LINDANE JMPR 1973
Explanation
Lindane was evaluated by the Joint Meeting in 1965 (FAO/WHO,
1965b), 1966 as gamma-BHC (FAO/WHO, 1967b), 1967 (FAO/WHO, 1968b),
1968 (FAO/WHO, 1969b), 1969 (FAO/WHO, 70b) and in 1970 (FAO/WHO,
1972b). Further information has since become available and is
summarized in the following monograph addendum.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
Biochemical aspects
Biotransformation
The metabolic fate of lindane in mammals has been examined by
several authors who conclude that the metabolic pathway is probably
more complex than previously described. Previously unidentified
metabolites from rat urine have been identified as 3,4-dichlorophenol,
2,4,6-trichlorophonol, 2,3,4,5 -and 2,3,4,1,6-tetrachlorophenol,
2,3,4,5,6-pentachloro -2- cyclohexen -1 - ol. These investigators
suggest that dehydrochlorination may not be a significant pathway in
mammals. (Chadwick and Freal, 1972; Karapally et al., 1973).
One author did not find the cyclohexenol metabolite in rabbit but
isolated the chlorophenols and chlorobenzones mentioned above as well
as several other organosoluble products (Karapally et al., 1973).
Effects on enzymes and other biochemical parameters
A study was carried out on the effect of lindane on lactate
dehydrogenase and its isoenzymatic spectrum in blood serum and liver
of rats (Alekbina and Khaikina, 1972). Lindane was administered at 1.7
mg/kg for over 180 days. A decrease in the total LDH in the serum
accompanied by a simultaneous change in the isoenzyme spectrum, e.g.
declining LHD1 and rising LDH4. The changes in the isoenzyme
spectrum of the liver were as follows: an increase in the activity of
LDH1, LDH2, LDH3, LDH4 and a decrease in LDH5 with reduced total
LDH activity in the liver. The effect of lindane on hexobarbital
sleeping time in rats was investigated by Koldomin-Hedman et al.,
1972. Pre-treatment with lindane shortened the sleeping time both from
a single intraperitoneal or from short-term feeding tests. The lowest
effective single dose was 15 mg/kg i.p. and 0.5 ppm lindane in the
diet for one month. 100 ppm in the diet for one month increased the
liver microsomal content of cytochrome P450 25% as compared with the
controls.
TOXICOLOGICAL STUDIES
Special studies on mutagenicity
In a host-mediated assay, lindane was administered orally (100
mg/kg) to a group of eight male mice and intramuscularly (12 or 25
mg/kg) to groups of 12 mice. At the same time an indicator organism
(Salmonella typhimurium C-42) was injected intraperitoneally as an
indicator. After three hours the animals were sacrificed and the
micro-organism extracted from the abdominal cavity and examined for
back mutations. The mutation quotient or the frequency of mutations in
the treated animals as compared to the frequency in the control were
sufficiently low to indicate that in this experiment lindane would
produce no definite mutagenic effects. No evidence of mutagenicity has
been reported with lindane based on host-mediated assays using
Salmonella or Serratia species as test organisms (Propping et al.,
1973; Buselmaier et al., 1972).
Groups of 10 male mice were administered single doses of 0, 12.5,
25 and 50 mg/kg of lindane by intraperitoneal administration. The day
after administration each male was mated with three females for seven
days in eight successive series in a "domininant lethal test".
Although several animals in the highest dose group died there were no
differences in the number of pregnant females, the number of embryos
per mother and the mutation indices. In this experiment lindane was
found to produce no dominant mutations (Frohberg and Bauer, 1972b).
Special studies on reproduction
Groups of Charles River CD-rats (10 male and 20 female per group)
were fed diets containing lindane at 0, 25, 50 and 100 ppm for 60 days
prior to mating and the initiation of a standard two-litter,
three-generation reproduction study. Over the course of three
generations, there was no consistent effect of lindane on any of the
parameters measured for the parent animals nor for the parameters
measured with regard to the progeny. Lindane had no effect on litter
size, breeding rate, and growth of pups in all generations. No
deformities were observed. The liver weights of young animals of both
sexes from the 100 ppm group were significantly increased. In the
other two groups, both sexes showed increased relative liver weights
which were significant only in females. Histological examination
of the livers of these animals showed that there was a greater
frequency of enlarged hepatocytes in the livers of animals in the two
highest dose levels with no other histological change evident. Lindane
at 100 ppm does not appear to affect reproduction in the rat. (Palmer
et al., 1972).
Lindane concentrations in tissues of the F2-A and F2-B
generations were measured. Lindane concentrations in fat, liver and
brain were increased over controls at all dietary levels, Brain and
liver concentrations in the F2A generation were related to dietary
concentrations: 0.14. 0.40, 1.07 and 1.17 ppm for liver and 0.17,
1.45, 1.92, and 3.30 ppm for brain for the groups fed 0, 25, 50 and
100 ppm in the diet respectively. Fat levels for the F2A generation
were highest in the 50 ppm group, 18.2 ppm compared to 1.2 ppm in
controls. In the F3A generation weanlings, only fat residues exceeded
controls at all three dietary levels, while at the 100 ppm dietary
level residues in liver and brain were also increased (Burrows and
Multen. 1971),
Groups of 13 pregnant rabbits were administered lindane orally at
doses of 0, 5, 10 and 20 mg/kg from day six to 18 of pregnancy. During
the dosing period lindane was found to have an effect on the parent
animals at all dosages. The pregnancy rate was unaffected although a
statistically significant increase in pre-implantation loss occurred
at 20 mg/kg. Litter parameters (litter size, fetal loss, litter and
mean pup weights) were similar to the control. Incidence of
malformations were unaffected by lindane although at 20 mg/kg there
was a statistically significant increase in 13 ribbed pups while at 5
mg/kg there was a significant decrease in this occurrence. Lindane
does not appear to have a significant effect on pregnancy in the
rabbit, (Palmer and Neuff, 1971).
Lindane fed to female rats for 90 days at 5 mg/kg had no effect
on reproduction. When fed at 10 mg/kg for 138 days a reduction of
litter size and fecundity was observed and residues were found in the
embryo. No teratogenic effects were noted (Trifonova et al., 1970).
Special studies on teratogenicity
Groups of pregnant mice (25 mice/group were orally administered
lindane suspended in aqueous CMC daily from day six to 15 of gestation
at dosage levels of 0, 12, 30 and 60 mg/kg. A similar series of
animals were treated with lindane from day 11 to 13 of gestation.
Lindane at 60 mg/kg was found to be toxic to the adult mice with a
significant number of mice in the group dying before term. In the high
treatment groups the number of abortions was significantly increased
compared to the control group and the mean number of fetuses as well
as the mean fetal weight was reduced. There was no apparent
relationship between the administration of lindane and malformations
observed in the study. It was concluded that lindane did not show any
teratogenic effects following oral administration although there was
considerable adult toxicity in the higher groups (Frohberg and Bauer,
1972a).
Groups of pregnant mice (25 mice/group) were administered lindane
in daily doses of 6 mg/kg from day 6 to 15 of gestation by
subcutaneous injection. A similar grouping was treated from day 11 to
13 of gestation. No deformed fetuses were observed and the mean number
of implantations and living embryos and the rate of abortions and
resorptions were within the normal biological limits. In that group
treated for 10 days the number of runts were significantly increased
compared to the control and to the group treated for three days.
Under the present test conditions lindane did not appear to show any
teratogenic or toxic effects in mice at a subcutaneous dosage level of
6 mg/kg per day (Frohberg and Bauer, 1972b).
Groups of 20 female CFY-rats were orally administered lindane at
dosage rates of 0, 5, 10 and 20 mg/kg from day 6 to 15 of pregnancy.
Females treated at 10 and 20 mg/kg showed decreased food consumption
and weight gain during the dosing period. Mortality was evident at 20
mg/kg. Pregnancy rate, as assessed by the number of pregnant animals
and pre-implantation loss, was unaffected by lindane. Litter size,
fetal loss and number and mean weight of pups was not adversely
affected by lindane at any of the dosage levels. There were no major
abnormalities in any of the animals receiving lindane. although
statistically significant differences in minor skeletal abnormalities
(an extra rib) was evident at 20 mg/kg. Supplementary ribs was the
only significant feature of this test resulting from the
administration of lindane. The teratogenic potential of lindane is not
great as the incidence of this skeletal abnormality falls within the
normal biological variation in this strain of rat. In this experiment,
lindane did not have a significant effect on pregnancy in rats (Palmer
and Lovell, 1971).
Short-term studies
Mouse. Groups of 20 male mice (ICR/JCL, strain) were fed HCH and the
isomers of HCH (alpha, beta, gamma, delta, epsilon,) and chlorsphenols
for six months at 600 ppm in the diet. (Goto et al., 1972a and b).
Enlarged livers were observed in all groups. Tumours were evident with
alpha, beta, delta, epsilon and gamma-BHC. Hepatoma O-1 was found in
all groups with a high incidence of malignant hepatomas observed in
those animals for the isomers only. HCH did not induce malignancies.
Rat. Administration of lindane to rats in the drinking-water for
2-12 months at 1 ppm resulted in ultra-structural changes in the liver
(Watari, 1973).
Rat and mouse. Nagasaki et al. (1972a and b) reported that
(gamma-BHC) lindane was carcinogenic in the liver of rats and less so
in mice. In mice isomers of HCH were fed for 24 weeks at 100, 250 and
500 ppm in the diet. Increased liver weight was observed in all
groups. Hepatoma was seen only in lindane-treated mice at 250 and 500
ppm. Rats were fed identical diet at 250, 500 and 1000 ppm for 24 and
48 weeks. At 24 weeks only enlarged livers were noted while at 48
weeks 1 of 7 rats showed hepatoma at 1000 ppm with gamma-BHC, 3/7
showed hypertrophic nodules without malignancy. Other isomers also
induced nodular formation.
Rabbit. Lindane was administered orally to rabbits twice weekly at
6.25 mg/kg for six months (Takahama et al.t 1972). Liver weight
increases were observed but not kidney weight as observed with DOT and
endrin in a similar test. No effects were noted on growth.
Dog. Two groups of dogs (four males and four females, three of each
sex were controls) were fed 200 ppm lindane in their diet for 32
weeks. One animal died after a fit of convulsions on the ninety-fourth
day while another animal had a short lasting convulsion on day 54.
Electroencephalograms (EEG) were recorded at the conclusion of the
study. Changes were observed in the sleeping patterns of the dosed
dogs. In general the dosed animals had more activity (higher aptitude)
and a larger low frequency (2-4 cycles) second component than the
control animals. The sleeping EEG in the treated animals showed an
increased delta-activity in comparison with control whereas the awake
EEG activities did not differ from normal. There was 11 increased
liver weight in animals on 200 ppm and the liver appeared to be
enlarged and friable on gross autopsy, No morphological change was
observed when histological examination was performed. There were no
significant changes in urinalysis or haematological values although
SAP levels were significantly increased throughout the test and SGPT
and SGOT were increased at 11 weeks but normal at the end of the
study. Several changes observed at 10 weeks were not evident at the
end of the study, i.e, serum sodium level reduced and urinary reducing
substances (Noel et al., 1971).
Groups of beagle dogs (four males and four females per group)
were fed lindane in the diet at levels of 0, 25, 50 and 100 ppm for
two years. Isolated convulsive episodes were observed in one control
animal and two animals receiving the low dose of lindane. One of the
two animals at 25 ppm died on day 613 probably preceded by a
convulsive episode. There were no convulsions observed at higher
levels of exposure. EEG examination with awake animals showed no
differences from those of the controls while EEGs from the sleeping
animals showed slight evidence of irregular slow waves superimposed on
the normal sleep pattern, At the conclusion of this study, SAP
activity was slightly increased in animals at 100 ppm. No adverse
effects were observed with regard to weight gain, urinalysis,
haematology, and ophthalmological examinations. Liver function tests
(BSP retention) showed no functional disturbance. At autopsy no
irregularities were found in the high dosed animals except for
somewhat darker coloration and a friable consistency of the liver.
Histological examination showed no morphological irregularity
corresponding to the gross observations.
The measured mean daily dosages and the tissue concentrations of
lindane determined in two dogs at the termination of the study were as
follows:
Diet Daily intake Tissue Levels (ppm)
(ppm) (mg/kg) Fat Liver Brain
0 (control) - 0.05 0.05 0.09
25 0.83 12.1 0.90 0.38
50 1.60 23.4 0.63 0.41
100 2.92 66.8 2.9 1.35
The apparent no-effect level in this study based upon gross
morphological changes in the liver and SAP elevations correspond to 50
ppm in the diet which was calculated to be 1.6 mg/kg per day based
upon actual food consumption data (Rivett et al., 1971).
Long-term studies
Mouse. Groups of mice (30 male and 30 female per group) were fed
lindane in the diet at levels of 0 and 400 ppm. (Beta BHC was also fed
at 200 ppm to another group) for two years. During the first three
months 10% of the males and 20% of the females died (12% of the males
and 25% of the females fed beta-BHC died). Liver enlargement with
nodular surfaces were described with both isomers as hyperplastic
nodules and in some cases neoplasms. There were no incidents of
neoplasms in nun hepatic tissues (Thorpe and Walker, 1973).
Observations in man
Milby and Samuels (1971) reported the results of clinical
biochemistry measurements on individuals occupationally exposed to
lindane and on individuals without occupational exposure. The mean
blood lindane levels of the exposed group was 11.9 parts per billion
(ppb) compared with 0.1 ppb for the unexposed group. With the
exception of the blood lindane values for the exposed groups, all
values were within the normal range for the general population.
However, statistically significant differences (P<0.01) were detected
between the two groups. These were: higher reticulocyte, total white
blood cells and polymorphonuclear counts and lower blood creatinine
levels for the lindane exposed group. No significant differences were
noted in: blood uric acid levels, alkaline phosphatase levels,
platelets, haematocrit, haemoglobin, lymphocytes, eosinophils, or
monocytes. The authors concluded that under conditions of their study
lindane did not produce haematologic disorders on the basis of a toxic
suppression of haematopoesis, and that the health significance of the
differences observed is unclear. They did not rule out the possibility
that lindane might produce impaired haematopoosis on an idiosyncratic
basis, which would not likely be detected with a study of this type.
Selby et al. (1969) reported a comparison of chlorinated
hydrocarbon pesticide residues in maternal blood and placental
tissues. Fifty-three hospitalized women in Louisiana were studied.
Detectable levels of lindane were found in 89% of the placenta samples
and 88% of the maternal blood. The mean concentration in maternal
blood was 0.39 ppb (range 0.1-6.0 ppb) and in placentas was 1.10 ppb
(range 0.1-6.0). The placenta/blood ratio for the paired samples was
2.8. In the placenta a concentration of 0.97 ppb in the fresh tissue
was equivalent to 295.9 ppb on a lipid basis.
Individuals occupationally exposed to lindane in Sweden were
examined for liver function and blood abnormalities. There were no
adverse effects attributable to lindane which was present in levels up
to 87 ng/ml plasma (Kolomodin-Hedman, 1973).
Thirty-five male workers having an occupational exposure to
lindane have been examined for neurological status (EEG) and lindane
level in the blood (GLC). The duration of the exposure varied from a
half to two years. In half of the subjects under study the blood level
of lindane did not exceed that of the controls (0.003-0.017 ppm).
Slight changes in the EEG and the neurological status of 15 subjects
were associated with a blood level of 0.02-0.34 ppm. The frequency of
clinical symptoms and changes in the EEG increase in subjects with a
lindane blood level above 0.02 ppm. (Czegledi-Janko and Avar, 1970).
The level of lindane in the fat tissue of the general population
in Bulgaria was found to be 0.24 ppm, while that of ß BHC was 0.52 ppm
(Kaloyanova et al., 1972).
Comments
Lindane was evaluated at the 1970 Joint Meeting and an ADI of
0.0125 was reconfirmed. Information reported to be in progress at that
time has been completed and was reviewed. In a two-year study in dogs,
hepatic lesions were evident at 100 ppm. A no-effect level was
considered to be 50 ppm in the diet corresponding to an intake of 1.6
mg/kg per day. Epileptiform convulsions seen in the control and one
test group were thought to be examples of hereditary canine epilepsy
and not due to lindane. Lindane at 100 ppm in the diet did not affect
reproduction in the rat although at 50 ppm and above hepatic lesions
were observed in the F3B generation. Lindane had no effect upon
maintenance of pregnancy in the rabbit, rat or mouse and two tests
currently used to evaluate the mutagenic potential were negative. No
further data have become available concerning the occurrence of blood
dyscrasias in humans exposed to lindane. It was noted that with mice
at high dietary intake, liver enlargement and nodular formation was
evident. Since the no-effect level for this effect on mouse liver has
not been established and since neither of the two long-term studies in
rats is fully adequate, the Meeting considered that a further
long-term carcinogenicity study was now required.
TOXICOLOGICAL EVALUATION
Level causing no toxicological effect
Rat: 25 ppm in the diet equivalent to 1.25 mg/kg bw
Dog: 1.6 mg/kg bw/day
Estimate of temporary acceptable daily intake for man
0-0.01 mg/kg bw
RESIDUES IN FOOD AND THEIR EVALUATION
Use pattern
In 1973, a book entitled "LINDANE, Monograph of an Insecticide"
was published (Ulmann, 1972) (in German, French, and English) which
summarizes the use patterns, tolerances (if any), and regulatory
procedures for lindane of virtually every country in the world. Prom
these summaries, and also data received from the governments of Canada
and France, it is clear that, in addition to its uses on agricultural
crops, lindane is needed and used for ectoparasite control on animals
by direct application (sprays, dips, oilers, back rubbers, smears, and
dusts).
Residues resulting from supervised trials
When pigs were sprayed twice with 0.5% solution of lindane,
residues in backfat averaged 5.2 ppm (range 4.2-6.0 ppm). This spray
treatment was 10 times the legally permitted dose and last treatment
was 10 days prior to slaughter instead of the required 30 days. Since
fat accumulation of most organochlorine pesticides is linearly dose
related, it can be calculated that fat residues under good
agricultural practice would not exceed 0.5 ppm (Davy et al., 1969).
Lindane (0.1 ppm) was added to the ration of laying hens and fed
for six weeks. Residues in eggs (yolks) reached a maximum of 0.056 ppm
after seven weeks, then fell to less than 0.001 ppm within five weeks
after feeding ceased. Charcoal in the diet had no effect on residues
and the residues had no effect on eggshell thickness or quality.
Lindane residues reached a maximum of 0.074 ppm in the abdominal fat
of the hens after six weeks on the treated diet, then fell to below
detectable levels in three weeks after the pesticide was removed from
the diet (Foster, et al., 1972).
Residues of lindane in whole milk and milk products from cows fed
either 1.4 mg/day or 4.2 mg/day in their ration were reported by Smart
et al., 1972. Unfortunately, the residue data were not corrected to a
standard butterfat content (usually 4%) or reported on a fat basis and
therefore cannot be used for estimating regulatory levels.
In field trials in Japan, rice and Chinese cabbage were treated
with various dosages (sometimes excessive) and numbers of applications
of lindane and samples of raw rice grains and cabbage were analysed at
various time intervals after application (Kanazawa, 1973). In rice
grains residues averaged 0.032 ppm (range 0.007-0.286 ppm); in cabbage
the average was 1.02 ppm (range 0.01-7.8 ppm). Since details of the
relation between applied dosage and residues found were omitted, these
data should not be regarded as typical of good agricultural practice.
Studies carried out by CELAMERCK (1972) on residues in sugarbeets
and in wine from treated grapes gave the results shown in Table 1.
Data was received from the Netherlands on results of supervised
trials on apples, pears, and head lettuce. When sprayed on apple and
pear trees at rates of 0.56, 0.7, or 1.4 g. a.i/tree, lindane residues
in fruit at 14 days post-treatment (recommended interval) ranged from
"not detectable" (<0.1 ppm) to 0.1 ppm (Schuddeboom, 1973).
When glasshouse lettuce was treated via a lindane smoke generator
at a rate of 3 g/100m2, lindane residues at seven days post-treatment
averaged 1.2 ppm (range 1.0-1.6 ppm) in one trial and 1.0 ppm (range
0.8-1.3 ppm) in a second trial.
Fate of residues
In animals
Five previously unreported metabolites from the urine of rats fed
lindane have been identified as 3,4-dichlorophenol,
2,4,6-trichlorophenol, 2,3,4,5-tetrachlorophenol,
2,3,4,6-tetrachlorophenol, and 2,3,4,5,6-pentachloro-2-cyclohexen-1-ol
by Chadwick and Freal (1972).
When lindane 14C was fed to rabbits for 26 weeks, 54% of the
dose was excreted in urine and 13% in faeces. Urinary metabolites
identified were 2,3,5-, 2,4,5-, and 2,4,6-trichlorophenol;
2,3,4,6-tetrachlorophenol, 2,3-, and 2,4-dichlorophenol, and
2,3,4,5-tetrachlorophonol. Seven more chlorophenols and six
chlorobenzones were tentatively identified (Karapally et al., 1973).
High protein diets and starvation accelerated the excretion of
lindane from all organs of female rats according to Oshiba and
Kawakita (1973); 70 to 90% of accumulated lindane was excreted in six
days.
In plants
Bean and corn seedlings immersed in aqueous solution of lindane
(0.05 mg/ml) for eight days took up insecticide through the roots. In
beans, the only nonpolar metabolic products were
gamma-pentachlorocyclohex-l-ene (gamma-PCCH) (4 ppm) and
1,2,4-trichlorobenzene (0.36 ppm); unchanged lindane amounted to 20
ppm. In corn, three nonpolar metabolites were found: gamma-PCCH,(5
ppm), 1,2,4-trichlorobenzene (0.3 ppm), and 1,2,3-trichlorobenzene
(0.14 ppm). These nonpolar metabolites accounted for 70% of the total
metabolites in these plants (Mostafa et al., 1971).
Studies in progress on lindane-14C metabolism in lettuce grown
hydroponically and on soil have shown the presence (in hydroponic
lettuce) of small mounts of trichlorobenzene,
2,3,4,6-tetrachlorobenzene, pentachlorobenzene,
pentachlorocyclohex-l-ene. dehydrolindane. and
2,3,4,6-tetrachloro-phenolmethyl ether; the major residue was
unchanged lindane (Korte, 1973).
TABLE 1. LINDANE RESIDUES (PPM) IN NEW WINE AND SUGARBEETS
Application Application Days between last treatment and sampling
Crop Number of concentration rate
treatments % (preparation) a.i. 118 178 183 193 197 198
Wine 1 3.75% gran. 0.45 g/stock 0.001
1 3.75% gran. 0.45 g/stock 0.002
Sugar beets 1 0.5% 1 600 g/ha 0.03
1 0.25% 800 g/ha 0.06
1 0.33% 1 600 g/ha 0.10
1 0.167% 800 g/ha 0.02
1 - 2 000 g/ha < 0.02
beets
< 0.02
leaves
1 3.75% G 94 g/ha < 0.02
beets
row treatment < 0.02
leaves
1 3.75% G 750 g/ha 0.07)
)
1 3.75% G 1 500 g/ha 0.10)
) control:
1 0.25% G 800 g/ha 0.11) 0.1 ppm
) lindane
1 0.5% 1 600 g/ha 0.12)
1 3.75% G 750 g/ha 0.04
1 3.75% G 1 500 g/ha < 0.02
1 0.25% 800 g/ha 0.03
1 0.5% 1 600 g/ha 0.10
In storage, processing or cooking
Lindane was fed to dairy cows at 1 mg/kg bw/day and the milk was
collected and processed into pasteurized whole milk, 30% fat cream,
butter, spray-dried whole milk, condensed whole milk, and cheddar
cheese (Li et al., 1970). The residue was very stable for ordinary
processing operations and remained essentially unchanged (on a fat
basis). However, spray drying reduced the lindane content by 34%.
Similar results were obtained by Smart et al., 1972 who fed either 0.2
ppm or 0.6 ppm to cows and prepared cheese, butter, whey, buttermilk,
and separated milk. Maximum residues of 0.05 ppm in cheese and 0.15
ppm in butter were reported.
Lindane was fed to broilers at 10 ppm throughout an eight-week
period. Tissue residues of 7.3 ppm (raw, dry) were 9.0 ppm after
baking, 5.5 ppm after frying, 3.9 ppm after steaming, and 1.5 ppm
after heating in a closed container for 90 minutes (Ritchey et al.,
1972).
Polished rice containing 0.012 ppm of lindane was boiled in a
home-type cooker with and without pressurization (Kanazawa, 1973). A
55% reduction in residues was obtained in either case. In another
experiment green tea containing 0.174 ppm lindane was extracted by hot
water for three minutes and for one day. Only about 1% was lost even
in the one-day extraction.
Evidence of residues in food in commerce or at consumption
In studies of residues in the total diet in Canada in 1971 (Smith
et al., 1973) lindane residues were found at average values (mg/kg) of
0.001 in dairy products, 0.013 in cereals, and 0.001 in oils and fats.
In a continuation of the market-basket survey in the United
States for the years June 1968 to April 1970, the daily intake of
lindane was found to be 0.001 mg for 1969 and 0.001 mg for 1970
(Duggan et al., 1972). This represents a three-four fold reduction
from previous years. In the period June 1968 to April 1969, the daily
intake was at trace levels (<0.001 mg) for all food classes except
beverages and root vegetables (none) and grains and cereals (0.001
mg). In the period June 1969 to April 1970, daily intake was less than
0.001 mg in all food classes.
Data from New Zealand (1973) on residue levels found in random
sampling at retail level and in crops known to be treated with lindane
is shown in the following table.
A. Random sampling at retain level
Year Crop Frequency Residue levels in ppm
1966 Leaf vegetables 6 samples in 70 0.2 (max.)
1966 Root vegetables 2 samples in 46 0.3 (max.)
1967 Leaf vegetables 8 samples in 72 0.8 (max.)
1967 Pipfruit 3 samples in 17 0.2 (max.)
1967 Stonefruit 2 samples in 14 0.01 (max.)
1968 Leaf vegetables 1 sample in 50 0.05
1968 Root vegetables 2 samples in 44 0.1 (max.)
1969 Leaf vegetables 1 sample in 38 0.7
1970 Leaf vegetables 1 sample in 43 0.02
1970 Stonefruit 2 samples in 6 0.02 (max)
1971 Leaf vegetables 2 samples in 57 0.2
1971 Root vegetables 5 samples in 32 0.03
1971 Stonefruit 1 sample in 10 0.02
1971 Potatoes 1 sample in 19 0.03
B. Residues in crops known to be treated with lindane
1968 Apples 9 samples 0.1 (max.)
1970 Apples 1 sample N.D.
1971 Apples 4 samples 0.2 (max)
Data from surveys on lindane residues on glasshouse lettuce
carried out by the Central Bureau of Fruit and Vegetable Auctions in
the Netherlands (1973) is shown in the following table.
Lindane residues: Percentage of samples in rangesa
ppm 1967/68 1968/69 1969/70 1970/71 1971/72 1972/73
N.D. 57.7 53.2 52.1 47.8 44.7 80.6
0.01-1 26.9 29.3 31.6 39.5 36.1 16.3
1-2 10.9 11.9 10.9 8.6 12,2 2.8
>2 4.6 5.6 5.4 4.1 6.9 0.3
a About 1000 lettuce samples each year except 1972/73 - 2000 samples.
In the Czechoslovak Socialist Republic in the years 1971 and
1972, the content of chlorinated insecticide residues in some
foodstuffs, especially butter, and in the whole-day's diet was
followed analytically, also the daily intake of the human organism was
calculated (Rosa, 1973). Butter samples were taken in five dairy
plants in Sloyakia representing more than half a million hectoliters
of milk. The whole day's diet samples were taken in six colleges
during one week in the spring and autumn. The results are presented in
the following table.
A. Lindane residues in milk fat and whole day's diet, 1971/72 (mg/kg)
Milk fat Whole day's diet
(133 samples) (123 Samples)
Residue Min. Max. Med. Min. Max. Med.
gamma-BHC 0.006 0.157 0.041 0.001 0.009 0.004
B. Daily intake in mg/kg bw
Product
Whole day's
Residue milk butter cheese together diet
gamma-BHC 0.000005 0.000005 0.000001 0.000011 0.000146
It was not clear whether these residues arise from the use of
lindane or technical BHC.
Investigations in France in 1970 and 1971 on the sources of
organochlorine pesticide residues in milk revealed that lindane
residues arose from three sources: animal feed (grain, cattle-cake,
etc.), local treatment Of grain storage facilities, and treatment of
stables (Marion, 1973 [via Demozay]). Milk residues from feed sources
ranged from 0.01 to 0.08 ppm; from storage facility treatment, 0.01 to
0.60 ppm; from stable treatment, 0.01 to 0.22 ppm. Milk residues fell
rapidly when the source of contamination was removed or after
treatment in the case of veterinary use.
Various surveys in Japan on pesticide residues in dairy products,
meat, fish, and imported meat (Takeda et al., 1972; Sakai et al.,
1972; Minagawa et al., 1972; and Otsuki of al., 1972) showed gamma-BHC
residues ranging from traces to 0.03 ppm in raw milk, 0.01 to 0.46 ppm
in butter, N.D. to 0.048 ppm in modified milk powder, trace to 0.016
ppm in cheese, 0.01 to 0.1 ppm in fresh-water fish, 0.001 to 0.036 ppm
in marine fish, 0.01 to 0.042 ppm in imported beef (fat), 0.013 to
0.024 ppm in imported chicken (fat), 0.01 ppm in imported horse (fat),
0.011 to 0.015 ppm in imported mutton (fat), 0.015 ppm in imported
lamb (fat), and 0.053 ppm in imported rabbit (fat). Such data,
however, cannot be interpreted to reflect uses of lindane since all
other BHC isomers were present in all samples and it is very probable
that technical BHC was the main source of residue.
Methods of residue analysis
The multi-residue methods of analysis for organochlorine
pesticides as published by the AOAC (Official Methods of Analysis of
the Association of Official Analytical Chemists, 11th ed., 1970,
29.001) for fruit, vegetables, milk, and milk products and subsequent
changes to include fish, meat, and dry cereals (J. Assoc. Off. Anal.
Chem., 54, 470 (1971); 55, 428 (1972)) are suitable for regulatory
purposes for lindane. Other suitable methods are references in LINDANE
(1972).
National tolerances
See LINDANE Monograph of an Insecticide, 1972, pp. 263-335.
Appraisal
Evidence was available to show the need for direct application of
lindane to animals for ectoparasite control. The Meeting recognized
that direct application to lactating dairy animals occurs but does not
consider this procedure to be good agricultural practice because it
would likely give rise to residues in milk exceeding the recommended
practical residue limit.
No new information was provided on the disappearance of lindane
residues during storage and processing of cocoa beans and derived
products or of cereals into cereal products. Since the requirement for
these data was introduced in 1968 and since there was no response from
either the lindane manufacturers or countries growing these crops in
providing the needed data, it is the consensus of this Meeting that
these requirements should only be considered as desirable.
Limited data was evaluated from supervised trials on pigs, laying
hens, dairy cows (milk and milk products), rice, cabbage. sugar beets,
grapes (wine), apples, pears, and glasshouse lettuce. The data did not
show a need for revision of the values of any existing tolerance
recommendation although a survey of world-wide tolerances for lindane
on fruits and vegetables (in LINDANE, Monograph of an Insecticide)
would appear to indicate little need for a value greater than 2 ppm on
those commodities. On the basis of new data available, a tolerance of
0.5 ppm is recommended on rice (rough), 0.2 ppm on sugar beets (both
roots and foliage) and 1 ppm on apples and pears. No significant
residues were found in wine.
In response to a written suggestion that the tolerance on
vegetables seems too high (at 3 ppm) and should be reduced to 2 ppm:
the Meeting received information on new work in progress to determine
residue levels from supervised trials in a variety of fruits and
vegetables. This data, when available, will be used in assessing the
need to revise the tolerance recommendation for vegetables and fruit.
Home cooking experiments with chicken and rice show that lindane
residues are reduced significantly (50% or greater) by steaming or
boiling. Since reductions by boiling are equivalent whether the
containers are closed or open, it is apparent that volatilization or
steam distillation is not the primary pathway of loss.
In order to be consistent with the recommendations for residue
limits in eggs as published for other pesticides, the recommendation
for a practical residue limit for residues of lindane is changed from
egg (yolk) to eggs (shell-free) and the value of the limit is adjusted
from 0.2 to 0.1 ppm to allow for the change in sample weight and
dilution by egg white.
Completely adequate methods suitable for regulatory purposes for
analysis for lindane residues have been developed. However,
considerable care is still required to confirm the qualitative
identification since there are numerous potential interferences.
RECOMMENDATIONS FOR TOLERANCES AND PRACTICAL RESIDUE LIMITS
As the ADI has been changed to temporary all previous tolerances
and PRL's are changed to temporary. The following temporary tolerances
are in addition to those previously recommended.
Temporary tolerances
Apples, pears 1 ppm
Rice (rough) 0.5 ppm
Sugarbeet roots, sugarbeet foliage 0.2 ppm
FURTHER WORK OR INFORMATION
Required (before 1977)
1. A long-term carcinogenicity study.
Desirable
1. The results of supervised trials currently in progress to determine
residues on a variety of fruits and vegetables.
2. Information from governments on residues of lindane found in cocoa
beans and cocoa products moving in commerce.
3. Further information from governments on the occurrence of lindane
residues on raw grains, the effect of processing on these residues,
and the fate of the residues in the various milled cereal fractions.
4. Further information and statistics on the occurrence of lindane
residues in animal foodstuffs and on the uses of lindane in
association with animals (such as stable treatments) with a view to a
re-evaluation of the practical residue limit of 0.1 mg/kg in the fat
of milk.
REFERENCES
J.A.O.A.C. (1970) Official methods of analysis of the Association of
Official Analytical Chemists, 11th edition
Bauer, A. and Frohberg, H. (1972) Lindane, testing for teratogenic
effects in mice following subcutaneous injection. Unpublished report
submitted by E. Merck
Burrows, I.E. and Multen, L.W. Effect of lindane on the reproductive
function of multiple generation in the rat. I. The determination of
dietary concentrations of lindane in rat tissues. Unpublished report
from Huntingdon Research Centre submitted by E. Merck
Buselmaier, W., Rohrborn, G. and Propping, P. (1972) Mutagenitäts
Untersuchengen mit pestiziden im host-mediated assay und mit dem
dominanten lethal test an der mans. Biol. Zbl., 91: 311-325
Celamerck. (1972) Reports of analysis. Private communication
Chadwick, R.W. and Freal, J.J. (1972) Bull. Environ. Contan. Toxicol.
7, No. 2/3: 137-146
Czegledi-Janko, G. and Avar, P. (1970) Occupational exposure to
lindane. Clinical and laboratory findings. Brit. J. Ind. Mod.,
27(3): 283-286
Davey, R.J. and Gerrits, R.J.J. (1969) Anim. Sci., 28: 872
Duggan, R.E. and Corneliusson, P.E. (1972) Pest. Monit. Jour. 5(4)
Foster, T. S., Motley, H. V., Purkayastha, R.,Greenhaigh, R. and Hunt,
J.R.J. (1972) Econ. Entomol. 65(4): 982-988
Frohberg, H. and Bauer, A. (1972a) Lindane, testing for teratogenic
effects in mice following oral administration. Unpublished report
submitted by E. Merck
Frohberg, H. and Bauer, A. (1972b) Lindane testing for mutagenic
effects Dominant Lethal Test in male mice. Unpublished report
submitted by E. Merck
J.A.O.A.C. (1971/72) Changes in methods, 54:.470; 55: 428
Kaloyanova-Simeonova, F. et al. (1972) Organochlorine pesticides in
the fat tissue of the general population in Bulgaria. Paper at the
XVII International Congress on Occupational Hygiene, Buenos Aires
Kanazawa, Jun. (1973) Japan Pesticide Information No. 11, pages 5-16
Karapally, J.C., Saha, J.G. and Lee, Y.W. (1973) Metabolism of lindane
14C in the rabbit: ether soluble urinary metabolites. J. Agr. Food
Chem., 21: 811-118
Klekmina, S. M. and Khaikina, B.I. (1972) The effect of lindane an the
activity of lactate dehydrogenase and its isoenzyme spectrum. Farmazia
i Toksikologia, 35(6): 734-737
Kolomodin-Hedman, B.. Alexanderson, N. and Sjöqvist, F, (1971)
Toxicol. Appl. Pharmacol. 20, 299
Kolomodin-Hedman, B.., Palmer, L., Gotell, P. and Skerfving, S. (1973)
Plasma levels of lindane p,p'-DDE and p,p'-DDT in occupationally
exposed persons in Sweden. Work-environm. Hlth, 10: 100-106
Korte, F. (1973) Progress report on lindane metabolism in lettuce
submitted to IUPAC Terminal Residues Commission
Li, C.F., Bradley, R.L. jr., and Schultz, L.H. (1970) J.A.O.A.C.,
53(11): 127
Marion, R. (1973) Report for I.T.E.B. (Provided by D. Demozay, PEPRO,
1973)
Milby, T.H. and Samuels, A.J.J. (1971) occup Med., 13: 256-258
Minagawa, O. et al. J. Food Hyg. Soc. Japan 13(4): 317 1972
Mostafa, I.Y., Moza, P.N. and Klein, W. (1971) Prepublication paper
submitted to IUPAC Terminal Residues Commission
Netherlands. (1973) Private communication
New Zealand. (1973) Private communication
Noel, R.B., Rivett, K.R., Sortwell, R.J., Cheshire, P.J., Street.,
A.E., and Mawdesley-Thomas, L.E. (1971) Lindane toxicity studies in
beagle dogs - dietary Intake (200 ppm) for 32 weeks. Unpublished
report from Huntingdon Research Center, submitted by E. Merek
Oshiba, K. and Kawakita, H. (1973) Osaka Shiritsu Elsei Kenkyusho
Kenyku Hokoku, 34: 158. (1971) English abstract Health Aspects of
Pesticides 6(4): 205
Oshiba, K., and Kawakita, H. (1973) Shokuhin Eiseigaku Zasshi,
13(5): 383. (1972) English abstract - Health Aspects of Pesticides,
6(3): 152
Otsuki, K. et al. (1972) J. Food Hyg. Soc. Japan 13(4): 338
Palmer, A.K., Cozens, D.D., Lovell, M.R., Spicer, E.J.F. (1972) and
Newman, A.J. Effect of lindane on reproductive function of multiple
generations in the rat - final report. Unpublished report from
Hungtingdon Research Centre submitted by E. Merck
Palmer, A.K. and Lovell, M.R. (1971) Effect of lindane on pregnancy of
the rat. Unpublished report from Huntingdon Research Centre submitted
by E. Merck
Palmer A.K. and Neuff, A.M. (1971) Effect of lindane on pregnancy of
the New Zealand white rabbit. Unpublished report from Huntingdon
Research Centre submitted by E. Merck
Propping, P., Buselmaier, W. and Rohrborn, G. (1973) Kritische
Betrachtung usher die intra-animale Kultur von Mikroorganismen, eine
Methode zum Nachweis chemisch induzierter Mutationen [Critical
considerations on the host-mediated assay, a method for detection of
chemically induced mutations], Arzneim-Forsch., 23(6): 746-749
Ritchey, S,J., Young, R.W, and Essary, E.O.J. (1972) Agr. Food Chem.
20(2): 291-293
Rivett, K.F., Sortwell, R.J., Spicer, E.J.F., Cheshire, P.J., Street,
A.E. and Burrows, I.E. (1971) Lindane, toxicity studies in beagle dogs
(Initial studies and dietary intake for 104 weeks). Unpublished report
from Huntingdon Research Centre submitted by E. Merck
Rosa, Dr Jaroslav. (1973) Private communication from the Foreign
Department of the Federal Ministry of Agriculture and Food of the CSSR
Sakai, K. et al. (1972) J. Food Hyg. Soc. Japan, 13(4), 310
Schuddeboom, L.J. (1973) Inspekteur van de Volksgezondheid, Private
communication
Selby, L.S., Newell, K.W., Hansen, O.A. and Junker, G. (1969)
Comparison of chlorinated hydrocarbon pesticides in maternal blood and
placental tissues. Environ. Res., 2: 247-255
Smart, N.A., Hill, A.R.C. and Roughan, Mrs P.A. (1972) Pestic. Sci.,
3: 415-419
Smith, D.C., Leduc, R. and Charbonneau, C. (1973) Pestic. Sci., 4:
211-214
Takeda, M. et al. (1972) J. Food Hyg. Soc. Japan, 13(4): 299
Trifonova, T.K., Gladenko, I.N. and Shulyak, V.D. (1970) Effect of
gamma-BHC and serum on reproduction. Veterinariya, 47(6): 91-93
Ulmann, E. (ed.) (1973) LINDANE Monograph of an Insecticide, Verlag K.
Schillinger, Freiberg im Breisgau, Wallstr. 14
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 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: 1989 evaluations Part II Toxicology)
Lindane (Pesticide residues in food: 1997 evaluations Part II Toxicological & Environmental)