Document ID: EPA-HQ-OPP-2014-0840-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-02-04T05:00Z

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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER
(April 15, 2014)
EPA Registration Division contact: Tony Kish, (703) 308-9443
 Syngenta Crop Protection, LLC PP# 4F8269
EPA has received a pesticide petition 4F8269 from Syngenta Crop Protection, LLC, PO 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 establish a tolerance for residues of fungicide acibenzolar-S-methyl / CGA-245704 (Benzo [1,2,3] thiadiazo1e-7-carbothioic acid-S-methyl ester in or on the raw agricultural commodities 

Pome Crop Group 11-10 at 0.03 parts per million (ppm) 
Citrus Crop Group 10-10 at 0.01 parts per million (ppm)

EPA has determined that the petition contains data or information regarding the elements set forth in section 180.561 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. Syngenta believes the metabolism of acibenzolar S-methyl has been well characterized.  Only 4.6% and 14.9% of the total radioactive residue (TRR) was non-extractable in lettuce at the recommended application rate and three times the recommended application rate, respectively.  Non-extractables were also low in a tomato metabolism study, 3.4% and 7.4% in tomatoes and foliage, respectively.  The metabolism in these crops proceeded via hydrolysis of benzo [1,2,3] thiadiazole-7-carbothioic acid S-methyl ester to benzo [1,2,3] thiadiazole-7-carboxylic acid (BTCA), followed by conjugation as ester, glycoside and/or other plant constituents.  The metabolism profile supports the use of an analytical enforcement method that accounts for acibenzolar S-methyl and metabolites containing the benzo [1,2,3] thiadiazole-7-carboxylic acid (BTCA) moiety.

   Analytical method.  Syngenta Analytical Method AG-671A is a practical and valid method for the determination and confirmation of acibenzolar S-methyl (CGA245704) in raw agricultural commodities (RAC) and processing substrates from the tobacco, leafy (including brassica) and fruiting vegetable crop groups at a limit of quantitation (LOQ) of 0.02 ppm.  Based on recoveries of dry bulb onion samples fortified at the lower limit of method validation, the limit of detection (LOD) and limit of quantitation (LOQ) were calculated as 0.013 and 0.040 ppm, respectively.  The method involves extraction, solid phase cleanup of samples with analysis by high performance liquid chromatography (HPLC) with ultraviolet (UV) detection or confirmatory LC/MS.  The validity is demonstrated by the acceptable accuracy and precision obtained on numerous procedural recovery samples (radiovalidation and field trial sample sets), and by the extractability and accountability obtained by the analysis of weathered radioactive substrates using Analytical Method AG-671A. 

   Magnitude of residues.  A total of 15 GLP residue studies containing 23 field trials have been conducted in Europe, New Zealand, Brazil, and the United States (ongoing) in pome fruit (apples and pears) and citrus (oranges) to determine the residues of acibenzolar-S-methyl resulting from various foliar spray and soil application regimes of the 50% w/w wettable granule formulation.  Foliar treatment regimes consisted of three to eight foliar applications at rates ranging from 20 to 100 g ai/A (1.4  -  7 oz/A) with PHIs ranging from 0 to >100 days after the last application. Soil applied drench application studies are ongoing in the U.S., but samples from exaggerated rate plots (4 applications at 227 g ai/A [16 oz 50WP] with a 0-day PHI) have been analyzed.

  Citrus
  In the orange trials, residues resulting from foliar applications were >LOQ (limit of quantitation; 0.01 ppm) throughout the 0 to 10-day sampling period and ranged from 0.02 to 0.20 ppm.  At a 30 day PHI in foliar applied samples, all residues were below 0.02 ppm. In the US orange trials receiving a 5X rate, applied as a soil drench, residues ranged from <0.01 ppm to 0.02 ppm (0 day PHI). Processing data indicates that residues do not concentrate in orange juice

   Oranges in California and Florida were treated with four soil applications (drench) of 0.5 lb ai/A Actigard(R) (5X rate) at 30 day intervals ending at 0-day PHI.  Three samples per site were analyzed for acibenzolar-S-methyl and its degradate, CGA-210007.   There were no residues greater than the level of quantitation (< 0.01 ppm) in any of the California samples (5X).  In Florida, the residues were < 0.02 ppm.
   
   Pome
   In apples and pears, residues resulting from foliar applications were < LOQ (limit of quantitation; 0.01 ppm) except when fruit were collected within seven days following the last application. The maximum residues found in the foliar application pear trials ranged from <0.01 to 0.08 ppm and <0.01 to 0.08 ppm in the foliar application apple trials (Table D-1).  At a 30 day PHI, all foliar applied residues were less than 0.02 ppm.  In the U.S. apple trials receiving an exaggerated 5X rate, applied as a soil drench, residues were <0.01 ppm. Processing data from pear trials indicate that residues will not concentrate in processed fractions.
   
   Apples trees growing in Washington and Michigan were treated with four soil drench applications of 0.5 lb ai/A Actigard(R) 50 WG (5X rate) at 30-day intervals ending at 0-day PHI.  Three samples per site were analyzed for acibenzolar-S-methyl and its primary degradate, CGA-210007.   There were no residues greater than the level of quantitation (< 0.01 ppm) in any of the 5X treated samples at either site.  

   B. Toxicological Profile
   
    Acute toxicity. Acibenzolar S-methyl (CGA245704) has favorable acute toxicity characteristics, resulting in toxicity categories III or IV for oral, dermal and inhalation exposure routes. The acute oral LD50 is greater than 5000 mg/kg and the acute dermal LD50 is greater than 2000 mg/kg.  The acute inhalation LC50 is greater than 5.022 mg/L.  Acibenzolar S-methyl is categorized as slightly irritating to skin and eyes and a potential skin sensitizer. 

      Genotoxicty. With the exception of the chromosome aberration study in CHO cells in culture (MRID 44014245), CGA245704 was negative for genotoxicity.  In the chromosome aberration study, there was evidence of a clastogenic response in CHO cells in the absence of S9 activation at 30 and 60 μg/mL at the 18-hour cell harvest time.  Compound precipitation was seen at 60 μg/mL.  Following the prolonged 42-hour cell harvest time, the number of polyploidy cells was increased at 30 and 60 μg/mL (1.8 to 4.3 fold increases, respectively) both with and without S9 activation.  There is also evidence of cell arrest at G2 both with and without S9 activation.  These findings, however, can only be considered to be suggestive evidence of a possible aneuploidy effect since the mouse micronucleus assay up to 4000 mg/kg (MRID 44014244) was negative (US EPA, 1999).  Regarding the mouse micronucleus assay, it is noted that data from the metabolism and pharmacokinetic study (MRID 44014250) indicated that the radioactive parent was found in the blood at 15-30 minutes.  Thus, there is evidence that the test material reached the bone marrow tissue in the mouse micronucleus assay.  Thus, the overall weight of evidence indicates that CGA245704 technical is not mutagenic or clastogenic and does not provoke unscheduled DNA synthesis when tested thoroughly in a battery of standard in vivo and in vitro independent assays, using both eukaryotes and prokaryotes, and with or without metabolic activation.
   
      3. Reproductive and developmental toxicity. The developmental toxicity characteristics of CGA245704 have been investigated in one guideline rabbit and two rat developmental toxicity studies.  There were no developmental toxicity findings in the rabbit study, and the maternal NOAEL was 50 mg/kg.  In the rat developmental toxicity study (MRID 44014236), EPA determined the maternal toxicity NOAEL to be 200 mg/kg/day and the developmental LOAEL to be 10 mg/kg/day based on umbilical hernias, which was the lowest LOAEL in the developmental toxicity studies.  Therefore, the current acute and chronic Population Adjusted Dose for females 13-50 years of age was determined to be 0.0033 mg/kg/day, which takes into account the FQPA 10x (sensitivity to pups) and the 3x (use of LOAEL instead of NOAEL) factors (HIARC; 12/9/1999). However, Syngenta has submitted additional information as part of a previous tolerance petition, which supports the conclusion that the umbilical hernia found at 10 mg/kg is not treatment related and that the additional uncertainty factors may be unwarranted.  Additional evidence was previously provided from additional rat developmental toxicity study (MRID 45089701), mechanistic developmental toxicity tests (MRID Nos. 440014238 and 44014239) and a rat developmental neurotoxicity study (MRID 45713601).  EPA later reviewed the additional support and agreed that the data supports the removal of some of the FQPA uncertainty factors.  
In a subsequent rat developmental study, the maternal NOAEL was 350 mg/kg, and the developmental NOAEL was considered to be 150 mg/kg based on increased incidence of lumbar rib.  The umbilical hernia finding was not reproduced (MRID 45089701).  Based on the weight of evidence, the maternal NOAEL should be considered to be 50 mg/kg/day based on reduced body weight development and hemorrhagic perineal discharge at 200 mg/kg/day.  With regards to the developmental findings, the umbilical hernia that was observed at 10 mg/kg in the rat developmental toxicity study (MRID 44014236) was not reproduced in the subsequent rat teratogenicity investigations.  Furthermore, this finding did not follow a dose-response correlation in the original study. Therefore, the developmental NOAEL of this study should be considered to be 50mg/kg based on skeletal variations found at 200 mg/kg. Syngenta has reviewed all of the related developmental, reproductive, and pharmacokinetic studies for acibenzolar-S-methyl, and is still of the opinion that, absent the consequences of severe maternal toxicity, acibenzolar-S-methyl is not teratogenic in rat. 
 In the rat multigeneration study, Acibenzolar S-methyl technical had no effect on rat reproductive parameters including gonadal function, estrus cycles, mating behavior, conception, parturition, lactation, weaning, and sex organ histopathology.  This is demonstrated by the results of the following reproductive and developmental studies:
      i. Prenatal developmental toxicity rats- Maternal NOAEL = 50 mg/kg/day.  LOAEL = 200 mg/kg/day based on reduced body weight development and hemorrhagic perineal discharge.  Developmental NOAEL = 50 mg/kg/day. LOAEL = 200 mg/kg/day based on increased incidence of skeletal variations.  Endpoints different from US EPA assessment, refer to weight of evidence assessment for further discussion of this endpoint
      ii. Prenatal developmental toxicity rabbits - Maternal NOAEL = 50 mg/kg/day. LOAEL = 300 mg/kg/day based on mortality, clinical signs of toxicity, decreased maternal body weight and food consumption.  Developmental NOAEL = 300 mg/kg/day. LOAEL = 600 mg/kg/day based on marginal increase in vertebral anomalies.
      iii. Prenatal developmental toxicity rats - Maternal NOAEL = 350 mg/kg/day. LOAEL >350 mg/kg/day based on no effects.  Developmental NOAEL = 150 mg/kg/day. LOAEL = 350 mg/kg/day based on increased incidence of lumbar rib.
      iv. Reproduction and fertility effects rats - Parental/Systemic NOAEL = 200 ppm (11-31 mg/kg/day). LOAEL = 2000 ppm (105-288 mg/kg/day) based on increased weights and hemosiderosis of the spleen.  Reproductive NOAEL = 4000 ppm (223-604 mg/kg/day). LOAEL is greater than 4000 ppm (223-604 mg/kg/day) based on no effects.
Offspring NOAEL = 200 ppm (11-31 mg/kg/day).  LOAEL = 2000 ppm (105-288 mg/kg/day) based on reduced pup body weight gains and lower pup body weights during lactation.
      v. Developmental Neurotoxicity - Maternal NOAEL = 4000 ppm (326.2  -  607.8 mg/kg/day) based on no adverse effects.  LOAEL = not determined.
Offspring NOAEL = 4000 ppm (326.2  -  607.8 mg/kg/day) based on no adverse effects on developmental neurotoxicity.  LOAEL = not determined.
      vi.	Special Developmental toxicity rats - Maternal and developmental NOAELs and LOAELs could not be identified by this protocol testing at 300 mg/kg/day. The most pronounced maternal and developmental toxicity occurred when dams were treated on GD6-15.
      vii.	Special Developmental toxicity rats - Maternal and developmental NOAELs and LOAELs could not be identified by this protocol testing at 400 mg/kg/day. The most pronounced maternal and developmental toxicity occurred when dams were treated on GD6-7 or GD8-9.
      viii.	Dermal developmental toxicity rats - Maternal and developmental NOAEL > 500 mg/kg/day. LOAEL >500 mg/kg/day based on no effects.
      ix. Range finding 1-generation reproduction rats- Parental/Systemic NOAEL = 209 mg/kg/day.  LOAEL = 410 mg/kg/day based on decreased body weight gain and food consumption in females.   Reproductive NOAEL = 410 mg/kg/day.  LOAEL = 728 mg/kg/day based on total resorptions in all dams.  Offspring NOAEL = 209 mg/kg/day. LOAEL = 410 mg/kg/day based on reduced pup body weight gains and lower pup body weights during lactation.
      4. Subchronic toxicity. No signs of neurotoxicity were noted with CGA245704 in both acute and subchronic studies even at the highest dose levels of 800 mg/kg and 8,000 ppm, respectively. The evaluated parameters included functional observation battery, motor activity measurement and neurohistopathologic assessment.  This is demonstrated by the results of the following studies:
      i. 90-Day oral toxicity rats- NOAEL: Males = 126 mg/kg/day; Females = 131 mg/kg/day. LOAEL: Males = 516 mg/kg/day; Females = 554 mg/kg/day based on decreased mean body weights, decreased food consumption and efficiency, and increased liver and spleen weights with correlates of glycogen and hemosiderosis for the liver and spleen, respectively.
      ii. 90-Day feeding study dogs- NOAEL = 50 mg/kg/day. LOAEL = 250 mg/kg/day based on decreased body weight, decreased haemoglobin-related parameters, hepatic and splenic hemosiderosis.
      iii. 28-Day dermal toxicity rats- NOAEL = 1,000 mg/kg/day; LOAEL = not identified
      iv. Subchronic Neurotox- Systemic NOAEL = 400 ppm (Males: 24.4 mg/kg/day; Females: 26.0 mg/kg/day). LOAEL = 2000 ppm (Males: 126 mg/kg/day; Females: 143 mg/kg/day) based on decreased body weight gain and food consumption.
      Neurotoxicity NOAEL = 8000 ppm (Males: 575 mg/kg/day; Females: 628 mg/kg/day) based on no effects. LOAEL = not determined.
      v.  28-Day dietary rats, special study- NOAEL = 4000 ppm (Males: 403 mg/kg/day; Females: 376 mg/kg/day). LOAEL = 12,000 ppm (Males: 1070 mg/kg/day; Females: 1000 mg/kg/day) based on decreased mean body weights, decreased liver weights, altered hematology parameters accompanied by increased spleen weights.
      vi.	 28-Day oral gavage rats, special study- NOAEL = 100 mg/kg/day. LOAEL = 800 mg/kg/day based on decreased body weights, and decreased hemoglobin-related parameters accompanied by hemosiderosis of the spleen, increased liver and spleen weights, and decreased thymus weights.
      vii.	 28-Day oral capsule dogs, special study- NOAEL = 50 mg/kg/day. LOAEL = 250 mg/kg/day based on decreased body weight, decreased hemoglobin-related parameters, hepatic and splenic hemosiderosis.
      viii.	 90-Day dietary mice, special study- NOAEL = 200 ppm (Males: 30.6 mg/kg/day; Females: 47.4 mg/kg/day). LOAEL = 1000 ppm (Males: 152 mg/kg/day; Females: 220 mg/kg/day) based on decreased mean body weights and body weight gain in males, increased spleen weights and splenic histopathology in both sexes.
      5. Chronic toxicity. Based on the available toxicity data, Syngenta believes the Reference Dose (RfD) for acibenzolar-S-methyl is 0.11 mg/kg/day. Currently, the chronic cPAD for Females (13-50 years) is 0.0033 mg/kg/day (US EPA, 1999, 2005). No carcinogenic activity was detected in mice and rats at the Maximum Tolerated Dose (MTD). There was no evidence of carcinogenicity in an 18-month feeding study in mice and a 24-month feeding study in rats. Dosage levels in both the mouse and the rat studies were adequate for identifying a cancer risk. Acibenzolar-S-methyl has been classified as a "Not Likely" human carcinogen based on the lack of carcinogenicity in rats and mice (US EPA, 1999, 2005).  This is based on the following studies:
      i.	 Combined Chronic/Carcinogenicity rats- NOAEL = 2500 ppm (Males: 96.9 mg/kg/day; Females: 111 mg/kg/day). LOAEL = 7500 ppm (Males: 312 mg/kg/day; Females: 388 mg/kg/day) based on decreased body weight, body weight gain and food efficiency, mild hemolytic anemia, and increased incidence of alveolar foam cells (females only).
      ii.	Chronic toxicity dogs- NOAEL = 25 mg/kg/day. LOAEL = 200 mg/kg/day based on effects consistent with hemolytic anemia, including hematological effects, hemosiderosis of the liver and spleen, extramedullary hematopoiesis of the spleen, and increased liver weights.
      iii.	Carcinogenicity mice- NOAEL = 100 ppm (Males: 11.1 mg/kg/day; Females: 10.8 mg/kg/day). LOAEL = 2000 ppm (Males: 237 mg/kg/day; Females: 234 mg/kg/day) based on mild hemolytic anemia and hemosiderosis of the liver, spleen, and bone marrow, and extramedullary hematopoiesis of the spleen. No evidence of carcinogenicity.
      6. Animal metabolism. Metabolism proceeded primarily via hydrolysis to form the corresponding carboxylic acid BTCA (CGA210007) which was subsequently conjugated with several amino acids including glycine, lysine and ornithine. Elimination was rapid in all cases. Oxidation of the aromatic ring of the acid was a very minor pathway observed in goats. The metabolic fate of CGA245704 in plants paralleled that observed in animals. The major metabolite in all test systems was the same hydrolysis product BTCA (CGA210007). Thus, the metabolism profile supports the use of an analytical enforcement method that accounts principally for parent and BTCA.
      7. Metabolite toxicology. In short-term toxicity studies in rats, benzo [1,2,3] thiadiazole-7-carboxylic acid (CGA210007) was found to be of , at most, equal or less toxicity than the parent compound.  As with parent CGA245704, the subchronic NOAEL for CGA210007 was 100 mg/kg bwt.
      8. Endocrine disruption. Acibenzolar S-methyl does not belong to a class of chemicals known or suspected of having adverse effects on the endocrine system.  Developmental toxicity studies in rats and rabbits and a reproduction study in rats gave no indication that acibenzolar S-methyl might have any effects on endocrine function related to development and reproduction.  Acibenzolar S-methyl is not a teratogenic hazard except at, or close to, the maximum tolerated dose.  The chronic studies also showed no evidence of a term effect related to the endocrine system.
  C. Aggregate Exposure
  
1. Dietary exposure.   Acute, short-term and chronic dietary exposure evaluations were completed for acibenzolar-S-methyl using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID, version 3.16).  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.  In addition to all current uses of acibenzolar-S-methyl, this exposure assessment included proposed foliar and soil drench treatment uses on pome fruits (Crop Group 11) and stone fruits  (Crop Group 12).  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 (food only) risk assessments were performed for all population subgroups using an acute reference dose (aRfD) of 0.082 mg/kg-bw/day, based upon a developmental toxicity study in the rat with a no observed adverse effect level (NOAEL) of 8.2 mg/kg-bw/day, an uncertainty factor (UF) of 10X for intra-species variations, a 10X UF for inter-species variations and a 1X FQPA safety factor.  For the purpose of the aggregate risk assessments, the exposure value was expressed in terms of margin of exposure (MOE), which was calculated by dividing the NOAEL by the exposure.  In addition, exposure was expressed as percent acute reference dose (%aRfD).  Acute exposure to the U.S. population resulted in a MOE of 1,123 or 8.9% of the aRfD (Benchmark MOE = 100; aRfD =0.082 mg/kg-bw/day).  Acute food exposure to the most sensitive subpopulation (children 1 to 2 years old) resulted in a MOE of 501 or 20.0% of the aRfD (Benchmark MOE =100; 0.082 mg/kg-bw/day).  Since the Benchmark MOE for this assessment was 100 and since the EPA generally has no concern for exposures below 100% of the aRfD, Syngenta believes that there is a reasonable certainty that no harm will result from acute food exposure to residues arising from all current and proposed uses for acibenzolar-S-methyl.
										
Chronic exposure:     The chronic food risk assessment for the general U.S. population (except children and females 13 to 49 years old) was performed using a chronic reference dose (cRfD) of 0.25 mg/kg-bw/day, based upon a carcinogenicity study in mice with a no observed adverse effect level (NOAEL) of 25 mg/kg/day, an uncertainty factor (UF) of 10X for intra-species variations, a 10X UF for inter-species variations and a 1X FQPA safety factor.  The chronic dietary (food only) risk assessments for children and females 13 to 49 years old was performed using a cRfD of 0.082 mg/kg-bw/day, based upon a developmental toxicity study in the rat with a no observed adverse effect level (NOAEL) of 8.2 mg/kg-bw/day, an uncertainty factor (UF) of 10X for intra-species variations, a 10X UF for inter-species variations, and a 1X FQPA safety factor.  For the purpose of the chronic aggregate risk assessments, 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 exposure to the U.S. population resulted in a MOE of 6,506 or 1.5% of the cRfD (Benchmark MOE = 100; cRfD = 0.25 mg/kg-bw/day).  Chronic exposure to the most exposed sub-population (children 1 to 2 years old) resulted in a MOE of 2,653 or 3.8% of the cRfD (Benchmark MOE = 100; cRfD = 0.082 mg/kg-bw/day).  Since the Benchmark MOE for this assessment was 100 and since the EPA generally 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 dietary (food) exposure to residues arising from all current and proposed uses for acibenzolar-S-methyl.

Cancer.  A chronic cancer exposure analysis was not performed, since acibenzolar-S-methyl has been classified as a "not likely" human carcinogen.  

ii. Drinking water. .  The Estimated Drinking Water Concentrations (EDWCs) of acibenzolar-S-methyl, determined as total toxic residues of acibenzolar-S-methyl and its degradate CGA-210007, were determined for the currently registered and proposed Section 3 uses on citrus and pome fruit using Tier l SCI-GROW (version 2.3), which estimates pesticide concentrations in ground water and Tier II PRZM/EXAMS (PE version 5.0) which estimates pesticide concentrations in surface water.  For ground water, the currently registered and proposed uses on citrus and pome fruit provided the highest EDWC of 0.482 ppb (acute and chronic).   For surface water, the currently registered and proposed use on apples provided the highest EDWCs of 23.5 ppb for acute and 7.55 ppb for chronic. The surface water EDWCs for apples have been corrected for a 0.95 PCA factor.  Since the surface water EDWCs exceed the ground water EDWC, the surface water values will be used for risk assessment purposes.	

Acute Exposure from Drinking Water:  The acute EDWC of 23.5 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] percentile of exposures were determined by taking the difference between the aggregate (food + drinking water) exposures and the food (alone) exposures for 
for each population subgroup.  Acute drinking water exposure U.S. population resulted in a MOE of 9,051 (1.1% of the acute RfD of 0.082 mg/kg-bw/day).  The most exposed sub-population was children (< 1 year old) with an acute MOE of 4,955 or 2.0% of the aRfD.  Since the Benchmark MOE for this assessment was 100, and since the EPA generally has no concern for exposures 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 uses of acibenzolar-S-methyl.

Chronic Exposure from Drinking Water:  The chronic EDWC of 7.55 ppb was input directly into the DEEM-FCID(TM) software as "water, direct and indirect, all sources" directly into the DEEM-FCID(TM) software to model the chronic drinking water exposures.  Chronic drinking water exposure to the U.S. population resulted in a MOE of 158,137 (0.1% of the cRfD of 0.25 mg/kg-bw/day).  The most sensitive subpopulation was infants (<1 year old) with a MOE of 61,330 (0.2% of the cRfD of 0.25 mg/kg-bw/day).  Since the Benchmark MOE for this assessment was 100 and since the EPA generally has no concern for exposures below 100% of the RfD, 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 uses of acibenzolar-S-methyl.

Cancer.  A chronic cancer exposure analysis was not performed, since acibenzolar-S-methyl has been classified as a "not likely" human carcinogen.  

2. Non-dietary exposure. Short-term exposure assessments were conducted to assess exposures resulting from non-dietary residential contributions of acibenzolar-S-methyl arising from uses on golf course, as well as for exposures due to off-site drift of agricultural products. Activity scenarios for adults (19+ years old) included high contact dermal events and golfer.  Activity scenarios for 11-16 year old youths included golfer.  Activity scenarios for 6-11 year old youths included golfer.  Activity scenarios for children 1-6 years included re-entry into areas potentially subject to off-site drift of agricultural products.  For adults 19+, the worst-case short-term MOE was 1,648 (adult residential drift).  For youths 11-16, the worst-case short-term MOE was 24,460 (youth golfer).  For youths 6-11, the worst-case short-term MOE was 20,835 (youth golfer).  For children 1-6, the worst-case short-term MOE was 922 (combined dermal + hand-to-mouth, via off-site drift of agricultural products).  Since the Benchmark MOE for this assessment was 100 and since the EPA generally has no concern for exposures above the benchmark, Syngenta believes that there is a reasonable certainty that no harm will result from short-term non-dietary exposures arising from all current and proposed uses for acibenzolar-S-methyl.
D. Cumulative Effects

Cumulative Exposure to Substances 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 EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to acibenzolar-S-methyl and any other substances, and acibenzolar-S-methyl 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 acibenzolar-S-methyl has a common mechanism of toxicity with other substances.

E. Safety Determination

1. US. Population. Using the conservative assumptions described above, and based on the completeness and reliability of the toxicity data, the acute aggregate exposure calculation for current and proposed uses of acibenzolar-S-methyl provided a MOE of 999 or 10.0% of the aRfD (Benchmark MOE = 100; aRfD = 0.082 mg/kg-bw/day) for the U.S. population.   The chronic aggregate exposure analysis showed that exposure from all current and proposed uses resulted in a MOE of 6,249 or 1.6% of the cRfD (Benchmark = 100; cRfD = 0.25 mg/kg-bw/day) for the U.S. population.  A cancer exposure analysis was not performed, since there is no evidence of human carcinogenic potential for acibenzolar-S-methyl.  Since the worst-case aggregate MOE of 999 exceeds 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 or chronic aggregate exposures arising from all current and uses of acibenzolar-S-methyl.

2. Infants and children Using the conservative assumptions described above, and based on the completeness and reliability of the toxicity data, the acute aggregate exposure calculation for current and proposed uses of acibenzolar-S-methyl provided a MOE of 478 or 20.9% of the aRfD (Benchmark MOE = 100; aRfD = 0.082 mg/kg-bw/day) for children 1-2 years old (the most sensitive population subgroup).  The chronic aggregate exposure analysis showed that exposure from all current and proposed uses resulted in a MOE of 2,590 or 3.9% cRfD (Benchmark MOE = 100; cRfD = 0.082 mg/kg-bw/day) for children 1-2 years old (the most sensitive population subgroup).  A short-term aggregate MOE of 463 (LOC = 100) was determined for children (1-6 years old).   Since the worst-case aggregate MOE of 463 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 or chronic aggregate exposures arising from the current and proposed uses for all current and proposed uses of acibenzolar-S-methyl.
      
F. International Tolerances
There are no Codex maximum residue levels established for acibenzolar-S-methyl.  Permanent, time-limited, or provisional MRLs for a variety of commodities have been established in countries including Canada, Japan, Poland, Italy, South Korea and France.