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    CHLORDANE

    EXPLANATION

         Chlordane was evaluated for acceptable daily intake by the Joint
    Meeting in 1963, and reviewed in 1970, 1977, and 1982 (Annex 1,
    FAO/WHO, 1964, 1965a, 1968a, 1971a, 1978a, and 1983a). Toxicological
    monographs were prepared in 1963, 1965, and 1967 (Annex 1, FAO/WHO,
    1971b, 1978b, and 1983b). The 1982 Joint Meeting required submission
    of a study of at least 90 days' duration in rats, using oxychlordane,
    and the results of the long-term studies then on-going in Japan.
    Submission of human monitoring data pertinent to oxychlordane and
    trans-nonachlor was considered desirable. These and other studies
    are summarized in this monograph addendum.

    EVALUATION FOR ACCEPTABLE INTAKE

    Biochemical aspects

    Absorption, distribution, and excretion

         In a comparative study, groups of three male Sprague-Dawley rats
    and three male C57 BL/6 JX mice received single oral doses of
    14C-cis-chlordane in corn oil (0-2 ml) and were sacrificed at
    intervals over the ensuing week. Faeces and urine were collected at
    12-hour intervals for three days and at 24-hour intervals thereafter,
    and blood was collected at sacrifice.

         The 14C-cis-chlordane was absorbed more quickly by rats than
    mice; peak blood radioactivity occurred after two hours in rats
    (81 mg/ml) and after eight hours in mice (112 mg/ml). The rate of
    dissipation of these peak levels was also faster in rats than in mice
    since, after 24 hours, 41% and 76% of peak levels remained in rats and
    mice, respectively. The proportions of peak radioactivity remaining in
    liver at this time were 11% and 19% in rats and mice, respectively.
    Although there was significant individual variability among mice, the
    elimination of radioactivity in urine and faeces was initially higher
    in mice than rats. After three days, the cumulative faecal excretion
    was 83% in both species, although urinary excretion remained lower in
    rats. The results of this study indicate significant quantitative
    differences in the absorption, distribution, and excretion of
    cis-chlordane in rats and mice (Ewing et al., 1985).

    Toxicological studies

    Special study on cardiovascular effects

         Groups of three male and three female baboons received technical
    chlordane (0, 0.1, or 1.0 mg/kg b.w.) in a diet enriched in saturated
    fat and cholesterol for 24 months. There were no significant effects
    on the weight gain of treated animals. No significant effects of
    treatment were found on the development of atherosclerosis, on the
    lipid composition of the aortic intima, or on serum lipid or
    lipoprotein concentrations. Similarly, there were no treatment-related
    effects on the activities of mitochondrial enzymes of the heart or
    liver. Only the high-dose chlordane treatment induced hepatic
    cytochrome P-450 activity. No consistent haematological effects or
    behavioural alterations were observed. Chlordane exposure had no
    apparent effect on blood lipoproteins, arteries, or cardiac muscle of
    the baboon (McGill et al., 1979).

    Special study on inhalational toxicity

    Rats

         Groups of 35 male and 35 female Wistar (Crl:(WI) BR) albino rats
    were exposed for eight hours per day, five days per week, to nominal
    atmospheric concentrations of 0, 0.1, 1.0, or 10.0 g/1 technical
    chlordane for 13 weeks, and then sacrificed. Recovery groups of nine
    males and nine females were held for 13 weeks after exposure before
    sacrifice.

         There were no clinical signs or deaths related to chlordane
    exposure. Some high-dose males and females appeared to become more
    sensitive to touch during the study, especially the females. There
    were no treatment-related effects on food or water consumption or on
    body-weight gain. Ophthalmoscopy findings were unremarkable.

         Apparent treatment-related findings were leucocytosis,
    cholesterolaemia, and elevation of serum glutamate dehydrogenase in
    the early part of the study. There was a dose-related increase in
    cytochrome-P450 levels at termination of exposure, which persisted for
    10-11 days thereafter.

         At necropsy, increased liver weight in the high-dose groups was
    accompanied by centrilobular enlargement of hepatocytes. Kidney
    weights were increased in mid- and high-dose males at week nine and in
    the high-dose groups at week 14. There was a tendency for increased
    thyroid weight in exposed groups (Hardy et al., 1984).

    Monkeys

         An inhalation study was conducted with Macaca irus monkeys
    using the same exposure regime as in the rat study just described.
    Thus, groups of six male and six female monkeys were exposed to mean
    atmospheric chlordane concentrations of 0, 0.1, 1.0, or 10 g/l for
    eight hours daily, five days per week, for 13 weeks.

         There were no effects or clinical signs due to chlordane
    exposure; food consumption and body-weight gain were unaffected.
    Rectal temperatures were found to be slightly increased during
    exposure, especially in the mid- and high-dose groups. Ophthalmoscopy
    showed no treatment-related effects. No adverse effects were found on
    pulmonary function (blood gases, lung function, and pulmonary
    ventilation parameters). No consistent treatment-related effects on
    haematological, serum biochemical, or urinalysis parameters were
    found.

         At necropsy, there were no significant macroscopic pathological
    changes in any group, although treatment-group mean liver and thyroid
    weights were greater than controls. No histopathological findings were
    related to chlordane exposure (Hardy et al., 1984).

    Special study on promotion of hepatic neoplasia

         In the initiation phase, groups of 40 male B6C3F1 hybrid mice
    received diethyl nitrosamine (0 or 200 ppm) in their drinking water
    for 14 weeks. After four weeks' recovery on basal diet, the groups
    received one of the following compounds in their diet for a further 25
    weeks, as the promotion phase: technical chlordane (25 or 50 ppm),
    technical heptochlor (5 or 10 ppm), DDT (50 ppm), or N-2-fluorenyl-
    acetamide (150 ppm). In addition, some groups received the chemicals
    before diethyl nitrosamine, to determine possible syncarcinogenic
    effects. Randomly-selected mice from several of the groups were
    sacrificed at weeks 14, 18, 26, and 34, and the remainder upon
    completion of exposure. Prior to the interim kills (and at termination
    with 8-10 mice), mice received s.c. injections of iron dextran (12.5
    mg iron/100 gm b.w.) to produce hepatic siderosis for the subsequent
    delineation of iron-excluding lesions.

         Diethylnitrosamine initiation was indicated by the presence of
    altered hepatic foci displaying abnormal alkaline phosphatase,
    adenosine triphosphatase, glucose-6-phosphatase, gamma-glutamyl
    transpeptidase, or iron accumulation in varying degrees. Abnormalities
    of glucose-6-phosphatase were most marked. Neoplasia was not observed
    at this stage.

         At termination, most exposed animals exhibited reduced
    body-weight gain, especially those in the high-dose chlordane and
    heptochlor groups. Liver weights were increased in mice in those
    groups which received diethyl nitrosamine followed by chlordane and
    heptochlor, but not in animals in those groups receiving only
    chlordane or heptochlor. While the number of hepatic foci found at
    week 43 was less than that found 12 or 20 weeks after cessation of
    exposure in mice given diethylnitrosamine alone, the number and size
    of foci were increased by chlordane or heptochlor exposure in
    initiated mice. N-2-Fluorenylacetamide increased the number, but not
    the size, of hepatic foci in initiated mice, but exposure to DDT,
    chlordane, heptochlor, or N-2-fluorenylacetamide alone did not
    increase the number of foci compared to untreated controls.

         Diethylnitrosamine produced squamous cell papillomas and
    carcinomas in the forestomach and pulmonary adenomas in treated mice.

         The incidence of hepatic neoplasms was particularly increased by
    treatment with diethyl nitrosamine (40%) compared to untreated
    controls (11%). Feeding of chlordane, heptochlor, DDT, or
    N-2-fluorenylacetamide further increased not only the incidence of
    hepatic neoplasms (to 66-85%), but also the multiplicity of liver
    neoplasms. In each case the number of adenomas exceeded that of
    adenocarcinomas. Mice given the higher doses of chlordane, heptochlor,
    or N-2-fluorenylacetamide alone had the same incidence of hepatic

    neoplasms as the controls, although the chlordane and heptochlor
    treatment included hepatocyte hypertrophy with nuclear enlargement.
    Chlordane, heptochlor, and DDT also increased the severity of cystic
    changes found in the livers of all mice previously treated with
    diethyl nitrosamine. Administration of the test chemicals in reverse
    sequence did not increase the incidence of liver neoplasms over that
    of controls.

         The results of this study indicate that chlordane, heptochlor,
    and DDT induce hepatocellular foci and enhance the development of
    hepatocellular adenomas and adenocarcinomas in mice pre-treated with
    diethylnitrosamine. However, the promotional effect seemed to be
    specific to the liver (Williams and Numoto, 1984).

    Long-term studies

    Mice

         In a combined chronic toxicity and carcinogenicity study, groups
    of 80 male and 80 female Charles River ICR:SPF mice were fed technical
    chlordane at dietary concentrations of 0, 1, 5, or 12.5 ppm for 104
    weeks. An interim sacrifice of eight mice of each sex was conducted at
    week 52. Chlordane had no apparent effect on the clinical condition of
    the treated mice, and their mortality was unaffected. No consistent
    influences on body-weight gain, food consumption, or food-conversion
    efficiency were observed during treatment. Urinalysis and full
    haematological examination, performed at weeks 52 and 104, were
    unremarkable. There was a tendency for increased serum aspartate
    aminotransferase and alanine aminotransferase among the mid- and
    high-dose groups. Similarly, gamma-glutamyl transpeptidase values were
    elevated among some high-dose females at 52 weeks.

         At terminal sacrifice there was a dose-related increase in
    hepatic size and relative and absolute liver weight in treated males;
    treated females exhibited less of an increase in hepatic weight,
    especially at the highest dose. Increased incidences of liver nodules
    were found in mid- and high-dose groups, especially in male mice.
    Histopathological lesions corresponding to the above changes were
    found. In males, hepatocellular swelling, with associated changes to
    hepatic cords and hepatocytes, increased in incidence from week 52 at
    the high dose and from week 79 at the mid dose. Hepatocellular fatty
    degeneration occurred at the high dose, while hepatocellular necrosis
    was increased in incidence in the mid- and high-dose groups at
    terminal sacrifice.

         There were increased incidences of hepatocellular adenomas and
    haemangiomas in the high-dose males at termination. Female mice
    exhibited a dose-related increase in the incidence of hepatocellular
    swelling, with a tendency for hepatocellular necrosis in only the
    high-dose group. The incidence of hepatic tumours in female mice was
    not increased by treatment. The results of this study indicate a
    no-observed-effect level of 1 ppm (Ihui et al., 1983a).

    Rats

         Groups of 80 male and 80 female F-344 SPF rats were fed technical
    chlordane in the diet at 0, 1, 5, or 25 ppm for 130 weeks before
    sacrifice. Interim sacrifices of groups of eight males and nine
    females were conducted at 26 and 52 weeks for pathological
    investigation.

         Treatment with chlordane produced no clinical signs of toxicity
    and had no effect on mortality. Body weights, food consumption, and
    food-conversion efficiency of treated animals were not consistently
    different from controls. Urinalysis of sample groups of eight male and
    eight female rats were unaffected by treatment after 26 and 52 weeks;
    however, all groups exhibited proteinuria and haematuria at week 130.
    Haematological and biochemical parameters, including serum hepatic
    enzyme levels (aspartate and alanine aminotransferases, gamma-glutamyl
    transpeptidase, and alkaline phosphatase), were not influenced by
    treatment. Serum bilirubin levels were increased in mid- and high-dose
    male groups at termination.

         At necropsy significant increases in absolute and relative liver
    weights in treated groups, as compared with controls, were noted;
    absolute hepatic weights were increased in high-dose females at 26 and
    52 weeks and in mid- and high-dose males at 130 weeks, while relative
    liver weights were significantly increased in both high-dose groups.

         Histopathological examination revealed a significantly-increased
    incidence of hepatocellular swelling centered on hepatic nodules in
    male and female high-dose rats and in some mid- and low-dose males,
    towards the end of the study. There was also an increased incidence of
    diffuse hepatocellular necrosis in some high- and some low-dose male
    rats dying after week 79, but this lesion was not found at terminal
    sacrifice. High-dose male rats also had an increased incidence of
    hepatocellular adenomas. The incidences of mammary fibroadenoma and
    adenoma were increased in treated females but not in a dose-related
    manner. A no-effect level of 1 ppm was indicated by this study
    (Ihui et al., 1983b).

    Observations in humans

         Clinical and epidemiological studies of chlordane exposure in man
    have been reviewed (IARC, 1979; IPCS, 1984). Additional studies are
    reviewed here.

         Table 1 summarizes surveys of blood concentrations of workers
    engaged in chlordane manufacture.

    Table 1.  Human blood chlordane concentrations in workers engaged in
              chlordane manufacture
                                                                        

                                     Blood chlordane concentration (ppb)
                                                                        
                  Number of
    Year          workers               Range               Mean
                                                                        

    1975           50                   0.7-32.0             6.6
    1976          135                   0.1-29.4             3.3
    1979          109                   0.8-76.9            11.2
                                                                        

         Adipose tissue concentrations ranged from 900-6400 ppm with an
    average concentration of 4067 ppm. Atmospheric concentrations in the
    plant typically range from 10-550 g/m3, although higher
    concentrations may occur in certain areas. Significant surface
    residues also contribute to exposure. Blood concentrations of
    chlordane and heptochlor and their metabolites ranged from 0-75 ppb
    (mean 1.5 ppb) among 411 pest-control operators (Khasawinah, 1986).

         A survey of 567 randomly-selected serum samples collected from
    citrus field workers found blood oxychlordane, heptochlor epoxide, and
    trans-nonachlor concentrations, where detected, ranging from
    0.2-2.9 ppb (Griffith & Duncan, 1985).

         A recent survey of 22 male and 21 female volunteer Japanese city
    dwellers has found the chlordane derivatives oxychlordane and trans-
    nonachlor to be the main terminal residues in blood at concentrations
    ranging from 0.18 - 1.16 mg/ml. A significant correlation was noted
    between the concentrations of trans-nonachlor and oxychlordane,
    between trans-chlordane and cis-chlordane, and between
    trans-chlordane and cis-nonachlor. Dietary exposure seemed
    to be the main source of the residues, although termite treatment of
    dwellings remained a possible exposure source in some cases (Wariishi
    et al., 1986).

         Results of a large-scale human monitoring programme indicated
    that the general U.S. population is exposed to relatively low levels
    of trans-nonachlor and oxychlordane. Blood concentrations were
    determined in approximately 21,000 individuals aged 12-74 years during
    the period 1976-1980. In only 4.4% of the general population were
    quantifiable levels of trans-nonachlor (median 1.4 ppb; range

    1-17 ppb) found; the proportion of population subgroups that were
    exposed increased with increasing age. Some 2.5% of the population had
    quantifiable oxychlordane (median 1.7 ppb, range 1-23 ppb) or
    heptochlor epoxide (median 1.7 ppb, range 1-23 ppb) in the blood
    (Murphy and Harvey, 1985).

         A follow-up prospective mortality study of workers occupationally
    exposed to chlordane during manufacture during the period January 1946
    to June 1985 has been reported. The study examined the rates of
    overall mortality, cerebrovascular deaths, and cancer mortality in 800
    employees with at least three months' exposure, in relation to
    standard mortality ratios. Chlordane exposure was ranked by
    consideration with the results of blood oxychlordane concentrations
    previously determined.

         Compared to other employees, production workers had less overall
    mortality, with lower standard mortality ratios for both heart disease
    and cancer. However, they did experience an apparent, although not
    statistically significant, mortality excess from cerebrovascular
    accident and trauma. Twenty cerebrovascular deaths occurred among 176
    deaths, when 11.7 were to be expected.

         This excess cerebrovascular mortality occurred in one
    occupational subgroup with high pesticide exposure and in another with
    low exposure. The apparent excess of cerebrovascular mortality
    contrasts with the observed overall deficit of cardiovascular disease.

         In comparison to the U.S. male population, overall cancer
    mortality was slightly reduced in production workers and was at the
    expected level for others. No type of cancer consistently occurred and
    there seemed to be an inverse relationship between cancer mortality
    and length of employment. The results of this study do not suggest any
    association between occupational exposure to chlordane and human
    mortality or cancer incidence (Shindell and Ulrich, 1986).

         A further follow-up study of the mortality of pesticide
    applicators has been conducted. Termite-control operators with a high
    probability of exposure to chlordane and hepatochlor were identified
    among a cohort of 16,126 male pesticide applicators employed in the
    period January 1968 to September 30, 1981. Although ascertainment was
    incomplete, the overall number of deaths among the cohort and the
    termite-control operators was less than expected. No single cause of
    death was significantly elevated, although the incidences of cancers
    of the lung, skin, and bladder were each slightly increased among the
    cohort, rather than the termite-control operators. Thus, there was no
    apparent association between chlordane exposure and increased
    mortality or human cancer in this study (McMahon et al., 1986).

    COMMENTS

         A comparative study of absorption, distribution, and excretion of
    orally-administered cis-chlordane (alpha-chlordane) in rats and mice
    indicated significant qualitative differences. It remains uncertain,
    however, whether one of these species is a better animal model for
    humans than the other.

         As previously noted, there has been uncertainty over the
    potential for chlordane, and to a lesser extent, heptochlor and/or
    their metabolites, to accumulate in tissues. The presence of
    trans-nonachlor and oxychlordane in human milk and adipose tissue
    has been previously recognized (IPCS, 1984). The 1982 JMPR noted the
    significant differences in the metabolism of chlordane by rats and
    humans, but was concerned that metabolites such as trans-nonachlor
    could accumulate in human tissues.

         Recent human data suggest the presence of low blood levels of
    cis- and trans-oxychlordane and cis- and trans-nonachlor and
    their metabolites in the general population. These studies do not
    indicate that either trans-nonachlor or oxychlordane are
    accumulating in human tissues to a significant extent. Hence, the need
    for further study with oxychlordane in rats has been superseded.

         An inhalation study indicates that the monkey, Macaca irus, is
    less susceptible to chlordane toxicity than rats. A study in baboons
    did not indicate that low dietary levels of chlordane adversely
    influenced serum lipoprotein or cholesterol levels, or the development
    of atherosclerosis.

         The recent chronic feeding study in rats has confirmed and
    extended the results of previous studies. Proliferative lesions in the
    liver were seen at a significant level at 25 ppm in male rats. Hepatic
    changes, suggestive of an adaptive response, occurred at lower doses,
    but these were not considered to represent an adverse toxicological
    effect.

         A further chronic feeding study has again confirmed the liver as
    the target organ for chlordane toxicity in mice. Liver tumours
    occurred in male mice at 12.5 ppm, but significant hepatic changes
    were seen at lower doses. Chlordane seems to act as a tumour promoter
    in the mouse liver.

         Additional epidemiological data from two mortality studies of
    occupationally-exposed individuals do not suggest that chlordane
    exposure adversely affects the mortality or development of
    cardiovascular diseases or cancer. However, the value of these data is
    limited by relatively small group-sizes and uncertainty of duration
    and degree of exposure.

         The temporary ADI was converted to an ADI at a lower level.

    TOXICOLOGICAL EVALUATION

    LEVEL CAUSING NO TOXICOLOGICAL EFFECT

         Mice:     1 ppm in the diet, equal to 0.12 mg/kg b.w./day.
         Dogs:     3 mg/kg in the diet, equal to 0.075 mg/kg b.w./day.
         Rats:     1 ppm in the diet, equivalent to 0.05 mg/kg b.w./day.

    ESTIMATE OF ACCEPTABLE DAILY INTAKE IN MAN

         0-0.0005 mg/kg b.w.

    FURTHER WORK OR INFORMATION

    STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE FOR THE CONTINUED
    EVALUATION OF THE COMPOUND

         Further human monitoring data.

         Investigation of the promotional activity of chlordane on the
    diethylnitrosamine-induced liver tumours in a species other than the
    mouse, with special emphasis on cytochrome P-450 induction.

    REFERENCES

    Ewing, A.D., Kadry, A.M., & Dorough, H.W., 1985. Comparative
         disposition and elimination of chlordane in rats and mice.
         Toxicology Letters, 26, 233-239.

    Griffith, J. & Duncan, R.C., 1985. Serum organochlordane residues in
         Florida citrus workers compared to the National Health and
         Nutrition Examination Survey sample. Bull. Environ. Contam.
         Toxicol., 35, 411-417.

    Hardy, C.J., Clark, G.C., Street, A.E., Read, L.E., Gopinath, C.,
         Gregson, R.L., & Down, W.H., 1984. Chlordane, a 90-day inhalation
         toxicity study in the rat and monkey. Unpublished report by
         Huntingdon Research Centre, Huntingdon, Cambridgeshire, England.
         Submitted to WHO by Velsicol Chemical Corp., Chicago, IL, USA.

    IARC, 1979. IARC monographs on the evaluation of the carcinogenic risk
         of chemicals to man: some halogenated hydrocarbons. Chlordane.
         International Agency for Research on Cancer, Lyon,
         Volume 20, pp. 45-65.

    IPCS, 1984. Chlordane, Environmental Health Criteria No 34.
         International Programme on Chemical Safety, WHO, Geneva.

    Ihui, S., Hayakawa, T. Yonemura, T., Takamura, F., Takahashi, Y., &
         Yamazaki, K., 1983a. Twenty-four month chronic toxicity and
         tumourigenicity test in mice by chlordane technical. Unpublished
         report by Research Institute for Animal Science in Biochemistry
         and Toxicology. Submitted to WHO by Velsicol Chemical Corp.,
         Chicago, IL, USA.

    Ihui, S., Hayakawa, T., Yonemura, T., Takamura, F., Takahashi, Y., &
         Hashizume, M., 1983b. Thirty-month chronic toxicity and
         tumourigenicity test in rats with chlordane technical.
         Unpublished report by Research Institute for Animal Science in
         Biochemistry and Toxicology. Submitted to WHO by Velsicol
         Chemical Corp., Chicago, IL, USA.

    Khasawinah, A.M., 1986. Plant workers and pest control operators
         exposure to chlordane and heptachlor. Unpublished report.
         Submitted to WHO by Velsicol Chemical Corp., Chicago, IL, USA

    McGill, H., Mott, G.E., Kruski, A.W., Montiel, M.M., Stavinoha, W.B.,
         Coelho, A.M., Carey, K.D., & McMahan, C.A., 1979. Pilot study of
         the effects of pesticides on blood lipoproteins, arteries and
         cardiac muscle of baboons. Unpublished report by University of
         Texas Health Science Center and Southwest Foundation for Research
         and Education. Submitted to WHO by Velsicol Chemical Corp.,
         Chicago, IL, USA

    McMahon, B., Wang, H., & Monson, R., 1986. A second follow-up of
         mortality in a cohort of pesticide applicators. Unpublished
         report. Submitted to WHO by Velsicol Chemical Corp.,
         Chicago, IL, USA

    Murphy, R. & Harvey, C., 1985. Residues and metabolites of selected
         persistent halogenated hydrocarbons in blood specimens from a
         general population survey. Environmental Health Perspectives,
         60, 115-120.

    Shindell, S. & Ulrich, S., 1986. Mortality of workers employed in the
         manufacture of chlordane: An update. J. Occup. Med., In Press.

    Wariishi, M., Suzuki, Y., & Nishiyama, K., 1986. Chlordane residues in
         normal human blood. Bull. Environ. Toxicol., 36, 635-643.

    Williams, G.M. & Numoto, S., 1984. Promotion of mouse liver neoplasms
         by the organochlorine pesticides chlordane and heptachlor in
         comparison to dichlorodiphenyltrichloroethane. Carcinogenesis,
         5, 1689-1696.
    


    See Also:
       Toxicological Abbreviations
       Chlordane (EHC 34, 1984)
       Chlordane (HSG 13, 1988)
       Chlordane (PIM 574)
       Chlordane (FAO Meeting Report PL/1965/10/1)
       Chlordane (FAO/PL:1967/M/11/1)
       Chlordane (FAO/PL:1969/M/17/1)
       Chlordane (AGP:1970/M/12/1)
       Chlordane (WHO Pesticide Residues Series 2)
       Chlordane (WHO Pesticide Residues Series 4)
       Chlordane (Pesticide residues in food: 1977 evaluations)
       Chlordane (Pesticide residues in food: 1982 evaluations)
       Chlordane (Pesticide residues in food: 1984 evaluations)