ZOXAMIDE Human Health Risk Assessment DP No. D411543



### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

MEMORANDUM

DATE: April 3

, 2014 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

SUBJECT: Zoxamide. Aggr egate Human Health Risk Assessment for the Proposed New
Use on Bulb Onions (Crop Subgroup 3-07 A).

PC Code: 101702 DP Barcode: D411543
Decision No.: 476622 Registration No.: 10163-6414

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

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

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

MRIDNo.: NA 40 CFR: §180.567

FROM: Nancy Tsaur, Chemist, Risk Assessor
Meheret Negussie, Chemist**/teA~** Vincent Chen, Toxicologist**_:-:-: J'** **-:::o.-~~.,.._~~::;** 

### __ _ Risk Assessment Branch 3
Health Effects Division (7509P)

THROUGH: Christine Olinger, Branch Chief /)

## Jr~ Risk Assessment Branch 3 

# /J- J:**~** Health Effects Division (7509P)

TO: Marcel Howard Fungicides Branch (FB) Registration Division (7505P)

The Registration Division ( RD ) requested that the Health Effects Division (HED) provide an evaluation of the proposed new agricultural use of zoxamide on bulb onions (crop subgroup 3- 07A). A summary of the findings and an assessmen t ofhuman health risk resulting from the proposed and registered uses of zoxamide are provided in this document.

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

c hemi stry review and dietary risk assessment were conducte d by Meheret Negussie; the occupational exposure risk assessment was conducted by Nancy Tsaur; and the aggregate human
health risk assessment was conducted by Nancy Tsaur.

Page 1 of28ZOXAMIDE Human Heal th Risk Assessmen t DP No

. 0411543



### Table of Contents

1.0 Executive S ummacy

.. .. .. . .. .. . .. . ... . .. .. .. .. . .. .. .. .. . . .. . .. .. .. . ...... . ......... . ....... . .. ...... .. .. ....... . ... .. .. .. ... .. .. . 4
2

. 0 HED Recomme

. ndations

.. . .. ... . . ...... . .. ... . ......... .. ...... .. ..... . . .. .. .. .. . .. .. .. . ....... . . .. .. .. .. .. ... .. .. . ...... .. ... 5

2.1

2

. 2
2.2

. 1

2

. 2.2
2.2.3

2.2.4
2.3 

### Data Deficiencies

.. .. . ............. . .. . ........... . .............. . .......... .. ................. .. .......... . . ..... ... . ....... 5
To lerance Considerations

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

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

................................... ........... ... . ....................................... 6
Revisions to Petitioned-For To l erances

............................................................. .... ... 6 International Harmonization

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

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

. . . . . .. .. . .. .. .. . .... . . . .. .. .. .. . .. ...... . ........ . .......... .. .. . ...... ... . .. . . .. ....... .... . ...... . . .. ... . .. ..... . .... . .. 7

3.1 

### Chemical Identity

........... . .......... .. . ... ................................................ . ................ . ............. 7

3

. 2 

### PhysicaVChemical Characteristics

......... . . . ............................ . .................................. ... . 8

3.3 

### Pesticide Use Pattern

.......................................................... ............... ............................. 8

3.4 

### Anticipated Exposure Pathways

..................................................... . ............................. 9

3

. 5 

### Consideration of Env ironmental Justice

........................................ .................... .......... 9
4.0 Hazard Characterization and Dose

- Response Assessment

.. . ... . ... . ... . .. ... . .. ... . ... . ... .. ... . ..... 10

4.1 

### Toxicology Studies Available for Analysis

.. . .. . ............................................... .. .......... 10

4

. 2 

### Absorption, Distribution, Metabolism and Ex cretion (ADME)

.. . ........................... 10
4.3 

### Toxicological Effects

........ ..................................... ......... ..... . .. ... . ... . ... . ... . ...................... 10

4.4 

### Safety Facto r for Infants and Children (FQPA Safety Factor)

... . ........................... 11

4.4.1 

### Completeness of the Toxicology Database

....... .. ................................................. 1 1

4

. 4.2 

### Evidence of Neurotoxicity

.. ................................................................... . .............. 11

4.4

. 3 

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

.. .. 1 1
4.4.4 

### Residual Uncertainty in the Exposure Database

................................................ 1 2

4

. 5 

### Toxicity Endpoint and Point of Departure Selection

............. ...... .... ......................... 12

4.5.1 

### Recommendation for Combining Routes of Exposure for Risk Assessment.

. . 12

4

. 5.2 

### Cancer Classification and Risk Assessment Recommendation

........................ 12

4

. 5

. 3 

### Summary of Points of Departure and Toxicity Endpo ints Used in Human Risk
Assessment

...... . ............................. . .. . ... . .. . ...... . ............................ . . ... .. .................................. 1 2
5

. 0 Dietary Exposure and Risk Assessment

.. .. .. ........ . .. .. . . . . . .. .. .. .. .. . ... .. .. .. .. . ... . ... .. .. .. ......... .. .. .. . 13

5

. 1 

### Residues of Concern Summary and Rationale

................. . .... .. ...... . ......................... .. 13

5.2 

### Food Residue Profile

.... .. ..... .. . . ................ . ...... . .. ... . ... . .......... .. ........... ......... ................... 14
5

. 3 

### Water Residue Profile

. .. .......... ..... ....................................... . .................................. . ... . . 14

5.4 

### Dietary Risk Assessment

................. . ... . ................ . .. . ........... . .................... .. .................. 1 5

5.4.1 

### Description of Residue Data Used in Dietary Assessment

................................ 15
5.4

. 2 

### Acute Dietary Risk Assessment

... ........................................................................ 1 5

5.4.3 

### Chronic Dietary Risk Assessment

.............................. . .... ... .. .. . .. .......................... 1 5

5.4.4 

### Cancer Dietary Risk Assessment..

....................................................................... 1 6


### 6.0 Residential (Non-Occupational) Exposure/Risk Characterization

.. . ................. .. ... .. .. .. . 16
6.1 Re s id ential By stander Post-Appl i cation Inhalation Exposure

.... . ...... . .................... 16


### 6.2 Spray Drift

. .......................................................................... . ..... . ....................... . . . ........ 1 7
7

. 0 Aggregate Exposure/Risk Characterization

..... . . . .. .. .. .. .. . ..... . .. ...... .. .. .. . ......... . ... .. .. .. .......... 17


### 8

. 0 Cumulat i ve Exposure/Risk Characterization ••••••••••••. •••• • •••••• • ••• • ••••••• • •••.••• •••••• .• •• .• ••• • .•• •• • 17
9.0 Occupational Exp osu re/Risk Characterization

.. ....... .. ....................... ... .. .. .. . .......... .. ....... 18

Page 2 of28

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 3 of 28 9.1 Short

- and Intermediate

- Term Handler Risk

................................ ........................... 18
9.2 Short

- and Intermediate

- Term Post

- Application Risk

................................ ............. 19
9.2.1 Dermal Post

- Application Risk

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

................................ ................................ ..................... 19
9.2.3 Inhalation Post

- Application Risk

................................ ................................ ........ 19
10.0 References

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

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

................................ ................................ ................... 21
A.2 Toxicity Profiles

................................ ................................ ................................ ............ 22 Appendix B. Physical/Chemical Properties

................................ ................................ ............. 26 Appendix C. Review of Human Research

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

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

................................ .................. 28

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 4 of 28 1.0 Executive Summary

Zoxamide is a benzamide

- class fungicide used to control oomy cete diseases (e.g. late blight and downy mildew). Its pesticidal mode of action is through preventing nuclear division by binding

the 

- subunit of tubulin and disrupting microtubulin polymerization. There are no mammalian molecular data to specifically show this mode of action in test animals.

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

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

- 6414), thus petitioning for
the associated tolerance. Gavel® 75 DF is a water dispersible granule (WG) formulation containing 8.3% active ingredient (ai) by weight.

Proposed Use Profile Gowan® 75DF may be applied as a foliar spray via groundboom, aircraft, chemigation, and handheld equipment. For bulb onions (crop group 3

- 07 A ), the proposed maximum single application rate is 2.0 lb product /A (0.17 lb ai/A) and applications may be repeated on a 7

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

Exposure Profi le Exposure pathways include dietary (food and drinking water) and occupational exposure sources. There are no proposed or registered residential uses at this time

. Dietary exposures are expected
for chronic duration. Occupational handler and post

- appli cation exposures are expected for
short

- and intermediate

- term durations only. The proposed label requires occupational handlers to wear long pants, long sleeves, shoes, socks, and chemical

- resistant gloves.

Toxicity/Hazard In the majority of studies, zo xamide did not cause any toxicity up to the limit dose. The toxicity data of zoxamide indicate that the primary target organ is the liver. L iver and thyroid weights increased along with liver histopathological change and increases in alkaline phosphatase. A
de rmal point of departure (POD) wa s not cho sen because systemic toxicity i s not seen in the 2 8

- day rat dermal toxicity study up to the li mit dose (1

, 000 mg/kg/day). The short

- and
intermediate

- term inhalation PODs are based on the results of a chronic oral toxicity study in dogs. Zoxamide is not acutely toxic; it is classified as Toxicity Category III or IV for all routes of exposure (der mal, oral, and inhalation). There are no concerns for neurotoxicity, immunotoxicity

, developmental toxicity

, or reproductive toxicity ; nor is there susceptibility in the developmental fetuses or pups. Therefore, the data support a reduction of the FQPA s afety
factor to 1X. Zoxamide is classified as “ not likely to be carcinogenic to h umans” based on the
lack of treatment

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

Dietary Exposure (Food and Water) and Risk Estimates

T he dietary exposure and risk estimate s changed slightly from the previous risk assessment. There was no indication of an adverse effect attributable to a single dose . Thus, an acute reference dose ( aRfD ) was not established, and an acute dietary exposure assessment was not
conducted. An un refined chronic dietary exposure assessment was performed for zoxamide using tolerance

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

concentr ation ( EDWC ) of 65.8 μ g/L was incorporated directly into the dietary assessment . The

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 5 of 28 results of the chronic dietary analysis for f ood and drinking water are below the HED’s level of

concern (LOC) for all population subgroups. The dietary exposure for foo d and water is
estimated at 1.5 % of the chronic Population Adjusted Dose (cPAD) for the general U.S. population and 4.8 %, of the cPAD for children 1 to 2 years old , the population subgroup with the highest estimated chronic dietary exposure to zoxamide

.

R esidential 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 estimate s

.

Occupational Handler Exposures and Risk Estimates The results of the occupational handler exposure and risk assessment indicate that short

- and
intermediate

- term inhalation risks are not of concern at baseline mitigation without personal protective equipment (PPE)

. Short

- and intermediate

- term MOEs range from 7,400 to 970,000

. Note that o nly engineering control (enclosed cockpit) data are available to assess risks to handlers operating aircrafts.

Occupational Post

-

A pplication Exposures and Risk Estimates An occupational post

- application dermal exposure and risk assessment was not conducted because a systemic dermal hazard was not identified for zoxamide. The 48

- hour REI listed on the label is adequate to protect agricultural workers fr om post

- applicati on exposures to zoxamide. 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 exposure assessment for zoxamide.

2.0 HED Recommendations

HED has examined the toxicology and residue chemistry database s for zoxamide. Pending
submission of a revised Section B (label) and a revised Section F (tolerances)

, there are no issues that would preclude granting registration for the requested uses of zoxamide on bulb onion s or establishment of the recommended tolerance for combin ed residues of zoxamide and its metabolites (see Table 2.2.3). The specific tolerance recommendations are discussed in Section 2.2, and label modifications are discussed in Section 2.3.

2.1 Data Deficiencies

860.1650 Submittal of Analytical Reference St andards
The a nalytical reference standard for zoxamide is depleted . A 5g standard needs t o be supplied to the repository

.

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 6 of 28 2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate analytical methods are available for enforcing zoxamide tolerances and collecting data on residues in plant commodities. The analytical methods , gas chromatography with electron capture detection (GC/ECD) and GC with mass selective detection (GC/MSD ) are available for
tolerance enforceme nt for plant commodities as primary and co nfirmatory methods, respectively.
For the acid metabolites ( RH

- 1452 and RH

- 1455 ), the GC/MSD is the primary method and the GC/ECD method is the confirmatory method. The methods have been ade quately validated for the determination of residues of zoxamide in plant commodities

. Adequate multiresidue methods testing data have been submitted. The data indicate that the multiresidue methods are adequate for enforcement of tolerances for zoxamide only.

2.2.2 Recommended Tolerances

Table 2.2. 3. Tolerance Summary for Zoxamide

Commodity Tolerance (ppm) Comments Correct Commodity Definition Established Proposed Recommended

40 CFR §180. 567 (a)( 2 )
Onion, bulb

-- 0.7 0.7 Onion, bulb, subgroup 3

- 07A



### 2.2.3 Revisions to Petitioned

- For Tolerances

Section B ( label ) must be revised to only indicate use on onion

, bulb

, subgroup 3

- 07A crops : garlic, bulb; onion, bulb; shal lot, bulb; cultivars, varieties.

According to HED’s Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner), the tolerance expressions for zoxamide should be revised as follow:

Under 40 CFR §180.567(a)(1): “Tolerances are established for residues of zoxamide including is metabolites and degradates, in or on the commo dities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only zoxamide ( 3,5

- dichloro

N

- (3

- chloro

- 1

- ethyl

- 1

- methyl

- 2

- oxopropyl)

- 4

- methylbenzamide).

Under 40 CFR §180.567 (a)(2): “Tolerances are esta blished for residues of zoxamide including is metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of zoxamide ( 3,5

- dichloro

- N

- (3

- chloro

- 1

- ethyl

- 1

- methyl

- 2

- oxopropyl)

- 4

- methylbenzamide) and its metabolites 3,5

- dichloro

- 1,4

- benzenedicarboxylic acid (RH

- 1455 and RH

- 141455) and 3,5

- dichloro

- 4

- hydroxymethylbenzoic acid (RH

- 1452 and RH

- 141452) calculated as the stoichiometric equivalent of zoxa mide.

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 7 of 28 2.2. 4 International Harmonization

There are no Codex or Canadian maximum residue limits (MRLs) established for residues of
zoxamide in/on bulb onion s. The US tolerance and Canadian MRL expressions are the same. The US and Canadian residue definitions include zoxamide for grapes and processed grapes and zoxamide and its metabolites for potatoes and processed potatoes. The US and Codex residue definitions are not in harmony. The Codex residue definition includes only zoxamide for all

crop s

. The International Residue Limit Status is detailed in Appendix D

.

2. 3 Label Recommendations

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

, bulb

, subgroup 3

- 07A crops : garlic, bulb; onion, b ulb; shal lot, bulb; cultivars, varieties.

3.0 In troduction

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 polymerizat ion. It is currently registered for use on cucurbit vegetables, grapes, potatoes, and tomatoes.

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

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

- 6414), thus petitioning for
the associated tolerance. Gavel® DF75 is a WG formulation containing 8.3% ai by weight.

3.1 Chemical Identity

Table 3.1

. Zoxamide Nomenclature Compound

Common name Zoxamide
Company experimental name RH

- 7281

IUPAC name ( RS )

- 3,5

- dichloro

- N

- (3

- chloro

- 1

- ethyl

- 1

- methyl

- 2

- oxopropyl)

- p

- toluamide

CAS name 3,5

- dichloro

- N

- (3

- chloro

- 1

- ethyl

- 1

- methyl

- 2

- oxopropyl)

- 4

- methylbenzamide
CAS registry number 156052

- 68

- 5

End

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

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 8 of 28 Table 3.1

. Zoxamide Nomenclature Compound

Common name RH

- 141452
Company experimental name RH

- 1452

Chemical name 3,5

- dichloro

- 4

- hydro xy methylbenzoic acid
Molecular weight 221.04 g/mol

CAS Name Not available Compound

Common name RH

- 141455
Company experimental name RH

- 1455

Chemical name 2,6

- dichlorobenzene

- 1,4

- dicarboxylic acid
Molecular weight 235.02 g/mol

CAS Name Not available



### 3.2 Physical/Chemical Characteristics

Zoxamide has a low vapor pressure ( 9.75 ×10

- 8 

### mm Hg at 25, 35, and 45 °C); therefore, inhalation
due to chemical vaporization is unlikely. Zoxamide has a log octanol/water partition coefficient (log P ow 

### ) of 3

. 76 and is considered relatively insoluble in water. Additionally, zoxamide has a molecular weight of 336.64 g/mol ; therefore, the potential to cross biological barriers, such as the skin, is somewhat limited. More detailed physicochemical properties of zoxamide are summarized in Appendix B

.

3.3 Pesticide Use Pattern

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

- 6414). The newly proposed use pattern is presented in Table 3.3

.

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 9 of 28 Table 3.3 . Summary of Proposed Use Directions for Gavel® DF75 Fungicide (EPA Reg. No. 10163

- 6414 )

Applic ation Timing, Type, and Equip ment Single

Maximum Application

Rate Maximum

Number of Applications

per Year Maximum

Annual Applic ation

Rate PHI a Use Directions and Limitations

days

Onions (dry bulb), Garlic
, and Shallots b

Broadcast
Foliar : g round, aerial, chemigation, or
handheld 2 lb

product /A
0. 1 7 lb ai/A 8 16 lb product /A
1.33 lb ai/A 7 Follow a protective spray schedule

starting when diseases are first reported in the area and repeat at 7

- day intervals throughout the season. Do not allow spray or drift to contact
bulbs after li fting from soil. Do not apply to exposed bulb.

a PHI = pre

- harvest interval.
b The label must be revised to only include bulb onions of crop subgroup 3

- 07A : garlic, bulb; onion, bulb; shallot, bulb; cultivars, varieties

.



### 3.4 Anticipated Exposure Pathways

Humans ma y be exposed to zoxamide via food and drinking water because zoxamide may be applied directly to growing crops

, and application may result in zoxamide reaching surface and ground sources of drinking water. There are no residential uses of zoxam ide so there is no exposure in residential or non

- occupational settings. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application. There is also a potential for post

- applicati on 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 pathway s based on the proposed

new use of zoxa mide , but also considers the existing uses as well, particularly for th e dietary
exposure assessment.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this
human heal th 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 f rom 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 co nsumption patterns are compiled by the US DA under the National Health and Nutrition Examination Survey/What We Eat in America (NHANES/WWEIA), and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age and ethnic group . Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pes ticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 10 of 28 evaluated. Further considerations are currently in development as OPP has committed resources and exp ertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

Zo xamide’s pesticidal mode of action is through preventing nuclear division by binding 

- subunit of tubulin and disrupting microtubulin polymerization. There are no mammalian molecular data to specifically show this mode of action in the test animals.

4.1 Toxicology Studies Available for Analysis

The toxicological database for zoxamide is complete . The submitted studies are of good quality and provide sufficient information to determine whether zoxamide poses as a human health
hazard

. All available toxic ity studies are listed in Appendix A. The following studies are currently available for risk assessment: s ubchronic ( 90

- day o ral in r ats and d ogs; 28

- day d ermal
in r ats ); c hronic ( 1

- year oral in dogs; 18

- month oral c arcinogenicity in m ice; 2

- year o ral

com bined c hronic/ c arcinogenicity in r ats ); r eproductive in rats); d evelopmental in rats and

r abbits ; c arcinogenicity in rats and m ice ; mutagenicity and g enotoxicity in bacterial and
mammalian m odel s ystems ); n eurotoxicity ( a cute and s ubchronic in r ats ); m etabolism in rats;
and p harmacokinetic in r ats

. Neither an immunotoxicity study nor a subchronic inhalation toxicity study is required for zoxamide at this time (TXR005 6 9 15 , K. Rury , 04/02/2014 )

4.2 Absorption, Distribution, Metabolism and Excretion (ADME)

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

- 11% AD) and bile (46

- 48% AD) elimination data

. Zoxamide was found in the largest quantities in the liver (7% AD) and kidneys (0.1% AD) in addition to the residual carcass (2 8 % AD). In the rest of the body, z oxamide 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 dehalogenati on, hydrolysis, and oxidation. The majority ( > 96% AD ) of elimination in the rat
occurred within 120 hours. There w ere no radiolabeled metabolites in the expired air and no
evidence for bioaccumulation. Based on excretion and tissue residue data, bioavailability is conservatively estimated at abo ut 59% of an administered dose.

Dermal penetration studies were evalua ted for two formulations (80 WP and 80 2F) to establish a dermal absorption factor of 3% (HIARC Memo, TXR 0 014464, 02/07/2001).

4.3 Toxicological Effects

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

H owever, the chronic and subchronic dog studies indicated that the primary target organ for oral exposure to zoxamide is the liver. Additionally, liver and thyroid weights were increased along

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 11 of 28 with liver histopathological changes and increases in alkaline phosphatase in the chronic study.
Zoxamide was not observed to cause neurotoxicity or developmental/reproductive toxicity at or above the limit dose. No increases in the incidence of tumors were seen in either the rat or

mouse carcinogenicity study

.

As an o omycete 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 res ults of the in vitro mutagenicity study with CHO cells which indicated an in crease in aneuploidy/polyploidy

. The results of a special metabolism study indicated that <0.01% of the administered dose reached the bone marrow; thereby reducing the concern for mutagenic potential in vivo

. Additionally, zoxamide was negative in the in vivo micronucleus assay in mice.

Zoxamide has low acute toxicity through the oral, dermal, and inhalation routes of exposure ( Toxicity Categories III

- IV) ; and is not a n ocular or dermal irritant ( Toxicity Categories III

- IV)

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

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

T he risk assessment team recommended that the FQPA Safety Factor be reduced to 1X for the
reasons detailed in Sections 4.4.1

- 4.4.4

.

4.4.1 Completeness of the Toxicology Database

The toxicology database is adequate for assess ing susceptibility in infants and children as required by FQPA

.

4.4.2 Evidence of Neurotoxicity

Zoxamide’s to xicological database did not provide any evidence of neurotoxicity. Neurotoxic
effects were not observed in the neurotoxicity screening battery (acute and subchronic) up to their limit doses; 2000 mg/kg in the acute study and 1509 mg/kg/day in the subchro nic study

. In the absence of neuropathology findings in the neurotoxicity battery and behavioral effects elsewhere in the database, a developmental neurotoxicity study is not required at this time.

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

The prenatal and postnatal toxi city studies include rat and rabbit prenatal developmental studies
in addition to a reproduction and fertility effects stud y in rats ; and the highest doeses used in
these studies are at or above th e limit dose

. There was no evidence of increased susceptibility ( quantitative or qualitative ) for the offspring in the reproduction studies or for fetuses following

in utero exposure in the developmental studies

.

In the developmental studies, maternal an d fetal toxicity was not observed up to the limit dose (1000 mg/kg/day)

. In the rat reproduction and fertility effects study, decreased body weights and

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 12 of 28 body weight gains was observed in only the parental females at the highest dose tested (1624.4 mg/kg/d ay).

4.4.4 Residual Uncertainty in the Exposure Database

The exposure databases are complete or are estimated based on data that reasonably account for potential exposures. The chronic dietary food exposure assessment was conservatively based on
100 % crop treated (CT) assumptions and conservative ground water drinking water modeling
estimates. There are no registered or proposed residential uses. All of the exposure estimates are based on conservative assumptions and are not likely to result in und erestimated risk.

4.5 Toxicity Endpoint and Point of Departure Selection

4.5. 1 Recommendation for Combining Routes of Exposure for Risk Assessment

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

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

exposures

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

In this case, o ral and inhalation endpoints are based on the sam e effect ( i.e., body weight changes, increases in liver and thyroid weights, and increases in alkaline phosphatase ), and
therefore these routes of exposure may be combined for risk assessment

. The dermal route of exposure does not need to be included in t he aggregate risk assessment because there were no identified dermal hazards and no developmental, reproduc tive, neurotoxicity, and immunotoxicity concerns

.

4.5.2 Cancer Classification and Risk Assessment Recommendation

Zoxamide was classified as “not li kely” to be a human carcinogen (HIARC Memo, TXR014464,
02/0 7 / 2001) based on the lack of treatment

- related tumors in both the combined chronic toxicity

carcino genicity rat study and carcinogenicity mouse study.

4.5. 3 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk
Assessment

Reference: HIARC 07 Feb 2001 Zoxamide Report (HED Document Number 014464)

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 13 of 28 Table 4. 5

. Summary of Toxicological Doses and Endpoints for Zoxamide for Use in Dietary and Occupational Human Health Risk Assessments a

Exposure/
Scenario Point of

Departure Uncertainty/

FQPA Safety
Factors RfD, PAD,

Level of
Concern for
Risk
Assessment Study and Toxicological Effects

Acute Dietary (General Population, including
Infants and Children) and
Females 13

- 49 years of

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

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

. An
aRfD was not established.

Chronic Dietary (All Populations) NOAEL =

48 mg/kg/day 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 changes, increases in liver and thyroid weights, and increases in alkaline phosphatase

.

Dermal Short

Term (1

- 30 days) None: There were no systemic or dermal toxicity findings in a 28

- day dermal toxicity study in

the rat up to the limit dose (1000 mg/kg/day) and there were no developmental , reproductive,
or neurotoxi city 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 changes, increases in liver and thyroid weights, and increases in alkaline phosphatase

.

Cancer (oral, dermal, inhalation) Classification: “Not like ly to be Carcinogenic to Humans ” based on the lack of treatment

related tumors in both the com bined 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 expos ure. LOC = level of concern.
b Toxicity by the inhalation route is assumed to be equivalent to the oral route. A subchronic inhalation toxicity study is not required for zoxamide at this time ( TXR 0056915 , K. Rury, 0 4 / 02 /201 4 ).



### 5.0 Dietary Exposure and Risk Assessment

5. 1 Residues of Concern Summary and Ration ale

The residues of concern for dietary risk assessment and the tolerance expression are summarized
in Table 5.1.

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 14 of 28 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 Z oxamide and its metabolites : RH

- 150721, RH

- 24549, RH

141288, RH

- 129151, and RH

- 139432



### 5.2 Food Residue Profile

Adequate field trial data are available to support the proposed use of zoxamide on bulb onions and members of crop subgroup 3

- 07A

. In the residue decline stud y , average residues of
zoxamide indicat ed an overall decline in residues with increasing PHIs.

The available storage stability data for zoxamide are adequate to support the storage durations and conditions of samples of bulb onions from the submitted crop field trials.

There are no livestock feedstuffs associated with the proposed u se of zoxamide on onion bulbs,
and there are no livestock feedstuffs associated with the existing uses of zoxamide except potato processing waste/cull potatoes. Exposure from the latter, a minor ruminant feed item, is not anticipated to yield quantifiable residues in livestock commodities.

Available confined rotational cr op 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 a pplication of zoxamide

.

5. 3 Water Residue Profile

The environmental fate database is adequate to characterize drinking water exposure for the parent compound. Limited fate data are av ailable for the degradates of zoxamide. The data indicate that zoxamide is moderately persistent but immobile in soil. The degradates seem to be more mobile than the parent. Model simulations show that zoxamide may reach surface drinking water supplies , but should not reach ground water in considerable amounts, because it is
immobile in soil

.

In addition to evaluating the EDWCs from the proposed use, EDWCs were r eevalu ated for all existing uses with PRZM

- GW

, 1 

### which models continued use of zoxamide over many years (DP 417061

, F

. Khan , 0 1 / 17 /201 4 )

. T he most conservative EDWC ( 65.8 μg/L ) wa s based on an existing potato/grape use, and wa s used in the chronic dietary assessment.

1 PRZM

- GW was approved for standard use in drinking water assessments as a Tier I/II exposure tool (12/2012).

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 15 of 28 Table 5.3 . Summary of Estimated Drinking Water Concentrations for Zoxamide a

Tier II Surface Water Model ( μg/L )

Crop Scenario Peak Exposure Annual Mean Exposure Average Annual Exposure

GA Onion STD Scenario b 10.09 1.20 0.81

Tier I Ground Water Model ( μg/L )

Crop Scenario Peak Exposure Annual Mean Exposure Average Annual Exposure

WI corn Scenario c 83.5 NA 65.8

Generic Scenario d 0. 452 0. 452 0.4 52

a EDWC modeling includes total toxic residue (TTR) of zoxamide and five major degradates: RH

- 150721, RH

24549, RH

- 141288, RH

- 129151, and RH

- 139432

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

.
c Highest EDWCs generated using PRZM

- GW model based on 1.60 lbs ai/A for grape and potato ( Gavel 80 WP

, EPA Reg. No.10163

- 6413)

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

.



### 5. 4 Dietary Risk Assessment

5.4 .1 Description of Residue Data Used in Dietary Assessment

An unrefined chronic d ietary (food and drinking water) exposure and risk assessment was performed for zoxamide . The assumptions include tolerance leve l r esidues

, 100% CT , and
default processing factors from the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID) V ersion 7.81 (except for grape, raisin and potato granules/flakes)

. EDWCs from EFED were also inclu ded : the average ground water exposure of
65.8 μ g/L was incorporated directly into the dietary assessment

.

5. 4

. 2 Acute Dietary Risk Assessment

There was no indication of an adverse effect attributable to a single dose

. Thus, a n aRfD was not established, and an acute dietary exposure assessment was not conducted.

5. 4

. 3 Chronic Dietary Risk Assessment

An un refined c hronic dietary (food and drinking water) exposure and risk assessment was conducted using the D EEM

- FCID Version 3.16 . This model uses 2003

- 2 008 food consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey, What We Eat in America (NHANES/WWEIA)

.

The results of the chronic dietary analysis for f ood and drinking water are below the Agency’s
LOC for the general U.S population and all population subgroups. T he dietary (food and drinking wate r ) exposure is estimated at 1.5 % of the chronic Population Adjusted Dose (cPAD) for the general U.S. populati on and 4.8 % of the cPAD for children 1 to 2 years old, the population subgroup with the highest estimated chronic dietary exposure to zoxamide

. The results of the chronic dietary exposure analys e s are reported in Table 5.4 .5

.

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 16 of 28 5.4 .4 Cancer Dietary Risk Assessment

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

no t assessed

.

5

. 4

. 5 Summary Table

Table 5. 4 .5 . Summary of Dietary Exposure and Risk for Zoxamide ( c PAD = 0. 48 mg/kg/day) a

Population Subgroup Chronic Dietary Exposure Estimates (Food and Drinking Water)
mg/kg/day % cPAD

General U.S. Population 0.007368 1.5

All Infants (< 1 year old) 0.0 10837 2.3

Children 1

- 2 years old 0.023241 4.8

Children 3

- 5 years old 0.018422 3.8

Children 6

- 12 years old 0.009842 2.1

Youth 13

- 19 years old 0.005483 1.1

Adults 20

- 49 years old 0.006082 1.3

Adults 50+ years old 0.005863 1.2

Females 13

- 49 years old 0.005954 1.2

a The population subgroup with the greatest exposure is in bold

.



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no existing or propose d residential uses at this time

.

6. 1 Residential Bystander Post

- A pplication Inhalation Exposure

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for zoxamide at this time primarily because of the low acute inhalation toxicity (Toxicity Categ ory IV), low vapor pressure (9.75 x 10

- 8 

### mm Hg at 2 5 , 3 5 , and
4 5 °C), and the low proposed use rate (0.1 7 lb ai/A). However, volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and i nput 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 2 

### . The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- application inhalation exposure into the Agency's risk assessments . If new policies or procedures are developed, the Agency may revisit the need for a quantitative post

- application inhalation exposure assessment
for zoxamide

.

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

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 17 of 28 6. 2 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for zoxamide . The Agency has been working with the Spray Drift Task Force, EPA Regional Offices

, and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information 3 

### . The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast

, and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce
off

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

Although a quantitative residential post

- application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers. This e xposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post

- application inhalation exposure scenarios

.

7.0 Aggregate Exposure/Risk Characterization

In ac cordance 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 compa red 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 pro posed 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 (r efer to Section 5. 4

. 5 ). Zoxamide is classified as “not likely to be carcinogenic to humans;” therefore, an aggregate cancer
assessment was not conducted.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as

to zoxamide and any other substances and zoxamide does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance ac tion, there fore,
EPA has not assumed that zoxamide has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism

3 Available: http://www.epa.gov/opp00001/fac tsheets/spraydrift.htm

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 18 of 28 determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.g ov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

Occupational handler and post

- application exposure may occur by the dermal and inhalation routes of exposure only. For short

- and intermediate

- term exposure, only inhalation exposures
were assessed s ince there is no systemic hazard from the dermal route of exposure

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

- and intermediate

term risk estimate s are not of concern ( N. Tsaur , DP 416655 , 0 3 /2 7 /201 4 ). Appendix E
summarize s all assessed occupational exposure and risk estimates.

9.1 Short

- and Intermediate

- Term Handler Risk

Based on the anticipated use patterns and current labeling, and types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios:

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

 Applying dry flowables with aerial and groundboom equipment; and

 Mixing/Loading/Applying with a mechanically pressurized handgun.
The label states that h uman flagging is prohibited. Flagging to support aerial application is limited to use of the Global Positioning System (GPS) or mechanical flaggers.

HED classifies exposures from 1 to 30 days as short

- term and exposures from 30 days to six
months as intermediate

- term. Exposure dura tion is determined by many things, including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the cultural practices surrounding that use site. For most agricultural uses, it is reasonable to believe
that oc cupational handlers will not apply the same chemical every day for more than a one

month time frame; however, there may be a large agribusiness and/or commercial applicators who may apply a product over a period of weeks (e.g., completing multiple applicat ions for
mult iple clients within a region). The area treated or amount handled is b ased on HED Exp oSAC Policy No. 9.1 (refer to Appendix E for these assumptions for each scenario).

It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical

- specific data, include the Pesticide Handlers Exposure Database ( PHED ) 1.1, the Agricultural Handlers Exposure Task Force ( AHETF ) database

, or other registrant

- su bmitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA ) . The standard values recommended for use in pre dicting handler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate
Reference Table 4 

### ”, which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website 5



### .

4 Available: http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf

5 Available: http://www.epa.gov/pesticides/science/handler

- exposure

- data.html

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 19 of 28 There are no risk estimates of concern at the baseline level of personal protective equipment (PPE); t he proposed l abel require s chemical

- resistant gloves as PPE

. A ll short

- and
intermediate

- term handler risk estimates (inhalation only ) resulted in MOEs ranging 7,400 to 970,000

. Note that o nly engineering control (enclosed cockpit) data are available to assess risks

to handlers operating aircrafts.

HED has no data to assess exposures to pilots using open cockpits. The only data available is for exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the engineering control (enclosed cockpits) and baseline attire (long

- sleeve shirt, l ong pants, shoes, and socks); per the Agency’s Worker Protection Standard stipulations for engineering controls, pilots are not required to wear protective gloves for the duration of the application. With this level of protection, there are no risk estima tes 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 re

entry exposure). Such exposures may occur when workers enter previ ously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post

- app lication exposure levels vary over time and depend on such things as the type of activity, the nature of the c rop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post

- application exposure

.

9.2.1 Dermal Post

- Application Risk

There is potential for short

- and intermediate

- term occupational exposure during post

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

.

9.2.2 Restricted Ent ry Interval

Zoxamide is classified as Toxicity Category III via the dermal route. It is a moderate irritant to eyes, it is not irritating to the skin, but it is a skin sensitizer. Typically, the REI specified on the proposed label is based on the acute toxicity of the active ingredient. Under 40 CFR 156.208 (c) (2) (iii), active ingredients classified as Acute III or IV for acute dermal, eye irritation

, and primary skin irrit ation are assigned a 12

- hour REI . Thus, the 48

- hour restricted entry interval (REI) on the proposed label is acceptable for bulb onions

.

9.2.3 Inhalation Post

- Application Risk

Based on the Agency's current practices, a quantitative post

- application inhalation exposure

a sses sment was not performed for zoxamide at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure (9.75× 10

- 8 

### mm Hg at 20 °C), and the low proposed use rate (0.1 7 lb ai/A) . However, there are multiple poten tial sources of post

application inhalation exposure to individuals performing post

- application activities in

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 20 of 28 previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contai n 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 6 

### . The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures to identify the need for

, and subsequen tly, the way to incorporate occupational post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post

- application inh alation exposure assessment for zoxamide

.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting fr om 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 ex posure scenarios.

10 .0 References

Khan

, Faruque . 0 1 / 17 /201 4 . DP Barcode 4 17061 . “ D rinking W ater E xposure A ssessment in support of the new use registration of zoxamide formulated product Gavel ® 

### 75DF on onions (dry bulb), garlic and shallots. ”

Negussie, Meheret. 0 1 /2 3 /201 4 . DP Barcode 416653 . “ Zoxamide. Petition for the Establishment of Permanent Tolerances for Use on Dry Onion Bulbs. Summary of Analytical Chemistry
and Residue Data

. ”

Negussie, Meheret. 0 1 /2 9 /201 4 . 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. 0 4 / 02 /2014. TXR 0056915

. “ Zoxamide: Summary of Hazard and Science Policy Council (HASPOC) Meetin g of February 27 , 2014 : Recommendations on the Need for
S ubchronic Inhalation and Immunotoxicity Studies

. ”

Tsaur, Nancy. 0 4 / 03 /201 4 . DP Barcode 416655 . “ Zoxamide. Occupational and Residential Exposure and Risk Assessment for the Proposed New Use on Bulb Onions (Crop Subgroup
3

- 07). ”

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

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 21 of 28 A ppendix A

. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The toxicology study requirements (40 CFR § 158. 500 ) for food use for zoxamide are in Table A.1. Use of the new guideline numbe rs does not imply that the new (1998) guideline protocols
were used.

Table A.1. Satisfication of Zoxamide Toxicology Data Requirements

Study Technical Required Satisfied
870.1100 Acute Oral Toxicity
870.1200 Acute Dermal Toxicity
870.1300 Acute Inhalation Toxicity
870.2400 Acute Eye Irritation
870.2500 Acute Dermal Irritation
870.2600 Skin Sensitization yes
yes
yes
yes
yes
yes yes

yes
yes
yes
yes
yes 870.3100 90

- Day Oral Toxicity in Rodents
870.3150 90

- Day Oral Toxicity in Non

- Rodents
870.3200 21/28

- Day Dermal Toxicity
870.3250 90

- Day Dermal Toxicity
870.3465 90

- Day Inhalation Toxicity yes
yes
yes CR a (no)
CR a (no) yes

yes
yes

no 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 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 C hronic Toxicity/Carcinogenicity yes

no
yes

--- yes

yes
yes
yes 870.5100 Bacterial Reverse Mutation Test yes yes 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 yes

yes

no
yes 870.6200 Neurotoxicity Screening Battery (Acute, Rat)
870.6200 Neurotoxicity Screening Battery (Subchronic, Rat)
870.6300 Developmental Neurotoxicity Study yes
yes CR a (no) yes

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

a CR = conditionally required.
b Waived by Hazard and Science Policy Council ( HASPOC ) on 02/2 7 /201 4 ( TXR0056915, K. Rury, 04/02/2014 )

.

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 22 of 28 A.2 Toxicity Profiles

Table A.2.1. Zoxamide Acute Toxicity Profile

Guideline No. Study Type MRID Results Toxicity Category

870.1100 Acute Oral Toxicity (Rat) 44731805 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 A.2.2. Zoxamide Subchronic, Chronic, and Other Toxicity Profiles

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

870.3100 90

- Day Oral

Toxicity in Rodents (Rat) 44731814 (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

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 23 of 28 Table A.2.2. Zoxamide Subchronic, Chronic, and Other Toxicity Profiles

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

Prenatal Developmental Toxicity Study (Rabbit) 44731824 ( 1997 )

mg/kg/day:
F: 0

, 100

, 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.

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 24 of 28 Table A.2.2. Zoxamide Subchronic, Chronic, and Other Toxicity Profiles

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

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.

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, both in the presence and absence of metabolic activation.

870.5395 Mammalian

Erythrocyte
Micronu cleus

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 Human Health Risk Assessment DP No. D411543

Page 25 of 28 Table A.2.2. Zoxamide Subchronic, Chronic, and Other Toxicity Profiles

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

44731836 ( 1998 ) mg/kg: Single: 1000
A cceptable / G uideline
Metabolite

- 14 C

- RH

- 141,452 Zoxamide was found in the largest quantities in the liver (7.21% AD) and kidneys (0.13% AD) in addition to the residual carcass (27.91% AD). In the rest of the body, Zoxamide residues were found in

tr ace 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 (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 ev idence for
bioaccumulation. Based on excretion and tissue residue data, bioavailability is conservatively
estimated at about 59% of an administered dose. 44731839 ( 1998 ) mg/kg: Single: 1000
A cceptable / G uideline
Metabolite

- 14 C

- RH

- 141,455

44731830 ( 1998 ) mg/kg: Single: 2000
A cceptable / G uideline

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 formulations, 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.

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 26 of 28 A ppendix B. Physical/Chemical Properties

Table B. Physico

- Chemical Properties

Parameter Value Reference
Molecular Weight 336.64 g/mol

MRID
49067102 Melting range 159.5

- 160.5 ° C (98.8% purity)
Density Relative Density 1.38 at 20 ° C
Water solubility (20°C) 0.681 ± 0.017 mg/L

Solvent solubility (20°C) Ethyl acetate: 20.0 g/L Acetone: 55.7 g/L Xylene: 1.56 g/L

n

- Octanol: 6.49 g/L

n

- Heptane: 0.038 g/L 1,2

- Dichloroethane: 12.5 g/L

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

- 5 Pa
9.75×10

- 8 mm Hg

Dissociation constant, pKa Not measurable by spectrophotometry, titration or conductivity. Absorbance did not change in acidic, neutral, or basic conditions; Solubility was too low for titration; with decrease in concentration, no increase in reading was observed. Octanol/water partition coefficie nt, log K OW (25°C) Log Kow 3.76 ± 0.04 at ambient temp
UV/visible absorption spectrum 212 nm. ε = 46330

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 27 of 28 Appendix C. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies, which comprise PHED and AHETF, have been determined to require a review of their ethical conduct and have received that
review. In this assessment, PHED and AHETF data were used to assess mixing, loading, and applying dry flowable formulations of zoxamide

.

Studies reviewed by the Human Studies Review Board:
None.

Appendix D. International Residue Limit Status

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

Residue Definition

US Canada Mexico b Codex

40 CFR 180. 567 (a)General

(1) 3,5

- dichloro

- N

- (3

- chloro

- 1

- ethyl

- 1

- methyl

- 2

- oxopropyl)

- 4

- methylbenzamide

(2) combined residues of zoxamide and its metabolites 3,5

- dichloro

- 1,4

- benzenedicarboxylic acid (RH

- 1455 and

RH

- 141455) and 3,5

- dichloro

- 4

- hydroxymethylbenzoic acid (RH

- 1452
and RH

- 141452) Grapes and raisins: 3,5

- dichloro

- N

- (3

- chloro

- 1

- ethyl

- 1

- methyl

- 2

-

o xopropyl)

- 4

- methylbenzamide

Potatoes, potato processed fractions (chips, flakes and granules): 3,5

- dichloro

- N

- (3

- chloro

- 1

- ethyl

- 1

- methyl

- 2

- oxopropyl)

- 4

- methylbenzamide, including the metabolites 3,5

- dichloro

- 1,4

- benzene

dicarboxylic acid and 3,5

- dichlor o

- 4

- hydroxymethyl
benzoic acid Zoxamide

Commodity a Toleranc e /Maximum Residue Limit

US Canada Mexico b Codex

ppm mg/kg

Onion, bulb, subgroup 3

- 07A 0.7

Completed: M. Negussie; 12/04/2013

a Includes only commodities of interest for this action.
b Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

### ZOXAMIDE Human Health Risk Assessment DP No. D411543

Page 28 of 28 Appendix E. Occupational Exposure/Risk Summary Table

Table E. 1. Occupational Handler Short

- and Intermediate

- Term Exposure and Risk Estimates for Zoxamide

Exposure Scenario Crop or Target a Baseline
Inhalation
Unit Exposure b Maximum

Application

Rate c Area

Treated or
Amount
Handled Daily d Baseline Inhalation

Dose e MOE f

μg/lb ai lb ai/A Acres mg/kg/day ST/IT
LOC = 100

Mixer/Loader

Mixing/Loadi ng Dry Flowables for Aerial and Chemigation Application Typical Field Crops
8.96 0.17 350 0.00651 7,400

Mixing/Loading Dry Flowables for Groundboom Application Typical Field Crops 0.17 80 0.00149 32,000

Applicator Applying Sprays for Aerial Application Typical Field Crops 0.068 0.17 350 0.0000494 970,000

Applying Sprays for Groundboom

Application Typical Field Crops 0.34 0.17 80 0.0000565 850,000

Mixer/Loader/Applicator
M/L/A Dry Flowables for Mechanically

- Pressurized Handgun

Sprayers Typical Field Crops (Foliar) 3.9 0.017 lb ai/gal 1000

gallons 0.000809 59,000

a “Typical Field Crops” include bulb onions ( Sub roup 3

- 07 A ).
b Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2012); Level of mitigation = Baseline. Aerial Application is in a closed system at baseline level (no PPE).

c Based on the maximum application rates on the proposed label (Reg. No. 10163

- 6414, Gavel® 75DF Fungicide).
d Exposure Science Advisory Council Policy #9.1.

e Inhalation Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW (80 kg).
f Inhalation MOE = Inhalation NOAEL ( 48 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).