[\<]{.mark}EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR
PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER
(7/1/2007)[\>]{.mark}

[\<]{.mark}EPA Registration Division contact: Laura Nollen, (703)
305-7390[\>]{.mark}

[\<]{.mark}Interregional Research Project #4 (IR-4)[\>]{.mark}

[\<]{.mark}Petition Number PP# 8E7450[\>]{.mark}

[\<]{.mark} 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-\[\[(2R,5S,6R)-5-(dimethylamino)tetrahydro-6-methyl-2H-pyran-2-yl\]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-\[\[(2R,5S,6R)-5-(dimethylamino)tetrahydro-6-methyl-2H-pyran-2-yl\]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-indaceno\[3,2-d\]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-\[(6-deoxy-3-O-ethyl-2,4-di-O-methyl-alpha-L-mannopyranosyl)
oxy\]-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.[\>]{.mark}

[\<]{.mark}*A. Residue Chemistry*[\>]{.mark}

[\<]{.mark} 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).[\>]{.mark}

[\<]{.mark} 2. *Analytical method.* Per the Federal Register of October
10, 2007 ([72 FR
57492](http://www.epa.gov/EPA-PEST/2007/October/Day-10/p19947.htm))
(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 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 and 0.01 ug/g,
respectively.[\>]{.mark}

[\<]{.mark} 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 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.[\>]{.mark}

[\<]{.mark}*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 [http://www.regulations.gov](http://www.regulations.gov/) in
docket EPA-HQ-OPP-2007-0310. Relevant information is summarized
below.[\>]{.mark}

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

[\<]{.mark} 2. *Genotoxicty.* All mutagenicity studies conducted on
spinetoram were negative.[\>]{.mark}

[\<]{.mark} 3. *Reproductive and developmental toxicity.* EPA has
concluded there is no evidence of[\>]{.mark} 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."

[\<]{.mark} 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.[\>]{.mark}

[\<]{.mark} 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.[\>]{.mark}

[\<]{.mark} 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.[\>]{.mark}

[\<]{.mark} 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.[\>]{.mark}

[\<]{.mark} 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."[\>]{.mark}

[\<]{.mark}*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 ([72 FR
57492](http://www.epa.gov/EPA-PEST/2007/October/Day-10/p19947.htm))
(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.[\>]{.mark}

[\<]{.mark} 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.[\>]{.mark}

[\<]{.mark} 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.)[\>]{.mark}

[\<]{.mark} 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.[\>]{.mark}

[\<]{.mark}

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 ([72 FR
57492](http://www.epa.gov/EPA-PEST/2007/October/Day-10/p19947.htm))
(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.[\>]{.mark}

[\<]{.mark}*D. Cumulative Effects*[\>]{.mark}

[\<]{.mark} Federal Register of October 10, 2007 ([72 FR
57492](http://www.epa.gov/EPA-PEST/2007/October/Day-10/p19947.htm))
(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.[\>]{.mark}

[\<]{.mark}*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.[\>]{.mark}

[\<]{.mark} 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. [\>]{.mark}

[\<]{.mark} 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 [\>]{.underline}180 and are, therefore,
not of concern to HED.[\>]{.mark}

[\<]{.mark}*F. International Tolerances*[\>]{.mark}

[\<]{.mark} 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
  ----------------------- ------------------------- ------------- --------

[\>]{.mark}