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    FAO/PL:1969/M/17/1

    WHO/FOOD ADD./70.38

    1969 EVALUATIONS OF SOME PESTICIDE RESIDUES IN FOOD

    THE MONOGRAPHS

    Issued jointly by FAO and WHO

    The content of this document is the result of the deliberations of the
    Joint Meeting of the FAO Working Party of Experts and the WHO Expert
    Group on Pesticide Residues, which met in Rome, 8 - 15 December 1969.

    FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS

    WORLD HEALTH ORGANIZATION

    Rome, 1970

    ETHOXYQUIN

    IDENTITY

    Chemical name

    6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline or
    1,2-dihydro-6-ethoxy-2,2,4-trimethylquinoline.

    Synonym

    Stop Scald, Santoquin

    In some countries formulations containing ethoxyquin may appear under
    different trade names.

    Structural formula

    CHEMICAL STRUCTURE 

    Other relevant chemical properties

    The technical material as manufactured in the USA (Santoquin) is
    claimed to contain 100 percent active ingredients, but is not 100
    percent ethoxyquin. E.g. "Stop Scald" is a 70 percent emulsion of
    Santoquin in water with added emulsifiers. It is a dark liquid varying
    in color from yellow to black. The color is claimed to be independent
    of the antioxidant or biological activity of the chemical.

    Boiling Point:     125C at 1-2 mm Hg.

    Specific gravity:  1.028 to 1.032

    Solubility:        Miscible with animal and vegetable fats and oils.
                       Insoluble in water.

    Viscosity at:       32F         20,000 centipoises
                        73              197      "
                       122               17      "
                       158                7      "

    (Monsanto, 1958).

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Absorption, distribution and excretion

    Studies in chickens resulted in a 99 percent recovery of a single dose
    of C14-labelled ethoxyquin within 48 hours. Continuous administration
    of 125-137 ppm of ethoxyquin in the diet resulted in accumulation of
    approximately 0.1 ppm of ethoxyquin and/or its metabolites in the
    liver and fat per week during the first 12 weeks. Accumulation in
    muscle and other edible tissue was barely detectable. Withdrawal of
    ethoxyquin from the diet resulted in a loss of 79-90 percent of the
    tissue residue in a 6 to 18 hour period. The excretion products
    comprised 15 percent unchanged ethoxyquin, the remainder probably
    being N-glucuronide and N-acetyl derivatives (Monsanto, 1956).

    When ethoxiquin was given in the diet of rats for 10 days at a
    concentration of 50 ppm, accumulation in the liver (2.1 - 4.8 ppm) and
    kidney (2.1 - 2.7 ppm) was observed. Concentrations in fat and
    skeletal muscle were less than 1 ppm (Wilson, 1956a; Wilson et al.,
    1959).

    Rats preconditioned for several weeks on a diet containing 50 ppm of
    unlabelled ethoxyquin were given a single oral dose of 1.5 mg of
    ethoxyquin C14-labelled in the 2 and 4 positions of the heterocyclic
    ring. In two days 30 percent of the radioactivity was excreted in
    urine, 34 percent in faeces. In four days and seven days 40-60 percent
    and 58 percent was excreted in respectively, and 30-40 percent and 36
    percent was excreted in faeces respectively. C14-carbon dioxide in
    respired air was detected on the first day only, and comprised 0.7
    percent of the administered dose (Wilson, 1956a Wilson et al., 1959).

    In rats, repeated administration of ethoxyquin results in residues in
    the kidney as well as in the fat and liver. A greater degree of
    metabolic breakdown may occur than in chicken, because about 1 percent
    of the C14 administered is exhaled as C14-carbon dioxide in rats as
    compared with 0.2 percent in chickens (Monsanto, 1956).

    Pregnant rats treated as above, and administered the labellet
    ethoxyquin nine days prior to parturition indicated that placental
    transfer of ethoxyquin occurs, because newborn young contained 0.12 to
    0.21 ppm ethoxyquin in their tissues. Milk samples from two female
    rats fed a diet of 50 ppm of ethoxyquin for 10 days had residues in
    milk of 0.12 ppm and 0.19 ppm (Wilson, 1956a; Wilson et al., 1959).

    Metabolic studies in dog indicated that ethoxyquin, per se, is not
    excreted in the urine to any appreciable extent, but is excreted as
    four unidentified metabolites (probably glucoronates). There was no
    evidence of the ethoxy-group being split from the molecule during
    metabolism. Results demonstrated that elimination is chiefly by the
    kidneys and only to a small degree by way of the faeces (Hanzal,
    1955).

    TOXICOLOGICAL STUDIES

    Special studies on reproduction

    Rat

    After 40 days on a slightly tocopherol-deficient diet containing 0,
    250, 500 or 1000 ppm ethoxyquin, rats were bred to produce three
    consecutive litters. The first litter offspring were utilized to
    produce a second generation litter. The top dose level was discarded
    after production of one litter. No effects on reproduction, as
    reflected by fertility, litter size, or survival of offspring were
    observed. The animals receiving the experimental diet produced young
    and raised them more successfully than the controls. The 500 ppm diet
    was more effective than the 250 ppm (Wilson, 1956b; Wilson and DeEds,
    1959).

    Groups, each of from five to nine rats, one to ten days pregnant, were
    fed 0, 125, 375 or 1125 ppm ethoxyquin in the diet. Litter size,
    stillbirths, survival to weanling, and weanling weights were all
    comparable to the control rats (Derse, 1956).

    Groups, each of eight or nine female rats, were placed on diets
    containing 0, 125, 375 or 1125 ppm ethoxyquin on the day of mating.
    Gestation time was comparable in all groups. However, litter size was
    slightly depressed at the 375 ppm level and above, and at 1125 ppm
    incidence of stillbirths was increased, and survival to weaning was
    decreased (Derse, 1956).

    Acute toxicity
                                                                                
                                       LD50
    Animal        Route           mg/kg body-weight    References
                                                                            

    Mouse         i.p.            800-1000             Wilson and DeEds, 1959

    Mouse         i.v.            178                  Wilson and DeEds, 1959

    Mouse         inhalation      3000                 Kel'man, 1965

    Rat           oral            ca.800               Wilson and DeEds, 1959

    Rat           inhalation      3150                 Kel'man, 1965

    Chicken       oral            8000-10000           Maclay, 1954
                                                                            
    
    Short-term studies

    Chicken

    Six groups of 70 four-day old cockerels were fed 0, 7.5, 15, 30, 75 or
    750 ppm ethoxyquin in the diet for 12 weeks. No adverse effects were
    observed on body-weight, food-consumption, mortality, gross-, or
    histopathology (Maclay, 1954).

    No adverse effects were observed in cockerels fed diets containing
    7.5, 15, 30, 75 or 750 ppm ethoxyquin for 12 weeks (Colorado A. and
    Experimental Station, ca. 1954).

    Nor were any adverse effects observed in chicks fed diets containing
    75, 750 or 1500 ppm for eight weeks (Halloran, 1952).

    Chicks were fed 0.25 percent of ethoxyquin in their diet for six
    weeks. The concentration of ethoxyquin in the livers was significantly
    higher when the dietary level of protein was 17 percent than when the
    level was 23 percent. (March et al., 1968).

    Dog

    Mixed groups, each of three dogs, were given oral doses by capsule
    five times weekly for one year at dose-levels of 0, 3, 10, 50 or 100
    mg/kg body-weight. Feeding the 100 mg/kg group was terminated after
    sit weeks due to toxic effects, and the dogs were sacrificed at nine
    weeks. One female animal at 3 mg/kg developed histoplasmosis about 40
    weeks after initiation of the study, resulting in abnormal findings
    when compared to the control dogs. All such finding could be
    attributed to the infection. In the remaining animals body-weight was
    depressed at 100 mg/kg; bromosulphthalein retention was increased at
    10 mg/kg and above, indicating liver dysfunction; abdominal tenderness
    was apparent in two of three dogs (male) at 10 mg/kg, and in two of
    three dogs (one male and one female) at 50 mg/kg; erythrocyte
    sedimentation rate was increased in one of three dogs at 50 mg/kg, and
    in all three dogs at 100 mg/kg; haemograms showed reduced haematocrit,
    haemoglobin, and erythrocyte counts in two of three dogs at 50 mg/kg,
    and in all dogs at 100 mg/kg; urin-analysis indicated dark amber,
    green or blackish brown urine at 50 and 100 mg/kg; there was increased
    heart, liver, and kidney to body-weight ratios in all dose-levels, but
    there does not appear to be any dose relationship in these increases;
    histopathology indicated liver-stress, and fatty renal nephrosis at
    the 10, 50 and 100 mg/kg dose-levels (Hanzal, 1955).

    Rabbit

    Undiluted ethoxyquin emulsion (70 percent) was applied to the clipped
    intact skin of three rabbits, and removed after 24 hours. Slight
    erythema occurred after 24 hours in all animals with barely

    perceptible redness remaining after 48 hours in only one animal. The
    compound was classed as a mild skin-irritant under the conditions
    described (Kelly 1960).

    Rat

    Three groups of 10 male and 10 female rats which were fed 0, 0.2, and
    0.4 percent ethoxyquin in their diet for 200 days displayed an initial
    depression in growth rate (statistically significant only at the 0.4
    level) in both test groups. The weight loss was not recovered during
    the course of the experiment. Haemograms in all groups were
    comparable. At autopsy, liver and kidney weights were elevated in both
    sexes in both test groups. Histological examination showed
    pyelonephritis in the males fed 0.2 and 0.4 percent, and doubtfully at
    0.4 percent in the females. Thyroid hyperplasia was noted in males at
    0.4 percent (Wilson and DeEds, 1959).

    Groups of 10 male rats were fed 0, 62, 125, 250, 500, 1000 or 2000 ppm
    ethoxyquin in the diet. Similarly, groups of 10 females were fed 0,
    500, 1000 or 2000 ppm, and groups of five females 125 or 250 ppm. Half
    the animals in some of the groups of 10 were autopsied after 200 days
    on the diet. Body-weight gain was depressed in both sexes at 2000 ppm.
    At autopsy, kidney to body-weight ratio was elevated in the males at
    250 ppm and above, and in the females at 2000 ppm. Liver to
    body-weight ratios were elevated at 1000 and 2000 ppm in males, and at
    2000 ppm in females, Wilson and DeEds, 1959). Histopathological
    examination showed kidney lesions at 500 ppm and above in the males,
    and at 2000 ppm in the females; inclusions were observed in liver cell
    cytoplasm in males at 2000 ppm, and in females at 2000 ppm (Cox,
    1953).

    Long-term studies

    Dog

    Ethoxyquin was fed to two groups of 14 dogs of mixed sex, at dietary
    levels of 0 or 300 ppm for five years. No effects were observed on
    haematology, urinalysis, clinical chemistry (aerum glutamic-oxalic
    transaminase, blood urea nitrogen and bromosulphthalein retention),
    organ weights or organ to body-weight ration, body-weight and 
    gross- or histopathology (Monsanto, 1966).

    Rat

    Groups, each of approximately 10 male and 10 female rats, were fed
    levels of 0, 62, 125, 250, 500, 1000, 2000 and 4000 ppm of ethoxyquin
    in their diets for periods of up to two years. The animals were
    sacrificed for autopsy after 200, 400, 600 or 715 days. Mortality
    rates at all dose levels were not significantly different from the
    controls. Reduced body-weight gain was significant at 2000 ppm after
    225 days in the male animals and after 21 days in the females. After
    200 days increased liver to body-weight and increased kidney to

    body-weight ratios were found at 250 ppm in the males and at 1000 ppm
    in the females. Haemoglobin values for both sexes were normal 100 and
    300 days after the start of the experiment in those rats fed 2000 and
    4000 ppm. Histological changes in the renal cortex were clearly
    evident after 200 days in the male rats receiving 2000 and 4000 ppm,
    but not in the females. All other organs were normal in both sexes
    after 200 days. After 400 days lesions in the kidneys
    (pyelonephritis), liver and thyroid were clearly evident in the males
    only. Similar lesions were evident for periods up to 717 days in both
    sexes, although more marked in the males, and occasional tumours were
    evident after 700 days but were unrelated to the dose-level, and were
    also evident in the controls. No clearly defined effects were evident
    from feeding 62 ppm, but minute lesions were present in the kidneys of
    two of the males receiving the 500 ppm diet. It appeared difficult to
    distinguish the abnormalities in the group examined after 700 days
    with pathological manifestations associated with senility after that
    time (Wilson and DeEds, 1959).

    OBSERVATION IN MAN

    In 20-years experience in the production of ethoxyquin there was no
    indication of any cases of skin irritation or sensitivity (Kelly,
    1960). However, cases of apparent sensitivity to ethoxyquin have been
    reported in fruit handlers. Multiple cases of dermatitis have occurred
    among employees handling freshly sprayed apples moist with solutions
    of 70 percent formulated ethoxyquin. Patch-testing in volunteers
    indicated that these skin reactions were not due to direct irritation,
    but were the result of sensitization (Wood, 1965).

    COMMENT

    Studies in the rat and the dog indicate that toxic effects upon the
    liver and kidney occur when dietary levels of 250 ppm and above are
    given to the rat and 10 mg/kg or higher daily doses are given to dogs.
    Administration of 300 ppm in the diet, however, was well tolerated by
    dogs over a five-year period. There was an increase in the number of
    stillbirths and a decrease in the litter size and in the incidence of
    survival-to-weaning in rats fed 1125 ppm but not in those fed 125 ppm.

    Lower doses (ca. 50 ppm) are rapidly excreted in the rat, dog and
    chicken. Ethoxyquin is apparently converted to water soluble
    metabolites and as long at these conversion mechanisms are functioning
    there appears little likelihood of storage of the compound in the body
    fat.

    The occurrence of dermatitis among fruit packers suggests that
    sensitization could be a problem among those who are handling
    ethoxyquin.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

    Dog:  300 ppm in diet, equivalent to 7.5 mg/kg body-weight/day

    Rat:  125 ppm in diet, equivalent to 6.25 mg/kg body-weight/day

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN

    0 - 0.06 mg/kg body-weight

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERN

    Pre-harvest treatments

    Ethoxyquin is used as a pre-harvest treatment for the control of scald
    of susceptible apple varieties. It is applied once as a full cover
    spray within two days of harvest at a dosage rate of 3 pints of a
    commercial formulation containing 70 percent active ingredient per 100
    gallons of water (2700 ppm active ingredient).

    Post-harvest treatments

    For a post-harvest treatment of apples and pears, ethoxyquin is used
    as a 15-30 sec. dip or a 15 sec. spray prior to or as the fruit passes
    over the grading line. The dosage rate used is 2 to 3 pints of a
    commercial formulation containing 70 percent active ingredient per 100
    gallons of water (1800-2700 ppm active ingredient). The fruit is
    treated no later than one week after harvest.

    The above information on use patterns was obtained from product labels
    from Canada, United States, United Kingdom and Italy.

    Other uses

    Ethoxyquin is also used as an antioxidant in spices, fish meal,
    poultry feeds, swine feeds and other animal feeds.

    Other information pertinent to use pattern

    This monograph is confined to information pertaining to only the
    pesticidal uses of ethoxyquin on apples and pears.

    Ethoxyquin manufactured in the United States is sold in the following
    countries: Sweden, Norway, Denmark, United Kingdom, Netherlands,
    Belgium-Luxembourg, France, W. Germany, Austria, Switzerland, Finland,
    Spain, Italy, Rep. of South Africa, Mexico, Colombia, Venezuela, Peru,
    Chile, Brazil, Philippines, Australia, New Zealand, United States and
    Canada (Monsanto - Direct communication, 1969).

    Information concerning uses in countries other than Canada, United
    States, United Kingdom and Italy, such as Israel, Japan, West Germany
    and Sweden, where it was understood that ethoxyquin was manufactured,
    was not available to the Joint Meeting.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

    The results reported in Tables 1, 2, 3 for apples and 6 and 7 for
    pears are from supervised trials made in various geographical
    locations in the United States (Monsanto, 1961). Those in Tables 4 and
    5 for apples, are from supervised trials carried out in New Zealand
    (Padfield et al., 1963).

    Summary of residue data

    The residues of ethoxyquin on apples and pears when applied as a dip
    or spray on a whole-fruit basis did not exceed 1.2 ppm from U.S.A.
    data. However, from New Zealand, levels up to 2.8 ppm on apples have
    been reported and one variety, Dougherty, which appears to have the
    ability to retain fairly high levels of residue, was reported to have
    levels up to 4.4 ppm. Results obtained in New Zealand also indicate
    that use of a warm dip may result in residues of ethoxyquin on apples
    as high as 6 ppm. Experimental results suggest that the uptake of
    ethoxyquin is likely to increase as apple fruit matures and cooled
    fruit appears to show lower residues than fruit treated at normal air
    temperature. The results of trials carried out in the United States
    indicate that residues found as a result of spraying fruit on the tree
    are generally less than when apples or pears are dipped post-harvest.

    FATE OF RESIDUES

    Ethoxyquin, instead of existing as a single molecule, changes
    spontaneously into a complex resulting from oxidation. These complex
    structures are still effective biologically. No major degradation
    change occurs in the ethoxyquin molecule. The structure of the
    oxidation product has not been definitely determined but the
    structures of the first reaction product(s) which fit the observations
    most closely are suggested to be:

    CHEMICAL STRUCTURE 


        TABLE 1
                                                                                                      

    Pre-harvest treatments - applied as a fruit and foliage spray just prior to picking of apples.

                                    Interval between
    Treatment Rate       Apple      Treatment and               Residue (ppm)
    (ppm ethoxyquin)    Variety     Sampling (days)    Fresh Apples       Stored Apples
                                                                                                      

         900            Paragon        13 - 14            0 - 0.2
                        Winesap

         1800               "          13 - 14         0.03 - 0.35

         1500           McIntosh       23 - 24            0 - 0.01
                                            44                                 0 - 0.11

         3000           McIntosh            23            0                    0 - 0.16

         2000           Wealthy             53                              0.01 - 0.10

           0            Greening            53                              0.00 - 0.11

         2000               "               22         0.00 - 0.13
                                            53                              0.01 - 0.11

         2000           McIntosh            20         0.00 - 0.01
                                            51                                     0.00
                                                                                                      

    TABLE 2
                                                                                       
    Post-harvest treatments - using a 15 second dip or applied as a spray.

                                    Interval between
    Treatment Rate       Apple      Treatment and               Residue (ppm)
    (ppm ethoxyquin)    Variety     Sampling (days)    Fresh Apples       Stored Apples
                                                                                       

         1000           Red
                        Delicious          2           0.07,  0.42
                                          31                                0.13,  0.07

         2000              "               3           0.20,  0.34
                                          32                                0.14,  1.17

         3000              "               3           0.48,  0.34
                                          32                                0.53,  1.00

         1000           Jonathon           4           0.03,  0.18
                                          32                                       0.11

         2000              "               4           0.62,  0.43
                           "              33                                0.04,  0.04

         3000              "               4           0.44,  0.81
                           "              33                                0.09  0.04

         2000           Wealthy           23           0.00 - 0.62
                           "              55                                0.00 - 0.20

         3000              "              23           0.01 - 0.81
                           "              55                                0.04 - 0.14

            0           Greening          50                                0.00 - 0.11

         2000              "              20           0.03 - 0.13
                           "              50                                       0.00

         2000           McIntosh          19                  0.00
                                          49                                       0.00
                                                                                       

    TABLE 3
                                                                                         

    Post-harvest treatments - using a 15 second dip.

    Treatment Rate      Apple       Interval               Residues (ppm)
    (ppm ethoxyquin)    Variety     (days)*      Peel           Pulp        Whole Apple
                                                                                         

            0           Jonathon       1       0.2 - 0.3                    0.03 - 0.04

         1000             "            1       3.6 - 4.1                    0.47 - 0.54

         2000             "            1       4.5 - 4.7                    0.61 - 0.64

         3000             "            1       5.4 - 5.7                    0.67 - 0.70

         4000             "            1       8.0 - 7.5                    0.94 - 1.00

            0           McIntosh       7       0.07, 0.11    0.08,  0.11    0.08,  0.11

         3600             "            7       1.45, 1.45    0.14,  0.14    0.29,  0.30

            0           Cortland       7       0.07, 0.16    0.07,  0.09    0.08,  0.08

         2700             "            7       1.75, 1.80    0.07,  0.11    0.30,  0.32
                                                                                         

    * Interval between treatment and sampling
    

        TABLE 4
                                                                   

    Residues on apples dipped or sprayed with 1800 ppm ethoxyquin.
    The samples of fruit for analysis were withdrawn from the
    line during normal operation and residue determinations were
    made as soon as possible after treatment.

                                       Residue (ppm)
    Apple                         First Pick     Second Pick
    Variety         Treatment     March-April    March-May
                                                                   

    Delicious       Cool dip          1.4           1.2

                    Warm dip          1.5           1.9

                    Spray             1.0           0.8

    Granny Smith    Cool dip          1.1           2.8

                    Warm dip          1.6           4.8

                    Spray             1.5           0.7

    Rome Beauty     Cool dip          0.7           1.4

                    Warm dip          2.4           1.8

                    Spray             0.9           1.3

    Sturmer         Cool dip          0.5           1.6

                    Warm dip          1.8           2.7

                    Spray             1.8           2.3

    Dougherty       Cool dip          2.6           4.4

                    Warm dip          1.9           6.0

                    Spray             2.2           3.0
                                                                   

    TABLE 5
                                                                                         

    Ethoxyquin residues on apples after treatment in commercial spay tunnels.
    Residue analyses were made as soon as possible after treatment.

    Treatment Rate      Apple            Fruit
    (ppm ethoxyquin)    Variety        Temperature      Residue (ppm)
                                                                                         

         1800           Sturmer        Air temp.                1.6
                                       Cooled 38F              0.7

         1800           Granny Smith   Air temp.          0.7 - 1.7
                                       Cooled 33F        0.5 - 1.0

         2700                          Air temp.                2.2
                                       Cooled 33f              1.5

    TABLE 6
                                                                                                   

    Pre-harvest treatments - applied an a fruit and foliage spray just
    prior to picking of pears.

                                    Interval between
    Treatment Rate       Pear       Treatment and               Residues (ppm)
    (ppm ethoxyquin)    Variety     Sampling (days)    Fresh Fruit        Stored Fruit
                                                                                                   

         1000           Anjou           23 - 25               0.01
                                        70 - 71                                  0.00

         2000             "             23 - 25        0.01 - 0.04
                                        70 - 71                                  0.00
                                                                                                   
    

        TABLE 7
                                                                                                   

    Post-harvest treatments using a 15 second dip.

                                                                            Residues (ppm)
    Treatment Rate      Pear            Interval                                   Whole     Stored
    (ppm ethoxyquin)    Variety         (days)*           Pulp          Peel       Fruit     Fruit
                                                                                                   

         900            Anjou           53                                                   0.00

         1800             "             53                                                   0.00

         1000             "             53                                                   0.03

         1500             "             53                                                   0.03

         2000             "             53                                                   0.01

         2700             "              7             0.04 - 0.05    4.7 - 4.9    0.66

         3600             "              7             0.04 - 0.09    7.6 - 8.3    1.09

         5400             "              7             0.04 - 0.08    7.9 - 9.2    1.07
                                                                                                   

    * Interval between treatment and sampling.
    
    Evidence of residues in food in commerce or at consumption

    No information available.

    METHODS OF RESIDUE ANALYSIS

    Methods using ultraviolet spectrophotometry of spectrofluorometry have
    been proposed for the determination of residues of ethoxyquin in food,
    feed and animal tissue. The spectrophotometric methods of Choy et al.
    (1963) and Alicino et al. (1963) both include clean-up stages to
    separate ethoxyquin from other anti-oxidants such as butylated
    hydroxyanisole and butylated hydroxytoluene before estimation of
    absorbance at 296 nm. A spectrofluorometric procedure for ethoxyquin
    in feeding stuffs (Gordon et al., 1964) was adapted for use on samples
    of eggs, chicken muscle and liver (Van Deren and Jaworski, 1966). It
    is relatively non-specific for ethoxyquin and residues of other
    pesticides or of other naturally occurring compounds may interfere.
    Collaborative study of this method (Van Deren and Jaworski, 1967) led
    to its adoption as an official, first action procedure (Anon, 1968).
    The ethoxyquin is extracted with iso-octane, cleaned-up by an
    acid-alkaline extraction procedure and determined by examining the
    fluorescence of an iso-octane solution. The suitability of this method
    for application to fruit for regulatory purposes needs further
    evaluation.

    NATIONAL TOLERANCES

    Tolerances for Fruit

    Canada      - 3 ppm on apples

    U.K.        - 3 ppm on apples

    U.S.A.      - 3 ppm on apples and pears
                   (for ethoxyquin and other naturally occurring
                    fluorescent materials).

    New Zealand - 3 ppm on apples

    Tolerances derived from use as additives in animal feeds

    Canada -  3 ppm in livers of poultry
              0.5 ppm in meat, poultry meat and eggs

    U.S.A. -  3 ppm in poultry livers and fat
              0.5 ppm in eggs and meat

    APPRAISAL

    In a review of the literature very few articles were found on
    ethoxyquin other than those on its efficacy in controlling scald. The
    abstracting journals reviewed were, Review of Applied Mycology,
    Biological Abstracts, Chemical Abstracts and Pesticide Documentation
    Bulletin.

    Data available are based on ethoxyquin as manufactured in the U.S.A.
    and used in several other countries. Ethoxyquin is also manufactured
    in Israel, Japan, West Germany and Sweden. The amount and nature of
    minor constituents and amount of ethoxyquin monomer in products other
    than U.S.A. manufacture in unknown. It is used for the control of
    scald in apples (and to a lesser extent pears), as both pre-harvest
    treatments and post-harvest dips and sprays.

    The residues of ethoxyquin on apples and pears when applied as a dip
    or spray on a whole-fruit basis did not exceed 1.2 ppm from U.S.A.
    data. However, from New Zealand, levels up to 2.8 ppm on apples have
    been reported and one variety, Dougherty, which appears to have the
    ability to retain fairly high residue, was reported to have levels up
    to 4.4 ppm. Results obtained in New Zealand also indicate that use of
    a warm dip may result in residues of ethoxyquin on apples as high as 6
    ppm. Experimental results suggest that the uptake of ethoxyquin is
    likely to increase as apple fruit matures. Cooled fruit appears to
    have lower residues than fruit treated at normal air temperature. The
    results of trials carried out in the U.S.A. indicate that residues
    found as a result of spraying fruit on the tree are generally less
    than when apples or pears are dipped post-harvest.

    Ethoxyquin, instead of existing as a single molecule, changes
    spontaneously into a complex resulting from oxidation. These complex
    structures are still effective biologically. No major degradation
    change occurs in the ethoxyquin molecule. The structure of the
    oxidation product has not been definitely determined, but the
    structures of the first reaction product(s) which fit the observations
    most closely are given in the monograph.

    The fluorometric method is relatively non-specific for ethoxyquin on
    apples and pears. Many naturally occurring fluorescent materials may
    interfere. It is also possible that residues of other pesticides used
    on apples may fluoresce or be converted into fluorescent compounds.
    More suitable spectrofluometric methods available for animal products
    should be adopted and evaluated.

    RECOMMENDATIONS FOR TOLERANCES, TEMPORARY TOLERANCES OR PRACTICAL 
    RESIDUE LIMITS

    TOLERANCES

    Apples and pears     3.0 ppm

    DESIRABLE

    1. Additional reproduction studies to investigate the effect on
       survival rate of offspring of rats.

    2. A method of analysis for apples and pears suitable for regulatory
       purposes.

    3. Composition and purity of this compound as manufactured in several
       countries and the amount of ethoxyquinmonomer in the products from
       various manufacturers.

    REFERENCES

    Alicino, N.J., Klein, H.C., Quattrone, J.J. and Choy, T.K. (1963)
    Determination of butylated hydroxyanisole, butylated, hydroxytoluene,
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    Anon (1968) Changes in Official Method of Analysis. J. Assoc. Offic.
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    Choy, T., Alicino, N.J., Klein, H.C. and Quattrone, J.J. (1963)
    Determination of ethoxyquin by ultraviolet spectrophotometry. J. Agri.
    Fd Chem., 11:340-2

    Choy, T., Alicino, N.J., Klein, H.C. and Quattrone, J.J. (1963)
    Determination of ethoxyquin by ultraviolet spectrophotometry. J.Agri.
    Fd Chem., 11:340-2

    Colorado, A. and M. Experimental Station. (1954) The chronic toxicity
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    Cox, A.J. (1953) 6-ethoxy, 2,2,4-trimethyl-1,2-dihydroquinoline
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    haematoxylin-eosin. Unpublished report submitted by Monsanto Chemical
    Company.

    Derse, P. (1956) Assay report. Unpublished report of Wisconsin Alumni
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    Gordon, R.S. Conkin, R.A. and Machlin, L.J. (1964) Determination of
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    Halloran, H.R. (1952) Chick toxicity tests on Santoflex AW.
    Unpublished report from the Poultry Products of Central California,
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    Hansal, R.F. (1955) Final report and addendum. Chronic oral
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    Kelly, R.G. (1960) Supplementary toxicity information on Santoquin
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    prepared and submitted by Monsanto Chemical Company

    Kel'man, G.Y. (1965) Comparative toxicity of Santoflex A
    (6-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline) and acetoneanyl
    (1,2-dihydro-2,2,4-trimethylquinoline). Keuchuk i Rezina 24:40-41
    [(Chem. Abstr. 63:1136g (1965)]

    Mackay, V.D. (1954) Toxicity data in support of the use of 0.015% of
    6-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline on alfalfa meal for
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    Research Branch, U.S.D.A., submitted by Monsanto Chemical Company

    March, B.E., Biely, J. and Coates, V. (1968) The influence of diet on
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    Monsanto (1956) Santoquin for use in Poultry Feeds, Unpublished report
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    Monsanto. (1956) Petition proposing the issuance of a regulation
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    Monsanto. (1961) Information to support label registration request for
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    and petition for tolerance for ethoxyquin on pears. Unpublished
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    Monsanto. (1966) Five year Santoquin feeding study in dogs.
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    Monsanto. (1969) Direct communication

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    Van Deren, J.M. and Jaworski, E.G. (1966) Ethoxyquin (Santonin (R) in
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    See Also:
       Toxicological Abbreviations
       Ethoxyquin (JMPR Evaluations 1998 Part II Toxicological)
       Ethoxyquin (JMPR Evaluations 2005 Part II Toxicological)