UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: 

Subject: 

From: 

Through: 

To: 

I O-March-2015 

Spinosad and Spinetoram - Human Health Risk Assessment to Support the 

Section 3 Registration Request for Application to Coffee; Label Amendments for 

Plum/Prune and Brassica (Cole) Leafy Vegetables Crop Group 5; and Updates to 

Several Crop Group/Subgroup Commodity Definitions. 

PC Codes: I 10008 and I I 0003 DP Barcodes: 0415812, 0415814, 0420288, 0420289, 

0420291 

Decision Nos.: 483225, 483254, 490184, Registration Nos.: 62719-541 , 62719-545, and 62719-621 490185,490186 

Petition Nos.: 3E8203 and 3E8204 Regulatory Actions: Section 3 Registrations; Label 

Amendments 

Risk Assessment Type: au!?.regate Case Nos.: 7448 and 7421 

TXR No.: not aoolicable CAS Nos.: 187166-40-1, 187166-15-0, and 131929-60-7 

MRJD Nos.: not aoolicable 40 CF'R: 180.495 and 180.635 

Tom Bloem, Chen~~""'::. . 

Jennifer 

Monique 

R. 

M. 

Ty

Perron

ler, Chemist 

, Sc.D.,fix~1co giJk- K-- W--~ ~ 

Risk Assessment Branch 1 BI , ealt~fe:_.ts2~is ~~ED, 7509P) 

Thruston Morton, Acting Branch Chief .IL//~ George F. Kramer, Ph.D., Senior Chem~5'7 ::!:~ RABl/HED (7509P) 

Barbara Madden/Sidney Jackson, RM 5; Richard Gebken/Olga Oddiott (RM l 1) 

Registration Division (RD; 7505P) 

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human 

health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and 

exposure data and conduct dietary, occupational, residential, and aggregate exposure 

assessments, as needed, to estimate the risk to human hea lth that will result from the proposed 

use of spinosad and spinetoram. A summary of the findings and an assessment of human health 

risk resulting from the proposed/registered uses of spinosad and spinetoram are provided in this 

document. The risk assessment, residue chemistry. and dietary exposure assessment were 

provided by Tom Bloem (RAB 1), the hazard characterization by Monjque Perron (RAB 1), the 

occupational/residential exposure (ORE) assessment by Jenni fer Tyler (RAB 1 ), and the drinking 

water assessment by Larry Liu of the Environmental Fate and Effects Division (EFED). 

Page I of 45 
Spinosad and Spinetoram Human Health Risk Assessment 041581 2 

Table of Contents 

1.0 EXECUTIVE SUMMARY ....................................................................................................................................................... 3 

2.0 RECOMMENDATIONS ........................................................................................................................................................... 6 

2.1 Data Deficiencies/Data ccds ............................................................................................................................................. 6 

2.2 Tolerance Considerations .................................................................................................................................................... 6 

2.2. I Enforcement Analytical Method ................................................................................................................................ 6 

2.2.2 Recommended Tolerances ......................................................................................................................................... 7 

2.2.3 Revisions to Petitioned-For Tolerances ...................................................................................................................... 9 

2.2.4 International Harmonization ...................................................................................................................................... 9 

2.3 Label Recommendations ................................................................................................................................................... I 0 

2.3.1 Recommendations from Residue Reviews ............................................................................................................... I 0 

2.3.2 Recommendations from Occupational Assessment.. ................................................................................................ 10 

2.3.3 Recommendations from Residential Assessment ..................................................................................................... 10 

3.0 I TRODUCTION ................................................................................................................................................................... I I 

3. 1 Chemical Identity .............................................................................................................................................................. 11 

3.2 Physical/Chemical Propenics ............................................................................................................................................ 12 

3.3 Pesticide Use Panem/Directions ........................................................................................................................................ 12 

3.4 Anticipated Exposure Pathways ........................................................................................................................................ 14 

3.5 Consideration of Environmental Justice ............................................................................................................................ 14 

-l.O 1 IAZARD Cl IARACTERIZATION AND DOSE-RESPONSE ASSESSMENT ................................................................... 15 

4. 1 Toxicology Studies Available for Analysis ....................................................................................................................... 15 

4.2 Absorption. Distribution. Metabolism. and Excretion (ADME) ........................................................................................ IS 

4.3 Toxicological Ellects ......................................................................................................................................................... 16 

4.4 Safety Factor for Infants and Children (FQPA SF) ........................................................................................................... 17 

4.4.1 Completeness of the Toxicology Database .............................................................................................................. 17 

4.4.2 Evidence ofNcurotoxicity ....................................................................................................................................... 17 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal. ........................................................... 17 

4.4.4 Residual Uncertainty in the Exposure Database ....................................................................................................... 17 

4.5 Toxicity Endpoint and Point of Dcpanure Selections ........................................................................................................ 17 

4.5. 1 Dose-Response Assessment ..................................................................................................................................... 18 

-l.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment .......................................................... 19 

4 .5.3 Cancer Classification and Risk Assessment Recommendation ................................................................................ 19 

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment .................................. 19 

5.0 DIETARY EX POSURE AND RISK ASSESSMENT ............................................................................................................ 21 

5.1 Residues of Concern Summary and Rationale ................................................................................................................... 2 1 

5.2 Food Residue Prolilc ......................................................................................................................................................... 22 

5.3 Water Residue Prolile ........................................................................................................................................................ 22 

5.4 Dietary Risk Assessment ................................................................................................................................................... 23 

5.4.1 Summary of Dietary Exposure/Risk Estimates ........................................................................................................ 23 

5.4.2 Percent CT Used in Dietary Assessment.. ................................................................................................................ 23 

6.0 RESIDENTIAL ( ON-OCCUPATIONAL) EXPOSURE/RI SK ............................................................................................ 24 

6. 1 Residential Bystander Post-Application Inhalation Exposure ........................................................................................... 26 

6.2 Spray Drift ......................................................................................................................................................................... 26 

7.0 AGGREGATE EXPOSURE/RISK CHARACTERIZATION ................................................................................................ 27 

8.0 CUMULATIVE RISK CllARACTERIZATIO /ASSESSME T .......................................................................................... 27 

9.0 OCCUPATIONAL EXPOSURE/RISK Cl IARJ\CTERIZATION .......................................................................................... 28 

9.1 Occupational I landlcr Exposure/Risk Assessment ............................................................................................................ 28 

9.2 Occupational Post-Application Exposure/Risk Assessment .......................................................................... .................... 29 

APPENDIX A. TOXICOLOGY ASSESSMENT ......................................................................................................................... 30 

APPE DIX B. CHEMICAL NAMES AND STRUCTURES ....................................................................................................... 40 

APPENDIX C. PHYSIOCI IEMICAL PROPERTI ES ................................................................................................................... 44 

APPENDIX D: REGISTERED RESIDENTIAL USES FOR SPINOSAD/SPINETORAM ......................................................... 45 

Page 2 of 45 
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 3 of 45

1.0 EXECUTIVE SUMMARY

Background: Spinosad, which consists of spinosyn A and spinosyn D (A:D of 85:15), is a 

fermentation product of Saccharopolyspora spinosa. Spinetoram, which consists of XDE-175-J 

and XDE-175-L (J:L of 3:1), is derived from the synthetic modification of Saccharopolyspora 

spinosa fermentation products. Spinosad and spinetoram are structurally similar with both 

registered for application to numerous crops for control of foliage-feeding pests including 

lepidoptera larvae (worms or caterpillars), Colorado potato beetles, dipterous leafminers, thrips, 

and/or certain psyllids. The insecticidal mode of action for both spinosad and spinetoram 

involves disruption of the nicotinic acetylcholine receptors. 

The Interregional Research Project No. 4 (IR-4) requested Section 3 Registrations and permanent 

tolerances for foliar application of spinosad and spinetoram to coffee (see Table 2.2.2.1 for 

proposed tolerances). IR-4 is also requesting label amendments for plum/prune and Brassica

(cole) leafy vegetables crop group 5 and updating existing spinosad and spinetoram crop 

group/subgroup commodity definitions to the following: bulb vegetable crop group 3-07; 

fruiting vegetable crop group 8-10; citrus fruit crop group 10-10; pome fruit crop group 11-10; 

stone fruit crop group 12-12; caneberry crop subgroup 13-07A; bushberry crop subgroup 13-07B 

(except lingonberry); small fruit vine climbing, except fuzzy kiwifruit, crop subgroup 13-07F; 

low growing berry crop subgroup 13-07G (except cranberry and lowbush blueberry), tree nut 

crop group 14-12; and cottonseed crop subgroup 20C. 

Hazard Assessment: Spinosad and spinetoram are considered toxicologically identical for the 

purposes of human health risk assessment based on their nearly identical chemical structures and 

similar toxicological profiles. The primary toxic effect observed from exposure to spinosad or 

spinetoram was histopathological changes in multiple organs (specific target organs were not 

identified). Vacuolization of cells and/or macrophages was the most common histopathological 

finding noted across both toxicological databases with the dog being the most sensitive species. 

In addition to the numerous organs observed with histopathological changes, anemia was noted 

in several studies. 

There was no evidence of increased quantitative or qualitative susceptibility from spinosad or 

spinetoram exposure. In developmental studies, no maternal or developmental effects were seen 

in rats or rabbits. In the rat reproduction toxicity studies, offspring toxicity (decreased litter size, 

survival, and body weights with spinosad; increased incidence of late resorptions and postimplantation loss with spinetoram) was seen in the presence of parental toxicity (increased organ 

weights, mortality, and histopathological findings) at approximately the same dose for both 

chemicals. Dystocia and/or other parturition abnormalities were observed with both chemicals in 

the reproduction toxicity studies. There was no evidence of neurotoxicity, immunotoxicity, or 

carcinogenicity from spinosad or spinetoram exposure. 

Food Quality Protection Act (FQPA) Safety Factor (SF) Decision: The RAB1 risk assessment 

team recommends that the FQPA SF be reduced to 1X for all exposure scenarios based on the 

following considerations: (1) the toxicology database for spinosad/spinetoram is adequate for 

FQPA SF consideration; (2) there is no evidence of neurotoxicity from spinosad/spinetoram 

exposure; (3) there is no evidence of increased pre- or post-natal susceptibility; and (4) the 

exposure databases are sufficient and unlikely to underestimate exposure.
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 4 of 45

Dose Response Assessment: Tables 4.5.4.1 and 4.5.4.2 provide summaries of the toxicological 

doses and endpoints used for assessment of dietary and occupational/residential exposure, 

respectively. Assessment of acute dietary and dermal (all durations) exposure are considered 

unnecessary as no endpoint of concern attributable to a single dose was observed and no hazard was 

identified following dermal exposure. The chronic toxicity study (dog; NOAEL = 2.49 mg/kg/day) 

was selected for assessment of chronic dietary exposure. The subchronic oral toxicity study (dog; 

NOAEL = 4.9 mg/kg/day) was selected for assessment of incidental oral (short- and intermediateterm) exposure and inhalation (short- and intermediate-term) exposure in both the residential and 

occupational settings. For all exposure scenarios, a 100x uncertainty factor (UF) was applied (10x 

interspecies extrapolation; 10x for intraspecies variation; 1x FQPA SF (when applicable)). 

Residue Chemistry and Drinking Water Assessments: Adequate residue chemistry data have 

been submitted to support the establishment of the proposed tolerances. In addition, adequate data 

are available for the generation of modeled estimated drinking water concentrations (EDWCs). 

Dietary Risk Estimates (Food + Drinking Water): A chronic dietary risk assessment was conducted 

using the Dietary Exposure Evaluation Model - Food Consumption Intake Database (DEEM-FCID, 

ver. 3.16) which incorporates food consumption data from the United States Department of 

Agriculture (USDA) National Health and Nutrition Examination Survey, What We Eat in America 

(NHANES/WWEIA; 2003-2008). Acute and cancer analyses were not conducted as toxicological 

effects attributable to a single dose were not identified and spinetoram and spinosad are classified as 

not likely to be carcinogens (cancer risk assessment is not required). The chronic analysis assumed 

100% crop treated, average field-trial residues or tolerance-level residues for crop commodities,

average residues from the livestock feeding studies, spinosad residue estimates for fish/shellfish 

(residues of spinetoram in fish/shellfish are expected to be insignificant), experimental processing 

factors when available, and modeled drinking water estimates. The resulting chronic exposure 

estimates do not exceed HED's level of concern (LOC; ≤64% chronic population-adjusted dose 

(cPAD); children 1-2 years old were the most highly exposed subpopulation).

Residential (Non-Occupational) Exposure and Risk Assessment: The proposed uses will not result 

in residential exposure. However, residential handler (short-term inhalation exposures) and postapplication (short-term incidental oral) exposures are expected as a result of the following registered 

uses (based on toxicological considerations, assessment of dermal exposure is unnecessary): (1) 

homeowner application of spinosad to gardens, turfgrass, and ornamentals; (2) homeowner application 

of spinetoram to lawns, gardens, and ornamentals; and (3) spot-on application of spinetoram to cats 

and kittens. Residential exposure resulting from these existing uses were reassessed to conform with 

the most recent policies and guidance with all handler and post-application exposure estimates 

resulting in margins of exposure (MOEs) which are not of concern to HED (LOC for MOEs < 100; 

calculated MOEs were ≥ 720). 

Aggregate-Risk Estimates: In accordance with the FQPA, HED aggregates dietary (food and 

water) and residential exposure to pesticides. Based on the anticipated exposure scenarios, and 

since acute and cancer risk assessments are not required, only short-term (residential, food, and 

water) and chronic (food and water) aggregate exposure assessments were conducted. The resulting 

aggregate exposure estimates do not exceed HED’s LOC (short-term MOEs ≥ 220; chronic 

exposure estimates ≤64% cPAD). HED notes that the short-term aggregate risk assessment is 

protective of intermediate-term exposure as the short-/intermediate-term PODs are identical.
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 5 of 45

Occupational Exposure and Risk Assessment: Occupational exposure assessments were only 

conducted for the proposed coffee use as the application scenarios for the proposed updates to the crop 

group/subgroup commodity definitions are identical to those currently registered (label amendment 

requests also do no warrant a new occupational exposure assessment). For the scenarios where 

baseline data are available, all inhalation risks for occupational handlers are not of concern to HED 

(i.e., MOE> the LOC of 100) with baseline protection (i.e., long-sleeve shirt, long pants, shoes, and 

socks). Only engineering control data (i.e., enclosed cockpits) are available for aerial application 

scenarios. All inhalation risks for occupational aerial applicators are above the LOC (100) with 

baseline clothing and enclosed cockpits. A quantitative occupational post-application inhalation 

exposure assessment was not performed as it is expected that handler inhalation exposure estimates, 

which included the airblast scenario, are protective of post-application inhalation exposure scenarios. 

Since no hazard was identified via the dermal route of exposure, dermal exposure assessments were 

not performed. 

Reentry Interval (REI): Spinosad and spinetoram are classified as Toxicity Category III or IV 

based upon data for acute dermal toxicity, acute inhalation toxicity, primary skin irritation, and 

primary eye irritation. Typically, the REI specified on the proposed label is based on the acute 

toxicity of the active ingredient. Under 40 CFR 156.208 (c) (2) (iii), active ingredients 

classified as Acute III or IV for acute dermal, eye irritation, and primary skin irrigation are 

assigned a 12-hour REI. However, it is noted that the proposed product label has a 4-hour REI 

listed. REIs may be further reduced from 12 hours if certain criteria are met for both the 

technical material and the different end-use products in accordance with the Pesticide

Registration (PR) Notice 95-3 (Reduction of Worker Protection Standard (WPS) Interim REIs 

for Certain Low Risk Pesticides; http://www.epa.gov/PR_Notices/pr95-3.html). Based only on 

the acute toxicity categories, spinosad and spinetoram are possible candidates for a 4-hour REI;

however, RD should ensure that the additional criteria listed in PR Notice 95-3 are met for both 

active ingredients and the end-use products.

Environmental Justice Considerations: Potential areas of environmental justice concerns, to 

the extent possible, were considered in this human health risk assessment, in accordance with 

U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority 

Populations and Low-Income Populations.”

Review of Human Research: This risk assessment relies in part on data from studies in which 

adult human subjects were intentionally exposed to a pesticide or other chemical. These data, 

which include studies from the Pesticide Handlers Exposure Database (PHED) 1.1, the 

Agricultural Handler Exposure Task Force (AHETF) database, and the Agricultural Reentry 

Task Force (ARTF) database are (1) subject to ethics review pursuant to 40 CFR 26, (2) have 

received that review, and (3) are compliant with applicable ethics requirements. For certain 

studies, the ethics review may have included review by the Human Studies Review Board. 

Descriptions of data sources, as well as guidance on their use, can be found at the following 

Agency websites: http://www.epa.gov/pesticides/science/handler-exposure-data.html and

http://www.epa.gov/pesticides/science/post-app-exposure-data.html. 
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 6 of 45

2.0 Recommendations

Spinosad: Provided revised Sections B and F are submitted, HED concludes that the toxicological, 

residue chemistry, and occupational/residential exposure (ORE) databases support the proposed label 

amendments, an unconditional coffee registration, and establishment of the permanent tolerances 

detailed in Table 2.2.2.1. In addition, per the request of RD, HED determined that the current 

asparagus tolerance of 0.2 ppm is incorrect and should be 0.02 ppm as previously recommended by 

HED (D277485, G. Herndon, 6-Aug-2001).

Spinetoram: Provided a revised Section F is submitted, HED concludes that the toxicological, 

residue chemistry, and ORE databases support the proposed label amendments, an unconditional 

coffee registration, and establishment of the permanent tolerances detailed in Table 2.2.2.1. 

2.1 Data Deficiencies/Data Needs

Toxicology: None

Residue Chemistry: Revised Sections B (see Section 2.3.1) and F (see Section 2.2.2). 

ORE: Revised Section B (see Section 2.3.2).

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Spinosad: Method RES 94025 (GRM 94.02) is a high-performance liquid chromatography 

method with ultraviolet detection (HPLC/UV) method which was originally submitted for the 

determination of spinosyn A and D in/on cottonseed and related commodities (LOQ = 0.01 ppm 

for spinosyn A and D). The method was successfully subjected to an independent laboratory 

validation (ILV) as well as an EPA laboratory validation and has been forwarded to the Food and 

Drug Administration (FDA) for tolerance enforcement (D228791, G. Herndon, 13-Aug-1996). 

The following additional methods have also been determined to be adequate for tolerance 

enforcement purposes and were forwarded to the FDA (LOQ = 0.01 ppm for all; D242940, G. 

Herndon, 18-Feb-1998; D237752, G. Herndon, 2-Mar-1998; D232203, G. Herndon, 2-Mar1998; D243795, G. Herndon, 2-Mar-1998): GRM 95.17 (leafy vegetables; HPLC/UV); GRM 

96.09 (citrus; HPLC/UV); GRM 96.14 (tree nuts; HPLC/UV); GRM 95.04 (fruiting vegetables; 

HPLC/UV); GRM 94.02.S1 (cotton gin byproducts; HPLC/UV); and GRM 96.16 (multiple 

commodities; immunoassay method). 

Since the coffee magnitude of the residue data submitted in support of the current petition were 

generated using an immunoassay method very similar to the current enforcement method GRM 96.16 

and since the study included adequate validation data, HED concludes that method GRM 96.16 is 

suitable for enforcement of the spinosad coffee tolerances recommended herein. The remaining 

recommended tolerances reflect an update to the current crop group/subgroup commodity definitions 

and, therefore, the current enforcement methods are sufficient.
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 7 of 45

Spinetoram: Method GRM 05.04 is a HPLC/mass spectrometry (MS)/MS method which has 

been determined to be adequate for enforcement of the currently-established spinetoram plant 

tolerances and was forwarded to FDA (D325387, T. Bloem, 12-Sep-2007; D343662, T. Bloem, 

12-Sep-2007). Since method GRM 05.04 has been validated on a wide-variety of crops 

(46695013.der), HED concludes that it is sufficient to enforce the coffee tolerances 

recommended as part of the current petition. The remaining recommended tolerances reflect an 

update to the current crop group/subgroup commodity definitions and, therefore, the current 

enforcement method is also sufficient.

2.2.2 Recommended Tolerances 

Table 2.2.2.1 is a summary of the petitioner-proposed and HED-recommended tolerances for 

spinosad (combined residues of spinosyns A and D) and spinetoram (combined residues of XDE175-J, XDE-175-L, ND-J, and NF-J). A revised Section F is requested for both spinosad and 

spinetoram which specifies the residue definitions indicated below and the commodity 

definitions/values indicated in Table 2.2.2.1. With the establishment of the tolerances listed in 

Table 2.2.2.1, the following spinosad and spinetoram tolerances should be deleted: cotton, 

undelinted seed; cranberry; grape; juneberry, lingonberry; okra; onion, green; pistachio; salal; 

strawberry; vegetable, bulb, group 3, except green onion; vegetable, fruiting, group 8; fruit, 

citrus, group 10; fruit pome, group 11; fruit stone, group 12; caneberry, subgroup 13A; 

bushberry, subgroup 13B; and nut, tree, group 14. 

Spinosad (40 CFR 180.495(a)): Tolerances are established for residues of the insecticide spinosad, 

including its metabolites and degradates, in or on the commodities in the table below. Compliance 

with the tolerance levels specified below is to be determined by measuring only the sum of spinosyn 

A (Factor A: CAS # 131929-60-7; (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)-2-[(6-deoxy-2,3,4-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,16b-tetradecahydro-14-methyl-1H-asindaceno[3,2-d]oxacyclododecin-7,15-dione; and spinosyn D (Factor D; CAS # 131929-63-0; 

(2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS)-2-[(6-deoxy-2,3,4-tri-O-methyl-α-L-mannopyranosyl)oxy]-13-[[5-(dimethyl-amino)-tetrahydro-6-methyl-2H-pyran-2-yl]oxy]-9-ethyl2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16b-tetradecahydro-4,14-methyl-1H-as-indaceno[3,2-

d]oxacyclododecin-7,15-dione, calculated as the stoichiometric equivalent of spinosad.

Spinetoram (40 CFR 180.635(a)): Tolerances are established for residues of the insecticide 

spinetoram, including its metabolites and degradates, in or on the commodities in the table below. 

Compliance with the tolerance levels specified below is to be determined by measuring only the sum 

of XDE-175-J (1-H-as-indaceno[3,2-d]oxacyclododecin-7,15-dione, 2-[(6-deoxy-3-O-ethyl-2,4-diO-methyl-α-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]oxacyclododecin7,15-dione, 2-[(6-deoxy-3-O-ethyl-2,4-di-O-methyl-α-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, 
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 8 of 45

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-α-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-α-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-asindaceno[3,2-d]oxacyclododecin-13-yl]oxy)-2-methyltetrahydro-2H-pyran-3-yl(methyl)formamide), 

calculated as the stoichiometric equivalent of spinetoram.

Table 2.2.2.1: Tolerance Summary.

Commodity

Proposed 

Tolerance 

(ppm)1

HEDRecommended 

Tolerance (ppm)

Comments

Spinosad (40 CFR 180.495(a))

Coffee, green bean 0.2 0.04 Based on the available field trial data and the Organization 

for Economic Co-operation and Development (OECD)

tolerance-calculation procedure, a tolerance of 0.04 is 

appropriate for coffee (green bean); tolerances in/on instant 

coffee and roasted bean are unnecessary.

Coffee, instant 0.4 --

Coffee, roasted bean 0.4 --

Onion, bulb, subgroup 3-07A 0.10 0.10

Based on the available data, the proposed updates to the 

crop group/subgroup commodity definitions are

acceptable. Some of the tolerance values were updated to 

conform with current practices concerning significant 

figures and/or for purposes of harmonization.

The commodity definitions for subgroups 13-07B and 13-

07G should be as follows: Bushberry, subgroup 13-07B1

and Berry, low growing, subgroup 13-07G, except 

cranberry.2 

Onion, green, subgroup 3-07B 2.0 4.0

Vegetable, fruiting, group 8-10 0.4 0.40

Fruit, citrus, group 10-10 0.3 0.30

Fruit, pome, group 11-10 0.20 0.20

Fruit, stone, group 12-12 0.20 0.20

Caneberry subgroup 13-07A 0.7 1.0

Nut, tree, group 14-12 0.10 0.10

Cottonseed subgroup 20C 0.02 0.02

Bushberry, subgroup 13-07B, except 

lingonberry 0.25 0.40

Fruit, small, vine climbing, except fuzzy 

kiwifruit, subgroup 13-07F 0.50 0.50

Grape, raisin -- 1.0

Berry, low growing, subgroup 13-07G, 

except blueberry, lowbush and cranberry 1.0 0.90

Spinetoram (40 CFR 180.635(a))

Coffee, green bean 0.2 0.04 Based on the available field trial data and the OECD 

tolerance-calculation procedure, a tolerance of 0.04 is 

appropriate for coffee (green bean); tolerances in/on instant 

coffee and roasted bean are unnecessary.

Coffee, instant 0.4 --

Coffee, roasted bean 0.4 --
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 9 of 45

Table 2.2.2.1: Tolerance Summary.

Commodity

Proposed 

Tolerance 

(ppm)1

HEDRecommended 

Tolerance (ppm)

Comments

Onion, bulb, subgroup 3-07A 0.10 0.10

Based on the available data, the proposed updates to the 

crop group/subgroup commodity definitions are

acceptable. Some of the tolerance values were updated to 

conform with current practices concerning significant 

figures and/or for purposes of harmonization. 

The commodity definitions for subgroups 13-07B and 13-

07G should be as follows: Bushberry, subgroup 13-07B1

and Berry, low growing, subgroup 13-07G, except 

cranberry.2 

Onion, green, subgroup 3-07B 2.0 2.0

Vegetable, fruiting, group 8-10 0.4 0.40

Fruit, citrus, group 10-10 0.3 0.30

Fruit, pome, group 11-10 0.20 0.20

Fruit, stone, group 12-12 0.20 0.30

Caneberry subgroup 13-07A 0.7 0.80

Fruit, small, vine climbing, except fuzzy 

kiwifruit, subgroup 13-07F 0.50 0.50

Nut, tree, group 14-12 0.10 0.10

Cottonseed subgroup 20C 0.04 0.04

Bushberry, subgroup 13-07B, except 

lingonberry 0.25 0.50

Berry, low growing, subgroup 13-07G, 

except blueberry, lowbush and cranberry 1.0 0.90

1

 Lingonberry is a member of the 13-07B and 13-07G subgroups (also a member of the 13-07H subgroup but this is not relevant here). 

The lingonberry tolerance will default to the highest of these and, therefore, excluding lingonberry is unnecessary. 

2 Since lowbush blueberry is not a member of the 13-07G subgroup, exclusion is unnecessary. Based on the magnitude of the residue 

data, a separate cranberry tolerance is required (D277485, G. Herndon, 6-Aug-2001). 

2.2.3 Revisions to Petitioned-For Tolerances

Based on the available coffee field trial and processing data and the OECD tolerance calculation 

procedure, HED concludes that the coffee (green bean) tolerances listed in Table 2.2.2.1 are correct 

and tolerances in/on coffee processed commodities are unnecessary. The remaining revisions pertain 

to alterations to the tolerance value for purposes of harmonization (see Section 2.2.4) or revisions to 

the commodity definitions and/or tolerance values so as to conform with current practices. 

2.2.4 International Harmonization

There are currently Canadian and Codex maximum residue limits (MRLs) in/on several of the 

relevant crops or crop groups/subgroups (Mexican MRLs are not established in/on any of the 

relevant commodities). As detailed in D416068 (T. Bloem, 10-Mar-2015), the HED-recommended 

tolerances were harmonized with the Canadian and/or Codex MRLs when possible.
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 10 of 45

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

Spinosad: Provided a revised Entrust® SC (soluble concentrate; EPA Reg. No. 62719-621) label is 

submitted which indicates that the maximum seasonal application rates consider foliar, soil, and/or

seed treatment applications, HED concludes that the proposed application scenarios are supported by 

the available data. 

2.3.2 Recommendations from Occupational Assessment

Spinosad and Spinetoram (note to RD): Spinosad and spinetoram are classified as Toxicity 

Category III or IV based upon data for acute dermal toxicity, acute inhalation toxicity, primary 

skin irritation, and primary eye irritation. Typically, the REI specified on the proposed label is 

based on the acute toxicity of the active ingredient. Under 40 CFR 156.208 (c) (2) (iii), active 

ingredients classified as Acute III or IV for acute dermal, eye irritation, and primary skin irrigation 

are assigned a 12-hour REI. However, it is noted that the proposed product label has a 4-hour REI 

listed. REIs may be further reduced from 12 hours if certain criteria are met for both the technical 

material and the different end-use products in accordance with the PR Notice 95-3 (Reduction of 

WPS Interim REIs for Certain Low Risk Pesticides; http://www.epa.gov/PR_Notices/pr95-3.html). 

Based only on the acute toxicity categories, spinosad and spinetoram are possible candidates for a 

4-hour REI; however, RD should ensure that the additional criteria listed in PR Notice 95-3 are 

met for both active ingredients and the end-use products.

2.3.3 Recommendations from Residential Assessment

None.
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 11 of 45

3.0 Introduction

3.1 Chemical Identity

Spinosad, which consists of spinosyn A and spinosyn D (A:D of 85:15), is a fermentation 

product of Saccharopolyspora spinosad. Spinetoram, which consists of XDE-175-J and XDE175-L (J:L of 3:1), is derived from the synthetic modification of Saccharopolyspora spinosa

fermentation products. The chemical structure and nomenclature for spinosad and spinetoram 

are presented in Table 3.1.1 and 3.1.2 respectively.

Table 3.1.1: Spinosad Nomenclature

Chemical Structure

Common name Spinosad

Company experimental name XDE-105

IUPAC name

Spinosyn A: (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)-2-(6-deoxy-2,3,4-tri-O-methyl-α-Lmannopyranosyloxy)-13-(4-dimethylamino-2,3,4,6-tetradeoxy-β-D-erythropyranosyloxy)-9-ethyl2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-hexadecahydro-14-methyl-1H-8-oxacyclododeca[b]asindacene-7,15-dione

Spinosyn D: (2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bR)-2-(6-deoxy-2,3,4-tri-O-methyl-α-Lmannopyranosyloxy)-13-(4-dimethylamino-2,3,4,6-tetradeoxy-β-D-erythropyranosyloxy)-9-ethyl2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-hexadecahydro-4,14-dimethyl-1H-8-

oxacyclododeca[b]as-indacene-7,15-dione

CAS name

Spinosyn A: 2-[(6-deoxy-2,3,4-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

Spinosyn D: 2-[(6-deoxy-2,3,4-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-4,14-methyl-1H-as-Indaceno[3,2-d]oxacyclododecin-7,15-dione

CAS # Spinosyn A: 131929-60-7; Spinosyn D: 131929-63-0

Table 3.1.2: Spinetoram Nomenclature.

Compound

Chemical Structure

 XDE-175-J XDE-175-L

O O

H3C

N

H3C

H3C

O

O

CH3

OCH3

OCH3

O

CH3

H3CH2C

O

O

H

H

H

H

H3CO

R

Spinosyn A: R = H

Spinosyn D: R = CH3

Rhamnose portion

Macrolide portion

Forosamine portion
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 12 of 45

Table 3.1.2: Spinetoram Nomenclature.

Common name Spinetoram (mixture of XDE-175-J and XDE-175-L)

Company experimental name XDE-175-J: TSN104472; 3’-O-ethyl 5,6-dihydro spinosyn J; 175-J

XDE-175-L: TSN104480; 3’-O-ethyl spinosyn L; 175-L

IUPAC name

XDE-175-J: (2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR)-13-{[(2R,5S,6R)-5-(dimethylamino)-6-

methyltetrahydro-2H-pyran-2-yl]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-2-yl 6-deoxy-3-O-ethyl-2,4-di-O-methyl-alpha-L-mannopyranoside

XDE-175-L: (2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS)-13-{[(2R,5S,6R)-5-(dimethylamino)-6-

methyltetrahydro-2H-pyran-2-yl]oxy}-9-ethyl-4,14-dimethyl-7,15-dioxo2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-hexadecahydro-1H-as-indaceno[3,2-

d]oxacyclododecin-2-yl 6-deoxy-3-O-ethyl-2,4-di-O-methyl-alpha-L-mannopyranoside

CAS name

XDE-175-J: 1H-as-indaceno[3,2-d]oxacyclododecin-7,15-dione, 2-[(6-deoxy-3-O-ethyl-2,4-di-Omethyl-a-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-Omethyl-a-L-mannopyranosyl)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)

CAS # XDE-175-J: 187166-40-1; XDE-175-L: 187166-15-0

3.2 Physical/Chemical Properties

The physical/chemical properties for spinosad and spinetoram are presented in Appendix C. 

Spinosad is moderately soluble in water, has a high Log Kow, and is nonvolatile. Spinetoram is 

weakly soluble in water, has a high Log Kow, and is nonvolatile.

3.3 Pesticide Use Pattern/Directions

IR-4 requested Section 3 Registrations for application of spinosad and spinetoram to coffee; label 

amendments which reduce the PHI for plums/prunes from 7 days to 1 day and permit applications 

directed to the base of Brassica (Cole) leafy vegetables group 5 crops (only foliar application is 

currently registered); and updates to the crop group/subgroup tolerance commodity definitions for 

the following: bulb vegetable crop group 3-07; fruiting vegetable crop group 8-10; citrus fruit crop 

group 10-10; pome fruit crop group 11-10; stone fruit crop group 12-12; caneberry crop subgroup 

13-07A; bushberry crop subgroup 13-07B (except lingonberry); small fruit vine climbing, except 

fuzzy kiwifruit, crop subgroup 13-07F; low growing berry crop subgroup 13-07G (except cranberry 

and lowbush blueberry), tree nut crop group 14-12; and cottonseed crop subgroup 20C. Table 3.3.1 

is a summary of the end-use products and target pests and Table 3.3.2 is a summary of the proposed 

application scenarios. Since the application scenarios for the crop group/subgroup commodity 

updates are identical to that currently registered, they are not included in Tables 3.3.1 and 3.3.2. 

The proposed labels also specify the following: (1) adjuvants may be added to the spray solution; 

(2) excluding the spinetoram labels concerning application to citrus grown in Florida, the labels 

specify a minimum spray volume for ground and aerial application of 5 gallons per acre (GPA) and 

3 GPA (10 GPA for tree, vine, grove, and orchard crops), respectively; the minimum spray volume 

for ground application of spinetoram to citrus grown in Florida is 2 GPA; (3) applications to crops 

grown in a greenhouse are permitted on the spinosad label but are prohibited on the spinetoram 

labels; (4) the spinosad label does not specify any rotational crop restrictions while the spinetoram 
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 13 of 45

labels indicates that labeled crops may be rotated immediately to a treated field and nonlabeled crops 

may be rotated 30 days after application; and (5) REI = 4 hours. HED request revised labels as 

described in Section 2.3. 

Table 3.3.1: Summary of End-Use Products.

Trade Name Conc. Formulation Label Date Target Crops Target Pests

Spinosad

Entrust® SC 

(EPA Reg. No. 

62719-621)

2 lb 

ai/gallon

soluble 

concentrate

not 

specified

coffee; Brassica (Cole) leafy vegetables group 5; bulb 

vegetable group 3-07; 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, except fuzzy kiwifruit 

subgroup 13-07F; low growing berry subgroup 13-07G 

(except cranberry and lowbush blueberry), tree nut crop 

group 14-12; and cottonseed subgroup 20C

Foliage feeding pests 

including lepidoptera 

larvae (worms or 

caterpillars), Colorado 

potato beetles, leafminers, 

and thrips.

Spinetoram

Delegate® WG 

(EPA Reg. No. 

62719-541)

25%

waterdispersible 

granule

not 

specified

coffee; Brassica (Cole) leafy vegetables group 5; bulb 

vegetable group 3-07; 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, except fuzzy kiwifruit 

subgroup 13-07F; low growing berry subgroup 13-07G 

(except cranberry and lowbush blueberry), tree nut crop 

group 14-12; and cottonseed subgroup 20C

Foliage feeding pests 

including lepidoptera 

larvae (worms or 

caterpillars), Colorado 

potato beetles, dipterous 

leafminers, thrips, and 

certain psyllids.

Radiant® SC 

(EPA Reg. No. 

62719-545)

1 lb 

ai/gallon

soluble 

concentrate

not 

specified

Table 3.3.2: Summary of Proposed Application Scenarios.

App. Timing;

Type; and Equip. Formulation Single App. Rate(lb ai/acre)

Max. # Apps.

Max. App. Rate

(lb ai/acre)

PHI

(days) Use Directions and Limitations

coffee

foliar broadcast 

spray

Spinetoram -

Radiant® 

Delegate®

0.03-0.08 6 0.30 7

-RTI = 5 days

-Do not make more than two consecutive 

applications. 

Spinosad -

Entrust® 0.06-0.16 6 0.45 7

-RTI = 5 days

-Do not make more than three consecutive 

applications. 

plum/prune1

foliar broadcast 

spray

Spinetoram -

Radiant® 

Delegate®

0.05-0.11 4 0.44 1

-RTI = 3-7 days

-Do not make more than three consecutive 

applications. 

Spinosad -

Entrust® 0.06-0.12 -- 0.45 1

-RTI = 7 days

-Do not make more than two consecutive 

applications. 

Brassica (Cole) leafy vegetables group 5 crops2

foliar broadcast 

spray

Spinetoram -

Radiant® 0.04-0.08 6 0.27 1

-RTI = 4 days; includes instructions for 

application to the base of the crop

Spinosad -

Entrust® 0.02-0.16 6 0.45 1

-RTI = 4 days; includes instructions for 

application to the base of the crop

1

 The proposed application scenario is identical to that currently registered except for a reduction in the PHI from 7 days to 1 day.

2

 The proposed application scenario is identical to that currently registered except for the addition of instructions concerning 

application to the base of the crop (currently only foliar application is registered). 
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 14 of 45

3.4 Anticipated Exposure Pathways

Spinosad and spinetoram are registered for application to numerous food/feed crops; spinosad is also 

registered for application as a mosquito larvicide and for application to livestock premises. As a result 

of these uses, dietary (food and water) exposure to spinosad and spinetoram is possible including 

exposure to spinosad residues in fish/shellfish as a result of the mosquito larvicide use; based on the 

registered uses, spinetoram residues in fish/shellfish are unlikely. Residential exposure to spinosad and 

spinetoram is also possible as a result of the registered turf, ornamental, garden, and/or pet spot-on 

uses. 

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations,” 

(http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf). As a part of every 

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to 

well-established procedures. In line with OPP policy, HED estimates risks to population 

subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water 

consumption, and activities in and around the home that involve pesticide use in a residential 

setting. Extensive data on food consumption patterns are compiled by the USDA under the 

NHANES/WWEIA (2003-2008) and are used in pesticide risk assessments for all registered food 

uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season 

of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary 

exposure to smaller, specialized subgroups and exposure assessments are performed when 

conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas postapplication are evaluated. Further 

considerations are currently in development as OPP has committed resources and expertise to the 

development of specialized software and models that consider exposure to bystanders and farm 

workers as well as lifestyle and traditional dietary patterns among specific subgroups.
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 15 of 45

4.0 Hazard Characterization and Dose-Response Assessment

Spinosad and spinetoram are nearly identical structurally. Spinosad consists of spinosyn A and 

D, while spinetoram consists of factors J and L (see Section 3.1). The pesticidal mode action for 

both chemicals is the disruption of nicotinic/gamma amino butyric acid (GABA)-gated chloride 

channels. 

4.1 Toxicology Studies Available for Analysis

The HED Hazard Assessment and Policy Committee (HASPOC) concluded that spinosad and 

spinetoram should be considered toxicologically identical for the purposes of human health risk 

assessment based on their nearly identical chemical structures and similar toxicological profiles 

(D340521, P. Shah, 18-Jun-2007). As a result, the toxicological databases for spinosad and 

spinetoram are considered together for evaluation. The HASPOC also noted that this is not a 

cumulative assessment. Spinosad and spinetoram should be considered toxicologically identical 

in the same manner that metabolites are generally considered toxicologically identical to a parent 

compound.

The toxicological database for spinosad/spinetoram is adequate for hazard characterization, 

toxicity endpoint selection, and FQPA SF evaluation. An immunotoxicity study with spinosad 

(MRID 48329601) has been submitted since the last risk assessment and the results incorporated 

into the current assessment. HED previously requested a subchronic inhalation study to 

characterize the effects of spinosad/spinetoram via the inhalation route; however, the registrant 

submitted a waiver request as well as a 14-day inhalation study with spinosad (MRID 49425601) 

showing no effects up to the highest dose tested (9.5 mg/m3). Although this study did not dose 

high enough to elicit adverse effects, it did demonstrate that exposure via the inhalation route 

was not more sensitive than the oral route. As a result, the HASPOC concluded using a weightof-evidence approach that the subchronic inhalation study is not required at this time (U. Habiba, 

15-OCT-2014, TXR #0057052).

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

Spinosad: There were no major differences between the bioavailability, routes of excretion, or 

metabolism of radiolabeled spinosyn A and spinosyn D in rats following oral administration. 

Approximately 80% (spinosyn A) and approximately 66% (spinosyn D) of the administered dose 

was absorbed with the remaining dose eliminated as unchanged parent in the feces. The major 

elimination route was fecal excretion for both spinosyn A (82-87% of the administered dose) and 

spinosyn D (84-92% of the administered dose). Excretion via the urine ranged from 7-10% and 

3-5% of the administered dose for spinosyn A and spinosyn D, respectively. In bile-cannulated 

rats with spinosyn D, 28-40% of the administered dose was found in the bile. Blood levels after 

single and multiple doses of spinosyn A (10 mg/kg) were highest 1 hour after dosing in both 

sexes. Half-lives (tmax) at this dose were 6 and 12 hours after dosing in males and females, 

respectively. The tissues and carcass contained very low levels of radioactivity 168 hours postdosing (<3% of the administered dose). The primary fecal, urinary, and biliary metabolites were 

identified as the glutathione conjugates of the parent and N- and O-demethylated forms of the 

parent. 
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 16 of 45

Spinetoram: There were no major differences between the bioavailability, routes of excretion, 

or metabolism of radiolabeled Factor J and Factor L in rats following oral administration. 

Absorption was ≥70% for both Factor J and Factor L with measurements in the plasma as soon 

as 15 minutes after administration. After 168 hours, 88-97% and 90-95% of the administered 

dose was recovered for Factor J and Factor L, respectively. The majority was recovered in 

excreta within 24 hours of dosing. The major route of elimination was fecal excretion (77-92% 

and 79-87% of the administered dose for Factor J and Factor L, respectively) with unchanged 

parent in the feces accounting for 7-26% of the eliminated radioactivity. Excretion via the urine 

ranged from 3-10% and 2-4% of the administered dose for Factor J and Factor L, respectively. 

Animals given an intravenous dose of Factor J eliminated a larger proportion of radioactivity in 

the urine and elimination of radioactivity in the feces was prolonged compared to orally-dosed 

animals; however the total amount excreted in the feces was similar regardless of route of 

administration indicating that a large portion of orally-administered chemical would be 

eliminated in the feces via biliary excretion. For Factor J, 0.2-3% of the administered dose was 

found in the carcass 168 hours post-dosing with ≤0.4% measured in all other tissues. For Factor 

L, 1-6% and 0.4-6% of the administered dose was found in the carcass and skin, respectively, 

168 hours post-dosing with ≤0.6% measured in all other tissues. The primary metabolites were 

identified as the glutathione and cysteine conjugates of the parent and N- and O-demethylated 

forms of the parent. 

Dermal Absorption: There are no dermal absorption studies available for spinosad/spinetoram; 

however, no hazard was identified for dermal exposure to spinosad or spinetoram (see Section 

4.5.1). As a result, a dermal absorption factor is not needed because a quantitative dermal 

assessment was not performed.

4.3 Toxicological Effects

The primary toxic effect observed from exposure to spinosad or spinetoram was 

histopathological changes in multiple organs (specific target organs were not identified). 

Vacuolization of cells and/or macrophages was the most common histopathological finding 

noted across both toxicological databases with the dog being the most sensitive species. In 

addition to the numerous organs observed with histopathological changes, anemia was noted in 

several studies. 

There was no evidence of increased quantitative or qualitative susceptibility from spinosad or 

spinetoram exposure. In developmental studies, no maternal or developmental effects were seen 

in rats or rabbits. In the rat reproduction toxicity studies, offspring toxicity was seen in the 

presence of parental toxicity at approximately the same dose for both chemicals (75-100 

mg/kg/day). Parental toxicity was evidenced by increased organ weights, mortality, and 

histopathological findings in several organs. Offspring effects included decreased litter size, 

survival, and body weights with spinosad while an increased incidence of late resorptions and 

post-implantation loss was seen with spinetoram. Dystocia and/or other parturition abnormalities 

were observed with both chemicals.

Spinosad and spinetoram are classified as having low acute toxicity via the oral, dermal, and 

inhalation routes of exposure (Toxicity Category III or IV). Neither chemical is an eye or dermal 

irritant. Spinetoram was found to be a dermal sensitizer. In acute and subchronic neurotoxicity 

studies, there was no evidence of neurotoxicity from exposure to spinosad or spinetoram. In an 
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 17 of 45

immunotoxicity study with spinosad, systemic effects (decreased body weights, increased liver 

weights, and abnormal hematology results) were seen at the highest dose tested (141 mg/kg/day); 

however, there was no evidence of immunotoxicity.

Spinosad and spinetoram are classified as “not likely to be carcinogenic to humans” based on 

lack of evidence of carcinogenicity in mice and rats and negative findings in mutagenicity assays 

(see Section 4.5.3). 

4.4 Safety Factor for Infants and Children (FQPA SF)

The RAB1 risk assessment team recommends that the FQPA SF be reduced to 1X for all 

exposure scenarios based on the following considerations outlined in more detail in the sections 

below: (1) the toxicology database for spinosad/spinetoram is adequate for FQPA SF 

consideration; (2) there is no evidence of neurotoxicity from spinosad/spinetoram exposure; (3) 

there is no evidence of increased pre- or post-natal susceptibility; and (4) the exposure databases 

are sufficient and unlikely to underestimate exposure.

4.4.1 Completeness of the Toxicology Database

The existing toxicological database is adequate for characterizing spinosad/spinetoram toxicity 

and quantification of hazard for dietary and occupational exposures. Developmental toxicity 

studies in rats and rabbits and two-generation reproduction toxicity studies in rats are available to 

assess potential fetal/offspring sensitivity. Acute and subchronic neurotoxicity studies in rats are 

available to assess potential neurotoxicity due to spinosad/spinetoram exposure.

4.4.2 Evidence of Neurotoxicity

There is no evidence of neurotoxicity from spinosad/spinetoram exposure. 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no evidence of quantitative or qualitative susceptibility to offspring in the 

developmental studies with rats and rabbits or the rat reproduction toxicity studies (see Section 

4.3). 

4.4.4 Residual Uncertainty in the Exposure Database

The dietary exposure assessment is considered conservative as it assumed 100% crop treated and 

residue estimates based on field trial data. The residential exposure assessment is also 

considered conservative as it incorporated default assumptions from the 2012 Residential SOPs.

4.5 Toxicity Endpoint and Point of Departure Selections

As noted previously, the HASPOC concluded that spinosad and spinetoram should be considered 

toxicologically equivalent for the purposes of human health risk assessment (P. Shah; 18-JUN2007; D340521); therefore, studies from both toxicological databases were considered for 
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 18 of 45

endpoint selection. No changes have been made to toxicity endpoints and points of departure 

since the last risk assessment for spinosad/spinetoram (T. Bloem; 12-OCT-2010; DP#376415) 

except one endpoint was selected to assess short- and intermediate-term durations for incidental 

oral exposure scenarios and one endpoint was selected to assess short- and intermediate-term 

durations for inhalation exposure scenarios.

4.5.1 Dose-Response Assessment

Acute Dietary Endpoint (all populations): There were no effects observed attributable to a single 

dose. Therefore, an endpoint was not selected for this exposure scenario.

Chronic Dietary Endpoint (all populations): Chronic dietary exposures were assessed using the 

spinetoram chronic oral toxicity study in dogs. The LOAEL of 5.36 mg/kg/day is based on 

arteritis and necrosis of the arterial walls of the epididymides in males and of the thymus, 

thyroid, larynx, and urinary bladder in females. The study and endpoint are appropriate for the 

route and duration of exposure. It is protective of adverse effects seen in rats, mice, and dogs 

after chronic repeated exposures to spinosad or spinetoram. The cPAD of 0.0249 is based on the 

NOAEL of 2.49 mg/kg/day from the chronic oral toxicity study in dogs and a 100-fold 

uncertainty factor (10X for interspecies extrapolation, 10X for intraspecies extrapolation, and 1X 

for FQPA SF).

Incidental Oral Exposure (short- and intermediate-term): The spinosad subchronic oral toxicity 

study in dogs was chosen for evaluating incidental oral exposures with a NOAEL of 4.9 

mg/kg/day. The LOAEL of 9.73 mg/kg/day is based on microscopic changes in multiple organs, 

clinical signs, decreases in body weight and food consumption, biochemical evidence of anemia, 

and liver damage. This endpoint is protective of adverse effects seen in rats, mice, and dogs after 

subchronic repeated exposures to spinosad or spinetoram. The LOC for incidental oral 

exposures is 100 (10X for interspecies extrapolation, 10X for intraspecies extrapolation, and 1X 

for FQPA SF).

Dermal Endpoints (all durations): A dermal endpoint was not selected. Since there is no 

concern for enhanced sensitivity/susceptibility to offspring from spinosad/spinetoram exposure, 

the effects of concern in adults and offspring are adequately assessed in the dermal toxicity 

studies with spinosad and spinetoram where no adverse dermal or systemic effects were 

observed up to the limit dose (1000 mg/kg/day).

Inhalation Endpoints (short- and intermediate-term): The spinosad subchronic oral toxicity study 

in dogs was chosen for evaluating inhalation exposures with a NOAEL of 4.9 mg/kg/day. The 

LOAEL of 9.73 mg/kg/day is based on microscopic changes in multiple organs, clinical signs, 

decreases in body weight and food consumption, biochemical evidence of anemia, and liver 

damage. This endpoint is protective of adverse effects seen in rats, mice, and dogs after 

subchronic repeated exposures to spinosad or spinetoram. The LOC for inhalation exposures is 

100 (10X for interspecies extrapolation, 10X for intraspecies extrapolation, and 1X for FQPA SF 

when applicable). Inhalation exposure is assumed to be equivalent to oral exposures.
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 19 of 45

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

When there are potential occupational and residential exposures to a pesticide, the risk 

assessment must address exposures from three major routes (oral, dermal, and inhalation) and 

determine whether the individual exposures can be combined if they have the same toxicological 

effects. For short- and intermediate-exposures, incidental oral and inhalation exposures can be 

combined for spinosad/spinetoram since the same endpoint was chosen for both routes. No 

dermal endpoint was selected.

4.5.3 Cancer Classification and Risk Assessment Recommendation

A cancer risk assessment is not required. The Agency classified spinosad as “not likely to be 

carcinogenic to humans” by all routes of exposure based upon lack of evidence of 

carcinogenicity in rats and mice. Based on the structural similarity of spinosad and spinetoram 

and similarities of the toxicological databases for these chemicals, spinetoram is classified as 

“not likely to be carcinogenic to humans” based on the spinosad carcinogenicity studies. 

Carcinogenicity studies with spinetoram have been submitted. No evidence of carcinogenicity 

was observed in rats. The carcinogenicity study in mice is currently under review and 

preliminary review yields no evidence of carcinogenicity. Mutagenicity studies conducted with 

spinetoram were also negative. 

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

Table 4.5.4.1: Summary of Toxicological Doses and Endpoints for Spinosad/Spinetoram for Use in Dietary and NonOccupational Human Health Risk Assessments.

Exposure/ Scenario Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, LOC for 

Risk Assessment Study and Toxicological Effects

Acute Dietary

(All Populations) A dose and endpoint of concern attributable to a single dose was not observed.

Chronic Dietary

(All Populations)

NOAEL = 

2.49 mg/kg/day

UFA = 10X

UFH = 10X

FQPA = 1X

cRfD = 0.0249 

mg/kg/day

cPAD = 0.0249 

mg/kg/day

Chronic Toxicity – Dog (Spinetoram)

LOAEL = 5.36/5.83 mg/kg/day 

(males/females) based on arteritis and 

necrosis of the arterial walls of the 

epididymides in males and of the thymus, 

thyroid, larynx, and urinary bladder in 

females 

Incidental Oral 

Short-Term (1-30 

days) and 

Intermediate-Term (1-

6 months) 

NOAEL = 

4.9 mg/kg/day

UFA = 10X

UFH = 10X

FQPA = 1X

Residential LOC for 

MOE < 100

Subchronic Oral Toxicity – Dog (Spinosad)

LOAEL = 9.73 mg/kg/day based on 

microscopic changes in multiple organs, 

clinical signs of toxicity, decreases in body 

weights and food consumption, and 

biochemical evidence of anemia and liver 

damage

Dermal

(All durations) 

No hazard was identified for dermal exposure; therefore a quantitative dermal assessment is not 

needed.
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 20 of 45

Table 4.5.4.1: Summary of Toxicological Doses and Endpoints for Spinosad/Spinetoram for Use in Dietary and NonOccupational Human Health Risk Assessments.

Exposure/ Scenario Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, LOC for 

Risk Assessment Study and Toxicological Effects

Inhalation

Short-Term (1-30 

days) and 

Intermediate-Term (1-

6 months)

NOAEL = 

4.9 mg/kg/day

Inhalation 

assumed 

equivalent to 

oral

UFA = 10X

UFH = 10X

FQPA = 1X

Residential LOC for 

MOE < 100

Subchronic Oral Toxicity – Dog (Spinosad)

LOAEL = 9.73 mg/kg/day based on 

microscopic changes in multiple organs, 

clinical signs of toxicity, decreases in body 

weights and food consumption, and 

biochemical evidence of anemia and liver 

damage

Cancer (oral, dermal, 

inhalation) Classified as “not likely to be carcinogenic to humans”

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning 

of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. 

LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = 

potential variation in sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. 

FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. 

LOC = level of concern. 

Table 4.5.4.2: Summary of Toxicological Doses and Endpoints for Spinosad/Spinetoram for Use in Occupational 

Human Health Risk Assessments.

Exposure/ Scenario Point of 

Departure Uncertainty Factors Level of Concern for Risk Assessment Study and Toxicological Effects

Dermal

(All durations) 

No hazard was identified for dermal exposure; therefore a quantitative dermal assessment is not 

needed.

Inhalation

Short-Term (1-30 

days) and 

Intermediate-Term (1-

6 months)

NOAEL = 

4.9 mg/kg/day

Inhalation 

assumed 

equivalent to 

oral

UFA = 10X

UFH = 10X

Occupational LOC 

for MOE < 100

Subchronic Oral Toxicity – Dog (Spinosad)

LOAEL = 9.73 mg/kg/day based on 

microscopic changes in multiple organs, 

clinical signs of toxicity, decreases in body 

weights and food consumption, and 

biochemical evidence of anemia and liver 

damage

Cancer (oral, dermal, 

inhalation) Classified as “not likely to be carcinogenic to humans” 

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning 

of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. 

LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = 

potential variation in sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. MOE 

= margin of exposure. LOC = level of concern. 
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 21 of 45

5.0 Dietary Exposure and Risk Assessment 

residue chemistry summary: D416068, T. Bloem, 10-Mar-2015

dietary exposure memorandum: D423657, T. Bloem, 10-Mar-2015

5.1 Residues of Concern Summary and Rationale

Tables 5.1.1 and 5.1.2 are summaries of the residues of concern for dietary risk assessment and 

the tolerance expression for spinosad and spinetoram, respectively. The following paragraphs 

are brief summaries of the available metabolism data.

Spinosad: The metabolic pathway in crops (primary and rotational), livestock, fish, and rat were 

similar and involved demethylation of the forosamine ring, demethylation of the rhamnose ring, 

and/or hydroxylation of the macrolide. In primary crops, spinosad was further degraded to 

multiple low molecular weight compounds which are subsequently incorporated into natural 

plant constituents.

Spinetoram: The metabolic pathway in crops, livestock, and rats were qualitatively similar. The 

metabolic pathway in primary crops involved demethylation of the forosamine ring, changes to 

the rhamnose ring producing the 3-O-deethyl, and/or cleavage of the rhamnose ring. Parent and 

the metabolites were ultimately subjected to opening of the macrolide ring system at several 

positions resulting in numerous components with this pathway predominating in the residue 

profile. The confined rotation crop study resulted in a similar metabolic profile as primary crops 

(soil application at 0.45 lb ai/acre). No significant metabolism of spinetoram was observed in 

ruminants, as the unchanged parent molecule was the primary residue component identified in 

milk and tissue samples. Ruminant liver and muscle contained one unidentified metabolite 

(XDE-175-J labeled study - <10% TRR; XDE-175-L labeled study - <27% TRR) and minor 

amounts of ND-J and ND-L. In hen, parent was the major residue in egg and all tissues except 

liver where parent and the demethylated and/or deethylated metabolites predominated. In the rat, 

the major route of metabolism was found to be glutathione conjugation with the parent 

compound, as well as glutathione conjugation with N-demethylated, O-deethylated, and 

hydroxylated forms of parent. 

Table 5.1.1: Residues for Tolerance Expression and Risk Assessment for Spinosad.

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression

Plants1spinosyn A and D spinosyn A and D

Hog and Ruminants1 oral and dermal - spinosyn A and D oral and dermal - spinosyn A and D

Poultry1,2

oral - spinosyn A and D; dermal (excluding liver) - spinosyn A 

and D; dermal (liver) - spinosyns A, B, D, J, N-demethyl D, and 

N-demethyl J

oral and dermal spinosyn A and D

Rotational Crops1spinosyn A and D spinosyn A and D

Drinking Water3total spinosad --

Fish/Shellfish4

adjustment of the TRRs in the edible tissues from the spinosyn A 

bioconcentration study (19 ppb data) for the EFED water 

concentration resulting from the mosquito larvicide use

spinosyn A and D

1

 D243816, G. Herndon, 03-Mar-1998; D264984, W. Donovan, 14-Jun-2002.

2

 D374794, T. Bloem, 25-Mar-2010.

3 D316077, T. Bloem et al., 02-Aug-2006.

4

 HED notes that these conclusions are appropriate for this mosquito larvicide petition only and will be reevaluated if the 

petitioner alters the aquatic application scenario (D316077, T. Bloem et al, 02-Aug-2006).
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 22 of 45

Table 5.1.2: Residues for Tolerance Expression and Risk Assessment.

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression

Plants XDE-175-J, XDE-175-L, ND-J, and NF-J XDE-175-J, XDE-175-L, ND-J, and NF-J

Rotational Crops

Not determined. Based on the available data and provided the application rate is ≤0.45 lb ai/acre, the following 

rotational crop restrictions are appropriate: labeled crops may be rotated immediately to a treated field and nonlabeled 

crops may be rotated 30 days after application. 

Ruminants1 XDE-175-J, XDE-175-L, ND-J, and NF-J XDE-175-J, XDE-175-L, ND-J, and NF-J

Hen1 XDE-175-J, XDE-175-L, ND-J, NF-J, 3'-O-deethyl-175-J,

3'-O-deethyl-175-L, and O-demethyl-175-L

2 XDE-175-J, XDE-175-L, ND-J, and NF-J

1

 ND-J and NF-J were included as residues of concern in livestock due to their presence in/on feed commodities.

2

 O-demethyl-175-L is either 2’-O-demethyl-175-L or 4’-O-demethyl-175-L or a mixture of both.

5.2 Food Residue Profile

Magnitude of the Residue Primary Crops: In support of the proposed application to coffee (spinosad 

and spinetoram), PHI reduction for plum/prune (spinosad and spinetoram), and the addition of 

instructions permitting application directed to the base crop group 5 crops (spinosad and spinetoram), 

the petitioner submitted adequate coffee (included processing data), plum (included processing data), 

and broccoli/cabbage field trial data. The remaining proposals pertain to updates to the crop 

group/subgroup tolerance commodity definitions; since the proposed application scenarios for crops are 

identical to that previously reviewed, no residue data were submitted and none are required. HED 

concludes that the available magnitude of the residue data are adequate and support the HED 

recommended tolerance listed in Table 2.2.2.1 (a revised Section F is requested). It is noted that the 

currently established spinosad and spinetoram stone fruit (i.e., plum) and crop group 5 tolerances are 

adequate to cover the proposed label amendments. 

Magnitude of the Residue – Rotational Crops: Based on the results of a spinosad confined 

rotational crop study and the proposed application rates, HED concludes that no rotational crop 

restrictions or tolerances are required for the currently-proposed crops (D243816, G. Herndon, 

03-Mar-1998). Field rotational crop data have not been submitted and are not required. 

Based on the results of a spinetoram confined rotational crop study and the proposed application 

rates, HED concludes that the proposed 30-day plant-back interval (PBI) for all nonlabeled crops is 

appropriate (46695021.der.doc; 47396301.der.doc). 

Magnitude of the Residue – Livestock: Since coffee, plum, and crop group 5 do not include any 

significant ruminant/hog/poultry feed commodities and since the proposed application scenario for 

the remaining crops is identical to that previously assessed, HED concludes that a discussion 

concerning the magnitude of the residue in meat, milk, poultry, and eggs is unnecessary. 

5.3 Water Residue Profile

Drinking water residues were incorporated directly into the chronic dietary analyses (“water, direct, all 

sources” and “water, indirect, all sources”) and were provided by EFED using the following models 

(D415816, L. Liu, 19-Feb-2015; D325409, L. Liu, 14-May-2007): Surface Water Concentration 

Calculator (SWCC) and Screening Concentration in Ground Water (SCIGROW). Table 5.3.1 is a 

summary of the modeled water concentrations. Based on these estimates, the chronic analysis 

assumed a water residue estimate of 21.7 ppb. The models and their description are available at the 

EPA internet site: http://www.epa.gov/ oppefed1/models/water/.
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 23 of 45

EFED provided Pesticide Root Zone Model – Groundwater (PRZM-GW) EDWCs for spinosad and 

spinetoram using only the proposed application scenarios. The resulting EDWCs were significantly 

lower than the surface water EDWCs generated using the same application scenario and the SWCC 

model. Based on this, HED concludes that generation of PRZM-GW EDWCs using the 

spinosad/spinetoram turf application scenario is unnecessary. 

Table 5.3.1: EDWCs for Spinosad/Spinetoram (ppb).

Surface/Ground (Model) Acute Chronic Long-term average

spinosad (turf application scenario; 4 x 0.4 lb ai/acre; RTI = 7 days)1

surface (SWCC) 25.0 21.7 14.2

ground (SCIGROW) 1.1 1.1 1.1

spinetoram (turf and fire ant mound application; 1 x 0.454 lb ai/acre)1

surface (SWCC) 8.6 5.9 3.8

ground (SCIGROW) 0.072 0.072 0.072

1

 D415816, L. Liu, 19-Feb-2015; D325409, L. Liu, 14-May-2007

5.4 Dietary Risk Assessment

5.4.1 Summary of Dietary Exposure/Risk Estimates

A chronic dietary risk assessment was conducted using DEEM-FCID (ver. 3.16) which incorporates 

food consumption data from the USDA NHANES/WWEIA (2003-2008). Acute and cancer analyses 

were not conducted as toxicological effects attributable to a single dose were not identified and 

spinetoram and spinosad are classified as not likely to be carcinogens (cancer risk assessment is not 

required). The chronic analysis assumed 100% crop treated, average field-trial residues or tolerancelevel residues for crop commodities, average residues from the livestock feeding studies, spinosad 

residue estimates for fish/shellfish (residues of spinetoram in fish/shellfish are expected to be 

insignificant), experimental processing factors when available, and modeled drinking water estimates. 

The resulting chronic exposure estimates do not exceed HED's level of concern (≤64% cPAD; children 

1-2 years old were the most highly exposed subpopulation). Table 5.4.1.1 is a summary of the dietary 

exposure and risk estimates. 

Table 14: Summary of Chronic Dietary (food and water) Exposure and Risk for Spinosad/Spinetoram.

Population Subgroup cPAD (mg/kg/day) Chronic

Exposure (mg/kg/day) %cPAD

general U.S. Population

0.0249

0.005029 20

all Infants (<1 year old) 0.007054 28

children 1-2 years old 0.015861 64

children 3-5 years old 0.010909 44

children 6-12 years old 0.006734 27

youth 13-19 years old 0.003924 16

adults 20-49 years old 0.004353 18

adults 50+ years old 0.003889 16

females 13-49 years old 0.003967 16

5.4.2 Percent CT Used in Dietary Assessment

The dietary analysis assumed 100% CT for all commodities. 
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 24 of 45

6.0 Residential (Non-Occupational) Exposure/Risk

D417200, J. Tyler, 10-Mar-2015

The proposed uses will not result in residential exposure. However, residential handler (shortterm inhalation exposures) and post-application (short-term incidental oral) exposures are 

expected as a result of the following registered uses and were reassessed to conform with current 

policies and guidance (see Appendix D for application scenarios; based on toxicological 

considerations, a dermal assessment is unnecessary): (1) homeowner application of spinosad to 

gardens, turfgrass, ornamentals and fire ant mounds; (2) homeowner application of spinetoram to 

lawns, gardens, and ornamentals; and (3) spot-on application of spinetoram to cats and kittens. 

The handler and post application risk estimates are summarized in Table 6.0.1 and 6.0.2, 

respectively, and are not of concern for all scenarios (LOC for MOEs < 100; calculated MOEs 

were ≥ 720). Table 6.0.3 are the residential risk estimates that are recommended for use in the 

aggregate assessment for spinosad and spinetoram and reflect the highest doses for each 

applicable lifestages for all exposure scenarios resulting from the uses which yield residential 

exposure. 

Aggregating exposure resulting from the turf and pet uses was not conducted as the products 

control different pests and, therefore, making application on the same day unlikely. In addition, 

current HED policy requires assessment for residential post-application exposures of short- (1 to 

30 days), intermediate- (1 to 6 months), and long-term (greater than 6 months) exposures from 

spot-on products due to the preventative nature of these products and the potential for extended 

usage in more temperate parts of the country. However, for spinetoram, there is no progression 

of toxicity with time; therefore, the short-term assessment is protective of intermediate- and 

long-term exposure.

In support of the turf uses, an adequate spinosad turf transferable residue (TTR) study has been 

submitted and was incorporated into the current assessment (D256668, S. Weiss, 28-Sep-1999). 

In addition, an adequate spinetoram study measuring dislodgeable residues from petting after 

topical administration to cats was submitted and was incorporated in this assessment (D395611, 

L. Venkateshwara, 20-Apr-2012). Spinosad and spinetoram dislodgeable-foliar residue (DFR)

studies are unnecessary at this time as there is no hazard via the dermal route of exposure. 

Table 6.0.1: Residential Handler Inhalation Exposures and Risk Estimates for Spinosad and Spinetoram.

Exposure Scenario Application 

Rate1

Area 

Treated 

Daily2

Inhalation Unit 

Exposure2

(mg/lb ai)

Inhalation Dose 

(mg/kg/day)3

Short-term 

Inhalation 

MOE4

Spinosad

Mixing/Loading/Applying Dust Formulations to Home 

Gardens and Ornamentals via Shaker Can, Hand Crank 

Duster, and Electric/power Duster 0.00001 lb 

ai/1000 feet2 1200 feet2

Baseline5: 18 Baseline: 

0.0000027

Baseline: 

1,800,000

Mixing/Loading/Applying Dust Formulations to Home 

Gardens and Ornamentals via Plunger Duster and Bulb 

Duster

Baseline: 1.7 Baseline: 

0.00000026

Baseline: 

19,000,000

Mixing/Loading/Applying Liquid Formulations to 

Lawns/Turf via Hose-end Sprayer

0.41 lb 

ai/acre

0.5 acre6

Baseline: 

0.022

Baseline: 

0.000056

Baseline: 

87,000

Mixing/Loading/Applying Liquid Formulations to 

Lawns/Turf via Manually-pressurized Handwand

Baseline: 

0.018

Baseline: 

0.000046

Baseline: 

110,000

Mixing/Loading/Applying Liquid Formulations to 

Lawns/Turf via Backpack Sprayer Baseline: 0.14 Baseline: 0.00036

Baseline: 

14,000
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 25 of 45

Table 6.0.1: Residential Handler Inhalation Exposures and Risk Estimates for Spinosad and Spinetoram.

Exposure Scenario Application 

Rate1

Area 

Treated 

Daily2

Inhalation Unit 

Exposure2

(mg/lb ai)

Inhalation Dose 

(mg/kg/day)3

Short-term 

Inhalation 

MOE4

Spinosad

Mixing/Loading/Applying SC Formulations to Fire Ant 

Mounds via Shaker Can

0.0013 lb 

ai/mound 5 mounds Baseline: 0.022

Baseline: 

0.0000018

Baseline: 

2,700,000

Spinetoram

Mixing/Loading/Applying DF Formulations Turf, Home 

Gardens and Ornamentals via Manually-pressurized 

Handwands and Backpacks 0.0005 lb 

ai/gal 

5 gallons Baseline: 1.1 Baseline: 

0.000034

Baseline: 

140,000

Mixing/Loading/Applying DF Formulations Turf, Home 

Gardens and Ornamentals via Sprinkler Can 5 gallons Baseline: 0.0014

Baseline: 

0.000000044

Baseline: 

110,000,000

Mixing/Loading/Applying DF Formulations to Lawns/Turf 

via Hose-end Sprayer 

0.061 lb 

ai/acre

0.5 acre Baseline: 0.022 Baseline: 

0.0000084

Baseline: 

580,000

1

 Application rate = maximum application rate from current labels (see Appendix D).

2

 Area treated and Unit Exposure values based on 2012 Residential SOPs.

3

 Dose (mg/kg/day) = Unit exposure (mg/lb ai) x App Rate (lb ai/acre or lb ai/gallon) x Area Treated or Amount Handled 

(acres/day or gallons/days) x %Absorption (100% inhalation) / Body weight (80 kg). 

4

 MOE = NOAEL (mg/kg/day) / Dose (mg/kg/day); where the short-term NOAEL = 4.9 mg/kg/day.

5

 Baseline Inhalation: no respirator.

6

 0.5 A is a typical assumption for broadcast applications per the 2012 Residential SOPs, and is considered conservative for 

manually-pressurized handwands and backpacks which are typically used for spot treatments.

Table 6.0.2: Residential Post-application Non-cancer Exposure and Risk Estimates for Spinosad/Spinetoram.

Lifestage

Post-application Exposure Scenario Application 

Rate1 TTR (ug/cm2

)

2 Dose 

(mg/kg/day)3 MOEs4

Use Site Route of Exposure

Child (1 to <2 

years)

Turf/Home 

Gardens/Ornamental

Liquid Formulations

Hand-to-mouth

0.41 lb ai/acre 0.05

0.0069 720

Object-to-mouth 0.00021 24,000

Soil Ingestion 0.00014 350,000

Cat Spot-on Hand-to-Mouth 231 mg ai/app. N/A 0.0039 1,200

1

 Based on registered labels (See Table 4.2).

2

 TTR based on submitted chemical-specific study (MRID 44828401; D256668). Predicted value from CA site used as 

conservative assumption.

3

 Dose (mg/kg/day) equations provided in 2012 Residential SOPs. FAR for cat spot-on dose calculations taken from chemicalspecific study (MRID 48595401; D395611).

4

 MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day).

Table 6.0.3: Recommendations for the Residential Exposures for the Spinosad/Spinetoram Aggregate Assessment.

Lifestage Exposure Scenario

Dose (mg/kg/day)1 MOE2

Inhalation Oral Inhalation Oral

Adults Mixing/Loading/Applying Liquid Formulations to 

Turf via Backpack Sprayer 0.00036 -- 14,000 --

Child (1 to <2 years) Hand-to-Mouth Exposure from Liquid Formulation 

on Turf/Home Gardens/Ornamentals -- 0.0069 -- 720

1 Dose = the highest dose for each applicable lifestages of all residential scenarios assessed.

2 MOE = the MOEs associated with the highest residential doses.
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 26 of 45

6.1 Residential Bystander Post-Application Inhalation Exposure

Volatilization of pesticides may be a source of post-application inhalation exposure to individuals 

nearby pesticide applications. The agency sought expert advice and input on issues related to 

volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific 

Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The agency has evaluated 

the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization 

Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). 

During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux 

studies, route-specific inhalation toxicological studies) or further analysis is required for

spinetoram and spinosad.

6.2 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is 

particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential 

source of exposure from the ground application methods (e.g., groundboom and airblast) employed 

for spinosad and spinetoram. The agency has been working with the Spray Drift Task Force (a task 

force composed of various registrants which was developed as a result of a Data Call-In issued by 

EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to 

develop the best spray drift management practices (see the agency’s Spray Drift website for more 

information; http://www.epa.gov/opp00001/factsheets/spraydrift.htm). The agency has also 

developed a policy on how to appropriately consider spray drift as a potential source of exposure in 

risk assessments for pesticides. The potential for spray drift will be quantitatively evaluated for 

each pesticide during the Registration Review process which ensures that all uses for that pesticide 

will be considered concurrently. The approach is outlined in the revised (2012) Standard 

Operating Procedures For Residential Risk Assessment (SOPs) - Residential Exposure Assessment 

Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines 

the quantification of indirect non-occupational exposure to drift. 
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 27 of 45

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED considers and aggregates pesticide exposures and risks from 

three major sources: food, drinking water, and residential exposures. In an aggregate assessment, 

exposures from relevant sources are added together and compared to quantitative estimates of hazard 

(e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures 

and risks from various sources, HED considers both the route and duration of exposure. 

Based on the anticipated residential exposure scenarios and since acute and cancer risk assessments 

are not required, only short-term (residential, food, and water) and chronic (food and water) 

aggregate exposure assessments were conducted. Since the aggregate chronic assessment is made up 

of only dietary sources (food and water), the dietary exposure estimates provided in Section 5.4.4 

represents chronic aggregate exposure; all chronic exposures were less than HED’s LOC (≤64% 

cPAD). 

For calculation of aggregate short-term exposure and as indicated in Section 6.0, residential 

exposure to adults (handler) and children (post-application ) resulting from the application of 

spinosad to turf/ornamentals/home garden yield the highest residential exposure and were therefore 

used in calculation of aggregate short-term exposure. Table 7.0.1 is a summary of the short-term 

aggregate exposures and risk estimates. Since the aggregate MOEs are ≥220 (LOC for MOEs 

<100), short-term aggregate exposure to spinosad and spinetoram do not exceed HED's LOC. HED 

notes that although only a short-term aggregate risk assessment was conducted, the short-term 

assessment is protective of intermediate-term exposure as the short-/intermediate-term PODs are 

identical.

Table 6.0.1: Short-Term Aggregate Risk Calculations.

Population NOAEL

(mg/kg/day)

Target

MOE

Chronic Food 

Water Exposure

(mg/kg/day)

Incidental Oral 

Exposure

(mg/kg/day)1

Handler Inhalation 

Exposure

(mg/kg/day)1

Aggregate MOE 

(food, water, and 

residential)2

General U.S. Population

4.9 100

0.005029 -- 0.00036 910

Children 1-2 years old 0.015861 0.0069 -- 220

Adults 20-49 years old 0.004353 -- 0.00036 1000

1

 See Section 6.0 and Table 6.0.1.

2

 Aggregate MOE = NOAEL ÷ (chronic dietary exposure + residential exposure).

8.0 Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to spinosad/spinetoram and any other substances and spinosad/spinetoram do not appear to 

produce a toxic metabolite produced by other substances. For the purposes of this tolerance 

action, therefore, EPA has not assumed that spinosad/spinetoram have a common mechanism of 

toxicity with other substances. For information regarding EPA’s efforts to determine which 

chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such 

chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning 

common mechanism determinations and procedures for cumulating effects from substances found 

to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative.
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 28 of 45

9.0 Occupational Exposure/Risk Characterization

D417200, J. Tyler, 10-Mar-2015

Occupational exposures were assessed for the proposed use on coffee. For the updates to the crop 

group/subgroups commodity definitions, no amendments to the use patterns (i.e., maximum use rates, 

RTIs, PHIs, REIs, PPE, use of adjuvants, etc.) have been proposed. Therefore, an occupational 

assessment for these uses was not performed, and are considered covered by previous assessments. In 

addition, the label amendment requests do no warrant a new occupational exposure assessment. 

9.1 Occupational Handler Exposure/Risk Assessment

Based on the anticipated use patterns and current labeling, types of equipment, and techniques that can 

potentially be used, short- and intermediate-term occupational handler exposure for the following 

scenarios are expected: (1) mixer/loader: open mixing/loading DF(dry flowable)/WDG and SC 

formulations for aerial and airblast applications; (2) applicator: applying sprays using aerial and 

airblast equipment; (3) flagger: flagging to support aerial applications; and (4) 

mixer/loader/applicator: open mixing/loading/applying DF (dry flowable), WDG, and SC 

formulations for applications via mechanically-pressurized handgun.

It is noted that no hazard was identified for dermal exposure (all durations); therefore a dermal 

assessment is unnecessary. For the scenarios where baseline data are available, all inhalation risks for 

occupational handlers are not of concern to HED (i.e., MOE> the LOC of 100) with baseline 

protection (i.e., long-sleeve shirt, long pants, shoes, and socks). Only engineering control data (i.e., 

enclosed cockpits) are available for aerial application scenarios. All inhalation risks for occupational 

aerial applicators are above the LOC (100) with baseline clothing and enclosed cockpits.

Table 9.1.1: Occupational Handler Non-Cancer Exposure and Risk Estimates for Spinosad and Spinetoram. 

Exposure Scenario Crop or 

Target

Inhalation Unit Exp (μg/lb ai)1 Max. App.

Rate (lb 

ai/acre)

2

Area Treated or 

Amount 

Handled Daily3

Inhalation

Mitigation Level Dose 

(mg/kg/day)4 MOE5

Mixer/Loader

DF/WDG – Aerial application

Coffee

Baseline: 8.96 0.08 350 acres 0.00314 1,600

DF/WDG – Airblast application 0.08 40 acres 0.000359 14,000

SC – Aerial application Baseline: 0.219 0.16 350 acres 0.000154 32,000

SC – Airblast application 0.16 40 acres 0.0000175 280,000

Applicator

Aerial applications Coffee Eng. control: 0.0049 0.16 350 acres 0.00000343 1,400,00

Airblast applications Baseline: 4.71 0.16 40 acres 0.000376 13,000

Flagger

Flagger Coffee Baseline: 0.35 0.16 350 acres 0.000245 20,000

Mixer/Loader/Applicator

DF/WDG – Mechanicallypressurized handgun

Coffee Baseline: 3.9

0.016

1000 gal

0.00078 6,300

SC – Mechanically-pressurized 

handgun 0.032 0.00156 3,100

1

 Unit Exposures are taken from “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table,” Feb. 2015. 

2

 Based on proposed Entrust® SC (EPA Reg No. 62719-621), Delegate® WG (EPA Reg No. 62719-541) and Radiant® SC (EPA 

Reg No. 62719-545) labels.

3

 Units Treated are taken from “Standard Values for Daily Acres Treated in Agriculture”; ExpoSAC SOP No. 9.1, 25-Sep-2001.

4

 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × 

Area Treated or Amount Handled (acres or gal/day) ÷ BW (80 kg).

5

 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). Inhalation NOAEL = 4.9 mg/kg/day.
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 29 of 45

9.2 Occupational Post-Application Exposure/Risk Assessment

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to 

perform job functions, including activities related to crop production, such as scouting for pests 

or harvesting. Post-application exposure levels vary over time and depend on such things as the 

type of activity, the nature of the crop or target that was treated, the type of pesticide application, 

and the chemical’s degradation properties. In addition, the timing of pesticide applications, 

relative to harvest activities, can greatly reduce the potential for post-application exposure.

A quantitative occupational post-application inhalation exposure assessment was not performed. 

However, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios. Furthermore, inhalation exposure during dusty mechanical 

activities such as shaking and mechanical harvesting is another potential source of postapplication inhalation exposure. However, the airblast applicator scenario is believed to 

represent a reasonable worst-case surrogate estimate of post-application inhalation exposure 

during these dusty mechanical harvesting activities. The non-cancer inhalation risk estimate for 

commercial airblast application is not of concern (i.e., MOE > 100).

It is noted that no hazard was identified for dermal exposure (all durations); therefore a dermal 

assessment is unnecessary. 

Spinosad and spinetoram are classified as Toxicity Category III or IV based upon data for 

acute dermal toxicity, acute inhalation toxicity, primary skin irritation, and primary eye 

irritation. Typically, the REI specified on the proposed label is based on the acute toxicity of 

the active ingredient. Under 40 CFR 156.208 (c) (2) (iii), active ingredients classified as Acute 

III or IV for acute dermal, eye irritation, and primary skin irrigation are assigned a 12-hour 

REI. However, it is noted that the proposed product label has a 4-hour REI listed. REIs may 

be further reduced from 12 hours if certain criteria are met for both the technical material and 

the different end-use products in accordance with the Pesticide Registration (PR) Notice 95-3 

(Reduction of Worker Protection Standard (WPS) Interim REIs for Certain Low Risk 

Pesticides; http://www.epa.gov/PR_Notices/pr95-3.html). Based only on the acute toxicity 

categories, spinosad and spinetoram are possible candidates for a 4-hour REI; however, RD 

should ensure that the additional criteria listed in PR Notice 95-3 are met for both active 

ingredients and the end-use products.

RDI: RAB1 (04-Mar-2015)

Appendix A. Toxicology Assessment

Appendix B. Chemical Names and Structures

Appendix C. Physiochemical Properties

Appendix D: Registered Residential Uses for Spinosad/Spinetoram
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 30 of 45

Appendix A. Toxicology Assessment

A.1. Toxicology Data Requirements

Study requirements for spinosad/spinetoram are presented below. Use of the new guideline 

numbers does not imply that the new (1998) guideline protocols were used.

Study

Technical

Required Satisfied

870.1100 Acute Oral Toxicity

870.1200 Acute Dermal Toxicity

870.1300 Acute Inhalation Toxicity

870.2400 Acute Eye Irritation

870.2500 Acute Dermal Irritation

870.2600 Skin Sensitization

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 90-Day Oral Toxicity (rodent)

870.3150 90-Day Oral Toxicity (nonrodent)

870.3200 21/28-Day Dermal Toxicity

870.3250 90-Day Dermal Toxicity

870.3465 90-Day Inhalation Toxicity

yes

yes

yes

no

no1

yes

yes

yes

--

--

870.3700a Prenatal Developmental Toxicity (rodent)

870.3700b Prenatal Developmental Toxicity (nonrodent)

870.3800 Reproduction and Fertility Effects

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)

870.4100b Chronic Toxicity (nonrodent)

870.4200a Carcinogenicity (rat)

870.4200b Carcinogenicity (mouse)

870.4300 Combined Chronic Toxicity/Carcinogenicity

yes

yes

yes

yes

yes

yes2

yes

yes2

yes

yes

870.5100 Mutagenicity—Bacterial Reverse Mutation Test

870.5300 Mutagenicity—Mammalian Cell Gene Mutation Test

870.5xxx Mutagenicity— Structural Chromosomal Aberrations

870.5xxx Mutagenicity—Other Genotoxic Effects

yes

yes

yes

yes

yes

yes

yes

yes

870.6200a Acute Neurotoxicity Screening Battery (rat)

870.6200b 90-Day Neurotoxicity Screening Battery (rat)

870.6300 Developmental Neurotoxicity

yes

yes

no

yes

yes

--

870.7485 Metabolism and Pharmacokinetics

870.7600 Dermal Penetration

870.7800 Immunotoxicity

yes

no

yes

yes

--

yes

1 HED HASPOC concluded that the subchronic inhalation study was not required at this time (U. Habiba, 15-OCT2014, TXR #0057052). 

2 The combined chronic toxicity/carcinogenicity study satisfies the requirement of the study. 
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 31 of 45

A.2 Toxicity Profiles

Table A.2.1: Acute Toxicity - Spinosad

Guideline No. Study Type MRID Results Toxicity Category

870.1100 Acute Oral-Rat 43770701; 43414515 LD50 = >2000 mg/kg III

870.1200 Acute Dermal-Rabbit 43414516 LD50 = >2000 mg/kg III

870.1300 Acute Inhalation-Rat 43414517 LC50 = >5.18 m/L IV

870.2400 Acute Eye Irritation 43414518 not an eye irritant IV

870.2500 Acute Dermal Irritation 43414519 not a skin irritant IV

870.2600 Dermal Sensitization 43414520 not a skin sensitizer N/A

Table A.2.2: Subchronic, Chronic, and Other Toxicity Studies - Spinosad

Guideline No./Study 

Type

MRID No. (year)/

Classification/Doses Results

870.3100

90-Day oral toxicity 

rodents-Mouse

43566602 (1992)

Acceptable/guideline 

0, 0.005, 0.015, 0.045, or 0.12% 

0, 7.5, 22.5, 67.5, or 180 

mg/kg/day

NOAEL = 7.5 mg/kg/day in males and females.

LOAEL = 22.5 mg/kg/day in males and females; based on 

cytoplasmic vacuolation of lymphoid organs, liver, kidney, stomach, 

female reproductive tract, and epididymis. Other tissues less severely 

affected are heart, lung, pancreas, adrenal cortex, bone marrow, 

tongue, and pituitary gland. 

870.3100

90-Day oral toxicity 

rodents-Rat

43566601 (1992)

Acceptable/guideline

0, 0.05, 0.1, 0.2, or 0.4%

0/0, 33.9/38.8, 68.5/78.1, 

133.5/151.6, or 273.1/308.2 

mg/kg/day; M/F

NOAEL = 33.9 mg/kg/day in males; 38.8 mg/kg/day in females.

LOAEL = 68.5 mg/kg/day in males; 78.1 mg/kg/day in females based 

on adrenal cortical vacuolation in males, lymph node histiocytosis in 

both sexes.

870.3100

90-Day oral toxicity 

rodents-Rat

43557502 (1994)

Acceptable/guideline

0, 0.003, 0.006, 0.012, or 0.06%

0/0, 2.2/2.6, 4.3/5.2, 8.6/10.4, or 

42.7/52.1 mg/kg/day; M/F

NOAEL = 42.7 mg/kg/day in males; 52.1 mg/kg/day in females 

(HDT).

LOAEL= Not observed in males and females.

870.3150

90-Day oral toxicity 

nonrodents-Dog

43444102 (1994)

Acceptable/guideline

0, 150, 300, or 1350/900 (males) 

900 (females) ppm

0/0, 4.89/5.38, 9.73/10.47, or 

33.4/29.9 mg/kg/day; M/F

NOAEL = 4.89 mg/kg/day in males; 5.38 mg/kg/day in females.

LOAEL = 9.73 mg/kg/day in males; 10.47 mg/kg/day in females 

based on microscopic changes in a variety of tissues, clinical signs of 

toxicity, decreases in mean body weights and food consumption, and 

biochemical evidence of anemia and possible liver damage.

870.3200

Repeated Dose Dermal 

Toxicity- Rabbit (21 

days)

43557503 (1984)

Acceptable/guideline

0, 100, 500, or 1000 mg/kg/day

NOAEL = 1000 mg/kg/day in males and females (HDT).

LOAEL = Not observed.

870.3465

Subchronic Inhalation 

Study

49425601 (1999)

Acceptable/non-guideline

0, 0.0003, 0.0014, or 0.0095 mg/L

NOAEL = 0.0095 mg/L

LOAEL = not established

870.3700a 

Prenatal developmental 

in rodents- Rat

43557505 (1993)

43770702 (1992; range finding)

Acceptable/guideline

0, 10, 50, or 200 mg/kg/day

Maternal: NOAEL = 200 mg/kg/day (HDT).

LOAEL = Not observed.

Developmental: NOAEL = 200 mg/kg/day (HDT).

LOAEL = Not observed.
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 32 of 45

Table A.2.2: Subchronic, Chronic, and Other Toxicity Studies - Spinosad

Guideline No./Study 

Type

MRID No. (year)/

Classification/Doses Results

870.3700b 

Prenatal developmental 

in nonrodents- Rabbit

43414521 (1994)

43770703 (1992; range finding)

Acceptable/guideline

0, 2.5, 10.0, or 50.0 mg/kg/day

Maternal: NOAEL = 50 mg/kg/day (HDT).

LOAEL = Not observed.

Developmental: NOAEL = 50 mg/kg/day (HDT).

LOAEL = Not observed.

870.3800 Reproduction 

and fertility effects- Rat

43701506 (1994)

Acceptable/guideline

0, 0.005, 0.02, or 0.2%

0, 3, 10, or 100 mg/kg/day

Parental/Systemic NOAEL = 10 mg/kg/day.

LOAEL = 100 mg/kg/day based on increases in heart, kidney, liver, 

spleen, and thyroid weights (both sexes), corroborative histopathology 

in the spleen and thyroid (both sexes), heart and kidney (males only), 

and histopathologic lesions in the lungs and mesenteric lymph nodes 

(both sexes), stomach (females only), and prostate. 

Reproductive NOAEL = 10 mg/kg/day.

LOAEL = 100 mg/kg/day based on increased incidence of dystocia 

and/or vaginal bleeding after parturition with associated increases in 

mortality in the dams.

Offspring NOAEL = 10 mg/kg/day. 

LOAEL = 100 mg/kg/day based on decreases in litter size, survival 

and body weights.

870.4100a

Chronic toxicity – Rat See 870.4300 See 870.4300

870.4100b 

Chronic toxicity- Dog

43701504 (1995)

Acceptable/guideline

0, 50/60, 100/120, or 300/360 ppm

0/, 1.44/1.33, 2.68/2.72, or 

8.46/8.22 mg/kg/day; M/F

NOAEL = 2.68 mg/kg/day in males, 2.72 mg/kg/day in females. 

LOAEL = 8.46 mg/kg/day in males; 8.22 mg/kg/day in females based 

on increases in serum alanine aminotransferase, aspartate 

aminotransferase, and triglycerides levels, and the presence of tissue 

abnormalities, including vacuolated cell aggregations, arteritis, and 

glandular cell vacuolation (parathyroid).

870.4200a

Carcinogenicity - Rat See 870.4300 See 870.4300

870.4200b

Carcinogenicity-Mouse

43701505 (1995)

Acceptable/guideline

0, 0.0025, 0.008, or 0.036%

0, 25, 80, or 360 ppm

M/F: 0/0, 3.4/4.2, 11.4/13.8, or 

50.9/67.0 mg/kg/day

And 44123601 (1996)

Acceptable/guideline

0, 0.0008, or 0.024%

M/F: 0/0, 1.1/1.3, or 32.7/41.5 

mg/kg/day

NOAEL = 11.4 mg/kg/day in males, 13.8 mg/kg/day in females. 

LOAEL = 50.9 mg/kg/day in males; 67.0 mg/kg/day in females based 

on decreased weight gains, increased mortality, the hematologic 

effects, and the gross finding of increased thickening of the gastric 

mucosa in females and the histologic changes in the stomach of 

males. 

No evidence of carcinogenicity.

870.4300 

Chronic/

Carcinogenicity- Rat

43701507, 43710503 (1995)

0, 0.005, 0.02, 0.05, or 0.1%

0/0, 2.4/3.0, 9.5/12.0, 24.1/30.3, or 

49.4/62.8 mg/kg/day; M/F

NOAEL = 9.5 mg/kg/day in males, 12.0 mg/kg/day in females. 

LOAEL = 24.1 mg/kg/day in males; 30.3 mg/kg/day in females based 

on vacuolation of the epithelial follicular cells of the thyroid in both 

sexes. No evidence of carcinogenicity.
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 33 of 45

Table A.2.2: Subchronic, Chronic, and Other Toxicity Studies - Spinosad

Guideline No./Study 

Type

MRID No. (year)/

Classification/Doses Results

870.5265

Reverse Mutation 

Assay

43414522 (1992)

Unacceptable/guideline

In the Ames Test, the mutation rates observed after treatment of 

Salmonella typhimurium strains (TA1535, TA1537, TA98, and 

TA100) and one strain of Escherichia coli (WP2/uvrA) with XDE105 

increased in a dose-related manner when compared to the vehicle 

control. The colonies were shown in a replica plate assay to be 

predominately auxotrophs and not revertants. No growth of 

auxotrophs is expected in the Ames assay, but their presence in this 

assay suggests that XDE-105 supported their growth. The 

investigators noted that trace amounts of histidine and other amino 

acids were present in the test substance, which is a fermentation 

product. Therefore, an Ames assay with XDE-105 may not be 

appropriate, and this assay is considered to be unacceptable.

870.5300

Mouse lymphoma 

cell/mammalian 

activation gene forward 

mutation assay

43414523 (1992)

Acceptable/guideline

0, 1, 5, 10, 15, 20, or 35 μg/ml

15 through 50 μg/ml with 

metabolic activation.

In a forward mutation assay using mouse lymphoma cells, spinosad 

did not induce forward mutations in mouse lymphoma L5178Y Tk+/-

cells at concentrations of 0, 1, 5, 10, 15, 20, or 35 μg/ml without 

metabolic activation or at concentrations of 15 through 50 μg/ml with 

metabolic activation.

870.5375

In Vitro mammalian 

cytogenetic assay

43414524 (1992)

Acceptable/guideline

20, 26, or 35 μg/ml

100, 250, or 500 μg/ml with 

metabolic activation.

In a chromosomal aberrations assay, spinosad did not increase the 

number of CHO cells with chromosome aberrations at concentrations 

of 20, 26, or 35 μg/ml without metabolic activation or at 

concentrations of 100, 250 or 500 μg/ml with metabolic activation.

870.5385

Micronucleus Assay

43414525 (1992)

Acceptable/guideline

0, 500, 1000, or 2000 mg/kg/day

In a mouse micronucleus test, spinosad did not increase the frequency 

of micronuclei in replicate assays with bone marrow cells from ICR 

mice treated with doses of 0, 500, 1000, or 2000 mg/kg/day for two 

consecutive days.

870.5550

Unscheduled DNA 

Synthesis

43414526 (1992)

Acceptable/guideline

0.01 to 5 μg/ml

10 to 1000 μg/ml

In the unscheduled DNA synthesis assay using primary rat 

hepatocytes, spinosad did not induce unscheduled DNA synthesis 

(UDS) in adult rat hepatocytes in vitro at concentrations of 0.01 to 5 

μg/ml. Concentrations from 10 to 1000 μg/ml of XDE-105 were 

cytotoxic.

870.6200a

Acute Neurotoxicity -

Rat

43557501 (1994)

Acceptable/nonguideline

0, 200, 630, or 2000 mg/kg

NOAEL = 2000 mg/kg in males and females (HDT).

LOAEL = Not established in both sexes.

870.6200b 

Repeat Dose 

Neurotoxicity-Rat

43557504 (1993)

Acceptable/nonguideline

0, 0.003, 0.006, 0.012 or 0.06%

0/0, 2.2/2.6, 4.3/5.2, 8.6/10.4, or 

42.7/52.1 mg/kg/day; M/F

NOAEL = 42.7 mg/kg/day in males; 52.1 mg/kg /day in females 

(HDT).

LOAEL = Not established in both sexes.

870.6200b 

Repeat Dose 

Neurotoxicity-Rat

43701507, 43701503 (1995)

Acceptable/guideline

0 or 0.1%

0/0 or 46.0/57.0 mg/kg/day, M/F

NOAEL = 46.0 mg/kg/day in males; 57.0 mg/kg/day in females 

(HDT).

LOAEL = Not established in both sexes.
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 34 of 45

Table A.2.2: Subchronic, Chronic, and Other Toxicity Studies - Spinosad

Guideline No./Study 

Type

MRID No. (year)/

Classification/Doses Results

870.7485 Metabolism 

and pharmacokinetics -

Rat

43701508 (1995)

Acceptable/guideline

10 or 100 mg/kg (single oral dose)

10 mg/kg (repeated dose 14 days)

Elimination via feces was major route of excretion (82-87% at 168 

hours post-dose), and ~7-10% was excreted in the urine. 

Approximately 70-80% was absorbed with ~20% of the dose 

eliminated unabsorbed in feces. Blood levels after single and multiple 

low doses were highest at 1 hour. Half-lives were 6 hours (males) and 

12 hours (females). Blood levels after high dose were highest at 6 

(males) and 2 hours (females). At low dose, kidney, liver and fat had 

the highest levels. At high dose, adrenals (females only), kidney, 

lymph nodes, fat, and thyroids had the highest levels. Total 

radioactivity remaining in tissues and carcass of low and high dose 

animals was <0.6% and <3%, respectively. At high dose, 

radioactivity observed in fat was 3X higher in females than males. 

Primary metabolites excreted were glutathione conjugates of the 

parent and O- and N-demethylated of parent. Absorption, disposition, 

and elimination demonstrated no differences due to dose or repeated 

dosing.

870.7485 Metabolism 

and pharmacokinetics -

Rat

43701509 (1995)

Acceptable/guideline

100 mg/kg (single dose)

Elimination via the feces was the major route of excretion (84 to 92% 

of the dose at 168 hours after dosing), and 3-5% of the dose was 

excreted in the urine. Greater than 68% of the administered 

radioactivity was recovered in the feces within the first 24 hours 

following dosing. The excretion kinetics was biphasic with the α and 

ß excretion halftimes (t1⁄2) of approximately 6 and 30 hours, 

respectively. The primary metabolites excreted were identified as the 

glutathione conjugates of the parent and O-demethylated XDE-105 

(spinosyn D). Metabolites in the tissues were characterized as the Nand O-demethylated forms of spinosyn D. The absorption, 

disposition, and elimination of 14C-XDE-105 (Factor D) demonstrated 

no appreciable differences based on, dose or repeated dosing.

870.7485 Metabolism 

and pharmacokinetics -

Rat

43701510 (1995)

Acceptable/guideline

100 mg/kg (single dose, bile 

cannulated)

Feces contained 23 to 55% of the dose (an average of 34%), and the 

bile had an average of approximately 36% (range of 28 to 40%) of the 

administered radioactivity. Approximately 21% of the dose was 

found in the tissues and carcass (range of 12 to 26%). The urine and 

CO2 accounted for 3.3 and <0.1% of the dose. The bile excretion rate 

results suggested an uptake phase for the first 4 hr after dosing which 

preceded a biphasic decrease in the biliary excretion rate. The 

maximum rate of bile excretion was ~644 μg equivalents per hour at 

2-4 hr; then the rate decreased to ~123 μg equivalents per hour at the 

12-24 hr interval. The results of the study suggested that metabolites 

in the bile included the glutathione conjugates of the unchanged form, 

as well as – and O-demethylated forms of XDE-105 (Factor D).

870.7800 

Immunotoxicity

48329601 (2010)

Acceptable/guideline

0, 8.65, 40.6, or 141 mg/kg/day

Systemic NOAEL = 40.6 mg/kg/day

Systemic LOAEL = 141 mg/kg/day based on decrease body weights, 

increased liver weights, and abnormal hematology results.

Immunotoxicity NOAEL = 141 mg/kg/day

Immunotoxicity LOAEL = not established
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 35 of 45

Table A.2.3: Acute Toxicity Profile - Spinetoram

Guideline No. Study Type MRID Results Toxicity Category

870.1100 Acute oral 46695031 LD50 (F) >5000 mg/kg IV

870.1200 Acute dermal 46695034 LD50 ≥5000 mg/kg IV

870.1300 Acute inhalation 46695037 LC50 >5.50 mg/L IV

870.2400 Acute eye irritation 46695040 slight eye irritant IV

870.2500 Acute dermal irritation 46695043 not a dermal irritant IV

870.2600 Dermal sensitization 46695046 positive --

Table A.2.4: Subchronic, Chronic, and Other Toxicity Studies - Spinetoram

Guideline No.

Study Type

MRID No. (year)/ 

Classification/dose Results

870.3100

90-Day oral toxicity 

Rat

46695104 (2005)

Acceptable/guideline

0, 120, 500, 1000, or 2000 ppm

M: 0, 7.9, 32.4, 65.8, and 128 mg/kg/d

F: 0, 9.5, 39.6, 79.3, 159, and 311 

mg/kg/d

NOAEL (F) = 120 ppm (9.5 mg/kg/day).

LOAEL (F) = 500 ppm (39.6 mg/kg/day) based on an 

increased incidence of very slight to slight kidney 

tubular vacuolization, very slight vacuolization of the 

follicular epithelial cells of the thyroid, and increased 

incidence of histiocytic aggregates of macrophages in 

the bone marrow, spleen and mesenteric lymph node.

NOAEL (M) = 500 ppm (32.4 mg/kg/day).

LOAEL (M) = 1000 ppm (65.8 mg/kg/day) based on an 

increased incidence of histiocytic aggregates of 

macrophages in lymph nodes, spleen, thymus, and 

ileum and jejunum (Peyer’s patches), and follicular 

epithelial cell vacuolization of the thyroid with colloid 

depletion. 

870.3100

90-Day oral toxicity Mouse

46695105 (2005)

Acceptable/guideline

0, 50, 150, or 450 ppm 

M: 0, 7.5, 22.8, and 70.5 mg/kg/d

F: 0, 10.2, 29.6, and 89.9 mg/kg/d 11 

mg/kg/d

NOAEL = 22.8/29.6 mg/kg/day (M/F).

LOAEL = 70.5/89.9 mg/kg/day (M/F).

870.3150

90-Day oral toxicity Dog

46568501 (2005) 

Acceptable/guideline

0, 150, 300 or 900 ppm

M: 0, 5.73, 9.82, and 27.1 mg/kg/d

F: 0, 4.97, 10.2, and 31.0 mg/kg/d 

NOAEL (M) = 150 ppm [(4.97/5.73 (females/males)] 

mg/kg/day).

LOAEL (M) = 300 ppm [9.8/10.2 (males/females) 

mg/kg bw/day in males/females, respectively], based on 

decreased body-weight gain (males), generalized 

vacuolization of macrophages within lymphoid tissue, 

arteritis and/or perivascular inflammation in numerous 

organs with necrosis of the bone marrow leading to 

regenerative anemia, and a decrease in thymus weights 

(males) with slight atrophy of the thymic cortex 

(males).

870.3200

21/28-Day dermal toxicity 

Rat

46695106 (2005)

Acceptable/ guideline

0, 100, 500, and 1000 mg/kg/d

NOAEL = 1000 mg/kg/day.

LOAEL = not established.

870.3700a

Prenatal developmental in 

Rat

46695108 (2005)

Acceptable/ guideline

0, 30, 100, and 300 mg/kg/d from GD 

6-20

Maternal NOAEL = 300 mg/kg/day.

Maternal LOAEL = not established

Developmental NOAEL = 300 mg/kg/day.

Developmental LOAEL = not established.

870.3700b

Prenatal developmental in 

46695107 (2005)

Acceptable/ guideline

Maternal NOAEL = 60 mg/kg/day.

Maternal LOAEL = not established 
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 36 of 45

Table A.2.4: Subchronic, Chronic, and Other Toxicity Studies - Spinetoram

Guideline No.

Study Type

MRID No. (year)/ 

Classification/dose Results

Rabbit 0, 2.5, 10, and 60 mg/kg/d from GD 7-

27

Developmental NOAEL = 60 mg/kg/day.

Developmental LOAEL = not established.

870.3800

Reproduction and fertility 

effects

Rat

46887501 (2006)

Acceptable/ guideline

0, 3, 10, or 75 mg/kg/d

Parental/Systemic NOAEL = 10.46 mg/kg/day (M) and 

9.87 mg/kg/day (F).

LOAEL = 78.97 mg/kg/day (M) and 74.87 mg/kg/day 

(F) based on thyroid histopathology (cytoplasmic 

vacuolation of follicular epithelial cells) in F0 and F1

animals of both sexes and decreased serum T4 and/or 

increased serum TSH in F0 females and F1 animals of 

both sexes. 

Reproductive NOAEL (F) = 9.87 mg/kg/day

LOAEL = 74.87 mg/kg/day based on dystocia/other 

parturition abnormalities and late resorptions/retained 

fetuses and increased postimplantation loss in F0 and F1

dams. 

Reproductive NOAEL (M) 78.87 mg/kg/day

LOAEL (M) was not identified. 

Offspring NOAEL 78.97 mg/kg/day (M) and 74.87 

mg/kg/day (F).

LOAEL was not identified.

870.4100a

Chronic toxicity - Rat See 870.4300 See 870.4300

870.4100b

Chronic toxicity - Dog

47011901 (2006)

Acceptable/ guideline

0, 50, 100, or 200 ppm

M: 0, 1.57, 2.96, and 5.36 mg/kg/d

F: 0, 1.31, 2.49, and 5.83 mg/kg/d

NOAEL = 100 ppm (2.49 mg/kg/day in females/2.96 

mg/kg/day in males).

LOAEL = 200 ppm (5.36 mg/kg/day in males/5.83 

mg/kg/day in females) based on arteritis and necrosis of 

the arterial walls of the epididymides in males, and the 

thymus, thyroid, larynx and urinary bladder in females.

870.4200a

Carcinogenicity - Rat See 870.4300 See 870.4300

870.4200b

Carcinogenicity - Mouse

47143801 (2007)

0, 25, 80, 150, or 300 ppm

M: 0, 3, 10, 18.8 or 37.5 mg/kg/day

F: 0, 4, 12.8, 23.9, or 46.6 mg/kg/day

Currently under review. Preliminary results show no 

evidence of carcinogenicity.

870.4300

Chronic/carcinogenicity 

Rat

47212901 & 47212902 (2007)

0, 50, 250, or 750 ppm 

M. 0, 2.12, 10.8, 21.6, & 32.9 

mg/kg/day

F: 0, 2.63, 13.2, 26.6, & 40 mg/kg/day

NOAEL = 250 ppm (10.8 mg/kg/day in males/ 13.2 

mg/kg/day in females).

LOAEL = 500 ppm (21.6 mg/kg/day in males/26.6 

mg/kg/day in females). Based on increased incidences 

of thyroid follicular cell vacuolation and of aggregates 

of marcrophages/ histiocytes inpeyer’s patches in the 

ileum and mediastinals lymph nodes and an increased 

severity of aggregates of marcrophages/histiocytes in 

mesenteric lymph nodes.

870.5100

In vitro Bacterial Gene 

Mutation (Salmonella 

typhimurium/ E. coli)/ 

mammalian activation gene 

mutation assay

466951109 (2005)

Acceptable/ guideline

0, 33, 100, 333, 1000, 2500, or 5000 

g/plate (+/- S9-activation) in the E. 

coli strain ; or 0, 1, 3.33, 10, 33.3, 100, 

333, and 1000 g/plate (-S9) and 0, 

There was no evidence of induced mutant colonies over 

background.

(Negative)
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 37 of 45

Table A.2.4: Subchronic, Chronic, and Other Toxicity Studies - Spinetoram

Guideline No.

Study Type

MRID No. (year)/ 

Classification/dose Results

3.33, 10, 33.3, 100, 333, 1000, and 

5000 g/plate (+S9) in the Salmonella

strains

870.5300

In Vitro Gene Mutation 

assay in Chinese Hamster 

Ovary cells

46695110 (2005)

Acceptable/ guideline

0, 10, 20, 30, 40, 50, 60, 70, 80, 100, 

120, 140, 160, 180, 200, 260, and 320 

g/mL (-S9),

0, 10, 20, 40, 80, 160, 200, 240, 280, 

and 320 g/mL (+S9)

There was no evidence of induced mutant colonies over 

background in the presence or absence of S9-activation.

(Negative)

870.5375

In vitro Mammalian 

Cytogenetics 

(Chromosomal Aberration 

Assay in Rat 

Lymphocytes)

46695111 (2005)

Acceptable/guideline

0, 2.5, 5, 10, 20, 30, 40, 50, or 100 

μg/mL (-S9),

0, 5, 10, 20, 30, 40, 50, 60, 80, or 100 

μg/mL (+S9).

There were no significant increases in the frequency of 

aberrant cells (excluding gaps) noted in the presence or 

absence of S9 at any exposure period. 

(Negative)

870.5395

In Vivo Mammalian 

Cytogenetics - Erythrocyte 

Micronucleus Assay in

Mice

46695112 (2005)

Acceptable/guideline

0, 500, 1000, or 2000 mg/kg

No statistically significant increases in the 

micronucleated polychromatic erythrocytes (MPCE) 

frequency or % of polychromatic erythrocytes (PCE) 

were observed in any treatment group when compared 

to controls. 

(Negative)

870.6200

Acute Neurotoxicity 

screening battery

46995113 (2005)

Acceptable/guideline

0, 200, 630, and 2000 mg/kg

NOAEL = 2000 mg/kg.

LOAEL was not observed.

870.7485

Metabolism and 

pharmacokinetics

Rat

46695114 (2005)

Acceptable/ guideline

single p.o. dose 10 or 100 mg/kg

14 daily doses 10 mg/kg

single i.v. dose 10 mg/kg

The absorbed dose ≥70%. After 168 h, total recoveries 

were 88.1-97.1% of the administered doses, with no 

differences observed between dose levels, single or 

multiple doses, or route of exposure. The majority of 

the radioactivity was recovered in the feces (77.4-89.6% 

of the administered dose), while urine (3.3-9.6%) was a 

minor route of elimination. The majority of the 

radioactivity in the feces was recovered during the first 

24 h, while the majority of radioactivity recovered in 

the urine was recovered during the first 12 h. Animals 

given an i.v. dose of the test compound eliminated a 

larger proportion of radioactivity in the urine and 

elimination of radioactivity in the feces was prolonged 

compared to orally-dosed animals. However the total 

amount of radioactivity excreted in the feces was 

similar regardless of route of administration. The 

carcass contained the highest levels of radioactivity 

(0.2-1.3% administered dose); no other tissue exceeded

0.4% of the administered dose. The highest 

concentrations of radioactivity were generally detected 

in fat, kidneys, liver, and lymph nodes, and in the 

ovaries in females. There was no evidence of 

bioaccumulation. The majority of radioactivity 

recovered from urine and fecal extract samples was 

present as parent and a total of seven metabolites, the 
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 38 of 45

Table A.2.4: Subchronic, Chronic, and Other Toxicity Studies - Spinetoram

Guideline No.

Study Type

MRID No. (year)/ 

Classification/dose Results

largest proportion of which were found in the fecal 

extracts. Metabolic profiles were qualitatively similar 

for all of the experimental groups. The major route of 

metabolism was found to be glutathione conjugation 

with the parent compound, as well as glutathione 

conjugation with N-demethylated, O-demethylated, and 

hydroxylated forms of the parent compound. Parent 

and identified compounds accounted for 70.9-83.4% of 

the administered dose, while unidentified metabolites 

accounted for 9.6-17.1% of the administered dose. The 

total administered dose accounted for in the excreta was 

86.4-94.7%. Parent compound accounted for 7.0-22.2% 

(40.0% in the 100 mg/kg males) of the total 

radioactivity eliminated, and was found almost 

exclusively in the fecal extracts. 

870.7485

Metabolism and 

pharmacokinetics

Rat

46695115 (2005)

Acceptable/ guideline

single p.o. dose 10 or 100 mg/kg

14 daily doses 10 mg/kg

single i.v. dose 10 mg/kg

Radioactivity was detected in the plasma at 15 minutes 

post-dosing indicating rapid absorption. It was 

considered likely that the fraction of the orally 

administered dose absorbed was 70% or greater in both 

the low and high oral dose groups. After 168 h, total 

recoveries ranged from 90.4-94.9% of the administered 

doses, with no differences observed between dose 

levels, single or multiple doses, or route of exposure. 

The majority of the radioactivity was recovered in the 

feces (78.5-86.7% of the administered dose), while 

urine (2.3-3.8%) was a minor route of elimination. The 

majority of the radioactivity in the feces was recovered 

during the first 24 h, while the majority of radioactivity 

recovered in the urine was recovered during the first 12 

h. Generally, tissues, carcass, and cage wash accounted 

for <8%, except for the i.v.-dosed females (13%). At 

168 h, the carcass (1.3-5.8% of the administered dose) 

and skin (0.4-5.9%) contained the highest mean levels 

of radioactivity; no other tissue (excluding the 

gastrointestinal tract) exceeded 0.6% of the 

administered dose. In general, the highest 

concentrations of radioactivity were detected in fat, 

lymph nodes, skin, and adrenals in the males, and in the 

fat, ovaries, lymph nodes, uterus, skin, and adrenals in 

females. Radioactivity was detected at low levels in 

other tissues. There was no evidence of 

bioaccumulation. The test compound was extensively 

metabolized regardless of the route of administration. 

The majority of radioactivity in urine and fecal extract 

samples was present as parent and a total of nine 

metabolites. Metabolic profiles were qualitatively 

similar across dose levels and route of exposure, and no 

major differences were noted between sexes. The major 

route of metabolism was found to be glutathione 

conjugation with the parent compound, as well as 

glutathione conjugation with N-demethylated and O-
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 39 of 45

Table A.2.4: Subchronic, Chronic, and Other Toxicity Studies - Spinetoram

Guideline No.

Study Type

MRID No. (year)/ 

Classification/dose Results

demethylated forms of the parent compound. In 

excreta, parent and identified compounds accounted for 

70.7-85.8% of the administered dose, while unidentified 

metabolites accounted for 0.8-16.1% of the 

administered dose. The total administered dose 

accounted for in the excreta was 82.0-89.1%. Parent 

compound accounted for 6.5-26.1% of the total 

radioactivity eliminated, and was found almost 

exclusively in the fecal extracts. 
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 40 of 45

Appendix B. Chemical Names and Structures

Spinosad

Common name Chemical structure

spinosyn A (parent) R1 = N(CH3)2, R2 = H, R3 = CH3, R4 = CH3, R5 = CH3

spinosyn B (N-demethyl spinosyn A) spinosyn A demethylated in the forosamine ring 

R1 = NH(CH3), R2 = H, R3 = CH3, R4 = CH3, R5 = CH3

spinosyn H (O-demethyl spinosyn A) spinosyn A demethylated in the rhamose ring 

R1 = N(CH3)2, R2 = H, R3 = H, R4 = CH3, R5 = CH3

spinosyn J (O-demethyl spinosyn A) spinosyn A demethylated in the rhamose ring 

R1 = N(CH3)2, R2 = H, R3 = CH3, R4 = H, R5 = CH3

spinosyn K (O-demethyl spinosyn A) spinosyn A demethylated in the rhamose ring 

R1 = N(CH3)2, R2 = H, R3 = CH3, R4 = CH3, R5 = H

N-demethyl spinosyn J spinosyn J demethylated in the forosamine ring 

R1 = NH(CH3), R2 = H, R3 = CH3, R4 = H, R5 = CH3

N-formyl spinosyn B

spinosyn A where one N-methyl group on the forosamine group has been removed 

and the other converted to CHO 

R1 = N(CH3)(CHO), R2 = CH3, R3 = CH3, R4 = CH3, R5 = CH3

spinosyn D (parent) R1 = N(CH3)2, R2 = CH3, R3 = CH3, R4 = CH3, R5 = CH3

N-demethyl spinosyn D spinosyn D demethylated in the forosamine ring 

R1 = NH(CH3), R2 = CH3, R3 = CH3, R4 = CH3, R5 = CH3

spinosyn L (O-demethyl spinosyn D) spinosyn D demethylated in the rhamose ring 

R1 = N(CH3)2, R2 = CH3, R3 = CH3, R4 = H, R5 = CH3

spinosyn O (O-demethyl spinosyn D) spinosyn D demethylated in the rhamose ring 

R1 = N(CH3)2, R2 = CH3, R3 = CH3, R4 = CH3, R5 = H

spinosyn Q (O-demethyl spinosyn D) spinosyn D demethylated in the rhamose ring 

R1 = N(CH3)2, R2 = CH3, R3 = H, R4 = CH3, R5 = CH3

N-demethyl spinosyn L spinosyn L demethylated in the forosamine ring 

R1 = NH(CH3), R2 = CH3, R3 = CH3, R4 = H, R5 = CH3
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 41 of 45

Spinetoram

Common name/code Chemical name Chemical structure

XDE-175-J

(2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR)-13-

{[(2R,5S,6R)-5-(dimethylamino)-6-

methyltetrahydro-2H-pyran-2-yl]oxy}-9-ethyl-14-

methyl-7,15-dioxo2,3,3a,4,5,5a,5b,6,7,9,10,11,12,13,14,15,16a,16boctadecahydro-1H-as-indaceno[3,2-

d]oxacyclododecin-2-yl 6-deoxy-3-O-ethyl-2,4-di-Omethyl-alpha-L-mannopyranoside

XDE-175-L

(2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS)-13-

{[(2R,5S,6R)-5-(dimethylamino)-6-

methyltetrahydro-2H-pyran-2-yl]oxy}-9-ethyl-4,14-

dimethyl-7,15-dioxo2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16bhexadecahydro-1H-as-indaceno[3,2-

d]oxacyclododecin-2-yl 6-deoxy-3-O-ethyl-2,4-di-Omethyl-alpha-L-mannopyranoside

N-demethyl-175-J

ND-J

(2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl14-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-asindaceno[3,2-d]oxacyclododecin-2-yl 6-deoxy-3-Oethyl-2,4-di-O-methyl-alpha-L-mannopyranoside

N-demethyl-175-L

ND-L

(2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS)-9-ethyl4,14-dimethyl-13-{[(2S,5S,6R)-6-methyl-5-

(methylamino)tetrahydro-2H-pyran-2-yl]oxy}-7,15-

dioxo2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16bhexadec

ahydro-1H-as-indaceno[3,2-d]oxacyclododecin-2-yl 

6-deoxy-3-O-ethyl-2,4-di-O-methyl-alpha-Lmannopyranoside

N-formyl-175-J

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-Lmannopyranosyl) oxy]-9-ethyl-14-methyl-7,15-

dioxo2,3,3a,4,5,5a,5b,6,7,9,10,11,12,13,14,15,16a,16boctadecahydro-1H-as-indaceno[3,2-

d]oxacyclododecin-13-yl}oxy)-2-methyltetrahydro2H-pyran-3-yl(methyl)formamide

N-formyl-175-L

NF-L

(2R,3S,6S)-6-

({(2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS)-2-[(6-

deoxy-3-O-ethyl-2,4-di-O-methyl-alpha-Lmannopyranosyl)oxy]-9-ethyl-4,14-dimethyl-7,15-

dioxo-2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16bhexadecahydro-1H-asindaceno[3,2-

d]oxacyclododecin-13-yl}oxy)-2-methyltetrahydro2H-pyran-3-yl(methyl)formamide
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 42 of 45

Spinetoram

Common name/code Chemical name Chemical structure

3’-O-deethyl-175-J

(2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR)-13-

{[(2S,5S,6R)-5-(dimethylamino)-6-

methyltetrahydro-2H-pyran-2-yl]oxy}-9-ethyl-14-

methyl-7,15-dioxo2,3,3a,4,5,5a,5b,6,7,9,10,11,12,13,14,15,16a,16boctadecahydro-1H-as-indaceno[3,2-

d]oxacyclododecin-2-yl 6-deoxy-2,4-di-O-methylalpha-L-mannopyranoside

3’-O-deethyl-175-L

(2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS)-13-

{[(2S,5S,6R)-5-(dimethylamino)-6-

methyltetrahydro-2H-pyran-2-yl]oxy}-9-ethyl-4,14-

dimethyl-7,15-dioxo2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16bhexadec

ahydro-1H-as-indaceno[3,2-d] oxacyclododecin-2-yl 

6-deoxy-2,4-di-O-methyl-alpha-L-mannopyranoside

2’-O-demethyl-175-J

(2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR)-13-

{[(2S,5S,6R)-5-(dimethylamino)-6-

methyltetrahydro-2H-pyran-2-yl]oxy}-9-ethyl-14-

methyl-7,15-dioxo2,3,3a,4,5,5a,5b,6,7,9,10,11,12,13,14,15,16a,16boctadecahydro-1H-as-indaceno[3,2-d] 

oxacyclododecin-2-yl 6-deoxy-3-O-ethyl-4-Omethyl-alpha-L-mannopyranoside

2’-O-demethyl-175-L

(2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS)-

13{[(2S,5S,6R)-5-(dimethylamino)-6-

methyltetrahydro-2H-pyran-2-yl]oxy}-9-ethyl 4,14-

dimethyl-7,15-dioxo2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16bhexadecahydro-1H-as-indaceno[3,2-

d]oxacyclododecin-2-yl 6-deoxy-3-O-ethyl-4-Omethyl-alpha-L-mannopyranoside

Aglycone-175-J

(2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl2,13-dihydroxy-14-methyl2,3,3a,4,5,5a,5b,6,9,10,11,12,13,14,16a,16bhexadecahydro-1H-as-indaceno[3,2-

d]oxacyclododecine-7,15-dione

Aglycone-175-L

(2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS)-9-ethyl2,13-dihydroxy-4,14-dimethyl2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16btetradecahydro-1H-as-indaceno[3,2-

d]oxacyclododecine-7,15-dione
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 43 of 45

Spinetoram

Common name/code Chemical name Chemical structure

C9-pseudoaglycone175-J

(2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR)-13-

{[(2S,5S,6R)-5-(dimethylamino)-6-

methyltetrahydro-2H-pyran-2-yl]oxy}-9-ethyl-2-

hydroxy-14-methyl2,3,3a,4,5,5a,5b,6,9,10,11,12,13,14,16a,16bhexadecahydro-1H-as-indaceno[3,2-

d]oxacyclododecine-7,15-dione

C9-pseudoaglycone175-L

(2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS)-13-

{[(2S,5S,6R)-5-(dimethylamino)-6-

methyltetrahydro-2H-pyran-2-yl]oxy}-9-ethyl-2-

hydroxy-4,14-dimethyl2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16btetradecahydro-1H-as-indaceno[3,2-

d]oxacyclododecine-7,15-dione

C9-

ketopseudoaglycone175-J

(3aR,5aR,5bS,9S,13S,14R,16aS,16bR)-13-

{[(2S,5S,6R)-5-(dimethylamino)-6-

methyltetrahydro-2H-pyran-2-yl]oxy}-9-ethyl-14-

methyl-3a,4,5,5a,5b,6,9,10,11,12,13,14,16a,16btetradecahydro-1H-as-indaceno[3,2-

d]oxacyclododecine-2,7,15(3H)-trione

C9-

ketopseudoaglycone175-L

(3aR,5aS,5bS,9S,13S,14R,16aS,16bS)-13-

{[(2S,5S,6R)-5-(dimethylamino)-6-

methyltetrahydro-2H-pyran-2-yl]oxy}-9-ethyl-4,14-

dimethyl-3a,5a,5b,6,9,10,11,12,13,14,16a,16bdodecahydro-1H-as-indaceno[3,2-

d]oxacyclododecine-2,7,15(3H)-trione

C17-

ketopseudoaglycone175-J

(2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl13-hydroxy-14-methyl-7,15-dioxo2,3,3a,4,5,5a,5b,6,7,9,10,11,12,13,14,15,16a,16boctadecahydro-1H-asindaceno[3,2-

d]oxacyclododecin-2-yl 6-deoxy-3-O-ethyl-2,4-di-Omethyl-alpha-Lmannopyranoside

C17-

ketopseudoaglycone175-L

(2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS)-9-ethyl13-hydroxy-4,14-dimethyl-7,15-dioxo2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16bhexadecahydro-1H-asindaceno[3,2-

d]oxacyclododecin-2-yl 6-deoxy-3-O-ethyl-2,4-di-Omethyl-alpha-Lmannopyranoside
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 44 of 45

Appendix C. Physiochemical Properties

Table C.1: Spinosad Physicochemical Properties.

Melting range Spinosyn A: 84-99.5°C; Spinosyn D: 161.5-170°C

pH (10% slurry of spinosad in water) 7.74

Density 0.512 g/ml (20°C)

Water solubility (ppm; distilled water) Spinosyn A: 89.4 ppm; Spinosyn D: 0.495 ppm

Vapor pressure (kPa; 25°C) Spinosyn A: 3.0 x 10-11; Spinosyn D: 2.0 x 10-11

Dissociation constant (pKa) not available

Octanol/water partition coefficient 

Log (KOW)

Spinosyn A: 2.8 (pH 5), 4.0 (pH 7), and 5.2 (pH 9)

Spinosyn D: 3.2 (pH 5), 4.5 (pH 7), and 5.2 (pH 9)

UV/visible absorption spectrum not available

Table C.2: Spinetoram Physicochemical Properties.

Melting points XDE-175-J: 143.4°C; XDE-175-L: 70.8°C

pH 6.46 (1% w/w aqueous solution)

Density 1.1485 g/ml (20°C)

Water solubility (purified water; pm; 20°C) XDE-175-J: 10.0 ppm; XDE-175-L 31.9 ppm 

Vapor pressure (Pa; 25°C) XDE-175-J: 5.3 x10-5; XDE-175-L: 2.1 x10-5

Dissociation constant (pKa) XDE-175-J: pKa = 7.86; XDE-175-L : pKa = 7.59

Octanol/water partition coefficient

Log Kow (20°C)

XDE-175-J: 2.44 (pH 5), 4.09 (pH 7), 4.22 (pH 9)

XDE-175-L: 2.94 (pH 5), 4.49 (pH 7), 4.82 (pH 9)

UV/visible absorption spectrum XDE-175-J: 245nm (max; 12200 , L/(mol*cm) extinction coefficient)

XDE-175-L: 243nm (max; 11100, L/(mol*cm) extinction coefficient)
Spinosad and Spinetoram Human Health Risk Assessment D415812

Page 45 of 45

Appendix D: Registered Residential Uses for Spinosad/Spinetoram

Spinosad is currently registered for residential uses including homeowner applications to 

gardens, turfgrass, and ornamentals. Spinetoram currently is registered for homeowner 

applications to gardens, lawns/ornamentals, and turfgrass, as well as for pet use as a spot-on 

formulation for cats and kittens that weigh more than 4 pounds. A summary of residential uses is 

listed in Table D.1. 

Table D.1. Summary of Representative Residential Use Patterns, Formulations, and Application Rates for 

Spinosad and Spinetoram.

Product Formulation Application Equipment Use Sites Max. App. Rates

Spinosad

Spinosad® Dust under the brand name 

Captain Jack’s Deadbug Brew® Dust 

(EPA Reg. No. 4-UT0)

Dust

Dust applicator, crank 

garden duster or bulb 

duster

Home Gardens1

0.00001 lb ai/1000 

ft2

Ornamentals2

Conserve SC Turf and Ornamental 

(EPA Reg. No. 62719-291)

Soluble 

Concentrate Broadcast Spray Turf and Ornamentals 0.41 lbs ai/acre

Conserve Fire Ant Bait (EPA Reg. No. 

62719-304) Granular Broadcast or Mound Treatment Control Fire Ants 0.0003 lbs ai/acre

Fruit fly bait (EPA Reg. No. NAF-550) Granular Broadcast Non-crop vegetation 0.0003lb ai/acre

Spinosad 0.5% SC (EPA Reg. No. 

62719-314)

Soluble 

Concentrate Broadcast spray Home Gardens 0.086 lb ai/acre

Spinosad 0.5% SC (EPA Reg. No. 

62719-314)

Soluble 

Concentrate Mound Treatment Control Fire Ants 0.0013 lb ai/mound

Spinoteram

AssurityTM (EPA Reg. No. 72642-9) Spot-on Spot-on applicator Cats and Kittens 

(8 weeks or older)

0.019 fl oz or 0.55 

ml: 231 mg 

ai/treatment

GF-1640 WG-NC (EPA Reg. No. 

62719-540)

GF-1587 SC-NC (EPA Reg. No. 

62719-544)

Dry Flowable

Soluble 

concentrate

Handheld sprayers

Home Lawns, 

Gardens and 

Ornamentals

0.0005 lb ai/gal 

(0.061 lb ai/acre)

1

 Crops include apple and other pome fruits, asparagus, bushberries and caneberries, citrus trees, cole crops (brassica 

vegetables), cucurbits, fruiting vegetables, grape, leafy and dried herbs, leafy vegetables, stone fruits, strawberry, succulent beans 

and peas, sweet corn and popcorn, tree nuts, tree fruits, tuberous and corm vegetables.

2 Includes outdoor ornamentals (herbaceous and woody plants).