### Page 3 of 53

A.2 Toxicity Profiles.................. ..........................................................4 5 Appendix B: EPA Review of Human Research

................................ ................................ ...... 51 Appendix C : Physical and Chemical Properties

..................... ......................................... 5 2

A ppendix D : International Residue Limit Status

............ ........................................................ 5 2 Appendix E: Chemical Names and Structures of Me tabolites

..................................... 5 3

### Page 4 of 53

1.0 EXECUTIVE SUMMARY

This assessment provides information to support a Section 3 registration for the use of propiconazole on dry and succulent beans, and addition of post

- harvest uses on citrus, stone fruit,

and tomato

. This document addresses risks associated with exposures from currently registered

uses as well as the proposed new uses of propiconozole. 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

Propicona zole 1

- [[2

- (2,4

- dichloropheny l)

- 4

- propyl

- 1,3

- dioxolan

- 2

- yl]methyl]

- 1 H

- 1,2,4

- triazole )

is a systemic triazole

- type fungicide that provides broad spectrum disease control on a variety of

food and non

- food crops. Permanent tolerances are established ( 40 CFR §180.434 ) for the

combined re sidues of propiconazole and its metabolites ( determined as 2,4

- dichlorobenzoic acid (2,4

- DCBA) ) in/on a variety of agricultural commodities at levels ranging from 0.0 5 ppm in/on meat and meat byproducts to 40 ppm in/on grass straw. Non

- food uses include u se on commercial, public and residential ornamentals , landscapes and turf. The mode of antifungal action of propiconazole is attributed to the inhibition of CYP51 (lanosterol

- 14

- a

- demethylase).

Inhibition of normal sterol production disrupts cell wall fo rmation and slows or stops the growth of the fungus . Agricultural applications of propiconazole are made using ground or a erial equipment

. Propiconizole is applied to non

- food areas by both occupational and residential handlers. Occupational application methods for non

- food uses include , seed piece dip, tree injection, and handheld equipment (i.e., low

- pressure handwand, handgun sprayer, backpack sprayer). Residential applications are made with handheld equipment.

Proposed New Uses

The Interregiona l Research Project No. 4 (IR

- 4) has submitted an application for the registration

of product s containing propiconazole for use on dry beans, snap beans, succulent shelled beans

,

a nd post

- harvest use on citrus fruit, stone fruit, and tomato

. The product s a re manufactured by Syngenta Crop Protection, Inc. under the trade name Tilt ® 

### Fungicide (EPA Reg. No. 100

- 617)

, Qu ilt ® 

### Fungicide (EPA Reg. No. 100

- 1178 ) , Qu ilt Xcel ® 

### Fungicide (EPA Reg. No. 100

- 1324 )

and Tilt 45W ® 

### Fungicide (EPA Reg. No. 100

- 780 )

. A 7 day PHI is proposed for dry beans and

a 0 day PHI is proposed for succulent beans

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

Hazard Identification

T he toxicology database fo r propiconazole is adequate for evaluating and characterizing toxicity and selecting endpoints for pu rposes of this risk assessment. The primary target organ for propiconazole toxicity in animals is the liver . Liver effects observed in subchronic and chr onic

oral studies in rats and mice include lesions

, hypertrophy and necrosis . Propiconazole is not a reproductive toxicant. In a rat developmental study, fetal effects in pups were observed at doses lower than doses at which maternal effects were seen pr oviding quantitative evidence of

### Page 5 of 53

increased susceptibility of fetuses to in utero exposure to propiconozole. Propiconozole does not appear to be neurotoxic based on an acute neurotoxicity study. The FQPA safety factor was

reduced to 1X because residual un certainties with regard to pre

- and/or postnatal toxicity are

minimal.

Propiconazole is classified as a Group C possible human carcinogen with risk quantitated using a reference d ose (RfD) approach

. Propiconazole showed no significant toxicity in a bat tery of acute toxicity tests (Toxicity Category III or I V in all tests). It is not a skin irritant but is a

dermal sensitizer. I mmunotoxicity and subchronic neurotoxicity studies are required as part of new 40 CFR Part 158 requirements for registration o f a pesticide.

Dose Response Assessment

Toxicological endpoints were selected for dietary/drinking water

, occupational and residential exposure scenarios

. Acute and chronic Population Adjusted Doses (PADs) were selected for

assessment of food and drin king water exposures. An acute PAD fo r the general population was

selected from an acute neurotoxicity study in rats. An a cute PAD for females 13

- 49 w as selected

from a developmental toxicity study in rats

. A chronic /cancer PAD for the general populatio n was selected from a carcinogenicity study in mice. Short and intermediate

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

directions

. T oxicological endpoint s for inhalation, dermal , and inci dental oral exposure s w ere selected from the acute neurotoxicity study in rats. Since an oral study was selected for dermal exposure, a 40% dermal absorption factor from a dermal absorption study in rates is used for route to route extrapolation. An unce rtainty factor of 100X was applied to endpoints selected for all exposure routes (10x for interspecies extrapolation, 10x for intraspecies variation).

Exposure/Risk Assessment and Risk Characterization

Risk assessments were conducted for dietary (food and water) , and occupational exposure pathways based on registered uses and request s for new uses of propiconazole. Worker

exposures were assessed for handler and post

- application activities. There are no new requested

residential uses expected with this registration, therefore residential risk was not assessed for the proposed new use. Conservative acute and chronic dietary and drinking water risk assessments
for propiconazole conclude that dietary and drinking water exposure estimates are below HED‘s

l evel of concern for the general population and all population subgroups

. Additionally, t he requested use s of propiconazole result ed in an increase in dietary exposure estimates for free triazole or conjugated triazoles. Therefore, dietary exposure analys es for the triazole metabolites

need ed to be updated (T. Morton, D 397591 , 1/ 26 /12). Aggregate risks from propiconazole are

not of concern. Occupational e xposure and risk estimates indicate that worker and residential handler and post

- application exposure s are not of concern at the maximum allowable application rates for the proposed new use s provided that handlers wear chemical resistant gloves as required

on the label

. The only residential use scenario that will result in potential intermediate term

exp osure to propiconazole is post application exposure to children from wood treatment (antimicrobial use). Table 17 shows the aggregate risk for intermediate term exposure to

Children 1

- 2 years old. The aggregate MOE is 74, which is less than the target M OE of 100.

### Page 6 of 53

However, a refined chronic food and water exposure results in an MOE >100. Therefore, this

scenario is not of concern.

Aggregate Assessment of Free Triazole & its Conjugates

The addition of the new proposed uses increase the aggregate expos ure to free triazoles and its conjugates. Therefore, the aggregate human health risk assessment was updated for free triazoles and its conjugates and the aggregate estimates remain below HED‘s level of concern

.

Use of Human Studies

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies , listed in Appendix 2.0, have been determined to require a review of their ethical conduct . S ome of these studie s 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.e h.doe.gov/oepa/guidance/justice/eo12898.pdf ).

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

- established procedures. In line with OPP policy, HED estimates risks to population subgroup s 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 o f pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development, as OPP has committed resources an d expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

### Page 7 of 53

Tolerance Recommendation

Pending submission of a revised Section F (see requirements under Proposed Tolerances) and revised Section B (see requirements under Data Deficiencies) , there are no residue chemistry issues that would preclude granting conditional Section 3 registration for the requested u se of propiconozole on dry and succulent beans, and addition of post

- harvest uses on citrus, stone fruit, and tomato, or establishment of the following tolerances for residues of propiconozole.

Bean, snap

................................ ................................ .......... 0.70 ppm Bean, succulent shelled

................................ ...................... 0.10 ppm Legum e, foliage

................................ ................................ .... 30 ppm Bean, dry seed

................................ ................................ .... 0.40 ppm

Tomato

................................ ................................ ................. 3.0 ppm Fruit, citrus, group 10

- 10

................................ ..................... 8.0 ppm Fruit, stone, group 12, except plum

................................ ..... 4.0 ppm

Plum

................................ ................................ ................... 0.60 ppm

Citrus oil

................................ ................................ ............ 1000 ppm

As previously noted, p ermanent tolerances are currently established for the combined residues of propiconazole and its 2,4

- DCBA containing metabolites at levels ranging from 0.1

- 40 ppm in/on plant commodities [40 CFR §180.434(a)]. However, HED has determined that the current tolerance expression should be amended to include only propicona zole per se because 1) there are a number of pesticides that have 2,4

- DCBA as common metabolite, and an enforcement agency may not be able to determine if residues are due to misuse of propiconazole or the proper use of other pesticides containing 2,4

- DCBA ; 2) propiconazole per se can be detected by FDA multiresidue methods; and 3) inclusion of only parent allows harmonization with the residue

definition for the Codex MRLs.

HED has determined that the current tolerance expression for plant and livestock co mmodities is

not appropriate and has previously recommended that the tolerance expression be revised to include only parent

.

Codex has established several maximum residue limits (MRLs) for propiconazole in/on various raw agricultural commodities. The Cod ex MRLs are expressed in terms of propiconazole per se , which is the same as the US tolerance expression . B oth Canada and Mexico have established

MRLs/tolerances on several commodities which also have U.S. tolerances. To the extent possible, U.S. toleran ces have been harmonized with Codex, Canadian, and Mexican MRLs.

2.0 Regulatory Conclusions and Recommendations

HED can recommend for a un conditional registration and permanent tolerance s for the proposed

use s of propiconazole

. Deficiencies are outlined in Section 2.1 below. The specific tolerance recommendations are discussed in Section 2.2, and label modifications are discussed in Section

2.3.

### Page 8 of 53

2.1 Data Deficiencies/Conditions of Registration

Note to PM:

Revised Section F required.

Revised Section B required. A 0

- day PHI is proposed for succulent beans

. However,

residue data were submitted for 5

- 8 day PHI. Therefore, the label must be amended to state a 7 day PHI for succulent beans.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate method, HPLC/UV Method AG

- 671A, is available for tolerance enforcement. This method has undergone a successful tolerance method validation by the Analytical Chemistry

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

a means of residue confirmation.

2.2.2 International Harmonization

The Codex Alimentarius Commission has established several maximum residue limits (MRLs) for pro piconazole in/on various raw agricultural commodities. The Codex MRLs are expressed in terms of propiconazole per se , which is the same as the US tolerance expression, recommended by the RED for existing tolerances and for the new uses. In addition, both Canada

and Mexico have established MRLs/tolerances on several commodities which also have U.S. tolerances. To the extent possible, U.S. tolerances have been harmonized with Codex, Canadian,

and Mexican MRLs.

2.2.3 Recommended Tolerances

The proposed use and the submitted data support the following tolerance s for residues of propiconazole on/on the following raw agricultural commodit ies

.

Bean, snap

................................ ................................ .......... 0.70 ppm Bean, succulent shelled

................................ ...................... 0.10 ppm Legume, foliage

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

Be an, dry seed

................................ ................................ .... 0.40 ppm

Tomato

................................ ................................ ................. 3.0 ppm Fruit, citrus, group 10

- 10

................................ ..................... 8.0 ppm Fruit, stone, group 12, except plum

................................ ..... 4.0 ppm

Plum

................................ ................................ ................... 0.60 ppm

Citrus oil

................................ ................................ ............ 1000 ppm

### Page 9 of 53

2.2.4 Revisions to Petitioned

- For Tolerances

IR

- 4 has submitted a petition, PP#1E7855, for the establishment of tolerances for the combined residues of the fungicide propiconazole 1

- [[2

- (2,4

- dichlorophenyl)

- 4

- propyl

- 1,3

- dioxolan

- 2

- yl]methyl]

- 1H

- 1,2,4

- triazole and its metabolites determined as 2,4

- dichlor obenzoic acid and expressed as parent compound, in or on the following commodities:

Bean, snap

................................ ................................ ............ 0.8 ppm Bean, succulent shelled

................................ ...................... 0.15 ppm Legume, foliage

................................ ................................ .... 25 ppm Bean, dry seed

................................ ................................ ...... 0.3 ppm

Tomato

................................ ................................ ................. 2.5 ppm Fruit, citrus, group 10

- 10

................................ ..................... 8.0 ppm Fruit, stone, group 12, except plum

................................ ..... 7.0 ppm

Plum

................................ ................................ ..................... 1.0 ppm

HED has concluded that the residues of concern should include propiconazole and all its metabolites containing the 2,4

- DCBA moiety, including conjugates for dietary risk assessment of food, as virtually all the residue da ta have been generated using a common moiety method that converts parent and all of the metabolites of concern to 2,4

- DCBA. The tolerance expression should also be amended to include only propiconazole per se because 1) there are a number of pesticides th at have 2,4

- DCBA as common metabolite, and an enforcement agency may not be able to determine if residues are due to misuse of propiconazole or the proper use of other pesticides containing 2,4

- DCBA; 2) propiconazole per se can be detected by FDA multiresi due methods; and 3) inclusion of only parent allows harmonization with the residue definition for the

Codex MRLs. The tolerance expression for propiconazole in 40 CFR §180. 434 (a)(1) should be stated according to HED‘s Interim Guidance on Tolerance Express ion (5/27/09, S. Knizer) as specified in Section 2.2.3

.

Adequate crop field trial data reflecting the proposed use patterns were submitted for purposes of establishing tolerances on the request ed new uses

. The Organization for Economic Cooperation

and De velopment tolerance calculation procedures w ere utilized in determining the appropriate

tolerance level for the requested new uses. Changes in recommended tolerances are based on the use of these calculation procedures and are shown in Table 1.

The highe st average field trial (HAFT) residue from the citrus field trials is 4.91 ppm. This residue multiplied by the processing factor for dried citrus pulp ( 4.91 X 1.4 ) yields 6.9 ppm. As

this is less than the recommended tolerance for citrus , at 8.0 ppm, no separate tolerance for is

necessary. When the HAFT is multiplied by the processing factor for citrus oil (4.91 X 185) the final residue is 908 ppm. Therefore, a tolerance for citrus oil should be proposed at 1000 ppm.

The proposed and recommended toler ances for propiconazole as a result of the subject action are presented in Table 1.

### Page 10 of 53

Table 1 . Tolerance Summary for Propiconazole

.

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

40 CFR §180. 434 (a)( 1 )

Bean, snap 0.8 0.70

Bean, succulent shelled 0.15 0.10

Legume, foliage 25 30

Bean, dry seed 0.3 0.40

Tomato 2.5 3.0

Fruit, citrus, group 10

- 10 8.0 8.0

Fruit, stone, group 12, except plum 7.0 4.0

Plum 1.0 0.60

Citrus oil none 1000 Tolerance needed based on, HAFT x proce ssing factor
*Changes are due to the use of the Organization for Economic Cooperation and Development tolerance calculation procedures, unless otherwise stated.



### 2.3 Label Modifications

A 0

- day PHI is proposed for succu lent beans

. However, residue data were submitted for 5

- 8 day PHI. Therefore, the label must be amended to state a 7 day PHI for succulent beans.

3.0 Ingredient Profile

3.1 Summary of Proposed Uses

Propiconazole is proposed for use on dry beans, snap beans, succulent shelled beans, and

post

- harvest use on citrus, stone fruit, and tomatoes. (Table 2 ).

### Page 11 of 53

Table 2 . Proposed Amended Uses of Propiconazole (Fungicide)

Pr oduct (EPA Reg. No.) Use Site Appl. Method Application Rate Range (lb ai/A) Comments

Tilt ® (100

- 6177)

41.8% 3.6 lbs ai/gal

Beans,

Group 06 Ground,

Aerial, 0.1125 Fungicide. Up to three applications may be made on

a 7

- 14 day interval. Do not apply more than 12 oz.

of Tilt / crop /Acre. 7 day PHI

Quilt Xcel TM (100

- 1324)

11.7% 1.02 lbs ai/gal Ground,

Aerial 0.084

- 0.114 Up to three applications may be made on a 7

- 14 day interval. Not for use on cowpea intended for

li vestock feeding only. Do not apply more the 42 oz. of product/crop/A. Do not apply more than 0.34 lb ai of propiconazole containing products. 7 day PHI.

QuiltTM (100

- 1178)

11.7% 1.04 lbs ai/gal Ground,

Aerial 0.114 Up to three applications may be made on a 7

- 14 day interval. Do not apply more than 42 oz. of product/crop/Acre. Do not apply more than 0.34 lb ai of propiconazole containing products. 7 day PH I

Product (EPA Reg. No.) Use Site App. Method App. Rate Range (lb. a.i./ gal)

or (lb a.i. / # lbs. fruit) Comments

Tilt ® 45W (100

- 780)

45%

Wettable Powder Tomato,

Group 8 In

- line

Dip/Drench 0.00113

- 0.00225

(lb ai / gal)

Use T

- Jet, CDA or similar application system.

Must be used in tank mixture with fludioxonil. May be used with a food grade equivalent.

Dip ap proximately 30 seconds and allow fruit to

drain. Must be used in tank mixture with fludioxonil. May be used with a food grade

equivalent Aqueous or Fruit Coating Spray Application ( 0.113

– 0.225 lb a.i.

/50,000 lbs. of Fruit)

Citrus, Group 10 In

- line

Dip/Drench 0.00225

- 0.0045

(lb ai / gal)

Aqueous or Fruit Coating Spray Application ( 0.225

– 0.45

lba.i. /250,000 lbs. of Fruit)

Stone Fruit (Group 12) In

- line

Dip/Drench

In

- line 0.000563

- 0.00113

(lb ai/gal)

Aqueous or Fruit Coating Spray Application ( 0.056

– 0.113 lb

a.i. /250,000 lbs. of

F ruit)

### Page 12 of 53

3.2 Structure and Nomenclature

Structure and nomenclature are reported in Table 3.

T able 3 . Nomenclature of Propiconazole

Compound

Common name Propiconazole

Company experim ental names CGA

- 64250

IUPAC name 1

- [2

- (2,4_dichlorophenyl)

- 4

- propyl

- 1,3

- dioxolan

- 2

- ylmethyl]

- 1 H

- 1,2,4_triazole

CAS name 1

- [[2

- (2,4

- dichlorophenyl)

- 4

- propyl

- 1,3

- dioxolan

- 2

- yl]methyl]

- 1 H

- 1,2,4

- triazole

CAS # 60207

- 90

- 1

End

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

- 617



### 3.3 Physical and Chemical Properties

The physicochemical properties of propiconazole are reported in Appendix C.

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new uses of propiconazole on dry beans, snap beans, succulent shelled beans, and postharvest use on citrus fruit, stone fruit and tomato. For do mestic uses, humans may be exposed to propiconazole in food and drinking water, since propiconazole may be applied directly to growing crops and application may result in propiconazole reaching surface and ground water sources of drinking water. In an occ upational 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. There are also

residential uses of propiconazole , so there is exposure in residential or non

- occupational settings.

Risk assessments have been previously prepared for the existing uses of propiconazole . This risk assessment considers all of the aforementioned exposure pathways based on th e proposed new

use s of propiconazole , but also considers the existing uses as well, particularly for the dietary

exposure assessment.

3.5 Consideration of Environmental Justice

Potential areas of envir onmental 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

.

### Page 13 of 53

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

- establishe d 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 res idential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data ar e 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 condition s or circumstances warrant. Whenever appropriate, nondietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas

post

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

4.0 Hazard Characterization/Assessment

4.1 Hazard and Dose

- Response Characterization

4.1.1 Database Summary

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

A recent risk assessment document (HED memoranda B. Daiss , 0 4 / 27 / 11 , DP3 89194 ) contain s detailed and up

- to

- date discussions of the toxicology and hazard evaluation of propiconazole

. Please refer to these documents for further extensive details. Also, please refer to Appendix 2 of this current risk assessment document for the toxicity profile tables.

4.1.2 Studies Available and Considered

The following data are available:

Acute

- Oral rat, dermal rat, inhalation rat, eye irritation rabbit, dermal irritation rabbit, and skin sensitization guinea pig.

Subchronic

- Oral 90

- day rat, ora l 90

- day mouse (3) , and oral 90

- day dog;

Chronic

- Oral rat and dog; Reproductive/developmental

- Oral developmental rabbit and rat, 2

- generation reproductive rat

Other

- Oral rat and mouse cancer studies, 21

- day dermal rabbit toxicity and dermal penetration

stud y , neurotoxicity, metabolism, mutagenicity screens and mechanistic studies (3)

.

4.1.3 Sufficiency of Studies/Data

The toxicity database for propiconazole is adequate for the purpose of this risk assessment (see Appendixes for Toxicity Profile tables).

### Page 14 of 53

4.1.4 Toxicological Effects

T he primary target organ for propiconazole toxicity in animals is the liver. Increased liver weights were seen in mice after subchronic or chronic oral exposures to propiconazo le. Liver lesions such as vacuolation of hepatocytes, ballooned liver cells, foci of enlarged hepatocytes, hypertrophy and necrosis are characteristic of propiconazole toxicity in rats and mice. Decreased body weight gain was also seen in subchronic, chr onic, developmental and reproductive studies in animal studies. Mice appear to be more susceptible to propiconazole toxicity than rats. Dogs appeared to be more sensitive to the localized toxicity of propiconazole as manifested by stomach irritations at 6 mg/kg/day and above.

In rabbits, developmental toxicity occurred at a higher dose than the maternal toxic dose, while in rats, developmental toxicity occurred at lower doses than maternal toxic doses. Increased incidences of rudimentary ribs occurred in rat and rabbit fetuses. Increased cleft palate malformations were noted in two studies in rats. In one published study in rats

, developmental effects (malformations of the lung and kidneys, incomplete ossification of the skull, caudal

vertebrae and di gits, extra rib (14 th 

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

Propiconazole was negative for mutagenicity in the in vitro BALB/3T3 cell transformation assay, bacterial reverse mutation assay, Chinese hamster bone marrow chromosomal aberration assay, unsch eduled DNA synthesis studies in human fibroblasts and primary rat hepatocytes, mitotic gene conversion assay and the dominant lethal assay in mice. It caused proliferative changes in the rat liver with or without pretreatment with an initiator, like pheno barbital, a known liver tumor promoter. Liver enzyme induction studies with propiconazole in mice demonstrated that propiconazole is a strong phenobarbital type inducer of xenobiotic metabolizing enzymes. Hepatocellular proliferation studies in mice sugg est that propiconazole induces cell proliferation followed by treatment

- related hypertrophy in a manner similar to the known hypertrophic agent phenobarbital.

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

4.1.5 Cancer Classification

Propiconazole was carcin ogenic to CD

- 1 male mice. Propiconazole was not carcinogenic to rats or to female mice. The HED Carcinogenicity Peer Review Committee (CPRC) classified propiconazole as Group C

- possible human carcinogen and recommended that for the purpose of

risk char acterization the reference Dose (RfD) approach be used for quantification of human risk (HED Doc. No. 009771, April 15, 1992 meeting).

### Page 15 of 53

4.2 Absorption, Distribution, Metabolism, Excretion (ADME)

The r at metabolism study labeled with 14 

### C at the triazole

- [3,5] position indicated that parent compound was extensively metabolized. An intravenous study labeled with (U

14 

### C)

- Phenyl found several metabolites, including CGA 1 18245 (61.8% in males, 2.4% in females), CGA 217495 (8.9% in males, 58.3% in females), CGA 91304 (2.3% in males only), and CGA 118244 (3.6% in females only). No parent material was detected in the feces in the iv group. The

metabolites seen in the iv stud y were detected to varying degrees in the urine and the feces of the orally dosed groups. Radiolabeled materials CGA 91305, CGA 118245 and CGA 177291 were reported ranging from 0.5%

- 10.9% of the fecal radioactivity in males and females or in one sex

al one. Most of the fecal radioactivity was not characterized. Metabolites CGA 217495 and CGA 177291 are not found in plant or livestock metabolism (see Appendix for structures). In two other (U

14 

### C)

- phenyl and 14 

### C

- triazole ring labeled propiconazole stud ies, the percentages of fecal metabolites extracted and distributed at various pH‘s were not substantially different between the triazole and phenyl labeled samples, which suggest that the bridge between the phenyl ring and the triazole ring remained intac t. The proposed metabolic pathway appears to involve the cleavage of the dioxolane ring through the oxidation of the propyl side chain, with subsequent dechlorination and conjugation. In a (U

14 

### C)

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

4.3 FQPA Considerations

The toxicology databa se used to assess pre

- and post

- natal exposure to propiconazole is

considered adequate

.

4.4 FQPA Safety Factor for Infants and Children

For propiconazole there are a cceptable developmental toxicity studies in the rat and rabbit and an acceptable multi

- generation reproduction stud y in the rat. An acceptable acute neurotoxicity study in the rat is al so available in the database. S ubchronic neurotoxicity and immunotoxicity

studies are required under 40 CFR Part 158 as a part of the new data requirements for registration of a pesticide (food and non

- food uses). Although quantitative susceptibility was observed in the rat developmental study, a clear NOAEL

. is established for the developmental effects. Furthermore, the acute dietary for females 13

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

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

### Page 16 of 53

4.5 Hazard Identification and Toxicity Endpoint Selectio n

Doses and endpoints were selected for exposure routes (i.e., oral, dermal and inhalation) depending upon the appropriateness of the endpoint and the relevancy of the endpoints to the population of concern. Developmental ( in utero exposure) endpoints we re selected to assess dietary risks for Females 13

- 49 years of age, whereas non

- developmental (systemic toxicity) endpoints were selected to assess dietary and non

- occupational (residential) risks to the general population, including children and infants.

A summary of toxicological endpoints for use in human health risk assessment is presented

below:

Table 4 . Summary of Toxicological Doses and Endpoints for Propiconazole for Use in Dietary Human Health Risk

Assessments

Exposure/Scenario Point of

Departu re Uncertainty/FQP

A Safety Factors RfD, PAD, LOC

for Risk

Assessment Study and Toxicological Effects

Acute Dietary (General Population) NOAEL =

30 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x Acute RfD = 0.3

mg/kg/day

aPAD = 0. 3 mg/kg/day Acute neurotoxicity study Rat 46604601

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

Acute Dietary (Females 13

- 49 years) NOAEL =

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

UF H =10x FQPA SF= 1x Acute RfD = 0.3

mg/kg/day

aPAD = 0.3 mg/kg/day Developmental Study

- Rat 40425001

LOAEL = 90 mg/kg/day based on increased incidence of rudimentary ribs, un

- ossified sternebrae, as well as increased incidence of shortened and absent renal papillae and increased

cle ft palate.

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

10 mg/kg/day UF A = 10x

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

0.1 mg/kg/day

cPAD =

0.1 mg/kg/day 24

- month oncogenicity study on CD

- 1 mice.

00129918 LOAEL = 50 mg/kg/day based on non

- neoplasti c liver effects (increased liver weight in males and

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

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed a dverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = u se of a LOAEL to extrapolate a NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = to account for the absence of key date (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute , c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level

of concern. N/A = not applicabl e

### Page 17 of 53

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

Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk

Assessment Study and Toxicological Effects

Dermal Short Term (1

- 30 days)

DAF = 4 0% NOAEL= 30

mg/kg/day UF A = 10x

UF H =10x Residential LOC

for MOE = 100

Occu pational LOC

for MOE = 100 Acute Neurotoxicity Study

- Rats

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

Dermal Intermediate

Term (1

- 6 months)

DAF = 4 0% NOAEL= 10

m g/kg/day UF A = 10x

UF H =10x Residential LOC

for MOE = 100 Occupational LOC

for MOE = 100 24 Month Oncogenicity Study

- Mice

LOAEL = 50 mg/kg/day based on non

- neoplastic liver effects (increased liver weight in males and

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

Inhalation Short

Term (1

- 30 days) NOAEL= 30

mg/kg/day UF A = 10x

UF H =10x Occupational LOC

for MOE = 100 Acute Neurotoxicity Study

- Rats

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

Inhalation

Intermediate Term (1

- 6 months) NOAEL= 10

mg/kg/day 24 Month Oncogenicity Study

- Mice

LOAEL = 50 mg/kg/day based on non

- neoplastic liver effects (increased liver weight in ma les and

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

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

DAF = Dermal Absorption Factor



### Based on the availabl e toxicity database and the Agency's current practices, the inhalation risk for propiconazole was assessed using an oral toxicity study. The Agency sought expert advice and input on issues related to this route to route extrapolation approach (i.e. the us e of oral toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP‘s final report on March 2, 2010 ( http://www.epa.gov/scipo ly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, reexamine and develop new policies and procedures for conducting inhalation risk assessments, including route to route extrapolati on of toxicity data. If any new policies or procedures are developed, the Agency may revisit the need for an inhalation toxicity study for propiconazole and/or a reexamination of the inhalation toxicity risk assessment.

4.5.1 Recommendation for combining routes of exposure for risk assessment

When there are potential residential exposures to the pesticide, the aggregate risk assessment must consider exposures from three m ajor sources: oral, dermal and inhalation exposures. T here

are potential residential post

- application exposures to adults via the dermal route and to children

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

- term dermal and inhalation due to a common toxicological endpoint (clinical signs in the ACN study). A common toxicological endpoint was identified from the cancer mouse study f or intermediate

-

### Page 18 of 53

and long

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

t hese routes can be aggregated for these scenarios for the appropriate population.

5.0 Dietary Exposure/Risk Characterization

Reference: Propiconazole. New use on Snap Beans, Succulent Shell Beans, Dry Beans, Citrus Fruit (post

- harvest), Stone Fruit (post

- harvest), and Tomato (post

- harvest)

. T. Morton , DP3 8 9670

, 1/2 6 /1 2

.



### 5.1 Pesticide Met abolism and Environmental Degradation

5.1.1 Metabolism in Primary Crops

The nature of propiconazole residues in plants is adequately understood ( DP D329394, Y. Donovan, 6/15/06 ). These data indicate that the major metabolic pathway in plants involves hydroxylation of the n

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

- 1,2,4

- triazole

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

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

5.1 .2 Metabolism in Livestock

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

5.1.3 Drinking Water Residue Profile

Reference: Drinking Water Exposure Assessment for the IR

- 4 Petition (1E7855) that Proposes Tolerances Residues of Propiconazole on Dry Beans, Succulent Beans, and Snap Beans. DP38 9673

, I. Abdel

- Saheb

, 1/4/ 1 2.



### For propiconazole, tur f, a previously registered crop, has the highest application rate (6.285 lb a.i./A, 8 applications of 0.786 lb a.i../A per year with a 14

- day interval between applications) ( 

## (DP 325821,328690, Dated 07/07/2006 ). EFED has provided EDWC s for the proposed ne w uses and has provided a comparison of these new EDWC s with the previously assessed turf use.

The previously assessed turf EDWC s are approximately one order of magnitude higher (more protective)

, than the EDWCs for new uses and therefore, the turf EDWCs were used for the updated dietary risk assessment.

This drinking water assessment used surface water models PRZM/EXAMS and groundwater model (SCI

- GROW).

### Page 19 of 53

These results are based on EDWCs for Turf (DP 325821, 328690 , 07/07/2006). The proposed

new use doe s not result in higher EDWCs than those estimated for turf uses.

The estimated surface water drinking water concentrations for propiconazole are:

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

21.61 ug /L for the 1 in 10 year an nual mean concentration (non

- cancer chronic) and

13.24 ug /L for the 30 year annual mean concentration (cancer chronic).

The SCI

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

Drinkin g 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 (sur face water) and SCIGROW (ground water) residue estimates are summarized in Table 5. HED notes that there were no detects of 1,2,4

- triazole in any of the 271 water samples analyzed by PDP, with a limit of quantification of 730 parts

- per

- trillion (0.73 ppb) . The surface water estimates are significantly greater than those for ground water, and were used in the assessments for free 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 6 . 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

Chro nic 0.011 0.001



### 5.1.4 Food Residue Profile

Residues of Concern

Reference: Propiconazole (122101): Reregistration Eligibility Decision (RED) Document; Revised Residue Chemistry Considerations DP 329394

. Y. Donovan, 6 /1 5 /0 6

.



### A summary of the metabolites and degradates to be included in the risk assessment and tolerance expression are presented below in Table 7. Detailed rationale for these conclusions were presented in a previous document (DP3 29394 , Y. Donovan, 0 6 /1 5 /0 6 ).

### Page 20 of 53

Table 7 . Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression

.

Matrix For Risk Assessment  For Tolerance Expression

Plants Parent plus all metabolites convertible to 2,4

-

DCBA Parent only

Rotational crop Parent plus all metabolites convertible to 2,4

-

DCBA Parent only

Livestock: Parent plus all metabolites convertible to 2,4

-

DCBA Parent only

Water Parent only N/A

Note: For all triazole

- containing pesticides, the triazole

- conta ining metabolites 1,2,4

- T, TA, and TAA should also be included as residues of concern for risk assessment purposes only for plant and livestock commodities. Since

these metabolites are common to the entire class of triazole

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

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

M1 = 5

- [(4

- chlorophenyl)methyl]

- 2

- methoxyl

- 2

- methyl

- 1

- (1 H

- 1,2 ,4

- triazol

- 1

- ylmethyl)

- 1

- cyclopentanol; M11 = 5

- [(4

- chlorophenyl)methoxyl]

- 2,2

- dimethyl

- 1

- (1 H

- 1,2,4

- triazol

- 1

- ylmethyl)

- 1

- cyclopentanol; M12 = 5

- [(4

- chlorophenyl)methyl]

- 2

- carboxyl

- 2

- methyl

- 1

- (1 H

- 1,2,4

- triazol

- 1

- ylmethyl)

- 1

- cyclopentanol; M31 = (1S*,3R*,5 S*)

- 3

- hydroxy

- cis

- metconazole; 1,2,4

- T = 1 H

- 1,2,4

- triazole; TAA = 1 H

- 1,2,4

- triazol

- 1

- yl acetic acid;

TA = 2

- amino

- 3

- (1 H

- 1,2,4

- triazol

- 1

- yl)propanoic acid.



### Crop Field Trials

Field trials have submitted supporting the new uses for propiconazole. The results from these studies are discussed in the appropriate data evaluation report (DER) and summarized in the following tables.

TABLE 8. Summary of Residue Data from Snap Bean Crop Field Trials with Propiconazole.

Commodity Analyte T otal App.

Rate (lb ai/A) PHI

(days) Residue Levels (ppm) 1

n Sample

Min. Sample

Max. L AFT 2 HAFT 2 Median Mean Std.

Dev.

Snap beans Propiconazole 0.3370

- 0.3509 4 6

- 8 7 0.0866 0.390 0.0883 0.375 0.230 0.222 0.115

T 7 <0.01 <0.01 <0.01 <0.01 0.01 0. 01 N/A 3

TA 7 0.0408 0.180 0.0414 0.166 0.0853 0.0945 0.0463

TAA 7 <0.01 0.0127 0.01 0.0121 0.0100 0.0106 0.0009

1 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and

standar d deviation, the LOQ (0.05 ppm for propiconazole, 0.01 ppm for T and TAA, and 0.03 ppm for TA) was used for any results reported as <LOQ in Table C.3.

2 LAFT = lowest

- average

- field

- trial; HAFT = highest

- a verage

- f ield

- t rial.

3 N/A = Not applicable.

4 Three applications of approximately 0.11 lb ai/A.

### Page 21 of 53

TABLE 9. Summary of Residue Data from Lima Bean Crop Field Trials with Propiconazole.

Commodity Analyte Total App.

Rate (lb ai/A) PHI

(days) Residue Levels (ppm) 1

n Sample

Min. Sample

Max. L AFT 2 HAF T 2 Median Mean Std. Dev.

Seed Propiconazole 0.3327

- 0.5744 4 6

- 8 5 <0.05 0.0878 0.05 0.0723 0.05 0.0545 0.010

T 5 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A 3

TA 5 0.134 0.870 0.147 0.833 0.282 0.376 0.267

TAA 5 <0.01 0.0106 0.01 0.0104 0.01 0.0101 0. 0002

Foliage Propiconazole 0.3327

- 0.5744 6

- 8 5 1.83 12.8 3.36 12.4 6.29 6.67 3.73

T 5 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A 3

TA 5 <0.01 0.138 <0.01 0.0108 0.0159 0.0409 0.0466

TAA 5 <0.01 0.0291 0.0108 0.0264 0.0143 0.0171 0.0068

1 Except fo r sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and standard deviation, the LOQ (0.05 ppm for propiconazole, 0.01 ppm for T and TAA, and 0.02 ppm for TA) was used for any results reported as < LOQ in Table C.3.

2 LAFT = lowest

- average

- field

- trial; HAFT = highest

- a verage

- f ield

- t rial.

3 N/A = Not applicable.

4 Three applications of approximately 0.11 lb ai/A.

TABLE 10. Summary of Residue Data from Dry Bean Crop Field Trials with Propiconazole.

Commodity Analyte Total App.

Rate (lb ai/A) PHI

(days) Residue Levels (ppm) 1

n Sample

Min. Sample

Max. L AFT 2 HAFT 2 Median Mean Std. Dev.

Dry bean

seed Propiconazole 0.3285

- 0.3641 4 5

- 8 12 <0.05 0.253 0.05 0.248 0.0796 0.0985 0.0593

T 12 <0.01 <0.01 0.01 0.01 0.01 0.01 N/A 3

TA 12 <0.04 0.233 0.04 0.226 0.111 0.115 0.065

TAA 12 <0.01 <0.01 0.01 0.01 0.01 0.01 N/A 3

1 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and standard deviation, the LOQ (0.05 ppm for propiconazole, 0.01 ppm for T and TAA, and 0.04 ppm for TA) was used for any results reported as <LOQ in Table C.3.

2 LAFT = lowest

- average

- field

- trial; HAFT = highest

- a verage

- f ield

- t rial.

3 N/A = Not applicab le.

4 Three applications of approximately 0.11 lb ai/A.

### Page 22 of 53

TABLE 11. Summary of Residue Data from Tomato Crop Field Trials with Propiconazole.

Commodity Treatment

Type Analyte Total App.

Rate

lb a.i./ 100 gal DAA Residue Levels (ppm) 1

n Sample

Min. Sample

Max. L AFT 2 HAFT 2 Median Mean Std.

Dev.

Tomatoes (large and small)

Tomato Dip Propiconazole Only 0.2242

-

0.2249 0 6 0.412 1.12 0.469 1.12 0.676 0.702 0.254

Drench 0.2246

- 0.2249 0 3 0.394 1.50 0.457 1.38 0.865 0.901 0.463

S pray 0.2250

- 0.2256 3 0 3 0.324 1.53 0.366 1.47 0.743 0.860 0.561

Tomato Dip Total Propiconazole (as 2,4

- DCBA, expressed as propiconazole equivalents) 0.2242

-

0.2249 0 6 0.331 1.23 0.423 1.13 0.602 0.679 0.259

Drench 0.2246

- 0.2249 0 3 0.331 1.52 0.379 1.4 4 1.04 0.953 0.536

Spray 0.2250

- 0.2256 3 0 3 0.284 1.76 0.324 1.51 0.715 0.850 0.604

1 Except for sample min/max, values reflect per trial averages; n = no. of field trials.

2 LAFT = lowest

- average

- field

- trial; HAFT = highest

- a verage

- f ield

- t rial.

3 The application rate was lb propiconazole/50,000 lb fruit.

4 N/A = Not applicable.

TABLE 12. Summary of Residue Data from Citrus Crop Field Trials with Propiconazole.

Commodity

Treatment

Type Analyte Total App.

Rate

lb a.i./ 100 gal 5 DAA Residue Le vels (ppm) 1

n Sample

Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std.

Dev.

Orange Dip Propiconazole 0.80405

- 0.80743 0 8 0.77 5.66 0.87 4.91 2.425 2.79 1.20

Spray 0.81752

- 0.82761 3 0 4 1.03 2.32 1.08 2.28 1.23 1.46 0.56

Grapefruit Dip Propiconazole 0.80405

- 0.80768 0 2 0.90 1.44 0.92 1.31 1.12 1.12 0.28

Spray 0.82437 3 0 1 1.19 1.41 1.30 1.30 N/A 4 N/A N/A

Lemon Dip Propiconazole 0.80405 0 2 1.92 3.19 2.11 2.99 2.55 2.55 0.62

Spray 0.82131

- 0.82622 3 0 2 0.92 1.14 0.93 1.12 1.03 1.03 0.13

1 Exc ept for sample min/max, values reflect per trial averages; n = no. of field trials.

2 LAFT = lowest

- average

- field

- trial; HAFT = highest

- a verage

- f ield

- t rial.

3 The application rate was lb propiconazole/250,000 lb fruit.

4 N/A = Not applicable.

5 Two appl ications of approximately 0.4 lb ai/100 gal.

### Page 23 of 53

TABLE 13. Summary of Residue Data for Propiconazole (as Propiconazole and as 2,4

- DCBA) from Stone

Fruit Crop Field Trials with Propiconazole.

Commodity Analyte1 Total App.

Rate 1 DAA Residue Leve ls (ppm) 2

n Sample

Min. Sample

Max. L AFT 3 HAFT 3 Median Mean Std.

Dev.

TRT 02 ( Peach High

- Volume Spray )

Peach, Fruit Propiconazole 0.11415

- 0.11861 0 2 0.14 0.20 0.14 0.20 0.17 0.17 0.04

Propiconazole (as, 2,4

- DCBA) 2 0.13 0.33 0.13 0.33 0.23 0.23 0.14

TRT 0 3 ( Peach Low

- Volume Spray )

Peach, Fruit Propiconazole 0.11365

- 0.11445 0 2 0.43 0.56 0.49 0.50 0.50 0.50 0.01

Propiconazole (as, 2,4

- DCBA) 2 0.42 0.43 0.42 0.43 0.43 0.43 0.01

TRT 0 4 ( Peach Dip )

Peach, Fruit Propiconazole 0.11252

- 0.11285 0 4 1.16 2.17 1.17 2.11 1.54 1.59 0.42

Propiconazole (as, 2,4

- DCBA) 4 0.73 2.52 0.73 2.52 1.68 1.65 0.89

TRT 0 5 ( Plum Low

- Volume Spray )

Plum, Fruit Propiconazole 0.11384

- 0.11596 0 2 0.15 0.20 0.16 0.19 0.18 0.18 0.02

Propiconazole (as, 2,4

- DCBA) 2 0.13 0.40 0.13 0.40 0.27 0.27 0.19

TRT 0 6 ( Plum Dip )

Plum, Fruit Propiconazole 0.11265 0 2 0.16 0.22 0.18 0.20 0.19 0.19 0.01

Propiconazole (as, 2,4

- DCBA) 2 0.11 0.13 0.11 0.13 0.12 0.12 0.01

TRT 0 7 ( Cherry Dip )

Cherry,

Fruit Propiconazole 0.1124 4

- 0.11265 0 2 0.65 1.00 0.67 0.85 0.76 0.76 0.13

Propiconazole (as, 2,4

- DCBA) 2 0.78 2.23 0.78 2.23 1.51 1.51 1.03

TRT 0 7 ( Cherry High

- Volume Spray )

Cherry,

Fruit Propiconazole 0.11208 0 1 0.16 0.17 0.17 0.17 0.17 0.17 N/A

Propiconazole (as, 2,4

- DC BA) 1 0.24 0.24 0.24 0.24 0.24 0.24 N/A

1 Spray application rate = lb ai/200,000 lb fruit for peach and plum and lb ai/25,000 lb fruit for cherry for the packing

- line treatment applications and lb ai/100 gal water for the dip treatment applications.

2 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and standard deviation, the LOQ (0.05 ppm for all analytes) was used for any results reported as <LOQ in Table C.3. N/A = Not applic able.

3 LAFT = lowest

- average

- field

- trial; HAFT = highest

- a verage

- f ield

- t rial.

### Page 24 of 53

TABLE 14. Summary of Residue Data for Triazole Metabolites from Stone Fruit Crop Field Trials with

Propiconazole.

Commodity Analyte Total App.

Rate 1 DAA Residue Levels (ppm) 2

n Sample

Min. Sample

Max. L AFT 3 HAFT 3 Median Mean Std.

Dev.

TRT 02 ( Peach High

- Volume Spray )

Peach, Fruit T 0.11415

- 0.11861 0 2 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

TA 2 0.06 0.06 0.06 0.06 0.06 0.06 0.00

TAA 2 <0.05 <0.05 0.05 0.05 0. 05 0.05 N/A

TRT 0 3 ( Peach Low

- Volume Spray )

Peach, Fruit T 0.11365

- 0.11445 0 2 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

TA 2 0.06 0.09 0.07 0.08 0.08 0.08 0.01

TAA 2 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

TRT 0 4 ( Peach Dip )

Peach, Fruit T 0.11252

- 0.112 85 0 4 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

TA 4 0.07 1.94 0.08 1.83 0.13 0.54 0.86

TAA 4 <0.05 0.17 0.05 0.16 0.05 0.08 0.06

TRT 0 5 ( Plum Low

- Volume Spray )

Plum, Fruit T 0.11384

- 0.11596 0 2 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

TA 2 <0.05 0.09 0.05 0.08 0.07 0.07 0.02

TAA 2 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

TRT 0 6 ( Plum Dip )

Plum, Fruit T 0.11265 0 2 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

TA 2 <0.05 0.08 0.05 0.08 0.07 0.07 0.02

TAA 2 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

TRT 0 7 ( Che rry Dip )

Cherry,

Fruit T 0.11244

- 0.11265 0 2 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

TA 2 0.10 0.59 0.12 0.47 0.30 0.30 0.25

TAA 2 0.05 0.08 0.05 0.07 0.06 0.06 0.01

TRT 0 7 ( Cherry High

- Volume Spray )

Cherry,

Fruit T 0.11208 0 1 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

TA 1 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

TAA 1 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

1 Spray application rate = lb ai/200,000 lb fruit for peach and plum and lb ai/25,000 lb fruit for cherry for the packing

- line treatment applications and lb ai/100 gal water for the dip treatment applications.

2 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and standard deviation, the LOQ (0.05 ppm for all analytes) was used for any results reported as <LOQ in Table C.3. N/A = Not applicable.

3 LAFT = lowest

- average

- field

- trial; HAFT = highest

- a verage

- f ield

- t rial.



### Processed Food and Feed

The submitted citrus processing study is acceptable. Processing of the orange RAC wit h quantifiable residues of propiconazole resulted in the concentration of residues in dried pulp (1.4x processing factor) and oil (185x processing factor), but not in juice (<0.01x processing factor)

. The observed concentration factors were less than the theoretical concentration factors.

### Page 25 of 53

TABLE 15

. Residue Data from Citrus Processing Study with Propiconazole.

RAC Processed Commodity Total Rate (lb a.i./250,000 lb fruit) DAA Propiconazole

Residues (ppm) Processing

Factor 1

Orange Fruit (RAC) 0.40844 0 0.9 4

-- Juice <0.01 <0.01x Dried pulp 1.29 1.4x

Oil 174 185x

1 Processing Factor = [Measured residue for analyte in the processed fraction] / [Measured residue for analyte in the RAC].



### The observed processing factors for juice and oil are less t han the theoretical concentration factors, based on separation into components, of 2x for juice and 1000x for oil (OPPTS 860.1520, Table 3).

The citrus processing results acquired in this study are adequate for satisfying these data requirements. It prod uced sufficient data at the 1x application rate which is reflective of the proposed treatment program for evaluating the potential concentration of residues. These results indicate that propiconazole residues do not appear to concentrate in citrus juice, but do so in oil at a processing factor of 185x. Based on the HAFT residue for oranges (4.91 ppm) and the processing factor, expected residues are 908 ppm in citrus oil. A citrus oil tolerance of 1000 ppm is therefore concluded to be appropriate with no limits being recommended for its other processed commodities.

Meat, Milk, Poultry, and Eggs

Acceptable ruminant and poultry feeding studies were submitted and evaluated in conjunction with previous propiconazole petitions (PP#4F3074 and PP#1F3974).

Field Accumulation in Rotational Crops

The nature of the residue in confined rotational crops is understood (D329394, Y. Donovan, 6/15/06) . Based on acceptable studies previously reviewed by EFED, the metabolism of propiconazole in rotational crops is similar to that in primary crops. Plant

- back restrictions have been established for propiconazole products registered for use on rotational crops based on the confined rotational crop studies. Labels specify that any food/feed crops not listed on the la bel should not be planted within 105 days of treatment. Tolerances for inadvertent residues of propiconazole in/on alfalfa planted in rotation with propiconazole

- treated crops have been established at 0.1 ppm for alfalfa forage and hay.

### Page 26 of 53

5.2 Dieta ry Exposure and Risk

Reference: Propiconazole: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Snap Beans, Succulent Shelled Beans, Dry Beans, Citrus Fruit (post

- h arvest), Tomato (post

harvest) and Stone Fruit (post

- harvest).T. Morton, DP390248.drs, 1/ 26 /12.



### A new dietary assessment was conducted for the proposed Section 3 uses The proposed Section 3 uses on results dietary risk estimates below HED‘s level of conce rn; see Table 1 6

.

Table 1 6 . Summary of Dietary Exposure and Risk for Propiconazole FOOD PLUS WATER.

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

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

General U.S. Population 0.076469 25 0.021362 21

N/A All Infants (< 1 year old) 0.087716 29 0.024867 25

Children 1

- 2 years old 0.231169 77 0.062701 63

Children 3

- 5 years old 0.166601 56 0.050566 51

Children 6

- 12 years old 0.107056 36 0.031980 32

Youth 13

- 19 years old 0.076315 25 0.020569 21

Adults 20

- 49 years old 0.058779 20 0.016313 16 Adults 50+ years old 0.048739 16 0.015572 16

Females 13

- 49 years old 0.062471 21 0.016676 17



### Dietary Assessment of Free Tri azole and its Conjugates

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

Address The Amended Propiconazole Section 3 Registration to Add Uses on Snap beans, succulent shelled beans, dry beans, tomat o (post

- harvest, citrus (post

- harvest), and stone fruit (post

- harvest); The Amended Difenoconazole Section 3 Registration to Add Use on Root and Tuber group 1C; and the Amended Flutriafol Section 3 Registration

to Add Use on Field Corn. T. Morton , DP 397591

. drs, 1 / 26 /1 2

.



### T he proposed Section 3 use s of propiconazole result s in an increase in dietary exposure estimates for free triazole or conjugated triazoles. Therefore, the last dietary exposure analyses for the triazole

metabolites need ed to be updated. T he proposed Section 3 uses on results dietary risk estimates below HED‘s level of concern; see Table 1 7

.

### Page 27 of 53

Table 1 7 . Summary of Dietary (Food and Drinking Water) Exposure and Risk for the Common Triazole Metabolites Adding the new Section 3 Uses fo r Propiconazole, Flutriafol, and Difenoconazole.

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

Gene ral U.S. Population 0.00 8892 30 0.001 409 2 8

Not Applicable Not

Applicable All Infants (< 1 year old) 0.01 2475 42 0.00 1923 39

Children 1

- 2 years old 0.0 23049 77 0.00 3723 75

Children 3

- 5 years old 0.01 7674 59 0.002 994 60

Children 6

- 12 years old 0.0 11632 39 0.001 891 3 8

Youth 13

- 19 years old 0.00 8196 27 0.001 266 2 5

Adults 20

- 49 years old 0.00 6959 23 0.00 1162 2 3 Adults 50+ years old 0.00 6050 20 0.00 1097 22

Females 13

- 49 years old 0.00 7007 23 0.00 1166 23 Triazolylalanine + Triazolylacetic Acid General U.S. Population

Not Applicable Not

Applicable 0.01 9824 22

Not Applicable Not

Applicable All Infants (< 1 year old) 0.0 20308 2 3

Children 1

- 2 years old 0.0 56263 63

Children 3

- 5 years old 0.0 45007 50

Children 6

- 12 years old 0 .0 28078 31

Youth 13

- 19 years old 0.01 8635 21

Adults 20

- 49 years old 0.01 5881 1 8 Adults 50+ years old 0.0 14719 1 6

Females 13

- 49 years old 0.0 86155 86 0.01 6036 1 8 * The values for the highest exposed population for each type of risk asse ssment are bolded.



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

No new residential uses are being requested at this time. S pecifics concerning residential handler exposure and risks are provided in the most recent o ccupational and r esidential e xposure

a ssessment for propiconazole (D3 49727, S. Oonnithan, 9/3 /06)

.

Spray drift is always a potential source of exposure to residents nearby to spraying operations

. This is particularly the case with aerial application (a method proposed to be employed for propiconazole) , but, to a lesser extent, could also be a potential source of exposure from the ground application method also employed for propiconazole . The Ag ency has been working with the Spray Drift Task Force, EPA Regional Offices

, and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. On a chemical by chemical basis, the Agency is now requir ing interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast

, and ground hydraulic methods. After the policy is in place, the Agency may impose further

r efinements in spray drift management practices to reduce off

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

### Page 28 of 53

7.0 Aggregate Risk Assessments and 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 residential) . In an aggregate assessment, exposures from re levant sources are added together and compared to quantitative estimates of hazard ( e.g. , a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers

both the route and duration of e xposure.

7.1 Acute & Chronic Aggregate Risk

Acute and chronic aggregate exposures include food plus drinking water exposures. As demonstrated under Section 5.2, acute and chronic aggregate risks are not of con cern.

7.2 Short

- and Intermediate

- Term Aggregate Risk

Short term aggregate exposure takes into account residential exposure plus average exposure levels to food and water (considered to be a backg round exposure level). Table 1 8 aggregates
the short

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

- term aggregate
risk does not exceed HED‘s level of concern. This assessment is considered very conservative in that the residential incidental oral post

- application exposure was calculated by combinin g three screening level assessments (which by themselves already have conservative estimates).

Table 1 8 : Short

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

- 2years)

E xposure Scenario Target

MOE Route of Exposure Exposure NOAELs MOE at Day 0 Combined

MOE 5

Average Food and Water N/A Oral 0.0 627

30 48 0 2

1 30 Hand to Mouth Activity on Turf

100 1 Oral 0.0269 1100 3

Object to Mouth Activity on Turf Oral 0.0067 4500 3

Soil Ingestion Oral 0.00009 330,000 3

Turf

– High

- Con tact Activities Dermal 0.1410 210 4

1 Target MOE= 100, Acute Neuortoxicity NOAEL=30

2 MOE food = [(short

- term oral NOAEL)/(chronic dietary exposure)]

3 MOE oral = [(short

- term oral NOAEL)/(hand

- to

- mouth residential exposure)]

4 MOE dermal = [(short

- term dermal NOAEL)/(high

- end dermal residential exposure)]

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



### Table 1 9 aggregates the short

- term risk for adults from residential hand ler exposure, and average food and water exposure (as a background). The lowest aggregate MOE is 110, which is greater

### Page 29 of 53

than the target MOE of 100. Adult handlers have some inhalation exposure, but there are no appropriate inhalation studies on propiconaz ole to assess their potential risk. Based on a recent effort to determine whether oral studies are predictive of inhalation toxicity, HED has concluded that the MOEs for inhalation exposure are sufficiently large that there is no concern for potential

inh alation risk.

Table 1 9 : Short

- term Aggregate Risk Estimates to Propiconazole for Adults from Handler Activities

Exposure Scenario Target

MOE Route of

Exposure Exposure or

Daily dose NOAELs MOE at Day 0 Combined MOE 4

Average Food and Water

(As backgrou nd) N/A Food and

water 0.0 163 30 1800 2 NA

Ornamentals w Low Pressure

Handwand

100 1 Dermal and

Inhalation 0.0069

30 4400 3 1300

Ornamentals w Hose

- end Sprayer 0.0008 40000 1700

Turf w Low Pressure

Handwand 0.0237 1300 750

Turf w Hose

- end Spraye r 0.0568 530 410

Applying Paint w Brush/

Roller 0.0323 330 280

Applying Paint w Airless Sprayer 0.2432 120 110

1 Target MOE= 100, Acute Neuortoxicity NOAEL=30

2 MOE food and water = [(short

- term oral NOAEL)/(chronic dietary exposure)]

3 MOE d ermal and inhalation = [(short

- term NOAEL)/(high

- end inhalation and dermal residential exposure)]

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



### Table 20 aggregates the shor t

- term risk for adults from residential post application, and average food and water (as a background). Based on the low vapor pressure of propiconazole, negligible post application inhalation exposure is anticipated to occur. The highest post applicat ion exposure from residential use on turf was used in the short term aggregate. The aggregate MOE is 290, which is greater than the target MOE of 100. This aggregate exposure assessment is considered very conservative because the assumptions used for ea ch of the scenarios separately are already high end (i.e., time spent outdoors, dislodgeable residues).

### Page 30 of 53

Table 20 : Short

- term Aggregate Risk Estimates to Propiconazole for Adults from Post

- Application Activities

Exposure Scenario Target

MOE Rout e of Exposure Exposure or

Daily dose NOAELs MOE at Day 0 Combined MOE 4

Average Food and Water

(As background) N/A Food and

water 0.0 163

30 1800 2

290 Residential Post

- application (Residential Turf Gen. High

Contact Activities)) 100 1 Dermal 0.085 350 3

1 Target MOE= 100, Developmental rat

- increased incidence of rudimentary risks. NOAEL = 30

2 MOE food and water = [(short

- term oral NOAEL)/(chronic dietary exposure)]

3 MOE dermal = [(short

- term dermal NOAEL)/(high

- end dermal residential exposure)]

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



### 7.2 Intermediate

- Term Aggregate Risk

The only residential use scenario that will result in potential intermediate term exposure to propico nazole is post application exposure to children from wood treatment (antimicrobial use).

Table 21 shows the aggregate risk for intermediate term exposure to Children 1

- 2 years old. The aggregate MOE is 74, which is less than the target MOE of 100

. Howe ver, a refined chronic food and water exposure results in an MOE >100. Therefore, this scenario is not of concern.

Table 21

. Intermediate

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

- 2years)

Exposure Scenario Target

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

Average Food and Water N/A Oral 0.0 627 10 16 0 2

74 Incidental oral 100 1 Oral 0.0056 10 1800 3

Dermal Contact Activities 100 1 Dermal 0.068 10 150 4

Note:

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

2 MOE food = [(intermediate

- term oral NOAEL)/(chronic dietary exposure)]

3 MOE oral = [(intermediate

- term oral NOAEL)/(hand

- to

- mouth residential exposure)]

4 MOE dermal = [(intermediate

- term dermal NOAEL)/(high

- end dermal residential exposure)]

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



### These aggregate exposure assessments are considered conservative estimates, that should not underestimate risks, for the following reasons: 1) the dietary inputs used tolerance

- level residues, 100% crop treated, and crop specific (turf) screening level drinking water modeling data (i.e., surface water modeling); 2) maximum application rates and minimum application intervals were used; and 3) conservative SOPs and upper level estimates of exposure were employed.

### Page 31 of 53

Updated Aggregate Assessment of Free Triazole & its Conjugates

Reference: Common Triazole Metabolites: Updated Aggregate Human Health Risk Assessment to Address Tolerance Petitions for Propiconazole, Difenoconazole, and Flutriafol . DP 397592 , T. Morton, 1 / 26 /1 2

.



### The addition of the new proposed use s increase the aggregate exposure to free triazoles and its conjugates. Therefore, the aggregate human health risk a ssessment for free triazoles and its conjugates was updated and the aggregate estimates are below HED‘s level of concern ( DP3 97592 , T. Morton, 1 / 26 /1 2 ).

8.0 Cumulative Risk Characterization/Assessment

Propiconazole is a member of the triazole

- containing class of pesticides. Although conazoles act similarly in plants (fungi) by inhibiting ergosterol biosynthesis, there is not necessarily a relationship between their pesticidal activity and their me chanism 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 conazoles, however, a variable pattern of toxicological responses is found ; s ome are hepatotoxic and hepatocarcinogenic in mice. Some induce thyroid tumors in rats. Some induce developmental, reproductive, and neurological effects in rodents.

Further more, 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 toxicologi cal outcomes. Thus, there is currently no evidence to indicate that conazoles share common mechanisms of toxicity and EPA is not following a cumulative risk approach based on a common mechanism of toxicity for the conazoles. For information regarding EPA ‘s procedures for cumulating effects from substances found to have a common mechanism of toxicity, see EPA‘s website at http://www.epa.gov/pesticides/cumulative

.

Propiconazole is a triazole

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

m etabolite 1,2,4

- triazole and two triazole conjugates ( triazolylalanine and triazolylacetic acid ). To support existing tolerances and to establish new tolerances for triazole

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

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

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

- level evaluation in 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 Agenc y retained 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 f ound in the propiconazole reregistration docket at http://www.regulations.gov , Docket Identification (ID) Number EPA

HQ

- OPP

- 2005

- 0497.

### Page 32 of 53

9.0 Occupational Exposure/Risk Pathway

Reference: The occupational exp osure and risk assessment was reviewed by the Exposure Science Advisory Council, the information provided in this Section comes from:

. Propiconazole : Worker Risk Analysis for new uses on Beans (crop group 06), Tomatoes (crop group 08), Citrus (crop group 10), and Stone Fruit (crop group 12).

DP3 90250

, J. Miller

, 1 / 19 /1 2

.



### Occupational handler and post

- application exposure scenarios were assessed for the proposed

new uses. Based on the product labels and information provided by the registrant, short

- and

intermediate

- term exposure is assessed for handlers and post

- application activities. Dermal and inhalation exposures are aggregated for propiconazole because the toxicity endpoints for these exposure routes are not based on common toxicological endpoints

. Labels for the propiconazole proposed uses require that applicators and other handlers wear personal protective equipment (PPE) consisting of long

- sleeved shirt, long pants a nd shoes with socks plus gloves.

9.1 Short

- and Intermediate

- Term Handler Ris k

The term ―handler‖ applies to individuals who mix, load, and apply the pesticide product. There is a potential for exposure to propiconazole during mixing, loading, and application

activities thro ugh the dermal and inhalation routes. Propiconazole products are applied using aerial, airblast, groundboom and chemigation equipment

.

The quantitative exposure/risk assessment developed for occupational handlers is based on the following exposure scena rios:

Mixer/Loaders

• M ixing / loading emulsifiable concentrates for aerial application

• M ixing / loading emulsifiable concentrates for groundboom application

Applicators

• A pplying sprays aerially

• A pply ing sprays with ground boom sprayer

Flaggers

• F lagging fo r aerial spray application

Chemical

- specific data for assessing exposure during pesticide handling activities were not submitted to the Agency in support of this Section 3 application. This risk assessment relies in part on data from studies in which adu lt human subjects were intentionally exposed to a pesticide or other chemical. These studies, which comprise the Pesticide Handlers Exposure Database (PHED), and the Agricultural Handler Exposure Task Force (AHETF), have been determined to

### Page 33 of 53

require a revie w of their ethical conduct, have received that review, and have been determined to

be ethical.

Summaries of the combined, dermal plus inhalation short

- , and intermediate

- term risks for each

exposure scen ario are presented in Table 1 8 . The combined derma l and inhalation exposure risks are not of concern (i.e., MOEs >100), provided the mixer/loaders wear chemical

- resistant gloves as directed on the label.

An occupational and residential assessment was completed for similar use patterns (aerial, groundbo om), which found that there we re no risks of concern (J. Miller, 06 /1 5/06, D 325817 ). It should be noted that in (D325817) , the evaluated use pattern for the aerial, and groundboom exposure scenarios were more conservative for rice (i. e ., 0.28 lb a

. i

. /acre ) for 1200 acres treated, than proposed in the current petition (i.e., 0.114 lb a.i./acre) for legume vegetables at 350 acres treated and therefore protective. Refer to; (J. Miller, 06/15/06, D325817) for toxicological endpoint data and previous calculat ion parameters. Margin of Exposure calcula tions were impacted due to a de crease in acres treate d (legume vegetables vs. rice ) , application rate, and updated unit exposures 1 

### adopted by the Health Effects Division (HED). Exposure scenarios listed within (m ixing/loading, applying, and flagging), risk estimates do not exceed HED‘s LOC (MOE < 100), and therefore not of concern to HED. See Table 22 for details.

1

. 1 Note; HED policies on use of surrogate data, including their sources, are presented in the ―Occupational Pesticide Handler Unit Exposure Surrogate Reference Table‖ ( http://www.epa.gov/pesticides/science/handler

- exposure

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

- exposure

- data.html)

### Page 34 of 53 Table 22 : Occupational Short and Intermediate

- Term Risk Assessment/ Amended Uses of Propiconazole

Exposure

Scenario Crops Applicatio

n Rate (lb a.i. /A) 1 Area

Treated (A/day) 2 Dermal

Unit Exposure ( m g/lb a

. i

. ) 3 Inhalation

Unit Exposure
( g/lb a

. i

. ) 3 Dermal

Daily Dose Inhalation

Daily Dose Short

Term Intermediate

T erm

(mg/kg/day) 4 MOE 5

Combined dermal/inhalation

Mixer/Loader ( emulsifiable concentrate ) 6

Groundboom Legume

Vegetables 0.114 80
0.22 0.219 0.0114 7 0.0000285 2,600 870

Aerial 350 0.05016 0.0001248 600 200

Applying ( emulsifiable concentrate )

Ground boom (Open Cab) Legume

Vegetables 0.114 80 0.0786 0.34 0.00409 6 0.0000443 7,200 2,400

Aerial (encl. Cockpit) 350 0.005 0.068 0.00114 0.000038 8 25,000 8,500

Flagging ( emulsifiable concentrate )

Aerial Flagging Legume

Vegetables 0.114 350 0.011 0.3 5 0.0 025 0.0002 11,000 3,700

1. Application rates are based on maximum values found in proposed labels. 2. Daily area treated is based on the area that can be reasonably applied in a single day for each exposure scenario

. (Standard EPA/OPP/HED values).

3 . HED policies on use of surrogate data, including their sources, are presented in the ―Occupational Pesticide Handler Unit Exposur e Surrogate Reference Table‖ ( http://www.epa.gov/pes ticides/science/handler

- exposure

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

- exposure

- data.html )

4 . Daily Dose (mg/kg/day) was calculated by Unit Exposure * 40% absorption for dermal only * Appl. rate * Area treated} / 70 kg.

5 . Short

- /Intermediate

- Term MOE (dermal and inhalation endpoints are the same, therefore the MOEs are combined) = Dermal + Inhalation Dose

/ NOAEL . Short

- term NOAEL= 30 mg/kg/day and Intermediate

- term NOAEL = 10 mg/kg/day . The LOC for the target MOE = 100.



### Flagger

The Agency has evaluated scenarios that may be limited in nature such as flagging during aerial applications b ecause engineering controls (i.e. Global Positioning Satellite technology) are now predominantly used as indicated by the 1998 National Agricultural Aviation Association (NAAA) survey of their membership. It appears, however flaggers are still used in

app roximately 10 to 15 percent of aerial application operations. In cases like these, the Agency strongly encourages the use of the engineering control system, but will continue to evaluate risks for flaggers and any other population where a clear exposure p athway exists until the potential for exposure is eliminated. The Agency is aware that NAAA is conducting another survey of its membership on exposure issues and will consider those results as is timely and appropriate. For pesticide handlers, HED present s estimates of dermal exposure for ―baseline‖ (i.e. workers wearing a single layer of work clothing consisting of a long sleeved shirt, long pants, shoes, plus socks and no protective gloves, as well as for ―baseline‖ and the use of protective gloves or ot her personal protective equipment (PPE), as might be necessary. The propiconazole product labels for foliar treatments recommend applicators and other handlers to wear long

- sleeved shirt and long pants, and shoes plus socks.

### Page 35 of 53

Handler Exposure

- Post Harve st Use Pattern

According to label; [( Tilt® 45W (EPA Reg. No.:100

- 780)]

, p ropiconazole can be applied to tomatoes, citrus, and stone fruit after harvest inside packing facilities using a T

- jet or CDA system. Application methods, maximum application rates, and use sites are summarized in Table 1. Handler exposure is expected to be short

- or intermediate

- term based on information provided on the proposed label.

Exposure Scenarios

The quantitative occupational exposure/risk assessment for the use of prop iconazole on post

harvest crops is based on the mixing and loading of wettable powders only.

Open Mixing and Loading of wettable powders Application of propiconazole solutions are typically automated with commodities passing through sprays/foams/brushes on conveyor belts or bins being mechanically dipped. The commodities are then manually sorted and packed by workers at the end of the process.

Note: Application of solutions by dipping, drenching, brushing, spraying are not typical ―applicator‖ scenari os. The assessment for automated application estimates exposures and risks for workers in the vicinity of the application process; therefore exposure during the application of a post

- harvest pes ticide is expected to be limited to mixing and loading

. See ( D. Jaquith, 11/2005) for details.

Personal Protecti ve Equipment

Baseline PPE: includes typical work clothing (i.e., a long

- sleeved shirt, long pants, shoes, socks, and no respiratory protection). It does not include chemical

- resistant gloves.

Baseline /Gloves PPE: includes chemical

- resistant gloves in addition to baseline PPE. Note: most labels call for handlers to don at least this level of protection

Data and Assumptions for Post Harvest Handler Exposure Scenarios

An Expo

- SAC draft policy (D. J aquith, 11/2005) is used to assess exposure from post

- harvest application to tomatoes, citrus, and stone fruit. The draft SOP indicates that procedures (and therefore exposure estimates) are essentially the same for all post

- harvest products. The draft

S OP outlines exposure estimates from application to harvested citrus because it is assumed that citrus facilities have the highest throughput compared to facilities treating other commodities. However, some label

- specific information was used in this asses sment.

### Page 36 of 53

The estimates of exposure and risk resulting from these calculations should be considered conservative for the following reasons: 1) workers are not assumed to wear any protective clothing while mixing/loading the material for post

- harvest treatm ents; 2) the material is not assumed to be recycled, while in practice some chemical solutions are recycled/re

- used 3 to 5 times before new formulation is mixed; and 3) when generic citrus estimates were used, other commodities may not have the throughput associated with a large citrus packing plant. Using the generic estimates in the draft SOP and label

- specific information, the exposure assessment was calculated using the following data and assumptions:

Unit Exposures

No chemical

- specific handler exp osure data were submitted in support of this registration. To assess handler exposures for regulatory actions when chemical

- specific monitoring data are not available, HED relies on the most scientifically

- reliable surrogate data currently available from various sources such as the Pesticide Handlers Exposure Database (PHED), and the Agricultural Handler Exposure Task Force (AHETF). Some of this data, such as the industry task force data, is compensatory, subject to the data protection provisions of FIFRA . HED policies on use of surrogate data, including their sources, are presented in the ―Occupational Pesticide Handler Unit Exposure Surrogate Reference Table‖ ( http://www.epa.g ov/pesticides/science/handler

- exposure

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

- exposure

- data.html)

.

Max Application Rates

The label

- specified amount of propiconazole to treat post

- harvest tomatoes was (8 oz

. per 50,000 lbs. of tomatoes )

.

The label

- specified amount of propiconazole t o treat post

- harvest citrus was (16 oz

. per 250,000 lbs. ) of citrus.

The label

- specified amount of propiconazole to treat post

- harvest stone fruit was (4 oz

. per 250,000 lbs. ) of stone fruit.

Amount Treated/ Processed

Based on the draft SOP (D. Jaquith , 11/2005)

, which uses citrus packing as the most conservative post

- harvest scenario, HED assumes that a facility can process up to 2,000 boxes per hour, each weighing 90 pounds. This throughput is protective for tomatoes and

stone fruit.

Body Weight

Th e average adult body weight of 70 kg.

, was used for calculations.

### Page 37 of 53

Absorption Factor s

The short

- and intermediate

- term dermal absorption factor is 40%

.

Equations and Calculations

Maximum Application Rate: The maximum application rate was calculated by using the proposed lbs. a.i. of product per lbs. of specific crop.

Max. App. Rate (lbs a.i./lbs specific crop.) = oz. product/lbs. specific crop x 1 lb/16 oz. x 45% a.i.



### Amount Treated/Processed per Day: The amount treated per day was calculated by using the proposed default values per day.

o Amount Processed : Default citrus value of 2,000 boxes per hour, each weighing

90 lbs. An 8

- hr workday is assumed

Amount processed (lbs crop/ day ) = 2,000 boxes/hr x 90 lbs x 8 hrs/day

For p ost harvest in

- line dip/drench and or a coating spray exposure scenario to Tomatoes (crop group 08), Citrus (crop group 10), and Stone Fruit (crop group 12), risk estimates do not exceed HED‘s LOC (MOE < 100), and therefore not of concern to HED. See Table 23 for details.

### Page 38 of 53

9.2 Short

- and Intermediate

- Term Post

- Application Risk

Agricultural workers performing typical post

- application a ctivities may receive exposure to propiconazole residues.

Occupational Post

- application Exposure and Risk

HED uses the term post

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

re

- entry exposure). Such exposure may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pest or harvesting. In the c ase for propiconazole , post

- application dermal exposure to field workers following foliar applications is probable, whereas propiconazole is a fungicide that can be applied to all stages of growth. Since no post

- application data were submitted in support of the registration action, dermal exposures during post

- application activities were estimated using dermal transfer coefficients from the Science Advisory Council for Exposure Policy Number 3 ( http://www.epa.gov/pesticides/science/exposac_policy3.pdf ), and summarized in T able 20

below. Table 23 . Occupational Handler Short

- and Intermediate

- Term Dermal and Inhalation Exposure and Risk Estimates for Tomato, Citrus, and Stone Fruit Post

- Harvest Use

Activity/ Exposure

Scenario

M ax App.

Rate 1

(lb a

. i

. /lbs. crop) Amount

Treated/

Processed Crop Specific 2

( lbs. crop / day) Inhalation

Unit Exp. 3
(mg/lb a

. i

. ) Dermal Unit

Exp. 3
(mg/lb a

. i

. ) ST & IT

Inhalation Daily Dose 4
(mg

a

. i

. /kg/day) ST & IT Dermal

Daily Dose 4
(mg a

. i

. /kg/day) Short

Term

MOE 5 Inter.

-

Term

MOE 5

Baseline W/

gloves Baseline W/ gloves Dermal +

Inhalation

Baseline 8 With

Gloves

Tomato (Crop Group 8) Wettable Powders 2

Open Mixing/ Loading 0.22 5 / 50,000 1,440,000 0.0434 3.7 .17 0.00402 0.137 0.0063 210 71 970

Citrus (Crop Group 10) Wettable Powders

Open Mixing/ Loading 0.4 50/250,000 1,440,000 0.0434 3.7 0.00161 0.0548 530 62,000

Stone Fruit (Crop Group 12) Wettable Powders

Open Mixing/ Loading 0.11 3/250,000 1,440,000 0.0434 3.7 0.00040 0.014 75,000 25,000

1. Max appl. Rate on label : [(oz. product/lbs. crop) x (lb/16 oz

. ) x (45% a

. i

. ) = (lb a.i. / lbs. crop )]

. Wettable Powder Formulation

- Tilt® 45W (EPA Reg

No.: 100

- 780) 45%

. 2. Amount T reated/Processed Per day (lbs. crop/day) = 2000 boxes/hr x 90 lbs/box x 8 hrs/day

3

. Unit Exposure Values

- Baseline PPE: includes typical work clothing (i.e., a long

- sleeved shirt, long pants, shoes, socks, and no respiratory protection).

It do es not include chemical

- resistant gloves...

. except for the tomato scenario, where gloves were added to achieve an MOE > 100

4 . Daily Dose

- [ Max. App Rate (lb s a.i./lbs. crop ) x Amount Treated/Processed (lb crop/day) x Unit Exposure (mg/lb a.i.) x absorp tion factor (.40 , applicable to dermal route only )]/ 70

- kg body weight

5 . Short /Intermediate

- Term MOE (dermal and inhalation endpoints are the same, therefore the MOEs are combined) = Dermal + Inhalation Dose / NOAEL

. Short

- term NOAEL= 30 mg/kg/day and Intermediate

- term NOAEL = 10 mg/kg/day . The LOC for the target MOE = 100

### Page 39 of 53

The following assumptions were used for all calculations:

Body Weight

The average adult body weight of 70 kg was used for calculations.

Absorpti on Factor s

The short

- and intermediate

- term dermal absorption factor is 40%

.

Application Rate

Application rate = 0.114 lbs a

. i

. /Acre

Exposure Duration

8 hours /Day

The fraction of a.i. retained on foliage is assumed to be 20% (0.2) on the day of app lication (= % dislodgeable foliar residue, DFR, after initial treatment) for agricultural crops. This fraction is assumed to further dissipate at the rate of 10% (0.1) per day on following days. These default

values have been established by HED ̳s Science Advisory Council (SAC) for Exposure.

Not e: For specifics concerning all post

- application studies as they refer to propiconazole

- specific dissipation data , (see Memorandum, DP #: 329393 titled, Propiconazole: Phase IV revised Occupational and Resident ial Exposure Assessment for the Re

- registration Eligibility Decision Document (RED) for details.

Post

- application MOEs were estimated for ―Day 0" exposure (i.e., the day of application). As

shown in Table 2 4 , the short

- /intermediate

- term MOEs are great er than 100 on the day of application for all agricultural crops.

### Page 40 of 53

Post

- application Exposure Calculations:

Daily Exposure : The next step in the risk assessment process was to calculate dermal exposures on each day after application using the following equation.

o DFR t 

### = AR x F x (1

- D) t 

### x CF1 x CF2

Where:

DFRt = dislodgeable foliage residue on day ―t‖ (μg/cm 2 

### )

AR = application Rate (lb ai/acre)

F = fraction of a

. i

. retained on foliage (unitless)

D = fractio n of residue that dissipates daily (unitless)

CF1 = conversion factor, 4. 54E + 8 

### μg/lb

CF2 = conversion factor, 2.47E - 8 

### acre/cm 2



### Daily Dermal Dose and Margins of Exposure : Once daily exposures are calculated, the

calculation of daily absorbed dose and the resulting Margin of Exposures use the equations

shown below . These calculations are completed for each day or appropriate block of time after application.

o Daily Dermal Dose = DFR t 

### x CF1 x TC x DA x ET) / BW

Where:

Daily De rmal dose = Absorbed dose received from exposure to a pesticide in a given scenario on day ―t‖ (mg/kg/day)

DFR t 

### = D islodgeable foliage residue on day ―t‖ (μg/cm 2 

### )

CF1 = C onversion factor, 1E

– 3 

### mg/μg

TC = T ransfer coefficient (cm 2 

### /hr)

DA = dermal absorption factor (unitless)

ET = exposure time (hr/Day)

BW = body weight (kg)

o MOE = POD (mg/kg/day) / Daily Dermal Dose (mg/kg/day)

Post

- application Expo sure Summary : Legume Vegetables

Risk estimates do not exceed HED‘s LOC (MOE < 100), and therefore not of concern to HED.

See Table 2 4 for details.

### Page 41 of 53

1 Maximum application rate from proposed label

2 DAT = Days after treatment needed to reach the LOC of 100; DAT 0 = the day of treatment/ assumed to be approx. 12 hours.

3 DFR (μg/cm 2 ) = dislodgeable foliar residues corresponding to DAT, based on 20% of application rate.

4 TC (cm 2 /hr) = transfer coefficients and associated activities from Expo

- SAC Policy Memo #003.1, 8/17/2000.

5 MOE = MOE on the corresponding DAT. MOE = NOAEL / Daily Dose.

Short

- Term NOAEL = 30 mg/kg/day

. Intermediate

- term NOAEL = 10 mg/kg/day.

The LOC is 100. * Daily Dose = [(DFR x TC x 40 % Dermal absorption x 8

- hr Exposure Time)] / [(CF: 1000 μg/mg) x (7 0

- kg Body Weight)



### Post Harvest

- Post

- application Exposure and Risk

Propiconazole is applied as a post harvest treatment to citrus, stone fruit and tomatoes either as a coating spray or during in

- line dip procedures. Post application exposure may occur during sorting/packing/culling operations. The estimates of post appl ication exposure can be derived from residue chemistry data, surface area calculations, and a reentry study for citrus found in the scientific literature, and a study monitoring the amount of material transferred during contact

with a treated surface. See a n Expo

- SAC draft policy (D. Jaquith, 11/2005) , for details.

Data and Assumptions for Post Harvest Handler Exposure Scenarios

The residue level of propiconazole in oranges from post

- harvest field trials is 4.91 ppm ( μ g/g); (see MRID No. 48438205).

Pe sticide residue is on the surface of the commodity. The chemical is not applied as a systemic product.

Workers are assumed to perform the sorting/culling tasks for 8 hours per day.

Dermal absorption is 40%.

The transfer efficiency of the chemical is l ess than 2%.

The transfer coefficient for the palmar surface of the hands only = 408 cm2 per hour. Table 2 4 . Summary of Estimated Post

- applica tion MOEs for Legume Vegetables

Crop Application

Rate
(lb a

. i

. /A) 1 DAT 2 DFR 3
(μg/cm 2 ) TC 4

(cm 2 /hr) Activity 4 Short

Term Int er

Term

MOE 5

Legume Vegetables
(Crop Group 06) 0.114 0 0. 256 70 Hand weeding, Thinning 37 ,000 12 ,000

210 Scouting 12 ,000 4,100

1,100 Scouting 2,3 00 780

1,900 Irrigation (hand set) 1,4 00 450

### Page 42 of 53

Post Harvest: P ost

- application Exposure Calculations:

Propiconazole residue on the surface of the Navel orange can be calculated as follows:

Propicona zole (μg /orange) = 4.91 μg/g x 165 g/orange = 810.15 μg/orange

The surfac e area of a ―Navel‖ orange is:

Surface Area = 167.42 cm 2



### The pesticide residue assumed to be on the surface and available for transfer would therefore be:

810.15 μ g/167.42 cm2 = 4.84 μg/cm2

Wit h a transfer coefficient of 408 cm2/hr and a transfer efficiency of 2%, the dermal dose of a 70 kg individual becomes:

Dermal dose calculation:

(408 cm2/hr) x (4.84 μg/cm2) x (8 hrs/day) x 0.4 x 0.02 x 0.001 mg/ μg 70 kg

= 0.00181 mg/kg/day

Post Harvest: Post

- application Exposure Summary :

Risk estimates do not exceed HED‘s LOC (MOE < 100), and therefore not of concern to HED.

See Table 2 5 for details.

### Page 43 of 53 Table 2 5 . Summary of Estimated Post Harvest Post

- applica tion MOEs for Citrus.

Commodity Chemical in Specific

Commodity Chemical Specific Commodity Specific

Surface area Surface

Residue Dermal Dose Short

Term

MOE 2 Int

Term

MOE 2

1 μg /g g /C ommodity μg / Commodity (cm2) (μg/cm 2 ) (mg /kg / day)



### Citrus (Navel Orange) 3 

### 4.91 165 810.15 167.42 4.84 0.00 181 16,600 5,500

1 Residue l evel calculations for Navel Orange : (MRID No. 48438205)

2 MOE = MOE = NOAEL / Daily Dose. Short

- Term NOAEL = 30 mg/kg/day . Intermedia te

- term NOAEL = 10 mg/kg/day. The LOC is 100 *Daily Dose = [(Surface Residue x TC (408 cm 2 /hr) x 40 % Dermal absorption x 2% transfer efficiency x 8

- hr Exposure Time)] / [(CF: 1000

μg/mg) x (7 0

- kg Body Weight) ].

3 Citrus : (Navel Orange ) use d in calculations because it has the highest residue from citrus crop field trials (MRID, and protective of other (Crop Group 10) commodities.



### Post

- Application Inhalation: Based on the Agency's current practices, a quantitative occupational post

- applica tion inhalation exposure assessment was not performed for propiconazole at this time; an inhalation exposure assessment was performed for occupational

handlers. This assessment resulted in risk estimates that did not exceed HED’s level of

concern at basel ine inhalation PPE. 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 estimates would be protective o f most occupational post

- application inhalation exposure scenarios. However, there are multiple potential sources of post

- application inhalation exposure to individuals performing post

application activities in previously treated fields. These potential s ources include volatilization of pesticides and re

- suspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Ro denticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP‘s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as we ll as available post

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

post

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

post

- application inhalation exposure assessment for propiconazole

.

### Page 44 of 53

App endix A: Toxicology Assessment

A.1 Toxicology Data Requirements

Table A.1. Propiconazole Toxicology Data Requirements

Guideline Data Requirements

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

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

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

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

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

yes

yes

yes

y es

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

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

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

- Day Dermal

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

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

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

yes

yes

no

yes yes

yes

yes

- yes

870.3700a Development al Toxicity (rodent)

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

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

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

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

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

................................ ........ 870.4200a Oncogenicity (rat)

................................ .......................... 870.4200b Oncogenicity (m ouse)

................................ .................... 870.4300 Chronic/Oncogenicity

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

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

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

— Gene Mutation

- mammalian

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

— Structural Chromosomal Aberrations

... 870.5900 Mutagenicity

— Other Genotoxic Effects

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

yes

yes

yes yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen)

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

- Day Neurotoxicity (hen)

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

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

- Day Neuro. Screening Battery (rat)

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

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

no

yes

yes

no -

- yes

no

-

870.7485 General Metabolism

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

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

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

no

y es yes

-

no

### Page 45 of 53

A.2 Toxicity Profiles

Table A.2 : Propiconazole Acute Toxicity Profile

Guideli neNo

. Study Type MRID # Results Toxicity Category

870.1100 Acute Oral Toxicity

– rat 00058591 LD 50 =1517 mg/kg III

870.1200 Acute Dermal Toxicity

- rabbit 00058596 LD 50 = >4000 mg/kg III

870.1300 Acute Inhalation Toxicity

– rat 41594801 LC 50 = >50.84 mg/L IV

870.2400 Acute Eye Irritation 00058597 Corneal opacity reversed in 72 h rs III

870.2500 Acute Dermal Irritation 00058598 No irritation IV

870.2600 Skin Sensitization 44949501 confirmed sensitizer

-

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

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

Classification /Doses Results

870.3100

90

- Day Feeding Study in Rat 00058606 (1997)

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

870.3100

3

- month oral toxicity

st udy

- mice 42050501 ,(1991)

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

870.3100

3

- month oral

- male

mice 42050502 (19 91)

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

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

870.3100

3

- month oral

- male

mice. 45215801 (1997)

Supplement to MRID

42050502: Reexamination

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

LOAEL

870.315 0

3

- month dog (dietary) 00058607(1979)

Acceptable/Guideline 0, 50, 250 or 1250 ppm (0, 1.25, 6.25, 31.25 mg/kg/day) LOAEL is 250 ppm (59 mg/kg/day) based on the finding of lymphoid follicles in the mucous membrane of the pyloric part of

the stomach.

NOAE L is 50 ppm (13mg/kg/day)

### Page 46 of 53

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

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

Classification /Doses Results

870.3200

21

- Day dermal toxicity

- rabbits 00116591 (1982)

Acceptable/Guideline 0, 3, 30 or 300 mg/kg/day LOAEL: 3 mg/kg/day based on mild dermal irritation (Hyperkeratosis, acanthosis, mild dilation of blood vessels and

mononu clear cells and/or heterophils in the proximal dermis). No systemic toxicity was reported.

NOAEL for skin lesions not established

870.3700a Developmental Toxicity

- Rat 40425001(1987)

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

Non

- guideline Developmental Toxicity

- Rat 40425002 (1987)

Acceptable/non

- guideline 0 or 300 mg/kg/day cleft pala te: 2/2064 fetuses of dosed animals vs. 0/1222 controls (lab.hist. control incidence: was 0/5431). This confirms findings of cleft palate noted in above study. Severe clinical toxicity in the treated animals (ataxia, coma, lethargy, prostation, labored re spiration and salivation)

870.3700b Developmental Toxicity

- Rabbit 40425004 (1986)

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

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

870.3800

2

- Generation reproduction

- Rat 00151514 (1985)

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

LOAEL = 2500 ppm (192

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

- 52 mg/kg/day)

870.4100

12

- Month Chronic Oral Toxicity (dietary)

- Dogs 00151515 (1985)

Acceptab le/guideline 0, 5, 50 or 250 ppm (0, 0.12, 1.25, or 6.25 mg/kg/day) LOAEL = 250 ppm (6.25 mg/kg/day), based on hyperemia of the stomach in males (indicating mild irritation of the mucosa). NOAEL is 50 ppm (1.25 mg/kg/day)

### Page 47 of 53

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

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

Classification /Doses Results

870.4100

24

- Month

Chronic/Carcin ogenic ity Feeding

- Rats 00129918 (1982)

Acceptable/guideline 0, 100, 500 or 2500 ppm (male 3.6, 18.1 and 96.4

, female 4.6, 23.3 and 100.6 mg/kg/day) LOAEL = 2500 ppm (96.4 mg/kg/day) based on liver lesions (vacuolation of hepatocytes in males, bal looned cells in the liver of males, foci of enlarged hepatocytes in females, and increased incidence of luminal dilation of the uterus) and reduced body weight gain in both males and females. NOAEL = 500 ppm (18.1 mg/kg/day). The test material was not ca rcinogenic at the doses

tested.

870.4200

24

- Month Carcinogenicity in

Mice 00129570 (1982 )

Acceptable/guideline 0, 100, 500 or 2500 ppm (M: 10.0, 49.4, and 344.3 F: 10.8, 55.6 and 340.3 mg/kg/day LOAEL = 500 ppm (49.5 mg/kg/day) based on non

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

870.4200

18

- month oncogenicity study

- mal e CD

- 1 mice 44381401 (1997)

Acceptable/guideline 0, 100, 500 or 850 ppm (0, 11, 59 or 108 mg/kg/day) LOAEL= 500 ppm (59.0 mg/kg/day) for males, based on hepatotoxicity (increased liver weight, hepatocellular hypertrophy, liver necrosis) and body weight gai n effects observed at the interim

and terminal sacrifices. NOAEL= 100 ppm (11.0 mg/kg/day) for males. Treatment related increase in hepatocellular adenoma and total hepatocellular neoplasia at the 850 ppm exposure level compared to concurrent controls, bu t were within the range of the inadequate historical control data submitted with the study report. Adequate dosing based on body weight gain and hepatotoxic effects seen at 500 and 850 ppm. Subsequently, the Registrant submitted

additional control data o n five groups of CD

- 1 male mice generated within the approximate time frame of the original study and in the same testing facility under similar experimental conditions (MRID 45215804) concerning the spontaneous occurrence of liver tumors.

The tumor inci dence observed in male livers at the 850 ppm dose is within the range of the new historical data.

870.6200

Acute neurotoxicity

in rats 46604601 (2005)

Acceptable/guideline

0, 30, 100 or 300 mg/kg by

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

NOAEL = 30 mg/kg.

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

NOAEL for neurobehavioral toxicity = 100 mg/kg

870

- 5100

Bacterial reverse

mutation 00058601 (1979)

Unacceptab le

25

- 2025 g/plate Negative in Salmonella strains with or without S

- 9 activation. Test material purity not specified, not tested up to cytotoxic dose.

### Page 48 of 53

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

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

Classification /Doses Results

870

- 5300

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

Acceptable/guideline

1.16

- 18.5 g/ml Did not cause a measurable increase in transformation of BALB/T3 cells. Highest dose produced 25% reduction in colony forming ability.

870

- 5385 (bone marrow

chromosomal aberration)

- Chinese

hamsters 00058603 (1979)

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

levels tested.

870

- 5550

Unscheduled DNA synthesis in human fibroblasts, 00133347 (1982)

Acceptable/guideline Negative for inducing Unscheduled DNA Synthesis at concentrations up to and including 9.32 μg/ml. Highest dose tested to allow at least 25% cell viability

870

- 5550

Unscheduled DNA synthesis in primary rat hepatocytes 00133348 (1982)

Acceptable/guideline Negative for inducing Unscheduled DNA Synthesis at concentrations up to and including 83.5μg/ml. Highest dose tested to allow at least 25% cell viability

870

- 5575 Mitotic gene conversion assay (Saccharomyces cerevisiae) 00133343 (1982)

Acceptable/guideline 10, 30, 90 or 270 g/ml No increase in convertants or revertants (did not induce mutation)

with or without activation. Concentrations of 30 g/ml had inhibitory effect on yeast cell growth.

870.5450 Dominant lethal assay

in mice 00058602 (1979)

Acceptable/guideline

165 or 495 mg/kg single dose oral gavage, No evidence of dominant lethal effects was observed in the progeny of mice treated with propiconazole.

870.7485

Metabolism and pharmacokinetics (Rat) 42403901 (1983)

Acceptable/guideline male rats: single oral

31 .4 mg/kg

- 14 C at the

triazole

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

870.7485

Metabolism and pharmacokinetics (Rat) 41326701 (19 89)

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

14 C)

- Phenyl label or 0.5 mg/kg/day unlabeled for 14 days followed with 0.5 mg/kg labeled or single oral dose 50 mg/kg labeled Oral or iv routes resulted in similar patterns of 14 C elimination suggesting bi liary excretion. >90% of 14 C excreted after 168 hours mostly within the 48 hrs. Females eliminated more in the urine than in the feces and vice versa for males in the orally dosed groups. No significant differences were seen in the excretion pattern

or we re seen between the low and high dose groups or the repeated dosing groups. Extensively metabolized (oxidative): 24 and 47 metabolites in urine and feces, respectively. Parent (27

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

### Page 49 of 53

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

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

Classification /Doses Results

870.7485

Metabolism and pharmacokinetics (Rat) 00074506 (1979)

00074507 (1981) Acceptable/guideline

triazole

- [3,5

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

- [U

14 C] single oral dose of 32.5 mg/kg to male rats. Study focused on urinary and fecal metabolites. Simi lar metabolic profiles for the two labels suggesting that the bridge between the phenyl ring and the triazole ring remained intact. Metabolic pathway: cleavage of dioxolane ring through the oxidation of the propyl side chain, with subsequent dechlorinatio n and conjugation and through the oxidation of the propyl side chain. Urinary and fecal metabolites except the presence of parent in feces.

870.7485

Metabolism and pharmacokinetics (Mouse) 00164795 (1986)

Acceptable/non

- guideline

Male and female mice fe d in the diet for 21 days at 5, 100 or 2500 ppm propiconazole followed by phenyl

- [U

14 C] single oral dose at corresponding

levels. Two male rats given single oral dose 9.4 mg/kg of the phenyl

- [U

14 C]compound Mice pre

- treated with the unlabeled CGA 64250 e xcreted 83

- 103%

of the administered 14 C radioactivity within 96 hours (mostly within

the first 24

- 48 hours) in the urine and feces (mostly in urine: 1.5

- 3.7x of the feces). The male rats excreted nearly equal amounts of the radioactivity in urine (48%) a nd feces (54%). Mouse urinary

metabolites 15

- 30. The major metabolic pathway in mice proceeds via elimination of the dioxolane ring. In males this represents 30% of the AD whereas in the females it represents 15% of the AD.

Mice cleaved the dioxolane ri ng to a greater extent (70% & and 40% for males and females, respectively) than do male rats (30%).

870.7600 Dermal penetration (Rat) 42415701 (1986)

Acceptable/guideline Propiconazole 14 C at the

triazole

- [3,5] position 0.01, 0.1, 1.0 mg/cm 2 The average dermal absorption of propiconazole over a 10 hour period at an exposure level of 0.01 mg/cm 2 is approximately 40%

Non

- guideline Special study 00151517 (1984)

Acceptable Tumor promotion

- rat 2000 ppm dietary up to 8

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

promoter.

### Page 50 of 53

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

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

Classification /Doses Results

Non

- guideline Special study

Mechanistic studies: Hepatic biochemical

parameters

- Mouse 45215803 (1998)

Male CD

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

group Total cytochrome P450 activity increased significantly (3

- 3.9x of the controls) at 850 ppm propiconazole. 7

- ethoxyresorufin activity, indicative of CYP1A1 induction was increased slightly but not to the extent observed following true induction. Lauric acid hydroxylation, specifically a result of peroxisome proliferation, was

not induce d by propiconazole. However, the activity of 7

- pentoxyresorufin

- O

- dealkylase, associated with CYP2B or PB

- type induction, was clearly increased 30

- 55

- fold by propi conazole.

Microsomal coumarin 7

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

- like induc tion. The microsomal activities of epoxide hydrolase and UDPGT and the cytosolic activity of GST were slightly increased with propiconazole treatment. The pattern of m icrosomal and cytosolic enzyme induction determined biochemically was entirely consistent

with PB

- type induction. Propiconazole resulted in a marked

increase of total testosterone oxidation. The results from the determination of microsomal and cytosolic enzyme activities, testosterone hydroxylation, and immunoblot analyses show that propiconazole is not a 3

- MC or mixed type inducer, but causes a pure PB

- type induction of cytochrome P450 activity. The effects of propiconazole treatment on mouse liver weigh ts and liver enzymes were comparable to those produced by phenobarbital, a known liver enzyme inducer and liver tumor promoter. The authors concluded that propiconazole can thus be considered a strong phenobarbital

- type inducer of xenobiotic metabolizing enzymes in the mouse.

### Page 51 of 53

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

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

Classification /Doses Results

Non

- guideline Special study

Mechanistic studies: Hepatocellular proliferation

- Mouse 45215802 (1999)

Male CD

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

- related increase in absolute and relative liver weights. All m ice developed hepatocellular hypertrophy (primarily in the centrilobular hepatocytes with mild effects in the midzonal hepatocytes). Liver necrosis and cytoplasmic vacuolation were noted. Increased mitotic activity was observed in all groups. Minimal to moderate hepatocellular nerosis of hypertrophic single or focal cells was found predominately in the high dose and PB group. Treatment with propiconazole or PB induced a >1000% increase in BrdU

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

the number of BrdU

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

BrdU

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

- and dose

related proliferation in the liver followed by a susta ined treatment

related hypertrophy in a manner similar to the known hypertrophic agent PB. The hepatomegaly was attributed to a sharp and transient induction of hepatocellular proliferation as well as to a time

- and

dose

- related increase in the severity o f hepatocellular hypertrophy.



### Appendix B : EPA Review of Human Research

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 For ce members Health Canada, U.S. Environmental Protection Agency, and the National Agricultural Chemicals Association, released February, 1995.

The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler Unit Exposure Surrogate Refe rence Table. U.S. Environmental Protection Agency. Released June 21, 2011.

### Page 52 of 53

Appendix C : Physical and Chemical Properties of Propiconazole

Table 3. Physicochemical Properties of Technical Grade Propiconazole



### .

Parameter Value Reference

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

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

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

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

Solvent solubility (temperature not specified) Completely miscible in ethanol, acetone,

toluene and n

- octanol. hexane = 47 g/L MRID No. 42030201

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

Dissociation constant (pK

a ) 1.09 MRID No. 43698701

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

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



### Appendix D: International Residue Limit Status



## Propiconazole (122101; 12/8/2011)

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 1 

### Codex 2



### 40 CFR 180 .434: Plant: propiconazole per se Livestock: propiconazole per se

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

US Canada Mexico 1 

### Codex
Bean, snap 0.70

Bean, succulent shelled 0.10
Legume, foliage 30
Bean, dry seed 0.40

Tomato 3.0
Fruit, citrus, group 10

- 10 8.0
Fruit, stone, group 12, except plum 4.0

Plum 0.60



### Citrus oil 1000

Completed:

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

2 * = absent at the limit of q uantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed hav e not been finalized by the CCPR and the CAC.

### Page 53 of 53

E. CHEMICAL NAMES AND STRUCTURES OF METABOLITE S