### F l u e n su l fo n e Human H ea l th Ri s k A ssess ment DP No. D424168



### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON , D

. C. 20460



### MEM ORAND U M

Dat e: 6 Januar y 20 1" OFF I CE OF CH EM ICA L SAFETY AND PO LLUTI O N PRE VEN T ION



### SU B JECT : Flu e n sulfo ne: Human H ea lth Risk Assessment of the Proposed Use on T urf.

P C Code: 0504 10 DP B a r code: D424 I 68 Dec i sion No.: 496677 R egistra t ion No.: 53883-GL T P

e t i ti o n No.: NA Regulat ory Action : Sect i on 3 Ri s k Asse ss ment Type: Single Chemical Aggregate Case No.: No n e TXR No.: NA CA S No.: 318290-98

- 1 MRJD No.: 49 5 52503 40 CFR: 180 .680



## F RO M: 

## Michael A. 

## Doh erty, Ph .D., Se nior Chemist 

# Jb.dJ**~** Jaime D ' Agostino

, Ph.D.

, To xicolog i s t

## ?-~~? 

# t2 ;/
Za ida F i g u eroa , D rPH
, Indu stria l H ygierus_!,.

. /

## G~1 

# /\-

- Risk Assessment Branc h 

### II (RA B 

### II ) : ',,-
H ea lth Effects Division**(H ED~**  

### 7:09Pi \



### THROUGH : C h ristina Swartz

, C hi ef

# ~**~** RAB II 

### HED ( 75 09P)



### TO: Rit a Kumar/Marianne Lewis/Meredith Laws I nv e rt e br a te and Vertebrate Branch 3 

### R eg i stration Di vis i o n (7505 P )

Pa ge 1of46

### Fluensulfone Human H ea lth Risk Assessment DP No. D424168

1.0 EXEC U T

I VE SUMMARY

·· ············ ·· ········ ·· ········· ······· ········ ·· ······················································ ·· ··· 3 2.0 HED RECOMME DATIONS

................... . ......... ... ........ ...... ....... ... .......... . .... ..... .... ......................... 4 2.1 Data D eficiencies/Conditions of Regi st ration

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

...................................................................................... . .......... .. . 4 2.3 Label Recommendation s

..................................................................................... . .......... . .. . . 5 3 .0 I NT ROD UCTIO

.. .......... ... ................................ .. ........ . ............. .. .................... ..... ........ . .... . ..... . .... 5 3 .1 Chemical Identity

... . ....................... . . .... ..... . ......... ... ........... .. ......... .. ......... .... ................... .. . . . 5 3.2 Physical/Chemical Characte ri s tics

.. ........ ........ ........ . .................... . .. .. .............................. .. .. 5 3 .3 Pesticide Use P a tt e rn

........................................................................................................... 6 3.4 A nticip ated Exposure Pathway s

... .. ......... .. ...................... .. .......... . ............. . .. . ........ .. ........... 6 3.5 Cons id eration of Environmental Justi ce

......... .. ........ .. ...................... .. ......... . ...... . ............... 7 4.0 HA ZARD CHARACTERIZATIO AND Dos E -R ES PO SE ASSESSME T

.......... . ............ . .... . .............. 7 4.1 Tox i cology Studies Avai lable for Ana l ysis

........... .. ................................ . .......................... 7 4.2 Absorption, Di stri bution

, Metabolism

, & 

### Eliminat i o n ( ADME )

..... ......... . ...................... . .. 8 4.2.1 Dermal Absorption

............................... ........................ ............ . ......... . ............... . .... 9 4.3 Toxi colo g ical Effects

....... ....... ... ........ ........ . .......... . ........... .. ........... ..... ..... .. ....................... 10 4.4 Safety Factor for Infant s and C hildren ( FQP A Safety Fac tor )

.. ..... ......... .. ........... .. ......... . 1 2 4.4.1 Co mp l eteness of the Toxico l ogy Database

.. . ........................................................ 1 2 4.4.2 Evidence of Ne urotoxici ty

.... ....... .... ..................... .... ............................................ 1 2 4.4.3 Evidenc e of Sensit i vity / Susceptib ili ty in the D eve l o ping or Young Animal

....... 1 2 4.4.4 R es idual Uncertainty in the Exposure Databa se

.. . ........... . ................... . ................ 1 3 4

. 5 Toxicity Endpoint and Point of Departure Selections

.. ... ..... ....... .. ................................... 1 3 4.5.1 Dose-R es ponse Assessment..

...... . .......... . ... .. ... .. . ........ . ............ .. ......... .... .. ............. 1 3 4 .5.2 R eco mm e ndati o n for Co mbinin g R outes of Exposures for Ri s k Assessment..

.... 15 4. 5.3 Cancer Classification and Ri s k Assessment R ecomme ndation

............................ 15 4 .5 .4 Summary of P oints of Departure and T oxicity E ndp oints Use d in 

### Human Risk Assessment.

. ... ........ ..... ..... . . ..... ......... ... ....... ....................... ......... ..... ........ .. .................. 1 6 5.0 DI ETARY EXPOSURE AND RI S K ASSESSMENT

.. ............. .. ........ . ... . .......... . .................................. 1 9 6.0 RE SIDE TIAL (No 

### -0 CCUPATIO AL) EXPOSURE / RI SK CHARACTERIZATIO

. . .................. .. .... 20 6.1 R es idential By s tander Post-Applicati o n Inhal a tion Ex posur e

... . .... ...... ........ . .......... .. . . ... . . 2 1 6.2 Spray Drift

................................................ . .......... . ............ .. ....... . .. .. .................................. 2 1 7.0 AGGREGATE EXPOS U RE/RISK CHARACTERI Z ATIO

........................... ..... .. ........... . .. . .......... .... .. 22 8.0 C UMULA TIV E EXPOSURE/RISK CH ARAC T E

RI ZAT IO

.. ....... ............................................... ....... 22 9.0 OC CU P ATIONAL EXPOSUR E/ RISK CHARACTER IZ ATION

........... .. ...... ...... .................................. 23 9 .1 Sho rt- and Int ermediate-Term Handler Risk

............................. .... .......... . ...... .. ....... ......... 23 9.2 Short- and I ntermediat e- Tenn Post-Applicat i on Risk

...................................... . ........... . .. . 24 I 0.0 REFERE CES

...................................................................................................................... 25 APPENDIX A. TOXICOLOGY PROFILE AN D EXECUTIVE SUMMARIES

........ . ...... ........ ..... ........ ........ 27 A

. I Tox icolo gy Dat a Requir eme nt s

... ..... ....... ...... ... ........ .. ..... .. .......... . ................. .... .............. . 27 A

. 2Toxicity Profil es

... .... ......................................................... .. ......... .. ................................... 28 A.3 Ha za rd I dentification and Endpoint Se l e ction

.. ........... .... .. .... ...... .................... . .. .. ....... . .. . . 39 APPE 1 

### DI X B. PH YS I CA L/ CHEMICAL P ROPERTI E S

..................................... . ..................................... 44 APPENDIX C. R EV I EW OF H UMAN RE SEARC H

....... . ...... .. ........ .................... ...................... . ........ .. ... 45 APPENDIX D

. SUMMARY OF SUBMITTED STUDI E S

................................... .. ........ ..... ........... .. .......... 46

Pa ge 2of46

### Fluensulfone Human Health Risk Assessment DP No. D424168

Page 3 of 46 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 residentia l 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 veget ables crop groups (Group 9 and Group 8

- 10, respectively).

Two use patterns are proposed. The first is for use on golf courses, spor ts 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 multipl e studies and species

. An acute n eurotoxicity 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 n ot quantitative, increased susceptibility of infants and children to the effects of fluensulfone was observed in the two

generation reproduction study in rats , wherein pu p loss was observed at a dose that resulted in body weight effects in the dams

. No evi dence 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

nas al 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 10 X 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 3 X ; however, a n additional 10 X factor is required because a no

- observed

adverse

- 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 reduc ed the required Food Quality Protection Act Safety Factor (FQPA SF) from 10 X to 1 X

.

### Fluensulfone Human Health Risk Assessment DP No. D424168

Page 4 of 46 In conducting this risk assessment, HED has relied on the dietary exposure estimates detailed in the most recent risk assessment for fluensulfone (D4 18204

, 10 June 2014, M. Doherty ). D ietary (food and water) risk estimates for fluensulfone are not of concern for both acute a nd 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., post

application) . Routes of exposure ar e dermal and inhalation for handlers

, dermal for post

application 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
exposur es 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 treatment s (MOE=140 for rescue application and MOE=280 for s tandard 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, t here 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 re lies 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

Page 5 of 46 There are no tolerance considerations for this action.

2.3 Label Recommendations

At the maximum single application rate, t here 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 th ose 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 techn ical

- grade material has a log K OW 

### 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 exposur e 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 su lfonic acids, these two metabolites are expected to be much more hydrophilic than the parent compound and also less volatile.

### Fluensulfone Human Health Risk Assessment DP No. D424168

Page 6 of 46 3.3 Pesticide Use Pattern

The proposed end

- use (EP) granular product MCW2 1.5% ( EPA Registration No. 53883

- GLT and alternate br and 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 C ourses, S ports Field s, Commercial Areas, Sod Farms a nd Residential Lawns

. Applic. Timing, Ty pe, 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 lim it 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 flue nsulfone

related residues from crops grown in treated soil and from migration of residues to surface and/or
g round water sources of drinking water

. From crops, the exposure will be to metabolites of

### Fluensulfone Human Health Risk Assessment DP No. D424168

Page 7 of 46 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 g round 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 appl ication, 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 L ow

- 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 acco rding 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 patter ns 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 depart ure 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

Page 8 of 46 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 s tudy 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 (t max 

### ) 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 (t max 

### ) was longer at 2

- 8 hours at the low dose and 48 hours at the high dose. The difference in whole blood and plasma
t m ax 

### 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 gastrointest inal 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 sulfi nic acid

### Fluensulfone Human Health Risk Assessment DP No. D424168

Page 9 of 46 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 s tudies), 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 Urin e Following Dosing with 14 C

- 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 vi tr o dermal absorption study with the EC formulation using rat and human skin (MRID 49700504) because they felt that a number of the conditions in t he 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 org anic

- solvent

- based receptor fluid. In contrast, the newly submitted in vitro stud y 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 condi tions. 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 new ly 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 fr om 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 ab sorbable) was found at 24 hrs post

- exposure using an application of 0.0953 mg/cm 2 

### ; (2) I n 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;

### Fluensulfone Human Health Risk Assessment DP No. D424168

Page 10 of 46 (4) Based on this ratio, a DAF for humans may be calculated using in vitro huma n 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 low est 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, DT 50 

### = 6

- 9 days) compared to plasma (DT 50 

### = 16

- 17 hours).

Other ef fects 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 decr eased 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 alb umin/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 bron chiolization (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 (mononucle ar 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 incidenc e/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.

### Fluensulfone Human Health Risk Assessment DP No. D424168

Page 11 of 46 Following a single oral administration, rats exhibited decreased locomotor ac tivity, 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 de rmal 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

- nat al 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 carcinom as. 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 ade nomas 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 s ulfone; 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 S 9 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 tec hnical

- 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 fo rmulation 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 bot h 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 LD 50 

### est imates

. Furthermore in the BSA and TSA acute toxicity studies, body weights of all animals were within

### Fluensulfone Human Health Risk Assessment DP No. D424168

Page 12 of 46 the normal range, no macroscopic findings were recorded at necropsy, and no clinical signs were observed except for three animals which exhibited slightl y 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 databa ses 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 i s 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 observe d 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 pre

and postnatal susceptibility

. Acceptable/guideline developmental toxicity studies in rats and rabbits and a reproduction study in rats, as well as acute and subchronic neuro toxicity 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 quantitat ive 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

### Fluensulfone Human Health Risk Assessment DP No. D424168

Page 13 of 46 reproduction study in rats

. Maternal effects observed in that study were decreased body weight and body weight gain; at the same dose, ef fects 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 uncertaintie s 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 reprodu ction 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 t hat 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 spont aneous 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

### Fluensulfone Human Health Risk Assessment DP No. D424168

Page 14 of 46 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 stu dy 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 male s and increased platelets in females at the LOAEL of 16 mg/kg/day

. The 90

- day dog study was considered co

critical 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 stud y, 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 do g 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 sh ort

- term exposure because the effects (hematology and clinical chemistry parameters) were seen starting at Week 6 in both studies and the re 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, includin g 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
tec hnical 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 representati ve 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 deriv e 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 the re 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

### Fluensulfone Human Health Risk Assessment DP No. D424168

Page 15 of 46 this study, decreased body weight, decreased thymus weight, and histopathological changes in the nasal cavity of males; prolong ed 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 inhalatio n 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 concentr ations (HECs) based on the inhalation toxicity N OAEL 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 dev iation [  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 adjus t 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) wa s estimat ed 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 protect ive 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, endpoi nts 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 sourc es (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 ar e 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 Recomme ndation 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

### Fluensulfone Human Health Risk Assessment DP No. D424168

Page 16 of 46 were not observed in the rat chronic toxicity/carcinogenicity study in either sex or in male mice

. There was no eviden ce 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 flue nsulfone 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) flu ensulfone 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 assessme nt (≤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 Non

Occupational 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 UF A = 10x

UF H =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) UF A = 10x

UF H =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 i n 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.

### Fluensulfone Human Health Risk Assessment DP No. D424168

Page 17 of 46 Table 4.5.4.1

. Summary of Toxicological Doses and Endpoints for use in Fluensulfone Dietary and Non

Occupational 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) UF A = 10x

UF H =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 LO AEL = 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 Short

an d Intermediate

Term (1

- 30 days and 1

- 6 months) NOAEL= 3.1

mg/kg/day (chronic dog)

DAF = 9.5% UF A =10x

UF H =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 ba sed 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 Intermediate

Term (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 UF A =3x

UF H =10x UF L =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

.

### Fluensulfone Human Health Risk Assessment DP No. D424168

Page 18 of 46 Table 4.5.4.1

. Summary of Toxicological Doses and Endpoints for use in Fluensulfone Dietary and Non

Occupational 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

. UF A = extrapolation from anim al to human (interspecies)

. UF H = potential variation in sensitivity among members of the human population (intraspecies)

. UF L = use of a LOAEL to extrapolate a NOAEL

. FQPA SF = FQPA Safety Factor

. PAD = population adjusted dose (a = acute, c = chronic)

. R fD = 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 Short

and Intermediate

Term (1

- 30 days and 1

- 6 months) NOAEL= 3.1 mg/kg/day

(chronic dog)

DAF = 9.5% UF A =10x UF H =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, incr eased TSH, and pigmented Kupffer cells in both sexes.

### Fluensulfone Human Health Risk Assessment DP No. D424168

Page 19 of 46 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 Intermediate

Term (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 UF A =3x UF H =10x UF L =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

. UF A = extrapolation from animal to human (interspecies)

. UF H = potential variation in sensitivity among members of the human population (intraspecies)

. UF L = use of a LOAEL to extrapolate a N OAEL

. MOE = margin of exposure

. LOC = level of concern

. DAF = dermal absorption factor



### 5.0 Dietary Exposure and Risk Assessment D418204, 10 June 2014, M. Doher ty


### The dietary exposure and risk estimates are based on limit

- of

- quantitation residues of flue nsulfone 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 201 4

, 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. Therefo re, 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 (95 th Percentile ) Chronic Cancer Exposure, mg/kg/day Risk, %

aPAD Exposure,

mg/kg/day Risk, %

cPAD Total US Population 0.00425 2 2.4 0.00111 1 3.7 See Chronic All Infants 0.0132 7 6 7.4 0.00284 5 9.5 Children 1

- 2 0.0065 4 3 3.6 0.00161 1 5.4 Children 3

- 5 0.0053 40 3.0 0.00136 0 4. 5 Children 6

- 12 0.004 084 2.3 0.0009 79 3.3 Youth 13

- 19 0.00354 8 2.0 0.00081 1 2.7 Adults 20

- 49 0.004176 2.3 0.00110 7 3.7 Adults 50

- 99 0.00375 4 2.1 0.00109 5 3. 6 Female 13

- 49 0.00424 5 2.4 0.00110 3 3.7 Bold entries are maximum exposure and risk estimates.

### Fluensulfone Human Health Risk Assessment DP No. D424168

Page 20 of 46 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 select ed 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 . T he d ermal 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 or al 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 fo r 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 c hildren

. 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 int o 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 Rate 1 Area

Treated or Amount Handled Daily 2 Dermal Inhalation

Dose (mg/kg/day) 3 MOE 4 Dose (mg/kg/day) 5 MOE 6

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/ft 2 1,200 ft 2 0.021 150 0.000024 6,800

Granules

– Shaker can (surrogate granules with cup) 0.11 0.13 0.00004132 lb ai/ft 2 100 ft 2 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 ft 2 )=0.00004132 lb ai/ft 2

. 2 Based on HED’s 2012 Residential SOPs ( http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/standard

operating

- procedures

- residential

- pesticide ). 3 Dermal Dose = Dermal Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or ft 2 ) × Dermal Absorption Factor (9.5%) x Area Treated (A or ft 2 /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 ft 2 ) × Area Treated (A /day or ft 2 /day) ÷ BW ( 80 kg). 6 Inhalation MOE = Inhalation HED (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). LOC=300.

### Fluensulfone Human Health Risk Assessment DP No. D424168

Page 21 of 46 Table 6.0.2

. Residential Post

- application Non

- cancer Exposure and Risk Estimates for Fluensulfone.

Lifestage Post

- application Exposure Scenario Application Rate 1 Dose

(mg/kg/day) 2 MOEs 3 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

- pesticide

risks/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

- A pplication 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

Page 22 of 46 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: Conside ration 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 risk s 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 aggreg ate 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 o f 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 backgr ound 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 aggreg ate 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 MOE 2

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. Lif estage Exposure Scenario Residential 1 Dietary MOE 2 Aggregate MOE 3
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

Page 23 of 46 Unlike other pesticides for which EPA has followed a cumulative risk approach based on a

co mmon 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 effec ts 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 potent ial. 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 A dvisory Council for Exposure (ExpoSAC) were used for parameters such as b ody weight and amount handled.

With three exceptions, a ll occupational handler scenarios for the proposed uses resulted in MOEs that are not of concern at baseline personal protecti ve 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 thro ugh 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

. Rate 2 Area Treated Daily 3 Dermal Inhalation

Mitigation Level Mitigation

Level Dose ( m/k/d ) 4 MOE 5 (LOC=100) Dose

(m/k/d ) 6 MOE 7 (LOC=300)

Mixer/Loader

Tractor

drawn spreader Golf course 8.4 [Baseline] 1.7 [Baseline] 1.8 lb ai/A 40 A 0.000718 4,300 0.00153 560

Tractor

drawn 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

Page 24 of 46 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

. Rate 2 Area Treated Daily 3 Dermal Inhalation

Mitigation Level Mitigation

Level Dose ( m/k/d ) 4 MOE 5 (LOC=100) Dose

(m/k/d ) 6 MOE 7 (LOC=300) (Rescue Treatment) 8.4 [Baseline] 0.34 [PF5 respirator] 0.00287 1,100 0.00122 700

Applicator

Tractor

drawn spreader Golf course 9.9 [Baseline] 1.2 [Baseline] 1.8 lb ai/A 40 A 0.000847 3,700 0.00108 790

Tractor

drawn 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 ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × 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 ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × 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 vol atilization 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

- 068 7

- 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.regulati ons.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 a ddition, 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 granul ar formulation

. The predicted D ay

- 0 residue value of 0.0022 ug/cm 2 

### 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/cm 2 

### adjusted 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 ri sk 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 (cm 2 /hr) TTR 1 Dermal Dose (mg/kg/day) 2 MOE 3

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 (t 0 ) = 0.0022 ug/cm 2 at 3.6 lb ai/A or 0.0011 ug/cm 2 at 1.8 lb ai/A from chemical

- specific study ( EPA MRID No. 49552503 ). 2. Daily Dermal Dose = [ TTR (μg/cm 2 ) × 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 no t a concern on D ay 0 (following application) for al l 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 Far ms 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

Page 27 of 46 A ppendix 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 protocol s 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 Aberratio ns 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 ye s

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 LD 50 = 671 III 870.1100 Acute oral

- rat 48574746 LD 50 > 300 mg/kg but < 2000 mg/kg III

870.1200 Acute dermal

- rat 48575035 LD 50 > 2000 mg/kg III 870.1300 Acute inhalation

- rat 48574748 LC 50 > 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 LD 50 > 2000 mg/kg III 870.1100 Acute oral

– rat, 1.5GR 49488608 LD 50 > 2000 mg/kg III 870.1200 Acute dermal

– rat , 15GR 49488604 LD 50 > 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 LD 50 > 2000 mg/kg III M e S Acute oral

- rat 48574787 LD 50 > 300 mg/kg but < 2000 mg/kg II

BSA Acute oral

- rat 48574792 LC 50 > 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

di etary

- 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

Page 29 of 46 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 e piglottis 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) observ ed 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 reproduction

rat 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=1 22.0, 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 fem ales; 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 ac tivation (

- 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 pres ence 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 p ositive 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).

Acceptabl e/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, 8 00, 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
μ g/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

neurotoxicity

rat 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

neurotoxicity

rat 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 ( [ thiazole

14 C] MCW

- 2 and [ butene

14 C] 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 posi tions; 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 probab ly reacts with glutathione to displace butene sulfinic acid, the major urinary metabolite

. 870.7485 2011

-

Metabolism and excretion, repeat oral

- rat ( [ butene

14 C] 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 kidn ey 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

-

p harmacokineti mg/kg/day =

5 and 500 48574741 The absorption of fluensulfone

- derived 14 C was rapid at both doses

. The kinetic

### Fluensulfone Human Health Risk Assessment DP No. D424168

Page 36 of 46 Table A.2.4 Toxicity Profile

- Fluensulfone

Guideline Study Type Doses Tested/Study Classification MRID Results

cs, single oral

rat ( [ thiazole

14 C] MCW

- 2 and [ butene

14 C] 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 co valent linkage to the thiazole group and displaces butene sulfinic acid. 870.7485 2011

-

toxicokinetic study

- rat ( [ thiazole

14 C] MCW

- 2 and [ butene

14 C] 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 C max for both sexes

. As predicted by the pharmacokinetic study, radioactivity from
t he thiazole label was slowly eliminated from red blood cells consistent with the derivatization of the hemoglobin cysteine thiol

. The ratio of residues at the C max compared to the DT 90 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 C max compared to DT 90 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 [ 14 C] fluensulfone to 1

- and 2

- carbon fragments with reincorporation in natural products (e.g

. protein, fa tty acids) with long turnover
rates. 870.7600 2011 Dermal

penetration in vivo

– male rat Mg/cm 2 = 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, re spectively

. 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

### Fluensulfone Human Health Risk Assessment DP No. D424168

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 A t 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 stud y 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 Alanine

aminotransferas 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 fluensulfone

treated 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 v itro 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/cm 2 =

0.1 and 4.8 480 EC formulation. 48574950 The total absorption was calculated to be 92.1 1 % and 81. 26 % (low and high dose), and 62.46% and 4.65% (low and high dose)

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Page 38 of 46 Table A.2.4 Toxicity Profile

- Fluensulfone

Guideline Study Type Doses Tested/Study Classification MRID Results

absorption ( MCW

- 2 [Ring

- U

14 C] ) Acceptable/non g uideline for rat and human skin membranes, respectively

. Based on percentages absorbed, the ratio between hum an 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

N o treatment

- related effects were observed in this study up to the highest dose tested. Special Study 2015

-

comparative in vitro dermal absorption mg/cm 2 =

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 = = 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.

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

Chronic RfD = = 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 NO AEL 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 extrap olation, 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 ch ronic 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

s tudy 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 emulsifiable

concentrate (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/cm 2 

### ; (2) I n 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 absor ption (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 (do g) 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 observ ed 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 interspec ies 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 con ducted 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 penetrati ons 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 v alue 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 pote ntial systemic exposure to fluensulfone from the 480 EC formulation

. 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

- 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 the re was lack of progression in the toxicity database with longer exposure (subchroni c 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

.

### Fluensulfone Human Health Risk Assessment DP No. D424168

Page 42 of 46 MRID No: 4 9 067003

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): H EC 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, respecti vely 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 intermediate

term Inhal ation Inhalation NOAEL = not

identified UF A = 3X UF H =10X UF L =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)

### Fluensulfone Human Health Risk Assessment DP No. D424168

Page 43 of 46 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 i n pharmacokinetics.

### Fluensulfone Human Health Risk Assessment DP No. D424168

Page 44 of 46 A ppendix 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/cm 3 ) 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 (pK a ) No acidic or basic functional groups Octanol/water partition coefficient Log(K OW ) 2.2

### Fluensulfone Human Health Risk Assessment DP No. D424168

Page 45 of 46 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) sub ject 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 s ources, as well as guidance on their use, can be found at the Agency website 2



### .

2 http://www.epa.gov/pesticides/science/handler

- exposure

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

- app

- exposure

- data.html

### Fluensulfone Human Health Risk Assessment DP No. D424168

Page 46 of 46 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 [ 14 C]

- MCW

- 2 formulated as MCW

- 2 480 EC

Through Rate and Human Skin Membranes ( in vitr o ). Project Number R

- 31433. Unpublished study prepared by Harlan Laboratories Ltd. Switzerland. 117p.