UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: 11/2112013: 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: Imazalil and Imazalil Sulfate: Human Health Assessment Seeping Document in Support 

of Registration Review. 

PC Code: 111901, 111902 

Decision No.: 478862 

Petition No.: NA 

Risk Assessment Type: NA 

TXRNo.: NA 

DP Barcode: D411858 

Registration No.: N/A 

Regulatory Action: Registration Review 

Case No.: 2325 

CAS No.: 35554-44-0 (imazalil); 58594-72-2 

(imazalil sulfate) 

MRID No.: NA 40 CFR .: 180.413 

FROM: 

Dennis 

Karlyn Middleton, 

McNeilly, Chemist 

Toxicologist 

f5J--~~ ~c-/1/2~ 

Risk 

Zaida 

Assessment 

Figueroa, Industrial 

Branch II 

Hygienist ~ 

' 

Health Effects Division (7509P) 

Office ofPesticide Programs 

THROUGH: Christina Swartz, Branch Chief~~-__;;.­ Risk Assessment Branch II 

Jess Rowland

and , Acting Associate Directo~ 

\_ ..__ ~ 

Dana Vogel, Associate Director 

Health Effects Division (7509P) 

Office of Pesticide Programs 

TO: Margaret Hathaway, Chemical Review Manager 

Pesticide Re-Evaluation Division (7508P) 

Office of Pesticide Programs 

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Imazalil Registration Review Scoping Document 

Executive Summary 

The Health Effects Division (HED) has evaluated the status of the human health risk assessment 

for imazalil and imazalil sulfate to determine the scope of work necessary to support the 

established tolerances and existing registrations during registration review. The primary source 

of information for this evaluation was the most recently completed human health risk assessment 

conducted to support the Registration Eligibility Document (RED) published in February 2002 

(D280708, A. Khasawinah, 2/7/2002). Updated exposure assessments were also considered 

(D326610, J. Miller, 12/30/2006). HED is currently evaluating a tolerance petition for the postharvest treatment of melons and a seed treatment use on sweet com. This petition has not been 

completed pending resolution of the cancer classification of imazalil. 

Based on the currently registered uses, exposure to imazalil can be expected to occur via the 

dietary (food and drinking water) and occupational (handler and post-application) exposure 

pathways and through the oral, dermal, and inhalation routes of exposure. 

Imazalil [ 1-(2-(2,4-dichlorophenyl)-2-(2-propenyloxy)ethyl)-lH-imidazole] is a systemic 

imidazole fungicide used for the control of a variety of pathogenic fungi. It inhibits cytochrome 

P-450 dependent biosynthesis of ergosterol, an essential component of the cell membrane of 

fungi. 

Imazalil is used for postharvest treatment of citrus fruits and bananas (imported) and for seed 

treatment of barley and wheat prior to planting. It is also used for disinfection of poultry and 

turkey egg hatchery equipment prior to introduction of eggs and in greenhouses on ornamentals 

(including bedding plants, cut flowers, flowering hanging baskets, foliage, potted flowering 

plants, and perennials). It can be appljed by seed treatment equipment, drenches, waxing and 

foaming equipment, foggers, hand wand sprayers, and smoke canisters. 

Imazalil exists as a base or as its sulfate salt. The acute toxicity profiles of the base and the 

sulfate salt are comparable and they are considered similar in their toxicological properties. The 

target organs for imazalil are the thyroid and the liver. 

The toxicology database for imazalil is complete except for a subchronic inhalation toxicity 

study. The study is required based on the potential for repeated inhalation exposure and high 

inhalation exposure estimates for occupational handlers (mixer/loader/applying) during citrus 

post-harvest activities and poultry hatcheries/poultry house treatments. In the absence of the 

inhalation study, the Agency will retain a 1 OX database uncertainty factor for inhalation 

exposure only. All previously required studies have been received (acute neurotoxicity) or 

waived by the Agency (subchronic and developmental neurotoxicity and immunotoxicity). 

The nature of the residue of imazalil in plants and livestock is adequately understood. The 

established tolerances for residues of imazalil inion plant commodities [ 40 CFR§ 180.413(a) (1 )] 

are expressed in terms of the combined residues ofimazalil and its metabolite R014821 [1-(2,4-

dichlorophenyl)-2-(lH-imidazole-1 -yl)-1-ethanol]. The established tolerances for residues of 

imazalil in livestock commodities [40 CFR §180.413(a)(2)] are expressed in terms ofthe 

combined residues of imazalil and 3-[2-(2,4-dichlorophenyl)-2-(2,3-dihydroxypropoxy)ethyl] 

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Imazalil Registration Review Scoping Document

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2,4-imidazolidinedione (FK772), and 3-[2-(2,4-dichlorophenyl)-2-(hydroxy)]-2,4-

imidazolidinedione (FK284). No tolerances are established or needed for residues in hog or 

poultry commodities. The HED Metabolism Committee (L. Cheng, 8/30/94) previously 

concluded that imazalil residues to be regulated in livestock commodities will include imazalil 

and any metabolite containing the 2,4-dichlorophenyl moiety. The tolerance expressions in 40 

CFR §180.413(a)(1) and (2) should both be updated to reflect current guidance regarding 

coverage and compliance statements.

The residue chemistry database is complete with the exception of an independent laboratory 

validation study required by the RED, which must be submitted to support the proposed 

enforcement method for livestock commodities. In addition, the RED stated that an egg and 

poultry fumigation study was required to determine residues present in poultry commodities as a 

result of the use. EPA has reviewed the product labels for use in poultry hatcheries (used for 

control of Aspergillus fumigatus via a smoke generator) and considers these uses to be non-food 

and therefore the egg and poultry fumigation study required in the February 7, 2002 HED human 

health risk assessment (completed in preparation for the imazalil RED) is no longer required. 

HED has concluded that no tolerances need to be proposed as a result of this use when eggs are 

not present in the room being fumigated.

Acute and chronic dietary risk assessments conducted to support the 2002 HED human health 

risk assessment indicated that dietary exposure and risk estimates were below the Agency’s level 

of concern. Acute dietary risk for the most sensitive sub-population, females 13-50 years of age, 

was 15% of the acute Population Adjusted Dose (aPAD) at the 99.9th percentile. For chronic 

dietary exposure, the most highly exposed population sub-group was children 1-6 years old, at 

3% of the chronic Population Adjusted Dose (cPAD). In the 2002 RED, the drinking water 

estimates were not directly combined with exposure from food; however, risks of concern were 

not expected based on very low concentrations expected in drinking water, using the drinking 

water level of comparison (DWLOC) approach. The lifetime cancer risk estimate, largely 

associated with the postharvest use of imazalil on citrus, was 2.0 X 10-6, based on the use of 

monitoring data; during registration review, HED may need to update the dietary exposure 

estimates with more recent monitoring data for citrus commodities. The cancer risk estimate did 

not include exposure from drinking water because of the negligible residues expected in ground 

and surface water sources of drinking water.

Since HED used percent crop treated information and monitoring data for the seed treatment uses 

and post-harvest treatment of citrus commodities, new dietary assessments will need to be 

conducted during registration review. In addition, EFED has concluded that pending the receipt 

and review of additional environmental fate and toxicity data for imazalil and its degradates, or 

changes in labeled use rates, the drinking water assessment will be reevaluated. However, if no 

new, relevant data regarding the environmental fate, toxicity, or use of imazalil or its degradates 

are submitted, the EDWCs from the 2002 drinking water assessment will be used in the 

registration review risk assessment.

Although no risks of concern were identified for occupational handler scenarios previously 

assessed, updated occupational handler exposure assessments are anticipated under registration 

review based upon revisions to the Agency’s scenario-specific surrogate handler exposure data, 
Imazalil Registration Review Scoping Document

Page 4 of 33

updated exposure methodologies related to commercial seed treatment, and post-harvest 

treatment of citrus fruits. Risk estimates of concern were identified for long-term and cancer 

post-application activities (e.g., thinning, weeding, and scouting) involving cut flowers and 

foliage (D326610, J. Miller, 12/30/2006). Additional information regarding post-application 

activities conducted in poultry hatcheries and chemical-specific data to evaluate post-application 

exposure associated with the greenhouse uses on ornamentals are needed to support registration 

review. Specifically, a dislodgeable foliar residue (DFR) study is required to refine postapplication exposures to support the greenhouse use on ornamentals/cut flowers. Occupational 

post-application (cancer and non-cancer) assessments will be required under registration review 

to incorporate the required DFR data, updated policies and procedures for assessing exposure 

from smoke generators and spray applications in poultry and turkey hatchery equipment and 

facilities, as well as any changes to the toxicology endpoints.

Introduction

HED has evaluated the most recent complete human health risk assessment for imazalil 

conducted in 2002 in conjunction with the RED, as well as recently conducted dietary and 

occupational assessments, to determine if sufficient data are available and if updates are needed 

to support registration review. HED has considered updates to its toxicity, exposure and usage 

databases, and the latest Agency science policy and risk assessment methodologies.

Imazalil is a systemic fungicide registered in 1983 to prevent, treat and control diseases caused 

by a variety of pathogenic organisms (fungi), which include (but are not limited to) Aspergillus 

in cleaned egg handling facilities and equipment prior to introduction of eggs, blue mold in citrus 

fruits and Fusarium in wheat and barley seeds.

The Imazalil Reregistration Eligibility Decision (RED) was approved on September 30, 2003. 

Imazalil is currently registered for use on post-harvest treatment of citrus fruits, seed treatment of 

barley, sudan grass and wheat prior to planting, and in greenhouses on ornamentals (including 

bedding plants, cut flowers, flowering hanging baskets, foliage, potted flowering plants, and 

perennials). Imazalil is also used to disinfect cleaned poultry and turkey hatchery equipment and

facilities prior to introduction of eggs.

Imazalil is formulated as a liquid ready-to-use, pressurized liquid, emulsifiable concentrate, 

water soluble granule, and impregnated material (used in smoke generators). Imazalil is applied 

as a seed and postharvest treatment using a foamer, spray brush, dips, wash tanks, wax and 

drenches. To disinfect cleaned poultry and turkey hatchery equipment prior to introduction of 

eggs, imazalil is applied by spray application, fogging, or using a smoke generator.

Imazalil sulfate was registered on March 4, 2004. Imazalil and imazalil sulfate are both systemic 

fungicides and considered as medium risk for resistance. Imazalil is effective against fungal 

pests on citrus fruits, wheat, barley and triticale. Imazalil sulfate is effective against fungal pests 

on citrus fruits. Imazalil sulfate is formulated as a soluble powder, water soluble granule, and a 

flowable concentrate and is applied using dip and wash tanks, drenchers, and wax line spray 

applications.
Imazalil Registration Review Scoping Document

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The structure, the chemical names, and other identifiers can be found in the chemical identity 

table in Attachment 1.

Hazard Identification/Toxicology

The toxicology database for imazalil is complete except for a subchronic inhalation toxicity 

study. The study is required based on the potential for repeated inhalation exposure and high 

inhalation exposure estimates for occupational handlers (mixer/loader/applying) during citrus 

post-harvest activities and during poultry and turkey hatchery equipment and facilities. 

Although the inhalation estimates using the current oral point of departure (PoD) are above the 

level of concern (LOC) of 100, HED uses margins of exposure (MOEs) of approximately 10 

times higher than the level of concern, or 1000X, as a benchmark for granting inhalation waivers. 

Currently, some inhalation exposure estimates for occupational handlers are well below 1000X. 

Once the missing study has been submitted, the need for revised regulatory endpoints and PoDs 

will be considered. In the absence of the inhalation study, the Agency will retain a 10X database 

uncertainty factor for inhalation exposure only. Previously, acute and subchronic neurotoxicity 

(ACN and SCN), developmental neurotoxicity (DNT), and immunotoxicity studies were required 

by the Agency for imazalil. However, the ACN study has been received and the Agency has 

waived the requirement for the other studies (TXR 0056756). Since the last risk assessment, a 

cellular proliferation study has also been submitted in support of a proposed mode of action for 

liver and thyroid tumors; the cellular proliferation study has been reviewed. HED anticipates 

receiving more mechanistic data from the registrant along with a cancer reclassification request. 

Imazalil exists as a base or as its sulfate salt. The acute toxicity profiles of the base and the 

sulfate salt are comparable and they are considered similar in their toxicological properties. The 

target organs for imazalil are the thyroid and the liver. In the liver, effects were observed after 

both subchronic and chronic oral exposure in mice, rats, and dogs. In rats, increased liver 

weights, dark and lobulated livers, swollen centrilobular hepatocytes, liver hypertrophy and liver 

vacuolation, along with decreased body weight and body weight gains were observed after 

subchronic exposure. After chronic exposure, there were increased incidences of 

intracytoplasmic inclusion bodies in hepatocytes, increased hepatocyte proliferation, and bile 

duct proliferation. In mice, subchronic exposure led to alterations in liver microsomal protein 

and microsomal cytochrome P450 content along with liver histopathology. Chronic exposure 

also resulted in liver histopathology at a similar dose. In dogs, a subchronic study is unavailable; 

however, increased liver weights and enzymes, decreased body weight, and clinical signs were 

observed after chronic exposure. In rabbits, swollen livers were observed after dermal exposure

in a preliminary study only. No liver effects were seen in the definitive dermal study. Thyroid 

effects were observed in rats after chronic exposure and consisted of increased absolute and 

relative weight as well as microscopic changes in the affected thyroids. 

There was no evidence of increased quantitative and/or qualitative susceptibility after in utero

exposure to imazalil in developmental toxicity studies in rats, rabbits, and mice. However, there 

was indication of increased qualitative susceptibility in a reproduction study in rats. Increased 

mortality was observed in offspring animals from birth to post-natal day (PND) 4 in both 

generations. The pup mortality was associated with dystocia in maternal animals, as well as
Imazalil Registration Review Scoping Document

Page 6 of 33

decreased body weight gain and liver vacuolation. It was determined that the pup deaths resulted 

from an increased susceptibility to imazalil from the milk intake during lactation. 

There were neurotoxic effects observed in an acute neurotoxicity study in rats at the high dose 

tested. Prior to or on the day of death, clinical signs were observed in females that included:

yellow material in the abdomen, hypoactivity, tremors, hunched posture, prostration and /or 

increased respiration. Decreased motor activity and Functional Observational Battery (FOB)

alterations (soiled fur, crusty deposits around nose, low arousal, gait changes, and no touch, 

olfactory or approach response) were also seen in female animals. There were no neurotoxic 

effects observed in males and toxicity was limited to decreased body weight gain and food 

consumption at the high dose. As previously mentioned, a subchronic neurotoxicity and 

developmental neurotoxicity study are not available for imazalil.

Imazalil is classified as “likely to be carcinogenic in humans” based on increases in 

hepatocellular adenomas and combined liver adenomas/carcinomas in male Swiss albino mice 

and Wistar rats and an increased incidence of combined thyroid follicular cell 

adenomas/carcinomas in rats. A linear low dose approach (Q1*) was used for quantification of 

human cancer risk. A cancer potency factor of 6.1 x 10-2(mg/kg/day)-1 was estimated based on 

the most potent liver tumors in mice. Imazalil was not mutagenic in both in vivo and in vitro 

mutagenicity assays. 

After evaluating the imazalil toxicity and exposure databases, HED determined that the 10x 

FQPA Safety Factor should be retained for assessing chronic dietary exposure and reduced for 

acute scenarios. It was concluded that the full 10x factor was appropriate for chronic exposure 

scenarios because of qualitative evidence of increased susceptibility in the 2-generation 

reproduction study in rats and because of a data gap for a developmental neurotoxicity study. For 

acute dietary, the 10X factor was reduced to 3X due to neurotoxicity data gap. Therefore, a total 

UF of 300x (10x intraspecies, 10x interspecies, and 3x FQPA) was applied to acute assessments 

and a total UF of 1000x (10x intraspecies, 10x interspecies, and 10x FQPA) was applied to 

chronic assessments. For dermal and inhalation risk assessments a 100x UF was applied (10x 

intraspecies, 10x interspecies, and 1x FQPA). These uncertainty factors will likely be revisited 

during registration review, in conjunction with current policies.

Acute lethality studies conducted with imazalil demonstrate moderate toxicity via the oral route 

(Category II) of exposure, and low toxicity via the dermal (Category III) and inhalation routes 

(Category IV) of exposure. It is a severe eye irritant (Category I); however, it is not a dermal 

irritant (Category IV) or a skin sensitizer.

In the most recent assessment for imazalil (D280708), endpoints were selected for acute and 

chronic dietary, as well as occupational short-, intermediate-, and long-term dermal and 

inhalation exposure. For acute dietary risk assessment for females 13-49, the NOAEL of 5 

mg/kg/day from a developmental toxicity study in rabbits was chosen based on an increased 

incidence of resorptions and a decreased number of fetuses at the LOAEL of 10 mg/kg/day. No 

endpoint was selected for acute dietary exposure for the general population. 

For chronic dietary exposure and risk assessment, the chronic study in dogs was selected. The 
Imazalil Registration Review Scoping Document

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NOAEL of 2.5 mg/kg/day was based on liver effects, body weight changes, and vomiting/soft 

stools observed at the LOAEL of 20 mg/kg/day. 

 

For short term dermal risk assessment, the 21 day dermal toxicity study was selected. The 

dermal NOAEL of 160 mg/kg/day was based on skin effects and swollen livers seen at the 

LOAEL of 250 mg/kg/day. For intermediate-term dermal risk assessments, the subchronic rat 

study was used with a NOAEL of 16 mg/kg/day, based on severe liver effects seen at the 

LOAEL of 32 mg/kg/day. The chronic dog study was used for long term dermal assessment. 

Since oral studies were used for estimating intermediate- and long- term dermal risks, a dermal 

absorption factor of 40% was applied.

For short-term inhalation risk assessment, the developmental toxicity study in rabbits was 

selected. For intermediate- and long-term inhalation risk assessment, the chronic dog study was 

used. For risk assessment purposes, inhalation toxicity is considered equivalent to oral toxicity.

Conclusions for Hazard Identification/Toxicology

A subchronic inhalation toxicity study is required for imazalil based on the potential for repeated 

inhalation exposure and high inhalation exposure estimates for occupational handlers 

(mixer/loader/applying) during citrus post-harvest activities and from poultry and turkey 

hatchery equipment and facilities treatments. Although the inhalation estimates using the current 

oral point of departure (PoD) are above the level of concern (LOC) of 100, HED uses margins of 

exposure (MOEs) of approximately 10 times higher than the level of concern, or 1000X, as a 

benchmark for granting inhalation waivers. Currently, some inhalation exposure estimates for 

occupational handlers are well below 1000X. Once the missing study has been submitted, the 

need for revised regulatory endpoints and PoDs will be considered. In the absence of the 

inhalation study, the Agency will retain a 10X database uncertainty factor for inhalation 

exposure only. Previously, acute and subchronic neurotoxicity (ACN and SCN), developmental 

neurotoxicity (DNT), and immunotoxicity studies were required by the Agency for imazalil. 

However, the ACN study has been received and the Agency has waived the requirement for the 

other studies (TXR 0056756). 

Dietary Exposure

The residue chemistry database for imazalil is incomplete. An independent laboratory validation 

(ILV) for the proposed enforcement method for livestock commodities has not yet been provided

as requested in the RED. HED has reviewed the imazalil labels for use in poultry hatcheries for 

control of Aspergillus fumigatus via a smoke generator and found these uses to be non-food and 

the egg and poultry fumigation study also required in the 2002 HED human health risk 

assessment is no longer required.

The qualitative nature of the residue of imazalil in plants and animals is adequately understood. 

The established tolerances for residues of imazalil in/on plant commodities [40 CFR§180.413(a)] 

are expressed in terms of the combined residues of imazalil and its metabolite R014821 [1-(2,4-

dichlorophenyl)-2-(1H-imidazole-1-yl)-1-ethanol]. The imazalil residues of concern in livestock 

include imazalil and any imazalil metabolite containing the 2,4-dichlorophenyl moiety. The 
Imazalil Registration Review Scoping Document

Page 8 of 33

established tolerances for residues of imazalil in livestock commodities [40 CFR §180.413(b)] 

are expressed in terms of the combined residues of imazalil and 3-[2-(2,4-dichlorophenyl)-2-

(2,3-dihydroxypropoxy)ethyl]-2,4-imidazolidinedione (FK772), and 3-[2-(2,4-dichlorophenyl)-

2-(hydroxy)]-2,4-imidazolidinedione (FK284). The HED Metabolism Committee (L. Cheng, 

8/30/94) concluded that imazalil residues to be regulated in livestock commodities will include 

imazalil and any metabolite containing the 2,4-dichlorophenyl moiety.

An adequate residue analytical method is available for determining the total toxic residues of 

imazalil in/on plant commodities but not in livestock commodities.

Method for determination of residues in/on plant commodities

The Pesticide Analytical Manual (PAM) Volume II lists a GC/ECD method, designated as 

Method I, for the quantitation of residues of imazalil and its metabolite R014821 in/on bananas, 

citrus fruits, cottonseed, and small grains. Plant commodity samples collected from studies 

pertaining to magnitude of the residues in plant were analyzed for residues of imazalil and its 

metabolite R014821 using this PAM Volume II method or its modification; in these field studies, 

method recoveries obtained from concurrent analyses of treated samples were acceptable. This 

enforcement method has been adequately radio-validated using samples from the banana 

metabolism study.

Methods for determination of residues in livestock commodities

The PAM Volume II also lists a GC/ECD method, designated as Method II, for the quantitation 

of residues of imazalil and the metabolites R014821 and R042243. The limits of detection range 

from 0.01 to 0.05 ppm, depending on the specific matrix. Method II also involves the conversion 

of the metabolites to the trimethylsilyl derivatives and separate determination of imazalil and its 

metabolites. It should be noted that this method is not a measure of the total toxic imazalil 

residues in meat, milk, poultry, and eggs, as determined by the results of livestock metabolism 

studies.

Because of the recommended changes in tolerance expression, a new enforcement method 

capable of determining imazalil and any metabolite containing the 2,4-dichlorophenyl group in 

livestock commodities was required in the RED. To accomplish this, HED suggested that the 

registrant develop an enforcement method capable of measuring all compounds containing the 

2,4-dichlorophenyl group using a method which converts these residues to a common moiety. 

Alternatively, the registrant was given the option of developing an enforcement method for a set 

of marker compounds that account for a high percentage of the total toxic residues in ruminant 

and poultry, which is the option they pursued.

Attempts by the registrant to develop a common moiety method, based on the oxidation of 

imazalil and five of its metabolites to 2,4-dichlorobenzoic acid, were unsuccessful due to 

extraction inefficiency and method recovery variability. The registrant is now pursuing the 

development of a new GC/ECD method capable of quantifying residues of imazalil and the 

appropriate marker metabolites. Preliminary validation data indicate that the proposed GC/ECD 

method is adequate for collecting data on residues of imazalil, FK772, and FK284 in milk and 
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Page 9 of 33

ruminant tissues, provided fortified control samples are analyzed concurrently with each set of 

treated samples to assure that acceptable method recoveries are being achieved for each analysis. 

Independent laboratory validation should be conducted prior to the method being sent to the 

Agency for validation as an enforcement method. This method was used in the analysis of 

samples collected from a recently reviewed ruminant feeding study (2006).

Adequate field trial data reflecting the label use pattern are available. Acceptable citrus 

processing studies, reflecting postharvest treatment, have been submitted and are adequate. The 

requirement for barley and wheat processing studies was waived due to the very low residue 

levels in the RAC resulting from seed treatment uses. An acceptable ruminant feeding study has 

been submitted. A confined or field accumulation study in rotational crops was not required 

because the use of imazalil on annual crops is limited to seed treatment prior to crop planting.

Dietary Exposure

The last dietary analysis for imazalil was conducted in connection with reregistration (D279084, 

Thurston Morton/David Hrdy, 11/15/2001). Imazalil acute and chronic dietary exposure 

assessments were conducted using the Dietary Exposure Evaluation Model (DEEMTM) software 

Version 7.75, which incorporates consumption data from USDA’s Continuing Surveys of Food 

Intakes by Individuals (CSFII), 1989-1992. The estimated acute dietary risk was not of concern. 

Use of USDA Pesticide Data Program (PDP) monitoring data and calculated livestock 

anticipated residues (ARs) results in a maximum dietary risk estimate of 15% of the aPAD at the 

99.9th percentile for females of child bearing age (13-50 years old). Estimated chronic dietary 

exposure was also below HED’s level of concern. Use of PDP monitoring data and calculated 

livestock anticipated residues (ARs) results in a maximum risk of 3% of the chronic PAD for 

children 1-6 years old, the most highly exposed population subgroup. Dietary risk for the 

general US population was estimated to be 1% cPAD. Estimated chronic dietary exposure for 

the general US population is 0.000034 mg/kg/day, based on use of PDP monitoring data and 

calculated livestock ARs. This exposure corresponds to a lifetime cancer risk estimate of 2.1 X 

10-6, with approximately 70% of the exposure resulting from residues in orange and grapefruit 

food commodities.

Due to issues related to residue analytical methods for livestock commodities, HED is using 

marker metabolites to represent the 2,4-dichlorophenyl group moiety which should adequately 

reflect the total toxic residue. For dietary assessment, the residues will be adjusted using the 

ratios of imazalil and the marker metabolites that were found in the livestock metabolism studies. 

The marker compounds in milk and ruminant tissues are imazalil, FK772, and FK284; these 

marker compounds collectively represent the following percentages of the total toxic residues, as 

determined by the ruminant metabolism studies: 21% in milk, 72% in muscle, 71% in kidney, 

44% in liver, and 33% in fat.

Drinking Water

In the 2001 RED the acute drinking water levels of concern (DWLOCs) were calculated based 

on the acute dietary (food) exposure, default body weights and water consumption figures. The 

acute DWLOC for females 13-50 years was 500 ppb. The estimated environmental 
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Page 10 of 33

concentrations (EECs) for surface water (GENEEC) and groundwater (SCI-GROW) were both 

less than the acute DWLOC’s, indicating that acute aggregate exposure to imazalil in food and 

water was less than HED’s level of concern. The peak GENEEC EEC was 0.072 ppb, while the 

estimated groundwater EEC was negligible.

The EECs for surface water (GENEEC, 0.013 ppb) and groundwater (SCI-GROW, 0 ppb) were 

less than the chronic DWLOC (87 ppb for general population and 25 ppb for children 1-6 years), 

indicating that chronic exposure to imazalil in food and water is less than HED’s level of 

concern. Cancer DWLOCs were not calculated since the dietary cancer risk estimate exceeds the 

level of concern of 1x10-6.

Since HED used percent crop treated information and monitoring data for the seed treatment 

uses, and post-harvest treatment of citrus commodities a new dietary assessment will need to be 

conducted. In addition, EFED has concluded that pending receipt and review of additional 

environmental fate and toxicity data for imazalil and it’s degradates, or changes in labeled use 

rates, the drinking water assessment will be reevaluated. However, if no new, relevant data 

regarding the environmental fate, toxicity, or use of imazalil or its degradates are submitted, the 

Estimated Drinking Water Concentrations (EDWCs) from the 2002 drinking water assessment 

will be used in the registration review risk assessment.

Conclusions for Dietary Exposure

The residue chemistry database for imazalil is incomplete. An ILV for the proposed 

enforcement method for livestock commodities has not yet been provided. HED will continue to 

correct residues, using marker compounds, to account for the total toxic residue for dietary risk

exposure assessment. Since HED used percent crop treated information and monitoring data in 

its dietary assessment for the 2003 RED, new dietary assessments will need to be conducted

during registration review. A new drinking water assessment might be needed to incorporate the 

use of the most current drinking water models. At the time of registration review, HED will 

compare include any updates in the modeled drinking water residues in the new dietary exposure 

assessment. 

Residential Exposure

Residential Handlers

A residential handler exposure assessment will not be needed for Registration Review because 

there are no registered residential uses for imazalil.

Residential Post-Application 

The Agency has not considered residential post-application exposure for imazalil since there are 

no registered residential uses at this time. Residential exposures from off-site transport (e.g., 

spray drift or volatilization) may occur as a result of imazalil applications to agricultural fields.

The Agency may conduct a spray drift assessment and examine the need for a volatilization 

assessment for imazalil during Registration Review.
Imazalil Registration Review Scoping Document

Page 11 of 33

Conclusions for Residential Exposure

Residential handler and conventional residential post-application assessments will not be 

conducted during Registration Review; however, the Agency may conduct a spray drift 

assessment and examine the need for a volatilization assessment for imazalil during Registration 

Review.

Aggregate Risk Assessment

The most recent aggregate risk assessment was performed in conjunction with the HED RED

chapter (D280708, A. Khasawinah, 2/7/2002). For aggregate risk assessment, risk estimates 

resulting from food, drinking water, and residential uses are usually combined. As no residential 

uses are registered for imazalil, only acute, chronic, and cancer aggregate risk assessments were 

conducted. The acute, chronic, and cancer aggregate risk assessments consisted of dietary 

exposures from food and drinking water only. The acute and chronic risk estimates were not of 

concern for the general U.S. population or any of the population subgroups. The cancer risk 

estimate for the general US population was 2.1×10-6. During registration review, updated 

aggregate assessments will be needed to include any potential updates to exposure from food and 

drinking water, revised regulatory endpoints, points of departure (PoDs) and uncertainty 

factors/safety factors (UF/SFs).

Occupational Exposure

Imazalil is registered for post-harvest treatment of citrus fruits, seed treatment of barley, sudan 

grass and wheat prior to planting, and in greenhouses on ornamentals (including bedding plants, 

cut flowers, flowering hanging baskets, foliage, potted flowering plants, and perennials). Imazalil 

is also used to treat cleaned poultry and turkey egg hatchery equipment and facilities prior to 

introduction of eggs. The Agency has determined that there is a potential for occupational 

handler and post-application exposures resulting from the registered uses of imazalil.

Occupational Handlers

The 2002 RED evaluated a number of occupational handler scenarios that represented the major 

imazalil short-, intermediate- and long-term occupational handler exposures based on application 

equipment and formulation type. That assessment indicated that occupational handler noncancer scenarios resulted in risk estimates not of concern at baseline and/or some level of 

mitigation (i.e., additional personal protective equipment (PPE) for a number of occupational 

handler scenarios). Cancer risk assessments for occupational handlers were completed and 

presented as total cancer risk estimates at baseline and with additional PPE for each exposure 

scenario as needed.

The 2002 RED indicated data requirements for post-harvest citrus treatments. Since the

“Exposure Study of Citrus Treatment Applicators (e.g., wax and foam applications)” required in 

the 2002 RED has not been submitted to the Agency, HED will evaluate exposures from postharvest citrus treatments according to the HED’s Science Advisory Council for Exposure 

(ExpoSAC) Guidance for the “Assessment of Occupational Exposure for Post-Harvest 
Imazalil Registration Review Scoping Document

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Commodity Pesticide Treatments.” The recommended methodology for post-harvest commodity 

treatments is largely based on one available worker exposure monitoring study. Some of these 

data are proprietary, and subject to the data protection provisions of the Federal Insecticide, 

Fungicide, and Rodenticide Act (FIFRA). 

In 2006, HED also conducted an exposure assessment addressing the potential risk estimates 

resulting from the proposed use of imazalil in commercial greenhouses as a total release 

(aerosol) fogger. No occupational handler scenarios were quantitatively assessed for total 

release foggers, based on the assumption that a typical handler will aim the fogger can away 

from their body/face and pull a tab, which then releases the product into the greenhouse. Then

the handler will place the can on the floor of the greenhouse and leave the area immediately. 

Based on existing registrations, the previous assessments identified most of the anticipated 

occupational handler exposure scenarios and risks were not of concern. However, since the 2002 

RED new exposure data and updated commercial seed treatment methodologies are available to 

assess exposure to occupational handlers. Because of these changes, HED will likely reevaluate 

the occupational handler assessment for imazalil. Additionally, all occupational handler 

scenarios will need to be reassessed to address updates to HED’s exposure policies, including 

updates to default exposure data used for handler scenarios and assumptions for body weights, 

and revised regulatory endpoints, points of departure (PoDs) and uncertainty factors/safety 

factors (UF/SFs)

Occupational Post-application

The 2002 RED evaluated a number of occupational post-application scenarios that represented 

the major imazalil occupational post-application exposure scenarios based on the registered uses. 

That assessment indicated that occupational post-application exposure scenarios were not of 

concern. While the post-application scenarios that were assessed were not of concern, the RED 

requested additional data (in the form of exposure monitoring studies) for some scenarios where 

information gaps precluded estimation of risk. Based on current policies and procedures, the 

“Post-application Inhalation and Dermal Exposure Monitoring Studies following Smoke 

Generator or Spraying Applications in Poultry Hatcheries” listed as data needs in the 2002 RED 

are no longer required. Since the 2002 RED, HED has developed new procedures and modeling 

tools that will be used to assess post-application exposures from smoke generators and spray 

applications in poultry and turkey hatcheries. Additional information about the use pattern 

and/or worker post-application activities in poultry and turkey hatcheries will be requested to 

accurately assess exposures and risks during registration review.

In 2006, HED also conducted a post-application (cancer and non-cancer) exposure assessment 

addressing the potential risks resulting from a proposed use of imazalil in commercial 

greenhouses as a total release (aerosol) fogger. This assessment indicates risk estimates of 

concern for long-term and cancer post-application activities (e.g., thinning, weeding, and 

scouting) involving cut flowers and foliage. However, these risk estimates were generated 

without a chemical specific DFR study.

In accordance with the updated Part 158 data requirements (2007), one or more DFR studies are 

required when a pesticide has occupational uses that could result in post-application dermal 
Imazalil Registration Review Scoping Document

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exposure. Since the RED, no DFR studies have been submitted for imazalil. HED analyzed a 

number of DFR studies and selected a new default value for the fraction of the application rate 

available to be dislodged after a foliar application (FAR). This default value is 25%. Of the 

analyzed DFR studies, the maximum FAR value seen was 89% or 3.6 times higher than the 

default residue transfer value. Therefore, HED has decided that a calculated MOE of 

approximately four times higher than the level of concern (e.g., an MOE > 400 if the LOC = 

100) using the default dislodged residue values would provide an adequate margin of safety for 

any potentially higher residues seen in a chemical-specific DFR study. This policy is described 

in the “Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable 

Foliar Residue (DFR) Studies” (Memo, J. Housenger, 12/12/12). A new DFR study is required 

for imazalil since estimated dermal MOEs for occupational workers exposed to thinning, 

weeding, and scouting cut flowers and foliage are not greater than 400.

Furthermore, under the requirements for the Worker Protection Standard for Agricultural 

Pesticides (WPS), imazalil is classified as a Category I in an acute toxicity eye irritation study.

Typically, according to WPS, a 48 hour restricted-entry interval (REI) is assigned to chemicals 

with acute Category I classifications. However, in the 2002 RED, a 2-hour REI was established 

for hatchery personnel transferring the eggs from storage room to setters because minimal 

contact with eggs or equipment is expected. In 2006, a 24-hour REI was assigned based on 

application techniques and worker post-application activities expected in greenhouses. These 

REIs may need to be reevaluated based on current scenario definitions and policies to ensure the 

REIs are adequate to protect workers from post-application exposures to imazalil. 

Since the previous review, there have been several updates to HED’s exposure policies, 

including updates to post-application transfer coefficients, transferable residue assumptions, and 

assumptions for body weights. Thus, these post-application scenarios will need to be updated in 

the Registration Review assessment to be sure they are assessed using current policies and 

updated exposure data.

Conclusions for Occupational Exposure and Risks

Updated occupational handler exposure assessments will be required under registration review 

based upon revisions to the Agency’s scenario-specific surrogate handler exposure data1, updated 

exposure methodologies related to commercial seed treatment and post-harvest treatment of 

citrus fruits. Additional information regarding application methods and post-application 

activities conducted in poultry and turkey hatcheries and chemical-specific data to evaluate postapplication exposure associated with the greenhouse uses on ornamentals are needed to support 

registration review. Specifically, chemical-specific DFR data are needed to support the 

greenhouse use on ornamentals/cut flowers. An updated occupational post-application 

assessment will be required under registration review to: 1) incorporate updated policies and 

procedures to assess exposure from smoke generators and spray applications in poultry and 

turkey hatcheries; 2) assess foliar applications of imazalil to ornamental crops based on 

revisions to transfer coefficients, transferable residue and body weight assumptions; 3)

incorporate the required DFR data based on existing and anticipated occupational post-

 

1

 Available at: http://www.epa.gov/pesticides/science/handler-exposure-table.pdf.
Imazalil Registration Review Scoping Document

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application risk estimates for ornamentals; and 4) incorporate revised regulatory endpoints, 

points of departure (PoDs) and uncertainty factors/safety factors (UF/SFs).

Public Health and Pesticide Epidemiology Data 

The OPP Incident Data System (IDS) and the Centers for Disease Control and 

Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event 

Notification System for Occupational Risk-Pesticides (SENSOR) databases were consulted for 

pesticide incident data on the active ingredients imazalil and imazalil sulfate (PC codes: 111901 

and 111902). The purpose of the database search is to identify potential patterns in the 

frequency and severity of the health effects attributed to imazalil and imazalil sulfate exposure. 

Imazalil and imazalil sulfate are not included in the Agricultural Health Study (AHS), and 

therefore the study does not provide information regarding incident data. 

A summary report listing incidents for imazalil reported to the Office of Pesticide Programs 

(OPP) Incident Data System (IDS) has been provided for the docket (D412205, S. Recore and E. 

Evans, 07/25/2013). The report represents incidents occurring in the U.S. from 1998 to 2009 

(Sensor-pesticides) and 2008-2013 (IDS records). 

OPP’s IDS includes reports of alleged human health incidents from various sources, including 

mandatory Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6(a)(2) reports 

from registrants, other federal and state health and environmental agencies, and individual 

consumers. Since 1992, OPP has compiled these reports in IDS. IDS contains reports from 

across the U.S. and most incidents have all relevant product information recorded. Reports 

submitted to the IDS represent anecdotal reports or allegations only, unless otherwise stated in 

the report. It should be noted there are two incidents reported as lawsuits to IDS that are not 

considered in this report. 

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

 

Main IDS contains incidents resulting in higher severity outcomes and provides 

more detail with regard to case specifics. This system stores incident data for 

death, major and moderate incidents, and it includes information about the 

location, date and nature of the incident. Main IDS incidents involving only one 

active ingredient (as opposed to pesticide products with multiple active 

ingredients) are considered to provide more certain information about the 

potential effects of exposure from the pesticide. 

Aggregate IDS contains incidents resulting in less severe human incidents (minor, 

unknown, or no effects outcomes). These are reported by registrants only as 

counts in what are aggregate summaries. 

Imazalil

For the Main IDS, from January 1, 2008 to June 11, 2013, there were 0 incidents reported for 

single chemical only in the database. There was 1 incident reported involving more than one 

chemical. This incident was classified as moderate severity. 
Imazalil Registration Review Scoping Document

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In Aggregate IDS, from January 1, 2008 to June 11, 2013, there were 2 reported incidents

involving imazalil. These incidents were classified as minor severity.

Imazalil Sulfate 

There were no incidents reported to either Main IDS or Aggregate IDS for imazalil sulfate from 

January 1, 2008 to June 11, 2013.

The SENSOR-Pesticides database covers 11 states from 1998-2009, although reporting varies 

from state to state. Cases of pesticide-related illnesses are ascertained from a variety of sources, 

including: reports from local Poison Control Centers, state Department of Labor workers’ 

compensation claims when reported by physicians, reports from State Departments of 

Agriculture, and physician reports to state Departments of Health. Although both occupational 

and non-occupational incidents are included in the database, SENSOR-Pesticides focuses on 

occupational pesticide incidents, and is of particular value in providing that information. The 

state coordinator at each of the 11 respective state Departments of Health conducts case followup activities such as obtaining medical records to verify symptoms and severity. Using 

standardized protocol and case definitions derived from poison center reporting, the state 

SENSOR-Pesticide coordinator enters the incident information into the state-based system which 

is sent to NIOSH annually to be aggregated. 

A query of SENSOR-Pesticides 1998-2009 finds a total of two cases, stemming from two events, 

involving imazalil. Of the two, one case involved a single active ingredient (ai). This case was 

work-related and low in severity and included dermal and ocular symptoms. The multiple ai 

case was moderate in severity; the case ate a banana and immediately had a severe allergic 

reaction, the 3 ais listed in this case are: bifenthrin, imazalil, and chlorpyrifos-methyl. Following 

is the recorded case detail, “A 62 year old male ate a banana at home and developed a serious 

allergic reaction within minutes of eating the produce. One hour later he was treated at the ER. 

He presented dermal and cardiovascular signs and complained of neurological and 

gastrointestinal symptoms. WSDA sampled the banana peel and the banana pulp. No pesticides 

were found the in the pulp. However, three pesticides were found in the peel. Concentrations of 

the pesticides were below the estimated tolerances for whole bananas. Nevertheless, symptoms 

experienced by the patient correlated well with an exposure with two of the pesticides used. 

Even though no pesticides were found in the pulp, he had contact with the peel before handling 

the pulp.”

2

The Agency has reviewed the available incident data for imazalil and imazalil sulfate (D412205, 

S. Recore,) and concludes that based on the low frequency and severity of incident cases 

reported for imazalil, there does not appear to be a concern at this time that would warrant 

further investigation. The Agency will continue to monitor the incident information and if a 

concern is triggered, additional analysis will be included in the risk assessment.

Tolerance Assessment and International Harmonization

 

2 The two chemicals correlating with symptoms are not specified in SENSOR; EPA is unable to determine which 

active ingredients may have contributed to the health effects reported.
Imazalil Registration Review Scoping Document

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Tolerances for residues in/on plant commodities are established under 40 CFR §180.413(a). 

They are currently expressed in terms of the combined residues of imazalil [1-(2-(2,4-

dichlorophenyl)-2-(2-propenyloxy)ethyl)-1H-imidazole] and its metabolite R014821 [1-(2,4-

dichlorophenyl)-2-(1H-imidazole-1-yl)-1-ethanol]. The qualitative nature of the residue in plants 

is adequately understood. HED has determined that the current tolerance expression for plant 

commodities needs updating to reflect current policy.

Tolerances for residues in livestock commodities are established under 40 CFR §180.413(b). 

They are currently expressed in terms of the combined residues of imazalil and 3-[2-(2,4-

dichlorophenyl)-2-(2,3-dihydroxypropoxy)ethyl]-2,4-imidazolidinedione (FK772), and 3-[2-

(2,4-dichlorophenyl)-2-(hydroxy)]-2,4-imidazolidinedione (FK284). The qualitative nature of 

the residue in livestock is adequately understood. The HED Metabolism Committee concluded 

that, in the absence of information to the contrary, any metabolite containing the 2,4-

dichlorophenyl moiety is of toxicological concern and must be included in the conduct of the 

dietary risk assessment. HED has determined that the current tolerance expression for livestock 

commodities needs updating to reflect current policy.

According to HED’s Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner), the 

tolerance expression for imazalil on plant commodities should be revised to state:

Plant Commodities

“Tolerances are established for residues of imazalil [1-(2-(2,4-dichlorophenyl)-2-(2-

propenyloxy)ethyl)-1H-imidazole], including its metabolites and degradates, in or on the 

commodities in the tables below. Compliance with the tolerance levels specified below is to be 

determined by measuring the sum of imazalil [1-(2-(2,4-dichlorophenyl)-2-(2-

propenyloxy)ethyl)-1H-imidazole] and its metabolite R014821 [1-(2,4-dichlorophenyl)-2-(1Himidazole-1-yl)-1-ethanol].”

Livestock Commodities

“Tolerances are established for residues of imazalil [1-(2-(2,4-dichlorophenyl)-2-(2-

propenyloxy)ethyl)-1H-imidazole], including its metabolites and degradates, in or on the 

commodities in the tables below. Compliance with the tolerance levels specified below is to be 

determined by measuring the sum of imazalil [1-(2-(2,4-dichlorophenyl)-2-(2-

propenyloxy)ethyl)-1H-imidazole] and its metabolites and 3-[2-(2,4-dichlorophenyl)-2-(2,3-

dihydroxypropoxy)ethyl]-2,4-imidazolidinedione (FK772), and 3-[2-(2,4-dichlorophenyl)-2-

(hydroxy)]-2,4-imidazolidinedione (FK284).”

A summary of imazalil tolerances is presented in Attachment A.3. 

There are no Codex, Canadian or Mexican Maximum Residue Limits (MRLs) established for 

livestock commodities; therefore, a discussion of harmonization of livestock tolerance 

expression or levels is not required for imazalil. Mexico adopts the U.S. or Codex MRLs for its 

export purposes.
Imazalil Registration Review Scoping Document

Page 17 of 33

The Codex/Canadian MRLs and the U.S. tolerances are not harmonized with respect to tolerance 

expression. The Codex Alimentarius Commission and Canada have established maximum 

residue limits (MRLs) for imazalil in/on various raw agricultural commodities. The Codex and 

Canadian MRLs are expressed in terms of the parent compound imazalil. The U.S. tolerances 

for plant commodities are in expressed terms of the combined residues of imazalil and its 

metabolite R014821. The expression of U.S. tolerances for livestock commodities is imazalil, 

metabolite FK772, and metabolite FK284.

Codex and U.S. have established MRLs/tolerances for bananas, citrus fruits, and wheat grain, 

forage, hay, and straw. The residue levels are not in harmony. However, because of the 

inclusion of the parent only in the Codex MRLs, it may not be possible to harmonize with the 

Codex values that are all lower than the current U.S. tolerances since the Codex MRL may not 

be adequate to cover the regulated residue in the U.S. (banana, citrus fruit, wheat grain and 

straw). Canada has lower MRLs for both banana and citrus fruit and the MRL is based on the 

parent compound only. HED will reexamine the available residue data as part of registration 

review to determination if harmonization is possible.

Pending Tolerances

HED is currently evaluating a tolerance petition for the postharvest treatment of melons and a 

seed treatment use on sweet corn. This petition has not been completed pending resolution of the 

cancer classification of imazalil. Tolerances were proposed to cover residues from these uses as 

follows: 

Melons 5.0 ppm

Corn, fresh (inc. sweet K + CWHR) 0.2 ppm

Corn, forage 0.2 ppm

Corn, fodder 0.2 ppm

Janssen Pharmaceutical previously submitted a tolerance petition, PP#7F3530, in an effort to 

register the preplant seed treatment of sweet corn and the postharvest treatment of melons 

(except watermelons). The petition, originally submitted in 1988, included proposals for 

tolerances on citrus fruits and animal commodities. The supporting residue chemistry data were 

reviewed by HED in memoranda dated 3/09/1988 (RCB#s 2524 and 2740, W. Chin) and 

11/02/1988 (RCB# 4155, W. Chin). The latter review concluded that the available data support 

the establishment of tolerances for the combined residues of imazalil and its metabolite 

R014821, as listed below, pending submission of a revised Section F to correct raw agricultural 

commodity names. The citrus use was subsequently registered as part of the reregistration 

process. The proposed tolerance level for melons is higher than the existing 2.0 ppm Codex 

MRL for melons, except watermelon. Harmonization with the lower Codex residue levels is not 

feasible, as residues of up to 4.5 ppm were observed in the submission. There are no 

Codex/Canadian MRLs for sweet corn, and there will not be a harmonization issue with this 

commodity.
Imazalil Registration Review Scoping Document

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3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in the 

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/nepa/tools/guidance/Volume1/2-6-EO_12898envjustice.pdf). The Office 

of Pesticide Programs (OPP) typically considers the highest potential exposures from the legal 

use of a pesticide when conducting human health risk assessments, including, but not limited to, 

people who obtain drinking water from sources near agricultural areas, the variability of diets 

within the U.S., and people who may be exposed when harvesting crops. Should these highest 

exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure 

that the risk estimates are based on the best available information.

Cumulative Risk Assessments 

EPA has not, at this time, made a determination as to whether imazalil shares a common 

mechanism of toxicity with any other substances. 

Human Studies

The previous imazalil risk assessments relied in part on data from studies in which adult human 

subjects were intentionally exposed to a pesticide or other chemical. Studies such as the 

Pesticide Handlers Exposure Database, Outdoor Residential Exposure Task Force, and 

Agricultural Handler Exposure Task Force have been reviewed by the Agency and found on the 

basis of available evidence to have been neither fundamentally unethical nor significantly 

deficient relative to standards of ethical research conduct prevailing when they were conducted. 

There is no barrier in EPA's "Protection of Human Subjects" Regulation to reliance on these 

studies.

Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and 

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of its most recent registration decision for imazalil and imazalil 

sulfate, EPA reviewed these data and selected the most sensitive endpoints for relevant risk 

assessment scenarios from the existing hazard database. However, as required by FFDCA 

section 408(p), imazalil and imazalil sulfate are subject to the endocrine screening part of the 

Endocrine Disruptor Screening Program (EDSP). 
Imazalil Registration Review Scoping Document

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EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of 

chemicals identified for EDSP screening was published on June 14, 20133and includes some 

pesticides scheduled for Registration Review and chemicals found in water. For further 

information on the status of the EDSP, the policies and procedures, the lists of chemicals, future 

lists, the test guidelines and the Tier 1 screening battery, please visit our website.4

In the interim, EPA is making no human health or environmental safety findings associated with 

the EDSP screening of imazalil and imazalil sulfate. Before completing this Registration 

Review, the Agency will make an EDSP FFDCA section 408(p) determination.

Data Requirements

The following toxicity studies are required to support the registration review of imazalil:

Guideline 875.3465 – 90-Day Subchronic Inhalation toxicity Study.

The following Residue Chemistry data are required to support the registration review of imazalil:

Guideline 860.1340 – Residue Analytical Method/Independent Laboratory Validation 

(ILV) for the livestock enforcement method.

The following ORE data are required to support the registration review of imazalil:

Guideline 875.2100 - Dislodgeable Foliar Residue (DFR) Dissipation Study for 

Ornamental Plants.

 

3

See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of 

chemicals.

4

http://www.epa.gov/endo/
Imazalil Registration Review Scoping Document

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References

D280708; Imazalil: HED Risk Assessment for the Reregistration Eligibility 

Decision (RED) Document. Chemical No. 111901. Reregistration Case No. 

2325; February 7, 2002.

D249557; Imazalil: HED Risk Assessment for the Reregistration Eligibility Decision (RED) Document. 

Chemical No. 111901. Case No.2325; April 28, 2000. 

D412205; Imazalil and Imazalil Sulfate: Tier I Review of Human Incidents. S.Recore and E. Evans; July 25, 2013.

D258087; Imazalil: The HED Toxicology Chapter for the Reregistration Eligibility Decision Document (RED);

PC Code 111901, Case 816389; February 9, 2000. 

D272790; Subject: Imazalil. Reregistration List B Chemical Number 111901; Case No. 2325; Revised Product 

and Residue Chemistry Chapters for the HED Risk Assessment; T. Morton and D. Hrdy; 01/31/2002; No MRIDs. 

D279084; Revised Acute and Chronic (non-cancer and cancer ) Dietary Exposure and Risk Analyses for the HED 

Human Health Risk Assessment; T. Morton; 11/15/2001.

D263159; Imazalil. Reregistration List B Chemical Number 111901; Case No. 2325. Residue Chemistry 

Chapter for the HED Risk Assessment; D. Hrdy; 03/23/2000; No MRIDs.

D254805, D257227, and D259593; Imazalil. Reregistration List B Chemical Number 111901; Case No. 2325; 

OPPTS GLN 860.1340: Residue Analytical Methods, and OPPTS GLN 60.1480: Meat, Milk, Poultry, Eggs; D. 

Hrdy; 1/19/2000; MRIDs: 44786501, 44858003, and 44918801. 

D170516; Reregistration of Imazalil. Janssen Pharmaceutical 97.5% T (EPA Reg. No. 438132. CBRS No. 8845; 

P. Deschamp; 10/08/1992; MRIDs: 41606106 and 41889801.

Imazalil. Laying Hen and Lactating Goat Metabolism. The Metabolism Committee Meeting Held on August 18, 

1994; L. Cheng; 08/30/1994; No MRIDs. 

Imazalil. DEB Phase 4 Review; S. Funk; 10/18/1990. 

RCB# 4155; PP#7F3530. Imazalil in or on Melons, Citrus and Sweet Corn. Amendment of 6/29/88; W. Chin; 

11/02/1988; MRID: 40713801, 40713802, 40713803, 40713804, and 40713805. 

RCB#s: 2524 and 2740; PP#7F3530. Imazalil in or on Melons, Citrus and Sweet Corn. Evaluation of Analytical 

Methods and Residue Data; W. Chin; 03/09/1988; MRIDs:40176401, 40204901, and 40204903. 

PP#4G3017. Imazalil on Fruiting Vegetables and Cucurbits. Evaluation of Analytical Methods and Residue 

Data; L. Cheng; 08/13/1984; MRIDs: 00144373.

D217005; Worker Exposure Assessment for the Active Ingredient Imazalil in the End-Use Product Nectec P Paste 

for Use on Tree Wounds; C. Lang; July 25, 1995.

D250163; Occupational and Residential Exposure Assessment and Recommendations for the Re Registration 

Eligibility Decision Document for Imazalil; S. Tadayan; April 15, 2000.

D270918; Revised Occupational and Residential Exposure Assessment and

Recommendations for the Re Registration Eligibility Decision Document for

Imazalil; S. Tadayan; December 25, 2000.

D326610 Imazalil: Occupational Exposure Assessment to support the Section 3

request for a new use Total Release (aerosol) Fogger in Commercial

Greenhouses; J. Miller; November 30, 2006.

Attachments

Attachment A.1. Chemical Identity

Attachment A.2. Chemical Names and Structures of Imazalil Residues of Concern

Attachment A.3. Imazalil International Residue Limits Table 

Attachment A.4. Toxicity Profile Tables

Attachment A.5. Summary of Toxicological Dose and Endpoints for Imazalil

Attachment A.6. Summary of Occupational Uses for Imazalil and Imzalil Sulfate
Imazalil Registration Review Scoping Document

Page 21 of 33

Attachment A.1. Imazalil Chemical Identity

Table A.1.1. Imazalil Nomenclature.

Chemical structure

Common name Imazalil

Company experimental name R023979

CAS name 1-[2-(2,4-dichlorophenyl)-2-(2-propenyloxy)ethyl]-1H-imidazole

CAS registry number 73790-28-0

End-use products (EPs) FecundalTM 100 EC (EPA Reg. No, 43813-14),

Fungaflor®500 EC (EPA Reg. No. 43813-6)

Table A.1.2. Physicochemical Properties of Technical Grade Imazalil.

Parameter Value Reference

Melting point 50°C Product Chemistry Chapter of Imazalil 

RED (DP# 294373, 02/01/2006, T. 

Morton and D. Hrdy)

pH 7.9 at 20oC DP# 170516, 10/08/1992, P. Deschamp

Density 1.348 x 103kg/m3Product Chemistry Chapter of Imazalil 

RED (DP# 294373, 02/01/2006, T. 

Morton and D. Hrdy)

Water solubility Slightly soluble in water; 

293 ppm at 20°C

Product Chemistry Chapter of Imazalil 

RED (DP# 294373, 02/01/2006, T. 

Morton and D. Hrdy)

Solvent solubility Very soluble in methanol, ethanol, 2-

propanol, dimethylbenzene, 

acetonitrile, N, N-dimethylformamide, 

tetrahydrofuran, 1-methyl-2-

pyrrolidinone, 1,2-ethanediol, 1,2-

propanediol, and glacial acetic acid 

(>500 g/L at 25°C)

Product Chemistry Chapter of Imazalil 

RED (DP# 294373, 02/01/2006, T. 

Morton and D. Hrdy)

Vapor pressure 3.6 x 10-4Pa at 25°C Product Chemistry Chapter of Imazalil 

RED (DP# 294373, 02/01/2006, T. 

Morton and D. Hrdy)

Dissociation constant, pKa pKa = 6.53 DP# 170516, 10/08/1992, P. Deschamp

Octanol/water partition 

coefficient, Log(KOW)

log Kow of 3.82 Product Chemistry Chapter of Imazalil 

RED (DP# 294373, 02/01/2006, T. 

Morton and D. Hrdy)

UV/visible absorption 

spectrum

Not available

Cl

Cl

O

N N CH2
Imazalil Registration Review Scoping Document

Page 22 of 33

Attachment A.2 Chemical Names and Structures of Imazalil Residues of Concern

Table A.2.1. Chemical Names and Structures of Imazalil Residues of Concern in Plant Commodities.

Compound Chemical Structure

Common Name: Imazalil

Janssen Research Code: R023979

Chemical Name: 1-[2-(2,4-dichlorophenyl)-2-(2-propenyloxy)ethyl]-1H-imidazole

Common Name: Despropenyl imazalil; ethanol metabolite

Metabolite Designation(s): R014821; FK411; T-824

Chemical Name: 1-[2,4-dichlorophenyl)-2-(1H-imidazole-1-yl]-1-ethanol

Cl

Cl

O

N N CH2

Cl

Cl

OH

N N
Imazalil Registration Review Scoping Document

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Table A.2.2. Chemical Names and Structures of Imazalil and Marker Metabolites In Milk and Ruminant.

Compound Chemical Structure

Common Name: Imazalil

Janssen Research Code: R023979

Chemical Name: 1-[2-(2,4-dichlorophenyl)-2-(2-propenyloxy)ethyl]-1H-imidazole

Metabolite Designation in Goat Metabolism Study: FK772

Janssen Research Code: R061000

Chemical Name: 3-[2-(2,4-dichlorophenyl)-2-(2,3-dihydroxypropoxy)ethyl]-2,4-imidazolidinedione

Metabolite Designation in Goat Metabolism Study: FK284

Janssen Research Code: R042449 or R043449

Chemical Names: 3-(2-(2,4-dichlorophenyl)-2-(hydroxy)-2,4-imidazolidinedione

or

1-[2-(2,4-dichlorophenyl)-2-hydroxyethyl]-2,4-imidazolidinedione

Cl

Cl

O

N N CH2

Cl

Cl

O

HN N

OH

OH

O

O

Cl

Cl

OH

HN N

O

O
Imazalil Registration Review Scoping Document

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Table 2.2.3. Chemical Names and Structures of Imazalil and Marker Metabolites In Eggs and Poultry.

Compound Chemical Structure

Common Name: Imazalil

Janssen Research Code: R023979

Chemical Name: 1-[2-(2,4-dichlorophenyl)-2-(2-propenyloxy)ethyl]-1H-imidazole

Metabolite Designation in Poultry Metabolism Study: FK858

Janssen Research Code: R042639 or bishydroxylated imazalil

Chemical Names: 3-[1-(2,4-dichlorophenyl)-2-(1H-imidazole-1-yl)ethoxy]-1,2-propanediol

or

1-[2-(2,4-dichlorophenyl)-2-(2,3-dihydroxypropoxy)ethyl]-1H-imidazole

Metabolite Designation in Poultry Metabolism Study: FK326

Janssen Research Code: R044085

Chemical Name: (±)-N-[2-(2,4-dichlorophenyl)-2-hydroxyethyl]urea

Cl

Cl

O

N N CH2

Cl

Cl

O

N N

OH

OH

Cl

Cl

OH

N

H

H2N

O
Imazalil Registration Review Scoping Document

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Table 2.2.3. Chemical Names and Structures of Imazalil and Marker Metabolites In Eggs and Poultry.

Compound Chemical Structure

Metabolite Designation in Poultry Metabolism Study: FK259

Janssen Research Code: R018238

Chemical Name: 1-(2,4-dichlorophenyl)-2-aminoethanol

Attachment 3. Imazalil International Residue Limits 

Table A.3. Summary of US and International Tolerances and Maximum Residue Limits.

Residue Definition:

 US Canada Mexico1 Codex2

§ 180.413 Imazalil; tolerances for 

residues.

(a) General . (1) Tolerances are 

established for the combined residues 

of the fungicide imazalil, 1-[2-(2,4-

dichlorophenyl)-2-(2-

propenyloxy)ethyl]-1 H -imidazole, and 

its metabolite, 1-(2,4-dichlorophenyl)-

2-(1 H -imidazole-1-yl)-1-ethanol

1-(β-allyloxy-2,4-

dichlorophenethyl)imidazol

e

Imazalil

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico1 Codex2

Banana 3.0 2 Po

Barley, grain 0.1

Barley, hay 0.5

Barley, straw 0.5

Citrus, dried pulp 25.0

Citrus, oil 200.0

Fruit, citrus, postharvest 10.0 5 citrus fruits 5 citrus fruits Po

Wheat, forage 0.5

Wheat, grain 0.1 0.01 (*)

Wheat, hay 0.5

Wheat, straw 0.5 0.1 wheat straw and 

fodder, dry

US [40 CFR §180.413(a)(2)] Canada Mexico2 Codex3

Cl

Cl

OH

H2N
Imazalil Registration Review Scoping Document

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Table A.3. Summary of US and International Tolerances and Maximum Residue Limits.

Residue Definition:

 US Canada Mexico1 Codex2

(2) Tolerances are established for 

the combined residues of the fungicide 

imazalil, 1-[2-(2,4-dichlorophenyl)-2-

(2-propenyloxy)ethyl]-1 H -imidazole, 

and its metabolites, 3-[2-(2,4-

dichlorophenyl)-2-(2,3-

dihydroxypropoxy)ethyl]-2,4-

imidazolidinedione (FK772) and 3-[2-

(2,4-dichlorophenyl)-2-(hydroxy)]-2,4-

imidazolidinedione (FK284)

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Codex3

Cattle, fat 0.01

Cattle, meat 0.01

Cattle, meat byproducts 0.2

Goat, fat 0.01

Goat, meat 0.01

Goat, meat byproducts 0.2

Horse, fat 0.01

Horse, meat 0.01

Horse, meat byproducts 0.2

Milk 0.02

Sheep, fat 0.01

Sheep, meat 0.01

Sheep, meat byproducts 0.2

MRLs with No US Equivalent

Cucumber 0.5

Gherkin 0.5

Melons, except watermelon 2 Po

Persimmon, Japanese 2 Po

Pome fruits 5 Po

Potato 5 Po

Raspberries, Red, Black 2 

Strawberry 2 

Completed: : M. Negussie; 06/10/2013

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

2 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = 

processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the 

fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.
Imazalil Registration Review Scoping Document

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Attachment A.4. Toxicity Profile Tables

Table A.4.1: Acute Toxicity.

Guideline Number and Study MRID # RESULT CATEGORY

870.1100 Acute Oral Toxicity –

Rat

00031596 LD50=227 - 343 

mg/kg

II

870.1200 Acute Dermal

Toxicity – Rabbit

41606104

44107213

LD50 2 g/kg

LD50 2 g/kg

 III

870.1300 Acute Inhalation 

Toxicity – Rat

41889802 LC50 2.0 mg/L 

LC50=2.43mg/L

 IV

870.2400 Acute Eye Irritation –

Rabbit

41606105 Irritating I

870.2500 Acute Dermal Irritation 

– Rabbit

41328801

44107216

Non-irritating

Non-irritating

IV

IV

870.2600 Skin Sensitization

Guinea Pig

41718701

40271701

Non-sensitizer

Non-sensitizer

NA

NA

Table A.4.2. Subchronic, Chronic and Other Toxicity.

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

870.3100

90-Day oral toxicity 

rats

43965704(1996)

Acceptable/non-guideline

0, 200, 400, 800 ppm

M: 0, 16, 32, 64, mg/kg/d

F: 0, 19, 38, 76 mg/kg/d

NOAEL: 200 ppm (15.8 and 18.7 mg/kg/day in ♂ and ♀, 

respectively.

LOAEL: 400 ppm (32.1 and 37.9 mg/kg/day in ♂ and ♀, 

respectively, based on increased absolute and relative liver 

weights in ♂ and ♀ at 1 month, possibly increased absolute 

and relative adrenal weights in females at 3 months, 

increased vacuolization in hepatocytes in ♀ at 1 month.

870.3100

90-Day oral toxicity 

rats

43965705(1996)

Acceptable/non-guideline

0, 800,1600, 2400, 3200 

ppm

M: 0, 65, 129, 181, 252 

mg/kg/d

F: 0, 79, 150, 236, 333 

mg/kg/d

NOAEL: <800 ppm ( 64.4 and 78.7 mg/kg/day in ♂ and ♀, 

respectively).

LOAEL: 800 ppm ( 64.4 and 78.7 mg/kg/day in ♂ and ♀, 

respectively), based on possibly decreased bw and bw gains 

in ♂ and ♀, possibly decreased triglyceride and phosholipid 

in ♂, dark and more pronounced lobulation of livers in ♀ 

possibly increased relative liver/bw ratios in ♂, mild 

hepatocellular hypertrophy in ♂ and ♀, and mild ‘fatty 

vacuolation’ in the livers of ♀.

870.3100

21/90-Day oral 

toxicity mice

43222601 & 43292402 

(1994)

Acceptable/nonguideline

0, 50, 200, 600 ppm

M: 0, 10, 39, 115 

mg/kg/day

NOAEL = 50 ppm (9.5 and 11.3 mg/kg/day in ♂ and ♀, 

respectively) 

LOAEL = 200 ppm (38.6 and 45.6 mg/kg/day in ♂ and ♀, 

respectively) based on increased incidence and severity of 

histopathologic effects, increased microsomal protein and 

increased microsomal cytochrome P450 content in the livers 
Imazalil Registration Review Scoping Document

Page 28 of 33

Table A.4.2. Subchronic, Chronic and Other Toxicity.

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

F: 0, 11, 46, 138 

mg/kg/day

of both sexes.

870.3150

90-Day oral toxicity 

Dog

See one year study See one year study

870.3200

21-Day dermal 

toxicity-Rabbit

42085201 (1991)

5/sex at 0, 10, 40 or 160 

mg/kg/day

6-day range finding at 0, 

63, 250 or 1000 

mg/kg/day

NOAEL :160 mg/kg/day

LOAEL : 250 mg/kg/day based on significant fissuring, 

scaling and swollen livers in the range finding study. No 

systemic toxicity was reported in main 21-day study.

870.3465

90-Day inhalation 

toxicity

DATA GAP

Note – if the registrant is willing to add personal protective equipment (PPE), i.e., 

PF5 or PF10 respirator, then the Agency will waive the requirement.

870.3700a

Prenatal 

developmental in 

rodents-rats

41026603 (1988)

Imazalil Sulfate technical: 

0, 40, 80 or 120 

mg/kg/day

Acceptable/guideline

Maternal NOAEL = <40 mg/kg/day

LOAEL = 40 mg/kg/day based on decreased food 

consumption

Developmental NOAEL = 40 mg/kg/day

LOAEL = 80 mg/kg/day based on decreased fetal weight

870.3700a

Prenatal 

developmental in 

rodents-mouse

41026603 (1991)

Imazalil Sulfate technical: 

0, 10, 40, 80 or 120 

mg/kg/day

Acceptable/guideline

Maternal NOAEL = 10 mg/kg/day

LOAEL = 40 mg/kg/day based on reduced bodyweight 

gains and corrected bodyweight gains

Developmental NOAEL =80 mg/kg/day

LOAEL =120 mg/kg/day based on increased resorption, 

postimplantation loss and reduced litter size

870.3700a

Prenatal 

developmental in 

rodents-mouse

44567802 (1992)

Imazalil Sulfate technical: 

0, 10, 40, 80 or 120 

mg/kg/day

Acceptable/guideline

Maternal NOAEL = 10 mg/kg/day

LOAEL = 40 mg/kg/day based on reduced bodyweight 

gains, corrected bodyweight gains and food consumption

Developmental NOAEL = 40 mg/kg/day

LOAEL = 80 mg/kg/day based on significant increase of 

fetuses and litters with extra 14th pair of ribs

870.3700b

Prenatal 

developmental in 

nonrodents - rabbit

42593601 (1992)

Imazalil Sulfate technical: 

0, 5, 10 or 20 mg/kg/day

Acceptable/guideline

Maternal NOAEL = 5 mg/kg/day

LOAEL = 10 mg/kg/day based on decreased body weight 

and food consumption and increased mortality

Developmental NOAEL = 5 mg/kg/day

LOAEL = 10 mg/kg/day based on increased resorption and 

decreased number of fetuses.

870.3800

Reproduction and 

fertility effects

2-generation, rat

42570701 & 42949402 

(1992)

0, 5, 20, 80 mg/kg/day

Acceptable/guideline

Parental/Systemic NOAEL = 20 mg/kg/day

LOAEL = 80 mg/kg/day based on decreased body weight 

gain (♂ and ♀) and increased liver vacuolation (♂).

Reproductive NOAEL = 20 mg/kg/day

LOAEL = 80 mg/kg/day based on increased duration of 

gestation.

Offspring NOAEL = 20 mg/kg/day

LOAEL = 80 mg/kg/day based on increased pup mortality 

from birth to day 4.

870.4100a

Chronic toxicity 

00162412 (1984)

18-Month study

NOAEL = 3.7 mg/kg/day

LOAEL = 15.5 mg/kg/day based on liver effects: increased 
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Table A.4.2. Subchronic, Chronic and Other Toxicity.

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

rodents - rats 0, 25, 100 or 400 ppm

47026101(1985) 

Chronic/Oncogenicity 

0, 25, 100 or 400 ppm

M: 0, 1, 3.7, 15.5 m/kg/d

F: 1.2, 4.7, 20 mg/kg/day

Unacceptable: not tested 

at adequate high dose

incidence of intracytoplasmic inclusion bodies in 

hepatocytes, increased hepatocyte vacuolization and bile 

duct proliferation.

870.4100b

Chronic toxicity 

dogs

41328802 (1989) 

12-Month Chronic Oral 

Toxicity (Capsule) -

0, 1.25, 2.5, or 20 

mg/kg/day

Acceptable/guideline

NOAEL = 2.5 mg/kg/day

LOAEL = 20 mg/kg/day, based on decreased body weight 

gain (♂ and ♀), increased alkaline phosphatase (♂ and ♀ ), 

increased liver weight (♂) and clinical symptoms of 

vomiting and soft stools.

870.4200

Carcinogenicity rats 44858001 (1999)

Chronic/Oncogenicity

0, 50, 200, 1200, 2400 

ppm

M: 0, 2.7, 10.8, 65.8, 

134.8 mg/kg/d

F: 0, 3.6, 14.6, 85.2, 

168.8 mg/kg/d

Acceptable/guideline

NOAEL = 10.8 & 14.6 mg/kg/day in ♂ and ♀ , respectively

LOAEL = 65.8 & 85.2 mg/kg/day in ♂ and ♀, respectively 

based on reductions in body weight and weight gain and 

macro and micro-scopic effects in the liver of ♂ and ♀, rats 

and thyroid of ♂ rats.

Positive for liver and thyroid neoplasm in male rats.

Classified by HED CARC (1999) as “Likely to be 

carcinogenic in humans” - with a Q1

*

of 6.11 x10-2

(mg/kg/day)-1

870.4300

Carcinogenicity 

mice

42972001 (1993)

23-Month 

Carcinogenicity in Mice

0, 50, 200 or 600 ppm

M: 0, 6.8, 28, 88 mg/kg/d

F: 0, 8.3, 35, 110 mg/kg/d

NOAEL = 50 ppm (6.8 mg/kg/day) in ♂; 200 ppm (110 

mg/kg/day) in ♀

LOAEL = 200 ppm (28 mg/kg/day) in ♂ and 600 ppm (35 

mg/kg/day) in ♀, based on increased liver histopathology

Positive for liver neoplasm in male mice.

Classified by HED CPRC (1994) and CARC (1998) as a 

Group C - Possible human carcinogen - with a Q1

*

of 6.11 

x10-2(mg/kg/day)-1

Gene Mutation

870.5100

40729301(1988)

Ames assay

5-500 μg/plate

Acceptable/guideline

Negative in Salmonella strains up to toxic concentrations of 

250-500 μg/plate with or without S-9 activation

Cytogenetics 

870.5375

40729302 (1986)

HED 006818

Acceptable, pre 1991 

guidelines

In an in vitro human lymphocytes chromosome aberration 

study, imazalil did not result in any increased chromosomal 

aberrations at concentrations ranging from 23 to 909 μg/ml 

culture

Other Effects 

870.5300

870.5395

43735003 (1988)

Acceptable, pre 1991 

guideline

00031599 (1979

HED Doc. 000057

Acceptable. Pre 1991 

guideline

In an in vitro cytogenetic study in mammalian cells (Chinese 

hamster V79 cells), imazalil, at doses ranging from 10 to 

100 μg/ml, was not mutagenic both with and without 

activation

In a mutagenicity Micronucleus Test in rats, imazalil did not 

result in any increase in micronucleated polychromatic 

erythrocytes in any of the intraperitoneally doses tested ( 0, 

20, 40 or 160 mg/kg
Imazalil Registration Review Scoping Document

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Table A.4.2. Subchronic, Chronic and Other Toxicity.

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

870.5500

870.5500

43965702 (1996)

Acceptable. 1991 

guideline

43780201(1990)

Acceptable pre 1991 

guideline

In an in vivo/in vitro unscheduled DNA synthesis assays in 

mice administered single oral doses of imazalil of 125 or 

250 mg/kg, imazalil was negative for genotoxicity but 

positive for cellular proliferation when tested at overtly toxic 

(250/ mg/kg; mortality 29/54) and cytotoxic doses

In an unscheduled DNA synthesis (UDS) assay in rat 

hepatocytes imazalil at concentrations ranging from 0.09 to 

9.0 μg/ml did not cause increased UDS.

870.6200a

Acute neurotoxicity 

screening battery

46820202 (2006)

Acceptable/Guideline

NOAEL=180 mg/kg/day

LOAEL= 600 mg/kg/day based on death in females, 

decreased body weight gain in males, and FOB and motor 

activity alterations at the time of peak effect on day 0 in 

females.

870.6200b

Subchronic 

neurotoxicity 

screening battery

Waived

870.6300

Developmental 

neurotoxicity

Waived

870.7485

Metabolism and 

pharmacokinetics

42012003 (1991)

Metabolism C14 - Rat 

Single IV dose 1.25 

mg/kg

Single oral 1.25 mg/kg

Single oral 20 mg/kg

14-day repeated oral 1.25 

mg/kg

Acceptable/guideline

14C- Imazalil rapidly absorbed, distributed, metabolized and 

excreted in roughly equal amounts in urine and feces within 

24 hours. Metabolized to more than 25 metabolites. Major 

metabolites identified. A metabolic pathway proposed. No 

significant bioaccumulation in tissues. No significant sex 

differences observed. No significant differences between 

dosing regiments.

870.7600

Dermal penetration

42913401 (1993)

Dermal Absorption-Rats

0.004, 0.04, 0.4 or 4.0 

mg/cm2

Acceptable/guideline

Peak blood concentration at 1 hour for the 0.00- 0.4 

mg/cm2; at 10 hours for the 4.0 mg/cm2. 

Percent absorption at 10 hours was 41%, 25%, 17% and 

26% and at 24 hours was 48%, 39%, 31% and 29% of the 

applied doses of 0.004, 0.04, 0.4 or 4.0 mg/cm2

870.7800

Immunotoxicity

waived
Imazalil Registration Review Scoping Document

Page 31 of 33

Attachment A.5. Summary of Toxicological Dose and Endpoints for Imazalil and Imazalil 

Sulfate

Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Imazalil and Imazalil sulfate for Use in 

Dietary and Non-Occupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/FQP

A Safety Factors

RfD, PAD, Level of 

Concern for Risk 

Assessment

Study and Toxicological 

Effects

Acute Dietary

females 13-50 

years of age

NOAEL = 5 

mg/kg/day

UFA= 10x

UFH=10x

UFDB=3x

FQPA SF= 1x

Acute RfD = 0.017 

mg/kg/day 

aPAD= 0.017 

mg/kg/day

Developmental StudyRabbits: 42593601

LOAEL = 10 mg/kg/day 

based on increased 

resorptions, decreased litter 

size 

Acute Dietary

general 

population

Not 

Applicable

NA

Chronic 

Dietary

all populations

NOAEL= 2.5 

mg/kg/day

UFA= 10x

UFH=10x

UFDB=10x

FQPA SF= 1x

Chronic RfD = 

0.0025 mg/kg/day 

cPAD = 0.0025 

mg/kg/day

12-m chronic study-dogs 

41328802

LOAEL = 20 mg/kg/day 

based on vomiting and soft 

stools, bw gain, alkaline 

phosphatase activity and 

liver weight 

Cancer (oral, 

dermal, 

inhalation)

Classification: Likely to be carcinogenic to humans; CARC 1999, HED# 013885; low-dose 

extrapolation approach for quantifying the carcinogenic risk Q1* = 6.11x10-2(mg/kg/day)-1

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. BMD = benchmark dose. BMDL = 

benchmark dose (lower confidence limit). UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). 

UFH = potential variation in sensitivity among members of the human population (intraspecies). UFDB = database uncertainty 

factor. FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE 

= margin of exposure. LOC = level of concern. N/A = not applicable. 

Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Imazalil and Imazalil sulfate for Use in 

Occupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological 

Effects

Short- term 

dermal (1 day 

to 30 days)

dermal study 

NOAEL= 160 

mg/kg/day

dermal absorption 

rate = 41%

UFA= 10x

UFH=10x

FQPA SF= 1x

Occupational LOC 

for MOE = 100

21 Day Dermal –Rabbit: 

42085201 

Skin effects and swollen 

livers at 250 mg/kg/day
Imazalil Registration Review Scoping Document

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Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Imazalil and Imazalil sulfate for Use in 

Occupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological 

Effects

Intermediateterm dermal (1-

6 months)

oral study 

NOAEL= 15.8 

mg/kg/day

dermal absorption 

rate = 41%

UFA= 10x

UFH=10x

FQPA SF= 1x

Occupational LOC 

for MOE = 100

Subchronic Study –

Rats:43965704

Severe liver effects at 32 

mg/kg/day

Long-term 

dermal (> 6 

months)

oral study 

NOAEL= 2.5 

mg/kg/day

dermal absorption 

rate = 41%

UFA= 10x

UFH=10x

FQPA SF= 1x Occupational LOC 

for MOE = 100

12-m chronic study-dogs 

41328802

LOAEL = 20 mg/kg/day 

based on vomiting and soft 

stools, bw gain, alkaline 

phosphatase activity and 

liver weight

Short- term 

Inhalation (1 

day to 30 days)

oral study 

NOAEL= 5 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Occupational LOC 

for MOE = 100

Developmental StudyRabbits: 42593601

LOAEL = 10 mg/kg/day 

based on increased 

resorptions, decreased litter 

size

Intermediateand long-term 

Inhalation (1-

> 6 months)

oral study 

NOAEL= 2.5 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Occupational LOC 

for MOE = 100

12-m chronic study-dogs 

41328802

LOAEL = 20 mg/kg/day 

based on vomiting and soft 

stools, bw gain, alkaline 

phosphatase activity and 

liver weight

Cancer (oral, 

dermal, 

inhalation)

Classification: Likely to be carcinogenic to humans; CARC 1999, HED# 013885; low-dose 

extrapolation approach for quantifying the carcinogenic risk Q1* = 6.11x10-2(mg/kg/day)-1

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). UFDB = database uncertainty factor. MOE = margin of exposure. LOC = level of concern. N/A = not 

applicable. 

Attachment A.6. Summary of Occupational Uses for Imazalil and Imazalil Sulfate

Table A.6.1. Summary of Occupational Uses Based on Registered Labels for Imazalil.

EPA Reg. No. Registration Name % ai Use site

11678-55 MAGNATE TECHNICAL 98.50 Technical label; for manufacturing use only.

43813-2 FUNGAFLOR 

TECHNICAL

98.94 Technical label; for manufacturing use only.

83991-3 IMAZALIL TECHNICAL 98.94 Technical label; for manufacturing use only in formulating products 

for seed treatment of wheat and barley.
Imazalil Registration Review Scoping Document

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Table A.6.1. Summary of Occupational Uses Based on Registered Labels for Imazalil.

EPA Reg. No. Registration Name % ai Use site

2792-51 DECCOZIL EC-289 22.20 Postharvest treatment of citrus fruits.

43813-6 FUNGAFLOR 500 EC 44.60 Postharvest treatment of citrus fruits.

66222-100 MAGNATE 75 SG 74.25 Postharvest treatment of citrus fruits.

264-976 RAXIL MD EXTRA 

FUNGICIDE

1.00 Seed treatment use on wheat, barley, and triticale.

264-997 RAXIL MD EXTRA W 

SEED TREATMENT

0.965 Seed treatment use on wheat, barley, and triticale.

66222-20 MAGNATE 500 EC 44.5 Seed treatment use on wheat and barley and for postharvest 

treatment of citrus.

83991-1 FECUNDAL 100EC 9.50 Seed treatment use on wheat and barley.

83991-2 FUNGAFLOR SEED 44.60 Seed treatment use on wheat and barley.

773-55 CLINAFARM EC 13.80 Treatment in poultry hatchery facilities/equipment.

773-56 CLINAFARM SMOKE 

GENERATOR

14.90 Treatment in poultry hatchery facilities/equipment.

53883-327 IMAZALIL 13.8 EC 13.80 Treatment in poultry and turkey hatchery facilities/equipment.

499-508 TC 246 14.00 Total release aerosol for greenhouse treatment on bedding plants, cut 

flowers, flowering hanging baskets, foliage, potted flowering plants, 

ornamentals and perennials. 

Table A6.1. Summary of Occupational Uses Based on Registered Labels for Imazalil Sulfate.

EPA Reg. No. Registration Name % ai Use site

43813-4 FUNGAFLOR 75 SP 100 Technical label; soluble powder for manufacturing use only.

43813-26 FUNGAFLOR 75 WSG 100 Postharvest treatment of citrus fruits.

43813-38 PHILABUSTER 400 SC 22.95 Postharvest treatment of citrus fruits.