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    LINDANE

    EXPLANATION

         Lindane was evaluated by JMPR in 1966, 1967, 1968, 1969, 1972,
    1974, 1975, 1977 and 1979 (Annex 1, FAO/WHO 1967a, 1968a, 1970a,
    1974a, 1975a, 1978a and 1980a).  An ADI at 0-0.01 mg/kg bw was
    established by the 1975 JMPR and confirmed in 1977.  Additional
    studies have become available and are reviewed in this monograph
    addendum.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA - TOXICOLOGICAL STUDIES

    Biochemical aspects

    Absorption, distribution and excretion

         The dermal absorption has been investigated in male Charles
    River Crl:CD(SD)BR rats and male Hra:(NZW)SPF rabbits (Bosch, 1987a,
    1987b).  The animals were exposed dermally with a 20% emulsifiable
    concentrate of lindane (unspecified purity to which 14C-lindane had
    been added) at dose levels corresponding to 2, 0.2, or 0.02 mg/cm2,
    respectively.  A significant fraction of the applied dose was found
    in the urine of all three dose levels and increased with time.  In
    rats urinary excretion accounted for 12-16% of the absorbed dose,
    and the corresponding values for rabbits were in the range 29-46%. 
    Much lower levels were found in feces.  Total absorption (24 hrs)
    increased in rats from 5% of the applied amount at the highest dose
    to 28% at the lowest exposure.  For rabbits, penetration is more
    rapid, and absorption at 24 hrs ranged from 27 to 56% of the applied
    dose.  The average absorption rates after 24 hrs were 4 g/cm2hr in
    the rat and 37 g/cm2hr in the rabbit at the highest dose.

         The residue levels following oral and topical application of
    labelled lindane to lactating goats has been investigated (Wilkes
     et al. 1987).  The dermal investigations were designed to simulate
    a total body spray or dip treatment.  The radioactivity in whole
    milk after oral administration reached a plateau value after 2-3
    days corresponding to a total concentration of 0.4 ppm (about 7 ppm
    in the milk fat) at the lower dose of 1 mg/kg bw/day and of about
    3 ppm (about 50 ppm in fat) at the highest exposure level
    (10 mg/kg/day).  Significant activity was also found in the milk
    after dermal administration, corresponding to levels in the range of
    0.1-0.7 ppm in whole milk.

    TOXICOLOGICAL STUDIES

    Acute toxicity

         The 4-hr acute LC50 to a lindane (99.6% pure) aerosol has been
    determined by inhalation exposure of KFM-HAN Wistar rats (outbred,
    SPF-Quality) and found to be about 1,600 mg/m3 mg/L) for both
    sexes.  At toxic doses various signs of central nervous system
    toxicity was observed like sedation, ataxia, excitation (higher
    doses), curved body posture during exposure, paddling movements and
    spasms (Ullmann  et al. 1986).

    Short-term toxicity studies

         The subchronic inhalation toxicity has been studied in male and
    female Wistar Han/Boe (SPF) rats (Oldiges  et al. 1983).  The
    animals were exposed to lindane (99.9%) aerosol at the time weighted
    average concentrations of 0, 0.02, 0,12, 0.60, or 4.54 mg/m3,
    6 hrs/day for 90 days.  An additional "recovery" group exposed to an
    average concentration of 4.8 mg/m3 were kept for an additional 6
    weeks without lindane exposure.  No mortalities occurred during the
    course of the study.  Significant findings were an increase of the
    relative kidney weight in males at the highest dose, a clear effect
    on the kidneys of males at the two highest treatment groups
    described as "cloudy swelling of the tubule epithelia",
    "proliferated" and "dilated renal tubules with protein containing
    contents", as well as induction of cytochrome P-450 in the liver. 
    In the recovery group theses effects were no longer significantly
    increased.

         A recently performed subchronic inhalation study in CD-1 mice
    revealed an unexpected high mortality in females at dose levels
    above 1 mg/m3 (Klonne & Kintigh, 1988).  In this study mortality
    seems to have been the only clearly treatment-related sign of
    toxicity.  Furthermore, the available autopsy data for mice that
    died during the study did not provide any clue as to the cause of
    death.  The significance of these findings are not clear, and the
    surprisingly high inhalation toxicity in mice as compared with rats
    raises the question of intake by other routes of exposure (e.g.,
    additional oral intake from deposits due to whole-body exposure as a
    result of grooming).

         In a 3-month subchronic oral toxicity study (Suter  et al.
    1983) 15 outbred Wistar KFM-HAN rats of each sex were administered
    lindane (99.85% pure) in the diet at a concentration of 0, 0.2, 0.8,
    4.9, 20.0, or 100.0 ppm.  (Based on diet analyses and food intakes
    the mean daily intake of lindane was calculated to be 0.02, 0.06,
    0.29, 1.55, and 7.25 mg/kg/day for males and 0.02, 0.06, 0.33, 1.67,
    and 7.90 mg/kg/day for females).  In addition, each group contained
    5 males and 5 females for study of recovery for a period of 6 weeks. 
    Observations were made for toxic signs, mortality, body weight, food

    consumption, hematology, clinical biochemistry, and urinalysis. 
    Clinical and hematological parameters were assessed on 10
    rats/group/sex before exposure to lindane, during weeks 5 and 12, as
    well as at the end of the recovery period.  The concentrations of
    lindane in liver, kidney, renal fat and brain were investigated at
    weeks 12 (end of administration) and 18 (end of recovery period). 
    Eye examination was performed on 10 animals/group/sex before and
    after completion of the study, or at the end of the recovery period. 
    Complete necropsy and histopathology were performed on rats which
    died during the study as well as on those which were sacrificed at
    the termination of dosing and recovery periods.

         Toxic signs were not observed in any group, and only one animal
    died (4 ppm group) during the fourth week of the recovery period. 
    The lindane administration had no effect on food consumption.  The
    mean body weight gain of all treated animals was generally
    comparable to those of the controls.  However, at the highest dose
    (100 ppm) there is an indication of a growth depression for male
    rats during the recovery period.  Further, there was a dose-related
    increase in absolute as well as relative weights of liver and kidney
    in males which was significantly different from controls at the
    highest dose level.  In females this was true for liver, but was
    less evident for the kidney.  Centrilobular hepatocellular
    hypertrophy was present in both females and males, the incidence and
    severity increasing in a dose-dependent manner.  The values obtained
    for the recovery group indicate that these effects were reversible.

         Diffuse grey foci covering the kidneys was observed for all
    males from the 120 and 100 ppm dose group, a finding which was not
    encountered in the other groups.  In animals from the two highest
    exposure levels, histopathology revealed tubular degeneration of
    dose-dependent severity, characterized by minimal to slight
    unicellular and multicellular necrosis in the proximal convoluted
    tubules, as well as tubular distention with cell debris in the
    straight proximal tubules.  Interstitial nephritis, sometimes
    associated with basophilic proximal tubules was also found in the
    two highest dose groups.  Although hyaline droplets were frequently
    encountered in the epithelial cells of the proximal tubules in rats
    from all dose groups, the incidence and severity was clearly
    dose-dependent.  Males were clearly much more affected with respect
    to these lesions than females.  After recovery, the incidence and
    extent of hyaline droplet formation was reduced to the level found
    in controls and tubular cell degeneration was absent.  However,
    tubular distention, interstitial nephritis as well as basophilic
    tubules still persisted.

    
    TABLE 1.  INCIDENCE OF RENAL LESIONS IN RATS ORALLY EXPOSED TO LINDANE

                                                                                                  
    DOSE (ppm)                              O         0.2       0.8       4.0       20        100
                                                                                                  

    MALES (15 animals/group)


    Observation

    a) macroscopic
    diffuse grey foci                       -          -         -         -         -        15

    b) microscopic
    tubular degeneration                    -          -         -         -         5         6
    tubular casts                           2          1         3         2         3         5
    tubular distension                      -          -         -         1        11        13
    interstitial nephritis                  -          -         2         -        11        15
    basophilic tubules                      -          -         -         1        14        15
    hyaline droplets                       10         11        14        15        15        15

    FEMALES (15 animals/group)

    Observation

    a) macroscopic
    diffuse grey foci                       -          -         -         -         -         -

    b) microscopic
    tubular degeneration                    -          -         1         -         5         5
    tubular casts                           1          1         -         -         3         1
    tubular distension                      -          -         -         -         -         -
    interstitial nephritis                  -          1         -         -         1         1
    basophilic tubules                      -          -         -         -         -         -
    hyaline droplets                        -          2         -         4         2         4
                                                                                                  
    

         Some transient and inconsistent variations in the hematological
    parameters could be noted, but at none of the dose levels could
    significant dose-related effects on the studied hematological
    parameters be attributed to exposure to lindane.

         Determination of enzyme activities in liver homogenates at week
    12 revealed significant increases in the levels of cytochrome P-450
    in females.  In males, the degree of induction was considerably
    less, and not considered statistically significant.  No
    corresponding increase in the rate of N-demethylation was found.

         No significant deviations could be detected by urinalysis.  A
    dose-related increase in plasma and organ levels of lindane was
    found at the termination of the exposure period study.  Among the
    tissues studied (liver, kidney, renal fat, and brain) the lindane
    concentrations were found to be highest in the renal fat. After
    recovery, the levels returned to normal.

         Lindane orally administered at dosages above 0.3 mg/kg bw/day
    to rats caused a reversible induction of cytochrome-P450, reversible
    increases in absolute and relative liver and kidney weights, as well
    as a reversible centrilobular hepatocellular hypertrophy.  At the
    same dose levels, renal tubular toxicity - characterized by hyaline
    droplet induction, tubular degeneration and distention, as well as
    interstitial nephritis with basophilic proximal tubuli - were
    induced, primarily in the male rat.  These lesions were only
    partially reversible.

         In a subchronic oral study of 13 weeks' duration, groups of 10
    Wistar RIV:TOX (C-S) rats/sex were administered lindane (99.8%) in
    the feed at the nominal dose levels of 0, 2, 10, 50, or 250 ppm
    diet, corresponding to an approximate, daily dose of 0, 0.15, 0.75,
    3.8 or 19 mg/kg bw/day (van Velsen  et al. 1984). Body weights were
    recorded on a once weekly basis, and water and food consumption
    monitored during study weeks 1,2,3,6,9, and 13, three times/week. 
    On week 11 blood samples were taken from the retro-orbital venous
    plexus for assessment of major hematological parameters.  During
    week 12, urine was collected for urinalysis, but kidney function
    tests were not performed.  Upon sacrifice, major organs were weighed
    and examined for gross pathological lesions, followed by an
    extensive histopathological investigation.  Blood was sampled again
    for the determination of IgC and IgM immunoglobulins, thyroid
    stimulating hormone (TSH), thyroxine T4, corticosterone,
    triglycerides, urea, glucose, Ca2+, phosphate, as well as the
    levels of plasma aspartate aminotransferase (ASAT) and alanine
    aminotransferase (ALAT).  Liver microsomes were prepared from the
    livers for the determination of the activities of aniline
    hydroxylase (AH), aminopyrene-N-demethylase (APDM),
    ethoxyresorufine-O-deethylase (EROD) as well as of the concentration
    of cytochrome P450.  Myelograms from the left femur were also

    performed.  The results were presented in a summarized form without
    individual data.

         In the 250 ppm group, clear clinical signs of toxicity were
    evident, such as increased mortality, depressed weight gain,
    aggressive behaviour (especially in females).  The relative, as well
    as absolute organ weights of adrenals and liver were significantly
    increased in the high dose females.  The relative weight of the
    thymus in the highest dose group, as well as the absolute and
    relative weights of ovaries were found to be increased at the two
    highest dose levels.  In males, an increase in the absolute and
    relative weights of liver and kidneys is obvious in the 50 ppm dose
    group as well as at 250 ppm.

         Main histopathological findings were centrilobular changes with
    induction of the smooth endoplasmic reticulum, enlargement of
    parenchymal cells, an increase in the number of binucleated cells in
    the liver of both sexes at the highest dose, as well as a
    dose-dependent increase in the incidence of hyaline droplet
    formation in the proximal convoluted tubules of the kidney of males. 
    Cell debris was often found to be present in the lumen of such
    tubuli.  Although these effects were seen already at 10 ppm, they
    were obviously slight at this level.  Vacuolization of the thyroid
    in males, as well as mild hyperkeratosis of the esophagus in both
    sexes exposed to the highest dose was also recorded.

         The only significant hematological effect recorded seems to
    have been a slight, but statistically significant, decrease in the
    number of erythrocytes, coupled with a decrease in hemoglobin
    concentration, at the highest dose in females.  Urinalysis revealed
    no clear abnormal findings.  However, many measurements were
    semi-quantitative and kidney function tests were not included. 
    Triglycerides were increased in a dose-dependent fashion in the
    plasma of male rats, and thyroxin levels increased at 2, 10, 50 ppm
    but not at 250 ppm in this sex.  At the highest dose level a modest
    induction of the aminopyrine-N-demethylase and ethoxyresorufine-O-
    deethylase, but not of aniline hydroxylase or of the levels of
    cytochrome P-450 were recorded.  A NOAEL of 0.75 mg/kg bw/day may be
    set for this study.

         In order to assess the effects of skin exposure, a 13-week
    dermal toxicity study was performed in Charles River rats
    (Crl:(WI)BR strain) at lindane (99.5% purity) dose levels of 0, 10,
    60, or 400 mg/kg bw/day for 13 weeks (Brown, 1988).  A separate
    group was retained for a 6-week recovery period.  There was no
    indication of treatment-related mortality among males, but among the
    treated females there was a total of 18 unscheduled deaths.  In
    addition, there was an unusually large number of replacements of
    female animals during the initial phase of the study.

         At the two highest dose levels, the relative weights of liver
    were increased in both females as well as in males, and those of the
    kidneys in males.  Histopathology revealed a marked increase in
    centrilobular hypertrophy in the liver of lindane-treated rats.  The
    lesion was, however, clearly reversible.  Although there was no
    evidence of dose-related increased in focal necrosis in the liver at
    the interim or terminal sacrifices, such lesions were found in a few
    males from the recovery group in an apparent dose-dependent fashion
    0/10, 1/10, 2/10 and 3/9), indicating a possible dose dependent
    effect of the lindane treatment.  Kidney toxicity was observed in
    treated males, demonstrated by increased intensity of hyaline
    droplet formation in the proximal convoluted tubules, tubular
    degeneration with necrosis, basophilic tubules (both regenerative
    and atrophic), as well as granular casts.  Evidence of tubular
    degeneration with necrosis persisted after the six-week recovery
    period to indicate that the histopathological changes in the rat
    kidney were not fully reversible.  The effects mentioned were
    evident at 60 and 400 mg/kg bw.  Although there was evidence of
    increased intensity of hyaline droplet formation at the lowest dose
    tested (10 mg/kg bw/day), this effect was very slight and this level
    could be considered to be close to a NOAEL for this study.

    Special studies

    Contact sensitization

         Lindane (99.6% pure) has been assessed in the Magnusson-Kligman
    Guinea Pig Maximization Test (Ullmann  et al. 1986b).  No positive
    sensitization reactions were observed, and the reactions of the
    lindane-treated guinea pigs were stated as being the same as those
    of the control (vehicle) treated animals.

    Mutagenicity and related short-term tests

         In Table 2 the results of short-term tests for mutagenicity are
    presented.

         Insignificant DNA-adduct formation in the liver upon  in vivo
    administration of lindane and related isomers to mice has been found
    in two investigations (Iverson  et al. 1984; Sagelsdorff  et al.
    1983).

         In a dominant lethal assay in rats males were given daily doses
    of lindane in olive oil at 1.5, 7.0, or 15.0 mg/kg bw by oral
    intubation for the whole mating period of 8 successive weeks
    (Rohrborn, 1977b).  This protocol was chosen in order to investigate
    if longer-term lindane exposure would have any cumulative action. 
    Eighty males and 633 females of the Ch bb:THOM (SPF) strain were
    used in this study.  There was no significant decrease in the number
    of living implants, nor any increase in dead implants or in
    pre-implantation losses.


        TABLE 2.  RESULTS OF GENOTOXICITY STUDIES WITH LINDANE

                                                                                                                                    

    TEST SYSTEM                TEST OBJECT            CONCENTRATION             PURITY       RESULTS      REFERENCE

                                                                                                                                    

    Reverse mutation           S. typhimurium         93, 139, 208              not          Negative     Rohrborn, 1977
    assay with metabolic       TA1535, TA1538,        ug/plate                  defined
    activation                 TA100, TA98

    Reverse mutation           S. typhimurium         up to 5000                99.5%        Negative     Oesch, 1980
    assay with metabolic       TA1535, TA1538         ug/plate activation
                               TA100, TA98

    Reverse mutation           E. coli                up to 5000                99.5%        Negative     Oesch, 1980
    assay with metabolic       WP2 uvrA               ug/plate activation

    Forward mutation           V79 hamster cells      0.5 to 500 ug/ml          99.8%        Negative     Oesch & Glatt, 1984
    assay with metabolic
    activation

    Forward mutation           V79 hamster cells      0.5 to 500 ug/ml          99.8%        Negative     Oesch & Glatt, 1985
    assay with metabolic
    activation (anaerobic)

    Forward mutation           V79 hamster cells      102 ug/ml                 not          Negative     Tsushimoto et al. 1983
    assay                                                                       specified

    Sex-linked recessive       Drosophila             10 ug/ml                  not          Negative     Benes & Sram, 1969
    lethals                                           injected in               specified
                                                      abdomen

    In vitro chromosome        Chinese hamster        63 ug/ml                  not          Equivocal    Ishidate & Odashima, 1977
    aberrations                fibroblasts                                      specified
                                                                                                                                    

    TABLE 2 (contd.)

                                                                                                                                    

    TEST SYSTEM                TEST OBJECT            CONCENTRATION             PURITY       RESULTS      REFERENCE

                                                                                                                                    

    Unscheduled DNA            SV-40 - transformed    290 ug/ml                 not          Negative     Ahmed et al. 1977
    synthesis with             human fibroblasts                                specified
    metabolic
    activation

    Unscheduled DNA            Primary rat            29 ug/ml                  not          Negative     Probst et al. 1981
    synthesis                  hepacytes                                        specified

    Host mediated assay        S. typhimurium         0.5, 5, 50 mg/kg          not          Weakly       Rohrborn, 1974
    in NMRI mice               TA1535                                           defined      positive

    Bone marrow                Chinese hamster        0.125, 1.25, 12.5         not          Negative     Rohrborn, 1974
    cyto-genetics                                     mg/kg                     defined

    In vivo                    Mouse                  75 mg/kg                  not          Negative     Jenssen & Ramel, 1980
    micro-nucleus                                                               defined
    test

    Dominant lethals           Chbb:THOM rats         1.5, 7.0, 25 mg/kg        99.95%       Negative     Rohrborn, 1977b
                                                      (orally*)

    In vivo sister             CF1 mice               l.3-50.0 mg/kg                         Negative     Guenard et al. 1984
    chromatid exchanges
                                                                                                                                    

    *Males dosed continuously during the whole mating period (8 weeks); see comments below.
    

         Eight-weeks old male Donryu rats given 0.06% A-HCH in the diet
    for 3 weeks exhibited a marked increase in the mitotic rate of live
    parenchymal cells as well as a marked increase in the number of
    tetraploid cells (31% vs. 0% in controls).  The cytogenetic changes
    were similar to those seen after partial hepatectomy (Hitachi
     et al. 1975).  Further, an increase in incidence of GGT positive
    preneoplastic foci were found in the liver of rats administered
    99.9% pure lindane in the feed at 76 ppm for 45 days after
    initiation with diethylnitrosamine (Pereira  et al. 1982).

    Teratology studies

    Rats

         The embryotoxic and teratogenic potential of lindane
    (unspecified purity) has been assessed by daily subcutaneous
    injections at doses of 0, 5, 15, or 30 mg/kg bw from day 6 through
    day 15 of gestation in rats (20 animals/group).  Maternal body
    weights, weight gains, food consumption, appearance and behaviour,
    survival rates, pregnancy rates, and reproduction data including
    offspring viability and development were recorded.  Increased
    mortality and signs of CNS-toxicity (hunched position, anorexia,
    excitability, tremors, convulsions) were observed at the highest
    dose; significant lower mean weight gains at the mid- and high-dose
    groups.  There was no evidence of embryotoxicity or teratogenicity
    at any dose level.

    Rabbits

         Lindale was administered at 0, 5, or 15 mg/kg during gestation
    days 6 to 18 in New Zealand white rabbits (15 animals/group).  One
    high-dose group received 45 mg/kg on days 6- 9 and 30 mg/kg on days
    10-18.  Decreased activity, immobilization of rear quarters, and a
    significant body weight loss were observed at the two highest doses. 
    There was no evidence of teratogenicity and embryotoxic effects were
    observed in rabbits only at the highest dose level (increased number
    of resorptions).  Fourteen of the 15 female rabbits of this group
    died, and fetuses from this group were not examined for
    teratological effects (Hazleton Laboratories, 1976a, 1976b).

    Neurotoxicological studies

         Groups of 15 Wistar rats (average weight 125 g) were fed a
    pelleted standard diet containing alpha, beta,
    gamma-hexachlorocyclohexane or gamma-pentachlorocyclohexane
    (gamma-PCCH) at dose levels of 0, 5.1, 54.2, or 106.2 mg/kg bw/day
    (alpha-HCH), 66.3 or 270.6 mg/kg bw/day (beta-HCH), 1.3, 12.3,
    25.4 mg/kg bw/day (lindane), and 38.0, 394.5, or 782 mg/kg bw/day
    (gamma-PCCH) for 30 days (Muller  et al. 1981).  Before feeding the
    test substances, EEG and motor nerve conduction velocity in the tail
    were recorded.  After termination of the treatment, the same

    parameters were recorded again.  Animals receiving alpha-HCH did not
    exhibit any significant effects on conduction velocity.  beta-HCH
    (both dose levels), lindane (highest dose), as well as gamma-PCCH
    (all dose levels) induced a significant conduction delay. 
    EEG-recordings were unremarkable.

    Effects on humans

         Several reports concerning increased incidences of abnormal
    EEG-findings in workers chronically exposed to lindane have
    previously appeared in the literature (Czgledi-Janko & Avar, 1970;
    Mayersdorf & Israeli, 1974).  In a neurological investigation
    (Baumann  et al. 1981) of 60 workers employed for times ranging
    from 1 to 30 years (geometric mean 7.2 years) in production of
    lindane, no pathological signs with respect to reflexes or
    sensibility, or manual skills tested by means of a tracking task
    were recorded.  Nerve conduction velocity as well as EEG recordings
    were also reported as normal. Exposure was presented for 10 workers
    as serum concentrations for the different isomers (lindane levels
    10-72 g/L).

    COMMENTS

         Following dietary administration of 2.3, 12.3 and 25.4 mg/kg
    bw/day to rats for 30 days, motor nerve conduction velocity in the
    tail was significantly reduced at the top dose level only.

         Two 13-week oral studies have been performed in rats.  In the
    first study dietary concentrations of 0, 0.2, 0.8, 4, 20 and 100 ppm
    lindane were presented to 15 rats/sex/group. Following autopsy of 10
    rats/sex/group, five others were withdrawn from treatment, and
    subsequently sacrificed after a further 6 weeks.  Liver and kidney
    changes were found and the renal tubular changes persisted in males
    after withdrawal from exposure.  The NOAEL was 4 ppm, equal to
    0.29 mg/kg bw/day.

         In the second 13-week study, groups of 10 rats received dietary
    concentrations of 0, 2, 10, 50 or 250 ppm lindane (99.8% purity). 
    Similar effects as observed in the first study were seen in the
    liver and kidney, the effects being negligible at 10 ppm.  No
    hematological effects were seen in males, but in females at 250 ppm
    decreased erythrocyte counts and decreased hemoglobin concentration
    were observed.  Induction of microsomal enzymes of the liver and
    associated changes occurred at the top dose level.  The NOAEL was
    10 ppm, equal to 0.75 mg/kg bw/day.

         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

         Rat:      10 ppm in the diet, equal to 0.75 mg/kg bw/day
         Dog:      l.6 mg/kg bw/day.

    Estimate of acceptable daily intake for humans

         0-0.008 mg/kg bw.

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

         Observations in humans.

    REFERENCES

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

    Baumann, K., Behling, K., Brassow, H.-L. & Stapel, K. (1981) 
    Occupational exposure to hexachlorocyclohexane III. 
    Neurophysiological findings and neuromuscular function in
    chronically exposed workers.  Int. Arch. Occup.   Environ. Health,
    48: 165-172.

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

    Bosch, A.L. (1987a)  Dermal absorption of 14C-lindane in male rats. 
    Report No. 6188-103 from Hazleton Laboratories America, Inc.,
    Madison, USA.  Submitted to WHO by CIEL (unpublished).

    Bosch, A.L. (1987b)  Dermal absorption of 14C-lindane in male
    rabbits.  Report No. 6188-104 from Hazleton Laboratories America,
    Inc., Madison, USA.  Submitted to WHO by CIEL (unpublished).

    Brown, D. (1988)  Lindane: 13-week dermal toxicity study (with
    interim kill and recovery period) in the rat.  HUK Project
    No. 580/2.  Report from Hazleton UK, Harrogate, North Yorkshire,
    England.  Submitted to WHO by Rhne-Poulenc (unpublished).

    Czgledi-Janko, G. & Avar, P. (1970)  Occupational exposure to
    lindane: Clinical and laboratory findings.   Brit. J. Ind. Med.,
    27: 283-286.

    Guenard, J., Eichelberger, H.P. & Terrier, Ch. (1984)   In vivo
    sister chromatid exchange assay in CF1-mouse bone marrow cells
    with lindane (oral application). Report No. 025705 from the Research
    and Consulting Co., Itingen, Switzerland.  Submitted to WHO by CIEL
    (unpublished).

    Guenard, J., Eichelberger, H.P. & Terrier, Ch. (1984)   In vivo
    sister chromatid exchange assay in CF1-mouse bone marrow cells with
    lindane (intraperitoneal injection).  Report No. 025716 from the
    Research and Consulting Co., Itingen, Switzerland.  Submitted to WHO
    by CIEL (unpublished).

    Hazleton Laboratories America Inc. (1976)  Teratology studies in
    rats - Lindane (gamma benzene hexachloride, USP).  Report submitted
    to WHO by CIEL (unpublished).

    Hazleton Laboratories America Inc. (1976b)  Teratology studies in
    rabbits - Lindane (gamma benzene hexachloride, USP).  Report
    submitted to WHO by CIEL (unpublished).

    Hitachi, M., Yamada, K.& Takayama, S. (1975)  Cytologic changes
    induced in rat liver cells by short-term exposure to chemical
    substances.   J. Natl. Cancer Inst., 54: 1245-1247.

    Ishidate, M. & Odashima, S. (1977)  Chromosome tests with 134
    compounds on Chinese hamster cells  in vitro - A screening for
    chemical carcinogens.  Mutat. Res., 48: 337-354.

    Iverson, F., Ryan, J.J., Lizotte, R. & Hierlihy, S.L. (1984)
     In vivo and  in vitro binding of alpha- and
    gamma-hexachlorocyclohexane to mouse liver macromolecules. 
     Toxicology Letters, 20: 331-335.

    Jenssen, D. & Ramel, C. (1980)  The micronucleus test as part of a
    short-term mutagenicity test program for the prediction of
    carcinogenicity evaluated by 143 agents tested.   Mut. Res., 75:
    292-202.

    Klonne, D.R. & Kintigh, W.J. (1988)  Lindane technical fourteen-week
    dust aerosol inhalation study in mice. Bushy Run Research Center,
    Export, PA, USA, Project BBRC# 51/524, October 7, 1988.  Report
    submitted by Rhne-Poulenc to WHO (unpublished).

    Mayersdorf, A. & Israeli, R. (1974)  Toxic effects of chlorinated
    hydrocarbon insecticides on the human electoencephalogram.   Arch.
     Environ. Health, 28: 159-163.

    Muller, D., Klepel, H., Macholz, R.M., Lewerenz, H.-J. & Engst, R.
    (1981)  Electroneurophysiological studies on neurotoxic effects of
    hexachlorocyclohexane isomers and gamma-pentachlorocyclohexene. 
     Bull. Environm. Contam. Toxicol., 27: 704-706.

    Oesch, F. (1980)  Bacterial mutagenicity tests of lindane with mouse
    liver preparations as metabolizing systems. Celamerck Report
    No. 111AA-457-006 from the University of Mainz, FRG.  Submitted to
    WHO by CIEL (unpublished).

    Oesch, F. & Glatt, H.R. (1984)  Mammalian cell (V79) mutagenicity
    test on lindane. Celamerck Report No. 111AC-457-019.  Report No. SP
    540-VT21 from the University of Mainz, Mainz, FRG.  Submitted to WHO
    by CIEL (unpublished).

    Oesch, F. & Glatt, H.R. (1985)  Mammalian cell (V79) mutagenicity
    test on lindane using anaerobic exposure conditions. Celamerck
    Report No. 111AA-457-023. Report No. SP 540-VT21b from the
    University of Mainz, Mainz, FRG.  Submitted to WHO by CIEL
    (unpublished).

    Oldiges, H., Heertel, R., Krdel, W., Hochrainer, D. & Mohr, U.
    (1983)  90-day inhalation study with lindane.  Report No. 104264
    from Frauenhofer Institut fr Toxikologie, Schmallenberg, FRG. 
    Submitted to WHO by CIEL.

    Pereira, N.A., Herren, S.L., Britt, A.L.& Khoury, M.M. (1982)  Sex
    differences in enhancement of GGT-ase-positive foci by
    hexachlorobenzene and lindane in rat liver.   Cancer Letters, 15:
    95-101.

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

    Rohrborn, G. (1974)  Cytogenetic analysis of bone marrow of Chinese
    hamster  (Cricetulus griseus) after sub-acute treatment with
    lindane.  Celamarck document No. 111AA-457-08.  Report dated 29 July
    1976.  Submitted to WHO by CIEL (unpublished).

    Rohrborn, G. (1977)  Mutagenicity of lindane in the
     Salmonella/microsome test: additional tests with
    sub-bacteriostatic doses.  Celamarck document No. 111AA-457-16 dated
    6 January 1977.  Submitted to WHO by CIEL (unpublished).

    Rohrborn, G. (1977b)  Dominant lethal test after treatment of male
    rats with lindane.  Celamerck document No. 111AA-457-04.  Report
    dated 25 January 1977.  Submitted to WHO by CIEL (unpublished).

    Sagelsdorff, P., Lutz, W.K. & Schlatter, C. (1983)  The relevance of
    covalent binding to mouse liver DNA to the carcinogenic action of
    hexachlorocyclohexane -isomers.   Carcinogenesis, 4: 1267-1273.

    Suter, P., Horst, K. & Luetkarmeier, H. (1983)  Three months
    toxicity study in rats with lindane.  Report No. 005220 from the
    Research and Consulting Co., Itingen, Switzerland.  Submitted to WHO
    by CIEL (unpublished).

    Tsushimoto, G., Chang, C.C., Trosko, J.E. & Matsumura, F. (1983) 
    Cytotoxic, mutagenic and cell- all communication inhibitory
    properties of DDT, lindane and chlordane on Chinese hamster cells
     in vitro.  Arch. Environ. Contam. Toxicol., 12: 721-730.

    Ullmann, L., Mohler, H. & Gembardt, Chr. (1986)  4-hour acute
    aerosol inhalation toxicity study with lindane in rats.  Report
    No. 061637 from the Research and Consulting Co., Itingen,
    Switzerland.  Submitted to WHO by CIEL (unpublished).

    Ullmann, L., Claire, R. & Bognar, G. (1986b) Test for delayed
    contact hypersensitivity in the albino guinea pig with lindane
    (maximization test).  Report No. 061650 from the Research and
    Consulting Co., Itingen, Switzerland.  Submitted to WHO by CIEL
    (unpublished).

    van Velsen, F.L., Franken, N.A.M., van Leeuwen, F.X.R. & Loeber,
    J.G. (1984)  Semichronisch oraal toxiciteitsonderzoek van gamma-HCH
    om de rat.  Report No. 618209 001 from Rijksinstituut voor
    Volksgezondheid en Milieuhygien, Bilthoven, The Netherlands. 
    Submitted to WHO (unpublished).

    Wilkes, L.C., Mulkey, N.S., Hallenbeck, S.A., Piznik, M.S. & Wargo,
    J.P. (1987) Metabolism study of 14C-lindane fed or topically
    applied to lactating goats.  Report No. ADC 957 from Analytical
    Development Corporation, Monument, USA.  Submitted to WHO by CIEL
    (unpublished).


    See Also:
       Toxicological Abbreviations
       Lindane (EHC 124, 1991)
       Lindane (HSG 54, 1991)
       Lindane (ICSC)
       Lindane (PIM 859)
       Lindane (FAO Meeting Report PL/1965/10/1)
       Lindane (FAO/PL:1967/M/11/1)
       Lindane (JMPR Evaluations 2002 Part II Toxicological)
       Lindane (FAO/PL:1968/M/9/1)
       Lindane (FAO/PL:1969/M/17/1)
       Lindane (WHO Pesticide Residues Series 3)
       Lindane (WHO Pesticide Residues Series 4)
       Lindane (WHO Pesticide Residues Series 5)
       Lindane (Pesticide residues in food: 1977 evaluations)
       Lindane (Pesticide residues in food: 1978 evaluations)
       Lindane (Pesticide residues in food: 1979 evaluations)
       Lindane (Pesticide residues in food: 1997 evaluations Part II Toxicological & Environmental)