Document ID: EPA-HQ-OPP-2013-0141-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-06-05T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: Shaunta Hill (703)347-8961 

Syngenta Crop Protection LLC. PP# 2E8123

	EPA has received a pesticide petition PP# 2E8123 from Syngenta Crop Protection LLC., P.O. Box 18300, Greensboro, NC 27419-8300 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 an import tolerance for residues of Benzovindiflupyr (SYN545192) in or on the raw agricultural commodity coffee, bean, green at 0.09 parts per million (ppm) and sugarcane, cane at 0.04 ppm. EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of  FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

	1. Plant metabolism. [Plant metabolism studies with benzovindiflupyr (SYN545192) were performed in wheat, soybean and tomatoes as representative crops in order to characterize the fate of benzovindiflupyr in all crops.  Two radiocarbon labels were studied in each crop, with [[14]C] labels positioned in the phenyl and pyrazole ring structures.  Benzovindiflupyr was the predominant component of residue in most crops.  The metabolism in all plants (soybean, wheat, tomatoes) was very similar.  In all crops, the main path was via oxidative metabolism of alicyclic system, N-demethylation of pyrazole ring, conjugation of hydroxylated  parent and cleavage between phenyl and pyrazole ring. There was, however, some variation on the extent and nature of conjugations between crops.]

	2. Analytical method. [The proposed definition of the residue for benzovindiflupyr (SYN545192) in commodities of plant origin is parent SYN545192 for both compliance monitoring and dietary risk assessment.  The corresponding definitions in commodities of animal origin are parent SYN545192 for monitoring and sum of SYN545192 and SYN546039 for dietary risk assessment. Method GRM042.03A (implemented as POPIT MET.125, POPIT MET.133 have used for analysis of SYN545192 and its metabolites SYN546039 in sugarcane and coffee samples, respectively.  The limit of quantitation (LOQ) for method POPIT MET. 125 and POPIT MET. 133 were 0.005 and 0.01, respectively.

 Both methods GRM042.03A and GRM042.04A for plant products have been developed to determine parent SYN545192 and its metabolite SYN546039 (and conjugates) with a limit of quantification (LOQ) of 0.01 mg/kg for both analytes.  GRM042.04A also determines metabolite SYN545720 with an LOQ of 0.01 mg/kg.  Method GRM042.08A has been developed for the determination of SYN545192 and its metabolites SYN546039 and SYN546206 in rotational crops, with an LOQ of 0.01 mg/kg for all three analytes.  Method GRM042.06A  for animal products has been validated for use in pre-registration development studies.  The method determines parent SYN545192 and its metabolites SYN546039 and SYN546422, with an LOQ of 0.01 mg/kg for each analyte.  Method GRM023.03A was used to analyse residues of SYN545720 in the storage stability study demonstrating the storage stability of SYN545720 residues in a range of commodities under frozen conditions.  QuEChERS multi-residue method (EN 15662:2009) has been validated and independently validated for post-registration monitoring of SYN545192 for compliance with MRLs and import tolerances in plant and animal commodities at an LOQ of 0.01 mg/kg.]

	3. Magnitude of residues. [twenty four supervised residue trials were conducted on coffee and sugarcane (12 trial/each crop) in 2010/11 in six provinces of Brazil using SYN545192 formulated as A17961A (an EC formulation containing SYN545192 and azoxystrobin) or A18126B (a WG formulation containing SYN545192 and azoxystrobin).  Detected residues of benzovindiflupy in all crops support the proposed tolerances based on parent only.]

B. Toxicological Profile

	1. Acute toxicity.  [The estimated acute medical lethal dose (MLD) for benzovindiflupyr (SYN545192) via the oral route was 55 mg/kg.  The median lethal concentration (MLC) following acute inhalation exposure was estimated to be greater than 0.56 mg/l. The acute dermal MLD was shown to be greater than 2000 mg/kg.  SYN545192 was only mildly irritating to the skin and moderately irritating to the eyes.  The acute toxicity studies place technical benzovindiflupyr in toxicity US EPA category II for oral and US EPA category III for dermal and inhalation. Benzovindiflupyr is not a dermal sensitizer.]

	2. Genotoxicty. [Benzovindiflupyr (SYN545192) has been examined in a range of in vitro and in vivo genotoxicity assays, including endpoints of bacterial and mammalian gene mutation and chromosomal damage.  In vitro, SYN545192 was negative for gene mutation in bacterial (Ames test) and mammalian cells (L5178Y TK[+/-] mouse lymphoma).  The L5178Y TK[+/-] assay, which is also able to detect chromosomal damage by assessment of colony sizes (small and large colony sizes are associated with clastogenic or mutagenic effects respectively), was also negative for clastogenicity.  In the in vitro cytogenetic assay using primary human lymphocyte cultures, SYN545192 did not induce any treatment-related chromosomal aberrations.  In vivo, SYN545192 was found to be non-clastogenic in the rat bone marrow micronucleus assay and did not induce micronuclei in bone marrow cells.]

	3. Reproductive and developmental toxicity. [Benzovindiflupyr (SYN545192) was evaluated for potential to cause effects on reproductive and developmental toxicity in a multi-generation reproductive toxicity study in the rat and in pre-natal developmental toxicity studies in the rat and rabbit.  
	Reproductive toxicity:  SYN545192 was evaluated in a two-generation reproduction study in the rat at dietary inclusion levels of 0, 25, 100, 250 ppm (females) or 600 ppm (males).
The parental NOAEL was considered to be 100 ppm (equivalent to 6.8 mg/kg/day for P generation males during pre-pairing).  The NOEL for reproduction was 600 ppm in males (equivalent to 40.5 mg/kg/day for P generation males during pre-pairing) and 250 ppm in females (equivalent to 19.4 mg/kg/day for P generation females during pre-pairing).  The offspring NOEL for general toxic effects was 100 ppm (equivalent to 7.8 mg/kg/day for F1 generation males during pre-pairing). 

	Developmental Toxicity: In a developmental study in the rat, SYN545192 was administered at dose levels of 0, 7.5, 15 and 30 mg/kg/day.  All female animals survived until the scheduled necropsy.  Marked clinical signs of toxicity (ataxia, hunched posture, prostrate, decreased activity and ruffled fur) were observed at 30 mg/kg/day. Mean food consumption, body weight and body weight gain were lower at 30 mg/kg/day.  Mean foetal body weight was lower at 30 mg/kg/day and there was a slight delay in ossification which was considered to be related to the treatment with the test item and secondary to maternal toxicity. The NOEL for maternal and developmental toxicity was 15 mg/kg/day.

In a rabbit dose-range finding study, a dose level of 100 mg/kg/day produced severe body weight loss and reduced food consumption that resulted in the early termination of all females at this dose level.  Excessive body weight losses and reduced food consumption also led to abortion and moribundity in individual females at 50 mg/kg/day indicating that this dose level was unsuitably high for a full developmental toxicity study.  On this basis, dose levels of 0, 10, 20, and 35 mg/kg/day were selected for the definitive prenatal development toxicity study the rabbit.  

In the definitive prenatal developmental toxicity study in rabbits, there
were no treatment-related effects on the dams at any dose level.  Marginal effects on maternal body weight gain were seen at 20 and 35 mg/kg/day during gestation days 13-20.  There were no effects on development.  The NOEL for maternal and developmental toxicity was 35 mg/kg/day.]

	4. Subchronic toxicity. [The short term toxicity of benzovindiflupyr has been evaluated by the oral route of administration in rats, mice and dog.  In addition, dermal toxicity was evaluated in rates in a 28-day study. 

Dietary administration of SYN545192 to rats for at least 90 days was associated with in-life effects (reduced body weights, food consumption and food utilization) at 750 ppm and above.  Covariant liver weights adjusted for body weight were statistically higher in male animals treated at 1500 ppm and in females at 750 ppm.  Centrilobular hepatocyte hypertrophy of the liver was noted at doses of 750 ppm and above in males and at 1500 ppm in females. The NOEL was considered to be 100 ppm for both males and females equating to an average of 7.6 mg/kg/day in males and 8.2 mg/kg/day in females.
 
Dietary administration of SYN545192 to mice at doses, 0, 100, 300 or 300 ppm for a period of at least 91 days was associated with significant initial body weight losses resulting in termination of two animals in the toxicokinetic satellite group at 500 ppm.  The NOEL for this study was considered to be 100 ppm for both sexes, equating to an average compound intake of 17.0 mg/kg/day in males and 20.9 mg/kg/day in females.  The NOEL is based on the occurrence of mortality in two animals at 500 ppm, initial body weight loss, decrease in body weight gain, an increased incidence of soft faeces in males, changes in clinical chemistry parameters and mucosal hyperplasia in the rectum and colon at 300 and 500 ppm. 
  
In a 28-day dermal toxicity in rats, no treatment-related effects were observed at any dose level up to the limit dose of 1000 mg/kg. Male and female Beagle dogs were dosed orally by capsule with SYN545192 at 0, 30, 375 or 750 mg/kg/day for a period of 13 weeks. At 375 and 750 mg/kg/day, there was an initial body weight loss, decreased food consumption, decreased body weight gain and some effects on clinical biochemistry.  Mild clinical signs were observed in dogs at 375 and 750 mg/kg/day.  There were no effects at 30 mg/kg/day which is considered to be the no effect level (NOEL) for this study.]

	5. Chronic toxicity. [Benzovindiflupyr (SYN545192) has been evaluated for chronic toxicity in the rat and for carcinogenic potential in the rat and the mouse.

In a 2 year combined chronic toxicity/carcinogenicity study in rats, SYN545192 was tested at dietary inclusion levels of  0, 25, 100 and 600 ppm (males) or 400 ppm (females).

Significantly lower body weight gain, food consumption and food utilization were observed in both sexes at the top dose.  .  Clinical chemistry values of ALP, ALT and AST were consistently lower than control values at the top dose.  In males at 600 ppm, liver weight adjusted for body weight was statistically significantly increased.  There were no other effects on organ weight.  The incidence of centrilobular hypertrophy in the liver was statistically significantly higher in top dose males and females at 52 and 104 weeks.  In males at 600 ppm, the incidence of eosinophilic cell foci in the liver was statistically significantly higher after 104 weeks, and a higher incidence of hepatocyte vacuolation was seen after 104 weeks. 

A higher incidence of pigmented hepatocytes was observed in females at 400 ppm after 52 and 104 weeks.  In males at 600 ppm, there was a treatment-related increase in the incidence of thyroid follicular cell adenomas.  There were no other treatment-related neoplastic findings.  A NOAEL was established at 100 ppm (4.88 mg/kg/day in males and 6.66 mg/kg/day in females).

Supplemental mechanistic studies were conducted in rats.  These studies demonstrated a Mode of Action (MOA) for induction of thyroid tumors at high dose levels in male rats that is secondary to enhanced clearance of thyroid hormones via induction of liver metabolizing enzymes.  This MOA is not considered relevant to humans.  

In a carcinogenicity study with SYN545192, four groups of 50 CD-1 mice/sex/group were fed diets containing 0, 20, 60 or 200 ppm SYN545192 for at least 80 consecutive weeks.  Statistically significantly lower group mean body weight was observed in males treated with 200 ppm during the first 7 weeks of the study.

The administration of SYN545192 at 200 ppm was associated with a higher incidence of simple mucosal hyperplasia in the large intestine (colon and caecum) of males and females.  There were no effects in the large intestine at 20 or 60 ppm in either sex.  There were no treatment related increases in neoplastic findings.

Based on the findings in this study, a No Observed Effect Level (NOEL) is established at 60 ppm, which is equivalent to 7.55 mg/kg/day in males and 8.67 mg/kg/day in females.]

	6. Animal metabolism. [The rat, goat, and hen metabolism studies were conducted to determine the nature of the benzovindiflupyr (SYN545192) residues in animals. The rat metabolism study has established that benzovindiflupyr is rapidly absorbed by rats following oral administration by gavage.  In both poultry and goat, the majority of the dosed radioactivity was excreted (mainly in the feces) and radioactivity remaining in dietary tissues, milk and eggs was low.  In the goat study, milk residues reached plateau residue concentrations (0.035  -  0.046 mg/kg), after 3 - 4 days dosing.  Residues in eggs from the hen study reached plateau residue concentrations after approximately 8 days (0.17  -  0.18 mg/kg in egg yolk and 0.03  -  0.04 mg/kg in egg white). 

In both species, the highest tissue residues were observed in liver (0.697  -  1.279 mg/kg in goat and 0.188  -  0.249 mg/kg in hen) and kidney (0.185  -  0.280 mg/kg in goat).  Residue levels in fat-rich tissues of hen and goat were much lower, 0.043 mg/kg - 0.1 mg/kg. 

There was very little transfer of residues into tissues, milk or eggs following the dosing of benzovindiflupyr to the hen or the goat.  Metabolic profiles observed in livestock commodities arise from three principal routes, 
   i) N-pyrazole demethylation of SYN545192 and
   ii) Oxidation resulting in monohydroxylation of the alicyclic ring
   iii) Alicyclic ring opening of alicyclic monohydroxylated metabolites resulting in a dihydroxylated metabolite.

Overall the biotransformation pathway of SYN545192 in ruminants and poultry is well understood and consistent with that observed in the rat.]

	7. Metabolite toxicology. [SYN546039 (formed via mono hydroxylation on the alicyclic ring has been assessed for acute and oral toxicity and in vitro genotoxicity (Bacterial reverse mutation).  SYN546039 was not acutely toxic to rats by oral route (MLD>2000 mg/kg) and was not genotoxic in vitro.  These data indicate that SYN546039 is of lower toxicity than parent SYN545192 and is not considered to be of toxicological relevance.

Metabolites CSAA798670 and CSCD465008 (pyrazole acid metabolites formed via cleavage between the pyrazole and phenyl ring) were also assessed for toxicity.  Both metabolites were not acutely toxic by oral route, were negative in vitro genotoxicity studies and were toxicologically benign up to the limit dose of 1000 mg/kg/day in 28-day and 90-day studies in rat.  In rabbit developmental toxicity studies, these metabolites were not teratogenic.
Based on these data, metabolites NOA449410 and SYN545720 can be characterized as having minimal toxic potential.

	8. Endocrine disruption. [Benzovindiflupyr (SYN545192) does not belong to a class of chemicals known as suspected of having adverse effects on the endocrine system.  There is no evidence in other relevant toxicity studies (e.g. sub-chronic and chronic toxicity, developmental toxicity and multi-generation reproductive studies) which would suggest that benzovindiflupyr has any endocrine disruptive potential. 

	9. Immunotoxicity. [A study was conducted, as specified in US OPPTS Guideline 870.7800, to provide information on suppression of the immune system which might occur as a result of repeated exposure to a test chemical.  Treatment of female CD-1 mice with benzovindiflupyr on a continuous basis in the diet at dose levels of 0, 100, 200 and 400 ppm for a minimum of 28 days resulted in no suppression of the humoral immune component of the immune system, based on evaluation of the spleen and thymus weights, spleen cell numbers, and the T-cell dependent antibody response of splenocytes (antibody forming cell (AFC) assay). 

The no observed-effect level (NOEL) for the AFC (humoral immune response) assay was 400 ppm (equivalent to 97.1 mg/kg of body weight/day), the highest dose level evaluated.

C. Aggregate Exposure

	1. Dietary exposure. Tier III acute, short-term, intermediate-term, and chronic aggregate exposure evaluations were completed for benzovindiflupyr (SYN545192) using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID, version 3.15).  DEEM-FCID software incorporates food consumption data from the National Health and Nutrition Examination Survey)/"What We Eat in America" (NHANES/WWEIA) dietary survey conducted in 2003-2008.  Assessments were conducted for all proposed uses on cereals (wheat, barley, oat, rye and triticale), corn, soybean, peanuts, cotton, pome fruits (Crop Group 11), grapes (Small Fruits Vine Climbing Sub-Group 13-07F except fuzzy kiwi fruit), pulses (dry beans and peas Crop Group 6C), potatoes (Tuberous and Corm Sub-Group 1C), cucurbit vegetables (Crop Group 9), fruiting vegetables (Crop Group 8-10), canola (Crop Group 20A), and a proposed non-food use on blueberries.  Import tolerances were proposed for coffee and sugarcane.  The definition of the residue for tolerance enforcement and risk assessment purposes for crops is parent benzovindiflupyr (SYN545192).  The assessments utilized residue data from field trials in which benzovindiflupyr was applied at the maximum intended use rate and samples were harvested at the minimum pre-harvest interval (PHI) to obtain maximum residues.  Percent of crop treated values were estimated based upon economic, pest, and competitive pressures.  Secondary residues in animal commodities were estimated based on "maximum reasonably balanced diets" and transfer information from feeding studies.  Drinking water estimates were incorporated directly into the dietary exposure assessment using the higher of the estimated drinking water concentrations (EDWCs) for surface and ground water.  

	i. Food. Acute Exposure.  The acute dietary risk assessments were performed for all population subgroups with an acute reference dose (aRfD) of 0.15 mg/kg-bw/day based on an acute no observed adverse effect level (NOAEL) of 15 mg/kg/day in a prenatal developmental toxicity study in rats and an uncertainly factor of 100X.  The 100X safety factor includes intra- and interspecies variations.  No additional FQPA safety factor was applied.  At the 99.9[th]%-ile of exposures, acute food exposure to the U.S. population resulted in an acute food MOE of 14,254 or 0.7% of the aRfD (Benchmark MOE =100; aRfD = 0.15 mg/kg-bw/day) of exposures.  Acute food exposure to the most sensitive subpopulation (children 1 to 2 years old) resulted in an acute food MOE of 5,342 or 1.9% of the aRfD (Benchmark MOE =100; 0.15 mg/kg-bw/day).  Since the Benchmark MOE for this assessment was 100 and since the EPA generally has no concern for exposures above the benchmark or below 100% of the aRfD, Syngenta believes that there is a reasonable certainty that no harm will result from acute dietary (food) exposure to residues arising from the proposed uses for benzovindiflupyr.

Chronic Exposure.  The benzovindiflupyr chronic dietary (food only) risk assessments were performed for all population subgroups with a chronic reference dose of 0.05 mg/kg-bw/day based on a combined chronic/carcinogenicity study on rats with no observed adverse effect level (NOAEL) of 4.9 mg/kg-bw/day and an uncertainty factor of 100X for intra- and inter-species variations.  No additional FQPA safety factor was applied.  For the purpose of the aggregate risk assessment, exposure values were expressed in terms of margins of exposure (MOE), which were calculated by dividing the NOAEL by the exposures for each population subgroup.  In addition, exposures were also expressed as percentages of the reference dose (%RfD).  Chronic (food only) exposure to the U.S. population resulted in a chronic food MOE of 143,136 (0.1% of the chronic RfD of 0.05 mg/kg-bw/day).  The most sensitive sub-population was children (1-2 years old) with a chronic food MOE of 58,902 (0.2% of the chronic RfD).  Since the benchmark MOE for this assessment was 100 and since the EPA has no concern for exposures resulting in an MOE above the Benchmark MOE or below 100% of the reference dose, Syngenta believes that there is a reasonable certainty that no harm will result from dietary (food only) exposure to residues arising from the proposed uses for benzovindiflupyr.

Cancer.  Benzovindiflupyr is considered "not likely to be a human carcinogen".  Therefore, no cancer risk assessment was performed for benzovindiflupyr.

	ii. Drinking water. To determine the Estimated Drinking Water Concentrations (EDWCs) for SYN545192 in surface water the Tier 1 model, FQPA Index Reservoir Screening Tool (FIRST v1.1.1), was used.  For groundwater the Tier 1 model, Screening Concentration in Ground Water (SCI-GROW v2.3), was used.  The maximum field application rate for multiple crops including corn, cucurbits, fruiting and corm vegetables, and grapes is 75 g ai/ha/application (0.068 lb. a.i./A/application) x 4 applications/year. A minimum 7 day retreatment interval is specified, and after the second application a fungicide with a different mode of action must be used.  The modeling was conducted using environmental fate parameters, in accordance with EPA's guidance, to identify the highest benzovindiflupyr (SYN545192) EDWCs from all proposed uses.  The predicted EDWCs were corrected with a Percent Cropped Area (PCA) adjustment factor of 0.95.  FIRST calculated a surface water acute EDWC of 6.515 ug/L (ppb) and a chronic EDWC of 1.596 ug/L (ppb).  SCI-GROW calculated a groundwater EDWC (acute and chronic) of 0.00428 ug/L (ppb).  Since the surface water EDWCs exceed the ground water EDWC, the surface water values are considered to be protective for any ground water concentration concerns.  

Acute Exposure from Drinking Water.  The acute surface water EDWC of 6.515 ppb was input directly into the DEEM-FCID(TM) software as "water, direct and indirect, all sources" to model the acute drinking water exposures.  Exposure contributions at the 99.9[th]%-ile of exposures were determined by taking the difference between the aggregate (food + drinking water) exposures and the food (alone) exposures for each population subgroup.  Acute drinking water exposure to the U.S. population resulted in an acute drinking water MOE of 38,265 (0.3% of the acute RfD of 0.15 mg/kg-bw/day).  The most exposed sub-population was infants (<1 year old) with an acute drinking water MOE of 20,107 (0.5% of the aRfD of 0.15 mg/kg/day).  Since the benchmark MOE for this assessment was 100 and since the EPA has no concern for exposures resulting in an MOE above the Benchmark MOE or below 100% of the reference dose, Syngenta believes that there is a reasonable certainty that no harm will result from drinking water exposure to residues arising from the proposed uses for benzovindiflupyr.

Chronic Exposure from Drinking Water.  The chronic surface water EDWC of 1.596 ppb was input directly into the DEEM-FCID(TM) software as "water, direct and indirect, all sources" to model the chronic drinking water exposures.  Chronic drinking water exposure to the U.S. population resulted in a chronic drinking water MOE of 146,624 (0.1% of the chronic RfD of 0.05 mg/kg-bw/day).  Chronic drinking water exposure to the most exposed sub-population (infants, <1 year old) resulted in a chronic drinking water MOE of 56,864 (0.2% of the chronic RfD of 0.05 mg/kg-bw/day).  Since the benchmark MOE for this assessment was 100 and since the EPA has no concern for exposures resulting in an MOE above the Benchmark MOE or below 100% of the reference dose, Syngenta believes that there is a reasonable certainty that no harm will result from drinking exposure to residues arising from the proposed uses for benzovindiflupyr.

	2. Non-dietary exposure. Non-dietary residential exposure risk assessments were performed for use of benzovindiflupyr formulated as an emulsifiable concentrate, soluble liquid or wettable granule for residential turf including sod farms, golf courses, and sports fields.  Residential exposure risk assessments were performed for use of benzovindiflupyr formulated as a wettable granule for ornamentals grown in greenhouses and outdoor nurseries and for vegetable transplants grown for resale to customers.  Benzovindiflupyr is labeled for professional use only; therefore no residential handler exposure assessments are required.  Assessments were performed using a short-term dermal and incidental oral endpoint of 15 mg/kg/day based on the NOAEL from a prenatal developmental toxicity study in rats and an intermediate-term endpoint of 7.6 mg/kg/day based on the NOAEL from a 90-day dietary toxicity study in rats.  Dermal absorption was assumed to be 1.27% based on the in vivo/in vitro relationship between the rat and human dermal absorption systems.  The maximum residential exposure to adults was due to gardening activities using greenhouse and nursery treated plants, resulting in short- and intermediate-term residential MOEs of 27,780 and 14,075, respectively.  The maximum residential exposure to youths age 6-11 years was due to gardening activities using greenhouse and nursery treated plants, resulting in short- and intermediate-term residential MOEs of 40,583 and 20,562, respectively.  The maximum residential exposure to youths age 11-16 years was due to activities on treated golf courses, resulting in short- and intermediate-term residential MOEs of 496,163 and 251,389, respectively.  The maximum residential exposure to children 1-2 years was due to play activities on treated turf, resulting in short- and intermediate-term residential MOEs of 12,030 and 6,095, respectively.

D. Cumulative Effects

	Cumulative Exposure to Substances with a Common Mechanism of Toxicity.  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 does not have, at this time, available data to determine whether benzovindiflupyr has a common mechanism of toxicity with other substances or how to include this pesticide in a cumulative risk assessment.  For the purposes of this tolerance action, the EPA has not assumed that benzovindiflupyr has a common mechanism of toxicity with other substances.

E. Safety Determination

	1. U.S. population. The acute aggregate exposure calculation for proposed uses of benzovindiflupyr provided an MOE of 10,390 or 1.0% of the aRfD (Benchmark MOE = 100; aRfD = 0.15 mg/kg-bw/day) for the U.S. population.  The chronic aggregate exposure calculation for proposed uses of benzovindiflupyr provided an MOE of 73,134 or 0.1% of the cRfD (Benchmark MOE = 100; cRfD = 0.05 mg/kg-bw/day) for the U.S. population.  Since the aggregate MOEs exceed the benchmark MOE of 100, Syngenta believes that there is a reasonable certainty that no harm will occur to the U.S. Population from acute, short-term, intermediate-term, or chronic aggregate exposures arising from the proposed uses for benzovindiflupyr.

	2. Infants and children. The acute aggregate exposure calculation for proposed uses of benzovindiflupyr provided an MOE of 4,869 or 2.1% of the aRfD (Benchmark MOE = 100; aRfD = 0.15 mg/kg-bw/day) for children 1-2 years old (the most sensitive subpopulation for the acute assessment).  The short-term aggregate assessment resulted in an MOE of 10,886 for the children (1-2 years old) population subgroup (Benchmark MOE = 100).  The intermediate-term aggregate assessment resulted in an MOE of 5,516 for the children (1-2 years old) population subgroup (Benchmark MOE = 100). The chronic aggregate exposure calculation for proposed uses of benzovindiflupyr provided an MOE of 37,292 or 0.3% of the cRfD (Benchmark MOE = 100; cRfD = 0.05 mg/kg-bw/day) for the children (1-2 years old) (the most sensitive subpopulation for the chronic assessment).  Since the worst-case aggregate MOE of 5,516 exceeds the benchmark MOE of 100, Syngenta believes that there is a reasonable certainty that no harm will occur to infants and children from acute, short-term, intermediate-term, or chronic aggregate exposures arising from the proposed uses for benzovindiflupyr

F. International Tolerances

	There are currently no Maximum Residue Limits (MRLs) set for benzovindiflupyr for crops by the Codex Alimentarius Commission and international MRLs for the fungicide benzovindiflupyr have not been established.