### Page 1 of 31 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460

OFFICE OF
CHEMICAL SAFE TY AND
POLLUTION PREVENTION



### Date: 6/ 22 /11

MEMORANDUM

SUBJECT: Hexythiazox. Human Health Risk Assessment to Support Amended Use

on Field Corn and New Use on Greenhouse Tomatoes.

PC Code: 128849 DP Barcode: 383744

Decision No.: 4 40296 Regi stration No. : 10163

- 277

Petition No.: 0E7787, 0F7773 Regulatory Action: Section 3 Registration Risk Assessment Type: Single Chemical Aggregate Case No.: N/A

T XR No.: NA CAS No.: 78587

- 05

- 0

MRID No.: NA 40 CFR: 40 CFR 180.448

FROM: Do nna S. Davis, Risk Assessor

Alexandra LaMay, Biologist Linda Taylor, Toxicologist

Risk Assessment Branch VII Health Effects Division (7509P)

THROUGH: Kit Farwell, DVM, Senior Toxicologist

Michael Metzger, Chief

Risk Asse ssment Branch VII Health Effects Division (7509P)

TO: Olga Odiott, Risk Manger

Kimberly Nesci, PM Team 11

Insecticide Branch Registration Division (7505P)

Attached please find the HED Human Health Risk Assessment for hexy thiazox to support an amended use on field corn and a new use on greenhouse tomatoes.

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 2 of 31 Table of Contents

1.0 Executive Summary

................................ ................................ ................................ . 3 Regulato ry Recommendation

................................ ................................ .......................... 5

2.0 Ingredient Profile

................................ ................................ ................................ ..... 6

2.1 Summary of Registered/Proposed Uses

................................ ............................... 6

2.1.1 Structure and Nomenclature

................................ ................................ ............. 8

2.3 Physical and Chemical Properties

................................ ................................ ........ 8

3.1 Hazard Characterization

................................ ................................ ....................... 9

3.2 Hazard Profile

................................ ................................ ................................ .... 10

3.3 Dose

- Response Assessment/Endpoint Selection

................................ ............... 10

3.4 FQPA Conside rations

................................ ................................ ......................... 11

3.5 Summary of Toxicological Doses and Endpoints for Use in Human Risk

Assessments and Levels

................................ ................................ ................................ 12

3.6 Endocrine disruptio n

................................ ................................ .......................... 13

4.0 Dietary Exposure/Risk Characterization

................................ ................................ 14

4.1 Food Residue Profile

................................ ................................ .......................... 14

4.2 Drinking Water Residue Profile

................................ ................................ ......... 15

4.3 Dietary Exposure and Risk

................................ ................................ ................. 16

4.3.1 Acute Dietary Exposure/Risk

................................ ................................ ..... 16

4.3.2 Chronic Dietary Exposure/Risk

................................ ................................ .. 16

4.3.3 Cancer Dietary Risk

................................ ................................ .................... 16

4.4 Anticipated Residue a nd Percent Crop Treated (%CT) Information

................. 17

5.0 Residential and Other Non

- Occupational Exposures/Risks

................................ .. 17

5.1 Residential Handler Exp osure and Risk

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

5.2 Residential Postapplication Exposure

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

5.3 Other

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

6.0 Aggregate Risk Assessments and Risk Characterization

................................ ....... 19

6.1 Acute Aggregate Risk

................................ ................................ ........................ 19

6.2 Short

- and Intermediate

- Term Aggregate R isks

................................ ................ 19

6.3 Long

- Term (Chronic) Aggregate Risk

................................ ............................... 21

7.0 Cumulative Risk Characterization/Assessment

................................ ..................... 21

8.0 Occupational Exposures and Risks

................................ ................................ ........ 22

9.0 Data Needs and Label Recommendations

................................ ............................. 23

9.1 Toxicology

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

9.2 Residue Chemistry

................................ ................................ ............................. 25

9.3 Occupational/Residential Exposure

................................ ................................ ... 26

10.0 Enviro nmental Justice

................................ ................................ ............................ 26

11.0 Human Studies

................................ ................................ ................................ ....... 26 Appendix A. Toxicity Profiles

................................ ................................ ......................... 28

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 3 of 31 1.0 Executive Summary

Gowan Company is proposing amended registration of the 1 lb/gal emulsifiable concentrate (EC) formulation of hexythiazox (Onager ® Miticide, EPA Reg. No 10163

- 277) to reduce the preharvest intervals (PHIs) for field corn from 4 5 to 30 days and to expand the use from its current regionally restricted u se to a national registration. In support of the proposed amendment, Gowan Company, under PP# 0F7773 , is proposing

th at the 40 CFR 180.448(a) be amended to reflect the following tol erances:

Corn, field, grain

................................ ................................ .. 0.02 ppm Corn, field forage

................................ ................................ . 6.0 ppm Corn, field, stover

................................ ............................... 6.0 ppm Aspirated grain fractions

................................ ...................... 0.50 ppm

In addition

, IR

- 4 is proposing a new use of hexythiazox (Onager ® Miticide, EPA Reg.

No 10163

- 277) on greenhouse tomatoes a nd under PP#0E7787 and has petitioned to establish a new tolerance under 40 CFR 180.448 (a) as follows:

Tomato

................................ ................................ ................. 0.50 ppm

T he toxicity database for hexythiazox is incomplete under the new 40 CFR Part 158 data requirements for conventional pesticides, whi ch requires certain generic testing, including acute and subchronic neurotoxicity studie s and an immunotoxicity study.
However, the Agency believes that the current toxicity database is adequate to evaluate

the hazards associated with th ese amended and ne w uses

.

Hexythiazox has low acute toxicity by the oral, dermal and inhalation routes of exposure. It produces mild eye irritation, is not a dermal irritant, and is negative for dermal sensitization. The target organs of hexythiazox are the liver and a drenal glands in dogs, rats and mice, with the dog bei ng the most sensitive species. Developmental toxicity was not observed in rabbits at the limit dose. Delayed ossification was observed in the rat at a dose level where decreased maternal body weight g ain and food consumption were observed. In the reproductive toxicity study, d ecreased pup body weight s were observed during lactation and delayed hair growth and/or eye opening were observed in the pups at the same dose levels where decreased p arental body weight gain and increased absolute and relative liver, kidney, and adrenal weights were observed. Reproductive toxicity was

not observed. The data provided no indication of increased susceptibility in rats or

rabbits from in utero and postnatal exposure to hexythiazox. The toxicology database for hexythiazox does not show any evidence of treatment

- related effects on the nervous system or the immune system. Hexythiazox is classified as “likely to be carcinogenic to

humans” ; however the evidence as a whol e is not strong enough to warrant a quantitative estimation of human risk. Since 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, the chronic RfD is consid ered protective of all chronic effects including potential carcinogenicity of hexythiazox.

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 4 of 31 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 study. 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 p arental bo dy

- weight gain and

increased liver, kidney, and adrenal 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, based on the fact that the oral equiva lent dose for this dermal exposure scenario

is 1.5

- fold greater than the limit dose.

The overall weight of evidence suggests that this chemical does not directly target either the nervous system or the immune system. Although acute and subchronic neurotox icity studies and an immunotoxicity study are required, the Agency does not believe that conducting these studies will result in lower POD s than th ose currently used for risk assessment, and therefore, a database uncertainty factor (UF DB 

### ) is not needed to account
for the lack of these studies. Further, since there is no evidence of reproductive or developmental toxicity, there is no increased sensitivity/susceptibility seen in the offspring, and exposure estimates are unlikely to underestimate risk; suffic ient evidence exists to reduce the FQPA safety fac tor to 1X. All quantitative risk assessments employed inter

- and intra

- species uncertainty factor s

.

The nature and magnitude of the residue in plants, animals and water has been adequately

delineated to support the proposed amended use on field corn and new use on greenhouse

tomatoes. The submitted labels are adequate to support the proposed uses. An adequate high performance liquid chromatography method with UV detection ( HPLC/UV ) exists

to enforce th e recommended revised and new tolerance s

. Increased tolerances for ruminant meat byproducts to 0.05 ppm and for field corn stover at 7.0 ppm are required to support the amended and new uses. A decrease in the field corn forage tolerance to 3.0

is recom mended. The current grain tolerance at 0.02 ppm is adequate to support the amended field corn use. A new tolerance on tomatoes at 0.5 ppm is required to support the proposed use on greenhouse tomatoes.

Codex MRLs are established for residues of hexyth iazox on “edible offal (mammalian)” and “poultry, edible offal” at 0.05 ppm. A Codex MRL is established for tomatoes at 0.1 ppm. No other Codex, Canadian or Mexican MRLs are established for the commodities that are the subject of these petitions. Codex and U.S. tolerance expressions are harmonized at this time. Revision of the U.S. tolerances for meat byproducts to 0.05 ppm

will result in harmonization with Codex for these commodities. Since the maximum

residue seen in the U.S. green house tomato data is 0.34 ppm, harmonizing with the Codex MRL of 0.1 ppm at this time is not possible as over tolerance residues in the U.S. could result if the Codex MRL were adopted.

An acute endpoint was not selected for hexythiazox; therefore, the Agency conducted

on ly a chronic dietary (food and drinking water) exposure and risk assessment. Chronic

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 5 of 31 dietary r isks are not of concern for the U.S. population and all subpopulations.

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 risk assessments for hexythiazox. There are no aggregate risks of concern.

A quantitative dermal risk assessment is not required for hexythiazox. Occupat ional

handler inhalation MOEs significantly exceed 100 for all scenarios assessed associated

with the field corn and greenhouse tomato uses and are not of concern . Further, there were no risks of concern identified for postapplication exposure to hexythia zox associated with the field corn and tomato uses of this active ingredient.

No additional personal protective equipment (PPE) is required

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

Potential areas of environmental justice 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 Minorit y Populations and Low

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

This assessment relies in part on data from studies in which adult human subjects we re intentionally exposed to a pesticide (i.e., from the Pesticide Handlers Exposure Database (PHED) and the Agricultural Reentry Task Force (ARTF)). A review of the ethical conduct of the applicable data has been completed and the studies met the criteria for being ethically conducted so their use in this Agency risk assessment is acceptable.

Regulatory Recommendation

Provide d the registrant submits revised Section F (see Table 9.2) and further pr ovided the toxicology studies detailed in Section 9.1 of t his memorandum are required as a condition of registration, there are no human health risks of concern that would preclude the

establishment

/revision of tolerances for the residues of hexythiazox and its metabolites containing the (4

- chlorophenyl)

- 4methyl

- 2

- oxo

- 3

- thiazolidine moiety under 40 CFR 180.448 (a) as follows:

Cattle, meat byproducts

................................ ....................... 0.05 ppm Goat, meat byproducts

................................ ......................... 0.05 ppm Hog, meat byproducts

................................ ......................... 0.05 ppm Horse, meat byproducts

................................ ....................... 0. 0 5 ppm Sheep, meat byproducts

................................ ....................... 0.05 ppm Corn, field, forage

................................ ................................ 3.0 ppm Cor n, field, stover

................................ ................................ 7 .0 ppm Grain, aspirated fractions

................................ ..................... 0.50 ppm

Tomato

................................ ................................ ................. 0.50 ppm

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 6 of 31 Note to RD : Expired Section 18 tolerances for field corn commodities currently listed in the 40 CFR for hexythiazox can be removed in conjunction with the establishment of

n ew/revised tolerances for field corn commodities

.

2.0 Ingredient Profile
Residue Chemistry Summary Document, D382910, D. Davis, 6/7/11



### 2.1 Summary of Registered/Proposed Uses

Gowan Company has submitted draft label langua ge to support the amended use of hexythiazox on field corn. The amended label would reduce the PHI for field corn from 45 days to 30 days, expand the use to all areas of the country, and remove the prohibition limiting application after the V15 growth sta ge. No change to the application rate, number of applications or application technique is proposed.

Additionally, IR

- 4 has submitted a proposed label for the new use on greenhouse tomatoes to permit foliar applications of hexythiazox to tomatoes with a 1

- day PHI as a single application at a rate of up to 0.1875 lb ai/A.

The amended use directions for field corn and the newly proposed use directions for greenhouse tomatoes are presented in Table 2.1.

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 7 of 31 Table 2.1. Summary of Directions for Use of Hexyt hiazox.

Applic. Timing, Type, and Equip. Formulation

[EPA Reg.
No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per

Season Max. Seasonal

Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations

Field Corn

Foliar, Broadcast,

Ground or

Aerial Onager

1 lb/gal EC [10163

- 277] 0.0469

-

0.1875 1 0.1875 30 Apply prior to adult mite

build

- up. Minimum spay volume for ground application of 15

– 20 gallons per acre (GPA). Minimum spray volume for aerial application of 5 GPA. Do not graze or

feed livestock on cov er crops growing in treated areas. Do not plant rotational crops other than

those on this label within 120 days of application. Onager is an emulsifiable

concentrate to be diluted with water for application in commercial plantings only.

Greenhouse Tomat oes

Foliar Onager

1 lb/gal EC [10163

- 277] 0.094

-

0.1875 1 0.1875 1 Apply prior to adult mite

build

- up. Minimum spray volume is 20 GPA. Onager is an emulsifiable

concentrate to be diluted with water for application in commercial plantings only.



### Conclu sions . The label directions for field corn and greenhouse tomatoes are adequate to allow evaluation of the residue data relative to those proposed revised uses. The labels for use of Onager Miticide on field corn and greenhouse tomatoes are acceptable an d are supported by the submitted data.

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 8 of 31 2.1.1 Structure and Nomenclature

Table 2.2 Structure and Nomenclature of Hexythiazox.

Compound

Common name Hexythiazox

Company experimental names DPX

- Y5893, NA

- 73

IUPAC name (4 RS ,5 RS )

- 5

- (4

- chlorophenyl)

- N

- cyclohex yl

- 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® 1E Ovicide/Miticide)

(4

- chlorophe nyl)

- 4

- methyl

- 2

-

oxo

- 3

- thiazolidine moiety

Common name PT

- 1

- 3 moiety

Chemical name 5

- (4

- chlorophenyl)

- 4

- methyl

- thiazolidin

- 2

- one



### 2.3 Physical and Chemical Properties

Table 2 .3

. Physicochemical Properties of Hexythiazox.

Parameter Value Reference 1

M elting 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 constant, 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

1 References and values as cited in the petition materials for PP#9F7556.

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 9 of 31 3. 0 Hazard Characterization/Assessment

3.1 Hazard Characterization

The toxicity database for hexythiazox is incomplete under the new 40 CFR Part 158 data requirements for conventional pesticides, which requires certain generic testing, including acute and subchronic neurotoxicity studies and an immunotoxicity study.

Howe ver, Gowan Co. has committed to submit these data by December 2011 (letter from K. Smith, Registration Specialist, Gowan Co. to M. Suarez, PM 22, US EPA dated October 19, 2010). At this time, t he Agency believes that the current toxicity database is adequ ate to evaluate the hazards associated with this new use.

Hexythiazox has a low order of acute toxicity and is classified as Toxicity Category IV for the oral, dermal and inhalation routes of exposure. It produces mild eye irritation (reddened conjunct iva) (Toxicity Category III), is not a dermal irritant (Toxicity Category IV), and is negative for dermal sensitization.

The target organs of hexythiazox (following both subchronic and chronic exposure) are the liver and adrenal glands in dogs, rats and mice, with the dog being the most sensitive species. In a subchronic toxicity study in rats, increased liver and adrenal weights, as well as adrenal histopathology (fatty degeneration of the adrenal zona fasciculata), were seen. In the chronic feeding/c arcinogenicity studies in rats and mice, effects included decreased body weight gain and increased liver weights. In a 4

- week range

- finding study in dogs, effects included increased liver and adrenal weights. In the chronic dog study,

increased liver and adrenal weights were observed, along with associated histopathology of the liver (hypertrophy) and adrenal glands (adrenal cortex hypertrophy).

Developmental toxicity was not observed in rabbits at the limit dose. Delayed

ossification was observed in the rat at a dose level where decreased maternal body weight gain and food consumption were observed. In the reproductive toxicity study, d ecreased pup body weight s were observed during lactation and delayed hair growth and/or eye opening were observed in the pups at the same dose levels where decreased p arental body weight gain and increased absolute and relative liver, kidney, and adrenal weights were observed. Reproductive toxicity was not observed. The data provided no indication of increased susceptib ility in rats or rabbits from in utero and postnatal exposure to hexythiazox. The toxicology database for hexythiazox does not show any evidence of

treatment

- related effects on the nervous system or the immune system.

EPA has classified hexythiazox as “likely to be carcinogenic to humans” 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 carci nogenicity 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 based on the following considerations: (1) the liver t umors in B6C3F1 mice are a very common tumor in that species and were only observed in high dose females; (2) the mammary tumors in

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 10 of 31 rats were benign and were only observed in high dose male rats; and, (3) hexythiazox was

shown to be non

- mutagenic in mammal ian somatic cells and germ cells. Additionally, the chronic NOAEL used for establishing the chronic RfD (2.5 mg/kg/day, from the one year toxicity feeding study in the dog), is approximately 65

- fold lower than the lowest dose that induced tumors (in fema le mice at 163 mg/kg/day). Therefore, the chronic RfD of 0.025 mg/kg/day is judged to be protective of all chronic effects including potential carcinogenicity of hexythiazox.

3.2 Hazard Profile

The hazard profiles for hexythiazox are contained in Appendix A of this memorandum.

3.3 Dose

- Response Assessment/Endpoint Selection

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

T he chronic dietary endpoint was selected from a one

- year toxicity feeding study 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 obse rved. 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 adjus ted dose (cPAD).

Short

- term and intermediate

- term incidental oral and inhalation endpoints for risk

assessment were selected 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 subchronic toxicity study in rats, inc reased liver and adrenal weights, as well as adrenal histopathology (fatty 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 assessment s , no quantification of risk is required, based on the fact that the dermal equivalent dose for this dermal exposure

scenario is 1.5

- fold greater than the limit dose considering the NOAEL of 30 mg/kg/day

from the oral reproduction study, and the estimated 2% dermal absorption for this compound

.

EPA has classified hexythiazox as “likely to be carcinogenic to humans” 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

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 11 of 31 concluded that the evidence as a whole was not strong enough to warrant quantitative estimation of carcinogenic risk to hum ans using a cancer slope factor.

3.4 FQPA Considerations

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

The toxicity database for hexythiazox is incomplete under the new 40 CFR Part

15 8 data requirements for conventional pesticides, which requires certain generic testing, including acute and subchronic neurotoxicity studies and an immunotoxicity study. However, the toxicology database does not show any

evidence of treatment

- related eff ects on the nervous system or the immune

system. The overall weight of evidence suggests that this chemical does not directly target either system. Although acute and subchronic neurotoxicity studies and an immunotoxicity study are required as a part of new data requirements in the 40 CFR Part 158 for conventional pesticide registrations, the Agency does not believe that conducting these studies will result in a lower POD than any currently used for risk assessment, and therefore, a database uncertainty f actor (UF DB 

### ) is

not needed to account for the lack of these studies. There is no evidence of increased susceptibility or sensitivity in rats or rabbits to

pre

- and/or post

- natal exposure to hexythiazox. There is no evidence of neurotoxicity in the databa se. A developmental neurotoxicity (DNT) study is not required. The dietary risk assessment is highly conservative and not expected to

underestimate risk.

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 12 of 31 3.5 Summary of Toxicological Doses and Endpoints for Use in Human Risk

Assessments and Levels

Table 3.5.1 Toxicological Doses and Endpoints for Hexythiazox for Use in Dietary and

Non

- Occupational Human Health Risk Assessments 1

Exposure/

Scenario Point of

Departure Uncertainty

/FQPA Safety

Factors RfD, PAD, Level

of Concern for

Risk Assessment Stu dy 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.

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 ope ning, and decreased parental body

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

13

- Week Oral Toxicity Study

– Rat NOAEL = 5.5 mg/kg/day LOAEL = 38 mg/kg/day, based

on increased absolute and relative liver weights in bot h 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 females, slight swelling of hepatocytes in central zone (both sexes), increased inciden ce 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 bas ed 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 prote ctive of all chronic effects including potential carcinogenicity of hexythiazox.

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 13 of 31 1 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 (intraspecies). UF H = poten tial variation in sensitivity among members of the human population (interspecies). 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.

Table 3.5.2 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 equivalen t 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

rel ative 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 ris k 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 co ncerns. 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 observed dose

- response data and used to mark the beginn ing 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 h uman (intraspecies). UF H = potential variation in sensitivity among members of the human population (interspecies). 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.



### 3.6 Endocrine disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 14 of 31 active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the

Administrat or may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Ti er 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine related effects caused by the substance, and establish a dose

- response relationship between the dose and the E, A, or T effect.

Hexythiazox is on the EDSP List 2 which contains approximately 134 chemicals, many of them pesticides. This list was published in the Federal Register on 11/17/2010 (Volume 75, Issue 221), and is out for comment before being finaliz ed, and before publi cation of the S chedule for Issuance of Test Orders

.

For further information on the status of the EDSP, the policies and procedures, the list s of chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/.

4.0 Dietary Exposure/Risk Characterization

4.1 Food Residue Profile
Residue Chemistry Summary Document, D382910, D. Davis, 6/7/11



### The nature of the resi due in plants, animals, and water has been adequately delineated. The residue of concern for the tolerance expression and risk assessment is for residues of the parent compound and its metabolites which contain the (4

- chlorophenyl)

- 4

- methyl

- 2

-

oxo

- 3

- thiazo lidine moiety. Residues of hexythiazox from foliar application tend to

remain surface residues.

The submitted labels are adequate to support the proposed uses. An adequate high performance liquid chromatography method with UV detection (HPLC/UV) exist s to
enforce the recommended revised and new tolerance s

.

The amended use on field corn is supported by adequate, geographically representative

residue data. The new use on greenhouse tomato is supported by an adequate number and variety (small

- fruited vs . large

- fruited) of residue data. The data support a reduction

in the fi eld corn forage tolerance to 3.0 ppm, and an increase in the field corn stover

tolerance to 7 .0 ppm. The current field corn grain tolerance of 0.02 ppm is adequate to support the ame nded use. The tomato greenhouse residue data support a new tolerance for tomatoes at 0.5 ppm. Updated maximum reasonably balanced diets (MRBD) for ruminants have been calculated and an increase in the meat byproduct tolerance is required. An adequate processing study to support the field corn use has been submitted. A tolerance of 0.5 ppm for aspirated grain fractions is required; no other

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 15 of 31 processing commodity tolerances are required to support the amended use on field corn.

Since the tomato use is l imited to greenhouse grown tomatoes which are intended for fresh market, processing data and processed commodity tolerances are not required. Codex MRLs are established for residues of hexythiazox on “edible offal (mammalian)” and “poultry, edible offal” at 0.05 ppm. A Codex MRL is established for tomatoes at 0.1 ppm. No other Codex, Canadian or Mexican MRLs are established for the commodities that are the subject of these petitions. Codex and U.S. tolerance expressions are

harmonized at this time. Re vision of the U.S. tolerances for meat byproducts to 0.05 ppm

will result in harmonization with Codex for these commodities. Since the maximum residue seen in the U.S. green house tomato data is 0.34 ppm, harmonizing with the Codex MRL of 0.1 ppm at this time is not possible as over tolerance residues in the U.S. could result if the Codex MRL were adopted.

4.2 Drinking Water Residue Profile
EFED Field and Sweet Corn Drinking Water Assessment, D 382948, D383019, A. Shelby, 1/3/10

EFED Greenhouse Tomato Drinki ng Water Assessment, D383745, A. Shelby, 12/1/10



### The drinking water residues used in the dietary risk assessment were provided by the

Environmental Fate and Effects Division (EFED) in the following memorandum: “Hexythiazox: Drinking Water Assessment for New Use on Field Corn, Sweet Corn, Dry Beans and Succulent Beans” (A. Shelby, D382948, D383019, 11/3/10) and incorporated directly into this dietary assessment. EFED evaluated the new use on greenhouse tomatoes (A. Shelby, D383745, 12/1/10) and concluded that water residues from the 11/3/10 uses would be higher and should represent this new use as well.

T he Agency does not have monitoring data available to perform a quantitative drinking water risk assessment for hexythiazox. Therefore, the potential f or hexythiazox residues in drinking water was evaluated through modeling.

Since previous assessments have indicated that surface water residue values greatly exceed groundwater estimated drinking water concentrations, EFED’s updated drinking

water asses sment addressed surface water residues only, and surface water residues were used in HED’s dietary risk assessment.

Surface water concentrations were estimated using the Tier II model Pesticide Root Zone Model 3 (PRZM3; ver. 3.12.2; 5/2/2005)/Exposure A nalysis Modeling System (EXAMS; ver. 2.98.04.06; 4/25/2005 )

. The model and its description are available at the EPA

internet site : http://www.epa.gov/oppefed1/models/water/

.

Since no environmental fate data has been submitted for the degradates of concern, EFED conducted a total residue exposure assessment. Because hexythiazox is used nationally on a variety of crops, the national default percent crop area (PCA) of 0.87 was applied.

EFED evaluate d scenarios intended to most closely match the existing and newly proposed uses, including application to corn in IL, MS, NC, OH and PA, as well as application of hexythiazox to beans in IL and soybeans in MS . Based on modeling results and the PCA adjustm ent, the maximum estimated surface water exposure

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 16 of 31 concentrations for total residues of hexythiazox for all currently proposed and established

uses were from the MS soybean scenario and were:

6.6 μg/L for the 1 in 10 year annual peak concentration 4.5 μg/ L for the 1 in 10 year annual average concentration 5.8 μg/L for the 21

- day average concentration, and 5.2 μg/L for the 60

- day average concentration

For the chronic dietary risk assessment, the 1 in 10 year annual average surface water

concentration of 4.5 μg/L was used.

4.3 Dietary Exposure and Risk
Dietary Exposure and Risk Memorandum

, D3 88134, D. Davis, 6/22 /11



### 4.3.1 Acute Dietary Exposure/Risk

No toxic effects attributable to a single dose of hexythiazox were observed in the toxicology database; ther efore, an acute dietary exposure and risk assessment for this

chemical was not conducted.

4.3.2 Chronic Dietary Exposure/Risk

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

dr inking water estimates, assumed 100% crop treated, and incorporated DEEM default

proc essing factors. This highly conservative risk assessment showed no risks of concern (<100% of the chronic population adjusted dose (cPAD)) for the U.S. General P opulation or any subpopulation. The estimated exposure to the U.S. General P opulation res ulted in a risk equivalent to 12 % 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 51 % of the

cPAD. Results for all subpopulat ions are summarized in Table 4.3 .3, below.

4.3.3 Cancer Dietary Risk

The HED Cancer Assessment Review Committee (CARC) has recently reconsidered hexythiazox and has classified the chemical as “Likely to be Carcinoge nic to Humans”, but has determined that there is insufficient evidence to quantify risk using a cancer slope factor. Rather, the committee concluded that regulation based on the chronic reference

dose will be protective for both chronic and carcinogenic r isks. As noted above there are

no chronic risks of concern.

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 17 of 31 Table 4.3.3 . Summary of Dietary (Food and Drinking Water) Exposure and Risk for Hexythiazox

Population Subgroup Acute Dietary (95th Percentile) Chronic Dietary Cancer

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

General U.S. Population

N/A N/A 0.003030 12 No concern for risks

associated with the carcinogenic potential of hexythiazox.

All Infants (< 1 year old) 0.005863 24

N/A N/A Children 1

- 2 years old 0.012761 51

Children 3

- 5 years old 0.008814 35

Children 6

- 12 years old 0.004476 18

Youth 13

- 19 years old 0.002321 9.3

Adults 20

- 49 years old 0.001951 7.8

Adults 50+ years old 0.002191 8.8

Females 13

- 49 years old 0.002086 8.3

* Most highly exposed subpopulation is highlighted in bold.



### 4.4 Anticipated Residue and Percent Crop Treated (%CT) Information

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

exposur e and risk assessment conducted to support the amended and ne w use s of hexythiazox on field corn and greenhouse tomatoes.

5.0 Residential and Other Non

- Occupational Exposures/Risks
D371715, A. LaMay, 3/23/10 , Residential Exposure and Risk Assessment



### There are no new residential uses proposed with the new use on greenhouse tomatoes and

amended use on field corn

. The r esidential handler and post

- occupational exposures and

risks were previously assessed in the memorandum cited above. Results of that

assessm ent are summarized in the tables below.

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 18 of 31 5.1 Residential Handler Exposure and Risk

Table 5.1 . Short

- term Exposure and Risks for Residential Handlers

Exposure Scenario (Data Source) Application

Rate 1 (lb ai/ gallon) Quantity

Handled/ Treated per day 2 Inhalation Unit

Exposure (μg/ lb ai) 3 Inhalation Dose

(mg/kg/ day) 4 Baseline Inhalation

MOE 5 *

Mixer/Loader/ Applicator Scenarios

Liquids/ Low Pressure

Handwand (ORETF data OMA006)

0.0625 lb

ai/ 100 gal 5 gallons 2.7 1.3E

- 7 220 ,000,000

Liquids/ Hose End Sprayer,

Lawn (ORETF data OMA004) 17 7.6E

- 7 40 ,000,000

Hose End Sprayer (ORETF data OMA006) 0.82 3.7E

- 8 820 ,000,000

Hose End Sprayer on trees and ornamentals (ORETF data OMA005) 1.5 6.7E

- 8 450 ,000,000

Handheld pump spray on

trees and ornament als (ORETF data OMA005) 3.8 1.7E

- 7 180 ,000,000

1 Application rates are based on maximum application rates of product.

2 Quantity treated daily values are back

- calculated from 5 gallons of finished spr ay solution being used per day (Revised

Residential SO Ps 2001) for outdoor products

. 3 Unit Exposure data sources are identified in the exposure scenario column. All exposure scenarios assess exposure reflecting applicators wearing short

- sleeved shirts and shorts and no respiratory protection.

4 Daily Inhalat ion Dose = (Inhalation Unit Exposure ( μ g ai / lb ai ) * Conversion Factor (1 mg/ 1000 μg) * Application Rate (lb /gal ) * Quantity handled ( gallons/day )) / Body Weight (70 kg)

5 Inhalation MOE = PoD (NOAEL of 30 mg/kg/day) / Daily inhalation dose (mg/kg/day )



### 5.2 Residential Postapplication Exposure

Table 5.2 . Residential Post

- application Short

- and Intermediate

- term Exposures and Risks for Hexythiazox Exposure Scenario Application

Rate 1 (lb ai/A) Exposed

Population & Exposure

Duration 2 Daily Dose

(mg/kg/day ) 3 MOE 4



### Treated Turf/ Lawn Exposure Scenarios

Hand

- to

- Mouth from

Treated Turf

0.19 Child ST 0.0028 11,000

Child IT 0.0013 22,000

Object

- to

- Mouth from

Treated Lawn Child ST, IT 0.00071 42,000

Soil Ingestion in

Lawn/ Garden Child ST, IT 9.52E

- 6 3,2 00,000

1 Application rates are based on maximum label application rate.

2 ST= short

- term duration; IT = intermediate

- term duration.

3 Daily Dose = Daily Dose algorithms for various residential post

- application scenarios outlined in D371715

. 4 MOE = PoD ( NOAEL of 30 mg/kg/day for short

- and intermediate

- term durations )/ Daily dose (mg/kg/day)

.



### 5.3 Other

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from groundboom application methods. The

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 19 of 31 Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. The Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT® computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target drift and risks associated with aerial as well as other application types where appropriate.

6.0 Aggregate Risk Assessments and Risk Characterization

6.1 Acute Aggregate Risk

No toxic effects attributable to a single dose of hexythiazox were observed in the toxicology database; therefo re, an acute aggregate risk assessment for this chemical is not required.

6 .2 Short

- and Intermediate

- Term Aggregate Risks

Short

- and intermediate

- term aggregate risks combine residential handler and post application exposures with average food and wat er exposures. Short

- and intermediate

term aggregate margins of exposure for adu lts and children ranged from 1,900 to 15 ,000.

Since the level of concern for these risk ass essments is for MOEs less than 100, there are

no short

- or intermediate

- term aggreg ate risks of concern. Table 6.2.1 summarizes the residential exposure values used in the short

- and intermed iate

- term aggregate
assessments and Table 6.2.2 summarizes the short

- and intermediate

- term aggregate
risks.

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 20 of 31 Table 6.2.1. Short

- and Intermediate

- Term Residential Exposure Values and Sources Used in the Hexythiazox Aggregate Risk Assessment

Population Handler Exposure (mg/kg/day) Postapplication Exposure (mg/kg/day) Residential Exp osure (mg/kg/day) 1



### Short

- Term

Adult Male 7.6 x 10 - 7

Source: Table 5.1 Liquids/ Hose End Sprayer, Lawn N/A 7.6 x 10 - 7



### Adult Female 7.6 x 10 - 7

Source: Table 5.1 Liquids/ Hose End Sprayer, Lawn N/A 7.6 x 10 - 7



### Child N/A 0.0028

Source: Table 5.2

Hand

- to

- Mouth from

Treated Turf 0.0028



### Intermediate

- Term

Adult Male N/A N/A N/A



### Adult Female N/A N/A N/A



### Child N/A 0.0013

Source: Table 5.2

Hand

- to

- Mouth from

Treated Turf 0.0013

1 Residential exposure is the sum of the handler (adults only) and post appl ication exposures.

2 N/A is not applicable because there is no dermal endpoint.

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 21 of 31 Table 6.2.2. Short

- Term and/or Intermediate

- Term Aggregate Risk Calculations

Population Short

- Term Scenario

NOAEL mg/kg/day LOC 1 Max

Allowable Exposure 2
mg/kg/day Av erage

Food &

Water Exposure mg/kg/day Residential

Exposure 3
mg/kg/day Aggregate MOE

(food and residential) 4

Adult Male 30 100 0.3 0.002191 7.6 x 10 - 7 14 ,000

Adult Female 30 100 0.3 0.002191 7.6 x 10 - 7 14 ,000

Child 30 100 0.3 0.012761 0.0028 1

, 9 00

In termediate

- Term Scenario

Adult Male 30 100 0.3 0.002191 N/A 14 ,000

Adult Female 30 100 0.3 0.002191 N/A 14 ,000

Child 30 100 0.3 0.012761 0.0013 2,1 00

1 The LOC of 100 is based on the standard inter

- and intra

- species extrapolation factors.

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

3 Residential Exposure values taken from Table 6.2.1.Average food & water exposure taken from Table

4.3.3.

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



### 6.3 Long

- Term (Chronic) Aggregate Risk

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

- term residential exposure, long

term aggregate risk includes average food and water residues only. As noted in Section 4.3.2 of this memorandum, there a re no chronic dietary (food and water) risks of concern.

7.0 Cumulative Risk Characterization/Assessment

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

a c ommon 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 produce a toxic metabolite produced by other substances. For the purposes of this

tolerance a ction, 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 cumulating effects from substances found to have a common mechanism on EPA’s

website at http://www.epa.gov/pesticides/cumulative/.

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 22 of 31 8.0 Occupational Exposures and Risks
D389550, A. LaMay, 5/10/11, Occupational Exposure and Risk Assessment



### An occupation exposure and risk assessment was conducted to s upport the amended use on field corn and the new use on greenhouse tomatoes. Full details of that assessment are included in the memorandum cited above and the results are briefly summarized here.

8.1 Occupational Handler Risk

The occupational exposure and risk assessment addresses risks to workers exposed in an occupational setting via the dermal and inhalation routes of exposure. However, for hexythiazox a quantitative dermal risk assessment is not required; therefore risks were quantitatively assesse d for inhalation exposure only. All occupational handler scenarios

assessed for the amended field corn and new greenhouse tomato uses resulted in estimated inhalation margins of exposure (MOEs) which were significantly greater than

100 with baseline inhal ation protection (no respirator). Therefore, inhalation risks are not of concern and inhalation personal protective equipment (PPE, i.e., respirators) is not required.

Occupational handler risks for field corn and greenhouse tomatoes are shown in Table

8.1.

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 23 of 31 Table 8.1. Short

- and Intermediate

- Term Inhalation Exposures and Risks for Occupational Handlers of Hexythiazox at Baseline Inhalation Protection (no respirator)

Exposure Scenario Crop Application

Rate 1 Inhalation Unit

Exposure 2
(μg/lb ai) Area/ Amount

Treated Daily 3 Inhalation Daily

Dose (mg/kg/ day) 4 Baseline

Inhalation

MOE 5

Mixer/Loader Scenarios

Mix/Load Liquids for Aerial Application

Field

Corn 0.19

lb ai/ A

0.219 1200 acres 0.000713 42,000

Mix/Load Liquids for Chemigation 350 acres 0.000208 140,000

Mix/Load Liquids for Groundboom Application 200 acres 0.000119 250,000

Mix/Load Liquid for High Pressure Handwand Application Tomato 0.19 lb ai/20 gal 1000 gallons 0.0000297 1,000,000

Mixer/Loader/ Applicator Scenarios

Mix/L oad/Apply Liquid Flowable by Handgun Spray Tomato 0.19

lb ai/ A 1.9 5 acres 0.0000258 1,200,000

Mix/ Load/ Apply Liquid by

Low Pressure Handwand
Tomato 0.19 lb ai/20 gal 30 40 gallons 1.63x10
- 4 180,000

Mix/ Load/ Apply Liquid by Backpack sprayer 30 40 gallons 1.63x10
- 4 180,000

Applicator Scenarios

Applying Sprays by Enclosed

Fixed

- Wing Aircraft 6 Field

Corn 0.19

lb ai/ A Eng. Control:

0.068 1200 acres 0.00022 140,000

Applying Sprays by Open Cab

Groundboom 0.34 200 acres 0.000185 160,000

High Press ure Handwand Tomato 0.19 lb ai/20 gal 79 1000 gallons 0.01072 2,800

Flagger Scenario

Flagging for Liquid Aerial Application Field

Corn 0.19

lb ai/ A 0.35 1200 acres 0.0011 26,000

1 Application rates are based on maximum values found on the label

. 2 Baseli ne inhalation unit exposures represent no respirator protection. All v alues are reported in the Occupational Pesticide Handler Unit Exposure Surrogate Reference Table dated May 2011, using PHED, AHETF, and ORETF data.

3 Area treated daily values are from th e EPA HED estimates of area treated in a single day for each exposure scenario of

concern.

4 Daily Inhalation Dose = (Inhalation Unit Exposure (μg ai / lb ai) * Conversion Factor (1 mg /1000 μg) * Application Rate (lb ai /A) * Area Treated (A/day or gal/da y)) / Body Weight (70 kg).

5 Inhalation MOE = PoD (NOAEL of 30 mg/kg/day for short

- and intermediate

- term exposure durations) / Daily inhalation dose (mg/kg/day)

. 6 Application by fixed

- wing aircraft has engineering control of enclosed cab.



### 8.2 Occupation al Post Application Risk

HED uses the term postapplication to describe exposures that 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 activities related to crop production, such as scouting for pests or harvesting. Postapplication exposure levels vary over time and depend of such things as the type of activ ity, the nature of the crop or target that was

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 24 of 31 treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for p ostapplication exposure.

For the occupational dermal exposure pathway, short

- and intermediate

- term quantitative risks assessment were not conducted since quantification of dermal risk is not required for hexythiazox. Therefore no occupational dermal ri sks of concern have been identified for hexythiazox.

Based on the Agency's current practices, a quantitative occupational postapplication inhalation exposure assessment was not performed for hexythiazox at this time. However, there are multiple potenti al sources of postapplication inhalation exposure to individuals performing postapplication activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pe sticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP ) in December 2009. The Agency received the SAP’s final repor t on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available postapplication inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational postapplication inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into pl ace, the Agency may revisit the need for a quantitative occupational postapplication inhalation exposure assessment for hexythiazox.

T he label Restricted Entry Interval (REI) of 12 hours is appropriate and in compliance Worker Protection Standard requirem ents

.

9.0 Data Needs and Label Recommendations

9.1 Toxicology

Based on revisions to the 40 CFR Part 158, additional toxicity data are required to support the continued registration of hexythiazox . The rule requires certain generic testing, including a cute and subchronic neurotoxicity studies, and an immunotoxicity study which have not been submitted for this active ingredient

. Since the toxicology

database does not show any evidence of treatment

- related effects on the nervous system or the immune syst em, these data requirements can be made a condition of registratio n

.

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 25 of 31 9.2 Residue Chemistry

The following residue chemistry deficiencies have been identified.

860.1550 Proposed Tolerances

The proposed tolerances must be revised as specified in Table 9. 2

.

Table 9.2. Tolerance Summary for Hexythiazox

Commodity Tolerance (ppm) Comments; Correct Commodity Definition Established Proposed Recommended

40 CFR §180.448(a)

Cattle meat byproducts 0.02

- 0.05 Cattle, meat byproducts An increase is require d based on updated MRBD calculations and to

harmonize with Codex MRL.

Goat meat byproducts 0.02

- 0.05 Goat, meat byproducts An increase is required based on updated MRBD calculations and to

harmonize with Codex MRL.

Hog meat byproducts 0.02

- 0.05 Hog, meat byproducts An increase is required based on updated MRBD calculations and to

harmonize with Codex MRL.

Horse meat byproducts 0.02

- 0.05 Horse, meat byproducts An increase is required based on updated MRBD calculations and to

harmonize with Codex MRL

. Sheep meat byproducts 0.02

- 0.05 Sheep, meat byproducts An increase is required based on updated MRBD calculations and to

harmonize with Codex MRL.

Field corn forage 6.0

- 3.0 Corn, field, forage

Recommended tolerance based on

outcome of OECD MRL calc ulator. Expired S18 tolerance under 180.448(b) can be removed from

CFR.

Field corn grain 0.02

- 0.02 Corn, field, grain Expired S18 tolerance under 180.448(b) can be removed from

CFR.

Field corn stover

- 6.0 7.0 Corn, field, stover

Recommended tolerance based on

outcome of OECD MRL calculator. Expired S18 tolerance under 180.448(b) can be removed from

CFR.

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 26 of 31 Table 9.2. Tolerance Summary for Hexythiazox

Commodity Tolerance (ppm) Comments; Correct Commodity Definition Established Proposed Recommended

Aspirated grain fractions

- 0.50 0.50 Grain, aspirated fractions Correction to commodity definition required.

Greenhouse tomatoes

- 0.50 0.50 Tom ato



### 9.3 Occupational/Residential Exposure

There are no data gaps with respect to occupational/residential exposure and risk assessment required to support the requested new use.

10.0 Environmental Justice

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

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

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

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Ext ensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categor ized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances war rant. 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 postapplication are evaluated. Further consider ations 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 specifi c subgroups.

11.0 Human Studies

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure data sources such as the Pesticide Ha ndlers Exposure

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 27 of 31 Database (PHED), the Agricultural Reentry Task Force (ARTF) Database , the Outdoor Residential Exposure Task Force (ORETF), and the Agricult ural Handler Exposure Task Force (AHETF). EPA has reviewed all the studies in these multi

- pesticide generic

exposure data sources , and on the basis of available evidence has found them to have been neither fundamentally unethical nor significantly deficie nt relative to standards of ethical research conduct prevailing when they were conducted. There is no regulatory barrier to continued reliance on these studies, and all applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been

satisfied.

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 28 of 31 Appendix A. Toxic ity Profiles

Table A.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.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/fe males, 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.

At the highest dose tested, 397.5/257.6 mg/kg/day, decreased body

- weight g ain 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

Pren atal 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 reproduct ion 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/females

LOAEL >180.67/207.67 m g/kg/day, males/females Offspring NOAEL = 29.73/34.77 mg/kg/day, males/females

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 29 of 31 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 (do g) 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 pronounced)

4

- week range

- findin g: 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 carcinogenicity

870.4300

Carci nogenicity (mouse) 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

rever se 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 Indep endently 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

In vitro mammalian cell cytogenetic 00156894 (1986)

Acceptable The test was negative up to precipitating doses accompanied by severe cytotoxicity ( 167 μg/mL +/

- S9).

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 30 of 31 Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

assay in CHO cells

Cytogenetics

870.5395

In vivo mouse micronucleus assay 44955708

Unacceptable The results were inconclusive because a positive response,

which was wi thin 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 should be repeated to confirm or refute the equivocal results.

Other Effects

870.5550

In vitro UDS assay in prima ry rat hepatocytes 00156893 (1985)

Acceptable The test was negative up to a lethal dose (250 μg/mL).

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 majority 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 hig h

- dose groups, respectively. 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 adrenal s. A sex

related difference 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

Sin gle 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 excreted 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). Significant sex differences e xisted for the pharmacokinetics

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 f eces. 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 acco unting for less than 1.4%. About 20% of the dose was excreted as unchanged NA

- 73 (97% of which

### Hexythiazox Human Health Risk Assessment for Field Corn an d Greenhouse Tomatoes

Page 31 of 31 Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

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 ra dioactivity 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.