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    HEPTACHLOR

    First draft prepared by Dr. W. Phang,
    US Environmental Protection Agency,
    Washington, D.C., United States

    EXPLANATION

         The JMPR evaluated heptachlor in 1970 (Annex I, 14) and concluded
    that an adequate carcinogenicity study in a second species of animal
    other than the rat was needed.  An estimated ADI of 0.0005 mg/kg/bw
    was allocated.  Since the last Meeting, several toxicology,
    metabolism, and epidemiology studies, along with many case reports,
    have become available, which are summarized in this monograph.  Some
    of the previously published reports reviewed in FAO/WHO monographs of
    1967 and 1970 (Annex I, 7 and 15) are also included.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical Aspects

    Absorption, distribution, and excretion

    Rat

         Although quantitative data on the absorption of heptachlor are
    not available, heptachlor is readily absorbed from the
    gastrointestinal tract as demonstrated by the presence of the parent
    compound and/or its metabolites in the urine, faeces, and tissues of
    rats which had been fed 14C-labelled heptachlor and in the serum of
    humans who had consumed undiluted raw milk products known to be
    contamin-ated with residues of heptachlor.

         Two male rats were given a single oral dose of 14C-heptachlor
    (0.464 Ci) in corn oil.  During a 10 day monitoring period, 6% of the
    administered radioactivity was found in the urine while 60% was found
    in the faeces.   Approximately 26% of the total radioactivity
    recovered from the faeces was unchanged heptachlor and the rest was in
    the form of metabolites (Tashiro & Matsumura, 1978).  Heptachlor has
    been shown to be readily metabolized to heptachlor epoxide which was
    found to be distributed in adipose tissue of dogs and rats (Radomski
    & Davidow, 1953; Davidow & Radomski, 1953).  When rats were fed a diet
    containing 35 ppm heptachlor for 2 months or more, the highest
    concentration of heptachlor epoxide was found in fat with
    substantially lower levels in liver, kidneys, and muscles.  However,
    no heptachlor or heptachlor epoxide was found in the brain (Radomski
    & Davidow, 1953).

         The rate of heptachlor epoxide accumulation and elimination from
    the body fat was examined by placing male and female rats on a diet
    containing heptachlor for 12 weeks and then on the untreated diet for
    12 more weeks.  In males, at approximately 2 to 8 weeks of dosing the
    heptachlor epoxide level in fat reached a plateau; by 6 weeks after
    dosing the level was below the detection limit.  In females, the
    heptachlor epoxide level in fat was much higher than that in males by
    2 weeks and throughout the remaining duration of the study; by the 8th
    week after dosing the level was below the limit of detection (Radomski
    & Davidow, 1953).

    Biotransformation

    Rat

         In a metabolism study on heptachlor reported by Tashiro and
    Matsumura (1978), two male rats were administered a single oral dose
    of 14C-heptachlor (0.464 Ci) in 250 l of corn oil; most of the

    radioactivity (approximately 60% of the administered dose) was
    recovered in the faeces.  The major metabolites in the faeces were
    heptachlor epoxide, 1-hydroxychlordene, 1-hydroxychlordene epoxide,
    and 1,2-dihydroxydihydrochlordane, as well as two unindentified
    products.  Similar metabolites were found in an  in vitro comparative
    and qualitative study using human or rat liver microsomes.  Based upon
    these findings, the metabolic scheme for heptachlor shown in Figure 1
    was proposed.

         Heptachlor epoxide was also isolated from fat of dogs which had
    been administered heptachlor at dose levels of 1 to 3 mg/kg and rats
    fed 30 mg/kg heptachlor for 3 months (Davidow & Radomski, 1953;
    Radomski & Davidow, 1953).

    Effect on enzymes and other biochemical parameters

         From the information published in the 1971 FAO/WHO Monograph, 
    heptachlor and aldrin appear to be substrates for the same enzyme,
    which is inhibited by the epoxide.   In vitro microsomal metabolism
    of heptachlor does not proceed beyond formation of the epoxide.  The
    treatment of rats with heptachlor increases the metabolism of
    fenitrothion (Annex 1, 15).

    Acute toxicity

         Some of the acute toxicity data of heptachlor and heptachlor
    epoxide were considered by the 1966 Joint Meeting and published in the
    1967 FAO/WHO Monograph.  Additional data have become available in the
    open literature; these data have been evaluated and are summarized
    with previously published data in Table 1.

         Clinical signs of acute toxicity of heptachlor include
    hypoactivity, tremor, convulsion, ataxia, and changes in EEG patterns. 
    Histopathologically, severe liver damage was reported.

    Acute toxicity of metabolites

         The oral LD50 for four other metabolites of heptachlor
    (chlordene, 3-chlorochlordene, 1-hydroxychlordene, and chlordene
    epoxide) was reported to be greater than 4600 mg/kg body weight in
    male and female rats (Annex 1, 15).

    FIGURE 1


        Table 1.  Acute toxicity data of heptachlor and heptachlor epoxide

                                                                                              

    Species              Sex         Route          LD50       Reference
                                                 (mg/kg bw)
                                                                                              

    A. Heptachlor

    Rat                  M           oral         71           Podowski et al. (1979)
                         M&F         oral         60-142a      Velsicol Corp. (1959)b

    Chick                d           oral         63           Sherman & Ross (1961)b

    Mouse                d           oral         70           Gak et al. (1976)

    Hamster              d           oral         100          Gak et al. (1976)

    Rat                  M           dermal       195c         Gaines (1969)
                         F           dermal       250c         Gaines (1969)

    B. Heptachlor epoxide

    Rat                  M&F         oral         34-48a       Velsicol Corp. (1959)b

    Mouse                M           oral         32-48        Velsicol Corp. (1959)b
                                                                                              

    a  Sex differences
    b  Data excerpted from the 1966 JMPR monograph (Annex 1, 7)
    c  Xylene was the solvent.
    d  Not stated
    

    Short-term studies

    Mouse

         Groups of 10 Charles River CD-1 mice/sex/dose were fed a mixture
    of heptachlor-heptachlor epoxide (25:75) at dietary concentrations of
    1, 5, 10, 25, and 50 mg/kg for 30 days.  Following 30 days of
    treatment, the animals were sacrificed and necropsied.  Microscopic
    examinations were conducted on liver tissue.

         No deaths occurred in the 1, 5, nor 10 mg/kg groups. One female
    died in the 25 mg/kg group, and 9 males and 8 females died in the 50
    mg/kg group. No marked differences were seen between the treated
    animals and the controls with respect to body weights and food
    consumption.  Mice which were sacrificed at the end of the study from
    the 10, 25 and 50 mg/kg groups showed liver enlargement associated
    with accentuated lobulation.  The liver weight of the only surviving
    male mouse from the 50 mg/kg group was markedly increased (control
    mean: 1.69 g; 50 mg/kg; 4.00 gm), and increased mean liver weight was
    also found in the 25 ppm male mice (control, 1.69 g; 25 ppm, 4.35 gm). 
    Histopathology findings indicated that livers of male mice in the 5,
    10, 25, and 50 ppm and of female mice in the 10, 25, and 50 ppm groups
    had enlargement of centrilobular and midzonal hepatocytes with
    replacement of the normal coarse cytoplasmic granularity by finely
    granular and homogeneous cytoplasm. The severity of this lesion was
    dose-related.  The incidences of the microscopic findings were not
    reported (Wazeter  et al., 1971a).  Based upon the histopathology
    findings, the NOAEL was 1 mg/kg.

    Rat

         Two short-term studies on heptachlor in rats were summarized in
    the 1971 monograph.  The dietary levels tested in these two studies
    ranged from 5 to 45 ppm.  At 10 ppm and above, rat liver cells showed
    an increase in smooth endoplasmic reticulum and mitochondria.  The
    liver effects regressed after the treated rats were placed on a
    control diet for 120 days (Annex 1, 15).

    Long-term studies

         Some of the unpublished long-term studies on heptachlor were
    evaluated by the 1966 Joint Meeting and published in the 1967
    Monograph.  To facilitate consideration of the toxicity of this
    chemical the older toxicity studies are also summarized here.

    Rat

         Groups of Carworth Farms (CF) rats (20/sex/dose) were fed diets
    containing heptachlor (purity not specified) at a concentration of 0,
    1.5, 3.0, 5.0, 7.0, or 10 ppm for 110 weeks.  The treatment diet was
    prepared by spraying standard rat diet with an ethanol solution of 

    heptachlor.  After 7 weeks on the test diet, 5 females and 5 males
    from each dose group were mated to determine whether or not heptachlor
    would affect the reproductive capacity of the treated animals or the
    survival and subsequent growth of the offspring.  Following similar
    procedures, another mating was conducted using different animals from
    each dose group after 22 weeks of treatment.  The offspring were kept
    with their mothers until weaning at 3 weeks of age.  After weaning,
    the offspring were placed on the control diet for 8 weeks for further
    observations.  After 110 weeks of treatment, the surviving animals
    were sacrificed, certain haematological parameters were examined. 
    Histopathology was conducted on the heart, liver, lungs, brain,
    spleen, kidneys, thyroids, and the adrenal glands.

         Heptachlor treatment did not affect mortality, body weight, or
    food consumption.  The limited reproductive parameters measured did
    not indicate any effect on the body weights at birth or at weaning. 
    Heptachlor administration did not appear to significantly affect the
    mortality of the offspring.  Organ weights of the heptachlor-treated
    rats were not markedly different from those of controls.  Haematology
    parameters (erythrocyte counts, haemoglobin, leukocyte counts, and 
    differential white cell counts) did not show any compound-related
    effect.  The histopathology data indicated 6/16 males and 3/18 females
    at 7.0 ppm and 2/12 males and 9/16 females at 10 ppm had slight
    hepatic cellular alterations characterized by swelling, homogeneity of
    the cytoplasm and peripheral arrangement of the cytoplasmic granules
    in the hepatic cell in the central zone of the lobules.  Under the
    conditions of this study, heptachlor at doses up to 10 ppm did not
    produce an increase in the tumour incidence in CF rats (Witherup
     et al., 1955).

         Groups of CFN (Carworth Farms, Nelson) rats (25/sex/dose) were
    fed heptachlor epoxide at dietary concentrations of 0, 0.5, 2.5, 5.0,
    7.5, and 10.0 ppm for 108 weeks. The test diet was prepared by
    spraying an ethanol solution of heptachlor epoxide on Purina
    Laboratory Chow.

         The survival rate was greater than 47% in the treated and control
    groups.  There was an increase in the liver weights of treated females
    and a slight increase in treated males.  The test chemical was not
    reported to cause any additional effects.  This study has
    methodological deficiencies which include uncertain concentrations in
    the feed and insufficient number of rats in each dose level. Also the
    report does not contain histopathological data and is therefore not
    adequate for evaluating the long-term toxicity of heptachlor (Witherup
     et al., 1959).  However, a panel of independent pathologists
    convened by the US National Academy of Sciences (1977) reviewed the
    histopathology and concluded that there was no increase in liver
    tumours in treated rats.

         Four groups of Charles River CD female rats (25/dose) were fed a
    3:1 mixture of heptachlor:heptachlor epoxide at dietary concentrations
    of 5, 7.5, 10, and 12.5 ppm.  A control group of 54 females was fed a
    diet containing the vehicle, corn oil.  Interim sacrifices were
    conducted at 5 and 19 months to determine the nature and degree of the
    histological changes in the liver.  At 5 months, 3 controls and 5 rats
    from the 7.5 ppm group were sacrificed. At 19 months, 5 controls, 2
    rats from 5 ppm, 2 rats from 10 ppm, and 1 rat from 12.5 ppm were
    sacrificed.  After 24 months of treatment, the surviving rats were
    sacrificed, and gross and histological examinations were conducted.

         There was an increase in mortality at 12.5 ppm relative to that
    of controls (control, 21%; 12.5 ppm, 50%).  The test article did not
    affect body weight gain.  Liver changes which were described as fatty
    liver and enlarged cells in the central zone of the hepatic lobules
    were reported.  However, no histopathology data were included in the
    report (Jolley, 1966).

         Groups of Osborne-Mendel rats (50/sex/dose) were fed technical
    grade heptachlor (73% heptachlor, 18%  trans-chlordane, and 2%
     cis-chlordane) in the diet at time-weighted doses of 38.9 and 77.9
    ppm for males and 25.7 and 51.3 ppm for females.  The matched controls
    consisted of 10 males and 10 females, and pooled controls were 60
    rats/sex.  The treated animals received the chemical for 80 weeks and
    were observed for 30 weeks.  During the 80 weeks of treatment, the
    dietary concentrations changed three times for each treatment group
    based on changes in body weight.

         There was a decrease in the mean body weight of high dose males
    which almost returned to the control level after the treatment was
    terminated.  There was also a slight increase in mortality in high
    dose male and female rats.  Histopathology data revealed numerous
    inflammatory, degenerative, and proliferative lesions with
    approximately equal frequencies in treated and control animals.  There
    was an increased incidence of thyroid follicular cell neoplasms,
    including combined adenomas and carcinomas in the high dose female
    rats (high dose, 14/38; low dose, 3/43; matched controls, 1/9;
    p<0.001) while, in male rats, a non-significant increase was observed
    only at the low dose (high dose, 3/38; low dose, 9/38; matched
    control, 1/8).  At the same time, the incidences of the thyroid C-cell
    neoplasms decreased in high dose female rats (high dose, 3/38; low
    dose, 7/43; matched controls, 3/9; p<0.05).  The results of analyses
    of the thyroid lesions were ambiguous and further complicated by
    variability in different experiments conducted at about the same time
    with this strain of rats (NCI, 1977).

    Dog

         Groups of Beagle dogs (4/sex/dose) were fed heptachlor epoxide
    (purity not specified) at concentrations of 0, 1, 3, 5, 7, and 10 ppm
    for two years.  After 2 years on test, 2 dogs/sex/dose were sacrificed

    and necropsied while the other two dogs/sex/dose were maintained on
    the control diet for an additional 6 months (recovery period).  In
    addition, the test animals in this study were also mated during the
    study and employed as the P1 parental animals for a 2-generation
    reproduction and teratology study.

         No death nor compound-related behavioural change was seen during
    the study.  The test article did not affect the body weights or food
    consumptions of the treated animals. The parameters for haematology
    and urinalysis were comparable between treated and control dogs. 
    There were increases in alkaline phosphatase activities in males and
    females at 3 ppm and above; these increases, in some dogs, were more
    marked towards the end of the treatment period and tended to persist
    throughout the recovery period.  The serum albumin and total protein
    levels were slightly decreased in 10 ppm male and female dogs during
    the treatment and the recovery periods.  An increase in the SGPT level
    was also seen in 10 ppm animals during the treatment, extending into
    the recovery period.  After one year of treatment, the animals in 7
    ppm group also showed an increase in the SGPT level which lasted into
    the recovery period.

         There was an increase in liver weights in 10 ppm male and female
    dogs relative to those of the controls, and this increase  persisted
    with a slight attenuation during the recovery period.  Histopathologic
    examination on dogs (2 dogs/sex/dose) sacrificed at the end of the
    treatment period showed an increase in the incidence of liver changes
    in animals at 3.0 ppm or above.  The changes were described as
    enlargement and vacuolation of groups of centrilobular hepatocytes or
    scattered individual hepatocytes, presence of finely granular, and a
    "ground glass" appearance of the cytoplasm of large numbers of
    hepatocytes.  These histopathological changes were also seen in dogs
    at 3 ppm and above after 6 months of recovery period.  No
    compound-related histopathology changes were seen in 1 ppm dogs. 
    Based upon the changes in biochemical parameters and the histological
    changes in the liver, the NOAEL was 1 ppm (Wazeter  et al., 1971b). 
    Although this study has certain deficiencies, including an
    insufficient number of experimental animals, the results provide
    useful information on the toxicity of the test compound in dogs.

         Groups of 23 to 27 week old beagle dogs (2 males or 3
    females/dose) were fed heptachlor epoxide at dietary concentrations of
    0, 0.5, 2.5, 5.5, and 7.5 ppm for sixty weeks.  The test diet was
    prepared by spraying an ethyl alcohol solution of heptachlor epoxide
    on the food.  The experimental results were limited to clinical
    observation, mortality, body weight changes, food consumption, and
    organ weights.  The limited results indicated that there was an
    increase in liver weights of all the heptachlor treated male and
    female dogs relative to that of the controls.  For 7.5 ppm males, the
    increase was approximately twice that of the controls.  However, the
    pathology data were not included in the report (Witherup  et al.,
    1958).

    Mouse

         Groups of Charles River CD-1 mice (100/sex/dose) received a
    mixture of heptachlor/heptachlor epoxide (25%/75%) at dietary
    concentrations of 0, 1.0, 5.0, and 10.0 ppm for 18 months.  A positive
    control group (100 mice/sex) received 2-acetaminofluorene at a dietary
    concentration of 250 ppm.  An interim sacrifice was performed on 10
    mice/sex/dose including the positive control group. Gross pathology
    and histology examinations were conducted on animals which died during
    the study or were sacrificed on schedule.

         There was a decrease in the number of survivors in 10 ppm male
    and female mice, in 5 ppm females, and in positive control males
    relative to those of the negative controls as shown in Table 2. Mean
    body weights and food consumptions of the treated mice were not
    affected.  There were increases in the mean liver weights of males and
    females in 5 and 10 ppm groups.

         An increase in the incidence of hepatocytomegaly was seen in all
    heptachlor-heptachlor epoxide treated mice relative to that of the
    controls.  The incidence of hepatic nodular hyperplasia was markedly
    increased in 5 and 10 ppm males and females relative to that of the
    controls.  For heptachlor-treated animals, hepatoma was observed in
    only one male mouse at 1 ppm (Wazeter, 1973).  Based on the incidence
    of hepatocytomegaly, a NOAEL was not established (LOAEL <1ppm).

         The histological slides of this study were later evaluated by a
    panel of pathologists convened by the Pesticide Information Review and
    Evaluation Committee of the National Academy of Sciences, USA.  The
    results of the evaluation are presented in Table 2.

         Levels of 1, 5, and 10 ppm of heptachlor-heptachlor epoxide did
    not produce a statistically significant increase in the incidence of
    hepatocellular carcinoma. However, at 10 ppm there was a statistically
    significant increase in the incidence of combined hepatocellular
    carcinomas and nodular changes (NAS, 1977).

         Epstein (1976) reported a previously unpublished study conducted
    by the US-FDA.  Groups of C3H mice (100/sex/dose) were fed 0 or 10 ppm
    of either heptachlor or heptachlor epoxide (purity unspecified) for 24
    months.  The liver histopathology was re-evaluated by a panel of
    pathologists convened by the Pesticide Information Review and
    Evaluation Committee of the US National Academy of Sciences.  Their
    results indicated a significant increase in hepatocellular carcinomas
    in females given heptachlor and in both males and females given
    heptachlor expoxide.

        Table 2.  The incidence of hepatocellular carcinomas and nodular
              changes in CD-1 mice fed heptachlor-epoxide

                                                                       

                               Male                      Female
    Group               HC           HC+N           HC            HC+N

                                                                       

    Control             1/59         2/59           1/74          1/74

    1 ppm H-HE          2/66         4/66           1/65          3/65

    5 ppm H-HE          2/66         4/66           1/65          3/65

    10 ppm H-HE         1/73         27/73*         4/52          16/52*

    AAF                 5/58         9/58           5/75          13/75
                                                                       

    HC     hepatocellular carcinomas
    HC+N   hepatocellular carcinomas and nodular changes
    *      (p<.001)
    
         Groups of B6C3F1 mice (50/sex/dose) received technical-grade
    heptachlor (72% heptachlor, 18%  trans-chlordane, and 2%
     cis-chlordane) in the diet at initial concentrations of 10 and 20
    ppm for males and 20 and 40 ppm for females. The initial
    concentrations were reduced due to adverse toxic effects, with
    time-weighted average concentrations of 6 and 14 ppm for males and 9
    and 18 ppm for females.  The mice were treated for 80 weeks and placed
    on the control diet for another 10 weeks.  Matched-controls consisted
    of 20 males or 10 females, and the pooled controls were 100 males and
    80 females.  Under the conditions of the study, heptachlor had no
    significant effects on the body weights. Survival at 90 weeks was
    high: 70% of treated and control males and 60% of treated and control
    females. Survival of female mice showed a significant trend towards
    lower survival in treated groups compared to that in the control
    group. The incidence of hepatocellular carcinomas was significantly
    increased in the high-dose males and females as shown in Table 3
    (NCI,1977).

         A review of liver histopathology from this study by a panel of
    pathologists convened by the Pesticide Information Review and
    Evaluation Committee of the US National Academy of Sciences concluded
    that there was a low incidence of induced hepatocellular carcinomas

    (Table 3).  According to this review, the incidence of hepatocellular
    carcinomas was statistically increased (p<0.001) in groups of males
    and females receiving heptachlor at the high dose only when combined
    with the diagnosis of nodular changes (NAS, 1977).

    
    Table 3.   Incidence of proliferative lesions of the liver in B6C3F1
               mice fed technical grade heptachlor

                                                                                     

    Lesion                             Pooled      Matched     Low  Dose    High Dose
                                       Control     Control
                                                                                     

    Males

    Hepatocellular
    carcinomas                          17/92       5/19         11/46       34/47*

    Nodular hyperplasia                 3/92        1/19         9/46         6/47

    Diffuse hyperplasia                 3/92        0/19         1/46         3/47

    Hepatocytomegaly                    0/92        0/19         1/46         0/47

    Females

    Hepatocellular carcinomas           3/78        1/10         3/47        30/42*

    Nodular hyperplasia                 2/78        0/10         3/47         0/42

    Diffuse hyperplasia                 1/78        0/10         0/47         0/42

    Hepatocytomegaly                    1/78        0/10         0/47         1/42
                                                                                     

         The denominator represents the number of tissues examined microscopically.
    *    p<0.001 (Fisher exact test)
    
    Reproduction studies

    Dogs

         Groups of 6-9 month old Beagle dogs (4/sex/dose) were fed
    heptachlor epoxide at dietary concentrations of 0, 1, 3, 5, 7, and 10
    ppm.  When the female dogs attained an age of 14 months, they were
    mated twice with male dogs from the same dose group.  The females were
    allowed to deliver and to nurse their pups.

         For the F2 generation, 4 female and 2 male pups of the F1
    generation were selected from each dose level to be the parental
    animals (P2) of the F2 generation.  At an approximate age of 14
    months, the animals were mated, and the pregnant females were allowed
    to deliver and to nurse their pups to 6 weeks of age.  At this time,
    the females and their pups were sacrificed.

         No clinical signs or behaviour changes were seen in treated P1,
    P2, or their offspring.  There were no indications that body weight
    or food consumption were affected by the test chemical.  Whether or
    not the test chemical produced any reproductive effects could not be
    determined with the very limited data presented in this report. There
    was a significant increase in the mortality rate of F1 pups in the 10
    ppm group (control, 9/20; 10 ppm, 17/18).  Only 1 male pup survived to
    the scheduled sacrifice, and no female was available to serve as a P2
    parental animal.  There were slight increases in death rates of F2
    pups at 3 and 7 ppm relative to the controls (Control, 0/4; 3 ppm,
    3/8; 7 ppm, 3/8).  The 5 ppm group had no pups.  Haematology and
    urinalysis results did not indicate any compound-related effects. Very
    limited clinical biochemistry data showed that alkaline phosphatase
    and/or SGPT activities in certain dogs were increased.  However, the
    changes in the clinical chemistry parameters could not be correlated
    with pathology findings because the necropsy data on animals showing
    clinical biochemistry changes were not presented in the report.  The
    limited necropsy data showed that, in F1 pups, 1/4 females at 7 ppm
    and 3/10 males and 3/7 females at 10 ppm had pale or greasy liver. 
    This observation was compound-related.  Based on the increase in the
    mortality rate, the NOAEL was 1 ppm (Wazeter  et al., 1971c).

    Rat

         Three reproduction studies in rats were evaluated by the JMPR in
    1966 and 1970.  In a 3-generation reproduction study, a group of 80
    rats were given 6.9 mg/kg of heptachlor daily for 3 months prior to
    mating.  Cataracts, which became obvious between the 19th and 26th
    days, were found in 6.8% of the young.  A similar lesion was present
    in 15.2% of the parental animals after 9 months.  The only effect on
    reproduction was a decrease in the litter size (Annex 1, 7).  In two
    other reproduction studies in rats, dietary levels of heptachlor
    ranging from 0.3 to 10 ppm were tested; no cataracts nor adverse

    effects on fertility and reproduction were found.  A slight increase
    in post-natal mortality of pups was seen at 10 ppm (Annex 1, 15).

    Special studies for teratology and embryotoxicity

    Rabbit

         A rabbit teratology study was previously evaluated by the 1970
    Joint Meeting, and it was concluded that no teratogenic effects could
    be attributed to the compound (Annex 1, 15).

    Special studies on genotoxicity

         In a large number of genotoxicity assays (Table 4), heptachlor
    did not induce genetic damage. Exceptions were the induction of small
    numbers of mutations in bacteria in the presence of plant extracts,
    mutations and a chromosomal aberrations in plants and in a single
    study, mutations at the highly sensitive  tk locus in mouse lymphoma
    cells.  Gap-junctional intercellular communication was inhibited in
    several  in vitro assays.

         In both a sister chromatid exchange assay and a chromosome
    aberration assay in Chinese hamster ovary cells, there were "positive"
    results in the presence of rat S9 metabolic activation. In the absence
    of metabolic activation the chromosome aberration assay was negative
    (NTP, 1985).  However, the tests were not repeated to confirm the
    positive results.

         The mutagenic potential of heptachlor epoxide was also tested. 
    The results are presented in the following table.


        Table 4.  Results of genotoxicity assays on heptachlor

                                                                                                                          

    Test system            Test object                 Concentration           Resultsa    Reference

                                                                                                                          

    Ames test              S. typhimurium              1000 g/plate           -/-         Marshall et al. (1976)
                           TA1535, TA1536
                           TA1537, TA1538

    Ames test              S. typhimurium              2500 g/ml              -/0         Simmon et al. (1977)
                           TA98, TA100,
                           TA1535,
                           TA1537, TA1538

    Ames test              S. typhimurium              not stated              -/-         Probst et al. (1981)
                           TA98, TA100, TA1535,
                           TA1537, TA1538, G46,
                           C3076, D3052
                           E. coli WP2 & WP2 uvr A-

    Ames test              S. typhimurium              0.1 g/plate            -/-         NTP (1983)
                           TA98, TA100, TA1535,        to 10 mg/plate
                           TA1537

    Ames test              S. typhimurium              5-10 g/ml              +/-b        Gentile et al. (1982)
                           TA98, TA100, TA1535

    Ames test              S. typhimurium              2500 g/ml              -/-         Moriya et al. (1983)
                           TA98, TA100, TA1535,
                           TA1537, TA1538
                           E. coli WP2 hcr
                                                                                                                          

    Table 4 (contd).

                                                                                                                          

    Test system            Test object                 Concentration           Resultsa    Reference

                                                                                                                          

    Rec assay              B. subtilis                 356 g/ml               -/-         Matsui et al. (1989)

    Differential           E. coli WP 2                2000 g/ml              0/-         Rashid & Mumma (1986)
    toxicity               S. typhimurium
                           TA1538

    Ames test              S. typhimurium              1 mg/ml                 -/-         Mersch-Sundermann (1988)
                           TA97, TA98, TA100,
                           TA102

    Ames test              S. typhimurium              167 g/ml               -/-         Zeiger et al. (1987)
                           TA98, TA100,
                           TA1535, TA1537

    Gene conversion        S. cerevisia                f                       -/-         Gentile et al. (1982)

    Mutation               Zea mays                    1.12 kg/ha              0/+         Gentile et al. (1982)

    Chromosomal            Lens sp.                    0.1-0.3%                0/+         Jain (1988)
    aberrations            Pisum sp.

    Micronuclei            Tradescantia                1.88 ppm                0/+         Sandhu et al.
                                                                                           (1989)
    SLRSc mutation         D. melanogaster             5 g/ml (feeding        0/-         Benes & Sram
                                                       solution)                           (1969)

    tk locus               Mouse lymphoma              25 g/ml                0/-         McGregor et al.
    L5178Y mutation        cells                                                           (1988
                                                                                                                          

    Table 4 (contd).

                                                                                                                          

    Test system            Test object                 Concentration           Resultsa    Reference

                                                                                                                          

    ARL-HGPRT              Adult rat liver             10-6 to 10-4 M          -/NAd       Telang et al.
                           epithelial cell line                                            (1982)

    Unscheduled DNA        Mouse, rat and hamster      10-5                    -           Maslansky & Williams (1981)
    synthesis assay        primary hepatocytes

                           Primary liver cell
                           explants from rats          10 nmole/ml             -           Probst et al. (1981)

                           SV-40 transformed human
                           fibroblasts                 100 & 1000 M           ?/-         Ahmed et al. (1977)
                           (VA-4)

    Dominant               Swiss mice                  4.8 & 24 mg/kg (IP)     -           Epstein et al. (1972)
    lethal                                             5 & 10 mg/kg (PO)

                           CD-1 mce                    7.5 & 15 mg/kg          -           Arnold et al. (1977)
                                                       25:75e

    Inhibition of          Mouse testicular cells      40 mg/kg                0/-         Seiler (1977)
    DNA synthesis          in vivo

    Inhibition of          Chinese hamster V79         10 g/ml                0/+         Kurata et al. (1982)
    metabolic              cells
    cooperation
                                                                                                                          

    Table 4 (contd).

                                                                                                                          

    Test system            Test object                 Concentration           Resultsa    Reference

                                                                                                                          

    Inhibition of          Rat hepatocytes             20 g/ml                0/+         Ruch et al. (1990)
    metabolic              Mouse hepatocytes
    cooperation
                                                                                                                          

    a  with S9 activation/without S9 activation; phi indicates that the test was not performed
    b  with plant S9
    c  sex-linked recessive lethal
    d  NA = not applicable
    e  25:75 blend w/w of heptachlor:heptachlor-epoxide
    f  concentration in original paper cited as "an appropriate amount".

    Table 5.  Results of genotoxicity assays on heptachlor epoxide

                                                                                                              

    Test system          Test object           Concentration      Resultsa     Reference

                                                                                                              

    Ames assay           S. typhimurium        1000 g/plate         -/-       Marshall et al. (1976)

    Unscheduled DNA      SV-40 transformed     100 & 1000 M         +/-       Ahmed et al. (1977)
    synthesis assay      human fibroblasts
                         (VA-4)

    Dominant lethal      Swiss mice            6 & 30 mg/kg (IP)      -        Epstein et al. (1972)
                                               8 mg/kg (PO)
                                                                                                              

    a  with S9 activation/without S9 activation
    

    Observations in humans

         In 1986, a study was conducted in the Midwest United States on a
    group of 45 dairy farm family members who had consumed undiluted raw
    milk products known to have been contaminated with heptachlor at
    concentrations as high as 89.2 ppm (fat basis).  The serum levels of
    heptachlor or its metabolites in the exposed individuals were compared
    to those from an unexposed group of 94 persons from the same
    geographical area and to results from the Second National Health and
    Nutrition Examination Survey (2nd NHANES).  The exposed group had
    significantly higher mean levels of primary metabolites such as
    heptachlor expoxide (0.841.0 vs 0.500.9 ppb) and oxychlordane
    (0.710.8 vs 0.491.1 ppb) than the unexposed group.  In addition, the
    percentage of individuals in exposed group with elevated serum
    concentrations of these same metabolites (21.2%) was higher than that
    for the unexposed group (heptachlor expoxide, 3.8%; oxychlordane,
    6.3%) and the second National Health and Nutrition Survey (2.5% for
    both metabolites) (Stehr-Green  et al., 1988).

         There is evidence of transplacental transfer of heptachlor
    epoxide.  The following heptachlor epoxide levels were detected in
    various tissues of mother and newborn infants (Polishuk, 1977a):

                 adipose tissue (maternal):  0.2856  0.3950 ppm
                 maternal blood:  0.2798  0.4626 ppm
                 uterine muscle:  0.4895  0.5086 ppm
                 fetal blood:     0.9959  0.9458 ppm
                 placenta:        0.5000  0.3950 ppm
                 amniotic fluid:  0.6730  1.1645 ppm

         Several investigators detected heptachlor epoxide levels ranging
    from non-detectable to 0.46 ppm in human milk (Kroger, 1972;  Polishuk
     et al., 1977b; Strassman & Kutz, 1977; Savage  et al., 1981;
    Takahashi  et al., 1981; Takei  et al., 1983).

         No adverse effects on human fetal development were reported
    following ingestion of milk containing heptachlor for 27 to 29 months
    among women of child bearing age in Oahu, Hawaii, USA.  The levels of
    heptachlor in milk fat ranged from 0.12 to 5.00 ppm (Le Marchand
     et al., 1986).

         A retrospective mortality study was conducted on workers employed
    in the manufacture of heptachlor and chlordane between 1946 and 1976. 
    The study group consisted of 1403 white males who were employed for
    more than 3 months at either of the two plants which produced
    heptachlor and chlordane in the United States.  The mortality
    information was obtained from the Social Security Administration files
    and supplemented by information collected by another investigator
    through follow-up. The results indicated an excess of death from
    cerebrovascular disease (17 observed, 9.3 expected) (Wang & MacMahon,
    1979a).

         The mortality of 16 126 males employed as pesticide applicators
    was evaluated.  The cohort was employed between 1967 and 1976 by any
    of the nationwide (US) pest control companies for 3 months or more. 
    The information on mortality was traced in Social Security
    Administration files.  The results did not demonstrate a significant
    difference in mortality from the norm in the cohort (Wang & MacMahon,
    1979b).  An update of the above study group was conducted by following
    the same cohort to the end of 1984.  The analysis showed an excess of
    lung cancer among the pesticide applicators. However, these
    applicators were exposed to a broad spectrum of pesticides, and the
    increased lung cancer risk among the pesticide applicators might not
    relate to their exposure to heptachlor alone (MacMahon  et al.,
    1987).

         A retrospective mortality study of 2141 workers from 4
    manufacturing plants of chlorinated hydrocarbon pesticides, which
    included chlordane, heptachlor, DDT, aldrin, dieldrin, and endrin was
    reported by Ditraglia  et al., 1981.  The workers in each plant were
    considered as a separate cohort, each had worked at least 6 months
    prior to 31 December 1964.  The results showed too few deaths to allow
    any meaningful conclusions (Ditraglia  et al., 1981).

         Another retrospective study was conducted by Shindell and
    Associates (1981) on a cohort of 1115 employees who worked 3 months or
    more at the Memphis, Tennessee, USA, plant of Velsicol Chemical Corp.,
    from 1 January 1952 to 31 December 1979.  The plant began to
    manufacture heptachlor in 1952. The data on morbidity and mortality
    were obtained for 93.1% of the male and 90% of the female cohort.  The
    workers were classified according to their job or product exposure. 
    Mortality data on the cohorts were compared to the overall mortality
    experience of like segments (by age and sex) of the United States
    population at large to determine whether Memphis plant exposure caused
    any discernible variations from the expected mortality from all causes
    and from selected significant causes.  No significant difference was
    found.

    COMMENTS

         Heptachlor is structurally similar to chlordane.  An  ADI of
    0.0005 mg/kg bw was estimated for heptachlor by JMPR in 1970. 
    Heptachlor is well absorbed through the GI tract and metabolized to a
    large extent to heptachlor epoxide and minor metabolites.  Heptachlor
    epoxide has been shown to accumulate in adipose tissue, and to cross
    the placenta, but it was not found in the brain.  In rats, the major
    route of elimination is via the faeces.

         In both short- and long-term studies in dogs, rats, and mice, the
    liver was found to be the target organ.  In a 30-day feeding study in
    mice at dietary concentrations of 0, 1, 5, 10, 25 or 50 ppm,
    histopathology findings indicated that males at 5 ppm or above and
    females at 10 ppm or above had enlargement of centrilobular and
    midzonal hepatocytes.  The severity was dose-related.  Based upon
    these results, the NOAEL was 1 ppm, equivalent to 0.15 mg/kg bw/day.

         Several long-term/carcinogenicity studies in rats were reviewed,
    but the majority of them had severe methodological limitations.  In
    one study, rats received time-weighted dietary concentrations of 39 or
    78 ppm (males) and 26 or 51 ppm (females) of heptachlor for 80 weeks. 
    On the basis of decreased body-weight in high-dose males and increases
    in mortality in high-dose males and females, the NOAEL was 26 ppm,
    equivalent to 1.3 mg/kg bw/day.  Deficiencies in this study precluded
    proper evaluation of the carcinogenic potential of heptachlor in rats.

         In a 2-year feeding study, dogs fed heptachlor epoxide at dietary
    concentrations of 0, 1, 3, 5, 7 or 10 ppm, exhibited an increase in
    liver weight at 10 ppm and an increase in the incidence of liver
    histopathological changes at 3 ppm and above.  The histopathological
    changes were enlargement and vacuolation of centrilobular or scattered
    hepatocytes.  Similar histological changes persisted through six
    months of the recovery period.  The NOAEL based upon these findings
    was 1 ppm, equivalent to 0.025 mg/kg bw/day.

         Heptachlor/heptachlor epoxide is carcinogenic in mice; two
    studies demonstrated an increase in liver tumour incidence in male and
    female Charles River CD-1 and B6C3F1 mice.

         Heptachlor/heptachlor epoxide also caused a marginal increase in
    the incidence of hepatocytomegaly in all treated CD-1 mice; a NOAEL
    was not established in this study.

         In a 2-generation reproduction study in dogs at dietary
    concentrations of 1, 3, 5, 7, or 10 ppm of heptachlor epoxide, there
    was an increase in mortality of F2 pups at 3 ppm and above.  The
    NOAEL based on this finding was 1 ppm.

         The available epidemiology studies have not shown a clear
    relationship between any effects in humans and exposure to heptachlor.

         After reviewing the available  in vitro and  in vivo short-term
    test data, it was concluded that, although it can interfere with
    intercellular communication,  heptachlor is not genotoxic.

         Many studies available for evaluation were conducted more than 20
    years ago and have severe deficiencies.  Because of these
    deficiencies, its carcinogenicity in mice and its ability to
    bioaccumulate, the Meeting recommended that heptachlor should not be
    used directly on food crops and its use in the production of food
    commodities should be phased out.  Because of its environmental
    persistence it is found as a contaminant in food commodities.  The
    Meeting therefore maintained an ADI, basing it on the NOAELs derived
    from studies in dogs.  However, recognizing the inadequacy of the data
    base, the Meeting increased the safety factor to 200-fold.  This ADI
    will provide a guideline for assessing the significance of dietary
    exposure to heptachlor residues.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Rat:      26 ppm, equivalent to 1.3 mg/kg bw/day
         Dog:      1 ppm, equivalent to 0.025 mg/kg bw/day
                   (reproduction study)
                   1 ppm, equivalent to 0.025 mg/kg bw/day (2-year study)

    Estimate of acceptable daily intake for humans

         0-0.0001 mg/kg bw

    REFERENCES

    Ahmed, F.E., Hart, R.W., & Lewis, N.J. (1977)  Pesticide induced DNA
    damage and its repair in cultured human cells.  Mutat. Res. 42:
    161-174.

    Arnold, D.W., Kennedy, G.L., Jr., Keplinger, M.L., Calandra, J.C., &
    Calo, C.J. (1977)  Dominant lethal studies with technical chlordane,
    HCS-3260, and heptachlor:heptachlor epoxide.  J. Toxicol. Environ.
     Health., 2: 547-555.

    Benes, V. & Sram, R. (1969)  Mutagenic activity of some pesticides in
     Drosophila melanogaster. Ind. Med., 38, 442-444.

    Davidow, B. & Radomski, J.D. (1953)  Isolation of an epoxide
    metabolite from fat tissues of dogs fed heptachlor.  J. Pharmacol.
     Expt. Therap., 107: 259-265.

    Ditraglia, D., Brown, D.P., Namekata, T., & Iverson, N. (1981) 
    Mortality study of workers employed at organochlorine pesticide
    manufacturing plants.  Scand. J. Work Environ. Health. 7
    (Supplemental 4): 140-146.

    Epstein, S.S. (1976)  Carcinogenicity of heptachlor and chlordane.
     Sci. Total Environ., 6(2): 103-154.

    Epstein, S.S., Arnold, E., Andrea, J., Bass, W., & Bishop, Y. (1972) 
    Detection of chemical mutagens by the dominant lethal assay in the
    mouse.  Toxicol. Appl. Pharmacol. 23: 288-325

    Gaines, T.B. (1969)  Acute toxicity of pesticides.  Toxicol. Appl.
     Pharmacol. 14:514-534

    Gak, J.C., Grillot, C., & Truhaut, R. (1976)  Use of the golden
    hamster in toxicology.  Lab. Animal Sci. 26(2): 274-280.

    Gentile, J.M., Gentile, G.J., Bultman, J., Sechriest, R., Wagoner,
    E.D. & Plewa, M.J. (1982)  An evaluation of the genotoxic properties
    of insecticides following plant and animal activation.  Mutat. Res.,
    101: 19-29.

    Jain, A.K. (1988)  Cytogenic effects of heptachlor on  Lens and
     Pisum species.  Geobios, 15, 61-69.

    Jolley, W.P., Stemmer, K. L., & Jolley, L. (1966)  The effects of
    feeding diets containing a mixture of heptachlor and heptachlor
    epoxide to female rats for two years. Unpublished report by The
    Kettering Laboratory, University of Cincinnati. Submitted to WHO by
    Velsicol Chemical Corp., Rosemont, Illinois, USA.

    Kroger, M. (1972)  Insecticide residues in human milk.  J. Pediatr.
    80: 401-405.

    Kurata, M., Hirose, K. & Umeda, M. (1982)  Inhibition of metabolic
    cooperation in Chinese hamster cells by organochlorine pesticides. 
     Gann, 73, 217-227.

    Le Marchand, L., Kolonel, L.N., Siegel, B.Z., & Dendle, W.H., III
    (1986)  Trends in birth defects for a Hawaiian population exposed to
    heptachlor and for the United States.  Arch. Environ. Health, 41(3):
    145-148.

    MacMahon, B., Monson, R.R., Wand, H.H., & Zheng, T. (1987)  A second
    follow-up of mortality in a cohort of pesticide applicators. A report
    to Velsicol Chemical Corp., dated June 5, 1987. Submitted to WHO by
    Velsico Chemical Corp., Rosemont, Illinois, USA.

    Marshall, T.C., Dorough, H.W., & Swim, H.E. (1976)  Screening of
    pesticides for mutagenic potential using  Salmonella typhimurium
    mutants.  J. Agri. Food Chem., 24(3): 560-563.

    Maslansky, C.J., & Williams, G.M. (1981)  Evidence for an epigenetic
    mode of action in organochlorine pesticide hepatocarcinogenicity: A
    lack of genotoxicity in rats, mouse, and hamster hepatocytes.
     J. Toxicol. Environ. Health, 8: 121-130.

    Matsui, S., Yamamoto, R. & Yamada, H. (1989)  The  Bacillus
     subtilis/microsome rec assay for the detection of DNA damaging
    substances which may occur in chlorinated and ozonated waters.   Water
     Sci. Technol., 21, 875-887.

    McGregor, D.B., Brown, A., Cattanach, P., Edwards, I., McBride, D.,
    Riach, C. & Caspary, W.J. (1988)  Response of the L5178Y tk+/tk-
    mouse lymphoma cell forward mutation assay: III. 72 coded chemicals.
     Environ. Mol. Mutagenesis, 12, 85-154.

    Mersch-Sundermann, V., Dickgiesser, N., Hablizel, U. & Gruber, B.
    (1988) Examination of the mutagenicity of selected herbicides and
    insecticides with the  Salmonella-microsome test (Ames-Test) in
    consideration of the pathogenetic potency of contaminated ground and
    drinking water (Ger.).  Zbl. Bakt. Hyg. B., 186, 247-260.

    Moriya, M., Ohta, T., Watanabe, K., Miyazawa, T., Kato, K. & Shirasu,
    U. (1983) Further mutagenicity studies on pesticides in bacterial
    reversion assay systems.  Mutat. Res., 116, 185-216.

    NAS (National Academy of Science) (1977)  An Evaluation of the
    carcinogenicity of chlordane and heptachlor. Report to the Chief
    Administrative Law Judge of the EPA, dated October, 1977. Submitted to
    WHO by Velsicol Chemical Corp., Rosemont, Illinois, USA.

    NCI (National Cancer Institute) (1977)  Bioassay of heptachlor for 
    possible carcinogenicity. CAS.No. 76-44-8. Technical Report Series 9.
    Bethesda, MD: Carcinogen Bioassay and Program Resources Branch,
    Carcinogenicity Program, Division of Cancer Cause and Prevention, 
    NCI, National Institute of Health. DHEW Publication (NIH) 77-809.

    NTP (National Toxicology Program) (1983)  National Toxicology Program
    Annual Plan for Fiscal Year 1983. NTP-82-119. Chemical Test Results
    for Mutagenicity in  Salmonella Assays in FY 1982. US Department of
    Health and Human Services.

    NTP (National Toxicology Program) (1985)  National Toxicology Program
    Annual Plan for Fiscal Year 1985. NTP-85-055. Chemical Test Results
    for Cytogenetic Effects in Chinese Hamster Ovary Cells in FY 1984. US
    Department of Health and Human Services.

    Podowske, A.A., Banerjee, C.C., Feroz, M., Dudek, M.A., Willey, & 
    R.L., Khan, M.A.Q. (1979)  Photolysis of heptachlor and
     cis-chlordane and toxicity of their photoisomers to animals.  Arch.
     Environ. Contam. Toxicol. 8: 509-518.

    Polishuk, Z.W., Ron, M, Wassermann, M., Cucos, S., Wassermann, D., &
    Lemesch, C. (1977a)  Pesticides in people. Organochlorine compounds in
    human blood plasma and milk.  Pestic. Nonit. J. 10(4): 121-129.

    Polishuk, Z.W., Wassermann, D., Wassermann, D., Cucos, S. & Ron, M.
    (1977b) Organochlorine compounds in mother and fetus during labor.
     Environ. Res. 13: 278-294.

    Probst, G.S., McMahon, R.E., Hill, L.E., Thompson, C.Z., Epp, J.K., &
    Neal, S.B. (1981)  Chemical-induced unscheduled DNA synthesis in
    primary rat hepatocyte cultures: A comparison with bacterial
    mutagenicity using 218 compounds.  Environ Mutat. 3: 11-32.

    Radomski, J.L. & Davidow, B. (1953)  The metabolite of heptachlor, its
    estimation, storage and toxicity.  J. Pharmacol. Exp. Therap. 107:
    266-272.

    Rashid, K.A. & Mumma, R.O. (1986)  Screening pesticides for their
    ability to damage bacterial DNA.  J. Environ. Sci. Health, B21,
    319-334.

    Ruch, R.J., Fransson, R., Flodstrom, S., Warngard, L. & Klaunig, J.E.
    (1990) Inhibition of hepatocyte gap junctional intercellular
    communication by endosulfan, chlordane and heptachlor.
     Carcinogenesis, 11, 1097-1101.

    Sandhu, S.S., Ma, T-H., Peng, Y., & Zhou, X. (1989)  Clastogenicity
    evaluation of seven chemical commonly found at hazardous industrial
    waste sites.  Mutat. Res., 224, 437-445.

    Savage, E.P., Keefe, T.J., Tessari, J.D.,  et al. (1981). National
    study of chlorinated hydrocarbon insecticide residues in human milk. 
    USA. I. Geographic distribution of dieldrin, heptachlor, heptachlor
    epoxide, chlordane, oxychlordane, and mirex.  Am. J. Epidemiol.
    113(4): 413-422.

    Seiler, J.P. (1977)  Inhibition of testicular DNA synthesis by
    chemical mutagens and carcinogens. Preliminary results in the
    validation of a novel short-term test.  Mutat. Res., 46, 305-310.

    Sherman, M. & Ross, E. (1961)  Toxicol. App. Pharmacol., 3: 521.

    Shindell and Associates (1981)  Report of epidemiologic study of the
    employees of Velsicol Chemical Corporation plant Memphis, Tennessee,
    January 1955-December 1979. Unpublished Report by Shendell and
    Associates, Milwaukee, Wisconsin. Submitted to WHO by Velsicol
    Chemical Corp., Rosemont, Illinois, USA.

    Simmon, V.F., Kauhanen, K. & Tardiff, R.G. (1977)  Mutagenic activity
    of chemicals identified in drinking water.  Dev. Toxicol. Environ.
     Sci., 2, 249-258.

    Stehr-Green, P.A., Wohlleb, J.C., Royce, W., & Head, S.L.(1988)  An
    evaluation of serum pesticide residue levels and liver function in
    persons exposed to dairy products contaminated with heptachlor.
     J. Am. Med. Assoc. 259(3): 374-377.

    Strassman, S.C. & Kutz, F.W. (1977)  Insecticide residues in human
    milk from Arkansas and Mississippi 1973-1974.  Pesticide Monit. J.
    10(4):130-133.

    Takahashi, W., Saidin, D., Takei, G., & Wong, L. (1981) 
    Organochloride pesticide residues in human milk in Hawaii 1979-1980. 
     Bull. Environ. Contam. Toxicol. 27: 506-511.

    Takei, G.H., Kauahikaua, S.M., & Leong, G.H. (1983)  Analyses of human
    milk samples collected in Hawaii for residues of organochlorine
    pesticides and polychlorobiphenyls.  Bull. Environ. Contam. Toxicol.
    30: 606-613.

    Tashiro, S. & Matsumura, F. (1978)  Metabolism of  trans-nonachlor
    and related chlordane components in rat and man.  Arch. Environ.
     Contam. Toxicol. 7: 113-127.

    Telang, S., Tong, C., & Williams, G.M. (1982)  Epigenetic membrane
    effects of possible tumour-promoting type on cultured liver cells by
    the nongenotoxic organochlorine pesticide chlordane and heptachlor.
     Carcinogenesis, 3(10): 1175-1178.

    Velsicol Corporation (1959) Unpublished report.

    Wang, H.H. & MacMahon, B. (1979a)  Mortality of workers employed in
    the manufacture of chlordane and heptachlor.  J. Occup. Med. 21(11):
    746-748.

    Wang, H.H. and MacMahon, B. (1979b). Mortality of pesticide
    applicators.  J. Occup. Med. 21(11): 741-744; (11):746-748.

    Wazeter, F.X., Goldenthal, E.I., Geil, R.G., Howell, D.G., & Dean,
    W.P. (1971a) 30-Day range-finding study in mice. Unpublished Report
    from International Research and Development Corp. Submitted to WHO by
    Velsicol Chemical Corp., Rosemont, Illinois, USA.

    Wazeter, F.X., Geil, R.G., Goldenthal, E.I., Cookson, K.M. & Howell,
    D.G. (1971b)  Two-year oral study in beagle dogs. Unpublished Report
    No. 163-048 from International Research and Development Corp. 
    Submitted to WHO by Velsicol Chemical Co., Rosemont, Illinois, USA.

    Wazeter, F.X., Geil, R.G., Goldenthal, E.I., & Howell, D.G. (1971c) 
    Two-generation reproduction and teratology study in beagle dogs.
    Unpublished Report No.163-048 from International Research and
    Development Corp. Submitted to WHO by Velsicol Chemical Corp.,
    Rosemont, Illinois, USA.

    Wazeter, F.X., Goldenthal, E.I., & Geil, R.G. (1973)  Eighteen-month
    oral carcinogenic study in mice. Unpublished Report No. 163-084 from
    International Research and Developmental Corp. Submitted to WHO by
    Velsicol Chemical Corp., Rosemont, Illinois, USA

    Witherup, S., Cleveland, F.P., Shaffer, F.E., Schlecht, H., & Musen,
    L. (1955)  The physiological effects of the introduction of heptachlor
    into the diet of experimental animals in varying levels of
    concentration: Report of experiment No.2. Unpublished report from The
    Kettering Laboratory, College of Medicine, University of Cincinnati,
    Ohio. Submitted to WHO by Velsicol Chemical Corp., Rosemont, Illinois,
    USA.

    Witherup, S., Cleveland, F.P., Stemmer, K.L., & Schlecht, H. (1958) 
    The physiological responses of beagle dogs to the consumption of diets
    containing various concentrations of heptachlor epoxide over a period
    of sixty weeks. Unpublished report from The Kettering Laboratory,
    College of Medicine, University of Cincinnati, Ohio. Submitted to WHO
    by Velsicol Chemical Corp., Rosemont, Illinois, USA.

    Witherup, S., Cleveland, F.P., & Stemmer, K. (1959)  The physiological
    effects of the introduction of hepatochlor epoxide in varying levels
    of concentration into the diet of CFN rats.  Unpublished report from
    the Kettering Laboratory, College of Medicine, University of
    Cincinnati, Ohio.  Submitted to WHO by Velsicol  Chemical Corp.,
    Rosemont, Illinois, USA.

    Zeiger, E., Anderson, B., Haworth, S., Lawlor, T., Mortelmans, K. &
    Speck, W. (1987)   Salmonella mutagenicity tests: III. Results from
    the testing of 255 chemicals.  Environ. Mutagenesis, 9(Suppl. 9):
    1-11.


    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 (AGP:1970/M/12/1)
       Heptachlor (WHO Pesticide Residues Series 4)
       Heptachlor (WHO Pesticide Residues Series 5)
       Heptachlor (CICADS 70, 2006)