### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON , D.C. 20460

MEMORANDUM
Date: 

### JO June 2015 OFFICE OF CHEMI CAL SAFETY A ND POLLUTION PRE V ENTI O N

SUBJECT: Ipconazole

- Hea lth Effects Draft Ri s k Assess ment in S upport of Reg istration Rev iew
PC Code: 125618 Decision No.: NA P

et it io n No.: NA Ri sk Assessment Type: Single-Chemical Aggregate TXR No.: None MRIDNo.: NA
F ROM: Mi c hael A. Dohe rty , Ph.D. , Senior Chem ist Ri s k Assessment Branch 11 H ea lth Effects Division (7509 P)
THROUGH: C hri stina Swartz , Branch C hi ef Ri s k Assessm ent Branch II Hea lth Effec ts Divi s ion (7509P)
TO: Brittany Pruitt/Tracy Pe rry/Ke ll y Sherman DP Barcode: D 427364 R

egistration No. : Multiple Regul atory Action : R egistration R e view Case No.: 7041 CAS No.: 125225-28-7 40 CFR : 180.646

# ~~

Ri s k Manage ment and I mp le mentation B r anch 3 Pestic ide Ree va luation Div is ion (7508P)

Page I of5Exec utiv e S ummary lpconazole is a triazole-derivat ive fungicide and is currently registered only for seed-treatment use on nume rous cro p s. The se uses are considered to be " non-food uses " for root and tuber vegetables (Crop Group 1 ) , leafy vegetables 

### (non-Brassica and 

### Brassica ; Crop Groups 4 and 5) , cucurbit vegetab les (Crop Group 9), sorghum, sunflower, canola, rape , mustard , and corn (fie ld , pop and sweet). Tolerances at the limit of quantitation (LOQ , 0.0 l ppm) hav e been established to s upport food uses on cotton , cereal grains (Crop Group 15) except rice , peanuts , and legume vegetables (Crop Group 6).
The Health Effects Divi s ion has conducted three risk assessme nt s for ipconazole. The most recent assessment was conducted in 20 1 3 [M. Doherty , 0413830, 8 August 2013; with an addendum dated 16 January 201 4 (M. Dohe rty, 0417425)).
The toxicology and residue chemistry databases for ipconazole are complete fo r purposes of assess in g ri s k under the Food Quality Protection Act of 1 996 (FQPA)

. Although the toxicolo gy database lacks an immunotoxicity study , this is not considered to be a data gap because the Offic e's Hazard and Science Policy Council (HAS POC ) waived the requirement for thi s study for all conazole compounds (U. Habiba , TXR No. 56730, 8 January 2014). A ll res idue chemistry data gaps identified in prev ious assessment s have been fulfilled (M. Doherty , D369458 , 31 March 2011 ). Ipconazole s hows low acute toxicity via the oral, dermal , and inhalation route s of exposure , and causes low to mi ld irritati on to the eyes and skin. S ubchronic and chronic st udi es show the li ver to be the primary target o rgan for ipconazole. For risk assessment, acute dietary exposures to women of child-b earing age have been assessed based on visceral and skeleta l variations observe d in rats and skele tal variations and malformations observed in rabbit s
. Acute dietary assessments for other population groups have not been conducted due to the Jack of an appropriate endpoint. Chronic dietary assessments have been based on skin reddening and decreased body weight gain (females only) observed in dogs. Dermal and inhalation risk assessments have been based on route-sp ecific studies. In the case of dermal exposure, the endpoints have been decreased body weight , body weight gain , and food consumption as we ll as increased d ermal irritation. Inhalation exposure endp oints are portal-of-entry spec ific and include hyperpla s ia in the hard palate and larynx mucosa, and mixed inflammatory ce ll s in the trachea.
The 2013 di etary exposure and risk estimates were derived u s in g screenin g- level assumption s (to lerance- level residues , I00% crop treated) and 2003-2008 food consumption data. The dietary risk est im ates were less than I% of the population-adjusted d ose (PAD) for both acute and chronic exposures for all population group s. Therefore , HED confirms its prev ious conclu s ion that dietary risk estimates for ipconazole are below our level of concern.
HED ha s no t assessed residential exposure and risk for ipconazole

. Although ipconazole is registered for use on turf , it is as a seed-treatment use and is not expected to r es ult in residentia l exposures. Consequently , aggregate expo s ure and risk estimates are equivalent to the dietary estimate s and are below HED 's level of concern for all population groups and scenarios.

Page 2 of 5The 2013 occ upational expos ure and risk estimates were based on a personal protective equipm ent (PPE) level of baseline clothing (long sleeve shirt , pants, socks and sho es)+ gloves. Furthermore , the 2013 assessment used the most current transfer coefficients and policies with respect to seed-treatment assessment. Occupational margins of exposure ranged from 41 , 000 to 140 , 000 for dermal exposure and from 2 , 000 to 20,000 for inhalation exposure. The levels of concern for occupational exposure are I 00 fo r dermal exposure and 300 for inhalation exposure ; therefore , HED confirms it s previous conclusion that all occupational risk estimates are not of concern. The restricted e ntry interval (REI) on the labels for ip conazo le is s upp orted by the acute toxicity categories.
Given that the most recent ri sk assessment for ipconazole reflects current risk assess ment policies and methodologies , there are no data gaps for th e ch emic al, and there are no risks of concern or in c ident data that wou ld warrant the need for mitigation , HED i s principally relyin g on it s 2013 assess ment in making its findings fo r ipconazole under registration review

. Endocrine di s ruption , which was not addressed in the 2013 assessment, and spray drift/volatilization , which is somewhat revi s ed , are presented below.
E n docrin e D isruptio n
As required by FIFRA and FFDCA, EPA reviews numerous stud ies to assess potential adverse outcomes from exposure to chem icals. Collect ively, these studies include acute , subchronic and chronic toxicity , including assessments of carcinogenicity , neurotoxicity , developmental, reproductive , and general or systemic toxicity. These stud ie s include endpoints which may be susceptibl e to endocrine influence, including effects on endocrine target organ histopathology , organ weights , estrus cyclic ity , sex ual maturation , fertility , pregnancy rates , reproductive loss , and sex ratios in offspring. For eco logical hazard assessments , EPA evaluates ac ute tests and chronic studies that assess growth , developmental and reproductive effects in different taxonomic groups
. As part of its most recent registration decision for ipconazole , EPA reviewed these data and selected the most sens iti ve endpoints for relevant risk assessment scenarios from the existin g hazard datab ase. However, as required by FFDCA section 408(p), ipconazole is s ubject to the endocrin e screeni ng part of th e Endocrine Di s ruptor Screening Pro gram (EDSP).
EPA has d ev e loped the EDSP to determine whether certain substances (including pesticide acti ve and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a ' ·naturally occurring estrogen , or other such endocrine effects as the Administrat or may designate. " The EDSP emp loys a two-tiered approach to making the statutorily required determinations. Tier I consists of a batte ry of 11 screenin g assays to identify th e potential of a chemical substance to interact w ith the estrogen , androgen , or thyroid (E, A , or T) hormonal systems. C h emicals that go through Tier 1 screeni ng and are found to have the potential to interact with E , A , or T hormonal systems wi ll proceed to the next stage of the E D SP where EPA will determine which, if any , of the Tier 2 tests are necessary based on the available data. T ier 2 testing is designed to identi fy any adverse e ndo cr ine-related effects caused by the s ubstance , and es tabli sh a dose-response relationship between the dose and the E, A, or T effect.
Under FFDCA sectio n 408(p) , the Agency must screen a ll pe s ticide chemicals. Between October 2009 and Fe bruary 2010 , EPA issued test orders /data call-ins for the first group of 67 chemicals ,

Page 3 of5which contains 58 pe sticide active in gre di ent s and 9 inert in g redi ents. A seco nd li st of chemicals identified for EDSP screening was publi s hed on June 14 , 2013 1 and includes some pesticide s scheduled for Regi stration Review and chemicals found in water. For further information on the status of the EDSP , the policies and procedures , the lists of chemica ls , future lists , th e test guidel ines and the Tier 1 screening battery , please visit our website. 2 Spray Drift and Volatilization
All of the currentl y registered uses of ipconaz ole are as a seed treatment ; there fore , spray drift is not a concern. Similarly , post-application inhalation exposure due to volatilization is expected to be neg ligible. Seed treatment assessments pro vide quantitative inhalation exposure assessments for seed treaters and secondary handlers ( i. e
. , planter s). It i s exp ec ted that tho se expos ure estimates are protective of any potential low- leve l post-application inhalation ex posure that could result from these types of app li cations.
Review of Human Incid ent Data
For this evaluation , the OPP Incident Data Syste m (IDS) , the Ce nters for Di sease Control and Prevention/National In stitute for Occupational Safety and Health (CDC/NIOSH) Sentine l Eve nt Notification System for Occupational Ri sk-Pestic ides (SENSOR) database , and by the National Pesticide Information Center (NPIC) database were consulted for pesticide incident data on the active in gred ient ipconazole (pc code: 125618). The purpose of the database search is to identify potential patterns in the frequency and severity of the health effects attributed to ipconazole exposure. l pconazole i s not included in the AHS , and therefore this study does not provide information for this report.
Based on the low freque ncy and low severity of incident cases reported for ipconazole in IDS , SENSOR- Pesticides , and NPIC , there does not appear to be a concern at this time that would warrant further inve stigati on. The Agency w ill continue to monitor the incident information and if a concern is triggered, addit ional analysis will be includ ed in the risk assessment.

References Doherty , M. D369458. 3 1 March 2011. Ip conazo le
- Evaluation of Conditional Residue Chemistry D ata Submitted in Support of New Seed Treatment Uses on Cotto n , Peanut , Soybean, Cereal Grains (Except Rice) , and Dry She ll ed Pea and Bean. Doherty , M. D413830. 8 August 2013. Revised lpconazo le Human Health Risk Assessment of the Proposed Use o n Legume Vegetables (Crop Group 6) Doherty , M. D417425. 16 January 2014. Addendum to th e R ev ised Ipconazole Human Health Risk Assessment of the Proposed Use on Legume Vegetables (Crop Group 6)

1 See h11p: //\\\\ w.regula1ions.gov/# !documentDe1ail;D = EPA

- HQ-OPPT-2009

- 0-l77

- 0074 for the final second li s t of chemical s

. 2 http ://w"" .epa.gov cndo 1

Page 4 of5Habiba , U

. TXR No. 56730. 8 January 2014. CONAZOLE FUNGICIDES: Summary of Hazard and Science Pol icy Cou ncil (HASPOC) Meeting on July 25, 2013: Recomme n datio n s o n Data Requirement for lmmunotox ic ity Studies fo r Conazo le Pestic ides. Recore , S. D427368. June 2015. I pconazole: Tier I (Scoping) Review of Human Inc idents

Page 5 of5