### Prot hi oco naz o l e Hu ma n H e a lt h Ri s k Assess m ent DP No

. D 403739



### UN I TE D STATES ENV IR ONME NT AL PRO TEC TION AGENCY

WAS HI N GTO N, D.C. 20460

ME MORA N D U M

D a te: J un e 1 5

, 2013 O FFI CE OF
CHEMICAL S A FETY AND

P O LLUTION PR E VENTI O N



### SU BJECT: Prot h iocona z o l e: Hum a n H ea l t h R is k A s s e ssm e n t f o r Pr o p ose d Us e s o n Low

Gr o win g B e r r y Subgroup ( e xcep t St r a wb e rry), Bu s hb e rr y S ub g r o up, a nd Cucurbit

V egetab l es.

P C C ode: I 13961

D ec i s i o n No .: 4654 57

Pe tit i on N o.: 91 7 6 77

Ri sk Assessment T y pe : S in g l e Chemical / Aggr e gate

TXR No.: N A



### M RID No.: N A DP Barcode: 0 403739

R eg i s tr a tion Nos

. : 2 6 4-8 25

Re g ulator y A c tio n : S ecti o n 3 R egis trat i on C a se N o

. : NA

C A S N o.: 17 8 92 8- 70

- 6

4 0 C FR: 

### § 1 8 0

. 626



### F ROM: C a ss i W a ll s
, S enior B io l og i s t**~..:Z ~**  

### S teve Fun k

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## ~**;:: e_** **~** My r on Ot tl ey, Senior

# oxic**t ~~**  Krist i n R ury
, Bi o l ogist 

# ¥J

Risk A sse s s ment Bran ch III

Hea l th Effect s D ivisi o n (7509P)



### THROUGH: C hri s t ine O ling e r
, Branch

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# ~ Ri s k Assess m e nt Branch I II

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# __ _ H ea l t h Effec t s D ivi s ion ( 7 5 0



### TO: To n y K i s h

, R ev i ew Ma n ager Team 22 Fungi c id e Bra n ch Registration Di v isio n ( 7505P )

Page 1 of 48

### Prothioconazole Human Health Risk Assessment DP No. D403739

Page 2 of 48 1.0 Executive Summary

................................ ................................ ................................ ........... 3

2.0 HED Recommendations

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

2.1 Data D eficiencies

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

2.2 Tolerance Considerations

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

2.2.1 Enforcement Analytical Method

................................ ................................ ............... 6

2.2.2 Recommended Tolerances

................................ ................................ ......................... 6

2.2.3 Revisions to Petitioned

- For Tolerances

................................ ................................ .... 6

2.2.4 International Harmonization

................................ ................................ ..................... 6

2.3 Label Recommendations

................................ ................................ ................................ 6

3.0 Introduction

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

3.1 Chemical Identity

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

3.2 Physical/Chemical Characteristics

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

3.3 Pesticide Use Pattern

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

3.4 Anticipated Exposure Pathways

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

3.5 Consideration of Environmental Justice

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

4.0 Hazard Characterization and Dose

- Response Assessment

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

5.0 Dietary Exposure and Risk Assessment

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

5.1 Residues of Concern Summary and Rationale

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

5.2 Food Residue Profile

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

5.3 Wate r Residue Profile

................................ ................................ ................................ .. 15

5.4 Dietary Risk Assessment

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

5.4.1 Description of Residue Data Used in Dietary Assessment

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

5.4.2 Percent Crop Treated Used in Dietary Assessment

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

5.4.3 Acute Dietary Risk Assessment

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

5.4.4 Chronic Dietary Risk Assessment

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

5.4.5 Summary Table

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

6.0 Resident ial (Non

- Occupational) Exposure/Risk Characterization

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

6.1 Residential Handler and Post

- Application Exposure

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

6.2 Spray Drift

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

7.0 Aggregate Exposure/Risk Characterization

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

7.1 Acute Aggregate Risk

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

7.2 Short

- and Intermediate

- Term Aggregate Risk

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

7.3 Chronic Aggregate Risk

................................ ................................ .............................. 19

8.0 Cu mulative Exposure/Risk Characterization

................................ ............................... 19

9.0 Occupational Exposure/Risk Characterization

................................ ............................ 20

9.1 Short

- and Intermediate

- Term Handler Risk

................................ ........................... 20

9.2.1 Dermal Post

- application Risk

................................ ................................ .................. 25

9.2.2 Inhalation Post

- application Risk

................................ ................................ ............. 26

10.0 References

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

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

A.1 Toxicology Data Requirements

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

A.2 Toxicity Profiles

................................ ................................ ................................ ............ 29 Appendix B. International Residue Limits

................................ ................................ .............. 47 Appendix C. Residue Summary Table

................................ ................................ ..................... 48

### Prothioconazole Human Health Risk Assessment DP No. D403739

Page 3 of 48 1.0 Executive Summary

Prothioconazole (2

- [2

- (1

- c hlorocyclpropyl)

- 3

- (2

- chlorophenyl)

- 2

- hydroxylpropyl]

- 1,2

- dihydro

3 H

- 1,2,4

- triazole

- 3

- thione) is a broad

- spectrum systemic fungicide used for the control of Ascomycetes, Basidiomycetes, and Deuteromycetes diseases in a variety of crops. It is in the

triazolinthione chemical class and is a de

- methylation

- inhibit or (DMI) which works through disruption of ergosterol biosynthesis (ergosterol is a precursor to Vitamin D 2 

### and is an important component of fungal cell walls).

A Section 3 registration is being requested by Bayer CropS cience (Bayer) for the following

pro posed new uses to be added to the Proline® 480 SC Fungicide label ( EPA Reg. No. 264

- 825 ) : bushberries (crop subgroup 13

- 07 B) ; low growing berries, excluding strawberry (crop subgroup

13

- 07H) ; and cucurbit vegetables (crop group 9). Bayer submitted for reg istration of the same crops with same use patterns within these crops , in both U.S. and Canada

. Therefore, a North American Free Trade Agreement (NAFTA) joint review of Proline® 480 SC Fungicide was conducted by Pest Management Regulatory Agency (PMRA) an d EPA where the project

administrative lead is Canada/PMRA.

Permanent tolerances are currently established in 40 CFR §180.626 for prothioconazole foliar and seed treatment uses on a variety of crops.

Use Profile

Proline ( EPA Reg. No. 264

- 825 ) is a suspension concentrate (SC) broad

- spectrum fungicide and contains 41% of the active ingredient (ai) prothioconazole (4 lb ai/gallon). For the proposed uses, Proline is applied as a foliar spray via ground, chemigation, airblast, or handheld equipment. T he proposed label requires occupational handlers to wear long pants, long sleeved shirts, chemical resi stant gloves, shoes, and socks. The restricted entry interval (REI) on the proposed label is 12 hours. There are no proposed or registered resid enti al u ses of prothio conazole

.

Hazard Characterization Prothioconazole breaks down into different compounds in different matrices. Of particular interest is prothioconazole

- desthio, a metabolite and degradate that is more toxic than th e parent compound . The most protective quantitative hazard estimates are used in this risk assessment, based on a selection of endpoints from the prothioconazole

- desthio toxicology database.

T he target organs of prothiocona zole (and its desthio metabolite) toxicity include the liver, kidney, bladder, thyroid and blood. In addition, the chronic studies showed body weight and food consumption changes, and toxicity to the lymphatic and gastrointestinal ( GI ) systems. Prothioconazole has low acute toxicity by oral, dermal, and inha lation routes. It is not a dermal sensitizer, or a skin or eye irritant. Prothioconazole

- desthio also has low acute toxicity by oral, dermal, and inhalation routes. It is not a dermal sensitizer, or a skin irritant, but it is a slight eye

irritant. Evi dence of quantitative and qualitative susceptibility of offspring was observed in the developmental studies; however, points of departure were based on the most sensitive endpoints in the offspring; therefore, the Food Quality Protection Act (FQPA) 10X saf ety factor wa s reduced to 1X. Prothioconazol e was classified as “not likely to be carcinogenic to humans” and,

### Prothioconazole Human Health Risk Assessment DP No. D403739

Page 4 of 48 therefore, a quantitative cancer risk assessment is not required. The level of concern (LOC) for all exposure scenarios is a margin of exposure (MOE) less than 100, based on the standard uncertainty factors for intraspecies variation (10X) and interspecies extrapolation (10X).

Dietary Exposure (food and drinking water)
The residue chemistry data and environmental fate data are adequate to assess human dietary exposure to prothioconazole . The assessments are based on reliable data and will not underestimate exposure or risk. The estimated drinking water concentrations ( EDWCs) from Tier II of the Pesticide Root Zone

Model

- Exposure Analysis Modeling System (PRZM

- EXAMS) for the a cute duration and the Tier 1

Rice Model for the chronic duration were incorporated directly into the dietary exposure assessments.

The acute and chronic dietary exposure assessments were partially refined assuming HED

recommended tolerance

- level residues for the proposed crops and average field trial residue levels for the existing crops, except sweet corn where the limit of quantification ( LOQ ) w as used. Furthermore, empirical processing factors (PFs) and average livestock residue values determined from the reasonably balanced dietary burden (RBDB) and the livestock feeding studies, and 100 percent crop treated (%CT) were also included in the acu te and chronic assessments. At the 95 th 

### percentile, t he

acute dietar y exposure estimates utilize d 30 % of the acute population adjusted dose (aPAD) for

f emales 13

- 49 years of age

, which was the only population subgroup included in the acute assessment

. The chronic dietar y exposure estimates utilize d 24 % of the chronic population adjusted dose (cPAD)

for the general U.S. population, and 57% for all infants (< 1 year old ) , the most highly exposed population subgroup. None of these risk estimates exceed HE D’s LOC.

Residential Exposure
Residential exposure and risk are not assessed in this document because there are no existing or proposed residential uses of prothioconazole

.

Aggregate Risk
As there are no existing or proposed residential uses, and subseq uently no expected residential exposure, aggregate risk is considered in the dietary (food and drinking water) exposure and risk

assessment.

Occupational Exposure and Risk Occupational Handlers The occupational handler exposure and risk estimates indicate that short

- and intermediate

- term

non

- cancer dermal and inhalation MOEs are not of concern to HED (i.e., MOEs > 100) with the personal protective equipment (PPE) required on the Proline label (chemical resistant gloves). With baseline attire, the combine d dermal and inhalation MOEs for all proposed use sites ranged from 84 to 2,000. With gloves, the combined dermal and inhalation MOEs for all proposed use sites ranged from 170 to 7,600.

Occupational Post

-

Application On the day of application, the occupational dermal post

- application MOEs ranged from 210 to 6,300 and are not of concern to HED. The proposed REI of 12 hours is adequate.

### Prothioconazole Human Health Risk Assessment DP No. D403739

Page 5 of 48 Based on the Agency's current practices, a quantitative non

- cancer occupational po st

- application inhalation exposure assessment was not performed for prothioconazole at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post

- application inhalation exposure assess ment for prothioconazole

.

Review of Human Research This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from

the Pesticide H andlers Exposure Database Version 1.1 (PHED 1.1) and the Agricultural Handler Exposu re Task Force (AHETF) database are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. For ce rtain studies that review may have included review by the Human Studies Review Board. Descriptions of data sources as well as guidance on their use can be found at http://www.e pa.gov/pesticides/science/handler

- exposure

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

- app

- exposure

- data.html

.

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 Lo w

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

.

2.0 HED Recommendations

Provided a revised Section B/label is submitted as indicated in Section 2.3.1 an d a revised Section F is submitted as indicated in Section 2.2, HED recommend s granting the registration for the proposed foliar uses of prothioconazole on bushberries (crop subgroup 13

- 07B) ; low growing berries, excluding strawberry (crop subgroup 13

- 07H) ; and cucurbit vegetables (crop group 9)

and for establishment of tolerances as shown in Table 2.2.3.

2.1 Data Deficiencies

Residue Chemistry

860.1340 Reside Analytical Methods

As originally required in conjunction with PP#4F6830, revisions are recommended for the enforcement methods, liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) Method RPA JA/03/01 for crop commodities, to include at least two ion

transiti ons to preclude the need for a confirmatory method. The methods are extremely conservative with no likelihood of a false negative. However, the lack of a confirmatory ion transition creates the possibility of a false positive; that is, identifying a

prot hioconazole residue that is, in fact, not present or is present in lesser amounts than quantitated.

2.2 Tolerance Considerations

### Prothioconazole Human Health Risk Assessment DP No. D403739

Page 6 of 48 2.2.1 Enforcement Analytical Method

The Bayer CropScience high

- performance liquid chromatograph/mass spectrometer/mass

spect rometer (HPLC/MS/MS) method RPA JA/03/01 is available for enforcing the currently

establishe d crop tolerances . Since this method is nearly identical to the data

- collection method

and adequate method validation data were submitted with the magnitude of the residue studies, HED concludes that the current enforcement method is appropriate for enforcement of the tolerances associated with this petition.

It is noted that the petitioner was previously requeste d to modify the tolerance

- enforcement method to include parameters for a second ion transition for purposes of confirmation (D303508, S. Funk, 8/21/06 ). Bayer has requested for additional time to generate data to satisfy the deficiency (D407465, M. Negussie, 5/15/13). Bayer is pr oposing multiple ion transitions that could be used to determine prothioconazole residu es in plants and ruminants. Bayer conveyed that they will submit the revised methods that include th e proposed ion transitions. Bayer also communicated that currently no validation data for the two ion transitions is available. The analytical method deficiency remains outstanding.

2.2. 2 Recommended Tolerances

Table 2.2.2.1 is a summary of the proposed and HED

- recommended tolerance s for the combined residues of prothi oconazole and prothioconazole

- desthio (expressed in parent equivalents).

Table 2.2.2.1 : Tolerance Summary.

Commodity Proposed

Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments

Bushberry, subgroup 13

- 07B 2.0 2.0 Revised Section F is requested with the appropriate tolerance levels and commodity

definitions. Berry, low growing, except strawberry, subgroup

13

- 07H 0.15 0.20

Vegetables, cucurbit, crop group 9 0.30 0.30



### 2.2. 3 Revisions to Petitioned

- For Tolerances

Based on the submitted residue data and the OECD tolerance calculation procedure, HED concludes that the tolerance listed in Table 2.2.2.1, for the combined residues of prothioconazole and prothioconazole

- desthio, are appropriate. The petition er is requested to submit a revised Section F specifying the appropriate tolerance levels and commodity definitions (see Table 2.2.2.1)

.

2.2. 4 International Harmonization

There are no Canadian, Codex, or Mexican maximum residue limits (MRLs) in/on the proposed commodities. Therefore, harmonization is not an issue for this petition. A summary of the International Residue Limits is provided in Appendix B.

2.3 Label Recommen dations

### Prothioconazole Human Health Risk Assessment DP No. D403739

Page 7 of 48 Provided the petitioner submits a revised Section B which indicates a 30

- day PBI for nonlabeled rotational crops following application to cucurbit vegetables, HED concludes that the proposed label is adequate

.

3.0 In troduction

3.1 Chemical Ident ity

Table 3.1.1: Nomenclature of Prothioconazole, its Regulated Metabolites, and Triazole Compounds.

Structure

Common name Prothioconazole

Company experimental name JAU6476

IUPAC name ( RS)

- 2

- [2

- (1

- chlorocyclopropyl)

- 3

- (2

- chlorophenyl)

- 2

- hydroxypropyl]

- 2,4

- dihydro

- 1,2,4

- triazole

- 3

- thione

CAS name 2

- [2

- (1

- chlorocyclopropyl)

- 3

- (2

- chlorophenyl)

- 2

- hydroxypropyl]

- 1,2

- 3H

- dihydro

- 1,2,4

- triazole

- 3

- thione

CAS registry number 178928

- 70

- 6

End

- use product (EP) Proline ® 480 SC (4 lb/gal SC formulation; EPA Reg. No. 264

- 825);

Chemical structure of regulated metabolite prothioconazole

desthio

α

- (1

- chlorocyclopropyl)

- α

- [(2

- chlorophenyl)

- methyl]

- 1 H

- 1,2,4

- triazole

- 1

- ethanol

Chemical structure of metabolite

4

- hydroxy prothioconazole (residue of concern for risk

assessment in livestock commodities)

2

- [2

- (1

- chlorocyclopropyl)

- 3

- (2

- chloro

- 4

- hydroxyphenyl)

- 2

- hydroxypropyl]

- 1,2

- dihydro

3 H

- 1,2,4

- triazole

- 3

- thione



### 3.2 Physical/Chemical Characteristics

### Prothioconazole Human Health Risk Assessment DP No. D403739

Page 8 of 48 Table 3.2.1 is a summary of the physical/chemical properties for prothioconazole.

Prothioconazole has a Log K
ow 

### values ranging from 2.00

- 4.16 depending on pH and has a molecular weight of 344.26 g/mol; therefore, the potential to cross biological barriers is somewhat limited. The vapor pressure of prothioconazole is considere d low (< 3 ×10 - 9 

### mm Hg at

25 oC), limiting the potential for volatilization.

Table 3. 2 .1: Physicochemical Properties of Prothioconazole

. Melting point 139.1 to 144.5 oC

DP#s 303508 & 314517, 8/21/06, S. Funk pH 5.8 (1% solution)

Density 1.36 g/mL at 20 oC

Water solubility (mg/L at 20 oC) pH 4 5 pH 8 300 pH 9 2000

Solvent solubility (g/L at 20 oC) Acetone >250

Acetonitrile 69

Dichloromethane 88 Dimethylsulfoxide 126 Ethyl acetate >250

n

- Heptane <0.1

1

- Octanol 58 Polyethylene glycol >250

2

- Propanol 87 Xylene 8

Vapor pressure (at 20 or 25 oC) <<4 x 10
- 7 Pa (3 x 10
- 9 mmHg) (calculated from determinations at 70 oC)

Dissociation constant, pK

a 6.9 (calculated from K OW )

Octanol/water partition coefficient (at 20 oC) [Log K(ow)] unbuffered water 4.05 pH 4 4.16 pH 7 3.82 pH 9 2.00

UV/visible absorption Peak maxima at 257 nm



### 3.3 Pesticide Use Pattern

The proposed new uses on the Proline® 480 SC Fungicide (EPA Reg. No. 264

- 825; 4 lbs ai/gallon) includes applications to the b ushberry crop subgroup 13

- 07B; low growing berry, except strawberry

, crop subgroup 13

- 07H; and cucurbit vegetables crop gr oup 9

. Table 3.3 is a summary of the use directions for the proposed application scenarios. See section 2.3 for HED’s recommended modifications to the proposed label.

### Prothioconazole Human Health Risk Assessment DP No. D403739

Page 9 of 48 Table 3.3 : Summary of Proposed Proline® 480 SC Fungicide (EPA Reg. No. 264

- 825) Use Directions.

App. Timing App. Rate Max. No. App. per Season Max. Seasonal

App. Rate PHI (days) Use Directions and Limitations

Low Growing Berry S ubgroup, Except S trawberry: bearberry; bilberry; cloudberry; cranberry; muntries; partridgeberry; and cultivars, varieties, and/or hybrids of these

as needed 0.156 2 0.312 45 - May be applied using ground or chemigation equipment.

- Retreatment interval (RTI) of 5

- 10 days.

Cucurbit V egetables: Chayote (fruit); Chinese waxgourd (Chinese preserving melon); citron melon; cucumber; gherkin; edible gourd (includes hyotan, cucuzza, hechima, Chinese okra); Momordica spp (includes balsam apple, balsam pear, bittermelon, Chinese cucumber); muskmelon (includes cantaloupe); pumpkin; squash (summer and winter, includes butternut squash, calabaza, hubbard squash, acorn squash, spaghetti squash); watermelon

as needed soil

- 0.178

foliar

- 0.178 soil

- 1

foliar

- 2 soil

- 0.178

foliar

- 0.356 7 - May be applied using ground or chemigation equipment.

- For control of Fusarium wilt or blight, apply at planting via drip/drench equipment and follow with foliar treatments during the season.

- RTI of 5

- 10 days.

B ushberry S ubgroup: Aronia berry; blueberry (highbush and lowbush); Chilean guava; highbush cranberry; currant (black, buffalo, and red); elderbe rry; European barberry; gooseberry; edible honeysuckle; huckleberry; jostaberry; juneberry (Saskatoon berry); lingonberry; native c urrant; salal; sea buckthorn; and cultivars, varieties, and/or hybrids of these.

as needed 0.178 2 0.356 7 - May be applied using ground or chemigation equipment.

- RTI of 7

- 10 days.



### 3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new use of prothioconazole on low growing berries (except strawberries), bushberries, and cucurbit vegetables. Humans may be exposed to prothioconazole in f ood and drinking water, since prothioconazole may be applied directly to growing crops and application may result in prothioconazole reaching surface and ground water sources of drinking water. There are no residential uses of prothioconazole, so there is not likely to be exposure in residential or non

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

application exp osure for workers re

- entering treated fields.

Risk assessments have been previously prepared for the existing uses of prothioconazole. This risk assessment considers all of the aforementioned exposure pathways based on the proposed

new uses of prothioconazole, but also considers the existing uses as well, particularly for the dietary exposure assessment.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in th is 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," ( ht tp://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

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

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compile d by the USDA and are used in

### Prothioconazole Human Health Risk Assessment DP No. D403739

Page 10 of 48 pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is abl e to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks

for ad ult 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 specialized so ftware 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

No new toxicity and/or metabolism data have b een received since the last risk assessment ( D 378763, B. O ’K eefe, 01/31/2011 ). This assessment includes summaries of prior assessments

.

The risk assessment and safety finding s for prothioconazole are based on an extensive and well

characterized toxicology data base which includes a full testing battery for both prothioconazole and its major metabolite prothioconazole

- desthio, and additional studies on two minor metabolites, prothioconazole sulfonic acid potassium salt, and prothioconazole

- deschloro).

Beca use prothioconazole

- desthio was found to be the most toxic with effects at doses considerably below that of the other chemicals, HED has decided , in conjunction with Canada’s PMRA, to use the toxicity data on prothioconazole

- desthio in the hazard and dose response characterization

. R efer to a previous prothioconazole risk assessment document for further details, including the e xecutive s ummaries of the individual toxicology studies ( D328967, B. O’Keefe, 01/23/07).

4.1 Hazard and Dose

- Response Characterization

Prothioconazole subchronic and chronic studies show that the target organs at the lowest observed adverse effect level ( LOAEL ) include the liver, kidney, bladder, thyroid and blood. In addition, the chronic studies showed body weight and food consumption changes, and toxicity to the lymphatic and GI systems.

Developmental studies show that p rothioconazole and its metabolites produce adverse effects including malformations in the c onceptus at levels equal to or below maternally toxic levels

, particularly those studies conducted using prothioconazole

- desthio. Reproduction studies in the rat with prothioconazole and prothioconazole

- desthio suggest that these chemicals do not
adversel y affect reproductive parameters or the offspring except at parentally toxic dose levels. Acute and subchronic neurotoxicity studies , as well as a developmental neurotoxicity study , raise no neurotoxicity concerns. Immunotoxicity data show that prothioco nazole is not an

immunotoxicant.

The available carcinogenicity and/or chronic studies in the mouse and rat, using both prothioconazole and prothioconazole

- desthio, show no increase in tumor incidence. The data from the mutagenicity studies battery also i ndicate that both prothioconazole and

### Prothioconazole Human Health Risk Assessment DP No. D403739

Page 11 of 48 prothioconazole

- desthio are not mutagenic. Therefore , HED has concluded that prothioconazole

and its metabolites are not carcinogenic, and are classified as “Not likely to be Carcinogenic to

Humans”.

Prothioconazole has low acute toxicity by oral, dermal, and inhalation routes. It is not a dermal sensitizer, or a skin or eye irritant. Prothioconazole

- desthio also has low acute toxicity by oral, dermal, and inhalation routes. It is not a dermal sensitizer, or a skin irritant, but it is a slight eye

irritant.

Prothioconazole was extensively metaboli z ed in the rat following oral administration. Eighteen metabolites and the parent compound were identified in urine, feces and bile. The

biotransformation of prothioconazole consisted of three major reaction types including desulfuration, oxidative hydroxylation of the phenyl moiety

, and glucuronic acid conjugation. The major route of excretion for prothioconazole was in the feces

.

4.2 Safety Factor or Infant s and Children ( FQPA Safety Factor)

The prothioconazole toxicity database is considered adequate for risk assessment, and supports the reduction of the FQPA SF to 1X. There were no concerns for neurotoxicity, based on the results of an acute and subchronic neurotoxicity battery, a developmental neurotoxicity study, and the other repeated dose studies in the database. Increased quantitative and qualitative susceptibil ities were observed in offspring in the developmental studies; however, basing the point of departure on the offspring in the most sensitive of these studies provides the needed protection of offspring. Lastly, t he exposure data are complete or are estima ted based on data that reasonably account for potential exposures. As such, there are no uncertainties with respect to the exposure database , and reduction of the FQPA SF to 1X is further supported.

4.2.1 Completeness of the Toxicology Database

The availab le data include the required oral subchronic and chronic (including carcinogenicity)

studies conducted in rodents and non

- rodents; oral developmental and reproduction studies, oral metabolism, neurotoxicity and immunotoxicity studies; in vitro and in vivo mutagenicity studies; and dermal subchronic study. The requirement for a subchronic inhalation study was waived ( TXR 0056563 , J. Van Alstine, 02/21/ 20 13 )

4.2.2 Evidence of Neurotoxicity

No neurotoxicity was seen in acute and subchronic neurotoxicity studies and other studies with prothioconazole or prothioconazole

- desthio . Although offspring neurotoxicity was found, characterized by peripheral nerve lesions in the developmental neurotoxici ty stud y on prothioconazole

- desthio, the increase was seen only in the highest dose group at 105 mg/kg/day. Further, a NOAEL was established for the peripheral nerve lesions and all of the points of departure used in the risk assessment were protective of this finding.

### Prothioconazole Human Health Risk Assessment DP No. D403739

Page 12 of 48 4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There are adequate data in the prothioconazole (including metabolites) database to characterize the potential for pre

- natal or post

- natal risks to infants an d children: two

- generation reproduction studies in rats; developmental studies in rats and rabbits; and a developmental neurotoxicity study in rats. The effects seen in these studies suggest that offspring are more susceptible: offspring effects were seen at levels below the LOAELs for maternal toxicity and, in general, were of comparable or greater severity compared to the effects observed in adults. However,

c lear NOAELs are established for offspring and fetal effects. The NOAEL for the most sensitive of these studies (the rabbit developmental toxicity) is lower than that of the other studies (2 mg/kg/day), and is based on effects observed in the fetus, not the parent. Therefore, the offspring are considered to be protected and there is no need to reta in the 10X FQPA factor, and

it is reduced to 1X.

4.2. 4 Residual Uncertainties in the Exposure Database

T here are no uncertainties with respect to the exposure database

. The exposure data are complete or are estimated based on data that reasonably accoun t for potential exposures. The dietary food exposure assessment utilized empirical processing factors, 100% crop treated, average crop field trial residue levels, and livestock maximum residues. Results from ruminant feeding studies and poultry metabolis m studies were used to determine the maximum residue levels for livestock commodities. The crop field trials were performed using maximum application rates and minimum pre

- harvest intervals. The dietary drinking water assessment utilized health protectiv e high

- end model EDWCs. Additionally, there is no potential for residential exposure.

4.3 Toxicity E ndpoint and Point of Departure Selections

There have been no changes to the prior dose

- re sponse assessment, or to prior recommendations for combining ro utes of exposure and/or cancer classification. The most sensitive and protective endpoints for risk assessment were selected from the prothioconazole

- desthio database (see

Tables 4.3.1 ). Appropriate endpoints were identified for acute and chronic dietary exposures and

short and intermediate

- term occupational scenarios. The weight of evidence evaluation of these

toxic effects and the doses selected for risk assessment were discussed in detail in Section 3 of previous prothioconazole risk assessment docume nt s ( D328967

, B. O’Keefe , 0 1/23/ 20 07 ; and

D347123

, B. O’Keefe , 0 1/ 0 5/ 20 09 ). Residential exposure scenarios are not anticipated based on

the registered and proposed use pattern s

.

### Prothioconazole Human Health Risk Assessment DP No. D403739

Page 13 of 48 Table 4.3.1 Summary of Points of Departure, Toxicological Doses and Toxicity Endpoints Based on

Prothioconazol e desthio for Use in Dietary, Non

- Occupational , and Occupational Human Health Risk

Assessments Exposure/

Scenario Point of

Departure Uncertainty/FQ

PA Safety

Factors RfD, PAD, LOC

for Risk

A ssessment Study and Toxicological Effects

Acute Dietary (Females 13

– 49) NOAEL =

2.0 mg/kg/day UF A =10X

UF H =10X FQPA SF=1X Acute RfD = 0.02

mg/kg/day

aPAD = 0.02 mg/kg/day Developmental Toxicity study in

rabbits LOAEL = 10 mg/kg/day based on

structural alterations including malformed vertebral body and ribs, arthrogryposis, and multiple

malformations. Acute Dietary (General Population, including infants

and children None None None No observed effects could be attributable to a single dose exposure

. Therefore, a dose and endpoint were not selected for this exposure scenario.

Chronic Dietary (All Populations) NOAEL=1.1

mg/kg/day UF A =10X

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

0.01 mg/kg/day

cPAD = 0.01 mg/kg/day Chronic/Oncogenicity study in rats

LOAEL = 8.0 mg/kg/day based on liver histopathology (hepatocellular vacuolation and fatty change (single cell, centrilobular, and periportal))

. Incidental Oral

Short

- and

Intermediate

Term (1

- 30 days

and 1

- 6 months) N/A N/A N/A Incidental oral exposure endpoint not identified because residential exposure is not anticipated.

Dermal Short

- and

Intermediate

Term (1

- 30 days

and 1

- 6 months) NOAEL=30

mg/kg/day UF A =10X

UF H =10X Occupational

LOC for MOE =

100 Dermal developmental study in rats

LOAEL = 100 mg/kg/day based on an increased incidence of supernumerary rib (14th rib)

. Inhalation Short

and Intermediate

term (1

- 30 days

and 1

- 6 months) NOAEL=2.0

mg/kg/day 1 UF A =10X

UF H =10X Occupational

LOC for MOE =

100 Developmental Toxicity study in

rabbits LOAEL = 10 mg/kg/day based on

structural alterations including malformed vertebral body and ribs, arthrogryposis, a nd multiple

malformations. Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant

tumor increases in two adequate rodent carcinogenicity studies.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human

exposures. LOC = level o f concern. The LOC for occupational exposure to prothioconazole desthio is based on the conventional uncertainty factor of 100 X (UF A = 10 X and UF H = 10 X ). NOAEL = no observed adverse effect level.

LOAEL = lowest observed adverse effect level. UF = unce rtainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic ). RfD = reference dose. MOE = margin of exposure. N/A = not applicable. 1 toxicity via the inhalation route is assumed to be equivalent to oral toxicity.

### Prothioconazole Human Health Risk Assessment DP No. D403739

Page 14 of 48 5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary and Rationale

For purposes of both tolerance enforcement and risk assessment, the residues of concern in plants are the sum of prothioconazole and its desthio metabolite, expressed as parent (see Table 5.1)

. The contribution of triazole derivatives ( 1,2,4

- T

, TA, and TA A ) from prothioconazole to the aggregate exposure for human

- health risk assessment has been considered ( DP411386

, T.

Morton

, 05/01/ 20 13 ). Furthermore, the residues of concern in rotational crops for tolerance enforcement and risk assessment purposes are t he same as in primary crops, parent and prothioconazole

- desthio

.

F or purposes of tolerance enforcement

, the residue of concern in livestock commodities consists of the sum of prothioconazole, the desthio metabolite, and conjugates that can be converted to either of these two compounds by acid hydrolysis, calculated as prothioconazole. For purposes

of risk assessment

, the residue of concern consists of prothioconazole, the desthio metabolite, the

4

- hydrox y prothioconazole metabolite, and conjugates that can be converted to any of these three compounds by acid hydro l ysis.

As documented in previous prothioconazole assessments, a total toxic residues approach was used for drinking water exposure modeling. Combined residues of concern inclu de the parent, prothioconazole

- desthio, and prothioconazole

- S

- methyl (D 378763, B. O ’K eefe, 01/31/2011)

.

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

.

Matrix Residues included in Risk

Assessment Residues included in Tolerance Expression

Plants Primary Crop s and

Rotational Crop s S um of P rothioconazole and its desthio metabolite, expressed

as parent S um of P rothioconazole and

its desthio metabolite, expressed as parent

Livestock Ruminant and Poultry P rothioconazole, the desthio metabolite, the 4

- hydroxy prothioconazole metabolite, and conjugates that can be converted to any of these three compounds by acid hydrolysis S um of P rothioconazole, the desthio metabolite, and conjugates that can be

converted to either of these two compounds by acid hydrolysis, calculated as prothioconazole

Drinking Water Prothioconazole,

P rothioconazole

- desthio and

P rothioconazole

- S

- methyl Not Applicable



### 5 .2 Food Residue Profile

Bayer submitted adequate blueberry (representative crop for bushberry crop subgroup 13

- 07B); cranberry (representative crop for low growing berry, except strawberry, crop subgroup 13

- 07H);

### Prothioconazole Human Health Risk Assessment DP No. D403739

Page 15 of 48 and cucumber, muskmelon, and summer squash (representative crops for cucurbit vegetables crop group 9) field trial data. The trial number and locations conform to the OCSPP 860.1500 data requirements for establishment of the proposed tolerances. In addit ion, the employed application scenarios (rates, retreatment intervals, and preharvest intervals) adequately represent the proposed application scenarios.

C ombined residues (and per

- trial averages) of p rothioconazole and prothioconazole

- desthio i n/on

blu eberry fruit were <0.092

- 1.07 ppm (0.167

- 1.04 ppm); the combined residues declined as the

PHI increased fro m 0 days to 21 days. C ombined residues (and per

- trial averages) of

p rothioconazole and prothioconazole

- desthio i n/on cranberry fruit were <0.040

- < 0.112 ppm (<0.040

- <0.106 ppm); the combined residues declined as the PHI increased from 35 days to 55 days . C ombined residues (and per

- trial averages) of p rothioconazole and prothioconazole

- desthio

i n/on cucumber, muskmelon

, and summer squash were <0.040

- <0.125 ppm (0.043

- 0.084 ppm),

<0.045

- 0.188 ppm (0.050

- 0.172 ppm), and <0.040

- 0.079 (0.040

- 0.079 ppm), respectively; the

combined residues declined as the PHI increased form 0 days to 21 days. Based on these data and using the OECD tolerance calculation pr ocedure, the following tolerances are appropriate (a revised Section F is requested): bushberry crop subgroup 13

- 07B

- 2.0 ppm ; low growing berry, except strawberry, crop subgroup 13

- 07H

- 0.20 ppm ; and cucurbit vegetables crop group 9

- 0.30 ppm

.

A su mmary of the blueberry, cranberry, cucumber, muskmelon, and summer squash field trial data for prothioconaz ole and prothioconazole

- desthio, and T, TA, and TAA submitted in support of the current petition is provided in Appendix B

.

5.3 Water Residue Profil e

A new drinking water assessment was supplied by EFED (D P405409 , C. Sutton, 1 1 /1 4 / 12 ). EFED provided EDWCs, which were determined using the PRZM

- EXAMS screening model for

surface water from corn applications, the Tier 1 Rice Model for surface water from cranberry applications, and the SCI

- GROW model for ground water.

The values recommended for use in HED’s risk assessment are listed in bold in Table 5.3. The surface water acute EDWC, based on corn use, has increased slightly (from 94.7 to 99.0 ppb) from the most recent DWA due to changes in the PCA factor implemented since that assessment was completed. The chronic EDWCs, based on cranberry use, have incr eased to 91.9 ppb from previous value of 84.3 ppb ( based on the corn use ) . The acute and chronic EDWCs provided for groundwater sources of drinking water (0.83 ppb) have not been updated from the most recent

DWA in which the recommended EDWCs were based o n use on nursery seedlings and were determined using SCI

- GROW.

### Prothioconazole Human Health Risk Assessment DP No. D403739

Page 16 of 48 Table 5.3 Estimated P rothioconazole Drinking Water Concentrations R ecommended for use in Dietary Risk

A ssessment s

.

DRINKING WATER SOURCE (MODEL USED) USE SCENARIO (rate modeled) National PCA ESTIMATED

DRINKING WATER

CONCENTRATION (EDWC) ( ppb)

Groundwater

(SCIGROW) Nursery seedlings

(0.178 1b a.i./A x 5 apps. ) N/A Acute and

Chronic 0.83

Surface Water

( PRZM/EXAMS ) IL Corn

(0.178 1b a.i./A x 4 apps. ) 0.91 Acute

(1

- in

- 10

- year) 99.0

Surface Water

[ Tier 1 Rice Model (with modified depth) ] Cranberry

(0.156 lb a.i./A x 2 apps. ) N/A Chronic 1 91.9

1 Exposure estimates for use on cranberries are for a single year, not 1

- in

- 10

- year values.



### 5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Partially refined acute and chronic dietary exposure assessments were conducted for prothioconazole. HED

- recommended tolerance values were used for all of the proposed uses. The acute assessment utilized average fiel d trial residue levels , since all of the plant commodities included in this assessment are blended food forms, except sweet corn. For sweet corn, residues from all field trials were below the LOQ, thus the LOQ was used. The chronic assessment also utilized average field trial residue levels. Empirical processing factors (PFs) and livestock residue values determined from the reasonably balanced dietary burden (RBDB) and the livestock feeding studies were in corporated. U pper bound EDWC for surface water sources impacted by corn uses provided by EFED was included in the acute assessment

. Upper bound EDWC value for surface water sources impacted by the rice uses was included in the chronic

assessment.

5.4.2 Percent Crop Treated Used in Dietary Assessment

100 percent crop treated was assumed in both the acute and chronic dietary assessments.

5.4.3 Acute Dietary Risk Assessment

Since the selected acute dietary endpoint is only relevant for females of childbearing ages,

f emales 13

- 49 years of age was the only population subgroup included in the acute assessment

. The acute dietary exposure analys i s result s in acute dietary risk estimates that is below the Agency’s level of concern for food and drinking water. The exposure for food plus drinking

water estimate was 0.006029 mg/ kg/day, which utilized 30 % of the acute population adjusted

### Prothioconazole Human Health Risk Assessment DP No. D403739

Page 17 of 48 dose ( aPAD ) for female s 13

- 49 yrs old at the 95 th 

### percentile

. Table 5.4.6 summarizes the acute dietary exposure and risk to prothioconazole

.

5.4.4 Chronic Dietary Risk Assessment

The dietary exposure analyses result in chronic dietary risk estimates that are below the Agency ’s level of concern

. The highest exposure for food plus drinking water estimate was 0.005709 mg/kg/day, which utilized 57% of the cPAD for all infants (< 1 year old) population subgroup. The exposure for food plus upper bound drinking water estimate was 0 .002392 mg/kg/day

, which utiliz ed 24 % of the cPAD for the General U.S. Population. Table 5.4.6 summarizes the chronic dietary exposures and risks to prothioconazole.

5.4.5 Summary Table

Table 5.4.6 . Summary of Dietary (Food and Drinking Water, or Drinking Water Only) Exposure and Risk for Prothioconazole

Population Subgroup Acute Dietary ( 95th Percentile) Chronic Dietary

Dietary Exposure (mg/kg/day) % aPAD* Dietary Exposure (mg/kg/day) % cPAD*

General U.S. Population

NA NA 0.00239 2 24

All Infants (<1 year old) 0.00570 9 57

Children 1

- 2 years old 0.004 404 44

Children 3

- 5 years old 0.00353 5 35

Children 6

- 12 years old 0.00245 7 25

Youth 13

- 19 years old 0.00179 5 18

Adults 20

- 49 years old 0.0022 70 23

Adults 50

- 99 years old 0.0022 40 22

Females 13

- 49 years old 0.0060 29 30 0.002265 23
*The subpopulation s with the highest risk estimate are highlighted in bold print



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

6.1 Residential Handler and Post

- Application Exposure

This document addresses t he proposed new agricultural uses of prothioconazole

. There are no proposed or registered residential uses of prothioconazole, therefore a residential risk assessment

has not been conducted.

6.2 Residential Bystander Post

- application Inhalation Exposure

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

- application inhalation exposure assessment was not performed for prothioconazole at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure ( 3.00 × 10 - 9 

### mmHg a t 20oC), and the low proposed use rate (0.18 lb ai/A). However, volatilization of pesticides may be a source of post

- application inhalation exposure to individua ls nearby pesticide applications.

### Prothioconazole Human Health Risk Assessment DP No. D403739

Page 18 of 48 The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the S AP’s final report on March 2, 2010 1 

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

- application inhalation

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

- application inhalation exposure assessment for prothioconazole.

6.2 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for prothioconazole

. T he Agency has been working with the Spray Drift Task Force, EPA Regional Offices

, and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more informa tion 2 

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

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

off

- target drift with specific products with significant risk e stimates associated with drift.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking 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 themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

7.1 Acute Aggregate Risk

HED’s c urrent practice is to include only food and water in the acute aggregate assessment. See

section 5.4.3 for a detailed discussion of the acute d ietary assessment.

7.2 Short

- and Intermediate

- Term Aggregate Risk

For this action, there is potential exposure to prothioconazole from food and drinking water, but not from residential use sites, as there are no proposed, or existing, residential uses for prothioconazole. Thus , a short

- and intermediate

- term aggregate risk assessment was not necessary to conduct.

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

2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm

### Prothioconazole Human Health Risk Assessment DP No. D403739

Page 19 of 48 7.3 Chronic Aggregate Risk

Chronic or long

- term aggregate assessments include exposures that will exceed six months.

HED’s c urrent practice is to include only food and water in t he chronic aggregate assessment.

See section 5.4.4 for a detailed discussion of the chronic dietary assessment.

8.0 Cumulative Exposure/Risk Characterization

Prothioconazole is a member of the triazole

- containing class of pesticides, often referred to as the triazoles. EPA is not currently following a cumulative risk approach based on a common mechanism of toxicity for the conazoles. The conazole pesticides, as a whole, tend to exhibit carcinogenic, developmental, repr oductive, and/or neurological effects in mammals. Additionally, all the members of this class of compounds are capable of forming, via environmental and metabolic activities, 1,2,4

- triazole, triazolylalanine and/or triazolylacetic acid.

These metabolites have also been shown to cause developmental, reproductive, and/or neurological effects. Structural similarities and sharing a common effect does not constitute a common mechanism of toxicity. Evidence is needed to establish that the chemicals operate “b y the same, or essentially the same sequence of major biochemical events. Hence, the underlying basis of toxicity is the same, or essentially the same, for each chemical” (EPA, 2002.) A number of potential events could contribute to the toxicity of conaz oles (e.g., altered cholesterol levels, stress responses, altered DNA methylation). At this time, there is not sufficient evidence to determine whether conazoles share common mechanisms of toxicity. Without such understanding, there is no basis to make a common mechanism of toxicity finding for the diverse range of effects found. Investigations into the conazoles are currently being undertaken by the EPA’s Office of Research and Development. When the results of this research are available, the Agency wi ll make a determination of whether there is a common mechanism of toxicity and, therefore, a basis for assessing cumulative risk. For information regarding EPA’s procedures for cumulating effects from substances found to have a common mechanism of toxicit y, see EPA’s website at http://www.epa.gov/pesticides/cumulative.

To support existing tolerances and to establish new tolerances for conazole pesticides, including prothioconazole, EPA conducted human health risk assessments for exposure to 1,2

, 4

- triazole

, triazolylalanine, and triazolylacetic acid resulting from the use of all current and pending uses of

triazole

- containing pesticides ( T. Morton, D411385, 05/01/2013). The risk assessment is a highly conservative, screening

- level evaluation in terms of ha zards associated with the common metabolites (e.g., use of maximum combination of uncertainty factors) and potential dietary and

non

- dietary exposures (i.e., high

- end estimates of both dietary and non

- dietary exposures). Acute and chronic aggregate risk e stimates associated with these compounds are below the Agency's level of concern for all durations of exposure and for all population subgroups, including those of infants and children. The Agency's risk assessment for these common

metabolites is availabl e in the propiconazole reregistration docket at http://www.regulations.gov, Docket Identification (ID) Number EPA

- HQ

- OPP

- 2005

- 0497.

### Prothioconazole Human Health Risk Assessment DP No. D403739

Page 20 of 48 9.0 Occupational Exposure/Risk Characterization

9.1 Short

- and Intermediate

- Term Handler Risk

Based on application rate and label information, occupational handler exposure is expected to

occur for short

- and intermediate

- term durations. Chronic exposure is not expected for the proposed use patterns. Applicators and other handlers of Proline must wear long sleeved shirts, long pants, chemical resistant gloves made of waterproof material, shoes, and socks. Occupational handler exposures of the proposed prothioconazole uses were assessed at maximum appl ication rates using ground, chemig ation, airblast, and handheld equipment while wearing labeled PPE.

The occupational handler exposure and risk estimates indicate that short

- and intermediate

- term dermal and inhalation MOEs are not of concern to HED (i.e. , MOEs > 100) with the PPE required on the Proline label. Wearing baseline attire, the combined dermal and inhalation MOEs for all proposed use sites ranged from 84 to 2,000. Wearing baseline attire and gloves,

the combined dermal and inhalation MOEs for all proposed use sites ranged from 170 to 7,600.

### Prothioconazole Human Health Risk Assessment DP No. D403739

Page 21 of 48 Table 9 .1.1 . Occupational Handler Short

- and Intermediate

- Term Exposure and Risk Estimates for Prothioconazole at Baseline PPE

.

Exposure Scenario Crop or Target Dermal Unit

Exposure ( μ g/lb ai) 1 Inhalation Unit

Exposure ( μ g/lb ai) 1 Maximum

Application

Rate 2 Area

Treated or

Amount

Handled Daily 3 Dermal Inhalation Total

Baseline Baseline Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Mixer/Loader

Mixing/Loading Liquids for Chemigation Application Bushberries,

Cucurbits 220 0.219 0.18 lb ai/A 350 Acres 0.201 150 0.00020 10,000 150

Low Growing Berry (except Strawberry) 220 0.219 0.16 lb ai/A 350 Acres 0.178 170 0.00018 11,000 170

Mixing /Loading Liquids

for Groundboom Application Bushberries,

Cucurbits 220 0.219 0.18 lb ai/A 80 Acres 0.046 650 0.000046 44,000 640

Low Growing Berry (except Strawberry) 220 0.219 0.16 lb ai/A 80 Acres 0.041 730 0.000041 49,000 720

Mixing /Loading Liquids for Airblast Application Bushberries 220 0.219 0.18 lb ai/A 40 Acres 3.19 1,300 0.0000229 87,000 1,300

Applicator

Applying Sprays

– Groundboom Bushberries,

Cucurbits 78.6 0.34 0.18 lb ai/A 80 Acres 0.016 1,800 0.000071 28,000 1,700

Low Growing Berry (except Strawberry) 78.6 0.34 0.16 lb ai/A 80 Acres 0.015 2,100 0.000063 32,000 2,000

Applying Sprays

– Airblast Bushberries 1,770 4.17 0.18 lb ai/A 40 Acres 0.184 160 0.000491 4,100 150

Mixer/ L oader/Applicator

Mixing/Loading Applying Sprays with Mechanically Pressurized Handgun (foliar) Bushberries,

Cucurbits 1300 3.9 0.018

lb ai/Gal 1,000

Gallons 0.34 88 0.00102 2,000 84

Low Growing Berry (except Strawberry) 1300 3.9 0.016

lb ai/Gal 1,000

Gallons 0.29 100 0.00088 2,300 96

Mixing/Loading Applying Sprays with Mechanically Pressurized Handgun (Soil Drench) Cucurbits 1300 3.9 0.018

lb ai/Gal 1,000

Gallons 0.34 89 0.00101 2,000 85

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( 3/2012 ); Level of mitigation: Baseline.

### Prothioconazole Human Health Risk Assessment DP No. D403739

Page 22 of 48 2 Based on registered or proposed label (Reg. No. 264

- 825 ).

3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Ar ea Treated or Amount Handled (A or gal/day) ÷ BW ( 69 kg).

5 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day). Dermal NOAEL = 30 mg/kg/day.

6 Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ BW ( 69 kg).

7 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). Inhalation NOAEL = 2 mg/kg/day.

8 Total MOE = 1 ÷ (1/Dermal MOE + 1/Inhalatio n MOE).

### Prothioconazole Human Health Risk Assessment DP No. D403739

Page 23 of 48 Table 9 .1. 2

. Occupational Handler Short

- and Intermediate

- Term Exposure and Risk Estimates for Prothioconazole with Label

- Specified PPE (Gloves)

.

Exposure Scenario Crop or Target Dermal Unit

Exposure ( μ g/lb ai) 1 Inhalation Unit

Exposure ( μ g/lb ai) 1 Maximum

Application

Rate 2 Area

Treated or

Amount

Handled Daily 3 Dermal Inhalation Total

Gloves Baseline Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Mixer/Loader

Mixing/Loading Liquids for Chemigation Application Bushberries,

Cucurbits 37.6 0.219 0.18 lb ai/A 350 Acres 0.034 870 0.00020 10,000 800

Low Growing Berry (except Strawberry) 37.6 0.219 0.16 lb ai/A 350 Acres 0.031 980 0.00018 11,000 900

Mixing /Loading Liquids

for Groundboom Application Bushberries,

Cucurbits 37.6 0.219 0.18 lb ai/A 80 Acres 0.0078 3,800 0.000046 44,000 3,500

Low Growing Berry (except Strawberry) 37.6 0.219 0.16 lb ai/A 80 Acres 0.0070 4,300 0.000041 49,000 4,000

Mixing/Loading Liquids for Airblast Application Bushberries 37.6 0.219 0.18 lb ai/A 40 Acres 0.00393 7,600 0.0000229 87,000 7,000

Applicator

Applying Sprays

– Groundboom Bushberries,

Cucurbits 16.1 0.34 0.18 lb ai/A 80 Acres 0.0034 8,900 0.000071 28,000 6,800

Low Growing Berry (except Strawberry) 16.1 0.34 0.16 lb ai/A 80 Acres 0.0030 10,000 0.000063 32,000 7,600

Applyi ng Sprays

– Airblast Bushberries 1590 4.71 0.18 lb ai/A 40 Acres 0.165 180 0.000491 4,100 170

Mixer/ L oader/Applicator

Mixing/Loading Applying Sprays with Mechanically Pressurized Handgun (foliar) Bushberries,

Cucurbits 390 3.9 0.018

lb ai/Gal 1,000

Gallons 0.102 290 0.00102 2,000 250

Low Growing Berry (except Strawberry) 390 3.9 0.016

lb ai/Gal 1,000

Gallons 0.088 340 0.00088 2,300 300

Mixing/Loading Applying Sprays with Mechanically Pressurized Handgun (Soil Drench) Cucurbits

390 3.9 0.018

lb ai/Gal 1,000

Gallons 0.101 300 0.00101 2,000 260

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( 3/2012 ); Level of mitigation: Gloves, No Respirator

.

### Prothioconazole Human Health Risk Assessment DP No. D403739

Page 24 of 48 2 Based on registered or proposed label (Reg. No. 264

- 825 ).

3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ BW ( 69 kg).

5 Dermal MOE = Dermal NOAE L (mg/kg/day) ÷ Dermal Dose (mg/kg/day). Dermal NOAEL = 30 mg/kg/day.

6 Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ BW ( 69 kg).

7 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). Inhalation NOAEL = 2 mg/kg/day.

8 Total MOE = 1 ÷ (1/Dermal MOE + 1/Inhalation MOE).

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 25 of 48 9.2 Short

- and Intermedia te

- Term Post

- Application Risk

9.2.1 Dermal Post

- application Risk

Based on the proposed prothioconazole use pattern for bushberries, low growing berries, and cucurbits, post

- application short

- and intermediate

- term dermal exposures are expected. HED utilized maximum application rates, standard val ues for exposure time and transfer coefficients,

and chemical

- specific data for dislodgeable foliar residue ( DFR ) values. The DFR data were

used to calculate DFR estimates for dry beans , and were extrapolated to those crops for which no

DFR data are avail able.

On the day of application, the occupational dermal post

- application MOEs ranged from 210 to 6,300 and are not of concern to HED. These estimates can be considered conservative because the highest measured DFR value was extrapolated to all crops. A more refined assessment would match measured available DFR values with similar crops.

Table 9.2. Post

- A pplication Short

- and Intermediate

- Term Exposure and Risk for Prothioconazole.

Crop Activity Transfer

Coefficient a (cm 2 /hr) DAT b DFR c (μg/cm 2 ) Short

- Term

Daily

Dermal

Dose d
(mg/kg/day) MOE e

Bushberries Hand weeding 70 0 (12 hours) 0. 664 0.00539 5,600

Transplanting 230 0 (12 hours) 0. 664 0.0177 1,700

Scouting, Hand pruning, Hand weeding, Bird control, Frost control 640 0 (12 hours) 0. 664 0.0493 610

Hand harvesting (low crop height,

full foliage) 1100 0 (12 hours) 0. 664 0 .0847 350

Hand harvesting (high crop height,

full foliage) 1400 0 (12 hours) 0. 664 0.108 280

Hand set irrigation 1900 0 (12 hours) 0. 664 0.146 210

Cucurbits Scouting, Hand weeding, Thinning

fruit, Hand pruning, Turning,

Training 90 0 (12 hours) 0. 664 0.00693 4,300

Transplanting, Mechanically assisted harvesting 230 0 (12 hours) 0. 664 0.0177 1,700

Hand harvesting, Turning 550 0 (12 hours) 0. 664 0.0423 710

Hand set irrigation 1900 0 (12 hours) 0. 664 0.146 210

Low Growing

Berries Hand pruning (shears), Hand weeding 70 0 (12 hours) 0.59 0.00479 6,300

Transplanting 230 0 (12 hours) 0.59 0.0157 1,900

Hand harvesting (raking), scouting 1100 0 (12 hours) 0.59 0.0752 400

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 26 of 48 a Transfer coefficients and associated activities from ExpoSAC SOP No. 003.1 “Agricultural Transfer Coefficients

, ” 8/17/2000.

b DAT = Days after treatment needed to reach the LOC of 100; DAT 0 = the day of treatment, after sprays have dried; assumed to be approximately 12 hours.

c DFR (μg/cm 2 ) based on MRID 47002601

. d Daily Dose = [(DFR x TC x Dermal absorption x 8

- hr Exposure Time)] / [(CF: 1000 μg/mg) x ( 69 kg Body Weight)] ( D ermal absorption factor = 100 % ).

e M OE = NOAEL/Daily Dose (Short

- and Intermediate

- T erm Dermal NOAEL = 30 mg/kg/day 

### )

.

The REI specified on the proposed label is based on the acute toxicity of prothioc onazole.

Prothioconazole is classified as Toxicity Category III via the dermal route and Toxicity Category IV for skin irritation potential. It is not a skin sensitizer. Prothioconazole

- D esthio is classified as Toxicity Category III via the dermal route and Toxicity Category III for skin irritation potential and is a slight skin irritant. Short

- and intermediate

- term post

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

- application activities.

Under 4 0 CFR 156.208 (c) (2) (iii), active ingredient’s classified as Acute III or IV for acute dermal, eye irritation and primary skin irrigation are assigned a 12

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

- application exposures to prothioconazole.

9.2.2 Inhalation Post

- application Risk

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

- application inhalation exposure assessment was not perform ed for prothioconazole at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure ( 3.00 × 10 - 9 

### mm Hg at
20oC ), and the low proposed use rate (0.18 lb ai/A). However, there are multiple potential

sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides . The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 20 10 3 

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

- application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the wa y to incorporate occupational post

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

- application inhalation exposure a ssessment for prothioconazole.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from a pplication of pesticides outdoors is likely to result in higher exposure than post

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

- application inhalation exposu re scenarios.

10.0 References

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

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 27 of 48 Bloem, T., 02/26/2013, DP#405653, Prothioconazole. Section 3 Registration Concerning Application to Bushberry Crop Subgroup 13

- 07B; Low Growing Berry, Except Strawberry, Crop Subgroup 13

- 07H; and Cucurbit Vegetables Crop Gro up 9. Summary of Analytical Chemistry

and Residue Data.

Morton, T., 05/01/2013, DP#411385, Common Triazole Metabolites: Updated Dietary (Food + Water) Exposure and Risk Assessment to Address The New Section 3 Registrations For Use of
Prothioconazole o n Bushberry Crop Subgroup 13

- 07B, Low Growing Berry, Except Strawberry, Crop Subgroup 13

- 07H, and Cucurbit Vegetables Crop Group 9; Use of Flutriafol on Coffee; and Ipconazole on Crop Group 6

.

Morton, T., 05/01/2013, DP#411386, Common Triazole Metabolites : Updated Aggregate

Human Health Risk Assessment to Address The New Section 3 Registrations For Use of Prothioconazole on Bushberry Crop Subgroup 13

- 07B, Low Growing Berry, Except Strawberry, Crop Subgroup 13

- 07H, and Cucurbit Vegetables Crop Group 9; Use of Flutriafol on Coffee; and Ipconazole on Crop Group 6

.

Negussie, M., 05/15/2013, DP#407465, Prothioconazole: Submission of Conditional data Requirement on Storage Stability and Analytical Methods of Plants and Ruminants.

Rury, K., 02/08/2013, DP #403739, Prothioconazole. Occupational and Residential Exposure Assessment for Proposed Uses on Low Growing Berry Subgroup (except Strawberry), Bushberry Subgroup, and Cucurbit Vegetables.

Sutton, C., 11/14/2012, DP#113961, Drinking Water Assessment in S upport of the Proposed Prothioconazole Section 3 New Uses on Bushberry (Crop Subgroup 13

- 07B), Low Growing Berry Subgroup, Except Strawberry (Crop Subgroup 13

- 07H) and Cucurbit Vegetables (Crop Group 9).

Walls, C., 05/28/2013, DP#405654, Prothioconazole: Acute and Chronic Aggregate Dietary Exposure and Risk Assessments for the Section Registration Action on Low Growing Berry Subgroup (except Strawberry), Bushberry Subgroup, and Cucurbit Vegetables.

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 28 of 48 A ppendix A

. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements
The requirements (40 CFR 158.340) for Food of Use Prothioconazole are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Primary Eye Irritation

................................ .................... 870.2500 Primary Dermal Irritation

................................ .............. 870.2600 Dermal Sensitization

................................ ...................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent)

................................ ......... 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

................................ .......................... yes

yes

yes

yes yes

yes

yes

waived

870.3700a Developmental Toxicity (rodent)

................................ ... 870.3700b Developmental Toxicity (nonrodent)

............................. 870.3800 Reproduction

................................ ................................ . yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (nonrodent)

................................ ........ 870.4200a Oncogenicity (rat)

................................ .......................... 870.4200b Oncogenicity (mouse)

................................ .................... 870.4300 Chronic/Oncogenicity

................................ .................... yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

................ 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations

... 870.5xxx Mutagenicity

— Other Genotoxic Effects

....................... yes

yes

yes

ye s yes

yes

yes

yes

870.6100a Acute Delayed Neurotox icity (hen)

............................... 870.6100b 90

- Day Neurotoxicity (hen)

................................ ........... 870.6200a Acute Neurotox icity Screening Battery (rat)

................. 870.6200b 90

- Day Neuro toxicity Screening Battery (rat)

............... 870.6300 Develop. Neuro toxicity

................................ ................. no

no

yes

ye s

yes -

- yes

ye s

yes

870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

no

yes yes

-

yes

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 29 of 48 A.2 Toxicity Profile s

Table A.2.1. Acute Toxicity of Prothioconazole technical and Desthio

Prothioconazole technical

Guideline Study Species Results Tox. Category MRID No.

Prothioconazole

870.1100 Acute oral

toxicity Rat LD 50 >= 6200 mg/kg (M, F) IV 46246230

870.1200 Acute dermal

toxicity Rat LD 50 >= 2000 mg/kg (M, F) III 46246244

870.1300 Acute inhalation

toxicity Rat LC 50 >= 4.99 mg/L

(M, F) IV 46246246

870.2400 Primary eye

irritation Rabbit Not an irritant IV 46246249

870.2500 Primary skin

irritation Rabbit Not an irritant IV 46246302

870.2600 Dermal

sensitization Guinea Pig Not a sensitizer Negative 46246305

Desthio

- prothioconazole

870.1100 Acute oral

toxicity Rat LD 50 = 2806 mg/kg (M, F) (approximate) III 46246231

870.1100 Acute oral

toxicity Mouse LD 50 = 2235 mg/kg (Males)

LD 50 = 3459 mg/kg (Females) III 46246242

870.1200 Acute dermal

toxicity Rat LD 50 >= 5000 mg/kg (M,F) IV 46246243

870.1300 Acute inhalation

toxicity Rat LC 50 >= 5.077 mg/L (M,F) IV 46246247

870.2400 Primary eye

irritation Rabbit Slight irritant (iritis, discharge) III 46246250

870.2500 Primary skin

irritation Rabbit Not an irritant IV 46246250

870.2600 Dermal

sensitization Guinea Pig Not a sensitizer Negative 46246304

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 30 of 48 Table A.2.2. Toxicity Profile for Prothioconazole (JAU6476) Technical

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3100

90

- day oral toxicity rodents (rat) 46246311 (1999)

0, 20, 100, 500 mg/kg/day

Acceptable/Guideline NOAEL = 100 mg/kg/day LOAEL = 500 mg/kg/day based on increased water consumption (males and females), increased cholesterol (males and females), liver effects [increased liver weights (females), hepatocellular hypertrophy (males and females) and cytoplasmic change (males and fe males)] and kidney effects [decreased urinary volume (males and females), increased urine protein levels (males and females), and the increased incidence and severity of basophilic tubules of the renal cortex (males)].

870.3100

90

- Day oral toxicity

rodent s (mouse) 46246427 (1999)

0, 25, 100, 400 mg/kg/day

Acceptable/Guideline NOAEL = 25 mg/kg/day LOAEL = 100 mg/kg/day based on increased cholesterol levels and increased liver enzyme activity in females, increased liver weights in both sexes, and increased incidence of hepatocellular hypertrophy and cytoplasmic change in the

liver of both sexes.

870.3100

28

- Day oral toxicity rodents (rat) 46246429 (1998)

0, 10000 ppm in both neat

or stabilized diet 0, 1000 mg/kg/day by

gavage Acceptable/Nonguideline No NOAEL or LOAEL were determined as this was a nonguideline study to compare routes of administration. Observations included clinical signs of toxicity, changes in BW, BWG, FC; liver and kidney effects (wt, histopathology), clinical chemistry changes.

8 70.3100

28

- Day oral toxicity rodents (rat) 46246428 (1997)

0, 400, 2000, 10000 ppm 0, 18.6/18.8, 145.7/151.0,

or 951.7/1032.5 (M/F) mg/kg/day

Acceptable/Nonguideline No NOAEL or LOAEL were determined. Observations included changes in body wt, food

consum ption, liver and kidney effects, clinical chemistry.

870.3150

90

- day oral toxicity nonrodents (dog) 46246435 (2000)

0, 25, 100, 300 mg/kg/day
Acceptable/Nonguideline No NOAEL or LOAEL were determined in this study, the specific observations included effects on liver and kidney enzyme activities and tissues concentrations of parent and metabolites were determined. This study included a 4 week recovery phase.

870.3150

90

- day oral toxicity nonrodents (dog) 46426313 (2001)

0, 25, 100, 300 mg/kg/day

Acc eptable/Guideline NOAEL = 25 mg/kg/day LOAEL = 100 mg/kg/day based on kidney (histopathological) and thyroid (T4 and TSH) findings at 100 mg/kg. This study included a 4 week recovery phase.

870.3200

21/28

- Day dermal toxicity (rat) 46426315 (2000)

0, 100, 300, 1000 mg/kg

Acceptable/Guideline NOAEL = 1000 mg/kg/day LOAEL > 1000 mg/kg/day

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 31 of 48 Table A.2.2. Toxicity Profile for Prothioconazole (JAU6476) Technical

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3700a Prenatal develop

mental in rats

– oral 46246316 (1996)

0, 80, 500, 1000 mg/kg/day

Acceptable/Guideline Maternal Toxicity NOAEL = 80 mg/kg/day LOAEL = 500 mg/kg/day based on increased urination and water consumption, and decreased body weight gain

. Developmental Toxicity NOAEL = 80 mg/kg/day LOAEL = 500 mg/kg/day based on increased incidence of delayed ossification, increased incidence of dyspla stic pubic bone, and increased incidence of left punctiform 14 th rib.

870.3700a
Prenatal develop

mental in rats

– oral 46246317 (2002)

0, 40, 200, 1000 mg/kg/day

Acceptable/Nonguideline Range finding study for above, no endpoints were

determined.

870.3700a Prenatal develop

mental in rodents (rat)

- dermal 46246323 (2001)

0, Technical 1000 mg/kg/day, 62.5 mg/kg/day diluted EC 250 formulation, 250 mg/kg/day EC 250

formulation

Acceptable/Nonguideline Maternal Toxicity NOAEL > 1000 mg/kg/day

L OAEL > 1000 mg/kg/day Developmental Toxicity NOAEL = 1000 mg/kg/day LOAEL > 1000 mg/kg/day

870.3700a
Prenatal develop

mental in rats

– oral 46923601 (2004)

0, 20, 80, 750 mg/kg/day

Acceptable/Nonguideline Maternal Toxicity NOAEL = 80 mg/kg/day LOAEL = 750 mg/kg/day based on increased water consumption, decreased food consumption and decreased body weight gain

.

Developmental Toxicity NOAEL = 80 mg/kg/day
LOAEL = 750 mg/kg/day based on increased incidence of rudimentary ribs (comma

- shaped).

870.3700b Prenatal develop

mental in nonrodents (rabbit) 46246330 (1997)

0, 80, 100, 300, 480 mg/kg/day pilot study

Acceptable/Nonguideline Maternal Toxicity NOAEL < 80 mg/kg/day LOAEL = 80 mg/kg/day based on reduced food consumption and body wts. Develop menta l NOAEL = 300 mg/kg/day LOAEL = 480 mg/kg/day based on decreased body wt, and

small fetuses.

870.3700b Prenatal develop

mental in nonrodents (rabbit) 46246328 (1998)

0, 10, 30, 80, 350* mg/kg/day * Additional group added after start of study

Acceptable/Guideline Maternal Toxicity NOAEL = 80 mg/kg/day LOAEL = 350 mg/kg/day based on decreased body wt and decreased food consumption. Developmental Toxicity NOAEL = 80 mg/kg/day LOAEL = 350 mg/kg/day based on abortions, total resorptions, and lower fetal body weight

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 32 of 48 Table A.2.2. Toxicity Profile for Prothioconazole (JAU6476) Technical

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3800 Reproduction and fertility effects 46246331 (1999)

0, 10, 100, 250, 500 mg/kg/day (pilot)

Acceptable/Nonguideline Parental Toxicity NOAEL = 250 mg/kg/day LOAEL = 500 mg/kg/day based on clinical signs (urine stain) Reproductive Toxicity NOAEL = 500 mg/kg/day LOAEL > 500 mg/kg/day Offspring Toxicity NOAEL = 500 mg/kg/day LOAEL > 500 mg/kg/day

870.3800 Reproduction and fertility effects 46246334 (2001)

0, 10, 100, 750 mg/kg/day

Combined with MRID

46246331

Acceptable/Guideline Parental Toxicity NOAEL = 100 mg/kg/day LOAEL = 750 mg/kg/day based on decreased body weights, body weight gains and increased food consumption, increased liver weights and kidney weights, decreased thymus, testicular, prostate, epicauda and epididymis w eights as well as histopathological findings in the liver and kidney. Reproductive Toxicity NOAEL = 100 mg/kg/day LOAEL = 750 mg/kg/day based on decreased number of estrous cycles in both generations and increased duration of estrous cycle in the P genera tion

. Offspring Toxicity NOAEL = 100 mg/kg/day LOAEL = 750 mg/kg/day based on decreased pup body weight and spleen wt.

870.4100a Chronic toxicity rodents (rat) 46246335 (2000)

0, 5, 50, 750 mg/kg/day Rat, 53 weeks

Acceptable/Guideline NOAEL = 50 mg/kg/day LOAEL = 750 mg/kg/day based on decreased body weight and body weight gain, alterations in hematology and clinical chemistry parameters indicative of liver and kidney damage, increased liver and kidney weights, and accompanying histopathological a lterations in the liver, kidney and urinary

bladder. FOB conducted at 27 and 52 weeks.

870.4100b Chronic toxicity

non

- rodent (dog) 46246336 (2001)

0, 5, 40, 125 mg/kg/day

one year

Acceptable/Guideline NOAEL = 5 mg/kg/day LOAEL = 40 mg/kg/day based on decreased T3 and T4 thyroid hormones, increased urine volume, and increased incidence of chronic inflammation and pigmentation in the kidneys of the male animals, and decreased T4 thyroid hormone, increased spleen weight, increased incidence of spleen pigm entation, and increased incidence of crystals present in the kidneys of the female animals.

870.4200 Carcinogenicity rats 46246338 (2001)

M: 0, 5, 50, 750/500 mg/kg/day F: 0,5,50,750/625 mg/kg/day

106 weeks

Unacceptable/Guideline

for Carcinogenicity

because dose levels too high. NOAEL = 50 mg/kg/day LOAEL = 500/625 (M/F) mg/kg/day based on increased mortality and decreased body weight/body weight gain, changes in clinical chemistry (APh, creatinine, urea) and hematological parameters , increased liver and kidney weights, and liver (hypertrophy and eosinophilic/clear cell focus) and kidney/urinary bladder pathology.

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 33 of 48 Table A.2.2. Toxicity Profile for Prothioconazole (JAU6476) Technical

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.4300 Carcinogenicity mice 46246339 (2001)

0, 10, 70, 500 mg/kg/day

80 weeks

Acceptable/Guideline NOAEL = 10 mg/kg/day LOAEL = 70 mg/kg/day based on kidney (tubular degeneration/regeneration in males) effects.

No evidence of carcinogenicity

870.6200a Acute neurotoxicity screening battery 46246417 (2000)

0, 200, 750, 2000 mg/kg/day

Acceptable/Guideline NOAEL = 200/750 (M/F) mg/kg/day LOAEL = 750/2000 (M/F) based on the transient effect of reduced motor and locomotor activity.

870.6200b

Subchronic neurotoxicity screening battery 46246416 (2001)

0, 100, 500, 1000 mg/kg/day

Acceptable/Guideline Systemic Toxicity NOAEL = 500 mg/kg/day LOAEL = 1000 mg/kg/day based on decreased body weight & body weight gain in males. No neurotoxicity was noted at dose levels tested.

870.7600 Dermal Absorption 46246426 (1997)

Rat N= 10 Pilot Study Absorption rate

49.41%

870.7600 Dermal Absorption 46246423 (2003)

Monkey N = 1 Pilot Study Absorption rate

4.06%

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 34 of 48 Table A.2.2. Toxicity Profile for Prothioconazole (JAU6476) Technical

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.7485

Metabolism 46246421 (2001)

Acceptable/Guideline JAU6476 was extensively metabolised in the rat following oral administration. Eighteen metabolites and the parent compound were identified in urine, faeces and bile. The biotransformation of JAU6476 consisted of 3 major reaction types including desulfurati on, oxidative hydroxylation of the phenyl moiety and glucuronic acid conjugation. Identification of the metabolites ranged from 26

- 63% of the administered dose. A higher percentage of metabolite isolation and

identification could not be achieved due to dif ficulties in

fecal extraction where 21

- 33% of the administered dose

remained in non

- extractable residues in the solids. The parent compound JAU6476 was the most abundant in the faeces (1

- 22% of the administered dose), followed by the JAU6476

- desthio metabo lite (3

- 18% of the administered dose). All other fecal metabolites represented less than 8% of the administered dose. The 1, 2, 4

- triazole metabolite was not detected in the faeces. The major urinary metabolite was

JAU6476

- S

- or O

- glucuronide (0.1

- 8% of th e administered dose) and was preferentially excreted in females. The 1, 2, 4

- triazole metabolite represented 0.8

- 2.3% of the administered dose following administration of single oral low and/or high doses. The remaining urinary metabolites each accounted f or 0

- 1.4% of the administered dose. JAU6476

- S

- or O

glucuronide was the most abundant metabolite in the bile, representing approximately 46% of the administered dose. This metabolite was excreted in females only in the urine;

however it was noted in the bi le in males. Desthio glucuronic acid metabolites in the bile represented 8

- 10% of the administered dose. Parent compound represented 3

- 5% of the administered dose in the bile. The 1, 2, 4

- triazole metabolite

was not detected in the bile.

870.7485

Metabolism 46246419 (2001)

Acceptable/Nonguideline The whole body autoradiography results are in agreement with the absorption, distribution and excretion pattern of JAU6476 in the main metabolism study (MRID 4624642 1). In summary, peak concentrations in males were noted 1 hour

post

- administration and continued to decline until sacrifice at 168 hours. In females, absorption was slightly delayed with peak concentrations in some tissues noted at 8 hours post

administrat ion. The highest concentrations were noted in liver (up to 1.78 μg/g in males and up to 0.97 μg/g in females), followed by kidney (renal medulla, up to 0.64 μg/g), brown/perirenal fat (up to 0.36 μg/g), thyroid (up to 0.23 μg/g) and adrenal gland (up to 0. 27 μg/g). All other tissues showed peak concentrations of <0.13 μg/g. Concentrations of radioactivity decreased rapidly from 24 to 168 hours post

administration, indicative of continued elimination from the

tissues.

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 35 of 48 Table A.2.2. Toxicity Profile for Prothioconazole (JAU6476) Technical

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.7800

Immunoto xicity 46246438 (2002)

Acceptable/Nonguideline Piloerection was noted in the high

- dose males from days 13

- 21.There were no significant effects on body weight, food consumption or spleen weights. Under the conditions of this study, JAU 6476 did not suppress the humoral immune response in a dose

- dependent manner in that it did not significantly decrease the IgM antibody

- forming cell response to the T

- dependent antigen (sheep erythrocytes). An increase in plaque

- forming cells was noted in the high

dose males (↑125%).

870.5100

Bacterial reverse

mutation test 462463 43 (1996)

Acceptable/Guideline JAU 6476 is considered negative for reverse mutation in this battery of S. typhimurium strains up to cytotoxic

concentrations.

870.5300

In vitro mammalian cell gene mutation

test 46246404 (1996)

Acceptable/Guideline JAU 6476 is considered non

- mutagenic in the V79

- HGPRT forward mutation assay.

870.5375

In vitro mammalian

chromosome

aberration test 46246406 (1996)

Acceptable/Guideline JAU 6476 may be considered clastogenic ( i.e. , induces

increases in structural aberration s), but this mutagenic activation may result from secondary cytotoxicity rather than direct structural DNA damage.

870.5395

Mammalian erythrocyte

micronucleus test 46246409 (1996)

Acceptable/Guideline The one i.p. dose of 250 mg/kg JAU 6476 ( prothioconazole)

is considered to be non

- clastogenetic in vivo

.

870.5395

Mammalian erythrocyte

micronucleus test 46246411 (2003)

Acceptable/Guideline JAU 6476 (prothioconazole) is not clastogenic or aneugenic in male mice treated up to overtly toxic and cytotoxic doses.

870.5550

Unscheduled DNA synthesis in

mammalian cells 46246412 (1998)

Acceptable/Guideline JAU 6476 is evaluated as equivocal in this assay. However, these results were clarified based on the negative findings in the in vivo UDS assay in rat hepatocytes from adult male rats exposed up to the 5000 mg/kg with the same Batch No. of the test materials. (MRID 46246413).

870.5550

Unscheduled DNA synthesis in

mammalian cells 46246413 (1999)

Acceptable/Guideline JAU 6476 ( prothioconazole) is negative for UDS

induction in hepatocytes drawn from male rats administered single oral doses of 2500 and 5000 mg/kg

.

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 36 of 48 Table A.2.2. Toxicity Profile for Prothioconazole (JAU6476) Technical

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

Special Study

Inhibition of enzymes in liver

microsomes 46246415 (1999)

Unacceptable/
Nonguideline Inhibition was found in microsomes of both rats and mice. The IC50 (Inhibitory Concentration) attained for its ECOD

metabolism was 5 u M JAU 6476 in rat preparations, and 9

u M in mouse microsomes. The inhibition of testosterone hydroxylation in rat micros omes by JAU 6476 was much weaker, since both hydroxylation and oxidation reactions correlated with different cytochrome P450 subtypes had to

occur, namely , 16alpha, 2alpha 6beta, and 7alpha hydroxylation; plus oxidation to androstendione. The

inclusive IC50 of most of these P450 subtypes was approximately 75 to 100 u M; for 7alpha hydroxylation (= subtype 2 A1), the IC50 was about 1000 u M.

No conclusions can be reached from this study because of the numerous study deficiencies

Special Study

Interaction with Thyroid Peroxidase

in vitro 46246436 (1996)

Acceptable/Nonguideline Thyroid peroxidase (TPO)

- catalyzed guaiacol oxidation was inhibited by compounds tested. 3

- mercapto

- 1,2,4

- triazole had

the low est IC50 value (i.e.: lowest concentration required to inhibit the reaction by 50%), followed by PTU then JAU 6476 and JAU 6953. This provided initial indication that TPO may be irreversibly inhibited.

PTU, ETU, JAU 6476, JAU 6953 and 3

- mercapto

- 1,2,4

- t riazole dose

- dependently suppressed TPO

- catalyzed iodine formation temporarily. Following suppression, iodine reappeared. The rate was then similar to controls. 3

- mercapto

- 1,2,4

- triazole suppressed the rate of the reappearing iodine formation longer tha n the other compounds.

This study showed inhibition of guaiacol and iodine oxidation with the compounds tested.

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 37 of 48 Table A.2.3. Toxicity Profile for Prothioconazole

- Desthio (SXX0665) Technical.

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3100

4

- Week oral toxicity

rodents

(rat) 46246430 (1992)

0, 100, 300, 1000 ppm

0, 11, 34/38, 117/ 121 (M/F) mg/kg/day

Acceptable/Guideline NOAEL = 11 mg/kg/day for males; < 11 mg/kg/day for

females

LOAEL = 34 mg/kg/day for males and 11 mg/kg/day for females based increased liver triglycerides and absolute and relative liver weights in males and on decreased relative and absolute ovary weight with histopathology.

870.3100

90

- Day oral toxicity

roden ts (rat) 46246309 (1999)

0, 30, 125, 500, 2000 ppm 2.2/3.0, 9.6/12.5, 36.9/50.7, 161.9/210.8 mg/kg/d M/F

Acceptable/Guideline NOAEL = 2.2/3.0 (M/F) mg/kg/day LOAEL = 9.6/12.5 mg/kg/day based on histological changes

in the liver of males and increased P450 in females.

870.3100

90

- Day oral toxicity

rodents (mouse) 46246310 (1999)

0, 40, 200, 1000, 5000

ppm 0, 11.5/16.0, 58.9/79.5, 294.0/392.3, 1454/2073 (M/F) mg/kg/day

Acceptable/Nonguideline NOAEL < 11.5/16.0 (M/F) mg/kg/day LOAEL = 11.5.16.0 (M/F) mg/kg/day based on decreased body weight gain in both sexes.

870.3150

39

- Day oral toxicity in nonrodents (dog) 46246431 (1999)

0, 10, 100/5000, 1000

ppm 0, 0.3, 3/150, 30 (M/F) mg/kg/day

Acceptable/Nonguideline Range finding study, no NOAEL or LOAEL were established, observations included dramatic reductions in uterine/oviduct absolute and relative organ weights at 10

ppm.

870.3150

90

- Day oral toxicity in nonrodents (dog) 46246314 (2000)

0, 40, 200, 1000 ppm

0 , 1.58/1.62, 7.81/8.53, 37.79/42.75 (M/F/) mg/kg/day

Unacceptable/Guideline NOAEL = 37.79/42.75 (M/F) mg/kg/day LOAEL > 37.79/42.75 (M/F) mg/kg/day

870.3465

90

- Day inhalation toxicity (rat) 46246432 (1991)

- Pilot

46246433 (1992) 0, 11.3, 46.8, 228.4 mg/m 3 /day

Unacceptable/Guideline NOAEL = 228.4 mg/m 3 /day LOAEL > 228.4 mg/m 3 /day

The requirement for a subchronic inhalation toxicity study has been waived (TXR0056563)

870.3700a Prenatal develop

mental in rodents (rat)

- dermal 46246326 (1991)

0, 30 mg/kg/day Pilot study, used with

46246325

Acceptable/Nonguideline Maternal Toxicity NOAEL = 30 mg/kg/day LOAEL > 30 mg/kg/day Developmental Toxicity NOAEL = 30 mg/kg/day LOAEL > 30 mg/kg/day

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 38 of 48 Table A.2.3. Toxicity Profile for Prothioconazole

- Desthio (SXX0665) Technical.

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3700a Prenatal develop

mental in rodents (rat)

- dermal 46246325 (1991)

0, 100, 300, 1000 mg/kg/day

Acceptable/Guideline

When combined with

46246326 Maternal Toxicity NOAEL = 1000 mg/kg/day LOAEL > 1000 mg/kg/day Developmental Toxicity NOAEL = 30 mg/kg/day LOAEL = 100 mg/kg/day based on structural alterations (14 th

rib)

870.3700a Prenatal develop

mental in rodents (rat)

- oral 46246322 (1991)

0, 1, 3 mg/kg/day

Acceptable/Nonguideline

results combined

with 46246321 Maternal Toxicity NOAEL = 3 mg/kg/day LOAEL > 3 mg/kg/day Developmental Toxicity NOAEL = 3 mg/kg/day LOAEL > 3 mg/kg/day

Combined with 46246321

870.3700a Prenatal develop

mental in rodents (rat)

- oral 46246321 (1991)

0, 10, 30, 100 mg/kg/day

Acceptable/Guideline

results combined with

46246322 Maternal Toxicity

NOAEL = 30 mg/kg/day LOAEL = 100 mg/kg/day based on decreased body weight gains, increased liver weight with histopathology Developmental Toxicity NOAEL < 10 mg/kg/day LOAEL < 10 mg/kg/day based on structural alterations (supernumery ribs) and incomplete/delayed ossification at all

levels.

Combined with 46346322

870.3700a Prenatal develop

mental in rodents (rat)

- oral 46246320 (1990)

0, 100 mg/kg/day

Acceptable/Nonguideline Maternal Toxicity NOAEL = 100 mg/kg/day

LOAEL > 100 mg/kg/day Developmental Toxicity NOAEL <100 mg/kg/day LOAEL = 100 mg/kg/day based on developmental delays

870.3700a Prenatal develop

mental in rodents (rat)

- oral 46246319 (1992)

0, 30 mg/kg/day oral

Acceptable/Nonguideline Maternal Toxicity

No NOAEL or LOAEL were determined Developmental Toxicity No NOAEL or LOAEL were determined, observations included structural abnormalities, developmental delays, death, shows 14 th rib not completely reversible after birth.
Follow up of MRID 46246320, 46246321.

870.3700b

Prenatal developmental in

nonrodents (rabbit)

- oral 46246327, (1991)

0, 2, 10, 50 mg/kg/day

Acceptable/Guideline Maternal Toxicity NOAEL = 10 mg/kg/day LOAEL = 50 mg/kg/day based on decreased body wt gain, decrease food consumption, increased resorptions, decreased number of fetuses, liver histopathology. Developmental Toxicity NOAEL = 2 mg/kg/day LOAEL = 10 mg/kg/day based on structural alterations including malformed vertebral body and ribs, arthrogryposis, and other multiple malfor mations.

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 39 of 48 Table A.2.3. Toxicity Profile for Prothioconazole

- Desthio (SXX0665) Technical.

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3700b

Prenatal developmental in

nonrodents (rabbit)

- dermal 46246329 (1991)

0, 100, 300, 1000 mg/kg/day dermal pilot study

Acceptable/Nonguideline Maternal Toxicity NOAEL = 300 mg/kg/day LOAEL = 1000 mg/kg/day based on local dermal toxicity Developmental Toxicity NOAEL = 1000 mg/kg/day LOAEL > 1000 mg/kg/day

870.3800 Reproduction and fertility effects 46246332 (1992)

0, 0.52, 2.49, 53.0, 79.6 mg/kg/day (pilot)

Acceptable/Nonguideline Parental Toxicity NOAEL = 0.52 mg/kg/day

LOAEL = 2.49 mg/kg/day based on incr. liver wt., liver

discoloration Reproductive Toxicity NOAEL = 2.49 mg/kg/day LOAEL = 53.0 mg/kg/day based on decreased litter size, birth index, live birth index and viability index Offspring Toxicity NOAEL = 2.49 mg/kg/day LOAEL = 53.0 mg/kg/day based on increased liver discoloration (increased cleft palate at 79.6)

870.3800 Reproduction and fertility effects 46246333 (2001)

0, 40, 160, 640 ppm 0, 2.7/3.0, 10.4/12.0, 42.6/49.5 (M/F) mg/kg/day

- premating 0, 2.5, 10.0, 41.2 mg/kg/day

- gestation 0, 4.8, 18.6, 72.6 mg/kg/day

- lactation

Acceptable/Guideline Parental Toxicity NOAEL = 10.4/12.0 (M/F) mg/kg/day LOAEL = 42.6/49.5 (M/F) mg/kg/day based on increased liver wt, liver histopathology, decreased food consumption during lactation (females only). Reproductive Toxicity NOAEL = 10.4/12.0 (M/F) mg/kg/day LOAEL = 42.6/49.5 (M/F) mg/kg/day based on increased incidence of dystocia, decreased viability and decreased pup body weight. Offspring Toxicity NOAEL = 10.4/12.0 mg/kg/d ay LOAEL = 42.6/49.5 (M/F) mg/kg/day based on decreased pup body weight and increased incidence of cleft palate, dilated renal pelvis, dilated ureters and dilated bladder.

870.4100b Chronic toxicity dogs 46246337 (2001)

0, 40, 300, 2000 ppm 0, 1.35/1.55, 10.1/11.1, 69.9/77.1 (M/F) mg/kg/day

30 weeks

Unacceptable/Guideline Not tested at high enough

doses

GLP deficiencies NOAEL = 69.9/77.1 (M/F) mg/kg/day LOAEL > 69.9/77.1 (M/F) mg/kg/day

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 40 of 48 Table A.2.3. Toxicity Profile for Prothioconazole

- Desthio (SXX0665) Technical.

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.4200 Carcinogenicity rats 46246342 (1999)

0, 20, 140, 980 ppm 0, 1.1/1.6, 8.0/11.2, 57.6/77.4 (M/F) mg/kg/day

Acceptable/Guideline NOAEL = 1.1/1.6 (M/F) mg/kg/day LOAEL = 8.0/11.2 (M/F) mg/kg/day based on clinical chemistry, histopathology (liver).

No evidence of carcinogenicity

870.4300 Carcinogenicity mice 46246340 (2000)

46246341 (2001) 0, 12.5, 50, 200 ppm 0, 3.1/5.1, 12.8/20.3, 51.7/80.0 (M/F) mg/kg/day

105 weeks

Acceptable/Guideline NOAEL =12.8/20.3 (M/F) mg/kg/day LOAEL = 51.7/80.0 (M/F) mg/kg/day based on decreased body weight gain in males, decreased triglyceride levels in both sexes, decreased cholesterol levels in males, changes in glucose levels in males, increased liver weights in both sexes, increased incidence of histopathological findings in the liver hepatocytes in both sexes, decreased blood urea levels in females, increased kidney weights in females, and increased incidence of eosinophilic droplets in the cortical tubules of the kidneys of females.

No evidence of carcinogenicity

870.6300 Developmental neurotoxicity rats 46246418 (2004)

4729 3901 (2007) 0, 40, 160, 500 ppm 0, 3.6, 15.1, 43.3 mg/kg/day during gestation 0, 8.1, 35.7, 104.6 during

lactation

Acceptable/Nonguideline Maternal Toxicity NOAEL = 15.1 mg/kg/day LOAEL = 43.3 mg/kg/day based on increased gestation and dystocia Developmental Toxicity NOAEL = 3.6 mg/kg/day LOAEL = 15.1 mg/kg/day based on increased number of stillborn pups and increased incidence of malocclusion and

deviated snout

870.7600 Dermal Absorption 46246425 (2003)

Monkey N=5 Absorption rate:

18.61%

870.7600 Dermal Absorption 46246424 (2003)

Monkey N=1 Pilot Study Absorption rate

7.11%

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 41 of 48 Table A.2.3. Toxicity Profile for Prothioconazole

- Desthio (SXX0665) Technical.

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.7485

Metabolism

- rat 46246422 (2001)

46246420 (2001)
Pilot study and autoradiography

Acceptable/Nonguideline In whole

- body autoradiography experiments, the quick onset of absorption of the test material was demonstrated. Absorption was not complete after one hour. The autoradiograms also showed that the blood concentration was less than the concentration presen t in the fatty tissues, demonstrating the lipophilic nature of SXX0665, and perhaps

of its metabolites. The mucous membrane of the stomach walls were observed with radioactivity throughout the various observation periods, which was considered an indicatio n of extrabiliary secretion of the absorbed radioactivity back into the stomach lumen. The muscle, heart, lung, brain, thyroid, and mineral portion of the bones showed minor concentrations of radioactivity. The testes had a radioactivity distribution pat tern indicative of the blood circulation in the organ. Medium amounts of radioactivity were observed in some glandular organs, including the preputial gland and the adrenals. The gums were also observed with increased radioactivity, with unknown physiolo gical significance. The distributions noted at one hour were fairly consistent for 48 hours, though declining due to excretion. The renal cortex contained radioactivity to a much greater extent than did the renal pelvis, indicating that the radioactivity was reabsorbed in the duodenum. As well, the radioactivity that is absorbed is likely not transformed into metabolites that are adequately polar to be eliminated by the kidney. This results in increased passage through the liver by the radioactive test

material.

870.7485
Pregnant Metabolism Study (single and multiple oral and dermal low and high dose administration)

- Rat 46246439 (2001)

Acceptable/Nonguideline The maximum concentrations (Cmax ) were comparable between single and multiple oral administration of 1 mg/kg and 3 mg/kg and dermal application of 30 mg/kg, respectively. The maximum concentration varied after single and multiple dermal application of 100 mg/kg. The time to

achieve max imum concentration was prolonged after dermal application compared with oral administration at all doses tested (single and multiple) but the delay was not dose

dependent. The longest terminal half

- life was observed in the high dose single dermal applicat ion (100 mg/kg) which was

34.4 h. The lowest terminal half

- life was observed in the low dose multiple dermal application group (30 mg/kg). The AUC values (representing an indirect measure for the fraction of SXX 0665 absorbed) increased only slightly aft er large increases in applied dose (both dermal and oral).

870.5100

Bacterial reverse

mutation test 46246344 (1990)

Acceptable/Guideline At no concentration up to cytotoxic levels in either assay, however, were increases in revertants induced by SXX 0665

, compared to concurrent negative controls, or compared to the laboratory’s historical control data. Marked increases were induced in all positive controls

. 870.5300

In vitro mammalian cell gene mutation 46246405 (1999) SXX 0665 is considered non

- mutagenic in the V79

- HGPRT Forward Mutation Assay.

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 42 of 48 Table A.2.3. Toxicity Profile for Prothioconazole

- Desthio (SXX0665) Technical.

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.5375

In vitro mammalian

chromosome

aberration test 46246407 (1995)

Acceptable/Guideline SXX 0665 is considered to be non

- clastogenic in CHO cells up to subcytotoxic concentrations.

870.5395

Mammalian erythrocyte

micronucleus test 64246410 (1993)

Acceptable/Guideline SXX 0665 is not considered to be a clastogen or aneugen in mice at the i.p. administration of 350 mg/kg.

870.5550

Unscheduled DNA synthesis in

mammalian cells 46246414 (1992)

Acceptable/Guideline There was no evidence that UDS, as determined by radioactive tracer procedures [nuclear silver grain counts],

was induced.

Special Study

Assessment of Ovarian Findings in

Rodents 46246441 (2001)

Acceptable/Non Guideline Currently, the only study where the ovary findings influence the study LOAEL is MRID 46246430 (Krotlinger, 1992). Although there is evidence that the ovary effects seen in this study are coincidental, the reviewers for this submission have

decided to consider this effect treatment related. A NOAEL for females was not achieved in this study; however, there is an adequate margin of safety to this LOAEL from the dose levels selected during risk assessmen t.

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 43 of 48 Table A.2.3. Toxicity Profile for Prothioconazole

- Desthio (SXX0665) Technical.

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

Special Study
Liver Foci Study

Rat 46246437 (1991)

Acceptable/Nonguideline The incidences of foci of altered hepatocytes (FAH) were slightly increased in males and females administered the test substance (9 80 ppm) for 6 weeks (groups 1 and 7) compared to their controls (groups 2 and 8). The incidence of FAH was slightly decreased in males and females administered the test substance (980 ppm) for 12 weeks (groups 3 and 9) compared to their controls (groups 6 and 12). The incidences of FAH were higher in the control males compared to the females. Administration of the test substance to animals previously treated with an initiator (NNM) and a regenerative proliferation inducer (DGA) (groups 4 and 10) produced only slightly elevated (no statistical significance) incidences of FAH relative to those in the corresponding control groups (groups 5 and 11). Severe cytoplasmic vacuolation, particularly following the 12

- week treatment, was found in the Zone II hepatoc ytes of nearly all males that had been exposed to the test substance and exhibited this increased activity (this correlation was absent in animal no. 19). These vacuoles appeared void to the eye in sections that had been

treated with solvents. In native s ections, these vacuoles were highly refractive. Isolated cellular destruction and mitosis of parenchyma1 cells were also observed in these animals.” In
males administered the test substance, there was an increase in the glucose

- 6 phosphate dehydrogenase ac tivity in 3/5 animals compared to 0/5 controls after 6 weeks, and in 5/5 animals compared to 1/5 controls after 12 weeks. “This rise in activity was limited to the Rappaport Zone I hepatocytes.” The enzyme induction in the periportal hepatocytes was

stron ger at 13 weeks in the males administered test substance

without NNM and DGA than with. There were no clear patterns with the incidence or severity of enzyme induction findings in the females. “No evident hepatocytic vacuolation

was observed in the femal es of any group. However, in animals that had been treated with the test substance, it was noted that the stored glycogen in perivenular cells was distributed very uniformly throughout the cytoplasm, whereas structures having the appearance of densely pac ked glycogen pools

- often concentrated at the cellular periphery

- were observed in the pertinent controls.”

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 44 of 48 Table A.2.4. Toxicity Profile for Prothioconazole

- Sulfonic Acid K Salt Technical.

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3100

90

- Day oral toxicity rodents (rat) 46246312 (2001)

0, 30, 125, 500, 2000 ppm 0, 2.1/2.6, 8.7/9.7, 34.3/40.4, 135.9/163.0 (M/F) mg/kg/day

Acceptable/Guideline NOAEL = 34.3/40.4 (M/F) mg/kg/day LOAEL = 135.9/163.0 (M/F) mg/Kg/day based on microscopic findings in the ovary in females (cysts), and the urinary bladder (transitional cell hyperplasia) and testes (focal degeneration germinal epithelium) in males

.

870.3700a Prenatal develop

mental in r odents (rat) 46246318 (2001)

0, 30, 100, 500, 1000 mg/kg/day

Range finding study

Acceptable/Nonguideline Maternal Toxicity NOAEL = 500 mg/kg/day LOAEL = 1000 mg/kg/day based on decreased FC, BW, clinical signs and high mortality. Developmental Toxicity NOAEL = >1000 mg/kg/day LOAEL > 1000 mg/kg/day

870.3700a Prenatal develop

mental in rodents (rat) 46246324 (2001)

0, 30, 150, 750 mg/kg/day

Acceptable/Guideline Maternal Toxicity NOAEL = 150 mg/kg/day LOAEL = 750 mg/kg/day based on clinical signs, decreased food consumption, decreased body wt, mortality Developmental Toxicity NOAEL < 30 mg/kg/day LOAEL ≤ 30 mg/kg/day based on increased incidence of supernumerary one ribs.

870.5100

Bacterial reverse

mutation test 46246402 (2000)

Unacceptable/Guideline No concentration in either assay did the test article significantly increased the number of revertants over negative

control values. However, the spontaneous revertant counts of strain TA100 as well as the response to the S9

- activat ed positive control were lower than expected.

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 45 of 48 Table A.2.5. Toxicity Profile for Prothioconazole

- Des

- chloro Technical.

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3700a Prenatal develop

mental in rodents (rat) 46246317 (2002)

0, 40, 200, 1000 mg/kg/day

Acceptable/Nonguideline Maternal Toxicity No NOAEL or LOAEL were established, observations included decreased food consumption, body weight, body weight gain Developmental Toxicity

No NOAEL or LOAE L were established, observations included decreased fetal wt, increased developmental delays

& structural abnormalities

870.5100

Bacterial reverse

mutation test 46246345 (2003)

Acceptable/Guideline No evidence of mutagenicity (increased revertants) was observed in either assay up to cytotoxic levels of the test

substance . Therefore, 6476 Des

- chloro is considered non

mutagenic in this bacterial test system.

870.5375

In vitro mammalian

chromosome

aberration test 46246408 (2003)

Acceptable/Guideline JAU 6476 Des

- Chloro is considered non

- clastogenic in this

test system.

Table A.2.6. Supplemental: Toxicity Profile for other Prothioconazole metabolites.

870.5100

Bacterial reverse

mutation test 46246346 (2002)

JAU 6476

- methyl

Acceptable/Guideline JAU 6476

- methyl is considered nonmutagenic in this battery

of S. typhimurium strains up to cytotoxic levels

.

870.5100

Bacterial reverse

mutation test 46246347 (2002)

JAU 64760

- asymmetric

isomer

Acceptable/Guideline The asymmetric isomer of JAU 6476 is co nsidered nonmutagenic in this battery of S. typhimurium cultures up to cytotoxic concentrations.

870.5100

Bacterial reverse

mutation test 46246348 (2001)

JAU 6476

- asymmetric

disulfide

Acceptable/Guideline JAU 6476

- asymmetric disulfide does not induce reverse mutation in this bacterial test system up to cytotoxic

concentrations.

870.5100

Bacterial reverse

mutation test 46246349 (2000)

JAU6476

- alpha

- hydroxy

desthio

Acceptable/Guideline The alpha

- hydroxy

- desthio derivative of JAU 6476 is

considered non

- mutagenic in this bacterial test system up to the cytotoxic/limit concentration.

870.5100

Bacterial reverse

mutation test 46246350 (2000)

JAU 6476

- triazolinone

Acceptable/Guideline JAU 6476

- triazolinone is considered nonmutagenic in this S. typhimurium test system.

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 46 of 48 Table A.2.6. Supplemental: Toxicity Profile for other Prothioconazole metabolites.

870.5100

Bacterial reverse

mutation test 46246401 (2000)

JAU

- 6476

- alpha

- acetoxy

desthio

Acceptable/Guideline JAU 6476

- alpha

- acetoxy

- desthio is considered non

mutagenic in this bacterial test system.

870.5100

Bacterial reverse

mutation test 46246403 (2000)

JAU

- 6476

- benzylpropyldiol JAU 6476

- Benzylpropyldiol does not induce reverse mutation in this bacterial test system up to cytotoxic

concentrations.

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 47 of 48 Appendix B

. International Residue Limits

Summary of US and International Tolerances and Maximum Residue Limits

Residue Definition

US Canada Mexico 2 Codex 

### Combined residues of prothioconazole (2

- [2

- (1

- chlorocylcopropyl)

- 3

- (2

- chlorophenyl)

- 2

- hydroxypropyl]

- 1,2

- dihydro

- 3H

- 1,2,4

- triazole

- 3

- thion) and prothioconazole

- desthio (α

- (1

- chlorocyclopropyl)

- α

- [(2

- chlorophenyl)methyl]

- 1H

- 1,2,4

- triazole

- 1

- ethanol) Plants: 2

- [2

- (1

- chlorocyclopropyl)

- 3

- (2

- chl orophenyl)

- 2

- hydroxypropyl]

- 2,4

- dihydro

- 3 H

- 1,2,4

- triazole

- 3

- thione, including the metabolite α

- (1

- chlorocyclopropyl)

- α

- [(2

- chlorophenyl)methyl]

- 1 H

- 1,2,4

- triazole

1

- ethanol

Livestock: 2

- [2

- (1

- chlorocyclopropyl)

- 3

- (2

- chlorophenyl)

- 2

- hydroxypropyl]

- 2,4

- dihyd ro

- 3 H

- 1,2,4

- triazole

- 3

- thione, including the metabolite α

- (1

- chlorocyclopropyl)

- α

- [(2

- chlorophenyl)methyl]

- 1 H

- 1,2,4

- triazole

1

- ethanol and their conjugates -- Plants /Animal : prothioconazole

desthio.

Tolerance/Maximum Residue Limit (ppm)

Commodity 1 US Canada Mexico 2 Codex
Bushberry (crop subgroup 13

- 07B) 2.0

-- -- -- Low growing berry subgroup, except strawberry (crop subgroup 13

- 07H) 0.20

-- -- --
Cucurbit vegetables (crop group 9) 0.30

-- -- -- Completed: M. Negussie: 03/22/2013

1 Includes only commodities of interest for this action. Tolerance values are HED recommendations and not those proposed by the applicant.

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

### Prothioconazole Human Health Risk Assessment DP No. 403739

Page 48 of 48 A ppendix C . Residue Summary Table

Summary of the Total Residue Data from Crop Field Trials

Commodity Total App. Rate

g ai/ha (lb ai/acre) PHI

(days) Combined Prothioconazole and Prothioconazole

- desthio Residues 1 (ppm)

n Min. Max. LAFT 2 HAFT 2 Median Mean Std. Dev.

B lueberry 394

- 420 (0.351

- 0.374) 5

- 7 11 <0.092 1.07 0.167 1.04 0.61 0.55 0.26

B ranberry 339

- 356 (0.302

- 0.317) 43

- 46 6 <0.040 <0.112 <0.040 <0.106 0.042 0.052 0.026

Cucumber 596

- 611 (0.53

- 0.55) 2

- 3 8 <0.043 <0.152 0.044 0.144 0.068 0.080 0.03

6

- 7 8 <0.040 <0.125 0.043 0.084 0.054 0.058 0.02

Muskmelon 594

- 605 (0.53

- 0.54) 2

- 3 8 <0.090 0.236 0.099 0.203 0.119 0.138 0.04

7 8 <0.045 0.188 0.050 0.172 0.086 0.102 0.04

Summer squash 597

- 607 (0.53

- 0.54) 2

- 3 8 <0.040 <0.094 0.040 0.097 0.050 0.059 0.02

5

- 7 8 <0.040 < 0.079 0.040 0.079 0.041 0.050 0.02

1 Combined prothioconazole and prothioconazole

- desthio; except for Min/Max, values reflect per

- trial averages.

2 LAFT = lowest

- average field trial; HAFT = highest

- average field trial.

Summary of the Total Residue Data from Crop Field Trials

Commodity Total App. Rate

g ai/ha (lb ai/acre) PHI

(days) Total Residues (combined ppm)

n Min. Max. LAFT 1 HAFT 1 Median Mean Std. Dev.

T

B lueberry 394

- 420 (0.351

- 0.374) 5

- 7 11 <0.01 <0.01

-- -- <0.01 <0.01

-- C ranberry 339

- 356 (0.302

- 0.317) 43

- 46 6 <0.01 <0.01

-- -- <0.01 <0.01

--

M uskmelon 594

- 605 (0.53

- 0.54) 2

- 3 8 <0.01 <0.01

-- -- <0.01 <0.01

-- 7 8 <0.01 <0.01

-- -- <0.01 <0.01

--

C ucumbers 596

- 611 (0.53

- 0.55) 2

- 3 8 <0.01 <0.01

-- -- <0.01 <0.01

-- 6

- 7 8 < 0.01 <0.01

-- -- <0.01 <0.01

--

S ummer squash 597

- 607 (0.53

- 0.54) 2

- 3 8 <0.01 <0.01

-- -- <0.01 <0.01

-- 5

- 7 8 <0.01 <0.01

-- -- <0.01 <0.01

--

TA

B lue berry 394

- 420 (0.351

- 0.374) 5

- 7 11 <0.01 0.024

-- -- <0.001 <0.01 <0.01

C ranberry 339

- 356 (0.302

- 0.317) 43

- 46 6 <0.01 <0.01

-- -- <0.01 <0.01

--

M uskmelon 594

- 605 (0.53

- 0.54) 2

- 3 8 0.014 0.181

-- -- 0.050 0.067 0.056

7 8 0.022 0.139

-- -- 0.062 0.067 0.042

C ucumbers 596

- 611 (0.53

- 0.55) 2

- 3 8 0.032 0.357

-- -- 0.058 0.097 0.108

6

- 7 8 0.038 0.780

-- -- 0.076 0.160 0.252

S ummer squash 597

- 607 (0.53

- 0.54) 2

- 3 8 0.016 0.208

-- -- 0.035 0.060 0.063

5

- 7 8 0.020 0.270

-- -- 0.046 0.078 0.083

TAA

B lu eberry 394

- 420 (0.351

- 0.374) 5

- 7 11 <0.01 0.024

-- -- <0.01 <0.01 <0.01

C ranberry 339

- 356 (0.302

- 0.317) 43

- 46 6 <0.01 <0.01

-- -- <0.01 <0.01

--

M uskmelon 594

- 605 (0.53

- 0.54) 2

- 3 8 <0.01 <0.01

-- -- <0.01 <0.01

-- 7 8 <0.01 <0.01

-- -- <0.01 <0.01

--

C ucumbers 596

- 611 (0.53

- 0.55) 2

- 3 8 <0.01 <0.01

-- -- <0.01 <0.01

-- 6

- 7 8 <0.01 <0.01

-- -- <0.01 <0.01

--

S ummer squash 597

- 607 (0.53

- 0.54) 2

- 3 8 <0.01 <0.01

-- -- <0.01 <0.01

-- 5

- 7 8 <0.01 <0.01

-- -- <0.01 <0.01

-- 1 Only a single sample from each plot was analyzed; therefore no HAFT or LAFT could be calculated.

T = 1,2,4

- triazole

TA = triazolylalanine

TAA = triazolylacetic acid