Document ID: EPA-HQ-OPP-2013-0727-0008
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: 3E8204   

-methyl-α- L
-manno-pyranosyl)oxy]-13-[[5-(dimethylamino)-tetrahydro-6-methyl-2H-pyra
n-2-yl]oxy]-9-ethyl-2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16b-tetradecahyd
ro-14-methyl-1H-as-Indaceno[3,2-d]oxacyclododecin-7,15-dione; and
Spinosyn D (Factor D; CAS # 131929–63–0) or 2-[(6-deoxy-2,3,4-tri- O
-methyl-α- L
-manno-pyranosyl)oxy]-13-[[5-(dimethyl-amino)-tetrahydro-6-methyl-2H-pyr
an-2-yl]oxy]-9-ethyl-2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16b-tetradecahy
dro-4,14-methyl-1H-as-Indaceno[3,2-d]oxacyclododecin-7,15-dione] 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 0.02 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 1.0 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.

	The Agency has concluded that spinosad is considered toxicologically
identical to another pesticide, spinetoram. 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. Per the Federal Register: April 15, 1998 (Vol 63,
No 72) OPP-300644; FRL-5785-7, the nature of the residue of spinosad in
plants has been studied in several plants (apple, cabbage, cotton,
tomato and turnip) and is adequately understood.  EPA determined the
rotational crop study showed no carryover of measurable spinosad related
residues in representative test crops (lettuce, radish, and wheat). 
Tolerances for enforcement are established for spinosad based on the
residue definition of Spinosyn A (Factor A) plus Spinosyn D (Factor D).

	2. Analytical method. EPA has determined that adequate analytical
methods are available for enforcement purposes for spinosad residues in
plant and animal matrices.  Enforcement methods are available for
spinosad residues in a variety of plant matrices including; a number of
high-performance liquid chromatography (HPLC)/ultraviolet (UV), and
HPLC/MS (mass spectrometry) methods as well as various immunochemical
methods. For more details on relevant enforcement methods, 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. The IR-4 spinosad MOR trials in coffee  
DOCVARIABLE  Cr1lc  \* MERGEFORMAT  support tolerances of 0.2 ppm for
coffee, green bean and 0.4 ppm for coffee, instant and coffee, roasted
bean.  Residues of spinosad were determined following three foliar
applications at five field locations in Hawaii and Puerto Rico during
the 1999 and 2008 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 4 to 7 days apart and timed so that green coffee
beans were collected 7 days after the final application. Additionally,
in each trial, one site was treated with 0.7 lb ai/A per application for
a total of 2.1 lb ai/A per season; in 2008, green coffee beans from this
exaggerated application rate were processed to roasted beans and
freeze-dried coffee.  In the 1999 trials, spinosad residues were
determined by the Department of Environmental Biochemistry at the
University of Hawaii, Honolulu, HI using a procedure based on Dow
AgroSciences methods GRM 96.11 and GRM 96.11.S1.  In the 2008 trials,
spinosad residues were determined by the Department of Molecular
Biosciences & Bioengineering at the University of Hawaii, Honolulu, HI
using a procedure based on Dow AgroSciences method GRM 00.6.S3.  The
lowest level of method validation (LLMV) was 0.01 ppm in green coffee
beans in the 1999 trial and 0.1 ppm in the 2008 trial, and 0.018 ppm in
roasted beans and freeze dried coffee in the 1999 trial and 0.2 ppm in
the 2008 trial.  All spinosad residues were below the LLMV for the green
coffee beans treated at the target application rate of 0.156 lb ai/A and
for the processed coffee commodities.  In the 1999 trials at the
exaggerated rate, residues in green coffee beans ranged from 0.061 to
0.065 ppm.

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.   Per the Federal Register: April 15, 1998
(Vol 63, No 72) OPP-300644; FRL-5785-7, EPA determined the toxicological
profile and endpoints for spinosad are adequate for risk assessment
evaluations and determination of FQPA.  For recent spinosad decisions,
per Federal Register: December 5, 2007 (Volume 72, Number 233);
FRL-8339-8, EPA employed slightly revised endpoints based on their
decision that spinetoram is toxicologically identical to spinosad.  EPA
selected 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.  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 spinosad or spinetoram.

	2. Genotoxicity. Assays for genotoxicity consisting of a bacterial
reverse mutation assay (Ames test), and in vitro assay for cytogenetic
damage using the Chinese hamster ovary cells, an in vitro mammalian gene
mutation assay using lymphoma cells, an in vitro assay for DNA damage
and repair in rat hepatocytes, and an in vivo cytogenetic assay in the
mouse bone marrow (micronucleus test) have been conducted with spinosad.
 These studies show a lack of genotoxicity.

	3. Reproductive and developmental toxicity. Spinosad caused decreased
body weights in maternal rats given 200 mg/kg/day by gavage in a
developmental study (highest dose tested).  This was not accompanied by
embryotoxicity, fetal toxicity, or teratogenicity.  The
no-observed-adverse-effect levels (NOAELs) for maternal and fetal
toxicity in rats were 50 and 200 mg/kg/day, respectively.  A
developmental study in rabbits showed that spinosad caused decreased
body weight gain and two abortions attributed to inanition in maternal
rabbits at 50 mg/kg/day (highest dose tested).  Maternal toxicity was
not accompanied by either embryo toxicity, fetal toxicity, or
teratogenicity.  The NOELs for maternal and developmental effects in
rabbits were 10 and 50 mg/kg/day, respectively.  In a two-generation
reproduction study in rats, parental toxicity was observed in both males
and females given 100 mg/kg/day (highest dose tested).  Effects in the
offspring (decreased litter size and pup weight) at 100 mg/kg/day were
attributed to maternal toxicity.  The systemic and reproductive NOAELs
were both 10 mg/kg/day.  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 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 chronic reference dose (cRfD) of 0.0249 mg/kg/day for both
spinosad and spinetoram.  Spinosad is considered ``Not likely to be
Carcinogenic to Humans''.

	6. Animal metabolism. The nature of spinosad residue in animals is
understood based on livestock studies in ruminants (oral and dermal) and
poultry (oral) (DP # 316077, August 2, 2006).  ADME studies in rats
indicate spinosad is rapidly absorbed and extensively metabolized.  Also
the rat metabolism studies showed no major differences between the
bioavailability, routes or rates of excretion, or metabolism of Factor A
or Factor D.  Urine and fecal excretions were almost completed in
48-hours post-dosing.  In addition, the routes and rates of excretion
were not affected by repeated administration.  EPA recently indicated
that for fish/shellfish within the risk assessment estimates of the
total residue within edible tissues is applicable (EPA, DP # 316077,
August 2, 2006).  Total edible residues in fish have been extensively
characterized within BCF studies (MRID 43557601, 44557734, 47355801).

	7. Metabolite toxicology. Results of the plant and animal metabolism
studies and toxicity testing have been assessed.  Per Federal Register:
April 15, 1998 (Vol 63, No 72)  FRL-5785-7,  EPA concluded that the
spinosad metabolites/fermentation impurities (Factor B, Factor B of D,
Factor K, and other related Factors) were not of greater toxicological
concern than the two parent compounds.  Metabolite toxicity has been
addressed by establishment of the residue for tolerance purposes as the
parent materials.  In addition, for risk assessment purposes, the total
residue in water and edible fish is now conservatively considered.

	8. Endocrine disruption. There is no evidence to suggest that spinosad
has an effect on any endocrine system.

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 the spinosyns have 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

?

摧礨*ᘀ?

I

¾

Ò

hÂ

abase 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. 

Spinosad

Commodity	Existing MRLa

(ppm)	Regulatory Authority

Coffee beans	0.02	EU, Iceland, Norway, Switzerland

Coffee beans	*0.01	Australia

Coffee	0.2	Brazil

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

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