Adverse Effects
Fipronil
CAS No.120068-37-3
 
 

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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

Table 5.35 - Thyroid hormone and TSH levels in males (page 124)
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

 
Day 7
Day 28
Dose of fipronil (ppm) T3 ng/dl T4 ug/dl TSH ng/ml T3 ng/dl T4 ug/dl TSH ng/ml
0 76.6 8.8 2.2 46.7 4.95 2.89
0.1 70.8 5.62 2.51 43.8 4.91 3.13
1 66.1* 5.62 2.87 43.2 4.61 3.54
5 66.5* 5.14* 3.05 47.9 4.63 4.84
30 65.3* 4.41*  334*
[sic? - 3.34]
 51.1  3.54* 6.27* 
      *statistically significant
Table 5.36 - Thyroid hormone and TSH levels in females (page 124)
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
 
Day 7
Day 28
Dose of fipronil (ppm) T3 ng/dl T4 ug/dl TSH ng/ml T3 ng/dl T4 ug/dl TSH ng/ml
0  76.3 4.08 0.83  76.5  3.72  0.93 
0.1  79.5 4.44  0.98  82.7  0.79 
1  82.3 4.27  0.77  86.3  3.88  0.67 
5  79.5 4.28  1.02  86.3  3.69  0.82 
30  66.7 3.32*  1.13  91.3  3.69  1.72* 
*statistically significant        

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]


 
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