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

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

**INSTRUCTIONS: 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. Simply re place the instructions that appear in**  **green , i.e.,**  **“ [**  **Company Name ]**  **,” with the information specific to your action. TEMPLATE:**  **BASF Corporation PP#** **3F 8163**  EPA has received a pesticide petition **( PP#** **3F 8163**  **)** from **BASF Corporation ,**  **26 Davis Drive, Research**  **Triangle Park, NC 27709** 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. 624 by

establishing a tolerance for residues of **metrafenone (** **( 3**  **- bromo**  **- 6** **- methoxy** **- 2**  **- methylphenyl)(2**  **,3,4 -** **trimethoxy -** **6 -**  **methylphenyl)methanone )**  in or on the raw agricultural commodity **Fruits, pome, group 11 -**  **10** at **1 .5**  parts per million (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 metabolism. **[ In plant metabolism studies conducted in grapevines with**  **metrafenone , the parent compound was the principal residue in grapes.**  **M etrafenone**  **is metabolized through methyl and ring oxidative bio** **- transformations, followed by**  **enzymatic glucoside c onjugation reactions to yield the conjugates from their**  **corresponding aglycons. All major metabolites, which were present at very low levels, are considered non** **- relevant as all were detected in the rat metabolism study as**  **aglycons or conjugates, and can t herefore be considered as not toxicologically**  **significant. Thus, only parent metrafenone**  **is considered relevant to define the residue in plants.**  **The results from a hydrolysis study designed to simulate different industrial and household processes (pasteu** **rization, brewing, boiling and sterilization) showed that**2

**metrafenone is stable. Therefore,**  **metrafenone as unchanged parent is proposed a** **s the relevant residues in grapes**  **and industrial or household preparations of grapes. ]**  2. Analytical method. **[ The residues of parent metrafenone in/on apple and**  **pear RAC samples were quantitated using an LC/MS/MS multi -** **residue QuEChERS method (BASF Study No. 398340)**  **. The method was successfully validated on apples**  **in conjunction with this study prior to analysis of the field samples. Acceptable**  **concurrent method recovery data for pome fruit RAC samples were also obtained for metrafenone. The validated limit of quantitation (LOQ) for residues of**  **metrafenone in/on pome fruits RAC samples was 0.01 ppm. The method limit of**  **detection (LOD) was 0.003 ppm, or approximately 30% of the LOQ.**  **An independent laboratory validation demonstrated good performance of the**  **QuEChERS method.**  **]** 3. Magnitude of residues. **[ BASF has submitted field trial data for**  **metrafenone (BAS 560 F) on representative crops (apple and pear) of the pome**  **fruits crop group (EPA Crop Group 11 -**  **10). A total of 18 trials was conducted on pome fruits during the 2010 growing season: twelve trials on apple in EPA Regions**  **1 (NY, two trials; PA, one trial), 2 (VA, one trial), 5 (MI, WI, one trial each), 9 (UT,**  **one trial), 10 (CA, one trial), and 11 (ID, WA, two trials each), and six trials on pear in EPA Regions 1 (NY, one trial), 10 (CA, two trials), and 11 (ID, two trials; WA,**  **one trial). The numbe** **r and locations of field trials are in accordance with OPPTS Guideline 860.1500. Field trials were carried out using the maximum label rates, the**  **maximum number of applications, and the minimum pre -** **harvest interval (PHI) for all the crops.**  **An apple proces sing study was conducted to determine the potential for**  **concentration of residues of metrafenone (BAS 560 F) in the processed fractions of apple. Two trials were conducted in EPA Regions 1 (NY, one trial) and 11 (ID, one**  **trial) during the 2010 growing sea son.**  **The apple RAC samples were separately processed using simulated commercial processing procedures into the currently**  **EPA -**  **regulated commodities of apple, wet pomace and juice. Apple sauce, canned apples, and dried apples were also generated and collect** **ed for analysis. A**  **comparison of the residues in the RAC samples with those in each processed fraction indicated that metrafenone residues do not concentrate appreciably**  **(processing factors <1 to 1.2, average of two trials) in any apple processed commodit** **ies, with the exception of apple sauce, in which the processing factor was 4.5x on average, with individual results of 4.8x and 4.1x calculated from the samples**  **collected at the sites in New York and Idaho, respectively.** B. Toxicological Profile 1. Acute toxicity. **[ In**  **an acute**  **toxicity study**  **with rats,**  **metrafenone was**  **practically non** **- toxic**  **(EPA Tox.**  **Category IV).**  **I n**  **an acute**  **neurotoxicity study**  **with rats, no signs of neurotoxicity were detected up to 2,000 mg/kg b.w., the highest dose**  **tested. ]** 3

2. Genotoxicty. **[ metrafenone**  **was evaluated**  **for its**  **potential genotoxicity**  **in vitro**  **using bacterial**  **and ma** **mmalian cell**  **mutagenicity tests**  **and a**  **chromosome damage**  **(clastogenicity) test.**  **T he**  **results of**  **these studies**  **demonstrated the**  **absence of**  **a genotoxic**  **effect. In**  **vivo ,**  **the test**  **substance was**  **assessed for**  **the induction**  **of micronuclei**  **i n**  **mice. The**  **result of**  **this study**  **showed that**  **metrafenone has**  **no chromosome** **- damaging potential.**  **It is therefore concluded, that metrafenone**  **has no mutagenic or genotoxic properties both**  **in vitro and**  **in vivo .**  **]** 3. Reproductive and developmental toxicity. **[ The**  **reproductive and**  **developmental toxicity**  **of metrafenone**  **was investigated**  **in a**  **2 -** **generation reproduction study in rats as well as in prenatal toxicity studies in rats and rabbits.**  **In the**  **definitive 2**  **- generation**  **reproduction study**  **in rats,**  **the NOAEL**  **for fertility**  **and reproduction**  **was 10,000**  **ppm (the**  **highest concentration**  **tested), equivalent**  **to approximately**  **811 mg** **/kg b.w./day**  **based on**  **food consumption**  **data during**  **the premating periods. The parental NOAEL of**  **metrafenone is 500 ppm (approximately**  **39 mg/kg**  **b .w./day**  **based on**  **food consumption**  **data). T**  **he 1,000**  **ppm treatment**  **showed statistically**  **significant decreases**  **in body**  **weight and**  **weight gain**  **in F1**  **parental males**  **and increased**  **absolute and**  **relative liver**  **weights in**  **females. T**  **he NOAEL**  **for pup**  **(offspring) to** **xicity was**  **1,000 ppm**  **(approximately 79**  **mg/kg b.w./day**  **based on**  **food consumption**  **data); the**  **10,000 ppm**  **treatment showed**  **a statistically**  **significant decrease**  **in pup**  **body weight**  **(31%) during**  **lactation, an**  **increase in**  **relative liver**  **weights at**  **weaning, and**  **a d** **elay in**  **vaginal opening**  **(F1 only).**  **In the**  **prenatal toxicity**  **study in**  **rats, there**  **was no**  **treatment -**  **related maternal**  **or developmental**  **toxicity observed,**  **even at**  **the highest**  **dose tested**  **(1,000 mg/kg**  **b.w./day). On**  **the basis**  **of these**  **data, the**  **ma ternal**  **NOAEL o**  **f metrafenone**  **is 1,000**  **mg/kg b.w./day**  **(highest dose**  **tested). T**  **he 1,000**  **mg/kg b.w./day**  **dose showed**  **a statistically**  **significantly increased**  **ratio of**  **liver weight**  **to terminal**  **body weights.**  **However, no**  **correlating microscopic**  **changes were**  **diagnosed, indicati** **ng that**  **the increased**  **relative liver**  **weight was**  **not considered**  **toxicologically significant.**  **T he**  **developmental NOAEL**  **for metrafenone**  **is 1,000**  **mg/kg b.w./day**  **(no effects**  **were observed**  **at the**  **highest dose**  **tested). B**  **ased on**  **the above**  **results, metrafenone**  **is not**  **selectively toxic to the fetus. In addition, metrafenone**  **was not teratogenic in rats. In**  **the rabbit**  **prenatal toxicity**  **study, developmental**  **toxicity was**  **observed in**  **the presence**  **of maternal**  **toxicity. Specifically,**  **the ma** **ternal NOAEL**  **is 50**  **mg/kg b.w./** **day based**  **on the**  **following: reduced**  **body weight**  **gains and**  **reduced feed**  **consumption (absolute**  **and relative)**  **at both**  **350 and**  **700 mg/kg**  **b.w./day. I** **n addition,**  **at these**  **two dose**  **levels, a**  **dose -** **related, statistically**  **significant increase**  **in absolute**  **and relati** **ve (to**  **body weight)**  **liver weights**  **occurred, as**  **compared to**  **controls. A** **lso, increased**  **incidences and/or**  **severities of**  **periportal hepatocellular**  **hypertrophy and diffuse and/or periportal hepatocellular vacuolation were observed**4

**at 350**  **and 700**  **mg/kg b.w./day** **. I** **n this**  **prenatal toxicity**  **study in**  **rabbits, the**  **developmental NOAEL of**  **metrafenone is 350 mg/kg b.w./day, as based on the slight**  **but statistically**  **significant reduction**  **in fetal**  **body weights**  **at 700**  **mg/kg b.w./day.**  **Therefore, because**  **developmental toxic** **ity was**  **only observed**  **at dose**  **levels that**  **were maternally**  **toxic, metrafenone**  **is not**  **selectively toxic**  **to the**  **fetus. I** **n addition,**  **metrafenone was not teratogenic in rabbits.**  **Overall, for the reproductive and developmental toxicity studies, the lowest NOAE** **L for**  **ma ternal/parental**  **toxicity was**  **39 mg/kg**  **b.w./day (two** **- generation**  **reproduction study)**  **and for**  **pup toxicity**  **was 79**  **mg/kg b.w./day**  **(two -** **generation reproduction**  **study). ]**  4. Subchronic toxicity. **[ The**  **subchronic toxicity**  **of metrafenone**  **was investigated**  **in a**  **dietary 28** **- day**  **study in**  **rats, a**  **28 -** **day oral**  **toxicity study**  **in dogs,**  **and 3**  **- month**  **toxicity studies**  **in rats,**  **mice, and**  **dogs. I** **n addition,**  **a 28** **- day**  **neurotoxicity study** **, as**  **well as**  **a 28** **- day**  **immunotoxicity study**  **were conducted**  **with rats**  **. The**  **signs of**  **toxicity observed**  **in the**  **three species**  **tested were**  **overall similar**  **and consisted**  **of reduced**  **body weight**  **gain at**  **the highest**  **tested dose**  **levels. T**  **he observed**  **effects on**  **clinical chemistry**  **in rats**  **and mice**  **can be**  **linked to**  **the microscopic**  **ef**

**fects observed**  **in the**  **liver. T**  **he effects**  **observed typically**  **included increased**  **cholesterol, total**  **protein, and**  **total bilirubin**  **(mice only).**  **O rgan**  **weights and/or**  **pathology indicated**  **the liver**  **to be**  **the only**  **consistent target**  **organ in**  **all three**  **species tes** **ted. T**  **he changes**  **included, periportal**  **cytoplasmic vacuolation**  **in rats,**  **centrilobular hepatocellular**  **hypertrophy in**  **mice, and**  **increased liver**  **weights in rats, mice, and dogs.**  **In the**  **28 -** **day neurotoxicity**  **study with**  **rats, there**  **was no**  **evidence of**  **neurotoxic ity**  **in all**  **treatment groups,**  **with a**  **No -** **Observed -** **Adverse -** **Effect Level**  **(NOAEL) for**  **neurotoxicity of**  **15,000 in**  **the diet**  **(equivalent to**  **1,371 mg/kg**  **b.w./day for**  **both sexes**  **, as based on food consumption data** **, which exceeds a limit dose of 1,000 mg/kg b.w./day** **). These**  **results, coupled**  **with the**  **lack of**  **neurotoxic effects**  **observed in**  **acute, sub**  **- chronic**  **and chronic**  **studies with**  **other species,**  **indicate that**  **metrafenone is not**  **potentially neurotoxic.**  **In the**  **28 -** **day immuno** **toxicity study**  **with fe** **male rats**  **, there**  **was n**  **o evidence**  **of immuno** **toxicity in**  **all treatment**  **groups, with**  **a No** **- Observed** **- Adverse** **- Effect**  **Level (NOAEL)**  **for immuno** **toxicity of**  **12 ,000**  **in the**  **diet (equivalent**  **to 1,**  **086 mg/kg**  **b.w./day ,**  **as based**  **on food**  **consumption data** **, which**  **exceeds a**  **lim it**  **dose of**  **1,000 mg/kg**  **b.w./day ).**  **T hese**  **res ults,**  **coupled with**  **the lack**  **of immuno** **toxic effects**  **observed in**  **acute, sub**  **- chronic**  **and chronic**  **studies with**  **other species,**  **indicate that**  **metrafenone is not potentially immuno** **toxic.]** 5. Chronic toxicity. **[ The**  **chronic toxicity**  **of metr** **afenone was**  **evaluated in**  **a 1**  **- year**  **oral administration**  **study in**  **dogs, a**  **24 -** **month feeding**  **study with**  **rats and**  **an 18** **- month feeding study with mice.** 5

**Administration of**  **metrafenone to**  **dogs for**  **one year**  **resulted in**  **mild increases**  **in mean**  **alkaline phosphatase**  **in males**  **after 9**  **and 12**  **months of**  **dosing at**  **500 mg/kg**  **b.w./day (highest**  **dose tested).**  **M ean**  **absolute and**  **relative liver**  **weights were**  **both statistically**  **significantly increased**  **in females**  **at 500**  **mg/kg b.w./day**  **and relative**  **liver weights**  **were statistically**  **significantly increased**  **in males**  **at 500**  **mg/kg b.w./day.**  **H owever,**  **there were**  **no associated**  **ma croscopic**  **or microscopic**  **findings in**  **the livers**  **of these**  **animals. T**  **herefore, the**  **slig ht**  **but statistically**  **significant differences**  **in liver**  **weights and**  **alkaline phosphatase**  **(in males)**  **were not**  **considered to**  **be of**  **toxicological significance.**  **A ll**  **other parameters**  **evaluated including**  **mo rtality,**  **clinical observations,**  **body weights**  **and food**  **con sumption**  **data, ophthalmology,**  **hematology, coagulation**  **and urinalysis**  **data, and**  **macroscopic and**  **microscopic examinations**  **revealed no**  **adverse effects**  **due to**  **administration of**  **metrafenone .**  **T herefore,**  **the NOAEL**  **for oral**  **administration of**  **metrafenone to**  **pure -** **b red Beagle Dogs was 500 mg/kg b.w./day, the highest dose tested.**  **Treatment of**  **Sprague -** **Dawley rats**  **with metrafenone**  **for 24**  **months resulted**  **in ma** **rkedly reduced**  **body weight**  **gains in**  **females at**  **5,000 (26%)**  **and 20,000/10,000**  **ppm (42%)**  **and a**  **lesser reduction**  **in body**  **weight gain**  **for males**  **at 20,000**  **ppm (14%).**  **M icroscopic**  **effects in**  **the liver**  **and kidney**  **were associated**  **with clinical**  **chemistry changes**  **in males**  **and females**  **at doses**  **of 5,000**  **ppm and**  **greater. S** **light anemia**  **was observed**  **in females**  **at 5,000**  **ppm and**  **hi gher,**  **which was**  **reversed at**  **24 months. An increase in the incidence of hepatocellular necrosis after 12 months and**  **benign hepatocellular**  **adenomas was**  **observed in**  **females at**  **5,000 ppm**  **and greater**  **which are**  **dietary concentrations**  **that exceeded**  **the MTD.**  **T he** **refore, the**  **NOAEL for**  **systemic toxicity**  **and for**  **oncogenic ef**  **fects following**  **dietary administration**  **of metrafenone**  **to Sprague** **- Dawley**  **rats for**  **24 months,**  **was 500**  **ppm (25**  **mg/kg b.w./day as based on food consumption data).**  **Treatment of**  **albino mice**  **with metraf**  **enone for**  **18 months**  **resulted in**  **statistically significant**  **increases in**  **the following:**  **liver weights**  **(absolute and**  **relative, in**  **females), hepatocellular**  **hypertrophy in**  **males, renal**  **chronic nephropathy**  **in males**  **and extramedullary**  **hematopoiesis in**  **the spleen**  **of females**  **at 1,000**  **ppm, the**  **next highest**  **concentration tested.**  **Therefore, the**  **NOAEL for**  **systemic toxicity**  **following dietary**  **administration of**  **metrafenone to**  **albino mice**  **for 18**  **months, was**  **250 ppm**  **(46 mg/kg b.w./day as based on food consumption data).**  **A statistically**  **significant (P<0.01)**  **increase in**  **the incidence**  **of hepatocellular**  **neoplasms (adenomas**  **and carcinomas)**  **was observed**  **in the**  **livers of**  **male mice**  **receiving 7,000**  **ppm (19/66,**  **28.8%), as**  **compared to**  **controls (6/65,**  **9.2%). T** **here was also a marginal**  **increase in the incidence of hepatocellular neoplasms in females**  **receiving 7,000**  **ppm (4/65),**  **as compared**  **to the**  **control mi** **ce (2/65).**  **The incidence**  **of 14/66**  **(21.2%) hepatocellular**  **adenoma for**  **males at**  **7,000 ppm**  **is slightly**  **above the**  **maximum range**  **of histori** **cal control**  **data at**  **the testing**  **laboratory (14.8%)**  **and at**  **Charles River**  **Laboratories (19.2%).**  **T he**  **incidence of**  **5/66 (7.6%)**  **hepatocellular carcinoma**  **in males**  **at 7,000**  **ppm is**  **within the**  **maximum range**  **of historical**  **control**6

**data at**  **both the**  **testing facility**  **( 9.2%)**  **and Charles**  **River Laboratories**  **(11.5%). Although the number of hepatocellular neoplasms in males receiving 1,000 ppm was**  **also slightly**  **increased (9/65,**  **13.8%) compared**  **to the**  **untreated controls**  **(6/65, 9.2%),**  **this slight**  **increase was**  **not statisticall** **y significant**  **(p<0.05) and**  **was within**  **the range**  **of the**  **historical controls**  **(9.2 -**  **18.5%) at**  **the testing**  **laboratory. T**  **he slight**  **increase in**  **hepatocellular neoplasms**  **in male**  **mice at**  **1,000 ppm**  **may have**  **resulted from**  **increased survival**  **observed at**  **termination i** **n male**  **mice at**  **1,000 ppm**  **as compared**  **to controls**  **(55 versus**  **45 in**  **the surviving**  **male controls).**  **T he**  **incidences of**  **hepatocellular neoplasms**  **in terminally**  **sacrificed male**  **mice were**  **5/45 or**  **11%, 3/53**  **or 6%,**  **8/55 or**  **15% and**  **18/54 or**  **33%, at**  **respective treatme** **nt levels**  **of 0,**  **250, 1,000 and 7,000 ppm.**  **For females, whereas the incidence of hepatocellular adenoma was the same (2/65 or 3.1%)**  **at 7,000**  **ppm and**  **for controls,**  **the incidence**  **of hepatocellular**  **carcinoma was**  **slightly increased**  **at 7,000**  **ppm (2/65**  **or 3.1%)**  **versus control**  **(0/65 or**  **0%). S** **ince this**  **incidence of**  **hepatocellular carcinoma**  **(3.1%) for**  **females at**  **7,000 ppm**  **is slightly**  **above the**  **maximum range**  **of historical**  **control data**  **at both**  **the testing**  **facility (1.5%)**  **and Charles**  **River Laboratories**  **(2.0%), the**  **inc idence**  **represents an**  **equivocal finding.**  **H owever,**  **because this**  **increase was**  **very small,**  **was not**  **statistically significant,**  **and did**  **not demonstrate**  **decreased latency**  **compared to**  **the controls,**  **this finding**  **was considered**  **to represent**  **only equivocal**  **toxicolog ic**  **significance. Therefore,**  **based on**  **the weight** **- of**  **- the** **- evidence**  **analysis, the**  **NOAEL for**  **oncogenicity is**  **1,000 ppm** **( approximately**  **190 mg/kg**  **of b.w./day,**  **calculated from**  **food consumption**  **data and**  **nominal concentrations)**  **based on**  **the increased**  **incidence of**  **h epatocellular**  **neoplasms observed**  **in male**  **mi ce**  **at 7,000**  **ppm, as**  **compared to controls. In**  **summary, long** **- term**  **exposure studies**  **with metrafenone**  **in dogs,**  **rats and**  **mice resulted**  **in increased**  **liver weights**  **with corresponding**  **changes in**  **clinico -** **chemical paramete**  **rs. M** **icroscopic pathological**  **changes were**  **identified in**  **the liver,**  **kidney, and**  **spleen for**  **rats and/or**  **mice. The**  **main target**  **organ was identified as**  **the liver**  **in all**  **species. A** **dditionally, increased**  **incidences of**  **primary hepatocellular**  **neoplasms were obse** **rved at the highest doses in rats and mice.]** 6. Animal metabolism. **[ M** **etrafenone was**  **rapidly absorbed**  **and efficiently**  **excreted following**  **oral administration**  **in the**  **rat. T**  **he amount**  **of absorption**  **ranged from**  **approximately 89**  **to 92%**  **of the**  **administered dose**  **of 10**  **mg/kg b.w.**  **M ost**  **of the**  **administered dose**  **was eliminated**  **via bile**  **within 72**  **hours (85.2**  **to 90.1%)**  **and feces**  **within 7**  **days (84.1**  **to 98.8%),**  **with a**  **small am** **ount (0.69**  **to 6.6%)**  **in urine.**  **metrafenone -** **related residues**  **showed no**  **potential for**  **accumulation as**  **<1.2% of**  **the applied**  **dose was**  **retained over**  **seven days,**  **with highest**  **levels of**  **residues found**  **in the**  **liver, GI**  **tract, plasma,**  **blood, kidney,**  **and fat.**  **T he**  **tissue retention**  **of the**  **orally administered**  **dose was less than 2% at 48 -** **72 hours and less than 1.2% at 168 hours. metrafenone**  **was extensively**  **metabolized in**  **the rat**  **to multipl** **e metabolites**  **formed**7

**via demethylation**  **of the**  **aromatic methoxy** **- group(s)**  **followed by**  **mono -** **O****** **glycosidation, hydroxylation**  **of the**  **bromophenyl ring,**  **and hydroxylation**  **of the**  **methyl substituent**  **to hydroxymethyl**  **followed by**  **O -** **glycosidation or**  **further oxidation t** **o aldehyde or lactone. ]**  7. Metabolite toxicology

. **[ In plant metabolism studies conducted in grapevines**  **with metrafenone** **, the**  **parent compound**  **was the**  **principal residue**  **in grapes.**  **metrafenone is**  **metabolized through**  **methyl and**  **ring oxidative**  **biotransformat ions,**  **followed by**  **enzymatic glucoside**  **conjugation reactions**  **to yield**  **the conjugates**  **from their**  **corresponding aglycons.**  **A ll**  **major metabolites,**  **which were**  **present at**  **very low**  **levels, are**  **considered non** **- relevant**  **as all**  **were detected**  **in the**  **rat metabolism**  **stu dy**  **as aglycons**  **or conjugates,**  **and can**  **therefore be**  **considered as**  **not toxicologically**  **significant. T**  **hus, only**  **parent metrafenone**  **is considered**  **relevant to**  **define the residue in plants. The**  **results from**  **a hydrolysis**  **study designed**  **to simulate**  **different ind** **ustrial and**  **household processes**  **(pasteurization, brewing,**  **boiling and**  **sterilization) showed**  **that metrafenone**  **is stable.**  **T herefore,**  **metrafenone as**  **unchanged parent**  **is proposed**  **as the relevant residue in grapes and industrial or household preparations of gr** **apes. Since**  **metrafenone is**  **not registered**  **for use**  **in the**  **United States,**  **the toxicity**  **of metabolites**  **formed in**  **ma trices**  **other than**  **the raw**  **or processed**  **treated commodity**  **(e.g., water, soil) is not relevant. ]**  8. Endocrine disruption

. **[ Data**  **from the**  **reprod uction**  **/ developmental**  **toxicity and**  **short -**  **and long** **- term**  **repeated dose**  **toxicity studies**  **with metrafenone**  **in the**  **rat, rabbit,**  **mouse, or**  **dog, do**  **not suggest**  **any endocrine**  **disruption activity.**  **T his**  **information is**  **based on**  **the absence**  **of any**  **treatment -**  **related effects**  **from the**  **histopathological examination of endocrine organs as well as the low level of concern for**  **possible ef** 

**fects on**  **fertility, reproductive**  **performance, or**  **any other**  **aspect of**  **reproductive function, or on growth and development of the offspring .**  **]** C. Aggregate Exposure 1. Dietary exposure. **[ Assessments**  **were conducted**  **to evaluate**  **the potential**  **risk due**  **to chronic**  **dietary exposure**  **of the**  **U.S. population**  **to residues**  **of m** **etrafenone. The**  **U.S. EPA**  **has not**  **established an**  **acute reference**  **dose for**  **either the**  **general population or females ages 13** 

**– 49 years because no study demonstrated**  **evidence of toxicity from a single dose exposure for these populations. Therefore, an acute**  **exposure ris**  **k evaluation**  **is not**  **required. T**  **he chronic**  **assessment was**  **conducted using**  **all currently**  **established tolerances**  **for metrafenone**  **listed in**  **40CFR180.624 and**  **the proposed**  **new tolerance**  **for the**  **Po me**  **Fruit Crop**  **Group 11**  **- 10 of 1.5 ppm.**  **] i.**  **Food. [** **The dietary**  **assessment analysis**  **followed an**  **initial tier**  **approach using**  **100% crop**  **treated, and**  **current tolerance**  **values for**  **grapes and**  **raisins and**  **the proposed**  **new tolerance**  **for the**  **Po me**  **Fruit Crop**  **Group 11**  **- 10**  **of 1.5**  **ppm** .8

**Dietary exposure**  **assessments wer** **e conducted**  **using Dietary**  **Exposure Evaluation**  **Module (DEEM -** **FCID Ver 3.12** **). Acute Dietary Exposure Assessment**  **An acute**  **assessment was**  **not conducted**  **because there**  **are no**  **relevant toxicological**  **endpoints for acute dietary exposure and a risk assessment is n ot required.**  **Chronic Dietary Exposure Assessment Results**  **of the**  **chronic exposure**  **estimates were**  **compared against**  **the chronic**  **Population Adjusted**  **Dose (cPAD)**  **of 0.25**  **mg /kg**  **b.w./day t** **hat was**  **based on**  **the NOAEL from the rat chronic toxicity study, a safet** **y factor of 100, and n o additional**  **FQ PA safety factor is required.**  **Results of**  **the chronic**  **dietary exposure**  **assessments are**  **listed in**  **Table 1.**  **T he**  **estimated chronic**  **dietary exposure**  **from im** **ported grapes**  **was less**  **than 11**  **% of**  **the cPAD for all subpopulations.**  **Table 1. Chronic Dietary Food Exposure Assessment for Metrafenone.**

**Population Exposure** 

**Estimate %cPAD**  **Subgroups (mg/kg** 

**b.w./day) US Population**  **0.003669 1.5**  **All infants (< 1 year) 0.020536**  **8.2 Children 1**  **- 2**  **0.027148 10.9**  **Children 3 -** **5 0.014828**  **5.9 Children 6** **- 12**  **0.005949 2.4**  **Youth 13 -**  **19 0.001885**  **0.8 Adults 20** **- 49**  **0.001546 0.6**  **Adults 50+ yrs 0.001961**  **0.8 Females 13**  **- 49 yrs**  **0.001743 0.7**  **The results in Table 1 demonstrate there are no safety concerns for any**  **subpopulation based on established and new uses, and that the results clearly meet the FQPA standard of reasonable certainty of no harm.**  **]** ii. Drinking water

. **[ The**  **drinking water**  **exposure values**  **used in**  **this assessment**  **are from**  **the most**  **recent U.S.**  **EPA risk**  **assessment for**  **Grapes (U.S.**  **EPA, March**  **1, 2010**  **“Metrafenone: Hum** **an Health**  **Risk Assessment**  **for Foliar**  **Use on**  **Grape”). T**  **he water**  **values calculated**  **by EPA**  **are the**  **higher values**  **than the**  **proposed use**  **on pome**  **fruit. The**  **chronic surface**  **water concentration**  **used in**  **the human exposure assessment was 2**  **2 .82**  **ug/L. Drinking**  **water contributions**  **were assessed**  **based on**  **a metrafenone**  **water**9

**concentration of**  **2 2.**  **82 ug/L**  **for chronic**  **exposure and**  **water consumption**  **and body**  **weights re** **ported in**  **CSFII, using**  **DEEM -** **FCID Ver**  **3.12 software.**  **T he**  **chronic estimated water exposure values are summarized in Table 2.**  **Table 2.**  **Summary of**  **chronic dietary**  **exposure assessment**  **for drinking**  **water considering direct and indirect sources.** 

**Population S**  **ubgroups Exposure Estimate**  **(mg/kg b.w./day) %cPAD**  **US Population 0.000478**  **0.2 All infants (< 1 year)**  **0.001232 0.5**  **Children 1 -** **2 0.000689**  **0.3 Children 3**  **- 5**  **0.000581 0.2**  **Children 6 -**  **12 0.000419**  **0.2 Youth 13**  **- 19**  **0.000348 0.1**  **Adults 20 -** **49 0.000477**  **0.2 Adults 50+ yrs**  **0.000471 0.2**  **Females 13 -**  **49 yrs 0.000475**  **0.2 %cPAD = percent of chronic population adjusted dose**  **Exposure based on the maximum estimated water concentration of 2**  **2. 82**  **ug/L Acute Aggregate Exposure (Food + Water)**  **An acute**  **assessment was**  **not needed**  **because there**  **are no**  **relevant toxicological**  **endpoints for**  **acute dietary**  **exposure and**  **an aggregate**  **risk assessment**  **is not**  **required. Short** **- and Intermediate Aggregate Exposure (Food + Water + Residential)**  **Metrafenone is**  **not registered**  **for any**  **use which**  **will result**  **in residential**  **exposure. Therefore,**  **a short** **- or**  **intermediate -** **term exposure**  **and aggregate**  **risk evaluation**  **is not required.**  **Chronic Aggregate Exposure (Food + Water) The**  **aggregate chronic**  **risk includes**  **residue s**  **of metrafenone**  **from food**  **and water**  **(Table 3).**  **T he**  **results demonstrate**  **there are**  **no safety**  **concerns for**  **any subpopulation**  **based on**  **established and**  **new uses,**  **and that**  **the results**  **clearly meet**  **the FQPA standard of reasonable certainty of no harm. Table 3**  **. Estimated chronic aggregate exposure and risk of Metrafenone**  **Population Subgroup cPAD**  **(mg/kg/day) Total** 

**Exposure, Food and**  **Water (mg/kg/day)**  **%**

**cPAD US Population**  **0.25 0.004147**  **1.7 All infants (< 1 year)**  **0.25 0.021768**  **8.7**10

**Children 1 -** **2 0.25**  **0.027837 11.1**  **Children 3 -** **5 0.25**  **0.015409 6.2**  **Children 6 -**  **12 0.25**  **0.006368 2.5**  **Youth 13 -**  **19 0.25**  **0.002233 0.9**  **Adults 20 -** **49 0.25**  **0.002023 0.8**  **Adults 50+ yrs 0.25**  **0.002432 1.0**  **Females 13 -**  **49 yrs 0.25**  **0.002218 0.9**  **]** 2. Non

-dietary exposure

. **[ Metrafenone is not**  **registered for any use which will result in non** **- dietary residential exposure.**  **]** D. Cumulative Effects **[ At**  **this time,**  **there is**  **no available**  **information to**  **indicate that**  **metrafenone or**  **its metabolites**  **have a**  **common mechanism**  **of toxicity**  **with other**  **substan ces.**  **Therefore, there**  **is no**  **reason to**  **include this**  **pesticide or**  **its metabolites**  **in a**  **cumulative risk**  **assessment. F** **or the**  **purposes of**  **this tolerance**  **action EPA**  **has not**  **assumed that**  **metrafenone and**  **its metabolites**  **have a**  **common mechanism**  **of toxicity with o** **ther substances. ]**  E. Safety Determination 1. U.S. population. **[ Results**  **of the**  **dietary exposure**  **analysis demonstrate**  **with reasonable**  **certainty that**  **no harm**  **to the**  **general U.S.**  **population or**  **any subpopulation**  **would results**  **from the**  **use of**  **metrafenone on**  **the current**  **and proposed uses**  **. ]**  2. Infants and children

. **[ Results**  **of the**  **dietary exposure**  **analysis demonstrate**  **with reasonable**  **certainty that**  **no harm**  **to the**  **general U.S.**  **population or**  **any subpopulation,**  **including infants**  **and children,**  **would results**  **from the**  **use of**  **metrafenone on the current and proposed uses. ]**  F. International Tolerances **[ No**  **maximum residue**  **levels (MRLs)**  **have been**  **established for**  **m etrafenone**  **by the Codex Alimentarius Commission (CODEX) or in Mexico. ]**