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    PROPOXUR      JMPR 1973

    IDENTITY

    Chemical name

         2-isopropoxy-phenyl-N-methyl carbamate

    Synonyms

         PHC (common name in Japan)
         Unden(R) (mainly for agricultural uses)
         Baygon(R), Blattanex(R)
         Bay 39007
         OMS-33
         Bö 58 12 315

    Structural formula

    CHEMICAL STRUCTURE 1


         The technical material contains at least 95% propoxur.

    Other information on identity and properties

    (a) Composition of technical propoxur

         Analysis of samples of technical propoxur gave the following
    results:

                                                                        
         Component                     %

         propoxur                      min. 95%

         O-isopropoxyphenol            max. 3%        )
                                                      )
         N,N dimethyl-O-isopropoxy                    ) together
                                                      ) max. 4.5%)
         phenyl allophanate            max. 2%        )

         1,2-diisopropoxybenzene       max. 0.5%
                                                                        

    (b) Physical and chemical properties

         Physical state:       white to cream coloured, crystalline powder
                               with mild phenolic odour

         Molecule weight:      209.2

         Melting point:        techn. product 86-89°C;
                               pure propoxur 91.5°C

         Vapour pressure:      6.5 x 10-6 mHg at 20°C;
                               1 x 10-2 mHg at 12°C

         Specific gravity:     D20 = 1.19
                                 4

         Solubility:           in water of 20°C approx. 0.2%;
                               soluble in most polar organic solvents

         Stability:            stable under normal storage and use
                               conditions

         Hydrolysis rate:      propoxur is hydrolyzable in alkaline media;
                               half life values in aqueous solutions
                               at 20°C and pH 10.8 - 40 minutes
                                           pH 11.8 - 11.5 minutes
                                           pH 12.8 - 1 minute;
                               in a 1% aqueous solution at pH 7, it
                               hydrolyzes at a rate of 1.5% per day

         Formulation used:     wettable powder 50%;
                               liquid (EC) 20% w/w, gravity d204
                               approx. 1.09;
                               dust 1 and 2%;
                               fly and cockroach baits 1 and 2%;
                               balls against flies 50 mg propoxur/ball

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    Biochemical aspects

    Absorption, distribution and excretion

         Radio-labelled propoxur was orally administered to rats at
    dosages of 5-8 mg/kg. Rats eliminated 85% of the administered
    radio-activity within 16 hours. Approximately 257 of the administered
    dose was obtained as volatile compounds (CO2 : acetone; 85: 15) with
    60% being found in the urine. Very small quantities of radio-activity
    were observed in faeces, indicating that rapid absorption was
    occurring. From this study, it is evident that propoxur is rapidly
    absorbed and excreted in rats following acute administration (Everett
    and Gronberg, 1970).

    Biotransformation

         The metabolic fate of propoxur has been studied in vivo in
    mammals, plants and insects and in vitro using preparations from
    various biological sources as well as using artificial systems to
    examine the non-biological and environmental fate (Dorough and Casida,
    1964; Oonnithan and Casida, 1966; Abdel-Wahab et al., 1966; Krishna
    and Casida, 1966; Dorough et al., 1963; Kuhr and Casida, 1967;
    Oonnithan and Casida, 1966, 1968; Tsukamoto and Casida, 1967a and b;
    Casida et al., 1968; Balba and Casida, 1968; Shrivastava et al., 1969;
    Kuhr, 1968, 1970; Everett and Gronberg, 1968; Gronberg, 1970; Metcalf
    and Fukuto, 1965; Metcalf et al., 1967; Everett and Gronberg, 1971).
    Incubation of propoxur with rat liver microsomes fortified with
    various cofactors resulted in the formation of 2 hydroxyphenyl
    methylcarbamate, 5 hydroxy propoxur, N-hydroxymethyl propoxur and
    2-isopropoxyphenol. In vitro, in the presence of UDP-glucuronic
    acid, these products would be conjugated. In vivo these same
    metabolites were observed with an additional compound being
    hydroxylated at the 2 carbon of the isopropoxy group. The major routes
    of metabolism are depropylation to 2-hydroxyphenol-N-methylcarbamate
    and hydrolysis to yield isopropoxy phenol. The minor routes of
    metabolism are ring hydroxylation at the 5 or 6 position with
    secondary hydroxylation at the 2 carbon of the allphatic sidechain and
    n-methyl hydroxylation of the carbamate. The metabolites identified in
    the rat appear to be the same as those found in plants, insects and
    derived from in vitro systems. In vitro studies on the
    photodecomposition of propoxur in solution resulted in the observation
    that, of six N-methyl carbamates, propoxur was the only compound to be
    completely stable under the conditions imposed (Crosby et al., 1965).
    When exposed to light on a solid surface, propoxur was found to be
    slightly degraded to two unidentified organic soluble materials
    (Abdel-Wahab at al., 1966).

    Effects on enzymes and other biochemical parameters

         Propoxur is a biologically active material because of its
    structural complimentarity to the active site of neptyl
    cholinesterase. As a cholinesterase inhibitor, propoxur behaves as a
    synthetic neurohormone that produces its toxic action by interrupting
    the normal action of acetyl cholinesterase so that the substrata
    acetylcholine accumulates at synaptic junctions. In vivo the signs
    of poisoning are manifested by irritability. tremors, incoordination,
    convulsions, paralysis and death. While several other carbamate
    insecticides (carbaryl, Landrin, and others) produce a transient
    anaesthetic effect following high dose administration, there is no
    such effect noted with propoxur (Vandekar et al., 1971). In vivo and
    in vitro studies have shown propoxur to be a potent inhibitor of
    various types of cholinesterase. The I50 (inhibitor concentration
    illiciting 50% inhibition) or the bimolecular rate constant
    (LM-1min-1) can be seen in the following table.

         The specificity of propoxur for true cholinesterase as evident by
    its specificity towards bovine and RBC rather than for plasma or serum
    cholinesterase is evident from the table. This selectivity was also
    noted in studies on the effect of propoxur on man (see section,
    Observations in man).

         Vandekar et al. (1971) observed that depression of cholinesterase
    activity in blood was determinable only during the short period of
    time in which signs of poisoning occur. Following acute administration
    of propoxur, it was observed that there was a correlation between the
    severity of the signs of poisoning and the degree of depression of
    erythrocyte cholinesterase. Signs of poisoning appeared initially when
    the activity of the cholinesterase dropped below 50% of normal.
    Following oral administration of propoxur to rats at a dose
    approximately LD50, blood and brain cholinesterase activity was found
    to be decreased by about 50% according to a spectrophotometric method
    of analysis; however, the determination of cholinesterase activity by
    an electrometric method or by a colorimetric method did not show this
    inhibition.

         As with other carbamate esters, propoxur does not appear to
    exhibit any offset on other enzymes or other biochemical parameters.

    TOXICOLOGICAL STUDIES

    Special studies on reproduction

         Groups of rats (10 male and 20 female per group) were fed
    propoxur in the diet at levels of 0, 250, 750, 2000 and 6000 ppm in a
    standard three-generation, two-litter/generation reproduction study.
    The two highest dietary levels affected the wellbeing of the parent
    generation which resulted in a reduction in lactation and further
    reduced the pup weight and the parental rate of growth. In addition,
    there were effects at 6000 ppm which included smaller litter size. At
    the conclusion of the study, examination of various tissues from the
    pups of the F3B generation fed 2000 ppm and above showed that there
    was a general reduction in the organ weights at three weeks of age.
    However, the organ to body weight ratio of these animals corresponded
    to that seen with the control, indicating as observed above that the
    presence of 2000 ppm in the diet resulted in restricted growth in the
    pups. Malformations were not observed in the histological examination
    of selected tissues, including those that were noted under gross
    examination to be small. Microscopic pathology showed no signs of
    alterations attributable to the administration of propoxur. The
    dietary concentration of 750 ppm and below did not effect fertility,
    litter size and lactation (Loser, 1968a; Mawdesley-Thomas, 1969a).

    
    CHOLINESTERASE INHIBITION

                                                                                      
    Enzyme          I50               Ki                  Referencea
    source          (M)               (LM-1min-1)
                                                                                      
    Bovine          7 x 10-7                              Vandekar et al., 1971
                                      0.5 - 1.0 x 105     (O'Brien, 1966;
                                                          (Reiner and Aldridge, 1967

    Fly             0.1 - 8 x 10-8                        (Weiden, 1971;
                                                          (Metcalf, 1971

                                      1 x 105             Metcalf, 1971

    Human serum                       0.95 x 103          Metcalf, 1971

    Haman plasma    2.3 x 10-5                            Wilhelm, 1967

    Human RBC       4.6 x 10-7                            Wilhelm, 1967
                                                                                      

    a All values were referenced from various sources, either reviewed or presented as
      original data in Bull. Wld Hlth Org., 1971, 44 (1,2,3), 1-470.
    
    Special studies on mutagenicity

         A "dominant-lethal study" was conducted on groups of 12 male mice
    where the mice were administered a single i.p. dose of propoxur at
    levels of 0, 2.5 or 5.0 mg/kg. For a period of six weeks, three virgin
    females were exposed to each male at weekly intervals and reproduction
    indices recorded. Males treated with 5 mg/kg had slightly lessened
    physical activity which lasted one to two days following the treatment
    and was reflected in the reduced number of implantations noted in the
    treated groups with the females fertilized in the first week after
    treatment. The acute administration of propoxur proved to have a
    transient effect on the reproduction capability of the males, but
    there was no evidence of early resorption which is indicative of an
    absence of mutagenic defect (Arnold et al., 1971).

    Special studies on neurotoxicity

         Adult white leghorn hens wore orally administered proPoxur at
    levels ranging from 100 to 1000 mg/kg in a single oral dose or as a
    single i.p. dose at levels ranging from 25 to 100 mg/kg. In two of the
    three trials, PAM (100 mg/kg) and atropine sulfate (50 mg/kg) were
    injected intraperitoneally prior to treatment. No neurotoxic signs of
    poisoning similar to that observed with TOCP were noted during periods
    of up to six weeks of observation after treatment (Kimmerle, 1964,
    1966a).

         Groups of eight adult white leghorn hens were fed propoxur in the
    diet at levels of 0, 300, 1500, 3000 and 4500 ppm for 30 days. No
    evidence of delayed neurotoxic signs of poisoning was seen either
    during the period of feeding or in a posttreatment observation period
    of four weeks. Histological examination of sciatic nerve and spinal
    cord showed no evidence of demyelination (Kimmerle, 1966a; Hobik,
    1967).

    Special studies on potentiation

         Intraperitoneal administration of propoxur to adult female rats
    in combination with 20 different anticholinesterase insecticides (19
    organophosphates and one carbamate) administered at a dose level of
    one-half of the LD50 did not result in an increase in the acute
    toxicity (DuBois and Raymund, 1961b and c; Nelson, 1967). Propoxur
    does not appear to potentiate antiesterase activity and, as it is a
    weak inhibitor of pseudocholinesterase (serum cholinesterase Ki = 9.5
    x 102 Lmol-1 min-1) it is doubtful that aliesterase inhibition, a
    better indicator of potentiation, would be significantly reduced.

    Special studies on teratogenicity

         Groups of 10 pregnant rats were fed propoxur in the diet at
    concentrations of 0, 1000, 3000 and 10 000 ppm during gestation.
    Administration of 3000 ppm and above had an adverse effect on the
    parents. At 10 000 ppm, there was a reduction in the number of fetuses
    and an increase in the number of resorption sites. This was not
    evident at 3000 ppm. There appeared to be a dose-dependent
    relationship between the reduction in fetal weight (although only the
    3000 and 10 000 ppm were statistically significant) accompanied by a
    dose-dependent decrease in placental weight. The dietary concentration
    of 1000 ppm was tolerated by the parents and the fetuses and, except
    for a slight reduction in the average fetal weight, this level showed
    no detrimental effects. Teratogenic abnormalities were not noted in
    this study at any dosage level (Lorke, 1970).

    Acute toxicity

        (a) Original compound

                                                                            
    Species      Sex     Route    LD50          Reference
                                  (Mg/kg)
                                                                            

    Rat          M & F   oral     80-191        Ben Dyke et al., 1970;
                                                DuBois and Raymund, 1961a;
                                                Gaines, 1969;
                                                Kimmerle, 1961, 1966b, 1971;
                                                Klimmer, 1963

    (cont'd)
                                                                            
    Species      Sex     Route    LD50          Reference
                                  (Mg/kg)
                                                                            
    Guinea-pig   M       oral     40            DuBois and Raymund, 1961a

    Chicken      F       oral     150-750       DuBois, 1962;
                                                Kimmerle, 1964
    Rat          M & F   i.p.     10-30         DuBois and Raymund, 1961a;
                                                Kimmerle, 1961;
                                                Klimmer, 1963;
                                                Nelson, 1967

    Guinea-pig   M       i.p.     16            DuBois and Raymund, 1961a

    Mouse        M & F   i.p.     14-20         DuBois and Raymund, 1961a

    Rat          M & F   dermal   1000->2400    Ben Dyke et al., 1970;
                                                DuBois and-Raymund, 1961a;
                                                Gaines, 1969;
                                                Kimmerle, 1961;
                                                Klimmer, 1963

    Rat                  i.v.     10.6          Vandekar, 1965

    Rat                  i.m.     53            Vandekar, 1965
                                                                            

    b) Metabolites
                                                                            
    Species              Sex   Route     LD50       Reference
                                         (mg/kg)
                                                                            

    2-bydroxyphenyl
    N-methylcarbamate

    Mice                       i.p.      >167       Balba and Casida, 1968

    5-hydroxy propoxur

    Mice                       i.p.      >56        Balba and Casida, 1968

    4-hydroxy propoxur

    Mice                       i.p.      52         Balba and Casida, 1968

    Propoxur

    Mice                       i.p.      12         Balba and Casida, 1968

    O-isopropoxyphenol

    Rat                  F     oral      >1000      DuBois, 1963
                               dermal
                                                                            
    
         The signs of poisoning shown by propoxur are typical of those
    induced by cholinesterase-inhibiting carbamate esters. Tremors, muscle
    spasm, lacrimation, salivation and secretion of red tears were
    observed in rats following acute dosing. The symptoms appeared rapidly
    after administration and recovery was fast.

         Following oral administration of propoxur to rats, i.p.
    administration of atropine sulfate was found to be antidotal, while
    treatment with oximes (PAM, 50 mg/kg and BH6, 20 mg/kg) afforded no
    protection and were contraindicated (Kimmerle, 1961b).
    Tetraethylammoniumchloride proved also to afford no protection from
    the acute effects of propoxur (Kimmerle, 1971).

    Subacute dermal toxicity

         Groups of rabbits (five males and five females per group) were
    treated dermally with propoxur at a level of 500 mg/kg for two weeks.
    Residues of the material remaining on the skin prior to each
    application were not washed off. Twenty-four hours after the final
    application., the skin was washed with soap and water and the animals
    observed for two further weeks. The treatment did not affect the
    general behaviour and weight gain of the animal and clinical
    examinations of blood, urine, liver and kidney function over the
    two-week period were normal (Kimmerle and Solmeeke, 1971). Propoxur
    was found to be nonirritating to the skin of rabbits when applied to
    the inside of a rabbit's ear for 24 hours. No signs of irritation or
    poisoning were observed when propoxur was applied to the shaved
    abdominal skin of rats and allowed to remain for four hours (Kimmerle,
    1961).

    Short-term studies

    Rat. Groups of rats (15 males and 15 females per group) were fed
    propoxur in the diet at levels of 0, 1000, 2000, 4000 and 8000 ppm
    (females were fed only dietary levels of 0 and 4000 ppm) for nine
    weeks. There was an increase in mortality in the animals fed 4000 and
    8000 ppm and a reduction in food consumption and weight gain was
    observed in all animals (Löser, 1965).

         Oral administration of propoxur to 25 male rats at a dose of 5
    mg/kg/day, six days a week for six months (20 male rats served as
    controls) resulted in no effects attributable to the administration of

    the compound. Growth and food consumption were similar to the
    controls, and gross and histological examination of tissues showed no
    effects attributable to the administration of propoxur (Klimmer,
    1963).

         Groups of rats (12 males and 12 females per group) were fed
    propoxur in the diet for 16 weeks at concentrations of 0, 5, 10, 50,
    100 and 200 ppm (those animals fed 100 and 200 ppm were increased
    after the first three weeks of feeding to 400 and 800 ppm respectively
    for the remainder of the study). The administration of propoxur at
    levels up to 800 ppm in the diet did not affect food consumption,
    growth, mortality or gross and histological examination of tissues.
    Cholinesterase activity, measured manometrically in the blood, brain
    and submaxillary glands, was not affected (Root et al., 1963).

         Rats were treated orally for four weeks at 0, 3, 10 and 30 mg/kg.
    The highest level caused signs of poisoning and cholinesterase
    depression was noted at 10 and 30 mg/kg, with no depression noted at
    the low level (Eben and Kimmerle, 1973).

         Groups of rats were fed propoxur in the diet at 0, 250, 750 and
    2000 ppm for 15 weeks. Propoxur was tolerated with no signs of
    poisoning and no consistent evidence of cholinesterase depression
    (Eben and Kimmerle, 1973).

         Groups of rats (10 males and 10 females per group) were fed
    propoxur in the diet at concentrations of 0, 250, 500, 1000 and 2000
    ppm for 16 weeks. Food consumption and body weight gain in the females
    receiving concentrations of 1000 ppm and above were reduced. No
    significant changes were noted with regard to organ weight data. The
    1000 and 2000 ppm levels caused depression of cholinesterase activity
    in whole blood after the twelfth week of testing and, on completion of
    the feeding study, cholinesterase activity was depressed in plasma,
    whole blood and brain. Although all clinical enzyme data were found to
    be within the normal range, some histopathological changes were noted
    in the livers of the animals which received 1000 and 2000 ppm. The
    no-effect level in this study was judged to be 500 ppm (Syrowatka et
    al., 1971).

    Dog. Groups of beagle dogs (four males and four females per group)
    were fed propoxur in the diet at concentrations of 0, 100, 250, 750
    and 2000 ppm for two years. Mortality was evident at 2000 ppm. One of
    the male dogs and none of the female dogs at this level survived to
    the end of two years. Food consumption was reduced at this high level.
    The animals receiving 2000 ppm at times exhibited signs of
    cholinesterase depression, especially in the first six months of
    testing. Dietary concentrations of 750 ppm and below did not affect
    appearance, behaviour, food consumption or growth of the animals.
    Haematological examinations and liver and kidney function tests showed
    no effects of propoxur at any dosage level examined. Activity of
    leucine-amino peptidase was slightly elevated at levels of 750 and
    2000 ppm. Gross examination of tissues showed that there was a

    slightly increased liver to body weight ratio in males at 2000 ppm.
    There was no indication of cellular damage in any tissue as evidenced
    by histological examination of tissues. Although there was a slight
    increase in leucine-amino peptidase activity at 750 ppm, based upon
    all other considerations, it was assumed that a level of 750 ppm is a
    no-effect level. Based on food consumption data, the no-effect level
    in dogs would be 50 mg/kg bw/day (Löser, 1968c; Mawdesley-Thomas,
    1969c).

    Long-term studies

        Groups of SPF rats (25 males and 25 females per group, 50 males
    and 50 females per control group) were fed propoxur in the diet at
    levels of 0, 250, 750, 2000 and 6000 ppm for two years. Dietary
    concentration of 6000 ppm caused a reduction in food consumption in
    male rats, while 2000 ppm and above resulted in a similar effect in
    females. This reduction in food intake was reflected in body weight
    gains Of these two groups. On gross examination, at the end of two
    years some slight effects were noted in some organs. especially liver
    which was enlarged relative to the body weight at the highest feeding
    level in male rats and at the highest three feeding levels in female
    rats. This increased liver weight was not reflected in liver function
    tests or in clinical chemistry examination. Cholinesterase examination
    in whole blood (performed only at six months) showed no depression of
    cholinesterase activity at 6000 ppm in males and females. Histological
    examination of tissues showed no effects relating to the feeding of
    propoxur. A no-effect level in this study, based upon increased
    relative liver to body weight ratio, is 250 ppm (Loser, 1968b;
    Mawdesley-Thomas, 1969b).

    Observations in man

         Because of the widespread experimental views of propoxur and
    control through the auspices of WHO, some significant observations in
    humans are available (Plestina, 1968; Dawson, 1964; Vandekar, 1969;
    Vandekar et al., 1968, 1971). In a study undertaken to develop a
    quantitative method for determining metabolites of propoxur. Dawson et
    al. (1964) showed that oral administration of 110 and 116 mg/person
    Produced no signs of illness. The level of urinary phenols reached 140
    ppm in the absence of clinical signs of poisoning. In persons engaged
    in spraying or other occupation exposure, urinary levels of 80 ppm are
    uniformly associated with illness. In another study, Vandekar et al.
    (1971) administered 135 mg/person to a male volunteer (1.5 mg/kg bw)
    and within 20 minutes after ingestion described clinical signs of
    poisoning due to the carbamate. Significant erythrocyte cholinesterase
    depression was evident coinciding with clinical signs of poisoning,
    while plasma cholinesterase depression was not observed. Two hours
    after the ingestion of propoxur, there were no signs of poisoning and
    the rapid disappearance of symptoms was consistent with the rapid
    recovery of erythrocyte cholinesterase activity. Absorption and
    excretion of propoxur was very rapid as evidenced by measurement of
    urinary phenols which reached a maximum value within four hours of

    almost 200 ppm. Of the total phenol content excreted, 81% was found
    within five hours after administration. In another experiment, a
    single dose of 0.36 mg/kg again produced a rapid fall of erythrocyte
    cholinesterase to 57% of normal within 10 minutes. Cholinesterase
    recovered to its normal value within three hours. Within 10 minutes of
    the administration of propoxur, short-lasting stomach discomfort,
    blurred vision, and moderate facial redness and sweating were evident
    in the volunteer.

         A number of experiments was carried out to study the effect of
    storage or build-up of propoxur in the body. Human volunteers took
    doses of either 0.15 or 0.2 mg/kg at half-hour intervals for a total
    of five doses. In each subject a symptomless depression of erythrocyte
    cholinesterase to about 60% of normal was observed. At the cessation
    of dosing, enzyme recovery was rapid, being complete within two hours.
    Similarly pronounced and as a rule symptomless daily depression and
    reactivation of cholinesterase was observed in persons who are
    occupationally exposed to propoxur. Studies in humans have shown that
    depression of erythrocyte cholinesterase (rather than plasma
    cholinesterase) is a significant indicator of exposure to propoxur.
    This is consistent with the difference observed in the in vitro
    affinity of propoxur for the two enzymes, the I50 values for
    erythrocyte and plasma cholinesterase being 4.6 x 10-7 M and 2.3 x
    10-5 M, respectively.

         Vandekar et al. (1968) published the results of studies carried
    out on spray operators and local inhabitants in Iran as part of a WHO
    control programme. It was reported that following over-exposure some
    spray operators and local inhabitants suffered mild temporary
    cholinergic signs of poisoning (headache, nausea). In most of the
    cases, the complaints were found to be due to heavy contamination of
    propoxur on the skin.

         It is evident from these studies that a single oral dose (between
    0.2 and 0.4 mg/kg) of propoxur may produce symptoms in man of short
    duration. Higher doses may be tolerated without evidence of poisoning
    (although there is appreciable inhibition of erythrocyte
    cholinesterase) if the higher doses are divided into portions and
    administered over reasonably short periods of time. Within two hours
    following exposure, cholinesterase depression would be expected to be
    normal.

    Comments

         Propoxur, an anticholinesterase carbamate ester, induces typical
    signs of cholinesterase inhibition in both laboratory animals and
    humans. Reversible depression of cholinesterase activity is evident a
    short time after exposure, although the sensitivity of various
    cholinesterase sources differ in different animal species. Erythrocyte
    cholinesterase is significantly more sensitive than plasma
    cholinesterase in humans. The sensitivity of brain and plasma
    cholinesterase appears to be of the same magnitude in rats. Although
    0.36 mg/kg resulted in signs of acute poisoning in man, the repeated

    administration of 0.2 mg/kg at half-hour intervals for 2.5 hours
    resulted in no signs of poisoning, although cholinesterase activity
    was depressed. This cholinesterase returned to normal within two hours
    following exposure.

         Propoxur is rapidly absorbed, metabolized and eliminated.
    Teratogenicity and mutagenicity studies in the rat gave negative
    results and reproduction was not affected by propoxur.

         A long-term rat study provided no evidence of carcinogenic
    activity. Liver weight was increased in both males and females at high
    dosage levels. No changes were found in liver function tests, clinical
    chemistry or on histological examination. In view of the histological
    changes in the livers of rats exposed over a short period to 1000 ppm,
    the increase in relative liver weight was considered a significant
    effect. 250 ppm in the diet was accepted as the no-effect level in the
    rat.

         In a two-year dog study, a slight increase in leucine-amino
    peptidase activity was not regarded as significant. The no-effect
    level as evidenced by liver damage was 750 ppm in the diet which,
    based on feed consumption data, was 50 mg/kg bw. Cholinesterase
    depression was not observed in either the two-year rat or dog studies.
    It was evident to the Meeting that the methodology used to determine
    cholinesterase activity in these studies was not adequate to measure
    depression caused by propoxur.

         The no-effect level in the long-term study in the rat was used as
    a basis for estimation of the ADI.

         The rapid reversibility of acute signs of poisoning in man and
    the fact that sensitivity to the toxic effects of propoxur decreased
    during prolonged exposure was reassuring in estimating the ADI.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Rat:    250 ppm in the diet equivalent to 12.5 mg/kg bw

         Dog:    50 mg/kg bw/day

    Estimate of acceptable daily intake for man

         0-0.02 mg/kg bw

    RESIDUES IN FOOD AND THEIR EVALUATION

    Metabolic aspects

         The metabolism of propoxur was studied in mammals by Dawson et
    al. (1964), Everett and Gronberg (1970), Krishna and Casida (1966),

    Waggoner and Olson (1971); in man by Dawson et al. (1964), Hayes
    (1971); in insects by Metcalf et al. (1967), Shrivastava (1969); in
    plants by Aba el Wahab (1966), Dorough and Casida (1964), Everett and
    Gronberg (1968), Gronberg (1970), Kuhr and Casida (1967).

         In vitro in animals studies were made by Crosby et al. (1965),
    Dorough and Casida (1964) and Oonithan and Casida (1966, 1968).

    In rats

         The metabolites identified in the rat (see below) include those
    found in plants, in insects and those derived from microsomes.

         Whereas the oxidative pathways and hydrolytic degradation occur
    in the same order of magnitude in mammals, the formation of oxidation
    products predominates in plants. In soil, however, hydrolytic
    degradation predominates.

         Adsorption, distribution and excretion in mammals, including
    biotransformation in rats: following oral administration in rats,
    propoxur is rapidly ingested to the digestive tract, metabolized in
    the body and excreted.

         The rats eliminated 85% of the radio-activity after oral
    administration of 14C carbonyl labelled, 14C isopropoxy labelled 3H
    isopropyl labelled propoxur within 16 hours; 60% of this and amount
    was excreted in the urine as conjugates and 20-25% as volatile
    compounds in a C02/acetone ratio of 85:15. Only 1-5% of the activity
    was found in the faeces in the same period (Everett and Gronberg,
    1970).

         Evidence was obtained by the same authors that the major routes
    of metabolism in rats are depropylation to
    2-hydroxyphenyl-N-Methylcarbamate (further indicated as metabolite
    A) and subsequent hydrolysis to isopropoxyphenol (metabolite I).

         Minor metabolic pathways are ring hydroxylation at the 5 or 6
    position (C and E), secondary hydroxylation of the 2-carbon atom of
    the isopropoxy group (D and G) and hydroxylation of the N-methyl
    group.

         From the conjugated compounds in the urine, the following
    metabolites were released by hydrolysis of the urine sample with
    glucuronidase and/or acid. They were identified by their infra-red and
    mass spectra as well as from the 3H/14C ratio yielded of double
    labelled propoxur: 2-hydrophenyl-N-methylcarbamate (A),
    2-isopropoxyphenyl-N-hydroxy methylearbamate (B) and
    2-isopropoxy-5-hydroxyphenyl-N-methylearbamate (C).

         The metabolic pathways of propoxur in rats as proposed by Everett
    and Gronberg (1970) is shown in the diagram on the following page.

    FIGURE 


         Krishna and Casida (1966) administered 14C carbonyl labelled
    propoxur intraperitoneally to rats. After 48 hours only 2.1% of the
    administered radio-activity remained in the body; 60% of the activity
    was excreted in the urine in the first 29 hours, whereas only 1.2% was
    excreted in the faeces. Within 48 hours 31.2% of the administered
    radio-activity was expired as CO2.

         From these data it may be concluded that the carbamate group was
    cleaved from one-third of the injected propoxur dose.

         In a similar experiment with 14C isopropyl labelled propoxur,
    70-75% of the activity was excreted in the urine, whilst 30%. of the
    administered activity was expired as 14CO2; 4% of the activity
    remained in the body and only 0.7% was excreted in the faeces.

         From this it may be concluded that the isopropyl group is cleaved
    from about one-quarter of the injected dose.

         Dorough and Casida (1964) incubated rat liver microsomes with
    propoxur and obtained 30% conversion to a metabolite from which with
    acid Isopropoxyphenol and formaldehyde were yielded. With
    cochromatography and infra-red spectroscopy the metabolite was
    confirmed with (B).

         Oonithan and Casida (1968) studied the metabolic fate of propoxur
    in a system containing rat liver microsomes and NADPH2. Two
    metabolites were formed, probably (A) and (B).

    In cattle

         Waggoner and Olson (1971) determined residues in tissues and milk
    of cattle after feeding on a diet containing propoxur for 28 days. In
    those cases where residues could be detected the amounts of the
    metabolite (A) was greater than the parent propoxur.

         After feeding 7.5 mg/kg/day of propoxur, the residues of the
    parent compound and the metabolite (A) were respectively:

                                            
                        ppm
                        propoxur       (A)
                                            
         kidney         0.04           0.13

         milk           0.001          0.0027
                                            

    In insects

         Metcalf et al. (1967) treated flies with 14C isopropoxy labelled
    propoxur and found metabolism to CO2. A pre-treatment with piperonyl
    butoxide reduced the formation of CO2 to one-third.

         Dorough et al. (1963) and Dorough and Casida (1964) found in
    cockroaches the metabolite (B) after injection of propoxur.

         Shrivastava et al. (1969) (see also Ruhr, 1968, 1970) studied
    in vivo and in vitro the metabolism of propoxur in houseflies.
    The following metabolites were isolated in order of decreasing amounts
    (C), (A) and acetone, B and 2-isopropoxyphenyl carbamate. These
    metabolites were all conjugated due to their hydroxyl groups and
    volatilized in acetone (see also Casida et al., 1968).

         Tsukamoto and Casida (1967a and b) investigated the metabolism of
    propoxur in a system of house-fly microsomes and NADPH2; they found
    the metabolites (A), (B) and (C) as major metabolites.

         Propoxur is a non-systemic carbamate insecticide which is used
    against a relatively broad spectrum of insects in field crops, fruit
    and vegetables (aphids, including woolly aphid, lygus bugs,
    leafhoppers, saw-flies, thrips, millipedes, etc.).

         The product is registered and used in several countries in Europe
    and in other parts of the world.

         Propoxur is used extensively for hygienic purposes against
    cockroaches, flies, etc. in homes, hotels, restaurants and warehouses.

    Pre-harvest treatments

         Major crops on which propoxur is used are rice, sugar cane, pome
    and stone fruits, small fruits, vegetables and potatoes. The following
    estimates can be given of the use in different areas:

         rice                          about 30%

         other field crops             about 30%

         cacao                         about 20%

         other crops such as fruit,
         vegetables, ornamentals       about 20%.

         The following table summarizes the recommendations in accordance
    with good agricultural practice, including rates of application and
    pre-harvest intervals.


                                                                                       

                                       Dosage rate      Minimum pre-harvest
    Crop                               g a.i./ha or     interval recommended
                                       g a.i./100 l     days
                                                                                   

    Field crops

      potatoes                         250-600 g/ha               7
      rice                             400-750 g/ha               7
      sugar cane                       750-1000 g/ha              7

    Cacao                              250-600 g/ha               7

    Fruits

    Pome fruits

      apple, pears                     50-75 g/100 l              7
                                       600-1200 g/ha

    Stone fruits

      peach, plums                     50-75 g/100 l              7
                                       900-1200 g/ha

    Small fruits

      blackberries, gooseberries,
      red currants, raspberries,
      strawberries                     50-75 g/100 l              7
                                       600-1200 g/ha

    Vegetables (outdoors)

      beans, cabbage, gherkins,
      leek, lettuce, onionp
      peas, spinach                    400-750 g/ha               4-7

    vegetables (glasshouses)

      bell peppers, cucumbers,
      gherkins, melons,
      tomatoes                         400-750 g/ha               4

    Leafy vegetables such as
      lettuce, spinach                 400-750 g/ha               14-21

                                                                           
    
    Post-harvest treatments

         No treatments recommended.

    Other uses

         Propoxur is used on ornamentals and flower crops.

         It is also extensively used in the hygienic sector in the form of
    aerosols, thermal fog concentrates, baits, wettable powder and
    emulsifiable liquids, against a number of household and domestic pests
    such as bugs, cockroaches, flies, mosquitos, beetles, silverfish, etc.

    Pre-harvest intervals officially established in
    various countries in days

    Austria

         35 days, all fruit and vegetables

    Belgium

         21 days, lettuce and endive (glasshouse cultures) during
         winter period

         14 days, lettuce and endive (outdoors and glasshouse)

         7 days, other vegetables except those mentioned below,
         agricultural crops

         3 days, gherkins, tomatoes (both under glass and outdoors),
         bell peppers, cucumber, melons

    Denmark

         14 days, fruit, vegetables and field crops

    Germany, Federal Republic of

         21 days, cereals

         14 days, potatoes

         7 days, leafy vegetables (except lettuce), tomatoes,
         gherkins, melons

         4 days, pome and stone fruit, gooseberries, red and black
         currants, raspberries, strawberries, cabbage, carrot,
         celery, garden beet, leek, lettuce, onion, radish, horse
         radish, sugar and fodder beet

    Netherlands

         21 days, lettuce and endive (glasshouse) between
         November/March

         14 days, lettuce and endive (outdoors.and glasshouse)

         7 days, fruit, including berries, vegetables except those
         mentioned below

         4 days, gherkins (glasshouse and outdoors)

         3 days, tomatoes, bell peppers, cucumbers, melons

    New Zealand

         21 days, all crops

    Poland

         7 days, potatoes

    Spain

         30 days, fruit, sugar beet, cotton

    Sweden

         14 days, vegetables

         7 days, all other crops

    United Kingdom

         7 days, all outdoor crops

         2 days, cucumbers, tomatoes (glasshouse)

    Yugoslavia

         21 days, fruit

    Residue data from supervised trials

         Residue data were obtained from trials on several fruits,
    vegetables and field crops, such as apples. sour and sweet cherries,
    peaches, plums, black and red currants, gooseberries, French beans,
    bell peppers, red and white cabbage, savoy, carrots, cucumbers,
    lettuce, leek, onions, peas, spinach, tomatoes, alfalfa, cereals,
    rice, tobacco, cocoa, grassland. These data are summarized in Tables 1
    and 2.


        TABLE 1. RESIDUES OF PROPOXUR IN ppm

                                                                                                                                               

                                     Application                        Pre-harvest intervals
    Crop          Country      Year                                                                                                           
                                     No.  rate kg a.i./ha  Formulation                                                                  >21
                                          (... g/100 l)                 0          2/3      4/6      7/8      10/13    14/17   20/21    (days)
                                                                                                                                               

    Fruit

    apples        Belgium      1964  1    (75 g/100 l)     w.p. 50%     0.3        n.d.              n.d.
                  Germany,     1966  1    (75 g/100 l)     w.p. 50%     1.6        0.96              0.48              0.43
                   Fed. Rep.   1966  1    (75 g/100 l)     w.p. 50%     2.0        0.95              0.95     0.95     0.8
                               1964  1    (50 g/100 l)     w.p. 50%     1.3        0.8      0.7      0.6      0.6
                               1964  1    (100 g/100 l)    w.p. 50%     2.0        1.4      0.7      0.6      0.6
                  Netherlands  1964       2 (l.v.)         w.p. 50%     1.0-1.4    0.5-0.7  0.4-0.5           0.2-0.4          0.1-0.2
                               1964       2 (h.v.)         w.p. 50%     0.6-1.1    0.2      0.2               0.1-0.3          0.1-0.3
                               1965       2.5 (h.v.)       w.p. 50%     0.33-1.6                              0.38-            0.31-
                                                                                                              0.80             0.44
                               1965       2.5 (h.v.)       w.p. 50%                                           0.29-            0.28-
                                                                                                              0.42             0.33
    cherries,     Germany,     1969  1    1.5              w.p. 50%     3.1                 0.45     0.18
     sour          Fed. Rep.         1    1.5              w.p. 50%     5.0                 0.3      0.24
    cherries,     Germany,     1968  1    (50 g/100 l)     w.p. 50%                                                    0.05
     sweet         Fed. Rep.         2    (50 g/100 l)     w.p. 50%                                                    0.06
    peaches       Germany,     1967  1    (50 g/100 l)     w.p. 50%     1.55                         0.5               0.25    0.2
                   Fed. Rep    1968  1    (75 g/100 l)     w.p. 50%     3                   2.0      1.25     0.65
                               1968  1    (75 g/100 l)     w.p. 50%     8.7                 2.36     1.65
                               1968  1    (75 g/100 l)     w.p. 50%     2.9                 1.8      0.9
                               1968  1    (75 g/100 l)     w.p. 50%     3.9                 1.5      0.5
    plums         Germany,     1967  1    (50 g/100 l)     w.p. 50%     0.55                n.d.              n.d.             n.d.
                   Fed. Rep.   1968  1    (75 g/100 l)     w.p. 50%     2.16                0.52     0.2
                               1968  1    (75 g/100 l)     w.p. 50%     3.71                1.75     1.5
                               1968  1    (75 g/100 l)     w.p. 50%     3.05                1.5      0.7
                               1968  1    (75 g/100 l)     w.p. 50%     1.6                 0.7      0.15
                               1968  1    (75 g/100 l)     w.p. 50%     2.75                1.45     0.7
                               1969  1    1.5              w.p. 50%     2.5                 1.35     <0.05

    TABLE 1. (Cont'd.)

                                                                                                                                               

                                     Application                        Pre-harvest intervals
    Crop          Country      Year                                                                                                           
                                     No.  rate kg a.i./ha  Formulation                                                                  >21
                                          (... g/100 l)                 0        2/3      4/6      7/8      10/13    14/17   20/21    (days)
                                                                                                                                               

                               1969  1    1.5              w.p. 50%     <0.05             <0.05    <0.05
    red           Netherlands  1965  1    0.75 (l.v.)      w.p. 50%     1.31-2.11                  <0.01-            <0.01-
                                                                                                   0.08              <0.01
     currants     Germany,     1968  1    (75 g/100 l)     w.p. 50%     7.25              0.75     0.45
                   Fed. Rep.   1968  1    (75 g/100 l)     w.p. 50%     14.1              0.64     0.61
                               1968  1    (75 g/100 l)     w.p. 50%     8.2               1.1      0.64
    black         Netherlands  1964  1    (50 g/100 l)     w.p. 50%              2.35                       0.7
     currants     Germany,     1968  1    (75 g/100 l)     w.p. 50%     15                0.7      0.45
                   Fed. Rep.   1968  1    (75 g/100 l)     w.p. 50%     13.4              0.6      0.4
                                     1    (75 g/100 l)     w.p. 50%     16.7              2.45     1.35
                                     1    (75 g/100 l)     w.p. 50%     4.2               1.3      0.45              0.11
    gooseberries  Germany,     1968  1    (75 g/100 l)     w.p. 50%     3.5               0.6      0.3
                   Fed. Rep.   1968  1    (75 g/100 l)     w.p. 50%     5.8               0.6      0.25
                               1968  1    (75 g/100 l)     w.p. 50%     3.6               0.45
                               1968  1    (75 g/100 l)     w.p. 50%     6.7               0.53     0.20
                               1968  1    (75 g/100 l)     w.p. 50%     6.3               0.83     0.23

    Vegetables

    French        Germany      1964  1    0.7              w.p. 50%     1.25     0.25              <0.1
     bean          Fed. Rep.   1969  1    0.45             w.p. 50%     1.65              0.55     0.20
                               1968  1    0.75             w.p. 50%     0.5               0.25
                               1968  1    0.75             w.p. 50%     1.6               1.1      1.0
                               1969  1    0.75             w.p. 50%     0.5               0.35     0.25
                               1969  1    0.75             w.p. 50%     0.6      0.4               0.25
                               1967  1    0.5              w.p. 50%     0.75     0.3               0.15
                               1968  1    0.45             w.p. 50%     0.9               0.2      0.1
                               1968  1    0.45             w.p. 50%     0.7               0.3      0.1
                               1969  1    0.45             w.p. 50%     1.6               0.5      0.08
                  UK           1964  1    0.7              w.p. 50%     0.25
                                                                        -1.55

    TABLE 1. (Cont'd.)

                                                                                                                                               

                                     Application                        Pre-harvest intervals
    Crop          Country      Year                                                                                                           
                                     No.  rate kg a.i./ha  Formulation                                                                  >21
                                          (... g/100 l)                 0        2/3      4/6      7/8      10/13    14/17   20/21    (days)
                                                                                                                                               

    bell peppers  Netherlands  1968  1    0.38             w.p. 50%     0.75     0.3               <0.1
     (glasshouse)
    red           Germany,     1964  1    0.15             w.p. 50%     1.0      0.4      0.2      <0.2
     cabbage       Fed. Rep.   1964  1    0.6              w.p. 50%     1.6      1.3      0.9      0.4
    savoy         Germany,     1964  1    0.15             w.p. 50%     3.9      0.9      0.2      <0.2
                   Fed. Rep.   1964  1    0.15             w.p. 50%     2.7      0.8      0.7      0.6
                               1968  1    0.6              w.p. 50%     5.3      2.1      0.7      1.2
                               1968  1    0.6              w.p. 50%     8.0      3.9      3.4      1.8
    white         Germany,     1964  1    0.15             w.p. 50%     2.2      1.3      0.6      <0.2
     cabbage       Fed. Rep.   1964  1    0.6              w.p. 50%     5.8      2.1      1.2      0.6
    carrots       Germany,     1968  1    0.45             w.p. 50%     0.1               n.d      n.d.
                   Fed. Rep.   1968  1    0.75             w.p. 50%     n.d.              0.2      0.25
                               1968  1    0.75             w.p. 50%     0.1               0.15     0.25
                               1969  1    0.75             w.p. 50%     n.d.              n.d.     n.d.
                               1969  1    0.75             w.p. 50%     0.3      0.7      0        0.3
    cucumbers     Netherlands  1970  1    0.5              dust 2%      0.05     0.07     n.d.
     (glasshouse)              1970  1    0.5              dust 2%      0.07     0.06     n.d.

    leek          Germany,     1968  1    0.45             w.p. 50%     0.5               n.d.     n.d.
                   Fed. Rep.   1968  1    0.45             w.p. 50%     0.6               0.1      n.d.
                               1968  1    0.45             w.p. 50%     10.9              1.1      1.0
                               1968  1    0.6              w.p. 50%     2.9               0.6      0.6
                               1968  1    0.75             w.p. 50%     2.3               0.25     0.1
                               1968  1    0.75             w.p. 50%     2.0               0.7      0.15
    lettuce       Germany,     1964  1    0.6              w.p. 50%     6.8      0.4      0.2      0.1
     (outdoor)     Fed. Rep.   1964  1    0.6              w.p. 50%     5.1      0.2      1.3      1.1
                                     1                     w.p. 50%     1.8      0.4      0.2      0.1
                                     1                     w.p. 50%     2.2      1.6      0.9      0.7
    lettuce       Netherlands  1963  1    0.66             w.p. 50%     17.2-    9.2-     5.4-     1.8-4.1  0.9-1.9  0.5-0.8
     (glasshouse)                                                       20.2     10.9     10.4

    TABLE 1. (Cont'd.)

                                                                                                                                               

                                     Application                        Pre-harvest intervals
    Crop          Country      Year                                                                                                           
                                     No.  rate kg a.i./ha  Formulation                                                                  >21
                                          (... g/100 l)                 0        2/3      4/6      7/8      10/13    14/17   20/21    (days)
                                                                                                                                               

                               1971  1    0.8-0.9          w.p. 50%     15.2     10.9                       4.1
                               1971  1    0.6-0.9          w.p. 50%     10.0     7.45                       3.1
                               1971  1    0.6-0.9          w.p. 50%     4.0      5.5                        1.9
                               1971  1    0.6-0.9          w.p. 50%     8.5      7.0                        2.7
                               1971  1    0.6-0.9          w.p. 50%     7.25     6.8                        2.4
    onions        Germany,     1968  1    0.45             w.p. 50%     n.d.              n.d.     n.d.
                   Fed. Rep.   1968  1    0.45             w.p. 50%     n.d.              n.d.     n.d.
                               1968  1    0.45             w.p. 50%     9.3               4.2      0.87
                               1968  1    0.45             w.p. 50%     <0.05             <0.05    <0.05
                               1968  1    0.45             w.p. 50%     <0.05             <0.05    <0.05
                               1969  1    0.75             w.p. 50%     n.d.              n.d.     n.d.
                               1969  1    0.75             w.p. 50%     n.d.              n.d.     n.d.
                               1969  1    0.75             w.p. 50%     n.d.              n.d.     n.d.
                               1969  1    0.75             w.p. 50%
    peas          Germany,     1964  1    0.7              w.p. 50%     0.3      n.d.              n.d.
     pods          Fed. Rep.   1964                                     0.4      0.1               <0.1
    spinach       Germany,     1968  1    0.45             w.p. 50%     5.7               n.d.     n.d.
                   Fed. Rep.   1968  1    0.45             w.p. 50%     6.8               n.d.     n.d.
                               1969  1    0.45             w.p. 50%     32                0.6      0.06
                               1969  1    0.45             w.p. 50%     33.5              0.7      0.06
                               1969  1    0.75             w.p. 50%     27       7.3               0.6
    tomatoes      Netherlands  1971  1    0.5              dust         0.28     <0.05    n.d.
     (glasshouse               1971  1    0.5              dust         0.33     <0.05    n.d.
                               1971  1    11 g/100 m3      smoke        0.07     n.d.

    Field Crops

    alfalfa       USA          1970  1    1.0              w.p. 70%     59.9     12.2
     green                           1    1.0              w.p. 70%     11.6     2.17
                                     1    1.0              w.p. 70%     15.5     2.06
                                     1    1.0              w.p. 70%     65.8     7.14

    TABLE 1. (Cont'd.)

                                                                                                                                               

                                     Application                        Pre-harvest intervals
    Crop          Country      Year                                                                                                           
                                     No.  rate kg a.i./ha  Formulation                                                                  >21
                                          (... g/100 l)                 0        2/3      4/6      7/8      10/13    14/17   20/21    (days)
                                                                                                                                               

                                     1    1.0              w.p. 70%     36.8     3.40              1.15              0.20             0.59(28)
                                     1    1.0              w.p. 70%     65.8     7.14              3.17              0.66             <0.12(29)
     hay                             1    1.0              w.p. 70%     16.4     3.67
                                     1    1.0              w.p. 70%     3.21     1.33
     seed hulls                      3    1.0              w.p. 70%                                                                   0.35(28)
                                     3    1.0              w.p. 70%                                                                   0.18(29)
                                     2    1.5              w.p. 70%                                                                   0.13(46)
                                     2    1.5              w.p. 70%                                                                   0.13(92)
     chaffs                          3    1.0              w.p. 70%                                                                   0.63(28)
                                     3    1.0              w.p. 70%                                                                   0.24(29)
                                                                                                                                      0.13(46)
                                                                                                                                      0.08(92)
    barley        USA          1970
     grain                           1    0.4a             w.p. 50%                                                  <0.05
                                     1    0.4a             w.p. 50%                                                  <0.24
     straw                           1    0.4a             w.p. 50%                                                  <0.03
                                     1    0.4a             w.p. 50%                                                  0.32
    oats          USA          1970
     grain                           1    0.4a             w.p. 50%                                                  0.09
                                     1    0.4a             w.p. 50%                                                  0.15
                                     1    0.4a             w.p. 50%                                                  0.10
                                     1    0.4a             w.p. 50%                                                                   <0.04(25)
     straw                           1    0.4a             w.p. 50%                                                  0.01
                                     1    0.4a             w.p. 50%                                                  0.07
                                     1    0.4a             w.p. 50%                                                  <0.19
                                     1    0.4a             w.p. 50%
                                     1    0.4a             w.p. 50%                                                                   0.01(25)
    rye           USA          1970
     grain                           1    0.4a             w.p. 70%                                                  <0.03
     straw                           1    0.4a             w.p. 70%                                                  0.04

    TABLE 1. (Cont'd.)

                                                                                                                                               

                                     Application                        Pre-harvest intervals
    Crop          Country      Year                                                                                                           
                                     No.  rate kg a.i./ha  Formulation                                                                  >21
                                          (... g/100 l)                 0        2/3      4/6      7/8      10/13    14/17   20/21    (days)
                                                                                                                                               

    wheat         USA
     grain                           1    0.4              w.p. 50%                                                  0.21
     straw                                                                                                           1.41
    pasture       USA                1    0.25             w.p. 70%     11.82             6.99     1.02
     grass                                                 U.L.V.
                                     1    0.5              w.p. 70%     0.63     0.59              1.20     0.76
    rangeland     USA                1    0.25             w.p. 70%     29.8     1.49              0.76
     grass
    cacao
     whole beans                     2    0.5              E.C. 20%                                                                   n.d.(24)
                                     2    0.25             E.C. 20%                                                                   n.d.(24)
     shell                           2    0.84             E.C. 20%                                0.3                       0.3      0.3(56)
                                     3    0.84             E.C. 20%              0.3
     nib                             3    0.84             E.C. 20%              <0.1
                                                                                                                                               

    a seed treatment 500 g/100 kg seed and foliar application

    h.v. = high volume;  l.v. = low volume;  U.L.V. = ultra-low volume

    TABLE 2. RESIDUES OF PROPOXUR IN ppm

                                                                                                                                       
                                           Application                                  Pre-harvest interval in days
    Crop           Country   Year    No.   rate          Formulation                                                                   
                                           kg a.i./ha                     1-10        11-20         21-30         31-40       41-50
                                                                                                                                       

    Rice hulled    Japan     1972    1     0.4           dust 1%          0.02        0.06-0.09
                                     1     0.4           dust 1%                      0.03          0.02-0.04
                                     1     0.4           dust 1%                      0.02                        0.02
                                     1     0.4           dust 1%                      0.02          <0.02-0.19
                                     1     0.4           dust 1%          <0.02                     0.02
                                     1     0.4           dust 1%          0.02-0.11
                                     1     0.4           dust 1%                      0.21          0.02
                                     1     0.4           dust 1%          0.02                                    0.06

    Paddy rice     Japan     1972    1     0.2-0.75      E.C. 25%         0.03        0.08-0.33
                                                                                                    0.05-0.56
                                                                                                                  0.26-0.40   <0.02-0.05
                                                                                                    0.47-0.54

    Upland rice    Japan     1972    1     0.2-0.75      E.C. 25%                     0.18
                                     1     0.2-0.75      E.C. 25%                                   0.19
                                     1     0.2-0.75      E.C. 25%                                                 0.11
                                     1     0.2-0.75      E.C. 25%                                                             0.13

                                                                                                                                       

    
    Fate of residues

    Influence of light

         Propoxur exposed to light shows no or very slight
    photo-decomposition. Crosby (1965) found that propoxur was the only
    one out of six N-methylcarbamates which was not converted to other
    cholinesterase inhibitors when exposed to ultra-violet light or
    sunlight.

         Propoxur on silica gel-coated plates exposed to long-wave length
    ultra-violet light did not produce degradation products, whereas after
    exposure to short-wave length ultra-violet light three metabolites,
    which gave a colour reaction with ninhydrin (Abdel-Wahab et al.,
    1966), were found.

         The product did not show any changes when such plates were
    exposed to sunlight, even when sensitizers were applied to the (Ivie
    and Casida, 1971).

    Inert surfaces

         Propoxur disappears from inert surfaces more or less rapidly
    mainly through volatilization. The rate of disappearance depends on
    the nature of the surface. Fifty per cent. of a propoxur residue on
    glass, kept under laboratory conditions, was still present after 1.8
    hours (Abdel-Wahab et al., 1966).

         The half-life of propoxur on porcelain saucers under field
    conditions was about three days (Wright and Jackson, 1971), whereas on
    polythene foils a half-life of two days was found (Marchart, 1970).

         Propoxur sprayed as an aqueous emulsion concentrate on filter
    papers, which were suspended vertically at 2.5 inch in a kitchen (mean
    temperature 23°C (21-29°C) and mean relative humidity 52% (42-68%),
    evaporated 50% in about six weeks (Links, 1965).

         After three months, 60% of the active ingredient was still
    present on Hessian bags, sprayed with a wettable powder and stored in
    an unheated large storage shed (Linke, 1965).

         When propoxur was applied to plywood panels, 50% of it evaporated
    in 15 days irrespective of the formulation used (Dorough and Crouch,
    1966).

         Inconsistencies in the results of different authors may not only
    be due to different temperatures but also to air movements (Marchart,
    1970), the influence of which is large but has not yet been studied
    quantitatively.

         The evaporation of propoxur from animate or inanimate substrates
    is of practical significance. A considerable proportion of residues on
    plants is eliminated by volatilization (Abdel-Wahab at al., 1966;
    Gronberg, 1970; Marchart, 1970, 1971). On the other hand, the activity
    of propoxur in the vapour phase is utilized for the control of storage
    pests and household and domestic pests (Gahan and Wilson, 1970; Wright
    et al., 1969).

    In water

         Propoxur is relatively stable in water at pH levels of less than
    7. The rate of hydrolysis, resulting in the formation of
    isopropoxyphenol increases rapidly from pH 7 upwards. The half-life of
    the parent compound in buffered solutions at 20°C and pH 8 was 16
    days, at pH 9, 38 hours and at pH 10, three hours (Aly and El-Dib,
    1971).

         At temperatures of 30°C and pH 7, the half-life of the parent
    propoxur was three days, at pH 9, 1.2 hours.

         Flint and Shaw (1971) determined the half-life of propoxur in
    field experiments in shallow open vessels filled with bottom silt and
    lake water. In these experiments, 50% of the propoxur disappeared in
    12.7 hours at pH 7 and 27-36°C.

         In similar experiments, in which smaller nearly air-tight vessels
    were used, and in a parallel experiment with a biologically sterile
    system, the half-lives were 54.9 and 80.8 hours respectively;
    temperature range was 5-22°C.

    In soil

         Propoxur evaporates from the soil; the amount which evaporates
    increases with increasing moisture content of the soil.

         The time required to decrease a soil residue to one-half of the
    initial concentration ranges from six to eight weeks, depending on
    soil type (Flint and Shaw, 1971).

    Metabolism in soil

         The metabolism of propoxur in different soil types was studied by
    Church-and Flint (1971) with radio-labelled compounds. After a soil
    application of 3H-isopropoxy, 14C-carbonyl labelled propoxur, the
    3H activity remained organosoluble, whereas the 14C activity was
    concentrated in the water-soluble fraction. The organosoluble activity
    was composed of isopropoxyphenol and traces of propoxur. The 14C
    activity was incorporated into unknown water-soluble materials which
    no longer behaved as carbamates.

         In sterile soils or under anaerobic soil conditions, the 14C
    activity decreased whilst the 3H activity remained almost constant.
    This indicates that in these conditions a simple chemical hydrolysis
    to isopropoxyphenol was occurring (Flint and Shaw, 1971).

         In biologically active soils, the 14C and 3H activity declined
    sharply after nine days, which gives an indication of microbial
    degradation. In this case, no conjugated compounds were found (Church
    and Flint, 1971).

         Flint and Shaw equilibrated aqueous solutions of propoxur with
    different soil types. The adsorption of propoxur to soil particles was
    poor under these conditions. The following adsorption co-efficients
    were found: 0.63 for sandy loam, 0.49 for silty clay loam and 1.12 for
    highly organic silty clay loam.

         In freshly tilled soils propoxur can be moved laterally by water.

         In soil leaching experiments, propoxur moved with the water front
    passing through the packed soil columns. In view of the poor stability
    of propoxur in aqueous systems, the normal use will give no risks of
    contaminating ground or superficial water.

         Propoxur at normal rates showed only a slight effect on soil
    microorganisms (Church and Flint, 1971; Houseworth and Tweedy, 1972)
    and on microorganisms in waste disposal lagoons.

    In plants

         A large proportion of propoxur applied to the leaf surface
    evaporates (Everett and Gronberg, 1968; Marchart, 1970, 1971;
    Abdel-Wahab et al., 1966).

         With radio-labelled propoxur, it was demonstrated that only a
    small amount penetrates from the leaf surface into the leaves. After
    five days the parent propoxur comprised 69-98% of the total 14C
    activity present. The material that penetrated was shown to be
    primarily the parent propoxur and water-soluble metabolites, mainly
    the ß glucoside of 2-hydroxyphenyl N-methylcarbamate.

         No downward translocation of propoxur could be demonstrated
    (Everett and Gronberg, 1968).

         The uptake of propoxur by plant roots from an aqueous solution
    was shown to be directly related to the water uptake. Propoxur and
    metabolites were translocated from the aqueous solution to the surface
    of the leaf from which there is some volatilization.

         14C carbonyl labelled propoxur injected into the stems of beans
    and cotton plants was found to be converted into watersoluble
    metabolites which remained stable for a relatively long period
    (Dorough and Casida, 1965). In subsequent experiments Abdel-Wahab at
    al. (1966) found that the water-soluble metabolites still possessed a
    carbamate structure. The half-life of the parent propoxur after
    injection into bean plants was one day.

         Kuhr and Casida (1967) identified with thin layer chromatography
    the water-soluble metabolites. Following incubation with ß
    glucosidase, ether-extractable aglycones of the water-soluble
    metabolites were yielded to the extent of 76%. Tentative
    identification by cochromatography showed that 91.3% of the mixture

    consisted of 2-hydroxyphenyl-N-methylearbamate (metabolite "A"
    according to the scheme of the metabolic pathway in the section "Fate
    in animals" as proposed by Everett and Gronberg (1970)) and 4.9% of
    metabolite B = 2-isopropoxyphenyl-N-hydroxymethylcarbamate.

         In these studies the metabolites (A) and (B) accounted for 30.2%
    and 1.5% respectively of the applied activity, six days after the
    injection of propoxur in the bean plant, together comprising 96% of
    the water-soluble metabolites.

         Five days after foliar application of 14C carbonyl labelled and
    isopropoxy labelled propoxur on bean and maize plants, the residue on
    the leaves consisted practically only of the parent compound. A
    negligible portion was metabolite (A) (<1%). Also in the plant the
    largest proportion of the radio-active material extractable with
    organic solvents consisted of propoxur. After 3, 5, 7, 9 and 14 days,
    its share of the measurable activity was 58.7%, 45.0%, 51.3%, 50.1%
    and 36.4% respectively.

         A large proportion of the carbonyl labelled material was present
    in the water phase, the proportion of isopropyl labelled being less,
    thus indicating that the isopropoxy group was cleaved from a
    considerable portion of the applied parent compound. This assumption
    was supported by the detection of acetone in the air pulled through
    the chamber (Everett and Gronberg, 1968).

         In an experiment in which carbonyl labelled and isopropoxy
    labelled propoxur was absorbed from water by the roots, the proportion
    of 14C active compound increased continuously during the 14-day
    study. The aglycones of the conjugated metabolites could be almost
    completely released with ß glucosidase. Cochromatography showed
    agreement with metabolites (A) and (B). The ratio of these compounds
    was 9:1 (Everett and Gronberg, 1968).

         In a later experiment, Gronberg (1970) found that 14 days after
    uptake of labelled propoxur by maize roots 50% of the residue in the
    plant was still the parent compound, 19.2% of the residue was
    accounted for by (A) and 3.5% by (B). Both metabolites were released
    from their conjugates by ß glucosidase and positively identified by
    infra-red spectroscopy. It was shown that 2-isopropoxy-4
    hydroxyphenyl-N-methylcarbate did not occur.

    Methods of residue analysis

         Bio-assay methods were developed for the detection of propoxur
    residues in soil using house crickets (Burkhardt and Fairchild, 1967)
    as test insects and on fruit crops using Daphnia magna (Parker et
    al., 1970). Voss (1968) developed an automated procedure for residue
    analysis of propoxur in aqueous extracts of fruits based on
    cholinesterase inhibition.

         The above-mentioned methods are not specific and therefore not
    suitable for regulatory purposes. The methods have become obsolete.

         Several colorimetric methods have been developed. The only
    satisfactory methods involve hydrolysis to isopropoxyphenol, which is
    converted to a dyestuff and measured photometrically (see following
    table).

         The limits of determination range from 0.05 to 0.1 ppm.

    TLC methods

         Several authors describe TLC methods for the analysis of
    propoxur. The most suitable are those based on cholinesterase
    inhibition, since they require the simplest clean-up procedure and can
    be used for various crop types.

         The limits of determination are usually about 0.1 ppm.

    GLC methods

         Since propoxur, in common with other carbamates, readily
    decomposes at high temperatures, GLC methods had to be developed in
    which propoxur is converted to a stable derivative, which permits
    detection with an electron capture detector. Also a method is
    described in which the flame photometric detector is used after
    derivatization.

        SPECTROMETRIC RESIDUE METHODS FOR PROPOXUR

                                                                                                 
    Crop                   Detection                     Sensitivity    Reference
                                                                                                 

    Sugar beet, tops,
    lettuce                IR; N-H-stretching bond       0.2 ppm        Niessen and Frehse (1963)

    Grapes                 IR; N-H-stretching bond       ?              Broderick (1966)

    Milk                   spectrophotofluorometry       1.4 ppm        Bowman and Beroza (1967)

    Fruits, vegetables,
    potatoes, cereals,
    hops                   Aminoantipyrinea              0.05-0.1 ppm   Niessen and Frehse (1964)

    Human urine            Aminoantipyrinea              10-20 ppm      Dawson et al. (1964)

    Lettuce                2,6-dibromo-benzoquinone-     0.1 ppm        van Gils (1970)
                           chloroimidea

    Sugar beets,           p-nitrobenzene
    potatoes               diazoniumfluoboratea          0.05 ppm       George (1967)
                                                                                                 
    a After saponification.
    
        THIN LAYER RESIDUE METHODS FOR PROPOXUR

                                                                                                                   

    Crop                Stationary        Solvent      Detection                      Sensitivity    Reference
                        phase             system
                                                                                                                    

    Water               silica gel        different    dimethylamino-benzaldehyde;    0.1 ppm        Abbot et al. (1967)
                                                       nitrobenzene-diazonium
                                                       fluoborate

    Water               silica gel        different    dimethylamino-benzaldehyde     0.1 ppm        El-Dib (1970)
                                                       

    Peas, carrots       silica gel        acetone +    cholinesterase                 10 ng          Mendoza and Shields
                                          hexane       inhibition                     (0.1 ppm)      (1971)
                                          20 + 80

    Tobacco             aluminiumoxide    acetone +    fast blue B;                   0.5 ppm        Nesemann and Seehofer
                                          hexane       dichloroquinone-chloroimide                   (1970)
                                          10 + 90      

    Apples, beets,      silica gel        acetone +    cholinesterase                 1 µg           Wales et al. (1968)
    cabbage, carrots,                     hexane       inhibition
    lettuce,
    raspberries,                          20 + 80
    poultry meat
                                                                                                                   

    GAS-CHROMATOGRAPHIC RESIDUE METHODS FOR PROPOXUR

                                                                                                                     

    Crop                  Column                  Derivativea             Sensitivity      Reference
                                                                                                                     

    Apples, cucumbers,    Chromosorb W DMCS       -chloroacetyl           0.04 ppm         Argauer (1969)
    tomatoes, milk        XE - 60

    Corn silage, milk     Gaschrom Q              -thiophosphoryl         0.02-0.04 ppm    Bowman and Beroza (1967)
                          DC-200

    Potatoes, sugar       Gaschrom Q              -trichloroacetyl        0.01-0.1 ppm     Butler and MeDonough (1968)
    beets, apples,        DC-200
    grass

    Water, peas,          Chromosorb GAWDMCS      -2,4-dinitrophenyl      0.2 ppm          Cohen et al. (1970)
    lettuce, apples       XE 60 + Epikote 1001

    Spinach               Anakrom A B S           -2,4-dinitroanilineb    0.05-0.2 ppm     Holden et al. (1969)
                          XE -60

    Soil                  Gaschrom Q              -trichloroacetyl        0.02 ppm         Stanley (1971)
                          OV -1

    Animal tissue,        Gaschrom Q              -trichloroacetyl        0.002-0.02 ppm   Stanley and Thornton (1972)
    milk                  OV -1

    Alfalfa, corn,        Gaschrom Q              -trichloroacetyl        0.02-0.05 ppm    Stanley et al. (1972)
    grass, cereals
                                                                                                                     

    a Of isopropoxyphenol.
    b From reaction with methylamine.
    

         Although the above-mentioned GLC methods are relatively
    time-consuming, they are nevertheless the methods of choice. They are
    very sensitive and specific (limits 0.002-0.05 ppm).

         TLC and GLC methods may be suitable or can be adapted for
    regulatory purposes.

         The determination of propoxur residues in the trials carried out
    by Bayer and reported in this monograph is carried out by the
    colorimetric method of Niessen and Frehse (1964). This method
    determines only the parent compound and is not fully specific.

         The method includes a step for precipitating plant constituents,
    which is also used in the methods referred to above.

         The analysis in the residue experiments carried out by Chemagro
    mentioned in the monograph was by GLC as described by Stanley et al.
    (1972). The method is rather complicated, but makes it possible to
    determine the parent compound and the main metabolites ((A) and (B),
    see page) separately with a high degree of sensitivity.

         The conjugated metabolites (A) (2-hydroxyphenyl methylcarbamate)
    and (B) (2-isopropoxyphenyl hydroxymethylcarbamate) are released by
    enzyme hydrolysis before clean-up. The metabolite (A) is then
    alkylated. Next, the compounds are saponified to the phenols and
    converted to their trichloroacetyl derivatives, which are determined
    by GLC with electron capture detection.

    National tolerances

    Belgium              Fruits and vegetables,          3 ppm
                         except potatoes

    Germany, Federal     Fruit                           3 ppm
    Republic of          Sugar Beets                     3 ppm
                         Vegetables, except              3 ppm
                         Cabbage                         4 ppm
                         Lettuce                         4 ppm
                         Other plant products            0.5 ppm

    France               Fruit and Vegetables            3 ppm

    Italy                Fruit and Vegetables            2.25 ppm

    Netherlands          Fruit and Vegetables            3 ppm

    RECOMMENDATIONS FOR TOLERANCES AND PRACTICAL RESIDUE LIMITS

    Appraisal

         Propoxur is a non-systemic carbamate insecticide which is used on
    a considerable scale in various countries against a relatively broad
    spectrum of insects in field crops, fruits and vegetables, e.g.
    aphids, lygus bugs, leafhoppers, thrips, sawflies, etc.

         Propoxur is also used extensively for hygienic purposes against
    cockroaches, flies, etc., and against insect pests on ornamentals and
    flower crops.

         The technical material contains minimal 95% of
    2-isopropoxy-phenyl-N-methyl carbamate. The impurities in the
    technical material are known.

         Propoxur is marketed in the form of wettable powder, emulsifiable
    concentrate, dust, fly and cockroach baits, and balls against flies.

         The concentration/rates of application vary depending on pest,
    crop and methods of application. Normal application rates are 250-1000
    g/ha.

         The residue data available were obtained from different countries
    and regions with different climatic and pest conditions. Most of the
    residue data obtained in Europe show only the parent compound. The
    trials carried out in the United States of America and a limited
    number of trials carried out elsewhere determined not only the parent
    propoxur but also the two main plant metabolites, (A)
    2-hydroxyphenyl-N-methylcarbamate and (B)
    2-isopropoxyphenyl-N-hydroxymethylcarbamate.

         Information is available on the fate of propoxur residues in
    soil, in plants. in mammals and in other animals, e.g. flies.

         Some data on products of animal origin after feeding the animals
    on treated crops are available indicating that residues are very low.
    It would be desirable to have the result of more critical studies
    which have been carried out on cows, pigs and chickens, in order to
    confirm that this is the true position.

         The breakdown of propoxur in plants and animals follows similar
    pathways. The same metabolites are identified in rats, plants and in
    vitro with microsomes.

         Whereas oxidative and hydrolytic degradation both occur and
    proceed to the same degree in rats, the formation of oxidation
    products predominates in plants. In soil, however, hydrolytic
    degradation predominates.

         The residues in foods of plant or animal origin, following
    recommended directions for use and recommended pre-harvest
    intervals, consist largely of the parent compound. In plant products,
    the above-mentioned metabolites (A) and (B) occur in a ratio of about
    9:1. These metabolites, however, normally represent less than
    one-third of the total residue determined.

         Little information is available on the rate of decrease in the
    level of residue of propoxur and its metabolites during storage and
    processing, including household cooking. Little information is
    available on propoxur residues in food moving in commerce.

         Thin layer chromatographic and gas chromatographic procedures,
    specific for propoxur and its main metabolites occurring in plants
    (i.e. the metabolites (A) and (B), see above) and/or in products of
    animal origin, are available.

         The above-mentioned GLC methods are rather time-consuming due to
    the fact that propoxur has to be converted to derivatives which are
    stable to the GLC conditions. These GLC methods and the TLC methods
    may be suitable or can be adapted for regulatory purposes. The most
    suitable TLC methods are those based on cholinesterase inhibition.

         The limit of determination of the TLC methods is usually about
    0.1 ppm. The GLC methods allow sensitive and specific analysis (limits
    of detection depending on commodity 0.002-0.05 ppm) of residues in
    most crops and products of animal origin.

    RECOMMENDATIONS

         The following tolerances are based on residues likely to be found
    at harvest following currently used patterns. The residues are
    determined as propoxur and the main metabolites and are expressed as
    propoxur.

                                                                            

                                                      Interval on which
                                      Tolerances      recommendations
                                                      are based (days)
                                                                            

    Fruit, including apples,
    pears, cherries, peaches,
    plums                             3               4-7

    Soft fruit, including red
    currants, blackberries,
    gooseberries, strawberries        3               4-7

    Vegetables, except potatoes
    and root vegetables               3               outdoor            4-7
                                                      glasshouse:
                                                      leafy vegetables   14,
                                                      other vegetables   3-7

    Potatoes, root vegetables                         -

    Raw cereals                       0.5             14

    Rice (hulled)                     0.1             7

    Cocoa beans                       0.05a           7

    Meat                              0.05a           -

    Milk (whole)                      0.05a           -

    Animal feedstuff                  5               7-14
                                                                            

    a At or about the limit of determination


         The time interval between application and harvest which has been
    used in determining the maximum residue limits is appropriate to the
    agricultural practices in numerous countries.

    FURTHER WORK OR INFORMATION

    Desirable

    1. Studies to elucidate the significance of the changes in relative
    liver weight in the rat.

    2. Studies, including pharmacokinetic studies, to elucidate the
    relationships between toxicity and effects on cholinesterase levels in
    various species.

    3. A long-term study in an animal species other than the rat.

    4. Continued epidemiological studies with emphasis on cholinesterase
    activity.

    5. Studies on behavioural responses especially with low-level
    exposure.

    6. Results of critical studies to determine the nature and level of
    residues in meat (including poultry), milk, and eggs to confirm
    recommendations for limits in animal products.

    REFERENCES

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    Thin-layer chromatographic separation, identification and estimation
    of residues of some carbamate and allied pesticides in soil and water.
    J. Chromatography, 30: 136-142

    Abdel-Wahab, A.M., Kuhr, R.J. and Casida, J.E. (1966) Fate of
    C14-carbonyl-labelled aryl methylearbamate insecticide chemicals in
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    Aly, O.M. and El-Dib, M.A. (1971) Studies on the persistence of some
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    Arnold, D., Kennedy, G., Keplinger, M.L. and Fancher, O.E. (1971)
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    Ben-Dyke, R., Sanderson, D.M. and Noakes, D.N. (1970) Acute toxicity
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    liver enzymes. Biochem. J. 125: 395-400

    DuBois, K.P., (1962) University of Chicago  The acute oral toxicity of
    Bayer 39 007 to chickens. Unpublished report submitted by Bayer AG

    DuBois, K.P. (1963) University of Chicago  The acute toxicity of some
    possible metabolites of Bayer 39 007, 44 646, 37 344 and Morestan.
    Unpublished report submitted by Bayer AG

    DuBois, K.P. and Raymund, A.B., (1961a) University of Chicago  The
    acute toxicity of Bayer 39 007 to rats. Unpublished report submitted
    by Bayer AG

    DuBois, K.P. and Raymund, A.B., (1961b) University of Chicago  The
    acute toxicity of Bayer 39 007 given in combination with other
    anticholinesterase insecticides to rats. Unpublished report submitted
    by Bayer AG

    DuBois, K.P. and Raymund, A.B., (1961c) University of Chicago  The
    acute toxicity of Bayer 39 007 and Bayer 37 344 in combination with
    some other anticholinesterase insecticides to rats. Unpublished report
    submitted by Bayer AG

    Eben, A. and Kimmerle, G. (1973) Propoxur, effect of acute and
    subacute oral doses on acetyl cholinesterase activity in plasma,
    erythrocytes and brain of rats. Unpublished report submitted by Bayer
    AG

    Eichelberger, J.W. and Lichtenberg, J.J. (1971) Persistence of
    pesticides in river water. Env. Sci and Techn. 5: 541-544

    El-Dib, M.A. (1970) Thin layer chromatographic detection of carbamate
    and phenylurea pesticide residues in natural waters. J. Ass. off.
    analyt. Chem. 53: 756-760

    Everett, L.J. and Gronberg, R.R. (1968) Plant metabolism of Baygon.
    Unpublished report submitted by Chemagro

    Everett, L.J. and Gronberg, R.R. (1970) The metabolic fate of Baygon
    (2-isopropoxyphenyl-N-methyl-carbamate) in the rat. Unpublished
    reported submitted by Chemagro

    Flint, D.R. and Shaw, H.R., II (1971) The mobility and persistence
    of Baygon in soil and water. Unpublished report submitted by Chemagro

    Gahan, J.B. and Wilson, H.G. (1970) Seven insecticides as residual
    sprays in buildings naturally infested with Anopheles
    quadrimaculatus. Mosquito News, 30: 410-416

    Gaines, T.B. (1969) Acute toxicity of pesticides. Toxicol. and Appl.
    Pharm. 14: 515-534

    George, D.A., Rusk, H.W., Powell, D.M. and Landis, B.J. (1967) An
    analytical method for o-isopropoxyphenyl methyl carbamate (Bayer
    39007), its aphicidal value and persistence in potatoes and sugar
    beets. J. Econ. Ent. 60: 82-84

    van Gils, W.F. (1970) Spectrophotometric determination of propoxur
    residues on vegetable matter. Analyst, 95: 88-90

    Gronberg, R.R. (1970) Metabolism of Baygon in corn plants. Unpublished
    report submitted by Chemagro

    Hadaway, A.B. and Barlow, F.A (1964) A note on the sorption of
    insecticides on tropical soils. Bull. Wld Hlth Org. 30: 146-148

    Hayes, W.J., jr (1971) Studies on exposure during the use of
    anti-cholinesterase pesticides. Bull. Wld Hlth Org. 44: 277-288

    Hobik, H.P. (1967) Histologische Untersuchungen von Ruckenmark und
    Nervi ischiadici aus Neurotoxizitatsversuchen an Huhnern mit, BAYER
    39007. Unpublished report submitted by Bayer AG

    Holden, E.R., Jones, W.M. and Beroza, M. (1969) Determination of  
    residues of methyl-and dimethyl-carbamate insecticides by gas
    chromatography of their 2,4-dinitroaniline derivatives. J. Agr. Food
    Chem. 17: 56-59

    Houseworth, L.D. and Tweedy, B.G. (1972) Effect of Baygon on microbial
    populations. Unpublished report submitted by Chemagro

    Ivie, G.W. and Casida, J.E. (1971) Sensitized photodecomposition and
    photosensitizer activity of pesticide chemicals exposed to sunlight on
    silica gel chromatoplates. Photosensitizers for the accelerated
    degradation of chlorinated another insecticide chemicals exposed to
    sunlight on bean leaves. J. Agr. Food Chem. 19: 405-416

    Kimmerle, G. (1961) Preparation Dr. Bocker 58 12 315 (39 007).
    Unpublished report submitted by Bayer AG

    Kimmerle, G. (1964) E 39 007 (Bocker 58 12 315; Ht.-Nr. 3410)/
    Neurotoxizitat. Unpublished report submitted by Bayer AG

    Kimmerle, G. (1966a) Neurotoxic studies on active ingredient Docker
    58: 12 315 (Unden active ingredient). Unpublished report submitted by
    Bayer AG

    Kimmerle, G. (1966b) Unden-Wirkstoff (Bocker 58 12
    315)/Antidotwirkung. Unpublished report submitted by Bayer AG

    Kimmerle, G.  (1966c) Unden-Wirkstoff/Inhalationstoxizitat.
    Unpublished report submitted by Bayer AG

    Kimmerle, G. (1971) Comparison of the antidotal actions of
    tetra-ethylammonium chloride and atropine in acute poisoning of
    carbamate insecticides in rats. Arch. Toxicol. 27: 311-314

    Kimmerle, G. and Solmecke, B. (1971) BAY 39 007/Subacute dermal
    application to rabbits. Unpublished report submitted by Bayer AG

    Klimmer, O.R., (1963) Pharmakologisches Institut der Universitat Bonn.
    Toxikologische Prufung von BAYER 39 007. Unpublished report submitted
    by Bayer AG

    Krishna, J.G. and Casida, J.E. (1966) Insecticide metabolism - fate in
    rats of the radiocarbon from ten variously labeled methyl-and
    dimethylcarbamate-14C insecticide chemicals and their hydrolysis
    products. J. Agr. Food Chem. 14: 98-105

    Kuhr, R.J. (1968) Metabolism of methylcarbamate insecticide chemicals
    in plants. J. Sci. Food Agr. pp. 44-49

    Kuhr, R.J. (1968) Metabolism of methylcarbamate insecticides by
    insects in vivo and in vitro. Mededel. Rijksfac.
    Landbouwetenschappen, 33 (3): 647-657

    Kuhr, R.J. (1970) Metabolism of carbamate insecticide chemicals in
    plants and insects. J. Agr. Food Chem. 18: 1023-1030

    Kuhr, R.J. and Casida, J.E. (1967) Persistent glycosides of
    metabolites of methylcarbamate insecticide chemicals formed by
    hydroxylation in bean plants. J. Agr. Food Chem. 15: 814-824

    Linke, W. Trials to determine the persistence of Arprocarb when used
    in food storage practice. Unpublished report submitted by Baywood
    Chemicals Ltd., Techn. Dept. Technical Report No. TCR/130

    Lorke, D. (1970) BAY 39 007/Untersuchungen auf embryotoxische
    Wirkungen an der Ratte. Unpublished report submitted by Bayer AG

    Löser, E. (1965) Fütterungsversuch Uber 2 Monate mit BAYER 39 007.
    Unpublished report submitted by Bayer AG

    Löser, E. (1968a) BAY 39 007/Generationsversuche an Ratten.
    Unpublished report submitted by Bayer AG

    Löser, E. (1968b) BAYER 39 007/Chronische toxikologische
    Untersuchungen an Ratten. Unpublished report submitted by Bayer AG

    Löser, E. (1968) BAY 39 007/Chronische toxikologische Untersuchungen
    an Hunden. Unpublished report submitted by Bayer AG

    Marchart, H. (1970) Insecticide residues in cocoa. Int. Atomic Energy
    Agency, P-309/1: 1-10

    Marchart, H. Evaluation of insecticides for the control of cocoa
    capsids in Ghana. FAO Plant Protection Bull. 19: 97-109

    Mawdesley-Thomas, L.E., (1969a) Huntingdon Research Centre, England.
    Pathology report of the generation experiment in rats of the toxicity
    of compound BAY 39 007 by oral administration. Unpublished report
    submitted by Bayer AG

    Mawdesley-Thomas, L.E. (1969b) Huntingdon Research Centre, England.
    Pathology report of the two-year experiment in rats of the toxicity of
    compound BAY 39 007 by oral administration. Unpublished report
    submitted by Bayer AG

    Mawdesley-Thomas, L.E., (1969c) Huntingdon Research Centre, England.
    Pathology report of the two-year toxicity in dogs of compound BAY 39
    007 by oral administration. Unpublished report submitted by Bayer AG

    Mendoza, C.E. and Shields, J.B. (1971) Esterase specificity and
    sensitivity to organophosphorus and carbamate pesticides: factors
    affecting determination by thin layer chromatography. J. Ass. off.
    analyt. Chem. 54: 507-512

    Metcalf, R.L. (1971) Structure-activity relationships for insecticidal
    carbamates. Bull. Wld Hlth Org. 44: 43-78

    Metcalf, R.L. and Fukuto, T.R. (1965) Carbamate insecticides. Effects
    of chemical structure on intoxication and detoxication of phenyl
    N-methyl-carbamates in insects. J. Agr. Food Chem. 13: 220-231

    Metcalf, R.L., Osman, M.F. and Fukuto, T.R. (1967) Metabolism of
    14C-labeled carbamate insecticides to 14CO2 in the house fly. J.
    Econ. Ent. 60: 445-450

    Nelson, D.L. A study of the acute toxicity of BAYGON in 1967
    combination with D.D.V.P. Unpublished report submitted by Bayer AG

    Nesemann, E. and Seehofer, F. (1970) Screening procedures for
    organophosphorus, organochlorine and carbamate pesticide residues on
    tobacco. Beiträge zur Tabakforschung, 5: 207-214

    Niessen, H. and Fretse, H. (1963) Eine infrarotspektroskopiscbe,
    Methods zur Bestimmung von N-Methylcarbamat-Rückständen in Pflanzen.
    Pflanzenschutz Nachrichten "Bayer", 16: 205-220

    Niessen, H. and Frehae, H. (1964) Kolorimetrische Methods zur
    Bestimung von Rücksthinden doe Insektizids Undon in pflanzlichem
    Material. Pflanzenschutz-Nachrichten "Bayer", 17: 25-32

    O'Brien, (1966) cited in Metcalf, 1971

    Oonnithan, E.S. and Casida, J.E. (1966) Metabolites of methyl- and
    dimethyl carbamate insecticide chemicals as formed by rat liver
    microsomes. Bull. of Env. Cont. and Tox. 1 (2): 59-60

    Oonnithan, E.S. and Casida, J.E. (1968) Oxidation of methyl- and
    dimethyl carbamate insecticide chemicals by microsomal enzymes and
    anticholinesterase activity of the metabolites. J. Agr. Food Chem.
    16: 28-44

    Pant, C.P. and Joshi, G.P. (1969) A field study of an airborne toxic
    effect of Baygon residual spray. Mosquito News, 29: 674-677

    Parker, B.L., Dewey, J.E. and Bache, C.A. (1970) Carbamate bio assay
    using Daphnia magna. J. Econ. Ent. 63: 710-714

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    Eigenschaften des o-Isopropoxyphenyömethylkarbamat. Magisterarbeit

    Reiner, E. (1968) The inhibitory power of
    2-isopropoxyphenyl-N-methyl-carbamate against serum cholinesterase of
    various individuals. Arch. Toxikol. 23 (3): 237-239

    Reiner and Aldrich (1967), cited in Metcalf, 1971

    Reiner, E. and Simeon, V. (1968) The inhibitory power of 2-isopropoxy
    1968 phenyl-N-methyl-carbamate against serum cholinesterase of various
    individuals. Archiv f. Toxikologiet 23: 237-239

    Root, M., Cowan, J. and Doull, J., University of Chicago. (1963)
    Subacute oral toxicity of RAYER 39 007 to male and female rats.
    Unpublished report submitted by Bayer AG

    Shrivastava, S.P., Tsukamato, M. and Casida, J.E. (1969) Oxidative
    metabolism of 14C-labeled Baygon by living house flies and by house
    fly enzyme preparations. J. Econ. Ent. 62: 483-498

    Stanley, C.W. (1971) A gas chromatographic method for the
    determination of Baygon in soils. Unpublished report submitted by
    Chemagro

    Stanley, C.W. and Thornton, J.S. (1972) Gas chromatographic method for
    residues of Baygon and its metabolites in animal tissues and milk. J.
    Agr. Food Chem. 20: 1269-1273

    Stanley, C.W., Thornton, J.S. and Katague, D.B. (1972) Gas
    chromatographic method for residues of Baygon and metabolites in plant
    tissues. J. Agr. Food Chem. 20: 1265-1269

    Steelman, C.D., Colmerg A.R., Cabes, L., Barr, H.T. and Tower, B.A.
    (1967) Relative toxicity of selected insecticides to bacterial
    populations in waste disposal lagoons. J. Econ. Ent. 60: 467-468

    Syrowatka, T., Jurek, A. and Nazarewiez, T. (1971) Short term chronic
    toxicity study of o-isopropoxyphenyl-N-methyl carbamate (propoxur).
    Rooz. Panstw. Zakl. Hig. 22: 579-589 (poln.)

    Tsukamoto, M. and Casida, J.E. (1967) Albumin enhancement of oxidative
    metabolism of methylearbamate insecticide chemicals by the house fly
    microsome-NADPH2 system. J. Econ. Ent. 60: 617-619

    Tsukamoto, M. and Casida, J.E. (1967) Metabolismus von Methylcarbamat
    Insektiziden durch das NADPH2-benötiginde Enzymsystem der Hausfliege.
    Nature (London), 213: 49-51

    Vandekar, M. (1969) The effect on cholinesterase activity of  storage
    of undiluted whole blood sampled from men exposed to
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    Vandekar, M., Hedayat, E., Plestina, R. and Ahmady, G. (1968) A study
    of the safety of o-isopropoxyphenylmetbyl-carbamate in an operational
    field-trial in Iran. Bull. Wld Hlth Org. 38: 609-623

    Vandekar, M., Plestina, R. and Wilhelm. K. (1971) Toxicity of
    carbamates for mammals. Bull. Wld Hlth Org. 44: 241-249

    Vandekar, M., Reiner, E., Svetlicic, B. and Fajdetic, T. (1965) Value
    of ED50 testing in assessing hazards of acute poisoning by carbamates
    and organophosphates. Brit. J. Industr. Med. 22: 317-320

    Vandekar, M. and Wilford, K. (1969) The effect on cholinesterase
    activity of storage of undiluted whole blood sampled from men exposed
    to o-isopropoxyphenyl methylcarbamate (OMS-33). Bull. Wld Hlth Org.
    40: 91-96

    Voss, G. (1968) Peacock plasma, a useful cholinesterase source for
    inhibition residue analysis of insecticidal carbamate. Bull. Env.
    Cont. and Tox. 3: 339-347

    Waggoner, T.B. and Olson, T.J. (1971) Effect of feeding
    organophosphorus and carbamate pesticides to cattle. Paper No. 45,
    Division of Pesticide Chemistry, 162nd National ACS Meeting, 12-17
    September, Washington, D.C.

    Wales, P.J., McLeod, H.A. and McKinley, W.P. (1968) Pesticide residues
    - TLC-enzyme inhibition procedure to detect some carbamate standards
    and carbaryl in food extracts. J. Ass. off. analyt. Chem. 51:
    1239-1242

    Weiden, M.H.J. (1971) Toxicity of carbamate to insects.  Bull. Wld
    Hlth Org. 44: 203-213

    Wilhelm (1967), cited in Vandekar et al., 1971

    Wit, Sj. (1963) Residues of acaricides and aphicides on glasshouse
    cultures (mevinphos, dichlorvos, naled, propoxur and nicotine).
    Unpublished report submitted by the Nat. Inst. Public Health
    Netherlands

    Wit, Sj. (1966) Residues of parathion and propoxur on red-currants.
    Unpublished report submitted by the Nat. Inst. Public Health
    Netherlands

    Wit, Sj. (1969) Residues of propoxur on gherkins (glasshouse).
    Unpublished report submitted by the Nat. Inst. Public Health
    Netherlands

    Wright, J.W., Fritz, R.F., Hocking, K.S,, Babione, R., Gratz, N.G.,
    Pal, R., Stiles, A.R. and Vandekar, M. (1969) Ortho-isopropoxyphenyl
    methyl-carbamate (OMS-33) as a residual spray for control of
    anopheline mosquitos. Bull. Wld Hlth Org. 40: 67-90

    Wright, C.G. and Jackson, M.D. (1971) Propoxur, chlordane and diazinon
    on porcelain china saucers after kitchen cabinet spraying. J. Econ.
    Ent. 64: 457-459

    


    See Also:
       Toxicological Abbreviations
       Propoxur (ICSC)
       Propoxur (PDS)
       Propoxur (Pesticide residues in food: 1981 evaluations)
       Propoxur (Pesticide residues in food: 1983 evaluations)
       Propoxur (Pesticide residues in food: 1989 evaluations Part II Toxicology)