### UNITED ST ATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D

. C. 20460

MEMORANDUM



### Date : December I 5 1

, 

### 20 1 5 OFFICE OF CHEMICAL SAF ET Y AND POLLUTION PREV ENTI ON



### SUBJECT : 

### Prot hi oco n azo l e. Hum a n H ea lth Asses sm e nt Sco pin g D oc um e nt in S u ppo rt of Reg i st r at i o n R eview

.

P C Cod e : 1 13961 DP Barcod e : 0 427290 Decision No

. : 50498 1 Registration No.: 264-824 P e titi o n N o .: A R e gu lat ory Ac ti o n: R egistrat i o n Rev i ew Ri s k A ss essme n t T y p e: S in g l e C h em i ca l / Agg r egate Ca s e No .: 7054 TXR No. : NA C AS No.: 178928-70

- 6 MRID No.: NA 40 CFR : § 180.626



### FROM: Min e r va M erca d o ,

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### R i sk Assessme n t Branc h 3 ( 3) H ea lth Effects Di v i s i o n ( 7 509 P )

THROUGH: C hri s tin e Olin ge r , B ran c h

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Risk Assessmen t Branc h 3 (RA B 

# '1.-pLH ea lth E ff ects Di v i s i o n ( 7 509 P

TO: B ri an Kett l

, C h emica l Review Ma n ager Ca thr y n Bri tto n , T ea m L eade r Risk Management and I mpleme n tat i o n B ranc h II P es ti c i de R eeva lu a tion Di v i s i o n (75 08P )

Execu t ive Summary



### To evaluate the scope of wo r k n ecessa r y t o s upp or t R eg i s t rat i o n R ev i ew, H E D h as co n s i de r ed
prev i ous r i sk assessmen t s , any new toxicity

, exposure a n d usage data

, and cu rr e nt Agency po l icy and m e th odo l og i es. Th e m os t r ece nt ri s k assess m e nt fo r pr o thi oco n azo l e was co ndu cte d in 20 1 3 for new proposed uses on l ow growing berry (except straw b er r y)

, bush b e r ry, and cuc ur b it
vege t ab l e s u bgro u ps (C . W a l l s, 6115 / 20 1 3

, D4 03 7 39)

. C urr e nt reg i s t e r e d u ses o f prothiocona z ole include fo l iar and seed tr eat m e n t of a va r iety of food cro p s (ce r ea l gra in s,

Page I of 3 1

### berries, oil seeds, vegetables, pea and beans, peanuts, suga r beets) and nonfood crops (conifer and hardwood seeds and seed lin gs). End-use products are fo rmul a t ed as so lu ble o r emulsifiab l e

conce nt rates t o be diluted before application by ground sprayer, ae rial

, chemigat i on and / or seed

treatment equipment.

The extensive prothiocona zo le toxicology database, which includes data fo r prothioconazo l e , desthio-prothioconazole and other metabo lit es , is adeq u ate fo r ri s k assessment. T h e target organ of prothioconazole and its desthio m etabo lit e is the liver. Effects were also observed in the k i dney a nd blad d er, male and female reproductive syste ms , and se rum l eve l s of th y roid hormone s. P oints of departure (PO Os) for prothiocona zo l e a r e based o n th e toxicology da t abase for it s metabolite / degradate, de st hio-prothioconaz o le

, which is more toxic than the parent compound. The P ODs are based on dev e l opmental effects in rabbit s fo r acu t e dietary and nondietary ( dem1al and i nh ala ti o n ) ri sk assessme n ts and li ver effects (vacuo l ation and fatty change) in r ats for chronic dietary ri sk assessments. Prothioconazole is class i fied as "No t likel y to be carcinogenic to h uma n s" based on th e l ack of evidence for carcinoge nicit y in stud i es conducted in mice an d ra t s wit h prothioconazol e and de s thio-prothioconazole. There is evidence for incr eased susceptib ili ty following in utero exposure and pre / post-nata l exposure to the des thi o metabolite. The conce rn is l ow fo r the obse r ved s u scep tibilit y because cl ea r NOAELs and LOAELs were estab li s h ed for the d eve l op m enta l and reproductive effects and the POD used for

ove r a ll risk assessment is derived from th e metabo lit e a nd wo ul d be protective of the developmental a nd reproductive effects obse r ved with the metabolite. There i s no r es idual uncertainty for pre / post-natal toxicity, therefore, the Food Quality Protection Act (FQ PA) safety factor (SF) is reduced to 1 X. Tox i c it y e ndp oints are n ot ant i c ip ated to cha n ge, however they w ill be screened and / or re- eva luated and updated as necessar y based o n current toxico l ogical evaluation pr actices and current policies.

The res i due c hemi stry database is sufficient to support the current registrat i o n s of prothioconazole. The natur e of the r esidue h as been adequately defined in crops, rotated crops , a nd li ves t ock. Ade qu ate field trial/proce ss in g da t a, ro t at ional crop data, storage stability data and e nforcement methods are available. New d i etary exposure and aggregate risk assess m ents

are not an ti cipated to be needed d urin g R egis trati o n R ev i ew

.

Tole r ance expressions are adequate for prothioconazole.

Th ere are no uses of prothioconazole in re sidentia l se tting s ; therefore

, a r es i de n tial expos ure and risk assessmen t i s not needed. The Agency w ill exa mine the n eed fo r sp r ay drift and volat ili zation assessments during R egis tration R eview for prothioconazole based on t he potential for exposure to bystanders from agricultural app lications.

T h ere i s s ufficient informat i on ava ilable to assess occupational exposure to prothioconazolc. All

scenar io s applicable t o current l y r eg i stered u ses have been adequate l y assessed in p r ev i o u s ri sk

assess m e nt s. Margi n s of exposure (MO Es) are not of concern to HED (i.e., MO Es > I 00) for all

current l y registered uses and scenarios

. A new occupational exposure assessment i s not anticipated to be n eeded durin g prothioconazole Registration Review. The c urr ent l abels h ave an RE I of 1 2 hours

, which would be of concern to H E D o nl y for nursery tree seedl in g uses (MOE =

P age 2of31

### Page 3 of 31

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, b asidiomycetes and d euteromycetes 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 vegetable s 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. E nd

- use products are for mulated as soluble or emulsified concentrate s 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 ha ve 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 l evel of

c oncern (LOC) for prothioconazole (TXR # 0056563, J. Van Alstine, 2/21/2013)

. The toxicology database is extensive and well

- characterized for both prothi oconazole 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 assessment s , 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 metabolit es 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,

sever al 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 met abolite 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 hormone s

. Developmental studies via the oral route show that desthio

- prothioconazole produce s fetal malformations at doses equal to or lower than the parent compound

. Moreover,

### Page 4 of 31

developmental studies via the dermal route show similar effects, but at higher doses tha n 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 neur otoxicity effects were observed in a cute
, 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 desthio

prothioconazole 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 develop mental 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 susce ptibility was observed in the rat reproductive study with desthio

- prothioconazole

. H owever, u sing the most sensitive of the desthio

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

Conclusion : The t oxicity 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 necessar y 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, peanut s , sugar beet s , goats, and hens are available to support the registered uses. The residue s 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 concer n 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 pa rent.

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 pro thioconazole 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.

### Page 5 of 31

Triazole Task Force (USTTF) submitted a multi

- year storage stability study f or 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 commodit ies

. The data requirements for testing with multiresidue methods have been fulfilled.

Adequate field trial, processing , rotational crop, and storage stability data are available to supp ort 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. Ba sed 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 h ave 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 metabol ism 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)

, 8/6/20 15 ] . 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 a cute and chronic dietary (food and drinking water) expo sure 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 d efault 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 a nd 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. Prothioconazol e residues in
g roundwater (acute and chronic)

, determined by the Screening Concentration in Ground W ater (SCI

- GROW) model

, w ere lower. HED will consult with EFED during Reg istration 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 95 th 

### 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

### Page 6 of 31

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

. Prothioconaz ole 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 die tary 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

T here are no residential uses of prothioconazole ; therefore

, a res idential 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 prothio conazole. 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 Screenin g Analysis 1



### . 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 durin g 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. S hort

- and intermediate

- term aggregate risk assessment s 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 da tabase 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

### Page 7 of 31

Occupational Exposure

Based on application rate and label information, occupational handler exposure (dermal and inhalation) an d occupational pos t

- applicat ion 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 trea tment ( mixing/loading/applying liquid formulation, b agging 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, t he 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 label s

. T he combined dermal and inhalation MOEs for current use scenarios ranged from 1 4 0 to 230

, 0 00.

For post

- ap plication 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 fo r dry beans, soybeans, sugar beets and peanuts. For other crops that had no prothioconazole DFR data, t he 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 the y had the highest measured DFR value s

. 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

. T he current label s ha s 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 o n 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 ne ed for a quantitative occupational post

- application inhalation exposure assessment for prothioconazole.

### Page 8 of 31

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 re

evaluated.

P ublic Health and Pesticide Epidemiology Data

An e valuation 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 single

chemical 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 hand s. 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. Beca use 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 incident s 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. O ne low severity case involving prothioconazole and multiple other active ing redients 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 : B ased 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 i ncident 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.

### Page 9 of 31

Tolerances are established for livestock commodities under 40 CFR §180.626(a)(2) for resid ues 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 proth ioconazole 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 a re 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 t he 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 id entified during Registration Review, the Agency will work with the registrants to determine if the Codex MR L s and U

. S

. tolerances can be harmonized

. Canada regulates parent and the prothioconazole

- desthio metabolite for both plant and livestock commoditie s; many tolerance levels in the U.S. and Canada are the same.

Conclusion: Tolerance expressions are adequate for prothioconazole.

Cumulative

Prothio conazole is a member of the triazole

- containing class of pesticides. Although conazoles act similarl y 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. Evi dence 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 E PA 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

### Page 10 of 31

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 e xposure 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

- pesti cide 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 conducte d. 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 c hemistry 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 She lled 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 Healt h 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 Prothioconazol e . 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 Nurs ery 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 V egetables 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 D3795 87 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 Requirem ents 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 S oybean) 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 D 374704 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, S orghum and Rice) and Sweet Corn. N. Tsaur D 374789 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), Po tatoes (Seed Piece Application), and Nursery Trees (Pines, Conifers, and Hardwoods).

### Page 12 of 31

Author DP/TXR # Date Title
K. Ru ry D 403739 2/08/ 13 Prothioconazole. Occupational and Residential Exposure Assessment for Proposed Uses on Low Growing Berry Subgroup (except Strawberry), B ushberry 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. E PA 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 Identi ty

Table A1.1. Prothioconazole Nomenclature.

Chemical Structure

Commo n 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 desthio

prothioconazole

α

- (1

- chlorocyclopropyl)

- α

- [(2

- chlorophenyl)

- methyl]

- 1 H

- 1,2,4

- triazole

- 1

- ethanol

Chemical structure of metabolite 4

- hydroxy prothioconazole (r esidue of concern for risk assessment in livestock commodities)

2

- [2

- (1

- chlorocyclopropyl)

- 3

- (2

- chloro

- 4

- hydroxyphenyl)

- 2

- hydroxypropyl]

- 1,2

- dihydro

3 H

- 1,2,4

- triazole

- 3

- thione

### 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, pK a 6.9 (calculated from K OW )

Octanol/water partition coefficient (at 20 oC) [Log K(ow)] unbuffered water 4.05 pH 4 4.16 pH 7 3.82 pH 9 2.00 UV/visible absorption Peak maxima at 257 nm

### Page 15 of 31

Attachment 2. Toxicity Profile Tables

Table A 2.1 Acute Toxicity Profile

– Prothioconazole and Desthio

- Prothioconazole

Guideline No. Study Type MRID(s) Results Toxicity Category

Prothioconazole

870.1100 Acute oral rat 46246230 LD 50 ≥ 6200 mg/kg IV

870.1200 Acute dermal rat 46246244 LD 50 ≥ 2000 mg/kg III

870.1300 Acute inhalation rat 46246246 LC 50 ≥ 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 LD 50 = 2806 mg/kg III

870.1100 Acute oral mouse 46246242 LD 50 = 2235 mg/kg males
LD 50 = 3459 mg/kg females III

870.1200 Acute dermal rat 46246243 LD 50 ≥ 5000 mg/kg IV

870.1300 Acute inhalation rat 46246247 LC 50 ≥ 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 A 2.2 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

t oxicity (rat)
Prothioconazole

Study to compare oral dose formulations; not designed for NOAEL/LOAL determination. 462464 29 (1998 )

Acceptable/ non

guideline 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) 1 and females (EH, GS

T); stabilized males (ECOD, EH, GS

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

- T, UDPGT ) and females (EH, GS

- T, UDPGT ). P arent 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

- S

t ransferase; UDPGT = UDP

- glucuronyltransferase

### Page 16 of 31

Table A 2.2 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

t oxicity (rat)
Prothioconazole
Dose

- range finding

s tudy; not designed for NOAEL/LOA E L determination. 46246428 (1997)

Acceptable/ non

guideline 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 l ower 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: E COD 1 , 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

t oxicity (rat)
Desthio

Prothioconazole 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 triglycerides 2 and absolute and relative liver weights 2 in 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 consumption 2 , increased cholesterol 2 , liver effects 2 [increased liver weight (female only), hepatocellular hypertrophy

, cy toplasmic change] and kidney effects [decreased urinary volume, increased urine protein levels, i ncreased incidence and severity of basophilic tubules of the renal cortex (males only )]

. 870.3100 90

- Day oral

toxicity (rat)
Desthio

Prothioconazole 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 21 1 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 P450 2 in 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 levels 2 and increased liver enzyme activity in females, increased liver weights 1 in both sexes, and increased incidence of hepatocellular hypertrophy 1 and 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 con servative according to current toxicological evaluation practices and may be reassessed during Registration Review.

### Page 17 of 31

Table A 2.2 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)
Desthio

Prothioconazo le 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)
Desthio

Prothioconazole

Dose

- range finding

s tudy; not designed for NOAEL/LOA E L determination. 46246431 (1999)

Acceptable/ non

guideline 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 con sumption markedly declined at 5000 ppm, therefore dose was changed to 100 ppm on day 14. Urine u rea 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: ECOD 1 , ALD, EH, UDPGT. EROD increased in 100/5000 ppm males only.

870.3150 90

- Day oral

toxicity (dog)
Desthio

Prothioconazole 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)
Desthio

Prothioconazole 46246432 (1991)

46246433 (1992) Unacceptable 0, 11, 47 or 228 mg/m 3 /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

- glucu ronyltransferase

### Page 18 of 31

Table A 2.2 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/ non

guideline 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 c onsumption 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
Desthio

Prothioconazole 46246320 (1990 )

46246319 (1992) Acceptable/ non

guideline 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 = 1 0 0 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
Desthio

Prothioconazole 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 N OAEL 3 mg/kg/day
LOAEL = 10 mg/kg/day based on structural
supernumer ar y ribs and incomplete/delayed ossification

870.3700a Prenatal

developmental toxicity (rat)

– dermal
Prothioconazole 46246323 (2001)

Acceptable/ non

guideline
Technical : 0 or 1000 mg/k g/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 A 2.2 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
Desthio

Prothioconazole 4624632 5, 4624632 6

(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 (14 th rib)

.

870.3700b Prenatal

developmental toxicity (rabbit)

– oral
Prothioconazole 46246330 (1997)

Acceptable/ non

guideline 0, 80, 100, 300 or 480 mg/kg/day Materna l NOAEL was not observed LOAEL = 80 mg/kg/day based on reduced food consumption and body w eig h t s Developmenta l NOAEL = 300 mg/kg/day LOAEL = 480 mg/kg/day based on decreased body

w eig h t and small fetuses.

870.3700b Prenatal

developmental toxicity (rabbit)

– oral
Prothioconazole 462463 28 (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

w eigh t 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
Desthio

Prothioconazole 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

w eigh t gain 1

, 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
Desthio

Prothioconazole 46246329 (1991)

Acceptable/ non

guideline 0, 100, 300 or 1000

m g/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 A 2.2 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
t hymus, 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 d ecreased 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)
Desthio

Prothioconazole 46246332 (1992)

46246333 (2001) Acceptable/guideline 0, 40, 160, 640 ppm
P remating males: 0, 2.7

, 10 or 4 3 mg/kg/day

P remating females: 0, 3.0, 12 or 50 mg/kg/day
G estation : 0, 2.5, 10 or 41 mg/kg/day

L actation : 0, 4.8, 19 or 7 3 mg/kg/day Parental NOAEL = 10 mg/kg/day
LOAEL = 43 mg/kg/day based on increased liver

w eight , 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 m g/kg/day
LOAEL = 4 3 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 A 2.2 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)
Desthio

Prothioconazole 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)

Una cceptable/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

, decreas ed body weight, changes in clinical chemistry (APh, creatinine, u rea) 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)
Desthio

Prothioconazole 46246342 (1999)

Acceptable/Guideline 0, 20, 140, 980 ppm 0, 1.1, 8.0 or 5 8 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

870.4 2 00 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 A 2.2 Subchronic, Chronic and Other Toxicity Profile

– Prothioconazole and Desthio

- Prothioconazole

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.4 2 00 Carcinogenicity

(mouse)
Desthio

Prothioconazole 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 =1 3 mg/kg/day
LOAEL = 52 mg/kg/day based on decreased bod y 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 se xes, 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 N egative 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 )

Desthio

Prothioconazole 46246344 (1990)

Acceptable/Guideline

0 or 8 to 5000 μg/plate N egative 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)

Desthio

Prothioconazole 46246405 (1999)

Acceptable/Guideline

0 or 12.5 to 5 0 0 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 M ay be considered clastogenic, but this may result from cytotoxicity rather than direct structural DNA damage.

### Page 23 of 31

Table A 2.2 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)
Desthio

Prothioconazole 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)
Desthio

Prothioconazole 46 246410 (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 4 0 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 inc reases in both grain counts and percent of cells in repair. Therefore, prothioconazole is evaluated as equivocal in th is assay.

870.5550 Unscheduled

DNA synthesis in mammalian cells ( in vivo rat hepatocytes)
Prothioconazole 46246413 (1999)

Acceptable/Guideline 0, 2500 or 5000 mg/kg N egative in hepatocytes drawn from male rats

.

870.5550 Unscheduled

DNA synthesis in mammalian cells (primary rat hepatocytes in culture)
Desthio

Prothioconazole 46246414 (1992)

Acceptable/Guideline
0 or 5 to 60 μg/mL N egative up to cytotoxic concentrations.

### Page 24 of 31

Table A 2.2 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)
Desthio

Prothioconazole 46246418 (2004)

47293901 (2007) 0, 40, 160, 500 ppm
G estation : 0, 3.6, 15 or 43 mg/kg/day

L actation : 0, 8.1, 36 or 10 5 mg/kg/day Acceptable/Non

guideline Maternal NOAEL = 15 mg/kg/day LOAEL = 43 mg/kg/day based on based on increas ed 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 non

radiolabelled and 4 mg/kg radiolabelled (whole body autoradiography experiment only) Oral absorption was rapid, t max = 10

- 41 min males, 10

- 60 min females. Oscillations in plasma time

course indicated enterohepatic circulation; more prominent in female s. Low dose (single and multiple) C max = 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

- tr iazole ; P

- desthio ; P

- 3

- OH

- desthio ; P

- 4,5

- 2OH

desthio ; P

- 4

- OH; P

- 4

- OH

- desthio ; P

- desthio

- 2OH

diene ; P

- desthio

- 2OH

- dienyl glucuronide ; P

- 2OH

desthio ; P

- 2OH

- desthio

- glucuronide ; P

- OH

- desthio

glucuronide; P

- OH

- OCH3

- desthio

- glucuronide ; P

N

- glucuronide ; P

- S

- or O

- glucuronide ; P

triazolinone

.

### Page 25 of 31

Table A 2.2 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)
Desthio

Prothioconazole 46246422 (2001)

46246420 (2001) Acceptable/Non

guideline 1 or 5 mg/kg gavage or intraduodenal A bsorbed from GI tract in < 4 minutes. C max = 0.0 52 μg/g at 1.5 hours (t max ). C max 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% urin e, 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

- desthio

dihydroxydiene , P

- desthio

- phenylhydroxy , P

desthio

- 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)
Desthio

Prothioconazole 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 t max = 1 hr; C max = 0.07 μg/mL for single and repeated dose. t1⁄2 = 17 hr single dose, 21 hr repeated dose.
Dermal : B iphasic absorptio n (single and repeated dose): first phase resulted in a plateau from 1 hr to 6 h r after application (end of exposure). After washing skin for single dose , second phase with t max = 8 h r , C max = 0.04 μg/mL, t1⁄2 = 24 hr. Multiple dose had slightly higher C max = 0.05 μg/mL at same
t max = 8 hr and shorter t1⁄2 = 16 hr. Estimated DAF = 71% based on repeated dose C max 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/cm 3 ) 0.067 mg 1:373 aqueous solution (0.0067 mg/cm 2 ) 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 appl ication 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 A 2.2 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/cm 2 ) 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 )
Desthio

Prothioconazole 46246424 (2003)

Not classified ( N=1 ) 240 μg (10 μg/cm 2 ) 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 non

occlusive cover and therefore not available for absorption. 83.3 % was recovered from the application site ). 97.5% r ecovery of radioactivity i ntravenously dosed, indicating 2.5 % may have remained in the body.

870.7600 Dermal

penetration (male rhesus monkey)
Desthio

Prothioconazole 46246425 (2003)

Not classified ( N=5 ) 144 μg dermal (6 μg/cm 2 ) 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/n on

guideline 0, 25, 100 or 400 mg/kg /day D id not suppress the humoral immune response in a dose

- dependent manner

. D id not significantly decrease the IgM antibody

- forming cell response to the T

- dependent antigen. An increase in plaque

forming 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 μ M ECOD assay 0, 25, 50, 75, 100, 500 or 1000 μ M testosterone assay No conclusions can be reached from t his 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 A 2.2 Subchronic, Chronic and Other Toxicity Profile

– Prothioconazole and Desthio

- Prothioconazole

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

Special Study H epatic and renal

enzyme activities after 13 week gavage and 4 week recovery period ( dogs )
Prothioconazole 46246435 (2000)

Supplementary/n on

guideline 0, 25, 100, 300 mg/kg/day After 13 weeks gavage, liver epoxide hydrolase (EH) was s ignificantly increased at 100 (58%) and 300 (85%) mg/kg /day compared to control but only in females. Kidney enzyme a ctivities 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

(r at )
Desthio

Prothioconazole 46246437 (1991)

Acceptable/n on

guideline 0 or 980 ppm C ompared to controls, incidences of foci of altered hepatocytes (FAH) were slightly increased at 6 weeks

, but slightly decreased at 12 weeks

. I n creased glucose

- 6

- phosphate dehydrogenase activity and s evere cytoplasmic vacuolation in the Zone II hepatocytes ( particularly after 12

- week )

were found in males

. E nzyme 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
p eroxida se in vitro
Prothioconazole and metabolites 46246436 (1996)

Acceptable/n on

guideline 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 dose

dependently suppressed TPO

- catalyzed iodine formation temporarily. Following suppression, iodine reappeared. 3

- mercapto

- 1,2,4

- triazole suppressed the rate of the reappearing iodine formation long er than the other compounds.
Special Study Assessment of

Ovarian Findings in Rodents
Desthio

Prothioconazole 46246441 (2001)

Acceptable/Non Guideline T he only study where ovary findings influence th e 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 safet y 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 Desthio

Prothioconazole) 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 UF A = 10X

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

mg/kg/day

aPAD = 0.02 mg/kg/day Developmental Toxicity S tudy in

R abbits

– 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 UF A = 10X

UF H =10X FQPA SF= 1X c RfD = 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 Intermediate

Term (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 UF A = 10X

UF H =10X Occupational LOC

for MOE = 100 D evelopmental Toxicity Study in

Rats

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

Inhalation Short

Term (1

- 30 days) Intermediate

- Term (1

- 6 months) NOAEL= 2.0

mg/kg/day UF A = 10X

UF H =10X

T oxicity via the inhalation route is assumed to be equivalent to oral toxicity Occupational LOC

for MOE = 100 D evelopmental Toxicity Study in

R abbits

– 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. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chr onic). 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 Mexico 1 

### Codex 2

40C FR §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

- triazole

1

- e thanol, calculate d as parent Plants: 2

- [2

- (1

- chlorocyclopropyl)

- 3

- (2

- chlorophenyl)

- 2

- hydroxypropyl]

- 2,4

- dihydro

3 H

- 1,2,4

- triazole

- 3

- thione, including the metabolite α

- (1

- chlorocyclopropyl)

- α

- [(2

- chlorophenyl)methyl]

- 1 H

- 1,2,4

- triazole

- 1

- ethanol Prothioconazole

desthio

The residue is not fat

soluble.



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

US Canada Mexico 1 

### Codex 2
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, bilberr ies, cloudberr ies, lingonberr ies, muntries , partridgeberries
2 lowbush blue berr ies, cranberr ies (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 Mexico 1 

### Codex 2

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

40 CFR §180.626 Canada Mexico 1 

### Codex 2
(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

- triazole

1

- 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

- dihydro

3 H

- 1,2,4

- triazole

- 3

- thione, including the metabolite α

- (1

- chlorocyclopropyl)

- α

- [(2

- chlorophenyl)methyl]

- 1 H

- 1,2,4

- triazole

- 1

- ethanol and their conjugates Prothioconazole

desthio

The residue is not fat

soluble.



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

US Canada Mexico 1 

### Codex 2
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 Mexico 1 

### Codex 2

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. MR Ls indicated as proposed have not been finalized by the CCPR and the CAC.