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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




    PROPARGITE

    Explanation

    Propargite was reviewed by the 1977 Joint Meeting (FAO, 1978), and
    a temporary ADI for man was estimated to be 0-0.08 mg/kg bw. 
    Propargite is moderately toxic when administered orally to rats. 
    Propargite is readily absorbed, metabolized, and excreted rapidly
    from the body.  The metabolic products are predominantly oxidative
    and/or hydrolytic reactions resulting in cleavage of the parent
    ester and of the ether moiety.  The metabolic products are polar
    compounds, readily excreted or incorporated into natural
    constituents in the body.  Propargite is not teratogenic, nor did
    it pose a problem with respect to reproduction in rats.  In a
    series of long-term and short-term studies in rats and dogs, there
    were no unusual toxicological events that would raise questions
    relative to the safety of the use of propargite. In a long-term
    study in the rat, at 2,000 mg/kg, growth reduction and mortality
    was seen.  These effects were accompanied by variations in the
    relative and absolute weight of several organs of the body noted in
    survivors at the conclusion of the study.  There is no indication
    in the long-term rat study that propargite is a carcinogen.  A
    no-effect level of 900 mg/kg (the highest level tested) was seen in
    the two-year dog study.

    It was considered at the previous Meeting that, as propargite is
    structurally related to `Aramite', a compound that is known to be
    a carcinogen in animal studies, the need for a more definitive
    carcinogenicity study was warranted.  Further data relative to the
    oncogenic potential of propargite in mice were made available to
    the Meeting and were reviewed.  These new data are considered in
    this monograph addendum.

    At the 1977 Meeting a number of temporary MRLs were recommended.

    In 1978 (FAO/WHO, 1979) additional information was reviewed with
    recommendations for new or revised temporary limits with some of
    these revised in 1979 (FAO/WHO, 1980) on the basis of new data.

    Propargite is scheduled for re-evaluation in 1981.  However,
    additional information has been received on the metabolic fate of
    propargite in plants.  This information, provided in response to
    information considered desirable in the 1977 Evaluations (1978), is
    reviewed in this addendum.  Additional information on residues, use
    patterns, and national tolerances are also evaluated.

    DATA CONSIDERED FOR DERIVATION OF ACCEPTABLE DAILY INTAKE

    TOXICOLOGICAL STUDIES

    Special study on carcinogenicity

    Mouse

    In the preliminary dose range-finding study, groups of albino mice
    (10 male and 10 female mice/group) were administered propargite in
    the diet at dosage levels of 0, 600, 900, 1,350, 2,000 or 3,000
    mg/kg for 30 days.  Daily observations were made with respect to
    general appearance and behaviour and for gross signs of toxicity
    and mortality.  Body weight and food consumption were recorded
    weekly and gross examination of major tissues and organs was
    performed on all animals.

    Mortality was observed at 3,000 mg/kg (all deaths were in one group
    of male mice housed together, but not in the other group of 5 males
    nor in the females).  Growth was depressed at 3,000 mg/kg in both
    males and females and at 2,000 and above in females.  Absolute and
    relative organ weight changes were observed at all dose levels,
    predominantly with respect to the liver.  The principal
    investigators considered that the increased liver weight was a
    physiological response induced by the presence of propargite and
    did not constitute a toxicological response.  It was concluded that
    a dosage not exceeding 1,000 mg/kg would be appropriate for a long-
    term carcinogenicity bioassay in mice (Gallo and Bailey, 1976).

    Groups of mice (60 male and 60 female, Charles River, CD-1
    mice/group) were fed propargite in the diet at dosage levels of 0,
    50, 160, 500 or 1,000 mg/kg for 18 months.  Another group of
    animals (15 male and 15 female mice/group) were fed 0, 500 or 1,000
    mg/kg in the diet for one year.  Animals were observed daily for
    mortality and changes in appearance or behaviour.  Growth and food
    consumption data were measured weekly for 28 weeks, after which
    data were recorded every other week.  Data were recorded on
    individuals for 36 weeks and then by groups of animals
    corresponding to their caging.  At 0, 52, and 78 weeks, haematology
    examinations were performed.  At the conclusion of the study
    (either 52 or 78 weeks) all surviving animals were sacrificed and
    subjected to gross and microscopic examinations of tissues and
    organs.  A statistical analysis was performed on all parameters to
    distinguish differences between control and test groups.

    There was no excessive mortality over the course of the study as a
    consequence of the presence of propargite in the diet.  There was
    no effect of propargite on food consumption or growth.  The
    appearance and behaviour characteristics of all treated animals
    were similar to those of controls.  Haematological values were
    unaffected by propargite at any dose level.  At the conclusion of
    the study, gross and microscopic examination revealed few
    significant compound-related effects.  There was no effect of

    propargite on the distribution of either neoplastic or 
    non-neoplastic lesions.  A slight reduction in kidney weight 
    was noted. An enlarged uterus was also reported in those animals
    fed 1000 mg/kg.  These gross changes were not accompanied by 
    pathological changes in the histological examination.

    In summary, there is no indication of a tumorigenic or carcinogenic
    effect of propargite in mice administered dietary levels up to
    1,000 mg/kg for 18 months (Cox and Re, 1979).

    Special studies on mutagenicity

    Propargite was examined for its mutagenic potential in a series of
    in vitro microbiological assays utilizing Salmonella spp. and
    Saccharomyces spp. indicator organisms.  Propargite was tested in
    the presence and absence of a liver microsomal enzyme preparation
    (S-9) obtained from Aroclor-induced rats.  The concentration of
    propargite ranged from 0.001 to 5 mg per plate.

    The higher concentrations of propargite induced cellular toxicity,
    but in all cases there were sufficient doses available to evaluate
    propargite for its potential mutagenic effects.  Propargite did not
    induce mutagenic activity in either of the microbial test systems
    and was considered to be nonmutagenic in these bioassays (Brusick
    and Weir, 1977).

    Special studies on teratogenicity

    Groups of female rats (20 pregnant rats/group) were administered
    propargite on days 6-15 of gestation at dosage levels of 0, 6, 25,
    105, and 450 mg/kg/body weight/day.  Propargite was administered as
    a corn oil suspension.  A positive control included in the study
    was aspirin administered at a dose level of 250 mg/kg/body
    weight/day.  All animals were sacrificed on day 20 of gestation and
    foetuses were removed and examined.  The number of corpora lutea,
    implantation sites, resorption sites, and live and dead foetuses
    were observed.  The foetuses were sexed and their body weight
    determined.  All foetuses were examined for gross abnormalities and
    representatives were further examined for somatic and skeletal
    malformations.

    Maternal mortality in the high-dose group, administered 450 mg/kg,
    was evident early in the study and this dose level was terminated. 
    Females at 105 mg/kg displayed signs of acute poisoning (blood
    nasal discharge, alopecia, urinary incontinence, and bloody vaginal
    discharge).  While there were occasional toxic signs of poisoning
    in the lower dose levels, there were no differences in any of the
    treatment groups with respect to the maintenance of pregnancy,
    implantation sites, numbers of live or dead foetuses or resorption
    sites.  Missing sternebrae and missing or reduced hyoid were
    significantly increased in the two highest-dosed test groups (25
    and 105 mg/kg), and an increased incidence of incomplete closure of
    the skull was noted at the highest test group.  There was an
    increased number of smaller pups and haemorrhagic abdomen was
    reported in more litters at the two higher dose groups than noted

    either in the lowest dose group or in the controls.  There were 
    no differences with respect to the average weight of live foetuses 
    in any of the groups.  Aspirin, the positive control, induced a 
    significantly higher percentage of dams with resorption sites, 
    fewer live foetuses/dam and a reduced foetal weight.  The 
    aspirin-treated parents gained less weight during the period of 
    gestation and the foetuses showed an increased incidence of 
    skeletal and soft tissue abnormalities compared to control 
    foetuses.  Such effects include missing sternebrae; incomplete 
    ossification of vertebrae; incomplete closure of the skull; 
    incomplete ossification of extremities, and missing and reduced 
    hyoid.

    Propargite is not teratogenic in the rat under conditions of this
    assay.  At a dose level of 25 mg/kg propargite-treated rats showed
    an increase in missing sternebrae and retarded hyoid development. 
    These malformations are believed to be of questionable significance
    in evaluating the teratogenic potential of propargite, as an
    increased number of incomplete vertebrae, missing or reduced hyoid,
    and an incomplete skull closure are indicative of retarded
    development rather than a teratogenic effect, probably reflective
    of the toxic maternal effect noted at the higher dose levels
    (Knickerbocker and Re, 1979).


    RESIDUES IN FOOD

    USE PATTERN

    The following represent current good agricultural practices in New
    Zealand.

                                                              
    Crop         Pest     Application Rates     Waiting Period
                                                              
    Apples       Mites    60 g ai/100 litres    14 days
    Berry fruit  Mites    60 g ai/100 litres     3 days
    Stone fruit  Mites    60 g ai/100 litres     2 days
                                                              

    These good agricultural practices are generally comparable with
    those reviewed by the 1977 Joint Meeting (FAO/WHO, 1978) except for
    the New Zealand 2-day pre-harvest interval for stone fruit which is
    significantly less than 14-day interval, on which basis limits were
    recommended in 1977. 


    RESIDUES RESULTING FROM SUPERVISED TRIALS

    Propargite residues resulting from supervised trials in New Zealand
    are given in Table 1.

    TABLE 1.  Propargite Residues From Supervised Trials

                                                                  
                                        Pre-Harvest     Residues
                                         Interval      at Harvest
    Crops         Application Details     (days)         (mg/kg)
                                                                  

    Apples        1  60 g ai/100 litres     5             2.5

    Strawberries  2  30 g ai/100 litres    16 h           3.7
                      (3.6 kg ai/ha)         1             3.1
                                             2             2.5
                                             3             2.0
                                             5             1.7
                                             7             1.4
                                            16             0.5

    Peaches       1  33 g ai/100 litres     0             7.6
                      (2.0 kg ai/ha)         1             6.0
                                             2             5.7
                                             3             6.1
                                             5             7.1
                                             7             6.9
                                            14             6.3

                  2  60 g ai/100 litres     1             2.0
                      (1.2 kg ai/ha)         3             1.26
                                             7             0.88
                                            14             1.0
                                                                  


    Apples

    The residue is within the 5 mg/kg limit recommended by the 1979
    Joint Meeting.

    Strawberries

    The residues are within the 7 mg/kg limit recommended by the 1977
    Joint Meeting, which used a 3-day pre-harvest interval.

    Peaches

    The residues are consistent with the 7 mg/kg limit recommended by
    the 1977 Joint Meeting and the 14-day-pre-harvest interval on which
    it was based.  Even at the 2-day pre-harvest interval, considered
    good agricultural practice in New Zealand, residues are consistent
    with the limit previously recommended.

    Propargite residues in raisins

    Summary data from residue trials in California, USA (Canada, 1980)
    are given in Table 2.

    TABLE 2.  Propargite Residues in Raisins

                                                                          
    Application Rate                 Interval from
      kg ai/ha or                    last Application   Propargite
         % ai          Formulation       (days)         Residue (mg/kg)
                                                                          

    0.054%             Omite 30W         7, 8           1.3, 0.1
                                         14             0.7, 0.3

    0.11%              Omite 30W         7, 8           0.9, 0.5
                                         14             1.3, 0.6

    1.8                Omite 30W         7,8            1.5, 0.1
                                         14             1.1, 0.7

    3.6                Omite 4D          7, 8           6.1, 0.5
                                         14             0.4, 0.4

    6                  Omite 30W         7              0.9, 1.0
                                                        1.7, 2.2
                                                        1.4, 1.2

    3.6                Omite 4D          7              2.9, 5.5
                                                        5.2, 5.9
                                                        0.3, 1.1
                                                                          

    These data indicate that propargite residues on raisins will not
    exceed the currently proposed 10 mg/kg limit on grapes if
    applications are within the recommended 1.7-3 kg ai/ha or 0.054%
    application rates and the 21-day recommended interval is observed.


    FATE OF RESIDUES

    In plants

    Previous studies have shown that propargite is the principle
    residue in plants and that residue loss is, at least in part, by
    volatilisation.  There are data supporting the view that propargite
    is generally "non-systemic".  It has been suggested that the
    principal metabolic degradation products in plants are propargyl
    alcohol and tert-butylphenoxy cyclohexanol with the possibility
    of further degradation to butylphenol and cyclohexanediol. 
    However, this postulated metabolic pathway was not confirmed by
    detection of residues of these products in plants.

    Three additional studies on the metabolism of propargite in plants
    have been submitted.  In one study mature red kidney bean plants
    were treated two times under greenhouse conditions with a
    14C-phenyl labelled-propargite Comite(R) formulation (Curtiss and
    Fuller, 1979) at rates equivalent to field usage rates of 1.4-2.1
    kg active/ha.  There was a 30-day interval between treatments and
    from last treatment until harvest.  Total residues in the dried pod
    at harvest were 36.9  6.85 mg/kg, of which approximately 60% was
    extractable with acetone and methanol.  Of these extractables 64.1%
    was shown by TLC/LSC to be propargite, 19% was unidentified as
    materials remaining at the origin, 6.7% was a compound with an Rf
    similar to that of the glycol ether
    [i.e.(2-[4-(1,1-dimethylethyl)phenoxy]cyclohexanol)] and the
    remaining 10.5% was unidentified.  Thus about 40% of the total
    residue was unextractable, and about 30% of the extracted residue
    was unidentified, that is 57% of the total residue was
    unidentified.  At a limit of detection of 0.05 mg/kg there were no
    residues of significance in the dried beans, thus supporting the
    view that residues are surface residues with little or no
    translocation from foliar applications.

    In another study (Henderson, 1979) Redhaven peaches were topically
    treated with (phenyl-14C) formulated Omite(R) with a solution
    concentration of 2600 mg/kg (0.26%) active or about 2 times the
    maximum rate reported as good agricultural practice (FAO/WHO,
    1978). Application was by micro-syringe in the field at a rate of
    1.3 mg propargite to each of nine peaches.  This would be 7 mg/kg
    on a fruit basis if a 190 gm fruit were used.  This approximates
    zero day residues of 1.3-10.5 mg/kg reported for a 0.1% application
    field trial application rate on nectarines (FAO/WHO, 1978). 
    Samples were analyzed by TLC/LSC at 0, 10, and 21 days after
    treatment.

    The peels and pulp were analyzed separately with results reported
    on a whole fruit basis.  Extraction was by multiple blendings with
    acetone, which was subsequently filtered.  Recoveries were said to
    be 98.8%. Analysis was on silica gel TLC plates developed with
    cyclohexane: ethylacetate (9:10) with unlabelled propargite
    visualized under UV light.  The 14C radioactivity of each segment
    of the plate was determined by LSC and unextractable residues by
    combustion.

    The recovery of applied 14C with time was 97.2, 96.67 and 71.3
    percent at 0, 10 and 21 days respectively with the extractable
    portion only decreasing from 98 percent at zero day to 92.5 percent
    at 21 days. Less that 3% of residual 14C material was in the pulp,
    again supporting the view that propargite is generally
    non-systemic. The distribution of residual 14C is shown in Table
    3.

    TABLE 3.  Percentage Distribution of Residual 14C

                                                                     
    
                     Extractable        Unextractable
     Time                                                   Total
    (days)    Propargite  Unidentified                   Unidentified
                                                                     
    

       0         94.0          4.1            2                6
      10         76.1         20.6            3.3             23.9
      21         82.5         10              7.5             17.5
                                                                     
    


    These data support other studies showing that propargite, per
    se, is the principal residue on plants and that there are
    substantial unidentified residues.  The TLC/LSC profiles at 0 and
    21 days indicate that any one component of the unidentified residue
    on peaches would be less than about 10% of the total extractables,
    although this can not be concluded from the 10-day profile.  There
    was no analysis for the glycol ether, which was tentatively
    identified in the bean study using a similar TLC system.

    In another study (Henderson, 1979) a 5000 mg/kg solution of
    propargite was topically applied to apples at 55.5 mg/kg level on
    a fruit basis to investigate whether residues of propargyl alcohol
    would result. Residues were analyzed by flame ionization gas
    chromatography at 0, 12 and 21 days after peeling and extraction
    with DMSO.  Detection limits were said to be 1.1 mg/kg propargyl
    alcohol with 84% recoveries.  No free propargyl alcohol residues
    were detected at 0, 12 or 21 days.


    RESIDUES IN COMMERCE OR AT CONSUMPTION

    Residues reported in apples in New Zealand commerce and based on
    biased sampling from crops known to be treated are as follows:

    1977 Apples    12 samples     N.D. - 1.5 mg/kg
                                  mean = 0.77 mg/kg

    These levels are well within the 5 mg/kg limit proposed by the 1975
    Joint Meeting.

    NATIONAL TOLERANCES REPORTED TO THE MEETING

                                                                 
    Country           Commodity                Tolerance (mg/kg)
                                                                 

    New Zealand       pome fruit, berry fruit
                      and stone fruit                 3

    Federal Republic   
    of Germany        hops (dried)                   30
                      citrus fruit, tea (dry
                      manufactured)                   5
                      fruit (except citrus)           3
                      cucumber, sugarbeet             0.5
                      beans (dried), cotton
                      seed, peanuts, maize
                      grain, potatoes, almonds,
                      walnut                          0.1
                                                                 


    EVALUATION

    COMMENTS AND APPRAISAL

    At the 1977 Meeting (FAO/WHO, 1978a, b) a temporary ADI for man was
    estimated to be 0-0.08 mg/kg bw/day.  Data have been provided in
    response to a request to provide a satisfactory carcinogenicity
    bioassay.  A long-term mouse carcinogenicity study showed that
    although there were increases in liver and other organ weights,
    propargite was not carcinogenic.

    Propargite is rapidly absorbed, degraded, and excreted from
    mammalian systems and does not appear to bioaccumulate.  It has a
    low order of acute toxicity, is not a mutagen or a teratogen, nor
    does it affect reproduction in the rat.  Propargite has shown no
    organ or tissue-specific effect when fed to rodents. 
    Administration of propargite to rats and dogs for two years failed
    to induce any abnormal effects attributable to propargite. 
    However, in a short-term teratology study, delayed maturation of
    foetuses at a dosage level of 25 mg/kg was observed.

    Three new studies on the metabolism of propargite in plants have
    been submitted.  In two of these 14C-phenyl labelled propargite was
    applied to bean plants and peaches respectively and in the other
    apples were fortified with unlabelled propargite.  The first two
    studies support earlier studies, which have indicated that
    propargite, per se, is the principal residue and that residues
    are primarily surface residues with little evidence of
    translocation.

    The nature of unidentified residues, which may be from 6 to 50% of
    the total residue depending on the commodity and time from
    application, is still largely unknown.  Although not entirely
    conclusive, the study on peaches does suggest that no one component
    of these unidentified residues is likely to be greater than about
    10% of total extractable residues.  However, this cannot be
    concluded in the bean study where 19% of the extractables remained
    at the origin of the TLC.

    The bean plant study gives some indication of possible residues of
    the glycol ether (2-[4-(1,1-dimethylethyl)phenoxy] cyclohexanol in
    bean pods at about 7% of extractable residues.  If confirmed, this
    would disprove earlier suggestions that residues of this compound
    are too volatile to result in residues.

    On the other hand, at a detection limit of 1.1 mg/kg, there is no
    evidence of terminal residues of free propargyl alcohol from the
    use of propargite on apples.  This does support, but does not
    prove, suggestions that this compound may be too volatile for
    residues.

    New or revised information was provided on use patterns, residues
    from supervised trials residues in commerce, and national
    tolerances of New Zealand.  Except in the case of raisins this
    information is consistent with limits previously recommended and
    does not require revisions in those recommendations.  In the case
    of raisins, the residue data show that residues on raisins from
    good agricultural practices will not exceed the existing 20 mg/kg
    limit on grapes.  There is therefore no need for a separate limit
    on raisins, which was based on a concentration factor of 2.5 times
    the 10 mg/kg level for grapes.

    Level causing no toxicological effect

    Rat: 300 mg/kg in the diet equivalent to 15 mg/kg bw/day
    Dog: 900 mg/kg in the diet equivalent to 47 mg/kg bw/day based on
    actual dietary intake.

    Estimate of temporary acceptable daily intake for man

    0-0.08 mg/kg bw/day

    The meeting concludes that the separate 25 mg/kg level for
    propargite on raisins should be withdrawn since residues are
    adequately covered by the 10 mg/kg limits on grapes.


    FURTHER WORK OR INFORMATION

    Required (by 1982)

    Clarification of the delayed maturation effects observed in the
    teratology study in the rat.

    Desirable

    1. Further confirmation of the postulated degradation pathway in
    plants with particular attention to the characterization of
    unidentified residues (free or conjugated) and the possibility of
    residues of the glycol ether.
    2. Additional data from supervised trials in countries other than
    the U.S.A.
    3. Information on the occurrence of residues in commodities in
    commerce.


    REFERENCES

    Brusick, D.J. and Weir, R.J. Mutagenicity evaluation of D104 -
    Final Report. (1977) Unpublished report (No. 2683) from Litton
    Bionetics, submitted to the World Health Organization by Uniroyal
    Chemical.

    Canada. Propargite residues in raisins. Data provided to FAO by the
    Canadian Inter-departmental Codex Committee on pesticide residues,
    (1980).

    Cox, G.E. and Re, T.A. Chronic oncogenic evaluation of Omite(R) in
    CD-1 mice following 78 weeks of dietary treatment.  (1979)
    Unpublished report from Food and Drug Research Laboratories, Inc.,
    submitted to the World Health Organization by Uniroyal Chemical.

    Curtiss, K. and Fuller, G.B. The metabolic fate of propargite in
    red kidney bean plants, Project No. 7918. (1979) Unpublished report
    submitted by Uniroyal Chemical, Inc.

    Gallo M.A. and Bailey, D.A. Range finding study with Omite(R) in
    albino mice. (1976) Unpublished report from Food and Drug Research
    Laboratories, Inc., submitted to the World Health Organization by
    Uniroyal Chemical, Inc.

    Henderson, S.K. Degradation of Omits (phenyl-14C) on Redhaven
    Peaches, Project Number 7952. (1979) Unpublished report submitted
    by Uniroyal Chemical, Inc.

    Henderson, S.K. Analysis of Apples treated with Omite(R) for
    propargyl alcohol, Report Number 7948. (1979) Unpublished report
    submitted by Uniroyal Chemical, Inc.

    Knickerbocker, M. and Re, T.A. Teratological evaluations of
    Omite(R) technical in Sprague-Dawley rats. (1979) Unpublished
    report from Food and Drug Research Laboratories, Inc., submitted to
    the World Health Organization by Uniroyal Chemical.

    


    See Also:
       Toxicological Abbreviations
       Propargite (Pesticide residues in food: 1977 evaluations)
       Propargite (Pesticide residues in food: 1978 evaluations)
       Propargite (Pesticide residues in food: 1979 evaluations)
       Propargite (Pesticide residues in food: 1982 evaluations)
       Propargite (JMPR Evaluations 1999 Part II Toxicological)