Document ID: EPA-HQ-OPP-2011-0086-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-07-06T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER
EPA Registration Division contact: Sidney Jackson (703) 305-7610 
Syngenta Crop Protection, Inc. on behalf of IR-4 
PP# 0E7818
EPA has received a pesticide petition (PP# 0E7818) from the Interregional Research Project No. 4 (IR-4), 500 College Road East, Suite 201W, Princeton, NJ 08540 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 by amending the tolerances in 40 CFR part 180.561 by combining the tables for sections (a)(1) and (a)(2) into one table under section (a)(1), and by removing section (a)(2). The petition further proposes to revise the tolerance expression under section (a)(1) to read as follows:  "Tolerances are established for residues of acibenzolar-S-methyl, benzo(1,2,3)thiadiazole-7-carbothioic acid-S-methyl ester, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only those acibenzolar-S-methyl residues convertible to benzo(1,2,3)thiadiazole-7-carboxylic acid (CGA-210007), expressed as the stoichiometric equivalent of acibenzolar-S-methyl, in or on the commodity."  Finally, the petition proposes to establish a tolerance for residues of acibenzolar S-methyl in or on the raw agricultural commodity Low growing Berry Subgroup 13-07G at 0.15 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 support 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.

Strawberries: 
Ten residue field trials were conducted in States of NY, WI, NC, FL, CA, and OR, as well as the Province of Quebec and Ontario, Canada.  A total of approximately 0.187 lb ai/A was applied in eight foliar applications of Actigard 50WG at a rate of approximately 0.0234 lb ai/A each.  An additional application was made in one trial, for a total of approximately 0.214 lb ai/A.  Mature strawberries were collected following the final application, after the test substance dried on the fruit and foliage.  Additional decline samples were collected at 3, 7, 10 and 14 days in one trial.

The maximum residues were 0.087 ppm at a 0-day PHI. Residues declined over time from a maximum of 0.064 ppm at 0 days to < 0.020 ppm by 10 days. Data from this study may be used to support a tolerance proposal for acibenzolar on strawberry (low growing berry subgroup 13-07G).  The establishment of a tolerance would provide growers with a safe and effective fungicide, yet would not expose humans or the environment to unreasonable adverse effects.
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 support 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. Tier III acute and Tier I chronic dietary exposure evaluations were performed for acibenzolar-S-methyl using the Dietary Exposure Evaluation Model (DEEM-FCIDTM, version 2.16) from Exponent.  Empirically derived processing factors for tomato paste (5.84X), tomato puree (2.61X), and tomato juice (0.88X) were used in these assessments.  All other processing factors used the DEEMTM version 7.87 defaults.  All consumption data for these assessments were taken from the USDA's Continuing Survey of Food Intake by individuals (CSFII) with the 1994-96 consumption database and the Supplemental CSFII children's survey (1998) consumption database.  These exposure assessments included all current, pending and proposed uses on non-bearing citrus trees (Crop Group 10) and strawberries.  Although the use on non-bearing citrus trees is a non-food use, citrus residues were included in the assessments.  The Tier III acute assessments utilized residue data from field trials where acibenzolar-S-methyl was applied at the maximum intended use rate and samples were harvested at a minimum pre-harvest interval (PHI) to obtain maximum anticipated residues; the Tier II chronic assessments utilized current and proposed tolerance values.  Percent of crop treated values were estimated based upon economic, pest and competitive pressures.  
       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 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 adult females 13-49 years.  For the purpose of aggregate risk assessment, 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 females 13-49 years subpopulation resulted in a MOE of 5,915 or 1.7% of the aRfD (Benchmark MOE = 100; aRfD =0.082 mg/kg-bw/day).  Since the Benchmark MOE for this assessment was 100 and since 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, pending and proposed uses for acibenzolar-S-methyl.
      Chronic exposure:  The chronic food risk assessment for the general U.S. population (except 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 assessment for 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 adult females 13-49 years.  For the purpose of 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 exposure to the most exposed sub-population (females 13-49 years old) resulted in a MOE of 2,744 or 3.6% of the cRfD (Benchmark MOE = 100; cRfD = 0.082 mg/kg-bw/day).  Since the Benchmark MOE for this assessment was 100 and since 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, pending and proposed uses for acibenzolar-S-methyl.
       Drinking water. The Estimated Drinking Water Concentrations (EDWCs) of acibenzolar-S-methyl and its degradate, CGA210007, reported as combined total residues (acibenzolar-S-methyl plus CGA210007), were determined for the currently registered uses and the proposed use pattern on non-bearing citrus 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 use on cucurbits provided the highest combined EDWC of 0.0811 ppb (acute and chronic).   For surface water, the currently registered cucurbit use provided the highest combined EDWCs of 16.8114 ppb for acute and 3.1739 ppb for chronic.  The surface water EDWCs have been corrected for a 0.87 PCA factor.   Since the surface water EDWCs exceed the ground water EDWC, the surface water values will be used for risk assessment purposes and considered protective for any ground water concentration concerns.
      
      Acute Exposure from Drinking Water:  The acute EDWC of 16.8114ppb was incorporated with food residues as "water, direct and indirect, all sources" directly into the DEEM-FCID(TM) software to model the aggregate (food and water) exposures.  The acute drinking water exposure contributions at the 99.9th percentile of exposures were determined by taking the difference between the aggregate (food + drinking water) exposures and the food (only) exposures for females 13-49 years (the only population subgroup for which an acute toxicological endpoint has been established) resulted in a MOE of 6,061 or 1.7% aRfD (Benchmark MOE = 100; aRfD = 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 drinking water exposure to residues arising from all current, pending and proposed uses of acibenzolar-S-methyl.
      Chronic Exposure from Drinking Water:  The chronic EDWC of 3.1739 ppb was incorporated with food residues as "water, direct and indirect, all sources" directly into the DEEM-FCID(TM) software to obtain chronic dietary exposures from water.  Chronic drinking water exposure to the most sensitive subpopulation was infants (< 1 year old), with a MOE of 113,056 or 0.1% cRfD (Benchmark MOE = 100; cRfD = 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 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, pending 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. There are currently no registered residential uses of acibenzolar-S-methyl, so residential exposure assessments were not performed.

 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.

Safety Determination
 US. population. An acute toxicological endpoint has not been established for the U.S. population, so an acute exposure assessment for the general population was not performed.  The chronic aggregate exposure analysis showed that exposure from all current uses and the proposed uses on strawberries and non-bearing citrus (Crop Group 10) resulted in a MOE of 6,768 or 1.5% of the cRfD (Benchmark = 100; cRfD = 0.25 mg/kg-bw/day) for the U.S. population, which exceeds the Benchmark MOE of 100.  A cancer exposure analysis was not performed, since there is no evidence of human carcinogenic potential for acibenzolar-S-methyl.  Short- and intermediate term aggregate assessments were not performed since there are no residential uses for acibenzolar-S-methyl at this time.  Based on the completeness and reliability of the toxicity data supporting these petitions, Syngenta believes that there is a reasonable certainty that no harm to the general US population will result from aggregate exposures from all current, pending and proposed uses of acibenzolar-S-methyl.
 Infants and children. An acute toxicological endpoint has not been established for infants and children, so an acute exposure assessment was not performed for that population subgroup.  The chronic aggregate exposure analysis showed that exposure from all current uses plus the proposed and pending uses on strawberries and non-bearing citrus (Crop Group 10) resulted in a MOE of 3,069 or 3.3% cRfD (Benchmark MOE = 100; cRfD = 0.25 mg/kg-bw/day) for children 1-2 years old, which exceeds the Benchmark MOE of 100.  Short- and intermediate-term aggregate assessments were not performed since there are no residential uses for acibenzolar-S-methyl at this time.  Based on the completeness and reliability of the toxicity data supporting these petitions, Syngenta believes that there is a reasonable certainty that no harm will result to infants and children from aggregate exposures from all current, pending and proposed uses of acibenzolar-S-methyl.
 Females 13-49 years of age.  The acute aggregate exposure analysis showed that exposure from all current uses plus the proposed and pending uses on strawberries and non-bearing citrus (Crop Group 10) resulted in a MOE of 2,993 or 3.3% aRfD (Benchmark MOE =100; aRfD = 0.082 mg/kg-bw/day) for females 13-49 years old, which exceeds the Benchmark MOE of 100.  The chronic aggregate exposure analysis showed that exposure from all current uses plus the proposed and pending uses on strawberries and non-bearing citrus (Crop Group 10) resulted in a MOE of 2,688 or 3.7% cRfD (Benchmark MOE = 100; cRfD = 0.082 mg/kg-bw/day) for females 13-49 years old, which exceeds the Benchmark MOE of 100.  Short- and intermediate term aggregate assessments were not performed since there are no residential uses for acibenzolar-S-methyl at this time.  Based on the completeness and reliability of the toxicity data supporting these petitions, Syngenta believes that there is a reasonable certainty that no harm to adult females will result from aggregate exposure from all current, pending 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.