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5.1.2 Summary of Environmental Degradation ............................................................... 32

5.1.3 Comparison of Metabolic Pathways....................................................................... 33

5.1.4 Residues of Concern Summary and Rationale........................................................ 33

5.2 Food Residue Profile..................................................................................................... 36

5.3 Water Residue Profile ................................................................................................... 36

5.4 Dietary Risk Assessment .............................................................................................. 41

5.4.1 Description of Residue Estimates Used in Dietary Assessment............................. 41

5.4.2 Percent Crop Treated Used in Dietary Assessment ................................................ 41

5.4.3 Acute Dietary Risk Assessment.............................................................................. 41

5.4.4 Chronic Dietary Risk Assessment .......................................................................... 42

5.4.5 Cancer Dietary Risk Assessment............................................................................ 42

5.4.6 Summary Table....................................................................................................... 42

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ................................... 43

6.1 Residential Bystander Post-Application Inhalation Exposure...................................... 43

6.2 Spray Drift .................................................................................................................... 43

7.0 Aggregate Exposure/Risk Characterization...................................................................... 44

8.0 Cumulative Exposure/Risk Characterization.................................................................... 44

9.0 Occupational Exposure/Risk Characterization ................................................................. 44

9.1 Short- and Intermediate-Term Handler Risk Estimates................................................ 45

9.2 Short- and Intermediate- Term Post-Application Risk Estimates................................. 50

9.2.1 Dermal Post-Application Risk Estimates................................................................ 50

9.2.2 Inhalation Post-Application Risk Estimates ........................................................... 53

10.0 References......................................................................................................................... 54

Appendix A. Toxicology Profile and Executive Summaries....................................................... 56

Appendix B. Sulfoxaflor Mode-of Action for Reproductive and Developmental Effects........ 132

Appendix C. Metabolism Summary Table ................................................................................. 156

Appendix D. Physical/Chemical Properties and Summaries of Field Trial and Processing Study 

Results......................................................................................................................................... 158

Appendix E. Review of Human Research ................................................................................. 166

Appendix F. Occupational Exposure/Risk Summary Tables .................................................... 167

Appendix G. Anticipated Post-Application Activities and Dermal Transfer Coefficients........ 174
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1.0 Executive Summary

Dow AgroSciences has petitioned the Agency to grant registrations and establish tolerances for 

the new insecticide sulfoxaflor {CAS name: cyanamide, N-[methyloxido[1-[6-(trifluoromethyl)-

3-pyridinyl]ethyl] λ4-sulfanylidene]}. Sulfoxaflor is the first member of a new class of 

insecticides, the sulfoximines, which act through a unique interaction with the nicotinic 

acetylcholine receptor (nAChR) in insects. Sulfoxaflor is a highly efficacious agonist of that 

receptor. The registration request is for one technical-grade product (File Symbol 62719-AGR)

and two end-use products, TransformTM WG (62719-AEL) and GF-2032 SC (62719-AEG). The 

requested use sites are identical for the two end-use products and include numerous agricultural 

crops (39 crops/crop groups in all), turfgrass (sod farms only), and ornamental plants. At this 

time, no uses have been requested that would result in residential exposure.

The toxicology database for sulfoxaflor is complete for risk assessment purposes, including the 

assessment of potential increased susceptibility of infants and children. Toxicity and 

mechanistic studies in rats, rabbits, dogs and mice indicate that the liver and the nervous systems 

are target organ systems. Liver effects in subchronic and chronic studies include organ weight 

and enzyme changes, hypertrophy, proliferation, and tumors; long-term studies resulted in 

hepatic effects at doses lower than in short-term studies. Based on the weight of evidence, 

including mode-of-action data, the Cancer Assessment Review Committee (CARC) determined 

that there is a “Suggestive Evidence of Carcinogenic Potential” for sulfoxaflor and that 

quantification of risk using a non-linear approach [i.e., reference dose (RfD)] will adequately 

account for all chronic toxicity, including carcinogenicity, that could result from exposure to 

sulfoxaflor. The nervous system effects were observed as frank neurotoxicity as well as 

secondary developmental effects due to prolonged contracture of fetal muscle resulting in limb 

flexure and bent clavicle in fetuses, and decreased survival of neonatal rats. As these 

developmental effects were observed only in rats, the petitioner conducted numerous nonguideline studies to investigate the cause of these effects and to determine their human relevance. 

Those studies are adequate to delineate the mode of action of the developmental effects and 

provide information regarding interspecies uncertainty. The database indicates that the 

developmental effects are unlikely to be relevant to humans; however, an additional study is 

required in order to make a final conclusion. Therefore, pending that study, the developmental 

effects are considered to be relevant to humans. Data are sufficient to support reducing the 

interspecies uncertainty factor to 3X for the developmental effects. The developmental, 

neuromuscular, or liver effects are the basis for this risk assessment, depending on the duration 

of exposure and the population group of interest.

HED has recommended that the required 10X FQPA Safety Factor be reduced to 1X based on

the completeness of the toxicological database, the adequacy of the submitted neurotoxicity and 

developmental neurotoxicity studies, the selection of endpoints and doses selected for risk 

assessment that are protective of observed developmental effects, special studies to address 

HED’s concern regarding human relevance for the developmental effects, and exposure

assessments that are unlikely to underestimate exposure.

No direct residential uses or commercial/professional uses at residential sites are being requested 

for sulfoxaflor at this time. Although there is a proposed use on ornamental plants, the proposed 
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use is only for nurseries and commercial greenhouses. Furthermore, exposure from homeowners 

buying turfgrass (sod) and planting it as a residential turf would be minimal. At this time, there 

are no uses of sulfoxaflor that will result in residential exposures. Therefore, if the requested 

registrations are granted, exposure to sulfoxaflor may occur via residues in food and/or drinking 

water. Data depicting the fate of sulfoxaflor in plants, animals, and the environment indicates 

that in systems that include an aerobic soil component (e.g., soil-directed applications, rotational 

crops, groundwater systems), breakdown of sulfoxaflor is quite extensive and rapid, with very 

little parent compound remaining. In those scenarios, the metabolite designated X11719474 is 

the major component. Contrary to that, the parent compound undergoes very little 

transformation in animals or via hydrolytic or photolytic processes. Some metabolism of the 

parent compound occurs in plants following foliar application, resulting in two major metabolites 

(X11719474 and X11721061). Plant metabolism studies also demonstrate that residues are 

distributed throughout the plant and are not restricted to treated surfaces. In residue field studies 

using foliar treatment (which is the requested use pattern), residues of sulfoxaflor were generally 

well above the limit of quantitation (LOQ) of 0.01 ppm in most commodities. The exception to 

that is in root crops and rotational crops where residues were approximately at or below the 

LOQ; presumably due to the involvement of the soil matrix in those situations. Typical food 

processing activities, such as baking, boiling and canning, are unlikely to significantly affect the 

nature and magnitude of sulfoxaflor residues. In processing studies, sulfoxaflor generally 

concentrated during production of dried foods and tended to be reduced in juices, though 

exceptions to those trends are evident in the database. In the case of drinking water, degradates 

are expected to be significantly greater in groundwater than in surface water. In addition, the 

residue profile for these two drinking water sources are expected to be quite different, with 

residue in surface water being comprised of sulfoxaflor almost exclusively and residues in 

groundwater being made up primarily of the metabolites X11719474 and, to a lesser extent, 

X11519540; parent sulfoxaflor is expected to be absent from groundwater. The different residue 

profiles, combined with toxicological information and risk assessment endpoints for sulfoxaflor 

versus these two metabolites, results in different strategies for risk assessment. In short, this 

assessment focuses on the following three combinations for evaluating aggregate exposure:

Neuromuscular effects (acute dietary exposure, general population): Assess sulfoxaflor 

in food and the metabolites designated X11719474 and X11519540 in groundwater;

Developmental effects (acute dietary exposure, women of child-bearing age; short- and 

intermediate-term dermal and inhalation exposure): Assess sulfoxaflor in food and 

surface water (note that at this time in the absence of residential uses, the dermal and 

inhalation exposure routes are not relevant to an aggregate assessment);

Liver effects (chronic dietary exposure, all populations): Assess sulfoxaflor in food and 

the metabolites designated X11719474 and X11519540 in groundwater, factoring in 

information on the relative potency of the metabolites to elicit the liver effects. Relative 

to sulfoxaflor, these factors are 0.3X for X11719474 and 10X for X11519540.

HED has used moderately refined, health-protective estimates of residue levels in foods and 

upper-bound residue estimates for drinking water, taking into account the toxicological 

endpoint/residue profile considerations described above, in combination with an extensive 

database of food and water consumption for the U.S. population, to estimate dietary exposure 

and risk that may result from the use of sulfoxaflor. Across all representative population 

subgroups, including those of infants and children, the maximum dietary risk estimates are 16% 
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and 18% of the acute and chronic population-adjusted dose (aPAD, cPAD), respectively. These 

estimates are well below 100% and are, therefore, below HED’s level of concern. In the absence 

of residential use sites, aggregate risk estimates are equivalent to dietary risk estimates and are, 

by extension, below HED’s level of concern. There are no aggregate risk issues that would 

preclude granting the requested registrations and establishing tolerances for residues of 

sulfoxaflor at the levels recommended in Table 2.2.3.

HED has also estimated risks for persons exposed to sulfoxaflor during occupational activities. 

These activities include application-related tasks (mixing, loading, applying, etc.) as well as postapplication tasks (scouting, weeding, irrigating, etc.). The current risk metric for assessing shortand intermediate-term occupational exposure to sulfoxaflor is a margin of exposure (MOE) that 

is less than 30. At a baseline level of personal protective equipment (PPE), estimated 

occupational MOEs range from 80 to 4,700,000, and the vast majority of the estimates are 

greater than 300. All estimated occupational MOEs indicate that risks are below HED’s level of 

concern. 

Although the proposed labels specify a 24-hour Restricted Entry Interval (REI), the acute 

toxicity categories for technical-grade sulfoxaflor indicate that a 12-hour REI is appropriate to 

protect agricultural workers from post-application exposures.

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 the Pesticide 

Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task 

Force (AHETF) database; the Outdoor Residential Exposure Task Force (ORETF) database; the 

Agricultural Re-entry Task Force (ARTF) database; other registrant-submitted exposure studies 

(MRID Nos. 47832415, 47832416); are subject to ethics review pursuant to 40 CFR 26, have 

received that review, and are compliant with applicable ethics requirements. For certain studies 

that 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:

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

http://www.epa.gov/pesticides/science/post-app-exposure-data.html.

2.0 HED Recommendations

HED is recommending for granting the registrations for use of sulfoxaflor on the requested crops

and for the establishment of permanent tolerances for residues of sulfoxaflor as specified in 

Section 2.2.3. HED further recommends that the labels be revised as specified in Section 2.3.

2.1 Data Deficiencies/Conditions of Registration

None.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method
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High performance liquid chromatographic (HPLC) methods with positive-ion electro spray (ESI) 

tandem mass spectrometry (LC/MS/MS) were developed for data collection and enforcement of 

sulfoxaflor residues and the two metabolites X11719474 and X11721061. Method 091116 was 

developed for plant commodities, and Method 091188 was developed for livestock commodities. 

Both methods use solvent extraction (acetonitrile+water, 80+20, v/v), solid-phase extraction 

clean up, and reverse-phase LC-MS/MS for separation and analysis. In addition, the plant 

method incorporates base- and enzymatic-hydrolysis steps to liberate conjugated residues. 

Successful validation of both methods was reported by the registrant and by an independent 

laboratory. Additionally, successful radiovalidation was reported for both methods. The lowest 

level of method validation (LLMV) was 0.01 mg/kg for each of sulfoxaflor, X11719474, and 

X11721061 in all matrices. The limit of detection (LOD) was reported as 0.003 mg/kg for each

analyte in all matrices.

FDA multiresidue methods are not suitable for analysis of sulfoxaflor; however, data were 

provided which indicate that the DFG S-19 multiresidue method may provide satisfactory 

results.

2.2.2 International Harmonization

At this time, there are no MRLs for sulfoxaflor. As a result of the global joint review process, 

HED expects that sulfoxaflor MRLs covering the majority of the commodities addressed in this 

assessment will be established by Australia, Canada and Codex. 

The U.S., Canada, and Australia have agreed on the residue definition for sulfoxaflor and the 

global partners are committed to harmonizing regulatory levels to the maximum extent allowed 

by each regulatory authority’s policies. In addition, we note that sufloxaflor was presented at the

Joint Meeting on Pesticide Residues (JMPR, 2011). As a pilot process to maximize 

harmonization, recommendations from that meeting were forwarded to the Codex Committee on 

Pesticide Residues (CCPR) prior to registration by any regulatory authority in an attempt to set

benchmark MRLs. To date, final CCPR recommendations have not been made and negotiations 

are ongoing between the JMPR and CCPR. All tolerances recommended by HED are 

harmonized with the MRLs being recommended by Canada.

2.2.3 Recommended Tolerances

HED recommends that 40 CFR be amended by establishing tolerances for residues of sulfoxaflor 

in the plant and livestock commodities listed in the Table 2.2.3. As the residue definitions for 

plant and animal commodities are the same, HED recommends that the same entry be used for 

both types of commodities. The tolerances should be defined as follows:

 

Tolerances are established for residues of the insecticide sulfoxaflor, 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 

sulfoxaflor (N-[methyloxido[1-[6-(trifluoromethyl)-3-pyridinyl]ethyl]-γ

4

-

sulfanylidene]cyanamide).
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Table 2.2.3. Tolerance Summary for Sulfoxaflor.

Commodity Tolerance, ppm Comments (correct commodity definition)

Proposed Recommended

Almond, hulls 4.0 6.0

Barley, grain 0.15 0.40

Barley, hay 0.8 1.0

Barley, straw 1.5 2.0 Tolerance is higher than the HAFT, but 

lower than the maximum residue. Since 

the CODEX Global MRL recommended 

by JMPR is 2.0 ppm, this value would be 

harmonized.

Bean, dry seed 0.25 0.20

Bean, succulent 0.7 4.0

Beet, sugar, dried pulp -- 0.07

Beet, sugar, molasses 0.03 0.25

Berry, low growing, subgroup 13-07G 0.06 0.70

Cauliflower 0.08 0.08 Individual tolerance is required because it 

exceeds a 5x factor.

Citrus, dried pulp 0.9 3.60

Cotton, hulls 0.4 0.35

Cotton, gin byproducts 8.0 6.0

Cottonseed subgroup 20C 0.2 0.20

Fruit, citrus, group 10-10 0.6 0.70

Fruit, pome, group 11-10 0.4 0.50

Fruit, small, vine climbing, subgroup 13-

07F, except fuzzy kiwi fruit 

1.3 2.0

Fruit, stone, group 12 0.6 3.0

Grain, aspirated fractions -- 20.0

Grape, raisin 5.0 6.0 The calculated tolerance was 5.4 ppm; 

however, HED recommends for a 6.0 ppm 

tolerance in order to harmonize with 

pending CODEX Global MRL.

Leafy greens, subgroup 4A 5.0 6.0

Leafy petiole, subgroup 4B 1.0 2.0

Nuts, tree, group 14 0.02 0.015

Onion, bulb, subgroup 3-07A 0.01 0.01

Onion, green, subgroup 3-07B 0.6 0.70

Pistachio 0.02 0.015 Pistachio requires a separate tolerance. 

Data from tree nuts are translated to 

pistachio.

Plum, prune, dried -- 1.90 Processing factor for dried cherry used to 

calculate concentration of residues.

Rapeseed, meal 0.5 0.50

Rapeseed subgroup 20A 0.3 0.30

Soybean, seed 0.2 0.20

Soybean, hay 1.8 3.0

Soybean, forage 1.9 2.0

Tomato, paste 1.6 2.60

Tomato, puree 0.7 1.20

Vegetable, brassica, leafy, group 5, 

except cauliflower

1.0 (5A)

1.6 (5B)

2.0

Vegetable, cucurbit, group 9 0.3 (except 0.40
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Table 2.2.3. Tolerance Summary for Sulfoxaflor.

Commodity Tolerance, ppm Comments (correct commodity definition)

Proposed Recommended

squash)

Vegetable, fruiting, group 8-10 1.2 0.70 The calculated tolerance was 0.9 ppm; 

however, HED recommends for a 0.7 ppm 

tolerance in order to harmonize with 

CODEX.

Vegetable, leaves of root and tuber, 

group 2

4.0 3.0 Based on sugar beet and radish top data

Vegetable, legume, foliage, group 7 -- 3.0

Vegetable, root and tuber, group 1 0.01 0.05

Watercress -- 6.0 Translated from subgroup 4A data, not a 

member of subgroup 4A.

Wheat, grain 0.07 0.08

Wheat, forage 0.8 1.0 Tolerance is higher than the HAFT, but 

lower than the maximum residue.

Wheat hay 1.1 1.50

Wheat, straw 2.0 2.0

Livestock Commodities*

Cattle, meat 0.1 0.15

Cattle, fat 0.04 0.10

Cattle, kidney 0.2 -- See Cattle, meat byproducts

Cattle, meat byproducts 0.25 0.40

Milk 0.08 0.15

Milk fat NA --

Goat, meat 0.1 0.15

Goat, fat 0.04 0.10

Goat, kidney 0.2 -- See Goat, meat byproducts

Goat, meat byproducts (except kidney) 0.3 -- See Goat, meat byproducts

Goat, meat byproducts -- 0.40

Hog, meat 0.01 0.01

Hog, fat 0.01 0.01

Hog, meat byproducts 0.04 0.01

Horse, meat 0.1 0.15

Horse, fat 0.04 0.10

Horse, kidney 0.2 -- See Horse, meat byproducts

Horse, meat byproducts (except kidney) 0.3 -- See Horse, meat byproducts

Horse, meat byproducts -- 0.40

Poultry, meat 0.01 0.01

Poultry, fat 0.01 0.01

Poultry, meat byproducts 0.03 0.01

Poultry, eggs 0.01 0.01

Sheep, meat 0.1 0.15

Sheep, fat 0.04 0.10

Sheep, kidney 0.2 -- See Sheep, meat byproducts

Sheep, meat byproducts (except kidney) 0.3 -- See Sheep, meat byproducts

Sheep, meat byproducts -- 0.40

* Quantifiable residues of sulfoxaflor are not expected in poultry or swine commodities; for 

harmonization purposes, however, HED is recommending tolerances at the LOQ level (0.01 

ppm) for sulfoxaflor in those commodities.
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2.2.4 Revisions to Petitioned-For Tolerances

Many of the proposed tolerances are different from those recommended by HED. The reason for 

the differences is that the registrant determined the proposed tolerances using the NAFTA 

(North American Free-Trade Agreement) tolerance calculation procedures rather than by using 

the OECD calculation procedures. In addition, the registrant proposed tolerances for some crops 

as both an individual crop and as members of a crop group. The registrant should submit a 

revised Section F in which the proposed tolerances are the same as those recommended by HED.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

The sulfoxaflor labels should be revised to specify that no more than two applications may be 

made to soybean forage, as supported by the available residue data.

2.3.2 Recommendations from Occupational Assessment

Sulfoxaflor is classified as Toxicity Category IV via the dermal route and for skin irritation 

potential. It is not a skin sensitizer. Short- and intermediate-term post-application risk estimates 

were not a concern on day 0 (12 hours following application) for all post-application activities. 

Under 40 CFR 156.208 (c) (2) (iii), ai’s classified as Acute III or IV for acute dermal, eye 

irritation and primary skin irrigation are assigned a 12-hour REI. Therefore, the [156 subpart K] 

Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers 

from post-application exposures to sulfoxaflor. It should be noted that the petitioner has 

proposed a REI of 24 hours for the proposed products based on their interpretation of the acute 

ocular toxicity study of the TransformTM WG formulated product resulting in a Toxicity 

Category II for eye irritation. HED recommends that RD ensure that the proper REI is listed on 

both proposed labels according to the acute toxicity profile of the active ingredient.

2.3.3 Recommendations from Residential Assessment

At this time, there are no residential uses for sulfoxaflor.

3.0 Introduction

3.1 Chemical Identity

Table 3.1. Sulfoxaflor Nomenclature.

Chemical Structure

N

S

N O

N

F3C
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Common name Sulfoxaflor

Company experimental names XDE-208

IUPAC name 1-(6-trifluoromethylpyridin-3-yl)ethyl](methyl)-oxido-λ

6

-

sulfanylidenecyanamide

CAS name cyanamide, N-[methyloxido[1-[6-(trifluoromethyl)-3-pyridinyl]ethyl] λ4-

sulfanylidene]

Molecular formula C10H10F3N3OS

CAS registry number 946578-00-3

End-use products (EP) GF-2032 SC, Transform WG

Chemical Class Sulfoximine

Known Impurities of Concern None

3.2 Physical/Chemical Characteristics

The physical/chemical properties of sulfoxaflor (Appendix D) do not indicate that there are any 

special considerations that need to be made in conducting this risk assessment. The compound is 

not particularly volatile (vapor pressure ≤ 1.4 x 10-6Pa) and based on the KOW (~6.35) it is not 

expected to partition into fatty tissue or bioaccumulate. In the soil, sulfoxaflor and its major 

degradate, X11719474, are expected to be highly mobile.

3.3 Pesticide Use Pattern

Sulfoxaflor products are intended to be used for insect control in a wide variety of crops as well 

as turf grass and ornamentals. Sulfoxaflor is generally applied 2-4 times with retreatment 

intervals ranging from 5 to 14 days, depending on crop, pest, and country/region. The end-use 

products may be applied through a variety of application methods including aerial, chemigation, 

ground-boom sprayer, and air-blast sprayer. The recommended application rates for agricultural 

crops range from 0.016-0.133 lb ai/A. A summary of the use directions is provided in Table 3.3.

Table 3.3. Summary of Proposed Directions for Use of Sulfoxaflor.

Applic. Timing, 

Type, and Equip.

Formulation Applic. 

Rate,

lb ai/A

Max. No. 

Applic. 

per 

Season

Max. Seasonal 

Applic. Rate,

lb ai/A

[g ai/ha]

PHI

(days)

Use Directions and 

Limitations

Barley/Triticale/Wheat

Ground, air blast, 

and aerial SC/WDG

0.012 -

0.043 2 0.09 [101]

7 (forage/

fodder/hay)

14 (grain/

straw)

14-day retreatment 

interval.

Brassica (Cole) Leafy Vegetables

Ground, air blast, 

and aerial SC/WDG 0.023 –0.090

4 0.266 [298] 3

7-day retreatment 

interval.

Bulb Vegetables (Crop Group 3-07)

Ground, air blast, 

and aerial SC/WDG 0.090 3 0.266 [298] 7

7-day retreatment 

interval.

Canola (Rapeseed) Subgroup 20A

Ground, air blast, SC/WDG 0.012 - 2 0.09 [101] 14 14-day retreatment 
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Table 3.3. Summary of Proposed Directions for Use of Sulfoxaflor.

Applic. Timing, 

Type, and Equip.

Formulation Applic. 

Rate,

lb ai/A

Max. No. 

Applic. 

per 

Season

Max. Seasonal 

Applic. Rate,

lb ai/A

[g ai/ha]

PHI

(days)

Use Directions and 

Limitations

and aerial 0.043 interval.

Citrus (Crop Group 10)

Ground, air blast, 

and aerial SC/WDG 0.023 -0.133 4 0.266 [298] 1

7-day retreatment 

interval.

Cotton

Ground, air blast, 

and aerial SC/WDG

0.012 -

0.090 4 0.266 [298] 14 5-day retreatment 

interval.

Cucurbit Vegetables (Crop Group 9)

Ground, air blast, 

and aerial

SC/WDG 0.023 -

0.090

4 0.266 [298] 1 7-day retreatment 

interval.

Fruiting Vegetables (Crop Group 8)

Ground, air blast, 

and aerial SC/WDG 0.022 -0.090

4 0.266 [298] 1

7-day retreatment 

interval.

Leafy Vegetables (except Brassica) Crop Group 4

Ground, air blast, 

and aerial

SC/WDG 0.023 -

0.090

4 0.266 [298] 3

7-day retreatment 

interval.

Leaves of Root and Tuber Vegetables (Crop Group 2)

Ground, air blast, 

and aerial SC/WDG 0.023 -0.090

4 0.266 [298] 7

7-day retreatment 

interval.

Pome Fruits (Crop Group 11)

Ground, air blast, 

and aerial SC/WDG 0.023 -0.090

4 0.266 (298) 7

7-day retreatment 

interval.

Root and Tuber Vegetables (Crop Group 1)

Ground, air blast, 

aerial, and 

chemigation.

SC/WDG 0.023 -

0.090

4 0.266 [298] 7

7-day retreatment 

interval.

Small Fruit Vine Climbing, except Fuzzy Kiwifruit (Subgroup 13-07F)

Ground, air blast, 

and aerial SC/WDG 0.043 -0.090

4 0.266 [298] 7

7-day retreatment 

interval.

Low Growing Berry (Subgroup 13-07G)

Ground, air blast, 

and aerial SC/WDG 0.043 -0.090

4 0.266 [298] 1

7-day retreatment 

interval.

Soybean

Ground, air blast, 

and aerial SC/WDG 0.012 -0.090

4* 0.266 [298] 7

7-day retreatment 

interval.

Stone Fruit (Crop Group 12)

Ground, air blast, 

and aerial SC/WDG 0.023 -0.133 4 0.266 [298] 7

7-day retreatment 

interval.

Succulent, Edible Podded, and Dry Beans

Ground, air blast, 

and aerial SC/WDG 0.023 -0.090

4 0.266 [298] 7

7-day retreatment 

interval.

Tree Nuts

Ground, air blast, 

and aerial SC/WDG 0.022 -0.133 4 0.266 [298] 7

7-day retreatment 

interval.

Turf grass/ Ornamentals

Ground and aerial 

(ornamentals only)

SC/WDG 0.043 -

0.133

Not 

specified 0.266 [298] NA 7-day retreatment interval. Greenhouse 
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Table 3.3. Summary of Proposed Directions for Use of Sulfoxaflor.

Applic. Timing, 

Type, and Equip.

Formulation Applic. 

Rate,

lb ai/A

Max. No. 

Applic. 

per 

Season

Max. Seasonal 

Applic. Rate,

lb ai/A

[g ai/ha]

PHI

(days)

Use Directions and 

Limitations

use.

*The residue data support two applications for soybean forage.

3.4 Anticipated Exposure Pathways

The requested uses may result in human exposure to sulfoxaflor and/or its metabolites in food 

and drinking water. At this time, there are no existing, pending, or requested registrations that 

would result in exposure from use in a residential setting. 

Sulfoxaflor presents a somewhat unique situation regarding the food and drinking water 

exposure pathway. Environmental fate data indicate that use of sulfoxaflor is likely to result in 

different residue profiles in surface water and groundwater. In surface water, the principal 

residue is expected to be sulfoxaflor whereas in groundwater, the expected residues are the 

metabolites X11719474 and, to a lesser extent, X11519540. 

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://www.eh.doe.gov/oepa/guidance/justice/eo12898.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 Continuing 

Survey of Food Intake by Individuals (CSFII) 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 post-application 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.

4.0 Hazard Characterization and Dose-Response Assessment

Sulfoxaflor is a member of the sulfoximine class of insecticides. It controls insects via a unique 

interaction with the insect nicotinic acetylcholine receptor. The proposed insecticidal mode-of-
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action (MOA) is similar to neonicotinoid insecticides, as both are nicotinic acetylcholine 

receptor (nAChR) agonists. However, sulfoxaflor differs from the neonicotinoids because it is 

not susceptible to in vitro metabolism and is proposed to have a different adverse outcome 

pathway.

4.1 Toxicology Studies Available for Analysis

The hazard database for sulfoxaflor is extensive and provides sufficient information to complete 

a human health risk assessment. Sulfoxaflor was evaluated for acute, subchronic and chronic 

oral toxicity in rats, mice and dogs, dermal toxicity in rats, teratogenicity in rats and rabbits, 

reproductive and postnatal toxicity in rats, carcinogenicity in mice and rats, neurotoxicity in rats, 

and immunotoxicity in rats. Additional guideline studies included bacterial reverse-mutation 

test, micronucleus test, and an in vitro chromosome aberration test. The database does not 

contain a subchronic inhalation study. HED has determined that this study is not required for 

sulfoxaflor (TXR# 0056310).

During the conduct of the guideline studies, limb flexure and/or increased deaths in neonatal rats

were observed in the developmental study, the reproduction and fertility study, and the 

developmental neurotoxicity study. In an attempt to further elucidate the biological processes 

underlying these effects and their potential relevance to humans, the registrant conducted 

mechanistic and pharmacokinetic studies beyond the guideline requirements. These studies 

included development and reproduction studies in the rat and rabbit, as well as in vitro studies in 

rat and human tissues. Mechanistic studies were also provided to support MOA proposals for 

Leydig cell tumors, hepatocellular tumors, and preputial gland tumors that were observed in the 

reproduction and chronic guideline studies. A detailed discussion of these studies can be found 

in the Cancer Assessment Review Committee (CARC) memorandum (TXR # 0056301). The 

guideline and mechanistic studies have been designed in such a manner as to be mutually 

supportive. For example: identical animal strains, vehicles, and routes of administration are used 

throughout the studies; plasma sulfoxaflor concentrations were measured in all studies for 

estimates of internal doses; and the same dose levels were used in multiple studies (e.g.,. the 2 

generation reproduction study and the DNT were both conducted at 0, 25, 150, or 400 ppm). 

This allows for a more integrated evaluation of studies across the sulfoxaflor toxicity profile.

As described in the following section, sulfoxaflor is resistant to in vivo metabolism. However, 

X11719474 is a major plant metabolite and environmental degradate of sulfoxaflor with a 

potential for human exposure through drinking water. A battery of studies have been conducted 

including an oral acute study, absorption and metabolism studies in rats; 28-day and 90-day oral 

studies in rats, rabbits, and dogs; a reproduction study in rats; a complete battery of mutagenicity 

studies; and in vitro rat and human receptor binding studies. Limited studies are also available 

for several other metabolites.

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

Several studies are available to evaluate the ADME of sulfoxaflor in the rat, including singledose studies, repeated-dose studies, and an intravenous-dose study to determine systemic 

availability. In addition, sulfoxaflor plasma concentrations were determined in many of the 
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studies, including guideline and non-guideline studies in the rat, rabbit, and mouse. Offspring 

and fetal sulfoxaflor plasma concentrations were determined in the reproduction and 

development studies in the rat and rabbit. This information allows the comparison of 

toxicokinetics across species, route of administration, duration, and life-stages. Furthermore, 

data are available reflecting ADME of the plant/environmental metabolites X11719474 and 

X11519540. Note that these metabolites were not found in the rat metabolism study.

ADME of Sulfoxaflor in the Rat

Sulfoxaflor is extensively and quickly absorbed following an oral dose. In single- and repeateddose studies using radiolabeled sulfoxaflor, absorption estimates ranged between 92 and 96%. 

Maximum plasma concentrations are reached within 2 hours. When compared to an intravenous 

dose, 92% of an oral dose is available systemically, confirming the high level of absorption. 

There were no significant differences between the low (5 mg/kg), high (100 mg/kg), or repeated 

(14 days @ 5 mg/kg) dose groups and plasma concentrations were dose-related indicating 

absorption was not saturated up to 100 mg/kg when given by oral gavage. 

Following absorption, sulfoxaflor is widely distributed throughout the body. When tissue 

distribution was determined at Cmax (i.e., maximum concentration of sulfoxaflor in the plasma), 

the tissues containing the largest proportions of radioactivity were the gastrointestinal tract, liver, 

kidney, and urinary bladder: all organs consistent with point-of-entry and excretion. By 168 

hours, an average of <1.5% of the administered dose remained in the body and that was 

distributed throughout the body in minor quantities.

The primary route of elimination for sulfoxaflor is through urine. Within 24 hours of an oral 

dose, 89-94% of the administered dose is eliminated through urine, compared to 5-8% through 

feces. The removal of sulfoxaflor from plasma occurs in 2 distinct phases; a rapid phase with a 

half-life of 4-6 hours followed by a much slower phase with a half-life of 39-45 hours. In the 90-

day oral study, the plasma half-lives were 8 and 9 hours in the males and females, longer than the 

28-day study of 4-5 and 7-8 hours for the males and females, respectively. Despite the longer 

second phase and the observation that elimination of sulfoxaflor is marginally slower in longerterm studies, little sulfoxaflor remains in vivo after the initial 24 hours and therefore there is no 

concern for bioaccumulation. 

In vivo metabolism of sulfoxaflor is minimal. As previously indicated, greater than 90% of an 

oral dose is eliminated within 24 hours; at least 93% of which is eliminated as the parent

compound. A glucuronide conjugate of the urea metabolite was identified at 2-4%. Five 

additional metabolites were observed; however, they were not identified and each accounted for 

<1% of the administered dose. Similarly, no major metabolites were identified in either the rat 

or mouse 28-day and 90-day oral studies. 

Fetal Exposure / Maternal Transfer in the Rat

To support the proposed MOA for developmental effects, the pharmacokinetics of sulfoxaflor 

were determined in a number of developmental and reproductions studies. Pharmacokinetics is a 

summation of the processes that control how sulfoxaflor is distributed in vivo, i.e., how it is 
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metabolized or eliminated, and, of critical importance to the developmental MOA, how it is 

presented to developing fetuses or newborn offspring. The distribution and clearance parameters 

of sulfoxaflor were described in the metabolism studies discussed above. The parameters 

relevant to fetal or offspring exposure were captured in the following reproduction and 

developmental studies. 

In the 2-generation reproduction study in the rat, plasma concentrations were determined in 

offspring and dams 4 days after parturition. Offspring levels were ≈ 30% of maternal levels 

across all dose levels indicating that the offspring internal dose was ≈ 1/3 of the maternal internal 

dose. In a cross-fostering and a developmental toxicity study in rats, the maternal and fetal 

sulfoxaflor blood concentrations were similar on GD 21. Similar findings regarding the 

comparison of maternal vs. offspring sulfoxaflor blood concentrations were reported in the rabbit 

developmental study. This suggests that sulfoxaflor moves readily across the placenta.

Lactational transfer was also determined in the cross-fostering study in the rat. On Lactation 

Day (LD) 0, the measured concentrations of sulfoxaflor in milk from sulfoxaflor-exposed dams

were approximately half the corresponding concentrations in plasma. Although milk 

concentrations were not determined in the 2-generation study, the offspring plasma 

concentrations of sulfoxaflor were approximately 30% of the maternal animals, supporting the 

observed reduction in lactational transfer. In a goat metabolism study, less than 2% of the 

dietary sulfoxaflor was found in the milk. Thus, lactational transfer ranges between 2 and 50% 

in goats and rats, respectively.

These studies clearly indicate that fetal plasma levels of sulfoxaflor are similar to the dams 

during gestation. However, after parturition when offspring exposure to sulfoxaflor is limited to 

lactational transfer through the milk, exposure to the rat pups is 2 to 3-fold lower than maternal 

doses. 

Sulfoxaflor Metabolites X11719474 and X11519540

Despite the lack of in vivo metabolism, there is a potential for exposure to environmental 

degradates of sulfoxaflor. In particular, X11719474 is a major degradate found in environmental 

fate studies, and is expected to be the major degradate in drinking water from groundwater 

sources. The toxicokinetics of X11719474 are similar to the parent sulfoxaflor; following an 

oral dose, X11719474 is highly absorbed (>98%), reaches a maximum plasma concentration 

quickly (≈1 hour), and is quickly eliminated through the urine >90% within 12 hours. Limited 

ADME data are also available for a second metabolite, X11519540, which has been observed in 

limited amounts in field and animal feeding studies. The elimination half-life of X11519540 is 

approximately 27 hours, longer than sulfoxaflor and X11719474. Both metabolites are largely 

absorbed and excreted unmetabolized in in vivo studies.

4.2.1 Dermal Absorption

The Registrant submitted an in vivo study in rats and an in vitro study utilizing split-thickness rat 

and human skin in which sulfoxaflor was applied at doses of 2360 μg/cm2, 4.8 μg/cm2, and 0.25 

μg/cm2. These doses represent sulfoxaflor concentrate, the highest in-use concentration, and the 
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lowest in-use concentration, respectively. The in vivo data showed that skin-bound residues of 

sulfoxaflor were absorbed for up to 144 hours after skin washing. The dermal absorption factor 

(DAF) for sulfoxaflor after 10 hours of dermal exposure (that included absorbable skin-bound 

residues) was 11% for both the highest and lowest in-use concentrations. These values were 

larger in magnitude than the concentrate. The in vitro data for rat skin after 24 hours of dermal 

exposure showed the largest magnitude potentially absorbable dose for the lowest in-use 

concentration. The Agency considered comparison of data at the 24-hour time point in the in 

vitro study to the 10-hour time point in the in vivo study on the basis that the estimates at the 24-

hour time point would be conservative surrogates for a 10-hour dermal exposure (because dermal 

absorption generally increases with time). The DAF for rat skin in vitro was 8%, a value that 

does not differ from the 11% DAF for rat skin from the in vivo study after standard errors in 

measurement are taken into account. This result indicated that the in vitro study design and 

execution was predictive of the in vivo results. The Agency’s policy is that if an in vitro study is 

shown to be predictive of an in vivo result, the Agency will use human skin from the in vitro

study to refine the DAF for human exposures. The DAF for human skin in the in vitro study at 

the lowest in-use concentration was 2.4% (Table 4.2.1). The Agency is using this human value 

of 2.4% as the DAF for determining dermal-equivalent doses in the sulfoxaflor risk assessment.

Table 4.2.1. Derivation of the Dermal Equivalent Dose for Human Health Risk Asssessment.

Parameters In Vivo Rat In Vitro Rat In Vitro Human

Study ID MRID No. 47832413

TXR No. 0055507

MRID No.47832414

TXR No.0055507

MRID No.47832414

TXR No.0055507

Test Material SC Formulation (24%) SC Formulation (24%) SC Formulation (24%)

Exposure 10 hours 24 hours 24 hours

Doses tested

(μg/cm2)

Low Mid Hi Low Mid High Low Mid High

0.25 4.8 2360 0.25 4.8 2360 0.25 4.8 2360

% Absorbed 10.77a11.35 1.22 8.02b8.72 1.67 2.38b2.44 0.35

Point of Departure Oral POD = Oral NOAEL = 1.8 mg/kg/day based on decreased neonatal survival at 7.1 

mg/kg/day observed in the DNT

Dermal Equivalent 

Dose (DED)

For short- and intermediate-term dermal exposure, the POD is 1.8 mg/kg/day.

POD = oral NOAEL = 1.8 mg/kg/day

DAF (In Vivo rat ) ≈ DAF (In Vitro rat) ≈ 11% 

In Vitro Human dermal absorption = 2.4%

Dermal Equivalent Dose = Oral POD/human DAF=1.8 mg/kg/day/ 0.024= 75 mg/kg/day

Comments:

Same formulation products were tested in all three studies. 

Doses are identical in the in vitro rat and human and the in vivo rat study.

In vitro absorption predicts in vivo absorption in the rat.

DED is calculated using the human dermal absorption factor.

a – Absorbed dose after 144 hours

b- Potential absorbable dose after 24 hours

4.3 Toxicological Effects

Sulfoxaflor is a member of the sulfoximine class of insecticides. It controls insects via agonism 

of the insect nicotinic acetylcholine receptor (nAChR) leading to sustained muscle contracture, 

paralysis, and death. In mammals, the pattern of toxicity attributed to sulfoxaflor exposure 

includes developmental effects (manifested as neuromuscular abnormalities and neonatal death), 
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hepatotoxicity, and generalized toxicity (e.g., decreases in body weight, body weight gain, and/or 

food consumption).

4.3.1 Developmental/Reproductive Effects, Mode of Action, and Human Relevance

Developmental/offspring toxicity, manifested as skeletal abnormalities and neonatal deaths, was 

observed in rats only. The skeletal abnormalities, forelimb flexure, bent clavicles, and hindlimb 

rotation likely result from skeletal muscle contraction due to agonism of the muscle nAChR in 

utero. Similarly, contraction of the diaphragm muscle prevents normal breathing in neonates 

resulting in increased mortality. The skeletal abnormalities were observed at high doses in the 

developmental and reproduction studies and decreased neonatal survival was consistently 

observed in the reproduction and developmental neurotoxicity studies. These developmental 

effects were not observed in the rabbit.

4.3.1.1 Mode of Action Framework

Given the known insecticidal MOA for sulfoxaflor, it was hypothesized that these effects could 

be related to an interaction between sulfoxaflor and the nAChR. In an attempt to test this 

hypothesis and further elucidate the biological processes underlying these effects and their 

potential relevance to humans, the registrant conducted numerous mechanistic studies beyond the 

guideline requirements. These studies included but were not limited to development and 

reproduction studies in the rat and rabbit, as well as in vitro studies in rat and human tissues. 

These studies were designed to assess if sulfoxaflor binds and activates the nAChR in rats, 

rabbits, and humans. Ultimately, the objective was to determine if the differences observed in 

sulfoxaflor’s developmental toxicity profile could be ascribed to a differential interaction with 

the nAChRs in these three species.

HED has used existing, peer reviewed frameworks in the analysis of the special data. In keeping 

with EPA’s Framework for Determining a Mutagenic Mode of Action and the International 

Programme on Chemical Safety (IPCS) Framework for Analyzing the Relevance of a NonCancer Mode of Action for Humans, the Agency conducted a mode of action framework analysis 

considering the relevance of the mode of action (MOA) to humans. This is consistent with the 

approaches taken by the Joint FAO/WHO Meetings on Pesticide Residues (JMPR) and the 

Organization for Economic Cooperation and Development (OECD). The MOA analysis 

framework relies on a weight-of-evidence approach, which is based on modified Bradford Hill 

criteria for causality (Hill, 1965). In line with the 2007 NRC report on Toxicity testing in the 

21st Century, some have considered the concept of adverse-outcome pathways (AOP) in addition 

to MOA. These concepts are fundamentally similar in that each considers key events (including 

an initiating event) leading from exposure to an adverse outcome. This document uses the MOA 

terminology instead of the AOP terminology. In brief, the MOA framework begins with a 

proposed set of key events and then describes the evidence for such events with particular focus 

on temporal and dose-response concordance. Consistent with the Bradford Hill criteria, the 

MOA analysis also takes into consideration the consistency, specificity, and biological 

plausibility of the findings. The analysis also involves explicit evaluation of alternative 

hypotheses, alternative MOAs, and remaining uncertainties. 
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Proposed Key Events

In light of observations in the guideline toxicity studies and the basic biological understanding of 

muscle nAChR ontogeny and function in mammalian systems, the registrant proposed a MOA by 

which the muscle effects (forelimb flexure, bent clavicles, and rotated hindlimbs) and deaths 

observed in rat neonates are caused by sulfoxaflor’s sustained agonism at the fetal-type 

muscle nAChR and subsequent sustained muscle contracture of the limb, shoulder girdle 

and diaphragm, respectively. This proposed MOA can be expressed in terms of four key 

events depicted in the Figure 4.3.1.1:

Figure 4.3.1.1. Key events of the sulfoxaflor MOA. Each box represents a key event, beginning 

with the availability of sulfoxaflor at the neuromuscular nAChR and concluding with the 

reproductive effects observed in the reproduction and development studies (KE=Key Event). 

Summary of the Evidence for the Key Events:

Key Event #1: Internal dose at the target tissue: As described in the ADME section of 

this document, sulfoxaflor is extensively and quickly absorbed following oral exposure

and distributed systemically. It is, therefore, available to interact with the target tissue.

Key Event #2: Muscle receptor binding: Two types of nAChRs are present in mammals, 

neuronal and muscle. The muscle nAChRs are found in the intramuscular junctions of 

skeletal muscles and are involved in muscle contraction; it is the muscle nAChRs which 

are the targets for sulfoxaflor. Disregulation of these receptors can result in improper 

muscle contraction, difficulties in breathing, and ultimately death (due to sustained 

diaphragm contracture). Two isoforms of the muscle nAChRs have been identified in 

mammals, a fetal isoform and an adult isoform. The transition from fetal to adult isoform 

occurs shortly after birth in rats and late during the 3rd trimester in humans. Furthermore, 

sulfoxaflor has been shown to bind the fetal isoforms of the nicotinic receptors of rats, 

rabbits, and humans in a series of mechanistic studies. These studies demonstrated a 

dose-dependent increase in sulfoxaflor binding to the fetal muscle nAChR in all three 

species.

Key Event #3: Receptor agonism: Sulfoxaflor binds the nAChR in the rabbit, rat, and 

human. A study was undertaken to determine if sulfoxaflor causes activation of the 

receptors. Rat and human muscle nAChRs were expressed in Xenopus oocytes– a model 

system used to evaluate activation of receptors. Rabbit receptors were not evaluated 

because the encoding proteins are not currently available for this species. The ability of 

sulfoxaflor to activate both fetal and adult muscle nAChRs was examined. This study 

indicated that the rat fetal-type nAChR was activated by sulfoxaflor. However, there was 

no activation in the adult rat, fetal human, or the adult human receptors. The implications 

Target Tissue

KE 1 

nAChR 

Binding

KE 2

nAChR 

Agonism

KE 3

Increased 

Muscle 

Contraction

KE 4

In Vivo 

Clinical Signs

KE 4
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for the lack of response in humans are discussed below in the human relevance section.

Key Event #4: Muscle contraction and clinical signs: Sustained contraction of fetal rat 

diaphragm muscles in the presence of sulfoxaflor was demonstrated in vitro. Contraction 

of the diaphragm during late gestation leads to asphyxiation and the observed increase in 

neonatal deaths. 

The muscle nAChRs transition from the fetal to the adult isoforms and the timing of this 

shift provides insight into the potential role of the fetal nAChR in the developmental 

effects observed in rats after sulfoxaflor exposure. Both the skeletal effects and the 

offspring deaths in rats are limited to the very early postnatal period when the fetal 

isoform is the predominant isoform present. However, beyond post-natal day 4 there is 

no increase in pup death and the skeletal effects noted shortly after birth (forelimb 

flexure, bent clavicles, and rotated hindlimbs) begin to recover. Thus, it appears that 

there is a time-concordance between the appearance of the adult isoform and recovery 

from the developmental effects strongly suggesting that the fetal isoform of the muscle

nAChR is critical to the manifestation of these types of effects. For a more detailed 

description of the agonism experiments refer to Appendix B.

Alternative MOAs: As discussed in Appendix B, a variety of alternative hypotheses were 

considered (i.e., neuronal nicotinic receptor activation, muscarinic receptor activation, 

fetal nicotinic receptor inactivation, and ACE inhibition). However, none of these were 

consistent with sulfoxaflor’s toxicological profile, particularly the adverse outcomes 

observed. 

Weight of the Evidence: In conclusion, there is compelling evidence that the proposed 

MOA is operative in the fetal rat and leads to the neonatal death and the skeletal effects 

seen in the guideline toxicity studies involving that species. As such, HED believes the 

developmental and reproduction MOA based on agonism of the fetal nAChR has been 

established. 

4.3.1.2. Human Relevance

As summarized above and discussed in detail in Appendix B, the MOA for the neonatal death 

and limb flexures based on agonism of muscular nicotinic receptor has been established. Given 

this finding, HED has used the Human Relevance Framework (HRF) to consider the degree to 

which the developmental and reproduction MOA is relevant to humans and thus relevant for risk 

assessment. The HRF entails both a qualitative and quantitative evaluation and comparison of 

the key events in animals and humans. Like the MOA analysis, the HRF analysis includes an 

evaluation of uncertainties and consideration of alternatives. An HRF analysis may be 

undertaken for a variety of reasons including:

Situations where the effects in animals would have potentially serious consequences if 

they occurred in humans, and

Situations where there are interspecies differences in either the type of effect or the dose 

levels at which an effect occurs.
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In addition to the guideline toxicity studies conducted with sulfoxaflor, an extensive mechanistic 

data set has been generated to further evaluate the interspecies sensitivity to sulfoxaflor’s 

developmental effects. These studies include both binding and agonism in vitro/ex vivo studies 

to ascertain if: (a) sulfoxaflor binds to the muscle nAChR receptor in rats, rabbits, and humans 

and (b) if the bound sulfoxaflor can activate the receptor. Data from these experiments indicate 

that although sulfoxaflor does bind to the fetal nAChR in rats, rabbits, and humans, it does not 

activate the human receptor.

Table 4.3.1.1. Key Events of the Developmental and Reproduction Sulfoxaflor MOA based on agonism of the rat 

fetal nAChR and the supporting events observed in rats and human tissues.

Key Event Evidence in Rodents Evidence in Humans

#1 Binding to the fetal-type muscle nAChR Yes Yes

#2 Agonism at the fetal-type muscle nAChR Yes

No; Plausible, but no agonism occurs 

with sulfoxaflor either at the fetal- or 

adult-type muscle nAChR. 

#3 Sustained fetal-type muscle nAChR 

agonism/sustained muscle contraction Yes

No data in humans. Presumably not 

possible via this MoA as key event #2

does not occur.

Apical Endpoints Forelimb Flexure, Hindlimb 

Rotation, Bent Clavicle, Neonatal Death Yes

No data in humans. Presumably not 

possible via this MoA as key event #2 

does not occur.

Close examination of the key events indicates significant differences in the key events between 

the rat and human. 

Key Event #1: Qualitatively, sulfoxaflor has demonstrated the ability to bind both rat and 

human nAChRs. As previously described, sulfoxaflor has been shown to bind the fetal 

isoforms of the nicotinic receptors of rats, rabbits, and humans.

Key Event #2: Despite binding, sulfoxaflor does not activate the human fetal muscle

nAChR. An in vitro study using fetal isoform for rat and human of the muscle nAChR 

expressed in Xenopus oocytes, examined the ability of sulfoxaflor to perturb the 

functionality of rat and human muscle nAChR isoforms. Treatment with sulfoxaflor 

resulted in increased response in the rat fetal isoform. In contrast, there was no indication 

of agonism by sulfoxaflor in the human isoform. Figure 4.3.1.2 is a graphical 

representation of the agonism of the rat and human fetal NAChRs by sulfoxaflor. Fetal 

rat and human nAChRs were expressed in Xenopus oocytes followed by exposure to 

sulfoxaflor (blue line). The endogenous agonist acetylcholine (ACh; red line) was also 

tested to ensure the integrity of the expressed receptors and for a quantitative comparison 

to sulfoxaflor-induced activity. ACh induced a clear and potent response at 10-6 M in the 

rat and human receptors. However, considerably higher concentrations of sulfoxaflor 

were required to initiate activity in the rat receptor (10-4 M), and the response was 

relatively low. It is especially important to note that the human receptor was refractory to 

sulfoxaflor-induced activity, even at concentrations exceeding 10-3 M, or approximately 

500-fold greater than the concentrations that resulted in activation in the rat receptor.
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Figure 4.3.1.2. Agonist activation of muscle nAChRs expressed in Xenopus oocytes. Data are 

shown for the (A) rat fetal, (B) human fetal muscle nAChR. AChRs were expressed by 

microinjection of cDNA or cRNA in Xenopus oocytes. ACh = acetylcholinesterase; IMI = 

imidacloprid; Sulfoxaflor metabolite X11719474.

Although the technology for cloning the rabbit muscle nAChR is not yet available, the 

lack of developmental effects in the rabbit is an indirect indicator of the unique sensitivity 

of the rat. In the rabbit developmental study, (MRID 47832066) and non-guideline rabbit 

survival study (MRID 47832138) there is no indication of the fetal anomalies observed in 

the rat developmental toxicity study, in particular the forelimb flexure, bent clavicle, and 

hindlimb rotation seen in the rat developmental toxicity. Furthermore, the sulfoxaflor 

plasma concentrations on gestation day (GD) 27 were ≈ 4-fold higher than the plasma 

concentration associated with neonatal death and neuromuscular/skeletal effects in the rat 

pups, indicating that the absence of developmental effects in the rabbit studies is due to a 

pharmacodynamic rather than a pharmacokinetic difference between rabbits and rats.

Key Events #3 and #4: Muscle contraction and in vivo clinical signs are not available for 

evaluation in humans. However, in the absence of Key Event #2, these final key events 

are not expected to occur in humans.

Weight of Evidence: Based on the lack of receptor activity, there is compelling evidence 

that the developmental and reproduction MOA based on agonism of the fetal nAChR is 

not likely to be relevant to humans. Furthermore, a comparison of the amino acid 

sequence of the rat and human γ subunit (specific to the fetus) revealed that, although the 

two subunits are similar (approximately 90% identical), they contain 53 amino acid

differences (Millar, 2010). There are several precedents for species-selective agonist 

activity of nAChR ligands. Given the evidence that as few as one or two amino acid 

differences can confer species-selective agonist activity upon nicotinic ligands, it seems 

entirely plausible that the differences in agonist activity of sulfoxaflor can be explained 

by differences in the amino acid sequence of the rat and human muscle nAChR γ 

subunits. The γ and ε subunits (fetal and adult isoforms, respectively) show even greater 

sequence differences than the human and rat γ subunit (even from the same species), 

where these subunits share only about 50% identity in amino acid sequence in the rat.
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Uncertainties: The use of Xenopus oocytes in the agonism study represents a residual 

uncertainty, albeit extremely low, that precludes the Agency from discounting the 

possibility of human relevance on a qualitative basis. The heterologous expression of 

mammalian receptors in Xenopus oocytes is a common technique that has been used for 

determining the structure and function of nicotinic receptors (Millar 2009). Expression in 

Xenopus oocytes offers several advantages over native mammalian cells including the 

following: limited expression of endogenous ion channels and receptors so that 

exogenous proteins can be studied with minimal contamination; some channels can only 

be expressed in oocytes and not in mammalian cells; and oocytes are well suited for 

electrophysiological recording. Past studies have indicated that the activity of muscle

nAChRs expressed in either oocytes and HEK were similar for muscle (Stern et. al. 1994) 

and neuronal (Luetje and Patrick 1991) type receptors. However, the unique matrixes 

provided by the oocytes and mammalian cells can lead to differential expression of 

receptors or channels. For example, the expression of the human neuronal nAChR α3β4 

results in different ratios of the α and β subunits for oocytes and HEK cells (Krashia e.t 

al. 2010; Boorman et. al. 2000). Altered subunit ratios have been shown to result in 

different sensitivities to the acetylcholine and other agonists (Krashia et al. 2010; Moroni 

et. al. 2006; Moroni et. al. 2008). Due to the severity of the endpoint (i.e, neonatal 

deaths), HED has a requested a confirmatory study; that is a study confirming the 

refractory response of a fetal human nicotinic receptor expressed in a mammalian cell. 

Pending the results of the confirmatory study in human receptors expressed in 

mammalian cells, HED considers the MOA relevant to humans. 

4.3.1.3. Interspecies Uncertainty Factor

The available information comparing rat and human muscle nAChR response to sulfoxaflor has 

bearing on the interspecies uncertainty factor (UFA) when assessing nAChR-mediated risks 

associated with sulfoxaflor exposure. HED recommends that the 10X interspecies factor be 

reduced to 3X for acute dietary risk assessment for women of reproductive age and for other

scenarios assessed using the neonatal death endpoint (i.e., dermal and inhalation risk 

assessments). This recommendation is based on the evidence gathered from the mechanistic data 

which indicate that rats may be uniquely sensitive to the developmental effects of sulfoxaflor. 

HED has used the 2005 IPCS document on Chemical Specific Adjustment Factors and the 

Agency’s 2011 external peer review draft of the Guidance on Data Derived Extrapolation 

Factors. In short, both approaches endorse the use of mechanistic and pharmacokinetic data to 

inform data derived extrapolation factors for inter- and intra-species extrapolation. In both 

approaches, the typical 10X factor is split between a PD and PK component. USEPA typically 

uses an even split of 3X and 3X. As discussed in 4.1.1, the developmental and reproduction 

MOA based on agonism of the fetal nAChR has been established for skeletal anomalies (e.g., 

forelimb flexure, bent clavicle, and rotated hindlimbs) and neonatal deaths in the rat and HED 

cannot currently rule out this MOA as being not relevant to humans. As such, the neonatal 

mortality is relevant for POD selection (see above). Although, HED believes that additional data 

are necessary to fully demonstrate the lack of human relevance, the existing mechanistic are high 

quality and provide a robust evaluation of the response to rat and human tissues for the agonism 

of the nAChR. Moreover, the nature and quality of these data are consistent with the kinds of 

data recommended by the International Programme on Chemical Safety (IPCS) Chemical-
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Specific Adjustment Factor (CSAF) and the EPA Data Derived Extrapolation Factors guidance 

documents. 

Quantitatively, the sulfoxaflor concentration required to initiate receptor activation in human 

fetal nAChR is at least 500-fold greater than that required to activate rat fetal nAChR. The 

absence of nAChR activation precludes the manifestation of skeletal abnormalities and neonatal 

deaths. Therefore, the data indicate that rats are uniquely sensitive to the developmental and 

reproduction MOA leading to neonatal death and neuromuscular effects. The Agency is 

proposing that the PD portion of the interspecies UF be reduced to 1X. Pharmacodynamics can 

be defined as what the chemical does to the body. In the case of sulfoxaflor, PD is expressed as 

the ability of the sulfoxaflor to interact with the nAChR. Since agonism of the nAChR is the 

critical key event, interspecies extrapolation can be assessed using the agonism data (i.e., data 

demonstrating sulfoxaflor-induced activity in the oocyte expressed rat and human nAChRs). As 

described in 4.3.1.2, sulfoxaflor does not elicit a response in the human nAChR at concentrations 

500-fold higher than the concentrations eliciting a response in the uniquely susceptible fetal rat 

receptor. In other words, based on this assay, human tissue is at minimum 500-fold less sensitive 

than is the rat tissue. Since humans are clearly not more sensitive pharmacodynamically to 

sulfoxaflor compared to the rat, reduction of the UF for PD to 1X, which assumes an equal 

response between humans and rats, is conservative. 

The PK portion of the inter-species factor is retained at 3X since there are PK studies in human 

tissues or physiologically-based pharmacokinetic models which allow for refinement of the PK 

component of the extrapolation factor.

4.3.2. Other Adverse Outcomes Observed for Sulfoxaflor

In terms of adults, sulfoxaflor systemic toxicity is manifested primarily in the form of 

hepatotoxicity in rat, mouse, and dog studies. Moreover, effects were observed following 

exposures as short as 8 days as well as in studies continuing for up to 2 years. Increased liver 

weight, hepatic hypertrophy, fatty liver, single cell necrosis, and changes in clinical chemistry 

(i.e., cholesterol, AST, or ALT) were consistently observed throughout the toxicology database. 

The longer term carcinogenicity studies resulted in hepatic effects at lower doses compared to 

the short-term studies. In addition, males appeared to be more sensitive to the hepatic toxicity. 

As indicated in section 4.2, male rats had a slower clearance rate compared to females. The

slower clearance rate in males in essence increases exposure and might account for the increased 

male sensitivity to hepatotoxicity in the longer-term studies. 

Aside from the developmental and hepatic effects, other effects seen in the sulfoxaflor database 

include decreases in food consumption and body weight as well as changes in the male 

reproductive system. Decreased body weight, body weight changes, and food consumption were 

observed during the first few days of several oral studies at the mid- and high-dose levels. As a 

result of decreased feeding early in the studies, body weights were typically lower in the midand high-dose groups compared to the controls, although the differences were not generally 

statistically significant. Decreased palatability is a likely contributor to this effect as body 

weight decreases were often observed at study initiation but were comparable to control animals 

within several weeks. 
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Effects in the male reproductive organs were observed in the chronic/carcinogenicity study in 

rats that included increased testicular and epididymal weights, atrophy of seminiferous tubules, 

and decreased secretory material in the coagulating glands, prostate, and seminal vesicles. 

Additionally, there was an increased incidence of interstitial cell (Leydig cell) tumors. The 

Leydig cell tumors observed after exposure to sulfoxaflor are not considered treatment related 

due to the lack of dose response, the lack of statistical significance for the combined tumors 

(unilateral and bilateral), and the high background rates for this tumor type in F344 rats. The 

primary effects on male reproductive organs are considered secondary to the loss of normal 

testicular function due to the size of the interstitial cell (Leydig Cell) adenomas. Consequently, 

the secondary effects to the male reproductive organs are also not considered treatment related.

Clinical indications of neurotoxicity were only observed at high doses in the acute neurotoxicity 

study in rats. At the highest dose tested, clinical signs included increased muscle tremors and 

twitches, convulsions, hindlimb splaying, increased lacrimation and salivation, decreased pupil 

size and response to touch, gait abnormalities and decreased rectal temperature. Decreased 

motor activity was also observed in the mid- and high-dose groups. While the muscle effects are 

consistent with perturbation of the neuromuscular nAChR, salivation, lacrimation, and pupil 

response are typically associated with muscarinic receptor activity. Since the neurotoxicity was 

observed only at a very high dose and is not entirely consistent with nicotinic receptor toxicity, it 

is unlikely that these effects are due to agonism of the nAChR. 

Finally, tumors were observed in chronic rats and mouse studies. In the rat, a significant 

increase in the incidence of hepatocellular adenomas and combined adenomas and/or carcinomas 

in the high-dose males was observed when compared to controls. As previously indicated, 

Leydig cell tumors were also observed in the high-dose group, but it was determined that these 

were not related to treatment with sulfoxaflor. There was also a significant increase in the 

incidence of preputial gland tumors in males in the high-dose group. Marginal increases were 

also observed in the low- and mid-dose groups; however, the incident values for these groups 

were within the range of historical control values. In male mice, treatment-related changes in 

the high-dose groups consisted of increased incidences of hepatocellular adenomas and/or 

carcinomas.

4.3.3. Metabolites

As indicated previously, the petitioner has provided several additional studies on sulfoxaflor 

metabolites and degradates. Sulfoxaflor has six known primary metabolites; all are formed by 

metabolism of the parent’s ethyl-sulfanylidene-cyanamide side chain and/or the side chain of its 

metabolites.

X11719474 is a major metabolite in terms of magnitude of residue and/or presence across 

matrices - soil, water and edible crops. The estimated half-life of X11719474 exceeds 1000 days 

in US soils and the compound has the potential to leach into ground water. Of the metabolites, 

X11719474 has the most complete toxicology database, which includes oral acute, subchronic, 

developmental, reproduction, and metabolism studies. Unlike sulfoxaflor, X11719474 does not 

cause agonism of the fetal rat muscle nAChR and prenatal exposure does not result in increased 
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neonatal deaths or skeletal abnormalities. The major target organ of X11719474 is liver and the 

LOAELs are based on hepatotoxicity. 

X11519540 is a minor soil and animal metabolite. It is also found as a low-level impurity of the 

manufacturing process. Repeat-dose studies in the rat show that the primary target organ is the 

liver. In addition, X11519540 resulted in a dose-dependent increase in the adrenal gland weight. 

When the LOAELs for the 28-day oral studies for sulfoxaflor and X11519540 are compared, the 

LOAEL for X11519540 is 10-fold lower than the LOAEL for sulfoxaflor. The oral LD50 for this 

metabolite is approximately half of the LD50 for sulfoxaflor. Therefore, it is apparent that 

X11519540 is more potent than sulfoxaflor. The 28-day rat study also indicates that X11519540 

has a longer half-life; 24-35 hours compared to 4-8 hours for sulfoxaflor, which could contribute 

to its increased potency. 

Other metabolites include X11721061, X11596066, X11579457, and X11718922. None of these 

metabolites are expected to contribute significantly to the potential toxicity of sulfoxaflor. 

As indicated above, the target organ for X11719474 and X11519540 is the liver. To determine if 

X11719474-induced hepatotoxicity is also mediated by nuclear receptor-mediated MOA, rats 

were given either 0 or 8000 ppm (583 mg/kg/day) X11719474 for 7 days in a non-guideline 

study. After 7 days, the key events identified in the sulfoxaflor MOA were determined to also 

occur after X11719474 exposure. Based on these observations, CARC determined that the 

metabolite X11719474 induced hepatocellular gene expression, enzyme activity, and 

proliferation in a manner very similar to sulfoxaflor. A similar study providing mechanistic data 

on the pathway leading to hepatotoxicity is not available for X11519540. However, due to 

structural similarity between X11519540 and X11719474, and the similar MOAs for X11719474 

and sulfoxaflor, HED assumes that the events leading to hepatotoxicity in X11519540 are similar 

to those for sulfoxaflor and X11719474.

As previously indicated, there is a complete database of toxicological studies for sulfoxaflor and 

there are numerous studies describing the toxicity of X11719474. However, the database for 

X11519540 is limited to two studies, a 28-day oral toxicity study in the rat and an acute LD50

study, also in the rat. Since the rat 28-day oral toxicity studies are common to all three chemical 

databases and the studies’ LOAELs are all based on the common toxic effect of hepatotoxicity, 

HED has estimated the relative potency of X11719474 and X11519540 based on results from the 

28-day oral toxicity study in the rat. The study LOAELs are 79.4, 244, and 7.7 mg/kg/day for 

sulfoxaflor, X11719474, and X11519540, respectively. Therefore the relative potency factors 

with respect to liver toxicity are 0.3 for X11719474 and 10 for X11519540.

4.4 Safety factor for Infants and Children (FQPA Safety Factor)

HED has recommended that the required 10X FQPA Safety Factor be reduced to 1X based on 

the following considerations: 1) the toxicology database for sulfoxaflor is complete with regard 

to FQPA consideration, including the required developmental and reproductive toxicity studies; 

2) the required neurotoxicity studies, including the developmental neurotoxicity study (DNT) 

have been submitted, are considered adequate; 3) although there is evidence of quantitative 

susceptibility in the DNT study, based on decreased survival of offspring up to postnatal day 4, 
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the endpoints and doses selected for risk assessment are protective for these effects; further, 

HED’s degree of concern for human susceptibility is reduced based on the special studies 

submitted in support of the mode of action; and 4) although some refinements are used in the 

exposure assessment, the dietary and drinking water assessments still result in upper-bound 

estimates of exposure. 

4.4.1 Completeness of the Toxicology Database

The toxicology database for sulfoxaflor is adequate for FQPA consideration including a 

developmental toxicity study in rats and rabbits, a 2-generation reproduction study in rats, and 

acute, subchronic, and developmental neurotoxicity studies in rats.

An acceptable guideline inhalation study is required for all food-use registrations; however in the 

case of sulfoxaflor, the use of an oral study is considered protective for inhalation exposure for 

the following reasons: 

1) The acute inhalation toxicity (Category IV) is lower than the acute oral LD50

(Category III); 

2) The vapor pressure is low (≤1.4×10-6Pa = 1.05×10-8 mm Hg at 20°C); 

3) There is adequate characterization of toxicity; 

4) Oral absorption is >90% – substantially higher absorption via the inhalation route is 

not expected; 

5) Oral absorption is rapid; 

6) Sulfoxaflor is not subject to enterohepatic circulation, making the absorbed oral dose 

available systemically; and 

7) Sulfoxaflor is not subject to in vivo metabolism and therefore potential first-pass 

effects are not relevant. 

Therefore, the subchronic inhalation study is waived for sulfoxaflor. The lack of a subchronic 

inhalation study is not considered a data gap and a database uncertainty factor is not required 

(TXR# 0056310). 

4.4.2 Evidence of Neurotoxicity

The level of concern for neurotoxicity is low because the effects are well characterized, the doseresponse curve for these effects is well characterized, and clear NOAELs have been identified. 

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

Although there was quantitative susceptibility observed in the DNT, there is no residual 

uncertainty because the effects are well characterized, a clear NOAEL was identified, and the 

endpoints chosen for risk assessment are protective of potential in utero and developmental 

effects. Quantitative susceptibility in the DNT was based on an increased rate of neonatal deaths 

at a dose where no maternal toxicity was observed. However, the apparent enhanced sensitivity 

may be due to the limited number of evaluations conducted in dams in the study rather than a 

true sensitivity of the young. Qualitative susceptibility was observed in the 2-generation 

reproduction study since neonatal deaths were observed at the same dose that resulted in 
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hepatotoxicity in parental animals. However, these effects occurred at a higher dose compared to 

the offspring effects observed in the DNT. Finally, there was no evidence of quantitative or 

qualitative susceptibility in the developmental studies in the rat or rabbit.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties with regard to dietary and occupational exposure. The dietary 

exposure assessments are based on high-end health protective residue levels (that account for 

parent and metabolites of concern), processing factors, and percent crop treated assumptions 

(100%). Actual exposure to sulfoxaflor will likely be lower than the estimated exposure. 

Furthermore, conservative, upper-bound assumptions were used to determine exposure through 

drinking water sources, such that these exposures have not been underestimated.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

Based on the use pattern and the toxicological profile of sulfoxaflor, HED selected endpoints and 

doses for acute and chronic dietary risk assessment. Endpoints and doses were not selected for 

non-dietary non-occupational exposures (i.e., incidental oral, dermal, or inhalation), since there 

are no proposed uses which would result in these exposure pathways. For occupational handlers 

and workers re-entering treated areas, HED selected endpoints and doses for dermal and 

inhalation exposure and risk assessment.

Endpoint Selection

Acute Dietary Endpoint for the General Population: The endpoint used for establishing the 

aPAD for the general population was selected from the acute neurotoxicity study in rats. An 

aPAD of 0.25 mg/kg/day was derived from a NOAEL of 25 mg/kg/day and a 100-fold factor 

that included 10x for inter-species extrapolations, 10x for intra-species variations, and a 1x 

FQPA SF. The LOAEL of 75 mg/kg was based on decreased motor activity on Day 1. More 

severe effects were observed at the high dose (750 mg/kg), including increased muscle tremors 

and twitches, convulsions, hindlimb splaying, increased lacrimation and salivation, decreased 

pupil size and response to touch, gait abnormalities and decreased rectal temperature. None of 

these effects were observed either 8 or 15 days after dosing. This endpoint is appropriate for the 

acute dietary exposure assessment because it is the result of a single dose, is an appropriate route 

of exposure (oral) and is protective of the general population.

Acute Dietary Endpoint for Females 13-49 years of age: The endpoint used for establishing the 

aPAD for females 13-49 years of age was selected from the DNT study in rats. An aPAD of 

0.06 mg/kg/day was derived from a developmental NOAEL of 1.8 mg/kg/day and a 30-fold 

factor that included 3x for inter-species extrapolation, 10x for intra-species variation, and 1x 

FQPA SF. The endpoint of concern is decreased neonatal survival in PND 0-4 offspring at the 

LOAEL of 7.1 mg/kg/day. Through a series of non-guideline developmental studies in the rat, 

the critical window of susceptibility for skeletal effects and neonatal deaths was determined to be 

gestation days (GD) 19-20. Therefore, this endpoint is appropriate because a single dose during 
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GD 19-20 can be adverse. Furthermore, it is of a relevant route of exposure (oral), and is 

protective for effects seen in the most sensitive subgroup (fetuses).

Chronic Dietary: The endpoint used for establishing the cPAD was selected from the 

chronic/carcinogenicity combined study in the rat. A cPAD of 0.05 mg/kg/day was derived from 

a NOAEL of 5.13 mg/kg/day and a 100-fold factor that included 10x for inter-species 

extrapolation, 10x for intra-species variability, and a 1x FQPA SF. The LOAEL of 21.3 mg/kg 

was based on liver effects including increased blood cholesterol, liver weight, hypertrophy, fatty 

change, single-cell necrosis and macrophages in males and females.

Dermal Absorption Factor: HED is using 2.4% as the factor for determining dermal-equivalent 

doses in the sulfoxaflor risk assessment based on a comparison of a rat in vivo and rat and human 

in vitro studies (see Section 4.2).

Inhalation Absorption Factor: HED is assuming an inhalation absorption factor of 100%.

Dermal and Inhalation (short- and intermediate-term): The endpoint used for short- and 

intermediate-term dermal exposure was selected from the DNT study in rats. The endpoint of 

concern is decreased neonatal survival in PND 0-4 offspring with a NOAEL of 1.8 mg/kg/day 

and a LOAEL of 7.1 mg/kg/day. A 30-fold uncertainty factor that includes a 3X factor for interspecies extrapolation and a 10x factor for intra-species variability will be retained for risk 

assessment. Although a route-specific dermal study was available for endpoint selection, the 

developmental endpoint was chosen from the DNT because it is protective of reproductive and 

developmental parameters not measured in the dermal study. As previously noted, in the case of 

sulfoxaflor, the use of an oral study is considered protective for assessing inhalation exposures.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

The developmental neurotoxicity study was selected for evaluating oral exposure as well as 

short- and intermediate-term dermal and inhalation exposures. Therefore, exposure estimates 

from these routes should be combined when assessing short- and intermediate-term risks based 

on the decreased neonatal survival endpoint.

4.5.3 Cancer Classification and Risk Assessment Recommendation

The CARC in accordance with the EPA's Final Guidelines for Carcinogen Risk Assessment 

(March, 2005), determined that there is a “Suggestive Evidence of Carcinogenic Potential” for 

sulfoxaflor, based on the preputial gland tumor response seen in rats. When there is suggestive 

evidence, the Agency does not attempt a dose-response assessment as the nature of the data 

generally would not support one. Therefore, the Agency has determined that quantification of 

risk using a non-linear approach (i.e., reference dose (RfD) will adequately account for all 

chronic toxicity, including carcinogenicity, that could result from exposure to sulfoxaflor. The 

CARC considered the following factors in their weight-of-evidence deliberation on assessing the 

carcinogenic potential of sulfoxaflor.
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(i) The liver tumors observed in male rats and male and female mice were considered to be 

treatment-related; 

(ii) The hypothesized mode of action (CAR mediated, mitogenic) for liver tumors was 

adequately supported by studies that clearly identified the sequence of key events, doseresponse concordance and temporal relationship to the tumor type. There is convincing 

evidence that the hepatocarcinogenic effects are not likely to occur below a defined dose 

range. The mode of action data met the criteria established by the Agency; 

(iii) The Leydig cell tumors were not considered to be treatment-related in male rats because 

there is a high background rate for this tumor type in the particular strain of rats (F344) 

tested;

(iv) There was evidence of a response for carcinomas of the preputial glands in male rats. 

Preputial gland tumors are not commonly diagnosed in bioassay studies. The available 

data were inadequate to draw confident conclusions regarding this response due to the 

small sample size and lack of histopathology data on all animals. Thus, it was not 

possible to determine whether the preputial gland tumors are due to treatment. If the 

response is positive, this would be an unusual finding. Because the tumors could not be 

discounted, they were used in the suggestive classification; and

(v) There is no mutagenicity concern from the in vivo or in vitro genetic toxicity assays.

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 Sulfoxaflor for Use in Dietary and NonOccupational Human Health Risk Assessments.

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/ 

FQPA Safety 

Factors

RfD & PAD for Risk 

Assessment Study and Toxicological Effects

Acute Dietary 

(General 

Population, 

including Infants 

and Children)

NOAEL= 

25 mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

RfD = 0.25 mg/kg/day

aPAD =0.25 

mg/kg/day

Acute Neurotoxicity Study

LOAEL = 75 mg/kg/day based on 

decreased motor activity.

Acute Dietary

(Females 13-49 

years of age)

NOAEL = 

1.8 mg/kg/day

UFA= 3x

UFH=10x

FQPA SF= 1x

RfD = 0.06 mg/kg/day

aPAD =0.06 

mg/kg/day

Developmental Neurotoxicity Study

LOAEL = 7.1 mg/kg/day based on 

decreased neonatal survival (PND 0-

4)

Chronic Dietary 

(All Populations)

NOAEL= 

5.13 mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

RfD = 0.05

mg/kg/day

cPAD = 0.05 

mg/kg/day

Chronic/Carcinogenicity Study - Rat

LOAEL = 21.3 mg/kg/day based on 

liver effects including increased 

blood cholesterol, liver weight, 

hypertrophy, fatty change, single cell 

necrosis and macrophages.

Cancer (oral, 

dermal, 

inhalation)

Sulfoxaflor is classified as “Suggestive Evidence of Carcinogenic Potential.” Quantification of 

risk using a non-linear approach (i.e., reference dose (RfD) will adequately account for all 

chronic toxicity, including carcinogenicity, that could result from exposure to sulfoxaflor.
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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). FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level 

of concern. N/A = not applicable.

Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Sulfoxaflor 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 Short-and 

Intermediate Term

NOAEL= 1.8 

mg/kg/day 

DAF: 2.4%

UFA=3x

UFH=10x 

Occupational LOC 

for MOE = 30

Developmental Neurotoxicity Study

LOAEL = 7.1 mg/kg/day based on 

decreased neonatal survival (PND 0-4).

Inhalation Shortand Intermediate 

Term 

NOAEL= 1.8 

mg/kg/day*

UFA=3x

UFH=10x

Occupational LOC 

for MOE = 30

Developmental Neurotoxicity Study

LOAEL = 7.1 mg/kg/day based on 

decreased neonatal survival (PND 0-4).

Cancer (oral, 

dermal, inhalation)

Sulfoxaflor is classified as “Suggestive Evidence of Carcinogenic Potential.” Quantification of 

risk using a non-linear approach (i.e., reference dose (RfD) will adequately account for all 

chronic toxicity, including carcinogenicity, that could result from exposure to sulfoxaflor.

* Inhalation absorption assumed equivalent to oral absorption.

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). MOE = margin of exposure. LOC = level of 

concern. N/A = not applicable. 

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

HED has reviewed studies depicting the metabolism of sulfoxaflor in plants, livestock, and rats. 

In plants, metabolism was investigated with lettuce, pea, rice, and tomato (with foliar and soil 

application for each). In addition, metabolism was studied in radish, lettuce, and wheat grown as 

rotational crops. Livestock metabolism studies were conducted with lactating goat and laying 

hen with both sulfoxaflor and the plant metabolite X11719474. All of the submitted studies meet 

guideline requirements and are considered to be acceptable.

In plants, metabolism of sulfoxaflor was similar in all four target crops. Oxidation of the cyanocarbon bond results in the formation of X11719474, followed by loss of the sulfur side chain to 

form X11721061. X117211061 is then conjugated with glucose, which may then be conjugated 

with malonic acid. Metabolism continues through incorporation of the radiolabeled carbon into 

natural plant constituents, such as lignin and starch. A very minor pathway (<1%) included 

degradation of the X11719474 urea side chain to form X1159540 and X11479457, which are 

further reduced to give X11721061. The primary difference noted between the foliar and soil 

metabolism studies was that parent sulfoxaflor was the predominant residue found from foliar 

applications, while X11719474 was the major residue found after application of sulfoxaflor to 
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the soil. Similarly, X11719474 was the predominant residue observed in the rotational crop 

studies.

Metabolism studies with goats, hens, and rats consistently showed that sulfoxaflor is rapidly 

absorbed and eliminated (chiefly via urine in mammals), and undergoes very little in vivo

transformation. The results of studies in which X11719474 was administered to goats and hens 

mirrored the studies conducted with sulfoxaflor in that the administered dose was rapidly 

absorbed and eliminated, primarily as unmetabolized X11719474.

5.1.2 Summary of Environmental Degradation

The fate of sulfoxaflor in the environmental is highly dependent on whether or not it is in a soil 

system, groundwater system, or surface water system. Environmental fate studies show 

sulfoxaflor to be stable to photolysis (soil and aqueous) as well as hydrolysis across a broad pH 

range (estimated t1⁄2 = 141 days in aerobic water, 637 days in anaerobic water). In soil systems, 

however, sulfoxaflor is rapidly degraded to X11719474 (estimated t1⁄2 = 0.4 days). Figure 5.1.2 

depicts the fate of sulfoxaflor in the environment. In terms of drinking water, the fate pathways 

and their kinetic properties result in sulfoxaflor being the expected predominant residue in 

surface water. Contrariwise, and despite its high mobility, sulfoxaflor is not expected in 

groundwater due to its rapid degradation to X11719474 and, to a much lesser extent, 

X11519540.
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Figure 5.1.2. Expected environmental degradation pathways and transformation profiles for 

sulfoxaflor. Diagram taken from D382617, M. Ruhman, 1 August 2012.

5.1.3 Comparison of Metabolic Pathways

Although some metabolism was noted in studies with target crops (foliar application), livestock, 

and rats, sulfoxaflor does not generally show significant metabolism in those systems. Crops 

treated foliarly with sulfoxaflor tend to show more metabolism than the other two systems, but 

even then, there is little breakdown beyond oxidative loss of the cyano group and formation of 

X11719474. Environmental fate and rotational crop studies indicate that once sulfoxaflor is in 

contact with the soil, the parent compound is short lived and X11719474 predominates. 

X11719474 was not detected in livestock or rats.

5.1.4 Residues of Concern Summary and Rationale

E. Holman, 6 April 2012, D398294

HED’s Residues of Concern Knowledgebase Subcommittee (ROCKS) has recommended the 

residues of concern summarized in Table 5.1.4 for sulfoxaflor. Although the global review 

partners concur with the recommended residue definition in terms of regulatory enforcement, 

risk assessment strategies differ in terms of metabolites of concern. 

X11519540

Rapid Bio-degradation 

(90th percentile t1⁄2= 0.4 days)

(Aerobic Soil System)

Slow Aqueous Photolysis

(t1/2= 261 days)

Very Slow Aqueous Photolysis

(Practically Stable)

Sulfoxaflor

X117189-22

X11719474

X115794-57

Very Slow Biodegradation*

(90th percentile t1⁄2= 825 days)

(Aerobic Soil System)

N

S

N O

F3C

NH2

O

N

S

NH O

F3C

N

S

O

O

F3C

X117210-61
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Table 5.1.4. Summary of Sulfoxaflor Residue Definitions for Risk Assessment and Tolerance Enforcement.

Matrix Risk Assessment Tolerance Expression 

Plants Cotton Sulfoxaflor Sulfoxaflor 

Rotational Crop Sulfoxaflor 1Sulfoxaflor

Livestock Ruminant Sulfoxaflor Sulfoxaflor

Poultry Sulfoxaflor Sulfoxaflor

Drinking Water Sulfoxaflor + X11719474 + X11519540 NA

1 Based on the proposed later season foliar application use pattern; decision may need to be revisited for future 

early season soil application uses.

Hazard Considerations 

HED has determined that X11719474 does not share the reproductive MOA that was presented 

for sulfoxaflor (CARC Memo, TXR 0056301). However, exposure to X11719474 does results 

in hepatotoxicity comparable to that observed for sulfoxaflor. Based on several toxicology 

studies, the hepatotoxicity of X11719474 is 3- to 7-times less potent than sulfoxaflor. 

X11579457, a minor soil metabolite, exhibits no genotoxicity, and no acute oral toxicity. 

Structurally, it is quite similar to X11719474, and is therefore considered to be substantially less 

toxic than parent sulfoxaflor. The other primary plant metabolite, X11721061, is also considered 

to be significantly less toxic than the parent based on subchronic toxicity studies and is not 

mutagenic. Little toxicity data are available for X11596066, however, it has no structural alerts 

for genotoxicity, is negative in the Ames test, is structurally similar to X11721061, and therefore, 

is of low concern for human health. Contrary to the other metabolites, X11519540 appears to 

have a relative hepatotoxic potency that is greater than sulfoxaflor, as demonstrated in LD50 and 

28-day studies in the rat.

Exposure Considerations

Water. Due to rapid degradation of sulfoxaflor to X11719474, for the purposes of drinking 

water modeling, initial X11719474 levels are expected to be essentially equivalent to the amount 

of parent that reaches the soil directly following application (not intercepted by foliage) and 

amounts washed-off foliage later. In the long term, there is potential for X11719474 to degrade 

to metabolites X11519540 and X11579457. Although not detected in U.S. aerobic soil 

metabolism studies, these metabolites were observed at higher levels in European studies. 

X11579457, a minor soil metabolite, is structurally quite similar to X11719474, which exhibits 

significantly less toxicity than parent sulfoxaflor. Therefore, X11579457 is excluded from the 

residue definition due to its decreased toxicity and low overall exposure levels. As previously 

noted, X11519540 appears to be more toxic than sulfoxaflor in terms of liver toxicity; therefore, 

despite the generally very low overall exposure to X11519540, this metabolite should be 

included, along with parent sulfoxaflor and X11719474, for the purposes of the drinking water 

risk assessment and modeling. 

Plants (Primary Crops). The parent compound together with the two main plant metabolites, 

X11719474 and X11721061, are present in most of the primary crops tested in crop field trials. 

It is noted that all field trials were conducted at higher rates than those proposed for actual use, 

making the anticipated exposure levels to these metabolites even lower than recorded in the field 

studies. Due to the lower toxicity of X11719474 and X11721061, as well as generally lower 

overall exposure compared to parent sulfoxaflor, these metabolites are excluded from the residue 
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definition. The metabolite X11519540 was only observed at low concentrations (<1% of the 

TRR) in the lettuce metabolism study and was not observed at all in the other plant metabolism 

studies. Consequently, X11519540 is excluded from the residue definition due to low potential 

for exposure through plant matrices. Therefore, the inclusion of only parent sulfoxaflor should 

be adequate for dietary risk assessment. For tolerance enforcement, parent sulfoxaflor is also 

considered an adequate indicator of misuse. Although the parent may not be a good marker for 

misuse in crops like potatoes, the metabolites would not be much better indicators based on the 

field trial results showing that residues in root crops are likely to be very low (<0.04 ppm).

Rotational Crops. Although X11719474 is the predominant residue observed in rotational crops,

assessing dietary risk based on exposure to parent only is appropriate. Field rotational crop 

studies demonstrate that the maximum amount of X11719474 taken up by succeeding crops is 

similar to the maximum amount present in primary crops after foliar treatments. As these 

summed levels of X11719474 are still low relative to the amount of parent sulfoxaflor in most 

primary crops, risk assessments based on parent sulfoxaflor will be protective for any 

X11719474 residues taken up by rotational crops. An exception to the preceding generalization 

regarding relative metabolite levels was noted for the root and tuber vegetables. However, for 

these crops, the maximum residue levels are low (<0.04 ppm). Thus, a separate residue of 

concern definition for rotational root and tuber vegetable crops was not considered necessary. 

Also, because there are few potential rotational crops that are not proposed for primary crop 

tolerances, concerns regarding rotational crop issues are low. Based on the above considerations 

combined with its substantially lower toxicity relative to sulfoxaflor, X11719474 is excluded 

from the residue definition. For tolerance enforcement, parent sulfoxaflor is considered an 

adequate indicator of misuse for the proposed application methods. Should there ever be soil 

directed applications of sulfoxaflor to primary crops, there is a potential for significant residues 

of X11719474 in rotated crops, requiring this decision to be revisited.

Livestock. Based on the available information, the inclusion of parent sulfoxaflor only should be 

sufficient for dietary risk assessment. With the exception of liver, the majority of the residue in 

milk, eggs, and edible tissues consisted of the parent compound, generally >80% of the residue. 

X11596066 was a major metabolite in ruminant and hen liver (14-18% TRR), but has been 

determined to have low overall toxicity; therefore, it is excluded from the residue definition. 

X11519540 was detected at trace levels in most of the edible samples (<2% of the TRR in the 

ruminant and ≤ 8% of the TRR in the hens). The actual ppm levels of X11519540 were <0.01 

ppm in all matrices. However, due to the potential for increased toxicity associated with 

X11519540, the sulfoxaflor team consulted with the HED Toxicology Science Advisory Council 

(ToxSAC) in order to adequately account for the relative potency of this metabolite. Following 

consultation with ToxSAC, the sulfoxaflor team has determined that it is appropriate to exclude 

residues of X11519540 in livestock commodities in the dietary risk assessment. It is noted that 

the draft 2011 JMPR decision excludes this metabolite from their residue definition due to the 

low overall observed concentrations. For tolerance enforcement, parent sulfoxaflor is considered 

an adequate indicator of misuse.
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5.2 Food Residue Profile

D. McNeilly, 12 September 2012, D398756

The petitioner is requesting establishment of tolerances for residues of sulfoxaflor in/on 39 

crops/crop groups. In support of that request, the petitioner has provided data from 583 field 

trials as well as supporting data related to metabolism, storage stability, analytical methods, 

processed commodities, residue transfer to livestock, and uptake in rotational crops. All of the 

studies are considered to be acceptable and adequate for evaluating regulatory levels and 

assessing risk.

Field trials were generally conducted in accordance with the proposed use directions; although 

application rates in the trials were somewhat exaggerated (1.4X) relative to the proposed labels. 

Generally, residues of sulfoxaflor were well above the limit of quantitation (LOQ) of 0.01 ppm 

in most commodities. The exception to that is in root crops where maximum residues were only 

slightly greater than the LOQ and rotational crops where residues were generally nonquantifiable. Studies indicate that residues are distributed throughout the crops and are not 

restricted to treated surfaces. Sulfoxaflor was stable in studies designed to mimic boiling, 

cooking, and pasteurization. Typical food processing activities, such as baking, boiling and 

canning, are unlikely to significantly affect the nature and magnitude of sulfoxaflor residues. In 

commodity-specific processing studies, sulfoxaflor generally concentrated during production of 

dried foods and tended to be reduced in juices, though exceptions to those trends are evident in 

the database. A summary of the field trial and processing study results are provided in Appendix 

D.

The request for registration of sulfoxaflor includes uses on a large number of commodities that 

are considered to be significant feed items. To account for transfer of sulfoxaflor residues from 

livestock feeds into livestock commodities, HED has derived maximum, reasonably balanced 

dietary burdens for beef cattle, dairy cattle, poultry, and swine and combined those estimates 

with data from dairy cattle and laying hen feeding studies in order to calculate anticipated 

residues in livestock commodities. For poultry and swine, quantifiable residues are not expected 

in any commodity. Nevertheless, HED is recommending for tolerances at the LOQ (0.01 ppm) 

for harmonization purposes. Quantifiable residues are more likely in commodities, including 

milk, derived from cattle, goats, horses, and sheep, and HED is recommending for tolerances 

ranging from 0.10 to 0.40 ppm in those commodities.

5.3 Water Residue Profile

M. Ruhman, 1 August 2012, D382617

Based on abiotic laboratory studies, sulfoxaflor is stable to photolysis on soil and to hydrolysis in 

acidic, neutral and alkaline systems. Aqueous photolysis is expected to be slow and may not be 

considered an important transformation route in the natural environment (t1⁄2 >1,000 days in deionized water and 637 days in natural water). In the aerobic soil system, sulfoxaflor degrades 

rather quickly to its major degradate X11719474 (90th percentile t1⁄2= 0.4 days). Other residues, 

forming as a result of aerobic soil biotransformation, include limited amounts of X-1157957 and 

X11519540. Anaerobic soil data suggest that anaerobic conditions produces the main degradate, 

X11719474. In contrast to the rapid degradation of sulfoxaflor in aerobic soil systems, the 
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chemical degrades rather slowly to X11719474 in both aerobic and anaerobic aquatic conditions 

(90th percentile t1⁄2= 141 days).

Sulfoxaflor is considered to be non-persistent in soil and exhibits low affinity to soil/sediment 

particles. The chemical is not expected to partition significantly into the air from wet or dry 

soils. Sources of surface water contamination include drift for parent and run-off for X11719474 

and X11519540 following the rapid degradation of parent in the soil. Parent compound that 

drifts into surface water is expected to degrade rather slowly to X11719474. In contrast, the 

source of ground water contamination is expected to be leaching of parent and/or its degradation 

products X11719474 and X11519540, all of which are considered to be highly mobile.

Monitoring data depicting residues of sulfoxaflor in drinking water are not available. The 

Environmental Fate and Effects Division has used modeling to estimate upper-bound 

concentrations of sulfoxaflor in surface and ground water. Two scenarios were modeled: (1) 

Use of sulfoxaflor on non-aquatic row and orchard crops and (2) use of sulfoxaflor on 

watercress. For the non-aquatic crops, screening-level estimated drinking water concentrations 

(EDWCs) were calculated using Tier II PRZM (Pesticide Root Zone Model) and EXAMS 

(Exposure Analysis Modeling System) for surface water sources and the Tier I SCI-GROW 

(Screening Concentration in Ground Water) model was used for calculating the EDWCs in 

ground water sources. Of the requested non-aquatic-crop uses, those on citrus resulted in the 

highest EDWCs and are presented in Table 5.3.1a. 

Table 5.3.1a. Estimated Drinking Water Concentrations (EDWCs) for Total Toxic Residues of Sulfoxaflor in 

Surface and Ground Waters from Use on Citrus.

Water Source*

Total Concentration, ppb

[Sulfoxaflor + X11719474 + X11519540]

Acute Peak 1 Non-cancer/Chronic 2 Cancer 3

Surface (PRZM/EXAMS)

26.4

[9.4 + 15.0 + 2.0]

13.5

[1.9 + 10.2 + 1.4]

9.3

[1.5 + 6.9 + 0.9]

Ground (SCI-GROW)

69.2

[0.0 + 60.9 + 8.3]

* Surface water EDWCs include sulfoxaflor + X11719474 + X11519540. Due to rapid degradation of sulfoxaflor 

in aerobic soil systems (half-life = 0.4 days), the EDWC for groundwater includes X11719474 + X11519540.

1

Peak value, from Florida citrus; 21-in-10-year annual mean values, California citrus; 3 1-in-10-year overall annual 

mean values, California citrus.

The Tier I rice model was used to obtain surface water EDWC from the use of sulfoxaflor on 

watercress. The results of those analyses are presented in Table 5.3.1b and include the 

accumulation of residues that is expected from multiple applications.

Table 5.3.1b. Estimated Drinking Water Concentrations (EDWCs) for Total Toxic Residues of Sulfoxaflor in 

Surface and Ground Waters from Use on Watercress.

Water Source*

Total Concentration, ppb

[Sulfoxaflor + X11719474]

One Application Two Applications Three Applications

Surface (Tier 1 Rice Model)

91.3

[26.5 + 64.8]

182.5

[52.9 + 129.6]

273.8

[79.4 + 194.4]

* Aquatic-use EDWCs include sulfoxaflor + X11719474.
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The values in Tables 5.3.1a and 5.3.1b represent upper-bound estimates of residue concentrations 

that might be found in drinking water due to the use of sulfoxaflor on non-aquatic crops and 

watercress, respectively. 

Risk Assessment Considerations

Although the EDWCs associated with the use of sulfoxaflor on watercress are higher than those 

for the non-aquatic crops, HED’s risk assessment is focusing on the non-aquatic-crop EDWCs. 

The 2007 census of agriculture estimates that approximately 680 acres of the U.S. are used for 

watercress production; thus, this use represents a very small fraction of the potential crop acreage 

that may be treated with sulfoxaflor. Moreover, the inputs to the Tier 1 rice model are quite 

conservative, especially with regard to application efficiency (the model assumes that there is no 

interception of the applied material by the watercress plants) and the 10-cm water column at the 

time of application (information from watercress growers indicates that watercress fields are 

drained prior to pesticide applications). Finally, the rice model predicts pesticide concentrations 

in water in the field and not drinking water per se where concentrations are expected to be lower 

due to dissipation processes such as degredation, stream flow, and dilution. While the use on 

watercress may impact drinking water for a few individuals, HED does not believe that the

EDWCs and residue profiles associated with the watercress use give a representative depiction of 

the potential exposure profile for the vast majority of the U.S. population. HED has 

quantitatively estimated risks based on the watercress EDCWs and found the risk estimates to be 

below our level of concern (D. McNeilly, D401670, 12 September 2012). We note that if a 

future use for sulfoxaflor is requested on rice or cranberry, the EDWCs of primary interest would 

likely be those coming from the rice model.

Based on the modeled estimates associated with non-aquatic crops, the potential exposure 

through drinking water is much higher from groundwater than from surface water. Due to the 

different relative toxicities of the X11719474 and X11519540 metabolites, HED requested that 

EFED provide estimates for each compound separately. Environmental fate data indicate that 

the residue in groundwater will be comprised, predominantly, of the X11719474 metabolite. 

Quantitatively, the 69.2 ppb EDWC for groundwater can be divided into 60.9 ppb from 

X11719474 and 8.3 ppb from X11519450. HED has used these estimates and the relative 

toxicities of the metabolites to adjust the drinking water component of the dietary risk 

assessment, as outlined below. As noted earlier, sulfoxaflor presents a somewhat unique 

situation regarding the food and drinking water exposure pathway. Environmental fate data 

indicate that use of sulfoxaflor is likely to result in different residue profiles in surface water and 

groundwater, namely that sulfoxaflor is likely to be the predominant residue in surface water and 

X11719747/X11519540 will predominate in groundwater. When the residue profiles are

coupled with the toxicological database, it becomes apparent that the EDWCs for assessing acute 

dietary exposure for the general population, acute dietary exposure for women of child-bearing 

age, and chronic dietary exposure for all populations need to be addressed differently. An 

explanation of the three scenarios and the rationale for the approaches taken by HED is provided 

below. The EDWCs used in the various dietary assessments are summarized in Tables 5.3.2a

and 5.3.2b.
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Acute Exposure

Separate acute endpoints were selected for the general population and females 13-49 years of 

age. For the general population, the point of departure is based on decreased motor activity 

observed in the acute neurotoxicity study. As there are no data available to examine the potency 

of X11719474 and X11519540 with respect to this endpoint, HED has assumed that the two 

metabolites possess similar toxicity relative to sulfoxaflor in order to assess acute dietary risk for 

the general population. The EDWC for groundwater is significantly greater than the acute 

estimate for surface water and, per HED policy, is being used in the acute dietary assessment for 

the general population. As it is a groundwater EDWC, it represents residues of the metabolites.

For females 13-49 years of age, the developmental endpoint of increased neonatal deaths was 

chosen because a single exposure during late gestation can adversely affect the developing fetus 

and the age group represents women of child-bearing age. As discussed in Section 4.3.4, the 

metabolites X11719474 and X1159540 are not likely to result in agonism of the muscle nicotinic 

receptor and, therefore, should be excluded from assessment scenarios using the developmental 

endpoint. Since the groundwater EDWC represents residues of these metabolites only, the acute 

surface water EDWC becomes the appropriate estimate for assessing dietary exposure for 

women of child-bearing age.

Chronic Exposure

The endpoint for assessing chronic dietary exposure is hepatotoxicity. As discussed in Section 

4.3.4, HED has determined that it is appropriate to combine residues of sulfoxaflor, X11719474, 

and X11519540 when assessing chronic exposure and, furthermore, there is sufficient evidence 

to adjust the assessment to account for the different potencies of the metabolites. Based on 

NOAELs in the 28-day oral toxicity studies in rats, the potencies of the metabolites, relative to 

sulfoxaflor, are 0.3X for X11719474 and 10X for X11519540. To account for the relative

toxicity, the EDWCs for each metabolite are multiplied by their respective potency factor.
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Table 5.3.2a. Adjusted Estimated Drinking Water Concentrations (EDWCs) from Use on Citrus for Estimating 

Dietary Risk.

Drinking Water 

Scenario

Water Source Toxic Residue, ppm Adjustment 

Factor

Adjusted 

Residue, 

ppm

Rationale

Acute – General 

Population

Groundwater Sulfoxaflor 0 1 0 EDWC: Groundwater > 

Surface Water

Endpoint is decreased motor 

activity. No information is 

available to rule out 

applicability or estimate 

relative toxicity.

X11719474 = 0.0609 1 0.0609

X11519540 = 0.0083 1 0.0083

Total 0.0692

Acute – Females 

13-49 years old

Surface water Sulfoxaflor = 0.0094 1 0.0094 Residues in groundwater are 

not appropriate for assessing 

the endpoint.

Chronic – All 

Populations

Groundwater Sulfoxaflor 0 1 0 EDWC: Groundwater > 

Surface Water

Endpoint is liver effects. 28-

day studies are available for 

sulfoxaflor, X11719474, and 

X11519540 to derive relative 

toxicities.

X11719474 = 0.0609 0.3 0.0183

X11519540 = 0.0083 10 0.083

Total 0.1013

Table 5.3.2b. Adjusted Estimated Drinking Water Concentrations (EDWCs) from Use on Watercress for Estimating 

Dietary Risk.

Drinking Water 

Scenario

Water Source Toxic Residue, ppm Adjustment 

Factor

Adjusted 

Residue, 

ppm

Rationale

Acute – General 

Population

Groundwater Sulfoxaflor = 0.0794 1 0.0794 EDWC: Groundwater > 

Surface Water

Endpoint is decreased motor 

activity. No information is 

available to rule out 

applicability or estimate 

relative toxicity.

X11719474 = 0.1944 1 0.1944

X11519540 = 0.0 1 0.0

Total 0.2738

Acute – Females 

13-49 years old

Surface water Sulfoxaflor = 0.0794 1 0.0794 Residues in groundwater are 

not appropriate for assessing 

the endpoint.

Chronic – All 

Populations

Groundwater Sulfoxaflor = 0.0794 1 0.0794 EDWC: Groundwater > 

Surface Water

Endpoint is liver effects. 28-

day studies are available for 

sulfoxaflor, X11719474, and 

X11519540 to derive relative 

toxicities.

X11719474 = 0.1944 0.3 0.0583

X11519540 = 0.0 10 0.0

Total 0.1377
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5.4 Dietary Risk Assessment

D. McNeilly, 12 September 2012, D401670

Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments 

were conducted using the Dietary Exposure Evaluation Model DEEM-FCIDTM (v. 2.03). This 

model uses food consumption data from the U.S. Department of Agriculture’s (USDA’s) 

Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998. Based 

on analysis of the 1994-96, 98 CSFII consumption data, which took into account dietary patterns 

and survey respondents, HED concluded that it is most appropriate to report risk for the 

following population subgroups: the general U.S. population, all infants (<1 year old), children 

1-2, children 3-5, children 6-12, youth 13-19, adults 20-49, females 13-49, and adults 50+ years 

old.

5.4.1 Description of Residue Estimates Used in Dietary Assessment

The data used in the acute assessment reflect several refinements relative to a screening-level 

assessment. Maximum residue values from field trials were used rather than tolerance-level 

residue estimates. For crop groups, the residue values were translated from representative crops 

to the other crops in the group using HED SOP 2000.1. For processed commodities, empirical 

processing factors were used for all commodities unless an empirical factor was not available, in 

which case the DEEM default estimate was used. Residue estimates for livestock were derived 

using maximum observed residues in the cattle and hen feeding studies.

For the chronic assessment, the same refinements were made as those described for the acute 

assessment, with two exceptions: (1) average residue levels from crop field trials were used 

rather than maximum values and (2) average residues from feeding studies, rather than maximum 

values, were used to derive residue estimates for livestock commodities.

Estimates of residues in drinking water were incorporated directly into the assessments. As 

previously discussed (Section 5.3), HED is focusing on the dietary risk estimates that incorporate 

the non-aquatic-crop EDWCs rather than the watercress EDWCs. Nevertheless, HED has 

estimated dietary risks using the watercress EDWCs and all estimates are below HED’s level of 

concern.

5.4.2 Percent Crop Treated Used in Dietary Assessment

HED has assumed 100% of crops covered by the registration request are treated with sulfoxaflor.

5.4.3 Acute Dietary Risk Assessment

Acute dietary exposure was estimated for all of the standard, representative population groups 

described above. As previously noted, the assessment for women of child-bearing age (females 

13-49 years old) is based on a different endpoint/point of departure and includes a different set of 

assumptions regarding residues in drinking water than were used for the other groups. Given the 

assumptions used in conducting the acute assessment, exposure and risk estimates (Table 5.4.6) 

should be considered moderately refined. The use of the highest residue values from field trials 

give some refinement in comparison to use of tolerance-level residues. However, crop field 
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trials are designed to result in worst-case residue levels and the assumption that all crops with 

proposed uses of sulfoxaflor are treated (100% crop treated) and that they bear residues at 

maximum levels is likely to overestimate actual acute exposure. Significant refinement to the 

dietary exposure estimates could likely be obtained by using the full distribution of field trial 

data in a probabilistic assessment. 

Acute dietary risk estimates range from 4% to 16% of the acute population-adjusted dose 

(aPAD), with the highest risk estimates being for children 1-2 years old and females 13-49 years 

old. Generally, HED is concerned when exposure estimates exceed 100% of the populationadjusted dose (PAD). Even with the conservatisms in the assessment, acute dietary risk 

estimates are below HED’s level of concern. 

5.4.4 Chronic Dietary Risk Assessment

Chronic dietary exposure was estimated for all of the standard, representative population groups 

described in Section 5.4 above. The chronic dietary exposure estimates reflect significant 

refinement with respect to residue levels, although overall, the use of field trial data and the 

assumption of 100% crop treated results in estimates that are moderately refined. Monitoring 

data, if available, and incorporation of use statistics (i.e., % crop treated) have the potential to 

provide significant refinements to the assessment.

Chronic dietary risk estimates range from 5% to 18% of the chronic population-adjusted dose 

(cPAD). The highest risk estimate is for infants and all of the risk estimates are below HED’s 

level of concern.

5.4.5 Cancer Dietary Risk Assessment

Sulfoxaflor is classified as having "suggestive evidence of carcinogenicity" and HED has 

concluded that assessments using a non-linear approach (e.g., a chronic RfD-based assessment) 

will adequately account for all chronic toxicity, including carcinogenicity that could result from 

exposure to sulfoxaflor. Chronic dietary risk estimates are below HED’s level of concern; 

therefore, cancer risk is also below HED’s level of concern.

5.4.6 Summary Table

Table 5.4.6. Summary of Acute and Chronic Dietary Exposure and Risk Estimates for Sulfoxaflor.

Population Subgroup

Acute (95th Percentile) Chronic Cancer

Estimated 

Exposure 

(mg/kg/day)

Estimated 

Risk, % 

aPAD

Estimated 

Exposure 

(mg/kg/day)

Estimated 

Risk, % 

cPAD

Exposure 

(mg/kg/day)

Estimated 

Risk

U.S. Population 0.015832 6 0.003343 7

See Chronic

All infants 0.031158 12 0.009110 18

Children 1-2 yrs 0.044887 16 0.007867 16

Children 3-5 yrs 0.032523 13 0.006210 12

Children 6-12 yrs 0.018338 7 0.003892 8

Youth 13-19 yrs 0.010829 4 0.002456 5

Adults 20-49 yrs 0.011137 4 0.002812 6

Adults 50+ yrs 0.011446 5 0.002992 6
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Table 5.4.6. Summary of Acute and Chronic Dietary Exposure and Risk Estimates for Sulfoxaflor.

Population Subgroup

Acute (95th Percentile) Chronic Cancer

Estimated 

Exposure 

(mg/kg/day)

Estimated 

Risk, % 

aPAD

Estimated 

Exposure 

(mg/kg/day)

Estimated 

Risk, % 

cPAD

Exposure 

(mg/kg/day)

Estimated 

Risk

Females 13-49 yrs 0.009495 16 0.002809 6

Entries with the highest acute and chronic risk estimates are bolded.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

No residential uses, and no commercial/professional uses at residential sites are being requested 

for sulfoxaflor at this time; therefore, no residential risk assessment has been conducted. There 

are proposed uses on ornamental plants and turfgrass, but those uses are for 

nurseries/commercial greenhouses and for sod farms, respectively. For sulfoxaflor, HED 

believes that the post-application exposure for homeowners buying and planting ornamental 

plants or turfgrass (sod) would be minimal based on the exposure data available, the time 

between application and purchase, and the watering-in of turf. At this time, there are no uses of 

sulfoxaflor that will result in residential exposures.

6.1 Residential Bystander Post-Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for sulfoxaflor at this time primarily because of the acute 

inhalation toxicity (Toxicity Category III and IV), low vapor pressure (≤1.4×10-6Pa = 1.05×10-8

mm Hg at 20°C), and the maximum seasonal proposed use rate (0.266 lb ai/A/season). 

However, 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 is in the process of evaluating the SAP report and may, as appropriate, develop policies 

and procedures to identify the need for and, subsequently, the way to incorporate postapplication inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are developed, the Agency may revisit the need for a quantitative post-application 

inhalation exposure assessment for sulfoxaflor.

6.2 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for sulfoxaflor. The 

Agency has been working with the Spray Drift Task Force, 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 at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 
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submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT computer model to 

its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. 

After the policy is in place, the Agency may impose further refinements in spray drift 

management practices to reduce off-target drift with specific products with significant risks 

associated with drift.

Although a quantitative residential post-application inhalation exposure assessment was not 

performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation 

exposure assessment was performed for flaggers. This exposure scenario is representative of a 

worse case inhalation (drift) exposure and may be considered protective of most outdoor 

agricultural and commercial post-application inhalation exposure scenarios. The risk estimate 

for flaggers (MOE ≥ 4,200, Table 9.1) is not of concern.

7.0 Aggregate Exposure/Risk Characterization

As there are no registered or requested residential uses of sulfoxaflor, aggregate exposure is 

equivalent to the dietary exposure discussed in Section 5. Therefore aggregate risk estimates are 

below HED’s level of concern.

8.0 Cumulative Exposure/Risk Characterization

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 sulfoxaflor and any other substances and sulfoxaflor does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that sulfoxaflor has 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/.

9.0 Occupational Exposure/Risk Characterization

Z. Figueroa, 18 September 2012, D382606

Two agricultural products are proposed for use on the various crops, turf grass and ornamentals: 

GF-2032 SC and Transform TM WG. 

GF-2032 SC is formulated as a suspension concentrate (SC) which contains 21.8% of the active 

ingredient, sulfoxaflor. The Personal Protective Equipment (PPE) statement on the proposed 

label requires applicators and other handlers to wear: long-sleeved shirt and long pants, and

shoes plus socks.

Transform TM WG is formulated as a water dispersible granule (WG) which contains 50% of the 

active ingredient, sulfoxaflor. The Personal Protective Equipment (PPE) statement on the 

proposed label adds protective eyewear to the PPE found on the GF-2032 SC label (i.e., long-
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sleeved shirt and long pants, shoes plus socks, and protective eyewear) due to the Category II 

finding in the acute ocular toxicity testing with Transform TM WG.

These end use products may be applied through a variety of application methods including: 

aerial, chemigation (for potatoes only), groundboom, airblast, backpack, and hand held 

equipment. There is a potential for occupational exposure associated with handler activities (i.e., 

mixing, loading, and applying) as well as with post-application activities (i.e., re-entering treated 

areas). No data on the number of exposure days per year was provided. Based on the proposed 

labels’ use pattern and directions (e.g., 2-4 applications per season with a minimum 5- to 14- day 

spray interval), only short- (1 to 30 days) and intermediate-term (1 to 6 months) exposures are 

expected for handlers. 

In the past HED has considered ornamentals and greenhouse uses to have the potential for longterm dermal exposure. However, the pests that are targets for sulfoxaflor have biological and 

life-stage properties that provide for short windows of opportunity for control. To avoid 

development of sulfoxaflor-resistant pests, the sulfoxaflor labels require switching periodically 

to another insecticide. Therefore, based on the proposed use pattern and resistance management 

strategies (i.e., avoid consecutive applications of insecticides with the same mode of action), 

long-term exposure is not expected to occur. 

9.1 Short- and Intermediate-Term Handler Risk Estimates

HED uses the term handlers to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct job functions or tasks related to 

applications, and that exposures can vary depending on the specifics of each task. Job 

requirements (e.g., amount of chemical used in each application), types of equipment used, the 

area treated or amount handled, and the level of protection used by a handler can cause exposure 

levels to differ in a manner specific to each application event. Detailed descriptions of the 

handler assessment are available in D382606 (Z. Figueroa, 18 September 2012) and a summary 

table of the handler exposure and risk estimates is provided in Appendix F. The occupational 

hander exposure and risk estimates rely on generic data from the Pesticide Handlers Exposure 

Database Version 1.1 (PHED 1.1), the Outdoor Residential Exposure Task Force (ORETF) 

database and the Agricultural Handler Exposure Task Force (AHETF) database.

All combined (dermal + inhalation) occupational handler scenarios for the proposed uses resulted 

in estimated MOEs that are greater than 30 (i.e., not of concern) at the baseline level of PPE (i.e.,

baseline clothing, no gloves, and no respirator) and engineering controls (enclosed cockpit) for 

aerial applications (Table 9.1). The highest risk estimate (MOE = 80) is associated with handlers 

conducting mixer/loader activities with dry flowable formulation (TransformTM WG) for aerial 

applications. 

HED has no data to assess exposures to pilots using open cockpits. The only available data are

for exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the 

engineering control (enclosed cockpits) and baseline attire (long-sleeve shirt, long pants, shoes, 

and socks); pilots are not required to wear protective gloves. With this level of protection, there 

are no risks of concern for applicators.
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Table 9.1. Summary of Occupational Handler Exposure and Risk Estimates for Sulfoxaflor.*

Activity Scenario Use Site Formulation Dermal Inhalation

Dose

(mg/kg/day)

MOE

(LOC=30)

Dose

(mg/kg/day)

MOE

(LOC=30)

Combined 

MOE

(LOC=30)

Mixer/Loader Groundboom 

Application 

(AHETF)

Brassica (Cole) Leafy Veg., Bulb Veg. 

(CG 3-07), Cucurbit Veg. (CG 9), 

Fruiting Veg. (CG 8), Leafy Veg. (Except 

Brassica CG 4 & Watercress), Leaves 

Root/Tuber Veg. (CG 2), Root/Tuber 

Veg. (CG 1), Small Fruit Vine (Sub CG 

13-07F), Low Growing Berry (Sub 13-

07G), Succulent, Edible Podded, Dry 

Beans

Transform TM WG 0.00057 3,200 0.00089 2,000 1,200

GF-2032 SC 0.00057 3,100 0.000023 79,000 3,000

Ornamentals, Turf grass (Sod Farm) Transform TM WG 0.00088 2,100 0.00140 1,300 800

GF-2032 SC 0.00085 2,100 0.000034 53,000 2,000

Barley, Tricale, Wheat, Canola (Sub CG 

20A)

Transform TM WG 0.00077 2,300 0.00120 1,500 900

GF-2032 SC 0.00069 2,600 0.000027 66,000 2,500

Cotton, Soybean Transform TM WG 0.0014 1,300 0.00220 810 490

GF-2032 SC 0.00140 1,300 0.000057 32,000 1,200

Aerial 

Application 

(AHETF)

Brassica (Cole) Leafy Veg., Bulb Veg. 

(CG 3-07), Cucurbit Veg. (CG 9), 

Fruiting Veg. (CG 8), Leafy Veg. (Except 

Brassica CG 4 & Watercress), Leaves 

Root/Tuber Veg. (CG 2), Root/Tuber 

Veg. (CG 1), Small Fruit Vine (Sub CG 

13-07F), Low Growing Berry (Sub 13-

07G), Succulent, Edible Podded, Dry 

Beans

Transform TM WG 0.00250 730 0.00390 460 280

GF-2032 SC 0.00250 720 0.00010 18,000 690

Citrus (CG 10), Pome Fruits (CG 11), 

Ornamentals, Stone Fruits (CG 12), Tree 

Nuts (CG 14 & Pistachio)

Transform TM WG 0.00380 470 0.00600 300 180

GF-2032 SC 0.00370 490 0.00015 12,000 470

Barley, Tricale, Wheat, Canola (Sub CG 

20A)

Transform TM WG 0.00460 390 0.00730 250 150

GF-2032 SC 0.00410 440 0.00016 11,000 420

Cotton, Soybean Transform TM WG 0.00850 210 0.01340 130 80

GF-2032 SC 0.00860 210 0.00034 5,300 200

Chemigation 

(AHETF)

Potatoes Transform TM WG 0.00250 730 0.00390 460 280

GF-2032 SC 0.00250 720 0.00100 18,000 690
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Table 9.1. Summary of Occupational Handler Exposure and Risk Estimates for Sulfoxaflor.*

Activity Scenario Use Site Formulation Dermal Inhalation

Dose

(mg/kg/day)

MOE

(LOC=30)

Dose

(mg/kg/day)

MOE

(LOC=30)

Combined 

MOE

(LOC=30)

Airblast 

Application 

(AHETF)

Citrus (CG 10), Pome Fruits (CG 11),

Ornamentals, Stone Fruits (CG 12), Tree 

Nuts (CG 14 & Pistachio)

Transform TM WG 0.00044 4,100 0.00069 2,600 1,600

GF-2032 SC 0.00042 4,200 0.000017 110,000 4,100

Applicator Groundboom 

Application 

(AHETF)

Brassica (Cole) Leafy Veg., Bulb Veg. 

(CG 3-07), Cucurbit Veg. (CG 9), 

Fruiting Veg. (CG 8), Leafy Veg. (Except 

Brassica CG 4 & Watercress), Leaves 

Root/Tuber Veg. (CG 2), Root/Tuber 

Veg. (CG 1), Small Fruit Vine (Sub CG 

13-07F), Low Growing Berry (Sub 13-

07G), Succulent, Edible Dry Podded, 

Beans

Transform TM WG 0.00020 9,200 0.000034 53,000 7,800

GF-2032 SC 0.00021 8,800 0.000035 51,000 7,500

Ornamentals, Turf grass (Sod Farm) Transform TM WG 0.00030 5,900 0.000052 34,000 5,100

GF-2032 SC 0.00030 5,900 0.000052 34,000 5,100

Barley, Tricale, Wheat, Canola (Sub CG 

20A)

Transform TM WG 0.00027 6,700 0.000046 39,000 5,700

GF-2032 SC 0.00024 7,300 0.000042 42,000 6,300

Cotton, Soybean Transform TM WG 0.00049 3,700 0.000085 21,000 3,100

GF-2032 SC 0.00051 3,500 0.000089 20,000 3,000

Aerial 

Application 

(AHETF)

Brassica (Cole) Leafy Veg., Bulb Veg. 

(CG 3-07), Cucurbit Veg. (CG 9), 

Fruiting Veg. (CG 8), Leafy Veg. (Except 

Brassica CG 4 & Watercress), Leaves 

Root/Tuber Veg. (CG 2), Root/Tuber 

Veg. (CG 1), Small Fruit Vine (Sub CG 

13-07F), Low Growing Berry (Sub 13-

07G), Succulent, Edible Dry Podded, 

Beans

Transform TM WG 0.000055 33,000 0.000030 61,000 21,000

GF-2032 SC 0.000057 32,000 0.000031 58,000 25,000

Citrus (CG 10), Pome Fruits (CG 11), 

Ornamentals, Stone Fruits (CG 12), Tree 

Nuts (CG 14 & Pistachio)

Transform TM WG 0.000084 21,000 0.000046 39,000 14,000

GF-2032 SC 0.000084 21,000 0.000046 39,000 19,000

Barley, Tricale, Wheat, Canola (Sub CG 

20A)

Transform TM WG 0.00010 18,000 0.000056 32,000 11,000

GF-2032 SC 0.000093 19,000 0.000051 35,000 12,000

Cotton, Soybean Transform TM WG 0.00019 9,600 0.0001 18,000 6,200

GF-2032 SC 0.00020 9,200 0.00011 17,000 6,000
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Table 9.1. Summary of Occupational Handler Exposure and Risk Estimates for Sulfoxaflor.*

Activity Scenario Use Site Formulation Dermal Inhalation

Dose

(mg/kg/day)

MOE

(LOC=30)

Dose

(mg/kg/day)

MOE

(LOC=30)

Combined 

MOE

(LOC=30)

Airblast 

Application 

(AHETF)

Citrus (CG 10), Pome Fruits (CG 11), 

Ornamentals, Stone Fruits (CG 12), Tree 

Nuts (CG 14 & Pistachio)

Transform TM WG 0.00340 530 0.00036 5,000 480

GF-2032 SC 0.00340 530 0.00036 5,000 480

Flagger Flagging for 

Aerial 

Application

(PHED)

All Low Acreage Crops Transform TM WG 0.00019 9,700 0.00024 7,600 4,200

GF-2032 SC 0.00019 9,700 0.00024 7,600 4,200

All High Acreage Crops Transform TM WG 0.00012 15,000 0.00015 12,000 6,700

GF-2032 SC 0.00013 14,000 0.00016 11,000 6,300

Mixer/ Loader/ 

Applicator

Mechanicallypressurized 

Handgun 

Sprayer

Ornamentals, Greenhouses Transform TM WG 0.00169 1,100 0.00231 780 450

GF-2032 SC 0.00169 1,100 0.00231 780 450

Turfgrass (Sod farms) Transform TM WG 0.00047 3,800 0.00040 4,400 2,100

GF-2032 SC 0.00047 3,800 0.00040 4,400 2,100

Backpack 

Sprayer

Ornamentals Transform TM WG 0.00025 7,200 0.00011 16,000 5,000

GF-2032 SC 0.00025 7,200 0.00011 16,000 5,000

Turfgrass (Sod farms) Transform TM WG 0.00016 11,000 0.000002 900,000 11,000

GF-2032 SC 0.00016 11,000 0.000002 900,000 11,000

Manuallypressurized 

Handwand

(PHED)

Ornamentals, Turfgrass (Sod farms)

Transform TM WG 0.00193 930 0.000023 78,000 920

GF-2032 SC

0.00193 930 0.000023 78,000 920

* From Z. Figueroa, 18 September 2012, D382606
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9.2 Short- and Intermediate- Term Post-Application Risk Estimates

9.2.1 Dermal Post-Application Risk Estimates

Occupational workers who enter treated fields to perform post-application activities such as hand 

weeding and scouting may be exposed to sulfoxaflor residues. Based on the use pattern, workers 

may be exposed to short- and intermediate-term exposure durations. 

Dislodgeable Foliar Residue Data: It is HED’s policy to use the best available data to assess 

post-application exposure. The registrant submitted dislodgeable foliar residue (DFR) studies for 

wheat and broccoli in support of the proposed agricultural uses. Both studies demonstrated that 

dislodgeable foliar residue values declined over time for all sites and both formulations. The 

available DFR data were matched to the proposed agricultural crops (except cotton; see below) 

as surrogate data based on available information about foliage type, region of use, use pattern, 

etc. Dermal post-application exposure resulting from application of sulfoxaflor was estimated 

using the best available surrogate DFR-predicted Day-0 residue value; Day-0 DFR values were 

adjusted by application rate. Maximum single application rates for each crop/crop groups were 

used in this assessment. 

Dislodgeable residue data were not submitted for cotton. Calculation of dermal post-application 

exposure resulting from application of sulfoxaflor to cotton during harvesting activities (e.g., 

module builder, picker operator, raker, tramper) requires an estimate of the "dislodgeable" 

residue on the cotton bolls. Since that information was unavailable, exposure was estimated 

using cotton field trial residues (see Appendix D). Additionally, since the proposed PHI for 

cotton is 14 days, the Day-14 residue value from the cotton field trials is considered adequate to 

estimate dermal post-application exposures and risks during harvesting activities. Adjusted to 

the proposed maximum seasonal application rate, the Day-14 residue is 0.000129 mg ai/g cotton. 

Note also that the cotton field trial residue data reflect solvent-extractable residues, which are 

likely to be significantly greater than dislodgeable cotton boll residue during harvesting 

activities. Therefore, use of the residue data from the cotton field trials, even after being reduced 

to account for the difference in application rate, results in a conservative estimate for the daily 

dose.

Turf transferable residue (TTR) data were not submitted for turfgrass (sod farms); therefore, 

default TTR values were used to assess dermal post-application exposure and risk.

Transfer Coefficients: Sources of generic post-application exposure data, used as surrogate data 

in the absence of chemical-specific data, are derived from Agricultural Reentry Task Force 

(ARTF) exposure monitoring studies, and, as proprietary data, are subject to the data protection 

provisions of FIFRA. The standard values recommended for use in predicting post-application 

exposure that are used in this assessment, known as “transfer coefficients, Tc” are presented in 

the “Science Advisory Council for Exposure (ExpoSAC) Policy 3” 

(http://www.epa.gov/pesticides/science/exposac_policy3.pdf), which, along with additional 

information about the ARTF data, can be found at: http://www.epa.gov/pesticides/science/postapp-exposure-data.html.
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Dermal exposures during post-application activities were estimated using standard default and 

surrogate contact activity values (see Appendix G), chemical-specific DFR for all agricultural 

crops except cotton, default TTR for sod farms, and field trial data for cotton.

A summary of the post-application exposure and risk estimates for all proposed crops except 

cotton is provided in Table 9.2.1. Only risk estimates for the highest contact activity are shown 

below. Post-application dermal exposure and risk estimates resulted in MOEs greater than 30 

and are not of concern on Day-0 (i.e., 12 hours after application). 

A summary of the post-application exposure and risk estimates from use of sulfoxaflor on cotton 

during harvesting activities is provided in Table 9.2.2. Post-application dermal exposure and risk 

estimates resulted in MOEs greater than 30 and are not of concern. 
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Table 9.2.1. Post-Application Exposure and Risk Estimates for use of Sulfoxaflor.*

Crop Group Proposed Uses/Groups Proposed 

Maximum 

Application 

Rate

(lb ai/A)

Activity Daily Dose 

(mg/kg/d)

MOE

DFR Data on Treated Wheat (MRID No. 47832415)

Field / Row 

Crop, 

Low/Medium

Barley, Wheat

Canola

0.047 Scouting 0.0000007 2,600,000

Cotton 0.090 Scouting 0.0000003 7,000,000

Soybean 0.090 Scouting 0.0000014 1,300,000

Succulent Edible 

Podded and Dry Beans

0.090 Irrigation

(Hand Set)

0.0000023 770,000

DFR Data on Treated Broccoli (MRID No. 47832416)

Vegetable, head 

and stem 

Brassica

Brassica (Cole) Leafy 

Vegetables

0.090 Hand Weeding 0.00001 130,000

Vegetable, 

"Root"

Bulb Vegetables (Crop 

Group 3-07)

0.090 Hand Weeding 0.00001 130,000

Leaves of Root and 

Tuber Vegetables (Crop 

Group 2); Root and 

Tuber Vegetables (Crop 

Group 1)

0.090 Irrigation

(Hand Set)

0.000006 280,000

Tree Fruit, 

Evergreen

Citrus (Crop Group 10) 0.133 Thinning Fruit 0.00002 100,000

Vegetable, 

Cucurbit

Cucurbits Vegetables 

(Crop Group 9)

0.090 Irrigation

(Hand Set)

0.00001 280,000

Vegetable, 

Fruting

Fruiting Vegetables 

(Crop Group 8)

0.090 Irrigation

(Hand Set)

0.00001 280,000

Vegetable, 

Leafy

Leafy Vegetables 

(except Brassica – Crop 

Group 4 & Watercress)

0.090 Irrigation

(Hand Set)

0.000006 280,000

Nursery/

Greenhouse 

(Unassigned)

Ornamentals 0.133 Irrigation

(Hand Set)

0.00001 190,000

Tree, "Fruit", 

Deciduous

Pome Fruits (Crop 

Group 11); Stone Fruits 

(Crop Group 12)

0.133 Thinning Fruit 0.00002 100,000

Vine/Trellis Small Fruit Vine 

Climbing (except fuzzy 

kiwifruit – Subgroup 

13-07F)

0.090 Turning, 

Girdling

0.0001 28,000

Berry, Low Low Growing Berry 

(Subgroup 13-07G)

0.090 Irrigation

(Hand Set)

0.000006 280,000

Tree, “Nut” Tree Nuts (Crop Group 

14 & Pistachio)

0.133 Hand Harvesting 0.000007 260,000

Default TTR Approach

Turf, Sod Turfgrass, Sod farms 0.133 Maintenance, 

Harvesting, Slab

Transplanting/ 

Planting

0.0000004 4,700,000

* Taken from Z. Figueroa, 18 September 2012, D382606
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Table 9.2.2. Post-Application Exposure and Risk Estimates for use of Sulfoxaflor on Cotton during Harvesting 

Activities.*

Crop

Proposed Maximum 

Seasonal 

Application Rate

(lb ai/A)

Activity

Days 

After 

Treatment

Residue 

from Cotton 

Field Trial 2

(mg ai/g 

cotton)

Daily Dose 

(mg/kg/d)3 MOE4

Cotton 0.266

Harvesting Mechanical 

(Module Builder)

14 0.000129

0.00034 5,300

Harvesting Mechanical 

(Picker Operator; Raker) 0.00089 2,000

Harvesting Mechanical 

(Tramper) 0.00189 950

* Taken from Z. Figueroa, 18 September 2012, D382606.

1. Transfer Coefficients from HED Policy No. 3.0., Non-Foliar Transfer Coefficient Table, March 2012 (p 

122). 

2. Residue Value from Cotton Field Trial (Table 9) adjusted to Max. Seasonal Application Rate (mg ai/g 

cotton) = (0.182 mg ai/kg cotton) (0.001 mg/g) ((0.266 lb ai/A)/(0.375 lb ai/A)) = 0.000129 mg ai/g 

cotton.

3. Dermal Dose (mg/kg/day) = [Cotton Field Trial Residue Value adjusted (mg ai/g cotton) x TC (g cotton/hr) 

x hr/day (8 hrs/day) x DAF (2.5%)]/ BW (69 kg).

4. Dermal MOE = NOAEL (1.8 mg/kg/day)/Dermal Dose (mg/kg/day); LOC = 30.

Restricted Entry Interval (REI)

Although acute toxicity testing of technical-grade sulfoxaflor and the GF-2032 SC end-use 

product support an REI of 12 hours, the petitioner has proposed REIs of 24 hours for both enduse products based on their interpretation of the TransformTM WG acute ocular toxicity study 

resulting in a Toxicity Category II. The petitioner believes that the higher toxicity of Transform 

TM WG is due to an inert ingredient in that product. It is the petitioner’s understanding that the 

REI for all products containing a particular active ingredient must be the maximum dictated by 

testing of the individual products. 

HED recommends that RD ensure that the proper REI is listed on both labels according to the 

acute toxicity profile and the formulation for each product.

9.2.2 Inhalation Post-Application Risk Estimates

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for sulfoxaflor at this time primarily because it has a low vapor 

pressure (1.05 × 10-8 mm Hg at 25°C) and it is applied at low application rates (maximum single 

application rate of 0.133 lb ai/A). However, volatilization of pesticides may be a potential 

source of post-application inhalation exposure to individuals nearby to 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. The Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). 
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Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational handlers. This 

assessment resulted in risk estimates that did not exceed HED’s level of concern at baseline 

inhalation PPE. 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, the Worker Protection Standard for Agricultural Pesticides contains requirements 

for protecting workers from inhalation exposures during and after greenhouse applications 

through the use of ventilation requirements [40 CFR 170.110, (3) (Restrictions associated with 

pesticide applications)].

10.0 References

Memoranda

Holman, E. 6 April 2012. D398294. “Sulfoxaflor. Report of the Residues of Concern 

Knowledgebase Subcommittee (ROCKS).”

McNeilly, D. 12 September 2012. D398756. “Sulfoxaflor. Petition for the Section 3 

Registration and Establishment of Tolerances for the New Insecticide Sulfoxaflor on: 

Barley, Brassica Leafy Vegetables, Bulb Vegetables, Canola (Rapeseed), Citrus, Cotton, 

Cucurbit Vegetables, Fruiting Vegetables, Leafy Vegetables (Except Brassica), Leaves of 

Root and Tuber Vegetables, Low Growing Berry, Okra, Ornamentals (Herbaceous and 

Woody), Pistachio, Pome Fruits, Root and Tuber Vegetables, Small Fruit Vine Climbing 

(Except Fuzzy Kiwifruit), Soybean, Stone Fruits, Beans Succulent, Edible Podded, and 

Dry Beans, Tree Nuts, Triticale, Turf Grass, Watercress, Wheat. Summary of Analytical 

Chemistry and Residue Chemistry Data.”

Figueroa, Z. 18 September 2012. D382606. “Sulfoxaflor. Occupational and Residential 

Exposure and Risk Assessment to Support the Registration of the New Active Ingredient 

on a Variety of Food Crops, Turfgrass (Sod Farms) and Ornamentals.”

Mcneilly, D. 12 September 2012. D401670. “Sulfoxaflor: Acute and Chronic Aggregate 

Dietary Exposure and Risk Assessment for Section 3 Uses on Barley, Brassica Leafy 

Vegetables, Bulb Vegetables, Canola (Rapeseed), Citrus, Cotton, Cucurbit Vegetables, 

Fruiting Vegetables, Leafy Vegetables (Except Brassica), Leaves of Root and Tuber 

Vegetables, Low-Growing Berries, Pistachio, Pome Fruits, Root and Tuber Vegetables, 

Small Fruit Vine Climbing (Except Fuzzy Kiwifruit), Soybean, Stone Fruits, Succulent 

Beans, Edible Podded, and Dry Beans, Tree Nuts, Triticale, Watercress, and Wheat.

Ruhman, M. 1 August 2012. D382617. “Estimated Drinking Water Concentrations of the 

New Chemical Sulfoxaflor from Proposed use on Beans, Berries, Canola, Citrus, Fruits 

(Pome & Stone), Ornamentals, Soybeans, Tree nuts, Turf grass, Vegetables (Brassica, 

Bulb, Cucurbits, Fruiting, Okra, Leafy, Root and Tuber) and Watercress for the Use in 

Human Health Risk Assessment.”

Kidwell, J. 26 April 2012. TXR No. 0056301. “SULFOXAFLOR: Report of the Cancer 

Assessment Review Committee.”
Sulfoxaflor Human Health Risk Assessment DP No. D382604

Page 55 of 176

Van Alstine J. 14 September 2012. TXR# 0056310. Sulfoxaflor: Summary of Hazard and 

Science Policy Council (HASPOC) Meeting of March 15, 2012: Recommendation on 

the need for a 28-day inhalation study.

Literature Studies

Boorman, J. P. B., P. J. GrootKormelink and L. G. Sivilotti (2000). "Stoichiometry of human 

recombinant neuronal nicotinic receptors containing the β3 subunit expressed in Xenopus 

oocytes." The Journal of Physiology 529(3): 565-577.

Hill, A. B. (1965). "The Environment and Disease: Association or Causation?" Proceedings 

of the Royal Society of Medicine 58: 295-300.

Krashia, P., M. Moroni, S. Broadbent, G. Hofmann, S. Kracun, M. Beato, P. J. GrootKormelink and L. G. Sivilotti (2010). "Human α3β4 Neuronal Nicotinic Receptors Show 

Different Stoichiometry if They Are Expressed in <italic>Xenopus</italic> Oocytes or 

Mammalian HEK293 Cells." PLoS ONE 5(10): e13611.

Luetje, C. W. and J. Patrick (1991). "Both alpha- and beta-subunits contribute to the agonist 

sensitivity of neuronal nicotinic acetylcholinesterase receptors." The Journal of 

Neuroscience 11(3): 837-845.

Millar, N. (2010). "Characterization of the Agonist Effects of XDE-208 on Mammalian 

Muscle Nicotinic Acetylcholine Receptors." Report of the University College London, 

London, UK.

Millar, N. S. (2009). "A review of experimental techniques used for the heterologous 

expression of nicotinic acetylcholine receptors." Biochemical Pharmacology 78(7): 766-

776.

Moroni, M. and I. Bermudez (2006). "Stoichiometry and pharmacology of two human α4β2 

nicotinic receptor types." Journal of Molecular Neuroscience 30(1): 95-96.

Moroni, M., R. Vijayan, A. Carbone, R. Zwart, P. Biggin and I. Bermudez (2008). "NonAgonist-Binding Subunit Interfaces Confer Distinct Functional Signatures to the 

Alternate Stoichiometries of the alpha4beta2 Nicotinic Receptor: An alpha4–alpha4 

Interface Is Required for Zn2+ Potentiation." The Journal of Neuroscience 28(27): 6884-

6894.

Stern, P., M. Cik, D. Colquhoun and F. A. Stephenson (1994). "Single channel properties of 

cloned NMDA receptors in a human cell line: comparison with results from Xenopus 

oocytes." The Journal of Physiology 476(3): 391-397.
Sulfoxaflor Human Health Risk Assessment DP No. D382604

Page 56 of 176

Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use for Sulfoxaflor are in Table 1. 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 Primary Eye Irritation ..................................

870.2500 Primary Dermal Irritation.............................

870.2600 Dermal Sensitization....................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent) .............................

870.3150 Oral Subchronic (nonrodent) .......................

870.3200 21-Day Dermal.............................................

870.3250 90-Day Dermal.............................................

870.3465 90-Day Inhalation ........................................

yes

yes

yes

no

yes

yes

yes

yes

-

waived

870.3700a Developmental Toxicity (rodent).................

870.3700b Developmental Toxicity (nonrodent)...........

870.3800 Reproduction................................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent).............................

870.4100b Chronic Toxicity (nonrodent) ......................

870.4200a Oncogenicity (rat) ........................................

870.4200b Oncogenicity (mouse)..................................

870.4300 Chronic/Oncogenicity ..................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial ...

870.5300 Mutagenicity—Gene Mutation -

mammalian......................................................................

870.5xxx Mutagenicity—Structural Chromosomal 

Aberrations......................................................................

870.5xxx Mutagenicity—Other Genotoxic Effects.....

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen) .............

870.6100b 90-Day Neurotoxicity (hen).........................

870.6200a Acute Neurotoxicity Screening Battery (rat)

870.6200b 90-Day Neurotoxicity Screening Battery 

(rat)..................................................................................

870.6300 Develop. Neurotoxicity................................

no

no

yes

yes

yes

-

-

yes

yes

yes

870.7485 General Metabolism.....................................

870.7600 Dermal Penetration ......................................

870.7800 Immunotoxicity............................................

yes

yes

yes

yes

yes

yes
Sulfoxaflor Human Health Risk Assessment DP No. D382604

Page 57 of 176

Study

Technical

Required Satisfied

Special Studies for Ocular Effects

Acute Oral (rat).............................................

Subchronic Oral (rat) ....................................

Six-month Oral (dog)....................................

no

no

no

-

-

-

A.2 Toxicity Profiles

Sulfoxaflor Acute Toxicity Profile

Guideline 

No.

MRID 

(Annex II Point)

Route/

method

Species/

strain (sex)

Result Classification

Sulfoxaflor

870.1100 47832144

(5.2.1)

Oral/

gavage

Rat/

Fischer 344 

(both)

LD50 =1000 

mg/kg

Category III

47832040

(5.2.1)

Oral/

gavage

Mouse/ CD1

(male)

LD50 =750 

mg/kg

Category III

870.1200 47832051

(5.2.2)

Dermal/

topical

Rat/

Fischer 344 

(both)

LD50 >5000 

mg/kg

Category IV

870.1300 47832052

(5.2.3)

Inhalation/

nose only

Rat/

Fischer 344 

(both)

LC50>2.09 mg/L 

(4hr)

Category IV

870.2400 47832055

(5.2.5)

Eye/

instillation

Rabbit/

NZW

(female)

Slight Irritation Category III

870.2500 47832053

(5.2.4)

Dermal/

topical

Rabbit/

NZW

(female)

Minimal 

Irritation

Category IV

870.2600 47832041

(5.2.6)

Dermal/

LLNA

Mouse/ CBA/J

(female)

No Sensitization None

Metabolites

Metabolite X11719474

Nonguideline

47832308

(5.8.1.2/1)

Oral/gavage

300 mg/kg/day 

Rat/F344 

(female) 

No Observed 

Effects

Not Applicable

870.1100 47832131

(5.8.1.2/2)

Oral/gavage

2000, 5000 

mg/kg/day 

Rat/F344 

(female)

No death LD50 

> 5000.

Signs for 48 

hours

Category IV

Nonguideline47832309 

(5.8.1.2/3)

Dermal

1000 mg/kg/day 

Rat/F344 

(female)

No death.

Irritation for 48 

hours

Not Applicable

Nonguideline47832309

(5.8.1.2/3)

Eye

0.1 ml (0.069 g)

Rabbit/NZW 

(female)

Conjunctivitis 

for 24 hours

Not Applicable
Sulfoxaflor Human Health Risk Assessment DP No. D382604

Page 58 of 176

Sulfoxaflor Toxicity Profile Table

Guideline 

No.

Study Dosages Effects at lowest observed effect level

870.3050 Oral 28-day F344 Rat

MRID 47832045

Annex 5.3.1/2

Acceptable/Guideline

0, 300, 1000, 2000, 3000 ppm

M/F: 0/0, 24.8/26.5, 

79.4/88.3, 155/170, 205/192 

mg/kg/day

LOAEL – 88.3 mg/kg/day based on liver 

effects including serum cholesterol, 

liver weight and hepatocellular 

hypertrophy with altered tinctorial 

properties.

NOAEL – 26.5 mg/kg/day 

870.3050 Oral 28-day CD1Mouse

MRID 47832042

Annex 5.3.1/4

Acceptable/Guideline

M: 0, 300/350, 1500, 3500 

ppm

F: 350, 1500, 3500 ppm

0/0, 43.9/53, 230/273, 

524638 mg/kg/day 

LOAEL – 230/273 M/F based on liver 

effects including ALT, AST, liver 

weight, hepatocellular hypertrophy in 

males and females. Fatty change, 

multifocal single cell necrosis and mitotic 

figures in males only

NOAEL- 43.9/53 mg/kg/day M/F

NonGuidelineOral 28-day in Beagle 

Dogs

MRID 47832043

Annex 5.3.1/6

Acceptable

Group 1 (dietary)-

F: 500 ppm

The only tolerable dose and route was 15 

mg/kg/day technical grade XDE-208 via 

oral gavage in Methocel vehicle. 

Exposure at 100 ppm via diet was well 

tolerated as determined by adequate food 

consumption, but test material intake was 

insufficient to justify its use as a high 

dose level for subsequent studies.

Group 2 (gelatin capsule)-

F: 15 mg/kg/day 

Group 3 (oral gavageanalytical grade XDE 208 in 

Methocel)-

F: 15 mg/kg/day 

Group 4 (dietary)-

F: 100 ppm

870.2600 47832130

(5.8.1.2/4)

Dermal

50% /rLLNA

CBA/J Mice 

(female)

Negative Category IV

Metabolite X11721061

870.1100 47832086

(5.8.2.2/1)

Oral/Gavage

1000, 2000, 

5000 mg/kg/day 

Rat/F344

(female)

LD50 > 2000 Category III

Metabolite X11596066

870.1100 47832067

(5.8.3.2/1)

Oral/gavage

2000 mg/kg/day 

Rat/F344 

(female) 

No deaths.; 

LD50 > 2000

Piloerection for 

24 hours

Category III

Metabolite X11579457

870.1100 47832145

(5.8.4.2/1)

Oral/gavage

2000 mg/kg/day 

Rat/F344 

(female)

No death; LD50 

> 2000

Piloerection for 

24 hours

Category III

Metabolite X11519540

870.1100 47832069

(5.8.5.2/1)

Oral/gavage

320,1000,2000 

mg/kg/day 

Rat/F344 

(female) 

LD50 565; No 

death at 320. 

Death at 1000 

and 2000

Category III
Sulfoxaflor Human Health Risk Assessment DP No. D382604

Page 59 of 176

Guideline 

No.

Study Dosages Effects at lowest observed effect level

Group 5 (oral gavagetechnical grade XDE 208 in 

Methocel)-

F: 15 mg/kg/day 

870.3100; 

870.6200; 

870.7800

90 day oral toxicity

Neurotoxicity Screening

Immunotoxicity

Oral 90-day F344 Rat 

with 28-day Recovery

MRID 47832046

Annex 5.3.2/1

Acceptable/Guideline

0, 100, 750, 1500 ppm

M/F: 0/0, 6.36/6.96, 

47.6/51.6, 94.9/101 

mg/kg/day 

LOAEL – 47.6/51.6 mg/kg/day (M/F) 

based on 11-13% body weight gain.

Liver - serum cholesterol, liver weight, 

hepatocellular hypertrophy with altered 

tinctorial properties, and multifocal single 

cell necrosis;Fatty change in males.

NOAEL = 6.36/6.96 mg/kg/day (M/F) 

There were no indications of 

neurotoxicity (NOAEL ≥ 94.9 

mg/kg/day)

There were no indications of 

immunotoxicity (NOAEL ≥ 94.9 

mg/kg/day)

870.3100 Oral 90-day CD1Mouse 

MRID 47832057

Annex 5.3.2/2

Acceptable/Guideline

M: 0, 100, 750, 1250 ppm

(0, 12.8, 98, 166 mg/kg/day)

F: 0, 100, 1500, 3000 ppm

(0, 16.2, 247, 489 mg/kg/day)

LOAEL – 98/247 mg/kg/day (M/F) based 

on liver effects including liver weight, 

hepatocellular hypertrophy with altered 

tinctorial properties, multifocal single cell 

necrosis.

Adrenal - very slight 

hypertrophy/vacuolization of zona 

fasciculata.

Females also had ALT, AST and 

triglycerides 

NOAEL – 12.8/16.2 mg/kg/day (M/F)

870.3150 Oral 90-day Dog/Beagle 

(gavage)

MRID 47832058

Annex 5.3.3/1

Acceptable/Guideline

0, 1, 3, 6 mg/kg/day 

(10 mg/kg/day days 1-5)

LOAEL – 10 mg/kg/day based on food 

consumption

NOAEL = 6 mg/kg/day 

870.3200 28-day Dermal F344 Rat 

MRID 47832059

Annex 5.3.7/1

Acceptable/Guideline

0, 100, 500, 1000 mg/kg/day LOAEL - > 1000 mg/kg/day ; 

Females: No effects

Males: 17% serum cholesterol; 6.5% 

absolute and 4.4% relative liver 

weights; very slight centrilobular to 

midzonal hepatocellular hypertrophy with 

altered tinctorial properties. Although 

treatment-related, these effects were not 

considered adverse.

NOAEL = 1000 mg/kg/day 
Sulfoxaflor Human Health Risk Assessment DP No. D382604

Page 60 of 176

Guideline 

No.

Study Dosages Effects at lowest observed effect level

870.3700 Developmental Toxicity 

in CD Rats (Definitive)

MRID 47832140 

Annex 5.6.10/2

Acceptable/Guideline

0, 25, 150, 1000 ppm

(0, 2, 11.5, 70.2 mg/kg/day)

Dam:

LOAEL – 70.2 mg/kg/day based on 

reduced feed consumption and body 

weight gain; increased liver weight.

NOAEL = 11.5 mg/kg/day 

Litter:

LOAEL – 70.2 mg/kg/day based on 

decreased fetal body weight; fetal 

abnormalities (forelimb flexure, bent 

clavicle, hindlimb rotation, 

convoluted/hydro-ureter).

NOAEL = 11.5 mg/kg/day 

870.3700 Developmental Toxicity

Dietary in NZW Rabbits 

(Definitive) 

MRID 47832066

Annex 5.6.11/3

Acceptable

0, 30, 150, 750 ppm

(0, 1.3, 6.6, 31.9 mg/kg/day )

Dam:

LOAEL – 31.9 mg/kg/day based on 

decreased feed consumption (8-21%), 

body weight gain, (12%) and fecal output.

NOAEL = 6.6 mg/kg/day 

Litter:

LOAEL > 31.9 mg/kg/day 

NOAEL = 31.9 mg/kg/day 

Toxicokinetics:

AUC α Dose, dose adjusted AUC similar 

to rat

870.3800; 

OECD 421 

Reproduction/

Developmental Probe 

CD Rat

MRID 47832143

Annex 5.6.1/1 

Acceptable/Guideline

0, 100, 500, 1000 ppm Reproduction:

LOAEL = 39.5 mg/kg/day based on 

decreased neonatal survival. Postnatal 

day (PND) 4 survival 81.2% (95.4% in 

controls).

NOAEL = 8.1 mg/kg/day (PND 4 pup 

survival 7.3%.)

Parental toxicity: 

NOAEL > 78.2 mg/kg/day – Decreased 

body weight gain was observed at 500 and 

1000 ppm in males and females. 

Increased liver weight in males at 500 and 

1000 ppm. Hepatocellular hypertrophy in 

males at 500 and 1000 ppm and females 

at 1000 ppm. These effects were 

considered minimal and not adverse.

Offspring:

LOAEL – 39.5 mg/kg/day based on 

decreased neonatal survival (see above).

NOAEL = 8.1 mg/kg/day 
Sulfoxaflor Human Health Risk Assessment DP No. D382604

Page 61 of 176

Guideline 

No.

Study Dosages Effects at lowest observed effect level

870.3800 2-Generation 

Reproduction in CD Rats

MRID 47832142

Annex 5.6.1/2

Acceptable/Guideline

0, 25, 100, 400 ppm

(1.52/1.91, 6.07/7.82, 

24.6/30.5 mg/kg/day [m/f])

Reproduction:

LOAEL – 24.6 mg/kg/day based on 

decreased neonatal survival (ca. 2-5%)

NOAEL = 6.07 mg/kg/day 

Parental toxicity:

LOAEL – 24.6 mg/kg/day based on 

increased liver weight in with correlating 

histopathologic changes

NOAEL = 6.07 mg/kg/day 

Offspring:

LOAEL – 24.6 mg/kg/day based on 

decreased neonatal survival and a slight 

delay in preputial separation (puberty 

onset) in F1 males

NOAEL = 6.07 mg/kg/day 

870.4100 Oral 1-year Beagle Dog 

(gavage)

MRID 48288906

Annex 5.3.4/1

Acceptable/Nonguideline

0, 1, 3, 6 mg/kg/day LOAEL > 6 mg/kg/day 

NOAEL = 6 mg/kg/day 

870.4200 18-month carcinogenicity

CD1 Mouse

MRID 47832054

Annex 5.5.3

Acceptable/Guideline

♂: 0, 25, 100, 750 ppm

0, 2.54, 10.4, 79.6 mg/kg/day 

LOAEL – 79.6 mg/kg/day based on liver 

effects including adenomas and 

carcinomas;

Increased weight, hypertrophy with 

eosinophilia, fatty change, single cell 

necrosis, eosinophilic/ vacuolated foci, 

mitosis. 

NOAEL = 10.4 mg/kg/day 

♀: 0, 25, 250, 1250 ppm

0, 3.43, 33.9, 176 mg/kg/day 

LOAEL – 176 mg/kg/day based on liver 

effects including carcinomas; increased 

weight, hypertrophy with eosinophilia, 

fatty change, single cell necrosis and 

eosinophilic/ vacuolated foci.

NOAEL = 33.9 mg/kg/day 
Sulfoxaflor Human Health Risk Assessment DP No. D382604

Page 62 of 176

Guideline 

No.

Study Dosages Effects at lowest observed effect level

870.4300 2-year combined toxicity 

and carcinogenicity 

dietary

F344 Rat

MRID 47832060

Annex 5.5.1 & 5.5.2

Acceptable/Guideline

0, 25, 100, 500 ppm 

M/F: 0/0, 1.04/1.28, 

4.24/5.13, 21.3/39 mg/kg/day 

Males:

1-year:

LOAEL – 21.3 mg/kg/day based on liver 

effects including increased blood 

cholesterol, liver weight, hypertrophy, 

fatty change, single cell necrosis and 

macrophages.

2-year: 

LOAEL – 21.3 mg/kg/day based on 

increased serum cholesterol 

concentrations, and histopathological liver 

effects in males; increased incidence and 

size of Leydig cell adenomas with 

secondary effects including preputial 

gland tumours; liver adenomas.

NOAEL = 4.24 mg/kg/day

Females: 1- and 2-year

LOAEL – 39 mg/kg/day based on liver 

effects including increased blood 

cholesterol, liver weight, hypertrophy, 

fatty change, single cell necrosis and 

macrophages.

NOAEL = 5.13 mg/kg/day 

870.5100 Bacterial Reverse 

Mutation Test

MRID 47832047

Annex 5.4.1

Acceptable/Guideline

S.typhimurium TA 98, TA 

100, TA 1535 & TA 1537

E. coli, WP2uvrA

100, 333, 1000, 2500, and 

5000 μg per plate +/- S9

Negative

870. 5300 In vitro Mammalian Cell 

Gene Mutation Test 

MRID 47832049

Annex 5.4.3/1

Acceptable/Guideline

Chinese hamster ovary cells 

CHO/HGPRT

0, 173.3, 346.6, 693.3, 1386.5, 

and 2773 g/ml +/- S9

Negative

870. 5375 In Vitro Mammalian 

Chromosome Aberration 

Test

MRID 47832050

Annex 5.4.2/1

Acceptable/Guideline

Rat lymphocytes

4 hr treatment 0, 693.3, 

1386.5, and 2773 g/ml +/-

S9; 24 hr treatment 0, 173.3, 

346.6, and 693.3 g/ml

Negative
Sulfoxaflor Human Health Risk Assessment DP No. D382604

Page 63 of 176

Guideline 

No.

Study Dosages Effects at lowest observed effect level

870.5395 Mammalian Erythrocyte 

Micronucleus Test

MRID 47832071

Annex 5.4.4

Mouse bone marrow 

polychromatic erythrocytes 

Male and female CD-1 mice, 

6/sex/dose, single oral gavage 

on two consecutive days at 0, 

100, 200, and 400 mg/kg/day

Negative

870.6200 Acute neurotoxicity in 

F344 Rats

MRID 47832134 

Annex 5.7.1/1

Acceptable/Guideline

0, 7.5, 75, 750 mg/kg; 

Additional motor activity 

work at 0, 2.5, 7.5, 25 mg/kg

LOAEL – 75 mg/kg/day. On Test Day 1, 

decreased motor activity in 750 and 75 

mg/kg groups. Effect was considered 

equivocal in 7.5 mg/kg group. 

Clinical findings on test days 2,3, or 4 –

decreased feces, red perioral soiling, 

perineal urine soiling (females)

750 mg/kg – muscle tremors and twitches, 

convulsions, splayed hindlimbs and 

perineal urine soiling, increased 

lacrimation and salivation, decreased 

pupil size and response to touch, 

decreased level of open-filed activity and 

gait abnormalities, decreased rectal 

temperature. One female death on day 1 –

cause unknown

No treatment-related histopathological 

findings.

NOAEL = 25 mg/kg 

870.6300 Developmental 

neurotoxicity in CD Rats

MRID 47832133 

Annex 5.7.5/1

Acceptable/Guideline

0, 25, 100, 400 ppm;

0, 1.8/1.9, 7.1/7.6, 27.7/29.8 

mg/kg/day

(gestation/lactation)

Maternal:

LOAEL –> 27.7 mg/kg/day. No 

treatment-related systemic or reproduction 

related effects observed in the dams

NOAEL = 27.7 mg/kg/day 

Offspring:

LOAEL – 7.1mkd based on reduction in 

postnatal survival (PND 0-4)

NOAEL = 1.8 mg/kg/day

NonGuidelineToxicokinetic – Rat and 

Mouse 

Probe looking at ADME: 

single oral dose

Rat/F344 & Mouse/CD1 

MRID 47832038

Annex 5.1.1/1

Acceptable

Oral gavage/

100 mg/kg bw

Rapid and almost complete absorption 

and elimination without detectable 

metabolism. 

Most (rat: 87-98%; mouse: 80-85%) of 

the elimination was via urine. 

Plasma t1⁄2 was 9h in male rats and 7h in 

female rats.

report also includes integrated plasma 

and urine TK data from 28- and 90-day 

rat, and 28-day mouse dietary toxicity 

studies
Sulfoxaflor Human Health Risk Assessment DP No. D382604

Page 64 of 176

Guideline 

No.

Study Dosages Effects at lowest observed effect level

870.7485 Toxicokinetic – F344 Rat

ADME: single oral dose 

with examinations at 

Cmax and 1⁄2Cmax

MRID 47832039

Annex 5.1.2/1

Acceptable/Guideline

Oral gavage/

5, 100 mg/kg bw

Rapid absorption, wide tissue distribution. 

Radioactivity detected mainly in portal of 

entry (GI tract, liver) and excretion 

(kidney, urinary bladder) tissues. 

No metabolite in tissues or plasma. 

Kinetics in tissues were parallel to plasma 

showing no potential for bioaccumulation.

870.7485 Toxicokinetic – F344 Rat

ADME: oral – single and 

repeat dose; IV – single 

dose with examinations 

at 168 h (7 days )

MRID 47832034

Annex 5.1.3/1

Acceptable/Guideline

Oral gavage/

5 mg/kg bw for 1 and 15 days

100 mg/kg bw for 1 day

Intravenous 5 mg/kg bw for 1 

day

Rapid and almost complete (at least 92-

96%) absorption of the oral dose. Low 

metabolism (<7%) and almost complete 

(89-94%) and rapid elimination of the oral 

dose in urine in the 1st 24 hours. 

No tissue accumulation, ≤1.2% remained 

in tissues 7 days after dosing.

NonGuidelineEx vivo gene expression 

and cell proliferation 

analyses

CD1Mouse (♀) & F344 

Rat

MRID 47832033

Annex5.5.4/1

Acceptable

Mice: 0, 3000, 4500.

Rats: 0, 2000

XDE-208-induced gene expression profile 

in mice and liver (hepatocellular) 

proliferation in both mice and rats 

characteristic of phenobarbital-like CAR 

agonism.

NonGuidelineTargeted gene 

expression, cell 

proliferation and 

cytochrome P450 

enzymatic activity in 

F344 

MRID 47832061

Annex 5.5.4/2

Acceptable

0, 100, 750, 1500 for 3 or 7 

days

XDE-208-induced liver effects were PBlike. Males were affected more than 

females. Neither AhR nor PPARα were 

involved.

NonGuidelineLiver Weight Effects in 

crl:cd1(icr) CD1 Mice 

MRID 47832062

Annex 5.5.4/3

Acceptable

Males: 0, 500, 750. Females: 

0, 1000, 1500 for 7 days

XDE-208-induced liver effects were 

consistent with CAR activation resulting 

in a PB-like MoA; males were more 

sensitive than females. Neither AhR nor 

PPARα were involved.
Sulfoxaflor Human Health Risk Assessment DP No. D382604

Page 65 of 176

Guideline 

No.

Study Dosages Effects at lowest observed effect level

NonGuidelineA Study to Characterize 

the Induction Profile of 

XDE-208 in the Livers 

Of C57BL/6J Mice 

MRID 47832276

Annex 5.5.4/4

Acceptable

0, 750, 1500 ppm XDE-208-induced liver effects in 

C57Bl/6J mice were similar to previously 

observed effects in CD1 mice

NonGuidelineLiver Effects Observed 

In Regulatory 

Toxicology Studies By 

Use Of Dual Car-PXR 

Knockout And 

Humanised Mice 

(Mouse/C57Bl/6J WT, 

Humanised and KO 

PXR/CAR)

MRID 47832255

Annex 5.5.4/5

Acceptable

0, 750 ppm for 7 days In WT C57BL/6J XDE-208 caused the 

same liver effects seen in CD1 mice.

In PXR/CAR KO mice, XDE-208 did not 

induce any liver changes, demonstrating 

that activation of one or both of these 

receptors is required to elicit the liver 

effects seen in WT mice.

In PXR/CAR humanised mice slight liver 

hypertrophic effects occurred but not 

hepatocellular proliferation.

This study demonstrated that XDE-208, 

like PB, acts via a CAR-mediated MoA 

and that mice carrying the human PXR 

and CAR receptors did not develop 

hepatocellular proliferation responsible 

for liver tumor induction. 

NonGuidelineA Dietary Reproductive 

Toxicity Cross-Fostering 

Study in Crl:CD(SD) 

Rats 

MRID 47832063 

Annex 5.6.12/1

Acceptable

Group 1: 0/0 ppm

Group 2: 

0/1000 ppm

Group 3:

1000/0 ppm

Group 4:

1000/1000 ppm

Groups 1 and 2 (negative control and 

lactation exposure only) had no effects 

Groups 3 and 4 (gestation exposure only 

and positive control) had decreased 

neonatal survival 

Dam:

Reduced feed consumption and body 

weight gain when dams given 1000 ppm

Litter:

All offspring exposed prior to birth died 

by PND 4. No effect on neonatal survival 

with lactation-only exposure. Therefore, 

pup survival effect due to in utero

exposure.

NonGuidelineNeonatal Survival in 

New Zealand White 

Rabbits 

MRID 47832138

Annex 5.6.12/2

Acceptable

0, 750 ppm

(0, 29 mg/kg/day)

Dam:

Decreased feed consumption and body 

weight gain.

Litter:

No Effects
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Guideline 

No.

Study Dosages Effects at lowest observed effect level

NonGuidelineCharacterization of the 

agonist effects of XDE208 on mammalian 

muscle nicotinic 

acetylcholine receptors 

MRID 47832035

Annex 5.6.12/3

Acceptable

0-3mM XDE-208 was an agonist to the rat fetal 

muscle nAChR

XDE-208 was not an agonist to human 

fetal, human adult, or rat adult muscle 

nAChR

NonGuidelinePhase 1; Critical window 

of exposure for fetal 

abnormalities and 

neonatal survival effects 

in Crl:CD(SD) rats 

MRID 47832137

Annex 5.6.12/4

Acceptable

Group 1:

0 ppm

Group 2:

1000 ppm GD 6-16

Group 3: 1000 ppm GD 16-

birth

Litter:

1000 ppm from GD 16-birth caused 

neonatal death and limb abnormalities in 

offspring. Also, all fetal abnormalities 

observed in developmental toxicity study 

reversed by PND 4.

1000 ppm from GD 6-16 produced no 

effects. 

NonGuidelinePhase 2; Critical window 

of exposure for fetal 

abnormalities and 

neonatal survival effects 

in Crl:CD(SD) rats 

MRID 47832136

Annex 5.6.12/5

Acceptable

Group 1:

0 ppm

Group 2:

1000 ppm GD 16-18

Group 3: 1000 ppm GD 18-20

Group 4:

1000 ppm

GD 20-22/LD0

Litter:

1000 ppm exposure for 48 hours starting 

on GD 20 caused neonatal death and limb 

abnormalities in offspring. All fetal 

abnormalities observed in developmental 

toxicity study reversed by PND 4.

1000 ppm from GD 16-18 or 18-20 

produced no effects.

NonGuidelineObservations on the 

effects of XDE-208 on 

the phrenic nervehemidiaphragm 

preparation from newborn rat. 

MRID 47832064

Annex 5.6.12/6

Acceptable

0, 0.1, 1.0mM XDE-208 induced nAChR-dependent 

sustained contracture of the neonatal rat 

diaphragm.

NonGuidelineHistopathological 

Evaluation Of Fetal Lung 

Samples From The 

Developmental Toxicity 

Study In Crl:Cd(Sd) Rats 

MRID 47832135

Annex 5.6.12/7

Acceptable

0, 1000 ppm Fetal lungs from the rat developmental 

toxicity study were normal. 
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Guideline 

No.

Study Dosages Effects at lowest observed effect level

NonGuideline

(GF-3032 

Formulation)

Comparative Dermal 

Absorption, in vitro rat 

and human skin

MRID 47832414

Annex IIIA 7.6.2

Acceptable

0.024, 0.48, 2.4 g/L for 24 

hours 

% AD absorbed for 0.024, 0.48, 2.4 g/L, 

respectively;

Human; 1.15, 1.54, 0.26% 

Rat: 4.34, 8.72, 1.3%

NonGuideline

(GF-3032 

Formulation)

Dermal Absorption in the 

rat, in vivo

MRID 47832413

Annex IIIA 7.6.3

Acceptable

0.024, 0.48, 2.4 g/L for 

10hours then skin washed 

with mild soap. Tissue 

collected for up to 192 hours.

The amount of applied dose removed by 

washing was 96%, 71%, and 67% of the 

applied dose. After 10 hours, 2%, 11%, 

and 13% of the AD was absorbed across 

the dose groups, respectively.
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Study type Route/method

Dose levels*

Effects at Lowest Observed Adverse Effects 

Level

1. Metabolite X11719474

ADME probe in F344 Rats

MRID 47832132

Annex 5.8.1.1/1

Acceptable/Non-guideline

Oral/gavage

100 mg/kg/day 

n/a

870.3050 

28-day Oral in F344 Rats 

MRID 47832099

Annex 5.8.1.3/2

Acceptable/Guideline

Oral/diet

0, 1000, 2000, 3000, 8000 ppm

0/0, 83.4/90.1, 167/184, 

244/278, 662/734 mg/kg/day 

(M/F)

LOAEL= 3000 ppm (241mg/kg/day) based on 

decreased triglycerides in the males

NOAEL= 2000 ppm (167 mg/kg/day). 

870.3100 ; 870.3100 

90-day Oral in F344 Rats

MRID 47832147

Annex 5.8.1.3/3

Acceptable/Guideline

Oral/diet

0, 500, 1000, 5000 ppm

At 5000 ppm ( 71.8 mg/kg/day) ↑Cholesterol, 

↑liver wt. with hypertrophy, eosinophilia, fatty 

change & SCN

870.3150 

90-day Oral in Beagle Dogs 

(males)

MRID 47832037

Annex 5.8.1.3/5

Acceptable/Guideline

Oral/gavage

0, 10, 25, 50 mg/kg/day 

No Observed Effects

870.5100

Ames S. typhimurium E. coli

MRID 47832097

Annex 5.8.1.4/1

Acceptable/Guideline

In vitro S9

0 - 5000 μg per plate

Negative

870. 5375 

Lymphocyte chromosome 

aberration in CD Rats (males)

MRID 47832096

Annex 5.8.1.4/2

Acceptable/Guideline

In vitro S9

0 - 2953 g/ml

Negative

870. 5300 

HGPRT Chinese hamster 

ovary 

MRID 47832095 

Annex 5.8.1.4/3

Acceptable/Guideline

In vitro S9

0 - 2953 g/ml

Negative

Targeted Gene Expression, 

Cell Proliferation, and 

Cytochrome p 450 Enzymatic 

Activities in Rats.

MRID 47832151

Annex 5.8.1.5/1

Acceptable/Non-Guideline

0 or 8000 ppm Increased expression of several CAR-related 

transcripts, along with the pregnane X receptor

(PXR)-related transcript Cyp3a, and PROD

enzyme activity, suggests that X11719474 may 

be agonist ligand for CAR, 

870.3550; OECD 421

Dietary reproduction &

Developmental Toxicity 

Screening Test in 

CRL:CD(SD) Rats 

MRID 47832094

Annex 5.8.1.6/1

Acceptable/Guideline

0, 1000, 2000, 5000 ppm

(0, 80.8/81.7, 162/167, 396/451 

mg/kg/day (M/F)

No Observed Effect
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Study type Route/method

Dose levels*

Effects at Lowest Observed Adverse Effects 

Level

870.3700 

Dietary Developmental 

Toxicity Study in 

CRL:CD(SD) Rats

MRID 47832087

Annex 5.8.1.6/2

Acceptable/Guideline

0, 1000, 2000, 5000 ppm No Observed Effect

2. Metabolite X11721061

870.3050 

28-day Dietary in F344 Rats

MRID 47832036

Annex 5.8.2.3/2

Acceptable/Guideline

Oral/diet

0, 1000, 3000, 8000 ppm

LOAEL= 8000 ppm (662/734 mg/kg/day 

(M/F)) based on increased liver weights, hepatic 

hypertrophy, and increased cholesterol levels

NOAEL = 3000 ppm (244/278 mg/kg /day 

(M/F)). 

870.5100

Ames S. typhimurium E. coli

MRID 47832085

Annex 5.8.2.4/1

Acceptable/Guideline

In vitro S9

0 - 5000 μg per plate

Negative

870. 5375 

Lymphocyte chromosome 

aberration in CD Rats (males)

MRID 47832078

Annex 5.8.2.4/2

Acceptable/Guideline

In vitro S9

0 - 1920 g/ml

Negative

870. 5300 

HGPRT Chinese hamster 

ovary 

MRID 47832077

Annex 5.8.2.4/3

Acceptable/Guideline

In vitro S9

0 - 1920 g/ml

Negative

3. Metabolite X11596066

870.5100

Ames S. typhimurium E. coli

MRID 47832076

Annex 5.8.3.4/1

Acceptable/Guideline

In vitro S9

0 - 5000 μg per plate

Negative

4. Metabolite X11579457

870.5100

Ames S. typhimurium E. coli

MRID 47832070

Annex 5.8.4.4/1

Acceptable/Guideline

In vitro S9

0 - 5000 μg per plate

Negative

870. 5375 

Lymphocyte chromosome 

aberration in CD Rats (males)

MRID 48288932

Annex 5.4.2/2

Acceptable/Guideline

In vitro S9

0 – 2525 g/ml

Negative
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Study type Route/method

Dose levels*

Effects at Lowest Observed Adverse Effects 

Level

870. 5300 

HGPRT CHO

MRID 48288933

Annex 5.8.4.4/3

Acceptable/Guideline

In vitro S9

0 – 2525 g/ml

Negative

5. Metabolite X11519540

870.3050 

28-day dietary in F344 Rats

Annex 5.8.5.3/2

MRID 48288941

Acceptable/Non-guideline

0, 100, 300, 1000, 2000 ppm

(0/0, 7.7/8.5, 23.1/24.9, 74/77, 

140/152 mg/kg/day (M/F))

LOAEL = 300 ppm (23.1 mg/kg/day) based on 

changes increased liver weight and 

histopathology along with degeneration of 

kidney tubules (in males). 

NOAEL= 100 ppm (7.7 mg/kg/day).

870.5100

Ames S. typhimurium E. coli

MRID 47832068

Annex 5.8.5.4/1

Acceptable/Guideline

In vitro S9

0 - 5000 μg per plate

Negative

870. 5375 

Lymphocyte chromosome 

aberration in CD Rats (males)

MRID 48288935

Annex 5.8.5.4/2

Acceptable/Guideline

In vitro S9

0 – 2540 g/ml

Negative

870. 5300 

HGPRT CHO 

Annex 5.8.5.4/3

MRID 48288934

Acceptable/Guideline

In vitro S9

0 – 2540 g/ml

Negative
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A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) - Females age 13-49

Study Selected: Developmental Neurotoxicity Study in the Rat

MRID No.: 47832133

Executive Summary: See Appendix A, Guideline § 870.6300 

Dose and Endpoint for Risk Assessment: NOAEL = 1.8 mg/kg/day based on decreased 

neonatal survival PND 0-4 seen at LOAEL = 7.1 mg/kg/day.

Uncertainty Factors: 30 (3 X for interspecies (UFA) and 10 X for intraspecies (UFH) 

variability).

Comments about Study/Endpoint/Uncertainty Factors: The DNT was selected because the 

effect is a single dose effect, and can be provided the exposure occurs between gestation days 20 

to birth. This endpoint is protective of decreased neonatal survival observed in the 2-generation 

reproduction study with a NOAEL of 6.63 mg/kg/day and offspring effects observed in the rat 

developmental study with a NOAEL of 11.5 mg/kg/day. This endpoint is appropriate for the 

females age 13-49 since it is protective of potential in utero and reproductive effects.

A.3.2 Acute Reference Dose (aRfD) - General Population, excluding females 13+

Study Selected: Acute Neurotoxicity Study in the Rat

MRID No.: 47832134

Executive Summary: See Appendix A, Guideline § 870.6200 

Dose and Endpoint for Risk Assessment: NOAEL = 25 mg/kg/day based on decreased motor 

activity on day 1 seen at LOAEL = 75 mg/kg/day.

Uncertainty Factors: 100 (10 X for interspecies (UFA) and 10 X for intraspecies (UFH) 

variability).

Comments about Study/Endpoint/Uncertainty Factors: The ACN was selected because of 

the following: the effect was observed on the day of exposure, the effect, neurotoxicity, is 

consistent with the proposed MOA for sulfoxaflor; and the oral route of exposure is appropriate 

for risk assessment. This study is appropriate for the general population because the effect is not 

specific to a single sex or lifestage. Decreased food consumption was also observed within the 

first 4 days of exposure in several studies. However, decreased food consumption was attributed 

to the palatability of sulfoxaflor and was transient. 

A.3.3 Chronic Reference Dose (cRfD) `

Study Selected: Combine Chronic/Carcinogenicity Study in the Rat

MRID No.: 47832060

Executive Summary: See Appendix A, Guideline § 870.4300 
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Dose and Endpoint for Risk Assessment: NOAEL = 5.13 mg/kg/day (females) based on liver 

effects including increased serum cholesterol, hypertrophy, necrosis of centrilobular hepatocytes, 

vacuolization, and increased severity of aggregates of macrophages/histiocytes observed in 

males (21.3 mg/kg/day) and females (39 mg/kg/day). Although the NOAEL for males was 

slightly lower at 4.24 mg/kg/day, HED is using the female NOAEL of 5.13 mg/kg/day as a PoD 

for risk assessment. HED considers 4.24 mg/kg/day to be artificially low as a result of dosespread and the NOAEL of 5.13 is supported by similar rat NOAELs in the 2-generation 

reproduction study (6.07 mg/kg/day), the 90-day oral study (6.36 mg/kg/day), and the 

development study (11.5 mg/kg/day).

Uncertainty Factors: 100 (10 X for interspecies (UFA) and 10 X for intraspecies (UFH) 

variability).

Comments about Study/Endpoint/Uncertainty Factors: The combined 

chronic/carcinogenicity study was selected because the effects were observed of 2 years of 

exposure and the route of exposure of is appropriate. Hepatotoxicity was also observed in 

several other oral studies including the 28-day, 90-day, and chronic studies in the rat and mouse. 

However, the selected endpoint occurs at a lower dose and is therefore protective of the observed 

hepatotoxicity.

A.3.4 Dermal Exposure (Short- and Intermediate-Term)

Study Selected: Developmental Neurotoxicity Study in the Rat

MRID No.: 47832133

Executive Summary: See Appendix A, Guideline § 870.6300

Dose and Endpoint for Risk Assessment: NOAEL = 1.8 mg/kg/day based on decreased 

neonatal survival PND 0-4 seen at LOAEL = 7.1 mg/kg/day.

Uncertainty Factors: 30 (3 X for interspecies (UFA) and 10 X for intraspecies (UFH) 

variability).

Comments about Study/Endpoint/Uncertainty Factors: The endpoint used for short- and 

intermediate-term dermal exposure was selected DNT study in rats. The endpoint of concern is 

decreased neonatal survival in PND 0-4 offspring with a NOAEL of 1.8 mg/kg/day and a 

LOAEL of 7.1 mg/kg/day. This study is appropriate for the durations of exposure as well as it is 

protective for the populations of concern (fetuses in utero who may be exposed when mothers 

are exposed in occupational settings). 

The dermal equivalent dose (DED) using a dermal absorption value of 2.5% is 25 mg/kg/day 

(1000 mg/kg/day x 0.025 = 25 mg/kg/day). The NOAEL for the route-specific 28-day dermal 

study is 1000 mg/kg/day (no effects in females up to the limit dose). The DED using the 28-

dermal study is greater than the dose where offspring effects were observed in the DNT and is 

therefore not protective of the developmental effects observed in the DNT. As such, use of the 

28-day dermal study is not appropriate for dermal exposure assessment.

A.3.5 Inhalation Exposure (Short- and Intermediate-Term) 

Study Selected: Developmental Neurotoxicity Study in the Rat

MRID No.: 47832133
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Executive Summary: See Appendix A, Guideline § 870.6300

Dose and Endpoint for Risk Assessment: NOAEL = 1.8 mg/kg/day based on decreased 

neonatal survival PND 0-4 seen at LOAEL = 7.1 mg/kg/day.

Uncertainty Factors: 30 (3 X for interspecies (UFA) and 10 X for intraspecies (UFH) 

variability).

Comments about Study/Endpoint/Uncertainty Factors: The endpoint used for short- and 

intermediate-term inhalation exposure was selected DNT study in rats. The endpoint of concern 

is decreased neonatal survival in PND 0-4 offspring with a NOAEL of 1.8 mg/kg/day and a 

LOAEL of 7.1 mg/kg/day. This study is an appropriate duration of exposure and it is protective 

for the populations of concern (fetuses in utero who may be exposed when mothers are exposed 

in occupational settings). A default inhalation absorption factor of 100% is assumed in the 

absence of an inhalation study.
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A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.350 28-Day Oral Toxicity

IIA 5.3.1/2 28-Day Oral Toxicity (feeding) Fischer 344 Rats; 

In a 28-day dietary toxicity study (MRID 47832045), groups of five male and five female 

Fischer 344 rats were given test diets formulated to supply 0, 300, 1000, 2000, or 3000 ppm 

sulfoxaflor for 28 days. These dose levels corresponded to 0, 24.8, 79.4, 155, or 205 mg/kg/day 

for males and 0, 26.5, 88.3, 170 or 192 mg/kg/day for females, respectively. Toxicokinetic 

analysis of blood plasma was completed. 

Administration of sulfoxaflor to male and female rats at 3000 ppm resulted in excessive 

reductions in feed consumption (31% and 36%) and body weight loss (21% and 19%) compared 

to controls after 9 days of administration, respectively. The 3000 ppm dose groups were 

euthanized (day 9). The lower feed consumption was attributed to decreased palatability of 

rodent feed containing sulfoxaflor and was responsible for the decreased body weights.

Animals in all other dose groups exhibited a dose-related decrease in feed consumption at the 

start of exposure, which was due to decreased palatability of treated diets containing sulfoxaflor. 

Males given 300, 1000 or 2000 ppm consumed 5%, 29% or 54% less feed than control animals 

after one day. Females given 300, 1000, or 2000 ppm consumed 7%, 26% or 48% less than 

control animals. Feed consumption increased in animals given 1000 or 2000 ppm for the 

remainder of the study. Feed consumption for males given 300 or 1000 ppm was comparable to 

controls by the end of the study and was 6% decreased at 2000 ppm. Females given 300, 1000 

or 2000 ppm consumed 8%, 6% or 11% less than controls at the end of the study. 

Animals given 1000 or 2000 ppm had decreased body weight after one day of exposure, and 

was considered a secondary effect of the reduced feed consumption. By day 28, males and 

females given 2000 ppm weighed 8.5% and 10% less, respectively, than controls. Males and 

females given 300 or 1000 ppm had body weights comparable to controls on day 28. 

Males and females (1000 or 2000 ppm) had dose related increases in serum total cholesterol 

levels, and both sexes given 1000 or 2000 ppm, also had total serum protein levels higher than 

controls. Albumin and globulin levels were higher than concurrent and historical controls and 

were considered to be treatment related in males given 1000 or 2000 ppm and females given 

2000 ppm. 

Males and females given 2000 ppm had treatment-related decreases in final body weights. 

Males and females given 1000 or 2000 ppm had increased absolute and relative liver weights 

that were dose and treatment related. 

There were a number of organ weights of males and females given 2000 ppm that were altered 

and included: relative brain (males and females), relative kidney (males), relative testes (males), 

relative thyroid (males and females), absolute heart (males), and absolute spleen (males and 

females). These differences in organ weights were considered to be secondary to the lower 

body weights of this dose group. This conclusion is supported by the absence of 

histopathological changes in these organs.
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Treatment-related histological effects were observed in the livers of males and females given 

1000 or 2000 ppm and consisted of a dose related increase in the severity (very slight to 

moderate) of hepatocellular hypertrophy, with altered tinctorial properties, involving the 

centrilobular to midzonal regions of the hepatic lobule. Effects were more prominent in males, 

compared to females, increasing to moderate severity in 2000 ppm males. Vacuolization, 

consistent with fatty change, involving hepatocytes primarily in the right lateral lobe was also 

occasionally seen in a multifocal distribution in males given 1000 or 2000 ppm and in one 

female given 2000 ppm. The restriction of this alteration to only one liver lobe, the minor 

nature of the effect (very slight or slight) and the lack of a clear dose response relationship in 

regards to severity suggests that this may not be a significant effect. 

Toxicokinetic analysis of the plasma showed that levels of sulfoxaflor (AUC24h) were 

effectively proportional to dose; 3.3 to 3.6 fold increase between 300 and 1000 ppm groups and 

a 2.0-fold increase between 1000 and 2000 ppm dose groups. Females were more efficient in 

eliminating the test material than males. The 24 hour systemic dose as measured by the 

AUC24h was 21, 15 and 14% lower in females than males at 300, 1000 and 2000 ppm dose 

groups, respectively (corresponding to 210, 693, 1371 μg h/ml versus 167, 591 and 1183 μg 

h/ml at the low, middle and high doses, respectively). Plasma elimination half-life of 

sulfoxaflor in male rats was between 7 and 8 hours; whereas it was 32-43% lower in females 

(between 4-5 hours). 

The no-observed-adverse-effect-level (NOAEL) for both sexes is 300 ppm (26.5 mg/kg/day) 

and the lowest-observed- adverse-effect-level (LOAEL) is 1000 ppm (88.3 mg/kg/day), based 

on enlarged livers (size and weight) with hepatocellular hypertrophy, slight vacuolization 

(males), and increased cholesterol levels. This study is Fully reliable (acceptable/nonGuideline): GLP compliant and acceptable for use as a range-finding study

IIA 5.3.1/4 28-Day Oral Toxicity [feeding] CD1(ICR) mice

In a 28 day toxicity study in mice (MRID 47832042, PMRA 1941272), groups of five male and 

five female CD-1 mice were fed diets supplying 0, 300, 1500, or 3500 ppm sulfoxaflor (purity, 

98.1%; Lot # C2120-16, TSN105885), equivalent to 0, 44, 230, 524 mg/kg/day in males and 0, 

53, 273, and 638 mg/kg/day in females, for at least 28 days. Parameters evaluated were daily 

cage-side observations, weekly detailed clinical observations, ophthalmic examinations, body 

weights, feed consumption, hematology, clinical chemistry, selected organ weights, and gross 

and histopathologic examinations. 

Feed consumption values for males and females given 1500 or 3500 ppm were lower than the 

controls during days 1-2, whereas feed consumption values were comparable to the controls after 

day 4. Slight treatment-related decreases in body weights and body weight gains were observed 

in males and females given 1500 or 3500 ppm during the first week of the study, however, they 

were comparable to controls through the rest of the study. 

Toxicokinetic analysis of the plasma showed that dose-proportional intake of sulfoxaflor was 

translated into a dose-proportional increase in plasma concentrations of sulfoxaflor. The 

systemic exposure of sulfoxaflor was ~40% higher in males than in females. The 24-hour urine 
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urinary elimination of sulfoxaflor in males was between 33 and 44% and in females was between 

23 and 65% of what they consumed during a 24-hour period, indicating that the majority of the 

dietary administered sulfoxaflor was excreted essentially unchanged in the urine.

At termination on day 30, males and females given 1500 or 3500 ppm had treatment-related 

elevations in mean serum ALP, ALT, AST activities and triglycerides. There were treatmentrelated increases in the mean liver weights and liver histopathology of males and females given 

1500 or 3500 ppm compared to controls. Males given 300 ppm had marginal treatment-related 

increases in liver weights over the respective control values, but were not associated with 

detectable hepatocyte hypertrophy or clinical chemistry changes and therefore, considered a 

non-adverse effect. Males given 3500 ppm had treatment-related elevations in absolute and 

relative adrenal gland weights that corresponded to hypertrophy of the zona fasciculata of the 

adrenal cortex. Males given ≥ 1500 ppm had treatment-related lower absolute and relative 

kidney weights. In summary, due to higher systemic exposure in male mice, higher toxicity of 

sulfoxaflor was observed. 

The no-observed-adverse-effect-level (NOAEL) in male and female mice is 300 ppm (44 and 53 

and mg/kg/day, respectively). The lowest-observed-adverse-effect-level (LOAEL) in male and 

female mice is 1500 ppm (230 and 273 mg/kg/day, respectively), based on increased liver weights, 

increased liver enzymes (ALT, AST), and hepatocellular hypertrophy in both sexes. Liver 

histopathology (necrosis) in male mice was also seen at this dose. At 3500 ppm (524 and 638 

mg/kg/day, respectively), the same effects were seen along with increased triglycerides and ALP in 

both sexes, liver histopathology in males (mitotic cells, vacuolization/fatty change) and females 

(necrosis), and adrenal effects (increased weights and hypertrophy) in males.

This study is fully reliable (acceptable/guideline).

IIA 5.3.1/6 28-day Palatability/Tolerability Probe Study in Beagle dogs; 

In a 28-day oral palatability probe study (MRID 47832043), sulfoxaflor (XDE-208 technical 

grade, 95.6% a.i.; lot no. E2162-34 or analytical grade, 99.7% a.i., lot no. 20062-464-9) was 

administered to Beagle dogs via dietary, capsule or oral gavage administration for up to 28 days. 

Using the same animals (with 1 or 2-week breaks of basal diet only between dosing regimens), 

routes of test material administration and dosing regimens were altered for a total of five dosing 

groups, during the course of the study as follows. Three female dogs received technical grade 

test material via the diet, ad libitum, for 6 consecutive days at a dose level of 500 ppm (Group 1). 

The dosing route for these animals was changed to analytical grade test material via oral gavage, 

once daily for 28 consecutive days, at a dose level of 15 mg/kg/day (Group 3). Another group of 

three female dogs received the technical test material via capsule, twice daily for 6 consecutive 

days, at a dose level of 15 mg/kg/day (Group 2). The dosing route for these animals was 

changed to dietary, ad libitum (technical grade) for 5 consecutive days, at a dose level of 100 

ppm (Group 4). The dosing route for these animals was once again changed to oral gavage 

(technical grade), once daily for 28 consecutive days, at a dose level of 15 mg/kg/day (Group 5). 

For both oral gavage groups, the vehicle was 0.5% methylcellulose in deionized water and the 

dose volume was 10 mL/kg. A previous, preliminary palatability probe study (MRID 47832056) 

did not identify adequate oral acceptance by diet and capsule administration.
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Observations for morbidity, mortality, injury and the availability of food and water were 

conducted twice daily for all animals. Clinical observations were conducted daily. Body 

weights and food consumption were measured and recorded daily. Blood samples for clinical 

pathology evaluations were collected from all animals pretest and on Days 6 and 29 (prior to 

necropsy), and urine samples were collected at necropsy from all animals on Day 29. Blood 

samples for determination of the plasma concentrations of the test article were collected from 

animals in Group 4 at designated time points on Day 5 (the last day of dietary dosing), and from 

animals in Groups 3 and 5 at designated time points on each respective Day 28 (prior to 

necropsy). At study termination, necropsy examinations were performed and organ weights 

were recorded. A complete set of tissues from Group 5 animals was sent to the Sponsor for 

microscopic evaluation. Findings were compared with historical range data due to the lack of 

concurrent controls.

All animals survived until the scheduled termination intervals. However, there were clinical 

findings and body weight findings that were associated with reduced food consumption (50% or 

more compared to pretreatment). In some instances, the reduced food consumption was 

accompanied by a lack of sufficient fluid intake which resulted in a loss of skin elasticity. In

addition, intermittent emesis and fecal alterations (discolored, mucoidal, and soft/watery feces) 

was likely test material-related. 

Oral gavage administration at 15 mg/kg/day was a tolerable route and concentration for the 

technical grade test material exposure as determined by adequate food consumption and tolerable 

in-life clinical signs. Exposure at 100 ppm via dietary route was well tolerated as determined by 

adequate food consumption, but the amount of test material consumed was not sufficient to 

justify it as a potential highest dose for subsequent studies. Exposure at 500 ppm via dietary 

route or 15 mg/kg/day via capsule route was not well tolerated as determined by insufficient food 

consumption. Therefore, the dietary route could not be considered a viable method of test 

material exposure over a sustained duration. Based on this information, oral gavage exposure 

was determined to be the most appropriate route for a sustained duration of test material 

exposure in Beagle dogs.

This non-guideline study is reliable with restrictions (acceptable/non-guideline). The study is 

not GLP compliant. However, all experiments were done according to GLP standards. 

Additionally, the study was well conducted and the Agency has confidence in the scientific 

integrity of the data. It was conducted to determine palatability and the appropriate method of 

oral administration for subchronic and chronic oral toxicity studies and not to satisfy guideline 

requirements.

IIA 5.8.1.3/2 X11719474: 28-Day Dietary Toxicity Study in F344/DuCrl Rats;

In a 28-day dietary toxicity study (MRID 47832099), five male and five female Fischer 344 rats 

per group were given test diets formulated to supply 0, 1000, 2000, 3000 or 8000 ppm 

X11719474 (Purity 99.5%; Lot # E-2695-1, TSN030626-0003) for 29 days. These 

concentrations corresponded to time-weighted average doses of 0, 83.4, 167, 244 or 662 mg/kg 

bw/day for males and 0, 90.1, 184, 278 or 734 mg/kg bw/day for females, respectively. 

Standard parameters were evaluated as well as toxicokinetic analyses of plasma and urine. 
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There were no treatment-related effects on clinical signs, ophthalmic observations, hematologic 

or coagulation parameters. 

In the 8000 ppm dose group, males and females exhibited reduced body weight gain compared 

to controls during the first five days of treatment, and this effect was considered secondary to 

reduced feed consumption. After five days of treatment, body weight gains for males and 

females were 27% or 20% lower than controls, respectively. By Day 29, body weights and 

body weight gains were similar to control values. Decreased in feed consumption during the 

first five days of the study was considered to reflect decreased palatability of the treated diet. 

Males and females consumed ~11% or ~7% less feed than controls, respectively, during this 

period. However, feed consumption was comparable to controls by the end of the study. Feed 

consumption values for males and females given 0, 1000, 2000 or 3000 ppm were either slightly 

higher or comparable to controls throughout the study. 

Also in the 8000 ppm dose group, blood cholesterol levels (25% in males and 22% in females), 

and liver weights (33% in males and 14% in females) were higher compared to controls. 

Triglyceride levels decreased 2-fold in males given 3000 and 8000 ppm X11719474. Males and 

females given 8000 ppm and males given 3000 ppm had slight treatment-related hypertrophy of 

hepatocytes. All other histopathologic observations were considered to be spontaneous 

alterations unassociated with exposure to X11719474. 

Absorption of the X11719474 from the diet was dose-proportional for both genders. The 

ingested X11719474 was rapidly eliminated from plasma upon the removal of the fortified diet 

(fasting) and dropped below the limit of quantification at the time of sacrifice in most of the 

rats. The elimination half-life of X11719474 from plasma was between 2.7 and 3.6 hours. 

Male rats eliminated an average of 54 ± 21% of what they consumed during a 24-hour period 

(range: 40 to 85%), while elimination by females averaged 81 ± 10% (range: 66 to 89%) of the 

test material consumed in 24 hours. Overall, these data show that X11719474 was significantly 

absorbed following dietary administration and quickly eliminated, primarily via urine as parent 

compound. The ratio of diastereomers was not substantially different in the plasma and urine 

samples when compared with the matrix samples added with the test material.

The lowest-adverse-effect-level (LOAEL) was 3000 ppm (241mg/kg bw/day) based on 

decreased triglycerides in the males. The no-observed-effect-level (NOAEL) was 2000 ppm 

(167 mg/kg bw/day). 

This subchronic toxicity study in the rats is Fully Reliable (acceptable/guideline) and satisfies the 

guideline requirement (OECD 407) for a repeat-dose oral study in rats.

IIA 5.8.2.3/2 X11721061: A 28-Day Oral Dietary Toxicity Study in Fischer 344/DuCrl 

Rats;

This study (MRID 47832036) was conducted to evaluate the potential toxicity of X11721061, a 

metabolite of the experimental insecticide sulfoxaflor, in rats when administered orally via the 

diet for 28 days. Three treatment groups of five male and five female Fischer 344 CDF®

[F-344/DuCRL] rats were administered the test article at dose levels of 1000, 2000, 3000, and 
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8000 ppm. One additional group of five animals/sex served as the control and received untreated 

diet. 

Standard parameters Observations for morbidity, mortality, injury, and the availability of food 

and water were conducted twice daily for all animals. Cageside observations were conducted 

daily. Detailed clinical observations were conducted weekly. Body weights were measured and 

recorded prior to randomization (Day –2 and -3) and on Days 1, 5, 8, 15, 22, and 29. Food 

consumption was measured and recorded pretest (Days -4 to -1) twice during the first week, and 

once weekly for the remainder of the study. Compound consumption was calculated during each 

interval food consumption was measured, beginning on Day 1. Ophthalmoscopic examinations 

were conducted pretest and prior to the terminal necropsy. Blood and urine samples for clinical 

pathology evaluations were collected from all animals prior to the terminal necropsy. Blood 

samples for plasma analysis were collected from all animals at designated time points on Days 

28 and 29. At study termination, necropsy examinations were performed and organ weights were 

recorded. Tissues were microscopically examined for animals at 0 (control) and 8000 ppm.

No treatment-related deaths occurred. There were no treatment-related effects on clinical signs, 

ophthalmic observations, hematologic or coagulation parameters. Slight reductions in food 

consumption noted in males and females at the highest dose (8000 ppm) during the first 5 days 

of treatment only were considered to reflect transient reduced palatability of the diet. No 

treatment-related clinical signs of toxicity or affects on body weight were observed.

Blood cholesterol levels for males and females given 8000 ppm were higher than the controls, 

statistically significant, and treatment related. Males and females given 8000 ppm had 

statistically-identified higher absolute (33% and 14%, respectively) and relative (37% and 18%, 

respectively) liver weights than the controls. These differences were interpreted to be treatment 

related. There were no other treatment-related alterations or statistical differences in the organ 

weights for males or females.

Males and females given 8000 ppm and males given 3000 ppm had a slight treatment-related

hypertrophy of hepatocytes in the centrilobular/midzonal region of the hepatic lobules. This 

effect was not considered adverse at 3000 ppm since liver weight and clinical chemistry were not 

significantly impacted at this dose. All other histopathologic observations were considered to be 

spontaneous alterations unassociated with exposure to X11721061.

Under the conditions of this study, the lowest-observed-adverse-effect-level (LOAEL) for males 

and females was 8000 ppm (662/734 mg/kg/day (M/F)) based on increased liver weights, hepatic 

hypertrophy, and increased cholesterol levels. The no-observed-adverse-effect level (NOAEL) 

for males and females was 3000 ppm (244/278 mg/kg /day (M/F)). 

IIA 5.8.5.3/2 X11519540: 28-day Dietary Toxicity Study in F344/DuCrl Rats;

In a 28-day repeated oral dose study (MRID 48288941), groups of five male and five female 

F344/DuCrl rats were given test diets formulated to supply 0, 100, 300, 1000 or 2000 ppm 

X11519540 (targeted doses of 0, 10, 30, 100, or 200 mg/kg/day, respectively) for at least 28 

days. These dose levels corresponded to time-weighted average doses of 0, 7.7, 23.1, 74.0, and 

140 mg/kg/day for males and 0, 8.5, 24.9, 77.2 and 152 mg/kg/day for females, respectively. 
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Standard parameters were evaluated, as well as toxicokinetic analysis of plasma and urine, and 

gene expression analysis of liver tissue.

Rats given 1000 or 2000 ppm had treatment-related lower body weights and body weight gains 

throughout the study, relative to controls. At study termination, the body weight gains of males 

given 1000 or 2000 ppm were 17.4 and 29.6% lower than controls, and the body weight gains of 

females given 1000 or 2000 ppm were 17.0 and 26.4% lower than controls, respectively. Males 

and females given 1000 or 2000 ppm also had treatment-related decrements in feed 

consumption. The lower feed consumption was interpreted to be caused by reduced palatability 

of the diets, resulting in lower body weight and body weight gains. There were no treatmentrelated effects on body weights, body weight gains, or feed consumption in male or female rats 

given 100 or 300 ppm.

Males and females given 1000 or 2000 ppm had treatment-related lower red blood cell counts, 

hemoglobin concentrations and hematocrit levels. The decrements in erythrocytic parameters 

were dose-related, and were interpreted to be secondary to lower feed consumption at these dose 

levels.

Males given 1000 or 2000 ppm had treatment-related higher serum alanine aminotransferase 

(ALT) activity, aspartate aminotransferase (AST) activity, total protein, albumin, and 

cholesterol concentrations, relative to controls. In addition, males given 2000 ppm had a 

treatment-related higher gamma-glutamyl transpeptidase (GGT) activity. Males given 300 ppm 

had treatment-related higher total protein, albumin and cholesterol concentrations. Females 

given 1000 or 2000 ppm had treatment-related higher GGT activity, total protein, albumin, 

globulin and cholesterol concentrations. Females given 300 ppm had treatment-related higher 

total protein, albumin and cholesterol concentrations.

The urine pH of males given 300, 1000 or 2000 ppm, and of females given 1000 or 2000 ppm, 

was slightly lower than controls. Males given 2000 ppm had slightly higher protein 

concentration in the urine, relative to controls. The alterations in urine pH and protein were 

interpreted to be treatment related.

Treatment-related decreases in final body weights occurred in both males and females given 

1000 (6.5 and 6.6%, respectively) and 2000 ppm (11.1% and 6.8%, respectively) when 

compared to controls. Treatment-related increases in the mean absolute and relative liver 

weights were noted in males and females given 100 (33.1 and 30.6%, and 19.9 and 25.7%, 

respectively), 300 (69.8 and 67.4%, and 53.3 and 59.8%, respectively), 1000 (101 and 116%, 

and 117.5 and 132.7%, respectively) or 2000 ppm (106.8 and 133.5%, and 143.4 and 161.4%, 

respectively), relative to controls. The higher liver weights corresponded with hypertrophy of 

centrilobular and midzonal hepatocytes at all dose levels.

Males and females from all dose levels had treatment-related higher absolute and relative 

adrenal gland weights. The higher adrenal weights corresponded with histopathologic findings 

of very slight or slight hypertrophy of the zona fasciculata in males and females given 300, 1000 

or 2000 ppm, and very slight or slight increased vacuolization of cortical cells in males from all 

dose groups and females given 300, 1000 or 2000 ppm.
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One female given 2000 ppm died, and one male given 1000 ppm and one female given 2000 

ppm were euthanized in a moribund condition, following blood collection for toxicokinetic 

plasma samples on test day 28. All three animals had large axillary hematomas secondary to 

jugular vein bleeding. Excessive hemorrhage was interpreted to be the cause of moribundity or 

death in these animals, and may have been reflective of a treatment-related impairment of 

coagulation. However, the prothrombin times and activated partial thromboplastin times were 

unaffected by treatment in males and females at all dose levels.

The liver was the primary target organ. Male and female rats from all dose levels had 

treatment-related hepatocellular hypertrophy with altered tinctorial properties (increased 

cytoplasmic eosinophila) of centrilobular and midzonal hepatocytes. The severity of this 

alteration (very slight to moderate) increased in a dose-related manner. Other treatment-related 

liver effects consisted of: very slight increased numbers of mitotic figures (males at all dose 

levels, females at 300, 1000 or 2000 ppm), very slight multifocal necrosis of individual 

hepatocytes (males and females at 300, 1000 and 2000 ppm), and very slight multifocal 

hepatocellular necrosis with accompanying inflammation (males at 1000 and 2000 ppm and 

females at 1000 ppm). The other primary treatment-related effect was an increase in the 

incidence of very slight multifocal degeneration of tubules in the kidneys, which occurred in 

males given 300, 1000 or 2000 ppm, and in females given 2000 ppm.

Males from all dose levels had treatment-related very slight or slight diffuse follicular cell 

hypertrophy of the thyroid gland, and females given 1000 or 2000 ppm had very slight diffuse 

hypertrophy of the thyroid gland. The thyroid hypertrophy may have been caused by a 

treatment-related induction of liver microsomal enzymes responsible for biliary excretion of 

thyroid hormones, with resultant chronic stimulation of the thyroid by thyroid stimulating 

hormone through disruption of the hypothalamic – pituitary – thyroid axis.

Males and females given 300, 1000 or 2000 ppm had treatment-related very slight or slight 

hypertrophy of the zona fasciculata of the adrenal glands. In addition, males from all dose 

levels, and females given 300, 1000 or 2000 ppm had treatment-related very slight or slight 

increased vacuolization of the adrenal cortex (zona glomerulosa, zona fasciculata and zona 

reticularis). Males given 1000 or 2000 ppm and females given 2000 ppm had very slight diffuse 

acinar cell hypertrophy of the submandibular salivary gland. The adrenal and salivary effects 

were interpreted to be secondary, stress-related effects.

Males and females given 1000 or 2000 ppm had treatment-related very slight or slight erythroid 

cell hyperplasia of the bone marrow. Males given 2000 ppm had a treatment-related increase in 

the incidence of very slight extramedullary hematopoiesis (erythroid cell) of the spleen. The 

bone marrow and spleen effects were interpreted to be reflective of a regenerative response to 

the lower red blood cell counts, hemoglobin concentrations and hematocrits in males and 

females given 1000 or 2000 ppm.

Males and females given 1000 or 2000 ppm had treatment-related very slight or slight atrophy 

of the mesenteric adipose tissue. Females given 1000 or 2000 ppm had treatment related very 

slight or slight decreased size of the uterus. Females given 2000 ppm also had treatment-related 
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slight decreased size of the cervix and vagina. The atrophy of mesenteric adipose tissue and 

decreased size of the female reproductive tract were interpreted to be secondary to lower feed 

consumption and lower body weight gains of animals given 1000 or 2000 ppm.

Toxicokinetic analysis of plasma after 28 days of dietary administration to X11519540 showed 

that the systemic exposure of X11519540 (as plasma AUC24h) deviated from linearity (in both 

sexes) between the low (100 ppm) and mid-low (300 ppm) dose groups. The mean plasma 

elimination half-lives of X11519540 were calculated to be 27 and 28 hours in male rats of the 

1000 and 2000 ppm dose groups, respectively; plasma elimination half-lives in female rats, of 

the 1000 and 2000 ppm dose groups, were 35 and 24 hours, respectively. Plasma elimination 

half-lives could not be reliably calculated for animals from the 100 and 300 ppm dose groups as 

the X11519540 concentrations in plasma at terminal sacrifice were in most cases roughly 

equivalent to plasma levels measured at the time at which the test material formulated feed was 

withdrawn from the animals. 

The amount of X11519540 eliminated in urine, over a 24 hour collection interval, deviated from 

linearity (in both sexes) between the low (100 ppm) and mid-low (300 ppm) dose groups. In 

male rats 47%, 31%, 18%, and 13% of the calculated daily TMI was eliminated over 24 hours in 

urine of low, mid-low, mid-high, and high dose groups. A similar pattern was observed in 

female rats with 51%, 28%, 15%, and 11% of the calculated daily TMI eliminated in urine of 

low, mid-low, mid-high, and high dose groups. 

Targeted gene expression analysis of Cyp2b1, Cyp2b2, and Cyp3a3 in the liver tissue showed 

significantly elevated transcripts at 100, 300 and 1000 ppm (2000 ppm was not tested for these 

endpoints). These data suggest that X11519540 may stimulate gene expression consistent with 

constitutive androstane nuclear receptor (CAR) activation, and were similar to those seen in 

previous studies with sulfoxaflor (the parent compound of X11519540) and X11719474 

(another metabolite of sulfoxaflor).

The Lowest-observed-adverse-effect-level (LOAEL) is 300 ppm (23.1 mg/kg/day) based on 

changes increased liver weight and histopathology along with degeneration of kidney tubules (in 

males). The no-observed-adverse-effect-level (NOAEL) is 100 ppm (7.7 mg/kg/day).

This subchronic toxicity study in the rats is acceptable and satisfies the guideline requirement 

(OECD 407) for a repeat-dose oral study in rats.

II 5.8.1.3/2 X11719474: 28-Day Dietary Toxicity Study in F344/DuCrl Rats; 

In a 28-day dietary toxicity study (MRID 47832099), five male and five female Fischer 344 rats 

per group were given test diets formulated to supply 0, 1000, 2000, 3000 or 8000 ppm 

X11719474 (Purity 99.5%; Lot # E-2695-1, TSN030626-0003) for 29 days. These 

concentrations corresponded to time-weighted average doses of 0, 83.4, 167, 244 or 662 

mg/kg/day for males and 0, 90.1, 184, 278 or 734 mg/kg/day for females, respectively. 

Standard parameters were evaluated as well as toxicokinetic analyses of plasma and urine. 

There were no treatment-related effects on clinical signs, ophthalmic observations, hematologic 

or coagulation parameters. 
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In the 8000 ppm dose group, males and females exhibited reduced body weight gain compared 

to controls during the first five days of treatment, and this effect was considered secondary to 

reduced feed consumption. After five days of treatment, body weight gains for males and 

females were 27% or 20% lower than controls, respectively. By Day 29, body weights and 

body weight gains were similar to control values. Decreased in feed consumption during the 

first five days of the study was considered to reflect decreased palatability of the treated diet. 

Males and females consumed ~11% or ~7% less feed than controls, respectively, during this 

period. However, feed consumption was comparable to controls by the end of the study. Feed 

consumption values for males and females given 0, 1000, 2000 or 3000 ppm were either slightly 

higher or comparable to controls throughout the study. 

Also in the 8000 ppm dose group, blood cholesterol levels (25% in males and 22% in females), 

and liver weights (33% in males and 14% in females) were higher compared to controls. 

Triglyceride levels decreased 2-fold in males given 3000 and 8000 ppm X11719474. Males and 

females given 8000 ppm and males given 3000 ppm had slight treatment-related hypertrophy of 

hepatocytes. All other histopathologic observations were considered to be spontaneous 

alterations unassociated with exposure to X11719474. 

Absorption of the X11719474 from the diet was dose-proportional for both genders. The 

ingested X11719474 was rapidly eliminated from plasma upon the removal of the fortified diet 

(fasting) and dropped below the limit of quantification at the time of sacrifice in most of the 

rats. The elimination half-life of X11719474 from plasma was between 2.7 and 3.6 hours. 

Male rats eliminated an average of 54 ± 21% of what they consumed during a 24-hour period 

(range: 40 to 85%), while elimination by females averaged 81 ± 10% (range: 66 to 89%) of the 

test material consumed in 24 hours. Overall, these data show that X11719474 was significantly 

absorbed following dietary administration and quickly eliminated, primarily via urine as parent 

compound. The ratio of diastereomers was not substantially different in the plasma and urine 

samples when compared with the matrix samples added with the test material.

The no-observed-adverse effect level (NOAEL) for males and females was 2000 ppm (167/184 

mg/kg/day (M/F)) based on increased triglyceride at 3000 ppm. Increased cholesterol levels 

along liver changes (increased weight and histopathology) were observed at 8000 ppm. . 

This subchronic toxicity study in the rats is Fully Reliable (acceptable/guideline) and satisfies the 

guideline requirement (OECD 407) for a repeat-dose oral study in rats.

870.3100 90-Day Oral Toxicity – Rat

IIA 5.3.2/1 90-Day Subchronic Oral Toxicity in rats;

In a 90-day oral toxicity study (MRID 47832046), ten male and ten female Fischer 344 rats per 

group were given test diets formulated to supply 0, 100, 750 or 1500 ppm sulfoxaflor (purity 

96.6%; Lot # E2198-17, TSN106108) corresponding to time-weighted average concentrations of 0, 

6.36, 47.6, or 94.9 mg/kg/day for males and 0, 6.96, 51.6, or 101 mg/kg/day for females, 

respectively. Parameters evaluated were daily cage-side observations, weekly detailed clinical 

observations, ophthalmic examinations, functional observational battery (FOB, pre-exposure and 

prior to necropsy, comprising cage-side, hand-held, and open field observations, rectal 
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temperature, fore- and hindlimb grip performance, landing foot splay, and motor activity), body 

weights, feed consumption, prothrombin time, hematology, urinalysis, clinical chemistry, selected 

organ weights and gross and histopathologic examinations, which included a specifically detailed 

review of the nervous system. The study also included integrated toxicokinetics and an assessment 

of immunotoxicity.

Males (all treated doses) and females (750 ppm and 1500 ppm) exhibited dose-related lower feed 

consumption, which was due to decreased palatability of diets containing sulfoxaflor. During the 

first four days males given 100, 750 or 1500 ppm consumed 5%, 12% or 24% less feed than 

controls, and females given 750 or 1500 ppm consumed 8% or 21% less feed than controls. 

However, feed consumption for males at all dose levels was comparable to controls by the end of 

the study. Female feed consumption in the 750 and 1500 ppm groups was 5% or 8% lower than 

controls at 90 days, respectively, and statistically identified.

Male and females given 750 or 1500 ppm gained less weight than controls during the first four 

days of treatment and were dose related. After four days of treatment, body weight gains of males 

given 750 or 1500 ppm were 24% or 45% lower than controls, respectively, and body weight gains 

of females given 750 or 1500 ppm were 13% or 60% lower than controls, respectively. These 

animals gained weight for the remainder of the study. By day 90, males and females given 750 or 

1500 ppm weighed 8% or 9% and 3% or 8% less than controls, respectively. By day 90, the body 

weight gain of males and females given 750 or 1500 ppm was 11% or 13% and 9% or 20% less 

than controls, respectively. All body weight effects were considered secondary to the lower feed 

consumption due to decreased palatability of the test material in the feed. Males and females given 

100 ppm had body weights comparable to the controls at the end of the 90-day study. 

Serum cholesterol levels in males (127%) and females (83%) given 1500 ppm were significantly 

greater than controls and considered adverse. All other clinical pathology values were 

comparable to control values. 

Rats given 750 or 1500 ppm had statistically identified higher absolute and relative liver weights 

that were dose related, and interpreted to be treatment related. The absolute liver weights of males 

and females given 750 or 1500 ppm was 6% or 5% and 25% or 17% higher than controls, 

respectively and the relative liver weights of males and females given 750 or 1500 ppm was 14%

or 8% and 41% or 27% higher than controls, respectively. There were a number of additional 

differences in organ weights of males and females given 750 or 1500 ppm that were statistically 

identified. These differences in organ weights were secondary to the lower body weights of these 

dose groups and did not reflect a primary target organ effect of sulfoxaflor. This conclusion was 

supported by the absence of histopathological changes in these organs. 

Treatment-related histological liver effects occurred in male and females given 750 or 1500 ppm 

and consisted of a dose-related increase in the severity (slight to moderate) of hepatocellular 

hypertrophy (with altered tinctorial properties) involving the centrilobular to midzonal regions of 

the hepatic lobule. Individual hepatocyte necrosis was also observed in the centrilobular region 

with a multifocal distribution to a very slight or slight degree. All effects were seen in both 

sexes but were more prominent in males compared to females. Vacuolization of hepatocytes, 

consistent with fatty change, was also observed in all males in the 750 and 1500 ppm groups at 

very slight, slight or moderate degrees. In addition, in the rats with the greatest degree of 
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hepatocellular hypertrophy, necrosis and vacuolization, there was an increase in the incidence of 

rats with multifocal aggregates of macrophages- histocytes. The microscopic changes were 

present in all three lobes of the liver examined in male and female rats; however, they were more 

readily apparent in the right lateral lobe. The microscopic changes in the liver were consistent 

with the increased liver weights and cholesterol levels noted for these rats. 

Assessment of immunotoxicity as measured by immune responsiveness in the sheep red blood 

cell antibody-forming cell assay indicated there was no effect on immune responsiveness in 

female rats up to and including the high dose level of 1500 ppm. There was no effect on immune 

responsiveness for male rats in the 100 and 750 ppm groups, while the 1500 ppm group 

displayed a lower, non-statistically significant, response (26% lower) when compared to the 

vehicle control group. The lower AFC response in the high dose male group coincided with 

considerable general toxicity, including decreased body weights and increases in liver weight 

(absolute and relative), hepatocellular hypertrophy, necrosis, vacuolization consistent with fatty 

change, multi-focal aggregates of macrophages, and elevated serum cholesterol, for which the 

overall NOEL was 100 ppm. Therefore, the lower AFC response in the high dose males was 

considered secondary to systemic toxicity and thus does not reflect primary immunotoxic 

potential for sulfoxaflor.

The potential to recover from the effects induced by sulfoxaflor was demonstrated in male and 

female rats given 0 or 1500 ppm for 90 days, followed by control feed for 28 days. Nearly 

complete recovery was seen in body weights (only ~5% lower for both sexes). Feed 

consumption during the 28-day recovery period was comparable to controls in both sexes. Also, 

the serum cholesterol levels that were elevated during the 90-day study in both males and 

females were normal following the 28-day recovery period and a complete recovery was seen in 

the absolute and relative liver weights of males and females given 1500 ppm. 

There was partial recovery of the microscopic hepatic effects. Two male rats in the 1500 ppm 

group still had recognizable hepatocellular hypertrophy of a very slight degree in the 

centrilobular and midzonal regions. One of these two rats also had multifocal, very slight 

individual hepatocellular necrosis. Multifocal, very slight or slight, hepatocellular vacuolization 

consistent with fatty change was present in most of the recovery males; however, the degree of 

involvement was substantially less severe in the recovery group. There were no microscopic 

treatment-related changes present in the liver in females given 1500 ppm. 

Toxicokinetic analysis of the plasma showed that the systemic exposure of sulfoxaflor was dose 

proportional. An ~8-fold increase in AUC24h was found between 100 and 750 ppm groups and a ~2-

fold increase between 750 and 1500 ppm doses. Females were more efficient at eliminating the test 

material from their system than males. The 24-hour systemic dose as measured by the plasma 

AUC24h was 15, 16 and 14 percent lower in females than males at 100, 750 and 1500 ppm nominal 

dose groups, respectively. Plasma elimination half-life of sulfoxaflor in male rats was ~9 hours; 

whereas, it was ~8 hours in females (12% lower). The chromatograms of the plasma samples taken 

from sulfoxaflor dosed rats (via diet) contained up to 5 minor peaks in addition to the parent 

compound. These peaks may represent metabolites of the test material or metabolites of test 

material impurities. Absolute quantitation of the minor metabolites could not be made, due to lack 

of reference standards. Elimination of sulfoxaflor in urine over 24 hours ranged between 51 and 

61% of the ingested dose, with the exception of high dose in males which was 37% of the ingested 
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dose, 26 days after the initiation of the study. Elimination of test material in 0-24 hr urine on days 

84 and 85 ranged between 52-69% for the lower two dose levels, but was somewhat lower at the 

high dose for both sexes (32-36% of ingested dose). In addition to parent sulfoxaflor, four urinary 

metabolites were detected. One peak was a known impurity in this lot of the test material. No 

definitive quantitation of the other three metabolites was obtained. 

In conclusion, during the first few days of the study decreased feed consumption and body weight 

gain was observed at all dose levels. Subsequently feed consumption and body weight gain 

returned to normal in the 100 ppm group. There were no other observations noted in the 

parameters evaluated at this dose level. At 750 ppm and 1500 ppm the primary toxicologically 

significant findings were increased serum cholesterol levels, increased liver weight and 

histopathological findings in the liver. All of the effects due to ingestion of the test material had 

recovered during the 28-day recovery phase, except minor histopathologic liver effects noted only 

in males given 1500 ppm.

The lowest-observed-adverse-effect level (LOAEL) for systemic toxicity is based on the 

observation of decreased body weight, elevated cholesterol levels, hepatoxicity (increased weight, 

hypertrophy, necrosis, and vacuolization) at 750 ppm (47.6 mg/kg/day). The no-observed-adverseeffect-level (NOAEL) is 100 ppm (6.36 mg/kg/day). 

There were no indications of neurotoxicity at any dose level, therefore, a LOAEL was not 

determined. The NOAEL is ≥ 1500 ppm (94.9 mg/kg/day) for neurotoxic effects.

There were no indication of immunotoxicity at any dose level, therefore, the LOAEL was not 

determined. The NOAEL is ≥ 1500 ppm (94.9 mg/kg/day) for immunotoxic effects.

This study is classified as fully reliable (acceptable/guideline) and satisfies the guideline 

requirement for a subchronic oral study (OPPTS 870.3100; OECD 408), subchronic 

neurotoxicity (OPPTS 870.6200; OECD 424), and immunotoxicity (OPPTS 870.7800) study in 

rats. 

870.3100 90-Day Oral Toxicity - Mouse

IIA 5.3.2/2 90-Day Dietary Toxicity Study in Crl:CD1(ICR) – Mice;

In a 90 day oral toxicity study (MRID 47832057, PMRA 1941277), groups of ten male and ten 

female CD-1 mice were fed diets supplying 0, 100, 750 or 1250 ppm and 0, 100, 1500, 3000 

ppm sulfoxaflor (purity 96.6%; Lot # E2198-17, TSN106108), respectively for at least 90 days. 

These concentrations supplied average doses of 0, 12.8, 98.0 or 166 mg/kg/day for males and 0, 

16.2, 247 or 489 mg/kg/day for females. Parameters evaluated were: daily cage-side 

observations, weekly detailed clinical observations, ophthalmic examinations, body weights, 

feed consumption, hematology, clinical chemistry, selected organ weights, and gross and 

histopathologic examinations. In addition, toxicokinetic analyses were conducted on urine (day 

80) and terminal blood plasma. 

There were no treatment-related effects on clinical signs, ophthalmic parameters, body weights 

or feed consumption. 
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Toxicokinetic analysis of the plasma showed that dose-proportional intake of sulfoxaflor 

translated into a dose-proportional increase in plasma concentrations of sulfoxaflor only up to 

the mid dose for both male (750 ppm, 92 mg/kg/day) and female (1500 ppm, 227 mg/kg/day) 

mice. In males, the systemic exposure, as measured by the plasma concentration of sulfoxaflor, 

became supra-linear between the mid (92 mg/kg/day) and high (152 mg/kg/day) doses (3.9-fold 

increase instead of 1.6-fold expected from the difference in the test material intake between the 

mid and high doses). Plasma concentrations of sulfoxaflor in females reached a plateau, 

remaining almost unchanged between the mid (227 mg/kg/day) and the high (467 mg/kg/day) 

doses. Total elimination of sulfoxaflor in 24-hour urine remained dose-proportional only up to 

the mid dose and showed less than dose-proportional increase at the highest dose, both in male 

and female mice. These data are consistent with a saturation of elimination of sulfoxaflor in 

male mice at the highest dose and a saturation of absorption of sulfoxaflor from the 

gastrointestinal tract in female mice at the highest dose. On the basis of these results, the 

kinetically-derived maximum dose (KMD) i.e., the dose above which kinetics become nonlinear was considered to be 92 (750 ppm) and 227 (1500 ppm) mg/kg/day for male and female 

mice, respectively.

Males given 750 or 1250 ppm and females given 1500 or 3000 ppm had treatment-related 

increases in absolute (20% and 74%; 36% and 54%, respectively) and relative liver weights 

(26% and 85%; 40% and 50%, respectively) compared to controls. Treatment-related organ 

weight changes consisted of increased absolute and relative adrenal weights in males given 1250 

ppm, and lower absolute kidney weights in males given 750 or 1250 ppm. The lower kidney 

weights were however, considered non-adverse. Males given 1250 ppm had a treatment-related 

200% increase in serum alanine aminotransferase (ALT), 43% increase in aspartate 

aminotransferase (AST) and 142% increase in alkaline phosphatase (ALP) activities. Serum 

total cholesterol and total bilirubin concentrations were decreased in males given 750 and 1250 

ppm, and were attributed to treatment. Females given 1500 or 3000 ppm had treatment-related 

elevations in serum ALT (125% and 171% increase, respectively) and AST activities (44% and 

31% increase, respectively), and decreased ALP activity (3000 ppm only) compared to controls. 

Serum triglycerides were elevated in females given 1500 or 3000 ppm and serum cholesterol 

concentration was elevated in females given 3000 ppm, and attributed to treatment. There was a 

minor, treatment-related reduction in hematocrit and hemoglobin concentration in females given 

1500 or 3000 ppm.

Males given 750 or 1250 ppm had slight or moderate, and females given 1500 or 3000 ppm had 

very slight, slight or moderate, treatment-related, centrilobular to midzonal hepatocyte 

hypertrophy with altered tinctorial properties. Other treatment-related histologic liver effects 

consisted of an overall, very slight or slight increase in the numbers of mitotic figures 

(hepatocytes in mitosis) in the liver of males given 1250 ppm, and very slight or slight fatty 

change in hepatocytes of males given 750 or 1250 ppm. Males given 750 or 1250 ppm had 

treatment-related, very slight or slight necrosis of scattered, individual hepatocytes, whereas this 

change in females given 1500 or 3000 ppm was infrequent or minimal. Males given 750 or 

1250 ppm and females given 1500 or 3000 ppm had treatment-related, very slight hypertrophy of 

the zona fasciculata of the adrenal cortex. A very slight, treatment-related fatty change was also 

present in the zona fasciculata of the adrenal cortex in some females given 1500 or 3000 ppm. 
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Four out of ten females given 3000 ppm had very slight, treatment-related increase in 

extramedullary erythrocytic hematopoiesis in the spleen.

The No-Observed-Adverse-Effect Level (NOAEL) for males and females is 100 ppm (13 and 16 

mg/kg/day, respectively). The Lowest-Observed-Adverse-Effect-Level (LOAEL) for males is 

750 ppm (98 mg/kg/day), based on increased liver weights and hypertrophy, liver histopathology 

(necrosis/fatty change), increased cholesterol and bilirubin, and adrenal hypertrophy. At 1250 

mg/kg/day (169 mg/kg/day), the same effects were observed, along with increased liver enzymes 

(ALT, AST, ALP), mitotic figures (hepatocytes), and increased adrenal weights. 

The LOAEL in females is 1500 ppm (247 mg/kg/day), based on increased liver weights, liver 

hypertrophy, increased liver enzymes (ALT, AST), increased triglycerides, decreased 

hemoglobin and hematocrit, and adrenal changes (hypertrophy and fatty change/vacuolization). 

At 3000 mg/kg/day (489 mg/kg/day), the same effects were observed, along with decreased 

ALP, increased cholesterol, and hematopoiesis in the spleen. The toxicokinetics data indicates 

that there is a saturation of absorption from the intestinal tract at 1500 ppm in females and a 

maximal excretory level at 750 ppm in males.

This study is fully reliable (US EPA Acceptable/Guideline). The subchronic toxicity study in the 

mice satisfies the guideline requirement for a subchronic oral study (OPPTS 870.3100; OECD 

408) in mice. 

870.3150 90-Day Oral Toxicity – Dog

IIA 5.3.3/1 90-Day Oral Gavage Toxicity Study in Beagle Dogs;

In a 90 day oral dog study (MRID 47832058), sulfoxaflor (XDE-208 technical, 95.6% a.i., lot 

no. E2162-34) was administered by gavage to 4 beagle dogs/sex/dose at dose levels of 0 (vehicle 

only), 1, 3 or 10 mg/kg/day. The 10 mg/kg/day dose level was reduced to 6 mg/kg/day on Day 5 

of the study due to intolerance (lack of food consumption). Controls received the vehicle, 0.5% 

methylcellulose (Methocel A4C) in water. The test material or vehicle was given once a day for 

90 consecutive days, at a dose volume of 10 mL/kg.

Observations for morbidity, mortality, injury, availability of food and water were conducted 

twice daily. Clinical observations were recorded weekly. Food consumption was measured 

daily from Days 1 to 7 and 9 to 35, twice weekly from Week 6 to 12, and once during Week 13. 

Blood and urine samples were collected from all animals pretest and during Weeks 6 and 13. 

Blood and urine samples were collected from all animals at intervals during Week 13 for plasma 

and urine concentrations of the test material. At termination, necropsies were performed, organ 

weights recorded, and selected tissues were microscopically examined.

All animals survived the study and there were no treatment-related clinical signs. Treatmentrelated decreased mean body weights were observed at the high dose level of 10 mg/kg/day in 

both sexes, primarily during the first week of exposure. However, mean body weights at this 

exposure level did not have any significant decreases beyond Week 2, after the dose was reduced 

to 6 mg/kg/day on Day 5. By approximately Week 9, the mean body weights at this exposure 

level had returned to pre-exposure values. The transient nature of the decreased mean body 
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weights was a clear indication that the effect was related to exposure at 10 mg/kg/day and not 

related to exposure at 6 mg/kg/day. 

Sulfoxaflor at 10 mg/kg/day was not tolerated, as determined by significant and unacceptable 

decreases in food consumption. However, reduction to 6 mg/kg/day after 5 days allowed for 

food consumption in the affected group comparable to controls for the remainder of the study. 

Treatment-related, decreased food consumption values at the high dose were observed in males 

and females during the first 2 weeks of the study. By Week 3, the mean food consumption values 

had stabilized and were similar to control values with males appearing to recover slightly sooner 

than females. Based on the data, the effect on food consumption was considered to be related to 

exposure at 10 mg/kg/day, with residual effects prolonging the instability in several animals into 

Week 3 of the study. There were no other notable food consumption findings related to intake of 

the test material for the remainder of the study. There were no other parameters under evaluation 

that showed treatment-related effects.

In Week 13, the steady-state systemic dose (AUC24 h) of sulfoxaflor to dogs after doses of 1, 3, 6 

mg/kg/day was 32 ± 6, 84 ± 23 and 147 ± 13 μg*h/ml in males and 22 ± 3, 71 ± 26 and 119 ± 19 

μg*h/ml in females, respectively. The increase in systemic dose was dose-proportional in female 

dogs and was approximately dose proportional in male dogs across all three dose levels. The 

dose-corrected AUC24 after oral gavage to dogs was 3- to 4-fold higher than that observed in 

dogs after 28 days of oral gavage and 3 to 5-fold higher than that observed in rats after 90 days 

of dietary exposure. Urinary elimination of sulfoxaflor was 70 ± 6, 76 ± 12, and 59 ± 33 percent 

of administered dose in male and 69 ± 4, 80 ± 6, and 74 ± 13 percent in female dogs at 1, 3, and 

6 mg/kg/day doses, respectively. The mean plasma elimination half-life of XDE-208 in Week 13 

of dosing was between 17 and 28 hours. 

The LOAEL is 10 mg/kg/day, based on excessively reduced food consumption and body weight 

loss prior to reduction of the dose on Day 5. The NOAEL is 6 mg/kg/day. 

This study is classified Fully Reliable (Acceptable/Guideline) and satisfies the guideline 

requirement for a subchronic oral toxicity (oral gavage) - Beagle dogs (OPPTS 870.3150 

(nonrodent); OECD 409; EEC Part B.27; JMAFF Subchronic Oral Toxicity Study). 

IIA 5.8.1.3/5 X11719474: A 90-Day Oral Gavage Toxicity Study In Male Beagle Dogs;

This study (MRID 47832037) was conducted for The Dow Chemical Company on behalf of 

Dow ArgoSciences, LLC., to act as a bridging study from the parent compound, sulfoxaflor, for 

which a full guideline compliant 90-day oral toxicity study in dogs was conducted. This study 

was required to enable a valid comparison of toxicity to be made between the test material, 

X11719474, and the parent compound using the minimum number of animals. In this respect, 

the study was limited to a single sex, males. Three treatment groups of four male beagle dogs 

were administered the test material at respective dose levels of 10, 25, and 50 mg/kg/day. One 

additional group of four animals served as the control and received the vehicle, 

0.5% Methylcellulose (Methocel A4C) in reverse osmosis water. The vehicle and test material 

were administered to all groups via oral gavage, once a day for 90 consecutive days, at a dose 

volume of 10 mL/kg/dose. 

Observations for morbidity, mortality, injury, and the availability of food and water were 

conducted twice daily for all animals. Clinical observations were conducted and body weights 
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were measured and recorded weekly. Food consumption was measured and recorded weekly 

beginning with Week -1. Physical examinations were conducted by a veterinarian pretest to 

confirm good-health status of each animal placed on study. Blood and urine samples for clinical 

pathology evaluations were collected from all animals pretest and during Weeks 6 and 13. Blood 

samples for determination of the plasma concentrations of the test article were collected from all 

animals at 0.5, 2, 4, 24 hours postdose and once during Week 13. At study termination, necropsy 

examinations were performed, organ weights were recorded, and tissues were collected for 

microscopic examination.

No treatment-related effects were noted during clinical examinations and no early deaths 

occurred. Body weight, food consumption, and clinical pathology parameters were unaffected 

by treatment with X11719474. There were no treatment-related histopathologic effects at any 

dose concentration. Toxicokinetic analysis of plasma after 13 weeks of oral gavage 

administration of sulfoxaflor metabolite X11719474 to male dogs showed that the systemic 

exposure of sulfoxaflor metabolite X11719474 (AUC24hr) was proportional across all dose levels. 

The mean plasma elimination half-lives of sulfoxaflor metabolite X11719474 were 8.4 ± 2.4 

hours, 7.8 ± 1.0 hours, and 7.7 ± 1.1 hours from dogs of the 10, 25, and 50 mg/kg/day dose 

groups, respectively.

In summary, X11719474 administered orally at doses up to 50 mg/kg/day for 90 days was well 

tolerated by male beagle dogs. There were no treatment-related histopathologic effects at any 

dose concentration. The no-observed-adverse-effect level (NOAEL) is 50 mg/kg/day. A lowestobserved-adverse-effect-level (LOAEL) was not identified.

This study was conducted using the following guidance, but it does not meet the specific criteria 

of using both sexes of Beagle dogs (OPPTS 870.3150 (nonrodent); OECD 409; EEC Part B.27; 

JMAFF Subchronic Oral Toxicity Study; Acceptable/Non-Guideline). 

870.3200 21/28-Day Dermal Toxicity – Rat

IIA 5.3.7/1 28-Day Dermal Toxicity Study in Rats;

In a repeated-dose dermal toxicity study (MRID 47832059), sulfoxaflor (XDE-208 technical 

grade, 95.6% a.i., lot no. E2162-34, TSN003725-0001) in 0.5% methylcellulose was applied 

dermally to 10 Fischer DuCrl 344 rats/sex/dose, exposed at a semi-occluded, shaved skin test site 

to 0, 100, 500 or 1000 mg/kg body weight/day for six hours per day for 28 consecutive days. 

Parameters evaluated were daily cage-side and weekly detailed clinical observations, dermal 

observations, ophthalmic examinations, body weight, feed consumption, hematology, clinical 

chemistry, urinalysis, toxicokinetics of blood plasma, selected organ weights, and gross and 

histopathologic examinations.

Systemic toxicity: At 1000 mg/kg/day, males showed marginal increases in absolute and relative 

liver weights (6.5% and 4.4%, respectively above controls, p<0.05). A treatment-related 

histopathologic change was observed in the livers of 6 of 10 males, consisting of very slight 

hepatocyte hypertrophy, with altered tinctorial properties (increased cytoplasmic eosinophilia), 

involving the centrilobular/midzonal regions of the hepatic lobule. These were minor changes, 

not associated with increases in liver enzymes in the blood and hence, considered adaptive and 

non-adverse. Recent mechanistic studies have demonstrated a phenobarbital-like mode of action 

for sulfoxaflor-induced liver effects. Mean serum cholesterol was 17% higher compared to 
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controls. This effect was considered treatment related but non-adverse. Toxicokinetic analysis 

showed that the average plasma concentration of test material at high dose (1000 mg/kg/day) was 

greater than dose proportional. Similar plasma concentrations were found prior to and 16 hr after 

test material removal, indicating some retention of test material at the application site. There 

were no treatment-related systemic effects observed in females at any dose. The NOAEL for 

systemic toxicity is 1000 mg/kg/day (mild liver effects observed in males indicated some dermal 

absorption, but were not considered adverse). A LOAEL for systemic toxicity was not 

determined (>1000 mg/kg/day).

Local dermal toxicity: There were no treatment-related gross or microscopic dermal effects at 

the application site. The NOAEL for local dermal toxicity is 1000 mg/kg/day. A LOAEL for 

local dermal toxicity was not determined (>1000 mg/kg/day).

This dermal toxicity study in the rat is classified as Fully Reliable (acceptable/guideline) and 

satisfies the guideline requirement for a repeat-dose dermal toxicity study (OPPTS 870.3200; 

OECD 410) in rats. 

870.3465 90-Day Inhalation – Rat

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study – Rat

IIA 5.6.10/2 Prenatal Developmental Study in Rats;

In a prenatal developmental study (MRID 47832140), groups of 26 time-mated female 

Crl:CD(SD) rats were administered diets containing 0, 25, 150, or 1000 ppm sulfoxaflor (Purity 

95.6%; Lot # E2162-34) on gestation day (GD) 6 through 21 corresponding to time-weighted 

average doses of 0, 1.95, 11.5, or 70.2 mg/kg/day, respectively, in order to evaluate the potential 

maternal and developmental toxicity of this compound. In-life maternal study parameters 

included clinical observations, body weight, body weight gain, and feed consumption. On GD 

21, all rats were euthanized and each dam and fetus was examined for gross pathologic 

alterations. In addition, blood was collected from dams and fetuses to determine blood levels of 

the test material. Liver, kidneys and gravid uterine weights were recorded, along with the 

number of corpora lutea, uterine implantations, resorptions and live/dead fetuses. All fetuses 

were weighed, sexed and examined for external alterations. Approximately one half of the 

fetuses were examined for visceral and craniofacial alterations, while skeletal examinations were 

conducted on the remaining fetuses.

Administration of 1000 ppm sulfoxaflor in rodent feed resulted in maternal and developmental 

toxicity. Maternal toxicity was evidenced by decreases in body weight and body weight gains, 

relative to controls, with concomitant decreased feed consumption, throughout the treatment 

period, and increased relative liver weights. Developmental toxicity was evidenced by decreases 

in fetal body weight and gravid uterine weight. In addition, clear increases in several fetal 

abnormalities (forelimb flexure, bent clavicle, hindlimb rotation, convoluted ureter, and 

hydroureter) occurred, which have subsequently been shown to reverse by postnatal day four. 

The terminal plasma concentrations of sulfoxaflor in both dam and fetal blood were dose-
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proportional throughout the entire range of dietary exposure concentrations with similar levels 

between the maternal and fetal blood compartments. Administration of 150 or 25 ppm 

sulfoxaflor in rodent feed produced no treatment-related maternal toxicity and no indications of 

embryo/fetal toxicity or teratogenicity. 

The LOAEL is 1000 ppm (70.2 mg/kg bw/day) for developmental toxicity based on increased 

resorption, increased postimplantation loss, decreased number of viable fetuses/litter, decreased 

fetal weights, convoluted ureter and hydroureter, forelimb flexure and hindlimb rotation, and 

skeletal alterations including bent clavicles. The NOAEL is 150 ppm (11.5 mg/kg bw/day).

The developmental toxicity study in the rat is classified as Fully Reliable (acceptable/guideline) 

and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; 

OECD 414) in rats.

IIA 5.8.1.6/2 X11719474: Dietary Developmental Toxicity Study in CRL:CD(SD) Rats;

In a dietary developmental toxicity study (MRID 47832087), groups of 26 time-mated female 

CD rats were given the sulfoxaflor metabolite X11719474 (purity 95.5% a.i. wt/wt, Lot # E2695-

1, TSN030626-0003) in feed at concentrations of 0, 1000, 2000, or 5000 ppm on gestation days 

(GD) 6 through 21, which corresponded to time-weighted average doses of 0, 74, 152, or 368 

mg/kg/day, in order to evaluate the maternal and developmental toxicity potential of this 

compound. 

Treatment-related effects were limited to a transient decrease in body weight gain in the 5000 

ppm group at the initiation of treatment, with a concomitant decrease in feed consumption. This 

finding was deemed of no toxicological significance as it was minor in nature, isolated to the 

first three days of treatment, and likely due to decreased palatability of the diet. There was no 

treatment-related maternal toxicity at 1000 or 2000 ppm. There was no treatment-related organ 

weight or gross pathologic findings at any tested dose level. Toxicokinetic analyses of dam and 

fetal plasma X11719474 concentrations revealed dose proportionality across all groups and 

concentrations that were similar in dams and fetuses from the same groups. There was no 

evidence of developmental toxicity at any dose level tested in this study. 

There was no indication of maternal or developmental toxicity at the highest dose tested and 

therefore a no-observed-adverse-effect-level (LOAEL) was not identified. The no-observedadverse-effect level (NOAEL) for maternal and developmental toxicity was 5000 ppm (368 

mg/kg/day).

The developmental toxicity study in the rat is classified as fully reliable (acceptable/guideline)

and satisfies the guideline requirement for a Prenatal Developmental Toxicity Study (OPPTS 

870.3700; OECD 414) in rats.

870.3700b Prenatal Developmental Toxicity Study – Rabbit

IIA 5.6.11/3 Prenatal Developmental Study – Rabbit;

In a dietary developmental toxicity study (MRID 47832066), groups of 26 time-mated female 

rabbits were administered sulfoxaflor (purity 95.6% a.i. wt/wt, Lot # E2162-34, TSN003725-
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001) at dietary concentrations of 0, 30, 150, or 750 ppm, which corresponded to time-weighted 

average doses of 0, 1.3, 6.6, or 31.9 mg/kg/day, on gestation days (GD) 7-28. In-life parameters 

evaluated for all rabbits included: clinical observations, body weight, body weight gain, and 

feed consumption. Maternal blood was collected for sulfoxaflor analysis from four rabbits/group 

over a 24-hour period starting on the morning of GD 27, and also at termination on GD 28. Fetal 

umbilical cord blood was also taken at termination. All rabbits surviving to GD 28 were 

euthanized and examined for gross pathologic alterations and changes in liver, kidney, and 

gravid uterine weight. The number of corpora lutea, uterine implantations, resorptions, and 

live/dead fetuses were determined. All fetuses were weighed, sexed, and examined for external 

and visceral alterations. Also, the heads were examined for craniofacial alterations by serial 

sectioning in approximately one half of the fetuses in each litter, while skeletal examinations 

were performed on all fetuses.

Animals in the 750 ppm dose group exhibited treatment-related maternal toxicity in the form of 

decreased feces in 7 of 26 animals, decreased mean body weight gain (55%) from GD 7-13, 

decreased mean body weight gain (12%) throughout treatment (GD 7-28), and decreased mean 

feed consumption (8-21%) from GD 7-17. There was no treatment-related maternal toxicity for 

animals in the 30 or 150 ppm dose groups. There was no treatment-related developmental 

toxicity in any dose group.

The daily systemic dose of sulfoxaflor on GD 27-28 was dose-proportional as indicated by the 

near identical mean dose-corrected AUC24 h values of 18, 19, and 19 μg sulfoxaflor /h/kg-1 for 

animals given 30, 150, and 750 ppm, respectively. Levels of sulfoxaflor in maternal and fetal 

blood were similar. The daily systemic dose in this dietary study was similar to that measured in 

prior gavage studies with sulfoxaflor. 

The maternal lowest-adverse-effect-level observed in this study was 750 ppm (31.9 mg/kg/day) 

based on decreased body weight and body weight gain. The no-observed-adverse-effect-level 

was 150 ppm (6.6 mg/kg/day). There was no treatment- related developmental toxicity;

therefore the developmental NOAEL was > 750 ppm (31.9 mg/kg/day).

This study is fully reliable (Acceptable/Guideline) and fulfills the guideline requirements for a 

prenatal developmental study in rabbits (OPPTS 870.3700, OECD 414 Test Guideline). 

IIA 5.6.12/1 A Dietary Reproductive Toxicity Cross-Fostering Study in Crl:CD(SD) Rats;

In a non-guideline cross-fostering dietary developmental toxicity study (MRID 47832063), 

groups of female Crl:CD(SD) rats (n=16) were administered sulfoxaflor (purity 95.6% wt/wt, 

Lot # E2162-34, TSN003725-001) at dietary concentrations of 0 or 1000 ppm. The purpose of 

this study was to determine whether the previously observed decreased survival of pups born to 

sulfoxaflor-treated dams resulted from in utero and/or lactational exposure. As part of this study, 

effects on general toxicity, toxicokinetic analysis of blood and milk, reproductive function and 

prenatal/early neonatal growth and survival were assessed. 

Groups of female Crl:CD(SD) rats were fed diets supplying 0 (control) or 1000 ppm sulfoxaflor 

for two weeks prior to mating through weaning on lactation day (LD) 21. As the control and 

treated females mated, they were subdivided into Foster dams and Donor dams. Cesarean-
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section was performed on gestation day (GD) 21 Donor dams, at which time, one or more 

batches of two of their offspring/sex were immediately cross-fostered to a Foster dam(s) that had 

their own litter removed that day (i.e., on LD 0). After cross-fostering was complete, each 

control and sulfoxaflor-treated Foster dam had mixed litters comprised of two pups/sex that 

originated from control Donor dams (five litters) and two pups/sex that originated from 

sulfoxaflor-treated Donor dams (eight litters). This design controlled for litter of origin effects, 

and enabled comparison of the survival of pups exposed to sulfoxaflor during gestation alone or 

during lactation alone with unexposed control pups and pups exposed during both gestation and 

lactation. 

Dams given 1000 ppm sulfoxaflor had treatment-related effects on body weight, body weight 

gain, and feed consumption consistent with effects seen at this dose level in the previous 

reproduction/developmental toxicity screening study (MRID 47832143). Time weighted average 

doses for treated animals were 81.2, 74.5, and 59.5 mg/kg/day in the pre-mating, gestation, and 

lactation periods, respectively. These corresponded to maternal sulfoxaflor blood concentrations 

of 23.0-29.3 μg/g plasma on GD 21 and 19.6-25.0 μg/g plasma on LD 0. The average measured 

plasma concentration of sulfoxaflor of male/female pups on GD 21 and LD 0 from these dams 

was 24.8/24.8 and 25.3/25.9 μg sulfoxaflor /g plasma, respectively. Thus, fetal and pup plasma 

levels of sulfoxaflor were very similar to one another, and very similar to dam plasma levels. 

The measured milk concentrations from the same dams on LD 0 were approximately half the 

corresponding plasma levels and ranged from 12.3-14.0 μg sulfoxaflor /g milk (mean = 13.3 

μg/g).

All offspring from dams exposed to 1000 ppm sulfoxaflor prior to birth died by postnatal day 

(PND) 4, irrespective of whether they were cross-fostered to control- or treated-foster dams (see 

results Table 1 below). Consistent with reduced viability, some offspring were cold to the touch, 

had bluish skin, autolyzed and cannibalized, and stomach void of milk. Conversely, there was 

no effect on neonatal survival for pups exposed to sulfoxaflor only after birth. Furthermore, 

PND 1 pup body weights were significantly decreased in prenatally exposed offspring. 

In conclusion, these data demonstrate that the effect of sulfoxaflor on pup survival was due to in 

utero, not lactational, exposure.

This cross-fostering study in the rat is classified as Fully Reliable (acceptable/non-guideline).

IIA 5.6.12/2 A Study of the Effect of Sulfoxaflor on Neonatal Survival in New Zealand 

White Rabbits;

In a non-guideline study (MRID 47832138), sulfoxaflor (purity 95.6%; Lot # E2162-34) , was 

offered on a continuous basis in the diet (with 0.5% apple flavoring) to a group of 12 litterexperienced, time-mated female New Zealand White [Hra:(NZW)SPF] rabbits from gestation 

day (GD) 7 through the initiation of parturition (25-26 consecutive days). Actual test material 

intake in the 750 ppm group was 29 mg/kg/day during GD 7-28. A concurrent control group of 

12 time-mated females received the apple-flavored control diet on a comparable regimen. 
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With the exception of one F0 female in the control and 750 ppm groups euthanized on LD 3 due 

to total litter loss, all females survived to the scheduled necropsies. No test substance-related 

maternal macroscopic findings were noted.

Lower mean body weight gains (24.2%) and food consumption (7.3%) were noted in the 

750 ppm group during the gestation exposure period compared to the control group. 

Corresponding incidences of decreased defecation were noted for three females in this group. 

Although mean body weights remained within 2.9% of control group values throughout

gestation, the reductions in mean body weight gains and food consumption were attributed to test 

substance exposure. Mean body weights, body weight gains, and food consumption in the 750 

ppm group were similar to the control group during LD 1-4.

No test substance-related effects were observed on the mean number of offspring born, offspring 

survival, or the general physical condition of the offspring.

When sulfoxaflor was continuously in the diet from GD 7 through the initiation of parturition to 

pregnant New Zealand White rabbits, there was no indication of maternal or developmental 

treatment-related toxicity; therefore the lowest-adverse-effect-level (LOAEL) was not 

determined. The no-adverse-effect-level (NOAEL) is 750 ppm (29 mg/kg/day).

This study is Fully Reliable (acceptable/non-guideline)

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat

IIA 5.6.1/1 Dietary Reproduction/Developmental Toxicity Screening Test in Crl:CD(SD) 

Rats;

In a reproduction/developmental toxicity screening study (MRID 47832143) sulfoxaflor (95.6% 

a.i. wt/wt, Lot # E2162-34, TSN003725-0001) was administered to Crl:CD (SD) rats 

(12/sex/dose group) at concentrations of 0, 100, 500 or 1000 ppm in the diet. These dose levels 

corresponded to time-weighted average doses for males of 0, 8.26, 40.7 or 79.1 mg/kg/day. The 

time weighted average doses for females during the various study phases ranged from 0, 8.12-

8.30, 39.5-44.1, and 78.2-81.6 mg/kg/day, respectively. Males were fed the test diets for two 

weeks prior to breeding and continuing throughout breeding until termination. The females were 

fed the test diets for two weeks prior to breeding, continuing through breeding (up to two weeks), 

gestation, lactation and weaning; pups were weaned on postnatal day 21. Effects on gonadal 

function, mating behavior, conception, development of the conceptus, parturition and postnatal 

growth and survival were evaluated. In addition, a gross necropsy and histopathological 

examination of the adults were conducted with an emphasis on organs of the reproductive 

system. In the offspring, litter size, pup survival, sex, body weight and the presence of gross 

external morphological alterations were assessed. 

Males in the 1000 and 500 ppm dose groups had a treatment-related decrease in food 

consumption and body weight (1000 ppm only) during the first week of treatment. Females in 

the 1000 and 500 ppm dose groups had treatment-related decreases in body weight gain during 
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the first week of gestation, and females in the 1000 ppm dose group had slightly lower food 

consumption during the pre-breeding and gestation phases. Body weight changes were minimal 

and not considered adverse.

Males of the 1000 and 500 ppm dose groups had increased absolute and relative liver weights that 

were dose and treatment related (liver weights for females at 1000 ppm were not recorded due to 

an effect on litter survival; there was no effect at 500 ppm). Treatment-related histological effects 

were observed in the livers of males given 1000 and 500 ppm and females given 1000 ppm and 

consisted of a dose-related increase in the severity of hepatocellular hypertrophy, with altered 

tinctorial properties, involving the centrilobular to midzonal regions of the hepatic lobule. 

Histological effects were very slight or slight severity in males and very slight in females. In 

addition, there was treatment-related multifocal hepatocyte vacuolization (slight severity) in 1000 

ppm females. These hepatic effects were minimal and not considered adverse.

There were no reproductive or developmental toxicity effects observed in any group up to PND 0 

(birth). Shortly after birth, there was a significant decrease in pup survival in the 1000 ppm dose 

group such that PND 1 survival was 46.3%, compared to 98.3% in controls. In addition, PND 1 

pup body weights were significantly decreased (22-25%) relative to controls. By PND 4, eleven 

of twelve dams had total litter loss resulting in 7.3% pup survival, compared to 95.4% in 

controls. Because only one of twelve litters remained, this dose group was terminated on PND 6. 

Pup survival was also affected in the 500 ppm group with 4 of 12 dams losing approximately 

half of their litters by PND 4, which resulted in a pup survival rate of 81.2% compared to 95.4% 

in controls. There were no effects on pup body weight in the 500 ppm group. There were no 

treatment-related effects on any other reproductive parameters at 1000 or 500 ppm, and no 

reproductive effects whatsoever at 100 ppm. 

The concentration of XDE-208 in pup and dam plasma was a dose proportionate from the 100, 

500, and 1000 ppm groups. Sulfoxaflor plasma levels in PND 4 pups were ≈35% of adult 

plasma concentrations. Individual (n = 3) concentrations of sulfoxaflor were equivalent in dam 

plasma and milk from dams of the 1000 ppm dose group.

The systemic LOAEL is 1000 (78.2 mg/kg/day) based on decreased pup body weight. The 

NOAEL is 500 ppm (39.5 mg/kg/day). 

The developmental LOAEL is 500 ppm (39.5 mg/kg/day) based on decreased pup survival. The 

NOAEL is 100 ppm (12.0 mg/kg/day).

This study is fully reliable (acceptable/guideline) and fully satisfies the guideline requirements 

for a reproduction/development screening study (OPPTS 870.3550; OECD 421) in rats.

IIA 5.8.1.6/1 X11719474: Dietary Reproduction/Developmental Toxicity Screening Test in 

CRL:CD(SD) Rats;

Groups of 12 male and 12 female Crl:CD(SD) rats were administered the sulfoxaflor metabolite 

X11719474 via the diet at concentrations supplying 0, 1000, 2000, or 5000 ppm, which 

corresponded to time-weighted average doses of 0, 80.8, 162, or 396 mg/kg/day for males, and 

ranged from 0, 81.7-114, 167-212, and 451-507 mg/kg/day during the female pre-breeding, gestation 
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and lactation phases (MRID 47832094). Males were fed the test diets for two weeks prior to 

breeding and continuing through breeding (up to two weeks) up until necropsy (test day 39). 

Females were fed the test diets for two weeks prior to breeding, through breeding (up to two weeks), 

gestation and lactation up until necropsy on post-partum day 22-24. Effects on gonadal function, 

mating behavior, conception, development of the conceptus, parturition, and postnatal growth and 

survival were evaluated. In addition, a gross necropsy and histopathologic examination of the adults 

were conducted with an emphasis on organs of the reproductive system. Offspring were evaluated 

through postnatal day (PND) 21 for litter size, survival, sex, body weight and the presence of gross 

external morphological alterations. Plasma concentrations of X11719474 were measured in PND 4 

culled pups to demonstrate systemic exposure.

There were no treatment-related clinical findings or adverse effects on feed consumption at any dose 

level. Body weight and/or body weight gain in the 2000 and 5000 ppm groups were slightly lower 

than controls during isolated gestation and lactation intervals. However, these findings were 

considered of no toxicological significance based on the lack of a dose-response relationship, the 

small magnitude of change, and lack of consistency across intervals. 

There was a treatment-related increase in the liver weights of males and females (15 and 7% increase 

in relative weight, respectively) in the 5000 ppm group. These findings corresponded with an 

increased incidence of very slight centrilobular and midzonal hepatocellular hypertrophy in all males 

and the majority of females (10/12) in the 5000 ppm group. There were no treatment-related organ 

weight or pathologic effects in the 1000 and 2000 ppm groups of either sex. Toxicokinetic data 

demonstrated dose-proportional systemic exposure in PND 4 pups. 

There were no treatment-related effects on reproductive endpoints or development of the offspring at 

any dose level.

There was no indication of maternal toxicity at the highest dose tested of 5000 ppm (396 mg/kg/day) 

and therefore a lowest-observed-adverse-effect-level (LOAEL) was not identified. The noobserved-adverse-effect-level (NOAEL) for maternal toxicity was 5000 ppm (396 mg/kg/day). 

There was no indication of reproductive or developmental toxicity at the highest dose tested of 5000 

ppm (396 mg/kg/day) and therefore a LOAEL was not identified. The reproductive and 

developmental NOAEL was 5000 ppm (396 mg/kg/day). 

This study is fully reliable (acceptable/guideline) and satisfies the guideline requirements for a 

dietary screening reproduction/developmental study in rats (OPPTS 870.3550; OECD 421).

IIA 5.6.1/2 Reproduction and Fertility Effects – Rats;

In a two-generation dietary reproduction toxicity study (MRID 47832142) sulfoxaflor (95.6% a.i. 

wt/wt, Lot # E2162-34, TSN003725-0001) was administered to Crl:CD (SD) rats (27/sex/dose 

group) at concentrations of 0, 25, 100 or 400 ppm in the diet for approximately ten weeks prior to 

breeding, and continuing through breeding, gestation and lactation for two generations. In-life 

parameters included clinical observations, feed consumption, body weights, estrous cyclicity, 

reproductive performance, pup survival, pup body weights, puberty onset and anogenital distance. 

In addition, post-mortem evaluations included gross pathology and organ weights in weanlings, 

toxicokinetic analyses, gross pathology, organ weights, oocyte quantitation and sperm count, 

motility and morphology, and histopathology, in adults.
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Parental toxicity at 400 ppm consisted of increased absolute and relative liver weights in the P1 

(12.8 and 10.9%, respectively) and P2 (6.5 and 7.8%, respectively) males. This effect on liver 

weight correlated with histopathological findings of very slight to slight centrilobular hepatocyte 

hypertrophy, often with a very slight increase in individual cell necrosis of centrilobular 

hepatocytes. No other systemic effects were noted at 400 ppm, and there were no treatmentrelated effects on P1 or P2 parameters in male or female rats at 25 or 100 ppm.

Offspring effects were limited to 400 ppm and comprised slightly decreased neonatal survival in 

both generations; this in turn led to a lower percentage of live pups up to culling on PND 4. In 

addition, there was an apparent treatment-related delay in preputial separation (PPS) for 400 ppm 

F1 males. This external marker of male puberty onset is androgen dependent, but the underlying 

reason for how sulfoxaflor induced this finding is not known; however, there were no other 

indications of androgenic or anti-androgenic effects. This included no treatment-related effects 

on anogenital distance, no effects on testis or accessory sex gland (i.e., prostate, seminal vesicle, 

and epididymis) weight or histopathology, no evidence of malformations like hypospadias or 

ectopic testes, no effects on mating, fertility, time to mating, or gestation length, and no 

treatment-related effects on preputial separation at the same dose level in a developmental 

neurotoxicity study with sulfoxaflor. Taken together, the weight of evidence across androgensensitive endpoints led to the conclusion that the data do not support any other sulfoxaflor -

mediated anti-androgenic effects. There were no effects on puberty onset or any other parameter 

of reproductive performance or offspring growth and survival at 25 or 100 ppm. 

Toxicokinetic data from LD 4 dams and culled PND 4 pups in the second generation show doseproportional systemic exposure to sulfoxaflor in dams and their offspring. Plasma concentrations 

of sulfoxaflor in rat pups were, on average, 32% of the levels measured in the dams.

The lowest-observed-adverse-effect-level (LOAEL) for systemic toxicity was 400 ppm (24.6 

mg/kg/day) based on hepatic toxicity (increased weight, hypertrophy, and necrosis) in the P1 and 

P2 males. The no-observed-adverse-effect-level (NOAEL) was 100 ppm (6.07 mg/kg/day).

The reproductive LOAEL is established at 400 ppm (24.6 mg/kg/day) based on decreased 

neonatal survival (ca. 2-5%).

The offspring toxicity LOAEL is 400 ppm (24.6 mg/kg/day) based on decreased neonatal 

survival and delay in preputial separation in F1 females. The NOAEL is established at 100 ppm 

(6.07 mg/kg/day).

This study is classified as fully reliable (acceptable/guideline) and satisfies the guideline 

requirement (OPPTS 8700.3800; OECD 416) for a reproduction and fertility study.

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity – Rat
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IIA 5.5.1/1 Combined Chronic Toxicity/Oncogenicity Study in F344/DuCrl Rats test by 

the oral route in the rat;

In a combined chronic carcinogenicity study in rats (MRID 47832060), groups of 60 male and 60 

female F344/DuCrl rats were treated orally by dietary administration with sulfoxaflor (96.5%, 

Lot # E2162-34, TSN003725-0001) at dose levels of 0, 25, 100, 500 (males only) or 750 

(females only) ppm for up to two years. The time-weighted average dosages ingested, based 

upon mean feed consumption and body weight data for 24-months were 0, 1.04, 4.24 or 21.3 

mg/kg/day for males and 0, 1.28, 5.13 or 39.0 mg/kg/day for females. Ten rats/sex/dose level 

were necropsied after one year (chronic toxicity group) and the remaining 50 rats/sex/dose level 

were fed the respective diets for up to two years. 

Animals were evaluated by daily cage-side examinations, bi-weekly clinical observations, 

periodic detailed clinical observations, body weights, feed consumption and toxicokinetics 

(plasma and urine). Clinical pathology examinations (hematology, clinical chemistry, and 

urinalysis) were conducted at regular intervals throughout the study. Ophthalmic examinations 

were conducted on all rats prestudy, and all surviving rats prior to the scheduled necropsies. All 

rats had a complete necropsy, with weights of multiple organs collected from all rats at the 

scheduled necropsies. Histopathological examination of an extensive set of organs was 

performed on all control and high-dose level rats and all rats that died spontaneously or were 

euthanized due to their moribund condition. Histopathological examination of rats from the lowand intermediate-dose levels of the 12-month chronic toxicity group was limited to the liver, 

adrenal glands, testes and relevant gross lesions. Histopathological examination of survivors 

from the low- and intermediate-dose levels of the 24-month oncogenicity group was limited to 

the liver, testes, epididymides, coagulating glands, prostate, seminal vesicles and relevant gross 

lesions.

No treatment related mortality or clinical signs were observed after sulfoxaflor exposure. Males 

given 500 ppm had decreases in body weights at most measurement intervals starting on Day 

512 and continuing through Day 729. On Day 729, the mean body weight and body weight gain 

for males given 500 ppm were 5.0% and 5.7% lower than controls, respectively. The decreases 

were statistically significant and lower than historical control for most time points; therefore, 

they were considered treatment related. Females given 750 ppm had treatment-related, 

statistically significant decreases in body weights, first noted on Day 57, and continuing through 

Day 729. On Day 729, the mean body weight and body weight gain for females given 750 ppm 

were 6.3% and 9.1% lower than controls, respectively. The decreases were outside of the 

historical control range. The body weights of males and females given 100 or 25 ppm were 

unaffected by treatment with sulfoxaflor.

High-dose level males and females had treatment-related, statistically significant increases in

cholesterol concentrations at 3, 6 and 12 months, and 3, 6, 12 and 18 months, respectively, with 

increases ranging from 17.5 to 32.9%. 

The liver was the primary target organ for histopathologic effects for males given 500 ppm and 

females given 750 ppm at 12 and 24 months. The absolute and relative liver weights for highdose males (500 ppm) and females (750 ppm) were only increased at 12 months, in the range of 

3.2 to 17%. Non-neoplastic liver effects at 12 and 24 months consisted of hypertrophy of 
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centrilobular and midzonal hepatocytes, necrosis of individual centrilobular hepatocytes, 

vacuolization (females only) consistent with fatty change of hepatocytes, and an increase in the 

severity of aggregates of macrophages/histiocytes in both sexes at 500 and 750 ppm. An 

additional treatment-related liver effect in females given 750 ppm at 24 months consisted of a 

lower number of basophilic foci of altered hepatocytes. A treatment-related neoplastic liver 

effect at 24 months consisted of a statistically significant increase in the incidence of benign 

hepatocellular adenomas in males given 500 ppm. Females given 750 ppm did not have a 

treatment-related increase in the incidence of liver tumors. There were no treatment-related liver 

effects in males or females given 25 or 100 ppm. A phenobarbital (PB) like mode of action 

(MOA) has been postulated for sulfoxaflor induced rodent liver tumors and studies were 

conducted (MRID 47832062) with sulfoxaflor investigating the proposed MOA, including a 

study with dual CAR/PXR knockout mice. A formal framework analysis investigating the 

proposed MOA is available (MRID 48288939) and the data adequately supports a threshold 

based, mitogenic MOA for rodent liver tumors.

At 24 months, males given 100 or 500 ppm had statistically significant increases in absolute and 

relative testes weights, and statistically significant decreases in absolute and relative epididymal 

weights. Absolute testes weights of males given 100 or 500 ppm were approximately 46% and 

62% higher than controls, respectively. The higher testes weights were reflective of larger 

interstitial (Leydig) cell adenomas in the testes of males at these dose levels. 

The incidence of interstitial cell adenomas in at least one testis of males from all dose groups 

was comparable to controls at 24 months. However, males given 500 ppm had a statistically 

significant increase in the incidence of bilateral interstitial cell adenomas of the testes, and a 

corresponding decrease in the incidence of unilateral interstitial cell tumors, relative to controls. 

An additional testicular effect consisted of a statistically significant, increase in the incidence of 

severe bilateral atrophy of seminiferous tubules in males given 100 or 500 ppm. The 

seminiferous tubular atrophy was reflective of the generally larger interstitial cell adenomas in 

these dose groups. 

At 24 months, males given 100 or 500 ppm had statistically significant decreases in absolute and 

relative epididymal weights. The lower epididymal weights were associated with a higher 

incidence of decreased spermatic elements (bilateral, severe) in the lumen of the epididymides of 

these males.

Males given 500 ppm had statistically significant increases in the incidence of decreased 

secretory material in the coagulating glands (severe), prostate (moderate), and seminal vesicles 

(severe) at 24 months. Males given 500 ppm also had an increased incidence of carcinoma of the 

preputial gland. The primary effect was interpreted to be the interstitial cell adenomas, and the 

effects on seminiferous tubules, epididymides, accessory sex glands were considered secondary 

to loss of normal testicular function due to the size of the interstitial cell adenomas, and possible 

alterations in the endocrine balance of these rats. Although the mode of action (MOA) for the

effects on reproductive organ was not investigated as part of this study, MOA data for the 

interstitial cells were submitted separately (MRID 48288942). A similar (shared) MOA with 

interstitial cell adenomas was postulated for the increased incidence of preputial gland 
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carcinomas; however, the MOA remains unclear since the available data are not fully supportive 

of the proposed MOA. 

Toxicokinetic analyses of plasma samples at 3 and 12 months indicated dose proportionality in 

systemic dose levels that were comparable between the two time points. There were no gender 

differences in plasma concentrations of sulfoxaflor across the dose levels and times analyzed. 

Urinary elimination of sulfoxaflor was also dose proportional for both male and female rats at 3, 

6 and 12 months, representing 58-127% of the average test material consumed in a 24-hour 

period.

The no observed adverse effect level (NOAEL) is 100 ppm (4.24 mg/kg/day) and the lowest 

observed adverse effect level (LOAEL) is 500 ppm (21.3 mg/kg/day), based on increased serum 

cholesterol concentrations, and histopathological liver effects in males. 

Note: Although male reproductive effects were seen at doses lower than the determined NOAEL, 

the effects were considered secondary to the increased incidence of interstitial cell (Leydig Cell) 

tumors. The CARC determined that the increased incidence of interstitial cell tumors were not 

treatment related; therefore, the male reproductive effects (seen in the presence of the tumors) 

are also considered to be not treatment-related. In contrast, PMRA determined that the LOAEL 

is 100 ppm, based on the male reproductive effects.

This study is fully reliable (US EPA Acceptable/Guideline): GLP compliant and fully compliant 

with the combined chronic/carcinogenicity study in rats (OPPTS 870.4300); OECD 453:

870.4100b Chronic Toxicity – Dog

IIA 5.3.4 Oral 1-year Chronic Toxicity (Dog);

In a chronic oral toxicity study (MRID 48288906), four Beagle dogs/sex/dose were administered 

sulfoxaflor (XDE-208 technical, 99.7% a.i., lot no. E2162-34) at doses of 0, 1, 3 or 6 mg/kg/day 

for 52 weeks. Test material was administered by a daily gavage dose in 0.5% aqueous 

methylcellulose vehicle (Methocel A4C; dosing volume 10 mL/kg). Dietary or capsule 

administration was not performed due to unsatisfactory food consumption using these methods. 

Observations for morbidity, mortality, injury and the availability of food and water were 

conducted twice daily for all animals. Toxicity was assessed by weekly detailed clinical 

observations, food consumption and body weight measurements, ophthalmoscopic examinations, 

and clinical pathology evaluations. Blood and urine samples for determination of plasma 

concentrations of the test material were collected from all animals at Weeks 13, 26 and 52. 

Toxicokinetic (TK) parameters were determined for the test article from concentration-time data. 

At study termination, necropsy examinations were performed, select organ weights were 

recorded, and tissues were preserved for subsequent microscopic examination.

No treatment-related deaths occurred. The increased frequency of soft and/or watery feces in two 

males at 6 mg/kg/day was considered treatment-related due to the high incidence in these animals 

relative to other groups, but was not considered adverse because these findings had no effect on 

food consumption or body weight/weight gain. A transient, treatment-related decrease in food 

consumption and body weight was observed in females at 6 mg/kg/day during the first two weeks 
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of dosing. The decreases in food consumption and body weight were considered non-adverse 

findings due to their transient nature. No definitive effects on hematological or clinical pathology 

parameters were noted. The systemic exposure of sulfoxaflor (AUC24h) in plasma was 

proportional across all dose levels in both sexes. With the exception of females at 52 weeks of 

exposure (urine values of high dose females fell below the regression line fitted to the mean 

values), toxicokinetic analysis of parent in urine showed that the systemic exposure of sulfoxaflor 

(AUC24h) was proportional across all dose levels and time points. There were no treatment-related 

organ weight changes or gross/histopathologic effects at any dose. 

The NOAEL is 6 mg/kg/day (soft/watery feces in males and a transient decrease in food 

consumption and body weight in females during the initial two weeks were considered treatmentrelated, but not adverse). A LOAEL was not identified (> 6 mg/kg/day). 

This study is classified fully reliable (US EPA acceptable/non-guideline) and satisfies the 

guideline requirement for a chronic oral toxicity study in the dog (OPPTS 870.4100; OECD 452). 

A.4.5 Carcinogenicity

870.4200a Carcinogenicity Study – Rat (See 870.4100a (p. 106))

870.4200b Carcinogenicity (feeding) – Mouse

IIA 5.5.3/1 Carcinogenicity – Mice [feeding];

In a carcinogenicity study in mice (MRID 47832054, PMRA 1941285), groups of 50 male 

Crl:CD1(ICR) mice were treated orally, by dietary administration, with sulfoxaflor (purity 

95.6%, Lot # E2162-34, TSN003725-0001), at dose levels of 0, 25, 100, or 750 ppm for 18 

months ; groups of 50 female Crl:CD1(ICR) mice were similarly treated at dose levels of 0, 25, 

250, or 1250 ppm. These concentrations corresponded to time-weighted average doses of 0, 

2.54, 10.4 or 79.6 mg/kg/day for males, and 0, 3.43, 33.9, or 176 mg/kg/day for females, 

respectively.

Animals were evaluated by daily cage side, bi-weekly observations, periodic handheld detailed 

clinical examinations, body weights, and feed consumption. Ophthalmic examinations were 

conducted pre-exposure and prior to necropsy. All mice had a complete necropsy examination 

with total white blood cell (WBC) and differential WBC counts, and organ weight recording at 

the scheduled necropsy. An extensive set of organs was examined histopathologically from all 

control and high-dose group mice, as well as those that died or were euthanized in moribund 

condition. The kidneys, liver, lungs, adrenal glands (females only) and all relevant gross lesions 

from the low- and intermediate-dose groups from the terminal necropsy were also examined 

histopathologically. 

There were no treatment-related changes in clinical observations, body weights and body weight 

gains, feed consumption, ophthalmologic observations, or total and differential WBC counts in 

any of the sulfoxaflor treated groups.
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Toxicokinetic analysis indicated that the daily systemic dose (steady-state plasma concentration) 

of sulfoxaflor in male and female mice remained essentially proportional to dose during the 

course of the study (3 and 12 months after study start) and concentrations of sulfoxaflor in urine 

also increased proportionally with dose for both male and female mice, and at both collection 

times (3 and 12 months).

The liver was the primary target of sulfoxaflor. The absolute and relative liver weights of males 

given 750 ppm were increased 87 and 79% respectively; in females given 1250 ppm they were 

increased 51 and 47%, respectively as compared to controls. At necropsy, there was a treatmentrelated increase in the incidence of mass nodules and multifocal pale foci in the liver of males 

given 750 ppm. Females given 1250 ppm had a treatment-related increased incidence of mass 

nodules in the liver, albeit at lower numbers compared to the high-dose males (750ppm). 

Histopathologic treatment-related changes consisted of hepatocellular adenomas and/or 

carcinomas in 60% of male mice given 750 ppm and in 10% of female mice given 1250 ppm. 

Although there were no statistically significant differences in the overall mortality rates between 

the controls and any of the sulfoxaflor treated groups, hepatocellular carcinomas or adenomas 

were attributed as the cause of death or moribundity in a small proportion of males (6 of 50) 

given 750 ppm. Treatment-related non-neoplastic liver effects consisted of increases in the 

incidences of eosinophilic and vacuolated foci of cellular alteration in males given 750 ppm; 

slight to moderate centrilobular/midzonal or panlobular hepatocellular hypertrophy with altered 

tinctorial properties (increased cytoplasmic eosinophilia) consistent with liver enzyme induction 

in males and females given 750 or 1250 ppm; very slight or slight multifocal individual cell 

necrosis of hepatocytes in males given 750 ppm and females given 1250 ppm (very slight); very 

slight fatty change in centrilobular/midzonal hepatocytes in males and females given 750 or 1250 

ppm and increased incidence of hepatocytes in mitosis in males given 750 ppm. 

The only treatment-related change in females given 250 ppm was an increased incidence of 

slight centrilobular/midzonal hepatocyte hypertrophy with altered tinctorial properties (increased 

cytoplasmic eosinophilia) consistent with liver enzyme induction. This was considered to be an 

adaptive response and non-adverse per se due to a complete lack of any associated changes 

including increase in liver weight or any other treatment-related histopathologic findings. 

Males given 750 ppm had an exacerbation in the cumulative incidence of spontaneous dermatitis 

which is common in CD-1 mice. Histologically, these were characterized by subacute to chronic 

inflammation, variable epidermal ulceration and acanthosis. Associated with the ulcerative 

dermatitis was an increased incidence of reactive plasmacytosis of the local submandibular 

lymph nodes of males given 750 ppm. The exacerbation of spontaneous dermatitis in males 

given 750 ppm was interpreted to be secondary to the general unthriftiness of these mice due to 

the excessive stress induced by the malignant and/or benign hepatocellular neoplasms. In 

females, a non-statistically significant increase in lymphosarcoma was seen at the HDT of 1250 

ppm. 

A phenobarbital (PB) like mode of action (MoA) has been postulated for sulfoxaflor induced 

rodent liver tumors and several studies were conducted (MRID 47832062) with sulfoxaflor that 

investigate the proposed MoA, including a study with dual CAR/PXR knockout mice. 

Additionally, a formal framework analysis has been submitted (MRID 48288939). The 
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available toxicity data and the framework analysis will be used to evaluate the carcinogenic 

potential of sulfoxaflor. 

The no-observed-adverse-effect levels (NOAELs) for males and females are 100 (10.4 

mg/kg/day) and 250 ppm (33.9 mg/kg/day), respectively. The lowest-observed-adverse-effect 

level (LOAEL) for males is 750 ppm (79.6 mg/kg/day) and for females is 1250 ppm (176 

mg/kg/day), based on increased liver weights, increased incidence of liver nodules, liver 

hypertrophy, and liver histopathology (necrosis, fatty change). In males, liver foci (eosinophilic 

and vacuolated) and gross (dermatitis) and histopathological changes (chronic inflammation, 

epidermal ulceration, and acanthosis) in the skin were also seen. This was accompanied by 

reactive plasmacytosis of the local submandibular lymph nodes.

This study is fully reliable (US EPA Acceptable/Guideline): GLP compliant and fully compliant 

with the carcinogenicity study in mice (OPPTS870.4200); OECD 451 (US EPA 

Acceptable/Guideline). 

IIA 5.5.4/1 Ex vivo gene expression and cell proliferation analyses

The purpose of this study (MRID 47832033) was to obtain preliminary information on the 

potential mode of action responsible for the liver weight increases observed in mice and rats 

administered Sulfoxaflor [N-(Methyloxido(1-(6-(trifluoromethyl)-3 

pyridinyl)ethyl)sulfanylidene)-cyanamide] via the diet. To accomplish this, specific gene 

expression was assessed by real-time PCR in liver samples from female CD1 mice exposed to 0 

and 4500 ppm sulfoxaflor in diet for four days in a previously conducted palatability probe study 

(MRID 47832048). In total, eight genes were selected for this study. Five genes, primarily 

Cyp2b10 but with four additional genes, were chosen to address whether sulfoxaflor induces a 

phenobarbital (PB)-like gene expression response. Two genes which are also induced by PB 

were selected specifically to investigate the effect on blood cholesterol seen in sulfoxaflortreated rodents. One gene, Cyp4a10, was included as a marker of peroxisome proliferatoractivated receptor alpha (PPAR alpha) to examine this potential mode of action. In addition, cell 

proliferation (seen as an early response to PB treatment) was assessed by Ki-67 

immunohistochemical staining in liver tissue from male and female F344 rats from a 28-day rat 

study (MRID 47832045; 0, and 2000 ppm dose) and CD1 mice from the mouse palatability study 

(0, 3000, and 4500 ppm doses). Sulfoxaflor -treated mice showed gene expression similar to that 

reported in the literature following PB exposure. The primary PB-like marker gene, Cyp2b10, 

was induced 148.5-fold. In addition, three of the four remaining PB-like response genes 

(Cyp3a11, Alas1, and NADPH-Cyp-reductase) were induced. The remaining PB-like gene, 

Slco1b2, was not induced in sulfoxaflor-treated mice. Sulfoxaflor stimulated the cholesterol 

synthesis-related genes, Dhcr7 and Sqle1, at levels similar to those reported in the literature 

following PB exposure. The lack of induction for both Cyp4a10 and an internal homeostasis 

control gene, Scd1, suggests that sulfoxaflor is not acting as a peroxisome proliferator. Mice 

exposed to 3000 ppm sulfoxaflor for seven days showed increased proliferation in both the 

centrilobular and midzonal regions, whereas both sexes of rat exposed to 2000 ppm sulfoxaflor 

for 28 days showed increased proliferation only in the centrilobular region. 

In conclusion, treatment with sulfoxaflor resulted in a gene expression profile similar to that 

reported for phenobarbital. Additionally, increased hepatocellular proliferation in both the 

centrilobulor and midzonal regions was seen in female mice following 3000 ppm treatment, 
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whereas both sexes of rats exposed to 2000 ppm sulfoxaflor showed increased proliferation only 

in the centrilobulor region. The carcinogenic potential of sulfoxaflor, along with the proposed 

MOA for liver tumors will be evaluated by the Cancer Assessment Review committee (CARC).

Although this study does not satisfy EPA guideline requirements, it provides supplementary 

information regarding the proposed mechanism of action for carcinogenicity of sulfoxaflor in 

rats and mice. This study fully reliable (acceptable/non-guideline).

IIA 5.5.4/2 Targeted gene expression, cell proliferation and cytochrome P450 enzymatic 

activity in rats;

In previous studies with sulfoxaflor, increased liver weight was observed. Targeted gene 

expression data in mice and hepatocellular proliferation data in both mice and rats suggest a 

possible phenobarbital (PB)-like mode of action (MoA) could be responsible for the observed 

liver weight increases, and subsequent liver tumors. The molecular response stimulated by PB is 

mediated by the constitutive androstane nuclear receptor (CAR), with peripheral involvement of 

the pregnane X receptor (PXR), and typically results in increased hepatocellular proliferation and 

hypertrophy, with associated increased liver weight, inhibition of apoptosis, hypertrophy, and 

eventual development of altered hepatic foci. In this study (MRID 47832061), five male and 

five female Fischer 344/DuCrl rats per group were given sulfoxaflor in the diet at 0, 100, 750, or 

1500 ppm for 3 or 7 days. The primary endpoints examined were liver weight, targeted gene 

expression, liver enzyme analysis, and hepatocellular proliferation. 

Decreased body weights and body weight gains were seen in males and females at 1500 ppm 

after 3 and 7 days. After 3 days, body weight was decreased 7% in males and 9% in females and 

body weight gain was decreased 60% and 100%, respectively. After 7 days, there was a 7% 

decrease in male body weight and 43% and 47% decrease in body weight gain in males and 

female, respectively. Food consumption in males at 750 and 1500 ppm for 3 days and 1500 ppm 

for 7 days was significantly lower (15 and 30% - day 3; 23% - day 7, respectively). A similar 

pattern of reduced food consumption was seen in females exposed to 750 and 1500 ppm for 3 

days and 1500 ppm for 7 days (18 and 35%, day 3; 20% day 7, respectively). 

Elevated cholesterol levels were seen in males on day 3 at 750 or 1500 ppm (19 and 29%, 

respectively) and day 7 at 750 or 1500 ppm (33% and 87%, respectively). In females, elevated 

cholesterol levels were seen after 7 days at 1500 ppm (41%). Relative liver weights were 

increased for males and females in the 1500 ppm group at 3 days (14 and 3%, respectively) and 

at 750 and 1500 ppm at 7 days (11 and 23% for males and 6 and 18% for females, respectively). 

Absolute liver weights were increased in male and females at 1500 ppm after 7 days (14 and 

16%, respectively). 

Cyp2b1 gene expression, the prototypical gene response following PB exposure, was induced 

over 800-fold in both male and female rats exposed to 1500 ppm sulfoxaflor for 3 and 7 days. 

To further examine similarities in PB-like response, Cyp2b2 and Cyp3a3 (CAR- and PXRrelated genes, respectively) expression levels, together with PROD and BROD enzyme activity 

were evaluated at 3 and 7 days. These molecular markers were elevated in males and females 

exposed to 750 and 1500 ppm at both time periods in a PB-like manner. At 7 days, male rats 

exposed to 750 and male and female rats at 1500 ppm sulfoxaflor showed significant 
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hepatocellular proliferation; for males it occurred in the centrilobular and midzonal regions, 

whereas for females it was evident in the centrilobular region. 

 

An additional aim of this study was to determine if other nuclear receptors might have played a 

role in sulfoxaflor-induced liver effects. Four nuclear receptors are primarily responsible for 

xenobiotic-induced liver weight increase; the aryl hydrocarbon receptor (AhR), CAR, PXR, and 

the peroxisome proliferator-activated receptor alpha (PPARα). Cyp1a1 gene expression and 

EROD enzyme activity were slightly but significantly elevated at day 3; however, EROD 

enzyme activity returned to control levels by day 7. Furthermore, gene expression of Cyp4a22

was not elevated in this study. From these data it is implied that sulfoxaflor is not likely an AhR 

or PPARα agonist. 

In conclusion, the data suggests that sulfoxaflor may be an agonist ligand for CAR, and this 

activation results in the observed phenobarbital-like response in the liver. However, the 

carcinogenic potential of sulfoxaflor, along with the proposed MOA for liver tumors will be 

evaluated by the Cancer Assessment Review Committee (CARC).

This non-guideline study is reliable with restrictions (acceptable/non-guideline). The study is 

not GLP compliant. However, all experiments were done according to GLP standards. 

Additionally, the study was well conducted and the Agency has confidence in the scientific 

integrity of the data. 

IIA 5.8.1.5/1 X11719474: Targeted Gene Expression, Cell Proliferation, and Cytochrome 

p 450 Enzymatic Activities in Rats;

The purpose of this study (MRID 47832151) was to generate information to aid in understanding 

the mode of action for liver effects in rats induced by X11719474 a metabolite of sulfoxaflor and 

to compare the results to those observed following exposure to sulfoxaflor. In this study, male 

F344/DuCrl rats were given test diets formulated to supply 0 or 8000 ppm X11719474 in the diet 

for 7 days which corresponded to time-weighted average doses of 0 or 583 mg/kg/day, 

respectively. The treatment level of 8000 ppm was the high dose level used in the rat 28-day 

toxicity study. The parameters evaluated were daily cageside observations, body weights, body 

weight gains, feed consumption, liver weights, histopathology of the liver, focused gene 

expression, liver cytochrome P450 enzyme activity, and hepatocellular proliferation using BrdU 

immunohistochemical methods. Results from this study were compared to an earlier work in 

which male F344/DuCrl rats were exposed to 1500 ppm sulfoxaflor for 7 days, resulting in a 

time-weighted average dose of 102 mg/kg/day.

At the end of the 7-day treatment period, males exposed to 8000 ppm X11719474 had body 

weight and body weight gains decrements of approximately 2% and 22% relative to controls, 

respectively. In addition, males given 8000 ppm X11719474 had statistically identified, 

treatment-related increases in liver weights (absolute: 16%; relative: 19%). X11719474 induced 

liver weight increases that correlated with treatment-related microscopic observations of very 

slight centrilobular/midzonal hypertrophy of hepatocytes that were present in all treated animals. 

At the end of the 7-day treatment period, males exposed to 8000 ppm X11719474 had the same 

types of treatment-related effects as parent sulfoxaflor, but were consistently less marked despite 

the almost 6-fold higher dose level.
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The constitutive androstane receptor (CAR)-related transcripts, Cyp2b1 and Cyp2b2, along with 

the pregnane X receptor (PXR)-related transcript Cyp3a3, were increased 806, 32, and 4-fold, 

respectively. Sulfoxaflor -induced gene expression showed a similar profile of 848, 21, and 9-

fold, respectively. The level of hepatocellular PROD enzyme activity, a CAR-associated 

biomarker, was increased 15-fold following X11719474 exposure. A similar level of induction 

(10-fold) was seen for sulfoxaflor -induced PROD enzyme activity. Hepatocellular proliferation, 

as measured by BrdU incorporation, was significantly elevated 4.5, 2.5, and 2.1-fold in the 

centrilobular, midzonal, and periportal regions, respectively. An earlier hepatocellular 

proliferation study with sulfoxaflor, as measured by Ki-67, showed increased proliferation in the 

centrilobular and midzonal regions of 3.4 and 2.9-fold, respectively.

In conclusion, the data suggests that sulfoxaflor and its metabolite X11719474 may be agonist 

ligand for CAR, and this activation results in the observed phenobarbital-like response in the 

liver. However, the carcinogenic potential of sulfoxaflor, along with the proposed MOA for 

liver tumors will be evaluated by the Cancer Assessment Review Committee (CARC).

This non-guideline study is reliable with restrictions (acceptable/non-guideline). The study is 

not GLP compliant. However, all experiments were done according to GLP standards. 

Additionally, the study was well conducted and the Agency has confidence in the scientific 

integrity of the data. 

IIA 5.5.4/3 Mode of Action Study Investigating Liver Weight Effects in crl:cd1(icr) Mice;

In a non-guideline study, (MRID 47832062) 5 male and 5 female Crl:CD-1 (ICR) mice were 

exposed to different dose levels of sulfoxaflor in the diet for 7 days. In previous studies with 

sulfoxaflor, increased liver weight was observed. Targeted gene expression data in mice and 

hepatocellular proliferation data in both mice and rats suggested a phenobarbital (PB)-like mode 

of action (MoA) could be responsible for the observed liver weight increase. The molecular 

response stimulated by PB is mediated by the constitutive androstane nuclear receptor (CAR), 

with peripheral involvement of the pregnane X receptor (PXR), and typically results in increased 

hepatocellular proliferation and hypertrophy, with associated increased liver weight, inhibition of 

apoptosis, hypertrophy, and eventual development of altered hepatic foci. In this study, male 

CD-1® mice were exposed to 0, 500, or 750 ppm, while female mice were exposed to 0, 1000, or 

1500 ppm sulfoxaflor in the diet for 7 days. Endpoints evaluated were daily cage-side 

observations, body and liver weights, feed consumption, serum clinical chemistries, focused 

gene expression, liver cytochrome P450 enzyme activity, and hepatocellular proliferation using 

BrdU and Ki-67 methods. Archived liver samples from previously conducted 28 and 90-day 

sulfoxaflor mouse studies were analyzed for targeted gene expression, liver enzyme activity, and 

hepatocellular proliferation (Ki-67). 

In the 7-day study, males exposed to 750 ppm had a statistically identified increase (17%) in 

relative liver weights compared to controls. Females exposed to 1000 and 1500 ppm had a 

statistically identified increase in relative (38 and 43%, respectively) and absolute (43 and 47%, 

respectively) liver weights compared to controls. These liver weight increases correlated with 

treatment-related observations of centrilobular and midzonal hepatocyte hypertrophy with very 

slightly increased cytoplasmic eosinophilia. Analysis by Oil Red O stain demonstrated slightly 
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increased amounts of lipid in the hepatocytes in males exposed to 750 ppm sulfoxaflor, however 

no changes were observed in females.

Cyp2b10 expression, considered to be the prototypical gene response following PB exposure 

through activation of CAR, was induced 42.1 and 54.8-fold in males exposed to 500 and 750 

ppm, respectively, and 20.0 and 30.8-fold, in females exposed to 1000 and 1500 ppm, 

respectively, relative to controls. Cyp2b10 gene expression in males from the 28 and 90-day 

studies was increased 61.7 (300 ppm) and 56.5-fold (750 ppm), respectively. Females exposed 

to 1500 ppm showed elevated Cyp2b10 expression at 28 and 90 days of 93.9- and 53.9-fold, 

respectively. Cyp3a11, a PB- and PXR-related gene, was significantly elevated in the 750 ppm 

males at 7 and 90 days, while in female mice it was significantly elevated at all doses and time 

periods (range of 3.4 to 6.6-fold). PROD and BROD liver enzyme activities, which give a 

measure of Cyp2b enzyme induction, were elevated in both male and female mice at all timepoints (range of 2.6 to 9.5-fold). 

Both BrdU and Ki-67 immunohistochemical techniques were used to measure hepatocellular 

proliferation in the 7-day study. For the BrdU analysis, males exposed to 500 ppm sulfoxaflor 

had elevated proliferation in the centrilobular region and at 750 ppm in both the centrilobular and 

midzonal regions. Females exposed to 1000 and 1500 ppm showed significant induction in all 

three regions. For Ki-67 analysis, males exposed to 500 and 750 ppm showed significant 

induction in the centrilobular region, however unlike the BrdU analysis, increased proliferation 

was not observed at 750 ppm in the midzonal region. In females, increased proliferation was not 

evident at any dose or zone by Ki-67 analysis. Ki-67 analysis of hepatocellular proliferation in 

the 28 and 90-day studies showed no induction at either time point in male or female mice. 

An additional aim of this study was to determine if other nuclear receptors might have played a 

role in sulfoxaflor -induced liver effects. Four nuclear receptors are primarily responsible for 

xenobiotic-induced liver weight increase; the aryl hydrocarbon receptor (AhR; Cyp1a), CAR 

(Cyp2b), PXR (Cyp3a), and the peroxisome proliferator-activated receptor alpha (PPARα; 

Cyp4a). AhR-related EROD liver enzyme activity was slightly elevated in this study at all timepoints in both male and female mice; however, the degree of induction was mild (none greater 

than 2.3-fold) and was most likely associated with the large induction of Cyp2b enzyme. 

Cyp4a10, a PPARα related gene, was not significantly altered in this study. 

These data suggests that sulfoxaflor may be an agonist ligand for CAR, and this activation results 

in the observed PB-like response and increased liver weight. However, the carcinogenic 

potential of sulfoxaflor, along with the proposed MOA for liver tumors will be evaluated by the 

Cancer Assessment Review committee (CARC).

This non-guideline study is reliable with restrictions (acceptable/non-guideline). The study is 

not GLP compliant. However, all experiments were done according to GLP standards. 

Additionally, the study was well conducted and the Agency has confidence in the scientific 

integrity of the data. 

IIA 5.5.4/4 Induction profile and gene expression in mice livers;
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In an induction profile study (MRID 47832276), sulfoxaflor (95.6% pure; batch number E2162-

34) was administered in the diet to 15 male mice at dose levels of 0, 750, or 1500 ppm 

(equivalent to 0, 160, and 310 mg/kg/day respectively) for 7 days. 

Administration of dietary sulfoxaflor to mice for 7 days resulted in decreased body weight at the 

high dose of 1500 ppm compared to control. There was a treatment-related increase in absolute 

and relative liver weights and ALT following seven days of exposure to sulfoxaflor. However, 

no significant increases in plasma AST, cholesterol and triglycerides were seen. Administration 

of sulfoxaflor at 750 ppm and 1500 ppm elicited a 3- and 5- fold increase in total hepatic P450, 

respectively, a 33-fold increase in PROD activity at both concentrations, a 47- and 82- folding 

increase in BROD activity, respectively, and a 4-and 7-fold increase in BQ activity, respectively.

The study examined the expression of two genes, Cyp2b10 and Cyp3a11. Gene expression 

indicated the presence of Cyp2b10 mRNA in only the treatment groups as it is constitutively 

expressed. The change in expression of Cyp2b10 from sulfoxaflor 750 ppm treatment to 

sulfoxaflor 1500 ppm treatment was 9.2-fold. Cyp3a11 is constitutively expressed in the mouse, 

and results can be expressed as a relative fold change over control values. Administration of 750 

and 1500 ppm sulfoxaflor resulted in a 2.4-and 5.6-fold increase in Cyp3a11 relative to controls. 

Sulfoxaflor induced gene expression data was confirmed by sodium dodecyl sulphatepolyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting.

In conclusion, the data suggest that sulfoxaflor exerts its enzyme induction properties via CAR 

and possibly PXR. However, the carcinogenic potential of sulfoxaflor, along with the proposed 

MOA for liver tumors will be evaluated by the Cancer Assessment Review Committee (CARC).

This study is Reliable with Restrictions (acceptable/non-guideline). The study is not GLP 

compliant. However, all experiments were done according to GLP standards. Additionally, the 

study was well conducted and the Agency has confidence in the scientific integrity of the data.

IIA 5.5.4/5 A Study To Investigate The Mode Of Action For Liver Effects Observed In 

Regulatory Toxicology Studies By Use Of Dual Car-PXR Knockout And Humanised Mice; 

The aim of this study (MRID 47832255) was to investigate: (1) if the constitutive androstane 

receptor (CAR) or pregnane X receptor (PXR) mediate sulfoxaflor-induced hypertrophy and 

hyperplasia in mice; and (2) if the human receptors (CAR and PXR) support these processes to a 

similar extent as the murine receptors. The mouse models used were wild type C57BL/6J (WT) 

mice, C57BL/6J mice null for PXR and CAR (PXRKO/CARKO) and C57BL/6J mice 

“humanised” for PXR and CAR (hPXR/hCAR).

In this study, groups of ten male mice of each strain were offered diets containing 0 or nominally 

750 ppm sulfoxaflor for seven days. The measured dietary concentration of sulfoxaflor was 740 

ppm (approximately 98.6% of target) with good homogeneity. Endpoints evaluated were daily 

clinical observations, body weights, body weight gain, feed consumption, plasma clinical 

chemistries, focused gene expression, protein quantification, liver cytochrome P450 enzyme 

activity, hepatocellular proliferation using nuclear incorporation of BrdU, and liver 

histopathology. 
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There were no treatment-related clinical observations or effects on body weight or body weight 

gain in any strain of mouse. There were treatment-related increases in absolute and relative liver 

weights in WT and hPXR/hCAR mice but not in the PXRKO/CARKO animals. Absolute liver 

weights for WT and hPXR/hCAR mice in the 750 ppm sulfoxaflor groups were 124 and 109% of 

controls respectively, and relative liver weights were 125 and 112% of controls respectively. 

In WT mice, sulfoxaflor treatment increased hepatocellular proliferation (as measured by 

approximately 4-fold but no such changes in proliferation were seen in either the hPXR/hCAR or 

PXRKO/CARKO mice. Treatment-related hepatocyte hypertrophy was observed in WT and 

hPXR/hCAR mice while increased mitotic figures were observed only in WT mice. Neither 

hepatocyte hypertrophy nor increased mitotic figures were seen in PXRKO/CARKO mice.

Sulfoxaflor behaved as a phenobarbital-like inducer in WT mice. A marked induction of total 

cytochrome P450, markedly increased PROD and BROD (Cyp2b selective substrates), increased 

expression of Cyp2b10 mRNA (demonstrated by RT-PCR), increases in Cyp2b10 protein 

(immunoblotting data) were observed after exposure to sulfoxaflor. However, in the 

hPXR/hCAR under the same conditions, induction of Cyp2b10 activity, protein and mRNA was 

markedly less than observed in the WT animals following treatment with sulfoxaflor. In 

PXRKO/CARKO animals, sulfoxaflor had no significant effect on Cyp2b10 expression or 

catalytic activity. 

Sulfoxaflor-mediated Cyp3a11 induction, as determined by BQ activity (Cyp3a selective 

reaction), RT-PCR and immunoblotting was observed in the “humanised” and WT mice, to 

similar extents, but was not seen in the PXRKO/CARKO mice.

In conclusion, sulfoxaflor exhibited markedly more activity towards the mouse CAR than the 

human CAR and relatively weak activity towards the mouse and human PXR. This suggests that 

the difference in hepatic response between wild type and humanised mice in this study may be 

mediated via CAR. Additionally, the data show that the human CAR/PXR support sulfoxaflorinduced hypertrophy but not hyperplasia. 

In conclusion, the data suggests that sulfoxaflor acts via a CAR-mediated mode of action in mice 

and it is possible that exposure would not result in human carcinogenicity. However, these 

findings, along with those in other mechanistic studies, will be used by the Cancer Assessment 

Review Committee (CARC) to evaluate the carcinogenic potential of sulfoxaflor and the 

proposed MOA (and human relevance) for liver tumors. 

This non-guideline study is reliable with restrictions (acceptable/non-guideline). The study is 

not GLP compliant. However, all experiments were done according to GLP standards. 

Additionally, the study was well conducted and the Agency has confidence in the scientific 

integrity of the data. 

A.4.6 Mutagenicity

Gene Mutation
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IIA 5.4.1 In vitro bacterial (Salmonella typhimurium and E. coli)/mammalian activation 

gene mutation assay;

In independent trials of a reverse gene mutation assay (MRID 47832047), sulfoxaflor (Purity 

96.6%; Lot/Batch No. E2198-17), prepared in dimethyl sulfoxide (DMSO), was tested in 4 

strains of S. typhimurium (TA100, TA98, TA1535 and TA1537) and in E. coli WP2uvrA in a 

pre-incubation reverse mutation assay at concentrations ranging from 100 to 5000 μg/plate (both 

trials) with and without S9 activation. The S9 fraction was derived from the livers of male 

Sprague-Dawley rats induced with Aroclor 1254.

In both assays, the test material was not cytotoxic or mutagenic for any strain at concentrations 

up to the limit dose for this test system either in the absence or presence of S9 activation. The 

numbers of revertant colonies in all strain-specific positive control groups were clearly 

increased. 

Under the conditions of this study, sulfoxaflor did not induce gene mutation in any of the strains 

employed, either with or without metabolic activation, at concentrations up to the limit dose for 

this test system.

The study is classified as fully reliable (acceptable/guideline) and satisfies the guideline 

requirements (OPPTS 870.5100; OECD 471) for in vitro mutagenicity (bacterial reverse gene 

mutation) data.

IIA 5.8.1.4/1 In vitro bacterial (Salmonella typhimurium)/mammalian activation gene 

mutation assay;

In independent trials of a reverse gene mutation assay (MRID 47832097), X11719474 (Purity 

99.6%; Lot/Batch No. XS9-36891-82, TSN106429 and Lot/Batch No. XS9-37307-78, 

TSN030626-0001), prepared in dimethyl sulfoxide (DMSO), was tested in 4 strains of S. 

typhimurium (TA100, TA98, TA1535 and TA1537) and in E. coli WP2uvrA in a pre-incubation 

reverse mutation assay at concentrations ranging from 100 to 5000 μg/plate (both trials) with and 

without S9 activation. The S9 fraction was derived from the livers of male Sprague-Dawley rats 

induced with Aroclor 1254.

In both assays, the test material was not cytotoxic or mutagenic for any strain at concentrations 

up to the limit dose for this test system either in the absence or presence of S9 activation. The 

numbers of revertant colonies in all strain-specific positive control groups were clearly 

increased. 

Under the conditions of this study, X11719474 did not induce gene mutation in any of the strains 

employed, either with or without metabolic activation, at concentrations up to the limit dose for 

this test system.

The study is classified as fully reliable (acceptable/guideline) and satisfies the guideline 

requirements (OPPTS 870.5100; OECD 471) for in vitro mutagenicity (bacterial reverse gene 

mutation) data.

IIA 5.8.2.4/1 Salmonella –Escherichia coli/mammalian-microsome reverse mutation assay 

preincubation method with a confirmatory assay with X11721061;
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In independent trials of a reverse gene mutation assay (MRID 47832085), [X11721061 Purity 

99%; Lot/Batch No. GF908627 (TSN030701-0003)], prepared in dimethyl sulfoxide (DMSO) 

was tested in 4 strains of S. typhimurium (TA100, TA98, TA1535 and TA1537) and in E. coli

WP2uvrA in a pre-incubation reverse mutation assay at concentrations ranging from 1.5 to 5000 

μg/plate (Initial cytotoxicity-mutation assay) and 50 to 5000 μg/plate (Confirmatory assay) both 

with and without S9 activation. The S9 fraction was derived from the livers of male SpragueDawley rats induced with Aroclor 1254.

In the initial assay, there was some indication of a slight cytotoxic effect (reduced revertant 

colony counts) for several strains at the highest concentration; however, this was not reproduced 

in the confirmatory trial. Nevertheless, the data are in good agreement and indicate that the test 

material was not mutagenic in any strain at concentrations up to the limit dose for this test 

system either in the absence or presence of S9 activation. The numbers of revertant colonies in 

all strain-specific positive control groups were clearly increased. 

Under the conditions of this study, X11721061 did not induce gene mutation in any of the strains 

employed, either with or without metabolic activation, at concentrations up to the limit dose for 

this test system.

The study is classified as fully reliable (acceptable/guideline) and satisfies the guideline 

requirements (OPPTS 870.5100; OECD 471) for in vitro mutagenicity (bacterial reverse gene 

mutation) data.

IIA 5.8.3.4/1 Salmonella –Escherichia coli/mammalian-microsome reverse mutation assay 

preincubation method with a confirmatory assay with X11596066;

In independent trials of a reverse gene mutation assay (MRID 47832076), the sulfoxaflor 

metabolite X11596066 [Purity 98%; Lot/Batch No. SYN-6268-05-06 (TSN031296-0002)], 

prepared in dimethyl sulfoxide (DMSO), was tested in 4 strains of S. typhimurium (TA100, 

TA98, TA1535 and TA1537) and in E. coli WP2uvrA in a pre-incubation reverse mutation assay 

at concentrations ranging from 1.5 to 5000 μg/plate (Initial cytotoxicity-mutation assay) and 15 

to 5000 μg/plate (Confirmatory assay) both with and without S9 activation. The S9 fraction was 

derived from the livers of male Sprague-Dawley rats induced with Aroclor 1254.

In both assays, concentrations ≥1500 μg/plate +/-S9 were cytotoxic for any strains. However, 

there were no increases in the number of revertant colonies at any noncytotoxic level, in any 

strains, both with and without S9. The numbers of revertant colonies in all strain-specific 

positive control groups were clearly increased. 

Under the conditions of this study, X11596066 did not induce gene mutation in any of the strains 

employed, either with or without metabolic activation, at concentrations up to those producing 

evidence of cytotoxicity.

The study is classified as fully reliable (acceptable/guideline) and satisfies the guideline 

requirements (OPPTS 870.5100; OECD 471) for in vitro mutagenicity (bacterial reverse gene 

mutation) data.

IIA 5.8.4.4/1 Salmonella –Escherichia coli/mammalian-microsome reverse mutation assay 

preincubation method with a confirmatory assay with X11579457;
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In independent trials of a reverse gene mutation assay (MRID 47832070), the sulfoxaflor 

metabolite X11579457 (Purity 99%; Lot/Batch No. SYN-5866-65 (TSN030941-0002), was 

prepared in distilled H2O, and tested in 4 strains of S. typhimurium (TA100, TA98, TA1535 and 

TA1537) and in E. coli WP2uvrA in a pre-incubation reverse mutation assay at concentrations 

ranging from 1.5 to 5000 μg/plate (Initial cytotoxicity-mutation assay) and 50 to 5000 μg/plate 

(Confirmatory assay) both with and without S9 activation. The S9 fraction was derived from the 

livers of male Sprague-Dawley rats induced with Aroclor 1254.

In both assays, the test material was not cytotoxic or mutagenic for any strain at concentrations 

up to the limit dose for this test system either in the absence or presence of S9 activation. The 

numbers of revertant colonies in all strain-specific positive control groups were clearly 

increased. 

Under the conditions of this study, X11579457 did not induce gene mutation in any of the strains 

employed, either with or without metabolic activation, at concentrations up to the limit dose for 

this test system.

The study is classified as fully reliable (acceptable/guideline) and satisfies the guideline 

requirements (OPPTS 870.5100; OECD 471) for in vitro mutagenicity (bacterial reverse gene 

mutation) data.

IIA 5.8.5.4/1 Salmonella –Escherichiacoli /mammalian-microsome reverse mutation assay 

preincubation method with a confirmatory assay with X11519540;

In independent trials of a reverse gene mutation assay (MRID 47832068), the sulfoxaflor 

metabolite X11519540 (Purity 98%; Lot/Batch No. 37307-15 (TSN106498), prepared in 

dimethyl sulfoxide (DMSO), was tested in 4 strains of S. typhimurium (TA100, TA98, TA1535 

and TA1537) and in E. coli WP2uvrA in a pre-incubation reverse mutation assay at 

concentrations ranging from 1.5 to 5000 μg/plate (Initial cytotoxicity-mutation assay) and 50 to 

5000 μg/plate (Confirmatory assay) both with and without S9 activation. The S9 fraction was 

derived from the livers of male Sprague-Dawley rats induced with Aroclor 1254.

In both assays, the test material was not cytotoxic or mutagenic for any strain at concentrations 

up to the limit dose for this test system either in the absence or presence of S9 activation. The 

numbers of revertant colonies in all strain-specific positive control groups were clearly 

increased. 

Under the conditions of this study, X11519540 did not induce gene mutation in any of the strains 

employed, either with or without metabolic activation, at concentrations up to the limit dose for 

this test system.

The study is classified as fully reliable (acceptable/guideline) and satisfies the guideline 

requirements (OPPTS 870.5100; OECD 471) for in vitro mutagenicity (bacterial reverse gene 

mutation) data.

Cytogenetics

IIA 5.4.3/1 In Vitro Gene Mutation assay in Chinese hamster ovary cells;
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In independent trials of a mammalian cell forward gene mutation assay (MRID 47832049), 

Chinese hamster ovary (CHO/HGPRT) cells were exposed to sulfoxaflor (Purity 96.6% Lot # 

E2198-17, TSN106108), prepared in dimethyl sulfoxide (DMSO), at concentrations ranging 

from 173.3 to 2773 μg/ml in the absence and presence of S9. The S9 liver homogenate was 

derived from the livers of Sprague-Dawley rats induced with Aroclor 1254. The highest 

concentration was the 10 mM limit for the assay system. Positive control chemicals used in this 

assay were ethyl methanesulfonate (EMS) in the absence of S9 and 20-methylcholanthrene (20-

MCA) in the presence of S9. 

Sulfoxaflor was tested up to the limit dose for this test system and failed to induce either a 

cytotoxic or mutagenic effect in either the absence or the presence of S9 activation. The expected 

responses were obtained with the negative and positive controls either with or without S9 

activation. It was, therefore, concluded that sulfoxaflor was not active in this test system. 

This study is classified as fully reliable (acceptable/guideline) and satisfies the guideline 

requirement (OPPTS 870.5300, OECD 476) for in vitro mutagenicity (mammalian forward gene 

mutation) data.

IIA 5.8.1.4/3 Evaluation of X11719474 in the Chinese hamster ovary cell/ hypoxanthineguanine-phosphoribosyl transferase (CHO/HGPRT) forward mutation assay;

In independent trials of a mammalian cell forward gene mutation assay (MRID 47832095), 

Chinese hamster ovary (CHO/HGPRT) cells were exposed to X11719474 (Purity 100%; Lot # 

XS9-36891-82, TSN106429), prepared in dimethyl sulfoxide (DMSO) at concentrations ranging 

from 184.6 to 2953 μg/ml in the absence and the presence of S9. The highest concentration was 

based on the 10 mM limit of the assay system. The S9 liver homogenate was derived from the 

livers of Sprague-Dawley rats Aroclor 1254-induced. The highest concentration was the 10 mM 

limit for the assay system. Positive control chemicals used in this assay were ethyl 

methanesulfonate (EMS) in the absence of S9 and 20-methylcholanthrene (20-MCA) in the 

presence of S9. 

X11719474 was tested up to the limit dose for this test system and failed to induce either a 

cytotoxic or mutagenic effect in either the absence or the presence of S9 activation. The expected 

responses were obtained with the negative and positive controls either with or without S9 

activation. It was, therefore, concluded that X11719474 was not active in this test system. 

This study is classified as fully reliable (acceptable/guideline) and satisfies the guideline 

requirement (OPPTS 870.5300, OECD 476) for in vitro mutagenicity (mammalian forward gene 

mutation) data.

IIA 5.8.2.4/3 Evaluation of X11721061 in the Chinese hamster ovary cell/ hypoxanthineguanine-phosphoribosyl transferase (CHO/HGPRT) forward mutation assay;

In independent trials of a mammalian cell forward gene mutation assay (MRID 47832077), 

Chinese hamster ovary (CHO/HGPRT) cells were exposed to the sulfoxaflor metabolite 

X11721061 (Purity 99%; Lot # GF908627, TSN030701-0003), prepared in distilled H2O, at 

concentrations ranging from 120 to 1920 μg/ml (both trials) in the absence and the presence of 

S9. The S9 liver homogenate was derived from the livers of Sprague-Dawley rats induced with 

Aroclor 1254. The highest concentration was the 10 mM limit for the assay system. Positive 
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control chemicals used in this assay were ethyl methanesulfonate (EMS) in the absence of S9 

and 20-methylcholanthrene (20-MCA) in the presence of S9. 

X11721061 was tested up to the limit dose for this test system and failed to induce either a 

cytotoxic or mutagenic effect in either the absence or the presence of S9 activation. The expected 

responses were obtained with the negative and positive controls either with or without S9 

activation. It was, therefore, concluded that X11721061 was not active in this test system.

 

This study is classified as fully reliable (acceptable/guideline) and satisfies the guideline 

requirement (OCSPP 870.5300, OECD 476) for in vitro mutagenicity (mammalian forward gene 

mutation) data.

IIA 5.8.4.4/3 Evaluation of X11579457 in the Chinese hamster ovary cell/ hypoxanthineguanine-phosphoribosyl transferase (CHO/HGPRT) forward mutation assay;

In independent trials of a mammalian cell forward gene mutation assay (MRID No. 48288933), 

Chinese hamster ovary (CHO/HGPRT) cells were exposed to X11579457 (Purity 99%; Lot# 

SYN-5866-65, TSN030941-0002), prepared in distilled H2O, at concentrations ranging from 

157.8 to 2525 μg/mL (both trials) in the absence and the presence of S9. The S9 liver 

homogenate was derived from the livers of Sprague-Dawley rats induced with Aroclor 1254. The 

highest concentration was the 10 mM limit for the assay system. Positive control chemicals used 

in this assay were ethyl methanesulfonate (EMS) in the absence of S9 and 20-

methylcholanthrene (20-MCA) in the presence of S9. 

X11579457 was tested up to the limit dose for this test system and failed to induce either a 

cytotoxic or mutagenic effect in either the absence or the presence of S9 activation. The expected 

responses were obtained with the negative and positive controls either with or without S9 

activation. It was, therefore, concluded that X11579457 was not active in this test system. 

This study is classified as fully reliable (acceptable/guideline) and satisfies the guideline 

requirement (OPPTS 870.5300, OECD 476) for in vitro mutagenicity (mammalian forward gene 

mutation) data.

IIA 5.8.5.4/3 Evaluation of X11519540 in the Chinese hamster ovary cell/ hypoxanthineguanine-phosphoribosyl transferase (CHO/HGPRT) forward mutation assay;

In independent trials of a mammalian cell forward gene mutation assay (MRID No. 48288934), 

Chinese hamster ovary (CHO/HGPRT) cells were exposed to the sulfoxaflor metabolite

X11519540 (Purity 98%; Lot # 37307-15, TSN106498), prepared in dimethyl sulfoxide (DMSO) 

concentrations ranging 158.8 to 2540 μg/ml in the absence and the presence of S9. The highest 

concentration was based on the 10 mM limit of the assay system. The S9 liver homogenate was 

derived from the livers of Sprague-Dawley rats Aroclor 1254-induced. The highest concentration 

was the 10 mM limit for the assay system. Positive control chemicals used in this assay were 

ethyl methanesulfonate (EMS) in the absence of S9 and 20-ethylcholanthrene (20-MCA) in the 

presence of S9. 

X1151940 was tested up to the limit dose for this test system and failed to induce either a 

cytotoxic or mutagenic effect in either the absence or the presence of S9 activation. The expected 
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responses were obtained with the negative and positive controls either with or without S9 

activation. It was, therefore, concluded that X11519540 was not active in this test system. 

This study is classified as fully reliable (acceptable/guideline) and satisfies the guideline 

requirement (OPPTS 870.5300, OECD 476) for in vitro mutagenicity (mammalian forward gene 

mutation) data

Other Genotoxicity

IIA 5.4.2/1 Evaluation of sulfoxaflor in an in vitro chromosomal aberration assay utilizing 

rat lymphocytes; 

In an in vitro chromosome aberration test (MRID 47832050), primary rat lymphocytes, derived 

from 10-11 week old Sprague-Dawley male rats, were exposed to sulfoxaflor (Purity 96.6%

Batch/Lot No. E2198-17, TSN106108) prepared in dimethyl sulfoxide (DMSO) at 0, 86.7, 173.3, 

346.6, 693.3, 1389.5, and 2773 g/mL without and with S9 activation for 4 hours and 

continuously for 24 hours at 0, 21.7, 43.3, 86.7, 173.3, 346.6, 693.3, 1386.5 and 2773 g/mL

without S9. The highest concentration tested approximates the limit dose of 10 mM and the S9 

liver homogenate was prepared from Aroclor 1254-induced male Sprague-Dawley rats. Base on 

the analysis of mitotic indices (MIs), cultures treated for 4 hours with 0, 693.3, 1386.5, and 2773 

g/mL +/-S9 and cultures treated continuously for 24 hours with 173.3, 346.6 and 693.3 g/mL 

–S9 were scored for structural and numerical chromosome aberrations. 

Relative MIs (RMIs) were ≥ 50% of control at 2773 g/mL –S9 (4-hour treatment); 2200 g/mL 

+S9 (4-hour treatment); and 346.6 g/mL –S9 (24-hour treatment). There were no significant 

increases in the frequencies of cells with aberrations in either the presence or absence of S9 

activation. Cultures treated with the positive control chemicals (mitomycin C without S9 and 

cyclophosphamide with S9) had significantly higher incidences of abnormal cells in all assays. 

Based upon these results, sulfoxaflor was not considered to be clastogenic in this in vitro

chromosomal aberration assay utilizing rat lymphocytes.

This study is classified as totally reliable (acceptable/guideline) and satisfies the guideline 

requirement (OPPTS 870.5375, OECD 473) for in vitro mammalian cytogenetics (chromosome 

aberrations) data.

IIA 5.8.1.4/2 Evaluation of X11719474 in an in vitro chromosomal aberration assay 

utilizing rat lymphocytes;

In an in vitro chromosome aberration test (MRID 47832096), lymphocytes, derived from male 

Sprague-Dawley rats were exposed to X11719474 (Purity 100%; Batch/Lot No. XS9-36891-82, 

TSN106429), prepared in dimethyl sulfoxide (DMSO) at concentrations ranging from 184.6 to 

2953 g/mL for 4 hours in the presence and absence of S9 activation and for 24 hours without 

S9. The highest concentration was based on the limit dose of 10 mM in this assay system. The 

S9 was derived from the livers of male Sprague-Dawley rats induced with Aroclor 1254. 

Metaphases, harvested from cultures treated with 738.25, 1476.5 and 2953 g/mL -S9 (4- and 24-

hour treatments) and 369.1, 738.25 and 2953 g/mL +S9 (4-hour treatment), were examined for 

the incidences of cells with structural aberrations and numerical aberrations. 
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X11719474 was not severely cytotoxic nor clastogenic at any concentration up to the limit dose 

for this test system following a 4-hour exposure. For the prolonged, 24-exposure, the MI was 

reduced to 32.3% of control at 2953 g/mL –S9; however, the test material was not clastogenic 

at any non-cytotoxic concentration. The expected responses were induced by the non-activated 

and S9-activated positive controls, mitomycin C and cyclophosphamide, respectively. Based 

upon these results, X11719474 was considered not to be clastogenic in this in vitro chromosomal 

aberration assay utilizing rat lymphocytes.

This study is classified as fully reliable (acceptable/guideline) and satisfies the guideline 

requirement (OPPTS 870.5375, OECD 473) for in vitro mammalian cytogenetics (chromosome 

aberrations) data.

IIA 5.8.2.4/2 Evaluation of X11721061 in an in vitro chromosomal aberration assay 

utilizing rat lymphocytes;

In an in vitro chromosome aberration test (MRID 47832078), lymphocytes, derived from male 

Sprague-Dawley rats were exposed to X11721061 (Purity 99%; Batch/Lot No. 

GF908627,TSN030701-0003), prepared in distilled water, at concentrations ranging from 30 to 

1920 g/mL for 4 hours in the presence and absence of S9 activation and at concentrations 

ranging from 15 to 1920 g/mL for 24 hours without S9. The highest concentration was based 

on the limit dose of 10 mM in this assay system. The S9 was derived from the livers of male 

Sprague-Dawley rats induced with Aroclor 1254. Metaphases, harvested from cultures treated 

with 480, 960 and 1920 g/mL +/-S9 (4-hour treatment) and 120, 240 and 480 g/mL –S9 (24-

hour treatment), were examined for the incidences of cells with structural aberrations and 

numerical aberrations. 

X11721061 was not severely cytotoxic nor clastogenic at any concentration up to the limit dose 

for this test system following a 4-hour exposure. For the prolonged, 24-exposure, MIs were 

≥50% of control at concentrations ≤480 g/mL –S9; however, the test material was not 

clastogenic at any non-cytotoxic concentration. The expected responses were induced by the 

non-activated and S9-activated positive controls, mitomycin C and cyclophosphamide, 

respectively. Based upon these results, X11721061 was considered not to be clastogenic in this 

in vitro chromosomal aberration assay utilizing rat lymphocytes.

This study is classified as totally reliable (acceptable/guideline) and satisfies the guideline 

requirement (OPPTS 870.5375, OECD 473) for in vitro mammalian cytogenetics (chromosome 

aberrations) data.

IIA 5.8.5.4/2 Evaluation of X11519540 in an in vitro chromosomal aberration assay 

utilizing rat lymphocytes;

In an in vitro chromosome aberration test (MRID 48288935), lymphocytes, derived from male 

Sprague-Dawley rats were exposed to X11519540 (Purity 98%; Batch/Lot No. 37307-

15,TSN106498), prepared in dimethyl sulfoxide (DMSO), at concentrations ranging from 39.7 to 

2540 g/mL for 4 hours in the presence and absence of S9 activation and at concentrations 

ranging from 19.8 to 2540 g/mL for 24 hours without S9. The highest concentration was based 

on the limit dose of 10 mM in this assay system. The S9 was derived from the livers of male 
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Sprague-Dawley rats induced with Aroclor 1254. Metaphases, harvested from cultures treated 

with 635, 1270 and 2540 g/mL +/-S9 (4-hour treatment) and 158.8, 317.5 and 635 g/mL –S9 

(24-hour treatment), were examined for the incidences of cells with structural aberrations and 

numerical aberrations. 

X11579457 was not severely cytotoxic nor clastogenic at any concentration up to the limit dose 

for this test system following a 4-hour exposure. For the prolonged, 24-hour exposure, MIs were 

≥50% of control at concentrations ≤635 g/mL –S9; however, the test material was not 

clastogenic at any non-cytotoxic concentration. The expected responses were induced by the 

non-activated and S9-activated positive controls, mitomycin C and cyclophosphamide, 

respectively. Based upon these results, X11519540 was not clastogenic in this in vitro

chromosomal aberration assay utilizing rat lymphocytes.

This study is classified as totally reliable (acceptable/guideline) and satisfies the guideline 

requirement (OPPTS 870.5375, OECD 473) for in vitro mammalian cytogenetics (chromosome 

aberrations) data.

IIA 5.4.2/2 Evaluation of X11579457 in an in vitro chromosomal aberration assay 

utilizing rat lymphocytes;

In an in vitro chromosome aberration test (MRID 48288932), lymphocytes, derived from male 

Sprague-Dawley rats were exposed to X11579457 (Purity 99%; Batch/Lot No. SYN-5866-

65,TSN030941-0002), prepared in distilled H2O, at concentrations ranging from 39.5 to 2525 

g/mL for 4 hours in the presence and absence of S9 activation and at concentrations ranging 

from 19.7 to 2525 g/mL for 24 hours without S9. The highest concentration was based on the 

limit dose of 10 mM in this assay system. The S9 was derived from the livers of male SpragueDawley rats induced with Aroclor 1254. Metaphases, harvested from cultures treated with 

631.3, 1262.5 and 2525 g/mL +/-S9 (all treatment times), were examined for the incidences of 

cells with structural aberrations and numerical aberrations. 

X11579457 was neither cytotoxic nor clastogenic at any concentration up to the limit dose for 

this test system. The expected responses were induced by the nonactivated and S9-activated 

positive controls, mitomycin C and cyclophosphamide, respectively. Based upon these results, 

X11579457 was considered not to be clastogenic in this in vitro chromosomal aberration assay 

utilizing rat lymphocytes.

This study is classified as fully reliable (acceptable/guideline) and satisfies the guideline 

requirement (OPPTS 870.5375, OECD 473) for in vitro mammalian cytogenetics (chromosome 

aberrations) data.

IIA 5.4.4/1 In vivo mammalian cytogenetics - erythrocyte micronucleus assay in mice;

In a bone marrow micronucleus assay (MRID 47832071), groups of 6 male and 6 female CD-1 

mice were treated orally, by gavage, with 0, 100, 200 or 400 mg/kg/day of sulfoxaflor (Purity 

95.6%; Lot/Batch No. E2162-34, TSN003725-0001) prepared in METHOCELTM on 2 

consecutive days. The highest dose level of 400 mg/kg bw was selected for the main assay based 

on the results of a range-finding test in which doses ≥1000 mg/kg bw/day caused more than 50% 

mortality in both sexes and 500 mg/kg bw/day caused unacceptable body temperature decreases 
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in males only. Therefore, both sexes were evaluated in the main study. Groups of animals were 

sacrificed at 24 hours after the second treatment for the collection of femoral bone marrow and 

evaluation of polychromatic erythrocytes (PCE, 2000 PCE/animal) with micronuclei (MN-PCE) 

from the first five animals in each group. The proportion of PCE was determined based upon 

200 erythrocytes per animal and the results expressed as a percentage. Mice treated with 120-

mg/kg bw cyclophosphamide monohydrate by a single oral gavage dose and sacrificed at 24 

hours served as the positive control. 

All animals survived to the end of the observation period. Treatment related clinical signs 

(decreased activity) occurred in 3/6 male mice at 400 mg/kg /day and two of these mice also had 

body temperature decreases of up to 5.8°C five hours post-dosing. There were no statistically 

significant increases in the frequencies of MN-PCE in groups treated with the test material as 

compared to the negative controls. There were no statistically significant differences in the 

percent PCE in groups treated with the test material compared to negative controls. By contrast, 

a significant increase in the frequency of MN-PCE and a significant decrease in the relative 

proportion of PCE: NCE (p<0.05) was seen in the positive control group as compared to the 

negative control group. 

Under the experimental conditions used, sulfoxaflor was not genotoxic in the mouse bone 

marrow micronucleus test.

This study is classified as fully reliable (acceptable/guideline) and satisfies the guideline 

requirement (USEPA OPPTS 870.5395; OECD 474) for an in vivo mammalian cytogenetics –

micronucleus assay in mice.

A.4.7 Neurotoxicity

870.6100 Delayed Neurotoxicity Study - Hen

870.6200 Acute Neurotoxicity Screening Battery

IIA 5.7.1/1 Acute Neurotoxicity – Rats;

In an acute neurotoxicity study (MRID 47832134), ten male and ten female F344/DuCrl rats per 

group were given a single, oral gavage dose of 0, 7.5, 75, or 750 mg sulfoxaflor/kg body weight 

to evaluate the potential for acute neurotoxicity. Body weights were recorded and a functional 

observational battery (FOB) and test for motor activity were conducted pre-exposure (baseline), 

the day of dosing (day 1, time-of-peak effect), day 8, and day 15. The FOB included hand-held 

and open-field observations as well as measurements of grip performance, landing foot splay 

and rectal temperature. Clinical observations were conducted on days 2, 3, and 4. At the end of 

the study all rats from the control and high-dose group and five rats/sex/low- and mid-dose 

group were perfused for histopathologic evaluation of the central and peripheral nervous 

systems, which was conducted on all of the control and high-dose group rats. A second motor 

activity study at dose levels of 0, 2.5, 7.5 and 25 mg/kg was conducted to investigate whether an 

apparent decrease in motor activity at 7.5 mg/kg was reproducible or treatment-related, and to 
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establish a clear no-observed-adverse-effect level (NOAEL). Motor activity was the only 

endpoint examined in this study phase.

One female rat given 750 mg/kg died following dosing on day 1, but the cause of death could 

not be determined. Treatment-related categorical observations on day 1 in males and females 

given 750 mg/kg included increased incidences of muscle tremors and twitches, convulsions, 

splayed hindlimbs and perineal urine soiling. Treatment-related ranked FOB observations on 

day 1 in males and females given 750 mg/kg were as follows: increased lacrimation and 

salivation, decreased pupil size and response to touch, increased level of urination (females 

only), decreased level of open-field activity and gait abnormalities. There were no treatmentrelated ranked or categorical FOB observations present on day 8 or day 15 in males or females 

given 750 mg/kg. There were no treatment-related ranked or categorical observations in males 

or females given 7.5 or 75 mg/kg during any FOB. 

There was a treatment-related decrease in body weight of the 750 mg/kg group when compared 

to controls on days 8 and 15, which was more prominent in males than in females. There was a 

treatment-related decrease in rectal temperature of the 750 mg/kg group when compared to 

controls on day 1, which was not present in the subsequent examinations on days 8 and 15. 

There were no treatment-related effects in grip performance or landing foot splay.

There was a treatment-related decrease in the day 1 total motor activity and an effect on the 

distribution of motor activity counts of males and females given 75 or 750 mg/kg. The effect on 

total motor activity of animals given 7.5 mg/kg was considered equivocal on day 1. There were 

no effects on motor activity on days 8 or 15 in rats of any dose group. In the follow-up motor 

activity study, there were no treatment-related effects on total motor activity or on the 

distribution of motor activity counts for males and females given 2.5, 7.5 or 25 mg/kg when 

compared to controls. 

Treatment-related clinical findings on days 2, 3 or 4 were limited to males and females given 750 

mg/kg, and included decreased or absent feces, red perioral soiling, and perineal urine soiling 

(females only). There were no treatment-related gross or histopathologic findings in the central or 

peripheral nervous system. 

The lowest-observed-adverse-effect-level (LOAEL) for neurotoxicity was 75 mg/kg based on 

decreased motor activity observed on day 1. The no-observed-adverse-effect-level (NOAEL) was 

25 mg/kg. No treatment-related effects were observed for neuropathology; therefore the NOAEL 

for neuropathology was ≥ 750 mg/kg, the highest dose level tested. 

The study is classified as fully reliable (acceptable/guideline) and satisfies the guideline 

requirements (OPPTS 870.6200; OECD 424) for an acute neurotoxicity study in rats. 

870.6200 Subchronic Neurotoxicity Screening Battery (See 870.3100 (p. 85))

870.6300 Developmental Neurotoxicity Study

IIA 5.7.5/1 Developmental Neurotoxicity Study
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In a developmental neurotoxicity study in rats (MRID 478321333), sulfoxaflor (purity 95.6%; 

Lot # E2162-34) was offered on a continuous basis in the diet to 3 groups of 25 bred female 

Crl:CD(SD) rats daily from gestation day 6 through lactation day 21. Target test substance 

concentrations were 25, 100, and 400 parts per million (ppm), which corresponded to predicted 

dosage levels of 2, 8, and 32 mg/kg/day, respectively. Actual overall mean test substance 

consumption in the 25, 100, and 400 ppm groups was 1.8, 7.1, and 27.7 mg/kg/day through 

gestation and 1.9, 7.6, and 29.8 mg/kg/day through lactation, respectively. A concurrent control 

group composed of 25 bred females received the basal diet on a comparable regimen. Dams 

were approximately 13 weeks of age at the beginning of test diet exposure.

There were no test substance-related mortalities in the dams during the study. There were no test 

substance-related clinical findings noted during the daily examinations. Detailed clinical 

observation parameters, as well as maternal body weights and food consumption during gestation 

and lactation were unaffected by test substance exposure.

There were no test substance-related differences noted between groups when comparing the 

mean length of gestation, the process of parturition, and internal macroscopic pathologic 

findings. The mean numbers of former implantation sites and unaccounted for sites, as well as 

maternal kidney and liver weights were similar across groups.

There were no test substance-related effects on F0 maternal parameters in this study. Therefore, 

the no-observed-adverse-effect level (NOAEL) for F0 systemic toxicity and F0 maternal 

reproductive toxicity (process of parturition and duration of gestation) of sulfoxaflor when 

administered orally in the diet was considered to be 400 ppm (equivalent to 27.7 mg/kg/day). 

There were no test substance-related effects on the mean number of pups born, live litter size, or 

the percentage of males at birth at any maternal exposure level. However, there was a reduction 

in postnatal survival from birth to PND 4 compared to the control group in the 100 and 400 ppm 

dose groups. Furthermore, mean pup body weights in the 400 ppm group were 11.8% and 6.5% 

lower than the control group at birth (PND 1) and on PND 4, respectively. The reduced pup 

body weights resulted in a statistically significant delay in surface righting response for pups in 

the 400 ppm group. Pup body weights in the 400 ppm group did not differ from the control 

group values on PND 7 or later time points. The decrease in postnatal survival at 100 and 400 

ppm is consistent with results from a previous probe reproduction study, in which dietary 

exposures of 500 and 1000 ppm resulted in decreased pup survival. The high dose level of 400 

ppm in this study was based on the treatment-related decrease in survival observed in the probe 

study. Postnatal survival and pup body weights and body weight gains in the 25 and 100 ppm 

groups were unaffected by maternal test substance exposure. The age of attainment of surface 

righting response in the 25 and 100 ppm groups and eye opening in the 25, 100, and 400 ppm 

groups were similar to the control group. The attainment of sexual developmental landmarks 

(balanopreputial separation and vaginal patency) were unaffected by maternal test substance 

exposure.

No remarkable clinical observations or macroscopic findings were noted for offspring at any 

exposure level. No test substance-related effects were observed with respect to detailed clinical 

observations, locomotor activity, auditory startle response, and learning and memory. 

Furthermore, there were no test substance-related effects on morphometric parameters or 

histopathology of the brain and/or central and peripheral nervous systems for offspring on PND 
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21 and 72. On PND 72, slight, statistically significant changes in brain weight (a decrease of 5% 

in males relative to controls; an increase of 4% in females relative to controls)) and brain length 

(a decrease of 4% in males relative to controls) were noted at 400 ppm.

The LOAEL for offspring is 100 ppm (7.1 mg/kg bw/day) based on the reduction in pup 

survival. The NOAEL is 25 ppm (1.8 mg/kg bw/day). 

The study is classified as fully reliable (acceptable/guideline) and may be used for regulatory 

purposes. It does not, however, satisfy the guideline requirement for a developmental 

neurotoxicity study in rats (OPPTS 870.6300; OECD 426 (draft)) due to the pending review of 

the positive control data. 

A.4.8 Metabolism

870.7485 Metabolism – Rat

IIA 5.1.1/1 Single and repeat dose oral study in rats (and mice);

In a metabolism probe study (MRID 47832038), the absorption, distribution, metabolism and 

elimination of 14C-sulfoxaflor (>97% radiochemical purity, specific activity 42.0 mCi/mmol; lot 

no. INV 2058) in Fischer 344 DuCrl rats and Crl:CD1 (ICR) mice was evaluated following a 

single oral gavage dose in 0.5% aqueous methylcellulose at a dosing volume of 5 mL/kg. One 

rat/sex and two mice/sex were administered 100 mg/kg 14C-sulfoxaflor. Time-course blood and 

excreta were collected from rats, whereas only excreta was collected from mice up to 72 hours 

post-dosing. The only tissues collected at the 72 hr sacrifice were plasma and RBC. Urine 

samples collected during the first 12 hours post-dosing were analyzed for parent compound and 

metabolite(s). Additionally, two rats (1/sex) and four mice (2/sex) were orally dosed with 100 

mg/kg 14C-sulfoxaflor and plasma collected at Cmax (2 hour post-dosing for rats and an estimated 

11⁄2 hour post-dosing for mice) and analyzed for parent and metabolite(s). This report also 

included results of the analysis of plasma and urine samples collected from 28-day rat, 90-day 

rat, and 28-day mouse dietary subchronic toxicity studies.

Orally administered 14C-sulfoxaflor was rapidly absorbed from the GI tract both by rats and 

mice. Total urinary elimination accounted for 87-98% of the dose in rats and 80-85% of the dose 

in mice, most of which occurred within the first 24 hours post-dosing. Fecal elimination 

accounted for only 5% in rats and 13% in mice, mostly apparently representing unabsorbed dose 

due to its recovery in feces within the GI transit time of 24 hours. Negligible or no radioactivity 

was eliminated via expiration. Elimination of radioactivity from blood was mono-exponential 

with t1⁄2 of 9 and 11 hours from the plasma and RBC of male rats, respectively; the t1⁄2 of 

elimination of 14C-sulfoxaflor from the plasma and RBC of female rats was 7 and 8 hours, 

respectively. Female rats eliminated 14C-sulfoxaflor from the body at a 1.2-fold faster rate than 

males, resulting in the same difference in the AUC. No metabolism of the test material was 

observed following a single oral dose of 14C-sulfoxaflor to rats or mice. Sulfoxaflor was 

excreted mostly as unmetabolized parent, with only low levels of metabolites identified. Both

parent sulfoxaflor and the X11602627 (XR-208) urea metabolite were observed in rat and mouse 

urine samples, but only parent sulfoxaflor was observed in rat plasma (mouse plasma not 

evaluated due to low radioactivity). The concentration of the urea metabolite was similar to that 
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detected in the test material itself as an impurity. In addition to the urea metabolite, 5 additional 

minor metabolites in the rat plasma and 3 possible minor metabolites rat urine were observed, 

whereas one metabolite was observed in mouse urine. Metabolite profiles were similar in urine 

and plasma samples from the 28- or 90-day dietary studies.

This study is classified as reliable with restrictions (acceptable/non-guideline). The study is not 

GLP compliant. However, all experiments were done according to GLP standards. Additionally, 

the study was well conducted and the Agency has confidence in the scientific integrity of the 

data. It was conducted as a metabolism probe study and not to satisfy guideline requirements for 

sulfoxaflor.

IIA 5.1.2/1 Toxicokinetic studies – Second single dose, oral route, in rats;

In a supplemental rat metabolism study (MRID 47832039), the tissue distribution of sulfoxaflor 

(

14C-sulfoxaflor, radiochemical purity 99.3% a.i.; lot no. INV 027474-0001) was evaluated 

following a single oral gavage administration of 5 or 100 mg/kg body weight to groups of four 

F344/DuCrl rats/sex/dose/sacrifice time. The 14C-sulfoxaflor test material was administered in 

0.5% aqueous methylcellulose vehicle (dosing volume 5 mL/kg body weight). Animals were 

sacrificed at predetermined times of either Cmax and 1⁄2Cmax for plasma radioactivity levels (i.e., 

ranges 0.5-2 and 6-8 hours post-dosing, respectively). Radioactivity was also determined in 

urine, feces and cage wash for the 1⁄2 Cmax groups. Additionally, the profile of sulfoxaflorderived metabolites in three representative tissues (liver, kidney and plasma) was characterized 

by HPLC/ESI/MS for groups dosed at 100 mg/kg. A probe study was performed on 3 rats/sex at 

100 mg/kg single gavage dose (sacrificed at Cmax) to develop extraction procedures for liver, 

kidney and plasma for identification of metabolites in the main study. 

Orally administered 14C- sulfoxaflor was rapidly absorbed without any apparent lag time based 

on Cmax times of 0.5 - 1 hr (5 mg/kg) and 2 hr (100 mg/kg). Total recovery of radioactivity from 

all the animals averaged 98% in both groups. 

Test material-derived radioactivity (as μg 14C- sulfoxaflor eq/g) was highest in the GI tract, liver, 

kidney and urinary bladder, consistent with portal of entry and primary excretion tissues. Plasma 

levels were approximately 50-60% of those found in the kidney and liver in both groups. 

Comparison of the Cmax and C1/2 max tissue radioactivity levels, together with comparisons of 

tissue to blood ratios, did not suggest the potential for bioaccumulation.

Parent sulfoxaflor, identified as its two diastereomers, was the only component detected in the 

kidney, liver and plasma samples above the limits of detection of 0.286, 0.563 and 0.146 μg 

equivalent sulfoxaflor /g tissue, respectively, indicating no metabolism of sulfoxaflor.

In summary, administered sulfoxaflor was rapidly absorbed, widely distributed without 

metabolism, with the highest levels in portal of entry and excretory tissues. Test materialderived radioactivity in tissues (other than portal of entry and excretory) tracked that of blood 

and did not indicate potential for bioaccumulation.

This study is classified Fully Reliable (acceptable/non-guideline). The study was conducted to 

provide supplemental information on tissue distribution and metabolite identification of 
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sulfoxaflor at Cmax and 1⁄2Cmax and on its own does not by itself satisfy guideline requirements for 

a general metabolism study in the rodent.

IIA 5.1.3/1 Toxicokinetic studies – Repeated dose, oral route, in rats;

In a rodent general metabolism study, (MRID 47832034), 14C-sulfoxaflor (radiochemical purity 

99.7% a.i.; lot no. INV 2066) was administered to four groups of male and female F344/DuCrl 

rats (4/group/sex) at the following doses: low dose of 5 mg/kg via gavage as a single dose or as 

multiple doses (14 daily doses of unlabeled sulfoxaflor followed by a single radiolabeled dose); 

single gavage high dose of 100 mg/kg, or a single intravenous (IV) low dose of 5 mg/kg). All 

oral doses were administered in 0.5% aqueous methylcellulose vehicle (5 mL/kg body weight). 

Animals were monitored for 168 hours (7 days) post-dosing to determine absorption, 

distribution, metabolism and excretion of 14C- sulfoxaflor. 

Orally administered sulfoxaflor was rapidly absorbed without any apparent lag time. The 

percent absorption of the administered dose in all three oral groups (single 5 mg/kg, multiple 5 

mg/kg or single 100 mg/kg) was at least 92-96%, based on recovery in urine, non-GI tissues and 

expired air. Total recovery of radioactivity from all the animals averaged 102 ± 4 and 108 ± 4% 

in the oral and IV dose groups, respectively. 

The oral doses were rapidly excreted in urine (92-97% of the administered dose) without any 

gender difference. The majority of the urinary elimination (89-94%) occurred within the first 24 

hours post-dosing. Only a small percent (5-8%) of the oral dose was eliminated in feces, also 

mostly within the first 24 hrs post-dosing. 

The IV-administered test material was also rapidly excreted in urine (97-101% of administered 

dose). The majority of the urinary elimination (91-95%) occurred in the first 24 hours postdosing. Only a small percent (6-9%) of the IV dose was eliminated in feces, mostly in the first 

24 hours post-dosing. Systemic bioavailability, calculated from the dose-corrected plasma AUC 

data for the low oral and IV dose groups, was 94% for both male and female rats. 

Only 0.2-1.2% of the administered 14C- sulfoxaflor (oral administration: low single, high single 

or multiple dose) remained in the tissues after 168 hours (7 days) post-dosing. An average of 

0.6-1.3% of the IV dosed 14C- sulfoxaflor remained in the tissues of the animals sacrificed 168 

hours post-dosing.

In the rats dosed orally with 14C- sulfoxaflor, elimination of the radioactivity from plasma was 

rapid during the elimination phase (t1⁄2α = 4-6 hours) followed by relatively slow elimination 

during the terminal phase (t1⁄2 = 39-45 hours). The area under curve (AUC) and Cmax of 

radioactivity in plasma were essentially dose proportional between the low and high dose groups, 

suggesting unsaturated kinetic behavior of sulfoxaflor up to 100 mg/kg body weight. The fate of 

the test-material derived radioactivity in RBC was similar to plasma. The time-course of 

radioactivity in RBC was essentially parallel to the plasma time-course concentration profiles 

with similar concentrations. Kinetics (absorption, elimination t1⁄2, AUC, clearance) of 

radioactivity in RBC were similar to plasma, except that detectable levels of radioactivity were 

found in RBC for an extended period of time compared to plasma. 
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A total of seven radiolabeled components were identified in urine and/or fecal samples. Parent 

sulfoxaflor was the primary component in both urine and fecal samples, accounting for >93% of 

the administered dose. A glucuronide conjugate of sulfoxaflor metabolite X11721061 was 

tentatively identified in urine samples only, comprising 2-4% of the administered dose. Three 

other unidentified minor components, all <1% of administered dose, were found only in pooled 

urine samples. Two different minor components, both <1% of the administered dose, were 

present only in extracts of fecal samples. 

In summary, sulfoxaflor was rapidly and highly absorbed, poorly metabolized and readily 

eliminated primarily in the urine from the rat, with low tissue residues. ADME of sulfoxaflor did 

not show significant gender differences.

This study is classified as fully reliable (acceptable/guideline) and satisfies the guideline 

requirements for a general metabolism study in the rodent.

IIA 5.8.1.1/1 X11719474: Probe Study to Determine Absorption, Metabolism and 

Elimination in F344/DuCrl Rats;

In a non-guideline metabolism probe study (MRID 47832132), absorption, metabolism and 

excretion of the sulfoxaflor metabolite 14C-X11719474 (radiochemical purity 98.8% a.i., lot #

XS9-100040-6, INV030930-0002) following a single oral dose of 100 mg test material/kg body 

weight was evaluated in 1 F344/DuCrl rat/sex. Pharmacokinetics, mass balance and urine 

metabolite profiles were determined. The profile of circulating metabolites in plasma was 

determined in 1 additional rat/sex.

Orally administered 14C-X11719474 was rapidly absorbed without any apparent lag time. Tmax

occurred at 1 hour. Total absorption was 95% of the administered dose in the male rat and 98% 

in the female. A total of 95-97% of the administered dose was excreted in the urine after 168 

hours post-dosing, with the majority (91-95%) rapidly eliminated by 12 hours post-dosing. A 

much lower percentage (2-3%) of the dose was eliminated in feces by 168 hours post-dosing. 

Total recovery of radioactivity from both animals was 98 and 99%. 

Elimination of radioactivity from plasma was biphasic, with most occurring during the rapid ( ) 

elimination phase (t1⁄2α ≤2 hours), with a slower ( ) elimination phase (t1⁄2 = 36 - 41 hours). The 

AUC of radioactivity in plasma was 505 and 351 μg h g-1for male and female, respectively.

Test-material derived radioactivity was also present in RBC, with Cmax concentrations ~27-31% 

lower levels than seen in plasma. Elimination of the radioactivity from RBC was monophasic 

with all of the elimination occurring during the rapid ( ) elimination phase (t1⁄2α <3 hours). The 

AUC of radioactivity in RBC was 377 and 240 μg h g-1, in the male and female, respectively.

The absorbed test material was essentially un-metabolized in the male and female rat. The 

primary component found in urine was parent compound, with two metabolites, or test material 

impurities, present at less than 1% of the administered dose. Only parent compound was found 

in the Cmax plasma samples. 

In summary, administered 14C-X11719474 was rapidly absorbed, mostly un-metabolized and 

eliminated very quickly from the rat.
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This study is classified Fully Reliable (acceptable/non-guideline). It was conducted as a probe 

metabolism study on a metabolite of sulfoxaflor and was not submitted to satisfy guideline 

requirements for a rodent general metabolism study.

870.7600 Dermal Absorption – Rat

IIIA 7.6.2 Comparative dermal absorption, in vitro using rat and human skin;

GF-2032 is a suspension concentrate (SC) formulation containing the active substance 

sulfoxaflor, an experimental insecticide. The nominal concentration of the active substance in 

GF-2032 is 240 g/L. The highest in-use spray dilution concentration is 0.48 g/L and the lowest 

in-use spray dilution concentration is 0.024 g/L. In an in vitro dermal penetration study (MRID 

47832414), sulfoxaflor was applied as GF-2032 to the dermal surface of groups of 5 human skin 

samples/group, or 8 rat skin samples/group at concentrations of 0.024, 0.48, or 2.4 g/L for 24 

hours at an application volume of 10 μL/cm2. 

The overall recovery of the radiolabeled sulfoxaflor was good (95-97%) for all the groups. 

Application of 0.024 and 0.48 g/L resulted in similar rates of absorbed dose, 1.15, and 1.54 % of 

the administered dose in the human and 4.34 and 8.72% in the rat skin, respectively. The 

absorbed dose for the 240 g/L group was lower, 0.26 and 1.3%, in the human and rat skin, 

respectively, indicating saturation of the skin at this level. In all dose groups, a greater 

percentage of sulfoxaflor was absorbed through the rat skin compared to the human skin. The 

rates were most similar in the 0.48 g/L group, with a rat absorbing 2.6-fold greater percentage of 

the applied dose compared to human skin. The differences in absorption rates were greater in the 

0.024 g/L (3.8-fold) and 240 g/L (5-fold) groups.

Although this study does not satisfy EPA guideline requirements, this dermal penetration study 

was done according to OECD 428 guidelines. This study fully reliable (acceptable/nonguideline).

IIIA 7.6.3 Dermal Absorption, In Vivo in the Rat;

5 groups of 4 male rats were dosed with radiolabeled sulfoxaflor as GF-2032 in a dermal 

penetration study (MRID 48732413). GF-2032 is a suspension concentrate (SC) formulation 

containing the active substance sulfoxaflor. The nominal concentration of the active substance in 

GF-2032 is 240 g/L. The highest in-use spray dilution concentration is 0.48 g sulfoxaflor/L. 

The lowest in-use spray dilution concentration is 0.024 g sulfoxaflor/L.

Rats were dosed with 0.024, 0.48, or 240 g/L sulfoxaflor as GF-2032. [14C]-Sulfoxaflor was 

applied to 10 cm2patch of shaved skin for 10 hours, and then washed off with a mild soap 

solution. Groups of rats were sacrificed at 24, 48, 96, 144, and 192 hours after dermal 

application and the extent of dermal penetration was determined. The amount of applied dose 

removed by washing the skin was 96%, 71% and 67% of the applied dose across the dose 

groups, respectively. 

Following a dermal exposure period of 10 h to sulfoxaflor formulation concentrate (240 g/L), 93-

99% of the applied radioactivity was readily removed from the skin surface by a mild detergent 

wash. Approximately 1-2% of the applied dose was absorbed over the exposure interval and 
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subsequent post exposure collection periods up to 192 h after exposure. The highest absorption 

was observed within the 48 hour group with 1.7%.

After a 10 h dermal exposure to the 0.48g/L spray dilution, the dosed material was not as readily 

removed from the skin surface with 62-79% of the applied radioactivity removed by a mild 

detergent wash. Approximately 2-3% of the applied radioactivity was absorbed after 24 h and 48 

h, increasing to 8% at 96 h. By 144 h and 192 h the absorption levels were similar at 11%, 

indicating that absorption of the dose was essentially complete.

After a 10 hour dermal exposure to the 0.024g/L spray, the amount of dislodgeable dose was 

similar to the 0.48g/L spray dilution with 3-71% of the applied radioactivity removed from the 

skin surface by the detergent wash. Approximately 1-3% of the applied radioactivity was 

absorbed after 24 h and 48 h increasing to 6% at 96 h. By 144 h and 192 h the absorption levels 

were similar at 13% and 11%, respectively, indicating that absorption of the dose was essentially 

complete.

This study is considered Fully Reliable (acceptable/guideline) and fulfills the requirements 

(OPPTS 870.7600; OECD 427) for a dermal penetration study in the rat.

A.4.9 Immunotoxicity

870.7800 Immunotoxicity (See 870.3100 (p.85))

A.4.9 Special/Other Studies 

IIA 5.6.12/3 Characterization of the agonist effects of XDE-208 on mammalian muscle 

nicotinic acetylcholine receptors;

Sulfoxaflor is a compound with insecticidal activity that acts as an agonist of insect nicotinic 

acetylcholine receptors (nAChRs). The aim of the work described in this report was to examine 

the influence of sulfoxaflor on mammalian muscle nAChRs. Competition radioligand binding 

was used to examine the ability of sulfoxaflor to bind to nAChRs from three mammalian species 

(human, rabbit and rat) (MRID 47832035). In addition, two-electrode voltage-clamp recording 

was used (with human and rat nAChRs) to examine whether binding of sulfoxaflor resulted in 

functional activation of muscle nAChRs. Radioligand binding experiments demonstrated that 

sulfoxaflor binds to human, rabbit and rat fetal muscle nAChRs. Electrophysiological studies 

revealed that sulfoxaflor is a partial agonist of the rat fetal muscle nAChR. In contrast, 

sulfoxaflor has no detectable agonist activity on the human fetal muscle nAChR or on the adult 

muscle nAChR (from either human or rat). In contrast to the clear agonist activity of sulfoxaflor 

on the rat fetal muscle nAChR, no agonist activity was observed with X11719474, a soil 

metabolite of sulfoxaflor.

This study demonstrates that sulfoxaflor is an agonist of the rat fetal muscle nAChR. In contrast, 

sulfoxaflor has no agonist activity on the equivalent human fetal nAChR or on the rat or human 

adult muscle nAChR. From these findings, it seems reasonable to conclude that the selective 

agonist activity of sulfoxaflor is due to species and age-dependent differences in the amino acid 
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sequences of the nAChR subunits. Furthermore, the soil metabolite, X11719474, had no agonistic 

activity on either the rat or human nAChR subtypes.

This study is reliable with restrictions (acceptable/non-guideline). 

IIA 5.6.12/4 Investigation of the critical window of exposure for fetal abnormalities and 

neonatal survival effects in Crl:CD(SD) rats;

In a non-guideline reproductive/developmental toxicity study (MRID 47832137) sulfoxaflor 

(95.6% a.i. wt/wt; Lot # E2162-34, TSN003725-0001) was administered to pregnant female 

Crl:CD(SD) rats (12/group) at concentrations of 0 (Group 1, control) or 1000 ppm (Groups 2 and 

3) in the diet (corresponding to doses of 0, 38.6, and 76.5 mg/kg/day for Groups 1, 2, and 3, 

respectively). Group 2 was fed the test substance from gestation day (GD) 6-16 to cover all of 

embryogenesis up to, but not including, the start of early fetal movements; Group 3 was fed the 

test substance from GD 16-birth to cover development of the muscle nAChR and its role in 

development of synchronized fetal limb movements up to onset of parturition. 

Treatment-related decreases in body weight were observed in dams in Group 1, resulting in 

decreased body weight gain from GD 6-16; similarly Group 2 dams had treatment-related 

decreases in mean body weight and body weight gain during the test substance treatment 

interval. The body weight effects were accompanied by lower feed consumption (23.3% and 

22.6% lower than controls during the treatment interval for Groups 2 and 3, respectively). No 

gross anatomical abnormalities were observed in any dams in any treatment group.

There were no treatment-related differences in the number of pups born alive or dead in Groups 

2 or 3 when compared to the control. There was a treatment-related 18.8-20.8% decrease in 

Group 3 mean pup body weight in both sexes (alpha=0.05)

 

Offspring from animals in Group 2 did not display previously described fetal abnormalities 

or reduced neonatal survival. Offspring in Group 3 had the same gross effects of limb 

contractures and reduced neonatal survival (alpha=0.05) seen in previous studies that had 

treatment with 1000 ppm sulfoxaflor throughout gestation. 

Daily examination of Group 3 offspring born with limb abnormalities indicated that these 

were fully reversible shortly after withdrawal of maternal dietary exposure to sulfoxaflor. 

In some cases, full reversal of the limb abnormalities was evident the day after birth and 

occurred for all affected animals that survived to postnatal day (PND) 4; reversal also 

occurred in some animals that subsequently died before PND 4. The visceral and skeletal 

findings of abnormal ureter and bent clavicle, the latter of which had a high incidence 

(30.1% of fetuses) in a previous definitive developmental toxicity study, were not present 

in this study at necropsy on PND 4 despite similar maternal sulfoxaflor blood 

concentrations and pup limb abnormality indices between these two studies. 

This study demonstrates that the critical period of developmental susceptibility to 

sulfoxaflor-induced fetal abnormalities (forelimb flexure and hindlimb rotation) and 

reduced neonatal survival is between GD 16-birth, and that all of the fetal abnormalities are 

rapidly reversible after birth.
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This study is Fully Reliable (acceptable/non-guideline).

IIA 5.6.12/5 Investigation of the critical window of exposure for fetal abnormalities 

and neonatal survival effects in Crl:CD(SD) rats (Phase 2);

In a non-guideline reproductive/developmental toxicity study (MRID 47832136) sulfoxaflor 

(95.6% a.i. wt/wt; Lot # E2162-34, TSN003725-0001) was administered in the diet to pregnant 

female Crl:CD(SD) rats (10/group) at concentrations of 0 ppm (Group 1, control) or 1000 ppm 

on gestation days (GD) 16-18 (Group 2), GD 18-20 (Group 3), or GD 20-22/LD 0 (Group 4), 

corresponding to mean intakes of 0, 63.9, 42.5, and 35.7 mg/kg/day for Groups 1, 2, 3, and 4 

respectively. 

Dams in all sulfoxaflor treatment groups (Groups 2-4) had treatment-related decreases in body 

weight gain during their respective treatment intervals. These body weight effects were 

attributed to lower feed consumption, consistent with decreased palatability of test material 

fortified diet observed in previous studies at 1000 ppm. No treatment- related clinical signs were 

observed in any dams in any test substance treatment group.

There were no sulfoxaflor treatment-related effects on gestation survival or sex ratios of the 

pups. There were no apparent treatment-related differences in the number of pups born alive or 

dead, pup body weight, or litter size.

Offspring from animals given 1000 ppm sulfoxaflor for 48 hours starting on the morning of GD 16 

or 18 (Groups 2 and 3) were similar to controls and did not display previously described fetal 

abnormalities or reduced neonatal survival. Offspring given 1000 ppm sulfoxaflor for 48 hours 

starting on the morning of GD 20 (Group 4) had fetal limb abnormalities (forelimb flexure and 

hindlimb rotation) as well as reduced neonatal survival (89.6% survival), demonstrating that 

exposure shortly before birth (GD 21 or 22) is sufficient to induce developmental toxicity.

In addition, daily examination of surviving Group 4 offspring born with limb abnormalities indicated 

that these were fully reversible in surviving offspring shortly after withdrawal of maternal dietary 

exposure to sulfoxaflor. In some cases, full reversal of the limb abnormalities was evident the day 

after birth and occurred for all affected animals that survived to postnatal day (PND) 4; reversal also 

occurred in some animals that subsequently died before PND 4. Likewise, the visceral and skeletal 

findings of abnormal ureter and bent clavicle, the latter of which had a high incidence (30.1% of 

fetuses), in the definitive developmental toxicity study were not present in this study at necropsy on 

PND 4. 

This study demonstrated that sulfoxaflor exposure between GD20-GD22/LD0 is sufficient to 

cause fetal abnormalities (forelimb flexure and hindlimb rotation) and reduced neonatal survival. 

Furthermore, these fetal abnormalities are reversible by PND 4. 

 

This study is Fully Reliable (acceptable/non-guideline).

IIA 5.6.12/6 Observations on the effects of XDE-208 on the phrenic nerve-hemidiaphragm 

preparation from new-born rat;
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Sulfoxaflor, a compound targeted to the insect nicotinic acetylcholine receptor (nAChR) has 

been shown to cause foetal limb contractions and reduced neonatal survival in rats following 

dietary exposure during gestation. The aim of the work described in this report was to make a 

qualitative investigation of the action of sulfoxaflor on isolated phrenic nerve-hemidiaphragm 

preparations from new-born rats (MRID 47832064). 

Sulfoxaflor consistently (n=5) produced a reversible, concentration-dependent contracture of the 

diaphragm that was blocked by the selective muscle-type nAChR antagonist, tubocurarine (10 

μM), showing that the contracture induced by sulfoxaflor is mediated via nAChR activation, 

rather than via a post-receptor mechanism. Furthermore, prolonged application of sulfoxaflor 

caused a sustained muscle contracture. Muscle twitches in response to phrenic nerve stimulation 

were not affected at low sulfoxaflor concentration (100 μM) but were reduced at high 

concentration (1 mM), demonstrating that sulfoxaflor can cause inhibition of nerve-evoked 

contraction of the diaphragm during sustained contracture, consistent with the observed 

impairment of respiration in the neonatal rat. 

The results of these experiments demonstrate that sulfoxaflor caused a contracture of the newborn rat diaphragm by acting on the nAChR. Prolonged application caused a sustained muscle 

contracture and a contracture-associated inhibition of the phrenic nerve-evoked muscle twitch, 

which is considered analogous to the situation in vivo which resulted in foetal limb contractions 

(sustained muscle contractions) and compromised respiration at birth (contracture-associated 

inhibition of the muscle twitch). 

Therefore, the results described in this report are entirely consistent with, and add additional 

support to, the hypothesis that sulfoxaflor causes neonatal death (and foetal abnormalities) via 

activation of the foetal muscle-type nAChR. 

This study is Reliable with Restrictions (acceptable/non-guideline).

IIA 5.6.12/7 Histopathological Evaluation Of Fetal Lung Samples From The 

Developmental Toxicity Study In Crl:Cd(Sd) Rats;

Dietary administration of 1000 ppm sulfoxaflor to Crl:CD(SD) rats during gestation has been 

previously shown to cause neonatal pup death. In order to determine if morphological alterations 

(e.g., increased collagen deposition) in any region of the lungs were responsible for pup death, 

one fetus/sex from five control and four 1000 ppm litters (18 samples total) from the definitive 

developmental toxicity study were collected and preserved in neutral, phosphate buffered 10% 

formalin (MRID 47832135). Sections from these preserved tissues were processed such that 

each slide contained sections of the trachea, bronchi, bronchioles, and alveoli. Slides were 

stained with hematoxylin and eosin and evaluated for histopathological changes. Tissues were 

archived with the developmental toxicity study.

There were no sulfoxaflor induced lesions in the trachea, bronchi, bronchioles and alveoli in any 

of the treated fetuses examined. There were no treatment-related increases in collagen 

deposition around the airways or alveolar walls or any other changes. All observations were 

considered within normal limits.
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This non-guideline study is reliable with restrictions (acceptable/non-guideline). The study is 

not GLP compliant. However, all experiments were done according to GLP standards. 

Additionally, the study was well conducted and the Agency has confidence in the scientific 

integrity of the data. 
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Appendix B. Sulfoxaflor Mode-of Action for Reproductive and Developmental Effects

The following Mode-of-Action was presented to an HED committee for comment on its acceptability and plausibility 

on Dec. 7, 2011. The general consensus of the committee was that the data supported the overall MOA in rats but 

the MOA was applicable to humans.

Sulfoxaflor is a member of a new class of insecticides, the sufoximines, with proposed uses on 

cotton, soybeans, cereals, citrus, leafy and fruiting vegetables, cole crops, grapes, apples, and a 

variety of other crops. It provides control for a broad spectrum of piercing/sucking insects. 

Sulfoxaflor is a nicotinic receptor agonist, similar to neonicotinoid insecticides such as 

acetamiprid, imidacloprid, and thiacloprid. However, unlike neonicotinoids, sulfoxaflor is not 

susceptible to in vivo metabolism by monooxygenase enzymes, which causes virtually all known 

cases of resistance in the field to this class of insecticides.

Toxicity and mechanistic studies in rats, rabbits, dogs and mice highlight the liver and the 

nervous systems as target organ systems. Liver effects in subchronic and chronic studies include 

organ weight and enzyme changes, hypertrophy, proliferation, and tumors. Neurological effects 

are manifested as limb flexure, bent clavicle and convoluted/hydroureter in rat fetuses and 

decreased neonatal survival. These effects were not observed at similar maternal and fetal 

systemic exposure levels in NZW rabbits. Finally, long term studies produced treatment related 

tumors in the rat and mouse including liver, Leydig, and preputial gland tumors. 

In rats, sulfoxaflor exposure during gestation caused effects on neonatal survival and fetal 

abnormalities, but neither effect occurred in rabbits. Similar maternal and fetal blood data 

showed that the interspecies difference between rats and rabbits was not due to toxicokinetics; 

therefore, the species difference is likely due to toxicodynamics.

Since the insecticidal MOA is based on agonism of the nicotinic acetylcholine receptor 

(nAChR), it is likely that the developmental effects were also related to nAChR binding. There 

are two types of mammalian nAChRs, neuronal and muscular. The neuronal nAChRs are 

principally located in the central and peripheral nervous system and disregulation is often 

manifested as the modification of biological setpoints such as tachycardia, blood pressure, 

inflammation, cognitive learning, arousal motor control and analgeisa. The muscle nAChRs are 

found in the intramuscular junctions of skeletal muscles. Disregulation of these receptors can 

result in muscle contraction, difficulties in breathing, and ultimately death. Furthermore, there 

are two subtypes of muscle nAChRs, a fetal form and an adult form. The switch from fetal to 

adult occurs shortly before birth in humans and shortly after birth in rats. Based upon the types 

of skeletal effects observed and their appearance during early development, the registrant has 

proposed a MoA involving the interaction of sulfoxaflor with the fetal muscle nAChRs. 

Postulated MOA for sulfoxaflor-induced muscle contracture and death in neonatal offspring 

Given that sulfoxaflor targets the insect nAChR, and that functional expression of the fetal-type 

neuromuscular junction nAChR occurs in late gestation and is involved with limb muscle 

function, it was hypothesized that the neonatal offspring abnormalities and deaths occur via 

a single MoA: sulfoxaflor’s sustained agonism at the fetal-type muscle nAChR and 
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subsequent sustained muscle contracture of the limb, shoulder girdle and diaphragm, 

respectively (MRID 48288940). 

A single MOA is considered to be responsible for the neonatal offspring findings since the 

sulfoxaflor-induced limb contracture, clavicle abnormalities, and neonatal deaths occurred at the 

same dose with similar incidences (Figure 1). In order for a single mode of action to be 

plausible, the findings should have a similar incidence across doses from all studies. Based upon 

similar dose-response curves for both effects (i.e., limb abnormalities and neonatal deaths), the 

data from multiple studies have a high degree of correlation (R2values of 0.93 and 0.91), 

supporting a single MOA with different apical end points rather than a different MOA for each 

of the two major effects in rats. 

Figure 1. Dose-response curves with non-linear regression analyses for the percent of 

neonatal offspring affected by death and/or limb contracture in rats. 

Study type abbreviations: 1st gen and 2nd gen, 1st and 2nd generations of the two-generation 

reproductive toxicity study; 421-like, reproductive toxicity screening study; X-foster, crossfoster study; CW 1, critical window study phase 1; CW 2, critical window study phase 2; 

DNT, developmental neurotoxicity study; DT, prenatal developmental toxicity study.

This MOA is proposed to progress through the following key events: (1) sulfoxaflor binding and 

(2) agonism at the fetal-type muscle nAChR, resulting in (3) sustained agonism/sustained muscle 

contracture in neonatal offspring (fetus and pup). This sustained muscle contracture results in 

limb contracture, bent clavicles, and abnormal neonatal respiration after birth with ensuing 

neonatal deaths.

 

The sequence of events in sulfoxaflor’s proposed MOA for muscle contracture and neonatal pup 

death:

Specific binding to the fetal-type muscle nAChR (Key Event #1)

Neonatal Death and

Limb Abnormalities

0 10 20 30 40 50 60 70 80

0

10

20

30

40

50

60

70

80

90

100

110

1st gen

2nd gen

421-like

X-Foster

DNT

CW 1

CW 2

DNT

DT

1st gen

2nd gen

Neonatal Death

Limb Abnormalities

CW 1

CW 2

Dose (mg/kg/day)

Affected Offspring (%)

R

2= 0.93

R

2= 0.91
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Agonism at the fetal-type muscle nAChR (Key Event #2)

Sustained agonism/sustained muscle contracture (Key Event #3)

Key Event #1: Specific binding to the fetal-type muscle nAChR

Competition radioligand binding was used to examine the ability of sulfoxaflor to bind nAChRs 

from three mammalian species (human, rabbit and rat). Initial radioligand binding studies were 

performed with [3H]-sulfoxaflor, the aim being to examine whether sulfoxaflor is able to bind to 

mammalian muscle nAChRs. However, technical difficulties were encountered in performing 

binding experiments with [3H]-sulfoxaflor that were associated with high levels of non-specific 

binding. Therefore, a series of experiments was performed to examine whether unlabelled 

sulfoxaflor was able to displace binding of the high-affinity nAChR radioligand [3H]-epibatidine 

from tissue homogenates prepared from rabbit fetal forelimb muscle, rat fetal forelimb muscle 

and human fetal recombinant nAChRs expressed in HEK (human embryonic kidney) cells 

(MRID 47832035). 

Dose-dependent displacement of [3H]-epibatidine binding was observed with increasing 

concentrations of sulfoxaflor for all three preparations examined (human, rabbit and rat). At 

higher concentrations of sulfoxaflor, almost complete displacement of bound [3H]-epibatidine 

was observed (Fig. 2). Although data obtained with human nAChRs and rabbit muscle are well 

fitted by the single-site model (solid lines in Fig. 2), the binding data from rat muscle were fitted 

with a two-site model (dotted line in Fig. 2) that revealed two distinct binding sites of different 

affinities (0.01 mM and 8.9 mM). The ability of sulfoxaflor to bind either a single (human and 

rabbit) or multiple (rat) sites on the nAChR is ambiguous. However, demonstration of the 

capacity of sulfoxaflor to bind mammalian nAChRs and potentially affect the functionality of the 

receptors is of great significance.
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Figure 2. Sulfoxaflor displacement of [3H]-epibatidine in (A) rabbit fetal muscle tissue, (B) rat 

fetal muscle tissue demonstrateing the 1-site and 2-site binding models, and (C) and in HEK-293 

cells expressing recombinant human fetal nAChRs 

Table 1. XDE-208: Dose Response for MoA Key Event #1: Fetal-type Muscle nAChR Binding

Media Conc. (μM)

Key Event 1 Fetaltype Muscle 

#

0.3 μM 5

+

3 μM 0

10 μM 0

30 μM 21

100 μM 31

300 μM 31

1000 μM 37

3000 μM 51

Dose
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10000 μM 100

#

Percent inhibition of maximum epibatidine binding

+ Within background of system and not considered biologically 

Key Event #2: Agonism at the fetal-type muscle nAChR

The ability of sulfoxaflor to act as an agonist of fetal and adult muscle nAChRs was examined by 

expression of rat and human nAChRs in Xenopus oocytes (MRID 47832035). In mammalian 

muscle cells, nAChRs are expressed at the neuromuscular junction (NMJ) and are composed of 

five nAChR subunits (α1, β1, γ, δ and ε). Transcription of the γ and ε subunits is differentially 

regulated during development, with the γ subunit expressed in "fetal" muscle and the ε subunit 

expressed in "adult" muscle (Mishina et al., 1986)(Figure 3). 

Figure 3. Subunit composition of the fetal-type and adult-type muscle nAChR.

Expression of the fetal- and adult-type nAChRs was achieved by microinjection of cDNA or 

cRNA encoding the appropriate rat or human muscle subunits in Xenopus oocytes. To generate 

the fetal form of the muscle nAChRs, α1, β1, γ and δ cDNAs or cRNAs were injected, whereas 

α1, β1, δ and ε were injected to generate the adult form. In each case, functional responses (i.e, 

membrane currents) were detected in response to application of the endogenous agonist 

acetylcholine (ACh). There have been no reports of the molecular cloning of nAChR subunits 

from rabbit and so rabbit muscle nAChRs were not examined in this manner. Two-electrode 

voltage-clamp recording from Xenopus oocytes was performed 1-5 days after micro-injection 

with cDNA or cRNA. 

Clear agonist-evoked responses were observed with sulfoxaflor (XDE-208) at the rat fetal-type 

nAChR (Fig. 4). Dose-dependent agonism at the fetal-type muscle nAChR was demonstrated; 

the lowest tested concentration having no agonism while incubation of the oocytes with higher 

concentrations of sulfoxaflor showed increasing agonism. There was no apparent agonism in 

either the adult rat or human (fetal and adult) type receptors (Table 2).

 Fetal-Type nAChR Adult-Type nAChR
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Figure 4. Representative whole-cell current responses in a Xenopus oocyte cell expressing 

fetal-type rat (α1)2β1γδ nAChRs. Inward currents are show from the same oocyte in 

response to application of acetylcholine (100 μM) and XDE-208 (3 mM). The length of 

agonist application (5 secs.) is indicated by the horizontal bar. Agonist activation is 

associated with downward deflection in the trace. Note, there was recovery of response 

after ACh or sulfoxaflor were washed off (Millar, 2010).

Table 2. Agonist-activation of nAChRs expressed in Xenopus oocytes by 

sulfoxaflor (3mM).

Maximum response (% + SEM; 

normalized to max. ACh response)

Rat fetal muscle 39 ± 2.4%

Rat adult muscle No response

Human fetal muscle No response

Human adult muscle No response
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Figure 5. Agonist activation of nAChRs expressed in Xenopus oocytes. Data are shown 

for the rat fetal (α1)2β1γδ nAChR (A) and rat adult (α1)2β1δε nAChR (B). AChRs were 

expressed by microinjection of cRNA in Xenopus oocytes. Dose-response curves are 

shown in which agonist-evoked responses are normalized to the maximal response detected 

with the endogenous agonist, acetylcholine (ACh). Note that no receptor desensitization 

occurs, which would have been seen as a diminished agonist response at higher doses. 

Data points are means of 3-7 responses. Adapted from Millar, 2010.

Table 3. Sulfoxaflor-induced agonism of rat Fetal-type muscle nAChRs 

expressed in Xenopus Oocytes

Media Conc. (μM 

sulfoxaflor)

% Response (normalized to 

maximum. ACh response)

10 μM 0

30 μM 1.0

100 μM 5.1

300 μM 28

1000 μM 71

3000 μM 100

10000 μM Not Determined

Sulfoxaflor Agonism at the Adult-type Muscle nAChR

100 to 3000 μM 0

Key Event #3: Sustained agonism at the fetal-type muscle nAChR and sustained muscle 

contracture

Sulfoxaflor readily perfuses into muscle from the blood (MRID 47832039) and therefore muscle 

sulfoxaflor concentrations would also be maintained at effective levels as long as dietary 
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treatment continued. At the neuromuscular junction, the neurotransmitter ACh binds to Ach 

receptors on muscle fibers causing contraction. ACh undergoes tightly regulated release 

followed by rapid hydrolysis by acetylcholinesterase (AChE), unlike sulfoxaflor which would 

remain at the nAChR synaptic cleft due to its lack of hydrolysis by AChE. Thus, upon fetal-type 

muscle nAChR activation, a sulfoxaflor-induced muscle contracture would be sustained for as 

long as sufficient sulfoxaflor molecules remain available for receptor binding.

To directly assess muscle contracture at the neonatal diaphragm, sulfoxaflor was tested for 

agonist action on the isolated phrenic nerve-hemidiaphragm preparation (Bulbring, 1946) from 

new-born rats (MRID 47832064). A number of issues were addressed in this study including 1)

Concentration-dependence of the contracture produced by sulfoxaflor, 2) Block of the 

response to sulfoxaflor by tubocurarine, and 3) Response to prolonged sulfoxaflor 

application. To accomplish this, diaphragm muscle preparations were mounted in a recording 

chamber and bathed in a physiological salt solution. A myograph wire attached to the muscle 

tendon was connected to a Harvard isometric strain gauge transducer to record muscle tension. 

The phrenic nerve was stimulated using a bipolar stimulating electrode placed at the nerve entry 

point to the muscle with supra-maximal rectangular voltage pulses of 0.2 ms duration at a 

frequency of 0.5 Hz. Strain gauge transducer and stimulating electrode were mounted on 

micromanipulators in order to allow accurate positioning relative to the muscle. Acetylcholine, 

tubocurarine, and sulfoxaflor were applied by manually switching taps controlling solutions 

flowing to the inflow manifold of the recording chamber. Recorded measures include 1) changes 

in muscle twitch, and 2) muscle contracture following test material application to the bath 

perfusion system. 

1) Concentration-dependence of the contracture produced by sulfoxaflor

1mM sulfoxaflor consistently produced a contracture of the neonatal diaphragm muscle 

and a decrease in muscle twitch response. At 100 μM sulfoxaflor, there was little effect on 

twitch tension.
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Figure 6. Rat fetal diaphragm tissue demonstrates contraction in the presence of 

sulfoxaflor.

Expanded time scale display of the sulfoxaflor response illustrates the muscle contracture 

and the accompanying decrease in twitch tension induced by sulfoxaflor. In five 

preparations, the muscle twitch response decreased to 34 ± 3.2% of control during 

responses to 1 mM sulfoxaflor.

Figure 7. Expanded time scale demonstrating decreased twitch tension in the presence of 

sulfoxaflor.
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2) Block of the response to sulfoxaflor by tubocurarine,

The response to sulfoxaflor was shown to be antagonized by the nicotinic antagonist, 

tubocurarine. Pre-incubation of the muscle tissue with tubocurarine prevents sulfoxaflor-induced 

muscle contractions, indicating that sulfoxaflor is acting via the nAChR and not via a postreceptor mechanism.

Figure 8. Pre-application of 10μM tubocurarine (Tubo) effectively blocks the muscle 

twitches and antagonises responses to 100μM or 1mM XDE-208 (Gibb, 2010).
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3) Response to prolonged sulfoxaflor application

During application of a high concentration of sulfoxaflor (1mM), the muscle contracture is 

sustained, suggesting little desensitization of the muscle nAChRs in response to this agonist. 

Although the muscle contracture is sustained in the presence of sulfoxaflor, the muscle recovers 

normal function on removal of sulfoxaflor from the solution bathing the muscle. 

Figure 9. Prolonged application (7 minutes) of 1 mM XDE-208 shows a sustained 

contracture by the diaphragm muscle (Gibb, 2010).

Dose Response of sustained muscle contracture (i.e., forelimb flexure and hindlimb rotation)

Increased receptor response with increasing sulfoxaflor exposure has been demonstrated for 

several key events including receptor binding, receptor agonism, diaphragm muscle contraction, 

and fetal effects in vivo.

Table 4. Dose response observations from in vitro mechanistic studies

Effect Sulfoxaflor conc.(μM)

Key Event #1 Increased displacement of nAChR 

radiolignad [H3]-epibatidine from 0 

to near 100% 

0.3-1000

Key Event#2 Increased agonism in fetal-type 

nAChR from 0 to 100%

10-3000

Key Event #3 Greater relative contraction of fetal 

rat diaphragm muscle at 1mM 

compared to 100 μM sulfoxaflor

100 μM and 1 mM

200 s 

XDE-208 1mM

Wash
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Temporal concordance of sulfoxaflor levels, nAChR fetal-type muscle receptors, muscle flexures, 

and neonatal deaths 

Ontogeny of fetal-type nAChRs

In rats, the muscle nAChR develops functional subunit expression at the neuromuscular junction 

between GD 15 and 17 (Kues et al., 1995) resulting in synchronized fetal limb movements 

(Robinson and Smotherman, 1988) and diaphragmatic responsiveness between GD 16 and 17 

(Bennett and Pettigrew, 1974), the latter being critical for the transition to extrauterine 

respiration. Replacement of the γ subunit by the ε subunit initiates late during the first postnatal 

week in rats and is largely complete by the end of the second postnatal week in limb and 

respiratory muscles (Missias et al., 1996).

Cross fostering – Gestation

A cross-fostering study demonstrated that the effect of sulfoxaflor on pup survival was due to in 

utero, not lactational exposure (MRID 47832063). Groups of female Crl:CD(SD) rats were fed 

diets supplying 0 (control) or 1000 ppm sulfoxaflor for two weeks prior to mating through 

weaning on lactation day (LD) 21. As the control and treated females mated, they were 

subdivided into Foster dams and Donor dams. Cesarean-section was performed on gestation day 

(GD) 21 Donor dams, at which time, one or more batches of two of their offspring/sex were 

immediately cross-fostered to a Foster dam(s) that had their own litter removed that day (i.e., on 

LD 0). After cross-fostering was complete, each control and sulfoxaflor-treated Foster dam had 

mixed litters comprised of two pups/sex that originated from control Donor dams (five litters) 

and two pups/sex that originated from sulfoxaflor-treated Donor dams (eight litters). 

All offspring from dams exposed to 1000 ppm sulfoxaflor prior to birth died by postnatal day (PND) 

4, irrespective of whether they were cross-fostered to control- or treated-foster dams (see results 

Table 5 below). Consistent with reduced viability, some offspring were cold to the touch, had bluish 

skin, autolyzed and cannibalized, and stomach void of milk. Conversely, there was no effect on 

neonatal survival for pups exposed to sulfoxaflor only after birth. Furthermore, PND 1 pup body 

weights were significantly decreased in prenatally exposed offspring. 

Table 5. Cross Foster or Treated Foster Dams Results

Foster

Dams

Donor

Pups Hypotheses for Pup Survival Outcome

Control

Control in utero

No effect expected

(negative control) No effect

Treated in utero

If pups die, effect comes from treated pups

(i.e. in utero effect)

All pups died

By PND4

sulfoxaflor

1000 ppm

Control in utero

If pups die, effect comes from treated

dams (i.e. lactational effect) No effect

Treated in utero

Pups death expected

(positive control)

All pups died

By PND4

Critical window studies – late gestation effect
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The cross fostering study clearly indicated that sulfoxaflor–induced deaths were dependent upon 

in utero exposure. In order to appropriately frame the incidence data presented in this mode-ofaction experiment, the findings presented here were compared to the guideline definitive 

developmental toxicity study in Crl:CD(SD) rats and the first critical window study. Treatmentrelated findings in the offspring were found at 1000 ppm in the developmental toxicity study 

(sulfoxaflor exposure GD 6-birth; MRID 47832140), Group 3 in critical window 1 (sulfoxaflor 

exposure GD 16-birth; MRID 47832137) and in Group 4 in the critical window 2 study 

(sulfoxaflor exposure GD 20-22/birth; MRID 47832136). See Table 6. When exposure was 

limited to between GD 6-20, regardless of dose, they were no treatment-related offspring effects. 

However, when exposure spanned the GD 20-birth, and were sufficiently high (i.e., 1000 ppm), 

offspring treatment related effects were observed.

Table 6. Comparison to Developmental Toxicity Study

Developmental Toxicity 

Study(MRID 47832140)

Critical Window 1

(MRID 47832137)

Critical Window 2 

(MRID 47832136)

Group: Group 2 Group 

3

Group 4 Group 2 Group 3 Group 2 Group 3 Group 4

Dose 

(ppm): 25 150 1000 1000 1000 1000 1000 1000

Treatment 

period: GD 6-21 GD 6-21 GD 6-21 GD 6-16 GD 16-Birth

GD 16-

18 GD 18-20 GD 20-22/LD 0

Avg.TMI 

(mg/kg/day) 1.95 11.5 70.2 76.5 38.6 62.9 42.5 35.7

TK plasma 

conc.

(μg/g)

0.843 

± 0.09

4.938 

± 0.87

35.245 

± 5.43

35.4 –

40.9 32.1 - 43.2 16.4 -33.3

23.0 -

30.2 5.41 - 16.1a

Offspring 

Effects NO NO YES NO YES NO NO YES

GD gestation day

a

Three of the four sampled rats had undergone parturition prior to blood collection

Reversibility when sulfoxaflor removed from diet

The incidence of limb abnormalities decreased over the first two-to-four days of postnatal life. 

While a portion of the decreased incidence was due to pup deaths, reversibility of the limb 

abnormalities was directly demonstrated in the two critical window studies as evidenced by a 0% 

incidence of forelimb flexure and hindlimb rotation by PND 2 or 4 (Table 7). Reversal of the 

bent clavicles was indirectly demonstrated by an absence of bent clavicles in PND 4 pups (of 86 

pups evaluated in the affected groups), which is significant as these findings were observed at a 

relatively high incidence (30.1%) in GD 21 fetuses from dams exposed to 1000 ppm sulfoxaflor 

in the developmental toxicity study. These reversibility data suggest that the limb abnormalities 

were transient, consistent with a pharmacologic MoA for sulfoxaflor.

Table 7. Reversibility of limb abnormalities in aging pups.
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Critical Window 1

(MRID 47832137)

Critical Window 2 

(MRID 47832136)

Treatment period GD 16-birth GD 20-22/LD0

PND 0 to 1 11 5

PND 1 to 2 6 2

PND 2 to 3 3 0

PND 3 to 4 1 0

Total reversals 21 7

Furthermore, the timing of the neonatal deaths indicates a distinct change in the 

pharmacodynamic activity of sulfoxaflor after PND 4. In the 2-generation reproduction study 

(MRID 47832142), pup deaths were slightly, but significantly, greater in the high dose group 

(400 ppm) compared to controls; 95.4% v. 97.2% for the F1 and 93.0% v. 98.5% in the F2 

generation prior to PND 4. However, survivability exceeded 99% for both generations after 

PND 4, despite the continued exposure of the pups to sulfoxaflor through LD 21. 
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Table 8. Concordance and dose response of offspring effects observed following treatment with sulfoxaflor

Internal 

Dose 

(μM)

Applied 

Dose 

(ppm)

Exposure 

Days

KE #1

Fetal-type 

Muscle 

nAChR 

Binding#

KE #2 

Fetal-type 

Muscle 

nAChR 

Agonism$ 

KE #3

Sustained Agonism & Sustained Muscle 

Contracture

Neonatal Apical Endpoints

Forelimb Flexure, Hindlimb 

Rotation, Bent Clavicle, Death&

Neonatal 

Diaphragm$

(Fetal-type 

Muscle nAChR) 

Reversible?

Neonatal 

Offspring 

Limb 

Contracture^

Reversible?

2.3 251 GD 6-21 - -

4.0 252 PrematingLD 21 - -

10 μM in vitro4- - -

15 1501 GD 6-21 - -

16 1002 PrematingLD 21 - -

ND 1003 X - -

30 μM in vitro4+ +

57 4002 PrematingLD 21 - +

ND 5003 ND++

60 10006+ Y +

89 10007 ND++++

100 μM in vitro4++ +

100 μM ex vivo8+ Y

101 10003 X ND++++

108 10001 GD 6-21 +++ +++

136 10005++ Y +++

300 μM in vitro4++ ++

1000 μM in vitro4+++ +++

1000 μM ex vivo8+++ Y

3000 μM in vitro4+++ +++

1Rat Developmental Toxicity, 2Two-Generation Reproduction, 3One-Generation Reproduction, 4Xenopus Oocytes-Recombinant Fetal-type Muscle 

nAChR, 5Critical Phase 1 Mode of Action, 6Critical 

Phase 2 Mode of Action, 7Cross Foster, 8Neonatal Diaphragm Ex Vivo Electrophysiology

4$ Dose-response curve evaluated for muscle nAChR agonism (100-3000 μM).

Dose
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4* Full dose-response data for fetal-type muscle nAChR binding and agonism showed in Table 3.

9Highest dose level from the One-Generation Reproduction and Rat Developmental Toxicity studies.

#

Percent inhibition of epibatidine binding: +, 0-25%; ++, 25-50%; +++, 50-100%

$

Percent of maximum XDE-208 response: +, 0-25%; ++, 25-50%; +++, 50-100%

^ Incidence (fetal/pup basis): +, 0-25%; ++, 25-50%; +++, 50-100%

& Maximum incidence (fetal/pup basis): +, 0-25%; ++, 25-50%; +++, 50-100%

ND, No Data

ND+, No data as early studies did not examine this parameter

Y, Yes
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Biological plausibility and coherence

The postulated MoA for the neonatal deaths in rats is considered biologically plausible and 

coherent. The observed sulfoxaflor-induced limb and shoulder girdle contracture abnormalities 

and neonatal death are biologically consistent with the functional ontogeny of the fetal-type 

muscle nAChR in the rat.

Alternative Modes of Action

The registrant has proposed a number of alternative MoAs, including consideration of 

sulfoxaflor-induced limb abnormalities and neonatal offspring deaths due to: agonism at other 

AChR types (adult-type muscle nAChR, neuronal nAChR, muscarinic AChR), action 

downstream of the fetal-type muscle nAChR, antagonism at the fetal-type muscle nAChR, 

maternally-mediated fetal immobilization, inhibition of acetylcholinesterase and inhibition of 

angiotensin-converting enzyme. A more detailed examination of each of the alternative MoAs 

can be found in Mode of Action Evaluation and Human Relevance Framework Analysis for 

XDE-208-Induced Fetal Abnormalities and Neonatal Death in Rats (MRID 48288940).

a) Agonism at other Acetylcholine Receptor Types (Adult-type muscle nAChR,

Neuronal nAChRs, Muscarinic AChR)

Adult-type nAChRs

In an in vitro study (MRID 47832035) in which recombinant adult-type nAChR were expressed 

in Xenopus oocytes, sulfoxaflor was found to bind to the receptor, however no functional 

agonism was demonstrated up to sulfoxaflor’s limit of solubility. Furthermore, in in vivo studies 

in adult rats or rats older than PND 4 in the two generation reproduction study, there was no 

evidence of nACHr related toxicity such as muscle fasciculation or limb contractions. Rather, 

continued dietary exposure to sulfoxaflor in older animals resulted in hepatic toxicity along 

decreased body weight and body weight gains.

Neuronal nAChRs

Although the interaction of sulfoxaflor with neuronal nAChRs, as opposed to the proposed 

skeletal muscle nAChRs is plausible, the absence of historic neuronal nicotinic manifestations 

such as muscle weakness or flaccidity makes this MoA unlikely. In contrast, sulfoxaflor-induced 

limb contractures result in rigid, contracted limbs. Breathing movements are also known to be 

partially regulated by neuronal nAChRs in the brainstem. Although, prenatal nicotine exposure 

has been demonstrated to alter fetal lung development in rats (Maritz and van Wyk, 1997), it 

does not cause death in normoxic conditions (Geller, 1959; Sobrian et al., 1995). Increased 

deaths in neonatal rats following exposed to sulfoxaflor and normal histopathology of GD 21 

fetal lung tissue (MRID 47832135) decrease the plausibility of this MoA.

Muscarinic AChRs

Agonism at muscarinic AChRs has also been explored as an alternative MoA. The most 

plausible target by which a compound could cause death in neonatal offspring would be via 

muscarinic activity would be the heart or lung. However, activity at these receptors would be 

accompanied by systemic clinical signs of mAChR activity such as salivation, lacrimation, and 
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convulsions, none of which were observed in the Guideline or MoA studies. Hearts were grossly 

normal on GD 21 visceral examination (including internal structures) in the prenatal 

developmental study in rats, and there were no adverse histological findings in the lungs. 

b) Agonsim downstream of the fetal-type muscle nAChR

Downstream agonism of diaphragm muscle has been demonstrated with the herbicide cartap, 

causing respiratory failure and irreversible contracture of adult-type diaphragm preparations. 

Rather than acting at the muscle nAChR directly, the diaphragm contracture is via post-receptor 

induction of extracellular Ca2+ influx, release of internal Ca2+, and an inhibition of 

[3H]ryanodine binding to the Ca2+ release channel of sarcoplasmic reticulum (Liao et al., 2000). 

In the phrenic-nerve hemidiaphragm experiments conducted with sulfoxaflor where sustained 

muscle contracture was demonstrated, a post-nAChR MoA would have been manifested by 

continued contraction in the presence of co-application with the nAChR antagonist tubocurarine. 

The sulfoxaflor-induced diaphragm contracture was completely eliminated with co-incubation 

with tubocurarine, thereby discounting a post-receptor MoA in the induction of the 

developmental effects of sulfoxaflor.

c) Fetal-type muscle nAChR inactivation

Nongenetic, pharmacologic antagonism of the fetal-type muscle nAChR also results in neonatal 

offspring death and limb abnormalities. A historical example of this includes the use of 

tubocurarine. Exposure to tubocurarine, a non-depolarizing neuromuscular blocking agent, 

during the last week of gestation in rats causes direct fetal paralysis capable of causing forelimb 

contracture, hindlimb rotation and death (Shoro, 1977). While this may appear similar to the 

effects seen with sulfoxaflor there are several important distinctions. First of all, neuromuscular 

blocking agents do not readily cross the placenta (Evans and Waud, 1973). Secondly, the limb 

contracture effects result in skeletal alterations in the limb cartilage, something that is not 

observed with sulfoxaflor. Finally, fetal paralysis additionally results in pulmonary hypoplasia, 

which has previously been mentioned to not occur following sulfoxaflor exposure.

d) Acetylcholinesterase Inhibition

Following sublethal exposures in rats, cholinergic signs of AChE toxicity are generally observed 

as clinical signs and in the absence of external, visceral, or skeletal abnormalities in fetuses. 

Therefore AchE inhibition does not fit the profile observed following sulfoxaflor exposure.

e) Angiotensin-converting enzyme (ACE) inhibition

Angiotensin-converting enzyme (ACE) inhibition presents another MoA that has been 

demonstrated to result in fetal limb contractures when exposure occurs during fetal development 

in humans (Buttar, 1997). The limb contactures which occur are secondary to renal failure 

associated oligohydramniosis. Other secondary fetal anomalies include potentially fatal 

hypotension, anuria, craniofacial deformities and hypoplastic lung development. Furthermore, 

rodents are relatively resistant to the teratogenic effects of ACE inhibitors and high doses of 

ACE inhibitors typically result only in fetal growth retardation and occasionally increased pup 

death.
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Table 9. Summary Evaluation for Other Possible MOAs in the Rat

Alternative 

MoA Example MoA Characteristics 

Plaubility/ 

Coherence Evidence

Adult-type 

NMJ 

nAChR 

agonism

Acetylcholine

Muscle fasciculations, 

tonic or clonic limb 

contractions; Fetal 

immobilization due to 

uterine contraction

- Plausibility/ 

Strong 

coherence 

across studies

XDE-208 causes no 

agonism at the adult-type 

NMJ in vitro; no clinical 

signs in dev. tox. and 

repro. tox. studies

Neuronal 

nAChR 

subtype 

agonism

Nicotine, 

Epibatidine

Clinical signs of 

cholinergic stimulation 

followed by 

desensitization 

(inhibition); Lung 

hypoplasia 

- Plausibility/ 

Strong 

coherence 

across studies

No indication of 

representative clinical 

signs in adults or 

offspring; normal lungs 

(including 

histopathology) in GD 21 

fetuses 

Muscarinic 

nAChR 

agonism

Muscarine, 

Carbamylcholine

Clinical signs of 

cholinergic stimulation 

and/or inhibition; death 

caused by action at 

heart or lungs 

- Plausibility/ 

Strong 

coherence 

across studies

No indication of 

representative clinical 

signs in adults or 

offspring; normal hearts 

(including internal 

structures) and lungs 

(incl. histopathology) in 

GD 21 fetuses

Agonism 

downstrea

m of the 

fetal-type 

NMJ 

nAChR

Cartap

Muscle contracture 

associated with 

intracellular calcium or 

ATP regulation; not 

blocked by NMJ AChR 

antagonists 

- Plausibility/ 

Limited 

coherence, 

only evaluated 

in ex vivo study

Diaphragm contracture 

completely blocked by 

co-exposure to the NMJ 

nAChR antagonist, αtubocurarine

Fetal-type 

NMJ 

nAChR 

inactivation

αTubocurari

ne

Decreased or 

eliminated fetal 

activity; Limb 

contracture 

characterized by 

hypotonia; Altered 

limb skeletal structures; 

Lung hypoplasia 

- Plausibility/ 

Good 

coherence 

across studies; 

Agents have 

limited 

placental 

transfer, 

requiring direct 

fetal injection

XDE-208-induced 

decreased activity likely 

due to respiratory 

difficulties; Limb tone 

and skeletal structures 

normal; Lungs normal 

AChE 

inhibition

Neostigmin

e

Clinical signs of 

cholinergic toxicity 

resulting in maternal 

- Plausibility/ 

Strong 

coherence 

No cholinergic clinical 

signs in adults or 

neonatal offspring in dev. 
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death; Sublethal 

exposures generally 

without 

across studies tox. and repro. tox. 

studies; no maternal 

death 

ACE 

inhibition

Captopril, 

Enalapril 

In humans, limb 

contractures secondary 

to renal failure 

associated 

oligohydramniosis; In 

rats, fetal growth 

retardation and 

occasionally increased 

pup death without limb 

contractures

- Plausibility/ 

Strong 

coherence 

across studies

Lack of similarity in 

neonatal abnormalities 

and resistance of rodents 

to ACE inhibitioninduced limb 

contractures

f) Conclusion of consideration of alternative MOAs

There is sufficient information to preclude many of the alternative MOAs. However, much of 

the evidence is indirect and does directly assess the mechanisms. For example, it is not likely 

that neuronal nicotinic receptors are responsible for the increased pup deaths; since the same 

isoforms of neuronal nicotinic receptors are present in both juveniles and adults, toxicity would 

be evident in adults as well as juveniles, which is not the case. Empirically determining the 

inability of sulfoxaflor to bind and adulterate the functionality of these neuronal receptors would 

provide a great deal more confidence in the decision to exclude this MOA. 

Human Relevance

DAS has postulated that the proposed MoA is not relevant to humans based upon data 

demonstrating fundamental qualitative differences in the agonism of sulfoxaflor at the rat or 

human fetal-type muscle nAChR. Specifically, binding but no agonism was evident with 

sulfoxaflor at the human fetal-type or human adult-type muscle nAChR (MRID 47832035)

(Figure 10.). Both muscle receptor types were examined as the transition from the fetal-type to 

adult-type human muscle nAChR occurs prenatally. 
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Figure 10. Agonist activation of nAChRs expressed in Xenopus oocytes. Data are shown for the 

human fetal (α1)2β1γδ nAChR (A) and human adult (α1)2β1δε nAChR (B). AChRs were 

expressed by microinjection of cDNA or cRNA in Xenopus oocytes. Dose-response curves are 

shown in which agonist-evoked responses are normalized to the maximal response detected with 

the endogenous agonist, acetylcholine (ACh). Data points are means of 3-7 responses. Adapted 

from Millar, 2010.

Table 10. Concordance of Key Events for Induction of Muscle Contracture and Associated 

Death in Neonatal Offspring in Rodents and Humans.

Key Event Evidence in Rodents Evidence in Humans

#1 Binding to the fetaltype muscle nAChR Yes Yes

#2 Agonism at the 

fetal-type muscle 

nAChR

Yes

No

Plausible, but no agonism 

occurs with XDE-208 either 

at the fetal- or adult-type 

muscle nAChR. 

#3 Sustained fetal-type 

muscle nAChR 

agonism/sustained 

muscle contraction

Yes

No data in humans. 

Presumably not possible via 

this MoA as key event #2 

does not occur.

Apical Endpoints

Forelimb Flexure, 

Hindlimb Rotation, 

Bent Clavicle, 

Neonatal Death

Yes

No data in humans. 

Presumably not possible via 

this MoA as key event #2 

does not occur.

The species-specificity of the effects in the rat is supported by the finding that although 

sulfoxaflor binds to the fetal rabbit muscle nAChR, it does not induce any developmental effects 

in this species despite similar systemic exposure. Furthermore, the amino acid sequence of the 
Sulfoxaflor Human Health Risk Assessment DP No. D382604

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rat and human γ subunit indicate they are 90% identical, and therefore sufficiently unique that 

pharmacodynamic differences can be expected. 

Conclusion

The Agency agrees that the proposed MoA is reasonable and likely. There is sufficient evidence 

with dose and time concordance to support the postulated MoA for skeletal abnormalities and 

increased neonatal pup deaths in rats. However, for the purposes of risk assessment, the Agency 

considers this MoA relevant to humans based on uncertainty regarding alternative MoAs.

Area of concern and potential study designs DAS should consider to reduce the uncertainty and 

increase confidence in the proposed MoA include the following:

Demonstrate the inability of sulfoxaflor to cause sustained contracture in rabbit fetal 

diaphragm muscle. Alternatively, DAS can explore the functional response of rabbit 

nicotinic receptors (fetal and adult isoforms) expressed in HEK cells.

Conclusively demonstrate that sulfoxaflor does not perturb the functionality of neuronal 

nicotinic receptors

III. Sulfoxaflor Metabolite -474 Considerations

X11719474 (-474) is the main soil metabolite of sulfoxaflor; it is found in treated crops and is 

predicted to have the potential to occur in ground and surface water (t1⁄2 > 1000 days). Due to the 

high potential for exposure, numerous toxicity studies were conducted with -474 including acute 

studies, 28- and 90-day studies in the rat and dog, a mutagenicity battery, a reproduction and 

development study, liver toxicity mechanistic studies, and an nAChR binding study. -474 was 

consistently less toxic than sulfoxaflor, approximately 7-fold, and does not have acute or 

developmental toxicity. Unlike sulfoxaflor, -474 does not bind the rat fetal muscle nAChR 

(MRID 47832035) and therefore does not share the developmental MoA described for 

sulfoxaflor. Otherwise, -474 and sulfoxaflor have similar toxicity profiles; the most reliable 

indicators of the relative toxicity are effects to the liver (e.g., liver weight increase, 

hepatocellular hypertrophy, fatty change (vacuolation), single cell necrosis and aggregates of 

macrophages). 

IV. Global Partner Comments

PMRA has reviewed the MoA characterizing the pup deaths as not relevant to humans. The 

overall evidence in support the proposed MOA for the fetal abnormalities and neonatal death was 

considered to be weak by the PMRA reviewer due to the inconsistencies noted in the findings as 

they relate to the proposed key events, and the fact that the possibility of alternate MoAs has not 

been fully discounted.

Key Event 1: Specific binding to the fetal-type muscle nAChR (Key Event #1)

Sulfoxaflor binding to other AChR types was discussed in the MoA rationale; however, 

these alternate MoAs were not fully explored and could not be discounted. It was postulated in 

the Leydig cell MoA that there was binding of sulfoxaflor to neuronal nAChRs which increases 

dopamine release; this effect was demonstrated in the recently submitted microdialysis assay.
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Furthermore, although there was a lack of muscarinic nAChR-mediated clinical signs, 

heart arrhythmia may be asymptomatic or the clinical signs could have been easily missed, 

especially when neonatal deaths occur very shortly after birth.

Agonism at the fetal-type muscle nAChR (Key Event #2)

Expression of the recombinant rat and human (fetal and adult) muscle nAChRs in a mammalian 

cell culture would have provided a more native cellular environment compared to Xenopus

ooctyes. Furthermore, the temperature at which the receptors are expressed would be 

significantly different (18oC in ooctyes and 37oC in mammalian cells) and may have a potential 

impact on the function of the receptor. Also, investigation of sulfoxaflor-induced agonist activity 

on fetal and adult rabbit muscle nAChRs could provide a useful comparison between species and 

additional weight of evidence to the proposed MoA. 

Sustained agonism/sustained muscle contracture (Key Event #3)

In the rat developmental toxicity and mechanistic studies, there was a lack of 

consistency in observations for fetal abnormalities;

o Forelimb flexure and hindlimb rotation were not seen in the one-generation 

reproductive toxicity range-finding study

o There were no treatment-related developmental findings reported in the reproductive 

toxicity range-finding study up to 1000 ppm

o Necropsy of (PND 4) neonates in the critical window mechanistic studies did not 

reveal any observations of bent clavicle, convoluted ureter, or hydroureter. However, 

there are literature studies of chemicals demonstrating postnatal remodeling (based on 

delay ossification) which was found to be reversible by PND 6 (caffeine toxicity) and 

PND 63 (ethylene glycol).
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References:

Bennett, M. R. and A. G. Pettigrew (1974). "The formation of synapses in striated muscle during 

development." J Physiol 241: 515-545.

Bulbringe, E. (1946). "Observations on the isolated phrenic nerve diaphragm preparation of the 

rat." Br. J. Pharmacol. Chemother. 1: 38-61.

Buttar, H. S. (1997). "An overview of the influence of ACE inhibitors on fetal-placental 

circulation and perinatal development." Molecular and Cellular Biochemistry 176(1): 61-

71.

Evans, C. A. and D. R. Waud (1973). "Do Maternally Administered Neuromuscular Blocking 

Agents Interfere With Fetal Neuromuscular Transmission?" Anesthesia & Analgesia

52(4): 548-552.

Geller, L. M. (1959). "Failure of nicotine to affect development of offspring when administered 

to pregnant rats." Science 129: 212-214.

Gibb, A. (2010). "Observations on the effects of XDE-208 on the phrenic nerve-hemidiaphragm 

preparation from new-born rat." Report of the University College London, London, UK.

Kues, W. A., B. Sakmann and V. Witzemann (1995). "Differential expression patterns of five 

acetylcholine receptor subunit genes in rat muscle during development." Eur J Neurosci 

7: 1376-1385.

Liao, J.-W., J.-J. Kang, S.-H. Liu, C.-R. Jeng, Y.-W. Cheng, C.-M. Hu, S.-F. Tsai, S.-C. Wang 

and V. F. Pang (2000). "Effects of Cartap on Isolated Mouse Phrenic Nerve Diaphragm 

and Its Related Mechanism." Toxicological Sciences 55(2): 453-459.

Maritz, G. S. and G. v. Wyk (1997). "Influence of maternal nicotine exposure on neonatal rat 

lung structure: protective effect of ascorbic acid." Comp Biochem Physiol C Pharmacol 

Toxicol Endocrinol 117: 159-165.

Millar, N. (2010). "Characterization of the Agonist Effects of XDE-208 on Mammalian Muscle 

Nicotinic Acetylcholine Receptors." Report of the University College London, London, 

UK.

Mishina, M., T. Takai, K. Imoto, M. Noda, T. Takahashi, S. Numa, C. Methfessel and B. 

Sakman (1986). "Molecular distinction between fetal and adult forms of muscle 

acetylcholine receptor." Nature 313: 364-369.

Missias, A. C., G. C. Chu, B. J. Klocke, J. R. Sanes and J. P. Merlie (1996). "Maturation of the 

Acetylcholine Receptor in Skeletal Muscle: Regulation of the AChR γ-to-ε Switch." 

Developmental Biology 179(1): 223-238.

Robinson, S. R. and W. P. Smotherman (1988). Behavior of the Fetus. Caldwell, New Jersey, The 

Telford Press.

Shoro, A. A. (1977). "Intra-uterine growth retardation and limb deformities produced by 

neuromuscular blocking agents in the rat fetus." J. Anat. 123: 341-350.

Sobrian, S. K., S. F. Ali, W. S. Jr. and R. R. Holson (1995). "Interactive effects of prenatal 

cocaine and nicotine exposure on maternal toxicity, postnatal development and behavior 

in the rat." Mol Neurobiol 11: 121-143.
Sulfoxaflor Human Health Risk Assessment DP No. D382604

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Appendix C. Metabolism Summary Table

Table C.1. Tabular Summary of Metabolites and Degradates

Chemical Name 

(other names in 

parenthesis)

Matrix

Approximate Percent TRR

Structure Matrices -

Major Residue 

(>10%TRR)

Matrices -

Minor Residue 

(<10%TRR)

Parent Tomato 33 --

N

S

N O N

F3C

Lettuce 17 --

Succulent Pea (pods) 60 --

Rice (grain) 35 --

Rotational Crops -- < 3

Ruminant > 80 --

Poultry > 80 --

Rat (urine and feces) > 93 --

Surface Water ~100 --

Groundwater -- --

X11719474 Tomato 20 --

N

S

N O

N

O

F

F

F

Lettuce 31 --

Succulent Pea (pods) 13 --

Rice (grain) -- 9

Rotational Crops ~40-90 --

Ruminant -- --

Poultry -- --

Rat (urine and feces) -- --

Surface Water -- --

Groundwater ~88 --

X11721061 

(including 

glucose and 

glucose/malonyl 

conjugates)

Tomato 16 --

N

OH

F

F

F

Lettuce -- 9

Succulent Pea (pods) 14 --

Rice (grain) 13 --

Rotational Crops -- Generally < 9

Ruminant -- < 3

Poultry -- --

Rat (urine and feces) -- < 4

Surface Water -- --

Groundwater -- --

X11519540 Tomato -- --

Lettuce -- --

Succulent Pea (pods) -- --

Rice (grain) -- --

Rotational Crops -- < 5

Ruminant -- < 2

Poultry -- < 8

Rat (urine and feces) -- --

Surface Water -- --

Groundwater 12 --

X11596066 Tomato -- --

N

F

F

F

Lettuce -- --

Succulent Pea (pods) -- --

Rice (grain) -- --

Rotational Crops -- --

Ruminant < 18 --

N

S

O

F O

F

F
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Table C.1. Tabular Summary of Metabolites and Degradates

Chemical Name 

(other names in 

parenthesis)

Matrix

Approximate Percent TRR

Structure Matrices -

Major Residue 

(>10%TRR)

Matrices -

Minor Residue 

(<10%TRR)

Poultry < 14 --

Rat (urine and feces) -- --

Surface Water -- --

Groundwater -- --

All crop metabolism studies were conducted at approximately a 2-fold exaggerated rate relative to the draft labels. 

Lettuce was harvested 7 days after the last treatment; tomatoes, peas, and rice were harvested 14 days after the last 

treatment. The proposed label lists PHIs ranging from 1 to 14 days, depending on the crop.

Livestock metabolism studies were conducted at levels of 12-14 mg/kg in the feed. The estimated dietary burdens 

are approximately 2 ppm for dairy cattle, 0.45 ppm for beef cattle, and 0.054 ppm for poultry.

Rats received a gavage dose at either 5 mg/kg (single and multiple doses) or 100 mg/kg, or a single intravenous 

dose at 5 mg/kg.
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Appendix D. Physical/Chemical Properties and Summaries of Field Trial and Processing 

Study Results

Parameter Value

Melting point/range (°C) 112.9

pH (24 oC, 1.00% w/w aqueous solution) 5.82

Density (g/cm3, Technical grade @ 19.7 oC) 1.5378 

Water solubility @ 20°C (g/L, 99.7% pure active ingredient)

pH 5 1.380

pH 7 0.570

pH 9 0.550

Unbuffered 0.670

Solvent solubility @ 20°C (g/L, technical-grade material)

Methanol 93.1

Acetone 217

p-Xylene 0.743

1,2-dichloroethane 39.6

ethyl acetate 95.2

n-heptane 0.000242

n-octanol 1.66

Vapor Pressure (Pa)

(99.5% pure @ 25 oC)

(technical grade @ 20 oC0)

2.7 x 10-7

1.1 x 10-7

Dissociation constant (pKa) NA

Octanol/water partition coefficient Log(KOW)

Unbuffered NA

pH 5 0.806

pH 7 0.802

pH 9 0.799

UV/visible absorption spectrum wavelength max absorption: 192, 211, and 260 nm

N/A = not available

Summary of Residues from the Crop Field Trials with Sulfoxaflor

(SC formulation unless otherwise specified).

Crop Matrix Applic. Rate

lb ai/A

(g a.i./ha)

PHI 

(days)

n Residues (ppm)

Min Max HAFT1 Median Mean Std. Dev

Crop Group 1 (proposed use = 0.266 lb ai/A total application rate, 7-day PHI)

Carrot roots 0.357-0.376

(401-423) 7 24 <0.01 0.032 0.031 0.010 0.015 0.008

Potato roots 0.355-0.374 

(399-420) 6-8 36 <0.01 <0.01 0.01 0.01 0.01 NA

Radish roots

(WDG 

formulation)

0.360-0.363 

(404-407) 7 12 <0.01 0.013 0.012 0.010 0.011 0.001

0.360-0.364 

(404-407) 7 6 <0.01 0.016 0.014 0.010 0.011 0.002

Sugar beet roots 0.351-0.374 

(394-420) 7 26 <0.01 0.025 0.023 0.010 0.011 0.003

Crop Group 2 (proposed use = 0.266 lb ai/A total application rate, 7-day PHI)

Carrot tops 0.360-0.366

(405-411) 7 8 0.311 2.283 2.069 0.515 0.857 0.764

Radish tops 0.360-0.364 7 12 0.183 0.506 0.478 0.258 0.297 0.108
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Summary of Residues from the Crop Field Trials with Sulfoxaflor

(SC formulation unless otherwise specified).

Crop Matrix Applic. Rate

lb ai/A

(g a.i./ha)

PHI 

(days)

n Residues (ppm)

Min Max HAFT1 Median Mean Std. Dev

(WDG 

formulation)

(404-407)

0.360-0.364 

(404-407) 7 6 0.242 0.465 0.441 0.398 0.370 0.099

Sugar beet tops 0.351-0.374 

(394-420) 7 25 0.141 1.685 1.615 0.716 0.744 0.452

Crop Group 3 (proposed use = 0.266 lb ai/A total application rate, 7-day PHI)

Dry Bulb Onion 0.357-0.365

(400-409) 7 12 <0.01 <0.01 0.01 0.01 0.01 NA

Green Onion 0.360-0.366 

(404-410) 7-8 12 <0.01 0.440 0.387 0.105 0.132 0.130

Crop Group 4 (proposed use = 0.266 lb ai/A total application rate, 3-day PHI)

Celery 0.360-0.361 

(404-405) 2-3 24 0.058 0.804 0.771 0.143 0.229 0.235

Head Lettuce 0.328-0.388

(369-436) 2-3 27 <0.01 0.528 0.494 0.040 0.148 0.177

Leaf Lettuce

(WDG 

formulation)

0.342-0.377

(384-424) 2-3 36 0.05 3.07 2.74 0.495 0.744 0.659

0.360-0.363

(404-407) 3 6 0.379 0.885 0.806 0.577 0.595 0.189

Spinach 0.343-0.372 

(385-418) 3 16 0.039 3.256 2.863 0.820 1.076 0.927

Crop Group 5 (proposed use = 0.266 lb ai/A total application rate, 3-day PHI)

Broccoli 0.347-0.379 

(390-426) 3 29 <0.01 1.600 1.584 0.070 0.201 0.395

Cauliflower 0.320-0.373 

(360-419) 3-4 20 <0.01 0.07 0.055 0.014 0.020 0.014

Cabbage 0.341-0.383 

(383-430) 2-3 28 <0.01 0.400 0.377 0.058 0.092 0.103

Mustard Greens 0.354-0.367

(397-411) 2-4 16 0.278 1.167 0.899 0.666 0.680 0.234

Crop Group 6 Beans (proposed use = 0.266 lb ai/A total application rate, 7-day PHI)

Succulent edible 

podded bean

0.352-0.372 

(393-411) 7 12 0.024 2.019 1.938 0.104 0.422 0.716

Dry shelled bean 0.350-0.365

(393-411) 7 12 0.020 0.112 0.104 0.078 0.068 0.029

Crop Group 7 (proposed use = 0.266 lb ai/A total application rate, 7-day PHI)

Soybean, Forage 0.178-0.183 

(200-205) 7-8 38 0.013 1.734 1.690 0.219 0.346 0.386

Soybean, Hay 0.358-0.368 

(401-414) 6-8 38 0.057 1.378 1.238 0.725 0.670 0.383

Crop Group 8 (proposed use = 0.266 lb ai/A total application rate, 1-day PHI)

Tomato 0.317-0.383 

(356-430) 1 88 <0.01 0.762 0.602 0.051 0.091 0.123

Pepper, bell 0.321 - 0.364 

(361-409) 1 24 <0.01 0.284 0.256 0.092 0.106 0.095

Pepper, non-bell 0.343 - 0.428 

(385-481) 1 15 0.017 0.46 0.44 0.090 0.156 0.145

Crop Group 9 (proposed use = 0.266 lb ai/A total application rate, 1-day PHI)

Cucumber (revised 0.355-0.374 1 36 <0.01 0.172 0.152 0.047 0.055 0.049
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Summary of Residues from the Crop Field Trials with Sulfoxaflor

(SC formulation unless otherwise specified).

Crop Matrix Applic. Rate

lb ai/A

(g a.i./ha)

PHI 

(days)

n Residues (ppm)

Min Max HAFT1 Median Mean Std. Dev

from Tier II 

removing Zucchini 

samples)

(399-420)

Squash, summer

/Zucchini (revised 

from Tier II adding 

Zucchini samples)

Squash, winter

0.357-0.367

(400-412) 1 10 <0.10 0.10 0.10 0.010 0.031 0.039

0.357-0.364

(400-408) 1 6 <0.01 0.021 0.018 0.011 0.013 0.004

Melon 0.356-0.375

(400-421) 0-2 31 <0.01 0.304 0.266 0.031 0.054 0.067

Crop Group 10 (proposed use = 0.266 lb ai/A total application rate, 1-day PHI)

Grapefruit 0.360 

(404) 1 16 <0.01 0.186 0.130 0.014 0.041 0.056

Lemons 0.360

(404) 1 12 0.025 0.317 0.136 0.050 0.098 0.100

Oranges 0.263-0.368 

(296-413) 1 61 0.037 0.46 0.44 0.114 0.167 0.120

Crop Group 11 Pome Fruit (proposed use = 0.266 lb ai/A total application rate, 7-day PHI)

Apples 0.289-0.374

(325-420) 6-8 56 <0.01 0.297 0.266 0.070 0.086 0.057

Pears 0.279-0.379 

(314-426) 7-8 32 0.044 0.267 0.261 0.142 0.146 0.063

Crop Group 12 (proposed use = 0.266 lb ai/A total application rate, 7-day PHI)

Apricot 0.337-0.345 

(379-388) 7 8 0.13 0.45 0.39 0.16 0.21 0.12

Cherry 0.337-0.365 

(379-410) 7 32 0.26 1.60 1.49 0.820 0.824 0.379

Nectarine 0.341-0.351 

(383-394) 7 18 0.074 0.247 0.232 0.150 0.154 0.045

Peach 0.338-0.373 

(380-419) 6-8 48 <0.01 0.636 0.541 0.121 0.164 0.118

Plum

(WDG 

formulation)

0.342-0.370 

(384-415) 7 14 0.021 0.221 0.212 0.049 0.074 0.064

0.358-0.366 

(401-410) 7 12 0.014 0.362 0.358 0.076 0.115 0.117

Crop Group 15 (proposed use = 0.266 lb ai/A total application rate, 7-day PHI)

Barley Grain 0.083-0.095

(94-108) 12-17 50 <0.010 0.37 0.32 0.048 0.060 0.060

Barley Hay 0.086-0.096

(97-108) 6-8 40 <0.010 0.643 0.642 0.213 0.249 0.174

Barley Straw 0.083-0.095

(94-108) 12-17 52 <0.010 2.2 1.46 0.189 0.322 0.413

Wheat Grain

(WDG 

formulation)

0.084-0.098

(94-110) 12-17 67 <0.01 0.067 0.059 0.013 0.019 0.013

0.089-0.093

(100-104) 14 6 <0.01 0.063 0.063 0.010 0.028 0.027

Wheat Forage 0.084-0.098

(94-110) 6-8 60 <0.01 1.400 1.400 0.108 0.187 0.225
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Summary of Residues from the Crop Field Trials with Sulfoxaflor

(SC formulation unless otherwise specified).

Crop Matrix Applic. Rate

lb ai/A

(g a.i./ha)

PHI 

(days)

n Residues (ppm)

Min Max HAFT1 Median Mean Std. Dev

(WDG 

formulation)

0.084-0.098

(94-110) 7 6 0.041 0.221 0.197 0.095 0.111 0.073

Wheat Hay

(WDG 

formulation)

0.084-0.096

(94-108) 6-8 60 0.024 1.024 0.848 0.246 0.292 0.202

0.089-0.093

(100-104) 7 6 0.101 0.167 0.159 0.150 0.139 0.030

Wheat Straw

(WDG 

formulation)

0.084-0.097

(94-109) 12-17 69 0.030 1.562 1.489 0.250 0.400 0.393

0.088-0.093

(99-104) 14 6 0.060 1.641 1.600 0.105 0.588 0.784

Crop Groups 13-07F & 13-07G (proposed use = 0.266 lb ai/A total application rate, 1-day or 7-day PHI)

13-07G

Strawberries

0.339-0.369

(381-414) 1 26 0.02 0.50 0.49 0.184 0.182 0.109

13-07F

Grape (all)

0.276-0.390

(310-438) 7-8 66 0.01 1.9 1.6 0.133 0.268 0.336

Crop Group 14 Tree Nuts (proposed use = 0.266 lb ai/A total application rate, 7-day PHI)

Almond nutmeat 0.355-0.367 7 12 <0.01 0.013 0.123 <0.01 0.011 0.001

Almons hulls 0.355-0.367 7 12 1.04 3.12 3.05 1.68 1.86 0.681

Pecan nutmeat 0.360-0.363

(404-407) 7 12 <0.01 <0.01 <0.01 <0.01 <0.01 NA

Crop Group 20 (proposed use = 0.266 lb ai/A total application rate, 14-day PHI)

Cotton gin 

byproducts

(14-Day PHI)

0.346-0.375 

(389-422) 14-15 42 0.037 4.20 4.03 0.476 0.869 1.12

Cotton, seed

(14-Day PHI)

0.346-0.375 

(389-422) 14-15 44 <0.01 0.182 0.176 0.019 0.037 0.038

Canola, seed

(14-Day PHI)

0.078-0.099 

(88.1-110.8) 13-15 36 <0.01 0.224 0.215 0.042 0.054 0.046

Canola, forage

(14-Day PHI)

0.078-0.099 

(88.1-110.8) 13-14 8 0.03 1.5 1.3 0.11 0.39 0.57

Soybean, Seed 0.357-0.371 

(400-416) 6-8 36 <0.01 0.214 0.199 0.010 0.026 0.044

1 HAFT = Highest Average Field Trial 

Identification of Radioactivity in Hydrolyzed Buffered Water*.

Analyte 14C-sulfoxaflor 14C-X11719474 14C-X11721061

pH 4 pH 5 pH 6 pH 4 pH 5 pH 6 pH 4 pH 5 pH 6

Sulfoxaflor 99.6 100.0 100.4 - - - - - -

X11719474 - - - 99.0 96.9 89.1 - - -

X11721061 - - - - - - 100.0 99.9 99.7

X11579457 - - - 0.4 3.8 11.6** - - -

Accountability 99.6 100.0 100.4 99.4 100.7 100.7 100.0 99.9 99.7

*Only the pH is reported in this table. Durations and Temperatures were pH 4 = 20 minutes at 90°C, pH 5 = 60 

minutes at 100°C, pH 6 = 20 minutes at 120°C. **Confirmed by LC/MS/MS.
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Residue data from processing studies with Sulfoxaflor (XDE-208)

RAC Processed Commodity

Total Rate

lb a.i./A

(g a.i./ha)

PHIa

(day) Residues (ppm) b,c,d Processing Factore

Apple

Apple Fruit RAC *

0.716

(802.2) 7

0.343 --

Washed apples 0.246 0.7x

Apple sauce 0.202 0.6x

Juice 0.128 0.4x

Wet pomace 0.365 1.1x

Dry pomace 1.431 4.2x

Canned apples (0.0098) 0.03x

Dried apples 0.118 0.3x

* Apple fruit RAC samples analyzed after collection had similar residues (0.362 ppm, 0.028 ppm,

and 0.009 ppm) to RAC samples analyzed prior to processing.

Barley

Grain (RAC)*

0.277

(311.7) 16

0.174 --

Pearl barley 0.130 0.7x

Pot barley 0.152 0.9x

Bran 0.167 1.0x

Flour 0.132 0.8x

Cleaned barley 0.165 0.9x

Brewing malt 0.163 0.9x

Malt sprouts 0.224 1.3x

Beer 0.029 0.2x

Spent grains 0.029 0.2x

Brewer’s yeast 0.026 0.1x

* Barley RAC samples analyzed after collection had similar residues (0.16 ppm, 0.014 ppm, and 

0.041 ppm) to RAC samples analyzed prior to processing.

Cabbage

Heads (upon collection of field 

samples)

0.734

(824) 3

0.429 --

Heads prior to processing (inc. 

wrapper leaves) 0.180 --

Inner leaves 0.014 0.1x

Outer (wrapper) leaves 0.322 1.8x

Cooked head (0.009) 0.1x

Cooking liquid (0.007) 0.1x

Sauerkraut 0.017 0.1x

Sauerkraut juice 0.013 0.1x

These values are not used in calculation of the processing factor. The cabbage RAC was stored 

under “cool” conditions prior to processing, and was not kept in frozen storage.

Oil seed, rape/

Taurus

Seeds prior to processing

0.264

(296.4) 14

0.033 --

Cleaned seeds 0.037 1.1x

Meal 0.063 1.9x

Crude oil ND 0.3x

Refined oil ND 0.3x

Solvent-extracted meal 0.072 2.2x

Canola RAC samples analyzed after collection had similar residues (0.038 ppm, ND, and <LOQ) 

to RAC samples analyzed prior to processing.

Carrot Carrot root (RAC) 1.092

(1,224)

7 0.0101 --

Washed and peeled root (0.0082), ND <1.0x

Cooked carrot ND, ND <1.0x

Cooking liquid 0.0130, (0.0085)

Avg. 0.012

1.1x

Carrot juice 0.0234, 0.0246

Avg. 0.0240

2.4x
Sulfoxaflor Human Health Risk Assessment DP No. D382604

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Residue data from processing studies with Sulfoxaflor (XDE-208)

RAC Processed Commodity

Total Rate

lb a.i./A

(g a.i./ha)

PHIa

(day) Residues (ppm) b,c,d Processing Factore

Canned carrot ND, ND <1.0x

Cherry

Whole cherries* (RAC) 

0.715

(803) 7

0.765 --

Washed cherries 0.648 0.8x

Canned cherries 0.737 1.0x

Juice 0.653 0.9x

Jam 0.838 1.1x

Dried cherries 3.950 5.2x

*Cherry fruit RAC samples analyzed after collection had similar residues (0.616 ppm, 0.035 ppm, 

and 0.039 ppm) to RAC samples analyzed prior to processing.

Cotton

Seed (RAC)

1.08

(1,213) 15

0.1001 --

Aspirated seed fractions 2.3197 23x

Delinted seed 0.0983 1.0x

Hulls 0.1846 1.8x

Meal 0.0822 0.8x

Meal press cake 0.0781 0.8x

Crude oil (0.0059) <0.1x

Refined oil ND <0.1x

Grape/

Pinot Noir

RAC 

0.739

(830) 7

0.243 --

Raisins 0.856 3.5x

Juice 0.164 0.7x

Wine bottled 0.171 0.7x

Pomace 0.237 1.0x

Head Lettuce

Heads with wrapper leaves (RAC)

0.748

(837.9) 3

0.592 --

Wrapper leaves 0.593 1.0X

Unwashed heads without wrapper 

leaves 0.354 0.6X

Washed heads 0.146 0.2X

Washings 0.045 0.1X

Head lettuce RAC samples analyzed after collection had similar residues (0.507 ppm, 0.081 ppm, 

and 0.07 ppm) to RAC samples analyzed prior to processing.

Leaf Lettuce

Unwashed lettuce (RAC) 0.728

(818) 3

0.654 --

Washed lettuce 0.488 0.7x

Washings 0.159 0.2x

Onion

Whole onion (RAC) 1.09

(1,225) 7

ND --

Peeled onion ND NC

Dried onion ND NC

Orange

(Valencia)

Pulp RAC*

1.79

(2.00) 1

(0.0039) --

Peel RAC* 0.3661 --

Whole orange RAC*

(peel +pulp) 0.0625 --

Juice (0.0042) <0.2X

Wet pulp 0.1567 2.5X

Dried pulp 0.5159 8.3X

Peel 0.5714 9.1X

Oil ND <0.2X

Marmalade ND <0.2X

Canned slices ND <0.2X

*Oranges were separated into peel and pulp prior to analysis. Processing factors were calculated 

using the whole orange RAC (peel + pulp) residues, which were calculated by the study reviewer 

as the sum of the peel and pulp residues, adjusted for the individual weights of the fractions. 
Sulfoxaflor Human Health Risk Assessment DP No. D382604

Page 164 of 176

Residue data from processing studies with Sulfoxaflor (XDE-208)

RAC Processed Commodity

Total Rate

lb a.i./A

(g a.i./ha)

PHIa

(day) Residues (ppm) b,c,d Processing Factore

Potato (Kuras)

Potato tubers* (RAC)

1.05

(1,176) 7

0.012 --

Washed potatoes 0.014 1.2X

Peeled potatoes 0.019 1.6X

Peel 0.022 1.8X

Potato flakes 0.030 2.5X

Micro-waved potatoes 0.013 1.1X

Boiled potatoes 0.012 1.0X

Cooking water (0.006) <0.8X

Potato chips 0.025 2.1X

Dried potatoes 0.043 3.6X

French fries 0.019 1.6X

*Unpeeled and unwashed; sampled just prior to processing.

Soybean

Seed (RAC)

1.10

(1,236) 7

0.0727 --

AGF 6.8871* 95X

Meal 0.0964 1.3X

Hulls 0.1079 1.5X

Pressed cake 0.0793 1.1X

Expeller crude oil 0.0220 0.3X

Solvent-extracted crude oil 0.0203 0.3X

Refined oil ND <0.1X

*Results are the mean of re-analysis.

Strawberry

Unwashed strawberry 

0.724

(812) 1

0.2003 --

Washed strawberry

0.1670

0.1859

[0.1765]

0.9X

Juice

0.0498

0.0564

[0.0531]

0.3X

Canned strawberry

0.1215

0.1180

[0.1198]

0.6X

Jam

0.0830

0.0702

[0.0766]

0.4X

Samples were analyzed in duplicate; average residues are bolded and reported in brackets. 

Residues <LOQ were assigned a value of 0.01 ppm when averaged with a detectable residue.

Sugar beet

Sugar beet root (RAC)

1.06

(1,191) 7

0.013 --

Pulp (0.005) <0.8x

Press water (0.006) <0.8x

Raw juice 0.018 1.4x

Thin juice 0.014 1.1x

Lime sludge (0.010) <0.8x

Thick juice 0.061 4.7x

Raw sugar 0.023 1.8x

White sugar (0.006) <0.8x

Molasses 0.135 10x

Dried pulp 0.039 3.0x

Tomato

Tomato RAC 0.719

(807.8) 1

0.119 --

Fruit, washed and peeled 0.141 1.2X

Juice 0.117 1.0X
Sulfoxaflor Human Health Risk Assessment DP No. D382604

Page 165 of 176

Residue data from processing studies with Sulfoxaflor (XDE-208)

RAC Processed Commodity

Total Rate

lb a.i./A

(g a.i./ha)

PHIa

(day) Residues (ppm) b,c,d Processing Factore

Canned 0.093 0.8X

Ketchup 0.250 2.1X

Puree 0.235 2.0X

Paste 0.518 4.4X

Wheat

Wheat Grain (RAC)

0.444

(499) 15

0.0650 --

Aspirated Grain Fraction 1.3817 21X

Total bran 0.0230 0.4X

Germ 0.0307 0.5X

Bran 0.0279 0.4X

Middlings 0.0109 0.2X

Shorts 0.0132 0.2X

Whole meal flour 0.0136 0.2X

Refined white flour (0.0079) <0.2X

Whole grain bread (0.0091) <0.2X

White bread (0.0046) <0.2X

Gluten ND <0.2X

Gluten feed meal (0.0073) <0.2X

Starch ND <0.2X

a PHI = Preharvest Interval. ND = Non Detectable where residues were below the limit of detection (<LOD). LOD 

= 0.003 ppm.

b Residue values in parenthesis are <LOQ but >LOD. The LOQ was 0.010 ppm and the LOD was 0.003 ppm.

c Control specimens were collected and analyzed. No residues were detected for the unfortified control samples nor 

were any analytical interferences present in any untreated control sample.

d Processing factors were calculated using the equation: Processing Factor = [Measured residue for analyte in the 

processed fraction] / [Measured residue for analyte in the RAC prior to processing]. Residues <LOQ and ND were 

assigned a value of 0.01 ppm for calculation purposes.

e NC = Not calculated because residues were not detected above the LOQ in the RAC and processed fraction.
Sulfoxaflor Human Health Risk Assessment DP No. D382604

Page 166 of 176

Appendix E. Review of Human Research

Aside from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural 

Handler Exposure Task Force (AHETF) database, the Outdoor Residential Exposure Task Force 

(ORETF) database, and the Agricultural Re-entry Task Force (ARTF) database, which were 

described at the end of the Executive Summary, no data from studies in which adult human 

subjects were intentionally exposed to a pesticide or other chemical were used in this risk 

assessment. 
Sulfoxaflor Human Health Risk Assessment DP No. D382604

Page 167 of 176

Appendix F. Occupational Exposure/Risk Summary Tables

Short- and Intermediate-term Occupational Handler Exposure and Risk Estimates for Proposed Uses of Sulfoxaflor (Transform TM WG).

Exposure 

Scenario

Crop or Target (Crop Group #) Dermal 

Unit 

Exposure1

(mg/lb ai)

(Mitigation 

Level)

Inhalation Unit 

Exposure1

(mg/lb ai)

(Mitigation 

Level)

Max Single 

App Rate

(lb ai/A or lb 

ai/gal)

2

Area Treated or 

Amount 

Handled Daily 

3

Dermal Inhalation Combined 

MOE8

(LOC=30)

Dose4

(mg/kg/day)

MOE5 Dose6

(mg/kg/day)

MOE7

Mixer/Loader

Dry Flowable 

for 

Groundboom 

Application 

(AHETF)

Brassica (Cole) Leafy Veg., Bulb 

Veg. (CG 3-07), Cucurbit Veg. (CG 

9), Fruiting Veg. (CG 8), Leafy 

Veg. (Except Brassica CG 4 & 

Watercress), Leaves Root/Tuber 

Veg. (CG 2), Root/Tuber Veg. (CG 

1), Small Fruit Vine (Sub CG 13-

07F), Low Growing Berry (Sub 13-

07G), Succulent, Edible Podded, 

Dry Beans

0.227

(Baseline)

0.00896

(No respirator)

0.086 80 A 0.00057 3,200 0.00089 2,000 1,200

Ornamentals, Turf grass (Sod Farm) 0.227

(Baseline)

0.00896

(No respirator)

0.133 80 A 0.00088 2,100 0.00140 1,300 800

Barley, Tricale, Wheat, Canola (Sub 

CG 20A)

0.227

(Baseline)

0.00896

(No respirator)

0.047 200 A 0.00077 2,300 0.00120 1,500 900

Cotton, Soybean 0.227

(Baseline)

0.00896

(No respirator)

0.086 200 A 0.0014 1,300 0.00220 810 490

Dry Flowable 

for Aerial 

Application 

(AHETF) 

Brassica (Cole) Leafy Veg., Bulb 

Veg. (CG 3-07), Cucurbit Veg. (CG 

9), Fruiting Veg. (CG 8), Leafy 

Veg. (Except Brassica CG 4 & 

Watercress), Leaves Root/Tuber 

Veg. (CG 2), Root/Tuber Veg. (CG 

1), Small Fruit Vine (Sub CG 13-

07F), Low Growing Berry (Sub 13-

07G), Succulent, Edible Podded, 

Dry Beans

0.227

(Baseline)

0.00896

(No respirator)

0.086 350 A 0.00250 730 0.00390 460 280

Citrus (CG 10), Pome Fruits (CG 

11), Ornamentals, Stone Fruits (CG 

12), Tree Nuts (CG 14 & Pistachio)

0.227

(Baseline)

0.00896

(No respirator)

0.133 350 A 0.00380 470 0.00600 300 180

Barley, Tricale, Wheat, Canola (Sub 

CG 20A)

0.277

(Baseline)

0.00896

(No respirator)

0.047 1200 A 0.00460 390 0.00730 250 150

Cotton, Soybean 0.277

(Baseline)

0.00896

(No respirator)

0.086 1200 A 0.00850 210 0.01340 130 80

Dry Flowable 

for 

Chemigation 

(AHETF)

Potatoes 0.227

(Baseline)

0.00896

(No respirator)

0.086 350 A 0.00250 730 0.00390 460 280

Dry Flowable 

for Airblast

Citrus (CG 10), Pome Fruits (CG 

11), Ornamentals, Stone Fruits (CG 

0.227

(Baseline)

0.00896

(No respirator)

0.133 40 A 0.00044 4,100 0.00069 2,600 1,600
Sulfoxaflor Human Health Risk Assessment DP No. D382604

Page 168 of 176

Short- and Intermediate-term Occupational Handler Exposure and Risk Estimates for Proposed Uses of Sulfoxaflor (Transform TM WG).

Exposure 

Scenario

Crop or Target (Crop Group #) Dermal 

Unit 

Exposure1

(mg/lb ai)

(Mitigation 

Level)

Inhalation Unit 

Exposure1

(mg/lb ai)

(Mitigation 

Level)

Max Single 

App Rate

(lb ai/A or lb 

ai/gal)

2

Area Treated or 

Amount 

Handled Daily 

3

Dermal Inhalation Combined 

MOE8

(LOC=30)

Dose4

(mg/kg/day)

MOE5 Dose6

(mg/kg/day)

MOE7

Application

(AHETF)

12), Tree Nuts (CG 14 & Pistachio)

Applicator

Sprays for 

Groundboom 

Application 

(AHETF)

Brassica (Cole) Leafy Veg., Bulb 

Veg. (CG 3-07), Cucurbit Veg. (CG 

9), Fruiting Veg. (CG 8), Leafy 

Veg. (Except Brassica CG 4 & 

Watercress), Leaves Root/Tuber 

Veg. (CG 2), Root/Tuber Veg. (CG 

1), Small Fruit Vine (Sub CG 13-

07F), Low Growing Berry (Sub 13-

07G), Succulent, Edible Podded, 

Dry Beans

0.0786

(Baseline)

0.00034

(No respirator)

0.086 80 A 0.00020 9,200 0.000034 53,000 7,800

Ornamentals, Turf grass (Sod Farm) 0.0786

(Baseline)

0.00034

(No respirator)

0.133 80 A 0.00030 5,900 0.000052 34,000 5,100

Barley, Tricale, Wheat, Canola (Sub 

CG 20A)

0.0786

(Baseline)

0.00034

(No respirator)

0.047 200 A 0.00027 6,700 0.000046 39,000 5,700

Cotton, Soybean 0.0786

(Baseline)

0.00034

(No respirator)

0.086 200 A 0.00049 3,700 0.000085 21,000 3,100

Sprays for 

Aerial 

Application 

(PHED)

Brassica (Cole) Leafy Veg., Bulb 

Veg. (CG 3-07), Cucurbit Veg. (CG 

9), Fruiting Veg. (CG 8), Leafy 

Veg. (Except Brassica CG 4 & 

Watercress), Leaves Root/Tuber 

Veg. (CG 2), Root/Tuber Veg. (CG 

1), Small Fruit Vine (Sub CG 13-

07F), Low Growing Berry (Sub 13-

07G), Succulent, Edible Podded, 

Dry Beans

0.005

(Engineerin

g Controls -

Enclosed 

cockpit)

0.000068

(Engineering 

Controls -

Enclosed 

cockpit)

0.086 350 A 0.000055 33,000 0.000030 61,000 21,000

Citrus (CG 10), Pome Fruits (CG 

11), Ornamentals, Stone Fruits (CG 

12), Tree Nuts (CG 14 & Pistachio)

0.005

(Engineerin

g Controls -

Enclosed 

cockpit)

0.000068

(Engineering 

Controls -

Enclosed 

cockpit)

0.133 350 A 0.000084 21,000 0.000046 39,000 14,000

Barley, Tricale, Wheat, Canola (Sub 

CG 20A)

0.005

(Engineerin

g Controls -

Enclosed 

cockpit)

0.000068

(Engineering 

Controls -

Enclosed 

cockpit)

0.047 1200 A 0.00010 18,000 0.000056 32,000 11,000

Cotton, Soybean 0.005

(Engineerin

g Controls -

Enclosed 

0.000068

(Engineering 

Controls -

Enclosed 

0.086 1200 A 0.00019 9,600 0.0001 18,000 6,200
Sulfoxaflor Human Health Risk Assessment DP No. D382604

Page 169 of 176

Short- and Intermediate-term Occupational Handler Exposure and Risk Estimates for Proposed Uses of Sulfoxaflor (Transform TM WG).

Exposure 

Scenario

Crop or Target (Crop Group #) Dermal 

Unit 

Exposure1

(mg/lb ai)

(Mitigation 

Level)

Inhalation Unit 

Exposure1

(mg/lb ai)

(Mitigation 

Level)

Max Single 

App Rate

(lb ai/A or lb 

ai/gal)

2

Area Treated or 

Amount 

Handled Daily 

3

Dermal Inhalation Combined 

MOE8

(LOC=30)

Dose4

(mg/kg/day)

MOE5 Dose6

(mg/kg/day)

MOE7

cockpit) cockpit)

Sprays for 

Airblast

Application

(AHETF)

Citrus (CG 10), Pome Fruits (CG 

11), Ornamentals, Stone Fruits (CG 

12), Tree Nuts (CG 14 & Pistachio)

1.77

(Baseline)

0.00471

(No respirator)

0.133 40 A 0.00340 530 0.00036 5,000 480

Flagger

Flagging for 

Aerial 

Application

(PHED)

All Low Acreage Crops 0.011

(Baseline)

0.00035

(No respirator)

0.133 350 A 0.00019 9,700 0.00024 7,600 4,200

Flagging for 

Aerial 

Application

(PHED)

All High Acreage Crops 0.011

(Baseline)

0.00035

(No respirator)

0.086 350 A 0.00012 15,000 0.00015 12,000 6,700

Mixer/Loader/Applicator

Mechanicallypressurized 

Handgun 

Sprayer

Ornamentals, Greenhouses

3.5

(Baseline)

(PHED)

0.120 

(No respirator)

(PHED)

0.00133 1,000 gal/day 0.00169 1,100 0.00231 780 450

Turfgrass (Sod farms)

1.96

(Baseline) 

(ORETF)

0.042

(No respirator)

(ORETF)

0.133 5 A 0.00047 3,800 0.00040 4,400 2,100

Backpack 

Sprayer

Ornamentals

13.2

(Baseline)

(AHETF)

0.140 

(No respirator)

(AHETF)

0.00133 40 gal/day 0.00025 7,200 0.00011 16,000 5,000

Turfgrass (Sod farms)

8.26

(Baseline)

(MRID 

44339801)

0.00258 

(No respirator)

(MRID 

44339801)

0.00133 40 gal/day 0.00016 11,000 0.000002 900,000 11,000

Manuallypressurized 

Handwand

(PHED)

Ornamentals, Turfgrass (Sod farms) 100

(Baseline)

0.030 

(No respirator) 0.00133 40 gal/day 0.00193 930 0.000023 78,000 920

1. Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (OPHED; March, 2012).

2. Application Rate is based on the proposed label.

3. Acres Treated per Day is based on Exposure SAC SOP #9: Standard Values for Daily Acres Treated.

4. Dermal Dose = [Dermal Unit Exposure (mg/lb ai) x Application Rate (lb ai/A) x Acres Treated (A/day) x % DAF (2.5%)]/%)/BW (69 kg).

5. Dermal MOE = Dermal NOAEL (1.8 mg/kg/day)/Dermal Dose (mg/kg/day); LOC = 30.

6. Inhalation Dose = [Inhalation Unit Exposure (mg/lb ai) x Application Rate (lb ai/A) x Acres Treated (A/day)]/)/BW (69 kg). 

7. Inhalation MOE = NOAEL (1.8 mg/kg/day)/Inhalation Dose (mg/kg/day); LOC = 30.

8. Combined MOE = NOAEL (1.8 mg/kg/day)/Combined Dose (mg/kg/day); LOC = 30.
Sulfoxaflor Human Health Risk Assessment DP No. D382604

Page 170 of 176

Short- and Intermediate-term Occupational Handler Exposure and Risk Estimates for Proposed Uses of Sulfoxaflor (GF-2032 SC).

Exposure Scenario Crop or Target (CG #) Dermal Unit 

Exposure1

(mg/lb ai)

(Mitigation 

Level)

Inhalation Unit 

Exposure1

(mg/lb ai)

(Mitigation 

Level)

Max Single 

App Rate

(lb ai/A or 

lb ai/gal)

2

Area Treated 

or Amount 

Handled 

Daily 3

Dermal Inhalation Combined 

MOE8

(LOC=30)

Dose4

(mg/kg/day)

MOE5 Dose6

(mg/kg/day)

MOE7

Mixer/Loader

Liquids for 

Groundboom 

Application 

(AHETF)

Brassica (Cole) Leafy 

Veg., Bulb Veg. (CG 3-

07), Cucurbit Veg. (CG 

9), Fruiting Veg. (CG 

8), Leafy Veg. (Except 

Brassica CG 4 & 

Watercress), Leaves 

Root/Tuber Veg. (CG 

2), Root/Tuber Veg. 

(CG 1), Small Fruit 

Vine (Sub CG 13-07F), 

Low Growing Berry 

(Sub 13-07G), 

Succulent, Edible 

Podded, Dry Beans

0.220 0.000219 0.090 80 A 0.00057 3,100 0.000023 79,000 3,000

Ornamentals, Turf grass 

(Sod Farm)

0.220 0.000219 0.133 80 A 0.00085 2,100 0.000034 53,000 2,000

Barley, Tricale, Wheat, 

Canola (Sub CG 20A)

0.220 0.000219 0.043 200 A 0.00069 2,600 0.000027 66,000 2,500

Cotton, Soybean 0.220 0.000219 0.090 200 A 0.00140 1,300 0.000057 32,000 1,200

Liquids for Aerial 

Application 

(AHETF) 

Brassica (Cole) Leafy 

Veg., Bulb Veg. (CG 3-

07), Cucurbit Veg. (CG 

9), Fruiting Veg. (CG 

8), Leafy Veg. (Except 

Brassica CG 4 & 

Watercress), Leaves 

Root/Tuber Veg. (CG 

2), Root/Tuber Veg. 

(CG 1), Small Fruit 

Vine (Sub CG 13-07F), 

Low Growing Berry 

(Sub 13-07G), 

Succulent, Edible 

Podded, Dry Beans

0.220 0.000219 0.090 350 A 0.00250 720 0.00010 18,000 690

Citrus (CG 10), Pome 

Fruits (CG 11), 

Ornamentals, Stone 

Fruits (CG 12), Tree 

Nuts (CG 14 & 

Pistachio)

0.220 0.000219 0.133 350 A 0.00370 490 0.00015 12,000 470

Barley, Tricale, Wheat, 0.220 0.000219 0.043 1200 A 0.00410 440 0.00016 11,000 420
Sulfoxaflor Human Health Risk Assessment DP No. D382604

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Short- and Intermediate-term Occupational Handler Exposure and Risk Estimates for Proposed Uses of Sulfoxaflor (GF-2032 SC).

Exposure Scenario Crop or Target (CG #) Dermal Unit 

Exposure1

(mg/lb ai)

(Mitigation 

Level)

Inhalation Unit 

Exposure1

(mg/lb ai)

(Mitigation 

Level)

Max Single 

App Rate

(lb ai/A or 

lb ai/gal)

2

Area Treated 

or Amount 

Handled 

Daily 3

Dermal Inhalation Combined 

MOE8

(LOC=30)

Dose4

(mg/kg/day)

MOE5 Dose6

(mg/kg/day)

MOE7

Canola (Sub CG 20A)

Cotton, Soybean 0.220 0.000219 0.090 1200 A 0.00860 210 0.00034 5,300 200

Liquids for 

Chemigation 

(AHETF)

Potatoes 0.220 0.000219 0.090 350 A 0.00250 720 0.00100 18,000 690

Liquids for 

Airblast

Application

(AHETF)

Citrus (CG 10), Pome 

Fruits (CG 11), 

Ornamentals, Stone 

Fruits (CG 12), Tree 

Nuts (CG 14 & 

Pistachio)

0.220 0.000219 0.133 40 A 0.00042 4,200 0.000017 110,000 4,100

Applicator

Sprays for 

Groundboom 

Application 

(AHETF)

Brassica (Cole) Leafy 

Veg., Bulb Veg. (CG 3-

07), Cucurbit Veg. (CG 

9), Fruiting Veg. (CG 

8), Leafy Veg. (Except 

Brassica CG 4 & 

Watercress), Leaves 

Root/Tuber Veg. (CG 

2), Root/Tuber Veg. 

(CG 1), Small Fruit 

Vine (Sub CG 13-07F), 

Low Growing Berry 

(Sub 13-07G), 

Succulent, Edible 

Podded, Dry Beans

0.0786

(Baseline)

0.00034

(No respirator)

0.090 80 A 0.00021 8,800 0.000035 51,000 7,500

Ornamentals, Turf grass 

(Sod Farm)

0.0786

(Baseline)

0.00034

(No respirator)

0.133 80 A 0.00030 5,900 0.000052 34,000 5,100

Barley, Tricale, Wheat, 

Canola (Sub CG 20A)

0.0786

(Baseline)

0.00034

(No respirator)

0.043 200 A 0.00024 7,300 0.000042 42,000 6,300

Cotton, Soybean 0.0786

(Baseline)

0.00034

(No respirator)

0.090 200 A 0.00051 3,500 0.000089 20,000 3,000

Sprays for Aerial 

Application 

(PHED)

Brassica (Cole) Leafy 

Veg., Bulb Veg. (CG 3-

07), Cucurbit Veg. (CG 

9), Fruiting Veg. (CG 

8), Leafy Veg. (Except 

Brassica CG 4 &

Watercress), Leaves 

Root/Tuber Veg. (CG 

2), Root/Tuber Veg. 

(CG 1), Small Fruit 

Vine (Sub CG 13-07F), 

0.005

(Engineering 

Controls -

Enclosed 

cockpit)

0.000068

(Engineering 

Controls -

Enclosed cockpit)

0.090 350 A 0.000057 32,000 0.000031 58,000 25,000
Sulfoxaflor Human Health Risk Assessment DP No. D382604

Page 172 of 176

Short- and Intermediate-term Occupational Handler Exposure and Risk Estimates for Proposed Uses of Sulfoxaflor (GF-2032 SC).

Exposure Scenario Crop or Target (CG #) Dermal Unit 

Exposure1

(mg/lb ai)

(Mitigation 

Level)

Inhalation Unit 

Exposure1

(mg/lb ai)

(Mitigation 

Level)

Max Single 

App Rate

(lb ai/A or 

lb ai/gal)

2

Area Treated 

or Amount 

Handled 

Daily 3

Dermal Inhalation Combined 

MOE8

(LOC=30)

Dose4

(mg/kg/day)

MOE5 Dose6

(mg/kg/day)

MOE7

Low Growing Berry 

(Sub 13-07G), 

Succulent, Edible 

Podded, Dry Beans

Citrus (CG 10), Pome 

Fruits (CG 11), 

Ornamentals, Stone 

Fruits (CG 12), Tree 

Nuts (CG 14 & 

Pistachio)

0.005

(Engineering 

Controls -

Enclosed 

cockpit)

0.000068

(Engineering 

Controls -

Enclosed cockpit)

0.133 350 A 0.000084 21,000 0.000046 39,000 19,000

Barley, Tricale, Wheat, 

Canola (Sub CG 20A)

0.005

(Engineering 

Controls -

Enclosed 

cockpit)

0.000068

(Engineering 

Controls -

Enclosed cockpit)

0.043 1200 A 0.000093 19,000 0.000051 35,000 12,000

Cotton, Soybean 0.005

(Engineering 

Controls -

Enclosed 

cockpit)

0.000068

(Engineering 

Controls -

Enclosed cockpit)

0.090 1200 A 0.00020 9,200 0.00011 17,000 6,000

Sprays for Airblast

Application

(AHETF)

Citrus (CG 10), Pome 

Fruits (CG 11),

Ornamentals, Stone 

Fruits (CG 12), Tree 

Nuts (CG 14 & 

Pistachio)

1.77

(Baseline)

0.00471

(No respirator)

0.133 40 A 0.00340 530 0.00036 5,000 480

Flagger

Flagging for Aerial 

Application

(PHED)

All Low Acreage Crops 0.011

(Baseline)

0.00035

(No respirator)

0.133 350 A 0.00019 9,700 0.00024 7,600 4,200

Flagging for Aerial 

Application

(PHED)

All High Acreage 

Crops

0.011

(Baseline)

0.00035

(No respirator)

0.090 350 A 0.00013 14,000 0.00016 11,000 6,300

Mixer/Loader/Applicator

Mechanicallypressurized 

Handgun Sprayer

Ornamentals, 

Greenhouses

3.5

(Baseline)

(PHED)

0.120 

(No respirator)

(PHED)

0.00133 1,000 gal/day 0.00169 1,100 0.00231 780 450

Turfgrass (Sod farms) 1.14

(Baseline) 

0.0019

(Baseline) 

(ORETF)

0.133 5 A 0.00047 3,800 0.00040 4,400 2,100
Sulfoxaflor Human Health Risk Assessment DP No. D382604

Page 173 of 176

Short- and Intermediate-term Occupational Handler Exposure and Risk Estimates for Proposed Uses of Sulfoxaflor (GF-2032 SC).

Exposure Scenario Crop or Target (CG #) Dermal Unit 

Exposure1

(mg/lb ai)

(Mitigation 

Level)

Inhalation Unit 

Exposure1

(mg/lb ai)

(Mitigation 

Level)

Max Single 

App Rate

(lb ai/A or 

lb ai/gal)

2

Area Treated 

or Amount 

Handled 

Daily 3

Dermal Inhalation Combined 

MOE8

(LOC=30)

Dose4

(mg/kg/day)

MOE5 Dose6

(mg/kg/day)

MOE7

(ORETF)

Backpack Sprayer

Ornamentals

13.2

(Baseline)

(AHETF)

0.140 

(No respirator)

(AHETF)

0.00133 40 gal/day 0.00025 7,200 0.00011 16,000 5,000

Turfgrass (Sod farms)

8.26

(Baseline)

(MRID 

44339801)

0.00258 

(No respirator)

(MRID 

44339801)

0.00133 40 gal/day 0.00016 11,000 0.000002 900,000 11,000

Manuallypressurized 

Handwand

(PHED)

Ornamentals, Turfgrass 

(Sod farms)

100

(Baseline)

0.030 

(No respirator) 0.00133 40 gal/day 0.00193 930 0.000023 78,000 920

1. Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (OPHED; March, 2012).

2. Application Rate is based on the proposed label.

3. Acres Treated per Day is based on Exposure SAC SOP #9: Standard Values for Daily Acres Treated.

4. Dermal Dose = [Dermal Unit Exposure (mg/lb ai) x Application Rate (lb ai/A) x Acres Treated (A/day) x % DAF (2.5%)]/%)/BW (69 kg).

5. Dermal MOE = Dermal NOAEL (1.8 mg/kg/day)/Dermal Dose (mg/kg/day); LOC = 30.

6. Inhalation Dose = [Inhalation Unit Exposure (mg/lb ai) x Application Rate (lb ai/A) x Acres Treated (A/day)]/)/BW (69 kg). 

7. Inhalation MOE = NOAEL (1.8 mg/kg/day)/Inhalation Dose (mg/kg/day); LOC = 30.

8. Combined MOE = NOAEL (1.8 mg/kg/day)/Combined Dose (mg/kg/day); LOC = 30.
Sulfoxaflor Human Health Risk Assessment DP No. D382604

Page 174 of 176

Appendix G. Anticipated Post-Application Activities and Dermal Transfer Coefficients

Anticipated Post-Application Activities and Dermal Transfer Coefficients.†

Proposed Crop Crop Group Transfer Coefficients, 

cm2/hr

Activities EPA MRID No.

Field / row crop, 

low/medium

Barley, Wheat 70 Hand weeding 42851302, 42689103, 42689104

1,100 Scouting 45005904, 45005908

Canola (Subgroup 20A) 1,100 Scouting 45005904, 45005908

Cotton 70 Hand weeding 42851302, 42689103, 42689104

210 Scouting 42851302

900 g cotton/hr Harvesting Mechanical (Module Builder) 42701601

2400 g cotton/hr Harvesting Mechanical (Picker Operator; 

Raker)

42701601

5050 g cotton/hr Harvesting Mechanical (Tramper) 42701601

Soybean 70 Hand weeding 42851302, 42689103, 42689104

1,100 Scouting 45005904, 45005908

Succulent Edible Podded 

and Dry Beans

70 Hand weeding 42851302, 42689103, 42689104

210 Scouting 42851302, 42974501

1100 Scouting 45005904, 45005908

1900 Irrigation (hand set) 45224801

Vegetable, head and stem 

Brassica

Brassica (Cole) Leafy 

Vegetables

230 Transplanting 45344501, 45469501, 45469502

330 Scouting 42974501

1400 Hand Weeding 45530102

1900 Irrigation (hand set) 45224801

4200 Weeding, Hand 45005906, 45005907, 45191701

Vegetable, "Root" Bulb Vegetables (Crop 

Group 3-07)

330 Scouting 42974501

1400 Hand Weeding 45530102

1900 Irrigation (hand set) 45224801

4200 Weeding, Hand 45005906, 45005907, 45191701

Leaves of Root and Tuber 

Vegetables (Crop Group 

2)

70 Weeding, Hand 42851302, 42689103, 42689104

210 Scouting 42851302, 42974501

230 Transplanting 45344501, 45469501, 45469502

1100 Harvesting, Hand 43013003, 40966503, 40966502, 45530103

1900 Irrigation (hand set) 45224801

Root and Tuber 

Vegetables (Crop Group 

1)

70 Weeding, Hand 42851302, 42689103, 42689104

210 Scouting 42851302, 42974501

1100 Harvesting, Hand 43013003, 40966503, 40966502, 45530103

1900 Irrigation (hand set) 45224801

Tree Fruit, Evergreen Citrus (Crop Group 10) 100 Hand weeding 43297602

230 Transplanting 45344501, 45469501, 45469502

580 Hand Pruning 45175102, 45480302
Sulfoxaflor Human Health Risk Assessment DP No. D382604

Page 175 of 176

Anticipated Post-Application Activities and Dermal Transfer Coefficients.†

Proposed Crop Crop Group Transfer Coefficients, 

cm2/hr

Activities EPA MRID No.

1400 Hand Harvesting 42830002, 40975308, 40966501, 45138202, 

45175101, 45432301,45432302

3600 Thinning Fruit 42428101

Vegetable, Cucurbit Cucurbits Vegetables 

(Crop Group 9)

90 Scouting 45005909

230 Transplanting 45344501, 45469501, 45469502

550 Turning 45480301, 45491902

1900 Irrigation (hand set) 45224801

Vegetable, Fruting Fruiting Vegetables (Crop 

Group 8)

70 Weeding, Hand 42851302, 42689103, 42689104

90 Scouting 45005909

210 Scouting 42851302, 42974501

230 Transplanting 45344501, 45469501, 45469502

550 Tying/Training, Hand Harvesting 45480301, 45491902

1100 Harvesting, Hand 43013003, 40966503, 40966502, 45530103

1900 Irrigation (hand set) 45224801

Vegetable, Leafy Leafy Vegetables except 

Brassica – (Crop Group 

4)& Watercress

70 Weeding, Hand 42851302, 42689103, 42689104

210 Scouting 42851302, 42974501

230 Transplanting 45344501, 45469501, 45469502

1100 Harvesting, Hand 43013003, 40966503, 40966502, 45530103

1900 Irrigation (hand set) 45224801

Nursery/Greenhouse

(Unassigned)

Ornamentals 230 Harvesting, Hand 45344501, 45469501, 45469502

1900 Irrigation (hand set) 45224801

Tree, "Fruit", Deciduous Pome Fruits (Crop Group 

11)

100 Orchard Maintenance, Propping, Hand 

Weeding

43297602

230 Transplanting 45344501, 45469501, 45469502

580 Scouting, Hand Pruning, Training 45175102, 45480302

1400 Harvesting, Hand 42830002, 40975308, 40966501, 45138202, 

45175101, 45432301, 45432302

3600 Thinning Fruit 42428101

Stone Fruits (Crop Group 

12)

100 Orchard Maintenance, Propping, Hand 

Weeding, Thinning Fruit, Bird Control 

43297602

230 Transplanting 45344501, 45469501, 45469502

580 Scouting, Hand Pruning, Training 45175102, 45480302

1400 Harvesting, Hand 42830002, 40975308, 40966501, 45138202, 

45175101, 45432301, 45432302

3600 Thinning Fruit 42428101

Vine /Trellis Small Fruit Vine 

Climbing (except fuzzy 

kiwifruit – Subgroup 13-

07F)

230 Transplanting 45344501, 45469501, 45469502

640 Scouting, Hand Pruning, Hand Weeding, 

Propagating, Bird Control, Trellis Repair, 

Tying/Training

45005910

1900 Irrigation (hand set) 45224801
Sulfoxaflor Human Health Risk Assessment DP No. D382604

Page 176 of 176

Anticipated Post-Application Activities and Dermal Transfer Coefficients.†

Proposed Crop Crop Group Transfer Coefficients, 

cm2/hr

Activities EPA MRID No.

5500 Leaf Pulling, Tying/Training, Hand 

Harvesting

43223907, 40985601

10100 Leaf Pulling, Tying/Training, Hand

Harvesting

45491901

19300 Turning, Girdling 40975304

Berry, Low Low Growing Berry 

(Subgroup 13-07G)

70 Hand Weeding, Hand

Pruning (shears),

Canopy Management

42851302, 42689103, 42689104

210 Scouting 42851302, 42974501

230 Transplanting 45344501, 45469501, 45469502

1100 Hand Harvesting (ranking), 

Scouting

43013003, 40966503, 40966502

45530103, 45005904, 45005908

1900 Irrigation (hand set) 45224801

Tree, “Nut” Tree Nuts (Crop Group 14 

& Pistachio)

100 Orchard Maintenance, Poling, Hand 

Weeding

43297602

190 Harvesting, Mechanical (shaking) 41848604

230 Transplanting 45344501, 45469501, 45469502

580 Scouting 45175102, 45480302

1400 Harvesting, Hand (net) 42830002, 40975308, 40966501

45138202, 45175101, 45432301

45432302

Turf/Sod Turfgrass, Sodfarms 6700 Maintenance, Harvesting, Slab

Transplanting/Planting

45432303

†The information in the table is based on proprietary and non-proprietary data.

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