Ipconazole Human H ealth Ri sk Assessment DP No. D41 3830

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON

, D

. C

. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

MEMORANDUM

Date:

SUBJE CT:

FROM:

THROUGH:

TO : 8 August 20 13

Revi sed Ip co n azo le Human Hea l t h Risk Assessment of the Prop ose d Use o n Legume Ve ge tables (Crop Group 6)

PC Co de : 125618 DP Barcode: D413830 D ecision No. : 469403 Registration No. : 400-544 Petition No .: 2F8076 Regulatory Action: Section 3 Risk Assessment Type: Single Chemica l

, Aggregate Case No.: 7041 TXR N o.: NA CAS No.: 125225-28-7 MRID No.: 4892840 I, 4892840 2, 48928403 40 CFR: 180.646

Michael A. Doherty, Ph .D.
,

# mi**st-..~~** Mar gari ta Collantes, B iolog i st

### ~cfvv Jaim e D ' Agostin o , Ph.D.,

## Jo,xi~**~** 

## ?;;i :S · William Drew, Chemist**~** Risk Assessment Branch II Hea lt h Effec t s Division ( 7 509 P )

Christina Swartz

, Chief

# ~ Risk Assessme nt Branch II Health Effects Division (7509P)

Dominic Schuler/Tony Kish (Team 22) Fun g icid e Branch R egistrat i on Division (7505P)

NOT E : This assessment incorporates updated estimates of ipconazole residues in drinking
water and presents the revised estimates of dietary exposure and risk that resulted from those updates. In addition

, the immunotoxicity study for ipconazole ha s been waived by the Hazard Science Policy Council (HASPOC), and this update has been included in the revised risk assessment. Otherwise, this assessment is identical to D406026.

P age 1 of29Ipconazole H uman Health Risk Assessment DP No

. 0413830

1.0 Execut i ve Summary

............................................................................................................. 3 2.0 HED Recommenda t ions

......... . .. .. ..... .. .. . ... . .. .. .. . ........... . .. .. .. .. .. . ... .. .. . ... . ... . ... .. ... . ... . ... . .... . .... . .. 4 2.1 Data De ficie ncie s

....... .. ..... .. .. .. ..... .. .................... .. .. .. .. .. .. .. .. .. ...... .. .......... .. .. .. .................... 4 2.2 Tolerance Considerations

................................................................................... . ............. 4 2.2

. 1 Enforcement Analytical Method

.. ...... .. .............. ........ ...... .. .. ...... .. ............................. 4 2.2.2 Recommended Tolerance s

.......... ....... ........................................ .. ................... .. .... . .. . 5 2.2

. 3 Revisions to Petitioned-For To l erances

...... .. ............................................................ 5 2.2.4 In ternational H armonization

......................................... .. ...... .. .. .. ...... .. ....... .. .... . .. .. .... 5 2.3 Label Recommendations

.................................................................................................. 5 3.0 Introduction

........ . .. . ...... . ... . .. .. .. . .. .. .. .. .. . ... .. .. . .. . ... .. . ..................................................... . . ......... 6 3. 1 Chemica l Identity

......................................................................................... .. .. .. .. ............ 6 3.1 Nomenc l ature

......... . .. . .. ...... .. .. .. ...... . .. .. . ...... .. .. .. .. ............. .. .. ... .......................................... 6 3.2 Physicochemical Characteristics

................................................. .. .. .. .. . ... .. .. .. ................... 6 3.3 Pesticide Use Pattern/Directions for Use (860.1200)

...................................................... 7 3.4 Anticipated Exposure Pathways

.. ..................................................................................... 8 3.5 Consideration of Environmental Justice

.......................................................................... 8 4.0 Hazard Characteriza tion and Dose-Response Assessment..

...... .. .. .. .. .. .. .. .. .......................... 8 4.1

. Summary ofToxicological Effects

.................................................................................. 9 4. 2 Safety Factor for Infants and Children (FQPA Safety Factor)

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

. 2.1 Completeness of the Toxicology Database

......................................... .. ...... .. ........ .. 11 4. 2.2 Evide nce ofNeurotoxicity

...................................................... .. . ............................ . 12 4.2

. 3 Evidence of Sensitivity/Susceptibility in the Deve l oping or Young Animal

......... 12 4.2.4 Residual Uncertainty i n the Exposure Database

.................................................. ... 12 4

. 3 Toxicity Endpoint and Point of Departure Select i ons

.................. ...... ............................ 12 5.0 Dietary Exposure and Risk Assessment

............................................................................ 14 5.1 Residues of Concern Summary and Rationale

.............................................. .. ...... .. .... .. . 14 5

. 2 Food Residue Profile

.................... .................................. ........................................ .. .. .. .. 15 5.3 Water Residue Profile

................................................................ ...... .............................. 1 5 5.4 Dietary Risk Assessme nt..

........................................................... . .. ...... .. .. .. .................... 16 6

. 0 Residential (Non

- Occupational) Exposure/Risk Characterization

.................................... 17 6

. 1 Spray Drift and Residential Bystander Post-App li cation Inhalation Exposure

............. 17 7.0 Aggregate Exposure / Risk Charac terization

....................................................................... 17 8.0 Cumulative Exposure/Risk Characterization

..................................................................... 17 9. 0 Occupational Expo su re

/Ris k Characterization

.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. . .. .. .. .. .. .. . 18 9.1 Short- and Intermediate

- Term Hand ler Risk

........................................................ .. ........ 18 9.2 Short

- and Intermediat e- Term Post-Application Risk

.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. ..................... 20 1 0

.

0 References

.............................. .. ..... .. ...... .. . .. .. .... .............. ........ ......... ...... .. .. .. .. .. .. ................. 20 Appendix A. Tox i cology Profile and Executive Summaries

.. ............................................... .. .... 22 A.l. Toxico l ogy Da ta Requirements ....................................................................................... 22 A

. 2. Toxicity Profiles

................... . ... . .. .. ................... . ............. . ......... . .... . .. ...... . .......................... 23 A.3. Exec utive Summaries

.. . ....................... . ...... . ... . ....................................... . .. ... . ... .. .. ... . ... ... ... 28 Appendix B. Review of Human Research

................ .. ...... .. .............................. . ......................... . 29

Page 2 of29Ipconazole Human Health Risk Assessment DP No. D413830

Page 3 of 29 1.0 Executive Summary

Chemtura Corporation has petitioned the Agency to establish a permanent tolerance for residues of ipconazole in/on legume vegetables (Crop Group 6) in support of the registration s of the end

use product Rancona 3.8 FS (EPA Reg. No. 400

- 544) and the technic al product (EPA Reg. No. 400

- 512) for use as a seed treatment on that crop group.

Ipconazole is a triazole

- derivative fungicide and is currently registered for seed treatment use on
numerous crops . These uses are considered to be non

- food uses for ro ot and tuber vegetables (Crop Group 1) , leafy vegetables ( non

- Brassica and Brassica ; Crop Groups 4 and 5 ), cucurbit vegetables (Crop group 9) , sorghum, sunflower, canola, rape, mustard and corn (field, pop and sweet) . Tolerances, at the limit of quantitat ion ( LOQ, 0.01 ppm)

, have been established to support food uses on cotton, cereal grains ( Crop Group 15 ) except rice , peanuts, dried shelled peas and beans (Crop Subgroup 6C) , and soybean.

The petitioner, Chemtura Corporation, has submitted a complete toxicological database for ipconazole. Ipconazole may cause local, portal

- of

- entry irritation following oral, dermal, or inhalation exposure. Systemic effects that were observed in laboratory animals following exposure to ipconazole include decreases in body weight, body weight gain, and food consumption; liver and kidney effects; and developmental effects (the latter being in the presence of maternal toxicity). Carcinogenicity studies showed no treatment

- related increases in tumors in rat s and mice afte r exposure to ipconazole

. Since HED’s last risk assessment for ipconazole (28 May 2008), the petitioner has submitted an in vivo mammalian cytogenetics study, which has been reviewed and incorporated into this assessment. There are no changes in risk ass essment points of departure or endpoints relative to the 2008 assessment.

The data demonstrate that ipconazole has low acute toxicity via the oral (Category III), dermal (Category III), and inhalation (Category III) routes of exposure. It causes low to m ild irritation to the eyes (Category III) and skin (Category IV); it is not a dermal sensitizer.

To support the expansion of the use of ipconazole from Crop Subgroup 6C and soybean to all of Crop Group 6, the petitioner submitted fiel d trials conducted wi th soybean. The trials were conducted at exaggerated rates and soybeans were harvested in both immature and mature forms; the former being representative of edible podded legumes and succulent shelled pea and bean which were not addressed previously. The submitted data support expansion to Crop Group 6

, with a tolerance for residues of ipconazole at 0.01 ppm.

HED has conducted a screening level assessment of dietary exposure to ipconazole , based on tolerance level residues in crop commodities, upper bound estimates of residues in drinking water, and the assumption of 100% crop treated . The assessment includes all of the previously registered uses as well as the expansion to Crop Group 6. Dietary risk estimates are below HED’s level of concern for al l durations and for all population subgroups. As there are no residential uses for ipconazole, there are no short

- term aggregate exposure scenarios; acute and chronic aggregate risk estimates are equivalent to the corresponding d ietary risk estimates, whi ch

are below HED’s level of concern.Ipconazole Human Health Risk Assessment DP No. D413830

Page 4 of 29 Based on the proposed use pattern, short

- and intermediate

- term durations of exposure are expected for occupational handlers. The durations of exposure for occupational handlers in commercial seed treatment facilities may exceed those typically addressed by short

- and intermediate

- term assessments. Due to the use of conservative assumptions, the occupational assessments are considered protective of longer

- term exposure and risk. Occupational risk estimates for both application and post

- application activities are well below HED’s level of concern for all scenarios.

Metabolism of ipconazole has been shown to result in the formation of one or more of the common triazole metabolites 1,2,4

- triazole, triazolylalanine, tri azolylacetic acid, and triazolylpyruvic acid. Dietary and aggregate r isk estimates from exposure to these compounds are below HED’s level of concern and are addressed in separate assessment s ( Morton, T. 1 May 2013

, D411385 and Morton, T. 1 May 2013, D411386 ).

In accordance with U.S. Executive Order 12898 ( Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations ), environmental justice considerations were evaluated during the prepar ation of this risk assessm ent. Based on the available information, there are no environmental justice issues associated with the requested

use.
This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or othe r chemical. These data are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. See Appendix B for more information.

2.0 HED Recommendations

HED has determined that there are n o risk estimates of concern associated with the petitioned

- for use. Therefore, HED is recommending for the requested registrations and the establishment of a permanent tolerance for resi d ues of ipconazole in/on members of Crop Group 6 at 0.01 ppm. Detailed information regarding specific tolerance recommendations are in the sections below.

2.1 Data Deficiencies

None.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

A method utilizing liquid chromatography with tandem mass spectro metric detection (LC

MS/MS), Method AC

- 3020, is adequate for the enforcement of tolerances for residues of ipconazole in or on crop commodities. The validated LOQ is 0.01 ppm. The limit of detection (LOD) is estimated to be approximately half of the LOQ.Ipconazole Human Health Risk Assessment DP No. D413830

Page 5 of 29 The FDA multiresidue methods in PAM Volume I are not adequate for tolerance enforcement, as ipconazole residues of concern are not adequately recovered by any of the tested multiresidue method protocols.

HED notes that a n analytical standard for ipconazole is currently available at EPA’s National Pesticide Standards Repository (NPSR). However, the standard expires on 30 June 2013. The registrant should resubmit a new analytical reference standard, or an updated certificate of analysis (COA) for the current standard, before its expiration date.

2.2. 2 Recommended Tolerances

HED is recommending for the establishment of a permanent tolerance as shown i n Table 2.2.2.

Table 2.2.2. Tolerance Summary for Ipconazole

Commodity Established/Proposed Tolerance (ppm) Recommended Tolerance (ppm) Comments
Vegetables, Legume, Group 6 0.01 0.01 See 2.2.3

Upon establishment of the tolerance for Crop Group 6, the tolerance listings for Crop Subgroup 6C and for soybean , seed should be removed from 40 CFR 180.646. The listing for soybean, forage may remain.

HED further notes that the tolerance expression in 40 CFR 180.646 does not adequately address coverage and compliance. The tolerance expression should be revised to the following : Tolerances are established for residues of ipconazole from seed treatment , including its metabolites and degradates, in or on the commodities listed in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only ipconazole ( 2

- [(4

- chlorophenyl)methyl]

- 5

- (1

- methylethyl)

- 1

- (1 H

- 1,2,4

- triazol

- 1

- ylmethyl)cyclopentanol ) in or on the commodity.

2.2. 3 Revisions to Petitioned

- For Tolerances

The petitioner has requested a tolerance for residues of ipconazole in/on “Legume Vegetables, Crop Group 6 (succulent or dried).” The correct commodi ty definition for this group is “Vegetables, Legume, Group 6.” The petitioner should submit a revised Section F with the correct commodity definition; otherwise, there are no revisions to the petitioned

- for tolerance.

2.2. 4 International Harmonization

The tolerance in legume vegetables (group 6) recommended by HED (0.01 ppm) is harmonized with the existing Canadian MRLs in grain lupine, and multiple dried peas and beans (0.01 mg/kg). Codex has not established MRLs in any of the legume vegetables.

2. 3 Label Recommendations

None.Ipconazole Human Health Risk Assessment DP No. D413830

Page 6 of 29 3.0 Introduction

3.1 Chemical Identity

Ipconazole is a systemic, broad

- spectrum fungicide registered for use as a seed treatment on various crops. A s a seed dressing , it is used to protect plants from soil

- borne and seed

- borne diseases. It is structurally similar to many other triazole compounds used as pesticides. Ipconazole exerts its effect by inhibiting sterol synthesis in fungi, and is efficacious at very low applicati on rates . It is currently registered for use on leafy vegetables, root and tuber vegetables, cucurbit vegetables, soybeans, subgroup 6C dried shelled peas and beans (except soybean), wheat, barley, sorghum, cotton, sunflower, canola, rape, mustard, turf g rass, and others

. Based on the results of radiotracer studies, HED determined that many of the seed treatment uses could be considered non

- food uses, and did not require the establishment of tolerances in the relevant commodities. The nomenclature for ip conazole is presented in Table 3.1, and the physicochemical properties are summarized in Table 3.2 (below).

3.1 Nomenclature

T able 3.1

. Test Compound Nomenclature

Chemical Structure

(1R, 2S, 5R)

– isomer (1R, 2S, 5S)

– isomer

Common name Ipconazole Company experimental name KNF

- 317 Molecular formula C 18 H 24 N 3 OCl Molecular weight 333.9 amu

IUPAC name (1 RS ,2 SR ,5 RS ;1 RS ,2 SR ,5 SR )

- 2

- (4

- chlorobenzyl)

- 5

- isopropyl

- 1

- (1 H

- 1,2,4

- triazol

- 1

- ylmethyl)cyclopentanol

CAS name 2

- [(4

- chlorophenyl)methyl]

- 5

- (1

- methylethyl)

- 1

- (1 H

- 1,2,4

- triazol

- 1

- ylmethyl)cyclopentanol CAS regis try number 125225

- 28

- 7 End

- use product (EP) Rancona 3.8FS seed treatment fungicide (41% ai; EPA Registration #400

- 544)

3.2 Physicochemical Characteristics

T able 3.2

. Physicochemical Properties of Technical Grade Ipconazole

Parameter Value Refere n ce Melting point/range ( C) 85.5

- 88
Mather, S. 24 N OV 2003

, D292379 pH (at 25 C) 5.35 (1% suspension) Density (g/mL at 20 C) 1.2
Water solubility (mg/L) cis

- cis isomer: 9.34 cis

- trans isomer: 4.97 C l

N

N

N O H

H 3 C C H 3Ipconazole Human Health Risk Assessment DP No. D413830

Page 7 of 29 T able 3.2

. Physicochemical Properties of Technical Grade Ipconazole

Parameter Value Refere n ce

Solvent solubility (g/L) acetone 570 1,2

- dichloroethane 425 dichloromethane 583 ethyl acetate 428 heptane 1.90 methanol 679

n

- octanol 230 toluene 156 xylenes 151 Vapor pressure (Pa, at 20 C) <5.05 x 10 - 5
Dissociation constant (pK a) Indeterminate via OCSPP Product Properties Test Guideline 830.7370 Octanol/water partition coefficient (Log [K OW ]) cis

- cis isomer: 4.65 cis

- trans isomer: 4.44

UV/visible absorption spectrum 222 nm ( 0.74541, major maximum) 268 nm ( 0.02653, minor maximum) No absorbance over 300 nm
Ipconazole is a solid under ambient conditions, and has a somewhat low volatility. The compound has a relatively low solubility in water, and high solubility in organic solvents. Its octanol/water partition coefficient suggests that the compound m ay have the potential accumulate in fatty tissues

. Actual behavior of ipconazole in the environment and in organisms will depend on factors other than its physicochemical properties.

3.3 Pesticide Use Pattern/Directions for Use (860.1200)

Proposed labels for the 97.4% technical active ingredient (ai) (EPA Registration #400

- 512), and the end

- use product (EP), Rancona 3.8FS (EPA Registration #400

- 544) were provided with the petition. This EP is a flowable suspension (FS) formulation of ipconazole con taining approximately 41% of the ai by weight, equivalent to 3.77 pounds of ai per gallon (lb ai/gal). The PPE statement on the propo sed label requires applicators and other handlers to wear long

sleeved shirt

, long pants, socks, shoes, and chemical

- resis tant gloves. The proposed use directions are summarized in Table 3.3, below.

T able 3.3

. Summary of Ipconazole Directions for Treatment of Seeds in Crop Group 6
Application Type; Timing; Equipment End

- Use

Product Use Rate

(oz ai/100 lb seeds) Max.

Uses per Season Seasonal

Use Rate (lb ai/A) 1 PHI 2

(Days) Use Directions and Limitations

Seed treatment; standard slurry or mist

- type commercial seed treatment equipment. 41% ai FS 0.04 1 ~0.00055

- 0.00165 NA 3 Not for use at agricultural

establishments in hopper

- box, planter

- box, slurry

- box or other seed treatment applications at or immediately before planting. 1. Based on typical seeding rates, and 2,600 soybean seeds/lb (for most commercial varieties). 2. PHI = Pre

- Harvest Interval. 3. NA = Not Applicable. (The requested use is a seed treatment.)Ipconazole Human Health Risk Assessment DP No. D413830

Page 8 of 29 3.4 Anticipated Exposure Pathways

At this time, there are no registered uses of ipconazole that would result in handler or post

application exposures in or around the home. Use of ipconazole as a seed treatment may result in residues of the fungicide in crops and in drinking water. Therefore, apart from occupational
exposures, only dietary exposure to ipconazole is expected. In an occupational setting, exposure to ipconazo le may occur during the seed treatment process as well as during activities associated with planting treated seed. The occupational exposures may be via dermal and/or inhalation
routes. Due to ipconazole use being for seed treatment only, exposure during post

- application activities, such as scouting, irrigating, and harvesting, is not expected.

3.5 Consideration of Environmental Justice

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

- Income Populations," ( http://www.eh.doe.gov/oe pa/guidance/justice/eo12898.pdf

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

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

- dietary exposures base d on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has committe d resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

A comprehensive risk assessment for ipconazole was conducted in 2008 ( Doherty , M. 28 May 2008, D337784)

. Since the last risk assessment, an in vivo mammalian cytogenetics study ( MRID 46827502 ) was received which fulfills a previ ously identified data gap

. In th at study, no evidence was found for an ipconazole

- induced increase in the incidence of micronucleated erythrocytes

. However, a decrease in the polychromatic erythrocyte ( PCE ) to total erythrocyte ratio was observed for all ipconazole treated groups 24 hours after two doses that were separated by 24 hours

. Since cell death takes up to 48 hours to fully manifest, HED concluded that the decreased ratio of PCE to total erythrocyt es could be the result of a single dose

. In addition, clinical signs suggestive of neurotoxicity were observed in the mid

- and high

- dose groups following a single dose of ipconazole

. The study was considered for endpoint selection,Ipconazole Human Health Risk Assessment DP No. D413830

Page 9 of 29 especially as an acut e dietary endpoint for the general population since no appropriate single dose effects were identified for the general population in the previous risk assessment

. Based on a weight of evidence (WOE) approach, however, HED has concluded that the decreased PCE to total erythrocytes ratio is not an appropriate acute endpoint for the general population , including infants and children

. The acute decrease in erythrocyte production is unlikely to result in an adverse impact on human health given the long lifetim e of erythrocytes in humans (100

- 120 days)

. Thus, despite the decrease in production of new erythrocytes there will be an ample number of erythrocytes in circulation

. In addition, erythrocyte production is rapid in humans allowing an individual to quickl y recover from the toxic insult

. No other signs supportive of bone marrow toxicity were observed in the ipconazole toxicity database

. Based on a WOE approach, HED has also concluded that the clinical observations suggestive of neurotoxicity are not an appropriate acute endpoint for the general population

. No signs of neurotoxicity were observed following acute, subchronic, or chronic dosing in multiple species in the ipconazole toxicity database, including a subchronic rat study and a chronic rat

canc er/toxicity study where neurological parameters were measured

. As a group, triazole fungicides typically show either no evidence of neurotoxicity or neurotoxicity at doses higher than the regulatory points of departure

. In line with the other tri azoles, the effects seen in the in vivo mammalian cytogenetics study were seen at relatively high doses, which far exceed the anticipated dietary exposure

. Thus, the doses where effects were seen are not of concern and would not result in any dietary risk to the general population.

Based on the reasoning provided above, HED has determined that in humans

, neither bone marrow toxicity nor neurotoxicity is likely after a single exposure

. T herefore, the cytogenetics study has not resulted in any changes have been ma de to the endpoints or points of departure used in the previous risk assessment

. However, HED has revised the endpoint and point of departure for assessing inhalation toxicity based on the systemic effects such as decreased body weight and body weight gai n, as well as portal

- of

- entry effects such as inflammation in the respiratory tract, observed in the route

- specific inhalation toxicity study.

4.1 Summary of Toxicological Effects

Subchronic and chronic studies show t he liver to be the primary target organ for ipconazole

. Liver effects (increased relative liver weights, hepatocyte vacuolization, fatty deposits, and centrilobular hepatocyte hypertrophy) were observed in the subchronic mouse and dog, 28

- day inhalation, chronic dog and mouse carc inogenicity studies

. Ipconazole exerts its pesticidal effects by inhibiting sterol synthesis in fungi

. The effects observed on the liver are consistent with this mode of action

. Effects on the liver are also consistent with the findings in the metabolis m studies where the highest radioactive residues were found in the liver and elimination was primarily through the bile

. Decreased body weight, body weight gain, and food consumption were also commonly observed in the toxicology database

. In subchronic studies, these effects were noted at approximately 30

- 40 mg/kg/day in rats and dogs; mice did not appear as sensitive, as effects were not observed at doses under 70 mg/kg/day

. Similar effects on body weight, body weight gain, and foodIpconazole Human Health Risk Assessment DP No. D413830

Page 10 of 29 consumption were o bserved in the 28

- day dermal, 28

- day inhalation, chronic dog, and mouse carcinogenicity studies

. Other effects observed following exposure included decreased absolute and relative uterine weights and increased incidence of kidney corticomedullary minerali zation in females of the subchronic rat study; increased incidence of cataracts, reddening of the skin, hair loss, and decreased thymus weights in the subchronic dog study; hair loss and increased leukocyte counts in females of the 28

- day inhalation study; erythema in the 28

- day dermal study; and reddening of the skin on various regions of the body in the chronic dog study

. Ipconazole also caused portal

- of

- entry irritation via all routes following repeated exposure in subchronic, but not chronic, studies in rats

. These effects include hyperkeratosis and hyperplasia of the nonglandular stomach after oral exposure, hyperkeratosis and hyperplasia of the treated skin following dermal exposure, and hyperplasia and inflammatory cells in the respiratory tract fo llowing inhalation exposure

. Ipconazole is classified as not likely to be carcinogenic to humans

. There was no evidence of increased incidence of tumors in the carcinogenicity study in mice or in the chronic/carcinogenicity study in rats

. Ipconazole i s not mutagenic or clastogenic

. No evidence of increased quantitative or qualitative susceptibility was seen in developmental toxicity studies in rats and rabbits or in a reproduction study in rats

. In the rat and rabbit developmental toxicity studies and the two generation study in rats, all effects in the fetuses or pups occurred in the presence of maternal toxicity, including changes in body weight gains and food consumption

. Developmental effects included decreased fetal body weight and increased incidences of visceral and skeletal variations in the rat developmental study; skeletal malformations and variations in the rabbit developmental study; and decreased pup body weights and body weight gains (both generations), increased relative spleen weigh ts, and thin build in the 2

- generation study in rats

. Although acute and subchronic neurotoxicity studies were not conducted, a limited neurotoxicity assessment was conducted in rat subchronic and chronic toxicity/carcinogenicity studies

. Clinical signs suggestive of neurotoxicity were observed in the in vivo mammaliam cytogenetics study; however, they occur at half the limit dose and no other signs were observed in any of the other studies

. HED has concluded that the acute and developmental neurotoxicit y studies are not required, and there is no concern for ipconazole

induced neurotoxicity.

Ipconazole is rapidly absorbed (females absorbed less than the males) and extensively metabolized following single or repeated oral doses in the rat

. The major routes of metabolism for ipconazole involved hydroxylation and glucuronidation, but cleavage of the triazole ring was also observed

. Some sex differences were observed, but the majority of the metabolites were observed in both sexes

. Free triazole was the major urinary component, accounting for 6.9% of the administered dose

. However, excretion was primarily via the bile and feces, with low levels of radioactivity in the urine

. Bioaccumulation was not observed

. A dermal absorption study with ipconazol e is not available

. A dermal absorption factor of 3% was derived by comparing the toxicity endpoints from a dermal toxicity study and an oral toxicity study of comparative durations. A route

- specific inhalation toxicity study indicated systemic effects s uch as decreased body weight and body weight gain, as well as portal

- of

- e ntry effects such as inflammation in the respiratory tract.Ipconazole Human Health Risk Assessment DP No. D413830

Page 11 of 29 Acute testing with i pconazole resulted in low toxicity via the oral ( Category III), dermal ( Category III), and inhalation ( Category III) routes of exposure. L ow to mild irritation to the eyes ( Category III) and skin ( Category IV) were observed and it was not a dermal sensitizer.

4.2 Safety F actor for Infants and Children (FQPA Safety Factor)

HED has determined that the req uired 10X FQPA Safety Factor should be reduced to 1X in assessing the risk posed by ipconazole

. This recommendation was based on the following considerations:

• The toxicity database is complete, with no data gaps for the assessment of the effects of ipcon azole following in utero and/or postnatal exposure

.

• There is no consistent evidence of neurotoxicity in the available database

. Clinical signs suggestive of neurotoxicity were observed in the in vivo mammaliam cytogenetics study; however, they occur at half the limit dose and no other signs were observed in any of the other studies

. An acute neurotoxicity study is not available but HED’s Hazard and Science Policy Council (HASPOC) has determined that the study is not required based on the lack of evidence of neurotoxicity in the database ; a developmental neurotoxicity study is not required

. The subchronic neurotoxicity study requirement is considered to be satisfied by the neurotoxicity assessments performed in both the rat subchronic and chronic toxicity/carcinogenicity studies in which no signs of neurotoxicity were observed

.

• There is no indication of quantitative or qualitative susceptibility of rats or rabbits to in
utero and/or postnatal exposure to ipconazole.

• The risk assessment does not und erestimate exposure, since t he dietary assessment is based on conservative assumptions such as tolerance

- level residues in foods, 100% crop treated, and upper

- bound modeled estimates of residues in drinking water

. In addition, there are no registered resi dential uses for ipconazole

.

4.2.1 Completeness o f the Toxicology Database

As summarized in Appendix A , the toxicology database is considered adequate for the purpose of assessing pre

- and postnatal susceptibility, lacking only an immunotoxicity study

. However, no effects on the immune system were reported in the available studies and the triazoles, as a chemical class, typically do not demonstrate immunotoxic effects

. HED’s HASPOC determined, based on weight

- of

- evidence considerations, that the immuno toxicity study is not required for the conazoles as a class, which includes ipconazole ( K. Rury, TXR# 0056730, 7/25/13)

. There is no concern for increased susceptibility in the developing young , and no evidence of frank neurotoxicity in the database

. The refore, a developmental neurotoxicity study is not required at this time

. The neurotoxicity parameters examined in the subchronic and combined chronic/carcinogenicity rat studies are considered adequate to fulfill the data requirement for a subchronic neu rotoxicity study

. HED’s HASPOC determined that an acute neurotoxicity study in the rat is not required based on lack of evidence of neurotoxicity in the available studies (Rury, K. 20 March 2013, TXR # 0056542 )

.Ipconazole Human Health Risk Assessment DP No. D413830

Page 12 of 29 4.2.2 Evidence of N eurotoxicity

No consistent evidence of neurotoxicity was observed following acute, subchronic, or chronic dosing in multiple species in the available ipconazole database and the triazole fungicides as a group typically show either no evidence of neurotoxicity or neurotox icity at doses significantly higher than the regulatory points of departure

. Clinical signs suggestive of neurotoxicity were observed in the in vivo mammaliam cytogenetics study; however, they occur at half the limit dose and no other signs were observed in any of the other studies

. These clinical signs were not considered to be evidence of frank neurotoxicity based on the results of the toxicity studies conducted with ipconazole as well as what is known about the triazole fungicides as a class. A develo pmental neurotoxicity study is therefore not required and there is no concern for ipconazole

- induced neurotoxicity

.

4.2.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

In rat developmental and reproductive toxicity studies, and in the rabbit developmental study,

o ffspring and fetal effects occurred only in the presence of maternal toxicity ; thus, there is no evidence of quantitative susceptibility. The skeletal effects observed in the offspring may appear to be more severe than the decreased body weight gain observed in the dams at the same dose ; however, at the LOAEL the decreased body weight gain was found to be statistically significant

, whereas the skeletal effects were not statistically significant until the next higher dose

. Therefore, HED conclude s that there is no increased quantitative or qualitative susceptibility to rat or rabbit offspring exposed in utero and/or post

- natally to ipconazole

, and there are no residual uncertainties with respect to pre

- or postnatal exposure

.

4.2.4 Residual Uncertainty in the Exposure Datab ase
There is no residual uncertainty in the exposure database

. There are no exposure data gaps and the current dietary exposure assessment is based on high

- end assumptions such as tolerance

- level residue values , 100% crop treated, and modeled estimates of drinking water residues

. There are currently no registered or proposed residential uses for ipconazole, so exposure is limited to dietary exposure. Therefore, the assessment is conservative and does not underestimate
exposure.

4.3 Toxicity Endpoint and Point of D eparture Selections

The toxicological endpoints and points of departure selected for dietary and occupational exposure and risk assessment are summarized in Tables 4.3.1 and 4.3.2

. The complete toxicological profile for ipconazole is summarized in Appendix A

. The NOAEL and LOAEL of the 28

- day inhalation study ( MRID 47048915) were updated based on observed portal

- of

- entry effects. In addition, a human equivalent concentration (HEC) and human equivalent dose (HED)

w ere calculated for use in MOE calculations using the methods and dosimetry equations describe d in EPA’s reference concentration (RfC) guidance (1994)

. There have been no changes
to any of the other previously selected endpoints, points of departure, or the cancer classification for ipconazole.Ipconazole Human Health Risk Assessment DP No. D413830

Page 13 of 29 Table 4.3.1

. Summary of Toxicological Doses and End points for Ipconazole Use in Dietary and Non

- Occupational

Human Health Risk Assessments
Exposure Scenario Point of

Departure Uncertainty/

FQPA Safety Factors RfD, PAD, Level

of Concern for Risk Assessment Study and Toxicological Effects

Acute Dietary (General population, including i nfants and c hildren) N/A N/A N/A No appropriate endpoint is available.

Acute Dietary (females 13

- 49) NOAEL =

10 mg/kg UF A =10X

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

0.1 mg/kg

aPAD = 0.1 mg/kg Co

- critical Developmental Toxicity

Studies in Rats and Rabbits LOAEL rats = 30 mg/kg/day, based on increased visceral and skeletal variations LOAEL rabbits = 50 mg/kg/day, based on increased incidence of skeletal variations and malformations

Chronic Dietary (all popula tions) NOAEL =

1.5 mg/kg/day UF A =10X

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

0.015 mg/kg/day

cPAD = 0.015 mg/kg/day Chronic Toxicity Study in Dogs

LOAEL = 5 mg/kg /day, based on skin reddening (both sexes) and decreased body weight gain in females
Cancer (oral, dermal, inhalation) No Evidence of Carcinogenicity 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 population (intraspecies)

. FQPA SF = FQPA Safety Factor

. PAD = population adjusted dose (a = acute, c = chronic)

. RfD = reference dose

. N/A = not applicable.Ipconazole Human Health Risk Assessment DP No. D413830

Page 14 of 29 Table 4.3.2

. Summary of To xicological Doses and Endpoints for Ipconazole Use in Occupational Human Health

Risk Assessments Exposure Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk Assessment Study and Toxicological Effects

Dermal Short

- Term (1

- 30 days) and Intermediate

term (1

- 6 months) NOAEL = 150

mg/kg /day UF A =10X

UF H =10X LOC for MOE =100 28

- day Dermal Toxicity Study in Rats LOAEL = 1000 mg/kg /day, based on decreased body weight, body weight gain, and food consumption, as well
as, increased incidences of dermal irritation

Inhalation Short

- Term (1

- 30 days) and Intermediate

term (1

– 6 months) NOAEL = not

established (<0.03 mg/ L )

HEC = 0. 00531 mg/ L HED = 0.2832 mg/kg/day UF A = 3 X

UF H =10X UF L = 10X LOC for MOE = 3 00 28

- Day Inhalation Toxicity Study in Rats LOAEL = 0.03 mg/ L , based on epithelial hyperplasia in the hard palate in males, epithelium squamos/squamoid hyperplasia in the larynx mucosa of both sexes, and mixed inflammatory cells in the trachea of females Cancer (o ral, dermal, inhalation) No Evidence of Carcinogenicity. Classified as “Not Likely to be Carcinogenic to Humans.”

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 anim al to human (interspecies)

. UF H = potential variation in sensitivity among members of the human population (intraspecies)

. UF L = use of a LOAEL to extrapolate a NOAEL MOE = margin of exposure

. LOC = level of concern

. HEC = human equivalent concentration

. HED = human equivalent dose. HEC = rat NOAEL *(daily duration adjustment) * weekly daily duration adjustment *RDDR = 0.03 mg/L * (6 hr/8 hr) * (1) *0.236 = 0.00531 mg/L HED = HEC * human

- specific conversion factor * daily duration = 0.00531 * 6 L/hr/kg * 8 hr = 0.2832 mg/kg/day

5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary and Rationale

Data have been submitted and reviewed depicting the metabolism of ipconazole in numerous crops and the environment. For a complete discuss ion of metabolism in crops and livestock, including chemical names and structures, refer to a previous residue chemistry summary document ( Doherty

, M. 28 May 2008 , D338246 ).

The residues of concern for dietary risk assessment and the tolerance expression are summarized in Table 5.1. The parent compound is an adequate indicator of misuse and is the only residue included in the tolerance expression. The residues of concern for risk assessment are ipconazole, 1,2,4

- triazole (1,2,4

- T), and the conjugated triazole metabolites triazolyl pyruv ic acid (TP), triazolylalanine (TA), and triazolylacetic acid (TAA). 1,2,4

- T, TP, TA and TAA are metabolites common to this class of fungicide and are assessed separately from the parent compound

.Ipconazole Human Health Risk Assessment DP No. D413830

Page 15 of 29 T able 5 .1

. Summary of Metabolites and Degradates to be in cluded in Risk Assessment and Tolerance Expression

Matrix Residues Included in Risk Assessment Residues Included in Tolerance Expression for Compliance Monitoring

Plants Primary Crops Ipconazole, 1

, 2

, 4

- T, TP, TA, TAA 1 Ipconazole

Rotational Crops Ipconazole, 1

, 2

, 4

- T, TP, TA, TAA Ipconazole 2

Livestock Ruminants Ipconazole, 1

, 2

, 4

- T, TP, TA, TAA Ipconazole 2

Poultry Ipconazole, 1

, 2

, 4

- T, TP, TA, TAA Unknown 3 Drinking Water Ipconazole, 1

, 2

, 4

- T, TP, TA, TAA Not Applicable 1. 1,2,4

- T = 1,2,4

- triazole ; TP = triazolyl pyruv ic acid ; TA = triazolyl alanine ; TAA = triazolyl acetic acid

. These metabolites are assessed separately from ipconazole. 2. Based on the available data, tolerance s are not required in r otational c rop s or r uminant s at this time. 3

. A poultry metabolism study has not been submitted to HED. Based on the available information, poultry metabolism and feeding studies are not required at this time.

5.2 Food Residue Profile ( Drew, W. 2 April 2013, D406708 )

Field trials using seed treated with ipconazole consistently result in ipconazole residues being less than the LOQ (0.01 ppm) in/on all harvested commodities , even in trials with seed treated at a rate 5

- fold greater than the labeled rate. Quantifiable residues of the common triazole metabolites, particularly triazolylalanine, are found in some harvested commodities at both 1X and 5X treatment rates. As previously noted, ri sk estimates associated with these metabolites are addressed in a separate assessment ( Morton, T. 1 May 2013, D411385 and Morton, T. 1 May 2013, D411386 )

. There are several livestock feedstuffs associated with the existing uses of ipconazole. E xpansion of the use of ipconazole to include all of Crop Group 6 is not expected to result in changes to livestock estimated dietary burdens. Therefore, and as determined in the previous assessment, uses of ipconazole fall under Category 3 of 180.6 [ a ] ; th at is , there is no reasonable expectation of finite residues of ipconazole in livestock commodities.

5.3 Water Residue Profile

I pconazole is persistent in soil and there is a potential for accumulation in soil on sites with use over consecutive years. T he maximum estimated drinking water concentrations (EDWCs) were obtained from modeling the use of ipconazole on ginseng.

The Environmental Fate and Effects Division (EFED) provided estimated ipconazole concentrations in drinking water in the following m emorandum: Revised Estimated Drinking Water Concentrations (EDWCs) from its Proposed New Use by Expansion of Uses from Crop Subgroup 6C to the Entire Crop Group 6 for Use in Human Health Risk Assessment ; D406894; Mohammed A. Ruhman; 15 July 2013) . The results, summarized in Table 5.3, are b ased on Tier II modeling: PRZM/EXAMS for surface water and PRZM

- GW for ground water. A description of the water models can be found at http://www.epa.gov/oppef ed1/models/water/

.

Table 5.3 Table 5.3. Summary of Estimated Surface Water and Groundwater Concentrations for Ipconazole

.

Scenario Surface Water Conc., ppb a Groundwater Conc., ppb b
Acute 0.173 1.01 Chronic (non

- cancer) 0.105 0. 8220 Chronic (cancer) c Not Applicable Not Applicable

a From the PRZM/EXAMS

.Ipconazole Human Health Risk Assessment DP No. D413830

Page 16 of 29 b From the PRZM

- GW model.

c EDWCs for use in a cancer assessment were provided; however, ipconazole is c lassified as “Not Like ly to be Carcinogenic to Humans ” and a cancer assessment is not necessary.

The surface water estimates, being greater than the groundwater estimates, were used quantitatively in the dietary exposure assessment (see Section 5.4) , and considered protective of potential drinking water residues from all sources of drinking water

.

5.4 Dietary Risk Assessment ( Drew, W. 8 August 2013. D413901 )

A cute and chronic dietary risk assessments were conducted using the Dietary Exposure Evaluation Model (DEEM

- FCIDTM, Version 3.16 ) which uses food consumption data from the U.S. Department of Agriculture’s National Health and Nutrition Examination Surveys of What We Eat in America (NHANES/WWEIA) data for 2003

- 200 8. Both the acute and chronic assessments used tolerance

- level residue s, assumed 100% crop treated, and incorporated model

derived, conservative estimates of ipconazole residues in ground water discussed in Section 5.3

. Given the assumptions regarding residue levels and occurrence (i.e. 100 % crop treated and all sources of drinking water contains residues of ipconazole) , these assessments should be characterized as screening

- level and highly conservative. Note: No acute endpoint attributable to a single exposure and relevant for the general population was identified in the toxicity database for ipconazole. A developmental endpoint suitable for acute assessment was identified; therefore, an acute assessment was performed only for women of child

- bearing age (females 13

- 49 years old).

Generally, HED has a concern when dietar y risk estimates exceed 100% of the acute and/or chronic population

- adjusted dose (aPAD and/or cPAD). Based on the screening

- level assumptions described above, the acute and chronic d ietary r isk estimates for ipconazole are well below HED’s level of conce rn for all population subgroups, including those of infants and children (Table 5.4) , with risk estimates of at most 1% aPAD and cPAD for all populations assessed

. Ipconazole is classified as “ Not Likely to be Carcinogenic to Humans ;” therefore,

cancer risk is not a concern for this compound.

Table 5.4. Summary of Dietary (Food + Water) Exposure and Risk Estimates for Ipconazole.

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

NA* NA 0.000065 <1 All Infants (<1 year old) 0.000122 <1 Children 1

- 2 years old 0.000142 <1 Children 3

- 5 years old 0.000133 <1 Children 6

- 12 years old 0.000095 <1 Youth 13

- 19 years old 0.000063 <1 Adults 20

- 49 years old 0.000058 <1 Adults 50+ years old 0.000047 <1 Females 13

- 49 years old 0.000 11 7 <1 0.000055 <1 * NA = Not Applicable. The population subgroup with the highest risk estimate is in bold typeface

.Ipconazole Human Health Risk Assessment DP No. D413830

Page 17 of 29 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

At this time, there are no existing or requested uses of ipconazole that would result in residential
exposure , therefore there is no residential risk.

6. 1 Spray Drift and Residential Bystander Post

- A pplication Inhalation Exposure

Quantitative spray drift and post

- application exposure assessments have not been completed since there is no application of pesticide directly to the fields (seeds are previously treated in seed treatment facilities). Therefore, expo sure is expected to be negligible.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

In the case of ipconazole, there are no uses expected to result in residential exposure. Therefore, aggregate exposure and risk estimates are equivalent to the dietary exposure and risk estimates discussed in Section 5.4. The risk estimates are below HED’s level of concern for all durations

an d population subgroups.

8.0 Cumulative Exposure/Risk Characterization

Ipconazole is a member of the triazole

- containing class of pesticides, often referred to simply as the triazoles. EPA is not currently following a cumulative risk approach based on a common mechanism of toxicity for the tri azoles. The tri azole pesticides, as a whole, tend to exhibit carcinogenic, developmental, reproductive, and/or neurological effects in mammals. Additionally, all the members of this class of compounds are capable o f forming, via environmental and metabolic activities, 1,2,4

- triazole, triazolylalanine and/or triazolylacetic acid. These metabolites have also been shown to cause developmental, reproductive, and/or neurological effects. Structural similarities and sha ring a common effect does 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. Hence, the underlying basis of toxicity is the same, or essentially the same for each chemical.” (EPA, 2002) A number of potential events could contribute to the toxicity of tri azoles (e.g., altered cholesterol levels, stress responses, altered DNA methylation). At this time, there is not sufficient evidence to determine whether tri azoles share common mechanisms of toxicity. Without such understanding, there is no basis to make a common mechanism of toxicity finding for the diverse range of effects found. Investigations into the tri azoles are curre ntly being undertaken by the EPA’s Office of Research and Development. When the results of this research are available, the Agency will make a determination of whether there is a common mechanism of toxicity and,Ipconazole Human Health Risk Assessment DP No. D413830

Page 18 of 29 therefore, a basis for assessing cumulativ e risk. 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.

To support existing tolerances and to establish new tol erances for tri azole pesticides, including ipconazole, EPA conducted human health risk assessments for exposure to 1,2

, 4

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

- containing pest icides (as of 9/1/05). The risk assessment is a highly conservative, screening

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

- dietary expo sures (i.e., high

- end estimates of both dietary and non

- dietary exposures). Acute and chronic aggregate risk estimates associated with these compounds are below the Agency's level of concern for all durations of exposure and for all population subgroups, including those of infants and children. The Agency's risk assessment for these common metabolites is available in the propiconazole reregistration docket at http://www.regulations.gov , Docket Identification (ID) N umber EPA

- HQ

- OPP

- 2005

- 0497. The assessment was recently update d to include another metabolite, triazolylpyrivic acid, as well as requested uses/label amendments for other triazole fungicides , including ipconazole ( Morton, T. 1 May 2013, D411386 ).

9.0 Occupational Exposure/Risk Characterization ( Collantes

, M. 25 June 2013

, D410928 )

9.1 Short

- and Intermediate

- Term Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each task. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target crop being treat ed, and the level of protection used by a handler can cause exposure levels to differ in a manner speci fic to each application event.

Based on the anticipated use patterns and current labeling, types of equipment and techniques that potentially can be used, occupational handler exposure is expected from the proposed uses. Typically

, for large

- scale commercial seed treatments, workers perform only specific individual tasks; however, HED assumed that workers also may perform multiple activities th roughout the day. As a result a “multiple activities” scenario (i.e. where one worker performs all seed treatment tasks such as loading/applying, bagging, cleaning, calibration, repair, forklift driver, etc.) w as a ss essed. The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios: Mixing, loading, applying liquid formulations for commercially and on

- farm treated seeds; Multiple activities ; and Planting treated seed.

T he proposed t reatment of seeds is expected to result in short

- and intermediate

- term exposure via both the dermal and inhalation routes

. Since the dermal and inhalation endpoints areIpconazole Human Health Risk Assessment DP No. D413830

Page 19 of 29 different, the dermal and inhalation exposure estimates were not combined into an overall margin of exp osure (MOE). The short

- term exposure and risk estimates are considered to be protective of intermediate

- term exposure and risk s ince the same doses and endpoints were selected to

assess short

- and intermediate

- term exposure

. Although the product is proposed for use on

- farm, the label specifies that seed should be treated using a water

- based slurry with other registered seed treatment insecticides and fungicides through standard slurry or mist

- type commercial seed
treat ment equ ipment , and that the product is not for use in hopper, planter or slurry boxes at, or immediately before, planting

. Treatment of the proposed seeds is expected to result in short

- and intermediate

- term exposure. However, since the same dermal and inhal ation endpoints were selected for their respective short

- and intermediate

- term exposure durations, short

- term exposure and risk estimates are considered to be protective of intermediate

- term exposure and a separate quantitative risk assessment for interme diate

- term durations was not provided. T he AHETF survey reports that 39% of soybean is treated downstream for a duration of 49 days (50 th percentile; range 4 to 150 days) , while soybean commercial facilities operate 210 days per year (50 th percentile; ran ge 1 to 270 days) . While these durations would be considered to potentially exceed the typical intermediate

- term duration used in HED’s occupational assessments, HED had no information to indicat e that the same chemical is used consecutively for a long

- te rm duration . Therefore, chronic occupational handler exposure for seed treatment was not assessed

. Furthermore, the dermal and inhalation unit exposure values specified in Policy 14 are based on open

- pour systems, whereas the majority of the seed treatme nt facilities with large throughputs are equipped with fully or partially automated closed mixing and loading systems. Therefore, HED concluded that a chronic exposure assessment for ipconazole seed treatment would result in overly conservative estimates of exposure.

Occupational handler exposure and risk estimates are summarized in Tables 9.1.1 (seed treaters) and 9.1.2 (seed planters). All margins of exposure (MOEs) are greater than 100 and reflect risk estimates that are not of concern to HED. All ex posure estimates were calculated with baseline clothing (long sleeved shirt, long pants, socks and shoes) and gloves (note that gloves are only assumed to be used during loading of seed into the planter, and not during planting seed into the field using a tractor).

Separate estimates have not been made for on

- farm seed treatment. Since on

- farm treatment equipment is similar to that used in commercial treatment facilities but with significantly less throughput, HED assumes that the commercial seed treatmen t risk assessment is protective o f

on

- farm seed treatment activities.

Table 9.1.1. Short

- term Occupational Seed

- Treatment Handlers Exposure and Risk Estimates for Ipconazole

Use Site PPE Application Rate a (lb ai/ lb seed) Amount

Treated b (lb seed/ day) Dose (mg/kg/day) Dermal MOE e Inhalation

MOE f Dermal c Inhalation d
Loader/Applicator Legume Vegetables (surrogate

– soybeans) Single Layer, Gloves 0.000025 281,250 0.0020 0.00003 74,000 9,4 00

Multiple Activities Legume Vegetables (surrogate

– soybeans) Single Layer, 0.000025 281,250 0.0037 0.00014 41,000 2 ,000Ipconazole Human Health Risk Assessment DP No. D413830

Page 20 of 29 Gloves

a Application Rate is based on Proposed Label for V

- 10208 3.2 FS (EPA Reg No. 59639

- 185.
b Amount of Seed Treated is based on information provided in the HED Interim Guidance SOP 15.1: Amount of Commercial Seed Treated Per Day (November 14, 2012).

c Dermal Dose (mg/kg/d ay ) = unit exposure (mg/lb ai) × application rate (lb ai/lb seed) × daily amounts treated ÷ body weight (80 kg). Unit exposure = 0.023 mg/lb ai for loader/applicator and 0.042 mg/lb ai for multiple activities
d Inhalation Dose (mg/kg/d ay ) = (unit exposure (mg/lb ai) × application rate (lb ai/lb seed) × daily amounts treated ÷ body weight (80 kg). Unit exposure = 0. 00034 mg/lb ai for loader/applicator and 0.0016 mg/lb ai for multiple activities

e Short

- term Dermal MOE = NOAEL ( 15 0 mg/kg/day) ÷ dermal dose (mg/kg/day).
f Short

- term Inhalation MOE = NOAEL ( 0.28 mg/kg/day) ÷ inhalation dose (mg/kg/day).

Table 9.1 .2

. Handler

- Seed Planters Exposure and Risk Estimates for Ipconazole

Use Site Mitigation

Level Application

Rate a (lb ai lb seed) Amount

Planted b (lbs seed) Dose (mg/kg/day) Dermal MOE e Inhalation

MOE f Dermal c Inhalation d

Legume Vegetables (surrogate

– soybeans) Single Layer, Gloves 0.000025 13,280 0.0010 0.000014 140,000 2 0,000

a Application Rate is based on Proposed Label for V

- 10208 3.2 FS (EPA Reg No. 59639

- 185).
b Amount planted is based on information provided in the HED Reviewer’s Aid to Calculating Occupational Exposures from Activities Related to Agricultural Seed Treatment (November 29, 2012) and the BEAD Acres Planted per Day and Seeding Rates of Crops Grown in the United States, Appendix B, Table B

- 1

. c D ermal D ose (mg/kg/d ay ) = (unit exposure (mg/lb ai) × application rate (lb ai/lb seed) × daily amounts treated / body weight (80 kg). Unit Exposure = 0.25 mg/lb ai. Note the dermal unit exposure is based on exposure resulting from loading treated seed into hopper while using gl oves and does not represent exposure for driver operating tractor (no gloves required).
d Inhalation Dose (mg/kg/d ay ) = (unit exposure (mg/lb ai) × application rate (lb ai/lb seed) × daily amounts treated / body weight (80 kg). Unit exposure = 0.0034 mg/lb ai.

e Short

- term Dermal MOE = NOAEL ( 150 mg/kg/day) / d ermal dose (mg/kg/day)

. f Short

- term Inhalation MOE = NOAEL ( 0.28 mg/kg/day) / inhalation dose (mg/kg/day)

.

9.2 Short

- and Intermediate

- Term Post

- Application Risk

HED uses the term post

- application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re

entry exposure). The potential for dermal and inhalation post

- applica tion exposures following the planting of ipconazole

- treated seeds is unlikely. S ustained contact with treated seed after it has been placed in the soil or other planting media is not expected because no routine cultural practice required for the production of agricultural commodities involves such an activity

, as defined in the no/low contact criteria in the Worker Protection Standard (WPS)

. Therefore, no quantitative post

- applicatio n assessment is required for seed treatment uses

. The labeling properly state s the exception to the Agricultural Use Requirements restricted entry interval (REI) of 12 hours.

10.0 References

Collantes, M. 25 June 2013

. D410928

. Ipconazole: Occupational and Residential Exposure/Risk Assessment of Ipconazole for Seed Treatment Uses on Legume Vegetables

. Doherty, M. 28 May 2008

. D337784

. Ipconazole. Human Health Risk Assessment for the Requested Seed Treatment Uses on Cotton, Peanut, Soybea n, Dry Shelled Pea and Bean (Subgroup 6C), and Cereal Grains (Groups 15 and 16) Except Rice

.Ipconazole Human Health Risk Assessment DP No. D413830

Page 21 of 29 Drew, W. 2 April 2013

. D406708

. Ipconazole. Petition to Establish Permanent Tolerances for Residues of the F ungicide Resulting from Food Use on Legume Vegetables, Group 6

. Summary of Analytical Chemistry and Residue Data

. Drew, W. 8 August 2013. D413901. Ipconazole. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Action; Food

/ Use on Legume Vegetables, Group 6 (Revised)

. Mather, S. 24 November 2003

. D292379

. Product C hemistry R eview for the N ew A ctive I ngredient "Ipconazole Technical" Morton, T. 1 May 2013

. D411385

. Common Triazole Metabolites: Updated Dietary (Food + Water) Exposure and Risk Assessment to Address The New Section 3 Registrations For Use of Prothioconazole on Bushberry Crop Subgroup 13

- 07B, Low Growing Berry, Except Strawberry, Crop Subgroup 13

- 07H, a nd Cucurbit Vegetables Crop Group 9; Use of Flutriafol on Coffee; and Ipconazole on Crop Group 6

. Morton, T. 1 May 2013

. D411386

. Common Triazole Metabolites: Updated Aggregate Human Health Risk Assessment to Address The New Section 3 Registrations For Use of Prothioconazole on Bushberry Crop Subgroup 13

- 07B, Low Growing Berry, Except Strawberry, Crop Subgroup 13

- 07H, and Cucurbit Vegetables Crop Group 9; Use of Flutriafol on Coffee; and Ipconazole on Crop Group 6

. Ruhman

, M

. 15 July 2013. D 406894. Revised Estimated Drinking Water Concentrations (EDWCs) from its Proposed New Use by Expansion of Uses from Crop Subgroup 6C to the Entire Crop Group 6 for Use in Human Health Risk Assessment

. Rury, K. 20 March 2012. TXR #0056542

. Ipconazole: Summary of Hazard and Science Policy Council (HASPOC) Meeting on December 19, 2012: Recommendations on Data Requirements for the Acute Neurotoxicity and Immunotoxicity Studies. Rury, K . TXR #0056730. CONAZOLE FUNGICIDES: Summary of Hazard and Science P olicy Council (HASPOC) Meeting on July 25, 2013: Recommendations on Data Requirement for Immunotoxicity Studies for Conazole Pesticides.Ipconazole Human Health Risk Assessment DP No. D413830

Page 22 of 29 A ppendix A . Toxicology Profile and Executive Summaries

A.1

. Toxicology Data Requirements

The requirements (40 CF R 158.340) for new food

- use registrations for ipconazole are in the table below. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study Technical Required Satisfied 870.1100 Acute Oral Toxicity 870.1200 Acute Dermal Toxicity 870.1300 Acute Inhalation Toxicity 870.2400 Primary Eye Irritation 870.2500 Primary Dermal Irritation 870.2600 Dermal Sensitization yes yes yes yes yes yes yes yes yes yes yes yes 870.3100 Oral Subchronic (rodent) 870.3150 Oral Subchronic (nonrodent) 870.3200 21

- Day Dermal 870.3250 90

- Day Dermal 870.3465 90

- Day Inhalation* yes yes yes

no yes yes yes yes

-- yes 870.3700a Developmental Toxicity (rodent) 870.3700b Developmental Toxicity (nonrodent) 870.3800 Reproduction yes yes yes yes yes yes 870.4100a Chronic Toxicity (rodent) 870.4100b Chronic Toxicity (nonrodent) 870.4200a Oncogenicity (rat) 870.4200b Oncogenicity (mouse) 870.4300 Chronic/Oncogenicity yes yes yes yes yes yes yes yes yes yes 870.5100 Mutagenicity

— Gene Mutation

- bacterial 870.5300 Mutagenicity

— Gene Mutation

- mammalian 870.5375 Mutagenicity

— Structural Chromosomal Aberrations 870.5385 Mutagenicity

— Other Genotoxic Effects yes yes yes yes yes yes yes yes
870.6100a Acute Delay ed Neurotox. (hen) 870.6100b 90

- Day Neurotoxicity (hen) 870.6200a Acute Neurotox. Screening Battery (rat) 870.6200b 90 Day Neuro. Screening Battery (rat) 870.6300 Develop. Neuro no

no

no **
yes

no --

--

-- yes** *

-- 870.7485 General Metabolism 870.7600 Dermal Penetration 870.7800 Immunotoxicity yes

no no*** yes

--
no *The requirement for a 90

- day inhalation toxicity study has been fulfilled by a 28

- day inhalation toxicity study in
rats. ** The study was waived by HED’s HASPOC.

** * The study was fulfilled by neurotoxicity measurements in the rat chronic/carcinogenicity study.Ipconazole Human Health Risk Assessment DP No. D413830

Page 23 of 29 A.2. Toxicity Profiles

Table A.2.1

. Acute Toxicity Profile for Ipconazole Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [rat] 45552702 LD50 M = 1338 mg/kg LD50 F = 888 mg/kg III

870.1200 Acute dermal [rabbit] 45552703 LD50 > 2000 mg/kg (both sexes) III 870.1300 Acute inhalation [rat] 46110501 LD50 > 1.88 mg/L (both sexes) III

870.2400 Acute eye irritation [rabbit] 45552705 Eye irritation present at 24 hours, cleared by day 7 III

870.2500 Primary dermal irritation [rabbit] 45552706 Primary irritation index = 0.8 IV

870.2600 Skin sensitization [guinea pig] 45552707 Non

sensitizer

Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Ipconazole Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results

870.3100 90

- Day oral toxicity (dietary) in rats (Fischer) 45552708 (1991)

Acceptable/guideline 0, 30, 120, 500, or 2000 ppm

M: 0, 1.82, 7.22, 29.89, or 118.5 mg/kg bw/day F: 0, 1.97, 7.95, 32.50, or 123.7 mg/kg bw/day NOAEL = 7.22/7.95 mg/kg bw/day M/F, respectively

LOAEL = 29.89/32.50 mg/kg bw/day M/F, respectively, based on increased incidences of erosion, hyperkeratosis, and hyperplasi a of the mucosal epithelium of the non

- glandular portion of the stomach in males and females

870.3100 90

- Day oral toxicity (dietary) in rats (Wistar) 47048910 (2006)

Acceptable/guideline 0, 30, 70, 150, or 300 ppm or 600 ppm (males only)

M: 0, 2.5, 5.8, 12.6, 25.9, or 52.2 mg/kg bw/day F: 0, 3.1, 7.0, 15.4, or 33.2 mg/kg bw/day Males NOAEL = 25.9mg/kg bw/day Males LOAEL = 52.2 mg/kg bw/day, based on decreased body weight gain and food conversion efficiency, and effects on the non

- glandular stomach

Fema les NOAEL = 15.4 mg/kg bw/day Females LOAEL = 33.2 mg/kg bw/day, based on decreased body weight gain and food conversion efficiency, and effects on the non

- glandular stomach, uterus, and kidneys

870.3100 90

- Day oral toxicity (mouse) 47048907 (2005)

Acceptable/guideline 0, 30, 150, or 500 ppm

M: 0, 4.4, 20.2, or 69.7 mg/kg bw/day F: 0, 5.1, 25.4, or 90.8 mg/kg bw/day NOAEL = 20.2/25.4 mg/kg bw/day LOAEL = 69.7/90.8 mg/kg bw/day, based on decreased body weight gains and food conversion efficiency, and indications of hepatotoxicity in both sexes

(hepatotoxicity includes increased relative liver weights, increased incidence of hepatocyte vacuolization and fatty deposits in males and females, and increased severity of centrilobular hepatocyte hypertrophy in males)

870.3150 90

- day oral (capsule) toxicity study in dogs 47048905 (2006)

Acceptable/guideline 0, 2, 10, or 40 mg/kg bw/day (males and females) NOAEL = 10 mg/kg bw/day LOAEL = 40 mg/kg bw/day, based on decreases in body weights, body weight gains, and food consumption and on effects on the skin, eyes, liver, and thymusIpconazole Human Health Risk Assessment DP No. D413830

Page 24 of 29 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Ipconazole Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results

870.3200 28

- Day dermal toxicity (rat) 47048916 (2006)

Acceptable/guideline 0, 10, 150, or 1000 mg/kg bw/day

Dose applied 6 hours/day, 5 days/week (total 20 application days) Systemic NOAEL = 150 mg/kg bw/day Systemic LOAEL = 1000 mg/kg bw/day, based on decreased body weight, body weight gain, food consumption, and increased incidence of dermal irritation

Dermal NOAEL = 10 mg/kg bw/day Dermal LOAEL = 150 mg/kg bw/day, based o n histopathological effects (hyperkeratosis and hyperplasia) in the treated skin

870.3465 28

- day inhalation toxicity study in rats 47048915 (2006)

Acceptable/guideline

0, 0.03, 0.1, 0.3, or 1 mg/L

0, 7.8, 26.1, 78.3, 261 mg/kg bw/day

Administered 6 hours/day, 5 days/week (total of 20 exposure days) NOAEL = not identified LOAEL = 0.03 mg/ L , based on epithelial hyperplasia in the hard palate in males, epithelium squamos/squamoid hyperplasia in the larynx mucosa of both sexes, and mixed inflammatory cel ls in the trachea of females.

870.3700a Prenatal developmental (gavage) in rats 45552710 (1990)

Acceptable/guideline F: 0, 3, 10, or 30 mg/kg bw/day Maternal NOAEL = 10 mg/kg bw/day Maternal LOAEL = 30 mg/kg bw/day, based on decreased body weight gain a nd food consumption

Developmental NOAEL = 10 mg/kg bw/day Developmental LOAEL = 30 mg/kg bw/day, based on decreased fetal body weight and increased incidences of visceral and skeletal variations

870.3700b Prenatal developmental (gavage) in rabbits 45552709 (1991)

Acceptable/guideline F 0, 2, 10, or 50 mg/kg bw/day Maternal NOAEL = 10 mg/kg bw/day Maternal LOAEL = 50 mg/kg bw/day, based on decreased body weight gain and food consumption

Developmental NOAEL = 10 mg/kg bw/day Developmental LOAEL = 50 mg/kg bw/day, based on skeletal malformations and variationsIpconazole Human Health Risk Assessment DP No. D413830

Page 25 of 29 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Ipconazole Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results

870.3800 Reproduction and fertility effects (rat) 47048914 (2006)

Acceptable/guideline 0, 30, 100, or 300 ppm

M: 0, 2.5, 8.2, or 25.6 mg/kg bw/day

F: 0, 2.8, 9.2, or 28.6 mg/kg bw/day Parental NOAEL = 8.2/9.2 mg/kg bw/day (100 ppm) M/F, respectively Parental LOAEL = 25.6/28.6 mg/kg bw/day (300 ppm) M/F, respectively, based on decreased gestational body weight gains in the females, decreased food consumption in males during pre

- mating an d in the females during gestation and lactation, and increased relative organ weights

Offspring NOAEL = 8.2/9.2 mg/kg bw/day (100 ppm) M/F, respectively Offspring LOAEL = 25.6/28.6 mg/kg bw/day (300 ppm) M/F, respectively, based on decreased pup body wei ghts and body weight gains in both generations, increased relative spleen weights, and thin build

Reproductive NOAEL = 25.6/28.6 mg/kg bw/day, M/F, respectively Reproductive LOAEL = not observed 870.4100b Chronic toxicity study (capsule) (dog) 47048906 ( 2007)

Acceptable/guideline 0, 1.5, 5, or 20 mg/kg bw/day NOAEL = 1.5 mg/kg bw/day LOAEL = 5 mg/kg bw/day, based on skin reddening in both sexes and decreased body weight gains in females

870.4200 Carcinogenicity (mouse) 47048909 (2007)

Acceptable/guideline 0, 15, 175, or 350 ppm

M: 0, 1.9, 24.1, or 45.3 mg/kg bw/day F: 0, 2.3, 26.0, or 56.8 mg/kg bw/day NOAEL = 24.1/26.0 mg/kg bw/day in M/F, respectively LOAEL = 45.3/56.8 mg/kg bw/day in M/F, respectively, based on decreased terminal bo dy weights, body weight gains, and food conversion efficiency in females, and evidence of hepatotoxicity in both sexes.

There was no evidence of carcinogenicity.Ipconazole Human Health Risk Assessment DP No. D413830

Page 26 of 29 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Ipconazole Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results

870.4300 Chronic/ Carcinogenicity (rat) 47048912 (2006)

Acceptable/guideline 0, 30, 80, 200, or 300 ppm in males 0, 30, 80, 120, or 200 ppm in females

M: 0, 1.3, 3.6, 9.0, or 13.3 mg/kg bw/day F: 0, 1.9, 4.9, 7.3, or 12.6 mg/kg bw/day*

*Both males and females began the study at dose levels of 0, 30, 80, 200, or 300 ppm. After the first w eek of treatment, the doses were reduced to 0, 30, 80, 120, or 200 ppm in females on the advice of EPA’s Dose Adequacy Review Team (memo TXR 0052298, 2/3/2004). This recommendation was based on findings of nonglandular stomach hyperplasia and kidney effec ts in the 90

- day study at 300 ppm which could progress in severity with longer exposure. NOAEL = 13.3/12.6 mg/kg bw/day, M/F, respectively LOAEL = not observed

The NOAEL of 12.6 mg/kg/day in females appears to be approaching the threshold effect level bas ed on the 90

- day study and effects during the first week in the chronic study when females were fed a diet consisting of 300 ppm ipconazole.

There was no evidence of carcinogenicity.

870.5100 Bacterial reverse mutation test 45552713 (1989)

Acceptable/gui deline

TA100, TA1535, TA1537 (

- S9): 0, 6.25, 12.5, 25, 50, 100 or 200 g/plate TA98 (

- S9): 0, 15.6, 31.3, 62.5, 125, 250, 500, or 1000 g/plate WP2uvrA (

- S9): 0, 313, 625, 1250, 2500, or 5000 g/plate

TA100, TA1535, TA1537 (+S9): 0, 31.3, 62.5, 125, 250, 500 or 1000 g/plate TA98 (+S9): 0, 15.6, 31.3, 62.5, 125, 250, 500, or 1000 g/plate WP2uvrA (+S9): 0, 313, 625, 1250, 2500, or 5000 g/plate No evidence of mutagenicity in Salmonella typhimurium strai ns TA1535, TA1537, TA98, or TA100 up to cytotoxic concentrations or in Escherichia coli WPuvrA up to the limit dose.Ipconazole Human Health Risk Assessment DP No. D413830

Page 27 of 29 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Ipconazole Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results

870.5300 Gene Mutation (CHO) 45542231 (2001)

Acceptable/guideline

- S9: 0, 5, 10, 20, 25, 30, 35, 40 or 50 g/mL for 4 hrs

+S9: 0, 25, 30 , 35, 40, 45, 50, 55, 60 or 70 g/mL for 4 hrs No evidence of a mutagenic response at cytotoxic concentrations.

870.5375 Cytogenetics

- Chinese hamster lung fibroblasts chromosome aberration test 45552712 (1989)

Acceptable/guideline

1 st assay (

- S9): 0, 4 , 8, or 16 g/mL for 24 or 48 hours followed by immediate harvest

2 nd assay (+/

- S9): 0, 17.5, 35, or 70 g/mL harvested 18 hours post exposure No evidence of a clastogenic response at cytotoxic concentrations.

870.5385 Mammalian Bone Marrow Chromosomal Aberration Test 4 6827502 ( 2005 )

Acceptable/guideline

M: 250, 500, or 1000 mg/kg F:375, 750, or 1500 mg/kg No evidence of structural chromosome aberrations.

870.5395 Mammalian Erythrocyte Micronucleus Test 46827502 (2005)

Acceptable/guideline

M: 0, 250, 500, or 1000 mg/kg F: 0, 375, 750, or 1500 mg/kg No evidence of micronucleated polychromatic erythrocytes in bone marrow.

870.5500 Bacterial DNA Damage/Repair Test 45552711 (1989)

Acceptable/guideline

0, 0.313, 0.625, 1.25, 2.5, 5, 10, or 20 g/disk (+/

- S9) Did not induce DNA damage/repair in DNA repair proficient (H17) or repair deficient (M45) strains of Bacillus subtilis up to cytotoxic concentrations.

870.7485 Metabolism and pharmacokinetics (rat) 47048917 (2007)

Acceptable/guideline Single dose of 2 or 100 mg/kg Repeat exposure to 2 mg/kg bw/day The test compound was rapidly absorbed. The highest levels of radioactivity were found in the liver. The majority of the radioactivity was recovered with in 48

- hours post

- dosing with the majority being recovered in the feces. Bile was a primary route of excretion. The compound was extensively metabolized through hydroxylation and glucuronidation. Cleavage of the triazole ring was also observed. The majo rity of metabolites were observed in both sexes.Ipconazole Human Health Risk Assessment DP No. D413830

Page 28 of 29 A .3 . Executive Summaries

The executive summary for the in vivo mammalian cytogenetics toxicity study is below. It is the only toxicology study that has been received since the 2008 risk assessment . T he executive summaries for the studies included in the 2008 assessment are included in that assessment.

OPPTS 870.5395

- In Vivo Mammalian Cytogenetics

- Erythrocyte Micronucleus A ssay in M ouse

In a CD

- 1 mouse bone marrow micronucleus assay (MRID 468275 02), five or seven (high dose) animals/sex/dose were treated orally by gavage with Ipconazole (98.4% w/w; batch # 89010). Animals were dosed twice, 24 hours apart, with 250, 500, or 1000 mg/kg (males) or with 375, 750, or 1500 mg/kg (females). The high d oses were based on a preliminary toxicity study in which no males died at ≤1000 mg/kg, whereas one or both males were killed in extremis at ≥1250 mg/kg; no females died at ≤1500 mg/kg, but both females were killed in extremis at 2000 mg/kg. Bone marrow ce lls were harvested at 24 hours post

- treatment. The vehicle was 1% w/v methylcellulose.

No adverse clinical signs were noted at the low dose, or in the negative and positive control animals. At the mid

- dose, males had signs including piloerection and und eractivity, and females had signs of underactivity and fast respiration. At the high dose, both sexes showed piloerection, underactivity, altered posture (hunched, prostrate, flattened), abnormal gait, fast and irregular respiration, and partially closed eyes. The high dose females also had absent righting reflex, tilted head, and watery discharge from the eyes. No premature deaths occurred at the two lower doses, but at the high dose, 1/7 males (at 1000 mg/kg) and 6/7 females (at 1500 mg/kg) were killed in extremis after the first or second treatment. Due to the survival of only one female, the high dose group was not analyzed, and therefore valid data for three test doses were only obtained for males. However, the overall study data indicated that mal es and females were similarly sensitive to ipconazole, allowing the testing of only one sex to fulfill OPPTS 870.5395 guideline requirements.

No evidence was found for an ipconazole

- induced increase in the incidence of micronucleated PCEs or micronucleated mature erythrocytes. The PCE/total erythrocyte ratio was significantly decreased for all ipconazole

- treated groups, but remained within 20% of the control value. The vehicle and positive controls induced the appropriate responses. There was no significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow after treatment. The animals were tested at adequate ly high doses (excessively high for females), based on the considerable toxicity observed at the mid and high doses for each sex.

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for Test Guideline OPPTS 870.5395; OECD 474 for in vivo cytogenetic mutagenicity data.Ipconazole Human Health Risk Assessment DP No. D413830

Page 29 of 29 Appendix B . Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from SOPs for Seed Treatment, Policy 14 , 15, and 15.1 are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data source s, as well as guidance on their use, can be found at http://www.epa.gov/pesticides/science/handler

- exposure

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

- app

- exposure

- data.html

.