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Abstracts
NTIS Reports
Activity: Acaracide,
Insecticide, Wood Preservative (pyrazole)
Structure:
Adverse
Effects:
Body
Weight Decrease
Bone
Brain
Cancer: Possible Human Carcinogen - THYROID
Cholesterol
Clastogenicity
CNS
Dermal
Endocrine:
Altered Sex Ratio
Endocrine: Pituitary - (disruption
in the thyroid-pituitary status)
Endocrine: Suspected Endocrine Disruptor
Endocrine: Testicular
Endocrine: Thyroid
Kidney
Liver
Lung
Reproductive/Developmental
Stomach
Environmental: Contamination
Environmental
-- Highly toxic to rainbow trout and very highly toxic to bluegill
sunfish
-- The sulfone metabolite is 6.3 times more toxic to rainbow trout
and 3.3 times more toxic than the parent compound to bluegill sunfish.
-- High toxicity to freshwater aquatic invertebrates. The sulfone
metabolite is 6.6 times more toxic and the desulfinyl photodegradate
1.9 times more toxic on an acute basis to freshwater invertebrates
than the parent compound.
-- Highly toxic to upland game birds.. The sulfone metabolite is
more toxic than the parent compound to certain bird species. This
metabolite has shown a very high toxicity toward upland game birds
...
-- Highly toxic to bees, lizards, and gallinaceous birds
•
As of February 14, 2005, this insecticide is permitted in
or on 18 food commodities
in the United States - see list at bottom of page.
•
August 2001: A Louisiana "court granted certification
for a class of crawfish farmers, finding they met all legal
requirements for class certification in the lawsuit filed
in Opelousas last year... During
the four days of trial, 36 witnesses testified, mainly crawfish
farmers and experts. More than a dozen farmers told the
same tale
- once their crawfish crop was contaminated
by Icon, the crawfish died. They became contaminated either
because the crawfish were harvested in Icon-treated rice
fields or because tailwater containing Icon or its metabolites
flooded the crawfish crop. Icon,
the product name for the chemical fipronil, was
commercially introduced in 1999. In 2000, Louisiana's crawfish
production dropped 40 percent. Although its purpose
is to kill the water weevils attacking rice plants, Icon,
according to the trial testimony of farmers and experts,
also kills crawfish..."
Ref:
AgJournal.com
http://www.fluorideaction.org/pesticides/fipronil.class.action.2002.htm
• 2009. Published study suggests that "fipronil is inherently a more potent disruptor of neuronal cell development than is chlorpyrifos."
• 2004. SPECIAL:
Louisiana crawfish farmers and landowners who suffered severe
losses due to Icon contamination receive $45 million in
a Class Action settlement. See:
•
A
little background on the geneology and events of the insecticide
Icon
• Index
to some documents and reports pertaining to the Class Action
•
News
Items related to the settlement
•
Australia: Fipronil is a broad-spectrum insecticide
that belongs to a relatively new class of pesticides. Fipronil
was first used in Australia as an agricultural chemical
product in 1994. It is now widely used in agriculture as
a seed dressing and for the control of locusts and a wide
range of other insect pests in pasture, agricultural crops
and domestic and commercial turf. Fipronil is also included
in a number of household products and commercial building
treatments such as cockroach baits and gels and in ant bait
stations. Fipronil is also used in veterinary chemical products
as a spray-on or concentrated spot-on formulation to control
fleas and ticks on cats and dogs. The veterinary chemical
use of fipronil has been registered since 1995.
Ref: September
2003 - The Reconsideration of Approvals and Registrations
Relating to FIPRONIL. REVIEW SCOPE DOCUMENT. Australian
Pesticides & Veterinary Medicines Authority Canberra Australia.
http://www.fluorideaction.org/pesticides/fipronil.australia.sept2003.pdf
Procedures
for destruction. Aventis has stated the following:
"Controlled
incineration of the formuation: as for active substances.
Incineration at 800ºC and 1200ºC, under excess oxygen,
with three minutes' retention time for the solids and
approximately two seconds' retention time for the gas,
results in a Destruction Removal Efficiency (DRE) of ≥99.99%
for the active ingredient. A large number of decomposition
products were identified especialy at 800ºC. A lesser
number of decomposition products were identified at 1200ºC.
Hydrogen fluoride was detected in the exhaust gas
with a concentration of approximately 330 mg/m3.
1.63% of the product stayed in the furnace after three
minutes of incineration at 800ºC, but only 0.54% stated
at approximately 200ºC. In both cass, less than 0.3% of
the active ingredient was measured in the residue".
(page 14).
Ref:
April 204. Evaluation
on : Fipronil (Horticultural Uses).
No. 212.
UK Dept. for Environment, Food and Rural Affairs, Pesticides
Safety Directory.
http://www.fluorideaction.org/pesticides/fipronil.uk.report.apr.2004.pdf
|
Body
Weight Decrease
(click on for all fluorinated pesticides)
--
18-month dietary study in mice. A
78-week dietary carcinogenicity study was carried out in the mouse
(52 animals/sex/group, CD-1-strain). ... At termination at 30
ppm, food consumption was decreased by 7% (mals) and 14% (females),
whilst bodyweight gain was decreased by 14% (males) and 19% (females,
P<0.05). Body weights of animals sacrificed at 53 weeks were
significantly decreased in males only at
30 ppm. ...(page 93)
Ref:
April 204. Evaluation
on : Fipronil (Horticultural Uses).
No. 212.
UK Dept. for Environment, Food and Rural Affairs, Pesticides Safety
Directory.
http://www.fluorideaction.org/pesticides/fipronil.uk.report.apr.2004.pdf
Australia: ANIMAL SAFETY
ISSUES. Adverse experiences involving veterinary chemical products
containing fipronil have been reported regularly since the products
were first registered. Patterns that appear to have emerged involve
the development of certain clinical signs including skin reactions,
neurological signs, lethargy, anorexia
and in some cases death. In Australia there have been 56 suspect
adverse experience reports for dogs classified as being either
probably or possibly associated with fipronil. In 21 of those
reports (38%) there was concurrent infestation with the dog paralysis
tick, Ixodes holocyclus. Of these reports, 9 involved death of
the dog...
Ref:
September
2003 - The Reconsideration of Approvals and Registrations Relating
to FIPRONIL. REVIEW SCOPE DOCUMENT. Australian Pesticides & Veterinary
Medicines Authority Canberra Australia.
http://www.fluorideaction.org/pesticides/fipronil.australia.sept2003.pdf
•
Reproductive and developmental toxicity. The
developmental toxicity NOELs in the rat
and rabbit were 20 mg/kg/day (HDT) and 1 mg/kg/day (HDT),
respectively.
Maternal toxicity was observed in the rat at the HDT as evidenced
by decreased body weight gain and
food efficiency. In
the rabbit, the maternal toxicity
NOAEL was less than 0.1 mg/kg/day, based
on reduced body weight gain and food efficiency at all
dose levels tested. The NOEL for reproductive toxicity
was 30 ppm (2.64 mg/kg/day for both sexes combined), based on
clinical signs of toxicity in pups,
decreased litter size, decreased pup body weights, decreased
mating, decreased fertility index, reduced pre- and postnatal
survival, and delays in physical development at
300 ppm (26.03 and 28.40 mg/kg/day for males and females, respectively).
• In
a developmental neurotoxicity study in the rat,
the NOAEL for maternal toxicity was 10 ppm
(0.91 mg/kg/day), based on decreased body weights and body
weight gain at 200 ppm (HDT; 15 mg/kg/day).
Considerable maternal toxicity at the HDT prevented adequate neurotoxicity
evaluation of pups at this dose level.
There was no evidence of neurotoxicity at 10 ppm (0.91
mg/kg/day), which was the NOAEL for developmental neurotoxicity.
The NOAEL for general developmental toxicity
was 0.5 ppm (0.05 mg/kg/day), based on systemic effects consisting
of decreases in pup weights during
lactation and increases in time of preputial
separation in males at 10 ppm.
• Subchronic
toxicity.The
NOAELs in the dog
were 2 and 0.5 mg/kg/day for male and female,
respectively, based on clinical signs of toxicity in males at
10 mg/kg/day and clinical signs of toxicity and decreased
body weight gain in females at 2 mg/kg/day.
The NOAEL for mice was 10 ppm (1.27
and 1.72 mg/kg/day for males and females, respectively), based
on a possible decreased body weight
gain at 25 ppm (3.2 and 4.53 mg/kg/day for males and females,
respectively). A repeated dose dermal study in the rabbit
had a systemic NOAEL of 5 mg/kg/day, based on decreased
body weight gain and food consumption at 10 mg/kg/day,
and a dermal irritation NOEL of 10.0 mg/kg/day (HDT).
•
Chronic toxicity.
The NOAEL for systemic toxicity in mice
was 0.5 ppm (0.06 mg/kg/day) based on decreased
body weight gain, decreased food conversion efficiency in males,
increased liver weights, and liver histopathology
at 10 ppm (1.3 mg/kg/day).
• Acute neurotoxicity. The
NOEL was 2 mg/kg, based on decreases in body weight gain and food
consumption in
males and females during the week following treatment, decreases
in locomotor activity, hind-limb splay and rectal temperature
6-hour post dosing in males and females, and decreases in the
proportion of males with an immediate righting reflex on days
7 and 14, at 12 mg/kg/day.
•
Subchronic toxicity. The
NOAEL in the rat was 3 ppm (0.18
and 0.21 mg/kg/day in males and females, respectively), based
on clinical signs of toxicity in both sexes and decreased
body weight and body weight gain in males at 10 ppm.
Ref: August 24, 2005.
Federal Register. Fipronil; Notice of Filing a Pesticide Petition
to Establish a Tolerance for a Certain Pesticide Chemical in or
on Food.
http://www.fluorideaction.org/pesticides/fipronil.fr.aug.24.2005.html
-- An acceptable subchronic
oral toxicity [capsule] study in the dog
established that the LOEL is 10.0 mg/kg/day for males (based on
clinical signs of toxicity) and 2.0 mg/kg/day for females (based
on clinical signs of toxicity and decreased
body-weight gain). The NOEL is 2.0 mg/kg/day for males
and 0.5 mg/kg/day for females.
-- An acceptable repeated dose dermal study using the
rat found that the systemic LOEL was 10 mg/kg/day based
on decreased body-weight gain and
food consumption; the dermal irritation LOEL is greater than 10.0
mg/kg/day. The systemic NOEL was 5.0 mg/kg/day; the dermal irritation
NOEL was greater than or equal to 10.0 mg/kg/day.
-- A acceptable carcinogenicity [feeding] study in the mouse
using fipronil found that the LOEL is 10 ppm (1.181 mg/kg/day
for males and 1.230 mg/kg/day for females) based on decreased
body-weight gain, decreased food conversion efficiency
(males), increased liver weights and increased incidence of hepatic
histopathological changes. The NOEL is 0.5 ppm (0.055 mg/kg/day
for males and 0.063 mg/kg/day for females). The study demonstrated
that fipronil is not carcinogenic to CD-1 mice when administered
at doses of 30 ppm.
-- Fipronil. a. An acceptable prenatal developmental study in
the rat found that the maternal toxicity
LOEL was 20 mg/kg/day based on reduced body-weight
gain, increased water consumption, reduced food consumption,
and reduced food efficiency. The maternal toxicity NOEL was 4
mg/kg/day. The developmental toxicity LOEL was greater than 20
mg/ [[Page 38486]] kg/day. Developmental toxicity NOEL was 20
mg/kg/day or higher.
-- An acceptable prenatal developmental study in the rabbit
found that the maternal toxicity LOEL was 0.1 mg/kg/day
or lower, based on reduced body-weight gain,
reduced food consumption and efficiency. Maternal toxicity NOEL
was less than 0.1 mg/kg/day. The developmental toxicity LOEL was
greater than 1.0 mg/kg/day. The developmental toxicity NOEL was
1.0 mg/kg/day or higher.
-- An acceptable acute neurotoxicity study in the rat
concluded that the NOEL was 2.5 mg/kg. The LOEL is 7.5
mg/kg, based on decreased body-weight gains,
food consumption and feed efficiency in females, decreased hindlimb
splay in males (at 7-hours post test) and decreased grooming in
females (14-days post test).
-- MB46513. An acceptable prenatal developmental study using the
rat found that the maternal toxicity LOEL was 2.5 mg/kg/day
and the NOEL was 1.0 mg/kg/day based an increase in clinical signs
of toxicity (reduced body-weight gain,
food consumption and food efficiency). The Developmental Toxicity
LOEL was 2.5 mg/kg/day and the NOEL was 1.0 mg/ kg/day based on
the slight increase in fetal and litter incidence of reduced ossification
of several bones.
-- The LOEL for reproductive toxicity was 300 ppm (26.03 mg/kg/day
for males and 28.40 mg/kg/day for females) based on clinical signs
of toxicity in the F1 and F2 offspring;
decreased litter size in the F1 and F2 litters;
decreased body weights in the F1
and F2 litters; decrease in the percentage of F1
parental animals mating; reduction in fertility index in F1
parental animals; reduced post- implantation survival and offspring
postnatal survivability in the F2 litters; and delay in physical
development in the F1 and F2 offspring.
The NOEL for reproductive toxicity was 30 ppm (2.54 mg/kg/day
for males and 2.74 mg/kg/day for females).
-- In a developmental neurotoxicity study, fipronil was administered
to 30 female rats/group in the diet
at dose levels of 0, 0.5, 10, or 200 ppm (0.05, 0.90, or 15 mg/kg/day,
respectively) from gestation day 6 to lactation day 10. This study
found that the maternal LOEL was 200 ppm (15 mg/kg/day), based
on decreased body weight, body- weight gain,
and food consumption. The maternal NOEL was 10 ppm (0.90 mg/kg/day).
The developmental toxicity LOEL is 10 ppm (0.9 mg/kg/day), based
on a marginal but statistically significant
decrease in group mean pup weights during lactation and
significant increase in time of preputial separation in males.
The NOEL for developmental toxicity is 0.5 ppm (0.05 mg/kg/day).
The developmental neurotoxicity LOEL is 200 ppm (15 mg/kg/day)
based on: Decreased auditory startle response; reduced swimming
direction scores, group mean angle measurements, and water ``Y''
maze times trails; and decreased absolute-brain weights. The NOEL
for developmental neurotoxicity is 10 ppm (0.90 mg/kg/day).
-- MB46513. An acceptable acute neurotoxicity study in the rat
concluded that the neurobehavioral LOEL for rats is 12
mg/kg based on decreases in body-weight
gains and food consumption for males and females during
the week following treatment, significant decreases in locomotor
activity 6-hours post dosing for both males and females, decreases
in hind-limb splay and rectal temperature at 6-hours post dose
in males and females, decreases in the proportion of high-dose
males with an immediate righting reflex on days 7 and 14. Decreased
forelimb grip strength in males on day 7 and increased forelimb
grip strength in high-dose females at 6-hours post dosing was
possibly related to the treatment, because there were also slight
increases in forelimb grip strength in high-dose males at 6 hours
and slight
-- MB46513. An acceptable 28-day dietary range-finding study in
the rat measured thyroid hormone
levels as well as standard study parameters. It found that the
LOEL is 30 ppm (2.20 and 2.32 mg/kg/day for males and females,
respectively), based on clinical signs including piloerection,
curling up and thin appearance; and decreased
body weights in both sexes. The NOEL is 3 ppm (0.23 and
0.24 mg/kg/day for males and females, respectively).
Ref: Federal Register: July 17, 1998. Fipronil;
Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Fipronil.FR.July.17.1998.htm
Bone
(click on for all fluorinated
pesticides)
Acute
neurotoxicity. The
NOEL was 2 mg/kg, based on decreases in body weight gain and food
consumption in
males and females during the week following treatment, decreases
in locomotor activity, hind-limb splay and rectal temperature
6-hour post dosing in males and females, and decreases in the
proportion of males with an immediate righting reflex on days
7 and 14, at 12 mg/kg/day. In a
rat developmental toxicity study, the NOEL was 1 mg/kg/day,
based on the slight increase in fetal
and litter incidence of reduced ossification of several bones
at 2.5 mg/kg/day.
Ref: August 24, 2005.
Federal Register. Fipronil; Notice of Filing a Pesticide Petition
to Establish a Tolerance for a Certain Pesticide Chemical in or
on Food.
http://www.fluorideaction.org/pesticides/fipronil.fr.aug.24.2005.html
The Developmental Toxicity
LOEL was 2.5 mg/kg/day and the NOEL was 1.0 mg/ kg/day based on
the slight increase in fetal and litter incidence of reduced ossification
of several bones... (hyoid,
5th/6th sternebrae, 1st thoracic vertebral body, pubic bone, and
one or two metatarsi)...
Ref: Federal Register. July 17, 1998. Fipronil;
Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Fipronil.FR.July.17.1998.htm
Brain
(click
on for all fluorinated pesticides)
... "Fipronil inhibited DNA and protein synthesis in undifferentiated PC12 cells and evoked oxidative stress to a greater extent than did chlorpyrifos, resulting in reduced cell numbers even though cell viability was maintained. In differentiating cells, fipronil displayed an even lower threshold for disruption of development, reducing cell numbers without impairing cell growth, and promoting emergence of neurotransmitter phenotypes; superimposed on this effect, the phenotypic balance was shifted in favor of dopamine as opposed to acetylcholine. Differentiation also enhanced the susceptibility to fipronil-induced oxidative stress, although antioxidant administration failed to provide protection from cell loss. At low concentrations maintained for prolonged periods, fipronil had a biphasic effect on cell numbers, increasing them slightly at low concentrations, implying interference with apoptosis, while nevertheless reducing cell numbers at higher concentrations. Our results suggest that fipronil is inherently a more potent disruptor of neuronal cell development than is chlorpyrifos. The neurodevelopmental effects are not predicated on GABA(A) antagonist properties, since PC12 cells lack the GABA(A) receptor..."
Ref: Lassiter TL, MacKillop EA, Ryde IT, Seidler FJ, Slotkin TA. 2009. Is fipronil safer than chlorpyrifos? Comparative developmental neurotoxicity modeled in PC12 cells. Brain Res Bull. 78(6):313-22. March 30.
http://www.ncbi.nlm.nih.gov/pubmed/18977280?ordinalpos=24&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
The NOEL for developmental
toxicity is 0.5 ppm (0.05 mg/kg/day). The developmental neurotoxicity
LOEL is 200 ppm (15 mg/kg/day) based on: Decreased auditory startle
response; reduced swimming direction scores, group mean angle
measurements, and water ``Y'' maze times trails; and decreased
absolute-brain weights. The NOEL for developmental neurotoxicity
is 10 ppm (0.90 mg/kg/day).
Ref: Federal Register. July 17, 1998. Fipronil;
Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Fipronil.FR.July.17.1998.htm
Fipronil
is the first phenylpyrazole insecticide introduced for pest control.
Although fipronil is known to inhibit GABA receptors, the detailed
mechanism of action remains to be seen. In order to elucidate
the mechanism of fipronil interaction with the mammalian GABAA
system, single-channel patch clamp experiments were performed
using rat dorsal root ganglion neurons. The amplitude of main
conductance state (27pS) current was not significantly altered
by co-application of 10 microM fipronil and 10 microM GABA. The
histograms of open time distribution were fitted to a sum of three
exponential functions. After application of 10 microM fipronil,
the proportion of the fastest component increased slightly and
that of the slowest component decreased slightly. Thus, the mean
open time was decreased from 11.4 ms to 7.8 ms by fipronil. The
histograms of closed time distribution were fitted to a sum of
four exponential functions. Fipronil 10 microM prolonged the slowest
time constant resulting in a prolongation of the mean closed time
from 29.7 ms to 52.8 ms. Thus, the frequency of channel openings
was reduced. Thus, the fipronil suppression
of GABA-induced whole-cell currents is caused in part by decreases
in the channel open time and the frequency of channel openings.
Ref: Pest
Manag Sci. 2004 May;60(5):487-92. Fipronil modulation of GABAA
receptor single-channel currents; by Ikeda T, Nagata K, Kono Y,
Yeh JZ, Narahashi T.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11052715&dopt=Abstract
Excerpt from absract:
The long-term objective is to define the fundamental basis for
the selective toxicity of insecticides acting
at the gamma-aminobutyric acid (GABA) receptor of mammals and
insects. This is the target of major neurotoxic insecticides acting
as both blockers and activators of the GABA-gated chloride channel.
More than 5,000,000,000 pounds of these channel blockers have
been used for pest control in the past 50 years and they range
in chlorine content from 52-73%. The major channel blockers used
at present, representing 6% of the insecticide market, are endosulfan
and lindane and this market share will increase
with expanded use of the newly-commercialized polyhalogenated
fipronil....
Ref: GABAERGIC
INSECTICIDE TOXICOLOGY; by CASIDA JE. From
Toxline at Toxnet. 2002. Supporting Agency: U.S. DEPT. OF HEALTH
AND HUMAN SERVICES; PUBLIC HEALTH SERVICE; NATIONAL INSTITUTES
OF HEALTH, NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES.
(See full abstract at
Toxline or
http://www.fluorideaction.org/pesticides/fipronil.abstracts.htm
The
long-term goal of the proposed study is to
elucidate the mechanism by which neuroactive insecticides exert
their toxic actions ... In
order to elucidate the physiological mechanisms of selective toxicity,
patch clamp data on the kinetics of receptors/channels and those
of insecticide modification will be compared between rat and cockroach
neurons for fipronil modulation of GABA
receptors, imidacloprid modulation of neuronal nicotinic
acetylcholine receptors (nnAChRs) ...
Ref:
Mode of Action of Insecticides: Electrophysiological; by
NARAHASHI T. 2002. Supporting Agency: U.S. DEPT. OF HEALTH
AND HUMAN SERVICES; PUBLIC HEALTH SERVICE; NATIONAL INSTITUTES
OF HEALTH, NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE.
(See
full abstract at
Toxline or
http://www.fluorideaction.org/pesticides/fipronil.abstracts.htm
Cancer:
Possible Human Carcinogen - THYROID (click
on for all fluorinated pesticides)
Group
C -- Possible Human Carcinogen.
Thyroid follicular cell adenomas,
carcinomas & combined adenomas/carcinomas (M); thyroid follicular
cell adenomas and combined adenomas/carcinomas (F); Charles River
CD rats.
Ref: April
26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the
Office of Pesticide Programs. From: Jess Rowland, Chief Science
Information Management Branch Health Effect Division (7509C) Office
of Pesticide Programs, USEPA.
http://www.fluorideaction.org/pesticides/pesticides.cancer.potential.2006.pdf
Group
C--Possible Human Carcinogen.
Reviewed 7/ 18/ 95.
Ref:
List of Chemicals Evaluated for Carcinogenic Potential. Science
Information Management Branch, Health Effects Division, Office
of Pesticide Programs, U. S. Environmental Protection Agency.
March 15, 2002.
http://www.biomuncie.org/chemicals_evaluated_for_carcinog.htm
Cancer.
The EPA's Health Effects Division Carcinogenicity
Peer Review Committee classified fipronil in Group
C - Possible Human Carcinogen, based on thyroid tumors observed
in rats at 300 ppm (HDT). Mechanistic data indicate that these
tumors are related to a disruption in the thyroid-pituitary status
and are specific to the rat. In addition,
there was no apparent concern for mutagenic activity. Thus, it
was recommended that RfD methodology, i.e. non-linear or threshold,
be used for the estimation of human risk.
Ref:
August 24, 2005. Federal Register. Fipronil; Notice of Filing
a Pesticide Petition to Establish a Tolerance for a Certain Pesticide
Chemical in or on Food.
http://www.fluorideaction.org/pesticides/fipronil.fr.aug.24.2005.html
-- Carcinogenic classification
and risk quantification. EPA has classified this chemical as a
Group C--Possible Human Carcinogen, based on increases in
thyroid follicular-cell tumors in both sexes of the rat,
which were statistically significant
by both pair-wise and trend analyses. EPA has used the RfD methodology
to estimate human risk because the thyroid
tumors are due to a disruption in the thyroid-pituitary
status. There was no apparent concern for mutagenicity.
Ref:
Federal Register: July 17, 1998. Fipronil; Pesticide Tolerance.
Final Rule.
http://www.fluoridealert.org/pesticides/Fipronil.FR.July.17.1998.htm
CNS
(click
on for all fluorinated pesticides)
•
Acute neurotoxicity. The
NOEL was 2 mg/kg, based on decreases in
body weight gain and food consumption
in males and
females during the week following treatment, decreases
in locomotor activity, hind-limb splay and
rectal temperature 6-hour
post dosing in males and females, and decreases
in the proportion of males with an immediate righting reflex
on days 7 and 14, at 12 mg/kg/day.
•
Subchronic toxicity. The
NOAEL in the rat was 3 ppm (0.18
and 0.21 mg/kg/day in males and females, respectively), based
on clinical signs of toxicity in both sexes and decreased body
weight and body weight gain in males at 10 ppm. The NOEL
for the mouse was 0.5 ppm (0.08
mg/kg/day), based on the aggressive and
irritable behavior with increased motor activity in males at 2
ppm. The
NOEL for the dog was 9.5 ppm
(0.29 mg/kg/day), based on behavioral changes
in females at 35 ppm (1.05 mg/kg/day).
• Subchronic
neurotoxicity study in
rats,
the NOEL was 5 ppm (0.301 and 0.351 mg/kg/day for males and females,
respectively), based on results of the functional
observational battery (FOB) at 150 ppm (8.89 and 10.8 mg/kg/day
for males and females, respectively).
•
Chronic toxicity. The
NOAEL for systemic toxicity in a 1-year feeding study in the
dog was 0.3 mg/kg/day in females and 1 mg/kg/day in males,
based on clinical signs of neurotoxicity at 1 and 2 mg/kg/day
in females and males, respectively.
• In
a developmental neurotoxicity study in the rat,
the NOAEL for maternal toxicity was 10 ppm
(0.91 mg/kg/day), based on decreased body weights and body weight
gain at 200 ppm (HDT; 15 mg/kg/day). Considerable maternal
toxicity at the HDT prevented adequate neurotoxicity evaluation
of pups at this dose level. There was no evidence of neurotoxicity
at 10 ppm (0.91 mg/kg/day), which was the NOAEL for developmental
neurotoxicity.
Ref: August 24, 2005.
Federal Register. Fipronil; Notice of Filing a Pesticide Petition
to Establish a Tolerance for a Certain Pesticide Chemical in or
on Food.
http://www.fluorideaction.org/pesticides/fipronil.fr.aug.24.2005.html
(pages 127-128) - Diagnosis of
poisoning. The applicant [Aventis] submits the following
proposal (shown by italic text). (The ACP advised that some amendments
should be made, these are indicated by struckthrough/bold font
for deleted/new text respectively).
Fipronil is a reversible gamma-aminobutyric acid (GABA)
receptor inhibitor. During intoxication, it
will induce neurological stimulation with possible convulsions.
Signs and symptoms which appear the most relevant for humans
may be observed after acute or repeated over-exposure.
These signs mainly consist of central nervous system (CNS) hyperexcitability:
over-activity, irritability, tremors, and, at a more severe
state, lethargy or convulsions. These symptoms are reversible
after termination of exposure.
In the rat, clear signs of toxicity were observed following
a single oral administation of fipronil at a dose of 50 mg/kg/body
weight while minimal symptoms were observed at 5 mg/kg bodyweight.
Due to slow absorption through the gut, symptoms of intoxication
may be delayed for several hours to one day. Fipronil does not
readily penetrate skin. Therefore absorption should be minimal
following dermal exposure. Symptoms are expected only after
repeated excessive exposure.
Measurement of fipronil and its metabolites in the blood (or
in the gastric lavage) is the only way to definitively
confirm exposure. In cases of suspected intoxication evidenced
by symptoms, a blood sample should be taken as soon after the
alleged exposure as possible and may be sent
to:
Aventis Rhone-Poulenc Agro
Toxicology Department
Centre de Recherche
355, Rue Dostoievski
B.P. 153
F-06903 Sophia Antipolis Cedex
FRANCE
Attention: Dr Pierre-Gerard Pontal
Ref:
April 204. Evaluation
on : Fipronil (Horticultural Uses).
No. 212.
UK Dept. for Environment, Food and Rural Affairs, Pesticides
Safety Directory.
http://www.fluorideaction.org/pesticides/fipronil.uk.report.apr.2004.pdf
Cholesterol
(click
on for all fluorinated pesticides)
An acceptable chronic
rat feeding study identified the following effects: seizures,
including seizures resulting in death, decreased body weight gain,
decreased food consumption and food conversion efficiency, decreased
hematology measures, alterations in clinical chemistry (cholesterol,
calcium, and protein), alterations in thyroid hormones, alterations
in urine chemistry, changes on gross necropsy, increase in liver
and thyroid weights, and progressive senile nephropathy (kidney
effects). The NOEL for systemic toxicity was 0.5 ppm. The LOEL
of 1.5 ppm was based on an increase in incidence of clinical signs
and alterations in clinical chemistry and thyroid parameters.
Based on this study, the RfD Committee recommended that the RfD
be established using the NOEL and an uncertainty factor of 100
to account for the interspecies extrapolation and intraspecies
variability. The RfD was set at 0.0002 mg/kg/day.
Ref: US EPA. New Pesticide Fact Sheet. May
1996.
http://www.fluoridealert.org/pesticides/Fipronil.EPA.Facts.May.1996.htm
Clastogenic
(click
on for all fluorinated pesticides)
-- Chinese hamster lung cells were treated at different concentations
of fipronil (batch number 1747, 98.3%pure) in 1995 in duplicate
cultures to examine its potential to induce chromosomal aberrations
in the presence or absence of S9 rat liver metabolic activating
fracion (derived from Arochlor induced rats). The concentrations
tested (see Table 5.14, page 87) were chosen on the basis of preliminary
cytotoxicity tests ...There was a dose related increase in aberrations
at six hours in the absence of S9 (statistically
significant at the top two doses), and a possible increase
in the presence of S9 (although the increase at 60 ug fipronil/ml
was not statistically significant). The increases in aberrations
were due to increases in chromatid breaks and chromatid exchanges.
The mechanism is not considered to be due to cytotoxicity (i.
as outlined by Kirkland/1) as large proportion of the aberrations
seen were chromatid exchanges, whereas only breaks usually characterise
the mechanism relating to cytotoxicity ... To
conclude fipronil was clastogenic under the conditions of this
assay. (pages 86-87).
Summary of genotoxicity studies
... Although the in vitro cytogenetics assay in Chinese
hamster lung cells was positive, the mouse micronucleus test indicated
that the test material was not actually clastogenic in vivo.
It is considered unlikely that a second in vivo assay in a diferent
tissue is likely to produce anything other than a negative result.
The lack of any tumours that could be attributed to direct genotoxic
action in the rat and mouse chronic studies also support the lack
of in vivo genotoxicity by fipronil. (page 89)
Ref:
April 204. Evaluation
on : Fipronil (Horticultural Uses).
No. 212.
UK Dept. for Environment, Food and Rural Affairs, Pesticides Safety
Directory.
http://www.fluorideaction.org/pesticides/fipronil.uk.report.apr.2004.pdf
Definitions:
In vivo
= In a living cell or organism.
In
vitro
= In an experimental situation outside the organism.
Biological or chemical work done in the test tube (in
vitro is Latin for "in glass") rather than in
living systems.
|
Dermal
(click
on for all fluorinated pesticides)
Australia: The APVMA
has received a number of human and animal adverse experience reports
involving products containing fipronil. Reports include skin
reactions in animals and humans, neurological signs and
deaths in target animals (often involving concurrent infestations
with paralysis ticks) and deaths following off- label use in domesticated
rabbits... The first reports of adverse effects in humans were
received in 1996 for the veterinary spray formulation and involved
reactions in humans who had applied the spray to pets. Since then,
53 reports of suspected adverse effects in humans involving both
the spray and the concentrated spot-on formulation have been received
(Table 1). Of these reports 43 have been considered by the APVMA
as possibly or probably linked to product use. The link to product
use is considered to be Òunlikely or unknownÓ for the remaining
ten reports (Table 2). Skin reactions are
the predominant adverse experience reported for pet owners.
Some reactions did not occur during the application of the products
but after skin contact with the treated cat fur or dog hair...
The existing toxicological database does
not predict an immune- mediated reaction in humans or the incidences
of dermal reactions in animals... Products containing fipronil
for use in agriculture or on animals are registered world- wide.
In the United States, the Department of Pesticide Regulation (Californian
Environmental Protection Agency) initiated a review of registered
pesticide products containing fipronil in November 2001 based
on human health concerns. Review findings have not yet been released...
Ref:
September
2003 - The Reconsideration of Approvals and Registrations Relating
to FIPRONIL. REVIEW SCOPE DOCUMENT. Australian Pesticides & Veterinary
Medicines Authority Canberra Australia.
http://www.fluorideaction.org/pesticides/fipronil.australia.sept2003.pdf
Endocrine:
Altered Sex Ratio
(click on for all fluorinated pesticides)
Abstract: Copepods
are the most abundant arthropods on earth and are often the most
important secondary producers in estuarine/marine food webs. The
new GABA (gamma-aminobutyric acid)-disrupting insecticide fipronil
(FP) induces unique sex-specific reproductive dysfunction in male
meiobenthic copepods, leading to trans-generational population
depression at environmentally realistic concentrations (0.63 microg/L).
Using a newly developed 96-well microplate lifecycle bioassay,
more than 700 individual Stage-I juveniles were reared to adulthood
in as short as 12 days in only 200 microL of control (CTL) or
0.63 microg-FP/L seawater solution. Individual virgin male: female
pairs were then cross-mated for all possible combinations within
and across rearing treatments and allowed to mate for an additional
12 days in CTL or 0.63 microg-FP/L solution. FP at 0.63 microg/L
caused no significant lethality to any mating combinations but
evoked 73% or 89% inhibition of reproduction when FP-reared males
were mated with either a control- or FP-reared female in FP solution,
respectively. In contrast, when CTL-reared males were mated with
FP-reared females in FP solution, there was no difference in reproductive
success compared to FP-free controls. When FP-reared males were
mated with either female group in FP-free solution, these mating
pairs displayed a 3-day delay in time to brood sac extrusion but
ultimately did reproduce. As fipronil (1)
has a high K(ow), (2) is persistent in sediments where meiobenthic
copepods live, and (3) has been detected in estuarine waters >0.7
microg/L, it may pose high risk to copepod production in estuarine
systems.
Ref:
Environ Sci Technol. 2004 Jan 15;38(2):522-8. Phenylpyrazole insecticide
fipronil induces male infertility in the estuarine meiobenthic
crustacean Amphiascus tenuiremis; by Cary TL, Chandler GT, Volz
DC, Walse SS, Ferry JL.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14750729
Endocrine:
Pituitary (click
on for all fluorinated pesticides)
-- Reproduction
toxicity studies. The data base for reproductive toxicity
is considered complete. No additional studies are required at
this time. An acceptable two-generation reproduction study in
the rat using fipronil concluded that the LOEL for parental (systemic)
toxicity was 30 ppm (2.54 mg/kg/day for males and 2.74 mg/kg/day
for females) based on increased weight of the
thyroid glands and liver in males and females;
decreased weight of the pituitary gland in females; and
an increased incidence of follicular epithelial
hypertrophy in the females. The NOEL for parental (systemic) toxicity
was 3 ppm (0.25 mg/ kg/day for males and 0.27 mg/kg/day
for females).
-- Carcinogenic classification and risk
quantification. EPA has classified this chemical as a Group
C--Possible Human Carcinogen, based on increases in
thyroid follicular-cell tumors
in both sexes of the rat, which were statistically significant
by both pair-wise and trend analyses. EPA has used the RfD methodology
to estimate human risk because the thyroid tumors are due
to a disruption in the thyroid-pituitary
status. There was no apparent concern for mutagenicity.
Ref: Federal Register: July 17, 1998. Fipronil;
Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Fipronil.FR.July.17.1998.htm
Reproductive
and developmental toxicity. In
a two-generation rat study, the NOEL for
parental (systemic) toxicity was 3 ppm (0.26 mg/kg/day for both
sexes combined), based on increased
weight of the thyroid glands and liver in males and females,
decreased weight of the pituitary gland in females, and
an increased incidence of follicular epithelial hypertrophy in
females at 30 ppm.
Ref: August 24, 2005.
Federal Register. Fipronil; Notice of Filing a Pesticide Petition
to Establish a Tolerance for a Certain Pesticide Chemical in or
on Food.
http://www.fluorideaction.org/pesticides/fipronil.fr.aug.24.2005.html
Endocrine:
Suspected Endocrine Disruptor (click
on for all fluorinated pesticides)
Endocrine
disruption.
Data from the reproduction/ developmental toxicity and short-
and long-term repeated dose toxicity studies with fipronil in
the rat, rabbit, mouse, or dog, do not suggest any endocrine disruption
activity. This information is based on the absence of any treatment-related
effects from the histopathological examination of reproductive
organs as well as the absence of possible effects on fertility,
reproductive performance, or any other aspect of reproductive
function, or on growth and development of the offspring. Evidence
of offspring toxicity was observed only in the presence of significant
parental toxicity. Fipronil disrupts the
thyroid-pituitary axis. However,
mechanistic studies have demonstrated that fipronil decreases
thyroid hormone levels in long-term studies via increased clearance,
rather than a direct effect on the thyroid. Concerns related to
long-term exposure of fipronil are addressed in human risk estimates,
as the chronic RfD (0.0002 mg/kg/day) is based on endpoints that
include thyroid hormone related effects in rats.
Ref:
August 24, 2005. Federal Register. Fipronil; Notice of Filing
a Pesticide Petition to Establish a Tolerance for a Certain Pesticide
Chemical in or on Food.
http://www.fluorideaction.org/pesticides/fipronil.fr.aug.24.2005.html
Abstract: The purpose
of the present study was to investigate possible reproductive
adverse effects of fipronil (Frontline TopSpot)
in female Wistar rats. The pesticide
was topically applied to rats (single dose) at different concentrations
(70, 140 and 280 mg/kg) and hormonal analysis, estrous cycle,
and pregnancy and outcome data were determined. Treatment
with fipronil altered cyclicity of
female rats lengthening the estrous cycle (days) after a single
topic administration of 70 mg/kg (9.7+/-1.18) or 280 mg/kg (14.5+/-1.45)
when compared to control (4.8+/-0.17). In
the mating study fipronil reduced
the pregnancy index (67%) in the highest
dose group (280 mg/kg). Plasma progesterone and estradiol
levels, obtained in different periods after treatment with fipronil
(70 mg/kg), were significantly different 96 h after treatment,
when compared to controls. In summary, the results of
the present study indicate that fipronil may alter the normal
functioning of the endocrine system and cause adverse reproductive
effects in female rats.
Ref:
Reproductive adverse effects of fipronil in Wistar rats. Ohi M,
Dalsenter PR, Andrade AJ, Nascimento AJ. Toxicol Lett. 2004 Jan
15;146(2):121-7.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14643964
Abstract:
Vitellogenin (VTG) has been widely used as a biomarker of estrogenic
exposure in fish, leading to the development of standardized assays
for VTG quantification. However, standardized quantitative assays
for invertebrate, particularly crustacean, lipovitellin (also
known as vitellin [VTN]) are lacking. In this study, a fluorescence-based
VTN enzyme-linked immunosorbent assay (ELISA) was developed to
quantify microquantities of VTN in the estuarine, sediment-dwelling
copepod Amphiascus tenuiremis. This ELISA utilizes a VTN-specific
polyclonal antibody developed against amphipod (Leptocheirus plumulosus)
embryo VTN and exhibits specificity toward female copepod proteins.
In routine assays, the working range of the ELISA was 31.25 to
1,000 ng/ml (75-25% specific binding/maximum antibody binding
[B/B0]) with a 50% B/B0 intra- and interassay variation of 3.9%
(n = 9) and 12.5% (n = 26), respectively. This ELISA is capable
of detecting VTN as low as 2 ng/ml, and can accurately detect
VTN in as few as four copepods. The ELISA significantly discriminated
positive (gravid female) and negative (male) samples, and was
suitable for screening endocrine toxicity in copepods. Stage-I
juvenile copepods were individually reared to adults in aqueous
microvolumes of the phenylpyrazole insecticide, fipronil, and
whole-body homogenate extracts were assayed for VTN levels. Fipronil-exposed
virgin adult females, but not males, exhibited significantly higher
levels of VTN relative to control males and females. This crustacean
VTN ELISA is likely useful for evaluating endocrine activity of
environmental toxicants in copepods and other crustacean species.
Ref: Environ Toxicol Chem. 2004 Feb;23(2):298-305.
An
enzyme-linked immunosorbent assay for lipovitellin quantification
in copepods: a screening tool for endocrine toxicity; by Volz
DC, Chandler GT.
The purpose of the
present study was to investigate possible reproductive adverse
effects of fipronil (Frontline TopSpot)
in female Wistar rats. The pesticide
was topically applied to rats (single dose) at different concentrations
(70, 140 and 280 mg/kg) and hormonal analysis, estrous cycle,
and pregnancy and outcome data were determined. Treatment
with fipronil altered cyclicity of female rats lengthening the
estrous cycle (days) after a single topic
administration of 70 mg/kg (9.7+/-1.18) or 280 mg/kg (14.5+/-1.45)
when compared to control (4.8+/-0.17).
In the mating study fipronil reduced
the pregnancy index (67%) in the highest dose group (280 mg/kg).
Plasma progesterone and estradiol levels, obtained in different
periods after treatment with fipronil (70 mg/kg), were significantly
different 96 h after treatment, when compared to controls. In
summary, the results of the present study indicate that fipronil
may alter the normal functioning of the endocrine system and cause
adverse reproductive effects in female rats.
Ref:
Toxicol Lett. 2004 Jan 15;146(2):121-7. Reproductive adverse effects
of fipronil in Wistar rats; by Ohi M, Dalsenter PR, Andrade AJ,
Nascimento AJ.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14643964
Suspected
Endocrine Disruptor
Ref:
PAN Pesticides Database
Suspected
Endocrine Disruptor
Ref: June 14, 2001 - Implementation of the
Community Strategy for Endocrine Disruptors - a range of substances
suspected of interfering with the hormone systems of humans and
wildlife. Communication from the Commission to the Council and
the European Parliament. Commission of the European Communities,
Brussels COM (2001) 262 final.
http://www.fluoridealert.org/pesticides/Endocrine.Disruptors.EC2001.pdf
More information available at:
http://europa.eu.int/eur-lex/en/com/cnc/2001/com2001_0262en01.pdf
Endocrine:
Testicular
(click
on for all fluorinated pesticides)
-- In
a developmental neurotoxicity study, fipronil was administered
to 30 female rats/group in the diet
at dose levels of 0, 0.5, 10, or 200 ppm (0.05, 0.90, or 15 mg/kg/day,
respectively) from gestation day 6 to lactation day 10. This study
found that the maternal LOEL was 200 ppm (15 mg/kg/day), based
on decreased body weight, body- weight gain,
and food consumption. The maternal NOEL was 10 ppm (0.90 mg/kg/day).
The developmental toxicity LOEL is 10 ppm (0.9 mg/kg/day), based
on a marginal but statistically significant decrease in group
mean pup weights during lactation and significant
increase in time of preputial [forseskin]
separation in males.
The NOEL for developmental toxicity is 0.5 ppm (0.05 mg/kg/day).
The developmental neurotoxicity LOEL is 200 ppm (15 mg/kg/day)
based on: Decreased auditory startle response; reduced swimming
direction scores, group mean angle measurements, and water ``Y''
maze times trails; and decreased absolute-brain weights. The NOEL
for developmental neurotoxicity is 10 ppm (0.90 mg/kg/day).
Ref: Federal Register: July 17, 1998. Fipronil;
Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Fipronil.FR.July.17.1998.htm
In
a developmental neurotoxicity study in the rat,
the NOAEL for general developmental
toxicity was 0.5 ppm (0.05 mg/kg/day), based on systemic effects
consisting of decreases in pup weights during lactation and
increases in time of preputial separation in males at 10 ppm.
Ref: August 24, 2005.
Federal Register. Fipronil; Notice of Filing a Pesticide Petition
to Establish a Tolerance for a Certain Pesticide Chemical in or
on Food.
http://www.fluorideaction.org/pesticides/fipronil.fr.aug.24.2005.html
Endocrine:
Thyroid
(click on for all fluorinated
pesticides)
•
Chronic toxicity. The
NOAEL for systemic toxicity in a 1-year feeding study in the
dog was 0.3 mg/kg/day in females
and 1 mg/kg/day in males, based on clinical signs of neurotoxicity
at 1 and 2 mg/kg/day in females and males, respectively.
The NOAEL for systemic toxicity in mice
was 0.5 ppm (0.06 mg/kg/day) based on decreased
body weight gain, decreased food conversion efficiency in males,
increased liver weights, and liver histopathology at 10 ppm (1.3
mg/kg/day). Fipronil was not carcinogenic when administrated to
mice at dose levels up to 60 ppm. The NOAEL in a 2-year dietary
study in the rat
was 0.5 ppm (0.019 and 0.025 mg/kg/day for
males and females, respectively) based on
clinical signs of toxicity and alterations
in clinical chemistry and thyroid parameters at 1.5 ppm
(0.059 and 0.078 mg/kg/day for males and
females, respectively).
• Cancer. The EPA's Health Effects
Division Carcinogenicity Peer Review Committee classified fipronil
in Group C - Possible Human Carcinogen,
based on thyroid tumors observed in rats at 300 ppm (HDT). Mechanistic
data indicate that these tumors are related to a disruption in
the thyroid-pituitary status and are specific to the rat.
In addition, there was no apparent concern
for mutagenic activity. Thus, it was recommended that RfD methodology,
i.e. non-linear or threshold, be used for the estimation of human
risk.
•
Reproductive and developmental toxicity.
In a two-generation rat study, the
NOEL for parental (systemic) toxicity was
3 ppm (0.26 mg/kg/day for both sexes combined), based on
increased weight of the thyroid glands and
liver in males and females, decreased
weight of the pituitary gland in females, and an
increased incidence of follicular epithelial hypertrophy in females
at 30 ppm.
• Subchronic
toxicity. The
NOAEL for systemic toxicity in
rat was 5 ppm (0.35 mg/kg/day for
both sexes combined), based on alterations
in serum protein values and increased weight of the liver
and thyroid at 30 ppm (1.93 and 2.28 mg/kg/day for males and females,
respectively).
•
Endocrine disruption.
Data from the reproduction/ developmental
toxicity and short- and long-term repeated dose toxicity studies
with fipronil in the rat, rabbit, mouse, or dog, do not suggest
any endocrine disruption activity. This information is based on
the absence of any treatment-related effects from the histopathological
examination of reproductive organs as well as the absence of possible
effects on fertility, reproductive performance, or any other aspect
of reproductive function, or on growth and development of the
offspring. Evidence of offspring toxicity was observed only in
the presence of significant parental toxicity. Fipronil
disrupts the thyroid-pituitary axis. However,
mechanistic studies have demonstrated that fipronil decreases
thyroid hormone levels in long-term studies via increased clearance,
rather than a direct effect on the thyroid. Concerns related to
long-term exposure of fipronil are addressed in human risk estimates,
as the chronic RfD (0.0002 mg/kg/day) is based on endpoints that
include thyroid hormone related effects in rats.
Ref:
August 24, 2005. Federal Register. Fipronil; Notice of Filing
a Pesticide Petition to Establish a Tolerance for a Certain Pesticide
Chemical in or on Food.
http://www.fluorideaction.org/pesticides/fipronil.fr.aug.24.2005.html
-- Reproduction
toxicity studies. The data base for reproductive toxicity
is considered complete. No additional studies are required at
this time. An acceptable two-generation reproduction study in
the rat using fipronil concluded that the LOEL for parental (systemic)
toxicity was 30 ppm (2.54 mg/kg/day for males and 2.74 mg/kg/day
for females) based on increased weight of the
thyroid glands and liver in males and females; decreased
weight of the pituitary gland in females;
and an increased incidence of follicular
epithelial hypertrophy in the females. The NOEL
for parental (systemic) toxicity was 3 ppm (0.25 mg/ kg/day for
males and 0.27 mg/kg/day for females).
-- Carcinogenic classification and risk
quantification. EPA has classified this chemical as a Group
C--Possible Human Carcinogen, based on increases in
thyroid follicular-cell tumors in both sexes of the rat,
which were statistically significant
by both pair-wise and trend analyses. EPA has used the RfD methodology
to estimate human risk because the thyroid
tumors are due to a disruption in the thyroid-pituitary
status. There was no apparent concern for mutagenicity.
Ref: Federal Register: July 17, 1998. Fipronil;
Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Fipronil.FR.July.17.1998.htm
Short-term toxicity.
-- 28 day dietary administration to rats.
Technical-grade fipronil (batch number IGB 464, purity, 93%) was
administered in the diet for four weeks to groups of five Cr1:CD
(SD) BR rats of each sex at concentrations of 25, 50, 100, 200,
or 400 ppm, equal to 3.4, 6.9, 13, 24, or 45 mg/kg bw per day
for males and 3.5, 6.7, 13, 25, or 55 mg/kg bw per day for females
... The target organs were the liver and
thyroid. Liver weights were significantly
increased in females at all doses and in males at 200 and 400
ppm. At necropsy, liver
enlargement was observed in one or both sexes starting at 50 ppm,
and five males and three females at 400 pm had enlarged livers.
Generalised hepatocyte enlargement was observed microscopically
in one male at 100 ppm, with increasing incidence in animals of
each sex at 200 and 400 ppm. Thyroid follicular-cell
hypertropy, generally of minimal severity but of moderate severity
in several males at 200 and 400 ppm, was found in almost all treated
animals but not in the controls. (page 77)
-- 90-day dietary administration to rats. In a 13-week
study, rats (CD strain 10/sex/group) received dietary administration
of either 1, 5, 30 or 300 ppm fipronil (batch number PGS 963,
95.4% purity). This was equivalent to 0.07, 0.3, 2.1 or 22 mg/kg/d.
Doses were selected after a preliminary 14-d study showed deaths
(3/10 animals by 5 d) and muscular spasms at 30 mg/kg/d ...Absolute
thyroid weights were elevated (4.2-100% at 5-300 ppm) achieving
statistical significance at ≥30 ppm in females and at 300
ppm in males ... Histopathological
examination found treatment-related effects at the top dose in
the thyroids and livers of both sexes. Oil
red O staining revealed a high incidence of fat deposits in all
liver samples, including controls. A
statistically significant increase in panacinar hepatic fatty
vacuolation (controls 0/10 and 7/10 at 300 ppm) was reported in
males only. (page 78-79)
Ref:
April 204. Evaluation
on : Fipronil (Horticultural Uses).
No. 212.
UK Dept. for Environment, Food and Rural Affairs, Pesticides Safety
Directory.
http://www.fluorideaction.org/pesticides/fipronil.uk.report.apr.2004.pdf
--2 year dietary study
in rats. The carcinogenic potential of fipronil was determined
in a 2-year study carried out in the rat (CD strain). Animals
(50/sex/dose) received dietary administration of fipronil (batch
number PGS, 95.4% purity) at either 0.5, 1.5, 30 or 300 ppm; equivalent
to 0.02, 0.06, 1.3 and 13 mg/kg/d (males) and 0.03, 0.08, 1.6
and 17 mg/kg/d (females). (page 89)
-- At study termination histopathological findings were confined
to a statistically signifiicant increase in progressive senile
nephropathy in males and thyroid "follicular
cysts" (growth anomaly) at ≤30 ppm in females. (page
91)
-- A
significant increase was observed
in the incidences of thyroid follicular
cell adenomas and carcinomas in both sexes at the top dose (300
ppm); these exceeded the historical control incidence)
(page 95)
--
Reproductive Toxicity. Dietary two-generation
study in rats. In a two-generation study, CD rats (30 animals/sex/dose)
werre administered fipronil (batch number PGS 974, 95.4% purity)
in the diet at 3, 30 or 300 pm, equivalent to 0.25, 2.5 or 26
mg/k/g bw per day for males and 0.27, 2.7 an 28 mg/kg bw per day
for females. FO adults were treated for 71 d before mating (1
male to 1 female pairing), throughout the mating period (up to
21 d) and then throughout gestation and lactation of the liter
(F1a). Approximately 10 d after weaning (25 d post partum) of
the F1a pups, animals administered 3 or 30 ppm, as well as the
control group, were paired a second time to produce an F1b generation.
The F1a litters were randomly adjusted to 8 pups on 4 d post partum
and, after weaning, 30 animals/sex/dose were selected to form
the F1 parents. F1 parents were treated from weaning for a minimum
of 10 weeks and then paired (1 male to 1 female) to produce an
F2 generation. F1 adult treatment continued until F2 pups were
weaned. ... At necropsy no treatment -related macroscopic changes
were noted in adults or pups. In adults there were increases,
often significant, in absolute and relative liver (10-15% and
15-40% at 30 and 300 ppm) and thyroid weights (15-25% and 25-50%
at 30 and 300 ppm). ... In F1 adults histopathological examination
showed a significant increaee in incidence of liver centrilobular
fatty vacuolation in females (1/29 in controls, 6/27 at 300 ppm)
and thyroid follicular hypertrophy in both
sexes (males 0/28 in controls, 9/30 at 300 ppm and females 0/29
in controls, 15/27 at 300 ppm). (pages 96-97)
Ref:
April 2004. Evaluation
on : Fipronil (Horticultural Uses).
No. 212.
UK Dept. for Environment, Food and Rural Affairs, Pesticides Safety
Directory.
http://www.fluorideaction.org/pesticides/fipronil.uk.report.apr.2004.pdf
Excerpts
from: Table 5.17 Treatment -related effects
in the 24 month rat dietary study (page 92)
Ref:
April 204. Evaluation
on : Fipronil (Horticultural Uses).
No. 212.
UK Dept. for Environment, Food and Rural Affairs, Pesticides
Safety Directory.
http://www.fluorideaction.org/pesticides/fipronil.uk.report.apr.2004.pdf
|
|
-Males- |
-Females- |
ppm |
|
0 |
0.5 |
1.5 |
30 |
300 |
0 |
0.5 |
1.5 |
30 |
300 |
Mg/kg/bw |
|
0 |
0.02 |
0.06 |
1.3 |
13 |
0 |
0.03 |
0.08 |
1.6 |
17 |
|
Week |
|
|
|
|
|
|
|
|
|
|
T4 |
24 |
4.58 |
3.81* |
3.35*** |
2.43*** |
0.76*** |
2.85 |
3.09 |
3/49** |
2.98 |
1.46*** |
|
50 |
5.95 |
5.51 |
4.83** |
3.9*** |
23.07*** |
3.31 |
3.46 |
3.00 |
2.06*** |
1.38*** |
Organ weights
(g) and macro-patholgology |
|
89
weeks males, 91 weeks females |
Thyroid
weight |
89/91 |
0.042 |
0.051* |
0.053* |
0.063** |
0.094** |
0.036 |
0.038 |
0.036 |
0.044 |
0.072* |
*P<0.05,
**P<0.01, ***P<0.001 |
Effects
on thyroid hormone levels.
A further study was carried out to determine the effects of fipronil
on circulating TSH, T3 and T4 levels. The concentrations of the
three hormones were determined by radioimmunoassay. Animals (10/sex/group,
Crl:CD (SD)BR) received dietary administration of fipronil (batch
number PGS 963, 98.4% purity) for 28 d ... The concentrations
of thyroid hormones and TSH for males and females respectively
can be found in Tables 5.35 and 5.36. The data presented are corrected
means, to allow an analysis of covariance to be carried out ...
The NOAEL for this study was 1 ppm (equivalent to 0.1 mg/kg/d),
based on increased thyroid follicular epithelial height at ≥5
ppm in males. (pages 123-125)
Ref:
April 204. Evaluation
on : Fipronil (Horticultural Uses).
No. 212.
UK Dept. for Environment, Food and Rural Affairs, Pesticides Safety
Directory.
http://www.fluorideaction.org/pesticides/fipronil.uk.report.apr.2004.pdf
Abstract: Of 240 pesticides
screened for carcinogenicity by the U.S. Environmental Protection
Agency Office of Pesticide Programs, at
least 24 (10%) produce thyroid follicular cell tumors in rodents.
Thirteen of the thyroid carcinogens also induce liver tumors,
mainly in mice, and 9 chemicals produce tumors at other sites.
Some mutagenic data are available on all 24 pesticides producing
thyroid tumors. Mutagenicity does not seem to be a major determinant
in thyroid carcinogenicity, except for possibly acetochlor; evidence
is less convincing for ethylene thiourea and etridiazole. Studies
on thyroid-pituitary functioning, including indications of thyroid
cell growth and/or changes in thyroxine, triiodothyronine, or
thyroid-stimulating hormone levels, are available on 19 pesticides.
No such antithyroid information is available for etridiazole,
N-octyl bicycloheptene dicarboximide, terbutryn, triadimefon,
and trifluralin. Of the studied chemicals, only bromacil lacks
antithyroid activity under study conditions.
Intrathyroidal and extrathyroidal sites of action are found:
amitrole, ethylene thiourea, and mancozeb are thyroid peroxidase
inhibitors; and acetochlor, clofentezine, fenbuconazole,
fipronil, pendimethalin, pentachloronitrobenzene, prodiamine,
pyrimethanil, and thiazopyr seem to enhance the hepatic metabolism
and excretion of thyroid hormone. Thus, with 12 pesticides that
mode of action judgments can be made, 11 disrupt thyroid-pituitary
homeostasis only; no chemical is mutagenic only; and acetochlor
may have both antithyroid and some mutagenic activity. More information
is needed to identify other potential antithyroid modes of thyroid
carcinogenic action.
Ref:
Environ Health Perspect. 1998 Aug;106(8):437-45. Mode
of carcinogenic action of pesticides inducing thyroid follicular
cell tumors in rodents. By Hurley PM. Office of Prevention,
Pesticides and Toxic Substances, U.S. Environmental Protection
Agency, Washington, DC 20460 USA.
Kidney
(click on for all fluorinated pesticides)
An acceptable chronic
rat feeding study identified the following effects: seizures,
including seizures resulting in death, decreased body weight gain,
decreased food consumption and food conversion efficiency, decreased
hematology measures, alterations in clinical chemistry (cholesterol,
calcium, and protein), alterations in thyroid hormones, alterations
in urine chemistry, changes on gross necropsy, increase in liver
and thyroid weights, and progressive senile
nephropathy (kidney effects).
The NOEL for systemic toxicity was 0.5 ppm.
Ref: US EPA Pesticide Fact Sheet. May 1996.
http://www.fluoridealert.org/pesticides/Fipronil.EPA.Facts.May.1996.htm
--2 year dietary study
in rats. The carcinogenic potential of fipronil was determined
in a 2-year study carried out in the rat (CD strain). Animals
(50/sex/dose) received dietary administration of fipronil (batch
number PGS, 95.4% purity) at either 0.5, 1.5, 30 or 300 ppm; equivalent
to 0.02, 0.06, 1.3 and 13 mg/kg/d (males) and 0.03, 0.08, 1.6
and 17 mg/kg/d (females). (page 89)
-- At study termination histopathological findings were confined
to a statistically signifiicant increase
in progressive senile nephropathy in males and
thyroid "follicular cysts" (growth anomaly) at ≤30
ppm in females. (page
91)
Ref:
April 204. Evaluation
on : Fipronil (Horticultural Uses).
No. 212.
UK Dept. for Environment, Food and Rural Affairs, Pesticides Safety
Directory.
http://www.fluorideaction.org/pesticides/fipronil.uk.report.apr.2004.pdf
Liver
(click
on for all fluorinated pesticides)
•
Reproductive and developmental toxicity. In
a two-generation rat study, the NOEL for
parental (systemic) toxicity was 3 ppm (0.26 mg/kg/day for both
sexes combined), based on increased
weight of the thyroid glands and liver
in males and females, decreased weight
of the pituitary gland in females, and
an increased incidence of follicular epithelial hypertrophy in
females at 30 ppm.
• Subchronic
toxicity. The
NOAEL for systemic toxicity in
rat was 5 ppm (0.35 mg/kg/day for
both sexes combined), based on alterations
in serum protein values and increased weight of the liver
and thyroid at 30 ppm (1.93 and 2.28 mg/kg/day
for males and females, respectively).
•
Chronic toxicity.
The NOAEL for systemic toxicity in mice
was 0.5 ppm (0.06 mg/kg/day) based on decreased
body weight gain, decreased food conversion efficiency in males,
increased liver weights, and liver histopathology at 10 ppm (1.3
mg/kg/day).
Ref: August 24, 2005.
Federal Register. Fipronil; Notice of Filing a Pesticide Petition
to Establish a Tolerance for a Certain Pesticide Chemical in or
on Food.
http://www.fluorideaction.org/pesticides/fipronil.fr.aug.24.2005.html
Short-term toxicity.
-- 28 day dietary administration to rats.
Technical-grade fipronil (batch number IGB 464, purity, 93%) was
administered in the diet for four weeks to groups of five Cr1:CD
(SD) BR rats of each sex at concentrations of 25, 50, 100, 200,
or 400 ppm, equal to 3.4, 6.9, 13, 24, or 45 mg/kg bw per day
for males and 3.5, 6.7, 13, 25, or 55 mg/kg bw per day for females
... The target organs were the liver and
thyroid. Liver weights were significantly increased in females
at all doses and in males at 200 and 400 ppm. At necropsy,
liver enlargement was observed in one or both sexes starting at
50 ppm, and five males and three females at 400 pm had enlarged
livers. Generalised hepatocyte enlargement was observed microscopically
in one male at 100 ppm, with increasing incidence in animals of
each sex at 200 and 400 ppm. Thyroid follicular-cell hypertropy,
generally of minimal severity but of moderate severity in several
males at 200 and 400 ppm, was found in almost all treated animals
but not in the controls. (page 77)
-- 90-day dietary administration to rats. In a 13-week
study, rats (CD strain 10/sex/group) received dietary administration
of either 1, 5, 30 or 300 ppm fipronil (batch number PGS 963,
95.4% purity). This was equivalent to 0.07, 0.3, 2.1 or 22 mg/kg/d.
Doses were selected after a preliminary 14-d study showed deaths
(3/10 animals by 5 d) and muscular spasms at 30 mg/kg/d ...
In males, the absolute liver weight was significantly increased
at the top dose only (42%). In females liver weights were elevated
in all treatment groups (4.6-35%) at 1-300 ppm), achieving statistical
significance at ≥5 ppm. Absolute thyroid weights
were elevated (4.2-100% at 5-300 ppm) achieving statistical significance
at ≥30 ppm in females and at 300 ppm in males ... Histopathological
examination found treatment-related effects at the top dose in
the thyroids and livers of both sexes. Oil red O staining revealed
a high incidence of fat deposits in all liver samples, including
controls. A statistically significant
increase in panacinar hepatic fatty vacuolation (controls
0/10 and 7/10 at 300 ppm) was reported in males only. (page 78-79)
Ref:
April 204. Evaluation
on : Fipronil (Horticultural Uses).
No. 212.
UK Dept. for Environment, Food and Rural Affairs, Pesticides Safety
Directory.
http://www.fluorideaction.org/pesticides/fipronil.uk.report.apr.2004.pdf
Lung
(click
on for all fluorinated pesticides)
The
rat chronic/carcinogenicity study was negative for carcinogenicity.
The LOAEL for females was 0.5 ppm (0.032 mg/kg/day), based on
clinical signs of toxicity. There was no NOEL established. For
males, the NOAEL was 2 ppm (0.098 mg/kg/day),
based on clinical signs of toxicity, and
stomach and lung histopathology at 10 ppm (0.497
mg/kg/day).
Ref: August 24, 2005.
Federal Register. Fipronil; Notice of Filing a Pesticide Petition
to Establish a Tolerance for a Certain Pesticide Chemical in or
on Food.
http://www.fluorideaction.org/pesticides/fipronil.fr.aug.24.2005.html
Reproductive
(click on for all fluorinated pesticides)
•
Reproductive and developmental toxicity. The
developmental toxicity NOELs in the rat
and rabbit were 20 mg/kg/day (HDT) and 1 mg/kg/day (HDT),
respectively.
Maternal toxicity was observed in the rat at the HDT as evidenced
by decreased body weight gain and
food efficiency. In
the rabbit, the maternal toxicity
NOAEL was less than 0.1 mg/kg/day, based
on reduced body weight gain and food efficiency at all
dose levels tested. In a two-generation
rat study, the NOEL for parental
(systemic) toxicity was 3 ppm (0.26 mg/kg/day for both sexes combined),
based on increased weight of the thyroid glands and liver
in males and females, decreased weight
of the pituitary gland in females, and
an increased incidence of follicular epithelial hypertrophy
in females at 30 ppm. The NOEL for reproductive toxicity
was 30 ppm (2.64 mg/kg/day for both sexes combined), based on
clinical signs of toxicity in pups, decreased
litter size, decreased pup body weights, decreased mating, decreased
fertility index, reduced pre- and postnatal survival, and delays
in physical development at 300 ppm (26.03 and 28.40 mg/kg/day
for males and females, respectively).
• In
a developmental neurotoxicity study in the rat,
the NOAEL for maternal toxicity was 10 ppm
(0.91 mg/kg/day), based on decreased body weights and body
weight gain at 200 ppm (HDT; 15 mg/kg/day).
Considerable maternal toxicity at the HDT prevented adequate
neurotoxicity evaluation of pups at this dose level. There
was no evidence of neurotoxicity at 10 ppm (0.91 mg/kg/day), which
was the NOAEL for developmental neurotoxicity. The
NOAEL for general developmental toxicity was 0.5 ppm (0.05 mg/kg/day),
based on systemic effects consisting of decreases
in pup weights during lactation and increases in time of preputial
separation in males at 10 ppm.
Ref: August 24, 2005. Federal Register.
Fipronil; Notice of Filing a Pesticide Petition to Establish a
Tolerance for a Certain Pesticide Chemical in or on Food.
http://www.fluorideaction.org/pesticides/fipronil.fr.aug.24.2005.html
Abstract: The purpose
of the present study was to investigate possible reproductive
adverse effects of fipronil (Frontline TopSpot)
in female Wistar rats. The pesticide
was topically applied to rats (single dose) at different concentrations
(70, 140 and 280 mg/kg) and hormonal analysis, estrous cycle,
and pregnancy and outcome data were determined. Treatment
with fipronil altered cyclicity of
female rats lengthening the estrous cycle (days) after a single
topic administration of 70 mg/kg (9.7+/-1.18) or 280 mg/kg (14.5+/-1.45)
when compared to control (4.8+/-0.17). In
the mating study fipronil reduced
the pregnancy index (67%) in the highest
dose group (280 mg/kg). Plasma progesterone and estradiol
levels, obtained in different periods after treatment with fipronil
(70 mg/kg), were significantly different 96 h after treatment,
when compared to controls. In summary, the results of the
present study indicate that fipronil may alter the normal functioning
of the endocrine system and cause adverse reproductive effects
in female rats.
Ref:
Reproductive adverse effects of fipronil in Wistar rats. Ohi M,
Dalsenter PR, Andrade AJ, Nascimento AJ. Toxicol Lett. 2004 Jan
15;146(2):121-7.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14643964
Stomach
(click
on for all fluorinated pesticides)
The
rat chronic/carcinogenicity study was negative for carcinogenicity.
The LOAEL for females was 0.5 ppm (0.032 mg/kg/day), based on
clinical signs of toxicity. There was no NOEL established. For
males, the NOAEL was 2 ppm (0.098 mg/kg/day),
based on clinical signs of toxicity, and
stomach and lung
histopathology at 10 ppm
(0.497 mg/kg/day).
Ref: August 24, 2005.
Federal Register. Fipronil; Notice of Filing a Pesticide Petition
to Establish a Tolerance for a Certain Pesticide Chemical in or
on Food.
http://www.fluorideaction.org/pesticides/fipronil.fr.aug.24.2005.html
Contamination
/ Environmental
(click on for all fluorinated pesticides)
--
2004. SPECIAL:
Louisiana crawfish farmers and landowners who suffered severe
losses due to Icon contamination receive $45 million in
a Class Action settlement. See:
• A
little background on the geneology and events of the insecticide
Icon
•
Index
to some documents and reports pertaining to the Class Action
•
News
Items related to the settlement
--
Crawfish farmers upset with Aventis
August
1, 2001
-- St. Landry Parish District Court Judge James Genovese
gave hundreds of Louisiana crawfish farmers a major victory
in their case against Aventis, the manufacturer of the rice
seed treatment Icon. In a July 30, 2001, ruling, the
court granted certification for a class of crawfish farmers,
finding they met all legal requirements for class certification
in the lawsuit filed in Opelousas last year. According
to Pat Morrow, an Opelousas attorney representing the farmers,
"Crawfish farmers who feel their crawfish harvests have
been damaged by Icon contamination can now come forward
and join this class action suit."
However, the court denied class status for local seed distributor
defendants. The class certification hearing began in April
and concluded in June.
Judge Genovese's ruling allows anyone claiming financial
losses and damages as a result of their crawfish crop's
exposure to Icon beginning in January 1999 to join the lawsuit
if he or she:
--
Purchased Icon-treated seed for rice operations in Louisiana,
or
-- Farmed crawfish in Louisiana, or
-- Participated in a sharecropping arrangement for the
farming of crawfish in Louisiana.
During
the four days of trial, 36 witnesses testified, mainly crawfish
farmers and experts. More than a dozen farmers told the
same tale - once their crawfish crop
was contaminated by Icon, the crawfish died. They became
contaminated either because the crawfish were harvested
in Icon-treated rice fields or because tailwater containing
Icon or its metabolites flooded the crawfish crop.
Icon,
the product name for the chemical fipronil, was commercially
introduced in 1999. In 2000, Louisiana's crawfish production
dropped 40 percent. Although its purpose is to kill the
water weevils attacking rice plants, Icon, according to
the trial testimony of farmers and experts, also kills crawfish.
Lousiana
State University (LSU) scientists last year announced a
possible link between Icon and crawfish mortality. In a
survey of more than 90 commercial ponds, LSU
scientists were told that in ponds where Icon-treated rice
had been seeded the year before, crawfish production was
generally well below average, says Dr. Greg Lutz,
an aquaculture specialist with the Louisiana Agricultural
Center. The survey was conducted in the 12 parishes that
have the greatest share of both rice fields and crawfish
ponds.
Dr. Ray McClain, professor at the LSU Ag Center's Rice Research
Station in Crowley, tested a worst-case scenario for crawfish
exposed to water that contained Icon-treated rice seed and
found that most did not survive.
"This was a study under extreme conditions that are unlikely
to occur in a natural setting," Dr. McClain says. "But we
felt if the crawfish could survive these simulated conditions,
then this would put to rest part of the controversy over
Icon. But it didn't."
McClain in 1999 conducted similar experiments in which water
containing Icon-treated seed did not significantly affect
crawfish. "We simulated normal crawfish-growing conditions
with the predominantly recommended rate of Icon," McClain
said of his 1999 research. These results were corroborated
by 1999 Aventis research. But in 2000, McClain increased
the temperature of the water, used the maximum allowable
rates of Icon and held the crawfish in the water longer.
Ref: AgJournal.com
http://www.fluorideaction.org/pesticides/fipronil.class.action.2002.htm
|
Environmental
(click
on for all fluorinated pesticides)
Note:
In the last 3 years several papers have been published on
adverse environmental effects. See abstracts
Fipronil
is considered highly toxic to rainbow
trout and very highly toxic to bluegill
sunfish with an LC50 of 0.246 ppm and 0.083 ppm, respectively.
In early life-stage studies on rainbow trout fipronil affected
larval growth with a NOEC of 0.0066 ppm and a LOEC (Lowest
Observable Effect Concentration) of 0.015 ppm. The
sulfone metabolite is 6.3 times more toxic to rainbow trout
and 3.3 times more toxic than the parent compound to bluegill
sunfish. Fipronil demonstrates
a high toxicity toward freshwater aquatic invertebrates
as well. In acute daphnia life cycle studies, fipronil affected
growth: daphnid length was decreased at concentrations greater
then 9.8 ppb. The sulfone metabolite is 6.6 times more toxic
and the desulfinyl photodegradate 1.9 times more toxic on
an acute basis to freshwater invertebrates than the parent
compound (U.S. EPA 1996).
-- according to the ecological effects data on upland game
birds, fipronil is highly toxic on
an acute oral basis and very highly toxic on a sub-acute
dietary basis. The oral LC50 for Bobwhite quail is 11.3
mg/kg, and the LC50 for 5-day dietary is 49 mg/kg (U.S
EPA, 1996).
-- The sulfone metabolite is
more toxic than the parent compound to certain bird species.
This metabolite has shown a very high
toxicity toward upland game birds and moderate toxicity
toward waterfowl on an acute oral basis (U.S. EPA 1996,
Bobe et al., 1997).
Ref: December
2001 - ENVIRONMENTAL
FATE OF FIPRONIL by Pete Connelly. Environmental Monitoring
Branch, Department of Pesticide Regulation, California Environmental
Protection Agency.
Vitellogenin
(VTG) has been widely used as a biomarker of estrogenic
exposure in fish, leading to the development of standardized
assays for VTG quantification ... Stage-I juvenile copepods
were individually reared to adults in aqueous microvolumes
of the phenylpyrazole insecticide, fipronil, and whole-body
homogenate extracts were assayed for VTN levels. Fipronil-exposed
virgin adult females, but not males, exhibited significantly
higher levels of VTN relative to control males and females.
This crustacean VTN ELISA is likely useful for evaluating
endocrine activity of environmental toxicants in copepods
and other crustacean species.
Ref: Environ Toxicol Chem. 2004 Feb;23(2):298-305.
An
enzyme-linked immunosorbent assay for lipovitellin quantification
in copepods: a screening tool for endocrine toxicity;
by Volz DC, Chandler GT.
...
One of its main degradation products, fipronil desulfinyl,
is generally more toxic than the parent compound and is
very persistent. There is evidence
that fipronil and some of its degradates may bioaccumulate,
particularly in fish. Further investigation on bioaccumulation
is warranted, especially for the desulfinyl degradate. The
suitability of fipronil for use in IPM must be evaluated
on a case-by-case basis. In certain
situations, fipronil may disrupt natural enemy populations,
depending on the groups and species involved and the timing
of application. The indications are that fipronil may be
incompatible with locust IPM; hence, this possibility requires
further urgent investigation. It is
very highly toxic to termites and has severe and long-lasting
negative impacts on termite populations. It thus presents
a long-term risk to nutrient cycling and soil fertility
where termites are "beneficial" key species in these ecological
processes. Its toxicity to termites also increases the risk
to the ecology of habitats in which termites are a dominant
group, due to their importance as a food source to many
higher animals. This risk has
been demonstrated in Madagascar, where two endemic species
of lizard and an endemic mammal decline in abundance because
of their food chain link to termites. Fipronil
is highly toxic to bees (LD50 = 0.004 microgram/bee),
lizards [LD50 for Acanthodactylus dumerili (Lacertidae)
is 30 micrograms a.i./g bw], and gallinaceous
birds (LD50 = 11.3 mg/kg for Northern bobwhite quail),
but shows low toxicity to waterfowl (LD50 > 2150 mg/kg for
mallard duck). It is moderately toxic to laboratory mammals
by oral exposure (LD50 = 97 mg/kg for rats; LD50 = 91 mg/kg
for mice). Technical fipronil is in toxicity categories
II and III, depending on route of administration, and is
classed as a nonsensitizer. There
are indications of carcinogenic action in rats at 300 ppm,
but it is not carcinogenic to female mice at doses
of 30 ppm. The acute toxicity of fipronil varies widely
even in animals within the same taxonomic groups. Thus,
toxicological findings from results on standard test animals
are not necessarily applicable to animals in the wild. Testing
on local species seems particularly important in determining
the suitability of fipronil-based products for registration
in different countries or habitats and the potential associated
risk to nontarget wildlife. Risk
assessment predictions have shown that some fipronil formulations
present a risk to endangered bird, fish, and aquatic and
marine invertebrates. Great
care should thus be taken in using these formulations
where they may impact any of these endangered wildlife groups.
Work in Madagascar has highlighted field evidence of this
risk. The dose levels at which fipronil
produces thyroid cancer in rats are very high and
are unlikely to occur under normal conditions of use. There
is also dispute as to whether this is relevant to human
health risk. However, as fipronil is a relatively new insecticide
that has not been in use for long enough to evaluate the
risk it may pose to human health, from data on human exposure
to the product, a precautionary approach
may be warranted. The use of some fipronil-based
products on domestic animals is not recommended where handlers
spend significant amounts of time grooming or handling treated
animals. In general, it would appear unwise to use fipronil-based
insecticides without accompanying environmental and human
health monitoring, in situations, regions, or countries
where it has not been used before, and where its use may
lead to its introduction into the wider environment or bring
it into contact with people. Further
work is needed on the impacts of fipronil on nontarget vertebrate
fauna (amphibians, reptiles, birds, and mammals)
in the field before the risk to wildlife from this insecticide
can be adequately validated. Further field study of the
effects of fipronil on the nutrient cycling and soil water-infiltration
activities of beneficial termites is required to assess
the ecological impacts of the known toxicity of fipronil
to these insects.
Ref:
Fipronil:
environmental fate, ecotoxicology, and human health concerns;
by Tingle CC, Rother JA, Dewhurst CF, Lauer S, King WJ.
Rev Environ Contam Toxicol. 2003;176:1-66.
Copepods
are the most abundant arthropods on earth and are often
the most important secondary producers in estuarine/marine
food webs. The new GABA (gamma-aminobutyric
acid)-disrupting insecticide fipronil (FP) induces unique
sex-specific reproductive dysfunction in male meiobenthic
copepods, leading to trans-generational population depression
at environmentally realistic concentrations (0.63 microg/L).
Using a newly developed 96-well microplate lifecycle bioassay,
more than 700 individual Stage-I juveniles were reared to
adulthood in as short as 12 days in only 200 microL of control
(CTL) or 0.63 microg-FP/L seawater solution. Individual
virgin male: female pairs were then cross-mated for all
possible combinations within and across rearing treatments
and allowed to mate for an additional 12 days in CTL or
0.63 microg-FP/L solution. FP at 0.63 microg/L caused no
significant lethality to any mating combinations but evoked
73% or 89% inhibition of reproduction when FP-reared males
were mated with either a control- or FP-reared female in
FP solution, respectively. In contrast, when CTL-reared
males were mated with FP-reared females in FP solution,
there was no difference in reproductive success compared
to FP-free controls. When FP-reared males were mated with
either female group in FP-free solution, these mating pairs
displayed a 3-day delay in time to brood sac extrusion but
ultimately did reproduce. As fipronil
(1) has a high K(ow), (2) is persistent in sediments where
meiobenthic copepods live, and (3) has been detected in
estuarine waters >0.7 microg/L, it may pose high risk
to copepod production in estuarine systems.
Ref: Environ Sci Technol. 2004 Jan
15;38(2):522-8. Phenylpyrazole
insecticide fipronil induces male infertility in the estuarine
meiobenthic crustacean Amphiascus tenuiremis; by Cary
TL, Chandler GT, Volz DC, Walse SS, Ferry JL
Excerpt
from Abstract: ... Because the presence of sublethal doses
or concentrations may also alter the behavior of foraging
insects, we attempted to devise a quantifiable and accurate
protocol for evidencing various alterations in free-flying
bees. Such a protocol was illustrated by testing new classes
of systemic insecticides. The protocol focused on video
recording to quantify the foraging activity of small colonies
of honey bees confined in insect-proof tunnels ... Two
plant-systemic insecticides were tested at contamination
levels 70 times lower than the 50% of the lethal concentration.
Imidacloprid, at 6 microg/kg, clearly induced a decrease
in the proportion of active bees. Fipronil,
at 2 microg/kg, induced an additional decrease in attendance
at the feeder. Such levels
are still higher than the corresponding lowest observable
effect concentration (LOEC). Our protocol, which
provided intermediate conditions between field and laboratory
conditions, allowed the quantification, with an enhanced
level of sensitivity, of sublethal effects on foraging bees.
Ref: A
method to quantify and analyze the foraging activity of
honey bees: relevance to the sublethal effects induced by
systemic insecticides. By Colin ME et al. Arch Environ
Contam Toxicol. 2004 Oct;47(3):387-95
Reptiles
in arid and semiarid zones are frequently exposed to insecticides
sprayed to control locusts and grasshoppers. We evaluated
the toxicity and pathogenicity of new biological and chemical
control agents to the fringe-toed lizard Acanthodactylus
dumerili in Mauritania, West Africa ... The second agent
tested was fipronil (Adonis), a phenylpyrazole insecticide.
A single dose of 30 microg fipronil/g body weight was administered
via contaminated prey or stomach instillation. The percentage
of dead or moribund lizards at four weeks posttreatment
was 62.5% in animals fed contaminated prey and 42.0% in
gavaged animals. In both tests, survivors showed significantly
reduced feeding activity, food consumption, body weight,
and organ-to-body-weight ratios (liver and/or fat body).
The high toxicity of fipronil to lizards
was not previously known, suggesting that follow-up studies
(e.g., subacute dietary tests) are needed to provide adequate
data for risk assessment.
Ref: Environ Toxicol Chem. 2003 Jul;22(7):1437-47.
Toxicity
and pathogenicity of Metarhizium anisopliae var. acridum
(Deuteromycotina, Hyphomycetes) and fipronil to the fringe-toed
lizard Acanthodactylus dumerili (Squamata: Lacertidae);
by Peveling R, Demba SA.
|
A
February 13, 2005, check at the Code
of Federal Regulations for Fipronil: this insecticide
(including its metabolitesis and
its photodegradate)
is permitted in
or on 18 food commodities
in the United States. The following
list identifies these crops for which EPA has set pesticide
tolerances.
|
[Code
of Federal Regulations]
[Title 40, Volume 22]
[Revised as of July 1, 2004]
From the U.S. Government Printing Office via GPO Access
[CITE: 40CFR180.517]
[Page 489-490]
TITLE 40--PROTECTION OF ENVIRONMENT
CHAPTER I--ENVIRONMENTAL PROTECTION AGENCY (CONTINUED)
PART 180_TOLERANCES AND EXEMPTIONS FROM TOLERANCES FOR PESTICIDE
CHEMICALS
IN FOOD--Table of Contents
Subpart C_Specific Tolerances
Sec. 180.517 Fipronil; tolerances for residues.
(a) General. Therefore, tolerances are established for
combined
residues of the insecticide fipronil (5-amino-1-[2,6-dichloro-4-
(trifluoromethyl)phenyl]-4-[(1R,S)-(trifluoromethyl)sulfinyl]-1H-
pyrazole-3-carbonitrile) and its metabolites
5-amino-1-[2,6-dichloro-4-
(trifluoromethyl)phenyl]-4-[(trifluoromethyl) sulfonyl]-1H-pyrazole-3-
carbonitrile and 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)
phenyl]-4-
[[Page 490]]
[(trifluoromethyl)thio]-1H-pyrazole-3-carbonitrile and
its
photodegradate 5-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl]-4-
[(1R,S)-(trifluoromethyl)]-1H-pyrazole-3-carbonitrile in or
on the
following items at the levels specified: |
Commodity |
As
of
September 30,
2003
PPM |
As
of
February 14,
2005
PPM |
CFR |
Corn,
field, forage |
0.15 |
0.15 |
180.517
|
Corn,
field, grain |
0.02 |
0.02 |
180.517
|
Corn,
field, stover |
0.30 |
0.30 |
180.517
|
Egg |
0.03 |
0.03 |
180.517
|
Fat
of cattle, goat, horse and sheep |
Not
listed this way |
0.40 |
180.517
|
Hog
Fat |
0.04 |
0.04 |
180.517
|
Hog
Liver |
0.02 |
0.02 |
180.517
|
Hog
Meat Byproducts, except liver |
0.01 |
0.01 |
180.517
|
Hog
Meat |
0.01 |
0.01 |
180.517
|
Liver
of cattle, goat, horse and sheep |
Not
listed this way |
0.10 |
180.517
|
Meat
Byproducts, except liver of cattle, goat, horse and sheep |
Not
listed this way |
0.04 |
180.517
|
Meat
of cattle, goat, horse and sheep |
Not
listed this way |
0.04 |
180.517
|
Milk,
fat (reflecting 0.05 ppm in whole milk) |
1.50 |
1.50 |
180.517
|
Poultry
Fat |
0.05 |
0.05 |
180.517
|
Poultry
Meat |
0.02 |
0.02 |
180.517
|
Poultry
Meat Byproducts |
0.02 |
0.02 |
180.517
|
Rice,
grain |
0.04 |
0.04 |
180.517
|
Rice,
straw |
0.10 |
0.10 |
180.517
|
HORSE,
FAT |
0.40 |
Not
listed this way |
180.517
|
HORSE,
LIVER |
0.10 |
Not
listed this way |
180.517
|
HORSE,
MBYP (EXC. LIVER) |
0.04 |
Not
listed this way |
180.517
|
HORSE,
MEAT |
0.04 |
Not
listed this way |
180.517
|
CATTLE,
FAT |
0.40 |
Not
listed this way |
180.517
|
CATTLE,
LIVER |
0.10 |
Not
listed this way |
180.517
|
CATTLE,
MBYP (EXC LIVER) |
0.04 |
Not
listed this way |
180.517
|
CATTLE,
MEAT |
0.04 |
Not
listed this way |
180.517
|
GOAT,
FAT |
0.40 |
Not
listed this way |
180.517
|
GOAT,
LIVER |
0.10 |
Not
listed this way |
180.517
|
GOAT,
MBYP (EXC. LIVER) |
0.04 |
Not
listed this way |
180.517
|
GOAT,
MEAT |
0.04 |
Not
listed this way |
180.517
|
SHEEP,
FAT |
0.40 |
Not
listed this way |
180.517
|
SHEEP,
LIVER |
0.10 |
Not
listed this way |
180.517
|
SHEEP,
MBYP (EXC LIVER) |
0.04 |
Not
listed this way |
180.517
|
SHEEP,
MEAT |
0.04 |
Not
listed this way |
180.517
|
(b)
Section 18 emergency exemptions. [Reserved]
(c) Tolerances with regional registrations. [Reserved]
(d) Indirect or inadvertent residues. [Reserved] |
|