Ipconazole Human Health Risk Assessment DP No. D41 3830 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: 

SUBJECT: 

FROM: 

THROUGH: 

TO: 

8 August 20 13 

Revised Ipconazole Human Health Risk Assessment of the Proposed Use on 

Legume Vegetables (Crop Group 6) 

PC Code: 125618 DP Barcode: D413830 

Decision No.: 469403 Registration No.: 400-544 

Petition No.: 2F8076 Regulatory Action: Section 3 

Risk Assessment Type: Single Chemical, Aggregate Case No.: 7041 

TXR No.: NA CAS No.: 125225-28-7 

MRID No.: 4892840 I, 48928402, 48928403 40 CFR: 180.646 

Michael A. Doherty, Ph.D., mist-..~~ Margarita Collantes, Biologist ~cfvv Jaime D' Agostino, Ph.D., Jo,xi~ ~ ?;;i :S · 

Risk 

William 

Assessment 

Drew, Chemist 

Branch 

~ 

II 

Health Effects Division (7509P) 

Christina 

Health 

Risk Assessme

Effects 

Swartz

Division 

nt 

, 

Branch 

Chief 

(7509P) 

II 

~ 

Dominic Schuler/Tony Kish (Team 22) 

Fungicide Branch 

Registration Division (7505P) 

NOTE: 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 has 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. 

Page 1 of29 
Ipconazole Human Health Risk Assessment DP No. 0413830 

1.0 Executive Summary ............................................................................................................. 3 

2.0 HED Recommendations ................................................... .................................................... 4 

2.1 Data Deficiencies ......... ....... .... ..................................................... ............ .... .................... 4 

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

2.2.1 Enforcement Analytical Method ............................................................................... 4 

2.2.2 Recommended Tolerances ........................................................................................ 5 

2.2.3 Revisions to Petitioned-For Tolerances ........ ............................................................ 5 

2.2.4 International Harmonization ..................................................................................... 5 

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

3.0 Introduction ........................... ........... .................................................................................... 6 

3. 1 Chemical Identity ........................................................................................... .... .............. 6 

3.1 Nomenclature ........................... ........... ................................... .......................................... 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 Characterization and Dose-Response Assessment.. .................... ............................ 8 

4.1 .Summary ofToxicological Effects .................................................................................. 9 

4.2 Safety Factor for Infants and Children (FQPA Safety Factor) ....................................... 11 

4 .2.1 Completeness of the Toxicology Database ........................................... .................. 11 

4.2.2 Evidence ofNeurotoxicity ...................................................................................... 12 

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ......... 12 

4.2.4 Residual Uncertainty in the Exposure Database ..................................................... 12 

4.3 Toxicity Endpoint and Point of Departure Selections .................................................... 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 .................................................................................................... 15 

5.4 Dietary Risk Assessment.. .............................................................................................. 16 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization .................................... 17 

6.1 Spray Drift and Residential Bystander Post-Application Inhalation Exposure ............. 17 

7.0 Aggregate Exposure/Risk Characterization ....................................................................... 17 

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

9. 0 Occupational Exposure/Risk Characterization .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. . .. .. .. .. .. .. . 18 

9.1 Short- and Intermediate-Term Handler Risk .......................................................... ........ 18 

9.2 Short- and Intermediate-Term Post-Application Risk .......... .... ................ ..................... 20 

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

Appendix A. Toxicology Profile and Executive Summaries ....................................................... 22 

A.l. Toxicology Data Requirements ....................................................................................... 22 

A.2. Toxicity Profiles ............................ .................................................................................... 23 

A.3. Executive Summaries ................................................................................... .... .............. ... 28 

Appendix B. Review of Human Research ................................................................................... 29 

Page 2 of29 
Ipconazole Human Health Risk Assessment DP No. D413830

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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 registrations of the enduse product Rancona 3.8 FS (EPA Reg. No. 400-544) and the technical 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 root 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 quantitation (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 rats and mice after 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 assessment 

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 mild 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 field trials conducted with 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 all 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 dietary risk estimates, which 

are below HED’s level of concern.
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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, triazolylacetic acid, and 

triazolylpyruvic acid. Dietary and aggregate risk estimates from exposure to these compounds 

are below HED’s level of concern and are addressed in separate assessments (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 preparation of this risk assessment. 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 other 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 no 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 residues 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 spectrometric detection (LCMS/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. 
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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 an 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 in 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-(1H-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 commodity 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

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3.0 Introduction

3.1 Chemical Identity

Ipconazole is a systemic, broad-spectrum fungicide registered for use as a seed treatment on 

various crops. As 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 

application 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 grass, 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 ipconazole is presented in Table 3.1, and the 

physicochemical properties are summarized in Table 3.2 (below). 

3.1 Nomenclature

Table 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 C18H24N3OCl

Molecular weight 333.9 amu

IUPAC name (1RS,2SR,5RS;1RS,2SR,5SR)-2-(4-chlorobenzyl)-5-isopropyl-1-(1H-1,2,4-triazol-1-

ylmethyl)cyclopentanol

CAS name 2-[(4-chlorophenyl)methyl]-5-(1-methylethyl)-1-(1H-1,2,4-triazol-1-

ylmethyl)cyclopentanol

CAS registry number 125225-28-7

End-use product (EP) Rancona 3.8FS seed treatment fungicide (41% ai; EPA Registration #400-544)

3.2 Physicochemical Characteristics

Table 3.2. Physicochemical Properties of Technical Grade Ipconazole

Parameter Value Reference

Melting point/range ( C) 85.5-88

Mather, S. 24 NOV

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

Cl

N

N

N

OH

H3C

CH3

Cl

N

N

N

OH

H3C

CH3
Ipconazole Human Health Risk Assessment DP No. D413830

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Table 3.2. Physicochemical Properties of Technical Grade Ipconazole

Parameter Value Reference

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 (pKa)

Indeterminate via OCSPP Product 

Properties Test Guideline 830.7370

Octanol/water partition coefficient (Log [KOW]) 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 may 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 containing 

approximately 41% of the ai by weight, equivalent to 3.77 pounds of ai per gallon (lb ai/gal). 

The PPE statement on the proposed label requires applicators and other handlers to wear longsleeved shirt, long pants, socks, shoes, and chemical-resistant gloves. The proposed use 

directions are summarized in Table 3.3, below. 

Table 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

PHI2

(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 NA3

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.) 
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3.4 Anticipated Exposure Pathways

At this time, there are no registered uses of ipconazole that would result in handler or postapplication 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 ipconazole 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 assessment, 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/oepa/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 

pesticide 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 the 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, ethnic group, and region of the 

country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups 

and exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated risks 

for adult 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 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 

patterns among specific subgroups.

4.0 Hazard Characterization 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 previously identified data gap. In that 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 erythrocytes 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, 
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especially as an acute 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 lifetime 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 quickly 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 

cancer/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 triazoles, 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. Therefore, the cytogenetics 

study has not resulted in any changes have been made 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 gain, 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 the 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 carcinogenicity 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 

metabolism 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 food 
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consumption were observed 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 mineralization 

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 

following 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 is 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 weights, 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 neurotoxicity studies are not required, and there is no concern for ipconazoleinduced 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 ipconazole 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 such as decreased 

body weight and body weight gain, as well as portal-of-entry effects such as inflammation in the 

respiratory tract.
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Acute testing with ipconazole resulted in low toxicity via the oral (Category III), dermal 

(Category III), and inhalation (Category III) routes of exposure. Low to mild irritation to the 

eyes (Category III) and skin (Category IV) were observed and it was not a dermal sensitizer.

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

HED has determined that the required 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 

ipconazole 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 underestimate exposure, since the 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 residential uses for ipconazole.

4.2.1 Completeness of 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 immunotoxicity 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. Therefore, 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 neurotoxicity 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). 
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4.2.2 Evidence of Neurotoxicity

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 neurotoxicity 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 

developmental neurotoxicity study is therefore not required and there is no concern for 

ipconazole-induced neurotoxicity.

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

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

offspring 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 concludes 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 Database

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 Departure 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)

were calculated for use in MOE calculations using the methods and dosimetry equations 

described 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.
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Table 4.3.1. Summary of Toxicological Doses and Endpoints 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 infants 

and children)

N/A N/A N/A No appropriate endpoint is available.

Acute Dietary

(females 13-49)

NOAEL = 

10 mg/kg

UFA=10X

UFH=10X

FQPA SF = 1X

Acute RfD = 

0.1 mg/kg

aPAD = 

0.1 mg/kg

Co-critical Developmental Toxicity 

Studies in Rats and Rabbits

LOAELrats = 30 mg/kg/day, based on 

increased visceral and skeletal 

variations

LOAELrabbits = 50 mg/kg/day, based on 

increased incidence of skeletal 

variations and malformations

Chronic Dietary

(all populations)

NOAEL = 

1.5 mg/kg/day

UFA=10X

UFH=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. UFA = extrapolation from animal to human (interspecies). UFH = 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.
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Table 4.3.2. Summary of Toxicological 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

Intermediateterm

(1 - 6 months)

NOAEL = 150 

mg/kg /day 

UFA=10X

UFH =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

Intermediateterm

(1 – 6 months)

NOAEL = not 

established 

(<0.03 mg/L)

HEC = 

0.00531 mg/L

HED = 0.2832 

mg/kg/day

UFA=3X

UFH=10X

UFL = 10X 

LOC for MOE =300 

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 (oral, 

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. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFL = 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 discussion 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 triazolylpyruvic 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.
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Table 5.1. Summary of Metabolites and Degradates to be included 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, TAA1

Ipconazole

Rotational Crops Ipconazole, 1,2,4-T, TP, TA, TAA Ipconazole2

Livestock Ruminants Ipconazole, 1,2,4-T, TP, TA, TAA Ipconazole2

Poultry Ipconazole, 1,2,4-T, TP, TA, TAA Unknown3

Drinking Water Ipconazole, 1,2,4-T, TP, TA, TAA Not Applicable

1. 1,2,4-T = 1,2,4-triazole; TP = triazolylpyruvic acid; TA = triazolylalanine; TAA = triazolylacetic acid. These 

metabolites are assessed separately from ipconazole.

2. Based on the available data, tolerances are not required in rotational crops or ruminants 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, risk 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. Expansion 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]; that is, there is no 

reasonable expectation of finite residues of ipconazole in livestock commodities.

5.3 Water Residue Profile

Ipconazole is persistent in soil and there is a potential for accumulation in soil on sites with use 

over consecutive years. The 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 memorandum: 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 based 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/oppefed1/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.
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b

From the PRZM-GW model.

c EDWCs for use in a cancer assessment were provided; however, ipconazole is classified as “Not Likely 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)

Acute 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 2003-2008. Both the acute and chronic 

assessments used tolerance-level residues, assumed 100% crop treated, and incorporated modelderived, conservative estimates of ipconazole residues in groundwater 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 dietary 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 dietary risk estimates for ipconazole are well 

below HED’s level of concern 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 (95th 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 0.000117 <1 0.000055 <1

* NA = Not Applicable. 

The population subgroup with the highest risk estimate is in bold typeface. 
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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-Application 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, exposure 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 

and 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 triazoles. The triazole 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 of 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 sharing 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 triazoles (e.g., altered cholesterol levels, 

stress responses, altered DNA methylation). At this time, there is not sufficient evidence to 

determine whether triazoles 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 triazoles are currently 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, 
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therefore, a basis for assessing cumulative 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 tolerances for triazole 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 pesticides (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 exposures 

(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) 

Number EPA-HQ-OPP-2005-0497. The assessment was recently updated 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 treated, and the level of protection used by a handler can cause exposure levels to differ in 

a manner specific 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 throughout 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.) was assessed. 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.

The proposed treatment 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 are 
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different, the dermal and inhalation exposure estimates were not combined into an overall margin 

of exposure (MOE). The short-term exposure and risk estimates are considered to be protective 

of intermediate-term exposure and risk since 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 

treatment equipment, 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 inhalation 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 intermediate-term durations was not provided. The AHETF survey reports that 

39% of soybean is treated downstream for a duration of 49 days (50th percentile; range 4 to 150 

days), while soybean commercial facilities operate 210 days per year (50th percentile; range 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 

indicate that the same chemical is used consecutively for a long-term 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 treatment 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 exposure 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 treatment risk assessment is protective of

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 9,400

Multiple Activities

Legume Vegetables 

(surrogate – soybeans)

Single 

Layer, 0.000025 281,250 0.0037 0.00014 41,000 2,000
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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/day) = 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/day) = (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 (150 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 20,000

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 Dermal Dose (mg/kg/day) = (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 gloves and does not represent exposure for driver operating tractor (no gloves required).

d

Inhalation Dose (mg/kg/day) = (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) / dermal 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 reentry exposure). The potential for dermal and inhalation post-application exposures following 

the planting of ipconazole-treated seeds is unlikely. Sustained 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-application assessment is required for seed treatment uses. The labeling 

properly states 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, Soybean, Dry Shelled Pea and Bean 

(Subgroup 6C), and Cereal Grains (Groups 15 and 16) Except Rice.
Ipconazole Human Health Risk Assessment DP No. D413830

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Drew, W. 2 April 2013. D406708. Ipconazole. Petition to Establish Permanent Tolerances for 

Residues of the Fungicide 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 Chemistry Review for the New Active 

Ingredient "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, and 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. D406894. 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 Policy 

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

Appendix A. Toxicology Profile and Executive Summaries

A.1. Toxicology Data Requirements

The requirements (40 CFR 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 Delayed Neurotox. (hen)

870.6100b 90-Day Neurotoxicity (hen)

870.6200a Acute Neurotox. Screening Battery (rat)

870.6200b 90 Day Neuro. Screening Battery (rat)

870.6300 Develop. Neuro

no

no

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

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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 Nonsensitizer

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 hyperplasia 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

Females 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 

thymus
Ipconazole Human Health Risk Assessment DP No. D413830

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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 on 

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 cells 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 and 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 variations
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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 and 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 

weights 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 body weights, 

body weight gains, and food conversion efficiency in 

females, and evidence of hepatotoxicity in both sexes.

There was no evidence of carcinogenicity.
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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 week 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 effects 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 based 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/guideline

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 strains 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

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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 

46827502 (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 within 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 majority of 

metabolites were observed in both sexes.
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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. The executive 

summaries for the studies included in the 2008 assessment are included in that assessment.

OPPTS 870.5395 - In Vivo Mammalian Cytogenetics - Erythrocyte Micronucleus Assay in 

Mouse 

In a CD-1 mouse bone marrow micronucleus assay (MRID 46827502), 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 doses 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 cells 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 underactivity, 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 males 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 adequately 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

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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 sources, 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.