Return
to Fluoxastrobin Index Page
Activity:
Fungicide
(strobin)
Structure:
Adverse
Effects:
Body
Weight
Bone
Decrease
Endocrine: Adrenal
Endocrine: Testicular
Endocrine: Thyroid
Endocrine: Uterus
Kidney
Liver
Reproductive
Spleen
Urinary tract
Environmental:
• Moderately to highly persistent
in soil.
•
Moderately toxic to estuarine/marine
fish.
• Highly toxic to freshwater fish and invertebrates.
• Very highly toxic to estuarine/marine invertebrates.
• Risks to endangered/threatened
freshwater fish species.
Body
Weight Decrease (click
on for all fluorinated pesticides)
-- Subchronic toxicity.
A subchronic toxicity feeding study with rats over 90 days demonstrated
a NOAEL of 7.3 and 18.3 mg/kg bwt/day for males and females, respectively,
based on reduced body weights and
alterations in several urinary tract-related
clinical chemistry parameters, at the higher dose levels. In a
subchronic feeding study in mice over 14 weeks, a NOAEL was not
established based on decreased alanine aminotransferase (ALAT)
and increased absolute and relative liver weights at the low dose
level (21.7 and 35.3 mg/kg bwt/day for males and females respectively).
A 14-week feeding study in dogs demonstrated a NOAEL of
3.0 mg/kg bwt/day based on decreased body
weights and food consumption, and
liver effects (enzyme induction, increased liver weights, cytoplasmic
change), and thyroid effects (decreased T3)
-- Chronic toxicity... A 1-year feeding
study with dogs demonstrated a NOAEL of 1.7 and 1.5 mg/kg bwt/day
for males and females, respectively based on decreased
body weights and slight liver effects
(increased alkaline phosphatase (Aph) and liver weights).
Ref: Federal Register: April 23, 2003. Fluoxastrobin;
Notice of Filing a Pesticide Petition to Establish a Tolerance
for a Certain Pesticide Chemical in or on Food.
http://www.fluoridealert.org/pesticides/Fluoxastrobin.FR.Apr23.2003.htm
• Reproduction
and fertility - rats. Offspring
systemic: decreased
body weights, delayed preputial separation, and incomplete
ossification in the F1 and/or F2 males and females. Parental
systemic: decreased
premating body weight gain of the P-generation
males and females and decreased premating absolute body
weight of the F1 males and females.
• Chronic toxicity-dogs. LOAEL
was 8.1 mg/kg/day for males and 7.7 mg/kg/day for females based
on body weight reductions and hepatocytomegaly
and cytoplasmic changes associated with increased serum liver
alkaline phosphatase indicative of cholestasis.
•
90-Day oral toxicity-rats. reduced
body weight gain and food intake, vacuolation
in the zona fasciculate of the adrenal cortex,
calculi in the urethra and kidney, and histological lesions in
kidney, urinary bladder, and urethra;
• 90-Day oral toxicity-dogs.
dose-related
reductions in net body weight gain
and food efficiency in addition to toxicity findings in the liver
in both sexes (cholestasis) and in kidneys (increased relative
weights in females and degeneration of the proximal tubular epithelium
in males).
•
Combined chronic toxicity / carcinogenicity--rats.
decreased body weight,
decreased body weight gain, and decreased
food efficiency in both sexes; decreased
spleen weight in males; and
microscopic lesions in the uterus of females. The apparent increase
in tumors in the uterus and thyroid were addressed and resolved
by an Agency committee, which
concluded that no carcinogenic concern exists for fluoxastrobin.
•
90-Day Subchronic Oral Toxicology-Dog.
dose-related reductions
in net body weight gain and food efficiency; toxicity findings
in the liver (cholestasis) in both sexes;
and toxicity findings in the kidneys (increased relative weights
in females and degeneration of the proximal tubular epithelium
in males).
Ref: Federal Register. September 16, 2005.
Fluoxastrobin; Pesticide Tolerances. Final Rule.
http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html
Bone
(click
on for all fluorinated pesticides)
Reproduction
and fertility - rats. Offspring
systemic: decreased body weights,
delayed preputial separation, and incomplete
ossification in the F1 and/or F2 males and females.
Ref: Federal Register. September 16, 2005.
Fluoxastrobin; Pesticide Tolerances. Final Rule.
http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html
Endocrine:
Adrenal (click
on for all fluorinated pesticides)
•
90-Day oral toxicity-rats. reduced
body weight gain and
food intake, vacuolation in the zona fasciculate of the
adrenal cortex, calculi in the urethra and
kidney, and histological lesions in kidney, urinary bladder, and
urethra;
Ref: Federal Register. September 16, 2005.
Fluoxastrobin; Pesticide Tolerances. Final Rule.
http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html
Definitions:
• the outer portion of the adrenal gland that secretes
hormones that are vital to the body. adrenal gland - the pair
of adrenal glands are located on top of both kidneys. Adrenal
glands work hand-in-hand with the hypothalamus and pituitary
gland.
androgen
hormone - a hormone secreted by the adrenal cortex which affects
the development of male characteristics. aldosterone - a hormone
secreted by the adrenal cortex which affects blood pressure
and saline balance. ...
www.chw.org/display/PPF/DocID/2687/router.asp
• The outer part of the adrenal gland, which secretes
a group of hormones involved in mineral metabolism and glucose
metabolism.
www.enzy.com/glossary/searchresults.asp
• An endocrine organ that secretes corticosteroids for
metabolic functions: aldosterone for sodium retention in the
kidneys, androgens for male sexual development, and oestrogens
for female sexual development.
www.mindsci-clinic.com/neuro_jargon.htm
• the cortex of the adrenal gland; secretes corticosterone
and sex hormones
wordnet.princeton.edu/perl/webwn
• In mammals, the adrenal glands (also known as suprarenal
glands) are the triangle-shaped endocrine glands that sit atop
the kidneys. They are chiefly responsible for regulating the
stress response through the synthesis of corticosteroids and
catecholamines, including cortisol and adrenalin.
en.wikipedia.org/wiki/Adrenal_cor
Endocrine:
Testicular (click
on for all fluorinated pesticides)
Offspring
systemic (rat): decreased body weights,
delayed preputial separation*, and
incomplete ossification in the F1 and/or F2 males and females.
Parental
systemic: decreased
premating body weight gain of the P-generation males and females
and decreased premating absolute body weight of
the F1 males and females.
Ref:
Federal Register. September 16, 2005. Fluoxastrobin; Pesticide
Tolerances. Final Rule.
http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html
* Note: Preputial separation is
an indicator of sexual maturation
Endocrine:
Thyroid
(click
on for all fluorinated pesticides)
-- Subchronic toxicity...
A 14-week feeding study in dogs demonstrated a NOAEL of 3.0 mg/kg
bwt/day based on decreased body weights
and food consumption, and liver effects (enzyme induction, increased
liver weights, cytoplasmic change), and thyroid
effects (decreased T3)
Ref: Federal Register: April 23, 2003. Fluoxastrobin;
Notice of Filing a Pesticide Petition to Establish a Tolerance
for a Certain Pesticide Chemical in or on Food.
http://www.fluoridealert.org/pesticides/Fluoxastrobin.FR.Apr23.2003.htm
-- In response to a
comment submitted to EPA by FAN Pesticide Project, EPA stated:
FAN suggested that a 14-week feeding
study using dogs showed an effect on the thyroid, which seems
to conflict with the statement that ``...There is no evidence
to suggest that fluoxastrobin has any primary endocrine disruptive
potential.'' FAN stated that a ``discussion or rationale'' addressing
this should have been provided. EPA does
believe that the thyroid effects seen in the dog study indicated
that fluoxastrobin is an endocrine disruptor. An effect
on the thyroid gland, even though this gland is part of the endocrine
system, does not necessarily mean that endocrine disruption has
or will occur. In this case, the effects
observed in the thyroid gland were induced by effects fluoxastrobin
had on liver enzymes and are therefore considered secondary.
--
Combined chronic toxicity / carcinogenicity--rats.
decreased body weight, decreased body weight
gain, and decreased food efficiency
in both sexes; decreased
spleen weight in males; and
microscopic lesions in the uterus of females. The
apparent increase in tumors in the uterus and thyroid were addressed
and resolved by an Agency committee, which
concluded that no carcinogenic concern exists for fluoxastrobin.
Ref: Federal Register. September 16, 2005.
Fluoxastrobin; Pesticide Tolerances. Final Rule.
http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html
Endocrine:
Uterus (click
on for all fluorinated pesticides)
Combined
chronic toxicity / carcinogenicity--rats. decreased
body weight, decreased body weight gain, and decreased food efficiency
in both sexes; decreased
spleen weight in males; and
microscopic lesions in the uterus of females. The
apparent increase in tumors in the uterus and thyroid were addressed
and resolved by an Agency committee, which
concluded that no carcinogenic concern exists for fluoxastrobin.
Ref: Federal Register. September 16, 2005.
Fluoxastrobin; Pesticide Tolerances. Final Rule.
http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html
The
incidence of uterus adenocarcinomas was statistically significantly
increased.
The RMS concluded that this was not a substance-related carcinogenic
effect. However, the range of the historical control is not the
only criterion for the biological relevance of an increased tumor
incidence. The incidence of the adenocarcinomas
in the uterus is significantly increased from 3/50 animals in
the control group to 10/49 animals in the highest dose and furthermore,
the incidence of uterine glandular hyperplasia is also clearly
increased from 1/50 to 6/49. A common (e.g. endocrine) mechanism
of both findings can not be excluded (page
2).
Ref: PEER REVIEW REPORT ON FLUOXASTROBIN.
August 15, 2005. European
Food Safety Authority.
http://www.fluorideaction.org/pesticides/fluoxastrobin.eu.comments.2005.pdf
Kidney
(click
on for all fluorinated pesticides)
•
90-Day oral toxicity-rats.
reduced body weight gain and food intake, vacuolation in the zona
fasciculate of the adrenal cortex,
calculi in the urethra and kidney, and histological
lesions in kidney, urinary bladder, and urethra;
• 90-Day oral toxicity-dogs.
dose-related
reductions in net body weight gain and food efficiency in addition
to toxicity findings in the liver in both
sexes (cholestasis) and in kidneys (increased
relative weights in females and degeneration of the proximal tubular
epithelium in males).
•
90-Day oral toxicity-mice. There was a dose
related increase in liver weight in both sexes and in kidney
weight in females, in addition to other effects whose toxicological
relevance was considered uncertain. Among
these effects were increased hepatocellular hypertrophy with cytoplasmic
changes in the high-dose males and minimal to moderate kidney
tubular hypertrophy in mid- and high-dose
females.
•
90-Day Subchronic Oral Toxicology-Dog.
dose-related reductions
in net body weight gain and food efficiency; toxicity findings
in the liver (cholestasis) in both sexes;
and toxicity findings in the kidneys (increased
relative weights in females and degeneration of the proximal tubular
epithelium in males).
Ref: Federal Register. September 16, 2005.
Fluoxastrobin; Pesticide Tolerances. Final Rule.
http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html
Liver
(click
on for all fluorinated pesticides)
2.3 SHORT TERM TOXICITY. The short-term toxicity of fluoxastrobin
has been investigated in dietary studies in rats (28-day and 90-day
studies), mice (2-week and 90-day studies) and dogs (90-day and
1-year studies). A 28-day dermal toxicity study in rats has also
been conducted. The liver is the main target
organ in all tested species (rats, mice and dogs). Histological
changes were seen in the urinary system of rats (high doses) and
dogs. Male rats were more sensitive than
females to the effects of fluoxastrobin/HEC 5725 on the liver
and urinary tract. Other target organs were adrenals, erythrocytes
and thyroid. Reduced body weight gain was a key finding in dog
studies. (page 12).
Ref: Conclusion regarding the peer review
of the pesticide risk assessment of the active substance fluoxastrobin
finalised: August 10, 2005. European Food Safety Authority.
http://www.fluorideaction.org/pesticides/fluoxastrobin.eu.review.2005.pdf
-- Subchronic toxicity.
A subchronic toxicity feeding study with rats over 90 days demonstrated
a NOAEL of 7.3 and 18.3 mg/kg bwt/day for males and females, respectively,
based on reduced body weights and alterations
in several urinary tract-related clinical chemistry parameters,
at the higher dose levels. In a subchronic feeding study in mice
over 14 weeks, a NOAEL was not established based on decreased
alanine aminotransferase (ALAT) and increased absolute and relative
liver weights at the low dose level
(21.7 and 35.3 mg/kg bwt/day for males and females respectively).
A 14-week feeding study in dogs demonstrated a NOAEL of 3.0 mg/kg
bwt/day based on decreased body weights
and food consumption, and liver effects
(enzyme induction, increased liver weights, cytoplasmic change),
and thyroid effects (decreased T3)
-- Chronic toxicity. A 24-month chronic/oncogenicity feeding study
in rats demonstrated a NOAEL of 53.0 and 35.2 mg/kg bwt/day for
males and females, respectively. An oncogenicity study in the
mouse revealed a NOAEL of 18.5 and 29.5 mg/kg bwt/day for males
and females, respectively based on liver
effects. There was no indication in the rat or mouse for
an oncogenic effect of fluoxastrobin. A 1-year feeding study with
dogs demonstrated a NOAEL of 1.7 and 1.5 mg/kg bwt/day for males
and females, respectively based on decreased
body weights and slight liver effects
(increased alkaline phosphatase (Aph) and liver weights).
Ref: Federal Register: April 23, 2003. Fluoxastrobin;
Notice of Filing a Pesticide Petition to Establish a Tolerance
for a Certain Pesticide Chemical in or on Food.
http://www.fluoridealert.org/pesticides/Fluoxastrobin.FR.Apr23.2003.htm
• Chronic
toxicity-dogs. LOAEL was
8.1 mg/kg/day for males and 7.7 mg/kg/day for females based on
body weight reductions and hepatocytomegaly
[see definition below] and cytoplasmic
changes associated with increased serum liver
alkaline phosphatase indicative of cholestasis.
• 90-Day oral toxicity-dogs.
dose-related
reductions in net body weight gain and food efficiency in addition
to toxicity findings in the liver
in both sexes (cholestasis) and in
kidneys (increased relative weights in females and degeneration
of the proximal tubular epithelium in males).
•
90-Day oral toxicity-mice. There was a dose
related increase in liver weight
in both sexes and in kidney weight in females, in addition to
other effects whose toxicological relevance was considered uncertain.
Among these effects were increased hepatocellular
hypertrophy [see
definition below] with
cytoplasmic changes in the high-dose males and minimal to moderate
kidney tubular hypertrophy in mid- and high-dose females.
•
90-Day Subchronic Oral Toxicology-Dog.
dose-related reductions in net body weight
gain and food efficiency; toxicity findings in the liver
(cholestasis) in both sexes; and
toxicity findings in the kidneys (increased relative weights in
females and degeneration of the proximal tubular epithelium in
males).
Ref: Federal Register. September 16, 2005.
Fluoxastrobin; Pesticide Tolerances. Final Rule.
http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html
Definitions:
Hepatocytomegaly is an enlargement
of the hepatocytes and is generally classified into three types:
hepatocellular hypertrophy, megalocytosis, and hepatocellular
vacuolation. Hepatocellular hypertrophy
is an enlargement of cellular diameter without accompanying
nuclear changes, leading to a net gain in the dry mass of the
liver. A common cause of hepatocellular hypertrophy is proliferation
of endoplasmic reticulum, indicating induction of cytochrome
P450, that is, exposure to cytochrome P450-inducing compounds.
Megalocytosis is characterized by enlargement of both the cell
and the nucleus, and hepatocellular vacuolation is characterized
by vacuolation, or formation of pockets of fluid within the
hepatocytes. Little is known about the
mechanism of the latter two types of hepatocytomegaly, but all
three types are associated with exposure to genotoxic contaminants.
Ref: Environmental Effects of Dredging
Technical Notes. Methods for the Assessment of the Genotoxic
Effects of Environmental Contaminants; Cellular and Organ/Organism
Effects. US Army Engineer Waterways Experiment Station. EEDP-04-25.
July 1995.
http://www.fluorideaction.org/pesticides/genotoxic.army.1995.report.pdf
Reproduction
and fertility (click
on for all fluorinated pesticides)
- Rats.
Offspring systemic:
decreased body weights, delayed
preputial separation*, and incomplete ossification in the
F1 and/or F2 males and females. Parental
systemic: decreased
premating body weight gain of the P-generation males and females
and decreased premating absolute body weight of
the F1 males and females.
Ref:
Federal Register. September 16, 2005. Fluoxastrobin; Pesticide
Tolerances. Final Rule.
http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html
*Note: Preputial separation is an indicator of sexual maturation
Spleen
(click
on for all fluorinated pesticides)
•
Combined chronic toxicity / carcinogenicity--rats.
decreased body weight, decreased body weight
gain, and decreased food efficiency in both sexes;
decreased spleen weight in males;
and microscopic lesions in the uterus of females. The apparent
increase in tumors in the uterus and thyroid were addressed and
resolved by an Agency committee, which concluded that no
carcinogenic concern exists for fluoxastrobin.
Ref: Federal Register. September 16, 2005.
Fluoxastrobin; Pesticide Tolerances. Final Rule.
http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html
Urinary
tract (click
on for all fluorinated pesticides)
-- Subchronic toxicity.
A subchronic toxicity feeding study with rats over 90 days demonstrated
a NOAEL of 7.3 and 18.3 mg/kg bwt/day for males and females, respectively,
based on reduced body weights and alterations
in several urinary tract-related clinical
chemistry parameters, at the higher dose levels...
Ref: Federal Register: April 23, 2003. Fluoxastrobin;
Notice of Filing a Pesticide Petition to Establish a Tolerance
for a Certain Pesticide Chemical in or on Food.
http://www.fluoridealert.org/pesticides/Fluoxastrobin.FR.Apr23.2003.htm
--
90-Day oral toxicity-rats. reduced
body weight gain and food intake, vacuolation in the zona fasciculate
of the adrenal cortex,
calculi in the urethra and kidney,
and histological lesions in kidney, urinary
bladder, and urethra.
Ref: Federal Register. September 16, 2005.
Fluoxastrobin; Pesticide Tolerances. Final Rule.
http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html
Environmental
(click on for all fluorinated
pesticides)
Soil:
Depending on the soil, fluoxastrobin was shown to be highly
persistent in soil and hence it was present in rotational
crops at plant back intervals up to 328 days as the major
residue. Decline of fluoxastrobin residues under processing
conditions does not occur (page 2)... Persistence of fluoxastrobin
in soil may be very variable. Fluoxastrobin
may behave as a moderate to high persistent compound.
Metabolite M48-E is moderate to medium persistent in soil.
Anaerobic metabolite M40 is moderately persistent in soil
under aerobic conditions (page 3).
A high risk is identified to aquatic
organisms. A bufferzone of
15 metres is needed to respect the Annex VI trigger
value for the long term risk for the use of fluoxastrobin
as a spray application in cereals (page 5).
A high risk to aquatic organisms
is identified which requires consideration of appropriate
risk mitigation measures. A bufferzone of 15 metres is needed
to respect the Annex VI trigger value for the long term
risk (page 41).
Ref:
Conclusion regarding the peer review of the pesticide risk
assessment of the active substance fluoxastrobin finalised:
August 10, 2005. European Food Safety Authority.
http://www.fluorideaction.org/pesticides/fluoxastrobin.eu.review.2005.pdf
Aquatic
Animals. Toxicity:
On an acute basis, Fluoxastrobin is moderately
toxic to estuarine/marine fish; highly toxic to freshwater
fish and invertebrates; and very highly toxic to estuarine/marine
invertebrates. Chronic LOCs are also exceeded for
estuarine/marine invertebrates and mollusks. Chronic effects
for estuarine/marine invertebrates include reduced survival
and reductions in wet weight of surviving adults following
a 28-day exposure duration. No data were available to assess
the chronic toxicity of fluoxastrobin to estuarine/marine
mollusks. Therefore, the NOAEC value was estimated based
on the acute-to-chronic ratio for mysid shrimp. .. The ecological
risks to fish and invertebrates are considered conservative
estimates because they are based on worst case exposure
and use scenarios. Nonetheless, because of the potential
for exposure and possible adverse effects of fluoxastrobin
to endangered and nonendangered fish and invertebrates,
the registrant is required to provide information on the
proximity of Federally listed freshwater fish and invertebrates
to the fluoxastrobin use sites...
Risk
to Endangered Species The
preliminary risk assessment for endangered species indicates
that fluoxastrobin exceeds the endangered species LOCs for
the following combinations of analyzed uses and species:
•
Use of fluoxastrobin on the following crop scenarios
indicate an exceedance of the endangered species LOC for
freshwater fish: Maine potatoes
(ground and aerial application), Florida
tomatoes, peanuts, and turf (at the maximum application
rate of 4 times per year).
•
Use of fluoxastrobin on Idaho potatoes
(aerial application only), Maine
potatoes (ground and aerial application), tomatoes,
peppers, cabbage, peanuts, and turf (at maximum
[4x/year] and reduced [2x/year] application rates) indicate
endangered LOC exceedances for endangered freshwater invertebrates.
•
Use of fluoxastrobin on Idaho and
Maine potatoes (aerial and ground application),
tomatoes, peppers, cabbage, peanuts,
and turf (at maximum [4x/year] and reduced [2x/year]
application rates) indicate endangered
acute and chronic LOC exceedances for estuarine/marine
invertebrates.
•
Use of fluoxastrobin on Maine potatoes
(ground and aerial application), Florida
tomatoes, peppers, cabbage, peanuts, and turf in
Florida (at maximum [4x/year] application rates only)
and Pennsylvania (for applications
of both 4 and 2x/year) indicate
chronic LOC exceedances for estuarine/marine mollusks.
The
list of endangered/threatened freshwater fish species where
potatoes, tomatoes, peppers, and peanuts are grown is comprised
of 84 different species representing 36 States. The three
States with the largest number of endangered/threatened
freshwater fish species include California,
Washington, and Oregon. Within these States, the
majority of endangered/threatened fish species are salmon
and steel head (Orcorhynchus sp.). The predominant endangered
fish species in Florida and North
Carolina, where tomatoes, peppers, and peanuts are
grown, is the sturgeon (Acipenser sp.).
The
list is of freshwater invertebrates is primarily comprised
of bivalves (70% of all listed invertebrates; present in
20 States), crustaceans (i.e., amphipods, crayfish, and
shrimp) (~19 of all listed invertebrates; present in 6 States),
and snails (~11% of all listed invertebrates; present in
2 States). While the majority of listed freshwater invertebrates
are bivalves, the amphipod (Gammarus acherondytes) was listed
as endangered in Illinois. The identification of an endangered
amphipod is a factor because this species was identified
as the most sensitive freshwater invertebrate from the available
effects data. It appears, however, that the endangered amphipods
in Illinois are present only in caves, where pesticides
are not likely to be present in water at concentrations
that would cause adverse effects.
The
Agency’s levels of concern for endangered and threatened
freshwater fish and invertebrates and estuarine/marine invertebrates
and mollusks are exceeded for the use of fluoxastrobin.
However, the Agency recognizes that there are no Federally
listed estuarine/marine invertebrates/mollusks.
The
registrant must provide information on the proximity of
Federally listed freshwater fish and invertebrates to the
fluoxastrobin use sites. This requirement may be satisfied
in one of three ways:
1)
having membership in the FIFRA Endangered Species Task
Force (Pesticide Registration [PR] Notice 2000-2);
2)
citing FIFRA Endangered Species Task Force data; or
3)
independently producing these data, provided the information
is of sufficient quality to meet FIFRA requirements.
The
information will be used by the OPP Endangered Species Protection
Program to develop recommendations to avoid adverse effects
to listed species. The registrant has satisfied this requirement
using option #1 above.
Reference: November
2005 - US EPA Pesticide Fact Sheet: Fluoxastrobin.
http://www.fluorideaction.org/pesticides/fluoxastrobin.epa.fact.sheet.2005.pdf
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