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-Has-indaceno[3,2-d]oxacyclododecin-7,15-dione, 2-[(6-deoxy-3-O-ethyl-2,4-di-O-methyla-L-mannopyranosyl)oxy]-13-[[(2R,5S,6R)-5-(dimethylamino)tetrahydro-6-methyl-2Hpyran-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-Lmannopyranosyl)oxy]-13-[[(2R,5S,6R)-5-(dimethylamino)tetrahydro-6-methyl-2Hpyran-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); NDJ:(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-dioxo2,3,3a,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-Oethyl-2,4-di-O-methyl-alpha-L-mannopyranosyl) oxy]-9-ethyl-14-methyl-7,15-dioxo2,3,3a,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 
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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; HumanHealth 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 
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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 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.”
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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 
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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 postapplication incidental oral risks for toddlers, based on applications to home lawns, home 

gardens and ornamentals. Additionally, short-term and intermediate-term postapplication incidental oral risks for toddlers were estimated based on a cat/kitten spot-on 

application.
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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.

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 <28% of the 

cPAD. Short-term post-application risks were estimated for toddlers, based on 

application to home lawns, home gardens, ornamentals, and pets and risks were not of 

concern given that resulting MOEs were >500. The resulting short-term aggregate MOE 

values were >300 and are, therefore, not of concern to HED. Intermediate-term postapplication risks were estimated for toddlers, based on application to pets and risks were 

not of concern given resulting MOEs were ≥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. 
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Spinetoram

Commodity Existing MRLa

(ppm)

Regulatory Authority

Coffee beans 0.1* EU

Coffee beans 0.01* Australia

a

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