UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PRE VENTI ON

MEMORANDUM

Feb ruary 27, 20 1 3

SUBJECT: Propiconazole Human Health Ri sk Assessment for a n Amended Sectio n 3

R eg i s tra t i on on Ce re a l Gra in s.

PC C ode: 122101

Decision No

. : 460659

Petitio n No .: 2 F 7975

Risk Ass essment e ate

TXR No.: NA

MRIDNo. : NA

FROM: T hur s ton G. Morton, Chemist

,

## ~ OP Barcode : 403631 Registration No.: 1 00-617, I 00- 1 178, and 100-

1324

R eg ulatory Action: Amended Sec tion 3

R

e istration

Case No.: 3125

James S Miller, Envi ronm enta l Sc i entist 

# _,;r

· · /1

Ab dallah Khasaw inah

, PhD

., Toxicolog i s !/' ,//

Risk Assessment Branch 4 · Hea lth E ffe c t s Div i sion (7509P)

THROUGH : E li ssa R e a ves, Ph.D., Branch C hi ef

## ~~,-(...../ 

# 7&

.......... S u san V

. Humme l

, Bran c h Senior Scientist

- 

### A

__ ,.,...,._ 

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.**~** Risk Assessment Branch 4, HED (7509P)**~**

TO: Heathe r Garv i e Fungicide Bran ch Registration Div i sion (750 5P)

Thi s document p r ov id es th e revised H ea l th Effects Di vision's (HED 's) r i sk asses s me n t of the

amended Section 3 use of propiconazole on cer eal grains. T he d ocumen t ha s been revised to
include an assessme nt of aggregate ri sk from residential exposures to propiconazol e

.

Page 1 of64Page 2 of 64 

### 1.0 EXECUTIVE SUMMARY ................................................................................................ 5

2.0 HED RECOMMENDATIONS .......................................................................................... 9

2.1 Data Deficiencies/Conditions of Registration................................................................ 9

2.2 Tolerance Considerations ............................................................................................... 9

2.2.1 Enforcement Analytical Method ............................................................................. 9

2.2.2 International Harmonization ................................................................................... 9

2.2.3 Recommended Tolerances...................................................................................... 10

2.2.4 Revisions to Petitioned-For Tolerances ................................................................ 11

2.3 Label Recommendations ............................................................................................... 11

3.0 INGREDIENT PROFILE ................................................................................................ 12

3.1 Chemical Identity .......................................................................................................... 12

3.2 Physical/Chemical Characteristics ............................................................................... 12

3.3 Pesticide Use Pattern ..................................................................................................... 12

3.3.1 Registered Products ................................................................................................ 12

3.3.2 Proposed New Uses ................................................................................................. 12

3.4 Anticipated Exposure Pathways................................................................................... 13

3.5 Considerations of Environmental Justice ................................................................... 13

4.0 HAZARD CHARACTERIZATION/ASSESSMENT ................................................... 14

4.1 Toxicology Studies Available for Analysis .................................................................. 14

4.2 Absorption, Distribution, Metabolism and Excretion ................................................ 14

4.3 Toxicological Effects ...................................................................................................... 15

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)................................. 16

4.4.1 Completeness of the Toxicology Database ............................................................ 16

4.4.2 Evidence of Neurotoxicity ...................................................................................... 16

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ...... 16

4.4.4 Residual Uncertainty in the Exposure Database.................................................. 17

4.5 Toxicity Endpoint and Point of Departure .................................................................. 17

4.5.1 Dose-Response Assessment .................................................................................... 17

4.5.2 Recommendations for Combining Exposure Routes ........................................... 18

4.5.3 Classification of Carcinogenic Potential ............................................................... 18

4.5.4 Summary of Points of Departure Used in Risk Assessment ............................... 18

5.0 DIETARY AND DRINKING WATER EXPOSURE AND RISK ASSESSMENT .... 20

5.1 Metabolite/Degradate Residue Profile ......................................................................... 20

5.1.1 Summary of Plant and Livest ock Metabolism Studies ........................................ 20Page 3 of 64 

### 5.1.2 Comparison of Metabolic Pathways ...................................................................... 21

5.1.3 Environmental Fate and Transport ...................................................................... 21

5.1.4 Residues of Concern Summary and Rationale ..................................................... 22

5.2 Food Residue Profile ..................................................................................................... 22

5.2.1 Residues in Crops .................................................................................................... 22

5.3 Water Residue Profile ................................................................................................... 23

5.3.1 Estimated Drinking Water Concentrations.......................................................... 27

5.4.1 Acute Dietary and Drinking Water Analysis ....................................................... 28

5.4.2 Chronic Dietary and Drinking Water Analysis ................................................... 29

6.0 RESIDENTIAL EXPOSURE AND RISK ASSESSMENT .......................................... 30

6.1 Residential Bystander Postapplic ation Inhalation Exposure .................................... 30

6.2 Spray Drift.................................................................................................................... .. 30

7.0 AGGREGATE EXPOSURE A ND RISK ASSESSMENT ............................................ 31

7.1 Acute & Chronic Aggregate Risk ................................................................................. 31

7.2 Short- and Intermediate-Term Aggregate Risk ......................................................... 31

7.3 Intermediate-Term Aggregate Risk ............................................................................. 34

8.0 CUMULATIVE RISK ...................................................................................................... 35

9.0 OCCUPATIONAL EXPOSURE/R ISK CHARACTERIZATION .............................. 36

9.1 Exposure Scenarios....................................................................................................... 36

9.2 Handler Exposure .......................................................................................................... 36

9.2.1 Handler Exposure Scenarios .................................................................................. 37

9.2.2 Handler Exposure Data .......................................................................................... 37

9.2.3 Handler Exposure Assumptions ............................................................................ 38

9.2.4 Handler Exposure and Risk Estimates ................................................................. 39

9.3 Post Application Exposure ............................................................................................ 40

9.3.1 Post Application Exposure Scenarios.................................................................... 42

9.3.2 Post Application Exposure Assumptions .............................................................. 42

9.3.3 Post-Application Exposure and Risk Estimates ................................................... 43

9.3.4 Restricted Entry Interval ....................................................................................... 44

10. REFERENCES .................................................................................................................. 4 4

A TOXICOLOGY DATA SUMMARY .............................................................................. 45

A.1 Guideline Data Requirements ................................................................................ 45

A.2 Toxicity Profiles .......................................................................................................... 46

A.3 Toxicological Endpoints ............................................................................................. 52Page 4 of 64 

### A.4 EXECUTIVE SUMMARIES .................................................................................... 57

Additional Developmental/Reproduction Toxici ty Information from Literature Sources

.............................................................................................................................. .................. 61

APPENDIX B. Chemical Names And Structures Of Metabolites ......................................... 63

APPENDIX C. Physical/Chemical Properties .......................................................................... 64

APPENDIX D. Studies Reviewed for Ethical Conduct .......................................................... 64Page 5 of 64 

### 1.0 EXECUTIVE SUMMARY

This document addresses the exposures and risk s associated with exposures from currently registered uses and the proposed amended use of propiconazole. It also assesses potential enhanced sensitivity of infants and children from dietary and/or residential exposure as required under the Food Quality Protection Act (FQPA) of 1996.

Under PP#2F7975, Syngenta is proposing increased tolerances along with an amended use for propiconazole on cer eal grains.

Use Profile

Propiconazole 1-[[2-(2,4-dichlorophenyl )-4-propyl-1,3-dioxolan-2-yl]methyl]-1 H -1,2,4-triazole) is a systemic triazole-type fungici de that provides broad spectrum disease control on a variety of food and non-food crops. Permanent tolerances are established (40 CFR §180.434) for the combined residues of propiconazole and its meta bolites (determined as 2,4-dichlorobenzoic acid (2,4-DCBA)) in/on a variety of agricultural comm odities at levels ranging from 0.05 ppm in/on meat and meat byproducts to 40 ppm in/on gr ass straw. Non-food uses include use on commercial, public and residentia l ornamentals, landscapes and turf. The mode of antifungal action of propiconazole is attributed to the inhibition of CYP51 (lanosterol-14- a -demethylase). Inhibition of normal sterol produc tion disrupts cell wall formation and slows or stops the growth of the fungus. Agricultural applications of propiconazole are made using ground or aerial equipment. Propicon a i zole is applied to non-food areas by both occupational and residential handlers. Occupational application methods for non-food uses include, seed piece dip, tree injection, and handheld equipment (i.e., low- pressure handwand, handgun sprayer, backpack sprayer). Residential ap plications are made with handheld equipment.

Proposed New Uses

Syngenta has submitted an application for the re gistration of products containing propiconazole for an amended use on cereal grains. Th e products are manufactured by Syngenta Crop Protection, Inc. under the trade name Tilt ® 

### Fungicide (EPA Reg. No. 100-617), Quilt ® 

### Fungicide (EPA Reg. No. 100-1178) and Quilt Xcel ® 

### Fungicide (EPA Reg. No. 100-1324). Syngenta is amending the use by lowering the pr e-harvest interval (PHI) to 7 days for forage and hay of cereal grains. The amended use is not proposed fo r residential use and residential exposures are not expected based on the proposed uses.

The toxicology database for propico nazole is adequate for evalua ting and characterizing toxicity and selecting endpoints for purposes of this risk assessment. The primary target organ for propiconazole toxicity in animals is the liver. Liver effects observed in subchronic and chronic

oral studies in rats and mice include lesions, hypertrophy and necr osis. In a rat developmental study, fetal effects were observed at doses lower than doses at whic h maternal effects were seen demonstrating quantitative evidence of increased susceptibility of fetuses to in utero exposure to propiconazole. While in rabbits, developmen tal toxicity occurred at higher doses than maternally toxic doses. In the two generati on reproduction study in rats , offspring toxicity occurred at a higher dose than the parental toxic dose suggesti ng lower susceptibility of thePage 6 of 64 

### offspring to the toxic doses of propiconazole. Propiconazole does not ap pear to be neurotoxic based on an acute neurotoxicity study. The concer n for susceptibility is low since clear NOAELs were established in the rat and rabbit developmen tal studies and the points of departure selected

for the risk assessment scenario s are protective of the suscep tibility observed in the rat developmental study. Therefore, the FQPA safety factor was reduced to 1X.

Propiconazole is classified as a Group C possible human carcinogen with risk quantitated using a reference dose (RfD) approach. Propiconazole showed no significant toxi city in a battery of acute toxicity tests (Toxicity Category III or IV in all tests). It is not a skin irritant but is a

dermal sensitizer.

Dose Response Assessment

Toxicological endpoints were sel ected for dietary/drinking water, occupational and residential exposure scenarios. Acute and chronic points of departure (PODs) were selected for assessment of food and drinking water exposur es. An acute POD for the ge neral population was selected from an acute neurotoxicity study in rats. An acute POD for females 13-49 was selected from a developmental toxicity study in rats. A chr onic/cancer POD for the general population was selected from a carcinogenicity study in mi ce. Short and intermediate-term occupational exposures via the dermal and inhalation routes may occur based on the use pattern and label directions. Toxicological endpoi nts for short-term inhalation, dermal, and incidental oral exposures were selected from the acute neurotoxi city study in rats. Toxicological endpoints for intermediate-term inhalation, dermal, and incide ntal oral exposures we re selected from a carcinogenicity study in mice. Si nce an oral study was selected for dermal exposure, a 40% dermal absorption factor from a dermal absorp tion study in rats is used for route to route extrapolation. An uncertainty f actor of 100X was applied to e ndpoints selected for all exposure routes (10X for interspecies extrapolati on, 10X for intraspecies variation).

Exposure/Risk Assessment and Risk Characterization

Risk assessments were conducted for dietar y (food and water), and occupational exposure pathways based on registered uses and request for the new use of propiconazole. Worker exposures were assessed for handler and post-appl ication activities. Ther e are no new requested residential uses expected with th is registration, therefore residentia l risk was not assessed for the proposed new use. Conservative acute and re fined chronic dietary a nd drinking water risk assessments for propiconazole conclude that di etary and drinking water exposure estimates are below HED’s level of concern for the general population and all populati on subgroups. At the

95 th 

### percentile, the exposure to th e general U.S. population is 26 % of the aPAD; the highest exposed subgroup (Children 1-2 yrs old) is 85% of the aPAD. The exposure to the general U.S. population is 7 % of the cPAD, and the most hi ghly exposed subgroup (Child ren 1-2 yrs old) is 24 % of the cPAD. Additionally, the requested use of propiconazole did not result in an increase in dietary exposure estimates for free triazole or conjugated triazoles. Therefore, dietary exposure analyses for the tri azole metabolites did not need to be updated (T. Morton, D403618, 8/1/12). Aggregate risks from propiconazole are not of concern. Occupational exposure and risk

estimates indicate that worker a nd residential handler and post-ap plication exposures are not of concern at the maximum allowable application rates for the proposed new uses provided thatPage 7 of 64 

### handlers wear chemical resistant gloves as re quired on the label. The only residential use scenario that will result in potential intermed iate term exposure to propiconazole is post application exposure to children fr om wood treatment (antimicrobial use). Table 15 shows the aggregate risk for intermediate term exposure to Children 1-2 years old. The aggregate MOE is 120, which is greater than the target MOE of 100. Therefore, this scenario is not of concern.

Aggregate Assessment of Free Triazole & its Conjugates

The addition of the new amended use does not in crease the aggregate exposure to free triazoles and its conjugates. Therefore, the previous aggregate human health risk assessment was not updated for free triazoles and its conjugates and the aggregate estimates remain below HED’s level of concern (T. Morton, D403619, 8/1/12).

Use of Human Studies

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pest icide or other chemical. Thes e studies, listed in Appendix 2.0, have been determined to require a review of their ethical conduct. Some of these studies are also subject to review by the Human St udies Review Board. All of the studies used have received the appropriate review.

Environmental Justice

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions

to Address Environmental Just ice in Minority Populations an d Low-Income Populations," http://www.eh.doe.gov/oepa/ guidance/justice/eo12898.pdf ).

As a part of every pesticide risk assessment , OPP considers a large variety of consumer subgroups according to well-esta blished procedures. In line with OPP policy, HED estimates risks to population subgroups fr om pesticide exposures that ar e based on patterns of that subgroup’s food and water consumption, and activ ities in and around the home that involve pesticide use in a residential setting. Whenever appropriate , non-dietary exposures based on home use of pesticide products and associated ri sks for adult applicators and for toddlers, youths, and adults entering or playing on treated ar eas post-application are evaluated. Further considerations are currently in development, as OPP has committed resources and expertise to the development of specialized software and mode ls that consider expo sure to bystanders and farm workers as well as lifestyle and traditiona l dietary patterns among specific subgroups.Page 8 of 64 

### Tolerance Recommendation

Pending submission of a revised Section F (see requirements under Propose d Tolerances), there are no residue chemistry issues that would precl ude granting an amended Section 3 registration for the requested amended use of propiconazole on cereal grains, or establishment of the following tolerances for resi dues of propiconazole.

Barley, hay ................................................................................................. 30 ppm Barley, stra w .............................................................................................. 20 ppm Barley, grain .............................................................................................. 3.0 ppm Rye, forage ................................................................................................ 9.0 ppm Oat, forage................................................................................................. 4.0 ppm Oat, hay ...................................................................................................... 15 ppm Oat, grain................................................................................................... 3.0 ppm Wheat, forage ............................................................................................. 15 ppm Wheat, hay ................................................................................................. 30 ppm Wheat, straw .............................................................................................. 20 ppm Barley, bran ............................................................................................... 6.0 ppm Rye, straw .................................................................................................. 10 ppm Grain, aspirated fr actions ......................................................................... 110 ppm



### As previously noted, permanent tolerances are cu rrently established for th e combined residues of propiconazole and its 2,4-DCBA containing metabo lites at levels rangi ng from 0.1-40 ppm in/on plant commodities [40 CFR §180.434(a)]. HED ha s determined that the current tolerance expression should be amended to include only propiconazole per se because 1) there are a number of pesticides that ha ve 2,4-DCBA as common metabolite, and an enforcement agency may not be able to determine if residues are due to misuse of propiconazole or the proper use of other pesticides containing 2,4-DCBA; 2) propiconazole per se can be detected by FDA multiresidue methods; and 3) inclusion of only parent allows harmonization with the residue

definition for the Codex MRLs.

However, the tolerance expression will not be changed to parent only at this time. The tolerance expression does need to be changed to reflect current HED guidance. In 2009 HED issued guidance on tolerance expression s (S. Knizner, 2009). We now conclude the tolerance expression should be as follows: Tolerances are established for residues of propiconazole, including its metabolites and degrad ates, in or on the commoditi es in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only those propiconazole residues convertible to 2,4-dichlorobenz oic acid (2,4-DCBA), expressed as the stoichiometric equivalent of propiconazole, in or on the commodity in the table below.

The Codex Alimentarius Commission has estab lished several maximum residue limits (MRLs) for propiconazole in/on various raw agricultura l commodities. In addition, both Canada and Mexico have established MRLs for propiconazo le in/on various commodities. The Codex and Mexican MRLs are expressed in terms of propiconazole per se . The Canadian MRLs are expressed in terms of combined residues of propiconazole and its metabolites containing the 2,4- DCBA moiety. Codex has MRLs for straw and fodder of barley, rye, and wheat along with MRL for barley grain. The U.S. cannot harmonize at this level due to the use pattern registered in the U.S along with the CODEX tolerance expre ssion. Canada has MRLs for barley, grain and oats, grain. The U.S. cannot harmonize at this leve l due to the use pattern registered in the U.S but will be harmonized on the tolerance expression for Canada only.Page 9 of 64 

### 2.0 HED RECOMMENDATIONS

2.1 Data Deficiencies/Condi tions of Registration

HED can recommend for registration and permanent tolerances for the proposed amended uses of propiconazole. Deficiencies are stated be low. The specific tolerance recommendations are discussed in Section 2.2, and label modi fications are discussed in Section 2.3.

Note to PM:

Immunotoxicity study remains outstanding. Revised Section F required.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate method, HPLC/UV Me thod AG-671A, is available for tolerance enforcement. This method has undergone a successful tolerance me thod validation by the Analytical Chemistry

Branch of BEAD. The method was forwarded to FDA for inclusion in PAM Volume II. This method has an LOQ of 0.02 ppm. The method in cludes optional detection via HPLC/MS, giving

a means of residue confirmation.

2.2.2 International Harmonization

The Codex Alimentarius Commission has es tablished several maximum residue limits (MRLs) for propiconazole in/on various raw agri cultural commodities. In addition, both Canada and Mexico have established MRLs for propico nazole in/on various commodities. The Codex and Mexican MRLs are expresse d in terms of propiconazole per se . The Canadian MRLs are expressed in terms of combined residues of propiconazole and its metabolites containing the 2,4- DCBA moiety. Codex has MRLs for straw and f odder of barley, rye, and wheat along with an MRL for barley grain. The U.S. cannot harmonize at this level due to the use pattern registered in the U.S along with the CODEX MRL expression. Canada has MRLs for barley, grain and oats, grain. The U.S. cannot harmonize at this leve l due to the use pattern registered in the U.S but will be harmonized on the tolerance expression for Canada only.Page 10 of 64 

### 2.2.3 Recommended Tolerances

Pending submission of revised Section F, there are no residue chemistry issues that would preclude granting registration for the requested amended use of pr opiconazole. Available data support the following tolerances under 40 CFR 180.434 for residues of propi conazole in/on the following raw agricultural commodities:

Barley, hay ................................................................................................. 30 ppm Barley, stra w .............................................................................................. 20 ppm Barley, grain .............................................................................................. 3.0 ppm Rye, forage ................................................................................................ 9.0 ppm Oat, forage................................................................................................. 4.0 ppm Oat, hay ...................................................................................................... 15 ppm Oat, grain................................................................................................... 3.0 ppm Wheat, forage ............................................................................................. 15 ppm Wheat, hay ................................................................................................. 30 ppm Wheat, straw .............................................................................................. 20 ppm Barley, bran ............................................................................................... 6.0 ppm Rye, straw .................................................................................................. 10 ppm Grain, aspirated fr actions ......................................................................... 110 ppm



### As previously noted, permanent tolerances are cu rrently established for th e combined residues of propiconazole and its 2,4-DCBA containing metabo lites at levels rangi ng from 0.1-40 ppm in/on plant commodities [40 CFR §180.434(a)]. HED ha s determined that the current tolerance expression should be amended to include only propiconazole per se because 1) there are a number of pesticides that ha ve 2,4-DCBA as common metabolite, and an enforcement agency may not be able to determine if residues are due to misuse of propiconazole or the proper use of other pesticides containing 2,4-DCBA; 2) propiconazole per se can be detected by FDA multiresidue methods; and 3) inclusion of only parent allows harmonization with the residue

definition for the Codex MRLs.

However, the tolerance expression will not be changed to parent only at this time. The tolerance expression does need to be changed to reflect current HED guidance. In 2009 HED issued guidance on tolerance expression s (S. Knizner, 2009). We now conclude the tolerance expression should be as follows: Tolerances are established for residues of propiconazole, including its metabolites and degrad ates, in or on the commoditi es in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only those propiconazole residues convertible to 2,4-dichlorobenz oic acid (2,4-DCBA), expressed as the stoichiometric equivalent of propiconazole, in or on the commodity in the table below.

Adequate crop field trial data reflecting the proposed use patterns were submitted for purposes of establishing tolerances on the requested am ended use. The Organization for Economic Cooperation and Development tolera nce calculation procedures were utilized in determining the appropriate tolerance level for the requested am ended use. Changes in recommended tolerance are based on the use of these calculation pr ocedures and are shown in Table 1, along with rounding to the appropriat e significant figures.

The proposed and recommended tolerances for propic onazole as a result of the subject action are presented in Table 1.Page 11 of 64 Table 1. Tolerance Summary for Propiconazole.

Commodity Proposed Tolerance (ppm) Recommended Tolerance (ppm) Comments

40 CFR §180.434(a)(1)

Barley, hay 30 30

Barley, straw 20 20

Barley, grain 3 3.0

Barley, bran none 6.0 The current tolerance for barley, bran is 0.6 ppm.

Rye, forage 9 9.0

Rye, straw 9 10

Oat, forage 4 4.0

Oat, hay 15 15

Oat, grain 3 3.0

Wheat, forage 15 15

Wheat, hay 30 30

Wheat, straw 20 20

Grain, aspirated fractions 108 110
*Changes are due to rounding of significant figures, not proposing a tolerance for a processed commodity, and correcting commod ity vocabulary.



### 2.2.4 Revisions to Petitioned-For Tolerances

Revised Section F, proposing the following tolerances

Barley, grain .............................................................................................. 3.0 ppm Rye, forage ................................................................................................ 9.0 ppm Oat, forage................................................................................................. 4.0 ppm Oat, hay ...................................................................................................... 15 ppm Oat, grain................................................................................................... 3.0 ppm Barley, bran ............................................................................................... 6.0 ppm Rye, straw .................................................................................................. 10 ppm Grain, aspirated fr actions ......................................................................... 110 ppm



### The existing tolerance for Rye, straw must remain at 10 ppm. The existing tolerance for Barley, bran of 0.6 ppm needs to be increased to 6.0 ppm.

2.3 Label Recommendations

No Label Recommendations are required.Page 12 of 64 

### 3.0 INGREDIENT PROFILE

3.1 Chemical Identity

Structure and nomenclature are reported in Table 2.

Table 2. Nomenclature of Propiconazole

Compound

Common name Propiconazole

Company experimental names CGA-64250

IUPAC name 1-[2-(2,4_dichlorophenyl)-4-propyl-1,3-dioxolan-2-ylmethyl]-1 H -1,2,4_triazole

CAS name 1-[[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]methyl]-1 H -1,2,4-triazole

CAS # 60207-90-1

End-use products/EP 3.6 lb/gal EC (EPA Reg. Nos. 100-617



### 3.2 Physical/Chemical Characteristics

The physicochemical properties of propicona zole are reported in Appendix C.

3.3 Pesticide Use Pattern

3.3.1 Registered Products

There are 155 active propiconazo le registrations, 139 Section 3s , 8 Section 18s, and 8 SLNs (24(c)s).

3.3.2 Proposed New Uses

Propiconazole is proposed for an amende d use on cereal grains (Table 3). N N N

O

O

Cl ClPage 13 of 64 1. 45 day for animal feed only. 2. 7 day PHI for forage and hay only.



### 3.4 Anticipated Exposure Pathways

The Registration Division has requested an assess ment of human health risk to support the proposed amended use of propiconazole on cereal grains. For domestic uses, humans may be exposed to propiconazole in food and drinking water, since propiconazole may be applied directly to growing crops and application may result in propi conazole reaching surface and ground water sources of drinking water. There ar e also residential uses of propiconazole, so there is exposure in residential or non-occupa tional settings. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application. There is a potential for post-app lication exposure for workers re-entering treated

fields.

Risk assessments have been previously prepared fo r the existing uses of propiconazole. This risk

assessment considers all of the aforementioned exposure pathways based on the proposed new uses of propiconazole, but also considers the exis ting uses as well, partic ularly for the dietary
exposure assessment.

3.5 Considerations of Environmental Justice

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, “Federal Actions

to Address Environmental Just ice in Minority Populations an d Low-Income Populations,” http://www.eh.doe.gov/oepa/ guidance/justice/eo12898.pdf

.

As a part of every pesticide risk assessment , OPP considers a large variety of consumer subgroups according to well-esta blished procedures. In line with OPP policy, HED estimates risks to population subgroups fr om pesticide exposures that ar e based on patterns of that Table 3. Label Directions for Proposed Uses of Propiconazole

Product EPA Reg.

No. Use Site Target Application

Methods Maximum Application

Rate (lb ai/A) PHI (day) REI (hr) Use Directions/

Limitations

Tilt ®
Fungicide

EC (100- 617)

Cereal

Grains: Wheat; Barley; Oats; Rye;

Triticale Broadcast

Foliar Aerial Chemigation

Groundboom 0.056 - 0.113 (2 app. /season) 14

7 (Forage

and Hay) 2 12

hr A minimum

retreatment interval (RTI) of 14 days is proposed.

Quilt Xcel ®
Fungicide

EC (100- 1324) 0.056-0.112 (2 app. /season) A minimum

retreatment interval (RTI) of 14 days is proposed.

Contains azoxystrobin

also. Quilt ®
Fungicide

EC (100- 1178) 0.056 - 0.114 (2 app. /season)Page 14 of 64 

### subgroup’s food and water consumption, and activ ities in and around the home that involve pesticide use in a residential se tting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered fo od uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess di etary exposure to smaller, specialized subgroups and exposure assessments are performed when c onditions or circumstances warrant. Whenever appropriate, nondietary exposures based on home use of pesticide products and associated risks for adult applicators and for t oddlers, youths, and adults enteri ng or playing on treated areas post-application are evaluated. Further considera tions are currently in development as OPP has committed resources and expertise to the developm ent of specialized software and models that consider exposure to bystanders and farm worker s as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 HAZARD CHARACTERIZATION/ASSESSMENT

4.1 Toxicology Studies Available for Analysis

The toxicology database for pr opiconazole is adequate for evaluating and characterizing propiconazole toxicity and sele cting endpoints for purposes of this risk assessment. An immunotoxicity is study require d as part of new 40 CFR Pa rt 158 data requirements for registration of a pestic ide. A waiver request for a 28-da y immunotoxicity study in rodents was submitted but denied by the Agency.

The following data are available:

Acute - Oral rat, dermal rat, inhalation rat, eye i rritation rabbit, dermal ir ritation rabbit, and skin sensitization guinea pig.

Subchronic - Oral 90-day rat, oral 90-day mouse (3), and oral 90-day dog;

Chronic - Oral rat, mouse and dog; Reproductive/developmental - Oral developmental rabbit and ra t, 2-generation reproductive rat

Other - Oral rat and mouse cancer studies, 21-day de rmal rabbit toxicity and dermal penetration study, acute neurotoxicity, metabo lism, mutagenicity screens a nd mechanistic studies (3).

4.2 Absorption, Distribution, Metabolism and Excretion

The rat metabolism study labeled with 14 

### C at the triazole-[3,5] positi on indicated that parent compound was extensively metabolized. An intr avenous (IV) study labeled with (U- 14 

### C)-Phenyl found several metabolites, including CGA 118245 (61.8% in males, 2.4% in females), CGA 217495 (8.9% in males, 58.3% in females), CG A 91304 (2.3% in males only), and CGA 118244 (3.6% in females only). No parent material was detected in the feces in the iv group. The metabolites seen in the iv study were detected to varying degrees in the urine and the feces of the orally dosed groups. Radiolabeled ma terials CGA 91305, CGA 11824 5 and CGA 177291 were reported ranging from 0.5% - 10.9% of the fecal radioactivity in males and females or in one sex alone. Most of the fecal radioactivity was not characterized. Me tabolites CGA 217495 and CGA 177291 are not found in plant or livestock metabolism (see Appe ndix for structures). In two other (U- 14 

### C)-phenyl and 14 

### C-triazole ring labeled propiconazo le studies, the percentages ofPage 15 of 64 

### fecal metabolites extracted and distributed at various pH’s were not substantially different between the triazole and phenyl labeled samples, which suggest that the bridge between the phenyl ring and the triazole ring remained intact . The proposed metabolic pathway appears to involve the cleavage of the dioxol ane ring through the oxidation of the propyl side chain, with subsequent dechlorination and conjugation. In a (U- 14 

### C)-phenyl labeled propiconazole metabolism study in mice, it was concluded that the major metabolic pathway in mice proceeds via elimination of the dioxolane ring leading to ketone formation (CGA 91304) and reduction to yield the corresponding alcohol (CGA 91305). Both CGA 91304 and CGA 91305 are found in plants and livestock.

4.3 Toxicological Effects

The primary target organ for propiconazole t oxicity in animals is the liver. Increased liver weights were seen in mice after subchronic or chronic oral exposures to propiconazole. Liver lesions such as vacuolation of hepatocy tes, ballooned liver cells , foci of enlarged hepatocytes, hypertrophy and necros is are characteristic of propiconazole t oxicity in rats and mice. Decreased body weight gain was also seen in subchronic, chronic, developmental and reproductive studies in animal studies. Dogs app eared to be more sensitive to the localized toxicity of propiconazole as manifested by st omach irritations at 6 mg/kg/day and above.

In rabbits, developmental toxicity occurred at a higher dose than the maternally toxic dose, while in rats, developmental toxicity occurred at lowe r doses than maternal toxic doses. Increased incidences of rudimentary ribs occurred in ra t and rabbit fetuses. Increased cleft palate

malformations were noted in two studies in rats . In one published study in rats, developmental effects (malformations of the lung and kidneys, incomplete ossification of the skull, caudal vertebrae and digits, extra rib (14 th 

### rib) and missing sternbrae were reported at doses that were not maternally toxic. In the two generation reproduction study in rats, offspring toxicity occurred at a higher dose than the parental toxic dose suggesti ng lower susceptibility of the offspring to the toxic doses of propiconazole.

The acute neurotoxicity study re sulted in decreased motor activ ity at 300 mg/kg. The current acute dietary assessment is based on an endpoint more sensitive than the neurotoxicity in the acute neurotoxicity study. Based on a weight of evidence evaluation by the HASPOC, the SCN

was waived.

Propiconazole was negative for mutagenicity in the in vitro BALB/3T3 cell transformation assay, bacterial reverse mutation assay, Chines e hamster bone marrow chromosomal aberration assay, unscheduled DNA synthesis studies in huma n fibroblasts and primary rat hepatocytes, mitotic gene conversion assay and the dominant leth al assay in mice. It caused proliferative changes in the rat liver with or without pretreatment with an initiator, like phenobarbital, a known liver tumor promoter. Liver enzyme i nduction studies with pr opiconazole in mice demonstrated that propiconazole is a str ong phenobarbital type inducer of xenobiotic metabolizing enzymes. Hepatocel lular proliferation studies in mice suggest that propiconazole induces cell proliferation followed by treatment- related hypertrophy in a manner similar to the known hypertrophic agent phenobarbital.Page 16 of 64 

### Propiconazole has low to moderate toxicity in experimental anim als by the oral (Category III), dermal (Category III) and inhalati on routes (Category IV), is mode rately irritating to the eyes (Category III), minimally irritating to the skin (Category IV) and is a dermal sensitizer.

The complete toxicity profile for prop iconazole is provided in Appendix A.

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

For propiconazole there are accepta ble developmental toxicity studies in the rat and rabbit and an acceptable multi- generation reproduction study in the rat. An acceptable acute neurotoxicity study in the rat is also available in the database which results in effects at higher doses. Based on a weight of the evidence (WOE) the SCN wa s recently waived by the HASPOC (TXR 0056387). Although quantitative susceptibility was obser ved in the rat developmental study, a clear NOAEL is established for the developmental effects. Furthermore, the acute dietary for females 13-49 years old is based on the developmen tal NOAEL from the st udy with quantitative susceptibility. Therefore, the risk assessment is protective of this suscep tibility and there are no remaining uncertainties for the young. Together, th e available data support the reduction of the FQPA factor to 1X.

4.4.1 Completeness of the Toxicology Database

The toxicological database for propi conazole is adequate for the purpos e of this risk assessment. Based on a WOE approach considering all the available propiconazole hazard and exposure information, the HASPOC concluded that a 28-d ay day inhalation study and a subchronic neurotoxicity study are not requir ed at this time (8/1/12, TXR #: 0056387). A previous risk assessment document (HED memoranda B. Dai ss, 04/27/11, DP389194) contains detailed and up-to-date discussions of the toxicology and hazard evaluation of propiconazole. Please refer to

these documents for further extensive details. Al so, please refer to Appendix 2 of this current

risk assessment document for th e toxicity profile tables.

4.4.2 Evidence of Neurotoxicity

In an acute oral neurotoxicit y study, single oral administrati on at the high dose of 300 mg/kg propiconazole produced severe clin ical signs of toxicity in rats within 5- 6 hours (e.g., decreased activity, cold, pale, pilo erection, subdued, tip toe gate, staini ng around the nose). Limited signs (piloerection, diarrhea, tip toe gait) were seen in the 100 mg/kg dosed animals. No treatment related clinical signs were obser ved at the low dose (30 mg/kg). Functional observational battery (FOB) and motor activity tests showed reduced ac tivity in males and females at the high dose. Based on weight of evidence the subchronic ne urotoxicity is waived (HASPOC, TXR 0056387).

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

The toxicology database for pr opiconazole is adequate for FQPA assessment. Although quantitative susceptibility was observed in the rat developmental study, a clear NOAEL is established for the developmental effects. Furt hermore, the acute dietary for females 13-49 yearsPage 17 of 64 

### old is based on the developmental NOAEL from the study with quantitati ve susceptibility. Therefore, the risk assessment is protective of this susceptibility and there are no remaining uncertainties for the young.

There are no residual uncerta inties with regard to pre- and/or postnatal toxicity. The dietary food exposure assessment uses conservative assumpti ons which result in protective estimates of dietary exposure. The dietary drinking water as sessment uses values generated by model and associated modeling parameters which are designed to provide protective, high-end estimates of

water concentrations.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainti es in the exposure database. The dietary risk assessment is conservative and will not underestimate dietary and/or non-dietary residential exposure to propiconazole.

4.5 Toxicity Endpoint and Point of Departure

4.5.1 Dose-Response Assessment

Toxicity endpoints and points of departure (P ODs) for dietary (food and water), occupational, and residential exposure scenarios are summarized below. A detailed description of the studies used as a basis for the selected endpo ints are presented in Appendix A.

An acute POD of 30 mg/kg for th e general population was selected from an acute neurotoxicity study based on clinical signs of t oxicity (piloerection, diarrhea, tip toe gait) at 100 mg/kg. An acute POD of 30 mg/kg (NOAEL) was select ed for females age 13-49 years from a developmental study in rats based on increased incidence of rudimentary ribs, un-ossified sternebrae, as well as increased incidence of shortened and absent renal papillae and increased cleft palate at 90 mg/kg/day. The developmental e ffects of concern are presumed to occur after a single exposure and are relevant only to females aged 13-49 years old since they occur in utero

. An uncertainty factor (UF) of 100x (10X to acc ount for intraspecies extrapolation and 10X for intraspecies variation) was applied to the NOAE L to obtain an acute reference dose (aRfD) of 0.3 mg/kg. Since the FQPA factor has been redu ced to 1X, the acute population adjusted dose (aPAD) is equivalent to the aRfD.

A chronic POD of 10.0 mg/kg/day (NOAEL) was se lected for the general population from a twoyear oncogenicity study in mice based on non-neoplasti c liver effects (increas ed liver weight in

males and increase in liver lesions: masses/rais ed areas/ swellings/nodular areas mainly at 50 mg/kg/day. An uncertainty factor (UF) of 100x (10X to account for intraspecies extrapolation and 10X for intraspecies variation) was applie d to the dose to obtain a chronic reference dose (cRfD/cPAD) of 0.1 mg/kg/day.

Incidental oral short term exposure was assess ed using a POD (NOAEL) of 30 mg/kg/day from an acute neurotoxicity study based on clinical signs of toxicity (piloerection, di arrhea, tip toe gait) at 100 mg/kg. An MOE of 100 is applie d to account for the intr a- and inter-speciesPage 18 of 64 

### variation. Incidental oral in termediate term exposure was assessed using a POD (NOAEL) of 10 mg/kg/day from an oncogenicity study in mi ce based on based on non-neoplastic liver effects (increased liver weight in males and increa se in liver lesions: masses/raised areas/ swellings/nodular areas mainly at 50 mg/kg/day. An MOE of 100 is applied to account for the intra- and inter-species variation.

A short-term dermal POD of 30 mg/kg/day was selected from the acute neurotoxicity study

described above. An intermediate-term dermal POD of 10 mg/kg/day wa s selected from the 24 month oncogenicity mouse study desc ribed above. An MOE of 100 is required for the short- and intermediate-term scenarios for dermal exposur e. This includes 10X for interspecies extrapolation and 10X for intraspecies variation.

A short-term inhalation POD of 30 mg/kg/day was selected from the acute neurotoxicity study

described above. An intermediate-term inhalatio n POD of 10 mg/kg/day was selected from the 24 month oncogenicity mouse study described above. An MOE of 100 is required for the shortand intermediate-term scenarios for inhalation exposure. This includes 10X for interspecies extrapolation and 10X for intraspecies variation.

4.5.2 Recommendations for Combining Exposure Routes

When there are potential residential exposures to the pesticide, the aggregate risk assessment must consider exposures from three major sources : oral, dermal and inhalation exposures. There are potential residential post-appli cation exposures to adults via th e dermal route and to children

via dermal and incidental oral routes of exposure. For the ge neral population, including infants and children, the short term oral exposure can be aggregated with the short-term dermal and inhalation due to a common toxicological endp oint (clinical signs in the ACN study). A common toxicological endpoint wa s identified from the cancer mouse study for intermediateand long-term oral, dermal (oral equivalent) and inhalation (oral equivalent ) routes. Therefore, these routes can be aggregated for thes e scenarios for the a ppropriate population.

4.5.3 Classification of Carcinogenic Potential

Propiconazole was carcinogenic to CD-1 male mice. Propiconazole was not carcinogenic to rats or to female mice. The HED Carcinogenicity Peer Review Committee (CPRC) classified propiconazole as Group C - possi ble human carcinogen and recomme nded that for the purpose of

risk characterization the referen ce Dose (RfD) approach be used for quantification of human risk (HED Doc. No. 009771, April 15, 1992 meeting).

4.5.4 Summary of Points of Departure Used in Risk Assessment

Toxicological doses/endpoints sele cted for the propiconazole ri sk assessment are provided in

Tables 4 and 5.Page 19 of 64 Table 4. Summary of Toxicological Doses and Endpoints for Propiconazole for Use in Dietary Human Health Risk

Assessments

Exposure/Scenario Point of Departure Uncertainty/FQP A Safety Factors RfD, PAD, LOC

for Risk

Assessment Study and Toxicological Effects

Acute Dietary (General Population) NOAEL =

30 mg/kg/day UF A = 10X

UF H =10X FQPA SF= 1X Acute RfD = 0.3 mg/kg/day

aPAD = 0.3 mg/kg/day Acute neurotoxicity study Rat MRID 46604601

LOAEL = 100 mg/kg/day based on clinical signs of toxicity (piloerection in one male, diarrhea in one female, tip toe gait in 3 females).

Acute Dietary (Females 13-49 years) NOAEL =

30 mg/kg/day UF A = 10X.

UF H =10X FQPA SF= 1X Acute RfD = 0.3 mg/kg/day

aPAD = 0.3 mg/kg/day Developmental Study - Rat MRID 40425001

LOAEL = 90 mg/kg/day based on increased incidence of rudimentary ribs, un-ossified sternebrae, as well as increased incidence of shortened and absent renal papillae and increased cleft palate.

Chronic Dietary (Adult Males and Females 50+ yrs) NOAEL =

10 mg/kg/day UF A = 10X

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

0.1 mg/kg/day

cPAD = 0.1mg/kg/day 24-month oncogenicity study on CD-1 mice.

MRID 00129918 LOAEL = 50 mg/kg/day based on non-neoplastic liver effects (increased liver weight in males and

increase in liver lesions: masses/raised areas/ swellings/nodular areas mainly). Cancer (all routes) Classification: Group C, possible hu man carcinogen, RfD approach for risk characterization

Point of Departure (POD) = A data point or an estimated point that is derived from obs erved dose-response data and used to mar k the beginning of extrapolation to determine risk associ ated 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. UF S = use of a short-term study for long-term risk assessment. UF DB = to account for the absence of key date (i.e ., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjust ed dose (a = acute, c = chronic). RfD = re ference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable

Table 5. Summary of Toxicological Doses and Endpoints for Propiconazole for Use in Residential and Occupational

Human Health Risk Assessments

Exposure/

Scenario Point of Departure Uncertainty

Factors Level of Concern

for Risk

Assessment Study and Toxicological Effects

Incidental Oral

short-term NOAEL= 30 mg/kg/day UF A = 10X

UF H =10X Residential LOC

for MOE = 100 Occupational LOC

for MOE = 100 Acute Neurotoxicity Study-Rats MRID 46604601 LOAEL = 100 mg/kg/day based on clinical signs of toxicity (piloerection in one male, diarrhea in one female, tip toe gait in 3 females).

Incidental Oral

Intermediate-term NOAEL= 10 mg/kg/day UF A = 10X

UF H =10X Residential LOC

for MOE = 100 Occupational LOC

for MOE = 100 24 Month Oncogenicity Study - Mice MRID

00129918
LOAEL = 50 mg/kg/day based on non-neoplastic liver effects (increased liver weight in males and

increase in liver lesions: masses/raised areas/ swellings/nodular areas mainly).

Dermal Short Term (1-30 days)

DAF = 40% NOAEL= 30 mg/kg/day UF A = 10X

UF H =10X Residential LOC

for MOE = 100 Occupational LOC

for MOE = 100 Acute Neurotoxicity Study-Rats MRID

46604601 LOAEL = 100 mg/kg/day based on clinical signs of toxicity (piloerection in one male, diarrhea in one female, tip toe gait in 3 females).Page 20 of 64 Table 5. Summary of Toxicological Doses and Endpoints for Propiconazole for Use in Residential and Occupational

Human Health Risk Assessments

Exposure/

Scenario Point of Departure Uncertainty

Factors Level of Concern

for Risk

Assessment Study and Toxicological Effects

Dermal Intermediate Term (1-6 months)

DAF = 40% NOAEL= 10 mg/kg/day UF A = 10X

UF H =10X Residential LOC

for MOE = 100 Occupational LOC

for MOE = 100 24 Month Oncogenicity Study - Mice MRID

00129918
LOAEL = 50 mg/kg/day based on non-neoplastic liver effects (increased liver weight in males and

increase in liver lesions: masses/raised areas/ swellings/nodular areas mainly).

Inhalation Short Term (1-30 days) NOAEL= 30 mg/kg/day UF A = 10X

UF H =10X Occupational LOC

for MOE = 100 Acute Neurotoxicity Study-Rats MRID

46604601 LOAEL = 100 mg/kg/day based on clinical signs of toxicity (piloerection in one male, diarrhea in one female, tip toe gait in 3 females).

Inhalation

Intermediate Term (1-6 months) NOAEL= 10 mg/kg/day 24 Month Oncogenicity Study - Mice MRID

00129918
LOAEL = 50 mg/kg/day based on non-neoplastic liver effects (increased liver weight in males and

increase in liver lesions: masses/raised areas/ swellings/nodular areas mainly).

Cancer (all routes) Classification: Group C, possible hu man carcinogen, RfD approach for risk characterization

DAF = Dermal Absorption Factor



### Based on the available toxicity da tabase and the Agency's current practices, the inhalation risk for propiconazole was assessed using an oral t oxicity study. The Agency sought expert advice and input on issues related to th is route to route extrapolation approach (i.e. the use of oral toxicity studies for inhalation risk assessment) from its Fede ral Insecticide, Fungicide, and

Rodenticide Act Scientific Advi sory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SA P/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, reexamine and develop new policies and procedures for conducting inhalati on risk assessments, in cluding route to route extrapolation of toxicity data. If any new polic ies or procedures are developed, the Agency may

revisit the need for an inhalation toxicity study for propiconazo le and/or a reexamination of the inhalation toxicity risk assessment.

5.0 DIETARY AND DRINKING WATER EXPO SURE AND RISK ASSESSMENT

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Livestock Metabolism Studies

The nature of propiconazole residues in plan ts is adequately u nderstood (DP D329394, Y. Donovan, 6/15/06). These data indi cate that the major metabolic pathway in plants involves hydroxylation of the n-propyl group on the dioxo lane ring of the cis/trans isomers of propiconazole, with subsequent conjugation to sugars. A possibl e alternative pathway involves

reductive deketalization of the dioxolane ring and sugar conjugati on of the resulting metabolite.Page 21 of 64 

### The alkyl bridge between the phenyl and tr iazole rings is metabolized and free 1 H -1,2,4-triazole

is released. The free triazole is readily conjugated with the am ino acid, serine/alanine, forming

triazole aniline which is further metabolized to triazole acetic acid possibly through the intermediate formation of triazole lactic acid. HED considers free triazole, triazole alanine, and

triazole acetic acid to be resi dues of concern in plants. Since these are common metabolites from several triazole containing pesticides, the risk assessment for triazole s has been assessed separately (HED memo of 11/3/10, T. Morton, D383609).

The nature of propiconazole residues in livesto ck is adequately understood based on acceptable goat and poultry metabolism studies (DP D329394, Y. Donovan, 6/15/06).

Structures and names of propiconazole me tabolites are provided in Appendix B.

5.1.2 Comparison of Metabolic Pathways

The rat metabolism study indicated that parent compound was extensively metabolized. An intravenous study found several metabo lites, including CGA 118245, CGA 217495, CGA 91304, and CGA 118244. No parent material was detected in the feces in the iv group. The metabolites seen in the iv study were detected to varying de grees in the urine and th e feces of the orally dosed groups. Radiolabeled materi als CGA 91305, CGA 11 8245 and CGA 177291 were present in the fecal radioactivity in males and fe males or in one sex alon e. Most of the fecal radioactivity was not charact erized. Metabolites CGA 21749 5 and CGA 177291 are not found in plant or livestock metabolism. The proposed metabolic pathway involves the cleavage of the dioxolane ring through the oxidation of the propyl side chain, with subsequent dechlorination and conjugation. In a (U- 14 

### C)-phenyl labeled propiconazole metabolism study in mice, it was concluded that the major metabolic pathway in mice proceeds via elimination of the dioxolane ring leading to ketone formation (CGA 91304) a nd reduction to yield the corresponding alcohol
(CGA 91305). Both CGA 91304 and CGA 913 05 are found in plants and livestock



### . The plant metabolism data indicate that the major metabo lic pathway in plants involves hydroxylation of the n-propyl group on the dioxolan e ring of the cis/trans isom ers of propiconazole, with subsequent conjugation to sugars. A possi ble alternative pathway involves reductive deketalization of the dioxolane ring and sugar conjugation of the resulting metabolite. The alkyl bridge between the phenyl and triazo le rings is metabolized and free 1 H -1,2,4-triazole is

released. The free triazole is readily conjugated with the am ino acid, serine/alanine, forming

triazole aniline which is further metabolized to triazole acetic acid possibly through the

intermediate formation of triazole lactic acid.

5.1.3 Environmental Fate and Transport

For propiconazole, turf, a previ ously registered crop, has the hi ghest application rate (6.285 lb a.i./A, 8 applications of 0.786 lb a.i.

. /A per year with a 14-day in terval between applications) ((DP 325821,328690, Dated 07/07/2006). EFED has provided EDWCs for the proposed new uses and has provided a comparison of these new ED WCs with the previously assessed turf use. The previously assessed turf EDWCs are approxi mately one order of magnitude higher (more protective), than the EDWCs for the new use and therefore, the turf EDWCs were used for the updated dietary risk assessment.Page 22 of 64 

### 5.1.4 Residues of Concern Summary and Rationale

A summary of the metabolites and degradates to be included in the risk assessment and tolerance expression are presented below in Table 6. De tailed rationale for th ese conclusions were presented in a previous docu ment (DP329394, Y. Donovan, 06/15/06).

Table 6. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression.

Matrix For Risk Assessment  For Tolerance Expression

Plants Parent plus all metabolites convertible to 2,4-

DCBA Parent only

Rotational crop Parent plus all metabolites convertible to 2,4-

DCBA Parent only

Livestock: Parent plus all metabolites convertible to 2,4-

DCBA Parent only

Water Parent only N/A

Note: For all triazole-containing pesticides, the triazole -containing metabolites 1,2,4-T, TA, and TAA should also be included as residues of concern for risk assessment purposes only for plant and livestock commodities. Since these metabolites are common to the entire class of triazole-derivative fungicides and because of differential toxicity between the metabolites and the various parent compounds, risks associated with exposure to 1,2,4-T and to TA/TAA are addressed in separate risk assessment documents.

M1 = 5-[(4-chlorophenyl)methyl]-2-methoxyl-2-methyl-1-(1 H -1,2,4-triazol-1-ylmethyl)-1-cyclopentanol; M11 = 5- [(4-chlorophenyl)methoxyl]-2,2-dimethyl-1-(1 H -1,2,4-triazol-1-ylmethyl)-1-cyclopentanol; M12 = 5-[(4- chlorophenyl)methyl]-2- carboxyl-2-methyl-1-(1 H -1,2,4-triazol-1-ylmethyl)-1-cyclopentanol; M31 = (1S*,3R*,5S*)-3-hydroxy- cis -metconazole; 1,2,4-T = 1 H -1,2,4-triazole; TAA = 1 H -1,2,4-triazol-1-yl acetic acid; TA = 2-amino-3-(1 H -1,2,4-triazol-1-yl )propanoic acid.



### 5.2 Food Residue Profile

5.2.1 Residues in Crops Field trials have submitted supporting the new uses for propiconazole. The results from these

studies are discussed in the a ppropriate data evaluation report (DER) and summarized in the following tables.Page 23 of 64 TABLE 7a. Summary of Residue Data from Barl ey Crop Field Trials with Propiconazole.

Commodity Analyte Total App.

Rate (lb ai/A) PHI (days) Residue Levels (ppm) 1

n Sample

Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std.

Dev.

Barley Hay Propiconazole 0.2188-

0.2311 7 9 0.436 4.46 0.436 4.19 1.70 1.77 1.25

Propiconazole and

Metabolites 9 2.08 13.1 2.08 11.9 4.27 6.13 3.95

T 9 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

TA 9 <0.05 0.210 <0.056 0.197 0.070 0.089 0.045

TAA 9 <0.02 0.065 <0.02 0.061 0.022 0.033 0.017

Propiconazole 14 9 0.157 2.10 0.175 1.72 0.483 0.671 0.509

Propiconazole and

Metabolites 9 1.73 6.61 1.78 5.87 2.85 3.53 1.42

T 9 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

TA 9 <0.05 0.184 <0.05 0.180 0.065 0.084 0.047

TAA 9 <0.02 0.077 <0.02 0.077 0.034 0.035 0.017

Barley

Grain Propiconazole 0.2213-

0.2290 16-49 9 <0.01 1.30 <0.01 1.12 0.0103 0.170 0.363

Propiconazole and

Metabolites 9 <0.05 2.22 <0.05 2.12 0.255 0.468 0.656

T 9 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

TA 9 <0.06 0.274 <0.06 0.247 0.069 0.096 0.061

TAA 9 <0.02 0.118 <0.02 0.107 0.022 0.038 0.029

Barley

Straw Propiconazole 16-49 9 0.0770 5.20 0.0821 4.99 0.287 1.50 1.91

Propiconazole and

Metabolites 9 0.891 10.3 0.918 10.1 2.90 4.21 3.50

T 9 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

TA 9 <0.01 0.024 <0.01 0.023 0.012 0.015 0.005

TAA 9 <0.01 0.042 <0.01 0.038 0.013 0.019 0.011

1 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and standard deviation, the LOQ was used for any results reported as <LOQ in Table C.3. N/A = Not applicable.

2 LAFT = lowest average field trial; HAFT = highest average field trial.Page 24 of 64 TABLE 7b. Summary of Residue Data from Oa t Crop Field Trials with Propiconazole.

Commodity Analyte Total App.

Rate (lb ai/A) PHI (days) Residue Levels (ppm) 1

n Sample

Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std.

Dev.

Oat Forage Propiconazole 0.2156-

0.2290 7 11 0.135 1.26 0.154 1.17 0.818 0.689 0.379

Propiconazole and

Metabolites 11 0.431 2.46 0.499 2.31 1.48 1.40 0.584

T 11 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

TA 11 0.0178 0.146 0.0184 0.128 0.0282 0.0423 0.0308

TAA 11 <0.01 0.0344 <0.01 0.0328 0.0100 0.0126 0.007

Propiconazole 14 11 0.0316 0.480 0.0404 0.449 0.262 0.240 0.150

Propiconazole and

Metabolites 11 0.303 1.51 0.389 1.39 0.975 0.919 0.378

T 11 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

TA 11 0.0189 0.212 0.0236 0.212 0.0434 0.0554 0.0536

TAA 11 <0.01 0.0433 <0.01 0.0431 0.0117 0.0165 0.0103

Oat Hay Propiconazole 0.2156-

0.2290 7 11 0.110 4.46 0.184 4.26 1.38 1.66 1.34

Propiconazole and

Metabolites 11 0.629 8.54 0.798 8.00 3.23 3.47 2.31

T 11 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

TA 11 <0.1 0.334 <0.1 0.325 0.100 0.133 0.0675

TAA 11 <0.01 0.0645 <0.01 0.0633 0.0145 0.0201 0.0160

Propiconazole 14 11 0.0620 2.69 0.0680 1.98 0.540 0.677 0.571

Propiconazole and

Metabolites 11 0.559 5.69 0.592 4.41 1.99 2.30 1.25

T 11 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

TA 11 <0.1 0.387 <0.1 0.373 0.100 0.140 0.0824

TAA 11 <0.01 0.110 <0.01 0.107 0.0239 0.0300 0.0276

Oat Grain Propiconazole 0.2188-

0.2331 25-48 11 <0.01 0.386 <0.01 0.368 0.0392 0.100 0.121

Propiconazole and

Metabolites 11 0.0630 1.61 0.0649 1.56 0.195 0.440 0.549

T 11 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

TA 11 0.0480 0.362 0.0498 0.353 0.125 0.169 0.108

TAA 11 <0.02 0.117 <0.02 0.115 0.0332 0.0476 0.0326

Oat Straw Propiconazole 25-48 11 0.0172 2.40 0.0191 1.21 0.0894 0.309 0.383

Propiconazole and

Metabolites 11 0.291 6.07 0.302 5.10 2.05 2.22 1.45

T 11 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

TA 11 <0.01 0.0438 <0.01 0.0435 0.0161 0.0181 0.0110

TAA 11 <0.01 0.0261 <0.01 0.0247 0.0137 0.0147 0.0052

1 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and standard deviation, the LOQ was used fo r any results reported as <LOQ in Tables C.3.1. and C.3.2 N/A = Not applicable.

2 LAFT = lowest average field trial; HAFT = highest average field trial.Page 25 of 64 TABLE 7c. Summary of Residue Data from Ry e Crop Field Trials with Propiconazole.

Commodity Analyte Total App.

Rate (lb ai/A) PHI (days) Residue Levels (ppm) 1

n Sample

Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std.

Dev.

Rye Forage Propiconazole 0.2222-

0.2263 6-8 4 0.895 1.62 0.895 1.52 1.11 1.16 0.263

Propiconazole and

Metabolites 4 2.29 3.99 2.37 3.75 2.85 2.95 0.677

T 4 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

TA 4 <0.02 0.0775 <0.02 0.0673 0.0356 0.0396 0.0199

TAA 4 <0.01 0.0263 <0.01 0.0224 0.0101 0.0132 0.006

Propiconazole 13-15 4 0.383 0.955 0.403 0.938 0.459 0.565 0.251

Propiconazole and

Metabolites 4 1.25 3.01 1.33 2.97 2.03 2.09 0.763

T 4 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

TA 4 <0.02 0.0945 <0.0207 0.0875 0.0313 0.0427 0.0303

TAA 4 <0.01 0.0272 <0.01 0.0260 0.0115 0.0147 0.0076

Rye Grain Propiconazole 0.2216-

0.2288 34-50 4 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

Propiconazole and

Metabolites 4 <0.05 0.160 <0.05 0.144 0.0729 0.0849 0.0410

T 4 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

TA 4 <0.06 0.615 <0.06 0.565 0.150 0.231 0.228

TAA 4 0.0319 0.141 0.0371 0.131 0.0764 0.0802 0.0389

Rye Straw Propiconazole 34-50 4 0.0384 0.650 0.0428 0.551 0.160 0.228 0.225

Propiconazole and

Metabolites 4 0.657 4.94 0.689 4.60 1.27 1.96 1.81

T 4 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

TA 4 0.0277 0.108 0.0299 0.102 0.0705 0.0682 0.0334

TAA 4 <0.03 0.0595 <0.03 0.0580 0.0329 0.0384 0.0133

1 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and standard deviation, the LOQ was used for any results reported as <LOQ in Table C.3. N/A = Not applicable.

2 LAFT = lowest average field trial; HAFT = highest average field trial.Page 26 of 64 TABLE 7d. Summary of Residue Data from Wheat Crop Field Trials with Propiconazole.

Commodity Analyte Total App.

Rate (lb ai/A) PHI (days) Residue Levels (ppm) 1

n Sample

Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std.

Dev.

Wheat Forage Propiconazole 0.2190-

0.2306 7 15 0.271 4.90 0.271 4.79 1.28 1.44 1.13

Propiconazole and

Metabolites 15 1.18 9.00 1.23 8.47 2.16 2.88 1.90

T 15 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

TA 15 <0.01 0.0975 <0.0110 0.0918 0.0193 0.0261 0.0207

TAA 15 <0.01 0.0336 <0.01 0.0324 0.0100 0.0130 0.0063

Propiconazole 14-20 15 0.0606 2.16 0.0813 2.13 0.538 0.611 0.528

Propiconazole and

Metabolites 15 0.717 5.85 0.778 5.46 1.35 1.75 1.14

T 15 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

TA 15 <0.01 0.0740 <0.01 0.0735 0.0190 0.0245 0.0159

TAA 15 <0.01 0.0444 <0.01 0.0442 0.0100 0.0148 0.0093

Wheat Hay Propiconazole 0.2190-

0.2306 7 15 0.444 9.82 0.444 9.57 2.01 2.75 2.30

Propiconazole and

Metabolites 15 1.98 22.5 1.98 21.6 5.31 7.22 5.01

T 15 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

TA 15 0.0218 0.250 0.0218 0.236 0.0525 0.0688 0.0541

TAA 15 <0.01 0.138 <0.01 0.135 0.0182 0.0300 0.0315

Propiconazole 14-20 15 0.149 5.48 0.156 5.41 0.784 1.24 1.28

Propiconazole and

Metabolites 15 1.57 18.7 1.62 17.4 3.65 4.78 4.13

T 15 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

TA 15 0.0158 0.174 0.0166 0.166 0.0409 0.0527 0.0400

TAA 15 <0.01 0.128 <0.0125 0.116 0.0242 0.0331 0.0274

Wheat

Grain Propiconazole 0.2140-

0.2308 24-64 15 <0.01 0.0842 <0.01 0.0779 0.0100 0.0153 0.0176

Propiconazole and

Metabolites 15 <0.05 0.169 <0.05 0.145 0.0556 0.0705 0.0286

T 15 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

TA 15 <0.02 0.286 <0.02 0.279 0.133 0.135 0.0744

TAA 15 <0.01 0.0720 <0.01 0.0718 0.0209 0.0283 0.0172

Wheat

Straw Propiconazole 24-64 15 0.0432 4.36 0.0462 4.04 0.455 1.16 1.41

Propiconazole and

Metabolites 15 0.570 13.3 0.597 12.6 2.74 4.50 4.05

T 15 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

TA 15 <0.01 0.0560 <0.01 0.0515 0.0124 0.0162 0.0109

TAA 15 <0.01 0.0510 <0.01 0.0497 0.0177 0.0200 0.0114

1 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and standard deviation, the LOQ was used fo r any results reported as <LOQ in Tables C.3.1. and C.3.2 N/A = Not applicable.

2 LAFT = lowest average field trial; HAFT = highest average field trial.Page 27 of 64 

### 5.3 Water Residue Profile

5.3.1 Estimated Drinking Water Concentrations

For propiconazole, turf, a previ ously registered crop, has the hi ghest application rate (6.285 lb a.i./A, 8 applications of 0.786 lb a.i../A per year with a 14-day interval between applications) ((DP 325821,328690, Dated 07/07/2006). EFED has provided EDWCs for the proposed new uses and has provided a comparison of these new ED WCs with the previously assessed turf use. The previously assessed turf EDWCs are approxi mately one order of magnitude higher (more protective), than the EDWCs for new uses and th erefore, the turf EDWCs were used for the updated dietary risk assessment.

This drinking water assessment used surface water models PRZM/EXAMS and groundwater model (SCI-GROW). These results are based on EDWCs for Turf (DP 325821, 328690, 07/07/2006). The proposed new use does not result in higher EDWCs than those estimated for

turf uses.

The estimated surface water drinking water c oncentrations for propiconazole are:

55.78 ug /L for the 1 in 10 year annual peak concentra tion (acute) 21.61 ug /L for the 1 in 10 year annual mean concentration (non-cancer chronic) and 13.24 ug /L for the 30 year annual mean c oncentration (cance r chronic).

The SCI-GROW estimated ground water drinking wate r concentrations for propiconazole are not expected to exceed 0.64 μ g/L

Drinking Water Data for Free Triazoles

Residues of 1,2,4-triazole in drinking water we re provided to HED by the EFED (I. Maher, DP320682, 28 Feb 2006). Due to the inter-conversion between 1,2,4-triazole, triazole alanine, and triazole acetic acid that may occur in the en vironment, the residue estimates used in these

assessments are a summation of all three residue s and, therefore, repres ent an overestimate of

actual concentrations of the co mmon triazole metabolites in drinking water. The Tier II PRZM/EXAMS (surface water) and SCIGRO W (ground water) residue estimates are

summarized in Table 8. HED notes that there we re no detects of 1,2,4-tria zole in any of the 271 water samples analyzed by PDP, with a limit of quantification of 730 parts-per-trillion (0.73 ppb). The surface water estimates are significantly greater than those for ground water, and were used in the assessments for free triazole as well as the conjugated metabolites. EFED stated that the new metconazole uses are covered by th e previous drinking water assessment for 1,2,4- triazole (DP320682, I. Maher, 2/28/06).

Table 8. Summary of Estimated Drinking Water Concentrations of 1,2,4-Triazole. Exposure Duration Surface Water Concentration, ppm Ground Water Concentration, ppm

Acute 0.041 0.001

Chronic 0.011 0.001Page 28 of 64 

### 5.4 Dietary and Drinking Water Exposure and Risk

Screening level acute and refi ned chronic dietary and drinki ng water exposure and risk assessments were conducted using the Dietary Ex posure Evaluation Model software with the Food Commodity Intake Database DEEM-F CIDTM, Version 3.16, which incorporates consumption data from USDA’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). This dietary survey was conducted from 2003 to 2008. Dietary risk assessment incorporat es both exposure and toxicity of a given pesticide. For acute and chronic dietary assessments, the risk is ex pressed as a percentage of a maximum acceptable dose (i.e., the dose which HED has concluded wi ll result in no unreasonable adverse health effects). This dose is referred to as the populatio n adjusted dose (PAD). The PAD is equivalent to the reference dose (RfD) divided by the addi tional Safety Factor, if applied. For acute and non-cancer chronic exposures, HED is concerned when estimated dietary risk exceeds 100% of

the PAD.

5.4.1 Acute Dietary and Drinking Water Analysis

A new dietary assessment was conducted for the proposed amended use. The proposed amended use results dietary risk estimates belo w HED’s level of concern; see Tabl e 9. The highest is children 1-2 years resulting in 85% of the aPAD.

Table 9. Results of Acute Dietary Exposure Analysis for Food and Drinking Water

Population Subgroup aPAD (mg/kg/day) 95th Percentile Exposure (mg/kg/day) % aPAD General U.S. Population

0.3 0.077562 26 All Infants (< 1 year old) 0.108099 36 Children 1-2 years old 0.253533 85 Children 3-5 years old 0.194271 65 Children 6-12 years old 0.106036 35 Youth 13-19 years old 0.073595 25 Adults 20-49 years old 0.061233 20 Adults 50+ years old 0.050898 17 Females 13-49 years old 0.060552 20

Dietary Assessment of Free Triazole and its Conjugates

Reference: Common Triazole Metabolites: Updated Dietary (Food + Water) Exposure and Risk Assessment to Address The Amended Propiconazole Section 3 Registration to Add Foliar Use on Sugarcane

. T. Morton, DP403618.drs, 8/1/12.



### The proposed amended use of propiconazole did not re sult in an increase in di etary exposure estimates for free triazole or conjugated triazoles. Therefore, the last dietary exposure analyses for the triazole metabolites did not need to be updated. The results from the previous dietary analysis are below HED’s level of concern; see Table 10.Page 29 of 64 Table 10. Summary of Dietary (Food and Drinking Water) Exposure and Risk for the Common Triazole Metabolites (Previous Assessment).

Population Subgroup Acute Dietary (95 th Percentile) Chronic Dietary Cancer

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

1,2,4-Triazole General U.S. Population 0.008282 28 0.001327 27

Not Applicable Not Applicable All Infants (< 1 year old) 0.012115 40 0.001843 37 Children 1-2 years old 0.023117 77 0.003832 77 Children 3-5 years old 0.018974 63 0.003064 61 Children 6-12 years old 0.010992 37 0.001665 33 Youth 13-19 years old 0.007222 24 0.001085 22 Adults 20-49 years old 0.006609 23 0.001137 23 Adults 50+ years old 0.005820 19 0.001073 22 Females 13-49 years old 0.006747 22 0.001110 22 Triazolylalanine + Triazolylacetic Acid+Triazolylpyruvic acid General U.S. Population

Not Applicable Not Applicable 0.018547 21

Not Applicable Not Applicable All Infants (< 1 year old) 0.021851 24 Children 1-2 years old 0.058600 65 Children 3-5 years old 0.047124 52 Children 6-12 years old 0.024837 28 Youth 13-19 years old 0.015657 17 Adults 20-49 years old 0.015272 17 Adults 50+ years old 0.014323 16 Females 13-49 years old 0.079772 80 0.014900 17 * The values for the highest exposed population for each type of risk assessment are bolded.



### 5.4.2 Chronic Dietary and Drinking Water Analysis

A new dietary assessment was conducted for the pr oposed amended use of propiconazole and results in dietary risk estimates below HED’ s level of concern; see Table 11.

Table 11. Results of Chronic Dietary Exposure Analysis for Food and Drinking Water

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

0.1 0.007432 7.4 All Infants (< 1 year old) 0.010280 10 Children 1-2 years old 0.023718 24 Children 3-5 years old 0.019121 19 Children 6-12 years old 0.009941 9.9 Youth 13-19 years old 0.006022 6.0 Adults 20-49 years old 0.006180 6.2 Adults 50+ years old 0.005618 5.6 Females 13-49 years old 0.005622 5.6Page 30 of 64 

### 6.0 RESIDENTIAL EXPOSURE AND RISK ASSESSMENT

Residential exposures are not expected based on the proposed uses, however the proposed new use will affect the aggregate e xposure, therefore an updated residential exposure assessment was conducted. The revision of residential exposures will impact the human health aggregate risk assessment for Propiconazole. Each assumption and factor is detailed in the 2012 Residential

SOPs (http://www.epa.gov/pesticides/science /residential-exposure-sop.html). The residential handler exposure/risk characterization for cereal grains is summarized in below.

Specifics concerning residential handler exposur e and risks are provided in the most recent occupational and residential exposure assessm ent for propiconazole (D349727, S. Oonnithan, 9/3/06).

6.1 Residential Bystander Postapplication Inhalation Exposure

Based on the Agency's current practices, a quant itative post-application inhalation exposure assessment was not performed for propiconazole at this time. Howe ver, volatilization of pesticides may be a potential source of post-app lication inhalation exposure to individuals nearby to pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticid es from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ) and is in the process of evaluating the SAP report. The Agency may, as appr opriate, develop policies and procedures to identify the need for a nd, subsequently, the wa y to incorporate postapplication inhalation exposure in to the Agency's risk assessments. If new policies or procedures are put into place, the Agency may re visit the need for a qua ntitative post-application inhalation exposure assessment for propiconazole.

6.2 Spray Drift

Spray drift is always a potential source of expos ure to residents nearby to spraying operations. This is particularly the case with aerial appl ication, but, to a lesser ex tent, could also be a potential source of exposure from the ground ap plication method employed for Propiconazole. The Agency has been working with the Spray Dr ift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and ot her parties to develop the best spray drift management practices (see the Agency’s Spra y Drift website for more information at (http://www.epa.gov/opp00001/f actsheets/spraydrift.htm) . On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has comp leted its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appr opriately apply the data and th e AgDRIFT computer model to its risk assessments for pesticides applied by ai r, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drif t with specific products with significant risks

associated with drift.Page 31 of 64 

### Although a quantitative residential post-applic ation inhalation exposure assessment was not performed as a result of pesticide drift from nei ghboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers. Th is exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post-application inhalation exposure scenarios

.

7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking wa ter, and residential exposures (dermal and residential). In an aggregate as sessment, exposures from relevant sources are adde d together and compared to quantitative estimates of hazard (e .g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

7.1 Acute & Chronic Aggregate Risk

Acute and chronic aggregate exposures include food plus drinking water exposures. As demonstrated under Section 5.4, acute and chro nic aggregate risks are not of concern.

7.2 Short- and Intermediate-Term Aggregate Risk

Short term aggregate exposure takes into acc ount residential exposure plus average exposure levels to food and water (considered to be a b ackground exposure level). Table 12 aggregates

the short-term risk for toddl ers from incidental oral, de rmal, and food and water (as a background). The highest incidental oral and dermal exposure scen arios are from residential use on turf, which were used in the short term aggregate risk assessment. The short-term aggregate risk MOE of 96 exceeds HE D’s level of concern (LOC=100). This assessment is considered very conservative in that the resident ial incidental oral post- application exposure was calculated by combining three screening level as sessments (which by themselves already have conservative estimates).Page 32 of 64 Table 12: Short-term Aggregate Risk Estimates to Propiconazole for Toddler (Children 1-2years)

Exposure Scenario Target

MOE Route of Exposure Exposure NOAELs MOE at Day 0 Combined

MOE 5

Average Food and Water N/A Oral 0.0237

30 1300 2

96 Hand to Mouth Activity on Turf

100 1 Oral 0.0269 2100 3

Object to Mouth Activity on Turf Oral 0.0067 68000 3

Soil Ingestion Oral 0.00009 490,000 3

Turf –High-Contact Activities Dermal 0.2827 110 4

1 Target MOE= 100, Acute Neuortoxicity NOAEL=30

2 MOE food = [(short-term oral NOA EL)/(chronic dietary exposure)]

3 MOE oral = [(short -term oral NOAEL) /(hand-to-mouth residential exposure)]

4 MOE dermal = [(short -term dermal NOAEL)/(high-end dermal residential exposure)]

5 Aggregate Combined MOE (food, water, and residential) = 1÷ [(1÷MOE food and water) + (1÷MOE oral) + (1÷MOE

dermal)].



### The residential handler exposure/ri sk characterization fo r cereal grains is summarized in Table

13.

For all residential handler e xposure scenarios, MOEs exceed HED’s LOC (Dermal LOC = 100),

and therefore not of concern to HED. Summaries of the short- term risk estimates for residential

handlers are included in Table 13.

Summaries of the short-term risk estimates for residential post-application activities are included

in Table 14.Page 33 of 64Table 13. Short-Term Residential Handler Exposure and Risk Estimates for Propiconazole.ExposureScenarioTargetMOEDermalUnitExposure(ug/lb ai)Inhl. UnitExposure(ug/lb ai)MaximumApplicationRatea(lb ai/ft2)Or(lb ai/Acre)AreaTreated orAmountHandledDailybDermalInhalationTotalDose(mg/kg/day)cMOEdDose(mg/kg/day)eMOEfMOEgMixer/loader/ApplicatorLow PressureHandwand/Ornamentals10063,000 185.5 x 10-81,200 ft20.000021 1,400,000 5.9 x10-95.1 x 1091.4 x 106Hose-endSprayer/Ornamentals58,000 1.4 0.000019 1,600,000 1.2 x 10-96.5 x 10101.6 x 106Low PressureHandwand/Turf/Lawns100Hose-end Sprayer is protectiveHose-endSprayer/Turf/Lawns13,400 22 1.8 0.5 Acres 0.060 500 0.000099300,000500Brush/RollerApplying paint100450,000 2000.0035lb ai/1 gal can0.016 1,900 0.0000074,300,001,900Airless SprayerApplying Paint63,000 18 0.0033 9.100 0.0000009532,000,0009,100a.Based on registered or proposed label (0.0024 lbai/A): [ 0.0024 lb ai/A x A/43,560 sq ft. = 5.5 x 10-8]or (0.000000055 lb ai/ft2)b.Exposure Science Advisory Council Policy #9.1.c.Dermal Dose = Dermal Unit Exposure (ug/lb ai) x Conversion Factor(0.001 mg/ug) x Application Rate(lb ai/acre or gal) x Area Treated or Amount Handled (A or gallons/day) x DAF (40%) / BW (80kg).d.Dermal MOE = Dermal NOAEL (mg/kg/day) / Dermal Dose (mg/kg/day).e.Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x ConversionFactor (0.001 mg/ug) x Application Rate (lb ai/acre or gal)x Area Treated or Amount Handled (A or gallons/day) / BW (kg).f.Inhalation MOE = Inhalation NOAEL (mg/kg/day) / Inhalation Dose (mg/kg/day).Total MOE = NOAEL (mg/kg/day) / (Dermal Dose + Inhalation Dose)ORTotal MOE = 1/ [(1/Dermal MOE) + (1/Inhalation MOE)].Page 34 of 64 Table 14: Short-Term Residential Post-application/ Incidental Oral Exposure and Risk Estimates for Propiconazole.

Lifestage Post-application Exposure Scenario Dose MOEs

Adult

Turf - sprays Dermal 0.142785 210

Inhalation N/A N/A

Child Dermal 0.282685455 110

Inhalation N/A N/A

Hand to Mouth 0.014490408 2,100

Object to Mouth 0.00044 68,000

Incidental Soil Ingestion 0.000061 490,000



### Table 14 aggregates the short-term risk for adults from residen tial post applica tion, and average food and water (as a background). Based on the low vapor pressure of propiconazole, negligible post application inhalation exposure is anticipate d to occur. The highest post application exposure from residential use on turf was used in the short term aggregate. The aggregate MOE is 200, which is greater than the target MOE of 100. This aggr egate exposure assessment is considered very conservative because the assumpti ons used for each of the scenarios separately are already high end (i.e., time spent outdoors, dislodgeable residues).

Table 14: Short-term Aggregate Risk Estimates to Prop iconazole for Adults from Post-Application Activities

Exposure Scenario Target

MOE Route of Exposure Exposure or Daily dose NOAELs MOE at Day 0 Combined MOE 4

Average Food and Water
(As background) N/A Food and

water 0.0062

30 4800 2

200 Residential Post-application(Residential Turf Gen. HighContact Activities)) 100 1 Dermal 0.143 210 3

1 Target MOE= 100, Developmental rat- increase d incidence of rudimentary risks. NOAEL = 30

2 MOE food and water = [(short-term oral NOAEL)/(chronic dietary exposure)]

3 MOE dermal = [(short -term dermal NOAEL)/(high-end dermal residential exposure)]

4 Aggregate Combined MOE (food, water, and residential) = 1÷ [(1÷MOE food and water) + (1÷MOE post appl. dermal)].



### 7.3 Intermediate-Term Aggregate Risk

The only residential use scenario that will result in potential intermediate term exposure to propiconazole is post app lication exposure to childre n from wood treatment (antimicrobial use). Table 15 shows the aggregate risk for intermediate term exposure to Children 1-2 years old. The aggregate MOE is 110, which is greater than the ta rget MOE of 100. Therefor e, this scenario is

not of concern.Page 35 of 64 Table 15. Intermediate -term Aggreg ate Risk Estimates to Propiconaz ole for Toddler (Children 1-2years)

Exposure Scenario Target

MOE Route of Exposure Exposure NOAELs MOE at Day 0 Combined MOE 5

Average Food and Water N/A Oral 0.0237 10 420 2

110 Incidental oral 100 1 Oral 0.0056 10 1800 3

Dermal Contact Activities 100 1 Dermal 0.059 10 170 4

Note:

1 Target MOE= 100, 24 Month oncogenicity study. NOAEL=10

2 MOE food = [(intermediate-term oral NOAEL)/(chronic di etary exposure)]

3 MOE oral = [(intermediate -term oral NOAEL)/(hand-to-mouth residential exposure)]

4 MOE dermal = [(intermediate -term dermal NOAEL)/(high-end dermal residential exposure)]

5 Aggregate Combined MOE (food, water, and residential) = 1÷ [(1÷MOE food and water) + (1÷MOE oral) + (1÷MOE

dermal)].



### These aggregate exposure assessments are consider ed conservative estimates, that should not underestimate risks, for the following reasons: 1) the dietary inputs used tolerance-level residues for many food commodities, and crop specific (t urf) screening level drinking water modeling data (i.e., surface water modeling); 2) maximu m application rates and minimum application intervals were used; and 3) conservative SO Ps and upper level estimates of exposure were employed.

Updated Aggregate Assessment of Free Triazole & its Conjugates

Reference: Common Triazole Metabolites: Updated Aggregate Human Health Risk Assessment to Address The Amended Propiconazole Section 3 Registration to Add Use on Sugarcane. DP403619, T. Morton, 8/1/12.



### The addition of the proposed amended use doe s not increase the aggregate exposure to free triazoles and its conjugates. Therefore, the prev ious aggregate human heal th risk assessment for free triazoles and its conjugates did not need updated and the aggregate estimates are below

HED’s level of concern (DP403619, T. Morton, 8/1/12).

8.0 CUMULATIVE RISK

Propiconazole is a member of the triazole-contai ning class of pesticides . Although conazoles act similarly in plants (fungi) by inhibiting ergoste rol biosynthesis, there is not necessarily a relationship between their pesticidal activity a nd 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 sa me, or essentially the same, sequence of major biochemical events (EPA, 2002). In conazoles, however, a variable patt ern of toxicological responses is found; some are he patotoxic and hepatocarcinogenic in mice. Some induce thyroid tumors in rats. Some induce developmental, repr oductive, and neurological effects in rodents. Furthermore, the conazoles produce a diverse ra nge of biochemical even ts including altered cholesterol levels, stress res ponses, and altered DNA methylati on. It is not clearly understood whether these biochemical events are directly co nnected to their toxicological outcomes. Thus,Page 36 of 64 

### there is currently no evidence to indicate that conazoles share common mechanisms of toxicity and EPA is not following a cumulative risk appr oach 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 mechan ism of toxicity, see EPA’s website at http://www.epa.gov/pesticides/cumulative

.

Propiconazole is a triazole-derived pesticide. This class of compounds can form the common metabolite 1,2,4-triazole and two tr iazole conjugates (triazolylalanine and triazolylacetic acid). To support existing tolerances and to establish ne w tolerances for triazole -derivative pesticides, including propiconazole, U.S. EPA conducted a huma n health risk assessment for exposure to 1,2,4-triazole, triazolylalanine, and triazolylacetic acid resulting fr om the use of all current and pending uses of any triazole-der ived fungicide. The risk asse ssment is a highly conservative, screening-level evaluation in te rms of hazards associated with common metabolites (e.g., use of a maximum combination of uncertainty factors) and potential dietary a nd non-dietary exposures (i.e., high end estimates of both dietary and non- dietary exposures). In addition, the Agency retained the additional 1X FQPA safety factor for the protecti on of infants and children. The

assessment includes evaluations of risks for va rious subgroups, including those comprised of infants and children. The Agency’s complete risk assessment is found in the propiconazole reregistration docket at http://www.regulations.gov , Docket Identification (ID) Number EPAHQ-OPP-2005-0497.

9.0 OCCUPATIONAL EXPOSURE /RISK CHARACTERIZATION

9.1 Exposure Scenarios

Occupational handler and post-ap plication exposure scenarios we re assessed for the proposed amended use. Based on the product labels and in formation provided by the registrant, short- and intermediate-term exposure is asse ssed for handlers and post-applic ation activities. Dermal and inhalation exposures are aggregat ed for propiconazole because th e toxicity endpoints for these exposure routes are not based on common toxicological endpoints. Labels for the propiconazole proposed uses require that appl icators and other handlers wear personal protective equipment (PPE) consisting of long-sleeved shirt, long pants and shoes with so cks plus gloves.

9.2 Handler Exposure

The term “handler” applies to individuals who mix, load, and apply the pesticide product. There is a potential for exposure to propicona zole during mixing, loading, and application activities through the dermal and inhalation rout es. Propiconazole products are applied using aerial, airblast, groundboom and chemigation equipment.

The quantitative exposure/risk a ssessment developed for occupati onal handlers is based on the following exposure scenarios:Page 37 of 64 

### 9.2.1 Handler Exposure Scenarios

Occupational handler exposure scenarios were a ssessed for the proposed use of propiconazole on cereal grains. For all dermal and inhalation expo sure scenarios, risk estimates do not exceed HED’s LOC (Dermal LOC = 100; Inhalation LO C = 100) with label-specified PPE and, therefore, are not of concern to HED. Sin ce the dermal and inhala tion endpoints are based on similar effects, the doses are combined fo r a total MOE. See table 3 for details.

Based on the anticipated use patterns and curr ent labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk a ssessment developed for occupati onal handlers is based on the following scenarios:

MIXER/LOADER

1. Open mixing/loading EC for aerial applications;

2. Open mixing/loading EC for chemigation applications;

3. Open mixing/loading EC for groundboom applications;

APPLICATORS

1. Applying sprays with aer ial equipme nt; 2. Applying sprays with groundboom equipment;

Note: Chemigation is an irrigation system that does not have an appl icator. It is applied mechanically.

FLAGGERS

1. Flagging for aerial applications;

9.2.2 Handler Exposure Data

Unit Exposures : It is the policy of HED to use the best av ailable data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, include the Pesticide Handlers Exposure Databa se Version 1.1 (PHED 1.1), the Agricultural Handler Exposure Task Force (AHETF) database , the Outdoor Residential Exposure Task Force (ORETF) database, or other registrant-submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in pred icting handler exposure that are used in this assessment, known as “unit exposures”, are outlin ed in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (http://www.epa.gov/opp00001/scie nce/handler-exposuretable.pdf) , which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at http://www.epa.gov/pesticides/scien ce/handler-exposure-data.html

.Page 38 of 64 

### 9.2.3 Handler Exposure Assumptions

Based on HED ExpoSAC Policy No. 9.1, the area treated in a day was assumed to be:

 1200 acres for mixing/loading to support aerial applications,

 350 acres for mixing /loading chemigation applications

 200 acres for mixing/loading to support groundboom applications,

 1200 acres for applying with aerial equipment,

 200 acres for applying with groundboom equipment, and

 350 acres for flagging to s upport aerial applications.

Body Weight The average adult body weight of 80 kg was used for estimating short-, and intermediate-term dermal and inhalation daily dose calculations.

Absorption Factors

The short- and intermediate-term dermal absorption factor is 40%.

Personal Protective Equipment (PPE) For pesticide handlers, this assessment presents “b aseline” and “label specific PPE (i.e. workers wearing a single layer of work clothing consisting of a long sleeved shirt, long pants, shoes, plus socks and protective eyewear) calcul ations. See table 3 for specifics.

Equations and Calculations

Daily Dose: Daily dose (dermal and inhalation) is calculate d by normalizing the daily exposure (dermal or inhalation) value by body weight an d accounting for absorption factors:

Average Daily Dose (mg/kg/day) = Daily E xposure (mg ai/day) x {Absorption Factor } Body Weight (kg)

Where:

Average Daily Dose = Absorbed dose received from exposure to a pesticide in a given scenario (mg pesticide ac tive ingredient/kg body weight/day), Daily Exposure = Amount (mg ai/day) deposite d on the surface of the skin that is available for dermal absorption or amount inhaled th at is available for inhalation absorption, Absorption Factor = A measure of the amount of chemical that crosses a biological boundary such as the skin or lungs, and Body Weight = Body weight determ ined to represent the population of interest in a

risk assessment.

Margin of Exposure (MOE): The daily dermal and inhalation dose received by occupational handlers was compared to the appropriate PoD (i.e. NOAELs) to assess the risk to occupational handlers. All MOE valuesPage 39 of 64 

### were calculated using the following formula:

MOE = NOAEL (mg/kg/day) Average Daily Dose (mg/kg/day)

Where:

MOE = Margin of exposure value used by HED to represent risk or how close a chemical exposure is to being a concern (unitless), ADD = Average daily dose (ADD) is abso rbed dose received from exposure to pesticide, and NOAEL = Dose level in a toxicity study, wh ere no observed adverse effects occurred in the study.

For all dermal and inhalation exposure scenario s, risk estimates do not exceed HED’s LOC (Dermal LOC = 100; Inhalation LOC = 100) with la bel-specified PPE and, therefore, are not of

concern to HED. Summaries of the combined s hort- and intermediate-term risk estimates for occupational handlers are included in Table 4.

9.2.4 Handler Exposure and Risk Estimates

Summaries of the combined, dermal plus inhala tion short-, and intermediate-term risks for each exposure scenario are presented in Table 18. The combined dermal and inhalation exposure risks are not of concern (i.e., MOEs >100), provi ded the mixer/loaders w ear chemical-resistant gloves as directed on the label.

Exposure scenarios listed within (mixing/loading, applying, and flagging), risk estimates do not exceed HED’s LOC (MOE < 100), and therefore not of concern to HED. See Table 16 for

details.Page 40 of 64Table 16. Agricultural Handler Exposure and Risk for Propiconazole Use on Cereal GrainsExposureScenarioMaxiumApp. Ratea(lb ai/A)AreaTreatedDailyb(acres)Unit Exposure(μg/lb ai)cDose(mg/kg/day)dMOEseCombinedShort-termCombinedInt.-termBaseline(BL)Baseline +Label Spec. PPEBaseline(BL)Baseline +Label Spec. PPEDermal +InhalationDermal +InhalationDermalInhal.DermalInhal.DermalInhal.DermalInhal.BLBL+PPEBLBL+PPEMixing/Loading “Cereal Grains”(Emulsifiable Concentrate)LOC = 100Aerial0.1141,200220 0.219 37.6 0.2190.015 0.00037 0.0257 0.00037 200 1,10066380Chemigation 3500.044 0.00011 0.0075 0.00011 680 3,900 230 1,300Groundboom 2000.0250.000062 0.0043 0.000062 1,200 6,900 400 2,300Applying “Cereal Grains”(Emulsifiable Concentrate)LOC = 100Aerial(EnclosedCockpit)0.1141,200No Data5(Eng.Control)0.068(Eng.Control)No Data0.00098(Eng.Control)0.0001(Eng.Control)No Data 8,500NoData2,800(Eng.Control)ChemigationN/AGroundboomEquipment(Open Cab)20078.6 0.34 16.1 0.34 0.009 0.000097 0.0018 0.000097 3,300 160,000 1,100 5,200Page 41 of 64Table 16. Agricultural Handler Exposure and Risk for Propiconazole Use on Cereal GrainsExposureScenarioMaxiumApp. Ratea(lb ai/A)AreaTreatedDailyb(acres)Unit Exposure(μg/lb ai)cDose(mg/kg/day)dMOEseCombinedShort-termCombinedInt.-termBaseline(BL)Baseline +Label Spec. PPEBaseline(BL)Baseline +Label Spec. PPEDermal +InhalationDermal +InhalationDermalInhal.DermalInhal.DermalInhal.DermalInhal.BLBL+PPEBLBL+PPEFlaggingLOC = 100Aerial0.175 35011 35 12 35 0.0034 0.00028 0.0037 0.00027 8,200 7,600 2,700 2,500a. Application rates = maximum application ratesfrom the parent labels.b. Area treated daily from Science Advisory Council Policy # 9.1.c. Unit Exposures are from the “Occupational PesticideHandler Unit Exposure Surrogate Reference Table,” dated 03/12, and located athttp://www.epa.gov/opp00001/science/handler-exposure-table.pdfand(http://www.epa.gov/pesticides/science/handler-exposure-data.html).d. Dermal and Inhalation Dose (mg/kg/day) daily unit exposure (μg/lb ai) x application rate (lb ai/acre) x acres treated x 1E-3 mg/μg/ body weight (80 kg adult).e. Combined MOE = NOAEL (30 mg/kg/day for ST and 10 mg/kg/dayfor IT) / combined dermal and inhalation daily dose (mg/kg/day).Level of concern = 100.Bold= MOE≤100.f. LOC = Level Of Concern (target Margin of Exposure or MOE).g. Aerial application rate for Sugarcane (0.175 lb ai/A) isprotective of cereal grains, therefore only flagger for sugarcane was assessed.Aerial: Enclosed Cockpit is anengineering control; therefore the unit exposures and MOEs reflect this.

### Page 42 of 64 9.3 Post Application Exposure

HED uses the term post-application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as a re-entry exposure). Such exposure may occur wh en workers enter previ ously treated areas to perform job functions, including activities related to crop production. In the case for propiconazole, post-application dermal exposur e to field workers following ground and aerial applications is probable.

Based on the Agency's current practices, a quant itative occupational post- application inhalation exposure assessment was not performed for propiconazole at this time. However, there aremultiple potential sources of post-application inhalation exposure to individuals performing postapplication activities in previously treated fiel ds. These potential sour ces include volatilization of pesticides and re-suspension of dusts and/or pa rticulates that contain pesticides. The Agency sought expert advice and input on is sues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rode nticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SA P/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post-applicat ion inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, s ubsequently, the way to incorporate occupational post-application inhalation exposur e into the Agency's risk asse ssments. 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 propiconazole.

Although a quantitative occupational post-applic ation inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resultin g from application of pesticides outdoors is likely to result in higher exposure than post -application exposure. Therefore, it is expect ed that these handler inhalation exposure estimates would be protec tive of most occupatio nal post-application inhalation exposure scenarios.

9.3.1 Post Application Exposure Scenarios

Post-application propiconazole resi dues are expected for individuals involved in hand weeding; scouting; thinning; hand harves ting, and irrigation. For all de rmal post-application exposure scenarios, risk estimates do not exceed HED’s LOC (Dermal LOC = 100), and therefore not of

concern to HED.

9.3.2 Post Application Exposure Assumptions

Transfer Coefficients : It is the policy of HED to use the best available data to assess postapplication exposure. Sources of generic post-application data, us ed as surrogate data in the absence of chemical-specific data, are derived from Agricultural Reentry Task Force (ARTF)

### Page 43 of 64 exposure monitoring studies, and, as proprietary data, are subject to the data protection provisions of FIFRA. The standard values r ecommended for use in predicting post-application exposure that are used in this as sessment, known as “transfer coefficients”, are presented in the “Science Advisory Council for Exposure (ExpoSAC) Policy 3” (http://www.epa.gov/pesticides /science/exposac_policy3.pdf), wh ich, along with additional information about the ARTF data, can be found athttp://www.epa.gov/pesticides/science/postapp-exposure-data.html

.



### Post-application Studies: A total of six studies are desc ribed in [memorandum; (D279301, J. Miller, 8/18/05)] and listed in this section. These studies described propiconazole residue dissipation and exposure for corn, peaches, rice, pecans, ornamentals and turf.

 MRID 42564003: Propiconazole – Dislodgeable Residue on Corn (North Carolina) EPA MRID 425640-03; Report dated 1991. Author Avakian, M; Sponsor: Ciba-G eigy Corporation Agriculture Division. Submitted by Environmental Technologies Institute, Inc. and EN-CAS Labs.

 MRID 44959701: Dissipation of Dislodgeable Foliar Residue of Two formulations of Propicoanzole (OrbitTM and OrbitTM 45W) Applied to Peaches. EPA MRID 44959701(0442); Report dated 1999; Author; Rosenheck, L. Report: Lab report Number: 260-98: 445 80: AG-561 Performing Laboratories: ABC Laboratories., Inc.

 MRID 45288601: Determi nation of Transferable Turf Resi due on Turf treated with Banner

MAXX ; Report dated (2000); Authors; Rosenheck, L.; Meyer, L. Lab Project Number 990046: 179-99. Performing Laboratories: Central Calif ornia Research Laboratories, Inc.

 MRID 40279806: Author; Honeycutt, R. CGA 64250 (Tilt) Wo rker Exposure in Pecans Unpublished. Sponsored by: Ciba-Geigy

 MRID 133390: Author; Honeycutt, R. (1983) CGA 64250 (T ilt) Worker Exposure in Rice: Report No. EIR-83011. ( Unpublished study r eceived Dec 12, 1983 und er 100-617; submitted by Ciba-Geigy Corp., Greensboro, NC; CDL:07222-C)

 MRID 44959702: Dissipation of Dislodgeable Foliar Residues of Propiconazole (Banner MAXX); Applied to Commercial Ornamentals . Rosenheck, L.; Meyer, L.(1999) Final report: Lab Project Number: 1134-99. Unpublished study prepared by Novartis Crop Protection, Inc. 51 p.



### HED evaluated these studies and decided that fo r this occupational post- application assessment, the rice study (MRID 133390) DFR values would be used for cereal grains.

9.3.3 Post-Application Exposure and Risk Estimates

For all dermal post-application exposure scenar ios, risk estimates do not exceed HED’s LOC (Dermal LOC = 100), therefore, ar e not of concern to HED.

A summary of post-application exposure and risk calculations, assumptions, and results is provided in Table 17.

### Page 44 of 64 1. Maximum application rate from propos ed labels. See table 2 for specifics. 2. DAT = Days after treatment needed to re ach the LOC of 100; DAT 0 = the day of treatment/ assumed to be approx. 12 hours. 3. DFR (μg/cm 2 ) = dislodgeable foliar residues corresponding to DAT, base d on chemical specific da ta and applic ation rate. 4. TC (cm 2 /hr) = transfer coefficients and associated activities from ExpoSAC Policy Number 3. ( http://www.epa.gov/pesticides/science/exposac_policy3.pdf )

5. MOE on corresponding DAT. MOE = NOAEL / Daily Dose. Daily Do se = [(DFR x TC x 40% Dermal absorption x 8 hr

Ex p. Time Exp. Time )] / [(CF: 1000 μg/mg) x (80-kg Body Weight). S hort-Term NOAEL = 30 mg/kg/ day; Intermediate-term NOAEL = 1 mg/kg/day. The LOC is 100. ** Cereal Grains DFR data (MRID 133390)



### 9.3.4 Restricted Entry Interval

Propiconazole has been classified in Toxicity Category III for acu te dermal and eye irritation and Category IV for primary skin irritation. Per the Worker Protection Standard (WPS), a 12-hr restricted entry interval (REI) is required for chemicals classi fied under Toxicity Category III/IV.

10. REFERENCES

Propiconazole. Amended Use on Cereal Grains. Analy tical Methods and Residue Data., T. Morton, D400030,

02/27/2013

Propiconazole: Acute and Chronic Aggregate Di etary (Food and Drinking Water) Exposure and Risk Assessments for Cereal Grains, T. Morton, D403630, 02/27/2013

Propiconazole: Assessment of Aerial; Chemigation; and Gr oundboom Applications to Sugarcane and Cereal Grains (Wheat; Barley; Oats; Rye, and Triticale). J.S. Miller, D403629, 11/15/2012

Drinking Water Exposure Assessment for the IR-4 Petition (1E7855) that Proposes Tolerances for Residues of Propiconazole on Dry Bean, Succulent Bean, and Snap Bean. – I. Abdel-Sahib, D389673, 1/4/12

Propiconazole: Summary of Hazard and Science Policy Counc il (HASPOC) Meeting of June 21, 2012: Recommendations on the need for a 28-day inhalation study and a subchronic neurotoxicity study, K. Rury, TXR#0056387, date. Table 17. Summary of Estimated Post -Application MOEs for Cereal Grains

Crop Application

Rate
(lb ai/A) 1 DAT 2 DFR 3
( μ g/cm 2 ) TC 4
(cm 2 /hr) Activity 4 MOE 5

LOC = 100

Short-Term IntermediateTerm

Cereal

Grains 0.114 0 0.184 ** 70 Hand Weeding, Thinning 5,800,000 1,900,000

210 Scouting, 1,900,000 650,000

1,100 Scouting, 370,000 120,000

1,900 Irrigation 210,000 72,000

### Page 45 of 64 APPENDICES

A TOXICOLOGY DATA SUMMARY

A.1 Guideline Data Requirements

Guideline Data Requirements

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity ....................................................... 870.1200 Acute Dermal Toxicity ..................................................

870.1300 Acute In halation Toxicity ..............................................

870.2400 Primar y Eye Irr itation

.................................................... 870.2500 Primar y Dermal Irr itation

.............................................. 870.2600 Derm al Sensiti zation...................................................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Su bchronic (rodent) ...............................................

870.3150 Oral Su bchronic (nonr odent) ......................................... 870.3200 21-Day Dermal .............................................................. 870.3250 90-Day Dermal ..............................................................

870.3465 28/90- Day Inhalation ..................................................... yes

yes

yes

no no* yes

yes

yes

-

-
870.3700a Developmental Toxicity (rodent) ................................... 870.3700b Developmental Toxicity (nonrodent).............................

870.3800 Reproduc tion ................................................................. yes

yes

yes yes

yes

yes

870.4100a Chronic T oxicity (rodent) ..............................................

870.4100b Chronic Toxi city (nonrodent) ........................................ 870.4200a Oncoge nicity (ra t) .......................................................... 870.4200b Oncogenicity (mouse) ....................................................

870.4300 Chroni c/Oncogeni city .................................................... yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity—G ene Mutation - bacterial ..................... 870.5300 Mutagenicity—Gene Mutation - mammalian ................ 870.5375 Mutagenicity—Struc tural Chromosomal Aberrations ... 870.5900 Mutagenicity—O ther Genotoxic Effects ....................... yes

yes

yes

yes yes

yes

yes

yes

870.6100a Acute Delaye d Neurotox. (hen) ..................................... 870.6100b 90-Day Neurotoxicity (hen) ...........................................

870.6200a Acute Neurotox. Screening Battery (rat) ....................... 870.6200b 90-Day Neuro. Screening Batte ry (rat) .......................... 870.6300 Develop. Neuro .............................................................. no

no

yes no*

no -

- yes

-

-

870.7485 Gene ral Metabo lism ......................................................

870.7600 Derm al Penetr ation ........................................................

870.7800 Immunotoxicity ............................................................. yes

no

yes yes

-

no

* waived per HASPOC TXR 0056387

### Page 46 of 64 A.2 Toxicity Profiles

Table A.2: Propiconazole Acute Toxicity Profile

Guideline

No. Study Type MRID # Results Toxicity Category

870.1100 Acute Oral Toxicity– rat 00058591 LD 50 =1517 mg/kg III 870.1200 Acute Dermal Toxicity-rabbit 00058596 LD 50 = >4000 mg/kg III 870.1300 Acute Inhalation Toxicity– rat 41594801 LC 50 = >50.84 mg/L IV 870.2400 Acute Eye Irritation 00058597 Corneal opacity reversed in 72 hrs III

870.2500 Acute Dermal Irritation 00058598 No irritation IV

870.2600 Skin Sensitization 44949501 confirmed sensitizer -

Table A.3 Subchronic, Chronic and Other Toxicity Profile: Propiconazole

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

Classification /Doses Results

870.3100 90-Day Feeding Study in Rat 00058606 (1997) Acceptable/Guideline 0, 240, 1200 or 6000 ppm (M: 0, 15.9, 76.1, 461.7, F: 0, 16.8, 77.6, 400.9 mg/kg/day ) LOAEL = 6000 ppm in males (462 mg/kg bw /day) and 1200 ppm in females (77.59 mg/kg bw/day) based on reduced body weight gain. NOAEL = 1200 ppm in males (76 mg/kg bw/day) and 240 ppm in females (16.82 mg/kg bw/day).

870.3100 3-month oral toxicity study - mice 42050501,(1991) Acceptable/Guideline 0, 20 500 or 2500 ppm (M: 0, 2.7, 65, or 352, F: 0, 3.4, 85, 434 mg/kg/day) Two additional male groups at 850, 1450 ppm (112, 194 mg/kg/day) LOAEL = 500 ppm (65 mg/kg/day) in males and 2500 ppm (434 mg/kg/day) in females based on increase in absolute and relative liver weights and histopathological changes (hypertrophy, necrosis). NOAEL is 20 ppm in males (2.7 mg/kg/day) and 500 ppm in females (85 mg/kg/day).

870.3100

3-month oral - male

mice 42050502 (1991) Acceptable/Guideline 0, 20, 500, 850, 1450 ,2500

ppm (0, 2.7, 65, 112, 194, 352 mg/kg/day LOAEL = 500 ppm (65 mg/kg/day), based on increase in absolute and relative liver weights and histopathological liver lesions (hypertrophy, necrosis, vacuolation) seen at 4, 8 and 13 weeks sacrifices. The NOAEL is 20 ppm (2.7 mg/kg/day)

870.3100

3-month oral - male

mice. 45215801 (1997) Supplement to MRID

42050502: Reexamination

of liver Confirms findings in MRID 42050502. No change to NOAEL or

LOAEL

870.3150 3-month dog (dietary) 00058607(1979) Acceptable/Guideline 0, 50, 250 or 1250 ppm (0, 1.25, 6.25, 31.25 mg/kg/day) LOAEL is 250 ppm (59 mg/kg/day) based on the finding of lymphoid follicles in the mucous me mbrane of the pyloric part of

the stomach. NOAEL is 50 ppm (13mg/kg/day)

### Page 47 of 64 Table A.3 Subchronic, Chronic and Other Toxicity Profile: Propiconazole

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

Classification /Doses Results

870.3200 21 - Day dermal toxicity - rabbits 00116591 (1982) Acceptable/Guideline 0, 3, 30 or 300 mg/kg/day LOAEL: 3 mg/kg/day based on mild dermal irritation (Hyperkeratosis, acanthosis, mild dilation of blood vessels and mononuclear cells and/or heterophils in the proximal dermis). No systemic toxicity was reported.

NOAEL for skin lesions not established

870.3700a Developmental Toxicity- Rat 40425001(1987) Acceptable/guideline 0, 30, 90 or 300 mg/kg/day Maternal Toxicity LOAEL = 300 mg/kg/day based on severe clinical toxicity (ataxia, coma, lethargy, prostation, labored respiration and salivation) NOAEL = 90 mg/kg/day Developmental Toxicity LOAEL = 90 mg/kg/day based on increased incidence of rudimentary ribs, cleft palate malformations (0.3%) unossified sternebrae, as well as increased incidence of shortened and absent renal papillae. NOAEL = 30 mg/kg/day

Non-guideline Developmental Toxicity- Rat 40425002 (1987) Acceptable/non-guideline 0 or 300 mg/kg/day cleft palate: 2/2064 fetuses of dosed animals vs. 0/1222 controls (lab.hist. control incidence: was 0/5431). This confirms findings of cleft palate noted in above study. Severe clinical toxicity in the treated animals (ataxia, coma, lethargy, prostation, labored respiration and salivation)

870.3700b Developmental Toxicity- Rabbit 40425004 (1986) Acceptable/guideline 0, 100, 250 or 400 mg/kg/day Maternal Toxicity LOAEL = 250 mg/kg/day based on reduced dam body weight gain and decreased food consumption during the dosing period NOAEL = 100 mg/kg/day Developmental Toxicity LOAEL = 400 mg/kg/day based on increased incidence of fetuses

/litters with 13 th rib and increased abortions. NOAEL = 250 mg/kg/day

870.3800

2-Generation reproduction- Rat 00151514 (1985) Acceptable/guideline 0, 100. 500 or 2500 ppm Parental Toxicity LOAEL = 500 ppm (42 mg/kg/day) based on increased incidence of hepatic clear cell change NOAEL = 8 mg/kg/day Reproductive Toxicity LOAEL =>2500 ppm (>263 mg/kg/day, HDT) Offspring Toxicity LOAEL = 2500 ppm (192-263 mg/kg/day based on decreased offspring survival and body weights and an increased incidence of hepatic cellular swelling NOAEL = 500 ppm (43-52 mg/kg/day)

870.4100

12-Month Chronic Oral Toxicity (dietary) - Dogs 00151515 (1985) Acceptable/guideline 0, 5, 50 or 250 ppm (0, 0.12, 1.25, or 6.25 mg/kg/day) LOAEL = 250 ppm (6.25 mg/kg/day), based on hyperemia of the stomach in males (indicating mild irritation of the mucosa). NOAEL is 50 ppm (1.25 mg/kg/day)

### Page 48 of 64 Table A.3 Subchronic, Chronic and Other Toxicity Profile: Propiconazole

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

Classification /Doses Results

870.4100

24-Month Chronic/Carcinogenic ity Feeding-Rats 00129918 (1982) Acceptable/guideline 0, 100, 500 or 2500 ppm (male 3.6, 18.1 and 96.4

 , female 4.6, 23.3 and 100.6

 mg/kg/day) LOAEL = 2500 ppm (96.4 mg/kg/day) based on liver lesions (vacuolation of hepatocytes in males, ballooned cells in the liver of males, foci of enlarged hepato cytes in females, and increased incidence of luminal dilation of the uterus) and reduced body weight gain in both males and females. NOAEL = 500 ppm (18.1 mg/kg/day). The test material was not carcinogenic at the doses

tested.

870.4200

24-Month Carcinogenicity in

Mice 00129570 (1982 ) Acceptable/guideline 0, 100, 500 or 2500 ppm (M: 10.0, 49.4, and 344.3 F: 10.8, 55.6 and 340.3 mg/kg/day LOAEL = 500 ppm (49.5 mg/kg/day) based on non-neoplastic liver effects (increased liver weight in males and increase in liver lesions (masses/raised areas/ swellings/nodular areas mainly)). The NOAEL was 100 ppm (10 mg/kg/day). Liver tumors at 2500 ppm in male mice.

870.4200

18 - month oncogenicity study -

male CD-1 mice 44381401 (1997) Acceptable/guideline 0, 100, 500 or 850 ppm (0, 11, 59 or 108 mg/kg/day) LOAEL= 500 ppm (59.0 mg/kg/day) for males, based on hepatotoxicity (increased liver weight, hepatocellular hypertrophy, liver necrosis) and body weight gain effects observed at the interim

and terminal sacrifices. NOAEL= 100 ppm (11.0 mg/kg/day) for males. Treatment related increase in hepatocellular adenoma and total hepatocellular neoplasia at the 850 ppm exposure level compared to concurrent controls, but were within the range of the inadequate historical control data submitted with the study report. Adequate dosing based on body weight gain and hepatotoxic effects seen at 500 and 850 ppm. Subsequently, the Registrant submitted additional control data on five groups of CD-1 male mice generated within the approximate time frame of the original study and in the same testing facility under simila r experimental conditions (MRID 45215804) concerning the spontaneous occurrence of liver tumors. The tumor incidence observed in male livers at the 850 ppm dose is within the range of the new historical data.

870.6200

Acute neurotoxicity

in rats 46604601 (2005)

Acceptable/guideline

0, 30, 100 or 300 mg/kg by

gavage LOAEL = 100 mg/kg based on clinical signs of toxicity (piloerection, diarrhea, tiptoe gait).

NOAEL = 30 mg/kg.

LOAEL for neurobehavioral toxicity = 300 mg/kg based on reduced motor activity.

NOAEL for neurobehavioral toxicity = 100 mg/kg

870-5100

Bacterial reverse

mutation 00058601 (1979) Unacceptable 25-2025 g/plate Negative in Salmonella strains with or without S-9 activation. Test material purity not specified, not tested up to cytotoxic dose.

### Page 49 of 64 Table A.3 Subchronic, Chronic and Other Toxicity Profile: Propiconazole

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

Classification /Doses Results

870-5300

In vitro cell transformation assay (BALB/3T3) 00133349 (1982) Acceptable/guideline 1.16-18.5 g/ml Did not cause a measurable increas e in transformation of BALB/T3 cells. Highest dose produced 25% reduction in colony forming ability.

870-5385 (bone marrow

chromosomal aberration) - Chinese

hamsters 00058603 (1979) Acceptable/guideline 0, 251, 502 or 1004 mg/kg Negative for induction of micronuclei in bone marrow cells at all

levels tested.

870-5550

Unscheduled DNA synthesis in human fibroblasts, 00133347 (1982) Acceptable/guideline Negative for inducing Unscheduled DNA Synthesis at concentrations up to and including 9.32 μg/ml. Highest dose tested to allow at least 25% cell viability

870-5550

Unscheduled DNA synthesis in primary rat hepatocytes 00133348 (1982) Acceptable/guideline Negative for inducing Unscheduled DNA Synthesis at concentrations up to and including 83.5μg/ml. Highest dose tested to allow at least 25% cell viability

870-5575 Mitotic gene conversion assay (Saccharomyces cerevisiae) 00133343 (1982) Acceptable/guideline 10, 30, 90 or 270 g/ml No increase in convertants or reve rtants (did not induce mutation)

with or without activation. Concentrations of

 30 g/ml had inhibitory effect on yeast cell growth.

870.5450 Dominant lethal assay

in mice 00058602 (1979) Acceptable/guideline 165 or 495 mg/kg single dose oral gavage, No evidence of dominant lethal effects was observed in the progeny

of mice treated w ith propiconazole.

870.7485

Metabolism and pharmacokinetics (Rat) 42403901 (1983) Acceptable/guideline male rats: single oral 31.4 mg/kg - 14 C at the triazole-[3,5] position Rapidly metabolized: 96% excreted in urine and feces (5:4 ratio) after 3 days. Extensively metabolized by hydroxylation, oxidation and conjugation.

870.7485

Metabolism and pharmacokinetics (Rat) 41326701 (1989) Acceptable/guideline0.5 mg/kg oral or iv (U14 C)-Phenyl label or 0.5 mg/kg/day unlabeled for 14 days followed with 0.5 mg/kg labeled or single oral dose 50 mg/kg labeled Oral or iv routes resulted in similar patterns of 14 C elimination suggesting biliary excretion. >90% of 14 C excreted after 168 hours mostly within the 48 hrs. Females eliminated more in the urine

than in the feces and vice versa for males in the orally dosed groups. No significant differences were seen in the excretion pattern or were seen between the low and high dose groups or the repeated dosing groups. Extensively metabolized (oxidative): 24 and 47 metabolites in urine and feces, resp ectively. Parent (27-30% of AD) only detected in the urine of iv animals.

### Page 50 of 64 Table A.3 Subchronic, Chronic and Other Toxicity Profile: Propiconazole

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

Classification /Doses Results

870.7485

Metabolism and pharmacokinetics (Rat) 00074506 (1979) 00074507 (1981) Acceptable/guideline triazole-[3,5- 14 C] labeled single oral dose of 31.4 mg/kg or phenyl-[U- 14 C] single oral dose of 32.5 mg/kg to male rats. Study focused on urinary and fecal metabolites. Similar metabolic profiles for the two labels sugges ting that the bridge between the phenyl ring and the triazole ring remained intact. Metabolic pathway: cleavage of dioxolane ring through the oxidation of the propyl side chain, with subsequent dechlorination and conjugation and through the oxidation of the pr opyl side chain. Urinary and fecal metabolites except the pr esence of parent in feces.

870.7485

Metabolism and pharmacokinetics (Mouse) 00164795 (1986) Acceptable/non-guideline

Male and female mice fed in the diet for 21 days at 5, 100 or 2500 ppm propiconazole followed by phenyl-[U- 14 C] single oral dose at corresponding

levels. Two male rats given single oral dose 9.4mg/kg of the phenyl-[U14 C]compound Mice pre-treated with the unlabeled CGA 64250 excreted 83-103%

of the administered 14 C radioactivity within 96 hours (mostly within the first 24-48 hours) in the urin e and feces (mostly in urine: 1.5- 3.7x of the feces). The male rats excreted nearly equal amounts of the radioactivity in urine (48%) and feces (54%). Mouse urinary metabolites 15-30. The major metabolic pathway in mice proceeds via elimination of the dioxolane ring. In males this represents 30% of the AD whereas in the females it represents 15% of the AD. Mice cleaved the dioxolane ring to a greater extent (70% & and 40% for males and females, respectively) than do male rats (30%).

870.7600 Dermal penetration (Rat) 42415701 (1986) Acceptable/guideline Propiconazole 14 C at the triazole-[3,5] position 0.01, 0.1, 1.0 mg/cm 2 The average dermal absorption of propiconazole over a 10 hour period at an exposure level of 0.01 mg/cm 2 is approximately 40%

870-7800

Immunotoxicity MRID 48799701, 2012 Waiver request denied (D401289). Data gap remains.

Non- guideline Special study 00151517 (1984) Acceptable Tumor promotion- rat 2000 ppm dietary up to 8

weeks Propiconazole caused proliferative changes, with or without pretreatment with an initiator (DENA;nitrosodiethylamine), in the rat liver similar to phenobarbital (500 ppm), a known liver tumor
promoter.

### Page 51 of 64 Table A.3 Subchronic, Chronic and Other Toxicity Profile: Propiconazole

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

Classification /Doses Results

Non- guideline Special study

Mechanistic studies: Hepatic biochemical parameters - Mouse 45215803 (1998) Male CD-1 mice, 6/dose propiconazole at 0, 850 or 2500 ppm (0, 149, 578 mg/kg/day) for 14 days. Phenobarbital 850 ppm (145 mg/kg/day) to one

group Total cytochrome P450 activity in creased significantly (3-3.9x of the controls) at

 850 ppm propiconazole. 7-ethoxyresorufin activity, indicative of CYP1A1 induction was increased slightly but not to the extent observed following true induction. Lauric acid hydroxylation, specifically a result of peroxisome proliferation, was not induced by propiconazole. However, the activity of 7- pentoxyresorufin-O-dealkylase, associated with CYP2B or PB-type induction, was clearly increased 30-55-fold by propiconazole. Microsomal coumarin 7-hydroxyla se, associated with enzymes belonging to the subfamily CYP2A was also induced by propiconazole treatment consistent with PB-like induction. The microsomal activities of epoxid e hydrolase and UDPGT and the cytosolic activity of GST were slightly increased with propiconazole treatment. The pattern of microsomal and cytosolic enzyme induction determined biochemically was entirely consistent with PB-type induction. Propiconazole resulted in a marked

increase of total testosterone oxidation. The results from the determination of microsomal and cytosolic enzyme activities, testosterone hydroxylation, and immunoblot analyses show that propiconazole is not a 3-MC or mixed type inducer, but causes a pure PB-type induction of cytochrome P450 activity. The effects of propicon azole treatment on mouse liver weights and liver enzymes were comparable to those produced by phenobarbital, a known liver enzyme inducer and liver tumor promoter. The authors concluded that propiconazole can thus be considered a strong phenobarbital-type inducer of xenobiotic metabolizing enzymes in the mouse.

### Page 52 of 64 Table A.3 Subchronic, Chronic and Other Toxicity Profile: Propiconazole

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

Classification /Doses Results

Non- guideline Special study

Mechanistic studies: Hepatocellular proliferation - Mouse 45215802 (1999)

Male CD-1 mice 40/dose propiconazole at 0, 850 or 2500 ppm (0, 127, 353 mg/kg/day) for up to 60 days. A group of 40 mice given 850 ppm PB. Five mice/group were sacrificed on days 1, 2, 3, 4, 7, 28, or 60 (IP injection of 100 mg/kg BrdU two hours prior to sacrifice) Test material and Phenobarbital (PB) induced a dose- related

increase in absolute and relative liv er weights. All mice developed hepatocellular hypertrophy (primarily in the centrilobular hepatocytes with mild effects in the midzonal hepatocytes). Liver necrosis and cytoplasmic vacuolation were noted. Increased mitotic activity was observed in all groups. Minimal to moderate hepatocellular nerosis of hypertrophic single or focal cells was found predominately in the high dose and PB group. Treatmentwith propiconazole or PB induced a >1000% increase in BrdUstaining hepatocellular nuclei within 24 hours from the start of the study that peaked at a >3600% in crease by 48 hours. Thereafter,

the number of BrdU-sta ined nuclei decreased dramatically and was not biologically different from controls 7 days after the start and through the remainder of the study. For all treatment groups, the BrdU-staining nuclei were found primarily in the centrilobular/midzonal portions of the liver. These data support theconclusion that propiconazole induced an initial time- and doserelated proliferation in the liver followed by a sustained treatmentrelated hypertrophy in a manner similar to the known hypertrophic agent PB. The hepatomegaly was attributed to a sharp and transient induction of hepatocellular prolifer ation as well as to a time- and dose-related increase in the severity of hepatocellular hypertrophy.



### A.3 Toxicological Endpoints

A.3.1 Acute Reference Dose (aRfD) - Females age 13-49

Selected Study: Developmental Toxicity in Rats (MRID 40425001). See Section 3.2.2 and Appendix C.

Dose and Endpoint for Establishing an aRfD : 30 mg/kg/day - De velopmental NOAEL of 30 mg/kg/day and a LOAEL of 90 mg/kg/day based on increased in cidence of rudimentary ribs, unossified sternebrae, as well as increased inci dence of shortened and absent renal papillae and increased cleft palate.

Uncertainty Factor (UF ): 100 – 10X for interspecies extrapolation and 10X for intraspecies variation.

Comments about Study/Endpoint : The developmental effects of concern are presumed to occur after a single exposure and are relevant to females aged 13- 50 years old since they occur in utero and to young children based on post-natal effects.

### Page 53 of 64 A.3.2

Acute

Referen ce Dose (aRfD) - General Population

Selected Study: Acute Neurot oxicity in Rats (MRID 46046401). See Section 3.2.1 and Appendix C.

Dose and Endpoint for Establishing an aRfD : 30 mg/kg/day - NOAE L of 30 mg/kg/day and a LOAEL of 100 mg/kg/day based on clinical signs of toxicity (i.e., piloerection in one male, diarrhea in one female, tip toe gait in 3 females).

Uncertainty Factor (UF ): 100 – 10X for interspecies extrapolation and 10X for intraspecies variation.

Comments about Study/Endpoint : The effects of concern are presumed to occur after a single exposure.

A.3.3 Chronic Reference Dose (cRfD) - All Populations

Selected Study: 24 Month Oncogeni city Study in Mice (MRIDs 00129570 & 93194037)

Oncogenicity Mouse Study - A 24-month propiconazole dietary oncogenicity study in CD-1 mice was conducted at doses of 0, 100, 500 or 2500 ppm (M: 10.0, 49.4, and 344.3 F: 10.8, 55.6 and 340.3 mg/kg/day selected by the HIA RC for deriving the chronic RfD. Nonneoplastic liver effects (increased liver wei ght in males and increase in liver lesions: masses/raised areas/ swellings/ nodular areas mainly) were obse rved at 50 mg/kg/day. (See Appendix B)

Dose and Endpoint for Establishing a cRfD: 10 mg/kg/day - NOAE L of 10 mg/kg/day and a LOAEL of 50 mg/kg/day based on non-neoplastic liver effects.

Uncertainty Factor (UF ): 100 – 10X for interspecies extrapolation and 10X for intraspecies variation.

Comments about Study/Endpoint : The lower NOAEL of 2.7 mg/kg/day in a 3-month oral feeding toxicity study in mice was not sele cted because a) there is a wide dose spread Acute RfD = 30 mg/kg (NOAEL) = 0.30 mg/kg/day

( Females 13-49 ) 100 ( UF )

Acute RfD = 30 mg/kg (NOAEL) =0.3 mg/kg/day

( General Po p ulation ) 100 ( UF )

### Page 54 of 64 between the NOAEL (2.7 mg/kg/day) and the LO AEL (65 mg/kg/day) in that study, b) the LOAEL (50 mg/kg/day) in the se lected study is lower than the LOAEL (65 mg/kg/day) of the 3-

month mouse oral feedin g study, and c) the liver toxicity s een in the 2 year mouse study is

consistent with that seen in an 18-month mi ce and 2-generation reproduction studies. In an 18- month oncogenicity study in mice, the NOAEL fo r liver toxicity was 11 mg/kg/day and the LOAEL 59 mg/kg/day). In a 24- month feeding study in rats, th e NOAEL for liver toxicity was 18 mg/kg/day and the LOAEL 96 mg /kg/day). In 2-generation reproduction study in rats, the NOAEL for liver toxicity was 8 mg/kg/day and the LOAEL 42 mg/kg/day). The dog study was

not selected since stomach irritatio ns were attributed to local e ffects and not systemic toxicity, and target organ (liver) t oxicity seen in mice and ra ts was not seen in dogs.

A.3.4 Incidental Oral Exposure ( Short- and Intermediate-Term)

Incidental Oral Exposure (Short-Term)

Selected Study: Acute Neurot oxicity in Rats (MRID 46046401).

See Section 3.4.2

Dose and Endpoint for Establishing an aRfD : 30 mg/kg/day - NOAE L of 30 mg/kg/day and a LOAEL of 100 mg/kg/day ba sed on clinical signs of toxi city (piloerection in one male, diarrhea in one female, tip toe gait in 3 females.

Uncertainty Factor (UF )/Level of Concern = 100 – 10X for interspecies extrapolation and 10X for intraspecies variation. FQPA 1X

Incidental Oral Exposu re (Intermediate-Term)

Selected Study: 24 Month Oncogeni city Study in Mice (MRIDs 00129570 & 93194037)

See Section 3.4.3

Dose and Endpoint for Establishing a cRfD: 10 mg/kg/day - NOAE L of 10 mg/kg/day and a LOAEL of 50 mg/kg/day based on non-neoplastic liver effects.

Uncertainty Factor (UF ): 100 – 10X for interspecies extrapolation and 10X for intraspecies variation. Chronic RfD = (NOAEL) 10 mg/kg = 0.1 (General Population) (UF) 100

### Page 55 of 64 A.3.5 Dermal Absorption

HIARC selected a 40% dermal absorption factor (DAF) based on the average dermal absorption of propiconazole over a 10 hour exposure period in rats at an expos ure level of 0.01 mg/cm 2


### (MRID’s 42415701, 45345901). Although another dermal absorption factor for propiconazole

of 1% was used in a recent Section 18 risk as sessment, the basis for th e lower absorption factor was not clear. Therefore, a DAF of 40% was used for this assessment.

A.3.6 Dermal Exposure (Short and Intermediate-Term)

Dermal Exposure (Short-Term)

Selected Study: Acute Neurotox icity in Rats (MRID 46046401).

See Section 3.3.1

Dose and Endpoint NOAEL of 30 mg/kg/day and a LOAEL of 100 mg/kg/day based on clinical signs of toxicity (piloerection in one male, diarrhea in one female, tip toe gait in 3

females.

Uncertainty Factor (UF )/Level of Concern= 100 – 10X for interspecies extrapolation and 10X for intraspecies variation. FQPA 1X

Comments about Study/Endpoint : Since an oral NOAEL was selected for dermal risk assessment, a dermal absorption factor of 40% based on a dermal absorption study in rats should be used. Although a dermal toxicity st udy is available, a POD from an oral study was selected because neurotoxicity, the primar y effect of concern for short-term exposure is not specifically evaluated in the availabl e dermal toxicity studies. The selected endpoint is protective of pot ential neurotoxic effects from dermal exposure.

Dermal Exposure (Intermediate-Term)

Selected Study: 24 Month Oncogeni city Study in Mice (MRIDs 00129570 & 93194037)

See Section 3.4.3

Dose and Endpoint for Establishing a cRfD: 10 mg/kg/day - NOAE L of 10 mg/kg/day and a LOAEL of 50 mg/kg/day based on non-neoplastic liver effects.

Uncertainty Factor (UF ): )/Level of Concern: 100 – 10X for interspecies extrapolation and 10X for intraspecies variation. FQPA 1X

Comments about Study/Endpoint : Since an oral NOAEL was selected for dermal risk assessment, a dermal absorption factor of 40% based on a dermal absorption study in rats

should be used.

### Page 56 of 64 A.3.7 Inhalation Exposure (Short and Intermediate-Term)

Inhalation Exposure (Short-Term)

Selected Study: Neurotoxicit y in Rats (MRID 46046401).

See Section 3.4.2

Dose and Endpoint : . NOAEL of 30 mg/kg/day a nd a LOAEL of 100 mg/kg/day based on clinical signs of toxicity (p iloerection in one male, diarrh ea in one female, tip toe gait

in 3 females.

Uncertainty Factor (UF )/Level of Concern: 100 – 10X for interspecies extrapolation and 10X for intraspecies variation. FQPA 1X

Comments about Study/Endpoint : Inhalation toxicity is assume d to be equivalent to oral toxicity.

Inhalation Exposure (Intermediate-Term)

Selected Study: 24 Month Oncogeni city Study in Mice (MRIDs 00129570 & 93194037)

See Section 3.4.3

Dose and Endpoint 10 mg/kg/day - NOAEL of 10 mg/kg/day and a LOAEL of 50 mg/kg/day based on non-neoplas tic liver effects.

Uncertainty Factor (UF )/Level of Concern: 100 – 10X for interspecies extrapolation and 10X for intraspecies variation. FQPA 1X

Comments about Study/Endpoint : Inhalation toxicity is assume d to be equivalent to oral toxicity.

### Page 57 of 64 A.4 EXECUTIVE SUMMARIES

870.3200 Dermal Toxicity

In a repeated dose dermal toxicity study (MRID 00116591 and 93194034), groups of 20 New Zealand rabbits received 15 daily dermal applicat ions of 0 (11 males and 9 females), 3 (11 males and 9 females), 30 (10 males and 10 females), or 300 (13 males and 7 females) mg/kg/day propiconazole technical(90.7%, Ba tch No. FL-810858) over a 21-day period. The test material was applied on the intact and abraded skin with an impervious cuff for 6 hours for five days a

week for three weeks. There were no treatment-re lated deaths or signs of systemic toxicity and no treatment-related effects on body weight, f ood consumption, or opthalmology, hematological and clinical chemistry parameters. One hi gh dose female rabbit died on day 3 following diarrhea, decreased activity and body tone. A male rabbit in the low dose group died on day 23, the day of necropsy. Both deaths were not cons idered compound-related. Diarrhea was observed in one control female, 2 males and 2 females in the low dose group, and 3 males and 1 female in the mid dose group. Skin irritations were not ed in the 30 and 1000 mg /kg/day groups beginning at day 2 and persisted for the remainder of the study with maximum irritation indexes of 1.0 and 4.1, respectively. Signs of irri tation were noted in the 3.0 mg /kg/day group beginning on day 15 in males only with the highest irritation index of 0.3 at day 19. There were no compound related gross necropsy, organ weight effect s or histopathological findings. There were mild to moderate

skin lesions which were dose rela ted in treated animals compared to controls. Hyperkeratosis, acanthosis, mild dilation of blood vessels and mononuclear cells and/or heterophils in the proximal dermis were noted in a dose related manner. The LOAEL for systemic effects was >1000 mg/kg/day (the highest dose tested). The NOAEL for systemic effects is 1000 mg/kg/day. The LOAEL for skin effects was 3 mg/kg/day based on mild dermal irritation (Hyperkeratosis, acanthosis, mild dilation of blood vessels and mononuclear cells and/or heterophils in the proximal derm is) at 3 and 30 mg/kg/day and m oderate dermal irritation at 1000 mg/kg/day. No NOAEL for skin lesions was established.

870.3700 Developmental Toxicity

Rat Developmental Toxicity - Study 1

In an acceptable/guideline developmental toxicity study (MRID 40425001), CGA 64250 technical(92.1% purity propiconazole, Batch no. FL 850083) was administered to 24 CL:COBS CD (SD) BR VAF/PLUS virgin female rats/dos e by oral gavage in aqueous suspensions (3% corn starch containing 0.5% Tween 80) at dose levels of 0, 30, 90 or 300 mg/kg/day from days 6 through 16 of gestation. High dose animals initia lly received 360 mg/kg/day up to five days, but because of severe symptoms it was reduced to 300 mg/kg/day. Severe compound-related maternal toxicity was observed at the high dos e level during the first five days of dosing beginning on day 8 of gestation at 360 mg/kg/day. These incl uded statistically significant

increases in the incidence of le thargy, ataxia, salivation, and biol ogically significant increases in rales, prostration, hypothermia and bradypnea. The in cidence of these effects versus control is as follows: lethargy (9/23 vs. 0/24 in controls), sa livation (4/23 vs. 0/24 in controls) and ataxia

### Page 58 of 64 (3/23 vs. 0/24 in controls). After lowering th e dose to 300 mg/kg/day on day 6, the severity and frequency of these effects decrea sed rapidly. At the lower doses w ith the exception of one animal of the 90 mg/kg/day group exhibiti ng rales, there were no treatment related clinical observations. Mean food consumption was significantly reduced (p<0.05) in the 300 mg/kg/day group on days 7-8, 8-9 and 9-10 and in the 90 mg/kg/day group on days 8-9 and 10-11. Maternal body weights were not affected by the treatments. Maternal body weight gains were significantly decreased (p<0.05) in the 90 mg/kg/day group (44% of c ontrols) and in the high dose group (38% of controls) during gestation days 6-8 only. This effect was considered to be temporary and not treatment related. No significant treatment-related effects on uterine weights, corpora lutea, live and dead fetuses, fetal weights, and resorption were reported. The maternal toxicity LOAEL of propiconazole is 300 mg/kg/day, based on sev ere clinical toxicity. The maternal toxicity NOAEL is 90 mg/kg/day. Fetotoxic effects observed includ ed a high incidence of rudimentary ribs, though not statistically significant but part of dose relate d trend (0.7%, 3% and 39% in the 30, 90 and 300 mg/kg/day groups, respectively vs. 0% in the controls), a high incidence of unossified sternebrae (57%, p< 0.05 in the 90 mg group, and 72%, p< 0.01 in the 300 mg group vs. 38% in the controls), as well as increased incide nce of shortened renal pa pillae (26% in the 90 mg group (not statistically significant) and 39% in the 300 mg group, p < 0.01 vs. 23% in the controls) and absent renal papillae ( 5% in the 90 mg group (not st atistically signif icant) and 11% in the 300 mg group, p < 0.01 vs. 3% in the contro ls) and dilated ureter ( 43% in the 300 mg group, p < 0.01 vs. 27% in the controls). External and visceral examination revealed a very low incidence of cleft plate malf ormations in the 90 mg group (0.3%) and in the 300 mg group (0.7%) and considered to be “probably compound re lated”. Historical cont rols in 19 teratology studies from this laboratory had no incidence of cl eft palate. The cleft palate incidence in the current study was probably under reported because only half of the fetuses were examined viscerally. It was also concl uded that the low incidence of this finding along with skeletal anomalies was indicative of delayed development. The cleft palate finding at 300 mg/kg/day was also confirmed in a separate st udy (MRID 40425002) where propiconazole was administered to pregnant rats at 0 or 300 mg/kg/day during th e gestation period. The developmental toxicity LOAEL of propicon azole is 90 mg/kg/day, based on increased incidence of rudimentary ribs, un-ossified st ernebrae, as well as increased incidence of shortened and absent renal papillae and increased cleft palate. The developmental toxicity NOAEL is 30 mg/kg/day.

Rat Developmental Toxicity - Study 2

In an acceptable/non-guideline developmental toxicity study (MRID 40425002), CGA 64250 technical (92.1% purity, Batc h No. FL 850083) was administer ed to CL:COBS CD (SD) BR VAF/PLUS virgin female rats by or al gavage in aqueous suspensi ons (3% corn starch containing 0.5% Tween 80) at dose levels of 0 or 300 mg/kg/ day from days 6 through 15 of gestation. The control group comprised 178 sperm positive animals and the compound treated group comprised 189 sperm positive animals. The study was intended to confirm the finding of cleft palate in the previous study (MRID 40425001). The death of two dams from the treated group was

considered incidental. Severe maternal to xicity was observed duri ng the treatment period beginning on gestation day 6 and included a statistic ally significant increase in the incidence of ataxia (42% vs. 0 in controls), coma (9% vs. 0 in controls), lethargy ( 44% vs. 0 in controls),

### Page 59 of 64 prostration (3% vs. 0 in controls), audible respiration (4 % vs. 0 in controls), labored respiration (11% vs. 0 in controls), and sa livation (20% vs. 0 in controls ) in addition to a biologically significant incidence of ptosis (0.5% vs. 0 in controls), lacrimation (2% vs. 0 in controls), pale color (2% vs. 0 in controls) and death (1% vs. 0 in controls). Mean food consumption was significantly lower (60-92% of th e control values, p<0.05) in th e treated group during the dosing period. Body weight gains were significantly lowe r (68% of controls, p<0.05) in dosed animals during GD 6-16. There were no sign ificant differences between dos ed and control animals with respect to fetal sex ratio or mean number of corpora lutea, implant ation sites and dead fetuses. The mean number of live fetuses was significantly (95% of controls, p<0.05) lower in dosed animals, due to lower mean implantation sites, and higher mean total resorption in the dosed animals, although not significantly different from controls. Mean feta l weights for both males and females (95% of controls, p<0.001) were signif icantly lower in dosed animals. Fetuses were examined for external abnormalities only and ther e were no statistically significant treatmentrelated, external gross ob servations among fetuses. Cleft pala te was reported in 2/2064 fetuses

of dosed animals and 0/1222 of control fetuses. Th e incidence of cleft palate in controls for all teratology studies (not includi ng this one) conducted at this laboratory during 1983-1985 was 0/5431. This study confirms the findings of cleft palate in the previous guideline study (MRID 40425001).

Rabbit Developmental Toxicity

In a developmental toxicity study (MRI D 00265796), CGA 64250 technical (92.1% purity propiconazole) was administered to groups (19/ group) of artificially in seminated New Zealand white rabbits by oral gavage in aqueous suspen sions (3% corn starch containing 0.5% Tween 80) at dose levels of 0, 100, 250 or 400 mg/kg/day from days 7 through 19 of gestation. One animal from each of the mid-dose groups was found dead. In high-dose animals, 5/19 does were sacrificed early due to abortion or early delivery (statistically significant, p<0.05 compared to control 1/19). In the mid dose (250 mg/kg/da y) group, one doe aborted early. One control animal delivered early. Among an imals of the high dose group, an increased incidence of stool alterations (decreased/no/soft; 18/19 vs. 11/ 19 in controls, p<0.05) was observed, possibly compound related. During the dosing period (days 7-19), the high and mid dose animals had a significant (p<0.05) decrease in food intake (43 - 63% of the contro ls and 58-78% of the controls in the high- and mid-dose groups, respectively) and a severe decrease in the maternal body weight gain, but rebounded to normal after w ithdrawal of the test compound. During GD 7-10, the maternal animals had a weight lo ss of 0.047 and 0.111 kg at 250 and 400 mg/kg, respectively, compared to a weight gain of 0.018 kg in controls. The weight gains during GD

10-20 were 67-77% and 11-43% of controls at 250 and 400 mg /kg/day, respectively. An

increased incidence of the formation of 13 th 

### rib was observed at 400 mg /kg/day. The incidence of this finding on fetuses/litter basis was 2.7, 3.9, 4.1 and 5.3 at 0, 100, 250 and 400 mg/kg/day, respectively. The incidence of fetuses at 400 mg/kg/day with this finding was statistically significant. Therefore, this fi nding was considered to be treatm ent-related. The increase in the number of resorptions at 400 mg/ kg/day was caused by the resorption of an entire litter. At 400 mg/kg/day there was also an incr eased incidence of abortions. The maternal toxicity LOAEL of propiconazole in the rabbit is 250 mg/kg/ day, based on reduced maternal body weight gains and decreased food consumption during th e dosing period. The maternal toxicity

### Page 60 of 64 NOAEL is 100 mg/kg/day. The developmenta l toxicity LOAEL was 400 mg/kg/day based

on increased incidence of fetuses/litters with 13 th 

### rib and increased abortions. The developmental toxicity NOAEL was 250 mg/kg/day.

870.7600 Dermal Absorption Studies

In a dermal absorption study (MRID’s 42415701, 45345901), groups (4/group) of young adult male, Harlan Sprague-Dawley rats (age not given) were exposed to triazole-[3,5-] 14 

### C- CGA64250 (95% radiochemical purity, specific activity 28.2 mCi/mg for low and mid-dose levels and 2.01 mCi/mg for the high-dose level) at doses of 0.1, 1.0 or 10 mg/rat (0.01, 0.1 or 1 mg/cm 2



### , respectively) to a 10 cm 2 

### shaven dorso-lumbar area. The radioactive test compound was added to the 3.6EC formulated product (45.8% active ingred ient and 54.2% inert substances) and applied as an aqueous suspension. One group of four rats/dose were exposed for 24 hours, while two other groups of four rats each/dose were e xposed for 10 or 24 hours followed by a 72-hour depletion phase. This study is an addendum to an earlier study where groups of four male rats each were treated similarly but exposed for 2, 4 or 10 hours (MRID 00164469). In both studies, following the exposure period, the test compound remaining on the skin was removed with a soap rinse. Fecal and urinary samples were collect ed at the end of the exposure periods and at 24 hour intervals (for the depletion groups) following the exposure.

At sacrifice time rats were anesth etized and blood collect ed. The radioactivity present in excreta, blood, carcass, skin, skin wash es and patch components were determined. The applied radioactivity was accounted fo r, with recoveries ranging from 82.8 to 108 % for MRID

42415701 and 86.6 to 112.6% for MRID 00164469.

The amount of test compound absorbed was directly proportional to the ap plied dose. The rate of absorption appeared to be saturated at the hi ghest dose level; at the low dose level, there was a time dependent increase in the amount of co mpound absorbed. After 24 hours, 57.1, 271 and

3010 μ g/cm 2 

### (57.13, 27.14 and 30.10% of total dose were absorbed at the low, mid and high dose levels, respectively). During the 72-hour de pletion phase essentia lly all of the compound was eliminated in the urine and feces; urinary elimination predominated at the mid and high dose levels. At the end of the 72 hour depletion pha se, less than 2% of th e test compound was still present in the carcass. The results of the earlier study (MRID 00164469) demonstrated that 26- 35% of the applied radioactivity (at all dose leve ls) is absorbed within the first two hours and remained fairly constant for the longer exposur e periods of 4 and 8 hours except for the low dose of 0.01 mg/cm 2 

### where it increased to 54%. The averag e dermal absorption of propiconazole over a 10 hour period at an exposure level of 0.01 mg/cm 2 

### is approximately 40%. The attached appendix provides a summary of both studies.

870.3800 Reproduction

Rat Reproduction Study

In an acceptable/guideline 2-generation reproducti on study (MRID 00151514), CGA 64250 technical (89.7% purity propicona zole, FL-830377) was administer ed to 15 male and 30 female

### Page 61 of 64 Charles river CD rats at dos e levels of 0, 100, 500 or 2500 ppm (mean doses of 8, 42 and 192 mg/kg/day for F0 males, 9.4, 43, 223 mg/kg/day for F0 females, 9.2, 48, 238 mg/kg/day for F1 males and 10, 52, 263 mg/kg/day for F1 females) in the diet. Test diets were administered to both F0 and F1 generation rats during pre-ma ting period and throughout ge station and lactation periods. Parental Toxicity : No compound-related clinical observations or mortality were reported. Female body weights in the F 0 

### and F 1 

### generation were significantly reduced in the high dose group at most of the body weight interval s(82-94% of the controls, p<0.05 and 0.01); body weight gains were also signifi cantly reduced during pre-mating ( 12 weeks)as well as gestation and lactation periods(77-85% of controls, p<0.01). Correspondingly, high dose females also had significantly reduced food intake ( 83-88% of controls). In the F 0 

### and F 1 

### generation male body weights were reduced in the high dose groups compar ed to controls (not st atistically significant); body weight gains in this group was 91-94% of c ontrols for the pre-mating period and during the entire duration of the study (7 months). F ood consumption was reduced significantly in high

dose F 0 

### males at week 1 (65% of the control, p< 0.01) and week 7 (86% of the control, p<0.01) and in high dose F 1 

### males and females at week 2, 6 and 10 (84-88% of contro ls). Histological examinations revealed that hepatic “cellular sw elling” was significantly increased in mid-dose males and high-dose males and females of the F 0 

### generation. In the F 1 

### parental animals, increase

in the incidence of this findi ng was significant for both sexes in the mid- and high-dose groups. The incidence of “hepatic clear-cell ch ange” was significantly increased in F 0 

### high-dose males,

F 1 

### mid-dose and high-dose males and F 1 

### high-dose females (p<0.05). The LOAEL for parental toxicity is 500 ppm (42 mg/kg/day) based on increased hepatic clear-cell change and the NOAEL for parental toxicity is 100 ppm (8 mg/kg/day). Reproductive parameters (mating, fecundity, gestation, male and female fert ility indices, litter re sorptions and gestation duration) were comparable in all groups. Offspring Toxicity : The number and percent of viable pups at birth and surviving through weaning we re comparable between the dose groups and

controls for both the F 1a 

### and F 1b 

### litters. In the F 2a 

### litters, however, the nu mber of pups delivered, delivered viable and surviving to day 4 of lact ation were significantly (p<0.01) reduced in the high-dose group. The percentages of high-dose pups delivered viable and surviving to day 4 were also reduced (not stat istically significant). The F 2b 

### litters of these dams had significantly reduced survival rates (both num ber and percent of surviving pups ) at lactation days 7, 14, and 21. The mean body weights of high-dose progeny were significantly redu ced at days 14 and 21 for pups of both generations (72-81% of controls). Reductions were also significant on days 4 and 7 (except for F 1b 

### litters) and at birth (F 2b 

### litters only). At necr opsy, no treatment related anomalies, organ weight changes and gr oss pathology findings were noted in pups. Histopathological evaluation of selected organs from F 1b 

### and F 2b 

### progeny revealed significantly (p<0.01) increased incidences of hepatic “cellula r swelling” in high-dose males and females.

This was considered to be a compound related effect. The LOAEL and NOAEL for offspring toxicity are at 2500 ppm (192- 263 mg/kg/day) and 500 ppm (43- 52 mg/kg/day), respectively, based on decreased offspring survival and bo dy weights and an increased incidence of hepatic lesions (cellular swelling) at 2500 ppm.

Additional Developmental/Reproduction Toxi city Information from Literature Sources

In a published study, propiconazole (Tilt 100 EC in the form of 10% solution) was administered to groups of pregnant female albino rats (15/ dose) at 0, 75.85 or 151.70 mg (ai)/kg/day on days

### Page 62 of 64 6-15 of gestation (Hassan, 1993. Embryotoxic and teratogenic eff ects of the organic fungicide tilt in albino rats. Bull. Fac. Pharm., Cairo Un iversity 31(3): 459-463). Ra ts were sacrificed on day 20 of gestation. Post-implantation deaths, re sorption sites and dead fetuses were counted. Fetuses were examined for morphological, visceral and skeletal malformations. Propiconazole

was fetotoxic at both doses causi ng significant (p<0.05) increased fe tal resorptions (8 and 21% at the low and high dose vs. 0% in the control), incr eased fetal deaths (10 and 24% at the low and high doses vs. 2% in the contro l) and decreased fetal weight). The mean number of stunted fetuses was significantly higher (p<0.05) at both dos es (1.43 and 3.57) at the low and high dose vs. 0.13 in the control), noting inco mplete ossification of the sku ll, caudal vertebrae and digits, extra rib (14 th 

### rib) and missing sternebrae. Malformations of the lung and kidneys were reported. No maternal toxicity was repor ted at either dose. The LOAEL for developmental toxicity in this study is 76 mg/kg/day (the lowest dose tested). A NOAEL is not established.

870.6200b Subchronic Neurotoxicity

Waived by HASPOC TXR 0056387

870.5100, 870-5300 Mutagenicity

Propiconazole was negative in si x acceptable mutagenicity studies:

1. In vitro cell transformation assay (MRID 00133349) 2. Bone Marrow Chromosomal Aberration (MRID 00058603) 3. Mutagenicity: Unschedule d DNA synthesis (MRID 00133347) 4. Mutagenicity: Unscheduled DNA synthesis (MRID 00133348) 5. Mitotic Gene Conversion Assay (MRID 00133343)

6. Dominant Leth al Assay in Mice (MRID 00058602)

870.7800 Immunotoxicity

CropLife America (CLA) has made available the results of a retrospective analysis on 78 immunotoxicity studies submitted to the Agency which suggests that immunotoxicity studies have not provided Points of De parture (PoD) lower than other guideline studies. OPP is also conducting an independent retrospective analys is of more than 160 immunotoxicity studies submitted to Agency. Preliminary findings of O PP’s retrospective analysis also suggest that immunotoxicity studies have not yet provided lower PoDs than ar e selected from other guideline experimental toxicology studies and thus, so far, immunotoxicity studies would not have impacted the Agency’s risk assessments. The OPP retrospective analysis is anticipated to be completed in the summer of 2012. In the interim,OPP interim, OPP recommends that the immunotoxicity continue to be required for re gistration and registrati on review chemicals.

The complete toxicity profile for prop iconazole is provided in Appendix A.

### Page 63 of 64 APPENDIX B. Chemical Names A nd Structures Of Metabolites



### * N

HC =

= CH

N N CH 2 C Cl

Cl

O O

CH 2 CH CH CH 3 CH 2

OH

N

HC =

= CH

N N CH 2 C Cl

Cl

O O

CH 2 CH CH 2 CH 2 OH N

HC =

= CH

N N CH 2 C Cl

Cl

O O

CH 2 CH COOH

CH 2 C Cl

Cl

O O

CH 2 CH COOH CH 2 N

HC =

= CH

N N N

HC =

= CH

N N CH 2 C Cl

Cl

O

N

HC =

= CH

N N CH 2 CH Cl

Cl

OH Cl

Cl HOOC N

HC =

= CH

N N CH 2 C Cl

Cl

O O

CH 2 CH CH 2 CH 3 CH 2



### CGA 64250 CGA 118244

CGA 118245 CGA 217495

CGA 217496 CGA 91304

CGA 91305 CGA 177291 A PPENDIX: REFERENCE COMPOUNDS

### Page 64 of 64 APPENDIX C. Physical/Chemical Properties

Table 3. Physicochemical Propertie s of Technical Grade Propiconazole

.

Parameter Value Reference

Boiling point 120 C at 1.9 Pa, >250 C at 101.325 kPa MRID No. 43698701

pH 4.9 at 25 C (1% aqueous dispersion) MRID No. 43698701

Density 1.289 g/cm 3 at 20 C MRID No. 43698701

Water solubility 0.10 g/L at 20 C MRID No. 41720301

Solvent solubility (temperature not specified) Completely miscible in ethanol, acetone, toluene and n-octanol. hexane = 47 g/L MRID No. 42030201

Vapor pressure 4.2 x 10 -7 mm Hg at 25 C MRID No. 41720301

Dissociation constant (pK

a ) 1.09 MRID No. 43698701

Octanol/water partition coefficient Log(K OW ) 3.72 at pH 6.6 and 25 C MRID No. 43698701

UV/visible absorption spectrum ( 8 max, nm) Not available MRID No. 40583703



### APPENDIX D. Studies Reviewed for Ethical Conduct

This risk assessment relies in part on data from st udies in which adult human subjects were intentionally exposed to a pesticide or other chemi cal. These studies were determined to require a review of their ethical conduct, have received that review and ha ve been determined to be ethical.

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

The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler Unit Exposure Surrogate Reference Table. U.S. Environm ental Protection Agency. Released June 21, 2011.