UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: 09-SEP-2014 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Hexythiazox. Human Health Risk Assessment to Support Emergency 

Exemption Use inion Sugar Beet. 

PC Code: 128849 DP Barcode: D421443 

Decision No.: 493021 Registration No.: 

10163-277 

Petition No.: 14ID02 Regulatory Action: Section 18 

Risk Assessment Type: Single Chemical 

Aggregate 

TXRNo.: NA 

MRlDNo.: NA 

FROM: Kate! ynn King, Risk Assessor 

Alexandra LaMay, Biologist 

Linda Taylor, Toxicologist 

Registration 

Case No.: N/A 

CAS No.: 78587-05-0 

40 CFR: 180.448 

(_ 

Risk Assessment Branch V 

Health Effects Division (7509P) 

THROUGH: Danette 

William 

Drew, 

Donovan, 

Chemist 

Chemis ~ r 

t~CJ,. - /} ~~ Michael Metzger, Chief {)..4_4 

Risk Assessment Branch II 

Health Effects Division (7509P) 

TO: Tawanda Maignan, Risk Manager 09 

Andrea Conrath, Risk Manager Reviewer 

Risk Integration, Minor Use & Emergency Response Branch 

Registration Division (7505P) 

Page 1 of32 
Hexythiazox Human Health Risk Assessment D421443 

Table of Contents 

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

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

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

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

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

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

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

2.2.4 International Harmonization ..................... ........ ........ .... ......... .... ................... 6 

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

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

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

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

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

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

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

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

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

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

4.1 Hazard Characterization ............................ .... .... .... .... .... .... ............. .... ............ 10 

4.2 Hazard Profile ....... ...................................... ..................................................... 11 

4.3 Dose-Response Assessment/Endpoint Selection .. ...................................... .... 11 

4.4 FQPA Considerations ..................................................... ..................... .... ..... .... 12 

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

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

5.0 Dietary Exposure/Risk Characterization ............ ........ ............ ............ ......... .... . 14 

5.1 Residue Chemistry Summary ... ... ..... .... ....... ..... ........... ................................... 14 

5.2 Drinking Water Residue Profile .................................................. ..... ............. . 15 

5.3 Dietary Exposure and Risk .. .... ....... .... .... ..... .................... ............................... 15 

5.4 Anticipated Residue and Percent Crop Treated (%CT) Information ........ 17 

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

6.1 Residential Handler Exposure and Risk ........................................................ 17 

6.2 Residential Post-application Exposure ........................................................... 17 

6.3 Other ... ... ....... ... ....... ....... .... ........... ........ ............ ........ ........ .... ........ .... ..... .... ........ 19 

7.0 Aggregate Risk Assessments and Risk Characterization .... ........ .... ............ ..... 20 

7.1 Acute Aggregate Risk. ...................................................................................... 20 

7.2 Short- and Intermediate-Term Aggregate Risks ..... ........ .... .... ........ ......... .... 20 

7.3 Long-Term (Chronic) Aggregate Risk ........................................................... 20 

8.0 Cumulative Risk Characterization/ Assessment ... .... .... .... .... .... ..... ... ......... ........ 21 

9.0 Occupational Exposures and Risks ................................... ........ ........ ........ ......... 21 

9.1 Occupational Handler Risk ............................................................................. 21 

9.2 Occupational Post Application Risk ..... ........ .... .... ............ .... ...... ... .... ............. 21 

10.0 Human Studies ..................................................................................................... 23 

Appendix A. Toxicology Assessment.. .. .... ........................ ........ ............ .... .. ....... .... .... ..... 24 

Appendix B: Toxicology Data Requirements ................................................................... 28 

Appendix C: Field Trial Residue Data .... ....... .... ................ ..... ............ .... .... ........ .... ......... . 29 

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Hexythiazox Human Health Risk Assessment D313192

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Appendix D: Maximum Residue Limits (MRL) .............................................................. 30

Appendix E: OECD Calculator MRL Output................................................................... 31

Appendix F: Estimated Drinking Water Concentration.................................................... 32
Hexythiazox Human Health Risk Assessment D313192

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1.0 Executive Summary

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

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

crops and outdoor residential settings. Hexythiazox is a contact pesticide which achieves 

control of eggs or immature mites via direct contact or contact with treated surfaces. 

The Idaho State Department of Agriculture (ISDA) is applying for a FIFRA Section 18 

emergency specific exemption for the use of hexythiazox, formulated as the product 

Onager Miticide on sugar beets in Idaho and Oregon. Gowan submitted the results of 

residue studies conducted with a target application rate of 0.1875 lb of ai/A and a target 

pre-harvest interval (PHI) of 45 days. One decline study was conducted depicting 

residues over a PHI range of 38-66 days, showing little change in residues over this time 

interval. The proposed supplemental Onager ® Miticide label specifies a PHI of 21 days

for sugar beet; however, the submitted residue data support a minimum PHI of 38 days. 

The use directions for sugar beet should be changed to indicate a minimum PHI of 38 

days. With this modification, the residue data support a tolerance level of 0.15 ppm for 

sugar beet roots.

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

toxicity of the liver and adrenals following sub-chronic and chronic exposure to dogs, rats 

and mice, with the dog being the most sensitive species. The prenatal developmental 

studies in rabbits and rats and the two-generation reproduction study in rats showed no 

indication of increased susceptibility to in utero and/or postnatal exposure to 

hexythiazox. Reproductive toxicity was not observed. There is no concern for 

neurotoxicity following exposure to hexythiazox. The toxicology database for 

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

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

since the effects seen in the study that serves as the basis for the chronic reference dose 

(RfD) occurred at doses substantially below the lowest dose that induced tumors, HED 

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

hexythiazox will adequately account for all chronic toxicity, including carcinogenicity, 

that could result from exposure to hexythiazox.

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

duration of exposure. Chronic risk is regulated based on effects seen in the adrenal 

glands in a one-year dog feeding study. Short-term and intermediate-term incidental oral 

and inhalation risks are regulated based on decreased pup body weight during lactation 

and delays in hair growth and/or eye opening, decreased parental body-weight gain and 

increased liver, kidney, and adrenal weights in the 2-generation reproduction study in the 

rat. For the short- and intermediate-term dermal risk assessment, no quantification of risk 

is required. As no dermal hazard has been identified for hexythiazox, quantification of 

dermal post-application risk is not required. 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 
Hexythiazox Human Health Risk Assessment D313192

Page 5 of 32

dose considering the NOAEL of 30 mg/kg/day from the oral reproduction study, and the 

estimated 2% dermal absorption for this compound.

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. 

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 (food, drinking water and residential) risk assessments for hexythiazox. Shortand 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 use and are not of concern. Further, there were no risks of concern 

identified for postapplication exposure to hexythiazox associated with this new use. 

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).

2.0 HED Recommendations

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

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

exemption use on sugar beets, and setting the recommended tolerance described in 

Section 2.2.2. 

2.1 Data Deficiencies

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

with this action. 

2.2 Tolerance Considerations
Hexythiazox Human Health Risk Assessment D313192

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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 

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 summarizes the recommended 

tolerance level and commodity definition required to support the proposed new 

emergency exemption use on sugar beets. This tolerance should be added to 40 CFR 

§180.448(b).

Table 2.2.2. Tolerance Summary for Hexythiazox.

Commodity Proposed Tolerance 

(ppm)

HED-Recommended 

Tolerance (ppm)

Comments

(correct commodity definition)

Sugar Beet Roots NA 0.15 Beet, sugar, root;

expiration date TBD

2.2.3 Revisions to Petitioned-For Tolerances

No tolerances were proposed by the petitioner. HED used the OECD tolerance 

calculation procedures to determine a recommended tolerance level of 0.15 ppm for sugar 

beet roots. The results of the OECD MRL calculations are presented in Appendix E. 

2.2.4 International Harmonization

The International Residue Limit (IRL) status sheet is included as Appendix D to this 

memorandum. As there are no Codex or Canadian MRLs for hexythiazox in/on sugar 

beets, there are no harmonization issues associated with this action.
Hexythiazox Human Health Risk Assessment D313192

Page 7 of 32

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

Two changes are recommended for the proposed supplemental Onager® Miticide label 

for sugar beet. 

 A 120-day PBI for rotational crops should be added to the label.

 The PHI should be changed from 21 days to 38 days.

These changes should be included in a revised supplemental label.

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

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 crops and in 

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

eggs or immature mites via direct contact or contact with treated surfaces. 

 

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 D313192

Page 8 of 32

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 D313192

Page 9 of 32

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 sugar 

beets. The newly proposed use pattern for sugar beet is summarized in Table 3.3.

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

Application 

Method

Formulation

[EPA Reg. No.]

Application

Rate

(lb ai/A)

Max. No. 

Application

per Season

Max. 

Seasonal 

Application

Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations

Sugar Beet

Aerial, 

ground, or 

chemigation 

applications

Onager® 

Miticide

[10163-277]

0.078-0.188 1 0.188 21

Restricted to use in 

Regions 11 and 12. Idaho 

may treat a maximum of 

134,000 acres of sugar 

beets and 25,125 lbs. ai. 

Oregon may treat 9,300 

acres of sugar beets and 

1,743.75 lbs. ai. Both 

states may use AI until 

September 31, 2014.

The following changes should be made to the supplemental label for sugar beet:

 A 120-day PBI for rotational crops is needed.

 The PHI should be changed from 21 days to 38 days.

3.4 Anticipated Exposure Pathways

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

the proposed new use of hexythiazox. Humans may be exposed to hexythiazox in food 

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

application may result in hexythiazox reaching surface and ground water sources of 

drinking water. Additionally humans may be exposed to hexythiazox in residential 

settings, since it may be applied to ornamental plantings in residences, public areas, and 

recreational sides, as well as on lawns and turf and to residential berries and fruit and nut 

trees. In an occupational setting, applicators may be exposed while handling the 

pesticide prior to application, as well as during application. There is a potential for postapplication exposure for workers re-entering treated fields. 

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

This risk assessment considers all of the aforementioned exposure pathways based on the 

proposed new use of hexythiazox, as well as the existing uses. 

3.5 Consideration of Environmental Justice
Hexythiazox Human Health Risk Assessment D313192

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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.

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 
Hexythiazox Human Health Risk Assessment D313192

Page 11 of 32

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 

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. 
Hexythiazox Human Health Risk Assessment D313192

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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.

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.
Hexythiazox Human Health Risk Assessment D313192

Page 13 of 32

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

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 D313192

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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.

Three field trials divided among regions 10 and 11 had hexythiazox residues in/on sugar 

beet roots that ranged from 0.021-0.053ppm, based on a 45-day PHI and an application 
Hexythiazox Human Health Risk Assessment D313192

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rate of 0.187 lb ai/A. Although residue data were also provided for sugar beet tops, HED 

notes that this commodity is no longer considered a significant livestock feedstuff (Table 

1 Feedstuffs (June 2008)). Thus, no tolerance or residue review is needed for sugar beet 

tops. One decline study showed residues over a PHI range of 38-66 days; residues were 

relatively constant over this range. Thus, these data support a minimum PHI of 38 days 

and the label should be modified to reflect this. Hexythiazox residues were stable at -

10°C for up to 7 months in radish roots (D247631/D260343, G.Kramer, 3/20/2000); these

data can be translated to sugar beet roots. Field trial residue data and storage stability 

conditions are presented in Appendix C: Field Trial Residue Data.

Processed commodities of sugar beets include refined sugar, dried pulp, and molasses.

No processing studies were submitted to support this section 18 request. For Section 3 

registration of this use, processing factor studies will be required. Dietary burden

including sugar beet feedstuffs was calculated assuming maximum theoretical 

concentration factors of 20x for molasses and dried pulp. The inclusion of sugar beet did 

not increase livestock dietary burdens. As a result, current livestock tolerance levels are 

adequate (D404573/ D410813, D. Davis, 05/013). 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; the proposed label should be modified to 

reflect this PBI.

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. No new drinking water assessment was required for this section 18 action. 

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 ppb from this scenario was used in the chronic dietary risk 

assessment which is protective of the new (revised using 0.87 PCA) 1-in-10 year annual 

average of 3.9 ppb (Appendix F). 

5.3 Dietary Exposure and Risk

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

No new dietary exposure analyses were required for this section 18 action. The addition 

of sugar beets to the most recent dietary exposure analysis did not change the risk 

estimates.

5.3.1 Acute Dietary Exposure/Risk
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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

N/A N/A

Children 1-2 years old 0.020483 82

Children 3-5 years old 0.013364 54

Children 6-12 years old 0.006416 26

Youth 13-19 years old 0.003220 13

Adults 20-49 years old 0.002878 12
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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

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

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

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

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

landscape plantings in residences, public areas, and recreational sites such as 

campgrounds, golf courses, parks and athletic fields, (2) ornamental lawns and turf 

(including residential), (3) residential pome fruit, stone fruit, and nut trees, and residential 

caneberries. 

6.1 Residential Handler Exposure and Risk

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

were conducted for residential handlers. Residential handler exposure is expected to be 

short-term in duration. Intermediate-term exposures are not likely because of the 

intermittent nature of applications by residential applicators. Residential handler 

inhalation margins of exposure (MOEs) significantly exceed 100 for all scenarios 

assessed and are not of concern. Residential handler MOEs range from 420,000 to 

330,000,000.

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 
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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. The short-term hand-to-mouth MOE for 

children is 11,000; the short-term object-to-mouth MOE for children is 350,000; and the 

short-and intermediate-term incidental soil ingestion MOE for children is 4,700,000. 

In accordance with 40CFR158, 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. In the absence of chemical-specific TTR data, 

EPA uses default values. The 2012 Standard Operating Procedures for Residential 

Pesticide Exposure Assessment includes an analysis of all TTR data, available at the time, 

which resulted in the selection of revised liquid and granular default values for the 

fraction of the application rate available for transfer after a turf application (FAR). These 

values are based on an analysis of 59 TTR studies performed with the Modified 

California Roller Method (36 studies using liquids, 11 studies using wettable 

powders/water dispersible granules, and 12 studies using granules). The liquid results 

(N=131) indicate a range of FAR values from 0.0005% to 6.1% and the granular results 

(N=37) indicate a range of 0.00064% to 0.69%. In both the liquid and granular data, a 

large range of transferability is observed and this variability can potentially be 

attributable to many factors such as active ingredient; formulation; field conditions in the 

studies; weather conditions (e.g., humidity); or many other difficult to quantify factors.

Although witnessed across multiple chemicals, this range in FAR values is not expected 

when considering TTR data for a single chemical. HED selected 1% and 0.2% as highend default values for liquid and granular products, respectively. Although there may be 

a small degree of uncertainty in the use of the default TTR value for hexythiazox (i.e., 

there is a small chance that the FAR value may exceed the applicable default value), it is 

likely that the health-protective aspects of EPA’s residential postapplication turf 

assessment methodology will more than compensate for this potential uncertainty (i.e., 

the methodology is likely to overestimate exposure by a factor greater than the factor than 

the highest measured FAR values exceed the defaults ). For example, when assessing 

residential post-application turf exposure, EPA assumes the following: exposures occur 

to zero-day (i.e., day of application ) residues every day of the assessed exposure 

duration (i.e., EPA assumes that no dissipation or degradation occurs, it doesn’t rain, the 

grass is not mowed, etc); individuals perform the same postapplication activities 

performed in the turf transfer coefficient study day after day (e.g., tumbling, playing on 

turf with toys, etc.); and individuals engage in these post-application activities for a highend amount of time every day that is represented by data reflecting time children spend 

outdoors and not specifically engaged in activities on turf, when in actuality children do 

not spend all of their outdoor time on turf and high-end levels of activity will not occur 

every day. 

 

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

Andrew Shelby. DP Barcode: 396529& 401798. 6/21/2012.
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Given the conservatisms discussed above and the potential compounding nature of these 

conservatisms, EPA is able to rely upon the calculated exposure estimates with 

confidence that exposure is not being underestimated. 

Since the estimated residential turf post-application exposure for residential turf using 

default TTR values for hexythiazox is minimal in comparison to the level of concern (i.e., 

the calculated MOE is greater than 10 times higher than the level of concern, MOE = 

11,000 compared to the LOC of 100); EPA is waiving the 40CFR TTR data requirement.

In this instance, it is unlikely that chemical-specific TTR data would be needed to further 

refine exposure assessments or would add appreciably to our general understanding of the 

availability of turf transferable pesticide residues.

6.3 Other

6.3.1. Spray Drift

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

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

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

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

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

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

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

management practices (see the agency’s Spray Drift website for more information). 2 The 

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

potential source of exposure in risk assessments for pesticides.

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

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

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

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

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

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

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

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

spray drift from agricultural hexythiazox applications.

6.3.2. Residential Bystander Post-Application Inhalation Exposure

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

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

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

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

SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The agency has 

 

2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
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evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

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

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

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

for hexythiazox.

7.0 Aggregate Risk Assessments and Risk Characterization

7.1 Acute Aggregate Risk

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

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. 

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, below. 

Table 7.2 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 a previous residential assessment (D.Davis, 5/6/2013).

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

7.3 Long-Term (Chronic) Aggregate Risk
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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

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).

The proposed Section 18 use is for sugar beets with an application rate of 0.1875 lb 

ai/acre. The applicable occupational handler scenarios for sugar beets have been 

previously assessed at the same rate for other agricultural crops. This includes 

application of the emulsifiable concentrate at 0.1875 lb ai/acre to field crops via aerial, 

chemigation and ground boom equipment. All occupational handlers scenarios 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. 

9.2 Occupational Post Application Risk
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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.

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

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

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

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

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

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

on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The agency has 

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

subsequent Volatilization Screening Analysis 

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

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

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

hexythiazox.

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

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

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

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

assessments.

Although a quantitative occupational post-application inhalation exposure assessment 

was not performed, an inhalation exposure assessment was performed for 

occupational/commercial handlers. Handler exposure resulting from application of 

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

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

protective of most occupational post-application inhalation exposure scenarios.

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)].

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 
Hexythiazox Human Health Risk Assessment D313192

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

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

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

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

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

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

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

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

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

agricultural workers from post-application exposures to hexythiazox. 

10.0 Human Studies

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

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

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

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

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

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

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

as well as guidance on their use, can be found at the Agency website3. 

 

3 http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html
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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 

207.67 mg/kg/day

Parental/Systemic NOAEL = 29.73/34.77 mg/kg/day, 

males/females

LOAEL = 180.67/207.67 mg/kg/day, males/females, based 

on decreased body weight gain and increased absolute and 

relative liver, kidney, and adrenal weights.

Reproductive NOAEL 180.67/207.67 mg/kg/day, 

males/females

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

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

LOAEL = 180.67/207.67 mg/kg/day, males/females, based 
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Table A.1.2. Toxicity Profile of Hexythiazox

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

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 

CHO cells

00156894 (1986)

Acceptable

The test was negative up to precipitating doses accompanied 

by severe cytotoxicity (167 μg/mL +/-S9).
Hexythiazox Human Health Risk Assessment D313192

Page 26 of 32

Table A.1.2. Toxicity Profile of Hexythiazox

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

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/non-guideline

0, 100, 1000, or 10000 

ppm 

Males: 0, 8.8, 88.7, or 

868.2 mg/kg/day 

Females: 0, 9.5, 90.1, or 

892.7 mg/kg/day 

(28 days)

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

mg/kg/day).

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

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

decreased body weight in males, increased adrenal weight in 

females, and increased liver weight in both sexes. 

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

assess sub-chronic neurotoxicity from hexythiazox exposure

870.7485

Metabolism and 

pharmacokinetics

00146558 (1985)

Acceptable/guideline

Single oral dose at 10 

mg/kg (Group B); 14 

daily oral doses (10 

mg/kg) of unlabeled 

material followed by one 

dose (10 mg/kg) of [14C] 

test material (Group C); 

and a single oral dose of 

880 mg/kg (Group D).

Absorption and distribution of dosed radioactivity were 

rapid. The radioactive material was rapidly eliminated in the 

urine and feces; the majority of the radioactivity was 

eliminated within 24 hours. There were no observable 

differences in the total elimination of NA-73 between male 

and female rats. The major route of elimination in both the 

male and female rats was by fecal excretion. The major 

metabolite found, PT-1-8 (cis), accounted for 8-12% of the 

administered radioactivity in the low dose groups. 

Approximately 11-20% and 65-69% of the dosed 

radioactivity was identified as unchanged NA-73 in the 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 D313192

Page 27 of 32

Table A.1.2. Toxicity Profile of Hexythiazox

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 D313192

Page 28 of 32

Appendix B: Toxicology Data Requirements

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

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

Table B. Toxicology Data Requirements

Study

Technical

Required Satisfied

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

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

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

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

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

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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

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

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

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

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

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

yes

yes

yes

no

CR

yes

yesD

noC

no

noA

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

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

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

yes

yes

yes

yes

yes

yes

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

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

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

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

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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

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

870.5375 Mutagenicity—Structural Chromosomal Aberrations...

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

yes

yes

yes

yes

yes

yes

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

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

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

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

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

no

no

yes

yes

CR

-

-

noA

yesB

no

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

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

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

yes

no

yes

yes

yes

yes

Special Studies 

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

subchronic neurotoxicity from hexythiazox exposure; C dermal equivalent dose 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 
Hexythiazox Human Health Risk Assessment D313192

Page 29 of 32

Appendix C: Field Trial Residue Data

Three trials were completed by Gowan Company in 2013 on sugar beets in regions 10 

and 11. Onager® 1E Miticide was applied to the sugar beets at 0.1875 lb ai/A. 

Residue Data from Sugar Beet Field Trials with Hexythiazox.

Location: 

State; Year

(Trial ID)

Region Crop/ 

Variety

Commodity 

Type

End-Use 

Product

Rate

lbs ai/A

(kg ai/ha)

PHI

(days)

Residues1(ppm)

Hexythiazox Average

ID; 2013

(TCI-13-382-03) 11 Sugar Beet/9120RR

Sugar Beet 

Root

Onager® 

1E

0.1868

(0.2094) 45 0.0229, <0.02 0.02145

CA; 2013

(TCI-13-382-04) 10 Sugar Beet/Phoenix

Sugar Beet 

Root

Onager®

1E

0.1848

(0.2071)

38 0.0493, 0.0580 0.05365

45 0.0597, 0.0455 0.0526

59 0.0528, 0.0635 0.05815

66 0.0453, 0.0469 0.0461

WA; 2013

(TCI-13-382-06) 11

Sugar Beet/ 

Hillesahog 

9294RR

Sugar Beet 

Root

Onager®

1E

0.1887

(0.2115) 45

0.0326, 0.0309 0.03175

0.9359

(1.049) 0.205, 0.213 0.209

1 Expressed as parent equivalents.

Summary of Residues from Sugar Beet Field Trials with Hexythiazox.

Crop 

Matrix Analyte End Use Product

Total 

Application 

Rate

lbs ai/A

(g ai/ha)

PHI 

(days) n

Residues1(ppm)

Min.2 Max.2 LAFT3 HAFT3 Median3 Mean3 SD3

Sugar Beet

Sugar 

Beet

Root

Hexythiazox

Onager® 

1E 

Miticide

0.1875

(0.2102)

38 1 0.0493 0.0580 0.0537 0.0537 0.0537 0.0537 ---

45 3 <LOQ 0.0597 0.02145 0.209 0.0422 0.0787 0.0878

59 1 0.0528 0.0635 0.0582 0.0582 0.0582 0.0582 ---

66 1 0.0453 0.0469 0.0461 0.0461 0.0461 0.0461 ---

1 Expressed as parent equivalents.

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. 

n = number of field trials.

Rounded MRL was calculated using the OECD calculator. Each completed field trial 

average was included in the calculation. The rounded MRL was 0.15 ppm for sugar beet 

roots. 

Sugar beet storage stability information was not included in this study. Sugar beets and 

radishes are both a part of the vegetable, root, and tuber, crop group 01, so radish storage 

data (D247631/D260343, G. Kramer, 3/20/2000) were translated to sugar beets. The 

field residue samples were stored frozen for a maximum of 7 months.

Summary of Storage Conditions.

Matrix

(RAC)

Storage Temperature 

(°C)

Actual Storage Duration

(months)

Interval of Demonstrated Storage Stability

(month)

Radish root -10°C 0-7 7
Hexythiazox Human Health Risk Assessment D313192

Page 30 of 32

Appendix D: Maximum Residue Limits (MRL)

Table B1. Summary of US and International Tolerances and Maximum Residue Limits for 

Hexythiazox (128849)

Residue Definition:

US Canada Mexico2 Codex3

40 CFR 180.448:

Plant: Compliance with the 

tolerance levels specified below is 

to be determined by measuring only

hexythiazox and its metabolites 

containing the (4-chlorophenyl)-4-

methyl-2-oxo-3-thiazolidine moiety, 

calculated as the stoichiometric 

equivalent of hexythiazox.

None Plant commodities: 

Hexythiazox 

Animal commodities: 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 

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex3

Beet, Sugar, Root 0.15

Completed: M. Negussie; 07/24/14

1

Includes only commodities of interest for this action. Tolerance values should be the HED 

recommendations and not those proposed by the applicant.

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

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

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

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

CCPR and the CAC.
Hexythiazox Human Health Risk Assessment D313192

Page 31 of 32

Appendix E: OECD Calculator MRL Output

Hexythiazox

Sugar Beet Root

USA 

0.1875 lbs ai/A PHI 45 days

Total number of data (n) 3

Percentage of censored data 0%

Number of non-censored data 3

Lowest residue 0.021

Highest residue 0.053

Median residue 0.032

Mean 0.035

Standard deviation (SD) 0.016

Correction factor for censoring (CF) 1.000

Proposed MRL estimate

- Highest residue 0.053

- Mean + 4 SD 0.099

- CF x 3 Mean 0.106

Unrounded MRL 0.106

Rounded MRL 0.15

High uncertainty of MRL estimate.

[Small dataset]

Residues (mg/kg)

0.021

0.053

0.032
Hexythiazox Human Health Risk Assessment D313192

Page 32 of 32

Appendix F: Estimated Drinking Water Concentration

Katelynn,

I’ve looked at the referenced assessments and it seems that I didn’t report the annual 

averages. Sorry about that! I’ve attached the DWA that was referenced in the recent 

assessments. The PRZM-EXAMS output on page 10 shows a 1-in-10 year annual 

average of 4.5325 ppb. Multiply this concentration by the percent cropped area of 0.87 

and the resulting EDWC is 3.9 ppb. 3.9 ppb should be used as the 1-in-10 year annual 

average.

Regards,

ANDREW SHELBY

PHYSICAL SCIENTIST

U.S. EPA OFFICE OF PESTICIDE PROGRAMS

ENVIRONMENTAL FATE AND EFFECTS DIVISION

PHONE: (703) 347-0119

From: King, Katelynn 

Sent: Monday, August 11, 2014 9:50 AM

To: Shelby, Andrew

Subject: Section 18

Importance: High

Hi Andrew,

I am also completing a section 18 risk assessment for hexythiazox on sugar beets. Could 

you please let me know if the EDWC is still 4.31 ppb for the 1-in10 year annual average? 

Thanks. 

Katelynn King

Biologist, EPA

Office: (703) 347-0193

Mail Code: 750P, Arlington, VA