UNI T ED S TATES ENVIRONMENTAL PROTE C TION AGENC Y
WASHIN G TON

, D .C. 20460

OFFIC E O F CHE MI CAL SAF E TY AND PO L L UT IO N P RE V ENTI O N

MEMORANDUM

December 2

, 20 15



### SUBJECT: P r opiconazo le Human H ea lth Risk Assessment fo r the New Use of Propicona zo l e o n I mp orte d Tea.

PC Code: 122101

Dec i s i on No.: 493436

Petitio n No.:4£8300

Risk Assessme n t T

TXRNo. : NA

MR ID No.: NA DP Barco d e: 426896

R e i s tratio n No.: I 00-6 1 7

R eg ul ato r y Act i o n : To l e rance
, No US

Reoi stratio n
Cas e No.: 3125

CAS No.: 60207-90-1

FROM: Thur s t o n G. Morton, Ch e mi s t

... 

### r, OL.

, 

# '1 O'**~IA..** Kell y O ' Rourk e
, Bi ologis t ·**~ j**  '

_ Abdallah Kha saw inah

, PhD

., Tox icol og i s t

### p~ Ri s k Assessme nt Branch 4

H ea l th E ffects Di v i s ion (7509 P )



### THROUGH: E li ssa Reaves

, Ph.D

., Chief

Risk Assessme n t Branch 4

, H E



### TO : Tamu e Gibson/Shaja Jo y n e r
, RM20

Fun gic ide Bran ch

R eg i s tration Di vision (7505 P )

This docum e nt provid es the H ea lth Effect s Di vis i o n 's (HEO's) risk a ssess m e nt for the n ew u se
of propico n azo le on imp o rted tea.

Page 1 of531.0 EXECUT IV E SUMMARY

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

2.0 HED RECOMMENDATI O NS

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

2 .1 Data Deficiencies /C onditions of Registration

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

2 .2 To l erance Conside ration s

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

2.2.1 Enforcement Ana l y tic a l Met hod

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

2.2.2 Int e rn at ional H a rmonization

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

2.2.3 Reco mmended Tolerances

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

2.2.4 Revisions to Petitioned

- For Tolerances

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

2.3 Label Recommendations

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

3 .0 IN GRED I ENT PROFILE

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

3.1 C h em ical Identity

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

3.2 Physical/Chemical Characteristics

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

3.3 P estic id e Use Pattern

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

3.3.1 Proposed New Uses

.. .... .... .. ...... ..... ....... .. ... ....... .. ...... .. ...... . ......... .............. . .............. l 0

3.4 A nti c ip ated E xpo s ure Path,vays

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

3.5 Co n s id era ti o n s of E nvironm e ntal Justice

.......... . .... . .. .. ... . .. .. ...... .. .... .......... ........ .. ........ 11

4.0 HAZARD CHARACTE RIZ AT IO N/ASSESSMENT

................... .. . ... ..... .. ............. . .. ... 11

4. 1 Toxico lo gy St udi es Available for Analysis

.. .. .. ... ...... . ..................... ... ..... ..... . ........ ....... 11

4

. 2 Absorption

, Distribution, Metabolism and Exc r et ion

. ........................ .. ..................... 12

4.3 Toxicological Effects

...... .. .. .. .. .. ....... . ............. . ......................................... . .. ........ .... . ... . ... 12

4.4 Safety Factor for Infant s and Ch ild ren (FQPA Safety Facto r)

................. . ............... 1 3

4.4.1 C ompleteness of the Toxico lo gy Database

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

4.4.2 Ev idenc e of Ne urot ox ici ty

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

4.4.3 Ev id e nc e of Se n s itivi ty/S u sce ptibility in the Developing or Young An imal..

.... 14

4.4.4 Residual U ncertainty in the Ex p os ur e Database

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

4

. 5 Toxicity E ndp oint and Point of D e p a rtur e

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

4

. 5.1 Dose -R espo n se Assess m ent

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

4.5.2 R eco mmendations for Comb inin g Expos ur e Route s

..................... .. ............... ..... 1 6

4.5.3 C l ass ific atio n of Ca rcino ge nic P ote nti a l

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

4.5.4 S umma ry of Points of Dep art ure Use d in Ri s k Assessme nt

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

5

. 0 DIETARY AND DRI NKING WATER EXPOSURE AND RISKASSESSMENT

.... 19

Page 2 of 53

### Page 3 of 53

5.1 Metabolite/Degradate Residue Profile

................................ ................................ ......... 19

5.1.1 Summary of Plant and Livestock Metabolism Studies

................................ ........ 19

5.1.2 Comparison of Metabolic Pathways

................................ ................................ ...... 19

5.1.3 Environmental Fate and Transport

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

5.1.4 Residues of Concern Summary and Rationale

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

5.2 Food Residue Profile

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

5.2. 1 Residues in Crops

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

5.3 Water Residue Profile

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

5.3.1 Estimated Drinking Water Concentrations

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

5.4.1 Acute Dietary and Drinking Water Analysis

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

5.4.2 Chronic Dietary and Drinking Water Analysis

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

6.0 RESIDENTIAL EXPOSURE AND RISK ASSESSMENT

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

6.1 Residential Bystander Postapplication Inhalation Exposure

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

6.2 Spray Drift

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

7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT

................................ ............ 28

7.1 Acute & Chronic Aggregate Risk

................................ ................................ ................. 28

7.2 Short

- and Intermediate

- Term Aggregate Risk

................................ ......................... 28

7.3 Intermediate

- Term Aggregate Risk

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

8.0 CUMULATIVE RISK

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

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION

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

10. REFERENCES

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

A TOXICOLOGY DATA SUMMARY

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

A.1 Guideline Data Requirements

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

A.3 Toxicological Endpoints

................................ ................................ ............................. 39

A.4 EXECUTIVE SUMMARIES

................................ ................................ .................... 44

APPENDIX B. Chemical Names And Structures Of Metabolites

................................ ......... 52

APPENDIX C. Physical/Chemical Properties

................................ ................................ .......... 53

APPENDIX D. Studies Reviewed for Ethical Conduct

................................ .......................... 53

### Page 4 of 53

1.0 EXECUTIVE SUMMARY

This document addresses the risks associated with exposures from currently registered uses and the proposed new use of propiconazole on imported tea

. A tolerance of 4.0 ppm for propiconazole residues in/on tea is proposed, but no registration is being pr oposed in the U. S. It also assesses potential enhanced sensitivity of infants and children from dietary and/or residential exposure as required under the Food Quality Protection Act (FQPA) of 1996.

Use Profile

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 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 metaboli tes (determined as 2,4

- dichlorobenzoic acid (2,4

- DCBA)) in/on a variety of agricultural commodities at levels ranging from 0.05 ppm in/on meat and meat byproducts 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

- demethylase).

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 aerial equipment. Propiconazole is applied to non

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

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

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

Proposed New Uses

Tea Association of the USA, Inc. (TAUSA) has submitted a request for a new use of propiconazole for use on tea imported into the United States. A tolerance of 4.0 ppm for propiconazole residues in/on tea is proposed, but no registration is being proposed in the U. S.

The use rate is 100 gr a.i

. /ha with a 7 day pre

- harvest interval (PHI).

T he toxicology database for propiconazole is complete for evaluating and characterizing toxicity and selecting 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, hypertrophy and necrosis. There are mixed effects

in the developmental and repr oduction rat studies. In a rat developmental study, fetal effects

were observed at doses lower than doses at which maternal effects were seen thereby demonstrating quantitative evidence of increased susceptibility of fetuses to in utero exposure to propicon a zole

. W hile in ra bbi ts, developmental toxicity occurred at higher doses than

maternal ly toxic doses. In the two generation reproduction study in rats, offspring toxicity occurred at a higher dose than the parental toxic dose suggesting lower su sceptibility of the rat offspring to propiconazole. Propiconazole does not appear to be neurotoxic based on an acute

### Page 5 of 53

and subchronic neurotoxicity studies

. The concern for susceptibility is low since clear NOAELs

were established in the rat and rabbit devel opmental studies and the points of departure selected for the risk assessment scenarios are protective of the susceptibility observed in the rat developmental study. Therefore, t he 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.

Dose Response 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 general population was selected from an acute neurotoxicity study in rats. An a cute 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 mice. Short

- and intermediate

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

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

intermediate

- term inhalation, dermal, and incidental oral exposures were selected from a carcinogenicity study in mice. Since an oral study was selected for dermal exposure, a 40% dermal absorption factor from a dermal absorption study in rats is used for route

- to

- route extrapolation. An uncertainty factor of 100X was applied to endpoints se lected for all exposure

routes ( 10X for interspecies extrapolation, 10X for intraspecies variation).

Exposure/Risk Assessment and Risk Characterization

A new r isk assessment w as conducted for dietary (food and water) only

. No updated occupational exposure assessment was required since the requested use is for imported tea

. For the current registration action, t here are no new residential uses and

, therefore

, residential risk

was not assessed for th is new use. However, for the aggregate assessment , the existing registered residential use that previously resulted in the greatest short

- term exposure was utilized (i.e., post

- application activity on treated turf).

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 the general population and all population subgroups. At the 95 th 

### percentile, the exposure to the general U.S. population is 2 6 % of the aPAD; t he highest exposed subgroup ( Children 1

- 2 yrs old) is 85 % of the aPAD. The exposure to the general U.S. population is 8 %

of the cPAD, and the most highly exposed subgroup ( Children 1

- 2 yrs old) is 2 4 % of the cPAD.

A dietary exposure assessment f or the free triazole or conjugated triazoles was also recently updated

.

### Page 6 of 53

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 9 6 [note that while this falls below HED’s LOC of 100, t his assessment is con sidered 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) ]. T he 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. T he aggregate risk (dietary + residential exposure) for intermediate

- term exposure to Children 1

- 2 ye ars old yields an MOE of 110 , which does not fall below the level of

concern of 100 and, t herefore, this scenario is not of concern.

An occupational exposure assessment is not required for imported tea.

Aggregate Assessment of Free Triazole & its Conjugates

The addition of the new use does not increase the aggregate exposure to free triazoles and its conjugates. The previous aggregate human health risk assessment was updated for free triazoles and its conjugates and the aggregate estimates remain below HED’s level of concern (T. Morton, D426493, 4/9/15).

Use of Human Studies

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include [studies from PHED 1.1; the AHETF database; the 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. Some of these studies are also subject to review by the Human Studies Review Board. All of the studies

used have received the appropriate review.

Environmental Justice

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

- Income Populations," http://www.archives.gov/federal

- register/executive

- orders/pdf/12898.pdf ).

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

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on pat terns of that

### Page 7 of 53

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 ad ult applicators and for toddlers, youths, and adults entering or playing on treated areas post

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

Tolerance Recommendation

T here are no residue chemistry issues that would preclude granting a toler ance on imported tea

. The proposed US tolerance for tea of 4. 0 ppm is adequate to cover this new use

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

- DCBA containing metabolites at levels ranging from 0.1

- 40 ppm in/on plant commodities [40 CFR §180.434(a)]. HED has determined that the 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 misus e of propiconazole or the proper use of other pesticides containing 2,4

- DCBA; 2) propiconazole per se can be detected by FDA multi

residue methods; and 3) inclusion of only parent allows harmonization with the residue

definition for the Codex MRLs.

A new section to be added to [40 CFR §180.434 as [40 CFR §180.434(a)(2) for the tolerance expression for parent only.

Following is the appropriate tolerance expression:

Propiconazole; tolerances for residues (a) General. Tolerances are established for residues of propiconazole, including its metabolites and degradates, in or on the commodities 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

- propy l

- 1,3

- dioxolan

- 2

- yl]methyl]

- 1 H

- 1,2,4

- triazole, in or on the commodity.

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

- DCBA moiety. Canada has an MRL for tea at 4 ppm

. There is no Codex MRL for tea

. The U.S. is

harmonized on the MRL level for Canada.

### Page 8 of 53

2.0 HED RECOMMENDATIONS

2.1 Data Deficiencies/Conditions of Registration

HED can recommend for registration for the proposed new use of propiconazole.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate method, HPLC/UV Method AG

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

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

a means of residue confirmation.

2.2.2 International Harmonization

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

- DCBA moiety. Canada has an MRL for tea at 4 ppm

. There are no Codex MRL for tea . The U.S. is

harmonized on the MRL lev el for Canada.

2.2.3 Recommended Tolerances

T here are no residue chemistry issues that would preclude granting a tolerance for propiconazole

on imported tea

. Available data support the proposed tolerance under 40 CFR 180. 434 for

residues of propiconazole in/on the following raw agricultural commodities:

Tea

................................ ................................ ................................ ............ 4. 0 ppm



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

- DCBA containing metabolites at levels ranging from 0. 1

- 40 ppm in/on plant commodities [40 CFR §180.434(a)]. HED has determined that the 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 multi

residue methods; and 3) inclusion of only par ent allows harmonization with the residue

definition for the Codex MRLs.

### Page 9 of 53

A new section to be added to [40 CFR §180.434 as [40 CFR §180.434(a)(2) for the tolerance expression for parent only.

Following is the appropriate tolerance expression:

Propiconazole; tolerances for residues (a) General. Tolerances are established for residues of propiconazole, including its metabolites and degradates, in or on the commodities 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, in or on the commodity.

Adequate crop field trial data reflecting the proposed use patterns were submitted for purposes of supporting the proposed tolerance for imported tea

.

2.2.4 Revisions to Petitioned

- For Tolerances

None

2.3 Label Recommendations

None

3 .0 INGREDIENT PROFILE

3.1 Chemical Identity

Structure and nomenclature are reported in Table 3.1

.

T able 3.1

. 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

### Page 10 of 53

3.2 Physical/Chemical Characteristics

The physicochemical properties of propiconazole are reported in Appendix C.

3.3 Pesticide Use Pattern

3.3. 1 Proposed New Uses

Propiconazole is proposed for Tilt (EPA Reg. # 100

- 617 ) for use on imported tea ( Table3 .3. 1 ).

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new use of propiconazole on imported tea . For the existing domestic uses, humans may be exposed to propiconazole in food and drinking water, since propiconazole may be applied directly to growing crops and application may result in propiconazole reaching surface and ground wa ter sources of drinking water. There are no residential uses associated with the proposed use on imported tea, however, the aggregate exposure was updated. An occupational exposure assessment is not required for imported tea.

Risk assessme nts have been previously prepared for the existing uses of propiconazole. This risk assessment considers all of the aforementioned exposure pathways based on the proposed new use of propiconazole, but also considers the existing uses as well, particularly for the dietary
exposure assessment. Table 3 .3.1 . Label Directions for Proposed New Use of the Propiconazole Product

Product EPA Reg. No. Use

Site Target Application

Methods Maximum

Application

Rate (lb ai/100 gal) PHI

(day) REI

(hr) Use Directions/

Limitations

Tilt® Fungicide EPA Reg. N o.

100

- 617 Tea High volume

spray, foliar sprays during

active vegetative growth stage Foliar 100 gr a.i/ha 7 NA

### Page 11 of 53

3.5 Considerations of Environmental Justice

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

- Income Populations," ( http://www.archives.gov/federal

- register/executive

- orders/pdf/12898.pdf ). As a part of every pesticide risk assessment, OPP considers a large v ariety of consumer subgroups according

to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities i n and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey/What We Eat in America, ( NHANES/WWEIA), are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult ap plicators and for toddlers, youths, and adults entering or playing on treated areas post

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

4.0 HAZARD CHARACTERIZATION/ASSESSMENT

4.1 Toxicology Studies Available for Analysis

T he toxicology database for propiconazole is complete for evaluating and characterizing propiconazole toxicity and selecting endpoints for purposes of this risk assessment

The following data are available:

 Acute

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

 Subchronic

- Oral 90

- day rat, oral 90

- day mouse (3), and oral 90

- day dog;

 Chronic

- Oral rat , mouse and dog;

 Reproductive/developmental

- Oral developmental rabbit and rat, 2

- generation reproductive rat

 Other

- Oral rat and mouse cancer studies, 21

- day dermal rabbit toxicity and dermal penetration study, acute and subchronic neurotoxicity, metabolism, mutagenicity screens and mechanistic studies (3).

### Page 12 of 53

4.2 Absorption, Distribution, Metabolism and Excre tion

The r at metabolism study labeled with 14 

### C at the triazole

- [3,5] position indicated that parent compound was extensively metabolized. An intravenous (IV) study 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 detected 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 of the orally dosed groups. Radiolabeled materials CGA 91305, CGA 118245 and CGA 177291 were reported ranging from 0.5%

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

- phen yl 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)

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

4.3 Toxicological Effects

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

In rabbits, developmental toxicity occurred at a higher dose than the maternal ly toxic dose, while in rats, developmental toxicity occurred at lower doses than maternal toxic doses. Increased incidences of rudimentary ribs occurred in rat and rabbit fetuses. Increased cleft palate

malformations were noted in two studies in rats. I n 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 stern e brae were reported at doses that were not maternally toxi c. 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.

### Page 13 of 53

Propiconazole was negative for mutageni city in the in vitro BALB/3T3 cell transformation assay, bacterial reverse mutation assay, Chinese hamster bone marrow chromosomal aberration assay, unscheduled DNA synthesis studies in human fibroblasts and primary rat hepatocytes, mitotic gene conversion assay and the dominant lethal assay in mice. It caused proliferative changes in the rat liver with or without pretreatment with an initiator, like phenobarbital, a known liver tumor promoter. Liver enzyme induction studies with propiconazole in mice

dem onstrated that propiconazole is a strong phenobarbital type inducer of xenobiotic metabolizing enzymes. Hepatocellular proliferation studies in mice suggest that propiconazole induces cell proliferation followed by treatment

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

Propiconazole has low to moderate acute 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.

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

4.4 Safety Factor for Infants and Children (FQPA Safety 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 su sceptibility was observed in the rat developmental study, a clear NOAEL is established for the developmental effects. Furthermore, the acute dietary for females 13

- 49 years old is based on the developmental NOAEL from the study with quantitative susceptib ility. 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 factor to 1X.

4.4.1 Completeness of the Toxicology Databas e

The toxicological database for propiconazole is complete for the purpose of this risk assessment. Based on a WOE approach considering all the available propiconazole hazard and exposure information, the HASPOC concluded that a 28

- day day inhalation st udy and a subchronic neurotoxicity study are not required at this time ( 8/1/12

, TXR #: 0056387). However, the registrant provided later an acceptable/guideline SCN study

.

4.4. 2 Evidence of Neurotoxicity

An acute neurotoxicity study is available for propiconazole. In this study, a single 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

### Page 14 of 53

toe gate, staining around the nose). Limited clinical 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). Funct ional observational battery (FOB) and motor activity tests showed reduced activity in males and females but only at the high dose (300 mg/kg) with no microscopic changes to the nervous tissues. Based on weight of evidence (WOE) the subchronic

neurotoxicit y is waived (HASPOC, TXR 0056387). Although the HASPOC waived the subchronic neurotoxicity (HASPOC, TXR 0056387), the registrant later submitted an acceptable/guideline SCN study in rats. In this study, propiconazole was not neurotoxic at the highest dose tested of 3500 ppm (equivalent to 222 mg/kg bw/day). Both the ACN and the SCN studies demonstrated that propiconazole is not neurotoxic at the doses tested. Additionally, neurotoxic and neurobehavioral effects were not seen in the propiconazole toxicity database. The liver is the primary target organ of propiconazole toxicity, and decreased body weight is the most sensitive endpoint in repeated

- dose studies.

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

The toxicology d atabase for propiconazole is complete for FQPA assessment. Although quantitative susceptibility was observed in the rat developmental study, a clear NOAEL is established for the developmental effects. Furthermore, the acute dietary for females 13

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

There are no residual uncertainties with regard to pre

- and/or postnatal toxicity. The dietary food exposure assessment uses conservative assumptions which result in protective estimates of

d ietary exposure. The dietary drinking water assessment uses values generated by model and associated modeling parameters which are designed to provide protective, high

- end estimates of

water concentrations.

4.4.4 Residual Uncertainty in the Exposure Data base

There are no residual uncertainties in the exposure database. The dietary and non

- dietary risk

assessment s are conservative and will not underestimate dietary and/or non

- dietary residential
exposure to prop iconazole.

4.5 Toxicity Endpoint and Point of Departure

4.5.1 Dose

- Response Assessment

Toxicity endpoints and points of departure (PODs) for dietary (food and water), occupational, and residential exposure scenarios are summarized below. A detailed description of the studies used as a basis for the selected endpoints are presented in Append ix A.

### Page 15 of 53

An acute POD of 30 mg/kg (NOAEL) for the general population was selected from an acute neurotoxicity study based on clinical signs of toxicity (piloerection, diarrhea, tip toe gait) at 100 mg/kg . An acute POD of 3 0 mg/kg (NOAEL) was selected for females age 13

- 49 years from a developmental study in rats 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 at 90 mg/kg/day . The dev elopmental effects of concern are presumed to occur after a single exposure and are relevant only to females aged 13

- 49 years old since they occur in utero

. An uncertainty factor (UF) of 100x ( 10X to account for intraspecies extrapolation and 10X for

intr aspecies variation) was applied to the NOAEL to obtain an acute reference dose (aRfD) of

0.3 mg/kg. Since the FQPA factor has been reduced to 1X, the acute population adjusted dose (aPAD) is equivalent to the aRfD.

A chronic POD of 1 0 .0 mg/kg/day (NOAEL) was selected for the general population from a two

year carcinogenicity study in mice based on non

- neoplastic liver effects (increased liver weight in males and increase in liver lesions: masses/raised areas/ swellings/nodular areas mainly at 50 mg/kg/day. An uncertainty factor (UF) of 100x ( 10X to account for intraspecies extrapolation

and 10X for intraspecies variation) was applied to the dose to obtain a chronic reference dose (cRfD/cPAD) of

0.1 mg/kg/day.

Incidental oral short term exp osure was assessed using a POD (NOAEL) of 30 mg/kg/day from an acute neurotoxicity study based on clinical signs of toxicity (piloerection, diarrhea, tip toe gait) at 100 mg/kg. The selected toxicity endpoint was the most sensitive to assess this exposure scenario. The NOAELs in the developmental rat (90 mg/kg/day) and rabbit ( 10 0 mg/kg/day) studies were much higher and would not be protective of the toxicity seen in the ACN study. An MOE of 100 is applied to account for the intra

- and inter

- species variat ion. Incidental oral intermediate term exposure was assessed using a POD (NOAEL) of 10 mg/kg/day from an carcinogenicity study in mice based on based on non

- neoplastic liver effects (increased liver weight in males and increase in liver lesions: masses/ra ised areas/ swellings/nodular areas mainly at 50 mg/kg/day. An MOE of 100 is applied to account for the intra

- and inter

- species variation.

A short

- term dermal POD of 30 mg/kg/day was selected from the acute neurotoxicity study

described above. An inter mediate

- term dermal POD of 10 mg/kg/day was selected from the 24

month carcinogenicity mouse study described above. An MOE of 100 is required for the short

and intermediate

- term scenarios for dermal exposure. This includes 10X for interspecies extrapola tion and 10X for intraspecies variation.

A short

- term inhalation POD of 30 mg/kg/day was selected from the acute neurotoxicity study

described above. An intermediate

- term inhalation POD of 10 mg/kg/day was selected from the

24 month carcinogenicity mouse study described above. An MOE of 100 is required for the

short

- and intermediate

- term scenarios for inhalation exposure. This includes 10X for interspecies extrapolation and 10X for intraspecies variation.

### Page 16 of 53

4.5.2 Recommendations for Combining Exposure Routes

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

are potential residential post

- application exposures to a dults 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

inhalation due to a com mon toxicological endpoint (clinical signs in the ACN study). A common toxicological endpoint was identified from the cancer mouse study for intermediate

and long

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

th ese routes can be aggregated for these scenarios for the appropriate population.

4.5.3 Classification of Carcinogenic Potential

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) approa ch be used for quantification of human risk ( TXR No. 0 009771, April 15, 1992 meeting).

4.5.4 Summary of Points of Departure Used in Risk Assessment

Toxicological doses/endpoints selected for the propiconazole risk assessment are provided in

Tables 4 .5.4.1 and 4.5.4.2

.

### Page 17 of 53

Table 4 .5.4.1 . Summary of Toxicological Doses and Endpoints for Propiconazole for Use in Dietary Human Health Risk

Assessments

Exposure/Scenario Point of

Departure Uncertainty/FQP

A Safety Factors RfD, PAD,

LOC for Risk

Assessment Study and Toxicological Effects

Acute Dietary (General Population) NOAEL =

30 mg/kg/day UF A = 10X

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

mg/kg/day

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

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

Acute Dietary (Females 13

- 49 years) NOAEL =

30 mg/kg/day UF A = 10X

.

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

mg/kg/day

aPAD = 0.3 mg/kg/day Developmental Study

- Rat 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 =

0.1 mg/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).

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

, TXR No.

0009771
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adver se 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 extr apolate a NOAEL. UF S = use of a short

- term study for long

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

of concern. N/A = not applicabl e

### Page 18 of 53

Table 4.5.4.2 . Summary of Toxicological Doses and Endpoints for Propiconazole for Use in Residential and Occupational Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk

Assessment Study and Toxicological Effects

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).

Inc id ental 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

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

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 Acute Neurotoxicity Study

- Rats MRID

46604601

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

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 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

L OAEL = 100 mg/kg/day based on clinical signs of to xicity (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 UF A = 10X

UF H = 10X 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). Cancer (all routes) Classification: Group C, possible human carcinogen, RfD approac h for risk characterization

, TXR No.

0009771
DAF = Dermal Absorption Factor

### Page 19 of 53

5.0 DIETARY AND DRINKING WATER EXPOSURE AND RISK ASSESSMENT

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Livestock Metabolism Studies

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

- propyl group on the dioxolane ring of the cis/trans isome rs 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 alkyl bridge between the phenyl and triazole rings i s 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 possibly through the

intermediate formation of triazole lactic acid. HED considers free triazole, triazole alanine, and triazole acetic acid to be residues of concern in plants. Since these are common metabolites from several triazole containing pesticides, the risk assessment for triazoles has been updated separately (HED memo of 1 0 / 24 / 1 3 , T. Morton, D 414951 ).

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

Structures and names of propiconazole metabolites are provided in Appendix B

.

5.1.2 Comparison of Metabolic Pathways

The r at metabolism study indicated that parent compound was extensively metabolized. An intravenous study found several metabolites, including CGA 118245, CGA 217495, CGA 91304, and CGA 118244. No parent material was detected in the feces in the iv group. The metabolites seen in the iv study were detected to vary ing degrees in the urine and the feces of the orally dosed groups. Radiolabeled materials CGA 91305, CGA 118245 and CGA 177291 were present in the fecal radioactivity in males and females or in one sex alone. Most of the fecal radioactivity was not char acterized. Metabolites CGA 217495 and CGA 177291 are not found in plant or livestock metabolism. The proposed metabolic pathway involve s the cleavage of the dioxolane ring through the oxidation of the propyl side chain, with subsequent dechlorination

and conjugation. In a (U

14 

### C)

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



### . The plant

metabolism data indicate that the major metabolic pathway in plants involves hydroxylation of

the n

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

- 1,2,4

- triazole is

### Page 20 of 53

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

intermediate formation of triazole lactic acid.

5.1.3 Environmental Fate and Transport

For propiconazole, turf, a previously regi stered crop, has the highest application rate (6.285 lb a.i./A, 8 applications of 0.786 lb a.i./A per year with a 14

- day interval between applications) ( (DP 325821,328690, Dated 07/07/2006 ). EFED did not provide a drinking water assessment for

the importe d tea use. I t was determined the previously assessed turf use resulted in the

maximum EDWCs . The previously assessed turf EDWCs are approximately one order of magnitude higher (more protective), than the EDWCs for the new use and therefore, the turf

EDWC s were used for the updated dietary risk assessment.

5.1.4 Residues of Concern Summary and Rationale

A summary of the metabolites and degradates to be included in the risk assessment and tolerance expression are presented below in Table 5.1.4

. Detailed rationale for these conclusions were presented in a previous document (DP329394, Y. Donovan, 06/15/06).

Table 5.1.4 . Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression

.

Matrix For Risk Assessment  For Tolerance Expression

Plants Parent plus all metabolites convertible to 2,4

-

DCBA Parent only

Rotational crop Parent plus all metabolites convertible to 2,4

-

DCBA Parent only

Livestock: Parent plus all metabolites convertible to 2,4

-

DCBA Parent only

Water Parent only N/A

Note: For all triazole

- containing pesticides, the triazole

- containing metabolites 1,2,4

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

these metabolites are common to the en tire class of triazole

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

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

### Page 21 of 53

5.2 Food Residue Profile

5.2.1 Residues in Crops

Reference: Propiconazole

. New Use of Propiconazole on Imported Tea . Summary of Analytical Chemistry and

Residue Data. T. Morton , D 422 887

, 12 / 1 /201 5



### Supervised trials were carried out in India in 2006

- 2007 to generate data on residues of propiconazole in made tea. In all three trials, one foliar spray application of propiconazole at either 100 g a.i./ha (1x Indian rate) or 200 g a.i./ha was made to tea plants. Samples were

collected at PHIs 0

- 14 days. Supervised trials were carried out in Sri Lanka in 2006

- 2008 to generate data on residues of propiconazole in made tea. In all five trials, one foliar spray application of propiconazole at 21 g a.i./ha (1 x Sri Lankan rate) was made to tea plants. Samples

were collected at PHIs of 0 and 6

- 7 days. In the decline trials, the leaf samples were collected on Day 0 (prior to spraying), Day 1 (2 hours after spraying), and Days 3, 5, 7, 10, 14 and 21.

Results fr om the field trials in India showed that, following one application of propiconazole (EC formulation; 250 g/L) at a rate of 100 g a.i./ha , residues were 0.42

- 1.8 ppm in/on black tea samples harvested at a PHI of 7 days

.

Results from the field trials in Sr i Lanka showed that, following one application of propiconazole (EC formulation; 250 g/L) at a rate of 21 g a.i./ha , residues were < 0.01

- 1.1 ppm in/on black tea samples harvested at a PHI of 6

- 7 days

.

The results from these studies are discussed in the appropriate data evaluation report (DER) and

summarized in the following table

.

Table 5.2.1 . Summary of Residues from Tea Trials with Propiconazole.

Matrix Appl. Rate

(g a.i./ha) PHI

(days) n Residues (ppm)

Min. # Max. # LAFT* HAFT* Median* Mean* SD*

INDIA (PMRA# 1955332)

Black tea
(Made tea) 100 7 3 0.42 1.8 0.42 1.66 0.64 0.907 0.662

SRI LANKA (PMRA# 2065596)

Black tea
(Made tea) 21 6

- 7 8 <0.01 1.1 <0.01 1.1 0.089 0.261 0.374

# Values based on total number of samples. * Values based on per

- trial averages. LAFT = Lowest Average Field Trial, HAFT = Highest Average Field Trial, SD = Standard Deviation. For computati on of the LAFT, HAFT, median, mean and standard deviation, values < LOQ are assumed to be at the LOQ.

### Page 22 of 53

5.3 Water Residue Profile

5.3. 1 Estimated Drinking Water Concentrations

The drinking water residues used in the dietary risk assessment were provided by the Environmental Fate and Effects Division (EFED) in the following memorandum

, “ Drinking Water Exposure Assessment for the petition (1F7892) that proposes tolerances for residues of propiconazole on sugarcane (I. Abdel

- Saheb, 09 / 26 /1 2

, D396031, D396034 ) ,” and incorporated directly into this dietary assessment. In the case of propiconazole, turf, a previously registered crop, has the highest application rate (6.285 lb a.i./A, 8 applications of 0.786 lb a.i../A per year

with a 14

- day interval between applications) ((DP 325821,328690, Dated 07/07/2006). The

propos ed new use does not result in higher EDWCs than those estimated for turf uses. Water

residues were directly incorporated in the DEEM

- FCID into the food categories “water, direct, all sources” and “water, indirect, all sources.”

The estimated surface water drinking water concentrations for propiconazole are:

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

24. 8 ug /L for the 1 in 10 year annual mean concentration (non

- cancer chronic) and

The highest estimates from surface water (acute, 64.1 ppb and chronic, 24.8 ppb) are directly entered into the exposure model to assess the contributions from drinking water.

Drinking Water Data for Free Triazoles

Residues of 1,2,4

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

- conversion between 1,2,4

- triazole, triazole alanine, and triazole acetic acid that may occur in the environment, the residue estimates used in these

assessments ar e a summation of all three residues and, therefore, represent an overestimate of actual concentrations of the common triazole metabolites in drinking water. The Tier II PRZM/EXAMS (surface water) and SCIGROW (ground water) residue estimates are

summarized in Table 5.3.1 . HED notes that there were no detects of 1,2,4

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

- per

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

Table 5.3.1 . Summary of Estimated Drinking Water Concentrations of 1,2,4

- Triazole. Exposure Duration Surface Water Concentration, ppm Ground Water Concentration, ppm

Acute 0.041 0.001

Chronic 0.011 0.001

### Page 23 of 53

5

. 4 Dietary and Drinking Water Exposure and Risk

Screening level acute and refined chronic dietary and drinking water exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database DEEM

- FCID, Version 3.16, which incorporates consumption data from USDA’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). This diet ary survey was conducted from 2003 to 2008. 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 dos e 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 by the additional Safety Factor, if applied. For a cute and non

cancer chronic exposures, HED is concerned when estimated dietary risk exceeds 100% of the

PAD.

Reference: Propiconazole: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk

Assessments for the New Use of Propiconazole on Imported Tea

. T. Morton, D 426895

, 12 / 1 /201 5



### 5

. 4 .1 Acute Dietary and Drinking Water Analysis

A new acute dietary assessment was conducted for the proposed new use. The proposed new use results in dietary risk estimates below HED’s level of concern; see Table 5.4.1.1

. The most highly exposed subgroup is children 1

- 2 years resulting in 8 5 % of the aPAD.

Table 5.4.1.1 . Results of Acute Dietary Exposure Analysis for Food and Drinking Water for Propiconazole

Population Subgroup aPAD (mg/kg/day) 95th Percentile Exposure (mg/kg/day) % aPAD General U.S. Population

0.3 0.07 8158 26 All Infants (< 1 year old) 0.108 192 36

Children 1

- 2 years old 0.25 4748 8 5

Children 3

- 5 years old 0.194 251 65

Children 6

- 12 years old 0.106 047 35

Youth 13

- 19 years old 0.07 3973 25

Adults 20

- 49 years old 0.061 394 20

Adults 50

- 99 years old 0.05 1211 17

Females 13

- 49 years old 0.06 1027 20

### Page 24 of 53

Dietary Assessment of Free Triazole and its Conjugates
Reference: Common Triazole Metabolites: Updated Dietary (Food + Water) Exposure and Risk Assessment to Address The New Section 3 Registrations For Use of Propiconazole on Tea, Dill, Mustard Greens, Radish, and Watercress; Use of Difenoconazole on Globe Artichoke, Ginseng and Greenhouse Grown Cucumbers and Conversion of the Established Foliar Uses/Tolerances for Stone Fruit and Tree Nut Crop Groups to Fruit, Stone, Group 12

- 12 and the Nut, Tree, Group 14

- 12.; and Use of Flutriafol on Hops. T. Morton

, DP4 26492.drs, 4/9/15

.



### The dietary exposure analyses for the triazole metabolites ( D426492 , T. Morton, 4/9/15 ) was recently updated. Addition of th is new use of propiconazole did not significantly change the dietary exposure for the triazole metabolites. The results from the triazole dietary analysis are below HED’s level of concern; see Table 5.4. 3 .2.

Table 5.4. 3 .2. Summary of Dietary (Food and Drinking Water) Exposure and Risk for the Common

Triazole Metabolites.

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

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

1,2,4

- Triazole General U.S. Population 0.00 7869 26 0.001 150 23

Not Applicable Not

Applicable All Infants (< 1 year old) 0.01 2319 41 0.00 2097 42

Children 1

- 2 years old 0.0 19569 65 0.00 3321 66

Children 3

- 5 years old 0.01 6613 55 0.00 2646 53

Children 6

- 12 years old 0.0 09615 32 0.001 431 29

Youth 13

- 19 years old 0.00 6804 23 0.00 0922 18

Adults 20

- 49 years old 0.00 6350 21 0.00 0979 20

Adults 50

- 99 years old 0.00 5587 19 0.00 0927 19

Females 13

- 49 years old 0.00 6416 21 0.00 0942 19

Triazolylalanine + Triazolylacetic Acid+Triazolylpyruvic acid General U.S. Population

Not Applicable Not

Applicable 0.01 5819 18

Not Applicable Not

Applicable All Infants (< 1 year old) 0.0 21523 24

Children 1

- 2 years old 0.0 50635 56

Children 3

- 5 years old 0.0 40816 45

Children 6

- 12 years old 0.0 21357 24

Youth 13

- 19 years old 0.01 3174 15

Adults 20

- 49 years old 0.01 2901 14

Adults 50

- 99 years old 0.0 12185 14

Females 13

- 49 years old 0.0 73349 73 0.01 2373 14 * The values for the highest exposed population for each type of risk assessment are bolded.



### 5

. 4 .2 Chronic Dietary and Drinking Water Analysis

A new chronic dietary assessment was conducted for the proposed new use of propiconazole and

results in dietary risk estimates below HED’s level of concern; see Table 5.4.2

.

### Page 25 of 53

Table 5.4.2 . Results of Chronic Dietary Exposure Analysis for Food and Drinking Water for Propiconazole

Population Subgroup cPAD(mg/kg/day) Exposure (mg/kg/day) % cPAD General U.S. Population

0.1 0.007 703 7. 7 All Infants (< 1 year old) 0.010 526 1 1

Children 1

- 2 years old 0.02 4051 24

Children 3

- 5 years old 0.019 424 19

Children 6

- 12 years old 0.0 10141 10

Youth 13

- 19 years old 0.006 213 6. 2

Adults 20

- 49 years old 0.006 449 6. 4

Adults 50

- 99 years old 0.005 932 5 .9

Females 13

- 49 years old 0.005 890 5. 9



### 6 .0 RESIDENTIAL EXPOSURE AND RISK ASSESSMENT

There are no proposed residential uses associated with this action; however, there are existing residential uses that have been reassessed in a previous document (D403629, J. Miller, 11/15/2012) to reflect upd ates to HED’s 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html ), along with policy changes for body weight assumptions. The revis ed Total MOEs (dermal + inhalation) for residential handler and post

- application exposure did not fall below the LOC of 100 , and therefore, are not of concern. Handler and Post

- application estimated risks are presented in Tables 6.1 and 6.2, respectively.

### Page 26 of 53

Table 6.1 . Short

- Term Residential Handler Exposure and Risk Estimates for Propiconazole.

Exposure
Scenario Target

MOE Dermal

Unit Exposure (ug/lb ai) Inhl. Unit

Exposure (ug/lb ai) Maximum

Application

Rate a (lb ai/ft 2 )

Or (lb ai/Acre) Area

Treated or

Amount

Handled Daily b Dermal Inhalation Total

Dose (mg/kg/day) c MOE d Dose (mg/kg/day) e MOE f MOE g

Mixer/loader/Applicator

Low Pressure

Handwand/

Ornamentals 100 63,000 18

5.5 x 10

- 8 1,200 ft 2 0.000021 1,400,000 5.9 x10

- 9 5.1 x 10 9 1.4 x 10 6

Hose

- end Sprayer/

Ornamentals 58,000 1.4 0.000019 1,600,000 1.2 x 10

- 9 6.5 x

10 10 1.6 x 10 6

Low Pressure

Handwand/

Turf/Lawns 100 Hose

- end Sprayer is protective

Hose

- end Sprayer/

Turf/Lawns 13,400 22 1.8 0.5 Acres 0.060 500 0.000099 300,000 500

Brush/Roller Applying paint 100 450,000 200

0.0035 lb ai/ 1 gal can 0.016 1,900 0.000007 4,300,00 1,900

Airless Sprayer Applying Paint 63,000 18 0.0033 9.100 0.00000095 3.2 x 10 7 9,100

Based on registered or proposed label (0.0024 lb ai/A): [ 0.0024 lb ai/A x A/43,560 sq ft. = 5.5 x 10 - 8 ] or (0.000000055 lb ai/ft 2 ) Exposure Science Advisory Council Policy #9.1. Dermal Dose = Dermal Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg /ug) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gallons/day) x DAF ( 40 %)/BW ( 80 kg). Dermal MOE = Dermal NOAEL (mg/kg/day)/Dermal Dose (mg/kg/day). Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal ) x Area Treated or

Amount Handled (A or gallons/day) /BW (kg). Inhalation MOE = Inhalation NOAEL (mg/kg/day)/ Inhalation Dose (m g/kg/day). Total MOE = NOAEL (mg/kg/day)/(Dermal Dose + Inhalation Dose) OR Total MOE = 1/[(1/Dermal MOE) + (1/Inhalation MOE)].

### Page 27 of 53

Table 6.2: Short

- Term Residential Post

- application/Incidental Oral Exposure and Risk Estimates for Propiconazole.

Lifestage Post

- application Exposure Scenario Dose MOEs

Adult

Turf

- sprays Dermal 0.142785 210

Inhalation N/A N/A

Child Dermal 0.282685455 110

Inhalation N/A N/A

Hand to Mouth 0.014490408 2,100

Object to Mouth 0.00044 68,000

Incidental Soil Ingestion 0.000061 490,000



### 6.1 Residential Bystander Postapplication Inhalation Exposure

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

- application inhalation exposure assessment was not performed for propiconazole at this time. Howe ver, volatilization of pesticides may be a potential source of post

- application inhalation exposure to individuals nearby to pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Feder al 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.go v/scipoly/SAP/meetings/2009/120109meeting.html ) and is in the process of evaluating the SAP report. The Agency may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

application inhalat ion 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 post

- application inhalation exposure assessment for propiconazole

.

6.2 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application metho d employed for Propiconazole

. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information at (http://www.epa.gov/opp00001/factsheets/spraydrift.htm) . On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Ta sk Force, a membership of U.S. pesticide registrants, and is

### Page 28 of 53

developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods.

Af ter the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target drift with specific products with significant risks

associated with drift.

Although a quantitative residential post

- application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation
exposure assessment was previously performed for flaggers. This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post

- application inhalation exposure scenarios

.

7 .0 AGGREGATE EXPOSURE AND RISK ASSESSMENT

In accordance with the FQPA, HED must consider and aggr egate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures (dermal and residential). In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estim ates 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.

T he previous aggregate human health risk assessment for fr ee triazoles and its conjugates was updated and the aggregate estimates are below HED’s level of concern ( DP 426493 , T. Morton,

4 / 9 / 15 ).

7.1 Acute & Chronic Aggregate Risk

Acute and chronic aggregate exposures include food plus drinking water exposures. As

demonstrated under Section 5. 4, acute and chronic aggregate risks are not of concern.

7.2 Short

- and Intermediate

- Term Aggregate Risk

Short

- term aggr egate exposure takes into account residential exposure plus average exposure levels to food and water (considered to be a background exposure level). The highest exposure

scenarios are from post

- application exposure associated with residential use on tur f, which were

used in the short

- term aggregate risk assessment.

Table 7. 2 .1 aggregates the short

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

- term aggregate risk MOE of 96 exceeds HED’s level of concern (LOC=100)

. This assessment is considered conservative since the short

- term endpoints are based on a conservative LOAEL that is 3x higher than the NOAEL. Therefore, the true NOAEL is likely higher and would result in MOEs g reater than 100. Further, the assessment is

### Page 29 of 53

based on a combination of tolerance

- level residues and reliable data on average field

- trial residues and 100 PCT, conservative assumptions in the ground and surface water modeling, and conservative assumptions t o 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. Although dietary (food and water) is not th e aggregate exposure driver, incorporating percent crop treated would likely increase the aggregate MOE further above 100. For example, the Agency’s latest PCT figures indicate that the highest average PCT reported for propiconazole residues on crops is 5 5%, which is much less than the 100 PCT the Agency used for all commodities in its assessment. 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 than offset by the con servative exposure assumptions and therefore not of concern.

Table 7. 2 .1

. Short

- term Aggregate Risk Estimates to Propiconazole for 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 0.024051

30 1 2 00 2

9 6 Hand to Mouth Activity on Turf 100 1 Oral 0.0269 2100 3

Turf

– High

- Contact Activities Dermal 0. 2827 1 10 4

1 Target MOE= 100, Acute Neurotoxicity NOAEL=30

2 MOE food = [(short

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

3 MOE oral = [(short

- term oral NOAEL)/(hand

- to

- mouth residential exposure)]

4 MOE dermal = [(short

- term dermal NOAEL)/(high

- end dermal residential exposure)]

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



### Table 7.2. 2 aggregates the short

- term risk for adults from residential post

- application, and average food and water (as a background). The aggregate MOE is 200 , which does not fall below HED’s LOC, and therefore is not of concern

.

Table 7.2. 2 : Short

- term Aggregate Risk Estimates to Propiconazole for Adults from Post

- Application Activities

Exposure Scenario Target

MOE Route of Exposure Exposure or

Daily dose NOAELs MOE at Day 0 Combined MOE 4

Average Food and Water
(As background) N/A Food and

water 0. 00 63

30 4 8 00 2

200 Residential Post

- application (Residential Turf Gen. High

Contact Activities)) 100 1 Dermal 0. 143 210 3

1 Target MOE= 100, Developmental rat

- increased incidence of rudimentary risks. NOAEL = 30

2 MOE food and water = [(short

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

3 MOE dermal = [(short

- term dermal NOAEL)/(high

- end dermal residential exposure)]

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

### Page 30 of 53

7. 3 Intermediate

- Term Aggregate Risk

The only 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 Children 1

- 2 years old. The aggregate MOE is 1 1 0 , which is greater than the target MOE o f 100. Therefore, this

scenario is not of concern.

Table 7.3 . Intermediate

- term Aggregate Risk Estimates to Propiconazole for 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. 02 3 9 10 4 2 0 2

1 1 0 Incidental oral 100 1 Oral 0.0056 10 1800 3

Dermal Contact Activities 100 1 Dermal 0. 059 10 170 4

Note:

1 Target MOE= 100, 24 Month carcinogenicity 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 Aggre gate Combined MOE (food, water, and residential) = 1÷ [(1÷MOE food and water) + (1÷MOE oral) + (1÷MOE dermal)].



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

- level residues for many food commodities , and crop specific (turf) screening level drinking water modeling data (i.e., surface water modeling); 2) maximum application rates and minimum application intervals were used; an d 3) conservative SOPs and high

- end estimates of exposure were employed.

Updated Aggregate Assessment of Free Triazole & its Conjugates

Reference: Common Triazole Metabolites: Updated Aggregate Human Health Risk Assessment to Address The

New Section 3 R egistrations For Use of Propiconazole on Tea, Dill, Mustard Greens, Radish, and Watercress; Use of Difenoconazole on Globe Artichoke, Ginseng and Greenhouse Grown Cucumbers and Conversion of the

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

- 12 and the Nut, Tree, Group 14

- 12.; and Use of Flutriafol on Hops. DP 426493 , T. Morton, 4 / 9 / 15

.



### 8.0 CUMULATIVE RISK

Propiconazole is a member of the triazole

- containing class of pesticides. Although conazoles act similarly in plants (fungi) by inhibiting ergosterol biosynthesis, there is not necessarily a relationship between their pesticidal activity and their mechani sm of toxicity in mammals. Structural similarities do not constitute a common mechanism of toxicity. Evidence is needed to establish that the chemicals operate by the same, or essentially the same, sequence of major biochemical events (EPA, 2002). In co nazoles, however, a variable pattern of toxicological

### Page 31 of 53

responses is found; some are hepatotoxic and hepatocarcinogenic in mice. Some induce thyroid tumors in rats. Some induce developmental, reproductive, and neurological effects in rodents. Furthermore, the conazoles produce a diverse range of biochemical events including altered cholesterol levels, stress responses, and altered DNA methylation. It is not clearly understood whether these biochemical events are directly connected to their toxicological o utcomes. Thus, there is currently no evidence to indicate that conazoles share common mechanisms of toxicity and EPA is not following a cumulative risk approach based on a common mechanism of toxicity for the conazoles. For information regarding EPA’s pr ocedures for cumulating effects from substances found to have a common mechanism of toxicity, see EPA’s website at http://www.epa.gov/pesticides/cumulative

.

Propiconazole is a triazole

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

metabo lite 1,2,4

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

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

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

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

- level evaluation in te rms of hazards associated with common metabolites (e.g., use of a maximum combination of uncertainty factors) and potential dietary and non

- dietary exposures (i.e., high end estimates of both dietary and non

- dietary exposures). Based on the completeness

o f the database , the Agency re duced the FQPA safety factor to 1X . The assessment includes evaluations of risks for various subgroups, including those comprised of infants and children. The Agency’s complete risk assessment is found in the propiconazole r eregistration docket at http://www.regulations.gov , Docket Identification (ID) Number EPA

- HQ

- OPP

- 2005

- 0497.

9 .0 OCCUPATIONAL EXPOSURE / RISK CHARACTERIZATION

This submission was for a use of propiconazole in imported tea, therefore, no occupational exposure assessment was performed.

10. REFERENCES

Propiconazole

. New Use of Propiconazole on Imported Tea . Summary of Analytical Chemistry and Residue Data.

T. Morton

, D 42288 7

, 12 / 1 /201 5

Propiconazole: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments

for the New Use of Propiconazole on Imported Tea

. , T. Morton

, D 42 6 8 95

, 12 / 1 /2015

Propiconazole: Summary of Hazard and Science Policy Council (HASPOC) Meeting of June 21, 2012:

Recommendations on the need for a 28

- day inhalation study and a subchronic neurotoxicity study

, K

. Rury,

TXR# 0056387

, date

.

### Page 32 of 53

APPENDICES

A TOXICOLOGY DATA SUMMARY

A .1 Guideline Data Requirements

Guideline Data Requirements

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity

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

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

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

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

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

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

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

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

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

- Day Dermal

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

- Day Dermal

................................ .............................. 870.3465 28/ 90

- Day Inhalation

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

yes

yes

no no* yes

yes

yes

-

-

870.3700a Developmental Toxicity (rodent)

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

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

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

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

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

................................ ........ 870.4200a 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

no no** yes

-

-

* waived per HASPOC TXR 0056387

** waived per HASPOC TXR 0056761 and TXR 0056730

.

### Page 33 of 53

A .2 Toxicity Profiles

Table A.2 : Propiconazole Acute Toxicity Profile

GuidelineNo

. Study Type MRID # Results Toxicity Category

870.1100 Acute Oral Toxicity

– rat 00058591 LD 50 =1517 mg/kg III

870.1200 Acute Dermal Toxicity

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

870.1300 Acute Inhalation Toxicity

– rat 41594801 LC 50 = >50.84 mg/L IV

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

870.2500 Acute Dermal Irritation 00058598 No irritation IV

870.2600 Skin Sensitization 44949501 confirmed sensitizer

-

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

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

Classification /Doses Results

870.3100

90

- Day Feeding Study in Rat 00058606 (1997)

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

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

870.3100

3

- month oral toxicity 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)

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), b ased on increase in absolute and relative liver weights and histopathological liver lesions (hypertrophy, necrosis, vacuolation) seen at 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 ppm (13mg/kg/day)

### Page 34 of 53

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

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

Classification /Doses Results

870.3200

21

- Day dermal toxicity

- rabbits 00116591 (1982)

Acceptable/Guideline 0, 3, 30 or 300 mg/kg/day LOAEL : 3 mg/kg/day based on mild dermal irritation (Hyperkeratosis, acanthosis, mild dilation of blood vessels and mononuclear cells and/or heterophils in the proximal dermis). No systemic toxicity was reported.

NOAEL for skin lesions not establ ished

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 mal formations (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: 2/206 4 fetuses of dosed animals vs. 0/1222 controls (lab.hist. control incidence: was 0/5431). This confirms findings of cleft palate noted in above study. Severe clinical toxicity in the treated animals (ataxia, coma, lethargy, prostation, labored 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

NOAEL = 8 mg/kg/day Reproductive Toxicity
LOAEL =>2500 ppm (>263 mg/kg/day, HDT) Offspring Toxicity

LOAEL = 2500 ppm (192

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

NOAEL = 500 p pm (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 (indica ting mild irritation of the mucosa).
NOAEL is 50 ppm (1.25 mg/kg/day)

### Page 35 of 53

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

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

Classification /Doses Results

870.4100

24

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

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

NOAE L was 100 ppm (10 mg/kg/day). Liver tumors at 2500 ppm in male mice.

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 ma les, 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. 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

### Page 36 of 53

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

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

Classification /Doses Results

870.6200b

90

- Day Neuro toxicity Screening Battery (rat) 49300503 (2014)

Acceptable/guideline ♂ 0, 200, 600, or 3500 ppm 0,13, 38, and 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

- 5300

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

Acceptable/guideline

1.16

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

870

- 5385 (bone marrow

chromosomal aberration)

- Chinese

hamsters 00058603 (1979)

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

levels te sted.

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 viabilit y

870

- 5550

Unscheduled DNA synthesis in primary rat hepatocytes 00133348 (1982)

Acceptable/guideline Negative for inducing Unscheduled DNA Synthesis at concentrations up to and including 83.5μg/ml. Highest dose tested

to allow at least 25% cell viability

870

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

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

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

870.5450 Dominant lethal assay

in mice 00058602 (1979)

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

of mice treated with propiconazole.

870.7485

Metabolism and pharmacokinetics (Rat) 42403901 (1983)

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

- 14 C at the

triazole

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

### Page 37 of 53

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

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

Classification /Doses Results

870.7485

Metabolism and pharmacokinetics (Rat) 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 follo wed 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 the 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 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. Similar metabolic profiles for the two labels suggesting that the bridge between the phenyl ring and the triazo le 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. 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 fed in the diet for 21 days at 5, 100 or 2500 ppm propiconazole followed by phenyl

- [U

14 C] single oral

dose a t 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%). Mouse urinary

metabolites 15

- 30. The major metabolic pathway in mice proceeds

via eliminat ion 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 extent (70% & and 40% for males and females, respectively) than do male rats (30%).

870.7 600 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%

870

- 7800

Immunotoxicity MRID 48799701, 2012

Waiver Request waived (TXR 0056761 and TXR 0056730).

.

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.

### Page 38 of 53

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

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

Classification /Doses Results

Non

- guideline Special study

Mechanistic studies: Hepatic biochemical

par ameters

- 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 cont rols) 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 induced by propiconazole. However, the activity of 7

- pentoxyresorufin

- O

- dealkylase, associated with CYP2B or PB

- type induction, was clearly increased 30

- 55

- fold by propi conazole.

Microsomal coumarin 7

- hydroxylase, associated with enzymes belonging t o 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 pa ttern of microsomal and cytosolic enzyme induction determined biochemically was entirely consistent

with PB

- type induction. Propiconazole resulted in a marked

increase of total testosterone oxidation.

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

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

- type induction of cytochrome P450 activity. The effects of propiconazole treatment on mouse liver 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

st rong phenobarbital

- type inducer of xenobiotic metabolizing enzymes in the mouse.

### Page 39 of 53

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

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

Classification /Doses Results

Non

- guideline Special study

Mechanistic studies: Hepatocellular proliferation

- Mouse 45215802 (1999)

Male CD

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

- rela ted 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. Increase d mitotic activity was observed in all groups. Minimal to moderate hepatocellular necrosis 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

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

the number of BrdU

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

BrdU

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

- and dose

related proliferation in the liver followed by a sustained 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 we ll as to a time

- and

dose

- related increase in the severity of hepatocellular hypertrophy.



### A.3 Toxicological Endpoints

A.3.1 Acute Reference Dose (aRfD)

- Females age 13

- 49

Selected Study: Developmental Toxicity in Rats (MRID 40425001).

See Section 3.2.2 and Appendix C.

Dose and Endpoint for Establishing an aRfD : 30 mg/kg/day

- Developmental NOAEL of 30 mg/kg/day and a LOAEL of 90 mg/kg/day based on increased incidence of rudimentary ribs, unossified sternebrae, as well as increased incidence of shortened and absent renal papillae and increased cleft palate.

Uncertainty Factor (UF ): 100

– 10X for interspecies extrapolation and 10X for intraspecies variation.

Comments about Study/Endpoint : The developmental effects of concern are presumed to

oc cur after a single exposure and are relevant to females aged 13

- 50 years old since they occur in utero and to young children based on post

- natal effects.

### Page 40 of 53

A .3. 2 Acute Reference Dose (aRfD)

- General Population

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

– 10X for interspecies extrapolation and 10X for intraspecies variation.

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

aRfD ( General Population ) = 30 mg/kg (NOAEL)

100 ( UF ) = 0. 3 mg/kg

A .3. 3 Chronic Reference Dose (cRfD)

- All Populations

Selected Study: 24 Month carcinogenicity Study in Mice (MRIDs 00129570 & 93194037)

C arcinogenicity Mouse Study

- A 24

- month propiconazole dietary carcinogenicity 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. Non

neoplastic liver effects (increased liver weight in males and increase in liver lesions: masses/raised areas/ swellings/nodular areas mainly) were observed at 50 mg/kg/day. (See Appendi x 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

– 10X for interspecies extrapolation and 10X for intraspecies variati on.

Acute RfD = 30 mg/kg (NOAEL ) = 0. 30 mg/kg/ (Females 13

- 49) 1 00(UF)

### Page 41 of 53

Comments about Study/Endpoint : The lower NOAEL of 2.7 mg/kg/day in a 3

- month oral feeding toxicity study in mice was not selected because a) there 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 year mouse study is

consistent with that seen in an 18

- month mice and 2

- generation reprod uction studies. In an 18

- month carcinogenicity 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 18 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 not systemic toxicity, and target organ (liver) toxicity seen in mice and rats was not seen in dogs.

cRfD ( General Population ) = 10 mg/kg/day (NOAEL)

100 ( UF ) = 0.1 mg/kg/day



### A .3.4 Incidental Oral Exposure (Short

- and Intermediate

- Term)

Incidental Oral Exposure (Short

- 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 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.

Comments about Study/Endpoint : The selected toxicity endpoint was the most sensitive to assess this exposure scenario. The NOAELs in the developmental rat (90 mg/kg/day) and rabbit ( 10 0 mg/kg/day) stud ies were much higher and would not be protective of the toxicity seen in the ACN study

.

Uncertainty Factor (UF )/Level of Concern = 100

– 10X for interspecies extrapolation and

10X for intraspecies variation. FQPA 1X

Incidental Oral Exposure (Intermediate

- Term)

Selected Study: 24 Month carcinogenicity Study in Mice (MRIDs 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.

### Page 42 of 53

Uncertainty Factor (UF ): 100

– 10X for interspecies extrapolation and 10X for intraspecies variation.

A .3.5 Dermal Absorption

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 factor 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.

A .3.6 Dermal Exposure (Short and Intermediate

- Term)

Dermal Exposure (Short

- Term)

Selected Study: Acute Neurotoxicity in Rats (MRID 46046401).

See Section 3.3.1

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 )/Level of Concern= 100

– 10X 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. Although a dermal toxicity study is available with no systemic toxicity at 300 mg/kg/day (propicona zole caused dermal irritation at 3 mg/kg/day and above dose) , a POD from an oral study was selected because clinical toxicity , the primary effect of

concern for short

- term exposure is not specifically evaluated in the available dermal toxicity study . The selected endpoint is protective of potential clinical effects from dermal exposure.

Dermal Exposure (Intermediate

- Term)

Selected Study: 24 Month carcinogenicity Study in Mice (MRIDs 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 ): )/Level of Concern: 100

– 10X for interspecies extrapolation

### Page 43 of 53

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.

A .3.7 Inhalation Exposure ( Short and Intermediate

- Term)

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 )/Level of Concern: 100

– 10X for interspecies extrapolation and

10X for intraspecies variation. FQPA 1X

Comments about Study/Endpoint : Inhalation toxicity is assumed to be equivalent to oral toxicity.

Inhalation Exposure (Intermediate

- Term)

Selected Study: 24 Month carcinogenicity Study in Mice (MRIDs 00129570 & 93194037)

See Section 3.4.3

Dose and Endpoint 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 )/Level of Concern: 100

– 10X for interspecies extrapolation and

10X for intraspecies variation. FQPA 1X

Comments about Stud y/Endpoint : Inhalation toxicity is assumed to be equivalent to oral toxicity.

### Page 44 of 53

A.4 EXECUTIVE SUMMAR IES

870.3 2 00 Dermal Toxicity

In a repeated dose dermal toxicity study (MRID 00116591 and 93194034), groups of 20 New

Zealand rabbits received 15 daily dermal applications of 0 (11 males and 9 females), 3 (11 males and 9 females), 30 (10 males and 10 females), or 300 (13 males and 7 females) mg/kg/day propiconazole technical(90.7%, Batch No. FL

- 810858) over a 21

- day period. The test material

was applied on the intact and abraded skin with an impervious cuff for 6 hours for five days a

week for three weeks. There were no treatment

- related deaths or signs of systemic toxicity and

no treatment

- related effects on body weight, food consumption, or opth almology, hematological and clinical chemistry parameters. One high dose female rabbit died on day 3 following diarrhea, decreased activity and body tone. A male rabbit in the low dose group died on day 23, the day of necropsy. Both deaths were not consi dered compound

- related. Diarrhea was observed in one control female, 2 males and 2 females in the low dose group, and 3 males and 1 female in the mid dose group. Skin irritations were noted in the 30 and 1000 mg/kg/day groups beginning at day 2 and persi sted for the remainder of the study with maximum irritation indexes of 1.0 and 4.1, respectively. Signs of irritation were noted in the 3.0 mg/kg/day group beginning on day 15 in males only with the highest irritation index of 0.3 at day 19.There were no c ompound related gross necropsy, organ weight effects or histopathological findings. There were mild to moderate skin lesions which were dose related in treated animals compared to controls. Hyperkeratosis, acanthosis, mild dilation of blood vessels and mo nonuclear cells and/or heterophils in the proximal dermis were noted in a dose related manner. The LOAEL for systemic effects was >1000 mg/kg/day (the highest dose tested). The NOAEL for systemic effects is 1000 mg/kg/day. The LOAEL for skin effects was 3 mg/kg/day based on mild dermal irritation (Hyperkeratosis, acanthosis, mild dilation of blood vessels and mononuclear cells and/or heterophils in the proximal dermis) at 3 and 30 mg/kg/day and moderate dermal irritation at 1000 mg/kg/day. No NOAEL for s kin lesions was established.

870.3700 Developmental Toxicity

Rat Developmental Toxicity

- Study 1

In an acceptable/guideline developmental toxicity study (MRID 40425001), CGA 64250 technical(92.1% purity propiconazole, Batch no. FL 850083) was admin istered to 24 CL:COBS CD (SD) BR VAF/PLUS virgin female rats/dose by oral gavage in aqueous suspensions (3% corn starch containing 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 days, but because of severe symptoms it was reduced to 300 mg/kg/day. Severe compound

- related maternal toxicity was observed at the high dose level during the first five days 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 biologically significant increases in rales, prostration, hypothermia and bradypnea. The incidence of these effects versus control is as

### Page 45 of 53

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 mg/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 days

7

- 8, 8

- 9 and 9

- 10 and in the 90 mg/kg/day group on days 8

- 9 and 10

- 11. Maternal body weights were not affected by 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

cont rols) during gestation days 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. Th e maternal toxicity LOAEL of propiconazole is 300 mg/kg/day, based on severe clinical toxicity. The maternal toxicity NOAEL is 90 mg/kg/day. Fetotoxic effects observed included a high incidence of rudimentary ribs, though not statistically significant bu t 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 co ntrols), as well as increased incidence of shortened renal papillae (26% in the 90 mg group (not statistically significant) and 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 p a late malformations in the 90 mg group (0.3%) and in the 300 mg group (0.7%) and considered to be “probably 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 p robably under reported because only half of the fetuses were examined viscerally. 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 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 increased 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 by oral gavage in aqueous suspensions (3% corn starch containing

0.5% Tween 80) at dose levels of 0 or 300 mg/kg/day from days 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 cle ft 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

### Page 46 of 53

beginning on gestation day 6 and included a statistically significa nt 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

si gnificantly 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 dos ed 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 f

or external abnormalities only and there were no statistically significant treatment

related, external gross observations among fetuses. Cleft palate was reported in 2/2064 fetuses of dosed animals and 0/1222 of control fetuses. The incidence of cleft p alate 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).

Rabbit Developmental Toxicity

In a developmental toxicity study (MRID 00265796), CGA 64250 technical (92.1% purity propiconazole) was administered to groups (19/group) of artificially inseminated New Zealand white rabbits by oral gavage in aqueous suspen sions (3% corn starch containing 0.5% Tween 80) at dose levels of 0, 100, 250 or 400 mg/kg/day from days 7 through 19 of gestation. One animal

from each of the mid

- dose groups was found dead. In high

- dose animals, 5/19 does were sacrificed early due to a bortion or early 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 animal delivered early. Among animals of the high dose group, an increased inci dence of st ool alterations (decreased/no/soft; 18/19 vs. 11/19 in controls, p<0.05) was observed, possibly compound related. During the dosing period (days 7

- 19), the high and mid dose animals had a significant (p<0.05) decrease in food intake (43

- 63% of the contr ols and 58

- 78% of the controls in the high

- and mid

- dose groups, respectively) and a severe decrease in the maternal body weight gain, but rebounded to normal 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, respectively, compared to a weight gain of 0.018 kg in controls. The weight gains during GD

10

- 20 were 67

- 77% and 11

- 43% of controls at 250 and 400 mg/kg/day, respectively. 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, respectively. The incidence of fetuses at 400 mg/kg/day with this finding was statistically signi ficant. 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 resorption of an entire litter. At 400

### Page 47 of 53

mg/kg/day there was also an increased incidence of abortions. Th e maternal toxicity LOAEL of propiconazole in the rabbit is 250 mg/kg/day, based on reduced maternal body weight gains and decreased food consumption during 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/day.

870.7600 Dermal Absorption Studies

In a dermal absorption study (MRID’s 42415701, 45345901), groups (4/group) of young adult male, Harlan Sprague

- Dawley rats (age not given) were exposed to triazole

- [3,5

- ] 14 

### C

- CGA

64250 (95% radiochemical purity, specific activity 28.2 mCi/mg for low and mid

- dose levels and 2.01 mCi/mg for the high

- dose level) at doses of 0.1, 1.0 or 10 mg/rat (0.01, 0.1 or 1 mg/cm 2



### , respectively) to a 10 cm 2 

### shaven dorso

- lumbar area. The radioactive test compound was added to the 3.6EC formulated product (45.8% active ingredient and 54.2% inert substances) and applied

as an aqueou s suspension. One group of four rats/dose were exposed for 24 hours, while two other groups of four rats each/dose were exposed for 10 or 24 hours followed by a 72

- hour depletion phase. This study is an addendum to an earlier study where groups of four ma le rats each were treated similarly but exposed for 2, 4 or 10 hours (MRID 00164469). In both studies, following the exposure period, the test compound remaining on the skin was removed with a soap rinse. Fecal and urinary samples were collected at the e nd of the exposure periods and at 24 hour intervals (for the depletion groups) following the exposure.

At sacrifice time rats were anesthetized and blood collected. The radioactivity present in excreta, blood, carcass, skin, skin washes and patch componen ts were determined. The applied radioactivity was accounted for, with recoveries ranging from 82.8 to 108 % for MRID

42415701 and 86.6 to 112.6% for MRID 00164469.

The amount of test compound absorbed was directly proportional to the applied dose. The r ate of absorption appeared to be saturated at the highest dose level; at the low dose level, there was a time dependent increase in the amount of compound absorbed. After 24 hours, 57.1, 271 and 3010 μg/cm 2 

### (57.13, 27.14 and 30.10% of total dose were abso rbed at the low, mid and high dose levels, respectively). During the 72

- hour depletion phase essentially all of the compound was eliminated in the urine and feces; urinary elimination predominated at the mid and high dose

levels. At the end of the 72 hour depletion phase, less than 2% of the test compound was still present in the carcass. The results of the earlier study (MRID 00164469) demonstrated that 26

- 35% of the applied radioactivity (at all dose levels) is absorbed within the first two hours and

re mained fairly constant for the longer exposure periods of 4 and 8 hours except for the low dose of 0.01 mg/cm 2 

### where it increased to 54%. The average dermal absorption of propiconazole over a 10 hour period at an exposure level of 0.01 mg/cm 2 

### is approxima tely 40%. The attached appendix provides a summary of both studies.

### Page 48 of 53

870.3800 Reproduction

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 f

or 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 administered 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% of controls, p<0.01). Correspondingly, high dose females also had significantly reduced fo od 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 d uring 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 (8 4

- 88% of controls). Histological examinations revealed that hepatic “cellular swelling” was significantly 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 find ing was significant for both sexes in the mid

- and high

- dose groups. The incidence of “hepatic clear

- cell change” was significantly 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 parameters (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 

### litter s, 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 sta tistically significant). The F 2b 

### litters of these dams had significantly reduced survival rates (both number and percent of surviving pups) at lactation days 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 days 4 and 7 (except for F 1b 

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

### litters only). At necropsy, no treatment related anomalies, organ weight changes and gross pathology fin dings 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 “cellular swelling” in high

- dose males and females. This was considered to be a compound rel ated 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,

### Page 49 of 53

based on decreased offspring survival and body weights and an increased incidence of hepatic lesions (cellular swellin g) 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 days

6

- 15 of gestation (Hassan, 1993. Embryotoxic and teratogenic effects of the organic fungicide tilt in albino rats. Bull. Fac. Pharm., 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 missing 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 establishe d.

870.6200b Subchronic Neurotoxicity

In a subchronic neurotoxicity study (MRID 49300503 ), Propiconazole (95.2% a.i. ) was administered to groups of ~6

- week

- old Crl

- CD(SD) rats (12/sex/dose) continuously in the diet for 13 weeks at concentrations of 0, 20 0, 600, or 1500 ppm (females) or 3500 ppm (males) (equivalent to 0,13, 38, and 222 mg/kg bw/day, respectively, in males and 0, 15, 45, and 111 mg/kg bw/day, respectively, in females). Dietary levels were chosen based on the findings of a

4

- week dietary ra nge

- finding neurotoxicity study ( MRID 49300502). Neurobehavioral assessment (functional observational battery (FOB) and motor activity testing) was performed in

12 animals/sex/group during pretest (Week

- 1) and Weeks 1, 3, 7, and 12. Cholinesterase

activi ty was not determined. At study termination, 5 rats/sex/group were euthanized and perfused in situ for neuropathological examination. Of the perfused animals, 5 rats/sex each from the control and high

- dose groups were subjected to histopathological evalu ation of brain and peripheral nervous system tissues.

Males at 3500 ppm had a statistically significant decrease in mean body weight gain over Days

1

- 7 (83% of controls) accompanied by a reduction in food consumption (88% of controls). Although not stat istically significant, overall body weight gain in high

- dose males was reduced to 89% of controls, indicating that the male rats fed the high dose were not able to completely recover from the reduction in body weight that occurred during the first week of treatment. No significant changes in body weight, body weight gain, or food consumption were noted in

females.

Dietary treatment with up 3500 ppm in male rats and 1500 ppm in female rats did not result in

### Page 50 of 53

any signs of neurotoxicity as indicated by clini cal observations, mortality, FOB observations, motor activity counts, or neurohistopathological evaluation, and no treatment

- related effects were noted during ophthalmoscopic examination, gross pathology or in brain weight and brain

dimension measurements. Positive control data were provided.

Based on the effects seen in this study, the LOAEL for Sprague

- Dawley male rats was 3500 ppm (equivalent to 222 mg/kg bw/day) based on significant reductions in body weight gain and food consumption, with a NOAEL of 600 ppm (equivalent to 38 mg/kg bw/day). The NOAEL in female Sprague

- Dawley rats was 1 500 ppm (equivalent to 111 mg/kg bw/day)

and a LOAEL was not established.

870.5100, 870

- 5300 Mutagenicity

Propiconazole was negative in six acceptable mutagenicity studies:

1. In vitro cell transformation assay (MRID 00133349 )

2. Bone Marrow Chromosomal Aberration (MRID 00058603 )

3

. Mutagenicity: Unscheduled DNA synthesis (MRID 00133347 )

4 . Mutagenicity: Unscheduled DNA synthesis (MRID 00133348 )

5. Mitotic Gene C onversion Assay (MRID 00133343) 6. Dominant Lethal Assay in Mice (MRID 00058602)

870. 7 800 Immunotoxicity

Propiconazole is one of the conazoles that were reviewed as a class by the Hazard and Science Policy Council (HASPOC) for the immunotoxicity test requirements (TXR 0056730). A waiver was recommended for an immunotoxicity study for the class of conazole pesticides based on the following considerations:

• There was no evidence of adverse effects on the immune system in mice, rats, or dogs in the data base for any of the conazole pesticides. • The liver, not the immune system, is generally the target organ for this chemical class, and hepatotoxicity or body weight changes are the primary toxicological endpoints of

concern and were used in risk assessments. • The conazoles do not belong to a class of chemicals (e.g., the organotins, heavy metals, or halogenated aromatic hydrocarbons) that would be expected to be immuno t oxic. There was no evidence of immunotoxicity with six other structurally

- related conazole fungicides, namely, flutriafol, metconazole, tebuconazole, tetraconazole

, triadimefon, triflumizole, and triticonazole. In the Immunotoxicity study for triflumizole

, the effects on the immune system occurred only at the highest dose tested. Immunotoxicity was demonstrated with difenoconazole, however it was observed in the presence of systemic toxicity and at a relatively high dose. PODs based on the most sensitive endpoints obtained via the appropriate routes of exposure in the most sensitive species are currently used for dietary and non

- dietary risk assessments.

### Page 51 of 53

All these factors indicate that an immunotoxicity study would most likely not result in an adverse effect that could be used as an endpoint for conazole risk as sessment. Based on a weight of evidence approach, the HASPOC concluded that immunotoxicity studies are not required as this time for propiconazole (TXR 0056730). An immunotoxicity study is not anticipated to provide a lower POD or result in a more sensitiv e endpoint than those already used. Therefore the waiver request is granted (TXR 0056761)

.

### Page 52 of 53

APPENDIX B. Chemical Names And Structures Of Metabolites

### Page 53 of 53

APPENDIX C. Physical/Chemical Properties

Physicochemical Properties of Technical Grade Propiconazole

.

Parameter Value Reference

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

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

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

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

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

toluene and n

- octano l. hexane = 47 g/L MRID No. 42030201

Vapor pressure 4.2 x 10

- 7 mm Hg at 25 C MRID No. 41720301

Dissociation constant (pK a ) 1.09 MRID No. 43698701

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

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



### APPENDIX D. Studies Reviewed for Ethical Conduct

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies were determined to require a review of their ethical conduct, have received that review and have been determined to be ethical.

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task Force

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

The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler Unit Exposure Surrogate Reference Tabl e. U.S. Environmental Protection Agency. Released June 21, 2011.