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    PESTICIDE RESIDUES IN FOOD - 1980


    Sponsored jointly by FAO and WHO






    EVALUATIONS 1980





    Joint meeting of the
    FAO Panel of Experts on Pesticide Residues
    in Food and the Environment
    and the
    WHO Expert Group on Pesticide Residues
    Rome, 6-15 October 1980




    DITHIOCARBAMATES

    Explanation

    Dithiocarbamate fungicides were reviewed by the Joint Meeting in
    1965, 1967, 1970, 1974, and 1977 (FAO/WHO, 1966, 1967, 1971 and
    1975; FAO, 1978).  The class of dithiocarbamates has been
    considered in the past as a single group predominantly because of
    the analytical procedures utilised in routine pesticide residue
    chemistry programmes.  The method of choice for regulatory residue
    determinations has been a non-specific analytical assay incapable
    of distinguishing individual dithiocarbamates.

    The 1977 meeting divided the dithiocarbamates into the three major
    classes: Dimethyl dithiocarbamates, ethylenebisdithiocarbamates and
    propylenebisdithiocarbamates.

    In previous toxicological evaluations of dithiocarbamates, data
    were requested on carcinogenic effects, effects on thyroid
    function, effects on reticuloendothelial and haematopoietic systems
    and on reproductive physiology.  Additionally in 1977, the U.S. EPA
    issued a Rebuttable Presumption Against Registration (RPAR) of
    pesticide products containing EBDC's.  The health aspect of this
    RPAR notice specified two major areas of concern: (1) oncogenicity
    and (2) teratogenicity.  The two areas of concern with respect to
    health considered toxicological data on both EBDC's and
    ethylenethiourea (ETU) (the major breakdown product). New data made
    available to WHO have been reviewed by the Meeting.  These data
    include special studies on teratogenicity and short-term dietary
    studies on specific EBDC fungicides and/or their major breakdown
    products, ethylenethiourea (ETU) and ethylenebisisothiocyanate
    pulphide (EBIS).  In addition, the problems discussed in the RPAR
    programme were considered by the Meeting.

    At the time of the last full review in 1977 the following
    requirements for further work or information on residues in food
    were established.

    Dithiocarbamates in general

    1. A comprehensive survey of the use patterns of thiram, ferbam and
    ziram.
    2. Data on residues of thiram, ferbam and ziram from supervised
    trials.
    3. Data on residues of dithiocarbamates from crops grown under
    glass.

    Ethylenebisdithiocarbamates

    1. Further data on the conversion of EBDC to ETU in various food
    processing procedures.
    2. Studies of procedures to minimise the formation of ETU during
    food processing.

    Propineb

    Information regarding the fate of residues during food processing,
    including cooking.

    This monograph addendum includes a summary of the relevant
    information that has been made available in response to these
    requests.

    DATA CONSIDERED FOR DERIVATION OF ACCEPTABLE DAILY INTAKE

    TOXICOLOGICAL STUDIES

    Special studies on teratogenicity

    Groups of rats (26-27 pregnant CD-1 rats/group) were administered
    zineb (Dithane(R) Z-78) at dosage levels of 0, 200, 632, or 2000
    mg/kg/day for 14 treatments from day 6 through 19 of gestation.

    Analytical chemical determinations on the purity of the zineb
    showed 85.5% EBDC containing 0.35% ETU.  The equivalent dosage
    levels were 0, 170, 543, and 1710 mg/kg bw/day for EBDC and 0, 0.7,
    2.2 or 7.0 mg/kg bw for ETU.

    Maternal body weight data and food consumption data were recorded.
    Pregnant rats were sacrificed at day 20 and a laparotomy was
    performed.  Foetal data included live, dead and resorbed foetuses
    as well as somatic and skeletal abnormalities.

    There was no maternal mortality but a substantial weight loss was
    noted at the highest dosage level.  Foetuses from the mothers
    administered 2000 mg/kg also showed a reduced body weight.  Foetal
    mortality was not noted and there were no significant anomalies
    noted on gross external examination.  A higher incidence of
    abnormalities of the tail were noted at the highest dosage level
    (short or kinky tails).

    Teratogenic events were recorded in foetuses at the highest dosage
    level.  A significant increase in lateral hydrocephalus and
    hydrocephalus of the third ventricle was noted at 2O00 mg/kg.  In
    addition, at this highest dose level, there was an increased
    incidence of skeletal anomalies (enlarged frontal fontanelle,
    enlarged occipital fontanelle, split centra and incomplete
    ossification of the supraoccipital).  The abnormalities were not
    noted at 632 and were suspected of being due to the presence of
    ETU, which would occur both in the formulation (up to 7 mg/kg/day
    was directly administered) and as a result of metabolism of zineb. 
    It was concluded that teratogenic anomalies were produced in rats
    by zineb at doses that were extraordinarily high and were
    maternally toxic.  The abnormalities may have been due, in part, to
    ETU known to be present in the formulation (Short et al., 1980).

    In a study identical with that reported above for rats, mice (CD-1)
    were administered zineb daily for 11 days of gestation (days 6-16)
    and were sacrificed on day 18.  Gross examination for maternal
    well-being and foetal anomalies (both somatic and skeletal) failed
    to show the occurrence of significant teratogenic events.  There
    were no teratogenic anomalies in mice as a result of administration
    of zineb at dosage levels of up to and including 2000 mg/kg bw
    (1710 mg/kg of zinc-EBDC and 7 mg/kg ETU) (Short et al., 1980).

    Maneb was administered to rats at dosage levels of 0, 400, 770 or
    1420 mg/kg by gavage as a single dose on day 11 of gestation.  Rats
    were sacrificed on day 18 of gestation and foetuses were examined
    for reproductive and teratogenic abnormalities.

    A substantially increased resorption rate was noted at 770 mg/kg.
    Gross malformations occurred in all surviving animals at 770 and
    1420 mg/kg.  (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
    experiment, maternal administration of zinc acetate (made in an
    attempt to relieve the incidence of teratogenic events) was
    somewhat therapeutic at a lower (750 mg/kg) dose but at a higher
    dose (1380 mg/kg), the frequency and type of malformations were
    unchanged (Larsson, et al.,  1976).

    Mancozeb was administered to rats at dosage levels of O, 380, 730,
    or 1320 mg/kg on day 11 of gestation in a study similar to that
    reported above with maneb.  Again, a substantial increase in
    malformations was observed at the highest dosage groups.  There
    were no effects noted at 730 mg/kg and below.  Similar foetal
    malformations were observed as reported for maneb (Larsson, et
    al., 1976).

    Propineb was administered to rats at dosage levels of 0, 400, 760,
    or 2300 mg/kg by gavage on day 11 of gestation.  The dams were
    sacrificed and foetuses examined for gross external and internal
    malformations on day 18 of pregnancy.

    Maternal toxicity was observed at all dosage levels.  At the
    highest dosage, propineb was foetotoxic and induced a variety of
    malformations in the surviving foetuses.  At 760 mg/kg propineb was
    slightly foetotoxic but did not induce malformations in surviving
    foetuses.  The pattern of foetal abnormalities was qualitatively
    similar to that noted in the maneb- and mancozeb-treated rats
    (Larsson et al., 1976).

    Maneb and two EBDC metabolites, ETU and EBIS, were examined in two
    rodent species for their potential to induce perinatal toxicity.
    Additionally, ETU was administered to guinea pigs and golden
    hamsters to evaluate the teratogenic potential in these species. 
    All compounds were administered during organogenesis by gavage. 
    The following is a summary of prenatal treatments:

                                                                 
    Compound    Species        Dosages           Treatment
                               (mg/kg)         (gestation day)
                                                                 

    Maneb        Rat          0,120, 240             7-16
                              & 480
                 Mouse        0, 375, 750            7-16
                              & 1500

    ETU          Rat          0, 5, 10, 20,          7-21
                              30, 40, & 80
                 Mouse        0, 100 & 200           7-16
                 Hamster      0, 75, 150             5-10
                              & 300
                 Guinea-pig   0, 50 & 100            7-25

    EBIS         Rat          0, 7.5, 25             7-21
                              & 30
                 Mouse        0, 50, 100             7-16
                              & 200
                                                                 

    In the prenatal teratology studies, rats were sacrificed on day 21,
    mice on day 18, hamsters on day 15 and guinea pigs on day 35 and
    foetuses examined for malformations (both somatic and skeletal).

    Additional postnatal studies were performed with rats using
    extended treatment periods.

    Compounds      Dosage

    Maneb          0, 240 & 480
    ETU            0, 20, 25 & 30
    EBIS           0, 15 & 30

    The treatment schedule included continuous exposure from day 7 of
    gestation through parturition to day 15 of lactation.  The pups
    were weaned normally and postnatal studies were performed at 6
    weeks for open-field behaviour.

    All three compounds were maternally toxic at high dose levels in
    the rat, less so in the mouse and (with ETU) the guinea pig and
    hamster.

    Maneb reduced rat maternal weight gain and increased the liver/body
    weight ratios at all dose levels.  A peripheral paralysis was
    induced in maternal rats at high dose levels.  Foetal data were
    affected only at the highest dose level (reduced foetal weight,
    reduced caudal ossification and hydrocephalus were noted).  In the
    mouse, maneb also affected the maternal liver and retarded
    development, causing a decrease in foetal caudal ossification
    centres (at all dosage levels).

    EBIS reduced maternal growth, increased the liver/body weight ratio
    and induced a peripheral paralysis at the highest dosage in rats.
    While mouse maternal growth was unaffected, the liver was enlarged
    at the highest dose level.  EBIS was not teratogenic as it did not
    affect foetal parameters.

    ETU induced maternal toxicity and reduced growth in the rat at 80
    mg/kg and was teratogenic to the rat, inducing substantial foetal
    effects at all dosage levels above 10 mg/kg.  Gross defects were
    seen in the skeletal system and the central nervous system.  Cleft
    palate was noted, predominantly at the highest dosage level.  The
    defects appeared to follow a dose relationship decreasing until at
    20 and 30 mg/kg an increased incidence of hydrocephalus was the
    only defect noted.  The maternal and foetal toxicity of ETU on the
    mouse, guinea pig, and hamster was substantially less severe than
    noted with the rat.  In mice, at the highest dose, an increased
    maternal liver weight and an increase in foetal supernumerary ribs
    were noted.  No effects were noted with other species.

    Postnatal studies with maneb and EBIS were uneventful with respect
    to the reproductive parameters and behaviourial studies performed. 
    ETU induced a variety of post-natal effects.  Maternal milk
    production was reduced or absent causing pup mortality at doses of
    30 mg/kg and above.  No significant dose-related behaviourial
    abnormalities were observed with ETU-exposed pups.

    Thus, maneb and EBIS were maternally toxic (inducing a peripheral
    paralysis) to the rat but not the mouse.  Maneb and ETU were
    teratogenic to the rat but not the mouse (or hamster and guinea pig
    with ETU).  EBIS did not induce a teratogenic response in any
    species tested (Chernoff et al., 1979).

    Groups of pregnant rats were administered ETU at dosage levels of
    0, 15, 30 or 45 mg/kg bw on day 15 of gestation and subjected to a
    variety of test conditions to evaluate pre- and post-natal effects.
    Mortality occurred postnatally at dosage levels above 15 mg/kg in
    pups from treated mothers 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 at a
    dosage of 30 mg/kg.  These pups died within 6 weeks of birth. 
    Motor defects were observed in some surviving (16/65) offspring of
    the 30 mg/kg group.  This was pathologically shown to be a direct
    result of the hydrocephalic condition, which was accompanied by
    atrophy of the cerebral cortex and subcortical white matter.  The
    defects were observed to be a direct result of in utero
    administration of LTU and not from exposure during lactation. 
    (Cross-fostered pups showed the same effects as pups weaned from
    treated dams).

    All female offspring of rats administered 30 mg/kg, when mated to
    normal male rats, gave birth to normal offspring.  The F2
    generation

    was not impaired although some of the parents had neurological
    defects.  In these experiments no effects were observed on the
    parameters examined at 15 mg/kg bw (Khera and Tryphonas, 1977).

    When oral doses of ETU were administered in combination with sodium
    nitrite, multiple foetal anomalies were produced in the mouse, a
    species generally refractory to treatment with either chemical
    alone (Teramoto et al., 1976).

    Special studies on reproduction

    Groups of rats (16 male and 16 female, ChR-CD rats/group) were fed
    maneb in the diet for 3 months at levels of 0, 125 or 250 mg/kg and
    mated in standard 3-generation, 2-litter per generation,
    reproduction study.  Groups of males and females from the F1b and
    F2b litters were fed maneb for three months after weaning and
    mated to become parents of the succeeding generation.

    There were no effects on reproduction reported over the entire
    study. The major reproduction indices were unaffected by maneb at
    dietary levels up to and including 250 mg/kg.  There was no
    histologic evidence of congenital anomalies in a variety of tissues
    and organs of the male and female rats (10 each group) of the F3b
    litter subjected to histopathologic examination (Sherman and Zapp,
    1966).


    Special studies on mutagenicity

    ETU was examined for its mutagenic potential in a series of
    microbial and mammalian bioassays.

    Microbial studies

    A reversion assay ('Ames test') was carried out with 5 strains of
    Salmonella and 2 strains of E. coli in the presence and
    absence of a male rat metabolic activation system.  Positive
    mutagenicity indications were obtained with TA 1535 and TA 100 at
    the highest concentrations (1 mg/plate) tested in the absence of a
    metabolic activation system.  ETU was suggested to have induced a
    weak mutagenic effect in certain microbial tester strains (Teramoto
    et al., 1977). Additional in vitro reversion studies on
    different histidine-requiring Salmonella typhimurium strains
    were performed in a semi-quantitative plate test. With strain his
    G46 at doses of 20, 50, 80 or 200 mg/plate, ETU data were not
    significantly different from that of the control.  However, a rise
    in the number of revertants per surviving cells was found with the
    repair-deficient strain TA 1530.  The increase over the spontaneous
    reversion frequency was by a factor of 7.1 at 20 mg/plate, 9.1 at
    40 mg/plate, 11.7 at 80 mg/plate and 11.1 at 200 mg/plate.  No
    induction of revertants could be observed in the frameshift mutants
    TA 1531, TA 1532, and TA 1964.  Thus, ETU-induced mutations were of
    the base-pair substitution type.  A large fraction of the induced
    lesions were eliminated by excision repair (Schupbach and Hummler,
    1977).

    In a host-mediated assay, a weak but significant increase of the
    reversion frequency (by a factor of 2.4 at a dose of 6000 mg/kg
    body weight) could be detected with strain TA 1530 used as the
    indicator organism in the mouse.  No mutation induction was
    observed at doses of 2000 mg/kg or below (Schupbach and Hummler,
    1977).

    Combinations of ETU and sodium nitrite have been reported to induce
    a mutagenic response in the 'Ames' assay in E. coli and a
    host-mediated assay (Shirasu et al.,  1977)

    Mammalian studies

    A Chinese hamster cell line was treated with ETU, cultured and
    examined for chromosomal abnormalities in an in vitro
    cytogenetic assay.  In addition, an in vivo cytogenetic assay
    on bone marrow cells was performed following treatment of rats
    orally (a single dose of 200 or 400 mg/kg or 2 to 5 consecutive
    24-hour doses of 50-400 mg/kg).

    Other than a severe cytotoxic effect noted at 3200 g ETU/ml in the
    in vitro cytogenetic assay, there were no cytogenetic effects
    noted with ETU.  Rat bone marrow cells were unaffected by ETU at
    any dose tested. In an evaluation of aneuploidy, the frequency of
    numerically aberrant cells, including aneuploid and polyploid
    cells, was somewhat high although not significantly higher than
    control values of 3-week old rats.

    In a micronucleus test, Swiss albino mice were treated twice within
    24 hours with 25, 700, 1860 or 6000 mg/kg ETU.  A total of 2000
    erythrocytes of the bone marrow of each animal was scored.  No
    increase in the number of erythrocytes containing micronuclei was
    found in treated animals (Schupbach and Hummler, 1977).

    Groups of male mice were administered ETU orally for 5 consecutive
    days at dosage levels of 0, 300 or 600 mg/kg and mated to begin a
    5-week dominant-lethal study.  There were no indications of a
    dominant-lethal effect at either dosage level tested (a positive
    control, EMS, reflected the susceptibility of the strain to
    inducing such effects as evidenced by reduced implantations and
    live embryos at weeks 1 and 2 of testing) (Teramoto et al., 
    1977).

    In another dominant-lethal test, male mice received single doses of
    500, 1000 or 3500 mg/kg respectively.  Although a slightly reduced
    fertility rate was observed in the highest dose group, no
    correlation between dose and incidence of dominant lethals was
    found (Schupbach and Hummler, 1977).

    Short-term studies

    Rat - ETU

    Groups of rats (20 male and 20 female Sprague-Dawley strain
    rats/group; 24 of each sex were used as controls) were fed ETU in
    the diet for 90 days at dosage levels of 0, 1, 5, 25, 125, or 625
    mg/kg. Additional groups of rats of both sexes were fed amitrole
    (50 mg/kg) and propylthiourea (PTU) (125 mg/kg) as a positive
    control group. Growth and food consumption were recorded weekly and
    daily observations were made for behaviourial changes and
    mortality.  At 30, 60 and 90 days, groups of 10 rats of each sex
    were sacrificed for examination of thyroid function tests (T-3,
    T-4, TBG, TSH, and 125I uptake).  Gross and microscopic analyses of
    tissues and organs were performed at these intervals.

    Clinical signs of poisoning, mortality, and growth reduction were
    observed at the highest dose level.  No adverse clinical signs were
    noted at lower ETU doses or in the amitrole or PTU animals.
    Biochemical changes reflecting effects on thyroid function were
    noted at dosages of ETU exceeding 25 mg/kg.  There were decreases
    in T3 and T4, an increase in TSH, and a decrease in iodine
    uptake.  These changes were also observed with the two positive
    controls groups. Based on biochemical indicators, the most
    sensitive parameters for evaluating thyroid function, a no-effect
    dietary level for this 90-day study is 25 mg/kg.  Gross and
    microscopic examinations showed substantial effects on a variety of
    organs and tissues at the highest ETU dose group.  At 125 mg/kg,
    thyroid hyperplasia was observed.  No effects were noted at 25
    mg/kg equivalent to an ETU uptake of 1.78 mg/kg bw (Freudenthal et
    al., 1977) 

    Rat - EBIS

    Groups of rats (60 male and 60 female Sprague-Dawley rats/group; 30
    of each sex ware used as controls) were fed EBIS in the diet at
    dosage levels of 0, 1, 10, 100 or 1000 mg/kg for 90 days. 
    [Positive controls for thyroid function tests were utilised to
    assure quality of the clinical procedures.  These controls were
    administered just prior to sacrifice and clinical assay and were
    not necessarily included in the feeding trial.  Positive controls
    included aminotriazole (administered to groups of 6 rats of each
    sex daily for 4 days by gavage at a dose of 4000 mg/kg) and
    methimazole (administered to groups of 6 rats of each sex twice
    daily for 4 days by gavage at a dose of 0.6 mg/kg)].  Growth was
    measured at weekly intervals over the 12-week trial.  Groups of 20
    of each sex were sacrificed monthly for thyroid function tests and
    gross and microscopic pathology.

    EBIS was toxic at 1000 mg/kg inducing a reversible paralysis of the
    hind legs followed by death if once affected the animals were
    continued on the dosing regimen.  Animals removed from the EBIS
    diet recovered from the paralysis.  However, they became
    reafflicted when exposed to EBIS at the high dosage level.  No
    histological lesion could be identified with the motor paralysis.

    Thyroid function was substantially affected by EBIS at 1000 mg/kg
    as was growth in both males and females.  Thyroxine (T-4) levels
    were significantly reduced as was iodine uptake.  At 100 mg/kg, no
    adverse effects of EBIS were noted on clinical parameters or on
    gross or histopathologic examinations.  A no-effect level in this
    study was 100 mg/kg in the diet based on data observed with
    clinical and histopathologic studies (Freudenthal et al., 1977).

    OBSERVATIONS IN MAN

    Epidemiological studies were conducted on workers in the rubber
    industry by Parkes (1974) and Smith (1976).  Parkes (1974) examined
    the records relating to the national or regional incidence of
    thyroid cancer, to evaluate what proportion of such cases might
    have originated amongst men employed in the rubber industry where
    ETU is used extensively.  Parkes concluded that, under the
    conditions in which ETU has been used in the past, there is no risk
    of man contracting thyroid cancer as a result of industrial
    exposure to ethylenethiourea.

    Smith (1976) conducted a detailed study involving 1,929 workers in
    rubber compounding plants in the Birmingham, England area.  No
    thyroid cancers were found in the health records of these workers. 
    Smith concluded that this study does not demonstrate any risk of
    thyroid cancer from the normal industrial use of ETU.

    Bruerman et al. (1980) studied a population of workers
    manufacturing Dithane(R), employing a battery of thyroid function
    tests as well as other parameters to evaluate their health status
    and to detect subtle thyroid function abnormalities.  Based on all
    data available, there were no abnormalities associated with the
    exposure to the EBDC's during their manufacture.


    RESIDUES IN FOODS

    ETHYLENETHIOUREA IN WINE

    Carbon-14 labelled zineb and ethylenethiourea (ETU) have been used
    to study the behaviour of the compounds during the wine-making
    processes. At the start of wine-making, zineb remains absorbed on
    the solid parts of the grapes where it undergoes extensive
    degradation to form some slightly soluble compounds, including ETU,
    ethyleneurea (EU), hydantoin and ethylenediamine.  Of the zineb
    present in the liquid portion of the must, 18% passes into the wine
    as metabolites, but of these ETU and EU are at levels well below
    0.01 mg/kg.  ETU added to the must reacts very rapidly with the
    natural components and remains in the solid part of the must. 
    There is thus little probability that significant amounts of ETU
    would be present in wines prepared from grapes that had been
    treated with zineb (Santi et al.,  1980).

    Improved analytical methods involving direct GLC of ETU, without
    derivatisation, using a flame photometric detector have enabled a
    detection limit of 0.01 mg/kg for ETU to be achieved in wines, with
    mean recoveries of about 71% at levels between 0.05 and 0.10 mg/kg.
    Together with an additional procedure to confirm identity, direct
    GLC has been used to examine wines from several countries, randomly
    purchased in France, ltaly and Federal Republic of Germany.  In
    none of the 39 samples reported was ETU observed at above the limit
    of detection of 0.01 mg/kg.  Any propylenethiourea that might have
    been present would also have been detected (Fabbrini et al.,
    1980).

    Both of these papers stress the need to obtain positive
    confirmation of identity for any 'apparent' ETU that may seem to be
    present.

    RESIDUES IN COMMERCIAL FOODSTUFFS

    A 'market basket' study of EBDC and ETU residues in food has
    recently been reported by Gowers and Gordon (1980).  Over 500
    samples of 34 foods were analysed, plus 26 samples of drinking
    water.  The water samples contained no residues, 53 of the food
    samples showed EBDC residues above the limit of detection of the
    method, but all were below the USA maximum limits while only two
    results were confirmed as positive for ETU, both around 0.01 mg/kg. 
    In a second study, 203 samples of tomato products were examined;
    none contained ETU but 19% contained EBDC residues in the range 0.2
    to 0.5 mg/kg.  On the basis of these analyses, estimates of daily
    dietary intake were 6.6  10-4 mg/kg bw for EBDC and 2.3  10-4
    mg/kg bw for ETU.

    Holt (1977) has also reported the results of a market basket survey
    for ETU and EBDC residues in food items purchased in 9 states of
    the USA (California, Colorado, Oregon, Texas, Illinois, Florida,
    North Carolina, New York and Massachusetts).  The foods studied
    were canned tomatoes, tomato juice, tomato paste, catsup, canned
    potatoes, instant potatoes, canned green beans, applesauce, carrots
    and pickles.  No EBDC residues were observed in any sample (<0.2
    mg/kg as maneb).  ETU was not observed in tomatoes, green beans,
    applesauce or pickles (<0.01 mg/kg) and only random trace positive
    results were found in the other foods.  Of the 189 samples
    analysed, 144 showed no ETU residue (<0.01 mg/kg) and none had
    values greater than 0.05 mg/kg.  Positive ETU results were
    confirmed by mass spectrometry.

    Typical food processing procedures, such as washing, scrubbing,
    trimming and peeling, remove about 87% of EBDC residues.  A 'table
    top' study in which whole prepared meals were analysed for ETU has
    also been described by Gowers and Gordon (1980).  Of 60
    home-prepared and 40 restaurant-prepared meals, only one showed any
    apparent ETU, which could not be confirmed as to identity.  Of the
    87 meals examined for EBDC, 11 were positive and the levels found
    averaged 0.3 mg/kg.  A second study of another group of 100 meals
    showed no ETU present while only four of the meals contained EBDC
    in the range 0.2 to 0.4 mg/kg. If the single result for ETU is
    taken to be real, the average daily intake for the group of 200
    meals would be 1.35  10-6 mg/kg bw; that 

    for EBDC is 7.5  10-4 mg/kg bw based on the overall average of
    0.03 mg/kg of EBDC in the meals.  Hydrolysis of EBDC residues
    during cooking can be a source of ETU but not always a dietary
    source since discarding the cooking water, as is frequently done,
    removes both the ETU and the EBDC residues.  Up to 10 - 15% of the
    EBDC residues present can be converted to ETU, which is not the
    only decomposition product.

    The stability of ETU and maneb residues in canned vegetables has
    been studied by Han (1977) using 14C-labelled material.  Samples
    of commercial canned tomato sauce and spinach were fortified
    separately and then re-sterilized by simulated commercial
    procedures.  Residues of intact ETU were found to diminish rapidly
    with time, dropping to 0.2% of the amount added to tomato sauce and
    to 10% of the amount added to spinach after 4 weeks storage at room
    temperature.  Similar results were found after addition of labelled
    maneb to the same vegetables.  Ethyleneurea and more polar
    materials accounted for the bulk of the 14C-residue.  These polar
    degradation products were shown to be incapable of releasing ETU on
    acidic or basic hydrolysis, thus ruling out the possibility that
    they are present as complexes or simple conjugates of ETU.  This
    rapid degradation of ETU is probably the most important factor
    involved in explaining why very little or no ETU is found in
    commercially processed crops, which may contain maneb residues at
    harvest.

    Only one sample of tomato crops contained ETU (0.03 mg/kg) after
    spraying maneb and mancozeb 5 to 8 times at intervals of 3-4 days
    (von Stryk and Jarvis, 1980).  However, in canned juice made from
    these whole fruits a mean ETU level of 0.02 mg/kg was found.  In
    canned peeled fruit, residues were lower (mean 0.01 mg/kg).  In a
    greenhouse experiment ETU residues (up to 0.08 mg/kg, mean 0.0097)
    were detected in more samples than under field conditions; mancozeb
    residues ranged up to 2.8 mg/kg with a mean of 0.7 mg/kg.

    Ripley et al (1978) studied residues of mancozeb and ETU on
    grapes and grape products.  Mean values of 6.8 mg/kg EBDC and 0.03
    mg/kg ETU were found immediately after application and these
    residues declined by 50% in the next 15-20 days.  Wine prepared
    from the treated grapes contained 0.037 mg/kg ETU but no residues
    of EBDC were detected.  Heat treatment of the harvested grapes
    demonstrated conversion of EBDC to ETU (18%).  Most commercial
    grape products analysed showed less than 0.02 mg/kg ETU except some
    concentrates that contained 0.06 mg/kg; EBDC was found in only one
    of these samples.

    Spraying tomatoes with maneb or mancozeb at rates of 2.7 kg/ha at
    intervals of 7-12 days resulted in levels of <0.05 mg/kg ETU in
    the fruits after 7 applications, whereas ETU residues in tomato
    juice and whole pack products prepared from these treated fruits
    sampled in the first 3 days after the 6th application of fungicides
    ranged from not detectable (<0.01) to 0.17 mg/kg.  Boiling of
    fruit increased ETU residues by up to 800% (from 0.04 to 0.36
    mg/kg).  Commercial tomato products contained ETU residues of
    <0.03 mg/kg, most containing <0.01 mg/kg (Ripley and Cox,
    1978).

    Ripley and Simpson (1977) monitored ETU residues on pears after
    spraying with zineb (5 kg/ha).  ETU residues ranged from 0.02-0.01
    mg/kg over the 21-day trial.  Four out of six samples of pear baby
    food contained residues of ETU in the range of 0.01-0.05 mg/kg. 
    Boiling pears containing a zineb residue converted 3-6% of zineb
    into ETU.  Higher percentages of EBDC conversion into ETU (9-25%)
    have been found by Casanova and Dachaud (1977).  Spinach leaves
    containing residues of maneb, zineb and mancozeb were boiled and
    the increase in ETU residue observed.  A considerable portion of
    the ETU formed was present in the boiled spinach leaves.

    In 1975, Ross et al (1978) studied residues of EBDC and ETU in
    apples and apple products.  In fresh apples harvested 42 days after
    the last of nine sprays each of either mancozeb or metiram the EBDC
    residues were 1.7 and 0.5 mg/kg respectively; residues of ETU were
    not found above the limit of determination of 0.01 mg/kg.  Canned
    apple juice and sauce prepared from apples treated with mancozeb
    both contained 0.05 mg/kg of ETU while the level in the pomace was
    0.17 mg/kg.  Apples that had been treated with metiram showed
    similar levels. Similar trials in 1976 yielded EBDC residues of
    less than 1 mg/kg on fresh fruit that had received one, two, three
    or four cover sprays of the compounds, while ETU was below the
    limit of determination in all cases.

    A very limited amount of data on residues of dithiocarbamate
    fungicides on crops grown in greenhouses was received from member
    countries.  It was, however, inadequate in extent and presentation
    for any conclusions regarding estimated maximum residue levels to
    be drawn.  The need remains for a clear presentation of residue
    data on glasshouse-grown crops, especially leafy vegetables and
    fruiting vegetables.

    REMOVAL OF RESIDUES

    Marshall and Jarvis (1979) have described methods claimed to be
    effective for the removal of residues of
    ethylenebisdithiocarbamates (EBDC) and ETU from field-treated
    tomatoes and hence in decreasing the residue levels in the derived
    fruit juices.  The preferred procedure involves a wash in dilute
    sodium hypochlorite followed by a dip in dilute sodium sulphite,
    the resulting residue levels then being below the detection limits. 
    Details of the mechanisms involved in the oxidative destruction of
    ethylenethiourea by alkaline hypochlorite have been given by
    Marshall and Singh (1977) and by Marshall (1978).


    METHOD OF ANALYSIS

    Lesage (1980) has drawn attention to the fact that copper can
    interfere in the analysis of residues of
    ethylenebisdithiocarbamates by carbon disulphide evolution methods,
    low results being obtained.

    Formulations

    A comparison of gas and liquid chromatographic procedures for the
    determination of ETU in maneb has shown a 5-fold bias in the gas
    chromatographic values when methanol extracts of six formulations
    were simultaneously analysed by both techniques (Fisher, 1977). 
    Hence, liquid chromatography is the preferred procedure.  Use of
    procedure on 35 samples of maneb produced at various locations in
    USA showed the average ETU content to be 813 mg/kg, with a range of
    249-1408 mg/kg (Keeler, 1977).

    Residues

    A procedure for the determination of those dithiocarbamates that
    can be regarded as ETU-precursors has been suggested by Greve and
    Hogendoorn (1978).  Acid hydrolysis of ethylenebisdithiocarbamates
    in the presence of tin (II) chloride yields ethylenediamine which
    is then allowed to react with pentafluorobenzylchloride to form
    1,2-bis(pentafluorobenzamide)ethane.  The detection limit of the
    method is about 0.1 mg/kg on endive and leek, recoveries of maneb
    and zineb being in the range 75-95%.

    The direct determination of alkylenebisdithiocarbamates by gel
    permeation chromatography with UV absorption detection has been
    reported by Pflugmacher and Ebing (1980).  The method has been
    tested for maneb, zineb, propineb, nabam and mancozeb added to
    apples, lettuce, potatoes, carrots, tomatoes, beans and cucumbers. 
    Recoveries ranged from 78 to 105% at levels from 0.25 to 2 mg/kg.

    The GLC method of Otto et al (1977) for ETU residues has been
    subjected to a collaborative study (GIFAP, 1979).  Amounts of ETU
    in the range 0.02-0.1 mg/kg were added to apples, tomatoes and
    grapes, recoveries averaging greater than 80%.  The conversion of
    maneb to ETU during the analysis was also studied; apart from one
    experiment in which 2.7% conversion was found, all determinations
    showed less than 1% conversion.  Results from four to five
    laboratories involved in the collaborative study (on samples of
    maneb-treated tomatoes, tomato juice, beer, and celery) were in
    good agreement at 0.01 to 0.1 mg/kg level.

    A method for the gas-chromatographic determination of ETU in
    apples, green beans, potatoes and tomatoes has been described by
    King (1977). Following derivatisation with trifluoromethylbenzyl
    chloride the determination is carried out by electron capture gas
    chromatography.

    A sensitive method for the analysis of ETU residues has been
    described by Hirvi, Pyysalo, and Savolainen (1979) in which amounts
    of more than 0.01 ng ETY can be detected quantitatively by gas
    chromatography with glass capillaries and without derivatisation. 
    FFAP, Carbowax 20M, OV-17, and OV-101 were successful as liquid
    phases.

    According to Newsome and Panopio (1978), residues of 2-imidazoline,
    a product of the degradation of ETU, can be determined by high
    pressure liquid chromatography.  At first the residues are absorbed
    to a cation exchange resin and then they are treated with
    p-nitrobenzoyl chloride and the derivative is detected by UV
    absorption.

    Singh et al (1979) developed a one-step extraction and
    derivatisation method for ETU determination.  ETU is derivatised
    with dichloroacetic anhydride and partitioned into CH2Cl2 using
    acetonitrile as a phase transfer agent.  GLC was performed on
    OV-330 or OV-17 columns with EC detection.  The method was used as
    a rapid screening procedure for the presence of ETU in water
    samples at the 0.01-0.05 mg/kg level.

    A collaborative study of a GLC headspace CS2 procedure for the
    determination of residues of dithiocarbamate fungicides, organised
    by the UK Committee for Analytical Methods for Residues has been
    completed and a report on the work is in course of preparation for
    publication (Abbott, 1980).  As a result of the study a method of
    analysis for lettuce was recommended which has been used, and can
    be further adapted for other crops.


    SPECIFICATIONS

    A booklet of FAO specifications for maneb, nabam, ferbam, ziram,
    thiram and metham-sodium is now available (FAO, 1979); a
    'tentative' specification for mancozeb has been published (FAO,
    1980).


    EVALUATION

    COMMENT AND APPRAISAL

    The Joint Meeting in 1977 considered the dimethyldithiocarbamates
    to be sufficiently similar in chemical structure, metabolism and
    toxicology to be grouped together.  Ferbam and ziram were allocated
    an ADI of 0-0.02 mg/kg bw/day, while thiram was allocated a
    temporary ADI of 0-0.005 mg/kg bw/day.  As further information was
    not received, no evaluation was made of the
    dimethyldithiocarbamates and the previous evaluation was
    reaffirmed.

    The ethylenebisdithiocarbamates, maneb, zineb and mancozeb, were
    also considered as a group by the 1977 Meeting.  These compounds
    are in part degraded or metabolised to ethylene thiourea(ETU).  ETU
    is a decomposition product, metabolite and contaminant of EBDC
    fungicides. It has been shown to be considerably more toxic than
    the parent molecule and has, in the past, given cause for concern
    because of its thyroid toxicity and tumorigenicity.  The 1977
    Meeting was aware of further work in progress and the temporary ADI
    of 0-0.005 mg/kg bw/day was reaffirmed for the
    ethylenebisdithiocarbamates.

    Propineb, a propylenebisdithiocarbamate, is degraded to
    propylenethiourea and was considered separately from other groups
    at the 1977 Meeting when a full review of available data was made. 
     A temporary ADI of 0.005 mg/kg/day was reaffirmed.

    Newly-submitted results derived from studies on the short-term
    toxicity and teratogenicity as well as the effect on reproduction
    of EBDC pesticides, including some of their major metabolites and
    breakdown products, have been evaluated.  Three EBDC pesticides,
    maneb, zineb and mancozeb, were maternally toxic at high doses in
    the rat, less so in mice, hamsters and guinea pigs, but were not
    teratogenic.  ETU was maternally toxic in the rat at 80 mg/kg bw,
    was teratogenic at doses higher than 10 mg/kg bw and also produced
    a variety of postnatal effects.  In short-term feeding studies (90
    days) ETU showed adverse effects on thyroid function at doses
    greater than 25 mg/kg (1.8 mg/kg bw).  EBIS also induced thyroid
    dysfunction in the rat.  The no-effect level based on thyroid
    function is 100 mg/kg (4.4 mg/kg bw).  ETU was weakly mutagenic in
    the Ames test (base-pair substitution) but with mammalian
    mutagenicity systems it proved to be negative both in vitro and
    in vivo.

    The concern of the Meeting regarding the toxicity of ETU has been
    alleviated by studies demonstrating no-effect levels for its
    teratogenicity and thyroid toxicity in the rat; the oral no-effect
    levels for ETU were established at 15 mg/kg bw and 1.8 mg/kg bw,
    respectively.

    Further residues results reported to this Meeting showed that there
    was little likelihood of significant amounts of ETU being present
    in wine or processed foods prepared from EBCD-treated produce.
    Information is still lacking on use patterns of thiram, ferbam and
    ziram and on their residue from supervised trials, as is adequate
    data on residues of dithiocarbamates from crops grown under glass. 
    The new data available did not enable any amendments to be made to
    the recommendations for limits made in 1977.

    For sake of clarity, the limits for dithiocarbamates (and guideline
    levels for ethylenethiourea (ETU) recorded in 1977 are repeated in
    Annex 1.  It was confirmed that the levels apply to residues,
    determined and expressed as CS2, arising from the use of the
    dimethyldithiocarbamates, the ethylenebisdithiocarbamates, and
    propineb as separate groups.  In those cases in which a member or
    members of more than one group may be present in a commodity, the
    MRLs should be regarded as additive.

    However, some analytical methods are now available that enable the
    EBDC compounds, which are ETU precursors, to be distinguished from
    the other dithiocarbamate fungicides, including propineb.  Further
    work to validate these methods is required, together with use of
    these procedures to obtain confirmatory residues data on some
    crops. Comparison with results obtained by a validated head-space
    GLC procedure for CS2 is also desirable.

    No-effect levels and ADI

    Dimethyldithiocarbamates

    Ferbam
    Level causing no toxicological effect
    Rat:  250 mg/kg in the diet equivalent to 12.5 mg/kg bw/day
    Dog:  5 mg/kg bw/day

    Estimate of acceptable daily intake for man
    0-0.02 mg/kg bw
    This applies to ferbam and ziram individually or as the sum of the
    two.

    Ziram
    Level causing no toxicological effect
    Rat:  250 mg/kg in the diet equivalent to 12.5 mg/kg bw/day
    Dog:  5 mg/kg bw/day 

    Estimate of acceptable daily intake for man
    0-0.02 mg/kg bw
    This applies to ferbam and ziram individually or as the sum of the
    two. 

    Thiram 
    Level causing no toxicological effect
    Rat:  48 mg/kg in the diet equivalent to 2.5 mg/kg bw/day
    Dog:  5 mg/kg bw/day 

    Estimate of temporary acceptable daily intake for man
    0-0.005 mg/kg bw.

    Propylenebisdithiocarbamates

    Propineb

    This was considered separately from the EBDC fungicides and
    although no further data was provided on this compound, or on its
    breakdown product propylenethiourea the data provided on ETU were
    taken into account considering its potential for thyrotoxicity and
    tumorigenicity (see FAO/WHO 1978a, p. 30).  The meeting decided to
    postpone a further evaluation of propineb until further data are
    available. 

    Level causing no toxicological effect
    Rat:  10 mg/kg in the diet equivalent to 0.5 mg/kg bw/day
    Dog:  3000 mg/kg in the diet equivalent to 75 mg/kg bw/day. 

    Estimate of temporary acceptable daily intake for man
    0-0.005 mg/kg bw

    Ethylenebisdithiocarbamates

    Maneb
    Level causing no toxicological effect
    Rat:  250 mg/kg in the diet equivalent to 12.5 mg/kg bw/day 

    Estimate of acceptable daily intake for man
    0-0.05 mg/kg bw, of which not more than 0.002 mg/kg bw may be
    present as ETU.
    This ADI applies to maneb, mancozeb, and zineb individually or the
    sum of any combination of them. 

    Mancozeb 
    Level causing no toxicological effect
    Rat:  100 mg/kg in the diet equivalent to 5 mg/kg bw/day. 

    Estimate of acceptable daily intake for man
    0-0.05 mg/kg, of which not more than 0.002 mg/kg bw may be present
    as ETU.
    This ADI applies to maneb, mancozeb, and zineb individually or the
    sum of any combination of them.

    Zineb
    Level causing no toxicological effect
    Rat:  not determined (but less than 500 mg/kg)
    Dog:  2000 mg/kg in the diet equivalent to 50 mg/kg bw/day

    Estimate of acceptable daily intake for man
    0-0.05 mg/kg bw, of which not more than 0.002 mg/kg bw may be
    present as ETU.
    This ADI applies to maneb, mancozeb, and zinab individually or as
    the sum of any combination of them.


    FURTHER WORK OR INFORMATION

    Required (by 1983)

    1. Further development and validation of the methods of analysis
    for the separate determination of ethylenebisdithiocarbamates which
    are ETU precursors.
    2. Residue data on a few crops obtained by use of a method specific
    for the ETU precursors as compared with use of a validated
    head-space CS2 GLC procedure.
    3. Information regarding the current use pattern of thiram, ferbam,
    ziram, and propineb together with residue data from supervised
    trials.
    4. Data on residues of dithiocarbamate fungicides from crops grown
    under glass.
    5. Studies to resolve the effects of thiram-inducing anaemia (as
    reported to the 1977 Meeting in abstract form only).
    6. Full evaluation of the teratogenic potential of thiram.

    Desirable

    1. Further studies to establish a no-effect level with zineb.
    2. Further studies on other EBDC fungicides such as Polyram(R) and
    metiram (and others that may give rise to ETU as a metabolite).


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    See Also:
       Toxicological Abbreviations
       Dithiocarbamates (WHO Pesticide Residues Series 4)
       Dithiocarbamates (Pesticide residues in food: 1983 evaluations)