UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: 02/08/2016 

SUBJECT: Hexythiazox. Human Health Risk Assessment to Support Amended Uses on 

Cotton and Citrus. 

PC Code: 128849 DP Barcode: D427090, DP427091; D426297 

Decision No.: 499597, 502652, 502653, 502854. Registration No.: 10163-277 and 10163-250 

Petition No.: 5F8356; 5F8346 Re2ulatory Action: Section 3 

Risk Assessment Tvoe: NA Case No.: 7404-1 

TXRNo.: NA 

MRIDNo.: NA 

FROM: 

CAS No.: 78587-05-0 

40 CFR: 40 CFR 180.448 

Katelynn King, Risk Assessor~~ 

Linda 

Kelly M. 

Taylor, 

Lowe, 

Ph.D., 

Environmental 

Toxicologist 

Scientist / ~ 

Risk Assessment Branch VII 

Health Effects Division (7509P) 

THROUGH: Michael 

RAB VNII, 

Metzger, 

HED 

Supervisory 

(7509P) 

Chemifrt 

itlt_)/}t7 , c{f J c ~ 

/, /~ 

and · 

TO: 

Danette Drew, Senior Chemist 

RAB VII, HED (7509P) 

Nerija Orentas, Risk Manager 

RichardGebken,ProductManager 10 

Invertebrate Vertebrate Branch 2 (IVB2) 

Registration Division (7505P) 

Page I of34 
Page 2 of 34 

Table of Contents 

1.0 Executive Summary ............................................................................................................. 4

2.0 HED Recommendations....................................................................................................... 5

2.1 Data Deficiencies ............................................................................................................. 5

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

2.2.1 Enforcement Analytical Method ............................................................................... 6

2.2.2 Recommended Tolerances ........................................................................................ 6

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

2.2.4 International Harmonization ..................................................................................... 7

2.3 Label Recommendations .................................................................................................. 7

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

2.3.2 Recommendations from Occupational Assessment .................................................. 7

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

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

3.1 Chemical Identity ............................................................................................................. 7

3.2 Physical/Chemical Characteristics ................................................................................... 8

3.3 Pesticide Use Pattern ........................................................................................................ 9

3.5 Consideration of Environmental Justice .......................................................................... 9

4.0 Hazard Characterization and Dose-Response Assessment ................................................ 10

4.1 Summary of Toxicological Effects ................................................................................ 10

4.2 Safety Factor for Infants and Children (FQPA Safety Factor) ....................................... 11

4.2.1 Completeness of the Toxicology Database ............................................................. 11

4.2.2 Evidence of Neurotoxicity ...................................................................................... 11

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ......... 11

4.2.4 Residual Uncertainty in the Exposure Database ..................................................... 11

4.2.5 Cancer Classification and Risk Assessment Recommendation .............................. 12

4.3 Toxicity Endpoint and Point of Departure Selections .................................................... 12

4.4 Endocrine Disruption ..................................................................................................... 14

5.0 Dietary Exposure/Risk Characterization ............................................................................ 15

5.1 Residue Chemistry Summary ......................................................................................... 15

5.2 Drinking Water Residue Profile ..................................................................................... 16

5.3 Dietary Exposure and Risk ............................................................................................. 17

5.3.1 Acute Dietary Exposure/Risk ................................................................................. 17

5.3.2 Chronic Dietary Exposure/Risk .............................................................................. 17

5.3.3 Cancer Dietary Risk ................................................................................................ 18

5.3.4 Summary Table ....................................................................................................... 18

6.0 Residential and Other Non-Occupational Exposures/Risks .............................................. 18

6.1 Residential Handler Exposure and Risk ......................................................................... 18

6.2 Residential Post-application Exposure ........................................................................... 19

6.3 Residential Risk Estimates for Use in Aggregate Assessment ............................................... 20

7.0 Aggregate Risk Assessments and Risk Characterization ................................................... 21

7.1 Acute Aggregate Risk .................................................................................................... 21

7.2 Short- and Intermediate-Term Aggregate Risks ............................................................ 22

7.3 Long-Term (Chronic) Aggregate Risk ........................................................................... 22

8.0 Cumulative Risk Characterization/Assessment ................................................................. 22

9.0 Occupational Exposures and Risks .................................................................................... 23
Page 3 of 34 

9.1 Occupational Handler Risk ............................................................................................ 23

9.2 Occupational Post-application Risk ............................................................................... 23

10.0 Human Studies ................................................................................................................... 24

Appendix A. Toxicology Assessment.......................................................................................... 25

Appendix B: Toxicology Data Requirements ............................................................................... 29

Appendix C: Field Trial Residue Data .......................................................................................... 30

Appendix D: Maximum Residue Limits (MRL) .......................................................................... 31

Appendix E: OECD Calculator MRL Output ............................................................................... 32
Page 4 of 34 

1.0 Executive Summary 

Hexythiazox, trans-5-(4-chlorophenyl)-N-cyclohexyl-4-methyl-2-oxothiazolidine-3-

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

outdoor residential settings. Hexythiazox is a contact pesticide which achieves control of eggs or 

immature mites via direct contact or contact with treated surfaces. 

Gowan Company has submitted citrus and cotton data to support the following requests: 

 Cotton tolerance changes and expanded use from regional to national, and 

 Citrus tolerance increase and pre-harvest interval (PHI) change. 

The toxicity database for hexythiazox is complete. Hexythiazox is associated with toxicity of the 

liver and adrenals following sub-chronic and chronic exposure to dogs, rats and mice, with the 

dog being the most sensitive species. The prenatal developmental studies in rabbits and rats, and 

the two-generation reproduction study in rats showed no indication of increased susceptibility to 

in utero and/or postnatal exposure to hexythiazox. Reproductive toxicity was not observed. 

There is no concern for neurotoxicity following exposure to hexythiazox. The toxicology 

database for hexythiazox does not show any evidence of treatment-related effects on the immune 

system. Hexythiazox is classified as “likely to be carcinogenic to humans”; however, since the 

effects seen in the study that serves as the basis for the chronic reference dose (RfD) occurred at 

doses substantially below the lowest dose that induced tumors, HED concluded that 

quantification of risk using a non-linear approach; i.e., RfD, for hexythiazox will adequately 

account for all chronic toxicity, including carcinogenicity, that could result from exposure to 

hexythiazox. 

No acute risk is expected since no hazard was identified in any toxicity study for this duration of 

exposure. Chronic risk is regulated based on effects seen in the adrenal glands in a one-year dog 

feeding 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 since no dermal hazard has been 

identified for hexythiazox. The dermal equivalent dose, after applying the estimated dermal 

absorption factor of 2% to the oral reproduction study no observed adverse effect level (NOAEL) 

of 30 mg/kg/day, is 1500 mg/kg/day, which is greater than the limit dose. 

 

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

chronic dietary (food and drinking water) exposure and risk assessment. The chronic dietary risk 

assessment used tolerance level residues, assumed 100% crop treated, included DEEM default 

processing factors, and modeled water values. This unrefined assessment resulted in estimated 

chronic dietary (food and water) risks of 18% of the chronic population adjusted dose (cPAD) 

for the U.S. population and 81% of the cPAD for children 1 – 2 years of age, the most highly 

exposed population subgroup. 

There are no new residential uses proposed with this action; however, there are registered uses 

on residential sites which have been previously assessed, including (1) ornamental landscape 
Page 5 of 34 

plantings in residences, public areas, and recreational sites such as campgrounds, golf courses, 

parks and athletic fields, (2) ornamental lawns and turf (including residential), (3) residential 

pome fruit, stone fruit, and nut trees, and residential caneberries. Residential handler inhalation 

margins of exposure (MOEs) significantly exceed 100 for all scenarios assessed and are not of 

concern. Child post-application incidental oral exposure to treated turf was assessed for 

hexythiazox, and risk estimates greatly exceed the LOC of 100 for all scenarios associated with 

children’s exposure to treated turf and are not of concern. 

Since there are no acute endpoints of concern, an acute aggregate risk assessment was not 

conducted. HED has conducted short- and intermediate-term (food, drinking water and 

residential), and long-term/chronic (food and drinking water) aggregate risk assessments for 

hexythiazox. Short- and intermediate-term aggregate margins of exposure (MOEs) significantly 

exceeded the level of concern (LOC) of 100 and are not of concern. The long-term (chronic) 

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

residential exposure scenarios. Chronic dietary risk is not of concern. 

The proposed amended uses on cotton and citrus do not include any changes to application 

methods and/or rates. Therefore, a new assessment of occupational exposure is not required, and 

a previous assessment (Memo, A. Lamay, D404018, 06-May-2013) is protective of the amended 

use pattern. In that assessment, occupational handler inhalation MOEs significantly exceeded 

100 for all scenarios assessed including mixers/loaders, applicators and flaggers. Based on the 

Agency's current practices, a quantitative non-cancer occupational post-application inhalation 

exposure assessment was not performed for hexythiazox. If new policies or procedures are put 

into place, the Agency may revisit the need for a quantitative occupational post-application 

inhalation exposure assessment for hexythiazox. The label restricted entry interval (REI) of 12 

hours is appropriate and in compliance with 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 Low-Income Populations," 

http://www.archives.gov/federal-register/executive-orders/pdf/12898.pdf).

2.0 HED Recommendations 

Provided the proposed label is amended as noted in Section 2.3.1, there are no hazard, exposure, 

or risk considerations that would preclude granting the requested use on cotton and citrus, and 

setting the recommended tolerance described in Section 2.2.2. 

2.1 Data Deficiencies 

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

this action. 

2.2 Tolerance Considerations 
Page 6 of 34 

2.2.1 Enforcement Analytical Method 

An adequate HPLC/UV analytical method is available for the enforcement of tolerances for 

residues of hexythiazox and its metabolites containing the PT-1-3 moiety in crop and livestock 

commodities. This method is listed in the U.S. EPA Index of Residue Analytical Methods under 

hexythiazox as method AMR-985-87. 

2.2.2 Recommended Tolerances 

Tolerances currently established under 40 CFR §180.448 need to be updated in order to comply 

with the HED recommendations. Table 2.2.2 summarizes the recommended tolerance levels and 

commodity definition required to support the altered uses of cotton and citrus. 

 

Table 2.2.2. Tolerance Summary for Hexythiazox. 

Commodity 40 CFR Established 

Tolerance (ppm) 

Registrant Proposed 

Tolerance (ppm) 

HED-Recommended 

Tolerance (ppm) 

Comments 

(correct commodity definition) 

Citrus, dried pulp 0.60 0.6 Revoke Revoke. A 0.5 ppm tolerance 

on dried citrus pulp is 

appropriate; however, the 

recommended 0.5 ppm 

tolerance for the citrus crop 

group 10-10 is adequate to 

cover any residues of 

hexythiazox in dried citrus 

pulp. 

Citrus, oil 24 26 25a N/A 

Fruit, citrus, 

group 10-10 

0.35 0.6 0.5 Harmonized with Codex. For 

use in CA, AZ, and TX only. 

Cotton, 

gin byproducts 

3.0 15 15b Established for CA and AZ 

only. Recommended for USA. 

Cotton, 

undelinted seed 

0.20 0.5 0.4b Established for CA and AZ 

only. Recommended for USA. a Processing factors used from citrus (orange) processing study (D334889, 07/03/2006, T. Bloem).

b Tolerance calculated using data collected from previously submitted (44574703) and recently submitted 

(49554501) studies.

2.2.3 Revisions to Petitioned-For Tolerances 

For citrus, dried pulp, there was no change from the established tolerance compared to the 

registrant proposed tolerance; however, HED recommends that the citrus, dried pulp tolerance be 

revoked as it is covered by the citrus group 10-10 tolerance. For citrus oil, the 40 CFR 

established tolerance of 24 ppm is lower than the registrant proposed tolerance of 26 ppm; HED 

recommends a tolerance of 25 ppm. This HED recommended tolerance was obtained by 

multiplying the citrus oil processing factor (104x) from the 2006 processing study (D334889, 

07/03/2006, T. Bloem) by the highest average field trial (HAFT) residue for lemons (0.243 ppm) 

from the recently submitted citrus study (MRID 49591801) since lemons are the citrus crop that 

produced the highest residues for fruit, citrus, group 10-10 which will continue to be a regional 

use only in California, Arizona, and Texas. 
Page 7 of 34 

For cotton gin byproducts, the 40 CFR established tolerance is currently at 3.0 ppm, however, 

the registrant proposes increasing the tolerance to 15 ppm and HED concludes that the data 

support that. For cotton, undelinted seed, the 40 CFR tolerance is currently at 0.20 ppm and the 

registrant proposes increasing the tolerance to 0.5 ppm. HED recommends a tolerance increase 

to 0.4 ppm; the difference is due to HED using new recently submitted data and old previously 

submitted data residue data to calculate the recommended Organization for Economic 

Cooperation & Development Maximum Residue Limit (OECD MRL). 

2.2.4 International Harmonization 

There are no Canadian or Mexican maximum residue limits (MRLs) established or proposed for 

residues of hexythiazox on citrus or cotton. Codex has established MRLs for “citrus, fruit, Crop 

Group 10-10” but not for cotton. The Codex plant residue definition is for hexythiazox as 

opposed to the U.S. definition which includes hexythiazox plus metabolites containing the (4-

chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety. The differences in U.S. and Codex residue 

definitions prohibit harmonization. A summary of U.S. and international tolerances and MRLs is 

presented in Appendix D. 

2.3 Label Recommendations 

2.3.1 Recommendations from Residue Reviews 

No label changes are required based on the chemistry assessment. 

2.3.2 Recommendations from Occupational Assessment 

No label changes are required based on the occupational assessment. 

2.3.3 Recommendations from Residential Assessment 

No label changes are required based on the residential assessment. 

3.0 Introduction 

Hexythiazox, trans-5-(4-chlorophenyl)-N-cyclohexyl-4-methyl-2-oxothiazolidine-3-

carboxamide, is an ovicide/miticide used to control mites on a variety of crops and in outdoor 

residential settings. Hexythiazox is a contact pesticide which achieves control of eggs or 

immature mites via direct contact or contact with treated surfaces. 

3.1 Chemical Identity

The chemical structure and nomenclature of hexythiazox and its common moiety, PT-1-3 is 

shown in Table 3.1. The physicochemical properties of the technical grade hexythiazox are 

presented in Table 3.2. 
Page 8 of 34 

Table 3.1. Nomenclature of Hexythiazox.

Compound 

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® Ovicide/Miticide) 

50% ai DF (EPA Reg. No. 10163-250; Savey® 50 DF Miticide) 

Compound 

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

oxo-3-thiazolidine moiety 

Common name PT-1-3 moiety 

Chemical name 5-(4-chlorophenyl)-4-methyl-thiazolidin-2-one 

3.2 Physical/Chemical Characteristics

Table 3.2. Physiochemical Properties of Hexythiazox. 

Parameter Value Reference 

Melting point/range 108.0-108.5 °C 00143533 

pH Not applicable 

Density 1.289 at 25 °C 00143533 

Water solubility 0.12 ppm 44006301 

Solvent solubility g/L 

chloroform 1379 

xylene 362 

acetone 160.0 

acetonitrile 28.6 

n-hexane 3.9 

methanol 20.6 

00143533 

Vapor pressure <10-8 mm Hg at 25 oC 44006301 

Dissociation 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 

N

S

H3C

O

Cl

N

H

O

S

N

H

O

H3C

Cl
Page 9 of 34 

3.3 Pesticide Use Pattern

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

10163-277) which includes proposed regionally restricted use directions for cotton and citrus. 

Gowan Company has also submitted a supplemental label for Savey® 50 DF (EPA Reg. No. 

10163-250) which includes proposed use directions for cotton. The newly proposed use patterns 

have been summarized in Table 3.3. 

Table 3.3. Summary of Proposed Directions for Use of Hexythiazox. 

Application 

Timing; Type 

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 

Cotton 

Before boll 

opening and 

prior to adult 

mite buildup; 

Ground App., 

Air App., & 

Chemigation 

Onager 

[10163-277] 

20 fl 

oz/A = 

0.156 lb 

ai/A 

1 0.156 35 No more than one 

application per year. 

Ground App. 

& Air App. 

Savey 50 

DF 

[10163-250] 

5 oz/A = 

0.156 lb 

ai/A 

1 0.156 35 No more than one 

application per year. 

Citrus 

Ground App., 

Air App., & 

Chemigation 

Onager 

[10163-277] 

24 fl 

oz/A = 

0.1875 

lb ai/A 

1 0.1875 7 No more than one 

application per year. 

Labels are adequate to allow evaluation of the residue data relative to the proposed use.

3.4 Anticipated Exposure Pathways 

The Registration Division has requested an assessment of human health risk to support the 

proposed amended use of hexythiazox. Humans may be exposed to hexythiazox in food and 

drinking water, since hexythiazox may be applied directly to growing crops and application may 

result in hexythiazox reaching surface and ground water sources of drinking water. Additionally 

humans may be exposed to hexythiazox in residential settings, since it may be applied to 

ornamental plantings in residences, public areas, and recreational sides, as well as on lawns and 

turf and to residential berries and fruit and nut trees. In an occupational setting, applicators may 

be exposed while handling the pesticide prior to application, as well as during application. There 

is a potential for post-application exposure for workers re-entering treated fields. 

Risk assessments have been previously prepared for the existing uses of hexythiazox. This risk 

assessment considers all of the aforementioned exposure pathways based on the proposed new 

use of hexythiazox, as well as the existing uses. 

3.5 Consideration of Environmental Justice
Page 10 of 34 

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

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

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

(http://www.archives.gov/federal-register/executive-orders/pdf/12898.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 U.S. Department of 

Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, 

(NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a 

pesticide. These data are analyzed and categorized by subgroups based on age and ethnic group. 

Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and 

exposure assessments are performed when conditions or circumstances warrant. Whenever 

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

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 

post-application are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 

patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

No new toxicity and/or metabolism data have been received since the last risk assessment. This 

assessment includes summaries of prior assessments (L. Taylor, 06/03/2015, D423491 & 

D423145). 

4.1 Summary of Toxicological Effects 

Hexythiazox was rapidly absorbed, distributed, and eliminated in rats following oral exposure, 

with the majority being eliminated within 24 hours in the urine and feces. There were no 

observable differences in the total elimination between male and female rats, and the major route 

of elimination in both sexes was by fecal excretion. Approximately 11-20% (low dose) and 65-

69% (high dose) of the dosed radioactivity was identified as unchanged hexythiazox. The highest 

tissue residues were detected in the fat, liver, and adrenals, with the residues in female tissues 

being two-fold higher than those found in male tissues. Hexythiazox was metabolized to a large 

number of metabolites that were excreted both in the urine and feces. The main metabolic 

reactions identified were hydroxylation of the cyclohexane ring and cleavage of the amide bond 

to the cyclohexane ring. A dermal absorption factor was derived from a dermal penetration study 

and was estimated to be 2%. 

Hexythiazox is associated with toxicity of the liver and adrenals following subchronic and 

chronic exposure to dogs, rats, and mice, with the dog being the most sensitive species. The 

prenatal developmental studies in rabbits and rats, and the two-generation reproduction study in 

rats, showed no indication of increased susceptibility to in utero and/or postnatal exposure to 

hexythiazox. Reproductive toxicity was not observed. There is no concern for neurotoxicity 
Page 11 of 34 

following exposure to hexythiazox. The toxicology database for hexythiazox does not show any 

evidence of treatment-related effects on the immune system. Hexythiazox is classified as “likely 

to be carcinogenic to humans”; however, 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, HED concluded that quantification of risk using a non-linear approach; i.e., RfD, for 

hexythiazox will adequately account for all chronic effects, including carcinogenicity, that could 

result from exposure to hexythiazox. 

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

The hexythiazox risk assessment team has recommended that the FQPA Safety Factor be 

reduced to 1X because (1) there is an adequate toxicity database for hexythiazox; (2) The 

prenatal developmental studies in rabbits and rats and the two-generation reproduction study in 

rats showed no indication of increased susceptibility to in utero and/or postnatal exposure to 

hexythiazox; (3) There is no concern for neurotoxicity following exposure to hexythiazox, and 

(4) There are no residual uncertainties identified in the exposure databases. 

4.2.1 Completeness of the Toxicology Database 

The database of toxicology studies for hexythiazox is complete and includes developmental 

toxicity studies in the rat and rabbit, a reproductive toxicity study in the rat, and a subchronic 

(28-day) neurotoxicity study in the rat. The Hazard and Science Policy Council (HASPOC) 

concluded that an acute neurotoxicity study is not required, and a new subchronic (90-day) 

neurotoxicity study is not required, since the 28-day neurotoxicity study is sufficient to assess 

subchronic neurotoxicity from hexythiazox exposure (TXR 0056434, dated 10/18/12). 

4.2.2 Evidence of Neurotoxicity 

Decreased motor activity was observed in rats following repeat oral exposure only at a dose level 

close to the limit dose, and a clear NOAEL was established. No other evidence suggestive of 

peripheral or central nervous system toxicity was observed in the toxicology database for 

hexythiazox. The points of departure used for all exposure scenarios are protective of any 

potential neurotoxic effects of hexythiazox. As noted above, HASPOC concluded that an acute 

neurotoxicity study was not required for hexythiazox. 

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

There is no evidence of increased quantitative susceptibility following in utero exposure to 

hexythiazox in either the rat or rabbit developmental toxicity study or following in utero and/or 

pre-/post-natal exposure to hexythiazox in the 2-generation reproduction study in rats. 

4.2.4 Residual Uncertainty in the Exposure Database 

The residential exposure assessment assumes maximum label use rate as well as other 

conservative assumptions. The dietary exposure estimates are unrefined and reflect tolerancelevel residue in food, 100% crop treated (CT), and upper-bound drinking water estimates based 
Page 12 of 34 

on modeling. Therefore, the Agency does not believe that exposure to hexythiazox will be underestimated. 

4.2.5 Cancer Classification and Risk Assessment Recommendation 

Hexythiazox is classified 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. However, 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, HED concluded that quantification of risk using a non-linear 

approach; i.e., RfD, for hexythiazox, will adequately account for all chronic effects, including 

carcinogenicity, that could result from exposure to hexythiazox. 

4.3 Toxicity Endpoint and Point of Departure Selections 

No new toxicity and/or metabolism data have been received since the last risk assessment. There 

have been no changes to the prior dose-response assessment or recommendations for combining 

routes of exposure, and no change in the cancer classification (D. Davis, D396526, D404477, 

9/15/12). The points of departure, uncertainty factors, and toxicity endpoints are presented in the 

following tables. 

Table 4.3.1. Toxicological Doses and Endpoints for Hexythiazox for Use in Dietary and Non-Occupational Human 

Health Risk Assessments. 1 

Exposure/ 

Scenario 

Point of 

Departure 

Uncertainty/F

QPA 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. 
Page 13 of 34 

Table 4.3.1. Toxicological Doses and Endpoints for Hexythiazox for Use in Dietary and Non-Occupational Human 

Health Risk Assessments. 1 

Exposure/ 

Scenario 

Point of 

Departure 

Uncertainty/F

QPA Safety 

Factors 

RfD, PAD, Level of 

Concern for Risk 

Assessment 

Study and Toxicological Effects 

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. 

Co-Critical 

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 

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 (interspecific). UFH = 
Page 14 of 34 

potential variation in sensitivity among members of the human population (intraspecific). 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 4.5.2 Summary of Toxicological Doses and Endpoints for Hexythiazox for Use in Occupational Human Health 

Risk Assessments. 

Exposure/ 

Scenario Point of Departure Uncertainty 

Factors 

Level of 

Concern for 

Risk 

Assessment 

Study and Toxicological Effects 

Dermal 

Short- and 

intermediate-Term 

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

Inhalation 

Short- and 

Intermediate-Term 

Oral NOAEL = 30 

mg/kg/day 

Inhalation hazard 

assumed to be 

equivalent to oral 

hazard 

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 (interspecific). UFH = 

potential variation in sensitivity among members of the human population (intraspecific). MOE = margin of exposure. LOC = level of concern. 

N/A = not applicable. 

4.4 Endocrine Disruption 

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and 

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of its reregistration decision for hexythiazox, EPA reviewed these 

data and selected the most sensitive endpoints for relevant risk assessment scenarios from the 

existing hazard database. However, as required by FFDCA section 408(p), hexythiazox is subject 

to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 
Page 15 of 34 

EPA has developed the EDSP to determine whether certain substances (including pesticide 

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. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of 

chemicals identified for EDSP screening was published on June 14, 20131 and includes some 

pesticides scheduled for registration review and chemicals found in water. Hexythiazox is on the 

second list. Neither of these lists should be construed as a list of known or likely endocrine 

disruptors. For further information on the status of the EDSP, the policies and procedures, the 

lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our 

website2.

5.0 Dietary Exposure/Risk Characterization 

5.1 Residue Chemistry Summary 

Residue Chemistry Memo DP# 427090 & 427091, 11/30/15, K.King (PP#5F8356 & 5F8346) 

Residue Chemistry Memo DP# 360414, 8/17/09, D. Davis (PP#7E7182) 

Residue Chemistry Memo DP# 347948, 2/14/08, T. Bloem (PP#5F6953) 

Residue Chemistry Memo No DP#, 2/12/87, F. Suhre (PP#7G3469) 

Residue Chemistry Memo No DP#, 1/13/86, E. Haeberer (PP#5F3254/5H5469) 

Acceptable apple, citrus, grape, pear, radish, tea and corn metabolism studies have been 

previously submitted and reviewed. The existing metabolism database is adequate to delineate 

the nature of the residue in all plants. The residues of concern in plants are the parent compound 

and its metabolites which contain the (4-chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety 

(also called PT-1-3). 

 

Metabolism data for cotton have not been submitted and are not required at this time because it is 

not expected to significantly differ from the metabolism data that was submitted for the seven 

other crops listed above. 

Gowan Company has petitioned (PP#5F8346 and PP#5F8356) to expand the hexythiazox use on 

cotton from a regional to a national (Section 3) use (EPA Reg. Nos. 10163-250 and 10163-277) 

 

1

 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of chemicals. 2 http://www.epa.gov/endo/
Page 16 of 34 

and, for citrus, to decrease the current PHI from 28 days to 7 days (EPA Reg. No. 10163-277). 

Field trial studies were submitted for cotton and citrus to support these changes, and no further 

information is required at this time. 

Cotton 

Regional tolerances are currently established on cotton, gin byproducts and undelinted seed. The 

submitted cotton study used an application rate of 0.1522-0.1619 lb ai/A, and undelinted 

cottonseed residues ranged from <0.02-0.175 ppm, while residues for cotton gin byproducts 

ranged from 1.96-5.70 ppm. The Organization for Economic Cooperation & Development 

(OECD) Maximum Residue Level (MRL) calculation procedures were used to calculate the 

tolerance for these two commodities. For the MRL calculation of undelinted cotton seed, ten 

values were used from two studies; one previously submitted and one from the current petition 

(MRID 44574703, MRID 49554501). For the MRL calculation of cotton gin byproducts, five 

values were used from the same two studies. The HED recommended tolerance for gin 

byproducts (15 ppm) was equal to the registrant proposed tolerance; however, the undelinted 

seed tolerance that HED recommended (0.3 ppm) was less than the registrant proposed tolerance 

(0.5 ppm). Adequate nature of the residue in confined rotational crops has been delineated and 

additional data are not required at this time. 

Citrus 

The citrus study used an application rate of 0.1827-1907 lb ai/A, and residues for the crop with 

the highest values (lemon) ranged from 0.100-0.264 ppm. Tolerances are currently established 

on fruit, citrus group 10-10 (CA, AZ, and TX only), and nationally in citrus, dried pulp, and oil. 

The OECD MRL calculation procedure was used to calculate the tolerance for citrus group 10-10 

and used five values from the new study (MRID 49591801). The HED recommended tolerance 

for citrus group 10-10 (0.5 ppm) is the same as the registrant proposed tolerance (0.6 ppm). HED 

has decided that the tolerance for citrus, dried pulp should be revoked because residues are 

covered by the citrus group 10-10 tolerance. As for citrus oil, the tolerance was calculated by 

multiplying the citrus oil processing factor (104x) by the HAFT residue value for lemons, and 

the HED recommended tolerance is 1 ppm less than the registrant proposed tolerance (26 ppm vs 

25 ppm). Adequate nature of the residue in confined rotational crops has been delineated and 

additional data are not required at this time. 

Dietary burden was calculated for beef cattle, dairy cattle, swine, and poultry, and did not exceed 

the dietary burden that was calculated in the last assessment. Dietary burden did not increase 

from the last assessment because cotton and citrus feedstuffs did not significantly exceed the 

other feedstuffs in the calculation. 

5.2 Drinking Water Residue Profile 

EFED Drinking Water Assessment, D429192, A. Shelby, 9/21/2015 

The potential for hexythiazox residues in drinking water was evaluated through modeling. The 

drinking water residues used in this dietary risk assessment were provided by the Environmental 

Fate and Effects Division (EFED) in the following memorandum: “Hexythiazox: Drinking Water 

Assessment for Proposed Expanded Use on Cotton” (A. Shelby, D429192, 9/21/2015). The 

citrus PHI amendment is not expected to change the estimated drinking water concentrations 

(EDWCs); therefore, the cotton drinking water assessment covers both cotton and citrus (Email 
Page 17 of 34 

communication with K. King and A. Shelby, 12/2/2015). EDWCs were incorporated directly 

into DEEM-FCID under food categories “water, direct, all sources” and “water, indirect, all 

sources.” Since no environmental fate data has been submitted for degradates of concern, EFED 

conducted the assessment for total residues. 

EFED estimated groundwater values by using PRZM-GW and an extended weather simulation to 

find that groundwater residues are not expected to exceed surface water residues. Therefore, 

EFED provided estimated drinking water concentrations (EDWCs) for various scenarios from 

the Tier II surface water model, SWCC, assuming a 0.95 percent cropped area (PCA) 

adjustment. The maximum estimated surface water concentrations for total residues of 

hexythiazox were from the MS soybean scenario. The 1-in-10 year annual average value of 4.3 

μg/L from this scenario was used in the chronic dietary risk assessment. 

Table 2. Hexythiazox Total Toxic Residues in Drinking Water 

Residue (μg/L) Time Range 

7.3 1 in 10 year Annual Peak Concentration 

4.3 1 in 10 year Annual Average 

3.5 30 year Annual Average 

5.3 Dietary Exposure and Risk 

Dietary Exposure and Risk Memorandum, D427237, K.King, XX/XX/2015 

HED conducted a chronic dietary (food and drinking water) risk assessment to support the 

proposed amended uses of hexythiazox on cotton and citrus. The assessment included all 

existing and proposed hexythiazox uses. 

5.3.1 Acute Dietary Exposure/Risk 

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

database; therefore, a quantitative acute dietary exposure and risk assessment for this chemical 

was not conducted. 

5.3.2 Chronic Dietary Exposure/Risk 

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

water estimates, assumed 100% crop treated, and incorporated DEEM default processing factors. 

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

and risk assessment. The dietary assessment could be substantially refined using anticipated 

residues, percent crop treated information and empirical processing data; however, these 

refinements were not conducted since risk estimates were not of concern. This highly 

conservative risk assessment showed no risks of concern (<100% of the chronic population 

adjusted dose (cPAD)) for the U.S. General Population and all subpopulations. The estimated 

exposure to the U.S. General Population resulted in a risk equivalent to 18% of the cPAD. The 

estimated exposure to children 1 – 2 years of age, the most highly exposed subpopulation, 

resulted in a risk equivalent to 81% of the cPAD. Results for all subpopulations are summarized 

in Table 5.3.4 below. 
Page 18 of 34 

5.3.3 Cancer Dietary Risk 

The HED Cancer Assessment Review Committee (CARC) classified hexythiazox as “Likely to 

be Carcinogenic to Humans”, but has determined that there is insufficient evidence to quantify 

risk using a cancer slope factor. Rather, the committee concluded that 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. 

5.3.4 Summary Table 

Table 5.3.4. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Hexythiazox.

Population Subgroup 

Chronic Dietary 

Dietary Exposure 

(mg/kg/day) % cPAD* 

General U.S. Population 0.004407 18 

All Infants (< 1 year old) 0.008114 33 

Children 1-2 years old 0.020350 81 

Children 3-5 years old 0.013375 54 

Children 6-12 years old 0.006521 26 

Youth 13-19 years old 0.003280 13 

Adults 20-49 years old 0.002937 12 

Adults 50+ years old 0.003269 13 

Females 13-49 years old 0.003108 12 

* Most highly exposed subpopulation is highlighted in bold. 

6.0 Residential and Other Non-Occupational Exposures/Risks 

Occupational and Residential Exposure and Risk Assessment, D404018, A. LaMay, 5/6/13 

Occupational and Residential Exposure and Risk Assessment, D396864, A. LaMay, 9/25/12 

There are no new residential uses proposed with this action; however, there are registered uses 

on residential sites which have been previously assessed, including (1) ornamental landscape 

plantings in residences, public areas, and recreational sites such as campgrounds, golf courses, 

parks and athletic fields, (2) ornamental lawns and turf (including residential), (3) residential 

pome fruit, stone fruit, and nut trees, and residential caneberries. 

6.1 Residential Handler Exposure and Risk 

Since hexythiazox does not pose a dermal risk, only inhalation exposure assessments were 

conducted for residential handlers. Residential handler exposure is expected to be short-term in 

duration. Intermediate-term exposures are not likely because of the intermittent nature of 

applications by residential applicators. Residential handler inhalation margins of exposure 

(MOEs) significantly exceed 100 for all scenarios assessed and are not of concern. Residential 

handler MOEs range from 420,000 to 330,000,000. 
Page 19 of 34 

 

Table 6.1.1. Short-term Residential Handler Non-cancer Exposure and Risk Estimates for Hexythiazox. 

Exposure Scenario Target 

MOE 

Inhalation 

Unit 

Exposure 

(mg/lb ai) 

Maximum 

Application Rate1

Area Treated 

or Amount 

Handled Daily2

Inhalation 

Dose 

(mg/kg/day)3 MOE4

Mixer/Loader/Applicator 

Lawns/ Turf; Gardens/Trees, 

WDG/DF, Manually-pressurized 

handwand / backpack 

100 1.1 0.000625 lb 

ai/gallon 5 gallons 0.000043 700,000 

Gardens/ Trees, WDG/DF, Hoseend sprayer 100 0.0014 4.375E-6 lb ai/ft2 1200 ft2 0.000000092 330,000,000 

Gardens/ Trees, WDG/DF, Hoseend sprayer 100 0.0014 0.000625 lb 

ai/gallon 11 gallons 0.00000012 250,000,000 

Lawns/ Turf, WDG/DF, Hose-end 

sprayer 

100 0.022 0.1875 lb ai/acre 0.5 acres 0.000026 1,200,000 

Gardens/Trees, WDG/DF, 

Manually-pressurized handwand / 

backpack 

100 1.1 4.375E-6 lb ai/ft2 1200 ft2 0.000072 420,000 

1 Based on registered label (Reg. No. #10163-251). 

2 Exposure Science Advisory Council Policy #9.1. 

3

Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or 

gallons/day) / BW (80 kg). 

4

 Inhalation MOE = Inhalation NOAEL (30 mg/kg/day) / Inhalation Dose (mg/kg/day). 

6.2 Residential Post-application Exposure 

There is the potential for post-application exposure for individuals exposed as a result of being in 

an environment that has been previously treated with hexythiazox. The quantitative 

exposure/risk assessment for residential post-application exposures is based on incidental oral 

exposure to treated turf. As no dermal hazard was identified, a quantitative dermal postapplication assessment is not required. Short-term exposure durations are anticipated for 

incidental oral exposures due to the intermittent nature of applications in residential 

environments. As the aerobic soil metabolism half-life for hexythiazox is 145.2 days3

, 

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

Child incidental oral exposure to treated turf was assessed for hexythiazox. Risk estimates 

greatly exceed the LOC of 100 for all scenarios associated with children’s exposure to treated 

turf and are not of concern. The short-term hand-to-mouth MOE for children is 11,000; the 

short-term object-to-mouth MOE for children is 350,000; and the short-and intermediate-term 

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

Table 6.2.1. Residential Post-application Non-cancer Exposure and Risk Estimates for Hexythiazox (ShortTerm for Hand-to-Mouth and Object-to-Mouth Exposure; Short- and Intermediate-Term for Incidental Soil 

Ingestion Exposure). 

Lifestage Post-application Exposure Scenario App rate1 Dose MOEs2

Child Turf - sprays Hand to Mouth 0.1875 lb ai/acre 0.0029 11,000 

Object to Mouth 0.00009 350,000 

 

3

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

Shelby. DP Barcode: 396529& 401798. 6/21/2012. 
Page 20 of 34 

Table 6.2.1. Residential Post-application Non-cancer Exposure and Risk Estimates for Hexythiazox (ShortTerm for Hand-to-Mouth and Object-to-Mouth Exposure; Short- and Intermediate-Term for Incidental Soil 

Ingestion Exposure). 

Lifestage Post-application Exposure Scenario App rate1 Dose MOEs2

Incidental Soil Ingestion 0.0000063 4,700,000 

1 Based on registered uses. 

2 MOE = POD (30 mg/kg/day) ÷ Dose (mg/kg/day). 

In accordance with 40 CFR158, TTR data are required for all occupational (e.g., sod farms, golf 

courses, parks, and recreational areas) or residential turf uses that could result in post-application 

exposure to turf. EPA is waiving the 40 CFR TTR data requirement for this use since the 

estimated residential turf post-application exposure using default TTR values for hexythiazox is 

less than the LOC. In this instance, it is unlikely that chemical-specific TTR data would be 

needed to further refine exposure assessments or would add appreciably to our general 

understanding of the availability of turf transferable pesticide residues. 

6.3 Residential Risk Estimates for Use in Aggregate Assessment 

Table 6.3.1 reflects the residential risk estimates that are recommended for use in the aggregate 

assessment for hexythiazox. 

 The recommended residential exposure for use in the adult aggregate assessment reflects 

inhalation exposure from application to gardens/trees via manually-pressurized handwand 

/ backpack sprayer; 

 The recommended residential exposure for use in the children 1<2 years old aggregate 

assessment reflects incidental oral exposures from post-application exposure to treated 

turf. 

Table 6.3.1. Recommendations for the Residential Exposures for the Hexythiazox Aggregate Assessment. 

Lifestage Exposure 

Scenario 

Dose (mg/kg/day)1 MOE2

Dermal Inhalation Oral Total Dermal Inhalation Oral Total 

Adults 

Handler; mixing/ 

loading/ applying 

using manuallypressurized 

handwand 

NA 0.000072 N/A 0.000072 NA 420,000 N/A 420,000 

Child 

Post-application; 

ST Incidental 

Oral (hand-tomouth) from 

treated turf 

NA NA 0.0029 0.0029 NA NA 11,000 11,000 

Post-application; 

IT Incidental Oral 

(soil ingestion) 

from treated turf 

NA NA 0.0000063 0.0000063 NA NA 4,700,000 4,700,000

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

incidental oral (where applicable). 

2 MOE = the MOEs associated with the highest residential doses. Total = 1 ÷ (1/Dermal MOE) + (1/Inhalation MOE) + 

(1/Incidental Oral MOE), where applicable. 

6.4 Non-Occupational Spray Drift Exposure and Risk Estimates 
Hexythiazox Human Health Risk Assessment D427090 

Page 21 of 34 

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

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

be a potential source of exposure from the ground application methods (e.g., ground 

boom and air blast) employed for hexythiazox. The agency has been working with the 

Spray Drift Task Force (a task force composed of various registrants which was 

developed as a result of a Data Call-In issued by EPA), EPA Regional Offices and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the agency’s Spray Drift website for more information). 4 The 

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

potential source of exposure in risk assessments for pesticides. 

The potential for spray drift will be quantitatively evaluated for each pesticide during the 

Registration Review process which ensures that all uses for that pesticide will be 

considered concurrently. The approach is outlined in the revised (2012) Standard 

Operating Procedures For Residential Risk Assessment (SOPs) - Residential Exposure 

Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. 

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

It is noted that the 0.19 lb ai/acre application rate for turf was modeled to estimate postapplication residential exposure of children. As this rate is equal to or higher than many 

of agricultural application rates, this scenario is protective of any exposure of children via 

spray drift from agricultural hexythiazox applications. 

6.5 Non-Occupational Residential Bystander Post-Application Inhalation 

Exposure and Risk Estimates 

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

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

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

Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the 

SAP’s final report on March 2, 2010 

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

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

and a subsequent Volatilization Screening Analysis 

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

During Registration Review, the agency will utilize this analysis to determine if data (i.e., 

flux studies, route-specific inhalation toxicological studies) or further analysis is required 

for hexythiazox. 

7.0 Aggregate Risk Assessments and Risk Characterization 

7.1 Acute Aggregate Risk 

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

 

4

 Available: http://www2.epa.gov/reducing-pesticide-drift 
Hexythiazox Human Health Risk Assessment D427090 

Page 22 of 34 

toxicology database; therefore, a quantitative acute aggregate risk assessment for this 

chemical is not required. 

 

7.2 Short- and Intermediate-Term Aggregate Risks 

The short- and intermediate-term aggregate risks combine residential handler (adult only) 

or post-application exposures (see Table 6.3.1) with average food and water exposures 

(see Table 5.3.4). Short- and intermediate-term aggregate margins of exposure (MOEs) 

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

intermediate-term estimated exposures and risks are shown in Table 7.2, below. 

Table 7.2 Short-Term and Intermediate-Term Aggregate Risk Calculations 

Population NOAEL 

(mg/kg/day) LOC1

Max 

Allowable 

Exposure2

(mg/kg/day) 

Average 

Food & 

Water 

Exposure3 

(mg/kg/day) 

Residential 

Exposure3

(mg/kg/day) 

Aggregate 

MOE for 

food and 

residential4

Short-Term Scenario 

Adult 30 100 0.3 0.002937 0.000072 9900 

Adult 

Female 30 100 0.3 0.003108 0.000072 9400 

Child 30 100 0.3 0.020350 0.0029 1100 

Intermediate-Term Scenario 

Adult 30 100 0.3 0.002937 N/A 9900 

Adult 

Female 30 100 0.3 0.003108 N/A 9700 

Child 30 100 0.3 0.020350 0.0000063 1500 1

 The LOC of 100 is based on the standard intra- and inter- species extrapolation factors. 

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

3 Average Food and Water Exposure: See Table 5.3.4. Residential Exposure: see Table 6.3.1. 

4

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

7.3 Long-Term (Chronic) Aggregate Risk 

As there are no uses that are expected to result in long-term residential exposure, longterm (chronic) aggregate risk includes only dietary (food and water) exposure. As noted 

in Section 5.3.2 of this memorandum, there is no chronic dietary risk of concern. 

8.0 Cumulative Risk Characterization/Assessment 

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

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

finding as to hexythiazox and any other substances and hexythiazox does not appear to 

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 
Hexythiazox Human Health Risk Assessment D427090 

Page 23 of 34 

website at http://www2.epa.gov/pesticide-science-and-assessing-pesticiderisks/cumulative-assessment-risk-pesticides.

9.0 Occupational Exposures and Risks 

Occupational and Residential Exposure and Risk Assessment, D404018, A. LaMay, 5/6/13 

9.1 Occupational Handler Risk 

While the uses on cotton and citrus are expected to result in occupational handler 

exposure, the amended uses do not include any changes to application methods and/or 

rates. Therefore, a new assessment of occupational exposure is not required, and a 

previous assessment (Memo, A. Lamay, D404018, 06-May-2013) is protective of the 

amended use pattern. In that assessment, a quantitative dermal risk assessment was not 

conducted since no hazard was identified via the dermal route. Occupational handler 

inhalation MOEs significantly exceeded 100 for all scenarios assessed including 

mixers/loaders, applicators and flaggers. No additional personal protective equipment 

(PPE) is required. 

9.2 Occupational Post-application Risk 

HED uses the term post-application 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. Post-application exposure levels vary over time 

and depend on such things as the type of activity, the nature of the crop or target that was 

treated, the type of pesticide application, and the chemical’s degradation properties. In 

addition, the timing of pesticide applications, relative to harvest activities, can greatly 

reduce the potential for post-application exposure. 

 Occupational Post-application Inhalation Exposure/Risk 

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

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

include volatilization of pesticides and re-suspension of dusts and/or particulates that 

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

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

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

on March 2, 2010 (http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP2009-0687-0037). The agency has evaluated the SAP report and has developed a 

Volatilization Screening Tool and a subsequent Volatilization Screening Analysis 

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

Registration Review, the agency will utilize this analysis to determine if data (i.e., flux 

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

hexythiazox. 
Hexythiazox Human Health Risk Assessment D427090 

Page 24 of 34 

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

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

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

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

assessments. 

Although a quantitative occupational post-application inhalation exposure assessment 

was not performed, an inhalation exposure assessment was performed for 

occupational/commercial handlers. Handler exposure resulting from application of 

pesticides outdoors is likely to result in higher exposure than post-application exposure. 

Therefore, it is expected that these handler inhalation exposure estimates would be 

protective of most occupational post-application inhalation exposure scenarios. 

Inhalation risks for occupational handlers are not of concern. 

Occupational Post-application Dermal Exposure/Risk 

As no dermal hazard has been identified for hexythiazox, quantification of dermal postapplication risk is not required. In accordance with the updated Part 158 data 

requirements (2007), one or more dislodgeable foliar residue (DFR) studies are required 

when a pesticide has residential or occupational uses that could result in post-application 

dermal exposure. However, as quantification of dermal risk is not required for 

hexythiazox, a DFR study is not required for hexythiazox at this time. 

The REI specified on the proposed label is based on the acute toxicity of hexythiazox. 

Hexythiazox is classified as Toxicity Category IV for acute dermal toxicity, Toxicity 

Category IV for acute dermal irritation, and Toxicity Category III for eye irritation. It is 

not a skin sensitizer. Under WPS for agricultural pesticides, active ingredient’s classified 

as Acute III or IV for acute dermal, eye irritation and primary skin irritation are assigned 

a 12-hour REI. Therefore, the WPS interim REI of 12 hours is adequate to protect 

agricultural workers from post-application exposures to hexythiazox. 

10.0 Human Studies 

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

were intentionally exposed to a pesticide or other chemical. These data, which include 

studies from PHED 1.1; the AHETF database; the Outdoor Residential Exposure Task 

Force (ORETF) database; the ARTF database; and the Residential SOPs, are (1) subject 

to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are 

compliant with applicable ethics requirements. For certain studies, the ethics review may 

have included review by the Human Studies Review Board. Descriptions of data sources, 

as well as guidance on their use, can be found at the Agency website5

. 

 

5 http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupational-pesticide-handlerexposure-data and http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupationalpesticide-post-application-exposure
Hexythiazox Human Health Risk Assessment D427090 

Page 25 of 34 

Appendix A. Toxicology Assessment

A.1 Toxicity Profiles

Table A.1.1. Acute Toxicity Data on Hexythiazox Technical 

Guideline No./ Study Type MRID No. Results Toxicity Category 

870.1100 Acute oral toxicity 00146549 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.1.2. Toxicity Profile of Hexythiazox 

Guideline No./ Study 

Type 

MRID No. (year)/ 

Classification /Doses 

Results 

870.3100 

90-Day oral toxicity rat 

45067101 (1983) 

Acceptable/guideline 

0, 10, 70, 500, or 3500 

ppm 

M: 0, 1.2, 8.1, 58.6, or 

397.5 mg/kg/day 

F: 0, 0.8, 5.4, 38.1 or 

257.6 mg/kg/day 

NOAEL = 8.1/5.4 mg/kg/day, males/females 

LOAEL = 58.6/38.1 mg/kg/day, males/females, based on 

increased absolute and relative liver weights in both sexes, 

increased relative ovarian and kidney weights, and fatty 

degeneration of the adrenal zona fasciculata. 

@ 397.5/257.6 mg/kg/day, decreased 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 

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 
Hexythiazox Human Health Risk Assessment D427090 

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Table A.1.2. Toxicity Profile of Hexythiazox 

Guideline No./ Study 

Type 

MRID No. (year)/ 

Classification /Doses 

Results 

 F: 0, 5.27, 34.77, or 

207.67 mg/kg/day 

Offspring NOAEL = 29.73/34.77 mg/kg/day, 

males/females 

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 mice 

00147577, 00156896 

(1985) 

Acceptable/guideline 

0, 40, 250, or 1500 ppm 

M: 0, 6.72, 41.6, or 267 

mg/kg/day 

F: 0, 8.38, 51.2, or 318 

mg/kg/day 

NOAEL = 41.6/51.2 mg/kg/day, males/females 

LOAEL = 267/318 mg/kg/day, males/females) based on 

decreased male body weight and body weight gain, and 

increased absolute and relative liver weights in both sexes. 

Evidence of carcinogenicity (causes liver tumors in 

females). 

Gene Mutation 

870.5100 

(Salmonella 

typhimurium and 

Escherichia coli

reverse gene mutation 

assay) 

44955710 (1983) 

Acceptable 

The test was negative up to the highest dose tested (6400 

μg/plate +/-S9. 

Gene Mutation 

870.5300 

(In vitro mammalian 

cell forward gene 

mutation assay in CHO 

cells) 

00155154 (1985) 

Acceptable 

Independently performed trials were negative up to 

precipitating doses (60 μg/mL) and severely cytotoxic 

concentrations (200 μg/mL -S9; 400 μg/mL +S9). 

Cytogenetics 

870.5375 

00156894 (1986) 

Acceptable 

The test was negative up to precipitating doses 

accompanied by severe cytotoxicity (167 μg/mL +/-S9). 
Hexythiazox Human Health Risk Assessment D427090 

Page 27 of 34 

Table A.1.2. Toxicity Profile of Hexythiazox 

Guideline No./ Study 

Type 

MRID No. (year)/ 

Classification /Doses 

Results 

In vitro mammalian 

cell cytogenetic assay 

in CHO cells 

Cytogenetics 

870.5395 

In vivo mouse 

micronucleus assay 

44955708 

Unacceptable 

There’s an update 

The results were inconclusive because a positive response, 

which was within the wide range of historical background 

data, was recorded for female mice at the mid-and 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). 

870.6200b 

Subchronic 

neurotoxicity 

Crj:CD(SD)IGS(SPF) 

rats 

48657401 (2004) 

Acceptable/nonguideline 

0, 100, 1000, or 10000 

ppm 

Males: 0, 8.8, 88.7, or 

868.2 mg/kg/day 

Females: 0, 9.5, 90.1, or 

892.7 mg/kg/day 

(28 days) 

NOAEL = 1000 ppm (males 88 mg/kg/day; females 90 

mg/kg/day). 

LOAEL = 10000 ppm (males 868 mg/kg/day; females 892 

mg/kg/day), based on decreased motor activity in both 

sexes, decreased body weight in males, increased adrenal 

weight in females, and increased liver weight in both sexes. 

HASPOC (D0056434): 28-day duration is sufficient to 

assess sub-chronic neurotoxicity from hexythiazox 

exposure 

870.7485 

Metabolism and 

pharmacokinetics 

00146558 (1985) 

Acceptable/guideline 

Single oral dose at 10 

mg/kg (Group B); 14 

daily oral doses (10 

mg/kg) of unlabeled 

material followed by one 

dose (10 mg/kg) of [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 

low-dose 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 

sex-related difference in the residue levels of all tissues 

was observed, with residues in female tissues being twofold higher than those found in male tissues. 

870.7485 

Metabolism and 

pharmacokinetics 

0146557 (1983) 

Acceptable/nonguideline 

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, 
Hexythiazox Human Health Risk Assessment D427090 

Page 28 of 34 

Table A.1.2. Toxicity Profile of Hexythiazox 

Guideline No./ Study 

Type 

MRID No. (year)/ 

Classification /Doses 

Results 

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 was in the feces). No significant sex difference 

was apparent with respect to metabolite formation. 

870.7600 

Dermal penetration 

40608402, 40787901 

(1985) 

Unacceptable 

The total percent of dose absorbed averaged 2%, 1%, and 

1.1% for cannulated rats (10-hour sacrifice) and 0.8%, 

0.2%, and 0.2% for non-cannulated rats (1-hour sacrifice) 

at the low, medium, and high dose levels, respectively. 

The amount of radioactivity in the blood, carcass, urine 

and other organs totaled <2% of the applied dose. The 

results of this study (2% dermal absorption) can be used 

for risk assessment purposes.

870.7800 

Immunotoxicity 

48685201 (2012) 

Acceptable/Guideline 

Immunotoxicity NOAEL is 4500 ppm (equivalent to 904 

mg/kg/day). A LOAEL was not established. 
Hexythiazox Human Health Risk Assessment D427090 

Page 29 of 34 

Appendix B: Toxicology Data Requirements 

The toxicology data requirements (40 CFR 158.340) for the food uses of hexythiazox are presented below. 

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

Table B. Toxicology Data Requirements 

Study 

Technical

Required Satisfied

870.1100 Acute Oral Toxicity....................................................... 

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

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

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

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

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

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes

yes 

yes 

yes

870.3100 Oral Subchronic (rodent) ............................................... 

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

870.3200 21-Day Dermal .............................................................. 

870.3250 90-Day Dermal .............................................................. 

870.3465 90-Day Inhalation ......................................................... 

yes 

yes 

yes 

no 

CR 

yes

yesD 

noC 

no 

noA 

870.3700a Developmental Toxicity (rodent) .................................. 

870.3700b Developmental Toxicity (nonrodent) ............................ 

870.3800 Reproduction ................................................................. 

yes 

yes 

yes 

yes 

yes 

yes 

870.4100a Chronic Toxicity (rodent) .............................................. 

870.4100b Chronic Toxicity (nonrodent) ........................................ 

870.4200a Oncogenicity (rat) ......................................................... 

870.4200b Oncogenicity (mouse) ................................................... 

870.4300 Chronic/Oncogenicity ................................................... 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.5100 Mutagenicity—Gene Mutation – bacterial .................... 

870.5375 Mutagenicity—Structural Chromosomal Aberrations... 

870.5550 Mutagenicity—Other Genotoxic Effects ....................... 

yes 

yes 

yes 

yes

yes 

yes 

870.6100a Acute Delayed Neurotoxicity (hen) ............................... 

870.6100b 90-Day Neurotoxicity (hen) .......................................... 

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

870.6200b 90-Day Neurotoxicity Screening Battery (rat) .............. 

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

no 

no 

yes

yes 

CR 

- 

- 

noA 

yesB 

no 

870.7485 General Metabolism ...................................................... 

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

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

yes 

no 

yes 

yes 

yes 

yes 

AHASPOC (D0056434): not required at this time. BHASPOC (D0056434): 28-day study is sufficient to assess subchronic neurotoxicity from hexythiazox exposure. C Dermal equivalent dose, after applying the estimated dermal absorption factor of 2% to the oral reproduction study 

NOAEL of 30 mg/kg/day, is 1500 mg/kg/day, which is greater than the limit dose. D Not required since there is a 4-week study and a 1-year study available. 

 
Hexythiazox Human Health Risk Assessment D427090 

Page 30 of 34 

Appendix C: Field Trial Residue Data 

Cotton DER, MRID 49554501, K.King, XX/XX/2015 

Citrus DER, MRID 49591801, K.King, XX/XX/2015

Table C.1. Summary of Residues from Citrus Field Trials with Hexythiazox.

Plot Total App. Rate 

lb ai/A 

(kg ai/ha) 

PHI 

(days)

n1 Residues (ppm) 

Min.2 Max.2 LAFT3 HAFT3 Median3 Mean3 SD3

Orange Trials 

Concentrate 

0.1892-0.1903 

(0.2121-0.2133) 

7 2 0.0392 0.0814 0.0415 0.0718 0.0567 0.0567 NA 

13-14 2 0.0222 0.0396 0.0281 0.0351 0.0316 0.0316 NA 

Dilute 0.1827-0.1907 

(0.2048-0.2137) 

7-8 3 0.0499 0.0891 0.0540 0.0764 0.0720 0.0675 0.0119 

13-14 3 0.0449 0.0798 0.0460 0.0761 0.0566 0.0596 0.0153 

Grapefruit Trials 

Concentrate 

0.1895-0.1898 

(0.2124-0.2127) 

7 2 0.0456 0.0853 0.0510 0.0818 0.0664 0.0664 NA 

14 2 0.0377 0.0572 0.0381 0.0547 0.0464 0.0464 NA 

Dilute 0.1837-0.1884 

(0.2059-0.2112) 

7 2 <0.02 0.0593 <0.02 0.0490 0.0345 0.0345 NA 

14 2 <0.02 0.0473 <0.02 0.0451 0.0326 0.0326 NA 

Lemon Trials 

Concentrate 

0.1869-0.1875 

(0.2095-0.2102) 

7 3 0.183 0.257 0.188 0.236 0.223 0.216 0.0248 

13-14 3 0.155 0.264 0.156 0.243 0.208 0.202 0.0438 

Dilute 0.1874-0.1883 

(0.2101-0.2111) 

7 2 0.102 0.177 0.107 0.167 0.137 0.137 NA 

14 2 0.100 0.174 0.117 0.164 0.141 0.141 NA 1 n = number of field trials. 

2 Values based on total number of samples. 

3 Values based on per-trial averages. LAFT = lowest average field trial, HAFT = highest average field trial, SD = 

standard deviation. Values <LOQ are assumed to be at the LOQ (0.02 ppm). NA = Not applicable. 

Table C.2. Summary of Residues from Cotton Field Trials with Hexythiazox.

Crop Matrix Total App. Rate 

lb ai/A 

(kg ai/ha) 

PHI 

(days) 

n1 Residues (ppm hexythiazox equivalents) 

Min.2 Max.2 LAFT3 HAFT3 Median3 Mean3 SD3

Cotton 

undelinted seed 

0.1522-0.1619 

(0.1706-0.1815) 

34-36 9 <0.02 0.175 <0.02 0.160 0.0374 0.0679 0.0557 

Cotton 

gin byproducts 

0.1522-0.1576 

(0.1706-0.1766) 

34-36 3 1.96 5.70 2.06 5.58 4.41 4.02 1.80 

1 n = number of field trials. 

2

 Values based on total number of samples. 

3 Values based on per-trial averages. LAFT = lowest average field trial, HAFT = highest average field trial, SD = 

standard deviation. For computation of the LAFT, HAFT, median, mean, and standard deviation, values < LOQ are 

assumed to be at the LOQ (0.02 ppm). 
Hexythiazox Human Health Risk Assessment D427090 

Page 31 of 34 

Appendix D: Maximum Residue Limits (MRL) 

Table D. Summary of US and International Tolerances and Maximum Residue Limits for 

Hexythiazox 

Residue Definition:

US Canada Mexico1 Codex2

40 CFR 180.448: 

hexythiazox and its metabolites containing 

the (4-chlorophenyl)-4-methyl-2-oxo-3-

thiazolidine moiety 

None Plants: Hexythiazox 

Livestock: sum of 

hexythiazox and all 

metabolites containing the 

trans-5-(4-chlorophenyl)-4- 

methyl-2-oxothiazolidinemoiety (PT-1-3-), expressed 

as hexythiazox. 

The residue is fat-soluble. 

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) 

US Canada Mexico1 Codex2

Cotton, gin byproducts 15 

Cotton, undelinted seed 0.3 

Citrus, fruit, Crop Group 10 0.6 0.5 citrus fruits 

Completed: M. Negussie; 09/21/15 

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

2

 Absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = 

processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured 

on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the 

CAC. 
Hexythiazox Human Health Risk Assessment D427090 

Page 32 of 34 

Appendix E: OECD Calculator MRL Output 

Hexythiazox

Cotton (Undelinted Seed)

USA

MRID 44574703-2 (PHI 28-35 days) & 49554501 (PHI 28-42 days) 

 

Total number of data (n) 11 

Percentage of censored data 0% 

Number of non-censored data 11 

Lowest residue 0.007

Highest residue 0.276

Median residue 0.053

Mean 0.076

Standard deviation (SD) 0.078

Correction factor for censoring (CF) 1.000

 

Proposed MRL estimate 

 

- Highest residue 0.276

- Mean + 4 SD 0.388

- CF x 3 Mean 0.228

Unrounded MRL 0.388

 

Rounded MRL 0.4 

Residues 

(mg/kg) 

0.067 

0.062 

0.037 

0.025 

0.128 

0.007 

0.020 

0.276 

0.132 

0.030 

0.053 
Hexythiazox Human Health Risk Assessment D427090 

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Hexythiazox

Cotton Ginned Byproducts

USA

MRID 44574703-2 (PHI 28-35 days) & 49554501 (PHI 28-42 

days) 

 

Total number of data (n) 5 

Percentage of censored data 0% 

Number of non-censored data 5 

Lowest residue 0.966 

Highest residue 5.580 

Median residue 2.055 

Mean 2.837 

Standard deviation (SD) 2.054 

Correction factor for censoring (CF) 1.000 

 

Proposed MRL estimate 

 

- Highest residue 5.580 

- Mean + 4 SD 11.053 

- CF x 3 Mean 8.511 

Unrounded MRL 11.053 

 

Rounded MRL 15 

 

 High uncertainty of MRL estimate. 

[Small dataset] 

Residues 

(mg/kg) 

1.174 

0.966 

4.410 

5.580 

2.055 

 
Hexythiazox Human Health Risk Assessment D427090 

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Hexythiazox

Citrus (Lemon)

USA

MRID 49591801 (PHI 7 Day)

 

Total number of data (n) 5 

Percentage of censored data 0% 

Number of non-censored data 5 

Lowest residue 0.107

Highest residue 0.236

Median residue 0.188

Mean 0.184

Standard deviation (SD) 0.051

Correction factor for censoring (CF) 1.000

 

Proposed MRL estimate 

 

- Highest residue 0.236

- Mean + 4 SD 0.389

- CF x 3 Mean 0.553

Unrounded MRL 0.553

 

Rounded MRL 0.6 

 

 High uncertainty of MRL estimate. 

[Small dataset] 

Residues 

(mg/kg) 

0.223 

0.107 

0.188 

0.167 

0.236