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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 Smethyl 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 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 Smethyl 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 AG671A. 

3. 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

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 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 
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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.
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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 
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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.
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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 nonfood 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. 

i. Food. Acute exposure: The acute dietary (food only) risk assessment for 

females 13 to 49 years old (the only population subgroup for which an acute 

toxicological endpoint has been established) was performed using an acute 

reference dose (aRfD) of 0.082 mg/kg-bw/day, based upon a developmental 
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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/kgbw/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 intraspecies 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 subpopulation (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.

ii.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, 
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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-FCIDTM 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-FCIDTM 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.
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D. Cumulative Effects

Cumulative Exposure to Substances with a Common Mechanism of Toxicity. 

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to 

establish, modify, or revoke a tolerance, the Agency consider “available 

information” concerning the cumulative effects of a particular pesticide’s residues 

and “other substances that have a common mechanism of toxicity.” Unlike other 

pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of 

toxicity finding as to acibenzolar-S-methyl and any other substances, and 

acibenzolar-S-methyl does not appear to produce a toxic metabolite produced by 

other substances. For the purposes of this tolerance action, the EPA has not 

assumed that acibenzolar-S-methyl has a common mechanism of toxicity with 

other substances.

Safety Determination

1. 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-Smethyl.

2. 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 intermediateterm 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.

3. 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 
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MOE of 2,993 or 3.3% aRfD (Benchmark MOE =100; aRfD = 0.082 mg/kgbw/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 nonbearing 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.
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