UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASIDNGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

MEMORANDUM 

DATE: 

SUBJECT: 

June 4, 2014 

Zoxamide. Human Health Scoping Document in Support of Registration 

Review. 

PC Code: 101702 DP Barcode: D417745 

Decision No.: 487334 Registration Nos.: 10163-6413, -6414, -6415 

Petition No.: NA Regulatory Action: Registration Review 

Case No.: 7032-1 Risk Assessment 1)'~e: NA 

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

MRIDNo.: NA 40 CFR: §180.567 

FROM: Nancy J. Tsaur, Chemist , ~ ~ 

Vincent Chen, Toxicologist _ / _ ~ 

Meheret Negussie, Chemist f1.e,J.,ey-c;r tv•0 ~ 

Risk Assessment Branch 3 

Health Effects Division (7509P) 

THROUGH: Christine Olinger, Branch Chief ~/ ot:: ~ Risk Assessment Branch 3 ~ ~ <:-----

Health Effects Division (7509P) 

TO: Tanja Crk, Chemical Review Manager 

Tom Myers, Team Leader 

Risk Management and Implementation Branch 2 

Pesticide Re-Evaluation Division (7508P) 

Page 1 of 16 
Executive Summary 

This document summarizes the review of the Health Effects Division (HED) human health 

assessments to support the Registration Review ofzoxamide. To determine the scope of work 

necessary to support Registration Review, HED has considered updates to Agency science policy 

and risk assessment methodologies and to the zoxamide toxicity, exposure, and usage databases. 

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

downy mildew). It is currently registered for use on cucurbit vegetables, grapes, potatoes, and 

tomatoes. The current residue chemistry, toxicology, and exposure databases for zoxamide are 

complete and the most recent assessment was conducted based on current risk and exposure 

assessment policies (DP411543, N. Tsaur, 04/03/2014). 

Zoxamide has low acute toxicity following oral, dermal and inhalation exposures and is a 

moderate dermal irritant. No target organ toxicity is identified in mice and rats following oral 

exposures and in rats following dermal exposures at doses including and up to the Limit Dose 

(1000 mglkg/day). In dogs, following oral exposures, the primary target organ is the liver and the 

thyroid glands. There is no evidence of neuro-, developmental, or reproductive toxicity. 

Zoxamide is classified as "not likely to be carcinogenic to humans" and there is no concern for 

mutagenicity. The exposure and toxicity databases are completed and there is no evidence for 

increased susceptibility following pre and post natal exposures. Consequently, there is no need 

for the FQPA Safety Factor (i.e. reduced to IX). 

At this time, all exposure and risk assessments reflect current policy and procedures and do not 

indicate risk estimates of concern. An updated aggregate risk assessment will not be required to 

support Registration Review. In the most recent risk assessment, water was directly incorporated 

into the dietary exposure assessment. The dietary (food and drinking water) exposure 

assessment did not exceed the level of concern for the general U.S. population, infants, and 

children. Updated drinking water and dietary (food and drinking water) exposure risk 

assessments are not needed at this time. Since there are no registered or proposed residential 

uses for zoxamide, an updated residential exposure assessment is not needed at this time. 

Updates to occupational handler dermal exposure and risk assessments also are not needed at this 

time. 

Introduction 

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

downy mildew) on various fruits and vegetables. The two registered formulations of zoxamide 

(dry flowable and water soluble powder) may be applied as a foliar spray via groundboom, 

airblast, aircraft, chernigation, and handheld equipment. The single maximum application rates 

range from of 0.17 pounds active ingredient (ai) per acre to 0.21 lb ail acre. The chemical 

identity and physicochemical properties of zoxamide are attached in Tables 1 and 2, respectively. 

HED has evaluated the status of the human health assessment for zoxamide to determine whether 

sufficient data are available and whether any updates are needed to support Registration Review. 

HED has considered the most recent human health risk assessment for zoxamide as well as HED 

Page 2 of 16 
Page 3 of 16

and Office of Pesticide Programs Information Network (OPPIN) databases. Note that a pending 

action for a new use on onions is under review in the Agency (Docket EPA-HQ-OPP-2013-0644; 

79 FR 29729; 5/23/14).

Hazard Identification/Toxicology

The toxicology database is complete and adequate for human health risk assessment. The 

appended toxicology Tables 5 through 7 provide additional details to the submitted studies. The 

Hazard Science and Policy Council (HASPOC) considered all of the available hazard and 

exposure information for zoxamide and concluded that a subchronic inhalation toxicity and the 

immunotoxicity studies are not required (TXR No.0056915). There was no evidence of target 

organ toxicity in mice or rats following repeated dietary exposures at the limit dose. In dogs, 

subchronic exposure resulted in increased liver weight and hepatocellular hypertrophy. 

Following chronic exposures to dogs, zoxamide caused decreases in body weight, increases in 

liver enzyme and liver weight as well as increases in thyroid weights. There was no evidence of 

neurotoxicity following acute and repeated oral exposures or following repeated dermal 

exposures at the limit dose. No developmental toxicity was seen in the pre-natal toxicity studies 

in rats and rabbits, and there were no adverse effects on reproduction. There is no evidence of 

increased susceptibility following in utero exposures to rats and rabbit or pre-/post-natal 

exposure to rats. Consequently, the FQPA Safety Factor is reduced (1X). Zoxamide is classified 

as “Not Likely to be Carcinogenic to Humans” based on lack of evidence for carcinogenicity in 

mice and rats. There is no evidence for mutagenicity.

An acute dietary risk assessment was not conducted since an endpoint of concern attributable to 

a single exposure was not identified. The chronic dietary risk assessment is based on the oral

point of departure (POD) of 48 mg/kg/day based on decreases in body weight, increases in liver 

and thyroid weights, and increases in alkaline phosphatase seen in the chronic oral toxicity study 

in dogs at 255 mg/kg/day (LOAEL). Quantification of dermal risk is not required due to lack of 

toxicity following repeated dermal exposures at the limit dose and there is no concern for neuro-, 

developmental-or reproductive toxicity. Inhalation exposure of all durations was assessed using 

the oral POD of 48 mg/kg/day in the chronic oral toxicity study in dogs. 

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.

Conclusion:

The toxicology database is adequate for human health risk assessment. All submitted studies are 

detailed in the attached toxicology tables (Table 5 through 7).

Dietary Exposure

Registered uses for zoxamide include the following crops: cucurbit vegetables, grapes, potatoes, 

and tomatoes.
Page 4 of 16

The residues of concern include zoxamide for grapes, processed grapes, tomatoes, and cucurbit 

vegetables; and zoxamide and its metabolites for potatoes and processed potatoes. Adequate 

analytical methods have been validated and are available for enforcing zoxamide tolerances and 

collecting data on residues 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.

The most recent dietary (food and drinking water) assessment for zoxamide included

conservative assumptions for food including 100% crop treated and tolerance-level residues for 

all registered and proposed commodities. The most protective estimated drinking water

concentrations (EDWCs) for zoxamide residues were from modeling the registered uses on 

grapes and potatoes. 

The chronic dietary (food and drinking water) exposure assessment indicated that exposure was 

well below the chronic reference dose (cPAD) for the general US population, and for children 1-

2 years old (the subpopulation with the highest estimated exposure). An acute risk assessment 

was not conducted as no acute toxicological endpoint was identified for zoxamide. A 

carcinogenic risk assessment was not conducted in the most recent human health risk assessment, 

as there is no evidence of carcinogenicity.

Conclusion:

With regard to residue chemistry, HED previously required storage stability data (Guideline 

860.1380) for tomatoes as a condition of registration (T. Alston, DP274785, 08/30/2001), and the 

data deficiency remains outstanding. However, the existing dietary exposure assessment is up to 

date and does not result in any risk estimates of concern. An updated dietary risk assessment is 

not needed at this time.

Residential Exposure

Residential exposures resulting from off-site transport (e.g., spray drift or volatilization) may 

occur as a result of applications of zoxamide. The Agency is in the process of evaluating these 

types of exposures and may, as appropriate, develop policies and procedures to identify the need 

for and, subsequently, the way to incorporate these post-application exposures into the Agency's 

risk assessments.

Conclusion:

Since there are no registered or proposed residential uses for zoxamide, an updated residential 

exposure assessment is not needed at this time. The need for spray drift and volatilization risk 

assessments for zoxamide will be examined during Registration Review. However, off-site 

transport neither affects existing residential risk estimates, nor contributes to the overall 

aggregate assessment.

Aggregate Risk Assessment

An acute dietary risk assessment was not conducted as no acute toxicological endpoint was 
Page 5 of 16

identified for zoxamide. The most recent aggregate risk assessment takes into account average 

exposure estimates from dietary (food only) consumption of zoxamide with direct incorporation 

of estimated residues in drinking water, as discussed above.

Conclusion:

Currently, there are no direct residential uses of zoxamide, so the aggregate exposures only 

include food and drinking water. The most recent risk estimates were below the Agency’s level 

of concern (DP411543, N. Tsaur, 04/03/2014). An updated aggregate assessment is not required 

at this time.

Occupational Exposure

The occupational exposure scenarios associated with the registered and proposed uses were 

assessed adequately based on current HED policies (DP416655, N. Tsaur 04/03/2014); therefore, 

a revised occupational assessment is not required. Zoxamide is registered for use as two end-use 

product formulations (dry flowable and water soluble packets). Table 8 summarizes the 

occupational handler use patterns and potential exposure scenarios. There are no risk estimates 

of concern at the baseline level of personal protective equipment (PPE); the existing labels state 

the requirement for chemical-resistant gloves as PPE. All short- and intermediate-term handler 

risk estimates (inhalation only) resulted in margins of exposure (MOEs) ranging from 7,400 to 

970,000. 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.

The zoxamide database lacks a turf transferable residue (TTR) study. In accordance with the 

updated Part 158 data requirements (2007), a TTR study is required for all occupational (e.g. sod 

farms, golf courses, parks, and recreational areas) or residential turf uses. However, A TTR 

study is not required for zoxamide at this time since there are no registered or proposed turf uses.

The zoxamide database also lacks dislodgeable foliar residue (DFR) studies (applicable to 

agricultural crops). In accordance with the updated Part 158 data requirements (2007), one or 

more DFR studies are required when a pesticide has residential or occupational uses that could 

result in post-application dermal exposure. Because there is no hazard via the dermal route of 

exposure, a non-cancer dermal post-application risk assessment was not performed for zoxamide. 

Therefore, DFR studies are not needed for zoxamide at this time. If the PODs change, the need 

for DFR studies may be reevaluated in the future to refine the post-application assessment. 

Conclusion:

Existing occupational handler dermal exposure and risk assessments reflect current policy and 

procedures for the existing agricultural uses, and updates are not needed at this time.

Public Health and Pesticide Epidemiology Data

Because there are no incident cases reported for zoxamide in either the Main or Aggregate 

Incident Data System (IDS) module, there does not appear to be a concern at this time that would 
Page 6 of 16

warrant further investigation (DP417744, S. Recore, 01/28/2014). The Agency will continue to 

monitor the incident information and, if a concern is triggered, additional analysis will be 

included in the preliminary risk assessment provided under registration review.

Conclusion:

There are no incident cases at this time.

Tolerance Assessment and International Harmonization

Currently, tolerances for residues of zoxamide have been established under 40 CFR 

§180.567(a)(1) on grapes at 3.0 ppm, grape raisins at 15.0 ppm, tomatoes at 2.0 ppm, and 

cucurbit vegetables at 1.0 ppm. Tolerances are established under 40 CFR §180.567(a)(2) for the 

combined residues of zoxamide and its metabolites on potatoes at 0.06 ppm, potato flakes and 

chips at 0.30 ppm, and potato wet peel at 0.10 ppm.

Codex and Canada have established maximum residue limits (MRLs) for zoxamide on grapes, 

tomato, and potato. In addition, Codex has established MRLs on cucurbit vegetables. 

The US tolerance and Canadian MRL expressions are the same. The US and Canadian residue 

definitions include zoxamide for grapes, processed grapes, tomatoes, and cucurbit vegetables;

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

residue definitions are not in harmony for potatoes and processed potatoes. The Codex residue 

definition includes only zoxamide for plants.

The Codex MRL values for grape raisin and tomatoes are in harmony. The Codex MRLs for 

cucurbit vegetables (2 ppm) and grapes (5 ppm) are higher than the US tolerance (1 ppm) and (3 

ppm), respectively. The US and Canadian MRLs are in harmony on all registered crops, except 

potato chips. The US did not establish a tolerance on potato chips. There are no Canadian MRLs 

on tomatoes and cucurbit vegetables. An International Residue Limit Status sheet is attached 

(Table 3).

Conclusion:

During the Registration Review process, HED will evaluate whether or not the US is able to 

harmonize with Codex.

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 United States Department of 
Page 7 of 16

Agriculture’s (USDA’s) National Health and Nutrition Examination Survey (NHANES), 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 children, youths, and adults 

entering or playing on treated areas following application are evaluated. Further considerations 

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

of specialized software and models that consider exposure to bystanders and farm workers as 

well as lifestyle and traditional dietary patterns among specific subgroups.

Cumulative

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. 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 OPP 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/.

Human Studies

Past zoxamide risk assessments rely in part on data from studies in which adult human subjects 

were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. 

These data, which include studies from the Pesticide Handlers Exposure Database Version 1.1 

(PHED 1.1); the Agricultural Re-entry Task Force (ARTF) database; and other registrantsubmitted exposure monitoring studies, are subject to ethics review pursuant to 40 CFR 26, have 

received that review, and are compliant with applicable ethics requirements. For certain studies 

that review may have included review by the Human Studies Review Board. Descriptions of 

data sources as well as guidance on their use can be found at 

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

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

Data Requirements

There are no outstanding toxicology or exposure data requirements for zoxamide. With regard to 

residue chemistry, HED previously required storage stability data (Guideline 860.1380) for 

tomatoes as a condition of registration, and this requirement remains outstanding (T. Alston, 

DP274785, 08/30/2001).

References
Page 8 of 16

Memoranda Relevant to Registration Review

Author DP Barcode Date Title

Alston, T. 274785 08/30/2001

PP#0F06093; ARIA Risk Assessment: Human Health Risk 

Assessment for Zoxamide to Support Request for New Uses on 

Cucurbits and Tomatoes

Khan, F. 417061 01/17/2014

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, M. 416653 01/23/2014

Zoxamide. Petition for the Establishment of Permanent 

Tolerances for Use on Dry Onion Bulbs. Summary of 

Analytical Chemistry and Residue Data.

Negussie, M. 416654 01/29/2014

Zoxamide: Chronic Aggregate Dietary (Food plus Drinking 

Water) Exposure and Risk Assessments in Support of a Section 

3 Registration on Dry Onion Bulbs.

Recore, S. 417744 01/28/2014 Zoxamide: Tier I Review of Human Incidents

Rury, K. TXR0056915 02/27/2014

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, N. 416655 04/03/2014

Zoxamide. Occupational and Residential Exposure and Risk 

Assessment for the Proposed New Use on Bulb Onions (Crop 

Subgroup 3-07).

Tsaur, N. 411543 04/03/2014 Zoxamide. Aggregate Human Health Risk Assessment for the 

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

Attachments

Table 1. Chemical Identity of Zoxamide

Table 2. Physicochemical Properties of Technical Grade Zoxamide

Table 3. Zoxamide Summary of US and International Tolerances and Maximum Residue Limits

Table 4. Zoxamide Endpoint Selection

Table 5. Satisfaction of Zoxamide Toxicology Data Requirements

Table 6. Zoxamide Acute Toxicity Profile

Table 7. Zoxamide Subchronic, Chronic, and Other Toxicity Profiles

Table 8. Summary of Representative Occupational Use Patterns, Formulations, and App Rates
Page 9 of 16

Attachments

Chemical Identity and Physicochemical Properties Table

Table 1. Chemical Identity of Zoxamide

Chemical Structure

Common Name Zoxamide

Company Experimental Name RH-7281

PC Code 101702

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

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

CAS No. 156052-68-5

Registration Review Case No. 7032-1

Chemical Class` Benzamide

End-Use Products Gavel® 75DF Fungicide 8.3% ai (combination of zoxamide + mancozeb)

Zoxium® 80WSP Fungicide 80% ai

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

N

H

Cl

Cl

Cl

O

O
Page 10 of 16

Table 2. Physicochemical Properties of Technical Grade Zoxamide

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

Tolerance/MRL Table

Table 3. Zoxamide Summary of US and International Tolerances and Maximum Residue Limits

Residue Definition

US Canada Mexicob Codex

[40 CFR §180.567]

(a) General. (1) zoxamide (3,5-dichloroN-(3-chloro-1-ethyl-1-methyl-2-

oxopropyl)-4-methylbenzamide) 

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

oxopropyl)-4-methylbenzamide

Plant and 

animal: 

zoxamide 

Commoditya

Tolerance/Maximum Residue Limit

US Canada Mexicob Codex

ppm mg/kg

Grape 3.0 3 5

Grape, raisin 15.0 15 raisins

15 (Dried 

grapes(currants, 

raisins, and 

sultanas)

Tomato 2.0 2

Vegetable, cucurbit, group 9 1.0 2
Page 11 of 16

Table 3. Zoxamide Summary of US and International Tolerances and Maximum Residue Limits

Residue Definition

US Canada Mexicob Codex

(a) General. (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) 

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

Plant and 

animal: 

zoxamide 

Commoditya

Tolerance/Maximum Residue Limit

US Canada Mexicob Codex

ppm mg/kg

Potato 0.060 0.06

Potato, granules/flakes 0.30 0.3

0.3 potato chips

Potato, wet peel 0.10

Completed: M. Negussie; 12/22/2013

a Includes all registered commodities.

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

Toxicology Tables

Table 4. Zoxamide Endpoint Selectiona

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(All 

Populations)

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 decreases, increases 

in liver and thyroid weights, and increases 

in alkaline phosphatase.

Dermal

(All Durations)

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 decreases, increases 

in liver and thyroid weights, and increases 

in alkaline phosphatase.
Page 12 of 16

Table 4. Zoxamide Endpoint Selectiona

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

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. See Table 7 for MRID numbers.

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).

Table 5. Satisfaction 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

---

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

yes

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
Page 13 of 16

a CR = conditionally required.

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

Table 6. Zoxamide Acute Toxicity Profile

Guideline

Number 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 7. Zoxamide Subchronic, Chronic, and Other Toxicity Profiles

Guideline

Number 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
Page 14 of 16

Table 7. Zoxamide Subchronic, Chronic, and Other Toxicity Profiles

Guideline

Number 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.

44731838 (1998)

μg/plate:

S9: 50, 200, 500, 2000,

5000

Acceptable / Guideline 

±S9: Negative up to 5000 μg/mL

No evidence of mutagenicity.
Page 15 of 16

Table 7. Zoxamide Subchronic, Chronic, and Other Toxicity Profiles

Guideline

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

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 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/RH-141,454

44731836 (1998)

mg/kg:

Single: 1000

Acceptable / Guideline

Metabolite -

14C-RH-141,452

44731839 (1998)

mg/kg:

Single: 1000

Acceptable / Guideline

Metabolite -

14C-RH-141,455
Page 16 of 16

Table 7. Zoxamide Subchronic, Chronic, and Other Toxicity Profiles

Guideline

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

44731830 (1998)

mg/kg:

Single: 2000

Acceptable / Guideline

(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.

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.

Occupational Exposure Scoping Tables

Table 8. Summary of Representative Occupational Use Patterns, Formulations, and Application Rates

EPA Reg. No. Product Type Application Equipment Use Sites

Maximum

Seasonal 

Application 

Rates 

lbs ai/A

10163-6413 Water Soluble 

Packets

groundboom, 

airblast (grapes only), aircraft, 

chemigation, and handheld 

equipment

cucurbits, grapes, 

potatoes, tomatoes 0.20

10163-6414 Dry Flowable cucurbits, grapes, 

potatoes, tomatoes

0.17 (all crops 

except grapes)

0.21 (grapes)