Page 1 of 31 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

MEMORANDUM

Date: July 29, 2010

SUBJECT: Propiconazole. ID#10FL02 Section 18 Emergency Exemption for the Use of Propiconazole on Avocado Trees in Commer cial Orchards of Florida to Control

Laurel Wilt.

PC Code: 122101 DP Barcode: D379849

Decision No.: 436555 Registration No.: 100-617

Petition No.: None Regulatory Action: Section 18 Risk Assessment Type: Single Chemical Aggregate Case No.: 3125

TXR No.: N/A CAS No.: 60207-90-1

MRID No.: N/A 40 CFR: § 180.434

FROM: Bonnie Cropp-Kohlligian, Environm ental Scientist/Risk Assessor

Risk Assessment Branch 4 Health Effects Division (7509P)

THROUGH: Susan Hummel, Chemist/ Senior Scientist

Risk Assessment Branch 4 Health Effects Division (7509P)

TO: Andrea Conrath/Barbara Madden, RM#5 Risk Integration, Minor Use and Emergency Response Branch Registration Division (7505P)

The Registration Division (RD) of the Office of Pesticide Programs (OPP) has requested that the Health Effects Division (HED) evaluate th e Section 18 Emergency Exemption request (ID#10FL02) for the first time use of the fungicide propiconazole to control laurel wilt on

avocado trees in commercial orchards of Flor ida; potentially treating up to 7,500 acres. The product to be used is Tilt ® Fungicide (EPA Reg. No. 100-617) , a 3.6 lb/gal emulsifiable concentrate (EC) formulation contai ning 41.8% propiconazole by weight.

Attached is the HED human health risk assessmen t of propiconazole for the purposes of issuing the subject Section 18 Emergency Use for this active ingredient. There are registered antimicrobial uses for propiconazole as well a nd the Antimicrobial Division (AD) has conductedPage 2 of 31 a risk assessment for all existing and potential antimicrobial uses. The present aggregate risk

assessment includes the risks from antimicrobial uses in mushroom houses (dietary) and in treated wood in play sets and residential decks (residential post application exposure).

Propiconazole is among the group of chemicals wh ich generate the common triazole metabolites, 1,2,4-triazole and its conjugates tria zolylalanine, triazoly lacetic acid and triazolylpyruvic acid. Issues concerning propiconazole and the common triazole metabolites have been addressed under a separate heading in the Executive Summary only.

Supporting documents completed for the subject Section 18 Registration are listed below: 1) Section 18 Drinking Water Assessme nt; EFED memo by J. Lin (D379850, 7 /15/10).

2) Section 18 Propiconazole Dietary Exposure and Risk Assessment; HED memo by T. Morton (D380158, 7/21/10). 3) Section 18 Common Triazole Meta bolites Updated Dietary Exposure and Risk Assessment; HED memo by T. Morton (D380341, 7/27/10). 4) Section 18 Occupational and Residen tial Exposure Assessment; HED memo J. Miller (D380160, 7/28/10).Page 3 of 31 TABLE OF CONTENTS

pg. 1.0 EXECUTIVE SUMMARY .................................................................................................4

2.0 INGREDIENT PROFILE ....................................................................................................9 2.1 Proposed New Uses ......................................................................................................... ....9

2.2 Structure and Nomenclature .............................................................................................11 2.3 Physical and Chemical Properties ......................................................................................12

3.0 HAZARD ASSESSMENT ...............................................................................................12

3.1 Hazard Profile ........................................................................................................... ........12 3.2 FQPA Hazard Considerations ...........................................................................................14 3.3 Summary of Toxicity Endpoint Selection ..........................................................................14 3.4 Endocrine Disruption ...................................................................................................... ...16

4.0 DIETARY EXPOSURE/RIS K CHARACTERIZATION .................................................16 4.1 Residue Chemistry Profile ................................................................................................. 16 4.2 Drinking Water Profile .................................................................................................... ..18 4.3 Dietary Exposure and Risk Assessment ............................................................................18

5.0 RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK

CHARACTERIZATION ...................................................................................................20 5.1 Residential Handler Exposure and Risk Characterization .................................................20 5.2 Residential Postapplication Expos ure and Risk Characterization .....................................22

6.0 AGGREGATE RISK ASSESSMENTS and CHARACTERIZATION ............................25 6.1 Acute and Chronic Aggregate Risk ...................................................................................25 6.2 Short-Term Aggregate Risk ...............................................................................................25 6.3 Intermediate-Term Aggregate Risk ...................................................................................27 6.4 Long-Term Aggregate Risk ...............................................................................................27

7.0 CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT ...................................28

8.0 OCCUPATIONAL EXPOSURE and RISK ......................................................................29 8.1 Occupational Handler Exposure and Risk .........................................................................29 8.2 Occupational Postapplica tion Exposure and Risk .............................................................31

9.0 REFERENCES ................................................................................................................ ..31Page 4 of 31 1.0 EXECUTIVE SUMMARY

Propiconazole is a triazole-deriv ative fungicide that provides br oad spectrum disease control on a variety of crops. It is a member of the class of the ergosterol biosynthesis inhibiting fungicides. The mode of antifungal action of propiconazole is attributed to the inhibition of CYP51 (lanosterol-14- a -demethylase).

Tolerances are currently established for the combined residues of propiconazole, 1-[[2-(2,4- dichlorophenyl)-4-propyl-1,3- dioxolan-2-yl]methyl]-1 H -1,2,4-triazole, and its metabolites determined as 2,4-dichlorobenzoic acid (2,4-D CBA) and expressed as parent compound in 40 CFR §180.434. Tolerances have been establis hed for plant commodities in 40 CFR §180.434(a), at levels ranging from 0.1 ppm for several commodities to 40 ppm for grass straw. Tolerances

for residues in livestock commodities are also established under 40 CFR §180.434(a), and range from 0.05 ppm for several commodities to 2.0 ppm for liver and kidney of cattle, goat, horse, and sheep; no tolerances in poultry and eggs have been established. Time-limited tolerances are established in 40 CFR §180.434(b) for nectarin e and peach (expiration date of 12/31/10); tolerances with regional regi stration are established in 40 CFR §180.434(c) for cranberry and wild rice; and tolerances for indirect or inadvertent resi dues are established in 40 CFR §180.434(d) for alfalfa forage and hay.

Proposed Uses The Florida Department of Agriculture and C onsumer Services has requested a Section 18 Emergency Exemption (ID#10FL02) to use propicon azole to control laurel wilt on avocado trees

in commercial orchards of Flor ida, most of which are in th e Miami-Dade County area. The product to be used is Tilt ® Fungicide (EPA Reg. No. 100-617) , a 3.6 lb/gal emulsifiable concentrate (EC) formulation containing 41.8% propiconazole by weight. The proposed emergency use does not include homeowner use or application to residential areas.

Application methods include: (1) soil drench (groundboom), (2) tree-directed (hand-held spray gun/applicator), and (3) tree-injection. These appl ication methods are not additive. One to three applications may be made for each application method; the maximu m single application rate is 7.1 lb ai/A and the maximum yearly rate is also 7.1 lb ai/A. A pre-harvest interval (PHI) of 0- days is proposed. Potentially up to 7,500 acres may be treated

Toxicity/Hazard Propiconazole has low to modera te toxicity in experimental animals by the oral, dermal and inhalation routes, is moderately ir ritating to the eyes, and minimally irritating to the skin, and it is a dermal sensitizer. The primary target organ fo r propiconazole toxicity in animals is the liver.

HED’s Hazard Identification Assessment Revi ew Committee (HIARC) concluded that the toxicology database for propiconazole is comple te for FQPA assessment. Endpoints and dose responses have been selected for acute dietary; chronic dietary; short- and intermediate-term incidental oral; short-, intermediate-, and long- term dermal; and short-, intermediate-, and longterm inhalation exposures. For the scenarios asso ciated with the new uses, HED concludes that the endpoints selected by HIARC are still appropriate.

The HIARC also concluded that the database was adequate to characterize any potential forPage 5 of 31 prenatal or postnatal risk for infants and children. There is low concern fo r pre- and/or postnatal toxicity resulting from exposure to propiconazole , and no residual uncertain ties were identified. The exposure databases (dietary food, drinking water, and residential) are complete and the risk assessment for each potential exposure scenario includes all metabolites and/or degradates of

concern and does not underestimate the potential risk for infants and children. The FQPA factor

is thus 1X.

The HED Carcinogenicity Peer Review Committee (CPRC) classified propiconazole as Group C - possible human carcinogen and recommended that fo r the purpose of risk characterization the Reference Dose (RfD) approach should be used and would be protective.

Dietary Exposure/Risk Assessment The nature of propiconazole residues in plants is adequately understood based on the available peanut, wheat, grape, rice, celery, and carrot me tabolism studies. HED has concluded that for plants, residues of propiconazole and all its metabolites conver tible to the 2,4-dichlorobenzoic acid moiety (2,4-DCBA), including conjugates, ar e of concern and should be included in the dietary (food) risk assessme nts, and that propiconazole per se should be included in the tolerance expression. Propiconazole per se should be included in the diet ary (water) risk assessments.

Propiconazole is also among the group of chem icals which generate the common metabolites, 1,2,4-triazole (T) and its conjuga tes triazolylalanine (TA), tr iazolylacetic acid (TAA) and triazolylpyruvic acid (TP). Issues concerning propiconazo le and the common triazole

metabolites are addressed below under a separate heading.

No acceptable avocado magnitude of the residu e data were submitted to support the proposed uses. HED has translated and extrapolated avai lable peach field trial data reflecting multiple foliar applications with a 3.6 lb/gal EC formula tion of propiconazole at 0.11 lb ai/A/application and a 0-day PHI. The maximum residue in/on peach es harvested at 0-days PHI, having received 5 applications of propiconazole at 0.11 lb ai/A/application wa s 0.78 ppm. Extrapolating for the proposed maximum use rate (7.1 lb ai/A/applicat ion) to avocado trees, the estimated maximum residue level for residues of pr opiconazole and its metabolites convertible to 2,4-DCBA in/on avocado would be 10 ppm. This estimate is expected to be highly conservative given the translation of residue data reflecting foliar appl ications to estimate residues resulting from the proposed soil drench, tree-directed (hand-he ld spray gun/applicator ) and tree-injection applications to avocado trees. No reasonably reliable data are available for estimating the maximum residue level of propiconazole per se in/on avocado for the propos ed uses. No triazole metabolite data were submitted to support the pr oposed uses. No Codex, Mexican, or Canadian maximum residue limits (MRLs) have been es tablished for residues of propiconazole in/on

avocado.

Acute and chronic aggregate di etary (food and drinking water) exposure and risk assessments were conducted for propiconazole residues of concern using the Diet ary Exposure Evaluation Model DEEM-FCIDTM, Version 2.03 which uses food consumption data from the U.S. Department of Agriculture’s Continuing Survey s of Food Intakes by Individuals (CSFII) from

1994-1996 and 1998.Page 6 of 31 The drinking water residues used in the di etary risk assessment were provided by the

Environmental Fate and Effects Division (EFED) and incorporated directly into this dietary assessment. Water residues were incorporat ed in the DEEM-FCID in to the food categories “water, direct, all sources” and “water, indirect, all sources.”

Acute Dietary (Food and Drinking Water) Ex posure Results and Characterization An acute dietary analysis for pr opiconazole residues of concer n was conducted using tolerance levels and 100 %CT for all existing and propos ed uses. The acute population adjusted dose (aPAD) is 0.3 mg/kg/day for all population s ubgroups (includes females 13-49 years). The results of the analysis indicat e that acute risk from the di etary exposure (food and water) to propiconazole from the requested uses did not exceed HED’s level of concern for the U.S. population or any population subgroup. At the 95 th percentile, the exposure to the U.S. population is at 7 % aPAD; the highest exposed s ubgroup (Children 1-2 yrs ol d) is at 17% aPAD.

Chronic Dietary (Food and Dr inking Water) Exposure Results and Characterization A chronic dietary analysis for propiconazole resi dues of concern was conducted using tolerance levels and 100 %CT for all existing and proposed uses. The chronic population adjusted dose (cPAD) is 0.1 mg/kg/day. Results of the analys is indicate that chronic risk from the dietary exposure (food and water) to propiconazole from the requested use did not exceed HED’s level of concern for the U.S. population or any popul ation subgroup. The exposure to the U.S. population is at 7 % cPAD, and the most highly exposed subgroup, Children 1-2 years old, is at

18 % cPAD.

Cancer Dietary (Food and Drinking Water) Exposure Results and Characterization The HED Carcinogenicity Peer Review Committee (CPRC) classified propiconazole as Group C - possible human carcinogen and recommended that fo r the purpose of risk characterization the Reference Dose (RfD) approach should be used and would be protective.

Residential Exposure/Risk Assessment No new residential uses are being requested at this time. However, adults, adolescents and toddlers may be exposed to propiconazole from its currently regist ered use on turf and ornamentals. These risks have been previous ly assessed. Homeowners can be exposed to propiconazole through dermal and inhalation rout es while applying home use products. All risk calculations were conducted using th e maximum turf application rate (1.8 lb ai/acre). None of the residential handler exposure scenarios exceeded HED’s level of concern. The residential use patterns result in postapplic ation dermal exposures to adults, and dermal and oral exposures to infants and children. These exposures are consid ered short-term only. In addition to using HED’s SOP for residential assessment, chemical sp ecific data on turf transferable residue (TTR)

was used in the calculation. The dermal and incidental oral exposure to infants and children were combined, and all margins of exposures (M OEs) do not exceed the level of concern. Risk to children playing on propicon azole-treated structures (from antimicrobial use) was also assessed using a screening leve l assessment; these exposures are considered short- and intermediate-term. This risk assessment, based on high end screening-level assumptions,

indicates no risk of concern.Page 7 of 31 Aggregate Risk Assessment Aggregate risk assessments were conducted for acute, chronic, short- and intermediate-term exposure duration. The risks do not exceed HED’ s level of concern. Acute aggregate risk included food and water only; chronic aggregat e risk also included food and water because no chronic exposure from residential uses is expe cted. Short-term aggregate risk included food, water, and residential/antimicr obial exposures. Intermediate-t erm aggregate risk included food, water, and residential exposure to Children 1-2 years old from treated wood used in deck and play structures.

Propiconazole and the Common Triazole Metabolites Propiconazole is a member of th e triazole-derivative fungicide class of pesticides. There is currently no evidence to indicate that triazole-derivative fungicides share common mechanisms of toxicity and EPA is not following a cumula tive risk approach based on a common mechanism of toxicity for these pesticides. However, propiconazole, like othe r triazole-derivative fungicides, can form the common metabolites 1,2,4-triazole and its triazole conjugates (triazolylalanine, triazolylacetic acid, and triazoly lpyruvic acid). To supp ort existing tolerances

and to establish new tolerances for triazole-derivative pesticides , including propiconazole, U.S.

EPA conducted a human health risk assessment fo r exposure to 1,2,4-triazole, triazolylalanine, triazolylacetic acid and triazolylpyruvic acid resulting from the use of all current and pending uses of any triazole-derivativ e fungicide. The risk assessmen t is a highly conservative, screening-level evaluation in te rms of hazards associated with common metabolites (e.g., use of a maximum combination of uncertainty factors) and potential dietary a nd non-dietary exposures (i.e., high end estimates of both dietary and non- dietary exposures). In addition, the Agency retained the additional 10X FQPA safety factor for the protection of infants and children. The

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

In support of the requested Section 18 Emergency Exemption (ID#10FL02), HED has completed an updated dietary exposure and risk analysis for the common tri azole metabolites 1,2,4-triazole (T), triazolylalanine (TA), triazolylacetic acid (TAA), and triazolylpyruvic acid (TP). [ For

details see the Section 18 Common Triazole Metabolites Updated Dietary Exposure and Risk Assessment; HED memo by T. Morton (D380341, 7/27/10) .] Acute and chronic aggregate dietary (food and drinking water) exposure and risk as sessments were conducted using the Dietary Exposure Evaluation Model DEEM-FCIDTM, Vers ion 2.03 which uses food consumption data from the U.S. Department of Agriculture’s C ontinuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998. No triazole metabo lite magnitude of the residue data were submitted or are available to support the proposed uses, so the dietary analysis was based on the recommended 10 ppm tolerance for resi dues of propiconazole in/on avocado.

Four assessments were conducted: acute and chronic durations for T, and acute and chronic durations for combined residues of TA, TAA, an d TP. All four assessments assume tolerance level residues, 100% crop treated and include conservative estimates for residues of the metabolites in drinking water. The resulting expo sure and risk estimates are based on healthprotective assumptions and should be characterized as conservativ e. For all four analyses,Page 8 of 31 dietary risk estimates are below HED’s leve l of concern for all population subgroups. Furthermore, the additional dietary exposure/ risk from the proposed Section 18 Emergency Exemption (ID#10FL02) is deemed so insignificant that a separate common triazole metabolite human health aggregate risk assessment in s upport of the Section 18 registration is not

warranted.

With regards to occupational exposure/risk asse ssment, HED expects that occupational exposure to 1,2,4-triazole (residential/occu pational exposure to residues of TA, TAA and TP are not expected) is likely to occur as a result of activi ties associated with a si ngle triazole-derivative fungicide. The risks associated with occupational exposure to this compound are addressed in the risk assessments for the parent compound. T hose risk estimates inherently include risk associated with occupational exposure to 1,2,4-tr iazole. Therefore, an occupational exposure and risk assessment for 1,2,4-triazole, per se , is not warranted. This is unlike the case for dietary exposure where it is likely that multiple triazole -derivative fungicides simultaneously lead to 1,2,4-triazole exposure.

Occupational Handler and Postapplic ation Exposure/Risk Assessment Occupational handler exposure is expected for certified applicat ors applying propiconazole to

avocado trees. Handler risks were assessed using Pesticide Handlers Exposure Database (PHED) Version 1.1 (Surrogate Exposure Guide) in the absence of chemi cal specific data. The relevant exposure scenarios for certified applicat ors applying propiconazole to avocado trees are (1) application via handgun sprayer, (2) applicati on via tree injection, and (3) application via soil drenching equipment (groundboom). Based on th e proposed use patterns, HED expects that occupational exposures will generally occur in short-term (1-30 days) durations only. The proposed Section 18 label specifies that applicat ors and other handlers must wear the following personal protective equipment (PPE): (1) long- sleeved shirt and long pants, (2) chemicalresistant gloves such as barrier laminate or viton, (3) shoes plus socks, and (4) protective eyewear. For all of the occupational handlers ex posure scenarios, the non-cancer short-term (1- 30 days) risks are below HED’s level of concern (i.e., MOEs are > 100) with label specific PPE

and therefore not of concern.

Based on the use patterns associated with the proposed Section 18 label, HED believes that postapplication exposure will be negligible. Ther efore, a postapplication quantitative assessment

was not conducted.

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

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

Review of Human Research This risk assessment relies in part on data from the Pesticide Handlers Exposure Database (PHED) and the Outdoor Residential Exposure Task Force (ORETF) studies in which adult human subjects were intentionally exposed to a pe sticide or other chemical. These studies have been determined to require a re view of their ethical conduct, and have received that review.Page 9 of 31 Tolerance Recommendations HED has no concerns regarding human health exposure and risk from the proposed Section 18 use of propiconazole on avocado trees in commercial orchards of Florida to control laurel wilt.

A time-limited tolerance should be establ ished for residues of propiconazole per se at 10 ppm

in/on avocado.

Notes to RD:

(1) The Section 18 submission indicates that IR -4 in conjunction with Syngenta Crop Protection and the University of Florida/ IFAS are planning magnitude of the residue trials in 2010 to support a Section 3 registration for the use of propiconazole on avocado trees. Given the unique app lication methods for this use when compared to other propiconazole agricul tural uses, a study protocol might be advisable. In any case, these parties shou ld be reminded that because propiconazole is a triazole-derivative fungicide, HED re quires that samples from any metabolism, feeding, field trial, and/or processing studies be analyzed for the triazole metabolites triazolylalanine (TA), triazolylacetic acid (TAA), triazolylpyruvic acid (TP) and 1,2,4-triazole (T). Guidance has been i ssued concerning these residue chemistry data requirements for the triazole-based metabolites under DP# 327788 (4/25/06, M. Doherty). (2) Although the Propiconazole RED (July, 2006) has previously recommended that the tolerance expression should be parent only, the current tolerance expression specified in 40 CFR §180.434 is for residues of propiconazole and its metabolites determined as 2,4-dichlorobenzoic acid (2,4-DCBA) and expressed as parent compound. In anticipation of the implemen tation of this recommendation, it might be advisable to analyze sample s for residues of propiconazole per se as well as for residues of propiconazole and its metabolite s determined as 2,4-dichlorobenzoic acid (2,4-DCBA) and expressed as parent compound.

2.0 INGREDIENT PROFILE

Propiconazole is a triazole-deriv ative fungicide that provides broad spectrum disease control through inhibition of sterol biosynthesis in fungi.

2.1 Proposed New Uses

The Florida Department of Agriculture and C onsumer Services has requested an emergency specific exemption to use propiconazole to cont rol laurel wilt on avocado trees in commercial orchards of Florida; potentia lly treating up to 7,500 acres. Th e product to be used is Tilt ®
Fungicide (EPA Reg. No. 100-617), a 3.6 lb/gal emulsifiable c oncentrate (EC) formulation containing 41.8% propic onazole by weight.Page 10 of 31 Application methods include: (1) soil drench (groundboom), (2) tree-directed (hand-held spray gun/applicator), and (3) tree-injection. These appl ication methods are not additive. One to three applications may be made for each application method; the maximu m single application rate is 7.1 lb ai/A and the maximum yearly rate is also 7.1 lb ai/A. A pre-harvest interval (PHI) of 0- days is proposed. The proposed use di rections are summarized in Table 2.1.

Table 2.1. Summary of Proposed Directions for Use of Propiconazole on Avocado Trees.

Applic. Timing, Type, and Equip. Formulation [EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No. Applic. per

Season Max. Seasonal Applic. Rate (lb ai/A/year) PHI (days) Use Directions and

Limitations

Soil drench

3.6 lb/gal EC [100-617] 7.1 1-3 7.1 0 These methods of application are not

additive.

Trees should be treated when sap is actively moving up in the trees, not during dormant periods.

It is expected that a single application per year will be

sufficient.

The use of an adjuvant is

recommended for treedirected applications.

This pesticide is toxic to fish. Do not apply directly to water, or to areas where surface water is present, or

to intertidal areas below the mean high water mark. Tree-directed (hand-held spray gun/applicator) 7.1 1-3 7.1 0

Tree-injection 7.1 1 7.1 0

The proposed Section 18 label specifies that applicators and other handlers must wear the following personal protective equipment (PPE): (1) long-sleeved shirt and long pants, (2) chemical-resistant gloves such as barrier laminate or viton, (3 ) shoes plus socks, and (4) protective eyewear. A restricted entry interval (REI) of 12 hours is specified.Page 11 of 31 2.2 Structure and Nomenclature

Table 2.2. Test Compound Nomenclature

Chemical Structure

Cl

Cl O O

N

N N CH 3

Empirical Formula C 15 H 17 Cl 2 N 3 O 2

Common name Propiconazole

Company experimental name CGA-64250

IUPAC name 1-((2-(2,4-Dichlorophenyl)-4-propyl- 1,3-dioxolan-2-yl)methyl)-1H-1,2,4-triazole

CAS name 1H-1,2,4-Triazole, 1-((2-(2,4-dichlorophe nyl)-4-propyl-1,3-dioxolan-2-yl)methyl)-

CAS Registry Number 60207-90-1

End-use product/EP Tilt® Fungicide 41.8% ai or 3.6 lb/gal (EPA Reg. No. 100-617)

Chemical Class Triazole

Known Impurities of Concern NonePage 12 of 31 2.3 Physical and Chemical Properties

All pertinent product chemistry data requirement s have been satisfied for the Novartis 95% T/TGAI, except that additional data are require d concerning stability and UV/visible absorption (OPPTS 830.6313 and 7050).

Table 2.3. Physicochemical Properties

Parameter Valu e Reference

Molecular Weight 342.23 MRID No.: 40583701

Boiling point/range >250°C at 101.325 kPa, 120°C

at 1.9 Pa MRID No.: 43698701

pH 4.9 @ 25°C (1% aqueous

dispersion) MRID No.: 43698701

Density 1.289 g/cm3 typical @ 20°C MRID No.: 43698701

Water solubility (20 °C) 0.10 g/L at 20°C MRID No.: 41720301

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

acetone, toluene and n-octanol.

n-hexane = 47 g/L MRID No.: 42030201

Vapor pressure (25°C) 4.2 x 10 -7 mmHg @ 25°C MRID No.: 41720301

Dissociation constant, pKa pKa 1.09 MRID No.: 43698701

Octanol/water partition coefficient, Log (K OW ) (25 °C) 3.72 @ pH 6.6 MRID No.: 43698701

UV/visible absorption spectrum ( λ max, nm) Not available

3.0 HAZARD ASSESSMENT

For a detailed discussion, refer to: Propiconazole FQPA Human Health Risk Assessment for the Section 3 Registrations on Garden Beets, Turnips, Parsley, Cilantro and Pineapple ; HED memo by Y. Donovan (D 347905, 9/30/08).

3.1 Hazard Profile

Propiconazole has low to moderate toxicity in experimental anim als by the oral (Category III), dermal (Category III) and inhalation routes (Category IV). It is m oderately irritating to the eyes (Category III), and minimally irrita ting to the skin (Category IV). It is a dermal sensitizer. Propiconazole is readily absorb ed by the rat skin with absorp tion within 10 hours of dermal application. The acute toxici ty profile of propiconazole is summarized in Table 3.1.Page 13 of 31 Table 3.1. Acute Toxicity Profile of Propiconazole

G. L. No. Study Type MRID # Results Toxicity Category

870.1100 Acute Oral – rat 00058591 LD 50 =1517 mg/kg III

870.1200 Acute Dermal-rabbit 00058596 LD 50 = >4000 mg/kg III

870.1300 Acute Inhalation – rat 41594801 LC 50 = >50.84 mg/L IV

870.2400 Primary Eye Irritation 00058597 Corneal opacity reversed in 72 hrs III

870.2500 Primary Skin Irritation 00058598 No irritation IV

870.2600 Dermal Sensitization 44949501 Not a sensitizer -

The primary target organ for propi conazole toxicity in animals is the liver. Increased liver weights were seen in mice after subchronic or ch ronic oral exposures to propiconazole at doses >50 mg/kg/day. 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. Mice appear to be more suscep tible to its toxicity th an rats. Decreased body weight gain in experimental animals was seen in subchronic, chroni c, developmental and reproductive studies. Dogs appeared to be mo re sensitive to the lo calized toxicity of propiconazole as manifested by stomach irritation 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 lowe r doses than maternal toxic doses. Increased incidences of rudimentary ribs occurred in ra t and rabbit fetuses. Increased cleft palate

malformations were noted in two studies in rats . In one published study in rats developmental effects (incomplete ossification of the skull, caudal vertebrae and digits, extra rib (14 th rib) and missing sternebrae, malformations of the lung and kidneys) were reported at doses that were not maternally toxic.

In the two generation reproduction study in rats, o ffspring toxicity occurred at a higher dose than the parental toxic dose suggesti ng lower susceptibility of the o ffspring to the toxic doses of propiconazole in this study.

Propiconazole was negative for mutagenicity in the in vitro BALB/ C 3T3 cell transformation assay, bacterial reverse mutation assay, Chines e hamster bone marrow chromosomal aberration assay, unscheduled DNA synthesis studies in huma n fibroblasts and primary rat hepatocytes, mitotic gene conversion assay and the dominan t lethal assay in mice. Hepatocellular proliferation studies in mice suggest that propiconazole induc es cell proliferation followed by treatment-related hypertrophy in a manner similar to the known hypertrophic agent phenobarbital.

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

risk characterization the Refere nce Dose (RfD) approach be us ed for quantification of human risk (HED Doc. No. TX0009771, April 15, 1992 meeting).Page 14 of 31 3.2 FQPA Hazard Considerations

HIARC (HED Doc. No. TX0052277, February 13, 2003 meeting) concluded that the toxicology database for propiconazole is complete for FQPA assessment. The HIARC concluded that there is low concern for pre- and/or pos tnatal toxicity result ing from exposure to propiconazole. In the developmental toxicity study in rats, the HIARC considered the fetal effects observed in this study at a dose lower than that e voking maternal toxicity to be qua ntitative evidence of increased susceptibility of fetuses to in utero exposure to propiconazole. In the developmental toxicity study in rabbits, the HIARC determined that ne ither quantitative nor qua litative evidence of increased susceptibility of fetuses to in utero exposure to propiconazole was observed in this study. In the 2-generation repr oduction study in rats, the HIA RC determined that neither quantitative nor qualitative evid ence of increased susceptibilit y of neonates (as compared to adults) to pre- and/or postnatal exposure to propiconazole was observe d in this study. Since there was quantitative evidence of increased suscep tibility of the young following exposure to propiconazole in the developmental rat study, HI ARC performed a Degree of Concern Analysis and concluded that the degree of concern for th e effects observed in this study was low and no

residual uncertainties were identified. The FQPA factor is thus 1X.

3.3 Summary of Toxicity Endpoint Selection

Table 3.3. Propiconazole: Summary of Toxicological Dosages and Endpoints Selected for Human Health Risk

Assessments.

Exposure

Scenario Doses Used in Risk Assessment, UF FQPA SF and Level

of Concern for Risk

Assessment Study and Toxicological Effects

Acute Dietary (Females 13-49) NOAEL = 30 mg ai/kg/day

UF =100

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

aPAD =

acute RfD FQPA SF = 0.3 mg/kg/day Developmental Toxicity Study - Rats. Developmental toxicity: increased incidence of rudimentary ribs, cleft palate malformations (0.3%), unossified sternebrae, as well as increased incidence of shortened and absent renal papillae.

Acute Dietary (General Population including infants and children) NOAEL = 30 mg kg/day

UF =100

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

aPAD =

acute RfD FQPA SF =0.3 mg/kg/day Acute Neurotoxicity Study – Rats.

Clinical signs (piloerection, diarrhea, tiptoe gait).

Chronic Dietary (All populations) NOAEL = 10 mg ai/kg/day

UF = 100

Chronic RfD = 0.1 mg/kg/day 1X

cPAD =

chronic RfD FQPA SF =0.1 mg/kg/day 24 Month Oncogenicity Study - Mice. Liver toxicity (increased liver weight in males and increase in liver lesions (masses/raised areas/ swellings/nodular areas mainly)).

Short-Term (1-30 days) Incidental

Oral NOAEL = 30 mg kg/day Residential MOE =

100 Occupational = NA Acute Neurotoxicity Study – Rats.

Clinical signs (piloerection, diarrhea, tiptoe gait).Page 15 of 31 Table 3.3. Propiconazole: Summary of Toxicological Dosages and Endpoints Selected for Human Health Risk

Assessments.

Exposure

Scenario Doses Used in Risk Assessment, UF FQPA SF and Level

of Concern for Risk

Assessment Study and Toxicological Effects

Intermediate-Term (1 - 6 months) Incidental

Oral NOAEL= 10 mg ai/kg/day Residential MOE =

100

Occupational = NA 24 Month Oncogenicity Study - Mice. Liver toxicity (increased liver weight in males and increase in liver lesions (masses/raised areas/ swellings/nodular areas mainly)).

Short-Term (1 - 30 days) Dermal NOAEL= 30 mg ai/kg/day

Dermal absorption

rate = 40% Residential MOE =

100

Occupational MOE =

100 Acute Neurotoxicity Study – Rats.

Clinical signs (piloerection, diarrhea, tiptoe gait).

Intermediate-Term dermal (1 - 6 months) and Long-Term

dermal (>6 months) NOAEL= 10 mg ai/kg/day (Dermal absorption rate = 40%) Residential MOE =

100

Occupational MOE =

100 24 Month Oncogenicity Study - Mice. Liver toxicity (increased liver weight in males and increase in liver lesions) (masses/raised areas/ swellings/nodular areas mainly)

Short-Term (1 - 30 days)

Inhalation NOAEL= 30 mg/kg/day

(Inhalation absorption rate = 100%) Residential MOE =

100

Occupational MOE =

100 Acute Neurotoxicity Study – Rats.

Clinical signs (piloerection, diarrhea, tiptoe gait).

Intermediate-Term (1- 6 months) and LongTerm Inhalation (>6 months) NOAEL= 10 mg/kg/day (Inhalation absorption rate = 100%) Residential MOE =

100

Occupational MOE =

100 24 Month Oncogenicity Study - Mice. Liver toxicity (increased liver weight in males and increase in liver lesions (masses/raised areas/ swellings/nodular areas mainly)

Cancer (Oral, dermal, inhalation) Group C, possible human carcinogen, and RfD approach for risk characterization.

UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no obser ved adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = reference dose, MOE = margin of exposure.

As per the FQPA of 1996, when there is potenti al for residential exposure to the pesticide, aggregate risk assessment must consider exposures from all routes, such as oral, dermal and inhalation. The toxicity endpoints selected for these routes of exposure may be aggregated as follows: the oral, dermal, and inhalation routes of exposure can be combin ed to assess aggregate

risks because of the selection of a common toxicity endpoint fo r all routes and durations of

exposure.Page 16 of 31 3.4 Endocrine Disruption

The Agency is required under the Federal Food, Drug and Cosmetic Act (FFDCA), as amended by FQPA, to develop a screening program to dete rmine whether certain substances (including all pesticide active and other ingredient s) “may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” In the available toxicity studies on propiconazole , there was no observed estrogen, androgen, and/or thyroid mediated toxicity. When a dditional appropriate screening and/or testing protocols become available, propiconazole may be subjected to further screening and/or testing to better characterize the effects related to endocrine disruption.

4.0 DIETARY EXPOSURE/RISK CHARACTERIZATION

Propiconazole is among the group of chemicals wh ich generate the common triazole metabolites, 1,2,4-triazole and its conjugates tria zolylalanine, triazoly lacetic acid and triazolylpyruvic acid. Issues concerning propiconazole and the common triazole metabolites have been addressed under a separate heading in the Executive Summary only.

4.1 Residue Chemistry Profile

Since the proposed Section 18 is for the use of propiconazole on avocado trees in commercial orchards of Florida, the following residue chemistr y guideline topics are not relevant and will not be discussed further: (1) GLN 860.1300 Nature of the Residu e in Livestock; (2) GLN 860.1480 Meat, Milk, Poultry, and Eggs; (3) GLN 860.152 0 Processed Food and Feed; and (4) GLN

860.1850 and 860.1900 Confined and Field Ac cumulation in Rotational Crops.

The nature of propiconazole residues in plants is adequately understood based on the available peanut, wheat, grape, rice, celery, and carrot me tabolism studies. HED has concluded that for plants, residues of propiconazole and all its metabolites conver tible to the 2,4-dichlorobenzoic acid moiety (2,4-DCBA), including conjugates, e xpressed as parent, are of concern and should be included in the dietary (food) risk assessments, and that propiconazole per se should be

included in the tolerance expression. Propiconazole per se should be included in the dietary (water) risk assessments.

For enforcing the proposed tolera nce, a gas chromatography (GC) method using flame ionization detection (Method AG-354) is available for determining residues of propiconazole per se in/on plant commodities, with a limit of quantitation (LOQ) of 0.05 pp m. In addition, FDA’s PAM 1 Multiresidue Methods Section 302 may be used to determine parent propiconazole in both plant

and livestock matrices.

No acceptable avocado magnitude of the residu e data were submitted to support the proposed uses. Stone fruit field trial data reflecting multip le foliar applications were previously submitted and reviewed by the Agency (MRID 41063802; PP#9F3758; No DP Barcode #, S. Malak, 11/28/89). In these tests, a 3.6 lb /gal EC formulation of propic onazole was applied 3-5 times by air or ground using 50 or 100 g ai/A/applicati on (0.11 or 0.22 lb ai/A/application). FreshPage 17 of 31 samples of apricots, nectarines, peaches, and plum s were taken at various harvest intervals of 0, 3, and 7 days after the last appl ication. Samples were analyzed with an analytical method, AG454, that determined residues of propiconazole and its metabolites c onvertible to the 2,4- dichlorobenzoic acid (2,4-DCBA ) moiety using a gas chromatography method with electron capture detection (GC/ECD). Results were report ed as propiconazole equivalents. [Note:

Method AG-454 if an earlier version of Method AG-454A which is published in PAM II as an acceptable enforcement method.] The maximu m residue level found was 0.78 ppm in/on a whole peach sample collected 0-days after the last of 5 foliar applications at 50 g ai/A/application (0.11 lb ai/A/application); total application was 0.55 lb ai/A. [Note: The reviewer notes that given the retreatment interval s, only the last two appl ications are likely to have had a significant effect on the resulting residue level.] Extrapolating these data to reflect an application rate of 7.1 lb ai/A, the maximum resi dues of propiconazole in/on peaches would be estimated at 10 ppm. Based on these data, the estimated maximum residue level for residues of propiconazole and its metabolites convertible to 2,4-DCBA in/ on avocado would be 10 ppm. This estimate is expected to be highly cons ervative given the transl ation of residue data reflecting foliar applications to estimate residue s resulting from the pr oposed soil drench, treedirected (hand-held spray gun/appl icator) and tree-injection applica tions to avocado trees. No reasonably reliable data are available for es timating the maximum level of propiconazole per se in/on avocado for the proposed uses; hence, the time -limited tolerance level will also have to be established at 10 ppm. No triazole metabolite da ta were submitted or are available to support the proposed uses.

[Note: The subject Section 18 submission did provi de a report of the re sults of an Australian magnitude of the residue study on avocado reflecti ng foliar applications of propiconazole (1993; Bull and Bodnaruk) and several worksheets with no details concerning the results of a US magnitude of the residue study reflecting soil drench and tree-inject ion applications of propiconazole to avocado trees (2010; Task No. TK0015676; R. Ploe tz, University of Florida). Neither study was deemed adequate for the purpose s of estimating residues for the dietary risk assessment or for establishing a tolerance for th e proposed uses. However, it should be noted that the US data (2009; Task No. TK0015676; R. Ploe tz, University of Flor ida) do suggest that a tree-injection applicatio n of propiconazole will result in de tectable, and possibly significant, residue levels of propiconazole in/on avocado. These data are considered supplemental in nature and scope and suggest that the recommended tim e-limited tolerance (10 ppm), based on the peach field trial data, is highly conservative.]

The Codex Alimentary Commission has establishe d several maximum residue limits (MRLs) for propiconazole in/on various raw agricultural comm odities. In addition, both Canada and Mexico have established MRLs for propiconazole in/ on various commodities. The Codex and Mexican MRLs are expressed in terms of propiconazole per se . The Canadian MRLs are expressed in terms of combined residues of propiconazole and its metabolites containing the 2,4-DCBA moiety. No Codex, Mexican, or Canadian MR Ls have been established for residues of propiconazole in/on avocado.Page 18 of 31 4.2 Drinking Water Profile

The drinking water residues used in the di etary risk assessment were provided by the Environmental Fate and Effects Division (E FED) in the following memorandum: “Drinking Water Assessment for Propiconazole Uses on Florida Avocado – Section 18 Emergency Exemption” (Jim Lin, 07/15/10, D379850).

The proposed new uses to avocado trees do not re sult in higher EDWCs than those estimated for the existing turf use which are based on 8 applica tions at a rate of 0.786 lb ai/A with a 14-day interval. Therefore, the dri nking water assessment was based on the existing turf use rate.

The PRZM/EXAMS 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 annual mean concentration (non-cancer chronic) and

13.24 ug /L for the 30 year annual mean c oncentration (cance r chronic).

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

The model and its description are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/

.

4.3 Dietary Exposure and Risk Assessment

For a detailed discussion refer to: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 18 Registration on Avocado in Florida ; HED memo by T. Morton, D380158,

7/21/10.

Propiconazole acute and chroni c aggregate dietary (food and dr inking water) exposure and risk assessments were conducted using the Dietary Ex posure Evaluation Model software with the Food Commodity Intake Database DEEM-FCID TM, Version 2.03 which uses food consumption data from the U.S. Department of Agriculture (USDA’s) Continuing Surveys of Food Intakes by Individuals (CSFII), 1994-1996 and 1998. The analys es were performed to support the Section 18 registration on avocado.

Acute Dietary (Food and Drinking Water) Ex posure Results and Characterization An acute dietary analysis for pr opiconazole residues of concer n was conducted using tolerance levels, including the recomm ended 10 ppm tolerance in/on avocado, and 100 %CT for all existing and proposed uses. The highest estimat es from surface water (acute, 55.8 ppb) were directly entered into th e exposure model to assess the contri butions from drinking water. The acute PAD is 0.3 mg/kg/day for all population subgroups (includes females 13-49 years). The results of the analysis indicat e that acute risk from the di etary exposure (food and water) to propiconazole from the requested uses did not exceed HED’s level of concern for the U.S. population or any population subgroup. At the 95 th percentile, the exposure to the U.S. population is at 7 % aPAD; the highest exposed s ubgroup (Children 1-2 yrs ol d) is at 17% aPAD.Page 19 of 31 Chronic Dietary (Food and Dr inking Water) Exposure Results and Characterization A chronic dietary analysis for propiconazole resi dues of concern was conducted using tolerance levels, including the recomm ended 10 ppm tolerance in/on avocado, and 100 %CT for all existing and proposed uses. The highest estimat es from surface water (chronic, 21.6 ppb) were directly entered into th e exposure model to assess the contri butions from drinking water. The cPAD is 0.1 mg/kg/day. Results of the analysis indicate that chronic risk from the dietary exposure (food and water) to propiconazole from the requested use did not exceed HED’s level of concern for the U.S. population or any popul ation subgroup. The exposure to the U.S. population is at 7 % cPAD, and the most highly exposed subgroup, Children 1-2 years old, is at

18 % cPAD.

Cancer Dietary (Food and Drinking Water) Exposure Results and Characterization The HED Carcinogenicity Peer Review Committee (CPRC) classified propiconazole as Group C - possible human carcinogen and recommended that fo r the purpose of risk characterization the Reference Dose (RfD) approach should be used and would be protective.

Results and Discussion

At the 95 th percentile, the acute dietar y exposure (food and water) to general US population is at 7 % of the aPAD, and the most highly exposed subgroup, Children 1-2 yrs old, is at 17 % of the aPAD. The chronic dietary exposure to general US population is at 7 % of the cPAD, and the most highly exposed subgroup, Children 1-2 yrs old, is at 18 % of the cPAD. All the dietary risk

estimates are below 100% of the PADs.

These analyses are highly conservative, Tier 1 di etary exposure assessments. Further refinement to the analyses could be made through the us e of anticipated residues, incorporation of percentages of crops treated w ith propiconazole, and/or monito ring data that better reflect residues at the time of consumption. Since ri sk estimates are well below HED’s level of concern, a more highly refined analys is is not needed at this time.

These Tier 1 analyses demonstrate that the reque sted uses for propiconazole will not result in dietary risk estimates that exceed HED’s level of concern for any of the regulated population subgroups, including those comprised of infants and children. A summary of the dietary exposure and risk analyses is given in Table 4.3.Page 20 of 31 Table 4.3. Summary of Dietary Exposure and Risk for Propiconazole (Food + Water).

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

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

General U.S. Population 0.022029 7 0.006790 7

N/A All Infants (< 1 year old) 0.048212 16 0.015833 16

Children 1-2 years old 0.051513 17 0.018203 18

Children 3-5 years old 0.039626 13 0.014752 15

Children 6-12 years old 0.027152 9 0.009621 10

Youth 13-19 years old 0.018020 6 0.005886 6

Adults 20-49 years old 0.017909 6 0.005682 6

Adults 50+ years old 0.013501 5 0.004553 5

Females 13-49 years old 0.016758 6 0.005366 5

5.0 RESIDENTIAL (NON-OCCUP ATIONAL) EXPOSURE/RISK

CHARACTERIZATION
5.1 Residential Handler Exposure and Risk Characterization

No new residential uses are being requested at this time. However, adults, adolescents and toddlers may be exposed to propiconazole from its currently registered uses on turf, ornamentals, and treated paints.

These risks have been previously assessed.

Propiconazole: Revised Occupational and Residential Exposure Assessment; James Miller, Environmental Scientist (D329393, 6/15/06) Propiconazole Occupational and Residential Exposur e Assessment of the Antimicrobial Uses; Timothy Leighton (D326306, 2/1/2006) Amendment to the Propiconazole RED for Children’s Postapplication Exposure fr om Treated Structures; Tim Leighton (D330159, 06/20/06)Page 21 of 31 The anticipated use patterns and current labeli ng indicate three major residential exposure scenarios based on the ty pes of equipment and techniques that can potentially be used to make propiconazole applications. Th e quantitative exposure/risk assessment developed for residential

handlers is based on these scenarios:

• Mixer/Loader/applying liqui ds and wettable powder in water soluble packets via 1) Low Pressure Handwand, and 2) Hose-End Sprayer.

• Applying treated paint using airl ess sprayer and Hose-end spray.

Residential handler exposure scenarios are consider ed to be short-term only due to the infrequent uses associated with homeowner products.

A series of assumptions and exposure factors serv ed as the basis for completing the residential handler risk assessments. Each assumption and fact or is detailed below. In addition to these factors, unit exposures were used to calculate risk estimates. Mostly, these unit exposures were taken from the Pesticide Handlers Exposure Da tabase (PHED) and the Outdoor Residential Exposure Task Force (ORETF) studies.

HED believes that the scenarios assessed in th is document represent worst-case exposures and risks resulting from use of propi conazole in residentia l environments. It should also be noted that there were many other scenarios where medi um to low quality PHED data were used to complete the assessment. Data quality should be considered in the interpretation of the uncertainties associated with each risk presented.

• Short-term estimated risks for residential ha ndlers are presented be low in Table 5.1. All

estimated risks are below HED’s level of concern (i.e., MOEs are > 100) assuming handlers are wearing short-sleeve shirt, short pants, shoes, and socks.Page 22 of 31 Table 5.1. Summary of Reside ntial Handler Exposure Estimates

Application. Equip. Crop(s)/Site Max Appl.

Rate1 Daily Area

Treated2 Handler

Scenario Short-Term

MOE

Lb ai/Acre

or

% in paint* Acre/day Or gal/day* M/L/A Derml+Inhln

Baseline

Low Pressure

Handwand Ornamentals (woody and flowering plants), Shade Trees, Woody

Shrubs and Vines 0.0024 5* (Liquids) 4400

(WP/WSP) N/A

Hose-end

Sprayer 5* (Liquids) 40,000

(WP/WSP) N/A

Low Pressure

Handwand

Turf (Lawns) 1.8 0.023 (Liquids) 1300

(WP/WSP) N/A

Hose-end

Sprayer 0.5 (Liquids) 530

(WP/WSP) N/A

Brush/Roller 3 Applying treated paint 0.35% 15* (Paint) 330

Airless Sprayer 3 2* (Paint) 120

Notes: 1 Application rates are the maximum rates provided for propiconazole in all cases. 2 Amount handled per day values are HED estimates of area treated or gallons applied based on Exposure SAC SOP #12 “Recommended Revisions to the Standard Operating Procedures for Residential Exposure Assessments,” HED estimates and AD Standard Assumptions.

3 Paint exposure scenarios are from the AD Occupationa l and Residential Exposure Assessment (T. Leighton, 2/1/2006, D326306). The density of paint is assumed to be 10 lb/gal.

None of the residential handler exposure scen arios exceeded HED’s level of concern. [Note: Although the risk for mixing/loading/applying propi conazole with a low pressure handwand is not a concern, (MOE = 1300) it is important to not e that most labels identify a hose-end sprayer as the method of application. Additionally, a ll risk calculations were conducted using the maximum turf application rate (1.8 lb ai/acre). However, a turf a pplication rate of 0.51 lb ai/acre was identified on a residential-use product labe l (EPA Reg # 100-773). This lower application rate may better represent homeowner use.

5.2 Residential Postapplication Ex posure and Risk Characterization

The existing residential use patt erns result in postapplication de rmal exposures to adults, and dermal and oral exposures to infants and childre n. These exposures are considered short-term only, due to the fact that postappl ication exposures were calculat ed using propiconazole as the parent compound, while compound specific TTR data in dicates that at the Indiana, California, and Pennsylvania test sites, average total propico nazole residues declined to below the minimum quantifiable limit (MQL) by DAT = 14, DAT = 10, a nd DAT = 8 respectively. These dissipationPage 23 of 31 rates, combined with label specific use rates and frequency of use specifications, reinforce the hand to mouth short-term exposure scenario; For short-term exposure to Children 1-2 years old, the driving factors for this ri sk assessment are hand to mout h, object to mouth, and dermal exposure. Soil ingestion is insignificant (MOE >300,000) compared to thes e factors, indicating that the postapplication scenario should be short-term only

In addition to using HED’s SOP for residential a ssessment, the study specific turf transferable residue (TTR) was used in the calculation. A summary of risk estimates for residential postapplication risks for adults and childre n is provided in the following tables.

Table 5.2.1. Short-term Risks to Adults and Children From Postapplication Exposure to Turf . 1

Exposure scenarios Max. appl. rate

(lb ai/A) Exposure

routes TC

cm2/hr Short-term

MOE 2

Adult, high-contact activities 1.8 dermal 70,000 350

Adult, mowing 1.8 dermal 500 50,000

Toddler, high contact activities 1.8 dermal 25,000 210

Toddler, hand-to-mouth activity 1.8 oral N/A 1,100

Toddler, object-to-mouth activity 1.8 oral N/A 4,500

Toddler, incidental soil ingestion 1.8 oral N/A 330,000

1. HED memo by J. Miller (D329393, 6/15/06). 2. Dermal exposure only.

The postapplication exposure results summarized in Table 5.2.1 a were not recalculated using the current TCs to bring this assessment up to today' s standards, even though chemical-specific turf transferable residue (TTR) studies are avai lable for such scenarios (J. Miller, D329393, 6/15/2006). The TTR data were generated usi ng the Modified California Roller Technique (ORETF roller) in all th e three locations. According to the ExpoSAC Policy No. 12, the TTR data generated by the ORETF roller have a lower tr ansfer efficiency (<0.5-1%) than that for the revised TCs (1-5%). Therefore, the ExpoSAC Policy No. 12 guida nce document advised against using the ORETF roller TTR data in conjunction with the revised TCs because it results in lower exposures to adults and children than the exposures estimated according by the current

residential SOP standards.

The aggregated risk to Toddlers from exposures to residential turf use is illustrated in Table 5.2.2. As shown in Table 5.2.2, the aggregat e MOE is 170 which is not of concern.Page 24 of 31 Table 5.2.2. Toddler Residential Risk Estimates for Postapplication Exposure to Propiconazole

Exposure Scenario TC

cm2/hr Route of Exposure Application Rate MOE at Day 0 Combined MOE

Outdoors

Hand to Mouth Activity on

Turf N/A Oral 1.8 lb ai/acre 1100

170 Object to Mouth Activity on

Turf N/A Oral 1.8 lb ai/acre 4500

Soil Ingestion N/A Oral 1.8 lb ai/acre 330,000

Turf – General High-Contact

Activities 25000 Dermal 1.8 lb ai/acre 210

Note: Combined MOE = NOAEL/(ADD hand-to-mouth + ADD object-to-mouth + ADD incidental soil ingestion + ADD dermal )

Level of Concern: MOE = 100

Residential postapplication scenarios from an timicrobial uses were also assessed. No postapplication exposure to adult is expected b ecause of propiconazole’s low vapor pressure (therefore, no inhalation exposur e) and the registrants’ deleti on of the only other use (i.e., materials preservative in fabrics, textiles, area carpet fibers). Propiconazole is used on many different types of wood including 1) green or fresh cut lumber, poles, posts, and timbers; 2) manufactured wood products such as logs (including for log home construction), wood chips/sawdust, plywood veneer, and particle board; 3) dry lumber; and 4) finished wood products such as millwork, shingles, shakes, siding, plyw ood, and structural lumber and composites. Except “dry lumber” uses, the other 3 groupings would result in minimal dermal and/or incidental oral exposure. Inha lation exposure (e.g., in log homes treated with propiconazole) is also expected to be negligible based on the lo w vapor pressure. For “dry lumber” uses, if propiconazole-treated lumber is us ed to build residentia l decks and/or play sets, then there is the potential for dermal and incidental oral exposures to treated lumb er used in decks and or play sets. AD assessed the risk to children playi ng on propiconazole-treat ed structures using screening level assessment. Tabl e 5.2.3 shows the result of aggregate risk from incidental oral and dermal exposure from propiconazole treated wood. This risk assessment, based on high end screening-level assumptions, indicates no risk of concern. Confirmatory data for the surface residues are needed to verify this screening-level assessment.

Table 5.2.3. Propiconazole Assessment of Children Playing on Treated Structures

. Exposure Dose (mg/kg/day) a MOEs (Target =100) b

Short-term Intermediate

Dermal Contact 0.0675 450 150 Incidental Oral 0.00563 5,300 1,800

Aggregate 0.0731 410 140 a Aggregate dose = dermal dose + oral dose. b MOEs = ST and IT NOAELs (mg/kg/day) / Dose (mg/kg/day). Where ST NOAEL = 30 mg/kg/day and IT NOAEL = 10 mg/kg/day. Target MOE = 100.Page 25 of 31 6.0 AGGREGATE RISK ASSESSMENT S AND RISK CHARCTERIZATION

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

6.1 Acute and Chronic Aggregate Risk

Acute and chronic aggregate exposures include food plus drinking water exposures. Acute and chronic aggregate risks are not of concern. See Section 4.3 for details.

6.2 Short-Term Aggregate Risk

Short-intermediate term aggregate exposure takes into accoun t residential exposure plus average exposure levels to food and water (considered to be a background exposure level). Based on the residential use pattern, propiconazole postapplic ation exposures to adults are from dermal exposure only, for infants and children are from dermal and oral routes. Table 6.2.1 aggregates

the short-term risk for Toddlers from incide ntal oral, dermal, and food and water (as a background). Although both residential and antimicr obial uses result in incidental oral and dermal exposure to children, the hi ghest incidental oral and derm al exposure scenarios are from residential use on turf, which were used in the sh ort-term aggregate risk assessment. The shortterm aggregate risk does not exceed HED’s level of concern. This assessment is considered very

conservative in that the reside ntial incidental oral postapplication exposure was calculated by combining three screening level assessments (which by themselves already have conservative estimates). HED also did a back-calculation to es timate room available in the risk cup for shortterm aggregate risk. In order to obtain a short-term aggregate MOE ≥ 100, the MOE resulting from additional short-term exposures to Children 1-2 (from possible dermal and incidental oral exposure from treated wood or other sources) needs to be ≥ 270. As stated above in Section 5.2 ( see Table 5.2.3 ), the combined short-term MOE (dermal and incidental oral) from antimicrobial use of propiconazole in treated wood for Toddler is 410, which is greater than 270.Page 26 of 31 Table 6.2.1. Short-term Aggregat e Risk Estimates to Propiconaz ole for Toddler (Children 1-2years)

Exposure Scenario Target

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

Average Food and Water

(As background) N/A Food and

water 0.0182 30 1650 2

160 Hand to Mouth Activity on

Turf 100 1 Oral 0.0269 30 1100 3

Object to Mouth Activity on

Turf 100 1 Oral 0.0067 30 4500 3

Soil Ingestion 100 1 Oral 0.00009 30 330,000 3

Turf – General High-Contact

Activities 100 1 Dermal 0.1410 30 210 4

Note:

1 Target MOE= 100, Developmental rat-severe maternal clinical toxicity. NOAEL=30

2 MOE food = [(short-term oral NOAE L)/(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 6.2.2 aggregates the short-term risk for a dults from residential postapplication, and average food and water (as a background). Base d on the low vapor pressure of propiconazole, no postapplication inhalation exposure is anticipated to occur. No postapplication exposures are expected to occur with antimicrobial uses. Th e highest postapplication e xposure from residential

use on turf was used in the shor t-term aggregate. The aggreg ate MOE is 320, which is greater than the target MOE of 100. This aggregate exposure assessment is considered very conservative because the assumptions used for each of the scenarios separately are already high end (i.e., time spent outdoors, dislodgeable residues).Page 27 of 31 Table 6.2.2. Short-term Aggregate Ri sk Estimates to Propiconazole for A dults from Postapplication Activities

Exposure Scenario Target

MOE Route of Exposure Exposure

Or

Daily dose NOAELs MOE at Day 0 Combined MOE 4

Average Food and Water

(As background) N/A Food and

water 0.0068 30 4400 2

320 Residential Postapplication(Residential Turf Gen. HighContact Activities)) 100 1 Dermal 0.085 30 350 3

Note:

1 Target MOE= 100, Developmental rat- increas ed 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)].

6.3 Intermediate-Term Aggregate Risk

The only residential use scenario that will resu lt in potential intermediate-term exposure to propiconazole is postapplic ation exposure to Children from w ood treatment (antimicrobial use). Table 6.3 shows the aggregate risk for intermediate-term exposure to Children 1-2 years old. The aggregate MOE is 110, which is gr eater than the ta rget MOE of 100.

Table 6.3. Intermediate -term Agg regate Risk Estimates to Propiconaz ole for Toddler (Children 1-2years)

Exposure Scenario Target

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

Average Food and Water

(As background) N/A Food and

water 0.0182 10 550 2

110 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 oncogenicity study. NOAEL=10

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

3 MOE oral = [(intermediate -term oral N OAEL)/(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)].

6.4 Long-Term Aggregate Risk

Since there are no residential uses that will likely result in ch ronic exposure to propiconazole, chronic aggregate includes food and water only. Water exposure has been included in the DEEM analysis; therefore, the re sult of chronic aggregate risk assessment is as shown in TablePage 28 of 31 4.3. Propiconazole does not possess a separate cancer dietary endpoint—t he RfD approach is considered protective; therefore, the results of only the acute and chroni c analyses are given.

7.0 CUMULATIVE RISK CHARA CTERIZATION/ASSESSMENT

Propiconazole is a member of the triazole-derivative fungicide class of pesticides. Although triazole-derivative fungicides act similarly in plants (fungi) by i nhibiting ergosterol biosynthesis, there is not necessarily a relatio nship between their pesticidal activity and their mechanism of toxicity in mammals. Structural similarities do not constitute a common m echanism of toxicity.

Evidence is needed to establish that the chemi cals operate by the same, or essentially the same, sequence of major biochemical events (EPA, 2002). In triazole-derivative fungicides, however, a variable pattern of toxicological res ponses is found. Some are hepatotoxic and hepatocarcinogenic in mice. Some induce thyroid tumors in rats. Some induce developmental, reproductive, and neurological effect s in rodents. Furthermore, th ey produce a diverse range of biochemical events including altered choleste rol levels, stress responses, and altered DNA methylation. It is not clearly understood wh ether these biochemical events are directly connected to their toxicological outcomes. Thus, there is currently no evidence to indicate that triazole-derivative fungicides sh are common mechanisms of toxici ty and EPA is not following a cumulative risk approach based on a common mechan ism of toxicity for the these pesticides. For information regarding EPA’s procedures fo r cumulating effects from substances found to have a common mechanism of toxicity, see EPA’s website at http://www.epa.gov/pesticides/cumulative

.

Propiconazole, like other triazo le-derivative fungicides, can form the common metabolites 1,2,4- triazole and its triazole conjuga tes (triazolylalanine, triazolyl acetic acid, and triazolylpyruvic acid). To support existing tolerances and to es tablish new tolerances for triazole-derivative pesticides, including propiconazo le, U.S. EPA conducted a human health risk assessment for exposure to 1,2,4-triazole, triazo lylalanine, triazolylacetic ac id and triazolylpyruvic acid resulting from the use of all current and pending uses of any triazole-der ivative fungicide. The risk assessment is a highly conservative, sc reening-level evaluation in terms of hazards associated with common metabolites (e.g., use of a maximum combination of uncertainty factors) and potential di etary and non-dietary exposures (i.e ., high end estimates of both dietary and non-dietary exposures). In addition, the Agen cy retained the additional 10X FQPA safety factor for the protection of infa nts and children. The assessment in cludes evaluations of risks for various subgroups, including thos e comprised of infants and child ren. The Agency’s complete risk assessment is found in the propi conazole reregistration docket at http://www.regulations.gov , Docket Identification (ID ) Number EPA-HQ-OPP-2005-0497.Page 29 of 31 8.0 OCCUPATIONAL EX POSURE AND RISK

For a detailed discussion refer to: Section 18 Emergency Exemption fo r Propiconazole (Tilt EPA Reg. No. 100- 617); for Use on Avocado Trees ; HED memo by J. Miller, D380160, 7/28/10.

8.1 Occupational Handler Exposure and Risk
Occupational handler exposure is expected for certified applicat ors applying propiconazole to

avocado trees. Handler risks were assessed using a Surrogate Exposures Guide from the Pesticide Handlers Exposure Database (PHED) Ve rsion 1.1. The occupati onal handler scenarios

resulted in MOEs that do not exceed HED's le vel of concern (i.e., MOEs > 100) while adhering to label specific PPE directi ons, (i.e., Long Sleeve Shirt, L ong Pants, Socks, Shoes, and Chemical Resistant Gloves).

Chemical-specific data were not submitted to the Agency in support of this Section 18 application, therefore it is HED policy to use data from the Pestic ide Handlers Exposure Database (PHED) Version 1.1 (Sur rogate Exposures Guide) to a ssess handler exposures in the absence of chemical specific data. According to the propiconazole label; (Tilt® EPA Reg. No. 100-617) relevant exposure scenarios for occupa tional handlers are (1) application via handgun sprayer, (2) application via tr ee injection, and (3) a pplication via soil drenching equipment (Groundboom). The unit exposures provided in th e PHED (Surrogate Exposures Guide) were used for exposure, dose and MOE (Mar gin of Exposure), calculations.

The average adult weight of 60 kg was used for estimating dermal and inhalation exposure. Furthermore, the use patterns presented on the propos ed label are expected to result in short-term (1-30 days) exposure only. For all occupational handler s exposure scenarios, risks are below HED’s level of concern (i.e., MOEs are > 100) wi th label specific PPE and therefore not of

concern.

Label specific directions state that the Pers onal Protection Equipment (PPE) required for this action falls under category G (long-sleeved shirt, long pants, chemical re sistant gloves, shoes plus socks, and protective eyewear ). Furthermore the restricted entry interval (REI) is 12 hours, unless soil injected, which under the WPS (Worker Protection Standards) allows workers to reenter treated areas if there will be no contact with treated materials.

For propiconazole a Q 1 * for carcinogenicity was not establ ished and the RfD approach is considered protective; therefore, a cancer ri sk assessment for handlers is not required.

The resulting doses and MOEs ar e presented in Table 8.1.Page 30 of 31 Table 8.1. Short-Term Occupa tional Handler Exposure and Risk for Pr opiconazole (Tilt® EPA Reg. No. 100-617)

Exposure
Scenario Crop App Rate (lb ai/A) a Acres

Treated

Daily Unit Exposure (mg/lb ai) b Dose (mg/kg/Day) Short-Term

MOEs

Dermal Long Sleeve Shirt, Long

Pants + Gloves Baseline

inhalation Dermal Long Sleeve Shirt, Long

Pants + Gloves Baseline

Inhalation Combined

MOE c

Open Mixer/Loader (Liquid)

1 Handgun Sprayer (PHED) Avocado

Trees 7.1 100 0.023 1.2 0.10886 0.0142 240

Applying (Liquid)

1 Handgun Sprayer (PHED) Avocado

Trees 7.1 5 0.34 1.4 0.08046 0.00008 370

Mixer/Loader/Applicator (Liquid)

2 Groundboom

Soil Drench

(PHED) Avocado

Trees 7.1 80 0.057 1.3 0.21584 0.01231 130

Applicator (Liquid)

2 Groundboom

Soil Drench

(PHED) Avocado

Trees 7.1 80 0.014 0.74 0.05301 0.00701 500

Applicator

Tree Injection Not Assessed: Handgun and Soil Drench are protective

1Handgun Sprayer (PHED) acres treated based on HED directions: 100 Acres mixed = 20 workers x 5 Acres . (Individual worker mixes = 100 Acres / day)

2 Soil Drench calculations Groundboom: 80 Acres / day

. PHED SOP.009 a. Application rate based on proposed uses on the label for (Tilt® EPA Reg. No. 100-617) b. Unit Exposures based on PHED Version 1.1. Surrogate Exposures Guide.

c. Combined MOE = inhalation + DermalPage 31 of 31 8.2 Occupational Postapplication Exposure and Risk

Based on the use patterns associated with the proposed Section 18 label, HED believes that postapplication exposure will be negligible. Ther efore, a postapplication quantitative assessment

was not conducted.

9.0 REFERENCES

1) Section 18 Drinking Water Assessme nt; EFED memo by J. Lin (D379850, 07 /15/10).

2) Section 18 Propiconazole Dietary E xposure and Risk Assessment; HED memo by T. Morton (D380158, 07/21/10). 3) Section 18 Common Tr iazole Metabolites Updated Dietary Exposure and Risk Assessment; HED memo by T. Morton (D380341, 7/27/10). 4) Section 18 Occupational and Residentia l Exposure Assessment; HED memo by J. Miller (D380160, 07/28/10). 5) Propiconazole – Fifth Carcinogenicity Peer Review; E. Doyle and E. Rinde (TXR 0009771, 9/11/92).
6) Propiconazole- 3 rd Report of the Hazard Identification Assessment Review Committee; J. Kidwell (TXR 0052277, 12/17/03).
7) Propiconazole Occupational and Residen tial Exposure Assessmentof the Antimicrobial Uses; T. Leighton (D326306, 2/1/2006). 8) Amendment to the Propiconazole RED fo r Children’s Postapplication Exposure from Treated Structures; T. Leighton (D330159, 06/20/06). 9) Propiconazole: Revised Occupational and Residential Exposure Assessment; HED memo by J. Miller (D329393, 6/15/06). 10) Reregistration Eligibility Decisi on (RED) for Propiconazole; July 2006.

11) HED re-registration eligib ility document (RED) for Propi conazole; HED memo by Y. Donovan (D329668, 6/28/06).
12) Propiconazole FQPA Human Health Risk Assessment for the Section 3 Registrations on Garden Beets, Turnips, Parsley, Cilantro and Pineapple; HED memo by Y. Donovan (D347905, 9/30/08). 13) Propiconazole (Tilt) in or on Wild Rice a nd Stone Fruit. Evaluation of Residue Data and Analytical Methods; HED memo by S. Malak (MRID 41063802; PP#9F3758; No DP Barcode #, 11/28/89).