ALDRIN/DIELDRIN JMPR 1977
Explanation
Dieldrin was reevaluated at the Joint FAO/WHO Meeting in 1970 (FAO/WHO
1971) and additional information on the significance of the hepatic
lesions observed in mice after dieldrin treatment was thought
desirable. Moreover further data on long term studies of industrial
workers, on teratogenicity, on comparative metabolism studies in
humans, monkey rat and mouse and data an possible photo-dieldrin
residues in foodstuff should become available for evaluation.
Since that last reevaluation results of several studies have been
presented and are summarized in the following monograph addendum,
together with data on the teratogenicity and carcinogenicity of
aldrin.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOCHEMICAL ASPECTS
Absorption, distribution, excretion and biotransformation
Dieldrin has been reported to produce hepatoma in certain mice strains
not however in other laboratory animals so far studied. Different
metabolic pathways and differences in excretion could be the reason
for this possible species-specific reaction of mouse liver on the
ingestion of dieldrin.
A comparative metabolism study in mice (strain Swiss White), rats,
rabbits, rhesus monkeys and chimpanzees showed that there are two main
metabolic pathways in mammals. The first involves direct oxidation,
supposedly by cytochrome oxidases, resulting in 12-hydroxydieldrin,
the second involves the opening of the epoxide ring by epoxide
hydrases resulting in aldrin-4,5-trans-dihydrodiol. Single oral
doses of 0.5 mg/kg of 14C labelled dieldrin were administered to the
test animals. Faeces and urine were collected separately for 10 days
following administration. The major metabolites in the excreta of all
five species under study were 12-hydroxydieldrin and
4,5-aldrin-transdiol. In all species the faecal excretion of unchanged
dieldrin was high in the first 48 h after administration and declined
rapidly thereafter. The urine contained no unchanged dieldrin.
Regarding the ratios of the two major metabolites, the rats and
primates seemed to metabolize dieldrin mainly by direct oxidation
resulting in 12-OH-dieldrin, whereas the common main metabolic pathway
of mice and rabbits seemed to be the opening of the epoxide ring to
the diol. The highest rate of metabolism was found in the mouse with
33% of the administered dieldrin being metabolized within 10 days,
compared to about 9% in rats, 2% in rabbits, 11% in rhesus monkeys and
3% in chimpanzees. The high rate in mice may result in relatively high
diol concentrations in the mouse liver. About 23% of the administered
dose was excreted as aldrin-trans-diol by mice compared with only 1-2%
in the other species examined (Müller at al., 1975a). Similar results
were also obtained by Bedford and Hutson (1976).
14C labelled dieldrin was administered to rhesus monkeys either as a
single i.v. injection of 2.5 mg/kg or as a single oral dose of 0.36 or
0.5 mg/kg. The excreta were separately collected for 75 days following
administration. After administration by injection there was a short
period of relatively high excretion; 13% of the administered dose was
eliminated within the first 5 days. The excretion rate decreased to
about 0.05% per day after 20 days. A total of 20% was excreted over
the whole period. Only 10% of the excreted radio-carbon was eliminated
with the urine during the initial excretion phase, after day 20 the
urinary excretion rate increased to 30-40%. The three identified
metabolites found in the excreta were 12-hydroxydieldrin,
4,5-aldrin-trans-dihydrodiol and the last one was assumed to be a
glucuronic acid conjugate of the diol. After oral administration 17%
and 25% of the administered dose respectively were eliminated within
10 days at the 0.36 and 0.5 mg/kg dose level. The faeces contained
predominantly dieldrin for the first two days. From the third day
urine and faeces contained the same metabolites found in the injection
study. 7% and 11% respectively were excreted as unchanged dieldrin, 8%
and 12% respectively as 12-hydroxydieldrin in the monkeys treated with
0.36 mg/kg and 0.5 mg/kg (Müller et al., 1975b).
Determination of the faecal and urinary radioactivity during the 7
days following a single oral dose of 14C-dieldrin to different rat
and mouse strains showed that the major route of excretion is via the
faeces. The nature of the excreted metabolites and the excretion rates
of individual metabolic products depended on species, strain and sex.
The major faecal metabolite in rat and mouse was
syn-12-hydroxydieldrin, the excretion rate of this metabolite being
much higher in rats than in mice. On the other hand the production of
the trans-diol was higher in mice than in rats. Similar amounts of the
tricyclic diacid were excreted in both species. Unchanged dieldrin was
also excreted via the faeces in rats and mice. Most of the urinary
label in the male rat (CFE strain) was dieldrin pentachloroketone;
this metabolite was found only in traces in the urine of female rats
or mice. Unchanged dieldrin and the diacid were excreted in the urine
of both rat and mouse.
The investigation of the metabolites in organs and tissues of rats
showed that dieldrin was present in all organs and tissues, the
adipose tissue being the major site of deposition. Dieldrin
pentachloroketone was also present in most tissues and organs, notably
in the kidney of male animals. No other metabolites were detected.
The monohydroxylated metabolite of dieldrin, syn-12-hydroxydieldrin is
formed after incubation of dieldrin with rat liver microsomes. Since
the production can be inhibited in vitro by the addition of
mono-oxygenase inhibitors such as sesamex, syn-12-hydroxydieldrin is
obviously formed by liver microsomal monooxygenase action. The bridged
pentachloroketone is also a sesamex-inhibited product of dieldrin
incubation with liver microsomes and seems to be formed also by
monooxygenase activity. It has been assumed that the trans-diol is
formed by the action of epoxide hydratase upon dieldrin. The formed
cis-diol is converted into the ketol by oxidation and the reduction of
the latter would lead to the trans-diol. Based on the results of
recent studies a novel pathway of the trans-diol formation is proposed
involving direct oxidative formation of the ketol from dieldrin,
reduction of which yields the cis- as well as the trans-diol.
In vitro experiments with cis- and trans-diols indicated that the
cis-diol was convertible into the trans-diol, but that the reverse
reaction did not occur (Bedford and Hutson, 1976).
TOXICOLOGICAL STUDIES
Special studies on mutagenicity
The compound did not produce any mutagenic response when tested
in vitro with or without microsomal activation against five
indicator organisms of histidine auxotroph tester strains of
Salmonella typhimurium. Tester strains that revert due to base
analogue and frameshift mutation in repair deficient as well as repair
competent strains had been utilized. Additionally two strains were
examined that are deficient in their lipo-polysaccharide coat which
allows for penetration of lipophilic compounds (Bidwell et al., 1975).
Preliminary results of a microbial mutagenicity study showed that also
metabolites of dieldrin, i.e. syn-12-hydroxydieldrin, aldrin
dicarboxylic acid, cis-aldrin diol, trans-aldrin diol and
pentachloroketone did not significantly increase the incidence of
reverse mutations of six histidine auxotroph tester strains of
Salmonella typhimurium (Dean and Brooks, 1977).
For the evaluation of possible host-activated mutagenic metabolites of
dieldrin, host-mediated assays and blood-and urine recovery studies
were performed in mice. The animals were treated daily for 5 days with
an oral dose of 20 mg/kg and then received injections of tester
bacteria. Mutation frequencies showed no significant increase in
mutation in the dieldrin-treated animals (Bidwell et al., 1975).
No mutagenic activity could be found in a further host-mediated assay.
Mice were treated with a single oral dose of 25 and 50 mg/kg dieldrin
(HEOD) or with repeated doses of 5 and 10 mg/kg on five consecutive
days. The indicator organism, injected after the fifth dose into the
peritoneal cavity, was a strain of the yeast
Saccharomyces cerevisiae (Dean at al., 1975).
The examination of blood and urine samples of mice treated with a
single oral dose of 20 mg/kg by spot test revealed no mutagenic
substances in blood or urine treated animals (Bidwell et al., 1975).
After oral treatment of male mice with 12.5, 25 and 50 mg/kg dieldrin
(HEOD) and mating with untreated females in a dominant lethal test no
adverse effects could be observed (Dean et al., 1975). Consistent
results were obtained when mice were treated with 0.08, 0.8 and 8
mg/kg dieldrin for 5 consecutive days before mating with untreated
females (Bidwell et al., 1975).
The oral administration of single doses of 30 and 60 mg/kg dieldrin
(HEOD) to Chinese hamsters did not cause any demonstrable chromosome
damage in bone marrow cells (Dean et al., 1975).
Standard metaphase analysis and micronuclei test after oral treatment
of mice with 0.8 and 8 mg/kg dieldrin for 5 days revealed no
cytogenetic abnormalities (Bidwell at al., 1975).
The heritable translocation test was carried out with male mice that
sired low numbers of pups after oral intake of 0.008, 0.08 and 0.2
mg/kg over a period of 6 weeks. The cytogenetic determination of
somatic cells utilizing the micronuclei test and the usual analysis of
spermatocytes did not reveal an increase in the number of
trans-locations that could have led to sterility or semisterility
(Bidwell et al., 1975).
Special Study on Teratogenicity
Foetotoxic and teratogenic effects were found after administration of
aldrin and dieldrin as single oral doses to hamsters and mice.
Hamsters were treated with 30 mg/kg of dieldrin and 50 mg/kg aldrin on
gestation day 7, 8 or 9, mice were treated with 15 mg/kg dieldrin and
25 mg/kg aldrin on day 9 of gestation. Foetotoxicity in hamsters
resulted in an increase of foetal death and foetal growth retardation.
High incidences of congenital anomalies such as cleft palate, open eye
and webbed foot were found as teratogenic defects. In treated mice
similar anomalies were found but without increase of foetal mortality
and growth retardation (Ottolenghi at al., 1974).
After daily oral administration of 1.5, 3 and 6 mg/kg dieldrin and
0.15, 0.3 and 0.6 mg/kg photodieldrin to mice and rats on gestation
days 6 through 16 no teratogenic effects were observed even at the
highest dose levels. The administration of 6 mg/kg dieldrin resulted
in a reduction of the average body weight gain in mice and rats, an
increase of the relative liver weights in mice and a 41% mortality in
rats. The highest dose of photodieldrin resulted in increased liver
weights in mice and a 15% mortality in rats (Chernoff et al., 1975).
No teratogenic activity of the compound could be found when dieldrin
(HEOD) was orally administered at dose levels of 1.5 and 4 mg/kg in
corn oil or 1.25, 0.5 and 1 mg/kg in DMSO to mice on days 6 through 14
of gestation. The only adverse effects such as reduced body weight
gains of the pregnant mice, some maternal deaths, lower foetal body
weights and increased incidence of delayed ossification of the foetal
bones were observed in the control and treatment groups when DMSO was
used as vehicle (Dix et al., 1975).
Special Study on Carcinogenicity
Mouse
Groups of 50 mice of each sex were maintained on a diet containing
dieldrin at doses of 2.5 and 5 ppm for a period of 80 weeks followed
by an observation period of 10-13 weeks. Matched controls consisted of
groups of 20 untreated male and 10 untreated female mice. Pooled
controls used for statistical evaluation consisted of the animals in
the matched control group combined with 92 male and 79 female
untreated animals from similar bioassays with other chemicals. All
surviving mice were killed at weeks 90-93. The treatment did not
affect the mean body weights or the survival rates. During the second
6 months of the study clinical signs such as tremors, abdominal
distention, alopoecia, tachnypnea and hyperexcitability appeared among
treated animals and increased in frequency during the second year of
study, together with pale mucous membranes and rough hair coat. In
male mice there was a marked dose-related increase in hepatocellular
carcinomas showing frequencies of 17/92 (18.5%) in the pooled
controls, 12/50 (24%) in the 2.5 ppm group and 16/45 (36%) in the 5
ppm group. The incidence of hepatocellular carcinoma was much higher
in male animals of the control and treated groups than in females. The
incidence in females was not dose-related. 3.8% of the females in the
pooled control group showed heptocellular carcinoma, 12% in the low
and 4% in the high dose groups. There was a low incidence of other
types of neoplasms involving various organs and tissues with no
obvious difference between control and treated animals (NCI, 1977a).
Groups of 50 mice of each sex were administered aldrin at time-
weighted dietary average doses of 4 and 8 ppm for males and 3 and 6
ppm for females. The diet was administered over a period of 80 weeks,
then the animals were observed for 10-13 weeks. The control groups
included the matched control animals and the 92 male and 79 female
untreated mice from the pooled control group. All surviving mice were
killed at 90-93 weeks.
The treatment did not affect the mean body weights. During the second
year of the study, clinical signs including rough hair coat, alopecia
and abdominal distention appeared with increasing frequency. No
dose-related increase in mortality in the male mice was found, whereas
in female mice there was a dose-related trend in mortality represented
by early deaths in the high-dose group. A dose-related increase of
hepatocellular carcinomas in the treated male mice was seen with
incidences of 10.8% in pooled control group, 33% in the low dose group
and 54% in the high dose group, whereas the frequency of this neoplasm
in the female mice was much lower and not dose-related with incidences
of 2.3% in pooled controls, 10% in the low dose and 5% in the high
dose group.
The low incidences of other types of neoplasms in various organs and
tissues were not considered to present a difference between treated
and control groups (NCI, 1977a).
Groups of 50 rats of each sex were administered dieldrin at time-
weighted average dietary dose levels of 29 ppm for a period of 80
weeks followed by an observation period of 30-31 weeks and 65 ppm for
59 weeks, followed by 51-52 weeks of observation. Matched controls
consisted of groups of 10 untreated rats of each sex. Pooled controls
used for statistical evaluation, consisted of the matched-control
groups combined with untreated animals from similar bioassays of other
chemicals, 58 male and 60 female rats. All surviving rats were killed
at 110-111 weeks.
Mean body weights showed no difference compared with those of the
controls during the first year of the study; however during the second
year the treated animals showed lower weights than the control. During
the first 6 months of treatment the treated animals were comparable to
the controls with respect to behaviour and appearance with the
exception of high-dosed animals having convulsions. During the second
6 months of the study clinical signs including diarrhoea, alopoecia,
epistaxis, haematuria, discoloured hair coats, tremors and weight loss
appeared and increased in frequency during the second year of study,
together with pale mucous membranes, vaginal bleeding, dermatitis,
dyspnoea, ataxia, tachypnea, abdominal distention, rough hair coats
and discoloured urine.
There was a marked increase in the mortality rate of rats during the
first 90 weeks of the study. However because of the high rates of
mortality in the control groups during the remaining study period,
mortality did not appear to be treatment-related. A significant
increase was found in the combined incidence of adrenal cortical
adenoma and carcinoma in the low-dosed females (6/45) compared with
the pooled controls (0/55). No dose-relationship could be seen.
There were instances where neoplasms occured only in treated animals
(adrenal cortical adenoma, spleen haemangiosarcoma) or with increased
frequency when compared to control groups (pituitary
chromophobe-adenoma). Incidence and severity of the lesions were not
considered to provide clear evidence of a carcinogenic effect of
dieldrin on rat (NCI, 1977).
Groups of 50 rats of each sex were maintained on a diet containing
aldrin at dose levels of 30 to 60 ppm. Male rats were treated for 74
weeks, followed by 37-38 weeks of observation, female rats were
treated for 80 weeks, followed by an observation period of 32-33
weeks. Matched controls consisted of groups of 10 untreated rats of
each sex. Pooled controls consisted of the matched-control groups
combined with 58 untreated males and 60 untreated females from other
bioassays. All surviving rats were killed at 111-113 weeks. During the
second year of the study mean body weights of the treated animals were
lower than those of the control animals. Hyperexcitability was
observed in all treated groups with increasing frequency and severity
during the second year. The mortality was not dose-relatedly affected
by the treatment. During the second 6 months of the study convulsions
were observed in several high-dosed female rats. Throughout the second
year of the study clinical signs including pale mucous membranes,
rough hair coats, weight loss and vaginal bleeding were apparent in
all treated groups.
The combined incidence of follicular-cell adenoma and -carcinoma of
the thyroid was increased in both sexes. These incidences however were
significantly increased only in the low-dose animals compared with the
pooled controls. Adrenal cortical adenoma incidence showed a
significant increase compared with pooled controls in the low-dose
females. There were instances where neoplasms occurred only in the
treatment groups or with increased frequency compared with those in
control groups. The incidence of tumors and the severity of lesions
are however not considered to be dose-related (NCI, 1977a).
Groups of 24 Fischer 344 rats of each sex were administered dieldrin
technical grade, purified and recrystallized, at 0, 2, 10, or 50 ppm,
for 104-105 weeks. The dose level of 50 ppm constitutes a maximum
tolerated dose. All surviving rats were killed at 104-105 weeks. Body
weights of the rats were essentially unaffected by the treatment, but
typical signs of organochlorine intoxication including
hyperexcitability, tremors and coma were observed in high-dose males
beginning in week 76 and in high-dose females beginning in week 80.
Survival was not adversely affected, and adequate numbers of rats were
available for meaningful statistical analysis of the incidence of
tumors: 67-70% of the high dose group, 75-83% of the mid-and low-dose
group, and 88-92% of the matched control group survived to the
termination of the study. A variety of neoplasm occurred in control
and treated rats; however, the incidences were not related to
treatment. Frequently interstitial-cell tumours of the testes
(80-100%), and lymphocytic and granulocytic leukaemia (8-21%)
occurred. It is concluded that under the conditions of this bioassay,
dieldrin was not carcinogenic in Fischer 344 rats (NCI, 1977b).
Hamster
145 female and 147 male Syrian hamsters received dietary
concentrations of 0, 20, 60 and 180 ppm dieldrin (purity 99%) for
life. The survival rate at 50 weeks of age was comparable to the
control being 66%. Among control females 12% showed tumors whereas in
treated females 3-15% had tumors. 8% of the control males had tumors
and between 16 and 23% of the treated males. The study showed that by
the treatment of hamsters no significant increase in tumor incidence
is observed (Cabral at al., 1977).
In view of the possible species-specific reaction of mouse liver to
ingested dieldrin several studies have been performed on the
interactions of dieldrin with liver cells at the subcellular level in
different mammalian species (Wright at al., 1977). The earliest
structural change observed in the livers of rats, mice and dogs
treated with dieldrin was the proliferation of the smooth endoplasmic
reticulum (SER). During the initial phase of the exposure to dieldrin
the increases in the SER in rats, dogs and mice were of the vesicular
type. Thereafter as an effect of microsomal enzyme induction
intracellular whorls of smooth membranes appeared in the liver cells
of rats and dogs. None of these structures was induced in mice liver.
All these structural changes were reversible. In contrast no
structural changes in the livers of rhesus monkeys were observed.
Dieldrin administered in large doses caused liver enlargement in the
rat, mouse and dog but not in monkeys. In vitro determinations,
being the most sensitive criterion for the effect produced by
dieldrin, showed that the activity of the liver microsomal
monooxygenase system was increased after treatment. Microsomal enzyme
induction was detected in all four species exposed to dieldrin. A
dietary concentration of about 1 ppm was reported to be sufficient to
produce monooxygenase induction in rat liver.
The possibility that dieldrin or one of its metabolites exerts its
tumorigenic action on mouse liver by means of a direct interaction
with DNA has been studied measuring the extent of binding of
14C-labelled dieldrin and/or its metabolites to liver DNA utilizing
one rat strain and two mouse strains. CF1 mice are susceptible to
liver tumor induction by dieldrin, whereas LACG mice represent a
strain which is not or only very weakly susceptible. The results
showed that the extent of binding was not correlated with
susceptibility. Binding was highest in the rat, intermediate in the
susceptible and lowest in the non-susceptible mouse strain. Based on
these results on the one hand and the uniformly negative results of
different mutagenicity tests on the other, the conclusion is drawn
that the increased incidence of liver tumors in dieldrin-treated mice
is not due to direct damaging effects on DNA.
Experiments determining the rate of semi-conservative DNA synthesis in
normal primary human fibroblasts (AH) as well as experiments
determining repair replication in AH cells and SV-40 transformed human
cells also gave no indication of damage to DNA or induction of repair
replication after treatment with dieldrin (Zelle and Lohman, 1977).
The treatment of SV-40 transformed human cells in culture with
dieldrin resulted in increased unscheduled DNA synthesis and in
induction of DNA repair. They reported that in these treated human
cells long-type excision repair of DNA could be found (Ahmed et al.,
1977).
Observations in Humans
Previous results of a long term study of occupationally exposed
industrial workers (Jager, 1970) were presented at the Joint FAO/WHO
Meeting in 1970 (FAO/WHO, 1971). A follow-up survey of the study has
been carried out (Versteeg and Jager, 1973). The figures from this
continuing study were updated. The population under study numbered
about 1,000 persons. Because not all of the workers had prolonged and
severe exposure, smaller groups with exposure meaningful enough for
carcinogenicity evaluation were taken. One group consisted of 166 men
(including still exposed, still employed workers, and also workers who
left the company) with a mean exposure time of 16.9 years (range 4-19)
and more than 15 years of observation (mean observation period 17
years, range 4-20). A sub-group of these comprised 69 men with a mean
exposure time of 14.9 years (range 10-19) and a mean observation
period of 17.2 years. Among these 166 workers, 51 were older than 50
years. One man with only 5 years of comparatively mild exposure died
because of a gastric carcinoma. A lymphosarcoma occurred in a man with
7 years of very mild exposure. Both incidences occurred before 1964.
No new cases were noted in the last 11 years and no undue mortality
from other causes that could have marked a higher cancer incidence was
observed.
The organochlorine pesticide concentrations of dieldrin, pp'DDE,
pp'DDD, pp'DDT, gamma-HCH, ß-HCH and HCB have been determined in the
blood from mothers and their babies as well as in mother's milk. The
results showed no evidence that breast-feeding resulted in higher
dieldrin concentrations in the blood of the babies than did
bottle-feeding. There was some evidence that the placenta restricted
the transmission of the pesticides to some extent. The daily intake of
dieldrin by mothers was assessed at 7-20 µg/person in the diet of the
U.K. population. Between 12 and 21% of the estimated daily intake of
dieldrin by mothers may be eliminated by lactation during the first 3
months after birth. Based on an average daily dieldrin intake of 10
µg/person a baby's daily intake could increase to 1.2-2.1 µg or
0.3-0.5 µg/kg b.w. (Van Raalte, 1977).
COMMENTS
The required teratogenicity studies in different animal species were
submitted and showed dieldrin not to be a teratogen. In several
studies where the test compounds were administered in repeated small
doses to pregnant mice no teratogenic effect could be found. However,
the administration of a single high dose of 15 mg/kg dieldrin to mice
(1/2 LD50) or 30 mg/kg to hamsters resulted in minor malformations
which were attributed to maternal toxicity.
Results of various carcinogenicity tests in mice and other mammalian
species indicate that there is a species-specific effect of dieldrin
and aldrin on the mouse liver, resulting in an increased frequency of
liver tumors only in this animal species. In all species examined
(mouse, rat, rabbit, rhesus monkey, chimpanzee) 12-hydroxydieldrin and
4, 5-aldrin-trans-dihydrodiol were the major metabolites. Regarding
the ratios of these two metabolites the mouse seems to metabolize the
test compound predominantly by the opening of the epoxide ring. This
metabolic pathway on the one hand and a high rate of metabolism
compared with other animal species examined on the other, could result
in relatively high concentrations of 4, 5-aldrin-trans-dihydrodiol
in the mouse liver.
Dieldrin, as well as other chlorinated pesticides, is a powerful
inducer of microsomal enzymes. Owing to their high rate of metabolism,
mice are especially susceptible to such effects (see section 3.1).
Compared with other animal species, it reacts rather anomalously and
the mouse, therefore, may not be an appropriate model for humans in
this case. The results of prolonged enzyme induction are proliferation
of the endoplasmic reticulum in the cells, and hypertrophy and
hyperplasia of the liver. These changes are fully reversible if
treatment is ceased before tumours have developed on the chronically
over-loaded and damaged cells. Similar effects are produced by
phenobarbital.
The results of the different experiments for the study of the possible
mechanism of the tumorigenic action of dieldrin on mouse liver at the
sub-cellular level are inconsistent.
A number of in vitro and in vivo mutagenicity tests have been
performed. In none of these studies did dieldrin reveal any mutagenic
activity.
These new findings again support the view that dieldrin and aldrin are
not carcinogens on the basis of knowledge available to the Meeting.
Therefore no change of the existing ADI for humans me considered
necessary.
TOXICOLOGICAL EVALUATION
Level causing no toxicological effect
Rat: 0.5 mg/kg in the diet, equivalent to 0.025 mg/kg bw
Dog: 1 mg/kg in the diet, equivalent to 0.025 mg/kg bw
ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR HUMANS
0-0.0001 mg/kg bw*
FURTHER WORK OR INFORMATION
* the ADI is applicable to aldrin and dieldrin separately or to the
sum of them if both are involved.
Desirable
1. Further studies on the possible mechanism of the tumorigenic action
on mouse liver.
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