Hymexazol Human Health Risk Assessment DP No. 0 425247 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

MEMORANDUM 

Date: December 03. 20 15 

WASHINGTON, D.C. 20460 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Hymexazol: Human Health Draft Risk Assessment in Support of Registration 

Review. 0425247. 

PC Code: 129107 

Decision No.: 499341 

Petition No.: NA 

DP Barcode: 425247 

Registration No.: 48210-1 

Regulatory Action: Registration Review 

Risk Assessment Type: Single Chemical Case No.: 70 16 

Aggregate 

TXR No.: NA CAS No.: I 0004-44-1 

MRlD No.: NA 40 CFR: NIA 

FROM: Matthew Lloyd; CIH; Risk Assess~r 

Austin Wray, PhD, Tmyecr!J:>gist /+,,_,.,,.._,.. 

Peter Savoia, Chemist(/c-ft::L. ~-------

Risk Assessment Branches V and JI (RAB V/VII) 

Health Effects Division (HED; 7509P) 

THROUGH: Danette Drew, Chemist t41I /) 1Jf7n 

Michael S. Metzger, Chie f, RAB VNII . AA _L...,~ r 

HED (7509P) .Qf?t:<..W<l v '<'~"4 

TO: Caitlin Newcamp, Chemical Review Manager 

& 

Tom Mori arty, Team Leader 

Risk Management and Implementation Branch I 

Pesticide Re-Evaluation Division (7508P) 
Hymexazol Human Health Risk Assessment DP No. D425247

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Table of Contents

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

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

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

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

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

2.2.2 International Harmonization..................................................................................... 7

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

2.3 Label Recommendations.................................................................................................. 8

3.0 Introduction.......................................................................................................................... 8

3.1 Chemical Identity ............................................................................................................. 8

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

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

3.4 Anticipated Exposure Pathways..................................................................................... 10

3.5 Consideration of Environmental Justice ........................................................................ 10

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

4.1 Toxicology Studies Available for Analysis ................................................................... 10

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME).................................... 11

4.3 Toxicological Effects ..................................................................................................... 12

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)....................................... 14

4.5 Toxicology Endpoint and Point of Departure Selections............................................... 14

4.6 Endocrine Disruption ..................................................................................................... 17

5.0 Dietary Exposure and Risk Assessment ............................................................................ 18

5.1 Metabolite/Degradate Residue Profile ........................................................................... 18

5.1.2 Summary of Environmental Degradation.............................................................. 19

5.1.4 Residues of Concern Summary and Rationale ...................................................... 19

5.2 Food Residue Profile...................................................................................................... 19

5.3 Water Residue Profile .................................................................................................... 19

5.4 Dietary Risk Assessment................................................................................................ 20

5.4.1 Overview of Residue Data Used .............................................................................. 20

5.4.2 Percent Crop Treated Used in Dietary Assessment .............................................. 20

5.4.3 Acute Dietary Risk Assessment............................................................................... 20

5.4.4 Chronic Dietary Risk Assessment........................................................................... 21

5.4.5 Cancer Dietary Risk Assessment............................................................................. 21

5.4.6. Dietary Assessment Summary Tables ............................................................................ 21

6.0 Residential (Non-Occupational) Exposure/Risk Characterization .................................... 22

6.1 Residential Handler Exposure........................................................................................ 22

6.2 Post-Application Exposure............................................................................................. 22

7.0 Non-Occupational Spray Drift Exposure and Risk Estimates........................................... 22

8.0 Non-Occupational Bystander Post-Application Inhalation Exposure and Risk Estimates 22

9.0 Aggregate Exposure/Risk Characterization....................................................................... 22

10.0 Cumulative Exposure/Risk Characterization..................................................................... 23

11.0 Occupational Exposure/Risk Characterization........................................................... 23

11.1 Short- and Intermediate-Term Handler Risk.............................................................. 23

11.2 Short- and Intermediate-Term Post-Application Risk................................................ 27

12.0 Human Incidents ............................................................................................................ 27

13.0 References.......................................................................................................................... 28
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Appendix A. Toxicology Assessment........................................................................................... 29

A.1 Toxicology Data Requirements...................................................................................... 29

A.2 Toxicity Profiles............................................................................................................ 30

A.3 Hazard Identification and Endpoint Selection .......................................................... 38

A.4 Executive Summaries................................................................................................... 40

Appendix B. Physical/Chemical Properties.................................................................................. 53

Appendix C. Review of Human Research .................................................................................... 54
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1.0 Executive Summary

This assessment has been conducted to address the requirement for a Draft Risk Assessment 

(DRA) to support Registration Review. As part of Registration Review, the Pesticide Reevaluation Division (PRD) of OPP has requested that HED evaluate the hazard and exposure 

data and conduct dietary and occupational and residential exposure assessments, as needed, to 

estimate the risk to human health that will result from the currently registered use of hymexazol. 

Background

Hymexazol is the common name for the isoxazole fungicide active ingredient 5-methyl-3(2H)-

isoxazolone (CAS Name). Hymexazol is a systemic fungicide for control of foliar and soil-borne 

plant diseases. There is only one existing registration as a commercial seed treatment for sugar 

beets. As a wettable powder (WP) intended for commercial seed treatment, the maximum 

application rate is for standard pelletization, at the rate of 45 to 90 grams of TACHIGAREN® 70 

WP per unit of 100,000 seeds (approx. 1 kilogram of raw sugar beet seed). Hymexazol may be 

applied only using commercial seed treatment equipment. Based on the existing seed treatment 

registration, occupational handler exposure is expected for the short- and intermediate-term for 

primary handlers treating seed, and for secondary handlers who plant the seed. 

Hazard Assessment

The toxicology database is complete for risk assessment purposes. In mammals, the primary 

target organ of hymexazol and the organismal response were species specific; however, the mode 

of action is currently unknown. Dogs were the most sensitive non-pregnant adult species 

exhibiting characteristics of thyroid toxicity (increase in thyroid weight and thyroid epithelial 

height, and increased prevalence of thyroid epithelial hyperplasia) from sub-chronic oral

exposure. Non-pregnant adult rodents were more tolerant: acute toxicity was low (Category III) 

and subchronic and chronic toxicity manifested as liver (increased liver weight with associated 

centrilobular hepatocyte enlargement and granulomatous inflammation, elevated liver enzymes) 

and systemic effects (reduced body weight and body weight gain) at doses 2-5x higher than those 

eliciting thyroid effects in dogs. At similar high doses, there was no evidence of carcinogenicity 

or effects that would compromise the immune system. Neurological effects (decreased brain 

weight and cerebral length) in rodents occurred only at doses approaching the limit dose, and 

were not strong indicators of a neurotoxic mode of action. Ingested hymexazol was rapidly 

eliminated, which limited tissue accumulation and progression of toxicity in all species tested.

Pregnant rodents and developing fetuses exhibited enhanced sensitivity to hymexazol exposure 

relative to non-pregnant adult rodents. Oral exposure in rats from the pre-mating period through 

parturition induced lower post-implantation survival and a subsequent reduction in litter size. 

This response was attributed to both compromised maternal health and in utero exposure and 

thus was not indicative of increased susceptibility in the young. Pregnant rats exposed

exclusively during the gestation period produced fetuses with developmental abnormalities 

including reduced ossification of the cervical, thoracic, lumbar, & caudal vertebrae, as well as in 

the pelvic girdle & in the fore- & hind- extremities, and significantly increased incidence of a 

bilateral 14th rib. These developmental effects were observed in the absence of maternal effects 

indicating enhanced sensitivity in the developing rat fetuses. The dose eliciting developmental 
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effects in rats was similar in developing rabbits exposed in utero, yet the effects themselves were 

distinct (heart/great vessel malformations, particularly incomplete inferior vena cava, reduced 

fetal weight and increased incidence of reduced sternebrae). In contrast to fetal rats, the rabbit 

fetuses were not more susceptible to oral exposure as the developmental effects were only 

observed in concert with compromised health in the rabbit dams. Reproduction was not affected 

by hymexazol exposure.

Hymexazol is a skin sensitizer; however, dermal exposure did not irritate the skin (dermal 

irritation: Category IV) and high dermal doses were required to elicit acute (Category III) and 

subchronic systemic toxicity. It was minimally toxic via acute inhalation exposure (Category III) 

but is a strong eye irritant (Category I).

Based on the toxicity, duration of exposure, and uses of hymexazol, the following toxicity 

endpoints were selected:

Acute dietary (general population, including infants and children): Maternal no 

observed adverse effect level (NOAEL) of 150 mg/kg/day based on mortality, abnormal 

clinical signs (unsteadiness, slumped posture, increased respiration, and salivation) 

observed in the rabbit developmental study within an hour of dosing, and decreased food 

consumption and body weight loss within 2 days of initial exposure at 450 mg/kg/day 

(maternal lowest observed adverse effect level (LOAEL)).

Chronic dietary (all populations): NOAEL of 31 mg/kg/day, derived from a parental 

LOAEL of 159 mg/kg/day based on increase in post-implantation loss and a decrease in 

litter size observed in the rat 2-generation reproduction study.

Dermal: Same as chronic dietary.

Inhalation: Same as chronic dietary.

HED has applied the traditional uncertainty factors of 10X for inter-species extrapolation and 

10X for intra-species variability, along with a database uncertainty factor of 10X based on a 

missing inhalation study1for the inhalation route only. Exposure routes are combined because 

toxic effects are common between the inhalation and dermal routes of exposure. A total 

aggregated risk index (ARI) was used for the worker assessment since the level of concern 

(LOC) values for dermal exposure (100) and inhalation exposure (1000) are different. 

Dietary (Food and Water) Exposure and Risk

Hymexazol is a non-food use chemical based upon plant metabolism data that showed it to be 

metabolized to carbon dioxide (CO2) and incorporated into sugars. However, there is potential 

for hymexazol to reach drinking water sources through its application to sugar beet seeds. 

Therefore, a drinking water assessment was performed. Acute and chronic dietary assessments of 

drinking water were conducted using model-derived estimated drinking water concentrations 

(EDWCs). Acute exposure to hymexazol in drinking water resulted in an estimated risk which 

was < 1% of the aRfD (acute reference dose) for the general U.S. population and all population 

subgroups at the 95th percentile which is well below the Agency’s level of concern. The 

estimated chronic exposure to hymexazol in drinking water is also not of concern with risk 

 

1 TXR 0057244
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estimates being <1% of the cRfD (chronic reference dose) for the general U.S. population and all 

population subgroups.

 

Residential (Non-Occupational) Exposure and Risk

Because hymexazol is registered only for use as a commercial seed treatment, there are no 

existing or proposed residential uses at this time and, therefore, no quantitative residential 

handler or post-application assessment was completed. 

Spray Drift

Hymexazol is registered only for use as a commercial sugar beet seed treatment. Based on that 

use pattern, no spray drift is anticipated (coated seed for planting) and no quantitative assessment 

was completed. 

Volatilization/Residential Bystander

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

individuals nearby pesticide applications. The agency has developed a Volatilization Screening 

Tool and a subsequent Volatilization Screening Analysis, and the Agency will utilize this 

analysis during Registration Review to determine if data (i.e., flux studies) or further analysis are 

required for hymexazol.

Aggregate

Although there is the potential for hymexazol to enter drinking water sources from the nonfood 

use on seeds, there are no food or residential uses or exposures; therefore, the aggregate risk 

includes only the contribution to exposure from drinking water. There are no risks of concern 

for hymexazol in drinking water. 

Occupational Exposure and Risk

No chemical-specific handler exposure data were submitted in support of this assessment; 

therefore, HED relied on surrogate data and default assumptions in accordance with standard 

policies. Based on the proposed use pattern, short- and intermediate-term durations of exposure 

are expected for occupational handlers. The estimates of exposure to pesticide seed treatment 

handlers (treatment and planting) are based upon ExpoSAC Policies 14 & 15 and a memorandum 

from the Biological and Economic Analysis Division (BEAD), “Acres Planted Per Day and 

Seeding Rates of Crops Grown in the United States” (J. Becker, March 2011). 

The maximum single application rate for sugar beet seed treatment is the “standard pellet” 

scenario. A lower application rate (“minimum buildup” scenario) is also an option based on the 

label, although it is rarely used in commercial seed treatment practice. Most “standard pellet” 

occupational handler scenarios are not of concern (based on the Aggregate Risk Index [ARI]

LOC of 1) with label-specified PPE. For the mixer scenario, the addition of a filtering facepiece 

respirator (PF5) results in an inhalation MOE of 1,500, although the ARI for the scenario is still 

below 1 (ARI = 0.6). However, for the handler mixing the wettable powder, the use of 
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engineering controls (i.e., water soluble packets) is required to reach MOEs which result in an 

ARI > 1.

The potential for dermal post-application exposures following the planting of hymexazol-treated 

seeds is unlikely because no routine cultural practices involve sustained levels of contact with 

treated seed after it has been placed in the soil or other planting media.

Commercial treatment of seeds is not within the scope of the Worker Protection Standard. 

Hymexazol is not registered for non-commercial seed treatment and does not require Worker 

Protection Standard labeling.

Similarly, a post-application inhalation exposure assessment is not required as exposure is 

expected to be negligible. 

Human Studies Review

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 Pesticide 

Handlers Exposure Database Version 1.1 (PHED 1.1); ExpoSAC Policy 14 and 15.1 (SOPs for 

Seed Treatment); 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 website2. 

2.0 HED Recommendations

2.1 Data Deficiencies

There are no data deficiencies for the Registration Review eligibility of hymexazol in regards to 

the toxicology, occupational and residential exposure, and chemistry databases. No tolerances 

are required, and label modifications are discussed in Section 2.3.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Because no tolerances are required to support the use of hymexazol, an enforcement analytical 

method is not required. 

2.2.2 International Harmonization

International harmonization is not an issue for consideration, because there are no tolerances 

established for hymexazol.

 

2 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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2.2.3 Recommended Tolerances

Hymexazol is only registered for application as a commercial seed treatment for sugar beet seeds

and is considered to be a non-food use chemical, which does not require the establishment of 

tolerances.

2.2.4 Revisions to Established Tolerances

There are no tolerances established or needed for hymexazol, and thus no revisions are required.

2.3 Label Recommendations

No label recommendations have been identified. A summary of the risk estimates has been 

provided, and shows that there are risk estimates of concern for registered uses of hymexazol

based on the use information, and label-required personal protective equipment (PPE). 

3.0 Introduction

3.1 Chemical Identity

Table 3.1. Chemical Identity of Hymexazol

Common Name Hymexazol

IUPAC name 5-methylisoxazol-3-ol

CAS name 5-methyl-3(2H)-isoxazolone

PC Code 129107

CAS registry number 10004-44-1

Chemical Structure 

3.2 Physical/Chemical Characteristics

Hymexazol is the common name for the isoxazole fungicide active ingredient 5-methyl-3(2H)-

isoxazolone (CAS Name). It is registered for use as a seed treatment on sugar beet seeds to 

control plant diseases which cause seeding loss. It appears as a colorless crystal in its technical 

form and is manufactured for use as a wettable powder (WP). It is stable under normal use 

conditions including that of heat and light. The environmental fate and characterization database 

for hymexazol illustrates that its biodegradation is a relatively rapid process. It reports a half-life 

of less than 8-days under aerobic conditions and less than 2-days under anaerobic conditions 

(D428894, J. Wolf, 09/02/15). Hymexazol is stable to abiotic hydrolysis and is very mobile 

based on its reported adsorption values (Kd & KOC). There is also the possibility of volatilization 

from soil and water based on the reported vapor pressure (1.37 x 10-3torr) and Henry’s Law 

constant value (2.7 x 10-9). A detailed summary of the physical/chemical characteristics of 

hymexazol are presented in Appendix B. 
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3.3 Pesticide Use Pattern

Hymexazol is a fungicide used in seed treatment for control of seedling diseases caused by 

Aphanomyces spp. and Pythium spp. in sugar beets. There are no existing registrations for 

agricultural foliar or residential use sites. Commercial seed treatment facilities may use the 

hymexazol wettable powder (WP) formulation in commercial seed treatment processing to 

apply hymexazol as either a “standard pellet” or a “minimum pellet” seed coating. In either 

case, hymexazol must be used with an EPA approved dye that imparts an unnatural color to the 

seed.

Federal Law requires that bags containing treated seeds shall be labeled with the following 

information. "This seed has been treated with Hymexazol fungicide. Do not use for feed, food or 

oil purposes. Store away from feeds and foodstuffs." 

For Application as a standard pellet: Apply as a commercial seed treatment on pelleted sugar 

beet seeds at the rate of 45 to 90 grams of TACHIGAREN® 70 WP per unit of 100,000 seeds 

(approx. 1 kilogram of raw sugar beet seed). Seed must be pelleted at a minimum weight to 

weight ratio of 2:1 pelleting mixture to raw seed.

An application rate with less active ingredient used “minimum pellet build-up” is also detailed on the 

available hymexazol product label. 

For Application as a minimum build-up pellet: Apply as a commercial seed treatment on 

minimum build-up pelleted sugar beet seeds at the rate of 20 to 30 grams of TACHIGAREN® 

70 WP per unit of 100,000 seeds (approx. 1 kilogram of raw sugar beet seed). Seed must be 

pelleted at a minimum weight to weight ratio of 3:10 pelleting mixture to raw seed.

The existing labeling restricts use of hymexazol “on agricultural establishments in hopper-box, 

planter-box, slurry-box or other seed-treatment applications at or immediately before planting.”

Commercial seed treatment uses are registered for sugar beet, and the one wettable powder 

(WP) formulation can be applied using only commercial seed treatment equipment. The 

existing use pattern is outlined below in Table 3.3.

Table 3.3. Summary of Existing Commercial Seed Treatment Uses of Hymexazol

Formulation

[EPA Reg. No.]

Trade Namea

Crop Max Application Rateb Use Directions and 

Limitations

70% TACHIGAREN® 70 

WP

[48210-1]

Sugar beet

Standard pellet 90 g product / kg seed 0.056 lb ai/lb seed

 90g/100,000 

seeds

 Seed must be 

pelleted at a 

minimum 

weight to 

weight ratio of 

2:1 pelleting 

mixture to raw 

seed.

a Formulation codes: WP = wettable powder.

b As registered rates are given as “mass ai per seed”, a seed count (# seeds per pound) is needed to convert to “mass 

ai per pound seed” for the purposes of estimating exposure. Based on the BEAD memo “Acres Planted Per Day 
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and Seeding Rates of Crops Grown in the United States” (J. Becker, March 2011), the following seed count 

conversions were used to convert lb ai/seed rates into lb ai/lb seed: sugar beet – 40,000 seeds per pound.

3.4 Anticipated Exposure Pathways

Since there are no food uses for hymexazol, exposure from food will not occur. The registered 

use patterns could result in residues in drinking water, so there is potential for exposure from 

drinking water. There are no residential uses of hymexazol; and no exposure to hymexazol via 

spray drift is anticipated. 

Short- and intermediate-term dermal and inhalation exposures are anticipated for occupational 

handlers commercially treating sugar beet seed, and secondary planters who are planting treated 

sugar beet seed in agricultural fields, and potentially from field volatilization of hymexazol 

treated seed.

3.5 Consideration of Environmental Justice

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

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

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

(http://www.archives.gov/federal-register/executive-orders/pdf/12898.pdf). As a part of every 

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to 

well-established procedures. In line with OPP policy, HED estimates risks to population 

subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water 

consumption, and activities in and around the home that involve pesticide use in a residential 

setting. Extensive data on food consumption patterns are compiled by the U.S. Department of 

Agriculture’s (USDA’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, season 

of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary 

exposure to smaller, specialized subgroups, and exposure assessments are performed when 

conditions or circumstances warrant. Whenever appropriate, non-dietary exposures are 

evaluated, 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. 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

Hymexazol (5-methyl-3(2H)-isoxazolone) is a systemic fungicide for control of foliar and soilborne plant diseases. The hymexazol toxicity database is adequate for risk assessment (See 

Appendix A).

4.1 Toxicology Studies Available for Analysis
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The hymexazol toxicity database is adequate for human health risk assessment; for additional 

information see Appendix A. The following studies were considered in designating the points of 

departure (PODs) for each exposure scenario:

- 90 day oral toxicity study – rat, mouse, and dog

- 90 day dermal toxicity study – rat 

- Prenatal developmental toxicity study – rat and rabbit

- Multi-generation reproduction and fertility toxicity study – rat

- 1 year chronic toxicity study – dog

- 2 year chronic toxicity/carcinogenicity study – rat 

- 2 year carcinogenicity study - mouse

- Mutagenicity battery

- Subchronic neurotoxicity study – rat 

- Metabolism pharmacokinetics study – rat 

- Immunotoxicity study

The Hazard Science Policy Council (HASPOC) recommended waiving the requirement for the 

acute neurotoxicity study (TXR 0056409) using a weight of evidence (WOE) approach including 

the following considerations: (1) the lack of neurotoxicity in the available toxicity studies for 

hymexazol; (2) the effects seen in the available subchronic neurotoxicity study are at the limit 

dose; and (3) the known target organ of hymexazol is the liver and not the nervous system. 

The HASPOC did not recommend a waiver for the missing 90-day inhalation study (TXR 

0057244) and instead required a subchronic developmental inhalation study based on the 

following hazard and exposure considerations: 1) the margin of exposure (MOE = 300) for the 

worst case inhalation scenario is not 10x greater than the level of concern (LOC = 100), 2) the 

adequate ventilation requirement is not well defined on the label and cannot be factored into risk 

estimates, and 3) developmental and maternal effects are more sensitive endpoints in rodents. In 

the absence of the inhalation study, a 10X database uncertainty factor will be applied only for 

assessing risk for inhalation scenarios until a developmental inhalation study is submitted or 

other information is provided to support a waiver. 

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

Absorption of hymexazol from the diet was complete irrespective of sex. Pharmacokinetics of 

absorption, however, was distinct in females and males for both low (40 mg/kg/day) and high 

(1000 mg/kg/day) dose exposures. Female rats absorbed more hymexazol over the exposure 

period at both doses and achieved a higher peak plasma concentration (Cmax – 49.3 and 545 ppm 

at low and high doses, respectively) compared to males (Cmax – 34.9 and 480 ppm at low and 

high doses, respectively). Accordingly, the time to reach the maximum concentration was 

slightly longer in females (Tmax = 1 hr in females vs. 30 minutes in males); however, Tmax was 

independent of dose indicating the rate of absorption scaled with increasing dose. 

An ephemeral difference in hymexazol distribution was apparent in males and females 

throughout the first day after dosing. At the low oral dose, female rats were observed to have 

greater concentrations of radioactivity in blood, bone, brain, fat, and heart compared to males 30 

minutes post-dose. Males, by contrast, showed greater concentrations in liver. A similar sexspecific idiosyncratic distribution pattern was observed at 1 hour in high dose exposures, though 
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the difference in tissue concentration between sexes were not as stark. At both dose levels the 

distribution disparity between sexes persisted for 24 hours, after which tissue concentrations 

were equivalent.

The route of elimination was identical for males and females despite initial differences in 

distribution. Urinary excretion is the dominant route of elimination for both sexes (>90%) with 

minimal fecal elimination at low doses that increased slightly at higher doses. No significant 

effects of repeated oral dosing were observed on the total percentage excreted by urine or feces. 

Elimination was rapid in both sexes at the low dose and was delayed slightly at the high dose. At 

both dose levels, females (t1⁄2 = 14.1 - 21.4 hr) eliminated hymexazol slower than males (t1⁄2 = 

4.25 - 7.25 hr). The recalcitrant nature of the high dose implies a saturation of elimination 

mechanisms. Regardless, a majority of the administered dose was excreted within 24 hours and 

was near completely eliminated after 7 days. Tissue accumulation was minimal (<1% of 

administered dose) and primarily sequestered in the carcass (0.22-0.34%) and fat (<0.01%) in all 

sexes at both dose levels. The concentration in the carcass and fat were higher in the females 

compared to males which may explain the longer half-life. 

Parent hymexazol and four metabolites were detected in urine and/or feces and tissues. The 

metabolites consisted of the sulfate and glucuronide conjugates of hymexazol, as well as the 

oxidative metabolites 3-hydroxybutanamide and 3-hydroxybutyric acid. In urine, the sulfate and 

glucuronide conjugates were identified as the major metabolites, with the sulfate predominating 

at the low dose level, while the glucuronide predominated at the high dose. In feces, parent 

compound was detected only in male rats. In blood, the percentages of hymexazol sulfate and 

hymexazol glucuronide were approximately equal in male rats over the first 2 hours post-dose at 

the low dose. In female rat blood, however, the percentage of hymexazol glucuronide increased 

from 28 to 52% of sample radioactivity within the first 2 hours. Liver and kidney were found to 

contain both conjugated as well as oxidative hymexazol metabolites within 30 minutes after dose 

administration. A minor pathway involves enzymatic reduction of hymexazol to 3-

hydroxybutamide, 3-hydroxybutyric acid, carbon dioxide, and possible natural products.

4.2.1 Dermal Absorption

The guideline dermal study was not used to set endpoints for the dermal assessment because the 

study did not address concerns for fetal sensitivity described in the rat developmental study. 

Instead, an oral endpoint from the reproduction study was selected to be protective of potential 

developmental effects. A dermal absorption study was not submitted for hymexazol; therefore, a 

conservative DAF of 100% was used in lieu of an empirically derived value. The physicochemical data and endpoints from the guideline studies could not be used to reduce the DAF to 

less than 100% and no structurally related chemicals were found in the database to inform the 

DAF derivation.

4.3 Toxicological Effects

Hymexazol is an oxazole fungicide that limits fungi growth through inhibition of RNA and DNA 

synthesis. In mammals, the primary target organ of hymexazol and the organismal response were

species specific; however, the mode of action is currently unknown. Dogs were the most 

sensitive adult non-pregnant animal. Subchronic oral exposure targeted the thyroid leading to 
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increased absolute and relative thyroid weight accompanied by minimal increase in epithelial 

height and minimal to moderate thyroid epithelial hyperplasia. Thyroid effects were only 

observed in dogs. Adult rabbits were comparatively less sensitive to hymexazol exposure; 

however, their response to exposure was unique from the other species. Mortality was observed 

during gestation in rabbits exposed to approximately twice the dose required to elicit the thyroid 

effects in dogs. Surviving female rabbits exhibited abnormal clinical signs (unsteadiness, 

slumped posture, increased respiration, and salivation) after the first dose and within an hour post 

dose. The internal concentration is predicted to peak at 1 hour, which is consistent with the onset 

of this acute response. Transient decreased food consumption and periods of body weight loss 

during the first two day exposure period further compromised the health of the pregnant rabbits 

and likely contributed to the developmental malformations in the young discussed below. Adult 

non-pregnant rodents were the least sensitive to oral hymexazol exposure requiring dietary doses 

at least 2x greater than rabbits and dogs to elicit liver (increased liver weight with associated 

centrilobular hepatocyte enlargement and granulomatous inflammation, elevated liver enzymes 

in serum) effects and significant reductions in body weight and body weight gain. High oral 

doses were also required to induce acute toxicity in rodents (Category III). Rodents were, 

however, susceptible to acute ocular exposure which manifested in severe eye irritation, and 

corneal opacity with hyperaemic blood vessels (Category I). Rapid elimination and low 

accumulation of ingested hymexazol limited progression of toxicity with increased exposure 

duration in all species tested. 

Pregnant rats and rabbits, and their developing fetuses exhibited enhanced sensitivity to 

hymexazol exposure relative to non-pregnant adult rodents. Gavage fed rat dams produced 

fetuses with reductions in ossification of the cervical, thoracic, lumbar, & caudal vertebrae, as 

well as in the pelvic girdle & in the fore- & hind- extremities (metacarpals & metatarsals), 

significantly increased incidence of bilateral 14th ribs, and reduced body weight without signs of 

maternal toxicity at 500 mg/kg/day. At a similar dose, fetal rabbits exhibited distinct effects in 

the heart (heart/great vessel malformations, particularly incomplete inferior vena cava), along 

with reduced fetal weight and increased incidence of reduced sternebrae. Contrary to the rats,

these effects were observed in concert with maternal toxicity (mortality, body weight loss and 

clinical signs described above) and, therefore, were not indications of susceptibility in 

developing rabbits. Dietary exposure at 159 mg/kg/day in the F0 and F1 rats from the pre-mating 

period through parturition caused a reduction in post implantation survival and litter size in the 

F1 and F2 offspring. The post-implantation loss and its subsequent impact on litter size were

attributed to both compromised health in the dams and in utero exposure. Reproduction was not 

affected by hymexazol exposure up to 159 mg/kg/day. 

Hymexazol is a skin sensitizer; however, dermal exposure did not irritate the skin (dermal 

irritation: Category IV) and high dermal doses were required to elicit acute (Category III) and 

subchronic systemic toxicity.

Other critical physiological systems (neurological, immune, and respiratory) were not principle 

targets of hymexazol. Neurological effects, decreased brain weight and cerebral length in males, 

were equivocal and only evident near the limit dose. The respiratory system was unaffected in 

oral and dermal exposures and rats were relatively tolerant of acute inhalation exposures 

(Category III). No effects on the immune system were observed in an oral exposure up to the 

limit dose.
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4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

Hymexazol is not a food-use chemical and has no tolerances set based upon plant metabolism 

data, which showed it to be metabolized to carbon dioxide (CO2) and incorporated into sugars. 

Therefore, FQPA does not apply.

4.4.1 Completeness of the Toxicology Database

The toxicity database is adequate for assessing the susceptibility of infants and children to 

hymexazol exposure. Qualitative and quantitative susceptibility at critical developmental life 

stages was addressed in two guideline developmental studies, and a 2 generation reproduction 

study. Additionally, a neurotoxicity battery and immunotoxicity study were available to assess 

unique toxicity in these systems. An inhalation study is not available for assessing route specific 

toxicity and may have implications on infant and child exposure. Based on a weight of evidence 

approach, the HASPOC recommended that a subchronic developmental inhalation study should 

be required (TXR 0057244). The decision was made after careful consideration of all the 

available hazard and exposure information including: 1) worst case inhalation MOE of 300 for 

workers without respiratory protection operating at the maximum single seed treatment 

application rate, 2) the adequate ventilation requirement is not well defined on the label and 

cannot be factored into risk estimates, and 3) developmental and maternal effects are more 

sensitive endpoints in rodents. In the absence of this study, a 10X database uncertainty factor 

will be applied only for assessing risk for inhalation scenarios until an inhalation study is 

submitted or other information is provided to support a waiver.

4.4.2 Evidence of Neurotoxicity

There was evidence of neurotoxicity in the subchronic neurotoxicity (SCN) study; however, 

concern is low as the effects were only seen in males at a dose approaching the limit dose, the 

effects have clear NOAEL/LOAEL values, there were no other effects on the nervous system 

observed in the database, and the risk assessment endpoints chosen are protective for these

effects. 

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

Developing rats were qualitatively and quantitatively more sensitive to hymexazol exposure 

compared to adults in the developmental rat study; however, concern for infant and young 

animal susceptibility is low. Clear NOAELs and LOAELs were established in both 

developmental studies and the 2 generation reproduction study and the selected endpoints are 

protective for these effects (see section 4.5.1).

4.5 Toxicology Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment
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Toxicity endpoints and points of departure (PODs) for dietary and non-dietary exposure 

scenarios to hymexazol are summarized below. Detailed descriptions of the studies used as a 

basis for the selected endpoints are presented in Appendix A.

An acute reference dose (aRfD) for the general population was established at 1.5 mg/kg/day 

based on acute maternal effects in the rabbit developmental study. The NOAEL for the maternal 

effects was 150 mg/kg/day based on mortality, abnormal clinical signs (unsteadiness, slumped 

posture, increased respiration and salivation) within an hour after the first dose, and decreased 

food consumption and body weight loss within 2 days of initial exposure at the LOAEL of 450 

mg/kg/day. These were the only acute effects observed across the gamut of submitted studies. 

The POD derived from this NOAEL is protective of acute developmental effects observed in the 

rat developmental study. The post implantation loss observed in the 2-generation reproduction 

study was also not used as a dietary POD for women 13-49. Post-implantation loss was not 

observed at a similar dose in the shorter duration rat development study indicating this effect 

required a longer exposure duration to manifest. A UF 100x (10x to account for interspecies 

extrapolation and 10x for intraspecies variation) was applied to the NOAEL to calculate the 

aRfD. 

A chronic reference dose (cRfD) was established at 0.31 mg/kg/day based on adverse offspring 

effects observed in the F1 and F2 offspring at the LOAEL in the two generation reproductive 

study. The NOAEL for the offspring effects was 31 mg/kg/day based on reduced postimplantation survival rate and decreased litter size at the LOAEL of 159 mg/kg/day. The 

offspring NOAEL in the reproduction study is the lowest POD in the toxicity database and is 

protective of the developmental effects observed at higher doses (450-500 mg/kg/day) in the rat 

and rabbit development study and the thyroid effects observed in the subchronic dog study. A UF 

100x (10x to account for interspecies extrapolation and 10x for intraspecies variation) was 

applied to the NOAEL to calculate the cRfD. 

The offspring NOAEL from the two general reproduction study was used to set points of 

departure (POD) for the short- (1-30 days) and intermediate-term (1-6 months) dermal exposures 

as well. The submitted dermal study did not examine potential developmental impacts from the 

dermal exposure that were observed in the developmental and reproduction studies. No dermal 

absorption study was submitted; therefore, a DAF of 100% was assumed for the exposure 

assessment. A 100x UF (10x to account for interspecies extrapolation and 10x for intraspecies 

variation) was applied to the NOAELs for these exposures. 

In the absence of a route specific study, the offspring NOAEL from the two general reproduction 

study was used for the short- (1-30 days) and intermediate-term (1-6 months) inhalation 

exposures. Toxicity from inhalation was assumed to be equivalent to an oral exposure. A 1000x 

UF (10x to account for interspecies extrapolation, 10x for intraspecies variation, and 10x 

database uncertainty factor) was applied to the NOAELs for these exposures as well. The 

HASPOC determined that a subchronic developmental inhalation study is required for 

hymexazol; therefore, a 10X database uncertainty factor was applied for assessing inhalation 

scenarios until a developmental inhalation study is submitted or other information is provided to 

support a waiver.

4.5.2 Recommendations for Combining Routes of Exposure for Risk Assessment
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When there are potential residential exposures to the pesticide, risk assessment must consider 

exposures from three major sources: oral, dermal and inhalation exposures. If the toxicity 

endpoints for dermal, oral, and inhalation routes of exposure are similar, the exposure or risk 

estimates from these exposure routes need to be combined. Exposure routes are combined in 

Section 11 (the worker assessment) because toxic effects are common between the inhalation and 

dermal routes of exposure. A total aggregated risk index (ARI) was used since the LOC values 

for dermal exposure (100) and inhalation exposure (1000) are different. 

4.5.3 Cancer Classification and Risk Assessment Recommendation

There is no evidence linking hymexazol to a carcinogenic and mutagenic mode of action. Rats 

and mice exposed to hymexazol at high doses (>500 mg/kg/day) for two years did not develop 

neoplastic tumors and no signs of mutagenicity were reported in gene mutation, mouse 

lymphoma, or micronucleus assays. In accordance with the Agency’s 2005 Guideline for 

Carcinogen Risk Assessment, the hymexazol team has classified hymexazol as “Not Likely to be 

Carcinogenic to Humans”. 

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

A summary of points of departure used in the hymexazol dietary/non-occupational (Table 

4.5.4.1) and occupational (Table 4.5.4.2) human health risk assessment are presented below. 

Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Hymexazol for Use in Dietary and NonOccupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary

(General 

Population)

NOAEL = 

150 

mg/kg/day

UFA= 10x

UFH=10x

aRfD = 1.5

mg/kg/day

Developmental – rabbit

Maternal LOAEL = 450 mg/kg/day 

based on mortality, abnormal clinical 

signs (unsteadiness, slumped posture, 

increased respiration, and salivation) 

within an hour of dosing, and decreased 

food consumption and body weight loss 

within 2 days of initial exposure

Acute Dietary

(Females 13-

49)

An acute RfD specific to Females 13-49 was not calculated because no effect attributable to a 

single day oral exposure that would be specific to this population subgroup was observed in the 

toxicity database including the developmental and reproduction studies.

Chronic 

Dietary (All 

Populations)

NOAEL = 

31 

mg/kg/day

UFA= 10x

UFH=10x

cRfD = 0.3 

mg/kg/day

2-generation reproduction – rat

Parental/Offspring LOAEL = 159 mg/kg 

based on increase in post-implantation 

loss, decrease in litter size
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Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Hymexazol for Use in Dietary and NonOccupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Incidental 

Oral, Dermal, 

Inhalation

There are no registered residential uses for hymexazol and no residential exposures anticipated 

from application adhering to the labels of registered uses. 

Cancer (oral, 

dermal, 

inhalation)

Hymexazol is not carcinogenic in long term studies with rats and mice and not mutagenic in the 

gene mutation, mouse lymphoma, and micronucleus assays. In accordance with the Agency’s 

2005 Guideline for Carcinogen Risk Assessment, hymexazol is classified as “Not Likely to be 

Carcinogenic to Humans”.

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 (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). RfD = reference dose. N/A = not applicable.

Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Hymexazol for Use in Occupational 

Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Dermal 

Short- and 

IntermediateTerm 

NOAEL = 

31 

mg/kg/day

UFA=10x

UFH=10x

LOC for MOE = 

100

2-generation reproduction – rat

Parental/Offspring LOAEL = 159 mg/kg 

based on increase in post-implantation 

loss, decrease in litter size

Inhalation 

Short- and 

IntermediateTerm

NOAEL = 

31 

mg/kg/day

UFA=10x

UFH=10x

UFDB=10x

LOC for MOE = 

1000

2-generation reproduction –rat

Parental/Offspring LOAEL = 159 mg/kg 

based on increase in post-implantation 

loss, decrease in litter size

Cancer 

(dermal, 

inhalation)

Hymexazol is not carcinogenic in long term studies with rats and mice and not mutagenic in the 

gene mutation, mouse lymphoma, and micronucleus assays. In accordance with the Agency’s 

2005 Guideline for Carcinogen Risk Assessment, hymexazol is classified as “Not Likely to be 

Carcinogenic to Humans”.

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 (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of 

concern. N/A = not applicable.

4.6 Endocrine Disruption

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

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

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

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

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

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 
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and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

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

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

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

hazard database. However, as required by FFDCA section 408(p), TCVP is subject to the 

endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 

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

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect.

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

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

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

chemicals identified for EDSP screening was published on June 14, 20133and includes some 

pesticides scheduled for Registration Review and chemicals found in water. Neither of these lists 

should be construed as a list of known or likely endocrine disruptors. 

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

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

website.4

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The nature of the residue in plants is adequately understood based on a sugar beet metabolism 

study that was submitted. Normally, the uptake of radioactivity would lead the Agency to 

conclude that the treatment of sugar beet seeds is a food use. However, considering the low level 

of activity and the substantial evidence that hymexazol has been metabolized/degraded to carbon 

dioxide (CO2), which in turn, is incorporated into sugars, the Agency considers the treatment of 

sugar beet seeds with hymexazol to be a non-food use for the registration of this seed treatment

(D200191, J. Morales, 04/04/1994).

 

3

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

chemicals.

4 http://www.epa.gov/endo/
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Data pertaining to livestock metabolism are not required to support hymexazol use on sugar beet 

seeds.

5.1.2 Summary of Environmental Degradation

The biodegradation of hymexazol is found to be a relatively rapid process. Its chemical species 

are short-lived and transient. The end products are carbon dioxide (CO2) under aerobic 

conditions and methane (CH4) under anaerobic conditions. The metabolite 5-methyl-2(3H)-

oxazolone was proposed as a possible intermediate in the degradation of hymexazol to CO2, but 

it was not identified in the aerobic soil metabolism study (D428894, J. Wolf, 09/02/2015).

5.1.3 Comparison of Metabolic Pathways

As mentioned in the previous section, the biodegradation of hymexazol was found to be a rapid 

process forming carbon dioxide (CO2) under aerobic conditions and methane (CH4) under 

anaerobic conditions. In plants, the submitted sugar beet metabolism study showed that 

hymexazol is metabolized to carbon dioxide (CO2) and incorporated into sugars. Rat metabolism 

data are also available which show the excretion of hymexazol derived radioactivity is largely 

through urine. The metabolites of hymexazol identified in this study include the glucuronic acid 

and sulfate conjugates of hymexazol, and the oxidative metabolites 3-hydroxybutamide and 3-

hydroxybutyric acid. Urine showed mainly hymexazol conjugates, while oxidative metabolites 

were found in liver and kidney of both sexes.

5.1.4 Residues of Concern Summary and Rationale

There are no uses for hymexazol which require residues of concern to be established for 

tolerance enforcement and risk assessment on food/feed crops and/or livestock. Dietary 

exposure may occur through drinking water. Because there are no toxic degradates and no new 

fate data have been received, the Risk Assessment Branch (RAB) V/VII risk assessment team 

has concluded that parent hymexazol only is the residue included in risk assessment for drinking 

water.

5.2 Food Residue Profile

The residue chemistry database is complete in supporting the use of the fungicide hymexazol for 

treating sugar beet seeds. A metabolism study was provided which demonstrated that hymexazol 

is a non-food-use chemical since it is metabolized to carbon dioxide (CO2) and incorporated into 

sugars (D200191, J. Morales, 04/04/1994). No additional residue chemistry data are thus 

required. The registered use will not result in residues on food.

5.3 Water Residue Profile

Drinking water exposure is considered since hymexazol is used outdoors as a seed treatment for 

sugar beets. The EDWCs used for dietary analyses were provided by EFED in the memorandum 

“Hymexazol: Drinking Water Assessment for Registration Review” (D428894, J. Wolf, 

09/02/2015). This drinking water assessment completed by EFED was conducted for parent 
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hymexazol only since there are no degradates of concern. The resulting EDWCs determined for 

hymexazol were incorporated into the DEEM-FCID program for analysis in the food categories 

“water, direct, all sources” and “water, indirect, all sources.” 

To estimate EDWCs, models including the Surface Water Concentration Calculator (SWCC) for 

surface water and PRZM-GW for groundwater were used. The assessment was based on the 

maximum seeding rate for sugar beets which results in application rates of 0.126 to 1.25 lb ai/A. 

The method of hymexazol chemical application is by seeding with incorporation or drilling 

which is assumed to be 7-days before crop emergence with zero spray drift since the pesticide is 

applied directly to the seed. Because there is no leeching study available, the EFED analyses 

assume that 100% of the hymexazol product applied to the seed will be available for leeching 

and runoff. 

EFED modeling found groundwater exposure concentrations to be higher than surface water 

estimates. Based upon groundwater modeling analysis using the Wisconsin central sands 

scenario, the recommended EDWCs for risk assessment were calculated to be 66.6 ppb for the 

peak, and 54.5 ppb for the chronic exposure. These models and their descriptions are available 

at the EPA internet site: http://www.epa.gov/oppefed1/models/water/. 

The recommended EDWCs for hymexazol calculated by EFED for risk assessment are 

summarized below in Table 5.3.

Table 5.3. Estimated Drinking Water Concentrations (EDWCs) for Hymexazol.

Drinking Water Source

[Model]

Scenario

[application rate]

Acute Chronic Cancer

Surface Water (SWCC)a MN Sugar Beets

[1.25 lb a.i./A]

1-in-10 yr 30-yr 

Avg.

μg/L

32.80 7.69 2.67

Groundwater (PRZM-GW) WI Central Sands Highest daily Conc. Post breakthrough Avg

[1.25 lb a.i./A] 66.6 54.5

a PCA was not applied since groundwater is greater than surface water.

5.4 Dietary Risk Assessment

5.4.1 Overview of Residue Data Used

Given that the only use of hymexazol is commercial sugar beet seed, there are no food or feed 

uses that require the establishment of tolerances. However, there is potential for hymexazol to 

reach drinking water sources through its outdoor application to sugar beet seeds which requires a 

drinking water assessment to be performed. Therefore, the dietary assessment conducted for 

hymexazol is performed using model-derived EDWCs. 

5.4.2 Percent Crop Treated Used in Dietary Assessment

Percent crop treated information is not relevant for analysis because a food dietary assessment is 

not required for hymexazol. 

5.4.3 Acute Dietary Risk Assessment
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The acute dietary (drinking water only) exposure analysis and risk assessment conducted is a 

conservative determination using model-derived EDWCs for all direct and indirect water sources 

provided by the Environmental Fate and Effects Division (EFED). It was conducted for the 

general U.S. population and all population subgroups since an acute toxicological endpoint was 

identified for all populations. The acute risk estimates were well below the Agency’s level of 

concern (LOC) (i.e., <100% of the acute reference dose (aRfD)). The estimated risk for 

hymexazol from drinking water for the general U.S. population and all population subgroups 

exposure is <1% of the aRfD at the 95

th percentile. 

5.4.4 Chronic Dietary Risk Assessment

The chronic dietary (drinking water only) exposure and risk assessment is also considered 

conservative and is based on model-derived EDWCs for all direct and indirect water sources. It 

was conducted for the general U.S. population and all population subgroups since a chronic 

toxicological endpoint was identified for all populations. The chronic dietary risk estimates for 

hymexazol are below the Agency’s level of concern for the general U.S. population and all 

population subgroups. For the general U.S. population and all population subgroups exposure is

<1% of the chronic reference dose (cRfD). 

5.4.5 Cancer Dietary Risk Assessment

A cancer dietary exposure and risk assessment was not conducted since hymexazol is not likely 

to be carcinogenic to humans.

5.4.6. Dietary Assessment Summary Tables

The results of the acute and chronic drinking water only dietary exposure analysis is reported in 

Table 5.4.6. Risks do not exceed the Agency’s level of concern. 

Table 5.4.6. Summary of Dietary (Drinking Water) Exposure and Risk for the Hymexazol.

Population Subgroup

Acute Dietary1

(95th Percentile) Chronic Dietary2

Dietary Exposure 

(mg/kg/day) % aRfD Dietary Exposure(mg/kg/day) % cRfD

General U.S. Population 0.003631 <1 0.001141 <1

All Infants (< 1 year old) 0.011374 <1 0.002943 <1

Children 1-2 years old 0.005600 <1 0.001646 <1

Children 3-5 years old 0.004544 <1 0.001387 <1

Children 6-12 years old 0.003472 <1 0.001000 <1

Youth 13-19 years old 0.003024 <1 0.000832 <1

Adults 20-49 years old 0.003574 <1 0.001139 <1

Adults 50-99 years old 0.003183 <1 0.001126 <1
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Table 5.4.6. Summary of Dietary (Drinking Water) Exposure and Risk for the Hymexazol.

Population Subgroup

Acute Dietary1

(95th Percentile) Chronic Dietary2

Dietary Exposure 

(mg/kg/day) % aRfD Dietary Exposure(mg/kg/day) % cRfD

Females 13-49 years old NA NA 0.001134 <1

1 Acute dietary analysis derived from a 1.5 mg/kg/day aRfD for the general population.

2 Chronic dietary analysis derived from a 0.31 mg/kg/day cRfD for the general population.

3 Highest exposures found for each assessment are noted in bold.

4 NA – “Not assessed” because no attributable effect was identified

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

6.1 Residential Handler Exposure

HED uses the term “handlers” to describe those individuals who are involved in the pesticide 

application process. There are currently no registered or proposed residential uses for 

hymexazol; therefore, a residential handler assessment was not performed. 

6.2 Post-Application Exposure

There are currently no registered or proposed residential uses for hymexazol; therefore, a 

residential post-application assessment was not performed. 

7.0 Non-Occupational Spray Drift Exposure and Risk Estimates

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

appropriate, 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. In the case of hymexazol, the only registered use is commercial seed treatment. 

Planting pelleted seed treated with hymexazol is not anticipated to result in spray drift. 

8.0 Non-Occupational Bystander Post-Application Inhalation Exposure and Risk 

Estimates

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

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

related to volatilization of pesticides from its FIFRA SAP in December 2009, and received the 

SAP’s final report on March 2, 2010.

5

 The Agency has evaluated the SAP report and has 

developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis.

6

 

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

studies) or further analysis are required for hymexazol.

9.0 Aggregate Exposure/Risk Characterization

 

5 http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

6 http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219
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In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. 

Although there is the potential for hymexazol to enter drinking water sources from the nonfood 

use on seeds, there are no food or residential uses or exposures; therefore, aggregate exposure 

includes only exposure from drinking water. There are no risks of concern for hymexazol in 

drinking water.

10.0 Cumulative Exposure/Risk Characterization

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 hymexazol and any other substances; additionally, hymexazol does not appear to produce a 

toxic metabolite produced by other substances. For the purposes of this action, therefore, EPA 

has not assumed that hymexazol 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 website7.

11.0 Occupational Exposure/Risk Characterization

11.1 Short- and Intermediate-Term Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct job functions or tasks related to 

applications and exposures can vary depending on the specifics of each task. Job requirements 

(amount of chemical used in each application), the kinds of equipment used, the target being 

treated, and the level of protective gear or controls used by a handler can cause exposure levels 

to differ in a manner specific to each application event. 

Based on the existing seed treatment registration (sugar beet), occupational handler exposure is 

expected. Occupational seed treatment handlers may experience short- and intermediate-term 

exposure to hymexazol while performing seed treatment activities in commercial settings. In 

addition, occupational handlers may experience short- and intermediate-term exposure while 

planting hymexazol-treated seeds (for the purposes of seed treatment risk assessment, planting 

treated seeds are referred to as ‘secondary handlers’). 

Treating Seed (Primary Handler)

Potential occupational exposure scenarios from the use of hymexazol as a commercial 

seed treatment include: mixing, loading, applying wettable powder formulations; bagging 

treated seed; sewing bags; and multiple activities. Typically, for large-scale commercial 

seed treatments, workers perform only those specific individual tasks listed above; 

however, it is assumed that workers also may perform multiple activities throughout the 

day. As a result a “multiple activities” scenario (i.e. where one worker performs all seed

 

7 Available: http://www.epa.gov/pesticides/cumulative/
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treatment tasks such as loading/applying, sewing, bagging, cleaning, calibration, repair, 

forklift driver, etc.) was addressed.

Planting Treated Seed (Secondary Handler)

Potential occupational exposure scenarios from the use of hymexazol as a commercial 

seed treatment include planting treated seed (secondary handler). Planting treated seed 

consists of the farmer purchasing bags of treated seed, placing the seed in the hopper and 

applying seed to fields.

The quantitative exposure/risk assessment developed for occupational handlers is based on the 

following scenarios:

 Mixer – wettable powder slurry

 Mixing/loading/applying wettable powders;

 Bagging treated seeds;

 Sewing bags with treated seeds;

 Multiple (commercial) seed treatment activities; and,

 Planting treated seeds.

Occupational Handler Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational 

handler risk assessments. Assumptions and factors, as well as algorithms used to estimate noncancer exposure and dose for occupational handlers, are detailed in the most recent ORE memo 

(Lloyd, 2015, D429298). 

Based on the registered use pattern for hymexazol (commercial seed treatment only), short- and 

intermediate-term exposures are expected, and the POD selected for dermal/inhalation risk 

assessment is protective of both exposure durations. Long-term exposures are not anticipated.

The maximum single application rate for sugar beet seed treatment is the “standard pellet” 

scenario. A lower application rate (“minimum buildup” scenario) is also an option based on the 

label, although it is rarely used in commercial seed treatment practice.

Applicators and mixer/loaders who handle hymexazol, such as in commercial seed treatment 

facilities, must wear long-sleeved shirt and long pants, chemical-resistant gloves made from 

any waterproof material, shoes plus socks, protective eyewear, and in the absence of adequate 

ventilation or dust control systems, a non-powered air purifying respirator equipped with a Ror P- series filter. Baggers and other persons who handle treated seed, such as in commercial 

seed treatment facilities, must wear the same protection as applicators and mixer/loaders minus 

the chemical resistant gloves.

Combining Exposures/Risk Estimates

Exposure routes are combined because toxic effects are common between the inhalation and 

dermal routes of exposure. A total aggregated risk index (ARI) was used since the LOC values 

for dermal exposure (100) and inhalation exposure (1000) are different. The target ARI is 1; 

therefore, ARIs of less than 1 are risk estimates of concern. The aggregate risk index (ARI) was 

calculated as follows.
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Aggregate Risk Index (ARI) = 1÷ [(Dermal LOC ÷ Dermal MOE) + (Inhalation LOC ÷ Inhalation MOE)]

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates

Occupational handler risk estimates are presented below in Table 11.1 (seed treaters) and 11.2 

(secondary planters). The occupational handler risk estimates for seed treatment are presented for 

the “standard pellet” application scenario (the maximum application rate). 

The results of the occupational handler exposure and risk assessment indicate that short- and 

intermediate-term combined dermal and inhalation risk estimates exceed HED’s LOC in some 

cases. Risk estimates of concern were identified for the following “standard pellet” scenarios:

 Mixer (wettable powder) – combined ARI of 0.22

 Multiple Activities (w/o gloves) – combined ARI of 0.87

Overall, dermal MOEs range from 76 to 2,100 for seed treaters (LOC = 100). The multiple 

activities (w/o gloves) scenario has a combined ARI below 1 (0.87) because the dermal MOE is 

97. Inhalation MOEs range from 300 to 81,000 for seed treaters (LOC = 1,000). For the mixer 

scenario, the addition of a filtering facepiece respirator (PF5) results in an inhalation MOE of 

1,500, although the ARI is still below 1. Combined risk estimates for the wettable powder mixer 

exceed the ARI LOC of 1 only when engineering controls (i.e., water soluble packets) are 

considered.
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Table 11.1 Summary of Short- and Intermediate-Term Handler Exposures and Risks for Hymexazol Seed Treatment

Seed Type

[sugarbeet]

Max Application 

Rate1

Unit Exposure2

(mg/lb ai)

Amount of 

Seed Treated3

Absorbed Dose

(mg/kg/day)4 MOE5

Total ARI6

lb ai/lb seed Dermal Inhal. lb seed/day Dermal Inhal.

Dermal

(LOC = 100)

Inhal.

(LOC = 1,000)

Mixer - Wettable Powder (single layer, gloves, no respirator)

Standard Pellet 0.056 0.170 0.0434 3,000 0.41 0.104 76 300 0.22

Mixer - Wettable Powder (double layer, gloves, no respirator)

Standard Pellet 0.056 0.130 0.0434 3,000 0.31 0.104 100 300 0.23

Mixer - Wettable Powder (double layer, gloves, PF5 respirator)

Standard Pellet 0.056 0.130 0.00868 3,000 0.31 0.021 100 1500 0.6

Mixer - Wettable Powder (water soluble packets, no respirator)

Standard Pellet 0.056 0.0098 0.0434 3,000 0.023 0.001 1,300 54,000 10.5

LOADER/APPLICATOR (single layer, gloves7)

Standard Pellet 0.056 0.023 0.00034 3,000 0.055 0.001 560 38,000 4.9

SEWER (single layer, no gloves)

Standard Pellet 0.056 0.0062 0.00023 3,000 0.0173 0.0006 2,100 56,000 15.3

BAGGER (single layer, no gloves)

Standard pellet 0.056 0.0091 0.00016 3,000 0.02532 0.00045 1,400 81,000 11.9

MULTIPLE ACTIVITIES (combination of loader/applicator without gloves7 + no coveralls, sewer without gloves, stacker without gloves)

Standard pellet 0.056 0.134 0.0016 3,000 0.320 0.0038 97 8,100 0.87

MULTIPLE ACTIVITIES (combination of loader/applicator with gloves7 + no coveralls, sewer with gloves, stacker with gloves)

Standard pellet 0.056 0.042 0.0016 3,000 0.100 0.0038 310 8,100 2.2

1 Application Rates based on existing label uses for hymexazol (see Table 4.1).

2 Unit Exposures from HED Exposure Science Advisory Council Policy 14.

3 HED default for lb seed treated per day from HED Exposure Science Advisory Council Interim Policy 15.1 and the BEAD memo “Acres Planted Per Day and Seeding Rates of Crops Grown in the United States” (J. Becker, 

March 2011).

4 Daily Absorbed Dose (mg/kg/day) = daily unit exposure (mg/lb ai) × application rate (lb ai/lb seed) × amount treated (lb seed/day) × Absorption (100% for dermal, 100% for inhalation) ÷ body weight (69 kg adult female for 

dermal exposure due to sex-specific toxicity; 

5 MOE = NOAEL (dermal = 31 mg/kg/day for short- and intermediate-term exposure; inhalation = 31 mg/kg/day for short- and intermediate-term) ÷ Absorbed Dose (mg/kg/day). LOC = 100.

6 ARI = Aggregate Risk Index = 1÷ [(Dermal LOC ÷ Dermal MOE) + (Inhalation LOC ÷ Inhalation MOE)].

7 Available data represents workers wearing chemical-resistant gloves and other label-represented PPE. 
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Table 11.2. Summary of Secondary Handler (Planter) Exposure and Risk Estimates for Hymexazol (Single 

Layer, Gloves during Loading Only).

Seed 

Type

Max 

Application 

Ratea

Unit Exposureb

(mg/lb ai)

Amount 

of Seed 

Planted 

Per 

Dayc

Absorbed Dose

(mg/kg/day) d MOEe

Total ARIf

lb ai/lb seed Dermal Inhal. lb 

seed/day Dermal Inhal.

Dermal

(LOC = 

100)

Inhal.

(LOC = 

1,000)

Standard 

Pellet 0.056 0.25 0.0034 871 0.174 0.0024 180 13,000 1.6

a Application Rates based on proposed label uses for hymexazol (see Table 4.1).

b Unit Exposures from HED Exposure Science Advisory Council Policy 14: Standard Operating Procedures for Seed Treatment. Available data 

represents workers wearing chemical-resistant gloves. Unit exposures representing workers without chemical-resistant gloves were calculated 

by increasing exposure to the hands-only portion of the total dermal exposure measurement assuming chemical-resistant gloves provide 90% 

protection (i.e., dividing non-gloved hand exposures by 0.1), the standard protection factor assumption for chemical-resistant gloves.

c HED default for lb seed planted per day for sugar beets from HED Exposure Science Advisory Council Interim Policy 15 and the BEAD 

memo “Acres Planted Per Day and Seeding Rates of Crops Grown in the United States” (J. Becker, March 2011).

d Daily Absorbed Dose (mg/kg/day) = daily unit exposure (mg/lb ai) × application rate (lb ai/lb seed) × amount treated (lb seed/day) × 

Absorption (100% for dermal, 100% for inhalation) ÷ body weight (69 kg).

e MOE = NOAEL (dermal = 31 mg/kg/day for short- and intermediate-term exposure; inhalation = 31 mg/kg/day for short- and intermediateterm) ÷ Absorbed Dose (mg/kg/day). LOC = 100.

f ARI = Aggregate Risk Index = 1÷ [(Dermal LOC ÷ Dermal MOE) + (Inhalation LOC ÷ Inhalation MOE)].

11.2 Short- and Intermediate-Term Post-Application Risk

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry 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. 

The potential for dermal and inhalation post-application exposures following the planting of 

hymexazol-treated seeds is unlikely because no routine cultural practices involve sustained 

levels of contact with treated seed after it has been placed in the soil or other planting media.

Commercial treatment of seeds is not within the scope of the Worker Protection Standard. 

Hymexazol is not registered for non-commercial seed treatment and does not require Worker 

Protection Standard labeling.

A post-application inhalation exposure assessment is not required as exposure is expected to be 

negligible.

12.0 Human Incidents

Because there were no reported incident cases for hymexazol in both IDS and SENSORPesticides, there does not appear to be a concern at this time that would warrant further 

investigation (Recore, 2015, D429771). The Agency will continue to monitor the incident 

information and if a concern is triggered, additional analysis will be included in the risk 

assessment.
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13.0 References

EFED DW – Wolf, J. (2015). D428894. Hymexazol. Drinking Water Assessment for 

Registration Review.

Bever, R. (2015). TXR# 0057244. Hymexazol HASPOC Recommendations on the Need for the 

Repeated Dose Inhalation Study.

Lloyd, M. (2015). D429298, Hymexazol: Occupational and Residential Exposure Assessment for 

Registration Review.

Recore, S. and Evans, E. (2015). D429771. Hymexazol: Tier I Update Review of Human 

Incidents/Epidemiology for Draft Risk Assessment

Savoia, P. (2015). D429383. Hymexazol. Acute and Chronic Dietary Exposure and Risk 

Assessments of Drinking Water to Support Registration Review.

Morales, J. (1994). D200191. 048210-R. Hymexazol in/on Sugar Beet Seeds. Determination of 

Food/Non-food Use. CBTS# 13,341. DP Barcode D200191. MRID# 428263-14.
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Appendix A. Toxicology Assessment

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.500) for non-food use for hymexazol are in Table 1. Use of the new guideline 

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

Study

Technical

Required Satisfied

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

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

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

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

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

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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

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

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

870.3200 28-Day Dermal..............................................................

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

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

yes

yes

no

yes

yes1

yes

yes

-

yes

no

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

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

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

yes

yes

yes

yes

yes

yes

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

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

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

870.4200 Oncogenicity (mouse)

870.4300 Chronic/Oncogenicity (rat)

yes

yes

yes

yes

no

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Bacterial reverse mutation assay ....................

870.5300 Mutagenicity—gene mutation test-mammalian ......................

870.53xx Mutagenicity—chromosome aberration test ..........................

870.53xx Mutagenicity—other .....................................................

yes

yes

yes

yes

yes

yes

yes

yes

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

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

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

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

870.6300 Developmental Neurotoxicity .......................................

no

no

waived2

yes

no

NA

NA

-

yes

no

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

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

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

yes

no

yes

yes

NA

yes

1Required by HASPOC (TXR 0057244)

2Waived by HASPOC (TXR 0056409)
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A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile - Hymexazol 

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [rat] 42960008 LD50 = 

M =1600 mg/kg

F = 1700 mg/kg

Both = 1.7 g/kg

III

870.1100 Acute oral [mouse] LD50 = 1700 

mg/kg

870.1200 Acute dermal [rat] 42960009 LD50 > 2000 

mg/kg

III

870.1300 Acute inhalation [rat] 42960010 LC50 > 0.65 mg/L

4 hour, aerosol, 

whole body

III

870.2400 Acute eye irritation [rabbit] 42960011 Severe ocular 

irritant/Severe 

corneal opacity w/ 

hyperaemic blood 

vessels 

I

870.2500 Acute dermal irritation [rabbit] 42997301 Non-irritant IV

870.2600 Skin sensitization [guinea pig] 42960012 Sensitizing 

(MagnussonKligman 

maximization test)

n/a
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Hymexazol

Guideline 

No. 

Study 

Type/Animal 

Species and Strain

MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral 

toxicity (rat)

Crl:CD (SO) BR 

rats

42960013, 42826304 

(rangefinding) (1990)

Acceptable/Guideline

Tachigaren Technical, 

92.7% a.i.; Lot No. 

8033102

0, 1250, 5000 or 20000 

ppm (equivalent to 0, 95, 

371, 1694 mg/kg/day in 

males and 113, 450, 2084 

mg/kg /day in females, 

respectively) via diet for 

13 weeks

LOAEL = 1694 mg/kg/day for males and 

2084 mg/kg/day for females based on 

decreases in body weight gain, food utilization 

efficiency, and urinary volume, pH, and protein 

level, and increases in urinary reducing 

substances, and absolute and relative liver 

weight concurrently with slightly elevated 

levels of SGOT and SGPT and one instance of 

centrilobular hepatocyte enlargement in 

females.

NOAEL = 371 mg/kg/day for males and 450 

mg/kg/day for females 

870.3100 90-Day oral 

toxicity (mouse)

CD-1 mice

42960014 (1990)

Acceptable/Guideline

97.3% a.i.; Batch 3 5050

0, 300, 1200, 5000, or 

20000 ppm (equivalent to 

0, 55, 225, 952, 4006 

mg/kg bw/day in males 

and 76, 326, 1295, 5433 

mg/kg bw/day in females, 

respectively) via diet for 

13 weeks

LOAEL = not established (>HDT)

NOAEL = 4006 mg/kg/day for males and 

5433 mg/kg/day for females

870.3150 90-Day oral 

toxicity (dog)

Pure-bred beagles

42960016 (1990)

Acceptable/Guideline 

92.2% a.i.; Batch number 

90211018

0, 500, 7500 or 22500 

ppm (equivalent to 0, 92, 

286, 885 mg/kg bw/day in 

males and 98, 292, 894 

mg/kg bw/day in females, 

respectively) via diet for 

13 weeks.

LOAEL = 286 mg/kg/day in males and 292 

mg/kg/day in females based on increased 

absolute and relative thyroid weight 

accompanied by minimal increased epithelial 

height and minimal thyroid epithelial 

hyperplasia.

NOAEL = 92 mg/kg/day for males and 98 

mg/kg/day for females
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Hymexazol

Guideline 

No. 

Study 

Type/Animal 

Species and Strain

MRID No. (year)/ 

Classification /Doses

Results

870.3150 90-day oral toxicity 

(dog)

Pure-bred beagles

42960017 (1990)

Acceptable/Guideline

92.2% a.i.; Batch number 

90211018

0, 900, 1500 or 2500 ppm 

(equivalent to 0, 35, 61, 

98 mg/kg bw/day in males 

and 37, 64, 109 mg/kg 

bw/day in females, 

respectively) via diet for 

13 weeks.

LOAEL = not established (> HDT)

NOAEL = 98 mg/kg/day for males and 109 

mg/kg/day for females

870.3200 21-Day dermal 

toxicity (rabbit) No study available

870.3250 90-day dermal 

toxicity study

(rat)

Sprague Dawley 

(Crl:CD (SD) from 

Charles River (UK) 

Ltd

49212101 (2013)

Acceptable/Guideline

99.29% a.i.; Batch 

Number 00315211

0 (purified water), 100, 

300 or 1000 mg/kg/day 

applied to shaved skin, 

covered with gauze and 

left undisturbed for 6 

hrs/day over 13 weeks.

Systemic and Dermal LOAEL = not 

established (> HDT)

Systemic and Dermal NOAEL = 1000 

mg/kg/day for males and females

870.3465 90-Day inhalation 

toxicity (rat) Required but no study available (TXR 0057244)
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Hymexazol

Guideline 

No. 

Study 

Type/Animal 

Species and Strain

MRID No. (year)/ 

Classification /Doses

Results

870.3700 Prenatal 

developmental in 

(rat)

Female CD 

(Sprague-Dawley) 

rats

42826307 & 42826306 

(range-finding) (1989)

Acceptable/Guideline

Tachigaren Technical, 

92.7% a.i.

0, 20, 100, or 500 

mg/kg/day administered 

by gavage on days 6-15 of 

gestation 

Maternal LOAEL = not established (> HDT)

Maternal NOAEL = 500 mg/kg/day 

Developmental LOAEL = 500 mg/kg/day

based on reductions in ossification of the 

cervical, thoracic, lumbar, & caudal vertebrae, 

as well as in the pelvic girdle & in the fore- & 

hind- extremities (metacarpals & metatarsals), 

significantly increased incidence in the percent 

of fetuses with bilateral 14th ribs and reduced 

fetal body weight.

Developmental NOAEL = 100 mg/kg/day 

870.3700 Prenatal 

developmental in 

(rabbit)

Time-mated New 

Zealand White

rabbits

42960022 (1993)

Acceptable/Guideline

99.3% a.i.; Lot no. 

10228211

0, 50, 150, or 450 mg/kg 

bw/day administered by 

gavage in 1% aqueous 

methylcellulose on 

gestation days (GDs) 7 

through 19, inclusive.

Maternal LOAEL = 450 mg/kg bw/day based 

on mortality, abnormal clinical signs 

(unsteadiness, slumped posture, increased 

respiration, and salivation), transient decreased 

food consumption, and body weight loss during 

GDs 7-9. 

Maternal NOAEL = 150 mg/kg bw/day

Developmental LOAEL = 450 mg/kg bw/day 

based on decreased fetal weight, heart/great 

vessel malformations, particularly incomplete 

inferior vena cava, reduced sternebrae, and 

increased supernumerary ribs. 

Developmental NOAEL = 150 mg/kg bw/day 
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Hymexazol

Guideline 

No. 

Study 

Type/Animal 

Species and Strain

MRID No. (year)/ 

Classification /Doses

Results

870.3800 Reproduction and 

fertility effects (rat)

Sprague 

Dawley:CD rats

42826309 (1991)

Acceptable/Guideline

92.2% a.i., lot #90211018

0, 100, 500, or 2500 ppm 

(equivalent to 0, 6.26, 

30.9, and 159 mg/kg 

bw/day for F0 males; 0, 

7.50, 37.5, and 192 mg/kg 

bw/day for F0 females; 0, 

7.74, 37.5, and 193 mg/kg 

bw/day for F1 males; and 

0, 9.04, 43.9, and 230 

mg/kg bw/day for F1

females.) administered via 

diet to F0 and F1 parental 

animals for at least 14 

weeks prior to mating, 

throughout mating (≤21 

days), gestation, and 

lactation, and until 

necropsy after weaning of 

litters on postnatal day 

(PND) 25. 

Parental LOAEL = 159 mg/kg/day for males 

and 192 mg/kg/day for females based on 

reduced post-implantation survival rate and 

litter size

Parental NOAEL = 31 mg/kg/day for males 

and 38 mg/kg/day for females

Offspring LOAEL = 159 mg/kg/day for 

males and 192 mg/kg/day for females based 

on reduced post-implantation survival rate and 

litter size

Offspring NOAEL = 31 mg/kg/day for 

males and 38 mg/kg/day for females

Reproductive LOAEL = not established (> 

HDT)

Reproductive NOAEL = 159 mg/kg/day for 

males and 192 mg/kg/day for females

870.4100 Chronic toxicity

(rat)

See guideline 870.4300

870.4100 Chronic Toxicity 

(Dog) – 1 Year

Pure-bred beagles

42997302 (1992)

Acceptable/Guideline

93.7% a.i.; Batch number 

90211018

0, 100, 500 or 2500 ppm 

(equivalent to 0, 3.55, 17, 

and 87 mg/kg/day in 

males and 0, 3.62, 18.18, 

and 91 mg/kg/day for 

females, respectively) via 

diet for 52 weeks.

LOAEL = not established (> HDT)

NOAEL = 87 mg/kg/day for males and 91 

mg/kg/day for females
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Hymexazol

Guideline 

No. 

Study 

Type/Animal 

Species and Strain

MRID No. (year)/ 

Classification /Doses

Results

870.4200 Carcinogenicity 

(mouse) -

2 years

CD-1

42960019 (1992)

Acceptable/Guideline

92.2% a.i., Batch 

90211018

0, 300, 2500, or 20,000 

ppm (equivalent to 0, 42, 

355, and 2994 mg/kg bw/ 

day for males and 0, 52, 

440, and 3733 mg/kg 

bw/day for females) via 

diet for 104 weeks.

LOAEL = 2994 mg/kg bw/day for males and 

3733 mg/kg bw/day for females based on 

increased absolute and relative liver weights 

with associated liver granulomatous 

inflammation. 

NOAEL = 355 mg/kg bw/day for males and 

440 mg/kg bw/day for females 

At the doses tested, there was not a treatment 

related increase in tumor incidence of any 

tumor type when compared to controls. Dosing 

was considered adequate based on decreased 

body weight and increased liver weights with 

associated histopathological lesions.

870.4300 Combined Chronic 

Toxicity/Carcinoge

nicity (rat) – 2 

Years

Sprague Dawley 

rats

42960018 (1992)

Acceptable/Guideline

92.2 – 93.7% a.i., Lot 

Number 90211018

0, 400, 2000, or 10,000 

ppm (equivalent to 0, 20, 

99, and 532 mg/kg 

bw/day for males and 0, 

28, 149, and 769 mg/kg 

bw/day for females) via 

diet for 104 weeks. 

LOAEL = 532 mg/kg/ day for males and 769 

mg/day based on decreased body weight in 

males and females

NOAEL = 99 mg/kg/day in males and 149

mg/kg/day in females

No incidences of neoplastic effects were 

observed in either sex exposed to the HDT. 

870.5100 Gene Mutation 

(Ames Assay)

Salmonella

typhimurium strains 

TA 98, TA 100, 

TA 1535, TA 1537, 

TA 1538, & 

Escherichia coli 

strain WP2 uvrA 

42960023 (1993)

Acceptable

Tachigaren Technical, 

99.3% a.i.

0, 312.5, 625, 1250, 2500, 

& 5000 μg/plate, with and 

without exogenous 

metabolic activation

Hymexazol was non-toxic to the Salmonella 

strains, but was toxic to the E. coli strain at 

2500 & 5000 μg/plate in the presence and 

absence of S-9. There was no evidence of 

induced revertant colonies over background at 

any dose tested, either with or without S-9 mix.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Hymexazol

Guideline 

No. 

Study 

Type/Animal 

Species and Strain

MRID No. (year)/ 

Classification /Doses

Results

870.5300 Mouse Lymphoma 

Assay

L5178Y mouse 

lymphoma cells

Examined the 

thymidine kinase 

locus

42960024 (1993)

Acceptable

Tachigaren Technical, 

99.3% a.i

500, 750, 1000, 1500, 

1750 or 2000 μg/mL with 

& without Aroclorinduced rat liver S-9 mix. 

No evidence of cytotoxicity or a mutagenic 

effect at the TK locus of L5178Y mouse 

lymphoma cells. 

870.5395 Micronucleus 

Assay

CD-1 mice

42960025 (1993)

Acceptable

Tachigaren Technical 

(99.3% a.i.)

0, 360, 720, or 1440 

mg/kg in 1% (v/v) 

methylcellulose via oral 

gavage 

A vehicle control (20 

mL/kg) and positive 

control (mitomycin C at 

12 mg/kg) were run 

concurrently 

Of 39 mice treated at 1440 mg/kg, 1 male & 3 

females died & were replaced with animals 

from a concurrently treated satellite group. 

Other signs of compound toxicity in the highdose group included piloerection, hunching, 

lethargy, increased respiratory rates, & 

twitching.

The incidence of micronucleated cells/1000 

PCEs was not increased relative to control and 

the ratio of PCE to NCE (normochromatic 

erythrocytes) was not decreased at any dose 

level at any time point assayed.

870.6200 Subchronic 

Neurotoxicity (rat)

Crl:CD®(SD)IGS 

BR rats

48716601 (2006)

Acceptable/Guideline 

99.6%, batch 3128-

2110(D)

0, 1250, 4,000 or 12,500 

ppm (equivalent to 0, 85 

and 107, 287 and 354 or

901 and 1111 mg/kg/day 

for males and females, 

respectively) via diet for 

13 weeks.

LOAEL = 901 mg/kg/day for males and 1111 

mg/kg/day for females mg/kg/day based on 

deaths in females and body weight effects and a 

decrease in brain weight and cerebral length in 

males.

NOAEL = 287 mg/kg/day for males and 354 

mg/kg/day in females. 
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Hymexazol

Guideline 

No. 

Study 

Type/Animal 

Species and Strain

MRID No. (year)/ 

Classification /Doses

Results

870.7485 Metabolism and 

pharmacokinetics

(rat)

male and female 

Sprague-Dawley

42826310 & 43253802

14CHymexazol was 

administered orally in 

water to groups 

(5/sex/dose) of male and 

female Sprague-Dawley 

rats at nominal doses of 

40 mg/kg (single and 

repeated low oral doses; 

IV dose) or 1000 mg/kg 

(single high oral dose). 

These groups were used 

for study of the 

disposition of hymexazol. 

Separate groups (4/sex) 

received hymexazol at 40 

or 1000 mg/kg for serial 

blood sampling to 

examine pharmacokinetics 

and temporal distribution 

of hymexazol. 

Metabolites in urine, 

feces, liver, kidney, and 

blood were characterized.

Absorption of hymexazol from the diet was 

complete irrespective of sex (93-110% of 

administered dose collected in the urine). 

Female rats showed a greater extent of 

absorption, as indicated by a higher area under 

the curve, Cmax, Tmax, & slower elimination 

half-life vs. male rats. Male rats showed an 

initial distribution of hymexazol derived 

radioactivity to the liver at 0.5 hrs post-dose, 

whereas females showed higher concentrations 

in blood, bone, brain, fat, & heart. Excretion of 

hymexazol derived radioactivity was largely 

through urine, where 93-110% of the dose was 

recovered for all dose groups. Fecal elimination 

accounted for only 0.53 - 1.73% of the 

administered low dose and slightly more of the 

high dose (2.59 - 4.47%). At 168 hours postdose, less than 1% of the administered 

radioactivity was found in any tissue of male 

and female rats from any dose group. On a μg/g 

tissue basis, fat and residual carcass were found 

to contain the highest levels of radioactivity, & 

were higher in female rats in all dose groups 

than in males. Metabolites of hymexazol 

identified in this study included the glucuronic 

acid and sulfate conjugates of hymexazol, & 

the oxidative metabolites 3-hydroxybutamide & 

3- hydroxybutyric acid. Urine showed mainly 

hymexazol conjugates, while oxidative 

metabolites were found in liver & kidney of 

both sexes.

Dermal Absorption A dermal absorption study was not submitted 

for hymexazol; therefore, a 100 % dermal 

absorption factor was used in lieu of an 

empirically derived value. The 

physicochemical data and endpoints from the 

guideline studies could not be used to estimate 

the DAF. The low molecular weight precluded 

reducing the DAF to 10% despite a low Kow. 

Likewise, a clear LOAEL was not reported for 

the dermal study and could not be compared to 

LOAEL established in the oral study.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Hymexazol

Guideline 

No. 

Study 

Type/Animal 

Species and Strain

MRID No. (year)/ 

Classification /Doses

Results

870.7800 Immunotoxicity 

(rat)

female Sprague 

Dawley 

48970401 (2012)

Acceptable/ Guideline

99.29% purity, Lot No. 

00315211

0, 3125, 6250, or 12,500 

ppm (equivalent to 0, 289, 

551, and 1023 mg/kg 

bw/day) via diet for 28 

days. 

A concurrent positive 

control group received the 

basal diet, but were 

treated with 50 mg/kg bw 

of cyclophosphamide 

(CPS) by intraperitoneal 

(IP) injection on Day 27 

of the study.

Systemic LOAEL = 1023 mg/kg/day based on 

decreased body weight gains

Systemic NOAEL = 551 mg/kg/day 

Immunotox LOAEL = not established (> 

HDT)

Immunotox NOAEL = 1023 mg/kg/day

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) - Females age 13-49

An acute RfD specific to Females 13-49 was not calculated because no effect attributable to a 

single day oral exposure that would be specific to this population subgroup was observed in the 

toxicity database including the developmental and reproduction studies. The post implantation loss 

observed in the 2-generation reproduction study was not used as a dietary POD for women 13-49. 

Post-implantation loss was not observed at a similar dose in the shorter duration rat development 

study indicating this effect required a longer exposure duration to manifest. Likewise, the 

developmental variations in the rat developmental study could not be unequivocally attributed to 

a single dose. Nevertheless, the acute general population POD is protective of these developmental 

perturbations.

A.3.2 Acute Reference Dose (aRfD) - General Population

Study Selected: Developmental - rabbit

MRID No.: 42960022

Executive Summary: See Appendix A, Guideline [§ 870.3700]

Dose and Endpoint for Risk Assessment: NOAEL = 150 mg/kg/day based on mortality, 

abnormal clinical signs (unsteadiness, slumped posture, increased respiration and salivation) 
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within an hour after the first dose, and decreased food consumption and body weight loss within 2 

days of initial exposure in the dams at the LOAEL = 450 mg/kg/day.

Uncertainty Factors: 100 – 10x for interspecies variation and 10x for intraspecies variation. 

Comments about Study/Endpoint: The post dose clinical signs, and decrease in food 

consumption and body weight loss on gestation days 7-9 in the high dose dams were the only 

treatment-related effects attributable to an acute exposure across the gamut of submitted studies. 

The UF 100x was applied to the NOAEL to calculate the aRfD. 

A.3.3 Chronic Reference Dose (cRfD) 

Study Selected: 2 generation reproduction - rat

MRID No.: 42826309

Executive Summary: See Appendix A, Guideline [§ 870.3800] 

Dose and Endpoint for Risk Assessment: NOAEL = 31 mg/kg/day based on reduced post 

implantation survival and litter size seen at LOAEL = 159 mg/kg/day.

Uncertainty Factors: 100 – 10x for interspecies variation and 10x for intraspecies variation. 

Comments about Study/Endpoint: The offspring NOAEL in the reproduction study is the lowest 

POD in the toxicity database and is protective of the developmental effects observed at higher 

doses (450-500 mg/kg/day) in the rat and rabbit development study and the thyroid effects 

observed in the subchronic dog study. The UF 100x was applied to the NOAEL to calculate the 

cRfD. 

A.3.4 Dermal Exposure (Short- and Intermediate-Term) 

Study Selected: 2 generation reproduction - rat

MRID No.: 42826309

Executive Summary: See Appendix A, Guideline [§ 870.3800] 

Dose and Endpoint for Risk Assessment: NOAEL = 31 mg/kg/day based on reduced post 

implantation survival and litter size seen at LOAEL = 159 mg/kg/day.

Uncertainty Factors: 100 – 10x for interspecies variation and 10x for intraspecies variation

Comments about Study/Endpoint: The 2 generation reproduction study provided the lowest 

points of departure for a duration that approximated a short and intermediate term exposure. The 

submitted 90 day dermal study was not selected because it did not address possible developmental 

effects for this route of exposure. No dermal absorption study was submitted; therefore, a DAF = 

100% was assumed for the exposure assessment.

A.3.5 Inhalation Exposure (Short- and Intermediate-Term) 

Study Selected: 2 generation reproduction - rat

MRID No.: 42826309

Executive Summary: See Appendix A, Guideline [§ 870.3800] 

Dose and Endpoint for Risk Assessment: NOAEL = 31 mg/kg/day based on reduced post 

implantation survival and litter size seen at LOAEL = 159 mg/kg/day.

Uncertainty Factors: 1000 – 10x for interspecies variation, 10x for intraspecies variation, and 

10x for the lack of a route specific inhalation study 

Comments about Study/Endpoint: The 2 generation reproduction study provided lowest points 

of departure for a duration that approximated a short and intermediate term exposure. An inhalation 
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study was not selected because no route specific study was available. Absorption from inhalation 

was assumed to be equivalent to an oral exposure.

A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.3100 90-Day Oral Toxicity - Rat

The test substance, hymexazol (Tachigaren Technical, 92.7% a.i.), was administered to SpragueDawley rats at dietary levels of 1250, 5000, and 20000 ppm (for males: 95, 371, and 1694 

mg/kg/day; for females: 113, 450, and 2084 mg/kg/day). The rats were observed for signs of 

toxicity; body weight and food and water consumption values were recorded. Hematology, 

clinical chemistry, urinalysis, and ophthalmological evaluations were performed prior to 

termination at 13 weeks. Organ weight, necropsy, and histopathology data were reported. At 

20000 ppm, evidence of toxicity consisted of decreased mean body weight gain in both sexes 

(37% less than control for males, 25% for females), although food intake was not affected and 

the efficiency of food utilization at the 20000 ppm dose level was decreased. Decreases in 

urinary volume, pH, and protein were observed at 20000 ppm, and treatment- related increases in 

the amount of total reducing substance (TRS) in the urine were observed in 100% of the males 

and 50% of the females at that dietary level. Additionally at 20000 ppm, slight increases in 

SGPT and SGOT levels, absolute and relative liver weights, and histopathology findings were 

suggestive of treatment-related effects in the liver, particularly in females. At the 5000 ppm 

level, only a slight (8%) decrease in mean body weight was observed in males.

The LOAEL is 1694 and 2084 mg/kg/day for males and females, respectively, based on 

decrease in body weight gain, decrease in urinary parameters, increase in total reducing 

substances in the urine, and increase in absolute and relative liver weights accompanied by 

slight increases in SGPT and SGOT levels and histopathological findings. The NOAEL is 

371 and 450 mg/kg/day for males and females, respectively.

This 90-day oral toxicity study in the rats is Acceptable/Guideline; this study satisfies guideline 

recommendations for a §82-1 subchronic toxicity study in rats.

870.3100 90-Day Oral Toxicity - Mouse

In a 90-day oral toxicity study (MRID 42960014) hymexazol (97.3% a.i., Batch 3 5050) was 

administered to 10 Crl:CD-1 (ICR) BR mice/sex/dose in the diet at concentration of 0, 300, 

1200, 5000, or 20000 ppm (equivalent to dose levels of 0, 55, 225, 952, and 4006 mg/kg bw/day

in males and 0, 76, 326, 1295, and 5433 mg/kg bw/day for females).

There were no mortalities, clinical signs of toxicity, or treatment related effects on food 

consumption, body weight, body weight gains, hematology, clinical chemistry, urinalysis, gross 

pathology or microscopic pathology.
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The LOAEL was not established. The NOAEL is 4006 and 5433 mg/kg/day in males and 

females, respectively. 

This 90-day oral toxicity study in the mice is Acceptable/Guideline and satisfies the guideline 

requirement for a 90-day oral toxicity study (OCSPP 870.3100; OECD 408) in mice. 

870.3150 90-Day Oral Toxicity - Dog

In a 90-day oral toxicity study (MRID 42960016), hymexazol (92.2% a.i.; batch number 

90211018) was administered to pure-bred beagles, 4/sex/dose in the diet at concentration levels 

of 0, 500, 7500 or 22500 ppm (equivalent to doses of 0, 92, 286, 885 mg/kg bw/day in males and 

98, 292, 894 mg/kg bw/day in females, respectively).

No adverse, treatment-related effects were noted on mortality, clinical signs, food consumption, 

ophthalmology, or urinalysis.

At the mid dose (92 mg/kg/day in males and 98 mg/kg/day in females), findings in females 

included increased absolute thyroid weight (↑61%) and increased incidences of the following 

histological findings: minimal follicular epithelial increased height (3/4 v. 0/4 in controls) and 

minimal follicular epithelial hyperplasia (2/4 v. 0/4 in controls). These symptoms became more 

prevalent and severe in at the high dose (885 mg/kg/day in males and 894 mg/kg/day in females). 

In addition, decreased alkaline phosphates was noted in the mid-dose females and was 

considered of equivocal biological significance. Effects on hemoglobin, erythrocyte count, 

hematocrit, serum total protein and albumin, were considered not adverse at the mid-dose and 

lower, due to the low magnitude of effect. 

Other effects noted at the high dose included: (i) decreased body weight in males; (ii) increased 

platelets in males; (iii) decreased hemoglobin, erythrocyte count, and hematocrit in both sexes, 

(iv) decreased serum albumin and total protein in males; (v) increased liver weight with 

increased incidence of parenchymal inflammatory foci in males; (vi) increased kidney weight in 

males; (vii) increased thyroid weight in both sexes; (viii) increased pituitary weight in females; 

(ix) enlarged thyroids in females; (x) increased incidence of thyroid epithelial follicular height 

and hyperplasia in both sexes. In addition, decreased alkaline phosphates was noted in the males 

and was considered of equivocal biological significance.

The LOAEL is 286 mg/kg/day in males and 292 mg/kg/day in females, based on increased 

absolute and relative thyroid weight accompanied by minimal increased epithelial height 

and minimal thyroid epithelial hyperplasia in females. The NOAEL is 92 mg/kg/day in 

males and 98 mg/kg/day in females.

This study is classified as Acceptable/Guideline and satisfies guideline recommendation for a 

90-day oral toxicity study (OCSPP 870.3150; OECD 409) in the non-rodent (beagle dog).

870.3150 90-Day Oral Toxicity – Dog
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In a 90-day oral toxicity study (MRID 42960017), hymexazol (92.2% a.i.; Batch # 90211018) 

was administered to pure-bred beagles, 4/sex/dose in the diet at dose levels of 0, 900, 1500 or 

2500 ppm (equivalent to 0, 35, 61, 98 mg/kg bw/day in males and 37, 64, 109 mg/kg bw/day in 

females, respectively). 

There were no mortalities during the study period and no significant treatment related effects in 

body weight, body weight gain, hematology, urinalysis, or clinical chemistry. Mid (61 and 64 

mg/kg/day in males and females, respectively) and high (98 and 109 mg/kg/day in males and 

females, respectively) dose males exhibited significantly increased absolute and relative liver 

weight and absolute lung weight. A non-significant increase in absolute liver and thyroid weight 

were observed in high dose females along with a significant increase in relative liver weight. No 

associated gross or histopathological anomalies were observed in these organs to indicate an 

adverse reaction to hymexazol treatment. 

No LOAEL was established for this study. The NOAEL is 98 and 109 mg/kg/day in males 

and females, respectively. 

This study is Acceptable/Non-guideline. Although the study was considered scientifically 

sound, the study does not satisfy the guideline recommendation for a 90-day oral toxicity study 

(OCSPP 870.3150; OECD 409) in the non-rodent (dog), because the animals could have 

tolerated a higher dose. An acceptable, guideline subchronic toxicity study in dogs was 

submitted (see MRID 42960016).

870.3200 90-Day Dermal Toxicity – Rat

In a 90-day dermal toxicity study (MRID 4921201), hymexazol (99.29% a.i.; Batch Number 

00315211) was applied to the shaved skin of Sprague Dawley (Crl:CD (SD) from Charles River 

(UK) Ltd.) rats for a period of 13 weeks. Four groups, each comprising ten males and ten 

females received Hymexazol at doses of 0 (Control; with purified water and were subject to the 

same semi-occlusion procedures) 100, 300 or 1000 mg/kg/day under semi-occluded conditions 

for approximately six hours each day.

No treatment-related effects were observed on clinical condition; body weight; food 

consumption; ophthalmic, hematology, or blood chemistry parameters; organ weights; or 

macropathology and histopathology findings. The dermal application of hymexazol for 13 

weeks at doses up to 1000 mg/kg/day saw no indication of irritation to the skin after repeated 

occluded application. 

Although a decrease (p<0.01) in body weight gain of 30% was noted in the 1000 mg/kg/day 

males, an increase (p<0.01) in body weight gain of 27% was noted in the 1000 mg/kg/day 

females. At 1000 mg/kg/day, terminal body weights were decreased (p<0.05) by 14% in males 

and increased (p<0.01) by 15% in females. However, the mean of the 1000 mg/kg/day males 

was within 1 standard deviation of the mean of the controls. In a 13-week oral (dietary) study, 

decreases in body weight gains were noted in the 1694 mg/kg/day males (↓ 37%) and 2084 

mg/kg/day females (↓ 25%). Thus, the oral study showed a comparable effect on body weight 
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gain in males but at a substantially higher dose. The effect on body weight and body weight gain 

is considered unclear in this dermal study. 

The LOAEL was not established. The NOAEL is 1000 mg/kg/day (limit dose) in both sexes.

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a 

90-day dermal toxicity study (OPPTS 870.3250; OECD 411) in the rat since the limit dose was 

tested.

870.3465 90-Day Inhalation – Rat

Required by HASPOC (TXR 0057244).

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study - Rat

Maternal Toxicity

The test substance, hymexazol (Tachigaren Technical, 92.7% a.i.), was administered by gavage 

to pregnant female CD (Sprague-Dawley) rats on days 6-15 of gestation at dose levels of 20, 

100, and 500 mg/kg/day. The rats were observed for signs of toxicity; body weight and food and 

water consumption values were recorded. On day 20 of gestation, the rats were sacrificed and 

necropsied. The uteri were examined, implantation sites were counted, and the numbers of 

corpora lutea were determined. The fetuses were removed, weighed, sexed, and examined for 

external anomalies. They were then processed for visceral and skeletal evaluation.

There was no evidence of treatment-related maternal toxicity in any treatment group.

The maternal LOAEL was not determined. The maternal NOAEL is greater than or equal 

to 500 mg/kg/day (highest dose tested). 

Developmental Toxicity

At 500 mg/kg/day, a dose which was not maternally toxic, mean fetal body weight was reduced 

9.3% below control. Indications of developmental delays were also observed in the skeletal 

evaluation data. These included reductions in ossification of the cervical, thoracic, lumbar, and 

caudal vertebrae, as well as in the pelvic girdle and in the fore- and hind- extremities 

(metacarpals and metatarsals). In addition, a significantly increased incidence in the percent of 

fetuses with bilateral 14th ribs was reported.

The developmental LOAEL is 500 mg/kg/day based on lower fetal body weight, skeletal 

defects, and increased incidence of fetuses with bilateral 14th rib. The developmental 

NOAEL is 100 mg/kg/day.

Minimum; this study satisfies minimum guideline recommendations for a §83-3(a) 

developmental toxicity (teratology) study in rats.

870.3700b Prenatal Developmental Toxicity Study - Rabbit
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In a developmental toxicity study (MRID 42960022), Hymexazol technical (99.3% a.i.; Lot no. 

10228211) was administered by gavage in 1% aqueous methylcellulose to groups of 18 mated 

female New Zealand White rabbits at dose levels of 0, 50, 150, or 450 mg/kg bw/day (constant 

dosing volume of 10 mL/kg bw) on gestation days (GDs) 7 through 19, inclusive. On GD 29, 

dams were sacrificed and necropsied. 

Maternal toxicity was evident at the highest dose level (450 mg/kg/day). Two high-dose animals 

were sacrificed ahead of schedule for humane reasons: one on GD 14 due to poor body 

condition, abnormal clinical signs (unsteadiness, hunched posture, “dark eyes,” and cold ears), 

and weight loss (783 g); the other on GD 23 after being found unable to stand following 

abortion. Treatment-related abnormal post-dosing observations were seen at 450 mg/kg/day. 

Among the 15 high-dose survivors, these included unsteadiness, slumped posture, increased 

respiration, and salivation (exhibited on one or more occasions by 11, 6, 7, and 7 animals, 

respectively). Additional treatment-related clinical signs included decreased appetite/reduced 

fecal output during GDs 7-9 in high-dose females and orange-stained tray paper in mid- (150 

mg/kg/day) and high-dose females. High-dose females had a treatment-related decrease in mean 

food consumption during GDs 7-8 (-46%; p<0.01) and a correlated mean body weight loss 

during GDs 7-9 (-148 g vs. +22 g for controls; p<0.05). There were not treatment related effects 

on gross pathology, number of litters or sex ratio. No abortions, premature deliveries, or dead 

fetuses occurred during the study period and no maternal intrauterine effects were evident. 

The maternal toxicity LOAEL is 450 mg/kg bw/day, based on mortality, abnormal clinical 

signs (unsteadiness, slumped posture, increased respiration, and salivation), transient 

decreased food consumption, and body weight loss during GDs 7-9. The maternal toxicity 

NOAEL is 150 mg/kg bw/day.

Various adverse findings were noted in the fetuses at 450 mg/kg/day. Mean fetal body weight 

was decreased by 7% and was considered an adverse, treatment related effect, although this 

effect was not reported to be statistically significant. Additionally at 450 mg/kg/day there was an 

increased percentage of fetuses per litter with reduced sternebrae. The total numbers of fetuses 

(and litters) evaluated in the control, low-, mid-, and high-dose groups were 140 (16), 115 (14), 

110 (13), and 108 (14), respectively. In these same respective groups, malformations were 

observed in a total of 2 (2), 3 (2), 4 (4), and 6 (4) fetuses (and litters). Heart/great vessel 

malformations were noted in 1 (1) mid-dose and 4 (4) high-dose fetuses (and litters) and were 

not seen in any control or low-dose litters (p<0.05 for high-dose litter incidence). Individual 

heart/great vessel malformations were noted as follows: incomplete inferior vena cava with 

persistent left posterior cardinal vein in 1/13 mid-dose and 3/14 high-dose litters; interventricular 

septal defect in 2/14 high-dose litters; and dilated ascending aorta/aortic arch, double outlet right

ventricle, narrow pulmonary trunk/ductus arteriosus, and dorsally displaced pulmonary trunk

each noted in 1/14 high-dose litters. Although the incidences were low and statistical 

significance was only attained for the grouped heart/great vessel findings, these findings are 

considered treatment-related and adverse. Fetal sex ratio was not affected by treatment, and there 

were no clear effects on deaths/resorptions. 
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The developmental toxicity LOAEL is 450 mg/kg bw/day, based on heart/great vessel 

malformations, particularly incomplete inferior vena cava, decreased fetal weight, reduced 

sternebrae, and increased supernumerary ribs. The developmental toxicity NOAEL is 150 

mg/kg bw/day.

This study is classified Acceptable/Guideline and satisfies the guideline recommendations for a 

developmental toxicity study (OCSPP 870.3700; OECD 414) in the rabbit.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat

In a two-generation reproduction study (MRID 42826309), hymexazol (92.2% a.i., lot 

#90211018) was administered to groups of 24 Sprague Dawley:CD rats/sex/dose in the diet at 

dietary concentrations of 0, 100, 500, or 2500 ppm. Pre-mating doses were, respectively: 0, 6.3, 

31, and 159 mg/kg bw/day for F0 males; 0, 7.5, 38, and 192 mg/kg bw/day for F0 females; 0, 7.7, 

38, and 193 mg/kg bw/day for F1 males; and 0, 9.0, 44, and 230 mg/kg bw/day for F1 females. 

Hereafter, the male/female F0 premating doses 0, 6.3/7.5, 31/38, and 159/192 mg/kg/day will be 

referred to as the control, low, mid, and high dose, respectively. F0 and F1 parental animals were 

administered the treated or control diets for at least 14 weeks prior to mating, throughout mating

(≤21 days), gestation, and lactation, and until necropsy after weaning of litters on postnatal day 

(PND) 25. One litter was produced by each generation. 

In F0 and F1 animals, there were no treatment-related effects on clinical signs, pre-mating body 

weight, body weight gain, food consumption, or postmortem observations, with one exception. 

One F0 female from the high dose group was found dead on GD 22 with a high degree of postimplantation loss revealed at necropsy. This mortality may have been treatment-related in light 

of the reduced post-implantation survival index in this group (see below) though it was the only 

mortality to occur during the study period. At the high dose, differences were observed in 

gestation length and in body weight gain during gestation and lactation. Gestation length was 

approximately 0.3 to 0.5 days longer in the F0 and F1 females, respectively; this was statistically 

significant in the F1 females. Because the difference was less than one full day and there was a 

lack of effect on corresponding parameters (e.g., dystocia, decreased live birth indices) this 

prolongation was not considered adverse. In the F0 females, there was a decrease in body weight 

gain during gestation (by 13% overall; 24% during GD 13-20), correlating with reduced postimplantation survival and litter size. Although not statistically significant, a slight body weight 

gain reduction in the F1 dams also was noted during GD 13-20 (↓10%). From LD 1 to LD 25, F0

and F1 dams in the 2500 ppm group lost approximately 4% body weight (vs. a 3% gain in F0

controls, and negligible change in the F1 controls). These changes were not considered treatment 

related because a comparable body weight loss was observed in the low dose F1 dams, and the 

mid dose F0 (↑2%) and F1 (↑4%) dams experienced an increase in body weight. Furthermore, the 

body weight changes during gestation and lactation were not considered adverse because 

absolute body weights were comparable across all groups. 
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Post-implantation survival rate and litter size was significantly reduced in the high dose F1

(↓17%) and F2 (↓20%) offspring compared to controls. Lower survival rates led to reduced litter 

size at birth/on postnatal day (PND) 1 in both the F1 (↓26-27%) and F2 (↓17%) generations. This 

reduction continued until PND 4 (pre-cull), with 16% fewer F1 pups and 19% fewer F2 pups per 

litter compared to controls. It was impossible to determine if this was a maternal or in utero

effect without more data; therefore, it was attributed to both.

The paternal toxicity LOAEL for hymexazol in rat pups is 159 mg/kg bw/day for males and 

192 mg/kg bw/day for females, based on reduced litter size due to lower post-implantation 

survival rate. The paternal NOAEL is 31 mg/kg bw/day for males and 38 mg/kg bw/day 

for females. 

As mentioned previously, smaller litter size caused by increased post-implantation loss was 

considered both an offspring and maternal effect. There were no treatment-related effects on the 

general physical condition, body weight, or developmental landmarks (pinna unfolding, hair 

growth, tooth eruption, and eye opening) of the F1 or F2 pups. No offspring or developmental 

adverse effects were observed in mid or low dose offspring. 

The offspring toxicity LOAEL for hymexazol in rat pups is 159 mg/kg bw/day for males 

and 192 mg/kg bw/day for females, based on reduced litter size due to lower postimplantation survival rate. The offspring NOAEL is 31 mg/kg bw/day for males and 38 

mg/kg bw/day for females. 

There was no definitive evidence of reproductive toxicity. Although there were no treatment 

related effects on mating performance, fertility, or reproductive organs, it should be noted that 

sperm enumeration and evaluation for motility and morphology was not done; ovarian follicle 

counts were not done (F1 parental females); and the age of vaginal opening and preputial 

separation were not determined for the F1 weanlings selected for mating. 

The reproductive toxicity LOAEL for hymexazol in rats was not determined. The 

reproductive toxicity NOAEL is greater than or equal to 159 mg/kg bw/day for males and 

192 mg/kg bw/day for females. 

This study is Acceptable/Guideline and satisfies the guideline requirement for a 2-generation 

reproductive toxicity study [OCSPP 870.3800; OECD 416] in rats. 

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity – Rat

In a carcinogenicity study (MRID 42960018), hymexazol (92.2 – 93.7% a.i., Lot Number 

90211018) was administered to groups of 50 male and female Sprague Dawley rats/sex/dose in

the diet at dose levels of 0, 400, 2000, or 10,000 ppm (equivalent to 0, 20, 99, and 532 mg/kg 

bw/day for males and 0, 28, 149, and 769 mg/kg bw/day for females) for 104 weeks. Hereafter, 
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the male/female dose groups 0, 20/28, 99/149, and 532/769 will be referred to as control, low, 

mid, and high dose, respectively. Satellite groups of 20 rats/sex/dose received the same dietary 

concentrations for 52 weeks before sacrifice. 

Treatment did not affect survival; however it did cause a statistically and biologically significant 

decrease in body weight of high dose males from week 13 to the end of the study (↓10 – 15%) 

and high dose females from week 26 through week 75 (↓8 – 21%). No biologically or 

toxicologically relevant effects were noted for food consumption, hematology, clinical 

chemistry, urinalysis, ophthalmology, or gross pathology. An increased incidence of 

centrilobular and periportal hepatocyte enlargement was observed in high dose male and female 

rats, respectively. However, neither high dose males nor females exhibited concomitant signs of 

liver toxicity in other liver parameters. Ostensibly, enzyme levels were elevated in high dose 

males, yet closer examination revealed a strong influence from two individuals resulting in 

artificially inflated values and high variability. Furthermore, liver weight was not different from 

controls in the high dose males. Conversely, liver weight of high dose females was statistically 

different from controls, yet the increase was slight and not biologically significant, and serum 

enzymes levels were comparable to controls. Based on the lack of corroborating evidence in 

other liver parameters, the liver enlargement anomalies were not considered adverse. 

The LOAEL is 532 mg/kg bw/day for males and 769 mg/kg bw/day for females based on 

decreased body weight. The NOAEL is 99 mg/kg/day in males and 149 mg/kg/day in 

females. 

Hymexazol given to male and female rats at a dose of 532 and 769 mg/kg bw/day, respectively, 

did not induce neoplastic effects. 

This study is classified as Acceptable / Guideline and satisfies the guideline recommendations 

for a carcinogenicity study [OCSPP 870.4200; OECD 451] in rats.

870.4100b Chronic Toxicity - Dog

In a chronic toxicity study (MRID 42997302), hymexazol (93.7% a.i.; Batch number 90211018) 

was administered to 4 pure-bred beagles/sex/dose in the diet at dose levels of 0, 100, 500 or 2500 

ppm (equivalent to 0, 3.55, 17, and 87 mg/kg/day in males and 0, 3.62, 18.18, and 91 mg/kg/day 

for females, respectively) for 52 weeks. 

Hymexazol treatment did not result in any unexpected mortalities and did not adversely affect 

body weight, body weight gain, food consumption, hematology, clinical chemistry, or urinalysis 

parameters. Significant increase in high dose female liver weight was not accompanied by 

adverse pathological anomalies in the liver indicating an adaptive response to exposure. Weight 

of all other organs were comparable to control. All gross and histopathological findings were 

minor and not attributed to treatment.

The LOAEL was not determined. The NOAEL is equal to or greater than 87 mg/kg/day for 

males and 91 mg/kg/day for females. 
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This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a 

chronic oral study [OCSPP 870.4100, OECD 452] in the dog. Although the animals could have 

tolerated higher doses than those tested, there was a clear NOAEL. 

A.4.5 Carcinogenicity

870.4200a Carcinogenicity Study - rat

See executive summary for 870.4100a.

870.4200b Carcinogenicity - Mouse

In a carcinogenicity study (MRID 42960019) hymexazol (92.2% a.i. Batch #90211018) was 

administered to 60 Crl:CD-1 (ICR) BR mice/sex/dose in the diet at dose levels of 0, 300, 2500, 

and 20000 ppm (equivalent to 0, 42, 355, and 2994 mg/kg bw/day in males and 0, 52, 440, and 

3733 mg/kg bw/day in females) for 91 weeks. Ten mice of each sex from each dosage level were 

sacrificed for interim study following 52 weeks of treatment.

Absolute (↑15% at interim, ↑10% at end of study) and relative (↑18% at interim, ↑19% at end of 

study) liver weight in high dose females and relative (↑18%) liver weight in high dose males was 

significantly increased at the high dose and coincided with increased incidence of granulomatous 

inflammation (males: 29/50, minimal to moderate severity in high dose v. 13/50, minimal to 

marked severity in controls; and females: 28/50, minimal to moderate severity in high dose v. 

17/50, minimal to moderate severity in controls). In combination these two liver effects were 

considered adverse. Similar liver were not observed in the low and mid dose animals. Significant 

weight increases in other organs were not accompanied by clear adverse gross or 

histopathological damage and were thus not considered adverse responses to treatment. Body 

weight gain was depressed for the entire study period in high dose males and females which 

correlated with significantly lower absolute body weight in high dose males and females from 

week 39 through week 91. However, the significance of the body weight findings were 

questionable because high mortality in treated and control groups from week 39 through week 91 

may have confounded the body weight statistical analysis. As a result, the body weight effects 

were not considered in the endpoint selection. There were no treatment related effects evident in 

the clinical examinations, food consumption, hematology or gross pathology analyses for any of 

the dose groups.

The LOAEL is 2994 mg/kg/day in males and 3733 mg/kg/day in females, based on

increased liver weight concurrent with liver granulomatous inflammation. The NOAEL is

355 mg/kg/day in males and 440 mg/kg/day in females.

At the doses tested, there was not a treatment related increase in tumor incidence when compared 

to controls. Dosing was considered adequate based increased liver weight accompanied by

increased incidence and severity of liver granulomatous inflammation in high dose males and 

females. 
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This carcinogenicity study in mice is Acceptable/Guideline and satisfies the guideline 

requirement for a carcinogenicity study [OPPTS 870.4200; OECD 451] in mice.

A.4.6 Mutagenicity

Gene Mutation

Guideline 870.5100, Gene Mutation

MRID 4290023

Acceptable

Hymexazol was non-toxic to the Salmonella strains, but was toxic to the 

E. coli strain at 2500 & 5000 μg/plate in the presence and absence of S-9. 

There was no evidence of induced revertant colonies over background at 

any dose tested, either with or without S-9 mix

Cytogenetics

Guideline 870.5300, Mouse Lymphoma 

Assay

MRID 42960024

Acceptable

No evidence of cytotoxicity or a mutagenic effect at the TK locus of 

L5178Y mouse lymphoma cells.

Micronucleus Assay

Guideline 870.5395, Micronucleus 

Assay

MRID 42960025

Acceptable

The incidence of micronucleated cells/1000 PCEs was not increased 

relative to control and the ratio of PCE to NCE (normochromatic 

erythrocytes) was not decreased at any dose level at any time point 

assayed.

A.4.7 Neurotoxicity

870.6100 Delayed Neurotoxicity Study - Hen

Not required

870.6200 Acute Neurotoxicity Screening Battery

Waived by HASPOC (TXR 0056409)

870.6200 Subchronic Neurotoxicity Screening Battery

In a subchronic neurotoxicity study (2006, MRID 48716601) Hymexazol (99.6%, batch 3128-

2110(D)) was administered to 10 Crl:CD®(SD)IGS BR rats/sex/group at dose levels of 0, 1250, 

4,000 or 12,500 ppm for 13 weeks. These doses were equivalent to 0, 85 and 107, 287 and 354 or 

901 and 1111 mg/kg/day for males and females for the control, low, mid or high dose test 

groups. Assessment for neurotoxicity as determined by FOB and motor activity were made at 

pretest, weeks 2, 4, 8 and 13 with 10 rats/sex/group. At termination, 5 rats/sex in the control and 

high dose groups were perfused in situ and subjected to neurohistopathological examination of 

the brain and peripheral nerves. 
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There were two deaths in the high dose group females that occurred in the later weeks of the 

study and although the exact cause could not be determined, they are considered to be related to 

treatment. At necropsy they were noted to have dark livers. Decreased body weight and gain 

were noted only the high dose (both sexes) but food consumption was not affected suggesting an 

effect on food efficiency. There was a statistically significant decrease in absolute brain weight 

(6.3%, p < 0.05) and a decrease in cerebral length (3.7%, p < 0.05) noted in the high dose group 

males. Although there was no associated histopathological change, the decrease in brain weight 

and cerebral length may be effects of hymexazol since brain weight is conserved when there is 

body weight loss. There were no differences in FOB parameters, motor activity or 

histopathology to indicate treatment related effects. 

The LOAEL is 901 in males and 1111 in females mg/kg/day based on deaths in females and 

body weight effects and a decrease in brain weight and cerebral length in males. The 

NOAEL is 287 in males and 354 in females mg/kg/day.

The study is classified as Acceptable/Guideline and satisfies the guideline requirement for a 

subchronic neurotoxicity study in rats (870.6200b).

870.6300 Developmental Neurotoxicity Study

Not required

A.4.8 Metabolism

870.7485 Metabolism - Rat

In MRID 42826310 and 43253802 14C-Hymexazol was administered orally in water to groups 

(5 sex/dose) of male and female Sprague-Dawley rats at nominal doses of 40 mg/kg (single and 

repeated low oral doses; intravenous dose) and 1000 mg/kg (single high oral dose). These groups 

were used for study of the disposition of hymexzaol. Separate groups (4/sex) received hymexazol 

at 40 and 1000 mg/kg for serial blood sampling to examine pharmacokinetics and temporal 

distribution of hymexazol. Metabolites in urine, feces, liver, kidney, and blood were 

characterized.

Bioavailability was essentially complete for all dose groups of male and female rats, but female 

rats showed a greater extent of absorption, as indicated by a higher area under the curve, cmax, 

and half-life vs. male rats. At 168 hours post-dose, less than 1% of the administered radioactivity 

was found in any tissue of male and female rats from any dose group. On a ug/g tissue basis, fat 

and residual carcass were found to contain the highest levels of radioactivity, and were higher in 

female rats in all dose groups than in males. Male rats showed an initial distribution of 

hymexzaol derived radioactivity in the liver at 0.5 hours post-dose, werheas females showed 

higher concentrations in blood, bone, brain, fat, and heart. Differences may exist in the 

biotransformation and/or distribution of hymexazol in male and female rats. Excretion of 

hymexazol derived radioactivity was largely through urine, where 95-110% of the dose was 
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recovered for all dose groups by this route. There were no significant dose- or sex-related 

differences in excretion. Metabolites of hymexazol identified in this study included the 

glucuronic acid and sulfate conjugates of hymexazol, and the oxidative metabolites 3-

hydroxybutamide and 3-hydroxybutyric acid. Urine showed mainly hymexazol conjugates, while 

oxidative metabolites were found in liver and kidney of both sexes.

These studies are classified as Minimum and together satisfy the guideline requirement for a 

metabolism study in rats (870.7485).

870.7600 Dermal Absorption - Rat

No study submitted. A 100% dermal absorption factor was assumed for concentrated and dilute 

solutions. 

A.4.9 Immunotoxicity

870.7800 Immunotoxicity

In an immunotoxicity study (MRID 48970401), hymexazol (99.29% purity, Lot No. 00315211) 

was administered to groups of 10 female Sprague Dawley rats/dose in the diet at concentrations 

of 0, 3125, 6250, and 12500 ppm (equivalent to 0, 289, 551, and 1023 mg/kg bw/day) for 28 

days. A concurrent positive control group received the basal diet, but were treated with 50 mg/kg 

bw of cyclophosphamide (CPS) by intraperitoneal (IP) injection on Day 27 of the study. All rats 

were given a single intravenous (IV) bolus dose of sheep red blood cell (SRBC, 2x108cells /mL, 

1 mL/animal) on Day 25. All rats were sacrificed on Day 29, and the spleen and thymus removed 

and weighed. Splenic cell suspensions were prepared for the plaque-forming cell (PFC) assay to 

determine the effect of dietary administration of hymexazol on the antigen specific activity of the 

immune system.

There were no treatment-related deaths and no clinical signs of toxicity were observed. Female 

rats treated with 12,500 ppm hymexazol had a ~24% decrease in body weight gain during Weeks 

1-4 of the study and a slight decrease in body weight (↓5%) compared to the control on Day 29. 

No treatment-related effects were found for rats treated with 3125 or 6250 ppm hymexazol. No 

effects on spleen or thymus absolute or relative to body weight were found for female rats treated 

with hymexazol. 

Under conditions of this study, the systemic LOAEL is 1023 mg/kg bw/day based on 

decreased body weight gains. The systemic NOAEL is 551 mg/kg bw/day.

There were no treatment-related effects on spleen cell number, and the PFC response to the Tcell dependent antigen SRBC (i.e., specific activity, and total spleen activity). A high interindividual variability was noted in all the treatment groups as well as in the control group. 

Evaluation of individual animal data did not show any trend or distribution that would 

demonstrate significant suppression of SRBC antibody response. The positive control animals 
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confirmed the ability of the test system to detect immunosuppressive effects and confirmed the 

validity of the study design. 

The Natural Killer (NK) cells activity was not evaluated in this study. The toxicology database 

for hymexazol does not reveal any evidence of immunotoxicity. The overall weight of evidence 

suggests that the chemical does not directly target the immune system. Under HED guidance a 

NK cell activity assay is not required at this time.

A LOAEL for immunotoxicity in female SD rats was not identified. The immunotoxicity 

NOAEL for hymexazol in female SD rats is 1023 mg/kg bw/day. 

This immunotoxicity study is classified Acceptable/Guideline and satisfies the guideline 

requirement for an immunotoxicity study (OCSPP 870.7800) in female rats.
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Appendix B. Physical/Chemical Properties

Physiochemical Properties of Hymexazol.1

Parameter Value

Molecular mass (g/mole) 99.09

Vapor pressure, at 25 ̊C 1.37 E-3 mmHg (torr)

Henry’s Law Constant 6.5 E-9 atm-m3/mole*

2.74E-9 atm-m3/mole (calculated @ pH7)

Solubility in water (g/L) , 20 ̊C @ pH7 5.82 g/mLb(pH 3) 58.2 g/L

6.51 g/mLb(pH 7) 65.1 g/L (bold value used to 

calculate Henry’s constant

6.78 g/mLb(pH 9) 67.8 g/L

There appears to be a conversion error in one of the 

sources of solubility data as (e.g., 6.51 g/mL does not 

equal 65.1 g/L).

pKa 5.92

1. D428894, J. Wolf, 09/02/2015.

* Estimated via EPISuite

a MRIDs 428263-01/-02/-03. Reviewed 03/29/1995. 

 b Solubility in the Problem Formulation (02/16/2010) solubility was reported in g/mL however in other sources report solubility 

 in g/L. 
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Appendix C. Review of Human Research

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 include studies from the 

Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1),and ExpoSAC Policy 14 and 

15.1 (SOPs for Seed Treatment) These data are subject to ethics review pursuant to 40 CFR 26, 

have received that review, and are compliant with applicable ethics requirements. For certain 

studies that 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 

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

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