### Page 1 of 58 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION 

### MEMORANDUM March 9 , 2011 SUBJECT: Revised Propiconazole Human Health Ri sk Assessment for a Section 3 Registration o n Mint, Bulb Vegetables, Caneberry Subgroup 13 - 07A, Bushberry Subgroup 13 - 07B, and Low Growing Berry Subgroup 13 - 07G. PC Code: 122101 DP Barcode: 385913 Decision No.: 425825 Registration No. : 

### 100 - 617 Petitio n No.: 9E7959 Regulatory Action: Section 3 Registration Risk Assessment Type: Single Chemical Aggregate Case No.: 3125 T XR No.: NA CAS No.: 60207 - 90 - 1 MRID No.: NA 40 CFR: 180. 434 

### FROM: Becky Daiss, Biologist

Iv an Nieves, Chemist Jerry Stokes , Chemist Risk Assessment Branch 4 Health Effects Division (7509P) THROUGH: Susan V. Hummel, Branch Senior Scientist

Risk Assessment Branch 4, HED (7509P) TO: Barbara Madden, Risk Manager

Emergency

Response Branch Registration Division (750 5 P) Th is document provides the revised Health Effects Division’s (HED’s) risk assessment of the Section 3 proposed use of propiconazole on mint, bulb vegetables, caneberry subgroup 13 - 07 A , bushberry

subgroup 13 - 07 B , and low growing berry subgroup 13 - 07 G . The do cument has been revised to include an assessment of aggregate risk from residential exposures to propiconazole. Supporting documents are listed below. Occupational Exposure Assessment

– I. Nieves , D , 10/19/2010 Residue Chemistry

Assessment

– J. Stokes , D 372878, 11/3/10 Dietary and Drinking Water Exposure Assessment

– B. Daiss, D375283, 11 / 3 / 10 Drinking Water Exposure Assessment

– R. Miller, D380135, 7/9/10

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TABLE OF CONTENTS pg. 1.0 EXECUTIVE SUMMARY ................................ ................................ ................................ . 4 2.0 IN GREDIENT PROFILE ................................ ................................ ................................ .... 7 2.1 Registered Products and Proposed New Uses ................................ ................................ ..... 7 2.2 Structure, Nomenclature and Phy sical/Chemical Properties ................................ ............... 7 3.0 HAZARD CHARACTERIZATION/ASSESSMENT ................................ ........................ 8 3.1 Hazard Characterization ................................ ................................ ................................ ...... 8 3.2 Absorption, Distribution, Metabolism and Excretion ................................ .......................... 9 3.3 FQPA Hazard Considerati ons ................................ ................................ ........................... 10 3.3.1 Neurotoxicity

Toxicity ................................ ................................ ......................... 10 3.3.2 Developmental Toxicity ................................ ................................ ........................ 10 3.3.3 Reproductive Toxicity ................................ ................................ ........................... 11 3.3.4 Pre - and/or Postnatal Toxicity ................................ ................................ ................ 11 3.3.5 FQPA F actor ................................ ................................ ................................ .......... 11 3.4 Toxicity

Endpoint Selection ................................ ................................ .............................. 12 3.4.1 Acute Reference Dose

– Females Age 13 - 49 ................................ ....................... 12 3.4.2 Acute Reference Dose

– General Population ................................ ......................... 12 3.4.3 Chronic Reference Dose

– Adult Males and Females Age 50+ ............................ 13 3.4.4 In cidental Oral Exposure

– Short - Term ................................ ................................ . 1 4 3.4.5 In cidental Oral Exposure

– Intermediate - Term ................................ ..................... 14 3.4.6 Dermal Absorption ................................ ................................ ................................ . 14 3.4.7 Dermal Exposure

– Short - Term ................................ ................................ ............. 14 3.4.8 Dermal Exposure

– Intermediate - Term ................................ ................................ . 15 3.4.9 Inhalation Exposure

– Short - Term ................................ ................................ ......... 15 3.4.10 Inhalation Exposure

– Intermediate - Term ................................ ............................. 15 3.4.11 Classification of Carci nogenic Potential ................................ ................................ 16 3.5 Margins of Exposure ................................ ................................ ................................ .......... 1 7 3.6 Recommendation for Aggregate Exposure ................................ ................................ ........ 17 3.7 Summary

of Endpoints Selected for Risk Assessment ................................ ...................... 17 3.8 Endocrine Disruption ................................ ................................ ................................ ......... 18 4.0 PUBLIC HEALTH AND EPIDEM IO LOGY ................................ ................................ ... 19 5.0 DI ETARY AND DRINKING WATER EXPOSURE ASSESSMENT ............................ 19 5.1 Residue Chemistry Profile ................................ ................................ ................................ . 19 5.1.1 Metabolism in Primary Crops and Livestock ................................ ........................ 19 5.1.2 Metabolism in Rotational Crops ................................ ................................ ............ 20 5.1.3 Residues of Concern ................................ ................................ .............................. 20 5.1.4 Residue Anal ytical Method s ................................ ................................ .................. 20 5.1.5 Residues in Crops ................................ ................................ ................................ .. 21 5.1 .6 Residues in Processed Commodities ................................ ................................ ..... 21

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5.1.7 Residues in Rotational Crops ................................ ................................ ................. 21 5.1.8 Storage Stability ................................ ................................ ................................ ..... 22 5.2 Drinking Water Profile ................................ ................................ ................................ ...... 22 5.2.1 Environmental Fate and Transport ................................ ................................ ......... 22 5.2.2 Estimated Drinking Water Concentrations ................................ ............................ 2 3 5.3 Dietary

and Drinking Water Exposure and Risk ................................ ............................... 23 6.0 RESIDENT IA L EXPOSURE AND RI SK ASSESSMENT ................................ ............ 24 7.0 AGGREGATE EXPOSURE AND RI SK ASSESSMENT ................................ ............... 24 7.1 Short Term Aggregate Risk ................................ ................................ ............................... 24 7.2 Intermediate Term Aggregate Risk ................................ ................................ .................... 26 8.0 OCCUPATI ONAL EXPOSURE AND RI SK ................................ ................................ ... 26 8.1 Occupational Exposure Scenarios ................................ ................................ ...................... 26 8.2 Occupational Handler Exposure ................................ ................................ ........................ 2 7 8.2.1 Handler Exposure Scenarios ................................ ................................ .................. 27 8.2.2 Handler Exposure Data ................................ ................................ .......................... 27 8.2.3 Handler Exposure Assumptions ................................ ................................ ............. 27 8.2.4 Handler Exposure and Risk Estimates ................................ ................................ ... 2 8 8.3 Occupational Post - Application Exposure Data and Assumptions ................................ ..... 29 8.3.1 Post - Application Exposure Scenarios ................................ ................................ .... 29 8.3.2 Post - Application Exposure Data ................................ ................................ ........... 30 8.3.3 Post - Application Exposure Assumptions ................................ .............................. 30 8.3.4 Post - Application Exposure and Risk Estimates ................................ ..................... 3 1 9.0 CUMULAT IVE RISK ................................ ................................ ................................ ....... 33 10.0 DAT A NEEDS ................................ ................................ ................................ ................... 32 10.1 Toxicity

Data Requirements ................................ ................................ .............................. 32 APPENDI CES A. GUIDELINE TOXI COLOGY DATA SUMMARY ................................ ......................... 33 A.1 Guideline Data Requirements ................................ ................................ ................ 33 A.2 Toxicity

Profiles ................................ ................................ ................................ ..... 34 B. STUDIES REVIEWED FOR ETHICAL CONDUCT ................................ ...................... 41 C. SUMMARIES OF KEY TOXICITY STUDIES ................................ ............................... 43 D. REFERENCES FOR TOXI CI TY STUDIES ................................ ................................ .... 52 E. CHEMI CAL NAMES AND STRUCTURES OF METABOLITES ................................ . 58

1.0 EXECUTIVE SUMMARY

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This assessment provides information to support an amended Section 3 registration for the use of propiconazole on mint, bulb vegetables, caneberry subgroup 13 - 07 A , bushberry subgroup 13 - 07 B , and low growing berry subgroup 13 - 07 G . This document addresses the exposures and risks associated with exposures from currentl y registered uses and the proposed new uses of propiconozole. Italso assesses potential enhanced sensitivity of infants and children from dietary

and/or residential exposure as required under the Food Quality Protection Act (FQPA) of 1996. Use Profile Propiconazole 1 - [[2 - (2,4 - dichlorophenyl ) - 4 - propyl - 1,3 - dioxolan - 2 - yl ]methyl] - 1 H - 1,2,4 - triazole ) is a sy stemic triazole - ty pe fungicide that provides broad spectrum disease control on a variety of food and non - food crops. Permanent tolerances are established ( 40 CFR §180.434 ) for the combined residues of propiconazole and its metabolites ( de termined 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 b yproducts to 40 ppm in/on grass straw. Non - food uses include use on commercial, public and residential ornamentals , landscapes and turf. The mode of antifungal action of propiconazole is attributed to the inhibition of CYP51 (lanosterol - 14 - a - demeth yl ase). Inhibition of normal sterol production disrupts cell wall formation and slows or stops the growth of the fungus . Agricultural applications of propiconazole are made using ground or a erial equipment . Propiconizole is applied to non - food areas b y 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 Use s The Interregional Research Project No. 4 (IR - 4) has submitted an application for the registration a product containing propiconazole for use on mint, bulb vegetables, caneberry subgroup 13 - 07 A , bushberry subgroup 13 - 07 B , and low growing berry subgroup 13 - 07 G . Registrations exist for the representative commodities of these subgroups. The IR - 4 petition requests expansion of the tolerance to the whole subgroup. The product is manufactured b y Sy ngenta Crop Protection, Inc. under the trade name Tilt ® 

### Fungicide (EPA Reg. No. 100 - 617) . It is an emulsifiable concentrate ( EC) product containing 41.8% active ingredient (ai) per gallon (3.6 lb ai/gal). Pre - harvest intervals (PHI s) of 30 day s are proposed for caneberry , bushberry and mint. A 14 day

PHI is proposed for bulb onion and a 0 day PHI is proposed for green onion. The new product is not proposed for residential use and residential exposures are not expected based on the proposed uses.

Hazard Identification The toxicology

database for propiconazole is adequate for evaluating and characterizing

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toxicity and sel ecting endpoints for purposes of this risk assessment. The primary target organ for propiconazole toxicity in animals is the liver . Liver effects observed in subchronic and chronic oral studies in rats and mice include lesions , hy pertrophy and necrosis . Propiconazole is not a reproductive toxicant. Ina rat developmental study , fetal effects in pups were observed at doses lower than doses at which maternal effects were seen providing quantitative evidence of increased susceptibility

of fetuses to in ute ro 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 uncertainties with regard to pre - and/or postnatal toxicity are minimal. Propic onazole 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 battery

of acute toxicity

tests (Toxicity

Category I II or IV in all tests). It is not a skin irritant but is a dermal sensitizer. Immunotoxicity and subchronic neurotoxicity studies are required as part of new 40 CFR Part 158 requirements for registration of a pesticide. Dose Response Assessment Toxicological endpoints were selecte d for dietary /drinking water , occupational and residential exposure scenarios . Acute and chronic Population Adjusted Doses (PADs) were selected for assessment of food and drinking 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 population was selected from a carcinogenicity study in mice. Short and intermediate ter m 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 incidental 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 uncertainty factor of 100X was applied to endpoints selected for all exposure routes (10x for interspecies extrapolation, 10x for intraspecies variation). Exposure/Risk Assessment and Risk Characterization Risk assessments were conducted for dietary (food and water) , and occupational exposure pathway s based on registered uses and re quest 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 level of concern for the general population and all population subgroups . Aggre gate risks from propiconazole are not a concern. Occupational e xposure and risk estimates indicate that worker and residential handler and post - application exposures are not of concern at the maximum allowable application rates for the proposed new use s p rovided that handlers wear chemical resistant gloves as required on the label. Use of Human Studies

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This risk assessment relies in part on data from studies in which adult human subjects were intentionall y exposed to a pesticide or other chemical. Th ese studies , listed in Appendix 2.0, have been determined to require a review of their ethical conduct . S ome of these studies are also subject to review b y the Human Studies Review Board. All of the studies used have received the appropriate review. En vironmental 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 Minori ty Populations and Low - Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ). As a part of every

pesticide risk assessment, OPP considers a large variety of cons umer subgroups according to well - established procedures. In line with OPP policy , HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Whenever appropriate, non - dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development, as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. Tolerance Recommendation Pending submission of a revised Section F (see requirements under Proposed Tolerances), there are no residue chemistry issues that would preclude granting con ditional Section 3 registration for the requested use of propiconozole on mint, bulb vegetables, caneberry subgroup 13 - 07A, bushberry subgroup 13 - 07B, and low growing berry subgroup 13 - 07G or establishment of the following tolerances for residues of propic onozole.

Mint, spearmint, tops 

### ................................ ..................... 10.0 ppm Mint, peppermint, tops 

### ................................ ................... 10.0 ppm Onion, bulb subgroup 3 - 07A 

### ................................ ............ 0. 2 ppm Onion, green , subgroup 3 - 07B 

### ................................ .......... 9.0 ppm Caneberry, subgroup 13 - 07A 

### ................................ ............ 1.0 ppm Bushberry, subgroup 13 - 07B 

### ................................ ............ 1.0 ppm Low growing berry subgroup 13 - 07G* 

### ............................. 1.3 ppm * except cranberry As previously

noted, p ermanent tolerances are currentl y 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

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current tolerance expression should be amended to include only propiconazole per se because 1) there are a number of pesticides that have 2,4 - DCBA as common metabolite, and an enforcement agency may not be able to determine if residues are due to misuse of propiconazole or the proper use of other pesticides containing 2,4 - DCBA; 2) propiconazole per se can be detected by FDA multiresidue methods; and 3) inclusion of only parent allows harmonization with the residue defin ition for the Codex MRL s. Codex has established several maximum residue limits (MRL s) for propiconazole in/on various raw agricultural commodities. The Codex MRL s are expressed in terms of propiconazole per se , which is the same as the US tolerance exp ression . B oth Canada and Mexico have established MRL s/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 MRL s. 2.0 INGREDIENT PROFILE 2.1 Registered and Proposed New Uses There are currently

264 active propiconazole registrations including 120 Section 3 registrations and fourteen 24(c) special local needs (SL Ns) and 129 Section 18 Emergency Exemption. The Interregional Research Proje ct No. 4 (IR - 4) has appli ed for registration of a new emulsifiable concentrate (EC) product containi ng 41.8% ai. The product is proposed for use on mint, bulb vegetables, caneberry subgroup 13 - 07 A , bushberry subgroup 13 - 07 B , and low growing berry

subgroup 13 - 07 G (Table 1) . The product is manufactured by Sy ngenta Crop Protection, Inc. under trade name Tilt ® 

### Fungicide (EPA Reg. No. 100 - 617) . Table 1 : Propiconazole: Proposed Use for Tilt® (EPA Reg. No. 100 - 617) Crops Appl. Method Maximum Application Rat es Mint Aerial Groundboom Chemigation Single 0.113 lb ai/A Seasonal 0.338 lb ai/A Bulb Vegetables Single 0.094 lb ai/A Seasonal 0.45 lb ai/A Caneberries & Bushberries Single 0.070 lb ai/A Seasonal 0.84 lb ai/A Lo w Growing Berries Single 0.047 lb ai/A Seasonal 0.45 lb ai/A 

### 2.2 Structure, Nomenclature, and Physical/Chemical Properties The nomenclature and physicochemical properties of propiconazole are provided in Tables 2 and 3.

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T able 2 . Nomenclature of Propiconazole Compound N N N

O O Cl Cl

Common name Propiconazole Company experimental names CGA - 64250 IUPAC name 1 - [2 - (2,4_dichlorophenyl) - 4 - propyl - 1,3 - dioxolan - 2 - yl methyl] - 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 Table 3. Physicochemical Properties of Technical Grade Propiconazole 

### . Parameter Value Reference Boiling point 120 C at 1.9 Pa, >250 C at 101.325 kPa MRID N o. 43698701 pH 4.9 at 25 C (1% aqueous dispersion) MRID No. 43698701 Density 1.289 g/cm3 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, aceton e, 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 (pKa) 1.09 MRID No. 43698701 Octanol/water partition coefficient Log(KOW) 3.72 at pH 6.6 and 25 C MRID No. 4369 8701 UV/visible absorption spectrum (  max, nm) Not available MRID No. 40583703 

### 3.0 HAZARD CHARACTERIZATION/ASSESSMENT 3.1 Hazard Characterization The toxicology

database for propiconazole is adequate for evaluating and characterizing toxicity and sele cting endpoints for purposes of this risk assessment. Subchronic neurotoxicity and immunotoxicity

studies are required as part of new 40 CFR Part 158 data requirements for registration of a pesticide. The primary

target organ for propiconazole toxicity i n animals is the liver. Increased liver weights were seen in mice after subchronic or chronic oral exposures to propiconazole. Liver lesions such as vacuolation of hepatocy tes, ballooned liver cells, foci of enlarged hepatocy tes, h ypertroph y and necrosis are characteristic of propiconazole toxicity in rats and mice. Decreased body weight gain was also seen in subchronic, chronic, developmental and reproductive studies in animal studies. 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 b y stomach irritations at 6 mg/kg/day and above.

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In rabbits, developmental toxicity occurred at a higher dose than the maternal toxic dose, while in rats, de velopmental toxicity occurred at lower doses than maternal toxic doses. In creased incidences of rudimentary ribs occurred in rat and rabbit fetuses. Increased cleft palate malformations were noted in two studies in rats. In one published study in rats developmental effects (malformations of the lung and kidneys, incomplete ossification of the skull, caudal vertebrae and digits, extra rib (14 th 

### rib) and missing 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 susceptibility of the offspring to the toxic doses of propiconazole. Propiconazole was negative for mutagenicity in the in vitro BALB/3T3 c ell transformation assay , bacterial reverse mutation assay , Chinese hamster bone marrow chromosomal aberration assay , unscheduled DNA sy nthesis studies in human fibroblasts and primary rat hepatocy

tes, 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 phenobarbital, a known liver tumor promoter. Liver enzy me induction studies with propiconazole in mice demonstrated that propiconazole is a strong phenobarbital ty pe inducer of xenobiotic metabolizing enzy mes. Hepatocellular proliferation studies in mice suggest that propiconazole induces cell proliferation followed by treatment - related h yp ertroph y in a manner similar to the known hy

pertro phic 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 - possible human carcinogen and recommended that for the purpose of risk characterization the reference Dose (RfD) approach be used for quantification of human risk (HED Doc. No. 009771, April 15, 1992 meeting). Propiconazole has low to moderate toxicity in experimental animals by the oral (Category III), dermal (Category

III) and inhalation routes (Category IV), is moderately

irritating to the eyes (Category

III), minimally

irritating to the skin (Category IV) and is a dermal sensitizer. Immunotoxicity and subchro nic neurotoxicity studies are required . These are new data requirement s under 40 CFR Part 158 as part of the data requirements for registration of a pesticide (food and non - food uses). The complete toxicity profile for propiconazole is provided in Appendix 1.2, Tables 2 and 3 . 3.2 Absorption, Distribution, Metabolism and Excretion The rat metabolism study labeled with 14 

### C at the triazole - [3,5] position indicated that parent compound was extensively metabolized. An intravenous stu dy labeled with (U 14 

### C) - Phenyl found several metabolites, including CGA 118245 (61.8% in males, 2.4% in females), CGA 217495 (8.9% in males, 58.3% in females), CGA 91304 (2.3% in males only), and CGA 118244 (3.6% in females only). No parent material was d etected in the feces in the iv group. The metabolites seen in the iv study were detected to varying degrees in the urine and the feces

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of the orall y dosed groups. Radiolabeled materials CGA 91305, CGA 118245 and CGA 177291 were reported ranging from 0.5% - 10.9% of the fecal radioactivity in males and females or in one sex alone. Most of the fecal radioactivity was not characterized. Metabolites CGA 217495 and CGA 177291 are not found in plant or livestock metabolism (see Appendix for structures). In two other (U 14 

### C) - phenyl and 14 

### C - triazole ring labeled propiconazole studies, the percentages of fecal metabolites extracted and distributed at various pH’s were not substantially different between the triazole and phenyl labeled samples, which suggest that the bridge between the phenyl ring and the triazole ring remained intact. The proposed metabolic pathway appears to involve the cleavage of the dioxolane ring 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 yi eld the corresponding alcohol (CGA 91305). Both CGA 91304 and CGA 91305 are found in plants and livestock. 3.3 FQ PA Hazard Considerations The toxicity

database for propiconazole is sufficient for a full hazard evaluation and is cons idered adequate to evaluate risks to infants and children. Acceptable developmental toxicity studies in the rat and rabbit, acceptable multi - and single generation reproduction studies in the rat. An acceptable acute neurotoxicity study in the rat is als o 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). Together, the available data support the reduction of the FQPA factor to 1X. 3. 3 .1 Neurotoxicity In an acute oral neurotoxicity study , s ingle oral administration at the high dose of 300 mg/kg propiconazole produced severe clinical signs of toxicity in rats within 5 - 6 hours (e.g., decreased activity , cold, pale, piloerection, subdued, tip toe gate, staining around the nose ). Limited signs (piloerection, diarrhea , tip toe gait) were seen in the 100 mg/kg dosed animals . No treatment related clinical signs were observed at the low dose ( 30 mg/kg). F unctional observational battery

(F OB ) and motor activity tests showed reduced activity in males and females at the high dose. 3.3.2 Developmental Toxicity In a developmental toxicity study in rat s, severe compound - related maternal toxicity was observed at the high dose level (360 mg/kg/day) during the first five day s of dosing. The high dose was lowered to 300 mg/kg/day on day 6 and the severity and frequency of these effects decreased rapidly . There were no treatment related clinical observations in maternal animals with the exception of one animal exhibiting rales. Fetotoxic effects included increased incidence of rudimentary

ribs, un - ossified sternebrae, shortened renal papillae, and dilated ureter at 90 and 300 mg/kg/day

(NOAEL of 30 mg/kg/day). In addition, cleft palate findings along with skeletal anomalies also seen at these doses were determined to be probable treatment related indications

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of delayed development. Cleft palate findings w ere confirmed in a subsequent development toxicity study in rats. HED toxicologists consider the fetal effects observed in th e rat study at a dose lower than that evoking maternal toxicity to be quantitative evidence of increased susceptibility

of fetuses to in utero exposure to propiconazole. In the developmental toxicity study in rabbits, neither quantitative nor qualitative evidence of increased susceptibility of fetuses to in utero exposure to propiconazole was observed . 3 . 3 . 3 Reproductive Toxicity A 2 - generation reproduction study showed no compound - related clinical observations or mortality in parents or off

- spring. Food consumption and body weight effects were observed at the high dose in parents and pups. H epatic effects (cellular swelling) were seen in mid - and high - dose parental animals and at the high dose in offspring. There were no signs of reproductive toxicity . 3 . 3 . 4 Pre - and/or Postnatal Toxicity The toxicology

database for propiconazole is sufficient for FQPA assessment. There is low concern for pre - and/or post - natal toxicity resulting from exposure to propiconazole. In the developmental toxicity

study in rats, fetal effects observed in this study at a dose lower than that evoking maternal toxicity are considered to be quantitative evidence of increased susceptibility of fetuses to in utero exposure to propiconazole. In the developmental toxicity study in rabbits, neither quantitative nor qualitative evidence of increased susceptibility of fetuses to in utero exposure to propiconazole was observed in this study . In the 2 - generation reproduction study in rats, neither quantitative nor qualitative evidence of increased susceptibility of neonates (as compared to adults) to pre - and/or postnatal exposure to propiconazole was observed in this study . There i s no evidence of neuropathology or abnormalities in the development of the fetal nervous s ys tem from the available toxicity studies conduct ed with propiconazole. In the rat acute neurotoxicity

study, there was evidence of mild neurobehavioral effects at 300 mg/kg, but no evidence of neuropathology from propiconazole administration. Since there was quantitative evidence of increased susceptibility of the young following exposure to propiconazole in the developmental rat study, the HED Hazard Identification Assessment Review Committee (HIARC) performed a Degree of Concern Anal ys is and concluded that the degree of concern for the effects observ ed in this study was low and no residual uncertainties were identified. 3.3.5 FQ PA Factor HED recommends the FQPA SF be reduced to 1 X based on the following:

- The toxicological data base is adequate for FQPA assessment.

- Residual uncertainties or con cerns for pre - and/or post - natal toxicity are minimal.

- Although an apparent increased quantitative susceptibility was observed in fetuses and offspring based on minimal toxicity at high doses of administration, clear NOAELs and LOAELs have been identified for all effects of concern, and a clear dose - response has been well defined. Since this increased susceptibility is occurring

### Page 12 of 58 at high doses and a clear dose response has been well defined for all effects of concern, residual uncertainties or concerns for pre - and/or post - natal toxicity are minimal. 3 . 4 Toxicity Endpoint Selection 3. 4 .1 Acute Reference Dose (aRfD) / aPAD
– Females 13 - 49 Selected Study : Developmental Toxicity in Rats (MRID 40425001 ). See Section 3.2. 2 and Appendix C . Dose and Endpo int for Establishing an aRfD : 30 mg/kg/day - Developmental NOAEL of 30 mg/kg/day

and a LOAELof 90 mg/kg/day based on increased incidence of rudimentary ribs, unossified sternebrae, as well as increased incidence of shortened and absent renal papillae an d increased cleft palate . Uncertainty Factor (UF ): 100

– 10 x for interspecies extrapolation and 10x for intraspecies variation. Comments about Study

/Endpoint : The developmental effects of concern are presumed to occur after a single exposure and are re levant to females aged 13 - 50 years old since they occur in utero and to young children based on post - natal effects.

3. 4 . 2 Acute Reference Dose (aRfD ) / aPAD
– Females 13 - 49 Selected Study : Acute Neurotoxicity in Rats (MRID 46046401 ). See Section 3.2. 1 and Appendix C . Dose and Endpoint for Establishing an aRfD : 30 mg/kg/day - NOAEL of 30 mg/kg/day and a LOAEL of 100 mg/kg/day based on clinical signs of toxicity ( i.e., piloerection in one male, diarrhea in one female, tip toe gait in 3 females ). Uncertainty Factor (UF ): 100

– 10 x for interspecies extrapolation and 10x for intraspecies variation. Comments about Study

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

Acute Rf D = 30 mg/kg (NOAEL ) = 0. 30 mg/kg/day (Females 13 - 49) 1 00 (UF)

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

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3. 4 . 3 Chronic Reference Dose ( c RfD) / cPAD
– All Population Selected Study : 24 Month Oncogenicity Study in Mice (MRID s 00129570 & 93194037 ) Oncogenicity Mouse Study - A 24 - month propiconazole dietary oncogenicity

study in CD - 1 mice was conducted at doses of 0, 100, 500 or 2500 ppm (M: 10.0, 49.4, and 344.3 F: 10.8, 55.6 and 340.3 mg/kg/day selected by

the HIARC for deriving the chronic RfD. N on neoplastic liver effects (increased liver weight in males and increase in liver lesions: masses/raised areas/ swellings/nodular areas mai nly) were observed at 50 mg/kg/day . (See Appendix B) Dose and Endpoint for Establishing a cRfD: 10 mg/kg/day - NOAEL of 10 mg/kg/day and a LOAEL of 50 mg/kg/day based on non - neoplastic liver effects . Uncertainty Factor (UF ): 100

– 10 x for interspeci es extrapolation and 10x for intraspecies variation. Comments about Study

/Endpoint : The lower NOAELof 2.7 mg/kg/day in a 3 - month oral feeding toxicity

study in mice was not selected because a) the re is a wide dose spread between the NOAEL (2.7 mg/kg/day) and the LOAEL(65 mg/kg/day) in that study , b) the LOAEL (50 mg/kg/day) in the selected study is lower than the LOAEL (65 mg/kg/day) of the 3 - month mouse oral feeding study , and c) the liver toxicity seen in the 2 ye ar mouse study is consistent with that seen in an 18 - month mice and 2 - generation reproduction studies. In an 18 - month oncogenicity

study in mice, the NOAEL for liver toxicity was 11 mg/kg/day

and the LOAEL 59 mg/kg/day). In a 24 - month feeding study in rats, the NOAEL for liver toxicity was 1 8 mg/kg/day

and the LOAEL 96 mg/kg/day). In 2 - generation reproduction study in rats, the NOAEL for liver toxicity was 8 mg/kg/day

and the LOAEL 42 mg/kg/day). The dog study was not selected since stomach irritations were attributed to local effects and n ot sy stemic toxicity, and target organ (liver) toxicity seen in mice and rats was not seen in dogs.

3.4 . 4 Incidental Oral Exposure ( S hort - Term) Selected Study : Acute Neurotoxicity in Rats (MRID 46046401 ). See Section 3. 4 . 2 Dose and Endpoint for Establishing an aRfD : 30 mg/kg/day - NOAEL of 30 mg/kg/day Chronic Rf

D = (NOAEL) 10 mg/kg = 0.1 ( General Population ) (UF) 100

### Page 14 of 58

and a LOAEL of 100 mg/kg/day based on clinical signs of toxicity (piloerection in one male, diarrhea in one female, tip toe gait in 3 females . Uncertainty Factor (UF ) /L evel of Concern = 100

– 10 x for interspecies extrapolation and 10x for intraspecies variation. FQPA 1X 3.4 . 5 Incidental Oral Exposure (Intermediate - Term) Selected Study : 24 Month Oncogenicity Study in Mice (MRID s 00129570 & 93194037 ) See Section 3.4.3 Dose and Endpoint fo r Establishing a cRfD: 10 mg/kg/day - NOAEL of 10 mg/kg/day and a LOAEL of 50 mg/kg/day based on non - neoplastic liver effects . Uncertainty Factor (UF ): 100

– 10 x for interspecies extrapolation and 10x for intraspecies variation. 3 . 4 . 6 Dermal Absorptio n HIARC selected a 40% dermal absorption factor (DAF) based on the average dermal absorption of propiconazole over a 10 hour exposure period in rats at an exposure level of 0.01 mg/cm 2 

### (MRID’s 42415701, 45345901). Although another dermal absorption fact or for propiconazole of 1% was used in a recent Section 18 risk assessment, the basis for the lower absorption factor was not clear. Therefore, a DAF of 40% was used for this assessment. 3 . 4 . 7 Dermal Exposure ( Short - Term ) Selected Study : Acute Neurot oxicity in Rats (MRID 46046401 ). See Section 3.3.1 Dose and Endpoint NOAELof 30 mg/kg/day and a LOAEL of 100 mg/kg/day based on clinical signs of toxicity

(piloerection in one male, diarrhea in one female, tip toe gait in 3 females . Uncertainty Fa ctor (UF ) /L evel of Concern= 100

– 10 x for interspecies extrapolation and 10x for intraspecies variation. FQPA 1X Comments about Study

/Endpoint : Since an oral NOAEL was selected for dermal risk assessment, a dermal absorption factor of 40% based on a der mal absorption study

in rats should be used. Although a dermal toxicity study is available, a POD from an oral study was selected because neurotoxicity , the primary effect of concern for short - term exposure is not specificall y evaluated in the available dermal toxicity studies. The selected endpoint is protective of potential neurotoxic effects from dermal exposure. 3 . 4 . 8 Dermal Exposure (Intermediate - Term )

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Selected Study : 24 Month Oncogenicity Study in Mice (MRID s 00129570 & 93194037 ) See Section 3.4 .3 Dose and Endpoint for Establishing a cRfD: 10 mg/kg/day - NOAEL of 10 mg/kg/day and a LOAEL of 50 mg/kg/day based on non - neoplastic liver effects . Uncertainty Factor (UF ): ) /L evel of Concern : 100

– 10 x for interspecies extrapolation and 10x for intraspecies variation. FQPA 1X Comments about Study

/Endpoint : Since an oral NOAEL was selected for dermal risk assessment, a dermal absorption factor of 40% based on a dermal absorption study in rats should be used. 3. 4 . 9 Inhalation Exposure ( Short - Term ) Selected Study : Neurotoxicity in Rats (MRID 46046401 ). See Section 3. 4.2 Dose and Endpoint : . NOAEL of 30 mg/kg/day and a LOAEL of 100 mg/kg/day based on clinical signs of toxicity (piloerection in one male, diarrhea in one female, tip toe gait in 3 females . Uncertainty Factor (UF ) /L evel of Concern : 100

– 10 x for interspecies extrapolation and 10x for intraspecies variation. FQPA 1X Comments about Study

/Endpoint : Inhalation toxicity is assumed to be equivalent to oral toxicity . 3. 4 . 1 0 Inhalation Exposure (Intermediate - Term ) Selected Study : 24 Month Oncogenicity Study in Mice (MRID s 00129570 & 93194037 ) See Section 3.4.3 Dose and Endpoint 10 mg/kg/day - NOAEL of 10 mg/kg/day and a LOAELof 50 mg/kg/day

based on non - neoplastic liv er effects . Uncertainty Factor (UF ) /L evel of Concern : 100

– 10 x for interspecies extrapolation and 10x for intraspecies variation. FQPA 1X Comments about Study

/Endpoint : Inhalation toxicity is assumed to be equivalent to oral toxicity . 3. 4 . 11 Class ification of Carcinogenic Potential

### Page 16 of 58

The HED Carcinogenicity Peer Review Committee (CPRC) classified propiconazole as Group C - possible human carcinogen and recommended that for the purpose of risk c haracterization the reference Dose (RfD) approach should be used and would be protective (HED Doc. No. 009771, April 15, 1992 meeting). This classification was based on increased hepatocellular adenomas and combined adenomas/carcinomas and increased hepatocellular carcinomas in male mice at the high dose (2500 ppm) in an oral feeding oncogenicity study (MRID 00129570). There was no treatment related increased tumor response in female mice. In a rat study conducted with acceptable doses of propiconazole ( 0, 100, 500, or 2500 ppm), no tumorogenic response was observed either (MRID 00250784). The CPRC determined that the high dose of 2500 used in the mouse study was excessively

toxic (based on survival, liver clinical pathology , histopathology , and body wei ght and body weight gains) but that the lower doses (100 & 500 ppm) were not adequate for assessing the carcinogenic potential of propiconazole. The 2500 ppm used in the oncogenicity study exceeded the MTD demonstrated in the 90 day

study based on the end

point of hepatic necrosis. Subsequently

the Registrant conducted an 18 - month oncogenicity study in male CD - 1 mice at 0, 100, 500 or 850 pm (MRID 44381401). There was a treatment related increase in hepatocellular adenoma incidences and total hepatocellular neoplasia (adenoma s and carcinomas) of 24% , at the 850 ppm exposure level when compared to concurrent controls which had unusually

low incidence of adenomas ( 2% ) and total neoplasia (4%) . Based on HED standard statistical computations, there was a si gnificant dose - related increasing trend, and a significant difference in the pair- wise comparison of the 850 ppm dose group with the concurrent controls, for liver adenomas and/or carcinomas combined . However, this increase in the total neoplasm was driven primarily by the adenomas. Dosing was considered adequate based on the body weight gain and hepatotoxic effects seen at 500 and 850 ppm. The percentage adenomas and carcinomas were within the range of the inadequate historical control data initially submitted by the registrant. Subsequently submitted adequate control data are more consistent with previous historical control data for the CD mouse and indicate that the study control in the second mouse study may be low. The tumor incidence observed in m ale livers at the 850 ppm dose is within the range of the new historical data. However, propiconazole will continue to be classified as possible human carcinogen (group C) and for the purpose of risk characterization the reference Dose (RfD) approach will continue to be used.

3 . 5 Margins of Exposure A summary

of target Levels of Concern for risk assessment is provided in Table 4. Table 4. Target Levels of Concern/Margin of Exposure for Propiconazole Route/Duration Short - Term (1 - 30 Days) Intermedi ate - Ter m (1 - 6 M onths) Long - Term (> 6 Months) Occupational (Worker) Exposure

### Page 17 of 58

Table 4. Target Levels of Concern/Margin of Exposure for Propiconazole Route/Duration Short - Term (1 - 30 Days) Intermedi ate - Ter m (1 - 6 M onths) Long - Term (> 6 Months) Dermal 100 100 100 Inhalation 100 100 100 Residential (Non - Dietary) Exposure Oral 100 100 N/A Dermal 100 100 100 Inhalation 100 100 100 

### 3.6 Recommendation for Aggregate Exposure Risk Assessments When there are potential residential exposures to the pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures. There are potential residential post - application exposures to adults via the dermal route and to children via dermal and i ncidental oral routes of exposure. For the general population, including infants and children, the short term oral exposure can be aggregated with the short - term dermal and inhalati on due to a common toxicological endpoint (clinical signs in the ACN study). A common toxicological endpoint was identified for intermediate - and long - term oral, dermal (oral equivalent) and inhalation (oral equivalent) routes. These routes can be aggreg ated for these scenarios for the appropriate population. 3.7 Summary of Endpoints Selected for Risk Assessment Toxicological doses/endpoints selected for the propiconazole risk assessment are provided in Tables 5 and 6. Table 5 . Summary of Toxicologica l Doses and Endpoints for Propiconazole for Use in Dietary Hum an Health Risk Assessments Exposure/Scenario Point of

Departure Uncertainty/FQP

A Safety Factors RfD, PAD, LOC for Risk Assessment Study and Toxicological Effects Ac ute Dietary (General Popul ation) NOAEL =

30 mg/kg/day UF A= 10x

UF H =10x FQPA SF= 1x Ac ute RfD = 0.3

mg/kg/day aPAD = 0. 3 mg/kg/day Ac ute neurotoxicity study Rat

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). Ac ute Dietary (Females 13 - 49 years) NOAEL =

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

UF H =10x FQPA SF= 1x Ac ute RfD = 0.3

mg/kg/day aPAD = 0.3 mg/kg/day DNT Study - Rat

LOAEL = 90 mg/kg/day based on increased incidence of rudimentary ribs, un - ossified ste rnebrae, as well as increased incidence of shortened and absent renal papillae and increased cleft palate. Chronic Dietary (Adult Males and Females 50+ yrs) NOAEL =

10 mg/kg/day UF A= 10x

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

0.1 mg/kg/day cPAD = 0.1 mg/kg/day 24 - mo nth oncogenicity study on CD - 1 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). Cancer (all routes) Classification: Group C, possible human carcinogen, RfD approach for risk characterization

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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 a ssociated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short - term study for long - term risk assessment. UF DB = to account for the absence of key date (i.e., lack of a criti cal 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 Table 6 . Summary of Toxicological Doses and Endpoint s for Propiconazole for Use in Residential and Occupational Hum an 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 Occupational LOC for MOE = 100 Ac ute 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 ga it in 3 females). Dermal Intermediate Term (1 - 6 months) DAF = 4 0% NOAEL= 10

mg/kg/day UF A= 10x

UF H =10x Residential LOC

for MOE = 100 Occupational LOC for MOE = 100 24 Month Oncogenicity Study - Mice

LOAEL = 50 mg/kg/day based on non - neoplastic liver e ffects (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 Ac ute 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 males and increase in liver lesions: masses/raised areas/ swellings/nodular areas mainly). Cancer (all routes) Classification: Group C, possible human carcinogen, RfD approach for risk characterization DAF = Dermal Absorption Factor 

### 3.8 Endocrine Disruption As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide activ e and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally

occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employ s a two - tiered approach to making the s tatutorily required determinations. Tier 1 consists of a battery of 11 screening assay s to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal sy stems. Chemicals that go through Tier 1 s creening and are found to have the potential to interact with E, A, or T hormonal sy stems will proceed to the next stage of the EDSP where EPA will determine which, if any , of the Tier 2 tests are necessary based on the available data. Tier 2 testing is de signed to identify any adverse endocrine related effects caused by the substance, and establish a dose - response relationship between the dose and the E, A, or T effect. Between October 2009 and February 2010, EPA issued test orders/data call - ins for the

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f irst group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. This list of chemicals was selected based on the potential for human exposure through pathway s such as food and water, residential activity , and certain po st - application agricultural scenarios. This list should not be construed as a list of known or likely endocrine disruptors. Propiconazole is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingl y, EPA anticipates issuing future EDSP test orders/data call - ins for all pesticide active ingredients . For further information on the status of the EDSP, the policies and proced ures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery , please visit our website: http://www.epa.gov/endo/. 4.0 PUBLIC HEALTH AND EPIDEMIOLOGY From the review of the Incident Data S ys tem, it appears that a majority of propiconazole cases involved skin s ymptoms such as rash, itching, and skin irritation and respiratory effects such as difficulty breathing. Poison Control Center data would tend to sup port the Incident Data Sy stem results; dermal irritation, ery thema, and difficulty

breathing were among the most common effects reported. Measures to limit skin and respiratory exposure are recommended for this pesticide. Appropriate personal protective equipment to protect the skin is also recommended for both handlers and field workers who are likel y to have substantial contact with propiconazole. (HED memo of J. Blondell, D319239, 07/26/05) 5.0 DIETARY AND DRINKING WATER EXPOSURE ASSESSMENT 5.1 Residue Chemistry Profile 5 .1. 1 Metabolism in Primary Crops and Livestock The nature of propiconazole residues in plants is adequatel y understood ( DP D329394, Y. Donovan, 6/15/06 ). These data indicate that the major metabolic pathway in plants involves hydrox yl ation of the n - propyl group on the dioxolane ring of the cis/trans isomers of propiconazole, with subsequent conjugation to sugars. A possible alternative pathway involves reductive deketalization of the dioxolane ring and sugar conjugation of the resulting metabolite. The alkylbridge between the phenyl and triazole rings is metabolized and free 1 H - 1,2,4 - triazole is released. The free triazole is readily conjugated with the amino acid, serine/alanine, forming triazole aniline which is further metabolized to triazole acetic acid possibl y 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 m etabolites from several triazole containing pesticides, the risk assessment for triazoles has been as sessed separately (HED memo of 11/3/10, T. Morton, D383609). The nature of propiconazole residues

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in livestock is adequatel y understood based on acceptabl e goat and poultry metabolism studies ( DP D329394, Y. Donovan, 6/15/06 ). 5.1.2 Metabolism 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 re viewed by

EFED, the metabolism of propiconazole in rotational crops is similar to that in primary crops. 5.1.3 Residues of Concern 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 data have been generated using a common moiety method that converts parent and all of the metabolites of concern to 2,4 - DCBA. Table 7. Compounds to be Inc luded in the Risk Assessment and Tolerance Expression. Matrix Residues Included in Risk Assessment Residue Included in Tolerance Expression for Compliance Monitoring 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 Parent only 

### 5 .1. 4 Residue Analytical Methods 5.1.4.1 Enforcement Method s An adequate method, HPLC/UV Method AG - 671A, is available for tolerance enforcement. This method has undergone a successful tolerance method validation by the Analy tical Chemistry

Branch of BEAD. The method was forwarded to FDA for inclusion in PAM Volume II. This meth od has an LOQ of 0.02 ppm. The method includes optional detection via HPL C/MS, giving a means of residue confirmation.
5.1.4.2 Data Collection Method s For plant commodities, samples were analyzed for propiconazole as 2,4 - dichlorobenzoic methyl este r using the working method “Working Analytical Method for the Determination of Propiconazole in Mint Leaves as 2,4 - Dichlorobenzoic Methyl Ester Using Gas Chromatography with Electron Capture Detector”. This method was adapted from “Determination of Total Residues of Propiconazole in Crops as 2,4 - Dichlorobenzoic Acid by Capillary Gas Chromatography” (Method No. AG - 454B). The lowest level of method validation (LLMV) in this study was 0.050 ppm. Based on recoveries of samples fortified at the LLMV, the limit of detection (LOD) and limit of quantitation (LOQ) were calculated as 0.023 ppm and 0.070 ppm, respectively.

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5 .1. 4.3 Multiresidue Method The FDA PESTDATA database (PAM Volume I, Appendix I) indicates that propiconazole is completely recovered (>80%) using Multiresidue Methods Section 302. The recovery of propiconazole metabolites CGA - 91305, CGA - 118244, and 1,2,4 - triazole is variable using Section 302. Propiconazole and metabolites CGA - 91305, CGA - 118244, and 1,2,4 - triazole are not recovered using Multiresidue Methods Sections 303 and 304. 5 .1. 5 Residues in Crops The available field trial data are adequate and support the proposed amended use patterns for propiconazole on mint. The number and geographic distribution of th e field trials are adequate, and the appropriate samples were collected at the proposed PHI. In five field trials in Regions 5 and 11 , propiconazole (3.6 lb/gal EC) was applied 3 times to established fields of mint as broadcast foliar applications at 0.11 25 lb ai/A/application at RTI s of 6 - 8 day s, for a total of 0. 3375 lb ai/A/season (1x rate). The initial application was made when plants were 2 - 4 inches in height, and all applications were made using ground equipment. Duplicate control and treated sampl es of fresh mint hay were harvested from each site at 7 day s after treatment ( DAT ) . Samples were stored frozen f rom collection to analy sis for an interval supported by available storage stability

data. Total residues of propiconazole and its DCBA contain ing metabolites in/on mint were determined using a validate GC/ECD Method AG - 454B ( LOQ is 0.0 7 ppm, and an LOD is 0.023 ppm). T otal propiconazole residues were 0. 114 - 5.453 ppm and averaged 3.316 ppm in/on 10 samples of mint hay harvested at 7 DAT. The ex isting tolerances for berry group 13 (1.0 ppm), onion, bulb (0.2 ppm), onion, green (9.0 ppm), and strawberry (1.3 ppm) are adequate to cover any propiconazole residues under new crop groupings: onion, bulb subgroup 3 - 07A (0.2 ppm), onion, green subgroup 3 - 07B (9.0 ppm), caneberry

subgroup 13 - 07A (1.0 ppm), bushberry subgroup 13 - 07B (1.0 ppm), and low growing berry

subgroup 13 - 07G (except cranberry) (1.3 ppm). 5.1.6 Residues in Processed Commodities Adequate data are available from two mint processi ng studies (DP Barcode D209468, W. Wassell, 4/25/95). In two field trials, propiconazole (EC) was applied to mint at rates up to 0.34 lb ai/A (1.5x labeled rate). Samples of fresh mint hay were cut 90 DAT, air dried, and distilled to yield mint oil. Samples of mint hay and oil were stored for up to 224 day s prior to anal ys is using an adequate GC/ECD method (AG - 454B). Total propiconazole residues were 0.12 ppm in fresh hay from both field trials and were <0.05 and 0.08 ppm in oil from the two sites, for an average processing factor of 0.5x for mint oil. Therefore, a separate tolerance for mint oil is not required . Previously

submitted processing studies, reflecting the measurement of total combined residues, are adequate for the p roposed uses of propiconazole on other commodities. 5.1.7 Residues in Rotational Crops

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Plant - back restrictions have been established for propiconazole products registered for use on rotational crops based on the confined rotational crop studies. La bels specify

that any food/feed crops not listed on the label 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 . 5.1.8 Storage Stability. Adequate storage stability data are available indicating that residues of propiconazole and its metabolites determined as 2,4 - DCBA are stable at ≤ - 15 C for up to 39 months in a variety of commodities. (D329394, Y. Donovan, 6/15/06) . 5.2 Drinking Water Profile 5 .2.1 Environmental Fate and Transport Acceptable and supplemental environmental fate data indicate that propiconazole is persistent in most soil and aqueous environments. Propiconazole is stable to hydrol ys is and photodegradation in water. It has an aerobic soil metabolism half - life of 69 day s and is persistent in aquatic environments (t1⁄2 = 426 day s). Aqueous photoly sis may occur in the presence of sensitizers (t1⁄2 = <1 day). Its princi pal route of dissipation in terrestri al environ ments appears to be adsorp tion to soil which increases with soil organic matter content (Kd 

### values=1.2 on sand to 9.34 on silty clay loam soils). Terres tri al field dissipation half - lives of about 100 day s were reported in four soils. In aquatic dissipation studies in rice fields, propiconaz ole dissipated rapidly (t1⁄2 = <5 days) although the route of dissipation was not appar ent. Propiconazole is moderatel y mobi le to relatively immobile in most soil and aqueous environments. Propiconazole is not volatile (vapor pressure is 1.3 x 10 - 6 

### Torr at 20 0 

### C). Propiconazole is broken down through hydrox yl ation of the propyl side chain and the dioxolane ring to give 1,2,4 - triazole and other products, including particle - bound material and carbon dioxide. CGA - 136735, CGA - 118245 and CGA - 71019 were identified as major degradates (>10% of applied) in environmental fate studies. Minor degradates include CGA - 91304 and CGA - 91305. 5 .2.2 Estimated Drinking Water Concentrations Drinking water residues provided b y the Environmental Fate and Effects Division (EFED) (D 372880 , J. Lin , 7 / 6 / 10) were incorporated directl y into the acute and chronic dietary anal ys es. EFED generated the surface water and ground water estimates using the Pesticide Root Zone Model 3 and Screening Concentration in Ground Water (SCIGROW; Tier 1) models, respectivel y. The estimated surface water drinking water concentrations (EDWCs) 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 ye ar annual mean concentration (cancer chronic). The SCI - GROW e stimated ground water drinking water concentrations for propiconazole are not expected to exceed 0.64 μg/L. These

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results are based on EDWCs for Turf (DP 325821, 328690 , 07/07/2006). The proposed new uses do not result in higher EDWCs than those estimate d for turf uses. 5 .3 Dietary and Drinking Water Exposure and Risk HED conducted screening - level acute and chronic dietary and drinking water exposure and risk assessments using the Dietary Exposure Evaluation Model with the Food Commodity Intake Dat a

base (DEEM - FCIDTM). Dietary risk assessment incorporates both exposure and toxicity of a given pesticide. For acute and chronic dietary assessments, the risk is expressed as a percentage of a maximum acceptable dose (i.e., the dose which HED has concluded will result in no unreasonable adverse health effects). This dose is referred to as the population adjusted dose (PAD). The PAD is equivalent to the reference dose (RfD) divided b y the additional Safety Factor, if applied. For acute and non - cancer chron ic exposures, HED is concerned when estimated dietary

risk exceeds 100% of the PAD. The resulting acute and chronic food and water exposure estimates were less than HED’s level of concern ( <100% aPAD) for the general U.S. population and all population sub - groups (Tables 8 and 9) . At the 95 th 

### percentile, the acute dietary exposure (food and water) to general US population is 7 % of the aPAD, and the most highl y exposed subgroup, Children 1 - 2 y rs old, is 17 % of the aPAD. The chronic dietary exposure t o general US population is 7 % of the cPAD, and the most highly exposed subgroup , Children 1 - 2 y rs old, is 18 % of the cPAD. All the dietary

risk estimates are below 100% of the PADs. Table 8 . Results of Acute Dietary Exposure Analysis for Food and Wate r Population Subgroup aPAD (m g/kg/day) 95th Percentile Exposure (mg/kg/day) % aPAD General U.S. Population

0.3 0.022053 7 All Infants (< 1 year old) 0.048257 16 Children 1 - 2 years old 0.051498 17 Children 3 - 5 years old 0.039652 13 Children 6 - 12 years old 0.027168 9 Youth 13 - 19 years old 0.018085 6 Adults 20 - 49 years old 0.017975 6 Adults 50+ years old 0.013576 5 Females 13 - 49 years old 0.016750 6 Table 9 . Results of Chronic Dietary Exposure Analysis for Food and Water Population S ubgroup cPAD (m g/kg/day) Exposure (mg/kg/day) % cPAD General U.S. Population

0.1 0.006794 7 All Infants (< 1 year old) 0.015851 16 Children 1 - 2 years old 0.018210 18 Children 3 - 5 years old 0.014763 15 Children 6 - 12 years old 0.009627 10 Youth 13 - 19 years old 0.005891 6 Adults 20 - 49 years old 0.005685 6 Adults 50+ years old 0.004556 5 Females 13 - 49 years old 0.005369 5

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6.0 RESIDENTIAL EXPOSURE AND RISK There are no new requested residential uses expected with this registration, therefore risks associated to propiconazole and the product Tilt ® 

### in a residential environment was not assessed. 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) 7 .0 AGGREGATE EXPOSURE AND RISK ASSESSMENT In accordance with the FQPA, when there are potential residential exposures to a pesticide, aggre gate risk assessment must consider exposures from three major routes: oral, dermal, and inhalation. There are three sources for these types of exposures: food, drinking water, and residential uses. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. The acute and chronic exposure estimates provided in the Dietary Exposure Section represent aggregate risk for acute and chronic exposures. 7.1 Short - Term Aggregate Risk Short term aggregate exposure takes into account residential exposure plus average exposure levels to food and water (considered to be a background exposure level). Table 10 aggregates the short - term risk for toddlers from incidental oral, dermal, and food and water (as a background). The highe st incidental oral and dermal exposure scenarios are from residential use on turf, which were used in 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 combining three screening level assessments (which by themselves already

have conservative estimates). Table 10: Short - termAggregate Risk Estimates to Propicon azole for Toddler (Children 1 - 2years) E xposure Scenario Target MOE Route of Exposure Exposure NOAELs MOE at Day 0 Com bined MOE 5 Average Food and Water N/A Oral 0.0182 30 1 6 00 2 160 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 - Contact Activities Dermal 0.1410 210 4 1 Target MOE= 100, Acute Neuro toxicity NOAEL=30 2 MOE food = [(short - term oral NOAEL)/(chronic dietary exposure)]

### Page 25 of 58 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÷MO E oral) + (1÷MOE dermal)]. 

### Table 11 aggregates the short - term risk for adults from residential handler exposure, and average food and water exposure (as a background). The lowest aggregate MOE is 120, which is greater than the target MOE of 100. Adult handlers have some inhalation exposure, but there are no appropriate inhalation studies on propiconazole 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 inhalation risk. Table 11 : Short - termAggregate Risk Estimates to Propiconazole for Adults from Handler Activities Exposure Scenario Target MOE Route of

E xposure Exposure or

Daily dose NOAELs MOE at Day 0 Combined MOE 4 Average Food and Water (As background) N/A Food and water 0.006 0 30 5000 2 NA Ornamentals w Low

Pressure Handwand

100 1 Dermal and Inhalation 0.0069

30 4400 3 2300 Ornamentals w Hose - end Sprayer 0.0008 40000 4400 Turf w Low Pressure Handwand 0.0237 1300 1000 Turf w Hose - end Sprayer 0.0568 530 480 Applying Paint w Brush/ Roller 0.0323 330 300 Applying Paint w Airless Sprayer 0.2432 120 120 1 Target MOE= 100, Acute Neuor toxicity NOAEL=30 2 MOE food and water = [(short - term oral NOAEL)/(chronic dietary exposure)] 3 MOE dermal 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 12 aggregates the short - term risk for adults from residential post application, and average food and water (as a background). Based on the low vapor pressure of propiconazole , negligible post application inhalation exposure is anticipated to occur. The highest post application exposure from residential use on turf was used in the short term aggregate. The aggregate MOE is 330, which is greater than the target MOE of 100. This aggregate exposure assessment is considered very conservative because the assumptions used for each of the scenarios separately

are already

high end (i.e., time spent outdoors, dislodgeable residues). Table 12 : Short - termAggregate Risk Estimates to Propiconazole for Adults fromPost - Application Activities

### Page 26 of 58

Exposure Scenario Target MOE Route of Exposure Exposure or

Daily dose NOAELs MOE at Day 0 Com bined MOE 4 Average Food and Water (As background) N/A Food and water 0.006 0 30 5000 2 330 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 ex posure)] 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 onl y residential use scenario that will result in potential intermediate term exposure to propiconazole is post application exposure to children from wood treatment (antimicrobial use). Table 7.3 shows the aggregate risk for intermediate term exposure to Ch ildren 1 - 2 years old. The aggregate MOE is 120, which is greater than the target MOE of 100. Table 13. 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 0.01 80 10 600 2 120 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 NOAEL)/(hand - to - mouth residential exposure)] 4 MOE dermal = [(intermediate - term dermal NOAEL)/(high - end dermal residential exposure)] 5 Aggreg ate Combined MOE (food, water, and residential) = 1÷ [(1÷MOE food and water) + (1÷MOE oral) + (1÷MOE dermal)]. 

### 8 .0 OCCUPATIONAL EXPOSURE AND RISK 8 .1 Occupational Exposure Scenarios Occupational handler and post - application exposure scenarios were a ssessed for the proposed new product on mint, bulb vegetables, caneberries, bushberries, and low growing berries. Based on the product labels and information provided b y the registrant, short - and intermediate - term exposure is assessed for handlers and po st - 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 and shoes with socks plus gloves.

### Page 27 of 58

8 .2 Occupational Handler Exposure The term “handler” applies to individuals who mix, load, and appl y the pesticide product. There is a potential for exposure to propiconazole during mixing, loading, and application activities through the dermal and inhalation routes. Propiconazole products are applied using aerial, airblast, groundboom and chemigation equipment . 8.2.1 Handler Exposure Scenarios 8.2.1.1 Mixing and Loading

• M ixing/loading emulsifiable concentrates for aerial application • M ixing/loading emulsifiable concentrates for groundboom application • M ixing/loading emulsifiable concentrates for airblast application • Mixing/loading emulsifiable concentrates for chemigation application • Applying spray s aerially 8 .2.1.2 Application

• Applying spray s aerially • Applying spray s with ground boom sprayer • Applying spray s with airblast sprayer • F lagging for aerial spr ay application 8.2.2 Handler Exposure Data Chemical - specific data for assessing exposure during pesticide handling activities were not submitted to the Agency in support of this Section 3 application. Therefore, data from the Pesticide Handlers Exposure Database (PHED) Version 1.1 to assess handler exposures for regulatory

actions (HED Science Advisory Council for Exposure Standard Operating Procedure #7, 1/28/99). 8 .2.3 Handler Exposure Assumptions

• Average body weight of an adult handler is 70 k g. • Dermal Absorption Factor is 40 % • Expo sure duration is short - term (1 - 30 day s) and intermediate - term (1 - 6 months) • Maximum label application rates:

- 0. 1125 lb ai/A for mint and low growing berries

- 0. 225 lb ai A for bulb vegetables

- 0. 16875 lb ai/A f

or bushberries • Area treated: (ExpSAC SOP N o. 9.1 )

- 350 acres per day

for aerial applications

- 350 acres for chemigation applications

- 80 acres for groundboom applications

### Page 28 of 58

- 40 acres for airblast applications 8.2.4 Handler Exposure and Risk Es timates Summaries of the combined, dermal plus inhalation short - , and intermediate - term risks for each exposure scen ario are presented in Table 14. The combined dermal and inhalation exposure risks are not of concern (i.e., MOEs >100), provided the mixer /loaders wear chemical resistant gloves as directed on the label. Table 14: Summary of Short- and Intermediate - Term Propiconazole Occupational Handler Non - Cancer Risk s Crops Exposure

Scenario Appl.

Rate (lb ai/acre) 1 Area Treatd (A/day) 2 Unit Exposu re

(m g/lb ai) 3 ST & IT Dose

(m g/k g/day) 4 ST MOE IT MOE Aggregate ST MOE Aggregate

IT MOE DermalInhalation DermalInhalation DermalInhalation DermalInhalation BL BL + Gloves BL BL+

Gloves BL* BL + Glove BL BL +

Gloves BL BL+ Gloves BL BL+ Gloves Mixer/Loader

- Liquids Mint Aerial 0.1125 350 2.9 0.023 0.0012 0.65 0.0052 0.000 7 46 5,800 44,000 15 1,900 15,000 46 5,100 15 1,700 Gr oundboom 80 2.9 0.023 0.0012 0.15 0.0012 0.000 2 201 25 ,000 190,000 67 8,500 65,000 201 22,000 67 7, 500 Chemigation 350 2.9 0.023 0.0012 0.65 0.0052 0.000 7 46 5,800 44,000 15 1,900 15,000 46 5,100 15 1 ,700 Bulb Veg Aerial 0.225 350 2.9 0.023 0.0012 1.31 0.0104 0.001 4 23 2 ,900 22,000 8 970 7,400 23 2,600 8 860 Gr oundboom 80 2.9 0.023 0.0012 0.29 0 .0024 0.0003 101 13,000 97,000 34 4,200 32,000 100 11,000 33 3,700 Chemigation 350 2.9 0.023 0.0012 1.31 0.0104 0.001 4 23 2,900 22,000 8 970 7,400 23 2,600 8 860 Cane berry Aerial 0.16875 350 2.9 0.023 0.0012 0.98 0.0078 0.0010 31 3,900 30,000 10 1,30 0 9,900 31 3,400 10 1,100

Airblast 40 2.9 0.023 0.0012 0.11 0.0009 0.0001 268 34,000 2 60,000 89 11,000 86,000 270 30,000 89 10,000 Chemigation 350 2.9 0.023 0.0012 0.9 8 0.0078 0.0010 31 3,900 30,000 10 1,300 9,900 31 3,400 10 1,100 Bush berry Aerial 0.16875 350 2.9 0.023 0.0012 0.9 8 0.0078 0.0010 31 3,900 30,000 10 1,300 9,900 31 3,400 10 1,100

Airblast 40 2.9 0.023 0.0012 0.11 0.0009 0.0001 268 34,000 260,000 89 11,000 86,000 270 30,000 89 10,000 Chemigation 350 2.9 0.023 0.0012 0.98 0.0078 0. 0010 31 3,900 30,000 10 1,300 9,900 31 3,400 10 1,100 Low Gr owing Berry Gr oundboom 0.1125 350 2.9 0.023 0.0012 0.65 0.0052 0.000 7 46 5,800 44,000 15 1,900 15,000 46 5,100 15 1,700 Chemigation 80 2.9 0.023 0.0012 0.15 0.0012 0.000 2 201 25,000 190,000 67 8,500 65,000 201 22,000 67 7,500 Aerial 350 2.9 0.023 0.0012 0.65 0.0052 0.000 7 46 5,800 44,000 15 1,900 15,000 46 5,100 15 1,700 Applicator Mint Aerial 0.1125 350 0.005 N/A 0.000 1 0.0011 N/A 0.0000 4 27,000 N/A 780 ,000 8,900 N/A 260,0 00 26,000 N/A 8 , 600 N/A Gr oundboom 80 0.014 0.014 0.0007 0.0007 0.0007 0.000 1 42,000 42,000 320 ,000 14,000 14,000 105,0 00 37,000 37,000 12 ,000 12,000 Bulb Veg Aerial 0.225 350 0.005 N/A 0.000 1 0.0023 N/A 0.000 1 13,000 N/A 390 ,000 4,000 N/A 131,0 00 13,000 N/A 4 ,300 N/A Gr oundboom 80 0.014 0.014 0.0007 0.0014 0.0014 0.000 2 21,000 21,000 160 ,000 6,900 6,900 53,0 00 18 ,000 18 ,000 6 ,100 6 ,100 Cane berry Aerial 0.16875 350 0.005 N/A 0.000 1 0.0017 N/A 0.000 6 18,000 N/A 520 ,000 5,900 N/A 170,0 00 17 ,000 N/A 5 , 7 00 N/A

Air blast 40 0.36 0.24 0.0045 0.014 0.0093 0.0004 2 ,200 3,200 69,000 720 1,100 23,000 2,100 3,100 700 1,030 Bush berries Aerial 0.16875 350 0.005 N/A 0.000 1 0.0017 N/A 0.000 1 18,000 N/A 520 ,000 5,900 N/A 170,0 00 17,000 N/A 5,700 N/A

Airblast 40 0.36 0.24 0.0045 0.014 0.0093 0.0004 2,200 3,200 69,000 720 1,100 23,000 2,100 3,100 700 1,030

### Page 29 of 58 Table 14: Summary of Short- and Intermediate - Term Propiconazole Occupational Handler Non - Cancer Risk s Crops Exposure

Scenario Appl.

Rate (lb ai/acre) 1 Area Treatd (A/day) 2 Unit Exposu re

(m g/lb ai) 3 ST & IT Dose

(m g/k g/day) 4 ST MOE IT MOE Aggregate ST MOE Aggregate

IT MOE DermalInhalation DermalInhalation DermalInhalation DermalInhalation BL BL + Gloves BL BL+

Gloves BL* BL + Glove BL BL +

Gloves BL BL+ Gloves BL BL+ Gloves Low Gr owing Berries Aerial 0.1125 350 0.005 N/A 0.000 1 0.0011 N/A 0.0000 4 27,000 N/A 780 ,000 8,900 N/A 260,0 00 26,000 N/A 8,600 N/A Gr oundboom 80 0.014 0.014 0.0007 0.0007 0.0007 0.000 1 42,000 42,000 320 ,000 14,000 14,000 105,0 00 37,000 37,000 12,000 12,000 Flagger Mint Flagger 0.1125

350 0.011 N/A 0.0004 0.0025

N/A 0.0002 12,000

N/A 150 ,000 4 , 040

N/A 51,0 00 11 ,000

N/A 3 ,700

N/A Bulb Veg 0.225 0.0050 0.000 4 6 ,060 76,000 2 , 020 25,0 00 5,600 1 ,900 Cane ber ry 0.16875 0.0037 0.000 3 8 ,080 102,000 2 ,700 34,0 00 7 ,500 2 ,500 Bush Berry 0.16875 0.0037 0.000 3 8 ,080 102,000 2 ,700 34,0 00 7 ,500 2 ,500 Low Gr owing Berry 0.1125 0.0025 0.000 2 12, 000 150 ,000 4 , 040 51,0 00 11 ,000 3 ,700

1. Baseline (BL*) and PPE unit exposure values are reported in the PHED Surrogate Exposure Guide dated August 1998 2 Application rates based on proposed label rate. 3. Amount treated based on information provided ExpoSAC Policy 9 4. Dermal dose (mg/kg/event) = [unit dermal exposure (mg/lb ai) * application rate (lb ai/A) * Amount treated / body weight ( 7 0 kg)]. 5 Inhalation dose (mg/kg/event) = [unit exposure (kg/lb ai) * (1mg/1000 kg) conversion * appl. rate (lb ai/lbs seed) * Amount treated / body weight (70 kg)]. 6. MOE = NOAEL (mg/kg/day) / Average Daily Dose (mg/kg/day) 7 . Agg MOE = 1/(1/Dermal MOE + 1/Inhalation MOE). 

### 8.3 Occupational Post -Application Exposure 8.3.1 Post -Application Exposure Scenarios

• Mint

– H edging , Irrigation , Hand Weeding , Scouting • Caneberries

– Hand Harvest, Hand Pruning, Training, Tying • Bushberries /L ow Growing Bushberries

– 

### Hand Harvest, Hand Pruning, Thinning, • Bulb Vegetables

– Hand Harvest, Thinning 8.3.2 Post Application Exposure Data Th e post - application risk assessment for propiconazole has been developed using chemical - specific dislodgeable foliar residue (DFR) data on corn, peach, and rice data. The following studies were used to determine the dislodgeable foliar residue levels:

• MRID 42564003: Propiconazole

– Dislodgeable Residue on Corn (North Carolina) EPA

### Page 30 of 58

• MRID 42564003; Report dated 1991. Author Avakian, M; Sponsor: Ciba - Geigy Corporation Agriculture Division. Submitted by Environmental Technologies Institute, Inc. and EN - CAS Lab s. • MRID 44959701 : Dissipation of Dislodgeable Foliar Residue of Two formulations of Propiconazole (OrbitTM and OrbitTM 45W) Applied to Peaches. • MRID 44959701(0442); Report dated 1999; Author; Rosenheck, L. Report: Lab report Number: 260 - 98: 44580: AG - 561 Pe rforming Laboratories: ABC Laboratories • MRID 00 133390 : Worker Exposure in Rice Author; Honeycutt, R. (1983) CGA 64250 (Tilt) Report No. EIR - 83011. ( Unpublished study received Dec 12, 1983 under 100 - 617; submitted by Ciba - Geigy Corp., Greensboro, NC; CDL: 07222 - C) 

### The available chemical/crop specific DFR data were extrapolated for the proposed uses based on similarities in application methods between the study and selected crop groups, the crop canop y, and application rates (i.e., between the study and current labels). The DFR values were adjusted to account for the differences in the application rate used in the study and on the proposed label. Corn d ata were used to complete all occupational assessments that were based on exposures to “root” vegetables . Peach data were used to complete all occupational assessments that were based on exposures to vine/trellis and low berries . Rice d ata were used to complete all occupational assessments that were based on exposures to low/medium field/row crops. DFR data used in the assessment are provided in Table 15. Table 15. Dislogeable Foliar Residue Data Location App. Rate

(lb ai/acre) App.

Me thod Corr.

Coeff. Slope

(Ln DFR vs. t) [T 0 ]

( μ g/cm2 ) T 1/2

(days) Day 0

(% trans.) Corn DFR Data (MRID 42564003) NC (Tilt 3.E) 0.1125 Groundboom 0.750 - 0.22061 0.0585 3.14 4.6 Peach DFR Data (MRID 449597 - 01) CA (Break EC) 0.1125 Airblast 0.900 - 0.0708 0.25 9.79 20.1 Rice DFR Data (MRID 00133390) Arkansas 0.28 Aerial 0.946 - 0.30837 0.184 2.25 5.9 

### 8.3.3 Post Application Expo sure Assumptions

• Average body weight of an adult handler is 70 kg. • Dermal Absorption Factor = 40 % • Exposure duration is 8 hrs per day for 1 - 30 day s • Maximum label application rates:

- 0. 1125 lb ai/A for mint and low growing berries

- 0. 225 lb ai A for bulb vegetables

- 0. 16875 lb ai/A for bushberries • Transfer Coefficients:

- 1500 cm 2 

### /hour for h edging , i rrigation , hand w eeding , s couting mint

- 1100 cm 2 

### /hour for hand h arvesting , h and p runing, training, tyi ng caneberries

- 1100 cm 2 

### /hour for hand h arvesti ng , h and p runing, thinning bushberries

- 1500 cm 2 

### /hour for hand h arvesting , h and p runing low growing bushberries

- 2500 cm 2 

### /hour for hand h arvesting, thinning bulb vegetables

### Page 31 of 58

• Initial fraction of ai retained on foliage is based on chemical/crop specific DFR data • Exposure is assumed to occur on the day of application (day

0) 8.3.4 Post -Application Exposure and Risk Estimates A summary

of the post application risks for each crop/activity combination are shown in Table 16 . O ccupational post - application s hort - and intermediate - term exposure do not exceed HED’s level of concern (i.e., MOEs > 100) at day 0. Table 16 : Propiconazole Non - cancer Post - application Worker Risk Estimates at Day 0 Crop Activity Transfer Coeff (cm 2 /hr) 1 Max App Rate (lb ai/A) 2 DF R0

(μg/cm 2 ) 3 Daily Dose (mg/kg/day) 4 Short Term MOE 5 Int Term MOE 6 Mint Hedging; Irrigation; Weeding,

Hand; Scouting 1500 0.1125 0.0739 0.0051 5,900 2,000 Caneberries Harvest, Hand; Pruning, Hand;

Training; T ying 1100 0.16875 0.375 0.0189 1,600 530 Bushberries Harvest, Hand; Pruning, Hand;

Thinning 1100 0.16875 0.375 0.0189 1,600 530 Lo w Growing Bushberries Harvest, Hand; Pruning, Hand 1500 0.1125 0.25 0.0171 1750 580 Bulb Vegetables Harvest, Hand; Thinning 2500 0.225 0.117 0.0134 2,200 750 1 TC c m2/hr = Transfer coefficients and associated activities (ExpoSAC Policy Memo #003.1) 2 Application rates are based on maximum values based on proposed label. 3 DFR (mg/cm2 ) = Dislodgeable Foliar Residues corresponding to day 0 . Application Rate (lb ai/A) x CF (4.54E+5 mg/lb) x CF (2.47E - 8 A/ cm2 ) x % initial fraction of ai retained on foliage from chemical specific DFR studies 4 Daily Dose (mg/kg/day) = DFR (mg/cm2 ) x TC ( cm2/hr) x 8 (hrs/day) / Body weight ( 70 kg). 5 ST MOE = short - term endpoint for dermal (NOAEL m g/k g/ d ay)/Daily Dose 6 IT MOE = intermediate - term endpoint for dermal (NOAEL mg/k g/ d ay)/Daily Dose 

### Since post - application risks were not a concern on day “ 0 ” (12 hours following application), the res tricted entry interval (REI) is based on the acute toxicity of propiconazole technical material which is classified as Category III for acute dermal , acute oral toxicity, and eye irritation potential and Category IV for acute inhalation, and skin irri tation potential. Under the Worker Protection St andard for Agricultural Pesticides, active ingredients classified as acute toxicity categories III or IV for these routes are assigned a 12 - hour REI. Therefore, the 12 - hour REIthat appears on the proposed label is adequate. Based on the Agency's current practices, a quantitative occupational post - application inhalation exposure assessment was not performed for propiconazole at this time. However, there are multiple potential sources of post - application inhalation exposure to individuals performing pos t - application activities in previously treated fields. These potential sources 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 vol atilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meetin g.html ). The Agency is in the process of evaluating the SAP report as well as available post - application inhalation exposure

### Page 32 of 58

data generated b y the Agricultural Reentry Task Force and may , as appropriate, develop policies and procedures, to identify the ne ed for and, subsequently , the way to incorporate occupational post - application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - a pplication inhalation exposure assessment for propiconazole . 9 .0 CUMULATIVE RISK Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify , or revoke a tolerance, the Agency consider “available information” concerning the cumulative effects of a particular pesticide's residues and “other substances that have a common mechanism of toxicity .” EPA does not have, at this time, available data to determine whether propiconazole has a common mechanism of toxicity with other substances. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to propiconazole and any other substances and, propiconazole does not appear to produce a toxic metabolite produced by other substances which have tolerances in the U. S. For the purposes of this tolerance reassessment action, therefore, EPA has not assumed that propiconazole has a common mechanism of toxicity with oth er substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by

EPA’s OPP concerning common mechanism d eterminations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/fedrgstr/EPA_PEST/2002/January /Day _16/ . 10. 0 DATA NEEDS 10.1 Toxicology Data Requirements

- Immunotoxicity

(GLN 870.7800)

- Subchronic Neurotoxicity (GLN 870.6200b)

### Page 33 of 58

APPENDI CES A. TOXICOLOGY DATA SUMMARY A.1 Guideline Data Requirements Guideline Data Require ments Test Technical Requir ed Satisfied 870.1100 Acute Oral Toxicity ................................ ....................... 870.1200 Acute Dermal Toxicity ................................ .................. 870.1300 Acute Inhalation Toxicity ................................ .............. 870.2400 Primary Eye Irritation ................................ .................... 870.2500 Primary Dermal Irritation ................................ .............. 870.2600 Dermal Sensitization ................................ ...................... yes yes yes yes yes yes ye s

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 Developmental Toxici ty (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 (mouse) ................................ .................... 87 0.4300 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 Mutage nicity

—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 34 of 58

A.2 Toxic ity Profiles A.2.1 Acute Toxicity Table 1: Propiconazole Acute Toxicity Pro file GuidelineNo . Study Type MRID # Results Toxicity Category 870.1100 Ac ute Oral Toxicity

– rat 00058591 LD 50 =1517 mg/kg III 870.1200 Ac ute Dermal Toxicity - rabbit 00058596 LD 50 = >4000 mg/kg III 870.1300 Ac ute Inhalation Toxicity

– rat 41594801 LC 50 = >50.84 mg/L IV 870.2400 Ac ute Eye Irritation 00058597 Corneal opacity reversed in 72 hrs III 870.2500 Ac ute Dermal Irritation 00058598 No irritation IV 870.2600 Skin Sensitization 44949501 confirmed sensitizer - 

### A.2.2 Subchronic, Chronic, Other Tox icity Table 4.1b Subchronic, Chronic and Other Toxicity Profile: Propiconazole Guideline No./ Study Ty pe 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 - mo nth oral toxicity study - mice 42050501 ,(1991)

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

870.3100 3 - mo nth oral - male mice 42050502 (1991)

Acceptable/Guideline 0, 20, 500, 850, 1450 ,2500 ppm (0, 2.7, 65, 112, 194, 352 mg/kg/day LOAEL = 500 ppm (65 mg/kg/day), based on increase in absolute and relative liver weights and histopatholo gical 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 - mo nth oral - male mice. 45215801 (1997)

Supplement to MRID 42050502: Reexamination of liver Confirms finding s in MRID 42050502. No change to NOAEL or LOAEL

### Page 35 of 58

Table 4.1b Subchronic, Chronic and Other Toxicity Profile: Propiconazole Guideline No./ Study Ty pe MRID No. (year)/

Classification /Doses Results 870.3150 3 - mo nth dog (dietary) 00058607(1979)

Acceptable/Guideline 0, 50, 250 or 1250 ppm (0, 1.25, 6.25, 31.25 mg/kg/day) LOAEL is 250 ppm (59 mg/kg/day) based on the finding of lymphoid follicles in the mucous membrane of the pyloric part of the stomach. NOAEL is 50 ppm (13mg/kg/day) 870.3200 21 - Day dermal toxicity - rabbits 00116591 (1982)

Acceptable/Guideline 0, 3, 30 or 300 mg/kg/day LOAEL: 3 mg/kg/day based on mild dermal irritation (Hy perkeratos is, acanthosis, mild dilation of blood vessels and mo nonuclear 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 Toxicity LOAEL = 300 mg/kg/day based on severe clinical toxicity (ataxia, coma, lethargy, prostation, labored respiration and salivation) NOAEL = 90 mg/kg/day Developmental Toxicity LOAEL = 90 mg/kg/day based on increased incidence of rudimentary ribs, cleft palate malformations (0.3%) unossified sternebrae, as well as increased incidence of shortened and absent renal papillae. NOAEL = 30 mg/kg/day Non - guideline Developmental Toxicity - Rat 40425002 (1987 )

Acceptable/non - guideline 0 or 300 mg/kg/day cleft palate: 2/2064 fetuses of dosed animals vs. 0/1222 controls (lab.hist. control incidence: was 0/5431). This confirms findings of cleft palate noted in above study. Severe clinical toxicity in the treate d animals (ataxia, coma, lethargy, prostation, labored respiration and salivation) 870.3700b Developmental Toxicity - Rabbit 40425004 (1986)

Acceptable/guideline 0, 100, 250 or 400 mg/kg/day Maternal Toxicity LOAEL = 250 mg/kg/day based on reduced dam bo dy 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 thrib and increased abortions. NOAEL = 250 mg/kg/day 870.380 0 2 - Generation reproduction - Rat 00151514 (1985)

Acceptable/guideline 0, 100. 500 or 2500 ppm Parental Toxicity LOAEL = 500 ppm (42 mg/kg/day) based on increased incidence of hepatic clear cell change NOAEL = 8 mg/kg/day Reproductive Toxicity LOAEL =>25 00 ppm

(>263 mg/kg/day, HDT) Offspring Toxicity LOAEL = 2500 ppm (192 - 263 mg/kg/day based on decreased offspring survival and body weights and an increased incidence of hepatic cellular swelling NOAEL = 500 ppm (43 - 52 mg/kg/day)

### Page 36 of 58

Table 4.1b Subchronic, Chronic and Other Toxicity Profile: Propiconazole Guideline No./ Study Ty pe MRID No. (year)/

Classification /Doses Results 870.4100 12 - Month Chronic Oral Toxicity (dietary) - Dogs 00151515 (1985)

Acceptable/guideline 0, 5, 50 or 250 ppm (0, 0.12, 1.25, or 6.25 mg/kg/day) LOAEL = 250 ppm (6.25 mg/kg/day), based on hyperemia of the stomach in males (indicating mild irritation of the mucosa). NOAEL is 5 0 ppm (1.25 mg/kg/day) 870.4100 24 - Month Chronic/Carcinogenic ity Feeding - Rats 00129918 (1982)

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

 , female 4.6, 23.3 and 100.6

 mg/kg/day) LOAEL = 2500 ppm (96.4 mg/kg/day) based on liver lesions (vacuolation of hepatocytes in males, ballooned cells in the liver of males, foci of enlarged hepatocytes in females, and increased incidence of luminal dilation of the uterus) and reduced body weight gain in both males and females. NOAEL = 500 ppm (18.1 mg/kg/day). The test material was not carcinogenic at the doses tested. 870.4200 24 - Month Carcinogenicity in Mice 00129570 (1982 )

Acceptable/guideli ne 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/no dular areas mainly)). The NOAEL was 100 ppm (10 mg/kg/day). Liver tumors at 2500 ppm in male mice. 870.4200 18 - mo nth oncogenicity study - male CD - 1 mice 44381401 (1997)

Acceptable/guideline 0, 100, 500 or 850 ppm (0, 11, 59 or 108 mg/kg/day) LOAEL= 500 ppm (59.0 mg/kg/day) for males, based on hepatotoxicity (increased liver weight, hepatocellular hypertrophy, liver necrosis) and body weight gain effects observed at the interim and terminal sacrifices. NOAEL= 100 ppm (11.0 mg/kg/day) for males. Treatment related increase in hepatocellular adenoma and total hepatocellular neoplasia at the 850 ppm exposure level compared to concurrent controls, but were within the range of the inadequate historical control data submitted with the study report. Adequate do sing based on body weight gain and hepatotoxic effects seen at 500 and 850 ppm. Subsequently, the Registrant submitted additional control data on five groups of CD - 1 male mice generated within the approximate time frame of the original study and in the same testing facility under similar experimental conditions (MRID 45215804) concerning the spontaneous occurrence of liver tumors. The tumor incidence observed in male livers at the 850 ppm dose is within the range of the new historical data. 870.6200 Ac ute neurotoxicity in rats 46604601 (2005)

Acceptable/guideline 0, 30, 100 or 300 mg/kg by gavage LOAEL = 100 mg/kg based on clinical signs of toxicity (piloerection, diarrhea, tiptoe gait). NOAEL = 30 mg/kg. LOAEL for neurobehavioral toxicity = 300 mg/k g based on reduced mo tor activity. NOAEL for neurobehavioral toxicity = 100 mg/kg

### Page 37 of 58

Table 4.1b Subchronic, Chronic and Other Toxicity Profile: Propiconazole Guideline No./ Study Ty pe MRID No. (year)/

Classification /Doses Results 870 - 5100 Bacterial reverse mutation 00058601 (1979)

Unacceptable 25 - 2025 g/plate Negative in Salmonella strains with or without S - 9 activation. Test material purity not sp ecified, not tested up to cytotoxic dose. 870 - 5300 In vitro cell transformation assay (BALB/3T3) 00133349 (1982)

Acceptable/guideline 1.16 - 18.5 g/ml Did not cause a measurable increase in transformation of BALB/T3 cells. Highest dose produced 25% reduc tion 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 Unsch eduled 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 grow th. 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.

### Page 38 of 58

Table 4.1b Subchronic, Chronic and Other Toxicity Profile: Propiconazole Guideline No./ Study Ty pe MRID No. (year)/

Classification /Doses Results 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 mo stly 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. 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. T wo 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%) and feces (54%). Mouse urinary metabolites 15 - 30. The major metabolic pathway in mice proceeds via elimination of the dioxolane ring. In males this represents 30% of the AD whereas in the females it represents 15% of the AD. Mice cleaved the dioxolane 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/cm2 The average dermal absorption of propiconazole over a 10 hour period at an exposure level of 0.01 mg/cm2 is approximately 40%

Non - guideline Special study 00151517 (1984)

Acceptable Tumor promotion - rat 2000 ppm dietary up to 8 weeks Propiconazole caused proliferative changes, with or without pretreatment with an initiator (DENA;nitrosodiethylamine), in the rat liver similar to phenobarbital (500 ppm), a known liver tumor promoter.

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Table 4.1b Subchronic, Chronic and Other Toxicity Profile: Propiconazole Guideline No./ Study Ty pe 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 - ty pe 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 cy tosolic activity of GST were slightly increased with propiconazole treatment. The pattern of microsomal and cytosolic enzyme induction determined biochemically was entirely consistent with PB - ty

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

### Page 40 of 58

Table 4.1b Subchronic, Chronic and Other Toxicity Profile: Propiconazole Guideline No./ Study Ty pe MRID No. (year)/

Classification /Doses Results Non - guideline Special study Mechanistic studies: Hepatocellular proliferation - Mouse 45215802 (1999)

Male CD - 1 mice 40/dose propiconazole at 0, 850 or 2500 ppm (0, 127, 353 mg/kg/day) for up to 60 days. A group of 40 mice given 850 ppm

PB. Five mice/group were sacrificed on days 1, 2, 3, 4, 7, 28, or 60 (IP injection of 100 mg/kg BrdU two hours prior to sacrifice) Test material and Phenobarbital (PB) induced a dose - related increase in absolute and relative liver weights. All mice developed hepatocellular hypertrophy (primarily in the centrilobular hepatocytes with mild effects in the midzonal hepatocytes). Liver necrosis and cytoplasmic vacuolation were noted. Increased mitotic activity was observed in all groups. Minimal to mo derate 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 treatment groups, the BrdU - staining nuclei were found primarily in the centrilobular/midzonal portions 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.

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B. STUDIES REVIEWED FOR ETHICAL CONDUCT The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task Force members Health Canada, U.S. Environmental Protection Agency , and the National Agricul tural Chemicals Association, released February , 1995. Agricultural Re - entry

Task Force (ARTF) data base (SOP #3.1)

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C. SUMMARIES OF KEY TOXICOLOGY STUDIES 870.3700 Developmental Toxicity Rat Developmental Toxicity - Study 1 In an acceptable/guidel ine developmental toxicity study (MRID 40425001), CGA 64250 technical(92.1% purity

propiconazole, Batch no. FL 850083) was administered to 24 CL :COBS CD (SD) BR VAF/PLUS virgin female rats/dose by oral gavage in aqueous suspensions (3% corn starch contai ning 0.5% Tween 80) at dose levels of 0, 30, 90 or 300 mg/kg/day from days 6 through 16 of gestation. High dose animals initially received 360 mg/kg/day

up to five day s, but because of severe s ymptoms it was reduced to 300 mg/kg/day . Severe compound - related maternal toxicity

was observed at the high dose level during the first five day s of dosing beginning on day

8 of gestation at 360 mg/kg/day . These included statistically significant increases in the incidence of lethargy , ataxia, salivation, and biolo gically significant increases in rales, prostration, h ypothermia and bradypnea. The incidence of these effects versus control is as follows: lethargy

(9/23 vs. 0/24 in controls), salivation (4/23 vs. 0/24 in controls) and ataxia (3/23 vs. 0/24 in controls ). After lowering the dose to 300 mg/kg/day on day 6, the severity and frequency of these effects decreased rapidly . At the lower doses with the exception of one animal of the 90 m g/kg/day

group exhibiting rales , there were no treatment related clinical observations. Mean food consumption was significantly reduced (p<0.05) in the 300 mg/kg/day group on day s 7 - 8, 8 - 9 and 9 - 10 and in the 90 mg/kg/day group on day s 8 - 9 and 10 - 11. Maternal body weights were not affected b y the treatments. Maternal body weight gains were significantly decreased (p<0.05) in the 90 mg/kg/day group (44% of controls) and in the high dose group (38% of controls) during gestation day s 6 - 8 only . This effect was considered to be temporary and not treatment related. No significant treatment - related effects on uterine weights, corpora lutea, live and dead fetuses, fetal weights, and resorption were reported. The maternal toxicity LOAEL of propiconazole is 300 mg/kg/day, based on severe clinical toxicity. The maternal toxicity NOAEL i s 90 mg/kg/day. Fetotoxic effects observed included a high incidence of rudimentary ribs, though not statistically significant but part of dose related trend (0.7%, 3% and 39% in the 30, 90 and 300 mg/kg/day groups, respectively vs. 0% in the controls), a high incidence of un ossified sternebrae (57%, p< 0.05 in the 90 mg group, and 72%, p< 0.01 in the 300 mg group vs. 38% in the controls), as well as increased incidence of shortened renal papillae (26% in the 90 mg group (not statistically significant) an d 39% in the 300 mg group, p < 0.01 vs. 23% in the controls) and absent renal papillae ( 5% in the 90 mg group (not statistically significant) and 11% in the 300 mg group, p < 0.01 vs. 3% in the controls) and dilated ureter ( 43% in the 300 mg group, p < 0 .01 vs. 27% in the controls). External and visceral examination revealed a very low incidence of cleft plate malformations in the 90 mg group (0.3%) and in the 300 mg group (0.7%) and considered to be “probabl y compound related”. Historical controls in 19 teratology studies from this laboratory had no incidence of cleft palate. The cleft palate incidence in the current study was probably under reported because only half of the fetuses were examined viscerall y. It was also concluded that the low incidence of this finding along with skeletal anomalies was indicative of delayed development. The cleft palate finding at 300 mg/kg/day was also confirmed in a separate study (MRID 40425002) where propiconazole was administered to pregnant rats at 0 or 300 mg/kg/ day during the gestation period. The

### Page 43 of 58

developmental toxicity LOAEL of propiconazole is 90 mg/kg/day, based on increased incidence of rudimentary ribs, un - ossified sternebrae, as well as increased incidence of shortened and absent renal papillae and increa sed cleft palate. The developmental toxicity NOAEL is 30 mg/kg/day. Rat Developmental Toxicity - Study 2 In an acceptable/non - guideline developmental toxicity study (MRID 40425002), CGA 64250 technical (92.1% purity , Batch No. FL 850083) was administered to CL :COBS CD (SD) BR VAF/PLUS virgin female rats b y oral gavage in aqueous suspensions (3% corn starch containing 0.5% Tween 80) at dose levels of 0 or 300 mg/kg/day from day s 6 through 15 of gestation. The control group comprised 178 sperm positive animals and the compound treated group comprised 189 sperm positive animals. The study was intended to confirm the finding of cleft palate in the previous study

(MRID 40425001). The death of two dams from the treated group was considered incidental. Severe maternal toxicity was observed during the treatment period beginning on gestation day 6 and included a statistically significant increase in the incidence of ataxia (42% vs. 0 in controls), coma (9% vs. 0 in controls), lethargy (44% vs. 0 in controls), prostration (3% vs. 0 in controls), audible respiration (4% vs. 0 in controls), labored respiration (11% vs. 0 in controls), and salivation (20% vs. 0 in controls) in addition to a biologically significant incidence of ptosis (0.5% vs. 0 in controls), lacrimation (2% vs. 0 in controls), pale color (2% vs. 0 in controls) and death (1% vs. 0 in controls). Mean food consumption was significantl y lower (60 - 92% of the control values, p<0.05) in the treated group during the dosing period. Body weight gains were significantly lower (68% of controls, p<0.05) in dosed animals during GD 6 - 16. There were no significant differences between dosed and control animals with respect to fetal sex ratio or mean number of corpora lutea, implantation sites and dead fetuses. The mean number of live fetuses was significantly (95% of controls, p<0.05) lower in dosed animals, due to lower mean implantation sites, and higher mean total resorption in the dosed animals, although not significantly different from controls. Mean fetal weights for both males and females (95% of controls, p<0.001) were significantly lower in dosed animals. Fetuses were examined for external abnormalities only and there were no statistically significant treatment related, external gross observations amon g fetuses. Cleft palate was reported in 2/2064 fetuses of dosed animals and 0/1222 of control fetuses. The incidence of cleft palate in controls for all teratology

studies (not including this one) conducted at this laboratory during 1983 - 1985 was 0/5431. This study

confirms the findings of cleft palate in the previous guideline study (MRID 40425001). Ra bbit Developmental Toxicity In a developmental toxicity study (MRID 00265796), CGA 64250 technical (92.1% purity propiconazole) was administered to gro ups (19/group) of artificially inseminated New Zealand white rabbits by

oral gavage in aqueous suspensions (3% corn starch containing 0.5% Tween 80) at dose levels of 0, 100, 250 or 400 mg/kg/day from day s 7 through 19 of gestation. One animal from each o f the mid - dose groups was found dead. In high - dose animals, 5/19 does were sacrificed earl y due to abortion or earl y delivery (statistically

significant, p<0.05 compared to control 1/19). In the mid dose (250 mg/kg/day) group, one doe aborted early . One control

### Page 44 of 58

animal delivered earl y. Among animals of the high dose group, an increased inci dence of stool alterations (decreased/no/soft; 18/19 vs. 11/19 in controls, p<0.05) was observed, possibl y compound related. During the dosing period (days 7 - 19), th e high and mid dose animals had a significant (p<0.05) decrease in food intake (43 - 63% of the controls and 58 - 78% of the controls in the high - and mid - dose groups, respectivel y) and a severe decrease in the maternal body weight gain, but rebounded to nor mal after withdrawal of the test compound. During GD 7 - 10, the maternal animals had a weight loss of 0.047 and 0.111 kg at 250 and 400 mg/kg, respectivel y, compared to a weight gain of 0.018 kg in controls. The weight gains during GD 10 - 20 were 67 - 77% an d 11 - 43% of controls at 250 and 400 mg/kg/day , respectivel y. An increased incidence of the formation of 13 th 

### rib was observed at 400 mg/kg/day . The incidence of this finding on fetuses/litter basis was 2.7, 3.9, 4.1 and 5.3 at 0, 100, 250 and 400 mg/kg/day, respectivel y. The incidence of fetuses at 400 mg/kg/day with this finding was statistically significant. Therefore, this finding was considered to be treatment - related. The increase in the number of resorptions at 400 mg/kg/day was caused by

the reso rption of an entire litter. At 400 mg/kg/day

there was also an increased incidence of abortions. The maternal toxicity LOAEL of propiconazole in the rabbit is 250 mg/kg/day, based on reduced maternal body weight gains and decreased food consumption durin g the dosing period. The maternal toxicity NOAEL is 100 mg/kg/day. The developmental toxicity LOAEL was 400 mg/kg/day based on increased incidence of fetuses/litters with 13 th 

### rib and increased abortions. The developmental toxicity NOAEL was 250 mg/kg/d ay. 870 - 3800 Reproductive Toxicity Rat Reproduction Study In an acceptable/guideline 2 - generation reproduction study (MRID 00151514), CGA 64250 technical (89.7% purity

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

for F0 males, 9.4, 43, 223 mg/kg/day for F0 females, 9.2, 48, 238 mg/kg/day for F1 males and 10, 52, 263 mg/kg/day for F1 females) in the diet. Test diets were admini stered to both F0 and F1 generation rats during pre - mating period and throughout gestation and lactation periods. Parental Toxicity : No compound - related clinical observations or mortality were reported. Female body weights in the F 0 

### and F 1 

### generation were significantly reduced in the high dose group at most of the body weight intervals(82 - 94% of the controls, p<0.05 and 0.01); body weight gains were also significantly reduced during pre - mating (12 weeks)as well as gestation and lactation periods(77 - 85% o f controls, p<0.01). Correspondingl y, high dose females also had significantl y reduced food intake (83 - 88% of controls). In the F 0 

### and F 1 

### generation male body weights were reduced in the high dose groups compared to controls (not statistically significant); body weight gains in this group was 91 - 94% of controls for the pre - mating period and during the entire duration of the study (7 months). Food consumption was reduced significantly in high dose F 0 

### males at week 1 (65% of the control, p<0.01) and week 7 (86% of the control, p<0.01) and in high dose F 1 

### males and females at week 2, 6 and 10 (84 - 88% of controls). Histological examinations revealed that hepatic “cellular swelling” was significantl y increased in mid - dose males and high - dose males and females of the F 0 

### generation. In the F 1 

### parental animals, increase in the incidence of this finding was significant for both sexes in the mid - and high - dose groups.

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The incidence of “hepatic clear- cell change” was significantl y increased in F 0 

### high - dose males, F 1 

### mid - dose and high - dose males and F 1 

### high - dose females (p<0.05). The LOAEL for parental toxicity is 500 ppm (42 mg/kg/day) based on increased hepatic clear - cell change and the NOAEL for parental toxicity is 100 ppm (8 mg/kg/day). Reproductive parameter s (mating, fecundity, gestation, male and female fertility indices, litter resorptions and gestation duration) were comparable in all groups. Offspring Toxicity : The number and percent of viable pups at birth and surviving through weaning were comparable between the dose groups and controls for both the F 1a 

### and F 1b 

### litters. In the F 2a 

### litters, however, the number of pups delivered, delivered viable and surviving to day 4 of lactation were significantly (p<0.01) reduced in the high - dose group. The percentages of high - dose pups delivered viable and surviving to day 4 were also reduced (not statistically significant). The F 2b 

### litters of these dams had significantl y reduced survival rates (both number and percent of surviving pups) at lactation day s 7, 14, and 21. The mean body weights of high - dose progeny were significantly

reduced at days 14 and 21 for pups of both generations (72 - 81% of controls). Reductions were also significant on day s 4 and 7 (except for F 1b 

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

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

### and F 2b 

### progeny revealed significantly (p<0.01) increased incidences of hepatic “ce llular swelling” in high - dose males and females. This was considered to be a compound related effect. The LOAEL and NOAEL for offspring toxicity are at 2500 ppm (192 - 263 mg/kg/day) and 500 ppm (43 - 52 mg/kg/day), respectively, based on decreased offspring survival and body weights and an increased incidence of hepatic lesions (cellular swelling) at 2500 ppm. Additional Developmental/Reproduction Toxicity Information from Literature Sources In a published study , propiconazole (Tilt 100 EC in the form of 10% solution) was administered to groups of pregnant female albino rats (15/dose) at 0, 75.85 or 151.70 mg (ai)/kg/day on day s 6 - 15 of gestation (Hassan, 1993. Embryotoxic and teratogenic effects of the organic fungicide tilt in albino rats. Bull. Fac. P harm., Cairo University 31(3): 459 - 463). Rats were sacrificed on day 20 of gestation. Post - implantation deaths, resorption sites and dead fetuses were counted. Fetuses were examined for morphological, visceral and skeletal malformations. Propiconazole was fetotoxic at both doses causing significant (p<0.05) increased fetal resorptions (8 and 21% at the low and high dose vs. 0% in the control), increased fetal deaths (10 and 24% at the low and high doses vs. 2% in the control) and decreased fetal weight) . The mean number of stunted fetuses was significantly

higher (p<0.05) at both doses (1.43 and 3.57) at the low and high dose vs. 0.13 in the control), noting incomplete ossification of the skull, caudal vertebrae and digits, extra rib (14 th 

### rib) and miss ing sternebrae. Malformations of the lung and kidneys were reported. No maternal toxicity

was reported at either dose. The LOAEL for developmental toxicity in this study is 76 mg/kg/day

(the lowest dose tested). A NOAEL is not established. 870.4200b Mouse Carcinogenity Study In a 24 - month oncogenicity study (MRIDs 00129570, 00151503, 00130844 and 93194037), CGA 64250 technical (Batch No. P4 - 6, 87.2 - 91.9% purity) was administered to groups of CD - 1 mice (52/sex/dose) in the diet at concentrations of 0 , 100, 500, or 2500 ppm (10.0, 49.4, and

### Page 46 of 58

344.3 mg/kg/day

for males and 10.8, 55.6 and 340.3 mg/kg/day for females, respectivel y). A satellite group (12 mice/sex/dose) was sacrificed at one year. Diets were prepared weekl y. During the first year of the study , the test material was ground directly into basal diet. During the second ye ar, the test substance was dissolved in ethyl acetate prior to incorporation into the diet to improve the homogeneity of the test material in the diet. However, the EPA reviewers questioned the use of the ethyl acetate and its impact on the study . The results of analy ses for purity (including identi fication of all impurities) and stability of the test material in the diet provided later b y the registrant were found to be satisfactory (HED doc. No. 005352). A review of the individual clinical observations revealed no obvious treatment - related in - life signs (HED doc. No. 005352). An increase in mortality was noted in males of the 2500 ppm group during the first 6 months. Th is finding is considered compound - related. Survival at 104 weeks for the control, 100, 500 and 2500 ppm groups was 46%, 38%, 40%, and 27% for the males and 54%, 63%, 46% and 62% for the females, respectively. However, sufficient number of animals were al ive at study termination to assess the carcinogenic potential of the test material. Sporadic decreases in body weight gain, particularly in the high dose male and female groups were noted. Food consumption was increased in high dose male mice only. There were no compound - related effects on hematological parameters examined. SGPT and SGOT were significantly increased in high dose males and females at 52 weeks and in high dose males at 100 weeks. SAP was increased in high dose males at week 100. These c hanges are considered indicative of liver damage. Urinal ys is results did not reveal any treatment - related effects. In creased liver weight was noted in high and mid dose males and in high dose females both at interim and terminal sacrifice. There was good correlation between gross and microscopic findings. Enlarged livers containing gross path ological changes were seen in high dose animals. Non - neoplastic changes in high dose males and females consisted of hepatocy te enlargement, vacuolation and fat dep osition. Liver histopathology of low and mid dose mice was comparable to those of controls. Amyloidosis occurred more frequentl y in treated animals compared to controls, but was not dose - related. Necrops y observations at the termination of the study i ndicated a treatment - related increase in liver lesions (masses/raised areas/ swellings/nodular areas mainl y) among mid - and high - dose males (150% and 140% of controls, respectivel y) and in high - dose females (367% of control). CGA 64250 treatment was assoc iated with earl y expression of malignant liver cell tumors in male mice. The incidences of malignant (presumably carcinomas) liver tumors at the one year interim sacrifice were 0/11, 0/11 1/11, and 3/9 in the control, low, mid and high dose males, respectivel y. No liver tumors were found in any of the female mice sacrificed at the 1 - ye ar interim sacrifice.

### Page 47 of 58

The total incidences of combined liver adenomas/carcinomas in males for the control, 100, 500 and 2500 ppm groups were 28/64, 14/64, 25/62 and 48/64, respectivel y. For females the incidence was 5/64, 1/64, 2/64 and 8/64 in the control, 100, 500 and 2500 ppm groups, respectivel y. The combined incidence of liver tumors was statistically significant (p< 0.001) at the high dose level for males. Male mice given CGA 64250 technical at 2500 ppm in the diet developed liver tumors. The LOAEL was 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).

### Page 48 of 58

D. REFERENCES FOR TOXICITY STUDIES 82 - 1 Subchronic Oral Toxicity: 90 - Day Study MRID Citation Reference 58606 Sachsse, K.; Suter, P.; Luetkemeier, H.; et al. (1979) CGA 64'250 Techn. Thr ee Months

Toxicity Study on Rats: Project No. 790014. Final rept. (Unpublished study received Jan 28, 1981 under 100 - 618; prepared by Ciba - Geigy Ltd., Switzerland, submitted by Ciba - Geigy

Corp., Greensboro, N.C.; CDL:244271 - Q) 58607 Sachsse, K.; Bathe, R .; Luetkemeier, H.; et al. (1979) CGA 64'250 3 - Month Toxicity

Stud y on Dogs. Final rept. (Unpublished study received Jan 28, 1981 under 100 - 618; prepared by Ciba - Geigy Ltd., Switzerland, submitted by Ciba - Geigy Corp., Greensboro, N.C.; CDL:244271 - R) 1467 71 Maruhn, D.; Bomhard, E. (1984) Triazolylalanine (THS 2212) Study for Subchronic

Toxicity to Rats (Three - mo nth Feeding Study): Report No. 12397. Unpublished study prepared by Bayer AG Institute of Toxicology. 258 p. 151511 Ciba - Geigy Corp. (1985) Respo nse by Ciba - Geigy to EPA Review of the 90 - day Feeding Study in Rats with Triazole Alanine: [Includes Clinical, Ophthalmological, and Analytical Chemistry

Data of Bayer Report 12397]. Unpublished compilation. 41 p. 42050501 Potrepka, R.; Turnier, J. (1991 ) Subchronic Dietary Toxicity Study with CGA- 64250 in

Mice: Lab Project Number: F - 00098. Unpublished study prepared by Ciba - Geigy Corp. 302 p. 42050502 Potrepka, R.; Turnier, J. (1991) 13 -We ekDietar y T oxicity Study with CGA- 64250 in

Male Mice: Lab Proje ct Number: F - 00107. Unpublished study prepared by Ciba - Geigy Corp. 226 p. 45215801 Hardisty, J. (1997) 13 -We ek Dietary Toxicity Study with CGA- 64250 in Male Mice: Final

Report: (Supplement for MRID No.42050502): Lab Project Number: 140 - 081: F - 00107: 799 - 97. Unpublished study prepared by Experimental Pathology Laboratories, Inc. 51 p. 93194032 Gillis, J.; Tisdel, M. (1990) Ciba - Geigy Corp. Phase 3 Summary of MRID 00058606. 90 - Day Toxicity Study in Rats: Propiconazole: Study # 790014. Prepared by CIBA - CEI GY Lim ited. 13 p. 93194033 Gillis, J.; Tisdel, M. (1990) Ciba - Geigy Corp. Phase 3 Summary of MRID 00058607. 90 - Day Toxicity Study in Dogs: Study # 785751. Prepared by CIBA- GEIGY Limited. 12 p. 93194083 Sachsse, K.; Suter, P.; Luetkemeier, H. et al. (19 90) Ciba - Geigy Corp. Phase 3

Reformat of MRID 00058606. Three Months Toxicity Study on Rats: Propiconazole: Stud y # 790014. Prepared by CBIA- GEIGY Limited. 195 p. 93194084 Sachsse, K.; Bathe, R.; Luetkemeier, H. et al. (1990) Ciba - Geigy Corp. Phase 3 Reform at of MRID 00058607. Three Month Toxicity Study on Dogs: Propiconazole: Stud y # 785751. Prepared by Ciba - Geigy Limited. 204 p. 

### 82 - 2 21 - day dermal - rabbit/rat MRID Citation Reference

### Page 49 of 58

116591 Larson, E.; Matthews, R.; Naismith, R.; et al. (198 2) 21 Day Dermal Toxicity Study in

Rabbits: (CGA- 64250 Technical): PH 430 - CG - 001 - 82. Rev. (Unpublished study received Oct 4, 1982 under 100 - 641; prepared by Pharmakon Research International, Inc., sub - mi tted by Ciba - Geigy Corp., Greensboro, NC; CDL:2484 42 - E) 93194034 Gillis, J.; Tisdel, M. (1990) Ciba - Geigy Corp. Phase 3 Summary of MRID 00116591. 21 - Day Dermal Study in Rabbit: Study # 430 - CG - 001 - 82. Prepared by Pharmakon Research International. 12 p. 

### 83 - 1 Chronic Toxicity MRID Citation Referenc e 74494 Hunter, B.; Slater, N.D. (1981) CGA 64 250: Potential Tumorigenic and Toxic Effects in

Prolonged Dietary Administration to Rats (84 W eekStatus Report): Tox. Dispo. 78 9023. (Unpublished study, including letter dated Apr 23, 1981 from N.D. Sl ater to R. Hess, received Jun 8, 1981 under 100 - EX - 69; prepared by Huntingdon Research Centre, England, submitted by Ciba - Geigy Corp., Greensboro, N.C.; CDL:070162 - A) 84153 Hunter, B. (1981) Letter sent to R. Hess dated Apr 23, 1981: CGA 64 250: Long ter m

feeding study in mice: Test No. 78 9022. (Unpublished study received Jun 8, 1981 under 100 - EX - 69; pre - pared by Huntingdon Research Centre, England, submitted by Ciba - Geigy

Corp., Greensboro, N.C.; CDL:070162 - B) 129570 Hunter, B.; Scholey, D.; Haywood , R.; et al. (1982) CGA 64 250: Long - term Feeding

Stud y in Mice: CBG/196/81827. Final rept. (Unpublished study received Jul 21, 1983 under 100 - 641; prepared by Huntingdon Research Centre, Eng., submitted by Ciba Geigy Corp., Greensboro, NC; CDL:250784 - A; 2 50785; 250786) 130844 Ciba - Geigy Corp. (19??) CGA- 64250: Long - term Feeding Study in Mice: Incidence of Liver Tumors in Males. (Unpublished study received Sep 14, 1983 under 100 - 641; CDL:251237 - A) 151502 Ciba - Geigy Corp. (1985) Response to EPA Review of the Two - Year Dietary Oncogenicity and Chronic Toxicity Study with CGA- 64250 Technical: [Includes Historical Control Data and an Addendum to the HRC Report No. CBG 193/8284]. Unpublished compilation. 373 p. 151503 Ciba - Geigy Corp. (1985) Response to the EPA Review of the Long - Term Feeding Stud y in Mice with CGA- 64250 Technical: [Includes Chem - istry Data of Test Material, Details of Diet Preparation, Summa - ry of Incidence of Clinical Signs, and Addendum to Report CBG 196/81827]. Unpublished compilation. 214 p. 151515 Johnson, W .; Thompson, S. (1985) One - ye ar Subchronic Oral Toxicity Study in Beagle

Dogs with CGA- 64250 Technical: (Final Report): FDRL Study No. 7737. Unpublished study prepared by Food and Drug Research Laboratories, Inc. 570 p. 40783302 Ballantine, L. (1988) Tolerance Assessment System: Routine Chronic Analysis

(Propiconazole - Celery). Unpublished study prepared by Ciba - Geigy Corp. 23 p. 40783304 Anon. (1988) Tolerance Assessment System Routine Chronic Analysis: Propiconazole Corn. Unpu blished study prepared by Ciba - Geigy Corp. 24 p. 40783307 Ballantine, L. (1988) Tolerance Assessment System Routine Chronic Analysis:

Propiconazole - Pineapple. Unpublished study prepared by Ciba - Geigy Corp. 23 p.

### Page 50 of 58

40783309 Ballantine, L. (1988) Tolerance Assessment System Routine Chronic Analysis:

Propiconazole -- Dry

Beans. Unpublished study prepared by Ciba - Geigy Corp. 28 p. 41063803 Ballantine, L. (1988) Tolerance Assessment System Routine Chronic Analysis

Propiconazole - Stoned Fruit. Unpublished study prepared by Ciba - Geigy Corp. 26 p. 93194035 Gillis, J.; Tisdel, M. (1990) Ciba - Geigy Corp. Phase 3 Summary of MRID 00129918 and Related MRIDs 00074494, 00151502. Combined Chronic Oncogenicity/ Toxicity Study in Rats: Study # 193/8284. Prepared by Hunting don Research Centre. 15 p. 93194036 Gillis, J.; Tisdel, M. (1990) Ciba - Geigy Corp. Phase 3 Summary of MRID 00151515. One - Ye ar Oral Toxicity Study in the Dog: Study # 7737. Prepared by Food & Drug Research Labs. Inc. 13 p. 

### 83 - 2 Oncogenicity MRID C itation Reference 129918 Hunter, B.; Slater, N.; Heywood, R.; et al. (1982) CGA 64 250: Potential Tumorigenic

and Toxic Effects in Prolonged Dietary Administration to Rats: CBG 193/8284 (Test No. 789023). Final rept. (Unpublished study received Jul 2 1, 1983 under 100 - 641; prepared by Huntingdon Research Centre, Eng., submitted by Ciba - Geigy Corp., Greensboro, NC; CDL:250787 - A; 250788; 250789; 250790) 130844 Ciba - Geigy Corp. (19??) CGA- 64250: Long - term Feeding Study in Mice: Incidence of Liver Tumors in Males. (Unpublished study received Sep 14, 1983 under 100 - 641; CDL:251237 - A) 151502 Ciba - Geigy Corp. (1985) Response to EPA Review of the Two - Year Dietary Oncogenicity and Chronic Toxicity Study with CGA- 64250 Technical: [Includes Historical Control Data and an Addendum to the HRC Report No. CBG 193/8284]. Unpublished compilation. 373 p. 151503 Ciba - Geigy Corp. (1985) Response to the EPA Review of the Long - Term Feeding Stud y in Mice with CGA- 64250 Technical: [Includes Chem - istry Data of Test Mater ial, Details of Diet Preparation, Summa - ry of Incidence of Clinical Signs, and Addendum to Report CBG 196/81827]. Unpublished compilation. 214 p. 151516 Wa echter, F.; Bentley, P.; Staeubli, W . (1984) The Effect of Propi - conazole on Drug

Metabolizing En zy me s in the Liver of Male Rats and Mice. Unpublished study prepared by Ciba - Geigy Ltd. 22 p. 151517 Froehlich, E.; Bentley, P.; Staeubli, W .; et al. (1984) Promo - tion Study with CGA

64250: [Study on the Influence of CGA 64250 in the Formation of Focal Proliferative Changes in the Rat Li - ver]: GU Explorator y Research Project No. 834015. Unpublished study prepared by Ciba - Geigy Ltd. 553 p. 41178301 Stevens, J. (1989) Propiconazole Technical: Perspective: Liver Tumor Response Noted

in Male Mice After th e Administration of an Excessive Level of Propiconazole. Unpublished study prepared by Ciba - Geigy Corp. 23 p. 44381401 Gerspach, R. (1997) CGA- 64250 Technical: 18 - Month Oncogenicity Study in Mice: Lab

Project Number: 943126. Unpublished study prepared by Novartis Crop Protection Ag. 453 p. 45215804 Gerspach, R. (1999) 18 - Month Oncogenicity Study in Mice: Final Report

### Page 51 of 58 (Propiconazole): Lab Project Number: 943126: 800 - 97. Unpublished study prepared by Novartis Crop Protection AG. 64 p. {OPPTS 870.4200} 9 3194035 Gillis, J.; Tisdel, M. (1990) Ciba - Geigy Corp. Phase 3 Summary of MRID 00129918 and Related MRIDs 00074494, 00151502. Combined Chronic Oncogenicity/ Toxicity Study in Rats: Study # 193/8284. Prepared by Huntingdon Research Centre. 15 p. 93194037 Gillis, J.; Tisdel, M. (1990) Ciba - Geigy Corp. Phase 3 Summary of MRID 00129570 and Related MRIDs 00084153, 00151503, 00130844. Long - Term Feeding Study in Mice: Propiconazole: Study # 196/81827. Prepared by Huntingdon Research Centre. 14 p. 

### 83 - 3 Te ratogenicity -- 2 Species MRID Citation Reference 58604 Fritz, H.; Becker, H. (1979) Report on CGA 64'250 Tech.: Teratology Study (Seg. II) in

Rats: Project No. 790011. (Unpublished study received Jan 28, 1981 under 100 - 618; prepared by Ciba - Geigy Lt d., Switzerland, submitted by Ciba - Geigy Corp., Greensboro, N.C.; CDL:244271 - O) 58605 Fritz, H.; Becker, H. (1979) Report on CGA 64'250 Tech.: Teratology Study (Seg. II) in

Rabbits: Project No. 790009. (Unpublished study received Jan 28, 1981 under 100 - 6 18; prepared by Ciba - Geigy Ltd., Switzerland, submitted by Ciba - Geigy Corp., Greens boro, N.C.; CDL:244271 - P) 132915 Clapp, M.; Killick, K.; Hollis, K.; et al. (1983) Triazole Alanine: Teratogenicity Study in

the Rat: Report No. CTL/P/875. (Unpub - lish ed study received Dec 12, 1983 under 100 - 617; prepared by Imperial Chemical Industries Plc., U.K., submitted by Ciba - Geigy Corp., Greensboro, NC; CDL:072208 - H) 143454 Ciba - Geigy Corp. (1984) Response by Ciba - Geigy to the April 12, 1984 Letter Regarding R at and Rabbit Teratology Studies with CGA - 64250 Technical. Unpublished com pilation. 467 p. 163322 Conn, R. (1986) Letter sent to H. Jacoby dated Sep 4, 1986: Tilt Fungicide ...:

Additional teratology information. Prepared by Ciba - Geigy Corp. 3 p. 16480 0 Raab, D.; Youreneff, M.; Giknis, L.; et al. (1986) CGA- 64250 Tech - nical: A Teratology

Stud y in New Zealand W hite Rabbits: Toxico - logy /Pathology Report 86043 (MIN 852172). Unpublished study prepared by Ciba - Geigy Corp. 437 p. 40425001 Giknis, M. (1987 ) CGA- 64250 Technical: Teratology (Segment II) Study in Rats:

Laboratory Project ID 86004. Unpublished study prepared by Ciba - Geigy Corporation, Pharmaceuticals Div.. 425 p. 40425002 Mallows, S.; Levy, E.; Goknis, M.; et al. (1987) CGA- 64250: A Modified Teratology

(Segment II) Study in Albino Rats ...: Laboratory Project ID 86189. Unpublished study prepared by Ciba - Geigy Corporation. 408 p. 40425004 Raab, D.; Youreneff, M.; Giknis, M.; et al. (1987) Propiconazole: A Teratology Study in

New Zealand Rabbi ts: Final Report Amendment No. 1: Laborator y Project ID 86043. Unpublished study prepared by Ciba - Geigy Corporation. 125 p. 93194038 Gillis, J.; Tisdel, M. (1990) Ciba - Geigy Corp. Phase 3 Summary of MRID 40425001. Teratology Study in Rats: Propiconazole: Study # MIN 852148. Prepared by CIBA GEIGY Corp. 12 p.

### Page 52 of 58

93194039 Gillis, J.; Tisdel, M. (1990) Ciba - Geigy Corp. Phase 3 Summary of MRID 40425002. Modified Teratology Study in Rats: Propiconazole: Study # MIN 862244. Prepared by CIBA- GEIGY Corp. 12 p. 9 3194040 Gillis, J.; Tisdel, M. (1990) Ciba - Geigy Corp. Phase 3 Summary of MRID 00164800 and Related MRIDs 40425004. Teratology Study in Rabbits: Propiconazole: Study # MIN 852172. Prepared by CIBA - GEIGY Corp. 12 p. 

### 83 - 4 2 - generation repro. - rat MRID Citation Reference 132916 Birtley, R. (1983) Triazole Alanine: Preliminary Reproduction Study in the Rat: Report

No. CTL/L/470. (Unpublished study received Dec 12, 1983 under 100 - 617; prepared by Imperial Chemical In - dustries Plc., U.K., submitted by Ciba - Geigy

Corp., Greensboro, NC; CDL:072208 - I) 132917 Birtley, R.; Milburn, G.; Corrigan, M.; et al. (1983) Triazole Alanine: Rat Multigeneration

Stud y: CTL Study No. RR0255/F0, Parental Generation and RR0255/F1, Subsequent Generation. Prog - ress rep t., Jun 21, 1983. (Unpublished study received Dec 12, 1983 under 100 - 617; prepared by Imperial Chemical Industries Plc., U.K., submitted by Ciba Geigy Corp., Greensboro, NC; CDL: 072208 - J) 133350 Fritz, H.; Giese, K.; Zak, F. (1981) Report on CGA 64250 T ech.: 2 - Generation Study in

Rats: Test No. 79 0010. (Unpublished study received Dec 12, 1983 under 100 - 617; prepared by Ciba - Geigy Ltd., Switz., submitted by Ciba - Geigy Corp., Greensboro, NC; CDL:072206 - K) 138167 Salamon, C.; Place, M.; Mayhew, D.; et a l. (1984) Two - generation Reproduction Study

in Albino Rats with CGA- 64250 Technical: Study No. 450 - 1202. Interim rept. (Unpublished study received Feb 8, 1984 under 100 - 617; prepared by Toxigenics, Inc., submit - ted by Ciba - Geigy Corp., Greensboro, NC; CDL :252368 - A; 252369) 151514 Borders, C.; Salamon, C. (1985) Two - Generation Reproduction Study in Albino Rats

with CGA- 64250 Technical: Toxigenics Study 450 - 1202. Unpublished study prepared by Toxigenics, Inc. 1886 p. 163164 Salamon, C. (1983) Two - genera tion Reproduction Study in Albino Rats Using CGA 64250 Technical: Study No. 450 - 1202. Unpublished study prepared by ToxiGenics, Inc. 20 p. 93194041 Tisdel, M. (1990) Ciba - Geigy Corp. Phase 3 Summary of MRID 00138167 and Related

MRIDs 00151514, 00163164. Two - Generation Reproduction Study in Rats: Study # 450 - 1202. Prepared by Toxigenics, Inc. 12 p. 

### 84 - 2 Interaction with Gonadal DNA MRID Citation Reference 58601 Arni, P.; Muller, D. (1979) Salmonella/Mammalian - Microsome Muta - genicity Test wit h

CGA 64 250: No. of Experiment: 78/2577. (Un - published study received Jan 28, 1981 under 100 - 618; prepared by Ciba - Geigy Ltd., Switzerland, submitted by Ciba - Geigy Corp., Greensboro, N.C.; CDL:244271 - L) 58602 Hool, G. (1979) Dominant Lethal Study: CGA 64 250: Mouse: No. of Experiment:

### Page 53 of 58 790034. (Unpublished study received Jan 28, 1981 under 100 - 618; prepared by Ciba Geigy Ltd., Switzerland, submit - ted by Ciba - Geigy Corp., Greensboro, N.C.; CDL:244271 - M) 58603 Hool, G.; Langauer, M. (1979) Nucleus Anoma ly Test in Somatic In - terphase Nuclei: CGA 64 250: Chinese Hamster: No. of Experiment: 79 - 0805. (Unpublished study received Jan 28, 1981 under 100 - 618; prepared by Ciba - Geigy Ltd., Switzerland, submitted by Ciba - Geigy Corp., Greensboro, N.C.; CDL:244271 - N) 132911 Herbold, B.; Lorke, D. (1983) THS 2212 Triazolylalanine: Salmonella/Microsome Test

for Point Mutagenic Effect: Report No. 11388. (Unpublished study received Dec 12, 1983 under 100 - 617; prepared by Bayer AG, W . Ger., submitted by Ciba - Geigy Corp ., Greensboro, NC; CDL:072208 - B) 132912 Herbold, B.; Lorke, D. (1982) THS 2212 (Triazolylalanine): Micro - nucleus Test for

Mutagenic Effect on Mice: Report No. 11054. (Unpublished study received Dec 12, 1983 under 100 - 617; prepared by Bayer AG, W . Ger., submitted by Ciba - Geigy Corp., Greensboro, NC; CDL:072208 - D) 132913 Herbold, B. (1983) THS 2212 (Triazolylalanine): Pol A1 Test on E. coli during Testing

for Effects Harmful to DNA: Report No. 11390. (Unpublished study received Dec 12, 1983 under 100 - 61 7; prepared by Bayer AG, W. Ger., submitted by Ciba - Geigy Corp., Greensboro, NC; CDL:072208 - E) 132914 Richold, M.; Allen, J.; W illiams, A.; et al. (1981) Cell Trans - formation Test for Potential

Carcinogenicity of R152056: ICI 394A/81153; CTL/C/1085. (Un published study received Dec 12, 1983 under 100 - 617; prepared by Huntingdon Research Centre, Eng., submitted by Ciba - Geigy Corp., Greensboro, NC; CDL: 072208 - F) 133342 Strasser, F. (1982) L5178Y/TK +/ - Mouse Ly mp hom a Mutagenicity Test: CGA 64 250

(in vit ro Test for Mutagenic Properties of Chemical Substances in Mammilian Cells): Experiment # 811516. (Unpub - lished study received Dec 12, 1983 under 100 - 617; prepared by Ciba - Geigy Ltd., Switz., submitted by Ciba - Geigy Corp., Greens - boro, NC; CDL:072206 - B) 133343 Arni, P. (1982) Saccharomyces cerevisiae D7/Mammalian - mi crosome Mu - tagenicity

Test in vitro with CGA 64 250 (Test for Mutagenic Properties in Yeast Cells): Experiment No. 811558. (Unpublished study received Dec 12, 1983 under 100 - 617; prepared by Ciba - Geigy Ltd., Switz., submitted by Ciba - Geigy Corp., Greensboro, NC; CDL:072206 - C) 133344 Strasser, F. (1982) Point Mutation Assay with Mouse Ly mphoma Cells Host - me diated

Assay with CGA 64 250 (Test for Mutagenic Proper- ties in Mammilian Cells): Ex periment No. 811513. (Unpublished study received Dec 12, 1983 under 100 - 617; prepared by Ciba - Geigy Ltd., Switz., submitted by Ciba - Geigy Corp., Greensboro, NC; CDL:072206 - D) 133345 Hool, G. (1982) Chromosome Studies in Male Germinal Epithelium: CGA 64 250:

Mouse (Test for Mutagenic Effects on Spermatogonia): Experiment No. 811511. (Unpublished study received Dec 12, 1983 under 100 - 617; prepared by Ciba - Geigy Ltd., Switz., submitted by Ciba - Geigy Corp., Greensboro, NC; CDL:072206 - E) 133346 Hool, G. (19 82) Chromosome Studies in Male Germinal Epithelium: CGA 64 250:

Mouse (Test for Mutagenic Effects on Spermatocytes): Ex - periment No. 811512. (Unpublished study received Dec 12, 1983 under 100 - 617; prepared by Ciba - Geigy Ltd., Switz., submitted by Ciba - Gei gy Corp., Greensboro, NC; CDL:072206 - F)

### Page 54 of 58

133347 Puri, E. (1982) Autoradiographic DNA Repair Test on Human Fibro - blasts: CGA 64

250 (in vitro Test for DNA- dam aging Properties): Experiment No. 811655. (Unpublished study received Dec 12, 1983 under 100 - 617; prepared by Ciba - Geigy Ltd., Switz., submitted by Ciba - Geigy Corp., Greensboro, NC; CDL:072206 - G) 133348 Puri, E. (1982) Autoradiographic DNA Repair Test on Rat Hepato - cytes: CGA 64 250

(in vitro Test for DNA- dam aging Properties): Experiment No. 811514 . (Unpublished study received Dec 12, 1983 under 100 - 617; prepared by Ciba - Geigy Ltd., Switz., submitted by Ciba - Geigy Corp., Greensboro, NC; CDL:072206 - H) 133349 Strasser, F. (1982) BALB/3T3 Cell Transformation Assay: CGA 64 250 (in vitro Test for

Trans formation - inducing Properties in Mammal - ian Fibroblasts): Experiment No. 790806. (Unpublished study re - ceived Dec 12, 1983 under 100 - 617; prepared by Ciba Geigy Ltd., Switz., submitted by Ciba - Geigy Corp., Greensboro, NC; CDL 072206 - J) 133361 Wa tk ins, P.; Rutty, D.; Topham, J.; et al. (1982) R152056: 3 - (1,2, 4, - Triaz ol - 1 - yl)

Alanine (ICI 156,342) -- Micronucleus Test in CBC Fl Mice: TOM/4. (Unpublished study received Dec 12, 1983 under 100 - 617; prepared by Imperial Chemical Industries Plc., U.K., submitte d by

Ciba - Geigy

Corp., Greensboro, NC; CDL: 072208 - C) 151504 Strasser, F. (1985) L5178Y+/ - Mouse Ly mp homa Mutagenicity Test: CGA 64250:

Supplement to the Report Dated August 10, 1982: Test No. 811516. Unpublished study prepared by Ciba - Geigy Ltd. 8 p. 151505 Arni, P. (1985) Saccharomyces cerevisae D7/Mammalian - Microsome Mutagenicity Test

in vitro: CGA 64250: Supplement to the Re - port Dated August 19, 1982: Test No. 811558. Unpublished study prepared by Ciba - Geigy Ltd. 5 p. 151506 Hool, G. (1985) Chro mo som e Studies on the Germinal Epithelium of Mouse

Spermatogonia: CGA 64250: Supplement to the Report Dated August 31, 1982: Test No. 811511. Unpublished study prepared by Ciba - Geigy Corp. 4 p. 151507 Hool, G. (1985) Chromosome Studies on the Germinal Ep ithelium of Mouse

Spermatocytes: CGA 64250: Supplement to the Report Dated August 13, 1982: Test No. 811512: Test No. 811512. Unpublished study prepared by Ciba - Geigy Ltd. 3 p. 151508 Puri, E. (1985) Autoradiographic DNA Repair Test on Human Fibro - blast s: CGA

64250: Supplement to the Report Dated August 12, 1985: Test No. 811655. Unpublished study prepared by Ciba - Geigy Ltd. 10 p. 151509 Puri, E. (1985) Autoradiographic DNA Repair Test on Rat Hepato: cytes: CGA 64250:

Supplement to the Report Dated Au gust 12, 1982: Test No. 811514. Unpublished study prepared by Ciba - Geigy Ltd. 12 p. 151510 Hool, G. (1985) Sister Chromatid Exchange Study in Somatic Cells of Chinese Hamster

Bone Marrow: CGA 64250: Supplement to the Re - port Dated October 18, 1982: Tes t No. 811515. Unpublished study prepared by Ciba - Geigy Ltd. 2 p. 163163 Hool, G. (1982) Sister Chromatid Exchange Study: Test for Muta - genic Effects on

Bone Marrow Cells: CGA 64 250: Chinese Hamster: Experiment No. 811515. Unpublished study prepared by Ciba - Geigy Limited. 8 p. 165468 Strasser, F. (1985) Point Mutation Assay with Mouse Ly mphoma Cells Host Mediated

Assay: (Test for Mutagenic Properties in Mammalian Cells): CGA 64250: Supplement to the Report Dated August 10, 1982: Test No. 811513. Unpubl ished study prepared by Ciba - Geigy

Ltd. 4 p.

### Page 55 of 58

41594802 Deparade, E. (1983) CGA- 64250 Technical: Salmonella/Mammalian - Micro some

Mutagenicity Test: Lab Project Number: 830121. Unpublished study prepared by Ciba Geigy Ltd. 31 p. 41594803 Strasser, F. (198 7) CGA- 64250 Technical: Micronucleus Test (Chinese Hamster): Lab

Project Number: 860359. Unpublished study prepared by Ciba - Geigy Ltd. 28 p. 42050504 Ogorek, B. (1983) Intrasanguine Host - Mediated Assay with S. typhim - urium: CGA64250: Lab Project Number : 830120. Unpublished study prepared by Ciba - Geigy Ltd. 21 p. 42050505 Strasser, F. (1984) Chromosome Studies on Human Ly mphocytes in vit - ro: CGA- 64

250: Lab Project Number: 840025. Unpublished study prepared by Ciba - Geigy Ltd. 19 p. 45215802 We ber, E . (1999) Assessment of Hepatic Cell Proliferation in Male Mice

(Propiconazole): Final Report: Lab Project Number: CB 97/23: 539 - 98. Unpublished study prepared by Novartis Crop Protection AG. 59 p. 93194042 Breckenridge, C. (1990) Ciba - Geigy Corp. Phase 3 Summary of MRID 41594802. Salm onella/Mammalian - Microsome Mutagenicity Test: Propiconazole: Study No. 830121. Prepared by Ciba - Geigy Limited. 12 p. 93194043 Breckenridge, C. (1990) Ciba - Geigy Corp. Phase 3 Summary of MRID 41594803. Micronucleus Test - Ch inese Hamster: Propiconazole: Study No. 860359. Prepared by Ciba - Geigy

Limited. 12 p. 93194044 Breckenridge, C. (1990) Ciba - Geigy Corp. Phase 3 Summary of MRID 00133348 and Related MRIDs 00151509. DNA Repair Test, Rat Hepatocytes: Propiconazole: Study # 811514. Prepared by CIBA - GEIGY Limited. 12 p. 

### 85 - 1 General metabolism MRID Citation Reference 74495 Marco, G.J.; Kahrs, R.A. (1981) CGA- 64250 -- Rice and Pecans: Resi - dues Observed

and Metabolism Data Including the Analytical Methods Used: Rep ort No. ABR - 81020. (Unpublished study received Jun 8, 1981 under 100 - EX - 69; submitted by Ciba - Geigy Corp., Greensboro, N.C.; CDL:070163 - A) 74505 Hambock, H. (1979) Distribution, Degradation and Excretion of CGA 64 250 in the Rat:

Project Report 24/79. (U npublished study received Jun 8, 1981 under 100 - EX - 69; prepared by Ciba - Geigy Ltd., Switzerland, submitted by Ciba - Geigy Corp., Greensboro, N.C.; CDL:070164 - K) 74506 Muecke, W. (1979) Characterization of Urinary and Faecal Metabo - lites of Rats after

Ora l Application of CGA 64 250: Project Report 35/79. (Unpublished study received Jun 8, 1981 under 100 - EX - 69; prepared by Ciba - Geigy Ltd., Switzerland, submitted by Ciba - Geigy

Corp., Greensboro, N.C.; CDL:070164 - L) 74507 Mucke, W. (1981) The Major Metaboli c Pathways of CGA 64 250 in the Rat: Project

Report 9/81. (Unpublished study received Jun 8, 1981 under 100 - EX - 69; prepared by Ciba - Geigy

Ltd., Switzerland, submitted by Ciba - Geigy Corp., Greensboro, N.C.; CDL:070164 - M) 129906 Sim oneaux, B. (1983) Dermal Absorption of Triazole - 14C - CGA- 64250 by Rats: Report

### Page 56 of 58 No. ABR - 82068. (Unpublished study re - ceived Jul 21, 1983 under 100 - 641; submitted by Ciba - Geigy Corp., Greensboro, NC; CDL:250782 - G) 131098 Sim oneaux, B. (1983) Dermal Absorption of Triazole - 14C - CGA- 64250 by Rats: Report

No. ABR - 82068. (Unpublished study received Sep 8, 1983 under 100 - 617; submitted by Ciba - Geigy Corp., Greensboro, NC; CDL:251239 - I) 132946 Sim oneaux, B. (1983) Dermal Absorption of Triazole - 14C - CGA- 64250 by Rats: M5 - 62 -

2A: Report No . ABR - 82068. (Unpublished study re - ceived Dec 12, 1983 under 100 - 617; submitted by Ciba - Geigy Corp., Greensboro, NC; CDL:072224 - V) 133385 Ciba - Geigy Corp. (1983) CGA- 64250: Pecans. (Compilation; unpub - lished study received Dec 12, 1983 under 100 - 617; C DL:072212 - A; 072213; 072214; 072215; 072216; 072217) 147861 Bissig, R. (19??) The Metabolism of [U - Carbon - 14] - phenyl CBA 64 250 in Mice after

Pretreatment with Unlabelled CGA 64 250: Project No. 12RB01. Unpublished study prepared by Agricultural Division Research and Development, Ciba - Geigy Corp. 16 p. 164470 Wa ng, L. (1959) Plasma volume, cell volume, total blood volume and F cells factor in

the normal and splenectomized Sherman rat. American Journal of Physiology 196(1):188 - 192. 164794 Ballantine, L . (1986) Propiconazole Animal Metabolism Update: Metabolism in Mice:

Dermal Absorption in the Rat: Report No. ABR - 86071. Unpublished compilation prepared by Ciba - Geigy Corp. 10 p. 164795 Bissig, R. (1986) The Metabolism of [U - Carbon 14] - pheny l - CGA 64 250 in Mice after

Pretreatment with Unlabelled CGA 64 250: Project Report 6/86. Unpublished study prepared by Ciba - Geigy Limited. 52 p. 164796 Hamboeck, H. (1979) Distribution, Degradation and Excretion of CGA 64 250 in the

Rat: Project Report 24/79. Unpubl ished study pre - pared by Ciba - Geigy Limited. 19 p. 164797 Muecke, W. (1981) The Major Metabolic Pathways of CGA 64 250 in the Rat: Project

Report 9/81. Unpublished study prepared by Ciba - Geigy Limited. 13 p. 164798 Muecke, W. (1983) The Metabolism of CGA 64 250 in the Rats: Project Report 24/83.

Unpublished study prepared by Ciba - Geigy Limited. 145 p. 41326701 Cresswell, D. (1989) (U - carbon - 14) - Phenyl CGA 64250: Absorption, Distribution,

Metabolism and Excretion in the Rat: Lab Project Number: 380/1 05. Unpublished study prepared by Hazleton UK. 520 p. 41594804 Cresswell, D. (1989) U - ?carbon 14| - pheny l CGA 64250: Absorption, Distribution,

Metabolism and Excretion in the Rat: Lab Project No. 380/105. Unpublished study prepared by Hazleton UK. 520 p. 42403901 Mucke, W. (1983) The Metabolism of CGA- 64250 in the Rat: Lab Project Number:

24/83. Unpublished study prepared by Ciba - Geigy Ltd. 148 p. 93194045 Hochman, J. (1990) Ciba - Geigy Corp. Phase 3 Summary of MRID 41326701. Propiconazole - Rat Metabol ism: Project 380/150. Prepared by Hazleton UK. 17 p.



### 85 - 2 Dermal penetration MRID Citation Reference

### Page 57 of 58

47154901 Schwartz, R. (2007) Studies of the Dermal Resorption of (Carbon 14) - Fenpropimorph.

Project Number: WO L/07/2905. Unpublished study prepared by Dr. Wo lm an Gm bH. 125 p. 

### 85 - 3 Dermal Penetration/Absorption MRID Citation Reference 164469 Murphy, T.; Brown, K.; Doornheim, D.; et al. (1986) Dermal Absorp - tion of [Carbon 14] -

Propiconazole in Rats after a Ten - hour Ex - posure Period : Report No. ABR - 86053. Unpublished study prepared by Ciba - Geigy Corp. 76 p. 164794 Ballantine, L. (1986) Propiconazole Animal Metabolism Update: Metabolism in Mice:

Dermal Absorption in the Rat: Report No. ABR - 86071. Unpublished compilation prepared by Ciba - Geigy Corp. 10 p. 42415701 Murphy, T. (1986) Dermal Absorption of ?carbon 14| - Propiconazole: Addendum to

ABR - 86053: Lab Project Number: ABR - 86064. Unpublished study prepared by Ciba Geigy Corp. 85 p. 45345901 Murphy, T. (2001) Dermal Absorption of (carbon 14) - Propiconazole: Addendum to

ABR - 86053: MRID 42415701: Lab Project Number: 1596 - 01. Unpublished study prepared by Syngenta Crop Protection, Inc. 7 p. {OPPTS 870.7600}

### Page 58 of 58

E. CHEMICAL NAMES AND STRUCTURES OF METABOLITE S



### * N HC =

= CH N N CH 2 C Cl Cl

O O CH 2 CH CH CH 3

CH 2 OH

N HC =

= CH N N CH 2 C Cl Cl

O O CH 2 CH CH 2

CH 2 OH N HC =

= CH N N CH 2 C Cl Cl

O O CH 2 CH COOH

CH 2 C Cl Cl O O CH 2 CH COOH

CH 2 N HC =

= CH N N N HC=

= CH N N CH 2 C Cl Cl

O

N HC=

= CH N N CH 2 CH Cl Cl

OH Cl Cl HOOC N HC =

= CH N N CH 2 C Cl Cl

O O CH 2 CH CH 2 CH 3

CH 2 

### CG A 64250 CGA 118244

CG A 118245 CGA 217495

CG A 217496 CGA 91304

CGA 91305 CGA 177291

APPENDIX: REFERENCE COMPOUNDS