Document ID: EPA-HQ-OPP-2008-0270-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-05-16T04:00Z

Notice of Filing of Pesticide Petition 7E7337

<EPA Registration Division contact: Susan Stanton>

<Syngenta Crop Protection, Inc. on behalf of IR-4>

<PP#7E7337>

<	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.>

<A. Residue Chemistry>

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

<	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. This petition is supported by eight
HYPERLINK  \l "_Appendix_1_FIELD"  field trials  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  HYPERLINK  \l "_Table_C.3:_Residue_Data from Crop F" results  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.>

<B. Toxicological Profile>

<	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.>

<	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>

<	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.>

<	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).>

<	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.>

<	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.>

<	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 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.>

<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.

>

<	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.

e 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.

EM-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.>

<	2. Non-dietary exposure. There are currently no registered residential
uses of acibenzolar-S-methyl, so residential exposure assessments were
not performed.>

<D. Cumulative Effects>

<	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.>

<E. Safety Determination>

<	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.>

<	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.>

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ᔔ왨堼ᘀ깨鉦䌀ᡊ帀ɊḀf 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.

<F. International Tolerances>

<There are no Codex maximum residue levels established for
acibenzolar-S-methyl.>

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