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    AGP:1970/M/12/1

    WHO/FOOD ADD/71.42

    1970 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, 9-16 November, 1970.

    FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS

    WORLD HEALTH ORGANIZATION

    Rome, 1971

    HEPTACHLOR

    Additional data on heptachlor have become available since the last
    complete monograph was produced (FAO/WHO, 1967). These data, as well
    as some pertinent older data, are summarized in this monograph
    addendum.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Biotransformation

    Information on the metabolism of heptachlor in mammals is still
    incomplete. The formation of heptachlor epoxide in vivo in several
    species of mammals and in vitro using rat and rabbit liver microsomes
    in the presence of NADPH has been described (Wong and Terriere, 1965;
    Nakotsugawa, 1965; FAO/WHO, 1967). It was suggested early on that
    heptachlor epoxide might be further metabolized to a diol (Davidow and
    Radomski, 1953),but the occurrence of such a compound has not yet been
    demonstrated. However, when 25 g of 14C-labelled heptachlor was
    administered to male and female rats, the radioactivity was largely
    encountered in the faeces as heptachlor epoxide, along with a second
    metabolite; this second metabolite was also encountered in the urine,
    but heptachlor epoxide was not. In both rats and rabbits treated with
    heptachlor, heptachlor epoxide was the main metabolite found in
    tissues. The urinary metabolite was found to be
    1-hydroxy-2,3-epoxychlordene (see Figure 1) (Korte, 1968; Klein et
    al., 1968). It is not known if this compound arises via heptachlor
    epoxide or via a direct hydrolysis of heptachlor first to form
    1-hydroxychlordene. The information available on the mammalian
    metabolism of heptachlor has been reviewed (Brooks, 1969). In
    experiments with rabbits and pig liver microsomes, the hydration of
    heptachlor epoxides to a diol has been demonstrated (Brooks and
    Harrison, 1969). See also "Fate of residues, in soil".

    Effect on enzymes and other biochemical parameters

    Heptachlor and heptachlor epoxide were administered to two or three
    male rats at dietary levels of 0 (eight rats) 1.0 or 5.0 ppm for two
    weeks. (Aldrin or dieldrin were also fed at the same levels to other
    groups). After completion of the feeding, the animals were sacrificed
    and microsomal preparations made from their livers. Microsomal
    epoxidation, as measured by the epoxidation of aldrin to dieldrin, was
    unaffected by 1.0 ppm, but was significantly affected by 5.0 ppm of
    heptachlor or its epoxide. The increase in the rate of epoxidation was
    correlated to the dietary level and to the concentration of the
    cyclodiene compounds in the microsomes. Both heptachlor and aldrin
    appeared to be substrates for the same enzyme, which is inhibited by
    the epoxide. Microsomal metabolism of the epoxides was not found to
    proceed farther (Gillett and Chan, 1968).

    FIGURE 

    FIGURE 


    Female rats were fed with heptachlor in the diet at a dose level
    corresponding to 5 mg/kg body-weight/day for three months. After this
    period 32P-labelled fenitrothion at a dose of 24 mg/kg body-weight
    was administered in oil per os, and radioactive measurements were made
    (five times during 24 hours) of the total activities of the liver and
    of the degradation products in blood and liver. The results were
    compared with those of the control group not pre-treated with
    heptachlor. Total activity in the liver of the group pre-treated with
    heptachlor was 50 percent higher than in the control group, with a
    maximum after four hours. In the control group, the values diminished
    gradually after the exposure to fenitrothion. The ratio of the oxygen
    analogue to fenitrothion in the blood and liver suggests that the
    conversion of fenitrothion to its oxygen analogue is enhanced and
    accelerated. Results of this experiment demonstrate that pre-treatment
    of rats with heptachlor increases the metabolism of fenitrothion
    (Mestitzova et al., 1970).

    TOXICOLOGICAL STUDIES

    Special studies on reproduction

    Chicken

    Groups comprising four male and twenty female chickens were fed
    dietary levels of 0, 0.02, 0.1 or 0.2 ppm of heptachlor epoxide for 25
    weeks. Body-weight increase was not affected by heptachlor epoxide.
    Mortality was low in all groups, and a slightly higher incidence in
    the 0.2 ppm group than in the other groups is of doubtful
    significance. No abnormal behaviour was observed. Total weekly egg
    production and mean weekly egg-weights were not significantly
    different between test and control groups. Hatchability was slightly
    decreased in the eggs from the groups fed 0.1 and 0.2 ppm; viability
    of hatched chicks was, however, not affected by heptachlor epoxide
    (Wolvin et al., 1969).

    Chicken egg

    Hatchability of hen eggs was not affected by injection of 1.5 mg
    heptachlor in the yolk of fertile eggs (Smith et al., 1970).

    Quail

    Japanese quails were given 10 and 50 ppm heptachlor in the diet. There
    was no obvious adverse effect on reproduction when the birds were ten
    weeks of age (Shellenberger and Newell, 1965).

    Rabbit

    Pregnant female rabbits were treated orally with 0 (22 animals) or 5
    mg/kg body-weight/day (20 animals) of heptachlor epoxide from days six
    to eleven of gestation. Foetuses were recovered on day 28 by caesarean
    section. There were no behavioural abnormalities apparent, and
    body-weight gain was not affected by heptachlor epoxide. There were no

    deaths. No compound-related effects were observed with respect to
    numbers of viable and non-viable term foetuses, resorptions, empty
    implantation sites, corpora lutea or non-gravid females. A significant
    increase in foetus weight was evident in the treated group; this
    increase was considered to be compound related. Survival time was not
    considered to be affected by heptachlor epoxide. There were no
    teratogenic effects attributable to the compound (Wazeter et al.,
    1969).

    Rat

    Male and female rats fed exclusively on diets containing a mixture of
    heptachlor and heptachlor epoxide (3.1) in amounts of 0, 0.3, 3 or 7
    ppm have been mated through three succeeding generations. The number
    of pregnancies in the F0 and F2 generations was slightly reduced in
    the 0.3 ppm group, but not at higher dose levels. There was a slight
    increase in the mortality of the pups in the second and third week
    after birth in the 3 ppm group. This was not consistent with other
    data obtained in these experiments. During three successive
    generations, the compound exerted no apparent effect upon the
    fertility of the progenitors or the ability of the progeny to survive
    (Witherup et al., 1967a).

    Male and female rats fed exclusively on diets containing 0, 0.3, 3, 6
    and 10 ppm heptachlor have been mated through three succeeding
    generations. In the second and third week after birth, mortality of
    the pups, only in the second generation, was slightly increased in the
    10 ppm group. No adverse effects have been reported in the successive
    lower dose levels (Witherup et al., 1967b).

    Toxicity studies on the metabolites

    The acute oral toxicity of four heptachlor metabolites, chlordene,
    3-chlorochlordene, 1-hydroxychlordene and chlordene epoxide, was found
    to be greater than 4,600 mg/kg body-weight for the LD50 to male or
    female rats (Mastri et al., 1969a). In another test in female rats,
    the oral LD50 of 1-hydroxy-2, 3-epoxychlordene was calculated to be
    between 4,600 and 10,200 mg/kg body-weight and for 2-chlorochlordene,
    >10,200 mg/kg (Mastri et al.,1969b).

    Groups each comprising 25 male and 25 female rats, were fed 0, 100,
    250, 500, 1000 or 2000 ppm of the heptachlor metabolite
    1-hydroxychlordene in their diet for up to 224 days. A rat of each sex
    was sacrificed at intervals for autopsy. After receiving the test diet
    for 110 days, three females from each level were selected and mated
    with males from the same level. Growth and food consumption were
    normal at all levels, and mortality appeared to be unaffected by the
    test compound. At 2000 ppm, the compound may have produced intestinal
    irritation. Within the one generation, 1-hydroxychlordene showed no
    adverse effects on fertility, litter size, litter weight or survival
    and growth of the young at any level. Gross pathology findings were
    limited to one hepatoma in a female fed 2000 ppm and one in a male at
    500 ppm; one female at 100 ppm had parotid gland tumours. A breast

    tumour was seen in a control animal. Histopathology revealed
    abnormalities only in the liver which at 1000 and 2000 ppm showed
    slight to moderate cytoplasmic margination, which was also evident to
    some extent in the controls and lower level groups. Hepatic cell
    enlargement which occurred was also doubtfully related to 1-hydroxy-
    chlordene (Ingle, 1965).

    Special studies on photodecomposition

    By irradiation of heptachlor, a caged photoisomerization product
    similar to that observed with other cyclodiene insecticides has been
    produced. It has been suggested that this compound may result from
    exposure of heptachlor to sunlight. It is more toxic to houseflies and
    mosquito larvae than heptachlor, but no information is available on
    its mammalian toxicity (Rosen, 1969). Present evidence indicates that
    neither photo-heptachlor nor photo-heptachlor epoxide contributes
    significantly to the terminal residues on plants or soil, even though
    films of heptachlor epoxide on glass were readily transformed into the
    photo-product (Polen, 1970).

    Short-term studies

    Rat

    Groups, each comprising ten female rats, were fed dietary levels of 0,
    5 or 10 ppm of heptachlor or 10 ppm of DDT for eight months.
    Examination of the liver cells of the groups fed 10 ppm of heptachlor
    or DDT revealed essentially the same pictures, with increase in the
    smooth endoplasmic reticulum and the mitochondria, although these
    changes occurred to a greater degree with DDT. At 5 ppm, heptachlor
    revealed the earlier stages of the development seen in animals fed 10
    ppm. Comparison of the described findings with heptoma cells, obtained
    from feeding carcinogenic aminoazo compounds, revealed a striking
    difference (Stemmer and Hamdi, 1964).

    A total of 269 rats of unspecified sex were fed 40, 45 or 60 ppm of
    heptachlor or 35, 40 or 45 ppm of heptachlor epoxide or 40, 45 or 60
    ppm of a 75 : 25 percent mixture of the two compounds. After feeding
    for 140 days, some animals were returned to a basic uncontaminated
    diet and others were continued on the test diet. The animals were then
    sacrificed after 10, 20, 30, 60, 80 or 120 days from the 140-day
    feeding period. Typical liver lesions were shown to regress after
    discontinuing feeding, as evidenced by the observations of the rats
    which were returned to a normal diet. After 120 days, a significant
    number had normal livers. The largest number of recoveries occurred in
    the group fed heptachlor, the next with the mixture and the least in
    the group fed heptachlor epoxide. Some rats fed a treated diet for 260
    days displayed a second type of lesion in the periphery of the liver
    lobule, consisting of enlargement of cells with cytoplasm of empty
    appearance. The nuclei were small and dense, with distinct cell
    boundaries. It was not reported if these lesions regressed after
    returning the animals to a normal diet. Evidence of hyperfunction of
    the adrenal medulla was also present in rats that had not had

    regression of their liver changes. There was indication of depletion
    of catecholamine, the cytoplasmic granules were diminished and some
    cells showed vacuolations (Stemmer and Jolly, 1964).

    Four groups, each comprising 10 male and 20 female rats, were given
    daily oral doses of 0, 5, 50 or 100 mg/kg body-weight of pure
    heptachlor starting at about four months of age. Administration was
    continued for 200 days or until the animals died. By the tenth day,
    all the animals in the groups fed 50 or 100 mg/kg had died. At day
    200, the surviving animals in the 5 mg/kg group and the controls were
    sacrificed for autopsy. Prior to death, the 50 and 100 mg/kg groups
    became irritable and had accelerated respiration by the second day.
    Convulsions preceded death. In the group given 5 mg/kg, no clinical
    abnormalities were seen until the 50th day, when hyper-reflexia, rapid
    respirations and chronic convulsions were observed. Two males and two
    females in this group died before completion of the experiment,
    compared to only one female in the controls. Weight gain was not
    affected by 5 mg/kg. Gross pathology revealed changes in liver, kidney
    and spleen. Histopathologic examination showed fatty degeneration of
    the liver cells and moderate fatty infiltration of the cells of the
    urinary tubules, as well as hyperplasia of the smooth endoplasmic
    reticulum of the liver and spleen in the group fed 5 mg/kg (Pelikan et
    al., 1968).

    COMMENT

    Since the last evaluation of heptachlor, which was made at the 1966
    Joint Meeting, considerable new information on the metabolism of
    heptachlor and its epoxide has become available. In acute and
    short-term feeding experimental these metabolites appeared to be less
    toxic than heptachlor or heptachlor epoxide. It was noted that liver
    cellular metabolism was affected by a dietary level of 5 ppm of
    heptachlor in the rat, and attention was drawn to its effect on the
    metabolism of a compound each as fenithrothion. As is the case with
    other organochlorine compounds, the toxicological significance of
    these findings could not be determined. In a three-generation
    reproduction study in rats, no dose related effects were observed. In
    view of the observations from other organochlorine pesticides, an
    adequate carcinogenicity study in a second species of animal other
    than the rat is needed.

    TOXICOLOGICAL EVALUATION

    Level causing no significant toxicological effect

    Rat: 5 ppm in the diet, equivalent to 0.25 mg/kg body-weight/day

    Dog: 2.5 ppm in the diet, equivalent to 0.06 mg/kg body-weight/day

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN

    0-0.0005 mg/kg body-weight

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERN

    The approximate distribution of the use of heptachlor outside of
    continental United States is as follows:

                   Area                     Percentage
                                                       

                   Europe                   60
                   Asia                     15
                   South America            15
                   Africa                    5
                   North America             5
                                                       
                   TOTAL                    100%

    In Europe the dominant use (probably >75%) is for seed treatment in
    the culture of sugar beets. Minor significant uses are for seed
    dressing of cereal grains and protection of potatoes.

    The major uses for heptachlor in Asia are in the control of soil
    insects in sugar cane, cereal grains and vegetables. In some areas, to
    a small degree, heptachlor is used for the protection of pineapple.

    In South America, the major uses of heptachlor are on sugar cane and
    maize. The protection of bananas is a minor significant use of
    heptachlor.

    In Africa and in North America, the most significant uses of
    heptachlor are on maize and small grains.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

    In cane berries

    No residues were detected (<0.01 ppm) in boysenberries, blackberries
    or red or black raspberries maturing in soils treated with 4.0 and 8.0
    lb/acre of heptachlor (Velsicol data).

    In carrots

    (Grown in soils previously subjected to treatment)

    Soil treatment at Wooster, Ohio, was made in May 1960 with 6 and 200
    pounds of heptachlor per acre. Soil readings three years later (1962)
    showed residue of 1.2 to 1.9 ppm (combined H and HE) at 6 pounds per
    acre. At the end of four and one half years, the readings at 6 pounds
    per acre were 0.52 to 1.25 ppm, and at 200 pounds per acre, 1.8 to
    16.5 ppm. Readings in carrots at the 6 pound rate were 0.07 ppm, and

    at 200 pounds, 0.5 ppm four and one-half years after treatment.
    Carrot/soil residue ratios are respectively: 0.056-0.195 and
    0.030-0.278 (Velsicol, soil and carrot data).

    Heptachlor was applied at the rate of 5 pounds per acre annually for
    five years (1958-1962) to a loam soil. In 1967, combined heptachlor
    and heptachlor epoxide reading was 0.78 ppm. Carrots grown in that
    soil in 1967 had combined residues at the end of the season of 0.36
    ppm. Carrot/soil residue ratio was 0.46 (Lichenstein et al., 1968).

    Loam soil treated five consecutive years with abnormally high rates of
    heptachlor (5 lb per acre, 25 cumulative) contained 4.6% of the
    applied heptachlor five years after cessation of treatment. The mean
    residue level (H+HE) in soil was 0.70 ppm; in carrots 0.413;
    carrot/soil residue ratio, 0.59. In a parallel test wherein one 25 lb
    per acre application was made, ten years after cessation of treatment,
    mean residue levels were: in soil 0.719 ppm; in carrots 0.223 ppm;
    carrot/soil residue ratio 0.310 (Lichtenstein et al., 1970).

    In simulated agricultural experiments, Harris and Sans (unpublished
    report, ca. 1969. Absorption of heptachlor epoxide residues by carrots
    from three different soil types) demonstrated the strong dependence of
    residue transmittal on soil organic content. At a constant level in
    soil of 2 ppm of heptachlor epoxide, residues in carrots were
    respectively 0.56, 0.03 and 0.01 ppm when grown in soils of 20 and 55
    percent organic matter. The respective carrot/soil residue ratios are
    0.28, 0.015 and 0.005.

    In citrus

    Negligible residues were found in oranges and lemons from trees on
    soil treated at 3 and 6 lb/acre in California. Soil treatment of 6
    lb/acre around grapefruit trees resulted in essentially no residue. A
    few samples had readings of 0.01-0.02 ppm for heptachlor and gamma
    chlordane, but there was no difference from the check samples
    (Velsicol data).

    In cottonseed and its products

    No residues were found in meal, crude oil, refined oil or soapstock
    made from cottonseed grown from heptachlor dressed seed treated at 4
    fluid oz /100 lb seed (Velsicol data).

    In maize and maize oil

    Maize grown on soil into which heptachlor had been incorporated at
    rates ranging from 0.75 to 4.0 lb/acre (both row and broadcast
    treatment) did not result in measurable residues in natural ear, grain
    samples or ensilage prepared from green plants. Stover or mature
    stalks contained up to 0.02 ppm of heptachlor, 0.06 ppm of heptachlor
    epoxide and 0.04 ppm of gamma chlordane in one experiment only,
    however, there did not appear to be any relationship between treatment
    level and residue level. Bruce at al. (1966) was able to show a linear

    relationship between residue levels of heptachlor epoxide in maize
    seed and residue levels in the soil in which the maize was grown using
    treatments of 2-20 lb/acre. Maize seed residues (H+HE) did not exceed
    0.01 ppm. Maize oil from maize grown in heptachlor treated soil did
    not contain measurable residues (Velsicol data).

    In peaches

    Heptachlor applied at rates of 1.5 and 3.0 lb/acre to soil around
    peach trees before petal fall did not result in measurable residues in
    the ripe peaches (Velsicol data).

    In peppers

    Essentially no residues were found in peppers grown in soils treated
    with 1-6 lb/acre of heptachlor. Although one sample had an apparent
    heptachlor epoxide residue of 0.07 ppm from a 3 lb/acre treatment, no
    residue was found in peppers from the 6 lb/acre treatment (Velsicol
    data).

    In pineapple

    Heptachlor was applied to pineapple in Hawaii as a foliar treatment at
    1, 2 and 4 lb/acre. Foliage samples collected two months after
    treatment showed heptachlor epoxide residues of 0.03 ppm at 1 lb/acre
    to 0.20 ppm at 4 lb/acre. Heptachlor and gamma chlordane residues also
    occurred in the foliage samples. One heptachlor reading was 2.40 ppm,
    while gamma chlordane was 0.94 ppm. Other than these two readings, the
    maximum foliage level of heptachlor was 0.65 ppm, and for gamma
    chlordane the highest reading was 0.26 ppm. All fruit samples gave
    negative readings for heptachlor, heptachlor epoxide and gamma
    chlordane. Low levels of residues occurred in samples of fruit shell.
    Raw bran samples showed maximum values of 0.05 ppm for heptachlor,
    0.11 ppm for heptachlor epoxide and 0.09 ppm for gamma chlordane at
    the high treatment rate of 4 lb/acre. Recommended rates gave maximum
    levels of 0.01 ppm heptachlor, 0.04 ppm heptachlor epoxide and 0.05
    ppm gamma chlordane. Samples analyzed seven months after foliar
    treatments gave negative results for fruit and fruit shell and low
    values for foliage and raw bran (Velsicol data).

    In small grains

    Small grains grown in soils treated (preplant) at rates up to 3
    lb/acre resulted in no measurable residues of heptachlor or heptachlor
    epoxide in the grain for barley, oats, rye and wheat. Gamma chlordane
    is reported at levels up to 0.02 ppm but in also observed in the check
    sample. Although significant residue appears in the soil from
    heptachlor treatment, it is not translocated to the mature grain. Some
    levels occur in the straw (Velsicol data).

    Seed treatment of small grains with heptachlor does not give residues
    in grain of oats, rye or wheat. Rye straw had up to 0.33 ppm of

    heptachlor epoxide, which appears to be contamination or an artifact.
    Wheat straw gave negative values from one test area and 0.02 ppm to
    0.04 ppm for heptachlor and gamma chlordane (Velsicol data).

    In sorghum

    Seed treatment tests on sorghum at recommended rates gave negative
    readings for heptachlor, heptachlor epoxide and gamma chlordane in
    samples of grain and straw grown from treated seed (Velsicol data).

    In soybeans

    Soil treatments were made in September 1966 at 3.0 and 6.0 lb ai/acre.
    Soybeans were planted and samples collected in 1967. From both EC and
    granular formulations, all green forage samples gave negative
    readings. In dry beans, at a 2 lb/acre rate, heptachlor and gamma
    chlordane readings were identical with the check samples. The
    heptachlor epoxide readings were 0.02 to 0.03 ppm.

    Green forage samples grown on soil treated the same year exhibit
    negative readings in all samples.

    In another experiment, soybeans grown in soil from a heptachlor
    treatment made the previous year at 1.0 lb ai/acre show negative
    readings for heptachlor expoxide. Heptachlor and gamma chlordane
    readings were identical with the check samples.

    Soybean processing fractions were obtained from soybeans grown in soil
    treated with heptachlor in previous years. Beans grown in 1967 from
    treatments made in 1965 show negative readings for heptachlor epoxide
    in meal, crude oil, refined oil and soapstock. Some heptachlor
    contamination in handling is indicated.

    Processing fractions grown in 1967 from a soil treatment in 1966 show
    heptachlor epoxide in crude oil at a level of 0.03 ppm. Meal, refined
    oil and soapstock contained no heptachlor epoxide.

    An extensive study was done at Texas A & M University. At 3.0 lb
    heptachlor per acre applied eight days before planting, heptachlor
    residues in the plants at time of pod formation were uniformly 0.01
    ppm or less. Heptachlor epoxide residue averaged about 0.02 ppm, with
    one highest reading of 0.04 ppm. Three pounds per acre soil treatment
    is the maximum permitted.

    At 3 lb/acre applied eight days before planting, heptachlor in the
    bean was uniformly less than 0.01 ppm and heptachlor epoxide averaged
    0.044 ppm, with the highest reading being 0.059 ppm. In the crude oil,
    these readings were increased about tenfold. For example, heptachlor
    readings in the crude oil averaged about 0.03 ppm, with the highest
    reading being 0.04 ppm. Heptachlor epoxide in the crude oil averaged
    about 0.38 ppm, with the highest reading being 0.52 ppm. These levels
    have been shown to be removed during the refining process.

    In sugarbeets

    Whole sugarbeet sampled five months after preplant broadcast treatment
    of soil at 3 lb/acre showed combined H and HE residues of 0.04 ppm,
    and at 6 lb/acre showed 0.19 ppm. Laboratory dried pulp showed 0.18
    ppm at 3 lb/acre and 0.31 ppm at 6 lb/acre. Pilot plant drying showed
    0.14 ppm at 3 lb/acre and 0.34 at 6 lb/acre.

    No residues were found in sugarbeets or sugarbeet pulp from furrow and
    coated seed treatments at 0.8-1.0 lb/acre (Velsicol data).

    Sugarbeets harvested after seed treatment with heptachlor had no
    cyclodiene residues (Harris et al., 1966).

    In tomatoes

    Tomatoes were grown in soil treated prior to planting with 1-3 lb/acre
    of granular formulation or 2,3 and 6 lb/acre of emulsifiable
    concentrate. No heptachlor epoxide residues were found in the tomatoes
    from the granular formulation, and all heptachlor residues were at the
    limit of sensitivity (0.01 ppm) except one value of 0.02 ppm. Residues
    from the E.C. formulation were mainly <0.01 ppm except one heptachlor
    at 0.01 ppm, one at 0.04 ppm (6 lb/acre) and one heptachlor epoxide at
    0.02 ppm (6 lb/acre). Maximum combined residue in any one sample at
    recommended rates (2-3 lb/acre) was 0.02 ppm.

    In a second similar test in soil treated at 2,3 and 6 lb/ acre, no
    residues of heptachlor, its epoxide or gamma chlordane were found in
    any of the ripened fruit.

    Soil samples contained 0.67 ppm heptachlor, 0.08 ppm heptachlor
    epoxide and 0.26 ppm gamma chlordane at the 6 lb/acre rate (Velsicol
    data).

    In soil

    In Kansas one year after heptachlor soil treatments, soil residues
    were: 2 lb/acre rate - 0.26 to 0.47 ppm (combined H and HE), 3 lb/acre
    rate - 0.18 to 0.32 ppm and 6 lb/acre rate - 0.63 to 2.24 ppm
    (Velsicol, soybean data)

    In Illinois, row treatments of 1.0 and 1.6 pounds heptachlor per acre
    showed no residues in the soil fifteen months later (Velsicol, soybean
    data).

    In Kansas, four months after treatment at three lb/acre soil showed
    0.21 to 0.40 ppm (combined H and HE), and 6 pounds per acre showed
    0.49 to 3.61 ppm (Velsicol, soybean data).

    In Mississippi, seed treatment at the rate of 0.07 pound heptachlor
    per acre showed no residues in soil five months after application
    (Velsicol, cotton data).

    In a survey of the soil of 31 farms in Ontario, Harris, Sans and Miles
    (1966) found heptachlor and/or epoxide residues (maximum 0.2 ppm) in
    three samples of four which had a previous history of treatment with
    heptachlor; one of the three had no recorded history of heptachlor
    treatment, but 27 others with history of no heptachlor treatment had
    no heptachlor residues. Two soils which had seed treatments (maize and
    sugarbeets) had no detectable heptachlor residues. Those samples which
    contained heptachlor or epoxide residues also contained residues of
    gamma chlordane.

    Studies on the mobility of organochlorine pesticides, including
    heptachlor and epoxide, in soil demonstrated that these residues do
    not move by leaching (Harris, 1969), but may be locally redistributed
    by mechanical cultivation (Harris and Sans, 1970).

    Under South African conditions, Wiese and Bossen (1966) found that
    rapidity of degradation of five chlorinated insecticides " ... was
    greater than reflected in most published literature ..." and that "
    ... heptachlor epoxide was the least persistent ..." In a survey of
    agricultural soils of the Atlantic Provinces of Canada, heptachlor and
    heptachlor epoxide were found in 9 percent of the soils in
    concentrations between 0.06 and 0.86 ppm (Duffy and Wong, 1967).

    In animal products

    A great deal of work has been carried out to elucidate the propensity
    of heptachlor and heptachlor epoxide residues, in or on feeds, to
    transmit to milk or store in meat. Much of this information is
    summarized by Saha (1969).

    Meat

    A one-year study on twenty beef cows and their calves was carried out
    by Virginia Polytechnic Institute and the U.S. Department of
    Agriculture (1968). Ten treated cows were fed a conventional ration of
    alfalfa hay containing 0.4 ppm heptachlor and heptachlor epoxide
    residues. In animals on contaminated feed continuously, the maximum
    residue accumulating in the fat was 1.53 ppm (about four times the
    residue level in the feed).

    In a similar study over a two-year period involving twenty yearling
    steers, the same investigators concluded the results were in good
    agreement with that reported previously for pregnant and lactating
    beef cows. The study showed clearly that with continued feeding of
    contaminated ration the residues stabilize around 1.00 ppm, after 18
    months on a residue-free regime, the combined H+HE residues in the
    cattle ranged from 0.19 to 0.94 ppm (Bovard et al., 1968).

    A 98-day feeding experiment, conducted with 56 beef steers in which
    half were fed alfalfa hay containing 0.16 ppm H+HE, resulted in 0.017
    to 0.020 ppm HE in the fat of treated animals and 0.004 to 0.007 ppm
    in the fat of control steers (Hall et al., 1965).

    Milk

    In a study at the University of Tennessee, alfalfa hay containing
    residues of 0.08 or 0.29 ppm heptachlor and heptachlor epoxide were
    fed to dairy animals. Supplemental grain was fed according to milk
    production. At the end of the 35-day feeding period, the milk fat from
    the high and the low level intake groups contained 0.34 and 0.22 ppm
    heptachlor epoxide, respectively. Converting to 4% butter fat milk,
    this would be 0.014 ppm residue for the high group and 0.009 ppm for
    the low group (Demott et al., 1967).

    In an extensive study, lactating cows were fed alfalfa hay containing
    residues of heptachlor and heptachlor epoxide resulting from treating
    alfalfa at three different levels with heptachlor. The hay, fed for 30
    days, contained average residues of heptachlor and heptachlor epoxide
    of 0.045 ppm, 0.086 ppm and 0.160 ppm from the 0.25, 0.5 and 1.0
    lb/acre treatments, respectively. The highest concentration of residue
    in milk occurred between the 18th and 24th days of the feeding period
    and averaged 0.013, 0.026 and 0.049 ppm for the test animals in each
    group. Removal of treated hay from the diet resulted in a sharp
    decline of residues in the milk, followed by a gradual disappearance
    of residue over 13 weeks (Waldron at al., 1968).

    Another study involved feeding lactating animals with measured
    quantities of heptachlor epoxide added to the feed. Heptachlor epoxide
    (in grain) was fed at the levels of 0.005 ppm and 0.020 ppm based on
    total roughage ingested (hay plus silage) assumed at 50 pounds per
    day. At the end of the feeding interval of 28 days, the residue of
    heptachlor epoxide in milk was 0.0027 and 0.0043 ppm, respectively,
    for the low and higher level fed. At 25 days the respective milk
    residue levels for heptachlor epoxide were 0.0029 and 0.0044 ppm
    (Hardee et al., 1964).

    In a practical test (W.A.R.F. report, 1967), cows were fed maize
    silage (50 pounds/day) and ground maize and cob meal (12 pounds/day),
    all grown on soil treated with heptachlor for at least eight
    consecutive years, at the recommended rate of one half pound per acre.
    This feed was supplemented with 10 pounds of alfalfa hay, grown, in
    rotation with maize in soil treated for two years, nonconsecutive, at
    one half pound/acre, with the most recent application being two years
    prior to the growing of the hay crop. The bedding for these cows,
    consisting of shredded maize stalks, was also obtained from soil
    treated with heptachlor for at least eight years. Milk samples gave
    equivalent heptachlor epoxide readings after 10, 20 and 30 days of
    feeding, varying between 0.004 and 0.007 ppm. There was no evidence of
    increased milk residues during the course of the study and there was
    no difference from the checks. All readings for heptachlor, in milk,
    were reported as less than 0.001 ppm, and gamma-chlordane was not
    detected in milk.

    A survey of milk collected in Iowa was made in 1965 to determine what,
    if any, residues could be detected. Heptachlor epoxide could be
    characterized as being virtually absent from milk samples. All

    readings averaged less than 0.002 ppm heptachlor epoxide, and only one
    of 20 readings was as high as 0.007 ppm (W.A.R.F. report, 1965).

    Poultry and eggs

    In a chart provided by the U.S. Food and Drug Administration to the
    Committee on Pesticides, Agricultural Research Institute (NAS/NRC)
    Meeting, May 14, 1969, it is estimated that the contribution to the
    diet of heptachlor epoxide from eggs is nil. Poultry is not shown by
    itself, but a correlation between poultry and eggs can be assumed.

    In a chicken feeding study (Velsicol data), chickens received
    heptachlor epoxide in their entire diet at levels up to more than ten
    times that which could occur in chicken feed from registered uses of
    heptachlor. The feeding continued for 21 weeks, and white meat, dark
    meat, fat and eggs were analyzed. White meat was negative as to
    residues except for negligible values in the low hundreths of a part
    per million range. Residues in the fat, from chickens fed at the level
    which would reasonably reflect a tolerance in commodities used as feed
    for chickens, were less than the 0.3 ppm non-actionable level in fat.
    Similarly, residues in eggs from chickens which had received
    heptachlor epoxide in their total diet for 21 weeks at a level
    appropriate for a tolerance, but certainly higher than is encountered
    in total feed, averaged 0.03 ppm, which is the non-actionable level in
    eggs.

    Heptachlor epoxide (in combination with other organochlorine
    insecticides) were fed to 60 laying hens for 20 weeks at levels of
    0.05, 0.15 and 0.45 ppm to determine residue levels in eggs. The
    plateau levels in eggs approximate the feeding levels of heptachlor
    epoxide; yolk/white concentration ratio is 99/1 (Cummings et al.,
    1966).

    FATE OF RESIDUES

    In soil

    1-Hydroxy chlordene, a conversion product, was found in a small number
    of soil samples treated with heptachlor (Duffy and Wong, 1967).

    Information on routes of metabolism of heptachlor by soil
    micro-organisms has recently become available. As is the case with
    mammals, 1-hydroxy 2,3-epoxychlordene was formed and by soil bacteria,
    and it was demonstrated that it was derived from 1-hydroxychlordene,
    but not from heptachlor epoxide. An unknown metabolite has also been
    produced from 1-hydroxychlordene; the structure 1-keto chlordene has
    been postulated for this compound but not proven. In addition, other
    routes of metabolism involving a reductive stop to chlordene have also
    been shown to occur in soil (Miles et al., 1969), but it is not known
    if this pathway occurs in mammals. The significance of these chlordene
    derivatives has been evaluated toxicologically (see "Toxicity studies
    on the metabolites").

    Effects of food processing on residues

    Evidence continues to accrue that residues of heptachlor epoxide and
    associated gamma chlordane are concentrated in the peels of sub-soil
    crops, such as rutabagas, carrots and potatoes (Saha and Stewart,
    1967). The residue distribution pattern discerned by older analytical
    methods (Fox et al., 1964) has now been confirmed by the more
    sensitive gas-liquid gas chromatography method (Stewart et al., 1965).

    Concentration of heptachlor-derived residues at the outer surfaces of
    crops with small surface to volume ratios simplifies effective residue
    reduction by several normal food preparation steps. Washing removes
    loosely held surface residues such as that contained in adherent soil
    (Farrow et al., 1969). Washing plus peeling is highly effective in
    residue removal and in frequently used for potatoes and root crops in
    home cooking, and always is used in commercial canning of these crops
    and tomatoes. Abrasive peeling is also effective; it is normally
    used in home cooking and in commercial canning.

    Commercial processing of edible vegetable oils frees the finished oil
    from residues of heptachlor and heptachlor epoxide, as well as other
    organochlorine pesticides (IUPAC Commission on Terminal Pesticide
    Residues, 1970; Smith et al., 1968).

    In the preparation of animal products, several normal food processing
    steps reduce residues. Heptachlor and epoxide, being lipophilic, tend
    to remain with fat when it is separated from meat by heating or
    mechanical trimming. Reduction of heptachlor and heptachlor epoxide
    residues has been reported in milk processing. Production of
    condensed, sterilized, spray dried and drum dried milks results in
    lower levels (fat basis) of heptachlor epoxide residues than the raw
    milk from which they were made (Liska and Stadelman, 1969).

    No evidence is available regarding the effect of normal storage
    procedures on heptachlor residues.

    Minimal evidence (Del Monte Corp., private communication, 1969)
    indicates that short, simple cooking of leafy vegetables, such as
    spinach, would not affect levels of residue from heptachlor treatment.

    Evidence of residues in food in commerce or at consumption

    In a series of papers, Duggan and others have assessed the dietary
    intake of pesticide chemicals in the United States and determined the
    pesticide residue levels in various food groups, domestic and
    imported.

    For heptachlor and heptachlor epoxide,a three year average (1964 to
    1967) was 0.000031 milligrams/kilogram body-weight/day for heptachlor
    and heptachlor epoxide combined. This assessment was based on the food
    intake of almost twice the "average" intake of the "average"
    individual. The value is 6 percent of the Acceptable Daily Intake for
    heptachlor and its epoxide (0.0005 mg/kg).

    The average levels of heptachlor and heptachlor epoxide residues in
    food and feed - domestic, imported and ready to eat - are summarized
    in Table I.

    Total diet studies in England and Wales (Abbott et al., 1969) detected
    heptachlor expoxide in three samples from the cereal group (less than
    0.01 ppm), in ten samples from the meat group (up to 0.006 ppm) and
    seven samples from the fats group (up to 0.008 ppm). In terms of total
    diet, one out of 66 composites contains 0.001 ppm of heptachlor
    epoxide; in all other cases the calculated concentration in the diet
    was less than 0.0005 ppm heptachlor epoxide. No heptachlor was
    detected at limit of detection of 0.0005 ppm.

    METHODS OF RESIDUE ANALYSIS

    Multidetection analytical techniques, such as those adopted (1969) by
    the IUPAC Commission on Pesticide Residue Analysis, can be used to
    determine residues of heptachlor, heptachlor epoxide, gamma-chlordane
    and nonachlor in crops, soils and animal products down to a lower
    sensitivity limit of 0.01 ppm. Procedures based on those given in the
    Pesticide Analytical Manual, Vol. I, USHEW, FDA, 1968, with slight
    modifications, and designated as AM 0237, AM 0486 and AM 0481, have
    been developed by Velsicol Co. for the analysis of residues in fruits,
    vegetables, grains, meat and poultry. The method of Cummings et al.
    (1966) is suitable for determining heptachlor and heptachlor epoxide
    in eggs. A method for the analysis of 1-hydroxychlordene in plant
    tissues is under development (Nash and Beall, 1970 pre-print).

    APPRAISAL

    The data on the absorption of heptachlor and heptachlor epoxide by
    carrots grown in soils containing residues, either from current or
    previous annual treatments at normal or high rates, indicates that the
    temporary practical residue limit should be increased from 0.1 ppm to
    0.2 ppm.

    New data on residues in maize grain grown in heptachlor treated soil
    shows that this commodity is within the practical residue limit of
    0.02 ppm established for raw cereals. This continues to be true for
    the grain of barley, oats, rye and wheat.

    Data from a total of eight studies on the relationship between the
    levels of heptachlor and heptachlor epoxide in feed to the levels in
    meat and milk show that the maximum residue level in animal feed, that
    can be permitted without exceeding the practical residue limits for
    these animal products, is 0.04 ppm of combined residues. If dried
    sugarbeet pulp is fed in the diet of beef or dairy animals and
    constitutes up to 20 percent of the feed, then the maximum permissible
    residues in the pulp would be 0.20 ppm and in the whole sugarbeet
    would be 0.04 ppm. Similar considerations would apply to maize stover,
    soybean forage and pineapple bran used in animal feeds.


        TABLE I

    Heptachlor epoxide (or heptachlor) residues in food and feed1
                                                                                                          

                                      RAW AGRICULTURAL PRODUCT                  READY-TO-EAT FOOD

    Food Category                Domestic                 Imported
                           Incidence    Average      Incidence    Average      Incidence     Average
                           percent      ppm          percent      ppm          percent       ppm
                                                                                                          

    Large Fruit              0.7        < 0.005         0.7       < 0.005         -            -
    Small Fruit              1.0        < 0.005         0.7       < 0.005         -            -
    Grain & Cereals
    for human use            0.2        < 0.005         -           -             4.1        < 0.001
    for animal use           2.5        < 0.005         -           -             -            -
    Vegetables
    Leaf and Stem            3.0        < 0.005         3.3       < 0.005         1.4        < 0.001
    Vine and Ear             2.4        < 0.005         2.3       < 0.005         5.4        < 0.001
    Root                     3.8        < 0.005         5.7       < 0.005         -            -
                             0.82       < 0.005         4.62      < 0.005         -            -
    Potatoes                                                                      5.4        < 0.001
    Beans                    0.4        < 0.005         1.2       < 0.005         1.4        < 0.001
    Eggs                     3.1        < 0.005         3.4       < 0.005
    Nuts                     0.5        < 0.005         -           -
    Processed
    (canned, frozen)
    Domestic                                                                      0.8        < 0.001
    Imported                                                                      0.7        < 0.001
    Fluid Milk              23.0          3.03
    (fat basis)              0.82      < 0.005
    Dairy Products          21.3          0.02          3.0       < 0.005
    (fat basis)              0.82      < 0.005         0.1       < 0.005
                                                                                                          

    1/ extracted from USA-FDA surveillance programme report (Duggan, 1968).
    2/ Heptachlor residues
    

    The committee received information on residues in pineapple fruit
    resulting from foliar treatment at 1,2 and 4 lb/acre. No residues of
    heptachlor, heptachlor epoxide or gamma chlordane were found in the
    fruit at the detection limit of 0.01 ppm for the method of analysis,
    thus supporting a negligible residue tolerance of 0.01 ppm.

    With the exception of carrots, the new data available did not indicate
    a need to change the previous recommendations for practical residue
    limits for the items listed. The previous practical residue limit of
    0.125 ppm for milk products was changed to 0.15 to allow for the
    limitations and variabilities of residue analytical procedures. Data
    was presented which suggested the addition of practical residue levels
    for tomatoes, cottonseed, soybeans, crude soybean oil, refined soybean
    oil, poultry fat and eggs (on a shell-free basis).

    RECOMMENDATIONS FOR TOLERANCES AND PRACTICAL RESIDUE LIMITS

    TOLERANCES (These are additional to those in previous recommendations)
                                                           ppm

    Pineapple (edible portions)                            0.01

    PRACTICAL RESIDUE LIMITS

                                                           ppm
    Milk and milk products (determined on the
    extracted fat)                                         0.15

    Fat of meat and poultry                                0.2

    Raw cereals, tomatoes, cotton seed, soybeans,
    refined soybean oil                                    0.02

    Vegetables (except where otherwise specified),
    eggs (shell-free basis)                                0.05

    Carrots                                                0.2

    Crude soybean oil                                      0.5

    Citrus fruit                                           0.01
                                                                   

    Remarks

    Residues of heptachlor and its epoxide should each be determined and
    the sum expressed as heptachlor. Tolerances apply to residues from
    application to seed and soil only.

    FURTHER WORK OR INFORMATION

    DESIRABLE

    An adequate carcinogenicity study in a second species of animal.

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    their offspring by the introduction of heptachlor and its epoxide into
    their daily diet. Unpublished report from the Kettering Laboratory,
    Cincinnati, submitted by Velsicol Chemical Corporation

    Witherup, S., Stemmer, K.L., Taylor, P. and Hull, L. (1967b) The
    effects exerted upon the fertility of rats and upon the viability of
    their offspring by the introduction of heptachlor into their daily
    diets. Unpublished report from the Kettering Laboratory, Cincinnati,
    submitted by Velsicol Chemical Corporation

    Wolvin, A.R., Jenkins, D.H. and Fancher, O.E. (1969) Toxicity residue
    and reproduction study on heptachlor epoxide chickens. Unpublished
    report by Industrial Bio-test Laboratories, submitted to Velsicol
    Chemical Corporation

    Wong, D.T. and Terriere, L.C. (1965) Epoxidation of aldrin, isodrin
    and heptachlor by rat liver microsomes. Biochem. Pharmacol., 14:
    375-377
    


    See Also:
       Toxicological Abbreviations
       Heptachlor (EHC 38, 1984)
       Heptachlor (HSG 14, 1988)
       Heptachlor (ICSC)
       Heptachlor (PIM 578)
       Heptachlor (FAO Meeting Report PL/1965/10/1)
       Heptachlor (FAO/PL:CP/15)
       Heptachlor (FAO/PL:1967/M/11/1)
       Heptachlor (FAO/PL:1968/M/9/1)
       Heptachlor (FAO/PL:1969/M/17/1)
       Heptachlor (WHO Pesticide Residues Series 4)
       Heptachlor (WHO Pesticide Residues Series 5)
       Heptachlor (Pesticide residues in food: 1991 evaluations Part II Toxicology)
       Heptachlor (CICADS 70, 2006)