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**(7/1/2006) EPA Registration Division contact:**  **[ Julie Chao, (703) 308**  **- 8735]**  **[ BASF Corporation**  **] [**  **3E8146 ]**  EPA has received a pesticide petition **( 3E8146**  **)** 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 ag**  **ricultural commodity [**  **tomato ]**  **at [0.**  **6 ]**  **parts per million (ppm); [**  **bell pepper ]**  **at [0.6**  **] ppm**  **and [eggplant** **] at**  **[0.6 ]**  **ppm .**  **EPA has determined that the petition contains data or information 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 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 metaflumizone. The major degradate was the ketone, M320I04 and an oxidized and cyclized metabolite,**  **M320I23, was present in lesser amounts. These four com pounds 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) an d 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 .**  [ **Crop field trials were conducted in Europe**  **to deter**  **m ine the**  **m a**  **gnitude of residues of Metaflumizone in/on r**  **aw agric u**  **ltu r**  **al**

**c o**  **mmodities o**  **f tomato and Pepper. Ten**  **field trials**  **and ten glasshouse trials were**  **conducted in north and**  **south Europe for tomato.**  **Fifteen glasshouse trials were conducted in north and south Europe for bell pepper.**  **Metaflumizone ( f**  **or m** **ulated as a representative 240 g/L SC Formulation with BASF fo**  **r m**  **ulation code BAS 320 00 I, tradena**  **m e of**  **ALVERDE ®** **) w**  **a s applied at the proposed**  **m ax** **i m** **u m l**  **abel use rate and at various p**  **r e**  **- h**  **ar v**  **est i n**  **ter v**  **als (PHI). In add**  **ition, a**  **processing study was**  **conducted on**  **tomato to determine the concentration factor**  **s during normal**  **processing of the raw agricultural commo dity**  **. ]**  **B. Toxicological Profile 1.**  **Acute toxi** 

**city. [**  **Based on**  **the available**  **acute toxicity**  **data, metaflumizone**  **and its formulated product do not pose acute 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 thre**  **e 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 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 mutation**  **assay] or for increased mutant frequencies w ith 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 potential under in vitro conditions, th is 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 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 piloerection and poor general state, in 5 of 5**  **an imals. 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 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 and the rat hepatocytes assay, should override the positive results obtained in the in vitro assay**  **only w ithout 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 Pr oduced 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. 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 investigated in a two -**  **generation reproduction toxicity stu dy**  **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), which 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 generations of rats, which were originally derived fr**  **om 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 l**  **actation. 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**  **generati ons), 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 be cause 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 ora l 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 b ody 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 t** **he 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 sacrif**  **iced 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**  **endpoint included the acute neurotoxicity study for which a LO**  **AEL 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**  **dose of**  **metaflumizone. T**  **he ef**  **fects co**  **nsisted 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) a**  **nd 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 incre ased 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, treatmen**  **t by**  **oral gavage**  **with metaflumizone**  **for a**  **subchronic duration**  **(90 -**  **day timepoint**  **in the**  **chronic toxicity**  **study) 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**  **3 0**  **mg/kg b.w./day.**  **U nder**  **the conditions of the study, the NOAEL for oral administration of metaflumizone for 90**  **days was 12 mg/kg b.w./day. Fo**  **r a subchronic (90**  **- day) dermal toxicity study conducted 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 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 metaflumizone in**  **Wistar rats, the results support a NOAEL of 0.03**  **m g/** **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 t**  **ract 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 co**  **nducted, 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 Wistar**  **Rat.” Results from both stud ies 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 gavag e**  **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 co**  **ntrols.] 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**  **metafl umizone 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 controls. Under the conditions of the**  **s tudy, 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 re sulted 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 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 studies 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**  **factor of 3 was applied to the NOAEL to account for**  **the higher absorpti on 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 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 me** **tabolism studies, the ma** **jority of the dose was rapidly excreted in the feces. The low levels that were absorbed were distributed throughout various tissues. Metaflumizone was the**  **ma jor component 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 detoxification. Cleavage of the semicarbazide bond to yield M320I04 al**  **so occurs, usually with accompanying conjugation. The only residue of concern is**  **metaflumizone.] 7.**  **Metabolite toxicology .**  **[Toxicity of the metabolites of metaflumizone with potential exposure 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 confirm no differences between the minor Z** **- isomer**  **component and metaf**

**lumizone 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 320I023**  **The metabolite M 320I023 of met aflumizone 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, 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 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 damage and repair), the weight** **- of** 

**- th**  **e -**  **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 320I023 of metaflumizone, no positive r**  **esponses 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 positiv**  **e 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 activation [cytogenicity study with V79**  **cell s].** **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 m ice 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 chromosomal**  **damage were observed, indicati ng 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 t he 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 ch**  **romosomal 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 co**  **nditions [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 of**  **ten 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 -** **the -**  **evidence presented above, the me** **tabolite 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 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 t he 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 rever**  **se 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 metaflumi** **zone.] 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 info**  **rmation 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 reproductiv**  **e 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 tolerance**  **values of**  **0.04 ppm**  **and tomato,**  **pepper an**  **d eggplant**  **at the**  **proposed tolerance of 0.6 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**  **in fants**  **and children.**  **Therefore, a**  **quantitative acute**  **dietary exposure**  **and risk**  **assessment for**  **these sub**  **** **populations i s**  **not required. Acute dietary assessments**  **were 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 aPAD**  **is 0.33**  **mg/kg bw/day.**  **The tier**  **1 acute**  **dietary exposure**  **estimates were**  **based on**  **established and**  **proposed tole**  **rance values**  **, 100**  **percent crop treated values, concentration/processing factors and**  **the USDA NHANES 2 -**  **day food**  **consumption data**  **for 2003**  **- 2008**  **and the**  **EP A**  **Food Commodity**  **Ingredient Database**  **(FCID) as**  **of February**  **2012 using**  **the Dietary**  **Exposure Evaluation**  **Mo dule**  **(DEEM -**  **FCID) software**  **, version**  **3.14 .**  **Drinking water**  **exposure was** **included in**  **the dietary**  **exposure analysis.**  **Tolerances for**  **meat, milk,**  **egg, and** 

**poultry are not required. Exposure**  **estimates for**  **the metaflumizone**  **acute dietary**  **assessments were**  **well below**  **U.S. EPA’s**  **level of**  **concern (See**  **tables below).**  **T he**  **estimated acute**  **dietary exposure**  **for females**  **13**

**– 49**  **years old**  **was 0.57**  **%. A**  **dditional refinements**  **such as**  **the use**  **of anticipated**  **residues and**  **predicted percent**  **crop treated**  **would further**  **reduce th e estimated acute dietary exposure.**  **Table 1. Summary of Acute Dietary Exposure and Risk for Metaflumizone Considering**  **Tomatoes, Bell Peppers, Eggplant, Grape, Crop Group 10**

**– Citrus**  **Fruits Group, Crop Group 14**

**– Tree Nuts G** **roup and Drinking W**  **ater.**

**Popula tion**  **Exposure Estimate %aPAD**  **Subgroups (mg/kg b.w./day)**  **Females (13 -**  **49 years old) 0.00190**  **0.57 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 exposure**  **estimates were**  **ba sed**  **on the**  **established and**  **proposed tolerance**  **values, 100**  **percent crop**  **treated values,**  **concentration/processing factors**  **and the**  **USDA NHANES**  **2 -**  **day food**  **consumption data for 2003**  **- 2008 and the EPA Food Commodity Ingredient Database (FCID) as of**  **February 2012**  **using the**  **Dietary Exposure**  **Evaluation Module**  **(DEEM -**  **FCID) software,**  **version 3.14.**  **Drinking water**  **exposure was**  **included in**  **the dietary**  **exposure analysis. Tolerances for meat, milk, egg, and poultry are not required. Exposure**  **estimates for**  **the metaflumizo**  **ne c**  **hronic dietary**  **assessments were**  **well below**  **U.S. EPA’s**  **level of**  **concern (See**  **tables below**  **. T**  **he most**  **highly exposed**  **sub**   ** group was children** **1 -**  **2 years**  **old and the exposure accounted for 3.2**  **% of the cPAD**  **. Additional refinements**  **such as the use of anticipa ted 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**  **Tomato, Bell Pepper, Eggplant, Grape, Crop Group 10** 

**– Citrus**  **Fruits Group, Crop Group 14** 

**– Tree Nuts Group,**  **and Drinking Water.**

**Population Exposure Estimate**  **%cPAD Subgroups**  **(mg/kg b.w./day) U.S. Population**  **0.00060 1.5**  **All Infants (< 1 year old) 0.00034**  **0.8 Children (1**  **- 2 years old)**  **0.00126 3.2** **Children (3 -**  **5 years old)**  **0.00124 3.1** 

**Children (6 -**  **12 years old) 0.00076**  **1.9 Youth (13**  **- 19 years old)**  **0.00051 1.3**  **Females (13 -**  **49 years old) 0.00054**  **1.4 Adults (20**  **- 49 years old)**  **0.00051 1.3**  **Adults (50+ years old) 0.00051**  **1.3 cPAD = chronic popul**  **ation adjusted dose (c PAD = 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**  **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 -**  **dietary exposure**

**. [**  **Metaflumizone is registered in th**  **e 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**  **o f**  **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 concern.**  **Table 3**  **. Summary of Residential and Recre ational 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 0.000048 2,100,000 Inhalation 0.00000015 52,000,000 Com bined

-- ARI = 15,000 Adult

– Residential Post

application Dermal 0.000334 300,000 Adult

– Golfer Post

application Dermal 2.36E

- 05 4,200,000 Adolescent

– Golfer Post

application Dermal 0.000028 3,600,000

Children (1 to <2 year olds)

– Post

- application Dermal 0.000655 150,000 Incidental oral hand

- to mo uth 6.04E

- 06 3,300,000 Incidental oral object

- to mo uth 3.70E

- 07 54,000,000 Com bined oral h

- t - m and

-- ARI = 1,513dermal

**Table 4. Summary of Recreational 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 .0000211 950,000 Incidental oral object

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

- to mouth and dermal -- ARI = 432

**3. Aggregate exposure.**  **[ Acute Aggregate Risk**  **: No**  **acute residential/recreational**  **exposure s**  **are expected.**  **T he**  **acute aggre**  **gate 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** **- /Intermediate**  **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**  **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** **- /Intermediate**  **Term Aggregate**  **Risk from**  **Fire Ant**  **Bait Use .**  **Food + water**  **Non -**  **dietary**

**oral Dermal**  **Aggregate Population Su**  **b -**  **Group MOE**  **MOE MOE**  **ARI** US population 33,501 NA 299,895 108 Children 1

- 2 15, 873 3,300,000 15 2 , 724 51**Table 6**  **. S**  **ummary of**  **Short -** **/Intermediate Term**  **Aggregate Risk**  **from Fly**  **Bait**

**Use. Food +**  **water Non**  **- dietary** 

**oral Dermal**  **Aggregate Population Sub**  **- Grou**  **p MOE**  **MOE MOE**  **ARI** US population 33,501 NA 85,684 99 Children 1

- 2 15,8 7 3 945,846 43,636 46 **The ARI**  **values are all greater than 1**  **which indicates acceptable exposure**  **s .** 
**Chronic Aggregate Risk: No**  **chronic resid**  **ential/recreational exposure**  **is expecte**  **d. 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 cons idering**  **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 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 metaflumizon e**  **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 Tolerances [**  **Maximum residue levels (MRLs) have been established for metaflumizone by the Codex Alimentarius Commisi**  **on (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, eggplant,**  **leafy brassica , Brussels sprout, lettuce**  **and si**  **milar 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, o**  **ffal) 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**  **Brussels sprout 1**  **Head cabbage 1**  **Leafy brassica 10**  **Lettu ce 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 ]**