UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

{)ate: 5/6/ 13 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

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

Grain Sorghum, Pepper/Eggplant Subgroup 8-1 OB, Pome Fruit Group 11-

10, Caneberry Subgroup 13-07 A, Small Vine Climbing, Except Fuzzy 

Kiwifruit Subgroup 13-07F, and Low Growing Berry Subgroup 13-070. 

PC Code: 128849 DP Barcode: 1)404015, 1)401797 

Decision No.: 466411, 463688 Registration No.: 10163-250, 10163-251 , 

10163-277 

Petition No.: 2F8054, 2E8016 Regulatory Action: Section 3 Registration 

Risk Assessment Type: Single Chemical Case No.: N/A Aggregate 

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

MRIDNo.: NA 40 CFR: 40 CFR 180.448 

FROM: l)onna S. {)avis, Risk Assesso~ / ")--' 

L

Alexandra 

inda Taylor, 

LaMay, 

Toxicologist

Biolog'st 

.----;~ 

/:( 

~~....<'~-

~ 

--....... A< / 

Risk Assessment Branch 

Health Effects l)ivision (7509P) 

THROUGH: Michael Metzger, Chief ~ /) (} ~ Risk Assessment Branch VII ~J ,! - Health Effects l)ivision (7509P) ' 

TO: Olga Odiott, Risk Manager 

Mark Suarez, Product Manager 

Insecticide Branch 

Registration l)ivision (7505P) 

Sidney Jackson, Risk Manager 

Barbara Madden, Team Leader 

Risk Integration Minor Use, and Emergency Response Branch 

Registration l)ivision (7505P) 

Page 1 of36 
Hexythiazox Human Health Risk Assessment D404015 

Table of Contents 

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

2.0 HED Recommendations ................................. .... ...................................................... 7 

2.1 

2.2 

2.2.1 

2.2.2 

2.2.3 

2.2.4 

2.3 

2.3. 1 

2.3.2 

2.3.3 

Data Deficiencies .................................................. ............ ................ .... ............. .. 7 

Tolerance Considerations ..................................................................................... 7 

Enforcement Analytical Method ...................................................................... 7 

Recommended Tolerances ...... ........................... .... ................................. .......... 8 

Revisions to Petitioned-For Tolerances ............................................................ 9 

International Harmonization ............................. .... .... .... ................. ........ .... ..... 10 

Label Recommendations .......................................... ........................ .... .............. 11 

Recommendations from Residue Reviews ..................................................... 11 

Recommendations from Occupational Assessment ............ ......................... .. 11 

Recommendations from Residential Assessment.. ......................................... 11 

3.0 Introduction ............................................................................................................ 11 

3.1 Chemical Identity .......... ..................................................................................... 12 

3 .2 Physical/Chemical Characteristics .............................. .... ............................. ... ... 13 

3.3 Pesticide Use Pattern ....................................................................................... ... 14 

3.4 Anticipated Exposure Pathways ... ........ ........... .... ............................................... 16 

3.5 Consideration of Environmental Justice ........................ ......... ...... .................. ... 16 

4.0 Hazard Characterization and Dose-Response Assessment .................................... 17 

4.1 Hazard Characterization ................................................................................. .... 17 

4.2 Hazard Profile .................................................................................................... 17 

4.3 Dose-Response Assessment/Endpoint Selection ... ............................................ 17 

4.4 FQP A Considerations ......................................................................................... 18 

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

Assessments and Levels........................................................... .... ... ......... . . . . . . . . . . . . . . . . . . . . . 1 9 

5.0 Dietary Exposure/Risk Characterization .. .... .................... .... ............ ........ .... ........ .. 20 

5.1 Residue Chemistry Summary ............................................................................. 20 

5.2 Drinking Water Residue Profile ......................................................................... 21 

5.3 Dietary Exposure and Risk ................................................................................. 22 

5.4 Anticipated Residue and Percent Crop Treated (%CT) Information ................. 23 

6.0 Residential and Other Non-Occupational Exposures/Risks ...................... .... ........ 23 

6.1 Residential Handler Exposure and Risk .......... ............ ............ ........................... 23 

6.2 Residential Post-application Exposure ........................................ ................ .... ... 24 

6.3 Other ....................... .............. .... ................................................................... .... ... 25 

7.0 Aggregate Risk Assessments and Risk Characterization .................................... ... 26 

7 .I Acute Aggregate Risk ........................................................................................ 26 

7.2 Short- and Intermediate-Term Aggregate Risks ................................................ 26 

7.3 Long-Term (Chronic) Aggregate Risk .... .... ........ .... ................................ .... ..... .. 28 

Page 2 of36 
Hexythiazox Human Health Risk Assessment D404015

Page 3 of 36

8.0 Cumulative Risk Characterization/Assessment ..................................................... 28

9.0 Occupational Exposures and Risks........................................................................ 28

9.1 Occupational Handler Risk ................................................................................ 28

9.2 Occupational Post Application Risk .................................................................. 30

10.0 Human Studies....................................................................................................... 31

Appendix A. Toxicology Assessment.............................................................................. 32

Appendix B: Toxicology Data Requirements................................................................... 36
Hexythiazox Human Health Risk Assessment D404015

Page 4 of 36

1.0 Executive Summary

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 fruit and nut 

crops. 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 PP# 2F8054 requesting the following:

A new regionally restricted use limited to OCSPP Harmonized Test Guideline 

860.1500 Regions 6, 7, and 8 on sorghum and establishment of tolerances on 

grain at 3 ppm, forage at 5 ppm, and stover at 6 ppm. The new use is to be 

included only on the label for the 1 lb/gal emulsifiable concentrate (EC) 

formulation (Onager® Miticide, EPA Reg. No 10163-277) of hexythiazox.

Increase the milk tolerance from 0.02 ppm to 0.05 ppm to harmonize with Codex.

Establish poultry tolerances for meat, meat byproducts, and eggs at 0.05 ppm to 

harmonize with Codex.

Increase livestock meat byproduct tolerances (including kidney and liver) from 

0.05 ppm to 0.5 ppm.

The Interregional Research Project No. 4 (IR-4) in PP# 2E8016 is proposing the 

following:

A new use of hexythiazox on the pepper/eggplant subgroup 8-10B on the 

Hexygon DF and Onager® Miticide labels and a tolerance for CSG 8-10B at 1.5 

ppm. 

Expansion of the use on the pome fruit group 11 to include all commodities in the 

updated pome fruit group 11-10 on the Savey® 50 DF and Onager® Miticide 

labels and a tolerance for CG 11-10 at 0.25 ppm.

Expansion of the use on the caneberry subgroup 13A to include all commodities 

in the updated caneberry subgroup 13-07A on the Savey® 50 DF label and a 

tolerance for CSG 13-07A at 1.0 ppm.

Expansion of the use to all members of small fruit, vine climbing, except fuzzy 

kiwifruit, subgroup 13-07F on the Onager® Miticide label based on the current 

use on grapes and a tolerance for CSG 13-07F at 1.0 ppm.

Expansion of the use of all members of the low growing berry subgroup 13-07G 

on the Savey® 50 DF label based on the current use on strawberry and a tolerance 

for CSG 13-07G at 3.0 ppm.

The toxicity database for hexythiazox is complete. 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 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, 
Hexythiazox Human Health Risk Assessment D404015

Page 5 of 36

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 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. 

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

delineated to support the proposed new and expanded uses. The submitted labels are 

adequate except as follows. The proposed supplemental label for use of Onager® 

Miticide on crop subgroup 8-10B should be revised to specify minimum spray volumes 

for ground and aerial application. Additionally, adequate residue data have not been 

submitted to support the requested use on crop subgroup 8-10B commodities on the 

Hexygon® DF label; therefore, the use on subgroup 8-10B commodities should be 

removed from the Hexygon® DF label. Lastly, the Savey® 50 DF label should be 

amended to specify a minimum spray volume for aerial application to pome fruit of 10 

gallons per acre. An adequate high performance liquid chromatography method with UV 

detection (HPLC/UV) exists to enforce the required crop and livestock tolerances. A 

reference standard is available at the EPA National Pesticide Standards Repository. The 

number and geographic representation of the submitted grain sorghum and pepper field 

trial data are adequate to support the requested geographically restricted use on sorghum 

in Regions 6, 7, and 8 and on the pepper/eggplant subgroup 8-10B for the EC formulation 

only. The residue data were generated by a validated data collection method, are 

supported by adequate storage stability data, and support the requested use pattern. No 

residue data are required to support the requested label expansions. The submitted data 

support tolerance of 3, 5, and 6 ppm on sorghum grain, forage, and stover, respectively, a 

tolerance of 5 ppm on aspirated grain fractions, and a tolerance of 1.5 ppm on the 

pepper/eggplant subgroup 8-10B. HED recommends in favor of the requested expansions 

listed above and tolerances for the new crop groups/subgroups at the same levels as the 

current tolerances from which they are extrapolated, with the exception of the pome fruit 

group 11-10 tolerance which should be set at 0.4 ppm and the low growing berry 

subgroup 13-07G which should be set at 6 ppm, both to harmonize with Codex. Updated 

dietary burden calculations for livestock indicated that the current livestock tolerances are 

adequate; however, HED recommends increasing the ruminant meat by product 

tolerances to 0.5 ppm and the egg tolerance to 0.05 ppm to harmonize with Codex. All 

other livestock tolerances are currently harmonized with Codex. The nature of the 

residue in rotational crops in not adequately understood, however, based on the available 

confined and limited rotational crop data, HED concludes that, in light of the 120 day 
Hexythiazox Human Health Risk Assessment D404015

Page 6 of 36

plant-back interval (PBI) on the label, no additional data with respect to rotational crops 

are required at this time.

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

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

chronic dietary risk assessment used tolerance level residues, assumed 100% crop treated, 

included DEEM default processing factors, and modeled water values. This unrefined 

assessment resulted in estimated chronic dietary (food and water) risks of 17% of the 

chronic population adjusted dose (cPAD) for the U.S. population and 82% of the cPAD 

for children 1 – 2 years of age, the most highly exposed population subgroup. 

This action does not include new residential uses; however, hexythiazox is registered for 

use in residential settings including uses on ornamental plantings, turf, and fruit and nut 

trees in residential settings. These uses were reassessed to reflect updates to HED’s 2012 

Residential SOPs as well as policy changes for body weight assumptions. Residential 

handler inhalation margins of exposure (MOEs) for all scenarios ranged from 420,000 to 

330,000,000; significantly exceeding the level of concern (LOC) of 100 and are not of 

concern. The MOEs for children’s incidental oral exposure to treated turf for all 

scenarios ranged from 11,000 to 4,700,000; greatly exceeding the LOC of 100 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-term, intermediate-term, and long-term (chronic) 

aggregate risk assessments for hexythiazox. Short- and intermediate-term aggregate 

MOEs ranged from 1,300 to 9,800; significantly exceeding the LOC of 100 and are not of 

concern. The long-term (chronic) aggregate assessment includes only dietary (food and 

water) exposure as there are no long-term residential exposure scenarios. Chronic dietary 

risk is not 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 new and expanded uses and are not of concern. Further, there were no risks of 

concern identified for postapplication exposure to hexythiazox associated with these new 

uses. 

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).
Hexythiazox Human Health Risk Assessment D404015

Page 7 of 36

2.0 HED Recommendations

Provided the proposed labels (Section B) are amended as noted in Section 2.3, below, and 

a revised Section F is submitted as noted in Section 2.2, below, there are no hazard, 

exposure, or risk considerations that would preclude granting the requested regionally 

restricted use on sorghum and the newly proposed use on the pepper/eggplant subgroup 

8-10B, as well as the necessary tolerances required to support those uses. 

Additionally, HED has no objection to the proposed expansions:

Expansion of the current use on CG 11 to include all commodities in the updated 

pome fruit group 11-10.

Expansion of the current use on the caneberry subgroup 13A to include all 

commodities in the updated caneberry subgroup 13-07A.

Expansion of the current use on grapes to all members of small fruit, vine 

climbing, except fuzzy kiwifruit subgroup 13-07F.

Expansion of the current use on strawberry to all members of the low growing 

berry subgroup 13-07G.

Lastly, Gowan Company has proposed new/increased livestock tolerances. HED has 

concluded that the current tolerances are adequate to cover secondary residues in 

livestock; however, HED is recommending that livestock tolerances be harmonized with 

Codex in conjunction with these requested new and expanded uses. 

2.1 Data Deficiencies

There are no data deficiencies with respect to toxicology associated with this action. 

All residue chemistry data requirements have been adequately addressed with the 

exception of the need for additional field trial data to support the requested use on crop 

subgroup 8-10B commodities on the Hexygon® DF (10163-251) label. Should the 

registrant desire to support the use of hexythiazox on subgroup 8-10B commodities, 

additional field trial data will be required, as outlined in Section 5.3 of this memorandum.

There are no data deficiencies with respect to occupational or residential exposure 

assessment with this action. 

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Hexythiazox and its metabolites are not consistently recovered through FDA’s multiresidue methods. No data were provided, or are required, for recovery through other 

common multi-residue methodology. 

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 
Hexythiazox Human Health Risk Assessment D404015

Page 8 of 36

livestock commodities. This method is listed in the U.S. EPA Index of Residue 

Analytical Methods under hexythiazox as method AMR-985-87. 

Briefly, residues are extracted with methanol or methanol/water, acidified, partitioned 

with dichloromethane (DCM), subjected to base hydrolysis, partitioned with acetonitrile, 

and re-partitioned with DCM. The extracts are cleaned up using column 

chromatography, and the ethyl acetate/hexane eluate is concentrated and analyzed by 

HPLC with UV detection. Residues are expressed in terms of hexythiazox using a 

molecular weight conversion factor of 1.55. The method LOQ is 0.02 ppm.

2.2.2 Recommended Tolerances

Tolerances currently established under 40 CFR §180.448 comply with the HED Interim 

Guidance on Tolerance Expressions (S. Knizner, 5/27/09); therefore, no revisions are 

recommended to the residue definition. Table 2.2.2, below summarizes the 

recommended tolerance levels and commodity definitions required to support the 

proposed new and expanded uses included in these petitions.

Table 2.2.2. Tolerance Summary for Hexythiazox.

Commodity Proposed Tolerance 

(ppm)

HED-Recommended 

Tolerance (ppm)

Comments 

(correct commodity definition)

40 CFR 180.448(a) Tolerance for residues.

Aspirated grain fractions - 5 Grain, aspirated fractions

Currently established at 0.5 ppm, 

increase required due to new use on 

sorghum

Pepper/eggplant subgroup 

8-10B

1.5 1.5 Pepper/Eggplant subgroup 8-10B

Fruit, pome, group 11-10 0.25 0.4 Fruit, pome, group 11-10

Set to harmonize with Codex. 

Established tolerance for fruit, pome, 

group 11 can be removed from 40 

CFR and replaced by this crop group 

tolerance.

Caneberry subgroup 13-

07A

1.0 1 Caneberry subgroup 13-07A

Established tolerance for caneberry 

subgroup 13A can be removed from 

40CFR and replaced by this subgroup 

tolerance.

Fruit, small, vine 

climbing, except fuzzy 

kiwifruit, subgroup 13-

07F

1.0 1 Fruit, small, vine climbing, subgroup 

13-07F, except fuzzy kiwifruit

Established tolerance for grape can 

be removed from 40CFR and 

replaced by this subgroup tolerance

Berry, low growing, 

subgroup 13-07G

3.0 6 Berry, low growing, subgroup 13-

07G

Established tolerance for strawberry 

can be removed from 40CFR and 

replaced by this subgroup tolerance.

Milk 0.05 No change in current 

tolerance required 

Milk

Currently established at 0.05 ppm
Hexythiazox Human Health Risk Assessment D404015

Page 9 of 36

Table 2.2.2. Tolerance Summary for Hexythiazox.

Commodity Proposed Tolerance 

(ppm)

HED-Recommended 

Tolerance (ppm)

Comments 

(correct commodity definition)

Ruminant meat 

byproducts

0.5 0.5 Cattle, meat byproducts

Current tolerance level is 0.2 ppm; 

Increase to harmonize with Codex. 

0.5 Goat, meat byproducts

Current tolerance level is 0.2 ppm; 

Increase to harmonize with Codex.

0.5 Horse, meat byproducts

Current tolerance level is 0.2 ppm; 

Increase to harmonize with Codex.

0.5 Sheep, meat byproducts

Current tolerance level is 0.2 ppm; 

Increase to harmonize with Codex.

Egg 0.05 0.05 Egg

Current tolerance level is 0.01 ppm; 

Increase to harmonize with Codex. 

Poultry, meat 0.05 -- Poultry, meat

There is no expectation of finite 

residues in poultry meat; therefore a 

tolerance is not required.

Poultry, meat byproducts 0.05 No change in current 

tolerance required

Poultry, meat byproducts

Currently established at 0.05 ppm

40 CFR 180.448(c) Tolerances with regional registrations.

Grain sorghum, grain13 3 Sorghum, grain, grain

Grain sorghum, forage15 5 Sorghum, grain, forage

Grain sorghum, stover16 6 sorghum, grain, stover

2.2.3 Revisions to Petitioned-For Tolerances

The registrant did not propose an increase in the aspirated grain fraction tolerance. 

However, the submitted residue chemistry data show that sorghum residues concentrate 

in AGF, and that the current AGF tolerance of 0.05 ppm is not adequate to cover residues 

in sorghum AGF. Therefore the Agency is requesting that Gowan Company petition for 

an increased tolerance of 5 ppm in AGF. 

Minor revisions to the petitioned-for tolerances for sorghum grain, sorghum forage, and 

sorghum stover to reflect standard Agency commodity definitions are requested, no 

change in the proposed tolerance level is required. 

Minor revision to the petitioned-for tolerance for CSG 13-07F to reflect standard Agency 

commodity definition has been requested, no change in the proposed tolerance level is 

required. 

HED is recommending revision to the proposed tolerance for CG 11-10 from the 

proposed level of 0.25 ppm to 0.4 ppm and to the proposed tolerance for CSG 13-07G 

from 3 ppm to 6 ppm to harmonize with Codex established and proposed MRLs. 

Minor revisions to the petitioned-for tolerances for ruminant meat byproducts to reflect 

standard Agency commodity definition have been requested, no change in the proposed 

tolerance levels are required. 
Hexythiazox Human Health Risk Assessment D404015

Page 10 of 36

The petitioner has requested a new tolerance for residue of hexythiazox on poultry meat; 

however poultry metabolism and feeding studies demonstrate that there are not likely to 

be residues in poultry meat; therefore a tolerance on poultry meat is not required. 

No revision to the petitioned-for tolerances for crop subgroup 13-07A, or eggs is 

required. The requested tolerance for milk has already been established with another 

petition; therefore no change to the established tolerance is required at this time. 

2.2.4 International Harmonization

Codex MRLs for plant commodities are established for eggplant at 0.1 ppm, pome fruit at 

0.4 ppm, grapes at 1.0 ppm, and strawberry at 6 ppm (proposed) for residues of 

hexythiazox and its metabolites containing the PT-1-3-moiety, expressed as hexythiazox. 

There are no Canadian or Mexican MRLs currently established. The International 

Residue Limit (IRL) status sheet is included as Attachment 3 to this memorandum.

The Agency is currently harmonized with Codex with respect to residue definition in 

plants, and is recommending tolerances for CG 11-10 (pome fruit), CSG 13-07F (small, 

vine climbing fruit, except kiwifruit), and CSG 13-07G (low growing berry) that are 

harmonized with the current Codex MRLs for pome fruit, grapes (representative 

commodity of CSG 13-07F), and strawberry (representative commodity of CSG 13-07G). 

Therefore; HED-recommended tolerances for plant commodities are harmonized with 

Codex established or proposed MRLs with exception of the tolerance for eggplant. 

Codex has established their current MRL of 0.1 ppm for eggplant based on a use in the 

Netherlands at a significantly lower application rate than the use currently proposed in 

the U.S. The Codex MRL would not cover residues seen in the U.S. field trial data; 

therefore harmonization with codex with respect to eggplants is not possible at this time. 

The Agency is currently harmonized with Codex with respect to the residue definition in 

livestock commodities. The current milk tolerance of 0.05 ppm is harmonized with the 

Codex MRL for milk. HED is recommending an increase in the ruminant meat 

byproduct tolerances to 0.5 ppm and an increase in the current egg tolerance to 0.05 ppm 

to harmonize with Codex. 

HED has reviewed the poultry metabolism and feeding studies and concludes that the use 

on poultry meat can be classified as 180.6(a)(3), no reasonable expectation of finite 

residues; therefore the U.S. will not need to set a tolerance for this commodity. The 

relevant Codex MRL has been set at 0.05 ppm with a footnote that states “absent at the 

limit of quantitation”. Effectively, the Codex MRL acknowledging the absence of 

residues and the U.S. determination that no tolerance is required results in a harmonized 

approach to residues in poultry meat. 
Hexythiazox Human Health Risk Assessment D404015

Page 11 of 36

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

The following label changes are recommended.

The proposed supplemental label for use of Onager® Miticide on crop subgroup 

8-10B should be revised to specify minimum spray volumes for ground and aerial 

application. The submitted residue chemistry data support a minimum spray 

volume of 20 gallons per acre (GPA) for ground application. Further, the 

petitioner must revise the directions to reflect a minimum spray volume for aerial 

applications of 2 GPA for crop subgroup 8-10B or submit additional data 

reflecting aerial application to representative commodities of that crop subgroup. 

Adequate residue data have not been submitted to support the requested use on 

crop subgroup 8-10B commodities on the Hexygon® DF label. The use on 

subgroup 8-10B commodities should be removed from the Hexygon® DF label. 

To support inclusion of these crops on the Hexygon® DF label, the data outlined 

in Section 3.3 of this memorandum will be required. 

The Savey® 50 DF label should be amended to specify a minimum spray volume 

for aerial application to pome fruit of 10 gallons per acre.

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

Gowan Company has submitted PP# 2F8054 requesting the following:

A new regionally restricted use limited to OCSPP Harmonized Test Guideline 

860.1500 Regions 6, 7, and 8 on sorghum and establishment of tolerances on 

grain at 3 ppm, forage at 5 ppm, and stover at 6 ppm. The new use is to be 

included only on the label for the 1 lb/gal emulsifiable concentrate (EC) 

formulation (Onager® Miticide, EPA Reg. No 10163-277) of hexythiazox.

Increase the milk tolerance from 0.02 ppm to 0.05 ppm to harmonize with Codex.

Establish poultry tolerances for meat, meat byproducts, and eggs at 0.05 ppm to 

harmonize with Codex.

Increase livestock meat byproduct tolerances (including kidney and liver) from 

0.05 ppm to 0.5 ppm.
Hexythiazox Human Health Risk Assessment D404015

Page 12 of 36

The Interregional Research Project No. 4 (IR-4) in PP# 2E8016 is proposing the 

following:

A new use of hexythiazox on the pepper/eggplant subgroup 8-10B on the 

Hexygon DF (EPA Reg No. 10163-251) and Onager® Miticide (EPA Reg No. 

10163-277) labels and a tolerance for CSG 8-10B at 1.5 ppm. 

Expansion of the use on the pome fruit group 11 to include all commodities in the 

updated pome fruit group 11-10 on the Savey® 50 DF and Onager® Miticide 

labels and a tolerance for CG 11-10 at 0.25 ppm.

Expansion of the use on the caneberry subgroup 13A to include all commodities 

in the updated caneberry subgroup 13-07A on the Savey® 50 DF label and a 

tolerance for CSG 13-07A at 1.0 ppm.

Expansion of the use to all members of small fruit, vine climbing, except fuzzy 

kiwifruit, subgroup 13-07F on the Onager® Miticide label based on the current 

use on grapes and a tolerance for CSG 13-07F at 1.0 ppm.

Expansion of the use of all members of the low growing berry subgroup 13-07G 

on the Savey® 50 DF label based on the current use on strawberry and a tolerance 

for CSG 13-07G at 3.0 ppm.

Tolerances are currently established under 40 CFR §180.448 for the combined residues 

of hexythiazox and its metabolites containing the (4-chlorophenyl)-4-methyl-2-oxo-3-

thiazolidine moiety (expressed as parts per million of the parent compound). 

3.1 Chemical Identity

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

carboxamide, is an ovicide/miticide used to control mites on a variety of fruit and nut 

crops. Hexythiazox is a contact pesticide which achieves control of eggs or immature 

mites via direct contact or contact with treated surfaces. 

 

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

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

hexythiazox are presented in Table 3.2. 
Hexythiazox Human Health Risk Assessment D404015

Page 13 of 36

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)

Compound

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

oxo-3-thiazolidine moiety

Common name PT-1-3 moiety

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

3.2 Physical/Chemical Characteristics

Table 3.2. Physicochemical Properties of Hexythiazox.

Parameter Value Reference

Melting point/range 108.0-108.5 °C 00143533

pH Not applicable

Density 1.289 at 25 °C 00143533

Water solubility 0.12 ppm 44006301

Solvent solubility g/L

chloroform 1379

xylene 362

acetone 160.0

acetonitrile 28.6

n-hexane 3.9 methanol 20.6

00143533

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

Dissociation 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
Hexythiazox Human Health Risk Assessment D404015

Page 14 of 36

3.3 Pesticide Use Pattern

Residue Chemistry Summary Document, D404573, D. Davis, 5/3/13

Gowan Company has submitted a supplemental label for Onager® Miticide (EPA Reg 

No. 10163-277) which includes proposed regionally restricted use directions for 

sorghum. The newly proposed use pattern for sorghum is summarized in the table below.

IR-4 has submitted supplemental labels for Onager® Miticide (EPA Reg No. 10163-277) 

and Hexygon® DF Ovicide/Miticide (EPA Reg No. 10163-251) which include proposed 

use directions for members of the pepper/eggplant subgroup 8-10B. The Hexygon® DF 

Ovicide/Miticide specifically includes use on green house grown members of the crop 

subgroup. The proposed new use pattern for crop subgroup 8-10B is summarized in the 

table below.

Table 3.3. Summary of Proposed 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

Sorghum

Foliar by 

ground or air 

equipment or 

through 

chemigation

Onager® 

Miticide

[10163-277]

0.1875 1 0.1875 30

Restricted to use in 

Regions 6, 7, and 8. 

Ground spray volume 

specified as 15 – 20 gal 

per acre (GPA). 

Minimum spray volume 

for air application is 5 

GPA. 

120 day plant-back 

interval

Pepper/Eggplant Subgroup 8-10B

Foliar by 

ground or air 

equipment

Onager® 

Miticide

[10163-277]

0.1875 1 0.1875 1

120 day plant-back 

interval

Foliar; ground 

or air not 

specified

Hexygon® 

DF

[10163-251]

0.1875 1 0.1875 1

120 day plant-back 

interval 

Additionally, IR-4 has submitted supplemental labels which propose the following:

Expand the pome fruit use from the currently registered crop group 11 

commodities to commodities in crop group 11-10 on the Savey® 50 DF (EPA 

Reg No. 10163-250) and Onager® Miticide labels. The proposed use pattern for 

crop group 11-10 commodities is identical to that currently registered on these 

two labels for crop group 11 commodities.

Expand the caneberry use from the currently registered crop subgroup13A 

commodities to commodities in crop subgroup13-07A on the Savey® 50 DF 

label. The proposed use pattern for crop subgroup 13-07A is identical to the use 

pattern for the currently registered crop subgroup 13A commodities. 
Hexythiazox Human Health Risk Assessment D404015

Page 15 of 36

Establish a use on crop subgroup 13-07F on the Onager® Miticide label based on 

the current registered use on grapes, the representative commodity for the 13-07F 

crop subgroup. The use pattern for the 13-07F crops is identical to the grape use 

currently on this label.

Establish a use on crop subgroup 13-07G on the Savey® 50 DF label based on the 

current registered use on strawberry, the representative commodity for the 13-7G 

crop subgroup. The use pattern for the 13-07F crops is identical to the strawberry 

use currently on this label. 

Conclusions. The proposed label directions are adequate to allow evaluation of the 

residue data relative to those proposed new uses. 

The proposed supplemental label for the geographically limited use of Onager® 

Miticide on sorghum is adequate and supported by the submitted residue data. No 

revisions to the sorghum use pattern on the Onager® label are required. 

The proposed supplemental label for use of Onager® Miticide on crop subgroup 

8-10B should be revised to specify minimum spray volumes for ground and aerial 

application. The submitted residue chemistry data support a minimum spray 

volume of 20 gallons per acre (GPA) for ground application. Further, the 

petitioner must revise the directions to reflect a minimum spray volume for aerial 

applications of 2 GPA for crop subgroup 8-10B or submit additional data 

reflecting aerial application to representative commodities of that crop subgroup. 

Provided the Onager® Miticide label is revised to specify appropriate minimum 

spray volumes, the proposed use is supported by adequate residue data.

Adequate residue data have not been submitted to support the requested use on 

crop subgroup 8-10B commodities on the Hexygon® DF (10163-251) label. 

Available residue data reflect application of the EC formulation only; no residue 

data have been provided using the DF formulation. Additional field trial data will 

be required to support use of this formulation on the pepper/eggplant crop 

subgroup 8-10B as outlined in Section 5.3. 

Provided the Savey® 50 DF label is amended to specify a minimum spray 

volume for aerial application to pome fruit of 10 gallons per acre, as required 

in the OCSPP Harmonized Test Guideline 860.1500 for aerial application to 

orchard crops in the absence of aerial application data, the proposed Savey® 50 

DF label for CG11-10 commodities is acceptable. The proposed Onager® 

Miticide label for CG11-10 commodities is acceptable.

The proposed supplemental Savey® 50 DF label for crop sugroup13-07A 

commodities is acceptable. 

The proposed supplemental Onager® Miticide label for crop subgroup 13-07F 

commodities is acceptable. 
Hexythiazox Human Health Risk Assessment D404015

Page 16 of 36

The proposed supplemental Savey® 50 DF label for crop subgroup 13-07G 

commodities is acceptable. 

3.4 Anticipated Exposure Pathways

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

the proposed new and expanded uses 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 uses of hexythiazox, as well as the existing uses as well. 

3.5 Consideration of Environmental Justice

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

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

"Federal Actions to Address Environmental Justice in Minority Populations and 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 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.
Hexythiazox Human Health Risk Assessment D404015

Page 17 of 36

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Hazard Characterization

The toxicity database for hexythiazox is complete and adequate for assessing risk. The 

Hazard and Science Policy Council (HASPOC) concluded that an acute neurotoxicity 

study is not required at this time, and a new subchronic neurotoxicity study is not 

required, since the 28-day neurotoxicity study is sufficient to assess subchronic 

neurotoxicity from hexythiazox exposure. The HASPOC also considered if an inhalation 

study was required for hexythiazox. Based on a weight of evidence (WOE) approach, the 

HASPOC concluded that a 28-day inhalation toxicity study is not required for 

hexythiazox at this time. The committee’s deliberations considered all of the available 

hazard and exposure information for hexythiazox, as well as the following factors: (1) the 

physical/chemical properties and low volatility (1.0x10-8 mm Hg @ 25°C) of 

hexythiazox; (2) the low acute inhalation toxicity of hexythiazox; (3) the primary target 

organ of hexythiazox toxicity is the liver and adrenal glands following repeated 

hexythiazox exposure; and (4) the use of an oral POD results in occupational inhalation 

MOEs greater than 1,400 (HASPOC Memo, TXR No. 0056434, 9/18/12). 

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

and chronic exposure to dogs, rats and mice, with the dog 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 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 Hazard Profile

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

4.3 Dose-Response Assessment/Endpoint Selection

No endpoint attributable to a single exposure was identified from the available 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 
Hexythiazox Human Health Risk Assessment D404015

Page 18 of 36

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 co-critical 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 

concluded that the evidence as a whole was not strong enough to warrant quantitative 

estimation of carcinogenic risk to humans using a cancer slope factor. HED concluded 

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

adequately account for all chronic toxicity, including carcinogenicity, that could result 

from exposure to hexythiazox. That conclusion is based on the following considerations: 

(1) the liver tumors found in the female mouse are common tumors; (2) the male 

mammary tumors were benign and of no biological significance; (3) hexythiazox is not 

mutagenic; (4) no carcinogenic response was seen in male mice or female rats.

4.4 FQPA Considerations

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

for the following reasons:

The toxicity database for hexythiazox is complete.

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

pre- and/or post-natal exposure to hexythiazox. 

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.
Hexythiazox Human Health Risk Assessment D404015

Page 19 of 36

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

Assessments and Levels

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

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

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.
Hexythiazox Human Health Risk Assessment D404015

Page 20 of 36

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 (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.

5.0 Dietary Exposure/Risk Characterization

5.1 Residue Chemistry Summary

Reside Chemistry Summary, D404573, D. Davis, 5/3/13

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

The residues of concern for the tolerance expression and risk assessment are the parent 

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

thiazolidine moiety.

The number and geographic representation of the submitted field sorghum samples are 

adequate to support the requested geographically restricted use in Regions 6, 7, and 8. 
Hexythiazox Human Health Risk Assessment D404015

Page 21 of 36

Data were also provided on aspirated grain fractions. All residue data were generated by 

a validated data collection method, are supported by adequate storage stability data, and 

support the requested use pattern. The available data are sufficient for establishing a 

tolerance of 1.5 ppm for the pepper/eggplant subgroup 8-10B. The data do not support 

the use of hexythiazox formulated as a dry flowable on this crop subgroup. 

No new field trial data were submitted to support the requested expansion of the current 

use on the pome fruit crop group (CG) 11 to the pome fruit CG 11-10, on the caneberry 

subgroup 13A to the caneberry subgroup 13-07A, on grapes to the small fruit vine 

climbing, except fuzzy kiwifruit subgroup 13-07F, and on strawberry to the low growing 

berry subgroup 13-07G. Since the original uses are already on the requested labels, and 

since the expansions are for the identical use pattern currently registered, no new data are 

required to support the requested expansions.

Updated maximum reasonably balanced diets (MRBD) for livestock have been calculated 

and indicated that the current livestock tolerances are adequate to cover secondary 

residues of hexythiazox. However, HED recommends increasing the ruminant meat by 

product tolerances to 0.05 ppm and the egg tolerance to 0.05 ppm to harmonize with 

Codex. 

There are no processing commodities associated with sorghum and the pepper/eggplant 

subgroup 8-10B; therefore a discussion of residues in processed commodities is not 

relevant to this action. 

The nature of the residue in rotational crops is not understood. However, HED 

previously concluded that, in consideration of the available confined and field rotational 

crop studies, a 120-day plant back interval (PBI) for all crops not listed on the label is 

appropriate. This conclusion remains unchanged.

5.2 Drinking Water Residue Profile

EFED Drinking Water Assessment, D401798, A. Shelby, 6/21/12

EFED Drinking Water Assessment, D404203, A. Shelby, 1/17/12

Currently, the Agency does not have drinking water monitoring data for hexythiazox. 

Therefore, the potential for hexythiazox residues in drinking water was evaluated through 

modeling. 

Surface water residues are expected to exceed ground water residues; therefore, EFED 

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

the Tier II PRZM/EXAMS surface water model 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 4.31 μg/L from this scenario was used in the chronic dietary risk 

assessment. 
Hexythiazox Human Health Risk Assessment D404015

Page 22 of 36

5.3 Dietary Exposure and Risk

Dietary Exposure and Risk Memorandum, D404574, D. Davis, 5/3/13

5.3.1 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. 

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. 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 or any 

subpopulation. The estimated exposure to the U.S. General Population resulted in a risk 

equivalent to 17% of the cPAD. The estimated exposure to children 1 – 2 years of age, 

the most highly exposed subpopulation, resulted in a risk equivalent to 82% of the cPAD. 

Results for all subpopulations are summarized in Table 5.3.3, below.

5.3.3 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. 

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

Hexythiazox

Population Subgroup

Chronic Dietary Cancer

Dietary 

Exposure

(mg/kg/day) % cPAD*

Dietary 

Exposure

(mg/kg/day) Risk

General U.S. Population 0.004356 17

No concern for risks associated with 

the carcinogenic potential of 

hexythiazox.

All Infants (< 1 year old) 0.008040 32

Children 1-2 years old 0.020483 82 N/A N/A

Children 3-5 years old 0.013364 54
Hexythiazox Human Health Risk Assessment D404015

Page 23 of 36

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

Hexythiazox

Population Subgroup

Chronic Dietary Cancer

Dietary 

Exposure

(mg/kg/day) % cPAD*

Dietary 

Exposure

(mg/kg/day) Risk

Children 6-12 years old 0.006416 26

Youth 13-19 years old 0.003220 13

Adults 20-49 years old 0.002878 12

Adults 50+ years old 0.003229 13

Females 13-49 years old 0.003068 12

* Most highly exposed subpopulation is highlighted in bold.

5.4 Anticipated Residue and Percent Crop Treated (%CT) Information

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

exposure and risk assessment. 

6.0 Residential and Other Non-Occupational Exposures/Risks 

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

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

uses on residential sites, 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. The estimated exposure and risk 

assessments for the existing residential uses that have been revised to reflect updates to 

HED’s 2012 Residential SOPs as well as policy changes for body weight assumptions.

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 estimated exposure and risks are shown in 

Table 6.1, below. 
Hexythiazox Human Health Risk Assessment D404015

Page 24 of 36

Table 6.1. Short-term Residential Handler 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, Hose-end 

sprayer

100 0.0014 4.375E-6 lb 

ai/ft2 1200 ft2

0.000000092 330,000,000

Gardens/ Trees, WDG/DF, Hose-end 

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, Manuallypressurized handwand / backpack 100 1.1 4.375E-6 lb 

ai/ft2 1200 ft2

0.000072 420,000

1 Based on registered or proposed 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 post-application 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 days1, 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. Post-application exposure and risk 

estimates are shown in Table 6.2, below.

Table 6.2. Residential Post-application Non-cancer Exposure and Risk Estimates for Hexythiazox 

(Short-Term for Hand-to-Mouth and Object-to-Mouth Exposure; Short- and Intermediate-Term 

for Incidental Soil Ingestion Exposure).

Lifestage Post-application Exposure Scenario App rate Dose MOEs

Child Turf - sprays

Hand to Mouth

0.1875 lb ai/acre

0.0029 11,000

Object to Mouth 0.00009 350,000

Incidental Soil Ingestion 0.0000063 4,700,000

 

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

Andrew Shelby. DP Barcode: 396529& 401798. 6/21/2012.
Hexythiazox Human Health Risk Assessment D404015

Page 25 of 36

6.3 Other

6.3.1. Spray Drift

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 the ground application method 

employed for hexythiazox. The 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 (see the Agency’s Spray 

Drift website for more information2. The Agency has completed its evaluation of the 

new database 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 

with specific products with significant risk estimates associated with drift.

Although a quantitative residential post-application inhalation exposure assessment was 

not performed as a result of pesticide drift from neighboring treated agricultural fields, an 

inhalation exposure assessment was performed for flaggers. This exposure scenario is 

representative of a worse case inhalation (drift) exposure and may be considered 

protective of most outdoor agricultural and commercial post-application inhalation 

exposure scenarios. 

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 farm 

children via spray drift from agricultural hexythiazox applications.

6.3.2. Residential Bystander Post-Application Exposure

Based on the Agency's current practices, a quantitative post-application inhalation 

exposure assessment was not performed for hexythiazox at this time primarily because of 

the low acute inhalation toxicity (Toxicity Category IV) and low vapor pressure (2.3 x 

10-8 mmHg). However, 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, 20103. The Agency is 

in the process of evaluating the SAP report and may, as appropriate, develop policies and 

procedures to identify the need for and, subsequently, the way to incorporate postapplication inhalation exposure into the Agency's risk assessments. If new policies or 

 

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

3 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
Hexythiazox Human Health Risk Assessment D404015

Page 26 of 36

procedures are developed, the Agency may revisit the need for a quantitative postapplication inhalation exposure assessment for hexythiazox.

Although a quantitative residential post-application inhalation exposure assessment was 

not performed, an inhalation exposure assessment was performed for handlers (i.e., 

groomers, treaters, etc). This exposure scenario is representative of a worse case 

inhalation exposure and should be considered protective of most post-application 

inhalation exposure scenarios.

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 

toxicology database; therefore, an 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)

and post application exposures with average food and water exposures. The residential 

estimated exposures used in the short- and intermediate-term aggregate risk assessments 

are shown in Table 7.2.1, below. 

Table 7.2.1. 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

0.000072

Source: Table 6.1

Gardens/Trees, 

handwand/backpack

N/A; no dermal endpoint 0.000072

Adult Female

0.000072

Source: Table 6.1

Gardens/Trees, 

handwand/backpack

N/A; no dermal endpoint 0.000072

Child N/A; only adults are 

assessed as handlers3

0.0029

Source: Table 5.2

Hand-to-Mouth from 

Treated Turf

0.0029
Hexythiazox Human Health Risk Assessment D404015

Page 27 of 36

Table 7.2.1. 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

Intermediate-Term

Adult Male N/A; intermediate term 

exposure not expected N/A; no dermal endpoint -

Adult Female N/A; intermediate term 

exposure not expected N/A; no dermal endpoint -

Child N/A; only adults are 

assessed as handlers

0.0000063

Source: Table 5.2

Incidental Soil Ingestion

0.0000063

1

Residential exposure is the sum of the handler (adults only) and post application exposures.

2 N/A is not applicable

3 HED’s 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential-exposure-sop.html)

Short- and intermediate-term aggregate margins of exposure for adults and children 

greatly exceed the LOC of 100 and are not of concern. Short- and intermediate-term 

estimated exposures and risks are shown in Table 7.2.2, below. 

Table 7.2.2. 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 0.003229 0.000072 9,100

Adult Female 30 100 0.3 0.003068 0.000072 9,600

Child 30 100 0.3 0.020483 0.0029 1,300

Intermediate-Term Scenario

Adult Male 30 100 0.3 0.003229 N/A 9,300

Adult Female 30 100 0.3 0.003068 N/A 9,800

Child 30 100 0.3 0.020483 0.0000063 1,500

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 7.2.1.Average food & water exposure taken from Table 

5.3.3.

4 Aggregate MOE = [NOAEL (Avg Food & Water Exposure + Residential Exposure)]
Hexythiazox Human Health Risk Assessment D404015

Page 28 of 36

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 

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

9.0 Occupational Exposures and Risks 

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

An occupation exposure and risk assessment was conducted to support the new uses on 

alfalfa and timothy. Full details of that assessment are included in the memorandum 

cited above and the results are briefly summarized here.

9.1 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. Based on the proposed uses, shortterm exposures are anticipated as the proposed uses indicate the product is only to be 

applied once per year. As the inhalation point of departure is the same for both short- and 

intermediate-term exposure durations, the short-term assessment is protective of possible 

longer-term exposures (i.e., commercial applicators that may apply a product over a 

period of weeks).

All occupational handler scenarios assessed for the new and expanded uses of 

hexythiazox 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. 
Hexythiazox Human Health Risk Assessment D404015

Page 29 of 36

Occupational handler risk estimates are shown in Table 9.1. 

1 Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ([March 2012]); includes data from 

PHED/ORETF/AHETF (level of mitigation: Baseline, PPE, Eng. Controls).

2 Based on registered or proposed label.

3 Exposure Science Advisory Council Policy #9.1.

Table 9.1.1. Short-/Intermediate-Term Occupational Exposure and Risk Estimates for Hexythiazox. All estimates are at 

baseline mitigation (without respirator). 

Exposure Scenario Crop or Target

Inhalation Unit 

Exposure (ug/lb ai)1 Maximum

Application Rate2

Area Treated or 

Amount Handled 

Daily3

Inhalation

Mitigation Level Dose 

(mg/kg/day)4 MOE5

Mixer/Loader

M/L, DF/WDG, Aerial, 

Broadcast Orchard, Field Crop

8.96 0.1875 lb ai/acre

350 acres 0.00735 4,100

M/L, DF/WDG, Airblast, 

Broadcast Orchard 40 acres 0.00084 36,000

M/L, DF/WDG, Chemigation, 

Broadcast

Orchard, Field Crop 350 acres 0.00735 4,100

Greenhouse 60 acres 0.00126 24,000

M/L, DF/WDG, Groundboom, 

Broadcast

Greenhouse 60 acres 0.00126 24,000

Field Crop 80 acres 0.00168 18,000

M/L, L/SC/EC, Aerial, 

Broadcast

Orchard, Field Crop

0.219 0.1875 lb ai/acre

350 acres 0.00018 170,000

High-acreage Field Crop 1200 acres 0.000616 49,000

M/L, L/SC/EC, Airblast, 

Broadcast Orchard 40 acres 0.0000205 1,500,000

M/L, L/SC/EC, Chemigation, 

Broadcast

Orchard, Field Crops 

(all) 350 acres 0.00018 170,000

M/L, L/SC/EC, Groundboom, 

Broadcast

Field Crop 80 acres 0.0000411 730,000

High-acreage Field Crop 200 acres 0.000103 290,000

Applicator

Applicator, Spray, Aerial, 

Broadcast

Orchard, Field Crop Engineering 

Control: 0.0049

0.1875 lb ai/acre

350 acres 0.000004 7,400,000

High-acreage Field Crop 1200 acres 0.000014 2,200,000

Applicator, Spray, Airblast, 

Broadcast Orchard 4.71 40 acres 0.000441 68,000

Applicator, Spray, 

Groundboom, Broadcast

Greenhouse

0.34

60 acres 0.0000479 630,000

Field Crop 80 acres 0.0000638 470,000

High-acreage Field Crop 200 acres 0.00016 190,000

Flagger

Flagger, Spray, Aerial, 

Broadcast

Orchard, Field Crop (all) 0.35 0.1875 lb ai/acre 350 acres 0.000288 100,000

Mixer/Loader/Applicator

M/L/A, DF/WDG, Backpack, 

Broadcast Greenhouse 140 0.000625 lb ai/gallon 40 gallons 0.0000438 680,000

M/L/A, DF/WDG, Manuallypressurized Handwand, 

Broadcast

Greenhouse 30 0.000625 lb 

ai/gallon 40 gallons 0.00000938 3,200,000

M/L/A, DF/WDG, 

Mechanically-pressurized 

Handgun, Broadcast

Greenhouse 120 0.000625 lb 

ai/gallon 1000 gallons 0.000938 32,000
Hexythiazox Human Health Risk Assessment D404015

Page 30 of 36

4

Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x 

Area Treated or Amount Handled Daily (A or gal/day) /BW (80 kg).

5

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

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.

Based on the Agency's current practices, a quantitative post-application inhalation 

exposure assessment was not performed for hexythiazox at this time primarily because of 

the low acute inhalation toxicity (Toxicity Category IV) and low vapor pressure (2.3 x 

10-8 mmHg). However, there are multiple potential sources of post-application inhalation 

exposure to individuals performing post-application activities in previously treated fields. 

These potential sources include volatilization of pesticides and resuspension of dusts 

and/or particulates that contain pesticides. The Agency sought expert advice and input on 

issues related to 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, 20104. The Agency is in the process of evaluating the 

SAP report as well as available post-application inhalation exposure data generated by 

the ARTF and may, as appropriate, develop policies and procedures, to identify the need 

for and, subsequently, the way to incorporate occupational post-application 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 post-application 

inhalation exposure assessment for hexythiazox.

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.

The Worker Protection Standard for Agricultural Pesticides contains requirements for 

protecting workers from inhalation exposures during and after greenhouse applications 

through the use of ventilation requirements [40 CFR 170.110, (3) (Restrictions associated 

with pesticide applications)].

 

4 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
Hexythiazox Human Health Risk Assessment D404015

Page 31 of 36

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 postapplication 

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, ai’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://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html
Hexythiazox Human Health Risk Assessment D404015

Page 32 of 36

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

F: 0, 5.27, 34.77, or 

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 D404015

Page 33 of 36

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

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

In vitro mammalian cell 

cytogenetic assay in 

00156894 (1986)

Acceptable

The test was negative up to precipitating doses accompanied 

by severe cytotoxicity ( 167 μg/mL +/-S9).
Hexythiazox Human Health Risk Assessment D404015

Page 34 of 36

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

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 subchronic 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 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) 
Hexythiazox Human Health Risk Assessment D404015

Page 35 of 36

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

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 D404015

Page 36 of 36

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.

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

Special Studies 

AHASPOC (D0056434): not required at this time; BHASPOC (D0056434): 28-day study is sufficient to assess 

subchronic neurotoxicity from hexythiazox exposure; Cdermal equivalent dose 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; Dnot required since there is a 4-week study and a 1-year study available