Document ID: EPA-HQ-OPP-2016-0537-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2016-11-30T05:00Z

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

EPA Registration Division contact: Heather Garvie, PM Team 24, (703)
308-0034

Syngenta Crop Protection, LLC, PO Box 18300, Greensboro, NC 27419

[Insert petition number]

	EPA has received a pesticide petition ([insert petition number]) from
Syngenta Crop Protection, LLC, PO Box 18300, Greensboro, NC 27419
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 a tolerance for residues of Sedaxane in or on the raw
agricultural commodities Grain, cereal, forage, fodder and straw, group
16 at 0.06 parts per million (ppm); Grain, cereal, group 15 at 0.01
parts per million (ppm); Peanut at 0.01 parts per million (ppm); and
Peanut, hay at 0.08 parts per million (ppm). Concurrently, Syngenta Crop
Protection, LLC requests to amend 40 CFR part 180.665 by removing
tolerances in or on Barley, grain at 0.01 ppm; Barley, hay at 0.04 ppm;
Barley, straw at 0.01 ppm; Corn, field, forage at 0.01 ppm; Corn, field,
grain at 0.01 ppm; Corn, field, stover at 0.01 ppm; Corn, pop, grain at
0.01 ppm; Corn, pop, stover at 0.01 ppm; Corn, sweet, forage at 0.01
ppm; Corn, sweet, kernel plus cob with husks removed at 0.01 ppm; Corn,
sweet, stover at 0.01 ppm; Oat, forage at 0.015 ppm; Oat, grain at 0.01
ppm; Oat, hay at 0.06 ppm; Oat, straw at 0.01 ppm; Rye, forage at 0.015
ppm; Rye, grain at 0.01 ppm; Rye, straw at 0.01 ppm; Sorghum, grain,
forage at 0.01 ppm; Sorghum, grain, grain at 0.01 ppm; Sorghum, grain,
stover at 0.01 ppm; Wheat, forage at 0.015 ppm; Wheat, grain at 0.01
ppm; Wheat, hay at 0.06 ppm; and Wheat, straw at 0.01 ppm upon approval
of the tolerances listed above. 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. Plant metabolism data were studied for corn,
wheat, soybean, Swiss chard, and canola to support the seed treatment
uses of sedaxane. Studies for all commodities reflected labeling in both
the phenyl and pyrazole rings. Application rates were equal to, or
exaggerations of the currently proposed use rates, and application
techniques reflect the requested use patterns.

The metabolic pathway in wheat, soybeans, and Swiss chard is
substantially similar. Radioactivity levels were too low from corn and
canola samples to elucidate the metabolic pathways in these crops.
Following seed treatment use of sedaxane in wheat, soybean, and Swiss
chard, sedaxane metabolism may be summarized as follows: 1) oxidative
metabolism of the phenyl and cyclopropane rings, 2) N-demethylation of
the pyrazole ring and 3) cleavage between pyrazole and phenyl rings.
Among the three crops studied, there is variation in the extent of the
three reaction processes and the nature of the observed conjugates
found.

The seed treatment data on the metabolism of sedaxane in wheat, soybean,
and Swiss chard demonstrate that residues are generally low, but do
translocate throughout the plants. The highest residues are generally
found in the foliage or forage portions of plants, and not in the seeds
or grains of these commodities. Crop field trial residue data were
consistent with the results of the plant metabolism studies.
Specifically, the magnitude of the residue studies showed no
quantifiable residues of sedaxane in any human food plant parts, but low
level residues were found in some livestock feedstuffs associated with
these plants.

	2. Analytical method. Various crops were analyzed for sedaxane (parent
only) using a procedure for analysis of sedaxane (SYN524464) that can
distinguish between its trans and cis isomers (SYN508210 and SYN508211).
Plant matrices using method GRM023.01A or modified method GRM023.01B are
taken through an extraction procedure with final determination by high
performance liquid chromatography with triple quadrupole mass
spectrometric detection (LC-MS/MS).

Method GRM023.01A (and therefore GRM023.01B, which uses the same
procedure) was validated on a range of plant commodities fortified with
the trans and cis isomers SYN508210 and SYN508211 at the proposed limit
of quantification (LOQ) of the method (0.005 mg/kg for SYN508210 and
SYN508211) and either at 10 times the LOQ or at the potential MRL.

The plant matrices included plants from each of the crop commodities
identified in OECD Guidance ENV/JM/MONO(2007)17, including wheat grain,
wheat straw, wheat whole plant, lentils, and oilseed rape seed as a few
of those crops tested. The mean SYN508210 and SYN508211 recoveries for
both primary quantification and confirmatory transitions at each
fortification level and overall for each crop commodity tested during
method validation were 76% – 102%. The limit of quantification for
SYN508210 and SYN508211 residues in crop commodities using method
GRM023.01A was established at 0.005 mg/kg.

	3. Magnitude of residues. Syngenta Crop Protection, LLC has submitted
complete residue data for peanut; peanut, hay; rice, grain; and rice,
straw.

B. Toxicological Profile

	1. Acute toxicity. Sedaxane has low acute toxicity by the oral, dermal
and inhalation routes. It is not a dermal sensitizer, causes no skin
irritation and only slight eye irritation.

	2. Genotoxicty. Sedaxane was negative (non-mutagenic) in an in vitro
bacterial reverse mutation assay, an in vitro gene mutation assay in
mammalian cells, an in vitro cytogenetics study, an in vivo unscheduled
DNA synthesis study, and an in vivo rat bone marrow micronucleus assay.

	3. Reproductive and developmental toxicity. Sedaxane was evaluated for
potential to cause effects on reproductive and developmental toxicity in
a multi-generation reproductive toxicity study in the rat and in
pre-natal developmental toxicity studies in the rat and rabbit. There
were no adverse effects on reproduction or fertility up to the top dose
level of 1500 ppm. Therefore this high dose represented the NOAEL for
reproductive toxicity.

There were no indications of any differences in sensitivity to sedaxane
between the different generations or between parental animals and
offspring. There were no adverse effects at a dose level of 500 ppm in
adults or pups, indicating that this was the NOAEL for parental and
offspring toxicity.

Data from both the rat and rabbit developmental toxicity studies with
sedaxane showed no potential for teratogenic effects, and the fetal
NOAEL values were equal to or higher than the maternal NOAEL values,
indicating a lack of sensitivity of developing offspring to the effects
of sedaxane.

	4. Subchronic toxicity. The short-term toxicity of sedaxane has been
evaluated by the oral route of administration in rats, dogs and mice. In
addition, dermal toxicity was evaluated in rats in a 28-day study.

Sedaxane is generally of a low order of toxicity in all species tested
in short term studies. Rats were slightly more sensitive to the general
systemic effects of sedaxane treatment than were dogs. Mice were
relatively non-responsive except at dose levels at a limit dose for
studies of this type (7000 ppm). A NOAEL of 28 mg/kg/day (300 ppm) was
achieved in the second 90-day rat study for female rats.

In rats, treatment-related effects were seen consistently in the liver,
indicating that this is a target organ for sedaxane. At dose levels of
2000 ppm and 1000 ppm in the 90-day rat studies, slight increases in
liver weight were seen in males and females, with no micropathological
findings. The increases are therefore consistent with adaptive changes
and were considered non-adverse. No effects on liver weights or
micropathology were seen at 250 or 300 ppm in these studies.

In male and female rats, increased incidence of thyroid follicular cell
hypertrophy was observed only at the 4000 ppm dose level in the second
90-day rat study. There were no effects in this organ in the first
90-day rat study. A chronic/carcinogenicity study in rats also showed
similar low level changes of follicular cell hypertrophy in male and
female rats after 52 weeks of treatment at 1200 and 3600 ppm dose
levels. Overall, the response in the thyroid of rats was relative mild
and was variable between studies and laboratories.

In dogs, liver weights were higher than control values in male and
female dogs after one year at 200 mg/kg/day, but in the absence of
micropathology findings this was considered non-adverse. In the 90-day
dog study, there were no effects on liver weights and no differences
from control animals in liver micropathology. There were no adverse
effects on the thyroid in any study in the dog including the 1 year
study. A NOAEL of 50 mg/kg/day was achieved in both the 90-day and
1-year dog studies, based on initially lower food consumption and
consistently lower cumulative bodyweight gains at 150 mg/kg/day and
higher. 

In mice, no adverse effects of treatment were observed in the 28-day
study at dose levels up to 7000 ppm. Decreased bodyweight gain and food
utilization were observed in male mice at 7000 ppm in the 90-day study,
but not in females. No micropathology changes were observed in either
study and the few differences in certain hematology, clinical chemistry
or organ weight values were inconsistent between the two studies and not
considered adverse. In the 90-day study, a NOAEL of 567 mg/kg/day (3500
ppm) was achieved in male mice.

In a 28-day dermal toxicity study in rats, no treatment-related effects
were observed at any dose level up to the limit dose of 1000 mg/kg/day.

In an acute neurotoxicity study in rats, no neuropathology was observed
at any dose level, and the NOAEL for neurotoxicity was 2000 mg/kg. The
NOAEL for general toxicity in this study was 30 mg/kg, based on effects
on body weight, food consumption, and clinical signs at 250 mg/kg. For
use in acute risk assessments, EPA derived an acute reference dose
(aRfD) of 0.30 mg/kg/day based on the NOAEL of 30 mg/kg from this acute
neurotoxicity study.

In a subchronic neurotoxicity study, sedaxane did not produce any
evidence of neurotoxicity in rats at dose levels of 0, 300, 1000 and
4000 ppm for 90 days. A NOAEL for general toxicity was observed at 1000
ppm, equivalent to 66.0/79.7 mg/kg/day in male and female rats,
respectively.

	5. Chronic toxicity. Sedaxane has been evaluated for chronic toxicity
in the rat and for carcinogenic potential in the rat and the mouse.

In a 2 year combined rat chronic toxicity/carcinogenicity study
conducted at dietary inclusion levels of 0, 200, 1200 and 3600 ppm,
there were no treatment related effects on survival. There was a marked
deficit in body weight gain at 3600 ppm which was evidenced throughout
the entire study. The extent of the body weight effect increased
substantially during the course of the study and by the end of the study
represented a 24% and 50% decrease in body weight gain in males and
females, respectively. The magnitude of the effect at 3600 ppm was
considered to be greater than that required for an adequate evaluation
of carcinogenic potential. At 1200 ppm, body weight gain was a maximum
of 11% lower than control in females, which was considered to be of
sufficient magnitude to provide a robust assessment of carcinogenic
potential. The NOEL was 200 ppm for both males and females, equating to
11 mg/kg/day in males and 14 mg/kg/day in females. The LOAEL was 1200
ppm.

In a carcinogenicity study in the mouse, groups of 50 male and 50 female
CD-1 mice were fed diets containing 0, 200, 1250 and 7000 ppm of
Sedaxane for a period of at least 80 weeks. There were no treatment
related effects on survival and no treatment-related clinical signs.
Effects at the LOAEL and above included decreased body weight and body
weight gain and food utilization in males and females. The NOAEL for
this study was 1250 ppm for both sexes, equating to achieved dose levels
of 157 mg Sedaxane/kg/day in males and 185 mg Sedaxane/kg/day in
females.

The EPA considered that sedaxane produced an increased incidence of
liver tumors and thyroid tumors in male rats, and uterine tumors in
female rats at the high dose of 3600 ppm. In the 18-month mouse study,
EPA considered that an increase in liver tumors in male mice was
treatment-related at the limit dose of 7000 ppm. Based on these results,
a Q1* value of 0.00464 (mg/kg/day)-1 was assigned for use in cancer risk
assessments with sedaxane. For non-cancer risk assessments of chronic
exposures, a chronic reference dose (cRfD) of 0.11 mg/kg/day was
assigned, based on the NOAEL of 11 mg/kg/day in the 2-year rat study.

	6. Animal metabolism. In both poultry and goat, the majority of the
dosed radioactivity was excreted (mainly in the feces of the goat) and
residues in tissues, milk and eggs were low. In the goat study, milk
residues reached plateau very rapidly, after just 2 days (reaching a
maximum of 0.045 mg/kg). Residues in eggs from the hen study reached a
plateau after approximately 9 days (reaching a maximum of 0.015 mg/kg in
egg white and 0.089 mg/kg in egg yolk).

	In both species, the highest tissue residues were observed in liver,
0.26 mg/kg in hen and 0.61 mg/kg in goat. Residues in muscle were <0.006
mg/kg and in fat were <0.016 mg/kg. In the goat kidney residues
represented <0.19 mg/kg.

	Metabolic profiles observed in livestock commodities and excreta arise
from just a few types of biotransformation. The principal routes of
metabolism are oxidation resulting in hydroxylation of the phenyl ring
or at the cyclopropane moiety. Additionally the same oxidations are
observed following demethylation of sedaxane. Overall results showed
that the biotransformation pathway of sedaxane in ruminants and poultry
is very similar to that observed in the rat.

	7. Metabolite toxicology. CSCD465008 (formed via cleavage of the
carboxamide link in the pyrazole labeled aerobic soil study) has been
assessed for acute oral toxicity, in vitro genotoxicity (Bacterial
reverse mutation, in vitro cytogenics and mammalian gene cell mutation)
and repeat oral toxicity for up to 28 days. CSCD465008 was not acutely
toxic by the oral route, not genotoxic in vitro and did not result in
any toxicologically significant effects at dose levels exceeding 1000
mg/kg-bw/day, the limit dose for a 28-day toxicity study in rats.

	8. Endocrine disruption. Sedaxane does not belong to a class of
chemicals known or suspected of having adverse effects on the endocrine
system. Furthermore, supporting developmental toxicity studies in rats
and rabbits, and a reproduction study in rats gave no indication of any
effects on endocrine function related to development and reproduction.
Subchronic and chronic treatment did not induce any morphological
changes in endocrine organs and tissues.

9. Immunotoxicity. A study was conducted, as specified in US EPA OPPTS
Guideline 870.7800, to provide information on suppression of the immune
system which might occur as a result of repeated exposure to a test
chemical.

Treatment of male CD-1 mice with sedaxane on a continuous basis in the
diet for a minimum of 28 days resulted in no suppression of the humoral
immune component of the immune system, based on an evaluation of the
spleen and thymus weights, spleen cell numbers, and the T-cell dependent
antibody response of splenocytes (antibody forming cell assay). The no
observed-effect level (NOEL) for suppression of the immune response in
male CD-1 mice offered sedaxane on a continuous basis in the diet for a
minimum of 28 days at 0, 500, 2000, and 5500 ppm was 5500 ppm
(equivalent to 1084 mg/kg/day). The only effect attributed to
sedaxane-treatment was a slightly higher mean adjusted liver weight for
the 5500 ppm group that was not considered adverse.

C. Aggregate Exposure

	1. Dietary exposure. Tier I acute, Tier III chronic and lifetime cancer
aggregate exposure assessments were performed for sedaxane (SYN524464),
a mixture of its cis- (SYN508210) and trans- (SYN508211) isomers using
the Dietary Exposure Model (DEEM-FCID™ Version 4.02, Evaluation Copy);
consumption data was from the USDA NHANES “What We Eat in America”
survey, 2005-2010. The definition of the residue for tolerance
enforcement and risk assessment purposes for crops is parent sedaxane
(SYN508210 plus SYN508211). Assessments were conducted for all current
uses and proposed seed treatment uses on peanut; grain, cereal, group
15; and grain, cereal, forage, fodder and straw, group 16. The Tier I
acute assessments incorporated established (40 CFR 180.665) or proposed
tolerances values for all crops where sedaxane was applied at the
maximum intended seed treatment use rate and crops harvested at the
minimum pre-harvest interval (PHI) to obtain the maximum expected
residues. Percent of crop treated (%CT) was conservatively assumed to be
100% for the acute assessments. The Tier III chronic assessments
incorporated field trial residue values where sedaxane was applied at
the maximum intended use rate and crops harvested at the minimum PHI to
obtain the maximum expected residues. Estimated %CT values were
incorporated into the Tier III chronic assessments based upon economic,
pest, and competitive pressures. Anticipated residues in meat, milk, and
eggs were estimated based on “maximum reasonably balanced diets” and
transfer information from goat and hen metabolism studies. Drinking
water estimates were selected using the higher of the estimated drinking
water concentrations (EDWCs) for surface and ground water.

	i. Food. Acute Exposure. Acute food-only risk assessments for parent
sedaxane (SYN508210 plus SYN508211) were performed for all population
sub-groups using an acute reference dose of 0.30 mg/kg-bw/day, based
upon a neurotoxicity study in rats 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). Acute food
exposure to the U.S. population resulted in a MOE of 222,615 (<0.1% of
the aRfD of 0.30 mg/kg-bw/day). The most exposed sub-population was
children (1-2 years old) with a MOE of 102,772 (0.1% of the aRfD of 0.30
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 acute food exposures
to residues arising from all current and proposed uses of sedaxane.

Chronic Exposure. Chronic food-only risk assessments for parent sedaxane
(SYN508210 plus SYN508211) were performed for all population sub-groups
using a chronic reference dose of 0.11 mg/kg-bw/day, based upon a
chronic rat study with a no observed adverse effect level (NOAEL) of 11
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 exposure to the U.S.
population resulted in a MOE of 359,417 (<0.1% of the cRfD of 0.11
mg/kg-bw/day). The most exposed sub-population was children (1-2 years
old) with a MOE of 138,273 (0.1% of the cRfD of 0.11 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 chronic food exposures to
residues arising from all current and proposed uses of sedaxane.

Cancer Risk from Food. Lifetime cancer food risk from sedaxane was
evaluated by comparing exposures to a Q1* value of 0.0046
(mg/kg-bw/day)-1 based on two rodent carcinogenicity studies. Lifetime
cancer food risk for the U.S. population was 1.43 x 10-7. The EPA’s
Benchmark range for lifetime cancer risks is 1 x 10-6 or less to be
negligible. Since the EPA generally has no concern for exposures at or
below the benchmark range, Syngenta believes that there is a reasonable
certainty that no harm will result from lifetime cancer food exposures
to residues arising from all current and proposed uses of sedaxane.

	ii. Drinking water. The estimated drinking water concentrations (EDWCs)
of sedaxane total toxic residues (TTR), a mixture of sedaxane and its
degradates (CDCD668094 and CDCD668095), were derived from Tier I
Screening Concentration In GROund Water (SCI-GROW v2.3) and Tier II
Pesticide Root Zone Model for Ground Water (PRZM-GW v1.07) for ground
water, Tier I FQPA Index Reservoir Screening Tool (FIRST v1.1.1) and
Modified Tier 1 Rice model for surface water from terrestrial and
aquatic uses, respectively. Model simulations included currently
registered uses and the proposed seed treatment uses on peanut; grain,
cereal, group 15; and grain, cereal, forage, fodder and straw, group 16.
The highest EDWC for ground water, generated from Tier II PRZM-GW based
on the registered seed treatment use on potato, was 0.32 ppb for acute
and chronic exposure durations. The highest EDWCs for surface water,
generated from Modified Tier I Rice Model modelling of the proposed seed
treatment use of sedaxane on rice grains, were 15.2 ppb and 13.5 ppb for
acute and chronic exposure durations, respectively. Percent cropped area
(PCA) adjustment factor of 0.91 was applied to the surface water EDWCs.
The acute and chronic surface water EDWCs were used for risk assessment
purposes and will be considered protective for any ground water exposure
concerns.

Acute Exposure from Drinking Water. The acute surface water EDWC of 15.2
ppb was input directly into the DEEM-FCID™ software as “water,
direct and indirect, all sources” to model the acute drinking water
exposures. Exposure contributions at the 95%-ile of exposures were
determined by taking the difference between the aggregate (food +
drinking water) exposures and the food (alone) exposures for each
population subgroup. Acute drinking water exposure U.S. population
resulted in a MOE of 40,268 (0.2% of the acute RfD of 0.30
mg/kg-bw/day). The most exposed sub-population was all infants (<1 year
old) with a MOE of 10,965 (0.9% of the acute RfD of 0.30 mg/kg/day).
Since the benchmark MOE for this assessment was 100 and since EPA
generally has no concern for exposures below 100% of the acute RfD,
Syngenta believes that there is a reasonable certainty that no harm will
result from acute drinking water exposure to residues arising from the
current and proposed uses for sedaxane.

Chronic Exposure from Drinking Water. The chronic surface water EDWC of
13.5 ppb was input directly into the DEEM-FCID™ software as “water,
direct and indirect, all sources” to model the chronic drinking water
exposures. Chronic drinking water exposure to the U.S. population
resulted in a MOE of 40,329 (0.2% of the chronic RfD of 0.11
mg/kg-bw/day). Chronic drinking water exposure to the most exposed
sub-population (infants, <1 year old) resulted in a MOE of 10,796 (0.9%
of the chronic RfD of 0.11 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 chronic RfD, Syngenta believes that there is
a reasonable certainty that no harm will result from chronic drinking
water exposure to residues arising from the current and proposed uses
for sedaxane.

	2. Non-dietary exposure. There are no currently registered residential
uses for sedaxane, 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 sedaxane because
HED has not yet determined that there are any other chemical substances
that have a mechanism of toxicity common with that of sedaxane.

E. Safety Determination

	1. U.S. population. The acute aggregate exposure analysis (food plus
water) for all current and proposed uses of sedaxane resulted in a MOE
of 34,079 for the U.S. population (0.3% of the aRfD of 0.30
mg/kg-bw/day) which exceeds the Benchmark MOE of 100. The chronic
aggregate exposure analysis (food plus water) for all current and
proposed uses of sedaxane resulted in a MOE of 36,260 for the U.S.
population (0.2% of the cRfD of 0.11 mg/kg-bw/day) which exceeds the
Benchmark MOE of 100. 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 occur to the U.S. population
from acute and chronic aggregate exposures arising from all current and
proposed uses of sedaxane. The lifetime cancer risk analysis for all
current and proposed uses of sedaxane resulted in a lifetime cancer risk
estimate of 1.4 x 10-6 for the U.S. population. The EPA generally
considers cancer risk in the range of 10-6 or less to be negligible. The
precision that can be assumed for cancer risk estimates is best
described by rounding to the nearest integral order of magnitude on the
log scale. Considering the precision with which cancer hazard can be
estimated, the conservativeness of low-dose linear extrapolation, and
the described rounding procedure, cancer risk is generally not assumed
to exceed the benchmark level of concern of the range of 10-6 until the
calculated risk exceeds approximately 3 x 10-6 (80 FR 43323). Based on
this approach, Syngenta considers the risks of cancer from exposure to
be negligible.

	2. Infants and children. The acute aggregate exposure analysis (food
plus water) for all current and proposed uses of sedaxane resulted in a
MOE of 10,221 (1.0% of the aRfD of 0.30 mg/kg-bw/day) for the most
sensitive population subgroup, all infants, which exceeds the Benchmark
MOE of 100. The chronic aggregate exposure analysis (food plus water)
for all current and proposed uses of sedaxane resulted in a MOE of
10,265 (0.9% of the cRfD of 0.11 mg/kg-bw/day) for the most sensitive
population subgroup, all infants, which exceeds the Benchmark MOE of
100. 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 exposure to residues arising from all current and proposed
uses of sedaxane.

F. International Tolerances

	Codex maximum residue levels (MRLs) have been established for residues
of sedaxane on cereals, rape seed, soya bean (dry) and animal
commodities.

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