Document ID: EPA-HQ-OPP-2016-0143-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2016-08-29T04:00Z

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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: Hope Johnson, 703-305-5410

Syngenta Crop Protection, LLC

5E8433

	EPA has received a pesticide petition (5E8433) from Syngenta Crop
Protection, LLC, 410 Swing Road, P.O. Box 18300, Greensboro, NC
27419-8300 requesting, 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 establishing import tolerances for residues of  isopyrazam  (SYN
520453)  in or on the raw agricultural commodity tomato at 0.5 parts per
million (ppm), sweet pepper at 0.6 parts per million (ppm) and the
cucurbit crop subgroup 9A (melons) at 0.3 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. Metabolism of SYN520453 has been studied on wheat,
grapes, and lettuce. The metabolic routes of SYN520453 in all three
crops were the same and the parent molecule was the primary constituent
of the Total Radioactive Residue (TRR) in all three matrices. The most
significant metabolite identified in plant was the primary alcohol, the
metabolites CSCD459488 and CSCD459489 (syn and anti-forms respectively).
Based on the results of the metabolism studies conducted, EPA concluded
that the definition of the residue for tolerance enforcement purposes is
parent isopyrazam only (SYN534968 plus SYN534969); however the
residue-of-concern for risk assessment purposes includes parent
isopyrazam (SYN534968 plus SYN534969) plus the metabolite

CSCD459488. The residue trials conducted included measurements of the
two isomers of the parent, the metabolite CSCD459488, as well as the
anti version of the latter,

CSCD459489.

	2. Analytical method. An adequate, validated method (GRM006.01B) is
available for enforcement purposes for the determination of residues of
isopyrazam, analyzed as the isomers SYN534968 and SYN534969, in crop
samples. The limit of quantification has been set at 0.005 mg/kg for
each isomer (0.01mg/kg for SYN520453 in total).

Samples are extracted by homogenization with acetonitrile:water (80:20
v/v for most crops and 50:50 v/v for straw). Extracts are centrifuged
and aliquots (equivalent to 0.2 g) are diluted with methanol:water
(50:50 v/v). Final determination is by LC-MS/MS. An analytical method
suitable for the determination of residues of the metabolites

CSCD459488 and CSCD459489 (syn and anti-forms respectively) in crop
samples using an external standardization procedure is also available.
The limit of quantification (LOQ) has been set at 0.005 mg/kg for both
analytes. Samples are extracted by homogenization with
acetonitrile:water (80:20 v/v). Extracts are centrifuged and aliquots
(equivalent to

0.09 g) are hydrolyzed with 0.1 M HCl at 60°C for 3 hours. Aliquots are
then diluted with acetonitrile and ultra-pure water. Final determination
is by LC-MS/MS.

	3. Magnitude of residues. 

Tomato:  Sixteen residue trials were conducted in the European Union
(EU) to determine the magnitude of the residue of isopyrazam in or on
tomatoes.  Eight of the sixteen trials were conducted on protected
cherry tomato varieties in the EU.

Isopyrazam was applied to tomatoes as an emulsifiable concentrate (EC)
formulation containing 125 grams isopyrazam per liter.  Two
applications, separated by 7 day intervals, were made at 125 g ai/ha
ending at 1 day prior to harvest.

Samples were analyzed for residues of isopyrazam (SYN520453; determined
as SYN534968 and SYN534969) and its metabolites CSCD459488 and
CSCD459489.  The limit of quantification (LOQ) for each analyte was
0.005 ppm.

The maximum residue level of SYN520453 (summed SYN534968 and SYN534969)
in tomatoes was 0.19 mg/kg at 1 day after last application (1 DALA). No
residues of CSCD459488 or CSCD459489 were detected at levels above the
Limit of Quantification (LOQ) of 0.005 ppm.

Sweet Pepper:  Fourteen supervised residue trials have been conducted on
peppers during 2010 and 2011, eight in protected crops in
northern/southern Europe and six in outdoor crops, two in northern and
four in southern Europe.

Isopyrazam was applied to peppers as an emulsifiable concentrate (EC)
formulation containing 125 grams isopyrazam per liter.  Two
applications, separated by 7 day intervals, were made at 125 g ai/ha
ending at 3 days prior to harvest.

Samples were analyzed for residues of isopyrazam (SYN520453; determined
as SYN534968 and SYN534969) and its metabolites CSCD459488 and
CSCD459489.  The limit of quantification (LOQ) for each analyte was
0.005 ppm.

The maximum residue level of SYN520453 (summed SYN534968 and SYN534969)
in peppers was 0.25 mg/kg at 3 days after last application (3 DALA). No
residues of CSCD459488 or CSCD459489 were detected at levels above the
Limit of Quantification (LOQ) of 0.005 ppm.

Cucurbit Crop Group 9A:  Twenty four supervised residue trials have been
conducted on melons between 2010 and 2013, eight in protected crops in
northern/southern Europe and sixteen in outdoor crops.

Isopyrazam was applied to melons as an emulsifiable concentrate (EC)
formulation containing 125 grams isopyrazam per liter.  Two
applications, separated by 7 day intervals, were made at 125 g ai/ha
ending at 7 days prior to harvest.

Samples were analyzed for residues of isopyrazam (SYN520453; determined
as SYN534968 and SYN534969) and its metabolites CSCD459488 and
CSCD459489.  The limit of quantification (LOQ) for each analyte was
0.005 ppm.

The maximum residue level of SYN520453 (summed SYN534968 and SYN534969)
in melons (whole fruit) was 0.16 mg/kg at 7 days after last application
(7 DALA). The maximum residue level of CSCD459488 detected was 0.008
mg/kg at 7 DALA.  No residues of CSCD459489 were detected at levels
above the LOQ (0.005 ppm).

B. Toxicological Profile

	1. Acute toxicity.  

SYN520453 is of low acute toxicity by the oral, dermal and inhalation
routes of exposure and is not irritating to the eyes or skin. On the
basis of the results of a local lymph node assay in the mouse, SYN520453
is considered to have potential to cause sensitization following contact
with skin. Three acute oral studies focused on the isomeric proportions
of SYN520453. The LD50 for isomeric mixtures containing more than 50% of
the syn isomer of isopyrazam was >2000 mg/kg.] 

	2. Genotoxicity. 

[In vitro, both specifications of SYN520453 (Tox Reserve and 70:30) were
negative for bacterial reverse mutation, in vitro cytogenetics, and
mammalian cells gene mutation (L5178Y TK+/- mouse lymphoma). The L5178
TK+/- assay, which is also able to detect chromosomal damage, was
negative for clastogenicity. In the in vitro cytogenetic assay using
primary human lymphocyte cultures, neither specification of SYN520453
induced chromosomal aberrations. In vivo, SYN520453 (Tox Reserve
specification) was found to be non-clastogenic in the rat bone marrow
micronucleus assay and there was also no evidence for any indication of
DNA damage or repair in the rat liver UDS (unscheduled DNA synthesis)
assay. 

	3. Reproductive and developmental toxicity. 

SYN520453 was assessed for reproductive toxicity in a multi-generation
reproduction study in the rat at dietary inclusion levels of 0, 100, 500
or 3000 ppm SYN520453. The parental toxicity NOAEL was 100 ppm based on
decreased body weight and food consumption in females at 500 ppm; and
increased liver weight and hepatocyte hypertrophy in F0 and F1 animals
at 500 ppm. The offspring NOAEL was 100 ppm based on increased liver
weights in F1 and F2 pups at 500 ppm. No treatment related reproductive
parameters were affected due to treatment with SYN520453 thus the
reproductive NOAEL was the top dose 3000 ppm and a LOAEL was not
established. There is no indication of increased sensitivity of
offspring to SYN520453 in a multi-generation reproduction study in rats.

Two developmental toxicity studies were conducted in the rat: one with
Tox Reserve material and the other with 70:30 material. In the study
with Tox Reserve, rats were given oral doses of SYN520453 at 0, 20, 75
or 250 mg/kg/day on gestation days 5 to 21. The maternal NOAEL was 75
mg/kg/day based on mortality, decreased body weight gain and food
consumption and clinical signs of toxicity at 250 mg/kg/day. The fetal
NOAEL was 75 mg/kg/day based on increased post-implantation loss, a
reduced number of live fetuses, decreased fetal weight and reduced
ossification at 250 mg/kg/day. The fetal effects were considered to be
secondary to maternal toxicity.

In the rat developmental toxicity study with 70:30 material, rats were
given oral doses of SYN520453 at 0, 20, 75 or 200 mg/kg/day. The fetal
and maternal NOAEL was 20 mg/kg/day based on decreased fetal body weight
and delayed ossification; and decreases in maternal body weight gain at
75 and 200 mg/kg/day. The fetal effects were considered to be secondary
to maternal toxicity.

In rabbits, two preliminary developmental toxicity studies were
conducted in the Himalayan rabbit and a preliminary and regulatory study
were conducted in the New Zealand White (NZW) rabbit. All studies were
conducted using the Tox Reserve material.

In the first preliminary study, Himalayan rabbits were given oral doses
of 0, 100, 200 or 400 mg/kg/day. Mean maternal food consumption was
decreased throughout treatment at 400 mg/kg/day. The only fetal effect
possibly related to treatment was the observation of 2 fetuses at 400
mg/kg/day with the variation of “eyes small, slight”

In the second preliminary study, Himalayan rabbits were given oral doses
of 0, 600, 800 or 1000 mg/kg/day. Maternal food consumption was slightly
decreased at 1000 mg/kg/day. There was a small effect on male fetal body
weights and a higher incidence of flexed or malrotated limbs at 1000
mg/kg/day. The main treatment related fetal finding was the observation,
eyes of smaller than expected size, which occurred either as an
abnormality or variation. The combined incidence of small eyes
(abnormality and variation) was increased in all dose groups, but not in
a dose-related manner. It was concluded that administration of SYN520453
at 600-1000 mg/kg/day was associated with effects in the eye consistent
with microphthalmia.

A preliminary rabbit developmental toxicity study was conducted in NZW
rabbits at doses of 0, 400, 700 or 1000 mg/kg/day. Maternal toxicity was
noted at all dose levels tested, evident as decreased food consumption
and decreased maternal weight gain throughout the treatment period. The
effects were sufficient to produce moribundity and/or abortion in
animals from each dose group. Maternal liver weight was increased at all
doses and hypertrophy and vacuolation were observed histopathologically.
At 1000 mg/kg/day, there was an increase in the incidence of
microphthalmia which was associated with the variations hemorrhagic ring
around the iris and/or reddened or red areas around the eyes.

In the regulatory developmental toxicity study, NZW rabbits were dosed
at 0, 30, 150 or 500 mg/kg/day. The maternal NOAEL was 30 mg/kg/day
based on clinical signs of toxicity (days 13-19), decreased food
consumption, increased liver weights and hepatocellular hypertrophy and
vacuolation at 150 and 500 mg/kg/day. The fetal NOAEL was 150 mg/kg/day
based only on the single incidence of microphthalmia observed at 500
mg/kg/day. The single incidence of microphthalmia at 500 mg/kg/day was
within the historical control range for the laboratory. However, based
on the data from the NZW range-finding study, which was conducted in the
same laboratory, an association between treatment and the single
incidence of microphthalmia at 500 mg/kg/day cannot be excluded.

4. Subchronic toxicity. 

Subchronic testing was conducted in the mouse, rat, and dog via the oral
route of exposure, including evaluation of the effect of isomer content
of SYN520453. Three 28-day studies conducted in rats showed similar
findings and confirmed the liver was the systemic target organ for
SYN520453. Liver effects were evident at doses of 500 ppm and above with
no liver effects observed at 300 ppm (approximately 28.1 mg/kg/day). The
only other evidence of systemic toxicity was the observed decrease in
body weight gain compared to controls which tended to occur at dose
levels of 2000 ppm and above; observed in conjunction with decreased
food utilization. The study conducted with pure syn and anti-isomers
demonstrated equivalent toxicological properties from both a qualitative
and quantitative perspective.

Two 90-day dietary studies in rats demonstrated similar toxicological
findings to the 28-day studies. The NOAELs from the two 90-day studies
were similar; a NOAEL of 300 ppm (21.3 mg/kg/day) in the Tox Reserve
study, and a NOAEL of 250 ppm for both Tox Reserve and 70:30
specification materials in the comparative study; based on decreased
body weight/weight gain, clinical chemistry changes, increased liver
weight, and hepatocellular hypertrophy and vacuolation at 1500 and 2000
ppm respectively.

The 90-day dietary study in mice was conducted with Tox Reserve material
at 0, 500, 2500 or 7000 ppm. The systemic toxicity findings in this
study were decreased body weight/weight gain observed at 2500 & 7000
ppm. Increased liver weight was seen at all dose levels and hepatocyte
hypertrophy was seen in both sexes at 2500 and 7000 ppm. Minimal
hypertrophy was seen in males at 500 ppm.

Two 90-day oral toxicity studies were conducted in dogs; one was
conducted using Tox Reserve and the other with 70:30 material. In the
first 90-day study with Tox Reserve material, dogs were dosed orally at
0, 30, 100 or 300 mg/kg/day. In the second 90-day study with 70:30
material, dogs were dosed orally at 0, 10, 30 or 250 mg/kg/day. The
findings were similar, an overall NOAEL of 30 mg/kg/day was based
initial body weight loss and/or decreased weight gain and decreased food
consumption; and increased liver weights (males only) at 100 and 250
mg/kg/day. One male dog at the mid-dose of 100 mg/kg/day also displayed
abnormal clinical signs/behavior, some of which were evident throughout
the study.

	5. Chronic toxicity. 

SYN520453 was evaluated for chronic toxicity in the dog and rat, and for
carcinogenic potential in the rat and the mouse.

In the 1 year dog study with Tox Reserve, dogs were dosed orally by
capsule at 0, 25, 100 or 250 mg/kg/day. The NOAEL was 25 mg/kg/day based
on decreased body weight gain and minor changes in clinical chemistry,
and increased liver weight (males only) at 100 and 250 mg/kg/day. No
clinical signs of toxicity were observed in the 1 year dog study up to a
dose level of 250 mg/kg/day.

In a 2 year rat combined chronic toxicity/carcinogenicity study
conducted at dietary inclusion levels of 0, 100, 500 or 3000 ppm, there
were no treatment related effects on survival. The NOAEL for the chronic
toxicity phase of the study was 100 ppm and the NOAEL for neoplastic
findings was 500 ppm (27.6 and 34.9 mg/kg/day in males and females
respectively) based on increased incidence of hepatocellular adenoma and
uterine carcinoma observed as a consequence of excessive dosing in
females at 3000 ppm. The overall NOAEL was 100 ppm (5.5 and 6.9
mg/kg/day in males and females respectively)

based on decreased body weight/weight gain in females at 500 ppm; and
minor changes in clinical chemistry and non-neoplastic findings in the
liver at 500.

In a carcinogenicity study in the mouse, mice were fed diets containing
0, 70, 500 or 3500 ppm SYN520453 for a period of up to 80 weeks. There
were no treatment related effects on survival. Apart from an increased
incidence of „discharge from the eye‟ in males at 3500 ppm, there
were no effects on the clinical condition of the animals. There were no
treatment-related neoplastic micropathology findings. The NOAEL for this
study was 70 ppm (7.8 mg/kg/day in males and 9.9 mg/kg/day in females)
based on reduced food utilization in females at 500 ppm; and
hepatocellular hypertrophy and increased liver weight at 500 ppm.

	6. Animal metabolism. 

SYN520453 was extensively metabolized by rats via oxidation to give a
range of hydroxy, dihydroxy, acid and hydroxy acid metabolites.
Oxidation of the N-desmethyl metabolite of SYN520453 produced an
equivalent range of N-desmethyl metabolites. Incubation of SYN534969
(pure syn) with rat liver microsomes resulted in oxidative
biotransformation to the tertiary alcohol CSCD459488; quantities
decreasing with increased incubation time, demonstrating that the
metabolite CSCD459488 is a short-liver metabolite. The major routes of
biotransformation appeared to be independent of dose level and sex and
also appeared to be the same for both syn and anti isomers of the parent
molecule. All metabolites accounting for >5% of the dose and the
majority of minor metabolites were identified. Therefore in total,
greater than 90% of the administered dose was accounted for by
identified metabolites.

	7. Metabolite toxicology. 

Acute oral toxicity testing was performed with two metabolites;
resulting in LD50 >2000 mg/kg for both CSCD465008 and CSCD459488.
Genotoxicity testing (bacterial reverse mutation, in vitro cytogenetics,
and mammalian cell gene mutation (mouse lymphoma) with metabolites
CSCD465008 and CSCD459488 indicated no genotoxicity. Subchronic toxicity
studies (28 day dietary in the rat) were conducted with metabolites
CSCD465008 and CSCD459488. CSCD465008 is toxicologically benign and is
of lower toxicity than parent SYN520453. The metabolite CSCD459488 is
considered to have equivalent toxicity to parent SYN520453 with both
compounds having a NOAEL of 300 ppm (equivalent to approximately 27-28
mg/kg/day) and both compounds having a primary effect upon xenobiotic
metabolizing enzymes in the liver with accompanying liver enlargement
and centrilobular hypertrophy.

	8. Endocrine disruption. 

The endocrine system includes the reproductive hormones estrogen and
androgens as well as the thyroid hormone system. There is no evidence of
any consistent treatment related effects with SYN520453 that could be
considered as perturbation of endocrine homeostasis. There were no
adverse affects related to female reproductive function or on
reproduction in the multi-generation reproductive toxicity study, and
there were no micropathology changes in the organs that had altered
weight effects. Overall, the database does not suggest that SYN5204534
is an endocrine disruptor.

C. Aggregate Exposure

	1. Dietary exposure. 

Tier II acute, chronic, and chronic cancer dietary exposure assessments
were performed for isopyrazam using the using the Dietary Exposure
Evaluation Model (DEEM-FCID™ Version 4.02) from US EPA; consumption
data was from  the USDA NHANES “What We Eat in America” survey,
2005-2010.  The definition of the residue for tolerance enforcement
purposes is parent isopyrazam only (SYN534968 plus SYN534969), however
the residue-of-concern for risk assessment purposes includes parent
isopyrazam (SYN534968 and SYN534969) as well as metabolites CSCD459488
and CSCD459489 (syn- and anti-isomers of the tertiary alcohol
metabolite).  These assessments include all current uses (imported
bananas, imported apples, and imported peanuts) plus proposed new
import-only uses on tomatoes, peppers, and melons.  Field trial residue
data were used for apples, tomatoes, peppers, and melons. 
Experimentally determined processing factors were used for apple peeled
fruit (0.37X), apple dried fruit (5.9X), apple sauce (0.18X), apple
juice (0.03X), tomato paste (2.5X), tomato puree (2.3X), dried tomato
(3.7X), and tomato juice (0.15X).  All other processing factors used
DEEMTM Version 7.87 defaults.  One hundred percent crop treated (100%CT)
was assumed for all commodities except “apple, fruit with peel”
fresh market apples.  For unpeeled fresh market apples, an estimated %CT
value of 6.0% was used to conservatively express imported fresh market
apples as a percent of all apples available for consumption in the
United States 2010-2014 (domestic + imports - exports).  Since the
current and proposed uses are not expected to result in transfer of
residues to livestock via consumption of treated feedstuffs, anticipated
residues of isopyrazam in meat, milk, or egg commodities were not
included in these assessments.  Additionally, since there are no
registered uses for isopyrazam in the United States, dietary exposures
via drinking water (surface water and/or ground water) were also not
considered.   

	i. Food. 

Acute Exposure: Acute dietary (food only) risk assessments were
performed for all population sub-groups using an acute reference dose
(aRfD) of 0.30 mg/kg-bw/day, based upon a 90-day study in dogs with a no
observed adverse effect level (NOAEL) of 30 mg/kg-bw/day and an
uncertainty factor of 100X.  The 100X safety factor includes intra- and
inter-species variations; no additional FQPA safety factor was applied. 
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 NOAEL by the exposure for each population subgroup.  In
addition, exposure was expressed as a percent of the acute reference
dose (%aRfD).  At the 99.9th percentile, acute (food only) exposure to
the U.S. population resulted in a MOE of 5,225 or 1.9% of the aRfD
(Benchmark MOE = 100, aRfD = 0.3 mg/kg-bw/day).  The most exposed
sub-population was all children 1-2 years old, with a MOE of 2,085 or
4.8% of the RfD (Benchmark MOE = 100, aRfD = 0.3 mg/kg-bw/day).  Since
the benchmark MOE for this assessment was 100 and since the EPA
generally has no concern for exposures above the benchmark or below 100%
of the reference dose, Syngenta believes that there is a reasonable
certainty that no harm will result from dietary (food only) exposure to
residues arising from all current and proposed uses of isopyrazam.

Chronic Exposure: Chronic dietary (food only) risk assessments were
performed for all population sub-groups using a chronic reference dose
of 0.055 mg/kg-bw/day, based upon a 2-year study in rats with a no
observed adverse effect level (NOAEL) of 5.5 mg/kg-bw/day and an
uncertainty factor of 100X.  The 100X safety factor includes intra- and
inter-species variations; no additional FQPA safety factor was applied. 
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 NOAEL by the exposure for each population subgroup.  In
addition, exposure was expressed as a percent of the chronic reference
dose (%cRfD).  Chronic (food only) exposure to the U.S. population
resulted in a MOE of 57,836 or 0.2% of the cRfD (Benchmark MOE = 100,
cRfD = 0.055 mg/kg-bw/day).  The most exposed sub-population was
children 1-2 years old with a MOE of 18,617 or 0.5% of the cRfD
(Benchmark MOE = 100, cRfD = 0.055 mg/kg-bw/day).  Since the benchmark
MOE for this assessment was 100 and since the EPA generally has no
concern for exposures above the benchmark or below 100% of the reference
dose, Syngenta believes that there is a reasonable certainty that no
harm will result from dietary (food only) exposure to residues arising
from all current and proposed uses of isopyrazam.

A cancer dietary risk assessment was performed for the U.S. population,
with a carcinogenic potency factor (Q*) of 0.00629 (mg/kg bw/day)-1,
based on the presence of thyroid follicular cell tumors in male rats and
liver and uterine tumors in female rats at doses that were adequate to
evaluate the carcinogenic potential of isopyrazam.  Cancer exposure to
isopyrazam results in a risk of 5.98E-07, or approximately 60% of the
one-in-one-million lifetime cancer risk benchmark of 1.00E-06.  These
are slightly refined dietary exposure assessments, and Syngenta believes
that lifetime cancer risk to the U.S. population has not been
underestimated. 

	ii. Drinking water. 

The proposed import tolerances on tomato, pepper and cucumbers are not
expected to have an impact of drinking water. In addition, isopyrazam is
not currently registered for domestic uses; therefore, there is no
drinking water exposure contribution to the aggregate risk

.

	2. Non-dietary exposure. 

There are no currently registered residential uses for isopyrazam, so a
non-dietary residential exposure assessment was not conducted. 

D. Cumulative Effects

Cumulative Exposure to Substances with a Common Mechanism of Toxicity. 
Section 408(b)(2)(D)(v) 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”.  Syngenta did not perform a cumulative
risk assessment as part of this tolerance action for isopyrazam because
HED has not yet determined that there are any other chemical substances
that have a mechanism of toxicity common with that of isopyrazam.	

E. Safety Determination

	1. U.S. population. 

Using the conservative assumptions described above, and based on the
completeness and reliability of the toxicity data, the acute aggregate
(food only) exposure calculation for all current and proposed uses of
isopyrazam resulted in a MOE of 5,225 or 1.9% of the aRfD (Benchmark MOE
= 100, aRfD = 0.3 mg/kg-bw/day) for the U.S. population.  The chronic
aggregate (food only) exposure analysis showed that exposure from all
current and proposed uses of isopyrazam resulted in a MOE of 57,836 or
0.2% of the cRfD (Benchmark MOE = 100, cRfD = 0.055 mg/kg-bw/day). 
Since the worst case aggregate MOE 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 and chronic exposures arising
from all current and proposed uses of isopyrazam.

	2. Infants and children.

Using the conservative assumptions described above, and based on the
completeness and reliability of the toxicity data, the acute aggregate
(food only) exposure calculation for all current and proposed uses of
isopyrazam resulted in a MOE of 2,085 or 4.8% of the aRfD (Benchmark MOE
= 100, aRfD = 0.3 mg/kg-bw/day) for children 1-2 years old.  The chronic
aggregate (food only) exposure analysis showed that exposure from all
current and proposed uses of isopyrazam resulted in a MOE of 18,617 or
0.5% of the cRfD (Benchmark MOE = 100, cRfD = 0.055 mg/kg-bw/day) for
children 1-2 years old.  Since the worst case aggregate MOE 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 and
chronic aggregate exposures arising from all current and proposed uses
of isopyrazam. 

3. Aggregate Cancer Risk.  

The aggregate cancer risk assessment for the U.S. population using a
carcinogenic potency factor (Q*) of 0.00629 (mg/kg bw/day)-1 resulted in
a cancer risk of 5.98E-07, which is within the 1.00E-06
(one-in-one-million) level of concern set by the EPA.   

F. International Tolerances

Codex maximum residue levels (MRLs) have been established for residues
of isopyrazam in a number of commodities including banana, barley, rye,
triticale, wheat, and livestock commodities including meat, milk, and
eggs. 

	

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