Document ID: EPA-HQ-OPP-2013-0730-0007
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-12-07T05:00Z

EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING OF PESTICIDE
PETITION 

EPA Registration Division contact: Sidney Jackson (703) 305-7610 

Interregional Research Project Number 4 

Pesticide Petition Number: 3E8203   

	EPA has received a pesticide petition (3E8203) from Interregional
Research Project #4, Interregional Research Project #4 (IR-4), Rutgers,
The State University of New Jersey, 500 College Road East, Suite 201 W,
Princeton, NJ 08540 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 or revising the tolerances for
residues of the insecticide spinetoram, including its metabolites and
degradates.  Compliance with the tolerance levels is to be determined by
measuring 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 commodity coffee, green bean at 0.2 parts per million
(ppm), coffee, instant at 0.4 ppm, coffee, roasted bean at 0.4 ppm,
cottonseed subgroup 20C at 0.04 ppm, caneberry subgroup 13.07A at 0.7
ppm, bushberry subgroup 13-07B, except lingonberry at 0.25 ppm, fruit,
small, vine climbing, except fuzzy kiwifruit subgroup 13-07F at 0.5 ppm,
berry, low growing, subgroup 13-07G, except blueberry, lowbush, and
cranberry at 1.0 ppm, fruit, pome group 11-10 at 0.2 ppm, vegetable,
fruiting, group 8-10 at 0.4 ppm, fruit, citrus, group 10-10 at 0.3 ppm,
fruit, stone, group 12-12 at 0.2 ppm, onion, bulb, subgroup 3-07A at 0.1
ppm, onion, green, subgroup 3-07B at 2.0 ppm, nuts, tree, group 14-12 at
0.1 ppm, Quinoa, grain at 0.04 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.

	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. EPA has determined that adequate analytical
methods are available for enforcement purposes for spinetoram in plant
and animal matrices.  Adequate enforcement methods are available for
spinetoram residues in a variety of plant matrices including a number of
high-performance liquid chromatography (HPLC)/Mass Spectrometry (MS)/MS
methods. For more details on relevant enforcement methods for
spinetoram, see EPA Memorandum – “SUBJECT: Spinosad and Spinetoram;
Human-Health Assessment Scoping Document in Support of Registration
Review” dated August 9, 2011. 

	3. Magnitude of residues. IR-4 supports translation of the proposed
tolerances for spinosad in coffee, green bean, coffee, instant, and
coffee, roasted bean to spinetoram. Per the Federal Register of April
15, 1998 (63 FR 18329)(FRL-5785-7), EPA previously concluded that the
translation of spinosad residue data to spinetoram for crops was
acceptable due to the similar chemical structures, similar residue
levels for similar application rates, and the similar or lower
application rates of spinetoram relative to spinosad.  Translation of
spinosad processing factors to spinetoram has also been deemed
acceptable (EPA, DP# 325387, April 28, 2009).  Based on this, and the
similar proposed use patterns of spinosad and spinetoram in coffee (with
maximal use rates being lower for spinetoram than for spinosad), the
IR-4 spinosad MOR trials in coffee—summarized in a separate Notice of
Filing—support spinetoram tolerances of 0.2 ppm for coffee, green bean
and 0.4 ppm for coffee, instant and coffee, roasted bean.

IR-4 requests revisions to the following crop groups/subgroups based
upon established tolerances: onion, bulb subgroup 3-07A; onion, green
subgroup 3-07B; fruiting vegetable group 8-10; citrus fruit group 10-10;
pome fruit group 11-10; stone fruit group 12-12; caneberry subgroup
13-07A; bushberry subgroup 13-07B, except lingonberry; small fruit vine,
climbing subgroup, except fuzzy kiwifruit 13-07F; low growing berry
subgroup 13-07G, except blueberry, lowbush, and cranberry; tree nut
group 14-12; and cottonseed subgroup 20C.

B. Toxicological Profile.  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 in the subsections below.  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.  Under the new 40 CFR
Part 158 data requirements for spinosad/spinetoram, there are no missing
studies at this time. There was no evidence of increased pre- and
post-natal susceptibility based on prenatal developmental toxicity
studies (rat and rabbit) and 2-generation reproductive toxicity studies
(rat) with either spinosad or spinetoram. In addition, there was no
evidence of neurotoxicity in the toxicity database that included acute
and subchronic neurotoxicity studies with spinosad and an acute
neurotoxicity study with spinetoram. An immunotoxicity study has been
conducted with Spinosad and EPA’s initial review indicate the level of
concern for immunotoxicity is low (EPA, DP# 446932, August 9, 2011).

	1. Acute toxicity.  No appropriate endpoint attributable to a single
dose was identified; the EPA has not established an acute reference dose
(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
no-observed-adverse-effects level (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 chronic reference dose (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), it 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

	1. Dietary exposure. i. Acute exposure. No quantitative acute dietary
exposure assessment has been required for spinosad.

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.

	i. Food. The chronic dietary exposure assessment (EPA, DP#380915,
August 18, 2010) was recreated in Dietary Exposure Evaluation Model -
Food Consumption Intake Database (DEEM-FCID) (version 3.14) as a
starting point.  The new proposed tolerance values for coffee
commodities were included in this dietary assessment.  The EPA analysis
assumed 100% crop treated for many commodities, tolerance-level
residues, and default processing factors, but with several exceptions:
average field trial residues were applied for the cucurbit vegetables
(group 9), citrus (group 10), pome fruit (group 11), cereal grain (group
15), herbs (group 19a), spices except black pepper (group 19b), banana
and plantain, strawberry, and grape; average USDA Pesticide Data Program
(PDP) detected residues were applied for cherry and peach, with the
peach residues applied to fennel as well; experimental processing
factors were applied for corn meal, corn oil, corn flour, corn starch,
wheat flour, wheat germ, apple juice, raisin, and orange juice, with the
orange juice processing factor applied to all citrus juice.  Ruminant
and hog residues were estimated based on reasonably balanced dietary
burdens and extrapolation from a dermal pour-on study (a cancelled use)
to the registered premise application for estimation of residues
resulting from dermal absorption.  Poultry residues were also estimated
based on reasonably balanced dietary burdens and the premise
application.

	ii. Drinking water. Drinking water estimates were previously determined
based on EPA screening models and concentrations were directly entered
into the dietary exposure model. For spinosad, estimated environmental
concentrations (EECs) for chronic exposures are conservatively
calculated based on a total residue approach to be 10.5 ppb for surface
water using the First Index Reservoir Screening Tool (FIRST) and 1.1 ppb
for ground water using the Screening Concentration in Ground Water
(SCI-GROW) model (EPA, DP#331271, July 28, 2006).  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.  This
value was supported by a 2010 drinking water assessment in support of a
seed treatment use for spinosad (EPA, DP#377550, November 15, 2010).

	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 similar
pests, EPA concluded these products will not be used in combination with
each other and combining the residential exposures is unnecessary.  The
most recent residential exposure assessment was performed in 2011 (EPA,
DP# 446932, August 9, 2011), however in 2012, new “Standard Operating
Procedures (SOPs) for Residential Pesticide Exposure Assessment” were
released by EPA.  Residential exposure assessments have been updated to
reflect the new SOPs.  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.  Additionally,
short-term and intermediate-term post-application incidental oral risks
for toddlers were estimated based on a cat/kitten spot-on application.

D. Cumulative Effects

	EPA has not made a common mechanism of toxicity finding as to spinosad
and any other substances and spinosad 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 spinosad 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 most recent dietary assessment for
spinetoram/spinosad (EPA, DP#380915, August 18, 2010) and the
residential assessment has been updated to reflect current EPA
practices.  The additional exposure from the proposed coffee use is
estimated to be 0 to 0.02% of the cPAD.  Short-term, intermediate-term,
and chronic aggregate exposure estimates all resulted in MOEs that were
above the established Level of Concern (LOC) of 100.  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 (food and drinking water)
exposure estimates are not of concern to HED; exposure for the general
population is estimated as <11% of the cPAD.  When the dietary exposure
is summed with the estimated residential inhalation exposure, the
resulting short-term aggregate MOE value was approximately 1800.

≥700.  The resulting intermediate-term aggregate MOE values were >200
and are, therefore, not of concern to HED.

F. International Tolerances

	International MRLs are in place for spinetoram on coffee beans in the
EU and Australia.  The USDA MRL database, the third party database
Homologa, the EU SANCO website, the Australian MRL website, and the
Japan MRL website were queried for MRLs germane to this petition.  These
MRLs are listed to the best of our knowledge; no claim is made regarding
the verification of these values relative to the national authorities. 

Spinetoram

Commodity	Existing MRLa

(ppm)	Regulatory Authority

Coffee beans	0.1*	EU

Coffee beans	0.01*	Australia

athe * and T notations are direct translations from the country website
listings.

 

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