ZOXAMIDE Human Health Risk Assessment DP No. D411543 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

DATE: April 3, 2014 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Zoxamide. Aggregate Human Health Risk Assessment for the Proposed New 

Use on Bulb Onions (Crop Subgroup 3-07 A). 

PC Code: 101702 DP Barcode: D411543 

Decision No.: 476622 Registration No.: 10163-6414 

Petition No.: 3F8164 Regulatory Action: Section 3 Registration 

CaseNo.: NA Risk Assessment Type: Single Chemical/ Aggregate 

TXRNo.: NA CAS No.: 156052-68-5 

MRIDNo.: NA 40 CFR: §180.567 

FROM: Nancy Tsaur, Chemist, Risk Assessor 

Meheret Negussie, Chemist /teA~ 

Vincent Chen, Toxicologist _:-:-:J'-:::o.-~~.,.._~~::; __ _ 

Risk Assessment Branch 3 

Health Effects Division (7509P) 

THROUGH: Christine Olinger, Branch Chief /) Jr~ Risk Assessment Branch 3 /J-J: ~ Health Effects Division (7509P) 

TO: Marcel Howard 

Fungicides Branch (FB) 

Registration Division (7505P) 

The Registration Division (RD) requested that the Health Effects Division (HED) provide an 

evaluation of the proposed new agricultural use of zoxamide on bulb onions (crop subgroup 3-

07A). A summary of the findings and an assessment ofhuman health risk resulting from the 

proposed and registered uses of zoxamide are provided in this document. 

The toxicology and hazard database review was conducted by Vincent Chen; the residue 

chemistry review and dietary risk assessment were conducted by Meheret Negussie; the 

occupational exposure risk assessment was conducted by Nancy Tsaur; and the aggregate human 

health risk assessment was conducted by Nancy Tsaur. 

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ZOXAMIDE Human Health Risk Assessment DP No. 0411543 

Table of Contents 

1.0 Executive Summacy .............................................................................................................. 4 

2.0 HED Recomme.ndations ....................................................................................................... 5 

2.1 

2.2 

2.2.1 

2.2.2 

2.2.3 

2.2.4 

2.3 

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

Tolerance Considerations .............................................................................................. 6 

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

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

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

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

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

3.0 Introduc·tion ........................................................................................................................... 7 

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

3.2 PhysicaVChemical Characteristics ............................................................................... 8 

3.3 Pesticide Use Pattern ...................................................................................................... 8 

3.4 Anticipated Exposure Pathways ................................................................................... 9 

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

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) .............................. 10 

4.3 Toxicological Effects .................................................................................................... 10 

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

4.4.1 Completeness of the Toxicology Database .......................................................... 11 

4.4.2 Evidence of Neurotoxicity .................................................................................... 11 

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

4.4.4 Residual Uncertainty in the Exposure Database ................................................ 12 

4.5 Toxicity Endpoint and Point of Departure Selection ................................................ 12 

4.5.1 Recommendation for Combining Routes of Exposure for Risk Assessment. .. 12 

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

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

Assessment ........................................................................................................................... 12 

5.0 Dietary Exposure and Risk Assessment ............................................................................ 13 

5.1 Residues of Concern Summary and Rationale .......................................................... 13 

5.2 Food Residue Profile .................................................................................................... 14 

5.3 Water Residue Profile .................................................................................................. 14 

5.4 Dietary Risk Assessment .............................................................................................. 15 

5.4.1 Description of Residue Data Used in Dietary Assessment ................................ 15 

5.4.2 Acute Dietary Risk Assessment ........................................................................... 15 

5.4.3 Chronic Dietary Risk Assessment ....................................................................... 15 

5.4.4 Cancer Dietary Risk Assessment.. ....................................................................... 16 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ................................ 16 

6.1 Residential Bystander Post-Application Inhalation Exposure ................................ 16 

6.2 Spray Drift .................................................................................................................... 17 

7.0 Aggregate Exposure/Risk Characterization ..................................................................... 17 

8.0 Cumulative Exposure/Risk Characterization ••••••••••••.•••••••••••••••••••••••••••.•••••••••.•••.•••••.••••• 17 

9.0 Occupational Exposure/Risk Characterization ............................................................... 18 

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9.1 Short- and Intermediate-Term Handler Risk ........................................................... 18

9.2 Short- and Intermediate-Term Post-Application Risk............................................. 19

9.2.1 Dermal Post-Application Risk ............................................................................. 19

9.2.2 Restricted Entry Interval ..................................................................................... 19

9.2.3 Inhalation Post-Application Risk ........................................................................ 19

10.0 References............................................................................................................................20

Appendix A. Toxicology Profile and Executive Summaries...................................................21

A.1 Toxicology Data Requirements................................................................................... 21

A.2 Toxicity Profiles............................................................................................................ 22

Appendix B. Physical/Chemical Properties.............................................................................26

Appendix C. Review of Human Research ................................................................................27

Appendix D. International Residue Limit Status....................................................................27

Appendix E. Occupational Exposure/Risk Summary Table..................................................28
ZOXAMIDE Human Health Risk Assessment DP No. D411543

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1.0 Executive Summary

Zoxamide is a benzamide-class fungicide used to control oomycete diseases (e.g. late blight and 

downy mildew). Its pesticidal mode of action is through preventing nuclear division by binding 

the -subunit of tubulin and disrupting microtubulin polymerization. There are no mammalian 

molecular data to specifically show this mode of action in test animals.

In PP#3F8164, Gowan has submitted a label amendment to add bulb onions (crop subgroup 3-

07A) to the label for Gavel® 75DF Fungicide (EPA Reg. No. 10163-6414), thus petitioning for 

the associated tolerance. Gavel® 75DF is a water dispersible granule (WG) formulation 

containing 8.3% active ingredient (ai) by weight.

Proposed Use Profile

Gowan® 75DF may be applied as a foliar spray via groundboom, aircraft, chemigation, and 

handheld equipment. For bulb onions (crop group 3-07A), the proposed maximum single 

application rate is 2.0 lb product/A (0.17 lb ai/A) and applications may be repeated on a 7-day 

interval, up to a maximum seasonal application rate of 16 lb product/A (1.33 lb ai/A) per year.

Exposure Profile

Exposure pathways include dietary (food and drinking water) and occupational exposure sources. 

There are no proposed or registered residential uses at this time. Dietary exposures are expected 

for chronic duration. Occupational handler and post-application exposures are expected for 

short- and intermediate-term durations only. The proposed label requires occupational handlers 

to wear long pants, long sleeves, shoes, socks, and chemical-resistant gloves.

Toxicity/Hazard

In the majority of studies, zoxamide did not cause any toxicity up to the limit dose. The toxicity 

data of zoxamide indicate that the primary target organ is the liver. Liver and thyroid weights 

increased along with liver histopathological change and increases in alkaline phosphatase. A 

dermal point of departure (POD) was not chosen because systemic toxicity is not seen in the 28-

day rat dermal toxicity study up to the limit dose (1,000 mg/kg/day). The short- and 

intermediate-term inhalation PODs are based on the results of a chronic oral toxicity study in 

dogs. Zoxamide is not acutely toxic; it is classified as Toxicity Category III or IV for all routes 

of exposure (dermal, oral, and inhalation). There are no concerns for neurotoxicity, 

immunotoxicity, developmental toxicity, or reproductive toxicity; nor is there susceptibility in 

the developmental fetuses or pups. Therefore, the data support a reduction of the FQPA safety 

factor to 1X. Zoxamide is classified as “not likely to be carcinogenic to humans” based on the 

lack of treatment-related tumors in acceptable/guideline carcinogenicity studies in rats and mice.

Dietary Exposure (Food and Water) and Risk Estimates

The dietary exposure and risk estimates changed slightly from the previous risk assessment. 

There was no indication of an adverse effect attributable to a single dose. Thus, an acute 

reference dose (aRfD) was not established, and an acute dietary exposure assessment was not 

conducted. An unrefined chronic dietary exposure assessment was performed for zoxamide

using tolerance-level residues and 100% crop treated (CT). The estimated drinking water 

concentration (EDWC) of 65.8 μg/L was incorporated directly into the dietary assessment. The 
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results of the chronic dietary analysis for food and drinking water are below the HED’s level of 

concern (LOC) for all population subgroups. The dietary exposure for food and water is 

estimated at 1.5% of the chronic Population Adjusted Dose (cPAD) for the general U.S. 

population and 4.8%, of the cPAD for children 1 to 2 years old, the population subgroup with the 

highest estimated chronic dietary exposure to zoxamide.

Residential Exposure and Risk Estimates

There are currently no registered or proposed residential uses for zoxamide.

Aggregate Exposure Risk Estimates

Since there are no existing or proposed residential uses for zoxamide, there are no exposures 

expected via the residential exposure pathway. Therefore, all aggregate risk estimates are 

expected to be equivalent to chronic dietary (food and drinking water) risk estimates.

Occupational Handler Exposures and Risk Estimates

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

intermediate-term inhalation risks are not of concern at baseline mitigation without personal 

protective equipment (PPE). Short- and intermediate-term MOEs range from 7,400 to 970,000. 

Note that only engineering control (enclosed cockpit) data are available to assess risks to

handlers operating aircrafts.

Occupational Post-Application Exposures and Risk Estimates

An occupational post-application dermal exposure and risk assessment was not conducted 

because a systemic dermal hazard was not identified for zoxamide. The 48-hour REI listed on 

the label is adequate to protect agricultural workers from post-application exposures to 

zoxamide. Based on the Agency's current practices, a quantitative non-cancer occupational postapplication inhalation exposure assessment was not performed for zoxamide at this time. If new 

policies or procedures are put into place, the Agency may revisit the need for a quantitative 

occupational post-application inhalation exposure assessment for zoxamide.

2.0 HED Recommendations

HED has examined the toxicology and residue chemistry databases for zoxamide. Pending 

submission of a revised Section B (label) and a revised Section F (tolerances), there are no issues 

that would preclude granting registration for the requested uses of zoxamide on bulb onions or 

establishment of the recommended tolerance for combined residues of zoxamide and its 

metabolites (see Table 2.2.3). The specific tolerance recommendations are discussed in Section 

2.2, and label modifications are discussed in Section 2.3.

2.1 Data Deficiencies

860.1650 Submittal of Analytical Reference Standards

The analytical reference standard for zoxamide is depleted. A 5g standard needs to be supplied 

to the repository.
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2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate analytical methods are available for enforcing zoxamide tolerances and collecting data 

on residues in plant commodities. The analytical methods, gas chromatography with electron 

capture detection (GC/ECD) and GC with mass selective detection (GC/MSD) are available for 

tolerance enforcement for plant commodities as primary and confirmatory methods, respectively. 

For the acid metabolites (RH-1452 and RH-1455), the GC/MSD is the primary method and the 

GC/ECD method is the confirmatory method. The methods have been adequately validated for 

the determination of residues of zoxamide in plant commodities. Adequate multiresidue 

methods testing data have been submitted. The data indicate that the multiresidue methods are 

adequate for enforcement of tolerances for zoxamide only.

2.2.2 Recommended Tolerances

Table 2.2.3. Tolerance Summary for Zoxamide

Commodity

Tolerance (ppm) Comments

Established Proposed Recommended Correct Commodity Definition

40 CFR §180.567(a)(2)

Onion, bulb -- 0.7 0.7 Onion, bulb, subgroup 3-07A

2.2.3 Revisions to Petitioned-For Tolerances

Section B (label) must be revised to only indicate use on onion, bulb, subgroup 3-07A crops:

garlic, bulb; onion, bulb; shallot, bulb; cultivars, varieties.

According to HED’s Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner), the 

tolerance expressions for zoxamide should be revised as follow:

Under 40 CFR §180.567(a)(1): “Tolerances are established for residues of zoxamide including 

is metabolites and degradates, in or on the commodities in the table below. Compliance with the 

tolerance levels specified below is to be determined by measuring only zoxamide (3,5-dichloroN-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide).

Under 40 CFR §180.567 (a)(2): “Tolerances are established for residues of zoxamide including 

is metabolites and degradates, in or on the commodities in the table below. Compliance with the 

tolerance levels specified below is to be determined by measuring only the sum of zoxamide 

(3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide) and its 

metabolites 3,5-dichloro-1,4-benzenedicarboxylic acid (RH-1455 and RH-141455) and 3,5-

dichloro-4-hydroxymethylbenzoic acid (RH-1452 and RH-141452) calculated as the 

stoichiometric equivalent of zoxamide.
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2.2.4 International Harmonization

There are no Codex or Canadian maximum residue limits (MRLs) established for residues of 

zoxamide in/on bulb onions. The US tolerance and Canadian MRL expressions are the same. 

The US and Canadian residue definitions include zoxamide for grapes and processed grapes and 

zoxamide and its metabolites for potatoes and processed potatoes. The US and Codex residue 

definitions are not in harmony. The Codex residue definition includes only zoxamide for all 

crops. The International Residue Limit Status is detailed in Appendix D.

2.3 Label Recommendations

The proposed use directions for onion bulb must be revised to only include onion, bulb,

subgroup 3-07A crops: garlic, bulb; onion, bulb; shallot, bulb; cultivars, varieties.

3.0 Introduction

Zoxamide is a benzamide-class fungicide used to control oomycete diseases (e.g. late blight and 

downy mildew). Its pesticidal mode of action is through preventing nuclear division by binding 

the -subunit of tubulin and disrupting microtubulin polymerization. It is currently registered for 

use on cucurbit vegetables, grapes, potatoes, and tomatoes.

In PP#3F8164, Gowan has submitted a label amendment to add bulb onions (crop subgroup 3-

07A) to the label for Gavel® DF75 Fungicide (EPA Reg. No. 10163-6414), thus petitioning for 

the associated tolerance. Gavel® DF75 is a WG formulation containing 8.3% ai by weight.

3.1 Chemical Identity

Table 3.1. Zoxamide Nomenclature

Compound

Common name Zoxamide

Company experimental name RH-7281

IUPAC name (RS)-3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-p-toluamide

CAS name 3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide

CAS registry number 156052-68-5

End-use product (EP) Gavel® 75DF Fungicide (This product is a combination of zoxamide + mancozeb.)

N

H

Cl

Cl

Cl

O

O
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Table 3.1. Zoxamide Nomenclature

Compound

Common name RH-141452

Company experimental name RH-1452

Chemical name 3,5-dichloro-4-hydroxymethylbenzoic acid

Molecular weight 221.04 g/mol

CAS Name Not available

Compound

Common name RH-141455

Company experimental name RH-1455

Chemical name 2,6-dichlorobenzene-1,4-dicarboxylic acid

Molecular weight 235.02 g/mol

CAS Name Not available

3.2 Physical/Chemical Characteristics

Zoxamide has a low vapor pressure (9.75×10-8 mm Hg at 25, 35, and 45°C); therefore, inhalation 

due to chemical vaporization is unlikely. Zoxamide has a log octanol/water partition coefficient 

(log Pow) of 3.76 and is considered relatively insoluble in water. Additionally, zoxamide has a 

molecular weight of 336.64 g/mol; therefore, the potential to cross biological barriers, such as 

the skin, is somewhat limited. More detailed physicochemical properties of zoxamide are 

summarized in Appendix B.

3.3 Pesticide Use Pattern

Gowan has submitted an amended label for Gavel® DF75 Fungicide (EPA Reg. No. 10163-

6414). The newly proposed use pattern is presented in Table 3.3.
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Table 3.3. Summary of Proposed Use Directions for Gavel® DF75 Fungicide (EPA Reg. No. 10163-6414)

Application

Timing, Type, 

and Equipment

Single 

Maximum 

Application 

Rate

Maximum 

Number of 

Applications

per Year

Maximum

Annual

Application

Rate

PHI a

Use Directions and Limitations

days

Onions (dry bulb), Garlic, and Shallotsb

Broadcast

Foliar: ground, 

aerial, 

chemigation, or 

handheld

2 lb

product/A

0.17 lb ai/A

8

16 lb

product/A

1.33 lb ai/A

7

Follow a protective spray schedule 

starting when diseases are first reported in 

the area and repeat at 7-day intervals 

throughout the season. 

Do not allow spray or drift to contact 

bulbs after lifting from soil.

Do not apply to exposed bulb.

a PHI = pre-harvest interval.

b The label must be revised to only include bulb onions of crop subgroup 3-07A: garlic, bulb; onion, bulb; shallot, 

bulb; cultivars, varieties.

3.4 Anticipated Exposure Pathways

Humans may be exposed to zoxamide via food and drinking water because zoxamide may be 

applied directly to growing crops, and application may result in zoxamide reaching surface and 

ground sources of drinking water. There are no residential uses of zoxamide so there is no

exposure in residential or non-occupational settings. In an occupational setting, applicators may 

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

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

Several risk assessments have been previously prepared for the existing uses of zoxamide. This 

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

new use of zoxamide, but also considers the existing uses as well, particularly for the dietary 

exposure assessment.

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.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the USDA under the National 

Health and Nutrition Examination Survey/What We Eat in America (NHANES/WWEIA), and 

are used in pesticide risk assessments for all registered food uses of a pesticide. These data are 

analyzed and categorized by subgroups based on age and ethnic group. Additionally, OPP is 

able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are 

performed when conditions or circumstances warrant. Whenever appropriate, non-dietary 

exposures based on home use of pesticide products and associated risks for adult applicators and 

for toddlers, youths, and adults entering or playing on treated areas post-application are 
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evaluated. Further considerations are currently in development as OPP has committed resources 

and expertise to the development of specialized software and models that consider exposure to 

bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

Zoxamide’s pesticidal mode of action is through preventing nuclear division by binding -

subunit of tubulin and disrupting microtubulin polymerization. There are no mammalian 

molecular data to specifically show this mode of action in the test animals.

4.1 Toxicology Studies Available for Analysis

The toxicological database for zoxamide is complete. The submitted studies are of good quality 

and provide sufficient information to determine whether zoxamide poses as a human health 

hazard. All available toxicity studies are listed in Appendix A. The following studies are 

currently available for risk assessment: subchronic (90-day oral in rats and dogs; 28-day dermal 

in rats); chronic (1-year oral in dogs; 18-month oral carcinogenicity in mice; 2-year oral 

combined chronic/carcinogenicity in rats); reproductive in rats); developmental in rats and 

rabbits; carcinogenicity in rats and mice; mutagenicity and genotoxicity in bacterial and 

mammalian model systems); neurotoxicity (acute and subchronic in rats); metabolism in rats;

and pharmacokinetic in rats. Neither an immunotoxicity study nor a subchronic inhalation 

toxicity study is required for zoxamide at this time (TXR0056915, K. Rury, 04/02/2014)

4.2 Absorption, Distribution, Metabolism and Excretion (ADME)

Absorption was determined to be ~55% of the administered dose (AD) based on urine (9-11% 

AD) and bile (46-48% AD) elimination data. Zoxamide was found in the largest quantities in the 

liver (7% AD) and kidneys (0.1% AD) in addition to the residual carcass (28% AD). In the rest 

of the body, zoxamide residues were found in trace quantities. Non-metabolized zoxamide was 

the major component in feces (12-23% AD). In addition, some of the major metabolites that 

were identified include M-3/RH-141,643 (7% AD) and M-7/RH-141,454 (6% AD). The 

metabolic pathway of zoxamide involved a combination of glutathione conjugation, reductive 

dehalogenation, hydrolysis, and oxidation. The majority (>96% AD) of elimination in the rat 

occurred within 120 hours. There were no radiolabeled metabolites in the expired air and no 

evidence for bioaccumulation. Based on excretion and tissue residue data, bioavailability is 

conservatively estimated at about 59% of an administered dose. 

Dermal penetration studies were evaluated for two formulations (80 WP and 80 2F) to establish a 

dermal absorption factor of 3% (HIARC Memo, TXR0014464, 02/07/2001).

4.3 Toxicological Effects

Zoxamide did not cause any toxicity up to the limit dose in the vast majority of the studies. 

However, the chronic and subchronic dog studies indicated that the primary target organ for oral 

exposure to zoxamide is the liver. Additionally, liver and thyroid weights were increased along 
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with liver histopathological changes and increases in alkaline phosphatase in the chronic study. 

Zoxamide was not observed to cause neurotoxicity or developmental/reproductive toxicity at or 

above the limit dose. No increases in the incidence of tumors were seen in either the rat or 

mouse carcinogenicity study. 

As an oomycete fungicide, zoxamide causes the disruption of the microtubule cytoskeleton and

arrests nuclear division by binding specifically to the -subunit of tubulin. This mechanism of

specific binding the -subunit of tubulin is consistent with the results of the in vitro mutagenicity

study with CHO cells which indicated an increase in aneuploidy/polyploidy. The results of a 

special metabolism study indicated that <0.01% of the administered dose reached the bone 

marrow; thereby reducing the concern for mutagenic potential in vivo. Additionally, zoxamide 

was negative in the in vivo micronucleus assay in mice.

Zoxamide has low acute toxicity through the oral, dermal, and inhalation routes of exposure 

(Toxicity Categories III-IV); and is not an ocular or dermal irritant (Toxicity Categories III-IV). 

However, it was determined to be a strong dermal sensitizer.

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

The risk assessment team recommended that the FQPA Safety Factor be reduced to 1X for the 

reasons detailed in Sections 4.4.1-4.4.4.

4.4.1 Completeness of the Toxicology Database

The toxicology database is adequate for assessing susceptibility in infants and children as 

required by FQPA.

4.4.2 Evidence of Neurotoxicity

Zoxamide’s toxicological database did not provide any evidence of neurotoxicity. Neurotoxic 

effects were not observed in the neurotoxicity screening battery (acute and subchronic) up to 

their limit doses; 2000 mg/kg in the acute study and 1509 mg/kg/day in the subchronic study. In 

the absence of neuropathology findings in the neurotoxicity battery and behavioral effects 

elsewhere in the database, a developmental neurotoxicity study is not required at this time.

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

The prenatal and postnatal toxicity studies include rat and rabbit prenatal developmental studies 

in addition to a reproduction and fertility effects study in rats; and the highest doeses used in 

these studies are at or above the limit dose. There was no evidence of increased susceptibility 

(quantitative or qualitative) for the offspring in the reproduction studies or for fetuses following 

in utero exposure in the developmental studies.

In the developmental studies, maternal and fetal toxicity was not observed up to the limit dose 

(1000 mg/kg/day). In the rat reproduction and fertility effects study, decreased body weights and 
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body weight gains was observed in only the parental females at the highest dose tested (1624.4 

mg/kg/day).

4.4.4 Residual Uncertainty in the Exposure Database

The exposure databases are complete or are estimated based on data that reasonably account for 

potential exposures. The chronic dietary food exposure assessment was conservatively based on 

100% crop treated (CT) assumptions and conservative ground water drinking water modeling 

estimates. There are no registered or proposed residential uses. All of the exposure estimates are 

based on conservative assumptions and are not likely to result in underestimated risk.

4.5 Toxicity Endpoint and Point of Departure Selection

4.5.1 Recommendation for Combining Routes of Exposure for Risk Assessment

As per FQPA, 1996, when there are potential residential exposures to a pesticide, aggregate risk 

assessment must consider exposures from three major sources: oral, dermal and inhalation 

exposures. When common toxicity endpoints are selected for these routes of exposure they may 

be aggregated. 

In this case, oral and inhalation endpoints are based on the same effect (i.e., body weight 

changes, increases in liver and thyroid weights, and increases in alkaline phosphatase), and 

therefore these routes of exposure may be combined for risk assessment. The dermal route of 

exposure does not need to be included in the aggregate risk assessment because there were no 

identified dermal hazards and no developmental, reproductive, neurotoxicity, and 

immunotoxicity concerns.

4.5.2 Cancer Classification and Risk Assessment Recommendation

Zoxamide was classified as “not likely” to be a human carcinogen (HIARC Memo, TXR014464, 

02/07/2001) based on the lack of treatment-related tumors in both the combined chronic toxicitycarcinogenicity rat study and carcinogenicity mouse study.

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

Assessment

Reference: HIARC 07 Feb 2001 Zoxamide Report (HED Document Number 014464)
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Table 4.5. Summary of Toxicological Doses and Endpoints for Zoxamide for Use in Dietary and 

Occupational Human Health Risk Assessmentsa

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(General 

Population, 

including 

Infants and 

Children) and 

Females 13-

49 years of 

age

None: There is no indication of an adverse effect attributable to a single dose. Additionally, 

developmental, neurotoxicity, and reproductive effects were not observed in the database. An 

aRfD was not established.

Chronic 

Dietary (All 

Populations)

NOAEL = 

48

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 

1X

cRfD = 0.48

mg/kg/day

cPAD = 0.48

mg/kg/day

Chronic Toxicity – Dog

LOAEL = 255 mg/kg/day

Based on body weight changes, increases in liver 

and thyroid weights, and increases in alkaline 

phosphatase.

Dermal ShortTerm (1-30 

days)

None: There were no systemic or dermal toxicity findings in a 28-day dermal toxicity study in 

the rat up to the limit dose (1000 mg/kg/day) and there were no developmental, reproductive,

or neurotoxicity concerns observed in the database.

Inhalationb

Short- Term 

(1-30 days)

and 

IntermediateTerm (1-6 

months)

NOAEL = 

48 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 

1X

Occupational 

LOC for 

MOE = 100

Chronic Toxicity – Dog

LOAEL = 255 mg/kg/day

Based on body weight changes, increases in liver 

and thyroid weights, and increases in alkaline 

phosphatase.

Cancer (oral, 

dermal, 

inhalation)

Classification: “Not likely to be Carcinogenic to Humans” based on the lack of treatmentrelated tumors in both the combined chronic toxicity-carcinogenicity rat study and 

carcinogenicity mouse study.

a 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). FQPA SF = FQPA Safety Factor. RfD = 

reference dose (a = acute, c = chronic). PAD = population adjusted dose (a = acute, c = chronic). MOE = margin 

of exposure. LOC = level of concern.

b Toxicity by the inhalation route is assumed to be equivalent to the oral route. A subchronic inhalation toxicity 

study is not required for zoxamide at this time (TXR0056915, K. Rury, 04/02/2014).

5.0 Dietary Exposure and Risk Assessment 

5.1 Residues of Concern Summary and Rationale

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

in Table 5.1.
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Table 5.1. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance 

Expression

Matrix Residues included in

Risk Assessment

Residues included in

Tolerance Expression

Plants

Primary Crop Zoxamide and its metabolites: RH-1452 and RH-1455

for grapes and potatoes

Zoxamide only for tomatoes/cucumbers

Rotational Crop

Livestock Ruminant Not Established Poultry

Drinking Water Zoxamide and its metabolites: RH-150721, RH-24549, RH141288, RH-129151, and RH-139432

5.2 Food Residue Profile

Adequate field trial data are available to support the proposed use of zoxamide on bulb onions

and members of crop subgroup 3-07A. In the residue decline study, average residues of 

zoxamide indicated an overall decline in residues with increasing PHIs. 

The available storage stability data for zoxamide are adequate to support the storage durations 

and conditions of samples of bulb onions from the submitted crop field trials.

There are no livestock feedstuffs associated with the proposed use of zoxamide on onion bulbs, 

and there are no livestock feedstuffs associated with the existing uses of zoxamide except potato 

processing waste/cull potatoes. Exposure from the latter, a minor ruminant feed item, is not 

anticipated to yield quantifiable residues in livestock commodities.

Available confined rotational crop data are adequate to satisfy data requirements and to delineate 

the nature of the residue in rotated crop commodities. Based on the results of the reviewed 

confined rotational crop study, it was concluded that there is no indication that zoxamide would

be detected in rotational crops planted more than 30 days after the application of zoxamide.

5.3 Water Residue Profile

The environmental fate database is adequate to characterize drinking water exposure for the 

parent compound. Limited fate data are available for the degradates of zoxamide. The data 

indicate that zoxamide is moderately persistent but immobile in soil. The degradates seem to be 

more mobile than the parent. Model simulations show that zoxamide may reach surface 

drinking water supplies, but should not reach ground water in considerable amounts, because it is 

immobile in soil.

In addition to evaluating the EDWCs from the proposed use, EDWCs were reevaluated for all 

existing uses with PRZM-GW,

1 which models continued use of zoxamide over many years

(DP417061, F. Khan, 01/17/2014). The most conservative EDWC (65.8 μg/L) was based on an 

existing potato/grape use, and was used in the chronic dietary assessment.

 

1 PRZM-GW was approved for standard use in drinking water assessments as a Tier I/II exposure tool (12/2012). 
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Table 5.3. Summary of Estimated Drinking Water Concentrations for Zoxamidea

Tier II Surface Water Model (μg/L)

Crop Scenario Peak Exposure Annual Mean Exposure Average Annual Exposure

GA Onion STD Scenariob 10.09 1.20 0.81

Tier I Ground Water Model (μg/L)

Crop Scenario Peak Exposure Annual Mean Exposure Average Annual Exposure

WI corn Scenarioc 83.5 NA 65.8

Generic Scenariod 0.452 0.452 0.452

a EDWC modeling includes total toxic residue (TTR) of zoxamide and five major degradates: RH-150721, RH24549, RH-141288, RH-129151, and RH-139432.

b PCA of 0.91 adjusted EDWCs generated using PRZM/EXAMS model for aerial application.

c Highest EDWCs generated using PRZM-GW model based on 1.60 lbs ai/A for grape and potato (Gavel 80 WP, 

EPA Reg. No.10163-6413).

d EDWCs generated using SCIGROW model and represent both acute and chronic.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

An unrefined chronic dietary (food and drinking water) exposure and risk assessment was 

performed for zoxamide. The assumptions include tolerance level residues, 100% CT, and 

default processing factors from the Dietary Exposure Evaluation Model software with the Food 

Commodity Intake Database (DEEM-FCID) Version 7.81 (except for grape, raisin and potato 

granules/flakes). EDWCs from EFED were also included: the average ground water exposure of

65.8 μg/L was incorporated directly into the dietary assessment.

5.4.2 Acute Dietary Risk Assessment

There was no indication of an adverse effect attributable to a single dose. Thus, an aRfD was not 

established, and an acute dietary exposure assessment was not conducted.

5.4.3 Chronic Dietary Risk Assessment

An unrefined chronic dietary (food and drinking water) exposure and risk assessment was

conducted using the DEEM-FCID Version 3.16. This model uses 2003-2008 food consumption 

data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition 

Examination Survey, What We Eat in America (NHANES/WWEIA). 

The results of the chronic dietary analysis for food and drinking water are below the Agency’s 

LOC for the general U.S population and all population subgroups. The dietary (food and 

drinking water) exposure is estimated at 1.5% of the chronic Population Adjusted Dose (cPAD) 

for the general U.S. population and 4.8% of the cPAD for children 1 to 2 years old, the 

population subgroup with the highest estimated chronic dietary exposure to zoxamide. The 

results of the chronic dietary exposure analyses are reported in Table 5.4.5.
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5.4.4 Cancer Dietary Risk Assessment

Zoxamide is classified as “not likely to be carcinogenic to humans;” therefore, cancer risk was 

not assessed. 

5.4.5 Summary Table

Table 5.4.5. Summary of Dietary Exposure and Risk for Zoxamide (cPAD = 0.48 mg/kg/day)a

Population Subgroup

Chronic Dietary Exposure Estimates

(Food and Drinking Water)

mg/kg/day % cPAD

General U.S. Population 0.007368 1.5

All Infants (< 1 year old) 0.010837 2.3

Children 1-2 years old 0.023241 4.8

Children 3-5 years old 0.018422 3.8

Children 6-12 years old 0.009842 2.1

Youth 13-19 years old 0.005483 1.1

Adults 20-49 years old 0.006082 1.3

Adults 50+ years old 0.005863 1.2

Females 13-49 years old 0.005954 1.2

a The population subgroup with the greatest exposure is in bold.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no existing or proposed residential uses at this time.

6.1 Residential Bystander Post-Application Inhalation Exposure

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

assessment was not performed for zoxamide at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV), low vapor pressure (9.75 x 10-8 mm Hg at 25, 35, and 

45°C), and the low proposed use rate (0.17 lb ai/A). However, volatilization of pesticides may 

be a source of post-application inhalation exposure to individuals nearby pesticide applications. 

The Agency sought expert advice and input on issues related to volatilization of pesticides from 

its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in 

December 2009, and received the SAP’s final report on March 2, 20102. The Agency is in the 

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

identify the need for and, subsequently, the way to incorporate post-application inhalation 

exposure into the Agency's risk assessments. If new policies or procedures are developed, the 

Agency may revisit the need for a quantitative post-application inhalation exposure assessment 

for zoxamide.

 

2 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
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6.2 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for zoxamide. The 

Agency has been working with the Spray Drift Task Force, EPA Regional Offices, and State 

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

management practices (see the Agency’s Spray Drift website for more information3. The 

Agency has completed its evaluation of the new database submitted by the Spray Drift Task 

Force, a membership of U.S. pesticide registrants, and is developing a policy on how to 

appropriately apply the data and the AgDRIFT computer model to its risk assessments for 

pesticides applied by air, orchard airblast, and ground hydraulic methods. After the policy is in 

place, the Agency may impose further refinements in spray drift management practices to reduce 

off-target drift with specific products with significant risk estimates associated with drift.

Although a quantitative residential post-application inhalation exposure assessment was not 

performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation 

exposure assessment was performed for flaggers. This exposure scenario is representative of a 

worse case inhalation (drift) exposure and may be considered protective of most outdoor 

agricultural and commercial post-application inhalation exposure scenarios.

7.0 Aggregate Exposure/Risk Characterization

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. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g. a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure. Since there are no existing or proposed residential uses for zoxamide, 

there are no exposures expected via the residential exposure pathway. Therefore, all aggregate 

risk would be equivalent to the dietary exposure estimate (refer to Section 5.4.5). Zoxamide is 

classified as “not likely to be carcinogenic to humans;” therefore, an aggregate cancer 

assessment was not conducted.

8.0 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 zoxamide and any other substances and zoxamide does not appear to produce a toxic 

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

EPA has not assumed that zoxamide 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 

 

3 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
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determinations and procedures for cumulating effects from substances found to have a common 

mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

Occupational handler and post-application exposure may occur by the dermal and inhalation 

routes of exposure only. For short- and intermediate-term exposure, only inhalation exposures 

were assessed since there is no systemic hazard from the dermal route of exposure. The results 

of the occupational handler exposure and risk assessment indicate that short- and intermediateterm risk estimates are not of concern (N. Tsaur, DP416655, 03/27/2014). Appendix E

summarizes all assessed occupational exposure and risk estimates.

9.1 Short- and Intermediate-Term Handler Risk

Based on the anticipated use patterns and current labeling, and types of equipment and 

techniques that can potentially be used, occupational handler exposure is expected from the 

proposed uses. The quantitative exposure/risk assessment developed for occupational handlers is 

based on the following scenarios: 

 Mixing/Loading dry flowables for aerial, chemigation, and groundboom application;

 Applying dry flowables with aerial and groundboom equipment; and

 Mixing/Loading/Applying with a mechanically pressurized handgun.

The label states that human flagging is prohibited. Flagging to support aerial application is 

limited to use of the Global Positioning System (GPS) or mechanical flaggers.

HED classifies exposures from 1 to 30 days as short-term and exposures from 30 days to six 

months as intermediate-term. Exposure duration is determined by many things, including the 

exposed population, the use site, the pest pressure triggering the use of the pesticide, and the 

cultural practices surrounding that use site. For most agricultural uses, it is reasonable to believe 

that occupational handlers will not apply the same chemical every day for more than a onemonth time frame; however, there may be a large agribusiness and/or commercial applicators 

who may apply a product over a period of weeks (e.g., completing multiple applications for 

multiple clients within a region). The area treated or amount handled is based on HED 

ExpoSAC Policy No. 9.1 (refer to Appendix E for these assumptions for each scenario).

It is the policy of HED to use the best available data to assess handler exposure. Sources of 

generic handler data, used as surrogate data in the absence of chemical-specific data, include the 

Pesticide Handlers Exposure Database (PHED) 1.1, the Agricultural Handlers Exposure Task 

Force (AHETF) database, or other registrant-submitted occupational exposure studies. Some of 

these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of the 

Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). The standard values 

recommended for use in predicting handler exposure that are used in this assessment, known as 

“unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate 

Reference Table4”, which, along with additional information on HED policy on use of surrogate 

data, including descriptions of the various sources, can be found at the Agency website5.

 

4 Available: http://www.epa.gov/opp00001/science/handler-exposure-table.pdf

5 Available: http://www.epa.gov/pesticides/science/handler-exposure-data.html
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There are no risk estimates of concern at the baseline level of personal protective equipment 

(PPE); the proposed label requires chemical-resistant gloves as PPE. All short- and

intermediate-term handler risk estimates (inhalation only) resulted in MOEs ranging 7,400 to 

970,000. Note that only engineering control (enclosed cockpit) data are available to assess risks 

to handlers operating aircrafts.

HED has no data to assess exposures to pilots using open cockpits. The only data available is for 

exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the 

engineering control (enclosed cockpits) and baseline attire (long-sleeve shirt, long pants, shoes, 

and socks); per the Agency’s Worker Protection Standard stipulations for engineering controls, 

pilots are not required to wear protective gloves for the duration of the application. With this 

level of protection, there are no risk estimates of concern for applicators.

9.2 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. Post-application exposure levels vary over time and depend on such things as the 

type of activity, the nature of the crop or target that was treated, the type of pesticide application, 

and the chemical’s degradation properties. In addition, the timing of pesticide applications, 

relative to harvest activities, can greatly reduce the potential for post-application exposure.

9.2.1 Dermal Post-Application Risk

There is potential for short- and intermediate-term occupational exposure during post-application 

activities. However, there are no dermal PODs selected for any exposure duration for zoxamide. 

9.2.2 Restricted Entry Interval

Zoxamide is classified as Toxicity Category III via the dermal route. It is a moderate irritant to 

eyes, it is not irritating to the skin, but it is a skin sensitizer. Typically, the REI specified on the 

proposed label is based on the acute toxicity of the active ingredient. Under 40 CFR 156.208 (c) 

(2) (iii), active ingredients classified as Acute III or IV for acute dermal, eye irritation, and 

primary skin irritation are assigned a 12-hour REI. Thus, the 48-hour restricted entry interval 

(REI) on the proposed label is acceptable for bulb onions.

9.2.3 Inhalation Post-Application Risk

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

assessment was not performed for zoxamide at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV), low vapor pressure (9.75×10-8 mm Hg at 20 °C), and 

the low proposed use rate (0.17 lb ai/A). However, there are multiple potential sources of postapplication inhalation exposure to individuals performing post-application activities in 
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previously treated fields. These potential sources include volatilization of pesticides and 

resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert 

advice and input on issues related to volatilization of pesticides from its Federal Insecticide, 

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

received the SAP’s final report on March 2, 20106. The Agency is in the process of evaluating 

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

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

subsequently, the way to incorporate occupational post-application inhalation exposure into the 

Agency's risk assessments. If new policies or procedures are put into place, the Agency may 

revisit the need for a quantitative occupational post-application inhalation exposure assessment 

for zoxamide.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios.

10.0 References

Khan, Faruque. 01/17/2014. DP Barcode 417061. “Drinking Water Exposure Assessment in 

support of the new use registration of zoxamide formulated product Gavel® 75DF on onions 

(dry bulb), garlic and shallots.”

Negussie, Meheret. 01/23/2014. DP Barcode 416653. “Zoxamide. Petition for the Establishment 

of Permanent Tolerances for Use on Dry Onion Bulbs. Summary of Analytical Chemistry 

and Residue Data.”

Negussie, Meheret. 01/29/2014. DP Barcode 416654. “Zoxamide: Chronic Aggregate Dietary 

(Food plus Drinking Water) Exposure and Risk Assessments in Support of a Section 3 

Registration on Dry Onion Bulbs.”

Rury, Kristin. 04/02/2014. TXR 0056915. “Zoxamide: Summary of Hazard and Science Policy 

Council (HASPOC) Meeting of February 27, 2014: Recommendations on the Need for

Subchronic Inhalation and Immunotoxicity Studies.”

Tsaur, Nancy. 04/03/2014. DP Barcode 416655. “Zoxamide. Occupational and Residential 

Exposure and Risk Assessment for the Proposed New Use on Bulb Onions (Crop Subgroup 

3-07).”

 

6 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The toxicology study requirements (40 CFR § 158.500) for food use for zoxamide are in Table 

A.1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols 

were used.

Table A.1. Satisfication of Zoxamide Toxicology Data Requirements

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

870.1200 Acute Dermal Toxicity

870.1300 Acute Inhalation Toxicity

870.2400 Acute Eye Irritation

870.2500 Acute Dermal Irritation

870.2600 Skin Sensitization

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 90-Day Oral Toxicity in Rodents

870.3150 90-Day Oral Toxicity in Non-Rodents

870.3200 21/28-Day Dermal Toxicity

870.3250 90-Day Dermal Toxicity

870.3465 90-Day Inhalation Toxicity

yes

yes

yes

CRa(no)

CRa(no)

yes

yes

yes

no

waivedb

870.3700 Prenatal Developmental Toxicity Study (Rodent)

870.3700 Prenatal Developmental Toxicity Study (Non-Rodent)

870.3800 Reproduction and Fertility Effects

yes

yes

yes

yes

yes

yes

870.4100 Chronic Toxicity (Rodent)

870.4100 Chronic Toxicity (Non-Rodent)

870.4200 Carcinogenicity (Two Rodent Species; Rat and Mouse)

870.4300 Combined Chronic Toxicity/Carcinogenicity

yes

no

yes

---

yes

yes

yes

yes

870.5100 Bacterial Reverse Mutation Test yes yes

870.5300 in vitro Mammalian Cell Gene Mutation Test

870.5375 in vitro Mammalian Chromosome Aberration Test

870.5385 Mammalian Bone Marrow Chromosomal Aberration Test

870.5395 Mammalian Erythrocyte Micronucleus Test

yes

yes

yes

yes

yes

yes

no

yes

870.6200 Neurotoxicity Screening Battery (Acute, Rat)

870.6200 Neurotoxicity Screening Battery (Subchronic, Rat)

870.6300 Developmental Neurotoxicity Study

yes

yes

CRa(no)

yes

yes

---

870.7200 Companion Animal Safety

870.7485 Metabolism and Pharmacokinetics

870.7600 Dermal Penetration

870.7800 Immunotoxicity

CRa(no)

yes

CRa(no)

yes

---

yes

---

waivedb

a CR = conditionally required.

b Waived by Hazard and Science Policy Council (HASPOC) on 02/27/2014 (TXR0056915, K. Rury, 04/02/2014).
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A.2 Toxicity Profiles

Table A.2.1. Zoxamide Acute Toxicity Profile

Guideline No. Study Type MRID Results Toxicity 

Category

870.1100 Acute Oral Toxicity (Rat) 44731805 LD50 > 5000 mg/kg IV

Acute Oral Toxicity (Mouse) 44731806 LD50 > 5000 mg/kg IV

870.1200 Acute Dermal Toxicity (Rat) 44731807 LD50 > 2000 mg/kg III

870.1300 Acute Inhalation Toxicity (Rat) 44731808 LC50 > 5.3 mg/L IV

870.2400 Acute Eye Irritation (Rabbit) 44731809

Corneal opacity beginning 24 hrs post dosing 

and ending at 72 hrs post dosing. 

Conjunctivitis beginning 1 hr post dosing 

and resolved by Day 07.

III

870.2500 Acute Dermal Irritation (Rabbit) 44731810 No irritation was noted IV

870.2600 Dermal Sensitization (Guinea Pig)

44731811

The chemical is a strong dermal sensitizer: 

All sites challenged with test material had 

scattered mild redness to intense redness and 

swelling; two sites had subcutaneous 

hemorrhaging.

---

44731812

Table A.2.2. Zoxamide Subchronic, Chronic, and Other Toxicity Profiles

Guideline Study Type MRID (year) / Doses / Classification Results

870.3100 90-Day Oral 

Toxicity in 

Rodents (Rat)

44731814 (1996)

ppm:

0, 70, 700, 2500, 7000

mg/kg/day:

M: 0, 12, 123, 436, 1212

F: 0, 17, 174, 574, 1666

Acceptable / Guideline

NOAEL (mg/kg/day): M = 1212 F = 1666

LOAEL (mg/kg/day): M > 1212 F > 1666

870.3150 90-Day Oral 

Toxicity in 

Non-Rodents 

(Dog)

44731816 (1997) 

ppm:

0, 1500, 7500, 30000

mg/kg/day:

M: 0, 54.5, 281.1, 1139.3

F: 0, 61.8, 321.6, 1054.5

Acceptable / Guideline

NOAEL (mg/kg/day): M = 321.6 F = 54.5

LOAEL (mg/kg/day): M = 1139.3 F = 321.6

M: Based on increased mean liver weight, evidence 

of corresponding hepatocellular hypertrophy, 

decrease in albumin and albumin/globulin ratios.

F: Based on increased mean liver weight

870.3200 21/28-Day

Dermal 

Toxicity 

(Rabbit)

44731818 (1998)

mg/kg/day:

M: 0, 150, 400, 1000

F: 0, 150, 400, 1000

Acceptable / Guideline

Systemic

NOAEL (mg/kg/day): M = 1000 F = 1000

LOAEL (mg/kg/day): M > 1000 F > 1000

Dermal

NOAEL (mg/kg/day): M < 150 F < 150

LOAEL (mg/kg/day): M < 150 F < 150

Based on dermal effects such as skin irritation. 

870.3700 Prenatal 

Developmental 

Toxicity Study 

(Rat)

44731823 (1994) 

mg/kg/day:

F: 0, 100, 300, 1000

Acceptable / Guideline

Maternal

NOAEL (mg/kg/day) ≥ 1000

LOAEL (mg/kg/day) > 1000

Developmental

NOAEL (mg/kg/day) ≥ 1000

LOAEL (mg/kg/day) > 1000
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Table A.2.2. Zoxamide Subchronic, Chronic, and Other Toxicity Profiles

Guideline Study Type MRID (year) / Doses / Classification Results

Prenatal 

Developmental 

Toxicity Study 

(Rabbit)

44731824 (1997) 

mg/kg/day:

F: 0, 100, 300, 1000

Acceptable / Guideline

Maternal

NOAEL (mg/kg/day) = 1000

LOAEL (mg/kg/day) > 1000

Developmental

NOAEL (mg/kg/day) = 1000

LOAEL (mg/kg/day) > 1000

870.3800 Reproduction 

and Fertility 

Effects 

(Rat)

44770001 (1998) 

ppm:

0, 1000, 5000, 20000

mg/kg/day:

M: 0, 71.4, 359.7, 1473.5

F: 0, 82.0, 409.3, 1624.4

Acceptable / Guideline

Parental

NOAEL (mg/kg/day): M = 1473.5 F = 409.3

LOAEL (mg/kg/day): M > 1473.5 F = 1624.4

F: Based on decreased body weights and body 

weight gains.

Offspring

NOAEL (mg/kg/day): M = 2091.3 F = 2239.1

LOAEL (mg/kg/day): M > 2091.3 F > 2239.1

870.4100 Chronic 

Toxicity (Dog)

44731817 (1998)

ppm:

0, 1500, 7500, 30000

mg/kg/day:

M: 0, 50, 255, 1016

F: 0, 48, 277, 994

Acceptable / Guideline

NOAEL (mg/kg/day): M = 50 F = 48

LOAEL (mg/kg/day): M = 255 F = 277

Based on body weight changes, increases in liver 

and thyroid weights, and increases in alkaline 

phosphatase.

870.4200 Carcinogenicity 

(Mouse)

44731819 (1998)

ppm:

0, 350, 1750, 7000

mg/kg/day:

M: 0, 51.1, 251, 1021

F: 0, 60.4, 326, 1289

Acceptable / Guideline

NOAEL (mg/kg/day): M = 1021 F = 1289

LOAEL (mg/kg/day): M > 1021 F > 1289

No evidence of carcinogenicity.

870.4300 Combined 

Chronic 

Toxicity/

Carcinogenicity 

(Rat)

44731821 (1998)

ppm:

0, 1000, 5000, 20000

mg/kg/day:

M: 0, 51, 260, 1058 

F: 0, 65, 328, 1331

Acceptable / Guideline

NOAEL (mg/kg/day): M = 1058 F = 1331

LOAEL (mg/kg/day): M > 1058 F > 1331

No evidence of carcinogenicity.

870.5100 Bacterial 

Reverse 

Mutation Test

(Salmonella 

typhimurium)

44731825 (1996)

μg/plate:

S9: 50, 200, 500, 2000,

5000

Acceptable / Guideline 

±S9: Negative up to 5000 μg/mL

No evidence of mutagenicity.

44731835 (1998)

μg/plate:

S9: 50, 200, 500, 2000,

5000

Acceptable / Guideline 

±S9: Negative up to 5000 μg/mL

No evidence of mutagenicity.
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Table A.2.2. Zoxamide Subchronic, Chronic, and Other Toxicity Profiles

Guideline Study Type MRID (year) / Doses / Classification Results

44731838 (1998)

μg/plate:

S9: 50, 200, 500, 2000,

5000

Acceptable / Guideline 

±S9: Negative up to 5000 μg/mL

No evidence of mutagenicity.

870.5300 in vitro

Mammalian 

Cell Gene 

Mutation Test

(Chinese 

Hamster Ovary

Cells)

44731826 (1994)

μg/mL:

-S9: 5, 10, 20, 30,

40, 50, 65

+S9: 2, 5, 10 20,

30, 40, 55

Acceptable / Guideline

S9: Negative up to the maximum dose

No evidence of mutagenicity.

870.5375 in vitro

Mammalian 

Chromosome 

Aberration 

Test

(Chinese 

Hamster Ovary

cells)

44731827 (1998)

μg/mL:

S9: 0.9689 - 100

Acceptable / Guideline

± S9: Negative up to cytotoxic concentrations

The test substance did not induce structural 

chromosome aberrations in cultured CHO cells 

treated up to the limit of toxicity, but did induce 

increased levels of numerical aberrations, both in the 

presence and absence of metabolic activation.

870.5395 Mammalian 

Erythrocyte 

Micronucleus 

Test

(Mouse, 

Gavage)

44742904 (1989)

mg/kg:

M: 0, 200, 1000, 2000

F: 0, 200, 1000, 2000

Acceptable / Guideline

The test substance is considered to be nonmutagenic 

in the mouse bone marrow micronucleus assay when 

tested up to the clinical limit dose.

None of the test article animals showed increases 

over vehicle control in the frequency of bone 

marrow micronucleated poly chromatic erythrocytes 

up to the limit dosing, in contrast to dose-related 

increases in the positive control animals.

870.6200 Neurotoxicity 

Screening 

Battery

(Acute Rat)

44731831 (1997)

mg/kg:

M: 0, 125, 500, 2000

F: 0, 125, 500, 2000

Acceptable / Guideline

NOAEL (mg/kg/day): M = 2000 F = 2000

LOAEL (mg/kg/day): M > 2000 F > 2000

Neurotoxicity 

Screening 

Battery

(Subchronic 

Rat)

44731815 (1996)

ppm:

0, 1000, 5000, 20000

mg/kg/day:

M: 0, 74, 372, 1509

F: 0, 80, 401, 1622

Acceptable / Guideline

NOAEL (mg/kg/day): M = 1509 F = 1622

LOAEL (mg/kg/day): M > 1509 F > 1622

870.7485 Metabolism 

and 

Pharmacokinet

ics (Rat, 

Gavage)

44731829 (1998)

mg/kg:

Single: 10, 1000

Repeated: 10

Bile-Cannulated: 10

Acceptable / Guideline

Absorption

Absorption was determined to be 54.62-59.02% of 

the administered dose (AD). The urine contained 

8.78-11.26% AD and the bile contained 45.84-

47.76% AD. 

Distribution
ZOXAMIDE Human Health Risk Assessment DP No. D411543

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Table A.2.2. Zoxamide Subchronic, Chronic, and Other Toxicity Profiles

Guideline Study Type MRID (year) / Doses / Classification Results

44731836 (1998)

mg/kg:

Single: 1000

Acceptable / Guideline

Metabolite -

14C-RH-141,452

Zoxamide was found in the largest quantities in the 

liver (7.21% AD) and kidneys (0.13% AD) in 

addition to the residual carcass (27.91% AD). In the 

rest of the body, Zoxamide residues were found in 

trace quantities.

Metabolism

Non-metabolized zoxamide was the major 

component in feces (12.1-23.0% AD). In addition, 

some of the major metabolites that were identified 

include M-3/RH-141,643 (7.44% AD) and M-7/RH141,454 (5.74% AD). The metabolic pathway of

zoxamide involved a combination of glutathione 

conjugation, reductive dehalogenation, hydrolysis, 

and oxidations.

Elimination

The majority (96-102%) of elimination in the rat 

occurred within 120 hours. There was no radiolabel 

in the expired air and no evidence for 

bioaccumulation. Based on excretion and tissue 

residue data, bioavailability is conservatively 

estimated at about 59% of an administered dose.

44731839 (1998)

mg/kg:

Single: 1000

Acceptable / Guideline

Metabolite -

14C-RH-141,455

44731830 (1998)

mg/kg:

Single: 2000

Acceptable / Guideline

85-3

870.7600

in vitro 

Dermal 

Penetration 

(Human & Rat)

HED Document Number 04464

(2001) HIARC - Dermal Absorption

For the 10 hour exposure period the percent dermal 

absorption proposed is 3% based on the 3.17% and 

2.51% absorbed at 10 hours for the 80 WP and 80 2F 

formulations, respectively.

44731832 (1998)

mg/kg/day:

M: 800, 15, 1.5

Acceptable / Guideline

The 80WP formulation was dosed at 800, 15 and 1.5 

g/cm2for exposure durations of 1, 10 and 24 hours. 

Dermal absorption was low at 0.56, 1.22 and 5.08 % 

per 24 hours for the respective doses. The 80 2F 

formulation was dosed at 2,400 and 1.5 ug/cm2for 

exposure durations of 10 and 24 hours. Dermal 

absorption was low at 0.42 and 6.38 % for the 

respective doses. At the only common dose (1.5 

g/cm2) there was no meaningful difference in 

dermal absorption between the two formulations.
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Appendix B. Physical/Chemical Properties

Table B. Physico-Chemical Properties

Parameter Value Reference

Molecular Weight 336.64 g/mol

MRID 

49067102

Melting range 159.5 - 160.5 °C (98.8% purity)

Density Relative Density 1.38 at 20 °C

Water solubility (20°C) 0.681 ± 0.017 mg/L

Solvent solubility (20°C)

Ethyl acetate: 20.0 g/L

Acetone: 55.7 g/L

Xylene: 1.56 g/L

n-Octanol: 6.49 g/L

n-Heptane: 0.038 g/L

1,2-Dichloroethane: 12.5 g/L

Vapor pressure (at 25, 35, and 45°C) <1.3 x 10-5 Pa

9.75×10-8 mm Hg

Dissociation constant, pKa

Not measurable by spectrophotometry, 

titration or conductivity. Absorbance did not 

change in acidic, neutral, or basic conditions; 

Solubility was too low for titration; with 

decrease in concentration, no increase in 

reading was observed.

Octanol/water partition coefficient, log KOW (25°C) Log Kow 3.76 ± 0.04 at ambient temp

UV/visible absorption spectrum 212 nm. ε = 46330
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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 studies, which comprise PHED and

AHETF, have been determined to require a review of their ethical conduct and have received that 

review. In this assessment, PHED and AHETF data were used to assess mixing, loading, and 

applying dry flowable formulations of zoxamide.

 

Studies reviewed by the Human Studies Review Board:

None.

Appendix D. International Residue Limit Status

Table D.1. Zoxamide Summary of US and International Tolerances and Maximum Residue Limits

Residue Definition

US Canada Mexicob Codex

40 CFR 180. 567 (a)General 

(1) 3,5-dichloro-N-(3-chloro-1-ethyl-1-

methyl-2-

oxopropyl)-4-methylbenzamide

(2) combined residues of zoxamide and 

its metabolites 3,5-dichloro-1,4-

benzenedicarboxylic acid (RH-1455 and 

RH-141455) and 3,5-dichloro-4-

hydroxymethylbenzoic acid (RH-1452 

and RH-141452) 

Grapes and raisins: 3,5-dichloro-N-(3-chloro-1-

ethyl-1-methyl-2-

oxopropyl)-4-methylbenzamide

Potatoes, potato processed fractions (chips, 

flakes and granules): 

3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-

oxopropyl)-4-methylbenzamide, including the

metabolites 3,5-dichloro-1,4-benzenedicarboxylic

acid and 3,5-dichloro-4-hydroxymethyl

benzoic acid

Zoxamide

Commoditya

Tolerance/Maximum Residue Limit

US Canada Mexicob Codex

ppm mg/kg

Onion, bulb, subgroup 3-07A 0.7

Completed: M. Negussie; 12/04/2013

a Includes only commodities of interest for this action.

b Mexico adopts US tolerances and/or Codex MRLs for its export purposes.
ZOXAMIDE Human Health Risk Assessment DP No. D411543

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Appendix E. Occupational Exposure/Risk Summary Table

Table E.1. Occupational Handler Short- and Intermediate-Term Exposure and Risk Estimates for Zoxamide

Exposure Scenario Crop or Targeta

Baseline 

Inhalation 

Unit 

Exposureb

Maximum

Application 

Ratec

Area 

Treated or 

Amount 

Handled 

Dailyd

Baseline Inhalation

Dosee MOEf

μg/lb ai lb ai/A Acres mg/kg/day ST/IT

LOC = 100

Mixer/Loader

Mixing/Loading Dry Flowables for 

Aerial and Chemigation Application Typical Field Crops

8.96

0.17 350 0.00651 7,400

Mixing/Loading Dry Flowables for 

Groundboom Application Typical Field Crops 0.17 80 0.00149 32,000

Applicator

Applying Sprays for Aerial 

Application Typical Field Crops 0.068 0.17 350 0.0000494 970,000

Applying Sprays for Groundboom 

Application Typical Field Crops 0.34 0.17 80 0.0000565 850,000

Mixer/Loader/Applicator

M/L/A Dry Flowables for 

Mechanically-Pressurized Handgun 

Sprayers

Typical Field Crops 

(Foliar) 3.9 0.017lb ai/gal

1000

gallons 0.000809 59,000

a “Typical Field Crops” include bulb onions (Subroup 3-07A).

b Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2012); Level of mitigation = 

Baseline. Aerial Application is in a closed system at baseline level (no PPE).

c Based on the maximum application rates on the proposed label (Reg. No. 10163-6414, Gavel® 75DF Fungicide).

d Exposure Science Advisory Council Policy #9.1.

e Inhalation Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × 

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

f Inhalation MOE = Inhalation NOAEL (48 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).