Prothioconazole Human Health Risk Assessment DP No. D403739 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: June 15, 2013 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Prothioconazole: Human Health Risk Assessment for Proposed Uses on Low 

Growing Berry Subgroup (except Strawberry), Bushberry Subgroup, and Cucurbit 

Vegetables. 

PC Code: I 13961 

Decision No.: 465457 

Petition No.: 91 7677 

Risk Assessment Type : Single Chemical/Aggregate 

TXR No.: NA 

MRID No.: NA 

DP Barcode: 0 403739 

Registra tion Nos.: 264-825 

Regulatory Action: Section 3 Registration 

Case No.: NA 

CAS No.: 178928-70-6 

40 CFR: § 180.626 

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Page 1 of 48 
Prothioconazole Human Health Risk Assessment DP No. D403739

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1.0 Executive Summary ........................................................................................................... 3

2.0 HED Recommendations .................................................................................................... 5

2.1 Data Deficiencies ............................................................................................................ 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 Water 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 Residential (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 Cumulative 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

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1.0 Executive Summary

Prothioconazole (2-[2-(1-chlorocyclpropyl)-3-(2-chlorophenyl)-2-hydroxylpropyl]-1,2-dihydro3H-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-inhibitor (DMI) which works through 

disruption of ergosterol biosynthesis (ergosterol is a precursor to Vitamin D2 and is an important 

component of fungal cell walls).

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

proposed new uses to be added to the Proline® 480 SC Fungicide label (EPA Reg. No. 264-825): 

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

13-07H); and cucurbit vegetables (crop group 9). Bayer submitted for registration 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) and 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. The proposed label requires occupational handlers to wear long pants, long sleeved 

shirts, chemical resistant gloves, shoes, and socks. The restricted entry interval (REI) on the 

proposed label is 12 hours. There are no proposed or registered residential uses of 

prothioconazole. 

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 the 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.

The target organs of prothioconazole (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 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. Evidence 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 safety factor was 

reduced to 1X. Prothioconazole was classified as “not likely to be carcinogenic to humans” and, 
Prothioconazole Human Health Risk Assessment DP No. D403739

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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 acute 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) was 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 acute and chronic assessments. At the 95th percentile, the 

acute dietary exposure estimates utilized 30% of the acute population adjusted dose (aPAD) for 

females 13-49 years of age, which was the only population subgroup included in the acute assessment. 

The chronic dietary exposure estimates utilized 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 HED’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 subsequently 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 combined 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. 
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Based on the Agency's current practices, a quantitative non-cancer occupational post-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 assessment 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 Handlers Exposure Database Version 1.1 (PHED 1.1) and the Agricultural Handler 

Exposure 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 certain 

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.epa.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 Low-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 and a revised 

Section F is submitted as indicated in Section 2.2, HED recommends 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 

transitions 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 

prothioconazole residue that is, in fact, not present or is present in lesser amounts than 

quantitated.

2.2 Tolerance Considerations
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2.2.1 Enforcement Analytical Method

The Bayer CropScience high-performance liquid chromatograph/mass spectrometer/mass 

spectrometer (HPLC/MS/MS) method RPA JA/03/01 is available for enforcing the currentlyestablished 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 requested 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 proposing multiple ion transitions that 

could be used to determine prothioconazole residues in plants and ruminants. Bayer conveyed 

that they will submit the revised methods that include the 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 tolerances for the combined 

residues of prothioconazole 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 petitioner 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 Recommendations
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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 Introduction

3.1 Chemical Identity

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 prothioconazoledesthio

α-(1-chlorocyclopropyl)-α-[(2-chlorophenyl)-methyl]-1H-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-dihydro3H-1,2,4-triazole-3-thione

3.2 Physical/Chemical Characteristics

Cl

Cl

OH

N N

N

H

S

Cl

Cl

OH

N N

N

Cl

Cl

OH

N N

N

H

S

HO
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Table 3.2.1 is a summary of the physical/chemical properties for prothioconazole. 

Prothioconazole has a Log Kow 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 considered 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, pKa 6.9 (calculated from KOW)

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 bushberry crop subgroup 13-07B; low growing berry, 

except strawberry, crop subgroup 13-07H; and cucurbit vegetables crop group 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.
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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 Subgroup, Except Strawberry:

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 Vegetables: 

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.

Bushberry Subgroup: 

Aronia berry; blueberry (highbush and lowbush); Chilean guava; highbush cranberry; currant (black, buffalo, and red); elderberry; 

European barberry; gooseberry; edible honeysuckle; huckleberry; jostaberry; juneberry (Saskatoon berry); lingonberry; native currant; 

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 food 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 nonoccupational 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 postapplication exposure 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 this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the USDA and are used in 
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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 able to assess dietary exposure to smaller, specialized subgroups 

and exposure assessments are performed when conditions or circumstances warrant. Whenever 

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

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 

post-application are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 

patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

No new toxicity and/or metabolism data have been received since the last risk assessment 

(D378763, B. O’Keefe, 01/31/2011). This assessment includes summaries of prior assessments.

The risk assessment and safety findings for prothioconazole are based on an extensive and wellcharacterized 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). 

Because 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. Refer to a previous prothioconazole risk assessment document for further 

details, including the executive summaries 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 prothioconazole and its metabolites produce adverse effects 

including malformations in the conceptus 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 

adversely 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 prothioconazole 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 indicate that both prothioconazole and 
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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 metabolized 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 Infants 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 

susceptibilities 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, the exposure data are complete or are estimated 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 available 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 

(TXR0056563, J. Van Alstine, 02/21/2013)

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 neurotoxicity study 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.
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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 and 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, 

clear 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 retain the 10X FQPA factor, and 

it is reduced to 1X.

4.2.4 Residual Uncertainties in the Exposure Database

There are no uncertainties with respect to the exposure database. The exposure data are 

complete or are estimated based on data that reasonably account 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 metabolism 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 protective high-end model EDWCs. Additionally, there is no potential for 

residential exposure. 

4.3 Toxicity Endpoint and Point of Departure Selections

There have been no changes to the prior dose-response assessment, or to prior recommendations 

for combining routes 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 documents (D328967, B. O’Keefe, 01/23/2007; and 

D347123, B. O’Keefe, 01/05/2009). Residential exposure scenarios are not anticipated based on 

the registered and proposed use patterns.
Prothioconazole Human Health Risk Assessment DP No. D403739

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

Prothioconazole 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 

Assessment

Study and Toxicological Effects

Acute Dietary 

(Females 13 – 49)

NOAEL = 

2.0 

mg/kg/day

UFA=10X

UFH=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

UFA=10X

UFH=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 

IntermediateTerm (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 

IntermediateTerm (1-30 days 

and 1-6 months)

NOAEL=30 

mg/kg/day

UFA=10X

UFH=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 Shortand Intermediateterm (1-30 days 

and 1-6 months)

NOAEL=2.0 

mg/kg/day1

UFA=10X

UFH=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, and 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 of concern. The LOC for occupational exposure to prothioconazole desthio is based on the 

conventional uncertainty factor of 100X (UFA = 10X and UFH = 10X). NOAEL = no observed adverse effect level. 

LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to 

human (interspecies). UFH = 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. 1toxicity via the inhalation route is assumed to 

be equivalent to oral toxicity.
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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 TAA) from prothioconazole to 

the aggregate exposure for human-health risk assessment has been considered (DP411386, T. 

Morton, 05/01/2013). Furthermore, the residues of concern in rotational crops for tolerance 

enforcement and risk assessment purposes are the same as in primary crops, parent and 

prothioconazole-desthio. 

For 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-hydroxy prothioconazole metabolite, and conjugates that can be converted to any of these three 

compounds by acid hydrolysis. 

As documented in previous prothioconazole assessments, a total toxic residues approach was 

used for drinking water exposure modeling. Combined residues of concern include the parent, 

prothioconazole-desthio, and prothioconazole-S-methyl (D378763, B. O’Keefe, 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 Crops and 

Rotational Crops

Sum of Prothioconazole and its 

desthio metabolite, expressed 

as parent

Sum of Prothioconazole and 

its desthio metabolite, 

expressed as parent

Livestock Ruminant and Poultry Prothioconazole, the desthio 

metabolite, the 4-hydroxy 

prothioconazole metabolite, 

and conjugates that can be 

converted to any of these three 

compounds by acid hydrolysis

Sum of Prothioconazole, the 

desthio metabolite, and 

conjugates that can be 

converted to either of these 

two compounds by acid 

hydrolysis, calculated as 

prothioconazole

Drinking Water Prothioconazole, 

Prothioconazole-desthio and 

Prothioconazole-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

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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 addition, the employed application 

scenarios (rates, retreatment intervals, and preharvest intervals) adequately represent the proposed 

application scenarios. 

Combined residues (and per-trial averages) of prothioconazole and prothioconazole-desthio in/on 

blueberry fruit were <0.092-1.07 ppm (0.167-1.04 ppm); the combined residues declined as the 

PHI increased from 0 days to 21 days. Combined residues (and per-trial averages) of 

prothioconazole and prothioconazole-desthio in/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. Combined residues (and per-trial averages) of prothioconazole and prothioconazole-desthio 

in/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 procedure, 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 summary of the blueberry, cranberry, cucumber, muskmelon, and summer squash field trial data 

for prothioconazole and prothioconazole-desthio, and T, TA, and TAA submitted in support of the 

current petition is provided in Appendix B.

5.3 Water Residue Profile

A new drinking water assessment was supplied by EFED (DP405409, C. Sutton, 11/14/12). 

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 increased 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 on use on nursery seedlings and were 

determined using SCI-GROW. 
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Table 5.3 Estimated Prothioconazole Drinking Water Concentrations Recommended for use in Dietary Risk 

Assessments.

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 Chronic1

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 field 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 incorporated. Upper 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, 

females 13-49 years of age was the only population subgroup included in the acute assessment. 

The acute dietary exposure analysis results 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

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dose (aPAD) for females 13-49 yrs old at the 95th 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 utilized 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

0.002392 24

All Infants (<1 year old) 0.005709 57

Children 1-2 years old 0.004404 44

Children 3-5 years old 0.003535 35

Children 6-12 years old 0.002457 25

Youth 13-19 years old 0.001795 18

Adults 20-49 years old 0.002270 23

Adults 50-99 years old 0.002240 22

Females 13-49 years old 0.006029 30 0.002265 23

*The subpopulations 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 the 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 at

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 individuals nearby pesticide applications. 
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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, 20101. 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. 

The Agency has been working with the Spray Drift Task Force, EPA Regional Offices, and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information2. The 

Agency has completed its evaluation of the new database submitted by the Spray Drift Task 

Force, a membership of U.S. pesticide registrants, and is developing a policy on how to 

appropriately apply the data and the AgDRIFT computer model to its risk assessments for 

pesticides applied by air, orchard airblast, and ground hydraulic methods. After the policy is in 

place, the Agency may impose further refinements in spray drift management practices to reduce 

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

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 current 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 dietary 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 
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7.3 Chronic Aggregate Risk

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

HED’s current practice is to include only food and water in the 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, reproductive, 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 “by 

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 conazoles (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 will 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 toxicity, 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 hazards 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 estimates 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 available in the propiconazole reregistration docket at http://www.regulations.gov, 

Docket Identification (ID) Number EPA-HQ-OPP-2005-0497.
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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 application rates using ground, chemigation, 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

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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 (μg/lb 

ai)1

Inhalation Unit 

Exposure (μg/lb 

ai)1

Maximum 

Application 

Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

Dermal Inhalation Total

Baseline Baseline Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7 MOE8

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/Loader/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.
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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 (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ 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 (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ 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).
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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 (μg/lb 

ai)1

Inhalation Unit 

Exposure (μg/lb 

ai)1

Maximum 

Application 

Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

Dermal Inhalation Total

Gloves Baseline Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7 MOE8

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

Applying Sprays –

Airblast

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

Mixer/Loader/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.
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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 (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ 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 (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ 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 Intermediate-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 values 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 available.

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-Application Short- and Intermediate-Term Exposure and Risk for Prothioconazole.

Crop Activity

Transfer

Coefficienta

(cm2/hr)

DATb DFRc

(μg/cm2)

Short-Term

Daily 

Dermal 

Dosed

(mg/kg/day)

MOEe

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/cm2) 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)] (Dermal 

absorption factor = 100%). 

e MOE = NOAEL/Daily Dose (Short- and Intermediate-Term Dermal NOAEL = 30 mg/kg/day).

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

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-Desthio 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 40 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 adequate 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 performed 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, 20103. 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 way to incorporate occupational post-application inhalation exposure into the 

Agency's risk assessments. If new policies or procedures are put into place, the Agency may 

revisit the need for a quantitative occupational post-application inhalation exposure assessment 

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 application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure 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 Group 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 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.

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 Support 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

Appendix 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

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)...............................

870.6100b 90-Day Neurotoxicity (hen)...........................................

870.6200a Acute Neurotoxicity Screening Battery (rat) .................

870.6200b 90-Day Neurotoxicity Screening Battery (rat)...............

870.6300 Develop. Neurotoxicity .................................................

no

no

yes

yes

yes

-

-

yes

yes

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

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A.2 Toxicity Profiles

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

Guideline Study Species Results Tox. 

Category

MRID No.

Prothioconazole

870.1100 Acute oral 

toxicity

Rat LD50 >= 6200 mg/kg (M, 

F)

IV 46246230

870.1200 Acute dermal 

toxicity

Rat LD50 >= 2000 mg/kg (M, F) III 46246244

870.1300 Acute inhalation 

toxicity

Rat LC50 >= 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 LD50 = 2806 mg/kg (M, F) 

(approximate)

III 46246231

870.1100 Acute oral 

toxicity

Mouse LD50 = 2235 mg/kg

(Males) 

LD50 = 3459 mg/kg 

(Females)

III 46246242

870.1200 Acute dermal 

toxicity

Rat LD50 >= 5000 mg/kg (M,F) IV 46246243

870.1300 Acute inhalation 

toxicity

Rat LC50 >= 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

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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 females)] 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 

rodents (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. 

870.3100

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 

consumption, 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

Acceptable/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

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Table A.2.2. Toxicity Profile for Prothioconazole (JAU6476) Technical

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

870.3700a

Prenatal developmental 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 dysplastic pubic 

bone, and increased incidence of left punctiform 14th rib.

870.3700a

Prenatal developmental 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 developmental 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

LOAEL > 1000 mg/kg/day 

Developmental Toxicity

NOAEL = 1000 mg/kg/day

LOAEL > 1000 mg/kg/day

870.3700a

Prenatal developmental 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 developmental 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.

Developmental NOAEL = 300 mg/kg/day

LOAEL = 480 mg/kg/day based on decreased body wt, and 

small fetuses.

870.3700b

Prenatal developmental 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 weights 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 generation.

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 alterations 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 pigmentation, 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

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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

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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 desulfuration, 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 difficulties 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 metabolite (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 the 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 for 

0-1.4% of the administered dose. JAU6476-S- or Oglucuronide 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 bile 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 46246421). 

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 postadministration. 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 postadministration, indicative of continued elimination from the 

tissues.
Prothioconazole Human Health Risk Assessment DP No. 403739

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Table A.2.2. Toxicity Profile for Prothioconazole (JAU6476) Technical

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

870.7800 

Immunotoxicity

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 highdose males (↑125%).

870.5100

Bacterial reverse 

mutation test

46246343 (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 aberrations), 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 UDSinduction 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 uM JAU 6476 in rat preparations, and 9 

uM in mouse microsomes. The inhibition of testosterone 

hydroxylation in rat microsomes 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 uM; for 7alpha hydroxylation (= 

subtype 2 A1), the IC50 was about 1000 uM.

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 lowest 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-

triazole 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 than 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 

rodents

(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/m3/day 

Unacceptable/Guideline

NOAEL = 228.4 mg/m3/day

LOAEL > 228.4 mg/m3/day

The requirement for a subchronic inhalation toxicity 

study has been waived (TXR0056563)

870.3700a

Prenatal developmental 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 developmental 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 (14th

rib)

870.3700a

Prenatal developmental 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 developmental 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 developmental 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 developmental 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 14th 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 malformations.
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/day

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)

47293901 (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 present 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 indication 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 pattern 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 physiological 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 maximum concentration was prolonged after dermal 

application compared with oral administration at all doses 

tested (single and multiple) but the delay was not dosedependent. The longest terminal half-life was observed in the 

high dose single dermal application (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 after 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 assessment.
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 StudyRat

46246437 (1991)

Acceptable/Nonguideline

The incidences of foci of altered hepatocytes (FAH) were 

slightly increased in males and females administered the test 

substance (980 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 hepatocytes 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 sections, 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 activity 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 

stronger 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 females 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 packed 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 developmental in rodents

(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 developmental 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-activated 

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 developmental 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 LOAEL 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 nonmutagenic 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 considered 

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-hydroxydesthio

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-acetoxydesthio

Acceptable/Guideline

JAU 6476-alpha-acetoxy-desthio is considered nonmutagenic 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

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Appendix B. International Residue Limits

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition

US Canada Mexico2 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-

chlorophenyl)-2-hydroxypropyl]-2,4-

dihydro-3H-1,2,4-triazole-3-thione, 

including the metabolite α-(1-

chlorocyclopropyl)-α-[(2-

chlorophenyl)methyl]-1H-1,2,4-triazole1-ethanol

Livestock: 2-[2-(1-chlorocyclopropyl)-3-

(2-chlorophenyl)-2-hydroxypropyl]-2,4-

dihydro-3H-1,2,4-triazole-3-thione, 

including the metabolite α-(1-

chlorocyclopropyl)-α-[(2-

chlorophenyl)methyl]-1H-1,2,4-triazole1-ethanol and their conjugates

--

Plants/Animal: 

prothioconazoledesthio.

Tolerance/Maximum Residue Limit (ppm)

Commodity1 US Canada Mexico2 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

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Appendix 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 Residues1(ppm)

n Min. Max. LAFT2 HAFT2 Median Mean Std. Dev.

Blueberry 394-420 (0.351-0.374) 5-7 11 <0.092 1.07 0.167 1.04 0.61 0.55 0.26

Branberry 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. LAFT1 HAFT1 Median Mean Std. Dev.

T

Blueberry 394-420 (0.351-0.374) 5-7 11 <0.01 <0.01 -- -- <0.01 <0.01 --

Cranberry 339-356 (0.302-0.317) 43-46 6 <0.01 <0.01 -- -- <0.01 <0.01 --

Muskmelon 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 --

Cucumbers 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 --

Summer 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

Blueberry 394-420 (0.351-0.374) 5-7 11 <0.01 0.024 -- -- <0.001 <0.01 <0.01

Cranberry 339-356 (0.302-0.317) 43-46 6 <0.01 <0.01 -- -- <0.01 <0.01 --

Muskmelon 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

Cucumbers 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

Summer 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

Blueberry 394-420 (0.351-0.374) 5-7 11 <0.01 0.024 -- -- <0.01 <0.01 <0.01

Cranberry 339-356 (0.302-0.317) 43-46 6 <0.01 <0.01 -- -- <0.01 <0.01 --

Muskmelon 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 --

Cucumbers 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 --

Summer 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