Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 1 of 27

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND

 POLLUTION PREVENTION

MEMORANDUM

Date: 7 June 2012

SUBJECT: Sulfoxaflor – Human Health Risk Assessment of the FIFRA Section 18 

Emergency Exemption Use on Cotton. 

PC Code: 005210 DP Barcode: D398591

Decision No.: 460686 Registration No.: 62719-AEL

Petition No.: 12MS02 Regulatory Action: Section 18

Risk Assessment Type: Single Chemical, Aggregate Registration Case No.: None

TXR No.: None CAS No.: 946578-00-3

MRID No.: None 40 CFR 180.None

FROM: Michael A. Doherty, Ph.D., Senior Chemist

Dennis McNeilly, Chemist

Elizabeth Holman, Chemist

Edward Scollon, Ph.D., Toxicologist

Zaida Figueroa, Industrial Hygienist

Risk Assessment Branch II

Health Effects Division (7509P)

THROUGH: Donna S. Davis, Chemist

P.V. Shah, Ph.D., Chief – Inert Ingredient Assessment Branch

Risk Assessment Review Committee

Health Effects Division (7509P)

Christina Swartz, Branch Chief

Risk Assessment Branch II

Health Effects Division (7509P)

TO: Debra Rate/Marcel Howard (Team 09)

Risk Integration, Minor Use & Emergency Response Branch

 Registration Division (7505P)

Jennifer Urbanski/Venus Eagle (Team 01)

Insecticide-Rodenticide Branch

Registration Division (7505P)
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 2 of 27

CONCLUSIONS

HED has evaluated the human health risks associated with the requested emergency exemption 

use of the insecticide sulfoxaflor on cotton. There are no residential uses for sulfoxaflor at this 

time; therefore, this risk assessment addresses the potential dietary (food + drinking water) and 

occupational exposures associated with the proposed use. HED concludes that there is a 

reasonable certainty that no harm will result from aggregate exposure to sulfoxaflor associated 

with the requested Section 18 use; further, there are no concerns for occupational exposure and 

risk estimates associated with the proposed use pattern. The supported tolerances and the 

tolerance definition are summarized below.

INTRODUCTION

The state of Mississippi1is requesting an emergency exemption under FIFRA Section 18 for the 

use of sulfoxaflor on cotton to control tarnished plant bug, Lygus lineolaris. This is the first 

Section 18 request for this use. Sulfoxaflor has been submitted to the Agency for registration on 

a large number of crops; however, at this time, there are no food or non-food registrations for 

products containing this active ingredient.

ASSESSMENT SUMMARY 

As previously noted, sulfoxaflor has been submitted to the Agency for full Section 3 registration 

as a new active ingredient. Sulfoxaflor is currently undergoing review by the Office of Pesticide 

Programs, and any conclusions made as part of this Section 18 evaluation should be considered 

tentative and applicable to the Section 18 evaluation only.

Sulfoxaflor {[N-methyloxido[1-[6-(trifluoromethyl)-3-pyridinyl]ethyl] λ4-sulfanylidene] 

cyanamide} is the first member of a new class of insecticides, the sulfoximines. The 

sulfoximines act through a unique interaction with the nicotinic acetylcholine receptor in insects. 

Sulfoxaflor is a highly efficacious agonist of the nicotinic receptor. Furthermore, the structural 

novelty of sulfoxaflor makes it stable in the presence of monooxygenase enzymes that degrade 

neonicotinoids and cause virtually all known cases of resistance in the field of this class of 

insecticides.

The Section 18 request is for application of TransformTM WG, a wettable granule containing 50% 

(w/w) sulfoxaflor. It is expected that sulfoxaflor will be applied to approximately 300,000 acres 

of cotton in Mississippi. Applications would be made from June through September of the 2012

growing season using either ground-based or aerial equipment. The proposed use directions are 

summarized in Table 1.

 

1 HED notes that Arkansas and Tennessee have also submitted Section 18 requests for use of sulfoxaflor on cotton. 

This risk assessment assumes that the entire U.S. cotton crop is treated with sulfoxaflor. Provided the use rates and 

timing are the same as those described for the use in Mississippi, this risk assessment implicitly includes other states 

seeking this emergency exemption.
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 3 of 27

Table 1. Summary of Proposed Use Directions on Cotton.

Use Timing; 

Type; and 

Equipment

Product

[File 

Symbol]

Single Use 

Rate

Maximum 

Uses per 

Season

Maximum 

Seasonal 

Use Rate

PHI

(Days)

Use Directions and Limitations

Cotton 

Cotton, foliar 

use. Application 

by both ground 

and aerial 

equipment.

TransformTM

WG 

[62719-AEL]

0.047–0.086 

lb a.i./acre

2 0.172 lb 

a.i./acre

14 No more than one application 

should be made to cotton in prebloom. Five day retreatment 

interval.

The nomenclature of sulfoxaflor and its major metabolites are summarized in Tables 2 and 3, 

below. The physical/chemical properties of sulfoxaflor (Appendix B) do not indicate that there 

are any special considerations that need to be made in conducting the 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.

Table 2. Test Compound Nomenclature

Compound

N

S

N O

N

F3C

Common name Sulfoxaflor

Company experimental name XDE-208

IUPAC name [methyl(oxo){1-[6-(trifluoromethyl)-3-pyridyl]ethyl}-λ

6

-

sulfanylidene]cyanamide

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

cyanamide

CAS # 946578-00-3

Table 3. Nomenclature of Significant Metabolites of Sulfoxaflor

Company Name IUPAC Chemical Name Structure

X11719474 N-(methyl)oxido){1-[6-(trifluoromethyl)pyridine-3-

yl]ethyl}-λ

6

-sulfanylidene) urea

N

S

N O

N

O

F

F

F

X11519540 5-(1-methanesulfonyl-ethyl)-2-trifluoromethylpyridine

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

assessment of potential increased susceptibility of infants and children. The Agency has not 

received a 28-day inhalation study in the rat; however, based on a weight of evidence 

considerations that included hazard and exposure considerations HED’s Hazard and Science 

N

S

O

F O

F

F
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 4 of 27

Policy Council (HASPOC) has granted a waiver for the 28-day inhalation toxicity study (TXR# 

0056309). The use of an oral POD does not underestimate risk via inhalation exposures (i.e., 

MOEs using an oral POD are above the Agency’s Level of Concern). 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, the 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., oral reference dose (RfD)] will 

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

exposure to sulfoxaflor (TXR# 0056301, 26 April 2012).

Sulfoxaflor also affects the neurological system by interacting with the fetal isoform of the 

intermuscular nicotinic acetylcholine receptor (nAChR). This interaction results in the 

contraction of skeletal muscles causing limb flexure and bent clavicle in fetuses and decreased 

neonatal survival due to the constriction of the diaphragm muscles. HED determined this mode 

of action (MOA) was plausible and supported by the available mechanistic data (Appendix A).

Although there is clear evidence that there are neurological effects following exposure to 

sulfoxaflor, the level of concern for neurotoxicity is low because the effects are well

characterized and clear NOAELs are established. Similarly, although there is increased 

quantitative susceptibility in the developmental neurotoxicity (DNT) study, the level of concern 

for the increased susceptibility is low because the effects are well characterized and the 

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

In addition, the exposure assessments are highly conservative and unlikely to underestimate 

exposure/risk. Therefore, HED is recommending that the required 10X FQPA Safety Factor be 

reduced to 1X.

HED further recommends that the 10X interspecies factor (UFA) be reduced to 3X for 

assessments based on nicotinic receptor-mediated effects (i.e., acute dietary risk assessment for 

women of reproductive age and for dermal and inhalation risk assessments). There is extensive 

mechanistic data indicating that rats may be uniquely sensitive to the developmental effects of 

sulfoxaflor: 1) there were no developmental effects observed in the rabbit and 2) when the 

different adult rat, adult human, or fetal human nAChR isoforms are expressed in Xenopus

oocytes, there was no indication of activation in the receptors in the presence of sulfoxaflor. 

Therefore, only the rat fetal isoform of the nAChR appears to be responsive to perturbation by 

sulfoxaflor. Quantitatively, the human fetal nAChR is at least 500-fold less sensitive than the rat 

fetal nAChR based on the highest concentration tested in the human receptor studies compared to 

the effective dose in the rat fetal receptor study. The absence of nAChR activation in the human 

receptors precludes the manifestation of skeletal abnormalities and neonatal deaths. The Agency 

is proposing that the interspecies UFA be reduced to 3X based on the evidence that the human 

nAChR is not more sensitive than the rat.

As previously noted, the toxicological database for sulfoxaflor is lacking a subchronic inhalation 

study. HED has determined that sufficient information is available to demonstrate that risks 

from exposure via the inhalation route would not be greater that from exposure via the oral route
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 5 of 27

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 for sulfoxaflor is being waived and a 

database uncertainty factor is not required.

A summary of the sulfoxaflor endpoints used for risk assessment is shown in the tables below.

Table 4. Sulfoxaflor Toxicological Doses and Endpoints for Use in Dietary Human Health Risk Assessments

Exposure/ Scenario Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD/PAD Study and Toxicological Effects

Acute Dietary (General 

Population, including 

Infants and Children)

NOAEL= 

25 mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Acute 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

Acute 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 on 

postnatal day (PND) 0 through 4

Chronic Dietary (All 

Populations)

NOAEL= 

5.13 mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Chronic RfD = 

0.05 mg/kg/day

cPAD = 

0.05 mg/kg/day

Chronic/Carcinogenicity Study in 

the 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

observed in the males and females.

Cancer (oral, dermal, 

inhalation)

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

Quantification of risk using a non-linear approach (i.e., RfD) will adequately account for 

all chronic toxicity, including carcinogenicity.

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. 
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 6 of 27

Table 5. Sulfoxaflor Toxicological Doses and Endpoints 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 = 2.5%

UFA=3x

UFH=10x

Occupational LOC 

for MOE = 30

Developmental Neurotoxicity Study

LOAEL = 7.1 mg/kg/day based on 

decreased neonatal survival on 

postnatal day (PND) 0 through 4

Inhalation 

Short-and 

Intermediate 

Term 

NOAEL= 1.8 mg/kg/day

Inhalation and oral 

absorption are equivalent

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., RfD) will adequately account for all chronic toxicity, including 

carcinogenicity.

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.

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

drinking water. Toxicology, residue chemistry, and environmental fate data submitted to the 

Agency show that there are a unique set of exposure profiles that need to be considered when 

assessing this insecticide. In short, given the toxicological endpoints being used for risk 

assessment, information on which chemical species can result in those effects, and differences in 

the residue profiles for foods, surface water, and groundwater, this assessment focuses on the 

following three combinations for evaluating dietary exposure:

Acute dietary exposure, general population: sulfoxaflor in food and the metabolites 

designated X11719474 and X11519540 in groundwater;

Acute dietary exposure, women of child-bearing age: sulfoxaflor in food and surface 

water;

Chronic dietary exposure, all populations: 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 being used as the endpoint in 

the assessment. Relative to sulfoxaflor, these factors are 0.3X for X11719474 and 10X 

for X11519540.

Further information regarding these assessments, the rationale for selecting the exposure profiles, 

and the toxicity factors are provided in the detailed sections below.

In evaluating dietary exposure, HED has examined the residue chemistry data submitted to 

support the Section 3 registration and has used conservative, health-protective assumptions 

regarding residue levels in cotton and drinking water. For cottonseed oil HED has assumed

100% of the U.S. cotton crop is treated with sulfoxaflor, tolerance-level residues are present in 

cottonseed, and an empirical processing factor that demonstrates sulfoxaflor residues are reduced 

in cottonseed oil. In the case of drinking water, residues are based on modeled upper-bound

estimates and include the relative potency factors for X11719474 (0.3X) and X11519540 (10X)

noted above. Despite these assumptions, dietary risk estimates are significantly below HED’s 
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 7 of 27

level of concern (typically 100% of the population-adjusted dose) for both acute and chronic 

dietary exposure and for all population subgroups. For acute exposures, the dietary risk estimate 

is ≤1% of the acute population adjusted dose (aPAD) for all population groups, except for all 

infants, which is 4% of the aPAD. Chronic risk estimates are 3% of the chronic population

adjusted dose (cPAD) for the U.S. population and 9% of the cPAD for all infants, the highest 

exposed population subgroup. We note that under the Section 18 use, residues of sulfoxaflor are 

not expected to transfer into livestock commodities from livestock consumption of cotton-based 

feeds that have been treated with sulfoxaflor.

Information on the submitted Section 18 label indicates that both handler and postapplication 

exposures may occur for short-term (up to 1 month) and intermediate-term (up to 6 months) 

durations. Estimated route-specific occupational margins of exposure (MOEs) range from 80 to 

220,000. The level of concern for dermal and inhalation exposures is 30 (i.e., MOEs of less than 

30 indicate a potential risk concern). Similarly, combined estimated MOEs are also greater than 

30. These estimated MOEs assume baseline levels of personal protective equipment (PPE) and

indicate that there are no risks of concern associated with occupational exposures.

Sulfoxaflor is a new active ingredient and does not appear to have a mode of action in common 

with other pesticide active ingredients or their metabolites; nor does sulfoxaflor have metabolites 

common to other active ingredients. Therefore, HED has not conducted a cumulative risk 

assessment involving sulfoxaflor and other active ingredients.

Residue data are available from cotton field trials and processing studies conducted with 

sulfoxaflor. Those data support the recommended tolerances shown in Table 6, below. 

HED concludes that there is a reasonable certainty that no harm will result from aggregate 

exposure to sulfoxaflor associated with the requested Section 18 use. In addition, there are no 

concerns for occupational exposure and risk estimates associated with the use on cotton. 

The residue chemistry data indicate that tolerances should be 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 in or on the commodity. An acceptable analytical method is 

available for enforcing these tolerances.

Table 6. Time-Limited Tolerances to Support the Emergency Exemption Use of Sulfoxaflor on Cotton.

Commodity Recommended Tolerance, ppm

Cotton, undelinted seed 0.2

Cotton, gin byproducts 6.0

Cotton, hulls 0.35

The recommended tolerances were derived using the OECD tolerance/MRL calculation 

procedures and are harmonized with those recently recommended at the Joint Meeting on 

Pesticide Residues (JMPR, 2011).
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 8 of 27

DETAILED TOXICOLOGICAL CONSIDERATIONS

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

doses for acute and chronic dietary risk assessment and for evaluating short- and intermediateterm exposure via dermal and inhalation pathways. As there are no residential uses at this time, 

endpoints for assessing incidental oral exposure were not selected, and exposure via the dermal 

and inhalation pathways is relevant for assessing occupational exposure only.

In support of the Section 3 registration request, Dow AgroSciences has submitted a large number 

of mechanistic studies designed to elucidate the mode of action of sulfoxaflor for the 

developmental effects observed in rats and its relevance for human health effects. These data

indicate that rats may be uniquely sensitive to the developmental effects resulting from agonism 

of the nicotinic receptor by sulfoxaflor. In fact, humans may not be susceptible to these effects 

based on the lack of responsiveness of the human nicotinic receptor to sulfoxaflor in the agonism 

study. Furthermore, the observation that no neonatal deaths or neuromuscular/skeletal effects 

were noted in the rabbit developmental toxicity study supports the conclusion that rats are 

uniquely sensitive to developmental toxicity due to sulfoxaflor exposure. In addition, there is 

support for the pharmacodynamic differences in how sulfoxaflor interacts with rat fetal receptors 

versus adult rat, fetal human, and adult human receptors. These differences suggest that to the 

extent that neonatal death in rats occurs as a result of sulfoxaflor binding to the fetal receptor, 

these effects would not be observed in humans. Overall, these data suggest as a conservative 

assumption that rats and humans are at most pharmacodynamically comparable. Consequently, 

HED recommends that the interspecies UF be reduced to 3x.

A comprehensive analysis of the mode-of-action studies is being completed in conjunction with 

the Section 3 evaluation and is not presented herein; rather, this assessment focuses on the doseresponse portion of the toxicological database. However, since the developmental and 

reproductive MOA described in the Assessment Summary is critical to endpoint selection, a brief 

review is given here. The developmental and reproductive MOA for sulfoxaflor describes the 

ability of sulfoxaflor to act as an agonist rat fetal intermuscular nicotinic acetylcholine receptor 

(nAChR). That is, sulfoxaflor interacts with the nAChR, causing an increase in skeletal muscle 

contraction. This leads to skeletal abnormalities (i.e., forelimb flexure and bent clavicles) and 

increased neonatal deaths from constriction of the diaphragm muscles. There receptors, although 

present, are slightly different in fetal and adult lifestages. The differences are such that 

sulfoxaflor only interacts with the fetal form. Therefore the developmental endpoints are only 

applicable to life stages with the fetal receptor isoform and only appropriate for assessing risks to

women of reproductive age.

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 

uncertainty factor that included 10x for inter-species extrapolations, 10x for intra-species 

variations, and a 1x FQPA safety factor. The LOAEL of 75 mg/kg is based on decreased motor 

activity on day 1 of dosing. 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 
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 9 of 27

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 

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

and 1x FQPA safety factor. The endpoint of concern is decreased neonatal survival in postnatal 

day (PND) 0-4 offspring at the LOAEL of 7.1 mg/kg/day. This endpoint is appropriate because 

it is a single dose effect, is of a relevant route of exposure (oral), and is protective for fetuses in 

utero.

Non-guideline critical window studies support the use of this endpoint for an acute exposure 

assessment. A series of non-guideline studies were conducted to accurately define the critical 

window of exposure for developmental effects. These studies indicate that a maternal oral dose 

of sulfoxaflor between gestation day 20 and parturition will result in decreased neonatal survival 

in rats. Due to the brevity of this critical window, it’s assumed that a single dose within this 

period can result in decreased offspring survival and skeletal abnormalities.

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

cPAD was selected from the chronic/carcinogenicity combined study in the rat. The cPAD of 

0.05 mg/kg/day was derived from a NOAEL of 5.13 mg/kg/day and a 100-fold uncertainty 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/day is based on liver effects including increased blood 

cholesterol, liver weight, hypertrophy, fatty change, single cell necrosis and macrophages in 

males and females. The selected study is appropriate for selecting the dose and endpoint based 

on duration and route of exposure.

Dermal Absorption Factor: HED has compared data depicting in vivo and in vitro dermal 

absorption of sulfoxaflor in rats with in vitro dermal absorption in human skin to derive a 

human-equivalent in vivo dermal absorption factor of 2.5%.

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. The level of concern (LOC) for these assessments is 30, which 

is derived from a 3X factor for inter-species extrapolation and a 10x factor for intra-species 

variability. Although a route-specific dermal study is available, the selected endpoint was 

chosen from the DNT because it is protective of developmental parameters not measured in the 

dermal study. As previously noted, the endpoint is appropriate for assessing risk to women of 

child-bearing age; nevertheless, this endpoint is protective of other effects and will be used to 

assess risk from dermal and/or inhalation exposure for other population groups as well.
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 10 of 27

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.

Cancer Classification: 

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 in 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. Rather, 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.

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.
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 11 of 27

Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

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

Exposure Task Force (AHETF) database; and the Agricultural Re-entry Task Force (ARTF) 

database; 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-exposuredata.html and http://www.epa.gov/pesticides/science/post-app-exposure-data.html.

DETAILED RESIDUE CHEMISTRY CONSIDERATIONS

Pesticide Metabolism and Environmental Degradation

HED has reviewed extensive metabolism data submitted by the registrant to support the Section 

3 registrations currently under evaluation and concluded that the nature of the residue is 

adequately understood in plants, livestock and rotational crops. HED has determined that for 

plants and livestock the residue of concern for tolerance setting and risk assessment is the parent, 

sulfoxaflor. In drinking water, residues of concern for risk assessment are sulfoxaflor and its two

metabolites designated X11719474 and X11519540.

Table 7. Summary of Sulfoxaflor Metabolites and Degradates to be included in the Risk Assessment and 

Tolerance Expression

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. 

Analytical Methods

HED has concluded that adequate analytical methods have been submitted for both data 

collection and for enforcement purposes. In the submitted field trial and processing studies, 

residues of sulfoxaflor and its metabolites in crops were determined using 2 different Dow 

analytical methods (designated as 091031 or 091116). The proposed method for tolerance 

enforcement in plant commodities is method 091116: Enforcement Method for the 

Determination of Sulfoxaflor (XDE-208) and its Main Metabolites in Agricultural Commodities 

using Offline Solid-Phase Extraction and Liquid Chromatography with Tandem Mass 

Spectrometry Detection. Method 091116 extracts residues with acetonitrile/water and includes

use of a deuterated internal standard, hydrolysis with NaOH to release base-labile conjugates, 

and clean up via solid-phase extraction. This method is applicable for the quantitative 

determination of residues of sulfoxaflor, [1-(6-trifluoromethylpyridin-3-yl)ethyl](methyl)-oxidoλ

6

-sulfanylidenecyanamide and its metabolites, X11719474, N-((methyl)oxido){1-[6-
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 12 of 27

(trifluoromethyl)pyridine-3-yl]ethyl}-λ

6

-sulfanylidene)urea and X11721061, 1-[6-

(trifluoromethyl)pyridin-3-yl]ethanol, in agricultural commodities and processed products. The 

method was adequately validated, with a limit of quantitation (LOQ) of 0.010 mg/kg for all 

matrices.

The FDA MRM was reported by the registrant to be not suitable for analysis of sulfoxaflor 

and/or its metabolites; the German multiresidue method S-19 may be suitable.

Drinking Water Residue Profile

References: D398590. Estimated Drinking Water Concentrations of Sulfoxaflor from Use in Cotton (FIFRA Section 18 

Emergency Use in Cotton) for the Use in Human Health Risk Assessment. Mohammed A. Ruhman, Ph.D., 8 May 

2012.

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. 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 de-ionized 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 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.

The screening-level estimated drinking water concentrations (EDWCs) in surface water sources 

were calculated using Tier II PRZM (Pesticide Root Zone Model) and EXAMS (Exposure 

Analysis Modeling System). The Tier I SCI-GROW (Screening Concentration in Ground 

Water) model was used for calculating the EDWCs in ground water sources. The estimates are 

presented in Table 8a for surface water and groundwater. Modeling included all available cotton 

scenarios using the maximum application rate, maximum number of applications (two 

applications) and the minimum application interval of 5 days. Results in Table 8a are for the 

highest modeled concentrations.
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 13 of 27

Table 8a. Estimated Drinking Water Concentrations (EDWCs) for Total Toxic Residues of Sulfoxaflor in Surface 

and Ground Waters from Use on Cotton.

Water Source*

Concentration, ppb

Acute Peak 1 Non-cancer/Chronic 2 Cancer 3

Surface 2.76 0.865 0.474

Ground 45.1

* 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; 21-in-10-year annual mean values; 3 1-in-10-year overall annual mean values.

The values in Table 8a represent upper-bound estimates of residue concentrations that might be 

found in surface water and ground water due to the use of sulfoxaflor as an insecticide in cotton. 

Based on the modeled estimates, 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 drinking water will be 

comprised, predominantly, of the X11719474 metabolite. Quantitatively, the 45.1 ppb EDWC 

for groundwater can be divided into 39.7 ppb from X11719474 and 5.4 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. 

Risk Assessment Considerations

Separate acute endpoints were selected for the general population and females 13+. 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 compare the relative potencies of the 

metabolites for other endpoints, this risk assessment assumes that the two metabolites will 

display similar toxicity relative to sulfoxaflor with respect to the motor activity endpoint used to 

assess acute dietary risk for the general population. The EDWCs used in the various dietary 

assessments are summarized in Table 8b.

For females 13+, the developmental endpoint of increased neonatal deaths was chosen because a 

single exposure during late gestation can lead to increased neonatal deaths. X11719474 and 

X1159540 are not likely to result in agonism of the muscle nicotinic receptor and are excluded 

scenarios assessed using the developmental endpoint. Unlike the parent sulfoxaflor, the 

X11719474 metabolite is not a nicotinic receptor agonist and therefore, cannot cause increased 

neonatal deaths or skeletal abnormalities. The Agency does not have any data regarding the 

ability of X1159540 to either bind the nicotinic receptor or act as an agonist; however, given that 

this metabolite is a degradate of X11719474, HED has assumed that X1159540 is not an agonist 

of the nicotinic receptor and will not cause developmental effects and neonatal deaths. 

Therefore, residues of X11719474 and X11519540 are not being considered in the acute dietary 

exposure and risk assessment for females 13-49 years of age. 

For the purposes of this section 18, HED is using relative potency factors in the water assessment 

to account for different potencies between sulfoxaflor and the major groundwater metabolites, 

X11719474 and X11519540 for estimates of chronic risk. 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 
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 14 of 27

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’

LOAEL 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. 

Hepatotoxicity is a common effect between sulfoxaflor and the metabolites in repeated dosing 

studies. In the 28 day studies, the LOAELs are based on increased liver weights and slight to 

moderate hepatocyte hypertrophy. Mechanistic studies were submitted to support liver tumors 

identified in the rat and mouse carcinogenicity studies for sulfoxaflor. CARC determined the 

data supported a nuclear receptor-mediated mode-of-action (MoA). The key events leading to 

tumor formation in the sulfoxaflor study were: (1) CAR receptor activation and (2) increased 

hepatocellular proliferation, leading to (3) hepatocellular tumors. Activation of rodent 

constitutive androstane receptor (CAR) and minor contribution of the pregnane X receptor 

(PXR) produces a cascade of alterations in gene transcription that leads to increased 

hepatocellular proliferation, a critical event in the development of liver tumors, similar to the 

established MOA for phenobarbital (PB). 

In a non-guideline study, rats were given either 0 or 8000 ppm (i.e, 583 mg/kg/day) X11719474 

for 7 days. After 7 days, the key events determined in the sulfoxaflor MOA were examined 

including increased liver weight and hypertrophy, increased CAR-related transcripts Cyp2b1 and 

Cyp2b2 and PROD activity, activation of PXR-related transcript, and hepatocellular proliferation 

as measured by BrdU incorporation. Based on these events, 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. Therefore, for chronic exposure scenarios using 

hepatotoxicity as the POD, HED is combining the exposures for parent and metabolites.

Furthermore, HED is adjusting the exposure values for the metabolites based on the doses at the 

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

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

are 0.3 for X11719474 and 10 for X11519540. 
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 15 of 27

Table 8b. Adjusted Estimated Drinking Water Concentrations (EDWCs) from Use on Cotton for Estimating Dietary 

Risk.

Drinking Water 

Scenario

Water Source Toxic 

Residue

Residue Estimates and 

Adjustments, ppm

Rationale

Acute – General 

Population

Groundwater Sulfoxaflor 0 EDWC: Groundwater > Surface Water

Endpoint is decreased motor activity. 

No information is available to rule out 

applicability or estimate relative 

toxicity.

X11719474 0.0397

X11519540 0.0054

Total 0.045

Acute – Females 

13-49 years old

Surface water Sulfoxaflor 0.0028 Residues in groundwater are not 

appropriate for assessing the endpoint.

Chronic – All 

Populations

Groundwater Sulfoxaflor 0 EDWC: Groundwater > Surface Water

Endpoint is liver effects. 28-day studies 

are available for sulfoxaflor, 

X11719474, and X11519540 to derive 

relative toxicities.

X11719474 0.0397 x 0.3 = 0.012

X11519540 0.0054 x 10 = 0.054

Total 0.066

Food Residue Profile

Reference. See Tier II summaries in Appendix B

No residue data were submitted with this Section 18 request for the use of sulfoxaflor on cotton. 

However, HED is currently evaluating a Section 3 request for the use of sulfoxaflor on cotton 

and numerous other crop groups and individual crops. In support of that request, Dow 

AgroSciences, LLC submitted field trial data for sulfoxaflor in/on cotton seed and gin 

byproducts from 22 field trials conducted during 2008, 2009, and 2010 in Australia, Brazil, 

Europe and the Unites States. Dow AgroSciences has also submitted a cotton processing study 

and livestock feeding studies. All of these studies are supported by adequate analytical methods

and storage stability data. The evaluations of the studies are included in Appendix B.

In the field trials, four approximately equal applications of sulfoxaflor were made at 7-day 

retreatment intervals. The total rate applied was 0.346-0.375 lb a.i./A (~384-400 g a.i./ha) and 

commercial adjuvants were added to the spray mixture. Residues of sulfoxaflor were 0.037-4.20 

ppm in/on cotton gin byproducts and <0.01-0.182 ppm in/on undelinted seed harvested at a ~14-

day PHI. A summary of the residue data most pertinent to the proposed Section 18 use on cotton 

(i.e., results from studies with a 14-day PHI) is shown in Table 9. The total application rate used 

in these studies is approximately 2-fold higher than that requested for this emergency exemption. 

Residues resulting from the use of a water-dispersible granule (WG) formulation, as requested 

for the Section 18 use, are not expected to be significantly different from those resulting from the 

soluble concentrate (SC) formulation used in the field trials due to the fact that both types of 

formulations undergo similar preparation before application and the PHI of 14 days is considered 

long enough to attenuate short-term effects.

In the processing studies (MRID 47832218), residues of sulfoxaflor were shown to concentrate

in aspirated seed fractions (23X) and slightly in hulls (1.8X), but not in delinted seed (1.0X), 

meal and meal presscake (0.8X), or crude or refined oil (<0.1X).
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 16 of 27

Although the field trials were conducted at a rate approximately 2-fold greater than that proposed 

for the Section 18 use, they are considered to be appropriate for assessing the Section 18 use and 

for establishing time-limited tolerances.

Table 9. Summary of residue data from cotton field trials with sulfoxaflor.a

Commodity EPb Total appl. rate

lb a.i./A

PHI 

(day) n

Sulfoxaflor Residue (ppm)

Min Max HAFTc Median

(STMdR)

Mean

(STMR)

Std. 

Dev.

Cotton,

gin byproducts

240

SC 0.346-0.375 14-15 42 0.037 4.20 4.03 0.476 0.869 1.12

Cotton, undelinted 

seed

240

SC 0.346-0.375 14-15 44 <0.010 0.182 0.176 0.019 0.037 0.038

a

 The LOQ (0.010 ppm) was used for all residue values reported as <LOQ in all calculations (mean, median, etc.). 

Data are on a per-sample basis and do not reflect per-trial averaging.

b

 EP = End-use Product; Test item was GF-2032 240 g/L SC formulation.

c HAFT = Highest Average Field Trial.

Cotton seed, gin byproducts, hulls, and meal are significant livestock feed items. Therefore, 

HED has evaluated the potential for residues of sulfoxaflor in edible livestock commodities as a 

result of sulfoxaflor residues in livestock feeds. Based on residue levels in cotton seed and 

cotton gin byproducts, and on factors from the processing study, HED has estimated the dietary 

burdens to be 0.032 ppm for beef cattle, 0.003 ppm for dairy cattle, 0.004 ppm for poultry, and 

0.003 ppm for swine (Table 10). 

Table 10. Estimated Reasonably Balanced Livestock Dietary Burdens*

Crop Commodity Type

Highest Residue 

or Median Residue %DM

% of 

Diet Contribution

Beef Cattle

Barley Grain Carbohydrate Median 0 88 50 0.000

Beet, sugar Molasses Carbohydrate Median 0 75 10 0.000

Corn Gluten Feed Carbohydrate Median 0 40 20 0.000

Cotton Meal Protein Median 0.0176 89 5 0.001

Cotton Gin byproducts Roughage Median 0.486 90 5 0.027

Cotton Hulls Roughage Median 0.0396 90 10 0.004

Total 100 0.032

Dairy Cattle

Barley Grain Carbohydrate Median 0 88 45 0.000

Cotton Undelinted seed Protein Median 0.022 88 10 0.003

Alfalfa Forage Roughage Highest Residue 0 35 20 0.000

Alfalfa Hay Roughage Highest Residue 0 89 20 0.000

Alfalfa Meal Roughage Highest Residue 0 89 5 0.000

Total 100 0.003

Poultry

Barley Grain Carbohydrate Median 0 75 0.000

Cotton Meal Protein Median 0.0176 20 0.004

Canola Meal Protein Median 0 5 0.000

Total 100 0.004
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 17 of 27

Table 10. Estimated Reasonably Balanced Livestock Dietary Burdens*

Crop Commodity Type

Highest Residue 

or Median Residue %DM

% of 

Diet Contribution

Swine

Barley Grain Carbohydrate Median 0 20 0.000

Corn Gluten Meal Carbohydrate Median 0 20 0.000

Corn Gluten Feed Carbohydrate Median 0 20 0.000

Corn, field Grain Carbohydrate Median 0 25 0.000

Cotton Meal Protein Median 0.0176 15 0.003

Total 100 0.003

* For cattle, contribution = residue ÷ (% Dry Matter/100) × % of Diet/100. For poultry and swine, contribution = 

residue × % of Diet/100.

As summarized in Tables 11 (cattle) and 12 (poultry), comparison of these dietary burden 

estimates to residue levels observed in the lactating cattle and laying hen feeding studies (Figures 

1 and 2), results in anticipated residues that are well below 0.01 ppm, which is the limit of 

quantitation for the livestock commodity analytical method. As there is no expectation of finite 

residues in livestock commodities, tolerances for residues in those commodities are not required 

[40 CFR 180.6(a)(3).]
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 18 of 27

Figure 1. Results of Sulfoxaflor Feeding Studies with Lactating Dairy Cattle. The maximum 

residue at each feeding level is shown.

Table 11. Summary of Maximum Residues from the Dairy Cattle Feeding Study and Anticipated Residues.

Dose Level, ppm Milk Muscle Fat Liver Kidney

0.45 0.038 0.026 0.014 0.061 0.04

2.37 0.123 0.155 0.057 0.375 0.21

6.75 0.288 0.311 0.139 0.758 0.566

35.19 1.679 1.691 0.915 4.03 2.442

Slope 0.0476 0.0481 0.0258 0.1146 0.0700

r

2

0.9995 0.9994 0.9985 0.9993 0.9982

Livestock Dietary Burden, ppm Anticipated Residues

Beef Cattle 0.032 NA 0.0015 0.0008 0.0037 0.0022

Dairy Cattle 0.003 0.0001 0.0001 0.0001 0.0003 0.0002

Swine 0.003 NA 0.0001 0.0001 0.0003 0.0002

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 Sulfoxaflor Residue, ppm

Feeding Level, ppm

Milk

Muscle

Fat

Liver

Kidney
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 19 of 27

Figure 2. Results of Sulfoxaflor Feeding Studies with Laying Hens. The maximum residue at 

each feeding level is shown.

Table 12. Summary of Maximum Residues from the Laying Hen Feeding Study and Anticipated Residues.

Dose Level, ppm Eggs Muscle Fat Liver

0.145 0.01 0.01 0.028 0.01

0.757 0.059 0.042 0.15 0.013

2.096 0.099 0.109 0.232 0.048

10.7 0.594 0.659 1.193 0.184

Slope 0.0553 0.0612 0.1119 0.0174

r

2

0.9984 0.9991 0.9970 0.9947

Livestock Dietary Burden, ppm Anticipated Residues

Poultry 0.004 0.0002 0.0002 0.0004 0.0001

DETAILED EXPOSURE AND RISK ANALYSES

Dietary Exposure and Risk

HED has conducted acute and chronic dietary risk assessments using Version 2.03 of the Dietary 

Exposure Evaluation Model with the Food Commodity Intake Database (DEEM-FCID), which 

incorporates consumption data from USDA’s continuing surveys of food intakes by individuals 

(CSFII), 1994-1996 and 1998. The assessments are based on tolerance-level residues, an 

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

0 2 4 6 8 10 12

Sulfoxaflor Residue, ppm

Feeding Level, ppm

Eggs

Muscle

Liver

Fat
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 20 of 27

assumption that all cotton in the U.S. is treated (i.e., 100% crop treated), an empirical factor to 

account for the reduction in sulfoxaflor residues during the processing of cottonseed into oil 

(which is the only human food associated with cotton), and the modeled, health-protective 

estimates of residues in drinking water discussed above. The dietary assessment should be 

considered to be a screening-level assessment; furthermore, we note that for this Section 18 

assessment, drinking water is the main contributor to exposure.

Dietary risk estimates (Table 13) are below HED’s level of concern for the U.S. population and 

all population subgroups, for both acute and chronic exposure scenarios. There are no dietary 

risk issues, including cancer risk issues, which would preclude granting the Section 18 

registration for use on cotton or establishing time-limited tolerances for residues of sulfoxaflor 

in/on cotton commodities.

Table 13. Summary of Dietary Exposure and Risk Estimates for Sulfoxaflor from the Section 18 Use on Cotton.

Population Subgroup

Acute (95th Percentile) Chronic

PAD Exposure 

(mg/kg/day) % PAD PAD Exposure (mg/kg/day) % PAD

U.S. Population (total)

0.25

0.002358 <1 

0.05

0.001392 3

All infants (< 1 year) 0.008871 4 0.004561 9

Children 1-2 yrs 0.003701 1 0.002067 4

Children 3-5 yrs 0.003373 1 0.001935 4

Children 6-12 yrs 0.002351 <1 0.001335 3

Youth 13-19 yrs 0.001919 <1 0.001006 2

Adults 20-49 yrs 0.002184 <1 0.001299 3

Adults 50+ yrs 0.001971 <1 0.001367 3

Females 13-49 yrs 0.06 0.000135 <1 0.001294 3

Populations with the highest exposure estimates are bolded.

Residential Exposure and Risk

At this time, there are no uses of sulfoxaflor that will result in residential exposures. 

Spray drift is always a potential source of exposure to residents nearby spraying operations. This 

is particularly the case with aerial application, but, to a lesser extent could also be a potential 

source of exposure from ground applications of 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 practices2. 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 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.

 

2

See http://www.epa.gov/opp00001/factsheets/spraydrift.htm for more information on spray drift.
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 21 of 27

Aggregate Exposure and Risk

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

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

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure.

In the case of sulfoxaflor, there are no residential uses at this time. Consequently, aggregate 

exposure and risk estimates are equivalent to the dietary (food + drinking water) exposure and 

risk estimates discussed above and summarized in Table 13. There are no aggregate risk issues 

that would preclude granting the Section 18 registration for use on cotton or establishing timelimited tolerances for residues of sulfoxaflor in/on cotton commodities.

Cumulative Exposure and Risk

As previously noted, sulfoxaflor is a new active ingredient and does not appear to have a mode 

of action in common with other pesticide active ingredients or their metabolites; nor does 

sulfoxaflor have metabolites common to other active ingredients. Therefore, HED has not 

conducted a cumulative risk assessment for sulfoxaflor.

DETAILED OCCUPATIONAL EXPOSURE CONSIDERATIONS

The proposed use is on cotton; therefore, there is the potential for occupational handler and postapplication exposure.

Handler Exposure

The requested use of sulfoxaflor on cotton is for the product TransformTM WG formulated as a 

wettable granule which contains 50% active ingredient. TransformTM WG can be applied to 

cotton using ground and air equipment. The personal protective equipment (PPE) proposed on 

the label requires applicators and other handlers to wear long-sleeved shirt and long pants, shoes 

plus socks, and protective eyewear. Based on information provided on the proposed label, 

handler exposure (mixing/loading/applying) is expected to be short- or intermediate-term in 

duration. Long-term exposure is not expected.

Exposure Scenarios

There are 5 handler scenarios that are expected to result in the highest exposure for the proposed 

use:

• Mixing/Loading Dry Flowable for Groundboom Application (Scenario 1),

• Mixing/Loading Dry Flowable for Aerial Application (Scenario 2),

• Applying Sprays with Groundboom Equipment (Scenario 3),

• Applying Sprays with Aerial Equipment (Scenario 4), and
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 22 of 27

• Flagging for Aerial Applications (Scenario 5).

Application Rate

The maximum single application rate on the proposed label was used to assess all handler 

exposure scenarios. The maximum single application rate is 0.086 lb ai/A for cotton. The 

maximum application per acre per year is 0.172 lb ai/A/yr (maximum number of application per 

year at the maximum single rate = 2).

Area Treated

Based on HED’s Exposure Science Advisory Council Policy Number 9.1, the following 

assumptions were used for acres per day treated:

• 200 acres/day for groundboom application, and

• 1,200 acres/day for aerial application.

Unit Exposures

Chemical-specific data for assessing exposure during pesticide handling activities 

(mixing/loading, applying, and flagging) were not submitted to the Agency in support of this 

Section 18 or with the Section 3 requests currently under review. HED’s policy is to use the best 

available data to assess handler exposure. Sources of generic handler data, used as surrogate 

data in the absence of chemical-specific data, include the Pesticide Handlers Exposure Database 

Version 1.1 (PHED 1.1), and the Agricultural Handler Exposure Task Force (AHETF) database. 

Some of these data are proprietary (e.g., AHETF data), and subject to the data protection 

provisions of FIFRA. The standard values recommended for use in predicting handler exposure 

that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational 

Pesticide Handler Unit Exposure Surrogate Reference Table” 

(http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), which, along with 

additional information on HED policy on use of surrogate data, including descriptions of the 

various sources, can be found at: http://www.epa.gov/pesticides/science/handler-exposuredata.html. 

For pesticide handlers, HED’s standard practice is to present estimates of dermal exposure for 

the “baseline” level of mitigation; that is, for workers wearing a single layer of work clothing 

consisting of a long sleeved shirt, long pants, shoes plus socks and no protective gloves; in 

addition, appropriate levels of mitigation are presented as needed, such as addition of gloves or 

other Personal Protective Equipment (PPE), in order to achieve an MOE greater than the LOC. 

The proposed product label involved in this assessment directs applicators and other handlers to 

wear long sleeved shirt and long pants, shoes plus socks, and protective eyewear.
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 23 of 27

Body Weight

An average female adult body weight of 69 kg was used to estimate exposure and risk to 

handlers because the selected dermal and inhalation endpoints were based on developmental 

effects. 

Occupational Handler Exposure and Risk Estimates

Table 14 presents the estimated short- and intermediate-term dermal and inhalation risk estimates

for occupational handlers (mixer/loaders, applicators, flaggers). All occupational handler 

scenarios for the proposed use resulted in estimated MOEs that are greater than 30 (i.e., not of 

concern) at some level of personal protection (i.e. baseline clothing, no gloves and no respirator; 

engineering controls (enclosed cockpit) for aerial applications). The estimated combined 

(dermal+inhalation) MOEs are also not of concern.
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 24 of 27

Table 14: Short- and Intermediate-term Occupational Handler Exposure and Risk Estimates for use of Sulfoxaflor on Cotton.

Exposure Scenario Max Single 

App Rate

(lb ai/A)1

Acres 

Treated 

Daily2

Dermal Unit 

Exposure3

(mg/lb ai)

(Mitigation Level)

Inhalation Unit 

Exposure3

(mg/lb ai)

(Mitigation Level)

Dermal Inhalation Combined 

Dose8

(mg/kg/day)

Combined 

MOE9 Dose4

(mg/kg/day)

MOE5 Dose6

(mg/kg/day)

MOE7

Mixer/Loader

Dry Flowable for 

Groundboom Application 

(AHETF)

0.086 200 0.227

(Baseline)

0.00896

(No respirator)

0.0014 1,300 0.0022 810 0.0036 500

Dry Flowable for Aerial 

Application (AHETF) 

0.086 1200 0.277

(Baseline)

0.00896

(No respirator)

0.0085 210 0.0134 130 0.0219 80

Applicator

Sprays for Groundboom 

Application (AHETF)

0.086 200 0.0786

(Baseline)

0.00034

(No respirator)

0.0005 3,700 0.000085 21,000 0.0006 3,000

Sprays for Aerial 

Application (PHED)

0.086 1200 0.005

(Engineering 

Controls -

Enclosed cockpit)

0.000068

(Engineering 

Controls - Enclosed 

cockpit)

0.00019 9,600 0.0001 18,000 0.00029 6,200

Flagger

Flagging for Aerial 

Application

(PHED)

0.086 1200 0.011

(Baseline)

0.00035

(No respirator)

0.00012 15,000 0.00015 12,000 0.00027 6,700

1. Application Rate is based on proposed Section 18 TransformTM WDG label.

2. Acres Treated per Day is based on Exposure SAC SOP #9: Standard Values for Daily Acres Treated.

3. Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (OPHED; March, 2012).

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).

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).

8. Combined Dose = Dermal Dose (mg/kg/day) + Inhalation Dose (mg/kg/day).

9. Combined MOE = NOAEL (1.8 mg/kg/day)/Combined Dose (mg/kg/day).
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 25 of 27

Post-Application Exposure 

Inhalation

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 (0.086 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). 

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.

Dermal

Farm 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. It is HED’s policy to use 

the best available data to assess post-application exposure. The registrant submitted dislodgeable 

foliar residue (DFR) studies in support of the proposed Section 3 uses. DFR data from treated 

wheat (see Appendix D) were used as surrogate DFR data for cotton to assess post-application 

dermal exposure and risk for the Section 18 use. Sources of generic post-application 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 postapplication 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.

Dermal exposures during post-application activities were estimated using standard default and 

surrogate contact activity values (Table 15), chemical-specific DFR and field trials data.
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 26 of 27

Table 15: Anticipated Post-Application Activities and Dermal Transfer Coefficients.†

Proposed Crop Crop Group Transfer Coefficients Activities EPA MRID No.

Field / row crop, 

low/medium

Cotton 70 cm2/hr Hand weeding 42851302, 42689103, 42689104

210 cm2/hr 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

†The information in the table is based on proprietary and non-proprietary data.

Post-Application Exposure and Risk Estimates

Dermal post-application exposure resulting from application of sulfoxaflor to cotton during foliar 

contact activities (e.g., hand weeding, scouting) was estimated using the best available surrogate 

DFR predicted Day-0 residue value from treated wheat (0.0210 ug/cm2) calculated by a firstorder dissipation kinetics and decay model.

A summary of the post-application exposure and risk estimates from use of sulfoxaflor on cotton 

during hand weeding and scouting activities is provided in Table 16. Post-application dermal 

exposure and risk estimates resulted in MOEs greater than 30 and are not of concern. 

Table 16. Post-Application Exposure and Risk Estimates for use of Sulfoxaflor on Cotton.

Crop

Proposed 

Maximum 

Application 

Rate

(lb ai/A)

Activity TC1

(cm2/hr)

Days After 

Treatment

Dislodgeable 

Foliar Residue2

(ug/cm2)

Daily Dose 

(mg/kg/d)3 MOE4

Cotton 0.086 Hand Weeding 70 00.0210 0.0000082 220,000

Scouting 210 0.000025 73,000

1. Transfer Coefficients from HED Policy No. 3.0., March 2012. 

2. Dislodgeable Foliar Residue (DFR) = 0.0210 ug/cm2is based on predicted day 0 residue value calculated from 

chemical-specific data (MRID No. 47832415). 

3. Dermal Dose (mg/kg/day) = [DFR (ug/cm2) x TC (cm2/hr) x hr/day (8 hrs/day) x (0.001 μg/mg) x DAF (2.5%)]/

BW 69 kg).

4. Dermal MOE = NOAEL (1.8 mg/kg/day)/Dermal Dose (mg/kg/day); LOC = 30.

Dermal post-application exposure resulting from application of sulfoxaflor to cotton during 

harvesting activities (e.g., module builder, picker operator, raker, tramper) was estimated using 

the Day-14 residue value from the cotton field trials (see Table 9). The Day-14 residue value 

was adjusted to the proposed maximum seasonal application rate. Since the proposed PHI for 

cotton is 14 days, the adjusted Day-14 residue value from the cotton field trials (0.000084 mg 

ai/g cotton) is considered adequate to estimate dermal post-application exposures and risks 

during harvesting activities. Note that the residue data reflect solvent-extractable residues, which 

are likely to be significantly greater than the residue that is available for transfer 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.
Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 27 of 27

A summary of the post-application exposure and risk estimates from use of sulfoxaflor on cotton 

during harvesting activities is provided in Table 17. Post-application dermal exposure and risk 

estimates resulted in MOEs greater than 30 and are not of concern. 

Table 17. Post-Application Exposure and Risk Estimates for Mechanical-Harvesting-Related Activities following Use of 

Sulfoxaflor on Cotton.

Crop

Proposed Maximum 

Seasonal 

Application Rate

(lb ai/A)

Activity TC1

(g cotton/hr)

Days 

After 

Treatment

Residue from 

Cotton Field 

Trial 2

(mg ai/g cotton)

Daily Dose 

(mg/kg/d)3 MOE4

Cotton 0.172

Module Builder 900

14 0.000084

0.00022 8,200

Picker Operator; Raker 2400 0.00058 3,100

Tramper 5050 0.00123 1,500

1. Transfer Coefficients from HED Policy No. 3.0., Non-Foliar Transfer Coefficient Table, March 2012. 

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) ((0.172 lb ai/A)/(0.375 lb ai/A)) = 0.000084 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)

The petitioner has proposed an REI of 24 hours for TransformTM WG based on their interpretation 

of the acute ocular toxicity study resulting in a Toxicity Category II. 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.

APPENDICES

Appendix A: Hazard Characterization and Toxicological Profile

Appendix B: Cotton Field Trial and Processing Tier II Summaries

Appendix C: Livestock Feed Study Tier II Summaries

Appendix D: Dislodgeable Foliar Residue Study in Wheat

REFERENCES FOR AGENCY MEMORANDA

D399696. Sulfoxaflor Acute and Chronic Dietary Exposure and Risk Assessment – Section 18 

Use on Cotton. 7 June 2012.

D398590. Estimated Drinking Water Concentrations of Sulfoxaflor from Use in Cotton (FIFRA 

Section 18 Emergency Use in Cotton) for the Use in Human Health Risk Assessment. 8 May 

2012.

D398294. Sulfoxaflor. Report of the Residues of Concern Knowlegebase Subcommittee 

(ROCKS). 6 April 2012.

TXR 0056301. SULFOXAFLOR: Report of the Cancer Assessment Review Committee. 26 

April 2012.

TXR 0056309. Sulfoxaflor: Summary of Hazard and Science Policy Council (HASPOC) 

Meeting of April 26, 2012: Recommendation on the need for a 28-day inhalation 

study. In preparation.