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

MEMORANDUM

Date: 11/2112013: OFFICE OF CHEMICAL SAFETY AND POLL UTION 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 Ri sk Assessment Type: NA TXRNo

. : NA DP Barcode: D411858 Registration No.: N/A Regulatory Action: Registrati on Revi ew Case No.: 2325 CAS No.: 35554-44-0 (imazalil); 58594-72-2 (imazalil sulfate) MRID No.: NA 40 CFR .: 180.413



### FROM: Kar l yn Middleton, Toxicologist

# ~~ Dennis McNeilly, Chemist 

## f5J--**~c-/1/2~** Zaida Figueroa

, Industrial Hygienist

### ~ Risk Assessment Branch II ' Health Effects Division (7509P) Office ofPesticide Programs



### THROUGH: Christina 

### Swartz, Branch

# Chief**~~-__;;.­** Risk Assessment Branch II
and

### \_**..__ ~**  Jess Rowland

, Acting Associate**Directo ~**  

### Dana Vogel, Associate Director Health Effect s Division (7509 P) Office of Pe st icide Programs

TO: Margaret Hathaway, Chemical Review Manager Pesticide Re- Eval uation Division (7508 P ) Office of Pe sticide Programs

1 of33Imazalil Registration Review Scoping Docum ent

Executive Summary

The Health Effects Division (HED) has evaluated the status of the human hea lth risk assessment for imazalil and imazalil sulfate to determine the scope of work necessary to s upport the established tolerances and existing registration s 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 disinfe ction of poultry and turkey egg hatchery equipment prior to introd uction 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 ac u te toxicity profiles of the base and the sulfate salt are comparable and they are considered s imilar in their toxicological properties. The target organs for ima za lil are the thyroid and the liver.

T he 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 /l oader / apply i ng) during citrus post-harvest activities and poultry hatcheries / poultry house t reatm ents. 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 (subchron ic and developmental neurotoxicity and immunotoxicity).

The na tu re of the residue of imazalil in plants and live stock is adequately understood. The estab lished 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 -y l ) -1- ethanol]. The established tolerances for residues of imazalil in livestock commodities [40 CFR §180.413(a)(2) ] are expressed in te rm s ofthe combined residues of imazalil and 3-[2-(2,4-dichlorophenyl)-2-(2

, 3-dihydroxypropoxy)ethyl]

Page 2 of33

### Imazalil Registration Review Scoping Document

Page 3 of 33 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 curre nt guidance regarding coverage and compliance statements

. The residue chemistry database is complete with the exception of a n independent laboratory validation study required by the RED , which must be submitted to support the proposed enforcement method f

or 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 (us ed for control of Aspergillus fumigatus via a smoke generator ) and consider s these uses to be non

- food and the refore the egg and poultry fumigation study required in the February 7, 2002 HED human health risk assessment ( completed in preparation for the im azalil 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 mor e recent monitoring data for citrus commodities. Th e 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 ad dition, EFED has concluded that pending the receipt and review of additional environmental fate and tox icity 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 o f 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 risk s of concern were identified for occupational handler scenarios previously assessed, u pd ated 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

- h arvest 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 )

. A dditional 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 post

application exposures to support the greenhouse use on ornamentals/cut flowers . O ccupational post

- application (cancer and non

- cancer) assessment s will be required under registration revi ew 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.

Intro duction

HED has evaluated the most recent complete human health risk assessment for i mazalil 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 198 3 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 a nd 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 equi pment 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, f ogging, 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, w heat, 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

Page 5 of 33 The structure, the chemical names, and other identifiers can be found in the chemical identity table in A ttachment 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 o f 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 i mmunotoxicity 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 als o 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 organ s for imazalil are the thyroid and the liver. In the liver, e ffects 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 duc t 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 sub chronic 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

. N o liv er effects were seen in the definitive dermal study. Thyroid effects were observed in rats after chronic expo sure and consisted of increased absolute and relative weight as well as m icroscopic 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, t here was indication of increased qualitative susceptibility in a reproduction study in rats. I ncreased 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.

T here w ere neurotoxic effects observed in an acute neurotoxi c ity study in rats at the high dose tested. Pr ior to or on the day of death, c linical signs were observed in females that included: yellow material in the abdomen, hypoactivity, tremors, hunched posture, prostration and /or increased respiration. D ecreased motor activity and F unctional O bservational B attery (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 d ecreased 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 (Q 1* 

### ) 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 3 X due to neurotoxic i ty 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 assessment s. For dermal and inhalation risk assessments a 100 x 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 s tudies conducted with imazalil demonstrate moderate toxic ity 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, i t is not a dermal irritant (Category IV) or a skin sensitizer.

In the most recent assessment for imazalil ( D 2 80708 ), 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 resorption s 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

Page 7 of 33 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 w ith 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

. Si nce 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 stud y 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 a nd 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 100 0X, 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 cons idered. 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 stu dies 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 fumigat us 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 expres sed 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. Chen g, 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 re sidues 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

m etabolite 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 sample s 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 met hod 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 c ompounds 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, wer e 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 validatio n data indicate that the proposed GC/ECD method is adequate for collecting data on residues of imazalil, FK772, and FK284 in milk and

### Imazalil Registration Review Scoping Document

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

sa mples 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 rot ational 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 (D EEMTM) 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 dat a 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 populat ion 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

- dichloro phenyl 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 com pounds 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 k idney, 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 f

emales 13

- 50 years was 500 ppb. The estimated environmental

### Imazalil Registration Review Scoping Document

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 popu lation 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 an d 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 E stimated D rinking W ater C oncentratio n s (EDWC s ) from the 2002 drinking water assessment will be used in the registration review risk assessment.

Conclusions for Dietary Exposure

The residue chemist ry 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 n eeded 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 assessmen ts 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 aggreg ate risk assessment was perfor med 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 n o residential

uses are registered for imazalil, only acute, chronic

, and cancer aggregate risk assessments were conducted. T he acute , chronic, and cancer aggregate risk assessment s consisted of dietary exposures from food and drinking water only . The acu te 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 assessment s will be n eeded 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

I mazalil is registered for post

- harvest treatment of citrus fruits, seed treatment of barley, sudan grass and wheat prior to planting, and in greenhouse s 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 200 2 RED evaluated a number of occupational handler scenarios tha t represented the major imazalil short

- , intermediate

- and long

- term occupational handler exposure s based on application equipment and formulation type. That assessment indicated that occupational handler non

cancer scenarios resulted in risk estimates no t 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 200 2 RED indicated data requirements for post

- harvest citrus treatments. Since the

“ Exposure Study of Citrus Treatment Applicators (e.g., wax and foam applicatio ns) ” required in the 2002 RED has not been submitted to the Agency, HED will evaluate exposures from post

harvest 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

Page 12 of 33 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 protectio n 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 quantitative ly 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 p roduct 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 sc enarios and risks were not of concern

. However, s ince 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 o ccupational 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 f or body weights

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

Occupational Post

- application

The 200 2 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 wer e 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 i n the 200 2 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 addre ssing 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, we eding

, 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 pe sticide has occupational uses that could result in post

- application dermal

### Imazalil Registration Review Scoping Document

Page 13 of 33 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 c alculated 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

- sp ecific 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 der mal 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), i mazalil is classified as a Category I in an acute toxicity eye irritation study

. Typically, a ccording to WPS, a 48 hour restricted

- entry interval (REI) is assigned to chemicals with acute Category I classifications

. However, i n the 200 2 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

- ap plication activities expected in greenhouses. These REI s 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 upd ated 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 occupationa l handler exposure assessments will be required under registratio n review based upon revisions to the Agency’s scenario

- specific surrogate handler exposure data 1 

### , 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 post

application exposure associated with the greenhouse uses on ornamentals are needed to support registration review. S pecifically, c hemical

- specific DFR data are needed to support the greenhouse use on ornamentals/cut flowers. A n 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

Page 14 of 33 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 Occupation al Risk

- Pesticides (SENSOR) databases were consulted for pesticide incident data on the active ingredients imazalil and imazalil sulfate ( PC code s : 111901 and 111902). The purpose of the database search is to identify potential patterns in the frequency a nd 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, 0 7/25/2013 ). 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, Fung icide 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. a nd 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 t hat 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 store s 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 ingred ients) 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 b y registrants only as counts in what are aggregate summaries.

Imazalil For the M ain IDS, from January 1, 200 8 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

Page 15 of 33 In A ggregate IDS , from January 1, 200 8 to June 11, 2013, there were 2 reported incident s 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, 200 8 to June 11, 2013.

The SENSOR

- Pest icides 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

- Pe sticides 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 follow

up activities such as obtaining medical rec ords 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 includ ed 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 ai s listed in this case are: bifenthrin , imazalil, and chlorpyrifos

- methyl

. F ollowing 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 neurolo gical 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 (D4 12205

, 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 w arrant 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

Page 16 of 33 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)

- 1 H

- imidazole] a nd its metabolite R014821 [1

- (2,4

- dichlorophenyl)

- 2

- (1 H

- 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 informati on 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 establ ished for residues of imazalil [1

- (2

- (2,4

- dichlorophenyl)

- 2

- (2

- propenyloxy)ethyl)

- 1 H

- 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 determin ed by measuring the sum of imazalil [1

- (2

- (2,4

- dichlorophenyl)

- 2

- (2

- propenyloxy)ethyl)

- 1 H

- imidazole] and its metabolite R014821 [1

- (2,4

- dichlorophenyl)

- 2

- (1 H

imidazole

- 1

- yl)

- 1

- ethanol].”

Livestock Commodities

“Tolerances are established for residues of imazalil [1

- (2

- (2,4

- dichlorophenyl)

- 2

- (2

- propenyloxy)ethyl)

- 1 H

- 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 su m of imazalil [1

- (2

- (2,4

- dichlorophenyl)

- 2

- (2

- propenyloxy)ethyl)

- 1 H

- 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

- imidazolidinedion e (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 l ivestock commodities; therefore, a discussion of harmonization of livestock tolerance
exp ression 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 fr uits, 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 w ill 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 o n 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, fora ge 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, or iginally 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. Chi n). 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 commod ity 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. H armoniz ation 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

Page 18 of 33 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 stud ies 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 review ed 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 "Pro tection 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 ac ute, 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 tha t 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

Page 19 of 33 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 “n aturally 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 chemical s, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 3 

### and 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 list s 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 envi ronmental 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 fo r 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

Page 20 of 33 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.

D 412205 ; 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 Eligibil ity 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 Ri sk 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. Chen g; 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 S ection 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]

- 1 H

- 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 10 3 kg/m 3 Product 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 a nd 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) Pro duct Chemistry Chapter of Imazalil RED (DP# 294373, 02/01/2006, T. Morton and D. Hrdy)

Vapor pressure 3.6 x 10 - 4 Pa at 25°C Product Chemistry Chapter of Imazalil RED (DP# 294373, 02/01/2006, T. Morton and D. Hrdy) Dissociation constant, pK a pKa = 6.53 DP# 170516, 10/08/1992, P. Deschamp Octanol/water partition coefficient, Log(K OW ) log K ow 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

### 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 Cod e: 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

### Imazalil Registration Review Scoping Document

Page 23 of 33 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 Cod e: 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

### Imazalil Registration Review Scoping Document

Page 24 of 33 Tabl e 2.2.3

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

. Compound Chemical Structure
Common Name: Imazalil Janssen Research Cod e: 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)ethox y]

- 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

### Imazalil Registration Review Scoping Document

Page 25 of 33 Tabl e 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 Mexico 1 Codex 2

§ 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

- dichloro phenethyl)imidazol

e Imazalil

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 Codex 2
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 Mexico 2 Codex 3

### Imazalil Registration Review Scoping Document

Page 26 of 33 Table A.3

. Summary of US and International Tolerances and Maximum Residue Limits

. Residue Definition :

US Canada Mexico 1 Codex 2 (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 (FK77 2) and 3

- [2

- (2,4

- dichlorophenyl)

- 2

- (hydroxy)]

- 2,4

- imidazolidinedione (FK284)
Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Codex 3 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 th e fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.

### Imazalil Registration Review Scoping Document

Page 27 of 33 Attachment A

. 4. Toxicity Profile Tables

Table A

. 4.1: A cute 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

. S ubchronic, C hronic and Other T oxicity.

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 ♀, possi bly 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 ‘fatt y 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

. S ubchronic, C hronic and Other T oxicity.

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 Mat ernal 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 incr eased 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 14 th 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 Materna l NOAEL = 5 mg/kg/day LOAEL = 10 mg/kg/day based on decreased body weight and food consumption and increased mortality Developmenta l 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

### Imazalil Registration Review Scoping Document

Page 29 of 33 Table A

. 4.2

. S ubchronic, C hronic and Other T oxicity.

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 hepatocyt es, 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 w eight 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 Q 1 * 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 Q 1 * 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 activatio n

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

Page 30 of 33 Table A

. 4.2

. S ubchronic, C hronic and Other T oxicity.

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 concentrat ions 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 C 14

- 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 14 C

- Imazalil rapidly absorbed, distributed, metabolized and excreted in roughly equal amounts in uri ne 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/cm 2 Acceptable/guideline Peak blood concentration at 1 hour for the 0.00

- 0.4 mg/cm 2 ; at 10 hours for the 4.0 mg/cm 2

. 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/cm 2

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 UF A = 10x

UF H =10x UF DB =3x FQPA SF= 1x Acute RfD = 0.017

mg/kg/day aPAD = 0.017 mg/kg/day Developmental Study

Rabbits: 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 UF A = 10x

UF H =10x UF DB =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. B MD = benchmark dose. BMDL = benchmark dose (lower confidence limit). UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF DB = 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 Toxicologica l 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% UF A = 10x

UF H =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

Page 32 of 33 Table 4.5.4.2 Summary of Toxicologica l 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

Intermediate

term dermal (1

- 6 months) oral study

NOAEL= 15.8 mg/kg/day dermal absorption rate = 41% UF A = 10x

UF H =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% UF A = 10x

UF H =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 UF A = 10x

UF H =10x FQPA SF= 1x Occupational LOC

for MOE = 100 Developmental Study

Rabbits: 42593601 LOAEL = 10 mg/kg/day based on increased resorptions, decreased litter size

Intermediate

and long

- term Inhalation (1

- > 6 months) oral study

NOAEL= 2.5 mg/kg/day UF A = 10x

UF H =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. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF DB = 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

Page 33 of 33 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.