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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 Smethyl 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.
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2. 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. 

3. 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® (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, 
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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-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

1. 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. 
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2. 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 
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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 
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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 
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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 
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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 
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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 interspecies 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-Smethyl 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-FCIDTM software as “water, direct and indirect, all sources” 
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to model the acute drinking water exposures. 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 (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-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 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-Smethyl 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 acibenzolarS-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 
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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-Smethyl 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.
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