Document ID: EPA-HQ-OPP-2008-0688-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-11-05T05:00Z

<EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  (7/1/2007)>

<EPA Registration Division contact: [George T. LaRocca, (703) 305-6100]>

 

<INSTRUCTIONS:  Please utilize this outline in preparing the pesticide
petition.  In cases where the outline element does not apply, please
insert “NA-Remove” and maintain the outline. Please do not change
the margins, font, or format in your pesticide petition. Simply replace
the instructions that appear in green, i.e., “[insert company
name],” with the information specific to your action.>

<TEMPLATE:>

<[Dow AgroSciences, LLC]>

<[Insert petition number]>

<	EPA has received a pesticide petition ([insert petition number]) from
[Dow AgroSciences, LLC], [9330 Zionsville Rd, Indianapolis, IN 46268]
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.>

<(Options (pick one)>

<<	1. by establishing a tolerance for residues of>>

<	2. to establish an exemption from the requirement of a tolerance for>

<	[the insecticide spinetoram, expressed as a combination of XDE-175-J:
1-H-as-indaceno[3,2-d]oxacyclododecin-7,15-dione,
2-[(6-deoxy-3-O-ethyl-2,4-di-O-methyl-a-L-mannopyranosyl)oxy]-13-[[(2R,5
S,6R)-5-(dimethylamino)tetrahydro-6-methyl-2H-pyran-2-yl]oxy]-9-ethyl-2,
3,3a,4,5,5a,5b,6,9,10,11,12,13,14,16a,16b-hexadecahydro
14-methyl-,(2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR); XDE-175-L:
1H-as-indaceno[3,2-d]oxacyclododecin-7,15-dione,
2-[(6-deoxy-3-O-ethyl-2,4-di-O-methyl-a-L-mannopyranosyl)oxy]-13-[[(2R,5
S,6R)-5-(dimethylamino)tetrahydro-6-methyl-2H-pyran-2-yl]oxy]-9-ethyl-2,
3,3a,5a,5b,6,9,10,11,12,13,14,16a,16b-tetradecahydro-4,14-dimethyl-,
(2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS);
ND-J:(2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl-14-methyl-13-[[(2S,5S
,6R)-6-methyl-5-(methylamino)tetrahydro-2H-pyran-2-yl]oxy]-7,15-dioxo-2,
3,3a,4,5,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-octadecahydro-1H-as-indac
eno[3,2-d]oxacyclododecin-2-yl
6-deoxy-3-O-ethyl-2,4-di-O-methyl-alpha-L-mannopyranoside; and NF-J:
(2R,3S,6S)-6-([(2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR)-2-[(6-deoxy-3-O-eth
yl-2,4-di-O-methyl-alpha-L-mannopyranosyl)
oxy]-9-ethyl-14-methyl-7,15-dioxo-2,3,3a,4,5,5a,5b,6,7,9,10,11,12,13,14,
15,16a,16b-octadecahydro-1H-as-indaceno[3,2-d]oxacyclododecin-13-yl]oxy)
-2-methyltetrahydro-2H-pyran-3-yl(methyl)formamide] in or on the raw
agricultural commodities [“Nut, tree, group 14”and “Pistachio”]
at [0.02] parts per million (ppm) and [“Almond, hulls”] at [3.5]
parts per million (ppm).  [A reduction to a 7 day PHI is also supported
with new MOR data.] 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 the residue in plants (turnip,
apple and lettuce) has been determined using radiolabeled spinetoram and
is adequately understood, per the EPA document entitled, ``Spinetoram:
Residue Chemistry Summary Concerning the Application of Spinetoram to
Numerous Crop'' dated August 9, 2007 (DP#325387).  Three metabolic
pathways are believed responsible for the breakdown of spinetoram in
plants.  The first involves changes to the N-demethyl moiety on the
forosamine sugar to give the N-demethyl and N-formyl metabolites; it is
believed photolysis plays a key role in this pathway.  The second
pathway involves cleavage of the macrolide ring system at one or more
positions and results in a complex residue mixture of numerous
components.  The third involves changes to the XDE-175-J only and
produces 3-O-deethyl and C9-pseudoaglycone (in apples) or the
C17-pseudoaglycone (in turnip tops). It is presumed the XDE-175-L
underwent degradation by the third pathway also, but too quickly to
allow detection of any metabolites.  Based on the plant metabolism
studies and the product ratio of 3:1 for XDE-175-J and XDE-175-L, HED
has established the residue of concern in plants for the purposes of
tolerances enforcement and risk as spinetoram (XDE-175-J and XDE-175-L)
plus the two metabolites: N-demethyl-XDE-175-J (also known as ND-J) and
N-formyl-XDE-175-J (also called NF-J).]>

<	2. Analytical method. [Per the Federal Register of October 10, 2007 ( 
HYPERLINK "http://www.epa.gov/EPA-PEST/2007/October/Day-10/p19947.htm" 
72 FR 57492 ) (FRL-8149-9), EPA has determined adequate analytical
methods are available for enforcement purposes for spinetoram in plant
and animal matrices.  The methods were noted as efficient and
well-documented.  The independent laboratory validation data were
acceptable.  Specific to the determination of residues for treenuts,
spinetoram  DOCVARIABLE  AI1TC  \* MERGEFORMAT   and its metabolites
were determined using liquid chromatography with positive-ion
atmospheric pressure chemical ionization tandem mass spectrometry
(LC/MS/MS) using the method GRM 05.04.  The limit of detection (LOD) and
limit of quantitation (LOQ) in almonds  DOCVARIABLE  Cr1lc  \*
MERGEFORMAT   and pecans were 0.003 ug/g  DOCVARIABLE  LOD  \*
MERGEFORMAT   and 0.01 ug/g  DOCVARIABLE  LOQ  \* MERGEFORMAT  ,
respectively.]>

<	3. Magnitude of residues. [The current tolerance for spinetoram in
tree nutmeats of 0.04 ppm was accomplished based on spinosad information
at a 14-day PHI.  New spinetoram specific MOR data provides grounds for
the establishment of a lower nutmeat tolerance of 0.02 ppm at a 7-day
PHI.

Dow AgroSciences conducted an MOR trial with a 7-day PHI.  The magnitude
of residues of spinetoram in almonds and pecans  DOCVARIABLE  Cr1lc  \*
MERGEFORMAT    DOCVARIABLE  Cr2lc  \* MERGEFORMAT   was determined
following four applications of spinetoram  DOCVARIABLE  AI1TC  \*
MERGEFORMAT   applied as GF-1640  DOCVARIABLE  FormNo1  \* MERGEFORMAT  
at a target rate of 0.11 lb ai/A.  Applications were on a 7-day
interval; normal harvest was 7 days after the last   DOCVARIABLE 
RTItext  \* MERGEFORMAT  application.  Six almond trials were conducted
at sites in California; six pecan trials were conducted across NAFTA
regions 2, 4, 6 and 8.  Spinetoram  DOCVARIABLE  AI1TC  \* MERGEFORMAT  
and its metabolites was determined using method GRM 05.04.

For pecans, only XDE-175-J was observed; no residues of the parent
XDE-175-L or metabolites were found.  Residues in pecan nutmeat ranged
from ND to a maximum of just above the LOQ, i. e. 0.0121 ppm.  For
almonds, with the exception of one observation of XDE-175-L, only
XDE-175-J was observed; no other residues of the parent XDE-175-L or
metabolites were observed; all residues in the almond nutmeats were
below the LOQ.  For almond hulls, the average residue concentrations
ranged from 2.29 to 0.61 ppm at the 7-day PHI.]>

<B. Toxicological Profile [Per ``Spinetoram: Human Health Risk
Assessment for Numerous Proposed Application Scenarios'' dated September
20, 2007 (DP#331741), EPA determined the toxicological profile and
endpoints for spinetoram are adequate for risk assessment evaluations
and determination of FQPA.  The toxicity database for spinetoram relies
on studies for spinetoram as well as studies for a similar spinosyn
insecticide, spinosad.  EPA concluded that spinetoram is toxicologically
identical to the pesticide spinosad “in the same manner that
metabolites are generally considered toxicologically identical to the
parent”.  Hence, EPA picked the lowest of the spinosad and spinetoram
endpoints for each exposure scenario.  HED’s Hazard Assessment and
Policy Committee noted that toxicologically equivalent does not imply a
cumulative assessment which involves the concepts of mechanism of
toxicity and potency.  The relevant information is summarized below.]>

<	1. Acute toxicity.  [No appropriate endpoint attributable to a single
dose was identified; the EPA has not established an acute RfD for
spinetoram.]>

<	2. Genotoxicty. [All mutagenicity studies conducted on spinetoram were
negative.]>

<	3. Reproductive and developmental toxicity. [EPA has concluded there
is no evidence of> increased susceptibility of rat and rabbit fetuses to
in utero exposure to spinetoram.  In the developmental toxicity study in
rats, no developmental effects were observed at dose levels that induced
maternal toxicity.  In the developmental study in rabbits, no
developmental toxicity was seen at dose levels that induced maternal
toxicity.  In the 2-generation reproduction study, no offspring toxicity
occurred.  Parental/systemic toxicity was observed at a lower dose than
the dose at which offspring showed no effects.  EPA has determined that
“reliable data show that it would be safe for infants and children to
reduce the 10x FQPA safety factor to 1x.”]

<	4. Subchronic toxicity. [Both Short-term endpoints (inhalation and
incidental oral) were established for spinetoram based on the Oral NOAEL
of 4.9 mg/kg/day from the subchronic feeding study in dogs with spinosad
and a LOC for MOEs of 100.]>

<	5. Chronic toxicity. [EPA used the lowest NOAEL of 0.249 mg/kg/day
from the chronic toxicity study in dogs for spinetoram and a 100X UF to
establish a cRfD of 0.0249 mg/kg/day.  Spinetoram is considered ``Not
likely to be Carcinogenic to Humans'' based on its similarity to
spinosad.]>

<	6. Animal metabolism. [From single and multiple dose ADME studies in
rats, it was estimated that the fraction of an orally administered dose
absorbed is 70% or greater for both isomers of spinetoram.  Fecal
excretion was the major route of elimination, while urine was a minor
route (10% or less of the absorbed dose).  At 168 hours post-dosing, the
radioactivity did not exceed 1% of the administered dose in any of the
analyzed tissues.  The majority of the radioactivity recovered for urine
and fecal extracts was present as parent plus several metabolites
including the glutathione and hydroxylated conjugates.  Livestock
metabolism studies conducted in the goat and hen were confirmatory that
excreta account for the majority of the recovered administered dose;
this especially true in the hen (91 to 93%).  In the hen, the highest
residues were observed in the fat followed by skin fat, liver, eggs and
muscle.]>

<	7. Metabolite toxicology. [Per the Federal Register of March 19, 2008
(Vol 73, No 54; FRL-8344-1), the results of the plant and animal
metabolism studies and toxicity testing have been assessed.  Metabolite
toxicity has been addressed by establishment of the total residue for
tolerance purposes as the parent materials XDE-175-J and XDE-175-L plus
the two metabolites: ND-J and NF-J.  Per the EPA Hunan Health Risk
Assessment for Spinetoram of Sept 20, 2007 (DP#331741), is was concluded
that the demethylated, deethylated and hydroxylated forms of the parent
are “highly unlikely” to be more toxic than the parent.]>

<	8. Endocrine disruption. [The EPA’s EDSP (Endocrine Disruptor
Screening Program) is still under development.  For now, the EPA has
concluded that “the NOAELs derived from the reproduction/fertility
study, are well defined and together with the 100X UF, will provide
adequate protection for potential endocrine effects.”]>

<C. Aggregate Exposure [The agency conducted an assessment of the
aggregate exposure for spinetoram in conjunction with the establishment
of the initial tolerances reported in the Federal Register of October
10, 2007 (  HYPERLINK
"http://www.epa.gov/EPA-PEST/2007/October/Day-10/p19947.htm"  72 FR
57492 ) (FRL-8149-9).  The EPA assumed toxicological equivalency of
spinosad and spinetoram in their aggregate exposure assessment. 
Anticipated exposure to spinetoram was deemed acceptable.  The proposed
lowering of the nutmeat tolerances in treenuts has negligible impact on
the dietary exposure.  An evaluation of the animal dietary burden
indicates no impact on the animal meat or milk tolerances.  No new
aggregate assessments are warranted.]>

<	1. Dietary exposure. [i. Acute exposure. No quantitative acute dietary
exposure assessment has been required for spinetoram. 

ii. Chronic exposure.  As previously stated, spinosad and spinetoram are
deemed toxicologically equivalent by EPA.  Based on the similarity of
the insecticides and the anticipated markets for each, it is unlikely
that spinosad and spinetoram will be applied to the same crop.  Hence,
EPA aggregated exposure by either assuming that all commodities contain
spinosad (because side-by-side spinosad and spinetoram residue data
indicated that spinetoram residues were less than or equal to spinosad
residues) or summing the percentage of a crop that would be treated with
spinosad and the percentage that would be treated with spinetoram.  The
approach of assuming 100 percent crop treated (PCT) was used for all
food commodities and the approach of summing the percent of commodities
projected to be treated with spinosad and spinetoram for feed
commodities.

Because almond hulls can be used as feed for livestock, an evaluation of
the potential impact of the almond hull tolerance to the animal dietary
burden was conducted.  The potential tolerance contribution of almond
hulls was determined to be 0.39 ppm (based on 10% dietary contribution
of 3.5 ppm and 90% DM).  

Higher values of other roughage components are already presumed in the
dairy diet (wheat forage, soybean forage and leaves of toot and tuber
vegetables), per the EPA Residue Chemistry Summary for Spinetoram of
August 9, 2007 (DP#325387).  There is no need to substitute almond hulls
into the dairy diet because the potential exposure is already adequately
represented by other feed commodities in the calculation.  There is no
need for a revision of the meat and milk animal commodity tolerances for
spinetoram.]>

<	i. Food. [The chronic dietary exposure assessment was recreated in
Dietary Exposure Evaluation Model - Food Consumption Intake Database 
(DEEM-FCID) (version 2.16) which incorporates the United States
Department of Agriculture (USDA) 1994-1996 and 1998 Continuing Surveys
of Food Intakes by Individuals (CSFII).  The residues of livestock were
refined through the incorporation of a refined dietary burden (average
field crop residues and projected PCT) with average milk residues for
spinosad from the ruminant dermal MOR study.  The analysis assumed DEEM
(ver 7.81) default processing factors for the majority of the food
commodities, 100% crop treated for all commodities and used average
field trial residues for several commodities: apple, leafy vegetables,
Brassica vegetables, citrus, fruiting vegetables, herbs, banana and
strawberry and tolerances values for all others.]>

<	ii. Drinking water. [Drinking water estimates were determined based on
EPA screening models and concentrations were directly entered into the
dietary exposure model.  For spinetoram, estimated environmental
concentrations (EECs) for chronic exposures are calculated to be 6.17
ppb for surface water using the First Index Reservoir Screening Tool
(FIRST) and 0.072 ppb for ground water using the Screening Concentration
in Ground Water (SCI-GROW) model.  However, for spinosad, average values
of 10.5 ppb for surface water and 1.1 ppb for ground water were
estimated based on additional uses.  Thus, for the joint chronic dietary
risk assessment, the water concentration value of 10.5 ppb was
conservatively used to assess the contribution to drinking water.]>

<

	2. Non-dietary exposure. [EPA has determined there is potential for
residential handler and post-application exposures to both spinosad and
spinetoram.  Because spinosad and spinetoram control the similar pests,
EPA concluded these products will not be used in combination with each
other and combining the residential exposures is unnecessary.  Per
Federal Register of October 10, 2007 (  HYPERLINK
"http://www.epa.gov/EPA-PEST/2007/October/Day-10/p19947.htm"  72 FR
57492 ) (FRL-8149-9), short-term residential inhalation risks were
estimated for adult residential handlers, as well as short-term
post-application incidental oral risks for toddlers, based on
applications to home lawns, home gardens and ornamentals.>

<D. Cumulative Effects>

<	[Federal Register of October 10, 2007 (  HYPERLINK
"http://www.epa.gov/EPA-PEST/2007/October/Day-10/p19947.htm"  72 FR
57492 ) (FRL-8149-9), EPA has not made a common mechanism of toxicity
finding as to spinetoram and any other substances and spinetoram does
not appear to produce a toxic metabolite produced by other substances. 
For the purposes of tolerance action, EPA has not assumed that
spinetoram has a common mechanism of toxicity with other substances.]>

<E. Safety Determination [Based on the assessment procedures described
earlier, the assessment results from Spinetoram: Human Health Risk
Assessment for Numerous Proposed Application Scenarios'' dated September
20, 2007 (DP#331741) covers the proposed actions of this petition.  Dow
AgroSciences concludes with reasonable certainty that no harm will
result to the general population or infants and children from the
aggregate exposure to spinetoram residues from registered uses.]>

<	1. U.S. population. [The resulting dietary exposure estimates are not
of concern to HED; exposure for the general population is estimated as
<35% of the cPAD.  When the food and water exposure is summed with the
estimated residential inhalation exposure for youth (over 12 years old)
and adults, the resulting short term aggregate MOE values range from 650
to 710.]>

<	2. Infants and children. [The resulting dietary exposure for the most
exposed subpopulation (children 1 to 2 years) is estimated as <81% of
the cPAD.  Short term post-application risks were estimated for
toddlers, based on application to home lawn, home gardens and
ornamentals and risks were not of concern given resulting MOEs were
>1200.  The resulting short term aggregate MOE values were >180 and are,
therefore, not of concern to HED.]>

<F. International Tolerances>

<	[There are currently no established CODEX, Canadian or Mexican maximum
residue limits (MRLs) for residues of spinetoram in/on various plant and
livestock commodities.  Based on a nomination from the U.S. delegation
to CODEX, the FAO/WHO Joint Meeting on Pesticide Residues (JMPR) will be
evaluating spinetoram data during 2008 to develop recommendations
supporting future establishment of CODEX MRLs.  The Agency notes that
spinetoram was evaluated as part of a joint review with Health Canada's
Pest Management Regulatory Agency (PMRA) and that in general the US
plant tolerances are based on translation of spinosad residue data
(i.e., translation of the spinosad tolerances).  The majority of the
spinosad plant tolerances were established prior to the use of the
tolerance spreadsheet calculator and the procedure used by EPA and PMRA
to establish these tolerances were different; therefore, many of the
plant tolerances are not harmonized with the Canadian MRLs although they
are based on the same residue data.  Since the EPA and PMRA spinetoram
tolerances are based on the same residue data, trade issues are not
expected to be an issue.  EPA harmonized the livestock tolerances with
the Canadian MRLs when possible.]>

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