UN I T E D STATES ENV I RONMENTAL PRO T EC T ION AG E NCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND PO L L U TION PR E VENTION

MEM ORAND UM

Decembe r 2, 2015

SUB J ECT: Propiconazo l e Human Health Risk Assessment for the New Uses of Propicona zo le on dill, leafy brassicas crop subgroup SB

, ti pa lm

, watercress, and quinoa

, alo n g with expans ion to fruit

, st one , group 12-12 ; except p l um , and nut

, tree

, group 14-12.

PC Co d e: 122101 DP B a r codc: 0426494

D ecis i o n No.: 496175 R eg i st r at i o n No.: I 00-617

, I 00-1178

, I 00

- I 3 12

, & I 00-1324

Petition No.:4E832 I R eg ul a tor y Ac tion: Section 3

Ri sk Assessme nt T y p e: Single Chemical Ae.e.regate Case No.: 3125

TXR No. : NA CAS No. : 60207-90- I

MRID No.: NA 40 C FR: 180.434.

F ROM

.

THROUG H:

TO:

# '/**~~** Thurston G. Morton

, C hemi s t Kelly O ' Rourke, Biologist

## ~ ;A)·

## O~\.A.--"'\ Abda llah Kha s awinah

, PhD.

, Toxicologi s t**~** Ri sk Assessment Branch 4


### Health Effects D ivision (7509P) 

# .h

E lis sa Reaves

, Ph.D., Chief

# ~ _,,

_ ______ ___ _ Risk Assessment Branch 4

, HED

## ~-

Sidney Jackson/Barbara Madden

Risk Int egration, Minor Use & Emergency R espo n se Branch Registration D i vision ( RD ) (7505 P)

This document provides the Health Effects Division 's (HED ' s) risk assessment fo r the n ew and

amended uses of propiconazole on Dill

, Crop subgroup SB Leafy Brassica greens, Radi sh, Ti

Palm

, Watercress, q u inoa

, and th e Ex pan s i on of Fruit

, stone

, gro up 1 2- 1 2, an d N ut

, tree

, group 14-12.

Page I of 581.0 EXECUT I VE SUMMARY

........................................................................ . ...... . ... . .. . ......... 4

2

. 0 BED RECOMMEN D A TIO NS

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

2.1 Data Deficiencies/Conditions of Registration

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

2.2 To l e r a n ce Cons id e r at ion s

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

2.2.1 E nforcement Ana l yt ical Method

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

2.2.2 International Harmonization

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

2 .2 .3 Recommended To l erances

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

2.2.4 R ev i s ion s to Petitioned-For To l e rance s

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

2.3 Label R ecom m e ndati ons

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

3.0 INGREDIENT PRO F IL E

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

3.1 C hemic a l Identity

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

3.2 Ph ys ical/Chemical C har ac t eristics

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

3.3 Pesticide Use Patter n

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

3.3.1 Proposed New Uses

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

3.4 A n tici p ated Ex po s ur e Pathways

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

3.5 Cons id erat ion s of Env ironm e ntal Justice

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

4.0 H AZARD CHARACTERIZATION/ASSESSMENT

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

4.1 Toxicology St udie s Available for A nal ys is

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

4.2 Absor p tion, Di stribu tion

, Metabo li s m a nd Excret i o n

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

4

. 3 Toxico l og ic a l Effects

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

4.4 Safety Factor for Infant s and C hildr e n (FQPA Safety Facto r )

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

4.4.1 Comp l ete n ess of t he Tox icol ogy Databas e

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

4.4.2 Evi d ence of Neu rotoxicity

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

4.4.3 Ev id ence of Se n sit i v i ty/S u scepti bili ty in the D eve lopin g or Yo un g An im a l

...... 17

4.4.4 Residual U ncertainty in t h e Expos ure Database

...... .. ....... . ................................ .. 18

4.5 Toxicity En dpoint and Point of Departure

............. . ...... ...... .. .. ..................... ..... .. .. .. .... 18

4.5. 1 Dose-Response Assessment

. ... .. . ... ...... .... .. .. . .... ... . . ..... ... ... .. .. . ... . .... .... . .. . ... .. .. . .. .. .. ... . 18

4.5 .2 Recommendations for Co mbinin g Exp o s ur e R o ute s

............................ . ......... . .... 19

4.5.3 C la ss ific a ti on of Ca rcin oge nic Po t entia l

..... . ......... . ........ . .... .. ...... ............. . ... . .. .. .... 19

4.5.4 S umma ry of Points of Departure Use d in Risk Assess m en t

....... . . .. ... ... .... .. ........ 19

5.0 DIET ARY AND DRINKING WATER EXPOSURE AND RISK ASSESSMENT

.... 22

5

. 1 Metabo li te/Degradate Residue Profile

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

Page 2 of 58Page 3 of 58

5.1.1 Summary of Plant and Livestock Metabolism Studies

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

5.1.2 Comparison of Metabolic Pathways

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

5.1.3 Environmental Fate and Transport

................................ ................................ ...... 23

5.1.4 Residues of Concern Summary and Rationale

................................ ..................... 23

5.2 Food Residue Profile

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

5.2.1 Residues in Crops

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

5.3 Water Residue Profile

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

5.3.1 Estimated Drinking Water Concentrations

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

5.4.1 Acute Dietary and Drinking Water Analysis

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

5.4.2 Chronic Dietary and Drinking Water Analysis

................................ ................... 29

6.0 RESIDENTIAL EXPOSURE AND RISK ASSESSMENT

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

6.1 Residential Bystander Postapplication Inhalation Exposure

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

6.2 Spray Drift

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

7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT

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

7.1 Acute & Chronic Aggregate Risk

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

7.2 Short

- and Intermediate

- Term Aggregate Risk

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

7.3 Intermediate

- Term Aggregate Risk

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

8.0 CUMULATIVE RISK

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

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION

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

10. REFERENCES

................................ ................................ ................................ .................. 36

A TOXICOLOGY DATA SUMMARY

................................ ................................ .............. 37

A.1 Guideline Data Requirements

................................ ................................ ................ 37

A.3 Toxicological Endpoints

................................ ................................ ............................. 44

A.4 EXECUTIVE SUMMARIES

................................ ................................ .................... 49

APPENDIX B. Chemical Names And Structures Of Metabolites

................................ ......... 57

APPENDIX C. Physical/Chemical Properties

................................ ................................ .......... 58

APPENDIX D. Studies Reviewed for Ethical Conduct

................................ .......................... 58Page 4 of 58

1.0 EXECUTIVE SUMMARY

This document addresses the risks associated with exposures from currently registered uses and the proposed new use s of propiconazole on dill, leafy brassicas crop subgroup 5B, ti palm,

watercress, and quinoa along with expansion to fruit, stone, group 12

- 12; except plum, and nut, tree, group 14

- 12 . It also assesses potential enhanced sensitivity of infants and children from dietary and/or residential exposure as required under the Food Quality Protection Act (FQPA) of
1996.

Use Profile

Propiconazole 1

- [[2

- (2,4

- dichlorophenyl)

- 4

- propyl

- 1,3

- dioxolan

- 2

- yl]methyl]

- 1 H

- 1,2,4

- triazole) is a systemic triazole

- type 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 propiconazole 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, public 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 a request to amend the use of propiconazole using Tilt (EPA Reg. No.

100

- 617), QuiltTM (EPA Reg. No. 100

- 1178), Inspire XTTM (EPA Reg. No. 100

- 1312) and QuiltXcelTM (EPA Reg. No. 100

- 1324) to add new uses on dill, crop subgroup 5B leafy Brassica greens, radish, Ti Palm, watercress, quinoa, along with expansion to fruit, stone, group 12

- 12, and nut, tree, group 14

- 12.

T he toxicology database for propiconazole is complete for evaluating and characterizing tox icity 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 a nd necrosis. There are mixed effects
in the developmental and reproduction rat studies. In a rat developmental study, fetal effects
were observed at doses lower than doses at which maternal effects were seen thereby 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, offsprin g toxicityPage 5 of 58

occurred at a higher dose than the parental toxic dose suggesting lower susceptibility of the rat offspring to propiconazole. Propiconazole does not appear to be neurotoxic based on an acute
and subchronic neurotoxicity stud ies

. The concern for susceptibility is low since clear NOAELs were established in the rat and rabbit developmental studies and the points of departure selected for the risk assessment scenarios are protective of the susceptibility observed in the rat developmental study. Ther efore, 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 water exposures. An acute POD for the genera l 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 mic e. 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 fro m 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 was selected for dermal exposure, a 40%
derma l 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 variatio n).

Exposure/Risk Assessment and Risk Characterization

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

. No updated occupational exposure assessment was required since registered use s are protective of proposed

uses

. For the current registration action, t here are no new residential uses and therefore

, residential risk was not assessed for th is new use. However, for the aggregate assessment, the existing registered residential use that previously resulted in the greatest short

- term exposure was utilized (i.e., post

- application activity on treated turf).

Conservative acute and refined chronic dietary and drinking water risk assessments for propiconazole conclude that dietary and drinking water exposure estimates are below HED ’s

l evel 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 8 4 % of the aPAD. The exposure to the general U.S. population is 8 %
of the cPAD, and the most highly exposed subgroup ( Children 1

- 2 yrs old) is 2 5 % of the cPAD.Page 6 of 58

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

.

Aggregate risks from propiconazole are not of concern. For adults

, the short

- term residential
dermal MOE estimated from post

- application activity on treated turf , when aggregated with dietary exposure, is 200, which does not fall below the LOC of 100 and is therefore not of concern. For children, the aggregated MOE (incidental oral + dermal + dietary) MOE was 96 [note that while this falls below HED’s LOC of 100, t his assessment is considered very conservative in that the residential incidental oral post

- application exposure was calculated by combining three screening level assessments (which by themselves already have conservative estimates) ]. T he only scenario that is expected to result in potential intermediate

- term exposure to propiconazole is post

- ap plication exposure to children from wood treatment

, which is from an
antimicrobial use. T he aggregate risk (dietary + residential exposure) for intermediate

- term exposure to Children 1

- 2 years old yields an MOE of 110 , which does not fall below the level of
concern of 100 and, t herefore, this scenario is not of concern.

An occupational exposure assessment was not required since previous uses are protective of the proposed and amended uses

.

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. The previous aggregate human health risk assessment was updated for free triazoles and its conjugates and the aggregate estimates remain below HED’s level of concern (T. Morton, D426493, 4/9/15).

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 data, which include [studies from PHED 1.1; the AHETF database; the Outdoor Residential Exposure Task Force (ORETF) database; and the ARTF database], are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics req uirements. 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 possibl e, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," http://www.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.pdf ).

As a part of every pesticide risk assessment, OPP considers a large variety of consumerPage 7 of 58

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
pest icide 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 a re 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 traditiona l dietary patterns among specific subgroups.

Tolerance Recommendation

T here are no residue chemistry issues that would preclude granting the tolerance s on the requested new uses.

As previously noted, permanent tolerances are currently established 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 only propiconazole 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 pr opiconazole or the proper use of other pesticides containing 2,4

- DCBA; 2) propiconazole can be detected by FDA multi

- residue methods; and 3) inclusion of only parent allows harmonization with the residue definition for the
Codex MRLs.

A new section was pr eviously recommended to be added to 40 CFR §180.434 as 40 CFR §180.434(a)(2) for the tolerance expression for parent only for imported tea

.

Following is the appropriate tolerance expression:

Propiconazole; tolerances for residues (a) General. Tolerance s 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 propiconazole, 1

- [[2

- (2,4

- d ichlorophenyl)

- 4

- propyl

- 1,3

- dioxolan

- 2

- yl]methyl]

- 1 H

- 1,2,4

- triazole, in or on the commodity.

Both the Codex Alimentarius Commission and Canada have established several maximum residue limits (MRLs) for propiconazole in/on various raw agricultural commo dities discussed in this action. The Codex 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. At this time, the U.S. to lerance expression is harmonized with Canadian expression for which MRLs are established included in this action, but not
CODEX. The US tolerance level for stone fruit and tree nuts cannot be harmonized with the Codex MRLs currently established. However, Canada has an MRL of 4 ppm for various stonePage 8 of 58

fruits and 0.1 ppm for various tree nuts, which the US will be harmonized on MRL levels.

2.0 HED RECOMMENDATIONS

2.1 Data Deficiencies/Conditions of Registration

HED can recommend for registration for the proposed new and expanded use s of propiconazole. A revised Section F indicating the correct commodity definition and tolerance levels should be
submitted.

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 a maximum residue limits (MRLs) for propiconazole in/on various raw agricultural commodities. In addition, both Canad a and Mexico have established MRLs for propiconazole in/on various commodities. The Codex and Mexican MRLs are expressed in terms of propiconazole per se . The Canadian MRLs are expressed in terms of combined residues of propiconazole and its metabolites containing the 2,4

- DCBA moiety. Canada has an MRL for tea at 4 ppm . The U.S. is harmonized on the MRL level for
Canada.

2.2.3 Recommended Tolerances

Pending submission of a revised Section F (see requirements under Proposed Tolerances), there

are no residue chemistry issues that would preclude granting conditional Section 3 registration for the requested new uses and expansion of requested crop groups of propiconazole, or establishment of the following tolerances for residues of propiconazole.Page 9 of 58

Those commodities to be added to §180.434(a)(1) are:

Dill weed , fresh leaves

................................ ................................ ................ 30 ppm

Dill weed , dried leaves

................................ ................................ ................ 80 ppm Dill, seed

................................ ................................ ................................ .... 15 ppm
Brassica leafy g reens, s ubgroup 5B

................................ ........................... 20 ppm Ti palm, leaves

................................ ................................ ........................... 10 ppm Ti palm, roots

................................ ................................ .......................... 0.3 0 ppm Watercress

................................ ................................ ................................ . 6 .0 ppm Fruit, stone, group 12

- 12; except plum

................................ ..................... 4.0 ppm Nut, tree, group 14

- 12

................................ ................................ ............. 0.1 0 ppm Quinoa, grain

................................ ................................ ............................. 3.0 ppm Radish, tops

................................ ................................ ............................. 0.2 0 ppm Radish, roots

................................ ................................ ........................... 0.04 ppm

As previously noted, permanent tolerances are currently established 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 only propiconazole because 1) there are a number of pestici des 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 can be detected by FDA multi

- resi due methods; and 3) inclusion of only parent allows harmonization with the residue definition for the
Codex MRLs.

A new section was previously recommended to be added to 40 CFR §180.434 as 40 CFR §180.434(a)(2) for the tolerance expression for parent only for imported tea

.

Following is the appropriate tolerance expression:

Propiconazole; tolerances for residues (a) General. Tolerances 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 propiconazole, 1

- [[2

- (2,4

- dichlorophenyl)

- 4

- propyl

- 1,3

- dioxolan

- 2

- yl]methyl]

- 1 H

- 1,2,4

- triazole, in or on the commodity.

Adequate crop field tr ial data reflecting the proposed use patterns were submitted for purposes of supporting the proposed tolerance s

.Page 10 of 58

Table 2.2.3 . Tolerance Summary for Propiconazole.

Commodity Proposed

Tolerance (ppm) Recommended Tolerance

(ppm) Comments

40 CFR §180.434(a)(1)

Dillweed, fresh 30 30 Dillweed, fresh leaves

Dillweed, dried 80 80 Dillweed, dried leaves

Dill, seed 15 15
Brassica leafy greens, subgroup 5B 20 20
Ti palm, leaves 10 10
Ti palm, roots 0.3 0.30

Watercress 6 6.0

Fruit, stone, group 12

- 12; except plum 4.0 4.0

Nut, tree, group 14

- 12 0.1 0.10
Quinoa, grain 3.0 3.0
Radish, tops 0.2 0.20

Radish, roots 0.04 0.04

*Changes are due to rounding of significant figures and correcting commodity vocabulary.

2.2.4 Revisions to Petitioned

- For Tolerances

The Organization for Economic Cooperation and Development tolerance calculation procedures were utilized in determining the appropriate tolerance level for the requested new uses. A revised Section F for Radish, tops at 0.20 ppm, Ti palm, roots at 0.30 ppm, watercress at 6.0 ppm, and Nut, tree, group 14

- 12 at 0.10 ppm must be submitted. In addition, the commodity vocabulary needs revised for Dillweed, fresh leaves; Dillweed, dried leaves; and Brassica, leafy greens, subgroup 5B. Changes are due to rounding of significant figures and correcting commodity vocabulary.

2.3 Label Recommendations

None

3 .0 INGREDIENT PROFILE

3.1 Chemical Identity

Structure and nomenclature are reported in Table 3.1

.Page 11 of 58

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

Current end

- use products containing propiconazole that is registered for use on feed/food crops is marketed under the trade names Tilt® Fungicide (EPA Reg. No. 100

- 617), QuiltTM (EPA Reg.

No. 100

- 1178), InspireTM XT (EPA Reg. No. 100

- 1312), and Qu iltXcelTM (EPA Reg. No. 100

- 1324).Page 12 of 58

Table 3. 3.1 Summary of Proposed Directions for Use of Propiconazole

. Applic. Timing, Type, and Equip. Formulation

[EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per

Season Max. Seasonal

Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations

Brassica Leafy Greens (sub group 5B)

Postemergence
Broadcast foliar Ground, aerial, or chemigation 3.6 lb/gal

Tilt

EC [100

- 617] 0.11 3 implied 0.34 7

- 7 to 10 day RTI

1.04 lb/gal Quilt

EC [100

- 1178] 0.11 3 implied 0.34 7

- 7 to 10 day RTI

2.08 lb/gal Inspire XT

EC [100

- 1312] 0.11 3 implied 0.34 7

- 7 to 10 day RTI

1.02 lb/gal Quilt Xcel

EC [100

- 1324] 0.11 3 implied 0.34 7

- 7 to 10 day RTI

Dill

Postemergence
Broadcast foliar Ground, aerial, or chemigation 3.6 lb/gal

Tilt

EC [100

- 617] 0.11 3 implied 0.34 7

- 7 to 10 day RTI

1.04 lb/gal Quilt

EC [100

- 1178] 0.11 3 implied 0.34 7

- 7 to 10 day RTI

1.02 lb/gal Quilt Xcel

EC [100

- 1324] 0.11 3 implied 0.34 7

- 7 to 10 day RTI

Radish

Postemergence
Broadcast foliar Ground, aerial, or chemigation 3.6 lb/gal

Tilt

EC [100

- 617] 0.11 4 implied 0.45 14

- 7 to 10 day RTI

1.04 lb/gal Quilt

EC [100

- 1178] 0.11 4 implied 0.45 14

- 7 to 10 day RTIPage 13 of 58

Table 3. 3.1 Summary of Proposed Directions for Use of Propiconazole

. Applic. Timing, Type, and Equip. Formulation

[EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per

Season Max. Seasonal

Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations

1.02 lb/gal Quilt Xcel

EC [100

- 1324] 0.11 4 implied 0.45 14

- 7 to 10 day RTI

Ti Palm

Postemergence
Broadcast foliar Ground, aerial, or chemigation 3.6 lb/gal

Tilt
EC [100

- 617] 0.11 4 implied 0.45 7

- 7 to 10 day RTI

Watercress

Postemergence
Broadcast foliar Ground, aerial, or chemigation 3.6 lb/gal

Tilt

EC [100

- 617] 0.11 4 0.45 3 - 7 to 10 day RTI

- Make no more than 2 applications before harvesting
of leaves

1.04 lb/gal Quilt

EC [100

- 1178] 0.11 4 0.45 3 - 7 to 10 day RTI

- Make no more than 2 applications before harvesting
of leaves

1.02 lb/gal Quilt Xcel

EC [100

- 1324] 0.11 4 0.45 3 - 7 to 10 day RTI

- Make no more than 2 applications before harvesting
of leaves

Quinoa

Broadcast foliar Ground, aerial, or chemigation 3.6 lb/gal

Tilt

EC [100

- 617] 0.11 2 0.22 0.11 if forage and hay
harvested 30

7 (Forage
and Hay) - 14 day RTI 1.04 lb/gal Quilt

EC [100

- 1178] 0.11 2 0.22

1.02 lb/gal Quilt Xcel
EC [100

- 1324] 0.11 2 0.22Page 14 of 58

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new use s of propiconazole. For the existing domestic uses, humans may be exposed to propiconazole in food and drinking water, since propiconazole may be app lied directly to growing crops and application may result in propiconazole reaching surface and ground wa ter sources of drinking water. There are no residential uses associated with the proposed new uses , however, the aggregate exposure was updated. A pr evious occupational exposure assessment is protective of the proposed new uses.

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 use 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, wer e considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf ) . As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to
well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive da ta on food consumption patterns are compiled by the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey/What We Eat in America, (NHANES/WWEIA), are used in pesticide risk assessments for all registered food uses
of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are p erformed when conditions or circumstances warrant. Whenever appropriate, non

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

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle an d traditional dietary patterns among specific subgroups.Page 15 of 58

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 and subchronic 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 only), and CGA 118244 (3.6% in females only). No parent material was detected in the feces in the iv group. The
metabolites seen in the iv study were detected to varying degrees in the urine and the feces of the orally dosed groups. Radiolabeled materials 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

C GA 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 n ot substantially different between the triazole and phenyl labeled samples, which suggest that the bridge between the phenyl ring and the triazole ring remained intact. The proposed metabolic pathway appears to involve the cleavage of the dioxolane ring t hrough 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 di oxolane 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.Page 16 of 58

4.3 Toxicological Effects

The primary target organ for propiconazole toxi city 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 characteristic of propiconazole toxicity in rats and mice. Decreased body weight gain was also seen in subchronic, chronic, developmental and reproductive studies in animal studies. Dogs appeared to be more sensitive to the localized toxicit y 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 toxi c doses. Increased 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 ossification of the skull, caudal vertebrae and digits, extra rib (14 th rib) and missing stern e brae were reported at doses that were not maternally toxic. In the two generation reproduction study in rats, offspring toxicity occurred at a higher dose than the parental toxic dose suggesting lower susceptibility of the offspring to the toxic doses of propiconazole.

Propiconazole was negative for mutagenicity in the in vitro BALB/3T3 cell transformation assay, bacterial reverse mutation assay, Chi nese hamster bone marrow chromosomal aberration assay, unscheduled DNA synthesis studies in human fibroblasts and primary rat hepatocytes, mitotic gene conversion assay and the dominant lethal assay in mice. It caused proliferative changes in the rat live r with or without pretreatment with an initiator, like phenobarbital, a known liver tumor promoter. Liver enzyme induction studies with propiconazole in mice demonstrated that propiconazole 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 known hypertrophic agent phenobarbital.

Propiconazole has low to moderate acute 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 se nsitizer.

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 available in the database with clinical toxicity at the high dose only with no microscopic changes

. A su bchronic neurotoxicity study in rats demonstrated no neurotoxicPage 17 of 58

effects (clinical or pathological) at the highest dose tested. Although quantitative susceptibility was observed in the rat developmental study, a clear NOAEL is established for the developme ntal 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 there are no remaining u ncertainties for the

young. Together, the available data support the reduction of the FQPA factor to 1X.

4.4.1 Completeness of the Toxicology Database

The toxicological database for propiconazole is complete for the purpose of this risk assessment.

B ased 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 (SCN) study are not required at this time ( 8/1/12

, TXR #: 0056387). However, the registrant provided later an acceptable/guideline SCN study.

4.4. 2 Evidence of Neurotoxicity

A cute and subchronic neurotoxicity stud ies are available for propiconazole. In the ACN study, a 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, staining around the nose). Limited clinical signs (piloerection, dia rrhea, 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 activity tests showed reduced activity in males and females but only at the high dose (300 mg/kg) with no microscopic changes to the nervous tissues

. Although the HASPOC waived the subchronic neurotoxicity (HASPOC, TXR 0056387) , the registrant later submitted an acceptable/guideline SCN study in rats. In this study, propiconazole was not neurotoxic at the highest dose tested of 3500 ppm (equivalent to 222 mg/kg bw/day). Both the A C N and the SCN studies demonstrated that propiconazole is not neurotoxic at the doses tested. Additionally

, neurotoxic and
neurobehavioral effects were not seen in the propiconazole toxicity database

. T he liver is the primary target organ of propiconazole toxicity, and decreased body weight is the most sensitive
end point in repeated

- dose studies.

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. F urthermore, 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 there are no remaining
uncertainties for the young.

There are no residual uncertainties with regard to pre

- and/or postnatal toxicity. The dietary foodPage 18 of 58

exposure assessment uses conservative assumptions which result in protective estimates of dietary exposure. The dietary drinking water asses sment uses values generated by model and associated modeling parameters which are designed to provide protective, high

- end estimates of
water concentrations.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. The dietary and non

- dietary risk

assessment s are conservative and will not underestimate dietary and/or non

- dietary residential
exposure to propiconazole.

4.5 Toxicity Endpoint and Point of Dep arture

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 (NOAEL) 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 dev elopmental 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 w as 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. The selected toxicity endpoint was the most sensitive to assess this exposure
scenari o. The maternal toxicity NOAELs in the developmental rat (90 mg/kg/day) and rabbit ( 10 0 mg/kg/day) studies were much higher and would not be protective of the toxicity seen in thePage 19 of 58

ACN study. An MOE of 100 is applied to account for the intra

- and inter

- spe cies variation. Incidental oral intermediate term exposure was assessed using a POD (NOAEL) of 10 mg/kg/day
from the carcinogenicity study in mice based on 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 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
describe d 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 inte rspecies 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 the
24 month car cinogenicity mouse study described 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 C ombining 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

- applicat ion exposures to adults via 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
inhal ation due to a common toxicological 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) rout es. Therefore, these routes 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 ( TXR No. 0 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 provide d in
Tables 4 .5.4.1 and 4.5.4.2

.Page 20 of 58

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 (Adult Males and Females 50+ yrs) NOAEL =

10 mg/kg/day UF A = 10X

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

0.1 mg/kg/day

cPAD =
0.1 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

, TXR No.

0009771
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 level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extr apolate 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 21 of 58

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 (1

- 30 days) 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 (1

- 6 months) 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/ nodular areas mainly).

Inhalation Short

Term (1

- 30 days) NOAEL= 30

mg/kg/day UF A = 10X

UF H = 10X Occupational

LOC for MOE =

100 Acute Neurotoxicity Study

- Rats MRID

46604601

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 UF A = 10X

UF H = 10X 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). Cancer (all routes) Classification: Group C, possible human carcinogen, RfD approach for risk characterizati on , TXR No.

0009771
DAF = Dermal Absorption FactorPage 22 of 58

5.0 DIETARY AND 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 updated separately (HED memo of 1 0 / 24 / 1 3 , T. Morton, D 414951 ).

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 isPage 23 of 58

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.

5.1.3 Environmental Fate and Transport

Propiconazole appears to be persistent and moderately mobile to relative immobile in most soil environments. In the aquatic environment, propiconazole degradation appears to be dependent solely on aqueous photolysis in the presence of photo sensitizers. In soil environment, propiconazole dissipation appears to depend on incorporation or binding to soil organic matter

content. Laboratory and terrestrial field dissipation data indi cate that propiconazole is stable in
soil and aqueous environments. However, in supplemental aquatic dissipation data using basin

irrigation and flow through irrigation systems in rice fields, propi c onazole was found to be dissipated rapidly (t 1/2 < 5 day s). Aqueous photolysis studies using sensitizers indicated rapid degradation (t 1/2 < 1 days) of propiconazole, which appears to be the case in rice fields. Furthermore, aquatic metabolism and dissipation studies indicate propiconazole dissipates by incorp oration or binding into the organic matter content of soil/sediment.

Propiconazole mobility in soil appears to be dependent on the soil's organic matter content. In general, propiconazole appears to be moderately mobile (Kd < 5) in soils with a low organi c

matter content (< 1 %). However, in soils with higher organic matter content (> I %), propiconazole appears to be relatively immobile (Kd > 5). Therefore, propiconazole may reach ground water in soils with low organic contents. Propiconazole may also con taminate surface water through off

- site runoff and spray drift.

5.1.4 Residues of Concern Summary and Rationale

A summary of the metabolites and degradates to be included in the risk assessment and tolerance expression are presented below in Table 5.1.4 . Detailed rationale for these conclusions were presented in a previous document (DP329394, Y. Donovan, 06/15/06).Page 24 of 58

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 en tire class of triazole

- derivative fungicides and because of differential toxicity between the metabolites and the various parent compounds, risks associated with exposure to 1,2,4

- T and to TA/TAA are addressed in separate risk assessment documents.

5.2 Fo od Residue Profile

5.2.1 Residues in Crops

Reference: Propiconazole : Propiconazole on Dill, C rop subgroup 5B Leafy Brassica greens, R adish , T i P alm

, Watercress, and the Expansion of Fruit, stone, group 12

- 12, and Nut, tree, group 14

- 12. T. Morton, D 423646

, 12 / 1 /201 5

Following the last of three foliar broadcast applications of a 3.6 lb ai/gal EC formulation of propiconazole at a total application rate of 0.33

- 0.34 lb ai/A, residues (and per

- trial averages) of propiconazole and metabolites determined as 2,4

- DCBA methyl ester were: 1.52

- 11.4 (1.61

- 11.1) ppm in/on dill, fresh leaves and stems and 5.36

- 41.1 (5.57

- 38.5) ppm in/on dill, dried leaves and stems, harvested at a 7

- day PHI and 0.0727

- 6.79 (0.0741

- 6.63) ppm in/on dill seed
harvested at a 36

- to 5 1

- day PHI. Residues of T were below the LOQ (<0.01 ppm) in/on dill, dried leaves and stems. Combined residues (and per

- trial averages) of TA and TAA were

<0.0276

- 0.0700 (<0.0281

- 0.0634) ppm in/on dill, dried leaves and stems.

In mustard green leaves harvested 6

- 8 days following the last of three foliar broadcast/directed applications of a 3.6 lb ai/gal EC formulation of propiconazole at a total application rate of 0.33

- 0.35 lb ai/A, residues (and per

- trial averages) of propicon azole and metabolites determined as 2,4

- DCBA methyl ester were <0.05

- 11.20 (<0.0960

- 10.78) ppm. Residues of T were below the LOQ (<0.01 ppm) in/on all samples of mustard green leaves. Combined residues (and per

- trial averages) of TA and TAA were <0.02

- 0. 225 (<0.02

- 0.214) ppm.

In radish tops and roots harvested 12

- 14 days following the last of four foliar broadcast applications of a 3.6 lb ai/gal EC formulation of propiconazole at a total application rate of 0.45

- 0.46 lb ai/A, residues (and per

- trial aver ages) of propiconazole and metabolites convertible toPage 25 of 58

2,4

- DCBA and residues of propiconazole per se , respectively, were: <0.05

- 5.01 (<0.0554

- 4.86)
and <0.01

- 0.109 (<0.01

- 0.108) ppm in/on radish tops; and <0.05

- 0.0852 (<0.05

- 0.0767) and

<0.01

- 0.0.0226 (< 0.01

- 0.0219) ppm in/on radish roots. Residues of T were below the LOQ (<0.01 ppm) in/on all samples of radish tops and roots. Combined residues (and per

- trial averages) of TA and TAA were <0.0224

- <0.117 (<0.0227

- <0.108) and <0.02

- <0.162 (<0.02

- <0.132) pp m, respectively, in/on radish tops and roots.

In watercress leaves and stems harvested 3 days following the second of four foliar broadcast applications (Plot 2; Harvest 1) of a 3.6 lb ai/gal EC formulation of propiconazole at a total application rate of 0.24

- 0.36 lb ai/A, residues (and per

- trial averages) of propiconazole and metabolites determined as 2,4

- DCBA methyl ester were 0.983

- 3.73 (1.08

- 3.38) ppm. Residues of T were below the LOQ (<0.01 ppm) in/on all samples of watercress leaves and stems.
Comb ined residues (and per

- trial averages) of TA and TAA were <0.0218

- <0.0572 (<0.0251

- <0.0524) ppm.

In watercress leaves and stems harvested 3 days following the last of four foliar broadcast applications (Plot 2; Harvest 2) of a 3.6 lb ai/gal EC formulation of propiconazole at a total application rate of 0.48

- 0.60 lb ai/A, residues (and per

- trial averages) of propiconazole and metabolites determined as 2,4

- DCBA methyl ester were 0.596

- 3.41 (1.30

- 2.88) ppm. Residues of T were below the LOQ (<0.01 ppm) in/on all samples of watercress leaves and stems. Combined residues (and per

- trial averages) of TA and TAA were <0.02

- 0.0344 (<0.02

- 0.0298)

ppm.

In watercress leaves and stems harvested 3 days following the second of four chemigation applications (Plot 3; Har vest 1) of a 3.6 lb ai/gal EC formulation of propiconazole at a total application rate of 0.24 lb ai/A, residues (and per

- trial averages) of propiconazole and metabolites determined as 2,4

- DCBA methyl ester were 0.684

- 0.950 (0.817) ppm. Residues of T

were below the LOQ (<0.01 ppm) in/on all samples of watercress leaves and stems. Combined residues (and per

- trial averages) of TA and TAA were below the combined LOQ (<0.02 ppm).

In watercress leaves and stems harvested 3 days following the last of four chem igation applications (Plot 3; Harvest 2) of a 3.6 lb ai/gal EC formulation of propiconazole at a total application rate of 0.48 lb ai/A, residues (and per

- trial averages) of propiconazole and metabolites determined as 2,4

- DCBA methyl ester were 0.495

- 0.545 (0.520) ppm. Residues of T were below the LOQ (<0.01 ppm) in/on all samples of watercress leaves and stems. Combined residues (and per

- trial averages) of TA and TAA were below the combined LOQ (<0.02 ppm).

Ti Palm

The ChemSAC Crop Grouping/Commodity D efinition Focus Group on February 4, 2013 had approved use of establishment of ti palm root and top tolerances for propiconazole based on current tolerances on root vegetables and tops of root and tuber vegetables.Page 26 of 58

Quinoa

With regard to quinoa, the ChemSAC concluded the following:

ChemSAC Meeting on July 29, 2015

ChemSAC Conclusion: “The ChemSAC concluded that if there are established tolerances for residues in wheat, barley (if barley has a higher tolerance than the wheat tolerance), or crop group 15, then the quinoa proposal does not need to come through ChemSAC, provided the quinoa and wheat, barley, or crop group 15 use patterns are the same. If there are no established tolerances for residues in wheat, barley, or crop group 15, or the use patt ern is different, then the quinoa proposal should come through ChemSAC.”

The established tolerance for propiconazole residues in/on barley, grain is established at 3.0 ppm. The use pattern for barley is the same as the proposed quinoa use pattern. Ther efore, this is an appropriate translation.

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: “Drinking Water Assessment for Proposed New Uses of Propiconazole on Dill, Radish, Leafy Brassica Subgroup SB, Watercress, Ti palm and Crop Group conversions for Stone Fruit Group 12

- 12 and Tree Nut Group 14

- 12.” (I. Abdel

- Saheb, 05/27/15, D423648) and incorporated directly into this dietary assessment. This assessment incorporated new models implemented since the previous

EDWCs. Water residues were directly incorporated in the DEEM

- FCID into the food categories “water, direct, a ll sources” and “water, indirect, all sources.”

The estimated drinking water concentrations for propiconazole are:

37.9 μ g /L for use in the acute dietary exposure assessment
35.1 μ g /L for use in the chronic dietary exposure assessment.

The highest estimates from ground water (acute, 37.9 ppb and chronic, 35.1 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 thesePage 27 of 58

assessments are a summation of all three residues and, therefore, represent an overestimate of actual concentrations of the common triazole metabolites in drinking water. The Tier II PRZM/EXAMS (surface water) and SCIGROW (ground w ater) 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 estimate s are significantly greater than those for ground water, and were used in the assessments for free triazole 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

- FCID, Version 3.16, which incorporates consu mption data from USDA’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). This dietary survey was conducted from 2003 to 2008. Dietary risk assessment 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 dose which HED has concluded will result in no unreasonable adverse health effects). This dose is referred to as the population adjust ed 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.

Reference: Propiconaz ole: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk
Assessments for the New Use of Propiconazole on Dill, Crop subgroup 5B Leafy Brassica greens, Radish, Ti Palm, Watercress, and the Expansion of Fruit, stone, group 12

- 12 , and Nut, tree, group 14

- 12. T. Morton, D 426495

, 12 / 1 /201 5

5

. 4 .1 Acute Dietary and Drinking Water Analysis

A new acute dietary assessment was conducted for the proposed new use. The proposed new use results in 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.Page 28 of 58

Table 5.4.1.1 . Results of Acute Dietary Exposure Analysis for Food and Drinking Water for Propiconazole

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

0.3 0.07 8719 26 All Infants (< 1 year old) 0.1 11352 37

Children 1

- 2 years old 0.25 2947 84

Children 3

- 5 years old 0.19 3824 65

Children 6

- 12 years old 0.106 303 35

Youth 13

- 19 years old 0.07 3978 25

Adults 20

- 49 years old 0.061 858 2 1

Adults 50

- 99 years old 0.05 3388 1 8

Females 13

- 49 years old 0.06 0911 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 Registrations For Use of Propiconazole on Tea, Dill, Mustard Greens, Radish, and Watercress; Use of Difenoconazole on Globe A rtichoke, Ginseng and Greenhouse Grown Cucumbers and Conversion of the Established Foliar Uses/Tolerances for Stone Fruit and Tree Nut Crop Groups to Fruit, Stone, Group 12

- 12 and the Nut, Tree, Group 14

- 12.; and Use of Flutriafol on Hops. T. Morton

, DP426492.drs, 4/9/15

.

The dietary exposure analyses for the triazole metabolites ( D426492 , T. Morton, 4/9/15 ) was recently updated. Addition of th is new use of propiconazole did not significantly change the dietary exposure for the triazole metabolites. The results from the triazole dietary analysis are below HED’s level of concern; see Table 5.4. 3 .2.Page 29 of 58

Table 5.4. 3 .2. Summary of Dietary (Food and Drinking Water) Exposure and Risk for the Common
Triazole Metabolites.

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 7869 26 0.001 150 23

Not Applicable Not

Applicable All Infants (< 1 year old) 0.01 2319 41 0.00 2097 42

Children 1

- 2 years old 0.0 19569 65 0.00 3321 66

Children 3

- 5 years old 0.01 6613 55 0.00 2646 53

Children 6

- 12 years old 0.0 09615 32 0.001 431 29

Youth 13

- 19 years old 0.00 6804 23 0.00 0922 18

Adults 20

- 49 years old 0.00 6350 21 0.00 0979 20

Adults 50

- 99 years old 0.00 5587 19 0.00 0927 19

Females 13

- 49 years old 0.00 6416 21 0.00 0942 19

Triazolylalanine + Triazolylacetic Acid+Triazolylpyruvic acid General U.S. Population

Not Applicable Not

Applicable 0.01 5819 18

Not Applicable Not

Applicable All Infants (< 1 year old) 0.0 21523 24

Children 1

- 2 years old 0.0 50635 56

Children 3

- 5 years old 0.0 40816 45

Children 6

- 12 years old 0.0 21357 24

Youth 13

- 19 years old 0.01 3174 15

Adults 20

- 49 years old 0.01 2901 14

Adults 50

- 99 years old 0.0 12185 14

Females 13

- 49 years old 0.0 73349 73 0.01 2373 14 * 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 chronic dietary assessment was conducted for the proposed new 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 for Propiconazole

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

0.1 0.00 8012 8.0 All Infants (< 1 year old) 0.01 1138 1 1

Children 1

- 2 years old 0.02 4493 25

Children 3

- 5 years old 0.019 799 20

Children 6

- 12 years old 0.0 10409 10

Youth 13

- 19 years old 0.00 6435 6. 4

Adults 20

- 49 years old 0.006 739 6. 7

Adults 50

- 99 years old 0.00 6270 6.3

Females 13

- 49 years old 0.00 6176 6.2Page 30 of 58

6 .0 RESIDENTIAL EXPOSURE AND RISK ASSESSMENT

No new residential uses are being proposed at this time; however, there are registered residential uses for propiconazole (ornamentals, lawns/turf, paint) that were assessed previously using the
2012 Residenti al SOPs (J. Miller, D403629, 11/15/12 ). There is potential for both handler (dermal and inhalation) and post

- application (dermal and incidental oral) exposures. Residential risk estimates were not a concern (i.e., MOE < 100), with the lowest MOE of 100 resulting from combined dermal and incidental oral exposure to children. Recommendations for the residential input of the aggregate remain unchanged from the previous memo. They are as follows:

 The recommended residential exposure for use in the adult aggregate assessment reflects dermal post

- application exposure from high contact activities on home lawns.

 The recommended residential exposure for use in the children 1 to <2 years old aggregate
assessment reflect s combined dermal plus incidental oral (hand

- to

- mouth) post

application exposure from high contact activities on home lawns.

A summary of the residential exposure/risk estimates is provided in Table 1 and the recommendations for aggregate assessment are p rovided in Table 2.

Table 6.0.1 . Summary of Residential Exposure/Risk Estimates

Exposure Scenario Route Dose 1 (mg/kg/day) MOE 2

(LOC = 100) Total MOE 3

(LOC = 100)

Residential Handler

Ornamentals Low

- pressure

handwand Dermal 0.000021 1,400,000 1,400,000

Inhalation 5.9 x10

- 9 5.1 x 10 9

Hose

- end sprayer Dermal 0.000019 1,600,000 1,600,000 Inhalation 1.2 x 10

- 9 6.5 x 10 10

Turf Hose

- end sprayer Dermal 0.060 500 500 Inhalation 0.000099 300,000

Paint Brush/roller Dermal 0.016 1,900 1,900 Inhalation 0.000007 4,300,00

Airless sprayer Dermal 0.0033 9,100 9,100 Inhalation 0.00000095 32,000,000

Residential Post

- application

Adults

high contact lawn

activities Dermal 0.143 210 N/A

Children
(1 to <2 years) Dermal 0.283 110 100 Incidental Oral

- HtM 0.0145 2,100

Incidental Oral

- OtM 0.00044 68,000 N/A

Incidental Oral

– Soil Ingestion 0.000061 490,000 N/A

1. Dose (mg/kg/day) calculated based on algorithms provided in 2012 HED Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html ).
2. MOE = POD (30 mg/kg/day) ÷ Dose (mg/kg/day).

3. Total MOE = 1 ÷ (1/dermal MOE) + (1/inhalation MOE) + (1/incidental oral MOE), where applicable.Page 31 of 58

Table 6.0.2 . Recommendations for the Residential Exposures for the Propiconazole Aggregate Assessment.

Lifestage Dose (mg/kg/day) 1 MOE 2

Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Short

- term Residential Post

- application

Adult
(high contact activities/turf) 0.143

N/A N/A 0.143 210

N/A N/A 210

Children (1 to <2 years)
(high contact activities/turf) 0.283 0.0145 0.298 110 2,100 100

1 Residential Post

- application Dose = the highest post

- application dose for each applicable lifestage of all scenarios assessed from Table

1. Total = dermal + incidental oral (where applicable).

2 Residential Post

- application MOE = the MOEs associated with the highest doses identified in Table 1. Total = Dermal MOE +

Incidental Oral MOE (where applicable).

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 exposure to individuals nearby to pesticide applications. The Agency sought expert advice and input on issues related to
volatiliza tion 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 procedu res 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

- appli cation 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, cou ld 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 State Lead Agencies for pesticide regulation and other parties t o 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 chemical basis, the Agency is now requiring interim mitigation meas ures 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.Page 32 of 58

After the policy is in place, the Agency may impose further refinements in spray drift

ma nagement practices to reduce off

- target drift with specific products with significant risks
associated with drift.

Although a quantitative residential post

- application inhalation exposure assessment was not performed as a result of pesticide drift from ne ighboring treated agricultural fields, an inhalation
exposure assessment was previously performed for flaggers. This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultu ral 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.

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 ( DP 426493 , T. Morton,

4 / 9 / 15 ).

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 residentia l exposure plus average exposure levels to food and water (considered to be a background exposure level). The highest exposure
scenarios are from post

- application exposure associated with residential use on turf, which were
used in the short

- term aggrega te risk assessment.

Table 7. 2 .1 aggregates the short

- term risk for toddlers from incidental oral, dermal, and food and water (as a background). The short

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

. This assessment is conside red conservative since the short

- term endpoints are based on a conservative LOAEL that is 3x higher than the NOAEL. Therefore, the true NOAEL is likely higher and would result in MOEs greater than 100. Further, the assessment is
based on a combination of tolerance

- level residues and reliable data on average field

- trial residues and 100 PCT, conservative assumptions in the ground and surface water modeling, andPage 33 of 58

conservative assumptions to assess post

- application exposure of children as well as incidental

o ral exposure of toddlers. Additionally, the assessment could be further refined by using PCT estimates and anticipated residues for all crops. Although dietary (food and water) is not the aggregate exposure driver, incorporating percent crop treated would likely increase the aggregate MOE further above 100. For example, the Agency’s latest PCT figures indicate that the highest average PCT reported for propiconazole residues on crops is 55%, which is much less than the 100 PCT the Agency used for all commod ities in its assessment. Accordingly, even though this
MOE for children 1

- 2 years old is slightly below the target MOE of 100, the difference is small and is more than offset by the conservative exposure assumptions and therefore not of concern.

Table 7. 2 .1

. Short

- term Aggregate Risk Estimates to Propiconazole for 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 4 5

30 1 2 00 2

9 6 Hand to Mouth Activity on Turf 100 1 Oral 0.0145 2100 3

Turf

– High

- Contact Activities Dermal 0. 2827 1 10 4

1 Target MOE= 100, Acute Neurotoxicity 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)].

Table 7.2. 2 aggregates the short

- term risk for adults from residential post

- application, and average food and water (as a background). The aggregate MOE is 200 , which does not fall below HED’s LOC, and therefore is not of concern

.

Table 7.2. 2 : 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 6 7

30 4 5 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 post appl. dermal)].Page 34 of 58

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 exposure to Children 1

- 2 years old. The aggregate MOE is 1 1 0 , which is greater than the target MOE o f 100. Therefore, this
scenario is not of concern.

Table 7.3 . Intermediate

- term Aggregate Risk Estimates to Propiconazole for 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 45 10 4 1 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 reas ons: 1) the dietary inputs used tolerance

- level residues for many food commodities , and crop specific (turf) screening level drinking water modeling data (i.e., surface water modeling); 2) maximum application rates and minimum application
intervals were us ed; and 3) conservative SOPs and high

- end estimates of exposure were employed.

Updated Aggregate Assessment of Free Triazole & its Conjugates

Reference: Common Triazole Metabolites: Updated Aggregate Human Health Risk Assessment to Address The
New Secti on 3 Registrations For Use of Propiconazole on Tea, Dill, Mustard Greens, Radish, and Watercress; Use of Difenoconazole on Globe Artichoke, Ginseng and Greenhouse Grown Cucumbers and Conversion of the
Established Foliar Uses/Tolerances for Stone Fruit and Tree Nut Crop Groups to Fruit, Stone, Group 12

- 12 and the Nut, Tree, Group 14

- 12.; and Use of Flutriafol on Hops. DP 426493 , T. Morton, 4 / 9 / 15

.

8.0 CUMULATIVE RISK

Propiconazole is a member of the triazole

- containing class of pesticides. Although conazoles act similarly in plants (fungi) by inhibiting ergosterol biosynthesis, there is not necessarily a relationship between their pesticidal activity and their mechani sm of toxicity in mammals. Structural similarities do not constitute a common mechanism of toxicity. Evidence is needed to establish that the chemicals operate by the same, or essentially the same, sequence of major biochemical events (EPA, 2002). In co nazoles, however, a variable pattern of toxicologicalPage 35 of 58

responses is found; some are hepatotoxic and hepatocarcinogenic 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 responses, and altered DNA methylation. It is not clearly understood whether these biochemical events are directly connected to their toxicological o utcomes. 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 pr ocedures for cumulating effects from substances found to have a common mechanism of toxicity, see EPA’s website at http://www.epa.gov/pesticides/cumulative

.

Propiconazole is a triazole

- derived pesticide. This class of compounds can form the common
metabo lite 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 resulting 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 te rms of hazards associated with common metabolites (e.g., use of a maximum combination of uncertainty factors) and potential dietary and non

- dietary exposures (i.e., high end estimates of both dietary and non

- dietary exposures). In addition, the Agency

ret ained the additional 1X FQPA safety factor for the protection of infants and children. The assessment includes evaluations of risks for various subgroups, including those comprised of infants and children. The Agency’s complete risk assessment is found i n the propiconazole reregistration docket at http://www.regulations.gov , Docket Identification (ID) Number EPA

HQ

- OPP

- 2005

- 0497.

9 .0 OCCUPATIONAL EXPOSURE / RISK CHARACTERIZATION

It has been determined that these new uses are not uniquely different from previously assessed uses for this active ingredient; therefore, a quantitative assessment is not necessary. A summary of the new uses is provided below, as well as a summary of the previous risk assessments which cover these proposed new uses.

In previou s exposure assessments for propiconazole, exposures to occupational handlers were
assessed for uses on alfalfa, almonds, berries, carrots, celery, cereals, corn, filberts, legume vegetables, mint, onions, peanuts, pineapple, rice, sorghum, soybeans, strawb erries, sugar beets, and tree nuts (J. Miller, D325817, 6/15/2006), as well as sugarcane and cereal grains (J. Miller, D403629, 11/15/2012) . Exposures associated with aerial, groundboom, airblast and chemigation applications were assessed at maximum appli cation rates ranging from 0.112 to 0.225 lb ai/A. Combined (dermal + inhalation) handler margins of exposure (MOEs) for intermediate

- term duration, which are also protective of short

- term exposure, ranged from 250 to 15,000 when wearing the label

- required personal protective equipment (gloves in addition to baseline clothing). These risk estimates were calculated using a dermal and inhalation no

- observed

-Page 36 of 58

adverse

- effect

- level (NOAEL) of 10 mg/kg/day (based on non

- neoplastic liver effects in mice at

a LOAEL of 50 mg/kg/day ), along with a dermal absorption factor of 40% and body weight of 80 kg. The level of concern (LOC) is 100 ( 10x interspecies factor, 10x intraspecies factor)

. These handler MOEs are representative of similar (or higher) application rates and use patterns to the proposed uses, and are not of concern to HED; therefore, the proposed uses are not of

concern to HED.

Post

- application intermediate

- term dermal MOEs ranged from 170 to 6,100,000 on the day of application. As these use patterns (i ncluding corn, with a transfer coefficent of 17,000) are more protective than the proposed uses, and do not fall below the LOC of 100, systemic toxicity from the proposed uses is not of concern. Therefore, the restricted entry interval (REI) specified on the proposed label is based on the acute toxicity of propiconazole. Propiconazole is classified as Toxicity Category III via the dermal route as well as for skin irritation potential and Toxicity Category IV for eye irritation potential. It was not found to be a dermal sensitizer. Under 40 CFR 156.208 (c) (2) (iii), ai’s classified as Acute III or IV for acute dermal, eye irritation and primary skin irritation are assigned a 12

- hour REI. Thus, the [156 subpart K] Worker Protection
Statement interim REI of 12 hours is adequate to protect agricultural workers from post

application exposures to propiconazole.

Note: It is HED policy to use the best available data to assess exposure. Several sources of generic data were used in the assessment as surrog ate data in the absence of chemical

- specific data, including Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1) ; the Agricultural Handler Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force (ORETF) database; the Agric ultural Reentry Task Force (ARTF) database; and the Residential SOPs (turf/lawns ) . Some of these data are proprietary, and subject to the data protection provisions of the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA).

10. REFERENCES

Pr opiconazole : Propiconazole on Dill, C rop subgroup 5B Leafy Brassica greens, R adish , T i P alm , W atercress

, Quinoa, and the Expansion of Fruit, stone

, group 12

- 12, and N ut

, tree

, group 14

- 12. Summary of Analytical Chemistry and Residue Data. T. Morton

, D 4 236 46

, 12 / 1 /201 5

Propiconazole: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments
for the New Use of Propiconazole on Dill, Crop subgroup 5B Leafy Brassica greens, Radish, Ti Palm, Watercress, Quinoa, and the Expansion of Fruit, stone, group 12

- 12, and Nut, tree, group 14

- 12. T. Morton, D 426495,

12 / 1 /2015

Propiconazole

. Occupational and Residential Exposure Assessment for Proposed New Uses on Dill, Brassica Leafy Greens, Radish, Ti Palm, Watercress, Stone Fruit, and Tree Nuts. K

. O’Rourke , D 428502, 8/6/15.

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

.Page 37 of 58

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

yes

no -

- yes

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 38 of 58

A .2 Toxicity Profiles

Table A.2 : Propiconazole Acute Toxicity Profile

GuidelineNo

. 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).

870.3100

3

- month oral

- male
mice 42050502 (1991)

Acceptable/Guideline 0, 20, 500, 850, 1450 ,2500

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

NOAEL is 20 ppm (2.7 mg/kg/day)

870.3100

3

- month oral

- male
mice. 45215801 (1997)

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

LOAEL

870.3150

3

- month dog (dietary) 00058607(1979)

Acceptable/Guideline 0, 50, 250 or 1250 ppm (0, 1.25, 6.25, 31.25 mg/kg/day) LOAEL is 250 ppm (59 mg/kg/day) based on the finding of lymphoid follicles in the mucous mem brane of the pyloric part of
the stomach.
NOAEL is 50 ppm (13mg/kg/day)Page 39 of 58

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

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

Classification /Doses Results

870.3200

21

- Day dermal toxicity

- rabbits 00116591 (1982)

Acceptable/Guideline 0, 3, 30 or 300 mg/kg/day LOAEL : 3 mg/kg/day based on mild dermal irritation (Hyperkeratosis, acanthosis, mild dilation of blood vessels and mononuclear cells and/or heterophils in the proximal dermis). No systemic toxicity was reported.
NOAEL for skin lesions not established

870.3465 28/90

- Day Inhalation waived per HASPOC TXR 0056387

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 mal formations (0.3%) unossified sternebrae, as well as increased incidence of shortened and absent renal papillae.
NOAEL = 30 mg/kg/day

Non

- guideline Developmental Toxicity

- Rat 40425002 (1987)

Acceptable/non

- guideline 0 or 300 mg/kg/day cleft palate: 2/2064 fetuses of dosed animals vs. 0/1222 controls (lab.hist. control incidence: was 0/5431). This confirms findings of cleft palate noted in above study. Severe clinical toxicity in the treated animals (ataxia, coma, lethargy, prost r ation, labored respi ration 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
dos ing period
NOAEL = 100 mg/kg/day Developmental Toxicity
LOAEL = 400 mg/kg/day based on increased incidence of fetuses
/litters with 13 th rib and increased abortions.
NOAEL = 250 mg/kg/day

870.3800

2

- Generation reproduction

- Rat 00151514 (1985)

Acceptable/guideline 0, 100. 500 or 2500 ppm Parental Toxicity LOAEL = 500 ppm (42 mg/kg/day) based on increased incidence of hepatic clear cell change
NOAEL = 8 mg/kg/day Reproductive Toxicity
LOAEL =>2500 ppm (>263 mg/kg/day, HDT) Offspring Toxicity

LOAEL = 2500 ppm (192

- 263 mg/kg/day based on decreased offspring survival and body weights and an increased incidence of hepatic cellular swelling
NOAEL = 500 ppm (43

- 52 mg/kg/day)Page 40 of 58

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

870.4100

24

- Month
Chroni c/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 ga in in both males and females.

NOAEL = 500 ppm (18.1 mg/kg/day). The test material was not carcinogenic at the doses tested.

870.4200

24

- Month Carcinogenicity in
Mice 00129570 (1982 )

Acceptable/guideline 0, 100, 500 or 2500 ppm (M: 10.0, 49.4, and 344 .3 F: 10.8, 55.6 and 340.3 mg/kg/day LOAEL = 500 ppm (49.5 mg/kg/day) based on non

- neoplastic liver effects (increased liver weight in males and increase in liver lesions (masses/raised areas/ swellings/nodular areas mainly)). The NOAEL was 100 ppm (10 mg/kg/day). Liver tumors at 2500 ppm in male mice.

870.4200

18

- month 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.

Tre atment 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. Adequa te dosing based on body weight gain and hepatotoxic effects seen at 500 and 850 ppm. Subsequently, the Registrant submitted additional control data on five groups of CD

- 1 male mice generated within the approximate time frame of the original study and in t he 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.

870.6 200 Acute neurotoxicity
in rats 46604601 (2005)

Acceptable/guideline 0, 30, 100 or 300 mg/kg by

gavage LOAEL = 100 mg/kg based on clinical signs of toxicity (piloerection, diarrhea, tiptoe gait).
NOAEL = 30 mg/kg.
LOAEL for neurobehavioral toxicity = 300 mg/kg based on reduced motor activity.
NOAEL for neurobehavioral toxicity = 100 mg/kgPage 41 of 58

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

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

Classification /Doses Results

870.6200b
90

- Day Neuro toxicity Screening Battery (rat) 49300503 (2014)

Acceptable/guideline ♂ 0, 200, 600, or 3500 ppm 0,13, 38, an d 222 mg/kg bw/day, ♀ 0, 200, 600, or 1500 ppm 0, 15, 45, and 111 mg/kg bw/day, LOAEL in males = 3500 (220 mg/kg/day) based on significant reductions in body weight gain and food consumption
NOAEL in males = 600 ppm (38 mg/kg/day).
NOAEL in females = 150 0 ppm (111/kg/day), the highest dose
tested

. LOAEL in females was not established.

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 marrow cells at all
levels tested.

870

- 5 550
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 evidence of dominant lethal effects was observed in the progeny of mice treated with propi conazole.Page 42 of 58

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) 42403901 (1983)

Acceptable/guideline male rats: single oral 31.4 mg/kg

- 14 C at the
triazole

- [3,5] position Rapidly metabolized: 96% excreted in urine and feces (5:4 ratio) after 3 days. Extensively metabolized by hydroxylation, oxidation and conjugation.

870.7485
Metabolism and pharmacokinetics (Rat) 41326701 (1989)

Acceptable/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 168 hours mostly within the 48 hrs. Females eliminated more in the urine
than in t he feces and vice versa for males in the orally dosed groups. No significant differences were seen in the excretion pattern or were seen between the low and high dose groups or the repeated dosing groups. Extensively metabolized (oxidative): 24 and 47

met abolites 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)

00074507 (1981) Acceptable/guideline
triazole

- [3,5

- 14 C] labeled single oral dose of 31.4 mg/kg or phenyl

- [U

14 C] single oral dose of 32.5 mg/kg to male rats. Study focused on urinary and fecal metabolites. Similar metabolic profiles for the two labels suggesting that the bridge between the phenyl ring and the triazole ring remained int act. 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 par ent 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
leve ls. 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 radioactivity 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
metaboli tes 15

- 30. The major metabolic pathway in mice proceeds via elimination of the dioxolane ring. In males this represents 30% of the AD whereas in the females it represents 15% of the AD. Mice cleaved the dioxolane ring to a greater extent (70% & and
40% for males and females, respectively) than do male rats (30%).

870.7600 Dermal penetration (Rat) 42415701 (1986)

Acceptable/guideline Propiconazole 14 C at the
triazole

- [3,5] position 0.01, 0.1, 1.0 mg/cm 2 The average dermal absorption of propiconazole ove r 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).

.Page 43 of 58

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

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

Classification /Doses Results

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.

Non

- guideline Sp ecial study
Mechanistic studies: Hepatic biochemical
parameters

- Mouse 45215803 (1998)

Male CD

- 1 mice, 6/dose propiconazole at 0, 850 or 2500 ppm (0, 149, 578 mg/kg/day) for 14 days. Phenobarbital 850 ppm (145 mg/kg/day) to one

group Total cytochrome P450 activity 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 44 of 58

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 necrosis 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 c ontrols 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 ind uced 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 hepatocel lular 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 45 of 58

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 inters pecies extrapolation and 10X for intraspecies variation.

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

aRfD ( General Population ) = 30 mg/kg (NOAEL)

100 ( UF ) = 0. 3 mg/kg

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 R fD = 30 mg/kg (NOAEL ) = 0. 30 mg/kg/ (Females 13

- 49) 1 00(UF)Page 46 of 58

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.

cRfD ( General Population ) = 10 mg/kg/day (NOAEL)

100 ( UF ) = 0.1 mg/kg/day

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.

Comments about Study/Endpoint : The selected toxicity endpoint was the most se nsitive to assess this exposure scenario. The NOAELs in the developmental rat (90 mg/kg/day) and rabbit ( 10 0 mg/kg/day) studies were much higher and would not be protective of the toxicity seen in the ACN study

.

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.Page 47 of 58

Uncertainty Factor (UF ): 100

– 10X for interspecies extrapolation and 10X for intraspecies variation.

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

10X for intraspecies variation. FQPA 1X

Comments about Study/Endpoint : Since an oral NOAEL was selected for dermal risk assessment, a dermal absorption factor of 40% based on a dermal absorption study in rats
should be used. Although a dermal toxicity st udy is available with no systemic toxicity at 300 mg/kg/day (propiconazole caused dermal irritation at 3 mg/kg/day and above dose), a POD from an oral study was selected because clinical toxicity, the primary effect of
concern for short

- term exposure is no t specifically evaluated in the available dermal toxicity study. The selected endpoint is protective of potential clinical effects from dermal exposure.

Dermal Exposure (Intermediate

- Term)

Selected Study: 24 Month carcinogenicity Study in Mice (MRIDs 0 0129570 & 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.Page 48 of 58

Uncertainty Factor (UF ): /Level of Concern: 100

– 10X for interspecies extrapolation and

10X for intraspecies variation. FQPA 1X

Comments about Study/Endpoint : Since an oral NOAEL was selected for dermal risk assessment, a dermal absorption factor of 40% based on a dermal absorption study in rats
should b e 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 assumed 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 49 of 58

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 applie d 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 opthalmol ogy, 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 considered 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 persisted 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 no compou nd 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 and mononu clear 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 m g/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 administe red 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 initially rec eived 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 gestation 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 control is asPage 50 of 58

f ollows: lethargy (9/23 vs. 0/24 in controls), salivation (4/23 vs. 0/24 in controls) and ataxia (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 dos es 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 and in the 90 mg/kg/day group on days 8

- 9 and 10

- 11. Maternal body weights were not affected by the treatments. Maternal body weight gains were significantly decreased (p<0.05) in the 90 mg/kg/day group (44% of 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 ma ternal 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 significant but pa rt 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 the contro ls), 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 statistically sign ificant) 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 p a late 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 was proba bly 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
incidence 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

- guid eline 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% Tween 80) at dose levels of 0 or 300 mg/kg/day from days 6 through 15 of gestation. The control group comprised 178 sperm positive animals and the compound treated group comprised 189 sperm positive animals. The study was intended to confirm the finding of cleft p alate 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 periodPage 51 of 58

beginning on gestation day 6 and included a statistically significant i ncrease in the incidence of ataxia (42% vs. 0 in controls), coma (9% vs. 0 in controls), lethargy (44% vs. 0 in controls), prostration (3% vs. 0 in controls), audible respiration (4% vs. 0 in controls), labored respiration (11% vs. 0 in controls), and sali vation (20% vs. 0 in controls) in addition to a biologically significant incidence of ptosis (0.5% vs. 0 in controls), lacrimation (2% vs. 0 in controls), pale color (2% vs. 0 in controls) and death (1% vs. 0 in controls). Mean food consumption was signif icantly 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 a nd 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 implantation sit es, 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
examined for e xternal 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 cleft palat e 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 Toxicity

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 containing 0.5% Tween 80) at dose levels of 0, 100, 250 or 400 mg/kg/day from days 7 through 19 of gestation. One animal
from each of the mid

- dose groups was found dead. In high

- dose animals, 5/19 does were sacrificed early due to abortion or early delivery (stati stically 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 (decreased/no/so ft; 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 controls

i n 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 250 and 4 00 mg/kg, respectively, compared to a weight gain of 0.018 kg in controls. The weight gains during GD

10

- 20 were 67

- 77% and 11

- 43% of controls at 250 and 400 mg/kg/day, respectively. An
increased incidence of the formation of 13 th rib was observed at 400 mg/kg/day. The incidence of this finding on fetuses/litter basis was 2.7, 3.9, 4.1 and 5.3 at 0, 100, 250 and 400 mg/kg/day, respectively. The incidence of fetuses at 400 mg/kg/day with this finding was statistically significant. Therefore, this 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 400Page 52 of 58

mg/kg/day there was also an increased incidence of abortions. The matern al toxicity LOAEL 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 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 o f 0.1, 1.0 or 10 mg/rat (0.01, 0.1 or 1 mg/cm 2

, respectively) to a 10 cm 2 shaven dorso

- lumbar area. The radioactive test compound was added to the 3.6EC formulated product (45.8% active ingredient and 54.2% inert substances) and applied

as an aqueous suspe nsion. One group of 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 t he exposure periods 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 appeared 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 μ g/cm 2 (57.13, 27.14 and 30.10% of total dose were absorbed at the low, mid and high dose levels, respectively). During the 72

- hour 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 deplet ion 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 levels) 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 ReproductionPage 53 of 58

Rat Reproduction Study

In an acceptable/guideline 2

- generation reproduction study (MRID 00151514), CGA 64250 technical (89.7% purity propiconazole, FL

- 830377) was administered to 15 male and 30 female Charles river CD rats at dose levels of 0, 100, 500 or 2500 ppm (mean doses of 8, 42 and 192 mg/kg/day f

or 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 fo od intake (83

- 88% of controls). In the F 0 and F 1 generation male 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 d uring the entire duration of the study (7 months). Food consumption was reduced significantly in high
dose F 0 males at week 1 (65% of the control, p<0.01) and week 7 (86% of the control, p<0.01) and in high dose F 1 males and females at week 2, 6 and 10 (8 4

- 88% of controls). Histological examinations revealed that hepatic “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 find ing was significant for both sexes in the mid

- and high

- dose groups. 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 clear

- 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 Toxicity : 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 litter s, however, the number of pups delivered, delivered viable and surviving 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 sta tistically significant). The F 2b litters of these dams had significantly 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). Reductions 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 fin dings were noted in pups. Histopathological evaluation of selected organs from F 1b and F 2b progeny revealed significantly (p<0.01) increased incidences of hepatic “cellular swelling” in high

- dose males and females. This was considered to be a compound rel ated 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 swellin g) at 2500 ppm.Page 54 of 58

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 effects 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 morphological, 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 and 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 skull, caudal vertebrae and digits, extra rib (14 th rib) and missing sternebrae. Malformations of the lung and kidneys were reported.
No maternal toxic ity was reported at either dose. The LOAEL for developmental toxicity in this study is 76 mg/kg/day (the lowest dose tested). A NOAEL is not established.

870.6200b Subchronic Neurotoxicity

In a subchronic neurotoxicity study (MRID 49300503 ), Propiconazole (95.2% a.i

. ) was administered to groups of ~6

- week

- old Crl

- CD(SD) rats (12/sex/dose) continuously in the diet for 13 weeks at concentrations of 0, 200, 600, or 1500 ppm (females) or 3500 ppm (males) (equivalent to 0,13, 38, and 222 mg/kg bw/d ay, respectively, in males and 0, 15, 45, and 111 mg/kg bw/day, respectively, in females). Dietary levels were chosen based on the findings of a

4

- week dietary range

- finding neurotoxicity study ( MRID 49300502). Neurobehavioral assessment (functional obser vational battery (FOB) and motor activity testing) was performed in

12 animals/sex/group during pretest (Week

- 1) and Weeks 1, 3, 7, and 12. Cholinesterase activity was not determined. At study termination, 5 rats/sex/group were euthanized and perfused i n situ for neuropathological examination. Of the perfused animals, 5 rats/sex each from the control and high

- dose groups were subjected to histopathological evaluation of brain and peripheral nervous system tissues.

Males at 3500 ppm had a statistically significant decrease in mean body weight gain over Days

1

- 7 (83% of controls) accompanied by a reduction in food consumption (88% of controls). Although not statistically significant, overall body weight gain in high

- dose males was reduced
to 89% of cont rols, indicating that the male rats fed the high dose were not able to completely recover from the reduction in body weight that occurred during the first week of treatment. No significant changes in body weight, body weight gain, or food consumption were noted in
females.

Dietary treatment with up 3500 ppm in male rats and 1500 ppm in female rats did not result in any signs of neurotoxicity as indicated by clinical observations, mortality, FOB observations,Page 55 of 58

motor activity counts, or neurohistopathologic al evaluation, and no treatment

- related effects were noted during ophthalmoscopic examination, gross pathology or in brain weight and brain dimension measurements. Positive control data were provided.

Based on the effects seen in this study, the LOAEL f or Sprague

- Dawley male rats was 3500 ppm (equivalent to 222 mg/kg bw/day) based on significant reductions in body weight gain and food consumption, with a NOAEL of 600 ppm (equivalent to 38 mg/kg bw/day). The NOAEL in female Sprague

- Dawley rats was 1 500 p pm (equivalent to 111 mg/kg bw/day)
and a LOAEL was not established.

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 00133343) 6. Dominant Lethal Assay in Mice (MRID 00058602)

870. 7 80 0 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, or halogenated aromatic hydrocarbons) that would be expected to be immuno t oxic. There was no evidence of immunotoxicity with six other structurally

- related conazole fungicides, namely, flutriafol, metconazole, tebuconazole, tetraconazole

, tr iadimefon, triflumizole, and triticonazole. In the Immunotoxicity study for triflumizole

, the effects on the immune system occurred only at the highest dose tested. Immunotoxicity was demonstrated with difenoconazole, however it was observed in the presenc e 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 factor s 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 weight ofPage 56 of 58

evidence approach, the HASPOC concluded that immunotoxicity studies are not requi red 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 already used. Therefore the waiver request is granted (TXR 0056761)

.Page 57 of 58

APPENDIX B. Chemical Names And Structures Of MetabolitesPage 58 of 58

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