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 µg/cm2hr in
the rat and 37 µg/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 µg/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.
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