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 

EPA has received a pesticide petition (3E8204) 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 spinosad, including its metabolites and degradates. 

Compliance with the tolerance levels is to be determined by measuring only the two 

related active ingredients: Spinosyn A (Factor A: CAS # 131929–60–7) or 2-[(6-deoxy2,3,4-tri- O -methyl-α- L -manno-pyranosyl)oxy]-13-[[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,16btetradecahydro-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-pyran-2-

yl]oxy]-9-ethyl-2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16b-tetradecahydro-4,14-methyl-1Has-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
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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 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.
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B. Toxicological Profile. Per the Federal Register: April 15, 1998 (Vol 63, No 72) OPP300644; 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 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.
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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, 
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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.

D. Cumulative Effects

EPA has not made a common mechanism of toxicity finding as to spinosad and 
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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.

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

A variety of international and CODEX MRLs are in place for spinosad. 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. 

Spinosad

Commodity Existing MRLa

(ppm)

Regulatory Authority

Coffee beans 0.02 EU, Iceland, Norway, 

Switzerland

Coffee beans *0.01 Australia

Coffee 0.2 Brazil
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a

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