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**(7/1/2006) EPA Registration Division contact:**  **[ Michael Walsh**  **, (703) 308 -**  **2972 ]** 

**INSTRUCTIONS: Please utilize this outline in preparing tolerance petition**  **documents. In cases where the outline e lement does not apply please insert “NA** **** **Remove” and maintain the outline. The comment notes that appear on the left ma**  **rgin represent hidden typesetting codes designed to expedite the processing of the Federal Register document. Please do not remove or al** **ter these comment notes or change the margins, font, or format in your document. Simply replace the**  **instructions that appear in italics and brackets, i.e., “[ insert company name** **],” with the information specific to your action.**  **] TEMPLATE:**  **[ BASF Corporatio**  **n ]**  **[ Petition Number:**  **4F8286 ]**  EPA has received a pesticide petition **( [**  **insert petition number**  **] )**  from **[BASF Corporation]**  **, [P.O. Box 13528, 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. 1. by establishing a tolerance for residues of **[metaflumizone] in or on the raw agricultural commodity**  **[ crop group 11**  **- 10:**  **pome fruit crop group ]**  **at [0.**  **04 ]**  **parts per million (ppm), [crop group 12**  **- 12:**  **stone fruit crop group]**  **at [0.04]**  **ppm ,**  **and updating existing crop groups to [crop group**  **10 -**  **10: citrus fruits group] at**  **[0.04] ppm and**  **[crop group 14 -**  **12: tree nuts group] at**  **[0.04] ppm.**  **EP A has determined that the petition contains data or information**  **reg arding the elements set forth in section 408 (d)(2) of the 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 three plant metabolism studies (cabbage, tomato and cotton), the major component of the residue was metaflum** **izone. The major degradate was the ketone, M320I04 and an oxidized and cyclized m**  **etabolite, M320I23, was present in lesser amounts. These four compounds were defined as the** 

**residues of concern and were incorporated into an analytical method. In the confined rotational crop studies plant uptake was very limited and the residues were**  **a mixture of minor and polar components.]**  **2. Analytical method.**  **[BASF Analytical Method No. 531/0 was developed to determine residues of metaflumizone and its**  **metabolites M320I04 and M320I23 in**  **crop matrices. In this method, residues of metaflumizone are extracted from plant**  **ma trices with methanol/water (70:30; v/v) and then partitioned into**  **dichloromethane. For oily matrices, the residues are extracted with a mixture of isohexane/acetonitrile (1:1; v/v). The final determination of metaflumizone and its**  **metabolite s is performed by LC/MS/MS.**  **] 3.**  **Magnitude of residues.** [ **A full set of citrus, grape, and tree nut field trial data were submitted to the EPA in 2011 which resulted in residues less than the**  **limit of detection (LOD) in/on samples harvested 5 da ys after a single application at**  **0.004 lbs ai/acre (1x). Residues were also <LOD in/on grape and orange RACs harvested 5 days after a single application at 0.02 lbs ai/acre (5x). BASF proposed**  **the translation of the citrus, grape, and tree nut metaflumiz one residue data**  **to pome fruit and stone fruit.**  **A metaflumizone granular product is currently registered for soil application as a fire ant bait to citrus, tree nuts, and grapes at 4 x 0.001 lbs ai/acre (retreatment**  **interval (RTI) = 4 weeks; preharvest in terval (PHI) = 5 days). Spot application to**  **fire ant mounds is also registered at 0.00008 lbs ai/mound (RTI = 4 weeks; PHI = 5 days). Based on the**  **citrus, grape and tree nut field trial and processing data, limit**  **of quantitation (LOQ) tolerances (0.04 pp m) in/on citrus, grape, and tree nuts were**  **established for the combined residues metaflumizone (e -**  **and z -**  **isomers) and M320I04 (D345540, T. Bloem, 26**  **- Jan**  **- 2010).**  **An adequate field rotational crop study was also submitted which resulted in <LOQ residues in l**  **ettuce, radish roots/tops, and wheat forage/hay/straw/grain planted 30 days after the last of four broadcast foliar applications (2 lb ai/gal SC) to tomato at**  **0.26 lb ai/acre (n=2; RTI = 6 -**  **8 days; 260x; D308394, T. Bloem, 30 -** **Nov -**  **2005). Based on the field**  **trial, processing, and rotational crop data and provided the pome fruit and stone fruit application scenarios are identical to the citrus, grape, and tree**  **nut application scenario, the ChemSAC concluded that the proposed translation is acceptable.**  **] B. To**  **xicological Profile 1.**  **Acute toxicity.**  **[ Based**  **on the**  **available acute**  **toxicity data,**  **metaflumizone and its formulated product do not pose acu**  **te toxicity risks. For metaflumizone: Oral LD50 Rat**  **LD50 > 5000 mg/kg b.w. categor** **y IV Oral LD50 Mouse**  **LD50 > 5000 mg/kg b.w. category IV**

**Dermal LD50 Rat LD50 > 5000 mg/kg b.w. category IV**  **Inhalation LC50 Rat > 5.2 mg/L category IV**  **Eye Irritation Rabbit Not irritating category IV**  **Skin Irritation Rabbit Not irritating category IV**  **Skin Sensitization Guinea pig Not sensitizing (Maximization Test)] 2.**  **Genotoxicty. [In a battery of three in vitro and two in vivo mutagenicity**  **assays consisting of all required end -** **points (point mutation, chromosomal damage, and DNA damage and repair), the weight** **- of**  **- the**  **- evidence for metaflumizone**  **indicates a lack of potent ial genotoxicity.**  **Specifically, for the battery of three in vitro mutagenicity assays with metaflumizone, no positive responses were observed for increased revertant**  **frequencies with and without metabolic activation [bacterial reverse mutation assay] or**  **for increased mutant frequencies with and without metabolic activation [HGPRT locus assay]. Although there was a positive result for a statistically**  **increased number of structurally aberrant metaphases in the chromosomes, which indicates clastogenic pote**  **ntial under in vitro conditions, this result was only observed without metabolic activation [cytogenicity study with V79 cells.**  **Importantly, the potential biological significance of this apparent chromosome damage observed in vitro only without metaboli**  **c activation, was evaluated in vivo using the mouse micronucleus assay. Testing in the in vivo micronucleus study with**  **NMRI mice was conducted at a high dose level (2000 mg/kg b.w.) that demonstrated clinical symptoms of toxicity, including piloerection a**  **nd poor general state, in 5 of 5 animals. No significant or dose**  **- related increases in chromosomal damage were**  **observed in this in vivo test, indicating that metaflumizone does not cause chromosomal aberrations in intact animals.**  **Moreover, it has als o been recognized by U.S. EPA that more weight should be**  **placed on in vivo systems than in vitro systems as expressed in the Agency’s weight****** **of -**  **evidence for genotoxic evaluation of a chemical included in the "Guidelines for Mutagenicity Risk Assessment" (F**  **ederal Register, September 24, 1986, Vol. 51: 34006**  **- 34012). Thus, the negative in vivo results (non**  **- clastogenicity for**  **chromosomal aberrations) observed in the mouse micronucleus assay and the rat hepatocytes assay, should override the positive results ob**  **tained in the in vitro assay only without metabolic activation. Furthermore, it has been noted that in vitro**  **systems may simulate abnormal physiological conditions from prolonged exposure to a chemical in the absence of S**  **- 9 metabolic activation [Brusick,**  **D.J. (editor) 1987. Genotoxicity Produced in Cultured Mammalian Cell Assay by Treatment**  **Conditions. Mutation Research, Vol. 189, No.1: 1 -**  **69] and [Sofuni, T. 1993. Japanese Guidelines for Mutagenicity Testing. Environmental and Molecular Mutagenesis,**  **Vol. 2 1, No.1: 2**  **- 7]. Consequently, based on the weight** **- of**  **- the**  **- evidence presented** **above, metaflumizone does not pose a genotoxic concern.] 3.**  **Reproductive and developmental toxicity. [Potential reproductive toxicity**  **of metaflumizone was investigated in a two -**  **g eneration reproduction toxicity study**  **in Wistar rats by oral gavage administration. Originally, the highest dose tested by oral gavage was 75 mg/kg b.w../day, which induced both excessive maternal toxicity**  **(very high incidences of poor general health in f emales during premating, gestation,**  **and lactation; and statistically decreased food consumption, body weights, and body weight gain) as well as excessive developmental toxicity (statistically impaired pup**  **body weights and body weight gain), which altogethe r resulted in high pup**  **mo rtality. Consequently, a meaningful assessment of the potential reproductive**  **toxicity of the test compound at this excessively toxic dose level was not possible. Thereafter, for the next two successive parental generations of rat**  **s, which were originally derived from the parents treated at 75 mg/kg b.w./day, the highest dose**  **tested was 50 mg/kg b.w./day. Subsequently, the NOAEL for parental toxicity was 20 mg/kg b.w./day, based on the**  **following effects for females at 50 mg/kg b.w ./day (highest dose tested for two**  **consecutive generations) --**  **increased incidences of poor general health in females during premating, gestation, and lactation; 3 of 25 dams with complete litter losses;**  **and statistically significantly reduced body weights during premating, gestation, and**  **lactation. The NOAEL for offspring/pup toxicity was 20 mg/kg b.w./day, based on a slight**  **increased incidence of pup mortality at 50 mg/kg b.w./day. Whereas the NOAEL for fertility in this study was 50 mg/kg b.w./day (h**  **ighest dose tested for two generations), the NOAEL for reproductive performance was considered to be 20**  **mg/kg b.w./day, based on 3 of 25 dams with complete litter losses, of which 2 of these 3 dams had indications of poor nursing for their first generation**  **of pups. It is noteworthy that because most of the pup mortality was due to poor nursing in only**  **2 of 25 dams, this finding may be considered to be incidental. Importantly, no comparable impairment of reproductive performance occurred for the succeeding**  **parental generation treated by oral gavage administration at 50 mg/kg b.w./day. In a developmental (teratology) toxicity study in the Wistar rat, the results indicated**  **that the NOAEL for maternal toxicity was 40 mg/kg b.w./day, based on statistical ly**  **decreased food consumption and body weight gains at 120 mg/kg b.w./day (highest dose tested). The NOAEL for fetal (prenatal)/developmental toxicity was 120 mg/kg**  **b.w./day (highest dose tested). In addition, there were no indications of any teratogenic**  **effects in the rat fetuses at 120 mg/kg b.w./day (highest dose tested). Therefore, metaflumizone is considered to be neither a developmental toxicant nor a**  **teratogenic agent in the rat. In a developmental (teratology) toxicity study in the Himalayan r**  **abbit, the results indicated that the NOAEL for maternal toxicity was 100 mg/kg b.w./day, based on**  **several clinical symptoms of toxicity (including ataxia and poor general state) occurring in 4 of 25 does at 300 mg/kg b.w./day, for which 2 of these 4 does**  **had**

**abortions prior to being sacrificed early, with a third doe at 300 mg/kg b.w./day being sacrificed moribund. Similarly, the NOAEL for fetal (prenatal) /**  **developmental toxicity was 100 mg/kg b.w./day, based on slightly decreased mean fetal body weights**  **as well as an increased rate for a certain skeletal variation, namely incomplete ossification of sternabrae. Because developmental toxicity was**  **only observed at dose levels that were maternally toxic, metaflumizone is not selectively toxic to the fetal r**  **abbit. Lastly, in this rabbit developmental toxicity study, there were no indications of any**  **teratogenic effects in the rabbit fetuses at 300 mg/kg b.w./day (highest dose tested). Therefore, metaflumizone is not teratogenic in the rabbit.**  **An acute**  **d ietary**  **endpoint was**  **not established**  **for the**  **general population,**  **including infants**  **and children**  **, since**  **an endpoint**  **of concern**  **(effect) attributable**  **to a**  **single dose**  **was not**  **identified in**  **the database.**  **S tudies**  **considered for**  **this endpoint**  **included the acute neurotoxicity study for which a LOAEL was not observed.** 

**An acute**  **dietary endpoint**  **was established**  **for females**  **13 -**  **49 years**  **old based**  **on a**  **developmental effect observed in the rabbit developmental toxicity study that can be potentially**  **due to**  **a single**  **dos e**  **of metaflumizone.**  **T he**  **ef fects**  **consisted of**  **an absent**  **subclavian artery**  **in the**  **offspring at**  **the LOAEL**  **of 300**  **mg/kg b**  **. w**  **. /day**  **metaflumizone (NOAEL**  **= 100**  **mg/kg b**  **. w**  **. /day).**  **A combined**  **uncertainty factor**  **(UF) of**  **300 was**  **applied to**  **account for**  **interspecies and**  **intraspecies extrapolation**  **(100) and**  **a 3X**  **FQ PA**  **safety factor**  **was retained**  **because the**  **rabbit developmental**  **toxicity study**  **was performed**  **via oral**  **gavage dosing,**  **resulting in**  **an ARfD**  **of 0.33**  **mg/kg b.w./day.** ] **4. Subchronic toxicity.**  **[In the Sprague -** **Dawley rat, treatment by oral gavage**  **with metaflumizone for a subchronic duration (90 -**  **day timepoint in the chronic toxicity/carcinogenicity study) resulted in reduced food consumption and/or**  **decreased mean body weight and/or body weight gains in males and females at 300**  **mg/kg b.w./day and in increased incidences of hepatocellular centrilobular hypertrophy in the livers of males at 300**  **mg/kg b.w./day. Under the conditions of the study, the NOAEL for oral administration of metaflumizone for 90 days was 60**  **mg/kg b.w ./day.**  **In the**  **beagle dog,**  **treatment by**  **oral gavage**  **with metaflumizone**  **for a**  **subchronic duration**  **(90 -**  **day timepoint**  **in the**  **ch ronic**  **toxicity study)**  **resulted in**  **reduced body**  **weight gain**  **and/or decreased**  **food consumption**  **in several**  **dogs at**  **30 mg/kg**  **b.w./day an**  **d slightly**  **decreased mean**  **MCHC at**  **30 mg/kg**  **b.w./day. U**  **nder the**  **conditions of the study, the NOAEL for oral administration o f m**  **etaflumizone for 90 days was 12 mg/kg b.w./day.**  **Fo r**  **a subchronic (90 -**  **day) dermal toxicity study condu cted with metaflumizone in** **Wistar rats, the results support a NOAEL of 100 mg/kg b.w./day, based on**

**decreased food consumption (females) and decreased body weight gain**  **in males and females at 300 mg/kg b.w./day, the next highest dose tested.**  **Several microscopic changes were observe**  **d in female animals at 300 mg/kg b.w./day and above,**  **but these**  **morphologic changes were regarded to be indirect effects of the impaired body weight gain.**  **Fo r a subacute (28**  **- day) inhalation toxicity study conducted with metaflumizone in**  **Wistar rats, th e results support a NOAEL of**  **0.03 mg/** **L , based on decreased food**  **consumption (females)**  **and decreased body weight / body weight**  **gain (females) and**  **several microscopic changes in the respiratory tract at 0.10**  **mg/ L**  **, the next high est**  **dose tested. Several micro scopic changes**  **in non -**  **respiratory tract tissues were**  **observed in animals at these two dose levels, but these**  **mo rphologic changes were**  **regarded to be indirect effects of the impaired body weight / body weight**  **gain. Testing for metaflumizone’s potential**  **immunotoxicity, two studies were conducted, namely “28**  **- Day Oral Immunotoxicity Study [by Thymic**  **- Dependent Antibody**  **Response (TDAR) Assay] in the Female Wistar Rat” and “28 -** **Day Oral Immunotoxicity Study [by Natural Killer (NK) Cell Assay] in the Female Wi**  **star Rat.” Results from both studies indicate a lack of immunotoxic potential for**  **metaflumizone (BAS 320 I) up to the highest dose tested (HTD). Both Study Reports have been submitted to U.S. EPA (in 2011).** 

**5. Chronic toxicity.**  **[In the Sprague -** **Dawley rat, treatment by oral gavage with metaflumizone for a 2**  **- year chronic duration resulted in dose**  **- related increased**  **incidences of hepatocellular centrilobular hypertrophy in the livers of males and females at 60 mg/kg b.w./day and at 300/200 mg/kg b.w**  **./day and hepatocellular basophilic alteration in males at 60 and 300 mg/kg b.w./day. [NOTE: Beginning the**  **first day of Week 3, the dose level of the high -**  **dose females was lowered from 300 to 200 mg/kg b.w./day, due to an adverse effect of**  **- 71% decreased**  **body weight gain as compared to controls.]**  **Therefore, the no -**  **observable -**  **adverse -**  **effect -** **level (NOAEL) for systemic toxicity following oral administration of metaflumizone for 24 months to Sprague**  **- Dawley**  **rats was 30 mg/kg b.w./day for males and females. Importantly, treatment with**  **metaflumizone to rats for 2 years resulted in no test substance -**  **related neoplastic findings, and therefore, the NOAEL for oncogenicity was 300/200 mg/kg b.w./day**  **(highest dose tested). In the CD**  **- 1 mouse, treatment by oral**  **gavage with metaflumizone for an 18 -**  **month chronic duration resulted in a treatment** **- related increased incidence of increased**  **brown pigment in the spleens of male and female animals administered 1000 mg/kg b.w./day (highest dose tested), as compared to contr**  **ols. Under the conditions of the study, the NOAEL for systemic toxicity following oral administration of**  **metaflumizone for 18 months to CD -**  **1 mice was 250 mg/kg b.w./day (the next highest dose tested) for males and females. Importantly, treatment with** 

**met aflumizone to mice for 18 months resulted in no test substance**  **- related neoplastic**  **findings, and therefore, the NOAEL for oncogenicity was 1000 mg/kg b.w./day (highest dose tested).**  **In the beagle dog, treatment via gelatin capsules with metaflumizone for a 12**  **- month**  **chronic duration resulted in reduced body weight gain and/or decreased food consumption in several dogs at 30 mg/kg b.w./day and slightly decreased mean**  **MCHC at 30 mg/kg b.w./day. Under the conditions of the study, the NOAEL for oral administrat** **ion of metaflumizone for 12 months was 12 mg/kg b.w./day. Threshold Effect. For estimated chronic exposure, the calculation of the chronic**  **reference dose (chronic RfD) is based on the results of the chronic toxicity studies in the rat, mouse, and dog, a**  **nd the two -**  **generation reproduction study in the rat. For metaflumizone, the lowest NOAEL for chronic toxic effects is 12 mg/kg b.w./day**  **from the 12 -**  **month dog s tudy. A safety factor of 100**  **a nd an additional FQPA safety**  **factor of 3 was applied to the NOAEL to**  **account for the higher absorption observed**  **with dietary exposures , resulting in a chronic RfD of 0.04**  **mg/kg b.w./day. Non**  **- Threshold Effect. Since there were no test substance**  **- related neoplastic**  **findings following long -** **term treatment with metalfumizon e to mice for 18 months**  **or to rats for 24 months, the NOAEL for oncogenicity in both studies was established at the respective highest doses tested. Therefore, metaflumizone should**  **be classified as "not likely to be a human carcinogen."] 6.**  **Animal metab**

**olism. [In the rat, goat and hen metabolism studies, the**  **ma jority of the dose was rapidly excreted in the feces. The low le** **vels that were absorbed were distributed throughout various tissues. Metaflumizone was the**  **ma jor component of the extractable resid**  **ues in all tissues, milk, eggs and is the only residue of concern. Metabolism of metaflumizone occurs by hydroxylation and**  **conjugation on either of the phenyl rings or at the ethylene bridge and are the major routes of detoxification. Cleavage of the sem** **icarbazide bond to yield M320I04 also occurs, usually with accompanying conjugation. The only residue of concern is**  **metaflu mizone.]**  **7. Metabolite toxicology**  **. [Toxicity of the metabolites of metaflumizone with**  **potential exposure to humans was concurrentl y evaluated during toxicity testing of**  **the parent except for the metabolite M320I23 that was not observed in the rat metabolism study. The Z** **- isomer (M320I02) of metaflumizone was evaluated in**  **additional toxicity tests to confirm no differences between the minor Z**  **- isomer**  **component and metaflumizone with a 9 to 1 E -** **isomer to Z -** **isomer ratio, respectively. The results show no toxicological concerns:**  **Toxicity Studies with the metabolite M320I23 of metaflumizone (a) Acute Toxicity Study with Metabolite M 320I**  **023 The metabolite M 320I023 of metaflumizone demonstrates low acute toxicity via the** 

**oral route of exposure in the rat. Oral LD50 > 2000 mg/kg b.w. (category III).**  **(b) Subchronic Toxicity Study with Metabolite M 320I023 In the Sprague**  **- Dawley rat, treat**  **ment by oral gavage with metabolite M 320I023 of metaflumizone for a subchronic (90**  **- day) duration resulted in systemic toxicity**  **effects of increased relative liver weights (females) and increased incidences of liver hepatocellular centrilobular hypertrophy**  **in males and females at 1000 mg/kg b.w./day (highest dose tested), as compared to controls. Under the conditions of the**  **study, the NOAEL for oral administration of the metabolite M 320I023 of metaflumizone for 90 days was 200 mg/kg b.w./day (next highest**  **dose tested) in males and females.**  **(c) Mutagenicity/Genotoxicity Studies with Metabolite M 320I023 In a battery of three in vitro and one in vivo mutagenicity assays consisting of all**  **required end -** **points (point mutation, chromosomal damage, and DNA d amage and**  **repair), the weight -**  **of**

**- the**  **- evidence for the metabolite M 320I023 (parent ketone) of**  **metaflumizone insecticide indicates a lack of potential genotoxicity. Specifically, for the battery of three in vitro mutagenicity assays with metabolite M**  **320I 023 of metaflumizone, no positive responses were observed for increased**  **revertant frequencies with and without metabolic activation [bacterial reverse mutation assay] or for increased mutant frequencies with and without metabolic**  **activation [HGPRT locus as say]. Although there was a positive result for a**  **statistically increased number of structurally aberrant metaphases in the chromosomes, which indicates clastogenic potential under in vitro conditions, this**  **result was only observed with metabolic activatio n [cytogenicity study with V79**  **cells]. Importantly, the potential biological significance of this apparent chromosome**  **damage observed in vitro only with metabolic activation, was evaluated in vivo using the mouse micronucleus assay. Testing in this in**  **vivo micronucleus study with NMRI mice was conducted at a high dose level (2000 mg/kg b.w.), that**  **demonstrated no clinical symptoms of toxicity but which represents the limit dose for this assay. No significant or dose**  **- related increases in in vivo chromos**  **omal damage were observed, indicating that the metabolite M 320I023 of metaflumizone**  **does not cause chromosomal aberrations in intact animals. Moreover, it has also been recognized by U.S. EPA that more weight should be**  **placed on in vivo systems than in vitro systems as expressed in the Agency’s weight** **** **of -**  **evidence for genotoxic evaluation of a chemical included in the "Guidelines for Mutagenicity Risk Assessment" (Federal Register, September 24, 1986, Vol. 51:**  **34006 -** **34012). Thus, the negative in vivo results (non**  **- clastogenicity for**  **chromosomal aberrations) observed in the mouse micronucleus assay should override the positive results obtained in the in vitro assay only with metabolic** **activation. Furthermore, it has been noted that in vitro systems may simulate** 

**abnormal physiological conditions [Brusick, D.J. (editor) 1987. Genotoxicity Produced in Cultured Mammalian Cell Assay by Treatment Conditions. Mutation**  **Research, Vol. 189, No.1: 1 -**  **69]. Additionally, it has been reported in the literature that S**  **- 9 metabolic activation does not often have adequate cofactors for activating**  **detoxifying mechanisms found in the whole animal system [Ashby, J. 1983. The unique role of rodents in the detection of possible human carcinogens and mutagens.**  **Mutation Research , Vol. 115: 117**  **- 213] [Galloway, S.M. 1994. Chromosome**  **Aberrations Induced In Vitro: Mechanisms. Delayed Expression, and Intriguing Questions. Environmental and Molecular Mutagenesis, Vol. 23, Supplement 24: 44**  **- 53]. Consequently, based on the weight** **- of**  **- t** **he -**  **evidence presented above, the metabolite M 320I023 of metaflumizone does not pose a genotoxic concern.**  **Therefore, as indicated from the results of the mammalian toxicity studies as well as the mutagenicity assays, metabolite M 320I023 of metaflumizon**  **e does not demonstrate more adverse toxicity when compared to metaflumizone.**  **Toxicity Studies with the Z -** **Isomer of metaflumizone (a) Acute Toxicity Study with Z** **- Isomer**  **The Z -** **isomer of metaflumizone demonstrates low acute toxicity via the oral route of exposure in the rat.**  **Oral LD50 > 5000 mg/kg b.w. (category IV). (b) Subchronic Toxicity Study with Z** **- Isomer**  **In the Sprague -** **Dawley rat, treatment by oral gavage with the Z -**  **isomer of metaflumizone for a subchronic (90**  **- day) duration resulted in impaired b**  **ody weight gain only in females at the mid**  **- dose (300 mg/kg b.w./day) and the high**  **- dose (1000**  **mg/kg b.w./day), as compared to controls. Several microscopic changes were observed in female animals at these two dose levels, but all morphologic changes**  **were r egarded to be indirect effects of the impaired body weight gain. Under the**  **conditions of the study, the NOAEL for oral administration of the Z -** **isomer of metaflumizone for 90 days was 1000 mg/kg b.w./day (highest dose tested) in males**  **and 100 mg/kg b.w./da y (lowest dose tested) in females.**  **(c) Mutagenicity/Genotoxicity Study with Z -** **Isomer In an in vitro mutagenicity assay with the Z** **- isomer of metaflumizone, there were no**  **positive responses observed for increased revertant frequencies with and without me** **tabolic activation [bacterial reverse mutation assay]. Therefore, as indicated from the results of the mammalian toxicity studies as well as**  **the mutagenicity assay, the minor isomer of metaflumizone, namely the Z isomer, does not demonstrate more adverse**  **toxicity when compared to metaflumizone.] 8.**  **Endocrine disruption .**  **[Data from the reproduction / developmental toxicity and short** **- and long**  **- term repeated dose toxicity studies with metaflumizone**  **in the rat, rabbit, mouse, or dog, do not suggest any endocr ine disruption activity.** **This information is based on the absence of any treatment -**  **related effects from the**

**histopathological examination of reproductive organs as well as a low level of concern for possible effects 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. i.**  **Food. [**  **A dietary**  **exposure analysis**  **was conducted**  **for all**  **registered uses**  **of Metaflumizone**  **at the**  **t olerance**  **value s**  **of 0.04**  **ppm, tomato**  **at the**  **pending tolerance**  **value of**  **0.6 ppm**  **(including paste**  **at 1.2**  **ppm), pepper**  **and eggplant**  **at the**  **p ending**  **tolerance values**  **of 1.5**  **ppm ,**  **and pome**  **fruit and**  **citrus fruit**  **at the**  **proposed tolerance**  **values of 0.04 ppm**  **. Acute**  **Dietary Food**  **Exposure :**  **The Health**  **Effects Division**  **(HED) of**  **EPA has**  **determined that**  **there are**  **no toxic**  **effects attributable**  **to a**  **single dose**  **of metaflumizone**  **for the**  **general populations**  **including infants**  **and children.**  **Therefore, a**  **quantitative acute**  **dietary exposure**  **and risk**  **assessment for**  **these sub**  **** **populations i s**  **not required. An**  **acute dietary**  **assessment was**  **conducted to**  **evaluate the**  **potential risk**  **due to**  **acute dietary**  **exposure to**  **females 13** 

**– 49 years old**  **. T**  **he ARfD for metaflumizone is**  **1.0 mg/kg**  **bw/day. T**  **he FQ**  **PA safety**  **factor for**  **metaflumizone has**  **been set**  **to 3;**  **therefore ,**  **the aP** **AD is**  **0.33 mg/kg**  **bw/day. The**  **tier 1**  **acute dietary**  **exposure estimate**  **was based**  **on e stablished and proposed tolerance values**  **in crops (including**  **tomato paste)**  **, 100**  **percent crop**  **treate d**  **values and**  **experimental and**  **default concentration/processing**  **factors .**  **R esidues**  **in fish/shellfish**  **were included**  **based on**  **the Aquatic**  **Bioaccumulation Model**  **(KABAM) piscivorous fish**  **residue estimate**  **for fish/shellfish.**  **T he**  **Dietary Exposure**  **Evaluation Mod**  **ule (DEEM** **- FCID)**  **software, version**  **3.14 updated**  **with the**  **USDA NHANES**  **2 -**  **day food**  **consumption data**  **for 2003**  **- 2008**  **and the**  **EPA Food**  **Commodity Ingredient**  **Database (FCID)**  **as of**  **February 2012**  **was used**  **for the**  **assessment. Drinking**  **water exposure**  **was included**  **in th e dietary exposure analysis.**  **Tolerances for meat, milk, egg, and poultry are not required.**  **The exposure**  **estimate for**  **the metaflum** **izone acute**  **dietary assessment**  **was well**  **below U.S.**  **EP A’s**  **level of**  **concern (See**  **table below).**  **T he**  **estimated acute**  **dietary e**  **xposure for**  **females 13** 

**– 49**  **years old**  **was 1.6**  **%. A**  **dditional refinements**  **such as**  **the use**  **of anticipated**  **residues and**  **predicted percent**  **crop treated**  **would further**  **reduce the estimated acute dietary exposure. Table 1. Summary of Acute Dietary Exposure and Ri**  **sk for Metaflumizone Considering**  **Crop Group 11 -**  **10: Pome Fruit Group, Crop Group 12 -**  **12: Stone Fruit Group, Crop Group 10**  **- 10: Citrus Fruits Group, Crop Group 14**  **- 12: Tree Nuts**  **Group, Grape, Tomato, Bell Pepper , Eggplant, and Drinking W**  **ater. Population**  **Expos ure Estimate**  **%aPAD Subgroups**  **(mg/kg b.w./day) Females (13**  **- 49 years old)**  **0.00 535**  **1.60 aPAD = acute popu**  **lation adjusted dose (aPAD = 0.33 mg/kg bw/day)**  **Chronic Dietary Food Exposure :**  **A tier**  **1 dietary**  **exposure assessment**  **was conducted**  **for all**  **sub -** **popul ations**  **includi ng**  **infants and**  **children. T**  **he ADI**  **for metaflumizone**  **is 0.12**  **mg/kg bw/day.**  **The FQ**  **PA safety**  **factor for**  **metaflumizone has**  **been set**  **to 3;**  **t herefore,**  **the cPAD**  **is 0.04**  **mg/kg bw/day.**  **T he**  **tier 1**  **chronic dietary**  **exposure estimates**  **were based**  **on esta** **blished and**  **proposed tolerance**  **values in**  **crops (including**  **tomato paste),**  **100 percent**  **crop treated**  **values and**  **experimental and**  **default concentration/processing**  **factors. Residues**  **in fish/shellfish**  **were included**  **based on**  **the Aquatic**  **Bioaccumulation Model**  **(KAB AM)**  **piscivorous fish**  **residue estimate**  **for fish/shellfish.**  **T he**  **Dietary Exposure**  **Evaluation Module**  **(DEEM -**  **FCID) software,**  **version 3.14**  **updated with**  **the USDA**  **NHANES 2**  **- day**  **food consumption**  **data for**  **2003 -**  **2008 and**  **the EPA**  **Food Commodity**  **Ingredient Database**  **(FCI D)**  **as of**  **February 2012**  **was used**  **for the**  **assessment. D**  **rinking water**  **exposure was**  **included in the dietary exposure analysis. Tolerances for meat, milk, egg, and poultry are not**  **required. Exposure**  **estimates for**  **the metaflumizone**  **c hronic**  **dietary assessme**  **nts were**  **well below**  **U.S. EP** **A’s level**  **of concern**  **(See table**  **below .**  **T he**  **most highly**  **exposed sub**  **** **group was children 1**  **- 2**  **years old and the exposure accounted for**  **6.9 % of the**  **cPAD .**  **Additional refinements such as the use of anticipated residues and predicted p**  **ercent crop treated would further reduce the estimated chronic dietary exposure.**  **Table 2. Summary of Chronic Dietary Exposure and Risk for Metaflumizone**  **Considering Crop Group 11**  **- 10: Pome Fruit Group, Crop Group 12**  **- 12: Stone Fruit**  **Group, Crop Group 10 -**  **10 : Citrus Fruits Group, Crop Group 14**  **- 12: Tree Nuts**  **Group, Grape, Tomato, Bell Pepper, Eggplant, and Drinking Water.**

**Population Exposure Estimate**  **%cPAD Subgroups**  **(mg/kg b.w./day) U.S. Population**  **0.00152 3.8**  **All Infants (< 1 year old) 0.00081**  **2.0 Ch**  **ildren (1 -**  **2 years old) 0.00277**  **6.9 Children (3**  **- 5 years old)**  **0.00152 6.0**  **Children (6 -**  **12 years old) 0.00081**  **4.1 Youth (13**  **- 19 years old)**  **0.00277 2.7**  **Females (13 -**  **49 years old) 0.00152**  **3.7 Adults (20**  **- 49 years old)**  **0.00081 3.8** **Adults (50+ years old) 0.0027**  **7 3.2** 

**cPAD = chronic popul ation adjusted dose (cPAD = 0.04**  **mg/kg bw/day)] ii.**  **Drinking Water** 

**. [**  **The estimated**  **drinking water**  **concentrations (EDWCs)**  **used in**  **this assessment**  **were from**  **the HED**  **human health**  **assessment of**  **metaflumizone, December**  **2 1**  **, 20**  **11**

. **P RZM**  **- EXAMS**  **model ing**  **resulted in**  **the highest**  **surface water**  **values .**  **The model**  **was run**  **using the**  **fly bait**  **application scenario**  **to turf**  **to represent**  **application to**  **use sites**  **such as**  **r ecreational**  **facilities and**  **outdoor recreational**  **areas including**  **parks, picnic**  **grounds, and**  **camp grounds**  **. The acute and chronic**  **surface water EDWCs were**  **1.14 and**  **0.597 ppb, respectively.**  **The acute and chronic ground water EDWC was 2.1**  **x 10 -** **3 ppb.**  **The drinking water exposure**  **was included in the dietary assessment. ]**  **2. Non**  **- die**  **tary exposure**

**. [**  **Metaflumizone is registered in the U.S.**  **for use as a**  **fire ant bait and a fly bait**  **. These**  **use s**  **can result in residential exposure. The exposure and MOE values for**  **these uses w ere**  **estimated using EPA’s 2012 Residential SOPs. The MOE values**  **were calculated using a short -** **term dermal NOAEL of**  **100 mg ai/kg bw/day and short** **- term incidental oral NOAEL**  **of 20 mg ai/kg bw/day. The calculated MOEs**  **for all adult**  **and infant**  **exposures are greater than 100 and therefore do not exceed EPA’s level of conc**  **ern. Table**  **3 . Summary of Residential and Recreational Post** **- Application Exposure and**  **Risks from use of Fire Ant Bait. Fire Ant Bait**  **Population and activity Route of Exposure**  **Dose (m g/kg bw/day)**  **MOE** Adult

-- Residential Handler Dermal 0.00012 833, 00 0 Inhalation 0.000000013 185,000,000 Com bined

-- ARI = 7,973 Adult

– Residential Post

application Dermal 0.00 008 1,250,000 Adult

– Golfer Post

application Dermal 5.90E

- 06 16,900,000 Adolescent

– Golfer Post

application Dermal 6.86E

- 06 14,600,000

Children (1 to <2 year olds)

– Post

- application Dermal 0.00016 625,000 Incidental oral hand

- to mo uth 1.50E

- 06 13,000,000 Incidental oral object

- to mo uth 4.00E

- 07 50,000,000 Com bined oral h

- t - m and dermal -- ARI = 5479 **Table 4. Summary of Recreation al Post** **- Application Exposure and Risks from use**  **of Metaflumizone Fly Bait. Fly Bait**  **Population and activity Route of Exposure**  **Dose (m g/kg bw/day)**  **MOE** Adult

– Post

- application Dermal 0.00117 86,000

Children (1 to <2 years old)

– Post

- application Dermal 0.00229 44,000 Incidental oral hand

- to mo uth 0.0000210 950,000 Incidental oral object

- to mo uth 0.0000013 15,000,000 Com bined oral hand

- to mouth and dermal -- ARI = 384

**3. Aggregate exposure.**  **[ Acute Aggregate Risk**  **: No**  **acute residential/rec**  **reational exposure**  **s are**  **expected. T**  **he acute**  **aggregate risk**  **includes only**  **exposure to**  **females 13**  **- 49**  **years old**  **from food**  **and water.**  **The food**  **and drinking**  **water exposure**  **accounts for**  **less than**  **1 %**  **aPAD which**  **is below HED’s level of concern. Short** **- /Interm**  **ediate Term** **Aggregate Risk :**  **There is**  **the potential**  **for short** **- term,**  **non -**  **dietary exposure**  **of children**  **and adults**  **to metaflumizone**  **from the**  **use as**  **a fire**  **ant bait**  **and a**  **fly bait**  **. Therefore,**  **the short** **- term**  **aggregate exposure**  **includes residential** **/recreational exposure**  **, food**  **and water**  **exposure. Because**  **the level**  **of concern**  **(LOC) for**  **oral exposure**  **is different**  **than the**  **LOC for**  **dermal exposure,**  **an Aggregate**  **Risk Index**  **(ARI) is**  **used. A**  **n ARI**  **>1 i**  **ndicates an**  **acceptable exposure.**  **In the**  **tables below,**  **the incidenta** **l oral**  **exposure for**  **the hand**  **- to**  **- mouth**  **exposure was**  **aggregated with**  **the dietary**  **and post** **- application**  **dermal exposure**  **for both**  **the fire ant and fly bait uses.**  **Table 5**  **. S**  **ummary of**  **Shor t** **- /Intermediate**  **Term Aggregate**  **Risk from**  **Fire Ant**  **Bait Use .**  **Food + wate**  **r Non**  **- dietary** 

**oral Dermal**  **Aggregate Population Sub**  **- Group**  **MOE MOE**  **MOE ARI**  US population 13,132 NA 833, 000 43.5 Children 1

- 2 7,228 13,300 , 000 625,000 24.0

**Table 6**  **. S**  **ummary of**  **Short -** **/Intermediate Term**  **Aggregate Risk**  **from Fly**  **Bait Use.** **Food + water**  **N on**  **- dietary** 

**oral Dermal**  **Aggregate Population Sub**  **- Group**  **MOE MOE**  **MOE ARI**  US population 13,1 00 NA 85, 500 41.6 Children 1

- 2 7,2 30 952, 000 43, 700 22.7 **The ARI**  **values are all greater than 1**  **which indicates acceptable exposure**  **s .**  **Chronic Aggregate Risk: No**  **chronic resid**  **ential/recreational exposure**  **is expected.**  **T he**  **chronic aggregate**  **risk includes**  **only exposure**  **from food**  **and water.**  **T he**  **chronic food**  **and drinking**  **water exposure for all sub -** **populations are below HED’s level of concern. ]**  **D. Cumulative Eff**

**ects [Section 408(b)(2)(D)(v) requires that, when considering**  **whether to establish, modify, or revoke a tolerance, the Agency consider ``available information'' concerning the cumulative effects of a particular pesticide's residues**  **and ``other substances that have a common mechanism of toxicity.**  **The EPA is currently developing methodology to perform cumulative risk assessments. At this time, there is no available data to determine whether**  **metaflumizone has a common mechanism of toxicity with other subs tances or how**  **to include this pesticide in a cumulative risk assessment.] E. Safety Determination**  **1. U.S. population.**  **[Using the conservative exposure assumptions described above and based on the completeness and the reliability of the toxicity data, B**  **ASF has estimated the aggregate exposure to metaflumizone**  **is well below the EPA’s level**  **of concern. ]**  **2. Infants and children** 

**. [All subpopulations based on age were considered.**  **Infants and children**  **aggregate risk is well below EPA’s level of concern. B**  **ASF, considering a worst** **- case situation, concludes with reasonable certainty that no**  **harm will result to infants or children from aggregate exposure to metaflumizone residues.]**  **F. International Tolerances [**  **Maximum residue levels (MRLs) have been establi shed for metaflumizone**  **by the Codex Alimentarius Commision (CODEX) in potato, tomato, pepper,**  **eggplant, Brussels sprout, Chinese cabbage, lettuce, and animal products. Harmonized EU**  **MRLs have been established for metaflumizone in potato, tomato,**

**pepper, e ggplant,**  **leafy brassica , Brussels sprout, lettuce**  **and similar**  **and animal products.**  **Codex (based on parent only)**  **Potato 0.02**  **Tomato 0.6**  **Pepper, inc chili pepper 0.6**  **Peppers chili, dried 6**  **Eggplant 0.6**  **Brussels sprout 0.8**  **Chinese cabbage 6**  **Lettuce 7**  **Swine (all) 0.02**  **Bovine (meat, kidney, liver, fat, offal) 0.02**  **Sheep, goat (meat, kidney, liver, fat, offal) 0.02**  **Milk 0.01**  **Cream 0.02**  **EU harmonized (based on parent + M320I04)**  **Potato 0.05**  **Tomato 0.6**  **Pepper, inc chili pepper 1**  **Eggplant 0.6**  **Bru ssels sprout**  **1 Head cabbage**  **1 Chinese cabbage**  **6 Leafy cabbage**  **10 Lettuce and similar**  **except scarole 10**  **Swine (all) 0.02**  **Bovine (meat, kidney, liver, fat, offal) 0.02**  **Sheep, goat (meat, kidney, liver, fat, offal) 0.02**  **Poultry (meat, liver, kidney, o ffal)**  **0.02 Poultry fat**  **0.1 Milk**  **and cream 0.02**  **Eggs 0.02**  **]**