Zoxamide Human Health Risk Assessment DP No. 0424990 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

DATE: February 3, 20 16 

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

Uses on Ginseng, Tomato Subgroup 8-1 OA; Small Fruit, Vine Climbing, Except 

Fuzzy Kiwifruit, Subgroup 13-07F; and Tuberous and Corm Vegetable Subgroup 

IC. 

PC Code: I 01702 DP Barcode: D424990 

Decision No.: 498225 Registration No.: 10163-6414 

Petition No.: 4E8335 Regulatory Action: Section 3 Registration 

Case No.: 

TXRNo.: 

MRID No.: 

FROM: 

THROUGH: 

TO: 

NA Risk Assessment Type: Single Chemical I Aggregate 

NA CAS No.: 156052-68-5 

NA 40 CFR: §180.567 

Laura Nollcn, Biologist, Risk Assessed. ____,,, J/J_Pl .._,,,L-_ 2/ 3 }t.J 

Meheret Ncgussie, Chemist Hc,Ae,;:e;:/- ;J~~ Vincent Chen, Toxicologist ~ /?:::... c:_ 

Risk Assessment Branch 3 (RAB3); ant( - <../ 

James S. Miller, Environmental Scientist, RAB 1 

Health Effects Division (7509P) 

Christine 

Risk Assessment 

Olinger, 

Branch 

Chief 

3 (RA ~~i ) _ ---- Health Effects Division (7509 

Barbara Madden, Team Leader; Sidney Jackson, Biologist 

Minor Use and Emergency Response Branch (MUERB); and 

Tony Kish (PM), Marcel Howard, Production Management Team #22 

Registration Division (7505P) 

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

evaluation of proposed new agricultural uses or the active ingredient (ai) zoxamide. A summary 

or the findings and an assessment of human 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 was conducted by Meheret 

Negussie; the occupational exposure risk assessment was conducted by James S. Miller; and the 

aggregate human health risk assessment was conducted by Laura Nollen. 

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Zoxamide Human Health Risk Assessment DP o. 0 424990 

Table of Contents 

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

2.0 HED Recommendations ....................................................................................................... 6 

2.1 Data Deficiencies ............................................................................................................ 6 

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

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

2.2.2 Recommended Tolerances ......................................................................................... 7 

2.2.3 Revisions to Petitioned-For Tolerances .................................................................... 7 

2.2.4 International Harmonization ..................................................................................... 8 

2.3 Label Recomn1endations ................................................................................................ 8 

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

3.1 Chemical Identity ........................................................................................................... 9 

3.2 Physical/Chemical Characteristics ............................................................................. 10 

3.3 Pesticide Use Pattern .................................................................................................... I 0 

3.4 Anticipated Exposure Path,vays ................................................................................. 11 

3.5 Consideration of Environmental Justice .................................................................... 11 

4.0 Hazard Characterization and Dose-Response Assessment ............................................. 12 

4.1 Studies Available for Analysis ..................................................................................... 12 

4.2 Absorption, Distribution, Metabolism and Excretion (ADME) .............................. 12 

4.2.1 Dermal Absorption ................................................................................................... 13 

4.3 Summary of Toxicological Effects .............................................................................. 13 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ............................... 13 

4.4.1 Completeness of the Toxicology Database .......................................................... 14 

4.4.2 Evidence of Neurotoxicity .................................................................................... 14 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal .... 14 

4.4.4 Residual Uncertainty in the Exposure Database ................................................ 14 

4.5 Toxicity Endpoint and Point of Departure Selection ................................................ 14 

5.0 Dietary Exposure and Risk Assessment ............................................................................ 15 

5.1 Residues of Concern Summary and Rationale .......................................................... 15 

5.2 Food Residue Profile .................................................................................................... 16 

5.3 Water Residue Profile .................................................................................................. 16 

5.4 Dietary Risk Assessment .............................................................................................. 17 

5.4.1 Description of Residue Data Used in Dietary Assessment ................................ 17 

5.4.2 Acute Dietary Risk Assessment ........................................................................... 18 

5.4.3 Chronic Dietary Risk Assessment ....................................................................... 18 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ................................ 18 

6.1 Residential Bystander Post-Application Inhalation Exposure ................................ 19 

6.2 Spray Drift .................................................................................................................... 19 

7.0 Aggregate Exposure/Risk Characterization ..................................................................... 19 

8.0 Cumulative Exposure/Risk Characterization .................................................................. 20 

9.0 Occupational Exposure/Risk Characterization ............................................................... 20 

9.1 Short- and Intermediate-Term Handler Risk ........................................................... 20 

9.2 Short- and Intermediate-Term Post-Application Risk ............................................. 21 

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Zoxamide Human Health Risk Assessment DP No. D424990

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9.2.1 Dermal Post-Application Risk ............................................................................. 21

9.2.2 Inhalation Post-application Risk ......................................................................... 21

10.0 References............................................................................................................................22

Appendix A. Toxicology Profile and Executive Summaries ....................................................23

A.1 Toxicology Data Requirements................................................................................... 23

A.2 Toxicity Profiles............................................................................................................ 24

Appendix B. Physical/Chemical Properties.............................................................................31

Appendix C. Review of Human Research ................................................................................31

Appendix D. International Residue Limit Status....................................................................32

Appendix E. Occupational Exposure/Risk Summary Table..................................................33

Appendix F. Chronic Food Plus Water Residue Input File- DEEM-FCID..........................35

Appendix G. Dislodgeable Foliar Residue (DFR) Waiver Summary ....................................38
Zoxamide Human Health Risk Assessment DP No. D424990

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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 via 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.

The Interregional Research Project Number 4 (IR-4) has submitted pesticide petition (PP#)

4E8335 in order to propose a tolerance for residues of zoxamide in or on ginseng; Tomato 

subgroup 8-10A; Small vine climbing fruit, except fuzzy kiwifruit, subgroup 13-07F; and 

Tuberous and corm vegetable subgroup 1C. In conjunction with this petition, section 3 

registration requests for Gavel® 75DF Fungicide (EPA Reg. No. 10163-6414) were submitted 

for ginseng and Tomato subgroup 8-10A. The registrant, Gowan Company, owns the EP 

associated with this action. 

Proposed Use Profile

Gavel® 75DF is a water dispersible granule (WG) that may be applied as a broadcast foliar spray 

via groundboom, aircraft, or chemigation application equipment. Ginseng proposed use 

directions specify up to 6 foliar applications with maximum single and seasonal application rates 

of 0.17 pounds (lb) ai/acre (A) and 0.96 lb ai/A, respectively, and a pre-harvest interval (PHI) of 

28 days. Tomato subgroup 8-10A is proposed for a single maximum application rate of 0.17 lb 

ai/A and a PHI of 5 days; regional-specific seasonal rates propose up to 4 foliar applications 

(0.66 lb ai/A) West of the Mississippi; up to 8 foliar applications are proposed East of the 

Mississippi, for a total seasonal application rate maximum of 1.33 lb ai/A. The label specifies a

48-hour restricted entry interval (REI) and requires occupational handlers to wear long pants, 

long sleeves, shoes, socks, and chemical-resistant gloves.

Exposure Profile

Exposure to zoxamide may occur from dietary (food and drinking water) and occupational 

exposure sources. Dietary exposures are expected for chronic durations. Occupational handler 

and post-application exposures are expected for short- and intermediate-term durations only. 

There are no proposed or registered residential uses of zoxamide. 

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. Following zoxamide 

exposures, liver and thyroid weights increased along with liver histopathological changes and 

increases in alkaline phosphatase. A dermal point of departure (POD) was not chosen because 

systemic toxicity was not seen in the 28-day rat dermal toxicity study up to the limit dose and 

there was no developmental effect seen at the limit dose in both rat and rabbit developmental 

study. No reproductive and offspring effects were found in the reproduction study at doses above 

the limit dose. The short- and intermediate-term inhalation PODs are based on effects seen in the

chronic dog oral toxicity study. 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 

concern regarding susceptibility to developing fetuses or pups. Therefore, the data support a 
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reduction of the Food Quality Protection Act (FQPA) safety factor to 1x. Zoxamide is classified 

as “not likely to be carcinogenic to humans” based on results from adequate carcinogenicity 

studies in rats and mice.

Dietary Exposure (Food and Water) and Risk Estimates

An adverse effect attributable to a single dose was not identified; 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 tolerancelevel residues and 100 percent crop treated (PCT). The estimated drinking water concentration 

(EDWC) of 65.8 μg/L was incorporated directly into the dietary assessment. The results of the 

chronic dietary analysis for food and drinking water are below the HED’s level of concern 

(LOC) for all population subgroups. 

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 and Post-Application Exposures and Risk Estimates

Occupational handler and post-application exposures to zoxamide are expected for short- and 

intermediate-term durations based on the proposed uses. A dermal risk assessment was not 

conducted for zoxamide because no systemic toxicity was seen at the limit dose in the routespecific dermal study, and no concerns for development or reproductive effects were seen 

elsewhere in the database. Results indicate that short- and intermediate-term inhalation risk

estimates are not of concern at baseline mitigation without personal protective equipment (PPE). 

Based on the Agency's current practices, a quantitative non-cancer occupational post-application 

inhalation exposure assessment was not performed for zoxamide. 

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, which include Pesticide 

Handlers Exposure Database Version 1.1 (PHED 1.1) and the Agricultural Handler Exposure 

Task Force (AHETF), 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 website1. 

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 

 

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

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

2.0 HED Recommendations

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

submission of a revised Section B, as well as the submittal of analytical reference standards as 

outlined in Section 2.1, there are no issues that would preclude the establishment of the 

recommended tolerances. 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

An analytical standard for zoxamide is currently available in the EPA National Pesticide 

Standards Repository; with expiration date of 11/30/2019. However, the standard for zoxamide 

metabolites (RH1452 and RH1455) and derivatives (RH147391 and RH147399) is expired or is

available only in 1 gram (personal email with Teresa Cole, ACB, 11/16/2015). The registrant is 

required to submit a reasonable amount of the analytical reference standard for the metabolites 

and derivatives. The reference standard should be sent to the Analytical Chemistry Lab, which is 

located at Fort Meade, Maryland, to the attention of either Theresa Cole or Thuy Nguyen at the 

following address:

USEPA

National Pesticide Standards Repository/Analytical Chemistry Branch/OPP

701 Mapes Road

Fort George G. Meade, MD 20755-5350

(Note that the mail will be returned if the extended zip code is not used.)

2.2 Tolerance Considerations

IR-4, on behalf of the Agricultural Experiment Station of the state of Michigan, has submitted 

PP# 4E8335 in order to propose a tolerance for residues of zoxamide in or on Tomato subgroup 

8-10A at 2.0 parts per million (ppm); and Small fruit, vine climbing, except fuzzy kiwifruit, 

subgroup 13-07F at 5.0 ppm. Additionally, IR-4 proposed a tolerance for residues of zoxamide 

and its metabolites in or on ginseng at 0.30 ppm and Tuberous and corm vegetable subgroup 1C

at 0.060 ppm.

2.2.1 Enforcement Analytical Method

Adequate analytical methods are available for tolerance enforcement purposes for the residues of 

concern in or on plant commodities. Gas chromatography with electron capture detection 

(GC/ECD) and GC with mass selective detection (GC/MSD) methods, are available for tolerance 

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

acid metabolites (RH-1452 and RH-1455) in or on potato tubers and potato processed fractions, 

GC/MSD serves as the primary method and GC/ECD is considered confirmatory. The methods 
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have been adequately validated for the determination of residues of zoxamide in plant 

commodities, and have been forwarded to the Food and Drug Administration. Adequate multiresidue methods testing data have been submitted. These data indicate that the multi-residue 

methods are adequate for enforcement of tolerances for zoxamide only.

2.2.2 Recommended Tolerances

Tolerances for residues of zoxamide are established under 40 CFR §180.567(a)(1), and 40 CFR 

§180.567(a)(2) for the combined residues of zoxamide and its metabolites RH-1452 and RH1455. The currently established tolerance expressions for zoxamide are adequate, and include

both coverage and compliance statements for enforcement purposes. HED recommends that 40 

CFR §180.567(a)(1) and 40 CFR §180.567(a)(2) be amended by establishing tolerances as listed 

in Table 2.2.2 below. 

Table 2.2.2. Tolerance Summary for Zoxamide

Commodity

Proposed 

Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Correct Commodity 

Definition/Comments

To be established under 40 CFR §180.567 (a) General. (1)

Tomato subgroup 8-10A 2.0 2.0 Established tolerance for tomato 

should be removed upon 

establishment of this subgroup 

tolerance.

Fruit, small, vine climbing, except 

fuzzy kiwifruit, Subgroup 13-07F 

5.0 5.0 Fruit, small vine climbing, except 

fuzzy kiwifruit, subgroup 13-07F. 

Previously established tolerance 

for grape should be removed upon 

establishment of this subgroup 

tolerance.

To be established under 40 CFR §180.567 (a) General. (2)

Vegetable, tuberous and corm, 

Subgroup 1C

0.060 0.06 Vegetable, tuberous and corm, 

subgroup 1C

Previously established tolerance 

for potato should be removed upon 

establishment of this subgroup 

tolerance.

Ginseng 0.30 0.30 Tolerance recommendation based 

on potato granules/flakes data

translation.

Note to RD: The existing tolerances for grape, tomato, and potato should be removed from 40 

CFR §180.567(a), as they will be superseded by the establishment of crop subgroup tolerances as 

recommended in Table 2.2.1.

2.2.3 Revisions to Petitioned-For Tolerances

HED has no recommended revisions to the petitioned-for tolerances of zoxamide. 
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2.2.4 International Harmonization

The residue definitions are harmonized for the U.S. and Canada. The U.S. and Canadian residue 

definitions include zoxamide for grapes and processed grapes and zoxamide and its metabolites 

(RH-1452 and RH-1455) for potatoes and processed potatoes. The Codex residue definition 

includes the parent zoxamide only for all crops, and is therefore not harmonized with the 

tolerance expression for certain U.S. commodities. 

The tolerance recommendation for Tomato subgroup 8-10A at 2.0 ppm in harmonized with a 

Canadian maximum residue limit (MRL) on tomatoes at 2 ppm and a Codex MRL on tomatoes 

at 2 ppm. A tolerance was proposed and recommended in or on Small vine climbing fruit, except 

fuzzy kiwifruit, subgroup 13-07F at 5.0 ppm, in order to harmonize with an established Codex 

MRL on grape at 5 ppm. The increased U.S. tolerance recommendation on subgroup 13-07F at 

5.0 ppm results in a lack of harmonization with an established Canadian MRL on grape at 3.0 

ppm. The tolerance recommendation for Tuberous and corm vegetable subgroup 1C at 0.06 ppm 

is harmonized with a Canadian MRL established on potato at 0.06 ppm; however, the U.S. 

tolerance is not harmonized with a Codex MRL at 0.02 ppm. The underlying residue data and 

residue definition used to support the Subgroup 1C tolerance supports a tolerance 

recommendation that is higher than the established Codex MRL on potato at 0.02 ppm. There are 

no Codex or Canadian MRLs for ginseng. The International Residue Limit Status is detailed in 

Appendix D.

2.3 Label Recommendations

The proposed use directions for Gavel® 75DF Fungicide (EPA Reg. No. 10163-6414) should be 

revised to include only ginseng and Tomato subgroup 8-10A. Reference to the following 

commodities should be removed, as the registrant has withdrawn these proposed registrations: 

Small vine climbing fruit, except fuzzy kiwifruit, subgroup 13-07F, except for the previouslyregistered use on grape; and Tuberous and corm vegetable subgroup 1C, except for the

previously-registered use on potato.

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. Zoxamide is currently 

registered for use on cucurbit vegetables, grapes, onions, potatoes, and tomatoes. In conjunction 

with this petition, section 3 registration requests were proposed for Gavel® 75DF Fungicide

(EPA Reg. No. 10163-6414) to add uses on ginseng and Tomato subgroup 8-10A (tomato is 

currently registered). The registrant, Gowan Company, owns the EP associated with this action. 
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3.1 Chemical Identity

Table 3.1. Zoxamide Nomenclature. 

Chemical structure

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

Molecular weight 336.64 g/mol

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 (EPA Reg. No. 10163-6414) (This product is a combination of 

zoxamide + mancozeb. Only zoxamide residues have been determined.)

Chemical structure

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

N

H

Cl

Cl

Cl

O

O
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Table 3.1. Zoxamide Nomenclature. 

Chemical structure

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 section 3 label amendments for the 75% WG EP formulation of zoxamide 

(Gavel® 75DF Fungicide; EPA Reg. No. 10163-6414) which are summarized in Table 3.3.

Gavel® 75 DF is a mixture of 8.3% zoxamide and 66.7% mancozeb. While additional section 3 

use directions were proposed for Small fruit, vine climbing, except fuzzy kiwifruit, subgroup 13-

07F; and Tuberous and corm vegetable subgroup 1C, they were subsequently withdrawn because 

there were no supporting tolerances for mancozeb, the co-formulated ai, in or on those 

subgroups.

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 (lb 

product/A or 

lb ai/A) 1

Maximum 

Number of 

Applications 

per Year

Maximum 

Seasonal 

Application Rate

PHI2

(days) Use Directions and Limitations

Ginseng3

Foliar: 

Ground, 

Aerial

2.0 lb 

product/A; 

0.17 lb ai/A

6

12 lb

product/A/season; 

0.96

lb ai/A/season

28

Start applications when 

environmental conditions are 

favorable for disease 

development. Use in a minimum 

spray volume of 80 gallons of 
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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 (lb 

product/A or 

lb ai/A) 1

Maximum 

Number of 

Applications 

per Year

Maximum 

Seasonal 

Application Rate

PHI2

(days) Use Directions and Limitations

water/acre and direct sprays to 

provide thorough coverage of 

foliage and stems. Consecutive 

sprays must be at least 7 day 

apart. Do not apply through any 

type of irrigation system.

Tomato subgroup 8-10A4

Foliar:

Ground, 

Aerial, 

Chemigation

2.0 lb product/A; 

0.17 lb ai/A

4

8 lb 

product/A/Season; 

0.66

lb ai/A/season 5

Start applications when 

seedlings emerge or transplants 

are set and repeat at 7 to 10 day 

intervals or when environmental 

conditions are favorable for 

disease development.

8 (East of 

Mississippi)

16 lb 

product/A/season; 

1.33 lb ai/A/season

1 Calculated lb ai/A assumes given density of active ingredient = 0.08 lb zoxamide/lb product). 

2 PHI = pre-harvest interval.

3 Ginseng proposed use pattern is based upon and similar to the existing registered use for potato, except for the 

PHI (14-days for potato). Proposal for translating the potato granules/flakes tolerance of 0.30 ppm to ginseng was 

approved by the ChemSAC (09/2013). 

3 Tomato is currently registered for EPA Reg. No. 10163-6414. 

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

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

applicators may be exposed dermally and by inhalation while handling zoxamide prior to 

application, as well as during application. There is also a potential for post-application dermal 

and inhalation 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 of zoxamide.

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.epa.gov/environmentaljustice/resources/policy/exec_order_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 
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subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water 

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

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

Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, 

(NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a 

pesticide. These data are analyzed and categorized by subgroups based on age and ethnic group. 

Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and 

exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 

post-application are evaluated. Spray drift can also potentially result in post-application 

exposure and it is also being considered whenever appropriate. Further considerations are also 

currently in development as OPP has committed resources and expertise to the development of 

specialized software and models that consider exposure to other types of possible bystander

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

subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

The pesticidal mode of action for zoxamide 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 Studies Available for Analysis

The toxicological database for zoxamide is considered complete and adequate for risk 

assessment. The studies available for risk assessment include an acute toxicity battery; 

subchronic oral toxicity studies in rats and dogs; a subchronic dermal toxicity study in rabbits; 

prenatal developmental toxicity studies in rats and rabbits; a reproduction and fertility effects 

study in rats; chronic toxicity studies in rats and dogs; carcinogenicity studies in rats and mice; a 

battery of mutagenicity studies; a neurotoxicity screening battery, including acute and subchronic 

studies in rats; and metabolism and pharmacokinetic studies 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). All available toxicity studies are listed in Appendix A.

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

conservatively estimated at about 59% of an administered dose.

4.2.1 Dermal Absorption

Dermal penetration studies were evaluated for two formulations of zoxamide (80 WP and 80 2F), 

in order to establish a dermal absorption factor (DAF) of 3% (TXR0014464, 02/07/2001).

4.3 Summary of Toxicological Effects

In general, the available data indicate low toxicity following exposure to zoxamide. In rat repeat 

dose oral and dermal toxicity studies, there were no indications of systemic toxicity up to the 

highest dose tested (HDT); most of the highest doses were at or above the limit dose (1,000 

mg/kg/day). In the dog repeat dose oral toxicity studies, effects included increased liver and 

thyroid weights, liver histopathology (i.e., hepatocellular hypertrophy), and increased alkaline 

phosphatase.

In the rat and rabbit prenatal developmental toxicity studies, there were no indications 

susceptibility, as there was neither maternal nor developmental toxicity up to the HDT. In the rat 

reproduction and fertility effects study, there were no indications of susceptibility, since parental 

effects (i.e., decreased maternal body weight) occurred in the absence of reproductive or 

offspring toxicity.

Zoxamide has been classified as “not likely to be carcinogenic in humans” based on the results of 

carcinogenicity studies in rats and mice. The mutagenicity studies do not indicate increased 

mutagenic potential in the battery of in vivo and in vitro assays. 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. In the acute and subchronic neurotoxicity studies, there 

were no indications of neurotoxicity up to the HDT.

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

a slight to moderate irritant to the eye and skin; and is a strong dermal sensitizer.

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

For all assessment scenarios, the default 10x FQPA Safety Factor (SF) can be reduced to 1x

because of the following conclusions: (1) the toxicological database for zoxamide is complete;

(2) there was no evidence of susceptibility following pre- or postnatal exposure in the young; (3) 

there was no evidence of neurotoxicity; and (4) there are no residual uncertainties in the 

exposure database. The details for these determinations are presented in the following sections: 
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4.4.1 Completeness of the Toxicology Database

The toxicity database for azoxystrobin is complete and adequate for risk assessment. 

Consequently, HED believes the existing data are sufficient for toxicity endpoint selection for 

exposure/risk assessment scenarios and for evaluation of the requirements under the FQPA.

4.4.2 Evidence of Neurotoxicity

There was no evidence of neurotoxicity in the acute and subchronic neurotoxicity studies in rats 

up to their respective limit doses. 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

There was no evidence for increased susceptibility following prenatal exposure in prenatal 

developmental toxicity studies in rats and rabbits. Additionally, there was no evidence for 

increased susceptibility following pre- or postnatal exposure in the reproduction and fertility 

effects study in rats.

4.4.4 Residual Uncertainty in the Exposure Database

The exposure databases are complete for the purposes of risk assessment. The chronic dietary 

food exposure assessment was conservatively based on 100 percent crop treated (PCT) 

assumptions and conservative drinking water modeling estimates. There are no registered or 

proposed residential uses. All of the exposure estimates are based on conservative assumptions 

that are not likely to result in underestimated risk.

4.5 Toxicity Endpoint and Point of Departure Selection

Since the last completed human health risk assessment (D411543, N. Tsaur, 04/03/2014), there 

have been no changes to the dose-response assessment; nor have there been any changes to the 

cancer classification.

Table 4.5 provides the summary of the toxicological doses and endpoints that were used in the 

dietary and occupational human health risk assessments for zoxamide.

Table 4.5. Summary of Toxicological Doses and Endpoints for use in Dietary and Occupational Human 

Health Risk Assessments1

Exposure 

Scenario

Point of 

Departure 

(POD)

Uncertainty / 

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary

(All Populations)

No endpoint was identified since there is no indication of an adverse effect attributable to a 

single dose and susceptibility, neurotoxicity, and immunotoxicity were not observed in the 

database.
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Table 4.5. Summary of Toxicological Doses and Endpoints for use in Dietary and Occupational Human 

Health Risk Assessments1

Exposure 

Scenario

Point of 

Departure 

(POD)

Uncertainty / 

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

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 

(All Durations)

No endpoint was identified because there are no residential uses or concerns for residential 

exposure; there was no systemic toxicity in a 28-day dermal toxicity study in the rat up to 

the limit dose (1000 mg/kg/day); and no developmental effects were seen in rats and rabbits 

at the limit dose. No susceptibility was found in the reproduction study. 

Inhalation2

Short Term 

(1-30 days)

Intermediate Term

(1-6 months)

Oral NOAEL = 

48 mg/kg/day

Note: Toxicity via 

the inhalation and 

oral routes are 

assumed to 

equivalent.

UFA = 10x

UFH = 10x

FQPA = 1x

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 and 

inhalation)

Classification: “Not Likely to be Carcinogenic to Humans” based on the results of 

carcinogenicity studies in rats and mice (TXR0014464, 07 February 2001).

1 Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data 

and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant 

human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. 

UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level 

of concern. 

2 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 and storage stability data are available to support the proposed uses of 

zoxamide on ginseng; Tomato subgroup 8-10A; Small fruit, vine climbing, except fuzzy 

kiwifruit, subgroup 13-07F; and Tuberous and corm vegetable subgroup 1C. No new residue 

data were submitted in conjunction with this action. Rather, residue field trial data were 

previously reviewed for the representative commodities associated with the petitioned-for crop 

subgroups associated with this action. Additionally, the proposed use of ginseng is based upon an 

approved translation of data from potato granules/flakes, as per a Chemistry Science Advisory 

Council (ChemSAC) decision (ChemSAC minutes dated 09/11/13 and 09/18/13).

Processing studies for the currently registered zoxamide uses are adequate. Zoxamide processing 

studies are available for potatoes and grapes, and tolerances are established on potato wet peel, 

potato flakes, and raisins. Livestock feedstuffs associated with the proposed uses of zoxamide 

include 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.

The proposed use on ginseng and the crop subgroup tolerances for zoxamide do not alter the 

Agency’s previous conclusion that there is no reasonable expectation of finite residues in 

ruminant and poultry commodities.

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. Data indicate 

that zoxamide is moderately persistent but immobile in soil; 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 of soil immobility.
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The EDWCs for zoxamide are based upon zoxamide (parent only) as well as the total toxic 

residues of zoxamide and its major metabolites, (RH-150721, RH-24549, RH-141288, RH129151 and RH-1 39432) in surface water and groundwater in support of human health risk 

assessment. The most conservative EDWC (65.8 μg/L) was based on an existing potato/grape 

use, and was used in the chronic dietary assessment.

Table 5.3. Summary of Estimated Drinking Water Concentrations for Zoxamide1

Zoxamide (Parent only) (μg/L)

Drinking Water 

Source Crop Scenario Peak Exposure Annual Mean Exposure Average Annual Exposure 

Surface Water NY Grape STD 

Scenario2 17.55 2.49 0.91

Ground Water FL Citrus 

Scenario3 0.00183 NA 0.000684

Total Toxic Residue (Zoxamide + Metabolites)4(μg/L)

Drinking Water 

Source Crop Scenario Peak Exposure Annual Mean Exposure Average Annual Exposure

Surface Water NY Grape STD2

Scenario 81.3 54.48 22.84

Ground Water WI Sands 

Scenario3 83.5 NA 65.8

1 EDWC modeling includes total toxic residue (TTR) of zoxamide and five major degradates.

2 Percent Crop Area of 0.91 adjusted EDWCs generated using Pesticide Root Zone Model/Exposure Analysis 

Modeling System (PRZM/EXAMS) model for aerial application.

3 Highest EDWCs generated using PRZM for Groundwater (PRZM-GW) model based on 1.60 lb ai/A for grape 

and potato (Gavel 80 WP, EPA Reg. No.10163-6413).

4 Metabolites = RH-150721, RH-24549, RH-141288, RH-129151, and RH-139432.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

HED conducted a screening-level chronic dietary (food and drinking water) risk assessment for 

zoxamide using exposure and risk estimates obtained from the Dietary Exposure Evaluation 

Model using the Food Commodity Intake Database (DEEM-FCID; version 3.16). The model 

uses food consumption data from the Department of Agriculture’s (USDA’s) 2003-2008 

National Health and Nutrition Examination Survey, What We Eat in America

(NHANES/WWEIA) database. The assessment incorporated tolerance-level residues and 100 

PCT for all established and proposed commodities. The assessment also utilized default

processing factors from the DEEM-FCID version 7.81 except for raisin and potato 

granules/flakes, where the processing factor was set at 1. EDWCs from EFED were also 

included: the average ground water exposure of 65.8 μg/L was incorporated directly into the 

dietary assessment. 

Since the last completed dietary risk assessment, no new residue data have been submitted to the 

Agency to support the requested tolerances. Therefore, all of the input files and assumptions are 

nearly identical to the last completed dietary risk assessment for zoxamide (M. Negussie, 

D416654, 01/29/2014), except that updates in DEEM-FCID version 3.16 were added to 
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incorporate the petitioned-for crop subgroups as well as to include Small vine climbing fruit, 

except fuzzy kiwifruit, subgroup 13-07F at 5.0 ppm; a petitioned-for tolerance request to 

harmonize with Codex. The inputs and results to this dietary assessment are presented in 

Appendix F.

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

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 1.8% of the chronic Population Adjusted Dose (cPAD) 

for the general U.S. population and 6.3% of the cPAD for children 1 to 2 years old, the 

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

percentages increased slightly from the last completed dietary risk assessment. The results of the 

chronic dietary exposure analyses are reported in Table 5.4.5.

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 0.008547 1.8 

All Infants (< 1 year old) 0.013444 2.8

Children 1-2 years old 0.030265 6.3

Children 3-5 years old 0.022592 4.7

Children 6-12 years old 0.011490 2.4

Youth 13-19 years old 0.005998 1.2

Adults 20-49 years old 0.006824 1.4

Adults 50+ years old 0.006701 1.4

Females 13-49 years old 0.006729 1.4

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 of zoxamide.
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6.1 Residential Bystander Post-Application Inhalation Exposure

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

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

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

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

March 2, 2010 (http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2009-0687-

0037). The agency has evaluated the SAP report and has developed a Volatilization Screening 

Tool and a subsequent Volatilization Screening Analysis 

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

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

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

zoxamide.

6.2 Spray Drift

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

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

potential source of exposure from the ground application methods (e.g., groundboom and 

airblast) employed for zoxamide. The agency has been working with the Spray Drift Task Force 

(a task force composed of various registrants which was developed as a result of a Data Call-In 

issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and 

other parties to develop the best spray drift management practices (see the agency’s Spray Drift 

website for more information). 2 The agency has also developed a policy on how to 

appropriately consider spray drift as a potential source of exposure in risk assessments for 

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

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

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

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

Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification 

of indirect non-occupational exposure to drift. 

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.

 

2 Available: http://www2.epa.gov/reducing-pesticide-drift 
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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 

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

This document presents an assessment of the proposed uses of zoxamide on ginseng and Tomato 

subgroup 8-10A. Based on application rate and label information, only short- and intermediateterm dermal and inhalation exposure is expected for occupational handlers and post-application 

workers. Chronic exposure is not expected for the proposed use pattern. 

9.1 Short- and Intermediate-Term Handler Risk

Based on the anticipated use patterns and current labeling, 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 and loading the WG formulation of zoxamide for aerial, chemigation, and 

groundboom applications; and

 Applying as a foliar treatment with via aerial, or groundboom equipment

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. Therefore, an 

occupational flagger assessment was not conducted for the proposed uses of zoxamide. 

For short- and intermediate-term exposure, only inhalation exposures were assessed since there 

is no systemic hazard from the dermal route of exposure. There are no risk estimates of concern 

at the baseline level of personal protective equipment (PPE). The proposed labels require 

occupational handlers to wear baseline clothing (long-sleeved shirts, long pants, shoes, socks) 

and chemical resistant gloves. MOEs ranged from 2,100 to 1,400,000 for short- and 

intermediate-term exposures. Appendix E summarizes all assessed occupational exposure and 

risk estimates.

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

handlers operating aircrafts. Dermal handler and post-application exposure and risk assessments 

were not conducted because a dermal hazard was not identified for zoxamide. HED has no data 

to assess exposures to pilots using open cockpits. The only data available are for exposures to 

pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the engineering control 
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(enclosed cockpits) and baseline PPE; 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; 

therefore, an occupational dermal post-application assessment and a dislodgeable foliar residue 

(DFR) study are not required at this time (see Appendix G). 

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 restricted entry 

interval (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 ginseng and Tomato 

subgroup 8-10A.

9.2.2 Inhalation Post-application Risk

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

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

include volatilization of pesticides and resuspension of dusts and/or particulates that contain 

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

pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel 

(SAP) in December 2009, and received the SAP’s final report on March 2, 2010 

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

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

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQOPP-2014-0219). During Registration Review, the agency will utilize this analysis to determine 

if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is 

required for zoxamide.
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In addition, the Agency is continuing to evaluate the available post-application inhalation 

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

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

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

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

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

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

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

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

inhalation exposure scenarios.

10.0 References

Seifu, Edom. 03/19/2015. DP Barcode 425825. “Drinking Water Exposure Assessment in 

support of the new use registration of zoxamide formulated product Gravel 75DF on ginseng, 

tomato subgroup (Subgroups 8-10A), small fruit vine climbing except fuzzy kiwifruit

(Subgroup 13-07F), and tuberous and corm subgroup (Subgroup 1 C).”

Negussie, Meheret. 09/17/2015. DP Barcode 429154. “Zoxamide. Petition for Ginseng and Crop 

Subgroup Expansions for Vegetable, Tuberous and Corm, Subgroup 1C; Tomato Subgroup 

8-10A; and Fruit, Small Vine Climbing, except Fuzzy Kiwifruit, Subgroup 13-07F. 

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.”

Miller, James S. 10/20/2015. DP Barcode 429635. “Zoxamide. Occupational and Residential 

Exposure and Risk Assessment for the Proposed Use on Ginseng, Grapes, Potatoes and 

Tomatoes.”

HIARC. 02/07/2001. HED Document Number 014464. “Zoxamide Report.”

Tsaur, Nancy. 04/03/2014. “Zoxamide. Aggregate Human Health Risk Assessment for the 

Proposed New Use on Bulb Onions (Crop Subgroup 3-07A).”
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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.500) for food uses are in the table below. Use of the new 

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

Table A.1: Toxicology Data Requirements

Guideline Study Type Required Satisfied

870.1100 Acute Oral Toxicity Yes Yes

870.1200 Acute Dermal Toxicity Yes Yes

870.1300 Acute Inhalation Toxicity Yes Yes

870.2400 Acute Eye Irritation Yes Yes

870.2500 Acute Dermal Irritation Yes Yes

870.2600 Skin Sensitization Yes Yes

870.3100 90-Day Oral Toxicity in Rodents Yes Yes

870.3150 90-Day Oral Toxicity in Non-Rodents Yes Yes

870.3200 21/28-Day Dermal Toxicity Yes Yes

870.3250 90-Day Dermal Toxicity CR NA

870.3465 90-Day Inhalation Toxicity CR Yes2

870.3700 Prenatal Developmental Toxicity Study (Rat) Yes Yes

Prenatal Developmental Toxicity Study (Rabbit) Yes Yes

870.3800 Reproduction and Fertility Effects Yes Yes

870.4100 Chronic Toxicity (Rodent) Yes Yes

870.4200 Carcinogenicity (Rat) Yes Yes

Carcinogenicity (Mouse) Yes Yes

870.5100 Bacterial Reverse Mutation Test Yes Yes

870.5300

870.5375

in vitro Mammalian Cell Gene Mutation Test

in vitro Mammalian Chromosome Aberration Test Yes1 Yes

870.5385

870.5395

Mammalian Bone Marrow Chromosomal Aberration Test

Mammalian Erythrocyte Micronucleus Test Yes1 Yes

870.6100 Delayed Neurotoxicity of Organophosphorus Substances (Acute, Hen) CR NA

Delayed Neurotoxicity of Organophosphorus Substances (28-Day, Hen) CR NA

870.6200 Neurotoxicity Screening Battery (Acute, Rat) Yes Yes

Neurotoxicity Screening Battery (90-Day, Rat) Yes Yes

870.6300 Developmental Neurotoxicity Study CR NA

870.7200 Companion Animal Safety CR NA

870.7485 Metabolism and Pharmacokinetics Yes Yes

870.7600 Dermal Penetration CR NA

870.7800 Immunotoxicity Yes Yes2

CR Conditionally Required

NA Not Applicable

1 Either guideline study type may be used to satisfy the data requirement (e.g., 870.5300 or 870.5375)

2 Study requirement waived (TXR0056915, 02 April 2014)
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A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile

Guideline Study Type MRID (year) / Doses / 

Classification Results

870.1100 Acute Oral 

Toxicity

(Rat)

44731805 (1996)

Gavage Doses (mg/kg):

M: 5000

F: 5000

Acceptable / Guideline

Toxicity Category:IV

LD50 (mg/kg): M > 5000

F > 5000

Combined > 5000

Acute Oral 

Toxicity

(Mouse)

44731806 (1998)

Gavage Doses (mg/kg):

M: 5000

F: 5000

Acceptable / Guideline

Toxicity Category:IV

LD50 (mg/kg): M > 5000

F > 5000

Combined > 5000

870.1200 Acute Dermal 

Toxicity

(Rat)

44731807 (1996)

Dermal Dose (mg/kg):

M: 2000

F: 2000

Acceptable / Guideline

Toxicity Category:III

LD50 (mg/kg): M > 2000

F > 2000

Combined > 2000

870.1300 Acute Inhalation 

Toxicity

(Rat)

44731808 (1996)

Inhalation Dose (mg/L):

M: 1.9, 5.3

F: 1.9, 5.3

Acceptable / Guideline

Toxicity Category:IV

LC50 (mg/L): M > 5.3

F > 5.3

Combined > 5.3

870.2400 Acute Eye 

Irritation

(Rabbit)

44731809 (1996)

Acceptable / Guideline

Toxicity Category:III

Based on corneal opacity beginning 24 hrs post 

dosing and ending at 72 hrs post dosing; and 

conjunctivitis beginning 1 hr post dosing and 

resolved by Day 07.

870.2500 Acute Dermal 

Irritation

(Rabbit)

44731810 (1996)

Acceptable / Guideline

Toxicity Category:IV

No irritation was noted

870.2600 Skin 

Sensitization

(Guinea Pig)

44731811 (1997)

Acceptable / Guideline

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.
Zoxamide Human Health Risk Assessment DP No. D424990

Page 25 of 38

Table A.2.2. Repeat-Dose and Other Toxicity Profile

Guideline Study Type

MRID (year) / 

Doses / 

Classification

Results

870.3100 90-Day Oral Toxicity 

in Rodents 

(Rat)

44731814 (1996)

Dietary 

Concentration 

(ppm):

0, 70, 700, 

2500, 7000

Dietary Dose 

(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)

Dietary 

Concentration 

(ppm):

0, 1500, 

7500, 30000

Dietary Dose 

(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 = 61.8

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)

Dermal Dose 

(mg/kg/day):

M: 0, 150, 400, 

1000

F: 0, 150, 400, 

1000

Acceptable / 

Guideline

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. 

Systemic

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

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

870.3465 90-Day 

Inhalation Toxicity

NA Study requirement waived (TXR0056915)

870.3700 Prenatal 

Developmental 

Toxicity Study

(Rat)

44731823 (1994)

Gavage Dose 

(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
Zoxamide Human Health Risk Assessment DP No. D424990

Page 26 of 38

Table A.2.2. Repeat-Dose and Other Toxicity Profile

Guideline Study Type

MRID (year) / 

Doses / 

Classification

Results

Prenatal 

Developmental 

Toxicity Study

(Rabbit)

44731824 (1997) 

Gavage Dose 

(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)

Dietary 

Concentration 

(ppm):

0, 1000, 

5000, 20000

Dietary Dose 

(mg/kg/day):

M0: 0, 71.4, 

359.7, 1473.5

F0: 0, 82.0, 

409.3, 1624.4

M1: 0, 100.1, 

489.2, 2091.3

F1: 0, 108.2, 

534.1, 2239.1

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

Reproductive / 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)

Dietary 

Concentration 

(ppm):

0, 1500, 

7500, 30000

Dietary Dose 

(mg/kg/day):

M: 0, 50, 255, 

1016

F: 0, 48, 278, 

994

Acceptable / 

Guideline

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

LOAEL (mg/kg/day): M = 255 F = 278

Based on body weight changes, increases in liver and 

thyroid weights, and increases in alkaline phosphatase.
Zoxamide Human Health Risk Assessment DP No. D424990

Page 27 of 38

Table A.2.2. Repeat-Dose and Other Toxicity Profile

Guideline Study Type

MRID (year) / 

Doses / 

Classification

Results

870.4200 Carcinogenicity

(Mouse) 

44731819 (1998)

Dietary 

Concentration 

(ppm):

0, 350, 1750, 

7000

Dietary Dose 

(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)

Dietary 

Concentration 

(ppm):

0, 1000, 

5000, 20000

Dietary Dose 

(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)

Applied Dose 

(μg/plate):

S9: 50, 200, 

500, 2000, 

5000

Acceptable / 

Guideline

±S9: Negative up to 5000 μg/mL

No evidence of mutagenicity.

44731835 (1998)

Applied Dose 

(μg/plate):

S9: 50, 200, 

500, 2000, 

5000

Acceptable / 

Guideline

±S9: Negative up to 5000 μg/mL

No evidence of mutagenicity.

44731838 (1998)

Applied Dose 

(μg/plate):

S9: 50, 200, 

500, 2000, 5000

Acceptable / 

Guideline

±S9: Negative up to 5000 μg/mL

No evidence of mutagenicity.
Zoxamide Human Health Risk Assessment DP No. D424990

Page 28 of 38

Table A.2.2. Repeat-Dose and Other Toxicity Profile

Guideline Study Type

MRID (year) / 

Doses / 

Classification

Results

870.5300 in vitro Mammalian 

Cell Gene Mutation 

Test

(Mouse Lymphoma 

Cells)

44731826 (1994)

Applied Dose 

(mg/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 (CHO) cells)

44731827 (1998)

Applied Dose 

(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)

44742904 (1989)

Gavage Dose 

(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 Acute Neurotoxicity 

Screening Battery

(Rat)

44731831 (1997)

Gavage Dose 

(mg/kg):

M: 0, 125, 500,

20000

F: 0, 125, 500, 

20000

Acceptable / 

Guideline 

Neurotoxicity

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

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

Systemic

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

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

90-Day Neurotoxicity 

Screening Battery

(Rat)

44731815 (1996)

Dietary 

Concentration 

(ppm):

0, 1000, 

5000, 20000

Intake Dose 

(mg/kg/day):

M: 0, 74, 372, 

1509

F: 0, 80, 401, 

1622

Acceptable / 

Guideline

Neurotoxicity

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

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

Systemic

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

LOAEL (mg/kg/day): M > 1509 F > 1622
Zoxamide Human Health Risk Assessment DP No. D424990

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Table A.2.2. Repeat-Dose and Other Toxicity Profile

Guideline Study Type

MRID (year) / 

Doses / 

Classification

Results

870.7485 Metabolism and 

Pharmacokinetics 

(Rat)

44731829 (1989)

Gavage Dose 

(mg/kg):

Single: 

10, 1000

Repeated: 10

Bile-Cannula: 

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 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 M3/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 ~59% of 

an administered dose.

44731836 (1998)

Metabolite: 14CRH-141,452

Gavage Dose 

(mg/kg):

Single: 

1000

Acceptable / 

Guideline

44731839 (1998)

Metabolite: 14CRH-141,455

Gavage Dose 

(mg/kg):

Single: 

1000

Acceptable / 

Guideline

44731830 (1998)

Gavage Dose 

(mg/kg):

Single: 

2000

Acceptable / 

Guideline

870.7600 Dermal Penetration (in 

vivo Rat)

TXR 0014464 

(2001)

44731832 (1998)

For the 10 hour exposure period, the dermal absorption 

factor (DAF) is 3% based on the 3.17% and 2.51% 

absorbed at 10 hours for the 80WP and 2F 

formulations, respectively. 
Zoxamide Human Health Risk Assessment DP No. D424990

Page 30 of 38

Table A.2.2. Repeat-Dose and Other Toxicity Profile

Guideline Study Type

MRID (year) / 

Doses / 

Classification

Results

44731832 (1998)

Formulation: 

80WP (80% a.i.)

Dermal Dose 

(g/cm2):

M: 1.5, 15, 

800

Formulation: 2F 

(24% a.i.)

Dermal Dose 

(g/cm2):

M: 1.5, 2400

Acceptable / 

Guideline

80WP

For 10 hours of exposure, dermal absorption was 3.17, 

0.80, and 0.56% in their respective dose groups.

For 24 hours of exposure, dermal absorption was 5.08, 

1.22, and 0.56% in their respective dose groups

2F

For 10 hours of exposure, dermal absorption was 2.51 

and 0.29% in their respective dose groups.

For 24 hours of exposure, dermal absorption was 6.38 

and 0.42% in their respective dose groups.

870.7800 Immunotoxicity NA Study requirement waived (TXR0056915)
Zoxamide Human Health Risk Assessment DP No. D424990

Page 31 of 38

Appendix B. Physical/Chemical Properties

Table B.1. Physicochemical Properties of Zoxamide.

Parameter Value Reference

Melting point/range 159.5 - 160.5 °C (98.8% purity) MRID 49067102

pH 6.9 at 24.3°C

Density Relative Density 1.38 at 20 °C

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

Solvent solubility (at 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)

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, KOW

Log Kow 3.76 ± 0.04 at ambient temp

UV/visible absorption spectrum 212 nm. ε = 46330

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, which include Pesticide 

Handlers Exposure Database Version 1.1 (PHED 1.1); and the Agricultural Handler Exposure 

Task Force (AHETF) database; are (1) subject to ethics review pursuant to 40 CFR 26, (2) have 

received that review, and (3) are compliant with applicable ethics requirements. For certain 

studies, the ethics review may have included review by the Human Studies Review Board. 

Descriptions of data sources, as well as guidance on their use, can be found at the Agency 

website3.

 

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

http://www.epa.gov/pesticides/science/post-app-exposure-data.html
Zoxamide Human Health Risk Assessment DP No. D424990

Page 32 of 38

Appendix D. International Residue Limit Status

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

Residue Definition: 

US Canada Mexico2 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-dichloroN-(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-ethyl1-methyl-2-

oxopropyl)-4-methylbenzamide, 

including the

metabolites 3,5-dichloro-1,4-

benzene-dicarboxylic

acid and 3,5-dichloro-4-

hydroxymethyl

benzoic acid

Zoxamide

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

US Canada Mexico2 Codex

Ginseng 0.30 0.3 potato flakes/granules

Tomato subgroup 8-10A 2.0 2 tomatoes 2 

tomatoes

Fruit, small, vine climbing, 

except fuzzy kiwifruit, subgroup 

13-07F

5.0 3 grapes 5 grapes

Vegetable, tuberous and corm, 

subgroup 1C

0.06 0.06 potatoes 0.02 

potato

Completed: M. Negussie; 09/17/15
Zoxamide Human Health Risk Assessment DP No. D424990

Page 33 of 38

Appendix E. Occupational Exposure/Risk Summary Table

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

Exposure Scenario Crop or Targetb

Baseline Inhalation Unit 

Exposurec

Maximum

Application 

Ratev

Area Treated 

Dailye

Baseline Inhalation

Dosef MOEg

μg/lb ai lb ai/A Acres mg/kg/day

ST/IT

LOC = 

100

Mixing/Loading "Dry Flowable"

Aerial / 

Chemigation

Orchard

(Grapes)

8.96

0.20

350

0.00784 6,100

Field Crops-Typical

(Ginseng, Tomatoes)

0.17

0.00666 7,200

Field Crops-High 

Acreage

(Potatoes)

1200 0.0229 2,100

Airblast

Orchard

(Grapes)

8.96

0.20 40 0.000896 54,000

Groundboom

Field Crops-Typical 

(Ginseng, Tomatoes)

0.17

80 0.00153 31,000

Field Crops-High 

Acreage

(Potatoes)

200 0.00381 13,000

Applicator

Aerial

Orchard

(Grapes)

0.0049

0.20

350

0.00000429 11,000,000

Field Crops-Typical

(Ginseng, Tomatoes)

0.17

0.00000365 13,000,000

Field Crops-High 

Acreage

(Potatoes)

1200 0.0000125 3,800,000

Airblast

Orchard

(Grapes)

4.71

0.20 40

0.000471 100,000

Groundboom 0.34

0.000034 1,400,000

Field Crops-Typical 

(Ginseng, Tomatoes)

0.17

80 0.0000578 830,000

Field Crops-High 

Acreage

(Potatoes)

200 0.000145 330,000

Manuel "Flagger" activity is prohibited. Label stipulates GPS only.

a Although short- and intermediate-term exposure and risk estimates for zoxamide are presented for orchard and field crop, high acreage 

scenarios, those assessed uses were subsequently withdrawn by the registrant. The MOEs applicable for the proposed use directions pertain 

only to field crops, typical = ginseng and Tomato subgroup 8-10A

b “Field Crops-Typical” include Ginseng (sub-group 1B), and Tomatoes (sub-group 8-10A), " Field Crop-High Acreage " include Potatoes 

(sub-group 1C) and "Orchard " are Grapes (sub-group 13-07F).
Zoxamide Human Health Risk Assessment DP No. D424990

Page 34 of 38

c Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (2013); Level of mitigation = Baseline except for 

aerial applicator which includes engineering controls.

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

e Exposure Science Advisory Council Policy #9.1.

f 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).

g Inhalation MOE = Inhalation NOAEL (48 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).
Zoxamide Human Health Risk Assessment DP No. D424990

Page 35 of 38

Appendix F. Chronic Food Plus Water Residue Input File- DEEM-FCID

U.S. EPA Ver. 3.16, 03-08-d

DEEM-FCID Chronic analysis for ZOXAMIDE

Residue file: C:\Documents and Settings\MNEGUSSI\My Documents\DEEM Version 

3.16\Zoxamide\OnionBulbs\Chronic_FoodWater2015.R08

 Adjust. #2 NOT used

Analysis Date 11-12-2015 Residue file dated: 11-05-2015/10:25:08

Reference dose (RfD) = 0.48 mg/kg bw/day

Comment:Crop Group Conversion-2015

----------------------------------------------------------------------------------

Food Crop Residue Adj.Factors

EPA Code Grp Food Name (ppm) #1 #2 

---------- ---- ------------------------------- ---------- ------ ------

0103015000 1CD Arrowroot, flour 0.060000 1.000 1.000 

0103015001 1CD Arrowroot, flour-babyfood 0.060000 1.000 1.000 

0103017000 1CD Artichoke, Jerusalem 0.060000 1.000 1.000 

0902021000 9B Balsam pear 1.000000 1.000 1.000 

0901075000 9A Cantaloupe 1.000000 1.000 1.000 

0103082000 1CD Cassava 0.060000 1.000 1.000 

0103082001 1CD Cassava-babyfood 0.060000 1.000 1.000 

0902088000 9B Chayote, fruit 1.000000 1.000 1.000 

0902102000 9B Chinese waxgourd 1.000000 1.000 1.000 

0902135000 9B Cucumber 1.000000 1.000 1.000 

0103139000 1CD Dasheen, corm 0.060000 1.000 1.000 

0301165000 3A Garlic, bulb 0.700000 1.000 1.000 

0301165001 3A Garlic, bulb-babyfood 0.700000 1.000 1.000 

0103166000 1CD Ginger 0.060000 1.000 1.000 

0103166001 1CD Ginger-babyfood 0.060000 1.000 1.000 

0103167000 1CD Ginger, dried 0.060000 1.000 1.000 

0101168000 1AB Ginseng, dried 0.060000 1.000 1.000 

1302174000 13B Gooseberry 5.000000 1.000 1.000 

1304175000 13D Grape 5.000000 1.000 1.000 

1304176000 13D Grape, juice 5.000000 1.200 1.000 

1304176001 13D Grape, juice-babyfood 5.000000 1.200 1.000 

9500177000 O Grape, leaves 5.000000 1.000 1.000 

9500178000 O Grape, raisin 15.000000 1.000 1.000 

1304179000 13D Grape, wine and sherry 5.000000 1.000 1.000 

0901187000 9A Honeydew melon 1.000000 1.000 1.000 

0301237000 3A Onion, bulb 0.700000 1.000 1.000 

0301237001 3A Onion, bulb-babyfood 0.700000 1.000 1.000 

0301238000 3A Onion, bulb, dried 0.700000 9.000 1.000 

0301238001 3A Onion, bulb, dried-babyfood 0.700000 9.000 1.000 

0103296000 1C Potato, chips 0.300000 1.000 1.000 

0103297000 1C Potato, dry (granules/ flakes) 0.300000 1.000 1.000 

0103297001 1C Potato, dry (granules/ flakes)-b 0.300000 1.000 1.000 

0103298000 1C Potato, flour 0.300000 1.000 1.000 

0103298001 1C Potato, flour-babyfood 0.300000 1.000 1.000 

0103299000 1C Potato, tuber, w/peel 0.060000 1.000 1.000 

0103299001 1C Potato, tuber, w/peel-babyfood 0.060000 1.000 1.000 

0103300000 1C Potato, tuber, w/o peel 0.060000 1.000 1.000 

0103300001 1C Potato, tuber, w/o peel-babyfood 0.060000 1.000 1.000 

0902308000 9B Pumpkin 1.000000 1.000 1.000 

0902309000 9B Pumpkin, seed 1.000000 1.000 1.000 

0902356000 9B Squash, summer 1.000000 1.000 1.000 

0902356001 9B Squash, summer-babyfood 1.000000 1.000 1.000 

0902357000 9B Squash, winter 1.000000 1.000 1.000 

0902357001 9B Squash, winter-babyfood 1.000000 1.000 1.000 

0103366000 1CD Sweet potato 0.060000 1.000 1.000 

0103366001 1CD Sweet potato-babyfood 0.060000 1.000 1.000 

0103371000 1CD Tanier, corm 0.060000 1.000 1.000 

0801374000 8A Tomatillo 2.000000 1.000 1.000 
Zoxamide Human Health Risk Assessment DP No. D424990

Page 36 of 38

0801375000 8A Tomato 2.000000 1.000 1.000 

0801375001 8A Tomato-babyfood 2.000000 1.000 1.000 

0801376000 8A Tomato, paste 2.000000 5.400 1.000 

0801376001 8A Tomato, paste-babyfood 2.000000 5.400 1.000 

0801377000 8A Tomato, puree 2.000000 3.300 1.000 

0801377001 8A Tomato, puree-babyfood 2.000000 3.300 1.000 

0801378000 8A Tomato, dried 2.000000 14.300 1.000 

0801378001 8A Tomato, dried-babyfood 2.000000 14.300 1.000 

0801379000 8A Tomato, juice 2.000000 1.500 1.000 

0801380000 8A Tomato, Tree 2.000000 1.000 1.000 

0103387000 1CD Turmeric 0.060000 1.000 1.000 

8601000000 86A Water, direct, all sources 0.065800 1.000 1.000 

8602000000 86B Water, indirect, all sources 0.065800 1.000 1.000 

0901399000 9A Watermelon 1.000000 1.000 1.000 

0901400000 9A Watermelon, juice 1.000000 1.000 1.000 

0103406000 1CD Yam, true 0.060000 1.000 1.000 

0103407000 1CD Yam bean 0.060000 1.000 1.000 

0301338000 3A Shallot, bulb 0.700000 1.000 1.000 

1100173500 11 Goji berry 2.000000 1.000 1.000 

Chronic Results files: Food Plus Water

U.S. EPA Ver. 3.16, 03-08-d

DEEM-FCID Chronic analysis for ZOXAMIDE NHANES 2003-2008 2-day

Residue file name: C:\Documents and Settings\MNEGUSSI\My Documents\DEEM Version 

3.16\Zoxamide\OnionBulbs\Chronic_FoodWater2015.R08

 Adjustment factor #2 NOT used.

Analysis Date 11-12-2015/10:57:35 Residue file dated: 11-05-2015/10:25:08

Reference dose (RfD, Chronic) = .48 mg/kg bw/day

COMMENT 1: Crop Group Conversion-2015

===============================================================================

 Total exposure by population subgroup

-------------------------------------------------------------------------------

 Total Exposure

 -----------------------------------

 Population mg/kg Percent of 

 Subgroup body wt/day Rfd 

-------------------------------------- ------------- ----------------

Total US Population 0.008547 1.8%

Hispanic 0.008687 1.8%

Non-Hisp-White 0.008653 1.8%

Non-Hisp-Black 0.007876 1.6%

Non-Hisp-Other 0.008371 1.7%

Nursing Infants 0.005495 1.1%

Non-Nursing Infants 0.016994 3.5%

Female 13+ PREG 0.007101 1.5%

Children 1-6 0.024630 5.1%

Children 7-12 0.010273 2.1%

Male 13-19 0.006127 1.3%

Female 13-19/NP 0.005870 1.2%

Male 20+ 0.006616 1.4%

Female 20+/NP 0.006902 1.4%

Seniors 55+ 0.006786 1.4%

All Infants 0.013444 2.8%

Female 13-50 0.006704 1.4%

Children 1-2 0.030265 6.3%

Children 3-5 0.022592 4.7%

Children 6-12 0.011490 2.4%

Youth 13-19 0.005998 1.2%

Adults 20-49 0.006824 1.4%

Adults 50-99 0.006701 1.4%
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Female 13-49 0.006729 1.4%

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Appendix G. Dislodgeable Foliar Residue (DFR) Waiver Summary

Dislodgeable Foliar Residue (DFR): In accordance with 40 CFR158, DFR data are required for 

all occupational (e.g., crop, nursery, greenhouse use sites) or residential (e.g., ornamental and 

vegetable gardens, pick your own farms, retail tree farms) uses that could result in postapplication exposure to foliage. In the absence of chemical-specific DFR data, EPA uses default 

values. The 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment 

includes an analysis of a number of DFR studies, which resulted in the selection of a revised 

default values for the fraction of the application rate available for transfer after a foliar 

application (FAR). These values are based on an analysis of 19 DFR studies. Since that time, the 

Agricultural Re-entry Task Force has submitted information (MRID 49299201) that corrects an 

application rate error made in the original submission of “ARF039 – Determination of Dermal 

and Inhalation Exposure to Reentry Workers During Chrysanthemum Pinching in a Greenhouse” 

(EPA MRID 45344501). As a result, the range of FAR values was revised from 2% - 89% to 2% 

- 47%. In the data, a large range of transferability is observed and this variability can potentially 

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

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

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

considering DFR data for a single chemical. At this time, the ARTF submission did not alter the 

selection of 25% as the reasonable, high-end default value. Because DFR data are not available 

for zoxamide, EPA would use the default value of 25%. Although there may be a small degree 

of uncertainty in the use of the default DFR value for zoxamide (i.e., there is a small chance that 

the FAR value may exceed the applicable default value), it is likely that the health-protective 

aspects of EPA’s occupational post-application assessment methodology would more than 

compensate for this potential uncertainty. For example, when assessing residential and 

occupational post-application exposure to gardens and ornamentals, EPA assumes the following: 

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

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

etc); individuals perform the same post-application activities performed in the transfer 

coefficient study day after day (e.g., weeding, harvesting, pruning, etc.); and individuals engage 

in these post-application activities for a high-end amount of time every day (represented by data 

reflecting time spent gardening based on survey data).

Given the conservatisms discussed above and the potential compounding nature of these 

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

exposure is not being underestimated. 

There is no hazard identified for zoxamide via the dermal route of exposure; therefore, a DFR 

study is not required at this time.