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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 C osmetic 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 inf**  **ormation regarding 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 befor**  **e 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 an**  **d cyclized metabolite, 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 res**  **idues 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 metaf lumizone 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 metaflumi** **zone 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 ha rvested 5 days 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 nu t metaflumizone 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; p reharvest interval (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) toleran ces (0.04 ppm) 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 r**  **esidues in lettuce, 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 accepta** **ble. ]**  **B. Toxicological 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. category 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 la ck of potential 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 mutati on**  **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 clas**  **togenic potential 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 with**  **out metabolic 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 pi** **loerection and 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 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 As**  **sessment" (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 and the rat hepatocytes assay, should override the positiv**  **e results obtained 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 activatio**  **n [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 Mutagen**  **esis, Vol. 21, 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 investigate d in a two**  **- generation 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 females 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), whi ch altogether 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 genera** **tions of rats, 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 (highest 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 firs**  **t 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 th**  **e 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**  **statistically 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 rabbit, 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 t**  **hese 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 rabbit. 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**  **dietary 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**  **endpo int**  **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 potentia** **lly due**  **to a**  **single dose**  **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**  **accou nt**  **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 to** 

**xicity. [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 we ight 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 metaflumizo**  **ne 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 sever**  **al dogs**  **at 30**  **mg/kg b.w./day**  **and 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 c ondu**  **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 m icroscopic**  **changes were observed 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 m**  **etaflumizone in Wistar rats, the 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 microscopic 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 (N K) Cell Assay] in the Female Wistar**  **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. Chr**  **onic 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 a dverse 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 dos e tested), as compared to controls. 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** 

**metaflumizone 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 ca** **psules 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 administration 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 studie**  **s in the rat, mouse, and dog, and 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**  **facto r 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 -** **t erm treatment with metalfumizone 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 metabolism.**  **[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 com ponent of the extractable residues 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 detox ification. Cleavage of the semicarbazide 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 exp**  **osure to humans was concurrently 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 con**  **firm 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 Toxici ty Study with Metabolite M 320I023** **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 I**  **n the Sprague -** **Dawley rat, treatment 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 hepatocel** **lular 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 2**  **00 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 damage 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 mutagenicit** **y assays with metabolite M 320I023 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 metab**  **olic 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 potential under in vitro conditions, this**  **result was only ob served with metabolic activation [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 micronucl**  **eus 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**  **- relat**  **ed increases in in vivo chromosomal 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 -** **3401 2). 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 re ported 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]. Consequ ently, based on the weight** **- of**  **- the**  **- 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, metab olite M 320I023 of metaflumizone 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 body 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 regarded 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./day (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**  **metabolic 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, doe**  **s 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 endocrine disruption activity.** **This information is based on the absence of any treatment -**  **related effects from the**

**histopathological examination of reproductive organs as well as a low level of concern for possible effects on ferti** **lity, 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 Metaf**  **lumizone at**  **the t**  **olerance values**  **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 quan**  **titative 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 metaflum** **izone 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**  **treated 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**  **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 (FCID)**  **as of**  **February 2012**  **was used**  **for the**  **assessment. Drinking**  **wa ter**  **exposure was**  **included in the 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).**  **The estimated**  **acute dietary**  **exposure 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 o**  **f Acute 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 Dri**  **nking W ater.** **Population Exposure 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 -** **populations 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 exposu**  **re estimates**  **were based**  **on established**  **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**  **Aqu atic**  **Bioaccumulation Model**  **(KABAM) 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**  **Com modity**  **Ingredient Database**  **(FCID) 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**  **metaflu mizone**  **c hronic**  **dietary assessments**  **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 percent**  **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**  **Al l Infants (< 1 year old)**  **0.00081 2.0**  **Children (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)**  **0.00277 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**

. **PRZM -** **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**  **re creational**  **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**  **- dietary 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 incident al 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 co**  **ncern. 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, 000 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 Recreati onal 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/r**  **ecreational 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** **- /Inte**  **rmediate 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** **/recreation al**  **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**  **a n**  **acceptable exposure**  **. In**  **the t**  **ables below,**  **the incidental**  **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 -** **/Intermedia te**  **Term Aggregate**  **Risk from**  **Fire Ant**  **Bait Use .**  **Food + water**  **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**  **Non -**  **dietary**

**oral Dermal**  **Aggregate Population Sub**  **- Gr**  **oup 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 Effects [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 pes**  **ticide'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 comm on mechanism of toxicity with other substances 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, BASF 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. BASF,**  **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 Toler** 

**ances [**  **Maximum residue levels (MRLs) have been established 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 es**  **tablished for metaflumizone in potato, tomato,**

**pepper, eggplant, 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 Eggpla**  **nt 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**  **T omato**  **0.6 Pepper, inc chili pepper**  **1 Eggplant**  **0.6 Brussels 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, offal)**  **0.02 Poultry fat**  **0.1 Milk**  **and cream 0.02**  **Eggs 0.02**  **]**