Interregional Research Project Number 4 (IR

- 4)

Petition #4E8272 EPA has received a pesticide petition (4E8272 ) from IR

- 4 , 500 College Road East, Suite 201 W, Princeton, NJ 08540 , proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cos metic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 .516 by

establishing the tolerance for residues of f ludioxonil [4

- (2, 2

- difluoro

1,3

- benzodioxol

- 4

- yl )

- 1

- H

-py rrole

- 3

- carbonitrile] in or on the raw agricultural commodity c arrot at 7 .0 parts per million ; and f ruit, stone , group 1 2

- 1 2 , at 5 parts per million

. Upon approval of the aforementioned tolerances, it is proposed that 40 CFR 180.5 16 be amended to remove the established tolerances for the residues of fludioxonil in or on the raw agricultural commodity f ruit, stone , group 1 2 , at 5 parts per million

. 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 su bmitted 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**. The metabolism of fludioxonil is adequately understood for**  **the pur pose of the proposed tolerances.**  2. Analytical method. **Syngenta has developed and validated analytical methodology for enforcement purposes. This method (Syngenta Crop Protection Method AG** **** **597B) has passed an Agency petition method validation for severa l commodities,**  **and is currently the enforcement method for fludioxonil. This method has also been forwarded to the Food and Drug Administration for inclusion into PAM II. An**  **extensive database of method validation data using this method on various crop com**  **modities is available.** 3. Magnitude of residues. **Complete residue data to support the requested tolerances**  **have been submitted. The requested tolerances are adequately supported. In support of the requested tolerance**  **s ,**  **IR -**  **4 has conducted the necessar y trials in**  **accordance with the requirements of the EPA Residue Chemistry Guidelines 860.1500 to determine the magnitude of residue of**  **fludioxonil in or on requested**  **commodities.** B. Toxicological Profile EPA has evaluated the available toxic ity data and considered its validity , completeness, and reliability

a s well as the relationship of the results of the studies to human risk. E PA has also considered available information concerning the variability of the sensitivities of major identifiabl e subgroups of consumers, including infants and children. S pecific information on the studies received and the nature of the toxic effects caused by2

fludioxonil as well as the no - observed

- adverse

- effect

- level (NOAEL) from the toxicity studies can be found at the following website: http://edocket.access.gpo.gov/2012/2012

- 19988.htm

. A

s ummary of the toxicological endpoints for fludioxonil used for human risk assessment is discussed in Unit III.A and B. of the final rule published in the Federal Register of August 15, 2012 (77 FR pages 48907

- 48915) (FRL

- 9357

- 5). C. Aggregate Exposure 1. Dietary exposure. **Tier III acute and chronic dietary exposure evaluations were performed for fludioxonil using the using the Dietary Exposure Evaluation Model**  **(DEEM -**  **FCIDTM V ersion 3.16) from Exponent; consumption data was from the**  **USDA NHANES “What We Eat in America” survey, 2003 -**  **2008. These exposure assessments included all current uses as well as a proposed post**  **- harvest use on**  **carrots and stone fruit crop group 12**  **- 12**  **. The**  **se assessments utilized residue data from field trials where fludioxonil was applied post** **- harvest at the maximum**  **intended use rate. Secondary residues in animal commodities were estimated based on “maximum reasonably balanced diets” and transfer informati**  **on from metabolism studies.**  i. Food. Acute exposure

. **The acute dietary (food only) risk assessment for females 13 to 49 years old (the only population subgroup for which an acute toxicological**  **endpoint has been established) was performed using an acute**  **reference dose (aRfD) of 1.0 mg/kg**  **- bw/day, based upon a rat teratology study with**  **a no observed adverse effect level (NOAEL) of 100 mg/kg/day and an uncertainty factor (UF) of 100X for**  **intra -**  **and inter -**  **species variations .**  **N o additional FQPA safety factor**  **was applied. For the purpose of the aggregate risk assessment, the exposure value was expressed**  **in terms of margin of exposure (MOE), which was calculated by dividing the no observed adverse effect level (NOAEL) by the exposure for each population**  **subgrou p. In addition, exposure was expressed as a percent of the acute reference**  **dose (% aRfD). At the 99.9th percentile, acute (food only) exposure to the females**  **13 -**  **49 years subpopulation resulted in a MOE of 1,683 (5.9% of the aRfD of 1 .0**  **mg/kg -**  **bw/day). Si nce the Benchmark MOE for this assessment was 100 and since**  **the EPA generally has no concern for exposures above the Benchmark MOE or below 100% of the aRfD**  **, Syngenta believes that there is a reasonable certainty that no harm will result from dietary (food**  **only ) exposure to residues arising from the**  **current, pending and proposed uses for fludioxonil.** Chronic exposure. **The chronic dietary (food only) risk assessment was performed for all population subgroups using a chronic reference dose (cRfD) of 0.033 m**  **g/kg**   ** bw/day, based upon a one** **- year study in dogs with a NOAEL of 3.3 mg/kg**  **- bw/day**  **and an uncertainly factor of 100X to account for intra -**  **and inter -**  **species variations. No additional FQPA safety factor was applied. For the purpose of the chronic**  **aggregate risk assessment, the exposure values were expressed in terms of margin of**  **exposure (MOE), which was calculated by dividing the no observed adverse effect level (NOAEL) by the exposure for each population subgroup. In addition,**  **exposure was expressed as a percent of the chronic reference dose (% cRfD).**  **Chronic (food only) exposure to the U.S. population resulted in a MOE of 747**3

**(13.4% of the cRfD of 0.033 mg/kg -**  **bw/day). The most exposed sub -**  **population was children (1**  **- 2**  **years old) with a MOE of 227 (44.0% of the cRfD of 0.033 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 MOE or below 100%**  **of the cRfD, Syngenta believes that there is a reasonable certainty tha t no harm will**  **result from dietary (food only) exposure to residues arising from the current, pending and proposed uses for fludioxonil.**  ii. Drinking water. **The Estimated Drinking Water Concentrations (EDWCs) of fludioxonil were determined using Tier l SC**  **I -**  **GROW and PRZM -**  **GW, which estimates pesticide concentrations in ground water and Tier II PRZM/EXAMS**  **which estimates pesticide concentrations in surface water. This drinking water assessment was conducted to assess all currently registered uses and**  **the pro**  **posed post** **- harvest use on carrots.**  **For ground water, the PRZM -**  **GW model provided the highest EDWCs of 25.7 ppb and 24.6 ppb for acute and chronic, respectively, based**  **on the currently registered use on turf. For surface water, the currently registered fie**  **ld grown and landscape ornamental provided the highest acute EDWC of 44.1 ppb (no Percent Cropped Area (PCA) adjustment) and the currently registered use**  **on turf provided the highest chronic EDWC of 34.8 ppb (adjusted for 0.95 PCA). Since the surface wate**  **r EDWCs exceed the ground water EDWC, the surface water values were used for risk assessment purposes and will be considered protective for**  **any ground water exposure concerns.** Acute Exposure from Drinking W ater : **The acute EDWC of 44.1 ppb was incorporate d**  **with food residues as “water, direct and indirect, all sources” directly into the DEEM**  **- FCIDTM software to obtain acute dietary (water) exposures. Drinking water**  **exposures at the 99.9th percentile to fludioxonil for females 13 -**  **49 years old (the only popul**  **ation subgroup for which an acute toxicological endpoint has been established) resulted in a MOE of 94,073 (0.1% of the aRfD of 1.0 mg/kg**  **- bw/day). Since the**  **Benchmark MOE for this assessment was 100, and since the EPA generally has no concern for exposure**  **s below 100% of the aRfD, Syngenta believes that there is a reasonable certainty that no harm will result from acute drinking water exposure to**  **residues arising from all current and proposed fludioxonil uses.** Chronic Exposure from Drinking W ater : **The chr onic EDWC of 34.8 ppb was**  **incorporated with food residues as “water, direct and indirect, all sources” directly into the DEEM**  **- FCIDTM software to obtain chronic dietary (water) exposures.**  **Chronic drinking water exposure to the U.S. population resulted in a MOE of 4,529**  **(2.2% of the cRfD of 0.033 mg/kg -**  **bw/day). The most sensitive sub -**  **population was all infants (<1 year old), with a MOE of 1,756 (5.7% of the cRfD of 0.033 mg/kg**  **** **bw/day). Since the Benchmark MOE for this assessment was 100 and since the EPA ge**  **nerally has no concern for exposures below 100% of the cRfD, Syngenta believes that there is a reasonable certainty that no harm will result from chronic drinking**  **water exposure to residues arising from all current and proposed fludioxonil uses .**  Cancer

. **A chronic cancer exposure analysis was not performed, since there is no**4

**evidence of human carcinogenic potential for fludioxonil.** 2. Non

- dietary exposure

. . **Residential exposure risk assessments were performed for use of fludioxonil formulated as Pal** **ladium TM**  **for ornamentals and Medallion ®**  **for turf and ornamentals and and Medallion**  **® TL**  **for turf. Palladium TM**  **may not be used on residential ornamental plants; therefore, no residential handler exposure**  **assessments are required for this product. Medallion ®**  **and Medallion ®**  **TL are intended primarily for professional use however, the product label does not exclude**  **residential uses; therefore, a residential handler exposure assessment was conducted. The following endpoints were used: a 10 mg/kg/day NOAEL for adu**  **lts (inhalation only) from a rabbit developmental tox study; a 10 mg/kg/day short**  **- term**  **NOAEL for children 1 -**  **6 years (incidental oral) from an oral rabbit developmental study; a 3.3 mg/kg/day intermediate**  **- term NOAEL for children 1**  **- 6 years (incidental**  **oral) from a one**  **- year feeding study in dogs. Residential handler exposure risk from**  **fludioxonil was acceptable (MOE = 69,140; short -**  **term) for youths (13 -**  **19 years) and adults (19+ years) treating residential turf with a hose**  **- end sprayer. Residential**  **handler ex posure scenarios are considered to be short** **- term only, due to the**  **infrequent use patterns associated with homeowner products. Since no dermal endpoints were selected short** **- and intermediate**  **- term assessments were not**  **conducted for post -**  **application exposure risk to children, youth or adults. Post**  **** **application non -**  **dietary oral hand -**  **to -**  **mouth exposure risks for children 1 -**  **6 years, resulting from contact with treated lawns were acceptable for short** **- term (MOE =**  **911) and intermediate -**  **term (MOE = 301) durations. S ince the MOEs for children**  **(1 -**  **6 years), youths (13 -**  **19 years) and adults (19+ years) were above the Benchmark MOE of 100, residential exposure risk for fludioxonil do not exceed the EPA’s Level**  **of Concern.** D. Cumulative Effects Cumulative Exposure to Subs tances with a Common Mechanism of Toxicity

. **Section 408(b)(2)(D)(v) of FFDCA 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.” Unlike other pesticides for**  **which the EPA has followed a cumulative risk approach based on a common mechanism of toxicity, the EPA has not made a common mechanism of to**  **xicity finding as to fludioxonil and any other substances, and fludioxonil does not appear**  **to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, the EPA has not assumed that fludioxonil has a common**  **mechani sm of toxicity with other substances.**  E. Safety Determination 1. U.S. population. **An acute toxicological endpoint has not been established for the U.S. population, so an acute exposure assessment was not performed for the U.S.**  **population. The chronic ag gregate exposure analysis showed that exposure from all** 5

**current and proposed fludioxonil uses resulted in a MOE of 641 or 15.6% of the cRfD (Benchmark MOE = 100; cRfD=0.033 mg/kg**  **- bw/day). A cancer exposure**  **analysis was not performed since there is no evid ence of human carcinogenic**  **potential for fludioxonil. Since the worst -**  **case aggregate MOE of 641 exceeds the benchmark MOE of 100, Syngenta believes that there is a reasonable certainty that**  **no harm will result from aggregate exposure to residues arising f rom all current,**  **pending and proposed fludioxonil uses, including anticipated dietary exposure from food, water, and all other types of non**  **- occupational exposures.**  2. Infants and children

. **An acute toxicological endpoint has not been established for infan**  **ts and children, so an acute exposure assessment was not performed for infants and children. The chronic aggregate exposure analysis showed that exposure from**  **all established and proposed fludioxonil uses resulted in a MOE of 212 or 47.2% of the cRfD (Ben**  **chmark MOE = 100; cRfD=0.033 mg/kg -**  **bw/day) for children (1 -**  **2 years old). A cancer exposure analysis was not performed, since there is no evidence**  **of human carcinogenic potential for fludioxonil. The short -**  **term aggregate assessment resulted in MOE of 422**  **, for the children (1 -**  **6 years old) population subgroup (Benchmark MOE = 100). The intermediate**  **- term aggregate assessment**  **resulted in MOE of 139, for the children (1 -**  **6 years old) population subgroup (Benchmark MOE**  **= 100). A cancer exposure analysis was n ot performed, since**  **there is no evidence of human carcinogenic potential for fludioxonil. Since the worst** **- case aggregate MOE of 139 exceeds the Benchmark MOE of 100, Syngenta**  **believes that there is a reasonable certainty that no harm will result from aggr egate**  **exposure to residues arising from all current, pending and proposed fludioxonil uses, including anticipated dietary exposure from food, water, and all other types of**  **non -**  **occupational exposures.** 3. Females 13

- 49 years of age

. **The acute aggregate exp osure analysis showed that**  **exposure to all current, pending and proposed fludioxonil uses would result in a MOE of 1,654 or 6.1% of the aRfD (Benchmark MOE = 100; aRfD=**  **1.0 mg/kg**  **** **bw/day) for females 13 -**  **49 years old. The chronic aggregate exposure analysis showed that exposure to all current and proposed fludioxonil uses would result in a**  **MOE of 773 or 12.9% of the cRfD (Benchmark MOE = 100; cRfD= 0.033 mg/kg**   ** bw/day) for females 13** **- 49 years old. A cancer exposure analysis was not performed,**  **since there is n o evidence of human carcinogenic potential for fludioxonil. Since the**  **worst -**  **case aggregate MOE of 773 exceeds the Benchmark MOE of 100, Syngenta believes that there is a reasonable certainty that no harm will result from aggregate**  **exposure to residues ari sing from all current, pending and proposed fludioxonil**  **uses, including anticipated dietary exposure from food, water, and all other types of non**  **- occupational exposures.**  F. International Tolerances **Codex Maximum Residue Limits (MRLs) for residues of flud ioxonil**  **per se have**  **been established on a number of commodities, apple pomace, dry, basil, basil, dry, beans (dry), beans, shelled, blackberries, blueberries, broccoli, cabbages, head,**  **carrot, cereal grains, chives, chives, dry, citrus fruits, cotton seed, cucumber,** 6

**dewberries (including boysenberry and loganberry), edible offal (mammalian), eggplant, eggs, grapes, kiwifruit, lettuce, head, meat (from mammals other than**  **ma rine mammals), melons, except watermelon, milks, mustard greens, onion, bulb,**  **peas (dr y), peas (pods and succulent=immature seeds), peas, shelled (succulent**  **seeds), peppers, sweet (including pimento or pimiento), pistachio nuts, pome fruits, pomegranate, potato, poultry meat, poultry, edible offal of, rape seed, raspberries,**  **red, black, soy a bean (dry), squash, summer, stone fruits, straw and fodder (dry) of**  **cereal grains, strawberry, sunflower seed, sweet corn (corn -**  **on -**  **the -**  **cob), sweet potato, tomato, watercress, and yams.**