### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, 

### D.C

. 20460



### MEMORANDUM

DA TE: December I 0, 2015 OF FI CE O F CHE MI CA L SAFETY AND
POLLUTION PRE V ENTION



### SUB JE C T: Propi conazole : Human H ea lth Ri sk Scop in g D oc um e nt in Su pport of Regi stratio n

R ev i ew

PC Code : 12210 I DP Bar code : D 429076

D ecisio n No.: 508972 Registration No: N I A

P eti t ion No.: None Regulatory Action: R egistration Review

Assess m e nt Type: Scop in g Do c um e nt Case No.: 3 1 25

TXR No.: None CAS No. : 60207-90

- 1

MRIDNo. : None 40CFR:**18~ ~** 



### FR OM: Th ur ston Morton

, Ri sk Assesso r / Chemist

# !)**£, /;**  C\

. 

### Kell y O ' R o urke

, ORE Assessor ] 

# rt/ 1 ' U**~** Abda llah Khasawinah

, PhD., Tox ic o l og i st

Risk Assessment Branch 4

He alth E ff ects Division (7509P)

Na th a n Mott!

, Bi o l og i st

# IV~**t~** Jenny Tao, Se ni o r Tox i cologist

# -;**J. ~** **~** },, 

# e,

.. <;<

# \3**;~"}** S umitra B ose Bi swas, C h e mi st

, H ED

### V~.>t;<" 

## .... ,.. '

Ri sk Assess men t Sc ienc e Sup p o rt Br a n c (RASSB)

Ant i microbi a l s Di v is i on (75 1 OP)

T HROUGH: Elissa Reav es, Ph .D., Chief 

# /':.fl

- -



# _ c)]/

Ri sk Assessme nt Bran c h 

### 4

, H E D (7509 P )

# ~------**~**

And

Steve n Weiss

, Chief 

# '5it£**(j/~** ,_j____,

Timothy L e i g hton

, Sen i o r Scie nti st 

### I

_,,.......,

## ~ Ri s k Assess ment Sc ien ce S upp o r t Br a nch (RAS SB)

, 

### AD (75 1 

### OP)

T O : L in sey Wal s h

, Ri sk Manager R ev i ewer
Ri sk Man age m en t and Impl e m e ntati on Br anc h (RM IB 3)

Pesticide R e-E valuation Divi s ion (7508P)

A nd

S andr a O ' Nei ll

, C h e mic a l R ev i ew Manager

Ri sk Management Bran c h II (RM Bll )

, AD (7510 P )

P age I of 3 5Propiconazole Human-H ea l th Assessment Scoping Docum e nt 0429076



### Attac h ed i s t h e Hea lth Effec t s D iv i s i o n ( H E D ) and Ant i m i cro bial s Di vis i o n (A D ) h um an h ealt h

r i sk assess m e n t scop in g doc um e nt fo r pr op i co n azo l e s ubmi tted in s up por t of R eg i st rat io n
R ev i ew . T o eva lu ate th e sco p e of wo rk n ecessa r y t o s u p p o rt R eg i strat i o n R ev i ew
, H E D and A D

h ave co n s id e r e d r ece n t ri s k a ssess m e nt s fo r pr o pi co n azo l e, the Hum a n H ea lth Ri s k Ass e ss m e n t

for t he 2 006 R e r eg i s t ra ti o n E li g ibili ty D ec i s i o n D oc um e nt (RED )

, upd a t es to it s t ox icity

, expos ure and u sage d atabases

, and th e l a t es t Age n cy sc i e n ce p o li cy a n d ri s k assess ment

m et h o d o l og i es. T h e m ost recen t HE D hum a n h ea l t h ri s k assess m e n t fo r prop i co n azo le was
conduc ted in 20 1 5 (Memo, 1 2 / 2 / 20 1 5

, T. 

### Mo rt on
, 0426494); the m os t recent AD hum an h ealth

ri sk assessment fo r propiconazo l e was conduc t ed in 2011 (Memo, 8 / 23 / 20 11

, T. L e i ghto n
, 0393026).

P age 2 o f 35Propiconazole Human

- Health Assessmen t Scoping Document D 429076

Page 3 of 35 

### E xecutive S ummary

Background: Propiconazole 1

- [[2

- (2,4

- dichlorophenyl)

- 4

- propyl

- 1,3

- dioxolan

- 2

- yl]methyl]

- 1 H

- 1,2,4

- triazole) is a systemic triazole

- type f ungicide that provides broad spectrum disease control on a variety of food and non

- food crops. Non

- food , conventional uses include use on commercial, public and residential ornamentals, landscapes and turf. In addition, propiconazole is registered for an timicrobial use as a material preservative and wood preservative which will be assessed by the Antimicrobial Division (AD). Propiconazole is formulated as a soluble concentrate (SC), emulsifiable concentrate (EC), ready

- to

- use (RTU), water dispersible gra nule (WDG), granular, and flowable concentrate (FlC). The most recent HED human health risk assessment was conducted in 2015 (T. Morton, 12 / 2 /2015

, D 426494); the most recent AD human health risk assessment for propiconazole was conducted in 2011(Memo, 8/23/2011, T. Leighton, D393026).

HED and AD evaluated the most recent propiconazole human health risk assessment to determine whether sufficient data are available and whether any updates are needed to support Registration Review. HED and AD have considered all registered uses for propic onazole with respect to its toxicity, exposure, and usage databases, and the most updated Agency science policy and risk assessment methodologies to determine the scope of work necessary to support Registration Review. The current do cument pertains only to the Registration Review data requirements for propiconazole.

Hazard Identification/Toxicology: T he toxicology database for propiconazole is complete for evaluating and characterizing toxicity and selecting endpoints for risk ass essment. Based on a weight

- of

- evidence (WOE) approach considering all the available propiconazole hazard and exposure information, the HED Hazard and Science Policy Council (HASPOC) concluded that a

28

- day da y inhalation study and a subchronic neurotoxici ty study are not required at this time (TXR # 0056387). In spite of the waiver, the registrant submitted an SCN study with propiconazole in December 2013 (MRID 49300503) and was reviewed in 2014 and found acceptable (TXR 0056920). HASPOC also waived the re qui rement for an immunotoxicity study for propiconazole (TXR 0056761 and TXR 0056730). The primary target organ for propiconazole toxicity in animals is the liver. No new toxicological data are required. The Agency does not anticipate the need to revise t he toxicological endpoints, points of departure, or safety factors for propiconazole during Registration Review.

Residue Chemistry and Dietary Exposure: Adequate metabolism (crops, livestock, and rotational crops) and magnitude of the residue data are av ailable to support the registered uses. Adequate methods are available for enforcement of the currently established tolerances. No additional residue chemistry data are needed to support the currently registered uses. The Agency does not anticipate the need for a revised dietary assessment during Registration Review unless dietary exposure models or the Estimated Drinking Water Concentrations (EDWCs) are updated. Although there are registered antimicrobial uses that could result in indirect food

contact , including a use on mushroom trays, these uses are expected to result in minimal dietary exposure compared to the conventional agricultural uses of propiconazole. Therefore, a dietary exposure assessment has not been conducted for the antimicrobial uses o f propiconazole.Propiconazole Human

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Page 4 of 35 

### Residential Exposure:

Conventional Uses: All registered residential uses for propiconazole (ornamentals, lawns/turf, paint) have been reassessed using the 2012 Residential SOPs (J. Miller, D403629, 11/15/12).

Residential risk estimates were not of concern ( i.e., margins of concern [ MOE s ] > 100). During Registration Review, HED anticipates conducting updated residential assessments to incorporat e required chemical

- specific turf transferrable residue (TTR) data . The Agency will examine the need for spray drift and volatilization assessments during Registration Review for propiconazole based on the potential for exposure to bystanders from agricultural applications.

Antimicrobial Uses: The Agency anticipates using proprietary ex posure studies received from the post

- RED Generic Data Call

- In (GDCI) to develop a new exposure assessment.

Residential handler exposures to propiconazole for paints and wood preservative stains (brush/roller and airless sprayer) are anticipated to be a ssessed, using proprietary data, for Registration R eview.

For residential post

- application exposure, the Agency will develop a new residential exposure assessment for dermal and incidental ingestion exposures for children playing on propiconazole

treate d wood decks or playground structures, using the propiconazole dislodgeable residue data (MRID 48825400; e.g., new wood wipe data) received from the post

- RED GDCI.

The Agency anticipates requir ing additional exposure data, including an applicator product use narrative (Series 875.1700) to clarify use rates and wood retentions, intended antimicrobial uses, and application equipment.

Aggregate Risk Assessment: As part of Registration Review, updated aggregate risk assessments may be necessary to reflect revised dietary or residential exposure estimates.

Occupational Exposure:

Conventional Uses: The HED occupational exposure database is adequate to support the Registration Review for propiconazole. The most recent occupational handler and post

application exposure assessment did not identify risks of concern. HED does not anticipate the

need for a revised occupational assessment during Registration Review; however, policy changes may occur that requ ire incorporation, as well as inclusion of the required chemical

- specific turf transferrable residue (TTR) data identified for the residential exposure assessment.

Antimicrobial Uses: The Agency anticipates conduct ing new occupational exposure

assessments for registration review to support wood and material preservation uses. Occupational exposure assessments are needed based on proprietary exposure data received from the post

- RED GDCI and new application rates. The Agency anticipates the need to use the new proprietary exposure data received from the RED data call

- in to assess metalworking, wood preservation, paint, and liquid pour exposures for a variety of different material preservative uses. In registration review, applicator product use data (875.1 700) is needed to clarify uses (particularly the use of plastics), application rates (wood retentions), and application equipment (verify sapstain and wood pressure treatments).Propiconazole Human

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### Summary

- Risk Assessment Updates, Data Deficiencies, and Label Revisions: B ased on the current use patterns, there are data deficiencies.

Conventional Use Risk Assessment Updates:

 Harmonization of tolerances with Codex and Canadian maximum residue limits (MRLs) will be evaluated along with tolerance expression revision.

 Revise d aggregate risk assessment may be necessary to reflect revised dietary exposure estimates, and/or residential exposure estimates.

 A turf transferable residue (TTR) study (Guideline 875.2100) is anticipated to be required

in order to determine exposure and risk associated with children contacting treated turf.

A re vised residential risk assessment may be necessary.

 The need for a spray drift and volatilization risk assessment for propiconazole will be examined during Registration Review.

HED notes that based on the assumptions and resulting risks associated with the currently registered uses, it is highly unlikely that revised risk assessments conducted in support of Registration Review will yield exposures greater than HED’s level of concern.

Antimi crobial Use Risk Assessment Updates:

 New occupational risk assessments will be necessary for metalworking (machinists) and
wood preservation (sapstain and pressure treatment workers). New occupational risk
assessments will also be necessary for material preservative exposures, such as airless
sprayer and paintbrush to paints and stains and liquid pour applications, in a variety of
material preservative products.

 New residential risk assessments will be necessary to reflect new exposure data for paint

and stain (airless sprayer and paintbrush) applications.

 New residential post

- application risk assessments will be needed for pressure treated
decks and playsets.

 Revised aggregate risk assessment may be necessary to reflect revised residential exposure estimates.

DETAILED CONSIDERATIONS

Registered Use Patterns

Conventional Uses

Propiconazole is formulated as a soluble concentrate (SC), emulsifiable concentrat e (EC), ready

to

- use (RTU), water dispersible granule (WDG), granular, and flowable concentrate (FlC). The maximum application rate is 0.29 lbs ai/A for applications to outdoor agricultural crops, 0.45 lb ai/100 gal as a fruit dip, and 2.8 lb ai/A for mus hroom houses. The maximum application rate is 1.8 lbs ai/A for applications to turf. Applications can be made using ground and aerial equipment. Propiconazole is a systemic triazole

- type fungicide that provides broad spectrum

disease control on a variet y of food and non

- food crops. Non

- food uses include use on commercial, public and residential ornamentals, landscapes and turf.Propiconazole Human

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Page 6 of 35 

### Antimicrobial Uses

Propiconazole is the active ingredient in material preservative products (Use Site Category VII) and in wood preservation products (Use Site Category X). As a materials preservative, the products are used in items such as metalworking fluids, adhesives, c aulks, coatings, stains,

p aints, inks, paper, textiles, canvas (i.e., awnings, boat covers, carpet backing, cordage, tents, tarpaulins, and wall coverings), cordage, leather, and leather finishing pastes, fat liquors, or finishes. As a wood preservative, the products can be used on green or fresh cut lumber, poles, posts, and timbers; manufactured wood products such as logs, wood chips/sawdust, plywood veneer, and particle board; dry lumber; and finished wood products such as millwork, shingles, shakes, si ding, plywood, and structural lumber and composites.

The majority of the products are intended for use at wood treatment facilities; however, propiconazole is also formulated for use in mushroom houses to protect timber trays and benches

and for use on cooling tower wood. The wood and wood products can be treated through non

pressure treatment methods and pressure treatment methods. The percentage of propiconazole in various products can range from 0.1% to 50%.

Hazard Identification/Toxicology

T he t oxicology database for propiconazole is complete for evaluating and characterizing toxicity and selecting endpoints for risk assessment. Based on a WOE approach considering all the available propiconazole hazard and exposure information, the HASPOC conclu ded that a 28

- day day inhalation study and a subchronic neurotoxicity study are not required at this time (TXR # 0056387)

. In spite of the waiver, the registrant submitted an SCN study with propiconazole in December 2013 (MRID 49300503) and was reviewed in 2014 and found acceptable (TXR 0056920). HASPOC also waived the requirement for an immunotoxicity study for propiconazole (TXR 0056761 and TXR 0056730). The primary target organ for propiconazole toxicity in animals is the liver. Liver effects observed in subchronic and chronic oral studies in rats and mice include lesions, hypertrophy and necrosis. There are mixed effects in the developmental and reproduction rat studies. In a rat developmental study, fetal effects were

observed at doses lower than do ses at which maternal effects were seen demonstrating quantitative evidence of increased susceptibility of fetuses to in utero exposure to propiconazole. While in rabbits, developmental toxicity occurred at higher doses than maternally toxic doses.

In t he two generation reproduction study in rats, offspring toxicity occurred at a higher dose than the parental toxic dose suggesting lower susceptibility of the rat offspring to propiconazole. Propiconazole does not appear to be neurotoxic based on acute a n d subchronic neurotoxicity

s t udies . The concern for susceptibility is low since clear NOAELs (No Adverse Effect Level) were established in the rat and rabbit developmental studies and the points of departure selected

for the risk assessment scenarios are protective of the susceptibility observed in the rat developmental study. Therefore, the FQPA safety factor was reduced to 1X.

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

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

dermal sensitizer.Propiconazole Human

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### Endpoints/Points of Departure (PODs) for Risk Assessment. Toxicological endpoints were selected for dietary/drinking water, occupational and residential exposure scenarios. Acute and chronic points of departure (PODs) were selected for assessment of food and drinking water exposures. An acute POD for the genera l population was selected from an acute neurotoxicity study in rats. An acute POD for females 13

- 49 was selected from a developmental toxicity study in rats. A chronic/cancer POD for the general population was selected from a carcinogenicity study in mic e. Short and intermediate

- term occupational exposures via the dermal and inhalation routes may occur based on the use pattern and label directions. Toxicological endpoints for

short

- term inhalation, dermal, and incidental oral exposures were selected fro m the acute neurotoxicity study in rats. Toxicological endpoints for intermediate

- term incidental oral exposure and intermediate

- and long

- term inhalation and dermal exposures were selected from a carcinogenicity study in mice. Since an oral study was se lected for dermal exposure, a 40% dermal absorption factor (DAF) from a dermal absorption study in rats is used for route to route extrapolation. A DAF of 1% and 26.6% for paints and stains, respectively, are used for assessment of antimicrobial uses in p aints and stains. An uncertainty factor of 100X was applied to endpoints selected for all exposure routes (10X for interspecies extrapolation, 10X for intraspecies variation). Therefore, the level of concern (LOC) for residential and occupational

exposur e and risk is for margins of exposure (MOEs) less than 100.

FQPA Factor. For propiconazole there are acceptable developmental toxicity studies in the rat and rabbit and an acceptable multi

- generation reproduction study in the rat. An acceptable acute neurotoxicity study in the rat is available in the database with clinical toxicity at the high dose only with no microscopic changes. A subchronic neurotoxicity study in rats demonstrated no neurotoxic effects (clinical or pathological) at the highest dose tested. Although quantitative susceptibility was observed in the rat developmental study, a clear NOAEL is established for the developmental effects. Furthermore, the acute dietary for females 13

- 49 years old is based on the develop mental NOAEL from the study with quantitative susceptibility. Therefore, the risk assessment is protective of this susceptibility and there are no remaining uncertainties for the young. Together, the available data support the reduction of the FQPA facto r to 1X.

A summary of toxicological doses and points of departure for propiconazole is presented in Table 3 in the Appendix. A toxicity profile of propiconazole is presented in Tables 4 and 5, and guideline data requirements in Table 6 of the Appendix.

C onclusions for Toxicology

T he toxicology database for propiconazole is complete. Based on a WOE approach considering all the available propiconazole hazard and exposure information, the HASPOC concluded that a

28

- day day inhalation study i s not required at this time (TXR # 0056387).

The Agency does not anticipate the need to revise the toxicological endpoints, points of departure, or safety factors for propiconazole during Registration Review.Propiconazole Human

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Page 8 of 35 

### Residue Chemistry and Tolerance Assessment

Propiconazole is registered for use on a large number of food and feed crops. The maximum application rate is 0.23 lbs ai/A for applications to outdoor agricultural crops, 0.45 lb ai/100 gal as a fruit dip, and 2.8 lb ai/A for mushroom houses. Applicatio ns can be made using handheld, bath, ground and aerial equipment.

Permanent tolerances are currently established for the combined residues of propiconazole, 1

- [[2

- (2,4

- dichlorophenyl)

- 4

- propyl

- 1,3

- dioxolan

- 2

- yl]methyl]

- 1 H

- 1,2,4

- triazole, and its

metabol ites determined as 2,4

- DCBA and expressed in parent equivalents, at levels ranging from 0.1 ppm on numerous plant commodities to 40 ppm in/on grass straw [40 CFR §180.434(a)]. Permanent tolerances are also established for the combined residues of propicon azole and its metabolites determined as 2,4

- DCBA at 0.05 ppm in fat, meat, and meat byproducts (except liver and kidney) of livestock, 2.0 ppm in liver and kidney of livestock, and at 0.05 ppm in milk; however, no tolerances have been established for eggs and poultry commodities. A time

- limited tolerance of 10 ppm is currently in effect for avocado [40 CFR §180.434(b)]. In addition, tolerances with regional restrictions have been established for combined propiconazole residues at 1.0 ppm in/on cranberry a nd at 0.5 in/on wild rice grain[40 CFR §180.434(c)]. Tolerances with inadvertent residues have been established for combined propiconazole residues at 0.1 ppm in/on alfalfa forage and alfalfa hay.

Available plant metabolism data (primary and rotated crop s) show that plants absorb, metabolize and translocate propiconazole throughout the plant. A major metabolic pathway in plants appears to be hydroxylation (primarily of the beta

- carbon) of the n

- propyl group on the dioxolane ring of the cis/trans isomers of propiconazole. These metabolites appear to readily form sugar conjugates. The majority of Total Radioactive Residue ( TRR ) was found in the stalks, such as peanut stalk, wheat forage and straw, grape leaves, and celery stalks. The nature of propiconaz ole residues in livestock is adequately understood based on acceptable goat and poultry metabolism studies. The HED Metabolism Assessment Review Committee (MARC) concluded that for plants and livestock, residues of propiconazole and all its metabolites

co ntaining the 2,4

- dichlorophenyl moiety (2,4

- DCBA), including conjugates, are of concern and should be included in the dietary (food) risk assessments, propiconazole per se should be included in the dietary (water) risk assessments. For tolerance expressi on, MARC concluded that the current tolerance expression for propiconazole should be amended to include residues of propiconazole only. For enforcement purpose, the Multiresidue Methods Section 302 (Luke Method; Protocol D) detects parent propiconazole.

Adequate crop field trial and processing data are available for all registered crops. There are no outstanding issues related to the use directions. Adequate methods are available for enforcement of the currently established tolerances in crops and lives tock. 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.

Conclusions: The current residue chemistry database is sufficient to support the registered uses; no additional residue chemistry data are required. During registration review the tolerancePropiconazole Human

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Page 9 of 35 

### expression will be changed to include parent only as recommended by the MARC

. In addition, HED is recommending to alter the significant figures in a number of tolerances to conform to

c urrent policy on establishing tolerances at two significant figures

. However, the residues of concern for risk assessment purposes will remain th e same.

Estimated Drinking Water Concentrations ( E DWCs )

Conventional Uses:

Propiconazole appears to be persistent and moderately mobile to relative ly immobile in most soil environments. In the aquatic environment, propiconazole degradation appears to be dependent solely on aqueous photolysis in the presence of photo sensitizers. In a soil environment, propiconazole dissipation appears to depend on incorporation or binding to soil organic matter content. Laboratory and terrestrial field dissipation data i ndicate that propiconazole is stable in soil and aqueous environments. However, in supplemental aquatic dissipation data using basin

irrigation and flow through irrigation systems in rice fields, propiconazole was found to be dissipated rapidly (t 1/2 

### < 5 days). Aqueous photolysis studies using sensitizers indicated rapid degradation (t 1/2 

### < 1 days) of propiconazole, which appears to be the case in rice fields. Furthermore, aquatic metabolism and dissipation studies indicate propiconazole dissipates by

inc orporation or binding into the organic matter content of soil/sediment. Propiconazole mobility in soil appears to be dependent on the soil's organic matter content. In general, propiconazole appears to be moderately mobile (Kd < 5) in soils with a low org anic matter content (< 1 %). However, in soils with higher organic matter content (> I %), propiconazole appears to be relatively immobile (Kd > 5). Therefore, propiconazole may reach ground water in soils with low organic contents. Propiconazole may also contaminate surface water through off

site runoff and spray drift.

The drinking water residues were provided by the Environmental Fate and Effects Division (EFED). in the following memorandum: “Drinking Water Assessment for Proposed New Uses of Propicona zole on Dill, Radish, Leafy Brassica Subgroup SB, Watercress, Ti palm and Crop Group conversions for Stone Fruit Group 12

- 12 and Tree Nut Group 14

- 12.” (I. Abdel

- Saheb, 05/27/15, D423648) and incorporated directly into th e most recent dietary assessment. The highest estimates from ground water (acute, 37.9 ppb and chronic, 35.1 ppb) are directly entered into the exposure model to assess the contributions from drinking water.

Antimicrobial Uses:

The drinking water exposure assessment conducted for the c onventional uses would be expected to result in higher potential residues in drinking water than would result from an assessment of

the antimicrobial uses. Therefore, no drinking water exposure assessment from the antimicrobial uses is anticipated to be c onducted for the propiconazole registration review.Propiconazole Human

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### Dietary Exposure

Conventional Uses:

Screening level acute and refined chronic dietary and drinking water exposure and risk assessments were recently conducted (T. Morton, D 426495

, 12 / 1 /2015) using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database DEEM

- FCID, Version 3.16, which incorporates consumption data from USDA’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). This dietary survey was

conducted from 2003 to 2008.

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

level of concern for t he general population and all population subgroups. At the 95 th 

### percentile, the exposure to the general U.S. population is 26 % of the aPAD; the highest exposed subgroup (Children 1

- 2 yrs old) is 84% of the aPAD. The exposure to the general U.S. populati on is 8 % of the cPAD, and the most highly exposed subgroup (Children 1

- 2 yrs old) is 25 % of the cPAD. A dietary exposure assessment for the free triazole or conjugated triazoles was also recently updated ( T. Morton, D426492, 4/9/15)

.

Antimicrobial Uses:

EPA has not established tolerances or tolerance exemptions for residues for the antimicrobial uses of propiconazole. Propiconazole has not been cleared as a food additive by the US Food and Drug Administration (US FDA) under the Federal Food, Drug, and Cosmetic Act (FFDCA) Section 409 (including the antimicrobial uses on paper and plastic).

Although there are registered antimicrobial uses that could result in indirect food contact, including a use on mushroom trays, these uses are expected to resul t in minimal dietary exposure compared to the conventional agricultural uses of propiconazole. There is also an existing tolerance for residues in/on mushrooms based on the conventional use pattern, which will adequately account for any potential residues due to the antimicrobial use. Additionally, the conventional agricultural uses of propiconazole do not result in dietary exposure risks of concern. Therefore, a dietary exposure assessment has not been conducted for the antimicrobial uses of propiconazole.

Conclusions for Dietary Exposure

The Agency does not anticipate the need for a revised dietary assessment during Registration Review unless dietary exposure models or the Estimated Drinking Water Concentrations (EDWCs) are updated.Propiconazole Human

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### Residential Exposure

Conventional Uses

All registered residential uses for propiconazole (ornamentals, lawns/turf, paint) have been reassessed using the 2012 Residential SOPs (J. Miller, D403629, 11/15/12 ). There is potential

for both handler (dermal and inhalation ) and post

- application (dermal and incidental oral) exposures. Residential risk estimates were not of concern (MOE s are > 100), with the lowest handler MOE of 500 resulting from application to turf using a hose

- end sprayer; the lowest post

application MOE of 100 resulted from combined dermal and incidental oral exposure for children (1 to <2 years old ) contacting treated turf.

In conjunction with the 2007 40 CFR Part 158 Data Requirements, HED typically requires

submission of a turf transferable residue (TTR) study in order to determine exposure and risk

associated with contacting treated turf. The estimated residential turf po st

- application exposure using default TTR values for propiconazole is not minimal in comparison to the level of concern. The calculated MOE is not greater than 10 times higher than the level of concern, with the lowest

combined MOE = 100 compared to the L OC of 100. Future refinements of this post

- application

exposure for propiconazole are anticipated in order to incorporate new TTR data and to incorporate any advances in EPA risk assessment methodology

. Therefore, EPA is requiring the

40CFR TTR data to f

acilitate any necessary exposure assessment refinements and to further

EPA’s general understanding of the availability of turf transferable pesticide residues.

Residential bystander exposures resulting from off

- site transport (e.g., spray drift or volati lization) may occur as a result of applications of propiconazole. The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered con currently. This document

outlines the quantification of indirect non

- occupational exposure to drift. In terms of volatilization, the Agency has developed a Volatilization Screening Tool and a subsequent

Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

OPP

- 2014

- 0219 ). During Registration Review, the Agency will utilize this analysis to determine

if data (i.e., flux studies, route

- speci fic inhalation toxicological studies) or further analysis is required for propiconazole.

Antimicrobial Uses

Residential handler dermal and inhalation exposures to propiconazole are anticipated to be assessed for the application of treated paints and stains. The residential exposure scenarios applicable to this use include applicator brush/roller and airless sprayer

. The Agency will likely

use brush/roller data submitted from the Antimicrobial Exposure Assessment Task Force (II) from the RED data call in, but the Agency anticipates need ing product use information for paints and stains for registration review (875.1700)

. The Agency does not anticipate assessing p ost

application/bystander inhala tion exposures and MOEs for use of paints (vapor exposure to adults and children) since the vapor pressure i s low (e.g., <1E

- 6 mm Hg).

Wood products commercially treated with end use products containing propiconazole may be

used for decks and children’s play sets, and therefore, residential post

- application exposure concerns may exist for dermal and incidental ingestion routes. Based on the potential concernsPropiconazole Human

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Page 12 of 35 

### from the past assessment, the Agency required wipe studies (Series 875.2300) in the RED to

meas ure residues from treated decks at the highest wood retention rate for propiconazole. The Agency received an acceptable residue study from the RED Data Call

- in (D405090). However, the agency also anticipates the need to require product use (875.2700) info rmation to clarify the maximum retention rate for wood preservative uses in registration review.

On March 8, 2006, the Agency published a Federal Register Notice announcing receipt of a request to cancel apparel, furnishings (except shower curtains), and carpet fiber applications of propiconazole and EPA issued cancellation orders for these uses on May 26, 2006. However, the Agency has identified some product labels that still have these uses. EPA is working with registrants to remove these uses; therefore , the apparel, furnishings (except shower curtains), and carpet fiber uses will not be considered in registration review.

Conclusions of Residential Exposure Assessment

Conventional Uses : During Registration Review, HED anticipates updat ing the residential

assessments to reflect incorporation of the required chemical

- specific TTR data . The need for spray drift and volatilization risk assessment for propiconazole will also be examined during Registration Review.

Antimicrobial Uses : AD anticipates need ing new product use information (875.1700) for handler exposures from paints and stains in registration review. AD also anticipates need ing new product use information (875.2700) to clarify exposures and retention rates of wood preservative

used to t reat decks and playsets. AD will likely use proprietary handler exposure data submitted

from the RED data call

- in for paints and stains and proprietary post

- application wood residue data submitted from pressure treated wood decks and playsets to conduct u pdated assessments.

Aggregate Risk Assessment

Currently, aggregate risks from propiconazole are not of concern. For adults, the short

- term residential dermal MOE estimated from post

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

, t his assessment is considered

conservative since the short

- term endpoints are based on a conservative LOAEL (Lowest Observed Adverse Effect Level) that is 3x higher than the NOAEL. Further, the assessment it is

based on a combination of tolerance

- level residues and reliable data on av erage field trial

residues and 100 PCT (percent crop treated) , conservative assumptions in the ground and surface water modeling, and conservative assumptions to assess post

- application exposure of children as well as incidental oral exposure of toddlers. Additionally, the assessment could be further refined by using PCT estimates and anticipated residues for all crops. Accordingly, even though this

MOE for children 1

- 2 years old is slightly below the target MOE of 100, the difference is small

and is more t han offset by the conservative exposure assumptions and therefore not of concern. Specifically, it aggregates the short

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

- term aggregate assessment is co nsidered very conservative in that the residential incidental oral post

- application exposure was calculated by combining screening level assessments (which by themselves already have conservative estimates). The chronic dietary exposure estimate is based o n average field trial residues,Propiconazole Human

- Health Assessmen t Scoping Document D 429076

Page 13 of 35 

### tolerance level residues and 100 percent crop treated. The highest average percent crop treated reported by BEAD in the April 2015 SLUA was 55%. In addition, the scenarios for hand to mouth activity on turf and turf high c ontact activity dermal exposure both use conservative default assumptions. A turf transferable residue study is unavailable but being requested from the registrant for registration review of propiconazole. In all probability this study will reduce

exposu re estimates for both of these pathways. The only scenario that is expected to result in potential intermediate

- term exposure to propiconazole is post

- application exposure to children from wood treatment, which is from an antimicrobial use. However, this scenario is likely to be refined based on newly submitted dislodgeable wood residue data received from the RED data

call

- in.

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

Conclusions:

As part of Registration Review, updated aggregate risk assessments are anticipated to be needed to reflect revised dietary or residential exposure estimates.

Occupational Exposure

Conventional Uses

Occupational handler and post

- application exposures are expected based on the registered uses of propiconazole. Propiconazole is currently formulated as liquid (emulsifiable, soluble, and

flowable conce ntrates packaged as “mix

- your

- own” and “ready

- to

- use” (RTU) products) and wettable powder in water

- soluble packets (WP/WSP). Applications are made by air, groundboom, chemigation, airblast, post

- harvest treatment equipment, seed piece dip, tree injection, and handheld equipment (i.e., low

- pressure handwand and handgun sprayer). Application rates vary depending upon the crop or use

- site, but range from 0.112 pounds active ingredient per acre (lb ai/A) to 0.225 lb ai/A for agricultural crops, 0.37 lb ai/A f or ornamentals, and 1.8 lb ai/A for turf. Occupational exposure scenarios applicable to propiconazole range from

short

- term (1 to 30 days) to intermediate

- term (30 days to six months) duration.

The occupational handler assessments indicate that, fo r the registered uses, all of the potential

exposure scenarios provide combined (dermal + inhalation) margins of exposure (MOEs) greater
than or equal to the LOC of 100 at some level of personal protection and/or engineering control (K. O’Rourke, D428502, 08/16/15)

. The labels for most uses require chemical

- resistant gloves

in addition to baseline clothing attire of long pants, long sleeved shirt and shoes plus socks.

Several levels of postapplication exposure activities have been identified ranging from “low”

activities such as weeding and scouting in immature plants to very high exposure activities such

as harvesting or thinning fruit from trees. Adequate d islodgeable foliar residue (DFR) data have recently been submitted for peaches (MRID 44959701) and are not likely to alter the conclusions of the previous assessments ; additional DFR data are not needed at this time. U sing default DFR

residue estimates, the short

- and intermediate

- term postapplication assessments indicate that thePropiconazole Human

- Health Assessmen t Scoping Document D 429076

Page 14 of 35 

### MOEs reach the LOC of 100 on the day of application for all use scenarios. The restricted entry
interval (REI) listed on the applicable labels is 12 hours

, which is adequately protective

.

Antimicrobial Uses

For wood preservatives, occupational workers are exposed to propiconazole wood preservatives during wood treatment activities such as dip treatment, double vacuum, and pressure treatment, and remedial uses such as applying wood stains using a brush/roller and/or airless sprayer on decks. In addition, occupational w orkers could potentially become exposed through the dermal and inhalation routes from material preservatives from pouring liquids or from mists and vapors during metalworking applications (e.g., machinists).

New inhalation exposure data from Park, 2009 wi ll be used to assess inhalation exposure for the machinist assessment. Dermal exposure will use assumptions from the 2

- hand immersion model

from ChemSTEER.

Handler exposure data were required in the post

- RED GDCI to assess dermal and inhalation

exposure t o workers. Specifically, dermal exposure data (Guidelines 875.1100 and 875.1200)

was required for painters (brush/roller and airless sprayer) and workers handling treated wood (pressure and non

- pressure uses). Inhalation exposure data (Guidelines 875.1300 and 875.1400)

was required for painters (brush/roller and airless sprayer) and workers handling treated wood (pressure and non

- pressure uses). These data are still needed to assess post

- application dermal

and incidental ingestion risks associated with children contacting pressure treated wood decks or playsets. Since these data are outstanding, surrogate proprietary data can be used to conduct dermal and inhalation routes of exposure and assess both handler and post

- application activities of wood preser vatives (dip and spray sapstain treatments, and pressure treatments). Surrogate proprietary unit exposure data generated by the Antimicrobial Exposure Assessment Task Force II (AEATF) and Sapstain Industry Group (SIG) could be used for these wood treatment assessments. Both the AEATF and SIG require compensation for the proprietary use of their unit exposure data. Surrogate proprietary unit exposure data generated by the AEATF can also be used to assess material preservatives (machinists and liquid pour) a nd the paint and wood stain uses (brush/roller and airless sprayer).

The duration of exposure for most of the occupational uses is believed to be best represented by the short (1 to 30 days) and intermediate

- term (30 days to 6 months) durations since wor kers are expected to engage in work for longer durations. For the wood preservation and machinist use, the Agency anticipates long

- term durations.

Conclusions :

Conventional Uses

The occupational exposure database is adequate to support the Registration Review process. Based on a review of the registered labels and the most recent risk assessment, HED previously conducted occupational handler assessments for the occupational handl er scenarios anticipated for the registered uses of propiconazole. HED does not anticipate the need for a revised occupational assessment during Registration Review; however, policy changes may occur thatPropiconazole Human

- Health Assessmen t Scoping Document D 429076

Page 15 of 35 

### require incorporation, as well as inclusion of the required chemical

- specific turf transferrable residue (TTR) data identified for the residential exposure assessment.

Antimicrobial Uses

AD anticipates the need to conduct new occupational exposure assessments for registration review to support wood and material preservation uses. Occupational exposure assessments are needed based on proprietary exposure data received from the RED data call in and new application rates. The Agency will use new proprietary exposure data anticipated from the post

RED GD CI to assess metalworking, wood preservation, paint, and liquid pour exposures for a variety of different material preservative uses. For registration review, AD anticipates the need to require product use data (875.1700) to clarify uses (particularly the use of plastics), application rates (wood retentions), and application equipment (verify sapstain and wood pressure treatments).

Public Health

, Pesticide Epidemiology , and Human Incidence Data

For this evaluation, both the OPP Incident Data System (IDS) and the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System for Occupational Risk

- Pesticides (SENSOR) databases were consulted for pesticide incident data on the a ctive ingredient propiconazole (S. Recore, 9/15/15, D429078). The purpose of the database search is to identify potential patterns in the frequency and severity of the health effects attributed to. Propiconazole is not included in the AHS, and, therefore, this study does not provide information for this report.

Based on the relatively low frequency and severity of incident cases reported for propiconazole

in both IDS and SENSOR

- Pesticides there does not appear to be a concern at this time that

would warran t further investigation. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the risk

assessment.

International Harmonization

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

not appropriate and has recommended that the tolerance expression be revised to include only parent and all tolerances converted to parent only . This will be done at the time of the

r egistration review risk assessment.

The Codex Alimentarius Commission has established several maximum residue limits (MRLs) for propiconazole in/on various raw agricultural commodities. In addition, both Canada and Mexico have established MRLs for propic onazole in/on various commodities. The Codex and Mexican MRLs are expressed in terms of propiconazole. The Canadian MRLs are expressed in terms of combined residues of propiconazole and its metabolites containing the 2,4

- DCBA moiety. At this time, the U .S. tolerance expression is harmonized with Canada but not Codex

. Once the tolerance expression is changed to propiconazole only, the tolerance expression will be

harmonized with Codex.Propiconazole Human

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Page 16 of 35 

### Attachment F is a summary of the Canadian, Mexican, and Codex ma ximum residue limits (MRLs) for residues of propiconazole. As part of registration review, HED will reevaluate the Canadian, Mexican, and Codex MRLs and harmonize when possible.

Cumulative

Propiconazole is a member of the triazole

- containing class o f pesticides. Although conazoles act similarly in plants (fungi) by inhibiting ergosterol biosynthesis, there is not necessarily a relationship between their pesticidal activity and their mechanism of toxicity in mammals.

Structural similarities do not c onstitute a common mechanism of toxicity. Evidence is needed to establish that the chemicals operate by the same, or essentially the same, sequence of major biochemical events (EPA, 2002). In conazoles, however, a variable pattern of toxicological

respon ses is found; some are hepatotoxic and hepatocarcinogenic in mice. Some induce thyroid tumors in rats. Some induce developmental, reproductive, and neurological effects in rodents. Furthermore, the conazoles produce a diverse range of biochemical events including altered cholesterol levels, stress responses, and altered DNA methylation. It is not clearly understood whether these biochemical events are directly connected to their toxicological outcomes. Thus, there is currently no evidence to indicate t hat conazoles share common mechanisms of toxicity and EPA is not following a cumulative risk approach based on a common mechanism of toxicity for the conazoles. For information regarding EPA’s procedures for cumulating effects from

substances found to hav e a common mechanism of toxicity, see EPA’s website at http://www.epa.gov/pesticides/cumulative

.

Human Studies

The 2006 RED as well as the 2012 and 2015 risk assessments relied in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from PHED 1.1; the AHETF database; t he Outdoor Residential Exposure Task Force (ORETF) database; and the ARTF database, are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 1



### .

Environmental Justice

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

- Income Populations," http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf . The Office of Pesticide Programs (OPP) typically considers the highest potential exposures from the legal use of a pesticide when conducting human health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diets within the U.S., and people who may be exposed when harvesting crops. Should these high

1 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.htmlPropiconazole Human

- Health Assessmen t Scoping Document D 429076

Page 17 of 35 

### exposures indicate potential risks of concern, OPP will further refine the risk assessments to

ensure that the risk estimates are based on the best available information.

Risk Assessment Updates and Data Deficiencies

The risk assessment updates tha t may be required under Registration Review are summarized

below.

The following data deficiencies were identified:

 Toxicology: T he toxicology database for propiconazole is complete.

 Residue Chemistry: None

 ORE:

o For conventional uses: A turf transferable residue (TTR) study (Guideline 875.2100) is required in order to determine exposure and risk associated with

children contacting treated turf.

o For antimicrobial uses: AD will need product use (Guideline 875.1700) data for

handlers of paints a nd stains to clarify use rates. AD will also need product use (Guideline 875.2700) data to clarify exposures retention rates for wood preservatives used to treat decks and playsets.

EPA anticipates the following risk assessment updates during Registrati on Review:

 Toxicology: the Agency does not anticipate the need to revise the toxicological endpoints, points of departure, or safety factors for propiconazole during Registration

Review.

 Dietary Exposure: The Agency does not anticipate the need for a rev ised dietary assessment during Registration Review unless dietary exposure models or the Estimated Drinking Water Concentrations (EDWCs) are updated.

 Residue Chemistry: Update the tolerance expression.

 Aggregate Exposure : As part of Registration Review, updated aggregate risk assessments may be necessary to reflect revised dietary or residential exposure estimates.

 Occupational/Residential Exposure:

o For conventional uses: Revised occupational/residential risk assessment may be necessary to reflect the submitted TTR data as well as need for spray drift and

volatilization risk assessment.

o For antimicrobial uses: New occupational risk assessments will be necessary for worker exposure to the following antimicrobial uses:

- metalworking (machinists),

- wood preservation (sapstain and pressure treatment workers),

- painting and staining (airless sprayer and paintbrush applications), and

- material preservatives (liquid pour applications).

o New residential risk assessments will be necessary to for paint and stain (airless sprayer and paintbrush) applications.Propiconazole Human

- Health Assessmen t Scoping Document D 429076

Page 18 of 35 

### Attachment A: References Attachment B: Chemical Identity and Physicochemical Properties

Attachment C: Toxicological Endpoint Selection Table

Attachment D: Hazard Profile Table Attachment E: Guideline Data Requirements

Attachment F: International Residue LimitsPropiconazole Human

- Health Assessmen t Scoping Document D 429076

Page 19 of 35 

### Attachment A: References

Author Barcode/TXR # D ate Title

S. Recore D429078 9/15/15 Propiconazole : Tier I (Scoping) Review of Human Incidents and Epidemiology

T. Morton D 426494 12 /1/15 Propiconazole Human Health Risk Assessment for the New Uses of Propiconazole on dill, leafy brassicas crop subgroup 5B, ti palm, watercress, and quinoa, along with expansion to fruit, stone, group 12

- 1 2; except plum, and nut, tree, group 14

- 12.

T. Morton D426495 12 /1/15 Propiconazole: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk

Assessments for the New Use of Propiconazole on Dill, Crop subgroup 5B Leafy Brassica greens, Radish, Ti Palm, Watercress, and the Expansion of Fruit, stone, group 12

- 12, and Nut, tree, group 14

- 12.

K. O’Rourke D428502 8/16/15 Propiconazole. Occupational and Residential Exposure Assessment for Proposed New Uses on Dill, Brassica Leafy Greens, Radish, Ti Palm, Watercress, Stone Fruit,

and Tree Nuts.

T. Morton D426492 &

D426496 4/9/15 Common Triazole Metabolites: Updated Dietary (Food + Water) Exposure and Risk Assessment to Address The New Section 3 Registrations For Use of Propiconazo le on Tea, Dill, Mustard Greens, Radish, and Watercress; Use of Difenoconazole on Globe Artichoke, Ginseng and

Greenhouse Grown Cucumbers and Conversion of the

Established Foliar Uses/Tolerances for Stone Fruit and Tree Nut Crop Groups to Fruit, Stone, Gro up 12

- 12 and the Nut, Tree, Group 14

- 12.; and Use of Flutriafol on Hops

. T. Morton 426493 &

426497 4/9/15 Common Triazole Metabolites: Updated Aggregate

Human Health Risk Assessment to Address The New Section 3 Registrations For Use of Propiconazole on T ea, Dill, Mustard Greens, Radish, and Watercress; Use of Difenoconazole on Globe Artichoke, Ginseng and

Greenhouse Grown Cucumbers and Conversion of the

Established Foliar Uses/Tolerances for Stone Fruit and Tree Nut Crop Groups to Fruit, Stone, Group 12

- 1 2 and the Nut, Tree, Group 14

- 12.; and Use of Flutriafol on Hops

. James S Miller D403629 &

406831 11/15/12 Propiconazole: Assessment of Aerial; Chemigation; and Groundboom Applications to Sugarcane and Cereal Grains (Wheat; Barley; Oats; Rye, and Triticale).

James S Miller D390250 2/16/12 Propiconazole : Worker Risk Analysis for new uses on Beans (crop group 06), Tomatoes (crop group 08), Citrus (crop group 10), and Stone Fruit (crop group 12).

Y. Donovan D329668 6/28/06 Propiconazole: Phase 4, HED Chapter of the Re

registration Eligibility Decision Document (RED).

Y. Donovan D329394 06/15/06 Propiconazole (122101): Reregistration Eligibility Decision (RED) Document; Revised Residue Chemistry

Considerations T. Leighton D324052 2/1/06 Revised Occupational and Residential Exposure Assessment of the Antimicrobial Uses to Support the Reregistration Eligibility Decision (RED) Document.Propiconazole Human

- Health Assessmen t Scoping Document D 429076

Page 20 of 35 J. Tao D365243 11/23/09 Propiconazole: Toxicological Review and Dermal Absorption Factor Determination for the Proposed Increase in Application Rate for Use in Paints and Stains.

N. Mottl D64956 4/21/10 Propi

- Shield and WocosenTM: Occupational and Residential Exposure Assessment for a Proposed Product with Non

- Food New Antimicrobial Uses (emul sions, adhesives, binders, latex paints, plastics and plastic coatings) of Propiconazole Proposed

Products T. Leighton D393026 8/23/11 Propiconazole: Update of the Paint and Stain Risk Assessment based on New Dermal Absorption Data.

N. Mottl D405090 3/13/14 Review of the Study: “ Determination of Dislodgeable Propiconazole Residues from Spruce and Southern Yellow Pine (SYP) Boards Pressure Treated with Formulation

AWP

- 0911

- 4”Propiconazole Human

- Health Assessmen t Scoping Document D 429076

Page 21 of 35 

### Attachment B

.

Nomenclature of Propiconazole Compound

Common name Propiconazole Company experimental

names CGA

- 64250

IUPAC name 1

- [2

- (2,4_dichlorophenyl)

- 4

- propyl

- 1,3

- dioxolan

- 2

- ylmethyl]

- 1 H

- 1,2,4_triazole

CAS name 1

- [[2

- (2,4

- dichlorophenyl)

- 4

- propyl

- 1,3

- dioxolan

- 2

- yl]methyl]

- 1 H

- 1,2,4

- triazole

CAS # 60207

- 90

- 1

End

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

- 617

Chemical structure of
1,2,4

- Triazole (1,2,4

- T)

Chemical structure of Triazolylalanine (TA)

Chemical structure of Triazolylacetic acid (TAA)

Physicochemical Properties of Technical Grade Propiconazole

. Parameter Value Reference

Boiling point 120 C at 1.9 Pa, >250 0 C at 101.325

kPa MRID No. 43698701

pH 4.9 at 25 0 C (1% aqueous dispersion) MRID No. 43698701 Density 1.289 g/cm 3 at 20 0 C MRID No. 43698701 Water solubility 0.10 g/L at 20 0 C MRID No. 41720301

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

- octanol. hexane = 47 g/L MRID No. 42030201
Vapor pressure 4.2 x 10

- 7 mm Hg at 25 0 C MRID No. 41720301 Dissociation constant (pK

a ) 1.09 MRID No. 43698701 Octanol/water partition coefficient Log(K OW ) 3.72 at pH 6.6 and 25 0 C MRID No. 43698701 UV/visible absorption spectrum (8max, nm) Not available MRID No. 40583703Propiconazole Human

- Health Assessmen t Scoping Document D 429076

Page 22 of 35 

### Attachment C :

Summary of Toxicological Doses and Endpoints for Propiconazole for Use in Dietary Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty/F

QPA Safety

Factors RfD, PAD, LOC

for Risk

Assessment Study and Toxicological Effects

Acute Dietary (General Population) NOAEL =

30 mg/kg/day UF A = 10X

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

mg/kg/day

aPAD = 0.3 mg/kg/day Acute neurotoxicity study Rat MRID 46604601

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

Acute Dietary (Females 13

- 49 years) NOAEL =

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

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

mg/kg/day

aPAD = 0.3 mg/kg/day Developmental Study

- Rat MRID 40425001

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

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

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

10 mg/kg/day UF A = 10X

UF H =10X FQPA SF= 1X Chronic RfD = 0.1

mg/kg/day

cPAD = 0.1mg/kg/day 24

- month carcinogenicity study on CD

- 1 mice.

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

neoplastic liver effects (increased liver weight

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

Incidental Oral

short

- term (1

- 30 days) NOAEL=

30 mg/kg/day UF A = 10X

UF H =10X Residential LOC

for MOE = 100 Occupational LOC

for MOE = 100 Acute Neurotoxicity Study

- Rats MRID

46604601 LOAEL = 100 mg/kg/day based on clinical signs of toxicity (piloerection in one male, diarrhea in one female, tip toe gait in 3 females).

Incidental Oral

Intermediate

- term (1

- 6 months) NOAEL=

10 mg/kg/day UF A = 10X

UF H =10X Residential LOC

for MOE = 100 Occupational LOC

for MOE = 100 24 Month carcinogenicity Study

- Mice MRID

00129918

LOAEL = 50 mg/kg/day based on non

neoplastic liver effects (increased liver weight

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

Dermal Short Term (1

- 30 days)

DAF * = 40% NOAEL=

30 mg/kg/day UF A = 10X

UF H =10X Residential LOC

for MOE = 100 Occupational LOC

for MOE = 100 Acute Neurotoxicity Study

- Rats MRID

46604601 LOAEL = 100 mg/kg/day based on clinical signs of toxicity (piloerection in one male, diarrhea in one female, tip toe gait in 3 females).

Dermal

Intermediate Term (1

- 6 months) and Long Term (>6 months) DA F * = 40% NOAEL=

10 mg/kg/day UF A = 10X

UF H =10X Residential LOC

for MOE = 100 Occupational LOC

for MOE = 100 24 Month carcinogenicity Study

- Mice MRID

00129918

LOAEL = 50 mg/kg/day based on non

neoplastic liver effects (increased liver weight

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

Inhalation Short Term (1

- 30 days) NOAEL=

30 mg/kg/day UF A = 10X

UF H =10X Occupational LOC

for MOE = 100 Acute Neurotoxicity Study

- Rats MRID

46604601 LOAEL = 100 mg/kg/d ay based on clinical signs of toxicity (piloerection in one male, diarrhea in one female, tip toe gait in 3 females).Propiconazole Human

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Page 23 of 35 Summary of Toxicological Doses and Endpoints for Propiconazole for Use in Dietary Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty/F

QPA Safety

Factors RfD, PAD, LOC

for Risk

Assessment Study and Toxicological Effects

Inhalation

Intermediate Term (1

- 6 months) and Long Term (>6 months) NOAEL=

10 mg/kg/day 24 Month carcinogenicity Study

- Mice MRID

00129918

LOAEL = 50 mg/kg/day based on non

neoplastic liver effects (increased liver weight

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

Cancer (all routes) Classification: Group C, possible human carcinogen, RfD approach for risk characterization, TXR No.

0009771

* DAF of 1% and 26.6% were used for paints and stains, respectively. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and us ed to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adver se effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapola tion 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 critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposur e. LOC = level of concern. N/A = not applicab le DAF = Dermal Absorption Factor

Propiconazole Acute Toxicity Profile: February 2015

Guideline

No. Study Type MRID # Results Toxicity Category

870.1100 Acute Oral Toxicity

– rat 00058591 (1978) LD 50 =1517 mg/kg III

870.1200 Acute Dermal Toxicity

- rabbit 00058596 (1979) LD 50 = >4000 mg/kg III

870.1300 Acute Inhalation Toxicity

– rat 41594801 (1988) LC 50 = >5.84 mg/L IV

870.2400 Acute Eye Irritation 00058597 (1978) Corneal opacity reversed in 72 hrs III

870.2500 Acute Dermal Irritation 00058598 (1978) No irritation IV

870.2600 Skin Sensitization 44949501 (1999) dermal sensitizer

-Propiconazole Human

- Health Assessmen t Scoping Document D 429076

Page 24 of 35 

### Attachment D :

Subchronic, Chronic and Other Toxicity Profile: Propiconazole: February 2015 Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3100

90

- Day Feeding Study in Rat 00058606 (1979)

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

NOAEL = 1200 ppm in males (76 mg/kg bw/day) and 240 ppm in females (16.82 mg/kg bw/day).

870.3100

3

- month oral toxicity study

- mice 42050501,(1991)

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

NOAEL is 20 ppm in males (2.7 mg/kg/day) and 500 ppm in females (85 mg/kg/day).

870.3100

3

- month oral

- male

mice 42050502 (1991)

Ac ceptable/Guideline 0, 20, 500, 850, 1450 ,2500

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

sacrifices.

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

870.3100

3

- month oral

- male

mice. 45215801 (1997)

Supplement to MRID

42050502: Reexamination

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

LOAEL

870.3150

3

- month dog (dietary) 00058607(1979)

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

the stomach.

NOAEL is 50 p pm (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 (Hyperkeratosis, acanthosis, mild dilation of blood vessels and

mononuclear cel ls and/or heterophils in the proximal dermis). No systemic toxicity was reported.

NOAEL for skin lesions not established

870.3465 28/90

- Day Inhalation Waived per HASPOC TXR 0056387

870.3700a Developmental Toxicity

- Rat 40425001(1987)

Acceptable/guideline 0, 30, 90 or 300 mg/kg/day Maternal Toxicity LOAEL = 300 mg/kg/day based on severe clinical toxicity (ataxia, coma, lethargy, prostation, labored respiration and salivation)

NOAEL = 90 mg/kg/day Developmental Toxicity LOAEL = 90 mg/kg/day based on increased incidence of rudimentary ribs, cleft palate malformations (0.3%) unossified sternebrae, as well as increased incidence of shortened and absent renal papillae.

NOAEL = 30 mg/kg/dayPropiconazole Human

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Page 25 of 35 Subchronic, Chronic and Other Toxicity Profile: Propiconazole: February 2015 Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

Non

- guideline Developmental Toxicity

- Ra t 40425002 (1987)

Acceptable/non

- guideline 0 or 300 mg/kg/day Cleft palate: 2/2064 fetuses of dosed animals vs. 0/1222 controls (laboratory historical control incidence: was 0/5431). This confirms findings of cleft palate noted in above study (MRID

40425 001). Severe clinical toxicity in the treated animals (ataxia, coma, lethargy, prostration, 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 body weight gain and decreased food consumption during the dosing period

NOAEL = 100 mg/kg/day Developmental Toxicity

LOAEL = 400 mg/kg/day based on increased incidence of fetuses

/litters with 13 th rib and increased abortions.

NOAEL = 250 mg/kg/day

870.3800

2

- Generation reproduction

- Rat 00151514 (1985)

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

N OAEL = 8 mg/kg/day Reproductive Toxicity

LOAEL =>2500 ppm (>263 mg/kg/day, HDT) Offspring Toxicity LOAEL = 2500 ppm (192

- 263 mg/kg/day based on decreased offspring survival and body weights and an increased incidence of hepatic cellular swelling

NOAEL = 500 ppm (43

- 52 mg/kg/day)

870.4100

12

- Month Chronic Oral Toxicity (dietary)

- Dogs 00151515 (1985)

Acceptable/guideline 0, 5, 50 or 250 ppm (0, 0.12, 1.25, or 6.25 mg/kg/day) LOAEL = 250 ppm (6.25 mg/kg/day), based on hyperemia of the

stomach in males (indicating mild irritation of the mucosa).

NOAEL is 50 ppm (1.25 mg/kg/day)

870.4100

24

- Month 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 ga in in both males and females.

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

870.4200

24

- Month Carcinogenicity in

Mice 00129570 (1982 )

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

- neoplastic liver effects (increased liver weight in males and increase in liver lesions (masses/raised areas/ swellings/nodular areas mainly).

NOAEL = 100 ppm (10 mg/kg/d ay). Liver tumors at 2500 ppm in male mice.Propiconazole Human

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Page 26 of 35 Subchronic, Chronic and Other Toxicity Profile: Propiconazole: February 2015 Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.4200

18

- month carcinogenicity study

- male CD

- 1 mice 44381401 (1997)

Acceptable/guideline 0, 100, 500 or 850 ppm (0, 11, 59 or 108 mg/kg/day) LOAEL = 500 ppm (59.0 mg/kg/day) for males, based on hepatotoxic ity (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. Ade quate dosing based on body weight gain and hepatotoxic effects seen at 500 and 850 ppm. Subsequently, the Registrant submitted additional control data on five groups of CD

- 1 male mice generated within the approximate time frame of the original study and i n 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.

87 0.6200 Acute neurotoxicity

in rats 46604601 (2005)

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

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

NOAEL = 30 mg/kg.

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

NOAEL for neurobehavioral toxicity = 100 mg/kg

870.6200b

90

- Day Neurotoxicity Screening Battery (rat) 49300503 (2014)

Acceptable/guideline ♂ 0, 200, 600, or 3500 ppm

0,13, 38, an d 222 mg/kg bw/day, ♀ 0, 200, 600, or 1500 ppm 0, 15, 45, and 111 mg/kg bw/day, LOAEL in males = 3500 (220 mg/kg/day) based on significant reductions in body weight gain and food consumption

NOAEL in males = 600 ppm (38 mg/kg/day).

NOAEL in females = 1500 ppm (111/kg/day), the highest dose

tested.

LOAEL in females was not established.

870

- 5100

Bacterial reverse

mutation 00058601 (1979)

Unacceptable

25

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

- 9 activation. Test material purity no t specified, not tested up to cytotoxic dose.

870

- 5300

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

Acceptable/guideline

1.16

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

870

- 5385 (bone marrow

chromosomal aberration)

- Chinese

hamsters 00058603 (1979)

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

levels tested.

870

- 5550

Unscheduled DNA synthesis in human fibroblasts, 00133347 (1982)

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

870

- 5550

Unscheduled DNA synthesis in primary rat hepatocytes 00133348 (1982)

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

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Page 27 of 35 Subchronic, Chronic and Other Toxicity Profile: Propiconazole: February 2015 Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870

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

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

inhibitory effect on yeast cell growth.

870.5450 Dominant lethal assay

in mice 00058602 (1979)

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

870.7485

Metabolism and pharmacokinetics (Rat) 42403901 (1983)

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

- 14 C at the

triazole

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

870.7485

Metabolism and pharmacokinetics (Rat) 41326701 (1989)

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

14 C)

- Phenyl label or 0.5 mg/kg/day unlabeled for 14 days followed with 0.5

mg /kg labeled or single oral dose 50 mg/kg labeled Oral or iv routes resulted in similar patterns of 14 C elimination suggesting biliary excretion. >90% of 14 C excreted after 168 hours mostly within the 48 hrs. Females eliminated more in the urine

than in t he feces and vice versa for males in the orally dosed groups. No significant differences were seen in the excretion pattern or were seen between the low and high dose groups or the repeated dosing groups. Extensively metabolized (oxidative): 24 and 47

met abolites in urine and feces, respectively. Parent (27

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

870.7485

Metabolism and pharmacokinetics (Rat) 00074506 (1979)

00074507 (1981) Acceptable/guideline

triazole

- [3,5

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

- [U

14 C] single oral dose of 32.5 mg/kg to male rats. Study focused on urinary and fecal metabolites. Similar metabolic profiles for the two labels suggesting that the bridge between the phenyl ring and the triazole ring remained intact. Metabolic pathway: cleavage of dioxolane ring through the oxidation of the propyl side chain, with subsequent dechlorination and conjugation and through the oxidation of the propyl side chain. The metabolic profile of both urine and feces appear to be similar except for the presence of parent material in the feces while the urine had conjugated phenolic metabolites.

870.7485

Metabolism and pharmacokinetics (Mouse) 00164795 (1986)

Acceptable/non

- guideline

Male and female mice fed

in the diet for 21 days at 5, 100 or 2500 ppm propiconazole followed by phenyl

- [U

14 C] single oral dose at corresponding

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

- [U

14 C]compound Mice pre

- treated with the unlabeled CGA 64250 excreted 83

- 103%

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

the first 24

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

- 3.7x of the feces). The male rats excreted nearly equal amounts of the radioactivity in urine (48%) and feces (54%). Mo use 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 ring to a greater ex tent (70% & and 40% for males and females, respectively) than do male rats (30%).

870.7600 Dermal penetration (Rat) 42415701 (1986)

Acceptable/guideline Propiconazole 14 C at the

triazole

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

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Page 28 of 35 Subchronic, Chronic and Other Toxicity Profile: Propiconazole: February 2015 Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.7600 Dermal penetration (Rat) 47736503 (2008) Acceptable/guideline Propiconazole (99.0% 14 C at

the triazole

- [3,5] position) in a commercial latex paint or alkyd stain solutions 0.45, 1.6, or 4.5 mg [ 14 C]

- propiconazole/kg ( corresponding to 0.1, 0.35

, or 1.0% [ 14 C]

- propiconazole prepared in latex paint or alkyd stain [ w/w ] ) A dermal absorption factor (DAF) of 1% and 26.6% was determined following 10

- hour exposure of propiconazole for commercial paints and stains, respectively.

870

- 7800 Immunotoxicity MRID 48799701, 2012

Waiver Request Waived (TXR 0056761 and TXR 0056730).

Non

- guideline Special study 00151517 (1984)

Acceptable/non

- guideline 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 li ver similar to phenobarbital (500 ppm), a known liver tumor

promoter.

Non

- guideline Special study

Mechanistic studies: Hepatic biochemical

parameters

- Mouse 45215803 (1998)

Acceptable/non

- guideline

Male CD

- 1 mice, 6/dose propiconazole at 0, 850 or

25 00 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

- ethoxyresorufin activity, indicative of CYP1A1 ind uction was increased slightly but not to the extent observed following true induction. Lauric acid hydroxylation, specifically a result of peroxisome proliferation, was not induced by propiconazole. However, the activity of 7

- pentoxyresorufin

- O

- dealkylas e, associated with CYP2B or PB

- type induction, was clearly increased 30

- 55

- fold by propi conazole.

Microsomal coumarin 7

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

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

with PB

- type induction. Propiconazole resulted in a marked

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

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

- type induction of cytochrome P450 activity. The effects of propiconazole treatment on mouse liver weights and liver enzymes were comparable to those produced by phenobarbital,

a k nown 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.Propiconazole Human

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Page 29 of 35 Subchronic, Chronic and Other Toxicity Profile: Propiconazole: February 2015 Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

Non

- guideline Special study

Mechanistic studies:

He patocellular proliferation

- Mouse 45215802 (1999)

Acceptable/non

- guideline

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 i n the centrilobular hepatocytes with mild effects in the midzonal hepatocytes). Liver necrosis and cytoplasmic vacuolation were noted. Increased mitotic activity was observed in all groups. Minimal to moderate hepatocellular necrosis of hypertrophic sing le or focal cells was found predominately in the high dose and PB group. Treatment with propiconazole or PB induced a >1000% increase in BrdU

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

the number of BrdU

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

BrdU

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

- and dose

related proliferation in the liver followed by a sustained treatment

related hypertrophy in a manner simil ar 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 of hepatocellular hypertrophy.Propiconazole Human

- Health Assessmen t Scoping Document D 429076

Page 30 of 35 

### Attachment E :

Guideline Data Requirements: Propiconazole: February 2015

Test Technical
Required Satisfied
870.1100 Acute Oral Toxicity 870.1200 Acute Dermal Toxicity 870.1300 Acute Inhalation Toxicity 870.2400 Primary Eye Irritation 870.2500 Primary Dermal Irritation

870.2600 Dermal Sensitization yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes 870.3100 Oral Subchronic (rodent) 870.3150 Oral Subchronic (non

- rodent)

870.3200 21

- Day Dermal

870.3250 90

- Day Dermal

870.3465 28/90

- Day Inhalation yes

yes

yes

no waived * yes

yes

yes

-

- 870.3700a Developmental Toxicity (rodent) 870.3700b Developmental Toxicity (non

- rodent) 870.3800 Reproduction yes

yes

yes yes

yes

yes
870.4100a Chronic Toxicity (rodent) 870.4100b Chronic Toxicity (non

- rodent) 870.4200a carcinogenicity (rat) 870.4200b carcinogenicity (mouse) 870.4300 Chronic/carcinogenicity yes

yes

yes

yes

yes yes

yes

yes

yes

yes 870.5100 Mutagenicity

— Gene Mutation

- bacterial 870.5300 Mutagenicity

— Gene Mutation

- mammalian 870.5375 Mutagenicity

— Structural Chromosomal Aberrations 870.5900 Mutagenicity

— Other Genotoxic Effects yes

yes

yes

yes yes

yes

yes

yes 870.6100a Acute Delayed Neurotox. (hen)

870.6100b 90

- Day Neurotoxicity (hen) 870.6200a Acute Neurotox. Screening Battery (rat)

870.6200b 90

- Day Neuro. Screening Battery (rat) 870.6300 Develop. Neuro no

no

yes

yes

no -

- yes

yes

- 870.7485 General Metabolism

870.7600 Dermal Penetration 870.7800 Immunotoxicity yes

yes waived ** yes

yes

-
* waived per HASPOC TXR 005638 ** waived per HASPOC TXR 0056761 and TXR 0056730.Propiconazole Human

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Page 31 of 35 

### Attachment F 

## :

Propiconazole (122101)

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :

US Canada Mexico 1 Codex 2

40 CFR 180.434:

Plant/Livestock: combined residues of the fungicide 1

- [[2

- (2,4

- dichlorophenyl)

- 4

- propyl

- 1,3

- dioxolan

- 2

- yl] methyl]

- 1H

- 1,2,4

- triazole and its metabolites determined as 2,4

- dichlorobenzoic acid and expressed as parent compound 1

- [[2

- (2,4

- diclorophenyl)

- 4

- propyl

- 1,3

- dioxolan

- 2

- yl] methyl]

- 1 H

- 1,2,4

- triazole, including all metabolites containing the 2,4

- dichlorophenyl

- 1

- methyl substituted moiety Plant and animal

commodities: propiconazole

The residue is fat

soluble.

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

US Canada Mexico 1 Codex 2

§180.434 (a) (1)
Almond, hulls 7.0

Banana 0.2 0.2 bananas, plantains 0.1 Barley, bran 6.0 Barley, grain 3.0 0.05 0.2 Barley, hay 30

Barley, straw 20 8 barley straw and fodder, dry

Bean, dry seed 0.40 0.1 0.07 soybean, dry

Bean, snap 0.70 0.25 edible podded ( jackbeans,

moth beans, runner beans, snap beans, soybeans, sword beans, wax beans, yardlong beans)

Bean, succulent

shelled 0.10 0.05 succulent shelled (broad beans, cowpeas, lima beans) Beet, garden, roots 0.30 0.3 Beet, garden, tops 5.5 5.5 Beet, sugar, dried pulp 1.0 Beet, sugar, molasses 1.5 1.5 Beet, sugar, roots 0.3 0.3 0.02 sugar beet
Beet, sugar, tops 10 Bushberry, subgroup

13

- 07B 1.0 1 1.3 lingonberries 0.3 cranberry

Caneberry, subgroup

13

- 07A 1.0 1

Carrot, roots 0.25 0.25

Cattle, fat 0.05 0.05 0.01 (*) mammalian fats (except milk fats) (prop o sed) Cattle, kidney 2.0 2 0.5 edible offal (mammalian) Cattle, liver 2.0 2Propiconazole Human

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Page 32 of 35 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :

US Canada Mexico 1 Codex 2

Cattle, meat 0.05 0.05 0.01 (*) meat (from

mammals other than marine mammals)
Cattle, meat byproducts, except liver and kidney 0.05 0.05

Cilantro, leaves 13
Citrus, oil 1000 1000 Corn, field, forage 12 Corn, field, grain 0.2 0.2 0.05
Corn, field, stover 30 Corn, pop, grain 0.2 02 0.05 Corn, pop, stover 30
Corn, sweet, forage 6.0
Corn, sweet, kernel plus cob with husks

removed 0.1 0.2 0.05

Corn, sweet, stover 30

Fruit, citrus, group 10

- 10 8.0 8 9 Po oranges, sweet, sour (including

orange

- like hybrids):

several cultivars

Fruit, stone, group 12, except plum 4.0 4 1 plums 5 peach Po 0.6 plums including prunes Po

Goat, fat 0.05 0.05 0.01 (*) mammalian fats (except milk fats) Goat, kidney 2.0 2 meat byproducts of goats 0.5 edible offal (mammalian) Goat, liver 2.0

Goat, meat 0.05 0.05 0.01 (*) meat (from

mammals other than marine mammals) Goat, meat byproducts, except liver and kidney 0.05 2 meat byproducts of goats 0.5 edible offal (mammalian) Grain, aspirated

fractions 110

Grass, forage 0.5 Grass, hay 0.5
Grass, straw 40 Hog, kidney 0.2 0.1 meat byproducts of hogs 0.5 edible offal (mammalian) Hog, liver 0.2

Horse, fat 0.05 0.05 0.01 (*) mammalian fats (except milk fats) Horse, kidney 2.0 2 meat byproducts of

horses 0.5 edible offal (mammalian) Horse, liver 2.0

Horse, meat 0.05 0.05 0.01 (*) meat (from

mammals other than marine mammals)

Horse, meat byproducts, except liver and kidney 0.05 2 meat byproducts of

horses 0.5 edible offal (mammalian)

Leaf petioles subgroup

4B 5.0 5Propiconazole Human

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Page 33 of 35 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :

US Canada Mexico 1 Codex 2
Low growing berry subgroup 13

- 07G, except cranberry 1.3 1.3

Milk 0.05 0.03 0.01 (*)

Mushroom 0.1 0.1 Nut, tree, group 14 0.1 0.1 0.02 (*) pecan Oat, forage 4.0 Oat, grain 3.0 0.05 Oat, hay 15

Oat, straw 10 8 oat straw and fodder, dry
Onion, bulb subgroup

3

- 07A 0.2 0.2

Onion, green, subgroup 3

- 07B 9.0 9

Parsley, fresh leaves 13 13 Parsley, dried leaves 35 35

Peanut 0.2 0.2 Peanut, hay 20 Peppermint, tops 10.0 10 Pineapple 4.5 4.5 0.02 (*) Pineapple, process

residue 7.0 0.02 (*)

Pistachio 0.1 0.1

Plum 0.60 1 0.6 plums including prunes Po Rapeseed subgroup

20A 0.30 0.02 rapeseeds (canola) 0.02 rapeseed

Rice, bran 15 15 Rice, grain 7.0 7
Rice, hulls 20
Rice, straw 18 Rye, bran 0.6 Rye, forage 9.0 Rye, grain 0.3 0.05 0.02

Rye, straw 10 15 rye straw and fodder, dry

Sheep, fat 0.05 0.05 0.01 (*) mammalian fats (except milk fats)

Sheep, kidney 2.0 2 meat byproducts of sheep 0.5 edible offal (mammalian) (proposed) Sheep, liver 2.0

Sheep, meat 0.05 0.05 0.01 (*) meat (from

mammals other than marine mammals) Sheep, meat byproducts, except liver and kidney 0.05 2 meat byproducts of sheep

Sorghum, grain, forage 12 Sorghum, grain, grain 3.5 3.5 Sorghum, grain, stover 15Propiconazole Human

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Page 34 of 35 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :

US Canada Mexico 1 Codex 2
Soybean, forage 11 Soybean, hay 30 5 soya bean fodder Soybean, seed 2.0 0.25 dry soybeans 0.07 soya bean (dry) Spearmint, tops 10.0 10 Sugarcane, cane 0.4 0.02 (*)

Tomato 3.0 3 3 Po Vegetable, foliage of legume, group 7 30

Wheat, bran 0.6 Wheat, forage 15 Wheat, grain 0.3 0.05 0.02 wheat, triticale Wheat, hay 30

Wheat, straw 20 15 wheat and triticale straw and fodder, dry MRLs with No US Equivalent

Coffee beans 0.02 Eggs 0.05 0.01 (*) Asparagus 0.1

Buckwheat 0.05 Dry (field peas, pigeon peas) 0.1

Edible

- podded (dwarf peas, peas, pigeon

peas, snow peas, sugar snap peas) 0.25

Fat of poultry 0.05 Meat of hogs 0.05 Meat of poultry 0.05

Pearl millet 0.05

Proso millet 0.05

Succulent shelled (English peas, garden

peas, green peas, peas, pigeon peas,

Teosinte 0.05
§180.434 (b) Section 18 emergency exemptions

Avocado Expiration date

12/31/16 10

§180.434 (c) Tolerances with regional registrations Cranberry 1.0 1.3 Rice, wild, grain 0.5 0.5
§180.434 (d) Indirect or inadvertent residues Alfalfa, forage 0.1 Alfalfa, hay 0.1

Recently proposed
Dill, fresh 30
Dill, dried 80
Dill, seed 15 Leafy Brassica Greens, crop subgroup 5B 20Propiconazole Human

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Page 35 of 35 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :

US Canada Mexico 1 Codex 2
Radish, tops 0.20 3

Radish, roots 0.04 3
Ti palm, leaves 10 Ti palm, roots 0.30

Watercress 6.0 Fruit, stone, group 12

- 12; except plum 4.0 4 apricots, fresh prune plums, nectarines, peaches, plumcots, sweet cherries,

tart cherries 5 peach Po 0.6 plums (including prunes) Po

Nut, tree, group 14

- 12 0.10 0.1 tree nuts 0.02 pecan (*)

Recently proposed under §180.434 (a) 2 (parent only)
Tea, dried 4.0 4 tea (dried leaves)

Completed: M. Negussie; 09/14/15

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

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

3 Tolerances are established for residues of propiconazole, including its metabolites and degradates, in or on the

c ommodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only propiconazole, 1

- [[2

- (2,4

- dichlorophenyl)

- 4

- propyl

- 1,3

- dioxolan

- 2

- yl]methyl]

- 1 H

- 1,2,4

- triazole