**Notice of Filing of Pesticide Petition 7E7337**

**[\<]{.mark}EPA Registration Division contact: Susan
Stanton[\>]{.mark}**

**[\<]{.mark}Syngenta Crop Protection, Inc. on behalf of
IR-4[\>]{.mark}**

**[\<]{.mark}PP#7E7337[\>]{.mark}**

**[\<]{.mark}** EPA has received a pesticide petition (7E7337) from
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 180.561 by establishing a tolerance for residues of
Acibenzolar S-methyl in or on the raw agricultural commodity Onion,
bulb, subgroup 3-07A at 0.07\] parts per million (ppm). EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408 (d)(2) 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.[\>]{.mark}

[\<]{.mark}*A. Residue Chemistry*[\>]{.mark}

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

[\<]{.mark} 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.[\>]{.mark}

[\<]{.mark} 3. *Magnitude of residues.* This petition is supported by
eight [field trials](#_Appendix_1_FIELD) conducted on dry bulb onions
during the 2005 or 2006 growing season, one in Michigan (EPA Region 5),
NY (Region 1), Oregon (Region 12), Texas (Region 6), Idaho (Region 11),
Colorado (Region 8), and two in California (Region 10).

All samples were analyzed for by the total residue method to determine
the combined residues of acibenzolar-S-methyl and metabolites, which
contain the benzo \[1,2,3\] thiadiazole-7-carboxylic acid (BTCA) moiety.

The [results](#_Table_C.3:_Residue_Data_from_Crop_F) from the trials
show that the maximum residue in dry bulb onion following a total
application of approximately 0.125 lb ai/A and a pre-harvest interval
(PHI) of approximately 7 days was 0.062 ppm acibenzolar and most of the
values were \<0.050, the lowest level validated. A tolerance of 0.07 ppm
for dry bulb onions has been proposed.[\>]{.mark}

[\<]{.mark}*B. Toxicological Profile*[\>]{.mark}

[\<]{.mark} 1. *Acute toxicity.* The risk from acute dietary exposure to
acibenzolar-S-methyl is considered to be very low. CGA-245704
(acibenzolar S-methyl) and the formulated 50 WG product have low orders
of acute toxicity by the oral, dermal and inhalation exposure routes.
Results from acute studies all fall within toxicity rating categories of
III or IV. CGA245704 technical has a low order of acute toxicity, is
only slightly irritating to the skin and eyes, but may cause
sensitization by skin contact. An LD50 of greater than 5,000
milligrams/kilograms (mg/kg) was observed for the acute oral toxicity
study in rats. The lowest no observed adverse effect level (NOAEL) in a
short-term exposure scenario, identified as 50 mg/kg/day in the rabbit
teratology study, is higher than the chronic NOAEL. The lowest observed
adverse effect level (LOAEL) in the rat teratology study was identified
as 10 mg/kg/day. The following are results from the acute toxicity tests
conducted on the technical material:

i\. Rat oral LD50 \> 5,000 mg/kg/bwt male/female (M/F) toxicity Category
IV.

ii\. Rat dermal LD50 \> 2,000 mg/kg/bwt (M/F) toxicity Categfory III.

iii\. Acute inhalation LC50 \> 5,000 mg/L (M/F) toxicityCategory IV.

iv\. Rabbit eye irritation: Minimally irritating-toxicity Category III.

v\. Rabbit dermal irritation: Slightly irritating-toxicity Category IV.

vi\. Dermal sensitization: Sensitizer.[\>]{.mark}

[\<]{.mark} 2. *Genotoxicty.* CGA245704 technical was not mutagenic or
clastogenic and did 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. These test are summarized below:

i\. Microbial/Microsome Mutagenicity Assay: Non-mutagenic.

ii\. Mammalian Cell Chinese Hamster Ovary (CHO) Mutagenicity Assay:
Non-mutagenic; Non-clastogenic.

iii\. Chinese Hamster (CH) Bone Marrow: Non-clastogenic; negative for
chromosome aberrations.

iv\. Mouse Micronucleus Test: non-clastogenic; negative for aberrations.

v\. DNA Damage and Repair Rat hepatocyte: Negative[\>]{.mark}

[\<]{.mark} 3. *Reproductive and developmental toxicity.*
Acibenzolar-S-methyl is not a teratogenic hazard except at levels close
to the maximum tolerated dose. In the rat multigeneration study,
CGA245704 technical had no effect on rat reproductive parameters
including gonadal function, estrus cycles, mating behavior, conception,
parturition, lactation, weaning, and sex organ histopathology. At 4,000
ppm, parental body weights (bwt) were reduced. This is demonstrated by
the results of the following studies:

i\. Rat oral teratology-Maternal NOAEL of 200 mg/kg based on
embryotoxicity and teratogenic effects; fetal LOAEL of 10 mg/kg.

ii\. Rabbit oral teratology study- Maternal NOAEL of 50 mg/kg based on
maternal toxicity and slightly delayed ossification; fetal NOAEL of 300
mg/kg based on changes in bwt.

iii\. Rat 2-generation reproduction study-NOAEL of 25 mg/kg based on
weight development in adults at 4,000 ppm and pups during lactation at
2,000 ppm and above. No adverse effects on reproduction or fertility.

A later developmental neurotoxicity study was performed showing no
adverse effects during gestation and lactation, even at the high dose of
4000 ppm (NOAEL) in rats.[\>]{.mark}

[\<]{.mark} 4. *Subchronic toxicity.* No signs of neurotoxicity were
noted with CGA245704 (acibenzolar S-methyl) 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.
These tests are summarized below:

i\. Rat 28 -day dermal study- NOAEL of 1,000 mg/kg/day.

ii\. Dog 90-day feeding study- NOAEL of 10 mg based on reduced bwt gain
at 50 mg/kg/day.

iii\. Mouse 90-day feeding study-NOAEL of 30 mg/kg based on reduced bwt
development at 1,000 ppm and above.

iv\. Rat 90-feeding study- NOAEL of 25 mg/kg based on inappetence and
reduced bwt development at higher dose levels (4,000 and 8,000
ppm).[\>]{.mark}

[\<]{.mark} 5. *Chronic toxicity.* Based on the available chronic
toxicity data, Syngenta Crop Protection, Inc. believes the reference
Dose (Rfd) for acibenzolar-S-methyl is 0.11 mg/kg/day. Acibenzolar
S-methyl is not oncogenic in rats or mice and is not likely to be
carcinogenic in humans. 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. Syngenta believes
that acibenzolar-S-methyl should be classified as a "Not likely"
carcinogen based on the lack of carcinogenicity in rats and
mice.[\>]{.mark}

[\<]{.mark} 6. *Animal metabolism.* Metabolism proceeded primarily via
hydrolysis to form the corresponding carboxylic acid (BTCA) 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. Thus, the metabolism profile supports the
use of an analytical enforcement method that accounts principally for
parent and BTCA.[\>]{.mark}

[\<]{.mark} 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.[\>]{.mark}

[\<]{.mark} 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.[\>]{.mark}

[\<]{.mark}*C. Aggregate Exposure*[\>]{.mark}

[\<]{.mark} 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-FCID^TM^, 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 DEEM^TM^
version 7.87 defaults. All consumption data for these assessments was
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 uses and a proposed new IR‑4 use on
Crop Group 3: Bulb Vegetables. These 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. Percent of crop
treated values were estimated based upon economic, pest and competitive
pressures. Tolerances have not been established for secondary residues
of acibenzolar-S-methyl in animal commodities, as none of the current
uses result in commodities that are commonly fed to
livestock.[\>]{.mark}

i.  [\<]{.mark}*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 0.0033 mg/kg-bw/day, based upon a developmental toxicity
study in the rat with a lowest observed adverse effect level (LOAEL) of
10 mg/kg/day, an uncertainty factor (UF) of 100X for intra- and
inter-species variations, an additional 3X UF for the lack of a no
observed adverse effect level (NOAEL), and an additional 10X 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 LOAEL by the
exposure. In addition, exposure was expressed as a percent of the acute
reference dose (%aRfD). Acute exposure to the females 13-49 years
subpopulation resulted in a MOE of 12,077 (25.1% of the acute RfD of
0.0033 mg/kg-bw/day). Since the Benchmark MOE for this assessment was
3,000 and since 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 acute dietary (food) exposure to residues arising
from all current and proposed uses for acibenzolar-S-methyl.

*Chronic exposure.*

The chronic dietary (food only) risk assessment for the general U.S.
population (except females 13 to 49 years old) was performed using a
chronic reference dose (cRfD) of 0.0367 mg/kg-bw/day, based upon a
carcinogenicity study in mice with a no observed adverse effect level
(NOAEL) of 11 mg/kg/day, an uncertainty factor (UF) of 100X for intra-
and inter-species variations, and an additional 3X FQPA safety factor.
The chronic dietary (food only) risk assessment for females 13 to 49
years old was performed using a cRfD of 0.0033 mg/kg-bw/day, based upon
a developmental toxicity study in the rat with a lowest observed adverse
effect level (LOAEL) of 10 mg/kg/day, an uncertainty factor (UF) of 100X
for intra- and inter-species variations, an additional 3X UF for the
lack of a no observed adverse effect level (NOAEL), and an additional
10X 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- or
lowest- observed adverse effect level (LOAEL or NOAEL) by the exposure
for each population subgroup. In addition, exposure was expressed as a
percent of the chronic reference dose (%cRfD). Chronic exposure to the
most exposed sub-population (females 13-49 years old) resulted in a MOE
of 4,363 (69.5% of the cRfD of 0.0033 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 RfD, 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.

[\>]{.mark}

[\<]{.mark} ii. *Drinking water.* Syngenta used PRZM/EXAMS Model Shell,
version 5.0 and SCI-GROW, version 2.3 to estimate concentrations for
drinking water exposures in surface water and ground water,
respectively. Modeling was conducted on the parent compound, CGA-245704
and its acid metabolite CGA-210007; model outputs were combined to
calculate estimated drinking water concentrations (EDWCs). The modeling
was conducted using environmental fate parameters by applying EPA's
guidance to identify the highest EDWCs from current, and proposed (bulb
onions, bulb daylily, fritillaria bulb, great-headed bulb garlic,
serpent bulb garlic, bulb lily, chinese bulb onion, pearly onion, bulb
potato onion, and bulb shallot) labeled use rates for
acibenzolar-S-methyl. The currently registered tomato use rate of 0.1872
lb a.i./A (0.0234 lb ai/A x 8 applications; 7 day interval) gave the
highest EDWCs. Using tomato use parameters from the Actigard® 50WG Plant
Activator label, and the PRZM Pennsylvania tomatoes crop scenario,
aerial application, a June 15th application date, and an 87% cropped
area factor, peak (acute) and annual average (chronic) surface water
EDWCs were 7.5 ppb and 1.28 ppb respectively. Using the SCI-GROW model
and tomato use parameters, the acute and chronic ground water EDWC was
0.03 ppb. In their final rule published in the February 16, 2005 Federal
Register/Vol. 70, No. 31, p. 7854, the US EPA reported estimated
environmental concentrations (EECs) of acibenzolar-S-methyl for acute
and chronic exposures in drinking water from surface and ground water.
Based on PRZM/EXAMS modeling, the EEC for acibenzolar-S-methyl for acute
exposure in surface water was slightly higher -- at 7.9 ppb - than the
corresponding value from Syngenta modeling. Since surface water
estimated concentrations exceeded the ground water estimated
concentrations, the surface water values were used for comparison
purposes and are considered protective for any ground water
concentration concerns.

*Acute Exposure from Drinking Water*: The acute EDWC (7.9 ppb) for
surface water was input directly into the DEEM-FCID™ software as "water,
direct and indirect, all sources" to obtain the acute dietary exposure
from water. Drinking water exposures at the 99.9%-ile were determined by
taking the difference between the aggregate exposures (food + drinking
water) and food exposures (food only) for females 13-49 years old (the
only population subgroup for which an acute toxicological endpoint has
been established), which resulted in a MOE of 18,182 (16.7% of the aRfD
of 0.0033 mg/kg-bw/day). Since the Benchmark MOE for this assessment was
3,000, 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
from all current and proposed uses of acibenzolar-S-methyl.

*Chronic Exposure from Drinking Water*: The chronic EDWC of 1.28 ppb was
incorporated as "water, direct and indirect, all sources" directly into
the DEEM-FCID™ software to obtain chronic drinking water exposures.
Chronic drinking water exposure to the most exposed sub-population,
females 13-49 years old, resulted in a MOE of 400,000 (0.8% of the cRfD
of 0.0033 mg/kg-bw/day). Since the Benchmark MOE for this assessment was
3,000 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 from all current and proposed uses of acibenzolar-S-methyl.

*Cancer*. A chronic cancer exposure analysis was not performed, since
acibenzolar-S-methyl has been classified as a "not likely" human
carcinogen.[\>]{.mark}

[\<]{.mark} 2. *Non-dietary exposure*. There are currently no registered
residential uses of acibenzolar-S-methyl, so residential exposure
assessments were not performed.[\>]{.mark}

[\<]{.mark}*D. Cumulative Effects*[\>]{.mark}

[\<]{.mark} 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.[\>]{.mark}

[\<]{.mark}*E. Safety Determination*[\>]{.mark}

[\<]{.mark} 1. *U.S. 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 new IR‑4 use for acibenzolar-S-methyl on Crop Group 3
(bulb vegetables) resulted in a MOE of 3,930 (7.6% of the cRfD of 0.0367
mg/kg-bw/day) for the U.S. population, which exceeds the Benchmark MOE
of 300. 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 and proposed uses of
acibenzolar-S-methyl.[\>]{.mark}

[\<]{.mark} 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
and the proposed new IR‑4 use for acibenzolar-S-methyl on Crop Group 3
(bulb vegetables) resulted in a MOE of 1,702 (17.6% of the cRfD of
0.0367 mg/kg-bw/day) for children 1-2 years old, which exceeds the
Benchmark MOE of 300. Short- and intermediate term aggregate assessments
were not performed since there are no residential uses for
acibenzolar-S-methyl at this time. Based on the completeness and
reliability of the toxicity data supporting these petitions, Syngenta
believes that there is a reasonable certainty that no harm will result
to infants and children from aggregate exposures from all current and
proposed uses of acibenzolar-S-methyl.[\>]{.mark}

*3. Females 13-49 years of age*. The acute aggregate exposure analysis
showed that exposure from all current uses and the proposed new IR‑4 use
for acibenzolar-S-methyl on Crop Group 3 (bulb vegetables) resulted in a
MOE of 7,257 (41.8% of the aRfD of 0.0033 mg/kg-bw/day) for females
13-49 years old, which exceeds the Benchmark MOE of 3,000. The chronic
aggregate exposure analysis showed that exposure from all current uses
and the proposed new IR‑4 use for acibenzolar-S-methyl on Crop Group 3
(bulb vegetables) resulted in a MOE of 4,316 (70.2% of the cRfD of
0.0033 mg/kg-bw/day) for females 13-49 years old, which exceeds the
Benchmark MOE of 3,000. 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 and
proposed uses of acibenzolar-S-methyl.

[\<]{.mark}*F. International Tolerances*[\>]{.mark}

[\<]{.mark}There are no Codex maximum residue levels established for
acibenzolar-S-methyl.[\>]{.mark}