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

**PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA**  **Registration Division contact:**  **Dominic Schuler , (703)**  **347 -**  **0260**

**INSTRUC TIONS:**  **Please utilize this outline in preparing the pesticide petition. In cases where the outline element does not apply, please insert “NA** **- Remove” and**  **maintain the outline. Please do not change the margins, font, or format in your pesticide petition. S**  **imply replace the instructions that appear in green**  **, i.e., “ [**  **insert company name**  **] ,” with the information specific to your action.**  **TEMPLATE: ISK Biosciences Corporation**  **3F8142** EPA has received a pes ticide petition **(3F8142 )**  from **ISK Biosciences Corporation**  **, 7470 Auburn Road, Suite A, Concord, Ohio, 44077,**  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 fungicide**  **i sofetamid**  **, N**  **- [**  **1,1 -**  **dim ethyl** **- 2**  **- [2**  **- methyl** **- 4**  **- (l** **- methylethoxy)phenyl]**  **- 2**  **- oxoethyl]**  **- 3**  **- methyl** **- 2**  **- thiophenecarboxamide (CA)**  **and its metabolite GPTC**  **, N**  **- [1**  **,l****** **dimethyl -**  **2 -**  **(4 -**  **β -** **D -**  **glucopyranosyloxy -**  **2 -**  **methylphenyl) -**  **2 -**  **oxoethyl] -** **3 -**  **methyl -**  **2 -**  **thiophenecarboxamide , expressed as**  **isofetamid** in or on the following raw agricultural commodities : **a lmond**  **,** at **0 .**  **0 2**  parts per million (ppm) ; **almond hulls at 0.2 ppm; l**  **ettuce, head, at 6.0 ppm; let tuce, leaf, at 7.0 ppm;**  **fruit, sm**  **all vine climbing , except**  **fuzzy kiwifruit, subgroup 13**  **- 07F**  **at 3**  **.0 ppm**  **; berry,**  **low growing , subgroup 13**  **- 07G**  **at 4.0 ppm; and rapeseed**  **subgroup 20A at 0.04 ppm .**  EPA has determined that the petition contains data or informati on 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 rul es on the petition. A. Residue Chemistry 1. Plant metabolism. **The plant metabolism of isofetamid**  **is understood for the purposes of this petition.**  **The residue of concern was defined on the basis plant metabolism studies conducted**  **in grapes, lettuce and bean s**  **and in rotational crops, as the sum of IKF** **- 5411 and its metabolite, GPTC, expressed as IKF**  **- 5411.**  **The metabolic pathway**  **was similar for all crops and the predominant metabolic**  **pathway involved O -**  **dealkylation of IKF -**  **5411 to for m 4HP followed by subsequent** 2

**conjugation to form GPTC (glucose conjugate) in primary crop s**  **and GPTC and malonyl** **- GPTC in rotational crop**  **s . Separation of the ring system also occurred in**  **both primary and rotational crop but was a very minor route of metaboli sm in**  **comparison to the formation of GPTC. The nature of the residue studies showed**  **that isofetamid**  **was the major identifiable residue with low levels of GPTC**  **in some crops**  **. The tolerance expression for the proposed crops**  **will include parent, isofetami**  **d , and the metabolite**  **GPTC .**  2. Analytical method. **The LC -** **MS/MS method proposed for residue analysis of plants and plant products determines the residues of parent IKF**  **- 5411 and its metabolite,**  **GPTC. The method involves extraction of samples with acetone or with acetonitrile:**  **water (80:20 v/v) mixture. Extracts are then subjected to SPE clean -**  **up, with subsequent quantification of residues by liquid chromatography with tandem mass**  **spectrometric determination (LC -** **MS/MS). The method h as been shown to provide**  **satisfactory recoveries and has a limit of quantification of 0.01 mg/kg.** 3. Magnitude of residues. **The results from five (5**  **) field trials**  **conducted on almonds**  **during the 201**  **1 growing season**  **show that the m aximum total residue (** **isofetamid +**  **GPTC )**  **after four**  **applications of**  **isofetamid at the target rate of**  **~ 0.446 lb a.i./A**  **at 10**  **(±1) day intervals applied at pink bud to petal fall**  **was 0.04**  **ppm on hulls and**  **were non -**  **detectable (less than 0.005 ppm) on nutmeats .**  **The results from 1**  **5 field trials conducted on**  **grape vineyards during the 2011**  **growing season show that the maximum total residue (isofetamid + GPTC) after three**  **applications of isofetamid at the target rate of**  **~ 0.581 lb a.i./A**  **at 10 (±1) day intervals**  **applied up**  **to 14 days before harvest**  **was 2.6**  **ppm. The results from**  **13 field trials conducted on**  **head lettuce and 13 field trials**  **conducted on leaf lettuce**  **during the 2011 growing season show that the maximum total residue (isofetamid + GPTC) after**  **two a** **pplications of isofetamid at the target**  **rate of ~** **0. 322**  **lb a.i./A at 10 (±1) day intervals applied**  **up to**  **14 days before harvest was**  **4.76 ppm**  **on head lettuce with wrapper leaves, 0.98 ppm on head lettuce without wrapper leaves and 5.29 ppm on leaf lettuce**  **. The results from**  **1 7**  **field trials conducted on canola**  **during the 2011 growing season show that the maximum total residue (isofetamid + GPTC) after**  **two applications of**  **isofetamid at the target rate of**  **~ 0.**  **268 lb a.i./A**  **at 6 to 29**  **day intervals applied at 20** 

**– 40% flowering**  **(BBCH 62 -**  **64) to end of flow**  **er ing**  **(BBCH 67 -**  **69) was**  **0.01 ppm.**  B. Toxicological Profile 1. Acute toxicity. **Results from a battery of acute toxicity studies place technical**  **isofetamid in Toxicity**  **Category III for oral LD**  **50 and dermal LD**  **50 ,**  **and Category IV for**  **inhalation LC 50**  **, dermal irritation**  **, and eye irritation. Technical**  **isofetamid was**  **n ot**  **a dermal sensitizer. In an acute neurotoxicity**  **study, no treatment related effects were observed at any dose. The NO**  **A EL w**  **as 2,000 mg/kg bw**  **, the highest rate tested .**  2. Genotoxicty. **A battery of four**  **tests has been conducted to assess the genotoxic potential of technical**  **isofetamid . Assays conducted included**  **in vitro**3

**reverse gene mutation tests in b acteria**  **, in vitro**  **gene mutation test in a mouse**  **lymphoma cells , a chromosomal damage test in mammalian cells, and an**  **in vivo micronucleus test in mice.**  **Isofetamid did not elicit a genotoxic response in any of**  **the studies conducted.** 3. Reproductive and developmental toxicity. **In a two -**  **generation reproductive toxicity study, general toxicity**  **effects were**  **observed on**  **body weight s**  **, liver weights and thyroid**  **weights at**  **1 0,000 ppm**  **(594 mg/kg bw/day) in dams during gestation**  **and lactatio n and in weanling pups. No reproductive effects were observed. The**  **NO A** **EL for reproductive effects was 10,000 ppm**  **(594 mg/kg bw/day males; 906 mg/kg bw/day females)**  **. The NO A** **EL for general**  **toxicity was 1**  **,000 ppm (57.1**  **mg/kg bw/day males; 90.5 mg/kg bw/day females)**  **. In a rat developmental study,**  **pregnant rats were dosed by gavage**  **with isofetamid**  **from Days 6**  **to 19 of gestation. There were no treatment -**  **related effects observed in the study. The NO**  **A EL for maternal**  **toxicity and embryo fetal toxicity**  **was 1,000 mg/kg bw/day.**  **In a rabbit developmental study, pregnant rabbits were dosed with isofetamid**  **on Days**  **6 to 2**  **7 of gestation. There were**  **maternal rabbit body weight changes in the high dose (1000 mg/kg/day) group. N**  **o treatment** **- related teratogenicity**  **effect s**  **were observed in the study. The NO**  **A EL for**  **developmental effects on fetuses was the highest dose tested, 1000 mg/kg/day. The maternal**  **general toxicity NOAEL**  **was 300**  **mg/kg bw/day. The developmental studies (prenatal developmental studies in rat and rabbi** **t and the two generation reproduction study in rat) provided no indication of increased**  **sensitivity of rats or rabbits from in utero or post -**  **natal exposure to isofetamid**  **. Thus, i**  **sofetamid is not**  **considered a developmental or reproductive toxicant.**  4. Subchronic toxicity. **The oral toxicity of isofetamid was investigated in mice,**  **rats, and dogs in 13 -** **week studies. In mice,**  **changes in the liver and adrenal gland occurred at the highest dose of 8000 ppm**  **(1067 mg/kg bw/day males; 1306 mg/kg**  **bw/day females) . T**  **he NOAEL was 1000 ppm (129 mg/kg/day in males and 161**  **mg/kg/day in females) .**  **In rats, changes in the liver, thyroid, and adrenal gland occurred at the 1000 and**  **10,000 ppm rates. The NO**  **A EL was**  **1 00 ppm which was equivalent to a do**  **sage of 6.65**  **mg/kg bw/day to males and 7.83**  **mg/kg bw/day to females. In**  **the 90 -**  **day dog study ,**  **body weight and**  **blood chemistry effects**  **were observed**  **at the 10,000**  **rate in both males and females and**  **at the 1000**  **ppm rate**  **( 32.7 mg/kg**  **bw/day) in females only .**  **The NOAEL was 100 0**  **ppm in males**  **(29.3 mg/kg/day** **) and 100**  **ppm in females (3.07 mg/kg/day** **).** 5. Chronic toxicity. **In a long -** **term feeding study, mice were fed**  **isofetamid in the diet for 78 weeks. There was no evidence of carcinogenicity**  **at any dose, up to**  **the maximum dose of 4000 ppm**  **(502 mg/kg bw/day) for males and 3000 ppm**  **(431 mg/kg bw/day)**  **for females. Base**  **d on bodyweight changes, the**  **NOAEL was 100 ppm for males (12 mg/kg/day) and 800 ppm for females (118 mg/kg/day).**  **In a 1 -** **year chronic toxicity stu dy in rats, treatment related effects were only seen at**  **the 5000 ppm level. The NOAEL for chronic effects was 500 ppm ( 22.7 mg/kg** **/day**4

**in males and 30.0 mg/kg /day**  **in females ).**  **An oncogenicit** **y study was conducted where i**  **sofetamid was**  **administered continuously for a period of 104 weeks to male and female**  **Wistar Hannover rats.**  **I t**  **was concluded that i sofetamid**  **was not carcinogenic in this study at levels up to 5000**  **ppm . The general toxicity NOAELs were 500 ppm (20.3 mg/kg bw/day) for m**  **ales and 100 ppm (5.02 mg/kg bw/day) in females**  **. In a chronic dog study,**  **three groups of**  **four dogs/sex/group received**  **isofetamid for**  **52 weeks. Blood chemistry and liver effects were observed in the high dose group of**  **6000 ppm. The NO**  **A EL was determined**  **t o be**  **200 ppm (5.34 mg/kg** **/day for males**  **and 5.58 mg/kg/day for females).** 6. Animal metabolism. **A study on the metabolism of**  **isofetamid in animals**  **using radioactive test material has**  **been conducted with isofetamid**  **, labeled with 14**  **C in two positions, the**  **pheny l**  **[ 14**  **C -**  **Ph ]**  **- or**  **thiophene [**  **14 C**  **- Th**  **] ring**  **at the dose levels of 5 and 200 mg/kg**  **. IKF** **- 5411 was readily excreted by the rat with biliary excretion**  **being the major route of elimination with evidence of re -**  **absorption of biliary excret**  **ed metabolites and subsequent preferential excretion in urine. Biliary and urinary excretion**  **and the residues in tissues and carcass showed that absorption**  **was greater than 9 3**  **% of the administered dose at both**  **dose levels. There was no evidence of retenti**  **on of IKF -**  **5411 or its metabolites as tissue and blood levels were negligible apart from the liver with no individual tissue containing greater than**  **0.5% of the administered dose. IKF** **- 5411 was shown to undergo extensive metabolism via O**  **- dealkylation,**  **hydrox ylation**  **with subsequent glucuronidation . There were quantitative, but not**  **qualitative, differences in metabolism due to position of the radiolabel in the metabolism of IKF**  **- 5411 and a quantitative sex difference related to the difference**  **in excretion patter ns between males and females. Cleavage between the benzene and**  **thiophene ring structures was only a minor metabolic route in the rat.** 7. Metabolite toxicology

. **Comparison of the metabolism of isofetamid**  **by plants and in animals**  **indicates a pathway**  **common to both plants and anima ls.**  **The data indicate that the final products of the metabolism of**  **isofetamid in animals and**  **plants represent differences in the extent of metabolism. Several of the metabolites resulting from**  **isofetamid are similar in plants and animals and, therefore, have**  **already been evaluated toxicologically.** 8. Endocrine disruption

. **An evaluation of the potential effects on the endocrine systems of mammals has not been determined; however,**  **no evidence of such effects was reported in subchronic, chronic or reproductive toxicology. There**  **was no observed pathological finding of the endocrine organs in these studies, and there were no reproductive effects at the maximum dose tested of 20,000 ppm**  **. There is no evidence at this time that**  **isofetamid causes endocrine effects.**  C. Aggregate Exposure 1. Dietary exposure. **Potential dietary exposures from food were estimated for**  **all proposed**  **tolerances for the**  **crops listed be** **low, using the Dietary Exposure** 5

**Evaluation Model -** **Food Consumption Intake Database (DEEM -**  **FCID TM** **) version**  **3.12 ,**  **and percent crop treated of 100%. The following raw agricultural co**  **mmodities were included: almonds;**  **lettuce, head and leaf; grapes**  **( subgroup 13**  **- 07F)**  **; low growing berries (**  **subgroup 13 -**  **07G) ;**  **an d rapeseed (**  **subgroup 20A). For chronic dietary exposure,**  **a conservative**  **chronic reference dose (RfD) of 0. 05**  **mg/kg bw/day was**  **used , based on the NOAEL from the**  **rat carcinogenicity study**  **( 5.02**  **mg/kg bw/day for**  **females ) and dividing by an uncertainty factor of 100. The**  **chronic population adjusted dose (cPAD) is also 0. 05**  **mg/kg bw/day since**  **the FQPA safety factor**  **should be 1 for**  **isofetamid .**  **A cute dietary exposure**  **analysis was not warranted based on the low order of acute**  **toxicity.** i. Food. **Tier 1 chronic dietary exposure analyses were conducted for**  **isofetamid in/on**  **the crops noted above to determine the exposure contribution of**  **these commodities to the diet and to ascertain the chronic**  **ri sk potential. The**  **estimates were based on proposed**  **tolerance level residues for all crops,**  **a grape processing study** **, conservative**  **ma rket share assumptions of 100% crop treated, and**  **consumption data from the USDA’s NHANES/WWEIA dietary**  **survey of food intak** **e conducted in 2003**  **- 2008**  **. Even using all of the worst case exposure scenarios listed above, the Tier 1 chronic**  **dietary (food + drinking water) exposure estimates resulted in an estimated**  **exposure for the general U.S. population of 0 .00**  **3 36**  **0 mg/kg bw/day. This e**  **xposure corresponds to**  **6.7 % of the cPAD of 0.**  **05 mg/kg bw/day. The highest exposure**  **estimate calculated was**  **for the subgroup**  **, children 1**  **- 2 years old**  **. This exposure was determined to be 0.0**  **0 88**  **08 mg/kg bw/day (**  **1 7.6**  **% of the cPAD) .**  **It can be concluded that the**  **long -** **term dietary exposure to isofetamid**  **through residues on treated**  **almonds, grapes (subgroup 13**  **- 07F** **) , leaf an**  **d head lettuce, rapeseed, (**  **subgroup 20A); and low gro wing berries (**  **subgroup 13 -**  **07G) should not**  **be cause for conce**  **rn.** ii. Drinking water

. **Since isofetamid**  **is intended for applicatio n outdoors to**  **turf and field grown crops, the potential exists for parent and or metabolites to**  **reach ground or surface water that may be used for drinking water. The**  **drinking water**  **component for the chronic risk assessment was**  **directly entered into the dietary exposure model**  **and is included in the exposure values noted above .**  2. Non

- dietary exposure

. **Isofetamid can**  **only be**  **commercially applied to**  **residential turf . Therefore,**  **n on**  **** **occupational exposure of isofetamid**  **to the general population is not expected,**  **however, postapplication exposure is possible. For Dermal Short** **- Term exposure,**  **no toxicity was found at 1000**  **mg/kg in a 28 -**  **day rat**  **dermal toxicity study .**  **In addition,**  **in vitro**  **rat skin, in**  **vitro human skin, and**  **in vivo**  **rat studies were**  **conducted that**  **suggest about 0.4% of isofetamid from the formulation and up to**  **10 %**  **of it from dilute spray tank would be**  **absorbed through human skin. Therefore, in the absence of any hazard identified for**  **dermal exposure , a**  **dermal**6

**post -**  **application risk assessment was not**  **conducted for**  **children or adults.**  **However, there is**  **potential for post -**  **application exposures to children resulting from lawn treatmen**  **t that need to be assessed based on the potential for non -**  **dietary incidental oral ingestion.**  **Potential inhalation exposure was not considered since it is negligible when assessing re**  **- entry risks.**  **The post application exposure to children**  **from incidental**  **oral exposures from residential lawn use**  **results in a MOE**  **of 963, which is**  **greater than 100 and therefore is**  **not of concern.** D. Cumulative Effects **Isofetamid is a**  **n SDHI type fungicide.**  **We do not**  **believe that**  **isofetamid has**  **a co**  **mmon mechanism of toxicity with any other pesticide ,**  **but it is unknown at this**  **time.** E. Safety Determination 1. U.S. population. **Dietary and occupational exposure will be the major**  **routes of exposure to the U.S. population. Ample margins of safety have been**  **demonstrated for both situations. For the general U.S. population, the chronic dietary exposure to**  **isofetamid is 0.00**  **336 0**  **mg/kg bw/day, which utilizes less than 6.7**  **% of the RfD for the overall U.S. population, assuming 100 % of the crops are**  **treated. A cancer dietary assessment was not conducted because this product**  **did not show any potential to be carcinogenic to animals.**  **Since there is no dermal point of concern, dermal post** **- application risk assessments were not conducted**  **and only inhalation exposure was determined for handlers. Using the pesticide handlers**  **exposure data base (PHED) updated by EPA in March 2010, the margins of exposure (MOE) for occupational exposure were greater than 98,000 to 124,000 for**  **use on turf and 5,000 to 172,000 for use on crops. Based on the completeness and**  **reliability of the toxicity data and the conservative exposure assessments, there is a reasonable certainty that no harm will result from the aggregate exposure of**  **residues of isofetamid in cluding all anticipated dietary exposure**  **, occupational exposure**  **and all other non -**  **occupational exposures.** 2. Infants and children

. **As noted above, c**  **hronic dietary exposure of the most highly exposed subgroup in the population,**  **chi ldren, 1**  **- 2 years old**  **, is 0.0 088**  **08 mg/kg bw/day or**  **17.6 % of the RfD.**  **Thus, it can be concluded that there is reasonable certainty that no harm will result to infants and children from acute or**  **chronic exposure to Isofetamid**  **. Based on the completeness and**  **reliability of the toxicity data, the lack of toxicological endpoints of special concern, the lack of any indication of greater**  **sensitivity of children, and the c onservative exposure assessment,**  **there is a reasonable certainty that no harm will result to i**  **nfants and children from the aggregate exposure to residues of**  **isofetamid from all anticipated sources of dietary**  **and non -**  **occupational exposur e.** 7

F. International Tolerances **Presently, t here**  **is no Codex maximum residue levels (MRLs) established for**  **residues of isofetamid**  **on any crop. Since this is being submitted as a Joint**  **Review with PMRA** **, similar**  **crop tolerances are being requested in Canada.**  **In addition,**  **submission s**  **are being made to the EU**  **and Japan for the**  **similar crops.**