UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON

, D.C. 20460

OF FI CE O F C HEMI CAL SA FETY A ND POLLUTI O N PRE V ENTI O N



### MEMO RA NDUM

Jul y l

, 2015

SUB J ECT : Difenoconazole: Human H ea lth Ri sk Assess m e nt for Proposed New Foliar Uses

on Globe Artichoke

, Ginseng and Greenhouse Grown Cucumbers and Co n v ersion

of th e Es t ab li s h e d Foliar Uses/To l e rance s for Stone Fruit Group 1 2 and Tree N ut
Cro p Group 14 to Stone Fruit Gro up 1 2 -1 2 and Tree N ut Group 14-1 2.

P C Co d e: 1 28847

Deci s ion No.: 491006 OP Bar codes: 0 426020

R eg i st r ation Nos

. : I 00-1262, I 00

- 1313, I 00-

1 317

Petitio n No.: 4E8274 Re g ul atory Ac ti on: Section 3 R egis tration

Ri s k Asse s sme nt T y p e: Si n gle C h e mic a l Aggregare Case No.: 70 1 4

TXR No.: NA CAS No.: 11 9446 -68- 3

MRID No.: NA 

# n
40

### F~**:** § 180

. 475



### F ROM: I van N i eves , Ri s k Assessor { 

# _/J\

--- --::: :--,,--

Thur s ton Morton

, Chemist

,

# Se**ni S~** **Rlist \**  r / -.....-.:.---.

Bonnie Cropp-Kohlligian, Environmenta l Sc if nti s t · Abda ll a h

, Khasawinah

, PhD. Toxicologist

## ,.,**~** 

# L°**0~** Ri sk Assessment Bran c h 4 · Health Effects Di v i s ion ( 7 509 P )



### THROUGH: C h a rle s Smith

, Ac tin g

# Chief**S:::v** Ri sk Assess m e nt Br a nch 4

# ~ Health Effects Divi s ion ( 7 5 09P)



### TO : L au ra No ll e n and Barbara Madden

, RM0 5

Minor Use a nd Emerg e nc y R es p o n se Branch

Re g i st r a ti on Di v i s i o n (7505 P )

This document provides the H ea lth Effects Di vis i on ' s ( HED ' s) ri s k assessment of propo se d n ew fo liar u ses o n g l o b e a rtichoke , g ins e n g and g r ee nhou se grow n c u c umb e rs and conversion of the

establ i s h ed foliar u ses / tolerance s fo r s t o n e fruit group 1 2 and tre e nut crop group 14 to sto ne fruit

g roup 1 2

- l 2 a nd tre e nut g r o up 14-1 2

.

Pa g e I of 47

### Tab l e of Conte n ts

1.0 EXECUT I VE SUMMARY

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

2.0 HED RECOMMENDAT I ONS

............ . ....... . ....... . ........... . .......... . .. .. .. .. .. . .. .. . . ... . ... . .. ... . .. .. .. . 7

2.1 Data Defic i enc i es

. . .. .. . ... . ... . .. .. ...... .. ....... .. .. .. .. ... .. .. . ... .. .. .. . ... . .. .. ... . ...... .. .. . ... . .. . ... . ... . .. .. ........ 7

2.2 Tolerance Conside r at i ons

.. . ... .. . .. ... .. . ... .. ... .. . ... .. ... . ... . ........... . .......... . .. .. .. . .............. . . .. .. . . . . 7

2.2.1 E nf orce m e n t A n a l ytica l Met h od

. .... . ... .. ... . .. . .... . ... . .. .. .. . .... . . . ... .. . . ... .. . . . . ... . ................ 7

2.2

. 2 Recommended To l era n ce s

. ... .. ... . .. ... ..... ... ... . . .... .. . .. ... . .. .. . . . .. .. .................................... 7

2

. 2

. 3 Revis i o n s to Pet i t i one d -Fo r To l era n ces

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

2

. 2.4 I nter n at i o n a l Har m onizatio n .

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

2.3 Labe l Recomme nd at i o n s

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

2.3. l Recom m e n dat io ns from Resid u e R eviews

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

3.0 INGREDIENT PR O F I LE

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

3.1 C h emica l Ide n tity

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

3.2 P h ys i cal/C h e mi ca l C h arac t e ri stics

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

3.3 Pesticide Use Patter n

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

3.4 A n tic ip ated Ex p os u re P at hl vays

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

3.5 Co n s i de r atio n s of Environmen t a l J u st i ce

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

4.0 HAZARD CHARACTE RI ZAT I ON AND DOSE-RES P ONSE ASSESSMENT

.. . .. . .. 1 4

4.1 Tox i co l ogy St u dies Ava il ab l e for A n a l ysis

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

4

. 2 Absor p tio n , D i s t r i b u tio n , Metabo li s m and Exc r e ti o n (ADME)

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

4.3 Tox i co l og i ca l E f fects

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

4.4 Safety Factor for I n fants a nd C h i l dre n (FQPA Safety Facto r )

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

4.4.1 Com pl e t e n ess of t h e Tox i co l ogy Database

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

4.4.2 Ev i dence of Ne ur otoxicity

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

4.4.3 Ev id ence of Se n sitiv i ty/Susceptib ili ty in the Deve l oping o r Yo u ng A n imal.

..... 16

4.4.4 Resi du a l U n cer t a i nty in th e Ex p os u re D ata b ase

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

4

. 5 Tox i city Endpo in t a n d Point of De p art u re Se l ectio n s

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

4.5.l Dose-Response Assess m ent

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

4.5

. 2 Recommendat i ons for Co m b i ni n g Ex p osure Ro ut es for Risk Assessme n t

....... 18

4

. 5.3 Ca n cer C l assificat i on a nd Risk Assessme n t Recomme nd at i o n s

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

4.5.4 S u mmary of Po i nts of D e p artu r e a n d Toxicity End p o int s Used in R i sk

As ses sment

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

5.0 DIET ARY EXPOSURE AND R I SK ASSESSMENT

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

5.J 

### Metabo li te / Degra d ate Res i d u e Pr ofile

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

P age 2 o f 47Page 3 of 47



### 5.1.1 Summary of Plant and Animal Metabolism Studies

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

5.1.2 Summary of Environmental Degradation

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

5.1.3 Comparison of Metabolic Pathways

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

5.1.4 Residues of Concern Summary and Rationale

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

5.2 Food Residue Profile

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

5.2.1 Residues in Crops

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

5.3 Water Residue Profile

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

5.3.1 Estimated Drinking Water Concentrations

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

5.4 Dietary Risk Assessment

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

5.4.1 Description of Residue Data Used in Dietary Assessment

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

5.4.2 Percent Crop Treated Used in Dietary Assessment

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

5.4.3 Acute Dietary Risk Assessment

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

5.4.4 Chronic Dietary and Drinking Water Analysis

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

6.0 RESIDENTIAL (NON

- OCCUPATIONAL) EXPOSURE/RISK
CHARACTERIZATION

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

6.1 Residential Bystander Postapplicat ion Inhalation Exposure

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

6.2 Spray Drift

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

7.0 AGGREGATE EXPOSURE/RISK CHARACTERIZATION

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

7.1 Acute & Chronic Aggregate Risk

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

7.2 Short

- Term Aggregate Risk

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

7.3 Intermediate

- Term Aggregate Risk

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

8.0 Cumulative Exposure/Risk Characterization

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

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION

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

9.1 Exposure Scenarios

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

9.2 Handler Exposure

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

9.2.1 H andler Exposure Scenarios

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

9.3 Post

- Application Exposure

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

9.3.1 Restricted Entry Interval

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

10. REFERENCES

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

APPENDIX A. TO XICOLOGY DATA SUMMARY

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

APPENDIX B. Chemical Names And Structures Of Metabolites

................................ ......... 45

APPENDIX C. Physical/Chemical Properties

................................ ................................ .......... 46

APPENDIX D. Studies Reviewed for Ethical Conduct

................................ .......................... 46Page 4 of 47



### 1.0 EXECUTIVE SUMMARY

The Interregional Research Project #4 ( IR

- 4 ) is proposing new foliar uses of difenoconazole on globe artichoke, ginseng and greenhouse grown cucumbers and conversion of registered uses of difenoconazole on stone fruit group 12 and tree nut group 14 to stone fruit group 12

- 12 and tree nut group, respectively.

This document addresse s the exposures and risks associated with exposures from currently registered uses and the proposed amended use of difenoconazole. 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

Difenoconazole is a broad spectrum fungicide belonging to the triazole group of fungicides. It is currently registered in the U.S. for use as a seed treatment on a number of cereal grain crops, cotton, canola, and potato seed pieces and for post

- harvest u se on members of tuberous and corm vegetables subgroup 1C and pome fruit group 11

- 10 (pending but imminent) and for multiple
late

- season foliar applications on numerous crops including stone fruit group 12 and tree nut group 14.

Difenoconazole acts by b locking demethylation during sterol biosynthesis which, in turn, disrupts membrane synthesis. Difenoconazole is available as emulsifiable concentrate, soluble concentrate, emulsion [oil] in water, flowable suspension, and ready

- to

- use formulations. As a seed treatment, it is applied with commercial grade seed treatment equipment. As a foliar treatment, it is applied to field and vegetable crops, landscape ornamentals and golf course turf by commercial applicators using aerial and ground application metho ds and equipment. It is applied to ornamentals by residential applicators using hand held sprayers.

Proposed New Uses

Under Section B of the petition 4E8274, IR

- 4 has submitted directions for use on artichoke (intended to be globe artichoke consistent with the submitted field trial data although not specified in the use directions), ginseng, stone fruit group 12

- 12 and tree nut group 14

- 12 for the 2.08 lb ai/gal EC formulation of difenoconazole (InspireTM Fungicide; EPA Reg. No. 100

- 1262)
and a 1.05 lb ai/gal multiple active ingredient (MAI) suspension concentrate (SC) formulation with azoxystrobin (Quadris TopTM Fungicide; EPA Reg. No. 100

- 1313). In addition, IR

- 4 has submitted directions for use on artichoke (intended to be globe artichoke consistent w ith the submitted field trial data although not specified in the use directions), stone fruit 12

- 12 and cucumber (greenhouse) for a 0.73 lb ai/gal MAI emulsion oil in water (EW) formulation with cyprodinil (Inspire Super TM 

### Fungicide; EPA Reg. No. 100

- 1317) . In addition, IR

- 4 submitted draft supplemental labels, which are substantially similar to Section B of the petition.Page 5 of 47



### This review addresses difenoconazole only. Other active ingredients and uses listed on the
new end

- use product label s will not be discussed herein. This assessment does address the updated aggregate assessment for free t riazole and its conjugates.

Toxicological Effects

T he toxicology database for difenoconazole is complete for evaluating and characterizing toxicity a nd selecting endpoints for purposes of this risk assessment. Subchronic and chronic toxicity studies with difenoconazole in mice and rats showed decreased body weights and effects
on the liver (e.g. hepatocellular hypertrophy, liver necrosis, fatty changes in the liver) . Acute and subchronic neurotoxicity studies showed evidence of neurotoxic effects. However, the observed
effects were transient and the dose

- response was well characterized with identified dose levels at
which no observed adverse effects wer e seen. The available developmental and reproduction toxicity studies indicated no increased susceptibility of rats or rabbits from in utero or postnatal exposure to difenoconazole. In an immunotoxicity study in mice

, difenoconazole produced
immunotoxic i ty at doses that caused systemic toxicity

. No evidence of carcinogenicity was seen in the chronic/cancer rat study. Evidence for carcinogenicity was seen in mice as induction of liver tumors at doses which were considered to be excessively high for carcinogenicity testing.
Difenoconazole has been classified as “Suggestive Evidence of Carcinogenic Potential” with risk quantified using a non

- linear (Margin of Exposure) approach ( TXR 0054532) . The cancer classification is based on excessive toxicity observed at the two highest doses, the absence of

t umors at the lower doses and the absence of genotoxic effects. The FQPA Safety Factor is reduced to 1X. Difenoconazole exhibits low acute toxicity by the oral, dermal and inhalation routes of exposure. It is not an eye or skin irritant and is not a sensit izer.

Dose Response Assessment

Toxicological points of departure (PODs) were selected for dietary and drinking water exposures for the assessment of proposed new uses of difenoconazole. Acute and chronic PODs were
selected for assessment of food and water exposures. An acute POD for all populations was selected from an acute neurotoxicity study in rats based on reduced grip strength. A chronic POD was selected from a chronic/carcinogenicity study in rats based on body weight effects.
Short and inte rmediate

- term incidental oral, dermal and inhalation PODs were selected from an oral rat reproduction study based on decreased body weight effects in pups and parental animals. A dermal absorption factor is applied when dermal exposure endpoints are selec ted from oral toxicity studies. A dermal absorption factor of 6%, based on triple pack data, was used for the dermal exposure assessment. Inhalation toxicity is assumed to be equivalent to oral toxicity. An uncertainty factor of 100X was applied endpoin ts selected for all exposures routes (10X for interspecies extrapolation, 10X for intraspecies variation , 1X FQPA SF ).

Exposure/Risk Assessment and Risk Characterization

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

### percentile,
the acute dietary exposure to the general U.S. population is 1 5 % of the aPAD; the highestPage 6 of 47



### exposed subgroup (All Infants < 1 yr) is 4 9 % of the aPAD. The chronic dietary exposure to the general U.S. population is 26% of the cPAD, and the most highly exposed subgroup (Children 1

- 2 yrs old) is 8 9 % of the cPAD. The previo us triazole dietary exposure assessment was updated (T. Morton, D426492, 4 / 9 / 15 )

. A new residential assessment was not performed since there are no proposed new residential uses at this time. The currently registered outdoor and indoor residential exposu re scenarios have been previously reassessed for all difenoconazole uses based

on the Revised Residential SOPs (2012) ; n o risk estimates of concern were identified (D421188, I. Nieves, 02/24/2015)

. Previously assessed residential exposure risk estimates were combined
with current dietary exposure estimates for the aggregate risk assessment. Aggregate risk
estimates were not of concern

. Risk estimates for occupational handler and post

- application

ex posure scenarios for all proposed uses have also been previously assessed at a similar and/or higher rate (D421188, I. Nieves, 02/24/2015)

. None of the existing or proposed new uses were
of concern at maximum use rates with label required PPE (i.e., long shirt, long pants, shoes, socks and gloves).

Aggregate Assessment of Free Triazole & 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 studies, listed in Appendix 2.0, have been determined to require a review of their ethical conduct. Some of these studies are also subject to review by the Human Studies Review Board. All of the studies used have received the appropriate review.

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were 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.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

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

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

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and fo r 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 tha t consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.Page 7 of 47



### 2.0 HED RECOMMENDATIONS

2.1 Data Deficiencies

Deficiencies are stated below. The specific tolerance recommendations are discussed in Section
2.2

. 3 Recommended Tolerances

.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate enforcement method, GC/NPD method AG

- 575B, is available for the determ ination of residues of difenoconazole per se in/on plant commodities. An adequate enforcement method,
GC/MSD method AG

- 676A, is also available for the determination of residues of difenoconazole per se in/on canola and barley commodities. A confirmatory method, GC/MSD method AG

- 676, is also available. The LOQs are 0.01

- 0.05 ppm.

2.2.2 Recommended Tolerances

HED has examined the residue chemistry database for difenoconazole. With regards to difenoconazole, pending submission of a revised Section B (see requirements under 860.1200 Directions for Use) and Section F (see requirements under 860.1550 Proposed Tolerances) of petition 4E8274, there are no residue chemistry issues that would preclude granting the proposed
foliar uses on globe artichoke, ginseng and greenhouse grown cucumbers or the expansion of existing foliar uses on stone fruit group 12 and tree nut group 14 to new crop groups fruit, stone, group 12

- 12 and nut, tree, group 14

- 12 or e s tablishment of tolerances for resid ues of difenoconazole in/on the following commodities:

Artichoke, globe

................................ ................................ ....... 1.5 ppm Ginseng

................................ ................................ ..................... 1.0 ppm Fruit, stone, group 12

- 12

................................ .......................... 2.5 ppm Nut, tree, group 14

- 12

................................ ............................... 0.03 ppm

Concomitantly, the tolerances for residues of difenoconazole in/on the following commodities
should be removed:

Fruit, stone, group 12

................................ ................................ 2.5 ppm Nut, tree, group 14

................................ ................................ .... 0.03 ppm
Pistachio

................................ ................................ .................... 0.03 ppm

Tolerances for plant commodities are established under §180.475(a)(1), and are expressed in
terms of difenoconazole per se . The tolerance expression proposed by IR

- 4 is in terms of
difenoconazole per se

. The tolerances proposed by IR

- 4 are listed in Table 2.2.2 along with the tolerance levels recommended by HED and correct commodity definitions.Page 8 of 47

Table 2.2.2. Tolerance Sum mary for Difenoconazole.
Commodity Proposed
Tolerance (ppm) Recommended

Tolerance (ppm) Correct Commodity Definition;

Comments

Artichoke, globe 1.5 1.5 Artichoke, globe
Ginseng 0.50 1.0 Ginseng
Fruit, stone, group 12

- 12 2.5 2.5 Fruit, stone, group 12

- 12
Nut, tree, group 14

- 12 0.03 0.03 Nut, tree, group 14

- 12
Fruit, stone, group 12 Remove Remove Currently established at 2.5 ppm
Nut, tree, group 14 Remove Remove Currently established at 0.03 ppm

Pistachio Remove Remove Currently established at 0.03 ppm



### 2.2. 3 Revisions to Petitioned

- For Tolerances

The recommended tolerance for residues of difenoconazole in/on ginseng (1.0 ppm) is not the same as the petitioned

- for tolerance (0.5 ppm) due to the finding that residues of difenoconazole appeared to increase significantly with a PHI longer than the proposed 0

- day PHI. Average

per

- trial residues increased by a factor of as much as 2.3x between the 0

- and 21

- day PHIs and based on this finding, ChemSAC (9/27/14) determined that average per

- trial res idues of difenoconazole for trials reflecting a 0

- day PHI should be adjusted by a factor of 2.3x to account for the maximum demonstrated increase in difenoconazole residues resulting from PHIs longer than the proposed 0

- day PHI and these adjusted residues have been used in the OECD tolerance calculation procedures.

2.2.4 International Harmonization

Codex maximum residue limits (MRLs) for residues of difenoconazole have been established at 0.08 ppm for ginseng; at 0.2 ppm for ginseng, dried including red ginseng; at 0.6 ppm for ginseng extracts; at 0.2 ppm for cherries and plums (including prunes); at 0.5 ppm for nectarines and peaches; and at 0.03 ppm for tree nuts. Canadian MRLs have been established for difenoconazole for individually listed members of stone fruit group 12

- 12 and tree nut group 14

- 12 at 2.5 ppm and 0.03 ppm, respectively. Mexico adopts U.S. tolerances and/or Codex MRLs for its export purposes. Based on the submitted/available magnitude of the residue data,
harmonization with establish ed Codex MRLs is not possible for ginseng, cherries, plums (including prunes), nectarines, peaches, because the Codex MRLs are too low. The U.S. tolerances for stone fruit (2.5 ppm) and tree nuts (0.03 ppm) are harmonized with the established
Canadian MRL s for individually listed members of these groups and with the established Codex MRL for tree nuts. There are no established Codex, Canadian or Mexican MRLs for residues of difenoconazole for globe artichoke so harmonization for this commodity is not poss ible.

2.3 Label Recommendations

2.3.1 Recommendations from Residue ReviewsPage 9 of 47



### Section B of petition 4E8274 pertaining to uses on artichoke should be revised to specify globe artichoke only. [Note: IR

- 4 submitted draft supplemental labels which are sub stantially similar to Section B of the petition and should be amended as well.]

3 .0 INGREDIENT PROFILE

3.1 Chemical Identity

The chemical structure and nomenclature of difenoconazole and its regulated livestock
metabolite CGA

- 205375, is presented in Tables 3.1.1.

Table 1. Difenoconazole Nomenclature

. Chemical structure of parent

mol. wt. 406.3

Common name Difenoconazole
Company experimental name CGA

- 169374

IUPAC name 1

- [2

- [2

- chloro

- 4

- (4

- chloro

- phenoxy)

- phenyl]

- 4

- methyl

- [1,3]dioxolan

- 2

- ylmethyl]

- 1 H

- [1,2,4]triazole

CAS name 1

- [[2

- [2

- chloro

- 4

- (4

- chlorophenoxy)phenyl]

- 4

- methyl

- 1,3

- dioxolan

- 2

- yl]methyl]

- 1 H

- 1,2,4

- triazole
CAS registry number 119446

- 68

- 3

Chemical structur e of
CGA

- 205375 livestock
metabolite

mol. wt. 349.2

Chemical structure of 1,2,4

- Triazole (1,2,4

- T)

Chemical structure of Triazolyl alanine (TA)

Chemical structure of Triazolyl a cetic acid (TAA)Page 10 of 47



### 3.2 Physical/Chemical Characteristics

The physicochemical properties of difenoconazole are reported in Appendix C.

3.3 Pesticide Use Pattern

Under Section B of the petition 4E8274, IR

- 4 has submitted directions for use on artichoke (intended to be globe artichoke consistent with the submit ted field trial data although not specified in the use directions), ginseng, stone fruit group 12

- 12 and tree nut group 14

- 12 for the 2.08 lb ai/gal EC formulation of difenoconazole (InspireTM Fungicide; EPA Reg. No. 100

- 1262) and a 1.05 lb ai/gal multiple active ingredient (MAI) suspension concentrate (SC) formulation with azoxystrobin (Quadris TopTM Fungicide; EPA Reg. No. 100

- 1313). In addition, IR

- 4 has submitted directions for use on artichoke (intended to be globe artichoke consistent with the
submitte d field trial data although not specified in the use directions), stone fruit 12

- 12 and cucumber (greenhouse) for a 0.73 lb ai/gal MAI emulsion oil in water (EW) formulation with cyprodinil (Inspire Super TM 

### Fungicide; EPA Reg. No. 100

- 1317). In addition, IR

- 4 submitted draft supplemental labels which are substantially similar to Section B of the petition. The subject
end

- use products are identified in Table 3.3.1, and the use directions based on Section B of the petition are summarized in Table 3.3.2.Page 11 of 47

T able 3.3.1. Summary of End

- Use Products and Crops Under Consideration

. Trade Name EPA Reg.

No. ai Content Formulation Type Target Crops Source of Use
Directions
InspireTM Fungicide 100

- 1262 Difenoconazole
2.08 lb ai/gal (23.2%) Emulsifiable

concentrate (EC) Artichoke 1

Ginseng

Stone Fruit Group 12

- 12: apricot; apricot, Japanese; capulin; cherry, black; cherry, Nanking; cherry, sweet; cherry, tart; Jujube, Chinese; nectarine; peach; plum; plum, American; plum, beach; plum, plumcot; sloe; cultivars,varieties, and/or hybrids
of these.

Tree Nuts Group 14

- 12: African

nut

- tree; almond 2 ; beechnut’ Brazil, nut; Brazilian pine; bunya; bur, oak; butternut; Cajou nut; candlenut; cashew; chestnut; chinquapin; coconut; coquito nut; dika nut; ginkgo; Guiana chestnut; hazelnut (filbert) 2 ; heartnut; hickory nut; Japanese
horse

- chestnut; macadamia nut; mongongo nut; monkey

- pot; monkey puzzle nut; Okari nut; Pachira nut; peach palm nut;

pecan 2 ; pequi; Pili nut; pine nut; pistachio 2 ; Sapucaia nut; tropical almond; walnut, black; walnut, English; yellowhorn; cultivars, varieties, and/or hybrids of these. Section B of petition which
is consistent
with the Draft Supplemental
Label

Date d
11/11/13

Quadris TopTM Fungicide 100

- 1313 Difenoconazole 1.05 lb ai/gal (11.4%)

Azoxystrobin 1.67 lb ai/gal (18.2%) Suspension

concentrate (SC) Section B of petition which
is consistent
with the Draft Supplemental
Label

Date d 11/8/13

Inspire SuperTM Fungicide 100

- 1317 Difenoconazole
0.73 lb ai/gal (8.4%)

Cyprodinil
2.09 lb ai/gal (24.1%) Emulsion oil

in water (EW) Artichoke 1

Cucumber (Greenhouse)

Stone Fruit Group 12

- 12: apricot; apricot, Japanese; capulin; cherry, black; cherry, Nanking; cherry, sweet; cherry, tart; Jujube, Chinese; nectarine; peach; plum; plum, American; plum, beach; plum, plumcot; sloe; cultivars,varieties, and/or hybrids
of these. Section B of
the Petition
which is
consistent with
the Draft Supplemental
Label

Date d
12/17/13

1 Although not specified in the use directions, the use on artichoke is intended to be for globe artichoke consistent with the supporting data.

2 While almonds, filberts, pecans and pistachios are listed among the target crops in Section B of the petition, they are listed separately on the currently registered end

- use product labels as indicated in Section B of the petition and there are specific use directions for them on the currently registered end

- use product labels. Some of these specific
use direction s are less restrictive.Page 12 of 47

Table 3.3.2. Summary of Directions for Use of Difenoconazole.

Appl. Timing, Type, and Equip. Formulation

[EPA Reg. No.] Max. Appl.

Rate (lb ai/A) Max. No.

Appl. per
Season Max.

Seasonal Appl. Rate (lb ai/A) PHI 1

(days) Use Directions

and
Limitations 2

Ginseng

Foliar, Broadcast, Ground (≥15 gal/A), aerial (≥10 gal/A) or chemigation (0.1

- 0.25 inches/A) 2.08 lb ai/gal EC [100

- 1262] 0.114

- 0.115 Not Specified (NS) 0.46 0 The minimum

retreatment interval is 7 days. 1.05 lb ai/gal
MAI SC [100

- 1313]

Artichoke 3

Foliar, Broadcast, Ground (≥ 50 gal/A), aerial (≥10 gal/A) or chemigation (0.1

- 0.25 inches/A) 2.08 lb ai/gal EC [100

- 1262] 0.114

- 0.115 NS 0.46 3 The minimum

retreatment interval is 14 days 1.05 lb ai/gal
MAI SC [100

- 1313]
0.73 lb ai/gal

MAI EW [100

- 1317]
Cucumber (Greenhouse)

Foliar, Broadcast, Ground (≥15 gal/A), aerial (≥10 gal/A) or chemigation (0.1

- 0.25 inches/A) 0.73 lb ai/gal
MAI EW [100

- 1317] 0.114

- 0.115 Not Specified (NS) 0.46 0 The minimum

retreatment interval is 7 days.

Stone Fruit 12

- 12 4

Foliar, Broadcast, Ground (≥15 gal/A) or aerial (≥10 gal/A) 2.08 lb ai/gal EC [100

- 1262] 0.114

- 0.115 Not Specified (NS) 0.46 0 The minimum

retreatment interval is 7 days. 1.05 lb ai/gal
MAI SC [100

- 1313]
0.73 lb ai/gal
MAI EW [100

- 1317] 2

Tree Nut 14

- 12 4 [ Note: While almonds, filberts, pecans and pistachios are listed among the target crops in Section B of the petition, they are listed separately on the currently registered end

- use product labels as indicated in Section B of the petition and there are specific use directions for them on the cu rrently registered end

- use product labels. Some of these specific use directions are less restrictive. ]Page 13 of 47

Table 3.3.2. Summary of Directions for Use of Difenoconazole.

Appl. Timing, Type, and Equip. Formulation

[EPA Reg. No.] Max. Appl.

Rate (lb ai/A) Max. No.

Appl. per
Season Max.

Seasonal Appl. Rate (lb ai/A) PHI 1

(days) Use Directions

and
Limitations 2

Foliar, Broadcast, Ground (≥15 gal/A) or aerial (≥10 gal/A) 2.08 lb ai/gal EC [100

- 1262] 0.114

- 0.115 NS 0.46 14 The minimum

retreatment interval is 14 days. 1.05 lb ai/gal
MAI SC [100

- 1313] 45

1 PHI = pre

- harvest interval.

2 All use directions include the following: Make no more than 2 sequential applications before alternating to another fungicide with a different mode of action.

3 Although not specified in the use directions, the use on artichoke is intended to be for globe artichoke consistent with the supporting data.

4 These are the same use direction currently on the labels for stone fruit group 12 an d tree nuts group 14.



### 3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed uses of difenoconazole on new foliar uses on globe a rtichoke, g inseng and g reenhouse

g rown c ucumbe rs and c onversion of the e stablished f oliar u ses/ t olerances for s tone f ruit group 12 and t ree n ut c rop group 14 to stone f ruit group 12

- 12 and tree nut group 14

- 12

. For domestic uses, humans may be exposed to difenoconazole in food and drinking water, since difenoconazole may be applied directly to growing crops and application may result in difenoconazole reaching surface and ground water sources of drinking water. There are also residential uses of difenoconazole, so there is exposure in residential or non

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

- application exposure for workers re

- entering treated fields.

Risk assessmen ts have been previously conducted for the existing uses of difenoconazole. This risk assessment considers all of the aforementioned exposure pathw ays based on the proposed

use s of difenoconazole, but also considers the existing uses as well.

3.5 Considerations of Environmental Justice

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

- Income Populations,” http://www.eh.doe.g ov/oepa/guidance/justice/eo12898.pdf

.

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

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pe sticide 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 data on food consumption patterns are compiled by the USDA und er the Continuing Survey of Food Intake by Individuals (CSFII) and are usedPage 14 of 47



### 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 performed 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 a nd expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 HAZARD CHARACTERIZATION AND DOSE

- RESPONSE ASSESSMENT

4.1 Toxicology Studies Available for Analysis

T he toxicology database for difenoconazole is complete for evaluating and characterizing difenoconazole toxicity and selecting endpoints for purposes of this risk assessment. All toxicity
studies required in accordance with new 40 CFR Part 158 data requirements have been
submitted. The Hazard and Science Policy Council (HASPOC) concluded that a 28

- day inhalation toxicity study is not required at this time (TXR 0054074)

.

4.2 Absorption, Distributi on, Metabolism and Excretion (ADME)

The absorption, distribution, metabolism, and excretion of difenoconazole were studied in rats. In one study, the test compound was labeled with C 14 

### at either the phenyl or triazole ring.
Animals were administered a si ngle oral gavage dose of 0.5 or 300 mg/kg of radiolabeled compound or 0.5 mg/kg unlabeled compound by gavage for 14 days followed by a single gavage dose of 0.5 mg/kg [ 14 

### C]

- difenoconazole on day 15. In a second follow

- up study [ 14 

### C]

- difenoconazole (phenyl ring label) was administered as single oral gavage dose of 0.5 or 300 mg/kg. The second study was conducted to address deficiencies in the initial study by providing biliary excretion and identification of metabolites.

Difenoconazole was rapidly absor bed and extensively distributed, metabolized, and excreted in rats for all dosing regimens. Distribution, metabolism and elimination of difenoconazole were not sex related in the first study. Recovery of administered dose was 96

- 108%. Biliary excretion, examined in the second study, constituted the main route of elimination with some dose and sex dependency (75% at the low dose for both sexes; 56% for males and 39% for females at the high dose). Urinary and fecal eliminations exhibited a dose

- related pa ttern at 48 hours. In bile duct cannulated rats, 9

- l4% of dose was eliminated in the urine at the low dose versus 1% in the high

- dose rats. In bile duct cannulated rats, 2

- 4% was eliminated in the feces at
the low dose versus 17

- 22% at the high dose. Hal f

- lives of elimination are approximately 20 hours for the low dose groups and 33

- 48 hours for the high dose group. Radioactivity in the blood peaked at 2 to 4 hours at the low and high dose respectively.

Difenoconazole undergoes successive oxidation a nd conjugation reactions. Following administration of 300 mg/kg of ( 14 

### C

- phenyl) difenoconazole, three major urinary metabolitesPage 15 of 47



### were identified as CGA 205375 and HO

- CGA 205375 (6% of dose), sulfate conjugates (and their isomers) of HO

- 205375 (3.9% of dose), and the hydroxyacetic metabolite of HO

- CGA 205375 (2.0% of dose). No single unknown urinary metabolite accounted for >1.1% of the dose.
Free triazole metabolite was detected in the urine of the triazole

- label groups and its byproduct
was detected i n the liver of phenyl labeled groups only.

The study results indicate that difenoconazole and/or its metabolites do not bioaccumulate appreciably following oral exposure since all tissues contained negligible levels (<1%) or radioactivity 7 days post expo sure.

A dermal absorption factor of 6% was derived based on data from a triple pack of a rat in vivo dermal absorption study and in vitro dermal absorption studies conducted with rat and human
skin (TXR 0056473) . Inhalation toxicity is assumed to be equi valent to oral toxicity.

4.3 Toxicological Effects

Subchronic and chronic studies with difenoconazole in mice and rats showed decreased body weights, decreased body weight gains and effects on the liver (e.g. hepatocellular hypertrophy, liver necrosis, fatty changes in the liver). No systemic toxicity was observed at the limit dose in the most recently submitted 28

- day rat dermal toxicity study.

The available toxicity studies indicated no increased susceptibility of rats or rabbits from in utero or postnatal exposure to difenoconazole. In prenatal developmental toxicity studies in rats and
rabbits and in the two

- generation reproduction study in rats, fetal/offspring toxicity, when observed, occurred at equivalent or higher doses than in the mate rnal/parental animals.

In a rat developmental toxicity study

, developmental effects were observed at doses higher than those which caused maternal toxicity. Developmental effects in the rat included increased
incidence of ossification of the thoracic v ertebrae and hyoid, decreased number of sternal centers of ossification, increased number of ribs and thoracic vertebrae, and decreased number of lumbar vertebrae. In the rabbit study, developmental effects (increases in post

- implantation loss and
resorpt ions and decreases in fetal body weight) were also seen at maternally toxic ( decreased body weight gain and food consumption ) doses . In the two

- generation reproduction study in rats, toxicity to the fetuses/offspring, when observed, occurred at equivalent or higher doses than in the maternal/parental animals.

In an acute neurotoxicity study in rats, reduced fore

- limb grip strength was observed on day 1 in
males at the LOAEL of 200 mg/kg . The effect in males is considered transient since it was not
obser ved at later observation points. Toxicity in females was observed only at the limit dose (2000 mg/kg) . In a subchronic neurotoxicity study in rats

, decreased hind limb strength was observed in males only at ≥ 17.5 mg/kg/day doses

. The effects observed in acute and subchronic neurotoxicity studies are transient, and the dose

- response is well characterized with identified NOAELs. Based on the toxicity profile, and lack of concern for neurotoxicity, a developmental neurotoxicity study in rats is not requi red.

In an immunotoxicity study in mice difenoconazole produced immunotoxic i ty at doses thatPage 16 of 47



### caused systemic tox icity.

In accordance with HED’s current policy and EPA’s 2005 Cancer Guidelines, difenoconazole is classified as “Suggestive Evidence of Ca rcinogenic Potential” based on liver tumors observed in mice at 300 ppm and higher, the absence of tumors at two lower doses of 10 and 30 ppm, excessive toxicity observed at the two highest doses of 2500 and 4500 ppm, the absence of genotoxic ity and no evi dence of carcinogenicity in rats ( TXR 0054532) . HED’s Cancer Peer Review Committee recommended use of an MOE approach to risk assessment using the chronic point of departure (POD) based on effects observed in the chronic mouse study relevant to tumor
deve lopment ( i.e. , hepatocellular hypertrophy, liver necrosis, fatty changes in the liver and bile stasis). The POD is considered protective of the cancer effects.

Difenoconazole possesses low acute toxicity by the oral, dermal and inhalation routes of

exp osure. It is not an eye or skin irritant and is not a sensitizer.

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

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

Based on the lack of quantitative or qualitative sensitivity and complete toxicity database for difenoconaozle, t he FQPA factor for increased susceptibility to infants and children may be
reduced to 1x

.

4.4.1 Completeness of the Toxicology Database

The toxicity database is sufficient for a full hazard evaluation and is considered adequate to
evaluate risks to infants and children. The Hazard and Science Policy Council (HASPOC)
concluded that a 28

- day inhalation toxicity study is not required at this time (TXR 0054074)

.

4.4.2 Evidence of Neurotoxicity

There are no clear signs of neurotoxicity following acute, subchronic or chronic dosing in multiple species in the difenoconazole database. The effects observed in acute and subchronic neurotoxicity studies are transient, and the dose

- response is well characterized with identified
NOAELs.

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

The available Agency g uideline studies indicated no increased qualitative or quantitative susceptibility of rats or rabbits to in utero and/or postnatal exposure to difenoconazole. In the prenatal developmental toxicity studies in rats and rabbits and the two

- generation reproduction study in rats, toxicity to the fe tuses/offspring, when observed, occurred at equivalent or higher doses than in the maternal/parental animals.

In a rat developmental toxicity study developmental effects were observed at doses higher than those which caused maternal toxicity. In the ra bbit study, developmental effects (increases inPage 17 of 47



### post

- implantation loss and resorptions and decreases in fetal body weight) were also seen at maternally toxic doses ( decreased body weight gain and food consumption ). In the two

generation reproduction study in rats, toxicity to the fetuses/offspring, when observed, occurred at equivalent or higher doses than in the maternal/parental animals.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. The dietary risk assessment is
conservative (tolerance level residues and 100% crop treated for the acute while the chronic used USDA Pesticide Data Program (PDP) monitor ing data, average field trial residues for some commodities, tolerance level residues for remaining commodities, and average percent crop treated for some commodities ) and will not underestimate dietary exposure to difenoconazole.

4.5 Toxicity Endpoint and Point of Departure Selections

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

u sed as a basis for the selected endpoints are presented in Appendix A.

An acute POD of 25 mg/kg/day (NOAEL) was selected from an acute neurotoxicity study in rats
based on reduced fore

- limb grip strength in males on day 1 at the LOAEL of 200 mg/kg/day. An uncertainty factor (UF) of 100x (10x to account for interspecies extrapolation and 10x for intraspecies variation) was applied to the NOAEL to obtain an acute reference dose (aRfD) of
0.25 mg/kg/day. Since the FQPA factor has been reduced to 1X, the a cute population adjusted dose (aPAD) is equivalent to the aRfD. The selected endpoint is considered appropriate for acute dietary exposure because effects were seen after a single dose. The endpoint is protective of the general population and all subpopu lations for effects seen in the acute neurotoxicity study in rats. It is also protective of developmental and maternal effects observed in the rabbit developmental toxicity study at the LOAEL of 75 mg/kg/day ( NOAEL of 25 mg/kg/day )

.

A chronic POD of 0.96 mg/kg/day (NOAEL) was selected from a chronic toxicity / carcinogenicity oral study in rats based on cumulative decreases in body weight gains in males observed at the LOAEL of 24 mg/kg/day. A UF of 100x (10x to account for interspecies extrapolation and 10x for intraspecies variation) was applied to the dose to obtain a chron ic reference dose (cRfD/cPAD) of 0.01 mg/kg/day. Since the FQPA factor has been reduced to 1X,
the chronic population adjusted dose (cPAD) is equivalent to the c RfD.

Short

- term incidental oral and short

- and intermediate term dermal and inhalation PODs of 1.25 mg/kg/day were selected from a two generation reproduction study in rats based on decreased pup weight in males at 12.5 mg/kg/day (LOAEL) on day 21, and reductions in body weight gain in F0 females. Although dermal toxicity studies are available, a POD from an oral study was selected because effects in young animals (decreased pup weight) the primary effect of concern for short, intermediate and long term exposure is not specifically evaluated in the available dermal toxicity studies that only ass ess adult animals. The selected endpoint is protective ofPage 18 of 47



### offspring effects from dermal exposure. An MOE of 100 is the level of concern (LOC) for the
short

- and intermediate

- term dermal and inhalation exposure scenarios based on the conventional

uncerta inty factor of 100 (10x for interspecies extrapolation and 10x for intraspecies variation). There are no residential uses for difenoconazole that would result in incidental oral exposure to
children.

A dermal absorption factor (DAF) is applied when dermal exposure endpoints are selected from oral toxicity studies. The dermal factor converts the oral dose to an equivalent dermal dose for
the risk assessment. A DAF of 6% was selected for use in risk as sessment based on available in

vivo dermal absorption studies in rat and in vitro dermal absorption studies conducted with rat
and human skin ( TXR 0056473)

.

4.5.2 Recommendations for Combining Exposure Routes for Risk Assessment

When there are potenti al residential exposures to the pesticide, the aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures. There are potential residential post

- application exposures to adults via the dermal route and to children via dermal and incidental oral routes of exposure. The common toxicological effect for the oral, dermal, and inhalation routes is body weight.

4.5.3 Cancer Classification and Risk Assessment Recommendations

Difenoconazole is not mutagenic, and no evidence of carcinogenicity was seen in rats. Evidence for carcinogenicity was seen in mice, where liver tumors were induced at doses which were considered to be excessively high for carcinogenicity testing. Liver tumors were observed in mice at 300 ppm and higher; however, based on excessive toxicity observed at the two highest doses of 2500 and 4500 ppm (females terminated after two weeks due to excessive toxicity resulting in moribundity and death), the absence of tumors at two lower d oses of 10 and 30 ppm, the absence of genotoxic effects, and no evidence of carcinogenicity in rats. In accordance with HED’s current policy and EPA’s 2005 Cancer Guidelines, difenoconazole is classified as “Suggestive Evidence of Carcinogenic Potential,” based on excessive toxicity observed at the two highest doses, the absence of tumors at the lower doses and the absence of genotoxic effects (TXR 0054532) . Based on the CPRC recommendation, the risk assessment uses an (MOE) approach utilizing the no

- obs ervable

- adverse

- effects

- level (NOAEL) of 30 ppm ( 4.7 and 5.6 mg/kg/day in males and females, respectively) and the lowest

- observable

- adverse

- effects

- level (LOAEL) of 300 ppm ( 46 and 58 mg/kg/day in males and females, respectively) from the mouse study usin g only those biological endpoints which were relevant to tumor development ( i.e.

, hepatocellular hypertrophy, liver necrosis, fatty changes in the liver and bile stasis). The chronic POD of 0.96 mg/kg/day selected based on bodyweight effects is protective of the cancer effects.

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Risk
Assessment

Toxicological doses/endpoints selected for the difenoconazole risk assessment are provided in
Tables 4 .5.4.1 and 4. 5 .4.2

.Page 19 of 47

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Difenoconazole for Use in Dietary and Non

Occupational Human Health Risk Assessments

Exposure
Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD, LOC

for Risk
Assessment Study and Relevant Toxicological

Effects

Acute Dietary (All populations) NOAEL = 25

mg/kg UF A = 10X

UF H = 10X

UF FQPA = 1X aRfD = aPAD =

0.25 mg/kg/day Acute Neurotoxicity Study in Rats

(MRID 46950327) LOAEL= 200 mg/kg in males based
on reduced fore

- limb grip strength

in males on day 1. Chronic Dietary (All populations) NOAEL = 0.96

mg/kg/day UF A = 10X

UF H = 10X

UF FQPA = 1X cRfD = cPAD =

0.01mg/kg/day Combined chronic

toxicity/carcinogenicity (rat; dietary

, MRID 42090019, 42710010 )
LOAEL = 24.1 /32.8 mg/kg/day (M/F) based on cumulative decreases in body

- weight gains.

Incidental Oral
Short

- Term (1

- 30 days) Oral NOAEL =

1.25 mg/kg/day UF A = 10X

UF H = 10X

UF FQPA = 1X Residential LOC

for MOE<100 Reproduction and fertility Study

(rat; dietary , MRID 42090018 )
Parental/ Offspring LOAEL = 12.5 mg/kg/day based on decreased pup weight in males on day 21 and reduction in body

- weight gain of F 0 females prior to mating, gestation
and lactation.

Dermal
Short

- and
Intermediate

Term (1

- 30 days
and 1

- 6 months)
DAF = 6% Oral NOAE L =

1.25 mg/kg/day UF A = 10X

UF H = 10X

UF FQPA = 1X Residential LOC

for MOE<100 Reproduction and fertility Study

(rat; dietary , MRID 42090018 )
Parental/ Offspring LOAEL = 12.5 mg/kg/day based on decreased pup weight in males on day 21 and
reduction in body

- weight gain of F 0 females prior to mating, gestation
and lactation.

Inhalation (Short

- and
Intermediate

- term)
Inhalation and oral absorption
assumed equivalent Oral NOAEL =

1.25 mg/kg/day UF A = 10X

UF H = 10X

UF FQPA = 1X Residential LOC

for MOE< 100 Reproduction and fertility Study

(rat; dietary , MRID 42090018 )
Parental/ Offspring LOAEL = 12.5 mg/kg/day based on decreased pup weight in males on day 21 and reduction in body

- weight gain of F 0 females prior to mating, gestation
and lactation.

Cancer (oral, dermal, inhalation) Difenoconazole is classified “Suggestive Evidence of Carcinogenic Potential” with a non

- linear

(MOE) approach for human risk characterization (CPRC Document, 7/27/94, Memo, P. V. Shah dated March 3, 2007, HED Doc. No. 0054532). 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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies DAF = Dermal Absorption Factor

Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for Difenoconazole for Use Occupational Human
Health Risk Assessments Exp osure Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD, Level of

Concern for Risk
Assessment Study and Toxicological Effects

Dermal
Short

- and Oral NOAEL

= 1.25 UF A = 10X

UF H = 10X Occupational LOC

for MOE<100 Reproduction and fertility Study

(rat; dietary , MRID 42090018 )Page 20 of 47

Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for Difenoconazole for Use Occupational Human
Health Risk Assessments Exp osure Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD, Level of

Concern for Risk
Assessment Study and Toxicological Effects

Intermediate

Term (1

- 30 days
and 1

- 6 months)
DAF = 6% mg/kg/day Parental/ Offspring LOAEL = 12.5 mg/kg/day based on decreased pup weight in males on day 21 and reduction in body

- weight gain of F 0 females prior to mating, gestation
and lactation.

Inhalation (Short

- and
Intermediate

- term)
Inhalation and oral absorption
assumed equivalent Oral NOAEL

= 1.25 mg/kg/day UF A = 10X

UF H = 10X Occupational LOC

for MOE<100 Reproduction and fertility Study

(rat; dietary

, MRID 42090018 )
Parental/ Offspring LOAEL = 12.5 mg/kg/day based on decreased pup weight in males on day 21 and reduction in body

- weight gain of F 0 females prior to mating, gestation
and lactation. Cancer (oral, dermal, inhalation) Difenoconazole is classi fied “Suggestive Evidence of Carcinogenic Potential” with a non

- linear

(MOE) approach for human risk characterization (CPRC Document, 7/27/94, Memo, P. V. Shah dated March 3, 2007, HED Doc. No. 0054532). 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 obse rved
adverse effect level. LOAEL = lowest o bserved 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). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposur e. LOC = level of concern. N/A = not applicable.



### 5.0 DIETARY EXPOSURE AND RISK ASSESSMENT

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The nature of the residue in plants is understood based on acceptable plant metabolism stud ies reflecting foliar applications in canola, grape, potato, tomato, and wheat, and seed treatment in
wheat. T he residue of concern for both tolerance enforcement and risk assessment for crops included in this petition is difenoconazole only . The nature of the residue in livestock is understood based on acceptable goat and hen metabolism studies. The residues of concern for
both tolerance enforcement and risk assessment for livestock commodities are difenoconazole
and its metabolite CGA

- 205375. In addit ion, metabolite OH

- CGA

- 169374, which comprised 15% of the TRR in goat milk from the phenyl

- labeled study, should be considered as a residue of

concern in milk for the dietary risk assessment.

The nature of the residue in rotational crops is adequately understood. The metabolism of difenoconazole in rotational crops is similar to that of primary crops. The available difenoconazole confined and limited field rotational crop trials are deemed ad equate to satisfy data requirements under Guidelines 860.1850 and 860.1900. Taken together, these data support
a 30

- day plantback interval (PBI) for cereal and root/tuber crops not already registered for foliar
use with difenoconazole and a 60

- day PBI fo r all other crops not already registered for foliar usePage 21 of 47



### with difenoconazole. With these PBIs, tolerances for residues of difenoconazole are not needed for rotational crops.

Structures and names of difenoconazole metabolites are provided in Appendix B

.

5.1. 2 Summary of Environmental Degradation

Difenoconazole has potential to reach surface water via run

- off, erosion, and spray drift, and is less likely to reach ground water except in soils of high sand and low organic matter content.
Environmen tal fate data indicate that difenoconazole is relatively stable to aerobic and anaerobic soil metabolisms and aerobic and anaerobic aquatic metabolism. When applied at 0.1

- 0.23 ppm to an aerobic soil, difenoconazole appears to degrade with half

- lives rangi ng from 84.5 to 533 days based on laboratory studies conducted on a variety of foreign and domestic soils. At concentrations of 10 ppm, difenoconazole degraded with the half

- lives of 1059

- 1600 days in aerobic, and 947 days anaerobic loam soil, respectivel y. In aquatic environment under aerobic conditions, difenoconazole microbially degraded with half

- lives ranging from 315 to 565 days at concentrations up to 0.17 mg ai/L, and 860 days in a concentration of 10 mg ai/L. Under anaerobic conditions, difenocon azole degraded in 370 days at a concentration of 0.04 mg ai/L, and 1245 days at concentrations of 10 mg ai/L. The longer half

- life values obtained for those higher concentration rates may imply that the rate of difenoconazole microbially mediated degradat ion may be concentration dependent. In laboratory studies on difenoconazole a significant amount of radioactivity was nonextractable (14.4 to 48.9%) from soils.

Considering abiotic degradation, difenoconazole is photolyzed in water (half

- life of 6 to 22 8 days), but stable in soil. The half

- life of 228 days was extrapolated from a 15

- day study in which difenoconazole slowly photolyzed from 100% to 91% under artificial light conditions (MRID 46950105). Also, the compound is stable to hydrolysis at pH valu es from 4 to 9.

Difenoconazole degraded with half

- lives ranging from 139 to 462 days in the terrestrial field dissipation studies. The overall stability of the compound in the terrestrial environment suggests that difenoconazole may accumulate in soil w ith successive applications from year to year.

5.1. 3 Comparison of Metabolic Pathways

Little information is available on the toxicity of the major difenoconazole metabolites. The
CGA

- 205375 metabolite formed in livestock appears to be formed in the rat also and is, therefore, part of the total toxic exposure for these animals.

5.1.4 Residues of Concern Summary and Rationale

Residues of concern were determined based on recommendations from the HED Residues of Concern Knowledgebase Sub

- committee (ROCKS) (D391350, 9/19/11). The residue of concern for plant commodities for tolerance enf orcement and risk assessment purposes is difenoconazole only . The HED ROCKS has determined that the parent compound and the CGA

- 205375
metabolite are the residues of concern in livestock commodities for both the tolerance
enforcement and the risk assessme nt. In addition, metabolite OH

- CGA

- 169374, whichPage 22 of 47



### comprised 15% of the TRR in goat milk from the phenyl

- labeled study, should be considered as
a residue of concern in milk for the dietary risk assessment. Based on available goat metabolism data, total resi dues of concern in milk for dietary risk assessments (parent, CGA

- 205375 and
OH

- CGA

- 169374), should be calculated by multiplying the tolerance in milk by a factor of 1.5x.
Table 5.1.4 summarizes tolerance expression and the residues of concern in plant an d livestock
commodities.

Difenoconazole belongs to the triazole group of fungicides. The triazole metabolites common to the group

, 1 ,2,4

- triazole (1,2,4

- T), triazolylalanine (TA) and triazolylacetic acid (TAA)

, are residues of concern for risk assessment purposes and are assessed separately from the parent compound.

Table 5.1.4 . Difenoconazole Residues of Concern in Plants and Ruminants.

Matrix Residues of Concern

For Risk Assessment For Tolerance Expression

Plants Primary and Rotational crops Parent Only Parent Only

Livestock Ruminant and Poultry Parent and CGA 205375 Parent and CGA 205375

Milk Parent, CGA 205375 and
OH

- CGA

- 169374 Parent and CGA 205375

Drinking Water Parent and CGA 205375 NA

Note: The triazole

- containing metabolites 1,2,4

- T, TA, and TAA should be included in the residues of concern for risk assessment purposes only for plant and livestock commodities. Since these metabolites are common to the entire class of
traizole

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

- T and to TA/TAA are addressed separately.



### 5.2 Food Residue Profile

5.2.1 Residues in Crops

The submitted globe artichoke field trial data conducted with an EW formulation of difenoconazole, the ginseng field trial data conducted with a SC formulation of difenoconazole and the greenhouse grown cucumber field trial data conducted with an EW formulation of
difen oconazole are adequate to support the proposed uses of difenoconazole on globe artichoke, ginseng and greenhouse grown cucumber. The number and locations of field trials reflecting the proposed uses are in accordance with Guideline 860.1500. U sing the Or ganization for Economic Cooperation and Development (OECD) tolerance calculation procedures , the recommended tolerances for residues of difenoconazole in/on artichoke, globe and ginseng are 1.5 ppm and 1.0 ppm, respectively. The existing tolerance of 0.70 ppm in/on vegetable, cucurbit, group 9 will cover residues incurred in/on greenhouse grown cucumber at the proposed use rate. The recommended tolerance in/on artichoke, globe is the same as the petitioned

- for tolerance; however, the recommended tolerance in/on ginseng (1.0 ppm) is not the same as the petitioned

for tolerance (0.50 ppm) due to the need to use an adjustment factor (2.3x) for the ginseng residue data reflecting the proposed 0

- day PHI based on residue decline data that indicated
that residues of difenoconazole incurred in/on ginseng could increase significantly with a longer PHI (ChemSAC 9/17/14).

No data were submitted in support of the proposed uses of the EC and SC formulation ofPage 2 3 of 47



### difenoconazole on globe artichoke or the EC formulation of di fenoconazole on ginseng; however, having considered the available bridging data comparing residues of difenoconazole from use of an EC formulation with that of an SC formulation or an EW formulation and given
that the recommended tolerances are well above the highest average field trial (HAFT) levels found in the supporting magnitude of the residue data, HED concludes that the recommended tolerances for residues of difenoconazole are likely to cover the proposed uses of the EC and SC
formulations of difenoc onazole.

The previously submitted cherry (tart and sweet), peach, plum, almond, and pecan field trial data and plum processing data which are adequate to support the currently registered uses of difenoconazole on stone fruit and tree nuts are adequate to support the proposed expansions of those uses to stone fruit group 12

- 12 and the tree nut group 14

- 12. No additional data are required. The recommended tolerances for residues of difenoconazole in/on fruit, stone, group

12

- 12 (2.5 ppm) and nut, tree, group 14

- 12 (0.03 ppm) are the same as the petitioned

- for
tolerances.

5.3 Water Residue Profile

5.3. 1 Estimated Drinking Water Concentrations

This assessment provides estimated drinking water concentrations (EDWCs) of difenoconazole and its major met abolite, CGA

- 205375 (M1) in surface water and groundwater in support of human health risk assessment on the Interregional Research Project Number 4 (IR4) proposed new uses on ginseng, artichoke, and conversion on stone fruit group 12

- 12 and tree nut group 14

- 12. The Residues of Concern Knowledgebase Subcommittee (ROCKS) of the Health Effects Division (HED) recommended to include CGA

- 205375 as a residue of concern for drinking water (USEPA, 2011, DP 391350 ). Therefore, this drinking water assessment was performed using total toxic residue (TTR; i.e. parent plus CGA 205375) method in support of the proposed Section 3 new uses following the approach used in a previous drinking water assessment for canola (US EPA 2013a, DP412614). Foliar spray applications (both aerial and ground spray applications) and chemigation, are being proposed for these crops. The EDWCs of difenoconazole and its major metabolite, CGA

- 205375 (M1) were generated using application

rates o f 0.46 to 0.52 lbs a.i./A.with the Surface Water Concentration Calculator model for surface water as well as the maximum application rate of 0.52 lbs a.i./A with the PRZM

- GW and
SCI

- GROW models for groundwater.

The Interregional Research Project Number 4 (IR

- 4) also revised the existing crop groupings by converting stone fruit Group 12 to stone fruit Group 12

- 12 and nut tree Group 12 to nut tree Group 14

- 12. Since there are no changes in the application rates and methods for the revised crop groupings, pr evious drinking water assessments (stone fruit; USEPA, 2010; DP426124 and tree nut; USEPA 2009, DP340378) fulfill the requirement for refining EDWCs for these crops. EFED noticed that the application rate for cucurbit is higher in the submitted Inspire Sup er (EPA Reg. No. 100

- 1317) label as compared to previous label, which was stamped on August 03, 2012. Since the maximum applicant rate of 0.52 lbs a.i./A for cucurbit is higher than previously assessed application rate of 0.46 lbs a.i./A (USEPA 2009; DP361 398 the EDWCs for the revised
rate of cucurbit was reassessed.Page 24 of 47



### Surface water and groundwater modeling were conducted for the maximum annual application rate of 0.46 to 0.52 lbs a.i./A for aerial application only as aerial applications produce
conservati ve estimates. Remaining model input parameters were chosen according to current guidance (USEPA, 2009 and USEPA, 2013b). For surface water, the EDWCs for new uses and the revised application rate for cucurbit did not exceed the previously recommended peak (acute) concentration of 20.0 μg/L, annual mean (non

- cancer chronic) concentration of 13.6 μg/L and the 30 year annual average concentration (cancer chronic) of 9.9 μg/L reported in the drinking water assessment based on grape use (US EPA, 2013; DP 398836 )

. Recently, PRGM

- GW scenarios were revised and consequently the estimated PZRM

- GW groundwater concentrations were reduced to 1.77 μg/L from 2.24 μg/L and chronic concentration of 0.66 μg/L from 0.78 μg/L for the maximum application rate for FL citrus scena rio. Recommended surface water and groundwater EDWCs for human health are listed in (Table 5.3.1.2 ).

Table 5.3.1. 2. Tier II Drinking Water Exposure Estimates for Total Toxic Residues of Difenoconazole

Source Peak Exposure ( μg /L) Annual Mean Exposure ( μg /L) 30

- year Average Exposure (μg/L)



### Surface water 20.0 13.6 9.9

Groundwater 1 

### 2.24

--- 0

. 82

1 Groundwater EDWCs are based on PRZM

- GW 100 years simulation and the highest application rate for
difenoconazole



### Drinking Water Data for Free Triazoles Residues of 1,2,4

- triazole in drinking water were provided to HED by the EFED (I. Maher, DP320682, 28 Feb 2006). Due to the inter

- conversion between 1,2,4

- triazole, triazole alanine, and triazole acetic acid that may occur in the environment, the residue estimates used in these assessments are a summation of all three residues and, therefore, represent an overestimate 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 5.3.1.3 . 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 estima tes are significantly greater than those for ground water, and were used in the assessments for free triazole as well as the conjugated metabolites. EFED stated that the new metconazole uses are covered by the previous drinking water assessment for 1,2,4

- triazole (DP320682, I. Maher, 2/28/06).

Table 5.3.1.3 . 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 Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

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 4.02, which incorporates consu mptionPage 25 of 47



### 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 2010. 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 adj usted 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.

5.4. 2 Percent Crop Treated Used in Dietary Assessment

The acute dietary exposure analyses assumed 100% crop treated (CT). Average %CT was used in the chronic dietary exposure analysis for the following crops: almond 5%, cabbage 2.5%, cucumbers 5%, garlic 5%, grape 5% , grapefruit 2.5%, onions 5%, orange 2.5%, pecan 2.5%, peach 1%, peppers 2.5%, pistachio 2.5%, pumpkin 2.5%, squash 5%, strawberry 2.5%, sugar beets 15%, tangerine 2.5%, tomatoes 25%, walnut 2.5%, watermelon 5%, and wheat 10%.

5

. 4

. 3 Acute Dietary Risk As sessment

A new dietary assessment was conducted for the proposed new use s

. The proposed use s result ed in dietary risk estimates below HED’s level of concern ( see Table 5.4. 3.1 )

. The highest is A ll I nfants ( <1

year old) resulting in 4 9 % of the aPAD.

Table 5.4. 3 .1 . Summary of Acute Dietary (Food plus Water) Exposure and Risk for Difenoconazole at the
95 th Percentile.

Population Subgroup aPAD (mg/kg/day) Exposure (mg/kg/day) %aPAD

General U.S. Population

0.25 0.038371 15

All Infants (< 1 year old) 0.1 22946 49

Children 1

- 2 years old 0.1 08065 43

Children 3

- 5 years old 0.074134 30

Children 6

- 12 years old 0.050183 20

Youth 13

- 19 years old 0.0 24840 10

Adults 20

- 49 years old 0.026003 10

Adults 50

- 99 years old 0.028849 12

Females 13

- 49 years old 0.025932 10

The bolded %aPAD is the highest.



### 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 Artichoke, Gi nseng 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 ) wasPage 26 of 47



### recently updated. Addition of these new uses of difenoconazole 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

.

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

. 4 Chronic Dietary and Drinking Water Analysis

A new dietary assessment was conducted for the proposed use s of difenoconazole and results in dietary risk estimates below HED’s level of concern ( see Table 5.4.2 )

.

Table 5.4. 4 . Summary of Chronic Dietary (Food plus Water) Exposure and Risk for Difenoconazole.

Population Subgroup cPAD (mg/kg/day) Exposure (mg/kg/day) %cPAD

General U.S. Population

0.01 0.002591 26

All Infants (< 1 year old) 0.007691 77

Children 1

- 2 years old 0.00 8894 89

Children 3

- 5 years old 0.006043 60

Children 6

- 12 years old 0.003709 37

Youth 13

- 19 years old 0.002016 20

Adults 20

- 49 years old 0.001893 19

Adults 50

- 99 years old 0.002095 21

Females 13

- 49 years old 0.001856 19Page 27 of 47

The bolded %cPAD is the highest.



### 5.4.5 Summary Table

Table 5. 4 .5 . Summary of Dietary (Food plus Water) Exposure and Risk for Difenoconazole

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

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

General U.S. Population 0.038371 15 0.002591 26

N/A All Infants (< 1 year old) 0.1 22946 49 0.007691 77

Children 1

- 2 years old 0.1 08065 43 0.00 8894 89

Children 3

- 5 years old 0.074134 30 0.006043 60

Children 6

- 12 years old 0.050183 20 0.003709 37

Youth 13

- 19 years old 0.0 24840 10 0.002016 20

Adults 20

- 49 years old 0.026003 10 0.001893 19

Adults 50

- 99 years old 0.028849 12 0.002095 21

Females 13

- 49 years old 0.025932 10 0.001856 19



### 6 .0 RESIDENTIAL (NON

- OCCUPATIONAL) EXPOSURE / RISK
CHARACTERIZATION

There are no proposed residential uses at this time; however, there are existing residential uses
that have been previously reassessed to reflect updates to HED’s 2012 Residential SOPs 1 

### along with policy changes for body weight assumptions. The revis ed residential exposure estimate s impact the human health aggregate risk assessment for difenoconazole

.

Based on the existing exposure pattern, residential exposure scenarios have been iden tified from

treatment of ornamental plants in commercial and residential landscapes and interior plantscapes. Potential exposure is expected to homeowners handling the product and/or from performing
post

- application activities in treated areas.

Represe ntative outdoor and indoor residential handler and post

- application exposure scenarios

were previously reassessed for all difenoconazole uses using the Revised Residential SOPs (2012), and the risk estimates were not of concern ( D 421188 , I. Nieves, 0 2/24/2 015). Table
6.0.1 presents a summary of the residential handler non

- cancer exposure and risk estimates for
the registered scenarios (MOEs ranged from 3,500 to 68,000; LOC =100). Table 6.0.2 summarizes the residential post

- application non

- cancer exposure and risk estimates for all
difenoconazole uses (MOEs ranged from 250 to 31 ,000; LOC=100)

.

1 

### Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.htmlPage 28 of 47 Table 6.0.1. Residential Handler Non

- cancer Exposure and Risk Estimates for Difenoconazole.

Exposure
Scenario Level of

Concern Dermal

Unit Exposure (mg/lb ai) Inhal ation

Unit Exposure (mg/lb ai) Maximum

Application
Rate 1 Area

Treated

or Amount
Handled Daily 2 Dermal Inhalation Total

Dose (mg/kg/day) 3 MOE 4 Dose

(mg/kg/day) 5 MOE 6 MOE 7

Mixer/Loader/Applicator on Ornamentals (Garden/Trees) with Liquid Formulation
Manually

pressurized
handwand

100 63 0.018

3.0x10

- 6

lb ai/ft 2

(0.13 lb ai/A) 1,200 ft 2 0.00017 7,400 0.0000008 1,600,000 7,400

Hose

- end Sprayer 58 0.0014 0.00016 8,000 0.000000063 20,000,000 8,000

Backpack 130 0.14 0.00035 3,600 0.0000063 200,000 3,500 Ready

- to

use Hose

end Sprayer 6.26 0.034 0.000017 74,000 0.0000015 820,000 68,000

1 Based on registered label (EPA Reg. No. 100

- 1262)
2 Based on HED’s 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html ).
3 Dermal Dose = Dermal Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A/day or gallons/day) × Dermal Absorption Factor (%) ÷ Body Weight (kg).
4 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day).
5 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Ar ea Treated or Amount Handled (A/day or gallons/day) ÷ Body Weight (kg).

6 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

7 Total MOE = NOAEL (mg/kg/day) ÷ (Dermal Dose + Inhalation Dose).

### Page 29 of 47

Table 6.0.2

. Residential Post

- application Non

- cancer Exposure and Risk Estimates for Difenoconazole.

Lifestage Post

- application Exposure Scenario Application Rate 1 Dose (mg/kg/day) 2 MOEs 3

Use Site Route of Exposure

Adult
Gardens

Dermal 0.13 lb ai/A 0.005 250

Child 6 < 11 yrs 0.003 360

Adult Trees and Retail

Plants 0.00046 2,700

Child 6 < 11 yrs 0.00031 4,000

Adult
Indoor Plants 0.000060 21,000

Child 6 < 11 yrs 0.000041 31,000

Adult

Golfing Dermal 0.25 lb ai/A 0.00044 2,800

Child 11 <16 years 0.00051 2,400

Child 6 < 11 yrs 0.00060 2,100

1. Based on registered or proposed label (Reg. No. 100

- 1262).
2. Dose (mg/kg/day) equations provided in Appendix [ A ].
3. MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day).



### Table 6.0.3 reflects the residential risk estimates that are recommended for use in the aggregate
assessment for difenoconazole.

 The recommended residential exposure for use in the adult aggregate assessment reflects
dermal and inhalation exposure from mixing/loading/applying difenoconazole with a backpack sprayer.

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

- application exposure to garden applications.

 The reco mmended residential exposure for use in the children 6 to 11 years old aggregate assessment reflects dermal exposure from post

- application exposure to garden applications.

Table 6.0.3. Recommendations for the Residential Exposures for the Difenoconazole Aggregate
Assessment. 1

Lifestage (Scenario) Dose (mg/kg/day) 2,4 MOE 3,5

Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Residential Handler

Adult (Backpack Sprayer) 0.00035 0.0000063 N/A 0.0003 6 3,600 200,000 N/A 3,500

Residential Post

- application

Adult (Garden) 0.005 N/A N/A 0.005 4 250 N/A N/A 250

Child 6<11 yrs (Gardens) 0.003 N/A N/A 0.003 0 360 N/A N/A 360

1 Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment.

2 Residential Handler Dose = the highest handler dose for each applicable lifestage of all residential handler scenarios
assessed. Total = dermal + inhalation.
3 Residential Handler MOE = the MOEs associated with the highest residential handler doses. Total = 1 ÷ (1/Der mal

### Page 30 of 47 MOE) + (1/Inhalation MOE).

4 Residential Post

- application Dose = the highest post

- application dose for each applicable lifestage of all post

application scenarios assessed. Total = dermal + inhalation + incidental oral.
5 Residential Post

- application MOE = the MOEs associated with the highest post

- application doses. Total = Dermal
MOE + Inhalation MOE + Incidental Oral MOE.



### 6.1 Residential Bystander Postapplication Inhalation Exposure

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

- applica tion inhalation exposure assessment was not performed for difenoconazole at this time primarily because of the low acute inhalation toxicity (Toxicity Category III and IV), low vapor pressure (2.5 x 10

- 10 

### mm Hg at 25 oC), and the low proposed use rate (0.1 3 lb ai/A). However, volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its

F ederal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 2 . The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative pos t

- application inhalation exposure assessment
for difenoconazole.

6.2 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for difenoconazole

. The Agency has been working with the Spray Drift Task Force (a task force composed of various registrants whi ch was developed as a result of a Data
Call

- In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray
Drift website for more infor mation). 3 

### The Agency is also taking means to qualitatively and qualitatively address spray drift as a potential source of exposure in risk assessments for pesticides through existing programs such as Ag Drift and chemical specific properties of pesticide s. The potential for spray drift will be quantitatively evaluated for each pesticide during
the Registration Review process which ensures that all uses for that pesticide will be considered concurrently.

7 .0 AGGREGATE EXPOSURE / RISK CHARACTERIZATION

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

2 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
3 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm

### Page 31 of 47

residential). In an aggregate assessment, exposures from relevant source s are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

7.1 Acute & Chronic Aggregate Risk

Acute and chronic aggregate exposures include food plus drinking water exposures. As
demonstrated under Section 5. 4, acute and chronic aggregate risks are not of concern.

7.2 Sh ort

- T erm Aggregate Risk

Short term aggregate exposure takes into account residential exposure plus average exposure levels to food and water (considered to be a background exposure level). The short term aggregate risk includes the estimated risk associated with combined risks f rom average food and drinking water exposures and dermal exposures from post

- application exposure to adults and children 6 to 11 years old re

- entering a treated garden . Short term aggregate risk estimates are provided in T able 7.2

.

Table 7.2

. Short

- Ter m Aggregate Risk Calculations

Population Short

- Term Scenario

NOAEL mg/kg/day LOC 1 Max

Allowable Exposure 2 mg/kg/day Average

Food and
Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Total

Exposure mg/kg/day 4 Aggregate

MOE (food, water, and residential) 5

Adult Male

1.25 100 0.0125 0.00 2 1 0.005 4 0.00 7 5 1 7 0

Adult Female 0.00 18 0 .0054 0.00 72 170

Child 0.003 7 0.003 0 0.00 67 190

1 10X for interspecies extrapolation, 10X for intraspecies variation.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

. 3 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure]. Refer to Table 6.0.3.

4 Total Exposure = Avg Food & Water Exposure + Residential Exposure)

. 5 Aggregate MOE = [NOAEL/ (A vg Food & Water Exposure + Residential Exposure)]

.



### Updated Aggregate Assessment of Free Triazole & its Conjugates

Reference: Common Triazole Metabolites: Updated Aggregate Human Health Risk Assessment to Address The New Section 3 Registrations For Use o f 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 Frui t, Stone, Group 12

- 12 and the Nut, Tree, Group 14

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

.



### 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,

xx / xx / xx ).

### Page 32 of 47

7. 3 Intermediate

- Term Aggregate Risk

There are no residential use scenario s that will result in potential intermediate term exposure to
difenoconazole . Theref

ore, a n intermediate

- term aggregate was not performed.

8.0 C umulative Exposure/Risk Characterization

Difenoconazole 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 mechan ism 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 c onazoles, however, a variable pattern of toxicological 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 outcomes. Thus, there is currently no evidence to indicate that conazoles share common mechanisms of toxicity and EPA is not following a cumulative risk approach based on a common mechanism of toxicity for the conazoles. For information regarding EPA’s p rocedures for cumulating effects from substances found to have a common mechanism of toxicity, see EPA’s website at http://www.epa.gov/pesticides/cumulative

.

Difenoconazole is a triazole

- derived pesticide. This class of compounds can form the common

meta bolite 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 ri sk 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 terms 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

r etained the additional 10X 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 foun d in the propiconazole reregistration docket at http://www.regulations.gov , Docket Identification (ID) Number EPA

HQ

- OPP

- 2005

- 0497.

9 .0 OCCUPATIONAL EXPOSURE / RISK CHARACTERIZATION

9 .1 Exposure Scenarios

### Page 33 of 47

Occupational handler and post

- application exposure scenarios have been identified for the proposed uses. Based on the product labels and information provided by the registrant, short

and intermediate

- term exposure is expected for occupational handlers a nd post

- application activities. Chronic exposure is not expected for the proposed use patterns.

9

. 2 Handler Exposure

The term “handler” applies to individuals who mix, load, and apply the pesticide product. There is a potential for exposure to difenoconazole during mixing, loading, and application activities through the dermal and inhalation routes.

9.2.1 Handler Exposure Scenarios

Occupational handler ex posure and risk estimates for the proposed new foliar u ses on globe

a rtichoke, g inseng

, g reenhouse g rown c ucumbers and c onversion of the e stablished f oliar

u ses/ t olerances for s tone f ruit group 12 and t ree n ut c rop group 14 to stone f ruit group 12

- 12 and tree nut group 14

- 12, are all expected to result in comparable /identical exposure scenarios to those previously assessed and discussed in a recent risk assessment for this chemical (D 421188

, I. Nieves, 0 2/24/2015 ). T he application rate s proposed for these new uses are identical to the

one s previously assessed (0. 11 lb ai/A) , and risk e stimates were q uantified at higher rates

, and/or higher amount used or area treated than the proposed uses. No risk estimates of concern were
identified for any of the previous uses utilizing label required PPE (i.e., long shirt, long pants, shoes, socks and gloves). Based on the premise that all uses require the same PPE previously labeled, and there have been no revisions to the toxicological database/endpoints and/or to the occupational SOPs since the date of the recent assessment , all proposed new us es are considered
to be not of concern to the Agency.

9.3 Post

- Application Exposure

HED uses the term post

- application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re

entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post

- application exposure l evels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications,
rel ative to harvest activities, can greatly reduce the potential for post

- application exposure.

Dermal Exposure

Post

- application dermal exposure and risk estimates for the proposed new uses are all expected to result in comparable/identical exposure scenari os to those discussed and assessed in a recent risk assessments for this chemical ( D 421188 , I. Nieves, 0 2/24/2015)

. The application rates proposed for these new uses are identical to the ones previously assessed (0.11 lb ai/A). No risk

### Page 34 of 47

estimat es of conce rn were identified for any of the previous uses. Based on the premise that no

new d islodgeable f

oliar r esidue (DFR) studies have been submitted, and there have been no revisions to the toxicological database/endpoints and/or to the occupational post

- appli cation
SOPs since the date of the recent assesment , all post

- applications activities related to the proposed new uses are considered to be not of concern to the Agency.

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

- appli cation inhalation exposure assessment was not performed for difenoconazole at this time primarily because of the low acute inhalation toxicity (Toxicity Category III and IV), low vapor pressure (2.5 x 10

- 10 

### mm Hg at 25 oC), and low proposed use rate s ( highest proposed rate = 0.11 lb ai/A) . However, there are multiple potential sources of post

- application inhalation exposure to individuals performing post

application activities in previously treated fields. These potential sources include volatilizatio n of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advi sory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 4 

### . The Agency is in the process of evaluating the SAP report as well as available post

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

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

- application inhalation exposure
assessment for difenoconazole.

Although a quantitative occupational post

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

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

- application inhalation exposure scenarios.

9.3. 1 Restricted Entry Interval

The REI specified on the proposed label is based on the acute toxicity of difenoconazole.
Difenoconazole is classified as Toxicity Category III for acute dermal toxicity and eye irriitation, and Toxicity Category IV for skin irritation potential. It is not a skin sensitizer. Short

- and
intermediate

- term post

- application risk estimates were not a concern on day 0 (12 hours following application) for all post

- application activities. Under 40 CFR 156.208 (c) (2) (iii), active ingredients classified as Acute III or IV for acute dermal, eye irritation and primary skin irritation are assigned a 12

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

- application exposures to difenoconazole

.

4 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

### Page 35 of 47

10. REFERENCES

Difenoconazole. Human Health Risk Assessment for propos ed new foliar uses on legume subgroup 6C and bushberry subgroup 13

- 07B; post

- harvest uses on pome fruit group 11

- 10; and ornamental plants and vegetable transplants grown in both indoor and outdoor production facilities

– I. Nieves; D422992

, D421429, D421216

, D421201, D421208, D421188, and D413471; 02/24 / 2015

Difenoconazole. New Foliar Uses 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. Summary of Analytical Chemistry and Residue Data.

- B. Cropp

Kohlligian

, D421089

, 01/28 / 2 015

Difeno conazole. Acute and Chronic Aggregate Dietary Exposure and Risk Assessments for the Petition for 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.

- T. Morton, D 426491

, 7 / 1 /1 5

D rinking W ater E xposure A ssessment in support of the new use registration of multiple difenoconazole formulated products on Artichoke, Berry Bushberry Subgroup 13

- 07B, Ginseng, and Bean and Pea, Dried Shelled (except Soybean) Subgroup 6C as well as Conversion of Stone Fruit Crop Group 12

- 12 and Tree Nuts Crop Group 14

- 12.

.

– F. Khan, D 421092

, 11 /1 3 /1 4

Difenoconazole. Occupational and Residential Exposure Assessment for a Proposed Use on Canola and Oilseed Subgroup 20A.

- I. Nieves

, D 4 12811

, 09 / 13 /201 3

Difenoconazole

. Occupational and Residential Exposure Assessment to Evaluate the Risk from Proposed Uses on

Post

- Harvest Potatoes, and the Expansion of Various Crop Groups Including: Citrus Fruit Group 10

- 10; Fruiting Vegetable Subgroups 8

- 10; Low Growing Berry Subgroup 13

- 07G, except cranberry; Pome Fruit, Crop Group 11

- 10 and Fruiting Vegetable, Crop Group 8

- 10).

- I. Nieves, D398608, 5/30/2012

Difenoconazole. Occupational and Residential Exposure Assessment for the Proposed New Use of Difenoconazole on Strawberry, Car rot, Chickpeas, Soybean, Stone Fruit: Gro up 12 and Golf Course Turfgrass.

- Rebecca Daiss; D371037; February 24, 2011.

Difenoconazole. Occupational and Residential Exposure/Risk Assessment for the Proposed New Uses of Difenoconazole on Fruiting Vegetables , Tuberous and Corm Vegetables, Pome Fru it, Sugar Beets and Ornamentals

- Mark I. Dow ; D340044; July 27, 2007.

### Page 36 of 47

APPENDICES

APPENDIX A. TOXICOLOGY DATA SUMMARY

A .1 Guideline Data Requirements

- Difenoconazole

Guideline
No. Study Type Technical MRID
No. Required Submitted

870.3100

870.3150
870.3200

870.3250
870.3465 Subchronic (Oral) Toxicity

- Rodent

................................ .........

Subchronic (Oral) Toxicity

- Non

- Rodent

................................ . 21/28

- Day Dermal Toxicity

................................ .......................

90

- Day Dermal Toxicity
90

- Day Inhalation Toxicity

................................ ....................... Y

Y

N

N

N * Y

Y

Y

N

N 42090022

42090021
42090013
42090013
46950310

870.3700a

870.3700b

870.3800 Prenatal Developmental Toxicity

- Rodent

................................

Prenatal Developmental Toxicity

- Non

- Rodent

........................

Reproduction and Fertility Effects

................................ ............. Y

Y

Y Y

Y

Y 42090016

42710008
42090017
42710008
42090018

870.4100a

870.4100b

870.4200a

870.4200b

870.4300 Chronic (Oral) Toxicity

- Rodent

................................ ..............

Chronic (Oral) Toxicity

- Non

- Rodent (Dog)

............................

Carcinogenicity

- Rat

Carcinogenicity

- Mouse

Combined Chronic Toxicity /Carcinogenicity Y

Y

Y

Y

Y Y

Y

Y

Y

Y 42090015

42710006
42090012
42710005
42090019
42710010
42090015
42710006 42090019,
42710010

870.6100a
870.6100b
870.6200a
870.6200b
870.6300
870.7485
870.7600

870.7800 Neurotoxicity

- Acute Delayed Neurotox.

- Hen

........................

Neurotoxicity

- Subchronic

- Hen

................................ ............. Neurotoxicity

- Acute

- Rat

................................ ........................ Neurotoxicity

- Subchronic

- Rat

................................ ................ Developmental Neurotoxicity..................
General Metabolism
Dermal Penetration

Immunotoxicity.............................

................................ .... N

N

Y

Y

N

Y

Y

Y N

N

Y

Y

N

Y

Y

Y ---

--- 46950327
46950329

-- 42090028
47453201
46950333
47453202
47453203
48696701

* The Hazard and Science Policy Council (HASPOC) concluded that a 28

- day inhalation toxicity study is not required at this time (TXR 0054074).

### Page 37 of 47

A .2 Toxicity Profiles

Table A.1. Acute Toxicity Profile

– Difenoconazole

Guideline No. Study Type MRID No. Results Toxicity Category

870.1100 Acute oral 42090006 LD 50 = 1450 mg/kg III

870.1200 Acute dermal 42090007 LD 50 > 2010 mg/kg III

870.1300 Acute inhalation 42090008 LC 50 > 3.3 mg/L III

870.2400 Eye irritation 42090009 Mild irritation reversible in 7 days III

870.2500 Dermal irritation 40789807 Slight irritation IV

870.2600 Skin sensitization 42090011, 42710004 Negative N/A

Table A.2. Subchronic, Chronic and Other Toxicity Profile of Difenoconazole

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

870.3100 90

- Day oral

toxicity (rat) 42090022 (1987)

Acceptable/guideline 0, 20, 200, 750, 1500 or 3000

ppm 0, 1, 10, 37.5, 75 and 150 mg/kg/d NOAEL = 20 ppm (1 mg/kg/day)
LOAEL = 200 ppm (10 mg/kg/day) based on the 10% decrease in body weight in the 200 ppm females (as well as a negative trend in feed consumption) and Increases in absolute liver weights in both sexes

870.3100 90

- Day oral

toxi city (mouse) 42090021 (1987)

Acceptable /guideline 0, 20, 200, 2500, 7500 or 15,000 ppm M: 0, 2.9, 30.8, 383.6, 1125 and 2250 mg/kg/d F: 0, 4.1, 41.5, 558.9, 1125 and 2250 mg/kg/d NOAEL = 20 ppm (2.9 mg/kg/day)
LOAEL = 200 ppm (30.8 mg/kg/day) based on body weight changes & liver histopathology.

870.3150 26

- Week oral

toxicity 42090012 (1987)

Acceptable / guideline 0, 100, 1000, 3000 or 6000 ppm M: 0, 3.6, 31.3, 96.6 and 157.8 mg/kg/d F: 0, 3.4, 34.8, 110.6 and 203.7 mg/kg/d NOAEL = 3000 ppm (31.3 mg/kg/day in males/34.8 mg/kg/day in females) LOAEL = 6000 ppm (96.6 mg/kg/day in males/110.6 mg/kg/day in females) , based primarily on microscopic
examination of CGA 169374

- related lenticular cataracts.

870.3200 21/28

- Day dermal

toxicity (rat) 42090013 (1987)

Acceptable / guideline 0, 10, 100 and 1000 mg/kg/d NOAEL = 10 mg/kg/day
LOAEL = 100 mg/kg/day based on statistically significant decrements in body weight, body weight gain, and food consumption.

870.3200 21/28

- Day dermal

toxicity (rat) 46950310 (2000)

Acceptable/ guideline 0, 10, 100 and 1000 mg/kg/d NOAEL (systemic) = 1000 mg/kg/day
LOAEL (systemic) was not determined.
NOAEL (dermal) = 100 mg/kg/day
LOAEL (dermal) = 1000 mg/kg/day based on hyperkeratosis at the ski n application site.

### Page 38 of 47

Table A.2. Subchronic, Chronic and Other Toxicity Profile of Difenoconazole

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

870.3700a Prenatal

developmental in (rat) 42090016, 42710007 (1987)

Acceptable / guideline 0, 2, 20, 100 or 200 mg/kg/d
from GD 6

- 15 (nominal doses differed widely from theoretical, this required altering NOAEL/LOAEL values) Maternal NOAEL = 16 mg/kg/day
LOAEL = 85 mg/kg/day based on decreased body weight gain and food consumption. Developmental NOAEL = 85 mg/kg/day
LOAEL = 171 mg/kg/day based on alterations in fetal
ossification.

870.3700b Prenatal

developmental in (rabbit) 4209001 7, 42710008 (1987)

Acceptable / guideline 0, 1, 25 or 75 mg/kg/d from GD

7

- 19 Maternal NOAEL = 25 mg/kg/day
LOAEL = 75 mg/kg/day based on decreased body weight gain and food consumption. Developmental NOAEL = 25 mg/kg/day
LOAEL = 75 mg/kg/day based on non

- significant increases in post

- implantation loss and resorptions/doe and a significant decrease in fetal weight.

870.3800 Reproduction and

fertility effects (rat) 42090018 (1988)

Acceptable / guideline 0, 25, 250 or 2500 ppm 0, 1.25, 12.5 and 125 mg/kg/d Parental/Systemic NOAEL = 25 ppm (1.25 mg/kg/day)
LOAEL = 250 ppm (12.5 mg/kg/day) based on reductions (statistically non

- significant) in body weight gain which appear to be part of a dose

- related trend days
70

- 77 prior to m ating, days 0

- 7 of gestation, and days 7

- 14 of lactation Offspring NOAEL = 25 ppm (1.25 mg/kg/day)
LOAEL = 250 ppm (12.5 mg/kg/day) based on a significant reduction in the body weight of F1 male pups at day 21 in the 250 ppm group.

870.4100b Chronic toxicity

(dog) 42090012, 42710005 (1988)

Acceptable / guideline 0, 20, 100, 500 or 1500 ppm M: 0, 0.71, 3.4, 16.4 and 51.2 mg/kg/d F: 0, 0.63, 3.7, 19.4 and 44.3 mg/kg/d NOAEL = 100 ppm (3.4 mg/kg/day in males/3.7 mg/kg/day in females)
LOAEL = 500 ppm (16. 4 mg/kg/day in males/19.4 mg/kg/day in females) , based on significant inhibition of body weight gain in females.

870.4200 Carcinogenicity

(rat) 42090019, 42710010 (1989)

Acceptable / guideline 0, 10, 20, 500 or 2500 ppm M: o, 0.48, 0.96, 24.12 and
123.7 mg/kg/d F: 0, 0.64, 1.27, 32.79 and 169.6 mg/kg/d NOAEL = 20 ppm (0.96 mg/kg/day in males/1.27 mg/kg/day in females)
LOAEL = 500 ppm (24.1 mg/kg/day in males/ 32.8 mg/kg/day in females) based on reductions in cumulative body weight gains in the 500 and 2 500 ppm groups.

No evidence of carcinogenicity

870.4300 Carcinogenicity

(mouse) 42090015, 42710006 (1989)

Acceptable / guideline 0, 10, 30, 300, 2500 or 3000

ppm M: 0, 1.51, 4.65, 46.29, 423.1 and 818.9 mg/kg/d F: 0, 1.9, 5.63, 57.79 and 512.6 mg/kg/d N OAEL = 30 ppm (4.7 mg/kg/day in males/5.6 mg/kg/day in females)
LOAEL = 300 ppm (46.3 mg/kg/day in males/57.8 mg/kg/day in females) based on reductions in the cumulative body weight gains and hepatocellular hypertrophy, liver necrosis, fatty changes in the liver and bile stasis in the 300, 2500 & 4500 ppm groups.

Evidence of carcinogenicity (liver adenoma/carcinoma in both sexes)

### Page 39 of 47

Table A.2. Subchronic, Chronic and Other Toxicity Profile of Difenoconazole

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

870.5100 In vitro bacterial

gene mutation (Salmonella typhimurium/ E. coli) / mammalian activation gene mutation assay 42090019, 42710010 (1989)

Acceptable / guideline

340

- 5447 μg /plate;
85

- 1362 μg /plate (repeat assay with TA1537 and TA98) There were sufficient and valid data to conclude that CGA 169374 technical was negative in the microbial gene mutation assay.

870.5300 in vitro

mammalian cell gene mutation assay in mouse lymphoma ce lls 42090024 (1986)

Unacceptable/ guideline No conclusion can be reached from the three non

activated and two S9 activated mouse lymphoma forward mutation assays conducted with difenoconazole technical. The study was seriously compromised.

870.5375 In vitro

Mammalian Cytogenetics (chromosomal aberrations) a ssay in Chinese
hamster CHO
cells 46950319 (2001)

Acceptable/ guideline 0, 21.99, 27.49, or 34.36 μg/mL (

- S9) 0, 34.36, 53.69 or 67.11 μg/mL (+S9) There was evidence of a weak induction of structural chromosomal aberrations over background in the presence of S9

- mix.

870.5375 In vitro

Mammalian Cytogenetics (chromosomal aberrations) a ssay in Chinese
hamster CHO
cells 46950321 (2001)

Acceptable/ guideline 0, 26.3, 39.5 or 59.3 μg/mL (

- S9) 0, 11.7 or 17 .6 μg/mL (+S9) There was evidence of a weak induction of structural chromosomal aberrations over background.

870.5375 In vitro

Mammalian Cytogenetics (chromosomal aberrations) a ssay in human lymphocytes 46950323 (2001)

Acceptable/ guideline 0, 5, 30 or 75 μg/mL (

- S9) 0, 5, 30 or 62 μg/mL (+S9) There was no evidence of structural chromosomal aberrations induced over background.

870.5385 In vivo

mammalian
chromosomal
aberration test Assay in Mice 42090023 (1986)

Unacceptable/guideline 250, 500 or 1000 m g/kg There was no evidence of a cytotoxic effect on the target organ or significant increase in the frequency of nuclear anomalies (micronuclei). However, the study was compromised.

870.5395 In vivo

mammalian cytogenetics

- erythrocyte
micronucleus assay in mice 41710011 (1992)

Acceptable/guideline Doses up to 1600 mg/kg Mice bone marrow

- No increase in micronucleated polychromatic erythrocytes occurred with CGA

- 1 69374 (91.2% a.i).

### Page 40 of 47

Table A.2. Subchronic, Chronic and Other Toxicity Profile of Difenoconazole

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

870.5550 Unsche duled

DNA Synthesis in
Mammalian Cells
in Culture 4210012 (1992)

Acceptable/ guideline Doses up to 50 μg /mL CGA

- i69374 tech. (92.2% a.i.) was considered to be negative in the unscheduled DNA synthesis assay in rat primary hepatocytes as measured by an au toradiographic method at concentrations up to 50.0 μg /mL.

870.5550 Unscheduled

DNA Synthesis in
Mammalian Cells
in Culture 42090027 (1985)

Unacceptable/ guideline
0.25

- 31.25 μg /mL No conclusion can be reached from the unscheduled DNA synthesis (UDS) primary rat hepatocyte assay
conducted with difenoconazole technical at concentrations ranging from 0.25 to 31.25 μg /mL. The sensitivity of the study was severely compromised.

870.5550 Unscheduled

DNA Synthesis in
Mammalian Cells
in Culture 42090026 (1985)

Unacceptable/ guideline
0.08

- 10 μg /mL No conclusion can be reached from the unscheduled DNA synthesis (UDS) human fibroblast assay conducted with difenoconazole tech. at conc. ranging from 0.08 to

10 μg /mL.

870.6200a Acute

neurotoxicity screening battery 46950327 (2006)

Acceptable/ guideline 0, 25, 200 or 2000 mg/kg/d NOAEL (M) = 25 mg/kg/day
LOAEL (M) = 200 mg/kg/day based on reduced fore

limb grip strength in males on day 1 and increased motor activity on Day 1

. NOAEL (F) = 200 mg/kg/day
LOAEL (F) = 2000 mg/kg/day based on decrea sed body weight, the following clinical signs: upward curvature of the spine, tip

- toe gait, decreased activity, piloerection and sides pinched in and decreased motor activity.

870.6200b Subchronic

neurotoxicity screening battery 46950329 (2006)

Acceptabl e/ guideline 0, 40, 250, or 1500 ppm M; 0, 2.8, 17.3 or 107.0 mg/kg/d F: 0, 3.2, 19.5, or 120.2 mg/kg/d NOAEL (M) = 40 ppm (2.8 mg/kg/day)
LOAEL (M) = 250 ppm (17.3 mg/kg/day) based on decreased hind limb strength.
NOAEL (F) = 250 ppm (19.5 mg/kg/day)
LOAEL (F) = 1500 (120.2 mg/kg/day) based on decreased body weight, body weight gain and food efficiency.

870.7800 Immunotoxicity

[dietary]

- Mouse 48696701 (2011)

Acceptable/ guideline 0, 20, 200, 1000, or 1500 pm (0, 3, 35, 177, or 247

mg /kg/day) for 28 days. Systemic toxicity NOAEL = 200 ppm (35 mg/kg/day) Systemic toxicity LOAEL = 1000 ppm (177 mg/kg/day)
based on decreased body weight gains and liver toxicity

Immunotoxicity NOAEL = 200 ppm (35 mg/kg/day) Immunotoxicity LOAEL = 1000 ppm (177 mg/kg/day)
based on decreased mean anti

- SRBC IgM levels

. 870.7600
Dermal
Penetration In vivo Dermal

Penetration in the Rat,

In vitro 47453201 (2007) See TXR 0056473

870.7600
Dermal
Penetration In vivo Dermal

Penetration in the Rat, 46950333 (2003) See TXR 0056473

### Page 41 of 47

Table A.2. Subchronic, Chronic and Other Toxicity Profile of Difenoconazole

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

870.7600
Dermal
Penetration In vitro

Absorption through Human Epidermis; 47453202 (2007) See TXR 0056473

870.7600
Dermal
Penetration In vitro

Absorption through Rat Epidermis; 47453203 (2007) See TXR 0056473

870.7485 Metabolism and

pharmacokinetics (rat) 42090028 (1990)

Acceptable/ guideline 14 daily doses of 0.5 or 300 mg/kg Male and female Sprague

- Dawley rats. Animals were administered a single oral gavage dose of 0.5 or 30 0 mg/kg [ 14 C]CGA

- 169374, or 0.5 mg/kg unlabeled GGA

169374 by gavage for 14 days followed by a single gavage dose of 0.5 mg/kg [ 14 C)CGA

- 169374 on day 15. The test compound was labeled with C 14 at either the phenyl or triazole ring.

870.7485 Metabolism and

pharmacokinetics (rat) 42090028 (1990)

42090029 (1987) 42090030 (1987) 42090031 (1988) Acceptable/ guideline Single oral dose 0.5 or 300 mg/kg 14 daily doses of 0.5 or 300 mg/kg Male and female Sprague

- Dawley rats. Animals were administered a single o ral gavage dose of 0.5 or 300 mg/kg [ 14 C]CGA

- 169374, or 0.5 mg/kg unlabeled GGA

169374 by gavage for 14 days followed by a single gavage dose of 0.5 mg/kg [ 14 C)CGA

- 169374 on day 15. The test compound was labeled with C 14 at either the phenyl or triazole ring.

[ 14 C] CCA 169374 was rapidly and extensively distributed, metabolized, and excreted in rats for all dosing regimens. The metabolism of difenoconazole appears to be extensive because the metabolites
accounted for mos t of the recovered radioactivity in the

excreta . Three major metabolites were identified in the feces (i.e. metabolites A, B, and C). Two of the metabolites were separated into isomers (i.e., Al, A2, B1, and B2). Metabolite C was detected only in the hig h

dose groups, indicating that metabolism of
difenoconazole is dose

- related and involves saturation of the metabolic pathway. Free triazole metabolite was
detected in the urine of triazole

- labeled groups and its byproduct was detected in the liver of pheny l labeled groups only. Other urinary metabolites were not
characterized.

### Page 42 of 47

870.7485 Metabolism and

pharmacokinetics (rat) 42090028 (1990)

42090029 (1987) 42090030 (1987) 42090031 (1988) Acceptable/ guideline in conjunction with MRIDs 420710013, 42710014 listed
below Single oral dose 0.5 or 300 mg/kg 14 daily doses of 0.5 or 300 mg/kg The absorption, distribution, metabolism, and excretion of CGA 169374 were studied in groups of male and female Sprague

- Dawl ey rats. Animals were administered a single oral gavage dose of 0.5 or 300 mg/kg [ 14 C]CGA

169374, or 0.5 mg/kg unlabeled GGA

- 169374 by gavage for 14 days followed by a single gavage dose of 0.5 mg/kg [ 14 C)CGA

- 169374 on day 15. The test compound
was labele d with C 14 at either the phenyl or triazole ring.

[ 14 C] CCA 169374 was rapidly and extensively distributed, metabolized, and excreted in rats for all dosing regimens. T he extent of absorption is undetermined pending determination of the extent of biliary excretion. The 4

- day recoveries were 97.94

- 107.75% of the administered dose for all dosing groups. The elimination of radioactivity in the feces (78.06

- 94.61% of administered dose) and urine (8.48

- 21.86%) were almost comparable for all oral dose groups, wi th slightly higher radioactivity found in the feces of the high

- dose group than the low

- dose groups. This was probably due to biliary excretion, poor absorption or saturation of the metabolic pathway. The radioactivity in the blood peaked at about 24

- 48 ho urs. Half

- lives of elimination appear to be approximately 20 hours for the
low

- dose groups and 33

- 48 hours for the high

- dose group. The study results also indicate that difenoconazole
and/or its metabolites do not bioaccumulate to an appreciable extent fo llowing oral exposure since all the tissues contained negligible levels (< 1%) of radioactivity 7 days post exposure.

The metabolism of difenoconazole appears to be
extensive because the metabolites accounted for most of the recovered radioactivity in the excreta . Three major metabolites were identified in the feces (i.e. metabolites A, B, and C). Two of the metabolites were separated into isomers (i.e., Al, A2, B1, and B2). Metabolite C was detected only in the high

- dose groups, indicating that
metaboli sm of difenoconazole is dose

- related and involves saturation of the metabolic pathway. Free
triazole metabolite was detected in the urine of triazole

labeled groups and its byproduct was detected in the liver of phenyl labeled groups only. Other urinary me tabolites
were not characterized.

These studies indicate that distribution, metabolism, and
elimination of CGA

- 169374 were not sex related. There was a slight dose difference in the metabolism and
elimination of CGA

- 169374. In phenyl and triazole labeling studies, fecal excretion of radioactivity was higher in the high dose animals compared to the low dose animals, and an additional metabolite was found in the

### Page 43 of 47

Table A.2. Subchronic, Chronic and Other Toxicity Profile of Difenoconazole

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

feces of the high dose animals compared to the low dose animals. There was no major difference in the distribution and excretion of radioactivity with labeling at the phenyl and triazole ring positions, however, there were some
different metabolites identified. The studies also showed that administration of 0.5 and 300 mg/kg CGA

- 169314
did not induce any treatment related clinical effects.



### A.3 Toxicological Endpoints

A.3.1 Acute Population Adjusted Doses (aPAD)

– All Populations

Selected Study: Acute Neurotoxicity Study in Rats
MRID 46950327 Dose and Endpoint for Establishing an aPAD : NOAEL is 25 mg/kg/day. LOAEL is 200 mg/kg/day based on reduced fore

- limb grip strength in males on day 1. Uncertainty Factor (UF ): 100

, this includes 10x for interspecies extrapolation and 10x for intraspecies variation , 1X FQPA SF

. Comments about Study/Endpoint : The selected endpoint is considered appropriate for acute dietary exposure because effects were seen after a single dose. The endpoint is protective of the general population and all subpopulations for effects seen in the acute neurotoxic ity study in rats. It is also protective of developmental and maternal effects observed in the rabbit developmental toxicity study at the LOAEL of 75 mg/kg/day and NOAEL of 25 mg/kg/day.

A.3.2 Chronic Population Adjusted Dose (cPAD)

– All Populations

Selected Study: Chronic/Oncogenicity Study in Rats
MRID 42090019/20 Dose and Endpoint for establishing an cPAD : The NOAEL is 0.96 mg/kg/day. The LOAEL is 24.12 mg/kg/day based on cumulative decreases in body weight gains at 24.12 mg/kg/day in
males. General Population aPAD = (NOAEL) 25 mg/kg = 0.25 mg/kg (UF) 100

General Population cPAD = (NOAEL ) 0.96 mg/kg/day = 0.0 1 mg/kg/day (UF) 100

### Page 44 of 47

Uncertainty Factor (UF ): 100 : This includes 10X for interspecies extrapolation

, 10x for intraspecies variation , 1X FQPA SF

.

A.3.3 Incidental Oral Exposure (Short

- Term)

Selected Study: Two Generation Reproduction Study in Rats
MRID 42090018 Dose and Endpoint for Establishing POD : The NOAEL is 1.25 mg/kg/day based on decreased pup weight in males at 12.5 mg/kg/day (LOAEL) on day 21, and reductions in body weight gain
in F0 females.

Unc ertainty Factor (UF ): An MOE 100 is required for the short

- and intermediate

- term scenarios for dermal exposure is based on the conventional uncertainty factor of 100. This includes 10x for interspecies extrapolation and 10x for intraspecies variation.

Comments about Study/Endpoint : There are no residential uses for difenoconazole that would result in incidental oral exposure to children. However, a short term oral exposure endpoint is required for aggregate risk assessment.

A.3.4 Dermal Absorption

A dermal absorption factor (DAF) is applied when dermal exposure endpoints are selected from oral toxicity studies. The dermal factor converts the oral dose to an equivalent
dermal dose for the risk assessment. A DAF of 6% was selected for use in risk assessment based on available in vivo dermal absorption studies in rat and in vitro dermal absorption studies
conducted with rat and human skin (TXR 0056473)

.

A.3.5 Dermal Exposure (Short and Intermediate

- Term)

Selected Study: Two Generation Reproduct ion Study in Rats (MRID 42090018)

Dose and Endpoint for Establishing POD : The NOAEL is 1.25 mg/kg/day based on decreased pup weight in males at 12.5 mg/kg/day (LOAEL) on day 21 and reductions in body weight gain in F0 females. Dermal absorption is 6%.

Un certainty Factor (UF ): An MOE 100 is required for the short

- and intermediate

- term scenarios for dermal exposure is based on the conventional uncertainty factor of 100. This includes 10x for interspecies extrapolation and 10x for intraspecies variation.

Comments about Study/Endpoint : Although dermal toxicity studies are available, a POD from an oral study was selected because effects in young animals (decreased pup weight) the primary effect of concern for short, intermediate and long term exposure is no t specifically evaluated in the available dermal toxicity studies that only assess adult animals. The selected endpoint is protective of offspring effects from dermal exposure. A DAF of 6% is applied to the

### Page 45 of 47

POD for dermal exposure.

A.3.6 Inhalation Ex posure (Short

- and Intermediate

- Term)

Selected Study: Two Generation Reproduction Study in Rats (MRID 42090018)

APPENDIX B. Chemical Names And Structures Of Metabolites

B.1 Chemical Names And Structures

Difenoconazole Nomenclature

. Chemical structure

Common name Difenoconazole
Company experimental name CGA

- 169374

IUPAC name 1

- ({2

- [2

- chloro

- 4

- (4

- chlorophenoxy)phenyl]

- 4

- methyl

- 1,3

- dioxolan

- 2

- yl}methyl)

- 1H

- 1,2,4

- triazole

CAS name 1

- [[2

- [2

- chloro

- 4

- (4

- chlorophenoxy)phenyl]

- 4

- methyl

- 1,3

- dioxolan

- 2

- yl]methyl]

- 1H

- 1,2,4

- triazole
CAS registry number 119446

- 68

- 3

Chemical structure of
CGA

- 205375 livestock
metabolite

Chemical structure of 1,2,4

- Triazole (1,2,4

- T)

Chemical structure of Triazolylalanine (TA)

### Page 46 of 47

Difenoconazole Nomenclature

. Chemical structure of Triazolylacetic acid (TAA)



### APPENDIX C. Physical/Chemical Properties

Physicochemical Properties of Difenoconazole.

Parameter Value Reference
Melting point 78.6 oC DP#s 172067 and 178394, 10/26/92, R.
Lascola pH 6

- 8 at 20 oC (saturated solution)
Density 1.37 g/cm 3 at 20 oC
Water solubility 3.3 ppm at 20 oC
Solvent solubility g/100 mL at 25 oC :

n

- hexane: 0.5

1

- octanol: 35
toluene: 77

acetone: 88
ethanol: 89
Vapor pressure 2.5 x 10

- 10 mm Hg at 25 oC
Dissociation constant, pK
a pure grade (99.3% ± 0.3%) difenoconazole in water (with 4% methanol) at 20oC is 1.1 DP# 375159, 5/26/10, B. Cropp

- Kohlligian

Octanol/water partition coefficient, Log(K OW ) 4.2 at 25 oC DP#s 172067 and 178394, 10/26/92, R.
Lascola
UV/visible absorption spectrum 
max at about 200 and 238 nm (in methanol at 26 oC) PMRA Proposed Regulatory Decision Document on Difenoconazole, 4/14/99 (PRDD99

- 01)



### 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 Februa ry, 1995.

### Page 47 of 47 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.

Klonne, D. (1999) Integrated Report for Evaluation of Potential Exposures to Homeowners and Professional Lawn Care Operators Mixing, Loading, and Applying Granular and Liquid Pesticides to Residential Lawns: Lab Project Number: OMA005: OMA001: OMA002. Unpublished study prepared by Riceerca, Inc., and Mors e Laboratories. 2213 p. (MRID 44972201).

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,
rele ased February, 199