UNITED ST ATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: December I 51

, 2015 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Prothioconazole. Human Health Assessment Scoping Document in Support of 

Registration Review. 

PC Code: 1 13961 DP Barcode: 0 427290 

Decision No.: 50498 1 Registration No.: 264-824 

Petition No.: A Regulatory Action: Registration Review 

Risk Assessment Type: Single Chemica l/Aggregate Case No.: 7054 

TXR No.: NA CAS No.: 178928-70-6 

MRID No.: NA 40 CFR: § 180.626 

FROM: 

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THROUGH: Christine Olinger, Branch hi e~/ £-//_:__ 

Risk Assessment Branch 3 (RAB '1.-pLHealth Effects Division (7509P 

TO: Brian Kettl, Chemical Review Manager 

Cathryn Britton, Team Leader 

Risk Management and Implementation Branch II 

Pesticide Reevaluation Division (7508P) 

Executive Summary 

To evaluate the scope of work necessary to support Registration Review, HED has considered 

previous risk assessments, any new toxicity, exposure and usage data, and current Agency policy 

and methodologies. The most recent risk assessment for prothioconazole was conducted in 2013 

for new proposed uses on low growing berry (except strawberry), bushberry, and cucurbit 

vegetable subgroups (C. Wal ls, 6115/20 13, D403 739). Current registered uses of 

prothioconazole include foliar and seed treatment of a variety of food crops (cereal grains, 

Page I of 3 1 
berries, oil seeds, vegetables, pea and beans, peanuts, sugar beets) and nonfood crops (conifer 

and hardwood seeds and seedlings). End-use products are formul ated as soluble or emulsifiable 

concentrates to be diluted before application by ground sprayer, aerial, chemigation and/or seed 

treatment equipment. 

The extensive prothioconazole toxicology database, which includes data for prothioconazole, 

desthio-prothioconazole and other metabolites, is adequate for risk assessment. The target organ 

of prothioconazole and its desthio metabolite is the liver. Effects were also observed in the 

kidney and bladder, male and female reproductive systems, and serum levels of thyroid 

hormones. Points of departure (PO Os) for prothioconazole are based on the toxicology database 

for its metabolite/degradate, desthio-prothioconazole, which is more toxic than the parent 

compound. The PODs are based on developmental effects in rabbits for acute dietary and nondietary (dem1al and inhalation) risk assessments and liver effects (vacuolation and fatty change) 

in rats for chronic dietary risk assessments. Prothioconazole is classified as "Not likely to be 

carcinogenic to humans" based on the lack of evidence for carcinogenicity in studies conducted 

in mice and rats with prothioconazole and desthio-prothioconazole. There is evidence for 

increased susceptibility following in utero exposure and pre/post-natal exposure to the desthio 

metabolite. The concern is low for the observed susceptibility because clear NOAELs and 

LOAELs were established for the developmental and reproductive effects and the POD used for 

overall risk assessment is derived from the metabolite and would be protective of the 

developmental and reproductive effects observed with the metabolite. There is no residual 

uncertainty for pre/post-natal toxicity, therefore, the Food Quality Protection Act (FQPA) safety 

factor (SF) is reduced to 1 X. Toxicity endpoints are not anticipated to change, however they will 

be screened and/or re-evaluated and updated as necessary based on current toxicological 

evaluation practices and current policies. 

The residue chemistry database is sufficient to support the current registrations of 

prothioconazole. The nature of the residue has been adequately defined in crops, rotated crops, 

and livestock. Adequate field trial/processing data, rotational crop data, storage stability data 

and enforcement methods are available. New dietary exposure and aggregate risk assessments 

are not anticipated to be needed during Registration Review. 

Tolerance expressions are adequate for prothioconazole. 

There are no uses of prothioconazole in residential settings; therefore, a residential exposure and 

risk assessment is not needed. The Agency will examine the need for spray drift and 

volatilization assessments during Registration Review for prothioconazole based on the potential 

for exposure to bystanders from agricultural applications. 

There is sufficient information available to assess occupational exposure to prothioconazolc. All 

scenarios applicable to currently registered uses have been adequately assessed in previous risk 

assessments. Margins of exposure (MO Es) are not of concern to HED (i.e., MO Es > I 00) for all 

currently registered uses and scenarios. A new occupational exposure assessment is not 

anticipated to be needed during prothioconazole Registration Review. The current labels have an 

REI of 12 hours, which would be of concern to HED only for nursery tree seedling uses (MOE = 

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97). The same use had a MOE = 190 at 24 hours, therefore an REI of 24 hours would be 

protective.

Introduction

Prothioconazole is a systemic fungicide for the control of ascomycetes, basidiomycetes and 

deuteromycetes diseases in agricultural crops. Foliar uses include peanut, sugar beet, rice, cereal 

grains, sweet corn, barley, oil seeds, dry peas and beans, chickpea, lentils, peanut, wheat, wheat 

forage, low growing berry, bushberry, cucurbit vegetables and nursery tree seedlings. Seed 

treatment uses include alfalfa, peas and beans, soybean, cereal grains, potatoes wheat, barley, 

triticale and nursery trees. There are no residential uses of prothioconazole. End-use products 

are formulated as soluble or emulsified concentrates to be diluted before application by ground

sprayer, aerial, chemigation and/or seed treatment equipment. The chemical identifiers, 

chemical structure and physicochemical properties of prothioconazole, as well as chemical 

structures of its regulated metabolites are presented in Appendix 1. The most recent risk 

assessment for prothioconazole was conducted in 2013 for proposed uses on (D403739, C. 

Walls, 6/15/2013).

Hazard Identification/Toxicology

No new toxicology data have been received since the last risk assessment (D403739, C. Walls, 

06/15/2013). The requirement for a subchronic inhalation toxicity study has been waived based 

on the low volatility, low acute inhalation toxicity and MOEs greater than the agency’s level of 

concern (LOC) for prothioconazole (TXR# 0056563, J. Van Alstine, 2/21/2013). The toxicology 

database is extensive and well-characterized for both prothioconazole and its main metabolite 

desthio-prothioconazole, and also includes some toxicology studies for two other minor 

metabolites (prothioconazole sulfonic acid potassium salt, and prothioconazole-deschloro). In all 

previous risk assessments, PODs for prothioconazole were based on the toxicology database for 

its metabolite/degradate desthio-prothioconazole, which is more toxic than the parent compound. 

The PODs are based on developmental effects in rabbits for acute dietary and non-dietary 

(dermal and inhalation) risk assessments and liver effects (vacuolation and fatty change) in rats 

for chronic dietary risk assessments

Prothioconazole is extensively metabolized in the rat following oral administration. Including 

desthio-prothioconazole, 18 metabolites and the parent compound were detected in excreta. The 

major route of excretion after oral exposure to prothioconazole or its desthio metabolite was in 

the bile, therefore in non-cannulated animals it was mostly detected in feces. Taken together, 

several non-guideline dermal penetration studies suggest that absorption of prothioconazole 

through the skin is ≤ 49%, and that the desthio metabolite may be found on the application area. 

However, penetration studies also suggest that ≤ 19% of the desthio metabolite is absorbed 

through the skin. 

The target organ of prothioconazole and its desthio metabolite is the liver. Effects were also 

observed in the kidney and bladder, male and female reproductive systems, and serum levels of 

thyroid hormones. Developmental studies via the oral route show that desthio-prothioconazole

produces fetal malformations at doses equal to or lower than the parent compound. Moreover, 
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developmental studies via the dermal route show similar effects, but at higher doses than oral 

studies. Reproductive toxicity was observed in rat studies with prothioconazole (decrease 

number and longer duration of estrous cycles) and its desthio metabolite (dystocia, decreased 

litter size and viability, and decreased pup weight). 

No neurotoxicity effects were observed in acute, subchronic or developmental neurotoxicity 

studies. An immunotoxicity study with prothioconazole did not show effects of concern. 

Prothioconazole is classified as “Not likely to be carcinogenic to humans” based on the lack of 

evidence for carcinogenicity in studies conducted in mice and rats with prothioconazole and 

desthio-prothioconazole Mutagenicity studies for both prothioconazole and desthioprothioconazole were negative. 

The prothioconazole toxicity database is extensive and 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 susceptibility of 

the offspring was observed in developmental studies with the desthio metabolite in rats and 

rabbits, while increased qualitative susceptibility was observed in the rat reproductive study with 

desthio-prothioconazole. However, using the most sensitive of the desthio-prothioconazole

studies to set the POD for risk assessment provides the needed protection of offspring. 

Conclusion: The toxicity database is adequate to support existing registrations, and there are no 

outstanding data requirements for prothioconazole. Toxicity endpoints are not anticipated to 

change, however they will be screened and/or re-evaluated and updated as necessary based on 

current toxicological evaluation practices and current policies.

Dietary Exposure

The nature of the residue in plants and livestock commodities has been adequately defined. 

Adequate metabolism studies on wheat, peanuts, sugar beets, goats, and hens are available to 

support the registered uses. The residues of concern for plants (primary and rotational crops) for 

the tolerance expression and risk assessment are prothioconazole and its desthio metabolite, 

expressed as parent. The residues of concern for livestock (ruminants and poultry) for the 

tolerance expression are prothioconazole, the desthio metabolite, and conjugates that can be 

converted to either of these two compounds by acid hydrolysis, calculated as parent. The 

residues of concern for livestock (ruminants and poultry) for the risk assessment are 

prothioconazole, the desthio metabolite, the 4-hydroxy prothioconazole metabolite, and 

conjugates that can be converted to any of these three compounds by acid hydrolysis, calculated 

as parent.

The residues of concern in drinking water for the risk assessment are prothioconazole, 

prothioconazole-desthio and prothioconazole-S-methyl.

The contribution of triazole derivatives [1,2,4-triazole, triazolylalanine, and triazolylacetic acid] 

from the use of prothioconazole to the aggregate exposure for human health risk assessment has 

been considered (D411386, T. Morton, 5/1/2013 and D322215, 2/7/06, M. Doherty). The U.S. 
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Triazole Task Force (USTTF) submitted a multi-year storage stability study for the triazole 

metabolites in representative crop matrices and processed commodities (MRID 47606601) which 

was reviewed by HED and found acceptable (D. Drew, D363016, 1/12/12).

Adequate enforcement methods are available for plant and livestock commodities. The data 

requirements for testing with multiresidue methods have been fulfilled. 

Adequate field trial, processing, rotational crop, and storage stability data are available to support 

the established tolerances. Since the confined rotational crop studies indicated the potential for 

quantifiable prothioconazole residues in rotational crops, limited field accumulation in rotational 

crops studies were conducted. Based on the limited field accumulation in rotational crop data, a 

30-day plant-back interval (PBI) was recommended for crops not on the label. No 

indirect/inadvertent tolerances for residues in rotational crops are needed.

Adequate dairy cattle and poultry feeding studies have been submitted. The poultry feeding 

study indicates that quantifiable residues are not likely to occur in poultry commodities [i.e., the 

registered uses fall under 40 CFR §180.6(a)(3)]. The existing tolerance for poultry liver was 

based on a metabolism study; since the subsequently-submitted poultry feeding study indicates 

that no quantifiable residues are expected to occur in poultry liver, the tolerance on poultry liver 

should be removed from the CFR as previously required (D363040, S. Funk, 1/15/10).

Analytical reference standards for prothioconazole and prothioconazole-desthio are currently 

available in the EPA National Pesticide Standards Repository [e-mail from Gregory Verdin, 

Analytical Chemistry Branch/Biological and Economic Analysis Division (ACB/BEAD), 

8/6/2015]. The expiration date for prothioconazole is 7/26/2018. The expiration dates for 

prothioconazole-desthio are 3/28/2016 or 4/3/2017.

The most recent acute and chronic dietary (food and drinking water) exposure assessments were 

conducted in 2013. Both assessments were moderately refined, using tolerance-level residues or 

average field trial residues for plants, anticipated residues based on livestock feeding studies for 

livestock commodities, empirical or default processing factors, and the assumption of 100 

percent crop treated. 

The acute estimated drinking water concentration (EDWC) of 99.0 ppb was based on surface 

water residues from the IL corn scenario determined using the Pesticide Root Zone Model and 

Exposure Analysis Modeling System (PRZM-EXAMS). The chronic EDWC of 91.9 ppb was 

based on the cranberry use using the Tier 1 Rice Model. Prothioconazole residues in 

groundwater (acute and chronic), determined by the Screening Concentration in Ground Water 

(SCI-GROW) model, were lower. HED will consult with EFED during Registration Review to 

determine if these estimates need update. If higher estimates are provided, the dietary assessment 

will also be updated.

Both acute and chronic dietary (food and drinking water) risk estimates are below the Agency’s 

LOC. The acute endpoint applied only to females of child bearing age. The dietary (food and 

drinking water) exposure at the 95th percentile is 30% of the acute population adjusted dose 

(aPAD) for females 13-49 years old. The dietary (food and drinking water) exposure is 24% of 
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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. Prothioconazole is 

classified as “not likely to be carcinogenic to humans;” therefore, cancer risk was not assessed.

Conclusions: The residue chemistry database supports the existing uses of prothioconazole and

there is sufficient information available to assess dietary exposure to prothioconazole. A new 

dietary exposure assessment is not anticipated to be needed during prothioconazole Registration 

Review since a dietary assessment was recently conducted. However, if re-evaluation of the 

toxicological database leads to changes in dietary PODs or updated EDWCs are provided, the 

dietary risk assessment will also be re-evaluated.

Residential Exposure

There are no residential uses of prothioconazole; therefore, a residential assessment is not 

needed. 

Residential bystander exposures resulting from off-site transport (e.g. spray drift or

volatilization) may occur as a result of applications of prothioconazole. The potential for spray 

drift will be evaluated for each pesticide during the Registration Review process which ensures 

that all uses for that pesticide will be considered concurrently. In terms of volatilization, the 

agency has developed a Volatilization Screening Tool and a subsequent Volatilization Screening 

Analysis1. During Registration Review, the agency will utilize this analysis to determine if data 

(i.e. flux studies, route-specific inhalation toxicological studies) or further analysis is required for 

prothioconazole.

Conclusion: There is sufficient information available to assess residential exposure to 

prothioconazole. A new residential exposure assessment that considers only residential 

bystander exposures from off-site transport due to agricultural uses will be conducted during 

Registration Review. 

Aggregate Risk Assessment

Aggregate assessments consider exposures from food, drinking water, and residential uses.

Since there are no residential uses of prothioconazole, aggregate risk considers only the dietary 

(food and drinking water) exposures. Acute and chronic dietary assessments were discussed in a 

previous section of this document. Short- and intermediate-term aggregate risk assessments are

not needed because residential exposure scenarios are not expected to occur with 

prothioconazole.

Conclusion: There is sufficient information available to assess aggregate exposure to 

prothioconazole. A new aggregate risk assessment is not expected for Registration Review. 

However if re-evaluation of the toxicological database leads to changes in dietary PODs, the 

aggregate risk assessment will also be re-evaluated.

 

1 http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219
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Occupational Exposure

Based on application rate and label information, occupational handler exposure (dermal and 

inhalation) and occupational post-application exposure (dermal only) are expected to occur for 

short- and intermediate-term durations. Occupational handler exposures involve foliar 

application (mixing/loading/applying by aerial, ground, chemigation, airblast, and handheld 

equipment) and seed treatment (mixing/loading/applying liquid formulation, bagging or planting 

treated seed). Occupational post-application exposures involve activities such as hand 

harvesting, pruning, irrigation, weeding and scouting. Chronic exposure is not expected for the 

existing use patterns. 

All scenarios applicable to currently registered uses have been adequately assessed in previous 

risk assessments (as listed in References section). At the time of Registration Review, HED will 

evaluate if all previous occupational exposure and risk assessments adequately adhere to current 

HED policies. Occupational exposures of prothioconazole were assessed at maximum 

application rates while wearing the Personal Protective Equipment (PPE) indicated in the labels.

For registered foliar and seed treatment uses of prothioconazole, 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) when chemical resistant gloves are worn in 

addition to baseline attire as required by current labels. The combined dermal and inhalation 

MOEs for current use scenarios ranged from 140 to 230,000.

For post-application dermal exposures, HED utilized maximum application rates, standard values 

for exposure time and transfer coefficients, and chemical-specific data for dislodgeable foliar 

residue (DFR) values. Crop-specific data for prothioconazole is available for dry beans, 

soybeans, sugar beets and peanuts. For other crops that had no prothioconazole DFR data, the 

data for dry beans was used. DFR data for dry beans was selected as the best surrogate to 

represent nursery tree seedlings with regard to application rate and climate/soil conditions. For 

all other crops, the dry beans estimates can be considered conservative because they had the

highest measured DFR values.

Twelve hours post-application, the occupational dermal MOEs for most crops ranged from 110

to 6,300 and are not of concern to HED (MOE > 100). One exception was an MOE = 97 at 12 

hours post-application for nursery tree seedlings uses. The current labels has an REI of 12 hours, 

which would be of concern to HED. The same use had a MOE = 190 at 24 hours, therefore an

REI of 24 hours on the label would be protective.

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment has not been performed for prothioconazole; 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). 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.
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Conclusion: There is sufficient information available to assess occupational exposure to 

prothioconazole. A new occupational exposure assessment is not anticipated to be needed during 

prothioconazole Registration Review. However, if re-evaluation of the toxicological database 

leads to changes in occupational PODs, the occupational risk assessment will also be reevaluated.

Public Health and Pesticide Epidemiology Data

An evaluation of the OPP Incident Data System (IDS) was conducted, which includes incidents 

from January 1, 2010 through May 27, 2015 (D428811, S. Recore, 8/25/2015). No singlechemical prothioconazole incidents were identified in the United States. There was 1 incident 

classified as moderate severity, reported for a diluted product containing both prothioconazole 

and penflufen. This incident involved a 50 year old male who got the product on his hands. He 

developed a burning sensation, redness, and weeping sores. He was evaluated by a doctor, 

treated with a steroid injection and prescribed a topical cream to apply to the area. In addition, 

there were 12 incidents classified as minor severity. Because these incidents fall within the 

categories reported as counts (which includes minor, unknown or no effects), there is no unique 

report that provides details about the incidents and single chemical incidents are not 

distinguished from multiple chemical incidents. 

An evaluation of the Sentinel Event Notification System for Occupational Risk (SENSOR)-

Pesticides database was conducted, which covers 12 states from 1998 to 2011. One low severity 

case involving prothioconazole and multiple other active ingredients was identified. The subject

was exposed to drift from an aerial application made to a nearby wheat field. The subject

experienced nausea, burning eyes and nose, dizziness and headache.

Prothioconazole is not included in the Agricultural Health Study (AHS), and therefore, the AHS 

does not provide information for this report. The Agricultural Health Study (AHS) is a high 

quality, prospective epidemiology study evaluating the link between pesticide use and various 

health outcomes. 

Conclusion: Based on the low frequency and severity of incident cases reported for 

prothioconazole in both IDS and SENSOR-Pesticides, there does not appear to be a concern at 

this time that would warrant further investigation. The Agency will continue to monitor the 

incident information and, if a concern is triggered, additional analysis will be included in the risk 

assessment.

Tolerance Assessment and International Harmonization

Tolerances are established for plant commodities under 40 CFR §180.626(a)(1) for residues of 

prothioconazole, 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2-

dihydro-3H-1,2,4-triazole-3-thion, including its metabolites/degradates. Compliance with the 

tolerance levels specified is to be determined by measuring only prothioconazole and its 

metabolite prothioconazole-desthio, or α-(1-chlorocyclopropyl)-α-[(2-chlorophenyl)methyl]-

1H-1,2,4-triazole-1-ethanol, calculated as parent.
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Tolerances are established for livestock commodities under 40 CFR §180.626(a)(2) for residues 

of prothioconazole, 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2-

dihydro-3H-1,2,4-triazole-3-thion, including its metabolites/ degradates. Compliance with the 

tolerance levels specified is to be determined by measuring only prothioconazole and its 

metabolite prothioconazole-desthio, or α-(1-chlorocyclopropyl)-α-[(2-chlorophenyl)methyl]-

1H-1,2,4-triazole-1-ethanol, and conjugates that can be converted to these two compounds by 

acid hydrolysis, calculated as parent.

No tolerances are established for Section 18s, regional registrations, or indirect/inadvertent 

residues.

As shown in Attachment 3, there are Codex maximum residue limits (MRLs) established for 

prothioconazole. The Codex and U.S. residue definitions differ, with residues of concern in the 

U.S. including parent and prothioconazole-desthio (and also including conjugates that can be 

converted to these two compounds by acid hydrolysis for livestock commodities), whereas 

Codex includes only prothioconazole-desthio as the residue of concern. Codex and U.S. 

tolerance levels are similar but not identical. Because both residues of concern and 

tolerance/MRL levels are different, there are harmonization issues for the U.S. with Codex at 

this time. If trade irritants are identified during Registration Review, the Agency will work 

with the registrants to determine if the Codex MRLs and U.S. tolerances can be harmonized. 

Canada regulates parent and the prothioconazole-desthio metabolite for both plant and livestock 

commodities; many tolerance levels in the U.S. and Canada are the same. 

Conclusion: Tolerance expressions are adequate for prothioconazole.

Cumulative

Prothioconazole is a member of the triazole-containing class of pesticides. Although conazoles 

act similarly in plants (fungi) by inhibiting ergosterol biosynthesis, there is not necessarily a 

relationship between their pesticidal activity and their mechanism of toxicity in mammals. 

Structural similarities do 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. In conazoles, however, a variable pattern of toxicological responses is 

found. Some are hepatotoxic and hepatocarcinogenic in mice; some induce thyroid tumors in 

rats; and some induce developmental, reproductive, and neurological effects in rodents. 

Furthermore, the conazoles produce a diverse range of biochemical events including altered 

cholesterol levels, stress responses, and altered DNA methylation. It is not clearly understood 

whether these biochemical events are directly connected to their toxicological outcomes. Thus, 

there is currently no evidence to indicate that conazoles share common mechanisms of toxicity 

and EPA is not following a cumulative risk approach based on a common mechanism of toxicity 

for the conazoles. 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.

Human Studies
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The risk assessments which have been previously conducted for prothioconazole relied in part on 

data from studies in which adult human subjects were intentionally exposed to a pesticide to 

determine their dermal and inhalation exposure. Many such studies, involving exposure to many 

different pesticides, comprise generic pesticide exposure databases such as the Pesticide 

Handlers Exposure Database (PHED), the Agricultural Reentry Task Force (ARTF) Database

and the Agricultural Handler Exposure Task Force (AHETF) Database. EPA has reviewed all 

the studies supporting these multi-pesticide generic exposure databases, and has found no clear 

and convincing evidence that the conduct of any of them was either fundamentally unethical or 

significantly deficient relative to the ethical standards prevailing at the time the research was 

conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of 

Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued 

reliance on these studies.

Data Requirements

No new toxicology, residue chemistry or exposure data are needed to support the registered uses 

of prothioconazole at this time.

References

Author DP/TXR # Date Title

Risk Assessment

M. Doherty D322215 2/7/06 1,2,4-Triazole, Triazole Alanine, Triazole Acetic Acid: Human Health 

Aggregate Risk Assessment in Support of Reregistration and Registration 

Actions for Triazole-derivative Fungicide Compounds.

B. O’Keefe D328967 1/23/07 Prothioconazole: Human Health Risk Assessment for Proposed Uses on Barley, 

Canola, Chickpea, Dried Shelled Peas and Beans (except Soybean), Lentils, 

Oilseed Crops (except Sunflower and Safflower), Peanut, Wheat, and Rice.

B. O’Keefe D329704 12/31/07 Prothioconazole: Human Health Risk Assessment for Proposed Uses on 

Soybeans.

B. O’Keefe D347123 1/5/09 Prothioconazole. Human Health Risk Assessment for Proposed Section 3 Seed 

Treatment Use on Wheat, Barley, and Triticale, Plus Increase Tolerance on 

Forage of Wheat, Barley, and Triticale.

B. O’Keefe D361313 2/5/09 Amendment: Prothioconazole. Human Health Risk Assessment for Proposed 

Section 3 Seed Treatment Use on Wheat, Barley, and Triticale, Plus Increase 

Tolerance on Forage of Wheat, Barley, and Triticale.

B. O’Keefe D363040 3/5/10 Prothioconazole. Human Health Risk Assessment for Proposed Section 3 Uses 

on Crop Group 15 and 16 (Cereal Grains and Forage, Fodder and Straw of the 

Cereal Grains Group Except Sweet Corn, Sorghum and Rice) and Sweet Corn.

B. O’Keefe D378126 5/20/10 Prothioconazole. Amended Human Health Risk Assessment for Proposed 

Section 3 Uses on Crop Group 15 and 16 (Cereal Grains and Forage, Fodder 

and Straw of the Cereal Grains Group, Except Sweet Corn, Sorghum and Rice) 

and Sweet Corn.

B. O’Keefe D378763 1/31/11 Prothioconazole: Human Health Risk Assessment for Proposed Foliar Use on 

Rice and Nursery Tree Seedlings (Pines, Conifers, and Hardwoods) and Seed 

Treatment Uses on Alfalfa, Dried Shelled Pea and Peas (except Soybean) 

Subgroup 6C, Soybean, Cereal Grains (Including Rice), Potatoes (Seed Piece 

Application), and Nursery Trees (Pines, Conifers, and Hardwoods).

B. O’Keefe D387591 11/30/11 Prothioconazole: Human Health Risk Assessment for Proposed Foliar Use on 

Dried Beans, Peanut and Sugarbeet.
Page 11 of 31

Author DP/TXR # Date Title

T. Morton D411386 5/1/13 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.

C. Walls D403739 6/15/13 Prothioconazole: Human Health Risk Assessment for Proposed Uses on Low 

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

Cucurbit Vegetables.

Residue Chemistry

S. Funk D303508 8/21/06 Prothioconazole. Petition for Establishment of Tolerances for Use on Barley, 

Oilseed (Except Sunflower and Safflower) Crop Group, Dried Shelled Pea and 

Bean (Except Soybean) Crop Subgroup, Peanut, Rice, and Wheat. Summary of 

Analytical Chemistry and Residue Data. PP#4F6830.

S. Funk D331663 1/31/08 Prothioconazole. Petitions for Establishment of Tolerances for Use on Sugar 

Beet (PP#6F7134) and Soybean (PP#6F7073). Summary of Analytical 

Chemistry and Residue Data.

S. Funk D363040 1/5/10 Prothioconazole. Tolerance Petition for Uses on Cereal Grain Crop Groups 15 

and 16 (Except Sweet Corn, Sorghum, and Rice) and Sweet Corn. Summary of 

Analytical Chemistry and Residue Data.

S. Funk D379587 1/31/11 Prothioconazole. Amended Registration Request for Seed Treatment Uses on 

Alfalfa, Potato, Rice, Soybean, Dried Shelled Peas and Beans (Subgroup 6C). 

Summary of Analytical Chemistry and Residue Data.

D. Drew D363016 1/12/12 Storage Stability of 1,2,4-Triazole, Triazolylalanine and Triazolylacetic Acid in 

Various Crop Matrices and Processed Commodities (up to four years under 

frozen storage).

M. 

Negussie

D407465 5/22/13 Prothioconazole: Submission of Conditional Data Requirements on Storage 

Stability and Analytical Methods of Plants and Ruminants.

S. Funk D418304 5/20/14 Prothioconazole. Revised Enforcement Methods for Plant and Livestock 

Commodities.

Dietary Exposure Assessment

C. Walls D405654 5/28/13 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.

Occupational Exposure Assessment

S. Winfield D303579 8/18/06 Prothioconazole: Occupational Exposure and Risk Assessment for Proposed 

Uses on Barley, Oilseed (except Sunflower and Safflower) Crop Group, Dried 

Shelled Pea and Bean (except Soybean) Subgroup, Peanut, Rice and Wheat. 

S. Winfield D331662 12/31/07 Prothioconazole: Occupational Exposure and Risk Assessment for Proposed 

Uses on Soybeans and Sugar Beets and revised post-application assessment for: 

Barley, Oilseed (except Sunflower and Safflower) Crop Group, Dried Shelled 

Pea and Bean (except Soybean) Subgroup, Peanut, and Wheat.

K. 

O’Rourke

D348881 12/04/08 Prothioconazole: Occupational and Residential Risk Assessment for Proposed 

Seed Treatment Use on Barley, Triticale and Wheat. 

B. O’Keefe D374704 03/05/10 Prothioconazole: Occupational and Residential Exposure Assessment for 

Proposed Uses on Crop Group 15 and 16 (Cereal Grains and Forage, Fodder 

and Straw of the Cereal Grains Group Except Sweet Corn, Sorghum and Rice) 

and Sweet Corn.

N. Tsaur D374789 1/12/11 Prothioconazole. Occupational and Residential Exposure Assessment for 

Proposed Foliar Use on Nursery Tree Seedlings (Pines, Conifers, and 

Hardwoods) and Seed Treatment Uses on Alfalfa, Beans and Peas (Crop 

Subgroup 6C, Including Soybean), Cereal Grains (Including Rice), Potatoes 

(Seed Piece Application), and Nursery Trees (Pines, Conifers, and Hardwoods).
Page 12 of 31

Author DP/TXR # Date Title

K. Rury D403739 2/08/13 Prothioconazole. Occupational and Residential Exposure Assessment for 

Proposed Uses on Low Growing Berry Subgroup (except Strawberry), 

Bushberry Subgroup, and Cucurbit Vegetables.

T. Kish Decision# 

502447

6/28/15 Label Amendment – Minor edits to the peanut table and updates to the storage 

and disposal section. Product Name: Proline 480 SC Fungicide. EPA 

Registration Number: 264-825 

Incident Report

E. Evans and 

S. Recore

D428811 8/25/2015 Prothioconazole: Tier I (Scoping) Review of Human Incidents and 

Epidemiology

Toxicology

J. Van 

Alstine

TXR 

0056563

2/21/2013 Prothioconazole: Summary of Hazard and Science Policy Council (HASPOC) 

Meeting of January 17, 2013: Recommendations on the Need for a Subchronic 

Inhalation Toxicity Study. 

Attachments

Attachment 1. Chemical Identity

Attachment 2. Toxicity Profile Tables

Attachment 3. Endpoint Tables

Attachment 4. International Residue Limits Table
Page 13 of 31

Attachment 1. Prothioconazole Chemical Identity

Table A1.1. Prothioconazole Nomenclature.

Chemical 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 products (EP) PROLINE 480 SC (41% a.i.); PROVOST 433 SC (12.9% a.i.); PROSARO 421 SC (19% 

a.i.); USF 0728 325 SC (16% a.i.); PROPULSE (17.4% a.i.); STRATEGO 731 (10.8% 

a.i.); STRATEGO YLD (10.8% a.i.); EVERGOL ENERGY (7.18% a.i.); PROCEED 

(6.9% a.i.); EMESTO SILVER (1.68% a.i.); PROCEED MD (1.47% a.i.)

Chemical structure of regulated 

metabolite desthioprothioconazoleα-(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

Cl

Cl

OH

N N

N

H

S

Cl

Cl

OH

N N

N

Cl

Cl

OH

N N

N

H

S

HO
Page 14 of 31

Table A1.2. Physicochemical Properties of the Technical Grade of Prothioconazole

Parameter Value Reference

Melting point/range 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
Page 15 of 31

Attachment 2. Toxicity Profile Tables

Table A2.1 Acute Toxicity Profile – Prothioconazole and Desthio-Prothioconazole

Guideline 

No. Study Type MRID(s) Results Toxicity Category

Prothioconazole

870.1100 Acute oral rat 46246230 LD50 ≥ 6200 mg/kg IV

870.1200 Acute dermal rat 46246244 LD50 ≥ 2000 mg/kg III

870.1300 Acute inhalation rat 46246246 LC50 ≥ 4.99 mg/L IV

870.2400 Acute eye irritation rabbit 46246249 Not an irritant IV

870.2500 Acute dermal irritation rabbit 46246302 Not an irritant IV

870.2600 Skin sensitization Guinea pig 46246305 Not a sensitizer NA

Desthio-Prothioconazole

870.1100 Acute oral rat 46246231 LD50 = 2806 mg/kg III

870.1100 Acute oral mouse 46246242 LD50 = 2235 mg/kg males

LD50 = 3459 mg/kg females

III

870.1200 Acute dermal rat 46246243 LD50 ≥ 5000 mg/kg IV

870.1300 Acute inhalation rat 46246247 LC50 ≥ 5.08 mg/L IV

870.2400 Acute eye irritation rabbit 46246250 Slight irritant (iritis, discharge) III

870.2500 Acute dermal irritation rabbit 46246250 Not an irritant IV

870.2600 Skin sensitization Guinea pig 46246304 Not a sensitizer NA

Table A2.2 Subchronic, Chronic and Other Toxicity Profile – Prothioconazole and 

Desthio-Prothioconazole

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3050 28-Day oral 

toxicity (rat)

Prothioconazole

Study to compare

oral dose 

formulations; not 

designed for 

NOAEL/LOAL 

determination.

46246429 (1998)

Acceptable/nonguideline

0, 10000 ppm neat

0, 10000 ppm stabilized 

in silica

0, 1000 mg/kg/day by

gavage

Lower body weight in neat males by day 7; neat or 

stabilized females by day 28. Blood urea increased, 

kidney, brain, adrenals, heart weights lower in 

gavage males. Liver weights higher in gavage 

females. Liver cytoplasmic change in gavage 

animals; basophilic kidney tubules in neat and 

gavage animals. Liver enzymes induced in neat 

males (ECOD, EH, GS-T)1and females (EH, GST); stabilized males (ECOD, EH, GS-T, UDPGT) 

and females (EH); gavage males (ECOD, GS-T, 

UDPGT) and females (EH, GS-T, UDPGT). Parent 

plasma concentrations (nmol/mL): males 11-29 

stabilized, 25-38 neat, 66-178 gavage; females: 19-

35 stabilized, 42-50 neat, 98-225 gavage. Desthio 

metabolite plasma concentrations: males 0.0-1.0 

stabilized, 0.8-1.6 neat, 1.2-4.7 gavage; females: 

0.1-0.8 stabilized, 0.7-1.2 neat, 1.0-3.9 gavage.

 

1 ECOD = 7-ethoxycoumarin deethylase; ALD = aldrin epoxidase; EH = epoxide hydrolase; GS-T = glutathione-Stransferase; UDPGT = UDP-glucuronyltransferase
Page 16 of 31

Table A2.2 Subchronic, Chronic and Other Toxicity Profile – Prothioconazole and 

Desthio-Prothioconazole

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3050 28-Day oral 

toxicity (rat)

Prothioconazole

Dose-range finding 

study; not designed 

for 

NOAEL/LOAEL 

determination.

46246428 (1997)

Acceptable/nonguideline

0, 400, 2000 or 10000 

ppm

0, 19, 146 or 952 

mg/kg/day males

0, 19, 151 or 1033 

mg/kg/day females

High dose (HD) males had lower food consumption 

and body weight by day 7, and high serum urea by 

end of study. HD females had decrease serum levels 

of T4 and increased TSH. Liver enzymes induced at 

HD: ECOD1, EH, GS-T, UDPGT. EROD and ALD 

were decreased. EH also increased at mid and low 

dose males, GS-T at mid dose in both sexes. HD 

liver weight lower in males but higher in females 

compared to controls; basophilic kidney tubules and 

tubular dilation was observed in both sexes. 

870.3050 28-Day oral 

toxicity (rat)

DesthioProthioconazole

46246430 (1992)

Acceptable/guideline

0, 11, 34, 117 mg/kg/day

males

0, 11, 38, 121 mg/kg/day

females

NOAEL = 11 mg/kg/day males; not observed in 

females

LOAEL = 34 mg/kg/day males, 11 mg/kg/day 

females based on increased liver triglycerides2and 

absolute and relative liver weights2in males and on 

decreased relative and absolute ovary weight with 

histopathology.

870.3100 90-Day oral 

toxicity (rat)

Prothioconazole

46246311 (1999)

Acceptable/guideline

0, 20, 100 or 500 

mg/kg/day

NOAEL = 100 mg/kg/day

LOAEL = 500 mg/kg/day based on increased water 

consumption2, increased cholesterol2, liver effects2

[increased liver weight (female only), hepatocellular 

hypertrophy, cytoplasmic change] and kidney 

effects [decreased urinary volume, increased urine 

protein levels, increased incidence and severity of 

basophilic tubules of the renal cortex (males only)].

870.3100 90-Day oral 

toxicity (rat)

DesthioProthioconazole

46246309 (1999)

Acceptable/guideline

0, 30, 125, 500 or 2000 

ppm

0, 2.2, 9.6, 37 or 162

mg/kg/day males

0, 3.0, 13, 51 or 211

mg/kg/day females

NOAEL = 2.2 mg/kg/day

LOAEL = 9.6 mg/kg/day based on histological 

changes in the liver of males and increased P4502in 

females.

870.3100 90-Day oral 

toxicity (mouse)

Prothioconazole

46246427 (1999)

Acceptable/guideline

0, 25, 100 or 400 

mg/kg/day

NOAEL = 25 mg/kg/day

LOAEL = 100 mg/kg/day based on increased 

cholesterol levels2and increased liver enzyme 

activity in females, increased liver weights1in both 

sexes, and increased incidence of hepatocellular 

hypertrophy1and cytoplasmic change in the liver of 

both sexes.

 

1 ECOD = 7-ethoxycoumarin deethylase; EROD = 7-Ethoxyresorufin deethylase ALD = aldrin epoxidase; EH = 

epoxide hydrolase; GS-T = glutathione-S-transferase; UDPGT = UDP-glucuronyltransferase

2 LOAEL may be conservative according to current toxicological evaluation practices and may be reassessed during 

Registration Review.
Page 17 of 31

Table A2.2 Subchronic, Chronic and Other Toxicity Profile – Prothioconazole and 

Desthio-Prothioconazole

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral 

toxicity (mouse)

DesthioProthioconazole

46246310 (1999)

Acceptable/guideline

0, 40, 200, 1000 or 5000

ppm

0, 12, 59, 294 or 1454 

mg/kg/day males

0, 16, 80, 392 or 2073 

mg/kg/day females

NOAEL =12 mg/kg/day

LOAEL = 59 mg/kg/day based on decreased body 

weight gain in both sexes.

870.3150 90-Day oral 

toxicity (dog)

Prothioconazole

46426313 (2001)

Acceptable/guideline

0, 25, 100, 300 

mg/kg/day

NOAEL = 25 mg/kg/day

LOAEL = 100 mg/kg/day based on kidney

(histopathological) and thyroid (T4 and TSH) 

findings at 100 mg/kg. 

870.3150 39-Day oral

toxicity (dog)

DesthioProthioconazole

Dose-range finding 

study; not designed 

for 

NOAEL/LOAEL 

determination.

46246431 (1999)

Acceptable/nonguideline

0, 10, 100/5000 or 1000

ppm

0, 0.3, 3 or 30 mg/kg/day

males

0, 0.3, 30 or 150

mg/kg/day females

Food consumption markedly declined at 5000 ppm, 

therefore dose was changed to 100 ppm on day 14. 

Urine urea levels increased in males when exposed 

to 5000 ppm. Liver and thyroid weights increased at 

mid and high dose. Ovary and uterine/oviduct 

weights decreased at all doses. Liver enzymes 

induced at mid and high dose: ECOD1, ALD, EH, 

UDPGT. EROD increased in 100/5000 ppm males 

only. 

870.3150 90-Day oral 

toxicity (dog)

DesthioProthioconazole

46246314 (2000)

Unacceptable

0, 40, 200 or 1000 ppm

0, 1.6, 7.8 or 38 

mg/kg/day males

0, 1.6, 8.5 or 43 

mg/kg/day females

NOAEL = 43 mg/kg/day

LOAEL was not observed

870.3200 21/28-Day 

dermal toxicity 

(rat)

Prothioconazole

46426315 (2000)

Acceptable/guideline

0, 100, 300, 1000 mg/kg

NOAEL = 1000 mg/kg/day

LOAEL was not observed

870.3465 90-Day 

inhalation 

toxicity (rat)

DesthioProthioconazole

46246432 (1991)

46246433 (1992)

Unacceptable 

0, 11, 47 or 228 

mg/m3/day

NOAEL = 228.4 mg/m3/day

LOAEL was not observed

The requirement for a subchronic inhalation toxicity

study has been waived (TXR 0056563, J. Van 

Alstine, 2/21/2013)

 

1 ECOD = 7-ethoxycoumarin deethylase; EROD = 7-Ethoxyresorufin deethylase; ALD = aldrin epoxidase; EH = 

epoxide hydrolase; UDPGT = UDP-glucuronyltransferase
Page 18 of 31

Table A2.2 Subchronic, Chronic and Other Toxicity Profile – Prothioconazole and 

Desthio-Prothioconazole

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3700a Prenatal 

developmental 

toxicity (rat) –

oral 

Prothioconazole

46246316 (1996)

46246317 (2002)

Acceptable/guideline

0, 80, 500 or 1000

mg/kg/day

Maternal NOAEL = 80 mg/kg/day

LOAEL = 500 mg/kg/day based on increased 

urination and water consumption and decreased 

body weight gain.

Developmental NOAEL = 80 mg/kg/day

LOAEL = 500 mg/kg/day based on increased 

incidence of delayed ossification, dysplastic pubic

bone and left punctiform 14th rib.

870.3700a Prenatal 

developmental 

toxicity (rat) –

oral 

Prothioconazole

46923601 (2004)

Acceptable/nonguideline

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

Maternal NOAEL = 80 mg/kg/day

LOAEL = 750 mg/kg/day based on increased water

consumption, decreased food consumption and 

decreased body weight gain.

Developmental NOAEL = 80 mg/kg/day

LOAEL = 750 mg/kg/day based on increased 

incidence of rudimentary ribs (comma-shaped).

870.3700a Prenatal 

developmental 

toxicity (rat) –

oral 

DesthioProthioconazole

46246320 (1990)

46246319 (1992)

Acceptable/nonguideline

0 or 100 mg/kg/day

0 or 30 mg/kg/day

Maternal NOAEL = 100 mg/kg/day

LOAEL was not observed

Developmental NOAEL was not observed

LOAEL = 100 mg/kg/day based on developmental 

delays

At 30 mg/kg/day, No NOAEL or LOAEL were 

determined, observations included structural 

abnormalities, developmental delays, death, shows 

14th rib not completely reversible after birth.

870.3700a Prenatal 

developmental 

toxicity (rat) –

oral 

DesthioProthioconazole

46246321, 46246322 

(1991)

Acceptable/guideline

0, 10, 30 or 100 

mg/kg/day (MRID 

46246322)

0, 1 or 3 mg/kg/day

(MRID 46246321)

Maternal NOAEL = 30 mg/kg/day

LOAEL = 100 mg/kg/day based on decreased body 

weight gains, increased liver weight with 

histopathology

Developmental NOAEL 3 mg/kg/day

LOAEL = 10 mg/kg/day based on structural 

supernumerary ribs and incomplete/delayed 

ossification

870.3700a Prenatal 

developmental 

toxicity (rat) –

dermal 

Prothioconazole

46246323 (2001)

Acceptable/nonguideline

Technical: 0 or 1000

mg/kg/day

EC 250 formulation: 0, 

63 or 250 mg/kg/day 

Maternal NOAEL = 1000 mg/kg/day

LOAEL was not observed

Developmental NOAEL = 1000 mg/kg/day

LOAEL was not observed
Page 19 of 31

Table A2.2 Subchronic, Chronic and Other Toxicity Profile – Prothioconazole and 

Desthio-Prothioconazole

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3700a Prenatal 

developmental 

toxicity (rat) –

dermal 

DesthioProthioconazole

46246325, 46246326

(1991)

Acceptable/guideline

Main study: 0, 100, 300 

or 1000 mg/kg/day

Follow-up study: 0, 10 or 

30 mg/kg/day

Maternal NOAEL = 1000 mg/kg/day

LOAEL was not observed

Developmental NOAEL = 30 mg/kg/day

LOAEL = 100 mg/kg/day based on structural 

alterations (14th rib).

870.3700b Prenatal 

developmental 

toxicity (rabbit) –

oral 

Prothioconazole

46246330 (1997)

Acceptable/nonguideline

0, 80, 100, 300 or 480

mg/kg/day

Maternal NOAEL was not observed

LOAEL = 80 mg/kg/day based on reduced food 

consumption and body weights

Developmental NOAEL = 300 mg/kg/day

LOAEL = 480 mg/kg/day based on decreased body 

weight and small fetuses.

870.3700b Prenatal 

developmental 

toxicity (rabbit) –

oral 

Prothioconazole

46246328 (1998)

Acceptable/guideline

0, 10, 30, 80 or 350

mg/kg/day

Maternal NOAEL = 80 mg/kg/day

LOAEL = 350 mg/kg/day based on decreased body 

weight and decreased food consumption.

Developmental NOAEL = 80 mg/kg/day

LOAEL = 350 mg/kg/day based on abortions, total 

resorptions, and lower fetal body weight

870.3700b Prenatal 

developmental 

toxicity (rabbit) –

oral 

DesthioProthioconazole

46246327, (1991)

Acceptable/guideline

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

Maternal NOAEL = 10 mg/kg/day

LOAEL = 50 mg/kg/day based on decreased body 

weight gain1, decrease food consumption, increased 

resorptions, decreased number of fetuses, liver 

histopathology.

Developmental NOAEL = 2 mg/kg/day

LOAEL = 10 mg/kg/day based on structural 

alterations including malformed vertebral body and 

ribs, joint contracture, and other multiple 

malformations.

870.3700b Prenatal 

developmental 

toxicity (rabbit) –

dermal 

DesthioProthioconazole

46246329 (1991)

Acceptable/nonguideline

0, 100, 300 or 1000

mg/kg/day

Maternal NOAEL = 300 mg/kg/day

LOAEL = 1000 mg/kg/day based on local dermal 

toxicity

Developmental NOAEL = 1000 mg/kg/day

LOAEL was not observed
Page 20 of 31

Table A2.2 Subchronic, Chronic and Other Toxicity Profile – Prothioconazole and 

Desthio-Prothioconazole

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3800 Reproduction 

and fertility 

effects (rat)

Prothioconazole

46246331 (1999)

46246334 (2001)

Acceptable/guideline

Pilot: 0, 10, 100, 250 or 

500 mg/kg/day

Main study: 0, 10, 100 or

750 mg/kg/day

Parental NOAEL = 100 mg/kg/day

LOAEL = 750 mg/kg/day based on decreased body 

weights, increased food consumption, increased 

liver weights and kidney weights, decreased 

thymus, testicular, prostate, and epididymis weights 

as well as histopathological findings in the liver and 

kidney.

Reproductive 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 NOAEL = 100 mg/kg/day

LOAEL = 750 mg/kg/day based on decreased pup 

body weight and spleen wt.

870.3800 Reproduction 

and fertility 

effects (rat)

DesthioProthioconazole

46246332 (1992) 

46246333 (2001)

Acceptable/guideline

0, 40, 160, 640 ppm

Premating males: 0, 2.7,

10 or 43 mg/kg/day

Premating females: 0, 

3.0, 12 or 50 mg/kg/day 

Gestation: 0, 2.5, 10 or 

41 mg/kg/day

Lactation: 0, 4.8, 19 or

73 mg/kg/day

Parental NOAEL = 10 mg/kg/day

LOAEL = 43 mg/kg/day based on increased liver 

weight, liver histopathology, decreased food 

consumption during lactation (females only).

Reproductive 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 NOAEL = 10 mg/kg/day

LOAEL = 43 mg/kg/day based on decreased pup 

body weight and increased incidence of cleft palate, 

dilated renal pelvis, dilated ureters and dilated 

bladder.

870.4100a Chronic toxicity 

(rat)

Prothioconazole

FOB conducted 

at 27 and 52 

weeks.

46246335 (2000)

Acceptable/guideline

0, 5, 50 or 750

mg/kg/day

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. 
Page 21 of 31

Table A2.2 Subchronic, Chronic and Other Toxicity Profile – Prothioconazole and 

Desthio-Prothioconazole

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.4100b Chronic toxicity 

(dog)

Prothioconazole

46246336 (2001)

Acceptable/guideline

0, 5, 40 or 125

mg/kg/day

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.

870.4100b Chronic toxicity 

(dog)

DesthioProthioconazole

46246337 (2001)

Unacceptable (not tested 

high enough; not GLP)

0, 40, 300, 2000 ppm

0, 1.4, 10 or 70 

mg/kg/day males

0, 1.6, 11 or 77

mg/kg/day females

NOAEL = 77 mg/kg/day

LOAEL was not observed

870.4200 Carcinogenicity 

(rat)

Prothioconazole

46246338 (2001)

Unacceptable/guideline

for carcinogenicity 

(dose levels too high)

0, 5, 50 or 750/500

mg/kg/day males

0, 5, 50, 750/625

mg/kg/day females

NOAEL = 50 mg/kg/day

LOAEL = 500/625 mg/kg/day (males/females) 

based on increased mortality, decreased body 

weight, 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.

870.4200 Carcinogenicity 

(rat)

DesthioProthioconazole

46246342 (1999)

Acceptable/Guideline 0, 

20, 140, 980 ppm

0, 1.1, 8.0 or 58 

mg/kg/day males

0, 1.6, 11 or 77

mg/kg/day females

NOAEL = 1.1 mg/kg/day

LOAEL = 8.0 mg/kg/day based on clinical

chemistry, histopathology (liver).

No evidence of carcinogenicity

870.4200 Carcinogenicity 

(mouse)

Prothioconazole

46246339 (2001)

Acceptable/guideline

0, 10, 70 or 500

mg/kg/day

NOAEL = 10 mg/kg/day

LOAEL = 70 mg/kg/day based on kidney (tubular

degeneration/regeneration in males) effects.

No evidence of carcinogenicity
Page 22 of 31

Table A2.2 Subchronic, Chronic and Other Toxicity Profile – Prothioconazole and 

Desthio-Prothioconazole

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.4200 Carcinogenicity 

(mouse)

DesthioProthioconazole

46246340 (2000)

46246341 (2001)

Acceptable/Guideline 

0, 12.5, 50, 200 ppm

0, 3.1, 13 or 52 

mg/kg/day males

0, 5.1, 20 or 80 

mg/kg/day females

NOAEL =13 mg/kg/day

LOAEL = 52 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 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

870.5100 Bacterial reverse

mutation test (S.

typhimurium)

Prothioconazole

46246343 (1996)

Acceptable/Guideline

0 and 16 to 5000 

μg/plate

Negative in strains TA1535, TA100, TA1537, 

TA98 and TA102 up to cytotoxic concentrations, 

with and without metabolic activation (S9).

870.5100 Bacterial reverse

mutation test (S.

typhimurium)

DesthioProthioconazole

46246344 (1990)

Acceptable/Guideline

0 or 8 to 5000 μg/plate

Negative in strains TA1535, TA100, TA1537 and

TA98 up to cytotoxic concentrations, with and 

without metabolic activation (S9).

870.5300 In vitro

mammalian cell 

gene mutation

test (Chinese 

hamster lung 

cells)

Prothioconazole

46246404 (1996)

Acceptable/Guideline

0 and 5 to 200 μg/mL

No increase in the frequency of mutations up to 

cytotoxic concentrations, with and without 

metabolic activation (S9).

870.5300 In vitro

mammalian cell 

gene mutation

test (Chinese 

hamster lung 

cells)

DesthioProthioconazole

46246405 (1999)

Acceptable/Guideline

0 or 12.5 to 500 μg/mL

No increase in the frequency of mutations up to 

cytotoxic concentrations, with and without 

metabolic activation (S9).

870.5375 In vitro 

mammalian

chromosome

aberration test

(Chinese hamster 

lung cells)

Prothioconazole

46246406 (1996)

Acceptable/Guideline

0, 75, 100, or 150 μg/mL

May be considered clastogenic, but this may result 

from cytotoxicity rather than direct structural DNA 

damage.
Page 23 of 31

Table A2.2 Subchronic, Chronic and Other Toxicity Profile – Prothioconazole and 

Desthio-Prothioconazole

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.5375 In vitro 

mammalian

chromosome

aberration test

(Chinese hamster 

lung cells)

DesthioProthioconazole

46246407 (1995)

Acceptable/Guideline

Not clastogenic up to cytotoxic concentrations, with 

and without metabolic activation (S9).

870.5395 Mammalian

erythrocyte

micronucleus test 

(mouse) 

Prothioconazole

46246409 (1996)

46246411 (2003)

Acceptable/Guideline

0 or 250 mg/kg

intraperitoneal (males 

and females)

0, 50, 100 and 200 

mg/kg (males only)

Not clastogenic or aneugenic in male mice treated 

up to overtly toxic doses.

870.5395 Mammalian

erythrocyte

micronucleus test 

(mouse) 

DesthioProthioconazole

46246410 (1993)

Acceptable/Guideline

0 or 350 mg/kg

intraperitoneal

Not clastogenic or aneugenic in mice.

870.5550 Unscheduled 

DNA synthesis 

in mammalian 

cells (primary rat 

hepatocytes in 

culture)

Prothioconazole

46246412 (1998)

Acceptable/Guideline

0 and 0.5 to 40 μg/mL

Produced slight non-dose-related increases in grain 

counts and in percent of cells in repair, compared to 

concurrent vehicle control. Positive control induced 

marked increases in both grain counts and percent 

of cells in repair. Therefore, prothioconazole is 

evaluated as equivocal in this assay.

870.5550 Unscheduled 

DNA synthesis 

in mammalian 

cells (in vivo rat 

hepatocytes)

Prothioconazole

46246413 (1999)

Acceptable/Guideline

0, 2500 or 5000 mg/kg

Negative in hepatocytes drawn from male rats.

870.5550 Unscheduled 

DNA synthesis 

in mammalian 

cells (primary rat 

hepatocytes in 

culture)

DesthioProthioconazole

46246414 (1992)

Acceptable/Guideline

0 or 5 to 60 μg/mL

Negative up to cytotoxic concentrations.
Page 24 of 31

Table A2.2 Subchronic, Chronic and Other Toxicity Profile – Prothioconazole and 

Desthio-Prothioconazole

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.6200a Acute 

neurotoxicity 

screening battery 

(rat)

Prothioconazole

46246417 (2000)

Acceptable/Guideline 

0, 200, 750, 2000

mg/kg/day

NOAEL = 200/750 mg/kg/day (male/female)

LOAEL = 750/2000 mg/kg/day (male/female) 

based on the transient effect of reduced motor and 

locomotor activity.

870.6200b Subchronic 

neurotoxicity 

screening battery

Prothioconazole

46246416 (2001)

Acceptable/Guideline 

0, 100, 500 or 1000

mg/kg/day

NOAEL = 500 mg/kg/day

LOAEL = 1000 mg/kg/day based on decreased 

body weight and body weight gain in males.

870.6300 Developmental 

neurotoxicity 

(rat)

DesthioProthioconazole

46246418 (2004)

47293901 (2007)

0, 40, 160, 500 ppm

Gestation: 0, 3.6, 15 or

43

mg/kg/day 

Lactation: 0, 8.1, 36 or

105 mg/kg/day 

Acceptable/Nonguideline

Maternal NOAEL = 15 mg/kg/day

LOAEL = 43 mg/kg/day based on based on 

increased gestation time and dystocia.

Offspring NOAEL = 3.6 mg/kg/day

LOAEL = 15 mg/kg/day based on increased number 

of stillborn pups and increased incidence of 

malocclusion and deviated snout.

870.7485 Metabolism and 

pharmacokinetics

(rat)

Prothioconazole

46246421 (2001)

46246419 (2001)

Acceptable/Guideline

2 or 150 mg/kg single 

gavage dose

2 mg/kg repeat gavage 

dose

4 mg/kg nonradiolabelled and 4 

mg/kg radiolabelled

(whole body 

autoradiography 

experiment only)

Oral absorption was rapid, tmax = 10-41 min males, 

10-60 min females. Oscillations in plasma time 

course indicated enterohepatic circulation; more 

prominent in females. Low dose (single and 

multiple) Cmax = 0.43-70 μg/mL males, 0.92-45 

μg/mL females. Bi-phasic elimination: phase I t1⁄2 = 

24-56 min males, 21-30 min females; phase II t1⁄2 = 

8-17 hr male, 9-18 hr female. After 7 day single 

dose, 0.11-1.5% was still in tissues, mostly in liver 

and GI tract. After 48 hr repeat dose amount still in 

tissues: 3.8% male, 0.8% females; mostly in liver

and GI tract. Most of the dose excreted in feces: 81-

96% males, 78-88% females. In bile cannulated 

males, up to 90% dose excreted in bile. Extensively 

metabolized, 18 metabolites and parent compound 

detected in excreta, 15 metabolites identified: 1,2,4-

triazole; P-desthio; P-3-OH-desthio; P-4,5-2OHdesthio; P-4-OH; P-4-OH-desthio; P-desthio-2OHdiene; P-desthio-2OH-dienyl glucuronide; P-2OHdesthio; P-2OH-desthio-glucuronide; P-OH-desthioglucuronide; P-OH-OCH3-desthio-glucuronide; PN-glucuronide; P-S- or O-glucuronide; Ptriazolinone.
Page 25 of 31

Table A2.2 Subchronic, Chronic and Other Toxicity Profile – Prothioconazole and 

Desthio-Prothioconazole

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.7485 Metabolism and 

pharmacokinetics 

(male rat)

DesthioProthioconazole

46246422 (2001)

46246420 (2001)

Acceptable/Nonguideline

1 or 5 mg/kg gavage or 

intraduodenal

Absorbed from GI tract in < 4 minutes. Cmax =

0.052 μg/g at 1.5 hours (tmax). Cmax lower than 

concentration in other tissues indicating rapid 

distribution from the plasma to the peripheral 

tissues. About 5% dose remained in body after 48 

hours: 3.0% liver, 1.9% GI tract. 83% excreted in 

feces, 11% urine, negligible in expired air. 

Elimination t1⁄2 = 44 hrs. In cannulated animals, 

85% of an intraduodenal dose was found in bile. 

Timing of excretion shows delayed fecal excretion, 

suggesting enterohepatic recirculation. Metabolites 

could not be isolated from fecal samples. 18 

potential metabolites were detected in bile, but only 

5 could be identified, accounting for 55% of the 

dose: P-desthio-dihydroxydiene, P-desthiodihydroxydiene, P-desthio-phenylhydroxy, Pdesthio-tetrahydroxyolefine and P-desthio-2OH. 

The 5 identified metabolites were also detected as 

their glucuronic acid conjugates, as well as a 

methylated form of P-desthio-2OH. 

870.7485 Metabolism and 

pharmacokinetics

(gestation day 6 

rats)

DesthioProthioconazole

46246439 (2001)

Supplemental

1 or 3 mg/kg gavage 

single or multiple dose

30 or 100 mg/kg dermal 

single or multiple dose

Oral: Absorption was fast with tmax = 1 hr; Cmax = 

0.07 μg/mL for single and repeated dose. t1⁄2 = 17 hr 

single dose, 21 hr repeated dose. 

Dermal: Biphasic absorption (single and repeated 

dose): first phase resulted in a plateau from 1 hr to 6 

hr after application (end of exposure). After 

washing skin for single dose, second phase with tmax

= 8 hr, Cmax = 0.04 μg/mL, t1⁄2 = 24 hr. Multiple 

dose had slightly higher Cmax = 0.05 μg/mL at same 

tmax = 8 hr and shorter t1⁄2 = 16 hr.

Estimated DAF = 71% based on repeated dose Cmax

for oral vs. dermal exposures

870.7600 Dermal 

penetration 

(male rat)

Prothioconazole

46246426 (1997)

Not classified (N=5)

25 mg emulsifiable 

concentrate (2.5 mg/cm3)

0.067 mg 1:373 aqueous 

solution (0.0067 

mg/cm2)

24 hr exposure

(results expressed as % 

of applied dose)

Emulsifiable Concentrate: Systemic absorption: 

10%. At application site (absorbable): 1.3%. Total 

potentially absorbed: 13%. Degradation products 

were 0.5% at application site but P-desthio not 

found; extraction efficiency 64%. 

Aqueous Solution: Systemic absorption: 13%. At 

application site (absorbable): 36%. Total potentially 

absorbed: 49%. Metabolite P-desthio found in skin 

rinse (6.3%) and skin (3.3%); extraction efficiency 

64%. 

Estimated DAF = 13% concentrate, 49% aqueous 

solution, based on total potentially absorbable dose
Page 26 of 31

Table A2.2 Subchronic, Chronic and Other Toxicity Profile – Prothioconazole and 

Desthio-Prothioconazole

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.7600 Dermal 

penetration 

(male rhesus 

monkey)

Prothioconazole

46246423 (2003)

Not classified (N=1)

240 μg intravenous

240 μg dermal (10 

μg/cm2) 8 hr exposure

Intravenous: Over 8 days, 35.7% recovered in urine, 

13.9% feces and 31.1% cage rinse; indicating that 

18.8% may have remained in the body

Dermal: Over 8 days, 3.3% dose recovered in 

excreta (1.9% urine, 0.9% feces, 0.3% cage rinse), 

89.2% from application site. 7.49% was 

unaccounted for. 

Estimated DAF = 4.1% based on total intravenous 

vs. dermal recovered doses

870.7600 Dermal 

penetration 

(male rhesus 

monkey)

DesthioProthioconazole

46246424 (2003)

Not classified (N=1)

240 μg (10 μg/cm2) 

dermal

240 μg intravenous

Dermal administration to one animal resulted in a 

dermally absorbed dose of 7.1% through 192 hours. 

10.5% applied dose was recovered from the nonocclusive cover and therefore not available for 

absorption. 83.3% was recovered from the 

application site). 97.5% recovery of radioactivity 

intravenously dosed, indicating 2.5% may have 

remained in the body.

870.7600 Dermal 

penetration 

(male rhesus 

monkey)

DesthioProthioconazole

46246425 (2003)

Not classified (N=5)

144 μg dermal (6 

μg/cm2)

Over 144 hr, 18.6% recovered in excreta (10.3 % 

urine, 5.8 % feces, 1.5% cage rinse, 1.1% pan rinse 

and chair wipe), 73.5% from site of application.

Estimated DAF: 19% based on total recovery in 

excreta

870.7800 Immunotoxicity

Prothioconazole

46246438 (2002)

Acceptable/nonguideline

0, 25, 100 or 400 

mg/kg/day

Did not suppress the humoral immune response in a 

dose-dependent manner. Did not significantly 

decrease the IgM antibody-forming cell response to 

the T-dependent antigen. An increase in plaqueforming cells was noted in the high-dose males.

1

Special 

Study

Inhibition of

enzymes in liver

microsomes

(rat and mouse)

Prothioconazole

46246415 (1999)

Unacceptable

0, 0.1, 0.3, 1, 10, 30 or 

100 μM ECOD assay

0, 25, 50, 75, 100, 500 or 

1000 μM testosterone 

assay

No conclusions can be reached from this study 

because of the numerous study deficiencies.

 

1 A LOAEL/NOAEL statement will be added to this study during Registration Review.
Page 27 of 31

Table A2.2 Subchronic, Chronic and Other Toxicity Profile – Prothioconazole and 

Desthio-Prothioconazole

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

Special 

Study

Hepatic and renal 

enzyme activities 

after 13 week 

gavage and 4 

week recovery 

period (dogs)

Prothioconazole

46246435 (2000)

Supplementary/nonguideline 

0, 25, 100, 300 

mg/kg/day

After 13 weeks gavage, liver epoxide hydrolase 

(EH) was significantly increased at 100 (58%) and 

300 (85%) mg/kg/day compared to control but only 

in females. Kidney enzyme activities were generally 

10-100X lower than liver activity and undetectable 

in some cases (ECOD, GLU-T). Kidney EH activity 

was reduced (36%) at 300 mg/kg/day After 

recovery, no significant differences in enzyme 

activities were noted in either sex

Special 

Study

Liver Foci Study

(rat)

DesthioProthioconazole

46246437 (1991)

Acceptable/nonguideline

0 or 980 ppm

Compared to controls, incidences of foci of altered 

hepatocytes (FAH) were slightly increased at 6 

weeks, but slightly decreased at 12 weeks. 

Increased glucose-6-phosphate dehydrogenase 

activity and severe cytoplasmic vacuolation in the 

Zone II hepatocytes (particularly after 12-week) 

were found in males. Enzyme induction in 

periportal hepatocytes was stronger at 13 weeks. 

There were no clear findings in the females. This 

study reaffirms that there were no liver tumors in 

the long-term studies and supports the findings that 

there are other effects in the liver (vacuolation and 

enzyme induction).

Special 

Study

Interaction with

thyroid 

peroxidase in 

vitro

Prothioconazole

and metabolites

46246436 (1996)

Acceptable/nonguideline

3-mercapto-1,2,4-triazole had the lowest IC50 

value, followed by PTU (positive control) then 

prothioconazole and JAU 6953. TPO may be 

irreversibly inhibited. PTU, ETU, prothioconazole, 

JAU 6953 and 3-mercapto-1,2,4-triazole dosedependently suppressed TPO-catalyzed iodine

formation temporarily. Following suppression, 

iodine reappeared. 3-mercapto-1,2,4-triazole 

suppressed the rate of the reappearing iodine 

formation longer than the other compounds.

Special 

Study

Assessment of

Ovarian Findings 

in Rodents

DesthioProthioconazole

46246441 (2001)

Acceptable/Non 

Guideline

The only study where ovary findings influence the 

study LOAEL is MRID 46246430. 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.
Page 28 of 31

Attachment 3. Prothioconazole Endpoints and Doses for Risk Assessment

Table A3.1 Summary of Toxicological Doses and Endpoints for Prothioconazole (Based on DesthioProthioconazole) for Use in Dietary, Non-Occupational and Occupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/FQ

PA Safety 

Factors

RfD, PAD, Level 

of Concern for 

Risk Assessment

Study and Toxicological Effects

Acute Dietary 

(General 

Population, 

including Infants 

and Children)

No observed effects could be attributable to a single dose exposure. Therefore, a dose and 

endpoint were not selected for this exposure scenario.

Acute Dietary

(Females 13-49 

years of age)

NOAEL = 2.0

mg/kg/day

UFA= 10X

UFH=10X

FQPA SF= 1X

aRfD = 0.02

mg/kg/day

aPAD = 0.02

mg/kg/day

Developmental Toxicity Study in 

Rabbits – Oral 

LOAEL = 10 mg/kg/day based on 

structural alterations including 

malformed vertebral body and ribs, 

arthrogryposis, and multiple 

malformations.

Chronic Dietary 

(All Populations)

NOAEL= 1.1

mg/kg/day

UFA= 10X

UFH=10X

FQPA SF= 1X

cRfD = 0.01 

mg/kg/day

cPAD = 0.01

mg/kg/day

Chronic/Oncogenicity Study in 

Rats – Oral 

LOAEL = 8.0 mg/kg/day based on 

liver histopathology (hepatocellular 

vacuolation and fatty change 

(single cell, centrilobular, and 

periportal).

Incidental Oral 

Short- (1-30 days)

and IntermediateTerm (1-6 months)

Incidental oral exposure endpoint not identified because residential exposure is not 

anticipated.

Dermal Short- (1-

30 days) and 

Intermediate-Term 

(1-6 months)

NOAEL= 30

mg/kg/day

UFA= 10X

UFH=10X

Occupational LOC 

for MOE = 100

Developmental Toxicity Study in 

Rats – Dermal 

LOAEL = 100 mg/kg/day based on 

an increased incidence of 

supernumerary rib (14th rib).

Inhalation ShortTerm (1-30 days)

Intermediate-Term 

(1-6 months)

NOAEL= 2.0 

mg/kg/day

UFA= 10X

UFH=10X

Toxicity via the 

inhalation route is 

assumed to be 

equivalent to oral 

toxicity

Occupational LOC 

for MOE = 100

Developmental Toxicity Study in 

Rabbits – Oral 

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. 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). UFL = use of a LOAEL to extrapolate a NOAEL. FQPA SF = FQPA Safety Factor. PAD = population adjusted 

dose (a = acute, c = chronic). RfD = reference dose. 
Page 29 of 31

Attachment 4. Prothioconazole International Residue Limits Table (as of 5/6/2015)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex2

40CFR §180.626 

(a)General. (1) Compliance with the 

tolerance levels specified below is to be 

determined by measuring only 

prothioconazole and its metabolite 

prothioconazole-desthio, or α-(1-

chlorocyclopropyl)-α-[(2-

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

Plants: 2-[2-(1-

chlorocyclopropyl)-3-(2-

chlorophenyl)-2-

hydroxypropyl]-2,4-dihydro3H-1,2,4-triazole-3-thione, 

including the metabolite α-(1-

chlorocyclopropyl)-α-[(2-

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

triazole-1-ethanol

Prothioconazoledesthio

The residue is not fatsoluble.

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico1 Codex2

Alfalfa, forage 0.02

Alfalfa, hay 0.02

Beet, sugar, roots 0.25 0.25 0.3

Berry, low growing, except 

strawberry, subgroup 13-07H

0.20 0.2 bearberries, bilberries,

cloudberries, lingonberries, 

muntries, partridgeberries

2 lowbush blueberries,

cranberries (in subgroup 13-07B 

also)

0.15 cranberry

Bushberry, subgroup 13-07B 2.0 2 1.5 bush berries 

Corn, sweet kernel plus cob with 

husks removed

0.04 0.04 0.02

Grain, aspirated grain fractions 11

Grain, cereal, forage, fodder and 

straw, group 16, except 

sorghum, and rice; forage

8.0

Grain, cereal, forage, fodder and 

straw, group 16, except 

sorghum, and rice; hay

7.0

Grain, cereal, forage, fodder and 

straw, group 16, except 

sorghum, and rice; stover

10 5 fodder (dry) of 

cereal grains

15 fodder of (maize 

(dry), sweet corn) 

(proposed)

Grain, cereal, forage, fodder and 

straw, group 16, except 

sorghum, straw

5.0

Grain, cereal, group 15, except 

sweet corn and sorghum

0.35 0.35 (except rice, sweet corn and 

sorghum)

0.2 barley

0.1 maize, popcorn 

0.1 wheat
Page 30 of 31

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex2

0.02 sweet corn 

(corn-on-the-cob) 

0.05 oats, rye, triticale

Pea and bean, dried shelled, 

except soybean, subgroup 6C

0.9 0.9 1 pulses (except 

soybean dry)

Peanut 0.02 0.02 0.02 (*)

Potato 0.02 0.02 0.02 (*) (proposed)

Rapeseed, seed 0.15 0.15 0.1

Rice, hulls 0.90

Soybean, forage 4.5

Soybean, hay 17

Soybean, seed 0.15 0.15 0.2 soya bean (dry) 

(proposed)

Vegetable, cucurbit, crop group 

9

0.30 0.3 0.2 fruiting 

vegetables, cucurbits 

(except watermelon) 

(proposed)

MRLs with NO US Equivalent

Subgroup 1C 0.02 

Crops in Subgroup 20A 0.15 

Crops in Subgroup 20B 0.2 

Peanut fodder 15 (proposed

40CFR §180.626 Canada Mexico1 Codex2

(a) General. (2) Compliance with the 

tolerance levels specified below is to be 

determined by measuring only 

prothioconazole and its metabolites 

prothioconazole-desthio, or α-(1-

chlorocyclopropyl)-α-[(2-

chlorophenyl)methyl]-1H-1,2,4-triazole1-ethanol, and conjugates that can be 

converted to these two compounds by 

acid hydrolysis, calculated as parent

Livestock: 2-[2-(1-

chlorocyclopropyl)-3-(2-

chlorophenyl)-2-

hydroxypropyl]-2,4-dihydro3H-1,2,4-triazole-3-thione, 

including the metabolite α-(1-

chlorocyclopropyl)-α-[(2-

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

triazole-1-ethanol and their 

conjugates

Prothioconazoledesthio

The residue is not fatsoluble.

Commodity

Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico1 Codex2

Cattle, fat 0.1 0.1

Cattle, meat 0.02 0.02 0.01 meat(from 

mammals other than 

marine mammals)

Cattle, meat byproducts 0.2 0.2 0.5 edible offal 

(mammalian)

Goat, fat 0.1 0.1
Page 31 of 31

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex2

Goat, meat 0.02 0.02 0.01 meat(from 

mammals other than 

marine mammals)

Goat, meat byproducts 0.2 0.2 0.5 edible offal 

(mammalian)

Hog, meat byproducts 0.05 0.05 0.5 edible offal 

(mammalian)

Horse, fat 0.1 0.1

Horse, meat 0.02 0.02 0.01 meat(from 

mammals other than 

marine mammals)

Horse, meat byproducts 0.2 0.2 0.5 edible offal 

(mammalian)

Milk 0.02 0.02 0.004 (*)

Poultry liver 0.02 0.02 meat byproducts of poultry

Sheep, fat 0.1 0.1

Sheep, meat 0.02 0.02 0.01 meat(from 

mammals other than 

marine mammals)

Sheep, meat byproducts 0.2 0.2 0.5 edible offal 

(mammalian)

MRLs with NO US Equivalents

Eggs 0.01

Meat of poultry 0.02 

Completed: M. Negussie; 8/24/15

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

2 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = 

processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the 

fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.