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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 Pro** 

**tection, LLC**  **PP #**  **4F8269 EPA has received a**  **pesticide petition 4F8269**  **from Syngen**  **t a 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**  **est ablish a tolerance**  **for residues of fu**  **ngicide acibenzolar -**  **S -**  **methyl / CGA -**  **245704 (Benzo [1,2,3] thiadiazo1e**  **- 7**  **- carbothioic acid**  **- S**  **- me**  **thyl ester in**  **or on the raw agricultural commodit** 

**ies 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**  **180.56 1**  **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**

. **Synge nta**  **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 metabo** **lism 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 conju**  **gation 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.** 2 **2. Analytical method.**  **Syngenta Analytica l 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 quanti tation**  **(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 invol ves 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.**  **3. Magnitude of residues.**  **A total of 15 G LP 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 af**  **ter 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 resul**  **ting 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® (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 .**  **Po me**  **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 followi**  **ng 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,**3 **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® 50 WG (5X rate) at 30**  **- day intervals ending at 0**  **- day PHI. Three samples per site were analyzed for acibenzolar**  **- S**  **- meth**  **yl and its primary degradate, CGA**  **- 210007. There we**  **re no residues greater than the level of quantitation (< 0.01 ppm) in any of the 5X treated samples at either site**  **. B** 

. **Toxicological Profile 1.**  **Acute toxicity**

. **Acibenzolar S -** **methyl (CGA24570 4) 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 5.0 22**  **mg/L. Acibenzolar S -** **methyl is categorized as slightly irritating to skin and eyes and a potential skin sensitizer.** 4 **2. Genotoxicty.**  **With the exception of the chromosome aberration study in**

**CHO cells in culture (MRID 44014245), CGA245704 was neg ative 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. Follo wing 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 ass**  **ay, 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 mou**  **se 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 submitt**  **ed additional information as part of**  **a previous tolerance petition, which support** **s the conclusion that the umbilical hernia found**  **at 10 mg/kg is not treatment related and that the additional uncertainty factors ma**  **y be unwarranted. A**  **dditional 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 4 5713601).**  **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 conside red 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**  **deve lopment 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** 5

**reproduced in the subsequent rat te ratogenicity 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. S yngenta 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 i**  **s demonstrated by the results of the following reproduc tive**  **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 discharg e. 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 deve** **lopmental 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 marg**  **inal 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 r** **ib. 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). LOAE L 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 Neur**  **otoxicity -**  **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**6

**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 base**  **d 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 g ains 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 param** **eters 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/da** 

**y. 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, respect**  **ively. 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 NOA** **EL = 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** 7

**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 m ice** **- 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, lysi**  **ne and ornithine. Elimination was rapid in all cases. Oxidation of the aromatic ring of the acid was a** 8

**very minor pathway observed in goats. The metabolic fate of CGA245704 in plants paralleled that observed in animals. The major metabolite in all test sys**  **tems 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 e**  **ffects 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 endocri**  **ne 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 concentratio**  **ns (EDWCs) for surface and ground water. i.**  **Foo d** 

. **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 aggreg ate 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** 9

**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: Th**  **e 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**  **** **speci es 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 observ ed 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 exposur e 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 refer ence 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 reasonabl e**  **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 c lassified as a “not likely” human carcinogen.** 

**ii. D rinking 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 high**  **est 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 p**  **urposes. Acute Exposure from Drinking Water**  **: The acute EDWC of 23.5 ppb**  **was input directly into the DEEM**  **- FCIDTM software as “water, direct and indirect, all sources”** 10

**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). T**  **he 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 conce rn 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 fr** **om Drinking Water : The chronic EDWC of**  **7.55 ppb was input**  **directly into the DEEM -**  **FCIDTM software as “water, direct and indirect, all sources” directly into the DEEM**  **- FCIDTM software to model the chronic drinking water**  **exposures. Chronic drinking water expos ure 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 ass essment 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 pr oposed**  **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 asses sm**  **ents 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 wa**  **s 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 der**  **mal + 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 tha**  **t 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** 11

**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 t oxicity.” 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 aRf**  **D (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 beli eves 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 assump tions 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 -**  **lim ited, or provisional MRLs for a variety of commodities have**  **been established in countries including Canada, Japan, Poland,**  **Italy, South Korea and France.** 12