### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D

. C. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### MEMORANDUM

Date: 02/08/2016

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

PC Code: 128849 DP Barcode: D427090, DP427091; D426297 Decision No.: 499597, 502652, 502653

, 502854

. Registration No.: 10163-277 and 10163-250 Petition No.: 5F8356; 5F8346 Re2ulatory Action: Section 3 Risk Assessment Tvoe: NA Case No.: 7404-1 TXRNo.: NA MRIDNo.: NA



### FROM: CAS No.: 78587-05-0 40 CFR: 40 CFR 180.448


### Katelynn King, Risk

# Assessor~~ Kelly M. Lowe, Environmental Scientist /

### ~ Linda Taylor, Ph.D., Toxicologist Risk Assessment Branch VII Health Effects Division (7509P)

THROUGH: Michael Metzger, Supervisory Chemi fr t 

# /} t7 f J

# /,**/~** RAB VNII, HED (7509P) 

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TO: Danette Drew, Senior Chemist RAB VII, HED (7509P)

Nerija Orentas, Risk Manager RichardGebken,ProductManager 10 Invertebrate Vertebrate Branch 2 (IVB2) Registration Division (7505P)

Page I of34Page 2 of 34 

### Table of Contents

1.0 Executive Summary ............................................................................................................. 4 2.0 HED Recommendations....................................................................................................... 5 2.1 Data Deficiencies ............................................................................................................. 5 2.2 Tolerance Considerations ................................................................................................. 5 2.2.1 Enforcement Analytical Method ............................................................................... 6 2.2.2 Recommended Tolerances ........................................................................................ 6 2.2.3 Revisions to Petitione d-For Tolerances .................................................................... 6 2.2.4 International Harmonization ..................................................................................... 7 2.3 Label Recommendations .................................................................................................. 7 2.3.1 Recommendations from Residue Reviews ............................................................... 7 2.3.2 Recommendations from Occupational Assessment .................................................. 7 2.3.3 Recommendations from Re sidential Assessment ..................................................... 7 3.0 Introduction .................................................................................................................. ........ 7 3.1 Chemical Identity ............................................................................................................. 7 3.2 Physical/Chemical Characteristics ................................................................................... 8 3.3 Pesticide Use Pattern ........................................................................................................ 9 3.5 Consideration of Environmental Justice .......................................................................... 9 4.0 Hazard Characterization and Dose-Response Assessment ................................................ 10 4.1 Summary of Toxicological Effects ................................................................................ 10 4.2 Safety Factor for Infants and Ch ildren (FQPA Safety Factor) ....................................... 11 4.2.1 Completeness of the Toxicology Database ............................................................. 11 4.2.2 Evidence of Neurotoxicity ...................................................................................... 11 4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ......... 11 4.2.4 Residual Uncertainty in the Exposure Database ..................................................... 11 4.2.5 Cancer Classification and Risk Assessment Recommendation .............................. 12 4.3 Toxicity Endpoint and Point of Departure Selections .................................................... 12 4.4 Endocrine Disruption ..................................................................................................... 14 5.0 Dietary Exposure/Risk Characterization ............................................................................ 15 5.1 Residue Chemistry Summary ......................................................................................... 15 5.2 Drinking Water Residue Profile ..................................................................................... 16 5.3 Dietary Exposure and Risk ............................................................................................. 17 5.3.1 Acute Dietary Exposure/Risk ................................................................................. 17 5.3.2 Chronic Dietary Exposure/Risk .............................................................................. 17 5.3.3 Cancer Dietary Risk ................................................................................................ 18 5.3.4 Summary Table ....................................................................................................... 18 6.0 Residential and Other Non-Occ upational Exposures/Risks .............................................. 18 6.1 Residential Handler Exposure and Risk ......................................................................... 18 6.2 Residential Post-application Exposure ........................................................................... 19 6.3 Residential Risk Estimates for Use in Aggregate Assessment ............................................... 20 7.0 Aggregate Risk Assessments and Risk Characterization ................................................... 21 7.1 Acute Aggregate Risk .................................................................................................... 21 7.2 Short- and Intermediate-T erm Aggregate Risks ............................................................ 22 7.3 Long-Term (Chronic) Aggregate Risk ........................................................................... 22 8.0 Cumulative Risk Characterization/Assessment ................................................................. 22 9.0 Occupational Exposures and Risks .................................................................................... 23Page 3 of 34 

### 9.1 Occupational Handler Risk ............................................................................................ 23 9.2 Occupational Post-application Risk ............................................................................... 23 10.0 Human Studies ................................................................................................................. .. 24 Appendix A. Toxicology Assessment.......................................................................................... 25 Appendix B: Toxicology Data Requirements ............................................................................... 29 Appendix C: Field Trial Residue Data .......................................................................................... 30 Appendix D: Maximum Residue Limits (MRL) .......................................................................... 31 Appendix E: OECD Calcul ator MRL Output ............................................................................... 32Page 4 of 34 

### 1.0 Executive Summary

Hexythiazox, trans-5-(4-chlorophenyl)- N -cyclohexyl-4-methyl-2-oxothiazolidine-3- carboxamide, is an ovicide/miticide used to contro l spotted spider mites on a variety of crops and outdoor residential settings. Hexythi azox is a contact pesticide which achieves control of eggs or immature mites via direct contact or contact with tr eated surfaces.

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

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

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

The toxicity database for hexythiaz ox is complete. Hexythiazox is a ssociated with toxicity of the liver and adrenals following sub-chronic and chro nic 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 show ed no indication of incr eased susceptibility to in utero and/or postnatal exposure to hexythiazox. Reproductive toxicity was not observed. There is no concern for neurotoxicity follo wing exposure to hexythi azox. The toxicology database for hexythiazox does not show any evid ence 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 serv es as the basis for the chronic reference dose (RfD) occurred at doses substantially below the lowest dose that induced tumors, HED concluded that quantification of risk us ing a non-linear approach; i.e., RfD, for hexythiazox will adequately account for all chronic toxicity, including carcinogenicity, that c ould result from exposure to hexythiazox.

No acute risk is expected since no hazard was iden tified in any toxicity st udy for this duration of exposure. Chronic risk is regulat ed based on effects seen in the adrenal glands in a one-year dog feeding study. Short-term and intermediate-t erm incidental oral a nd 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 ga in and increased liver, kidney, and adrenal weights in the 2-generation reprodu ction study in the rat. For the short- and intermediate-term dermal risk assessment, no quantif ication of risk is required since no dermal hazard has been identified for hexythiazox. The dermal equivale nt dose, after applying the estimated dermal absorption factor of 2% to th e oral reproduction study no observed adverse e ffect level (NOAEL) of 30 mg/kg/day, is 1500 mg/kg/day, wh ich is greater than the limit dose.

An acute endpoint was not selected for hexythi azox; therefore, the Agency only conducted a chronic dietary (food and drinking water) exposure a nd risk assessment. The chronic dietary risk assessment used tolerance level residues, assu med 100% crop treated, included DEEM default processing factors, and modeled water values. This unrefined assessment resulted in estimated chronic dietary (food and water) risks of 18% of the chronic population adjusted dose (cPAD) for the U.S. population and 81% of the cPAD for children 1 – 2 years of age, the most highly exposed population subgroup.

There are no new residential uses proposed with this action; howe ver, there are registered uses on residential sites which have been previous ly assessed, including (1) ornamental landscapePage 5 of 34 

### plantings in residences, public areas, and recreational sites such as campgrounds, golf courses, parks and athletic fields, (2) or namental lawns and turf (includi ng residential), (3) residential pome fruit, stone fruit, and nut trees, and residential caneberries. Residential handler inhalation margins of exposure (MOEs) significantly exceed 100 for all scenarios assessed and are not of concern. Child post-application incidental oral exposure to tr eated turf was assessed for hexythiazox, and risk estimates greatly exceed the LOC of 100 for all scenarios associated with children’s exposure to treated tu rf and are not of concern.

Since there are no acute endpoints of concern, an acute aggregate risk assessment was not conducted. HED has conducted short- and in termediate-term (food, drinking water and residential), and long-term/chr onic (food and drinking water) a ggregate risk assessments for hexythiazox. Short- and intermediate-term aggr egate margins of exposure (MOEs) significantly exceeded the level of concern (L OC) of 100 and are not of concern. The long-term (chronic) aggregate assessment includes only dietary (food a nd water) exposure as there are no long-term residential exposure scenarios. Chroni c dietary risk is not of concern.

The proposed amended uses on cotton and citrus do not include any changes to application methods and/or rates. Therefore, a new assessm ent of occupational expos ure is not required, and a previous assessment (Memo, A. Lamay, D404 018, 06-May-2013) is protective of the amended use pattern. In that assessment, occupationa l handler inhalation MOEs significantly exceeded 100 for all scenarios assessed including mixers/loa ders, applicators and flaggers. Based on the Agency's current practices, a quantitative non-c ancer occupational post- application inhalation exposure assessment was not performed for hexythi azox. If new policies or procedures are put into place, the Agency may revisit the need fo r a quantitative occupational post-application inhalation exposure assessment for hexythiazox. The label restricted entry interval (REI) of 12 hours is appropriate and in compliance with Wo rker Protection Standa rd requirements.

Potential areas of environmental ju stice concern, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions to Address Environmental Just ice in Minority Populations an d Low-Income Populations," http://www.archives.gov /federal-register/ex ecutive-orders/pdf/12898.pdf ).

2.0 HED Recommendations

Provided the proposed label is amended as noted in Section 2.3.1, there are no hazard, exposure, or risk considerations that w ould preclude granting the reques ted use on cotton and citrus, and setting the recommended toleran ce described in Section 2.2.2.

2.1 Data Deficiencies

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

2.2 Tolerance ConsiderationsPage 6 of 34 

### 2.2.1 Enforcement Analytical Method

An adequate HPLC/UV analytical method is avai lable for the enforcement of tolerances for residues of hexythiazox and its metabolites contai ning the PT-1-3 moiety in crop and livestock commodities. This method is listed in the U.S. EPA Index of Residue Analytical Methods under hexythiazox as method AMR-985-87.

2.2.2 Recommended Tolerances

Tolerances currently established under 40 CFR §180.448 need to be updated in order to comply with the HED recommendations. Table 2.2.2 summa rizes the recommended tolerance levels and commodity definition required to support the altered uses of cotton and citrus.

Table 2.2.2. Tolerance Summary for Hexythiazox. Commodity 40 CFR Established Tolerance (ppm) Registrant Proposed Tolerance (ppm) HED-Recommended Tolerance (ppm) Comments ( correct commodity definition ) Citrus, dried pulp 0.60 0.6 Revoke Revoke. A 0.5 ppm tolerance on dried citrus pulp is appropriate; however, the

recommended 0.5 ppm tolerance for the citrus crop group 10-10 is adequate to cover any residues of hexythiazox in dried citrus pulp. Citrus, oil 24 26 25 a N/A Fruit, citrus, group 10-10 0.35 0.6 0.5 Harmonized with Codex. For use in CA, AZ, and TX only. Cotton, gin byproducts 3.0 15 15 b Established for CA and AZ only. Recommended for USA. Cotton, undelinted seed 0.20 0.5 0.4 b Established for CA and AZ only. Recommended for USA.

a Processing factors used from citrus (orange) processing study (D334889, 07/03/2006, T. Bloem). b Tolerance calculated using data collected from previously submitted (44574703) and recently submitted (49554501) studies.



### 2.2.3 Revisions to Petitioned-For Tolerances

For citrus, dried pulp, there was no change from the established tolerance compared to the registrant proposed tolerance; how ever, HED recommends that the ci trus, dried pulp tolerance be revoked as it is covered by the citrus group 10-10 tolerance. For ci trus oil, the 40 CFR established tolerance of 24 ppm is lower than the registrant pr oposed tolerance of 26 ppm; HED recommends a tolerance of 25 ppm. This HED recommended tolerance was obtained by multiplying the citrus oil processing factor (104x) from the 2006 processing study (D334889, 07/03/2006, T. Bloem) by the highest average fiel d trial (HAFT) residue for lemons (0.243 ppm) from the recently submitted citrus study (MRI D 49591801) since lemons are the citrus crop that produced the highest residues for fruit, citrus, gr oup 10-10 which will cont inue to be a regional use only in California, Arizona, and Texas.Page 7 of 34 

### For cotton gin byproducts, the 40 CFR established tolerance is currently at 3.0 ppm, however, the registrant proposes increasi ng the tolerance to 15 ppm and HED concludes that the data support that. For cotton, undelinted seed, the 40 CFR tolerance is currently at 0.20 ppm and the registrant proposes increasing the tolerance to 0.5 ppm. HED recommends a tolerance increase to 0.4 ppm; the difference is due to HED using new recently submitted data and old previously submitted data residue data to calculate the recommended Organization for Economic Cooperation & Development Maximu m Residue Limit (OECD MRL).

2.2.4 International Harmonization

There are no Canadian or Mexican maximum resi due limits (MRLs) established or proposed for residues of hexythiazox on citrus or cotton. Codex has establishe d MRLs for “citrus, fruit, Crop Group 10-10” but not for cotton. The Codex plan t residue definition is for hexythiazox as opposed to the U.S. definition which includes he xythiazox plus metabolites containing the (4- chlorophenyl)-4-methyl-2-oxo-3-thia zolidine moiety. The differences in U.S. and Codex residue definitions prohibit harmonization. A summary of U.S. and interna tional tolerances and MRLs is presented in Appendix D.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

No label changes are required ba sed on the chemistry assessment.

2.3.2 Recommendations from Occupational Assessment

No label changes are required base d on the occupational assessment.

2.3.3 Recommendations from Residential Assessment

No label changes are required ba sed on the residen tial assessment.

3.0 Introduction

Hexythiazox, trans-5-(4-chlorophenyl)- N -cyclohexyl-4-methyl-2-oxothiazolidine-3- carboxamide, is an ovicide/miticide used to cont rol mites on a variety of crops and in outdoor residential settings. Hexythi azox is a contact pesticide whic h achieves contro l of eggs or immature mites via direct contact or contact with treated surfaces.

3.1 Chemical Identity

The chemical structure and nomenclature of he xythiazox and its common moiety, PT-1-3 is shown in Table 3.1. The physicochemical proper ties of the technical grade hexythiazox are presented in Table 3.2.Page 8 of 34 Table 3.1. Nomenclature of Hexythiazox. Compound

Common name Hexythiazox Company experimental names DPX-Y5893, NA-73 IUPAC name (4 RS ,5 RS )-5-(4-chlorophenyl)- N -cyclohexyl-4-methyl-2-oxo-1,3-thiazolidine-3- carboxamide
CAS name trans -5-(4-chlorophenyl)- N -cyclohexyl-4-methyl-2-oxo-3- thiazolidinecarboxamide
CAS # 78587-05-0 End-use product/EP 1 lb/gal EC (EPA Reg. No. 10163-277; Onager® Ovicide/Miticide) 50% ai DF (EPA Reg. No. 10163-250; Savey® 50 DF Miticide) Compound

(4-chlorophenyl)-4-methyl-2- oxo-3-thiazolidine moiety

Common name PT-1-3 moiety Chemical name 5-(4-chlorophenyl)-4-methyl-thiazolidin-2-one



### 3.2 Physical/Chemical Characteristics

Table 3.2. Physiochemical Properties of Hexythiazox.
Parameter Value Reference Melting point/range 108.0-108.5 °C 00143533 pH Not applicable Density 1.289 at 25 °C 00143533 Water solubility 0.12 ppm 44006301 Solvent solubility g/L chloroform 1379 xylene 362 acetone 160.0 acetonitrile 28.6 n-hexane 3.9 methanol 20.6 00143533

Vapor pressure <10 -8 mm Hg at 25 oC 44006301 Dissociation constant, pK a Not applicable Octanol/water partition coefficient Log(P O W ) 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 C H 3

O Cl N H O

S N H

O C H 3

ClPage 9 of 34 

### 3.3 Pesticide Use Pattern

Gowan Company has submitted a supplemental label for Onager® Miticide (EPA Reg No. 10163-277) which includes proposed regionally restri cted use directions for cotton and citrus. Gowan Company has also submitted a supplemen tal label for Savey® 50 DF (EPA Reg. No. 10163-250) which includes proposed use directions for cotton. The newly proposed use patterns have been summarized in Table 3.3.

Table 3.3. Summary of Proposed Directions for Use of Hexythiazox.
Application Timing; Type Formulation [EPA Reg. No.] Applic. Rate (lb ai/A) Max. No. Applic. per

Season Max. Seasonal Applic. Rate

(lb ai/A) PHI (days) Use Directions and Limitations

Cotton Before boll opening and prior to adult mite buildup; Ground App., Air App., & Chemigation Onager [10163-277] 20 fl oz/A = 0.156 lb

ai/A 1 0.156 35 No more than one application per year.

Ground App. & Air App. Savey 50 DF [10163-250] 5 oz/A = 0.156 lb

ai/A 1 0.156 35 No more than one application per year.

Citrus
Ground App., Air App., & Chemigation Onager [10163-277] 24 fl oz/A = 0.1875 lb ai/A 1 0.1875 7 No more than one application per year.



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

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assess ment of human health risk to support the proposed amended use of hexythiazox. Humans may be exposed to hexythiazox in food and drinking water, since hexythiazox may be applied directly to gr owing crops and application may result in hexythiazox reaching surface and ground water sources of drinking water. Additionally humans may be exposed to hexythiazox in resi dential settings, since it may be applied to ornamental plantings in residen ces, public areas, and recreational sides, as well as on lawns and turf and to residential berries a nd fruit and nut trees. In an oc cupational 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-enteri ng treated fields.

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

3.5 Consideration of Environmental JusticePage 10 of 34 

### Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions to Address Environmental Just ice in Minority Populations an d Low-Income Populations," ( http://www.archives.gov/federal -register/executive-orders/pdf/12898.pdf ). As a part of every pesticide risk assessment, OPP considers a larg e 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 pa tterns are compiled by the U.S. Department of Agriculture’s National Health and Nutrition Ex amination 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 categ orized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary e xposure to smaller, specialized subgroups and exposure assessments are performed when condi tions or circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for t oddlers, youths, and adults enteri ng or playing on treated areas post-application are evaluated. Further considera tions are currently in development as OPP has committed resources and expertise to the developm ent of specialized software and models that consider exposure to bystanders and farm worker s as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

No new toxicity and/or metabolism data have been received since the last risk assessment. This assessment includes summaries of prior assessments (L. Taylor, 06/03/2015, D423491 & D423145).

4.1 Summary of Toxicological Effects

Hexythiazox was rapidly absorbed, distributed, and eliminated in rats following oral exposure, with the majority being eliminated within 24 hours in the urine and feces. There were no observable differences in the total elimination be tween male and female ra ts, and the major route of elimination in both sexes was by fecal excr etion. Approximately 11-20% (low dose) and 65- 69% (high dose) of the dosed radioactivity was identified as unchanged hexythiazox. The highest tissue residues were detected in the fat, liver, and adrenals, with the residues in female tissues being two-fold higher than those found in male tissues. Hexythiazox was me tabolized to a large number of metabolites that were ex creted both in the urine and feces. The main metabolic reactions identified were hydroxyl ation of the cyclohexane ring and cleavage of the amide bond to the cyclohexane ring. A dermal absorption fact or was derived from a de rmal penetration study and was estimated to be 2%.

Hexythiazox is associated with toxicity of the liver and adrenals following subchronic and chronic exposure to dogs, rats , and mice, with the dog being th e most sensitive species. The prenatal developmental studies in rabbits and rats, and the two-genera tion reproduction study in rats, showed no indication of increased susceptibility to in utero and/or postnatal exposure to hexythiazox. Reproductive toxic ity was not observed. There is no concern for neurotoxicityPage 11 of 34 

### following exposure to hexythiazox. The toxicology database for hexythiazox does not show any evidence of treatment-related eff ects 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 subs tantially below the lowest dose that induced tumors, HED concluded that quantificati on of risk using a non-linear approach; i.e., RfD, for hexythiazox will adequately account for all chroni c effects, including carcinogenicity, that could result from exposure to hexythiazox.

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

The hexythiazox risk assessment team has reco mmended that the FQPA Safety Factor be reduced to 1X because (1) there is an adequate toxicity database for hexythiazox; (2) The prenatal developmental studies in rabbits and rats and the two-genera tion reproduction study in rats showed no indication of increased susceptibility to in utero and/or postnatal exposure to hexythiazox; (3) There is no concern for neurot oxicity following exposure to hexythiazox, and (4) There are no residual uncertainties id entified in the exposure databases.

4.2.1 Completeness of the Toxicology Database

The database of toxicology studies for hexythi azox is complete and includes developmental toxicity studies in the rat and rabbit, a reproductive toxicity st udy in the rat, and a subchronic (28-day) neurotoxicity study in the rat. Th e Hazard and Science Policy Council (HASPOC) concluded that an acute neurot oxicity study is not required, and a new subchronic (90-day) neurotoxicity study is not required, since the 28 -day neurotoxicity study is sufficient to assess subchronic neurotoxicity from hexythiaz ox exposure (TXR 0056434, dated 10/18/12).

4.2.2 Evidence of Neurotoxicity

Decreased motor activity was observe d in rats following repeat oral exposure only at a dose level close to the limit dose, and a clear NOAEL was established. No other evidence suggestive of peripheral or central nervous system toxicity was observed in the toxicology database for hexythiazox. The points of depa rture used for all exposure sc enarios are protective of any potential neurotoxic effects of hexythiazox. As noted above, HASPOC concluded that an acute neurotoxicity study was not required for hexythiazox.

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

There is no evidence of increased qu antitative susceptibility following in utero exposure to hexythiazox in either the ra t or rabbit developmental toxicity study or following in utero and/or pre-/post-natal exposure to hexythiazox in the 2-generation reproduction study in rats.

4.2.4 Residual Uncertainty in the Exposure Database

The residential exposure assessment assumes maximum label use rate as well as other conservative assumptions. The dietary exposure es timates are unrefined and reflect tolerancelevel residue in food, 100% crop treated (CT), and upper-bound drinking water estimates basedPage 12 of 34 

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

4.2.5 Cancer Classification and Ri sk Assessment Recommendation

Hexythiazox is classified as “likely to be carcinogenic to humans” based upon increased incidences of malignant and combined benign/ malignant liver tumors in high-dose female B6C3F1 mice, and benign mammary gland tumors, observed in high dose male rats. There was no evidence of carcinogenicity in male mice and fema le rats. However, since the effects seen in the study that serves as the basis for the chroni c RfD occurred at doses substantially below the lowest dose that induced tumors , HED concluded that quantifica tion of risk using a non-linear approach; i.e., RfD, for hexythiazox, will adequately account for all chronic effects, including carcinogenicity, that could resultfrom exposure to hexythiazox.

4.3 Toxicity Endpoint and Point of Departure Selections

No new toxicity and/or metabolism data have been received since th e last risk assessment. There have been no changes to the prior dose-respons e assessment or recommendations for combining routes of exposure, and no change in th e cancer classification (D. Davis, D396526, D404477, 9/15/12). The points of departure, uncerta inty factors, and toxicity e ndpoints are presented in the following tables.

Table 4.3.1. Toxicological Dose s and Endpoints for Hexythiazox for Use in Dietary and Non-Occupational Human Health Risk Assessments. 1
Exposure/ Scenario Point of Departure Uncertainty/F QPA Safety

Factors RfD, PAD, Level of Concern for Risk Assessment Study and Toxicological Effects

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

Chronic Dietary All Populations NOAEL=2.5 mg/kg/day UF A = 10x UF H = 10x FQPA SF= 1x Chronic RfD = 0.025 mg/kg/day

cPAD = 0.025 mg/kg/day One-Year Toxicity Feeding Study - Dog

LOAEL = 12.5 mg/kg/day based on increased absolute and relative adrenal weights and associated adrenal histopathology.Page 13 of 34 Table 4.3.1. Toxicological Dose s and Endpoints for Hexythiazox for Use in Dietary and Non-Occupational Human Health Risk Assessments. 1
Exposure/ Scenario Point of Departure Uncertainty/F QPA Safety

Factors RfD, PAD, Level of Concern for Risk Assessment Study and Toxicological Effects

Short- andIntermediateTerm Incidental oral NOAEL=30 mg/kg/day UF A = 10x UF H = 10x FQPA SF= 1x Residential LOC for MOE = 100 2-Generation Reproduction Study – Rat

LOAEL = 180 mg/kg/day, based on decreased pup body weight during lactation and delayed hair growth and/or eye opening, and decreased parental body-weight gain and increased absolute and relative liver, kidney, and adrenal weights.

Co-Critical 13-Week Oral Toxicity Study – Rat NOAEL = 5.5 mg/kg/day LOAEL = 38 mg/kg/day, based on increased absolute and relative liver weights in both sexes, increased relative ovarian and kidney weights, and fatty degeneration of the adrenal zona fasciculata.

@ 397.5/257.6 mg/kg/day, decreased body-weight gain in females, slight swelling of hepatocytes in central zone (both sexes), increased incidence of glomerulonephrosis in males, increased adrenal weights Dermal Short- andintermediateTerm N/A N/A N/A No dermal hazard identified.

Inhalation Short- andIntermediateTerm Oral NOAEL = 30 mg/kg/day

Inhalation hazard assumed to be equivalent to oral hazard UF A =10x UF H =10x Residential LOC for MOE = 100

Occupational LOC for MOE = 100 2-Generation Reproduction Study – Rat

LOAEL = 180 mg/kg/day, based on decreased pup body weight during lactation and delayed hair growth and/or eye opening, and decreased parental body-weight gain and increased absolute and relative liver, kidney, and adrenal weights

Co-critical 13-Week Feeding Study – Rat LOAEL = 38.1 mg/kg/day, based on increased absolute and relative liver weights in both sexes, increased relative ovarian and kidney weights, and fatty degeneration of the adrenal zona fasciculate.

Cancer (oral, dermal, inhalation) Classification: “Likely to be Carcinogenic to Humans ”. Insufficient evidence to warrant a quantitative estimation of human risk using a cancer slope fact or 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 mu tagenic 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 associ ated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecific). UF H =Page 14 of 34 potential variation in sensitivity among members of the human popula tion (intraspecific). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure . LOC = level of concern. N/A = not a pplicable.

Table 4.5.2 Summary of Toxicological Doses and Endpoint s 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 UF A =10x UF H =10x Residential LOC for MOE = 100

Occupational LOC for MOE = 100 2-Generation Reproduction Study – Rat

LOAEL = 180 mg/kg/day, based on decreased pup body weight during lactation and delayed hair growth and/or eye opening, and decreased parental body-weight gain and increased absolute and relative liver, kidney, and adrenal weights

Co-critical 13-Week Feeding Study – Rat LOAEL = 38.1 mg/kg/day, based on increased absolute and relative liver weights in both sexes, increased relative ovarian and kidney weights, and fatty degeneration of the adrenal zona fasciculate.

Cancer (oral, dermal, inhalation) Classification: “Likely to be Carcinogenic to Huma ns”. ”. Insufficient evidence to warrant a quantitative estimation of human ri sk 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 on ly in high dose male rats in the absence of mutagenic concerns. The chronic RfD is protec tive 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 associ ated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecific). UF H = potential variation in sensitivity among members of the human popula tion (intraspecific). MOE = margin of exposure. LOC = lev el of concern. N/A = not applicable.



### 4.4 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews num erous studies to asse ss potential adverse outcomes from exposure to chemicals. Collectiv ely, these studies includ e acute, subchronic and chronic toxicity, including asse ssments of carcinogenicity, ne urotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include e ndpoints which may be susceptible to endocrine influe nce, including effects on endocri ne target organ histopathology, organ weights, estrus cyclicity, sexual maturatio n, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess gr owth, developmental and reprod uctive effects in different taxonomic groups. As part of its reregistrati on decision for hexythiazox, EPA reviewed these data and selected the most sensitive endpoints fo r relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), hexythiazox is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).Page 15 of 34 

### EPA has developed the EDSP to determine whet her certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or ot her such endocrine effect s as the Administrator may designate.” The EDSP employs a two-tiered approach to making th e statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine-related eff ects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pest icide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP scr eening was published on June 14, 2013 1 

### and includes some pesticides scheduled for registration review and chemicals found in water

. Hexythiazox is on the second list. Neither of these lists should be construed as a list of known or likely endocrine disruptors. For further information on the status of the EDSP, the polic ies and procedures, the lists of chemicals, future lists, the test guideline s and the Tier 1 screeni ng battery, please visit our website 2



### . 5.0 Dietary Exposure/Risk Characterization

5.1 Residue Chemistry Summary Residue Chemistry Memo DP# 427090 & 427091, 11/30/15, K.King (PP#5F8356 & 5F8346) Residue Chemistry Memo DP# 360414, 8/17/09, D. Davis (PP#7E7182) Residue Chemistry Memo DP# 347948, 2/14/08, T. Bloem (PP#5F6953) Residue Chemistry Memo No DP#, 2/12/87, F. Suhre (PP#7G3469) Residue Chemistry Memo No DP#, 1/13/86, E. Haeberer (PP#5F3254/5H5469)



### Acceptable apple, citrus, grape, pear, radis h, tea and corn metabolism studies have been previously submitted and reviewed. The existing metabolism database is adequate to delineate the nature of the residue in all plants. The residues of concern in plants are the parent compound and its metabolites which cont ain the (4-chlorophenyl)-4-methyl -2-oxo-3-thiazolidine moiety (also called PT-1-3).

Metabolism data for cotton have not been submitted a nd are not required at this time because it is not expected to significantly differ from the metabolism data that was submitted for the seven other crops listed above.

Gowan Company has petitioned (PP#5F8346 and PP#5F8356) to expand the hexythiazox use on cotton from a regional to a national (Secti on 3) use (EPA Reg. Nos. 10163-250 and 10163-277)

1 See http://www.regulations.gov/#!docum entDetail;D=EPA- HQ-OPPT-2009-0477-0074 for the final second list of chemicals.

2 http://www.epa.gov/endo/Page 16 of 34 

### and, for citrus, to decrease the current PHI fr om 28 days to 7 days (EPA Reg. No. 10163-277). Field trial studies were submitted for cotton and citrus to support these changes, and no further information is required at this time.

Cotton Regional tolerances are currently established on cotton, gin byproducts a nd undelinted seed. The submitted cotton study used an applicati on rate of 0.1522-0.1619 lb ai/A, and undelinted cottonseed residues ranged from <0.02-0.175 ppm , while residues for cotton gin byproducts ranged from 1.96-5.70 ppm. The Organization for Economic Cooperation & Development (OECD) Maximum Residue Level (MRL) calculati on procedures were used to calculate the tolerance for these two commodities. For the MRL calculation of undelinted cotton seed, ten values were used from two studies; one previo usly submitted and one from the current petition (MRID 44574703, MRID 49554501). For the MRL calcula tion of cotton gin byproducts, five values were used from the same two studi es. The HED recommended tolerance for gin byproducts (15 ppm) was equal to the registrant proposed tole rance; however, the undelinted seed tolerance that HED recommended (0.3 ppm) wa s less than the registra nt proposed tolerance (0.5 ppm). Adequate nature of the residue in co nfined rotational crops has been delineated and additional data are not re quired at this time.

Citrus The citrus study used an application rate of 0.1827-1907 lb ai/A, and residues for the crop with the highest values (lemon) ranged from 0.100-0.264 pp m. Tolerances are currently established on fruit, citrus group 10-10 (CA, AZ, and TX only), and nationally in citrus, dried pulp, and oil. The OECD MRL calculation procedure was used to calculate the tolerance for citrus group 10-10 and used five values from the new st udy (MRID 49591801). The HED recommended tolerance for citrus group 10-10 (0.5 ppm) is the same as the registrant proposed tolerance (0.6 ppm). HED has decided that the tolerance for citrus, dr ied pulp should be revoked because residues are covered by the citrus group 10-10 tolerance. As for citrus oil, the tolerance was calculated by multiplying the citrus oil processing factor ( 104x) by the HAFT residue value for lemons, and the HED recommended tolerance is 1 ppm less than the registrant propose d tolerance (26 ppm vs 25 ppm). Adequate nature of the residue in conf ined rotational crops has been delineated and additional data are not required at this time.

Dietary burden was calculated for beef cattle, da iry cattle, swine, and poultry, and did not exceed the dietary burden that was calculated in the la st assessment. Dietary burden did not increase from the last assessment because cotton and citr us feedstuffs did not significantly exceed the other feedstuffs in the calculation.

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


### The potential for hexythiazox residues in drinki ng water was evaluated through modeling. The drinking water residues used in this dietary ri sk assessment were provided by the Environmental Fate and Effects Division (EFED) in the follo wing memorandum: “Hexythiazox: Drinking Water Assessment for Proposed Expanded Use on Cotton” (A. Shelby, D429192, 9/21/2015). The citrus PHI amendment is not expected to cha nge the estimated drinking water concentrations (EDWCs); therefore, the cotton drinking water assessment covers both cotton and citrus (EmailPage 17 of 34 

### communication with K. King and A. Shelby, 12/2/ 2015). EDWCs were incorporated directly into DEEM-FCID under food categories “water, di rect, all sources” and “water, indirect, all sources.” Since no environmental fate data has been submitted for degradates of concern, EFED conducted the assessment for total residues.

EFED estimated groundwater valu es by using PRZM-GW and an ex tended weather simulation to find that groundwater residues are not expected to exceed surface water residues. Therefore, EFED provided estimated drinking water concentr ations (EDWCs) for various scenarios from the Tier II surface water model, SWCC, assuming a 0.95 percent cropped area (PCA) adjustment. The maximum estimated surface water concentrations for total residues of hexythiazox were from the MS soybean scenario . The 1-in-10 year annual average value of 4.3
μ g/L from this scenario was used in the chronic dietary risk assessment.

Table 2. Hexythiazox Total Toxic Residues in Drinking Water Residue ( μ g/L) Time Range 7.3 1 in 10 year Annual Peak Concentration 4.3 1 in 10 year Annual Average 3.5 30 year Annual Average



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



### HED conducted a chronic dietar y (food and drinking water) risk assessment to support the proposed amended uses of hexythiazox on cotton and citrus. The assessment included all existing and proposed hexythiazox uses.

5.3.1 Acute Dietary Exposure/Risk

No toxic effects attributable to a single dose of hexythiazox were observed in the toxicology database; therefore, a quantitati ve 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 tolera nce level residues, incl uded modeled drinking water estimates, assumed 100% crop treated, and inco rporated DEEM default processing factors. Anticipated residues and percent crop treated info rmation were not used in the dietary exposure and risk assessment. The dietary assessment c ould be substantially refined using anticipated residues, percent crop treated information a nd empirical processing data; however, these refinements were not conducted since risk es timates 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 Po pulation and all subpopulations. The estimated exposure to the U.S. General Popu lation resulted in a risk equivalent to 18% of the cPAD. The estimated exposure to children 1 – 2 years of age, the most highly exposed subpopulation, resulted in a risk equivalent to 81% of the cP AD. Results for all s ubpopulations are summarized in Table 5.3.4 below.Page 18 of 34 

### 5.3.3 Cancer Dietary Risk

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

5.3.4 Summary Table

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

Population Subgroup Chronic Dietary

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

General U.S. Population 0.004407 18

All Infants (< 1 year old) 0.008114 33

Children 1-2 years old 0.020350 81

Children 3-5 years old 0.013375 54

Children 6-12 years old 0.006521 26

Youth 13-19 years old 0.003280 13

Adults 20-49 years old 0.002937 12

Adults 50+ years old 0.003269 13

Females 13-49 years old 0.003108 12 * Most highly exposed subpopulati on is highlighted in bold.



### 6.0 Residential and Other Non-O ccupational Exposures/Risks Occupational and Residential Exposure and Risk Assessment, D404018, A. LaMay, 5/6/13 Occupational and Residential Exposure and Risk Assessment, D396864, A. LaMay, 9/25/12



### There are no new residential uses proposed with this action; howe ver, there are registered uses on residential sites which have been previous ly assessed, including (1) ornamental landscape plantings in residences, public areas, and recreational sites such as campgrounds, golf courses, parks and athletic fields, (2) or namental lawns and turf (includi ng residential), (3) residential pome fruit, stone fruit, and nut tr ees, and residential caneberries.

6.1 Residential Handler Exposure and Risk

Since hexythiazox does not pose a dermal risk, only inhalation exposure assessments were conducted for residential handlers. Residential handler exposure is expected to be short-term in duration. Intermediate-term exposures are not likely because of the intermittent nature of applications by residential applicators. Resi dential handler inhalation margins of exposure (MOEs) significantly exceed 100 for all scenarios assessed and are not of concern. Residential handler MOEs range from 420,000 to 330,000,000.Page 19 of 34 Table 6.1.1. Short-term Residentia l Handler Non-cancer Exposure and Risk Estimates fo r Hexythiazox.

Exposure Scenario Target MOE Inhalation Unit Exposure (mg/lb ai) Maximum Application Rate 1 Area Treated or Amount Handled Daily 2 Inhalation

Dose (mg/kg/day) 3 MOE 4

Mixer/Loader/Applicator Lawns/ Turf; Gardens/Trees, WDG/DF, Manually-pressurized handwand / backpack 100 1.1 0.000625 lb ai/gallon 5 gallons 0.000043 700,000

Gardens/ Trees, WDG/DF, Hoseend sprayer 100 0.0014 4.375E-6 lb ai/ft 2 1200 ft 2 0.000000092 330,000,000

Gardens/ Trees, WDG/DF, Hoseend sprayer 100 0.0014 0.000625 lb ai/gallon 11 gallons 0.00000012 250,000,000

Lawns/ Turf, WDG/DF, Hose-end
sprayer 100 0.022 0.1875 lb ai/acre 0.5 acres 0.000026 1,200,000

Gardens/Trees, WDG/DF, Manually- p ressurized handwand / backpack 100 1.1 4.375E-6 lb ai/ft 2 1200 ft 2 0.000072 420,000

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

2 Exposure Science Advisory Council Policy #9.1.

3 Inhalation Dose = Inhalation Unit Exposure (mg /lb ai) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gallons/day) / BW (80 kg).

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



### 6.2 Residential Post-application Exposure

There is the potential for post-app lication exposure for individuals e xposed as a result of being in an environment that has been previously treated with hexythiazox. The quantitative exposure/risk assessment for residential post-appl ication exposures is based on incidental oral exposure to treated turf. As no dermal hazard was identifi ed, a quantitative dermal postapplication assessment is not required. Short-term exposure durations are anticipated for incidental oral exposures due to the intermitte nt nature of applications in residential environments. As the aerobic soil meta bolism half-life for hexythiazox is 145.2 days 3



### , intermediate-term exposure is also possible fo r incidental soil i ngestion exposure.

Child incidental oral exposure to treated turf was assessed for hexythiazox. Risk estimates greatly exceed the LOC of 100 for all scenarios a ssociated with children ’s exposure to treated turf and are not of concern. The short-term hand-to-mouth MOE for children is 11,000; the short-term object-to-mouth MOE for children is 350,000; and the short- and intermediate-term incidental soil ingestion MO E for children is 4,700,000.

Table 6.2.1. Residential Post-application Non-cancer Exposure and Risk Estimate s for Hexythiazox (ShortTerm for Hand-to-Mout h and Object-to-Mouth Exposure; Short- and Intermediate-Term fo r Incidental Soil Ingestion Exposure). Lifestage Post-application Exposure Scenario App rate 1 Dose MOEs 2

Child Turf - sprays Hand to Mouth 0.1875 lb ai/acre 0.0029 11,000 Object to Mouth 0.00009 350,000

3 Hexythiazox: Drinking Water Assessment for New Use on wheat, alfalfa, timothy, eggplant and peppers. Andrew Shelby. DP Barcode: 396529& 401798. 6/21/2012.Page 20 of 34 Table 6.2.1. Residential Post-application Non-cancer Exposure and Risk Estimate s for Hexythiazox (ShortTerm for Hand-to-Mout h and Object-to-Mouth Exposure; Short- and Intermediate-Term fo r Incidental Soil Ingestion Exposure). Lifestage Post-application Exposure Scenario App rate 1 Dose MOEs 2 Incidental Soil Ingestion 0.0000063 4,700,000 1 Based on registered uses. 2 MOE = POD (30 mg/kg/day) ÷ Dose (mg/kg/day).


### In accordance with 40 CFR158, TTR data are required for all occupational (e.g., sod farms, golf courses, parks, and recreational areas) or residential turf uses that could result in post-application exposure to turf. EPA is waiving the 40 CFR TTR data requirement for this use since the estimated residential turf post-application exposu re using default TTR values for hexythiazox is less than the LOC. In this instance, it is unlik ely that chemical-specific TTR data would be needed to further refine exposure assessments or would add appreciably to our general understanding of the availability of tu rf transferable pe sticide residues.

6.3 Residential Risk Estimates fo r Use in Aggregate Assessment

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

 The recommended residential exposure for use in the adult aggregate assessment reflects inhalation exposure from application to gard ens/trees via manually-p ressurized handwand / backpack sprayer;

 The recommended residential exposure for use in the children 1<2 years old aggregate assessment reflects incidental oral exposures from post-app lication exposure to treated turf.

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

Lifestage Exposure Scenario Dose (mg/kg/day) 1 MOE 2

Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Adults Handler; mixing/ loading/ applyingusing manuallypressurized handwand NA 0.000072 N/A 0.000072 NA 420,000 N/A 420,000

Child Post-application; ST IncidentalOral (hand-tomouth) from treated turf NA NA 0.0029 0.0029 NA NA 11,000 11,000

Post-application; IT Incidental Oral (soil ingestion) from treated turf NA NA 0.0000063 0.0000063 NA NA 4,700,000 4,700,000

1 Dose = the highest dose for each applicable lifestage of all residential scenarios assessed. Total = dermal + inhalation + incidental oral (where applicable). 2 MOE = the MOEs associated with the highest residential doses. Total = 1 ÷ (1/Dermal MOE) + (1/Inhalation MOE) + (1/Incidental Oral MO E), where applicable.



### 6.4 Non-Occupational Spray Drift Exposure and Risk Estimates

### Hexythiazox Human Health Risk Assessment D427090

Page 21 of 34 Spray drift is a potential source of exposure to those nearby pe sticide applications. This is particularly the case with ae rial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., ground boom and air blast) employed for hexythiazox

. The agency has been working with the Spray Drift Task Force (a task force co mposed of various registrants which was developed as a result of a Data Call-In i ssued by EPA), EPA Regi onal Offices and State Lead Agencies for pesticide regulation and ot her parties to develop the best spray drift management practices (see the agency’s Sp ray Drift website for more information). 4 

### The agency has also developed a policy on how to appropriately consid er spray drift as a potential source of exposure in risk assessments for pesticides.

The potential for spray drift will be quantita tively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently. The approa ch is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs) - Residential Exposure Assessment Standard Operating Procedures Ad denda 1: Consideration of Spray Drift.

This document outlines the quantification of indirect non-occupati onal exposure to drift. It is noted that the 0.19 lb a i/acre application rate for turfwas modeled to estimate postapplication residential ex posure of children. As this rate is equal to or higher than many of agricultural application rate s, this scenario is protective of any exposure of children via spray drift from agricultural hexythiazox applications.

6.5 Non-Occupational Residential Bystander Post-Application Inhalation Exposure and Risk Estimates

Volatilization of pes ticides may be a source of post-ap plication inhala tion exposure to individuals nearby pesticide ap plications. The agency sough t expert advice and input on issues related to volatilization of pesticides from its Federal Ins ecticide, Fungicide, and Rodenticide Act Scientific Advisory Pa nel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.regulations.gov/#!documen tDetail;D=EPA-HQ-OPP-2009-0687-0037). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docke tDetail;D=EPA-HQ-OPP-2014-0219).

During Registration Review, the agency will utili ze this analysis to determine if data (i.e., flux studies, route-specific inhala tion toxicological st udies) or further an alysis is required for hexythiazox.

7.0 Aggregate Risk Assessments and Risk Characterization

7.1 Acute Aggregate Risk

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

4 Available: http://www2.epa.gov/redu cing-pesticide-drift

### Hexythiazox Human Health Risk Assessment D427090

Page 22 of 34 toxicology database; therefore, a quantitative acute aggregate risk assessment for this chemical is not required.

7.2 Short- and Intermediate-Term Aggregate Risks

The short- and intermediate-term aggregate ri sks combine residential handler (adult only) or post-application exposures (see Table 6.3.1) with averag e food and water exposures (see Table 5.3.4). Short- and intermediate-t erm aggregate margins of exposure (MOEs) for adults and children greatly exceed the LOC of 100 and are not of concern. Short- and intermediate-term estimated exposures and risks are shown in Table 7.2, below.

Table 7.2 Short-Term and In termediate-Term Aggregate Risk Calculations

Population NOAEL (mg/kg/day) LOC 1 Max Allowable Exposure 2 (mg/kg/day) Average Food & Water Exposure 3 (mg/kg/day) Residential Exposure 3 (mg/kg/day) Aggregate MOE for food and residential 4

Short-Term Scenario Adult 30 100 0.3 0.002937 0.000072 9900 Adult Female 30 100 0.3 0.003108 0.000072 9400

Child 30 100 0.3 0.020350 0.0029 1100 Intermediate-Term Scenario Adult 30 100 0.3 0.002937 N/A 9900 Adult Female 30 100 0.3 0.003108 N/A 9700

Child 30 100 0.3 0.020350 0.0000063 1500

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

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

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

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



### 7.3 Long-Term (Chronic) Aggregate Risk

As there are no uses that are expected to re sult in long-term reside ntial 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 Char acterization/Assessment

Unlike other pesticides for which EPA has fo llowed 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 subs tances 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 mech anism of toxicity and to evaluate the cumulative effects of such chemicals, see th e policy statements released by EPA’s Office of Pesticide Programs concer ning common mechanism determin ations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s

### Hexythiazox Human Health Risk Assessment D427090

Page 23 of 34 website at http://www2.epa.gov/pesticid e-science-and-assessing-pesticiderisks/cumulative-assessment-risk-pesticides.

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



### 9.1 Occupational Handler Risk

While the uses on cotton and citrus are exp ected to result in occupational handler exposure, the amended uses do not include a ny changes to application methods and/or rates. Therefore, a new assessment of occupational exposure is not required, and a previous assessment (Memo, A. Lamay, D 404018, 06-May-2013) is protective of the amended use pattern. In that assessment, a quantitative dermal risk assessment was not conducted since no hazard was identified via the dermal route. Occupational handler inhalation MOEs significantly exceeded 100 for all scen arios assessed including mixers/loaders, applicators and flaggers. No additional personal protective equipment (PPE) is required.

9.2 Occupational Post-application Risk

HED uses the term post-application to describe exposures that occur when individuals are present in an environment that has been previ ously treated with a pesticide (also referred to as re-entry exposure). Such exposures may occur when work ers enter previously treated areas to perform job functions, in cluding activities rela ted to crop production, such as scouting for pests or harvesting. Po st-application exposure levels vary over time and depend on such things as the type of activit y, the nature of the cr op 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 ac tivities, can greatly reduce the potential for pos t-application exposure.

Occupational Post-applicati on Inhalation Exposure/Risk

There are multiple potential sources of post-app lication inhalation exposure to individuals performing post-applicati on activities in previously treated fields. These potential sources include volatilization of pestic ides and re-suspension of dusts and/or particulates that contain pesticides. The agency sought expe rt advice and input on issues related to volatilization of pesticid es from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (S AP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.regulations .gov/#!documentDetail;D=EPA-HQ-OPP2009-0687-0037). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!doc ketDetail;D=EPA-HQ-OPP-2014-0219 ). During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is required for hexythiazox.

### Hexythiazox Human Health Risk Assessment D427090

Page 24 of 34 In addition, the Agency is continuing to eval uate the available post- application inhalation exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post-application i nhalation exposure into the agency's risk
assessments.

Although a quantitative occupational post-ap plication inhalation exposure assessment was not performed, an inhalation expo sure assessment was performed for occupational/commercial handlers. Handler exposure resulting fr om application of pesticides outdoors is likely to result in hi gher exposure than post- application exposure. Therefore, it is expected that these handl er inhalation exposure estimates would be protective of most occupational post-app lication inhalation ex posure scenarios. Inhalation risks for o ccupational handlers ar e not of concern.

Occupational Post-application Dermal Exposure/Risk

As no dermal hazard has been identified fo r hexythiazox, quantification of dermal postapplication risk is not re quired. 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 occupationa l uses that could result in post-application dermal exposure. However, as quantificat ion of dermal risk is not required for hexythiazox, a DFR study is not requir ed for hexythiazox at this time.

The REI specified on the proposed label is ba sed on the acute toxic ity of hexythiazox. Hexythiazox is classified as Toxicity Category IV for acute dermal toxicity, Toxicity Category IV for acute dermal irritation, and T oxicity Category III for eye irritation. It is not a skin sensitizer. Under WP S for agricultural pesticides, ac tive ingredient’s classified as Acute III or IV for acute de rmal, eye irritation and primar y skin irritation are assigned a 12-hour REI. Therefore, the WPS interi m REI of 12 hours is adequate to protect agricultural workers from post-appli cation 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 Revi ew Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 5



### .

5 http://www2.epa.gov/pesticide-scienc e-and-assessing-pesticide-risks/occupational-pesticide-handlerexposure-data and http://www2.epa.gov/pesticide- science-and-assessing-pesticide-risks/occupationalpesticide-post-application-exposure

### Hexythiazox Human Health Risk Assessment D427090

Page 25 of 34 Appendix A. Toxicology Assessment

A.1 Toxicity Profiles

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

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

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

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

870.2400 Primary eye irritation 00146551 Reddened conjunctiva III

870.2500 Acute dermal irritation 00146552 Non irritant IV

870.2600 Skin sensitization 00146553 Non sensitizer N/A

Table A.1.2. Toxicity Profile of Hexythiazox Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results

870.3100 90-Day oral toxicity rat 45067101 (1983) Acceptable/guideline 0, 10, 70, 500, or 3500
ppm M: 0, 1.2, 8.1, 58.6, or 397.5 mg/kg/day F: 0, 0.8, 5.4, 38.1 or 257.6 mg/kg/day NOAEL = 8.1/5.4 mg/kg/day, males/females LOAEL = 58.6/38.1 mg/kg/day, males/females, based on increased absolute and relative liver weights in both sexes, increased relative ovarian and kidney weights, and fatty degeneration of the adrenal zona fasciculata.

@ 397.5/257.6 mg/kg/day, decreased 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 Materna l NOAEL  1080 mg/kg/day LOAEL >1080 mg/kg/day Developmenta l NOAEL  1080 mg/kg/day LOAEL >1080 mg/kg/day

870.3800 Two-Generation reproduction and fertility effects rat 00147578 (1985) Acceptable/guideline 0, 60, 400, or 2400 ppm Average doses across generations: M: 0, 4.45, 29.73, or 180.67 mg/kg/day 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

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Page 26 of 34 Table A.1.2. Toxicity Profile of Hexythiazox Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results

F: 0, 5.27, 34.77, or 207.67 mg/kg/day Offspring NOAEL = 29.73/34.77 mg/kg/day, males/females LOAEL = 180.67/207.67 mg/kg/day, males/females, based on decreased pup body weight during lactation, and delayed hair growth and/or eye opening.

870.4100b Chronic toxicity dog 00151359, 00146556, 00156895 (1984) Acceptable 0, 100, 500, or 5000 ppm (0, 2.5, 12.5, or 125 mg/kg/day) M: 0, 2.87, 13.1, or 153 mg/kg/day F: 0, 3.17, 13.9, or 148 mg/kg/day 4-week: 0, 125, 500, 2000, 8000 ppm NOAEL = 2.5 mg/kg/day LOAEL = 12.5 mg/kg/day based on increased absolute and relative adrenal weights and associated adrenal histopathology (adrenal cortex hypertrophy). @ 125 mg/kg/day, relative adrenal weights and associated adrenal cortex hypertrophy (more pronounced)

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

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

No evidence of carcinogenicity

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

Evidence of carcinogenicity (causes liver tumors in females).

Gene Mutation 870.5100 (Salmonella typhimurium and Escherichia coli reverse gene mutation assay) 44955710 (1983) Acceptable The test was negative up to the highest dose tested (6400 μg/plate +/-S9.

Gene Mutation 870.5300 ( In vitro mammalian cell forward gene mutation assay in CHO cells) 00155154 (1985) Acceptable Independently performed trials were negative up to precipitating doses (  60 μg/mL) and severely cytotoxic concentrations (200 μg/mL -S9; 400 μg/mL +S9).

Cytogenetics 870.5375 00156894 (1986) Acceptable The test was negative up to precipitating doses accompanied by severe cytotoxicity (  167 μg/mL +/-S9).

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Page 27 of 34 Table A.1.2. Toxicity Profile of Hexythiazox Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results

In vitro mammalian cell cytogenetic assay in CHO cells

Cytogenetics 870.5395 In vivo mouse micronucleus assay 44955708 Unacceptable

There’s an update The results were inconclusive because a positive response, which was within the wide range of historical background data, was recorded for female mice at the mid-and highdoses (500 and 1000 mg/kg). The assay should be repeated to confirm or refute the equivocal results.

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

870.6200b Subchronic neurotoxicity Crj:CD(SD)IGS(SPF)
rats 48657401 (2004)Acceptable/nonguideline 0, 100, 1000, or 10000
ppm Males: 0, 8.8, 88.7, or 868.2 mg/kg/day Females: 0, 9.5, 90.1, or 892.7 mg/kg/day (28 days) NOAEL = 1000 ppm (males 88 mg/kg/day; females 90 mg/kg/day). LOAEL = 10000 ppm (males 868 mg/kg/day; females 892 mg/kg/day), based on decreased motor activity in both sexes, decreased body weight in males, increased adrenal weight in females, and increased liver weight in both sexes.

HASPOC (D0056434): 28-day duration is sufficient to assess sub-chronic neurotoxicity from hexythiazox
exposure

870.7485 Metabolism and pharmacokinetics 00146558 (1985) Acceptable/guideline

Single oral dose at 10 mg/kg (Group B); 14 daily oral doses (10 mg/kg) of unlabeled material followed by one dose (10 mg/kg) of [ 14 C] test material (Group C); and a single oral dose of 880 mg/kg (Group D). Absorption and distribution of dosed radioactivity were rapid. The radioactive materi al was rapidly eliminated in the urine and feces; the major ity of the radioactivity was eliminated within 24 hours. There were no observable differences in the total elimination of NA-73 between male and female rats. The major route of elimination in both the male and female rats was by fecal excretion. The major metabolite found, PT-1-8 (cis), accounted for 8- 12% of the administered radioactivity in the low dose groups. Approximately 11-20% and 65-69% of the dosed radioactivity was identified as unchanged NA-73 in the low-dose and high-dose groups, respectively. All other metabolites were present at low concentrations (<2%). There was no apparent sex difference in metabolite formation. Significant levels of NA-73 equivalent [ 14 C]- residues were detected in the fat, liver, and adrenals. A sex-related difference in the residue levels of all tissueswas observed, with residues in female tissues being twofold higher than those found in male tissues.

870.7485 Metabolism and pharmacokinetics 0146557 (1983)Acceptable/nonguideline

Single low dose (10 mg/kg/day) Total recovery of radioactivity 72 hours after treatment accounted for 101.9-103% of th e 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% (fe male) of the administered radioactivity remained in the tissues, with the highest concentration in the fat (2.3 ppm, males; 5.4 ppm,

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Page 28 of 34 Table A.1.2. Toxicity Profile of Hexythiazox Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results

females). Significant sex differences existed for the pharmacokinetics of NA-73 in these rats, with females exhibiting slower elimination rats and higher tissue residues (about double) than males. NA-73 was metabolized to a large number of metabolites that were excreted both in the urine and feces. Seven metabolites were structurally identified in addition to the parent compound in both excreta of both sexes, with the major fecal metabolite, PT-1-8 (c is) accounting for 10% of the dosed radioactivity. The others were all minor metabolites accounting for less th an 1.4%. About 20% of the dose was excreted as unchanged NA-73 (97% of which was in the feces). No significant sex difference was apparent with respect to metabolite formation.

870.7600 Dermal penetration 40608402, 40787901 (1985) Unacceptable The total percent of dose absorbed averaged 2%, 1%, and 1.1% for cannulated rats (10-hour sacrifice) and 0.8%, 0.2%, and 0.2% for non-cannulated rats (1-hour sacrifice) at the low, medium, and high dose levels, respectively. The amount of radioactivity in the blood, carcass, urine and other organs totaled <2% of the applied dose. The results of this study (2% dermal absorption) can be used for risk assessment purposes.
870.7800 Immunotoxicity 48685201 (2012) Acceptable/Guideline Immunotoxicity NOAEL is 4500 ppm (equivalent to 904 mg/kg/day). A LOAEL was not established.

### Hexythiazox Human Health Risk Assessment D427090

Page 29 of 34 Appendix B: Toxicology Data Requirements

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

Table B. Toxicology Data Requirements

Study Technical
Required Satisfied
870.1100 Acute Oral Toxicity....................................................... 870.1200 Acute Dermal Toxicity .................................................. 870.1300 Acute In halation Toxicity ............................................. 870.2400 Primar y Eye Irr itation

................................................... 870.2500 Primar y Dermal Irr itation

.............................................. 870.2600 Derm al Sensiti zation ..................................................... yes yes yes yes yes yes yes yes yes yes yes yes
870.3100 Oral Su bchronic (rodent) ............................................... 870.3150 Oral Su bchronic (nonr odent) ......................................... 870.3200 21-Day Dermal .............................................................. 870.3250 90-Day Dermal .............................................................. 870.3465 90-D ay Inhala tion ......................................................... yes yes yes

no CR yes yes D

no C

no

no A
870.3700a Developmental Toxicity (rodent) .................................. 870.3700b Developmental Toxicity (nonrodent) ............................ 870.3800 Reproduc tion ................................................................. yes yes yes yes yes yes
870.4100a Chronic T oxicity (rodent) .............................................. 870.4100b Chronic Toxi city (nonrodent) ........................................ 870.4200a Oncoge nicity (ra t) ......................................................... 870.4200b Oncogenicity (mouse) ................................................... 870.4300 Chroni c/Oncogeni city ................................................... yes yes yes yes yes yes yes yes yes yes 870.5100 Mutagenicity—G ene Mutation – bacterial .................... 870.5375 Mutagenicity—Struc tural Chromosomal Aberrations... 870.5550 Mutagenicity—O ther 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 -

-

no A
yes B

no

870.7485 Gene ral Metabo lism ...................................................... 870.7600 Dermal Penetration........................................................ 870.7800 Immunotoxicity ............................................................. yes

no
yes yes
yes
yes

A HASPOC (D0056434): not requir ed at this time.

B HASPOC (D0056434): 28-day study is sufficient to assess s ubchronic neurotoxicity from hexythiazox exposure.

C Dermal equivalent dos e, after applying the estimated dermal absorpti on factor of 2% to the oral reproduction study NOAEL of 30 mg/kg/day, is 1500 mg/kg/day, which is greater than the limit dose.

D Not required since there is a 4-week study and a 1-year study available.

### Hexythiazox Human Health Risk Assessment D427090

Page 30 of 34 Appendix C: Field Tria l Residue Data

Cotton DER, MRID 49554501, K.King, XX/XX/2015 Citrus DER, MRID 49591801, K.King, XX/XX/2015

Table C.1. Summary of Residues from Citrus Field Trials with Hexythiazox. Plot Total App. Rate lb ai/A (kg ai/ha) PHI (days) n 1 Residues (ppm)
Min. 2 Max. 2 LAFT 3 HAFT 3 Median 3 Mean 3 SD 3

Orange Trials

Concentrate 0.1892-0.1903 (0.2121-0.2133) 7 2 0.0392 0.0814 0.0415 0.0718 0.0567 0.0567 NA
13-14 2 0.0222 0.0396 0.0281 0.0351 0.0316 0.0316 NA

Dilute 0.1827-0.1907 (0.2048-0.2137) 7-8 3 0.0499 0.0891 0.0540 0.0764 0.0720 0.0675 0.0119
13-14 3 0.0449 0.0798 0.0460 0.0761 0.0566 0.0596 0.0153 Grapefruit Trials

Concentrate 0.1895-0.1898 (0.2124-0.2127) 7 2 0.0456 0.0853 0.0510 0.0818 0.0664 0.0664 NA
14 2 0.0377 0.0572 0.0381 0.0547 0.0464 0.0464 NA

Dilute 0.1837-0.1884 (0.2059-0.2112) 7 2 <0.02 0.0593 <0.02 0.0490 0.0345 0.0345 NA
14 2 <0.02 0.0473 <0.02 0.0451 0.0326 0.0326 NA

Lemon Trials

Concentrate 0.1869-0.1875 (0.2095-0.2102) 7 3 0.183 0.257 0.188 0.236 0.223 0.216 0.0248
13-14 3 0.155 0.264 0.156 0.243 0.208 0.202 0.0438

Dilute 0.1874-0.1883 (0.2101-0.2111) 7 2 0.102 0.177 0.107 0.167 0.137 0.137 NA
14 2 0.100 0.174 0.117 0.164 0.141 0.141 NA

1 n = number of field trials.

2 Values based on total number of samples.

3 Values based on per-trial averages. LAFT = lowest average field trial, HAFT = highest average field trial, SD = standard deviation. Values <LOQ are assumed to be at the LOQ (0.02 ppm). NA = Not applicable.

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

Crop Matrix Total App. Rate lb ai/A (kg ai/ha) PHI (days) n 1 Residues (ppm hexythiazox equivalents)
Min. 2 Max. 2 LAFT 3 HAFT 3 Median 3 Mean 3 SD 3

Cotton undelinted seed 0.1522-0.1619 (0.1706-0.1815) 34-36 9 <0.02 0.175 <0.02 0.160 0.0374 0.0679 0.0557

Cotton gin byproducts 0.1522-0.1576 (0.1706-0.1766) 34-36 3 1.96 5.70 2.06 5.58 4.41 4.02 1.80

1 n = number of field trials.

2 Values based on total number of samples.

3 Values based on per-trial averages. LAFT = lowest average field trial, HAFT = highest average field trial, SD = standard deviation. For computation of the LAFT, HAFT, median, mean, and st andard deviation, values < LOQ are assumed to be at the LOQ (0.02 ppm).

### Hexythiazox Human Health Risk Assessment D427090

Page 31 of 34 Appendix D: Maximum Re sidue Limits (MRL)

Table D. Summary of US and International Tole rances and Maximum Residue Limits for Hexythiazox Residue Definition : US Canada Mexico 1 Codex 2
40 CFR 180.448: hexythiazox and its metabolites containing the (4-chlorophenyl)-4-methyl-2-oxo-3- thiazolidine moiety None Plants: Hexythiazox Livestock: sum of hexythiazox and all metabolites containing the trans-5-(4-chlorophenyl)-4-methyl-2-oxothiazolidinemoiety (PT-1-3-), expressed as hexythiazox. The residue is fat-soluble.


### Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 

### Codex 2 Cotton, gin byproducts 15 Cotton, undelinted seed 0.3 Citrus, fruit, Crop Group 10 0.6 0.5 citrus fruits Completed: M. Negussie; 09/21/15

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

2 Absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processi ng of treated stored wheat . (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.

### Hexythiazox Human Health Risk Assessment D427090

Page 32 of 34 Appendix E: OECD Calculator MRL Output

**H exythiazox**  **Cotton (Undelinted Seed)**

**U S**  **A MRID 44574703-2 (PHI 28** 

**- 3**  **5 days) & 49554501 (PHI 28**

**- 4**  **2 days)**

**Total number of data (n)** 11 **Percentage of censored data** 0%
**Number of non-censored data** 11
**Lowest residue** 0.007 **Highest residue** 0.276
**Median residue** 0.053

**Mean** 0.076 **Standard deviation (SD)** 0.078 **Correction factor for censoring (CF)** 1.000

**Proposed MRL estimate**

**- Highest residue** 0.276
**- Mean + 4 SD** 0.388
**- CF x 3 Mean** 0.228
**Unrounded MRL** 0.388

**Rounded MRL 0.4** 

**Residues (mg/kg)** 

0.067

0.062

0.037

0.025

0.128

0.007

0.020

0.276

0.132

0.030

0.053

### Hexythiazox Human Health Risk Assessment D427090

Page 33 of 34 **Hexythiazox Cotton Ginned Byproducts** 

**U S**  **A MRID 44574703-2 (PHI 28** 

**- 3**  **5 days) & 49554501 (PHI 28**

**- 4**  **2 days)** 

**Total number of data (n)** 5 **Percentage of censored data** 0%
**Number of non-censored data** 5 **Lowest residue** 0.966 **Highest residue** 5.580
**Median residue** 2.055

**Mean** 2.837 **Standard deviation (SD)** 2.054 **Correction factor for censoring (CF)** 1.000

**Proposed MRL estimate**

**- Highest residue** 5.580
**- Mean + 4 SD** 11.053
**- CF x 3 Mean** 8.511
**Unrounded MRL** 11.053

**Rounded MRL 1**  **5**

High uncertainty of MRL estimate. [Small dataset]

**Residues (mg/kg)** 

1.174
0.966
4.410

5.580
2.055

### Hexythiazox Human Health Risk Assessment D427090

Page 34 of 34 **H exythiazox** 

**C itrus (Lemon)** 

**U S**  **A MRID 49591801 (PHI 7 Day)** 

**Total number of data (n)** 5 **Percentage of censored data** 0%
**Number of non-censored data** 5 **Lowest residue** 0.107 **Highest residue** 0.236
**Median residue** 0.188

**Mean** 0.184 **Standard deviation (SD)** 0.051 **Correction factor for censoring (CF)** 1.000

**Proposed MRL estimate**

**- Highest residue** 0.236
**- Mean + 4 SD** 0.389
**- CF x 3 Mean** 0.553
**Unrounded MRL** 0.553

**Rounded MRL 0.6** 

High uncertainty of MRL estimate. [Small dataset]

**Residues (mg/kg)** 

0.223
0.107

0.188
0.167
0.236