UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D

. C. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

MEMORANDUM

Fe bruary 2 7

, 20 14

SUBJECT: Propiconazole Human Health Risk Assessment fo r the Section 3 Regis trati o n on Rapes eed C rop Sub g r ou p 20 A.

PC Code: 1 2210 1 DP Bar code: 4036 3 1

Decision No .: 460659 Registration No

. : 100-617, 1 00-1 1 78, and 100-

1324

Petition No.: 2F8 1 35 Regulatory Action : S ection 3

Risk Assessment Type: Sing l e C hemical A g gregate Case No. : 3 1 25

TXRNo.: NA CAS No.: 60207 -9 0

- 1

MRJDNo.: NA 40 CFR: 180.434

ROM: Thursto n G. Morto n , C h emis t

# y F James S Miller, E n v ironm e ntal

# S~ Abdallah Kha saw inah

, PhD., Toxicologist

Ri s k Assess m en t Bran ch 4

H ealt h E ffects Division (7509 P )

THROUGH: E li ssa Reaves, Ph.D., Br anc h C hie f

# ?./~**-- ~--­**  Susan V. Hummel

, Branch Senior

## Scie**nt ~~**  -- Ri sk Assess m e n t Branch 4, HED (7509P)

TO: Erin Malone Fungicide Br anc h

Re gistra t i on Division (7505 P)

This docum ent pro vides the re vised Health Effects Division ' s ( H ED's) risk assess m ent of the

Sect ion 3 use of propiconazole o n Rapeseed Crop Su b gro up 20A. The document includes an

assessment of aggr eg a te ri s k from resid en tial expo s ures to prop i conazo l e.

Page 1 of61

### 1.0 EXEC U TIVE SUMMARY

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



### 2

. 0 HED RECOMMENDATIONS

.. . .. .. .. . ... . ........• • •• ••••••••••••••••••.••• .•.•...•. •. •• •. •. •. .•

.. .....•....•••...•.. 8

2.1 Data Deficiencies/Conditions of Registration

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

2

. 2 Tolerance Considerations

.... .. .. .. .. . ... . ... . ... . ......... . ... . ... . ... . ... .. ...... . ......•..

. ... .. .. .. .. ....... .•.

... .. 9

2

. 2

. 1 

### Enforcement Analytical Method

. . . . . . . . . . . . ....... .. ...... . ... . ... .. ...... . ...•.

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



### 2.2

. 2 International Harmonization

.. . ......... . .. .. .. •..

.. .. .. .. .. .•.....

. . ....... .. .. . •..

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

2

. 2.3 

### Recommended Tolerances

.. .. .. .. .. . ....... . .......... ..... . ........... . .•.

.. .. .. . . •

........ . ... . ... . .. .. ....... • 9



### 2

. 2.4 Revisions to Petitioned-For Tolerances

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

2.3 Label Recommendations

.. . ... . ..... . .. ••

.. •.....

...... .. ..........•.

.. . ..... . . . . .. .. .. . ...•...• •

... .. . .•.............. 10

3.0 

### INGRE

- DIENT PROFILE

.. ........ . ... . ... . ... . .. .. ......... . .. .. .. .. .. ... . . ... .. . ... .. .. ...•.....

. ... . ... .. ... . ... . .... tO



### 3.1 Chemical Identity

.. .. .. .. . . . .. .. . ... . ... . .. .. ................. . .. .. ... ...................... . .. •....

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

3.2 Physical/Chemical Characteristics

..... . .. .. .. .. ...... .. .. . ... ...... .. .. . ... .. .. .. .. .•

.. .. .. .. ... . ......... ... .. . 1 1

3.3 Pesticide Use Pattern

. . ... . .. . ... .. .. . .. ... ....... .. ... . .. .. . ...................... . .... .. ... .•........

. . . . . . .. .. .. ... . . .. 11

3

. 3

. 1 Proposed New Use

- s

.. . .. .. . ... . . . . . . . . . .. .. .. ....... . ... . ...... .. .. ... . .. .. . ....... .. .. .. . .... .. .. ... . .. .. ..... . .... 11

3

. 4 Anticipated Exposure Pathways

. ... . ... . ... . . . ... . ... . ... ...................•.........•.... .•

.. .. ••

... . . . . . . .. . . . . 12

3.5 Considerations of Environmental Justice

...... . ..... . ... .. .. .. .. . ..... . . .. .. .. .. .. ......... . ... ... . ... . ..... 12

4.0 HAZARD CHARACTERIZATION/ASSESSMENT

.. .. .. ................. . ...... ................ ..... 13

4.1 Toxicology Studies Ava i lable for Analysis

..... . ....... . ... ...... . ......... . . . . . . . . .. .. ... .. .. .. .. . ... ... .. . 13

4.2 Absorption, Distribution, Metabolism and Excretion

.. ...... .. .. .. ...... ... ............ .. .. ........ . 13

4.3 Toxicolog

· ical Effects

. .. .. .. .. .. . .. . ... .. .. ... . ... .... .. .. .. .. .. .. •.

... . ... . ..... . ... . ... . .. . . . •

. . . . . . .......... . ... .. .. ... 1 3

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

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

4.4.1 Completeness of the Toxicology Database

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

4.4

. 2 Evidence of Neurotoxicity

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

4

. 4

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

...... 15

4

. 4

. 4 Residual Uncertainty in the Exposure Database

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

4.5 Toxicity Endpoint and Point of Departure

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

4.5.1 Dose-Response Assessment

.. ...... . ...... .. ...... .. ... . ••

... . .. .. .. .. ..... . .. ...... .. . . ... . ... . .. . .. .. ... . ... • 16

4.5.2 Recommendations for Combining Exposure Routes

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

4.5.3 Classification of Carcinogenic Potential

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

4.5.4 Summary of Points of Departure Used in Risk Assessment

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

5.0 DIETARY AND DRINKING WATER EXPOS U RE AND RISK ASSESSMENT

.. .. 20

5.1 Metabolite/Degradate Residue Profile

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

5.1.1 Summary of P l ant a nd L i vestock Metabolism Studies

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



### 5

. 1.2 Comparison of Metabolic Pathways

. ... . ... . ... . ... . ... . ... . ... . ... . ... . ... . •

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

Page 2 of61Page 3 of 61



### 5.1.3 Environmental Fate and Transport

................................ ................................ ...... 21

5.1.4 Residues of Concern Summary and Rationale

................................ ..................... 21

5.2 Food Residue Profile

................................ ................................ ................................ ..... 21

5.2.1 Residues in Crops

................................ ................................ ................................ .... 21

5.3 Water Residue Profile

................................ ................................ ................................ ... 22

5.3.1 Estimated Drinking Water Concentrations

................................ .......................... 22

5.4.1 Acute Dietary and Drinking Water Analysis

................................ ....................... 24

5.4.2 Chronic Dietary and Drinking Water Analysis

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

6.0 RESIDENTIAL EXPOSURE AND RISK ASSESSMENT

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

6.1 Residential Bystander Postapplication Inhalation Exposure

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

6.2 Spray Drift

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

7.0 AGGREGATE E XPOSURE AND RISK ASSESSMENT

................................ ............ 27

7.1 Acute & Chronic Aggregate Risk

................................ ................................ ................. 27

7.2 Short

- and Intermediate

- Term Aggregate Risk

................................ ......................... 27

7.3 Intermediate

- Term Aggregate Risk

................................ ................................ ............. 30

8.0 CUMULATIVE RISK

................................ ................................ ................................ ...... 31

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION

.............................. 32

9.1 Exposure Scenarios

................................ ................................ ................................ ....... 32

9.2 Handler Exposure

................................ ................................ ................................ .......... 32

9.2.1 Handler Exposure Scenarios

................................ ................................ .................. 33

9.2.2 Handler Exposure Data

................................ ................................ .......................... 33

9.2.3 Handler Exposure Assumptions

................................ ................................ ............ 34

9.2.4 Handler Exposure and Risk Estimates

................................ ................................ . 35

9.3 Post Application Exposure

................................ ................................ ............................ 38

9.3.1 Post Application Exposure Scenarios

................................ ................................ ... 38

9.3.2 Post Application Exposure Assumptions

................................ .............................. 38

9.3.3 Post

- Application Exposure and Risk Estimates

................................ ................... 39

9.3.4 Restricted Entry Interval

................................ ................................ ....................... 40

10. REFERENCES

................................ ................................ ................................ .................. 40

A TOXICOLOGY DATA SUMMARY

................................ ................................ .............. 41

A.1 Guideline Data Requirements

................................ ................................ ................ 41

A.3 Toxicological Endpoints

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

A.4 EXECUTIVE SUMMARIES

................................ ................................ .................... 53

APPENDIX B. Chemical Names And Structures Of Metabolites

................................ ......... 60Page 4 of 61



### APPENDIX C. Physical/Chemical Properties

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

APPENDIX D. Studies Reviewed for Ethical Conduct

................................ .......................... 61Page 5 of 61



### 1.0 EXECUTIVE SUMMARY

This document addresses the exposures and risks 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 residentia l exposure as required under the Food Quality Protection Act (FQPA) of 1996.

Under PP# 2F 8135

, Syngenta is proposing a tolerance for propiconazole on Rapeseed Crop Subgroup 20A

.

Use Profile

Propiconazole 1

- [[2

- (2,4

- dichlorophenyl)

- 4

- propyl

- 1,3

- dioxol an

- 2

- yl]methyl]

- 1 H

- 1,2,4

- triazole) is a systemic triazole

- type fungicide 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 propiconazol e and its metabolites (determined as 2,4

- dichlorobenzoic acid (2,4

- DCBA)) in/on a variety of agricultural commodities at levels ranging from 0.05 ppm in/on meat and meat byproducts to 40 ppm in/on grass straw. Non

- food uses include use on commercial, publ ic and residential 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 production disrupts cell wall formation and slows or stops the growth of the fungus. Agricultural applications of propiconazole are made using ground or aerial equipment. Propiconazole is applied to non

- food areas by both occupational and r esidential 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 applications are made with handheld equi pment.

Proposed New Uses

Syngenta has submitted an application for the registration of products containing propiconazole

for a new use on rapeseed crop subgroup 20A . The 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

- 1 178 ) and Quilt Xcel ® 

### Fungicide (EPA Reg. No. 100

- 1324). The

new use is not proposed for residential use and residential exposures are not expected based on the proposed uses.

T he toxicology database for propiconazole is complete for evaluating 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 necrosis. There are mixed effects

in the developmental and repr oduction rat studies. In a rat developmental study, fetal effects

were observed at doses lower than doses at which maternal effects were seen demonstrating quantitative evidence of increased susceptibility of fetuses to in utero exposure to propicon a zole

. W hile in ra bbi ts, developmental toxicity occurred at higher doses than maternal ly toxic doses. In the two generation reproduction study in rats, offspring toxicity occurred at a higher dose than the parental toxic dose suggesting lower susceptibility o f the rat offspring to propiconazole.Page 6 of 61



### Propiconazole does not appear to be neurotoxic based on an acute neurotoxicity study. The concern for susceptibility is low since clear NOAELs were established in the rat and rabbit developmental studies and the point s of departure selected for the risk assessment scenarios are protective of the susceptibility observed in the rat developmental study. Therefore, t he 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 toxicity 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 selected for dietary/drinking water, occupational and residential exposure scenarios. Acute and chronic points of departure ( PODs ) were selected for assessment of food and drinking w ater exposures. An acute POD for the general population was selected from an acute neurotoxicity study in rats. An a cute POD for females 13

- 49 was selected from a developmental toxicity study in rats. A chronic/cancer POD for the general population was selected from a carcinogenicity study in mice. Short and intermediate

- term occupational exposures via the dermal and inhalation routes may occur based on the use pattern and label

directions. Toxicological endpoints for short

- term inhalation, dermal, and incidental oral exposures were selected from the acute neurotoxicity study in rats. Toxicological endpoints for

intermediate

- term inhalation, dermal, and incidental oral exposures were selected from a carcinogenicity study in mice. Since an oral study w as selected for dermal exposure, a 40% dermal absorption factor from a dermal absorption study in rats is used for route to route extrapolation. An uncertainty factor of 100X was applied to endpoints selected for all exposure

routes ( 10X for interspecies extrapolation, 10X for intraspecies variation).

Exposure/Risk Assessment and Risk Characterization

A new r isk assessment w as conducted for dietary (food and water) only . The occupational

exposure assessment did not ne ed to be updated since cereal grains were assessed recently ( J.S. Miller, D403629, 11/15/2012 ) . The proposed use pattern for rapeseed is similar to cereal grains

. Worker exposures were assessed for handler and post

- application activities. There are no ne w requested residential uses expected with this registration, therefore residential risk was not assessed for the proposed new use.

Conservative acute and refined chronic dietary and drinking water risk assessments for propiconazole conclude that dietar y and drinking water exposure estimates are below HED’s level of concern for the general population and all population subgroups. At the 95 th 

### percentile, the exposure to the general U.S. population is 2 6 % 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 highly exposed subgroup ( Children 1

- 2 yrs old) is 2 4 % of the cPAD.

A dietary exposure assessment f or the free triazole or conjugated triazoles was also conducted

. Aggregate risks from propiconazole are not of concern.Page 7 of 61



### Occupational exposure and risk estimates indicate that worker and residential handler and post

application exposures are not of concern at the maximum allowable applic ation rates for the proposed new uses provided that handlers wear chemical resistant gloves as required on the label. The only residential use scenario that will result in potential intermediate term exposure to propiconazole is post application exposure to children from wood treatment (antimicrobial use).

Table 7.3 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 o f concern.

Aggregate Assessment of Free Triazole & its Conjugates

The addition of the new use does not increase the aggregate exposure to free triazoles and its conjugates. However , the previous aggregate human health risk assessment and dietary exposure

assessment were updated for free triazoles and its conjugates and the aggregate estimates remain

below HED’s level of concern

.

Use of Human Studies

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These 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 Studies Review Board. All of the studies used have received the appropriate review.

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were cons idered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

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

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

- established procedures. In line with OPP policy, HED estimates

risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated. Further considerations are currently in development, as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle a nd traditional dietary patterns among specific subgroups.

Tolerance Recommendation

Pending submission of a revised Section F (see requirements under Proposed Tolerances), there are no residue chemistry issues that would preclude granting a Section 3 re gistration for thePage 8 of 61



### requested use of propiconazole on rapeseed crop subgroup 20A

, or establishment of the following tolerance s for residues of propiconazole

.

Rapeseed subgroup 20A

................................ ................................ .......... 0.30 ppm



### As previously noted, permanent tolerances are currently establis hed for the combined residues of propiconazole and its 2,4

- DCBA containing metabolites at levels ranging from 0.1

- 40 ppm in/on plant commodities [40 CFR §180.434(a)]. HED has determined that the current tolerance expression should be amended to include on ly propiconazole per se because 1) there are a number of pesticides that have 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 contain ing 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 expressions (S. Knizner, 2009). We now conclude the tolerance expression should be as follows: Toler ances are established for residues of propiconazole, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only

those propiconazole resid ues convertible to 2,4

- dichlorobenzoic 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 established a maximum residue limits (MRLs) for propiconazole in/on various raw agricultural commodities. In addition, both Canada and Mexico have established MRLs for propiconazole in/on various commodities. The Codex and Mexican MRLs are expressed in terms of propic onazole 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 an MRL for rapeseed at 0.02 ppm . The U.S. cannot harmonize at this level due to the use pattern registered in the U.S along with the CODEX tolerance expression. The U.S. will be harmonized on the tolerance expression and MRL level for Canada since the same

action was submitted to Canada

.

2.0 HED RECOMMENDATIONS

2.1 Data Deficiencies/Conditions of Registration

HED can recommend for registration and permanent tolerance for the proposed use of propiconazole. Deficiencies are stated below. The specific tolerance recommendations are discussed in Section 2.2, and label modifications are discussed in Section 2.3.

Note to PM:

Revised Section F required.Page 9 of 61



### 2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate method, HPLC/UV Method AG

- 671A, is available for tolerance enforcement. This method has undergone a successful tolerance method 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 includes optional detection via HPLC/MS, giving

a means of residue confirmation.

2.2.2 International Harmonization

The Codex Alimentarius Commission has established several maximum residue limits (MRLs) for propiconazole in/on various raw agricultural commodities. In addition, both Canada and Mexico have established MRLs for propiconazole in/on various commodities. T he 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 MRL for rapeseed at 0.02 ppm . 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. will be harmonized on the tolerance expression and MRL level for Canada since th e same action was submitted to Canada

.

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 use of propiconazole

. Available data support the following tolerances under 40 CFR 180. 434 for residues of propiconazole in/on the following raw agricultural commodities:

Rapeseed subgroup 20A

................................ ................................ .......... 0.30 ppm



### As previously noted, permanent tolerances are currently established for the combi ned residues of propiconazole and its 2,4

- DCBA containing metabolites at levels ranging from 0.1

- 40 ppm in/on plant commodities [40 CFR §180.434(a)]. HED has determined that the current tolerance expression should be amended to include only propiconazole per se because 1) there are a number of pesticides that have 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 expressions (S. Knizner, 2009). We now conclude the tolerance expression should be as follows: Tolerances are established for residues of propiconazole, including its metabolites and degradates, in or on the commodities in the table below.Page 10 of 61



### Compliance with the tolerance levels specified below is to be determined by measuring only

those propiconazole residues convertible to 2,4

- dichloroben zoic 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 amended use. The Organization for Economic Cooperation and Development tolerance calculation procedures were utilized in determining the appropriate tolerance level for the requested amended use . Change in recommended tolerance is

based on appropriate significant figures

.

The proposed and recommended tolerances for propiconazole as a result of the subject action are presented in Table 2.2.3

.

Table 2.2.3 . Tolerance Summary for Propiconazole.

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

40 CFR §180.434(a)(1)

Rapeseed subgroup 20A 0.3 0. 30
*Changes are due to signif i cant figures.



### 2.2.4 Revisions to Petitioned

- For Tolerances

Revised Section F, proposing the following tolerances

Rapeseed subgroup 20A

................................ ................................ .......... 0.30 ppm



### 2.3 Label Recommendations

No Label Recommendations are required.

3 .0 INGREDIENT PROFILE

3.1 Chemical Identity

Structure and nomenclature are reported in Table 3.1

.Page 11 of 61

T able 3.1 . 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 propiconazole are reported in Appendix C.

3.3 Pesticide Use Pattern

3.3. 1 Proposed New Uses

Propiconazole is proposed for a new use on Rapeseed Crop Subgroup 20A ( Table 3 .3. 1 ).

Table 3 .3. 1 . 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)

Rapeseed

Crop Subgroup

20A Broadcast

Foliar Aerial

Chemigation

Groundboom 0.07

- 0.113 30 12

hr No more than one application

per year A18993 Fungicide 100

-

RUTLPage 12 of 61



### 3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new use of propiconazole on rapeseed crop subgroup 20A . 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 propiconazole reaching surface and ground water sources of drinking water. There are also residential uses of propiconazole, so there is exposure i n residential or non

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

- application exposure for workers re

- enterin g treated

fields.

Risk assessments have been previously prepared for 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 existing uses as well, particularly for the dietary

exposure assessment.

3.5 Considerations of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Lo w

- 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 accordi ng to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve

p esticide use in a residential setting. 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 food uses of a pest icide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are per formed when conditions or circumstances warrant. Whenever appropriate, nondietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas

post

- a pplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.Page 13 of 61



### 4.0 HAZARD CHARACTERIZATION/ASSESSMENT

4.1 Toxicology Studies Available for Analysis

T he toxicology database for propiconazole is complete for evaluating and characterizing propiconazole toxicity and selecting endpoints for purposes of this risk assessment

The following data are available:

Acute

- Oral rat, dermal rat, inhalation rat, eye irritation rabbit, dermal irritation 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 rat, 2

- generation reproductive rat

Other

- Oral rat and mouse cancer studies, 21

- day dermal rabbit toxicity a nd dermal penetration study, acute neurotoxicity, metabolism, mutagenicity screens and mechanistic studies (3).

4.2 Absorption, Distribution, Metabolism and Excretion

The r at metabolism study labeled with 14 

### C at the triazole

- [3,5] position indicated that parent compound was extensively metabolized. An intravenous (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), CGA 91304 (2.3% in males o nly), 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 material s CGA 91305, CGA 118245 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. Metabolites CGA 217495 and

CGA 177291 are not found in plant or livestock metabolism (see Appendix for structures). In two other (U

14 

### C)

- phenyl and 14 

### C

- triazole ring labeled propiconazole studies, the percentages of fecal metabolites extracted and distributed at various pH’s were not substantially differ ent 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 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) 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 toxicity 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 hepatocytes, ballooned liver cells, foci of enlarged hepatocytes, hypertrophy and necrosis are chara cteristic of propiconazole toxicity in rats and mice. Decreased body weight gain was also seen in subchronic, chronic, developmental andPage 14 of 61



### reproductive studies in animal studies. Dogs appeared to be more sensitive to the localized toxicity of propiconazole as manifested by stomach irritations at 6 mg/kg/day and above.

In rabbits, developmental toxicity occurred at a higher dose than the maternal ly toxic dose, while in rats, developmental toxicity occurred at lower doses than maternal toxic doses. Increas ed incidences of rudimentary ribs occurred in rat 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 ossific ation 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 pare ntal toxic dose suggesting lower susceptibility of the offspring to the toxic doses of propiconazole.

The acute neurotoxicity study resulted in decreased motor activity at 300 mg/kg. The current acute dietary assessment is based on an endpoint more sens itive than the neurotoxicity in the

acu t e 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, Chinese hamster bone marrow chromosomal aberration assay, unscheduled DNA synthesis studies in human fibroblasts and primary rat hepatocytes, mitotic gene conversion assay and the domin ant lethal 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 induction studies with propiconazole in mice demonstrated that propi conazole is a strong phenobarbital type inducer of xenobiotic metabolizing enzymes. Hepatocellular proliferation studies in mice suggest that propiconazole induces cell proliferation followed by treatment

- related hypertrophy in a manner similar to the

kno wn hypertrophic agent phenobarbital.

Propiconazole has low to moderate toxicity in experimental animals by the oral (Category III), dermal (Category III) and inhalation routes (Category IV), is moderately irritating to the eyes (Category III ), minimally irritating to the skin (Category IV) and is a dermal sensitizer.

The complete toxicity profile for propiconazole is provided in Appendix A.

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

For propiconazole there are acceptable 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 da tabase which results in effects at higher doses

. Based on a weight of the evidence (WOE) t he SCN was recently waived by the HASPOC (TXR 0056387). Although quantitative susceptibility was observed in the rat developmental study, a clear

NOAEL is establish ed for the developmental effects. Furthermore, the acute dietary for females

13

- 49 years old is based on the developmental NOAEL from the study with quantitative susceptibility. Therefore, the risk assessment is protective of this susceptibility and ther e are no remaining uncertainties for the young. Together, the available data support the reduction of the FQPA factor to 1X.Page 15 of 61



### 4.4.1 Completeness of the Toxicology Database

The toxicological database for propiconazole is complete for the purpose of this risk assessment. Based on a WOE approach considering all the available propiconazole hazard and exposure information, the HASPOC concluded that a 28

- day day inhalation study and a subchronic neurotoxicity study are not required at this time ( 8/1/12

, TXR #: 0056387). A previous risk assessment document (HED memoranda B. Daiss, 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. Also, please refer to Appendix 2 of this current risk assessment document for the toxicity profile tables.

4.4. 2 Evidence of Neurotoxicity

In an acute oral neurotoxicity study, single oral administration at the high dose of 300 mg/kg propiconazole produced severe clinical signs of toxicity in rats within 5

- 6 hours (e.g., decreased activity, cold, pale, piloerection, subdued, tip toe gate, st aining 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 observed at the low dose (30 mg/kg). Functional observational battery (FOB) and motor activi ty tests showed reduced activity in males and females at the high dose. Based on weight of evidence the subchronic neurotoxicity is waived (HASPOC, TXR 0056387).

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

The toxicology database for propiconazole is complete for FQPA assessment. Although quantitative susceptibility was observed in the rat developmental study, a clear NOAEL is established for the developmental effects. Furthermore, the acute dietary for fe males 13

- 49 years old is based on the developmental NOAEL from the study with quantitative susceptibility. Therefore, the risk assessment is protective of this susceptibility and there are no remaining uncertainties for the young.

There are no residua l uncertainties with regard to pre

- and/or postnatal toxicity. The dietary food exposure assessment uses conservative assumptions which result in protective estimates of dietary exposure. The dietary drinking water assessment uses values generated by mode l 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 uncertaintie s in the exposure database. The dietary risk assessment is conservative and will not underestimate dietary and/or non

- dietary residential exposure to propiconazole.Page 16 of 61



### 4.5 Toxicity Endpoint and Point of Departure

4.5.1 Dose

- Response Assessment

Toxicity endpoints and points of departure (PODs) 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 endpoints are presented in Append ix A.

An acute POD of 30 mg/kg for the general population was selected from an acute neurotoxicity study based on clinical signs of toxicity (piloerection, diarrhea, tip toe gait) at 100 mg/kg . An

acute POD of 3 0 mg/kg (NOAEL) was selected 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 development al effects 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 account for intraspecies extrapolation and 10X for intraspecies variation) was applied to the NOAEL to obtain an acute reference dose (aRfD) of

0.3 mg/kg. Since the FQPA factor has been reduced to 1X, the acute population adjusted dose (aPAD) is equivalent to the aRfD.

A chronic POD of 1 0 .0 mg/kg/da y (NOAEL) was selected for the general population from a two

year carcinogenicity study in mice based on non

- neoplastic liver effects (increased liver weight in males and increase in liver lesions: masses/raised 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 applied to the dose to obtain a chronic reference dose (cRfD/cPAD) of 0.1 mg/kg/day.

Incidental oral short term exposure was assessed using a POD (NOAEL) of 30 mg/kg/day from an acute neurotoxicity study based on clinical signs of toxicity (piloerection, diarrhea, tip toe gait) at 100 mg/kg. An MOE of 100 is applied to account for the intra

- and inter

- species

variation. In cidental oral intermediate term exposure was assessed using a POD (NOAEL) of 10 mg/kg/day from an carcinogenicity study in mice based on based on non

- neoplastic liver effects (increased liver weight in males and increase in liver lesions: masses/raised are as/ 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 was selected from the 24

month carcinogenicity mouse study described above. An MOE of 100 is required for the short

and intermediate

- term scenarios for dermal exposure. 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 inhalation POD of 10 mg/kg/day was selected from thePage 17 of 61



### 24 month carcinogenicity mouse study d escribed above. An MOE of 100 is required for the

short

- and 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. T here

are potential residential post

- application exposures to adults vi a the dermal route and to children

via dermal and i ncidental oral routes of exposure. For the general population, including infants and children, the short term oral exposure can be aggregated with the short

- term dermal and

inhalation due to a common toxi cological endpoint (clinical signs in the ACN study). A common toxicological endpoint was identified from the cancer mouse study for intermediate

and long

- term oral, dermal (oral equivalent) and inhalation (oral equivalent) routes. Therefore,

these rout es can be aggregated for these scenarios for the appropriate 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

- possible human carcinogen and recommended that for the purpose of risk characterization the reference 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 selected for the propiconazole risk assessment are provided in

Tables 4 .5.4.1 and 4.5.4.2

.Page 18 of 61

Table 4 .5.4.1 . 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

L OAEL = 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 (A dult 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 =

0.1 mg/kg/day 24

- month carcinogenicity 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 human carcinogen, RfD approach for risk characterization

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adver se effect le vel. 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 adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level

of concern. N/A = not applicabl ePage 19 of 61

Table 4.5.4.2 . 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).

Inc id ental 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 carcinogenicity 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 = 4 0% 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

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

Dermal Intermediate

Term (1

- 6 months)

DAF = 4 0% NOAEL= 10

mg/kg/day UF A = 10X

UF H = 10X Residential LOC

for MOE = 100 Occupational LOC

for MOE = 100 24 Month carcinogenicity 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/nodul ar 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

L OAEL = 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 carcinogenicity 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 human carcinogen, RfD approach for risk characterization

DAF = Dermal Absorption Factor



### Based on the available toxicity database and the Agency's current practices, the inhalation risk for propiconazole was assessed using an oral toxicity study. The Agency sought expert advice and input on issues related to this route to route extrapolation approach (i.e. the use of oral toxicity studies for inhalation risk assessment) 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 ( htt p://www.epa.gov/scipoly/SAP/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 inhalation risk assessments, including route to route extrapolation of toxicity data. If any new policies or procedures are developed, the Agency may revisit the need for an inhalation toxicity study for propiconazole and/or a reexamination of the inhalation toxicity risk assessment.Page 20 of 61



### 5.0 DIETARY AN D DRINKING WATER EXPOSURE 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 plants is adequately understood (DP D329394, Y. Donovan, 6/15/06). These data indicate that the major metabolic pathway in plants involves hydroxylation of the n

- propyl group on the dioxolane ring of the cis/trans i somers of propiconazole, with subsequent conjugation to sugars. A possible alternative pathway involves reductive deketalization of the dioxolane ring and sugar conjugation of the resulting metabolite. The alkyl bridge between the phenyl and triazole rin gs is metabolized and free 1 H

- 1,2,4

- triazole is released. The free triazole is readily conjugated with the amino acid, serine/alanine, forming triazole aniline which is further metabolized to triazole acetic acid possibly through the

intermediate formatio n of triazole lactic acid. HED considers free triazole, triazole alanine, and triazole acetic acid to be residues of concern in plants. Since these are common metabolites from several triazole containing pesticides, the risk assessment for triazoles has b een assessed separately (HED memo of 11/3/10, T. Morton, D383609).

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

Structures and name s of propiconazole metabolites are provided in Appendix B

.

5.1.2 Comparison of Metabolic Pathways

The r at metabolism study indicated that parent compound was extensively metabolized. An intravenous study found several metabolites, 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 vary ing degrees in the urine and the feces of the orally dosed groups. Radiolabeled materials CGA 91305, CGA 118245 and CGA 177291 were present in the fecal radioactivity in males and females or in one sex alone. Most of the fecal radioactivity was not char acterized. Metabolites CGA 217495 and CGA 177291 are not found in plant or livestock metabolism. The proposed metabolic pathway involve s 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) and reduction to yield the c orresponding alcohol
(CGA 91305). Both CGA 91304 and CGA 91305 are found in plants and livestock



### . The plant

metabolism data indicate that the major metabolic pathway in plants involves hydroxylation of

the n

- propyl group on the dioxolane ring of the cis/ trans isomers of propiconazole, with subsequent conjugation to sugars. A possible alternative pathway involves reductive deketalization of the dioxolane ring and sugar conjugation of the resulting metabolite. The alkyl bridge between the phenyl and triaz ole rings is metabolized and free 1 H

- 1,2,4

- triazole is released. The free triazole is readily conjugated with the amino acid, serine/alanine, forming triazole aniline which is further metabolized to triazole acetic acid possibly through the

intermediate f

ormation of triazole lactic acid.Page 21 of 61



### 5.1.3 Environmental Fate and Transport

For propiconazole, turf, a previously registered crop, has the highest 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 EDWCs with the previously assessed turf use. The previously assessed turf EDWCs are approximately on e 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.

5.1.4 Residues of Concern Summary and Rationale

A summary of the metabolites and degradates t o be included in the risk assessment and tolerance expression are presented below in Table 5.1.4 . Detailed rationale for these conclusions were presented in a previous document (DP329394, Y. Donovan, 06/15/06).

Table 5.1.4 . 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 metabol ites 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 use for propiconazole. The results from these studies are discussed in the appropriate data evaluation report (DER) and summarized in the following table s

.Page 22 of 61

TABLE 5.2.1.1

. Summary of Residue Data from Canola Crop Field Trials with Propiconazole.

Commo

dity Analyte EP Total App.

Rate

, g a.i./A (lb a.i./A) PHI

(days) Residue Levels (ppm) 1

n Sample

Min. Sample

Max. L AFT 2 HAFT 2 Median Mean Std.

Dev.

Canola

seed Propiconazole 250 g

a.i./L EC 117.7

- 138.06

(0.105

- 0.123) 29

- 35 13 <0.01 0.014 <0.01 0.013 0.010 0.010 0.001

Propi conazole

and Metabolites 13 <0.01 0.22 <0.01 0.20 0.084 0.084 0.058

Propiconazole 200 g

a.i./L

SL/L 124.88

- 125.96 (0.111

- 0.112) 29

- 30 3 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

Propi conazole

and Metabolites 3 <0.01 0.10 <0.01 0.094 0.010 0.038 0.048

Propiconazole EC or

SL/L 117.7

- 138.06 (0.105

- 0.123) 29

- 35 16 <0.01 0.014 <0.01 0.013 0.010 0.010 0.001

Propiconazole

and Metabolites 16 <0.01 0.22 <0.01 0.20 0.077 0.075 0.058

1 Exc ept 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 fi eld trial; HAFT = highest a verage f ield t rial.

TABLE 5.2.1.2. Residue Data from Canola Processing Study with Propiconazole.

RAC Processed

Commodity Total Rate

g a.i./ha (lb a

. i

. /A) PHI

(days) Residues (ppm) 1 Processing Factor 2

Propiconazole Propiconazole

and Metabolites Propiconazole Propiconazole

and Metabolites

Elgin, MB; 2011 (T948)

Canola Seed (RAC) 371.60 (0.331) 31 <0.01 0.24

--- ---
Meal <0.01 0.38 NC 3 1.6x

Refined oil NA 4 <0.05

--- <0.21x

Rosthern, SK; 20 11 (T949)

Canola Seed (RAC) 382.7 (0.341) 31 0.069 0.43

--- ---
Meal 0.060 0.59 0.87x 1.4x

Refined oil NA <0.05

--- <0.12x

Average

Canola Meal 371.60

- 382.7 (0.331

- 0.341) 31 0.87x 1.5x

Refined oil

--- <0.16x

1 The LOQ for residues of propiconazole and propiconazole and metabolites, respectively, were 0.01 and 0.05 ppm for each

canola matrix.

2 Processing Factor = average residue in processed fraction ÷ average residue in un processed RAC commodity.

3 NC = Not calculated. Residues were below the LOQ in both the RAC and the processed fraction samples.

4 NA = Not analyzed. The petitioner indicated that samples were not analyzed because residue levels of propiconazole and metabolites were below the LOQ.



### 5.3 Water Residue Profile

5.3. 1 Estimated Drinking Water Concentrations

The drinking water residues used in the dietary risk assessment were provided by the Environmental Fate and Effects Division (EFED) in the following memorandum: “ Propiconazole:

Techni cal Screen, Drinking Water Assessment, and Ecological Risk Assessment for New Use on Rapeseed
subgroup 20A 

### ” (I. Abdel

- Saheb , 0 3 / 19 / 1 3 , D 408485 ) and incorporated directly into this dietary assessment. Water residues were incorporated in the DEEM

- FCID into the food categories “water, direct, all sources” and “water, indirect, all sources.”Page 23 of 61



### In the case of propiconazole, turf, a previously regis tered crop, has the highest 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). The proposed new use does not result in higher EDWCs than those estimated for turf uses.

The estimated surface water drinking water concentrations for propiconazole are:

55.78 ug /L for the 1 in 10 year annual peak concentration (acute)

21.68 ug /L for the 1 in 10 year annual mean concentration (non

- cancer chro nic) and

The SCI

- GROW estimated ground water drinking water concentrations for propiconazole are not expected to exceed 0.64 μg/L

The highest estimates from surface water (acute, 55.78 ppb and chronic, 21.68 ppb ) are directly entered into the exposure model to assess the contributions from drinking water.

Drinking Water Data for Free Triazoles

Residues of 1,2,4

- triazole in drinking water were 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 environment, the residue estimates used in these assessments are a summation of all three residues and, therefore, represent an overestimate o f actual concentrations of the common triazole metabolites in drinking water. The Tier II PRZM/EXAMS (surface water) and SCIGROW (ground water) residue estimates are

summarized in Table 5.3.1 . HED notes that there were no detects of 1,2,4

- triazole 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 tr iazole as well as the conjugated metabolites.

Table 5.3.1 . 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 0.001



### 5

. 4 Dietary and Drinking Water Exposure and Risk

Screening level acute and refined chronic dietary and drinking water exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database DEEM

- FCIDTM, Version 3.16, which incorporates consumption data from USDA’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). This die tary survey was conducted from 2003 to 2008. Dietary risk assessment incorporates both exposure and toxicity of a given pesticide. For acute and chronic dietary assessments, the risk is expressed as a percentage of a maximum acceptable dose (i.e., the do se which HED has concluded will result in no unreasonable adverse health effects). This dose is referred to as the population adjusted dose (PAD). The PAD is equivalent to the reference dose (RfD) divided by the additional Safety Factor, if applied. For acute and

non

- cancer chronic exposures, HED is concerned when estimated dietary risk exceeds 100% of

the PAD.Page 24 of 61



### 5

. 4 .1 Acute Dietary and Drinking Water Analysis

A new dietary assessment was conducted for the proposed new use. The proposed new use results dietary risk estimates below HED’s level of concern; see Table 5.4.1.1

. The most highly exposed subgroup is children 1

- 2 years resulting in 8 4 % of the aPAD.

Table 5.4.1.1 . 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 0.0 77544 26 All Infants (< 1 year old) 0. 108047 36

Children 1

- 2 years old 0.2 54417 84

Children 3

- 5 years old 0. 194196 65

Children 6

- 12 years old 0. 106032 35

Youth 13

- 19 years old 0. 073705 25

Adults 20

- 49 years old 0. 061213 20

Adults 50

- 99 years old 0. 050880 17

Females 13

- 49 years old 0. 060562 20

Dietary Assessment of Free Triazole and its Conjugates

Reference: Common Triazole Metabolites: Updated Dietary (Food + Water) Exposure and Risk Assessment to

Address The New Section 3 Registration s For Use of Propiconazole on Rapeseed Crop Subgroup 20A; Use of Difenoconazole on Rapeseed Crop Subgroup 20A; and Use of Teb uconazole on Imported Oranges

. . T. Morton

, DP 4 14951

. drs, 9

/ 26 /1 3

.



### The proposed new use of propiconazole did not result in an increase in dietary 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 5.4.1.2

.Page 25 of 61

Table 5.4.1.2 . 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 0.00 8240 27 0.001 276 26

Not Applicable Not

Applicable All Infants (< 1 year old) 0.01 2026 40 0.00 1822 36

Children 1

- 2 years old 0.0 22883 76 0.00 3629 73

Children 3

- 5 years old 0.01 8815 63 0.00 2896 58

Children 6

- 12 years old 0.0 10932 36 0.001 588 3 2

Youth 13

- 19 years old 0.00 7167 24 0.001 036 2 1

Adults 20

- 49 years old 0.00 6581 22 0.00 1101 2 2 Adults 50+ years old 0.00 5808 19 0.00 1036 21

Females 13

- 49 years old 0.00 6730 22 0.00 1073 22 Triazoly lalanine + Triazolylacetic Acid+Triazolylpyruvic acid General U.S. Population

Not Applicable Not

Applicable 0.01 7658 20

Not Applicable Not

Applicable All Infants (< 1 year old) 0.0 21510 2 4

Children 1

- 2 years old 0.0 54965 61

Children 3

- 5 years old 0.0 44098 49

Children 6

- 12 years old 0.0 23459 26

Youth 13

- 19 years old 0.01 4759 16

Adults 20

- 49 years old 0.01 4662 1 6 Adults 50+ years old 0.0 13721 1 5

Females 13

- 49 years old 0.0 78443 78 0.01 4260 1 6 * 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 proposed amended use of propiconazole and results

in dietary risk estimates below HED’s level of concern; see Table 5.4.2

.

Table 5.4.2 . 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. 007434 7.4 All Infants (< 1 year old) 0. 010284 10

Children 1

- 2 years old 0.02 3722 2 4

Children 3

- 5 years old 0. 019125 19

Children 6

- 12 years old 0. 009943 9.9

Youth 13

- 19 years old 0. 006024 6.0

Adults 20

- 49 years old 0.0 06192 6.2

Adults 50

- 99 years old 0.0 05620 5.6

Females 13

- 49 years old 0.0 05625 5.6Page 26 of 61



### 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 expos ure , therefore an updated residential exposure assessment was conducted. The revision of residential exposures will impact the h uman 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

.

S pecifics concerning residential handler e xposure and risks are provided in the most recent occupational and residential exposure assessment for propiconazole (D349727, S. Oonnithan, 9/3/06).

6.1 Residential Bystander Postapplication Inhalation Exposure

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

- application inhalation exposure assessment was not performed for propiconazole at this time. However, volatilization of pesticides may be a potential source of post

- application inhalation exposu re to individuals nearby to pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. 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 appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

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

- application inhalation exposure assessment for propiconazole

.

6.2 Spray Drift

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

. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and St ate Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information at (http://www.epa.gov/opp00001/factsheets/spraydrift.htm) . On a chemical by chemi cal basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in plac e, the Agency may impose further refinements in spray drift management practices to reduce off

- target drift with specific products with significant risks

associated with drift.Page 27 of 61



### Although a quantitative residential post

- application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers. This exposure scenario is representative of a worse case inhalation (drift) exposure an d 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 water, and residential exposures (dermal and residential). In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

7.1 Acute & Chronic Aggregate Risk

Acute and chronic aggregate exposures include food plus drinking water exposures. As

demonstrated under Section 5. 4, acute and chronic aggregate risks are not of concern.

7.2 Short

- and Intermediate

- Term Aggregate Risk

Short term aggregate exposure takes into account residential exposure plus average exposure levels to food and water (considered to be a background exposure level). Table 7. 2 .1 aggregates
the short

- term risk for toddlers from incidental oral, dermal, and food and water (as a background). The highest incidental oral and dermal exposure scenarios are from residential use on turf, which were used in the short term aggregate risk as sessment. The short

- term aggregate risk MOE of 9 6 exceeds HED’s level of concern (LOC=100)

. This assessment is considered very conservative in that the residential incidental oral post

- application exposure was calculated by combining three screening leve l assessments (which by themselves already have conservative estimates).Page 28 of 61

Table 7. 2 .1

. 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. 02 37

30 1 3 00 2

9 6 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 1 10 4

1 Target MOE= 100, Acute Neuortoxicity NOAEL=30

2 MOE food = [(short

- term oral NOAEL)/(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/risk characterization for cereal grains is summarized in Table

7.2.2

.

For all residential handler exposure 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 7.2.2

.

Summaries of the short

- term risk estimates for residential post

- application activities are included

in Table 7.2.3

.Page 29 of 61

Table 7.2.2

. Short

- Term Residential Handler Exposure and Risk Estimates for Propiconazole.

Exposure

Scenario Target

MOE Dermal

Unit Exposure (ug/lb ai) Inhl. Unit

Exposure (ug/lb ai) Maximum

Application

Rate a (lb ai/ft 2 )

Or (lb ai/Acre) Area

Treated or

Amount

Handled Daily b Dermal Inhalation Total

Dose (mg/kg/day) c MOE d Dose (mg/kg/day) e MOE f MOE g

Mixer/loader/Applicator

Low Pressure

Handwand/

Ornamentals 100 63,000 18

5.5 x 10 - 8 1,200 ft 2 0.000021 1,400,000 5.9 x10 - 9 5.1 x 10 9 1.4 x 10 6

Hose

- end Sprayer/

Ornamentals 58,000 1.4 0.000019 1,600,000 1.2 x 10 - 9 6.5 x 10 10 1.6 x 10 6

Low Pressure

Handwand/

Turf/Lawns 100 Hose

- end Sprayer is protective

Hose

- end Sprayer/

Turf/Lawns 13,400 22 1.8 0.5 Acres 0.060 500 0.000099 300,000 500

Brush/Roller Applying paint 100 450,000 200

0.0035 lb ai/ 1 gal can 0.016 1,900 0.000007 4,300,00 1,900

Airless Sprayer Applying Paint 63,000 18 0.0033 9.100 0.00000095 32,000,000 9,100

Based on registered or proposed label (0.0024 lb ai/A): [ 0.0024 lb ai/A x A/43,560 sq ft. = 5.5 x 10 - 8 ] or (0.000000055 lb ai/ft 2 )
Exposure Science Advisory Council Policy #9.1. 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 ( 80 kg). Dermal MOE = Dermal NOAEL (mg/kg/day) / Dermal Dose (mg /kg/day). Inhalation Dose = Inhalation 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) / BW (kg). Inhalation MOE = Inhalation NOAEL (mg/kg/day) / Inhalation Dose (mg/kg/day). Total MOE = NOAEL (mg/kg/day) / (Dermal Dose + Inhalation Dose) OR Total MOE = 1/ [(1/Dermal MOE) + (1/Inhalation MOE)].Page 30 of 61

Table 7.2.3 : 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 7.2.4 aggregates the short

- term risk for adults from residential post application, and average food and water (as a background). Based on the low vapor pressure of propiconazole, negligible post application inhalation exposure is anticipated 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 aggregate exposure assessment is considered very conservative because the assumptions used for each of the scenarios separately are already high end (i.e., time spent outdoors, dislodgeable residues).

Table 7.2.4 : Short

- term Aggregate Risk Estimates to Propiconazole 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. 00 62

30 48 00 2

200 Residential Post

- application (Residential Turf Gen. High

Contact Activities)) 100 1 Dermal 0. 143 210 3

1 Target MOE= 100, Developmental rat

- increased 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 po st 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 application exposure to children from wood treatment (antimicrobial use).

Table 7.3 shows the aggregate risk for intermediate term exposur e to Children 1

- 2 years old. The aggregate MOE is 1 1 0 , which is greater than the target MOE of 100. Therefore, this

scenario is not of concern.Page 31 of 61

Table 7.3 . Intermediate

- term Aggregate Risk Estimates to Propiconazole for Toddler (Children 1

- 2years)

Ex posure Scenario Target

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

Average Food and Water N/A Oral 0. 02 37 10 4 2 0 2

1 1 0 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 carcinogenicity study. NOAEL=10

2 MOE food = [(intermediate

- term oral NOAEL)/(chronic dietary 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 considered 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 (turf) screening level drinking water modeling data (i.e., s urface water modeling); 2) maximum application rates and minimum application intervals were used; and 3) conservative SOPs and upper level estimates of exposure were employed.

Updated Aggregate Assessment of Free Triazole & its Conjugates

Reference: Com mon Triazole Metabolites: Updated Aggregate Human Health Risk Assessment to Address The

New Section 3 Registration s For Use of Propiconazole on Rapeseed Crop Subgroup 20A; Use of Difenoconazole on Rapeseed Crop Subgroup 20A; and Use of Tebuconazole on Imp orted Oranges

. DP4 14952 , T. Morton, 9 / 30 /1 3

.



### The addition of the proposed new use s do not increase the aggregate exposure to free triazoles and its conjugates. However, t he previous aggregate human health risk assessment for free

triazoles and its conjugates was updated and the aggregate estimates are below HED’s level of concern ( DP4 14952 , T. Morton, 9 / 30 / 13 ).

8.0 CUMULATIVE RISK

Propiconazole is a member of the triazole

- containing class of pesticides. Although conazoles act similarly i n plants (fungi) by inhibiting ergosterol biosynthesis, there is not necessarily a relationship between their pesticidal activity and their mechanism of toxicity in mammals. Structural similarities do not constitute a common mechanism of toxicity. Eviden ce is needed to establish that the chemicals operate by the same, or essentially the same, sequence of major biochemical events (EPA, 2002). In conazoles, however, a variable pattern of toxicological responses is found; some are hepatotoxic and hepatocarc inogenic in mice. Some induce thyroid tumors in rats. Some induce developmental, reproductive, and neurological effects in rodents. Furthermore, the conazoles produce a diverse range of biochemical events including altered cholesterol levels, stress res ponses, and altered DNA methylation. It is not clearly understoodPage 32 of 61



### whether these biochemical events are directly connected to their toxicological outcomes. Thus, there is currently no evidence to indicate that conazoles share common mechanisms of toxicity and EPA is not following a cumulative risk approach based on a common mechanism of toxicity for the conazoles. For information regarding EPA’s procedures for cumulating effects from substances found to have a common mechanism of toxicity, see EPA’s websi te 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 triazole conjugates ( triazolylalanine and triazolylacetic acid ). To support existing tolerances and to establish new tolerances for triazole

- derivative pesticides, including propiconazole, U.S. EPA conducted a human health risk assessment for exposure to 1,2,4

- triazole, triazolylalanine, and triazolylacetic acid res ulting from the use of all current and pending uses of any triazole

- derived fungicide. The risk assessment is a highly conservative, screening

- level evaluation in terms of hazards associated with common metabolites (e.g., use of

a maximum combination of u ncertainty factors) and potential dietary and 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 protection of infants and children. Th e assessment includes evaluations of risks for various 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 Identifica tion (ID) Number EPA

HQ

- OPP

- 2005

- 0497.

9 .0 OCCUPATIONAL EXPOSURE / RISK CHARACTERIZATION

9 .1 Exposure Scenarios

Occupational handler and post

- application exposure scenarios were assessed for the proposed

amended use . Based on the product labels and information provided by the registrant, short

- and

intermediate

- term exposure is assessed for handlers and post

- application activities. Dermal and inhalation exposures are aggregated for propiconazole because the toxicit y endpoints for these exposure routes are not based on common toxicological endpoints. Labels for the propiconazole proposed uses require that applicators and other handlers wear personal protective equipment (PPE) consisting of long

- sleeved shirt, long p ants and shoes with socks 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 propiconazole during mixing, loading, and application activities through the dermal and inhalation routes. Propiconazole products are applied using aerial, airblast, groundboom and chemigation equipment.

The quantita tive exposure/risk assessment developed for occupational handlers is based on the following exposure scenarios:Page 33 of 61



### 9.2.1 Handler Exposure Scenarios

Occupatio nal handler exposure scenarios were assessed fo r the proposed use of propiconazole on cereal grains. For all dermal and inhalation exposure scenarios, risk estimates do not exceed HED’s LOC (Dermal LOC = 100; Inhalation LOC = 100 ) with label

- specified PPE and, therefore, are not of concern to HED. Since the dermal and inhalation endpoints are based on similar effects, the doses are combined for a total MOE.

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handl er exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios:

MIXER/LOADER

1. Open mixing/loading EC for aerial applications;

2. Open mixing/loading EC for c hemigation applications;

3. Open mixing/loading EC for groundboom applicati o ns;

APPLICATORS

1. Applying sprays with ae r ial equipm e nt;
2

. Applying sprays with groundboom equipment ;

Note: Chemigation is an irrigation system that does not have an ap plicator. 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 available 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 Database Version 1.1 (PHED 1.1), t he 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 predicting handler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Refere nce Table” (http://www.epa.gov/opp00001/science/handler

- exposure

table.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/science/handler

- exposure

- data.html

.Page 34 of 61



### 9.2. 3 Handler Exposure Assumptions

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

 12 0 0 acres for mixing/l oading to support aerial applications,

 350 acres for mixing /loading chemigation applications

 20 0 acres for mixing/loading to support groundboom applications,

 12 0 0 acres for applying with aerial equipment,

 20 0 acres for applying with groundboom equipment, and

 350 acres for flagging to support 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 Factor s
T he short

- and intermediate

- term dermal absorption factor is 40%.

Personal Protective Equipment (PPE) For pesticide handlers, this assessment presents “baseline” 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 ) calculations.

Equations and Calculations

Daily Dose: Daily dose (dermal and inhalation) is calculated by normalizing the daily exposure (dermal or inhalation) value by body weight and accoun ting for absorption factors:

Average Daily Dose (mg/kg/day) = Daily Exposure (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 active ingredient/kg body weight/day), Daily Exposure = Amount (mg ai/day) deposited on the surface of the skin that is available for dermal absorption or amount inhaled that 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 determined 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 35 of 61



### 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 absorbed dose received from exposure to

pesticide, and

NOAEL = Dose level in a toxicity study, where no observed adverse effects occurred

in the study.

For all dermal and inhalation exposure scenarios, risk estimates do not exceed HED’s LOC (Dermal LOC = 100; Inhalation LOC = 100 ) with label

- specified PPE and, therefore, are not of

concern to HED. Summaries of the combined short

- and intermediate

- term risk estimates for occupational handlers are included in Table 9.2.4

.

9.2. 4 Handler Exposure and Risk Estimates

Summaries of the combined, dermal plus inhalation short

- , and intermediate

- term risks for each exposure scenario are presented in Table 9.2.4 . The combined dermal and inhalation exposure risks are not of concern (i.e., MOEs >100), provided the mixer/loaders wear chemical

- resistant gloves as directed on the label.

Exposure scenarios listed within (mixing/loading, applying, and flagging), ris k estimates do not exceed HED’s LOC (MOE < 100), and therefore not of concern to HED. See Table 9.2.4 for

details.Page 36 of 61 Table 9.2.4 . Agricultural Handler Exposure and Risk for Propiconazole Use on Cereal Grains

Exposure

Scenario Maxium

App. Rate a

(lb ai/A) Area

Treated
Daily b

(acres) Unit Exposure
( μ g/lb ai) c Dose
(mg/kg/day) d MOEs e

Combined

Short

- term Combined

Int.

- term

Baseline
(BL) Baseline +

Label Spec. PPE Baseline
(BL) Baseline +

Label Spec. PPE Dermal +

Inhalation Dermal +

Inhalation

Dermal Inhal. Dermal Inhal. Dermal Inhal. Dermal Inhal. BL BL+

PPE BL BL+

PPE

Mixing/Loading “Cereal Grains” (Emulsifiable Concentrate) LOC = 100

Aerial

0.114 1,200

220 0.219 37.6 0.219 0.015 0.00037 0.0257 0.00037 200 1,100 66 380

Chemigation 350 0.044 0.00011 0.0075 0.00011 680 3,900 230 1,300

Groundboom 200 0.025 0.000062 0.0043 0.000062 1,200 6,900 400 2,300

Applying “Cereal Grains” (Emulsifiable Concentrate) LOC = 100

Aerial (Enclosed
Cockpit)

0.114 1,200 No Data 5 (Eng. Control) 0.068

(Eng. Control) No Data 0.00098 (Eng. Control) 0.0001

(Eng. Control) No Data 8,500 No

Data 2,800

(Eng. Control)

Chemigation N/A

Groundboom Equipment (Open Cab) 200 78.6 0.34 16.1 0.34 0.009 0.000097 0.0018 0.000097 3,300 160,000 1,100 5,200Page 37 of 61 Table 9.2.4 . Agricultural Handler Exposure and Risk for Propiconazole Use on Cereal Grains

Exposure

Scenario Maxium

App. Rate a

(lb ai/A) Area

Treated
Daily b

(acres) Unit Exposure
( μ g/lb ai) c Dose
(mg/kg/day) d MOEs e

Combined

Short

- term Combined

Int.

- term

Baseline
(BL) Baseline +

Label Spec. PPE Baseline
(BL) Baseline +

Label Spec. PPE Dermal +

Inhalation Dermal +

Inhalation

Dermal Inhal. Dermal Inhal. Dermal Inhal. Dermal Inhal. BL BL+

PPE BL BL+

PPE

Flagging LOC = 100

Aerial 0.175 350 11 35 12 35 0.0034 0.00028 0.0037 0.00027 8,200 7,600 2,700 2,500

a. Application rates = maximum application rates from the parent labels. b. Area treated daily from Science Advisory Council Policy # 9.1. c. Unit Exposures are from the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table,” date d 03 /1 2 , and located at http://www.epa.gov/opp00001/science/handler

exposure

- table.pdf and (http://www.epa.gov/pesticides/science/handler

- exposure

- data.html)

. d

. Dermal and Inhalation Dose (mg/kg/day) dail y 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/day for 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) is protective of cereal grains, therefore only flagger for sugarcane was assessed. Aerial : Enclosed Cockpit is an engineering control; therefore the unit exposures and MOEs reflect this.

### Page 38 of 61

9.3 Post Application Exposure

HED uses the term post

- application to describe exposures that occur when indiv iduals 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 when workers enter previously treated areas to perform job functions, including activities related to crop production. In the case for propiconazole , post

- application dermal exposure to field workers following ground and aerial applications is probable.

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

- application inhalation

expo sure assessment was not performed for propiconazole at this time. However, there are multiple potential sources of post

- application inhalation exposure to individuals performing post

application activities in previously treated fields. These potential so urces include volatilization of pesticides and re

- suspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rod enticide 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 ). The Agency is in the process of evaluating the SAP report as wel l as available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational

post

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

post

- application inhalation exposure assessment for propiconazole

.

Although a quantitative occupational post

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

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

- application inhalation exposure scenarios.

9.3.1 Post Application Ex posure Scenarios

Post

- application propiconazole residues are expected for individuals involved in hand weeding; scouting; thinning; han d harvesting, and irrigation

. For all dermal post

- application exposure scenarios, risk estimates do not exceed HED’s LOC (D ermal 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 post

application exposure. Sources of generic post

- application data, used as surrogate data in the

absence of chemical

- specific data, are derived from Agricultural Reentry Task Force (ARTF)

### Page 39 of 61

exposure monitoring studies, and, as proprietary data, are subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting post

- application exposure that are used in this assessment, known as “transfer coefficient s”, are presented in the “Science Advisory Council for Exposure (ExpoSAC) Policy 3” (http://www.epa.gov/pesticides/science/exposac_policy3.pdf), which, along with additional information about the ARTF data, can be found at http://www.epa.gov/pesticides/science/post

app

- exposure

- data.html

.



### Post

- application Studies: A total of six studies are described 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 42 5640

- 03; Report dated 1991. Author Avakian, M; Sponsor: Ciba

- Geigy 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 : 44580: AG

- 561 Performing Laboratories: ABC Laboratories., Inc.

 MRID 45288601: Determination of Transferable Turf Residue on Turf treated with Banner

MAXX ; Report dated (2000); Authors; Rosenheck, L.; Meyer, L. Lab Project Number 990046: 179

- 99. Performing Laboratories: Central California Research Laboratories, Inc.

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

- Geigy

 MRID 133390 : Author; Honeycutt, R. (1983) CGA 64250 (Tilt) Worker Exposure in Rice: Report No.

EIR

- 83011. ( Unpublished study received Dec 12, 1983 under 100

- 617; submitted by Ciba

- Geigy Corp., Greensboro, NC; CDL:07222

- C)

 MRID 44959702 : Dissipation of Dislodgeab le 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 studi es and decided that for 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 scenarios, risk estimates do not exceed HED’s LOC (Dermal LOC = 100) , therefore, are not of concern to HED.

A summary of post

- application exposure and risk calculations

, assumptions, and results is provided in Table 9.3.3

.

### Page 40 of 61

1. Maximum application rate from proposed label s. 2. DAT = Days after treatment needed to reach 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, based on chemical specific data and application 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 Dose = [(DFR x TC x 40% Dermal absorption x 8 hr Ex p. Time )] / [(CF: 1000 μg/mg) x (8 0

- kg Body Weight). Short

- Term NOAEL = 30 mg/kg/day; I ntermediate

- 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 acute 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 classified under Toxicity Category III/IV.

10. REFERENCES

Prop iconazole. New Foliar Use and Tolerance in/on Rapeseed subgroup 20A. Summary of Analytical Chemistry

and Residue Data. T. Morton

, D 408507

, 2 /2 7 /201 4

Propiconazole: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for Rapeseed Crop Subgroup 20A.

, T. Morton

, D4 14627

, 2 / 2 7 /201 4

Propiconazole: Assessment of Aerial; Chemigation; and Groundboom Applications to Sugarcane and Ce real Grains (Wheat; Barley; Oats; Rye, and Triticale). J.S. Miller, D 403629, 11/15/2012

Propiconazole : Summary of Hazard and Science Policy Council ( 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 9.3.3 . Summary of Estimated Post

- Application MOEs for Cereal Grains

Crop Application

Rate
(lb ai/A) 1 DAT 2 DFR 3
(μg/cm 2 ) TC 4

(cm 2 /hr) Activity 4 MOE 5

LOC = 100

Short

- Term Intermediate

Term

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 41 of 61

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 Inhalation Toxicity

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

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

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

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

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

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

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

- Day Dermal

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

- Day Dermal

................................ .............................. 870.3465 28/ 90

- Day Inhalation

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

yes

yes

no no* yes

yes

yes

-

-

870.3700a Developmental Toxicity (rodent)

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

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

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

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

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

................................ ........ 870.4200a carcinogenicity (rat)

................................ ....................... 870.4200b carcinogenicity (mouse)

................................ ................ 870.4300 Chronic/ carcinogenicity

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

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

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

— Gene Mutation

- mammalian

................ 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

... 870.5900 Mutagenicity

— Other Genotoxic Effects

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

yes

yes

yes yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen)

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

- Day Neurotoxicity (hen)

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

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

- Day Neuro. Screening Battery (rat)

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

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

no

yes no*

no -

- yes

-

-

870.7485 General Metabolism

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

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

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

no no** yes

-

-

* waived per HASPOC TXR 0056387

** waived per HASPOC TXR 0056761 and TXR 0056730

. .

### Page 42 of 61

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 h rs 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/d ay).

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).

87 0.3100

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 42 050502. No change to NOAEL or

LOAEL

### Page 43 of 61

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

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

Classification /Doses Results

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 membrane of the pyloric part of

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

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 no t 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 papill ae. 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 incide nce 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)

### Page 44 of 61

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

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

Classification /Doses Results

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 hy peremia of the stomach in males (indicating mild irritation of the mucosa). NOAEL is 50 ppm (1.25 mg/kg/day)

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 hepatocytes 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 a reas/ 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 carcinogenicity 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 th e original study and in the same testing facility under similar 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 neuro behavioral toxicity = 300 mg/kg based on reduced motor activity.

NOAEL for neurobehavioral toxicity = 100 mg/kg

### Page 45 of 61

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

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

Classification /Doses Results

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.

870

- 5300

In vitro cell transformation assay (BALB/3T3) 00133349 (1982)

Acceptable/guideline

1.16

- 18.5 g/ml Did not cause a measurable increase 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 m arrow 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 revertants (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 ev idence of dominant lethal effects was observed in the progeny of mice treated with 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.

### Page 46 of 61

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) 41326701 (1989)

Acceptable/guideline 0.5 mg/kg oral or iv (U

14 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 16 8 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 o r the repeated dosing groups. Extensively metabolized (oxidative): 24 and 47 metabolites in urine and feces, respectively. Parent (27

- 30% of AD) only detected in the urine of iv animals.

870.7485

Metabolism and pharmacokinetics (Rat) 00074506 (1979)

000 74507 (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 sugg esting 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 propyl side chain. Urinary and fecal metabolites except the presence 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 9.4 mg/kg of the phenyl

- [U

14 C]compound Mice pre

- treated with the unlabeled CGA 64250 excreted 83

- 103%

of the administered 14 C radi oactivity within 96 hours (mostly within

the first 24

- 48 hours) in the urine 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 ma les 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 waived (TXR 0056761 and TXR 0056730).

.

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 47 of 61

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

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

Classification /Doses Results

Non

- guideline Special st udy

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 increased 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 a cid 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 propi conazol e. Microsomal coumarin 7

- hydroxylase, associated with enzymes belonging to the sub family CYP2A was also induced by propiconazole treatment consistent with PB

- like induc tion. The microsomal activities of epoxide hydrolase and UDPGT and the cytosolic act ivity 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 test osterone 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 c ytochrome P450 activity. The effects of propiconazole 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 ca n thus be considered a strong phenobarbital

- type inducer of xenobiotic metabolizing enzymes in the mouse.

### Page 48 of 61

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 liver weights. All mice developed hepatocellular hypertrophy (primarily in the centrilobular hepatocytes with mild effects in the midzonal hepatocytes). Liver necrosis and cytoplasmic vacuolat ion 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. Treatment with propiconazole or PB induced a > 1000% increase in BrdU

staining hepatocellular nuclei within 24 hours from the start of the study that peaked at a >3600% increase by 48 hours. Thereafter,

the number of BrdU

- stained nuclei decreased dramatically and was not biologically different from co ntrols 7 days after the start and through the remainder of the study. For all treat ment groups, the

BrdU

- staining nuclei were found primarily in the centrilobular/midzonal por tions of the liver. These data support the conclusion that propiconazole indu ced an initial time

- and dose

related proliferation in the liver followed by a sustained treatment

related hypertrophy in a manner similar to the known hypertrophic agent PB. The hepatomegaly was attributed to a sharp and transient induction of hepatocell ular proliferation 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

- Developmental NOAEL of 30 mg/kg/day and a LOAEL of 90 mg/kg/day based on increased incidence of rudimentary ribs, unossified sternebrae, as well as increased incidence 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 49 of 61

A .3. 2 Acute Reference Dose (aRfD)

- General Population

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

Dose and Endpoint for Establishing an aRfD : 30 mg/kg/day

- NOAEL 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 extrap olation 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 carcinogenicity Study in Mice (MRIDs 00129570 & 93194037)

C arcinogenicity Mouse Study

- A 24

- month propiconazole dietary carcinogenicity 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 HIARC for deriving the chronic RfD. Non

neoplastic liver effects (increased liver weight in males and increa se in liver lesions: masses/raised areas/ swellings/nodular areas mainly) were observed at 50 mg/kg/day. (See Appendix B)

Dose and Endpoint for Establishing a cRfD: 10 mg/kg/day

- NOAEL of 10 mg/kg/day and a LOAEL of 50 mg/kg/day based on non

- neoplasti c 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 Acute RfD = 30 mg/kg (NOAE L ) = 0. 30 mg/kg/day (Females 13

- 49) 1 00 (UF)

Acute RfD = 30 mg/kg (NOAEL ) = 0.3 mg/kg/day (General Population) 1 00 (UF)

### Page 50 of 61

oral feeding toxicity study in mice was not selected be cause a) there is a wide dose spread between the NOAEL (2.7 mg/kg/day) and the LOAEL (65 mg/kg/day) in that study, b) the LOAEL (50 mg/kg/day) in the selected study is lower than the LOAEL (65 mg/kg/day) of the 3

- month mouse oral feeding study, and c) the liver toxicity seen in the 2 year mouse study is

consistent with that seen in an 18

- month mice and 2

- generation reproduction studies. In an 18

- month carcinogenicity study in mice, the NOAEL for liver toxicity was 11 mg/kg/day and the LOAEL 59 mg/kg/day). In a 24

- month feeding study in rats, the 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 s elected since stomach irritations were attributed to local effects and not systemic toxicity, and target organ (liver) toxicity seen in mice and rats was not seen in dogs.

A .3.4 Incidental Oral Exposure (Short

- and Intermediate

- Term)

Incidental Oral Exposure (Short

- Term)

Selected Study: Acute Neurotoxicity in Rats (MRID 46046401).

See Section 3.4.2

Dose and Endpoint for Establishing an aRfD : 30 mg/kg/day

- 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

Incidental Oral Exposure (Intermediate

- Term)

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

See Section 3.4.3

Dose and Endpoint for Establishing a cRfD: 10 mg/kg/day

- NOAEL 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 51 of 61

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 exposure 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 assessment, the basis for the 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 Neurotoxicity 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

1 0X 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 stu dy is available, a POD from an oral study was selected because neurotoxicity, the primary effect of concern for short

- term exposure is not specifically evaluated in the available dermal toxicity studies. The selected endpoint is protective of potential n eurotoxic effects from dermal exposure.

Dermal Exposure (Intermediate

- Term)

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

See Section 3.4.3

Dose and Endpoint for Establishing a cRfD: 10 mg/kg/day

- NOAEL 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

### Page 52 of 61

should be used.

A .3.7 Inhalation Exposure (Short and Intermediate

- Term)

Inhalation Exposure (Short

- Term)

Selected Study: Neurotoxicity in Rats (MRID 46046401).

See Section 3.4.2

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 : Inhalation toxicity is assume d to be equivalent to oral toxicity.

Inhalation Exposure (Intermediate

- Term)

Selected Study: 24 Month carcinogenicity 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

- neoplastic liver effects.

Uncertainty Factor (UF )/Level of Concern: 100

– 10X for interspecies extrapolation and

10X for intraspecies variation. FQPA 1X

Comments about Stud y/Endpoint : Inhalation toxicity is assumed to be equivalent to oral toxicity.

### Page 53 of 61

A.4 EXECUTIVE SUMMAR IES

870.3 2 00 Dermal Toxicity

In a repeated dose dermal toxicity study (MRID 00116591 and 93194034), groups of 20 New

Zealand rabbits received 15 daily dermal applications 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%, Batch 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

- related deaths or signs of systemic toxicity and

no treatment

- related effects on body weight, food consumption, or opt halmology, hematological and clinical chemistry parameters. One high 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 noted in the 30 and 1000 mg/kg/day groups beginning at day 2 and pers isted for the remainder of the study with maximum irritation indexes of 1.0 and 4.1, respectively. Signs of irritation 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 n o compound related gross necropsy, organ weight effects or histopathological findings. There were mild to moderate skin lesions which were dose related in treated animals compared to controls. Hyperkeratosis, acanthosis, mild dilation of blood vessels an d 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 dermis) at 3 and 30 mg/kg/day and moderate 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/dose 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 init ially 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 dose level during the first five days of dosing beginning on day 8 of gestatio n at 360 mg/kg/day. These included statistically significant increases in the incidence of lethargy, ataxia, salivation, and biologically significant increases in rales, prostration, hypothermia and bradypnea. The incidence of these effects versus contro l is as follows: lethargy (9/23 vs. 0/24 in controls), salivation (4/23 vs. 0/24 in controls) and ataxia

### Page 54 of 61

(3/23 vs. 0/24 in controls). After lowering the dose to 300 mg/kg/day on day 6, the severity and frequency of these effects decreased rapidly. At the lower doses with the exception of one animal of the 90 mg/kg/day group exhibiting 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 a nd 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 controls) 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 severe clinical toxicity. The maternal toxicity NOAEL is 90 mg/kg/day. Fetotoxic effects observed included a high incidence of rudimentary ribs, though not statistically significa nt but part of dose related 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 un

ossified sternebrae (57%, p< 0.05 in the 90 mg group, and 72%, p< 0.01 in the 300 mg group vs.

38% in t he controls), as well as increased incidence of shortened renal papillae (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 statistic ally significant) and 11% in the 300 mg group, p < 0.01 vs. 3% in the controls) 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 malformations in the 90 mg group (0.3%) and in the 300 mg group (0.7%) and considered to be “probably compound related”. Historical controls in 19 teratology studies from this laboratory had no incidence of cleft palate. The cleft palate incidence in the current study w as probably under reported because only half of the fetuses were examined viscerally. It was also concluded 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 study (MRID 40425002) where propiconazole was administered to pregnant rats at 0 or 300 mg/kg/day during the gestation period. The developmental toxicity LOAEL of propiconazole is 90 mg/kg/day, based on increased

incid ence of rudimentary ribs, un

- ossified sternebrae, 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, Batch No. FL 850083) was administered to CL:COBS CD (SD) BR VAF/PLUS virgin female rats by oral gavage in aqueous suspensions (3% corn starch containing

0.5% Tw een 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 toxicity was observed during the treatment period beginning on gestation day 6 and included a statistically signi ficant increase in the incidence of ataxia (42% vs. 0 in controls), coma (9% vs. 0 in controls), lethargy (44% vs. 0 in controls),

### Page 55 of 61

prostration (3% vs. 0 in controls), audible respiration (4% vs. 0 in controls), labored respiration (11% vs. 0 in controls), and salivation (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 wa s significantly lower (60

- 92% of the control values, p<0.05) in the treated group during the dosing period. Body weight gains were significantly lower (68% of controls, p<0.05) in dosed animals during GD 6

- 16. There were no significant differences between dosed and control animals with respect to fetal sex ratio or mean number of corpora lutea, implantation 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 implanta tion sites, and higher mean total resorption in the dosed animals, although not significantly different from controls. Mean fetal weights for both males and females (95% of controls, p<0.001) were significantly lower in dosed animals. Fetuses were

examin ed for external abnormalities only and there were no statistically significant treatment

related, external gross observations among fetuses. Cleft palate was reported in 2/2064 fetuses

of dosed animals and 0/1222 of control fetuses. The incidence of cle ft palate in controls for all teratology studies (not including 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 Tox icity

In a developmental toxicity study (MRID 00265796), CGA 64250 technical (92.1% purity propiconazole) was administered to groups (19/group) of artificially inseminated New Zealand white rabbits by oral gavage in aqueous suspensions (3% corn starch co ntaining 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 deliver y (statistically significant, p<0.05 compared to control 1/19). In the mid dose (250 mg/kg/day) group, one doe aborted early. One control animal delivered early. Among animals of the high dose group, an increased inci dence of stool alterations (decreas ed/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 controls and 58

- 78% of the co ntrols in the high

- and mid

- dose groups, respectively) and a severe decrease in the maternal body weight gain, but rebounded to normal after withdrawal of the test compound. During GD 7

- 10, the maternal animals had a weight loss of 0.047 and 0.111 kg at 2 50 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 observe d 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 finding was considered to be treatment

- 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 increased incidence of abortions. The maternal toxicity LOAE L of propiconazole in the rabbit is 250 mg/kg/day, based on reduced maternal body weight gains and decreased food consumption during the dosing period. The maternal toxicity

### Page 56 of 61

NOAEL is 100 mg/kg/day. The developmental 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

- CGA

64250 (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 m g/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 ingredient and 54.2% inert substances) and applied as an aqueous suspension. One group o f four rats/dose were exposed for 24 hours, while two other groups of four rats each/dose were exposed 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 collected at the end of the exposure period s and at 24 hour intervals (for the depletion groups) following the exposure.

At sacrifice time rats were anesthetized and blood collected. The radioactivity present in excreta, blood, carcass, skin, skin washes and patch components were determined. The applied radioactivity was accounted for, 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 applied dose. The rate of absorption appeare d to be saturated at the highest dose level; at the low dose level, there was a time dependent increase in the amount of compound absorbed. After 24 hours, 57.1, 271 and 3010 μg/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 depletion phase essentially 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 phase, less than 2% of the 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 exposure periods of 4 and 8 hours except for the low dose of 0.01 mg/cm 2 

### where it increased to 54%. The average 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 reproduction study (MRID 00151514), CGA 64250

tech nical (89.7% purity propiconazole, FL

- 830377) was administered to 15 male and 30 female

### Page 57 of 61

Charles river CD rats at dose 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

- mating period and throughout gestation 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 intervals(82

- 94% of the controls, p<0.05 and 0.01); body weight gains were also significantly 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 mal e body weights were reduced in the high dose groups compared to controls (not statistically significant); body weight gains in this group was 91

- 94% of controls for the pre

- mating period and during the entire duration of the study (7 months). Food consump tion 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 controls). Histological examinations revealed that hep atic “cellular swelling” 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 finding was significant for both sexes in the mid

- and high

- dose gro ups. The incidence of “hepatic clear

- cell change” 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 c lear

- cell change and the NOAEL for parental toxicity is 100 ppm (8 mg/kg/day). Reproductive parameters (mating, fecundity, gestation, male and female fertility indices, litter resorptions and gestation duration) were comparable in all groups. Offspring T oxicity : The number and percent of viable pups at birth and surviving through weaning were comparable between the dose groups and

controls for both the F 1a 

### and F 1b 

### litters. In the F 2a 

### litters, however, the number of pups delivered,

delivered viable and s urviving to day 4 of lactation 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 statistically significant). The F 2b 

### litters of these dams had sign ificantly reduced survival rates (both number and percent of surviving pups) at lactation days 7, 14, and 21. The mean body weights of high

- dose progeny were significantly reduced at days 14 and 21 for pups of both generations (72

- 81% of controls). Reduc tions were also significant on days 4 and 7 (except for F 1b 

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

### litters only). At necropsy, no treatment related anomalies, organ weight changes and gross pathology findings were noted in pups. Histopathological evaluation of select ed organs from F 1b 

### and F 2b 

### progeny revealed significantly (p<0.01) increased incidences of hepatic “cellular 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 body weights and an increased incidence of hepatic lesions (cellular swelling) at 2500 ppm

.

### Page 58 of 61

Additional Developmental/Reproduction Toxicity 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

6

- 15 of gestation (Hassan, 1993. Embryotoxic and teratogenic eff ects of the organic fungicide tilt in albino rats. Bull. Fac. Pharm., Cairo University 31(3): 459

- 463). Rats were sacrificed on day 20 of gestation. Post

- implantation deaths, resorption sites and dead fetuses were counted.

Fetuses were examined for mor phological, visceral and skeletal malformations. Propiconazole was fetotoxic at both doses causing significant (p<0.05) increased fetal resorptions (8 and 21% at the low and high dose vs. 0% in the control), increased fetal deaths (10 and 24% at the low a nd high doses vs. 2% in the control) and decreased fetal weight). The mean number of stunted fetuses was significantly higher (p<0.05) at both doses (1.43 and 3.57) at the low and high dose vs. 0.13 in the control), noting incomplete ossification of the s kull, caudal vertebrae and digits, extra rib (14 th 

### rib) and missing sternebrae. Malformations of the lung and kidneys were reported. No maternal toxicity was reported at either dose. The LOAEL for developmental toxicity in this study is 76 mg/kg/day (t he 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 six acceptable mutagenicity studies:

1. In vitro cell transformation assay (MRID 00133349 )

2. Bone Marrow Chromosomal Aberration (MRID 00058603 )

3

. Mutagenicity: Unscheduled DNA synthesis (MRID 00133347 )

4 . Mutagenicity: Unscheduled DNA synthesis (MRID 00133348 ) 5. Mitotic Gene Conversion Assay (MRID 0013334 3) 6. Dominant Lethal Assay in Mice (MRID 00058602)

870. 7 800 Immunotoxicity

Propiconazole is one of the conazoles that were reviewed as a class by the Hazard and Science Policy Council (HASPOC) for the immunotoxicity test requirements (TXR 0056730). A waiver was recommended for an immunotoxicity study for the class of conazole pesticides based on the following considerations:

• There was no evidence of adverse effects on the immune system in mice, rats, or dogs in the data base for any of the conazole pesticides. • The liver, not the immune system, is generally the target organ for this chemical class, and hepatotoxicity or body weight changes are the primary toxicological endpoints of

concern and were used in risk assessments. • The conazoles do not belong to a class of chemicals (e.g., the organotins, heavy metals,

### Page 59 of 61

or halogenated aromatic hydrocarbons) that would be expected to be immuno t oxic. There was no evidence of immunotoxicity with six other structurally

- rela ted conazole fungicides, namely, flutriafol, metconazole, tebuconazole, tetraconazole

, triadimefon, triflumizole, and triticonazole. In the Immunotoxicity study for triflumizole

, the effects on the immune system occurred only at the highest dose tested. Im munotoxicity was demonstrated with difenoconazole, however it was observed in the presence of systemic toxicity and at a relatively high dose. PODs based on the most sensitive endpoints obtained via the appropriate routes of exposure in

the most sensitive species are currently used for dietary and non

- dietary risk assessments. All these factors indicate that an immunotoxicity study would most likely not result in an adverse effect that could be used as an endpoint for conazole risk assessment.

Based on a we ight of evidence approach, the HASPOC concluded that immunotoxicity studies are not required as this time for propiconazole (TXR 0056730). An immunotoxicity study is not anticipated to provide a lower POD or result in a more sensitive endpoint than those a lready used. Therefore the waiver request is granted (TXR 0056761)

.



### The complete toxicity profile for propiconazole is provided in Appendix A.

### Page 60 of 61

APPENDIX B. Chemical Names And Structures Of Metabolites

### Page 61 of 61

APPENDIX C. Physical/Chemical Properties

Physicochemical Properties 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 (  max, nm) Not available MRID No. 40583703



### APPENDIX D. Studies Reviewed for Ethical Conduct

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

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

The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler Unit

E xposure Surrogate Reference Table. U.S. Environmental Protection Agency. Released June 21, 2011.