### UN ITED STATES ENV IRO NMENT AL PROTECTION AGENCY

MEMORANDUM

Date: 29-0CT-2015 WASHINGTON, D.C. 20460

OFF I CE OF C llEMI CALSAFE TY ANO P O LL UT I ON PREVENT I ON



### SUBJECT: Cyproconazole. Scoping Document in Support of Registration Review For Human Health Risk Assessment.

PC 

### Co d e : 128993 

### D ec i s i o n No .:**50~'175** 

### Petition No.: N I A DP 

### Barcode: 04 29084 

### R eg i st ration No.: N I A 

### Regulatory Action: Registration Review Scoping D ocument 

### Case No.: 7011 

### Risk Assessme nt Type: N I A 

### TXR 

### No.: N I A 

### CAS No.: 94361-06-5 40 

### CF R: § 180.485 

### MRID 

### No.: N I A



### F RO M:

. George F. Kramer, Ph.D., Sen i or

# Chemi**~** L

# ~ Anwar Y. Dunbar

, Ph.D.

, Pharmacologist · •**~** 

### Jo shua G. Go dsh a ll

, Biologist 

## QrRisk Assessment Branch I 

## (RA.Bf) Health Effects Division (HED

, 7509P)

Jenny Tao
, Senior Toxicolog·st

# C.**, A_.:.~**  ' 

### Na than Mott!, Bio l og i st

# /'.J1.v/1~.,.ll i"IJ,il 

# f

Risk Assessment Science Support Branch (RASSB) Antim icrobials Division (A O

, 751 OP)



### T HRO UGH: Charles Smith, Branch Chief

, RAB RABl/HED (7509P)

Steven Weiss

, Branch Chief Timothy Leighton, Senior Scientist RASSB I AD (7510P)



### TO: M i gue l Zava la

, Chemica l R ev i ew Manager Pesticide Re-Evaluation Division (PRD) (7508P)

Rachel Ricciardi

, Chemical Review Manager Antimicrobials Division (AD

, 751 OP)

Attached is HED's and AD ' s h uman health risk assessment scop i ng document for cyproconazo l e to support Registration Review.
Page I of28

### T a ble of Cont e nt s
Executive Summary

............... . ........................................................................................................ 3

1.0 Introduction

.... . ................................................................................................................ . ........ 5

2.0 Hazard Characterization/ Assessment..

................................................... . ......... . ........ . ..... . ........ 5

3.0 Res i due Chemistry

....................................................... . ....... . ....... . .......... . ...... . ..... . .. . .... . .. . ..... .. . 6

4.0 D i etary Expos u re

.. . ... . .. .. .. . ... .. ...... ... ... . .. .. .... .. .. . .... .. ....... .. ...... .. ...... .. ..... .. .. . ... . .. . ..... . .. . ........... . .. . 7

5.0 Reside n tial Exposure

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

6.0 Aggregate-Risk Assessment

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

7.0 Occupational Exposure

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

8 .0 Public Hea l th and P esticide Ep i dem i o l ogy Data

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

9.0 Tolerance Assessment and I nternat i ona l Harmonizat i on

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

10.0 Environmenta l Justice

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

11.0 Cumulative

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

12.0 Human Studies

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

1 3 .0 Risk Assessment Updates

, Data D eficienc i es , and Labe l Revisio n s

......... . .. .. .... . .. . .... .. ....... 1 4

14.0 References

........**~** 

### ................................... . ............... . .... . .. .. ... . ... . ... . .. .. ..... ... . . ...... . ..... . .. . ..... . ...... 15

Attac h ment I: Chemical I dent i ty Tab l e .

. .. .. ........ .. ........ . ........ . ..................................................... 17

Attachment 2: Cyproconazole E ndpoint Selection Tables ( from 2012 Ri sk Assessment)

... . ...... 19

Attachment 3: Cyproconazo l e Acute. Subchronic

, and Chronic Toxicity Profi l e

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

Attachment 4: Summary of Re g istered Uses

...... .. ........ . ... .. . ... ... . ... . ...... . .......... . ........................... 26

Attachment 5: Cyproconazole In ternationa l R es i due L i mit S t atus Sheet

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

Pa ge 2 of28Cyproconazole Registration Review Human Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 3 of 28 

### Executive Summary

HED and AD have prepared a scoping document to support Registration Review of the broad

spectrum triazole (Group 3) fungicide cyproconazole

. Cyproconazole is currently registered as a post

- emergence foliar applied fungicide to corn (field, and seed), cereal s (wheat and triticale), soybeans, and peanuts. Several products are registered, all of which are s uspen sion concentrate (SC) formulations. The most recent HED human health risk assessment was performed in 201 2 for the use of cyproconazole on peanuts ( D399957

, S. Levy et al.

, 03

- OCT

- 2012 ). There are currently no pending PRIA actions for cyproconazole

. AD registered a new antimicrobial cyproconazole product as a composite wood preservative in 2015. The new AD product (EPA Reg. 72616

- 9) contains 4.5% cyproconazole and 45% triadimefon. All other antimicrobial products for this active ingredient have been voluntarily cancelled by the registrant

, and there are no other pending PRIA actions for cyproconazole.

HED and AD have evaluated the status of the human health assessments for cyproconazole to determine whether sufficient data are av ailable and whether any updates are needed to support Registration Review. HED and AD have considered all available data and human health risk assessments for cyproconazole with respect to its toxicity, exposure, and usage databases, and the most updated Agency science policy and risk assessment methodologies to determine the scope of work necessary to support Registration Review.

The toxicity database for cyproconazole is complete and adequate to support Registration Review requirements. No new data are required. For Registration Review, points of departure (PODs) and uncertainty/ safety factors ( UF/ SFs) for cyproconazole will be re

- evaluated as appropriate

. The residue chemistry database for cyproconazole is adequate to support current Registration Rev iew data requirements. Adequate metabolism (crops, livestock, and rotational crops), storage stability, magnitude of the residue, and processing data are available to support the registered uses. Adequate methods are available for enforcement of the curr ently established tolerances.

The dietary

- exposure database for cyproconazole is adequate to support current registration requirements. The most recent risk assessment provided unrefined acute and chronic dietary (food + drinking water) exposure estimat es that are below HED’s level of concern (LOC) for the general U.S. population and all population subgroups. Acute dietary (food + drinking water) risk estimates were <100% population

- adjusted dose (aPAD) at the 95 th 

### percentile of the exposure; females 13 to 49 years old were the population with the greatest risk (3 2 % aPAD ). Chronic dietary (food + drinking water) risk estimates were <100% chronic population

- adjusted dose (cPAD); all infants (<1 years old) were the most highly exposed population ( 28 % cPAD ). A chronic cancer dietary assessment was not conducted since it was determined that cyproconazole is not a possible human carcinogen

. HED notes that the 201 2 acute and chronic dietary assessments did not incorporate ground water estimated drinking water concentrations (EDWCs) modeled using the Pesticide Root Zone Model for GroundWater (PRZM

- GW). The impacts of using this model to estimate ground water concent rations of cyproconazole will need to be considered during Registration Review. As part of Registration Review, a revised dietary

exposure analysis may be required to reflect the most recent dietary

- exposure models

, potential revised EDWCs (specifically, use of PRZM

- GW) , and/or revised toxicological PODs

. There are no proposed or registered products containing cyproconazole at this time that wouldCyproconazole Registration Review Human Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 4 of 28 

### result in residential exposure. Therefore, a residential handler and post

- application exposure assessment is not currently required for Registration Review.

In accordance with the Food Quality Protection Act (FQPA), HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. Bec ause there are no residential uses for cyproconazole, only food and water were included in previous aggregate assessments. There is sufficient information available to assess aggregate exposure; however , a new aggregate risk assessment may be required dur ing Registration Review to incorporate revised dietary exposure analyses and/or toxicological PODs

. Application of cyproconazole also results in potential exposures to the metabolites T (1,2,4

- triazole), TA (triazolylalanine), TAA (triazolylacetic acid) , and THP ( triazolyl hydroxypropionic acid ). These compounds are considered to be toxicologically different from cyproconazole

. HED recently conducted an aggregate risk assessment for these compounds with the resulting exposure estimates less than HED’s level of concern (D426493, T. Morton, 0 9

- APR

- 2015). As part of Registration Review , a revised triazole risk assessment may be required.

Revised o ccupational handler and post

- application exposure and risk assessments are needed for the conventional uses during Registration Review to account for recent changes in exposure assessment assumptions, including body weight, amount treated, and transfer coefficients (TCs)

. AD recently conducted an occupational and residential assessment for the only registered cyproconazole label on 0 9

- S EP

- 2015 (D428952). No data or additional assessments were required in this risk assessment. AD did not conduct an occupational handler risk assessment since the label specifically restricts applications to closed loa ding systems. Additionally, residential exposure was not applicable since the wood uses specified on the label were for engineered and composite wood that is not used to manufacture decks and playsets.

The Agency will examine the need for spray drift and volatilization assessments during Registration Review for cyproconazole based on the potential for exposure to bystanders from agricultural applications.

No data deficiencies were identified for cyproconazole

. EPA notes the following risk assessment upd ates will need to be completed during Registration Review:

o Toxicology:

o Re

- evaluation of PODs and UF/SFs

. o Residue Chemistry/ Dietary Exposure:

o A revised dietary

- exposure analysis may be required to reflect the most recent dietary

- exposure models

, potential ly revised EDWCs (specifically, use of PRZM

GW) , and/or revised toxicological PODs and UF/SFs

. o Occupational/Residential Exposure:

o Revised occupational handler and post

- application risk assessments will be
necessary for the conventional uses of cy proconazole to reflect the most recent HED policies and/or toxicological PODs and UF/SFs

. o S pray drift and bystander assessment s may be necessary to reflect current HED policies

. o Aggregate Exposure:

o Revised aggregate exposure analyses may be required to reflect revised dietary exposure estimates and/or changes to the toxicological PODs and UF/SFs

.Cyproconazole Registration Review Human Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 5 of 28 

### 1.0 Introduction

HED has prepared a scoping document to support Registration Review of the broad

- spectrum triazole (Group 3) fungicide cyproconazole. Cyproconazole is a mixture of two distereoisomers (2RS,3RS:2RS,3SR; ~1:1) and acts by inhibiting sterol biosynthesis in fungi. It is effective for the control of several plant diseases, such as yellow Sigatoka ( Mycosphaerella musicola ) and black Sigatoka ( Mycosphaerella fijiensis var. difformis ) in bananas, early leaf spot ( Cercospora arachidicola ) and stem rot ( Sclerotitum rolfsii ) in peanuts, and rust ( Puccinia spp. ) and powdery mildew ( Erysiphe spp. ) in wheat and soybean. Several products are registere d, all of which are SC formulations. The most recent human health risk assessment was performed in 2012 and was for the use of cyproconazole on peanuts ( D399957 , S. Levy et al. , 03

- OCT

- 2012 ). There are currently no pending P RIA actions for the convention al uses of cyproconazole.

AD has only one registered antimicrobial product of cyproconazole and one use , which is a composite wood preservative for structural lumber that contains 4.5% cyproconazole and 45% triadimefon

. AD recently conducted an occupational and residential assessment for th is label on 09

- SEP

- 2015 (D428952).

2.0 Hazard Characterization/Assessment

Consistent with other triazole

- fungicides (e.g., tetraconazole), the most sensitive mammalian toxicological effects for cyproconazole following oral exposure occur in the liver. A t higher doses greater than those causing liver toxicity

, increased macrophages in the lung, increased white blood cell counts and globulins were observed through both the oral and dermal routes

. Additionally , increased hemosiderin deposition in the spleen of females and evidence of thyroid hypertrophy of the follicular epithelium were observed only through the dermal route.

There was no evidence of increased susceptibility following in utero exposure to rats. There was no evidence of offspring toxicity in the two

- generation reproduction toxicity study. In the prenatal developmental toxicity study in rabbits, t here was evidence of an increased quantitative fetal susceptibi lity, such that malformations were seen at a dose below maternal toxicity. However, t here are no residual uncertainties for pre and/or post

- natal toxicity since: 1) Clear no

observed adverse

- effect levels (NOAELs) were established for the observed fetal effects and; 2) The POD is used for acute dietary risk assessment for the most sensitive population and are protective of the prenatal susceptibility.

Cyproconazole is not acutely toxic through the oral, dermal, and inhalation routes (Toxicity Category III). It is neither an ocular nor a dermal irritant (Toxicity Category IV). Cyproconazole did not cause dermal sensitization.

The endpoints presented in Attachment 3 are from the most recent risk assessment for cyproconazole ( D399957 , S. Levy et al.

, 03

- OCT

- 2012 ). As part of Registration Review, the PODs and UF/ SFs for cyproconazole will be re

- evaluated as appropriate. Using a weight

- of

evidence approach, HED’s Hazard Science and Policy Council (HASPOC) determined that acute and subchronic neurotoxic ity studies, immunotoxicity

, and subchronic inhalation studies are not required at this time (K. Rury et al ., TXR# 0052355 , and J. Bever et al. , TXR# 0057282 ). The hazard profile table containing all of the currently reviewed data is presented in Attachme nt 2

.

Conclusions: The toxicity database for cyproconazole is complete and adequate to supportCyproconazole Registration Review Human Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 6 of 28 

### Registration Review requirements. No new data are required. For Registration Review, PODs and UF/ SFs for cyproconazole will be re

- evaluated as needed/appro priate

.

3.0 Residue Chemistry

Cyproconazole is currently registered to Syngenta Crop Protection for use on peanuts, soybeans, and cereal grains. Permanent tolerances are established for the free and conjugated residues of the fungicide cyproconazole, α

- (4

- chlorophenyl)

- α

- (1

- cyclopropylethyl)

- 1 H

- 1,2,4

- triazole

- 1

- ethanol, in or on imported green coffee beans, aspirated grain fractions, field corn raw agricultural commodities (RACs), peanut RACs, soybean RACs, wheat RACs, the fat and meat byproducts of ca ttle, goat, horse and sheep [40 CFR §180.485(a)(1)]. A tolerance is established for the combined free and conjugated residues of cyproconazole and its metabolite [δ

- (4

- chlorophenyl)

- β,δ

- dihydroxy

- γ

- methyl

- 1 H

- 1,2,4

- triazole

- 1

- hexenoic acid in or on milk [4 0 CFR §180.485(a)(2)]. In addition, tolerances are established for the combined free and conjugated residues of cyproconazole and its metabolite 2

- (4

- chlorophenyl)

- 3

- cyclopropyl

- 1

- [1,2,4]triazol

1

- yl

- butane

- 2,3

- diol, in or on the liver of cattle, goat, ho rse and sheep [40 CFR §180.485(a)(3)].

The nature of cyproconazole residues in plants is adequately understood for purposes of currently registered crops. For purposes of establishing tolerances and risk assessment, the residues of concern are free and conjugated cyproconazole (D 352237 , M. Rust

- Clock et al. , 02

- MAY

- 2008). The nature of cyproconazole residue in livestock is adequately understood. Based on the available ruminant metabolism data and the results of the dairy cattle feeding study, HED

conc luded that the residues of concern for the tolerance expression and risk assessment in milk are cyproconazole (free and conjugated) and metabolite M36

. In liver

, the residues of concern for the tolerance expression and risk assessment are cyproconazole (f ree and conjugated) and Metabolite M14

. In meat, meat byproducts (except liver), and fat ; the residues of concern for the tolerance expression and risk assessment are free and conjugated cyproconazole (D 352237 , M. Rust

- Clock et al. , 02

- MAY

- 2008).

HED has also determined that T, TA, TAA, and THP are also potential residues of concern in plants and livestock for all triazole fungicides. However, these triazole

- related residues will not be regulated for specific triazole pesticides, but will be evaluated fo r the entire class of triazole compounds. Issues related to T, TA, TAA, and THP are addressed in a separate document ( D426493, T. Morton, 09

- APR

- 2015 ).

An adequate gas chromatograph/nitrogen

- phosphorus detection (GC/NPD) method is available for enforcing tolerances of cyproconazole (free and conjugated) on plant commodities (Method AM

- 8022

- 0994

- 3). Syngenta has also submitted a copy of a method (Method A M

- 0842

- 0790

- 0), which is essentially identical to the current tolerance enforcement method, except that it includes the option for analysis by either NPD or mass

- selective detection (MSD). The validated method limit of quantitation (LOQ) is 0.01 ppm. LC

- MS/MS method (Syngenta Method RAM 499/01) is adequate for enforcement for residues cyproconazole in livestock commodities. The method has also undergone a successful ILV trial and radiovalidation. Syngenta has provided LC/MS/MS enforcement methods for th e determination of residues of M14 in liver (Method GRM033.03A), and for the determination of residues of M36 in milk (Method GRM033.02A). HED has determined these methods are suitable as enforcement methods as defined in Standard Operating Procedure (SOP ) No. ACB

- 019 (9/15/08).Cyproconazole Registration Review Human Health Assessment Scoping Document

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Page 7 of 28 

### Multiresidue Method testing data for cyproconazole were submitted and forwarded to FDA. The 1/94 FDA PESTDATA database (PAM Volume I) indicates that residues of free cyproconazole are completely recovered (>80%) using multiresidu e method Sections 302, but are not recovered using Sections 303 and 304.

Adequate field trial and processing data are available to support all registered use s of cyproconazole . An adequate number of trials were conducted in the appropriate geographical regions using the appropriate formulation s applied at the maximum use rate s . These studies are also supported by adequate storage stability data and processing data. Adequate magnitude of the residue data in livestock are also available.

The previousl y submitted confined/limited field rotational crop trial data reflecting a total application rate of 0.073 lb ai/A/season are adequate, and support the rotational crop restrictions on the current labels

. Primary crops may be replanted immediately, if crop is lost. Cotton and

c ereal grains other than wheat can be planted 180 days after last application

. All other crops (including leafy vegetables) can be planted 270 days after last application.

A nalytical standards for cyproconazole (expiration date 4/30/2017) and metabolite s M14 (2

- (4

- chlorophenyl)

- 3

- cyclopropyl

- 1

- [1,2,4]triazol

- 1

- yl

- butane

- 2,3

- diol ; expiration date 12/31/2016 ) and M36 (δ

- (4

- chlorophenyl)

- β,δ

- dihydroxy

- γ

- methyl

- 1 H

- 1,2,4

- triazole

- 1

- hexenoic acid; expiration date 12/31/2016) are currently available in the National Pesticide Standards Repository (personal communication s with Theresa Cole, 9 / 1 /1 5 and 9/14/15 ).

Conclusions : The residue chemistry database is adequate to support current Registration Review data requirements. Adequate metabolism (crops, livestock, and rotational crops), storage stability, magnitude of the residue, and processing data are available to support the registered uses. Adequate methods are a vailable for enforcement of the currently established tolerances.

4.0 Dietary Exposure

Unrefined acute and chronic aggregate dietary (food + drinking water) exposure and risk assessments were conducted for cyproconazole using the Dietary Exposure Eval uation Model software with the Food Commodity Intake Database (DEEM

- FCID) Version 3.16, which uses food consumption data from the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). Th is dietary survey was conducted from 2003 to 2008. The acute and chronic analyses were performed to support a Section 3 request on peanuts. The unrefined acute and chronic analyses assumed tolerance

- level residues, 100% crop treated (CT), and DEEM (ver. 7.81) default processing factors. EDWCs were incorporated directly into DEEM

- FCID under the food categories “water, direct, all sources” and “water, indirect, all sources.” Tier 1 EDWCs from surface water were estimated using the FQPA Index Reservoir Scr eening Tool (FIRST) (Version 1.1.1) and EDWCs in ground water were estimated using the S creening C oncentration I n Gro und W ater model (SCI

- GROW) (Version 2.3). Since the EDWC estimates from surface water were higher than those from groundwater, EDWC estima tes in surface water were used in both acute and chronic dietary risk
assessments.

An acute dietary risk analysis was conducted only for females 13

- 49 years old since an endpoint of concern attributable to a single dose for general population was not id entified. The resulting acute (food + drinking water) risk estimate for female 13

- 49 years old was 32% of the aPAD at the 95 th 

### percentile of the exposure distribution; i.e., below HED’s LOC (<100% aPAD).Cyproconazole Registration Review Human Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 8 of 28 

### Therefore, the acute dietary exposure to cyproconazole is not of concern to HED.

The resulting chronic (food + drinking water) risk estimates were less than HED’s LOC (< 100% of the cPAD) for U.S. general population (13% of the cPAD) and all population sub

- groups; the most highly exposed population subgroup was all infants (<1 years old) at 28% of the cPAD. Therefore, the chronic dietary exposure to cyproconazole is not o f concern to HED. A chronic cancer dietary assessment was not conducted since it was determined that cyproconazole is not a possible human carcinogen.

HED note s that the 201 2 acute and chronic dietary assessment s did not incorporate ground water EDWCs m odeled using PRZM

- GW. The impacts of using this model to estimate ground water concentrations of cyproconazole will need to be considered during Registration Review.

EPA has not established tolerances or tolerance exemptions for residues for the antimic robial uses of cyproconazole. Cyproconazole has not been cleared as a food additive by the US Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act (FFDCA) Section 409. There are no currently registered antimicrobial uses that could result in direct or indirect food contact. Therefore, these uses are not expected to contribute to the dietary exposure for the conventional agricultural uses of cyproconazole (i.e., direct treatment to growing crops intended for human or livestock consumption). Additionally, the conventional agricultural uses of cyproconazole do not result in dietary exposure risks of concern. Therefore, a dietary exposure assessment has not been conducted for the antimicrobial uses of cyproconazole.

Conclusio ns: The dietary

- exposure database is adequate to support current registration requirements. In the most recent risk assessment, chronic dietary exposures were not of concern to HED. However, as part of Registration Review, a revised dietary

- exposure ana lysis may be required to reflect the most recent dietary

- exposure models and potential revised EDWCs (specifically, use of PRZM

- GW) and/or revised toxicological PODs

.

5.0 Residential Exposure

There are no proposed or registered conventional or antimicrobial products containing cyproconazole at this time that would result in residential exposure. Therefore, a residential handler and post

- application exposure assessment is not currently required for Registration Review.

AD does n ot expect r esidential post

- application exposure to decks or play sets (D428952). The engineered and wood composite uses on the label include oriented strand board, waferboard, fiberboard, particleboard, plywood, laminated veneer lumber (LVL), and parallel

- strand lumber (PSL)

. T hese types of wood products are most useful for interior construction uses

, such as I

joist framing, and structural beams , but also have outdoor construction uses

. LVL is used in both bearing and non

- bearing walls, as planks, beams, headers, door and window frames, sliding door rails, steps, as well as in the roof trusses ; PSL is used for load bearing posts and beams. AD anticipates that homebuilders would not use t h is wood to construct wood decks or playground
structures

. AD expects limited dermal post

- application contact to children

. D rywall would prevent dermal contact from many of the interior wood structural uses

. Dermal exposure to the types of outdoor wood uses listed on the label (e.g., door frames, posts, beams, and windowsills ) would be minimal

. Inhalation exposure is negligible based on the low vapor pressure of cyproconazole (less than 1 x 10

- 6 

### mm Hg).Cyproconazole Registration Review Human Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 9 of 28 

### Non

- Occupational Spray Drift Exposure and Risk Estimates : Residential bystander exposures resulting from off

- si te transport (e.g., spray drift or volatilization) may occur as a result of applications of cyproconazole. The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process

, which ensures that all uses for that pesticide will be considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs)

– Residential Exposure Assessment Standard Operating Proce dures Addenda 1: Consideration of Spray Drift. This document outlines the quantification of indirect non

- occupational exposure to drift. In terms of volatilization, the agency has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

OPP

- 2014

- 0219 ). During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for cyproconazole.

Conclusions : There are no proposed or current registrations for products containing cyproconazole that allow residential use. Therefore, residential handler and post

- application exposure assessments will not be needed during Registration Review. The need for spray drift and volatilization risk assessment for the conventional uses of cyproconazole will be examined during Registra tion Review.

6.0 Aggregate

- Risk Assessment

The most recent aggregate

- risk assessment was performed in conjunction with the 201 2 HED human health risk assessment ( D399957, S. Levy et al. , 03

- OCT

- 2012 ). The Agency conducts aggregate exposure assessments by summing dietary (food and water) and residential exposures. Since there are no registered/proposed uses of cyproconazole that result in residential exposure, the acute and chronic aggregate risk assess ments are equal to the acute dietary and chronic dietary estimates (food and water only), respectively. Short

- , intermediate

- , and long

- term aggregate

- risk assessments were not performed because there are no registered or proposed uses of cyproconazole th at result in residential exposures. A cancer aggregate

- risk assessment was not performed because cyproconazole is classified as “not likely” to be carcinogenic to humans

. Application of cyproconazole also results in potential exposures to the metabolites T, TA, TAA, and THP. These compounds are considered to be toxicologically different from cyproconazole

. HED recently conducted an aggregate risk assessment for these compounds with the resulting exposure estimates less than HED’s level of concern (D4264 93, T. Morton, 0 9

- APR

- 2015). As part of Registration Review , a revised triazole risk assessment may be required.

Conclusions: There is sufficient information available to assess aggregate exposure. However, new aggregate risk assessments may be requi red during Registration Review to incorporate revised dietary exposure estimates and/or toxicological PODs.

7 .0 Occupational Exposure

Cyproconazole is currently registered as a fungicide in post

- emergence foliar applications to cereal grain s, soybeans, and peanuts

. Cyproconazole is registered as a n engineered and composite wood

- based product. There are no existing pressure

- treated antimicrobial wood

preservative products. There is potential for short

- and intermediate

- term occupational expos ure to cyproconazole during handling (mixing, loading, and applying) and post

- application activities.Cyproconazole Registration Review Human Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 10 of 28 

### Previous conventional assessments ( D322542, M. Clock

- Rust, 07

- OCT

- 2005; D330711, K. Lowe, 06

- SEP

- 2007; D400184, J. Tyler, 0 3

- O CT

- 2012) estimated exposure for various occupational handler scenarios and found no risks of concern. Based on existing registrations, the previous assessments identified the anticipated occupational handler and post

- application exposure scenarios, so no additional scenarios need t o be included in Registration Review. Additionally, since the previous reviews, there have been several updates to HED’s exposure policies, including updates to default exposure data used for handler scenarios and assumptions for body weights (Registratio n Review will need to consider these updates).

A previous antimicrobial assessment ( D428952, T. Dole, 09

- SEP

- 2015) estimated exposure for a wood product use and concluded that a quantitative risk assessment was not needed for occupational handlers or post application exposures since the label specifically restricts applications to closed loading systems. Since this is a recent action, no additional risk
assessments are anticipat ed in registration review.

Occupational Handler Exposure/Risk Estimates The registered cyproconazole labels require occupational handlers to wear long

- sleeved shirts, long pants, shoes, socks, and chemical

- resistant gloves. Applications can be made usin g groundboom, aerial, and chemigation equipment. The updated occupational exposure assessment policies and body

- weight assumptions were incorporated into the peanut cyproconazole exposure assessment and all current occupational handler margins of exposure (MOEs) for peanuts are not of concern (MOE >100) ( D400184, J. Tyler, 03

- OCT

- 2012 ). However, updated assessments will be needed for occupational handlers of cyproconazole for the treatment of corn, cereals, and soybeans due to the updated occupational exp osure policies.

AD considered that t he potential for occupational dermal and inhalation exposure during the mixing and loading of cyproconazole into the processes used to manufacture engineered and composite wood products are expected to be negligible s ince closed loading and delivery systems are required

. AD does not typically conduct occupational handler risk assessments and considers data waivers for low vapor pressure chemicals if the label specifically restricts applications to closed loading systems (78 FR 26935).

Occupational Post

- Application Exposure/Risk Estimates Occupational post

- application short

- and intermediate

- term dermal exposures are possible for workers contacting treated crops. The MOEs in the most recent occupational post

- application exposure assessment for peanuts are not of concern (MOE >100) and it i ncorporated the updated exposure assessment policies utilizing changes in TCs and body weight assumptions ( D400184, J. Tyler, 03

- OCT

- 2012 ). Therefore, an updated occupational post

- application exposure assessment will only be required for the cyproconazole uses on cereal grains and soybeans during Registration Review.

A D does not intend to conduct a post

- application exposure asses s ment in registration review

. Occupational dermal post

- application exposures from the use of cyproconazole in engineered and c omposite wood products are not expected

. AD considers the o ccupational post

- application inhalation exposures to cyproconazole as a vapor is to be minimal based on the low vapor pressure of cyproconazole (less than 1 x 10

- 6 

### mm Hg).

Dislodgeable Foliar Residue (DFR): In accordance with 40 CFR 158, DFR data are required for all occupational (e.g., crop, nursery, greenhouse use sites) or residential (e.g., ornamental andCyproconazole Registration Review Human Health Assessment Scoping Document

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Page 11 of 28 

### vegetable gardens, pick

- your

- own farms, retail tree farms) uses that could result in post

application exposure to foliage. In the absence of chemical

- specific DFR data, EPA uses default values. The 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment includes an analysis of a number of DFR studies, which resul ted in the selection of a revised default value for the fraction of the application rate available for transfer after a foliar application (F AR 

### ). These values are based on an analysis of 19 DFR studies. Since that time, the Agricultural Re

- entry Task For ce (ARTF) has submitted information (MRID 49299201) that corrects an application rate error made in the original submission of “ARF039

– Determination of Dermal and Inhalation Exposure to Reentry Workers During Chrysanthemum Pinching in a Greenhouse” (EPA MRID 45344501). As a result, the range of F AR 

### values was revised from 2%

- 89% to 2%

- 47%. In the data, a large range of transferability is observed and this variability can potentially be attributable to many factors such as active ingredient; formula tion; field conditions in the studies; weather conditions (e.g., humidity); or many other difficult to quantify factors. Although witnessed across multiple chemicals, this range in F AR 

### values is not expected when considering DFR data for a single chemical . At this time, the ARTF submission did not alter the selection of 25% as the reasonable, high

- end default value. Because DFR data are not available for cyproconazole, EPA is using the default value of 25%. Although there may be a small degree of uncert ainty in the use of the default DFR value for cyproconazole (i.e., there is a small chance that the F AR 

### value may exceed the applicable default value), it is likely that the health

- protective aspects of EPA’s occupational post

- application assessment method ology will more than compensate for this potential uncertainty. For example, when assessing residential and occupational post

- application exposure to gardens and ornamentals, EPA assumes the following: exposures occur to zero

- day (i.e., day of applicatio n ) residues every day of the assessed exposure duration (i.e., EPA assumes that no dissipation or degradation occurs, it doesn’t rain, etc); individuals perform the same post

- application activities performed in the TC study day after day (e.g., weeding, h arvesting, pruning, etc.); and individuals engage in these post

- application activities for a high

- end amount of time every day (represented by data reflecting time spent gardening based on survey data).

Given the conservatisms discussed above and the pote ntial compounding nature of these conservatisms, EPA is able to rely upon the calculated exposure estimates with confidence that exposure is not being underestimated. Cyproconazole’s largest MOE for post

- application exposure is 520 ( > 5 times the LOC of 100 )

, which exceeds the waiver criteria. As a result, a chemical

- specific DFR data are not required

.

Conclusions: There is sufficient information available to assess occupational handler and post

application exposures. Updated occupat ional handler and post

- application exposure assessments will be conducted during Registration Review for cyproconazole use on corn, cereals, and soybeans. No risk assessments are required for the AD composite wood preservative use. Based on existing and anticipated occupational post

- application risk estimates and the current toxicological PODs, DFR studies are not anticipated to be needed at this time.

8.0 Public Health and Pesticide Epidemiology Data

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

- Pesticides (SENSOR) databases were consulted for pesticide incident dat a on the active ingredient cyproconazole. The purpose of the database search is to identify potential patterns in the frequency and severity of the health effects attributed to cyproconazole exposure. Cyproconazole is not included in the Agricultural Hea lthCyproconazole Registration Review Human Health Assessment Scoping Document

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Page 12 of 28 

### Study (AHS) , and therefore this study does not provide information for this report.

OPP’s IDS includes reports of alleged human health incidents from various sources, including mandatory Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6(a)(2) reports from registrants, other federal and state health and environmental age ncies, and individual

consumers. Since 1992, OPP has compiled these reports in IDS. IDS contains reports from across the U.S. and most incidents have all relevant product information recorded. Reports submitted to the IDS represent anecdotal reports or allegations only, unless otherwise stated in the report.

IDS records incidents in one of two modules: Main IDS and Aggregate IDS:

o Main IDS contains incidents resulting in higher severity outcomes and provides more detail with regard to case specifics . This system stores incident data for death, major and moderate incidents, and it includes information about the location, date, and nature of the incident. Main IDS incidents involving only one active ingredient (as opposed to pesticide products with m ultiple active ingredients) are considered to provide more certain information about the potential effects of exposure from the pesticide.

o Aggregate IDS contains incidents resulting in less severe human incidents (minor, unknown, or no effects outcomes). These are reported by registrants only as counts in what are aggregate summaries.

For the Main IDS, from January 1, 2010 to May 27, 2015, there were no incidents reported involving cyproconazole.

In Aggregate IDS, from January 1, 2010 to May 27, 2015, there were two incidents reported involving cyproconazole. One incident was classified as minor severity and the other was classified as having no or unknown effects. Overall, there are few incident s reported to IDS involving cyproconazole.

The SENSOR

- Pesticides database covers 12 states from 1998

- 2011, although reporting varies from state to state. Cases of pesticide

- related illnesses are ascertained from a variety of sources, including: reports from local Poison Control Centers, state Department of Labor workers’ compensation claims when reported by physicians, reports from State Departments of Agriculture, and physician reports to state Departments of Health. Although both occupational and non

- occupational incidents are included in the database, SENSOR

- Pesticides focuses on occupational pesticide incidents, and is of particular value in providing that information. The state coordinator at each of the 12 respective state Departments of Health co nducts case follow

up activities such as obtaining medical records to verify symptoms and severity. Using standardized protocol and case definitions derived from poison center reporting, the state SENSOR

- Pesticide coordinator enters the incident informati on into the state

- based system which is sent to NIOSH annually to be aggregated.

A query of SENSOR

- Pesticides 1998

- 2011 identifies three cases involving cyproconazole. All three cases involved multiple active ingredients. All three cases were low in se verity.

The AHS is a high

- quality

, prospective epidemiology study evaluating the link between pesticide use and various health outcomes including cancer. The AHS includes private and commercialCyproconazole Registration Review Human Health Assessment Scoping Document

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Page 13 of 28 

### pesticide applicators and their spouses

. If there are AHS f indings relevant to a particular pesticide going through registration review, the Agency will ensure they are considered in the problem formulation/scoping phase of the process and, if appropriate, fully reviewed in the risk assessment phase of the process

. The AHS includes information on use of 80 different pesticide active ingredients commonly used in agriculture. Cyproconazole is not included in the AHS, and therefore this study does not provide information for this report.

Conclusions: Based on the low frequency and severity of incident cases reported for cyproconazole in both IDS and SENSOR

- Pesticides there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident informa tion and if a concern is triggered, additional analysis will be included in the risk
assessment.

9 .0 Tolerance Assessment and International Harmonization

U.S. permanent tolerances (listed in 40 CFR §180.485 ) are summarized in Attachment 5. Codex maximum residue limits (MRLs) are established for residues of cyproconazole per se in/on numerous commodities. T he U.S. tolerance expressions in 40 CFR §180.485(a)(2) and §180.485(a)(3) include an additional metabolite than the Codex MRL expression. The numerical values are harmonized for all commodities except for field corn stover, soybean seed, wheat grain, wheat straw and livestock commodities; for which U.S. tolerance values are lower than the corresponding MRL s

. There are currently no establi shed Canadian MRLs. Harmonization of U.S. tolerances and Codex MRLs will be considered during Registration Review.

10 .0 Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in the
most recen t cyproconazole 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 a



### . ” The OPP typically considers the highest potential exposures from the legal use of a pesticide when conducting human health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variab ility of diets within the U.S., and people who may be exposed when harvesting crops. Should these highest exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure that the risk estimates are based on the best avail able information.

11.0 Cumulative

Cyproconazole 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 mechanism of toxicit y in mammals. Structural similarities do not constitute a common mechanism of toxicity. Evidence is needed to establish that the chemicals operate by the same, or essentially the same, sequence of major biochemical events (EPA, 2002). In conazoles, howe ver, a variable pattern of toxicological 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 conazole s produce a diverse range of biochemical events including altered cholesterol levels, stress responses, and altered DNA methylation. It is not clearly understood

a http://www.archives.gov/federal

- register/executive

- orders/pdf/12898.pdfCyproconazole Registration Review Human Health Assessment Scoping Document

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Page 14 of 28 

### whether these biochemical events are directly connected to their toxicological outcomes. Thu s, there is currently no evidence to indicate that conazoles share common mechanisms of toxicity and EPA is not following a cumulative risk approach based on a common mechanism of toxicity for the conazoles. For information regarding EPA’s procedures for cumulating effects from substances found to have a common mechanism of toxicity, see EPA’s website at http://www.epa.gov/pesticides/cumulative

.

1 2

. 0 Human Studies

Past cyproconazole risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as the Pesticide Handlers Exposur e Database (PHED) , the Outdoor Residential Exposure Task Force (ORETF) Database, the Agricultural Handler Exposure Task Force (AHETF), the Antimicrobial Exposure Assessment Task Force (AEATF)

, and the ARTF Database. EPA has reviewed all the studies supporting these multi

- pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevailing at the time the research was conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued re liance on these studies.

1 3 .0 Risk Assessment Updates, Data Deficiencies, and Label Revisions

No data deficiencies were identified for cyproconazole . EPA notes the following assessment updates will need to be completed during Registration Review:

o Toxi cology:

o Re

- evaluation of PODs and UF/SFs

. o Residue Chemistry/Dietary Exposure:

o A revised dietary

- exposure analysis may be required to reflect the most recent dietary

- exposure models, potentially revised EDWCs (specifically, use of PRZM

GW), and/or revise d toxicological PODs.

o Occupational/Residential Exposure:

o Revised occupational handler and post

- application risk assessments for the conventional uses of cyproconazole will be necessary to reflect the most recent HED policies and/or toxicological PODs and UF/SFs

. o Spray drift and bystander assessments may be necessary to reflect current HED policies.

o Aggregate Exposure:

o Revised aggregate exposure analyses may be required to reflect revised dietary exposure estimates and/or changes to the toxicological PODs and UF/SFs

.Cyproconazole Registration Review Human Health Assessment Scoping Document

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Page 15 of 28 

### 1 4 .0 References

Memoranda Relevant to Registration Review. Author Barcode Date Title G. Kramer D217295 13

- JUN

- 199 6 PP# 5F04537. Cyproconazole in/on Peanuts, Wheat, Beef Liver and Imported Bananas. Evaluation of Residue Data and Analytical Methods

. G. Kramer D235159 09

- JUL

- 1997 Tolerance Petition for Residues of Cyproconazole in/on Imported Coffee. G. Kramer D330713 16

- NOV

- 2007 PP# 6F7072. Cyproconazole. Petition for Tolerances on Soybeans, Wheat, and Corn. Summary of Analytical Chemistry and Residue Data. M. Rust

- Clock et al. D330274 16

- NOV

- 2007 Petition No: 6F7072. Cyproconazole: Human

- Health Risk Assessment for Proposed Uses on Corn, Soybean and Wheat. G. Kramer D349906 27

- FEB

- 2008 PP# 6F7072. Cypr oconazole. Petition for Tolerances on Soybeans, Wheat, and Corn. Revised Summary of Analytical Chemistry and Residue Data. M. Rust

- Clock et al. D349841 27

- FEB

- 2008 Petition No: 6F7072. Cyproconazole: Revised Human

Health Risk Assessment for Proposed Uses on Corn, Soybean and Wheat. M. Sahafeyan D349907 28

- FEB

- 2008 PP# 6F7072. Cyproconazole. Revised Tier I Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Se ction 3 Registration Action on Soybean, Wheat, and Corn. M. Rust

- Clock et al. D 352237 02

- MAY

- 2008 Cyproconazole. Updated Revised Human

- Health Risk Assessment for Proposed Uses on Corn, Soybean and Wheat. S. Levy et al. D399957 03

- OCT

- 2012 Cyproconazole. Tolerance Petition for Residues in/on Peanuts. Human

- Health Risk Assessment. S. Levy D400183 03

- OCT

- 2012 Cyproconazole. Acute and Chronic Aggregate Dietary (Food + Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Action Use on Peanuts. G. Kramer D400182 03

- OCT

- 2012 Cyproconazole. Proposed New Use on Peanuts. Summary of Analytical Chemistry and Residue Data. G. Kramer D391959 29

- AUG

- 2012 Cyproconazole. Petition for Tolerances on Soybeans, Wheat, and Corn. Response to Health Effects Division (HED) Review of 27

- FEB

- 2008 (DP# 349906). T. Morton D426493 09

- APR

- 2015 Common Triazole Metabolites: Updated Aggregate Human Health 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. G. Kramer D408524 21

- JUL

- 2015 Cyproconazole. Petition for Tolerances on Soybeans, Wheat, and Corn. Submission of Final Report on Field Accumulation in Rotational Crops. S. Recore D429119 15

- SEP

- 2015 Cyproconazole: Tier I (Scoping) Review of Human Incidents and Epidemiology T. Dole D428952 0 9

- SEP

- 2015 Risk Assessment of New use of Cyproconazole for the Protection of Engineered and Composite Wood ProductsCyproconazole Registration Review Human Health Assessment Scoping Document

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Page 16 of 28 

### Attachments:

Attachment 1: Chemical Identity Table. Attachment 2: Cyproconazole Endpoint Selection Tables. Attachment 3: Cyproconazole Acute, Subchronic, and Chronic Toxicity Profile. Attachment 4: Summary of Register ed Uses

. Attachment 5: Cyproconazole International Residue Limit Status Sheet.

cc: G. Kramer (RAB1) RDI: RAB1 ( 9 / 16 /1 5 )

, J. Rowland ( 10 / 7 /1 5 ) , J. Dawson (10/7/15) G.F. Kramer:S10957:PY

- S:(703)305

- 5079:7509P:RAB1Cyproconazole Registration Review Human Health Assessment Scoping Document

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Page 17 of 28 

### Attachment 1: Chemical Identity Table

.

Table A1. 1. Cyproconazole Nomenclature

. Chemical structure

Common name Cyproconazole Company experimental name SAN619
IUPAC name (2RS,3RS)

- 2

- (4

- chlorophenyl)

- 3

- cyclopropyl

- 1

- (1 H

- 1,2,4

- triazol

- 1

- yl)butan

- 2

- ol
CAS name α

- (4

- chlorophenyl)

- α

- (1

- cyclopropylethyl)

- 1 H

- 1,2,4

- triazole

- 1

- ethanol CAS registry number 94361

- 06

- 5
End

- use products (EP) 0.83 lb ai/gal SC/L (Alto ® 100SL Fungicide; EPA Reg. No. 100

- 1226)
Chemical structure

Common name M14 Company experimental name NOA 421153
Chemical name 2

- (4

- chlorophenyl)

- 3

- cyclopropyl

- 1

- [1,2,4]triazol

- 1

- yl

- butane

- 2,3

- diol CAS registry number NA
Chemical structure

Common name M36 Company experimental name NOA 405872
Chemical name δ

- (4

- chlorophenyl)

- β,δ

- dihydroxy

- γ

- methyl

- 1 H

- 1,2,4

- triazole

- 1

- hexenoic acid CAS registry number NA Compound

Common name (Abbr) Triazole (T)
Chemical Name 1 H

- 1,2,4

- triazole CAS registry number 288

- 88

- 0 Compound

Common name (Abbr) Triazole alanine (TA)
Chemical Name α

- amino

- 1 H

- 1,2,4

- triazole

- 1

- proanoic acidCyproconazole Registration Review Human Health Assessment Scoping Document

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Page 18 of 28 Table A1. 1. Cyproconazole Nomenclature

. CAS registry number 114419

- 45

- 3 Compound

Common name (Abbr) Triazole acetic acid (TAA)
Chemical Name 1 H

- 1,2,4

- triazole

- 1

- acetic acid CAS registry number 28711

- 29

- 7

Table A1. 2. Physicochemical Properties of Cyproconazole.

Parameter Value Reference Melting range 99

- 106°C D179678, R. Lascola, 9/24/91 pH at 22oC 6.7 ± 0.2 Bulk Density at 20oC 0.5 ± 0.1 g/mL Water solubility at 25oC 108 mg/L at pH 4.1 93 mg/L at pH 7 109 mg/L at pH 10 MRID 46840803

Solvent solubility (g/100 mL at 25°C) n

- Hexane 0.2 Diisopropyl ether 2.2 Toluene 10.9 Xylene 11.2 Acetone >20 D179678, R. Lascola, 9/24/91

Vapor pressure at 25oC 2.6 x 10

- 5 Pa MRID 46840803 Dissociation constant, pK a Compound does not dissociate D179678, R. Lascola, 9/24/91 Octanol/water partition coefficient, Log(K OW ) 2.91 ± 0.12

UV/visible absorption spectrum Not reportedCyproconazole Registration Review Human Health Assessment Scoping Document

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Page 19 of 28 

### Attachment 2: Cyproconazole Endpoint Selection Tables (from 2012 Risk Assessment).

Table A2.1. Summary of Toxicological Doses and Endpoints for Cyproconazole for Use in Dietary and Non

- occupational Human Health Risk Assessments.

Exposure Scenario POD Uncertainty/ FQPA SF RfD, PAD,

LOC for Risk Assessment Study and Toxicological Effects

Acute Dietary (General population, including infants and children) N/A N/A N/A A dose and endpoint attributable to a single dose were not identified in the database including the developmental toxicity studies. Acute Dietary (Females 13

- 49 years of age) NOAEL = 2

mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X aPAD = aRfD

= 0.02 mg/kg/day Prenatal Developmental toxicity

Study

– New Zealand white rabbits. Developmental LOAEL = 10 mg/kg/day based on increased incidence of malformed fetuses and litters with malformed f etuses. Chronic Dietary (All populations) NOAEL =

1.0 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X cPAD = cRfD

= 0.01 mg/kg/day Chronic oral toxicity study

-

dog. LOAEL = 3.2 mg/kg/day based on liver effects (P450 induction in females and histopathology, laminar eosinophilic intrahepatocytic bodies in males). Short (1

- 30 days)

- and Intermediate (1

- 6 months)

- Term Incidental Oral NOAEL =

1.5 mg/kg/day UF A = 10X

UF H = 10X

FQPA SF = 1X Residential

LOC for MOE = 100 90

- day oral toxicity

– rat.

LOAEL = 27.3 mg/kg/day based on decreased body

- weight gain in males and increased liver weight in females. Short (1

- 30 days)

- and Intermediate (1

- 6 months)

- Term Dermal NOAEL = 10

mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Residential

LOC for MOE = 100 28

- Day Derma l Study

– rat.

LOAEL = 100 mg/kg/day, based on increased plasma globulin, protein and cholesterol, and hemosiderin deposition in the spleen in females, and hypertrophy of the thyroid follicular epithelium in both males and females

. Short (1

- 30 days)

- and Intermediate (1

- 6 months)

- Term Inhalation NOAEL = 2

mg/kg/day

(inhalation

absorption rate = 100% oral equivalent) UF A = 10X

UF H = 10X FQPA SF = 1X Residential

LOC for MOE = 100 Prenatal Developmental toxicity

Study

– New Zealand white rabbits. Develop mental LOAEL = 10 mg/kg/day based on increased incidence of malformed fetuses and litters with malformed fetuses. Cancer (oral, dermal, inhalation) HED classified cyproconazole as “not likely to be carcinogenic to humans” according to

EPA Proposed Guideli nes for Carcinogen Risk Assessment (10

- APR

- 1996). 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 adverse

- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivit y among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population

- adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. A = 11% dermal absorption

- factor fr om dermal

- penetration study (43173701). N/A = not applicable.Cyproconazole Registration Review Human Health Assessment Scoping Document

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Page 20 of 28 Table A2.2. Summary of Toxicological Doses and Endpoints for Cyproconazole for Use in Occupational Human Health Risk Assessments.

Exposure Scenario POD Uncertainty/ FQPA SF RfD, PAD,

LOC fo r Risk Assessment Study and Toxicological Effects

Short (1

- 30 days)

- and Intermediate (1

- 6 months)

- Term Dermal NOAEL = 10

mg/kg/day UF A = 10X

UF H = 10X Occupational

LOC for MOE = 100 28

- Day Dermal Study

– rats.

LOAEL = 100 mg/kg/day, based on increased plasma globulin, protein and cholesterol, and hemosiderin deposition in the spleen in females, and hypertrophy of the thyroid follicular epithelium in both males and females

. Short (1

- 30 days)

- and Intermediate (1

- 6 months)

- Term Inhalation NOAEL = 2

mg/kg/day

(inhalation

absorption rate = 100% oral equivalent) UF A = 10X

UF H = 10X Occupational

LOC for MOE = 100 Prenatal Developmental toxicity

Study

– New Zealand white rabbits. Developmental LOAEL = 10 mg/kg/da y based on increased incidence of malformed fetuses and litters with malformed fetuses. Cancer (oral, dermal, inhalation) HED classified cyproconazole as “not likely to be carcinogenic to humans” according to

EPA Proposed Guidelines for Carcinogen Risk Assessment (10

- APR

- 1996). 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 adverse

- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human p opulation (intraspecies). FQPA SF = FQPA Safety Factor. MOE = margin of exposure. LOC = level of concern. A = 11% dermal absorption

- factor from dermal

- penetration study (43173701).Cyproconazole Registration Review Human Health Assessment Scoping Document

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Page 21 of 28 

### Attachment 3: Cyproconazole Acute, Subchronic, and Chronic Toxicity Profile.

Table A3 .1. Acute Toxicity of Cyproconazole.

Guideline No. Study Type Results Toxicity Category 870.1100 (81

- 1) Acute Oral (rat) M: 1020 mg/kg F: 1330 mg/kg III

870.1100 (81

- 1) M

- 36 metabolite, Acute Oral (rat) MRID

- 43674701, > 2000 mg/kg III

870.1100 (81

- 1) M

- 36 metabolite, Acute Oral (mouse) MRID

- 43674732 >2000 mg/kg III

870.1200 (81

- 2) Acute Dermal (rabbit) LD50 >2000 mg/kg III

870.1300 (81

- 3) Acute Inhalation (rat) LC50 >5.6 mg/L III

870.2400 (81

- 4) Primary Eye Irritation (rabbit) Not an eye irritant IV

870.2500 (81

- 5 ) Primary Skin Irritation (rabbit) Not a dermal irritant IV

87.2600 (81

- 6) Dermal Sensitization (guinea pig) Not a dermal sensitizer N/A

Table A3 .2. Subchronic, Chronic, and Other Toxicity Profile of Cyproconazole. Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.3050 28

- Day oral (rat) 40624305 (1986) Acceptable/non

guideline 0, 10, 30,100, 300, and 1000 ppm 0, 0.5, 1.5, 5.0, 15, 50 mg/kg/day NOAEL= 5 mg/kg/day. LOAEL = 15 mg/kg/day, based on elevated LDH, increased liver weight (relative and absolute) and liver vacuolization.

870.3100 90

- Day oral

toxicity (rat) 40607718 (1986)

Acceptable/non

guideline 0, 20, 80, or 320 ppm 0, 1, 4, and 16 mg/kg/day NOAEL = 20 ppm (1 mg/kg/day). LOAEL = 80 ppm (4 mg/kg/day) based on increased incidences of centrilobular hepatocyte hypertrophy.

870.3100 90

- Day oral

toxicity (rat) 43078601 (1993)

Acceptable/ supplementary 0, 20, 350, 700, or 1400
ppm M/F: 0/0, 1.5/2.0, 27.3/35.4, 55.8/74.3, and 114.5/139.4 mg/kg/day NOAEL = 20 ppm (1.5/2.0 mg/kg/day in males/females). LOAEL = 350 ppm (27.3/35.4 mg/kg/day in males/females), based on decreased body

- weight gain in males and increased liver weights in females.Cyproconazole Registration Review Human Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 22 of 28 Table A3 .2. Subchronic, Chronic, and Other Toxicity Profile of Cyproconazole. Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.3100 90

- Day oral

toxicity (rat) 46152901 (1999)

Acceptable/guideline 0, 20, 350, 700, or 1400 ppm (equivalent to 0/0, 1.4/1.6, 24.7/29.6, 52.8/57.3, and 106.8/118.1 mg/kg/day in males/females) NOAEL = 20 ppm (equivalent to 1.4/1.6 mg/kg/day in males/ females). LOAEL = 350 ppm (equivalent to 24.7/29.6 mg/kg/day in males/females), based on increased liver weight and increased incidence of liver hypertrophy in both sexes and increased incidence of liver fatty change in males.

870.3100 90

- Day oral

toxicity (mouse) 46950013 (1987)

Acceptable/non

guideline 0, 5, 15, 300, or 600 ppm M: 0, 0.7, 2.2, 43.8, or 88.7 mg/kg bw/d F: 0, 1.0, 3.2, 70.2, or 128.2 mg/kg bw/day NOAEL = 15 ppm (2.2 and 3.2 mg/kg bw/day in males and females). LOAEL = 300 ppm (4 3.8 and 70.2 mg/kg bw/day in males and females), based on decreased body

weight gain in both sexes and evidence of liver effects (increased liver weight in both sexes, periacinar hepatocytic eosinophilia in males, and single

- cell hepatocyte necrosis in bot h sexes). 870.3150 90

- Day oral

toxicity (dog) 40607719 (1985)

Acceptable/guideline 0, 20, 100, 500 ppm 0, 0.8, 4.0, and 20.0 mg/kg/day NOAEL = 4.0 mg/kg/day. LOAEL = 20.0 mg/kg/day, based on slack muscle tone, inhibited body weight gain, liver effects (increased alkaline phosphatase and gamma glutamyl transferase) and histopathological evidences (hepatocytomegaly, degeneration of single hepatocytes and cytoplasmic inclusions). 870.3200 21

- Day dermal

toxicity (rat) 40624306 (1988)

Acceptable/guideline 0, 50, 250, 1250 mg/kg/day NOAEL = 250 mg/kg/day. LOAEL = 1250 mg/kg/day, based on decreased body

- weight gain and food consumption (M), increased AST (males), creatinine (females), and cholesterol (both sexes). 870.3200 28

- Day derm al

toxicity (rat) 48840824 (2000)

Acceptable/guideline 0, 10, 100, 1000 mg/kg/day NOAEL = 10 mg/kg bw/day. LOAEL = 100 mg/kg bw/day, based on increased plasma globulin, protein and cholesterol, and hemosiderin deposition in the spleen in females, and hypertrophy of the thyroid follicular epithelium in both males and females

. 870.3700a Prenatal

developmental in (rat) 40607721 (1985)

Acceptable/guideline 0, 6, 12, 24, 48 mg/kg/day Maternal NOAEL = 6 mg/kg/day. Maternal LOAEL = 12 mg/kg/day, based on decreased body

- weight gain during dosing. Developmental NOAEL = 6 mg/kg/day. Developmental LOAEL = 12 mg/kg/day, based on increased incidence of supernumerary ribs, malformations (hydrocephaly) at 24 & 48 mg/kg/day and cleft palate at 48 mg/kg/day. 870.37 00b Prenatal

developmental in (chinchilla rabbit) 40607720 (1986)

Unacceptable/guideline 0, 2, 10, 50 mg/kg/day Maternal NOAEL = 10 mg/kg/day. Maternal LOAEL = 50 mg/kg/day, based on inhibited body

- weight gain during treatment. Developmental NOAEL <2 mg/kg/day. Developmental LOAEL = 2 mg/kg/day, based on incidence of hydrocephalus internus. 870.3700b Prenatal

developmental in (New Zealand White rabbit) 42175401 (1991),

Acceptable/guideline 0, 2, 10, 50 mg/kg/day Maternal NOAEL = 10 mg/kg/day. Materna l LOAEL = 50 mg/kg/day, based on decreased body

- weight gain. Developmental NOAEL = 2 mg/kg/day. Developmental LOAEL = 10 mg/kg/day, based on increased incidence of malformed fetuses and litters with malformed fetuses.Cyproconazole Registration Review Human Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 23 of 28 Table A3 .2. Subchronic, Chronic, and Other Toxicity Profile of Cyproconazole. Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.3800 Reproduction and

fertility effects (rat) 40607723 (1987)

Acceptable/guideline 0, 4, 20, 120 ppm 0, 0.28/0.33, 1.39/1.67, or 8.29/9.88 mg/kg/d Parental NOAEL = 20 ppm (1.39 mg/kg/day). Parental LOAEL = 120 ppm (8.29 mg/kg/day), based on liver effects (increased lipid storage and relative weight in males and increased relative weight in females). Reproductive NOAEL = 120 ppm (8.29 mg/kg/day), although gestation length was slightly increased and litter sizes were decreased, the changes are not considered treatment

- related. Reproduct ive LOAEL was not determined. Offspring NOAEL = 120 ppm (8.29 mg/kg/day). Offspring LOAEL was not determined. 870.4100b Chronic toxicity

(dog) 41212901 (1988)

Acceptable/guideline 0, 30, 100, and 350 ppm M/F: 0/0, 1.0/1.0, 3.2/3.2, and 12.1/12.6 mg/kg/d) NOAEL = 30 ppm (1.0 mg/kg/day). LOAEL = 100 ppm (3.2 mg/kg/day), based on liver effects (P450 induction in females and histopathology, laminar eosinophilic intrahepatocytic bodies in males).

870.4200b Carcinogenicity

(mouse) 41147201(1989)

Acceptable/guideline 0, 5, 15, 100,200 ppm M/F: 0/0.69/1.03, 1.84/2.56, 13.17/17.65, or 27.85/36.30 mg/kg/d NOAEL = M/F: 1.8/2.6 mg/kg/day. LOAEL = M/F: 13.2/17.7 mg/kg/day, based on increased incidence of hepatocytic single

- cell necrosis; increased inc idence of hepatocellular adenomas and carcinomas.

870.4300 Combined Chronic

Toxicity/Carcinoge nicity (rat) 41164701 (1988)

Acceptable/guideline 0, 20, 50, or 350 ppm M/F: 0/0, 1.0/1.2, 2.2/2/7 and 15.6/21.8 mg/kg/d NOAEL = 50 ppm (2.2 mg/kg/day). LOAEL = 350 ppm (15.6 mg/kg/day), based on decreased body weight and increased incidence of fatty infiltration in liver (M). Dosing was inadequate in females.

870.5100 Bacterial Reverse

Mutation Test 40607725 (1986)

Acceptable/guideline 0, 1, 5, 10, 100, 500, 1000 ug/plate w/wt rat S9 mix. Negative.

870.5100 Bacterial Reverse

Mutation Test 40624307 (1985)

Unacceptable/guideline 0, 10, 100, 250, 400, 500, or 550 ug/plate w/wt rat S9 mix. Negative.

870.5300 In Vitro Gene

Mutation assay in Chinese Hamster Ovary cells 40607726 (1985)

Acceptable/guideline 0, 20, 50, 100, or 200 ug/mL w/wt S9. Negative.

870.5375 In Vitro

Mammalian Chromosomal Aberration 41757801 (1990)

Unacceptable/guideline 60.1, 100.0, 150.0, or 200 ug/mL wt S9; 45.0, 59.9, 99.9

, or 150.0 with S9. Cannot be interpreted.Cyproconazole Registration Review Human Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 24 of 28 Table A3 .2. Subchronic, Chronic, and Other Toxicity Profile of Cyproconazole. Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.5375 In Vitro

Mammalian Chromosomal Aberration 46950019 (1995)

Acceptable/guideline 0, 50, 100, 200, or 400 μg/mL without S9. 0, 25, 50, 100, or 200 μg/mL with metabolic activation. 0, 50, 100, 200, or 400 μg/mL without S9. 0, 100, 200, 400, or 800 μg/mL with metabolic activation. Negative.

870.5375 In Vitro

Mammalian Chromosomal Aberration 41757701 (1988)

Unacceptable/guideline 100, 150 or 200 ug/mL wt S9; 100, 150, 200, or 250 with S9. Positive w/wt S9.

870.5395 In Vivo

Mammalian Cytogenetics

- Erythrocyte Micronucleus Assay in Mice 40607728 (1984)

Acceptable/guideline 0, 16.7, 55.7, 167 mg/kg Negative.

Cell Transformation 40607724 (1985)

Acceptable 0, 20, 50, 100, or 200 ug/mL w/wt S9 (assumed) Negative.

870.5450 Rodent Dominant

Lethal 41961401 (1991)

Acceptable/guideline 20, 40, or 80 mg/kg/d Negative.

870.5550 Unscheduled DNA

Synthesis in Mammalian Cells in Culture 40607729 (1988)

Unacceptable/guideline 0.15,0.5, 1.5, 5, 15, 50, 100, 150 ug/mL Cannot be evaluated.

870.5550 Unscheduled DNA

Synthesis in Mammalian Cells in Culture 40607727 (1985)

Unacceptable/guideline 0.15,0.5, 1.5, 5, 15, 50, 100, 150 ug/mL Cannot be evaluated.

870.7485 Metabolism and

pharmacokinetics (rat) 41701901 (1987)

Acceptable/guideline oral

- 10 mg/kg , 910 mg/kg x 14 days; iv

- 10 and 130 mg/kg Absorption, distribution, excretion, and blood kinetics were examined. Almost completely absorbed in males (84%) and females (106%), extensively metabolized; diastereomers A & B of parent + 13 metabolites identified & isolated; 35 metabolites detected; me tabolic profiles for urine, feces, bile similar; major metabolic reactions include oxidative elimination of triazole ring; hydroxylation of C bearing CH3 group; oxidation of CH3 group to carbinol & further to oxidation carboxylic acid; rapid excretion with majority appearing in feces (biliary excretion); residual 14 C found within renal fat, adrenals, liver; potential liver accumulation in long

- term studies.Cyproconazole Registration Review Human Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 25 of 28 Table A3 .2. Subchronic, Chronic, and Other Toxicity Profile of Cyproconazole. Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.7485 Metabolism and

pharmacokinetics (rat) 46152903 (2003)

0.5 mg/kg. Animals were dosed with the radioactive test substance daily for up to 14 days. The majority of the total administered dose (96.5%) was recovered in the feces (56.3%) and urine (40.2%). The highest blood levels were found ten days after the start of dosing (0.08

- ppm cyproconazol e equivalents). Three days after the final dosing, radioactivity was almost completely excreted. The calculated half

- life for the depletion of radioactivity (assuming mono

- phasic first

- order kinetics) from the tissues ranged from one to three days. The greater persistence and longer half

- life of radioactivity in blood compared to plasma indicated some partitioning of radioactivity into the red blood cells. The highest concentrations of radioactivity were observed in the liver (1.37

- ppm cyproconazole
equ ivalents), adrenals (0.93 ppm), lungs (0.56 ppm), fat (0.49 ppm), kidneys (0.25 ppm), pancreas, (0.22 ppm), and ovaries (0.16 ppm) seven days after the start of dosing. Urine was found to contain at least 21 metabolite fractions by two

- dimensional thin

- la yer chromatography (TLC). Individual fractions were detected in similar proportions on Days 0

- 1, 6

- 7, and 13

- 14. The combined urinary metabolite fractions accounted for 20.8

- 41.0% of the daily

administered doses. 870.7600 Dermal penetration

(rat) 43 173 701 (1993),

Acceptable/guideline 0, 2.5, 15, and 120 ug/cm 2 for 0.5, 1, 2, 4, 10, and 24 hr. At dose levels of 2.5, 15, and 120 μg ai/cm 2 cyproconazole, the percent absorbed (0.87

- 7.69, 0.59

- 11.88, and 0.92

- 0.89, respectively) increased with duration of ex posure and decreased with dose. The quantity absorbed increased with dose and duration of exposure. At the 10

- hour exposure time point, 10.8 1% of the low dose was absorbed. % absorbed = 11% for 10 hoursCyproconazole Registration Review Human Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 26 of 28 

### Attachment 4: Summary of Registered Uses

.

Table A4

. 1

. Summary of Cyproconazole Application Scenarios. App. Timing; Type; and Equip. Formulation (EPA Reg.

No.) App. Rate

fl oz/A Max. #. App.

per Season Max. Seasonal App.

Rate (lb ai/acre) Use Directions and Limitations

Soybeans

Foliar

Broadcast application

Groundboom, chemigation, aerial Alto 100SL ® SC

0.83 lb ai/gal EPA Reg. No. 100

- 1226 2.75

– 5.5

Not specified 11 fl oz/A/season

0.072 lb ai/A/year

 REI = 12 hours

 PHI = 30 days

 PGI = 14 days

 Do not use soybean forage or hay as livestock feed if making for than one application at 6.8 fl oz product/A (0.036 lb ai/A/year). Azure TM Xtra SC 0.67 lb ai/gal EPA Reg. No. 228

- 728; Quadris Xtra ® SC 0.67 lb ai/gal EPA Reg. No. 100

- 1225 4.0

– 6.8 13.6 fl oz/season

0.072 lb ai/A/year Aproach ® Prima SC 0.67 lb ai/gal EPA Reg. No. 352

- 883 5.0

– 6.8 2

Peanuts
Foliar

Broadcast application

Groundboom, chemigation, aerial Alto 100SL ® SC

0.83 lb ai/gal EPA Reg. No. 100

- 1226 5.5 2 11.0 fl oz/A/season

0.072 lb ai/acre/year  REI = 12 hrs

 PHI = 30 days

Cereals

- Wheat & Triticale

Foliar

Broadcast application

Groundboom, chemigation, aerial Alto 100SL ® SC

0.83 lb ai/gal EPA Reg. No. 100

- 1226 1.5

– 5.5

not specified 5.5 fl oz/A/season

0.036 lb ai/A/season

 REI = 12 hrs

 PHI wheat = 30 days

 PHI forage or hay = 21 days Azure TM Xtra SC 0.67 lb ai/gal EPA Reg. No. 228

- 728; Quadris Xtra ® SC 0.67 lb ai/gal EPA Reg. No. 100

- 1225 3.5

– 6.8 6.8 fl oz/A/season

0.036 lb ai/A/season Aproach ® Prima SC 0.67 lb ai/gal EPA Reg. No. 352

- 883 3.4

– 6.8 2  REI = 12 hours

 PHI grain = 45 days

 PHI forage or hay = 21 days
Corn

- field & seed

Foliar Broadcast application

Groundboom, chemigation, aircraft Alto 100SL ® SC

0.83 lb ai/gal EPA Reg. No. 100

- 1226 2.75

– 5.5

2 5.5 fl oz/A/season

0.036 lb ai/A/season

 REI = 12 hrs

 PHI grain or ear = 30 days

 PHI silage = 21 days Quadris Xtra ® SC 0.67 lb ai/gal; EPA Reg. No. 100

- 1225; Aproach ® Prima SC 0.67 lb ai/gal EPA Reg. No. 352

- 883; Azure TM Xtra SC 0.67 lb ai/gal EPA Reg. No. 228

- 728 3.5

– 6.8 6.8 fl oz/A/season

0.036 lb ai/A/season

Abbreviations: REI = r estricted

- e ntry interval , PHI = p ost h arvest i nterval, PGI = p re

- g razing i nterval.Cyproconazole Registration Review Human Health Assessment Scoping Document

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Page 27 of 28 

### Attachment 5: Cyproconazole International Residue Limit Status Sheet.



## International Residue Limits

Cyproconazole ( 128993 ; Date of Request: 08/31/2015) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 

### Codex 3 40 CFR §180.485 (a) General. (1) Compliance with the proposed tolerance levels specified below is to be determined by measuring only cyproconazole (α

- (4

- chlorophenyl)

- α

- (1

- cyclopropylethyl)

- 1 H

- 1,2,4

- triazole

- 1

- ethanol) None Cyproconazole The residue is fat soluble.

Commodity Tolerance (ppm)/Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex 3 Aspirated grain fractions 2.5 Cattle, fat 0.01 Cattle, meat byproducts (except liver) 0.01 0.5 edible offal (mammalian) Coffee bean, green (Imported) 1 0.1 0.07 coffee beans 0.1 coffee beans roasted Corn, field, forage 0.60 Corn, field, grain 0.01 0.01 (*) Corn, field, stover 1.2 2 maize fodder (dry) Goat, fat 0.01 Goat, meat byproducts (except liver) 0.01 0.5 edible offal (mammalian) Horse, fat 0.01 Horse, meat byproducts (except liver) 0.01 0.5 edible offal (mammalian) Peanut 0.01 Peanut, hay 6.0 Sheep, fat 0.01 Sheep, meat byproducts (except liver) 0.01 0.5 edible offal (mammalian) Soybean, forage 1.0 Soybean, hay 3.0 3 soya bean fodder Soybean, oil 0.10 0.1 soya bean oil, refined Soybean, seed 0.05 0.07 soya bean (dry) Wheat, forage 0.80

Wheat, grain 0.05 0.08 cereal grains (except maize, rice and sorghum) Wheat, grain, milled byproducts 0.10 Wheat, hay 1.3

Wheat, straw 0.90 5 straw and fodder (dry) of cereal grains (except maize, rice and sorghum) MRLs with No US Equivalent Beans (dry) 0.02 (*)Cyproconazole Registration Review Human Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 28 of 28 Meat (from mammals other than marine mammals) 0.02 (fat)

Peas (dry) 0.02 (*) Peas, shelled (succulent seeds) 0.01 Rape seed 0.4 Sugar beet 0.05 

### Residue Definition : US Canada Mexico 2 

### Codex 3 40 CFR §180.485 (a) General. (2) Compliance with the tolerance level specified below is to be determined by measuring only the sum of cyproconazole (α

- (4

- chlorophenyl)

- α

- (1

- cyclopropylethyl)

- 1 H

- 1,2,4

- triazole

- 1

- ethanol) and its metabolite δ

- (4

- chlorophenyl)

- β,δ

dihydroxy

- γ

- methyl

- 1 H

- 1,2,4

- triazole

- 1

- hexenoic acid, calculated as the stoichiometric equivalent of cyproconazole Same as above

Commodity Tolerance (ppm)/Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex 3
Milk 0.02 0.01 

### Residue Definition : US Canada Mexico 2 Codex 3 40 CFR §180.485 (a) General. (3) Compliance with the tolerance level specified below is to be determined by measuring only the sum of cyproconazole (α

- (4

- chlorophenyl)

- α

- (1

- cyclopropylethyl)

- 1 H

- 1,2,4

- triazole

- 1

- ethanol) and its metabolite 2

- (4

- chlorophenyl)

- 3

- cyclopropyl

- 1

- [1,2,4]triazol

- 1

- yl

- butane

- 2,3

- diol, calculated as the stoichiometric equivalent of cyproconazole Same as above

Commodity Tolerance (ppm)/Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex 3 Cattle, liver 0.50 0.5 edible offal (mammalian) Goat, liver 0.50 Hog, liver 0.01 Horse, liver 0.50 Sheep, liver 0.50 MRLs with No US Equivalent Eggs 0.01 (*) Poultry meat 0.01 (*) Poultry, edible offal of 0.01 (*) Completed: M. Negussie; 09/04/15

1 There are no U.S. registrations as of February 15, 2008 for use on coffee bean.

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

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