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    ENDOSULFAN

    EXPLANATION

         Endosulfan was evaluated for acceptable daily intake (ADI) by
    the Joint Meeting of Pesticide Residues (JMPR) in 1963, 1965, 1967,
    and 1968, and reviewed in 1971, 1974, 1975, 1982, and 1985 (Annex 1,
    FAO/WHO 1964, 1965a, 1968a, 1969a, 1972a, 1975a, 1976a, 1983a, and
    1986a).  Toxicological monographs were prepared in 1964, 1965, 1967,
    and 1968 (Annex 1, FAO/WHO 1964, 1965b, 1968b, and 1969b).
    Essentially all of the toxicology data available to evaluate
    endosulfan during these proceedings were presented at the meetings
    held between 1963 and 1968. The 1967 JMPR was unable to set an ADI
    for endosulfan, pending evaluation of the results of a reproduction
    study in rats.  The reproduction study was evaluated by the 1968
    JMPR and a temporary ADI of 0 to 0.0075 milligrams/kilograms per
    body weight (mg/kg bw) was determined, based partly on the results
    of that study and long-term rat and dog feeding studies.  The
    chronic rat and dog feeding studies were characterized as providing
    sufficient information on the long-term effects of endosulfan. 
    However, the rat reproduction and teratology studies were performed
    by IBT and were not independently validated.  In 1982, JMPR
    recommended that the ADI be replaced by a temporary ADI at the same
    level, pending receipt of data validation and/or replacement studies
    for the non-validated data.  The 1985 JMPR extended the temporary
    ADI and concluded that a complete re-evaluation of endosulfan was
    required with toxicological data obtained following up-to-date
    protocols.  Since that time additional toxicological data (including
    replacement reproduction and teratology studies) have become
    available and are reviewed in the monograph addendum.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical aspect

    Absorption, distribution, and excretion

    Rats

         The pharmacokinetics of orally administered alpha and beta
    endosulfan in rats and sheep was described in a recent review paper
    (Stumpf & ABhauer, 1986). In addition, dermal absorption studies in
    rats (Craine, 1986) and monkeys (Lachmann, 1987) were also
    available.

         Following the administration of a single oral dose (1.2 mg/kg)
    of radiolabelled endosulfan to male rats, 40 to 60% of the substance
    was absorbed over 48 hours.  Approximately 54 to 82% was excreted
    (15 to 22% in feces, 29 to 47% in bile, and 10 to 13% in urine). 
    Similar results were obtained following a single oral dose (2 mg/kg)
    to female rats, i.e., 90% of the radiolabelled substance was
    excreted in 120 hours, with an excretion T of 30 to 40 hours
    (Stumpf & ABhauer, 1986).

         During a 14-day study in the rat with doses of 5 or 25 mg/kg
    administered in the daily diet, followed by a 14-day elimination
    phase, 65% was excreted during the dosing period and an additional
    8% during the ensuing 14-day elimination phase.  Tissue distribution
    studies conducted with the 5 mg/kg daily dietary dose indicated an
    accumulation of endosulfan in rat kidney (value of 3 mg/kg).  Levels
    were lower in liver and body fat (< 1 mg/kg) and in muscle and
    brain (< 0.07 mg/kg).  After discontinuation of feeding the stored
    radioactivity was rapidly eliminated with a T of 3 to 7 days
    (Stumpf & ABhauer, 1986).

         The dermal absorption of single doses (0.10, 0.76, or
    10.13 mg/kg bw) of aqueous suspensions of 14C-endosulfan (94.6%
    pure) was examined following exposure periods of 30 minutes to 24
    hours to the suspension in 114 male Crl:CD(SD)BR rats.  Over a
    24-hour time period approximately 25% of each applied dose was
    absorbed and 55% remained bound to skin;  about 20% was removed by
    washing.  Of the 25% absorbed at 24 hours, about 10% was excreted in
    feces and urine (Craine, 1986).

    Monkeys

         The dermal absorption of single doses (2.2 to 3.0 mg/kg) of
    aqueous suspensions of 14C-endosulfan (94.6% pure) was studied
    after a 10-hour exposure period to shaved skin in two Rhesus
    monkeys. Absorption of endosulfan occurred as indicated by gradually

    increasing levels of radioactivity in blood and plasma over the
    first 24 to 36 hours of the study.  Plateau levels occurred at 36
    hours in blood (25 mg/mL) and plasma (35 mg/mL).  At the end of the
    experiment (96 hours), 4.3% and 3.7% of the administered radioactive
    dose was excreted in feces and urine, respectively, 11% was detected
    in treated skin, and 10.5% was found in the carcasses.  The total
    recovery at 96 hours averaged 51% for both monkeys. Tissue
    distribution studies revealed low (< 0.05 ppm) levels of
    radioactivity in kidney, fat, liver, and brain.  The respective
    levels in liver, fat, and kidney were 19X, 9X and 3X greater than
    the levels found in blood (Lachmann, 1987).

    Sheep

         Following the administration of a single oral dose (0.3 mg/kg)
    of radiolabelled endosulfan to sheep, 50% of the dose was excreted
    in feces, 41% in urine, and 1% in milk, over a period of 22 days
    (Stumpf & ABhauer, 1986).

    Biotransformation

         Two biotransformation pathways have been described for
    endosulfan in mammals (i.e., rats) (Stumpf & ABhauer, 1986).  The
    first pathways involves hydrolysis and oxidation to various
    sulfur-free metabolites, namely endosulfan diol, endosulfan ether,
    hydroxy-endosulfan ether, and endosulfan lactone (which is also
    converted to endosulfan hydroxylactone in insects only), and polar
    conjugates.  The second pathway involves the formation of various
    sulfur-containing metabolites, namely endosulfan sulfate, endosulfan
    sulfuric acid ester, and endosulfan bicarbonic acid (postulated).

         The proposed metabolic pathway is described in Figure 1.

         Studies in the rat suggest that those components excreted
    primarily in the feces after administration of a single oral dose
    (1.2 mg/kg) of endosulfan are unchanged parent compound, endosulfan
    sulfate, and all of the sulfur-free metabolites.  The urine
    contained mainly endosulfan diol and polar conjugates, in addition
    to some unchanged parent compound (Stumpf & ABhauer, 1986).

         Studies in monkeys following dermally administered
    14C-endosulfan indicated that the unchanged parent compound was
    present in small amounts of feces (0.1% of an applied dose) whereas
    a metabolite referred to a "x" (presumed to be endosulfan
    hydroxycarboxylic acid) was present to the extent of 0.4% of the
    applied dose.  In urine, endosulfan diol was the most prevalent
    metabolite (1.5% of the dose), followed by "x" (0.6% of the dose)
    plus negligible amounts of parent compound (Lachmann, 1987).

    FIGURE 1

    Toxicological Studies

    Acute toxicity

         An acute nose-only inhalation toxicity test of endosulfan in
    Wistar rats resulted in LC50 values of 0.0345 mg/L of air in males
    and 0.9126 mg/L of air in females.  Clinical signs of intoxication
    were dyspnea, passivity, disequilibrium, trembling, tremors,
    tono-clonic convulsions, and subdued reflex activity. Gross necropsy
    changes in animals that died consisted of sporadic dark red pinhead
    foci in the lungs (Hollander & Weigand, 1983).

    Short-term studies

    Mice

         Groups of 10 male and 10 female Hoe:NMRKf(SPF 71) mice were fed
    diets containing 0 or 18 ppm technical endosulfan for 42 days.  The
    18 ppm dose level was calculated to be equivalent to 3.7 mg/kg
    bw/day in males and 4.6 mg/kg bw/day in females.  The results
    obtained indicated that deaths occurred in 2/10 treated mice (one
    female on day 28 and another female on day 38), and absolute and
    relative liver weights were significantly increased in females.  In
    addition, the body weight gain was slightly elevated throughout the
    study, with the increase observed on day 36 being statistically
    significant.  There were no other changes in females or in males
    with respect to food consumption, behaviour or general condition
    (including ocular and dental examinations), or macroscopic
    examinations of organs.  The NOAEL was less than 4.6 mg/kg bw/day in
    females (based on deaths and increased liver weights) and equal to
    3.7 mg/kg bw/day in males (Donaubauer  et al. 1985).

         In a 13-week study, groups of 20 male and 20 female CD-1 mice
    received dietary levels of 0, 2, 6, 18, or 54 ppm of technical
    endosulfan.  These concentrations were equivalent to doses of
    approximately 0, 0.24-0.27, 0.74-0.80, 2.13-2.39, or 7.3-7.5 mg/kg
    bw/day, respectively.

         Adverse findings appeared to be confined primarily to the
    highest dose level of endosulfan (i.e., 54 ppm).  The observed
    changes included deaths (12/20 males and 10/20 females at various
    study intervals), convulsions and salivation (1/20 males and 1/20
    females), reduced neutrophils (males on weeks 6 and 13), increased
    total serum lipids (females on week 13), reduced spleen weight
    (males), and slight vascular congestion in the lungs (11/20 males
    and 6/20 females).  All of those parameters were unchanged in all
    other treatment groups.  At dose levels of 6, 18, and 54 ppm, body
    weight gain was depressed in male mice at study week 1 only, and
    blood glucose levels were depressed in females at study week 6 only. 
    Neither of these changes persisted throughout the study and are thus
    not considered to be of toxicological importance.  Similarly, food

    consumption was reduced only on study weeks 1 and 2 in mice of both
    sexes at the 54 ppm dose level.  From the above data, the NOAEL was
    considered to be 18 ppm, equivalent to 2.13 to 2.39 mg/kg bw/day in
    the diet, respectively, in male and female mice (Barnard  et al.
    1984).

    Rats

         Endosulfan was fed for 4 weeks in the daily diet to groups of
    100 male Wistar rats at concentrations of 360 and 720 ppm.  These
    concentrations were said to be equivalent to doses of 34.0 and
    67.8 mg/kg bw/day, respectively.  An additional 20 male rats served
    as control animals.  At the end of 4 weeks treatment, one-half of
    the animals in each group were killed (main study group) and the
    other half were allowed to recover for 4 more weeks before being
    sacrificed (recovery group).  Rats were examined daily for behaviour
    and general health conditions.  Body weights and food consumption
    were recorded weekly.  At autopsy, all animals were examined
    grossly, and the relative weights of three organs (liver, kidneys,
    brain) were calculated.  Histological exams were performed on the
    left kidney, and a piece of liver from six animals/dose level; the
    right liver, another piece of liver and the brain from two
    animals/dose level were examined by electron microscopy.  The
    remaining parts of the above organs not used for histological study
    were used to identify residues of endosulfan in tissue.

         Two deaths occurred due to unknown causes (one rat at 360 ppm
    on day 29 and one rat at 720 ppm on day 8).  There were no
    treatment-related effects in the appearance or general health of the
    animals (including signs of neurological disturbances, corneal
    opacity, oral mucosal lesions, or changes in dental growth), in body
    weight gain, or in food consumption.  The relative weights of the
    liver were increased at both dose levels, and relative kidney and
    brain weights were increased at the highest dose level.  Upon gross
    examination, the kidneys appeared darkened in colour at both dose
    levels.  Histopathological examination showed proliferation and
    enlargement of lysosomes of the cells of the proximal convoluted
    tubules, and granular pigmentation of the same cells, at both doses
    of endosulfan. Lysosomal changes were not seen in brain or liver. 
    The above findings were not seen in animals in the 4-week recovery
    group.  The identification of residues of endosulfan in tissues was
    unsuccessful.  There was no NOAEL in this study due to the observed
    renal and liver changes at 360 ppm, equivalent to 34.0 mg/kg bw/day
    in the diet (Leist & Kramer, 1985).

         In a follow-up report, the results of repeat tissue residue
    analysis studies after dietary dosing with 360 and 720 ppm in Wistar
    rats for 4 weeks, and with a recovery period of an additional 4
    weeks, were made available.  The findings indicated that
    alpha-endosulfan, and to a considerably lesser extent
    beta-endosulfan, was temporary stored in the kidneys in proportion

    to the administered dose.  Only endosulfan-sulfate and
    endosulfan-lactone were detected in any appreciable quantities in
    the kidneys.  It was also noted that endosulfan and its metabolites
    were minimally detectable in the blood.  In the liver,
    endosulfan-sulfate and endosulfan-lactone were the dominant
    compounds, although their levels were many times lower than the
    concentrations of alpha-endosulfan measured in the kidneys.  It was
    also observed that the storages were reversible; 30 days after the
    end of the treatment phase alpha-endosulfan was detected only in
    traces, and beta-endosulfan not at all (Leist & Mayer, 1987).

         In a 13-week study, groups of 25 male and 25 female CD rats
    were fed diets containing 0, 10, 30, 60, or 360 ppm technical
    endosulfan.  Daily dosages were equivalent to 0, 0.64, 1.92, 3.85,
    and 23.41 mg/kg bw/day in males, and 0, 0.75, 2.26, 4.59, and
    27.17 mg/kg bw in females.  At the end of the 13-week treatment
    period all animals were sacrificed except for 5 rats/sex dose group
    that were withdrawn from treatment and followed for an additional
    4-week recovery period. Ophthalmoscopic exams were performed on
    control and high-dose rats before treatment and at week 13. 
    Neurological exams (locomotor reflexes) were performed on 10
    rats/sex from the control and high-dose levels before treatment and
    on weeks 2, 6, and 13; in addition, all animals were examined for
    grip reflex and evidence of ataxia on week 13.  Blood was sampled at
    0, 6, and 12/13 weeks from 10 rats/sex/dose for assessment of
    hematology and clinical chemistry parameters.  A standard battery of
    tests/examinations was performed and, in addition, blood and plasma
    cholinesterase estimations were made at 5 and 12 weeks in 10
    rats/sex/dose level.  Urine was collected on weeks 4 and 13 for
    standard urinalysis determinations.  Similar studies were performed
    in the rats that were allowed to complete the recovery period.

         Three deaths occurred during the treatment period (1/20 female
    controls, 1/20 females at 60 ppm due to anesthetic shock during
    routine blood sampling, and 1/20 females at 320 ppm on day 19).  No
    deaths occurred in rats during the recovery period.

         The only clinical sign of toxicity observed was hair loss in
    females receiving 60 and 360 ppm endosulfan.  Body weight gain was
    reduced in male and female rats to a slight degree over the course
    of the study.  Food consumption was reduced in females given 360 ppm
    during study weeks 1 and 2 only.  All of these changes regressed by
    the end of the recovery period.  No adverse ophthalmological or
    neurological findings were observed in treated rats.

         A variety of hematological changes were observed during the
    treatment period.  Red blood cells were reduced at week 13 (and
    after week 6) in male rats at doses of 30 to 360 ppm.  MCV was
    increased in female rats at weeks 13 and 6 at doses of 60 and
    360 ppm.  Finally, PCV was reduced at weeks 13 and 6 in male rats
    given 360 ppm.  In most cases, these effects were still evident in

    rats, especially males, at recovery week 17.  Changes involving
    clinical chemistry parameters included increases in serum phosphorus
    in females (weeks 12 and 6) at 30 and 360 ppm, reductions in serum
    electrocytes (Na+ and K+) in males (weeks 12 and 6) at 60 and
    360 ppm, and increased in total lipids and cholesterol in females
    (weeks 12 and 6) at 360 ppm.  In the case of urinalysis
    determinations, a darkened urine was observed in male rats (week 13)
    at 60 and 360 ppm, and in females (week 13) at 360 ppm.  The urine
    of the male rats at 60 and 360 ppm also contained elevated levels of
    ketones and proteins.  The clinical chemistry and urinalysis changes
    regressed by the end of the recovery period.

         Lower plasma and red blood cells cholinesterase activities were
    observed in females (weeks 12 and 5) given 360 ppm endosulfan.  In
    contrast, increased brain cholinesterase activity was seen in
    females treated with 60 and 360 ppm.  These changes regressed during
    the recovery period.

         At necropsy, increases were noted in the relative weights of
    the kidney (male rats at 60 and 360 ppm, and female rats at
    360 ppm), liver (males and females at 360 ppm), brain (females at 60
    and 360 ppm), and epididymes (males at 360 ppm).  Increased kidney
    weights were also seen in high-dose males at the end of the recovery
    period.  Macroscopic findings included enlarged kidneys and enlarged
    liver. Histopathological findings also involved the kidneys and the
    liver.  Two main findings occurred in the kidneys.  The first was
    the observation of occasional cells of the proximal convoluted
    tubules showing yellowish discoloration of the cytoplasma (incidence
    in males).  The second was another type of darker and more
    particulate granular and/or clumped pigment in the straight portions
    and occasionally in the proximal convoluted tubules.  In addition,
    male rats given 360 ppm endosulfan also showed yellowish coloured
    protein aggregations in the proximal convoluted tubule and
    intracytoplasmic eosinophilic droplets in the tubules.  During the
    recovery period the discoloration decreased whereas granular pigment
    still persisted.  In the liver, minimal centrilobular enlargement of
    hepatocytes was observed.  The liver change was not seen in the
    recovery group rats.

         The NOAEL is estimated to be 10 ppm in female rats, equivalent
    to 0.75 mg/kg bw/day in the diet.  The lowest effect level is 30 ppm
    (i.e., 2.26 mg/kg bw/day) based upon the findings of increased serum
    phosphorus levels and yellow discolored cells in the renal proximal
    convoluted tubules of 1/20 females.  Both of these changes were
    produced by higher doses of endosulfan in female rats in a
    dose-related fashion.  The NOAEL for male rats is less than 10 ppm
    (lowest dose tested), equivalent to 0.64 mg/kg bw/day in the diet. 
    This is based upon the finding of yellow discolored cells in the
    renal proximal convoluted tubules in 14/20 males (Barnard  et al.
    1985).

         In a dermal toxicity study, endosulfan was applied to the skin
    of male and female Wistar rats (6/sex/dose) at doses of 0, 1, 3, 9,
    and 27 mg/kg bw, and to males only at 81 mg/kg bw for 21
    applications over 30 days.  Toxic effects of the test compound
    occurred at doses of 9 mg/kg bw or more and included deaths, liver
    abnormalities (enlarged parenchymal cells with loss of cytoplasmic
    basophilia, isolated cell necrosis, and frequent mitosis) in
    occasional animals and significantly elevated absolute and relative
    spleen weights in females.  The deaths that were observed in female
    rats were accompanied by tono-clonic convulsions.  The NOAEL for
    subchronic dermal toxicity is 3 mg/kg bw/day (Ebert  et al. 1985a).

         In a similar dermal toxicity study, endosulfan was applied to
    the skin of Wistar rats at doses of 0, 12, 48, 96, and 192 mg/kg bw
    in males and 0, 3, 6, 12, and 48 in females for 21 applications over
    29 days.  In this study, male rats exhibited increases in relative
    kidney weights at doses of 12, 96 and 192 mg/kg bw (attributed by
    the study authors to slightly lower body weights in males), deaths
    in 36 percent of the animals at 192 mg/kg bw and a discrete
    deposition of pigment in a few cells of the proximal convoluted
    tubule in one high dose rat.  In female rats, clinical signs of
    toxicity were first observed at 12 mg/kg bw, and included
    piloerection, salivation and lacrymation, blood from the eyes and
    nose with increasing doses of the chemical, and deaths in 18% of the
    animals due to the tono-clonic convulsions at 48 mg/kg bw.  No other
    treatment-related effects were noted (Ebert  et al. 1985b).

         In an inhalation study, groups of 15 male and 15 female SPF
    Wistar rats were administered 0, 0.0005, 0.0010, and 0.0020 mg
    endosulfan/L of air for 21 exposures (6 hours/day) for 29 days.  Two
    control groups (air and ethanol-PEG 400 vehicle) were used.  Five
    animals/test group were held for a 4-week recovery period after
    receiving the test aerosol.  The NOAEL is 0.001 mg/l of air in males
    (based upon the decrement in weight gain of 12 to 16% seen in
    recovery animals) (Hollander  et al., 1984).

    Dogs

         Endosulfan technical was fed for one year in the daily diet to
    groups of 6 male and 6 female beagle dogs at concentrations of 0, 3,
    10, 30, and 30-60 ppm. The latter dietary level was increased in
    stages from 30 to 45 ppm after 54 days of treatment, and then to
    60 ppm after 106 days of treatment.

         No spontaneous deaths were observed in endosulfan-treated
    animals.  However, 13 dogs were sacrificed  in extremis.  These
    included one male in the 30 ppm dose group after 9 months due to a
    poor overall general condition (resulting from refusal to eat and
    severe purulent mediastinitis), and all high-dose males and females
    after 4 to 5 months due to marked and progressive nervous symptoms.
    These took the form of extreme sensitivity to noise and optic

    stimuli, tonic contractions of muscles in the extremities, face and
    cheeks, and weakened or abolished placing and righting reactions. 
    Similar nervous symptoms (i.e., violent contraction of the abdominal
    muscles and convulsive movements of the cheeks) also occurred in
    most of the surviving dogs in the 30 ppm dose group.

         Food consumption was reduced in male and female dogs at 30 ppm
    (on weeks 1 to 7) and at 3-60 ppm (from week 16 until the time of
    sacrifice).  Similarly, body weight gain was reduced in male dogs at
    30 ppm (from week 43 onward) and in dogs of both sexes at 30-60 ppm
    (from week 10 until the time of sacrifice).  No adverse
    ophthamological findings were observed in treated dogs, and tests to
    examine hearing and dental status were normal.  Standard
    examinations for hematology, clinical chemistry, and urinalysis were
    reported to be normal, as were determinations of cholinesterase
    activity in serum, red cells, and brain.  No treatment-related
    alterations in bromsulphthalein retention of phenolsulphon-pthtalein
    elimination were noted in special tests to assess hepatic and renal
    function, respectively.

         No dose-related changes in organ weight or in gross or
    microscopic pathology were observed.  The only histopatholopical
    findings of interest were the occurrence of acute liver congestion
    in 3/6 high-dose male dogs, and the presence of brown pigment in the
    renal epithelium of 1/6 high-dose male dogs.  The NOAEL in the study
    was 10 ppm, equivalent to 0.65 mg/kg bw/day in the diet for males
    and 0.57 mg/kg bw/day for females (Brunk, 1989).

    Long-term/carcinogenicity studies

    Mice

         Groups of B6C3F1 mice were fed diets containing endosulfan
    technical (98.8% ppm) for 78 weeks.  The time-weighted average (TWA)
    dietary concentrations were 3.5 and 6.9 parts per million (ppm) for
    males (50/dose group) and 2 and 3.9 ppm for females (50/dose group). 
    Twenty mice/sex were used as concurrent controls. The TWA dietary
    concentrations of endosulfan were equivalent to approximately 0.52
    and 1.0 mg/kg bw/day in males, and 0.3 and 0.58 mg/kg bw/day in
    females.

         High early mortality was observed among male mice.  Eleven
    high-dose males and two low-dose males died on week 19.  Survival at
    term was 15% (3/20) in control males, 38% (19/50) in low-dose males,
    and 10% (5/50) in high-dose males.  The deaths in the controls may
    have been due to fighting.  No common cause of death was found for
    the high-dose males.  Survival was high among all female mice (85%
    of control, 94% of low dose, and 96% of high-dose females survived
    to term).  No effects of treatment on body weight or clinical signs
    of toxicity were observed.  No dose-dependent non-neoplastic lesions
    were noted in female mice.  However, the abbreviated lifespan of

    male mice was considered to preclude any accurate analysis of
    late-occurring tumours.  The NOAEL in this study was less than
    3.5 ppm (i.e., 0.25 mg/kg bw/day; lowest dose tested) in male mice
    due to mortality, and 3.9 ppm (i.e., 0.58 mg/kg bw/day; highest dose
    tested) in female mice (NCI, 1978).

         A second chronic feeding study of endosulfan technical (97.9%
    pure) was performed in Hoe:NMRKf(SPF 71) mice in which 60
    animals/sex/dose level received dietary concentrations of 0, 2, 6,
    and 18 pm for 24 months.  An additional 10 mice/sex/dose were
    sacrificed at interim periods of 12 and 18 months, respectively. 
    The administered concentrations were calculated to be equivalent to
    0, 0.28. 0.84, and 2.51 mg/kg bw/day in males and 0, 0.32, 0.097,
    and 2.86 mg/kg bw/day in females.

         Survival was significantly reduced in female mice with 18 ppm
    endosulfan in the main portion of the study (total deaths in females
    = 33/60 or 55% controls, 36/60 or 60% low dose, 38/60 or 63.3% mid
    dose, and 43/60 or 71.7% high dose).  Survival was not affected by
    the test compound in male mice in the main study (total deaths in
    males = 27/60 or 45% controls, 33/60 or 55% low dose, 37/60 or 61.7%
    mid dose, and 35/60 or 58.3% high dose).  There was no
    compound-related effect on mortality in either female or male mice
    at the 12- and 18-month  interim sacrifice periods.  Body weight
    gain was slightly reduced (about 10%) in male mice throughout the
    main study at 18 ppm endosulfan.  Female weights were slightly
    elevated in the 12- and 18-month satellite groups, body weight was
    either slightly increased or remained unchanged from controls in
    animals of all treatment groups.  There were no treatment-related
    effects on food consumption, behavioural or general health
    conditions of the animals, or hematological or clinical chemistry
    parameters.

         Gross and microscopic examination were performed at 12, 18, and
    24 months. Reductions in several organ weights occurred with the
    18 ppm dose level of endosulfan;  these included decreases in the
    weights of the liver (males at 18 months only), and ovaries (females
    at 12 and 18 months).  No treatment-related pathological changes or
    tumours were seen after gross or histopathological examination of
    tissues at 12, 18, or 24 months.  The NOAEL was 6 ppm endosulfan,
    equivalent to 0.84 mg/kg bw/day in male mice and 0.97 mg/kg bw/day
    in female mice (Donaubauer, 1988).

    Rats

         Groups of Osborne-Mendel rats were fed diets containing
    endosulfan (technical grade; 98.8% pure) for 78 weeks.  The TWA
    dietary concentrations were 408 and 952 ppm for males (50/dose
    group) and 223 and 445 ppm for females (50/dose group).  Twenty
    rats/sex were used as concurrent controls.  The TWA dietary

    concentrations of endosulfan were equivalent to approximately 20.4
    and 47.6 mg/kg bw/day in males, and 11.1 and 22.1 mg/kg bw/day in
    females.

         Endosulfan produced early mortality (dose-related) in male
    rats.  By study week 54, 52% of the high-dose males died and by week
    74, 88% were dead.  The high-dose males were sacrificed on week 74. 
    For the low-dose males, only 10/50 (20%) survived to term, and these
    were sacrificed on week 82.  Survival was adequate in control males.
    In the case of female rats, no compound-related deaths occurred (70%
    of control, 60% of low dose, and 50% of high-dose females survived
    to term).  Body weight was also depressed in a dose-related fashion
    in treated male rats from week 22 onward.  At the time of sacrifice,
    body weight was depressed about 25% in both low- and high-dose male
    rats compared to the control male group.  Body weight was not
    markedly changed in female rats.  Several clinical signs of toxicity
    were also seen in treated rats of both sexes; these included hunched
    appearance, reddened and squinted eyes, rough fur, and abdominal
    urine stains.

         Upon histopathological examination, toxic nephropathy was seen
    in both male (0/20 controls, 47/50 low dose, 43/47 high dose) and
    female (0/20 controls, 27/50 low dose, 29/50 high dose) rats.  This
    abnormality was characterized by degenerative changes in the
    proximal convoluted tubules at the corticomedullary junction, with
    cloudy swelling, fatty degeneration and necrosis of the tubular
    epithelium.  Some affected tubules contained hyaline casts and
    enlarged dark-staining regenerative tubular epithelial cells, and
    the kidneys often had inflammatory cell infiltration, fibrotic
    changes, and focal mineralization.  Parathyroid gland hyperplasia
    was also seen in male rats (0/20 controls, 21/40 low dose, 18.47
    high dose) and was attributed to the effects of chronic renal
    failure.  Medial calcification of the blood vessels, perhaps related
    to the parathyroid hyperplasia, occurred frequently in treated male
    rats.  Finally, testicular atrophy occurred in male rats (3/19
    control, 18/47 low dose, 24/47 high dose) and was characterized by
    degeneration and necrosis of the germinal cells lining the
    seminiferous tubules, multinucleated cells (fusion bodies), and
    calcium deposition resulting in aspermatogenesis.

         No conclusions concerning the carcinogenicity of endosulfan
    could be drawn from the bioassay of male rats because of the high
    early mortality and abbreviated lifespans of these animals. 
    Survival in female rats was considered to be sufficient for the
    evaluation of late occurring tumours;  endosulfan was not
    carcinogenic in female rats.  The results of this long-term bioassay
    in rats indicate that the lowest dietary concentrations of
    endosulfan tested in males (408 ppm TWA - equivalent to
    20.4 mg/kg/day) and females (223 ppm TWA - equivalent to
    11.1 mg/kg/day) were toxic and that a NOAEL could not be established
    (NCI, 1978).

         A second chronic feeding study of endosulfan technical (97.1%
    pure) was performed in Charles River Crl:CD(SD)BR rats in which 50
    animals/sex/dose level received dietary concentrations of 0, 3, 7.5,
    15, and 75 ppm for 104 weeks.  An additional 20 rats/sex/dose
    received similar doses of endosulfan and were used to obtain
    hematology, clinical chemistry, and urinalysis data at various
    intervals throughout the study.  Gross and microscopic examinations
    were performed on all animals.  The administered concentrations of
    endosulfan were calculated to be equivalent to 0.1, 0.3, 0.6, and
    2.9 mg/kg bw/day in males and 0.1, 0.4, 0.7, and 3.8 mg/kg bw/day in
    females.

         There were no compound-related effects on mortality, clinical
    signs of toxicity, food and water consumption, or ophthalmoscopic
    parameters.  Adverse findings were mainly observed at the highest
    dose of endosulfan.  These included significant reductions in body
    weight gain over the study in males (-17%) and females (-18%), a
    reduced food utilization efficiency in females, hematological
    changes at week 103 in males (increased platelets, and reductions in
    mean corpuscular volume, total white cells, and lymphocytes), and
    clinical chemistry changes at week 103 in males (increased plasma
    globulin and urinary protein levels, and reduced GPT and serum
    albumin levels).  The reductions in total white cells and
    lymphocytes, and the increased urinary protein levels, were said to
    be within expected limits of variation.  It should be noted that
    body weight gain was also reduced in males given 15 ppm endosulfan
    on study weeks 6 to 18 only (-9% reduction);  this effect, however,
    was not progressive after week 18 and was not considered to be
    toxicologically significant.

         Gross and microscopic examination of all animals in the study
    indicated that the primary target organ for toxicity was the kidney. 
    This was noted from an increased number of enlarged kidneys seen
    grossly for females at 75 ppm (10/70 controls, 18/70 at 3 ppm, 19/70
    at 7.5 ppm, 17/70 at 15 ppm, and 26/70 at 75 ppm), and an elevated
    incidence of marked progressive glomerulonephritis in males at
    75 ppm, 24/70 at 15 ppm, and 30/70 at 75 ppm) and also in females at
    75 ppm (1/70 controls, 6/70 at 3 ppm, 6/70 at 7.5 ppm, 5/70 at
    15 ppm, and 8/70 at 75 ppm).  In addition, blood vessel aneurysms
    were elevated in male rats at 75 ppm (10/70 controls, 6/70 at 3 ppm,
    14/70 at 7.5 ppm, 10/70 at 15 ppm, and 21/70 at 75 ppm).  The
    aneurysms were considered to be possibly related to the renal
    lesions.

         Other observations in the study at 75 ppm in male rats included
    a greater number of enlarged lumbar lymph nodes (14/70 controls,
    10/70 at 3 ppm, 8/70 at 7.5 ppm, 7/70 at 15 ppm, and 19/70 at
    75 ppm), inflammatory cells in the liver (15/70 controls, 16/70 at
    3 ppm, 15/70 at 7.5 ppm, 18/70 at 15 ppm, and 25/70 at 75 ppm), and
    polyarteritis in the pancreas (0/70 controls, 2/70 at 3 ppm, 4/70 at
    7.5 ppm, 1/70 at 15 ppm, and 8/70 at 75 ppm) and testes (16/70

    controls, 15/70 at 3 ppm, 23/70 at 7.5 ppm, 18/70 at 15 ppm, and
    27/70 at 75 ppm).  Finally, the mean weights of the testes were
    reduced at 15 ppm and 75 ppm of endosulfan, but the response was not
    strictly dose-related and was within expected limits of variation.

         Endosulfan was not carcinogenic in either male or female rats. 
    The NOAEL was said to be 15 ppm, equivalent to 0.6 mg/kg bw/day in
    male rats and 0.7 mg/kg bw/day in female rats (Ruckman  et al.
    1988).

    Reproduction studies

    Rats

         Male and female Charles River SD-CD rats were administered
    endosulfan (97% purity) in the diet for two generations at
    concentrations of 0, 3, 15, and 75 ppm (equal to approximately 0.2,
    1.0, and 6.0 mg/kg bw/day).  Females were mated to males on a
    one-to-one basis with 32 males/32 females per dose in the F0
    generation, and 28 males/28 females per dose for the F1 generation. 
    F0 generation rats were administered endosulfan from 6 weeks of age
    through 18 weeks of age, at which time they were mated to produce
    F1a litters.  F1a young were sacrificed 21 days postpartum, and the
    F0 generation remated to produce the F1b litters.  After weaning of
    the F1b pups, the F0 generation rats were sacrificed. The F1b rats
    were continued on their respective diets for approximately 98 days
    prior to mating to produce the F2a litters (which were sacrificed
    after weaning) and the F2b litters (likewise sacrificed after
    weaning).  Endosulfan was administered continuously throughout the
    experiment.

         There were no compound-related effects on mortality, food/water
    consumption, or body weight gain, although F1b females given 3 ppm
    demonstrated slightly lower body weights than controls from week 4
    through 36.  Pregnancy rate, mating performance and gestation period
    for both F0 and F1b generations were unaffected by treatment. 
    Both matings of the F0 generation demonstrated significant
    decreases in litter weight at 75 ppm from day 4 through day 21 but
    not in either F1b mating.  Also, F0 generation litter weights were
    significantly reduced on days 4 to 21 during the second mating at
    15 ppm as well.  Although the trend for cumulative litter loss (%)
    was increased in the first mating at 75 ppm, it was not evident in
    the second mating nor in either mating of the F1b generation.  The
    mean pup weight was unaffected throughout both F0 and F1b matings. 
    Sex ratio appeared to be unaffected throughout the study.

         F0 and F1b generation parents presented evidence of increased
    absolute organ weights for heart, liver, kidneys, and brain at
    75 ppm.  These were not demonstrated in the offspring from either
    mating of these parents.  There was no consistent dose-related
    effect.  Histopathology of F1b adults and F2b weanlings

    demonstrated no compound-related effects.  F0 and F1b generation
    females and offspring were examined for skeletal and visceral
    abnormalities and no consistent dose-related trends were evident,
    except for isolated incidences of microphthalmia (2), anophthalmia
    (2), kinked/missing tail (3), shortened/malformed digits or limbs
    (5), retinal hemorrhage (1) and spina bifida (1).

         There were no dose-related or compound-related effects on
    reproductive performance.  Decreases in litter weight at 15 and
    75 ppm occurred in the F1a and F1b litters; however, this finding
    was not considered to be adverse since the reductions in litter
    weight were marginal and there were no significant corresponding
    reductions in pup weight or litter size.  The visceral and skeletal
    examinations of fetuses for assessing teratogenic effects were
    within normal variation for the strain/species studied.  It is
    considered that endosulfan, at dietary levels up to and including
    75 ppm (approximately 6 mg/kg/day in the diet) caused no adverse
    effects on reproduction in rats in this study (Edwards  et al.
    1984).

         However, as noted below, renal changes occurred in F1b adult
    rats at all of the doses of endosulfan that were tested.  In an
    addendum to the above study, a histological review of the kidneys of
    adult rats from the F1b generation and of weanling rats from the F2b
    generation was reported.  The effort was initiated because yellowish
    discoloration and pigment deposits were noted in renal proximal
    convuluted tubules in rats in a 13-week oral toxicity study of
    endosulfan followed by a 4-week withdrawal period (see Barnard
     et al. 1985).  The histological data obtained indicated the
    presence of yellowish discolored cells in the proximal convoluted
    tubules in F1b adult rats given dietary doses of 3, 15, and 75 ppm
    endosulfan.  The incidences in males were:  0/28 controls, 11/28 at
    3 ppm, 13/28 at 15 ppm, and 28/28 at 75 ppm.  The incidences in
    females were: 0/28 controls, 0/28 at 3 ppm, 0/28 at 15 ppm, and 9/28
    at 75 ppm.  In addition, granular/clumped pigment was also noted at
    a dietary dose of 75 ppm in F1b adult rats.  The incidences at
    75 ppm were 14/28 males and 1/28 females vs. an incidence of 0/28 in
    males and females from the control, 3 ppm, and 15 ppm dose groups. 
    In the F2b generation weanling rats, no comparable renal changes
    were observed following treatment with endosulfan (Offer, 1985). 
    These findings were not considered to be adverse since the yellow
    pigment in kidneys was identified as endosulfan and its metabolites,
    being stored and metabolized in lysosomes prior to excretion.

    Special studies on teratogenicity

    Rats

         Groups of 25 pregnant CD Sprague-Dawley rats were administered
    endosulfan (97.3% purity), via oral gavage, at dose levels of 0,
    0.66, 2, and 6 mg/kg bw/day from days 6 to 19 of gestation.

    (Day 0 = day sperm found).  Ten additional animals were added to the
    high dose (due to mortality) and five to the control groups (due to
    loss of tissue during processing).  On day 20 of gestation, all dams
    were killed by asphyxiation with CO2 and fetuses delivered by
    cesarean section.

         Maternal toxicity was evident in the mid- and high-dose groups,
    expressed by significantly reduced body weight and body weight gain
    during gestation, and by various clinical signs of toxicity (e.g.,
    rats rubbing their faces, alopecia, rough coats, lethargy,
    flaccidity, and hyperactivity).  Several animals died as the result
    of improper gavage tube insertion.  Fetal and embryolethality were
    not apparent in any group and all pregnant animals had viable
    litters.  Mean fetal weight and crown-rump length were significantly
    reduced in the high-dose group, but not in the lower dose groups.  A
    number of external, visceral, and skeletal abnormalities were
    observed in the fetuses in the high-dose group. The most prominent
    effect was a significant increase in the incidence of small fourth
    and unossified fifth sternebrae in the high-dose fetuses.  However,
    there was no clear evidence of a teratogenic effect due to the
    significant maternal toxicity expressed at the same level.  The
    NOAEL for maternal toxicity was 0.66 mg/kg bw/day and that for
    fetotoxicity was 2 mg/kg bw/day by oral gavage (MacKenzie  et al.
    1980a).

         A range-finding study with endosulfan in pregnant CD
    Sprague-Dawley rats (4-6/group) was performed for the purpose of
    setting doses for the above described rat teratology study. 
    Endosulfan was administered by gavage on days 6 to 19 of gestation
    (Day 0 = day sperm found) at doses of 0 (corn oil vehicle), 1.25,
    2.5, 5, 10, 20 and 40 mg/kg bw/day.  Toxic signs in dams included
    reductions in body weight gain at doses of 1.25 mg/kg bw/day and
    greater, various clinically observed adverse effects at doses of
    2.5 mg/kg bw/day and greater (e.g., salivation, piloerection, poor
    muscle tone, lethargy, head-rubbing behaviour, hyperactivity,
    spasticity, tremors and convulsions, and deaths (67 to 100%
    mortality) at 10 mg/kg bw/day and greater.  The changes were dose
    related and most marked at higher doses of endosulfan.  No effects
    on pregnancy maintenance or fetal survival were observed (MacKenzie
     et al. 1980b).

    Rabbits

         Groups of pregnant New Zealand White rabbits (20/group) were
    administered endosulfan (97.3% purity) via oral gavage in corn oil
    at dose levels of 0, 0.3, 0.7, and 1.8 mg/kg bw/day from days 6 to
    28 of gestation (Day 0 = day of mating).  Animals were observed
    throughout the test period for toxic signs. Six additional pregnant
    rabbits were added to the high-dose group due to mortality. On day
    29 of gestation, the dams were asphyxiated with CO2, and the entire
    reproductive tract was removed.

         Maternal toxicity was evident at the high dose, expressed as
    rapid breathing, hyperactivity, convulsions and mortality.  Group
    mean body weights were not affected by treatment.  All pregnant dams
    had viable fetuses, with the exception of one high-dose dam which
    died on test and which had nine late resorptions.  There were no
    compound-related effects on the number of corpora lutea,
    implantation efficiency, litter size, sex ratio, mean fetal length
    or weight, or the number of live/dead or resorbed fetuses.  There
    were no gross external abnormalities and the visceral and skeletal
    examinations revealed no dose-related increase in variations or
    anomalies.  The NOAEL for maternal toxicity was 0.7 mg/kg bw/day. 
    Endosulfan was not teratogenic in rabbits at doses up to and
    including  1.8 mg/kg bw, although maternal toxicity was expressed at
    that level (MacKenzie  et al. 1981a).

         A range-finding study with endosulfan in pregnant New Zealand
    White rabbits (3 to 10/group) was conducted to set doses for the
    above described rabbit teratology study.  Endosulfan was
    administered by gavage on days 6 to 28 of gestation (Day 0 = day of
    mating) at doses of 0 (corn oil), 1, 2, 4, 8, and 12 mg/kg bw/day. 
    Standard observations and necropsy procedures were performed.  Toxic
    signs in dams included deaths at 2 mg/kg bw/day or more (20 to 100%
    mortality) and various clinical adverse effects at 2 mg/kg bw/day or
    more (e.g., hyperactivity, opisthotonos, clonic and tonic
    convulsions, paralysis, tremors, and loss of mobility).  Fetal
    survival appeared to be adversely affected at 2 mg/kg bw or more as
    indicated by an increase in the percent of dead fetuses and a
    decrease in the percent of live fetuses in dams.  No prominent
    effects on weight gain or pregnancy rate occurred (MacKenzie  et al.
    1981b).

    Special study on mutagenicity

         Endosulfan was tested for mutagenic activity in a variety of
    bacterial, yeast, and mammalian cell systems and was negative in
    each test (Table 1).


        TABLE 1.  RESULTS OF MUTAGENICITY STUDIES ON ENDOSULFAN

                                                                                                                          

                                                                CONCENTRATION
    TEST SYSTEM                  TEST OBJECT                    OF ENDOSULFAN       RESULTS      REFERENCE

                                                                                                                          

    Ames Testa                   S.typhmurium                   6-5000 ug/plate     Negative     Shirasu et al. 1978
                                 TA98, TA100, TA1535,
                                 TA1537, TA1538

    Yeast Forward Mutation       Schizosaccharomyces pombe      62.5-500 ug/plate   Negative     Milone 1984a
    Testa

    Yeast Gene-Conversion/       S. cerevisiae                  100-5000 ug/ml      Negative     Milone, 1984b
    DNA Repair Testa             (D4 strain)

    Mouse Lymphoma Assaya        Mouse L51786 TK+/- Cells       6.25-100 ug/ml      Negative     Cifone, 1984a

    DNA Repair Assaya            B. subtilis H17 and            20-2000 ug/disk     Negative     Shirasu et al. 1978
                                 M45 (rec-)

    Unscheduled DNA Synthesis    Primary-Hepatocytes (Rat)      0.102-51 ug/ml      Negative     Cifone, 1984b

    Unscheduled DNA              Human Cell Line A 549          1-1000 ug/ml        Negative     Muller, 1988
    Synthesisa

    Micronucleus Assay           NMRI Mice                      O.2-5 mg/kg,        Negative     Jung et al. 1983
    (Bone Marrow)                                               Orallyb

    Micronucleus Assay           Swiss Albino Male Mice         43.3 mg/kg          Negative     Usha Rani et al. 1980
    (Bone Marrow)                                               Orallyb

    Chromosome Aberration        Cultured Human Lymphocytes     0.05-100 ug/ml      Negative     Milone, 1986
    Testa                        in vitro
                                                                                                                          

    TABLE 1 (CONTD).

                                                                                                                          

                                                                CONCENTRATION
    TEST SYSTEM                  TEST OBJECT                    OF ENDOSULFAN       RESULTS      REFERENCE

                                                                                                                          

    In vivo Cytogenicity         Male Albino Rats               11-55 mg/kg/day     Negative     Dikshith & Datta, 1978
    Test (Bone Marrow                                           Orally for 5 days
    and Spermatogonia)
                                                                                                                          

    a  With and without metbolic activation.
    b  Administered twice orally at an interval of 24 hours.
    

    Special study on neurotoxicity

         The acute delayed neurotoxicity of endosulfan was assessed in
    adult domestic hens.  The study consisted of three parts.  First,
    the LD50 determination was performed using oral (gavage) doses of
    0, 40, 60, 90, 110, and 135 mg/kg bw endosulfan (5 hens/dose group). 
    The observed LD50 was 96 mg/kg bw.  All deaths occurred within 2
    hours of dosing.  Toxic signs observed were subdued behaviour and
    weight loss.  Second, a protection assessment was performed using an
    oral dose of 96 mg/kg bw of endosulfan alone, or in combination with
    either phenobarbital (15 mg/kg bw i.m.), diazepam (2 mg/kg bw p.o.),
    or atropine (10 mg/kg bw i.m.) plus 2-PAM (25 mg/kg bw i.m.). There
    were 5 hens/group.  The results did not provide evidence that any of
    the protections reduced the number of mortalities occurring after
    dosing with endosulfan.  Third, a neurotoxicity assessment was
    performed using groups of 10 hens.  A vehicle control group was
    dosed orally with corn oil, a positive control group with 500 mg/kg
    bw TOCP, and four test groups were each dosed with the LD50
    (96 mg/kg bw) dose of endosulfan.  Dosing was followed by a 21-day
    observation period, a redosing, and a final 21-day observation
    period.  Surviving hens were sacrificed at 42 days. 
    Histopathological examination of brain, spinal cord and peripheral
    nerve tissues were performed on 9 of the 40 animals dosed with
    endosulfan (these were the survivors to 42 days), 10/10 control
    hens, and 10/10 TOCP-treated hens.  The results indicated that
    endosulfan did not produce any clinical signs of neurotoxicity or
    neuropathological (i.e., histological) effects on the central or
    peripheral nervous system.  In contrast, hens treated with TOCP
    displayed ataxia as well as significant axonal degeneration in the
    spinal cord and in the peripheral (tibial) nerve (Roberts  et al.
    1983).

    Special study on skin sensitization

         Endosulfan had no sensitizing potential (delayed contact
    hypersensitivity) in guinea pigs when tested by the Buehler method
    (Jung & Weigand, 1983).

    COMMENTS

         In rats, the absorption of single oral doses of endosulfan
    required 2 or more days;  subsequent urinary and fecal excretion was
    also slow, requiring 5 or more days.  The biotransformation pathways
    involve hydrolysis and oxidation to sulfur-free metabolites and
    polar conjugates, and the formation of various sulfur-containing
    moieties.  Endosulfan preferentially accumulated in the kidney, with
    lower levels in other tissues, the elimination half-time from
    tissues being 3 to 7 days.

         Endosulfan at dietary dose levels of 10 ppm and higher in
    subchronic studies in rats produced yellow pigmentation of renal
    cells.  In contrast, renal cellular pigmentation was not observed in
    subchronic studies in mice at similar dose levels (see reproduction
    studies below).

         In a one-year dietary study in dogs, doses of 30 to 60 ppm
    resulted in early sacrifices due to clinical signs of neurotoxicity
    (e.g., convulsive muscular activity).  Reduced food consumption and
    weight gain also occurred.  In this study, the NOAEL was 10 ppm,
    equal to 0.57 mg/kg bw/day.

         Long-term carcinogenicity studies were performed in mice and
    rats.  Treatment-related increases in neoplasms were not observed. 
    The NOAELs (based on non-neoplastic effects) were 6 ppm (equal to
    0.84 mg/kg bw/day) in mice and 15 ppm (equal to 0.6 mg/kg bw/day) in
    rats.

         A two-generation, 2 litters per generation reproduction study
    was conducted in rats.  Endosulfan was associated with a reduction
    in weight of the F1a and Flb litters at dietary levels of 15 and
    75 ppm, and the presence of yellowish pigment in cells in the renal
    proximal convoluted tubules at dose levels of 3, 15 and 75 ppm in
    F1b adult rats.  The Meeting did not consider these findings to be
    adverse since the reduction in litter weights were marginal and
    occurred in the absence of corresponding reductions in pup weight or
    litter size. The yellow pigment in kidneys was identified as
    endosulfan and its metabolites, being stored and metabolized in
    lysosomes prior to excretion.

         In teratology studies performed in rats and rabbits, NOAELs of
    approximately 0.7 and 1.8 mg/kg bw/day were identified for maternal
    toxicity and fetotoxicity, respectively.  Endosulfan was not
    teratogenic at 6 mg/kg bw/day in rats and 1.8 mg/kg bw/day in
    rabbits, the highest dose levels tested.

         After reviewing all available  in vitro and  in vivo
    short-term tests, the Meeting concluded that there was no evidence
    of genotoxicity.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Mouse:     6 ppm in the diet, equal to 0.84 mg/kg bw/day
         Rat:      15 ppm in the diet, equal to 0.6 mg/kg bw/day
         Dog:      10 ppm in the diet, equal to 0.57 mg/kg bw/day.

    Estimate of acceptable daily intake for humans

         0-0.006 mg/kg bw.

    Studies which will provide information valuable in the continued
    evaluation of the compound

         Observations in humans.

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    Endosulfan-active ingredient technical: 13-week toxicity study in
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    Brunk, R. (1989)  Endosulfan-substance technical:  Testing for
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    Cifone, M.A. (1984a)  Mutagenicity evaluation of HOE 002671-
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    Dikshith, T.S.S., Datta, K. (1978)  Endosulfan: lack of cytogenetic
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    Forschung Toxikologie, Hoechst AG.  Submitted to WHO by Hoechst AG,
    Frankfurt, FRG.

    Lachmann, G.(1987)  Dermal absorption of 14C-Endosulfan in rhesus
    monkeys.  Unpublished Report No. A36685 from Battelle-Institut,
    Frankfurt, FRG.  Submitted to WHO by Hoechst AG, Frankfurt, FRG.

    Leist, K.H., Kramer, P. (1985)  Endosulfan-active ingredient
    technical.  30-day feeding study in adult male Wistar rats. 
    Unpublished Report No. A30776 from Pharma Forschung Toxikologie,
    Hoechst AG.  Submitted to WHO by Hoechst AG, Frankfurt, FRG.

    Leist, K.H., Mayer, D. (1987)  Endosulfan-active ingredient
    technical. 30-day feeding study in adult male Wistar rats. 
    Unpublished Report No. A37112 from Pharma Forschung Toxikologie,
    Hoechst AG.  Submitted to WHO by Hoechst AG, Frankfurt, FRG.

    MacKenzie, K.M., Felton, S.M., Dickie, S.M., Jackson, T.A.,
    Zelinger, D.J. (1981a)  Teratology study with FMC 5462 in rabbits. 
    Unpublished Report No.  A23192 (Raltech Study No. 80070) from
    Raltech Scientific Services, Wisconsin.  Submitted to WHO by Hoechst
    AG, Frankfurt, FRG.

    MacKenzie, K.M., Felton, S.M., Jackson, T.A., Balk, M., Zelinger,
    D.J. (1981b) Range-finding study with FMC 5462 in pregnant rabbits.
    Unpublished Report No.  A37682 (Raltech Study No. 79032) from
    Raltech Scientific Services, Wisconsin.  Submitted to WHO by Hoechst
    AG, Frankfurt, FRG.

    MacKenzie, K.M., Felton, S.M., Jackson, T.A., Balk, M., Zelinger,
    D.J. (1980a) Teratology study with FMC 5462 in rats.  Unpublished
    Report No. A21393 (Raltech Study No. 79041) from Raltech Scientific
    Services, Wisconsin.  Submitted to WHO by Hoechst AG, Frankfurt,
    FRG.

    MacKenzie, K.M., Felton, S.M., Jackson, T.A., Balk, M. (1980b) 
    Range-finding study with FMC 5462 in pregnant rats.  Unpublished
    Report No. A37680 (Raltech Study No. 79031) from Raltech Scientific
    Services, Wisconsin.  Submitted to WHO by Hoechst AG, Frankfurt,
    FRG.

    Milone, M.F. (1984a)  Study of the mutagenic activity  in vitro of
    the compound endosulfan-technical with  Schizosaccharomyces pombe. 
    Unpublished Report No.  A29312 from Instituto di Richerche
    Biomediche "Antoine Marxer", Italy.  Submitted to WHO by Hoechst AG,
    Frankfurt, FRG.

    Milone, M.F. (1984b)  Study of the mutagenic activity  in vitro of
    the compound endosulfan-technical with  Saccharomyces cerevisiae. 
    Unpublished Report No.  A29313 from Instituto di Richerche
    Biomediche "Antoine Marxer", Italy.  Submitted to WHO by Hoechst AG,
    Frankfurt, FRG.

    Milone, M.F. (1986)  Study of the capacity of the test article
    Endosulfan, substance technical, to induce chromosome aberration in
    human lymphocytes cultured in vitro.  Unpublished Report No. A33127
    from Instituto di Richerche Biomediche "Antoine Marxer", Italy. 
    Submitted to WHO by Hoechst AG, Frankfurt, FRG.

    Muller, W. (1988)  Evaluation of Endosulfan-substance, technical in
    the unscheduled DNA synthesis test in mammalian cells in vitro. 
    Unpublished Report No. A38455 from Pharma Research Toxicology and
    Pathology, Hoechst AG.  Submitted to WHO by Hoechst AG, Frankfurt,
    FRG.

    National Cancer Institute (NCI) (1978)  Bioassay of Endosulfan for
    possible carcinogenicity.  Technical Report No. 62 from US
    Department of Health, Education and Welfare, NIH.  Submitted to WHO
    by Hoechst AG, Frankfurt, FRG.

    Offer, J.M. (1985)  Addendum to HST 204: effect of Endosulfan-
    technical on the reproductive function of multiple generations in
    the rat.  Histopathological review of the kidneys in adult rats of
    the F1B generation and in weanling rats of the F2B generation. 
    Unpublished Report No. A30757 (Huntingdon Addendum to Report HST
    204/83768) from Huntingdon Research Centre, England.  Submitted to
    WHO by Hoechst AG, Frankfurt, FRG.

    Roberts, N.L., Phillips, C.N.K., Gopinath, C., Cooke, L., Gibson,
    W.A. (1983)  Acute delayed neurotoxicity study with Endosulfan-
    technical in the domestic hen.  Unpublished Report No. A32153
    (Huntingdon Report No. HST 225/83888) from Huntingdon Research
    Centre, England.  Submitted to WHO by Hoechst AG, Frankfurt, FRG.

    Ruckman, S.A., Waterson, L.A., Crook, D., Gopinath, C., Majeed,
    S.K., Anderson, A., Chanter, D.O. (1988)  Endosulfan, active
    technical ingredient.  Combined chronic toxicity/carcinogenicity
    study (104-week feeding in rats).  Unpublished Report No. HST
    289/881067) from Huntingdon Research Centre, England.  Submitted to
    WHO by Hoechst AG, Frankfurt, FRG.

    Shirasu, Y., Moriya, M., Ohta, T. (1978)  Microbial mutagenicity
    testing on Endosulfan.  Unpublished Report No. A21215 from Institute
    of Environmental Toxicology, Tokyo, Japan.  Submitted to WHO by
    Hoechst AG, Frankfurt, FRG.

    Stumpf, K., ABhauer, J. (1986)  An up-to-date review of the
    environmental safety of Endosulfan.  Unpublished Report No. A35180
    from the Analytical Laboratory, Hoechst AG.  Submitted to WHO by
    Hoechst AG, Frankfurt, FRG.

    Usha Rani, M.V., Reddy, O.S., Reddy, P.P. (1980)  Mutagenicity
    studies involving aldrin, dieldrin, endosulfan, dimethoate,
    phosphamidon, carbaryl and ceresan.   Bull. Environ. Contam.
     Toxicol., 25: 277-282.


    See Also:
       Toxicological Abbreviations
       Endosulfan (EHC 40, 1984)
       Endosulfan (HSG 17, 1988)
       Endosulfan (PIM 576)
       Endosulfan (FAO Meeting Report PL/1965/10/1)
       Endosulfan (FAO/PL:1967/M/11/1)
       Endosulfan (FAO/PL:1968/M/9/1)
       Endosulfan (WHO Pesticide Residues Series 1)
       Endosulfan (WHO Pesticide Residues Series 4)
       Endosulfan (WHO Pesticide Residues Series 5)
       Endosulfan (Pesticide residues in food: 1982 evaluations)
       Endosulfan (JMPR Evaluations 1998 Part II Toxicological)