### Zoxamide Human H ealth Risk Assessment DP No. 0424990

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASH IN GTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

MEMORAND U M

DATE: 

### February 3, 20 16

SUBJECT : Zoxam id c. 

### Human Health Agg r egate Ri sk Assessment for the Proposed New
Uses on G in seng, Tomato Subgroup 8-1 OA; Sma ll Fruit

, Vin e Climbi n g, Except Fuzzy Kiwifruit

, Subgroup 1 3-07F; and Tuberous and Corm Vegetable Subgroup IC

.

PC Co d e: I 

### 01702 DP Barcode: 

### D424 990
D ec i s i o n N o.: 

### 498225 Re g i s tration No. : 

### 1016 3 -6414
Petition No.: 

### 4E8335 Regulatory Act ion : 

### Section 3 Registration
Case No.:
TXRNo.:
MRI D No .:

FROM :

THROUGH:

TO: 

### NA Ri s k Assessme nt Type: 

### Single Chemical I 

### Aggregate
NA CAS No.: 

### 156052-68-5 NA 40 CFR: 

### §180.567

Laura Nollcn, Biologist

, Ri sk Assessed.

____,,, 

# J/J_Pl .._,,,L-_ 

# 2/ 3 

# }t.J

Meheret Ncgussie

, Chemist 

### H c,A e ,;:e;:/-

## ;J~~ Vincent Chen, Toxico l og i st**~** 

# /?:::... c:_ Ri sk Assessmen t Branch 3 (RAB3); a nt(

- 

### <../

J ames S. Mill er, Env ironm e ntal Sc i en ti s t
, RAB 1 H ea lth Effec ts Di v ision (7509P)

Christine Olinger, Chief

# ~~i Risk Assessment Branch 3 (RA )

_ 

# --- - Health Effec t s Division (7509

Barbara Madden, Team L eade r ; Sidney Jack so n , Biologist Minor Use and Eme r gency Response Branch ( MU ERB); and Tony Kish ( PM ), Marcel H oward

, Production Management Team #22 R egis trati o n Division (7505 P)

Th e Registration Divi s ion (RD) 

### requested that th e Health Effects Division ( H E D) provide an

eva luation of proposed new agricultural uses or th e active ingredient (a i ) zoxa mide. A summary

or the findings and an assessmen t of human health risk resulting from the proposed and registered uses of zoxamide a r e provided in this document. The toxicology and hazard database review was conducted by Vincent Chen; the r esidue chem i s try re view was conducted by Meheret Negussie; the occupational exposure ri sk assessment was conducted by Jam es S. Miller; and the

agg r egate hum an h ea lth risk assessment was conducted by Laura Nollen.

Page I 

### of 38

### Zo x amid e Hum an He a lth Ri sk Assess m e nt DP o

. 

### 0 424990

Table of Co ntents

1.0 Exec uti ve Summary

.............................................................................................................. 4
2.0 HED Recommendations

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

............................................................................................................ 6
2.2 Tolerance Cons ider at ion s

.............................................................................................. 6
2.2.1 E n fo rcem e nt A nal yt ical Method

............................................................................... 6 2.2.2 Recommended Tolerances

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

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

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

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

................................................................................................. .. ........................ 8
3.1 C hemical Identity

. ... . .. .. ...... .. .. .. .. .. .. .. .. .. .... . ... ....... .. ........ ....... ...................... . ............ ..... . . 9 3.2 Physical/Chemical Cha racteri stics

............................................................................. 

### 10
3.3 Pesticide Use Pattern

.................................... . ...................... ......... .. ..... .. .. . ......... ..... . ..... I 0 3.4 Anticipated Exposure Path,vay s

................................................................................. 11
3.5 Co n s id era tion of Env ironm e nt a l Justice

.............................. ..... ...... .. ......... .............. .. 11
4.0 Hazard Characterization and Dose-Re s ponse Assessment

............................................. 12 4.1 St udie s Available for Ana ly s i s

... ... ...... .. ...... .............. ................. .................................. 12
4.2 Absorp tion

, Distribution

, Metabolism and Excret ion (ADME)

.............................. 12
4.2.1 Dermal Absorption

. ... ......................................................................................... . ..... 1 3
4.3 S umm ary of Toxicological Effects

. .... . .. . ... ... . ... . ... . ... . ... ...... . .. .. . .................. . ....... . .. . .. . .. 13
4.4 Safety Facto r for Infants and C hildr en (FQPA Safety Factor)

..................... .. ..... .. . 13
4.4.1 Com pl eteness of the Toxicology Database

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

4.4.2 Evi dence of Neurotoxicity

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

4.4.3 Evidence of Sens iti v i ty/Susceptib ility in the Developing or Young Anima l

.... 14

4.4.4 Residual Uncerta in ty in the Exposure Databa se

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

4

. 5 Toxicity Endpo int and Point of Departure Se l ectio n

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

### 5.0 Dietary Ex po s ur e and Risk Asses s m ent

...... . ......................... . .. ..... ............ .......... ............. . 

### 1 5
5.1 Residues of Concern Summary a nd Rationale

.................................. .. ........... . .......... 

### 15 

### 5.2 Food Residue Profile

. ............... . ... . .... . ... . .... . ... . ... . ....... . ...... .. .. . .. .. ............ . ...... .. . . .. . ... . .... 16
5 .3 Water Residue Profile

................................................. ...... ................ .............. ............. 1 6 5.4 Dietary Risk Assessment

............................................... .......... ............ .... .... ...... ........... 

### 1 7 5.4.1 Description of Residue Data Used in Dietary Assessment

................................ 

### 1 7

5.4.2 Acute Dietary Risk Assessment

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

5.4.3 Chronic Dietary Ri s k Assessment

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

6.0 Residential (Non -O ccupatio n a l ) Exposure/Risk Characterizat i on

................................ 

### 18
6.1 Re s identi a l By s tander Post-Application Inhalation Expos ur e

................ . . ... ........... 1 9 6.2 Spray Drift

.................. . ................... .................... . ... . ... .. . ... . ...... .. . .. .. ..... .. . .. . ...... . ..... .. . .. .. 19
7.0 Aggregate Exposure/Risk C haracteri zat ion

.... . .. .. ...... .. .............. . .. .. .. . .. .. ..... . .. ........ .. .. . .. . .. 19 8.0 Cu mulative Exposure/Risk Characterization

.................................................................. 20
9.0 Occupational Expo s ure / Risk Characterization

. . ............................................................. 20 9.1 S h ort- and Int ermediate-Term Handler Risk

....... .. .. ...... . ...... .. .. . ..... . ................ . .. . .... 20
9.2 S hort- and Intermediate-Term Post-Application Ri s k

............................................. 21



### Pa ge 2 of 38

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 3 of 38 9.2.1 Dermal Post

- Application Risk

................................ ................................ ............. 21

9.2.2 Inhalation Post

- application Risk

................................ ................................ ......... 21

10.0 References

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

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

................................ ................................ ................... 23 A.2 Toxicity Profiles

................................ ................................ ................................ ............ 24 Appendix B. Physical/Chemical Properties

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

................................ ................................ ................ 31 Appendix D. International Residue Limit Status

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

................................ .................. 33 Appendix F. Chronic Food Plus Water Residue Input File

- DEEM

- FCID

.......................... 35 Appendix G. Dis lodgeable Foliar Residue (DFR) Waiver Summary

................................ .... 38

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 4 of 38 1.0 Executive Summary

Zoxamide is a benzamide

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

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

The Interregional Research Project Number 4 (IR

- 4) has submitted pesticide petition ( PP# ) 4E8335 in order to propose a tolerance for residues of zoxamide in or on ginseng; Tomato subgroup 8

- 10A; Small vine climbing fruit, except fuzzy kiwifruit, subgroup 13

- 07F; and Tuberous and corm vegetable subgroup 1C. In conjunction with this petition, section 3 registration request s for Gavel® 75DF Fungicide ( EPA Reg. No. 1 0163

- 6414 ) were submitted for ginseng and Tomato subgroup 8

- 10A

. The registrant, Gowan Company, owns the EP associated with this action.

Proposed Use Profile Gavel ® 75DF is a water dispersible granule (WG) that may be applied as a broadcast f oliar spray via groundboom, aircraft, or chemigation application equipment

. Ginseng proposed use directions specify up to 6 foliar applications with maximum single and seasonal application rates of 0.17 pounds ( lb ) ai/ acre ( A ) and 0.96 lb ai/A, respectively, and a pre

- harvest interval (PHI) of 28 days. Tomato subgroup 8

- 10A is proposed for a single maximum application rate of 0.17 lb ai/A and a PHI of 5 days; regional

- specific seasonal rates propose up to 4 foliar applications ( 0.66 lb ai/A ) West of the Mississippi; up to 8 foliar applications are proposed East of the Mississippi , for a total seasonal application rate maximum of 1.33 lb ai/A. T he label specifies a 48

- hour restricted entry interval (REI) and requires occupational handlers to wear long pants, long sleeves , shoes, socks, and chemical

- resistant gloves.

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

exposure sources. Dietary exposures are expected for chronic duration s

. Occupational handler and post

- application exposures are expected for short

- and int ermediate

- term durations only. There are no proposed or registered residential uses of zoxamide

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

- day rat dermal toxicity study up to the limit dose and there was no developmental effect seen at the limit dose in both rat and rabbit developmental study. No reproduct ive and offspring effects were found in the reproduction study at doses above the limit dose. The short

- and intermediate

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

, developmental toxicity

, or reproductive toxicity ; nor is there concern regarding susceptibility to developin g fetuses or pups. Therefore, the data support a

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 5 of 38 reduction of the Food Quality Protection Act ( FQPA ) safety factor to 1x

. Zoxamide is classified

as “ not likely to be carcinogenic to h umans” based on results from adequate carcinogenicity studies in rats and mice.

Dietary Exposure (Food and Water) and Risk Estimates An adverse effect attributable to a single dose was not identified; t hus, an acute reference dose ( aRfD ) was not established and an acute dietary exposure assessment was n ot conducted

. An

un refin ed chronic dietary exposure assessment was performed for zoxamide using tolerance

level residues and 100 percent crop treated ( P CT). The estimated drinking water concentration ( EDWC ) of 65.8 μ g/L was incorporated directly into the dietary assessment. The results of the chronic dietary analysis for food and drinking water are below the HED’s level of concern (LOC) for all population subgroups.

Residential Exposure and Risk Estimates There are currently no registered or proposed residential uses for z oxamide.

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 t o chronic dietary (food and drinking water) risk estimate s

.
Occupational Handler and Post

- Application Exposures and Risk Estimates Occupational handler and post

- application exposures to zoxamide are expected for short

- and intermediate

- term durations based on the proposed uses. A dermal risk assessment was not conducted for zoxamide because no systemic toxicity was seen at the limit dose in the route

specific dermal study, and no concerns for development or reproductive effects were seen elsewhere in t he database

. Results indicate that short

- and intermediate

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

. Based on the Agency's current practices, a quantitative non

- cancer occupational post

- application inhalation exposure assessment was not performed for zoxamide

.
Review of Human Research This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1) and the Agricultural Handler Exposure Task Force (AHETF) , are (1) subject to ethics review pursuant to 40 CFR 26 ; (2) have received that review ; and (3) are co mpliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 1



### .

Enviro nmental Justice Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions

1 http://www.epa.gov/pesticides/science/handler

- exposure

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

- app

- exposure

- data.html

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 6 of 38 to Address Environmental Justice in Minority P opulations and Low

- Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

2.0 HED Recommendations

HED has examined the toxicology and residue che mistry databa ses for zoxamide. Pending submission of a revised Section B, as well as the submittal of analytical reference standards as outlined in Section 2.1, there are no i ssues that would preclude the establishment of the recommended tolerance s

. S pecific tolerance recommendatio ns are discussed in Section 2.2 and label modifications are discussed in Section 2.3.

2.1 Data Deficiencies

860.1650 Submittal of Analytical Reference Standards A n a nalytical standard for zoxamide is currently available in the EPA National P estici de Standards Repository; with expir ation date of 11/30/ 201 9

. However, the standard for zoxamide metabolites (RH1452 and RH1455) and derivatives (RH147391 and RH147399) is expired or is available only in 1 gram (personal e mail w ith Teresa Cole, ACB, 11/16/2015). T he registrant is required to submit a reasonable amount of the analytical reference standard for the metabolites and derivatives . The reference standard should be sent to the Analytical Chemistry Lab, which is located at Fort Meade, Marylan d, to the attention of either Theresa Cole or Thuy Nguyen at the following address:

USEPA National Pesticide Standards Repository/Analytical Chemistry Branch/OPP 701 Mapes Road Fort George G. Meade, MD 20755

- 5350 ( Note that the mail will be returned if the extended zip code is not used .)

2.2 Tolerance Considerations

I R

- 4

, on behalf of the Agricultural Experiment Station of the state of Michigan, has submitted PP# 4E8335 in order to propose a tolerance for residues of zoxamide in or on Tomato subgrou p 8

- 10A at 2.0 parts per million (ppm) ; and Small fruit

, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F at 5.0 ppm . Additionally, IR

- 4 proposed a tolerance for residues of zoxamide and its metabolites in or on ginseng at 0.30 ppm and Tuberous and corm vegetable subgroup 1C

at 0.060 ppm

.

2.2.1 Enforcement Analytical Method

Adequate analytical methods are available for tolerance enforcement purposes for the residues of concern in or on plant commodities

. G as chromatography wit h electron capture detection (GC/ECD) and GC with mass selective detection (GC/MSD) methods

, are available for tolerance enforcement for plant commodities as primary and confirmatory methods, respectively. For the acid met abolites (RH

- 1452 and RH

- 1455) in or on potato tubers and potato processed fractions, GC/MSD serves as the primary method and GC/ECD is considered confirmatory

. The methods

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 7 of 38 have been adequately validated for the determination of residues of zoxamide in plant commoditi es , and have been forwarded to the Food and Drug Administration

. Adequate multi

residue methods tes ting data have been submitted. The se data indicate that the multi

- residue methods are adequate for enforcement of tolerances for zoxamide only.

2.2.2 Recommended Tolerances

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

, and 40 CFR §180.567(a)(2) for the combined residues of zoxamide and its metabolites RH

- 1452 and RH

1455

. The currently establishe d tolerance expression s for zoxamide are adequate, and include both coverage and compliance statements for enforcement purposes. HED recommends that 40 CFR §180.567(a)(1) and 40 CFR §180.567(a)(2) be amended by establishing tolerances as listed in Table 2.2.2 below

.

Table 2.2. 2. T o lerance Summary for Zoxamide

Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Correct Commodity Definition/Comments

To be established under 40 CFR §180.567 (a) General. (1) Tomato subgroup 8

- 10A 2.0 2.0 Established tolerance for tomato should be removed upon establishment of t his subgroup tolerance. Fruit, small, vine climbing, except fuzzy kiwifruit, Subgroup 13

- 07F 5 .0 5.0 Fruit, small vine climbing, except fuzzy kiwifruit, subgroup 13

- 07 F

. Previously e stablished tolerance for grape should be removed upon establishment of t his subgroup tolerance. To be established under 40 CFR §180.567 (a) General. (2) Vegetable, tuberous and corm, Subgroup 1C 0.06 0 0.06 Vegetable, tuberous and corm, subgroup 1C Previously e stablished tolerance for potato should be removed upon establishment of t his subgroup tolerance. Ginseng 0.3 0 0.30 T olerance recommendation based

on potato granules/flakes data translation

.



### Note to RD : T he existing tolerances for grape, tomato, and potato should be removed from 40 CFR §180.567(a)

, as they will be superseded by the establishment of crop subgroup tolerances as recommended in Table 2.2.1

.

2.2.3 Revisions to Petitioned

- For Tolerances

HED ha s no recommended revisions to the petitioned

- for tolerances of zoxamide

.

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 8 of 38 2.2.4 International Harmonization

The residue definitions are harmonized for the U

. S

. and Canad a . The U

. S

. and Canadian residue definitions include zoxamide for grapes and processed grapes and zoxamide and its metabolites (RH

- 1452 and RH

- 1455) for po tatoes and processed potatoes. The Codex residue definition includes the parent zoxamide only for all crop s , and is therefore not harmonized with the tole rance expression for certain U.S. commodities

.

The tolerance recommendation for Tomato subgroup 8

- 10A at 2.0 pp m in harmonized with a Canadian maximum residue limit ( MRL ) on tomatoes at 2 ppm and a Codex MRL on tomatoes at 2 ppm. A tolerance was propose d and recommend ed in or on Small vine c limbing fruit

, except f uzzy k iwifruit

, subgroup 13

- 07F at 5.0 ppm

, in order to h armonize with a n established Codex
MRL on grape at 5 ppm

. T h e increased U.S. tolerance recommendation on subgroup 13

- 07F at 5.0 ppm results in a lack of harmonization with a n established Canadian MRL on grape at 3.0 ppm. The tolerance recommendation for Tuberous and corm vegetable subgroup 1C at 0.06 ppm is harmonized with a Canadian MRL established on potato at 0.06 ppm; ho wever, the U.S. tolerance is not harmonized with a Codex MRL at 0.02 ppm. The underlying residue data and residue definition used to support the Subgroup 1C tolerance supports a tolerance recommendation that is higher than the established Codex MRL on pota to at 0.02 ppm. There are no Codex or Canadian MRLs for ginseng. The International Residue Limit Status is detailed in Appendix D.

2.3 Label Recommendations

The proposed use directions for Gavel® 75DF Fungicide ( EPA Reg. No. 10163

- 6414 ) should be revised to include only ginseng and Tomato subgroup 8

- 10A. Reference to the following commodities should be removed , as the registrant has withdrawn these proposed registrations : Small vine c limbing fruit

, except f uzzy k iwifruit

, subgroup 13

- 07F

, except for th e p reviously

registered use on grape ; and Tuberous and corm vegetable subgroup 1C

, except for the previously

- registered use on potato

.

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 polymerization

. Zoxamide is currently registered for use on cucurbit vegetables, grapes, oni ons, potatoes, and tomatoes. In conjunction with this petition, section 3 registration request s were proposed for Gavel® 75DF Fungicide ( EPA Reg. No. 10163

- 6414 ) to add uses on ginseng and Tomato subgroup 8

- 10A (tomato is currently registered) . The registr ant, Gowan Company, owns the EP associated with this action.

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 9 of 38 3.1 Chemical Identity

Table 3. 1

. Zoxamide Nomenclature.

Chemical structure

Common name Zoxamide Company experimental name RH

- 7281

IUPAC name ( RS )

- 3,5

- dichloro

- N

- (3

- chloro

- 1

- ethyl

- 1

- methyl

- 2

- oxopropyl)

- p

- toluamide Molecular weight 336.64 g/mol

CAS name 3,5

- dichloro

- N

- (3

- chloro

- 1

- ethyl

- 1

- methyl

- 2

- oxopropyl)

- 4

- methylbenzamide CAS registry number 156052

- 68

- 5

End

- use product (EP) Gavel ® 75DF Fungicide (EPA Reg. No. 10163

- 6414 ) (This product is a combination of zoxamide + mancozeb. Only zoxamide residues have been determined.)

Chemical structure

Common name RH

- 141452 Company experimental name RH

- 1452

Chemical name 3,5

- dichloro

- 4

- hydroxymethylbenzoic acid Molecular weight 221.04 g/mol

CAS Name Not available

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 10 of 38 Table 3. 1

. Zoxamide Nomenclature.

Chemical structure

Common name RH

- 141455 Company experimental name RH

- 1455

Chemical name 2,6

- dichlorobenzene

- 1,4

- dicarboxylic acid Molecular weight 235.02 g/mol

CAS Name Not available



### 3.2 Physical/Chemical Characteristics

Zoxamide has a low vapor pressure ( 9.75 ×10

- 8 

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

### ) of 3

. 76 and is considered relatively insolub le 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 som ewhat limited. More detailed physicochemical properties of zoxamide are summarized in Appendix B.

3.3 Pesticide Use Pattern

Gowan has submitted s ection 3 label amendments for the 75% W G EP formulation of zoxamide (Gavel® 75DF Fungicide ; EPA Reg. No. 10163

- 6414 ) whic h are summarized in Table 3.3. Gavel ® 75 DF is a mixture of 8.3% zoxamide and 66.7% mancozeb. While additional section 3 use directions were proposed for Small fruit, vine c limbing, except f uzzy k iwifruit

, subgroup 13

- 07F ; and Tuberous and corm vegetable subgroup 1C, they were subsequently withdrawn because there were no supporting tolerances for mancozeb

, the co

- formulated ai , in or on those subgroup s

.

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

- 6414 )

Application Timing, Type, and Equipment Single

Maximum Application Rate (lb product/A or lb ai/A) 1 Maximum

Number of Applications per Year Maximum

Seasonal Application Rate PHI 2

(days) Use Directions and Limitations

Ginseng 3

Foliar : G round, A erial 2 .0 lb

product/A; 0.1 7 lb ai/A 6 1 2 lb product /A /season; 0.96 lb ai/A /season 28 Start applications when

environmental conditions are favorable for disease development. Use in a minimum spray volume of 80 gallons of

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 11 of 38 Table 3.3 . Summary of Proposed Use Directions for Gavel® DF75 Fungicide (EPA Reg. No. 10163

- 6414 )

Application Timing, Type, and Equipment Single

Maximum Application Rate (lb product/A or lb ai/A) 1 Maximum

Number of Applications per Year Maximum

Seasonal Application Rate PHI 2

(days) Use Directions and Limitations

water/acre and direct spra ys to provide thorough coverage of foliage and stems. Consecutive sprays must be at least 7 day apart. Do not apply through any type of irrigation system. Tomato subgroup 8

- 10A 4

Foliar : Ground, A erial, C hemigation 2.0 lb product/A;

0.17 lb ai/A 4 8 lb product/A/Season; 0.66 lb ai/A /season 5 Start applications when

seedlings emerge or transplants are set and repeat at 7 to 10 day intervals or when environmental conditions are favorable for disease development. 8 (East of Mississippi) 16 lb

product/A/season; 1.33 lb ai/A /season
1 Calculated lb ai/A assumes given density of active ingredient = 0.08 lb zoxamide/lb product). 2 PHI = pre

- harvest interval. 3 Ginseng proposed use pattern is based upon and similar to the existing registered use for potato, except for the PHI (14

- days for potato). P roposal for translating the potato granules/flakes tolerance of 0.30 ppm to ginseng was approved by the ChemSAC (09/2013). 3 Tomato is currently registered for EPA Reg. No. 10163

- 6414.



### 3.4 Anticipated Exposure Pathways

Humans 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 drinking water so urces

. There a re no residential uses of zoxamide

, so there is no anticipated exposure in residential or non

- occupational settings. In an occupational setting, applicators may be exposed dermally and by inhalation while handling zoxamide prior to application, as well as d uring application. There is also a potential for post

- application dermal and inhalation exposure for workers re

- entering treated fields.

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

. This risk assessment consid ers all of the aforementioned exposure pathway s based on the proposed

new use of zoxamide , but a lso considers the existing uses of zoxamide

.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.epa.gov/environmentaljustice/resources/policy/exec_order_12898.pdf ). As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP po licy, HED estimates risks to population

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 12 of 38 subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticid e. These data are analyzed and categorized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

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

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

- application exposure and it is also being considered whenever appropriate. Further considerations are also currently in development as OPP has committed resources and expertise to the development of specialized software and mod els that consider exposure to other types of possible bystander

exposure s and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

The pesticidal mode of act ion for zoxamide is through preventing nuclear division by binding 

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

4.1 Studies Available for Analysis

The toxicological database for zoxamide is considered complete and adequate for risk assessment. The studies available for risk assessment include an acute toxicity battery; subchronic oral toxicity studies in rats and dogs; a subchronic dermal toxicity study in rabbits; prenatal developmental toxicity studies in rats and rabbits; a reproduction and fertility effects study in rats; chronic toxicity studies in rats and dogs; carcinogenicity studies in rats and mice; a battery of mutagenicit y studies; a neurotoxicity screening battery, including acute and subchronic studies in rats; and metabolism and pharmacokinetic studies in rats. Neither an immunotoxicity study nor a subchronic inhalation toxicity study is required for zoxamide at this ti me ( TXR0056915, K. Rury, 04/02/2014). All available toxicity studies are listed in Appendix A.

4.2 Absorption, Distribution, Metabolism and Excretion (ADME)

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

- 11% AD) and bile (46

- 48% AD) elimination data. Zoxamide was found in the largest quantities in the liver (7% AD) and kidneys (0.1% AD) in addition to the residual carcass (28% AD). In the rest of the body, zoxamide residues were found in trace quantities. Non

- metaboli zed 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 co njugation, reductive dehalogenation, hydrolysis, and oxidation. The majority (>96% AD) of elimination in the rat occurred within 120 hours. There were no radiolabeled metabolites in the expired air and no

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 13 of 38 evidence for bioaccumulation. Based on excretion an d tissue residue data, bioavailability is conservatively estimated at about 59% of an administered dose.

4.2.1 Dermal Absorption

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

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

4.3 Summary of Toxicological Effects

In general

, the available data indicate low toxicity following exposure to zoxamide

. I n rat repeat dose oral and dermal toxicity studies, there were no indicati ons of systemic toxicity up to the highest dose tested (H DT) ; most of the highest doses were at or above the limit dose (1

, 000 mg/kg/day) . In the dog repeat dose oral toxicity studies, effects included increased liver and thyroid weight s , liver histopathology (i.e., hepatocellular hypertrophy), and increased alkaline phosphatase.

In the rat and rabbit prenatal developmental toxicity studies, there wer e no indications susceptibility, as there was neither maternal nor developmental toxicity up to the HDT . In the rat reproduction and fertility effects study, there were no indications of susceptibility

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

Zoxamide has been class ified as “not likely to be carcinogenic in humans” based on the results of carcinogenicity studies in rats and mice. The mutagenicity studies do not indicate increased mutagenic potential in the battery of in vivo and in vitro assays. As an oomycete fungic ide, zoxamide causes the disruption of the microtubule cytoskeleton and arrests nuclear division by binding specifically to the 

- subunit of tubulin. This mechanism of specific binding the 

- subunit of tubulin is consistent with the results of the in vitro mutagenicity study with CHO cells which indicated an increase in aneuploidy/polyploidy. The results of a special metabolism study indicated that <0.01% of the administered dose reached the bone marrow; thereby reducing the concern for mutagenic potential in vivo

. In the acute and subchronic neurotoxicity studies, there were no indications of neurotoxicity up to the HDT

.
Zoxamide has low acute toxicity through the oral, dermal, an d inhalation routes of exposure; it is a slight to moderate irritant to the e ye and skin; and is a strong dermal sensitizer.

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

For all asses sment scenarios, the default 10 x FQPA Safety Factor (SF) can be reduced to 1x because of the following conclusions: (1) the toxicological data base for zoxamide is complete ; (2) there was no evidence of susceptibility following pre

- or postnatal exposure in the young ; (3) there was no evidence of neurotoxicity ; and (4) there are no residual uncertaint ies in the exposure data base

. Th e details for the se determination s are presen ted in the following sections :

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 14 of 38 4.4 .1 Completeness of the Toxicology Database

The toxicity database for azoxystrobin is complete an d adequate for risk assessment. Consequently, HED believes the existing data are sufficient for toxicity endpoint selection for exposure/risk assessment scenarios and for evaluation of the requirements under the FQPA

.

4.4 .2 Evidence of Neurotoxicity

There was no evidence of neurotoxicity in the acute a nd subchronic neurotoxicity studies in rats up to their respective limit doses. In the absence of neuropathology findings in the neurotoxicity battery and behavioral effects elsewhere in the database, a developmental neurotoxicity study is not required at this time.

4.4 .3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There was no evidence for increas ed susceptibility following pre natal exposure in prenatal developmental toxicity studies in rats and rabbits . Additionally, there w as no evidence for increased suscep tibility following pre

- or post natal exposure in the reproduction and fertility effects study in rats.

4.4 .4 Residual Uncertainty in the Exposure Database

The exposure databases are complete for the purposes of risk a ssessment . The chronic dietary food exposure assessment was conservatively based on 100 percent crop treated ( P CT) assumptions and conservative drinking water modeling estimates. There are no registered or proposed residential uses. All of the exposure est imates are based on conservative assumptions that are not likely to result in underestimated risk.

4.5 Toxicity Endpoint and Point of Departure Selection

Since the last completed human health risk assessment (D411543, N. Tsaur, 04/03/2014) , there have been no changes to the dose

- response assessment; nor have there been any changes to the cancer classification.

Table 4.5 provides the summary of the toxicological doses and endpoints that were used in the dietary and occupational human health risk assessments for zoxamide.

Table 4. 5. Summary of Toxicological Doses and Endpoints for use in Dietary and Occupational Human

Health Risk Assessments 1

Exp osure Scenario Point of

Departure (P O D) Uncertainty /

FQPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects

Acute Dietary ( All Populations ) No endpoint was identified since there is no indication of an adverse effect attributable to a

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

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 15 of 38 Table 4. 5. Summary of Toxicological Doses and Endpoints for use in Dietary and Occupational Human

Health Risk Assessments 1

Exp osure Scenario Point of

Departure (P O D) Uncertainty /

FQPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects

Chronic Dietary (All Populations) NOAEL =

48 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x cRfD =

0.48 mg/kg/day

cPAD = 0.48 mg/kg/day Chronic Toxicity

– Dog

LOAEL = 255 mg/kg/day Based on body weight changes, increases in liver and thyroid weights, and increases in alkaline phosphatase.
Dermal ( All Durations ) No endpoint was identified because there are no residential uses or concerns for resident ial

exposure; there was no systemic toxicity in a 28

- day dermal toxicity study in the rat up to the limit dose (1000 mg/kg/day) ; and no developmental effects were seen in rats and rabbits

at the limit dose. No susceptibility was fou nd in the reproduction study.
Inhalation 2
Short Term (1

- 30 days)

Intermediate Term (1

- 6 months) Oral NOAEL =

48 mg/kg/day

Note: Toxicity via the inhalation and oral routes are assumed to equivalent. UF A = 10x

UF H = 10x FQPA = 1x LOC for MOE = 100 Chronic Toxicity

– Dog LOAEL = 255 mg/kg/day Based on body weight changes, increases in liver and thyroid weights, and increases in alkaline phosphatase. Cancer (oral, dermal and inhalation) Classification: “Not Likely to be Carcinogenic to Humans” based on the results of

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

1 Point of Departure (P O D) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. 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. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. 2 To xicity by the inhalation route is assumed to be equivalent to the oral route. A subchronic inhalation toxicity study is not required for zoxamide at this time (TXR0056915, K. Rury, 04/02/2014).



### 5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary and Rationale

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

.

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 16 of 38 Table 5.1. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression

Plants Primary Crop Zoxamide and its metabolites: RH

- 1452 and RH

- 1455 for grapes and potatoes

Zoxamide only for tomatoes/cucumbers Rotational Crop

Livestock Ruminant Not Established Poultry

Drinking Water Zoxamide and its metabolites: RH

- 150721, RH

- 24549, RH

141288, RH

- 129151, and RH

- 139432



### 5.2 Food Residue Profile

Adequate field trial and storage stability data are available to support the proposed use s of zoxamide on ginseng; Tomato subgroup 8

- 10A; Small fruit

, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F; and Tuberous and corm vegetable subgroup 1C. No new residue data were submitted in conjunction with this action. Rather, r esidue field trial data were previously reviewed for the representative commodities associated with the petitioned

- for crop subgroups associated with this action

. Additionally , t he proposed use of ginseng is based upon an approved translation of d ata from potato granules/ flakes , as per a Chemistry Science Advisory Council (ChemSAC) decision (ChemSAC minutes dated 09/11/13 and 09/18/13 )

.
Processing studies for the currently registered zoxamide uses are adequate. Z oxamide processing studies are available for potatoes and grapes, and tolerances are established on potato wet peel, potato flakes

, and raisins. Livestock feedstuffs associated with the proposed uses of zoxamide include potato processing waste/cull potatoe s. Exposure from the latter, a minor ruminant feed item, is not anticipated to yield quantifiable residues in livestock commodities.

Available confined rotational crop data are adequate to satisfy data requirements and to delineate the nature of the resid ue 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

.
The proposed use on ginseng and the crop subgroup tolerances for zoxamide do not alter the Agency’s previous conclusion that there is no reasonable expectation of finite residues in ruminant and poultry commodities

.

5. 3 Water Residue Profile

The environmental fate database is adequate to characterize drinking water exposure for the parent compound. Limited fate data are available for the degradates of zoxamide. D ata indicate that zoxamide is moderately pe rsistent but immobile in soil; degrada tes seem to be more mobile than the parent. Model simulations show that zoxamide may reach surface drinking water supplies, but should not reach ground water in considerable amounts, because of soil immobility

.

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 17 of 38 The EDWCs for zoxamide are based upon zoxamide (parent only) as well as the total toxic residues of zoxamide and its major metabolites, (RH

- 150721, RH

- 24549, RH

- 141288, RH

129151 and RH

- 1 39432) in surface water and groundwater in support of human health risk

assessment. 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.

Table 5.3. Summary of Estimated Drinking Water Concentrations for Zoxamide 1

Zoxamide (Parent only) ( μg/L ) Drinking Water Source Crop Scenario Peak Exposure Annual Mean Exposure Average Annual Exposure

Surface W ater NY Grape STD

Scenario 2 17.55 2.49 0.91

Ground W ater FL Citrus

Scenario 3 0.00183 NA 0.000684

Total Toxic Residue (Zoxamide + Metabolites) 4 ( μg/L ) Drinking Water Source Crop Scenario Peak Exposure Annual Mean Exposure Average Annual Exposure

Surface Water NY Grape STD 2

Scenario 81.3 54.48 22.84

Ground Water WI Sands

Scenario 3 83.5 NA 65.8

1 EDWC modeling includes total toxic residue (TTR) of zoxa mide and five major degradates. 2 P ercent Crop Area of 0.91 adjusted EDWCs generated using Pesticide Root Zone Model/Exposure Analysis Modeling System ( PRZM/EXAMS ) model for aerial application

. 3 Hig hest EDWCs generated using PRZM for Groundwater (PRZM

- G W ) model based on 1.60 lb ai/A for grape and potato ( Gavel 80 WP

, EPA Reg. No.10163

- 6413)

. 4 Metabolites = RH

- 150721, RH

- 24549, RH

- 141288, RH

- 129151, and RH

- 139432.



### 5. 4 Dietary Risk Assessment

5.4 .1 Description of Residue Data Used in Dietary Assessment

HED conducted a screening

- level chronic dietary (food and drinking water) risk assessment for zoxamide using exposure and risk estimates obtained from the Dietary Exposure Evaluation Model using the Food Commodi ty Intake Database (DEEM

- FCID; v ersion 3.16). The model uses food consumption data from the Department of Agriculture’s (USDA’s) 2003

- 2008 National Health and Nutrition Examination Survey, What We Eat in America ( NHANES/WWEIA ) database

. The assessment incorporated tolerance

- level residues and 100 PCT for all established and proposed commodities. The assessment also utilized default processing factors from the DEEM

- FCID v ersion 7.81 except for raisin and potato granules/flakes , where the processing factor was set at 1 . EDWCs from EFED were also incl uded: the average ground water exposure of 65.8 μ g/L was incorporated directly into the dietary assessment.

Since the last completed dietary risk assessment, no new residue data have been submitted to the Agency to support the requested tolerances. There fore, a ll of the input files and assumptions are nearly identical to th e last completed dietary risk assessment for zoxamide ( M. Negussie, D416654, 01/29/2014 ), except that updates in DEEM

- FCID v ersion 3.16 were added to

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 18 of 38 incorporate the petitioned

- for crop subgroups as well as to include Small vine climbing fruit, except fuzzy kiwifruit, subgroup 13

- 07F at 5.0 ppm ; a petitioned

- for tolerance request to harmonize with Codex. T he inputs and results to this dietary assessment are presented in Appendix F.

5. 4

. 2 Acute Dietary Risk Assessment

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

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

5. 4

. 3 Chronic Dietary Risk Assessment

The results of the chronic dietary analysis for food and drinking water are below the Agency’s LOC for the general U.S population and all population subgroups. The dietary (food and drinking water) exposure is estimated at 1.8 % of the chronic Population Adjusted Dose (cPAD) for the general U.S. population and 6.3 % of the cPAD for children 1 to 2 years old, the population subgroup with the highest estimated chronic dietary exposure to zoxamide

. These percentages increased slightly from the last completed dietary risk a ssessment. The results of the chronic dietary exposure analyses are reported in Table 5.4 .5

.

5.4 .4 Cancer Dietary Risk Assessment

Zoxamide is classified as “not likely to be carcinogenic to 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 0.008547 1.8
All Infants (< 1 year old) 0.013444 2.8

Children 1

- 2 years old 0. 030265 6.3

Children 3

- 5 years old 0.022592 4.7

Children 6

- 12 years old 0.011490 2.4

Youth 13

- 19 years old 0.005998 1.2

Adults 20

- 49 years old 0.006824 1.4
Adults 50+ years old 0.006701 1.4

Females 13

- 49 years old 0.006729 1.4

a The population subgroup with the greatest exposure is in bold

.



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no existing or propose d residential uses of zoxamide

.

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 19 of 38 6. 1 Residential Bystander Post

- A pplication Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPP

- 2009

- 0687

- 0037 ). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www. regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219). During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicol ogical studies) or further analysis is required for zoxamide.

6. 2 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray dri ft can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for zoxamide. The agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was de veloped as a result of a Data Call

- In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the agency’s Spray Drift website for more information). 2 

### The agency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk assessments for pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during the Regis tration Review process which ensures that all uses for that pesticide will be considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs)

- Residential Exposure Assessment St andard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification of indirect non

- occupational exposure to drift.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking wat er, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard ( e. g. a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and dura tion of exposure. Since there are no existing or proposed residential uses for zoxamide, there

ar e 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;” therefor e, an ag gregate cancer assessment was not conducted.

2 Available: http://www2.epa.gov/reducing

- pesticide

- drift

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 20 of 38 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 toxic ity finding as

to zoxamide and any other substances and zoxamide does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that zoxamide has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements release d by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://w ww.epa.gov/pesticides/cumulative/

.

9.0 Occupational Exposure/Risk Characterization

This document presents an assessment of the proposed uses of zoxamide on ginseng and Tomato subgroup 8

- 10A. Based on application rate and label information, only short

- and intermediate

term dermal and inhalation exposure is expected for o ccupational handler s and post

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

9.1 Short

- and Intermediate

- Term Handler Risk

Based on the anticipate d use patterns and current labeling, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios:

 Mixing and loading t he WG formulation of zoxamide for aerial, chemigation, and groundboom application s ; and

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

The label states that human flagging is prohibited. Flagging to support aerial application is limited to use of the Global Positioning System (GPS) or mechanical flaggers. Therefore, an occupational flagger assessment was not conducted for the proposed uses of zoxamide.

For short

- and intermediate

- term exposure, only inhalation exposures were assessed since ther e is no systemic hazard from the dermal route of exposure. There are no risk estimates of concern at the baseline level of personal protective equipment (PPE)

. The proposed labels require occupational handlers to wear baseline clothing (long

- sleeved shirts , long pants, shoes, socks) and chemical resistant gloves. MOEs rang ed from 2,100 to 1,400,000 for short

- and intermediate

- term exposures

. Appendix E summarizes all assessed occupational exposure and risk estimates.

Note that only engineering control (en closed cockpit) data are available to assess risks to handlers operating aircrafts. Dermal handler and post

- application exposure and risk assessments were not conducted because a dermal hazard was not identified for zoxamide. HED has no data to assess expo sures to pilots using open cock pits. The only data available are for exposure s to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the engineering control

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 21 of 38 (enclosed cockpits) and baseline PPE ; per the Agency’s Worker Protection S tandard stipulations for engineering controls, pilots are not required to wear protective gloves for the duration of the application. With this level of protection, there are no risk estimates of concern for applicators.

9.2 Short

- and Intermediate

- Term Post

- Application Risk

HED uses the term post

- application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re

entry e xposure). Such exposures may occur w hen workers enter previously treated areas to perform job functions, including activities related to crop production, such as sco uting for pests or harvesting. Post

- application exposure levels vary over time and depend on such things as the type of activit y, the nature of the crop or target that was treated, the type of pesticide application, and the chem ical’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 durin g post

- application activities. However, there are no dermal PODs selected for any exposure duration for zoxamide ; the refore, an occupational dermal post

- application assessment and a dislodgeable foliar residue (DFR) study are not required at this time (see Appendix G ).

Restricted Entry Interval

Zoxamide is classified as Toxicity Cate gory III via the dermal route. It is a moderate irritant to eyes, it is not irritating to the skin, but it is a skin sensitizer. Typically, the restricted entry interval (REI) specified on the proposed label is based on the acute toxicity of the active ingredient. Under 40 CFR 156.208 ( c) (2) (iii), active ingredients classified as Acute III or IV for acute dermal, eye irritation, and primary skin irritation are assigned a 12

- hour REI. Thus, the 48

- hour restricted entry interval (REI) on the proposed label is acceptable for ginseng and T omato subgroup 8

- 10A.

9.2.2 Inhalation Post

- application Risk

There are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particu lates that contain pesticides. The A gency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Sci entific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The A gency has evaluated the SAP report and has developed a Volatilization Screening Too l and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

OPP

- 2014

- 0219 ). During Registration Review, the agency will util ize this analysis to determine if data (i.e., flux studies, route

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

.

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 22 of 38 In addition, the Agency is continuing to evaluate the available post

- application inhalation

exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the agency's risk assessment s.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for oc cupational/commercial handlers. Handler exposure resulting from application of pesticides outd oors is likely to result in higher exposure than post

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.

10 .0 References

Seifu, Edom. 03/19/2015. DP Barcode 425825. “ Drinking Water Exposure Assessment in support of the new use registration of zoxamide formulated product Gravel 75DF on ginseng, tomato subgroup (Subgroups 8

- 10A), small fruit vine climbing except fuzzy kiwifruit (Subgroup 13

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

Negussie, Meheret. 09/17/2015 . DP Barcode 429154 . “ Zoxamide. Petition for Ginseng and Crop Subgroup Expansions for Vegetable, Tuberous and Corm, Subgroup 1C; Tomato Subgroup 8

- 1 0A; and Fruit, Small Vine Climbing, except Fuzzy Kiwifruit, Subgroup 13

- 07F. 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) Meeting of February 27 , 2014: Recommendations on the Need for Subchronic Inhalation and Immunotoxicity Studies.”

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

. Occupational and Residential Exposure and Risk Assessment for the Proposed Use on Ginseng, Grapes, Potatoes and
Tomatoes. ”

HIARC . 02/07/ 2001

. HED Document Number 014464 . “ Zoxamide Report .”

Tsaur, Nancy. 04/03/2014. “ Zoxamide

. Aggregate Human Health Risk Assessment for the Proposed New Use on Bulb Onions (Crop Subgroup 3

- 07A) .”

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 23 of 38 Appendix A . Toxicology Profile and Executive Summaries

A.1 Toxic ology Data Requirements

The requirements (40 CFR 158.500) for food uses are in the table below. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1 : Toxicology Data Requirements Guideline Study Type Required Satisfied 870.1100 Acute Oral Toxicity Yes Yes
870.1200 Acute Dermal Toxicity Yes Yes 870.1300 Acute Inhalation Toxicity Yes Y es 870.2400 Acute Eye Irritation Yes Yes 870.2500 Acute Dermal Irritation Yes Yes
870.2600 Skin Sensitization Yes Yes 870.3100 90

- Day Oral Toxicity in Rodents Yes Yes 870.3150 90

- Day Oral Toxicity in Non

- Rodents Yes Yes
870.3200 21/28

- Day Dermal Toxicity Yes Yes 870.3250 90

- Day Dermal Toxicity CR NA
870.3465 90

- Day Inhalation Toxicity CR Yes 2

870.3700 Prenatal Developmental Toxicity Study (Ra t) Y es Yes

Prenatal Developmental Toxicity Study ( Rabbit ) Yes Yes
870.3800 Reproduction and Fertility Effects Yes Yes 870.4100 Chronic Toxicity (Rodent) Yes Yes

870.4200 Carcinogenicity ( Rat ) Yes Yes

Carcinogenicity ( Mouse ) Yes Yes 870.5100 Bacterial Reverse Mutation Test Y es Yes
870.5300 870.5375 i n vitro Mammalian Cell Gene Mutation Test

i n vitro Mammalian Chromosome Aberration Test Y es 1 Yes

870.5385 870.5395 Mammalian Bone Marrow Chromosomal Aberration Test

Mammalian Erythrocyte Micronucleus Test Y es 1 Yes

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

Delayed Neurotoxicity of Organophosphorus Substances (28

- Day, Hen) CR NA

870.6200 Neurotoxicity Screening Battery (Acute, Rat) Yes Yes

Neuro toxicity Screening Battery (90

- Day , Rat) Yes Yes
870.6300 Developmental Neurotoxicity Study CR NA
870.7200 Companion Animal Safety CR NA
870.7485 Metabolism and Pharmacokinetics Yes Yes 870.7600 Dermal Penetration CR NA
870.7800 Immunotoxicity Yes Yes 2
CR Conditionally Required
NA Not Applicable
1 Either guideline study type may be used to satisfy the data requirement (e.g., 870.5300 or 870.5375)
2 Study r equirement waived (TXR0056915, 02 April 2014)

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 24 of 38 A.2 Toxicity Profiles

Table A.2 .1 Acute Toxicity Profile

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

870.1100 Acute Oral

Toxicity (Rat) 44731805 (1996)

Gavage Doses (mg/kg):
M: 5000
F: 5000 Acceptable / Guideline Toxicity Category: IV
LD 50 (mg/kg): M > 5000

F > 5000 Combined > 5000

Acute Oral Toxicity (Mouse) 44731806 (1998)

Gavage Doses (mg/kg):
M: 5000
F: 5000 Acceptable / Guideline Toxicity Category: IV
LD 50 (mg/kg): M > 5000

F > 5000 Combined > 5000

870.1200 Acute Dermal

Toxicity (Rat) 44731807 (1996)

Dermal Dose (mg/kg):
M: 2000
F: 2000 Acceptable / Guideline Toxicity Category: III
LD 50 (mg/kg): M > 2000

F > 2000 Combined > 2000

870.1300 Acute Inhalation

Toxicity (Rat) 44731808 (1996)

Inhalation Dose (mg/L):
M: 1.9, 5.3 F: 1.9, 5.3 Acceptable / Guideline Toxicity Category: IV LC 50 (mg/L): M > 5.3

F > 5.3 Combined > 5.3

870.2400 Acute Eye

Irritation (Rabbit) 44731809 (1996)

Acceptable / Guideline Toxicity Category: III Based on corneal opacity beginning 24 hrs post dosing and ending at 72 hrs post dosing; and conjunctivitis beginning 1 hr post dosing and resolved by Day 07.
870.2500 Acute Dermal

Irritation (Rabbit) 44731810 (1996)

Acceptable / Guideline Toxicity Category: IV No irritation was noted

870.2600 Skin

Sensitization (Guinea Pig) 44731811 (1997)

Acceptable / Guideline The chemical is a strong dermal sensitizer: All sites challenged with test material had scattered mild redness to intense redness and swelling; two sites had subcutaneous hemorrhaging.

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 25 of 38 Table A.2 .2. Repeat

- Dose and Other Toxicity Profile

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

870.3100 90

- Day Oral Toxicity

in Rodents (Rat) 44731814 (1996) Dietary Concentration (ppm): 0, 70, 700, 2500, 7000 Dietary Dose (mg/kg/day):
M: 0, 12, 123, 436, 1212
F: 0, 17, 174, 574, 1666 Acceptable / Guideline NOAEL (mg/kg/day): M = 1212 F = 1666

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

870.3150 90

- Day Oral Toxicity

in Non

- Rodents (Dog) 44731816 (1997) Dietary Concentration (ppm): 0, 1500, 7500, 30000 Dietary Dose (mg/kg/day):
M: 0, 54.5, 281.1, 1139.3
F: 0, 61.8, 321.6, 1054.5 Acceptable / Guideline NOAEL (mg/kg/day): M = 321.6 F = 61.8

LOAEL (mg/kg/day): M = 1139.3 F = 321.6 M: Based on increased mean liver weight, evidence of corresponding hepatocellular hypertrophy, decrease in albumin and albumin/globulin ratios. F: Based on increased mean liver weight

870.3200 21/28

- Day

Dermal Toxicity (Rabbit) 44731818 (1998) Dermal Dose (mg/kg/day):
M: 0

, 150, 400, 1000
F: 0

, 150, 400, 1000 Acceptable / Guideline Dermal

NOAEL (mg/kg/day): M < 150 F < 150 LOAEL (mg/kg/day): M = 150 F = 150 Based on dermal effects such as skin irritation.

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

870.3465 90

- Day

Inhalation Toxicity NA Study requirement waived (TXR0056915)

870.3700 Prenatal

Developmental Toxicity Study (Rat) 44731823 (1994) Gavage Dose (mg/kg/day):
F: 0

, 100 , 30 0

, 100 0 Acceptable / Guideline Maternal

NOAEL (mg/kg/day) = 1000 LOAEL (mg/kg/day) > 1000

Developmental NOAEL (mg/kg/day) = 1000 LOAEL (mg/kg/day) > 1000

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 26 of 38 Table A.2 .2. Repeat

- Dose and Other Toxicity Profile

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

Prenatal Developmental Toxicity Study (Rabbit) 44731824 (1997) Gavage Dose (mg/kg/day):
F: 0 , 100, 300, 1000 Acceptable / Guideline Maternal

NOAEL (mg/kg/day) = 1000 LOAEL (mg/kg/day) > 1000

Developmental NOAEL (mg/kg/day) = 1000 LOAEL (mg/kg/day) > 1000

870.3800 Reproduction and

Fertility Effects (Rat) 44770001 (1998) Dietary Concentration (ppm): 0, 1000, 5000, 20000 Dietary Dose (mg/kg/day):
M 0 : 0, 71.4, 359.7, 1473.5
F 0 : 0, 82.0, 409.3, 1624.4

M 1 : 0, 100.1, 489.2, 2091.3
F 1 : 0, 108.2, 534.1, 2239.1 Acceptable / Guideline Parental

NOAEL (mg/kg/day): M = 1473.5 F = 409.3 LOAEL (mg/kg/day): M > 1473.5 F = 1624.4 F: Based on decreased body weights and bod y weight gains

Reproductive / Offspring NOAEL (mg/kg/day): M = 2091.3 F = 2239.1 LOAEL (mg/kg/day): M > 2091.3 F > 2239.1

870.4100 Chronic Toxicity

(Dog) 44731817 (1998) Dietary Concentration (ppm): 0, 1500,
7 500 , 30000 Dietary Dose (mg/kg/day):
M: 0, 50, 255, 1016
F: 0, 48, 278, 99 4 Acceptable / Guideline NOAEL (mg/kg/day): M = 50 F = 48

LOAEL (mg/kg/day): M = 255 F = 278 Based on body weight changes, increases in liver and thyroid weights, and increases in alkaline phosphatase.

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 27 of 38 Table A.2 .2. Repeat

- Dose and Other Toxicity Profile

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

870.4200 Carcinogenicity

(Mouse) 44731819 (1998) Dietary Concentration (ppm): 0, 350, 1750, 7000 Dietary Dose (mg/kg/day):
M: 0, 51.1, 251, 1021
F: 0, 60.4, 326, 1289 Acceptable / Guideline NOAEL (mg/kg/day): M = 1021 F = 1289

LOAEL (mg/kg/day): M > 1021 F > 1 289

No evidence of carcinogenicity.

870.4300 Combined Chronic

Toxicity / Carcinogenicity (Rat) 44731821 (1998) Dietary Concentration (ppm): 0, 1000, 5000, 20000 Dietary Dose (mg/kg/day):
M: 0, 51, 260, 1058
F: 0, 65, 328, 1331 Acceptable / Guideline NOAEL (mg/kg/day): M = 1058 F = 1331

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

No evidence of carcinogenicity.

870.5100 Bacterial Reverse

Mutation Test ( Salmonella typhimurium ) 44731825 (1996) Applied Dose (μg/plate):

 S9: 50, 200, 500, 2000, 5000 Acceptable / Guideline ±S9: Negative up to 5000 μg/mL

No evidence of mutagenicity.

44731835 (1998) Applied Dose (μg/plate):

 S9: 50, 200, 500, 2000, 5000 Acceptable / Guideline ±S9: Negative up to 5000 μg/mL

No evidence of mutagenicity.

44731838 (1998) Applied Dose (μg/plate):

 S9: 50, 200, 500, 2000, 5000 Acceptable / Guideline ±S9: Negative up to 5000 μg/mL

No evidence of mutagenicity.

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 28 of 38 Table A.2 .2. Repeat

- Dose and Other Toxicity Profile

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

870.5300 in vitro Mammalian

Cell Gene Mutation
Test (Mouse Lymphoma Cells) 44731826 (1994) Applied Dose (mg/mL):

- S9: 5, 10, 20, 30, 40, 50, 65 +S9: 2, 5, 10, 20, 30, 40, 55 Acceptable / Guideline ±S9: Negative up to the maximum dose

No evidence of mutagenicity.

870.5375 in vitro Mammalian

Chromosome Aberration Test (Chinese Hamster Ovary (CHO) cells) 44731827 (1998) Applied Dose (μg/mL):

 S9: 0.9689

- 100 Acceptable / Guideline  S9: Negative up to cytotoxic concentrations

The test substance did not induce structural chromosome aberrations in cultured CHO cells treated up to the limit of toxicity, but did induce increased levels of numerical aberrations, both in the presence and absence of metabolic activation.

870.5395 Mammalian

Erythrocyte Micronucleus Test (Mouse) 44742904 (1989) Gavage Dose (mg/kg):
M: 0 , 200, 1000, 2000
F: 0 , 200, 1000, 2000 Acceptable / Guideline The test substance is considered to be nonmutagenic in

the mouse bone marrow micronucleus assay when tested up to the clinical limit dose.

None of the test article animals showed increases over vehicle control in the frequency of b one marrow micronucleated poly chromatic erythrocytes up to the limit dosing, in contrast to dose

- related increases in the positive control animals.

870.6200 Acute Neurotoxicity

Screening Battery (Rat) 44731831 (1997) Gavage Dose (mg/kg):
M: 0, 125, 500, 20000
F: 0, 125, 500, 20000 Acceptable / Guideline Neurotoxicity

NOAEL (mg/kg/day): M = 2 000 F = 2000 LOAEL (mg/kg/day): M > 2000 F > 2000

Systemic NOAEL (mg/kg/day): M = 2 000 F = 2000 LOAEL (mg/kg/day): M > 2000 F > 2000

90

- Day Neurotoxicity Screening Battery (Rat) 44731815 (1996) Dietary Concentration (ppm): 0, 1000

, 5000 , 2000 0 Intake Dose (mg/kg/day):
M: 0, 74 , 372, 1509
F: 0, 80, 401, 1622 Acceptable / Guideline Neurotoxicity

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

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

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 29 of 38 Table A.2 .2. Repeat

- Dose and Other Toxicity Profile

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

870.7485 Metabolism and

Pharmacokinetics (Rat) 44731829 (1989) Gavage Dose (mg/kg): Single: 10, 1000 Repeated: 10 Bile

- Cannula: 10 Acceptable / Guideline Absorption

Absorption was determined to be 54.62

- 59.02% of the administered dose (AD). The urine contained 8.78

- 11.26% AD and the bile contained 45.84

- 47.76% AD.

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

Metabolism
Non

- metabolized zoxamide was the major component in feces (12.1

- 23.0% AD). In addition, some of t he 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.

Eliminat ion The majority (96

- 102%) of elimination in the rat occurred within 120 hours. There was no radiolabel in the expired air and no evidence for bioaccumulation. Based on excretion and tissue residue data, bioavailability is conservatively estimated at ~59% of an administered dose. 44731836 (1998) Metabolite: 14 C

RH

- 141,452 Gavage Dose (mg/kg): Single: 1000 Acceptable / Guideline 44731839 (1998) Metabolite: 14 C

RH

- 141,455 Gavage Dose (mg/kg): Single: 1000 Acceptable / Guideline
44731830 (1998) Gavage Dose (mg/kg): Single: 2000 Acceptable / Guideline
870.7600 Dermal Penetration ( in

vivo Rat) TXR 0014464 (2001) 44731832 (1998) For the 10 hour exposure period, the dermal absorption

factor (DAF) is 3% based on the 3.17% and 2.51% absorbed at 10 hours for the 80WP and 2F formulations, respectively.

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 30 of 38 Table A.2 .2. Repeat

- Dose and Other Toxicity Profile

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

44731832 (1998) Formulation: 80WP (80% a.i.) Dermal Dose (  g/cm 2 ): M: 1.5

, 15, 800

Formulation: 2F (24% a.i.) Dermal Dose (  g/cm 2 ): M: 1.5 , 2400

Acceptable / Guideline 80WP

For 10 hours of exposure, dermal absorption was 3.17, 0.80, and 0.56% in their respective dose groups.

For 24 hours of exposure, dermal absorption was 5 .08, 1.22, and 0.56% in their respective dose groups

2F For 10 hours of exposure, dermal absorption was 2.51 and 0.29% in their respective dose groups.

For 24 hours of exposure, dermal absorption was 6.38 and 0.42% in their respective dose groups.

870.7800 Immunotoxicity NA Study requirement waived (TXR0056915)

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 31 of 38 A ppendix B. Physical/Chemical Properties

Table B.1. Physicochemical Properties of Zoxamide.

Parameter Value Reference Melting point/range 159.5

- 160.5 ° C (98.8% purity) MRID 49067102 pH 6.9 at 24.3 ° C Density Relative Density 1.38 at 20 ° C Water solubility (at 20°C) 0.681 ± 0.017 mg/L Solvent solubility (at 20°C) Ethyl acetate: 20.0 g/L Acetone: 55.7 g/L Xylene: 1.56 g/L

n

- Octanol: 6.49 g/L

n

- Heptane: 0.038 g/L 1,2

- Dichloroethane: 12.5 g/L Vapor pressure (at 25, 35, and 45°C) 9.75×10

- 8 mm Hg

Dissociation constant, pK a 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, K OW Log Kow 3.76 ± 0.04 at ambient temp

UV/visible absorption spectrum 212 nm. ε = 46330



### Appendix C. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); and the Agricultural Handler Exposure Task Force (AHETF) database; are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 3



### .

3 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html an d http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 32 of 38 Appendix D. International Residue Limit Status

Table D.1. Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 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 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)
US Canada Mexico 2 Codex Ginseng 0.30 0.3 potato flakes/granules

Tomato subgroup 8

- 10A 2.0 2 tomatoes 2

tomatoes Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F 5.0 3 grapes 5 grapes

Vegetable, tuberous and corm, subgroup 1C 0.06 0.06 potatoes 0.02 potato

Completed: M. Negussie; 09/17/15

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 33 of 38 Appendix E. Occupational Exposure/Risk Summary Table

Table E.1. Occupational Handler Short

- and Intermediate

- Term Exposure and Risk Estimates for Zoxamide a

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

Application
Rate v Area Treated

Daily e Baseline Inhalation

Dose f MOE g

μg/lb ai lb ai/A Acres mg/kg/day ST/IT LOC = 100 Mixing/Loading "Dry Flowable"

Aerial / Chemigation Orchard

(Grapes)

8.96 0.20

350 0.00784 6,100

Field Crops

- Typical (Ginseng, Tomatoes) 0.17 0.00666 7,200

Field Crops

- High Acreage (Potatoes) 1200 0.0229 2,100

Airblast Orchard

(Grapes)

8.96 0.20 40 0.000896 54,000

Groundboom Field Crops

- Typical

(Ginseng, Tomatoes) 0.17 80 0.00153 31,000

Field Crops

- High Acreage (Potatoes) 200 0.00381 13,000

Applicator

Aerial Orchard

(Grapes)

0.0049 0.20

350 0.00000429 11,000,000

Field Crops

- Typical (Ginseng, Tomatoes)
0.17 0.00000365 13,000,000

Field Crops

- High Acreage (Potatoes) 1200 0.0000125 3,800,000

Airblast Orchard

(Grapes) 4.71

0.20 40 0.000471 100,000

Groundboom 0.34 0.000034 1,400,000

Field Crops

- Typical (Ginseng, Tomatoes) 0.17 80 0.0000578 830,000

Field Crops

- High Acreage (Potatoes) 200 0.000145 330,000

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

a Although short

- and intermediate

- term exposure and risk estimates for zoxamide are presented for orchard and field crop, high acreage scenarios, those assessed uses were subsequently withdrawn by the registrant. The MOEs applicable for the proposed use direct ions pertain only to field crops, typical = ginseng and Tomato subgroup 8

- 10A b “Field Crops

- Typical” include Ginseng (sub

- group 1B), and Tomatoes (sub

- group 8

- 10A), " Field Crop

- High Acreage " include Potatoes (sub

- group 1C) and "Orchard " are Grapes (sub

- gro up 13

- 07F).

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 34 of 38 c Based on the “Occupational Pesticide Handler Unit Expos ure Surrogate Reference Table” ( 201 3) ; Level of mitigatio n = Baseline except for aerial applicator which includes engineering controls. d Based on the maximum application rates on the proposed label s (Reg. No. 10163

- 6414, Gavel® 75DF Fungicide ).

e Exposure Science Advisory Council Policy #9.1. f Inhalation Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Am ount Handled Daily (A or gal/day) ÷ BW ( 80 kg).

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

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 35 of 38 Appendix F. Chronic Food Plus Water Residue Input File

- DEEM

- FCID

U.S. EPA Ver. 3.16, 03

- 08

- d

DEEM

- FCID Chronic analysis for ZOXAMIDE
Residue file: C: \ Documents and Settings \ MNEGUSSI \ My Documents \ DEEM Version
3.16 \ Zoxamide \ OnionBulbs \ Chronic_FoodWater2015.R08 Adju st. #2 NOT used Analysis Date 11

- 12

- 2015 Residue file dated: 11

- 05

- 2015/10:25:08 Reference dose (RfD) = 0.48 mg/kg bw/day Comment:Crop Group Conversion

- 2015

---------------------------------------------------------------------------------- Foo d Crop Residue Adj.Factors EPA Code Grp Food Name (ppm) #1 #2

---------- ---- ------------------------------- ---------- ------ ------ 0103015000 1CD Arrowroot, flour 0.060000 1.000 1.000 0103015001 1CD Arrowroot, flour

- babyfood 0.060000 1.000 1.000 0103017000 1CD Artichoke, Jerusalem 0.060000 1.000 1.000 0902021000 9B Balsam pear 1.000000 1.000 1.000 0901075000 9A Cantaloupe 1.000000 1.000 1.000
0103082000 1CD Cassava 0.060000 1.000 1.000
0103082001 1CD Cassava

- babyfood 0.060000 1.000 1.000 0902088000 9B Chayote, fruit 1.000000 1.000 1.000 0902102000 9B Chinese waxgourd 1.000000 1.000 1.000
0902135000 9B Cucumber 1.000000 1.000 1.000 0103139000 1CD Dasheen, corm 0.060000 1.000 1.000 0301165000 3A Garlic, bulb 0.700000 1.000 1.000
0301165001 3A Garl ic, bulb

- babyfood 0.700000 1.000 1.000 0103166000 1CD Ginger 0.060000 1.000 1.000 0103166001 1CD Ginger

- babyfood 0.060000 1.000 1.000 0103167000 1CD Ginger, dried 0.060000 1.000 1.000 0101168000 1AB Ginseng, dried 0.060000 1.000 1.000 1302174000 13B Gooseberry 5.000000 1.000 1.000 1304175000 13D Grape 5.000000 1.000 1.000 1304176000 13D Grape, juice 5.000000 1.200 1.000 1304176001 13D Grape, juice

- babyfood 5.000000 1.200 1.000 9500177000 O Grape, leaves 5.000000 1.000 1.000 9500178000 O Grape, raisin 15.000000 1.000 1.000 1304179000 13D Grape, wine and sherry 5.000000 1.000 1.000 0901187000 9A Honeydew melon 1.000000 1.000 1.000 0301237000 3A Onion, bulb 0.700000 1.000 1.000 0301237001 3A Onion, bulb

- babyfood 0.700000 1.000 1.000 0301238000 3A Onion, bulb, dried 0.700000 9.000 1.000 0301238001 3A Onion, bulb, dried

- babyfood 0.700000 9.000 1.000 0103296000 1C Potato, chips 0.300000 1.000 1.000 0103297000 1C Potato, dry (granules/ flakes) 0.300000 1.000 1.000 0103297001 1C Potato, dry (granules/ flakes)

- b 0.300000 1.000 1.000 0103298000 1C Potato, flour 0.300000 1.000 1.000 0103298001 1C Potato, flour

- babyfood 0.300000 1.000 1.000 0103299000 1C Potato, tuber, w/peel 0.060000 1.000 1.000 0103299001 1C Potato, tuber, w/peel

- babyfood 0.060000 1.000 1.000 0103300000 1C Potato, tuber, w/o peel 0.060000 1.000 1.000
0103300001 1C Potato, tuber, w/o peel

- babyfood 0.060000 1.000 1.000 0902308000 9B Pumpkin 1.000000 1.000 1.000 0902309000 9B Pumpkin, seed 1.000000 1.000 1.000 0902356000 9B Squa sh, summer 1.000000 1.000 1.000 0902356001 9B Squash, summer

- babyfood 1.000000 1.000 1.000 0902357000 9B Squash, winter 1.000000 1.000 1.000 0902357001 9B Squash, winter

- babyfood 1.000000 1.000 1.000 0103366000 1CD Sweet potato 0.060000 1.000 1.000 0103366001 1CD Sweet potato

- babyfood 0.060000 1.000 1.000 0103371000 1CD Tanier, corm 0.060000 1.000 1.000
0801374000 8A Tomatillo 2.000000 1.000 1.000

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 36 of 38 0801375000 8A Tomato 2.000000 1.000 1.000
0801375001 8A Tomato

- babyfood 2.000000 1.000 1.000 0801376000 8A Tomato, paste 2.000000 5.400 1.000 0801376001 8A Tomato, paste

- babyfood 2.000000 5.400 1.000 0801377000 8A Tomato, puree 2.000000 3.300 1.000 0801377001 8A Tomato, puree

- babyfood 2.000000 3.300 1.000 0801378000 8A Tomato, dried 2.000000 14.300 1.000 0801378001 8A Tomato, dried

- babyfood 2.000000 14.300 1.000 0801379000 8A Tomato, juice 2.000000 1.500 1.000 0801380000 8A Tomato, Tree 2.000000 1.000 1.000
0103387000 1CD Turmeric 0.060000 1.000 1.000 8601000000 86A Water, direct, all sources 0.065800 1.000 1.000 8602000000 86B Water, indirect, all sources 0.065800 1.000 1.000
0901399000 9A Watermelon 1.000000 1.000 1.000 0901400000 9A Watermelon, juice 1.000000 1.000 1.000 0103406000 1CD Yam, true 0.060000 1.000 1.000
0103407000 1CD Yam bean 0.060000 1.000 1.000
0301338000 3A Shallot, bulb 0.700000 1.000 1.000 1100173500 11 Goji berry 2.000000 1.000 1.000

Chronic Results files: Food Plus Water

U.S. EPA Ver. 3.16, 03

- 08

- d

DEEM

- FCID Chronic analysis for ZOXAMIDE NHANES 2003

- 2008 2

- day Residue file name: C: \ Documents and Settings \ MNEGUSSI \ My Documents \ DEEM Version
3.16 \ Zoxamide \ OnionBulbs \ Chronic_FoodWater2015.R08 Adjustment factor #2 NOT used. Analysis Date 11

- 12

- 2015/10:57:35 Residue file dated: 11

- 05

- 2015/10:25:08 Reference dose (RfD, Chronic) = .48 mg/kg bw/day COMMENT 1: Crop Group Conversion

- 2015

============================== ================================================= Total exposure by population subgroup

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

Total Exposure

----------------------------------- Population mg/kg Percent of Subgroup body wt/day Rfd

-------------------------------------- ------------- ---------------- Total US Population 0.008547 1.8% Hispanic 0.008687 1.8%

Non

- Hisp

- White 0.008653 1.8%

Non

- Hisp

- Black 0.007876 1.6%

Non

- Hisp

- Other 0.008371 1.7% Nursing Infants 0.005495 1.1%

Non

- Nursing Infants 0.016994 3.5%
Female 13+ PREG 0.007101 1.5%
Children 1

- 6 0.024630 5.1%
Children 7

- 12 0.010273 2.1%
Male 13

- 19 0.006127 1.3%
Female 13

- 19/NP 0.005870 1.2%
Male 20+ 0.006616 1.4% Female 20+/NP 0.006902 1.4%
Seniors 55+ 0.006786 1.4%
All Infants 0.013444 2.8%
Female 13

- 50 0.006704 1.4%
Children 1

- 2 0.030265 6.3%
Children 3

- 5 0.022592 4.7%
Children 6

- 12 0.011490 2.4%
Youth 13

- 19 0.005998 1.2%
Adults 20

- 49 0.006824 1.4%
Adults 50

- 99 0.006701 1.4%

### Zoxamide Human Health Risk Assessment DP No. D424990

Page 37 of 38 Female 13

- 49 0.006729 1.4%

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### Zoxamide Human Health Risk Assessment DP No. D424990

Page 38 of 38 Appendix G. D islodgeable Foliar Residue (D FR ) Waiver Summary

Dislodgeable Foliar Residue (DFR): In accordance with 40 CFR158, DFR data are required for all occupational (e.g., crop, nursery, greenhouse use sites) or residential (e.g., ornamental and vegetable gardens, pick your own farms, retail tree farms) uses that could result in post

application exp osure to foliage. In the absence of chemical

- specific DFR data, EPA uses default values. The 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment includes an analysis of a number of DFR studies, which resulted in the selection of a revised default values for the fraction of the application rate available for transfer after a foliar application (F AR 

### ). These values are based on an analysis of 19 DFR studies. Since that time, the Agricultural Re

- entry Task Force has submitted inf ormation (MRID 49299201) that corrects an application rate error made in the original submission of “ARF039

– Determination of Dermal and Inhalation Exposure to Reentry Workers During Chrysanthemum Pinching in a Greenhouse” (EPA MRID 45344501). As a resu lt, the range of F AR 

### values was revised from 2%

- 89% to 2%

- 47%. In the data, a large range of transferability is observed and this variability can potentially be attributable to many factors such as active ingredient; formulation; field conditions in t he studies; weather conditions (e.g., humidity); or many other difficult to quantify factors. Although witnessed across multiple chemicals, this range in F AR 

### values is not expected when considering DFR data for a single chemical. At this time, the ARTF s ubmission did not alter the selection of 25% as the reasonable, high

- end default value. Because DFR data are not available for zoxamide , EPA would use the default value of 25%. Although there may be a small degree of uncertainty in the use of the default DFR value for zoxamide (i.e., there is a small chance that the F AR 

### value may exceed the applicable default value ), it is likely that the health

- protective aspects of EPA’s occupational post

- application assessment methodology would more than compensate for this potential uncertainty. For example, when assessing residential and occupational post

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

exposures occur to zero

- day (i.e., day of application ) residues every day of the assessed exposure duration (i.e., EPA assumes that no dissipation or degradation occurs, it doesn’t rain, etc); individuals perform the same post

- application activities performed in the transfer coefficient study day after day (e.g., weeding, harvesting, p runing, etc.); and individuals engage in these post

- application activities for a high

- end amount of time every day (represented by data reflecting time spent gardening based on survey data).

Given the conservatisms discussed above and the potential compou nding nature of these conservatisms, EPA is able to rely upon the calculated exposure estimates with confidence that exposure is not being underestimated.

There is no hazard identified for zoxamide via the dermal route of exposure; therefore, a DFR study is not required at this t ime.