Acibenzolar-S-Methyl Human Health Risk Assessment DP No. 424596

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D

. C

. 20460



### Date: Aug 13, 2015



### MEMORANDUM OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### SUBJECT: Acibenzolar-S-Methyl. Human Health Risk Assessment to support Section 3 Use of Acibenzolar-S-Methyl Uses on Citrus Crop Group 10-10, and Pome Crop Group 11-10.

PC Code: 061402 Decision No.: 490192 Petition No.: 4F8269 DP Barcode: 424596 Registration Nos.: 100-921 (tech), I 00-922 Regulatory Action: Section 3 Registration Case No.: 7031 Risk Assessment Type: Single Chemical Aggregate TXRNo

. : NA MRID No.: NA



### FROM: CAS Nos.: 135158-54-2 40 CFR: 180

. 561



### Dennis McNeilly, Risk Assessor 

# 9.-- /v'J- { 

# ,/A

Bonnie Cropp-Kohlligian, Environmental

# S~i;n9;t**~....** 

# ?-

Shirley Keel, Ph.D., Biologist

### ~ ( 

### f,L(_ Ivan Nieves, Biologist 

## {1--- e,;/ _;__

. Abdallah Khasawinah
, Toxicologist 

# /1**{~** Risk Assessment Branch 4 Health Effects Division (7509P)



### THROUGH : Charles Smith, Acting Branch

# Chiu_~, Risk Assessment Branch 4 Health Effects Division (7509P)



### TO: Erik Kraft/Heather Garvie (RM 24) Fungicide Branch Registration Division (7505P)

Page 1 of 58Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 2 of 58 Table of Contents

1.0 Executive Summary

................................ ................................ ................................ ............. 4
2.0 HED Recomme ndations

................................ ................................ ................................ ...... 6 2.1 Data Deficiencies/Conditions of Registration

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

................................ ................................ ................................ .. 7 2.2.1 Enforcement Analytical Method

................................ ................................ ............ 7 2.2.2 International Harmonization

................................ ................................ .................. 7 2.2.3 Recommended Toleran ces

................................ ................................ ..................... 7 2.2.4 Revisions to Petitioned

- For Tolerances

................................ ................................ . 8 2.3 Label Recommendations

................................ ................................ ................................ ... 8 2.3.1 Recommendations from Residue Reviews

................................ ............................. 8 2.3.2 Recommendations from Occupational Assessment

................................ ............... 8 2.3.3 Recomme ndations from Residential Assessment

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

................................ ................................ ................................ ......................... 8 3.1 Chemical Identity

................................ ................................ ................................ .............. 8 3.2 Physical/Chemical Characteristics

................................ ................................ .................... 9 3.3 Pesticide Use Pattern

................................ ................................ ................................ ......... 9 3.4 Anticipated Exposure Pathways

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

................................ ................................ ......... 11
4.0 Hazard Characterization and Dose

- Response Assessment

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

................................ ................................ .... 12 4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

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

................................ ................................ ............................... 13 4.3 Toxicological Effects

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

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

................................ .......................... 15 4.4.2 Evidence of Neurotoxicity

................................ ................................ ................... 15 4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

....... 15 4.4.4 Residual Uncertainty in the Exposure Database

................................ .................. 15 4.5 Toxicity Endpoint and Point of Departure Selections

................................ ..................... 16 4.5.1 Dose

- Response Assessment

................................ ................................ ................. 16 4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

..... 17 4.5.3 Cancer Classification and Risk Assessment Recommendation

........................... 17 4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

................................ ................................ ................................ ......................... 17
5.0 Dietary Exposure and Risk Assessment

................................ ................................ ............ 19 5.1 Metabolite/Degradate Residue Profile

................................ ................................ ............ 19 5.1.1 Summary of Plant and Animal Metabolism Studies

................................ ............ 19 5.1.2 Summary of Environmental Degradation

................................ ............................ 20Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 3 of 58 5.1.3 Comparison of Metabolic Pathways

................................ ................................ .... 20 5.1.4 Residues of Concern Summ ary and Rationale

................................ ..................... 20 5.2 Food Residue Profile

................................ ................................ ................................ ....... 22 5.3 Water Residue Profile

................................ ................................ ................................ ..... 22 5.4 Dietary Risk Assessment

................................ ................................ ................................ . 23 5.4.1 Description of Residue Estimates Used in Dietary Assessment

.......................... 23 5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ ............. 24 5.4.3 Acute Dietary Risk Assessment

................................ ................................ ........... 24 5.4.4 Chronic Dietary Risk Assessment

................................ ................................ ........ 25
6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ .... 26 6.1 Residential Post

- Application Exposure

................................ ................................ ........... 26 6.2 Residential Bystander Post

- application Inhalation Exposure

................................ ......... 26 6.3 Spray Drift

................................ ................................ ................................ ....................... 27 6.4 Residential Risk Estimates for Use in Aggregate Assessment

................................ ....... 27
7.0 Aggregate Exposure/Risk Characterization

................................ ................................ ....... 28 7.1 Short

- a nd Intermediate

- Term Aggregate Risk

................................ ............................... 28
8.0 Cumulative Exposure/Risk Characterization

................................ ................................ ..... 29
9.0 Occupational Exposure/Risk Character ization

................................ ................................ .. 29 9.1 Short

- and Intermediate

- Term Handler Risk Estimates

................................ .................. 30 9.2 Short

- and Intermediate

- Term Post

- Application Risk Est imates

................................ .... 33 9.2.1 Dermal Post

- Application Risk Estimates

................................ ............................. 33 9.2.2 Inhalation Post

- Application Risk Estimates

................................ ......................... 35
10.0 References

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

................................ ....................... 37 A.1 Guideline Data Requirements

................................ ................................ ......................... 37 A.2 Toxicity Profiles

................................ ................................ ................................ .............. 38 A.3 Toxicological Endpoints

................................ ................................ ................................ . 44 A.3.1 Acute Reference Dose (aRfD)

- General Population

................................ ........... 44 A.3.2 Chronic Reference Dose (cRfD)

- Females age 13

- 49 and Young Children

....... 44 A.3.3 Chronic Reference Dose (RfD)

– Adult Males and Females 50+ years

.............. 45 A.3.4 Incidental Oral Exposure (Short

- and Intermediate

- Term)

................................ .. 47 A.3.5 Dermal Absorption

................................ ................................ ............................... 47 A.3.6 Dermal Exposure (Short and Intermediate

- Term)

................................ ............... 47 A.3. 7 Inhalation Exposure (Short and Intermediate

- Term)

................................ ........... 48 A.4 Executive Summaries

................................ ................................ ................................ ...... 49 Appendix B. Chemical Names and Structures of Metabolites

................................ .................... 55 Appendix C. Physical/Chemical Properties

................................ ................................ ................. 57 Appendix D. Studies Reviewed for Ethical Conduct

................................ ................................ ... 58Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 4 of 58 1.0 Executive Summary

This assessment support s the Section 3 registration for use of acibenzolar

- S

- methyl on citrus and pome fruit

. It addresses the exposures and human health risks associated with exposures from currently registered us es and the proposed new uses of acibenzolar

- S

- methyl. It also assesses potential enhanced sensitivity of infants and children from dietary and/or residential exposure as required under the Food Quality Protection Act (FQPA) of 1996.

Acibenzolar

- S

- methyl is a p lant activator

. It is a member of the benzothiadiazole class of compounds. Acibenzolar

- S

- methyl is registered to Syngenta Crop Protection, Inc for use on a number of leafy and fruiting v egetable crops and tobacco for the control or suppression of downy mildew, black rot, white rust, bacterial leaf spot and speck, and blue mold. P erm a nent tolerances ranging from 0.1

- 3.0 ppm are established under §180.561(a) . Acibenzolar

- S

- methyl is also used in commercial seed treatment operations for protection against certain early season seed and seed

- borne nematodes in cotton and on sod farms, golf courses, collegiate athletic fields, and lawns around commercial and industrial buildings to control turf diseases. Agricultural

a pplications may be made using ground or aerial equipment.

Syngenta Crop Protection, LLC is requesting new uses of acibenzolar

- S

- methyl, formulated as a 50% water dispersible granule (WDG; Actigard® 50WG; EPA Reg. No. 100

- 922), on citrus crop group 10

- 10 and pome crop gro up 11

- 10. Acibenzolar

- S

- methyl is proposed for multiple soil applications ( i.e., drench, drip or micro

- irrigation) on citrus crop group 10

- 10 and pome crop group 11

- 10 as well as for multiple foliar applica tions on pome crop group 11

- 10. It is also propose d for paint applications to pome fruit trees.

Acibenzolar

- S

- methyl has an active experimental use permit (100

- EUP

- 115; expiration date 12/31/2015) for use on apple, grapefruit and pear at rates similar to those under consideration, but allowing foliar use on grapefruit and a 30

- day PHI for foliar use on apple , grapefruit, and pear.

Hazard Identification

T he toxicology database for acibenzolar

- S

- methyl is adequate for evaluating and characterizing toxicity and selecting endpoints for purposes of this risk assessment.

In subchronic and chronic oral studies in rats, dogs and mice, signs of mild regenerative hemolytic anemia were consistently observed in all three species. Additional toxic effects observed in these studies included decreases in body weight , body weight gain and/or food consumption. No other significant treatment

- related effects of toxicological concern were observed in these subchronic and chronic oral studies. No neurotoxic effects were seen at the highest dose tested in a subchronic neuro toxicity study in rats. In a 28 day dermal toxicity study in rats, no systemic or dermal effects were seen at the limit dose.Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 5 of 58 In a developmental toxicity and developmental neurotoxicity studies in rats, t reatment related effects were observed in fetuses at levels that were not toxic to the parent indicating increased sensitivity of rat fetuses compared to adults. Increased sensitivity was not observed in a developmental toxicity study in rabbits , n or in 1

- and 2

- generation reproduction studies in rats. I n a 28 day dermal developmental toxicity study in rats, no maternal or developmental toxicity was observed at dose levels up to 500 mg/kg/day, the highest dose level tested.

Acibenzolar

- S

- methyl was classified by HED’s Hazard Identification Assessment R eview Committee ( HIARC) as “not likely” to be a human carcinogen based on negative carcinogenicity findings in male and female rats and mice and negative results in an acceptable battery of genotoxicity studies.

Acibenzolar

- S

- methyl technical grade mate rial showed no significant toxicity in a battery of acute toxicity tests (Toxicity Category III or IV in all tests) but showed considerable skin

sensitivity. The end

- use product (Actigard TM 50W G ) displayed no significant acute toxicity and no dermal sensit izing potential.

An immunotoxicity stud y required as part of new 40 CFR Part 158 data requirements for registration of a pesticide has been submitted and reviewed. Acibenzolar

- S

- methyl did not produce systemic toxicity or immunotoxicity at any dose ( up to 406 m g /k g /d ay ) including the hig hest dose tested in this study.

Dose Response Assessment

Toxicological endpoints were selected for dietary/drinking water, occupational and residential exposure scenarios. Acute and chronic reference doses (RfDs) were sel ected for assessment of food and drinking water exposures. An acute POD of 8.2 mg/kg/day (NOAEL) was selected for females 13

- 49 years old and children 1

- 12 years old from a developmental neurotoxicity study in
rats based on changes in brain morphometrics i n the cerebellum at the LOAEL of 82 mg/kg/day. No acute endpoint was identified for adults. The developmental neurotoxic effects of concern are presumed to occur after a single exposure and are relevant to females aged 13

- 49 years old since they occur in u tero and to young children based on post

- natal effects. A chronic POD of 8.2 mg/kg/day (NOAEL) was selected for females 13

- 49 and young children from a developmental neurotoxicity study in rats based on changes in brain morphometrics in the cerebellum at the LOAEL of 82 mg/kg/day. The effects observed in this study can occur after single or multiple doses. Selection of a chronic endpoint from this study ensures that the chronic exposure assessment is protective of f emales of reproductive age and their offs pring. A chronic RfD (cPAD=0. 25 mg/kg/day) for the general population was selected on the basis of hemolytic effects seen in a c hronic feeding study in dogs and other co

- critical toxicity studies

. Toxicological endpoints for inhalation, dermal, and incid ental oral exposures were selected from the developmental neurotoxicity study in rats. A dermal absorption factor was selected from aAcibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 6 of 58 dermal absorption study in rats. An uncertainty factor of 100X was applied to endpoints selected for all exposure routes ( 10x for interspecies extrapolation, 10x for intraspecies variation).

Exposure/Risk Assessment and Risk Characterization

Risk assessments were conducted for dietary (food and water) and occupational exposure pathways based on the request for the use of ac ibenzolar

- S

- methyl on c itrus and p ome f ruit

. A revised residential assessment was conducted to update the residential exposures based on the revised SOPs

. Refined acute and screening level chronic dietary and drinking water risk assessments for acibenzolar

- S

- methyl demonstrate that dietary and drinking water exposure estimates are below HED’s level of concern for the general population and all population subgroups. Occupational exposure and risk estimates indicate that worker handler and post

application ex posures are not of concern at the maximum allowable application rates for the proposed new uses. Aggregate risks are not of concern.

Use of Human Studies

This risk assessment relies in part on data from studies in which adult human subjects were intentio nally exposed to a pesticide or other chemical. These studies , listed in Appendix D, have been determined to require a review of their ethical conduct . S ome of these studies are also subject to review by the Human Studies Review Board. All of the studies used have received the appropriate review.

2.0 HED Recommendations

HED has no objection to granting the registrations for use of acibenzolar

- S

- methyl on the requested crops or to the establishment of permanent tolerances for residues of acibenzolar

- S

met hyl as specified in Section 2.2.3.

2.1 Data Deficiencies/Conditions of Registration

ORE: In accordance with 40 CFR 158, dislodgeable

- foliar residue (DFR) data are required for all occupational (e.g., crop, nursery, greenhouse use sites) uses that could result in post

application exposure to foliage. The proposed uses for acibenzolar

- S

- methyl could result in occupational post

- application exposure; however, chemical

- specific DFR data are not available. Since the highest estimated occupational post

- applic ation exposure using default DFR values for acibenzolar

- S

- methyl is not minimal in comparison to the LOC (i.e., the calculated MOE is not greater than two times higher than the LOC, MOE = 160 compared to the LOC of 100); EPA is requiring the 40 CFR DFR dat a to facilitate any necessary exposure assessments refinements and to further EPA’s general understanding of the availability of dislodgeable foliar pesticide residues. These data should be submitted with any future uses of acibenzolar

- S

- methyl.Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 7 of 58 2.2 T olerance Considerations

2.2.1 Enforcement Analytical Method

HPLC/UV Method AG

- 617A is available for tolerance enforcement. This method has undergone a successful tolerance method validation by the Analytic al Chemistry Branch of BEAD. The method was forwa rded to FDA f or inclusion in PAM Volume II. Briefly, the method consists of an initial hydrolysis with NaOH to convert acibenzolar

- S

- methyl to CGA

- 210007 fo llowed by methanol extraction. Residues are then diluted with HCl and purified by a series of solid

- phase extraction steps. Prior to HPLC/UV analysis, residues are partitioned into ethyl acetate, dried down, and re

- dissolved in phosphoric acid. This method has a limit of quantitation (LOQ) of 0.02 ppm

. The method includes optional detection via HPLC/MS, giving a means of residue confirmation.

2.2.2 International Harmonization

There are no Codex, Mexican, or Canadian maximum residue limits for acibenzolar

- S

- methyl in/on any commodity. Therefore, international harmonization is not an issue.

2.2.3 Recomm ended Tolerances

HED recommends that 40 CFR § 180. 561 be amended by establishing tolerances for residues of acibenzolar

- S

- methyl in the plant commodities listed in Table 2.2.3 , at the recommended levels shown therein

.

TABLE 2.2. 3 Tolerance Summary for Aci benzolar

– S

- Methyl Commodity as Proposed by Petitioner Proposed Tolerance (ppm) Recommended Tolerance (ppm) Correct Commodity Definition ; Comments Fruit, citrus, group 10

- 10 0.01 0.0 2 ppm Fruit, citrus, group 10

- 10 * (Tolerance is recommended at the LOQ of the enforcement method.) Fruit, pome, group 11

- 10 0.03 0.03 ppm Fruit, pome, group 11

- 10 * *Note: Time

- limited tolerances (expiration date 12/31/2015) are established under §180.561(a)(2) at 0.05 ppm in/on apple, grapefruit and pear to cover incurred re sidues from the experimental use permit (EUP) of acibenzolar

- S

- methyl on these crops (100

- EUP

- 115 permit; expiration date 12/31/2015) at rates similar to those under consideration, except allowing foliar use on grapefruit and a much shorter PHI for foliar uses (30 days). As a result of the current risk assessment action, the permanent tolerances will be lower than the current temporary tolerances.
Tolerances are currently listed in 40 CFR §180.561 for residues of acibenzolar

- S

- methyl, benzo(1,2,3)thiadiaz ole

- 7

- carbothioic acid

- S

- methyl ester, including its metabolites and degradates. Compliance with the tolerance levels specified is to be determined by measuring only those acibenzolar

- S

- methyl residues convertible to benzo(1,2,3)thiadiazole

- 7

- carboxylic

a cid (CGA

- 210007), expressed as the stoichiometric equivalent of acibenzolar

- S

- methyl, in or onAcibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 8 of 58 the commodity. The current tolerance expression is in accordance with current guidance (Knizner, 5/27/09).

2.2.4 Revisions to Petitioned

- For Tolerances

The rec ommended tolerance for fruit, pome, group 11

- 10 (0.03 ppm) is the same as the petitioned

- for tolerance ; however the recommended tolerance level for fruit, citrus, group 10

- 10 (0.0 2 ppm) is at the LOQ of the enforcement method which is higher than the petit ioned

- for tolerance (0.01 ppm).

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

The revised draft label (dated 8/12/15) should be further revised, consistent with the supporting pome data, to specify a 30

- day minimum RTI for the soi l use on pome.

Section B of the petition should be revised, consistent with the supporting pome data, as follows: (1) specify 60

- day PHIs for the proposed foliar and paint uses on pome and (2) specify 30

- day and 7

- day minimum retreatment intervals (RTIs) for the proposed soil and foliar uses on pome, respectively.

2.3.2 Recommendations from Occupational Assessment

None

.

2.3.3 Recommendations f rom Residential Assessment

None.

3.0 Introduction

3.1 Chemical Identity

Table 3.1

. Acibenzolar

- S

- Methyl Nom enclature

. Chemical structure

N N S O S C H 3

Common name acibenzolar

- S

- methylAcibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 9 of 58 Table 3.1

. Acibenzolar

- S

- Methyl Nom enclature

. Company experimental

name CGA

- 245704

IUPAC name benzo[1,2,3]thiadiazole

- 7

- carbothioic acid

- S

- methyl ester CAS name S

- methyl, 1,2,3

- ben z othiadiazole

- 7

- carbothioate CAS registry number 13 5158

- 54

- 2 End

- use product (EP) Actigard® 50 WG (EPA Reg. No. 100

- 922) Structure of metabolite CGA

- 210007

N N S C O O H

1,2,3

- benzothiadiazole

- 7

- carboxylic acid

3.2 Physical/Chemical Characteristics

A detailed description of the physiciochem ical properties of acibenzolar

- S

- methyl is provided in Appendix C

. Acibenzolar

- S

- methyl exhibits relatively low solubility in water and higher solubility in organic solvents. It has a very low vapor pressure. Acibenzolar

- S

- methyl does not present significa nt concerns for bioaccumulation based on the lipophilicity of the compound and mammalian metabolism studies.

3.3 Pesticide Use Pattern

Under Section B of the petition, Syngenta has submitted directions for proposed uses of acibenzolar

- S

- methyl on citrus and pome formulated as a water dispersible granule (WDG) containing 50% acibenzolar

- S

- methyl as the sole active ingredient (Actigard® 50WG; EPA Reg. No. 100

- 922). Subsequent to the submission of Section B of the petition, Syngenta submitted a revised draf t label (dated 8/12/15) to provide updated and more complete proposed use directions. The revised draft label (dated 8/12/15) is the basis for the following proposed use rate discussion.

Acibenzolar

- S

- methyl is proposed for multiple soil (i.e., drench, d rip or micro

- irrigation) applications on citrus/pome, multiple foliar applications on pome and paint applications to pome trees. The proposed maximum use rate, for any of these treatments, is 0.1 lb ai/A/application (0.4 lb ai/A/year) with a 0

- day pre

- har vest interval (PHI) for soil treatment and a 60

- day PHI for foliar or paint treatment. The use directions, based on the revised draft label (dated 8/12/15), are summarized in Table 3.3

.Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 10 of 58 Table 4. Summary of Directions for Use of Acibenzolar

- S

- methyl 1

Ap plic. Timing, Type, and Equip. Formulation [EPA Reg. No.] Applic. Rate (lb ai/A) Max. No. Applic. per

Season Max. Seasonal Applic.

Rate (lb ai/A) PHI (days) Use Directions and Limitations

Citrus Crop Group 10

- 10
Soil drench/ Chemigation 2 ; Ground Equip. 3 using ≥ 10 gal/A 3

Note: Aerial application is not indicated for use on this crop. 3 50% WDG [100

- 922] 0.1 4 (Implied) 0.4 0 day For suppression of citrus canker: Apply around the tree base at 0.0012 to 0.035 oz Actigard®/tree

- within the first 4

- 6 inches around the tree base. Determine rate based on tree age. For prevention, make up to 12 applications on a 30

- day minimum retreatment interval (RTI).

General Use Instruction 3 Adjuvants may be used. Do not apply using ultra

- low volume (ULV) spray systems. Pome Crop Group 11

- 10 4
Foliar; Ground Equip. 3 using ≥ 10 gal/A 3

Note: Aerial application is not indicated for use on this crop. 3 50% WDG [100

- 922] 0.1 4 (Implied) 0.4 60 days 4 For suppression of fire blight: Apply 2

- 3 times between 20% bloom and petal fall in a tank mix with antibiotic products to achieve best results. The minimum RTI is 7

- days. 4

General Use Instruction 3 Adjuvants may be used. Do not apply using ultra

- low volume (ULV) spray systems. Soil drench/ Chemigation 2 ; Ground Equip. 3 using ≥ 10 gal/A 3

Note: Aerial application is not in dicated for use on this crop. 3 0 day For suppression of fire blight: Application should begin at green tip. Apply around the tree base at 0.0012 to 0.035 oz Actigard®/tree

- within the first 4

- to 6

- inches around the tree. Determine rate based

on tree age. The minimum RTI is not specified. 4

General Use Instruction 3 Adjuvants may be used. Do not apply using ultra

- low volume (ULV) spray systems. Paint Application 60

- days 4 For suppression of fire blight: Paint application after canker cut

- outs or grafts. Mix 1 oz Actigard ® in 1 quart of 1% Pentrabark or similar penetrant. Apply to the branch area immediately below canker after cutting to an area extending 1 to 1.5 feet. One quart will treat approximately 500
cuts. 1 Based on the revi sed draft label (dated 8/12/15) that was submitted subsequently to Section B of the petition. providing updated and more complete use directions. 2 May be applied via drip irrigation or microsprinkler irrigation.Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 11 of 58 3 Not specified in Section B of the peti tion but listed under general use instructions for the end

- use product on the revised draft label (dated 8/12 /15) as appropriate unless otherwise indicate under crop

- specific directions. 4 For pome, use directions in Section B of the petition differed fro m the revised draft label (dated 8/12/15) as follows: (1) specified a 30

- day PHI for foliar use; (2) did not specify a PHI for paint use; (3) specified a 7

- day RTI for soil use; and (4) did not specify a RTI for foliar use

.
Conclusions

. The use directio ns are adequate to assess the proposed uses. Based on the revised draft label ( dated 8/12 /15 ) that provided updated and more complete proposed use directions than the earlier Section B of the petition, the submitted use information is considered adequate t o allow evaluation of the residue data relative to the proposed uses of acibenzolar

- S

- me thyl on citrus and pome fruit.

The revised draft label (dated 8/12/15) should be further revised, consistent with the supporting pome data, to specify a 30

- day minimu m RTI for the soil use on pome.

Section B of the petition should be revised, consistent with the supporting pome data, as follows: (1) specify 60

- day PHIs for the proposed foliar and paint uses on pome and (2) specify 30

- day and 7

- day minimum retreatme nt intervals (RTIs) for the proposed soil and foliar uses on pome, respectively.

3.4 Anticipated Exposure Pathways

Dietary (food and water) and residential exposures are expected based on existing uses of acibenzolar

- S

- methyl and the proposed use s of aci benzolar

- S

- methyl on citrus, and pome fruit

. A residential exposure assessment is not required for this assessment because there are no residential uses or exposures associated with the proposed new use. The short

- term aggregate exposure assessment, which takes into account residential exposure plus average exposure levels to food and water, has been updated to incorporate dietary exposure from the use of acibenzolar

S

- methyl on citrus and pome fruit

.

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.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pestici de use in a residential setting. Extensive data on food co nsumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and/or the CDC under the National Health and Nutrition Examination Survey/What We Eat i n America (NHANES/WWEIA), and are used in pesticide risk assessments for all regist ered food uses of a pesticide. These data are analyzed andAcibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 12 of 58 categorized by subgroups based on age, season of the year, ethnic gro up, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when condit ions or circumstances warrant. Whenever appropriate, non

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

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specia lized 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

4.1 Toxicology Studies Available for Analysis

T he toxicology database for acibenzolar

- S

- methyl is adequate for evaluating and characterizing acibenzolar

- S

- methyl toxicity and selecting endpoints for purposes of this risk assessment

4.2 Absorption, Distribution, Metabolism, & Elimination (AD ME)

The absorption, distribution, metabolism, and excretion of acibenzolar

- S

- methyl were studied in
rats. In the rat metabolism study [U

14 C Phenyl ] acibenzolar

- S

- methyl was administered by stomach tube to male and female rats at sin gle doses of 0.5 (low dose) or 100 mg/kg (high dose) or at a single dose of 0.5 mg/kg following 14 repeated daily doses of 0.5 mg/kg of nonlabeled acibenzolar

- S

- methyl.

For all treatment groups, acibenzolar

- S

- methyl was rapidly and nearly completely ab sorbed (>90% of the administered dose) from the gastrointestinal tract into the general circulation. Peak blood levels were reached at 15

- 30 minutes after the low dose and at 4

- 8 hours a fter the high dose. Tissue levels of radioactivity were highest in blo od, liver, kidney, ske letal muscle, heart and lungs. Radioactivity was rapidly excreted predominantly in the u rine (88

- 95% within 48 hours). Only a small amount of radioactivity was excreted in the fec es (3.1

- 4.5% within 48 hours). Insignificant radioactiv ity wa s excreted in the expired air. There was no signific ant enterohepatic circulation. After 7 days, levels of radioactivity remaining in the tissues were extremely low. Absorption, distribution, pharmacokinetic and excretion profiles were largely indepe ndent of dose level and sex

. Three urinary fractions were identified. Fraction U3 (79

- 92% of the administered dose) was identified as the carboxylic acid derivative of the parent

. Fraction U2 (0.4

- 2%) was identified as the corresponding glycine derivativ e of the carboxylic a cid (fraction U3) derivative. Fraction U1 (1

- 4.5%) was a mixture of at least three polar compounds that were not identified due to insufficient sample m aterial. No parent com po und was detected in the urine. Radioactivity in the feces represented <5% of the administered dose. No single metabolite in the feces exceeded 3% of the administered dose. Fraction F2 (0.7

- 3% of the administered dose) was identified as theAcibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 13 of 58 carboxylic acid derivative of the parent . Fraction F3 (0.1

- 1%) was ident ified as parent compound. Frac tion F1 (0.2

- 0.4%) was a very polar compound(s) that was not further identified. The metabolic fate of acibenzolar

- S

- methyl was independent of dose level, sex, and pretreatment.

4.2.1 Dermal Absorption

In a dermal absorpti on study in rats
, acibenzolar

- S

- methyl was applied dermally to a shaved dorsal area of 10 cm2 at two dose levels of 10 μg/cm2 and 100μg/cm2 to two groups of animals

con sisting of six animals/group. T wo animals from each group were sacrificed at 4, 8, and 2 4 hours after dosing
, and the amount of radioactivity in blood, urine
, feces, liver, kidneys, spleen, and rem aining carcass was determined. Amount of radioactivity remaining in/ on the skin and on the cover wa s also determined. For the groups for which the skin was washed after 8 hours, mean dermal absorption values were 43.55% and 5.92%, and mean radioactivity levels remaining at the skin were 46.64%, and 90.22%, respectively at 10 μ g/cm 2 and 100 μ g/cm 2 dose levels. Given the uncertainty regarding actual der mal deposition under actual field conditions, it is considered appropriate to derive an estimate of dermal absorption based on the results from the low dose group (10 μ g/cm 2 ), since percent dermal absorption wa s greatest at this dose level. Based on the li kely worker exposure time frame, it is considered most appropriate to adopt the dermal absorption value calculated for the group of animals for which the skin site was washed after 8 hours. Mean dermal absorption for this group of animals was 43.55%. (TXR 0054866 and/or MRID 47430503 )

4.3 Toxicological Effects

In subchronic and chronic oral studies in rats, dogs and mice, signs of mild regenerative hemolytic anemia were consistently observed in all three species. These signs frequently included decreased erythrocyte counts, decreased hemoglobin, decreased hematocrit, increased reticulocyte counts, increased hemosiderosis in the spleen, liver and/or bone marrow, extramedullary hematopoiesis in the spleen, and increased spleen weights in both males and fema les. A compensatory response (increased erythrocyte production) regularly followed the initial anemia. Additional toxic effects observed in these same studies included decreases in body weight, body weight gain and/or food consumption. No other significant treatment

- related effects of toxicological concern were observed in these subchronic and chronic oral studies. In a 28

- day dermal study in rats, no systemic or dermal effects were observed at dose levels up to 1 000 mg/kg/day, the limit dose. No neurotoxic effects were observed at any dose in a subchronic neurotoxicity study in rats

.

T reatment

- related developmental malformations, anomalies and variations were observed in a developmental toxicity study in rats at or below the no observable adverse effect l evel ( NOAEL ) for maternal toxicity. At the highest dose tested in this study (400 mg/kg/day), both maternal toxicity (hemorrhagic perineal discharge) and considerable developmental toxicity (including total litter resorptions, fetal malformations, anomalie s and variations) were observed. The fetalAcibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 14 of 58 malformations noted at this dose included treatment

- related effects on nervous system tissues (hydrocephaly, craniorachisis and anophthalmia/ microphthalmia). At the next lower dose tested (200 mg/kg/day), treatme nt

- related visceral malformations and skeletal variations were demonstrated in the absence of significant maternal toxicity. A similar increased sensitivity of fetuses or pups (as compared to adults) was not observed in a developmental toxicity study in

ra bbits or in 2

- generation and 1

- generation (range

- finding) stud ies in rats. In a dermal developmental toxicity study in rats, no maternal or developmental toxicity was observed at dose levels up to 500 mg/kg/day, the highest dose tested.

In a battery of mu tagenicity studies, results were negative in all studies except in an in vitro chromosome aberration study in Chinese hamster ovary (CHO) cells, in which there was evidence of a clastogenic response in the absence of S

- 9 activation.

In a 2

- year chronic toxicity/carcinogenicity study in rats and an 18

- month carcinogenicity study in mice, acibenzolar

- S

- methyl was negative for carcinogenicity when administered at dose levels adequate for the testing of carcinogenic potential.

Acibenzolar

- S

- methyl showe d no significant toxicity in a battery of acute toxicity tests (Toxicity Cat egory III or IV in all tests). Considerable skin sensitizing (contact allergenic) potential was demonstrated in a dermal sensi tization study in guinea pigs. T he formulated end

- use product (ActigardTM 50 WG) also demonstrated no significant acute toxicity; additionally, the end

- use product did not show dermal sensitization in guinea pigs.

The complete toxicity profile for acibenzolar

- S

- methyl is provided in Appendix A.

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

The FQPA factor for increased susceptibility to infants and children is reduced to 1x based on the following cons iderations. The toxicology data base for acibenzolar

- S

- methyl is complete and adequate for assessing increased susceptibility under FQPA. The pre

- and postnatal toxicity database for acibenzolar

- S

- methyl includes developmental toxicity studies in rats and rabbits, a DNT study in rats, and a two

- generation reproduction toxicity study in rats. Bas ed on the developmental toxicity in rats and the developmental neurotoxicity studies in rats
, t he re is concern for increased qualitative and/or quantitative susceptibility following in utero exposure to acibenzolar

- S

- methyl. However, the degree of concern for the increased susceptibility seen in these studies is low
, as there are no residual uncertainties with regard to pre

- and/or postnatal toxicity since (1) NOAELs and LOAELs have been identified for all effects of concern, (2) a clear dose response has b een well defined, and (3) the points of departure ( PODs ) selected for risk assessment are protective of the fetal/offspring effects. Additionally, the dietary and residential risk assessment s are conservative and will not underestimate dietary exposure
, an d
t here are no residual uncertainties in the exposure database. Further discussion may be found in the following sections.Acibenzolar

- S

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Page 15 of 58 4.4.1 Completeness o f the Toxicology Database

The toxicity database for acibenzolar

- S

- methyl is sufficient for a full hazard evalua tion and is considered adequate to evaluate risks to infants and children. Acceptable studies are available for developmental , reproduction, developmental
, subchronic neurotoxicity and immunotoxicity

.

4.4.2 Evidence of N eurotoxicity

In a developmental ne urotoxicity study
, a maternal LOAEL was not observed. The maternal NOAEL is 326 mg/kg/day, the highest dose tested. No treatment

- related offspring effects were seen on survival, clinical signs, FOB, developmental land marks, br ain weights or neuropatholog y. No conclusions can be drawn on the effects of the compound on motor activity due to the lack of consistency in the observations. Significant morphometric changes (decreased thickness of the molecular layer of the cerebellum) were observed in male offspr ing on PND 63 at 82 mg/kg/day. At the high dose, treatment

- related offspring effects included decreased body weights, increased auditory startle response and increased thickness in the corpus callosum in females. In a subchronic neurotoxicity study in rats
, no compound

- related effects were observed in the FOB, motor activity, gross pathology or neuropathology at the highest doses ( 575/628 mg/kg/day, M/F ) tested

.

4.4.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

In the rat deve lopmental toxicity study treatment related visceral malformations and skeletal variations were observed in fetuses at 200 mg/kg/day, th e NOAEL for maternal toxicity. In the developmental neurotoxicity study, offspring toxicity was observed at 82 mg/kg/day while no maternal toxicity was observed at 326 mg/kg /day, the highest dose tested. Additional developmental toxicity studies in rats and rabbits and reproduction studies in rats provided no indication of increased susceptibility of rat or rabbit fetuses or neonates compared to adult animals.

4.4.4 Residual Uncertainty in the Exposure Datab ase
There are no residual uncertainties in the exposure database. The refined acute dietary assessment utilizes maximum percent crop treated estimates but is still consi dered conservative
, since it is based on field trial data evaluating samples taken at the shortest preharvest interval and treated at the maximum use rate . The chronic dietary and residential risk assessments are also conservative. These assessments will not underestimate dietary and/or non

- dietary residential exposure to acibenzolar

- S

- methyl.Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 16 of 58 4.5 Toxicity Endpoint and Point of D eparture Selections

Toxicity endpoints and points of departure (PODs) for dietary (food and water), occupational, and resid ential exposure s cenarios are summarized below. A detailed description of the studies used as a basis for the selected endpoints is presented in Appendix A.

4.5.1 Dose

- Response Assessment

An acute POD of 8.2 mg/kg/day (NOAEL) was selected for females 13

- 49 years old and children 1

- 12 years old from a developmental neurotoxicity study in rats based on changes in brain morphometrics in the cerebellum at the LOAEL of 82 mg/kg/day. An uncertainty factor (UF) of 100x (10x to account for interspecies extrapolat ion and 10x for intraspecies variation) was applied to the NOAEL to obtain an acute reference dose (aRfD) of 0. 082 mg/kg/day. Since the FQPA factor has been reduced to 1X, the acute population adjusted dose (aPAD) is equivalent to the aRfD. The development al neurotoxic effects of concern are presumed to occur after a single exposure and are relevant to females aged 13

- 49 years old since they occur in utero and to young children based on post

- natal effects. No acute endpoint was appropriate for adults.

[Not e: B ased on a reevaluation of the DNT study regarding the potential for post

- natal toxicity, the acute dietary analysis has been revised to include only females 13

- 49 years old and children 1

- 12 years old .]

A chronic POD of 8.2 mg/kg/day (NOAEL) was selec ted for females 13

- 49 and young children years old from a developmental neurotoxicity study in rats based on changes in brain morphometrics in the cerebellum at the LOAEL of 82 mg/kg/day. A UF 100x (10x to account for interspecies extrapolation and 10x for intraspecies variation) was applied to the dose to obtain a chronic reference dose (cRfD/cPAD) of 0. 082 mg/kg/day. The effects observed in this study can occur after single or multiple doses. Selection of a chronic endpoint from this study ensures that the chronic exposure assessment is protective of f emales of reproductive age and their offspring.

[Note: In earlier risk assessments (D361893, 3/3/09), only the subpopulation females 13

- 50 years old was assessed for chronic dietary exposure based on in utero effects observed in the DNT study. However, based on a reevaluation of the DNT study regarding the potential for post

- natal toxicity, the chronic dietary analysis the chronic dietary exposure analysis has been revised to include an assessment of die tary risks to young children using the NOAEL from the DNT study for this and more recent previous assessments (D379425, 8/19/10).]

A chronic POD of 25 mg/kg/day (NOAEL) was selected for adult males and females (50+ years) based on hemolytic effects seen i n a chronic dog study and other co

- critical toxicity studies. A UF of 100x (10x to account for interspecies extrapolation and 10x for intraspecies variation) was applied to the dose to obtain a chronic reference dose (cRfD/cPAD) of 0.25 mg/kg/day. The NOAE L of 25 mg/kg/day, taken from the chronic dog study, is based on the totality of the database with a LOAEL of 105 mg/kg/day (the lowest LOAEL is from the reproduction study)Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 17 of 58 based on hemolytic anemia with compensatory response. The NOAEL and LOAEL

recommen ded for use in the risk assessment come from different studies conducted in different species

. Typically, a combination of NOAELs/LOAELs from studies conducted in different species is not recommended. However, in the case of acibenzolar

- S

- methyl
, the same endpoint (hemolytic anemia) is observed across species at a relatively close range of LOAELs (105

- 312 mg/kg/day). Therefore, the HED Toxicity Science Advisory Committee concluded that, in this instance, it would be appropriate to base the point of departur e for the risk assessment on the NOAEL from the dog chronic toxicity study using the LOAEL from the reproduction study in rats for the basis of the endpoint (hemolytic anemia).

Short

- term incidental oral and short

- and intermediate term dermal and inhalat ion PODs of 8.2 mg/kg/day were selected from the developmental neurotoxicity study in rats. The selected endpoint is protective of offspring effects from dermal exposure. Two acceptable dermal toxicity studies, including a dermal developmental study are av ailable. However s ince neurological effects observed in the oral developmental neurotoxicity study are not measured in the dermal studies, the findings from these studies may not be protective of neurological effects. A dermal absorption factor (DAF) is ap plied when dermal exposure endpoints are selected from oral toxicity studies. The dermal factor converts the oral dose to an equivalent dermal dose for the risk assessment. A dermal absorption factor of 44% was used for the dermal exposure
assessment based on a dermal absorption study in rats

. An MOE of 100 is required for incidental oral, dermal and inhalation exposure scenarios based on the conventional uncertainty factor of 100 ( 10x for interspecies extrapolation and 10x for intraspecies vari ation).

4.5 .2 Recommendation for Combining Routes of Exposures for Risk Assessment

Risk assessment must consider exposures from three major sources: oral, dermal, and inhalation exposures. In the case of acibenzolar

- S

- methyl ; incidental oral
, dermal, and inhalation exposure routes may be combined where appropriate since the same toxicity study and effects were chosen to evaluate all three exposure routes.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Acibenzolar

- S

- methyl has been designated by HED a s “Not Likely to be Carcinogenic to Humans” in accordance with the 2005 EPA Guidelines for Carcinogenic Risk Assessment based on negative carcinogenicity studies in rats and mice and on generally negative mutagenicity studies.

4.5.4 Summary of Points of D eparture and Toxicity Endpoints Used in Human Risk Assessment
Toxicological doses/endpoints selected for the acibenzolar

- S

- methyl risk assessment are provided in Tables 4.5.4a and 4.5.4b.Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 18 of 58 The acute endpoint (8.2 mg/kg/day) was derived from the developmen tal neurotoxicity study (DNT) based on changes in brain morphometrics in the cerebellum. The developmental neurological effects of concern are presumed to occur after a single exposure and are relevant to females aged 13

- 49 years old since they occur in ut ero and to young children based on post

- natal effects.

Also the same endpoint was applied for chronic endpoint for females age 13

- 49 and young children. The effects observed in this DNT study can occur after single or multiple doses. Selection of a chron ic endpoint from this study ensures that the chronic exposure assessment is protective of females of reproductive age and their offspring.

This endpoint was not relevant for adult males and females 50+ years, so a different endpoint was selected for this population.

Table 4.5.4a . Summary of Toxicological Doses and Endpoints for Acibenzolar

- S

- methyl for Use in Dietary Human Health Risk Assessments Exposure/ Scenario Point of Departure Uncertainty/ FQPA Safety Factors RfD, PAD, LOC for Risk

Assessment Stu dy and Toxicological Effects

Acute Dietary ( Females 13

- 49 years old &

c hildren 1

- 12 years old ) NOAEL = 8.2 mg/kg/day UF A = 10x UF H =10x FQPA SF= 1x Acute RfD = 0.082 mg/kg/day aPAD = 0.082 mg/kg/day Developmental Neurotoxicity Toxicity

- Rat Development al LOAEL = 82 mg/kg/day based on changes in brain morphometrics in the cerebellum in offspring.
Maternal LOAEL = was not observed NOAEL = 326.2 mg/kg/day HDT

Chronic Dietary (Females 13

- 49 years old &

c hildren 1

- 12 years old ) NOAEL = 8.2 mg/kg/day U F A = 10x. UF H =10x FQPA SF= 1x Chronic RfD = 0.082 mg/kg/day

c PAD = 0.082 mg/kg/day Developmental Neurotoxicity Toxicity

- Rat Developmental LOAEL = 82 mg/kg/day based on changes in brain morphometrics in the cerebellum in offspring.
Maternal LOAEL = was not observed NOAEL = 326.2 mg/kg/day HDT
Chronic Dietary (Adult m ales and f emales 50+ yrs

. ) NOAEL = 25 mg/kg/day UF A = 10x UF H =10x FQPA SF= 1x Chronic RfD = 0.25 mg/kg/day cPAD = 0.25 mg/kg/day Chronic Toxicity

- Dog; Co

- critical; Chronic/Cancer

- Rat & Mouse, Reproduction Toxicity

- Rat LOAEL = 105 mg/kg/day based on hemolytic anemia with compensatory response.

Incidental Oral NOAEL= 8.2 mg/kg/day UF A = 10x UF H =10x Occupational LOC for MOE = 100 Developmental Neurotoxicity Toxicity

- Rat Developm ental LOAEL = 82 mg/kg/day based on changes in brain morphometrics in the cerebellum in offspring.
Maternal LOAEL = was not observed NOAEL = 326.2 mg/kg/day HDT Cancer (all routes) A “not likely” human carcinogen

Point of Departure (POD) = A data poi nt 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. LO AEL = lowest observed adverseAcibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 19 of 58 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). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = to account for the absence of key date (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjust ed dose (a = acute, c = chronic). RfD = refere nce dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Table 4.5.4b . Summary of Toxicological Doses and Endpoints for Acibenzolar

- S

- methyl for Use in Occupational Human Health Risk Assessments Exposure/ Scenario Point of Departure Uncertainty Factors LOC for Risk Assessment Study and Toxicological Effects

Dermal Short (1

- 30 days) and Intermediate (1

- 6 months) Term DAF = 44% NOAEL= 8.2 mg/kg/day UF A = 10x UF H =10x Occupational LOC for MOE = 100 Developmental Neurotoxici ty Toxicity

- Rat Developmental LOAEL = 82 mg/kg/day based on changes in brain morphometrics in the cerebellum in offspring.
Maternal LOAEL = was not observed NOAEL = 326.2 mg/kg/day HDT

Inhalation Short (1

- 30 days) and Intermediate (1

- 6 months) Term NOAEL= 8.2 mg/kg/day UF A = 10x UF H =10x Occupational LOC for MOE = 100 Developmental Neurotoxicity Toxicity

- Rat Developmental LOAEL = 82 mg/kg/day based on changes in brain morphometrics in the cerebellum in offspring.
Maternal LOAEL = was not observ ed NOAEL = 326.2 mg/kg/day HDT Cancer (all routes) A “not likely” human carcinogen

DAF = Dermal Absorption Factor. Since no inhalation absorption data are available, toxicity by the inhalation route is considered to be equivalent to the estimated toxi city by the oral route of exposure (100% absorption factor).

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

Adequate metabolism studies with [phenyl

- U

14 C]acibe nzolar

- S

- methyl on lettuce, tomato, rice, wheat, and tobacco have previously been submitted and reviewed. The metabolic pathway for acibenzolar

- S

- methyl was similar in all tested crops and involves the hydrolysis of the S

- methyl ester to form the carboxyl ic acid metabolite (CGA

- 210007). Further hydroxylation of CGA

210007 at the C

- 4 and C

- 5 positions results in the formation of the minor metabolites CGA

324041 (all crops tested) and CGA

- 323060 (lettuce and tomato), which may also form acyl sugar conjugates

. The nature of the residue in livestock is adequately understood based on recently submitted goat and hen metabolism studies. These metabolism studies demonstrated very low transfer of residues to milk, egg and muscle tissue (≤0.013 ppm TRR) from high ly exaggerated feeding levels. The metabolic pathway for acibenzolar

- S

- methyl involves the hydrolysis of the S

- methylAcibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 20 of 58 ester to form the carboxylic acid metabolite, benzo(1,2,3)thiadiazole

- 7

- carboxylic acid (CGA

210007), which is the main component of the residue in milk, egg and tissues. CGA

- 210007 may be subsequently conjugated; however, these conjugates were only minor components of the residues with the exception of the glycine conjugate (MET

- 2U) in milk and unidentified conjugates/metabolites in goat muscle and egg whites which were hydrolyzed to CGA

- 210007 with 6N HCl at 100° C for 16 hours

. No residues of parent were found in milk
, egg and tissues.

5.1.2 Summary of Environmental Degradation Laboratory and field studies indicate that acibenzolar

- S

- me thyl does not have a high pote ntial to leach to ground water or move to surface water based on its short resident times in soil and soil
water. The major degradate observed was benzo[1,2,3]thiadiazole

- 7

- carboxylic acid (CGA 210007) in the hydrolysis and so il photolysis studies (up to 100 percent). CGA

- 210007 has a longer soil residence time, lower Freundlich Kd adsorption values, and is much more water soluble than acibenzolar

- S

- methyl, thereby exhibiting greater potential than the parent for lateral

or ve rtic al movement after application. Acibenzolar

- S

- methyl mainly degrades by ph otolysis and microbial action. Aqueous and soil photolysis irradiated half lives for parent are 0.6 hours and 1 day, respectively. The aerobic soil metabolism, anaerobic aquatic m etabolism and aerobic aquatic half lives are 5.3 hours, 4. 0 and < 1 day(s) respectively. Field dissipation half

- liv es ranged from < 1 to 27 days. Under aerobic soil, aerobic aquatic, and anaerobic aquatic conditions
, acibenzolar q uickly degrades to CGA 210 007. CGA 210007 is in its anionic form at environmentally significant pH ’ s (pH 6

- 9) and appears to be more soluble than its parent, although measured at much lower pH’s (approx. 225 ppm at 250 O C pH 3.6

- 3.8 v . 7.7 ppm at 250 O C pH 7.5

- 7.9). CGA 210007 has lo nger resident field times than parent (aerobic soil half

life at 16.5 days) and
, based on the batch equilibrium and aged soil column leaching studies, is considerably more mobile. Acibenzolar is not considered likely to bioaccumulative.

5.1.3 Comparison of Metabolic Pathways

CGA 210007 represented the vast majority of the urinary radioactivity in the rat metabolism study and is therefore part of the total toxic mammalian exposure

. CGA 210007 was also the principal metabolite in plant studies. As noted b elow, residues of the 4

- and 5

- hydroxy metabolites (CGA

- 324041 and CGA

- 323060) of CGA

- 210007 should be considered to be of equivalent toxicity to that of the parent compound acibenzolar

- S

- methyl.

5.1.4 Residues of Concern Summary and Rationale

The HED Me tabolism Assessment Review Committee ( MARC ) determined that the residues of concern in plants for tolerance e nforcement are residues convertible to benzo(1,2,3)thiadiazole

7

- carboxylic acid (CGA

- 210007), expressed as acibenzolar

- S

- methyl. For purposes of r isk assessment, residues of the 4

- and 5

- hydroxy metabolites (CGA

- 324041 and CGA

- 323060) of CGA

- 210007 should also be considered. For this purpose, the toxicity of CGA

- 324041 and CGA

- 323060 should be considered to be equivalent to that of the parent compou nd acibenzolar

S

- methyl. These residues occur in significant quantities in lettuce and tomato. At this time,Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 21 of 58 acibenzolar

- S

- methyl does not have common metabolites with other agrochemicals. The residues of concern for drinking water are the same as those listed in the tolerance expression; that is, residues convertible to CGA

- 210007.

The residues of concern for drinking water are the same as those listed in the tolerance expression; that is, residues convertible to CGA

- 210007.

Based on the available met abolism data, the current acibenzolar

- S

- methyl risk assessment team has determined that the residues of concern in livestock for tolerance enforcement are residues of acibenzolar

- S

- methyl and its hydrolysis metabolite, benzo(1,2,3)thiadiazole

- 7

- carboxylic acid (CGA

- 210007), expressed as acibenzolar

- S

- methyl . In addition residues of concern for risk assessment should include residues convertible to CGA

- 210007 for ruminant muscle and egg and the glycine conjugate of CGA

- 210007 (MET

- U2) for milk. No livestoc k feeding studies have been submitted for acibenzolar

- S

- methyl and none are needed for the current petition since, based on the available data, there is no reasonable expec ta tion of finite residues in livestock commodities for currently registered and prop osed uses of acibenzolar

- S

- methyl. However, feeding studies might be required to support future uses (i.e., more likely foliar uses rather than soil uses) if livestock dietary burdens for acibenzolar

- S

- methyl increase significantly. In that event, only re sidues of parent and CGA

- 210007 need to be determined in milk, egg and tissues. Other residues of concern for risk assessment could be estimated from the available metabolism data.

Table 5.1.4 provides a summary of the MARC decisions regarding plant resi dues of concern for acibenzolar

- S

- methyl

.

Table 5.1.4. Summary of MARC D ecisions for Acibenzolar

- S

- methyl

Matrix Residues of Concern 1 For Risk Assessment For Tolerance Expression Plants 2 Residues of acibenzolar

- S

- methyl, benzo(1,2,3) thiadiazole

- 7

- carbothioic acid

- S

- methyl ester, convertible to benzo(1,2,3)thiadiazole

- 7

- carboxylic acid (CGA

- 210007), expressed as acibenzolar

- S

- methyl & 4

- hydroxy CGA

- 210007 (CGA

- 323060) 5

- hydroxy CGA

- 210007 (CGA

- 324041) Residues of acibenzolar

- S

- methyl, benzo(1,2,3 ) thiadiazole

- 7

- carbothioic acid

- S

- methyl ester, convertible to benzo(1,2,3)thiadiazole

- 7

- carboxylic acid (CGA

- 210007), expressed as acibenzolar

- S

- methyl

Livestock 3 Residues of acibenzolar

- S

- methyl, benzo(1,2,3) thiadiazole

- 7

- carbothioic acid

- S

- methyl es ter and benzo(1,2,3)thiadiazole

- 7

- carboxylic acid (CGA

210007), expressed as acibenzolar

- S

- methyl & For ruminant muscle and egg, residues convertible to CGA

- 210007 For milk, the glycine conjugate of CGA

- 210007 (MET

U2) Residues of acibenzolar

- S

- methyl, be nzo(1,2,3) thiadiazole

- 7

- carbothioic acid

- S

- methyl ester and benzo(1,2,3)thiadiazole

- 7

- carboxylic acid (CGA

- 210007), expressed as acibenzolar

- S

- methyl

1 The residues of concern for drinking water are the same as those listed in the tolerance expression 2 If a future petition is received for rice, residues of CGA

- 379019 should be included in the risk assessment

3 No reasonable expectation of finite residues, i.e., Category 3 of 40CFR 180.6(a) for currently registered and proposed uses

.Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 22 of 58 5.2 Food Residue Pro file

5.3 Water Residue Profile

Drinking water residues provided by the Environmental Fate and Effects Division (EFED) (D427617, C. Koper , 6/4/15) were incorporated directly into the acute and chronic dietary analyses. Surface water EDWCs were generated for the total residues of acibenzolar

- S

- methyl and CGA 210007 using the Pesticide Root Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS) model for all proposed uses. Exposure in ground water due to leaching was assessed with the Pesticide Root Zon e Model for Ground Water ( PRZM

- GW ) model.

For surface water, the EDWCs for the citrus and pome fruit scenarios modeled in this new use assessment (Table 5.3 ) did not exceed the EDWCs reported in a previous drinking water assessment to support an Experim ental Use Permit (D392519, R. Miller, 12/13/11) dated 13 December 2011. It is important to note, however, that the recommended EDWCs were revised using the current PCA adjustment factor of 0.91 for agricultural uses according to recently implemented PCA g uidance and incorporating the TTR approach (previous recommended chronic values were for CGA

- 210007 only). Therefore, the recommended EDWCs for surface water include the acute concentration of 47.19 μg/L (citrus), and the annual mean concentration of 13.3 3 μg/L (apple) for the chronic analysis.

For ground water, four applications at 0.1 lbs. a.i./acre for a maximum yearly application rate of 0.4 lbs a.i/A were modeled for citrus and pome fruit using PRZM

- GW to determine drinking water exposure in ground water based on the Actigard® 50 WG (EPA Reg. No.100

- 922) label.

Table 5.3. Recommended EDWCs for Acibenzolar

– S

- methyl following the Total Toxic Residue (TTR) Approach

Drinking Water Source Crop Scenario 1

- in

- 10 year acute ( μg/L ) 1

- in

- 10 year chronic ( μg/L ) 30

- year average ( μg/L ) Surface Water FL Citrus 1 47.19

-- -- PA Apple 1

-- 13.33 8.45
Ground Water WI Corn Scenario Central Sand Region 2 (Pome Fruit use) 25.00 NA

--

WI Corn Scenario Central Sand Region (Citrus use) -- NA 22.70

1 Previously reported maximum EDWCs from Experimental Use Permit assessment generated using PRZM/EXAMS model for direct soil (citrus) and aerial (apple) applications (D392519, R. Miller, 12/13/11) with a revised PCA factor of 0.91.
2 Highest EDWCs generated for New Use assessment using PRZM

- GW model based on the maximum annual rate of 0.4 lbs a.i/A for Citrus and Pome Fruit (Actigard®50 WG (EPA Reg. No.100

- 922). NA = not applicableAcibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 23 of 58 5.4 Dietary Risk Assessment

5.4.1 Description of Residue Estimates Used in Dietar y Assessment

Acute and chronic aggregate dietary [food and drinking water] exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID) Version 3.16

. This software us es 2003

- 2008 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)

. In the chronic dietary exposure analysis, tolerance level residues were used an d 100 percent crop treated was assumed for all commodities. DEEM default processing factors were used for apple juice, dried apples, cranberry juice, dried apple, dried pears, dried onion, dried banana, dri ed plantain, and dried tomato. A processing factor was not used for tomato paste because a separate tolerance has been established for this processed commodity. In the submitted tomato processing study (D246673, M. Doherty, 3/15/2000), processing factors of 1.0 and 2.9 were reported for tomato juice and tomato puree, respectively. These processing factors were used in the dietary exposure assessment. Residues of acibenzolar

- S

- methyl did not concentrate in citrus juice or oil based on a processing study
, so a proc essing factor of 1.0 was used.

Available lettuce metabolism data for a 7

- day PHI were used to determine the relative abundance of the hydroxy metabolites (CGA

- 323060 and CGA

- 324041) and residues convertible to the carboxylic acid metabolite (CGA

- 210007). Based on the lettuce metabolism data, a f actor of 1.5x was applied to estimates of acibenzolar

- S

- methyl residues to account for all of the residues of concern for dietary risk (including CGA

- 210007, CGA

- 323060 and CGA

- 324041). Lettuce metabolism data are provided in Table 5.4.1.

Table 5.4.1

. Lettuce metabolism data (Washed, 7

- day PHI) Compound ppm Residues Acibenzolar

- S

- Methyl 0.171 CGA

- 210007 0.255 CGA

- 323060 0.204 CGA

- 324041 0.006 Total Identified 0.636

1.5x = 0.636 / (0.171+0.255)
Residues Used in the Acute Analysis

A probabili stic assessment was performed for the acute analysis (D246852, D. McNeilly, 7/28/15) . Foods were classified as blended, partially blended, or nonblended based on guidance given in the Draft DEEM

- FCID Classification of Food Forms with Respect to Level of B lending (F. Fort ). The acute analysis assumed a distribution of residues based on field trial data for nonblended and partially blended commodities. For blended commodities, the mean field trialAcibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 24 of 58 values were used as a point estimate. A value of 1⁄2 LOQ was us ed for samples that contained less than LOQ residues. Time

- limited tolerance values were used (0.05 ppm) for the EUP commodities, i.e., apple, pear, and grapefruit. Section 3 tolerance

- level residues were used for all other citrus and pome fruit commoditie s. DEEM default processing factors were used for apple juice, cranberry juice, dried apples, dried pears, dried onion, dried banana, dried plantain, a nd dried tomato. Empirical processing factors were used for citrus juice (1.0), tomato paste (7.1),
tomat o puree (2.9), and tomato juice (1.0). Residues of acibenzolar

- S

- methyl did not concentrate in citrus juice or oil

. The acute analysis used available maximum percent crop treated estimates from the Biological and Economic Analysis Division’s (BEAD’s) scre ening

- level analysis (Dec 6, 2012). If no percent crop treated data were available, 100% crop treated was assumed. As previously noted, a factor of 1.5 X was applied to the estimate of residues convertible to CGA

210007 for all commodities to account for al l of the resid ues of concern for dietary risk.

5.4.2 Percent Crop Treated Used in Dietary Assessment

Acute Analysis The acute analysis used available maximum percent crop treated estimates from the Biological and Economic Analysis Division’s (BEAD’s) s creening

- level analysis (Dec 6, 2012). The following maximum percent crop treated estimates were used in the acute dietary risk assessment for the following crops that are currently registered for a cibenzolar

- S

- methyl : broccoli: 10%; cabbage: 2.5%; caulifl ower: 10%; lettuce: 10%; peppers: 10%; spinach: 50; and tomatoes: 10%. If no percent crop treated data were available 100% crop treated was assumed.

Chronic Analysis 100% percent crop treated estimates were used in the chronic dietary risk assessment.

5. 4.3 Acute Dietary Risk Assessment

A refined (probabilistic) acute dietary exposure analysis was performed for the general population and all population subgroups. The acute analysis assumed time

- limited tolerance level values (since the EUP is still activ e) for apple, pear, and grapefruit. The Section 3 HED

recommended tolerance levels are used for all other Crop Group 10

- 10, and Pome Crop Group 11

- 10 commodities

. M aximum screening

- level percent crop treated estimates were used for commodities for which da ta were available. If no percent crop treated data were available, 100% crop treated was assumed. The acute analysis incorporated the 1 in 10 year peak surface drinking water estimate from application of acibenzolar

- S

- methyl to citrus in FL. Acute dietary risk estimates are not of concern for females 13

- 4 9 years old, or children 1

- 12 years old. The subgroup with the highest risk estimate was children 1

- 2 years old with an exposure estimate of 33% of the acute p opulation a djusted d ose (aPAD) at the 99.9 th percentile of exposure. The percent aPAD for females 13

- 49 years old was 14% at the 99.9 th percentile of exposure.Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 25 of 5 8 Table 5.4.3: Summary of Acute Dietary Exposure and Risk (Food and Water) for Acibenzolar

- S

- Methyl
Population Subgroup aPAD (mg/kg/day) Acute (99.9 th Percentile) Exposure (mg/kg/day) % aPAD Females 13

- 49 years old

0.082 0.011114 14 All Infants (< 1 year old) 0.019436 24 Children 1

- 2 years old 0.027120 33 Children 3

- 5 years old 0.025341 31 Children 6

- 12 years old 0.019608 24

5.4.4 Chronic Dietary Risk Assessment

A conservative chronic dietary exposure analysis was performed for the general U.S. population and various population subgroups. Tolerance level residues and 100% crop treated assumptions were used. T emporary toleran ce values were used for apple, pear, and grapefruit, since they are higher that the new Section 3 tolerances, and do not expire until 12/31/2015. Section 3 tolerance levels are used for all other c rop group 10

- 10, and pome crop group 11

- 10 commodities

. DEE M default and empirical processing factors were used to modify the tolerance values. The chronic analysis incorporated the 1 in 10 year annual average surface drinking water estimate from application of acibenzolar

- S

- methyl to apples in Pennsylvania . The p opulation subgroups females 13

- 49 and young children had a more protective chronic population adjusted dose (cPAD, 0.082 mg/kg/day) than the general U.S. population and all other population subgroups (0.25 mg/kg/day). Chronic dietary risk estimates are not of concern for general population or other population subgroups. The subgroup with the highest risk estimate was children 1

- 2 years old with a cPAD of 13%. The estimated cPAD for the general U.S. population was 2%.

The results of the chronic dietary expo sure analysis are reported in Tables 5.4.4.a and 5.4.4.b

.
Table 5.4.1a: Summary of Chronic Dietary Exposure and Risk to Female (13

- 49) and Young Children Population for Acibenzolar

- S

- Methyl
Population Subgroup cPAD (mg/kg/day) Chronic Exposure (mg /kg/day) % cPAD Females 13

- 49 years old

0.082 0.003547 4.3 All Infants (< 1 year old) 0.005266 6.4 Children 1

- 2 years old 0.010647 13 Children 3

- 5 years old 0.009355 11 Children 6

- 12 years old 0.005724 7.0

Table 5.4.4.b: Summary of Chronic Die tary Exposure and Risk to Adults 50+ and Adult Males (13+) for Acibenzolar

- S

- Methyl
Population Subgroup cPAD (mg/kg/day) Chronic Exposure (mg/kg/day) % cPAD General U.S. Population

0.25 0.004189 1.7 Youth 13

- 19 0.003304 1.3 Adults 20

- 49 0.003562 1 .4 Adults 50

- 99 years old 0.003522 1.4Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 26 of 58 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no residential uses associated with this action, however, a revised postapplication residential exposure assessment was conducted to upd ate the residential exposures based on the 2012 revised Residential SOPs.

6.1 Residential Post

- A pplication Exposure

There is the potential for post

- application exposure for individuals exposed as a result of being in an environment that has been previous ly treated with acibenzolar

- S

- methyl

. The quantitative exposure/risk assessment for residential post

- application exposures is based on the following scenarios: Adult, 11 to <16 years old, and 6 to <11 years old dermal exposure from playing golf
on treate d lawn.

Short

- term dermal exposure and r isk estimate s are summarized in Table 6.1. All assessed scenarios resulted above the LOC and therefore, are not of concern to HED (i.e. an MOE > 1 00). MOEs ranged from 21,000 to 25,000.

Table 6 .1. Residential Po st

- application Non

- cancer Exposure and Risk Estimates for Acibenzolar

- S

- Methyl.

Lifestage Post

- application Exposure Scenario Application Rate 1 Dose (mg/kg/day) 2 MOEs 3 Use Site Route of Exposure 6 to <11 years Golfing Dermal 0.022 0.00039 21,000

Ad ult & 11 to <16 years 0.00033 25,000

1 Based on registered or proposed label (Reg. No. 100

- 1364). 2 Dose (mg/kg/day) equations provided in Appendix A. 3 MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day). 4 Combined MOE = 1 ÷ (1/dermal MOE) + (1/incidental o ral MOE), where

applicable.
In accordance with 40CFR158, TTR data are required for all occupational (e.g., sod farms, golf courses, parks, and recreational areas) or residential turf uses that could result in post

- application exposure to turf. EPA is waiv ing the 40CFR TTR data requirement since the estimated residential turf post

- application exposure for residential turf using default TTR values for acibenzolar

- S

- methyl is minimal in comparison to the level of concern (i.e., the calculated MOE is greater t han 10 times higher than the level of concern, MOE = 21 ,000 compared to the LOC of 100). In this instance, it is unlikely that chemical

- specific TTR data would be needed to further refine exposure assessments or would add appreciably to our general unders tanding of the availability of turf tra nsferable pesticide residues.

6.2 Residential Bystander Post

- application Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applica tions. The Agency sought expert advice and input on issuesAcibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 27 of 58 related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings /2009/120109meeting.html). The Agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDe t ail;D=EPA

- HQ

- OPP

- 2014

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

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

- S

- methyl

.

6. 3 Spray Drif t

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application met hods (e.g., groundboom and airblast) employed for acibenzolar

. The A gency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call

- In issued by EPA), EPA Regional Offices
, and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the agency’s Spray Drift website for more information). 1 The A gency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk assessments for pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures for Residential Risk Assessment (SOPs)

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

- occupational exposure to drift.

6.4 Residential Risk Estimates for Use in Aggregate Assessment

Table 6.4 reflects the residential risk estimates that are recommended for use in the aggregate

assessmen t for acibenzolar

- S

- methyl.

• The recommended residential exposure for use in the adult aggregate assessment reflects post

- application dermal potential risk from playing golf on treated turf

.
• The recommended residential exposure for use in the 11 to < 16 year s old aggregate assessment reflects post

- application dermal potential risk from playing golf on treated turf

.
• The recommended residential exposure for use in the 6 to < 11 years old aggregate assessment reflects post

- application dermal potential risk from p laying golf on treated turf

.Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 28 of 58 Table 6.4 . Recommendations for the Residential Exposures for the Acibenzolar

- S

- Methyl Aggregate Assessment. Lifestage Exposure Scenario Dose (mg/kg/day) 1 MOE 2 Dermal Inhal. Oral Total Dermal Inhal. Oral Total 6 to <11 years old Golfing 0.00039

N/A N/A 0.00039 21,000

N/A N/A 21,000

Adult & 11 to <16 years old 0.00033 0.00033 25,000 25,000

1 Dose = the highest dose for each applicable lifestage of all residential scenarios assessed. Total = dermal + incidental or al

. 2 MOE = the MOEs associated with the highest residential doses . Total = 1 ÷ (1/Dermal MOE) + (1/Incidental Oral MOE)

.
7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposur es and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks th emselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

Acute and chronic aggregate exposures include food plus drinking water exposures only for acibenzolar

- S

- methyl

. A cute and chronic aggregate risks are not of concern (see Section 5.4.3 and 5.4.4 above)

.

7.1 Short

- and Intermediate

- Term Aggregate Risk

There is potential short

- term exposure to acibenzolar

- S

- methyl via the dietary pathway (which is considered backgroun d exposure) and the residential pathway

. Since the short

- and intermediate

- term PODs are the same and short

- term exposure estimates are greater than their intermediate

- term counterparts , the short

- term aggregate risk assessment is protective of the interm ediate

- term aggregate exposure.

T he short

- term aggregate exposure assessment for adults and for children 11 to < 16 years old include s dietary (food and drinking water) and dermal postapplication exposures. For each population group assessed, the most c onservative scenario was chosen.

Table 7.1. Short

- Term Aggregate Risk Calculations

- Residential Post

- Application Exposure

Population Subgroup NOAEL mg/kg/day LOC 1 Average Food and Water Exposure mg/kg/day Residential Exposure mg/kg/day2 Total Exposur e mg/kg/day 3 Aggregate MOE (food, water, and residential) 4
Children 6 to <11 years old 8.2 mg/kg/day 100 0.005724 0.00039 0.006114 1300

Adult & Children 11 to <16 years old 8.2 mg/kg/day 100 0.005724 0.00033 0.006054 1400Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 29 of 58 1 Indicate in this footnote th e basis for the LOC (include the standard inter

- and intra

- species uncertainty factors totaling 100, as well as additional uncertainty factors/safety factors as appropriate.)

2 Residential Exposure = Aggregate MOE = [NOAEL (8.2 mg/kg/day )/ (Avg Food & Wat er Exposure + Residential Exposure)]

. Adult residential post

- application exposure from golfer scenario.
3 Total Exposure = Avg Food & Water Exposure + Residential Exposure)
4 Aggregate MOE = [NOAEL  / (Avg Food & Water Exposure + Residential Exposure)]

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 acibenzolar

- S

- methyl and any other substances
, and acibenzolar

- S

- methyl 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 acibenzolar

- S

- methyl has a common mechanism of toxicity w ith 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 Program s concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at : http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization D 426853 , I . Nieves, 8/13/2015
Syngenta submitted directions for use of acibenzolar

- S

- methyl on citrus and pome fruit formulated as a water dispersible granule (WDG) containing 50% acibenzolar

- S

- methyl as the sole active ingredient (Actigard ® 50WG; EPA Reg. No. 100

- 922). Acibenzolar

- S

- methyl is proposed for multiple soil ( i.e., drench, drip or micro

- irrigation) or foliar applications on pome fruit, and for soil applications on citrus fruit.

The Personal Protective Equipment (PPE) statement on the proposed label re quires applicators and other handlers to wear : long

- sleeved shirt and long pants, chemical

- resistant gloves, and shoes plus socks

. The end use product may be applied through a variety of application methods including: aerial, chemigation
, ground boom, airb last, backpack, and hand held equipment. There is a potential for occupational exposure associated with handler activities (i.e., mixing, loading, and applying) as well as with post

- application activities (i.e., re

- entering treated areas). No data on the n umber of exposure days per year was provided. Based on the proposed label ’ s use pattern and directions
, only short

- (1 to 30 days) and intermediate

- term (1 to 6 months) exposu res are expected for handlers.

Dermal and inhalation exposures to workers are c ombined for acibenzolar

- S

- methyl because the toxicity endpoints for these exposure routes are based on common toxicological effects.Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 30 of 58 9.1 Short

- and Intermediate

- Term Handler Risk Estimates

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications, and that exposures can vary depending on the specifics of each task. Job requirements (e.g., amount of chemical used in ea ch application), types of equipment used, the area treated or amount handled, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event. Detailed descriptions of the handler assessment are available in D 426853 ( I

. Nieves
, 8/13/2015 ) and a summary table of the handler exposure and risk estimates is provided

. The occupational hander exposure and risk estimates rely on generic data from the Pesticide Handlers Exposure Database Version 1.1 ( PHED 1.1), the Outdoor Residential Exposure Task Force (ORETF) database and the Agricultural Handler Exposure Task Force (AHETF) database.

The occupational handler exposure and risk estimates indicate that the short

- and intermediate

term dermal and inhal ation combined MOEs are not of concern to HED (i.e., MOE > 100) with label required PPE (i.e ., single layer of clothing, gloves, and no respirator). MOEs were presented at baseline and with label required PPE (i.e., gloves). Combined MOEs at baseline

ran ged from 58 to 4,100 and with label

- required PPE from 320 to 19,000.Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 31 of 58 Table 9 .1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Acibenzolar

- S

- Methyl

.

Exposure Scenario Crop

or Target Level of Concern Dermal Unit Exposure ( μg /lb ai) 1 Inh alation Unit Exposure ( μg /lb ai) 1 Maximum Application Rate 2 Area Treated

or Amount Handled

Daily 3 Dermal Inhalation Total

Baseline /Gloves No Respirator Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Mixer/Loader M/L of liquids

to support chemi gation applications Pome crop group 11

- 10 and Citrus crop group 10

- 10 100 Baseline: 22 0 Gloves: 51.6 8.96 0.1 lb ai/A 350 A Baseline: 0.051 Gloves: 0.012 Baseline: 160 Gloves: 710 0.00012 1800 Baseline: 150 Gloves: 510

M/L of liquids

to support

airblast

a pplications 40 A Baseline: 0.0058 Gloves: 0.0013 Baseline: 1
, 400 Gloves:

6,300 0.000014 16000 Baseline: 1,300 Gloves: 4,500 M/L of liquids

to support groundboom applications Applicator

Airblast Baseline: 1
, 770 Gloves: 1,590 4.71
0.1 lb ai/A 40 A Baseline: 0.045 Gloves: 0.041 Baseline: 180 Gloves: 200 0.00027 30,000 Baseline: 180 Gloves: 200

Groundboom Baseline: 78.6 Gloves: 16.1 0.34 40 A Baseline: 0.0020 Gloves: 0.00041 Baseline: 4,100 Gloves: 20,000 0.000020 420,000 Baseline: 4 ,100 Gloves: 19,000 Mixer/loader/Applicator
Backpack Pome crop group 11

- 10 and Citrus crop 100 Baseline/Gloves: 8
, 260 2.58

0.01 lb ai/gallon 40 gallons Baseline/Gloves: 0.021 Baseline/Gloves: 390 0.000015 550,000 Baseline/Gloves: 390

Mechani cally

pressurized

Handgun Baseline: 1300 Gloves:390 3.9 1000 gallons Baseline:0.083 Gloves:0.025 Baseline :99 Gloves: 330 0.00057 15,000 Baseline: 98 Gloves:320Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 32 of 58 Table 9 .1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Acibenzolar

- S

- Methyl

.

Exposure Scenario Crop

or Target Level of Concern Dermal Unit Exposure ( μg /lb ai) 1 Inh alation Unit Exposure ( μg /lb ai) 1 Maximum Application Rate 2 Area Treated

or Amount Handled

Daily 3 Dermal Inhalation Total

Baseline /Gloves No Respirator Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

group 10

- 10 Loader/Applicator

Brush/Roller Pome crop group 11

- 10 and Citrus crop group 10

- 10 100 Baseline : 180,000 Gloves:24,000 280 0.12 lb ai/gallon 1 gallon Baseline:0.083 Gloves:0.025 Baseline :58 Gloves: 4 30 0.00050 16,000 Baseline: 58 Gloves:420

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( March 2014 ); Level of mitigation: Baseline, PPE (i.e.,gloves)

. 2 Based on registered or proposed label (Reg. No. 100

- 922). 3 Exposure Science Advisory Council Policy #9.1. 4 Dermal 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 (A or gal/day) × DAF (44%) ÷ BW

(69 kg). 5 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day). 6 Inhalation Dose = Inhalation Unit Exposure ( μg /lb ai) × Conversion Factor (0.001 mg/ μg ) × Ap plication Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ BW (kg). 7 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). 8 Total MOE = NOAEL (mg/kg/day) ÷ Dermal Dose + Inhalation Dose OR Total MOE = 1 ÷ (1/Dermal MOE + 1/Inhalation MOE).Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 33 of 58 9.2 Short

- and Intermediate

- Term Post

- Application Risk Estimates

9.2.1 Dermal Post

- Application Risk Estimates

Occupational workers who enter treated fields to perform post

- application activities such as hand weed ing and scouting may be exposed to acibenzolar

- S

- methyl residues. Based on the use pattern, workers may be exposed to short

- and intermediate

- term exposure durations.

Exposure Duration: HED classifies exposures from 1 to 30 days as short

- term and exposu res 30 days to six mo nths as intermediate

- term. For acibenzolar

- S

- methyl , short

- and intermediate

- term exposures are expec ted since the use directions allow multiple applications per season

. In addition, the short

- and intermediate

- term PODs are the same; therefore, short

- term risk estimates are protective of longer

- term exposures.

Table 9 .2.1 provides a summary of the anticipated post

- application activities and associated transfer coefficients for the proposed crops/use sites.

Table 9.2

. 1. Anticipated Post

- Application Activities and Dermal Transfer Coefficients.

Proposed Crops Policy Crop Group Category Crop Height Foliage Density Transfer Coefficients

(cm 2 /hr ) Activities

Pome crop group 11

- 10 Tree, “fruit”, deciduous High Full 3,600 Thinning Fruit
High Full 1,400 Hand Harvesting
High/Low Full 580 Hand Pruning; Training
High Full/Min 580 Scouting

Low Min 230 Transplanting
High Full 100 Orchard Maintenance; Propping
High/Low Full 100 Hand Weeding

Citrus crop group 10

- 10 Tree, “fruit ”, evergreen High Full 1,400 Hand harvesting
High Full 580 Pruning
High/Low Full 580 Scouting

Low Full/Min 230 Transplanting

High Full 100 Baiting/Trapping ; Orchard Maintenance High/Low Full 100 Hand WeedingAcibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 34 of 58 Occupational Post

- application N on

- Cancer Dermal Risk Estimates The short

- and intermediate

- term post

- application exposure scenarios associated with the proposed uses for acibenzolar

- S

- me t hyl are summarized in Table 9 .2.2. All scenarios resulted in MOEs greater than the LOC of 1 00 (rangi ng from 1 60 to 5,700 ) on day 0 (12 hours after application) and, therefore, are not of concern to HED.

Table 9.2.2. Occupational Post

- application Non

- Cancer Exposure and Risk Estimates for A cibenzolar

- S

- methyl.

Crop/Site Activities Transfer Coefficient (cm 2 /hr) DFR 1 (μg/cm 2 ) Dermal Dose (mg/kg/day) 2 MOE 3

Short

- & Intermediate

- term
Pome crop group 11

- 10 Thinning Fruit 3,600

0.28 0.052 160

Pome crop group 11

- 10 & Citrus crop group 10

- 10 Hand Harvesting 1400 0.020 410 Hand Pruning; Scouting; Training (Pome fruit ); 580 0.083 990

Transplanting 230 0.0033 2,500
Orchard maintenance; Propping (Pome fruit ); Baiting/Trapping (Citrus) 100 0.0014 5,700

1 DFR = Application Rate × F × (1

- D) t × 4.54E8 μg/lb × 2.47E

- 8 acre/cm 2 ; where F = 0.25 and D = 0.10 p er day OR 2 Daily Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption ( 44 %)] ÷ BW ( 69 kg). 3 MOE = POD (mg/kg/day) / Daily Dermal Dose.
In accordance with 40 CFR 158, DFR data are required for all occupationa l (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 exposure to foliage. In the absence of chemical

- specific DFR data, EPA uses default values. The 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment includes an analysis of a number of DFR studies, which resulted in the selection of a revised default values for the fraction of the application rat e available for transfer after a foliar application (F AR ). These values are based on an analysis of 19 DFR studies. Since that time, the ARTF has submitted information (MRID 49299201) that corrects an application rate error made in the original submissi on of “ARF039

– Determination of Dermal and Inhalation Exposure to Reentry Workers During Chrysanthemum Pinching in a Greenhouse” (EPA MRID 45344501). As a result, the range of F AR values was revised from 2

- 89% to 2

- 7%. In these data, a large range of tr ansferability is observed and this variability can potentially be attributable to many factors such as active ingredient, formulation, field conditions in the studies, weather conditions (e.g., humidity), and many other difficult

- to

quantify factors. Alth ough 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 submission did not alter the selection of 25% as the reasonable, high

- end default value. Because DF R data are not available for acibenzolar

- S

- methyl , EPA is using the default value of 25%. Although there may be a small degree of uncertainty in the use of the default DFR value for acibenzolar

- S

-Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 35 of 58 methyl (i.e., there is a small chance that the F AR value ma y exceed the applicable default value), it is likely that the health

- protective aspects of EPA’s occupational post

- application assessment methodology will more than compensate for this potential uncertainty. For example, when assessing residential and occ upational 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

o ccurs, it doesn’t rain, etc); individuals perform the same post

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

- application activities for a h igh

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

Given the conservatisms discussed above and the potential compounding nature of these conservatisms, EPA is able to rely upon the calculated expos ure estimates with confidence that exposur e is not being underestimated. However, s ince the highest estimated occupational post

application exposure using default DFR values for acibenzolar

- S

- methyl is not minimal in comparison to the LOC (i.e., the calcul ated MOE is not greater than two times higher than the LOC, MOE = 160 compared to the LOC of 100); EPA is requiring the 40 CFR DFR data to facilitate any necessary exposure assessments refinements and to further EPA’s general understanding of the availabil ity of dislodgeable foliar pesticide residues.

Restricted Entry Interval The REI specified on the proposed label is based on the acute toxicity of acibenzolar

- S

- methyl. This active ingredient is classified as Toxicity Category III via the dermal route, To xicity Category IV for skin irritation potential, and Toxicity Ca tegory III for eye irritation. It is a skin sensitizer. Short

- and intermediate

- term post

- application risk estimates were not a concern on day 0 (12 hours following application) for al l post

- application activities. Under 40 CFR 156.208 (c) (2) (iii), ai’s classified as Acute III or IV for acute dermal, eye irritation and primary skin irritati on are assigned a 12

- hour REI. Therefore, the [156 subpart K] Worker Protection Statement interim REI o f 12 hours is adequate to protect agricultural workers from post

application exposures to acibenzolar

- S

- methyl.

9.2.2 Inhalation Post

- Application Risk Estimates

There are multiple potential sources of post

- application inhalation exposure to individuals p erforming post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The A gency sought expert advice and input on issues re lated to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109me eting.html). The A gency 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 determineAcibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 36 of 58 if data (i.e., flux studies, route

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

. 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 A gen cy ’ s risk assessments.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed previously , an inhalation exposure assessment was performed for occupational/commercial handlers

. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post

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

- applicati on inhalation exposure scenarios.

Furthermore, inhalation exposure during dusty mechanical activities such as shaking and mechanical harvesting is another potential source of post

- application inhalation exposure. However, the airblast applicator scenario is believed to represent a reasonable worst case surrogate estimate of post

- application inhalation exposure during these dusty mechanical harvesting activities. The non

- cancer inhalation risk estimate for commercial airblast application is not of concern (i.e., MOE > 100)

.

10.0 References

Acibenzolar

- S

- Methyl. Soil Treatment Use on Citrus Crop Group 10

- 10 and Soil/Foliar /Paint Treatment Uses on Pome Crop Group 11

- 10. Summary of Analytical Chemistry and Residue Data. B

. Cropp

Kohlligian , D 426850
, 8/13/ 15

Acibenzolar

- S

- Methyl. Acute and Chronic Dietary and Drinking Water Exposure and Risk Assessment to Support Section 3 Use of Acibenzolar

– S

- Methyl Uses on Citrus Crop Group 10

- 10, and Pome Crop Group 11

- 10. D . M cNeilly , D 426852 , 0 8 / 10 /201 5

Acibenzolar

- S

- Methyl : Acibenzolar

- S

- Methyl. Occupational and Residential Exposure Assessment for a Proposed Use on Pome Crop Group 11

- 10 and Citrus Crop Group 10

- 10. I. Nieves
, D 426853, 8/13/2015

Acibenzolar: Subchronic Neurotoxicity Study in Rats, K. Oo, D392694 , 8/3/11

Absorption and Excretion of [U

14C ]Phenyl CGA 245704 in the Rat after Dermal Application, K. Oo, D392695, 8/3/11.

Acibenzolar, Drinking Water Exposure Assessment

– C. Koper , D427617, 6/4/15

Revised Residential SOPs: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.htmlAcibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 37 of 58 A ppendix A

. Toxicology Profile and Executive Summaries

A. TOXICOLOGY DATA SUMMARY

A.1 Guideline Data Requirements

Table A.1

. Guideline Data Requirements Guideline No. Study Type Technical MRID No. Required Submitted 870.1100 870.1200 870.1300 870.2400 870.2500 870.2500 Acute Oral Toxicity

................................ ................... Acute Dermal Toxicity

................................ .............. Acute Inhalation Toxicity

................................ .......... Primary Ey e Irritation

................................ ................ Primary Dermal Irritation

................................ .......... 870.2600 Dermal Sensitization yes yes yes yes yes yes yes yes yes yes yes yes 44014214 44014216 44014219 44014220 44014220 44014225

870.3100

870.3150 870.3200

870.3250 870.3465 Subchronic (Oral) Toxicity

- Rod ent

......................... Subchronic (Oral) Toxicity

- Non

- Rodent

................. 21/28

- Day Dermal Toxicity

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

90

- Day Dermal Toxicity 90

- Day Inhalation Toxicity

................................ ....... Y

Y N

N N * Y

Y Y

N N 44014230 44014228 44014232 42090013 46950310

---

---
870.3700a

870.3700b 870.3800 Prenatal Developm ental Toxicity

- Rodent

................ Prenatal Developmental Toxicity

- Non

- Rodent

....... Reproduction and Fertility Effects

............................. Y

Y Y Y

Y Y 44014236 45089701 44014237 44014241 870.4100a 870.4100b 870.4200a 870.4200b 870.4300 Chronic (Oral) Toxicity

- Rodent

.............................. Chronic (Oral) Toxicity

- Non

- Rodent (Dog)

............ Carcinogenicity

- Rat..................

......................... Carcinogenicity

- Mouse Combined Chronic Toxicity /Carcinogenicity Y Y Y Y Y Y Y Y Y Y 44014325 44014234 44014243 44014325 44014325 870.5100

870.5300
870.5375

870.53 95

870.555 0 Mutagenicity

— Gene Mutation

- bacterial

................. Mutagenicity

— Gene Mutation

- mammalian

............ Mutagenicity

— Structural Chromosomal Aberrations

................................ ................................ Mammalian erythrocyte micronucleus test

....... Mutagenicity

— UDS rat primary hepatocytes

............ Y Y Y

Y

Y Y Y Y

Y

Y 44014247 44014246

44014245

440 14244

44014248

870.6100a 870.6100b 870.6200a 870.6200b 870.6300 870.7800 Neurotoxicity

- Acute Delayed Neurotox.

- Hen

........ Neurotoxicity

- Subchronic

- Hen

............................. Neurotoxicity

- Acute

- Rat

................................ ....... Neurotoxicity

- Subchronic

- Rat

................................ Developmental Neurotoxicity.................. Imm unotoxicity.............................

.................... N N Y Y N Y N N Y Y Y Y ---

---

--- 45713601 46046401 48688301Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 38 of 58 A.2 Toxic ity Profiles

Table A.2 Acute Toxicity Profile Acibenzolar

- S

- methyl
Acibenzolar

- S

- methyl
Guideline No./

Study Type MRID No. Results Toxicity Category
8 70.1100 Acute oral toxicity 44014214 LD 50 >5000 mg/kg IV 870.1200 Acute dermal toxicity 44014216 LD 50 >2000 mg/kg IV 870.1300 Acute inhalation toxicity 44014219 LC 50 >5.022 mg/L IV 870.2400 Acute eye irritation 44014220 minimal III
870.2500 Acute derma l irritation 44014220 slight IV
870.2600 Skin sensitization 44014225 positive NA Actigard 50WG 870.1100 Acute oral toxicity 44014215 LD 50 >5000 mg/kg IV 870.1200 Acute dermal toxicity 44014217 LD 50 >2000 mg/kg IV 870.1300 Acute inhalation toxicity 440 14218 LC 50 >2.79 mg/L IV 870.2400 Acute eye irritation 44014221 minimal III
870.2500 Acute dermal irritation 44014223 moderate III
870.2600 Skin sensitization 44014224 negative NAAcibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 39 of 58 Table A.3 Subchronic, Chronic and Other Toxicity Pro file for Acibenzolar

- S

- methyl

Guideline No.

Study Type MRID No. (year) Classification

Dose Levels Results

870.3100 90

- day oral toxicity rodents (rat) 44014230 (1993) Acceptable/Guideline M : 0, 2.42, 24.6, 126, 516 mg/kg/day; F: 0, 2.64, 26.3, 131, 554 mg/kg/day NOAEL :126 mg/kg/day Males or M); 131 mg/kg/day (Females or F) LOAEL :516 mg/kg/day (M); 554 mg/kg/day females based decreased body weight, reduced food intake and efficiency and increased liver and spleen weights

870.3150 90

- day oral toxicity non

rodents (dog) 44014232 (1994) Acceptable/Guideline M & F: 0, 10, 50, 200 mg/kg/day (capsules) NOAEL :50 mg/kg/day (M & F) LOAEL :200 mg/kg/day (F) based on regenerative hemolytic anemia evidenced by decreased erythroid parameters, pigmentation in the liver and spleen, splenic congestion, and by activation of medullary (bone marrow) and extramedullary (splenic) erythropoiesis.
870.3100 90

- day oral toxicity rodents (mice) 44014228 (1993) Acceptable/Guideline 0, 30.6, 152, and 624 mg/kg/day for males, and 0, 47.4, 220, and 803 mg/kg/day for females, respectively. NOAEL : 30.6 mg/kg/day (M); 47.4 mg/kg/day (F) LOAEL :152 mg/kg/day (M); 220 mg/kg/day females based decreased body weight and body weight gain, increased spleen weight and microscopic changes in the sp leen

870.3200 21/28

- day dermal toxicity (rat) 44014233 (1994) Acceptable/guideline M & F: 0, 10, 100, 1000 mg/kg/day NOAEL = 1000 mg/kg/day LOAEL = not identified

870.3700a Developmental Toxicity in rodents (rat) 44014236 (1994) Acceptable/guideline F: 0,10, 50, 200, 400 mg/kg/day Maternal NOAEL 200 mg/kg/day Developmental NOAEL 50 mg/kg/day Maternal LOAEL 400 mg/kg/day based on clinical signs of hemorrhagic perineal discharge Developmental LOAEL 200 mg/kg/day based on developmental malformations, anoma lies, and skeletal variations
870.3700a Developmental Toxicity in rodents (rat) 45089701 (1998) Acceptable/guideline of 0, 10, 75, 150, or 350 mg/kg/day Maternal NOAEL 350 mg/kg/day Developmental NOAEL 200 mg/kg/day Maternal LOAEL

– not established (>350) Developmental LOAEL 350 mg/kg/day based on increased incidences of rudimentary and long lumbar ribs

870.3700b Developmental Toxicity in

non

- rodents (rabbit) 44014237 (1994) Acceptable/guideline F: 0, 10, 50, 300, 600 mg/kg/day Materna l NOAEL = 50 mg/k g/day LOAEL = 300 mg/kg/day based on mortality, clinical signs of toxicity, decreased maternal body weight and food consumption. Developmenta l NOAEL = 300 mg/kg/day LOAEL = 600 mg/kg/day based on a marginal increase in vertebral anomalies.Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 40 of 58 Table A.3 Subchronic, Chronic and Other Toxicity Pro file for Acibenzolar

- S

- methyl

Guideline No.

Study Type MRID No. (year) Classification

Dose Levels Results

870.6300 Develo pmental Neurotoxicity Toxicity in rodents (rat) 46046401 (2002) Acceptable/non

- guideline 0/0, 8.2/15.5, 82.0/153.6, and 326.2/607.8 mg/kg/day [gestation/lactation]. Maternal NOAEL 326.2 mg/kg/day Developmental NOAEL 8.2 mg/kg/day Maternal LOAEL Not Obser ved Developmental LOAEL 82 based on changes in brain morphometrics in the cerebellum

870.3800 Reproduction and fertility effects in rats 4014241 (1995) Acceptable/guideline M & F: 0, 1

- 3, 11

- 31, 105

- 288, 223

- 604 mg/kg/day Parental/Systemic NOAEL = 11

- 3 1 mg/kg/day LOAEL = 105

- 288 mg/kg/day based on increased weights and hemosiderosis of the spleen. Reproductive NOAEL = 223

- 604 mg/kg/day LOAEL > 223

- 604 mg/kg/day based on no effects. Offspring NOAEL = 11

- 31 mg/kg/day LOAEL = 105

- 288 mg/kg/day based on red uced pup body weight gains and lower pup body weights during lactation.
870.6200b Subchronic Neurotoxicity 45713601 (1997) acceptable/nonguideline pending submission of positive control data for neuropathological and FOB
assessments 0/0, 24/26, 126/143, and 575/628 mg/kg/day [M/F], respectively The study may be upgraded pending submission of acceptable positive control data. NOAEL 126/143 mg/kg/day, M/F LOAEL 575/628 mg/kg/day, M/F based on decreased body weights, body weight gains, and food consumption

.

870.4100 Chronic toxicity in dogs 44014234 (1996) Acceptable/guideline M & F: 0, 5, 25, 200 mg/kg/day (capsules) NOAEL 25 mg/kg/day LOAEL 200 mg/kg/day based on hematological effects, hemosiderosis of the liver and spleen, extraniedullary hematopoiesis in the spleen, and increases in liver weight.

870.4300 Chronic toxicity/ carcinogenicity in rodents (mice) 44014325 (1996) Acceptable/guideline M: 0, 1.14, 11.1, 237, 698 mg/kg/day F: 0, 1.14, 10.8, 234, 696 mg/kg/day NOAEL 11.1/10.8 mg/kg/day, M/F LOAEL 237/234 mg/kg/day based on mild hemolytic anemia and related microscopic changes (hemosiderosis) in the spleen, liver, and bone marrow and extramedullary hematopoiesis in the spleen.

870.4200 Carcinogenicity study in rat 44014243 (1996) Acceptable/guideli ne M: 0, 0.77, 7.77, 96.9, 312 mg/kg/day F: 0, 0.90, 9.08, 111, 388 mg/kg/day NOAEL 96.9/111 (M/F) LOAEL 312/388 / 191.0 mg/kg/d (M/F) based on decreased body weights, body weight gain and food efficiency, mild hemolytic anemia, and increased incidence of alveolar foam cells (females only).Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 41 of 58 Table A.3 Subchronic, Chronic and Other Toxicity Pro file for Acibenzolar

- S

- methyl

Guideline No.

Study Type MRID No. (year) Classification

Dose Levels Results

870.5100 Bacterial reverse mutation assay (Ames test) 441014247 (1993) Acceptable/guideline 312.5, 625, 1250, 2500, 5000
μ g/plate Negative with and without S

- 9 activation at 5000 μ g/plate and less.

870.5100 Bacterial reverse mutation assay (Ames test) Test Material: CGA

- 362020 (isomer of acibenzolar

- S

methyl) 44537025 (1998) Acceptable/guideline 61.73 to 5000 μ g/plate (+S

- 9) 30

- 86 to 2500 μ g/plate (

- S

- 9) Positive in S. typhimurium strain TA1537 at 277.8 μ g/plate and higher in the absence of S

- 9. Negative with S

- 9 activation at 5000
μ g/plate and less.

870.5100 Bacterial reverse mutation assay (Ames test) Test Material: NOA

- 419191 (by

- product of acibenzolar

- S

methyl) 44537024 (1998) Acceptable/guideline 312.5 to 5000 μ g/plate (± S

- 9) Negative with or without S

- 9 activation at 5000 μ g/plate and less

870.5100 Bacterial reverse mutation assay (Ames test) Test Material: CGA

- 3 23060 (plant metabolite of acibenzolar

- S

- methyl) 44537026 (1997) Acceptable/guideline 312.5 to 5000 μ g/plate (± S

- 9) Negative with or without S

- 9 activation at 5000 μ g/plate and less

870.5300 In vitro mammalian gene mutation assay 44014246 (1993) Accepta ble/guideline 3.70 to 100 μ g/ml (

- S

- 9), 37.04 to 1000 μ g/ml (+S

- 9) Negative with S

- 9 activation up to 1000 μ g/ml. Negative without S

- 9 activation up to 100 μ g/ml. Compound tested to cytotoxic concentrations.

870.5375 In vitro mammalian chromosome aberrati on (CHO cells) 44014245 (1993) Acceptable/guideline 7.5 to 60 μ g/ml (

- S

- 9 and +S

9) Suggestive of clastogenicity in the absence of S

- 9 activation at 30 and 60 μ g/mL at the 18

- hour cell harvest time; effect observed only in the presence of cytotoxicity. I ncrease in polyploid cells at 30 and 60 μ g/mL at the 42 hour harvest time both with and without S

9. Evidence of cell cycle arresting activity at G 2
. 870.5395 Mammalian erythrocyte micronucleus test 44014244 (1993) Acceptable/guideline 1000, 2000, 4000 m g/kg (oral gavage) Negative at 16, 24, and 48, hour sacrifices.

870.5550 UDS in primary rat hepatocytes 44014248 (1993) Acceptable/guideline 9.77 to 500 μ g/ml Negative at 500 μ g/ml and less.

870.7485 Metabolism and pharmacokinetics
rats 44014250 (1995) A cceptable/guideline 0.5, 100 mg/kg Following oral treatment of rats, acibenzolar

- S

- methyl was rapidly and nearly completely (>90% of administered dose) absorbed from the gastrointestinal tract into the general circulation. The majority (88

- 95%) of the adm inistered dose was excreted in the urine within the first 48 hours. The major metabolite (79

- 92%) in the urine was the carboxylic acid derivative of the parent.Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 42 of 58 Table A.3 Subchronic, Chronic and Other Toxicity Pro file for Acibenzolar

- S

- methyl

Guideline No.

Study Type MRID No. (year) Classification

Dose Levels Results

870.7600 Dermal penetration 47430503 (1995) Acceptable/guideline 10 μg/cm2 and 100μg/cm2 An estimate of dermal absorption based on the results from the low dose group (10 μg/cm2), was derived. Mean dermal absorption for this group of animals where the skin was washed after 8 hours of exposure was 43.55%. Special studies :

28

- Day dietary
rats 44014227 (1992) Acceptable/nonguideline M: 0, 45.9, 403, 1070 mg/kg/day; F: 0, 44.8, 376, 1000 mg/kg/day NOAEL = M: 403 mg/kg/day; F: 376 mg/kg/day LOAEL = M: 1070 mg/kg/day; F: 1000 mg/kg/day based on decreased mean body weights, decreased liver weig hts, altered hematology parameters accompanied by increased spleen weights.

28

- Day oral gavage
rats 44014229 (1993) Acceptable/nonguideline 0, 10, 100, 800 mg/kg/day NOAEL = 100 mg/kg/day LOAEL = 800 mg/kg/day based on decreased body weights, and decrea sed hemoglobin

- related parameters accompanied by hemosiderosis of the spleen, increased liver and spleen weights, and decreased thymus weights. 28

- Day oral capsule dogs 44014231 (1994) Acceptable/nonguideline 0, 50, 250, 500 mg/kg/day NOAEL = 50 mg/kg/da y LOAEL = 250 mg/kg/day based on decreased body weight, decreased hemoglobin

- related parameters, hepatic and splenic hemosiderosis. 90

- Day Dietary mice 44014228 (1993) Acceptable/nonguideline M: 0, 30.6, 152, 624 mg/kg/day; F: 0, 47.4, 220, 803 mg/kg/day NOAEL = M: 30.6 mg/kg/day; F: 47.4 mg/kg/day LOAEL = M: 152 mg/kg/day; F: 220 mg/kg/day based on decreased mean body weights and body weight gain in males, increased spleen weights and splenic histopathology in both sexes.

90

- Day Dietary dog 44014232 (1994) Acceptable/nonguideline 0, 10, 50, or 200 mg/kg/day NOAEL = 50 mg/kg/day LOAEL = 200 mg/kg/day in male and female dogs, based on regenerative hemolytic anemia evidenced by decreased erythroid parameters, pigmentation in the liver and spleen, spleni c congestion, and by activation of medullary (bone marrow) and extramedullary (splenic) erythropoiesis. 90

- Day Dietary
rat 44014230 (1993) Acceptable/nonguideline males: 0,2.42, 24.6, 126, or 516 mg/kg/day; females: 0,2.64,26.3, 131, or 554 mg/kg/day) NO AEL = 126 mg/kg/day in males and 131 mg/kg/day in females LOAEL = 516 mg/kg/day males and 554 mg/kg/day females based on decreased mean body weights, reduced food intake, reduced food efficiency, and increased liver and spleen weights with correlates for the liver and spleen of glycogen deposition and hemosiderosis, respectively. Special Developmental toxicity
rats 44014238 (1994) Acceptable/nonguideline 300 mg/kg/day, GD 6

- 15, 6

- 7, 8

- 9, 10

- 11, 12

- 13, or 14

- 15 Maternal and developmental NOAELS and LOAEL S could not be identified by this protocol. The most pronounced maternal and developmental toxicity occurred when dams were treated on GD 6

- 15.Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 43 of 58 Table A.3 Subchronic, Chronic and Other Toxicity Pro file for Acibenzolar

- S

- methyl

Guideline No.

Study Type MRID No. (year) Classification

Dose Levels Results

Special Developmental toxicity
rats 44014239 (1994) Acceptable/nonguideline 400 mg/kg/day, GD 6

- 7, 8

- 9, 10

- 11, 12

- 13, or 14

- 15 Maternal and developmental NOAELS and LOAELS could not be identified by this protocol. The most pronounced maternal and developmental toxicity occurred when dams were treated on GD 6

- 7 and 8

- 9. Dermal developmental toxicity
rats 44014240 (1994) Acceptable/nonguideline 0, 10, 100, 500 mg/kg/day, GD 6

- 15 Maternal NOAEL ≥ 500 mg/kg/day LOAEL >500 mg/kg/day based on no effects. Developmental NOAEL ≥ 500 mg/kg/day LOAEL >500 mg/kg/day based on no effects. Range

- finding 1

- generation reproductio n rats 44681301 (1993) Acceptable/nonguideline 0, 199

- 209, 382

- 410, 700

- 728 mg/kg/day Parental/Systemic NOAEL = 209 mg/kg/day LOAEL = 410 mg/kg/day based on decreased body weight gain and food consumption in females. Reproductive NOAEL = 410 mg/kg/day LO AEL = 728 mg/kg/day based on total resorptions in all dams. Offspring NOAEL = 209 mg/kg/day LOAEL = 410 mg/kg/day based on reduced pup body weight gains and lower pup body weights during lactation.Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 44 of 58 A.3 Toxicological Endpoints

A .3.1 Acute Reference Dose (aRfD)

– Females 13

- 49 years old and Children 1

- 12 years old

Selected Study: Developmental Neurotoxicity in R ats (MRID 46046401 ). See Section 3.2. 3

Dose and Endpoint for Establishing an a RfD : 8.2 mg/kg/day based on an offspring NOAEL of 8.2 mg/kg/ day and an offspring LOAEL of 82 mg/kg/day based on changes in brain morphometrics in the cerebellum.

Uncertainty Factor (UF ): 100

– 10 x for interspecies extrapolation and 10x for intraspecies variation.

Comments about Study/Endpoint : The developmenta l neurological effects of concern are presumed to occur after a single exposure and are relevant to females aged 13

- 50 years old since they occur in utero and to young children based on post

- natal effects.

[Note: B ased on a reevaluation of the DNT stud y regarding the potential for post

- natal toxicity, the acute dietary analysis should include females 13

- 49 and children 1

- 12 for this assessment.]

A .3. 2 Chronic Reference Dose ( c RfD)

- Females age 13

- 49 and Young Children

Selected Study: Developm ental Neurotoxicity in R ats (MRID 46046401 ). See Section 3. 2

. 3

Dose and Endpoint for Establishing a cRfD: 8.2 mg/kg/day based on an offspring NOAEL of 8.2 mg/kg/day and an offspring LOAEL of 82 mg/kg/day based on changes in brain morphometrics in the cerebellum.

Uncertainty Factor (UF ): 100

– 10 x for interspecies extrapolation and 10x for intraspecies variation.

Comments about Study/Endpoint : The effects observed in this study can occur after single or multiple doses. Selection of a chronic endpo int from this study ensures that the chronic exposure assessment is protective of f emales of reproductive age and their offspring. Acute RfD = 8.2 mg/kg (NOAEL ) = 0. 0.082 mg/kg/day (General Pop ulation) 1 00 (UF)Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 45 of 58 [Note: In the previous risk assessment (D361893, 3/3/09) only the subpopulation females 13

- 50 years old was assessed for c hronic dietary exposure based on in utero effects observed in the DNT study. However, based on a reevaluation of the DNT study regarding the potential for post

- natal toxicity, the chronic dietary analysis the chronic dietary exposure analysis has been

rev ised to include an assessment of dietary risks to children using the NOAEL from the DNT study.]

A .3. 3 Chronic Reference Dose (RfD)

– Adult Males and Females 50+ years

Selected Stud ies : Co

- critical studies Chronic Feeding Study in Dogs (MRID 4401423 4 ); Oncogenicity Study Mouse (MRID 44014235) ; Chronic/Oncogenicity Study Rat (MRID 44014243) ; Reproductive Study Rat ( 44014241 )

Chronic Dog Study

- In a chronic oral toxicity study acibenzolar

- S

- methyl was administered to 4 beagle dogs per sex per dose le vel in gelatin capsules at levels of 0, 5, 25, or 200 mg/kg/day for 52 weeks. No biologically significant toxic effects were observed in either males or females receiving 25 mg/kg/day or less of the test material. At 200 mg/kg/day, there was an indication of hemolytic anemia in dogs of both sexes i.e., effects consistent with prior or current hemolytic anemia including hematological effects, hemosiderosis of the liver and spleen, extraniedullary hematopoiesis in the spleen, and increases in liver weight. Significant treatment

related changes were found in clinical chemistry in the dogs fed the test, substance at 200 mg/kg/day, ( increase in triglycerides in both sexes, increase of cholesterol in females at week 13, decrease in total protein in males at week s 26 and 52, and decrease in albumin in both sexes at week 13. These clinical chemistry changes are suggestive of possible nutritional deficiencies. The LOAEL is 200 mg/kg/day in both sexes based on effects consistent with prior or current hemolytic anemi a

. The NOAEL is 25 mg/kg/day

. Oncogenicity Mouse Study

- In an oncogenicity study acibenzolar

- S

- methyl w as administered in the diet to groups of 60 male and 60 female Tif:MAGf (SPF) mice at concentrations of 0, 10, 100, 2000, or 6000 ppm ( 1.14, 11.11, 237, and 698 mg/kg/day for males and 1.14, 10.8, 234, and 696 mg/kg/day for females ) for 18 months. Ten mice per group were reserved for measurements of hematology parameters after 12 and 18 months of treatment. Treatment did not result in a significant decrease in survival. The overall food efficiency was decreased in females by 22% at 6000 ppm

. The red blood cell count, hemoglobin, and hematocrit at 53 and 79 weeks were decreased in females at 2000 ppm and 6000 ppm

. M ean corpuscular volume was decrea sed in high dose males at 79 weeks . M ean corpuscular hemoglobin concentration distribution increased at 6000 ppm

. Reticulocyte counts in high

- dose females was significantly increased. The hematology data are consistent with hemolytic anemia Chronic RfD = (NOAEL) 8.2 mg/kg = 0.082 ( F emales 13

- 49 /Young Children ) (UF) 100Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 46 of 58 especially i n females at 2000 and 6000 ppm. Macroscopic and microscopic findings consistent with a mild hemolytic anemia in both sexes included increased incidences of enlarged spleen
, increased incidences of hemosiderosis in liver
, spleen
, and bone marrow . I ncidenc e of
extra m edullary hematopoiesis in the spleen and pancreatic exocrine hyperplasia was increased in males at 2000 and 6000 ppm. Incidences of alveolar foam cells in the lungs were increased at 6000 ppm in both sexes

. The LOAEL is 2000 ppm (237 /234 mg/kg /day males / females), based on mild hemolytic anemia and related microscopic changes (hemosiderosis) in the spleen, liver, and bone marrow and extramedullary hematopoiesis in the spleen. The NOAEL was 100 ppm (11.1 mg/kg/day males; 10.8 mg/kg/day females).

Chronic/Oncogenicity Rat Study

- In a chronic toxicity/oncogenicity study, acibenzolar

S

- methyl was administered in the diet to groups of 80 male and 80 female (Tif:RAIf (SPF)) Sprague

- Dawley derived rats at concentrations of 0, 20, 200, 2500, or 7500 pp m ( 0, 0.77, 7.77, 96.9, and 312 mg /kg /day male and 0, 0.90, 9.08, 111, and 388 mg/kg/day female )

. Ten animals per sex per dose were sacrificed at 52 weeks for interim evaluation; the remaining animals were used for hematologic and clinical chemistry evalu ation (20 per sex per group) and evaluation of carcinogenic potential (50 animals per sex per group). No treatment

- related effects were observed at 20
, 200 or 2500 ppm for any parameter. Treatment related effects on b ody weight, weight gain, food consump tion, and food efficiency were observed in both sexes a t 7500 ppm

. Other treatment

- related effects at 7500 ppm included a slight hemolytic anemia in both sexes as evidenced by decreases in erythrocyte count, increased mean corpuscular volume, elevated
ret iculocyte counts, increased serum bilirubin, increased severity of hemosiderin deposition in the spleen, and increased incidence of hemosiderin deposition in Kupifer cells of the liver. Hemosiderin deposition in the spleen was accompanied by a statistical ly significant increase in spleen weight. There was also a statistically significant increase in the incidence of foam cells in the lungs of females fed the 7500

- ppm diet. The LOAEL was 7500 ppm (312 /388 mg/kg/day males/ females) based on decreased body w eights, body weight gain and food efficiency, mild hemolytic anemia, and increased incidence of alveolar foam cells (females only). The NOAEL was 2500 ppm (96.9 mg/kg/day males and 111 mg/kg/day females).

Reproducti ve Study in Rats

- See Section 3.2. 2

Dose and Endpoint for Establishing cRfD : 25 mg/kg/day based on a NOAEL of 25 mg/kg/day from the chronic dog study and a LOAEL of 105 mg/kg/day from the rat reproduction study based on hemolytic anemia with compensatory response.

Uncertainty Factor(s) : 1 00

– 10x for interspecies extrapolation and 10x for intraspecies variation.

Comments about Study/Endpoint/Uncertainty Factor : The NOAEL of 25 mg/kg/day, taken from the chronic dog study, is based on the totality of the database with a LOAEL of 105 mg/kg/ day (the lowest LOAEL is from the reproduction study) based on hemolytic anemia with compensatory response. The NOAEL and LOAEL recommended for use in the risk assessmentAcibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 47 of 58 come from different studies conducted in different species

. Typically, a combinatio n of NOAELs/LOAELs from studies conducted in different species is not recommended. However, in the case of acibenzolar

- S

- methyl the same endpoint (hemolytic anemia) is observed across species at a relatively close range of LOAELs (105

- 312 mg/kg/day). The refore, the ToxSAC concluded that, in this instance, it would be appropriate to base the point of departure for the risk assessment on the NOAEL from the dog chronic toxicity study using the LOAEL from the reproduction study in rats for the basis of the en dpoint (hemolytic anemia).

A

. 3

. 4 Incidental Oral Exposure ( S hort

- and I ntermediate

- Term)

Selected Study: Developmental Neurotoxicity in R ats (MRID 44014236 ). See Section 3.2. 3

Dose and Endpoint : 8.2 mg/kg/day based on an offspring NOAEL of 8 .2 mg/kg/day and an offspring LOAEL of 82 mg/kg/day based on changes in brain morphometrics in the cerebellum.

Uncertainty Factor (UF ): 100

– 10 x for interspecies extrapolation and 10x for intraspecies variation.

Comments about Study/Endpoint : This e ndpoint is considered appropriate based on the post

- natal component of the DNT.

A

. 3

. 5 Dermal Absorption

A dermal absorption factor (DAF) is applied when dermal exposure endpoints are selected from oral toxicity studies. The dermal factor converts th e oral dose to an equivalent dermal dose for the risk assessment. A DAF of 44% was selected for use in risk assessment based on a dermal absorption study in rats.

A

. 3

. 6 Dermal Exposure ( Short and Intermediate

- Term )

Selected Study: Developmental Neurot oxicity in R ats (MRID 44014236 ). See Section 3.2. 3

Dose and Endpoint : 8.2 mg/kg/day based on an offspring NOAEL of 8.2 mg/kg/day and an offspring LOAEL of 82 mg/kg/day based on changes in brain morphometrics in the cerebellum. Chronic RfD = 25 mg/kg/day (NOAEL ) = 0. 25 mg/kg/day (Adult Male) 1 00 (UF)Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 48 of 58 Uncertainty Factor (U F ): 100

– 10 x for interspecies extrapolation and 10x for intraspecies variation.

Comments about Study/Endpoint : Two acceptable dermal toxicity studies, including a dermal developmental study were available. However s ince neurological effects observed i n the oral developmental neurotoxicity study are not measured in the dermal developmental study, the findings from the dermal study may not be protective of these neurological effects

. Since an oral NOAEL was selected for dermal risk assessment
, a dermal absorption factor of 44% should be used

. This factor is based on a dermal absorption study in rats.

A .3. 7 Inhalation Exposure ( Short and Intermediate

- Term )

Selected Study: Developmental Neurotoxicity in R ats (MRID 44014236 ). See Section 3.2. 3

Dose a nd Endpoint : 8.2 mg/kg/day based on an offspring NOAEL of 8.2 mg/kg/day and an offspring LOAEL of 82 mg/kg/day based on changes in brain morphometrics in the cerebellum.

Uncertainty Factor (UF ): 100

– 10 x for interspecies extrapolation and 10x for intr aspecies variation.

Comments about Study/Endpoint : Since an oral NOAEL was selected for inhalation risk assessment, an inhalation absorption factor of 100% should be usedAcibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 49 of 58 A.4 E xecutive S ummaries

870.3700 Developmental Toxicity

In a non

- guideline d evelopmental toxicity study (MR I D 44014238), twelve presumed pregnant Tif:RAT f(SPF) (hybrids of RTT / 1 x RII/2) rats per group were administered CGA 245704 Technical (97.9%; Batch No. P.303011) in a 0.5% aqueous solution of sodium carboxymethylcellulose by gavage at a dose of 300 mg/kg/day. Groups 2

- 7 were administered test article on gestation days (GD) 6

- 15,6

- 7, 8

- 9, 10

- 11 , 12

- 13, or 14

- 15, respectively. Group 1 consisted of twelve animals which served as controls and were treated with 0.5% sodium carbox ymethylcellulose on GD 6

- 15. On GD 21, dams were sacrificed, subjected to gross necropsy, and all fetuses examined externally. Visceral and skeletal examinations were not performed. All animals survived until scheduled sacrifice on GD 21. Bloody, vaginal discharge was observed in 8/12 dams in Group 2, 3/ 1 2 dams in Group 3, 5/12 dams in Group 4, 4/12 dams in Group 5, and in 5/12 dams in Group 6. This f in ding was observed for one to four days starting on GD 13 and was not observed in controls or in animals i n Group 7. No other treatment

- related clinical signs of toxicity were observed. No statistically significant differences in absolute body weights or body weight changes occurred at any time between the treated groups and the control group. Body weight gain by Group 2 was 80% of the control level during the treatment interval (GD 6

- 1 6), with the greatest reduction in weight gain (77% of controls) during GD 11

- 16. Food consumption was not affected. There were no statistically significant differences between control and treatment groups for number of corpora lutea, number of implantation sites, live fetuses/dam, pre

- and post

- implantation loss, or fetal sex ratios. Fetal body weights from the Group 2 dams were significantly (p <0.01) less than the controls. Al though not statistically significant, Group 2 dams also had fewer live fetuses per litter (10.9 vs 14.8 for controls) and a greater post implantation loss (30.1% vs 2.9% for controls) from early resorptions due to one dam with whole liner resorption ( 1 7/17 ) and 2 additional dams with 13/16 and 8/9 resorptions/number of implantation sites. The overall incidence rates for litters containing fetuses with major external malformations in Groups 1

- 7 were 0/12, 1/10, 0/ 10 , 1/ 11 , 0/ 11 , 0/10, and 0/12, respectively. In one Group 2 litter, generalized edema was observed in 5/14 fetuses. In addition, two of the five also had a position anomaly of the hindlimb and one of the two also had gastroschisis. These five fetuses also had greatly reduced body weights. Generalize d edema was also seen in one fetus from Group 4. Maternal and developmental toxicity NOAELs and LOAELs could not be identified by this protocol, which investigated the critical period of organogenesis. The most pronounced maternal and developmental toxici ty occurred when dams were treated on GD 6

- 15, inclusive at a dose level of 300 mg/kg/day. This study is classified as Acceptable/non

- guideline as a developmental toxicity study (83

- 3a) in rats.

In a non

- guideline developmental toxicity study (MR I D 440142 39), eight presumed pregnant Tif: RAT f (SPF) (hybrids of RII/1 x R II 2) rats per group were administered CGA 245704 Technical (97.9%; Batch No. P.303011) by gavage at a dose of 400 mg/kg/day. Groups 2

- 6 were administered test article on gestation days (GD) 6

- 7, 8

- 9, 10

- 11, 12

- 13, or 14

- 15, respectively. Group 1 consisted of eight animals which served as controls and were treated with 0.5%Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 50 of 58 carboxymethylceliulose (vehicle) on GD 6

- 15. On GD 21, dams were sacrificed, subjected to gross necropsy, and all fetuse s examined externally. Visceral and skeletal examinations were not performed. One Group 2 dam was found dead on GD 20. Prior to death, this animal had bloody perineal discharge and necropsy findings including mottled kidney and thymus. One Group 4 dam del ivered on GD 20 and was sacrificed. All other animals survived until scheduled sacrifice on GD 21. Bloody, perineal discharge was observed in 4/8 dams in Group 3. This f in ding was observed for three to four days starting on GD 16. The same 4 dams were late r observed to have total lifter resorptions. No other treatment

- related clinical signs of toxicity were observed. No statistically significant differences in body weights, body weight gains, or food consumption occurred at any time between the treated grou ps and the control group. There were no differences between the control group and Groups 4, 5, and 6 for number of corpora lutea, number of implantation sites, live fetuses/dam, pre

- and post

- implantation loss, fetal body weights, or fetal sex ratios. Gro up 2 had a slightly greater number of early resorptions/dam (2.7 vs 0.9 for controls) and an increased postimplantation loss (18.7% vs 5.4% for controls). The four Group 3 dams observed with bloody discharge had complete litter resorption resulting in incr eased postimplantation loss (53.4%). Group 3 also had an increase in early rcsorptions (8.0/dam vs 0.9/dam for controls) and decreased mean live fetuses/litter (8.5 vs 16.0 for controls). Another Group 3 dam had fused placenta between two fetuses. The o verall incidence rates for liners containing fetuses with major external malformations in Groups 1

- 6 were 0/8, 0/6, 0/4, 1/7, 0/8, and 0/8, respectively. One Group 4 fetus had cleft palate and another fetus from the same lifter had a kinked tail. No treatm ent

- related external m alformations /variations were observed in any fetus from any group. Maternal and developmental toxicity NOAELs and LOAELs could not be identified by this protocol, which investigated the critical period of organogenesis. Pronounced ma ternal and developmental toxicity occurred when dams were treated on GD 6

- 7 and 8

- 9 at a dose level of 400 mg /kg/day.

870.7600 Dermal Toxicity Studies

In a dermal developmental toxicity study (MRID 44014240 ) , 24 pregnant Tif: RA I f (SPF) rats (Sprague

- Daw ley derived) per group were administered acibenzolar

- S

- methyl (97.9% a.i.) in aqueous carboxymethylcellulose (0.5% w/w) in 0.1% aqueous Polysorbate 80, by dermal application at doses of 0 (vehicle), 10, 100, or 500 mg/kg/day on gestation days (GD) 6

- 15, in clusive. Exposure duration was 6 hours per day. On GD 21, all dams were sacrificed and all fetuses were sexed, weighed, and examined for external malformations/variations, then sacrificed. Approximately one

- half of each litter was placed in Bouin’s fixati ve for subsequent visceral examination and the remainder w ere prepared and stained for skeletal examination. All animals survived until scheduled sacrifice. No clinical signs of toxicity were observed at any treatment level. Gestational body weights, bo dy weight changes, and food consumption were not statistically significantly different for any treatment level throughout the gestational period. Therefore, the maternal toxicity NOAEL is 500 mg/kg/day based on no adverse maternal effects at the highest ad ministered dose. The maternal toxicity LOAEL was >500 mg/kg/day. No
treatment

- related effects were observed for gravid uterine weights, number of fetuses/litter, pre

and post

- implantation losses, numbers of corpora lutea/dam, number of implantations/dam
,Acibenzolar

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- Methyl Human Health Risk Assessment DP No. 424596

Page 51 of 58 resorptions/dam, fetal body weights, or fetal sex ratios. No biologically relevant statistically significant differences in the incidence rates of any external, visceral, or skeletal malformations/ anomalies/variations were observed in the treated litte rs as compared to the controls. There were statistically significantly decreased incidences of absent ossification of the proximal phalanx of anterior digit

- 2 in all treatment groups and poor ossification of the proximal phalanx of posterior digit

- 2 in th e 500 mg/kg/day treatment group as compared to the control group. However, these decreases were not considered to be biologically significant. Therefore, the developmental toxicity NOAE L is 500 mgfkglday based on no adverse developmenta l effects at the hi ghest dose administered. The developmental toxicity LOAEL was >500 mg/kg/day.

In a 28

- day repeated dose dermal toxicity study (MRID 44014233), groups of 5 females Tif: RAIf (SPF) albino rats were treated with acibenzolar

- S

- methyl technical in 0.5% (w/v) carboxymethyl cellulose/0.1% (w/v) aqueous polysobate 80 at doses of 0, 1, 10, 100 or 1000 mg/kg/day. Animals were treated by dermal occlusion for 6 hours/day, 5 days/week for 4 weeks. No animals died during the study. There were no treatment

- related c linical signs, dermal effects, effects on body weight, food consumption, hematology, clinical chemistry, or organ weight. No gross or microscopic pathology were noted at necropsy. The systemic and dermal NOAEL is the limit dose of 1000 mg/kg/day. A derm al and systemic LOAEL were not identified.

870.3800 Reproduction

In a 1

- generation range

- finding reproduction study in rats ( Nonguideline study, MRID 44014241 ) CGA 245704 Technical (97.9% a.i.; Batch No. P.303011) was administered to groups of 15 male and 15 female Tif: RAT f (SPF), hybrids of RTTI 1 x P11/2 (Spra gu e

- Dawley derived) rats at dietary concentrations of 0, 2000, 4000, or 8000 ppm for one generation (MR I D 44681301). I n this range

- finding study, F0 adults were administered test or control di et for two weeks prior to mating. Premating doses were 199.4, 382.0, and 700.1 mg/kg / day, respectively, for F0 males and 208.7, 409.9, and 727.8 mg/kg/day, respectively, for F0 females. Males were terminated at the end of mating and females were terminated at weaning of their pups. All offspring, except five litters per dose group, were necropsied at weaning. After weaning, five litters per dose group were retained on treatment for an additional three weeks and then necropsied. The only clinical sign of to xicity in the parental animals was perineal hemorrhage during late gestation in five high

- dose females. Gross necropsy was unremarkable. Absolute body weights, body weight gains, and food consumption values for the low

- and mid

- dose males and low

- dose fema les were similar to the controls throughout the study. High

- dose males had significantly (p > 0.01; 88

- 91% of control) lower body weights than the controls beginning on day 8 and continuing until study termination. Overall weight gain by the high

- dose male s was 69% of the control level. Body weights and body weight gains of the high

- dose females were significantly (p > 0.01; body weights 88

- 90% of controls) Tess than the controls during the premating interval. Overall body weight gain by the high

- dose grou p was only 30% of the control group level. Mid

- dose females had significantly (p > 0.05) lower body weight gains than the controls during days 1

- 8. Reduced body weight gains in the high

- dose males and femalesAcibenzolar

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- Methyl Human Health Risk Assessment DP No. 424596

Page 52 of 58 and mid

- dose females correlated with significa ntly (p > 0.05 or 0.01) reduced food consumption by these treated groups during study days 1

- 8. Lower body weights, body weight gains, and food consumption continued for the mid

- and high

- dose females during gestation and lactation. Body weights of the hig h

- dose group were significantly (p > 0.05 or 0.01) lower than the controls throughout gestation with overall weight gain by the high

- dose females during gestation 27% (p

> 0.01) of the control group level. Mid

- dose females had significantly (p > 0.05 or 0. 01) lower body weights than the controls on GD 21 and on lactation days 7, 14, and 21. Weight gains by the mid

- dose group during gestation and lactation were 92% and 83%, respectively of the control group levels. Food consumption by the high

- dose group was significantly (p > 0.05 or 0.01) less than the controls throughout gestation. Food consumption by the mid

- dose group was significantly (p > 0.01) less than the controls throughout lactation. Therefore, the LOAEL for parental toxicity is 4000 ppm based on reduced food consumption and lower body weight gains in F0 females. The parental toxicity NOAEL is 2000 ppm. Mating and fertility indices, mean precoital interval, mean gestation length, and mean numbers of corpora lutea and implantation sites per dam wer e similar between the treated and control groups. Mating and fertility indices for the high

- dose group were similar to the control group, but no live lifters were produced by the high

- dose group (i.e. all pregnancies were lost). Live births and pup surviva l were similar between the low

- and mid

- dose groups and the control group. Therefore, the LOAEL for reproductive toxicity is 8000 ppm based on total resorptions in all dams. The reproductive toxicity NOAEL is 4000 ppm. No treatment

- related clinical signs of toxicity were observed in the pups during lactation. Absolute body weights of pups in the low

- dose group were similar to the controls throughout lactation. Body weights of the mid

- dose pups were significantly (p > 0.05 or 0.01; 76

- 89% of controls) less than the controls beginning on lactation day 7 and continuing throughout lactation and postweaning. The lower body weights of the mid

- dose pups were a result of significantly (p > 0.05 or 0.01; 69

- 89% of controls) lower body weight gains from postnatal day 4 through postnatal day 28. Recovery of body weight gains occurred during the postweaning intervals of days 28

- 35 and 35

- 42. Therefore, the LOAEL for developmental toxicity is 4000 ppm based on reduced pup body weight gains and lower pup body weights duri ng lactation and early postweaning. The developmental toxicity NOAEL is 2000 ppm.

870.6200b Subchronic Neurotoxicity

In a subchronic neurotoxicity study (MRID 45713601 ), CGA

- 245704 ( Acibenzolar, 97.9% a.i., Batch No. P.303011 ) was administered in the die t to 10 Sprague

- Dawley derived rats/sex/gr oup at dose levels of 0, 400, 2000, or 8000 ppm (equivalent to 0/0, 24/26, 126/143, and 575/628 mg/kg/day [M/F], respectively) for at least 90 days. Neurobehavioral assessment (functional observational battery [FO B] and motor activity testing) was performed using all rats at pre

dosing and Weeks 4, 8, and 13. At study termination, 5 rats /sex/group were anesthetized and perfused in situ for neuropathological examination. The tissues from the perfused animals in th e control and 8000 ppm groups were subjected to histopathological evaluation of brain and peripheral nervous system tissues. Positive control data were not provided. No compound

- related effects were observed in mortality, clinical signs of toxicity, FOB, m otor activity, or gross or neuropathology. At 8000 ppm, body weights were generally decreased throughout the study inAcibenzolar

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- Methyl Human Health Risk Assessment DP No. 424596

Page 53 of 58 the males (decreased 11

- 14%, not statistically significant) and females (decreased 8

- 13%, attaining statistical significance at Weeks 2

- 5 , 7 and 8, and 11

- 13). Also at this dose, cumulative body weight gains were decreased throughout the study in the males (decreased 19

- 35%, attaining statistical significance at Weeks 2

- 4 and 6

- 9), and in the females (decreased 24

- 40%). A decreasing trend (p<0.01) in body weight and body weight gain was also generally noted in both sexes at this dose. These decreases in body weight gain corresponded with decreases in food consumption which was sporadically decreased in the 8000 ppm males (decreased 9

- 21% at Weeks 1

- 3, 5

- 7, and 11, but only attaining statistical significance during Week 1), and females (decreased 14

- 18%, p<0.01 at Weeks 1 and 3). A decreasing trend (p<0.01) in food consumption was also generally noted in the males at 8000 ppm during the we eks reported above. No neurological effects were observed at any dose in either sex.

The LOAEL was 8000 ppm (equivalent to 575/628 mg/kg/day, M/F) based on decreased body weights, body weight gains, and food consumption

. The NOAEL is 2000 ppm (equivalent to 126/143 mg/kg/day, M/F)

. The subchronic neurotoxicity study in rats (MRID 45713601) on Acibenzolar had been reviewed and is classified as acceptable/non

- guideline.

870.5100, 870

- 5300, 870.5375, 870.5900 Mutagenicity

Five acceptable mutagenicity s tudies on technical grade acibenzolar

- S

- methyl are available:

1. Reverse gene mutation, S. typhimuriumlE. Coli (MRID 44014247) 2. Forward gene mutation, Chinese hamster V79 lung cells in culture/HGPRT locus (M RID 44014246) 3. Chromosome aberration, Ch inese hamster ovary (CHO) cells in culture ( MRID 44014245) 4. Unscheduled DNA synthesis assay, primary rat hepatocytes in culture (MRID 44014248) 5. In vivo cytogenetics, micronucleus assay in mice (MRID 44014244) Results in all five studies were negati ve for genotoxicity. The five studies on the technical grade product satisf’ the new revised mutagenicity guideline requirements for a new chemical (published in 1991).

Three additional acceptable mutagenicity studies on a) an iso mer (CGA

- 362020) of acib enzolar S

- methyl, b) a by

- product (NOA 419191) of acibenzolar

- S

- methyl, and c) a plain metabolite (CGA

- 323060) of acibenzolar

- S

- methyl are also available.

1. Reverse gene mutation, S. typhimuriumlE. Coli; Test Material: CGA

- 362020 (MRID 44537025). This study was POSITIVE for evidence of induced mutant colonies over background in S. typhimurium strain TA1537 at concentrations of 277.8 and higher in the absence of 59

- mix. 2. Reverse gene mutation, S. typhimuriumlE. Coli; Test Material: NOA 419191 (MRID 4 4537024). This study was negative.Acibenzolar

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- Methyl Human Health Risk Assessment DP No. 424596

Page 54 of 58 3. Reverse gene mutation, S. typhimuriumfE. Coli; Test Material: CGA

- 323060 (M R lD 44537026). This study was negativeAcibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 55 of 58 A ppendix B

. Chemical Names a nd Structures o f Metabolites

N N S S C H 3 O

Acibenzolar N N S C O O H

CGA 210007

N N S C O O H

H O

CGA 324041

N N S C O O H

O H

CGA 323060 S C O O H

O C H 3

CGA 379019

CGA 379789

S C O O H

O C H 3

O

CGA 379018 S C O O H

C H 3 TRR, % ppm Lettuce 0.6 0.006 Tomato Fruit 7.3 0.023 Leaves 1.5 0.011 Wheat Forage 2.4 0.007 Straw 1.3 0.004 Grain 4.8 <0.001 Rice Straw 0.5 0.009 TRR, % ppm Lettuce 20.1 0.204 Tomato Fruit 4.8 0.015 Leaves 6.1 0.044 Wheat Forage 2.4 0.007 Straw 1.3 0.004 Grain 4.8 <0.001 TRR, % ppm Lettuce 25.1 0.255 Tomato Fruit 65.2 0.203 Leaves 19.2 0.138 Wheat Forage 57.9 0.168 Straw 43.5 0.149 Grain 39.3 0.001 Rice Grain 5.6 0.005 Hulls 16.8 0.027 Straw 56.2 1.120 TRR, % ppm Lettuce 16.9 0.171 Tomato Fruit 0.8 0.002 Leaves ND ND Wheat ND ND Rice ND ND

TRR, % ppm Rice Grain 18.8 0.016 Hulls 7.9 0.013 Straw 8.8 0.175

also found in paddy water

TRR, % ppm Rice Grain 3.6 0.003 Straw 0.1 0.002

also found in paddy water TRR, % ppm Rice Straw 0.7 0.014

also found in paddy waterAcibenzolar

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- Methyl Human Health Risk Assessment DP No. 424596

Page 56 of 58Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 57 of 5 8 A ppendix C. Physical/Chemic al Properties

Physicochemical Properties of Acibenzolar

- S

- Methyl

. Parameter Value Reference Melting point/range 133 oC DP# 250963, 2/10/99, H. Podall pH 7

. 9 (1% solution in water) at 25

o C Density 1.54 g/cc at 22 o C (bulk density) Water solubility 0.0077 g/L Solvent solubility Methanol 4.2 g/L Acetone 28 g/L Toluene 36 g/L

n

- Octanol 5.4 g/L

n

- Hexane 1.3 g/L Ethyl acetate 25 g/L Dichloromethane 160 g/L European Commission, 6506/VI/99

- fin al, 5/21/02

Vapor pressure 3.6 x 10

- 6 Torr at 25 oC DP# 250963, 2/10/99, H. Podall Dissociation constant, pK a No dissociation constant in an accessible pH range (1.0

- 9.0) European Commission, 6506/VI/99

- final, 5/21/02 Octanol/water partition coefficie nt, Log(K OW ) Log ( P OW ) 3.1 at 25 oC DP# 250963, 2/10/99, H. Podall UV/visible absorption spectrum 253 nm ε : 14.7 10 3 l mol

- 1 cm - 1 288 nm ε : 5.4 10 3 324 nm ε : 7.2 10 3 European Commission, 6506/VI/99

- final, 5/21/02Acibenzolar

- S

- Methyl Human Health Risk Assessment DP No. 424596

Page 58 of 58 A ppendix D. Studies Reviewed for E thical Conduct

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task Force members Health Canada, U.S. Environmental Protection Agency, and the National Agricultural Chemicals Association, released February, 1995.

Agric ultural Re

- entry Task Force (ARTF) data base (SOP #3.1)