 

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

<EPA Registration Division contact: Laura Nollen, (703) 305-7390>

 

<Interregional Research Project #4 (IR-4)>

<Petition Number PP# 8E7450>

<	EPA has received a pesticide petition PP# 8E7450 from Interregional
Research Project #4 (IR-4), 500 College Road East, Suite 201 W,
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 180.635 by establishing a tolerance for residues of 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 pineapple at 0.02 parts per million (ppm),
pomegranate at 0.3 ppm, date at 0.1 ppm, Spice, subgroup 19B, except
black pepper at 1.7 ppm, hop, dried cones at 22 ppm, and pineapple,
process residue at 0.08 ppm.  Additionally, the petition proposes to
increase the levels of existing tolerances for Nut, tree, group 14 and
Pistachio from 0.04 to 0.08 ppm and Almond, hulls from 2.0 ppm  to
9.0ppm. A reduction to a 1-day PHI is proposed based on new MOR data for
the increased tolerances in tree nuts. 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. 

It is also noted that the Agency has concluded that spinetoram should be
considered toxicologically identical to another pesticide, spinosad.
This conclusion is based on the following: (1) Spinetoram and spinosad
are large molecules with nearly identical structures; and (2) the
toxicological profiles for each are similar (generalized systemic
toxicity) with similar doses and endpoints chosen for human-health risk
assessment. Spinosad and spinetoram should be considered toxicologically
identical in the same manner that metabolites are generally considered
toxicologically identical to the parent.>

<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) supported by DP # 325387, August 9, 2008, 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.  Spinetoram  DOCVARIABLE  AI1TC  \*
MERGEFORMAT   and its metabolites are determined using liquid
chromatography with positive-ion atmospheric pressure chemical
ionization tandem mass spectrometry (LC/MS/MS).  The limit of detection
(LOD) and limit of quantitation (LOQ) in crop and animal matrices are
typically 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 bridging to spinosad at a
14-day PHI.  The revised tree nut proposal is supported by bridging to a
new IR-4 spinosad MOR study in almonds with a 1-day PHI and the recently
submitted Dow AgroSciences spinetoram MOR decline trial in almonds and
pecans with a 1-day PHI time point (MRID 47468301).

The IR-4 spinosad MOR trial in almonds   DOCVARIABLE  Cr1lc  \*
MERGEFORMAT  supports a 1-day PHI.  Residues of spinosad were determined
following three foliar applications at five field locations in
California during the 2003 and 2004 growing seasons.  Spinosad was
applied at a target rate of 0.156 lb ai/A, for a total of approximately
0.468 lb ai/A.  Applications were made 6 to 7 days apart and timed so
that mature hulls and nutmeat were collected at both 1 and 3 days after
the final application (except at one trial at 4 days after application
due to rainfall.)  Spinosad residues were determined by the IR-4 Western
Region Satellite Laboratory using a procedure derived from Dow
AgroSciences method GRM 96.14.  The lowest level of method validation
(LLMV) was 0.02 ppm.  All spinosyn D residues were below the LLMV for
the nutmeats.  Spinosyn D residues in the hulls ranged from 0.0367 to
0.689 ppm for the 1-day PHI.  Spinosyn A residues in nutmeat ranged from
<0.02 to 0.0467 ppm.  Spinosyn A residues in the hulls ranged from 0.255
to 4.42 ppm for the 1-day PHI.

From the Dow AgroSciences decline trial, spinetoram residues at 1-day
PHI were determined as 0.008 and 0.011 ppm in the almond nutmeats; in
pecan nutmeat, residues were noted as 0.01 and 0.011 ppm.  Almond hulls
residues at the 1-day PHI for total spinetoram were determined as 1.6
and 1.7 ppm.  The almond hull residue contained contributions from both
parent and metabolites.

The IR-4 MOR data supports a reduction of the PHI for spinosad to 1-day
in almonds and pistachios with a tolerance of 0.08 ppm in the nutmeats
and 9.0 ppm for the almond hulls.  The 1-day data point within the
decline study for spinetoram provides evidence that bridging the
spinosad action to spinetoram is reasonable.  Final rationale for the
full tree nut group at 1-Day PHI for spinetoram is provided by a
combination of data from four studies conducted on almonds and/or pecans
treated with spinosad or spinetoram.  The data shows that the magnitude
of residues on pecans is not dissimilar from residues on almonds and
that residues of spinetoram are typically lower than spinosad on tree
nuts.  Thus, residue data presented for spinosad allows bridging to
spinetoram and almond data from these studies allows for bridging to
pecans.

IR-4 supports bridging from spinosad uses to spinetoram for: hops,
spices and pineapple.  In EPA’s previous 2007 joint dietary assessment
of spinosad/spinetoram, hop and pineapple and spices are already
included based on values for spinosad.  

IR-4 supports bridging from the established spinetoram tolerance for
avocado to pomegranate.  This translation is consistent with the
on-going discussions for crop grouping schemes between IR-4, USDA and
EPA.   Pomegranate is scheduled to be placed into the inedible peel
smooth skin except papaya and banana tropical fruit crop subgroup E and
the representative crop for this subgroup will be avocado.

IR-4 requests that California (EPA Region 10) plum data for spinosad be
bridged to dates for spinetoram.  This request for dates is congruent
and lower than the established spinetoram tolerance for “Fruit, Stone,
group 12”.  The use pattern for dates will be the same as for plums. 
Five trials were conducted in California by Dow AgroSciences and
submitted to EPA (PP No. 8F5002, MRID No. 44597716). Three trials were
on plum and two trials were on prune type plums.  The plum residues
ranged from ND to 0.014 ppm with an average residue of 0.003 ppm. The
fresh prune-type plum residues ranged from 0.04 to 0.08 ppm with an
average of 0.063 ppm. The dried prune-type plum residues ranged from
0.03 to 0.08 ppm with an average of 0.058 ppm.  Concentration of
spinosad into dried prune type plums was not detected.>

<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”.  EPA picked the lowest of the spinosad and spinetoram
endpoints for each exposure scenario.  A summary of the toxicological
endpoints for spinosad and spinetoram used for human risk assessment can
be found at   HYPERLINK "http://www.regulations.gov" 
http://www.regulations.gov  in docket EPA-HQ-OPP-2007-0310.  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 exposure
in pineapple, spices and hop was already included based on previous
spinosad uses.  The proposed changes for nutmeat tolerances and the
addition of dates and pomegranate have an extremely small 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.  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.

Pineapple process residue and almond hulls are potential cattle feed
items. However, a comparison of their potential tolerance contribution
to the higher values of other roughage commodities already assumed in
the theoretical animal dietary burden calculations indicates there is no
need to substitute almond hulls or pineapple, process residue into the
spinetoram cattle diets.  The potential exposure is already adequately
represented by other feed commodities in the calculation.  Thus, there
is no need for a revision of the meat and milk animal commodity
tolerances for spinetoram.>

<	i. Food. The chronic dietary exposure assessment (EPA, DP#33531,
September 12, 2007) 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 many food commodities, EPA specified processing
factors for corn, grape, and wheat, 100% crop treated for food
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, except fish/shellfish which were conservatively
represented as 12.5 ppm (3X fold of the 4 ppm tolerance for spinosad.)>

<	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
conservatively estimated based on additional uses.  Thus, for the joint
chronic dietary risk assessment, EPA has used the water concentration
value of 10.5 ppb 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
spinosad/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. 
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.  For the
purposes of tolerance action, it is not assumed that spinetoram has a
common mechanism of toxicity with other substances.>

<E. Safety Determination The proposed actions of this petition have been
added via DEEM to EPA’s initial assessment for spinetoram/spinosad
(EPA, DP#33531, September 12, 2007).  The addition exposure is estimated
to be <0.1% of the cRfD.  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
these 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. EPA has determined that reliable data allow a
reduction of the FQPA safety factor to 1X for 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.  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.

In addition, the third party database Homologa was queried for MRLs
germane to this petition.  IR-4 makes no claim regarding the
verification of these values relative to the national authorities. 

EU Harmonized	Spices	0.1	PPM

EU Harmonized	NUTS	0.05	PPM

EU Harmonized	POMEGRANATE	0.05	PPM

EU Harmonized	DATE	0.05	PPM

EU Harmonized	HOPS	0.1	PPM

EU Harmonized	PINEAPPLE	0.05	PPM

>

 PAGE   

 PAGE   8 

