### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASIDNGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREV ENTI ON



### MEMORANDUM

DATE :

SUBJEC T: June 4, 2014



### Zoxamide. Human Health Scoping Document in Support of Registration

Review.



### P C Code: 101702 

### DP Barcode : D417745



### Decision No. : 487334 

### Registration Nos.: 10163-6413, -6414

, -6415



### Petit i on 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 N eguss ie, Chemist f1.e,J.,ey-c;r 

### tv• 

### 0**~** Risk Assessment Branch 3

H ealth E ffects 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 Re view, HED has considered updates to Agency science polic y
and risk assessment methodologies and to the zoxamide tox i c i ty

, exposure, and usage databases.

Zoxamide is a benzamide fungicide used to control oomycete diseases (e.g. la te blight and downy mildew). It i s currently registered for us e on cucurbit vegetables, grapes, potatoes

, and

tomatoes. The current re sidue 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 Limi t Do se (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 suscep tibility fo llowing pre and post natal exposures. Consequent l y, there is no ne ed

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

### IX ).

At this t ime

, all exposure and risk assessments refl ect 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 zoxami de

, 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 so luble powder) may be applied as a foliar spray via groun dboom

, airblast, aircraft

, cherniga t ion, and handheld equipment. The single maximum application rates

ran ge 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 Tab l es 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 t o support Registratio n Review.

HED has considered the most recent human health risk assessment for zoxam ide 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 avai lable 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 l imit d ose. In dogs, subchronic exposure resulted in in creased liver weight and hepatocellular hypertrophy. Following chronic exposures to dogs, zoxa mide caused de creases in body weight, increases in liver enzyme and liver weight as well as inc reases in thyroid weights. There was no evidence of neurotoxicity following acute and repeated oral exposures or following repeated dermal exposures at the l imi t d ose . No developmental toxicity was seen in the pre

- natal toxicity studies in rats and rabbits, and there w ere no adverse effects on reproduction. There is no evidence of increased susceptibility following in utero exposures to rats and rabbit or pre

- /po st

- 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.

A n 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 b ased on decreases in bod y 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 derm al exposures at the l imit d ose 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 a n 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 s tudies are

detail ed in the attached t oxicology t ables (Table 5 through 7)

.

Dietary Exposure

R egistered use s for zoxamide include th e following crops: cucurbit veg e tables, grapes, potatoes,

a nd 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 p otatoes 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 me thods 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

concentration s (E DWC s ) for zoxamide residues were from modeling the registered use s on grapes and potatoes.

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

well below the chronic reference dose (c PAD ) for the g eneral 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 r ecent human health risk assessm en t

, as there is no evidence of carcinogenicity.

Concl usion: 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, t he 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 drif t 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 inc orporate 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 toxicologic al 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 estimate s we re 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

T he occupational exposure scenarios associated with the registered and proposed use s were assessed adequately based on current HED policies ( DP41 6655, 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 w ater 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); t he existing l abel s state
the require ment for chemical

- resistant gloves as PPE

. A ll 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 post

application 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 exposur e 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 requi red for all occupational (e.g. sod farms, golf courses, parks, and recre ational 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 h azard 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 o ccupational handler dermal exposure and risk assessments reflect current policy and procedures for the existing agricultural use s, 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 inves tigation (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, t olerances 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

.

T he 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

definitio n includes only zoxamide for plant s.

The Codex MRL values for grape raisin and tomatoes are in harmony. The Codex MRLs for cucurbit vegeta bles (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. The re 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 U S 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 Mino rity 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 aro und 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 pestic ide 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 e xpertise 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 foll owed 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

. Z oxamide 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 rel y in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to de termine 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 registrant

submitted 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

dat a 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 reg ard 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,

DP 274785, 08/30/2001 )

.

References

### Page 8 of 16

Memoranda Relevant to Regist ration 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.

Rec ore, 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)

.



### Attachment s

Table 1. Chemical Identity of Zoxamide

Table 2. Physicochemical Properties of Technical Grade Zoxamide

Table 3. Zoxamide Summary of US and International Tolerances and Max imum Residue L imits

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

Attachment s

Chemical Identity and Physicochemical Properties T able

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

### 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 K OW (25°C) Log Kow 3.76 ± 0.04 at ambient temp

UV/visible absorption spectrum 212 nm. ε = 46 330



### Tolerance/MRL T able

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

Residue Definition

US Canada Mexico b Codex

[40 CFR §180.567] (a) General. (1) zoxamide (3,5

- dichloro

N

- (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

Commodity a Tolerance/Maximum Residue Limit

US Canada Mexico b Codex

p pm 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 Mexico b 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

- methylb enzamide, including the metabolites 3,5

- dichloro

- 1,4

- benzene

dicarboxylic acid and 3,5

- dichloro

- 4

- hydroxymethyl

benzoic acid Plant and

animal:

zoxamide

Commodity a Tolerance/Maximum Residue Limit

US Canada Mexico b Codex

p pm 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 Table s

Table 4

. Zoxamide Endpoint Selection a

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 UF A = 10X

UF H = 10X FQPA SF = 1X c RfD = 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

.

Inhalation b

Short

- Term (1

- 30 days) and

Intermediate

Term (1

- 6 months) NOAEL = 48

mg/kg/day UF A = 10X

UF H = 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 Selection a

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 like ly to be Carcinogenic to Humans ” based on the lack of treatment

related 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 observe d adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = 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 ass umed 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 CR a (no)

CR a (no) Y es

yes

yes

--- waived b

870.3700 Prenatal Developmental Toxicity Study (Rodent)

870.3700 Prenatal Developmental Toxicity Study (Non

- Rodent)

870.3800 Reproduction and Fertility Effects yes

yes

yes y es

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

--- Y es

yes

yes

yes 870.5100 Bacterial Reverse Mutation Test yes y es
870.5300 i n vitro Mammalian Cell Gene Mutation Test

870.5375 i n vitro Mammalian Chromosome Aberration Test

870.5385 Mammalian Bone Marrow Chromosomal Aberration Test

870.5395 Mammalian Erythrocyte Micronucleus Test yes

yes

yes

yes y es

yes

yes

yes
870.6200 Neurotoxicity Screening Battery (Acute, Rat)

870.6200 Neurotoxicity Screening Battery (Subchronic, Rat)

870.6300 Developmental Neurotoxicity Study yes

yes CR a (no) y es

yes

--- 870.7200 Companion Animal Safety

870.7485 Metabolism and Pharmacokinetics

870.7600 Dermal Penetration

870.7800 Immunotoxicity CR a (no)

yes CR a (no)

yes ---

yes

--- waived b

### 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 LD 50 > 5000 mg/kg IV

Acute Oral Toxicity (Mouse) 44731806 LD 50 > 5000 mg/kg IV

870.1200 Acute Dermal Toxicity (Rat) 44731807 LD 50 > 2 000 mg/kg III

870.1300 Acute Inhalation Toxicity (Rat) 44731808 LC 50 > 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 (199 6 )

ppm: 0, 70

, 700

, 2500

, 7000 mg/kg/day : M: 0, 1 2

, 12 3

, 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

- R odents (Dog) 44731816 (199 7 )

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 = 5 4.5 LOAEL (mg/kg/day) : M = 1139.3 F = 321.6

M: B ased 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 (Ra bbi t) 4 473181 8 (199 8 )

mg/kg/day : M: 0

, 150

, 400

, 1000

F: 0

, 150

, 400

, 1000

A cceptable / G uideline 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

, 30 0

, 1000 Acceptable / Guideline Maternal NOAEL (mg/kg/day) ≥ 100 0 LOAEL (mg/kg/day) > 100 0

Developmental NOAEL (mg/kg/day) ≥ 100 0 LOAEL (mg/kg/day) > 100 0

### 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

, 30 0

, 1000 Acceptable / Guideline Maternal NOAEL (mg/kg/day) = 100 0 LOAEL (mg/kg/day) > 100 0

Developmental

NOAEL (mg/kg/day) = 100 0 LOAEL (mg/kg/day) > 100 0

870.3800 Reproduction

and Fertility

Effects (Rat) 44770001 (199 8 )

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

T oxicity (Dog) 44731817 (199 8 )

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 = 10 2 1 F = 1289

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

No evidence of carcinogenicity

.

870.4300 Combined

Chronic Toxicity/ Carcinogenicity ( Rat) 44731821 (199 8 )

ppm: 0, 100 0

, 5 00 0

, 20 00 0 mg/kg/day:

M: 0

, 51

, 260

, 1058

F: 0, 6 5

, 328

, 1 33 1 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 (199 6 )

μg/plate :

 S9: 5 0, 200

, 5 00, 2000

,

5000 Acceptable / G uideline ±S9 : Negative up to 5 000 μg/mL

No evidence of mutagenicity.

44731835 (199 8 ) μg/plate :

 S9: 5 0, 200

, 5 00, 2000

,

5000 Acceptable / G uideline ±S9 : Negative up to 5 000 μg/mL

No evidence of mutagenicity.

44731838 (199 8 ) μg/plate :

 S9: 5 0, 200

, 5 00, 2000

,

5000 Acceptable / G uideline ±S9 : Negative up to 5 000 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 i n vitro

Mammalian

Cell Gene

Mutation Test ( Chinese Hamster Ovary Cells) 44731826 (19 94 )

μg/ mL:

- S9: 5, 10

, 20

, 30

,

40, 50, 65

+S9: 2, 5, 10 20,

30, 40, 55 Acceptable / G uidelin e  S9: Negative up to the maximum dose

No evidence of mutagenicity.

870.5375 i n vitro

Mammalian

Chromosome

Aberration

Test ( C hinese

H amster O vary cells ) 447 3182 7 (19 9 8)

μg/ mL:

 S9: 0.9689

- 100 Acceptable / G uideline ± 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, bo th in the presence

and absence of metabolic activation.

870.5395 Mammalian

Erythrocyte

Micronucleus

Test (Mouse

, Gavage ) 44742904 (1989)

mg/kg:

M: 0, 20 0

, 1000

, 2000

F: 0, 200

, 1000

, 2000 Acceptable / G uideline 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

A cceptable / G uideline 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 (199 8 )

mg/kg: Single: 10, 1000 Repeated: 10

Bile

- Cannulated: 10

A cceptable / G uideline 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 ca rcass (27.91% AD). In the rest of the body, Zoxamide residues were found in trace quantities.

Metabolism

Non

- metabolized zoxamide was the major component in feces (12.1

- 23.0% AD). In addition, some of the major metabolites that were identified include M

3 / RH

- 141,643 (7.44% AD) and M

- 7/ RH

- 141,454 44731836 ( 1998 ) mg/kg: Single: 1000

A cceptable / G uideline

Metabolite

- 14 C

- RH

- 141,452

44731839 ( 1998 ) mg/kg: Single: 1000

A cceptable / G uideline

Metabolite

- 14 C

- 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

A cceptable / G uideline (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

o ccurred 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

(200 1 ) 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

for mulations, respectively.

4473 1832 (1998) mg/kg/day : M: 800

, 15

, 1.5

A cceptable / G uideline The 80WP formulatio n was dosed at 800, 15 and 1.5

 g/cm 2 for 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/cm 2 for exposure durations o f 10 and 24 hours. Dermal absorption wa s low at 0.42 and 6.38 % for the respective doses. At the onl y common dose (1.5

 g/cm 2 ) there was no meaningful difference in dermal absorption between the two formulations.



### Oc cupati onal Exposure Scoping Tables

Table 8

. Summary of Representative Occupational Use Patterns, Form ulations, 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)