UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON

, D

. C

. 20 460

MEMORANDUM

D ate : 06 / 03 / 2 01 5 OFFICE OF CHEMICAL SAFETY AND POLLUT I O N PREVENTION

SUBJECT: Hexytb i azox. Human Health Risk Assessme nt to Support New Uses on Wh ea t and P e pper / Eggp l a nt S ub group 8-1 OB.

PC Code: 128849 DP B a rcode: D4 23 491

, 0423145

Dec i sion No.: 4956 1 6 & 495311 Reg i strat ion No.: 10163-251

Pet iti on No.: 4F83 J 5 Regu l atory Action: Sec ti on 3

R egist r ation

Ri s k Assessment Type: S in g l e C h e mical Case No.: N I A Aim.re ga t e TXRNo. : NA CAS No

. : 7 8587-05

- 0

MRID No.: NA 40 CFR: 40 CFR 180.448

FROM: K a t e l ynnK in g, Ri skAssessor

# ~!\)·**A.** 

# (o(Cf 

# (/S

A l exan dra LaMay, Biologist c (

·-

### .·v?G**~.....,,.... ._** **)** Linda Taylor

, Tox i cologist**r~** Ri sk Assess m e nt Branch VI I
H ealth Effect s Di v i s i o n (7509P)

THROUGH: Michael Met zge r , C hi ef ( /

# ~ /)

# ~ 

# 1

Ri s k Assessment Branch V 

### N II

# ~**~** ). · 

# V' Q

Health Effects Divi s ion ( 750 9 P )

TO: T awanda M a i g nan , Risk Manage r 09
Andrea Conrat h

, Ri s k Manager Re v i ewer Ri sk Inte gra ti o n , Minor Use & E m e r gency R es ponse Branch

R eg i strat ion Di vis ion (7505 P )

Page I of 33H exythiazox Hum an H ea lth R isk Assess ment 0423491

, 04 23 1 45

Table of Co ntent s

1.0 Exec uti ve Summary

.... ... ...... . ........ . ................................... . ....... .. . ... . ...... . ... . .. ......... 4
2.0 HED R ecom mendations

... ..... ...... ... ...... .. ....... ... .......................................... .. ........ . 5
2.1 Data D efic i e ncie s

. ...... . ..... .. ..... .... . ... . .... . .. .. ....... ..... ... ...... . ........................ .. ......... . 5
2.2 Tolerance Considerations

.......................... . ................. .. ................ .. .................. 5
2

. 2.l E nforcement Analytical Method

............................. .. .... .......... .. .. .................. 5
2 .2.2 Recommended Tolerance s

.... .......... ....................... .................. .. ... ................. 6
2.2.3 Revisions to Petitioned-For Tolerances

...... ...... .. .......... . ...... ..... ..... ............. .. 6
None

. ....... . ..................................................... . .......... .. ...... ... ..... ....... .................. .............. 6
2.2.4 Int e rnational Harmonization

.......................... .. .. .. .. .. ......... .. ......... . ............. ... 6
2.3 Labe l Recommendations

..... ... ...... ... ....... ..................... .... ... ........ ..... ..... .......... .... 7
2.3.1 Recommendations from Residue Reviews

.. .. .. .. .. .... ... .............. ..... .... .... . ....... 7
2

. 3

. 2 Recommendations from Occupational Assessment..

................ .. ..... ..... ....... 7
2.3.3 Recommendations from Residential Assessment..

... ...... ..... ............. .. ..... .. . .. 7
3.0 Introduction

.............................................................. .. ..... .... ........ .. ....................... .. 7
3.1 C hemical Identity

..................................... .. .......... .. .. .. .. .. .. . ... ..... ............ ...... . .. .. .. 7
3.2 Physical/Chemical Characteristics

................... ... ...... ... .................................... 8
3.3 Pesticide Use Pattern

............. ...... ... ...... .. ....... .. ...... .. .. .. .. . ... ..... ..... ......... .. .. . .. .. .. .. . 9
3.5 Co nsideration of Environmental Justice

.. .. ........................................... .. ......... 9
4

. 0 Hazard C haracterization and Dose-Response Assessment..

. . .... ... . ................ .. 10
4.1 Hazard Characterization

......... . ........ .. .. .. . ................ ..... . ................. . ..... ...... ..... 10
4.2 Hazard Profile

... .. ......... .. ... ...... .. ........ . .. .. ....... .. ...... . .............. .. ..... .. .. . .... .. .. . ... .... 11
4.3 Dose-Response Assessment / Endpoint Se lection

.... .................. ................... ... 11
4.4 FQPA Considerations

.... .. .............................................................. . .... .. ...... ..... 1 2
4.5 Summary of Toxicological Doses and E ndpoints for Use in Human Ri sk
Assessments and Levels

... ..... ...... .. ....... .. .................... . ... .. ..... ...... . ...... .. .. .. ..... .............. 1 2
5.0 Dietary Ex po s ure/Ri sk C haracterization

.... .. ...... .. ........ ... ...... . ................ ... ....... 14
5.1 Residue Chemistry Summary

. .. .. .. .. .... . .. .. .. ............. .... ... .......... .. . .. ......... .... ..... 1 4
5

. 2 Drinking Water Re si due Profile

.. ...... ........... ..................... ...... .... ...... .. ....... .... 16
5.3 Dietary Expos ure and Risk

...................... .. ............. . ......... .. ............. ..... .... ... .. . 1 6
5.4 A nticipated Residue and Percent Crop Treated (%CT) Information

.. ..... . 1 7
6.0 Re si dential and Other Non-Occupational Exposures/Risks

..... . .... .. .............. .. 18
6.1 Residential Handler Expos ure and Ri s k

................... .. ........ .. ......... .. .............. 18

6

. 2 Residential Post-application Exposure

. ... .......... . ....... .. .............. .. .......... ........ . 1 8
6.3 Other

. ................ ..... ............ .... . ... . .... . ... ... .. ...... .. ..................... . ... . .. ............ ...... .. . . 20
7.0 Aggregate Ri s k Assessments and Ri s k Characterization

........................ .. ....... 20
7.1 Ac ute Aggregate Risk

........................................................... .. ......... . ................ 20
7.2 Short- and Intermediate-Term Aggregate Ri s ks

.. .... ... ....................... .. ........ 2 1
7.3 Long-Term (C hronic) Aggregate Risk

.. . ............ . ... ........................... ... .... ...... 2 1
8.0 Cumulative Ri s k Characterization/Asses s ment

..................................... .. ......... 2 1
9.0 Occupational Ex po s ure s and Risks

.................................................. . ........ .. ...... . 22
9.1 Occupational Handler Risk

........ . ........ .. .. .. .. .. .. .. .. ....................... .. ...... ............ . 22 9.2 Occupationa l Po s t Application Risk

..................................................... .. ........ 22
10.0 Human S tudie s

................................... . ... .. .. .. .. ....... ... ..... .. ......... .. ...... . .. .. ...... .. . .. .... 24

A pp e ndix A

. Tox icol ogy Assessment..

. ... ...... ... ...... .... ..... . ....... . .. .. ...... ... .... .. . ... ..... ...... ..... 25 Appe ndi x B: Tox ic o l ogy Data Requir e ment s .

................. ..... . ........................................... 29

P age 2of33

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 3 of 33 Appendix C: Field Trial Residue Data

................................ ................................ .............. 30 Appendix D: Maximum Residue Limits (MRL)

................................ .............................. 32 Appendix E: OECD Calculator MRL Output

................................ ................................ ... 33

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 4 of 33 1.0 Executive Summary

Hexythiazox, trans

- 5

- (4

- chlorophenyl)

- N

- cyclohexyl

- 4

- methyl

- 2

- oxothiazolidine

- 3

- carboxamide, is an ovicide/miticide used to control spotted spider mites on a variety of

crops and outdoor residential settings . Hexythiazox is a contact pesticide which achieves control of eggs or immature mites via direct contact or contact with treated surfaces.

Gowan Company has submitted pepper/eggplant subgroup 8

- 10B and wheat data t o support the following requests:

 Proposed tolerances for wheat commodities

 Registration on pepper/eggplant subgroup 8

- 10B o f a new formulation

The toxicity database for hexythiazox is complete. Hexythiazox is associated with toxicity of the liver and adrenals following sub

- chronic and chronic exposure to dogs, rats and mice, with the dog bei ng the most sensitive species. The prenatal developmental
studies in rabbits and rats and the two

- generation reproduction study in rats showed no
indication of incr eased susceptibility to in utero and/or postnatal exposure to hexythiazox. Reproductive toxicity was not observed. There is no concern for neurotoxicity following exposure to hexythiazox. The toxicology database for hexythiazox does not show any evidence of treatment

- related effects on the immune system. Hexythiazox is classified as “likely to be carcinogenic to humans”; however,

s ince the effects seen in the study that serves as the basis for the chronic reference dose (RfD) occurred at doses substantially below the lowest dose that induced tumors, HED concluded that quantification of risk using a non

- linear approach; i.e., RfD, for hexythiazox will adequately account for all chronic toxicity, including carcinogenicity,
that could result from exposure to hexythiazox.

No acute risk is expected since no hazard was identified in any toxicity study for this duration of exposure. Chronic risk is regulated based on effects seen in the adrenal glands in a one

- year dog feeding stud y. Short

- term and intermediate

- term incidental oral and inhalation risks are regulated based on decreased pup body weight during lactation and delays in hair growth and/or eye opening, decreased parental body

- weight gain and increased liver, kidney, and a drenal weights in the 2

- generation reproduction study in the
rat. For the short

- and intermediate

- term dermal risk assessment, no quantification of risk is required since no dermal hazard has been identified for hexythiazox. For the short

- term and intermed iate

- term dermal risk assessments, no quantification of risk is required
because the dermal equivalent dose , after applying the estimated dermal absorption factor
of 2% to the oral reproduction study NOAEL of 30 mg/kg/day, is 1500 mg/kg/day, which is great er than the limit dose.

An acute endpoint was not selected for hexythiazox; therefore, the Agency conducted only a chronic dietary (food and drinking water) exposure and risk assessment. The chronic dietary risk assessment used tolerance level residues

, assumed 100% crop treated

, included DEEM default processing factors, and modeled water values . This unrefined
assessment resulted in estimated chronic dietar y (food and water) risks of 17 % of the chronic population adjusted dose (cPAD) for the U.S. popula tion an d 82 % of the cPAD

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 5 of 33 for children 1

– 2 years of age, the most highly exposed population subgroup.

Since there are no acute endpoints of concern, an acute aggregate risk assessment was not
conducted. HED has conducted short

- term, intermediate

- term

, and lon g

- term (chronic) aggregate (food, drinking water and residential ) risk assessments for hexythiazox. Short

and intermediate

- ter m aggregate MOEs ranged from 1,290 to 9,637 ; significantly exceeding the LOC of 100 and are not of concern. The long

- term (chronic) aggregate assessment includes only dietary (food and water) exposure as there are no long

- term residential exposure s cenarios. Chronic dietary risk is not of concern.

A quantitative dermal risk assessment is not required for hexythi azox. Occupational
handler inhalation MOEs significantly exceed 100 for all scenarios assessed associated
with the new use and are not of concern . Further, there were no risks of concern identified for postapplication exposure to hexythiazox associated w ith th is new use.

No additional personal protective equipment (PPE) is required

. T he label restricted entry interval (REI) of 1 2 hours is appropriate and in compliance with Worker Pro tection Standard requirements.

Potential areas of environmental j ustice concern, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

2.0 HED Recommendations

Provided the proposed label is amended as noted in Section 2.3 .1 , there are no hazard, exposure, or risk considerations that would preclude granting the requested use on wheat and pepper/eggplant subgroup 8

- 10B

, and setting the recommended tolerance described
in Section 2.2.2.

2.1 Data Deficiencies

There are no data deficiencies with respect to chemistry , ORE , and toxicology associated
with this action.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate HPLC/UV analytical method is available for the enforcement of tolerances for residues of hexythiazox and its metabolites co ntaining the PT

- 1

- 3 moiety in crop and
livestock commodities. This method is listed in the U.S. EPA Index of Residue Analytical Methods under hexythiazox as method AMR

- 985

- 87.

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 6 of 33 Briefly, residues are extracted with methanol or methanol/water, acidified, p artitioned
with dichloromethane (DCM) , subjected to base hydrolysis, partitioned with acetonitrile,
and re

- partitioned with DCM. The extracts are cleaned up using column chromatography, and the ethyl acetate/hexane eluate is concentrated and analyzed by
HPLC with UV detection. Residues are expressed in terms of hexythiazox using a molecular weight conversion factor of 1.55. The method LOQ is 0.02 ppm.

Hexythiazox and its metabolites are not consistently recovered through FDA’s multi

residue methods. No data were provided, or are required, for recovery through other

commo n multi

- residue methodology.

2.2. 2 Recommended Tolerances

Tolerances currently established under 40 CFR §180.448 comply with the HED Interim Guidance on Tolerance Expressions (S. Knizner, 5/27/09); therefore, no revisions are
recommended to the residue definition. Table 2.2.2 summarizes the recommended
tolerance level s and commodity definition required to support the proposed new use on wheat and pepper/eggplant subgroup 8

- 10B. The wheat tolerance s should be added to 40 CFR §180.448(b)

.

Table 2.2.2 . Tolerance Summary for Hexythiazox

. Commodity Established/Proposed Tolerance (ppm) HED

- Recommended Tolerance (ppm) Comments ( correct commodity definition ) Wheat, Forage 6.0 6.0 Wheat, forage (EPA Zone 11 only)* Wheat, Hay 30 30 Wheat, hay (EPA Zone 11 only)* Wheat, Grain 0.02 0.02 Wheat, grain (EPA Zone 11 only) Wheat, Straw 8.0 8.0 Wheat, straw (EPA Zone 11 only)* Pepper/Eggplant 8

- 10B 1.5 1.5 Pepper/Eggplant subgroup 8

- 10B



### * Recommended tolerance based on outcome of OECD MRL calculation from 2012 memo D396862.



### 2.2. 3 Revisions to Petitioned

- For Tolerances

None.

2.2. 4 International Harmonization

The International Residue Limit (IRL) status sheet is included as Appendix D to this
memorandum. As there are no Codex or Canadian MRLs for hexythiazox in/on wheat

, there are no harmonization issues associated with this action. However, there is one Codex MRL for eggplant at 0.1 ppm which is less than the established US tolerance for pepper/eggplant subgroup 8

- 10B at 1.5 ppm. Residue values used to establish the US tolerance for pepper/eggplant 8

- 10B are significantly higher than the Codex MRL for eggplant so harmonization could not be completed at this time

.

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 7 of 33 2.3 Label Recommendations

2.3.1 Recomme ndations from Residue Reviews

The label must provide a 120

- day plant

- back interval (PBI).

2.3.2 Recommendations from Occupational Assessment

No label changes are required based on the occupational assessment.

2.3.3 Recommendations f rom Residential As sessment

No label changes are required based on the residential assessment.

3.0 Introduction

3.1 Chemical Identity

Hexythiazox, trans

- 5

- (4

- chlorophenyl)

- N

- cyclohexyl

- 4

- methyl

- 2

- oxothiazolidine

- 3

- carboxamide, is an ovicide/miticide used to control mites on a variety of crops and in outdoor residential settings . Hexythiazox is a contact pesticide which achieves control of eggs or immature mites via direct contact or contact with treated surfaces.

The chemical structure and nomenclature of hexythiazox and its common moiety, PT

- 1

- 3 is shown in Table 3.1. The physicochemical properties of the technical grade hexythiazox are presented in Table 3.2.

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 8 of 33 T able 3. 1. Nomenclature of Hexythiazox.
Compound

Common name Hexythiazox
Company experimental names DPX

- Y5893, NA

- 73

IUPAC name (4 RS ,5 RS )

- 5

- (4

- chlorophenyl)

- N

- cyclohexyl

- 4

- methyl

- 2

- oxo

- 1,3

- thiazolidine

- 3

- carboxamide

CAS name trans

- 5

- (4

- chlorophenyl)

- N

- cyclohexyl

- 4

- methyl

- 2

- oxo

- 3

- thiazolidinecarboxamide

CAS # 78587

- 05

- 0

End

- use product/EP 1 lb/gal EC (EPA Reg. No. 10163

- 277; Onager® Ovicide/Miticide)
Compound

(4

- chlorophenyl)

- 4

- methyl

- 2

-

oxo

- 3

- thiazolidine moiety

Common name PT

- 1

- 3 moiety

Chemical name 5

- (4

- chlorophenyl)

- 4

- methyl

- thiazolidin

- 2

- one



### 3.2 Physical/Chemical Characteristics

Table 3.2. Physicochemical Properties of Hexythiazox.

Parameter Value Reference
Melting point/range 108.0

- 108.5 °C 00143533
pH Not applicable
Density 1.289 at 25 °C 00143533
Water solubility 0.12 ppm 44006301
Solvent solubility g/L
chloroform 1379 xylene 362
acetone 160.0
acetonitrile 28.6

n

- hexane 3.9
methanol 20.6 00143533

Vapor pressure <10

- 8 mm Hg at 25 oC 44006301

Dissociation consta nt, pK a Not applicable
Octanol/water partition coefficient Log(P OW ) 560 (average) 0143533, 00146531

UV/visible absorption spectrum (molecular absorption coefficients) Maximum at 223 nm in acetonitrile, no absorption in the visible range. Not available

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 9 of 33 3.3 Pesticide Use Pattern

Gowan Company has submitted a supplemental label for Onager® Miticide (EPA Reg
No. 10163

- 277) which includes proposed regionally restricted use directions for wheat

. Gowan Company has also submitted a supplemental label for Hexygon® Miticide (EPA Reg. No. 10163

- 251) which includes proposed use directions for pepper/eggplant subgroup 8

- 10B. The newly proposed use pattern s have been summarized in T able 3.3

.

Table 3. 3 . Summary of Proposed Directions for Use of Hexythiazox.

Application
Method Formulation

[EPA Reg. No.] Application

Rate (lb ai/A) Max. No.

Applic ation per Season Max.

Seasonal Application
Rate (lb ai/A) PHI

(days) Use Directions and

Limitations

Wheat

Foliar
Broadcast Onager®

Miticide [ 10163

- 277 ] 0.625

- 1.5 1 1.5 14 Oregon and Washington

Pepper/Eggplant Subgroup 8

- 10B

Foliar
Broadcast Hexygon® 50

DF Miticide [10163

- 251] 0.1875

-

0.375 1 1.5 1 No geographical use
restriction



### The following changes should be made to the supplemental label for wheat :

 Use restricted to Region 11

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new use of hexythiazox. Humans may be exposed to hexythiazox in food and drinking water, since hexythiazox may be applied directly to growing crops and appl ication may result in hexythiazox reaching surface and ground water sources of drinking water. Additionally humans may be exposed to hexythiazox in residential settings, since it may be applied to ornamental plantings in residences, public areas, and

recr eational sides, as well as on lawns and turf and to residential berries and fruit and nut trees. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application. There is a potential for post

application exposure for workers re

- entering treated fields.

Risk assessments have been previously prepared for the existing uses of hexythiazox. This risk assessment considers all of the aforementioned exposure pathways based on the proposed new use of hexythiazox, as well as the existing uses.

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. E xecutive Order 12898,

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 10 of 33 "Federal Actions to Address Environmental Justice in Minority Populations and Low

Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on pat terns 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 consumpti on patterns are compiled by the U.S. Department of Agriculture’s National
Healt h and Nutrition Examination 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 catego rized by subgroups based on age
and ethnic group. Additio nally, 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 associ ated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

4.1 Hazard Characterization

The toxicity datab ase for hexythiazox is complete and adequate for assessing risk

. The Hazard and Science Policy Council (HASPOC) concluded that an acute neurotoxicity study is not required at this time, and a new subchronic neurotoxicity study is not required, since the 28

- day neurotoxicity study is sufficient to assess subchronic

neurotox icity from hexythiazox exposure. The HASPOC also concluded that a 28

- day inhalation toxicity study is not required for hexythiazox at this time ( HASPOC Memo,
TXR No. 0056434, 9/18/12 )

.

Hexythiazox is associated with toxicity of the liver and adrenals following subchronic and chronic exposure to dogs, rats and mice, with the dog bei ng the most sensitive species. The prenatal developmental studies in rabbits and rat s and the two

- generation reproduction study in rats showed no indication of increased susceptibility to in utero and/or postnatal exposure to hexythiazox. Reproductive toxicity was not observed. There is no concern for neurotoxicity following exposure to hexythiazox. The toxicology database for hexythiazox does not show any evidence of treatment

- related effects on the immune system. Hexythiazox is classified as “likely to be carcinogenic to humans”; however, s ince the effects seen in the study that serves as the basis for the chronic RfD occurred at doses substantially below the lowest dose that induced tumors, HED concluded that quantification of risk using a non

- linear approach; i.e., RfD, for hexythiazox will adequately account for all chronic effects , i ncluding carcinogenicity, that could result from exposure to hexythiazox.

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 11 of 33 4.2 Hazard Profile

The hazard profile for hexythiazox is contained in Appendix A of this memorandum.

4.3 Dose

- Response Assessment/Endpoint Selection

No endpoint attributable to a single exposure was identified from the available toxicity database; therefore, an acute dietary risk assessment for hexythiazox is not required.

The chronic dietary endpoint was selected from a one

- year toxicity feeding st udy in the dog with a NOAEL of 2.5 mg/kg/day. At the study LOAEL of 12.5 mg/kg/day, increased absolute and relative adrenal weights and associated adrenal histopathology were observed. A 100X uncertainty factor was applied to account for inter

- and intra

species variability resulting in a chronic reference dose (cRfD) of 0.025 mg/kg/day. Since the FQPA factor is reduced to 1X, the RfD is equivalent to the chronic population adjusted dose (cPAD).

Short

- term and intermediate

- term incidental oral and inhal ation endpoints for risk
assessment were from a two

- generation reproduction study conducted in the rat with a NOAEL of 30 mg/kg/day. At the study LOAEL of 180 mg/kg/day, decreased pup body weight during lactation and delayed hair growth and/or eye opening , and decreased parental body

- weight gain and increased absolute and relative liver, kidney, and adrenal weights were observed. In a co

- critical subchronic toxicity study in rats, increased liver and adrenal weights, as well as adrenal histopathology (fatt y degeneration of the adrenal zona fasciculata), were observed. Inhalation hazard is assumed to be equivalent to oral
hazard.

For the short

- term and intermediate

- term dermal risk assessments, no quantification of risk is required because the dermal equ ivalent dose , after applying the estimated dermal absorption factor of 2% to the oral reproduction study NOAEL of 30 mg/kg/day, is 1500 mg/kg/day, which is greater than the limit dose.

EPA has classified hexythiazox as “likely to be carcinogenic to huma ns” based upon increased incidences of malignant and combined benign/malignant liver tumors in high

dose female B6C3F1 mice, and benign mammary gland tumors, observed in high dose male rats. There was no evidence of carcinogenicity in male mice and female rats. EPA concluded that the evidence as a whole was not strong enough to warrant quantitative estimation of carcinogenic risk to humans using a cancer slope factor. HED concluded that quantification of risk using a non

- linear approach; i.e., RfD, for h exythiazox will adequately account for all chronic toxicity, including carcinogenicity that could result from exposure to hexythiazox. That conclusion is based on the following considerations: (1) the liver tumors found in the female mouse are common tumor s; (2) the male mammary tumors were benign and of no biological significance; (3) hexythiazox is not mutagenic; (4) no carcinogenic response was seen in male mice or female rats

.

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 12 of 33 4 .4 FQPA Considerations

The Agency has determined that it is appropriate to reduce the FQPA safety factor to 1X for the following reasons:

 The toxici ty database for hexythiazox is complete.

 There is no evidence of increased susceptibility or sensitivity in rats or rabbits to

pre

- and/or post

- natal exposure to hexythiazox.

 Th ere is no evidence of neurotoxicity in the database. A developmental neurotoxicity (DNT) study is not required.

 The dietary risk assessment is highly conservative and not expected to
underestimate risk.

4.5 Summary of Toxicological Doses and Endpoint s for Use in Human Risk
Assessments and Levels

Table 4.5.1. Toxicological Doses and Endpoints for Hexythiazox for Use in Dietary and Non

Occupational Human Health Risk Assessments 1

Exposure/
Scenario Point of

Departure Uncertaint

y/FQPA Safety
Factors RfD, PAD, Level

of Concern for
Risk Assessment Study and Toxicological
Effects

Acute Dietary
All Populations No risk is expected from this exposure scenario as no hazard was identified in any toxicity study

for this duration of exposure

Chronic Dietary
All Populations NOAEL=2.5

mg/kg/day UF A = 10x

UF H = 10x FQPA SF=
1x Chronic RfD = 0.025

mg/kg/day

cPAD = 0.025 mg/kg/day One

- Year Toxicity Feeding Study

-

Dog

LOAEL = 12.5 mg/kg/day based on
increased absolute and relative
adrenal weights and associated adrenal histopathology.

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 13 of 33 Table 4.5.1. Toxicological Doses and Endpoints for Hexythiazox for Use in Dietary and Non

Occupational Human Health Risk Assessments 1

Exposure/
Scenario Point of

Departure Uncertaint

y/FQPA Safety
Factors RfD, PAD, Level

of Concern for
Risk Assessment Study and Toxicological
Effects

Short

- and
Intermediate

Term
Incidental oral NOAEL=30

mg/kg/day UF A = 10x

UF H = 10x FQPA SF=
1x Residential LOC for

MOE = 100 2

- Generation Reproduction Study

–

Rat

LOAEL = 180 mg/kg/day, based on
decreased pup body weight during lactation and delayed hair growth and/or eye opening, and decreased parental body

- weight gain and increased absolute and relative liver, kidney, and adrenal weights

.

Co

- Critical
13

- Week Oral Toxicity Study

– Rat NOAEL = 5.5 mg/kg/da y LOAEL = 38 mg/kg/day, based on
increased absolute and relative liver weights in both sexes, increased relative ovarian and kidney weights, and fatty degeneration of the adrenal
zona fasciculata.

@ 397.5/257.6 mg/kg/day, decreased body

- weight gain in fe males, slight swelling of hepatocytes in central zone (both sexes), increased incidence of glomerulonephrosis in males, increased adrenal weights

Cancer (oral, dermal, inhalation) Classification: “Likely to be Carcinogenic to Humans”. Insufficient evidence to warrant a

quantitative estimation of human risk using a cancer slope factor based on the common liver tumors (benign and malignant) observed only in high dose female mice, and benign mammary gland tumors of no biological significance, observed only in high dose male rats in the absence of mutagenic concerns. The chronic RfD is protective of all chronic effects including potential carcinogenicity of hexythiazox.

1 Point of De parture (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 adver se effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapola tion from animal to human (inter speci fic ). UF H = potential variation in sensitivity among members of the human population (intraspecific ).
UF L = use of a LOAEL to extrapolate a NOAEL. FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 14 of 33 Table 4.5.2 Summary of Toxicological Doses and Endpoints for Hexythiazox for Use in Occupational Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty

Factors Level of

Concern
for Risk
Assessment Study and Toxicological

Effects

Dermal
S hort

- and
intermediate

- Term N/A N / A N/A No dermal hazard identified

Inhalation
Short

- and
Intermediate

- Term Oral NOAEL = 30

mg/kg/day

Inhalation hazard
assumed to be equivalent to oral
hazard UF A =10x

UF H =10x Residential

LOC for
MOE = 100

Occupational
LOC for
MOE = 100 2

- Generation Reproduction Study

– Rat

LOAEL = 180 mg/kg/day, based on decreased pup body weight during lactation and delayed hair growth and/or eye opening, and decreased parental body

- weight gain and increased absolute and relative liver, kidney, and adrenal weights

Co

- critical
13

- Week Feeding Study

– Rat LOAEL = 38.1 mg/kg/day, based
on increased absolute and relative liver weights in both sexes,
increased relative ovarian and kidney weights, and fatty degeneration of the adrenal zona
fasciculate.

Cancer (oral, dermal, inhalation) Classification: “Likely to be Carcinogenic to Humans”. ”. Insufficient evidence to warrant

a quantitative estimation of human risk using a cancer slope factor based on the common liver tumors (benign and malignant) observed only in high dose female mice, and benign mammary gland tumors of no biological significance, observed only in h igh dose male rats in the absence of mutagenic concerns. The chronic RfD is protective of all chronic effects including potential carcinogenicity of hexythiazox.

1 Point of Departure (PoD) = A data point or an estimated point that is derived from observ ed 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 = uncertai nty factor. UF A = extrapola tion from animal to human (inter specific ). UF H = potential variation in sensitivity among member s of the human population (intra specific ).
UF L = use of a LOAEL to extrapolate a NOAEL. FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.



### 5 .0 Dietary Exposure/Risk Characterization

5.1 Residue Chemistry Summary Reside Chemistry Summary, D 427236

, K.King

, 05/19 /2015 Data Evaluation Record, D404573, D.Davis, 05/02/2013



### The nature of the residue in plants, animals, and water has been adequately delineated.
The residue s of concern for the tolerance e xpression and risk assessment are the parent

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 15 of 33 compound and its metabolites which contain the (4

- chlorophenyl)

- 4

- methyl

- 2

- oxo

- 3

- thiazolidine moiety

.

The Onager® Miticid e label will be amended to include the use of hexythiazox on wheat. Gowan Company has petitioned (PP#1F7934) for the Environmental Protection Agency (EPA) to establish a tolerance on wheat, alfalfa, and timothy. All required studies were submitted by the r egistrant for these tolerances including the most recently submitted processing study on wheat consisted of one trial in WA

. This study used an application rate of 0.1873 lb ai/A and all but one average residues were less than LOQ (0.02 ppm)

. The wheat re gistration is restricted to EPA Zone 11 . Tolerances are established on t he following wheat commodities; forage, hay, grain, and straw. The Organization for Economic Cooperation & Development (OECD) Maximum Residue Level (MRL) calculation procedures were us edto calculate the tolerance for wheat aspirated grain fractions (AGF) . The estimated tolerance was less than the established tolerance for AGF, so a new tolerance is not required for this commodity. The observed processing factor was 8.5x for aspirated gr ain fractions (AGF) and all other commodities’ processing factors were not calculated because residues were less than the LOQ in the raw agricultural commodity (RAC) and processed fraction. The nature of the residue in confined rotational crops has not bee n adequately delineated. However, provided the
labels maintain a 120

- day plant

- back interval (PBI), additional data are not required at
this time.

The Hexygon® Miticide label will be amended to include the use of pepper/eggplant subgroup 8

- 10B as the Ona ger® Miticide label already includes this subgroup . Gowan Company has submitted the magnitude of the residue study for hexythiazox on greenhouse grown bell peppers. Two side by side field trials were completed in the 2013 growing season at EPA Region 3 and 10. Residue values ranged from 0.174

- 0.456ppm for Onager® Miticide, and the residue range for Hexygon® Miticide was from 0.139

- 0.363ppm

. Application rates for both formulations were at 0.1875 lbs ai/A with a 1 day
PHI. Adequate storage stability data are available to support sample storage durations and
conditions.

Seven residue values were used in the Organization for Economic Cooperation and Development (OECD) Maximum Residue Level (MRL) calculator . Two of the values were from the current study that was completed in the 2013 growing season with Onager® Miticide on bell pepper

. The other five values were from a study that was completed in the 2009 growing season with the same formulation, application rate, and use pattern.

Dietary burden was calculat ed for beef cattle, dairy cattle, swine, and poultry and did not exceed the dietary burden that was calculated in the last assessment. Dietary burden did not increase from the last assessment because there are no pepper/eggplant subgroup 8

- 10B feedstuffs a nd the wheat feedstuffs did not significantly impact the calculation.

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 16 of 33 5.2 Drinking Water Residue Profile

EFED Drinking Water Assessment, D4 25222 , A. Shelby, 2/10 / 2015



### T he potential for hexythiazox residues in drinking water was evaluated through modeling.

The drinking water residues used in this dietary risk assessment were provided by the Environmental Fate and Effects Division (EFED) in the following memorandum : “He xythiazox: Drinking Water Assessment for Proposed New Use on Wheat” (A. Shelby, D425222, 02/10/2015) . Estimated drinking water concentrations were incorporated directly into DEEM

- FCID under food categories “water, direct, all sources” and “water, indirect , all sources.” Since no environmental fate data has been submitted
for degradates of concern, EFED conducted the assessment for total residues.

Table 2. Hexythiazox Total Toxic Residues in Drinking Water

Residue (μg/L) Time Range
7.3 1 in 10 year Annual Peak Concentration
4.3 1 in 10 year Annual Average
3.5 30 year Annual Average



### EFED estimated groundwater values by using PRZM

- GW and an extended weather simulation to find that groundwater residues are not expected to exceed surface water
residu es. Therefore, EFED provided estimated drinking water concentrations (EDWCs) for various scenarios from the Tier II surface water model, SWCC, assuming a 0.95 percent cropped area ( PCA ) adjustment. T he maximum estimated surface water
concentrations for to tal residues of hexythiazox were f rom the MS soybean scenario. The
1

- in

- 10 year annual average value of 4.3 μg/L from this scenario was used in the chronic dietary risk assessment.

5.3 Dietary Exposure and Risk Dietary Exposure and Risk Memorandum

, D 427237

, K.King

, 04/08/2015 /2015



### HED conducted a chronic dietary (food and drinking water) risk assessment to support proposed new uses of hexythiazox on wheat, and amended uses on pepper/eggplant crop subgroup 8

- 10B. The assessment included all existing and proposed hexythiazox uses. Chronic dietary risk estimates for the U.S. population and all population subgroups were not of concern. These risk assessments are highly conservative and are unlikely to
underestimate risk.

5 .3.1 Acute Dietary Exposure /Risk

No toxic effects attributable to a single dose of hexythiazox were observed in the toxicology database; therefore, a quantitative acute dietary exposure and risk assessment
for this chemical was not conducted.

5 .3.2 Chronic Dietary Exposure/Risk

The chronic dietary risk assessment used tolerance level residues, included modeled

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 17 of 33 drinking water estimates, assumed 100% crop treated, and incorporated DEEM default

proc essing factors. The dietary assessmen t could be substantially refined using anticipated residues, percent crop treated information and empirical processing data;
however these refinements were not conducted since risk estimates were not of concern.
This highly conservative risk assessment sh owed no risks of concern (<100% of the chronic population adjusted dose (cPAD)) for the U.S. General P opulation and all subpopulation s . The estimated exposure to the U.S. General P opulation res ulted in a risk equivalent to 18 % of the c PAD. The estimated exposure to children 1

– 2 years of age, the most highly exposed subpopulation, res ulted in a risk equivalent to 81 % of the cPAD. Results for all subpopulat ions are summarized in Table 5 .3 .3, below.

5 .3.3 Cancer Dietary Risk

The HED Cancer Assessment Review Committee (CARC) classified hexythiazox as “Likely to be Carcinogenic to Humans”, but has determined that there is insufficient evidence to quantify risk using a cancer slope factor. Rather, the committee concluded
that re gulation based on the chronic reference dose will be protective for both chronic and carcinogenic risks. As noted above there are no chronic risks of concern.

Table 5.3.3. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Hexythiazox

Population Subgroup Chronic Dietary Cancer

Dietary Exposure (mg/kg/day) % cPAD* Dietary Exposure (mg/kg/day) Risk

General U.S. Population 0.004404 18 No concern for risks associated with the carcinogenic potential of hexythiazox.

All Infants (< 1 year old) 0.008113 33

N/A N/A Children 1

- 2 years old 0.020343 81

Children 3

- 5 years old 0.013368 54

Children 6

- 12 years old 0.006516 26

Youth 13

- 19 years old 0.003277 13

Adults 20

- 49 years old 0.002935 12

Adults 50+ years old 0.003268 13

Females 13

- 49 years old 0.003106 12

* Most highly exposed subpopulation is highlighted in bold.



### 5 .4 Anticipated Residue and Percent Crop Treated (%CT) Information

Anticipated residues and percent crop treated information were not used in the dietary exposure and risk assessment

.

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 18 of 33 6.0 Residential and Other Non

- Occupational Exposures/Risks Occupational and Residential Exposure and Risk Assessment, D404018, A. LaMay, 5/6/13 Occupational and Residential Exposure and Risk Assessment, D396864, A. LaMay, 9/25/12



### There are no new residential uses proposed with this action; however, there are registered
uses on residential sites which have been previously assessed , including (1) ornamental landscape plantings in residences, public areas, and recreational s ites such as campgrounds, golf courses, parks and athletic fields, (2) ornamental lawns and turf (including residential), (3) residential pome fruit, stone fruit, and nut trees, and residential
caneberries.

6.1 Residential Handler Exposure and Risk

Sin ce hexythiazox does not pose a dermal risk, only inhalation exposure assessments were conducted for residential handlers. Residential handler exposure is expected to be
short

- term in duration. Intermediate

- term exposures are not likely because of the
int ermittent nature of applications by residential applicators. Residential handler inhalation margins of exposure (MOEs) significantly exceed 100 for all scenarios
assessed and are not of concern. Residential handler MOEs range from 420,000 to 330,000,000.

6.2 Residential Post

- application Exposure

There is the potential for post

- application exposure for individuals exposed as a result of being in an environment that has been previously treated with hexythiazox. The quantitative exposure/risk assessment for residential post

- application exposures is based on incidental oral exposure to treated turf. As no dermal hazard was identified, a quantitative dermal post

- application assessment is not required. Short

- term exposure durations are anticipated for inci dental oral exposures due to the intermittent nature of applications in residential environments. As the aerobic soil metabolism half life for hexythiazox is 145.2 days 1 

### , intermediate

- term exposure is also possible for incidental soil ingestion exposure.

Child incidental oral exposure to treated turf was assessed for hexythiazox. Risk estimates greatly exceed the LOC of 100 for all scenarios associated with children’s exposure to treated turf and are not of concern. The short

- term hand

- to

- mouth MOE fo r children is 11,000; the short

- term object

- to

- mouth MOE for children is 350,000; and the
short

- and intermediate

- term incidental soil ingestion MOE for children is 4,700,000.

In accordance with 40CFR158, TTR data are required for all occupational (e.g., sod farms, golf courses, parks, and recreational areas) or residential turf uses that could result in post

- application exposure to turf. In the absence of chemical

- specific TTR data,

1 Hexythiazox: Drinking Water Assessment for New Use on wheat, alfalfa, timothy, eggplant and peppers

. Andrew Shelby. DP Barcode: 396529 & 401798. 6/21/2012

.

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 19 of 33 EPA uses default values. The 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment includes an analysis of all TTR data, available at the time, which resulted in the selection of revised liquid and granular default values for the fraction of the application rate availabl e for transfer after a turf application (F AR 

### ). These values are based on an analysis of 59 TTR studies performed with the Modified California Roller Method (36 studies using liquids, 11 studies using wettable powders/water dispersible granules, and 12 stu dies using granules). The liquid results (N=131) indicate a range of F AR 

### values from 0.0005% to 6.1% and the granular results (N=37) indicate a range of 0.00064% to 0.69%. In both the liquid and granular data, a large range of transferability is observed and this variability can potentially be attributable to many factors such as active ingredient; formulation; field conditions in the studies; weather conditions (e.g., humidity); or many other difficult to quantify
factors. Although witnessed across mult iple chemicals, this range in F AR 

### values is not expected when considering TTR data for a single chemical. HED selected 1% and 0.2% as high

- end default values for liquid and granular products, respectively. Although there may be a small degree of uncerta inty in the use of the default TTR value for hexythiazox (i.e., there is a small chance that the F AR 

### value may exceed the applicable default value ), it is likely that the health

- protective aspects of EPA’s residential postapplication turf

assessment methodology will more than compensate for this potential uncertainty (i.e., the methodology is likely to overestimate exposure by a factor greater than the factor than the highest measured F AR 

### values exceed the defaults ). For example, when assessing

res idential post

- application turf exposure, EPA assumes the following: exposures occur
to zero

- day (i.e., day of application ) residues every day of the assessed exposure duration (i.e., EPA assumes that no dissipation or degradation occurs, it doesn’t rain , the grass is not mowed, etc); individuals perform the same postapplication activities performed in the turf transfer coefficient study day after day (e.g., tumbling, playing on turf with toys, etc.); and individuals engage in these post

- application activ ities for a high

end amount of time every day that is represented by data reflecting time children spend outdoors and not specifically engaged in activities on turf, when in actuality children do not spend all of their outdoor time on turf and high

- end le vels of activity will not occur every day.

Given the conservatisms discussed above and the potential compounding nature of these conservatisms, EPA is able to rely upon the calculated exposure estimates with confidence that exposure is not being undere stimated.

Since the estimated residential turf post

- application exposure using default TTR values for hexythiazox is minimal in comparison to the level of concern (i.e., the calculated MOE is greater than 10 times higher than the level of concern, MOE = 11,000 compared
to the LOC of 100 ); EPA is waiving the 40 CFR TTR data requirement. In this instance, it is unlikely that chemical

- specific TTR data would be needed to further refine exposure assessments or would add appreciably to our general understa nding of the availability of turf transferable pesticide residues.

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 20 of 33 6.3 Other

6.3.1. 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 les ser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., ground
boom and air blast) employed for hexythiazox

. The agency has been working with the Spray Drift Task Force (a task force composed of variou s 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 websi te for more information). 2 

### 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) Standar d Operating Procedures For Residential Risk Assessment (SOPs)

- Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift.
This document outlines the quantification of indirect non

- occupational exposure to drift

. It is noted that the 0.19 lb ai/acre application rate for turf was modeled to estimate post

application residential exposure of children. As this rate is equal to or higher than many of agricultural application rates, this scenario is protective of any exposure of children via spray drift from agricultural hexythiazox applications.

6.3.2. Residential Bystander Post

- Application Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s fina l report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulatio ns.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 hexythiazox

.

7.0 Aggregate Risk Assessments and Risk Characterization

7.1 Acute Aggregate Risk

No toxic effects attributable to a single dose of hexythiazox were observed in the

2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 21 of 33 toxicology database; therefore, a quantitative acute aggregate risk assessment for this chemical is not required.

7.2 Short

- and Intermediate

- Term Aggregate Risks

The short

- and intermediate

- term aggregate risks combine residential handler (adult only)

or post application exposures with average food and water exposures.

Short

- and intermediate

- term aggregate margins of exposure for adults and children greatly exceed the LOC of 100 and are not of concern. Short

- and intermediate

- term estimated exposures and risks are shown in Table 7 .2 , below.

Table 7.2 Short

- Term and Intermediate

- Term Aggregate Risk Calculations

Population NOAEL

(mg/kg/day) LOC 1 Max
Allowable Exposure 2 (mg/kg/day) Average

Food &
Water Exposure (mg/kg/day) Residential

Exposure 3 (mg/kg/day) Aggregate

MOE for
food and
residential 4

Short

- Term Scenario
Adult 30 100 0.3 0.003406 0.000072 8626
Adult
Female 30 100 0.3 0.003113 0.000072 9419

Child 30 100 0.3 0.020343 0.0029 1291
Intermediate

- Term Scenario
Adult 30 100 0.3 0.003406 N/A 8808
Adult
Female 30 100 0.3 0.003113 N/A 9637

Child 30 100 0.3 0.020343 0.0000063 1474

1 The LOC of 100 is based on the standard intra

- and inter

- species extrapolation factors.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC = 30/100 = 0.3 mg/kg/day.

3 Residential Exposure values taken from a previous residential assessment (D. Davis, 5/6/2013).

4 Aggregate MOE = [NOAEL / (Avg Food & Water Exposure + Residential Exposure)]



### 7.3 Long

- Term (Chronic) Aggregate Risk

As there are no uses that are expected to result in long

- term r esidential exposure, long

term (chronic) aggregate risk includes only dietary (food and water) exposure. As noted
in Section 5.3.2 of this memorandum, there is no chronic dietary risk of concern.

8.0 Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to hexythiazox and any other substances and hexythiazox does not appear to

pro duce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that hexythiazox has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to
determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 22 of 33 cumulating effects from substances found to have a common mechanism on EPA’s
website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposures and Risks Occupational and Residential Exposure and Risk Assessment, D404018, A. LaMay, 5/6/13 Occupational and Residential Exposure and Risk Assessment, D396864, A. LaMay, 9/25/12



### 9.1 Occupational Handler Risk

The occupational exposure and risk assessment addresses risks to workers exposed in an

occ upational setting via the dermal and inhalation routes of exposure. However, for hexythiazox a quantitative dermal risk assessment is not required; therefore risks were quantitatively assessed for inhalation exposure only. Based on the proposed uses, sho rt

term exposures are anticipated as the proposed uses indicate the product is only to be applied once per year. There is, however, potential for intermediate

- term exposures for commercial applicators who may apply a products over a period of weeks or mon ths

. As the inhalation point of departure is the same for both short

- and intermediate

- term exposure durations, both short

- and intermediate

- term exposure durations are assessed
and the MOEs are the same for both durations

.

The proposed Section 3 use s for pepper/eggplant and wheat had an application rate of 0.1875 lb ai/acre. The applicable occupational handler scenarios for sugar beets have been previously assessed at the same rate for other agricultural crops. This includes application of the emuls ifiable concentrate at 0.1875 lb ai/acre to field crops via aerial, chemigation and ground boom equipment. All occupational handlers scenarios resulted in estimated inhalation margins of exposure (MOEs) which were significantly greater
than 100 at baselin e (no respirator). Therefore, inhalation risks are not of concern and inhalation personal protective equipment (PPE, i.e., respirators) is not required.

9.2 Occupational Post Application Risk

HED uses the term post

- application to describe exposures th at occur when individuals are present in an environment that has been previously treated with a pesticide (also referred

to as re

- entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including act ivities related to crop production, such as scouting for pests or harvesting. Post

- application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide appli cation, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post

- application exposure.

Occupational Post

- application Inhalation Exposure/Risk

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 re

- suspension of dusts and/or particulates that

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 23 of 33 contain pesticides. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). 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
studi es, route

- specific inhalation toxicological studies) or further analysis is required for hexythiazox

.

In addition, the Agency is continuing to evaluate the available post

- application inhalation exposure data generated by the Agricultural Reentry Task Forc e. 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.

Although a quantitative occupational post

- applic ation inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than po st

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios. Inhalation risks for occupational handlers are not of concern.

The Worker Protection Standard for Agricultural Pesticides contains requirements for protecting workers from inhalation exposures during and after greenhouse applications through the use of ventilation requirements [40 CFR 170.110, (3) (Restrictions assoc iated with pesticide applications)].

Occupational Post

- ap p lication Dermal Exposure/Risk

As no dermal hazard has been identified for hexythiazox, quantification of dermal post

application risk is not required. In accordance with the updated Part 158 dat a requirements (2007), one or more dislodgeable foliar residue (DFR) studies are required when a pesticide has residential or occupational uses that could result in post

- application dermal exposure. However, as quantification of dermal risk is not require d for hexythiazox, a DFR study is not required for hexythiazox at this time.

The REI specified on the proposed label is based on the acute toxicity of hexythiazox. Hexythiazox is classified as Toxicity Category IV for acute dermal toxicity, Toxicity
Cate gory IV for acute dermal irritation, and Toxicity Category III for eye irritation. It is
not a skin sensitizer. Under WPS for agricultural pesticides, active ingredient ’s classified as Acute III or IV for acute dermal, eye irritation and primary skin irritation are assigned

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 24 of 33 a 12

- hour REI. Therefore, the WPS interim REI of 12 hours is adequate to protect agricultural workers from post

- application exposures to hexythiazox

.

10.0 Human Stu dies

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; the AHETF database; the Outdoor Residential Exposure Task Force (ORETF) database; the ARTF database; and the Residential SOPs, are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain st udies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 3



### .

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

- exposure

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

- app

- exposure

- data.html

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 25 of 33 Appendix A. Toxicology Assessment

A.1 Toxicity Profiles

Table A.1.1. Acute Toxicity Data on Hexythiazox Technical
Guideline No./ Study Type MRID No. Results Toxicity Category

870.1100 Acute oral toxicity 00146549 LD 50 = >5000 mg/kg IV

870.1200 Acute dermal toxicity 00146550 LD 50 = >5000 mg/kg IV

870.1300 Acute inhalation toxicity 00146554 LC 50 = >2.0 mg/L IV

870.2400 Primary eye irritation 00146551 Reddened conjunctiva III

870.2500 Acute dermal irritation 00146552 Non irritant IV

870.2600 Skin sensitization 00146553 Non sensitizer N/A

Table A.1.2. Toxicity Profile of Hexythiazox

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3100
90

- Day oral toxicity rat 45067101 (1983) Acceptable/guideline 0, 10, 70, 500, or 3500

ppm M: 0, 1.2, 8.1, 58.6, or 397.5 mg/kg/day F: 0, 0.8, 5.4, 38.1 or 257.6 mg/kg/day NOAEL = 8.1/5.4 mg/kg/day, males/females LOAEL = 58.6/38.1 mg/kg/day, males/females, based on increased absolute and relative liver weights in both sexes, increased relative ovarian and kidney weights, and fatty degeneration of the adrenal zona fasciculata.

@ 397.5/257.6 mg/kg/day, decreased bo dy

- weight gain in females, slight swelling of hepatocytes in central zone (both sexes), increased incidence of glomerulonephrosis in males, increased adrenal weights

870.3700a Prenatal developmental toxicity rat 44955711 (1984) Acceptable/guideline 0, 240, 720, or 2160 mg/kg/day Maternal NOAEL = 240 mg/kg/day LOAEL = 720 mg/kg/day based on decreased maternal body weight gain, and decreased food consumption. Developmental NOAEL = 240 mg/kg/day LOAEL = 720 mg/kg/day based on delayed ossification.

870.3700b Prenatal developmental toxicity rabbit 00146555 (1984) Acceptable/guideline 0, 120, 360, or 1080 mg/kg/day Materna l NOAEL  1080 mg/kg/day LOAEL >1080 mg/kg/day Developmenta l NOAEL  1080 mg/kg/day LOAEL >1080 mg/kg/day

870.3800
Two

- Generation reproduction and fertility effects rat 00147578 (1985) Acceptable/guideline 0, 60, 400, or 2400 ppm Average doses across generations: M: 0, 4.45, 29.73, or 180.67 mg/kg/day F: 0, 5.27, 34.77, or 207.67 mg/kg/day Parental/Systemic NOAEL = 29.73/34.77 mg/kg/day,
males/females LOAEL = 180.67/207.67 mg/kg/day, males/females, based on decreased body weight gain and increased absolute and relative liver, kidney, and adrenal weights. Reproductive NOAEL  180.67/207.67 mg/kg/day,
males/fema les LOAEL >180.67/207.67 mg/kg/day, males/females Offspring NOAEL = 29.73/34.77 mg/kg/day, males/females

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 26 of 33 Table A.1.2. Toxicity Profile of Hexythiazox

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

LOAEL = 180.67/207.67 mg/kg/day, males/females, based on decreased pup body weight during lactation, and delayed hair growth and/or eye opening

.

870.4100b Chronic toxicity dog 00151359, 00146556, 00156895 (1984) Acceptable 0, 100, 500, or 5000 ppm (0, 2.5, 12.5, or 125 mg/kg/day) M: 0, 2.87, 13.1, or 153 mg/kg/day F: 0, 3.17, 13.9, or 148 mg/kg/day

4

- week: 0, 125, 500, 2000, 8000 ppm NOAEL = 2.5 mg/kg/day LOAEL = 12.5 mg/kg/day based on increased absolute and relative adrenal weights and associated adrenal histopathology (adrenal cortex hypertrophy).
@ 125 mg/kg/day, relative adrenal weights and associated adrenal cortex hypertrophy (more pron ounced)

4

- week range

- finding: relative adrenal weight increased at 2000 ppm (50 mg/kg/day) and 8000 ppm (200 mg/kg/day)

870.4300 Chronic Toxicity/ Carcinogenicity rat 00146559 (1984) Acceptable/guideline 0, 60, 430, or 3,000 ppm M: 0, 3, 23, or 163 mg/kg/day F: 0, 4, 29, or 207 mg/kg/day NOAEL = 23/29 mg/kg/day, males/females LOAEL =163/207 mg/kg/day, males/females based on decreased body weight and body weight gain and increased absolute and relative liver weights in both sexes.

No evidence of car cinogenicity

870.4300 Carcinogenicity mice 00147577, 00156896 (1985) Acceptable/guideline 0, 40, 250, or 1500 ppm M: 0, 6.72, 41.6, or 267 mg/kg/day F: 0, 8.38, 51.2, or 318 mg/kg/day NOAEL = 41.6/51.2 mg/kg/day, males/females
LOAEL = 267/318 mg/kg/day, males/females) based on decreased male body weight and body weight gain, and increased absolute and relative liver weights in both sexes.

Evidence of carcinogenicity (causes liver tumors in females).

Gene Mutation
870.5100 (Salmonella typhimurium and
Escherichia coli reverse gene mutation assay) 44955710 (1983) Acceptable The test was negative up to the highest dose tested (6400 μg/plate +/

- S9.

Gene Mutation
870.5300 ( In vitro mammalian cell forward gene mutation assay in CHO cells) 00155154 (1985) Acceptable Independently performed trials were negative up to precipitating doses (  60 μg/mL) and severely cytotoxic concentrations (200 μg/mL

- S9; 400 μg/mL +S9).

Cytogenetics
870.5375 00156894 (1986) Acceptable The test was negative up to precipitating doses accompanied by severe cytotoxicity (  167 μg/mL +/

- S9).

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 27 of 33 Table A.1.2. Toxicity Profile of Hexythiazox

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

In vitro mammalian cell cytogenetic assay in
CHO cells

Cytogenetics
870.5395
In vivo mouse micronucleus assay 44955708 Unacceptable

There’s an update The results were inconclusive because a positive response, which was within the wide range of historical background data, was recorded for female mice at the mid

- and high

doses (500 and 1000 mg/kg). The assay shou ld be repeated to confirm or refute the equivocal results.

Other Effects
870.5550
In vitro UDS assay in primary rat hepatocytes 00156893 (1985) Acceptable The test was negative up to a lethal dose (250 μg/mL).

870.6200b
Subchronic neurotoxicity Crj:CD(SD)IGS(SPF)

rats 48657401 (2004) Acceptable/non

- guideline 0, 100, 1000, or 10000

ppm Males: 0, 8.8, 88.7, or 868.2 mg/kg/day Females: 0, 9.5, 90.1, or 892.7 mg/kg/day (28 days) NOAEL = 1000 ppm (males 88 mg/kg/day; females 90 mg/kg/day).
LOAEL = 10000 ppm (males 868 mg/kg/day; females 892 mg/kg/day), based on decreased motor activity in both sexes, decreased body weight in males, increased adrenal weight in females, and increased liver weight in both sexes.

HASPOC (D0056434): 28

- day duration i s sufficient to assess
sub

- chronic neurotoxicity from hexythiazox exposure

870.7485
Metabolism and pharmacokinetics 00146558 (1985) Acceptable/guideline

Single oral dose at 10 mg/kg (Group B); 14 daily oral doses (10 mg/kg) of unlabeled
material followed by one dose (10 mg/kg) of [ 14 C] test material (Group C); and a single oral dose of 880 mg/kg (Group D). Absorption and distribution of dosed radioactivity were rapid. The radioactive material was rapidly eliminated in the urine and feces; the ma

jority of the radioactivity was
eliminated within 24 hours. There were no observable
differences in the total elimination of NA

- 73 between male and female rats. The major route of elimination in both the male and female rats was by fecal excretion. The major metabolite found, PT

- 1

- 8 (cis), accounted for 8

- 12% of the administered radioactivity in the low dose groups. Approximately 11

- 20% and 65

- 69% of the dosed radioactivity was identified as unchanged NA

- 73 in the low

dose and high

- dose groups, respecti vely. All other metabolites were present at low concentrations (<2%). There was no apparent sex difference in metabolite formation. Significant levels of NA

- 73 equivalent [ 14 C]

- residues were detected in the fat, liver, and adrenals. A sex

related diffe rence in the residue levels of all tissues was observed, with residues in female tissues being two

- fold higher than those found in male tissues.

870.7485
Metabolism and pharmacokinetics 0146557 (1983) Acceptable/non

- guideline

Single low dose (10 mg/kg/day) Total recovery of radioactivity 72 hours after treatment
accounted for 101.9

- 103% of the dose. The distribution of radioactivity 72 hours after dosing was as follows: 1) 30% (male and female) was excreted in the urine, 2) 60% (female) to 67% (male) was ex creted in the feces, and 3) about 4% (male) to 10% (female) of the administered radioactivity remained in the tissues, with the highest concentration in the fat (2.3 ppm, males; 5.4 ppm, females).

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 28 of 33 Table A.1.2. Toxicity Profile of Hexythiazox

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

Significant sex differences existed for the pharmacokineti cs of NA

- 73 in these rats, with females exhibiting slower elimination rats and higher tissue residues (about double)
than males. NA

- 73 was metabolized to a large number of
metabolites that were excreted both in the urine and feces.
Seven metabolites were structurally identified in addition to the parent compound in both excreta of both sexes, with the major fecal metabolite, PT

- 1

- 8 (cis) accounting for 10% of the dosed radioactivity. The others were all minor metabolites accounting for less than 1.4%. A bout 20% of the dose was excreted as unchanged NA

- 73 (97% of which was in the feces). No significant sex difference was apparent with respect to metabolite formation.

870.7600 Dermal penetration 40608402, 40787901 (1985) Unacceptable The total percent of dose absorbed averaged 2%, 1%, and 1.1% for cannulated rats (10

- hour sacrifice) and 0.8%, 0.2%,
and 0.2% for non

- cannulated rats (1

- hour sacrifice) at the low, medium, and high dose levels, respectively. The amount of radioactivity in the blood, carcass, urine and other organs totaled <2% of the applied dose. The results of this study (2% dermal absorption) can be used for risk
assessment purposes.

870.7800
Immunotoxicity 48685201 (2012)
Acceptable/Guideline Immunotoxicity NOAEL is 4 500 ppm (equivalent to 904 mg/kg/day). A LOAEL was not established.

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 29 of 33 Appendix B : Toxicology Data Requirements

The toxicology data requirements (40 CFR 158.340) for the food uses of hexythiazox are presented below. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table B. Toxicology Data Requirements

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Primary Eye Irritation

................................ ................... 870.2500 Primary Dermal Irritation

................................ .............. 870.2600 Dermal Sensitization

................................ ..................... yes
yes
yes
yes
yes
yes yes

yes
yes
yes
yes
yes

870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent)

................................ ......... 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

................................ ......................... yes
yes
yes

no CR yes

yes D

no C

no

no A

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

.................... 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

.. 870.5550 Mutagenicity

— Other Genotoxic Effects

....................... yes
yes
yes y es

yes
yes
870.6100a Acute Delayed Neurotoxicity (hen)

............................... 870.6100b 90

- Day Neurotoxicity (hen)

................................ .......... 870.6200a Acute Neurotoxicity Screening Battery (rat)

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

.............. 870.6300 Develop. Neurotoxicity

................................ ................. no

no

yes
yes CR -

-

no A

yes B

no

870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

no

yes yes

yes

yes
Special Studies

A HASPOC (D0056434): not required at this time; B HASPOC (D0056434): 28

- day study is sufficient to assess subchronic neurotoxicity from hexythiazox exposure ; C dermal equivalent dose , after applying the estimated dermal absorption factor of 2% to the oral reproduction study NOAEL of 30 mg/kg/day, is 1500 mg/kg/day, which is greater
than the limit dose ; D not required since there is a 4

- week study and a 1

- year study available

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 30 of 33 Appendix C: Field Trial Residue Dat a

Magnitude of the Residue for Bell Peppers, MRID 49465401, K.King, 04/14/2015

Gowan Company completed one trail in 2013 on wheat, and 2 side by side trials on bell peppers with two formulations. Onager® and Hexygon® Miticide was applied to the

crops at 0.1875 lb ai/A.

Residue Data from Wheat Processing Study with Hexythiazox.
Location: City,
State ; Year (Trial ID) Commodity Plot Analyte Residues (ppm) [Average] 1 Processing

Factor 2 Median

Processing
Factor 3
Ephrata, W A ; 2013 (TCI

- 13

- 360

- 01 ) Grain (RAC) Trt 2 (1x) Hexythiazox ND, ND [<0.02 ] -- --

AGF 0.171, 0.168 [0.170] >8.5 NA

Grain (RAC) Trt 3

(5x) Hexythiazox ( 0.0 09), ND [<0.02] -- --

Bran (0.009), (0.012) [ <0.02 ] NC NA

Flour ND, ND [<0.02 ] NC NA

Middlings ND, ND [<0.02 ] NC NA

Shorts ND, ND [<0.02 ] NC NA

Germ (0.011), (0.010) [ <0.02 ] NC NA

1 ND = Nondete ctable (<LOD). The LOQ was 0.02 ppm, and the LOD was 0.007 ppm. Residues between the LOD and LOQ are in parentheses. The LOQ was used for residues <LOQ in calculating average residues and processing
factors.

2 Processing Factor = [Measured residue for analyte in the processed fraction] / [Measured residue for analyte in the RAC]. NC = Not calculated ; residues were below the LOQ in the RAC and processed frac tion.

. 3 Median processing factor is NA (not applicable) because there was only one processing trial.

Residue Data from Bell Pepper Field Trials with Hexythiazox.

Location: City, State;
Year (Trial ID) Region Crop/ Variety End

- Use
Product Rate

lbs ai/A (kg ai/ha) PHI

(days) Residues (ppm) 1

Hexythiazox Average

Zellwood, FL;
2013 (TCI

- 13

- 386

- 01) 3 Bell Pepper/
California
Wonder Onager® 1E 0.1872 (0.2098) 1 0.417, 0.456 0.437

Hexygon®
50DF 0.1894

(0.2123) 0.363, 0.240 0.302

Porterville, CA;
2013 (TCI

- 13

- 386

- 02) 10 Bell Pepper/ Fantasy Onager® 1E 0.1910 (0.2141) 1 0.210, 0.174 0.192

Hexygon®
50DF 0.1888

(0.2116) 0.159, 0.139 0.149

1 Expressed as parent equivalents



### The OECD MRL calculator was followed to estimate the tolerances Each completed field trial average was included in the calculation. Pepper/eggplant subgroup 8

- 10B and AGF
has an established tolerance that the OECD MRL calculator tolerance result did not

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 31 of 33 exceed. Calculated tolerances from the OECD MRL calculator did no t exceed the recommended tolerances from Gowan Company for wheat; forage, hay, grain, and straw.

Sample storage conditions and durations are summarized in Table B.7.7.3.1

- 4. Processing took place within 55

- 62 days (1.8

- 2.0 months) of harvest . The maximum storage intervals for samples from harvest/processing to extraction were 77 days (2.5 months) for wheat grain (RAC) and 11

- 19 days for AGF and processed commodities. Samples were analyzed within 2

- 6 days of extraction. The available freezer stora ge stability data indicate that residues of hexythiazox were stable when stored frozen in wheat grain for up to 287 days (9.4 months) (refer to DP# 396862, 6/18/12, D. Drew). Storage stability data are not needed to support the processed commodities since storage duration was <30 days. The available storage stability data are adequate to support the storage conditions and durations for samples from the submitted processing study.

The available freezer storage stability data indicate that residues of hexy thiazox were stable when stored frozen at ≤0 o 

### C for a variety of crops including tomato (MRID 48867601 and MRID 48798701). Translating these results to bell pepper covers the maximum storage interval of 91 days incurred in the present magnitude of the resi due study.

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 32 of 33 Appendix D: Maximum Residue Limits (MRL)

Table B1. Summary of US and International Tolerances and Maximum Residue Limits for Hexythiazox Residue Definition : US Canada Mexico 2 Codex
40 CFR 180.448:

Plant/Livestock: Hexythiazox and its metabolites containing the (4

- chlorophenyl)

- 4

- methyl

- 2

- oxo

- 3

- thiazolidine moiety (expressed as parent) None Plant commodities: Hexythiazox
Animal commodities: Sum of hexythiazox and all metabolites containing the

trans

- 5

- (4

- chlorophenyl)

- 4

- methyl

- 2

- oxot hiazolidine

moiety (PT

- 1

- 3), expressed as hexythiazox
The residue is fat

- soluble



### Commodity 1 

### Tolerance (ppm) /Maximum Residue Limit (mg/kg)
US Canada Mexico 2 

### Codex Wheat, Forage 6.0 Wheat, Hay 30 Wheat, Grain 0.02 Wheat, Straw 8.0 Pepper/Eggplant Crop Subgroup 8

- 10B 1.5 0.1 eggplant

Completed: M. Negussie; 04/2 8 /15

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

### Hexythiazox Human Health Risk Assessment D423491, D423145

Page 33 of 33 Appendix E: OECD Calculator MRL Output

Hexythiazox Pepper/Eggplant Subgroup 8

- 10B

USA

Total number of data (n) 7 Percentage of censored data 0%

Number of non

- censored data 7

Lowest residue 0.069 Highest residue 0.234

Median residue 0.183

Mean 0.168
Standard deviation (SD) 0.051 Correction factor for censoring (CF) 1.000

Proposed MRL estimate

- Highest residue 0.234

- Mean + 4 SD 0.372

- CF x 3 Mean 0.505

Unrounded MRL 0.505

Rounded MRL 0.5

High uncertainty of MRL estimate.

[Small dataset]

Residues (mg/kg)

0.151

0.183

0.162

0.234

0.069

0.187

0.191