**EPA REGISTRATION DIVISION -**  **COMPANY NOTICE OF FILING FOR PESTICIDE**

**PETITIONS Docket ID N** **um ber**  **: EPA -** **HQ -** **OPP -** **2011 -** **0985 EPA Registration Division Contact: Sidney Jackson (703**  **- 305** **- 7610)**  **Pesticide Petition**  **Number :**  **1 E7** **942** EPA has received a pesticide petition **( PP) 1E7942**  from the **Interregional Research Project Number 4 (IR** **- 4),**  **IR -** **4 Project**  **Headquaters ,**  **500 College Road East, Suite 201W, Princeton, New Jersey, 08540,**  proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance for residues of **the combined residues of the insecticide flonicamid [N** **- (cyanomethyl)** **- 4**  **- (** **trifl uoromethyl)** **- 3**  **- p** **y ridinecarboxamide** **]and its metabolites TFNA [4**  **- trifluoromethylnicotinic acid], TFNA** **- AM [4**  **- trifluoromethylnicotinamide] and TFNG [N** **- (4**  **- trifluoromethylnicotinoyl)glycine] in or on the raw agricultural commodities**  **: B**  **erry, low growing, subgroup**  **13 -** **07G at**  **1 .4 parts per million (ppm),**  **C ucumber**  **at 1 .3**  **ppm and**  **R apeseed subgroup 20A**  **at 1.5**  **ppm.** EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition. A. Residue Chemistry **1. Plant**  **metab olism**  **. Wheat,**  **potato and**  **peach metabolism**  **studies were**  **conducted using**  **[14C] -** **pyridyl -** **flonicamid. T**  **he metabolic**  **profile was**  **similar for**  **all three**  **matrices. The**  **major metabolites**  **for the**  **various crops**  **were: T**  **FNA in**  **peach, TFNA**  **and TFNG**  **in potato**  **and TFNG**  **in wheat.**  **The metabolism**  **of flonicamid**  **in plants**  **shows the**  **main pathway**  **of metabolism**  **involves hydrolysis**  **of -** **CN and**  **BCONH2 functional**  **groups in**  **the molecule. The metabolism of flonicamid in plants is well understood.**  **2. Analytical**  **method**

**. A** **nalytical methodology**  **has been**  **developed to**  **determine the**  **residues of**  **flonicamid and**  **its three**  **major plant**  **metabolites, TFNA,**  **TFNG, and**  **TFNA****** **AM in**  **various crops.**  **T he**  **residue analytical**  **method for**  **the ma** **jority of**  **crops includes**  **an initial**  **extraction with**  **acetonitrile (ACN)/deionized**  **(DI) water,**  **followed by**  **a liquid** **- liquid**  **partition with**  **ethyl acetate.**  **T he**  **residue meth**  **od for**  **wheat straw**  **is similar,**  **except that**  **a C18**  **solid phase**  **extraction (SPE)**  **is added**  **prior to**  **the liquid** **- liquid**  **partition. T**  **he final**  **samp le**  **solution is**  **quantitated using**  **a liquid**  **chromatograph (LC)**  **equipped with**  **a reverse**  **phase column and a triple quadruple mass spectrometer (MS/MS).**

**3. Magnitude**  **of residues**  **. Residue**  **data were**  **collected on**  **B erry,**  **low growing,** 2

**subgroup 13**  **- 07G**  **; greenhouse**  **cucumber ;**  **and R** **apeseed subgroup**  **20A during**  **field trials.**  **Maximum total residues for strawberry,**  **representative of low growing berry**  **crops (total of 8**  **field trials)**  **ranged from**  **0. 140**  **to 0.**  **768 parts**  **per million**  **(ppm) strawberry**  **samples. Maximum**  **total residues for greenhouse**  **cucumber as a separate commodity (total of**  **4 field**  **trials) ranged**  **from 0.0**  **76 to**  **0. 76**  **ppm. M** **aximum total**  **residues for**  **canola ,**  **representative of**  **rapeseed (total of**  **9 field trials) ranged from**  **0.027 to 0.**  **855 ppm.**  **In one**  **tria l** **, samples**  **we re**  **processed into**  **canola meal**  **and oil** 

. **Processed canola**  **samples (meal**  **and oil)**  **had lower**  **residues than**  **the unprocessed**  **canola seed**  **that had**  **been treated**  **at the**  **same rate,**  **thus it**  **is demonstrated**  **that flonicamid**  **does not**  **concentrate in**  **process ed**  **canola matrices. B. Toxicological Profile**  **1. Acute**  **toxicity .**  **A battery**  **of acute**  **toxicity studies**  **was conducted**  **which placed**  **flonicamid technical in Toxicity Category III for oral LD50, Category IV for dermal LD50,**  **inhalation LC50, dermal**  **irritation, and**  **eye irritation.**  **Flonicamid technical**  **is not**  **a dermal**  **sensitizer. In an acute neurotoxicity study, the no observed adverse effect levels (NOAELs)**  **for neurotoxicity**  **were 600**  **mg/kg in**  **males and**  **1000 mg/kg**  **in female (highest**  **doses tested).**  **The systemic NOAELs were 600 mg/kg in males and 300 mg/kg in females.**  **2. Genotoxic** **i ty** **. Flonicamid**  **technical did**  **not cause**  **mutations in**  **the bacterial**  **reverse mu**  **tation or**  **mouse lymphoma**  **tests with**  **or without**  **metabolic activation,**  **chromosome damage**  **in the**  **mouse mi** **cronucleus or**  **cytogenetics tests**  **with and**  **without metabolic**  **activation, an**  **increas e**  **in DNA**  **damage in**  **the comet**  **assay or**  **in an**  **in vivo**  **rat unscheduled**  **DNA synthesis**  **(UDS) study.**  **B ased**  **on the**  **weight of**  **evidence, it**  **is concluded**  **that flonicamid technical is not genotoxic. 3.**  **Reproductive and**  **developmental toxicity.**  **A developmental**  **toxicity study**  **in rats**  **resulted in**  **the maternal**  **and developmental**  **no observed**  **effect levels**  **(NOELs) of**  **100 mg/kg/day. The maternal lowest observed effect level (LOEL) was**  **500 mg/kg/day based on the**  **treatment -** **related effects**  **observed on**  **the liver**  **and kidney**  **of the**  **dams in**  **the highest**  **dose group.**  **T he**  **developmental lowest**  **observed effect**  **level (LOEL)**  **was 500**  **mg/kg/day based**  **on i** **ncidences of**  **fetal skeletal**  **variations seen**  **on ly**  **at maternally**  **toxic doses**  **of 500**  **mg/kg/day. In**  **the rabbit**  **developmental toxicity**  **study, the**  **ma ternal**  **and developmental**  **NOELs were**  **7.5 mg/kg/day**  **and >**  **25 mg/kg/day**  **(HDT), respectively.**  **T he**  **ma ternal**  **LOEL was**  **25 mg/kg/day**  **based on decreased body weights , body weight gains and food consumption. No**  **adverse effects on the fetuses were observed at the highest dose. In**  **the multigeneration**  **rat reproduction**  **study, the**  **NOAEL was**  **50 ppm**  **for parental**  **animals (3.7**  **and 4.4**  **mg/kg/day, respectively,**  **for males**  **and f**  **emales) and**  **300 ppm**  **for their**  **offspring (22.3**  **and 26.5**  **mg/kg/day, respectively,**  **for males**  **and females).**  **T he**  **effects at**  **the highest**  **dose of**  **1800 ppm**  **included the**  **following: increased**  **kidney weights**  **and gross**  **and histopathological alterations in the kidney.**  **Findings noted in the top dose females included delayed**  **vaginal opening**  **and increased**  **liver, kidney**  **and spleen**  **weights in**  **the F1** 3

**generation and**  **reduced ovary**  **and adrenal**  **weights in**  **the parental**  **generation and**  **decreased uterine**  **weights in**  **the F1**  **female we**  **anlings. T**  **here was**  **an increase**  **in the**  **FSH and**  **LH levels**  **in F1**  **females tested**  **for these**  **endpoints. T**  **hese findings**  **did not**  **affect the**  **reproductive performance or survival of offspring in the study. 4.**  **Subchronic toxicity** **. The**  **no observed**  **adverse effect**  **level (NOAEL)**  **for flonicamid**  **technical in**  **the rat**  **28 -** **day dermal**  **toxicity study**  **was 1000**  **mg/kg/day, which**  **was the**  **highest dose tested. In a 90** **- day rat feeding study the NOAEL was established at 200 ppm (12.11 mg/kg/day)**  **for males and 1000 ppm (72.3 mg/kg/da y) for females. The LOAELs were 1000 ppm (60.0**  **mg/kg/day) for males and 5000 ppm (340 mg/kg/day) for females based on effects on hematology, triglycerides, and pathology in the liver and kidney.**  **In a 13 -** **week mouse study, the NOAEL was 100 ppm (15.25 mg/kg/day in males and 20.1 mg/kg/day in females). The LOAEL is 1000 ppm (153.9 mg/kg/day in males and 191.5**  **mg/kg/day in females) based on hematology effects and changes in glucose, creatinine, bilir** **ubin, sodium, chloride and potassium levels, increased liver and spleen weights and histopathology findings in the bone marrow, spleen and kidney.**  **In a subchronic toxicity study in dogs with capsule administration, the NOAEL was 8 mg/kg/day in males and**  **20 mg/kg/day in females based on findings of severe toxicity at a dose exceeding the maximum tolerated dose; symptoms included collapse, prostration and**  **convulsions leading to early sacrifice at the LOAEL of 50 mg/kg/day. In a subchronic neurotoxicity stud** **y in rats, the NOAEL for dietary administration was 200 ppm for males and 1000 ppm for females (13 mg/kg/day in males and 81 mg/kg/day i** **n females). The LOAEL**  **was 1000 and 10,000 ppm (67 and 722 mg/kg/day) in males and females, respectively (highest dose t** **ested) based on decreased motor activity, body weight**  **and food consumption effects. 5.**  **Chronic toxicity** **. In**  **the chronic**  **dog study**  **with administration**  **via using**  **capsules, the**  **NOEL was**  **8 mg/kg/day.**  **T he**  **LOAEL was**  **20 mg/kg/day**  **based on**  **reduced body**  **weights in females and effects on the circulating red blood cells.**  **In a**  **rat 24**  **- month**  **combined chronic**  **and oncogenicity**  **study, flonicamid**  **technical was**  **not carcinogenic**  **in rats.**  **T he**  **NOAEL was**  **200 ppm**  **(7.32 mg/kg/day)**  **for males**  **and 1000**  **ppm (44.1**  **mg/kg/d ay)**  **for females. The LOAEL was 1000 ppm for ma** **les and 5000 ppm for**  **females based on histopathology in the kidney, hematology effects, hepatic effects including**  **changes in**  **biochemical parameters,**  **increased organ**  **weights, and**  **histopathological changes.**  **A tro** **phy of**  **striated muscle**  **fibers, cataract**  **and retinal**  **atrophy observed**  **in the**  **high dose**  **females were**  **considered to**  **be due**  **to acceleration**  **of spontaneous**  **age -** **related lesions.**  **In the**  **18 -**  **month mouse**  **study, effects**  **were observed**  **in the**  **lung, liver,**  **spleen and**  **bo ne**  **ma rrow**  **at 250**  **ppm or**  **higher. F** **indings included**  **centrilobular hepatocellular**  **hypertrophy, extramedullary**  **hematopoiesis and**  **pigment deposition**  **in the**  **spleen and**  **decreased cellularity**  **(hypocellularity) in**  **the bone**  **marrow. T**  **here were**  **statistically signifi** **cant increases**  **in the**  **incidence of**  **alveolar/bronchiolar adenomas**  **in both**  **sexes of**  **treated groups**  **with hyperplasia/hypertrophy**  **of epithelial**  **cells in**  **terminal bronchioles.**  **There was**  **a statistically**  **significant increase**  **in the**  **incidence of**  **alveolar/bronchio lar** 4

**carcinomas in**  **males at**  **750 ppm**  **and 2250**  **ppm and**  **in females**  **at 2250**  **ppm only.**  **T hese**  **effects in**  **the lungs**  **of mice**  **were not**  **life -** **threatening as**  **most of**  **effects were**  **observed at**  **the terminal**  **sacrifice and**  **there was**  **no effect**  **of treatment**  **on mortality**  **in t** **he study.**  **A n**  **o observed**  **adverse effect**  **level (NOAEL)**  **could not**  **be determined**  **from the**  **dose levels**  **administered. M** **echanism -** **of -**  **action studies**  **have indicated**  **that the**  **lung effects**  **are unique**  **to the**  **mouse and are not likely to translate to**  **other species incl** **uding the rat. A second 18 -**  **month mouse**  **study was conducted in CD -**  **1 m ice at dose levels ranging from 10 to 250 ppm**  **to establish**  **a NOAEL**  **for hyperplasia/hypertrophy**  **of epithelial**  **cells in**  **terminal bronchioles**  **and for**  **the incidence**  **of alveolar/bronchiolar**  **ad enomas**  **and carcinomas**  **in both**  **sexes. T**  **here was**  **a statistically**  **significant increase**  **in the**  **incidence of**  **alveolar/bronchiolar adenomas**  **in males**  **at 250**  **ppm. I** **n females,**  **there was**  **no statistically**  **significant increase**  **in the**  **incidence of**  **pulmonary neoplast** **ic lesions**  **at any**  **dose level.**  **T he**  **incidence of**  **hyperplasia/hypertrophy of**  **epithelial cells**  **lining the**  **terminal bronchioles**  **of the**  **lungs was**  **statistically increase** **d at**  **250 ppm**  **in both**  **sexes. T**  **here were**  **no treatment** **** **related increases**  **in neoplastic or non -** **n eoplastic**  **lesions at dose levels of 80 ppm or lower in either sex. The NOAELs were 10.0 and 11.8 mg/kg body weight/day for males and females,**  **respectively. T**  **his study**  **confirmed a**  **threshold for**  **these effects**  **at 80**  **ppm. F** **lonicamid technical was not carcin**  **ogenic in the rat. 6.**  **Animal metabolism**  **. Rat,**  **goat and**  **poultry metabolism**  **studies were**  **conducted using [**  **14 C]**  **- pyridyl** **- flonicamid.**  **The majority**  **of the dose was rapidly excreted. Flonicamid was**  **a ma** 

**jor component**  **of rat**  **urine 48**  **hours after**  **dosi ng.**  **T FNA** **- AM**  **was the**  **ma jor**  **metabolite found**  **in rats**  **(urine), goats**  **(milk and**  **tissues) and**  **in laying**  **hens (tissues**  **and eggs).**  **T FNG**  **was found**  **between 8**  **- 24%**  **of the**  **total radioactive**  **residue (TRR)**  **in the**  **livers of rats sacrificed at intervals between 0.5**  **- 6 hours after dosing. The liver samples at**  **these time**  **intervals had**  **14 C**  **- residues**  **of 2.3%**  **- 4.6%**  **of the**  **dose. T** **FNA was**  **not a**  **major component**  **in animal**  **tissues. T**  **he metabolism**  **of flonicamid**  **in animals**  **shows the**  **main pathway**  **of metabolism**  **involves hydrolys** **is of**  **- CN**  **and -** **CONH 2**  **functional groups**  **in the**  **molecule, identical**  **to plant**  **metabolism. T**  **he main**  **metabolic reactions**  **were hydrolysis**  **of cyano**  **to the**  **am ide**  **function and**  **ring hydroxylation.**  **I n**  **rats flonicamid**  **was further**  **metabolized by**  **several routes,**  **including nitrile**  **hydrolysis, amide**  **hydrolysis, N** **- oxidation,**  **and hydroxylation**  **of the**  **pyridine ring,**  **leading to**  **multiple metabolites.**  **The metaboli** **sm of**  **flonicamid in animals is well understood. 7.**  **Metabolite toxicology .**  **The main**  **metabolites of flonicamid were**  **examined in acute**  **oral toxicity**  **studies in**  **rats and**  **bacterial reverse**  **mutation tests.**  **A ll**  **the metabolites**  **were less toxic than flonicamid**  **and not mutagenic. 8.**  **Endocrine disruption**  **. No**  **special studies**  **investigating potential**  **estrogenic or**  **other endocrine**  **effects of**  **flonicamid have**  **been conducted.**  **S om** **e suggestions**  **of possible**  **endocrine effects**  **were reported**  **at the**  **highest dose**  **tested (1800**  **ppm) in**  **the multi** **** **generation reproduction**  **s tudy**  **which showed**  **increased FSH**  **and LH**  **levels, a**  **delay in**  **the time to vaginal opening in the F1 generation, and reduced ovary and adrenal weights in the**  **parental generation.**  **H owever,**  **there were**  **no effects**  **on reproductive**  **performance or**  **survival of**  **the off** 

**spring in**  **the study.**  **A t**  **levels that**  **are expected**  **to be**  **found in**  **the**5

**environment, flonicamid will not cause any endocrine -** **related effects. C. Aggregate Exposure**  **1. Dietary**  **exposure .**  **Exposure assessments were conducted to evaluate the potential risk due**  **to dietary exposure of the U.S. population to residues of flonicamid. For acute dietary exposure, an Acute Reference Dos**  **e (aRfD) is not identified for f lonicamid**  **since there**  **was no**  **evidence of**  **initial acute**  **effects in**  **the acute**  **toxicity studies.**  **Furthermore, endpoints from the acute neurotoxicity and developmental toxicity studies, as well**  **as from**  **other short** **- a** **nd long** **- term**  **studies, were**  **not appropriate**  **for assessing**  **acute dietary risk.**  **For chronic dietary exposure, the chronic reference dose (cR fD) is**  **0.04 mg/kg/day** , **based on the NOEL of 3.7 mg/kg/day from the**  **2 -** **generation reproduction toxicity rat study and**  **a 100** **- fold**  **uncertainty factor.**  **The chronic**  **population adjusted**  **dose (cPAD)**  **is also**  **0.04 mg/kg/day since**  **the FQPA safety factor for**  **flonicamid is 1x .**  **i. Food**  **. Potential dietary exposures from food were estimated using the proposed**  **tolerances for all crops using the Dietary Exposure Evaluation Model (DEEM -** **FCID TM** **) and**  **percent crop treated of 100%. The following raw agricultural commodities were included: head and stem brassica, leafy brassica greens, leafy vegetables (except brassica),**  **cotton, tuberous and corm vegetables, fruiting vegetables, cucurbits, stone fruits , pome**  **fruits, vegetable root crops except sugarbeet, radish tops, turnip greens, hops, okra, berry, low growing, greenhouse cucumber, canola seed and resulting secondary residues in meat,**  **milk, poultry and eggs. C**  **hronic dietary e** **xposure estimates resulted in an estimated exposure for the gen**  **eral U.S. population of 0.004240**  **mg/kg bwt/day. This exp osure corresponds to**  **10.6% of the cPAD**  **of 0.04 mg/kg bwt/day. The highest exposure estimate calculated was for the subgroup**  **children, 1 -** **2 years . This exposure was determined to**  **be 0.009081 mg/kg bwt/day (22.7% of**  **the cPAD) .**  **ii. Drinking water** **. Since**  **flonicamid is intended for application outdoors to field**  **grown crops, the potential exists for parent and/or metabolites to reach ground or surface**  **water that may be used for drinking water. An**  **e stimated concentration**  **of 1.5 ppb of flonicamid in drinking water**  **was provided by EFED**  **for crops uses in 2007 .**  **T his**  **value was used in the chronic DEEM dietary assessment** **. 2.**  **Non -** **dietary exposure** **. There**  **are currently**  **no residential**  **uses of**  **flonicamid registered or pending action that need to be added to the total risk from exposure.**  **D. Cumulative Effects Unlike**  **other pesticides**  **for which**  **EPA has**  **followed a**  **cumulative risk**  **approach**6

**based on**  **a com** **mon mechanism**  **of toxicity,**  **EPA has**  **not made**  **a common**  **mechanism of**  **toxicity finding**  **as to**  **flonicamid and**  **any other**  **substances, and**  **flonicamid does**  **not appear**  **to produce**  **a toxic**  **metabolite produced**  **by other**  **substances. E**  **PA concluded**  **that the**  **evidence did**  **no t**  **support a**  **finding of**  **common mechanism**  **for flonicamid**  **and other**  **substances. E. Safety Determination**  **1. U.S.**  **population .**  **Using conservative**  **exposure assessment**  **analyse s,**  **t he**  **chronic dietary**  **exposure estimates**  **for the**  **various population**  **groups are**  **well below**  **the cPAD**  **of 0.04 mg/kg bw/day. Based on this information, it can be concluded that there is reasonable**  **certainty that no harm will result from acute or chronic exposure to flonicamid.**  **2. Infants and children**  **. Based on the available developmental and reproductive data**  **on flonicamid,**  **it can**  **be concluded**  **that reliable**  **data support**  **use of**  **the standard**  **100 -** **fold uncertainty**  **factor, and**  **that an**  **additional uncertainty**  **factor is**  **not needed**  **to protect**  **the safety**  **of infants**  **and children**  **under the**  **FQ PA.**  **Although the**  **reproduction study**  **indicated signs**  **of toxicity**  **to some**  **reproductive organs/systems**  **at the**  **high dose**  **of 1800**  **ppm in**  **the diet,**  **other signs**  **of toxicity**  **such as**  **effects on**  **the kidney**  **accompanied these;**  **there were**  **no effe** **cts observed**  **at a**  **dose level**  **of 300**  **ppm .**  **T here**  **were no**  **effects on**  **reproduction or**  **survival at a ny dose level. Since**  **chronic aggregate exposure assessme nts are well below the**  **cPAD ,**  **there is**  **reasonable certa** **inty that**  **no harm**  **will result**  **to infants**  **and children**  **from aggregate exposure to flonicamid residues.**  **F. International Tolerances Canad**  **a has**  **established MRLs**  **for flonicamid**  **and its**  **metabolites on**  **head and**  **stem brassica,**  **leafy brassica**  **greens, leafy**  **vegetables (except**  **brassica), tuberous**  **and corm**  **vegetables, fruiting**  **vegetables, cucurbits,**  **stone fruits,**  **pome fruits,**  **vegetable root**  **crops except**  **sugarbeet, radish**  **tops, turnip**  **greens, hops,**  **and resulting**  **secondary residues**  **in meat, milk, poultry an**  **d eggs. There**  **are no**  **Mexican residue**  **limits or**  **Codex MRLs**  **for the**  **insecticide flonicamid**  **and its**  **metabolites TFNA, TFNA -** **AM and TFNG.**