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: D 3985 9 1

Decision No.: 460686 Registration No. : 62719

- AEL

Petition No.: 12MS02 Regulatory Action: Section 18 Risk Assessment Type: Single Chemical, Aggregate Registration Case No.: None

T XR 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, P h.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 Divisio n (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 Sectio n 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 Mississippi 1 is reques ting an emergency exemption under FIFRA Section 18 for the use of sulfoxaflor on cotton to control tarnished plant bug, Lygus lineolaris . Th is 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 bee n 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

tenta tive and applicable to the Section 18 evaluation only.

Sulfoxaflor { [N

- methyloxido[1

- [6

- (trifluoromethyl)

- 3

- pyridinyl]ethyl] λ 4

- 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 th at 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 Transform TM WG

, a wettable granule containing 50% (w/w) sulfoxa flor. It is expected that s ulfoxaflor will be applied to approximately 300,000 acres of cotton in Mississippi. Applications would be made from June through September of the 201 2 growing season using either ground

- based or aerial equipment. The proposed use directions are

summarize d 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. Transform TM

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 pre

bloom. 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 th e risk assessment . The compound is not particularly volatile (vapor pressure ≤ 1.4 x 10 - 6 Pa) and based on the K OW (~6.35) it is not expected to partition into fatty tissue or bioaccumulate.

Table 2. Test Compound Nomenclature Compound

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] λ 4

- 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

X11519540 5

- (1

- methanesulfonyl

- ethyl)

- 2

- trifluoromethyl

pyridine

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 ScienceSulfoxaflor 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 underestimat e risk via inhalation exposures (i.e., MOEs using a n 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 effec ts in subchronic and chronic studies include organ weight and enzyme changes, hypertrophy, proliferation, and tumors ; long

- term studies result ed in hepatic effects at

doses lower than in short

- term studies

. Based on the weight of evidence, the CARC determ ined that there is a “Suggestive Evidence of Carcinogenic Potential” for sulfoxaflor and that quantification of ri sk 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 i n 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, a lthough 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 c haracterized 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 recommendin g that the required 10X FQPA Safety Factor be

reduced to 1X

.

HED further recommends that the 10X interspecies factor (UF A ) be reduced to 3X for assessments based on nicotinic receptor

- mediated effects (i.e., acute dietary risk assessment for women of repr oductive age and for dermal and inhalation risk assessments ) . Th ere is extensive

mechanistic data indicat ing 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, t here 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 l ess 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 manifestati on of skeletal abnormalities and neonatal deaths. The Agency is proposing that the interspecies UF A be reduced to 3 X based on the evidence that the human

nAChR is not more sensitive than the rat

.

As previously noted, the toxicological database for sulfo xaflor 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 routeSulfoxaflor Human Health Risk Assessment DP No. D398591

Page 5 of 27 for the following reas ons: 1) The acute inhalation toxicity (Category IV) is lower than the acute

oral LD 50 (Category III); 2) the vapor pressure is low ( ≤1.4×10 - 6 Pa (1.05×10 - 8 mm Hg) at 20°C ); 3) there is adequate characterization of toxicity; 4) oral absorption is >90%

– substantially higher

ab s orption 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 ri sk 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 UF A = 10x

UF H =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 UF A = 3x

UF H =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 UF A = 10x

UF H =10x FQPA SF= 1x Chronic RfD =

0.0 5 mg/kg/day

cPAD =

0.0 5 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

. ” Q uantification 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 th at 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 ef fect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = 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% UF A =3x

UF H =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

I nhalation and oral absorption are equivalent UF A =3x

UF H =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

. ” Q uantification 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 r elevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members o f the human population (intraspecies). MOE = margin of expos ure. 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 f ate 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 sp ecies 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 m etabolites 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. 3 X 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 t reated 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

. 3 X) and X11519540 (10X)

noted above

. Despite these assumptions, dietary risk estimates are significantly below HED’sSulfoxaflor 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 ( a PAD) for all population groups, except for all infants, which is 4 % of the aPAD

. Chron ic risk estimates are 3 % of the chronic population adjusted dose ( c PAD) for the U.S. population and 9 % of the c PAD 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 r oute

- 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 indic ate 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 ex posures.

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 es timates 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. Com pliance 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 Emer gency 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 intermediate

term 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 AgroSci ences 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 developm ental 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 t o 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 pharmacodynam ically comparable. Consequently, HED recommends that the interspeci es UF be reduced to 3x.

A comp r e hensive analysis of the mode

- of

- action studies is being completed in conjunction with the Section 3 evaluation and is not presented herein ; r ather, this as sessment focuses on the dose

response 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 diffe rences 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 Die tary 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

un certainty 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 andSulfoxaflor Human Health Risk Assessment DP No. D398591

Page 9 of 27 decr eased 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) a nd 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 i nter

- 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 condu cted 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 b revity 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

0.0 5 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 variabil ity, 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 stud y 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 i s available, the selected endpoint was chosen from the DNT because it is protective of developmental parameters not measured in the dermal study. As pr eviously 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 w ell.Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 10 of 27 T he 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 LD 50 (Category III); 2) the vapor pressure is low ( ≤1.4×10 - 6 Pa (1.05×10 - 8 mm Hg) at 20°C ); 3) there is adequate characterization of toxicity; 4) oral absorption is >90%

– substantially higher

ab s orption 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 releva nt. Therefore, the subchronic inhalation study is waived for sulfoxaflor . T he 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 th e 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 poten tial 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 iden tified the sequence of key events, dose

response 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 c riteria 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 h istopathology 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

- exposure

data.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 p lants, 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 sulfoxaflo r 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 1 Sulfoxaflor

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 s eason soil application uses.

Analytical Method s

HED has concluded that adequate analytical methods have been submitted for both data collection and for enforcement purpo ses. In the submitted field trial and processing studies,

r esidues of sulfo x aflor 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 Detecti on. 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 quantitativ e determination of residues of s ulfoxaflor , [1

- (6

- trifluoromethylpyridin

- 3

- yl)ethyl](methyl)

- oxido

λ 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 su itable 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

E nvironmental 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, neutr al 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, sulf oxaflor degrades rather quickly to its major degradate X 11719 474 (90 th percentile t1⁄2= 0.4 days). Other residues, forming as a result of aerobic soil biotransformation, include limited amounts of X

- 1157957 and X 11519 540. Anaerobic soil data suggest that anaerobic conditi ons produces the main degradate

, X 11719 474. In contrast to the rapid degradation of sulfoxaflor in aerobic soil systems, the chemical degrades rather slowly to X 11719 474 in both aerobic and anaerobic aqu atic conditions (90 th percentile t1⁄2= 141 days).

Sulfoxaflor is considered to be non

- persist ent 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

. Sour ce s of surface water contamination include drift for parent and run

- off for X 11719 474

and X 11519 540 following the rapid degradation of parent in the soil. P arent compound that

drifts into sur face water is expected to degrade rather slowly to X 11719 474. I n contrast, the source of ground water contamination is expected to be leaching of parent and /or its degradation products X 11719 474 and X 11519 540 , 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). T he T ier I SCI

- GROW ( S creening C oncentration in Gro und

W ater) model was used for calculating the EDWCs in ground water sources. The estimates are presented in Table 8 a 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 appli cation interval of 5 days. Results in Table 8 a are for the highest modeled concentrations.Sulfoxaflor Human Health Risk Assessment DP No. D398591

Page 13 of 27 Table 8 a

. Estimated Drinking Water Concentrations (EDWCs) f or Total Toxic Residues o f Sulfoxaflor i n Surface

a nd Ground W aters 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; 2 1

- in

- 10

- year a nnual mean values; 3 1

- in

- 10

- year o verall annual mean values.

The values in Table 8 a 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 pote ntial 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. En vironmental 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 Consideration s

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 compar e 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 t he 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 caus e 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 meta bolite is a degradat e of X11719474 , HED has assumed that X1159540 is not an agonist of the nicotinic receptor and will no t caus e developmental effects and neonatal deaths. Therefore, residues of X11719474 and X11519540 are not being considered in the acut e 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 me tabolites,

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 twoSulfoxaflor Human Health Risk Assessment DP No. D398591

Page 14 of 27 studies, a 28

- day oral toxicity st udy in the rat and an acute LD 50 study, also in the rat. Since the

rat 28

- day oral toxicity stud ies are common to all three chemical databases and the stud ies’ LOAEL are all based on the common toxic effect of hepatotoxicity, HED has estimated the

relativ e potency of X11719474 and X11519540 based on results from the 28

- day oral toxicity study in the rat.

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

studies . In the 28 day studies, the LO A ELs are based on increased liver weights and slight to moderate hepatocyte hypertrophy. Mechanistic studies were submitted to support l iver 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 ro dent 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 t umor s, similar to the

established MO A 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

includin g 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 B rdU inco r poration . Based on these events, CARC determin ed 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 . T herefore, 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 stud ies. 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 Concentrati ons (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. 01 2

X11519540 0.0054 x 10 = 0.054

Total 0. 0 66

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 suppor t 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 al so submitted a cotton processing study and livestock feeding studies. All of these stud ies are supported by adequate analytical method s and storage stability data. The evaluations of the studies are included in Appendix B.

In the field trials, four appr oximately equal applications of sulfoxaflor were made at 7

- day retreatment intervals. The total rate applied was 0.34 6

- 0.3 75 lb a.i./A (~384

- 400 g a.i./ha) and commercial adjuvants were added to the spray mixture. R esidues 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 n ot 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 c onsidered 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 m eal 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, the y are considered to be appropriate for assessing the Section 18 use and

fo r establishing time

- limited tolerances

.

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

Commodity EP b Total appl. rate

lb a.i./A PHI

(day) n Sulfoxaflor Residue (ppm)

Min Max HAFT c 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 byproduct s, 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

burden s 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 0.004Sulfoxaflor 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), result s in anticipated residues that are well below 0.01 ppm, which is the limit of quantitation f

or 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 0.0 015 0.0 008 0.0 037 0.0 022 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. 0002Sulfoxaflor 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 0.0 0 4 0. 00 02 0.0 0 02 0.0 0 04 0.0 0 01

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

FatSulfoxaflor 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

accou nt 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 assess ment 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 1 3 ) 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

- l imited tolerances for residues of sulfoxaflor

in/on cotton commodities

.

Table 1 3 . Summary of Dietary Exposure and Risk Estimates for Sulf oxaflor 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 0.001 392 3

All infants (< 1 year) 0.008871 4 0.00 4561 9

Children 1

- 2 yrs 0.003701 1 0.002 067 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 0.001 006 2

Adults 20

- 49 yrs 0.002184 <1 0.001 299 3
Adults 50+ yrs 0.001971 <1 0.001 367 3

Females 13

- 49 yrs 0.06 0.000135 <1 0.001 294 3
Populations with the highest exposure estimates are bolded.

Residential Exposure and Risk

At this time, t here 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 regul ation and other parties to develop the best spray drift management practices 2 . 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 S ee http://www.epa.go v/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, ex posures 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 an d 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 summ arized in Table 13

. There are no aggregate risk issues that would preclude granting the Section 18 registration for use on cotton or establishing time

limited 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. Ther efore, 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 post

application exposure.

Handler Exp osure

The requested use of sulfoxaflor on cotton is for the product Transform TM WG formulated as a wettable granule which contains 50% active ingredient. Transform TM 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), andSulfoxaflor 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 app lication 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 activit ies (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 gener ic 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 proprietar y (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 H andler 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 a t: http://www.epa.gov/pesticides/science/handler

- exposure

data.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

ot her Personal Protective Equipment (PPE)

, in order to achieve a n 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 protec tive 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 1 4 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 MO Es 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 1 4 : Short

- and Intermediate

- term Occupational Handl er Exposure and Risk Estimates for use of Sulfoxaflor on Cotton. Exposure Scenario Max Single App Rate (lb ai/A) 1 Acres

Treated Daily 2 Dermal Unit

Exposure 3
(mg/lb ai) (Mitigation Level) Inhalation Unit Exposure 3
(mg/lb ai) (Mitigation Level) Dermal Inhalation Combined

Dose 8
(mg/kg/day) Combined

MOE 9 Dose 4
(mg/kg/day) MOE 5 Dose 6
(mg/kg/day) MOE 7

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 0.000 085 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 Transform TM WDG label.

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

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

- A pplication Exposure

Inhalat ion

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 vol atilization 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/2009/120109meetin g.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 H ED’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 e stimates 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 duration s. I t is HED ’s policy to use the best available data to assess post

- application exposure. The registrant submit ted dislodgeable

foliar r esidue (DFR) stud ies in support of th e proposed Section 3 uses. DFR data from treated

wheat (see Appendix D) were used as s urrogate 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 rec ommended 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_p olicy3.pdf), which, along with additional information about the ARTF data, can be found at: http://www.epa.gov/pesticides/science/post

app

- exposure

- data.html.

Dermal exposures during post

- application activities were estimated using standard default and

su rrogate 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

- A pplication Activities and Dermal Transfer Coefficients. † Proposed Crop Crop Group Transfer Coefficients Activities EPA MRID No.
Field / row crop,

low / medium Cotton 70 cm 2 /hr Hand weeding 42851302, 42689103, 42689104

210 cm 2 /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

- A pplication 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 D ay

- 0 residue value from treated wheat (0.0210 ug/cm 2 ) c alculated by a first

order 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 3 0 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 TC 1

(cm 2 /hr) Days After

Treatment Dislodgeable

Foliar Residue 2
(ug/cm 2 ) Daily Dose

(mg/kg/d) 3 MOE 4

Cotton 0.086 Hand Weeding 70 0 0.0210 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/cm 2 is based on predicted day 0 residue value calculated from

chemical

- specific data (MRID No. 47832415).

3. Dermal Dose (mg/kg/day) = [ DFR (ug/cm 2 ) x TC (cm 2 /hr) x hr/day (8 h rs/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) w as estimated using the Day

- 14 r esidue value from the co tton field t rial s ( see T able 9)

. The Day

- 14 residue value

was adjusted to the proposed maximum seasonal application r ate . Since the proposed PHI for cotton is 14 days, the adjusted Day

- 14 residue v alue from the co tton field t rial s (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 b e 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 3 0 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 M aximum

Seasonal Application Rate (lb ai/A) Activity TC 1
(g cotton/hr) Days

After

Treatment Residue from

Cotton Field

Trial 2

( mg ai/g cotton) Daily Dose

(mg/kg/d) 3 MOE 4

Cotton 0.172 Module Builder 900

14 0.00008 4 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 Re sidue 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)

T he petitioner has proposed an REI of 24 hours for Transform TM 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 Characterizat i on and Toxicological Profile Appendix B: Cotton Field Trial and Processing Tier II Summaries Appendix C: Livestock Feed Study Tier II Summaries Appendix D: Dislodgeable Fol iar 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 th e Cancer Assessment Review Committee . 26 April 2012.

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

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

- day inhalation study. In preparation.