Fluensulfone Human Health Risk Assessment DP No. D424168 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: 6 January 201" 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Fluensulfone: Human Health Risk Assessment of the Proposed Use on Turf. 

PC Code: 0504 10 DP Barcode: D424 I 68 

Decision No.: 496677 Registration No.: 53883-GL T 

Petition No.: NA Regulatory Action: Section 3 

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

TXR No.: NA CAS No.: 318290-98- 1 

MRJD No.: 49552503 40 CFR: 180.680 

FROM: Michael 

Jaime D' 

A. 

Agostino

Doherty, 

, Ph.D.

Ph.D., 

, To

Se

xicolog

nior Chemist 

ist ?-~~? 

Jb.dJ 

t2 ;/ 

~ 

Zaida Figueroa, DrPH, Industrial Hygierus_!,. ./ G~1 /\- - Risk Assessment Branch II (RAB II) :',,-

Health Effects Division (HED~ 7:09Pi\ 

THROUGH: C

RAB 

hristina 

II 

Swartz, Chief ~ ~ 

HED (7509P) 

TO: Rita Kumar/Marianne Lewis/Meredith Laws 

Invertebrate and Vertebrate Branch 3 

Registration Division (7505P) 

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Fluensulfone Human Health Risk Assessment DP No. D424168 

1.0 EXECUTIVE SUMMARY ··············································································································· 3 

2.0 HED RECOMME DATIONS ......................................................................................................... 4 

2.1 Data Deficiencies/Conditions of Registration .................................................................... 4 

2.2 Tolerance Considerations .................................................................................................... 4 

2.3 Label Recommendations ..................................................................................................... 5 

3.0 INTRODUCTIO .......................................................................................................................... 5 

3.1 Chemical Identity ................................................................................................................ 5 

3.2 Physical/Chemical Characteristics ...................................................................................... 5 

3.3 Pesticide Use Pattern ........................................................................................................... 6 

3.4 Anticipated Exposure Pathways ......................................................................................... 6 

3.5 Consideration of Environmental Justice ............................................................................. 7 

4.0 HAZARD CHARACTERIZATIO AND DosE-RESPO SE ASSESSME T ........................................... 7 

4.1 Toxicology Studies Available for Analysis ............. ........................................................... 7 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME) ........................................ 8 

4.2.1 Dermal Absorption .................................................................................................. 9 

4.3 Toxicological Effects ........................................................................................................ 10 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ......................................... 12 

4.4.1 Completeness of the Toxicology Database ........................................................... 12 

4.4.2 Evidence of Neurotoxicity .................................................................................... 12 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ....... 12 

4.4.4 Residual Uncertainty in the Exposure Database ................................................... 13 

4.5 Toxicity Endpoint and Point of Departure Selections ...................................................... 13 

4.5.1 Dose-Response Assessment.. ............................ .................................................... 13 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment.. .... 15 

4.5.3 Cancer Classification and Risk Assessment Recommendation ............................ 15 

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

Assessment. ................................................................................................................. 16 

5.0 DIETARY EXPOSURE AND RISK ASSESSMENT .. ............... .......................................................... 19 

6.0 RESIDE TIAL (No -0CCUPATIO AL) EXPOSURE/RISK CHARACTERIZATIO .......................... 20 

6.1 Residential Bystander Post-Application Inhalation Exposure .......................................... 21 

6.2 Spray Drift ........................................................................................................................ 21 

7.0 AGGREGATE EXPOSURE/RISK CHARACTERIZATIO ................................................................. 22 

8.0 CUMULATIVE EXPOSURE/RISK CHARACTERIZATIO ............................................................... 22 

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION ........................................................... 23 

9.1 Short- and Intermediate-Term Handler Risk .................................................................... 23 

9.2 Short- and Intermediate-Tenn Post-Application Risk ...................................................... 24 

I 0.0 REFERE CES ...................................................................................................................... 25 

APPENDIX A. TOXICOLOGY PROFILE AND EXECUTIVE SUMMARIES ............................................ 27 

A. I Toxicology Data Requirements ........................................................................................ 27 

A.2Toxicity Profiles .................................................................. .............................................. 28 

A.3 Hazard Identification and Endpoint Selection .................................................................. 39 

APPE 1DIX B. PHYS ICAL/CHEMICAL PROPERTIES ........................................................................... 44 

APPENDIX C. REVIEW OF HUMAN RESEARCH ................................................................................ 45 

APPENDIX D. SUMMARY OF SUBMITTED STUDIES ......................................................................... 46 

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Fluensulfone Human Health Risk Assessment DP No. D424168

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1.0 Executive Summary

Makhteshim-Agan of North America (MANA) has petitioned the Agency to register the 

nematicide fluensulfone for use on turfgrass, including golf courses, sports fields, commercial 

areas, sod farms, and residential lawns. This document presents the HED aggregate human health 

risk assessment for fluensulfone.

Fluensulfone {5-Chloro-2-[(3,4,4-trifluoro-3-buten-1-yl)sulfonyl]thiazole} is a nematicide in the 

fluoroalkenyl class, and this action is the first registration request for this ingredient formulated 

as a granular product. This is also the first registration request for fluensulfone in a residential 

setting. Fluensulfone is currently registered for use on members of the cucurbit and the fruiting 

vegetables crop groups (Group 9 and Group 8-10, respectively).

Two use patterns are proposed. The first is for use on golf courses, sports fields, commercial 

areas, sod farms, and residential lawns, for which 1-4 applications may be made at maximum 

single application rates ranging from 0.9 to 1.8 lb a.i./A, with a maximum annual application rate 

of 3.6 lb a.i./A/year. The second use is on sod farms only, as a rescue treatment, with a single 

application of 3.6 lb a.i./A. 

In mammals, exposure to fluensulfone results in effects on the hematopoietic system (decreased 

platelets, increased white blood cells, hematocrit, and reticulocytes), kidneys, and lungs. 

Changes in clinical chemistry as well as in body weight were also observed across multiple 

studies and species. An acute neurotoxicity screening assay showed evidence of potential 

neurotoxicity; however, neurotoxic effects were not observed in any other study, including a 

subchronic neurotoxicity study. Evidence of potential qualitative, but not quantitative, increased 

susceptibility of infants and children to the effects of fluensulfone was observed in the twogeneration reproduction study in rats, wherein pup loss was observed at a dose that resulted in

body weight effects in the dams. No evidence of either qualitative or quantitative susceptibility 

was observed in developmental toxicity studies in rats or rabbits. Dietary and inhalation studies 

in rats showed evidence of portal-of-entry effects in the forestomach, pharynx, epiglottis, and 

nasal cavity. Overall, the most sensitive endpoints for assessing human health risk are the 

increased pup-loss effects for acute dietary exposure; body weight, hematological and clinical

chemistry changes for chronic dietary as well as dermal exposures (short/intermediate term); and 

clotting time, decreased thymus weight, and portal-of-entry effects (histopathology of the 

epiglottis and nasal cavity) for inhalation exposures (short/intermediate term). For assessing 

occupational oral and dermal exposures, the standard inter- and intra-species uncertainty factors 

of 10X are appropriate and result in a level of concern (LOC) of 100. For assessing occupational 

inhalation exposure, the use of a reference concentration for humans (RfC) supports reducing the 

interspecies factor to 3X; however, an additional 10X factor is required because a no-observedadverse-affect level (NOAEL) was not found for the portal-of-entry effects, resulting in an LOC

of 300. Given the different endpoints at the regulatory points of departure for the dermal and 

inhalation routes of exposure, risk estimates from these two routes were not combined. Based on 

the completeness of the toxicity data, the use of the most sensitive endpoints for risk assessment 

and the resulting low degree of concern regarding the observed qualitative susceptibility, and the 

conservatisms in the exposure assessments, HED has reduced the required Food Quality 

Protection Act Safety Factor (FQPA SF) from 10X to 1X. 
Fluensulfone Human Health Risk Assessment DP No. D424168

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In conducting this risk assessment, HED has relied on the dietary exposure estimates detailed in 

the most recent risk assessment for fluensulfone (D418204, 10 June 2014, M. Doherty). Dietary

(food and water) risk estimates for fluensulfone are not of concern for both acute and chronic 

exposure durations.

The use of fluensulfone on turf may result in short-term residential exposures for persons 

handling and applying fluensulfone as well as short-term exposures after application (i.e., postapplication). Routes of exposure are dermal and inhalation for handlers, dermal for postapplication activities for adults, youth and children, and incidental oral for children only.

Residential risk estimates for fluensulfone are not of concern for adult handlers or for adults and 

children engaged in post-application activities on treated turf.

Aggregate risk estimates from combined dermal and oral exposures, including food and drinking 

water sources, are not of concern. Inhalation exposures were not aggregated with dermal and oral 

exposures due to differences in toxic effects from those routes of exposure.

For occupational scenarios, long-term exposures (> 6 months) are not expected to occur; 

however, short-term (1-30 days) and intermediate-term (1-6 months) exposures may occur. With 

the exception of the rescue treatment on sod, all occupational handler and post-application risk 

estimates are not of concern. HED has estimated a risk of concern from inhalation exposure for 

the sod treatments (MOE=140 for rescue application and MOE=280 for standard application; 

LOC=300) when assuming baseline clothing with no gloves and no respirator. Inclusion of a PF5 

respirator for the mixer/loader activities associated with the sod rescue treatment results in risk 

estimates above the LOC (i.e., the risks are not of concern) for handlers mixing, loading, or 

applying fluensulfone to turf.

Aside from the potential occupational risk issue noted above, there are no human health risk 

concerns that would preclude granting the requested registrations for fluensulfone. 

Potential areas of environmental justice concerns were considered in this human health risk 

assessment to the extent possible. For more information, see Section 3.5.

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

intentionally exposed to a pesticide or other chemical. Those studies are subject to ethics review, 

have received that review, and are compliant with applicable ethics requirements.

The last risk assessment for fluensulfone was conducted in 2014 (D403767, 18 June 2014, M. 

Doherty et al.).

2.0 HED Recommendations

2.1 Data Deficiencies/Conditions of Registration

None.

2.2 Tolerance Considerations
Fluensulfone Human Health Risk Assessment DP No. D424168

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There are no tolerance considerations for this action.

2.3 Label Recommendations

At the maximum single application rate, there are handler inhalation risks of concern at baseline 

clothing (i.e., long-sleeved shirt, long pants, shoes plus socks). HED notes a potential risk of 

concern for occupational exposure during mixing/loading and applying the product to sod. Use 

of a PF5 respirator for those uses (see Section 9.1 for specific scenarios) results in risk estimates 

that are not of concern. 

3.0 Introduction

3.1 Chemical Identity

Table 3.1. Fluensulfone Nomenclature.

Compound Chemical Structure

Common name Fluensulfone

Company experimental name MCW-2

IUPAC name 5-chloro-1,3-thiazol-2-yl 3,4,4-trifluorobut-3-en-1-yl sulfone

CAS name 5-chloro-2-[(3,4,4-trifluoro-3-buten-1-yl)sulfonyl]thiazole

CAS # 318290-98-1

End-use product/EP 66222-GLT – Granular formulation (1.5% a.i.)

Chemical Class Fluoroalkenyl

Known Impurities of Concern None

3.2 Physical/Chemical Characteristics

Technical-grade fluensulfone is a solid at room temperature but may be a liquid at warmer,

environmentally relevant temperatures. The compound is moderately volatile; thus, there is some 

likelihood for exposure to fluensulfone in the vapor phase. The technical-grade material has a log 

KOW of 2.2 indicating a somewhat-fat-soluble compound, but not to the degree that 

bioaccumulation is of particular concern. A listing of the physical/chemical properties of 

fluensulfone are provided in Appendix C.

The exposure profile from dietary sources is primarily to the two main metabolites BSA and 

TSA rather than to the parent compound (which was generally <LOQ in crop metabolism and 

field trials). Physicochemical properties were not provided for either BSA or TSA. As sulfonic 

acids, these two metabolites are expected to be much more hydrophilic than the parent 

compound and also less volatile.
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3.3 Pesticide Use Pattern

The proposed end-use (EP) granular product MCW2 1.5% (EPA Registration No. 53883 -GLT

and alternate brand names: Quali-Pro® Nimitz® 1.5 G Nematicide or Quali-Pro® Nimitz PRO 

G Nematicide) may be applied broadcast overtop turfgrass at a maximum single application rate 

of 1.8 lb ai/A (3.6 lb ai/A per year) using typical ground spreaders (including tractors, rotary or 

drop spreaders). In addition, this EP could be applied as a one-time rescue treatment on sod

farms at a maximum single application rate of 3.6 lb ai/A.

Treated areas should be irrigated following applications in order to get the active ingredient into 

the root zone and soil. The label recommends this product be applied by a licensed applicator; 

however, it is not a restricted use product. Rotation with nematicides with a different mode of 

action is suggested.

The proposed label requires handlers to wear long-sleeved shirts, long pants, shoes, socks, and 

chemical-resistant gloves.

Table 3.3. Summary of Directions for Use of Fluensulfone on Golf Courses, Sports Fields, Commercial Areas, Sod 

Farms and Residential Lawns.

Applic. 

Timing, 

Type, and 

Equip.

Formulation 

[EPA Reg. 

No.]

Applic. Rate 

(lb ai/A)

Max. No. 

Applic. per 

Season

Max. 

Seasonal 

Applic. 

Rate

(lb ai/A)

PHI 

(days) Use Directions and Limitations

Broadcast;

Ground 

spreaders 

MCW2 1.5%

[53883 -

GLT]

Granular; 

1.5% ai

0.9-1.8 1-4

(rate

dependent)

3.6 NA

Treated areas should be irrigated 

following applications in order to get 

the active ingredient into the root zone 

and soil. 

May be applied at 0.9 lb ai/A - 1 

month intervals for 4 consecutive 

months limited to 3.6 lb ai/A/year.

May be applied at 1.2 lb ai/A for 1 

month intervals for 3 consecutive 

months limited to 3.6 lb ai/A/year. 

May be applied at 1.8 lb ai/A in spring 

or early summer with a second 

application 2-6 months following the 

initial broadcast application with a 

limit of 3.6 lb ai/A/year. 

3.6 (for sod 

farms only 

as a rescue 

treatment)

1 3.6 NA

Rescue treatment. Broadcast 

application 1-2 months prior to 

harvesting or cutting turfgrass sod.

3.4 Anticipated Exposure Pathways

Fluensulfone is registered for use on cucurbit vegetables (e.g., cucumbers, melons, squash) and 

fruiting vegetables (e.g., tomatoes, peppers, eggplant). The product is meant to be applied to soil 

prior to transplanting crops into the field. Humans may, therefore, be exposed to fluensulfonerelated residues from crops grown in treated soil and from migration of residues to surface and/or 

ground water sources of drinking water. From crops, the exposure will be to metabolites of 
Fluensulfone Human Health Risk Assessment DP No. D424168

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fluensulfone (primarily BSA and TSA). In drinking water, the residues may include BSA and 

TSA as well as parent fluensulfone, dechlorinated fluensulfone, and the MeS metabolite. The 

distribution of residues between these compounds will be dependent on the source of the 

drinking water (surface or ground water) as well as the amount of elapsed time since application 

of the product.

In addition, residential exposures may occur from the proposed use on turfgrass. For persons 

applying fluensulfone, that exposure may be via the dermal and inhalation routes. After 

application, exposures may occur via the dermal route and, for children only, the oral route from 

ingestion of granules or from hand-to-mouth activities.

In an occupational setting, persons may be exposed to fluensulfone while handling the pesticide 

prior to application, during application, and during post-application activities. Handler/applicator 

exposure may be via the dermal and inhalation routes, and post-application exposure would be 

via the dermal route only.

3.5 Consideration of Environmental Justice

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

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

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

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide 

exposures that are based on patterns of that subgroup’s food and water consumption, and 

activities in and around the home that involve pesticide use in a residential setting. Extensive 

data on food consumption patterns are compiled by the USDA under the National Health and 

Nutrition Survey/What We Eat in America (NHANES/WWEIA) and are used in pesticide risk 

assessments for all registered food uses of a pesticide. These data are analyzed and categorized 

by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary 

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

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

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

and adults entering or playing on treated areas post-application are evaluated. Further 

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

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

workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicology database for fluensulfone is complete and acceptable for selecting toxicity 

endpoints and points of departure for risk assessment. Since the last risk assessment (D403767), 

a second in vitro comparative dermal absorption study with rat and human skin for the EC 
Fluensulfone Human Health Risk Assessment DP No. D424168

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formulation was submitted to refine the dermal absorption value. This study was reviewed by 

HED and incorporated into the calculation of the dermal absorption factor in section 4.2.1. 

The available toxicology studies include the following: 

 subchronic oral toxicity studies in rats, mice and dogs

 28-day dermal toxicity study in rats

 90-day inhalation study in rats

 developmental toxicity studies in rats and rabbits 

 2-generation reproduction study in rats 

 chronic toxicity studies in rats and dogs 

 carcinogenicity studies in mice and rats 

 battery of genotoxicity studies 

 dermal penetration study in rats and two in vitro comparative dermal absorption study 

with rat and human skin (all three testing an EC formulation of fluensulfone)

 acute and subchronic neurotoxicity studies in rats

 an immunotoxicity study in mice

 multiple ADME studies in rats

 acute oral, dermal, and inhalation toxicity studies

 primary eye and dermal irritation studies

 a dermal sensitization study

For the BSA and TSA metabolites of fluensulfone, toxicology studies include:

 acute oral studies in rats

 28-day oral studies in rats

 Bacterial and mammalian cell mutagenicity studies

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

In rats, fluensulfone is rapidly absorbed following oral dosing. The time to maximum plasma 

levels (tmax) was 2-4 hours in males and females at the low dose (5 mg/kg) and 1-8 hours at the 

high dose (500 mg/kg/day). The time to maximum whole blood levels (tmax) was longer at 2-8 

hours at the low dose and 48 hours at the high dose. The difference in whole blood and plasma 

tmax is related to fluensulfone reacting with the free thiol moiety of globin in the erythrocyte. The 

majority of the dose was absorbed, as indicated by recovery of about 85% of the applied dose in 

the urine (including cage wash) at both doses tested (5 and 500 mg/kg), suggesting that there was 

no saturation of absorption. Urine was the major route of excretion accounting for 75-88% of the 

administered dose (AD) with feces accounting for 5-13% AD. Most of the AD (~80%) was 

excreted during the first 24 hours at the 5 mg/kg dose level. Fluensulfone-related compounds did 

not accumulate in tissues; the total residual radioactivity in tissues/organs was ~3.1% AD at 51 

hours post-dosing. The highest tissue levels were observed in the liver, kidney, and 

gastrointestinal tract. Identification of compounds in the urine (Table 4.2) showed no parent 

fluensulfone and indicates that fluensulfone cleaves at the sulfonyl bridge. The metabolic 

pathway begins with fluensulfone reacting with glutathione to displace butene sulfinic acid 
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which is then oxidized to BSA. The glutathione adduct of the thiazole ring can then be cleaved to 

the cysteine conjugate, which is acetylated to the mercapturate. The glutathione ring is also 

cleaved to thiazole thiol (not detected in metabolism studies), which can either be oxidized to 

TSA or conjugated with glucuronic acid to give the two glucuronides. No major sex-related 

differences were observed in absorption, distribution, metabolism, or excretion.

Table 4.2. Summary of Compounds in Rat Urine Following Dosing with 14C-Fluensulfone.

Chemical Identity % of Applied Dose

Butene-Radiolabel Thiazole-Radiolabel

5 mg/kg 500 mg/kg 5 mg/kg 500 mg/kg

Fluensulfone ≤ 0.1 ≤ 0.1 ≤ 0.1 ≤ 0.1

Butene sulfinic acid 32-35 53-57 -- --

Butene sulfonic acid (BSA) 4-5 4 -- --

Thiazole mercapturate -- -- 38-40 49-54

Thiazole glucuronide I and II -- -- 24-27 20-22

Thiazole sulfonic acid (TSA) -- -- 3-5 1-3

-- = this metabolite was not detectable because it did not contain the radiolabel.

4.2.1 Dermal Absorption

In the previous risk assessment, a dermal absorption value was calculated using the results from 

an in vivo dermal absorption study with the EC formulation refined by the results from an in 

vitro dermal absorption study with the EC formulation using rat and human skin (MRID 

48574950). Since that risk assessment, the registrant submitted a second in vitro dermal 

absorption study with the EC formulation using rat and human skin (MRID 49700504) because 

they felt that a number of the conditions in the original study led to an overestimation of dermal 

absorption including: the occlusive nature of the application, the use of a 24-hour exposure 

period, and the use of an organic-solvent-based receptor fluid. In contrast, the newly submitted in 

vitro study was not occlusive, exposed the skin for only 8 hours, and used physiological saline as 

a receptor fluid. These parameters are in line with the OECD test guideline 428 for in vitro 

dermal absorption studies and more closely represent worker exposure conditions. Therefore, the 

newly submitted dermal absorption study is considered more relevant for risk assessment and 

was used to refine the in vivo dermal absorption value. The dermal absorption in the newly 

submitted study was considerably lower (43.6%) than that determined in the previous study 

(93.5%).

The data demonstrated an inverse relationship between dosing concentration and percent 

absorption. Based on in vivo dermal absorption observed in the rat and in vitro comparative 

rat:human absorption data from the newly submitted study, an estimated human dermal 

absorption factor (DAF) was obtained as follows (all absorption values adjusted for recovery): 

(1) In the rat in vivo dermal absorption study, a dermal absorption of 58.0% (directly 

absorbed plus absorbable) was found at 24 hrs post-exposure using an application of 

0.0953 mg/cm2; 

(2) In vitro exposure of split-thickness rat skin under the same exposure and assessment 

conditions gave a dermal absorption of 43.6% (directly absorbed plus absorbable); 

(3) The ratio of the rat in vitro to the rat in vivo absorption is 0.75 (43.6/58.0) which is 

close to 1, indicating that the in vitro data is predictive of in vivo absorption; 
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(4) Based on this ratio, a DAF for humans may be calculated using in vitro human dermal 

absorption (7.1%, directly absorbed plus absorbable) observed in vitro under the same 

exposure conditions. The DAF for humans is therefore 7.1%/0.75= 9.5%.

4.3 Toxicological Effects

The hematopoietic system was the major target of fluensulfone activity in rats, dogs, and mice. 

Effects on the hematopoietic system included increased white blood cells (rats and mice), 

increased hematocrit (mice), decreased platelets (mice), and increased reticulocytes (dogs) in 

subchronic dietary studies at the lowest observable effect levels (LOAEL) with additional effects 

on the hematopoietic system observed at higher doses. Effects on the hematopoietic system were 

also observed in chronic dietary studies for all species and, in the case of the chronic rat and dog

studies, these effects were observed at the LOAELs. Effects on the hematopoietic system are 

consistent with results from rat metabolism studies which demonstrate that fluensulfone can react 

with the free thiol moiety of globin, forming a covalent linkage to the thiazole group displacing 

butene sulfinic acid. This led to slower elimination of the thiazole portion of fluensulfone from 

whole blood (time from dose to 50% of peak concentration, DT50 = 6-9 days) compared to 

plasma (DT50 = 16-17 hours).

Other effects commonly observed in mice, rats, and dogs included changes in clinical chemistry 

parameters and decreased body weights, both of which were often seen at the LOAELs in 

subchronic and chronic studies. Altered clinical chemistry parameters included decreased plasma 

alanine amino transferase (ALAT, rats and dogs), increased cholesterol (rats), increased 

triglycerides (rats), increased phospholipids (rats), increased (mice) or decreased (dogs) 

bilirubin, decreased protein (dogs), decreased albumin and albumin/globulin ratio (dogs), 

decreased glucose (dogs), and increased TSH (dogs) in subchronic studies. For the 

hematological, clinical chemistry, and body weight effects observed in all three species, the dog 

appeared to be slightly more sensitive than mice and rats. 

Fluensulfone also caused effects on the kidney in male rats; however, the effects are consistent 

with accumulation of α-2-microglobulin in the kidneys which is a male rat specific process that 

is not relevant for human health risk assessment (USEPA 1991).

Effects on the lung were observed following chronic dietary exposure in mice and rats. These 

effects consisted of an increased incidence and severity of lung interstitial inflammation in the 2-

year rat study and an increased incidence of bronchiolization (change from flattened epithelium 

to cubodial epithelium) in the 18-month mouse study. 

Fluensulfone also appeared to cause portal-of-entry effects in rats. This included the forestomach 

(diffuse basal cell hyperplasia) and pharynx (mononuclear infiltrates) in dietary subchronic 

studies; the epiglottis (squamous metaplasia, epithelial hyperplasia, and focal mononuclear cell 

infiltrates) and nasal cavity (squamous epithelial hyperplasia) in the 90-day inhalation study; and 

an increased incidence/severity of acanthosis/hyperkeratosis in the 28-day dermal study. The 

dermal effects were considered adaptive due to the moderate degree of acanthosis/hyperkeratosis 

observed.
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Following a single oral administration, rats exhibited decreased locomotor activity, decreased 

spontaneous activity, decreased rearing, and impaired righting response only on Day 1 in the 

acute neurotoxicity study. No evidence of neurotoxicity was observed in any other study, 

including a subchronic neurotoxicity study. Following dermal exposure for 28-days, systemic 

effects including increased reticulocytes, and increased cholesterol were observed, but only at a 

very high dose (2000 mg/kg/day, which is twice the highest dose required by the guidelines for a 

dermal study). There was no evidence of immunotoxicity in the mouse. 

No evidence of increased quantitative or qualitative susceptibility was seen in developmental 

toxicity studies in rats and rabbits. In the rat developmental toxicity study, decreased fetal weight 

was observed in the presence of decreased body weight in maternal animals. In the rabbit 

developmental toxicity study, decreased fetal weight and incomplete ossification of digit 5 of the 

medial phalanx in both forelimbs were observed in the presence of decreased body weight in 

maternal animals. In the two generation reproduction study, there was no evidence of 

quantitative susceptibility; evidence for qualitative susceptibility was manifested as decreased 

pup weight, decreased spleen weight, and an increase in post-natal pup loss [post-natal days 

(PND) 1-4] which were seen at the same dose that caused decreases in body weight in the 

parental animals.

Chronic dietary exposure to fluensulfone in female mice resulted in an increased incidence of 

lung adenomas and carcinomas. No treatment-related tumors were observed in a long-term study 

in rats. The Cancer Assessment Review Committee (CARC) classified fluensulfone as having 

“Suggestive Evidence of Carcinogenicity” based on an increased incidence of 

alveolar/bronchiolar adenomas and carcinomas in the lung of mid- and high-dose female mice in 

the carcinogenicity study. All genotoxicity studies that were conducted on fluensulfone and three 

of its metabolites (thiazole sulfonic acid; TSA, butene sulfonic acid; BSA, and methyl sulfone; 

MeS) were negative, except for MeS with Salmonella typhimurium strain TA 100 in the absence 

of metabolic activation during a bacterial reverse mutation assay. There is little concern for the 

positive results as it was abolished by the presence of S9 and was not observed in the other tester 

strains specific for base-pair changes. Based on the results of the genetic toxicology studies, it 

was concluded that there is no mutagenic concern for fluensulfone or the fluensulfone 

metabolites tested.

Testing in acute lethality studies with fluensulfone technical-grade material resulted in low 

toxicity classifications via the oral (Toxicity Category III), dermal (Toxicity Category III), and 

inhalation (Toxicity Category IV) routes of exposure. Fluensulfone technical-grade material was 

not an irritant to eyes (Toxicity Category IV) or skin (Toxicity Category IV) but was a skin 

sensitizer. Similar results were obtained in acute lethality studies with a granular formulation 

(Appendix A.2); however, the granular formulation was determined not to be a skin sensitizer.

Oral acute lethality studies were also conducted with the metabolites MeS, BSA, or TSA, each at 

2000 mg/kg bw. By the oral route of exposure, MeS was of moderate toxicity (Toxicity Category 

II) and both BSA and TSA were of low toxicity (Toxicity Category III). HED notes that all 

animals treated with BSA or TSA survived the entire study period and that the toxicity category 

for those metabolites is based on the dosing level rather than on actual LD50 estimates. 

Furthermore in the BSA and TSA acute toxicity studies, body weights of all animals were within 
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the normal range, no macroscopic findings were recorded at necropsy, and no clinical signs were 

observed except for three animals which exhibited slightly ruffled fur two hours after 

administration of TSA, which persisted up to the three-hour observation in two animals. In 28-

day rat oral toxicity studies with BSA and TSA, no treatment-related effects were observed at 

any dose (limit-dose = 1000 mg/kg/day). Based on the available data addressing toxicity of the 

BSA and TSA metabolites, the Agency has determined that they are not of toxicological concern.

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

The toxicology and the exposure databases for fluensulfone support a reduction of the required 

10X FQPA safety factor to 1X based on the following considerations: the completeness of the 

toxicity database including adequate studies to assess the potential susceptibility in the young; 

there is no indication of quantitative susceptibility in the developmental and reproductive toxicity 

studies, and there are no residual uncertainties concerning pre- or post-natal toxicity; the 

endpoints and doses chosen for risk assessment are protective of the qualitative susceptibility 

observed in the 2-generation reproduction study; acute and subchronic neurotoxicity studies 

(ACN and SCN) are available. In addition, all endpoints used in the risk assessment are 

protective of the potential neurotoxicity observed in the ACN, and a developmental neurotoxicity 

study is not required. The dietary assessment is based on reliable data and modeled drinking 

water residues, and will not underestimate exposure.

4.4.1 Completeness of the Toxicology Database

The toxicology database is considered complete and is adequate for the purpose of assessing preand postnatal susceptibility. Acceptable/guideline developmental toxicity studies in rats and 

rabbits and a reproduction study in rats, as well as acute and subchronic neurotoxicity studies in 

rats are available for FQPA assessment. A developmental neurotoxicity study is not required. 

4.4.2 Evidence of Neurotoxicity

Decreased locomotor activity in females, and decreased spontaneous activity, decreased rearing, 

and impaired righting response in both sexes were observed in the acute neurotoxicity study at 

the lowest dose tested. However, no other evidence for neurotoxicity was observed in the other 

studies in the toxicity database, including a subchronic neurotoxicity study. The doses and 

endpoints chosen for risk assessment are all protective of the effects seen in the acute 

neurotoxicity study. For example, the endpoint used for acute dietary exposure (NOAEL = 16 

mg/kg/day) from the 2-generation reproduction study is 6-times lower than the dose at which 

effects were observed in the acute neurotoxicity study (100 mg/kg). A developmental 

neurotoxicity study is not required.

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

No evidence of quantitative or qualitative susceptibility was seen in developmental toxicity 

studies in rats and rabbits. Offspring effects in those studies occurred in the presence of maternal 

toxicity and were not considered more severe than the parental effects. However, there was 

evidence of increased qualitative, but not quantitative, susceptibility of pups in the 2-generation 
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reproduction study in rats. Maternal effects observed in that study were decreased body weight 

and body weight gain; at the same dose, effects in offspring were decreased pup weights, 

decreased spleen weight, and increased pup loss (PND 1-4).

Although there is evidence of increased qualitative susceptibility in the 2-generation 

reproduction study in rats, there are no residual uncertainties with regard to pre- and/or post-natal 

toxicity following in utero exposure to rats or rabbits and pre- and/or post-natal exposures to rats. 

Considering the overall toxicity profile, the clear NOAEL for the pup effects observed in the 2-

generation reproduction study, and that the doses and endpoints selected for risk assessment are 

equal to or less than the NOAEL from that study, the degree of concern for the susceptibility is 

low. 

4.4.4 Residual Uncertainty in the Exposure Database

There is no residual uncertainty in the exposure database. The current dietary assessment is 

based on high-end assumptions such as tolerance-equivalent residue levels of the parent 

compound in foods, 100% crop treated, and modeled estimates of residues in drinking water. All 

of the exposure estimates are based on conservative assumptions and are not likely to 

underestimate risk.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

The toxicity endpoints and points of departure are presented in Table 4.5.4.1 and Table 4.5.4.2, 

and the details for selecting toxicity endpoints and points of departure for various exposure 

scenarios are presented in Appendix A.

For fluensulfone, HED has selected endpoints from the available data to establish points of 

departure (PODs) for the risk assessment that are protective of the observed adverse effects 

across the entire database. 

For acute dietary exposure, two studies with effects after one or two doses are available at 

similar LOAELs: pup mortality in the 2-generation reproduction toxicity study in rats (122 

mg/kg/day) and decreased motor activity in the ACN in rats (100 mg/kg/day). The POD for acute 

dietary exposure was chosen from the 2-generation reproductive toxicity study in rats. In this 

study, an increase in pup loss between PND 1 and 4 in the F1 and F2 offspring was observed at 

122.0/169.1 mg/kg/day (M/F) with a NOAEL of 16.2/23.0 mg/kg/day (M/F). The majority of the 

pup deaths occurred on post-natal day 2, although there were also a number that occurred on 

post-natal day 1. Therefore, the deaths may be attributable to a single dose. Effects observed in 

the ACN in rats also support the POD for acute dietary risk assessment. In this study, decreased 

motor activity in females and decreased spontaneous activity, decreased rearing, and impaired 

righting response in both sexes were observed at the lowest dose tested (100 mg/kg) on the day 

of dosing only. The decrease in motor activity had a steep dose-response curve, with a decrease 

of 26% at 100 mg/kg/day, 42% at 400 mg/kg/day, and 58% at 1200 mg/kg/day. The POD was 
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chosen from the 2-generation reproduction study because it had a clear NOAEL for the pup 

death and is protective of the effects observed at 100 mg/kg/day in the ACN.

The chronic dog study was chosen for the chronic dietary endpoint over the chronic dietary 

studies from others species because the dog was the most sensitive species for effects of 

fluensulfone having the lowest NOAELs and LOAELs amongst the chronic dietary studies. The 

POD for chronic dietary exposure was based on a NOAEL of 3.1 mg/kg/day with decreased 

body weight, increased mean hemoglobin concentration distribution width, increased relative and 

absolute reticulocyte counts in both sexes, decreased prothrombin time in males and increased 

platelets in females at the LOAEL of 16 mg/kg/day. The 90-day dog study was considered cocritical due to the similar toxic effects occurring at the same LOAEL (17 mg/kg/day) with no 

progression of toxicity over time. In the 90-day dog study, increased relative and absolute 

reticulocyte counts, decreased bilirubin, albumin, and A/G ratio, and pigmented Kupffer cells in 

both sexes, decreased body weight in females, and decreased protein in males were observed at 

the LOAEL. While the 90-day dog study had a slightly lower NOAEL than the 1-year dog study 

(1.6 mg/kg/day), this is due to dose spacing in the two studies. 

For incidental oral exposure to children, HED also chose the co-critical dog studies. The two dog 

studies are appropriate for short-term exposure because the effects (hematology and clinical 

chemistry parameters) were seen starting at Week 6 in both studies and there was lack of 

progression in the toxicity database with longer exposure (subchronic and chronic studies of all 

species had similar NOAELs and LOAELs). Furthermore, the effects observed were on the 

target organ and the dog was identified as the most sensitive species. The effects in the dog 

studies are also protective of all other effects observed in the database, including offspring 

effects observed in the 2-generation reproduction study.

For short- and intermediate-term residential/occupational exposure scenarios involving dermal 

exposure, HED did not chose the 28-day dermal toxicity study in rats conducted with the 

technical material. Although that study is of the appropriate route and duration, the results using 

the technical material do not appear to reflect the high dermal absorption of the emulsifiable 

concentrate (480 EC) observed in the in vivo and in vitro dermal penetrations studies. The dermal 

toxicity study shows minimal toxicity following exposure of 2000 mg/kg/day to technical-grade 

fluensulfone, and has a NOAEL of 400 mg/kg/day. At that NOAEL, the oral-equivalent dose 

assuming 60% absorption (approximate rat in vivo value at 10 hours) is 240 mg/kg/day, which is 

approximately 6-fold higher than the LOAELs from oral subchronic toxicity studies with rats. 

Given the lack of toxic response in the dermal toxicity study, HED has concluded that it is not 

representative of potential systemic exposure to fluensulfone from the 480 EC formulation, to 

which exposure would actually occur. Therefore, HED chose the co-critical oral dog studies 

discussed above, with a 9.5% dermal absorption factor (see Section 4.2.1), to derive the point-ofdeparture. The two dog studies are appropriate for short- and intermediate-term exposure 

because the effects (hematology and clinical chemistry parameters) were seen starting at Week 6 

in both studies and there was lack of progression in the toxicity database with longer exposure 

(subchronic and chronic studies of all species had similar NOAELs and LOAELs). 

For short- and intermediate-term residential/occupational exposure scenarios involving 

inhalation exposure, the POD was chosen from the 90-day inhalation toxicity study in rats. In 
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this study, decreased body weight, decreased thymus weight, and histopathological changes in 

the nasal cavity of males; prolonged prothrombin time in females; and histopathological changes 

in the epiglottis in both sexes were observed at the lowest dose tested (0.04 mg/L). Since a 

NOAEL could not be identified in this study, an additional 10X uncertainty factor for the use of 

a LOAEL to extrapolate to a NOAEL was applied to short- and intermediate-term inhalation 

residential/occupational exposure scenarios. 

The methods and dosimetry equations described in EPA’s reference concentration (RfC) 

guidance and OPP’s guidance on the application of the RfC methodology are suited for 

calculating human-equivalent concentrations (HECs) based on the inhalation toxicity NOAEL 

for use in margin of exposure (MOE) calculations. The regional-deposited-dose ratio (RDDR), 

which accounts for the particulate diameter (mass median aerodynamic diameter [MMAD] and 

geometric standard deviation [g] of aerosols), can be used to estimate the different dose 

fractions deposited along the respiratory tract. The RDDR is also based on interspecies 

differences in ventilation and respiratory-tract surface areas. Thus, the RDDR can be used to 

adjust an observed inhalation particulate exposure of an animal to the predicted inhalation 

exposure for a human. For the 90-day inhalation study with fluensulfone, an RDDR for the 

extrathoracic region (based on effects observed in the nasal cavity) was estimated at 0.143 based 

on the reported MMAD of 1.02 μm, standard deviation (g) of 1.59, and the respiratory-tract 

surface area of the rat relative to the human. The extrathoracic region was chosen for the RDDR 

calculation as it provides an HED which is protective of both the portal of entry and systemic 

effects. See section A.3.6 in Appendix 3 for the calculation of the HECs. The level of concern 

(LOC) for all exposure scenarios was 300, which includes interspecies (3X), intraspecies (10X), 

and LOAEL-to-NOAEL (10X) extrapolations. The interspecies factor was reduced from 10X to 

3X due to the HEC calculation accounting for pharmacokinetic (not pharmacodynamic) 

interspecies differences.

Long-term dermal and inhalation exposures are not expected; therefore, endpoints and doses 

were not selected. 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

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

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

determine whether the individual exposures from these routes can be combined based on the 

same toxicological effects. For fluensulfone, incidental oral and dermal exposures can be 

combined since the risk assessments are based on studies with the same toxicological effects. 

Inhalation exposure cannot be combined with either incidental oral or dermal exposures since the 

toxicological effects observed were different.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Report of the Cancer Assessment Review Committee, TXR No. 0056419, J. Rowland; K. Middleton, 7 May 2014

The Cancer Assessment Review Committee (CARC) classified fluensulfone as “Suggestive 

Evidence of Carcinogenicity” based on an increased incidence of alveolar/bronchiolar adenomas 

and carcinomas in the lung of mid- and high-dose female mice in the oncogenicity study. Tumors 
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were not observed in the rat chronic toxicity/carcinogenicity study in either sex or in male mice. 

There was no evidence of genotoxicity. Although the mouse study showed that fluensulfone was 

associated with alveolar/bronchiolar adenomas and carcinomas in the female, the EPA has 

determined that quantification of cancer risk using a non-linear approach (i.e., RfD) for 

fluensulfone will adequately account for all chronic toxicity, including carcinogenicity, that 

could result from exposure to fluensulfone. That conclusion is based on the following 

considerations: (1) the tumors occurred in only one sex in one species; (2) fluensulfone and its 

metabolites are not mutagenic; (3) no carcinogenic response was seen in either sex in the rat; and 

(4) the tumors in the mouse study were observed at a dose (39 mg/kg/day) that is ≥12.6-times 

higher than the doses chosen for risk assessment (≤3.1 mg/kg/day).

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

Assessment

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for use in Fluensulfone Dietary and NonOccupational Human Health Risk Assessments.

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/ 

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(All 

Populations, 

including 

Infants and 

Children and 

Females 13-49 

years of age)

Offspring 

NOAEL= 16.2 

mg/kg/day 

UFA= 10x

UFH=10x

FQPA SF= 1x

Acute RfD = 

0.16 mg/kg/day

aPAD = 0.16 

mg/kg/day

2-generation reproduction – rat

Offspring LOAEL = 122.0 mg/kg/day 

based on an increase in pup loss between 

PND 1 and 4 in the F1 and F2 offspring 

with the majority of deaths occurring on 

day 2.

Chronic 

Dietary (All 

Populations)

NOAEL = 3.1 

mg/kg/day 

(chronic dog)

UFA= 10x

UFH=10x

FQPA SF= 1x

Chronic RfD = 

0.03

mg/kg/day

cPAD = 0.03 

mg/kg/day

Co-critical 90-day dog and chronic dog

Chronic: LOAEL = 16 mg/kg/day based 

on decreased body weight, increased 

mean hemoglobin concentration 

distribution width, and increased 

relative and absolute reticulocyte 

counts in both sexes, decreased 

prothrombin time in males and 

increased platelets in females.

Subchronic: NOAEL = 1.6 mg/kg/day 

LOAEL = 17.1 mg/kg/day based on 

decreased body weight in females and 

increased relative and absolute 

reticulocyte counts, decreased 

bilirubin, decreased albumin, decreased 

A/G ratio, increased TSH, and 

pigmented Kupffer cells in both sexes.
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Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for use in Fluensulfone Dietary and NonOccupational Human Health Risk Assessments.

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/ 

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Incidental Oral 

(Short-term)

NOAEL = 3.1 

mg/kg/day 

(chronic dog)

UFA= 10x

UFH=10x

FQPA SF= 1x

Residential 

LOC for MOE = 

100

Co-critical 90-day dog and chronic dog

Chronic: LOAEL = 16 mg/kg/day based 

on decreased body weight, increased 

mean hemoglobin concentration 

distribution width, and increased 

relative and absolute reticulocyte 

counts in both sexes, decreased 

prothrombin time in males and 

increased platelets in females.

Subchronic: NOAEL = 1.6 mg/kg/day 

LOAEL = 17.1 mg/kg/day based on 

decreased body weight in females and 

increased relative and absolute 

reticulocyte counts, decreased 

bilirubin, decreased albumin, decreased 

A/G ratio, increased TSH, and 

pigmented Kupffer cells in both sexes.

Dermal Shortand 

IntermediateTerm (1-30 

days and 1-6 

months)

NOAEL= 3.1 

mg/kg/day 

(chronic dog)

DAF = 9.5%

UFA=10x

UFH=10x

Residential 

LOC for MOE = 

100

Co-critical 90-day dog and chronic dog

Chronic: LOAEL = 16 mg/kg/day based 

on decreased body weight, increased 

mean hemoglobin concentration 

distribution width, and increased 

relative and absolute reticulocyte 

counts in both sexes, decreased 

prothrombin time in males and 

increased platelets in females.

Subchronic: NOAEL = 1.6 mg/kg/day 

LOAEL = 17.1 mg/kg/day based on 

decreased body weight in females and 

increased relative and absolute 

reticulocyte counts, decreased bilirubin, 

decreased albumin, decreased A/G 

ratio, increased TSH, and pigmented 

Kupffer cells in both sexes.

Inhalation 

Short- and 

IntermediateTerm (1-30 

days and 1-6 

months)

NOAEL= not 

established 

(<0.04 mg/L)

See section 

A.3.6 in 

Appendix 3 

for HEC and 

HED 

calculations

UFA=3x

UFH=10x

UFL=10x

Residential 

LOC for MOE = 

300

90-day inhalation toxicity – rat

LOAEL = 0.04 mg/L (lowest dose tested) 

based on weight loss in males, prolonged 

prothrombin time in females, decreased 

thymus weight in males, histopathological 

changes in the epiglottis in both sexes, and 

histopathological changes in the nasal 

cavity of males. 
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Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for use in Fluensulfone Dietary and NonOccupational Human Health Risk Assessments.

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/ 

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Cancer Classification: Suggestive evidence of carcinogenicity in humans based on lung tumors in 

female rats. The RfD is protective of potential cancer effects. 

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

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity 

among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. FQPA SF 

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

margin of exposure. LOC = level of concern. 

Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for use in Fluensulfone Occupational Human 

Health Risk Assessments.

Exposure/ 

Scenario

Point of Departure Uncertainty 

Factors

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Dermal Shortand 

IntermediateTerm (1-30 

days and 1-6 

months)

NOAEL= 3.1 mg/kg/day 

(chronic dog)

DAF = 9.5%

UFA=10x

UFH=10x

Occupational 

LOC for MOE 

= 100

Co-critical 90-day dog and chronic 

dog

Chronic: LOAEL = 16 mg/kg/day 

based on decreased body 

weight, increased mean 

hemoglobin concentration 

distribution width, and 

increased relative and absolute 

reticulocyte counts in both 

sexes, decreased prothrombin 

time in males and increased 

platelets in females.

Subchronic: NOAEL = 1.6 

mg/kg/day LOAEL = 17.1 

mg/kg/day based on decreased 

body weight in females and 

increased relative and absolute 

reticulocyte counts, decreased 

bilirubin, decreased albumin, 

decreased A/G ratio, increased 

TSH, and pigmented Kupffer 

cells in both sexes.
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Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for use in Fluensulfone Occupational Human 

Health Risk Assessments.

Exposure/ 

Scenario

Point of Departure Uncertainty 

Factors

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Inhalation 

Short- and 

IntermediateTerm (1-30 

days and 1-6 

months)

NOAEL= not established 

(<0.04 mg/L)

See section A.3.6 in 

Appendix 3 for HEC and 

HED calculations

UFA=3x

UFH=10x

UFL=10x

Occupational 

LOC for MOE 

= 300

90-day inhalation toxicity – rat

LOAEL = 0.04 mg/L (lowest dose 

tested) based on weight loss in 

males, prolonged prothrombin time 

in females, decreased thymus 

weight in males, histopathological 

changes in the epiglottis in both 

sexes, and histopathological 

changes in the nasal cavity of 

males. 

Cancer Classification: Suggestive evidence of carcinogenicity in humans based on lung tumors in 

female mice. The RfD is protective of potential cancer effects.

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

mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL 

= no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation 

from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population 

(intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. MOE = margin of exposure. LOC = level of concern. DAF = 

dermal absorption factor

5.0 Dietary Exposure and Risk Assessment 

D418204, 10 June 2014, M. Doherty

The dietary exposure and risk estimates are based on limit-of-quantitation residues of 

fluensulfone in/on cucurbit vegetables (Crop Group 9) and fruiting vegetables (Crop Group 8-

10), as described in the previous aggregate risk assessment (D403767, 18 June 2014, Doherty, 

M. et al.) and associated dietary exposure assessment (D418204, 10 June 2014, M. Doherty). The 

Enviromental Fate and Effects Division has evaluated the proposed use on turf and has 

determined that the use on the vegetable field crops result in higher estimated drinking water 

concentrations than those from the use on turf. Therefore, the previous dietary exposure and risk 

estimates are appropriate for evaluating the use on turf. The dietary (food+water) exposure and 

risk estimates are summarized in Table 5.

Table 5.0.1. Summary of Dietary Exposure and Risk Estimates for Fluensulfone (D418204, 10 June 2014).

Population Subgroup

Acute (95th Percentile) Chronic Cancer

Exposure, 

mg/kg/day

Risk, % 

aPAD

Exposure, 

mg/kg/day

Risk, % 

cPAD

Total US Population 0.004252 2.4 0.001111 3.7 See Chronic

All Infants 0.013276 7.4 0.002845 9.5

Children 1-2 0.006543 3.6 0.001611 5.4

Children 3-5 0.005340 3.0 0.001360 4.5

Children 6-12 0.004084 2.3 0.000979 3.3

Youth 13-19 0.003548 2.0 0.000811 2.7

Adults 20-49 0.004176 2.3 0.001107 3.7

Adults 50-99 0.003754 2.1 0.001095 3.6

Female 13-49 0.004245 2.4 0.001103 3.7

Bold entries are maximum exposure and risk estimates.
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6.0 Residential (Non-Occupational) Exposure/Risk Characterization

D430164, 4 December 2015, Z. Figueroa

For persons applying fluensulfone to turf, exposure may occur via the dermal and inhalation 

routes. Such exposures are expected to be of short-term duration. Although dermal and 

inhalation exposures both resulted in similar clinical signs (e.g., decrease body weight), the 

inhalation endpoint selected for risk assessment was based on portal of entry effects since these 

effects resulted in lower Human Equivalent Concentrations (HECs) than the HEC for systemic 

effects. Therefore, the portal of entry HEC is protective of the systemic effects. The dermal and 

inhalation exposure estimates were not combined since the toxicological effects are different for 

these routes of exposure. All residential post-application assessments assume exposures occur on 

the same day as treatment.

The child dermal and oral routes of exposure have been combined as it is likely that they can 

occur simultaneously based on the use pattern and because the toxicological effects across these 

routes of exposure are the same.

The residential handler exposure and risk estimates for fluensulfone are summarized in Table 

6.0.1 and the post-application exposure and risk estimates in Table 6.0.2. All MOEs indicate that 

residential risk estimates are not of concern. A MOE of 40 (LOC=100) was obtained for episodic 

granular ingestion for children. However, the episodic oral ingestion of pellets is listed only as a 

poisoning scenario and its likelihood is diminished because the label instructs users to irrigate 

(“water-in”) treated areas following applications in order to get the product into the root zone 

and soil.

Table 6.0.1. Residential Handler Non-cancer Exposure and Risk Estimates for Fluensulfone.

Exposure Scenario 

Dermal 

Unit 

Exposure 

(mg/lb ai)

Inhalation 

Unit 

Exposure 

(mg/lb ai)

Maximum 

Application 

Rate1

Area 

Treated or 

Amount 

Handled 

Daily2

Dermal Inhalation

Dose 

(mg/kg/day)3 MOE4 Dose (mg/kg/day)5 MOE6

Mixer/Loader/Applicator

Granules – Push-type 

rotary spreader

0.81 0.0026 1.8 lb ai/A 0.5 A 0.00087 3,600 0.000029 5,600

Granules – Belly 

grinder

360 0.039 0.00004132 

lb ai/ft2 1,200 ft2 0.021 150 0.000024 6,800

Granules – Shaker can 

(surrogate granules 

with cup)

0.11 0.13 0.00004132 

lb ai/ft2 100 ft2 0.00000054 5,700,000 0.000001 240,000

1 Based on proposed label (EPA Reg. No. 53883-GLT). AR=1.8 lb ai/A (1 A/43,560 ft2)=0.00004132 lb ai/ft2.

2 Based on HED’s 2012 Residential SOPs (http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/standardoperating-procedures-residential-pesticide).

3 Dermal Dose = Dermal Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or ft2) × Dermal Absorption Factor (9.5%) x 

Area Treated (A or ft2/day) ÷ Body Weight (80 kg).

4 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day). LOC=100.

5 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or ft2) × Area Treated (A/day or ft2/day) ÷

BW (80 kg).

6 Inhalation MOE = Inhalation HED (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). LOC=300.
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Table 6.0.2. Residential Post-application Non-cancer Exposure and Risk Estimates for Fluensulfone.

Lifestage

Post-application Exposure 

Scenario Application 

Rate1

Dose 

(mg/kg/day)2 MOEs3

Combined Routes

(X indicates 

included in 

Combined MOE)

Combined 

MOEs

Use Site Route of 

Exposure

Adult

Turf (High 

Contact 

Activities)

Dermal 1.8 lb ai/A 0.00039 7,900 N/A

Turf (Mowing 

Turf) Dermal 1.8 lb ai/A 0.0000072 430,000 N/A

Turf (Golfing) Dermal 1.8 lb ai/A 0.0000270 110,000 N/A

Youth 11 < 16 

old years old

Turf (Mowing 

Turf) Dermal 1.8 lb ai/A 0.0000082 380,000 N/A

Turf (Golfing) Dermal 1.8 lb ai/A 0.0000320 96,000 N/A

Children 6 < 

11 years old Turf (Golfing) Dermal 1.8 lb ai/A 0.0000378 82,000 N/A

Child 1 < 2 

years old

Turf (High 

Contact 

Activities)

Dermal 1.8 lb ai/A 0.0007695 4,000

X 3,700 Hand-to-Mouth 1.8 lb ai/A 0.0000747 41,000

Object-to-Mouth 1.8 lb ai/A 0.0000046 680,000 N/A

Soil Ingestion 1.8 lb ai/A 0.0000610 51,000 N/A

Episodic 

Granular 

Ingestion

1.8 lb ai/A 0.41 40 N/A

1. Based on proposed label (EPA Reg. No. 53883-GLT).

2. Dose (mg/kg/day) algorithms provided in 2012 Residential SOPs (http://www2.epa.gov/pesticide-science-and-assessing-pesticiderisks/standard-operating-procedures-residential-pesticide).

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

4. Combined MOE = 1 ÷ (1/dermal MOE) + (1/inhalation MOE) + (1/incidental oral MOE), where applicable.

6.1 Residential Bystander Post-Application Inhalation Exposure

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

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

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

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

March 2, 2010 (http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2009-0687-

0037). The agency has evaluated the SAP report and has developed a Volatilization Screening 

Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!

docketDetail;D=EPA-HQ-OPP-2014-0219). During Registration Review, the agency will utilize 

this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological studies) 

or further analysis is required for fluensulfone.

6.2 Spray Drift

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

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

potential source of exposure from the ground application methods employed for fluensulfone. 

The agency has been working with the Spray Drift Task Force (a task force composed of various 

registrants which was developed as a result of a Data Call-In issued by EPA), EPA Regional 

Offices and State Lead Agencies for pesticide regulation and other parties to develop the best 

spray drift management practices (see the agency’s Spray Drift website for more information). 1 

 

1 Available: http://www2.epa.gov/reducing-pesticide-drift 
Fluensulfone Human Health Risk Assessment DP No. D424168

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The agency has also developed a policy on how to appropriately consider spray drift as a 

potential source of exposure in risk assessments for pesticides. The potential for spray drift will 

be quantitatively evaluated for each pesticide during the Registration Review process which 

ensures that all uses for that pesticide will be considered concurrently. The approach is outlined 

in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs) -

Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of 

Spray Drift. This document outlines the quantification of indirect non-occupational exposure to 

drift. 

7.0 Aggregate Exposure/Risk Characterization

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.

As previously noted, the residential exposures are expected to be of short-term duration.

Therefore, acute and chronic aggregate risk estimates are equivalent to the dietary risk estimates 

(Section 5.0) and are not of concern. 

In estimating short-term aggregate risk, HED combines the residential risk estimates discussed 

above based on toxicological effects and the likelihood of co-occurrence to derive sentinel 

exposure and risk estimates from residential sources. Those estimates (Table 7.0.1) are combined 

with the highest chronic dietary exposure estimates (Table 5.0.1) matching the sentinel 

population, as an estimate of background dietary exposure, to obtain aggregate risk estimates

(Table 7.0.2). In considering aggregate inhalation risk, HED has not included the dietary 

component due to the different toxicities occurring via the oral (dietary) and inhalation routes. 

The aggregate risk estimates are not of concern.

Table 7.0.1. Recommendations for the Residential Exposures for the Fluensulfone Aggregate Assessment.

Lifestage Exposure 

Scenario

Dose (mg/kg/day)1 MOE2

Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Adult Turf 0.021 0.000029 N/A NA 150 5,600 N/A NA

Child 1 < 2 

years old

Turf (High 

Contact 

Activities)

0.0007695 N/A 0.0000747 0.0008442 4,000 N/A 41,000 3,700

1. Dose = the highest dose for each applicable lifestage of all residential scenarios assessed. Total = dermal + inhalation + incidental oral (where 

applicable).

2. MOE = the MOEs associated with the highest residential doses; consolidated from Tables 6.0.1 and 6.0.2. 

Table 7.0.2. Short-Term Aggregate Risk Estimates for Fluensulfone.

Lifestage Exposure Scenario Residential1 Dietary MOE2 Aggregate MOE3

Adult Turf 150 (Dermal) 2,700 140

Child 1 < 2 years old Turf (High Contact Activities) 3,700 (Total) 1,900 1,200

1 From Table 7.0.1.

2 Dietary MOE = Short-term NOAEL ÷ Maximum Chronic Dietary Exposure Estimate for the Population (Table 5.0.1)

3 Aggregate MOE = 1 ÷ (1/Residential MOE + 1/Dietary MOE)

8.0 Cumulative Exposure/Risk Characterization
Fluensulfone Human Health Risk Assessment DP No. D424168

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

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

to fluensulfone and any other substances and fluensulfone does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that fluensulfone has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

D430164, 4 December 2015, Figueroa, Z.

Based on the proposed application rate and label information, only short- and intermediate-term 

dermal and inhalation exposures are expected for occupational handlers and post-application 

workers. Fluensulfone is classified as Toxicity Category III via the dermal route and Toxicity 

Category IV for skin and eye irritation potential. The granular formulation is not a skin 

sensitizer. 

9.1 Short -Term Handler Risk

No chemical-specific handler exposure data were submitted in support of this draft risk 

assessment; therefore, HED relied on the best available data to assess handler exposure. Default 

assumptions established by HED’s Science Advisory Council for Exposure (ExpoSAC) were 

used for parameters such as body weight and amount handled. 

With three exceptions, all occupational handler scenarios for the proposed uses resulted in MOEs 

that are not of concern at baseline personal protective equipment (PPE; baseline attire with no 

gloves and no respirator). For mixer/loader scenarios for sod (typical application and rescue 

treatment) and for the applicator rescue treatment for sod, risk estimates that are not of concern 

can be achieved through the use of a PF 5 respirator (Table 9.1.1).

Table 9.1.1. Occupational Handler Non-Cancer Exposure and Risk Estimates for Fluensulfone.

Exposure 

Scenario Crop or Target

Dermal Unit 

Exposure 

(μg/lb ai)1

Inhalation Unit 

Exposure

(μg/lb ai)1

Maximum

Applic.

Rate2

Area 

Treated 

Daily3

Dermal Inhalation

Mitigation 

Level

Mitigation 

Level

Dose 

(m/k/d)

4

MOE5

(LOC=100)

Dose 

(m/k/d)

6

MOE7

(LOC=300)

Mixer/Loader

Tractordrawn 

spreader

Golf course 8.4 [Baseline] 1.7 [Baseline]

1.8 lb ai/A 40 A 0.000718 4,300 0.00153 560

Tractordrawn 

spreader

Sod

(Typical 

Application)

8.4 [Baseline] 1.7 [Baseline]

1.8 lb ai/A 80 A

0.00144 2,200 0.00306 280

8.4 [Baseline] 0.34 [PF5 

respirator] 0.00144 2,200 0.000613 1,400

Sod 8.4 [Baseline] 1.7 [Baseline] 3.6 lb ai/A 80 A 0.00287 1,100 0.00613 140
Fluensulfone Human Health Risk Assessment DP No. D424168

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Table 9.1.1. Occupational Handler Non-Cancer Exposure and Risk Estimates for Fluensulfone.

Exposure 

Scenario Crop or Target

Dermal Unit 

Exposure 

(μg/lb ai)1

Inhalation Unit 

Exposure

(μg/lb ai)1

Maximum

Applic.

Rate2

Area 

Treated 

Daily3

Dermal Inhalation

Mitigation 

Level

Mitigation 

Level

Dose 

(m/k/d)

4

MOE5

(LOC=100)

Dose 

(m/k/d)

6

MOE7

(LOC=300)

(Rescue 

Treatment)

8.4 [Baseline] 0.34 [PF5 

respirator] 0.00287 1,100 0.00122 700

Applicator

Tractordrawn 

spreader

Golf course 9.9 [Baseline] 1.2 [Baseline]

1.8 lb ai/A 40 A 0.000847 3,700 0.00108 790

Tractordrawn 

spreader

Sod

(Typical 

Application)

9.9 [Baseline] 1.2 [Baseline]

1.8 lb ai/A 80 A 0.00170 1,800 0.00216 390

Sod

(Rescue 

Treatment)

9.9 [Baseline] 1.2 [Baseline]

3.6 lb ai/A 80 A 0.00338 920

0.00433 200

0.24 [PF5 

respirator] 0.000864 990

Loader/Applicator

Belly 

grinder

Landscaping, 

turf (lawns, 

athletic fields, 

parks)

10,000 

[Baseline]

62 [Baseline]

1.8 lb ai/A 1 A 0.0214 140 0.0014 610

Rotary 

spreader

Golf course, 

Landscaping, 

turf (lawns, 

athletic fields, 

parks)

440 [Baseline] 10 [Baseline]

1.8 lb ai/A 5 A 0.0047 660 0.00113 430

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (September, 2015); Level of mitigation: Baseline, 

PPE (Pf 5 respirator).

2 Based on registered or proposed label (EPA Reg. No. 53883-GLT).

3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose (mg/kg/day) = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Area 

Treated Daily (A/day) × DAF (9.5%) ÷ BW (80 kg).

5 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day). LOC=100.

6 Inhalation Dose (mg/kg/day) = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Area 

Treated Daily (A/day) ÷ BW (80 kg).

7 Inhalation MOE = Inhalation HED (mg/kg/day) ÷ Inhalation Dose (mg/kg/day

9.2 Short- and Intermediate-Term Post-Application Risk

Inhalation

There are multiple potential sources of post-application inhalation exposure to individuals 

performing post-application activities in previously treated fields. These potential sources 

include volatilization of pesticides and resuspension of dusts and/or particulates that contain 

pesticides. The agency sought expert advice and input on issues related to volatilization of 

pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel 

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

(http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2009-0687-0037). The agency 

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

subsequent Volatilization Screening Analysis 
Fluensulfone Human Health Risk Assessment DP No. D424168

Page 25 of 46

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

Review, the agency will use this analysis to determine if data (i.e., flux studies, route-specific 

inhalation toxicological studies) or further analysis is required for fluensulfone.

In addition, the Agency is continuing to evaluate the available post-application inhalation 

exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the 

Agency will continue to identify the need for and, subsequently, the way to incorporate 

occupational post-application inhalation exposure into the agency's risk assessments.

Dermal

A chemical-specific turf transferable residue (TTR) study was used to assess post-application 

exposures from turf following treatment with a granular formulation. The predicted Day-0 

residue value of 0.0022 ug/cm2 was from the New York site at an application rate of 3.6 lb ai/A, 

and it was used to estimate occupational post-application dermal exposure and risk for sod farms 

(rescue treatment only). A residue value of 0.0011 ug/cm2adjusted by the proposed maximum 

single application rate of 1.8 lb ai/A was used to estimate occupational post-application exposure 

and risk for sod/turf (typical application) and golf courses. The post-application dermal risk 

estimates are not of concern (Table 9.2.1).

Table 9.2.1. Occupational Post-application Non-Cancer Exposure and Risk Estimates for Fluensulfone.

Crop/Site Activities Transfer Coefficient 

(cm2/hr)

TTR1 Dermal Dose

(mg/kg/day)2

MOE3

Short- and Intermediate-term

Sod Farm 

(Rescue Treatment)

Maintenance, 

Harvesting, Slab

Transplanting/Planting

6,700 0.0022 0.000032 25,000

Sod Farm/Turf 

(Typical Application)

0.0011 0.000064 49,000

Golf Course Maintenance (greens 

only)

2,500 0.0011 0.000024 130,000

Maintenance 3,700 0.0011 0.000035 88,000

1. Predicted TTR at initial concentration (t0) = 0.0022 ug/cm2at 3.6 lb ai/A or 0.0011 ug/cm2at 1.8 lb ai/A from chemical-specific study (EPA 

MRID No. 49552503).

2. Daily Dermal Dose = [TTR (μg/cm2) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (9.5%)]  BW (80 kg).

3. MOE = POD (mg/kg/day) / Daily Dermal Dose. LOC=100.

Restricted Entry Interval

Fluensulfone is classified as Toxicity Category III via the dermal route and Toxicity Category IV 

for skin and eye irritation potential. The granular formulation is not a skin sensitizer. Short- and 

intermediate-term post-application risk estimates were not a concern on Day 0 (following 

application) for all post-application activities. 

10.0 References

D418204. 5 June 2014. Doherty, M. Fluensuflone Acute and Chronic Aggregate Dietary (Food 

and Drinking Water) Exposure and Risk Assessments for the First Food Use Section 3 

Registration Action on Fruiting and Cucurbit Vegetables.
Fluensulfone Human Health Risk Assessment DP No. D424168

Page 26 of 46

D430164. 4 December 2015. Figueroa, Z. Fluensulfone. Occupational and Residential 

Exposure Assessment for a Proposed Uses on Golf Courses, Sports Fields, Commercial 

Areas, Sod Farms and Residential Turfgrass Lawns.

D403767. 18 June 2014. Doherty, M., D’Agostino, J., Figuroa, Z. Fluensulfone – New Active 

Ingredient Human Health Risk Assessment of Proposed Uses on Cucurbit Vegetables 

and Fruiting Vegetables.
Fluensulfone Human Health Risk Assessment DP No. D424168

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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The toxicology data requirements (40 CFR 158.340) for fluensulfone are presented in Table 1. Use of the new 

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

Test Technical Fluensulfone

Required Satisfied

870.1100 Acute Oral Toxicity

870.1200 Acute Dermal Toxicity

870.1300 Acute Inhalation Toxicity

870.2400 Primary Eye Irritation

870.2500 Primary Dermal Irritation

870.2600 Dermal Sensitization

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

870.3150 Oral Subchronic (nonrodent)

870.3200 21/28-Day Dermal

870.3250 90-Day Dermal

870.3465 90-Day Inhalation

yes

yes

yes

no

yes

yes

yes

yes

-

yes

870.3700a Developmental Toxicity (rodent)

870.3700b Developmental Toxicity (nonrodent)

870.3800 Reproduction

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)

870.4100b Chronic Toxicity (nonrodent)

870.4200a Oncogenicity (rat)

870.4200b Oncogenicity (mouse)

870.4300 Chronic/Oncogenicity

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial

870.5300 Mutagenicity—Gene Mutation - mammalian

870.5375 Mutagenicity—Structural Chromosomal Aberrations

870.5550 Mutagenicity—Other Genotoxic Effects

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)

870.6100b 90-Day Neurotoxicity (hen)

870.6200a Acute Neurotoxicity Screening Battery (rat)

870.6200b 90-Day Neurotoxicity Screening Battery (rat)

870.6300 Developmental Neurotoxicity

no

no

yes

yes

no

--

--

yes

yes

--

870.7485 General Metabolism

870.7600 Dermal Penetration

870.7800 Immunotoxicity

yes

yes

yes

yes

yes

yes
Fluensulfone Human Health Risk Assessment DP No. D424168

Page 28 of 46

A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile - Fluensulfone technical

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral - rat 48574745 LD50 = 671 III

870.1100 Acute oral - rat 48574746 LD50 > 300 mg/kg 

but < 2000 mg/kg

III

870.1200 Acute dermal - rat 48575035 LD50 > 2000 mg/kg III

870.1300 Acute inhalation - rat 48574748 LC50 > 5.1 mg/L IV

870.2400 Acute eye irritation - rabbit 48574750 Non-irritant IV

870.2500 Acute dermal irritation - rabbit 48574749 Non-irritant IV

870.2600 Skin sensitization - guinea pig 48574751 Sensitizer N/A

Table A.2.2 Acute Toxicity Profile - Fluensulfone granular formulations

Guideline No.

Study Type MRID(s) Results (from study 

report)

Toxicity Category

870.1100 Acute oral – rat, 15GR 49488603 LD50 > 2000 mg/kg III

870.1100 Acute oral – rat, 1.5GR 49488608 LD50 > 2000 mg/kg III

870.1200 Acute dermal – rat, 15GR 49488604 LD50 > 2000 mg/kg III

870.1300 Acute inhalation - rat waived - -

870.2400 Acute eye irritation – rabbit, 15GR 49488605 Non-irritant IV

870.2500 Acute dermal irritation – rabbit, 

15GR

49488606 Slightly irritating IV

870.2600 Skin sensitization – mice, 15GR 49488607 Not a sensitizer N/A

Table A.2.3 Acute Oral Toxicity Profile - Fluensulfone Metabolites

Metabolite Study Type MRID(s) Results Toxicity Category

TSA Acute oral - rat 48574783 LD50 > 2000 mg/kg III

MeS Acute oral - rat 48574787 LD50 > 300 mg/kg 

but < 2000 mg/kg

II

BSA Acute oral - rat 48574792 LC50 > 2000 mg/kg III

Table A.2.4 Toxicity Profile - Fluensulfone

Guideline Study Type Doses Tested/Study 

Classification

MRID Results

870.3100 2003-90-day 

dietary-rat

mg/kg/day =

M: 0, 4.3, 8.3, 34.9, 139.0

F: 0, 4.8, 11.7, 53.1, 148.7

Acceptable/Guideline

48575035 NOAEL (mg/kg/day): 

M=8.3, F=11.7

LOAEL (mg/kg/day): M=34.9, F=53.1 

based on kidney effects, observations in the 

pharynx and forestomach, increased 

cholesterol in females, and decreased body 

weight and body weight gain in males. 

870.3100 2002-28-day 

dietary-rat 

mg/kg/day=

M: 0, 10.4, 42.5, 152.0

F: 0, 12.2, 37.2, 165.9

Acceptable/Guideline

48575023 NOAEL (mg/kg/day): 

M=10.4, F=12.2

LOAEL (mg/kg/day):

M=42.5, F=37.2 based on decreased body 

weight gain in both sexes, increased WBC 

in females, increased cholesterol in males 
Fluensulfone Human Health Risk Assessment DP No. D424168

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Table A.2.4 Toxicity Profile - Fluensulfone

Guideline Study Type Doses Tested/Study 

Classification

MRID Results

and renal pathology in males.

870.3100 2003-90-day 

dietary-mouse

mg/kg/day =

M: 0, 11, 51, 228

F: 0, 18, 68, 252

Acceptable/Guideline

48574753 NOAEL (mg/kg/day): 

M=11, F=18

LOAEL (mg/kg/day): 

M=51, F=68 based on increased bilirubin, 

hematology effects in males, and reduced 

food consumption in females.

870.3100 2003-28-day 

dietary-mouse

mg/kg/day =

M: 0, 30, 101, 375

F: 0, 41, 155, 353

Acceptable/Guideline

48575024 NOAEL (mg/kg/day): 

M=30, F=41

LOAEL (mg/kg/day): 

M=101, F=155 based on decreased food 

consumption, decreased platelets in males, 

decreased absolute heart weight in males, 

and increased relative liver weight in 

females.

870.3150 2002-90-day 

dietary-dog 

mg/kg/day =

M: 0, 0.2, 1.6, 17.1

F: 0, 0.2, 1.8, 18.0

Acceptable/Guideline

48574755 NOAEL (mg/kg/day): 

M=1.6, F= 1.8

LOAEL (mg/kg/day): M=17.1, F=18.0

based on decreased plasma and liver 

ALAT, liver effects, hematological 

findings, altered clinical chemistry, 

increased TSH, decreased body weight 

gains and decreased body weight in 

females.

870.3150 2002-28-day 

dietary-dog 

mg/kg/day =

M: 0, 1.9, 7.3, 31

F: 0, 2.0, 7.9, 30

Acceptable/Guideline

48574752 NOAEL (mg/kg/day): 

M=7.3, F= 7.9

LOAEL (mg/kg/day): M=31, F=30

based on slight decreases in body weight 

and slight increases in liver and thyroid 

weight.

870.3200 2011-28-day 

dermal-rat

mg/kg/day =

0, 80, 400, 2000

Acceptable/Guideline

48574758 Systemic: NOAEL (mg/kg/day):

400

LOAEL (mg/kg/day): 2000 based reduced 

body weight gain, increased prothrombin 

time and increased relative spleen weight in 

males; increased reticulocytes and 

increased cholesterol in females.

870.3465 2012-90-day 

inhalation-rat

mg/L/day =

0, 0.04, 0.2, 1.0

Acceptable/Guideline

48575045 NOAEL (mg/L/day):

Not determined

LOAEL (mg/kg/day): 

0.04 based on weight loss in males, 

prolonged prothrombin time in females, 

decreased thymus weight in males, 

histopathological changes in the epiglottis 

in both sexes, and histopathological 

changes in the nasal cavity of males.

870.3700 2003-

developmental 

tox-rat

mg/kg/day =

0, 8, 50, 300

Acceptable/Guideline

48574771 Maternal: NOAEL (mg/kg/day): 50

LOAEL (mg/kg/day): 300 based on 

decreased body weight and food 

consumption.
Fluensulfone Human Health Risk Assessment DP No. D424168

Page 30 of 46

Table A.2.4 Toxicity Profile - Fluensulfone

Guideline Study Type Doses Tested/Study 

Classification

MRID Results

Developmental: NOAEL (mg/kg/day): 50

LOAEL (mg/kg/day): 300 based on 

decreased body weight.

870.3700 2009-

developmental 

tox-rabbit

mg/kg/day =

0, 2.5, 10, 40

Acceptable/Guideline

48574770 Maternal: NOAEL (mg/kg/day): 10 

LOAEL (mg/kg/day): 40 based on transient 

weight loss and decreased food 

consumption, GD6-9.

Supported by significant toxicity at 50 

mg/kg/day (marked body weight loss, cold 

ears, decreased food intake, and discolored 

urine) observed in the range finding study.

Developmental: NOAEL (mg/kg/day): 10

LOAEL (mg/kg/day): 40 based on reduced 

body weight and incomplete ossification of 

digit 5 of the medial phalanx in both 

forelimbs.

870.3800 2011-2-

generation 

reproductionrat

mg/kg/day =

P, male: 0,1.9, 15.4, 114.2, 

P, female: 0, 2.7, 22.8, 

164.8

F1, male: 0, 2.0, 17.0, 

129.7

F1, female: 0, 2.9, 23.3, 

169.1

Acceptable/Guideline

48574769 Parental: 

NOAEL (mg/kg/day):

M=16.2, F=23.0 

LOAEL (mg/kg/day):

M=122.0, F=169.1 based on decreased 

body weight

Reproductive:

NOAEL (mg/kg/day):

M=16.2, F=23.0 

LOAEL (mg/kg/day): M=122.0, F=169.1 

based on an increase in post-natal pup loss 

in both P and F1 generations.

Offspring: 

NOAEL (mg/kg/day):

M=16.2, F=23.0 

LOAEL (mg/kg/day): M=122.0, F=169.1 

based on decreased pup and spleen weights.

870.4100 2011-1-year 

dietary-dog

mg/kg/day =

M: 0, 0.1, 1.5, 3.1, 16.0

F: 0, 0.1, 1.5, 3.3, 16.2

Acceptable/Guideline

48574756 NOAEL (mg/kg/day): 

M=3.1, F= 3.3

LOAEL (mg/kg/day): M=16.0, F=16.2 M: 

based on decreased body weight and 

changes in hematological and clinical 

chemistry parameters in both sexes.

870.4200 2011-18-month 

carcinogenicity

-mouse

mg/kg/day =

M: 0, 4.2, 27.6, 152.3

F: 0, 6.4, 39.0, 188.4

Acceptable/Guideline

48574766 NOAEL (mg/kg/day):

M=4.2, F=6.4

LOAEL (mg/kg/day):

M=27.6, F=39.0 based on an increased 

incidence of lung bronchiolization and 

decreased body weight and body weight 

gain in males.

Increased incidence of lung adenomas 
Fluensulfone Human Health Risk Assessment DP No. D424168

Page 31 of 46

Table A.2.4 Toxicity Profile - Fluensulfone

Guideline Study Type Doses Tested/Study 

Classification

MRID Results

above historical controls was observed in 

females; combined adenoma/carcinomas 

was also increased (carcinoma only 

increased trend).

870.4300 2011-2-year 

toxicity/carcino

genicity-rat

mg/kg/day =

Oncogenicity group

M: 0, 1.4, 9.6, 57.7

F: 0, 1.7, 11.6, 69.3

Chronic toxicity group

M: 0, 1.6, 11.0, 66.3

F: 0, 1.9, 13.1, 75.2

Acceptable/Guideline

48574765 NOAEL (mg/kg/day):

M=9.6, F=11.6

LOAEL (mg/kg/day): 

M=57.7, F=69.3 based on decreased body 

weight in males, and hematology and 

clinical chemistry findings and

histopathological changes in the lungs and 

esophagus in both sexes.

870.5100 2002-Bacterial 

reverse 

mutation assay 

(MCW-2)

Test 1: 0, 16, 50, 158, 500, 

1581, or 5000 g/plate 

(Salmonella typhimurium) 

in the presence and 

absence of metabolic 

activation (+ S9).

Test 2: 0, 1000, 2000, 

3000, 4000, 5000, or 6000

g/plate (Salmonella 

typhimurium) in the 

presence and absence of 

metabolic activation (+

S9).

Test 3: 0, 375, 750, 1300, 

2600, or 5200 g/plate 

(Salmonella typhimurium) 

in the absence of 

metabolic activation (-S9).

Acceptable/Guideline

48574759/

48575015

Negative with strains TA1535, TA1537, 

TA98, and TA102.

Weakly positive with strain TA 100.

870.5100 2008-Bacterial 

reverse 

mutation assay 

(MCW-2)

Test 1: 0, 3, 10, 33, 100, 

333, 1000, 2500, or 5000

g/plate (Salmonella 

typhimurium-Escherichia 

coli) in the presence and 

absence of metabolic 

activation (+ S9).

Test 2: 0, 33, 100, 333, 

1000, 2500, or 5000

g/plate (Salmonella 

typhimurium-Escherichia 

coli) in the presence and 

absence of metabolic 

activation (+ S9).

48574760 Negative 
Fluensulfone Human Health Risk Assessment DP No. D424168

Page 32 of 46

Table A.2.4 Toxicity Profile - Fluensulfone

Guideline Study Type Doses Tested/Study 

Classification

MRID Results

Acceptable/Guideline

870.5100 2011-Bacterial 

reverse 

mutation assay 

(MCW-2)

Test 1: 0, 10, 32, 100, 316, 

1000, 2500, or 5000

g/plate (Salmonella 

typhimurium-Escherichia 

coli) in the presence and 

absence of metabolic 

activation (+ S9).

Test 2: 0, 3, 10, 32, 100, 

316, 1000, 2500, or 5000

g/plate (Salmonella 

typhimurium-Escherichia 

coli) in the presence and 

absence of metabolic 

activation (+ S9).

Acceptable/Guideline

48574761 Negative 

870.5100 2010-Bacterial 

reverse 

mutation assay 

(MCW-2 

metabolite 

#3625)

Test 1: 0, 3, 10, 33, 100, 

333, 1000, 2500, or 5000

g/plate (Salmonella 

typhimurium-Escherichia 

coli) in the presence and 

absence of metabolic 

activation (+ S9).

Test 2: 0, 33, 100, 333, 

1000, 2500, or 5000

g/plate (Salmonella 

typhimurium-Escherichia 

coli) in the presence and 

absence of metabolic 

activation (+ S9).

Acceptable/Guideline

48574784 Negative

870.5100 2010-Bacterial 

reverse 

mutation assay 

(MCW-2 

metabolite 

#3626)

Test 1: 0, 3, 10, 33, 100, 

333, 1000, 2500, or 5000

g/plate (Salmonella 

typhimurium-Escherichia 

coli) in the presence and 

absence of metabolic 

activation (+ S9).

Test 2: 0, 33, 100, 333, 

1000, 2500, or 5000

g/plate (Salmonella 

typhimurium-Escherichia 

coli) in the presence and 

absence of metabolic 

activation (+ S9).

Test 3: 0, 100, 333, 1000, 

2500, 3750, or 5000

g/plate (Salmonella 

typhimurium-Escherichia 

coli) in the presence and 

48574788 Negative, except positive with Salmonella 

typhimurium strain TA100 in the absence 

of metabolic activation
Fluensulfone Human Health Risk Assessment DP No. D424168

Page 33 of 46

Table A.2.4 Toxicity Profile - Fluensulfone

Guideline Study Type Doses Tested/Study 

Classification

MRID Results

absence of metabolic 

activation (+ S9).

Acceptable/Guideline

870.5100 2010-Bacterial 

reverse 

mutation assay 

(MCW-2 

metabolite 

#3627)

Test 1: 0, 3, 10, 33, 100, 

333, 1000, 2500, or 5000

g/plate (Salmonella 

typhimurium-Escherichia 

coli) in the presence and 

absence of metabolic 

activation (+ S9).

Test 2: 0, 33, 100, 333, 

1000, 2500, or 5000

g/plate (Salmonella 

typhimurium-Escherichia 

coli) in the presence and 

absence of metabolic 

activation (+ S9).

Acceptable/Guideline

48574793 Negative

870.5300 2003-In vitro

mammalian cell 

gene mutation 

assay (MCW-2)

Without activation: 0, 24, 

32, 40, 48, 56, 64, 72 

g/ml

With activation: 0, 20, 30, 

40, 50, 60, 70, 80 g/ml

Acceptable/Guideline

48574763 Negative

870.5300 2011-In vitro

mammalian cell 

gene mutation 

assay (MCW-2 

metabolite 

#3626)

Without activation: test1 = 

0, 3.8, 7.5, 15, 30, 40, 50, 

60 g/ml, test 2 = 0, 5.5, 

10.9, 21.9, 43.8, 87.5, 

131.3, 175 g/ml

With activation: test 1 = 0, 

37.5, 75, 150, 300, 600, 

800, 1000 g/ml, test 2 = 

0, 87.5, 175, 350, 700, 

800, 900, 1000 g/ml

Acceptable/Guideline

48574789 Negative

870.5375 2010-In vitro

mammalian cell 

chromosome 

aberration test 

(MCW-2)

0, 62.5, 125, 250, 500, 

1000 μg/mL with and 

without metabolic 

activation 

Acceptable/Guideline

48574762 Negative

870.5375 2010-In vitro

mammalian cell 

chromosome 

aberration test 

(MCW-2 

Test 1: 0, 9.3, 18.5, 37, 

74.1, 148.1, 296.3, 592.5, 

1185, 2370 μg/mL with 

and without metabolic 

activation 

48574785 Negative
Fluensulfone Human Health Risk Assessment DP No. D424168

Page 34 of 46

Table A.2.4 Toxicity Profile - Fluensulfone

Guideline Study Type Doses Tested/Study 

Classification

MRID Results

metabolite 

#3625) Test 2: 0, 9.3, 18.5, 37, 

74.1, 148.1, 296.3, 592.5, 

1185, 2370 μg/mL without 

metabolic activation and 

148.1, 296.3, 592.5, 1185, 

2370 μg/mL with 

metabolic activation

Acceptable/Guideline

870.5375 2010-In vitro

mammalian cell 

chromosome 

aberration test 

(MCW-2 

metabolite 

#3627)

Test 1: 0, 8.3, 16.6, 33.3, 

66.6, 133.2, 266.4, 532.8, 

1065.5, 2131 μg/mL with 

and without metabolic 

activation 

Test 2: 0, 8.3, 16.6, 33.3, 

66.6, 133.2, 266.4, 532.8, 

1065.5, 2131 μg/mL 

without metabolic 

activation and 133.2, 

266.4, 532.8, 1065.5, 2131 

μg/mL with metabolic 

activation

Acceptable/Guideline

48574794 Negative

870.5395 2003-

mammalian 

erythrocyte 

micronucleus 

test (MCW-2)

mg/kg/day = 0, 75, 150, 

300

Acceptable/Guideline

48574764 Negative

870.5395 2011-

mammalian 

erythrocyte 

micronucleus 

test (MCW-2 

metabolite 

#3625)

mg/kg/day = 0, 500, 

1000, 2000

Acceptable/Guideline

48574786 Negative

870.5395 2011-

mammalian 

erythrocyte 

micronucleus 

test (MCW-2 

metabolite 

#3626)

mg/kg/day = 0, 125, 250, 

500

Acceptable/Guideline

48574791 Negative

870.5395 2010-

mammalian 

erythrocyte 

micronucleus 

test (MCW-2 

metabolite 

#3627)

mg/kg/day = 0, 500, 

1000, 2000

Acceptable/Guideline

48574795 Negative
Fluensulfone Human Health Risk Assessment DP No. D424168

Page 35 of 46

Table A.2.4 Toxicity Profile - Fluensulfone

Guideline Study Type Doses Tested/Study 

Classification

MRID Results

870.5550 2011-

unscheduled 

DNA synthesis 

(MCW-2 

metabolite 

#3626)

mg/kg/day = 0, 250, 500

Acceptable/Guideline

48574790 Negative

870.6200 2010-Acute 

neurotoxicityrat

mg/kg/day = 0, 100, 400, 

1200

Acceptable/Guideline

48574773 NOAEL (mg/kg/day): not identified

LOAEL (mg/kg/day): 100 based on 

decreased spontaneous activity, decreased 

rearing, impaired righting response, and 

reduced locomotor activity in females.

870.6200 2011-90-day 

neurotoxicityrat

mg/kg/day =

M: 0, 6, 31, 153

F: 0, 7, 34, 162

Acceptable/Guideline

48574774 NOAEL (mg/kg/day): M=31, F=34

LOAEL (mg/kg/day): M=153, F=162 based 

on decreased food consumption, decreased 

body weight gain, and decreased body 

weight in males.

870.7485 2011-

Metabolism 

and excretion, 

single oral-rat 

([thiazole14C]MCW-2 

and [butene14C]MCW-2)

mg/kg/day =

5 and 500 

Acceptable/Guideline

48574742 The recovery of radioactivity was 91.3-

97.3% of the administered dose for all 

groups of rats. The disposition and 

excretion of radiolabel for males and 

females were generally similar. Urine was 

the major route of excretion for both 

radiolabel positions; 75-88% of the 

administered dose was excreted in urine 

depending on the dosing. Unmetabolized 

fluensulfone was not detected as a 

significant residue in either urine or feces. 

The study investigators indicated that 

initially the parent compound probably 

reacts with glutathione to displace butene 

sulfinic acid, the major urinary metabolite. 

870.7485 2011-

Metabolism 

and excretion, 

repeat oral-rat (

[butene14C]MCW-2)

mg/kg/day =

5 

Acceptable/Guideline

48574744 The recovery of excreted radiolabel was 

94-99% for individual rats. Radiolabel was 

found mainly in urine (71-83%), feces (9-

11%) and the cage wash (6-16%). One day 

after dosing with radiolabeled fluensulfone, 

an average of 0.6-0.8% of the administered 

radiolabel was in liver and 0.1% in kidney 

with 1.7-2.1% in the carcass (selected 

tissues removed) and 4.5-4.7% remained in 

the gastro-intestinal tract. By 7 days after 

treatment with radiolabeled fluensulfone, 

an average of 0.1-0.2% of the administered 

radiolabel remained in liver and 0.03% in 

kidney.There were no significant sex 

differences in either elimination or tissue 

residues. Analysis of urine showed four 

major metabolites identified as thiazole 

sulfonic acid (TSA), glucuronide I, 

glucuronide II and thiazole mercapturate.

870.7485 2010-

pharmacokineti

mg/kg/day =

5 and 500

48574741 The absorption of fluensulfone-derived 14C 

was rapid at both doses. The kinetic 
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Page 36 of 46

Table A.2.4 Toxicity Profile - Fluensulfone

Guideline Study Type Doses Tested/Study 

Classification

MRID Results

cs, single oralrat ([thiazole14C]MCW-2 

and [butene14C]MCW-2)

Acceptable/Guideline

parameters for males and females were 

generally similar for the butene radiolabel, 

while for the thiazole label, male rats 

demonstrated a slightly higher absorption 

based on AUC values in whole blood. 

Fluensulfone reacts with the free thiol 

moiety of globin (protein of hemoglobin) to 

form a covalent linkage to the thiazole 

group and displaces butene sulfinic acid.

870.7485 2011-

toxicokinetic 

study-rat 

([thiazole14C]MCW-2 

and [butene14C]MCW-2)

mg/kg/day =

5 and 500

Acceptable/Guideline

48574743 Residues were generally similar between 

males and females. For both labels and both 

dose levels, the gastrointestinal tract, liver 

and kidney were among the tissues 

containing the highest radioactivity levels 

at Cmax for both sexes. As predicted by the 

pharmacokinetic study, radioactivity from 

the thiazole label was slowly eliminated 

from red blood cells consistent with the 

derivatization of the hemoglobin cysteine 

thiol. The ratio of residues at the Cmax

compared to the DT90 was near the 

expected 10% for plasma, but for the 

thiazole label (low and high doses) was 

>25% for numerous tissues/organs. For the 

butene label (low and high doses), the ratio 

of residues at Cmax compared to DT90 was 

also >25% for numerous tissues/organs

except those involved with the digestive 

system. The slow elimination of 

radioactivity with the thiazole and butene 

labels may reflect metabolism of [14C]

fluensulfone to 1- and 2-carbon fragments 

with reincorporation in natural products 

(e.g. protein, fatty acids) with long turnover 

rates.

870.7600 2011 Dermal 

penetration in 

vivo – male rat

Mg/cm2 = 0.1 (label 

dilution of commercial 

formulation) and 4.8 

(undiluted commercial 

formulation) 480 EC 

formulation. Equivalent to 

10 g a.i./L and 480 g 

a.i./L, respectively. All 

animals exposed for 10 

hours, then monitored at 

24, 72 or 120 hrs.

48574949 MCW-2 as the MCW-2 480 EC 

formulation penetrated rat skin at both high 

and low dose levels at a relatively high 

level (63.71 and 19.16% AD at 10 hours, 

respectively), which was mainly excreted in 

the urine. The maximum potentially 

absorbable % AD for the low and high dose 

groups is 64% at 10 hrs and 21% at 24 h, 

respectively. After five days, 2.2% of low 

dose and 0.66% of high dose radioactivity 

remained in the animals. The calculated 

penetration rates did not increase in a 

proportional fashion with dose.

870.7800 2011-28-day 

immunotoxicity

-mice

mg/kg/day =

0, 17, 86, 204

Acceptable/Guideline

48574779 Systemic: NOAEL (mg/kg/day):

86

LOAEL (mg/kg/day): 204 based on 

mortality, clinical signs and decreased body 
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Page 37 of 46

Table A.2.4 Toxicity Profile - Fluensulfone

Guideline Study Type Doses Tested/Study 

Classification

MRID Results

weight and food consumption.

Immunotoxicity: NOAEL (mg/kg/day):

204

LOAEL (mg/kg/day):

not determined

Special 

study

2011 – 3 or 7-

day dietary 

study 

evaluating 

BrdU 

incorporation in 

lungs – female 

mice

0 or 1200 ppm

Acceptable/nonguideline

48574767 At 1200 ppm increased cell proliferation 

was observed in the lungs as determined by 

BrdU incorporation. The effect was 

transient, observed at 3 days but not after 7 

days.

Special 

study

2011 –

Comparative 

biotransformati

on in human vs. 

mouse lung 

microsomes

2 or 20 μM, in vitro

incubation 

Acceptable/nonguideline

48574768 Fluensulfone was extensively metabolized 

by mouse lung microsomes but not by 

human lung microsomes. Mouse Cyp2f2 

appeared to be involved in the metabolism.

Special 

study

2009 –

Inhibition of 

Alanineaminotransferas

e (ALAT) in a 

28-day dog 

dietary study

0, 50, 200 or 900 ppm

Acceptable/nonguideline

48574775 Liver, serum and liver cytosolic fractions of 

untreated dogs, spiked with serum or 

cytosolic fractions from fluensulfonetreated dogs, did not show inhibition of 

ALAT activity in the untreated dogs. The 

decrease in ALAT activity was therefore 

not likely to be due to direct inhibition of 

the enzyme by fluensulfone/ metabolites, or 

inhibition of the ALAT gene or protein 

expression in the liver.

Special 

study

2011 – 2-week 

dietary study in 

dog –

evaluation of 

MOA for 

decreased 

ALAT activity

0 or 500 ppm

Acceptable/nonguideline

48574776 Reduced ALAT activity was not due to 

decreased mRNA or protein expression, or 

decreased cofactor pyridoxal 5’-phosphate.

Special 

study

2010 – in vitro

inhibition of 

ALAT activity 

by fluensulfone 

from liver 

microsomes of 

untreated dogs

Up to approximately 19.1 

μM, in vitro incubation

Acceptable/nonguideline

48574777 Fluensulfone did not cause a direct 

inhibition of ALAT activity when 

incubated with dog liver homogenates.

Special 

study

2009 –

Determination 

of hepatic 

ALAT in 

untreated dogs

Untreated animals 48574778 An historical database for adult male and 

female beagle dogs was established based 

on data collected between 6/09 and 9/09

Special 

Study

2011-

comparative in 

vitro dermal 

mg/cm2 =

0.1 and 4.8 480 EC 

formulation.

48574950 The total absorption was calculated to be 

92.11% and 81.26% (low and high dose), 

and 62.46% and 4.65% (low and high dose) 
Fluensulfone Human Health Risk Assessment DP No. D424168

Page 38 of 46

Table A.2.4 Toxicity Profile - Fluensulfone

Guideline Study Type Doses Tested/Study 

Classification

MRID Results

absorption 

(MCW-2 

[Ring-U14C])

Acceptable/nonguideline

for rat and human skin membranes, 

respectively. Based on percentages 

absorbed, the ratio between human and rat 

skin membrane was 1:1.5 for the low dose 

level and 1:18 for the high dose level.

Special 

Study

2014-28-Day 

Dietary – rat 

[BSA]

mg/kg/day =

M: 0, 6.4, 30, 82, 732

F: 0, 8.6, 39, 120, 1024

Acceptable/nonguideline

49387602 NOAEL (mg/kg/day): None

LOAEL (mg/kg/day): None

Aside from marginal (<25%) decreases in 

mean serum aspartate aminotransferase 

levels in both sexes and alanine 

aminotransferase levels in males at the high 

dose of 10,000 ppm, no treatment-related 

effects were observed in this study up to the 

highest dose tested.

Special 

Study

2014-28-Day 

Dietary – rat 

[TSA]

mg/kg/day =

M: 0, 10, 41, 113, 1194

F: 0, 12, 43, 123, 1779

Acceptable/nonguideline

49387601 NOAEL (mg/kg/day): None

LOAEL (mg/kg/day): None

No treatment-related effects were observed 

in this study up to the highest dose tested.

Special 

Study

2015-

comparative in 

vitro dermal 

absorption

mg/cm2 =

0.09 and 4.5 480 EC 

formulation.

49700504 The total absorption was calculated to be 

43.6% and 24.2% (low and high dose), and 

7.1% and 1.0% (low and high dose) for rat 

and human skin membranes, respectively.
Fluensulfone Human Health Risk Assessment DP No. D424168

Page 39 of 46

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) – General Population Including Females age 13-49

Study Selected: 2-generation reproductive toxicity study.

MRID No: 48574769

Dose and Endpoint for Risk Assessment: Offspring NOAEL = 16.2/23.0 mg/kg/day (M/F) 

based on increased post-natal pup loss by Day 2 in the F1 and F2 generations at the LOAEL of 

122.0/169.1 mg/kg/day (M/F). 

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA 

Safety Factor)

Acute RfD = 

100( )

16.2 / /

UF

mg kg day

= 0.16 mg/kg/day

Comments about Study/Endpoint/Uncertainty Factor: 

The endpoint of concern in this study is protective of all populations and is appropriate for the 

exposure duration of concern. This study has a clearly defined NOAEL and the effect could be 

considered to be the result of a single dose. The study is also protective of the effects observed in 

the ACN in rats at 100 mg/kg based on consideration of the dose response curve at the doses 

tested, and absence of findings at 100 mg/kg in the range-finding study for the ACN.

A.3.2 Chronic Reference Dose (cRfD) 

Study Selected: Co-critical chronic toxicity (dog) and 90-day toxicity (dog).

MRID Nos: 48574756 and 48574755

Dose and Endpoint for Risk Assessment: NOAEL = 3.1 mg/kg/day (chronic dog) based on 

hematological and clinical chemistry changes, and decreased body weights at the LOAEL of 16 

mg/kg/day observed in both the chronic and subchronic studies. The higher NOAEL from the 

chronic dog study (3.1 vs. 1.6 mg/kg/day) was used as the point of departure since the 

differences in doses are an artifact of dose selection.

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)

Chronic RfD = 

100( )

3.1 / /

UF

mg kg day

= 0.03 mg/kg/day

Comments about Study/Endpoint/Uncertainty Factor: The endpoint of concern in the chronic 

and subchronic studies is protective of all populations and appropriate for the exposure duration 

of concern. The 90-day and chronic dog toxicity studies exhibit similar toxic effects occurring at 

the same LOAEL (16-17 mg/kg/day) with no progression in toxicity over time. The NOAEL of 
Fluensulfone Human Health Risk Assessment DP No. D424168

Page 40 of 46

3.1 mg/kg is also protective of the effects observed in the rat and mouse carcinogenicity studies, 

as well as potential developmental effects. 

A.3.3 Incidental Oral Exposure (Short-Term)

Study Selected: Co-critical chronic toxicity (dog) and 90-day toxicity (dog).

MRID Nos: 48574756 and 48574755

Dose and Endpoint for Risk Assessment: NOAEL = 3.1 mg/kg/day (chronic dog) based on 

hematological and clinical chemistry changes, and decreased body weights at the LOAEL of 16 

mg/kg/day observed in both the chronic and subchronic studies. The higher NOAEL from the 

chronic dog study (3.1 vs. 1.6 mg/kg/day) was used as the point of departure since the 

differences in doses are an artifact of dose selection.

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)

Comments about Study/Endpoint/Uncertainty Factor: The endpoint of concern in the chronic 

and subchronic studies is protective of all populations and appropriate for the exposure duration 

of concern. The 90-day and chronic dog toxicity studies exhibit similar toxic effects occurring at 

the same LOAEL (16-17 mg/kg/day) with no progression in toxicity over time. The NOAEL of 

3.1 mg/kg is also protective of the offspring effects observed in the 2-generation reproduction 

study in rats. 

A.3.4 Dermal Absorption

An in vivo dermal absorption study in the rat and two in vitro dermal absorption study using rat 

and human skin were submitted. All three studies used fluensulfone in an emulsifiableconcentrate (EC) formulation as the test material. The data demonstrated an inverse relationship 

between dosing concentration and percent absorption. Based on in vivo dermal absorption 

observed in the rat and in vitro comparative rat:human absorption data, an estimated human 

dermal absorption factor (DAF) was obtained as follows (all absorption values adjusted for 

recovery):

(1) In the rat in vivo dermal absorption study, a dermal absorption of 58.0% (directly 

absorbed plus absorbable) was found at 24 hrs post-exposure using an application of 

0.0953 mg/cm2; 

(2) In vitro exposure of split-thickness rat skin under the same exposure and assessment 

conditions gave a dermal absorption of 43.6% (directly absorbed plus absorbable); 

(3) The ratio of the rat in vitro to the rat in vivo absorption is 0.75 (43.6/58.0) which is 

close to 1, indicating that the in vitro data is predictive of in vivo absorption; 

(4) Based on this ratio, a DAF for humans may be calculated using in vitro human dermal 

absorption (7.1%, directly absorbed plus absorbable) observed in vitro under the same 

exposure conditions. The DAF for humans is therefore 7.1%/0.75= 9.5%.

A.3.5 Dermal Exposure (Short- and Intermediate-Term) 
Fluensulfone Human Health Risk Assessment DP No. D424168

Page 41 of 46

Study Selected: Co-critical chronic toxicity (dog) and 90-day toxicity (dog).

MRID Nos: 48574756 and 48574755

Dose and Endpoint for Risk Assessment: NOAEL = 3.1 mg/kg/day (chronic dog) based on 

hematological and clinical chemistry changes, and decreased body weights at the LOAEL of 16 

mg/kg/day observed in both the chronic and subchronic studies. The higher NOAEL from the 

chronic dog study (3.1 vs. 1.6 mg/kg/day) was used as the point of departure since the 

differences in doses are an artifact of dose selection.

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)

Comments about Study/Endpoint/Uncertainty Factors: The endpoint of concern in the 

chronic and sub-chronic studies is protective of all populations and appropriate for the exposure 

duration of concern. These two studies are appropriate for short- and intermediate-term 

exposures because of the timing of the effects (effects on hematology and clinical chemistry 

parameters were seen starting at week 6 in both studies) and the lack of progression in the 

toxicity database (subchronic and chronic studies of all species had similar NOAELs and 

LOAELs). 

For short- and intermediate-term residential/occupational exposure scenarios involving dermal 

exposure, HED did not chose the 28-day dermal toxicity study in rats conducted with the 

technical material. Although that study is of the appropriate route and duration, the results do not 

appear to reflect the high dermal absorption of the emulsifiable concentrate (480 EC) observed in 

the in vivo and in vitro dermal penetrations studies. The dermal toxicity study shows minimal 

toxicity following exposure of 2000 mg/kg/day to technical-grade fluensulfone, and has a 

NOAEL of 400 mg/kg/day. At that NOAEL, the oral-equivalent dose assuming 60% absorption 

(approximate rat in vivo value at 10 hours) is 240 mg/kg/day, which is approximately 6-fold 

higher than the LOAELs from oral subchronic toxicity studies with rats. Given the lack of toxic 

response in the dermal toxicity study, HED has concluded that it is not representative of potential 

systemic exposure to fluensulfone from the 480 EC formulation. Therefore, HED chose the cocritical oral dog studies discussed above, with a 9.5% dermal absorption factor (see Section 

4.2.1), to derive the point-of-departure. The two dog studies are appropriate for short- and 

intermediate-term exposure because the effects (hematology and clinical chemistry parameters) 

were seen starting at Week 6 in both studies and there was lack of progression in the toxicity 

database with longer exposure (subchronic and chronic studies of all species had similar 

NOAELs and LOAELs). 

A.3.6 Inhalation Exposure (Short- and Intermediate-Term) 

Study Selected: 90-day inhalation toxicity study in rats. 
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MRID No: 49067003

Dose and Endpoint for Risk Assessment: NOAEL = not identified based on decreased weight 

gain in males, increased prothrombin time in females, decreased thymus weight in males and 

histopathology in the epiglottis in both sexes seen at LOAEL= 0.04 mg/L (lowest dose tested). 

HEC (occupational): rat NOAEL x (daily duration adjustment) x weekly daily duration 

adjustment x RDDR = 0.04 mg/L x (6 hr/8 hr) x (5 days/5 days) x 0.143 = 0.00429 mg/L.

HEC (residential handler): rat NOAEL x RDDR = 0.04 mg/L x 0.143 = 

0.00572 mg/L.

HED (occupational): HEC x conversion factor for breathing rate in L/hr-kg bw x activity factor 

specific to the exposure scenario x absorption ratio x human daily exposure duration in hours = 

0.00429 mg/L x 11.8 L/hr-kg bw x 0.6, 1.2, and 2.1 for low, medium, and high, respectively x 1 

x 8 = 0.244, 0.491, 0.853 mg/kg/day for low, medium, and high respectively.

 

HED (residential handler): HEC x conversion factor for breathing rate in L/hr-kg bw x activity 

factor specific to the exposure scenario x absorption ratio x human daily exposure duration in 

hours = 0.00429 mg/L x 11.8 L/hr-kg bw x 1.2 x 1 x 8 = 0.164 mg/kg/day for low, medium, and 

high respectively.

Fluensulfone: HECs and HEDs: 90-day Subchronic Inhalation Study in Rats (MRID 49067003)

Short and 

intermediateterm 

Inhalation

Inhalation NOAEL = not 

identified

UFA= 3X

UFH =10X

UFL=10X

Residential and 

Occupational LOC 

for MOE = 300

Inhalation LOAEL = 0.04 

mg/L based on weight loss 

in males, prolonged 

prothrombin time in 

females, decreased thymus 

weight in males, 

histopathological changes 

in the epiglottis in both 

sexes, and 

histopathological changes 

in the nasal cavity of males.

Exposure Scenario HECs HEDs

Occupational 

Handler 

HECs and 

HEDs

Ventilation rate=8.3 L/min

0.00429 mg/L

0.244 mg/kg/day

Ventilation rate=16.7 L/min 0.491 mg/kg/day

Ventilation rate=29 L/min 0.853 mg/kg/day

Residential 

HECs and 

HEDs

Handler 0.00572 mg/L 0.164 mg/kg/day

Uncertainty Factor: 300x (3x interspecies extrapolation, 10x intraspecies variability, 10x 

extrapolation from LOAEL to NOAEL)
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Comments about Study/Endpoint/Uncertainty Factors: The 90-day inhalation toxicity study 

in rats was chosen because it is the only study available of the appropriate route and duration. An 

additional uncertainty factor of 10x for the extrapolation from a LOAEL to a NOAEL was 

applied. The interspecies uncertainty factor was reduced to 3x because of adjustment for species 

differences in pharmacokinetics.
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Appendix B. Physical/Chemical Properties

Table C-1. Physicochemical Properties of Technical-Grade Fluensulfone

Parameter Value Reference

Molecular weight (g/mole) 291.7 EPA/PMRA joint review of 

fluensulfone technical-grade 

active ingredient. 

Monograph Volume 3, Parts 

B1 and B2. B. Kitchens. 

December 2013.

Melting point/range (°C) 34.8 ± 0.5

pH 5.11 (1% solution at 21°C)

Density (g/cm3) 1.876

Solubility (g/L at 20°C) Water 0.5453

Acetone 350.49

Dichloromethane 306.14

Ethyl acetate 350.76

n-Heptane 19.01

Methanol 359.29

n-Octanol 90.42

Xylene 356.18

Vapor pressure at 25°C (Pa) 3.0x10-2

Dissociation constant (pKa) No acidic or basic functional groups

Octanol/water partition coefficient Log(KOW) 2.2
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Appendix C. 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 

PHED 1.1 and the AHETF database are (1) subject to ethics review pursuant to 40 CFR 26, (2) 

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

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

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

website2.

 

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

http://www.epa.gov/pesticides/science/post-app-exposure-data.html
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Appendix D. Summary of Submitted Studies

MRID No. Citation

48574731 Marin, J. (2010) Method Validation of an Analytical Method for the Determination of MCW-2 and its 

Metabolites in Plant Matrices. Project Number: R/23334/OCR, 1977W. Unpublished study prepared 

by PTRL West, Inc. 138p.

49700504 Bernard, F. (2015) MCW2: Percutaneous Penetration of [14C]-MCW-2 formulated as MCW-2 480 EC 

Through Rate and Human Skin Membranes (in vitro). Project Number R-31433. Unpublished study 

prepared by Harlan Laboratories Ltd. Switzerland. 117p.