Document ID: EPA-HQ-OPP-2014-0285-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-12-17T05:00Z

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

EPA Registration Division contact: Susan Lewis and (703) 305-7090

Valent U.S.A. Corporation 

3E8182

EPA has received a pesticide petition ([3E8182]) from Valent U.S.A.
Corporation, 1600 Riviera Ave., Suite 200, Walnut Creek, CA  94596,
proposing, pursuant to section 408(d) of the Federal Food, Drug, and
Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by
establishing a tolerance for residues of mandestrobin (S-2200),
(2-[(2,5-dimethylphenoxy)methyl]-α-methoxy-N-methyl-benzeneacetamide)
in or on the raw agricultural commodity small fruit vine climbing except
fuzzy kiwifruit crop subgroup 13-07F, fruit at 5 parts per million
(ppm), juice at 7 ppm and dried fruit at 10 ppm; low growing berry
subgroup 13-07G, fruit at 3 ppm; and rapeseed crop subgroup 20A, seed at
0.6 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. The nature of residues in crops is well
understood.  Nature of the residue studies (OCSPP Harmonized Guideline
860.1300) were conducted in wheat, lettuce and oilseed rape as
representative crops in order to characterize the fate of S-2200 in all
crop matrices.  Two radiocarbon labeling positions were studied in each
crop, Phenoxy and Benzyl.  Plant metabolism studies have been presented
covering the crop categories of cereal/grass crop (wheat), pulses and
oilseeds (oilseed rape) and leafy crop (lettuce).  The route of
metabolism of S-2200 has been shown to be similar in the three crop
groups, with the extent of metabolism being greater at longer
pre-harvest intervals.  Parent S-2200 was a major component of the
residue in all crops.  Glycoside conjugates of 2-CH2OH-S-2200 and
glycoside and malonyl-glycoside conjugates of 4-OH-S-2200 were major
components of the residue in wheat and oilseed rape commodities, and
De-Xy-S-2200 was also a major component of the residue in wheat grain
and straw.  These metabolites were all found in the lettuce study, but
occurred at levels below 10% TRR.  In addition, glycoside conjugates of
5-CH2OH-S-2200 were observed in the rotational crops in the confined
rotational crop study.

	2. Analytical method. An independently validated analytical method has
been submitted for analyzing parent S-2200 residues with appropriate
sensitivity in all crop commodities for which tolerances are being
requested.

	3. Magnitude of residues. Field trials were carried out to determine
the magnitude of the residue in/on canola, grape and strawberry, and
canola and grape processed fractions.  The number and locations of field
trials were in accordance with OPPTS Guideline 860.1500.  Field trials
were carried out using the maximum label rates, the maximum number of
applications, and the minimum pre-harvest interval (PHI) proposed for
all the crops.  Tolerances are proposed for Small Fruit Vine Climbing
Except Fuzzy Kiwifruit Crop Subgroup 13-07F, fruit at 5 ppm, juice at 7
ppm and dried fruit at 10 ppm; Low Growing Berry Subgroup 13-07G, fruit
at 3 ppm; and Rapeseed Crop Subgroup 20A, seed at 0.6 ppm.  There was no
concentration of residues into the processed fractions of canola,
therefore no separate tolerances are proposed for those fractions.

B. Toxicological Profile

A complete, valid and reliable database of mammalian and genetic
toxicology studies has been submitted to EPA that supports the proposed
tolerances for S-2200 on Rapeseed Subgroup 20A, Small Fruit Vine
Climbing, Except Fuzzy Kiwifruit Subgroup 13-07F and Low Growing Berry
Subgroup 13-07G. 

	1. Acute toxicity.  The acute toxicity of technical grade S-2200 is low
by all routes. S-2200TG has a low oral, dermal and inhalation toxicity
to rats. It is considered a non-irritating to the eyes and skin and is
not a skin sensitizer. The battery of acute toxicity studies place
S-2200 in EPAToxicity Category III.  

	2. Genotoxicty. In an array of in-vitro and in-vivo genotoxicity
studies compliant with the most recent genetic toxicity testing
strategies, S-2200TG showed no evidence of genotoxicity.

	3. Reproductive and developmental toxicity. S-2200TG was examined in a
2 generation reproductive toxicity study in the rat and in developmental
toxicity studies in the rat and rabbit.  In the multigeneration study,
S-2200TG showed no evidence of an effect on fertility or reproductive
function.  In a gavage developmental toxicity study, administration to
pregnant rats at the limit dose elicited a slight reduction in food
consumption over the first 3 days of dosing only. Administration of
S-2200TG by oral gavage to pregnant rabbits elicited no systemic
toxicity to maternal female rabbits.  There was no evidence of
embryotoxicity or developmental effects at any dose level tested.

	4. Subchronic toxicity. S-2200TG was tested in short term repeat dose
dietary toxicity studies up to 90 days in the rat and mouse and up to 1
year in the dog.  Rats and mice tolerated limit doses (up to, or in
excess of, 1000 mg/kg bw/day) without obvious ill-health.  The target
organ in all species was the liver (weight increase and histological
hypertrophy).  Dogs tolerated the upper limit dose least well of the 3
species tested.  In dogs, high dose treatment resulted in marked
retardation of development and weight gain, increased liver weights,
histological pigmentation, centrilobular swelling and fibrosis, with
associated marked blood biochemical changes.  When dietary
concentrations were refined in the 52 week study effects were limited to
altered liver function.  Similar but lesser effects were seen in the rat
and drove the NOAEL in this species.  In addition in the rat, thyroid
follicular hypertrophy and hyaline droplet male nephropathy
(α2-µglobulin) were also seen. The modes of action with respect to the
thyroid follicular cell effects and male nephropathy are shown with
mechanistic studies and in the literature not to be relevant to the
human risk assessment. S-2200TG was not toxic to the immune system in
rats.  The mouse appeared to be the least sensitive species with
increased liver weights only.  S-2200TG elicited no signs of toxicity in
a 28 day repeat dose dermal toxicity study in rats up to the limit dose
of 1000 mg/kg bw day.

The potential for S-2200TG to cause neurotoxicity was assessed in acute
and subchronic neurotoxicity studies.  The only treatment-related
finding in the acute neurotoxicity study was a decrease in mean
locomotor activity, seen at 2000 mg/kg bw at 8 hours post-dose, and was
considered likely attributable to transient systemic toxicity rather
than typical neurotoxicity.  In a 90-day subchronic neurotoxicity study,
no evidence of specific neurotoxicity was found at up to 15,000 ppm. 
After 28 days dietary administration, S-2200TG was not toxic to the
immune system in rats.

	5. Chronic toxicity.  In the rat combined chronic toxicity and
carcinogenicity study the NOAEL was driven by decreased body weight
gain, decreased food consumption, alterations in the liver and changes
to blood biochemistry parameters. S-2200TG did not reveal any
carcinogenic potential.  An increased incidence of ovary sex-cord
stromal tumor (SCST) was observed in female rats.  But, the lesions are
unlikely to be direct effects of treatment with S-2200TG and are
considered not toxicologically significant.

In the mouse carcinogenicity study there were no effects on survival or
on the incidence or morphology of tumors to indicate any oncogenic
potential.  In the absence of adverse effects, the NOAEL was set at the
top dose.

	6. Animal metabolism. The absorption, distribution, metabolism and
elimination of [14C]S-2200 were investigated in rats at doses of 5 mg/kg
bw and 1000 mg/kg bw.  At the low dose absorption of S-2200 was rapid
and greater than 90%.  At the high dose, systemic exposure (AUC) to
S-2200 derived radioactivity was sub-proportional, indicating saturation
of absorption processes.  Radioactivity was widely distributed
throughout the body.  There was no evidence of accumulation into
tissues.  There were no significant sex or label differences in the
pharmacokinetic parameters.  Clearance from the plasma was almost
complete by 120 hours post-administration of 5 or 1000 mg/kg bodyweight.
 Excretion into expired air was negligible.  Fecal elimination, via the
bile, was the primary route of elimination.  However, renal elimination
was also important for the excretion of metabolites.  More than 70% of
radioactivity was eliminated within 48 hours of administration.  There
did not appear to be any gender-, dose- or radiolabel related
differences in rates or routes of excretion.  S-2200 was extensively
metabolised to numerous metabolites (unchanged parent formed <0.2% of
administered dose at low dose).  The primary routes of metabolism were
by oxidation and subsequent conjugation with glucuronic acid,
demethylation with subsequent oxidation, or oxidation with subsequent
demethylation.  There was generally no discernible shift in metabolism
at high or repeat doses except in the kidney.  Kidney metabolite
profiles exhibited both gender and repeat dose differences, in the type
and number of metabolites observed.  

	7. Metabolite toxicology. In appropriate assays, none of the
metabolites of S-2200:  2-COOH-S-2200, 5-COOH-S-2200, 2-CH2OH-S-2200,
4-OH-S-2200, nor De-Xy-S-2200 was considered to be mutagenic.  None of
the metabolites was classifiable for acute oral toxicity with the
exception of 5-COOH-S-2200 for which the LD50 lay between 300 and 2000
mg/kg bw.  All of the free metabolites/aglycones found in crops are also
found in the rat.  2-CH2OH-S-2200 and 5-CH2OH-S-2200 are considered to
be produced as the intermediates for 2-COOH-S-2200 and 5-COOH-S-2200. 
Therefore their toxicity is considered to have been adequately covered
by the toxicity studies performed on S-2200.    

	8. Endocrine disruption. Several special studies to evaluate the
potential endocrine effects of S-2200 have been conducted.  These
studies show no interaction with the estrogen receptor and
steroidogenesis by in vitro assays.   Additional in vivo studies include
an evaluation of the potential effects on reproduction and development,
and an evaluation of the pathology of the endocrine organs following
short- or long-term exposure.  These studies revealed no
endocrine-related effects.

C. Aggregate Exposure

	1. Dietary exposure. Dietary exposures from food and water were
considered for the petitioned uses on commercial/residential turf and
tolerances in or on the raw agricultural commodity Rapeseed Crop
Subgroup 20A, Small Fruit Vine Climbing Except Fuzzy Kiwifruit Crop
Subgroup 13-07F, fruit at 5 ppm; and Low Growing Berry Subgroup 13-07G,
fruit at 3 ppm as follows:  

	i. Food. Chronic dietary exposures to S-2200 Fungicide were calculated
using Dietary Exposure Evaluation Model DEEM-FCIDTM, Version 3.16. A
Tier I chronic dietary exposure assessment was conducted using
tolerance-level residues, 100% crop treated, and default processing
factors for processed commodities lacking supporting residue data.  As
S-2200 Fungicide is not acutely toxic, no quantitative assessment of
acute dietary exposure is required. For the chronic dietary assessment,
the chronic population adjusted dose (cPAD) of 0.19 mg/kg/day has been
calculated from the chronic toxicity endpoint using an uncertainty
factor of 100X to account for inter- and intra-species variability.

	ii. Drinking water. Estimated drinking water concentrations (EDWCs)
using the PRZM-GW model were included as part of the dietary exposure
assessment.  The maximum EDWC is from ground water and is estimated to
be 55.7 ppb based on the application of S-2200 Fungicide to turf at a
maximum seasonal application rate of 2 lb ai/acre/year (4 applications
at 0.5 lb ai/acre).  

	2. Non-dietary exposure. There is potential for short-term
post-application exposure to the general population from contact with
treated golf courses and residential turf.  The primary route of
exposure would be dermal, although non-dietary ingestion can be a route
for toddlers on treated lawns.  Using NOAEL’s from subchronic duration
dermal and oral toxicity studies of 1000 mg/kg/day and 91 mg/kg/day,
respectively, and default transfer coefficients, short-term residential
post-application margins of exposure were calculated and incorporated
into the non-dietary and aggregate risk assessment.

D. Cumulative Effects

FFDCA Section 408(b)(2)(D)(v) requires that the Agency must consider
“available information'' concerning the cumulative effects of a
particular pesticide's residues and ``other substances'' that have a
common mechanism of toxicity.  There are currently no available data or
other reliable information indicating that S-2200 Fungicide shares a
common mechanism of toxicity with any other substance.  Only the
aggregate exposure of S-2200 Fungicide has been considered in this risk
assessment.

E. Safety Determination

FFDCA section 408 provides that EPA shall apply an additional margin of
safety, up to ten-fold, for added protection for infants and children in
the case of threshold effects, unless EPA determines that a different
margin of safety will be safe for infants and children.  The
toxicological database for evaluating prenatal and postnatal toxicity
for S-2200 Fungicide is complete with respect to current data
requirements, and there are no special prenatal or postnatal toxicity
concerns for infants and children.  This therefore, warrants reducing
the FQPA Safety Factor for protection of infants and children to 1X.  

	1. U.S. population. Based on a highly conservative risk assessment,
Valent USA Corporation concludes that there is a reasonable certainty
that no harm will result to the general population from the aggregate
exposure to S-2200 Fungicide from the proposed uses.  The newly proposed
uses of S-2200 Fungicide result in an estimated dietary exposure to the
U.S. Population equivalent to 3% of the cPAD.   Chronic aggregate
exposures below 100% of the cPAD are generally considered to represent a
reasonable certainty of no harm to exposed populations.

	2. Infants and children. Based on a highly conservative risk
assessment, Valent USA Corporation concludes that there is a reasonable
certainty that no harm will result to infants and children from the
aggregate exposure to S-2200 Fungicide from the proposed uses.  The most
highly exposed subgroup is children 1-2 years of age with an estimated
dietary exposure equivalent to 13.3% of the cPAD.  Chronic aggregate
exposures below 100% of the cPAD are generally considered to represent a
reasonable certainty of no harm to exposed populations. When dietary
exposures are aggregated with non-dietary exposures from
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F. International Tolerances

There are no CODEX maximum residue levels (MRLs) established or proposed
for residues of S-2200 in Small Fruit Vine Climbing, Except Fuzzy
Kiwifruit Subgroup 13-07F, Low Growing Berry Subgroup 13-07G and
Rapeseed Subgroup 20A.  There are currently no tolerances for residues
of S-2200 in these crops in Canada or Mexico.  

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