to hydrogen sulfide  seems to depend  on  the
presence  of an N-H  group.  Monoalkyldithiocarbamates, such  as
EBDCs,  are not stable in alkaline medium and, in acidic medium,
decompose  either to carbon disulfide or hydrogen sulfide (Joris
et al., 1970).  The rate of decomposition to carbon disulfide is
two  orders  of  magnitude  lower  in  monoalkyldithiocarbamates
compared  with that in the  corresponding dialkyldithiocarbamate
(Zuman  & Zahradnik, 1957).  In the case of metiram sodium at pH
9.5,  methylisothiocyanate (MIT) and sulfur are formed,  whereas
in  acid  solution,  the  compound  is  decomposed  into  carbon
disulfide,  hydrogen  sulfide,  N,N'-dimethylthiuram   disulfide,
methylamine, and MIT (Turner & Corden, 1963).

4.1.1.  Water

    EBDCs  decompose rapidly in  water, mancozeb having  a half-
life of less than 1 day in sterile water (pH range, 5 - 9).  The
nature  and  abundance  of  the  degradation  products  are  pH-
dependent, and include ETU and EU (Lyman & Lacoste, 1974, 1975).
Photolytic  degradation is  a major  pathway for  ETU  in  water
(Cruickshank  &  Jarrow,  1973; Ross  &  Crosby,  1973), and  is
enhanced by the presence of photosensitizers such as chlorophyll
(Ross & Crosby, 1973).

    The half-life of thiram in water was 46.7 days at pH  7  and
9.4 h  in an acid  medium (pH 3.5).  About  5.2% of a  sample of
thiram was still present in water of pH 7 after 200 days.

4.1.2.  Soil

    The mobility of EBDCs in soil varies considerably, depending
on  water solubility  and soil  type.  They  are generally  more
mobile in wet and in sandy soils than in dry soil or  soil  rich
in  organic  matter  (peat or  muck).  Thin-layer chromatography
studies have shown that nabam is more mobile than  maneb,  which
in turn is more mobile than zineb, zineb being  almost  immobile
(Helling et al., 1974).

    The leaching of radioactive 14C-mancozeb and its degradation
products  was  studied  in  five  different  soils,  the organic
content  of which ranged from  0.4% to 15%, while  the pH ranged
from  4.7 to 7.4.  An  aqueous slurry of 14C-mancozeb  (15.6 mg)
was  mixed with a soil sample and applied to the top of a column
of soil.  Water (2.5 cm) was added to the top of the column once
a  week  for  9  weeks.   The  water  was  collected   and   its
radioactivity  measured and, after 9 weeks, the columns were cut
into  2.5 cm sections.  The results showed that no radioactivity
leached  through four of the  five columns (only 2  - 5% of  the
activity leached through the Cecil clay column; the  reason  for
this is not known).  Losses of radioactivity  by  volatilization
or by metabolism to carbon dioxide were significant in all soils
(Lyman & Lacoste, 1974).

4.2.  Biotransformation

4.2.1.  Microbial degradation

    Sterilized  and unsterilized samples of sewage, fresh water,
sea-water,  and  agricultural soil  were  incubated with  50  or
100 mg thiram per litre or kg.  Thiram disappeared  from  sewage
and  fresh water within  12 days, and  from soil after  40 days.
After  8  months, 20%  of the thiram  was still present  in sea-
water.   Disappearance  was  faster  in  unsterilized  than   in
sterilized  soil,  indicating  that microorganisms  seem  to  be
involved (Odeyemi, 1980).

    The  results of a study  on one soil (Hagerstown  silt loam)
used  in the leaching study  mentioned in section 4.1.2,  showed
that  mancozeb  is  readily  degraded  by  soil  microorganisms,
releasing ethylene C atoms as carbon dioxide.  No carbon dioxide
was  released  from  sterile  soil,  but  mancozeb  was  rapidly
degraded to carbon dioxide in non-sterile soil.   The  half-life
in  soil at a concentration of 20 mg mancozeb/kg was 50 days; at
10 mg/kg, the half-life was 90 days (Lyman & Lacoste, 1974).

4.2.2.  Photodegradation

    Ziram is stable to ultraviolet radiation (UVR). It is slowly
photo-hydrolysed  in  water and  is  stable in  media containing
quantities of organic acids.  When precipitated to the bottom of
bodies of water, it remains toxic for a month (IRPTC, 1982).

5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    The  only  exposure of  the  general population  to  dithio-
carbamates  and their breakdown products results from occasional
residues in the diet.  However, dithiocarbamates degrade rapidly
after application to crops, the rate being influenced by oxygen,
humidity, temperature, organic sensitizers, and pH.  A number of
degradation   products  have  been  identified,  including  ETU,
ethylene thiuram disulfide (ETD), and DIDTa.

5.1.  Food

    Studies  in  Canada  and  the  USA  have  shown  that,  when
vegetables,  such as spinach, carrots, and potatoes, are treated
with  EBDCs after harvest, a significant percentage of the EBDCs
is converted to ETU during subsequent cooking  (Blazquez,  1973;
Newsome & Laver, 1973; Watts et al., 1974) (ETU section 5.1).

    The  results of a study by Phillips et al. (1977) to examine
the  effects of food processing  on EBDC residues confirmed  and
extended   the  results  described   above.   Washing  the   raw
agricultural  products prior to  processing removed 33 -  87% of
the  EBDC residues and  the majority of  the ETU residues.   The
results  for  raw and  processed  commodities are  summarized in
Table 3.

    Human exposure to EBDCs was calculated for the population of
the  USA  on  the basis  of  estimated  consumption  of  dietary
residues  of ETU in treated crops.  Upper limit (worst case) and
lower  limit (lowest  case) estimates  of exposure  to ETU  were
3.65 µg/kg   and 0.24 µg/kg  body  weight per day,  respectively
(US EPA, 1982b).

    EBDC residues would be expected to be lower in  root  crops,
such  as carrots and potatoes, as they are not systemic and tend
to  remain on the external  portions of the plant.   However, in
leafy  crops, such  as spinach  and lettuce,  EBDC residues  are
generally  higher.  Culling, such as  discarding the discoloured
leaves  of lettuce  and the  rinds of  melons, could  presumably
reduce  the residue level.  Washing reduced the majority of EBDC
residues by at least 50%.

------------------------------------------------------------------
a   In  many  publications, it  has  been stated  that ethylene-
    thiuram   monosulfide  (ETM)  was  identified  in  metabolic
    studies;  however, it is now  clear that this metabolite  is
    5, 6-dihydro-3 H-imidazo   [2, 1-C]-1,2,4-dithiazole-3-thione
    (DIDT)  (Pluygers et al., 1971; Benson et al., 1972; Alvarez
    et al., 1973).

Table 3.  Summary of EBDC/ETU residues (mg/kg 
product) before and after processing
-----------------------------------------------
               Eastern USA        Western USA  
               EBDC     ETU       EBDC    ETU
-----------------------------------------------
Tomatoes

Unwashed       0.3      -         2.1     0.01
Washed         0.2      -         0.6     0.01
Canned         -        0.03      0.5     0.11

Carrots

Unwashed       0.6      -         0.1     0.01
Washed         0.3      -         0.1     0.01
Diced          0.1      -         0.1     -
Frozen         -        -         -       -
Canned         -        0.03      0.1     -

Spinach

Unwashed       2.4      -         61.9    0.34
Washed         1.5      -         9.7     0.02
Frozen         0.1      0.04      0.6     0.50
Canned         -        0.18      0.1     0.71
-----------------------------------------------
Note: Mancozeb was applied at the rate of 
      0.7 ai/0.5 ha in all cases. Spray 
      schedules were as follows: spinach, 1 
      treatment with 10-day pre-harvest 
      interval; carrot, 6 treatments at 7- to 
      10-day intervals (7-day pre-harvest 
      interval); tomato (eastern), 4 treatments 
      at 7- to 10-day intervals (16-day pre-
      harvest interval); tomato (western), 3 
      treatments at 7-day intervals (5-day pre-
      harvest interval). From: IUPAC (1977). 

5.2.  Monitoring and Market Basket Studies

    In  a market-basket study, over 500 samples of 34 foods were
analysed, together with 26 samples of drinking-water.  The water
samples  and 338  food samples  did not  contain  any  residues.
Doubtful positive values at approximately the limit of detection
were  found in 110 food  samples, and 53 samples  were positive.
Only 21 of all the samples contained ETU residues.

    Tomato  products (203 samples)  were analysed in  a separate
market-basket  study, and 19% contained  dithiocarbamates in the
range of 0.2 - 0.5 mg/kg product (Gowers & Gordon, 1980).

    A  more  realistic  review of  the  actual  exposure of  the
general  population was obtained by a "table-top" study in which
100  whole meals (60  from homes and  40 from restaurants)  were

analysed for dithiocarbamates and ETU.  In the 87 meals analysed
for   dithiocarbamates,   11  contained   residues  of  apparent
dithiocarbamates  averaging 0.3 mg/kg, or 0.04 mg/kg if averaged
over  the  87 meals.   In a second  study of 100  meals, 4 meals
contained  apparent dithiocarbamates in the  range of 0.2 -  0.4
mg/kg  or 0.02 mg/kg as an average of the 100 meals.  From these
studies, an overall average would be 0.03 mg dithiocarbamates/kg
meal.   ETU residues were  not found in  either study (Gowers  &
Gordon, 1980).

6.  KINETICS AND METABOLISM

    Dithiocarbamates  penetrate  the  organism  mainly  via  the
respiratory  tract  (aerosol,  dust), skin  and mucous membranes
(occupational exposure), and the digestive tract.

6.1.  Absorption, Distribution, and Excretion

    Thirty  minutes after intragastric administration  of 500 mg
ziram/kg body weight to rats, the compound was detected  in  the
blood,  the liver, and  the kidneys, the  highest  concentration
being  in  the  liver (26.2  mg/kg  tissue).   After  16 h,  the
concentration of ziram in the blood and liver (about  5.5  mg/kg
tissue)  decreased considerably, while the  concentration in the
intestines and the kidneys increased (in the kidneys, to 3 mg/kg
tissue).  At the end of the first day, the  ziram  concentration
in the intestines reached a maximum and then  dropped  abruptly,
57%  of  unchanged  ziram being  detected  in  the  faeces;  the
compound was also detected in the spleen and the adrenal glands.
Maximum concentrations in the organs (6.8 mg/kg and  2.4  mg/kg,
respectively)  were attained the  following day.  Ziram  was  no
longer  present in the adrenal  glands after 3 days,  and in the
spleen  after  6 days.   The circulation of  ziram in the  blood
continued for 2 days (Vekshtein & Khitsenko, 1971).

    After  the  oral  administration of  a  dose  of  2 mg  35S-
ziram  per  animal to  white rats (100  - 120 g), the  brain and
thyroid  contained high levels of radioactivity during the first
2  days.   During  the  12 h  following  administration,  higher
amounts  of ziram (or its metabolites) were found in the ovaries
than  in the uterus or the placenta.  Ziram passed the placental
barrier and accumulated in the organs and tissues of  the  fetus
(skin, liver, heart) at levels several times higher  than  those
in the placenta and the uterus wall.  The level of radioactivity
in  the fetal liver exceeded  the maximum level in  the liver of
mature  animals;  at  12 h, it  was  more  than 5  times  higher
(Chernov   &   Khistenko,   1973).   Twenty-four   hours   after
administering  35S-ziram  to  female rats,  Izmirova  &  Marinov
(1972)  found  radioactivity  in the  thyroid,  blood,  kidneys,
spleen, ovaries, and liver.

    When 14C-labelled maneb was orally administered to rats at a
dose of 360 mg/kg body weight by stomach tube, approximately 55%
of  the radioactivity  was eliminated  in the  faeces and  urine
within  3 days.  Almost no  unmetabolized maneb was found.   The
amounts  of radioactivity in organs  after day 1 and  day 5 were
1.2%  and 0.18%, respectively.  The  highest levels after 1  day
were found in blood (0.23%), liver (0.78%), and kidneys (0.18%).
Less was found in the thyroid (0.07%)  (Seidler et al., 1970).

    Similar  results were obtained  with rats administered  35S-
ferbam or 14C-ferbam.  Approximately 50% was absorbed  from  the
gastrointestinal tract in the first 24 h.  Rats  receiving  35S-
ferbam  showed 18%, 23%, and 1% in expired air, urine, and bile,
respectively,  whereas with 14C-ferbam, the figures were < 0.1%,

43%, and 1.4%, respectively.  Other tissues contained only small
amounts  of labelled material.  In addition, 14C was excreted in
the milk of lactating rats (Hodgson et al., 1974).

    Blackwell-Smith  et al. (1953) found that approximately 70 -
75%  of ingested zineb passed through the gastrointestinal tract
of rats and appeared in the faeces within 24 - 72 h.

    Rats  dosed via a stomach  tube with 20 mg 14C-mancozeb  per
day  for  7 days  (equivalent  to approximately  100 mg/kg  body
weight)  were  killed  one  day  after  the  last dose  and  the
radioactivity  in  excreta  and  organs  was  measured.   In the
faeces, urine, organs and tissues, and carcass, 71%, 16%, 0.31%,
and 0.96% of the total radioactivity was detected, respectively.
Specifically,  the liver contained  0.19%, the kidneys,  0.076%,
the  thyroid gland,  0.003%, and  all other  organs,  less  than
0.01%.   Most  of  the  labelled  material  in  the  faeces  was
mancozeb,  indicating that mancozeb was poorly absorbed from the
gastrointestinal tract (Lyman, 1971).

6.2.  Metabolic Transformation

    Dialkyldithiocarbamates,  such as thiram and disulfiram, and
EBDCs,  such as  nabam, maneb,  and zineb,  are metabolized  via
different mechanisms.

6.2.1.  Mammals

    In general, the metabolism of dialkyldithiocarbamates (e.g.,
disulfiram)  in  mammals  (including  man)  is  straightforward,
diethylthiocarbamic  acid being formed as  the principal metabo-
lite.   This is found either as the free acid or as the  S-glucu-
ronide  conjugate  (Fig. 1)  (Kaslander,  1963;  Strömme,  1965;
Dekhuyzen  et al., 1971; Aldridge  & Magos, 1978) in  the urine,
faeces, or tissues of animals.  Other metabolic products include
carbon  disulfide (Prickett & Johnston,  1953), methyldiethyldi-
thiocarbamate   (Gessner   &  Jakubowski,   1972),  and  sulfate
(Strömme,  1965; Strömme &  Eldjarn, 1966), but  free disulfiram
was not detected.

    One of the most important enzymatic processes in  the  meta-
bolism  of  dialkyldithiocarbamates  is  glucuronidation,  which
takes  place  in the  liver  (Strömme, 1965).   Glucuronic  acid
conjugation  might  be  overloaded after  the  administration of
diethyldithiocarbamate  but  not  after  the  administration  of
disulfiram,  which  is taken  up by the  liver at a  much slower
rate.    Methylation  of  diethyldithiocarbamates   by  S-adenosyl
methionine  transmethylase in the  kidneys and liver  can  occur
subsequently   and  leads  to   sulfate  excretion  (Gessner   &
Jakubowski, 1972).  In the case of 35S-disulfiram, more than 50%
of  the 35S was recovered as sulfate in the urine, partly in the
free  form and partly esterified (Eldjarn, 1950; Strömme, 1965).
A different enzymatic process is involved in  the  desulfuration
of  the  carbon  disulfide formed  from dithiocarbamates.  After
administration  of 14C-carbon disulfide, some  label was exhaled

as  14C-carbon dioxide.  This  break-up of the  carbon disulfide
molecule  is catalysed by microsomal  mixed-function oxidase (De
Matteis & Seawright, 1973; Dalvi et al., 1974).

FIGURE 1

    Thiram  and the dimethylamine salt of dimethyldithiocarbamic
acid  were the major  metabolites in the  urine, whereas  carbon
disulfide  and dimethylamine were  detected in the  expired air.
The  body tissues contained tetramethylthiourea, the methylamine
salt  of  dimethyldithiocarbamic  acid,  carbon  disulfide,  and
methylamine.   Overall, the results  indicate that, in  the rat,
ferbam  and  ziram  are transformed  into dimethyldithiocarbamic
acid, which is subsequently coupled to give thiram, or is broken
down   to  carbon  disulfide  and   dimethylamine  (Vekshtein  &
Khitsenko, 1971; Hodgson et al., 1974).

    The  in vivo  metabolic decomposition of EBDCs is complex and
results  in the formation of carbon disulfide, hydrogen sulfide,
EDA,    ethylene    bisthiuram    disulfide,   DIDT,    ethylene
diisothiocyanate  (EDI)  (unstable), ETU,  EU, and 2-imidazoline
(Seidler et al., 1970; Lyman, 1971) (Fig. 2).  The decomposition
of monoalkyldithiocarbamates is detailed in Fig. 3.

    When  14C-maneb was given to  rats in a single  oral dose of
390 mg/kg  body weight, only 55% of the 14C was recovered in the
excreta.   It was therefore suggested  that a large part  of the
dose  might have been metabolized  to carbon disulfide and  14C-
EDA,  followed by oxidation of  the latter to carbon  disulfide.

The concentration of the radioactivity was highest  after  24 h,
and  EDA and ETU were identified in the excreta (Seidler et al.,
1970).   ETU and DIDT  were the major  metabolites found in  the
urine  of rats  treated with  zineb, and  carbon  disulfide  was
detected in the expired air.

6.3.  Metabolism in Plants

    ETU  is one  of several  metabolites found  when  EBDCs  are
applied  to plants.   In plants,  nabam, maneb,  and  zineb  are
transformed  to ETU, DIDT, EU, 2-imidazoline, a diisothiocyanate
(EDI), and other metabolites (Fig. 2).

    Nash & Beall (1980) have studied the fate of maneb and zineb
in  microagroecosystem chambers (enclosed glass chambers), under
the following conditions: pH, 6.7; organic matter content, 5.2%;
soil type, Galestown sandy loam; soil water content, 15.6%.  The
fungicides were applied twice to tomato plants at  2 kg/ha,  and
the residual fungicides (measured as EDA and ETU) were monitored
on  the  fruit,  leaves, and in the soil, water, and air for 100
days  after treatment.  ETU was detected at < 20 µg/kg  on whole
fruit  after 3  days, but  had completely  disappeared  after  3
weeks.  Maneb and zineb were present on whole fruit at < 1 mg/kg
and were still present in measurable amounts (as EDA)  after  10
weeks.   Both had half-concentration  times (C) of  14 days  on
leaves.  Half-concentration times for ETU, maneb, and  zineb  in
soil were < 3, 36, and 23 days, respectively, and that  for  ETU
in air was 9 days.

FIGURE 2

    Note to Figure 2: Ion mechanisms leading to ETU formation are
not completely understood; however, a number of hypotheses have
been advanced.  According to Marshall (1977), intermediary
products of the thermal bisdithiocarbamate degradation to ETU are
beta-amino ethylene dithiocarbamate and DIDT, but not ethylene
diisothiocyanate (EDI).  EDI was, however, postulated and detected
several times as a secondary reaction product of the ethylene
bisdithiocarbamate degradation at normal temperatures (Engst &
Schnaak, 1970a).  ----> indicates a postulated conversion.

FIGURE 3

    Besides ETU, other degradation products of EBDCs include ETD
and DIDT.  The main volatile components of zineb's decomposition
are  carbon disulfide, carbonyl  sulfide, and EDA.   Almost  all
zinc is converted into zinc sulfide and zinc oxide  (Melnikov  &
Trunov, 1966).

6.4.  Decomposition in Water and Soil

    Thiram  and dimethyldithiocarbamic acid give rise in soil to
methyl  isothiocyanate and sulfur, and, under acidic conditions,
to  carbon  disulfide,  hydrogen sulfide,  methylamine,  methyl-
isocyanate,  and the bisdisulfide of  methyldithiocarbamic acid.
Two  of  the  products,  carbon  disulfide  and   dimethylamine,
evaporated  from the soil (Raghu et al., 1975).  Dimethyldithio-
carbamic  acid also  binds with  heavy metals  in soil  to  form
complexes.

    The  various metal derivatives of ethylene bisdithiocarbamic
acid  appear to be  converted in the  soil to DIDT,  ETU, carbon
disulfide,  hydrogen sulfide, and carbonyl sulfide (Moje et al.,
1964; Kaars Sijpesteijn & Vonk, 1970).  The conversion  by  soil
bacteria  and fungi of DIDT into ETU has been demonstrated (Vonk
& Kaars Sijpesteijn, 1976).  Even though ETU is slowly converted
into EU in soil, pure cultures of soil bacteria and  fungi  were
unable  to effect this transformation (Kaars Sijpesteijn & Vonk,
1970).

6.5.  Metabolism in Microorganisms

    Microorganisms  readily  form  ETU from  DIDT, a spontaneous
decomposition  product  of  EBDCs.  This  conversion  also takes
place  after addition of  reducing compounds such  as  cysteine,
glutathione,  or ascorbic acid.  It consists of the reduction of
the  S-S  bond of  DIDT, with the  subsequent release of  carbon
disulfide to form ETU.  It was shown by Vonk & Kaars Sijpesteijn
(1976) that DIDT was reduced by NADH in the presence  of  enzyme
extracts   from  Pseudomonas   fluorescens,   Escherichia   coli,
 Saccharomyces cerevisiae, or  Aspergillus niger.

7.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

7.1.  Microorganisms

    There  is some evidence that dithiocarbamates, at concentra-
tions  10 times  that of  normal field  application, may  reduce
microbial biomass and increase the bacterial:fungal ratio.

7.2.  Aquatic Organisms

7.2.1.  Acute toxicity

    Toxicity  studies using dithiocarbamates are hindered by the
fact  that they are  chemically and biologically  degradable and
may  also  be  contaminated with  degradation  products.   Their
stability  in  water depends  on the pH  and on the  presence of
metal  ions with which they form complexes.  The soluble dithio-
carbamates  dissociate in water,  whereas the polymers  are only
slightly  soluble in water.  As the breakdown products will also
influence  toxicity,  toxicity  testing of  dithiocarbamates  is
complex.

    According  to US  EPA (1977,  1982a), the  use of  pesticide
products  containing  maneb  against  cranberry  fruit  rot   at
application  rates  of  up to  6.7  kg  ai/ha would  result in a
concentration of 4.4 mg/litre in a 15-cm layer of water.  McCann
&  Pitcher  (1973)  reported  a  96-h  LC50  of 1  mg/litre  for
bluegills,  while Worthing & Walker (1983)  reported a 48-h LC50
for  carp of 1.8 mg/litre.   Zineb used against cranberry  fruit
rot at an application rate of up to 5.4 kg ai/ha could result in
a concentration of 3.52 mg/litre in a 15-cm layer of  water.   A
26-h LC50 of 0.2 mg/litre has been reported for  Daphnia magna.

    Van  Leeuwen (1986) carried out  an extensive study with  18
dithiocarbamates  and  three  metabolites  of  these  compounds,
including ETU, in fish  (Poecilia reticulata), crustacea  (Daphnia
 magna),    algae    ( Chlorella    pyrenoidosa,    Phytobacterium
 phosphoreum), and   two   nitrifying  bacteria  (Nitrosomonas and
 Nitrobacter).  The results are summarized in Tables 4 and 5.

    Worthing  & Walker (1983)  gave the following  LC50  values:
propineb:    rainbow   trout,   1.9   mg/litre;   golden   orfe,
133 mg/litre;   thiram:    carp,  4   mg/litre;  rainbow  trout,
0.13 mg/litre; bluegill, 0.23 mg/litre; metiram: harlequin fish,
17 mg/litre.

    The  susceptibility to  maneb of  the early  life stages  of
rainbow trout has been studied using fertilized eggs (before and
after  water hardening), early  eye point eggs,  late eye  point
eggs,  sac fry, and early fry.  The sac fry and early fry stages
appeared  to be  the most  sensitive.  The  96-h LC50s  for  the
different  stages were: for 0-h  egg, 6 mg/litre; for  24-h egg,
5.6  mg/litre; for early eyed  egg (14 days), 1.8  mg/litre; for
late  eyed egg (28 days),  1.3 mg/litre; for sac  fry (42 days),
0.32  mg/litre; and, for early fry (77 days), 0.34 mg/litre (Van
Leeuwen, 1986).

Table 4.  Acute toxicity of dithiocarbamates and breakdown 
products for fisha
-------------------------------------------------------------
Organism               Compound     96-h LC50 
                                    (95% confidence
                                    limit) (mg/litre)
-------------------------------------------------------------
 Poecilia reticulatab  nabam        5.8 (4 - 8.5)
                       maneb        3.7 (3.2 - 5.6)
                       zineb        7.2 (5 - 10.3)
                       mancozeb     2.6 (2.1 - 3.3)
                       metiram      6.4 (4 - 10.4)
                       Na-DMDC      2.6 (2.1 - 3.2)
                       ziram        0.75 (0.56 - 1)
                       ferbam       0.09 (0.06 - 0.18)
                       thiram       0.27 (0.22 - 0.33)
                       Na-DEDC      6.9 (5.5 - 8.5)
                       Zn-DEDC      0.49 (0.40 - 0.61)
                       disulfiram   0.32 (0.24 - 0.43)
                       ETU          7500 (5600 - 10 000)
                       EU           13 000 (10 000 - 18 000)

Rainbow troutc         thiram       0.26 (0.24 - 0.32)
 (Salmo gairdneri)
-------------------------------------------------------------
a   From: Van Leeuwen (1986).
b   Studies according to OECD guidelines 203.
c   24-h LC50; water temperature 15 ± 1 °C; 
    weight of fish, 34 ± 4.7 g.

Table 5.  Short-term toxicity studies with dithiocarbamates and
breakdown productsa
--------------------------------------------------------------------
Compound      Daphnia      Chlorella   Photobacterium  Nitrosomonas
              magna        pyrenoidosa phosphoreum     Nitrobacter

             48-h LC50    96-h EC50    15-min EC50     3-h MIC
             (mg/litre)   (mg/litre)   (mg/litre)      (mg/litre)
--------------------------------------------------------------------
Nabam        0.44         2.4          102             32
Maneb        1            3.2          1.2             56
Zineb        0.97         1.8          6.2             18
Mancozeb     1.3          1.1          0.08            32
Metiram      2.2          1.8          0.37            32
Na-DMDC      0.67         0.8          0.51            26
Ziram        0.14         1.2          0.15            100
Ferbam       0.09         2.4          0.20            10
Thiram       0.21         1            0.10            18
Na-DECD      0.91         1.4          1.22            43
Zn-DEDC      0.24         1.1          1.70            > 320
Disulfiram   0.12         1.8          1.21            > 320
ETU          26.4         6600         2100            1
EU           5600         16 000       3300            1000
--------------------------------------------------------------------
a   From: Van Leeuwen (1986).

7.2.2.  Short- and long-term toxicity and reproduction studies

7.2.2.1.  Fish

    In   sublethal   toxicity   studies  carried   out  on  Salmo
 gairdneri,   groups   of  10   fish  were  exposed   to   thiram
(0.18 mg/litre)  for 24 h.   Blood parameters (decreased  haemo-
globin  and leukopenia, decreased glucose  levels, and increased
glucose-6-phosphate dehydrogenase activity) and liver parameters
(increased  lipid content, increased lactate dehydrogenase) were
changed,  and it was  concluded by the  author that thiram  is a
cytotoxic chemical (Van Leeuwen, 1986).  In a further study, the
60-day toxicity for early life stages was tested on  S. gairdneri
using   a number of  dialkyldithiocarbamates, EBDCs, and  break-
down  products.   The  LC50s  ranged  from  approximately  1  to
9 µg/litre   for dialkyldithiocarbamates and 211 - 2100 µg/litre
for  EBDCs,  but  ETU and  EU  were  not toxic,  even  at levels
exceeding 1000 mg/litre.

    Embryotoxic  and teratogenic effects were  also observed for
all  the compounds studied, and there was an overlap between the
responses for skeletal malformations and lethality over  a  wide
concentration  range.  The teratogenic effects  in rainbow trout
proved  to  be  in agreement  with  those  observed in  mammals.
Exposure  of  rainbow  trout  during  embryo-larval  development
revealed  that  malformations  induced by  dithiocarbamates were
almost  exclusively confined to  the notochord, which  increased
considerably  in both  length and  diameter.  As  a result,  the
notochord  became  twisted and  distorted.  Ectopic osteogenesis
was observed in almost every affected notochord.  Other effects,
such  as the disruption of  the integrity of myomeres  and organ
dislocations,  were  closely  related to  the  notochordal  ano-
malies. Also, compression and fusion of vertebrae and "waviness"
of  various skeletal elements were found.  Concentration-related
changes  in the liver  were observed in  short-term exposure  of
juvenile  rainbow trout, while  at high levels  proliferation of
bile  duct  epithelial cells  and  necrosis of  hepatocytes were
seen.   Ziram and thiram induced  brain haemorrhages as well  as
intraspinal extravasates of blood cells (Van Leeuwen, 1986).

7.2.2.2.  Invertebrates

    Short-term  toxicity studies using  the compounds listed  in
Table 5 were carried out to investigate the effects of prolonged
exposure  (21-day) on survival, fecundity, and growth of  Daphnia
 magna. Growth  and reproduction were not specifically inhibited,
since  effects on these characteristics  were generally detected
at  levels comparable with the 21-day LC50s.  For dialkyldithio-
carbamates,  the 21-day LC50s  ranged from approximately  10  to
30 µg/litre,   for EBDCs, from 80 to 110 µg/litre,  and, for ETU
and  EU, the levels were 18 and 3200 mg/litre, respectively (Van
Leeuwen, 1986).

7.2.3.  Bioaccumulation

    Van  Leeuwen (1986) determined the log  n-octanol/water  par-
tition  coefficient  for  a few  dithiocarbamates  and breakdown
products.  The results are summarized in Table 6.   In  general,
the  higher the log  n-octanol/water  partition  coefficient, the
greater the tendency to bioaccumulate.

Table 6.  log  n-octanol/water partition 
coefficients for some dithiocarbamates
------------------------------------------
Compound          log  n- octanol/water 
                  partition coefficient
------------------------------------------
Disulfiram        4
                  
Thiram            1.82

ETU               0.67

EU                0.96
------------------------------------------

    In   short-term   studies   on  rainbow   trout  of  uptake,
distribution,  and  retention  of 14C-labelled  zineb and ziram,
both compounds were found to be rapidly  distributed  throughout
the  tissues.  Whole-body accumulation was  low, with bioconcen-
tration factors of less than 100.  Relatively high radioactivity
levels  were found in  the liver, gall  bladder, and  intestinal
contents, suggesting the prominent role of hepatic biotransform-
ation and biliary excretion.  With ziram, the eyes and skin also
appeared  to be distribution sites.   Whole-body elimination was
rapid, with about 75% of radioactivity being  eliminated  within
the  first  4 days.   With ziram, 45%  of the initial  total 14C
content in the body was still present at the end of  the  16-day
depuration  period.   Differences  in the  extent of elimination
were  most noteworthy for the  eyes, skin, and kidneys.   Whole-
body  autoradiography showed the radioactivity  in the digestive
tract,  liver, bile, gills,  thyroid follicles, melanophores  of
the skin, choroid epithelium complex of the eyes, and  in  other
melanin-containing  tissues, such as  the kidneys (Van  Leeuwen,
1986).

8.  EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

8.1.  Single Exposures

    In  general, the toxicity of dithiocarbamates for mammals is
relatively low.  Some commonly used dithiocarbamates included in
the WHO recommended classification of pesticides by hazard (WHO,
1986a),  which is based primarily  on the acute oral  and dermal
toxicity  of the technical  material for the  rat, are given  in
Annex III.

    Acute oral and dermal toxicity data for a number  of  animal
species  of various dithiocarbamates are given in Table 7.  From
this Table, it is clear that nabam and metam-sodium are the most
toxic   dithiocarbamates,   other  compounds   having  only  low
toxicity.    As  for  many  compounds,  the  toxicity  is  often
influenced  by the method  of application, e.g.,  solvents used,
age  and sex of animal, type of diet, etc.  Thus, in rats fed an
isocaloric diet containing 3.5% protein, the LD50 of  nabam  was
210 mg/kg body weight, compared with 565 mg/kg in rats  fed  the
same diet plus 26% protein (Periquet & Derache, 1976).

    Ivanova-Chemishanska  (1969)  found  that rats  treated with
zineb,  maneb,  or  mancozeb  showed  dose-dependent  signs   of
depression,   adynamia,   decreased   tonus,   disturbances   in
coordination,  paresis,  and  paralysis of  extremities combined
with general weakness, lack of appetite, and prostration.

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

8.2.  Short- and Long-Term Exposures

8.2.1.  Oral exposure

8.2.1.1.  Rat

    In 1-month feeding tests, no growth retardation was noted in
rats fed diets containing 100 mg ferbam/kg diet,  but  decreased
growth occurred with 500 mg/kg diet and increased mortality with
5000 mg/kg diet (Hodge et al., 1952).

    Groups  of 40 weanling rats  (20 females and 20  males) were
given  diets containing  500, 1000,  2500, 5000,  or  10 000  mg
zineb/kg diet for up to 30 days.  Thyroid enlargement  was  seen
at  all dose levels,  but unequivocal histopathological  changes
were observed only at 10 000 mg/kg diet (Blackwell-Smith et al.,
1953; Kampmeier & Haag, 1954).

    Ferbam  administered  daily at  23,  66, or  109 mg/kg  body
weight to male rats for 13 weeks caused death and weight loss at
the highest dose, but did not have any effect  on  reproduction.
Daily  feeding (equivalent  to 15  or 51 mg/kg  body weight)  to
females  for 2 weeks  caused severe weight  loss at the  highest
dose level (Minor et al., 1974).

    In  a 2-year feeding study,  25, 250, and 2500  mg ferbam or
ziram/kg  diet shortened the life span of rats and caused growth
depression  and neurological lesions (manifested  at the highest
dose level by the crossing of hind legs when animals were lifted
by their tail) (Hodge et al., 1956).
Table 7.  Acute toxicity (LD50) of dithiocarbamates for experimental
animals
--------------------------------------------------------------------------
Compound       Animal               Dose            Reference
                             (mg/kg body weight)
                             oral         dermal
--------------------------------------------------------------------------
Ferbam         mouse         1000                   FAO/WHO (1965b)

               rat           > 4000                 Hodge et al.
                                                    (1956)

               guinea-pig    450 - 2000

               rabbit        2000 - 3000

Metham-sodium  mouse         285                    Worthing & Walker
(vapam)                                             (1983)

               rat           1700 - 1800            Worthing & Walker
                                                    (1983)

               rabbit                     1300      Worthing & Walker
                                                    (1983)

Ziram          rat           1400                   Hodge et al.
                                                    (1952)

               guinea-pig    100 - 150              Hodge et al.
                                                    (1952)

               rabbit        100 - 1020             Hodge et al.
                                                    (1952)

Thiram         mouse         1500 - 2000            Worthing & Walker
                                                    (1983)

               rat           865 - 1300             Van Esch (1956)
                                                    
               rat           780 - 865              Worthing & Walker
                                                    (1983)

               rat                        > 2000    Ben Dyke et al.
                                                    (1970)

               rabbit        210                    Lehman (1951)

               cat           230
--------------------------------------------------------------------------

Table 7.  (contd.)
--------------------------------------------------------------------------
Compound       Animal              Dose             Reference
                             (mg/kg body weight)
                             oral         dermal
--------------------------------------------------------------------------
Disulfiram     rat           > 4000                 Van Esch (1956)

Zineb          rat           > 5200                 Blackwell-Smith
                                                    (1953)

               rat           9000                   Ivanova-Chemi-
                                                    shanska (1969a)

Maneb          mouse         4100                   Engst et al.
                                                    (1971)

               rat           4500                   Engst et al.
                                                    (1971)

               rat (male)    6750                   Worthing & Walker
                                                    (1983)

Nabam          rat           395                    Blackwell-Smith et
                                                    al. (1953)

Mancozeb       rat (female)  12 800                 Ivanova-Chemi-
                                                    shanska (1969b)

               rat (male)    14 000                 Ivanova-Chemi-
                                                    shanska (1969)

               rat           > 8000                 Worthing & Walker
                                                    (1983)

Propineb       rat           8500         > 1000    Worthing & Walker
                                                    (1983)

               rabbit        2500

               cat           2500

               hen           2500

Metiram        mouse         5400                   Worthing & Walker
                                                    (1983)

               rat           > 10 000

               guinea-pig    2400 - 4800
               (female)
--------------------------------------------------------------------------

    Groups  of 24 rats  (12 females and  12 males) were  given a
diet containing 48 mg thiram/kg diet for 2 years (a 3-generation
study).   No effects on growth,  reproduction, blood parameters,
or  mortality  rate  were found,  neither  were  there gross  or
histological changes (Van Esch, 1956).  In a further  study,  12
female  and  12  male rats given 200 mg/kg diet for 8 months did
not  show any appreciable changes  in growth or mortality  rate,
and a dose of 300 mg/kg diet for 65 weeks did not give  rise  to
specific  evidence of poisoning (Tollenaar, 1956).  Groups of 24
rats (12 females and 12 males) fed diets containing  300,  1000,
or  2500 mg thiram/kg diet for 65 weeks showed weakness, ataxia,
various   degrees   of   paralysis,  and   histological  changes
(calcification in the brain stem and cerebellum  and  dystrophic
changes in the leg muscles).  At 2500 mg/kg diet, there  was  an
increased  mortality rate (Fitzhugh et al., 1952).  Groups of 20
young  rats administered diets  containing 100, 300,  or 500  mg
thiram/kg diet for 2 years all showed a small reduction  in  the
growth  rate.  At concentrations of  300 and 500 mg/kg  diet, an
increased  mortality rate  was seen,  while at  500 mg/kg  diet,
convulsions,  thyroid  hyperplasia,  and  calcification  in  the
cerebellum,  hypothalamus,  and medulla  oblongata were observed
(Griepentrog, 1962; IARC, 1976).

    Groups  of  25  male  and  25  female  rats were  fed  diets
containing  25, 250, 1250, or 2500 mg maneb/kg diet for 2 years.
At  1250 mg/kg diet,  there was some  depression, impaired  food
consumption,  and increased  mortality rate.   At the  end of  2
years,  the animals receiving 1250  mg/kg diet had an  increased
liver/body  weight ratio, and  those receiving 2500  mg/kg  diet
also showed thyroid hyperplasia and nodular goitre  (Worthing  &
Walker, 1983).

    Groups  of 10 young male  and 10 young female  rats were fed
diets  containing 500, 1000, 2500,  5000, or 10 000 mg  zineb/kg
diet  for 2 years.  At the two highest dose levels, there was an
apparent  increase in the mortality  rate among the female  rats
and,  at  10 000  mg/kg  diet,  there  was  a  tendency  towards
diminished  growth in both sexes.  The results of haematological
studies  were normal, but a  goitrogenic effect was seen  at all
dose  levels.   Kidney  damage was  seen  in  6 animals  at  the
10 000  mg/kg dose level and in one animal in each of the groups
receiving  1000,  2500, or  5000 mg/kg diet,  but not at  all at
500 mg/kg  diet.   The  tumour incidence  was  not significantly
greater  among  any of  the treated animals  than it was  in the
controls  (Blackwell-Smith  et  al.,  1953;  Kampmeier  &  Haag,
1954).

    Weanling  rats in groups of 25 males and 25 females were fed
diets  containing 25, 250, or 2500 mg ziram/kg diet for 2 years.
The  growth rate and  life span were  normal in all  groups, but
neurological  changes  were  observed in  the  animals receiving
2500 mg/kg diet, though no cystic lesions were discovered in the
levels.  In some of the male animals, the testes were atrophied,
and  there  was  a  slight  indication  of  thyroid hyperplasia,
notably  in the 2500  mg/kg diet group.   However, there was  no

increase  in tumour incidence in  the treated animals (Hodge  et
al.,  1956).  A comparable study  with the same dose  levels was
carried  out  with  ferbam, and  again  no  increase  in  tumour
incidence was found (IARC, 1976).

8.2.1.2.  Dog

    A dog given ferbam and ziram together for one month, each at
a dose of 5 mg/kg body weight per day, remained  healthy  except
for  slight anaemia.  The same  result was observed when  ferbam
was  given alone for one month at a dose of 25 mg/kg body weight
per  day,  or  for one  week at  50 mg/kg  body weight  per day.
Raising  the  dose to  100 mg/kg body  weight per day,  however,
immediately  provoked severe vomiting and malaise (Hodge et al.,
1952).  Pairs of adult dogs were given daily doses of 0.5, 5, or
25  mg ferbam/kg body weight for one year.  Convulsions occurred
at the highest dose level, but urine analysis, blood parameters,
organ  weights,  and tissue  histology  (including that  of  the
thyroid gland) were normal (Hodge et al., 1956).

    When pairs of dogs were fed maneb orally at the rate  of  2,
20,  75, or 200 mg/kg  body weight per day  for one year,  toxic
effects were observed at the two highest dose levels, but not at
20 mg/kg body weight (Worthing & Walker, 1983).

    Three  groups of three dogs  each were fed diets  containing
20,  2000,  or 10 000  mg zineb/kg diet  for one year.   All the
animals  survived, and no persistent changes in growth rate were
seen  in any  of the  groups.  There  were no  histopathological
changes  in  the  tissues, except  in  the  thyroid  gland,  and
haematological  findings  were  normal.  At  10 000  mg/kg diet,
thyroid  hyperplasia  was  noted (Blackwell-Smith  et al., 1953;
Kampmeier & Haag, 1954).

8.2.1.3.  Bird

    Sodium  diethyldithiocarbamate (NDDC), the dimethyl compound
(NDMC), and ferbam, ziram, and thiram were given orally to young
and adult domestic fowl (Thorber's gog cockerels) at  330,  210,
205,  56, and 178 mg/kg body weight, respectively, and the birds
were  killed after 6, 12, 18, or 20 weeks.  All of the compounds
had an adverse effect on body weight gain,  retarded  testicular
development,  and produced degeneration in the seminiferous epi-
thelium  of mature birds.  Nerve fibre degeneration was produced
in the medulla and spinal cord of chicks by NDDC and in those of
cocks  by  NDMC.   Chicks exposed  to  thiram  became  lame  and
exhibited  swollen epiphyses  of the  long bones  due  to  endo-
chondrial  ossification giving rise to a thickened cartilaginous
epiphyseal plate (Rasul & Howell, 1974).

8.2.2.  Inhalation exposure

8.2.2.1.  Rat

    Studies  concerning  toxicity following  inhalation exposure
are scarce.

    Ivanova-Chemishanska  et  al. (1972)  studied the inhalation
toxicity  in rats with zineb  (70% purity), maneb (80%  purity),
and mancozeb (80% purity), applied 6 days per week over a period
of 4“ months, at concentrations of 2, 10, 50, 100, or 135 mg/m3.
The  pesticides were given  in the form  of dispersed  aerosols,
with  95% of the dust particles ranging from 1 to 5 µm  in size,
and  the remainder from  5 to 10 µm.    Local irritation of  the
mucosa   of   the  upper   respiratory   tract  was   noted  and
concentration-related  non-specific  changes  in the  liver  and
kidneys were evident.  However, only slight changes  were  found
at a concentration of 2 mg/m3.

    Davydova (1973) studied the influence of inhaled  thiram  on
the  estrous cycle and genital function of rats.  Groups of rats
were  exposed  to 0,  0.45, or 3.8 mg/m3  thiram for 6 h/day,  5
days/week,  over  a period  of 4“ months.   An extension of  the
estrous  cycle was seen at  the highest dose level,  and genital
function  was disturbed, as shown by a reduction in the capacity
to  conceive, a  reduction in  fertility, and  of  fetal  weight
gain.

8.3.  Skin and Eye Irritation; Sensitization

    Nabam  (19% solution) and  zineb (65% wettable  powder) were
each  applied to the right eye of 10 rabbits, the left eye being
used as a control.  Nabam did not produce signs  of  irritation,
while  zineb produced mild irritation (erythema), which subsided
within  6 - 8 h.  No oedema  was seen.  The mild  irritation may
have  been caused by the  non-specific foreign body reaction  to
the  dry, insoluble powder.   When this procedure  was  repeated
with both compounds diluted and suspended for  agricultural  use
(for  nabam,  0.5%  of the  commercial  19%  solution plus  zinc
sulfate,  0.125% in water; for zineb, a 0.188% suspension of the
commercial 65% wettable powder in water), no irritation was seen
(Blackwell-Smith et al., 1953).

    In   studies   performed   on  guinea-pigs,   intracutaneous
injections,   10  times  daily,  followed   by  an  epicutaneous
challenge  test, provided evidence of the marked sensitizing and
cross-sensitizing properties of thiram and metiram (Griepentrog,
1960).

    It  has  been reported  that  a number  of  dithiocarbamates
(mancozeb,  metham-sodium,  metiram,  zineb, ziram,  and thiram)
cause skin and/or eye irritation (Worthing & Walker, 1983).

8.4.  Reproduction, Embryotoxicity, and Teratogenicity

8.4.1.  Reproduction

8.4.1.1.  Rat

    Groups  of rats (16 male and 16 female Charles River-CD rats
per group) were fed maneb for 3 months at levels of 0,  125,  or
250  mg/kg diet, and were  mated in a standard  3-generation, 2-
litters-per-generation  reproduction study.  Groups of males and

females from the F1b and F2b litters were fed maneb for 3 months
after  weaning and  mated to  become parents  of the  succeeding
generation.   The major reproduction indices  were unaffected by
maneb  at dietary  levels up  to and  including 250 mg/kg  diet.
There  was no histological evidence of congenital anomalies in a
variety of tissues and organs of the male and female rats of the
F3b litter subjected to histopathological examination (Sherman &
Zapp, 1966).

    Maneb,  zineb,  and  mancozeb exert  dose-dependent damaging
effects  on the gonads of  rats of both sexes.   The dose levels
were 96 - 960 mg zineb/kg body weight, 140 - 1400 mg mancozeb/kg
body weight, and 14 - 700 mg maneb/kg body weight, given twice a
week for 4.5 months.  Both reproductive and endocrine structures
were affected at all dose levels, leading to decreased fertility
(Ivanova-Chemishanska  et  al.,  1973,  1975a).   In  a  4-month
inhalation  study on rats using maneb at 4.7 mg/m3, no effect on
sperm mobility was detected (Matokhnyuk, 1971).

    Ivanova-Chemishanska  & Antov (1980) studied  the effects of
EndodanR  (50%  ethylenethiuram  monosulfide) on  the gonads and
reproduction in rats during long-term daily oral doses of 3.8 or
38 mg/kg  body  weight.   The  parental  generation  (F0)  and 3
consecutive  generations (F1  - F3)  were examined.   In  F0,  a
decrease  in  succinic  dehydrogenase and  ATPase  activities in
testes homogenates was found, as well as an increase in glucose-
6-phosphate dehydrogenase (G6PDH) activity compared with control
levels.  Changes in the liver and brain enzyme systems were also
noted.

    The same results were obtained with zineb (78%  purity).   A
rapid  loss of mobility and  changed resistance (to osmotic  and
acidic effects) of spermatozoa were found.  A decreased index of
fertility  was also found for  both sexes in the  F0 generation.
Decreased  index  of fertility  and  enzymatic changes  in organ
homogenates were detectable in the F1 - F3 generations (Ivanova-
Chemishanska et al., 1973).

    In extracts of testes of white rats, exposed  by  inhalation
to zineb and maneb at a concentration of 100 mg/m3 for 4 months,
Izmirova  et al. (1969)  found an increase  in lactate  dehydro-
genase  (LDH), LDH2, and LDH4.  Bogartykh et al. (1979)  did not
find  any  changes in  LDH or G6PDH  activities in testes  homo-
genates of Wistar rats orally treated with zineb (2.5 mg/kg body
weight) for 3 months.

    Thiram  at doses of 225,  300, 450, 600, 900,  or 1200 mg/kg
diet given to male Wistar rats for 29 days produced  changes  in
many  of the parameters studied.  A significant effect on testes
and  seminal vesicle weight was  found at 450 mg/kg diet,  and a
decrease  in  body  weight was  found  at  300 mg/kg.  The  most
sensitive parameters studied were found to be the weights of the
epididymal  and  perirenal fat  pads,  which were  decreased  by
thiuram  doses in the range 130 - 184 mg/kg diet.  The no-effect

level, calculated using an extrapolation model, did  not  differ
significantly from the earlier reported value of  48 mg/kg  diet
(Lowy et al., 1979, 1980).

    Ferbam was fed to groups of 20 Charles River-CD male rats at
concentrations  of 0, 500, 1200, or 2500 mg/kg diet for 13 weeks
before mating with untreated females.  Six of the rats  fed  the
highest dose level died.  The indices of  fertility,  gestation,
viability,  and  lactation for  the  females mated  with treated
males were normal (Short et al., 1976).

    When thiram was incorporated into the diet at concentrations
of  0,  500,  1000, and 2500 mg/kg diet and fed to male weanling
Charles River rats for 13 weeks prior to mating, food intake and
growth  was mainly  decreased at  the two  highest dose  levels.
Loss of hair and rough coats were also seen in these groups.  At
the highest dose level, high mortality occurred.  Males  in  the
highest dose group failed to inseminate the females.   In  these
animals,  there was evidence  of testicular hypoplasia,  tubular
degeneration,  and atypical spermatoids  in the epididymus.   At
the  two lower  dose levels,  no influence  on reproduction  was
found (Short et al., 1976).

    Female rats fed 400 or 2000 mg thiram/kg diet for  at  least
14  days prior to mating  showed a significant reduction  in the
number  of implants  per dam  and pups  per dam.   The  delaying
effect on the estrous cycle was reversible.  At the highest dose
level, a number of animals died.  A comparable study with ferbam
using  the  same  dose levels  did  not  show any  influence  on
fertility,  gestation,  viability,  or lactation  (Short et al.,
1976).

    Administration  of 50 mg ziram/kg  and 100 mg zineb/kg  body
weight  to  rats  for a  period of  2, 4,  or 6  months produced
delayed  insemination,  sterility,  resorption of  fetuses,  and
anomalies in development (Rjazanova, 1967).

8.4.1.2.  Bird

    Thiram  (99.9%  purity) has  been  reported to  decrease egg
production  for the domestic chicken  (Gallus domesticus), pigeon
 (Columba   livia), and pheasant  (Phasianus colchicus torquatus).
A   dose  level of  8.8 mg/kg body weight  per day caused  a 50%
reduction in egg laying in bobwhite quail  (Colinus virginianus).
During   this  period of  reduced egg laying,  it seems that  an
alteration of hormone levels took place resulting in significant
weight  losses of ovary and  oviduct, decrease in serum  calcium
level  (which  is controlled  by  estrogen), and  alteration  in
normal maturation of the ova (Wedig et al., 1968).

    In a study by Van Steemis & Van Logten (1971),  tecoram  (an
oxidation product of disodium EBDC and sodium  dimethyl  dithio-
carbamate  with  ammonium  persulfate) in  propylene  glycol  or
saline  was administered to chick embryos at doses of 0.01, 0.1,
1,  or  10 mg/egg.   Paralysis, shortening  of  the extremities,

muscular atrophy, dwarfing and death occurred.  Microscopically,
signs of peripheral neuropathy confined to the distal  parts  of
the peripheral nerves, and muscular atrophy were found.

8.4.2.  Teratogenicity

    Some  dithiocarbamates  are  potentially teratogenic  in the
rat,  but not  in the  mouse.  In  most cases,  the  teratogenic
effects have been observed at high dose levels.

8.4.2.1.  Rat

    Kaloyanova et al. (1967) have studied the effects on progeny
of  albino rats  of 0,  700, and  1400 mg maneb/kg  body  weight
administered  twice per week for 4.5 months.  Three groups of 20
rats  (10 males and 10 females) were used and a first generation
was  bred.  Congenital deformities were found in the facial part
of the skull, caudal vertebrae, palates, limbs, and  tail.   The
same type of changes were also found after a single oral dose of
2000 - 8000 mg zineb or 1000 - 4000 mg maneb/kg body  weight  on
days 11 - 13 of pregnancy.

    No  teratogenic  effects or  adverse  effects on  the intra-
uterine  development  of progeny  were  observed when  rats were
given  1000 mg zineb or 500 mg maneb/kg body weight, from days 2
to  21 of pregnancy, or were exposed in an inhalation chamber to
a  concentration of 100 mg  zineb/m3 for 4 h/day  from day 4  of
pregnancy  (Antonovich et al., 1972; Petrova-Vergieva & Ivanova-
Chemishanska, 1973; Ivanova-Chemishanska et al., 1975a).

    In a study on Sprague Dawley rats using maneb at dose levels
of  0, 120, 240,  or 480 mg/kg body  weight on days  7 -  16  of
gestation,  fetotoxic  effects  (reduced fetal  weight,  reduced
ossification, and hydrocephalus) were seen at the  highest  dose
level (Chernoff et al., 1979).

    In  studies by Larsson et al. (1976), maneb was administered
to  Sprague  Dawley  rats at  dose  levels  of 0,  400,  770, or
1420 mg/kg body weight, by gavage, as a single dose on day 11 of
gestation.   Rats were  sacrificed on  day 18  of gestation  and
fetuses  were examined for reproductive  and teratogenic abnorm-
alities.   A substantially increased resorption rate was seen at
770 mg/kg  body  weight.  Gross malformations  occurred  in  all
surviving  animals at  770 and  1420 mg/kg body  weight, but  no
malformations were observed in the single litter of the low-dose
group.  These abnormalities included cleft palate, hydrocephaly,
and other serious defects.  In another study,  maternal  admini-
stration  of  zinc acetate  (made in an  attempt to relieve  the
incidence of teratogenic events) had some preventive  effect  at
750 mg/kg  body  weight, but,  at  1380 mg/kg body  weight,  the
frequency and type of malformations were unchanged  (Larsson  et
al., 1976).

    Mancozeb  was administered to rats at dose levels of 0, 380,
730, or 1320 mg/kg body weight on day 11 of gestation in a study
similar to that reported above with maneb.  Again, a substantial
increase in malformations, similar to those produced  by  maneb,
was  observed at the highest dose level, but not at lower levels
(Larsson et al., 1976).

    Propineb  was administered to rats at dose levels of 0, 400,
760,  or  2300 mg/kg  body  weight,  by  gavage,  on day  11  of
gestation.   The dams were  sacrificed and fetuses  examined for
gross  external  and  internal  malformations  on  day   18   of
pregnancy.  Maternal toxicity was observed at all  dose  levels.
At  the highest dose level, propineb was fetotoxic and induced a
variety of malformations in the surviving fetuses. At 760 mg/kg,
propineb was slightly fetotoxic but did not induce malformations
in  surviving fetuses.  The  pattern of fetal  abnormalities was
qualitatively  similar to that noted in the maneb- and mancozeb-
treated rats (Larsson et al., 1976).

    Cypromate  (zinc  propylene bisdithiocarbamate)  was studied
for  its teratogenic  potential in  white rats  using  either  a
single oral dose of 250, 500, or 1000 mg/kg body weight  on  the
11th  or 13th day  of gestation or  repeated treatment from  the
first day of gestation through the whole pregnancy at  62,  250,
and 500 mg/kg body weight. A spectrum of malformations involving
the  nervous and skeletal systems,  facial cranium, extremities,
etc., were induced with a single dose of 500 mg/kg  body  weight
or  more, and  at all  dose levels  given  repeatedly  (Petrova-
Vergieva, 1976).

    Groups  of rats (26 - 27  pregnant CD1 rats per  group) were
administered zineb (purity 85.5% containing 0.35% ETU)  at  dose
levels of 0, 200, 632, or 2000 mg/kg body weight per day on days
6  - 19 of gestation.  Maternal body weight and food consumption
data were recorded.  Pregnant rats were sacrificed at day 20 and
a laparotomy was performed.  Fetal data included live, dead, and
resorbed  fetuses as well as somatic and skeletal abnormalities.
There was no maternal mortality, but a substantial  weight  loss
was  seen  at  the highest  dose  level.   Fetuses from  mothers
administered  2000 mg/kg  also  showed a  reduced  body  weight.
Fetal  mortality was not observed, and there were no significant
anomalies  noted  on  gross external  examination.   However,  a
higher  incidence  of teratogenic  anomalies  was noted  at  the
highest  dose level (short  and kinky tails,  hydrocephalus, and
increased  incidence of skeletal  anomalies).  At the  632 mg/kg
level,  these  teratogenic  anomalies were  absent.  The abnorm-
alities  found at the highest  dose level may have  been due, in
part, to the presence of ETU in the formulation (Short  et  al.,
1980).

    Ferbam administered to rats on days 6 - 15 of  gestation  at
150 mg/kg  body weight resulted in death, increased resorptions,
decreased  fetal weights,  and a  slight increase  in  soft  and

skeletal  tissue anomalies (Minor et al., 1974).  CD-1 rats were
treated on days 6 - 15 of gestation, by gavage, with 0,  11,  or
114 mg ferbam/kg body weight.  Twenty-five percent of  the  dams
administered 114 mg/kg died, but the surviving dams showed small
litters,  increased  resorptions,  and decreased  fetal  weight.
Also,   a   number  of   malformations  (unossified  sternebrae,
malformed cranium, hydrocephalus, and cleft palate) were found.

    When  thiram  was administered at  doses of 0, 40,  90, 136,
164,  or  200  mg/kg  body weight on  days 6 -  15 or 7  - 12 of
gestation, the 200 mg/kg dose reduced the number of  mated  rats
that delivered litters, and only 33% of the dams  survived.   At
doses of 136 mg/kg or more, a decrease in the number of implants
and fetuses per dam, an increase in resorptions, a  decrease  in
fetal   body  weight,  and  an  increase  in  malformations,  as
described for ferbam, were observed (Short et al., 1976).

8.4.2.2.  Mouse

    Pregnant  female  NMRI  and Swiss-Webster  mice were treated
orally  during days 6 - 17 of pregnancy with thiram at 179, 357,
714,  or  1071 mg/kg  body  weight  and  250,  500,  1000,   and
1500 mg/kg  body weight, respectively.  Increased  resorption of
embryos,   clearly  retarded  fetal  development,  and  skeletal
malformation  (cleft  palate, wavy  ribs,  curved long  bones of
extremities, and micrognathia) were seen in both  strains.   The
12th  and 13th days  seemed to be  the most sensitive  period of
embryonic  development.   The  lowest  dose  had  only  a slight
effect, but the next dose level was clearly  teratogenic  (Roll,
1971; Matthiaschk, 1973).

    Thiram did not reduce body weight gain during  gestation  at
doses  of 100  or 300 mg/kg  body weight,  administered on  days
6 - 14, and no changes in litter size, incidence of resorptions,
or fetal weight were observed.  However, an increase in malform-
ations was seen (Short et al., 1976).

    In studies by Larsson et al. (1976), doses of 0,  400,  770,
or  1420 mg maneb/kg  body weight  or 0,  380, 730,  or  1330 mg
mancozeb/kg  body weight were given on a single occasion to NMRI
mice  on days 9  or 13, and  mice were sacrificed  on day 18  of
gestation.   No  adverse  maternal  or  fetal  effects  could be
detected.

    In  a study on CD1 mice administered 0, 375, 750, or 1500 mg
maneb/kg  body  weight  on  days 7 - 16  of  gestation, maternal
toxicity  was found at the  highest dose level, together  with a
decrease in fetal caudal ossification centres at all dose levels
(Chernoff et al., 1979).

    Ferbam  administered to mice at 30 and 300 mg/kg body weight
on  days  6 -  16 of gestation  did not produce  any teratogenic
effects (Minor et al., 1974), and, when given at 23 or 228 mg/kg
body  weight  on  days 6 - 14, it did not affect the survival or
body  weight of Swiss-Webster dams during gestation.  No changes

in litter size, incidence of resorptions, or fetal  weight  were
observed,  but,  at  the highest  dose  level,  an  increase  in
malformations was seen (Short et al., 1976).

    Groups of CD-1 mice were administered zineb  (85.5%  purity)
daily,  at dose levels of 0, 200, 632, or 2000 mg/kg body weight
per day, for 11 days from day 6 of gestation and  sacrificed  on
day  18.  Gross examination  for maternal well-being  and  fetal
anomalies,  both  somatic  and  skeletal,  failed  to  show  any
teratogenic effects (Short et al., 1980).

8.4.3.  Embryotoxicity

    Korhonen  et  al. (1982a,b)  used  a system  called  chicken
embryo  test  to  study  the  embryotoxic  potential  of dithio-
carbamates and found early and late death and malformed embryos.
It was thought that this test could have a predictive value as a
simple teratogenicity test, but many limitations were  found  in
doing so, and the interpretation of the results were difficult.

8.5.  Mutagenicity and Related End-Points

    Seiler (1973) studied the mutagenicity of maneb  and  ziram.
Maneb  proved negative in tests with  Salmonella strains his G46,
TA1530,  TA1531,  TA1532, and  doubtful  in TA1534.   Ziram  was
positive  in TA1534,  doubtful in  TA1530, and  negative in  the
other strains.

    In  studies by Fahrig (1974),  ziram was non-mutagenic in  a
variety  of  other  microorganisms  (Escherichia  coli,   Serrata
 marcescens, and  Saccharomyces cerevisiae), but Pilinskaya (1971)
found that it induced chromosome breaks, most of  them  confined
to chromosome 2, in cultured peripheral human lymphocytes.

    Shirasu  et al. (1976)  studied mutagenicity with  the  rec-
assay  procedure, a sensitivity test using H17 rec+ and M45 rec-
strains  of  Bacillus  subtilis, and  with  reversion  assays  on
plates  using  E.  coli (WP2) and  S.  typhimurium TA1535, TA1536,
TA1537, and TA1538.  In these tests, ferbam, thiram,  and  ziram
were non-mutagenic.

    Certain  dithiocarbamates given intraperitoneally to mice at
100 mg/kg  body  weight  caused chromatid  aberrations  in  bone
marrow  cells (Kurinny &  Kondratenko, 1972; Hedenstedt  et al.,
1979), the order of effectiveness being thiram > ziram  >  maneb
and  zineb.  Thiram was also  shown to induce gene  mutations in
 Salmonella and  Aspergillus (Szymezyk,   1981; Zdienicka et  al.,
1981).

    Hedenstedt  et al. (1979) found that the mutagenic effect of
tetramethylthiuram   monosulfide  (TMTM)  was  enhanced  in  the
presence of metabolizing systems (S-9 mix), but that tetraethyl-
thiuram disulfide (TETD or AntabuseR) was not mutagenic.

    Propylene  bisdithiocarbamate was tested for cytogenicity by
bone marrow analysis and for dominant lethal mutations by giving
a  single oral  dose to  male rats.   There was  a  considerable
increase  in  the  number of  chromosomal aberrations (chromatid
fragments),  reaching  a  maximum after  24 h (Vachkova-Petrova,
1977).  In studies on the cytotoxic effects of ziram on cultures
of  human lymphocytes  in vitro (Pilinskaya, 1971),  the ratio of
chromatid-type  aberrations  to chromosome-type  aberrations was
2.7:1, which suggests that most chromosomal damage took place at
the  S-stage and  the G2  stage of  the mitotic  cycle.   Ziram-
induced  chromosomal breaks were observed to be non-random, most
of them occurring in chromosome 2.

    Propineb  and  its  main metabolite  propylenethiourea (PTU)
were  investigated  by  the  micronucleus  test  in  mice.   The
following  doses were given by  ip injection twice, with  a 24-h
interval:  propineb (unknown purity),  62.5, 125, or  250  mg/kg
body  weight in a 5% aqueous solution of Tween 80; propineb (78%
purity),  the same doses,  but in 5%  gum arabic; and  PTU, 100,
200, 400, or 600 mg/kg body weight in distilled water.  Controls
received  methanesulfonate at doses of  10, 20, 40, or  80 mg/kg
(twice,  in distilled water) and  mitomycin at 1.75, 3.5,  7, or
14 mg/kg   (twice,   in  distilled   water).   No  statistically
significant  increase  in  the  percentage  of  micronuclei  was
observed  at any of  the tested doses  of propineb or  PTU.  The
positive   control  groups  showed  the   expected  dose-related
increase  in  the  number  of  polychromatic  erythrocytes  with
micronuclei (Rolandi et al., 1984).

    Vachkova-Petrova  (1981) studied the mutagenic  potential of
EndodanR  (ethylenethiuram  monosulfide) in  short-term studies.
Several  doses of EndodanR were administered to groups of 6 rats
either  twice at an interval  of 24 h or for  5 successive days,
and  the animals were killed 6 h after the last dose.  The cells
in metaphase were analysed for aneuploidy and  aberrations,  but
no  mutagenic effects that could  be attributed to the  chemical
were detected.

    Zineb and ziram were not mutagenic when tested in  Drosophila
 melanogaster (Benes & Sram, 1969).

8.6.  Carcinogenicity

8.6.1.  Mouse

    In studies by Innes et al. (1969), groups of 18 mice of each
sex  from two hybrid strains were given various dithiocarbamates
from  7  days  of age up to 18 months.  The compounds were given
daily,  by gavage, from day 7 to weaning and thereafter added to
the diet.  The compounds and the respective amounts were: ferbam
at 10 mg/kg body weight, then 32 mg/kg diet; maneb at 46.4 mg/kg
body  weight, then  158 mg/kg  diet; nabam  at 21.5  mg/kg  body
weight, then 73 mg/kg diet; thiram at 10 mg/kg body weight, then
26  mg/kg  diet;  and  zineb  at  464  mg/kg body  weight,  then
1298 mg/kg diet.  No significant increase in tumours was found.

    On  the  basis of  all  experimental data  and  experimental
designs, IARC (1976)  suggested that there was no definite proof
for the carcinogenicity of maneb, though ETU, one of  its  meta-
bolites, was able to produce thyroid carcinomas.  However, zineb
and  maneb have been  reported to induce  pulmonary adenomas  in
mice  when  treated orally  (Chernov  & Khistenko,  1969; Balin,
1970).

8.6.2.  Rat

    A 2-year feeding study of the effects of zineb on  rats  was
carried  out using  60 young  male and  60 female  albino  rats.
These were divided into groups of 10 each and administered diets
containing  0, 500,  1000, 2500,  5000, or  10 000  mg/kg  diet.
Growth,  mortality, haematology, and organ weights were examined
and  histopathology  was carried  out.   No clear  influence  on
growth  and mortality was observed,  and haematological findings
were  within normal limits.  A  goitrogenic effect (hyperplasia)
was  observed  in  50% of  the  animals  at 500 mg/kg,  and,  at
1000 mg/kg diet or more, this effect was more  pronounced.   The
interpretation   of   thyroid   weight/body  weight   ratio  was
complicated  because of the small number of animals still alive.
Microscopically,  no evidence of  malignancies was present.   At
the  highest dose level,  kidney damage (congestion,  nephritis,
nephrosis)  was seen.  Although 10 000 mg zineb/kg diet produced
moderate  goitrogenic  effects, this  effect  was also  seen  at
500 mg/kg  in some  rats, and  was not  clearly  dose  dependent
(Blackwell-Smith et al., 1953).

    Cases  of goitre and thyroid  adenoma were found in  Sprague
Dawley  rats fed  for 2  years on  a diet  containing 120 mg  or
360 mg metiram/kg diet (Griepentrog, 1962).

8.6.3.  Dog

    When  nine mongrel dogs (three groups of three animals each)
were  administered 20, 2000,  or 10 000 mg  zineb/kg diet for  1
year, no haematological changes were found.  The thyroids of the
group  given the  highest dose  level were  enlarged and  showed
hyper-plastic changes, but, at lower dose levels, they  did  not
show any histological changes (Blackwell-Smith et al., 1953).

    Doses  of  45  mg metiram/kg  body  weight  for 90  days  or
7.5 mg/kg  body  weight  for 23  months  did  not cause  any ill
effects (Worthing & Walker, 1983).

8.6.4.  Dithiocarbamates in combination with nitrite

    The above-mentioned studies were carried out with individual
dithiocarbamates.    Other   studies   have  shown   that  these
dithiocarbamates, in the presence of nitrite, can  be  converted
to  N-nitroso derivatives, which may be carcinogenic.

    Thiram,  ferbam, ziram (Eisenbrand et al., 1974; Sen et al.,
1974),  and  disulfiram  (Lijinsky  et  al.,  1972;  Elespuru  &

Lijinsky,  1973)  react with  nitrite  under mildly  acidic con-
ditions  to  form  N-nitroso  compounds.   Formation of  N-nitroso-
dimethylamine (NDMA) by the action of microorganisms  in  sewage
and soil containing 0.1% thiram has been reported to occur under
experimental  conditions  (Ayanaba  et al.,  1973).   Nitrite is
formed by the reduction of nitrate, which can be found  in  some
unrefrigerated  vegetables (e.g., spinach and beets), especially
after cooking (Phillips, 1968), in human saliva  (Tannenbaum  et
al.,  1974), and in  cured meats.  Thus,  in vivo nitrosation of
dithiocarbamates in the stomach cannot be totally excluded.

    As has been 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.  The crucial information, however, is the quantity
produced  in man under  the prevailing conditions.   The concen-
tration  of both reactants, the  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,  compared
with that of experimental animals, has to be considered.

    Sen  et  al.  (1974) concluded  that  it  is  unlikely  that
significant amounts of NDMA would be produced from the ingestion
of trace amounts of the dithiocarbamates and the  normal  intake
of nitrite.

8.7.  Mechanisms of Toxicity; Mode of Action

8.7.1.  Thyroid

    In weaning rats, a diet containing 500 mg nabam/kg given for
9 days caused thyroid hyperplasia and a decrease in  the  weight
of the thymus (Seifter & Ehrich, 1948).

    Male   and  female  albino  rats   were  administered  diets
containing  0, 500, 1000, 2500, 5000, or 10 000 mg zineb/kg diet
for up to 30 days.  Animals were killed sequentially in order to
study the changes in the thyroid gland. Only in the 10 000 mg/kg
group  were  effects  seen.  In two out of five males and in one
out  of five females,  hyperplasia of the  thyroid was  observed
(Blackwell-Smith  et al., 1953).  Przezdziecki et al. (1969) fed
female Wistar rats a diet containing 1300 mg zineb/kg or 1875 mg
maneb/kg diet for 7 months.  Significant increases in the weight
of the thyroid gland and decreases in the weight of the kidneys,
adrenal glands, and ovaries were observed.

    Thyroid hyperplasia has been reported in rats  given  maneb,
zineb,  or mancozeb in  amounts ranging from  500 to 2500  mg/kg
diet for periods of up to 2 years (FAO/WHO, 1965b, 1971b).  In a
2-year  feeding  study,  2500 mg maneb/kg  diet produced thyroid
hyperplasia and nodular goitre and increased mortality, but 1250
and  250 mg/kg diet  did not  cause any  ill  effects  (FAO/WHO,
1965b).

    Zineb was given orally to white rats at dose levels of 96 or
960 mg/kg  body weight for  4.5 months.  Compared  with that  of
untreated  animals, the thyroid was enlarged with microfollicles
and  columnar  cells.   Succinic  dehydrogenase  and  cytochrome
oxidase activities were raised in these cells, while the colloid
in the follicles showed reduced PASa-positive   granules.  These
changes  were consistent with an increase in thyroid-stimulating
hormone  (TSH).  An increased  number of basophilic  cells  con-
taining  PASa-positive    granules  was observed  in  the adeno-
hypophysis  (anterior pituitary).  These effects  were seen only
at  the highest dose  level.  The uptake  of 131iodine was  also
increased at the highest dose level, and a high plasma TSH level
was recorded in treated animals.  The changes observed  in  both
thyroid and pituitary were probably a compensatory  response  to
the   antithyroid   effect  of   the  dithiocarbamate  (Ivanova-
Chemishanska et al., 1975b).

    After oral administration of zineb to rats at dose levels of
9.6  or 960 mg/kg body weight, twice a week, for 4“ months,  the
gonadotropic  and  thyroid-stimulating  functions of  the adeno-
hypophysis  were significantly increased compared  with those of
control values, more markedly in those receiving the higher dose
(Ivanova-Chemishanska et al., 1974).

    Albino  rats  were  orally  administered  doses  of  2400 mg
zineb/kg  or 3500  mg maneb/kg  body weight,  and,  after  24 h,
radioactive  iodine was administered intraperitoneally.  Reduced
assimilation  of  131iodine  by  the  thyroid  was  found, which
suggests   that  the  dithiocarbamates,  or   certain  of  their
metabolites, possess a marked antithyroid effect and inhibit the
synthesis  of  thyroxine  (Ivanova-Chemishanska  et  al.,  1967,
1974).   In similar studies with mancozeb, a single oral dose of
7000  mg/kg  body  weight resulted  in  a  decreased  uptake  of
131iodine (Ivanova-Chemishanska et al., 1967).

    The  condition of  the thyroid  gland was  studied  in  male
albino  rats, which were  administered 700 mg  maneb/kg, 960  mg
zineb/kg,  or 1400 mg mancozeb/kg  body weight.  After 30  days,
the    distinct   morphological   changes   observed   indicated
stimulation of the thyroid by TSH.  Hypophyseal  stimulation  is
the  consequence of release from negative feedback by thyroxine,
the  plasma level of which  is depressed by the  action of EBDCs
(Ivanova-Chemishanska et al., 1971, 1974).

    Rats  fed a diet containing 10 000 mg metiram/kg for 2 weeks
showed  increased thyroid weight and a decrease in the uptake of
131iodine, but no ill effects were produced by  1000 mg/kg  diet
(Worthing & Walker, 1983).


----------------------------------------------------------------
a   PAS = periodic acid-Schift reagent.

8.7.2.  Interaction of dithiocarbamates and alcohol

    Hald et al. (1948) found that dithiocarbamates interact with
ethanol  (ethyl  alcohol),  and  since  then,  certain   dithio-
carbamates,  particularly  disulfiram,  have been  used  in  the
treatment  of chronic alcoholism.  Disulfiram  has been proposed
to act in two different ways.  The first possibility is that the
drug  or one of  its metabolites (e.g.,  diethyldithiocarbamate,
carbon  disulfide)  interferes  with the  normal  metabolism  of
ethanol  and,  consequently, gives  rise  to an  accumulation of
toxic  amounts of intermediary  products, such as  acetaldehyde.
The  second possible method of action is that ethanol interferes
with  the normal metabolism  of disulfiram and  therefore  makes
disulfiram more toxic in some way.

    Ethanol  is  detoxified  in many  tissues,  particularly the
liver,  by oxidation, firstly  to acetaldehyde, then  to  acetic
acid,  and  finally to  carbon  dioxide and  water.   Disulfiram
interferes  with various enzyme systems including those involved
in the oxidation of ethanol. After administration of disulfiram,
the    blood   acetaldehyde   level   increases   significantly.
Peripheral neuropathy and optic neuritis have been  observed  in
alcoholics  treated  with  125  -  150  mg  disulfiram  per  day
(Gardner-Thorpe & Benjamin, 1971).

    Van  Logten  (1972)  studied  this  phenomenon  of   alcohol
intolerance extensively in rats.  Zineb and maneb did not induce
alcohol  intolerance, whereas most of  the alkyldithiocarbamates
(such  as ziram and nabam) and thiuram sulfides (such as thiram)
did.   In general, the dithiocarbamates with a free H atom bound
to  the  N  atom did  not  induce  intolerance.  Apart  from the
accumulation  of  acetaldehyde  in blood,  disturbance of sulfo-
bromophthalein  (BSP)  elimination,  increased  serum  glutamic-
pyruvic  transaminase,  hypothermia, increased  glucose content,
changes in blood morphology, atrophy of spleen and  thymus,  and
increase  in the weight of adrenals and brain were all observed.
Studies on adrenalectomized rats showed the involvement  of  the
adrenals  in  the alcohol  intolerance.  Hyperglycaemia, eosino-
penia,  lymphopenia,  and  neutrophilia  were  not  seen  in the
animals  without  adrenals, and  spleen  and thymus  atrophy was
reduced.   However, the effect on  the red blood cells  was more
pronounced,  and the accumulation  of acetaldehyde in  the blood
was unaffected by adrenalectomy.

    Oral  treatment of rats with ethanol after administration of
alkyldithiocarbamates  or thiuram sulfides lowers  the catechol-
amine content of the adrenals.  Since the lowest level  was  not
reached  until 24 h or  more after alcohol  treatment, it  seems
likely  that  the  influence on  the  adrenals  of  the  dithio-
carbamate-ethanol interaction is of secondary importance.  There
was  no clear indication that the ethanol intolerance in the rat
is accompanied by changes in brain catecholamine level.

    As  in human beings, the dithiocarbamate-ethanol reaction in
the rat is characterized by a severe hypotension,  which  starts
almost immediately after the administration of the  ethanol  and
lasts  at  least  8 h.   It  is  evident  that,  during  alcohol
intolerance,   body  fluids  shift  from  the  plasma  into  the
interstitial tissue or cells, possibly thereby causing the hypo-
tension or shock.  The observed hypothermia also  starts  almost
immediately after ethanol administration and may last  for  many
hours.    Adrenalectomy   did   not  prevent   the  hypothermia.
Therefore,  this  phenomenon must  be  considered as  a  primary
effect, along with the plasma accumulation of acetaldehyde.

    Since heat loss is not increased during the dithiocarbamate-
ethanol reaction, the hypothermia is probably due  to  decreased
heat  production.  However, the  serotonin concentration in  the
brain  was  increased,  and so  a  disturbance  of  the  thermo-
regulation  cannot be  ruled out.   It seems  doubtful that  the
dithiocarbamate-ethanol  reaction is due to acetaldehyde  per se.
Intraperitoneal   injection of acetaldehyde, which resulted in a
blood  level twice as high as during the dithiocarbamate-ethanol
reaction,  did  not  influence BSP  elimination,  serum  glucose
level, body temperature, organ weights, catecholamine content of
the adrenals, or blood pressure.

    No  indications  were  available that  the  accumulation  of
acetaldehyde  in the blood was  due to an accelerated  biotrans-
formation  of  alcohol.  More  work needs to  be done to  decide
whether  the accumulation of  acetaldehyde and pyruvate  in  the
blood   is  a  consequence  of  a  disturbance  of  carbohydrate
metabolism.   The  specificity  of ethanol  is  remarkable.  The
combination  of thiram with either methanol or 1-propanol has no
effect on BSP elimination or on blood glucose level.

    The  sensitivity of the rat  for the dithiocarbamate-alcohol
reaction is of the same magnitude as that of  man.   Administra-
tion  of 1.9 mg  thiram/kg body  weight in  the rat  elicits  an
accumulation  of acetaldehyde  in the  blood.  Thus,  it may  be
concluded  that 60 ml of  gin, 0.5 litre of  beer, or even  less
should be sufficient to induce alcohol intolerance.

    Eight  days  after  the administration  of  certain  dithio-
carbamates,  a dithiocarbamate-alcohol reaction may  be observed
when ethanol is given.  The maximum level of acetaldehyde in the
blood is reached within 15 min of ethanol treatment.

    A  90-day  study  with  several  dietary  levels  of  thiram
revealed  a  no-toxic-effect  level of  100 mg/kg  diet.   After
feeding  rats  with  10 mg thiram/kg  diet  for  6  weeks,  oral
administration of a single dose of 6 ml ethanol/kg  body  weight
caused a significant decrease in the body  temperature.   Higher
doses  of thiram with alcohol  induced hyperglycaemia, accumula-
tion  of acetaldehyde in the blood, and other abnormalities.  In
contrast,  the  combination  of  100 mg  thiram/kg  diet  and 5%
ethanol  continuously  in the  drinking-water  did not  have any
effect (Van Logten, 1972).

8.7.3.  Neurotoxicity

    In  an  80-week  study  on  the  neurotoxic  and behavioural
effects of thiram, 12 male and 12 female rats per group were fed
thiram  at dose levels of  0, 100, 400, or  1000 mg/kg diet (the
concentration  of  the compound  in  the diet  was  periodically
increased  in order to give a relatively constant consumption on
the  basis of body weight).   A second study was  carried out on
two groups of 24 female rats administered 0 or 1000 mg thiram/kg
diet, for 36 weeks.  The neurotoxic effects  were  characterized
by ataxia and paralysis of the hind legs, although these effects
were  only seen  at the  highest dose  level (1000  mg/kg  diet,
equivalent  to 65 mg/kg body weight) in females.  Demyelination,
degeneration   of  the  axon  cylinders,  and  the  presence  of
macrophages  in the nerve bundle of the sciatic nerve were seen.
Degeneration in the ventral horn of the lower lumbar  region  of
the  spinal  cord was  demonstrated  by chromatolysis  of  motor
neurons,  pyknosis, and satellitosis.  Electromyograms indicated
a  loss of motor unit function, and the histopathology suggested
that the peripheral nerve is the primary site of the lesion (Lee
& Peters, 1976).

    In another study, groups of 12 males and 12 females were fed
ferbam  in  the dose  levels that gave  actual intake levels  of
approximately  8.5, 34,  and 87  mg/kg body  weight (average  of
males  and females) per day.   The neurotoxic effects of  ferbam
are  less than those of thiram.  In this study, only 3 of the 24
rats  fed the highest dose  level developed ataxia or  paralysis
(Lee & Peters, 1976). Neurotoxic effects have also been observed
for ziram by Hodge et al. (1956).

    In  a study on rats, zineb (490 and 2450 mg/kg body weight),
maneb  (350 and 1750 mg/kg  body weight), and mancozeb  (700 and
3500 mg/kg body weight) were administered orally at twice weekly
doses for 4 months.  Mortality was high, and paresis in the hind
limbs appeared in the third month of the study and progressed to
complete paralysis (Ivanova-Chemishanska, 1969a).

    Dishovski  & Ivanova-Chemishanska (1979) studied  the ultra-
structural   changes  in  the   neocortex  of  rats   repeatedly
administered  propineb  (70%  purity) at  85 mg/kg and 425 mg/kg
body  weight  for 40  days.  At the  higher dose level,  intense
ultrastructural  changes  in  the  sensorimotor  neocortex  were
detected  using an electron microscope,  primarily affecting the
pyramidal cells.  The concentration of ribosomes and hypertrophy
of  the  Golgi  apparatus  suggested  an  increase  in synthetic
processes in the neurons.

    Edington  & Howell (1966, 1969) found lesions in the central
nervous system of adult Dutch-New Zealand rabbits who were given
ip   injections  of  sodium  diethyldithiocarbamate   (NDDC)  at
330 mg/kg body weight, for 6 days/week, for 30 weeks.  The first
changes  were seen at 6  weeks in the accessory  cuneate nucleus
and in Clarke's column; 12 weeks later, degeneration was seen in
the  spinocerebellar tracts in the cerebellum medulla.  After 24

weeks, severe nerve fibre degeneration in the  peripheral  white
matter  of the spinal  cord (both involved  the axon and  myelin
sheath) was observed.  It was suggested that these changes might
be connected with changes in the level of copper in the serum.

    Kim  & Rizzuto (1975) studied the effect of NDDC (0.23, 2.3,
and  23 µg/ml  nutrient medium)  on myelinated cultures  of new-
born  mouse cerebellum.  Exposure time  was 24 - 120  h, and the
cultures  were  examined  by  light  and  electron   microscopy.
Treatment  of the cultures  for 24 -  48 h produced  swelling of
axons and presynaptic endings, morphologically characteristic of
dystrophic  axons.   Continued  exposure  induced  an  extensive
degeneration  of axons and myelin sheath (Wallerian degeneration
in axons).

8.7.4.  Dithiocarbamates in combination with metals

    Truhaut et al. (1971) studied the chelating action of sodium
diethyldithiocarbamate  to copper and the fact that this element
is indispensable for the activity of  dopamine beta-hydroxylase.
The  authors put forward the  hypothesis that the inhibition  of
this enzyme system, which catalyses the conversion  of  dopamine
to  norepinephrine and participates  in the biogenesis  of cate-
cholamines in the central nervous system, may play a role in the
etiology of neurotoxic effects.

    Maj et al. (1970) studied the effect of disulfiram, diethyl-
dithiocarbamate  (DDC), and dimethyldithiocarbamate on serotonin
(5-HT)  and 5-hydroxyindole-3-acetic acid (5-HIAA)  in the brain
of  rats.  The total  dose levels ranged  from 150 to  500 mg/kg
body weight.  It was concluded that these three compounds do not
affect  the 5-HT  level in  the rat  brain.  The  5-HIAA  levels
increased, but not significantly.

    Possibly,  reactions  of carbon  disulfide with pyridoxamine
could  lead  to  the depletion  of  pyridoxal  phosphate in  the
tissues,  which may, in turn, cause neurological changes.  Long-
term poisoning of rabbits with carbon disulfide has  been  shown
to  result  in  increased excretion  of  zinc  in the  urine and
disturbances of copper and zinc concentrations in  the  tissues.
Also,  after NDDC treatment, increased  levels of copper in  the
liver and nervous tissue have been found (Cavanagh, 1973).

    Aaseth  et al. (1981) showed  that oral treatment of  Wistar
rats with tetramethylthiuram disulfide (TMTD) at 1000 mg/kg diet
for  one week increased  the brain levels  of endogenous  copper
and  zinc.  In  further studies,  rats were  administered an  iv
injection  of 203HgCl2 (5 µmol/kg  body weight in saline) at day 
17  of pregnancy.  DDC was  given immediately after the  mercury 
injection   (500 µmol/kg   body  weight).   The  maternal  brain 
concentration of mercury increased significantly, and the kidney 
levels,  measured  after 24  and 48 h,  also increased.  In  the 
fetuses,  the mercury in  the brain, liver,  kidneys, and  blood 
(but  also in the  placenta) were significantly  increased after 
24 h, but, after 72 h, only the levels in fetal blood were still 

elevated.   Mice of the NMRI strain were similarly injected with
203HgCl2 (2.5 µmol/kg  body weight) and fed diets containing DDC
(10 000 mg/kg diet), disulfiram and TMTD (1000 mg/kg  diet),  or
carbon  disulfide (3000 mg/kg diet) for 4 days.  The brain level
of  mercury  was  significantly  increased  after  DDC  or  TMTD
treatment  and marginally after  disulfiram or carbon  disulfide
treatment (Aaseth et al., 1981).

    Lakomaa  et al. (1982) studied  the effect of DDC  on copper
and  zinc concentrations in  different regions of  the brain  of
Long-Evans  rats  during  acute or  repeated  treatment.   Acute
treatment (250 mg/kg body weight) produced no effect after 24 h,
whereas  repeated treatment (250  mg/kg, 5 times  per week,  for
4  weeks)  increased copper  levels in the  brain stem,  cortex,
hippocampus, and the rest of the brain, but did not  alter  zinc
concentrations.

    Dithiocarbamates, with their metal-chelating properties, and
thiuram  derivatives, have been  demonstrated to cause  a marked
increase  in the concentration of lead in the brain as well as a
redistribution of lead in the rest of the body (Oskarsson, 1983,
1984; Danielsson et al., 1984).  Thus, after injection of a dose
of   labelled  lead  (203Pb),  the   brain  concentrations  were
increased by up to 100 times in thiuram-treated rats.

    Male  Sprague Dawley rats  (10 groups of  5 rats each)  were
administered  different combinations of thiram, disulfiram, DDC,
or  dimethyldithiocarbamate in combination with  sodium or lead.
The  study demonstrated that treatment with dithiocarbamates and
thiram  derivatives in rats exposed for 6 weeks to lead causes a
substantial (up to 4-fold) increase in the lead concentration of
the brain.  This effect can be explained by the formation  of  a
lipophilic  lead-dithiocarbamate  complex,  which  probably   is
retained  longer and  has a  higher capacity  to  penetrate  the
blood-brain barrier and bind to lipid-rich brain  tissue  compo-
nents than inorganic lead itself.  The chemical form of the lead
when it is in the brain remains uncertain.  The lead complex may
decompose  in the  brain into  inorganic lead,  which  exerts  a
neurotoxic  effect, or it may be very stable in the brain and of
low toxicity for the central nervous system (Oskarsson  &  Lind,
1985).

    There  are several reports on the effect of dithiocarbamates
on  the  distribution in  the body of  other metal ions  such as
cadmium,  thallium, nickel, copper, zinc, and mercury (Oskarsson
& Lind, 1985).

    DDC  has been  shown to  have a  strong inducing  effect  on
levels  of metallothionein, a low molecular weight, heavy-metal-
binding  protein,  in  rat  liver  and  kidney.   The  mechanism
probably  reflects enhanced uptake  of copper and  depletion  of
hepatic glutathione (Sunderman & Fraser, 1983).

8.7.5.  Miscellaneous reactions

    Dithiocarbamates,   with  their  chelating   capacity,  also
interfere with a number of enzyme systems containing metals such
as zinc and copper (e.g., dopamine beta-hydroxylase).  They also
inhibit sulfhydryl (SH)-containing enzymes and a number of other
enzyme systems involved in glucose metabolism (e.g., hexokinase,
glyceraldehyde-3-phosphate    dehydrogenase,    and   glucose-6-
phosphate  dehydrogenase).   The  effect of  dithiocarbamates on
liver  enzymes  has consequences  for  the metabolism  of  other
chemicals.   Thus,  the  toxicity  of  carbon  tetrachloride  is
decreased by diethyldithiocarbamate (Lange & Jung, 1971; Lutz et
al.,  1973), and the  toxicity of other  chemicals, e.g.,  ethyl
alcohol, may be increased (section 8.7.2).

9.  EFFECTS ON MAN

9.1.  Occupational Exposure

9.1.1.  Acute toxicity - poisoning incidents

    The  acute toxicity of  dithiocarbamates is low  and, there-
fore, acute intoxication in human beings is unlikely to occur.

    A case was reported of a 62-year-old man with  acute  kidney
insufficiency  after  maneb  application.  However,  the precise
cause of maneb exposure was not clear, since the patient  had  a
history   of  hypertension,  cerebral   infarction,  gastrectomy
because  of stomach cancer,  and chemotherapy.  The  patient was
treated  with  haemodialysis  and was  discharged  from hospital
(Koizumi et al., 1979).

    Thiram  (100 mg/m3)  has  been  shown  to  cause  headaches,
vertigo,  impairment  of  mental capacity,  muscle  twitch,  and
paraesthaesia (Sprecher & Grigorowa, 1967).

9.1.2.  Case reports, short-term and epidemiological studies

9.1.2.1.  Dermal

    The irritant and allergic potential of most dithiocarbamates
is  evident  in  occupational  exposure.   Skin  irritation  and
sensitization  were studied in  man using a  conventional  patch
test.   A  cotton square  was dipped in  19% nabam solution  and
placed  on the inner surface of the forearm, and, 14 days later,
this  procedure was repeated on the opposite forearm.  Zineb was
tested  in the same  manner, except that  the cotton square  was
dipped in 65% wettable powder.  The patches were left  in  place
for  48 h.  Of the  25 subjects included  in the nabam  study, 2
showed  irritation (mild erythema and itching).  Thirteen of the
25 reacted to the retest (from mild erythema to severe erythema,
oedema,  and vesiculation), indicating sensitization.  Of the 50
subjects used in the zineb study, no reaction at all was seen in
49 of them.  One reacted in such a way that it indicated primary
irritation  rather  than sensitization  (Blackwell-Smith et al.,
1953).  Schultheiss (1957) reported a case of contact dermatitis
with  thiram.   Zadorozhny et  al.  (1981) found  dermatitis and
eczema in 241 industrial workers exposed to TMTD and other types
of pesticides.  Twenty-one of them showed contact dermatitis, 25
allergic dermatitis, and 7 eczema.

    Cases  of diffuse erythema  and eczematoid epidermatitis  of
the  eyelids and inguinal regions, probably with elements of sun
sensitization,  were observed among agricultural  workers (grape
and  tobacco industries) in contact with zineb (Babini, 1966) or
maneb  (Laborie  &  Laborie,  1966;  Zorin,  1970).   These were
largely  allergic in character with only a few manifestations of
contact   dermatitis.   Decreased  resistance  of  the  workers,
vitamin  deficiency,  chronic  liver disease,  and other factors
apparently contributed to these effects.

9.1.2.2.  Exposure via different routes

    Kaskevich et al. (1981) carried out an epidemiological study
on  137 workers engaged  in zineb manufacturing  (51 men and  86
women).   The duration of exposure  to zineb for 52  workers was
between 1 and 3 years, and for 85 workers between 4 and 5 years.
Control  groups in  this study  consisted of  193  persons,  not
exposed to chemicals and matched for age, period  of  employment
rate,  and sex.  The  concentrations in the  air of the  working
area  never  exceeded  1 mg/m3.   Among  workers  occupationally
exposed  to  zineb, the  following  changes were  found: hepato-
cholecystitis  (28.4%  of  workers, versus  13.5%  in controls);
vegetovascular  dystonia connected with disorders in the central
nervous  system  (34.9%,  versus  22.3%  in  controls);  chronic
bronchitis  (4.4%, versus 0.5% in  controls); contact dermatitis
(11.9%, versus 0.1% in controls); and disorders in the menstrual
cycle (16.91%, versus 4.3% in controls).  These studies indicate
a change in catecholamine metabolism.

    In a study with cultured lymphocytes from 15 workers working
in  different stages of zineb manufacture, the mean incidence of
aberrant metaphases was 6% greater than that in  controls.   The
incidence  of  chromosomal  aberrations  (chromatid  breaks)  in
cultured  human  lymphocytes treated  with  maneb (0.5,  15,  or
30 µg/ml)   was 10 - 20% greater than in controls (Antonovich et
al., 1972).

    A number of studies on maneb and mancozeb production workers
have been carried out.  In the earliest study (1965), 54 produc-
tion workers were given medical examinations that included blood
and  urine analyses.  Since this study predated the availability
of  immunoassay  techniques  for thyroid  hormone determination,
protein-bound  iodine was used as a measure of thyroid function.
No thyroid or other medical abnormalities could be attributed to
EBDC  exposure.   In a  second study (1975),  57 exposed and  98
unexposed  production workers were examined for thyroid function
by  measuring  triiodothyronin  (T3), thyroxine  (T4),  and TSH.
Again,  no  effects  attributable to  work-place  exposure  were
identified.  Workers exposed to EBDC levels ranging from 0.13 to
5.46  mg/m3 were found to have elevated ETU and manganese levels
in the urine.  In a 1976 mortality study, 992 past  and  present
production  workers  (over  the period  1948-75)  were  studied.
Compared  with the local general population, neither the overall
death rate nor the death rate due to cancer was  elevated.   The
number  of cancer deaths observed (10) was too small to evaluate
cancer-specific mortality (Gowers & Gordon, 1980).

    In  the most extensive study,  42 currently exposed and  112
previously exposed workers were compared with equal size control
groups  matched for age, period of employment, race, and type of
job.  All participants were given thorough physical examinations
by   specialists  in  diagnostic  medicine,  including  detailed
questionnaires  and interviews about  health history and  family
health.   A  separate thyroid  examination  was carried  out  by

thyroid  specialists.   Thyroid  parameters that  were  measured
included  total  T3, T3  resin uptake, T4,  TSH, free T4  index,
thyroglobulin   antibodies,  and  microsomal   antibodies.    In
addition,  urine was analysed  for ETU, EBDC,  zinc,  manganese,
creatine,  iodide, specific gravity,  and pH.  Blood  levels  of
glucose,  urea  nitrogen, sodium,  potassium, calcium, chloride,
carbon  dioxide,  cholesterol,  total protein,  protein albumin,
bilirubin,  uric  acid, creatinine,  inorganic phosphate, lactic
dehydrogenase,  and serum glutamic oxaloacetic transaminase were
also  determined.   As in  earlier  studies, the  occurrence  of
unusually high levels of ETU in the urine of  currently  exposed
workers   confirmed   their   exposure.   However,   a  detailed
statistical  analysis  of the  data  revealed no  differences in
thyroid function, blood and urine indicators of liver and kidney
function,  or general health, between exposed and control groups
(Gowers & Gordon, 1980; Charkes et al., 1985).

PART B 
ETHYLENETHIOUREA (ETU) AND PROPYLENETHIOUREA (PTU)

CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR ETHYLENETHIOUREA (ETU)
AND PROPYLENETHIOUREA (PTU)

INTRODUCTION

1. SUMMARY

   1.1   Sources, environmental transport and distribution
   1.2   Environmental levels and human exposure
   1.3   Kinetics and metabolism
   1.4   Effects on organisms in the environment
   1.5   Effects on experimental animals and  in vitro test systems
         1.5.1   Ethylenethiourea
         1.5.2   Propylenethiourea
   1.6   Effects on man

2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

   2.1   Identity
   2.2   Physical and chemical properties
   2.3   Analytical methods
         2.3.1   Extraction
         2.3.2   Clean-up
         2.3.3   Derivatization
         2.3.4   Determination
                 2.3.4.1   Gas-liquid chromatography (GLC)
                 2.3.4.2   Thin-layer chromatography (TLC)
                 2.3.4.3   Polarography
                 2.3.4.4   Radioisotope dilution
                 2.3.4.5   High-pressure liquid chromatography (HPLC)

3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

   4.1   Soil
   4.2   Water
   4.3   Plants

5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

   5.1   Food and drinking-water
   5.2   Monitoring and market basket studies

6. KINETICS AND METABOLISM

   6.1   Absorption, distribution, and excretion
   6.2   Metabolic transformation

7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT

8. EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

   8.1   Single exposures
   8.2   Short- and long-term exposures
   8.3   Teratogenicity
   8.4   Mutagenicity
   8.5   Carcinogenicity
         8.5.1   Mouse
         8.5.2   Rat
         8.5.3   Hamster
   8.6   ETU in combination with nitrite
   8.7   Mechanisms of toxicity; mode of action
   8.8   Probineb and Propylenethiourea (PTU)
         8.8.1   General
         8.8.2   Toxicological information

9. EFFECTS ON MAN

   9.1   Epidemiological studies

INTRODUCTION

    One of the metabolic products of ethylene bisdithiocarbamate
decomposition  in  mammals,  plants,  and  lower  organisms   is
ethylenethiourea (ETU).  It may also be present as  an  impurity
in  these dithiocarbamates, and their  residues on crops may  be
partly transformed into ETU during food processing. A comparable
breakdown takes place with propineb, giving rise  to  propylene-
thiourea (PTU).


1.  SUMMARY

1.1.  Sources, Environmental Transport, and Distribution

    Ethylenethiourea  (ETU) is found  together with residues  of
the  parent ethylene bisdithiocarbamates (EBDCs) in and on crops
that have been treated with these pesticides.   During  storage,
processing,  and  cooking, the  amount  of the  parent  compound
decreases  while that of  ETU increases.  ETU  is easily  photo-
oxidized  (in the presence of  photosensitizers) to ethyleneurea
(EU).

1.2.  Environmental Levels and Human Exposure

    In  certain crops, such  as spinach, carrots,  and potatoes,
treated  with  EBDCs,  high levels  of  ETU  can be  found after
cooking.    In  general,  however,  the  ETU  levels  are  below
0.1 mg/kg product.

    Estimates of the exposure of the general population  of  the
USA are of the order of 0.24 - 3.65 µg  ETU/kg body  weight  per
day,  and, in Canada,  estimates based on  market-basket studies
are around 1 µg ETU/kg body weight per day.

1.3.  Kinetics and Metabolism

    ETU  is  rapidly  absorbed,  metabolized,  and  excreted  in
mammals.   Up  to 90%   is eliminated via  the urine and  only a
small  amount via the faeces.   Distribution of ETU in  the body
appears  to be fairly uniform  with the exception of  a relative
accumulation  in the thyroid.   ETU is broken  down to  ethylene
diamine  (EDA), urea,  carbon dioxide,  or oxalic  acid,  or  is
transformed to imidazole derivatives in mammals, plants, and the
environment.

1.4.  Effects on Organisms in the Environment

    The  available LC50 levels of ETU and EU for fish are in the
range of 7500 - 13 000 mg/litre.

1.5.  Effects on Experimental Animals and  In Vitro Test Systems

1.5.1.  Ethylenethiourea

    The  acute oral toxicity in experimental animals is low, and
the long-term effects are mainly characterized by an antithyroid
action.

    At  dose levels > 25 mg/kg  body weight, decreases in  serum
T3, T4, and protein-bound iodine (PBI) and increases in thyroid-
stimulating  hormone  (TSH)   have  been  found  in  studies  on
experimental animals.  At higher dose levels (> 100  mg/kg  body
weight),  increases in thyroid weight  and hyperplasia occurred,
which  finally  resulted  in the  development of adenocarcinoma.

The  effects of short-term exposure to low levels of ETU seem to
be  reversible, but those of long-term exposure to higher levels
become,   at  a  certain   stage,  irreversible.   A   level  of
approximately 5 mg/kg body weight seems to be without effects.

    Most  mutagenicity  studies  on ETU,  especially  those with
mammalian test systems, have given negative results.

    A number of carcinogenicity studies have been carried out on
mice, rats, and hamsters.  In addition to an antithyroid action,
ETU  has  been found  to  induce, subsequently,  thyroid tumours
(hyperplastic  goitre,  solid-cell adenomas,  and follicular and
papillary  carcinomas) in mice and rats.  In an earlier study on
mice,  liver  tumours, lung  tumours,  and lymphomas  were  also
detected,  but  these  findings  have  not  been  confirmed.  No
tumours except thyroid tumours have been found in rats,  and  in
hamsters, no tumours of the thyroid gland or other  organs  were
observed, even at 200 mg/kg diet.

    At dose levels above approximately 10 mg/kg body weight, ETU
has  clear teratogenic effects  in rats and  hamsters, different
types  of central nervous  system and skeletal  anomalies  being
induced.  However, in mice, no teratogenic effects were found at
much higher dose levels (up to 800 mg/kg body weight).

1.5.2.  Propylenethiourea

    In  a long-term study on mice using propylenethiourea (PTU),
an  increased incidence of hepatocellular  adenomas was observed
at  dose levels of  10 mg/kg diet  or more.  No  thyroid tumours
were found, but increased thyroid hypercellularity occurred at a
dose  level of 1000  mg/kg diet.  In  rats, goitrogenic  effects
were seen with PTU at dose levels as low as 1 mg/kg diet.

1.6.  Effects on Man

    Epidemiological  studies on workers  exposed to ETU  did not
reveal any increase in the incidence of thyroid tumours.

2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

2.1.  Identity

    The chemical structure of ethylenethiourea (ETU) is:

                            CH2-NH
                            |    \
                            |     C=S
                            |    /
                            CH2-NH

2.2.  Physical and Chemical Properties

    ETU is a fairly stable compound.  Some physical and chemical
properties are listed in Table 8.

Table 8.  Some physical and chemical properties of ETU
-------------------------------------------------------------------
Empirical formula               C3H6N2S

Common synonym                  2-imidazolidinethione

Appearance                      white, crystalline

Relative molecular mass         102.17

Odour                           odourless

Melting point                   203 - 204 °C

Solubility                      in water: 20 000 mg/litre at 30 °C;
                                in ethanol: moderately soluble;
                                in chloroform: nearly insolublea

CAS registry number             96-45-7
-------------------------------------------------------------------
a   From: IARC (1974), IUPAC (1977), US EPA (1984).

2.3.  Analytical Methods

    Residue  analysis  consists  of  sampling  the  contaminated
material,  extracting  the  pesticide residue,  cleaning  up the
extract   of   interfering   substances,  and   identifying  and
quantifying  the pesticide residue.   The main methods  used are
summarized in Table 9.

2.3.1.  Extraction

    Methanol and ethanol have been used as  extraction  solvents
for  biological samples, due  to the high  solubility of ETU  in
polar  solvents.   Mixed  solvents such  as  methanol/chloroform
(Onley  & Yip, 1971) or methanol/acetone (Phillips et al., 1977)
have  also been employed,  and the addition  of  trichloroacetic

acid  has been  reported to  improve recovery  with  the  latter
solvent.   Sodium  ascorbate has  also  been found  effective in
ensuring good recovery of ETU (IUPAC, 1977; Otto et al., 1977).

2.3.2.  Clean-up

    The  simplest procedures involve extraction  of a derivative
from aqueous acid and alkali (Newsome, 1972; Nash,  1974;  King,
1977).   Another approach has been to purify the initial extract
by  column chromatography before proceeding  with derivatization
(Onley  &  Yip,  1971; Haines  &  Adler,  1973; Onley,  1977) or
determination steps (Otto et al., 1977). Where ETU is determined
without  derivatization, a solvent-partitioning step is included
to provide further clean-up (IUPAC, 1977; Otto et al., 1977).

2.3.3.  Derivatization

    In all cases, derivatization involves first an alkylation of
the  thiocarbonyl group.  The various derivatives that have been
used  are given in Table 9.  Careful attention to reagent purity
is  essential to ensure quantitative results (Onley & Yip, 1971;
Pecka  et al., 1975;  King, 1977).  The  benzyl chlorides  react
smoothly  by refluxing in alcohol  for 30 min, while  alkylation
with butyl bromide is carried out at room temperature in aqueous
dimethylformamide   containing   sodium  hydroxide   and  sodium
borohydride.  Solutions of ETU in aqueous dimethylformamide have
been  found  to  be  extremely  unstable  and  must  be  reacted
immediately (Phillips et al., 1977).  The  n-butyl  (Onley & Yip,
1971) and  m-trifluoromethyl  benzyl (King, 1977) derivatives are
sufficiently  volatile  to  be analysed  directly  by gas-liquid
chromatography,   whereas   the   benzyl  derivatives   must  be
concentrated  and acetylated before  quantifying.  Care must  be
exercised  during  the  concentration  step  to  prevent  losses
through  evaporation  (Pecka et  al., 1975).  Pentafluorobenzoyl
chloride  (Nash, 1974) and  trifluoroacetic anhydride have  been
used  as  acetylating reagents,  the  former requiring  a column
chromatographic  step to remove  excess reagent and  by-products
before moving to gas-liquid chromatography.  Although the excess
trifluoroacetic  anhydride is easily removed by evaporation, the
trifluoroacetate  derivative  is  unstable in  the  presence  of
moisture and must be determined soon after removal of the excess
reagent (IUPAC, 1977).

2.3.4.  Determination

    Gas-liquid  chromatographic  methods predominate  because of
their  greater sensitivity, specificity, and  accuracy.  Methods
of determining ETU in plant samples were reviewed in 1976 by the
IUPAC  Commission on Pesticide Terminal  Residues (IUPAC, 1977),
and  an extensive review  of methods for  ETU determination  has
been produced by Bottomley et al. (1985).

2.3.4.1.  Gas-liquid chromatography (GLC)

    A variety of column packings and conditions have  been  used
in the determination of ETU and its derivatives.  Detectors used

include  thermionic (Onley & Yip, 1971), flame photometric (FPD)
(Haines  &  Adler, 1973;  Onley, 1977; Otto  et al., 1977),  and
electron  capture  (EC)  (Nash,  1974;  King,  1977).   Although
quantification  by  GLC/EC enables  the  use of  smaller samples
(5 - 10 g)  for monitoring ETU residues at the 0.01 mg/kg level,
it  requires confirmation of suspected residues by mass spectro-
metry  (MS),  a  second  derivative,  or  by   element-selective
detectors.    Methods  employing  GLC/FPD  with   large  samples
(40 - 100 g)   have  the  advantage  of   both  quantifying  and
confirming ETU residues.

2.3.4.2.  Thin-layer chromatography (TLC)

    A  variety of adsorbents  and developing solvents  have been
used  to detect ETU in  plants (Vonk & Kaars  Sijpesteijn, 1970;
Onley  & Yip, 1971; Blazquez, 1973; Engst & Schnaak, 1974).  The
limit of detection is 0.02 mg/kg using alumina plates and Grotes
reagent   for   visualization   (Onley  &   Yip,  1971).   Semi-
quantitative  determinations are possible by comparison with ETU
standards run simultaneously (IUPAC, 1977).

2.3.4.3.  Polarography

    This  technique  involves  clean-up on  an  alumina  column,
followed  by  paper  chromatography  and  determination  of  the
nitroso derivative by polarography (Engst & Schnaak, 1974).

2.3.4.4.  Radioisotope dilution

    A reverse isotope dilution method has been used to determine
ETU in the presence of its metabolites, and is useful in the low
milligram range (Graham & Bornak, 1973; IUPAC, 1977).

2.3.4.5.  High-pressure liquid chromatography (HPLC)

    High-pressure  liquid chromatography has  been used for  the
determination  of ETU without derivatization.   Detection can be
by  ultraviolet absorption or  electro-conductivity measurement,
the minimum level being 0.025 mg ETU/litre or kg (Prince, 1985).
Massey  et al. (1982)  reported an HPLC  method applied for  ETU
determination  in  a  beer extract  with  a  detection limit  of
10 µg/kg.    The method has been  found to give spuriously  high
results  in the determination of ETU in beer due to the presence
of  co-eluting matrix components.   The more powerful  resolving
ability  of  column-switching high-performance  liquid chromato-
graphy,  using polar-bonded columns of  different selectivities,
has  proved highly effective  in separating ETU  from these  co-
eluting materials.


    
Table 9.  Methods for the determination of ETU in plant samplesa
----------------------------------------------------------------------------------------------------
Extraction   Extraction/      Derivative formation   Analysis           Detect-  Reference
solvent      clean-up                                measurementb       ability
                                                                        (mg/kg)
----------------------------------------------------------------------------------------------------
Plant        ethanol          none                   silica gel/TLC     10.0     Vonk & Kaars Sij-
extract                                                                          pesteijn (1970)

Plant        ethanol          none                   paper electro-     -        Vonk & Kaars Sij-
extract                                              phoresis                    pesteijn (1971)

Ethanol and  cellulose        2-(butylthio) -        GLC/thermionic     0.02     Onley & Yip
chloroform   column           2-imidazoline          detector                    (1971)

Methanol     cellulose                               GLC/FPD            0.002    Watts et al.
             column                                                              (1974)

Methanol     chloroform/                             GLC/ECD            0.005    Newsome (1972)
             HCl

Methanol     Al2O3 column     2-(butylthio)-         GLC/FPD            0.05     Haines & Adler
                              2-imidazoline                                      (1973); Onley
                                                                                 (1977)

Dioxane and  none             none                   silica             -        Blazquez (1973)
water                                                gel/TLC

Methanol/    Al2O3 column     none                   GLC/FPD            0.01     Otto et al.
Na-ascorbate                                                                     (1977)

Table 9 (contd.)
----------------------------------------------------------------------------------------------------
Extraction   Extraction/      Derivative formation   Analysis           Detect-  Reference
solvent      clean-up                                measurementb       ability
                                                                        (mg/kg)
----------------------------------------------------------------------------------------------------

Methanol     florisil         2-(benzylthio)-1-      GLC/ECD            0.005    Nash (1974)
             column           (pentafluorobenzoyl)-
                              2-imidazoline

Ethanol      ether/HCl        2-( m-trifluoromethyl-  GLC/ECD            0.01     King (1977)
             partition        benzylthio)-ETU

Acetone      methanol/        2-(benzylthio)-1-      GLC/ECD            0.01     Newsome (1978)
             acetone;         (pentafluorobenzyl)-
             Al2O3 column     2-imidazoline
             acetonitrile/
             dichloromethane 
             silica column 
----------------------------------------------------------------------------------------------------
a   From: IUPAC (1977).
b   TLC = thin-layer chromatography; GLC = gas-liquid chromatography; FPD = flame photometric 
    detection; ECD = electron capture detection.
3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    During  recent years, much  attention has been  paid to  the
finding that ETU may occur in plant samples following the use of
dithiocarbamate  fungicides.  It may be present in the fungicide
when  applied,  or  may result  from  subsequent  transformation
(Bontoyan et al., 1972).  Similarly, propylenethiourea (PTU) may
occur  in residues of the fungicide propineb (IUPAC, 1977).  The
amounts  of ETU present in commercial formulations vary from one
sample  to  another, and  depend on the  length of time  between
manufacture  and  use  and the  storage  conditions,  especially
temperature and moisture.  Bontoyan & Looker (1973)  found  that
ETU  increased, during  storage for  39 days  at 49 °C  and  80%
relative  humidity, from an  initial content of  0.02 - 2% to  a
final  level  of  0.13 - 14.5%.   The  degradation  dynamics  of
formulations  from  different  manufacturers  varied,   products
containing both manganese and zinc forming the least ETU (IUPAC,
1977).

    ETU  is one of the  important residues in plants  and in the
environment   following   the   agricultural  use   of  ethylene
bisdithiocarbamates  (EBDCs).   It  is also  a metabolite formed
when EBDCs are ingested by animals and man.

    Sources  of human and environmental exposure to ETU are also
discussed in sections 3, 4, and 5 of Part A and sections 4 and 5
of Part B.

4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    ETU is a fairly stable compound with respect  to  hydrolytic
reactions   but  is  easily   oxidized  to  ethyleneurea   (EU).
Oxidation  to EU takes place primarily in biological systems and
by  photolytic reaction, especially  in the presence  of  photo-
sensitizers (Cruickshank & Jarrow, 1973; Ross &  Crosby,  1973).
In  studies by Kaars Sijpesteijn & Vonk (1970), pure cultures of
soil  bacteria and fungi were  unable to effect this  transform-
ation

    After   ultraviolet  irradiation  of  ETU   on  silica  gel,
Cruickshank  &  Jarrow  (1973)  found  nine  secondary  reaction
products.    2-Imidazolidinone   was  identified   as  the  main
degradation  product  and there  were  smaller amounts  of 3-(2-
imidazolin-2-yl)-2-imidazolidinethione  (Jaffe's  base).   Other
secondary  reaction products of the photooxidation of ETU are 2-
imidazoline  and glycine (Ross  & Crosby, 1973)  via the  inter-
mediate hydantoin (IUPAC, 1977) (Fig. 4).

4.1.  Soil

    ETU degradation was found to be slower in  autoclaved  soils
than in non-sterile soils (Kaufman & Fletcher, 1973),  and  only
EU  was  identified.   In  biologically  active  soils,  ETU was
oxidized  to carbon dioxide and four other degradation products,
two  of which  were identified  as hydantoin  and Jaffe's  base.
Degradation  of ETU to carbon  dioxide in non-sterile soils  was
reported by Lyman & Lacoste (1974).  These results indicate that
ETU  is  oxidized  under  both  biological  and   non-biological
conditions to EU, which is considerably more stable than ETU and
can be considered a major breakdown product.  EU,  however,  can
be oxidized photochemically, using a catalyst, to  give  glycine
and  carbon dioxide  (Ross &  Crosby, 1973),  or microbially  in
soil.  In this context, Jaffe's base might be considered  as  an
intermediate product in ETU degradation.

    According  to Lyman & Lacoste (1974) and Rhodes (1977), half
of  the  ETU  (present  at  a  concentration  of  10  mg/kg)  in
Hagerstown silt loam soil was degraded to carbon dioxide  in  22
days.  Normal microbial carbon dioxide production was unaffected
by ETU at this concentration.  Because this value was determined
on the basis of 14C-carbon dioxide formation  from  14C-labelled
precursor,  it does not represent a half-life of ETU, since 14C-
carbon dioxide formation did not parallel the  disappearance  of
labelled  starting material from the soil.  The actual half-life
of ETU is less than one day.

    According to Kaufman & Fletcher (1973), ETU is  oxidized  to
EU, whereas carbon dioxide is only formed slowly.  In Hagerstown
silt loam, ETU at 2 or 20 mg/kg was entirely converted  into  EU
within  2 days, while 200 mg ETU/kg took 8 days.  In contrast, 4
days after treatment of soil with 2, 20, and 200 mg ETU/kg, only
43.4%, 8.9%, and 0.9%, respectively, had been degraded to carbon
dioxide.  A slow but constant conversion of ETU to EU  was  also

found  in  autoclaved  soil,  whereas  the  formation  of carbon
dioxide  was  only  observed  in  non-sterile  soil  (Kaufman  &
Fletcher, 1973; Lyman & Lacoste, 1974).

FIGURE 4

    Rhodes  (1977) found that when  14C-ETU was applied to  soil
sections of Keyport silty loam at a rate of 2.2 kg/ha, total 14C
residues disappeared with a half-life of < 4 weeks.   The  half-
life  of intact ETU was < 1 week.  Most of the radioactivity was
confined to the top 2.5 - 12.5 cm of the soil column,  and  only
small amounts (0.2%) were found at depths of 20 - 30 cm after 12
weeks.   It was concluded from this study that ETU did not leach
to any great extent.

    Nash  & Beall (1980) reported that ETU is weakly adsorbed to
soil,  and is highly  mobile in moist  soil but immobile  in dry
soil.   The presence of  organic matter in  soil seems to  be of
great importance in the leaching of ETU.  Degradation appears to
be  accomplished readily by  both chemical and  biological means
and, thus, ETU does not persist in soil.

    Many studies have been carried out concerning  the  environ-
mental fate and transport of ETU (US EPA, 1984).

    Parallel  results were obtained  in laboratory studies  with
propineb,  which, in a similar fashion, forms PTU, propyleneurea
(PU), and, eventually, carbon dioxide (Vogeler et al., 1977).

    The  results  of  these  studies  show  that,  under  normal
practical  conditions,  it  is unlikely  that  ETU  or PTU  will
accumulate in soil.

4.2.  Water

    ETU is stable in de-ionized water in the absence  of  photo-
sensitizers,  but  is rapidly  oxidized  in their  presence.  In
studies  by Ross & Crosby (1973), several sensitizers were added
at 10 mg/litre to a 25 mg/litre solution of ETU and  exposed  to
sunlight.   After 4 days  with riboflavin as  a sensitizer,  the
concentration  of ETU was  less than 5%  of that in  the control
solution  kept in darkness.  To  minimize microbial degradation,
the procedure was repeated after filtering and boiling the water
samples,  with the same  results.  Furthermore, ETU  degradation
was  investigated  in  several boiled  samples  of  agricultural
drainage water to which 0.5 mg ETU/litre had been  added  before
irradiation.  The results are given in Table 10.

    Numerous  samples  of  natural  water  were  collected  from
rivers,  lakes,  and  agricultural  areas  and,  almost  without
exception,  they were found  to degrade ETU  to EU in  sunlight.
The same samples degraded ETU in the dark but only  after  prior
exposure  to sunlight, indicating that stable photo-oxidants had
been  generated.  The substances  responsible for ETU  oxidation
were  isolated and identified as the amino acids tryptophane and
tyrosine.   The pure amino acids  also caused the conversion  of
ETU  to  EU in  the light, apparently  by their ability  to form
hydroperoxides or other strong oxidants (Ross &  Crosby,  1973).
As  both the amino acids  and photosensitizers such as  acetone,
riboflavin,  and chlorophyll are  known to occur  world wide  in
water  and soil, and this photolysis also has been shown to take
place  rapidly on a silica surface (Cruickshank & Jarrow, 1973),
the degradation of ETU to harmless products in the  field  seems
entirely plausible (IUPAC, 1977).

Table 10.  Photodecomposition of ETU in agricultural 
watersa
--------------------------------------------------------
Source              Irradiation       Remaining ETU (%)
--------------------------------------------------------
Irrigation ditch    3 days, lamp      10 - 20
(sugar beet)        3 days, dark      100

Paddy flooding      24 days, sun      25 - 50
ditch (rice)        24 days, dark     100

Paddy (rice)        24 days, sun      10 - 25
                    24 days, dark     100
--------------------------------------------------------
a   From: Ross & Crosby (1973).

4.3.  Plants

    In  studies in which the roots of corn, lettuce, tomato, and
pepper  seedlings were treated with ETU, it was rapidly absorbed
by roots, translocated subsequently to the foliar  tissues,  and
then  degraded  very rapidly;  virtually  no ETU  was detectable
after 20 days (Hoagland & Frear, 1976).  When cucumber seedlings
were  exposed to aqueous  solutions of nabam  or suspensions  of
zineb  or  maneb,  ETU was  rapidly  absorbed  by the  roots and
translocated within the plants.  ETU appeared to be  stable  for
at  least  2 weeks  in seedlings and,  inside the plant,  a slow
conversion  of ETU into 2-imidazoline was detected (Vonk & Kaars
Sijpesteijn, 1970, 1971).

    In  greenhouse studies, 14C-ETU  was applied either  to  the
soil or to the leaves of 4-week-old potato plants and 8-week-old
dwarf  tomato  plants.   Radioactivity was  monitored in various
parts of the plant at different time intervals.  The application
of 40 mg 14C-ETU/kg to the leaves of potato plants  resulted  in
negligible  radioactivity in the  roots and tubers  60 - 90 days
after  application.  The application  of 17 - 22 kg/ha  to  soil
around the base of the plants resulted in a negligible amount of
radioactivity  in  the  tubers,  roots,  and  foliage  of potato
plants,  60 - 90 days later.   Comparable results were  obtained
with tomato plants, using other dose levels and periods (Lyman &
Lacoste, 1974).

    After systemic uptake of ETU by plants, EU and 2-imidazoline
were  identified as metabolites.  Surface deposits of ETU, which
may  have occurred  as a  result of  EBDC treatment,  formed  an
additional  unidentified  substance  as the  main metabolite and
ethylene  diamine  (EDA).   Propineb  and  PTU  also  formed  an
identical   but  unidentified  major  metabolite  under  similar
conditions (Vogeler et al., 1977).

    Nash  (1975)  reported  the  presence  of  7 - 10  different
degradation products in methanol extracts of soybeans after soil
or  foliar treatment with EBDCs, as well as after treatment with
ETU.  In these cases, EU was a degradation product.

    More recently, Nash & Beall (1980) studied the fate of maneb
and  zineb in microagroecosystem chambers (Part A, section 6.3).
ETU  on the tomato fruit and leaves, and in the soil, water, and
air  was  monitored  for 100  days  after  treatment.   ETU  was
detected  at < 20 µg/kg   on whole fruit  after 3 days,  but had
completely  disappeared after 3 weeks.  The half-life of ETU was
< 3 days.

5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    The  amount of ETU in  commercial formulations of EBDCs  has
been shown to increase with increasing temperature and humidity.
ETU  formation during storage  appears to be  greatest in  maneb
formulations (up to 14%), followed by zineb and  mancozeb.   The
relative  proportions  of  degradation  products  appear  to  be
different for the various EBDCs.

    Studies with propineb on apples and grapes, carried  out  by
Vogeler  et  al.   (1977), showed  that  PTU  could be  detected
shortly  after treatment, and that it was rapidly transformed to
an  unknown metabolite, together with  small amounts of PU,  and
other unidentified reaction products.

5.1. Food and Drinking-Water

    The residue levels of ETU are mainly below 0.1 mg/kg product
following treatment (with different formulations) at the maximum
recommended EBDC levels (Newsome, 1976; Phillips et al., 1977).

    Studies  in Canada and the  USA have shown that  vegetables,
such as spinach, carrots, and potatoes, that have  been  treated
with EBDCs contain high levels of ETU after  cooking  (Blazquez,
1973;  Newsome & Laver,  1973; Watts et  al., 1974).   Snapbeans
treated  with maneb were found  to contain ETU after  commercial
canning  (US EPA, 1977).  Farrow & Ralls (1970) demonstrated the
disappearance of zineb, ziram, and maneb residues  from  spinach
and  apricots during normal canning operations.  There have been
many studies on ETU residues in crops, such as those of  Sato  &
Tomizawa (1960) on zineb-treated cucumbers.

    The  levels of  ETU formed  from residues  of  mancozeb  and
polyram  present on  apples that  were processed  to make  apple
juice,  apple sauce, and  apple pomace were  determined  (IUPAC,
1977).   The results showed  that ETU residues  were  0.17 mg/kg
pomace  and  0.05 mg/kg juice.   A  surprisingly high  level  of
unchanged   mancozeb  remained  in  the   pomace,  despite  heat
treatment  for  15 h  at 150 °C.   However,  it  seems that  ETU
residues diminish during storage.

    Residues of intact 14C-labelled ETU were found  to  diminish
with  time in canned tomato  sauce, spinach, pickles, and  apple
sauce (Rose et al., 1980).  EU and more polar products accounted
for  most of the  14C-labelled residues.  These  polar materials
were resistant to extraction and appeared to be bound.

    A  study sponsored by the US EPA (Phillips et al., 1977), on
the effects of food processing on EBDC residues,  confirmed  and
extended  the  results  previously described.   Washing  the raw
agricultural  products prior to  processing removed 33 - 87%  of
the  EBDC  residue  and the  majority  of  the ETU  residue.  An
interesting   result  was  that  although  almost  instantaneous
conversion of mancozeb to ETU took place in boiling water, field

weathered  residues of mancozeb appeared to be more resistant to
degradation  to  ETU.   A summary  of  the  results for  raw and
processed material is given in Table 3.

5.2.  Monitoring and Market-Basket Studies

    A  monitoring programme initiated  in 1972 by  the  Canadian
government  showed that 33% of food samples contained detectable
ETU  residues.   In particular,  samples  of canned  spinach and
orange  peel  had  average  values  of  0.047 mg/kg  product and
0.083 mg/kg, respectively (Pecka et al., 1975; US EPA, 1977).

    Studies  on the actual level of ETU in products prepared for
commercial  sale  show  it to  be  generally  present  in  small
amounts.   The highest level,  0.61 mg/kg product, was  found in
canned  peaches,  while levels  in  orange peel,  tomato  paste,
instant potatoes, strawberries, peaches, and cucumbers were less
than 0.2 mg/kg product (US EPA, 1982a,b).

    The US EPA has estimated an upper limit for dietary exposure
to  ETU in the general  population of the USA  to be 3.65 µg/kg
body weight per day.  This estimate is a maximum value, since it
was assumed that residues are present at the tolerance level and
that all of the EBDC residue is quantitatively converted to ETU.
Using  actual residue data and experimentally derived conversion
factors,  the US EPA estimated  the dietary intake of  ETU to be
0.24 µg/kg body weight per day.

    In  a market-basket study, over 500 samples of 34 foods were
analysed, plus 26 samples of drinking-water.  No  water  samples
and only 21 of the food samples contained ETU residues (Gowers &
Gordon,   1980).   Exposure  estimates  based  on  market-basket
studies  range  from 0.01  to 1 µg  ETU/kg  body weight per  day
(Gowers & Gordon, 1980; Rose et al., 1980).

    Tomato  products  (203  samples) were  analysed  in  another
market-basket  study, but none  contained ETU (Gowers  & Gordon,
1980).

    A  more  realistic  review of  the  actual  exposure of  the
general  population was obtained by a "table-top" study.  Of 200
meals  (some from homes  and some from  restaurants) which  were
analysed  for ETU, none contained any residues (Gowers & Gordon,
1980).

6.  KINETICS AND METABOLISM

6.1.  Absorption, Distribution, and Excretion

    ETU  is rapidly absorbed from the gastrointestinal tract and
cleared  from the body  in all the  mammalian species that  have
been  tested.  After only  5 min, ETU appeared  in the blood  of
rats administered an oral dose of 100 mg 14C-ETU/kg body weight.
Within  48 h, 82 - 99% of  an oral dose  was eliminated via  the
urine  and  about  3% via the faeces (Kato et al., 1976; Rose et
al.,  1980).  Newsome (1974)  and Ruddick et  al. (1976a)  found
that approximately 70% was eliminated in the urine and 1% in the
faeces.   Comparable  results  were  found  for  mice  while, in
monkeys,  55% was eliminated via the urine within 48 h, and less
than 1.5% via the faeces (Allen et al., 1978).

    To  study the accumulation and  elimination of radioactivity
by  the thyroid gland of rats dosed with 14C-ETU, dose levels of
2  and 200 µg  labelled ETU were administered daily for 14 days.
In another study, rats were dosed with 0, 0.1, 1, 10, 50, or 100
mg 14C-ETU/kg diet, daily, for 7 days.  The first  study  showed
that  the concentration  of ETU  and/or its  metabolites in  the
thyroid  is dose dependent, and the second that the level of 14C
in  the thyroid did not increase appreciably when the daily dose
was increased above 50 mg/kg diet.  Withdrawal of ETU  from  the
diet  led to an 80 - 94%  reduction in the radioactivity  in the
thyroid after 17 days (Lyman & Lacoste, 1974).

    ETU  and its metabolites have been found to have a half-life
of  about  28 h in  monkeys, 9 - 10 h in  rats, and 5 h  in mice
(Rose et al., 1980).

    In  cows  administered  1 mg 14C-ETU/kg diet,  Lyman  (1971)
found  a small quantity of  unchanged ETU in both  the urine and
the  milk  of  the test  animals.   Higher  levels of  14C  were
detectable  in metabolites, such as glycine and urea, and in the
lactose and protein in the milk (Table 11).

6.2.  Metabolic Transformation

    It  has  been demonstrated  that  ETU degradation  leads  to
traces  of EU and other  metabolites in the urine  and that 14C-
carbon  dioxide  is  exhaled  following  the  administration  of
labelled ETU.  Kato et al. (1976) suggested that the metabolites
of  ETU in the rat  were produced primarily by  fragmentation of
the imidazoline ring and decarboxylation of the fourth and fifth
carbon atoms.  A small amount of radioactivity was also found in
a protein fraction of rat fetal tissue.  Ruddick et al. (1976a),
however,  concluded that  ETU metabolism  in the  rat  does  not
appear  to  result  in  any  release  of  14C into  the  general
metabolic  pool.  Mice metabolize  ETU to EU  and other  unknown
metabolites, while cats metabolize it to  S-methyl-ETU and EU.

    Lyman  (1971) detected EU,  EDA, oxalic acid,  glycine,  and
urea  as  major  metabolites in  cow  urine.   In addition,  14C

originating from 14C-ETU was found in the protein and lactose in
the  milk (Table 11).  From  these results, it appears  that the
metabolism  of ETU in ruminants  is different from that  in non-
ruminants.   The  degradation  products  of  ETU  in  plants are
similar to those found in animals.

    A  summary of the secondary metabolites of ETU in biological
and non-biological systems is given in Fig. 4 (Part  B,  section
4).

Table 11.  14C Activity in the milk and urine of 
cows fed with 1 mg 14C-ETUa/kg diet for 6 weeks
------------------------------------------------------
                    Milk                 Urine
Substance    Concentra-  % of      Concentra-   % of
             tion        total     tion         total    
             (mg/litre)  14C       (mg/litre)   14C
------------------------------------------------------
ETU          0.011       31        0.12         7

EU           0.0025      8         0.27         18

EDA          -           -         0.14         14

Glycine      -           -         -            6

Oxalic acid  -           -         -            12

Urea         -           -         -            11

Fat          -           3         -            -

Protein      -           18        -            -

Lactose      -           16        -            -

    Total (%)            76                     68
------------------------------------------------------
a   From: Lyman (1971) and IUPAC (1977).

7.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

    Only  limited information is available on the effects of ETU
on  organisms  in  the  environment,  and  none   is   available
concerning  the impact of  ETU on terrestrial  organisms.   Data
concerning  the toxicity for  aquatic organisms of  ETU and  its
breakdown  product EU are  summarized in Tables  4 and 5.   From
these  results, ETU appears to have a low toxicity for bacteria,
algae,  crustacea,  and  fish.   Because  of  the  low partition
coefficient  (Table  6)  and  rapid  biotransformation  of  ETU,
bioaccumulation  will  be  insignificant or  absent (Van Leewen,
1986).

8.  EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

8.1.  Single Exposures

    Lewerenz et al. (1975) reported an acute oral LD50  for  the
rat of 900 mg/kg body weight.  The values determined by Graham &
Hansen  (1972) and Teramoto et  al. (1978a) were 1832 mg/kg  and
545 mg/kg  body weight, respectively.   Teramoto et al.  (1978a)
reported  values of  3000 mg/kg body  weight for  the mouse  and
> 3000 mg/kg body weight for the hamster.

8.2.  Short- and Long-term Exposures

    Administration  of ETU to laboratory rats causes enlargement
of the thyroid gland.  This effect was noted by Seifter & Ehrich
(1948), and has since been confirmed in various short- and long-
term studies.  The accumulation of ETU in the thyroid  gland  is
associated with biochemical and morphological effects comparable
with   those  induced  by   known  antithyroid  drugs   such  as
thiouracil.

    Graham & Hansen (1972) fed rats with diets containing ETU at
dose  levels  of  0, 50, 100, 500, or 750 mg/kg diet for 30, 60,
90,  or 120 days, and at 100 mg/kg or more, thyroid changes were
seen.   Ross Hart &  Valerio (1973) fed  doses of up  to 1000 mg
ETU/kg  diet to rats.  An increase in thyroid weight was seen at
159 mg/kg or more, and the larger doses produced hyperplasia.

    When Freudenthal et al. (1977) carried out studies  on  rats
at  dose levels of up  to 625 mg ETU/kg diet  for 30, 60, or  90
days, biochemical changes reflecting effects on thyroid function
were  observed.  A  dose of  125 mg/kg diet  produced, after  30
days, a decrease in T3, T4, and serum PBI levels and an increase
in  TSH  concentration.   A dose  of  25 mg/kg  diet produced  a
decrease  in  T4  content after  60  days.   Thyroid weight  was
increased  in all groups receiving  25 mg/kg or more.  After  90
days, tumours (adenomas) were found in the 125 mg/kg group.  The
group receiving 625 mg/kg died within 7 weeks.

    From  these short-term studies, it can be concluded that the
no-observed-adverse-effect  level  lies below  25 mg ETU/kg diet
and  is  probably of  the order of  5 mg/kg diet (equivalent  to
0.25 mg/kg body weight).

8.3.  Teratogenicity

    ETU  was administered orally to  rats and rabbits in  single
daily  doses of 0, 5, 10, 20, 40, or 80 mg/kg body weight.  Rats
were  treated from 21 - 42 days  before conception to day  15 of
pregnancy,  or on days  6 - 15 or 7 - 20  of pregnancy,  whereas
rabbits were treated on days 7 - 21 of pregnancy.  ETU  at  dose
levels   of   10   mg  or   more  induced  meningoencephalocele,
meningorrhagia,  meningorrhea, hydrocephalus, obliterated neural
canal, abnormal pelvic limb posture with equinovarus, and short,
kinky  tail in all rats.   Fetal survival was not  affected, and

fetal  growth was  retarded only  at 40  and 80 mg/kg.   Rabbits
showed  an increased incidence of resorption sites and decreased
brain  weight  at 80 mg/kg  body  weight, but  no  malformations
(Khera, 1973).

    ETU was studied in rats and mice for its ability  to  induce
perinatal  toxicity and in  guinea-pigs and golden  hamsters for
its teratogenic potential.  The ETU was administered  by  gavage
and  during  organogenesis.   Table 12  summarizes  the prenatal
treatments.  Additional postnatal studies were performed on rats
using  extended treatment periods (ETU at 0, 20, 25, or 30 mg/kg
body  weight),  including  continuous  exposure  from  day  7 of
gestation  through parturition to day 15 of lactation.  The pups
were  weaned  normally  and  postnatal  studies  on   open-field
behaviour  were performed  at 6  weeks.  ETU  at  80 mg/kg  body
weight induced maternal toxicity and reduced growth in  the  rat
and  was  teratogenic for  the  rat, inducing  substantial fetal
effects  at all dose levels  above 10 mg/kg body weight.   Gross
defects  were  seen  in the  skeletal  and  the central  nervous
systems,  and cleft palate was noted, mainly at the highest dose
level.    At  20  and   30 mg/kg,  an  increased   incidence  of
hydrocephalus was the only defect noted.  The maternal and fetal
toxicity  of ETU  for the  mouse, guinea-pig,  and  hamster  was
substantially  less than for the  rat.  In mice, at  the highest
dose,  an  increase  in  maternal  liver  weight  and  in  fetal
supernumerary  ribs was noted, but no effects were seen in other
species (Chernoff et al., 1979; FAO/WHO, 1980b).

Table 12.  Summary of prenatal treatmentsa
---------------------------------------------------------
Compound   Species      Dose (mg/kg      Treatment
                        body weight)     (gestation days)
---------------------------------------------------------
ETU        rat          0, 5, 10, 20,    7 - 21
                        30, 40, 80

           mouse        0, 100, 200      7 - 16

           hamster      0, 25, 50, 100   5 - 10

           guinea-pig   0, 50, 100       7 - 25
---------------------------------------------------------
a   Modified from: Chernoff et al. (1979).

    ETU  has  been  found to  induce  a  variety  of  postnatal
effects,  including  reduction  or  absence  of  maternal   milk
production, thereby causing pup mortality at doses  of  30 mg/kg
body  weight  or  more.  However,  no  significant  dose-related
behavioural  abnormalities  were  observed in  ETU-exposed  pups
(Chernoff et al., 1979; FAO/WHO, 1980b).

    In  studies by Khera & Tryphonas (1977), groups of pregnant
rats  were administered  ETU at  dose levels  of 0,  15, 30,  or
45 mg/kg body weight on day 15 of gestation and  then  subjected
to a variety of test conditions to evaluate pre-  and  postnatal

effects.   Postnatal  mortality  occurred in  pups  from mothers
treated  with  dose levels  exceeding  15 mg/kg or  pups  cross-
fostered  to evaluate lactation exposure.  All pups from mothers
treated  with  45 mg/kg died  within 4 weeks  of birth.  A  high
incidence  of hydrocephalus and  microphthalmia was observed  in
pups of mothers treated with 30 mg/kg and these pups died within
6  weeks of  birth.  Motor  defects observed  in some  survivors
(16/65)   of  this  group,  were   shown  to  result  from   the
hydrocephalic condition, which was accompanied by atrophy of the
cerebral  cortex  and  subcortical white  matter.  These defects
were found to be a direct result of  in utero exposure to ETU and
not of exposure during lactation (cross-fostered pups showed the
same effects as pups weaned from treated dams).  When mated with
normal  male  rats, all  female  offspring of  rats administered
30 mg/kg  gave birth to normal offspring.  The F2 generation was
not  impaired,  though  some  of  the  parents  had neurological
defects.   In  these  studies,  no  effects  on  the  parameters
examined   were  observed  at  15 mg/kg  body  weight  (Khera  &
Tryphonas, 1977).

    Teramoto  et al. (1978a) investigated the teratogenicity of
ETU  in rats, mice, and hamsters.  It was teratogenic when given
orally  to rats at 20 - 50 mg/kg body weight per day on days 6 -
15 of pregnancy and to hamsters at 270 - 810 mg/kg  body  weight
per  day on days 6 - 13 of pregnancy.  However, no malformations
were induced in mice up to a daily oral dose of  800 mg/kg  body
weight  when given on  days 7 - 15  of pregnancy.  In  hamsters,
cleft  palate, kinky tail,  oligodactyly, and anal  atresia were
noted  as  gross  external malformations.   Skeletal examination
revealed a high incidence of defects in the ribs  and  vertebral
column,  but  no apparent  defect  was observed  during visceral
examination.  An oral dose of 100 or 200 mg ETU/kg  body  weight
given to pregnant rats consistently produced brain abnormalities
in  the fetuses, when given  on day 12 or  13 of pregnancy,  and
forelimb  abnormalities,  when  given  on  day  13  of pregnancy
(Teramoto   et  al.,  1978a).   Histological   studies  revealed
extensive  cell necrosis in the  brain and forelimbs of  embryos
24 h after the treatment.  These lesions were considered  to  be
the  main cause of the abnormalities observed.  However, neither
malformations nor cell necrosis were found in the  fetuses  that
had been injected with 200 µg  ETU/conceptus into  the  amniotic
sac  on day 12  of pregnancy (Teramoto  et al., 1980).   Studies
with  2-14C-ETU revealed that this  dose was sufficient to  test
the   direct   effects  of   ETU  on  the   embryos,  since  the
incorporation  of radioactive substance was five times higher in
the  embryos injected with 200 µg  into the amniotic sac than it
was  in those embryos  whose mothers were  treated with an  oral
dose of 100 mg/kg body weight (Teramoto et al., 1980).

    The   teratogenic  potential  of  the   ETU  metabolite  1-
methylthiourea  has been investigated by Teramoto et al. (1981).
It  caused almost the same types of malformations in rat fetuses
when given orally to mothers at 250 - 500 mg/kg body  weight  on
day  12  or  day 14  of  pregnancy  as those  observed following

treatment  with ETU.  However,  1-methylthiourea did not  induce
malformations  in mouse fetuses whose mothers were given an oral
dose  of  1000 mg/kg  on  day  10  of  pregnancy.   There  is  a
structural  similarity  between 1-methylthiourea  and ETU:  C=S,
and -NH- groups seem essential for producing teratogenic effects
(Teramoto  et al., 1981).  However,  the structure of ETU  seems
quite specific for the induction of teratogenicity since Ruddick
et  al. (1976b) tested  16 compounds related  to ETU,  including
ethylenethiuram  monosulfide, another metabolite, and  only one,
4-methylenethiourea, was teratogenic.

8.4.  Mutagenicity

    Tests  with a large  number of  S. typhimurium strains  gave
mostly  negative results, though  a few (weak)  positive results
were  observed in  the case  of some  strains of  S.  typhimurium
(Shirasu   et al., 1977). The  addition of rat liver  microsomes
seemed  to enhance the  mutant reversion.  Schüpbach  &  Hummler
(1976,  1977)  concluded that  ETU appeared to  induce base-pair
mutations   but  not  frameshift  mutations   in  S.  typhimurium
TA 1530,    although   frameshift   mutations   appeared   in  S.
 typhimurium TA 98, TA 1537, and TA 1538 when exposed to  ETU  in
the  presence  of  dimethylsulfoxide  (DMSO)  and/or  rat  liver
microsomes (Rose et al., 1980).

    Teramoto  et al. (1977)  did not find  mutagenicity with  S.
 typhimurium TA 1536, TA 1537, TA 1538, G46,  E. coli WP2 hcr+ and
hcr-,  or  B.   subtilis H17  rec+  and  rec-  at  concentrations
of 10 000 µg  ETU/plate.  However, a weak reaction was seen with
 S.    typhimurium TA  1535,  and Seiler  (1974)   reported  weak
(dose-unrelated)  mutagenicity in  S. typhimurium strain G46.

    ETU was also found to be mutagenic in a host-mediated assay
of  S.   typhimurium TA 1530  when  mice were  dosed with 6000 mg
ETU/kg  body weight,  but not  at doses  of 2000  mg/kg or  less
(Schüpbach  & Hummler, 1977).   Cytogenetic effects of  ETU have
been reported in bone marrow cells of mice and Chinese hamsters.
On  the other hand, there was no significant evidence to suggest
that   ETU   was   mutagenic  in   host-mediated   assays  of  S.
 typhimurium G 46 or in tests with other strains of bacteria, rat
bone  marrow (including the  micronucleus test) Chinese  hamster
DON   cells,  rat  lymphocytes,   or  human  fibroblast   cells.
Furthermore,  ETU  did not  increase  the frequency  of dominant
lethal mutations in rodents or  Drosophila melanogaster  (Seiler,
1973,  1974; Schüpbach &  Hummler, 1977; Shirasu  et al.,  1977;
Teramoto et al., 1978b; Rose et al., 1980).  A large  number  of
mutagenicity  tests  are summarized  in a report  of the US  EPA
(1984).

    ETU  has been  tested in  the hepatocyte  DNA repair  test,
which is used to determine pro-carcinogenic potential as well as
DNA  damage.   ETU did  not induce DNA  damage (Althaus et  al.,
1982)  nor cause chromosomal damage in cultured rat liver cells,
and  it  did  not induce  chromatid  exchange  in  CHO  cells  in

 vitro or in mice  in vivo.   A micronucleus test with  mice  bone
marrow  cells  in vivo  also gave  negative results (De  Serres  &
Ashby, 1981).

    This   evidence  indicates  that   ETU  is  generally   not
mutagenic, especially in mammalian test systems.

8.5.  Carcinogenicity

    The  carcinogenicity  of ETU  has  been evaluated  by  IARC
(1974,  1982).  It  was classified  in group  2B, i.e.,  limited
evidence  for activity in short-term  tests; sufficient evidence
for   carcinogenicity   in  animals;   inadequate  evidence  for
carcinogenicity in human beings.

    ETU has been studied for oncogenic potential in mice, rats,
and hamsters.

8.5.1.  Mouse

    In   a  comprehensive  programme  screening  chemicals  for
carcinogenicity, two strains of hybrid mice (X and Y) were given
215  mg  ETU/kg  body  weight  from  day  7 until  weaning,  and
thereafter  646 mg/kg diet for  more than 18  months.  In the  X
strain  [(C57B1/6XC3H/Anf)F1], the incidence of  lung tumours in
the  ETU-treated females  was higher  than that  of the  control
group  (3/18  versus 3/87),  but it was  lower than that  of the
controls (0/16 versus 1/90) in the Y  strain  [(C57B1/6XAKR)F1].
In  the  males,  the incidence  was  higher  in the  ETU-treated
animals  (3/18  versus 1/90).   The  incidence of  lymphomas was
slightly  increased in treated  Y-strain females.  The  hepatoma
incidence   in  the  ETU-treated  groups  of  both  strains  was
significantly  higher than that of  the control group (in  the X
strain,  14/18 and 18/18, for males and females respectively; in
the  Y strain, 18/18 and 9/18; in controls, 0/18 and 3/18).  The
thyroid  glands were not examined  for histopathological changes
(Innes et al., 1969).

    Graham  et  al.  (1975),  found  that  ETU  induced thyroid
hyperplasia  and  other  research  groups  have  confirmed  this
finding.

8.5.2.  Rat

    Ulland  et al.  (1972) and  Weisburger et  al.  (1981)  fed
groups  of  26  male and  female  Charles  River-CD  rats  diets
containing  0, 175, or 350 mg  ETU (97%)/kg diet.  Five  females
and  five males  of the  high-dose group  were killed  after  18
months  and the remainder after 24 months.  Hyperplastic goitre,
solid  cell  adenomas,  and thyroid  (follicular  or  papillary)
carcinomas  were  found.   Two of  the  animals  also  had  lung
tumours, which might have been metastases.  The  thyroid  tumour
incidence  was dose dependant; (in  the 175 mg/kg group,  it was
3/26 and 3/26, for males and females, respectively, and  in  the

350 mg/kg group it was 17/26 and 8/26).  No  thyroid  carcinomas
were observed in the control animals.  A few of the treated rats
had hyperplastic nodules in the liver.

    Graham et al. (1973, 1975) studied the long-term effects on
the  thyroid gland of ETU ingestion.  Five groups of 68 male and
68 female Charles River rats were fed ETU at levels of 0, 5, 25,
125,  250, or 500 mg/kg diet for 2 years.  Growth depression was
evident  at  the highest  dose  level.  The  thyroid/body weight
ratio  was  significantly increased  at  250 and  500 mg/kg, and
slightly  increased  at  125 mg/kg after  24  months.  Thyroidal
uptake of 131iodine per mg tissue was significantly decreased in
male  rats fed  500 mg ETU/kg  diet for  18 or  24 months.   The
thyroids  of females fed at  the three highest dose  levels were
hypofunctioning  at 6 months, and hyperfunctioning at 12 months,
and  at 24 months  thyroid function was  similar to that  of the
controls.  At the two highest dose levels (250  and  500 mg/kg),
thyroid adenomas and carcinomas were induced.  At all lower dose
levels   hyperplasia  occurred  more  frequently   than  in  the
controls, but there were no adenomas or carcinomas.  No increase
in liver tumours was observed in this study.

    Gak  et al. (1976) studied the effects of feeding rats with
0, 5, 17, 60, or 200 mg ETU/kg diet for 24 months.  Body weight,
food consumption, serum enzyme activities (e.g. glutamic pyruvic
transaminase,  alkaline phosphatase), hepatic  enzyme activities
(glutamic pyruvic transaminase, alkaline phosphatase, glucose-6-
phosphate dehydrogenase), cholesterol levels, weights of thyroid
and    other   organs,   and   histopathology    were   studied.
Hypercholesterolemia  was found at  dose levels of  5 mg/kg  and
above.  At 60 mg/kg or more, a significant increase  in  thyroid
tumours  was found, but at lower levels the tumour incidence was
not significantly different from that of the controls.

8.5.3.  Hamster

    Gak  et  al.  (1976) studied the effect of 0, 5, 17, 60, or
200 mg  ETU/kg diet  on hamsters  for 18  months.  Growth,  food
intake,  biochemical parameters in  the serum and  liver,  organ
weights,  and histology were studied.  A significant increase in
thyroid  tumours was found at 60 mg ETU/kg or more, but at lower
doses  values were not significantly different from those of the
control group.

8.6.  ETU in Combination with Nitrite

    When the mutagenicity of ETU was assayed before  and  after
nitrosation   with   sodium   nitrite  under   acid  conditions,
nitrosation was found to cause a 160-fold increase in the number
of  revertant  colonies  of  S.   typhimurium TA 1535 (Shirasu et
al., 1977).  The interactive mutagenicity of ETU and nitrite was
also  found in the mouse dominant lethal test by Teramoto et al.
(1978b).   However, no dominant-lethal mutations were induced in
a  group of mice treated  with 30 mg ETU  plus 10 mg  nitrite/kg
body  weight.  A large  increase in pre-implantation  losses was

noted  5 and 6 weeks after completing a 5-day treatment of males
with  a  combined oral  dose of 150 mg  ETU/kg and 50 mg  sodium
nitrite/kg body weight.

8.7.  Mechanisms of Toxicity; Mode of Action

    The   biochemical  changes  induced  by  antithyroid  drugs
include  reduced  production of  thyroid  hormones (T3  and T4),
followed  by increased  production of  TSH in  response  to  low
thyroid  hormone levels in  the blood.  Pathological  changes in
the  thyroid  gland  begin with  diffuse  microfollicular hyper-
plasia,  and are followed by diffuse and nodular hyperplasia and
later by nodular hyperplasia with papillary and  cystic  changes
induced by the TSH.  If hyperstimulation of the thyroid  by  TSH
is severe and prolonged, it provides conditions conducive to the
formation of tumours.

      Antithyroid drugs can  inhibit T4 production  in  various
ways.  The chemical similarity of ETU to thiourea and thiouracil
suggests that ETU acts by blocking the iodination  of  thyroxine
precursors, thus reducing the synthesis of the thyroid hormones.
Iodide peroxidase catalyses the iodination of tyrosine  and  the
coupling  of the resultant  iodotyrosyl residues to  produce the
active hormones T3 and T4.

    Graham   &   Hansen   (1972)  found   that   ETU  inhibited
iodide  peroxidase   in vitro.   The resulting decreased level of
thyroid  hormones causes stimulatory  feedback of the  pituitary
gland and consequently an increased release of TSH (Rose et al.,
1980).

    Lu  &  Staples  (1978) studied  the  influence  of  ETU  in
pregnant hypothyroid and euthyroid rats to determine whether ETU
teratogenicity  occurs as a  result of altered  maternal thyroid
function.   Doses of 40 mg  ETU/kg body weight,  administered on
days 7 - 15 of gestation, resulted in 84 - 100% of  the  fetuses
in all treated groups being malformed, regardless of the thyroid
status  of the  dams.  The  authors concluded  that the  thyroid
status of the mother is not of importance in causing teratogenic
effects.

    Rose  et al. (1980)  reported that the  effects of  feeding
rats 125 - 625 mg ETU/kg diet for 2 - 12 weeks,  which  included
thyroid hyperplasia and dose related suppression of serum T3 and
T4 (with corresponding TSH elevation), were reversible within 22
weeks of placing on control diets.

    Long-term  studies using ETU showed significantly increased
thyroid/body  weight ratios in rats  fed 125, 250, or  500 mg/kg
diet for periods of up to 2 years (Graham et al.,  1975).   This
effect was not reversed in rats placed on a control  diet  after
66 weeks of continuous exposure to 5 - 500 mg ETU/kg  diet.   It
is likely that by that time the thyroid was severely damaged.

    In  studies by Arnold et al. (1982, 1983), decreased levels
of  serum thyroid hormones  and increased thyroid  weights  were
reversed in Sprague Dawley rats fed diets containing 0, 75, 100,
or  150  mg  ETU/kg diet  for  7  weeks.  The  reversibility  of
microscopic  changes in the thyroids of male rats exposed to ETU
was  studied.  The rats were  fed diets containing 75  or 150 mg
ETU/kg diet for 7 - 82 weeks and then returned to a control diet
for periods ranging from 2 to 42 weeks.  The severity and extent
of  reversibility of thyroid hyperplasia were found to depend on
the  duration of exposure  to ETU.  Above  a certain  threshold,
hyperplasia did not regress significantly.

    Numerous  studies with  ETU suggest  that the  rat is  more
sensitive than other species to the effects of the  thyroid.   A
recent study with propylthiouracil, a thyroid inhibitor  with  a
mode  of  action  similar to  that  of  ETU, has  confirmed that
monkeys  are  much less  sensitive  than rats.   The sensitivity
difference   was   not   quantified  in  vivo,  but,   in   an  in
 vitro study,  the concentration of inhibitor required to produce
the   same   level   of  thyroid   peroxidase   inhibition   was
approximately  100 times greater for  monkey enzyme than it  was
for rat enzyme (Takayama et al., 1986).

8.8.  Propineb and Propylenethiourea (PTU)

8.8.1.  General

    The toxicology of propineb was reviewed at JMPR meetings in
1977,  1980, and 1983.  Because of concern expressed at the 1977
meeting   regarding   the   potential  for   thyrotoxicity   and
tumourigenicity  of propylenethiourea (PTU), a breakdown product
of propineb, the meeting estimated only a temporary ADI for man.
Further  evaluation  of  propineb  was  postponed  pending   the
submission of additional data.  Data submitted for evaluation in
1985  consisted of long-term mouse and rat studies, mutagenicity
studies, and a special study into the effects of PTU on DNA.  In
addition,  data previously submitted for evaluation in 1983 were
re-examined.   These data included  several studies on  propineb
(acute  toxicity studies, a short-term study on thyroid function
in  rats,  mutagenicity studies,  and  an oncogenicity  study on
mice)  and on PTU (pharmacokinetic studies on rats and  a  long-
term thyroid function study on rats)  (FAO/WHO, 1986a,b).

8.8.2.  Toxicological information

    An  oncogenicity  study  on mice  with  propineb  indicated
increased  hepatocellular  adenomas  in male  mice and increased
pulmonary adenomas in female mice at 800 mg/kg diet, the highest
dose level tested. Thyroid tumours were not induced  in  treated
mice in this study.  A no-observed-adverse-effect level for non-
neoplastic  effects could not be determined in this study, owing
to insufficient data (FAO/WHO, 1986a, b).

    In  a long-term study into  the effects of PTU  on mice, an
increased  incidence in male mice of hepatocellular adenomas was
observed  at 1000 mg/kg diet (the highest dose level tested) and
of hepatocellular carcinomas at 10 mg/kg diet or more.   In  the
same  study, increased incidences of hepatocellular adenomas and
carcinomas  were observed in  female mice at  100 mg/kg diet  or
more.   Thyroid tumours attributable  to PTU were  not observed,
but increased thyroid hypercellularity was noted in male mice at
1000 mg/kg diet (FAO/WHO, 1986a, b).

    In long-term rat studies with propineb, previously reviewed
by  the JMPR, an increased  incidence of benign thyroid  tumours
was observed at 1000 mg/kg diet or more.  Non-neoplastic thyroid
effects  were observed in  the same study  at 100 mg/kg  diet or
more.  In another study, increased liver and kidney weights were
observed  at 100 mg/kg diet  or more and a  no-observed-adverse-
effect  level of 10 mg/kg  diet was determined.  In  a long-term
study   on  the  effects  of   PTU  on  rats,  thyroid   tumours
attributable  to  PTU  were  only  found  at  1000  mg/kg  diet.
Goitrogenic  effects in the  thyroid were observed,  however, at
dose  levels  as  low as  1  mg/kg  diet, the  lowest dose level
tested.    A  no-observed-adverse-effect  level  could   not  be
determined in this study (FAO/WHO, 1986a, b).

    Short-term  studies on the  effects of propineb  on thyroid
function in rats did not establish an  unequivocal  no-observed-
adverse-effect level for effects on the thyroid.  In a long-term
study  with PTU, effects  on thyroid function  were observed  at
1000  mg/kg  diet,  but  at  lower  dose  levels  effects   were
ambiguous.    Pharmacokinetic   studies  on   rats  demonstrated
preferential  uptake of radioactivity  from 14C-labelled PTU  by
the thyroid (FAO/WHO, 1986a, b).

    Mutagenicity  studies on propineb and PTU produced negative
or  inconclusive  results.   However,  PTU  has  been  shown  to
increase  DNA synthesis in  mouse spleen cells,  but it did  not
bind to mouse liver cell DNA.

    In view of the carcinogenic response to PTU in the liver of
mice  and the lack of a no-observed-adverse-effect level for the
effects  of propineb on the thyroid in a long-term study on mice
or short-term studies on rats, or for PTU in a  long-term  study
on  rats,  the  JMPR recommended  that  the  temporary  ADI  for
propineb should be withdrawn.

    In view of the established carcinogenic potential  of  this
compound,  the meeting recommended  that propineb should  not be
used where its residues can arise in food (FAO/WHO, 1986a,b).

9.  EFFECTS ON MAN

9.1.  Epidemiological Studies 

    Smith  (1976)  conducted  a detailed  study  involving 1929
workers in rubber-compounding plants in Birmingham, England.  No
thyroid  cancers  were  found in  the  health  records of  these
workers.

    Clinical  examinations  and  thyroid  function  tests  were
carried  out over a period  of 3 years on  eight process workers
and  five  mixers  in a  factory  producing  ETU in  the  United
Kingdom.   Matched  controls  were also  examined.   The results
showed that the exposed mixers, but not the process workers, had
significantly  lower levels of T4  in their blood compared  with
the  controls.  No effect  was found on  TSH or  thyroid-binding
globulin (Smith, 1984).

PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    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  for various
dithiocarbamates  on several occasions.   Annex III includes  an
overview of the JMPR meetings in which these compounds, ETU, and
PTU  have been evaluated,  with their references,  together with
the WHO recommended classification of pesticides by  hazard  for
individual  dithiocarbamates.  The existence of IARC evaluations
and  the availability  of WHO/FAO  Data Sheets  and  IRPTC  Data
Profiles  and Legal Files  are also indicated.   These documents
include  more detail concerning  the product and  legal aspects,
toxicological    evaluation,   and   residues    of   individual
dithiocarbamates in different food items.

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 reaction  by the rat. ]  Terborg, The Netherland, Fa. Lammers (in
Dutch).

VAN STEENIS, G. & VAN LOGTEN, M.J.  (1971)  Neurotoxic effect of
the  dithiocarbamate tecoram on the chick embryo.  Toxicol. appl.
 Pharmacol., 19: 675-686.

VEKSHTEIN,  M.SH. & KHITSENKO, I.L.  (1971)  Ziram metabolism in
warm-blooded animals.  Gig. i Sanit., 36: 28-33.

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

VOGELER,  K., DREZE, Ph., RAPP, A., STEFFAN, H., & ULLEMEYER, H.
(1977)   Distribution and metabolism  of propineb in  apples and
grapes, including their breakdown products propylenethiourea and
ethylenethiourea  in apples.   Pflanzenschutz-Nachrichten  Bayer
30: 72-97.

VONK,  J.W. & KAARS SIJPESTEIJN, A.  (1970)  Studies on the fate
in  plants  of  ethylene bisthiocarbamate  fungicides  and their
decomposition products.  Ann. appl. Biol., 65: 489-496.

VONK,   J.W.   &   KAARS  SIJPESTEIJN,   A.   (1971)   Tentative
identification  of 2-imidazoline as a  transformation product of
ethylenebisdithiocarbamate      fungicides.   Pestic.    Biochem.
 Physiol., 1: 163-165.

VONK,  J.W.  &  KAARS  SIJPESTEIJN,  A.   (1976)   Formation  of
ethylenethiourea    from    5,6-dihydro-3 H-imidazo[2,1-C]-1,2,4-
dithiazole-3-thione  by  microorganisms and  reducing agents.  J.
 environ. Sci. Health, B11: 33-47.

WATTS, R.R., STORHERR, R.W., & ONLEY, J.H.  (1974)   Effects  of
cooking    on   ethylene   bisdithiocarbamate   degradation   to
ethylenethiourea.  Bull. environ. Contam. Toxicol., 12: 224-226.

WEDIG, J., COWAN, A., & HARTUNG, R.  (1968)  Some of the effects
of  tetramethylthiuram disulfide (TMTD)  on reproduction of  the
bobwhite quail  (Colinus virginianus).  Toxicol. appl. Pharmacol.,
12: 293.

WEISBURGER,  E.K.,  ULLAND,  B.M.,  NAM,  J.M.,  GART,  J.J.,  &
WEISBURGER,  J.H.   (1981)   Carcinogenicity  tests  of  certain
environmental  and  industrial chemicals.  J.  Natl Cancer Inst.,
67: 75-88.

WHO   (1986a)   The WHO recommended  classification of pesticides
 by hazard. Guidelines to classification 1986-1987, Geneva, World
Health Organization (Unpublished report VBC/86.1, rev. 1).

WHO   (1986b)   Environmental   Health  Criteria   64:  Carbamate
 pesticides:   a  general  introduction,   Geneva,  World  Health
Organization, pp. 137.

WHO  (1988)   Environmental   Health Criteria  76:  Thiocarbamate
 pesticides:   a  general  introduction,   Geneva,  World  Health
Organization, pp. 49.

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

YIN-TAK   WOO    (1983)    Carcinogenicity,  mutagenicity,   and
teratogenicity   of  carbamates,  thiocarbamates,   and  related
compounds.  An overview of structure-activity  relationships and
environmental concerns.  J. environ. Sci. Health, C1(1): 97-133.

ZADOROZHNY, B.A., PETROV, B.R., OLTIRENKO, V.A., & KIRILKO, V.A.
(1981)    [Occupational  dermatoses  and  their   control  under
conditions  of pesticide manufacture.]  Vestn Dermatol. Venerol.,
6: 48-51 (in Russian).

ZDIENICKA,  M., ZIELENSKA, M., HRYMIEWICA,  M., TROJANOWSKA, M.,
ZALEJSKA,  M., & SZYMCZYK, T.   (1981)  The mutagenicity of  the
fungicide  thiram. In: Kappas, A., ed.  Progress in environmental
 mutagenesis  and  carcinogenesis, Amsterdam,  Oxford, New  York,
Elsevier Science Publishers, Vol. 2, pp.  79-86.

ZORIN, P.M.  (1970)  [Allergic dermatitis arising as a result of
contact  with  zineb.]  Vestn  Dermatol. Venerol., 44:  65-68 (in
Russian).

ZUMAN, P. & ZAHRADNIK, R.  (1957)  [Kinetics  and  decomposition
mechanism  of  dithiocarbamic  acids  solutions.   Polarographic
study.]  Z. Phys. Chem., 208: 135-140 (in German).


Annex I.  Names and structures of selected dithiocarbamates
--------------------------------------------------------------------------------------------------------
Common    Trade/other   Chemical structure            CAS chemical name/    Molecular    Relative  Water
name      name                                        CAS registry number   formula      mole-     solu-
                                                                                         cular     bility
                                                                                         mass      (25°C)
---------------------------------------------------------------------------------------------------------
dibam     Methylnamate          S                     sodium dimethyldi-    C3H6NS2Na    143.21
                                ||                    thiocarbamate
                        (CH3)2N-C-SNa                 (128-04-1)

disul-    Antabuse              S    S                tetraethylthiuram     C10H20N2S4             2 mg/      
firam                           ||   ||               disulfide                                    litrea
                        (C2H5)2NC-SS-CN(C2H5)2        (29925-58-4)

ferbam    Fermate                S                    iron, tris(dimethyl-  C9H18FeN3S6  416.51    130         
          Fuklasin               ||                   carbamodithioato-                            mg/litre
          Hokmate       [(CH3)2N-C-S-]3Fe              S,S' )-,
          Karbam Black                                (14484-64-1)
          Niacide

mancozeb  Aazimag                                     manganese, [[1,2-     indefinite,            insol-
          Fore          [-SCSNHCH2CH2NHCSSMn-]x(Zn)y  ethanediylbis-[carba- variable               uble
          Dithane M-45                                modithioato]](2-)]-,
          Manzate 200                                 in combination with
                                                      [[1,2-ethanediylbis-
                                                      [carbamodithioato]]-
                                                      (2-)]zinc
                                                      (8018-01-7)

maneb     Amazin                                      manganese, [[1,2-     C4H6MnN2S4   265.29    insol-
          Blitex        [-SCSNHCH2CH2NHCSS-Mn-]x      ethanediylbis-                               uble
          Dithane M-22                                [carbamodi-     
          Manzate                                     thioato]](2-)]       
          Martemick                                   (12427-38-2)
          Mancid
          Tubothane

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

Annex I.  (contd.)
---------------------------------------------------------------------------------------------------------
Common    Trade/other   Chemical structure            CAS chemical name/    Molecular    Relative  Water
name      name                                        CAS registry number   formula      mole-     solu-
                                                                                         cular     bility
                                                                                         mass      (25°C)
---------------------------------------------------------------------------------------------------------
metam-    Carbam              S                       carbamodithioic       C2H4NaNS2    129.18    722
sodium    Masposol            ||                      acid, methyl-,                               mg/
          Sistan        CH3NH-C-S- Na+                sodium salt                                  litreb
          Trapex                                      (137-42-8)
          Vapam

metiram   Zinc-metiram                                ammonia complex of    indefinite,            insol-
          Polyram                                     zineb and poly        variable               uble
                                                      (ethylene thiuram
                                                      disulfide),
                                                      zineb ethylene   
                                                      thiuram disulfide
                                                      (9006-42-2)      

nabam     Nabasan              S           S          carbamodithioic acid, C4H6Na2N2S4  256.34    200 g/
          Parzate              ||          ||         1,2-ethanediylbis-,                          litre
          Spring-Bak    Na+ -S-C-NHC2H4-NH-C-S- Na+   disodium salt
                                                      (142-59-6)

polyram (see metiram)

propineb  Antracol          S            S            zinc, [[(1-methyl-    C5H8N2S4Zn   289.9     insol-
          Cypromate         ||           ||           1,2-ethanediyl)-bis                          uble 
          Mezineb       [-S-C-NHCH2CH-NH-C-S-Zn-]x    [carbamodithioato]]
                                   |                  (2-)]-,            
                                   CH3              (12071-83-9)

sulfal-   Vegadex                S                    carbamodithioic acid, C8H14NClS2   223.8     92 mg/
late      CDEC                   ||                   diethyl-, 2-chloro-                          litre
                        (C2H5)2N-C-S-CH2-C=CH2        2-propenyl ester
                                         |            (95-06-7)
                                         Cl
---------------------------------------------------------------------------------------------------------

Annex I.  (contd.)
---------------------------------------------------------------------------------------------------------
Common    Trade/other   Chemical structure            CAS chemical name/    Molecular    Relative  Water
name      name                                        CAS registry number   formula      mole-     solu-
                                                                                         cular     bility
                                                                                         mass      (25°C)
---------------------------------------------------------------------------------------------------------
thiram    Arasan                S     S               thioperoxydicarbonic  C6H12N2S4    240.44    30 mg/
          Cyuram                ||    ||              diamide, tetramethyl                         litre
          Fernasan      (CH3)2N-C-S-S-C-N(CH3)2       (137-26-8)
          Mercuram
          Normersan
          TMTD

zineb     Aspor-Z           S           S             zinc, [[1,2-ethane-   C4H6N2S4Zn   275.73    10 mg/
          Carbane           ||          ||            diylbis[carbamodi-                           litre
          Dithane-Z78   [-S-C-NHC2H4-NH-C-S-Zn-]x     thioato]](2-)]-
          Lonacol                                     (12122-67-7)
          Murphane
          Novozir
          Parzate
          Perozine 75B
          Sudothane
          Zebenide
          Zelmone

ziram     Cuman                  S                    zinc, bis(dimethyl-   C6H12N2S4Zn  305.81    65 mg/
          Fuklasin               ||                   carbamodithioato-                            litre
          Milbam        [(CH3)2N-C-S-]2Zn              S,S')-
          Zerlate                                     (137-30-4)
---------------------------------------------------------------------------------------------------------
a  At 38 °C.
b  At 20 °C.


Annex II.  Names and structures of degradation products of ethylene 
bisdithiocarbamates
-------------------------------------------------------------------------------------
Common name        Chemical     CAS chemical name/              Molecular  Relative
                   structure    CAS registry number             formula    molecular
                                                                           mass
-------------------------------------------------------------------------------------
Ethylenethiourea   CH2-NH       2-imidazolidinethione           C3H6N2S    102.2
(ETU)              |    \       (96-45-7)
                   |     C=S
                   |    /
                   CH2-NH


                          S
                          ||
                          C-S
DIDT                    /   |   5,6-dihydro-3- H-imidazo[2,      C4H4N2S3   176.3
                   CH2-N    |   1-C]1,2,4-dithiazole-3-thione,
                   |    \   |   (33813-20-6)
                   |      C-S
                   |    //
                   CH2-N


                          S
                          ||
                   CH2-NH-C-S
Ethylenethiuram    |        |   1,2,4,7-dithiadiazocine-        C4H6N2S4   210.3
disulfide (ETD)    |        |   3,8-dithione, tetrahydro
                   CH2-NH-C-S   (3082-38-0)
                          ||
                          S
-------------------------------------------------------------------------------------


Annex III. Dithiocarbamates and ETU: JMPR reviews, ADIs, Evaluation by IARC, Classification by Hazard, 
WHO/FAO Data Sheets, IRPTC Data Profile and Legal Filea
--------------------------------------------------------------------------------------------------------
Compound    Year   ADIb                  Evaluation   IARCd        Availability    WHO recom-    WHO/FAO     
            of     (mg/kg                by JMPRc:    Evaluation     of IRPTCe:    mended clas-  Data    
            JMPR   body                  Published    of Carcino-  Data    Legal   sification    Sheets  
            meet-  weight)               in:          genicity     Profile fileg   of pesticides on Pest-
            ing                          FAO/WHO                                   by hazardh    icidesf 
--------------------------------------------------------------------------------------------------------
Ferbam      1983   0-0.02                1984a        Vol. 12      +       +       0
                                                      page 121
            1980   0-0.02                1981b        Vol. 13
                                                      page 243
                                         1981a          
                                                            
            1977   0-0.02                1978b
                                         1978a
            1974   0-0.05                1975b
                   (temporary)
                   (sum of all di-       1975a
                   thiocarbamates)
            1970   0-0.025               1971b
                   (temporary)
                   (applicable to the    1971a
                   parent compounds
                   only, and to the sum
                   of all the dithio-
                   carbamate fungicides
                   if more than one is
                   present)
            1967   0-0.025               1968b
                   (temporary)
                   (alone or in com-     1968a
                   bination with other
                   dimethyl-dithiocar-
                   bamates (thiram and
                   ziram))
            1965   no ADI                1965b
                                         1965a
            1963   no ADI                1964
--------------------------------------------------------------------------------------------------------

Annex III. (contd.)
--------------------------------------------------------------------------------------------------------
Compound    Year   ADIb                  Evaluation   IARCd        Availability    WHO recom-    WHO/FAO     
            of     (mg/kg                by JMPRc:    Evaluation     of IRPTCe:    mended clas-  Data    
            JMPR   body                  Published    of Carcino-  Data    Legal   sification    Sheets  
            meet-  weight)               in:          genicity     Profile fileg   of pesticides on Pest-
            ing                          FAO/WHO                                   by hazardh    icidesf 
--------------------------------------------------------------------------------------------------------
Mancozeb    1983   0-0.05i               1984a                     +       +       0
            1980   0-0.05i (indivi-      1981b
                   dually of the sum     1981a
                   of mancozeb, maneb,
                   and zineb)
            1977   0-0.005               1978b
                   (temporary)
                   (sum of mancozeb,     1978a
                   maneb, and zineb)
            1974   0-0.005               1975b
                   (temporary)
                   (sum of dithio-       1975b
                   carbamates)           1975b
                                         1975a
            1970   0-0.025               1971b
                   (temporary)
                   (applicable to the    1971a
                   parent compound
                   only, and the sum
                   of all the ethylene
                   bisdithiocarbamate
                   fungicides if more
                   than one is present)
            1967   0-0.025               1968b
                   (temporary)
                   (alone or in com-     1968a
                   bination with
                   other ethylene
                   bisdithiocarbamates
                   (maneb and zineb),
                   including zineb
                   derived from nabam
                   plus zinc sulfate)
--------------------------------------------------------------------------------------------------------

Annex III. (contd.)
--------------------------------------------------------------------------------------------------------
Compound    Year   ADIb                  Evaluation   IARCd        Availability    WHO recom-    WHO/FAO     
            of     (mg/kg                by JMPRc:    Evaluation     of IRPTCe:    mended clas-  Data    
            JMPR   body                  Published    of Carcino-  Data    Legal   sification    Sheets  
            meet-  weight)               in:          genicity     Profile fileg   of pesticides on Pest-
            ing                          FAO/WHO                                   by hazardh    icidesf 
--------------------------------------------------------------------------------------------------------
Maneb       1983   0-0.05i               1984a                     +       +       0
            1980   0-0.05                1981b
                   (individual or        1981a        Vol. 12
                   the sum of manco-                  page 137
                   zeb, maneb, and
                   zineb)
            1977   0-0.005               1978b
                   (temporary)
                   (sum of manco-        1978a
                   zeb, maneb, and
                   zineb)
            1974   0-0.005               1975b
                   (temporary)
                   (sum of all di-       1975a
                   thiocarbamates)
            1970   0-0.025               1971b
                   (temporary)
                   (applicable to the    1971a
                   parent compound
                   only, and to the
                   sum of all the di-
                   thiocarbamate fung-
                   icides if more than
                   one is present)
            1967   0-0.025               1968b
                   (temporary)
                   (alone or in com-     1968a
                   bination with
                   other ethylene
                   bisdithiocarbamates
                   (mancozeb and zineb)
                   including zineb
                   derived from nabam
                   plus zinc sulfate)
--------------------------------------------------------------------------------------------------------

Annex III. (contd.)
--------------------------------------------------------------------------------------------------------
Compound    Year   ADIb                  Evaluation   IARCd        Availability    WHO recom-    WHO/FAO     
            of     (mg/kg                by JMPRc:    Evaluation     of IRPTCe:    mended clas-  Data    
            JMPR   body                  Published    of Carcino-  Data    Legal   sification    Sheets  
            meet-  weight)               in:          genicity     Profile fileg   of pesticides on Pest-
            ing                          FAO/WHO                                   by hazardh    icidesf 
--------------------------------------------------------------------------------------------------------
Maneb       1965   no ADI                1965b
(contd.)                                 1965a
            1963   no ADI                1964

Nabam       1983   no ADI                1984a                     +       +       II
            1977   no ADI                1978b
                                         1978a
            1974   0-0.005               1975b
                   (temporary)
                   (sum of all di-       1975a
                   thiocarbamates)
            1970   0-0.025               1971b
                   (temporary)
                   (applicable to the    1971a
                   parent compound
                   only, and to the
                   sum of all the di-
                   thiocarbamate fung-
                   icides if more than
                   one is present)
            1967   0-0.025               1968b
                   (temporary)           
                   (as nabam alone       1968a
                   or in combination
                   with other ethylene
                   bisdithiocarbamates
                   (mancozeb, maneb,
                   and zineb) including
                   zineb derived from
                   nabam plus zinc
                   sulfate)
            1965   no ADI                1965b
                                         1965a
            1963   no ADI                1964
--------------------------------------------------------------------------------------------------------

Annex III. (contd.)
--------------------------------------------------------------------------------------------------------
Compound    Year   ADIb                  Evaluation   IARCd        Availability    WHO recom-    WHO/FAO     
            of     (mg/kg                by JMPRc:    Evaluation     of IRPTCe:    mended clas-  Data    
            JMPR   body                  Published    of Carcino-  Data    Legal   sification    Sheets  
            meet-  weight)               in:          genicity     Profile fileg   of pesticides on Pest-
            ing                          FAO/WHO                                   by hazardh    icidesf 
--------------------------------------------------------------------------------------------------------
Propineb    1985   ADI withdrawn         1986b                                     0
            1984   0-0.005               1985b
                   (temporary)
            1983   0-0.005               1984b
                   (temporary)
            1980   0-0.005               1981b
                   (temporary)
            1977   0-0.005               1978b

Thiram      1983   0-0.005               1984a        Vol. 12      +       +       III
                   (temporary)                        page 225
            1980   0-0.005               1981b
                   (temporary)           1981a
            1977   0-0.005               1978a
                   (temporary)
            1974   0-0.005               1975b
                   (temporary)
                   (sum of all           1975a
                   dithiocarbamates)
            1970   0-0.025               1971b
                   (temporary)
                   (applicable to the    1971a
                   parent compound
                   only, and to the
                   sum of all the di-
                   thiocarbamate fung-
                   icides if more than
                   one is present)
            1967   0-0.025               1968b
                   (temporary)
                   (alone or in com-     1968a
                   bination with
                   other dimethyl di-
                   thiocarbamates
                   (ferbam and ziram))
--------------------------------------------------------------------------------------------------------

Annex III. (contd.)
--------------------------------------------------------------------------------------------------------
Compound    Year   ADIb                  Evaluation   IARCd        Availability    WHO recom-    WHO/FAO     
            of     (mg/kg                by JMPRc:    Evaluation     of IRPTCe:    mended clas-  Data    
            JMPR   body                  Published    of Carcino-  Data    Legal   sification    Sheets  
            meet-  weight)               in:          genicity     Profile fileg   of pesticides on Pest-
            ing                          FAO/WHO                                   by hazardh    icidesf 
--------------------------------------------------------------------------------------------------------
Thiram      1965   0-0.025               1965b
(contd.)                                 1965a
            1963   0-0.025               1964

Zineb       1983   0-0.05i               1984a        Vol. 12      +       +       0
            1980   0-0.05                1981b        page 245
                   (individually         1981a
                   or the sum of
                   mancozeb, maneb,
                   and zineb)
            1977   0-0.005               1978b
                   (temporary)
                   (sum of mancozeb,     1978a
                   maneb, and zineb)
            1974   0-0.005               1975b
                   (temporary)
                   (sum of all di-       1975a
                   thiocarbamates)
            1970   0-0.025               1971b
                   (temporary)
                   (applicable to the    1971a
                   parent compound
                   only, and to the
                   sum of all the di-
                   thiocarbamate fung-
                   icides if more than
                   one is present)
            1967   0-0.025               1968b
                   (temporary)
            1967   (alone or in com-     1968a
                   bination with
                   other ethylene
                   bisdithiocarbamates
                   (mancozeb and maneb)
                   including zineb
                   derived from nabam
                   plus zinc sulfate)
--------------------------------------------------------------------------------------------------------

Annex III. (contd.)
--------------------------------------------------------------------------------------------------------
Compound    Year   ADIb                  Evaluation   IARCd        Availability    WHO recom-    WHO/FAO 
            of     (mg/kg                by JMPRc:    Evaluation     of IRPTCe:    mended clas-  Data        
            JMPR   body                  Published    of Carcino-  Data    Legal   sification    Sheets  
            meet-  weight)               in:          genicity     Profile fileg   of pesticides on Pest-
            ing                          FAO/WHO                                   by hazardh    icidesf 
--------------------------------------------------------------------------------------------------------
Zineb       1965   no ADI                1965b
(contd.)                                 1965a
            1963   no ADI                1964

Ziram       1983   0-0.02                1984a        Vol. 12      +       +       III           No. 73 
                                                      page 259                                   (in 
                                                                                                 prepar-
                                                                                                 ation)
            1980   0-0.02                1981b
                                         1981a
            1977   0-0.02                1978b
                                         1978a
            1974   0-0.005               1975b
                   (temporary)
                   (sum of all di-       1975a
                   thiocarbamates)
            1970   0-0.025               1971b
                   (temporary)
                   (applicable to the    1971a
                   parent compound
                   only, and to the
                   sum of all the di-
                   thiocarbamate fung-
                   icides if more than
                   one is present)
            1967   0-0.025               1968b
                   (temporary)
                   (alone or in com-     1968a
                   bination with
                   other dimethyl
                   dithiocarbamates
                   (ferbam and thiram))
            1965   no ADI                1965b
            1965a  
            1963   no ADI                1964
--------------------------------------------------------------------------------------------------------

Annex III. (contd.)
--------------------------------------------------------------------------------------------------------
Compound    Year   ADIb                  Evaluation   IARCd        Availability    WHO recom-    WHO/FAO 
            of     (mg/kg                by JMPRc:    Evaluation     of IRPTCe:    mended clas-  Data        
            JMPR   body                  Published    of Carcino-  Data    Legal   sification    Sheets  
            meet-  weight)               in:          genicity     Profile fileg   of pesticides on Pest-
            ing                          FAO/WHO                                   by hazardh    icidesf 
--------------------------------------------------------------------------------------------------------
ETU (see    1980   0.002                 1981b        Vol. 7,      
dithio-                                               p. 45           
carbamates) 1974   -                     1975b        Suppl. 4,       
                                                      p. 128          
PTU (see    1985   no ADI                1986a
propineb)          (withdrawn)
--------------------------------------------------------------------------------------------------------
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 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 (1986a).
i   Not more than 0.002 mg/kg body weight may be present as ETU.

     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 an person 
     handling the 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
-----------------------------------------------------------------------------------


    See Also:
       Toxicological Abbreviations