Document ID: EPA-HQ-OPP-2019-0385-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2019-08-30T04:00Z

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE (7/1/2006)

EPA Registration Division Contact: []

INSTRUCTIONS:  Please utilize this outline in preparing tolerance petition documents.  In cases where the outline element does not apply please insert "NA-Remove" and maintain the outline.  The comment notes that appear on the left margin represent hidden typesetting codes designed to expedite the processing of the Federal Register document.  Please do not remove or alter 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 Corporation]

[Insert petition number]

	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 [apple] at [1] ppm, [coffee] at [0.15] ppm, [crop group 9A: melon subgroup] at [1] parts per million (ppm), [crop group 10-10A: orange subgroup] at [3] ppm,), [citrus oil ] at [42] ppm,  [crop group 10-10B: lemon/lime subgroup] at [3] ppm,  [crop group 13-07G: grape] at [5] ppm, [Raisin] at [10] ppm, [cattle fat] at [0.05] ppm, [sheep fat] at [0.05] ppm, [goat fat] at [0.05] ppm, [horse fat] at [0.05] ppm and [milk fat] at [0.1] 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 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. 531/1 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 matrices with methanol/water (70:30; v/v) and then partitioned into dichloromethane.  Clean up steps were used only when necessary. The final determination of metaflumizone and its metabolites is performed by LC/MS/MS.]

	3. Magnitude of residues.  [Field trials were conducted on multiple crops and crop groups in Brazil to support the foliar use of metaflumizone product.  Residue field trials were conducted for apple, coffee, citrus fruit (oranges and lemons), grape and melon. The number and locations of field trials are in accordance with NAFTA Guidance Document on Data Requirements for Tolerances on Imported Commodities in the United States and Canada. Field trials were carried out using the maximum label rates, the maximum number of applications, the minimum retreatment interval and the minimum pre-harvest interval (PHI) for all the crops. Detected residues of metaflumizone in all crops support the proposed tolerances.  Processing factors were determined for all processed commodities per OPPTS Guideline 860.1520.  Processing studies for citrus and grape commodities were also conducted.   
Values for tolerances/MRLs were determined for each commodity using parent residues (isomers E and Z) plus metabolite M320I04 and the OECD MRL calculator.]

B. Toxicological Profile

	1. Acute toxicity.  [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 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 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 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 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 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 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 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 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. 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 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), which altogether resulted in high pup mortality.  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 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 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 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 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 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.  Studies 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 dose of metaflumizone.  The effects 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 FQPA 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 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 30 mg/kg b.w./day.  Under the conditions of the study, the NOAEL for oral administration of metaflumizone for 90 days was 12 mg/kg b.w./day.

For 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.    

For a subacute (28-day) inhalation toxicity study conducted with metaflumizone 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 highest dose tested.  Several microscopic changes in non-respiratory tract tissues were observed in animals at these two dose levels, but these morphologic 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 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. 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 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 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 study.  A safety factor of 100 and 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 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 majority of the dose was rapidly excreted in the feces.  The low levels that were absorbed were distributed throughout various tissues.  Metaflumizone was the major 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 also 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 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 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
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-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 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 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, this result was only observed 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 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 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: 34006-34012).  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-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, 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 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, 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 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 fertility, reproductive performance, or any other aspect of reproductive function, or on growth and development of the offspring.]

C. Aggregate Exposure

	1. Dietary exposure. 

 Food. [
Metaflumizone and its metabolite M320I04 are expressed as the parent compound (metaflumizone). A dietary exposure analysis was conducted for all registered uses of Metaflumizone at the tolerance values and apple at the pending tolerance value of 1 ppm (including processing factors of 0.2 for dried apple and 0.5 for juice), crop group 9A at the pending tolerance of 1 ppm, crop group 10-10A and 10-10 B at the pending tolerance value of 3 ppm (including oil at 42 ppm and processing factors of 0.02 for juice), coffee at the pending tolerance value of 0.15 ppm, crop group 13-07G at pending tolerance of 5 ppm (including raisin at 10 ppm and processing factors of 0.1 for wine and 1.2 for juice, the last one based on default value). Fat from cattle, goat, sheep and horse at 0.05 ppm, as well as milk fat at 0.1 ppm was also included to account for livestock feed items associated with these crops. 

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 is not required.  
   
An acute dietary assessment was conducted to evaluate the potential risk due to acute dietary exposure to females 13  -  49 years old.  The ARfD for metaflumizone is 1.0 mg/kg bw/day.  The FQPA 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 estimate was based on established and proposed tolerance values in crops (including citrus oil), proposed tolerances in meat fat and milk fat, 100 percent crop treated values and experimental and default concentration/processing factors.  Residues in fish/shellfish were included based on the Aquatic Bioaccumulation Model (KABAM) piscivorous fish residue estimate for fish/shellfish.   The Dietary Exposure Evaluation Module (DEEM-FCID) software, version 4.02 updated with the USDA NHANES 2-day food consumption data for 2005-2010 and the EPA Food Commodity Ingredient Database (FCID) as of August 2014 was used for the assessment.  Drinking water exposure was included in the dietary exposure analysis.  

The exposure estimate for the metaflumizone acute dietary assessment was well below U.S. EPA's level of concern (See table below).  The estimated acute dietary exposure for females 13  -  49 years old was 4.2%.  Additional 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 Risk for Metaflumizone considering registered crops, new uses (all pending) and drinking water.  
                                  Population
                               Exposure Estimate
                                     %aPAD
                                   Subgroups
                               (mg/kg b.w./day)
                                        
                           Females (13-49 years old)
                                    0.01397
                                      4.2
aPAD = acute population 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 including infants and children.  The cRfD for metaflumizone is 0.12 mg/kg bw/day.  The FQPA safety factor for metaflumizone has been set to 3; therefore, the cPAD is 0.04 mg/kg bw/day.  The tier 1 chronic dietary exposure estimates were based on established and proposed tolerance values in crops (including citrus oil), proposed tolerances in meat fat and milk fat, 100 percent crop treated values and experimental and default concentration/processing factors. Residues in fish/shellfish were included based on the Aquatic Bioaccumulation Model (KABAM) piscivorous fish residue estimate for fish/shellfish.   The Dietary Exposure Evaluation Module (DEEM-FCID) software, version 4.02 updated with the USDA NHANES 2-day food consumption data for 2005-2010 and the EPA Food Commodity Ingredient Database (FCID) as of August 2014 was used for the assessment.  Drinking water exposure was included in the dietary exposure analysis. 

Exposure estimates for the metaflumizone chronic dietary assessments were well below U.S. EPA's level of concern (See table below.  The most highly exposed sub-group was children 1-2 years old and the exposure accounted for 76.5% 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 registered crops, new uses (all pending) and drinking water.  
                                  Population
                               Exposure Estimate
                                     %cPAD
                                   Subgroups
                               (mg/kg b.w./day)
                                        
                                U.S. Population
                                    0.00554
                                     13.9
                         All Infants (< 1 year old)
                                    0.01031
                                     25.8
                           Children (1-2 years old)
                                    0.03059
                                     76.5
                           Children (3-5 years old)
                                    0.01882
                                     47.0
                           Children (6-12 years old)
                                    0.00822
                                     20.6
                            Youth (13-19 years old)
                                    0.00341
                                      8.5
                           Adults (20-49 years old)
                                    0.00353
                                      8.8
                                Adults 50+ yrs
                                    0.00384
                                      9.6
                           Females (13-49 years old)
                                    0.00358
                                      9.0
   cPAD = chronic  population 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 21, 2011.  PRZM-EXAMS modeling 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 recreational 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 the U.S. for use as a fire ant bait and a fly bait.  These uses can result in residential exposure.  The exposure and MOE values for these uses were 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 concern.  

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 (mg/kg bw/day)
                                      MOE
Adult -- Residential Handler
                                    Dermal
                                    0.00012
                                    833,000

                                  Inhalation
                                  0.000000013
                                  185,000,000

                                   Combined
                                      --
                                  ARI = 7,973
Adult  -  Residential Post-application
                                    Dermal
                                    0.00008
                                   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-mouth
                                   1.50E-06
                                  13,000,000

                        Incidental oral object-to-mouth
                                   4.00E-07
                                  50,000,000

                        Combined oral h-t-m and dermal
                                      --
                                  ARI = 5479

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 (mg/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-mouth
                                   0.0000210
                                    950,000

                        Incidental oral object-to-mouth
                                   0.0000013
                                  15,000,000

                    Combined oral hand-to-mouth and dermal
                                      --
                                   ARI = 384

  
	3. Aggregate exposure. 
    [Acute Aggregate Risk:  
    No acute residential/recreational exposures are expected.  The 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 5% 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.  An ARI >1 indicates 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.  Summary of Short-/Intermediate Term Aggregate Risk from Fire Ant Bait Use and Imported Commodities.
    

                                 Food + water
                               Non-dietary oral
                                    Dermal
                                   Aggregate
                             Population Sub-Group
                                      MOE
                                      MOE
                                      MOE
                                      ARI
US population
                                     3681
                                      NA
                                    833,000
                                     12.3
Children 1-2
                                      674
                                  13,300,000
                                    625,000
                                      2.2
     

    
    Table 6.  Summary of Short-/Intermediate Term Aggregate Risk from Fly Bait Use and Imported Commodities.
    

                                 Food + water
                               Non-dietary oral
                                    Dermal
                                   Aggregate
                             Population Sub-Group
                                      MOE
                                      MOE
                                      MOE
                                      ARI
US population
                                     3681
                                      NA
                                    85,500
                                     12.1
Children 1-2
                                      673
                                    952,000
                                    43,700
                                      2.2
     
The ARI values are all greater than 1 which indicates  acceptable exposures.  

Chronic Aggregate Risk:

No chronic residential/recreational exposure is expected.  The chronic aggregate risk includes only exposure from food and water.  The 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 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 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 Tolerances

	[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 established for metaflumizone in several crops 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 only)
Fruiting vegetables
(a) solanacea
Tomatoes
0.6
Sweet peppers/bell peppers
1
Aubergines/eggplants
0.6
(b) cucurbits with edible peel
Cucumbers
0.4
Gherkins
0.4
Courgettes
0.4
Others
0.4
Brassica vegetables (excluding brassica roots and brassica baby leaf crops)
(a) flowering brassica
Broccoli
3
Cauliflowers
1.5
(b) head brassica
Brussels sprouts
1
Head cabbages
1
(c) leafy brassica
Chinese cabbages/pe-tsai
7
Leaf vegetables, herbs and edible flowers
(a) lettuces and salad plants
Lamb's lettuces/corn salads
10
Lettuces
5
Cresses and other sprouts and shoots
10
Land cresses
10
Roman rocket/rucola
10
Red mustards
10
Baby leaf crops (including brassica species)
10
Others
10
Legume vegetables
Beans (with pods)
0.9
Peas (with pods)
1.5
Stem vegetables
Globe artichokes
0.9
Oilseeds
Cotton seeds
0.07
Swine (all)
0.02
Bovine (meat, kidney, liver, fat, offal)
0.02
Sheep, goat (meat, kidney, liver, fat, offal)
0.02
Equine (meat, kidney, liver, fat, offal)
0.02
Other farmed terrestrial animals (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