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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

 OFFICE OF

CHEMICAL SAFETY 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.: 440296 Registration No.: 10163-277

Petition No.: 0E7787, 0F7773 Regulatory Action: Section 3 Registration

Risk Assessment Type: Single Chemical 

Aggregate Case No.: N/A

TXR No.: NA CAS No.: 78587-05-0

MRID No.: NA 40 CFR: 40 CFR 180.448

 

FROM: Donna 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 Assessment 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 hexythiazox to support 

an amended use on field corn and a new use on greenhouse tomatoes. 
Hexythiazox Human Health Risk Assessment for Field Corn and Greenhouse Tomatoes

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Table of Contents

1.0 Executive Summary................................................................................................. 3

Regulatory 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 Considerations......................................................................................... 11

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

Assessments and Levels................................................................................................ 12

3.6 Endocrine disruption .......................................................................................... 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 and Percent Crop Treated (%CT) Information ................. 17

5.0 Residential and Other Non-Occupational Exposures/Risks .................................. 17

5.1 Residential Handler Exposure 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 Risks ................................................ 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 Environmental Justice............................................................................................ 26

11.0 Human Studies....................................................................................................... 26

Appendix A. Toxicity Profiles......................................................................................... 28
Hexythiazox Human Health Risk Assessment for Field Corn and Greenhouse Tomatoes

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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 45 to 30 days and to 

expand the use from its current regionally restricted use to a national registration. In 

support of the proposed amendment, Gowan Company, under PP#0F7773, is proposing 

that the 40 CFR 180.448(a) be amended to reflect the following tolerances: 

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 and under PP#0E7787 and has petitioned to 

establish a new tolerance under 40 CFR 180.448 (a) as follows: 

Tomato .................................................................................0.50 ppm

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. 

However, the Agency believes that the current toxicity database is adequate to evaluate 

the hazards associated with these amended and new 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 adrenal glands in dogs, 

rats and mice, with the dog being 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 gain and food consumption were 

observed. In the reproductive toxicity study, decreased pup body weights were observed

during lactation and delayed hair growth and/or eye opening were observed in the pups at 

the same dose levels where decreased parental 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 whole 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 considered protective of all chronic effects including potential 

carcinogenicity of hexythiazox. 
Hexythiazox Human Health Risk Assessment for Field Corn and Greenhouse Tomatoes

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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 parental body-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 equivalent 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 neurotoxicity 

studies and an immunotoxicity study are required, the Agency does not believe that 

conducting these studies will result in lower PODs than those currently used for risk 

assessment, and therefore, a database uncertainty factor (UFDB) 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; sufficient evidence 

exists to reduce the FQPA safety factor to 1X. All quantitative risk assessments 

employed inter- and intra- species uncertainty factors. 

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 the recommended revised and new tolerances. 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 recommended. 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 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. 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 

only a chronic dietary (food and drinking water) exposure and risk assessment. Chronic 
Hexythiazox Human Health Risk Assessment for Field Corn and Greenhouse Tomatoes

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dietary risks 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 long-term (chronic) 

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

A quantitative dermal risk assessment is not required for hexythiazox. Occupational 

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 hexythiazox 

associated with the field corn and tomato uses of this active ingredient. 

No additional personal protective equipment (PPE) is required. The label restricted entry 

interval (REI) of 12 hours is appropriate and in compliance Worker Protection Standard 

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 Minority Populations and LowIncome 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 were 

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

Provided the registrant submits revised Section F (see Table 9.2) and further provided the 

toxicology studies detailed in Section 9.1 of this 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 .......................................................0.05 ppm

Sheep, meat byproducts.......................................................0.05 ppm

Corn, field, forage ................................................................3.0 ppm

Corn, field, stover ................................................................7.0 ppm

Grain, aspirated fractions.....................................................0.50 ppm

Tomato .................................................................................0.50 ppm
Hexythiazox Human Health Risk Assessment for Field Corn and Greenhouse Tomatoes

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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 

new/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 language 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 stage. 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. 
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Table 2.1. Summary of Directions for Use of Hexythiazox.

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 cover 

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 Tomatoes

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. 

Conclusions. 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 and are 

supported by the submitted data. 
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2.1.1 Structure and Nomenclature

Table 2.2 Structure and Nomenclature of Hexythiazox.

Compound

N

S

H3C

O

Cl

N

H

O

Common name Hexythiazox

Company experimental names DPX-Y5893, NA-73

IUPAC name (4RS,5RS)-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® 1E Ovicide/Miticide)

(4-chlorophenyl)-4-methyl-2-

oxo-3-thiazolidine moiety

S

N

H

O

H3C

Cl

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 Reference1

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 constant, pKa Not applicable

Octanol/water partition coefficient 

Log(POW)

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.
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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. 

However, 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, the Agency believes that the current toxicity database is 

adequate 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 conjunctiva) (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/carcinogenicity 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, decreased 

pup body weights were observed during lactation and delayed hair growth and/or eye 

opening were observed in the pups at the same dose levels where decreased parental 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.

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

increased incidences of malignant and combined benign/malignant liver tumors in highdose 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 based on the 

following considerations: (1) the liver tumors in B6C3F1 mice are a very common tumor 

in that species and were only observed in high dose females; (2) the mammary tumors in 
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rats were benign and were only observed in high dose male rats; and, (3) hexythiazox was 

shown to be non-mutagenic in mammalian 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 female 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. 

The 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 observed. A 100X uncertainty factor was applied to account for inter- and intraspecies 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 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, increased 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 assessments, 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 highdose 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 
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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. 

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 

158 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 effects 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 factor (UFDB) 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 database. A developmental 

neurotoxicity (DNT) study is not required.

The dietary risk assessment is highly conservative and not expected to 

underestimate risk.
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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

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

UFA = 10x

UFH = 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 

IntermediateTerm 

Incidental 

oral

NOAEL=30 

mg/kg/day

UFA = 10x

UFH = 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

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 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 

females, 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. 
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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. UFA = extrapolation from 

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

= use of a LOAEL to extrapolate a NOAEL. FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = 

chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. 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

Short- and 

intermediateTerm 

N/A N/A N/A No dermal hazard identified

Inhalation

Short- and 

IntermediateTerm 

Oral NOAEL = 30 

mg/kg/day

Inhalation hazard 

assumed to be 

equivalent to oral 

hazard

UFA=10x

UFH=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 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 Departure (PoD) = A data point or an estimated point that is derived from observed dose-response data and 

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

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

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

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

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

of exposure. LOC = level of concern. 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 
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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 

Administrator 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 Tier 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 finalized, and before 

publication of the Schedule for Issuance of Test Orders. 

For further information on the status of the EDSP, the policies and procedures, the lists 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 residue 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-thiazolidine 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) exists to 

enforce the recommended revised and new tolerances.

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 field 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 amended 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 
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processing commodity tolerances are required to support the amended use on field corn. 

Since the tomato use is limited 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. 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. 

4.2 Drinking Water Residue Profile

EFED Field and Sweet Corn Drinking Water Assessment, D382948, D383019, A. Shelby, 1/3/10

EFED Greenhouse Tomato Drinking 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. 

The Agency does not have monitoring data available to perform a quantitative drinking 

water risk assessment for hexythiazox. Therefore, the potential for 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 assessment 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 Analysis 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 evaluated 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 adjustment, the maximum estimated surface water exposure 
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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, D388134, 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; therefore, 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 

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

processing factors. This highly conservative risk assessment showed no risks of concern 

(<100% of the chronic population adjusted dose (cPAD)) for the U.S. General Population

or any subpopulation. The estimated exposure to the U.S. General Population resulted in 

a risk equivalent to 12% of the cPAD. The estimated exposure to children 1 – 2 years of 

age, the most highly exposed subpopulation, resulted in a risk equivalent to 51% of the 

cPAD. Results for all subpopulations 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 Carcinogenic 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 risks. As noted above there are 

no chronic risks of concern. 
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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/kg/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 

exposure and risk assessment conducted to support the amended and new uses 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 residential handler and post-occupational exposures and 

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

assessment are summarized in the tables below. 
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5.1 Residential Handler Exposure and Risk

Table 5.1. Short-term Exposure and Risks for Residential Handlers 

Exposure Scenario 

(Data Source)

Application 

Rate1 (lb ai/ 

gallon)

Quantity 

Handled/ 

Treated per 

day2

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 ornamentals 

(ORETF data OMA005)

3.8 1.7E-7 180,000,000

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

2Quantity treated daily values are back-calculated from 5 gallons of finished spray solution being used per day (Revised 

Residential SOPs 2001) for outdoor products.

3Unit 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 Inhalation Dose = (Inhalation Unit Exposure (μg 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 

Rate1 (lb 

ai/A)

Exposed 

Population & 

Exposure 

Duration2

Daily Dose 

(mg/kg/day)

3

MOE4

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 3,200,000

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 
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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; therefore, 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 water exposures. Short- and intermediateterm aggregate margins of exposure for adults and children ranged from 1,900 to 15,000. 

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

no short- or intermediate-term aggregate risks of concern. Table 6.2.1 summarizes the 

residential exposure values used in the short- and intermediate-term aggregate 

assessments and Table 6.2.2 summarizes the short- and intermediate-term aggregate 

risks.
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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 Exposure

(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 application exposures. 

2

N/A is not applicable because there is no dermal endpoint.
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Table 6.2.2. Short-Term and/or Intermediate-Term Aggregate Risk Calculations 

Population

Short-Term Scenario

NOAEL

mg/kg/day LOC1

Max 

Allowable

Exposure2

mg/kg/day

Average

Food & 

Water

Exposure

mg/kg/day

Residential 

Exposure3

mg/kg/day

Aggregate MOE

(food and

residential)4

Adult Male 30 100 0.3 0.002191 7.6 x 10-714,000

Adult Female 30 100 0.3 0.002191 7.6 x 10-714,000

Child 30 100 0.3 0.012761 0.0028 1,900

Intermediate-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 2,100

1 The LOC of 100 is based on the standard inter- and intra-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 Table 6.2.1.Average food & water exposure taken from Table 

4.3.3.

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

6.3 Long-Term (Chronic) Aggregate Risk

As there are no uses that are expected to result in long-term residential exposure, longterm aggregate risk includes average food and water residues only. As noted in Section 

4.3.2 of this memorandum, there are 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 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 

produce 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 

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

website at http://www.epa.gov/pesticides/cumulative/.
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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 support 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 assessed 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 inhalation 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. 
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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 

Rate1

Inhalation Unit 

Exposure2

(μg/lb ai)

Area/ Amount 

Treated Daily 3

Inhalation Daily 

Dose (mg/kg/ 

day)4

Baseline 

Inhalation 

MOE5

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/Load/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 1.63x10-4180,000

Mix/ Load/ Apply Liquid by 

Backpack sprayer 30 40 gallons 1.63x10-4

180,000

Applicator Scenarios

Applying Sprays by Enclosed 

Fixed-Wing Aircraft6

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 Pressure 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

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

2Baseline inhalation unit exposures represent no respirator protection. All values are reported in the Occupational 

Pesticide Handler Unit Exposure Surrogate Reference Table dated May 2011, using PHED, AHETF, and ORETF data. 

3Area treated daily values are from the 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/day)) / 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 Occupational 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 activity, the nature of the crop or target that was 
Hexythiazox Human Health Risk Assessment for Field Corn and Greenhouse Tomatoes

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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 postapplication 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 risks 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 potential 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 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. The Agency 

received the SAP’s final report 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 place, the Agency may revisit the 

need for a quantitative occupational postapplication inhalation exposure assessment for 

hexythiazox.

The label Restricted Entry Interval (REI) of 12 hours is appropriate and in compliance 

Worker Protection Standard requirements.

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 acute 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 system, these data requirements can be made a condition of registration.
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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 required 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 calculator. 

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. 
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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 Tomato

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 concerns, to the extent possible, were considered 

in this human health risk assessment, in accordance with U.S. Executive Order 12898, 

"Federal Actions to Address Environmental Justice in Minority Populations and LowIncome Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED 

estimates risks to population subgroups from pesticide exposures that are based on 

patterns of that subgroup’s food and water consumption, and activities in and around the 

home that involve pesticide use in a residential setting. Extensive data on food 

consumption patterns are compiled by the USDA under the 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 categorized 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 warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and 

associated risks for adult applicators and for toddlers, youths, and adults entering or 

playing on treated areas postapplication 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.

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 Handlers Exposure 
Hexythiazox Human Health Risk Assessment for Field Corn and Greenhouse Tomatoes

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Database (PHED), the Agricultural Reentry Task Force (ARTF) Database, the Outdoor 

Residential Exposure Task Force (ORETF), and the Agricultural 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 deficient 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.
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Appendix A. Toxicity 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 LD50 = >5000 mg/kg IV

870.1200 Acute dermal toxicity 00146550 LD50 = >5000 mg/kg IV

870.1300 Acute inhalation toxicity 00146554 LC50 = >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/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. 

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

decreased body-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

Maternal NOAEL 1080 mg/kg/day 

LOAEL >1080 mg/kg/day 

Developmental 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/females

LOAEL >180.67/207.67 mg/kg/day, males/females

Offspring NOAEL = 29.73/34.77 mg/kg/day, males/females
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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 pronounced)

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 carcinogenicity

870.4300

Carcinogenicity 

(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

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

In vitro mammalian 

cell cytogenetic 

00156894 (1986)

Acceptable

The test was negative up to precipitating doses accompanied 

by severe cytotoxicity ( 167 μg/mL +/-S9).
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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 within the wide range of historical background 

data, was recorded for female mice at the mid-and highdoses (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 

primary 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 [14C] 

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 lowdose and high-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 [14C]-

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

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 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 existed 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 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%. About 20% of 

the dose was excreted as unchanged NA-73 (97% of which 
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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 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.