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

OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION



### MEMORANDUM

December 1, 2010

SUBJECT: Cyprodinil Human Health Risk Assessment for Amended Use and Amended

Tolerance Petition for Pome Fruit

PC Code: 288202 DP Barcode: D383614

Decision No .: 428920 Registration No.: 100-828 and 100-1317

Petition No.: 0F7696 Regulatory Action: Amended Section 3 Risk Assessment Type: Single Chemical Aggregate Case No.: 7025

TXR No.: NA CAS No.: 121552-61-2

MRID No.: NA 40 CFR: 180.532



### FROM: Becky Daiss, Biologist Bonnie Cropp-Kohlligian, Environmental Scientist Thurston Morton, Chemist

Risk Assessment Branch 4 Health Effects Division (7509P)

THROUGH: Susan V. Hummel, Branch Senior Scientist Risk Assessment Branch 4, HED (7509P)

TO: Lisa Jones, Risk Manager Reviewer Fungicide Branch Registration Division (7505P)

This document provides Health Effects Di vision’s (HED’s) risk assessment of the amended Section 3 registration for use of cyprodinil on pome fruit. Supporting documents are

listed below.

Residue Chemistry Assessment – B. Cropp-Kohlligian, D378920, 10/27/10 Dietary and Drinking Water Exposure Assessment – T. Morton, D384458, 12/01/10 Drinking Water Exposure Assessment – J. Melendez, D428848, 11//8/10

TABLE OF CONTENTS

Page 1 of 38

### Page 2 of 38 pg. 1.0 EXECUTIVE SUMMARY .................................................................................................4

2.0 INGREDIENT PROFILE ....................................................................................................7 2.1 Registered Products ........................................................................................................ .....7 2.2 Registered and Proposed New Uses ....................................................................................7 2.3 Structure, Nomenclature and Physical/Chemical Properties ...............................................8

3.0 HAZARD CHARACTERIZ ATION/ASSESSMENT ........................................................9

3.1 Hazard Characterization ................................................................................................... ..9 3.2 FQPA Hazard Considerations ...........................................................................................10 3.2.1 Neurotoxicity .......................................................................................................10 3.2.2 Developmental Toxicity ......................................................................................10 3.2.3 Reproductive Toxicity ..........................................................................................11 3.2.4 Pre-and/or Postnatal Toxicity ................................................................................12 3.2.5 FQPA Factor ..........................................................................................................12 3.3 Toxicity Endpoint Selection ..............................................................................................12

3.3.1 Acute Reference Dose – Females 13- 49...............................................................12 3.3.2 Acute Reference Dose – General Population ........................................................13 3.3.3 Chronic Reference Dose – All Populations ...........................................................13 3.3.4 Classification of Carcinogenic Potential................................................................14 3.4 Recommendation for Aggregate Exposure........................................................................14 3.5 Summary of Endpoints Selected for Risk Assessment......................................................14 3.6 Endocrine Disruption....................................................................................................... ..15

4.0 DIETARY AND DRINKING WATER EXPOSURE ASSESSMENT ............................16 4.1 Residue Chemistry Profile .................................................................................................1 6 4.1.1 Metabolism in Primary Crops, Livestock and Rotational Crops...........................16

4.1.2 Residues of Concern ..............................................................................................16 4.1.3 Residue Analytical Method ...................................................................................16 4.1.4 Residues in Crops ..................................................................................................17

4.1.5 Residues in Livestock ............................................................................................17

4.1.6 Residues in Processed Commodities .....................................................................18 4.1.7 Residues in Rotational Crops.................................................................................18 4.1.8 Storage Stability.....................................................................................................18

4.2 Drinking Water Profile .................................................................................................... ..18 4.2.1 Environmental Fate and Transport ........................................................................18 4.2.2 Estimated Drinking Water Concentrations ............................................................19 4.3 Dietary and Drinking Water Exposure and Risk ...............................................................19 4.3.1 Acute Dietary and Drinking Water Analysis.........................................................19 4.3.2 Chronic Dietary and Drinking Water Analysis......................................................20

5.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT ...............................................20

### Page 3 of 38 6.0 CUMULATIVE RISK.......................................................................................................21

7.0 DATA NEEDS................................................................................................................. ..22 7.1 Toxicity Data .............................................................................................................. .......22

APPENDICES

A. GUIDELINE TOXI COLOGY DATA SUMMARY .........................................................23 A.1 Guideline Data Requirements................................................................................23 A.2 Toxicity Profiles ....................................................................................................24

B. STUDIES REVIEWED FOR ETHICAL CONDUCT ......................................................29

C. ADDITIONAL TOXICITY STUDIES .............................................................................30

D. METABOLIC PROFILE...................................................................................................34

E. TOXICITY ST UDY REFERENCES ................................................................................33

### Page 4 of 38 1.0 EXECUTIVE SUMMARY

This assessment provides information to support an amended Section 3 registration for the use of cyprodinil on pome fruit. This document addresses the dietary and drinking water exposure and risk associated with currently registered uses and the proposed new use of cyprodinil. It provides a reassessment of tolerances (pesticide residue limits in food) to ensure that they meet the safety standard established by the Food Quality Protection Act (FQPA) of

1996.

Use Profile

Cyprodinil (4-cyclopropyl-6-methyl- N-phenyl-2-pyrimidinamine) is a systemic anilinopyrimidine fungicide. Permanent tolerances are established (40 CFR §180.532(a)) for residues of cyprodinil per se in/on a variety of crop commodities, at levels ranging from 0.02 ppm in/on almonds to 340 ppm in citrus oil. Cyprodinil is a systemic fungicide and is active through inhibition of methionine biosynthesis. Cyprodinil is applied to food crops with aircraft and ground application equipment. Cyprodinil is us ed on ornamentals and landscaped areas on golf courses and around residential, institutional, public, commercial and industrial buildings, parks, recreational areas and athletic fields. It is applied to non-food areas with ground-boom and handheld spray equipment. Since the label does not limit use to “professional” or certified applicators, the Agency believes it is possible for residential “handlers” to obtain and to apply the product. Residential exposures are limited to residential applicators since cyprodinil is used

on ornamentals but not on turf.

Proposed Amended Uses

In conjunction with this petition, Syngenta Crop Protection, Inc. is requesting an amended use of their 75% water-dispersible granular (WDG) formulation of cyprodinil, VangardTM Fungicide (EPA Reg. No. 100-828), on pome fruit to reduce the preharvest interval (PHI) from 72- to 0-days; the current maximum use rate of this product on pome fruit (0.23 lb ai/A/application (1.4 lb ai/A/season)) will remain unchanged. They are also requesting an amended use of their emulsion [oil] in water (EW) formulation of cyprodinil/difenoconazole, Inspire Super TM 

### Fungicide (EPA Reg. No. 100-1317), on pome fruit to increase the maximum use rate of cyprodinil from 0.04 lb ai/A/application (0.16 lb ai/A/season of cyprodinil from Inspire SuperTM) to 0.20 lb ai/A/application (1.0 lb ai/A/season of cyprodinil from Inspire SuperTM) and reduce the PHI from 86- to 14-days.

In addition, the petitioner, Syngenta Crop Protection, Inc. proposes to amend the tolerance in 40 CFR §180.532 for residues of the fungicide cyprodinil (2-pyrimidinamine, 4- cyclopropyl-6-methyl-N-phenyl) in or on fruit, pome, group 11 from 0.1 ppm to 1.7 ppm.

### Page 5 of 38 Hazard Identification

The toxicology database for cyprodinil is adequate for evaluating and characterizing toxicity and selecting endpoints for purposes of this risk assessment.

Cyprodinil has low acute toxicity via the oral, dermal, and inhalation routes (Toxicity Category III). Cyprodinil is mildly irritating to the eyes (Toxicity Category III) and negligibly irritating to the skin (Toxicity Category IV). It is a dermal sensitizer.

The major target organs of cyprodinil are the liver in both rats and mice and the kidney in rats. Liver effects observed consistently in subchronic and chronic studies in rats and mice include increased liver weights, increases in serum clinical chemistry parameters associated with adverse effects on liver function, hepatocyte hypertrophy, and hepatocellular necrosis. Adverse kidney effects include tubular lesions and infl amation following subchronic exposure of male rats. The hematopoietic system also appeared to be a target of cyprodinil, causing mild anemia in rats exposed subchronically. Chronic effects in dogs were limited to decreased body-weight gain, decreased food consumption and decreased food efficiency. There was no evidence of increased susceptibility in the developmental rat or rabbit study following in utero exposure or in the two-generation reproduction study following pre- or post-natal exposure. There was no evidence of neuropathological or other neurol ogical effects in the available subchronic neurotoxicity study. The results of a prelimin ary immunotoxicity study provided no evidence for immunotoxicity. There was no evidence of carcinogenic potential in either the rat chronic toxicity/carcinogenicity or mouse carcinogenicity studies.

An acute neurotoxicity study (870.6200a) is required in accordance with the revised 40 CFR Part 158 Toxicology Data Requirements. The available preliminary immunotoxicity study is considered Upgradeable/Guideline. The registrant needs to either submit the required Natural Killer cell activity assay or provide justification for why it is not needed.

Dose Response Assessment

Toxicological points of departure (PODs) we re selected for dietary and drinking water exposure scenarios. A POD for acute dietary exposure was selected for the population subgroup females 13-49 years old based on a developmental toxicity study in rabbits. No acute endpoint was identified for the remaining population subgroups. The POD for chronic dietary exposure was selected from a chronic/carcinogenicity feedi ng study in rats. An uncertainty factor of 100x was applied to PODs for both acute and chronic dietary exposure (10x for interspecies extrapolation, 10x for intraspecies variation).

Exposure/Risk Assessment and Risk Characterization

### Page 6 of 38 Risk assessments were conducted for dietary (food and water) based on registered uses and requests for reduced PHI and increased tolerance for use of cyprodinil on pome fruit. Conservative acute chronic dietary and drinking water risk assessments for cyprodinil conclude that dietary and drinking water exposure estimates are below HED’s level of concern for the general population and all population subgroups. The proposed uses do not involve residential exposure and previous assessments of worker e xposure to liquid formulations applied at higher application rates than those proposed show no risks of concern (D362494, M. Dow, 8/4/09). Therefore new occupational and residential risk assessments are not required for this action. Aggregate risks from dietary and post-application residential exposures are not of concern.

Use of Human Studies

This risk assessment is limited to dietary and drinking water exposures and does not rely on data from studies in which adult human subjects were intentionally exposed to a pesticide or

other chemical.

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development, as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

Regulatory Recommendation

Provided the petitioner submits a revised Section F, HED recommends in favor of the request to amend the registration of VangardTM Fungicide (EPA Reg. No. 100-828) to reduce the preharvest interval (PHI) on pome fruit from 72- to 0-days as well as the request to amend the registration of Inspire Super TM 

### Fungicide (EPA Reg. No. 100-1317) to increase the maximum use rate of cyprodinil on pome fruit from 0.04 lb ai/A/application (0.16 lb ai/A/season of cyprodinil from Inspire SuperTM) to 0.20 lb ai/A/application (1.0 lb ai/A/season of cyprodinil from Inspire SuperTM) and reduce the PHI from 86- to 14-days. Furthermore, HED recommends increasing the permanent tolerances for residues of cyprodinil in/on pome fruit from 0.1 ppm to 1.7 ppm

### Page 7 of 38 and in apple wet pomace from 0.15 ppm to 4.6 ppm. Tolerances should be revised, as needed, to reflect the correct commodity definitions as specified in the Chemistry Summary Document (D378920, 10/27/10).

Based on the proposed amended uses of cyprodinil on pome fruit, the currently established 0.02 ppm tolerance levels for meat byproducts of cattle, goats, horses, and sheep are adequate but the currently established tolerance expression for livestock commodities should be changed to reflect measurement of both parent and metabolite CGA-304075. Separate tolerances should be established under 40 CFR §180.532(a) for residues of cyprodinil and CGA-304075 (free and conjugated), expressed in parent e quivalents, on meat byproducts of cattle, goats, horses, and sheep at 0.02 ppm (LOQ).

2.0 INGREDIENT PROFILE

2.1 Registered Products

There are currently 5 active Section 3 cyprodinil registrations in the OPPIN data base.

Table 1. Registered Cyprodinil Products Reg # Name % ai Company Name

100-811 Cyprodinil Technical 99

100-828 Vangard WG Fungicide 75

100-953 Switch 62.5 WG 37.5

100-1317 Inspire Super 24.1

100-RGEI Palladium (Fungicide) 37.5 Syngenta Crop Protection, Inc.



### 2.2 Registered and Proposed New Uses

Cyprodinil is a systemic anilino-pyrimidine fungicide registered to Syngenta Crop Protection in the United States for use on a wide variety of fruit, nut, herb and vegetable crops for the control of various plant diseases. It is formulated as a 75% water-dispersible granule (WDG), a 62.5% WDG multiple active ingredient (MAI) product containing 37.5% cyprodinil and 25% fludioxonil, and as a 67.5% oil emulsion in water (EW) MAI containing 24.1% lb/gal cyprodinil and 8.4% of difenoconazole. The current application proposes amending existing registrations for two products. Use of VangardTM Fungicide on pome fruit would be amended to reduce the PHI from 72- to 0-days. Use of Inspire Super TM 

### Fungicide on pome fruit would be amended to increase the maximum use rate of cyprodinil from 0.04 lb ai/A/application (0.16 lb ai/A/season of cyprodinil from Inspire SuperTM) to 0.20 lb ai/A/application (1.0 lb ai/A/season of cyprodinil from Inspire SuperTM) and reduce the PHI from 86- to 14-days. In addition, the petitioner, Syngenta Crop Protection, Inc. proposes to amend the tolerance in 40 CFR §180.532 for residues of the fungicide cyprodinil (2-pyrimidinamine, 4-cyclopropyl-6-methyl-N-phenyl) in or on fruit, pome, group 11 from 0.1 ppm to 1.7 ppm. Maximum rates based on a review of active and proposed labels are provided in Table 2.Table 2. Maximum Application Rates for Cyprodinil Existing and Proposed New Uses

Application Site Max % AI Max Single AR Reg No.
root, leafy, and fruiting vegetables, legumes, citrus, pome, and stone fruits, berries, nuts, herbs. 75 1.3 lb/ai A

canola grown in Canada 62.5 0.33 lb/ai A 100-828



### 2.3 Structure, Nomenclature, and Physical/Chemical Properties

The nomenclature and physicochemical properties of cyprodinil are provided in Tables 3

and 4.

Table 3. Cyprodinil Nomenclature.

Chemical structure

N N

CH 3 N H

Common name Cyprodinil

Company experimental name CGA219417

IUPAC name (4-cyclopropyl-6-methyl -pyrimidin-2-yl)-phenyl-amine

CAS name 2-pyrimidinamine , 4-cyclopropyl-6-methyl- N-phenylCAS registry number 121552-61-2

Molecular weight 225.29

End-use products (EP) 75% water-dispersible granule (W DG) formulation (VangardTM Fungicide; EPA Reg. No. 100- 828); a multiple active ingredient (M AI) end-use product (Inspire Super TM Fungicide; EPA Reg. No. 100-1317) formulated as an emulsi on [oil] in water (EW), containing 8.4% difenoconazole and 24.1% cyprodinil

Table 4. Physicochemical Properties of Technical Grade of Cyprodinil.

Parameter Value Reference Melting point/range 75.9 C pH 9.5 at 25 C (1% aqueous dispersion) Density 1.21 g/cm 3 at 20 C Water solubility (mg/L at 25 C) 16 at pH 7.6, 20 at pH 5, 13 at pH 7, 5 at pH 9 Solvent solubility (g/L at 25 C) ethanol-160, acetone-610, toluene-460, n-octanol-160, n-hexane-30
Vapor pressure 3.8 x 10 -6 mm Hg at 25 C Dissociation constant, pK

a 4.44 at 20 C Octanol/water partition coefficient, Log(K OW ) at 25 C 3.9 at pH 5, 4.0 at pH 7, 4.0 at pH 9

UV/visible absorption spectrum (molar absorption coefficients for the absorbance maximum) 29,200 L/mol·cm at 270.8 nm (neutral) 29,200 L/mol·cm at 251.6 nm (acidic) 29,200 L/mol·cm at 316.8 nm (acidic) 28,400 L/mol·cm at 270.8 nm (basic) DP# 345970, W. Cutchin,

6/4/08



### Page 8 of 38

### Page 9 of 38 3.0 HAZARD CHARACTERIZATION/ASSESSMENT

3.1 Hazard Characterization

The toxicology database for cyprodinil is adequate for evaluating and characterizing cyprodinil toxicity and selecting endpoints for purposes of this risk assessment.

Cyprodinil has low acute toxicity via the oral, dermal, and inhalation routes (Toxicity Category III). Cyprodinil is mildly irritating to the eyes (Toxicity Category III) and negligibly irritating to the skin (Toxicity Category IV). It is a dermal sensitizer.

The major target organs of cyprodinil are the liver and the kidney. Liver effects were consistent among male and female rats and mice in both subchronic and chronic studies and typically included increased liver weights along with increases in serum clinical chemistry parameters associated with adverse effects on liver function ( i.e. , increased cholesterol and phospholipid levels). Microscopic lesions in rats and mice included hepatocyte hypertrophy and hepatocellular necrosis. In the kidneys, adverse effects were manifested as chronic tubular lesions and chronic kidney inflamation following subchronic exposure of male rats. Chronically, cyprodinil caused increased kidney weights and progressive nephropathy in male rats. Chronic effects in dogs were limited to decreased body-weight gain, decreased food consumption and decreased food efficiency; liver toxicity was not seen in the dog. The hematopoietic system also appeared to be a target of cyprodinil, causing mild anemia in rats exposed subchronically (reductions in hematocrit and hemoglobin and microcytosis). Although increases in thyroid weight and/or hypertrophy of thyroid follicular ce lls were observed at higher doses in the rat 28- day oral-toxicity studies (both feeding and oral gavage) and in the 90-day oral-toxicity study in rats, treatment-related changes in thyroid weight s or gross/microscopic observations were not observed in the chronic rat study or in other studi es (thyroid hormones were not evaluated in any study). A preliminary subchronic immunotoxicity in mice showed no treatment-related effects on absolute, adjusted, or relative spleen or thymus weights; no effects on specific activity or total activity of splenic IgM antibody-forming cells to the T cell-dependent antigen sRBC.

A subchronic neurotoxicity study showed no treatment related effects on mortality, clinical signs, or gross or histological neuropa thology. FOB and motor activity testing revealed no treatment related effects up to the highest dose tested. No clinical signs suggestive of

neurobehavioral alterations or evidence of ne uropathological effects were observed in the available oral-toxicity studies. There was also no evidence of a neurodevelopmental effect in the rat or rabbit developmental-toxicity studies or in the rat two-generation reproductive-toxicity study.

Based on pharmacokinetic/metabolism studies in the rat biphasic first order kinetics were noted for absorption and excretion of cyprodinil, with durations of 0.3-1.2 hours for the first phase, and 27-65 hours for the second phase. Excretion was rapid and almost complete, with urine as the principal route of excretion (48-68 %), and >90% of the administered dose detected

in the urine and feces within 48 hours.

### Page 10 of 38 There was no evidence of increased susceptibility in the developmental rat or rabbit study following in utero exposure or in the two-generation reproduction study following pre- and postnatal exposure. Fetal toxicity, manifested as significantly lower fetal weights and an increased incidence of delayed ossification in the rat and a slight increase in litters showing extra ribs (13 th 

### ) in the rabbit, was reported in developmental toxicity studies. In a rat two-generation reproduction study, significantly lower pup weights for F 1 

### and F 2 

### offspring were observed. However, each of these fetal/neonatal effects occurred at the same dose levels at which maternal toxicity (decreased body weight gain) was observed and were considered to be secondary to maternal toxicity.

An acute neurotoxicity study (870.6200a) is required in accordance with the revised 40 CFR Part 158 Toxicology Data Requirements. The available preliminary immunotoxicity study is considered Upgradeable/Guideline due to the omission of a NK cell activity assay. The registrant needs to either submit the NK assay or provide justification for why it is not needed.

The complete toxicity profile for cyprodinil is provided in Appendix 1.2, Tables 2 and 3.

3.2 FQPA Hazard Considerations

The toxicity database for cyprodinil is sufficient for a full hazard evaluation and is considered adequate to evaluate risks to infants and children. Acceptable developmental toxicity studies in the rat and rabbit, acceptable multi- and single generation reproduction studies in the rat, and an acceptable subchronic neurotoxicity study in the rat have been submitted.

3.2.1 Neurotoxicity

In a subchronic neurotoxicity study (MRID 45906101) cyprodinil technical (99.2%) was administered to 10 /Tif: RAIf Sprague-Dawley albino rats/sex/group at doses of 0, 80, 800, or 8000 ppm (equivalent to 0, 5.8, 54.5 and 601 mg/kg/day in males and 0, 6.3, 58.7, and 631 mg/kg/day in females). There were no treatment related effects on mortality, clinical signs, or gross or histologic neuropathology. Functional Observational Battery (FOB) and motor activity testing revealed no treatment related effects up to the highest dose tested. Based on the results of this study, the neurotoxicity LOAEL for male and female rats was not identified. The neurotoxicity NOAEL is > 8000 (601 mg/kg/day in males, 631 mg/kg/day in females.

3.2.2 Developmental Toxicity

3.2.2.1 Rat Developmental Study

In a developmental toxicity study (MRID 43709033), cyprodinil technical (99.5%) was administered in 3% aqueous corn starch su spension by oral gavage to 20-23 Tif:RAIf(SPF) females albino rats per dose of 0, 20, 200 or 1000 mg/kg/day or gestation days 6-15. Treatment related findings included reduced locomotor activity (one high dose female),

### Page 11 of 38 significantly lower mean body weight (16%), body we ight gain (65%), gravid uterine weight (18%), and mean carcass weight (10%), and significantly decreased food consumption (32-42%) in high-dose females. The LOAEL for maternal toxicity is 1000 mg/kg/day based on lower body weight/body weight gain and reduced f ood consumption. The NOAEL was 200 mg/kg/day.

There were significantly lower mean fetal weights (11%) in the high-dose group compared to controls as well as a significant increase in skeletal anomalies in the high-dose group relative to the control, which was due to abnormal ossification (4/20 litters in the high dose group compared to 0 in any other group), primarily as absent or reduced metacarpal 5

ossification. The skeletal anomalies/variations we re considered to be a transient developmental delay that occurs secondary to the maternal toxicity noted in the high-dose group. The LOAEL for developmental toxicity is 1000 mg/kg/day based on lower mean fetal weights and an increased incidence of delayed ossification. The NOAEL for developmental toxicity is 200 mg/kg/day.

3.2.2.2 Rabbit Developmental Study

In a developmental toxicity study (MRID 43709032), cyprodinil technical (99.5%) was administered in 3% aqueous corn starch suspension to 19 inseminated female rabbits (Russian Chbb:HM, SPF)/dose by gavage at dose levels of 0, 5, 30, 150, or 400 mg/kg/day from days 7 through 19 of gestation. Mean maternal body weight gain (p <0.01) and food consumption (not significant) decreased, mainly during the first week of treatment in the 400 mg/kg/day group. Mean body weight gain was 622% less than controls (p <0.01) in this group between days 7 and 13 of gestation. The maternal LOAEL is 400 mg /kg/day, based on decreased body weight gain. The maternal NOAEL is 150 mg/kg/day.

Fetuses at the 400 mg/kg/day dose exhibited indications of an increased incidence of a 13th rib (not significant). Although there were i ndications of developmental delays in fetal skeletons, such as poor or absent ossification of the sternebrae and metacarpals at all dose levels, only the extra rib is likely to be compound related. Uni- or bilateral hyperflexion of the carpal joint at the 400 and 150 mg/kg/day doses (not signi ficant) was not associated with the skeletal changes. The fetal developmental LOAEL is 400 mg/kg/day based on a slight increase of litters showing extra (13th) ribs. The fetal developmental NOAEL is 150 mg/kg/day.

3.2.3 Reproductive Toxicity

In a two-generation reproduction study (MRID No. 43709034), Tif:RAIf rats (30 rats/sex/dose), with one litter per generation received cyprodinil (99.5 %) in the diet at doses of, 10, 100, 1000 or 4000 ppm (actual intake, males: 0, 0.7, 6.7, 68 or 273; females: 0, 0.8, 8.2, 81 or 326 mg/kg/day) for a 10 week pre-mating period. Signs of toxicity at 4000 ppm consisted of lower body weights (12.5%) in the F0 females after the pre-mating period. Increased liver weight in 1000 (marginal) and 4000 ppm males and fe males was not supported by histopathologicalfindings. Although these were considered treatment related, they were considered to be nonadverse. The LOAEL for maternal systemic toxicity is 4000 ppm (about 326 mg/kg/day) based

### Page 12 of 38 on lower body weights in the F0 females during the pre-mating period. The NOAEL for maternal systemic toxicity was 1000 ppm (about 81 mg/kg/da y). Reviewers determined that pre-mating body weight gain (not absolute body weight) should be used as the basis of the NOAEL. Signs of fetal effects included significantly lower F1 and F2 pup weights in the high-dose group during lactation, which continued to be lower than controls post-weaning and after the pre-mating period (examination in F1 generation only). The LOAEL for reproductive/developmental toxicity is 4000 ppm (about 326 mg/kg/day) base d on decreased pup weights (F1 and F2). The NOAEL for reproductive toxicity is 1000 ppm (about 81 mg/kg/day).

3.2.4 Pre-and/or Postnatal Toxicity

The database is considered adequate for selection of study endpoints and determination of a dose/response to characterize the potential prenatal or postnatal toxicity of cyprodinil to infants and children. No increase in susceptibility was seen in developmental toxicity studies in rat and rabbit or reproductive toxicity studies in the rat. Toxicity to offspring was observed at dose levels the same or greater than those causing maternal or parental toxicity. Based on the results of developmental and reproductive toxicity studies, there is not a concern for increased qualitative and/or quantitative susceptibility following in utero exposure to cyprodinil.

A developmental neurotoxicity study is not required. Based on available data there is no evidence of neurotoxic potential for cyprodinil. Neurotoxicity was not observed in subchronic neurotoxicity study or the prenatal developmental toxicity studies in rats and rabbits. Although an acute neurotoxicity study is not available, the NOAEL from an acute study is unlikely to be appreciably lower than the NOAEL of 600 mg/kg/da y from the subchronic neurotoxicity study.

3.2.5 FQPA Factor

Since there are adequate developmental studies in rats and rabbits and an adequate multigeneration study in rats, no residual uncertainties that indicate the need for a factor, and no evidence of neurotoxicity based on available data, the FQPA factor has been reduced to 1X.

3.3 Toxicity Endpoint Selection

3.3.1 Acute Reference Dose (aRfD) – Females 13-49

Selected Study : Developmental toxicity in the rabbit; MRID 43709032. See Section 3.2.1

Dose and Endpoint for Establishing a POD : NOAEL = 150 mg/kg/day day based developmental LOAEL of 400 mg/kg/day was based on a slight increase in the incidence of litters showing extra (13 th 

### ) ribs, which is presumed to occur after a single exposure.

Uncertainty Factor (UF) : 100x (10x for interspecies variation and 10x for intraspecies variation)

### Page 13 of 38 Acute RfD = 150 mg/kg (NOAEL) = 1.5 mg/kg 100 (UF)



### 3.3.2 Acute Reference Dose (aRfD) – General Population

For the general population, no effects that could be attributed to a single exposure were observed in the oral-toxicity studies, including the developmental toxicity studies in rats and rabbits. Therefore, an acute RfD was not established for this population subgroup.

3.3.3 Chronic Reference Dose (cRfD) - All Populations

Selected Study: Combined Chronic Toxicity/Carcinogenicity-Rat; MRID 43737602,

44429401 and 44417902

In a 24-month chronic toxicity/oncogenicity study Tif:RAIf rats (50 rats/sex/dose - carcinogenicity portion, plus 20/sex/dose laboratory investigations) were fed diets containing 0, 5, 75, 1000 or 2000 ppm (M - 0.177, 2.7, 35.6 or 73.6 mg/kg/day; F - 0.204,3.22,41.2 or 87.1 mg/kg/day) cyprodinil (99.2-99.6%). An additi onal 10/sex/dose were fed test diets for 12 months (interim sacrifice). Survival was slightly lower in males at 2000 ppm relative to control and other dose groups. Toxicologically significan t findings included increased liver weights in high-dose males (10.7%) and a dose-related increase in the incidence of spongiosis hepatis in the liver of 1000 and 2000 ppm males (5, 5, 3, 17 and 23 %, controls to high dose). For chronic toxicity, the NOAEL was 75 ppm (2.7 mg/ kg/day) and the LOAEL was 1000 ppm (35.6 mg/kg/day) based on degenerative liver lesions (spongiosis hepatis) in males.

Dose and Endpoint for Establishing a POD : 2.7 mg/kg/day (NOAEL) based on the histopathological alterations in the liver (spongiosis hepatis) in males at 35.6 mg/kg/day (LOAEL).

Uncertainty Factor (UF) : 100x (10x for interspecies variation and 10x for intraspecies variation)

Comments about Study/Endpoint : The selected NOAEL is the lowest NOAEL observed in the most sensitive species following long-term exposure.

Chronic RfD = 2.7 mg/kg (NOAEL) = 0.027 mg/kg 100 (UF)

### Page 14 of 38 3.3.4 Classification of Carcinogenic Potential

Based on the lack of evidence of carcinogenicity in mice and rats at doses that were judged to be adequate to assess the carcinogenic potential, cyprodinil was classified as “not likely to be carcinogenic to humans”, according to EPA Proposed Guidelines for Carcinogen Risk Assessment (July 1999).

3.4 Recommendation for Aggregate Exposure Risk Assessments

When there are potential residential exposures to the pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures. Since there are no residential incidental oral exposur es to cyprodinil, aggregate exposure from food and non-food oral exposures is not required. However, an aggregate risk assessment of combined short-term dermal, inhalation and background dietary exposure is required for residential handlers because PODs selected for these exposure routes are based on common toxicological effects (i.e., liver effects).

3.5 Summary of Endpoints Selected for Risk Assessment

Toxicological doses/endpoints selected for the cyprodinil risk assessment are provided in

Table 6 and 7.

Table 6. Summary of Toxicological Doses and Endpoints for Cyprodinil for Use in Dietary Hu man Health Risk Assessments

Exposure/Scenario Point of Departure Uncertainty/F QPA Safety

Factors RfD, PAD, LOC

for Risk

Assessment Study and Toxicological Effects

Acute Dietary Females 13-50 years NOAEL = 150 mg/kg/day UFA= 10x

UFH=10x FQPA SF= 1x Acute RfD = 1.5 mg/kg/day

aPAD = 1.5 mg/kg/day Developmental Toxicity - rabbit Developmental LOAEL = 400 mg/kg/day based on slight increase of litters showing extra ribs (13 th ).

Chronic Dietary (All Populations) NOAEL= 2.7 mg/kg/day UFA= 10x

UFH=10x FQPA SF= 1x Chronic RfD =

0.027 mg/kg/day

cPAD = 0.027mg/kg/day 2-Year Chronic Toxicity/ Carcinogenicity- rat LOAEL = 35.6 mg/kg/day based on degenerative liver lesions (spongiosis hepatitis) in males.

Cancer (all routes) Classification: “Not likely to be carcinogenic to humans”
Point of Departure (POD) = A data point or an estimated point that is derived from observed dos e-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). 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.

### Page 15 of 38 Table 7. Summary of Toxicological Doses and Endpoints fo r Cyprodinil for Use in Residential Human Health Risk

Assessments

Exposure/

Scenario Point of Departure Uncertainty

Factors Level of Concern

for Risk

Assessment Study and Toxicological Effects

Dermal Short-Term (1-30 days) (dermal absorption rate = 30%) Oral NOAEL= 62 mg/kg/day UF A = 10x

UF H =10x Residential LOC

for MOE = 100 28-Day Feeding/Range-finding - rat LOAEL = 299 mg/kg/day based on decreased body-weight gain, increased cholesterol and phospholipid levels, microcytosis, and hepatocyte hypertrophy.

Inhalation Short- Term (1-30 days) Oral NOAEL= 62 mg/kg/day UF A = 10x

UF H =10x Residential LOC

for MOE = 100 28-Day Feeding/Range-finding - rat LOAEL = 299 mg/kg/day based on decreased body-weight gain, increased cholesterol and phospholipid levels, microcytosis, and hepatocyte hypertrophy.

Cancer (all routes) Not likely human carcinogen



### 3.6 Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (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 pr oceed 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.

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. This list of chemicals was selected based on the potential for human exposure through pathways such as food and water, residential activity, and certain post-application agricultural scenarios. This list should not be construed as a list of known or likely endocrine disruptors.

Cyprodinil is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all pesticide active ingredients.

For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, please visit our website:

### Page 16 of 38 http://www.epa.gov/endo/.

4.0 DIETARY AND DRINKING WATER EXPOSURE ASSESSMENT

4.1 Residue Chemistry Profile

4.1.1 Metabolism in Primary Crops, Livestock and Rotational Crops

The nature of the residue in plants is adequately understood based on acceptable metabolism studies on apple, peach, potato, tomat o, and wheat. These studies indicated that cyprodinil is metabolized primarily by hydroxylation followed by sugar conjugation. Cleavage of the amino bridge, opening of the pyrimidine ring, opening of the cyclopropyl ring and formation of thiolactic acid conjugates are minor pathways. Incorporation into starch was observed in potato tubers and wheat grain. The nature of the residue in ruminants is adequately understood based on acceptable lactating goat metabolism studies. ARIA and HED have

concluded that the residues of concern for both risk assessment and the tolerance definition should include the combined residues of cyprodinil and free and conjugated CGA-304075 (4-[(4- cyclopropyl-6-methylpyrimidin-2-yl)amino]-phenol , expressed in parent equivalents (D345970 and D345182, G. Kramer, 6/4/08). The nature of the residue in confined rotational crops is understood (DP# D257898, S. Levy, 2/8/2000). Ade quate confined rotational crop studies conducted at 2.2x and 1.5x the current maximum use rate for rotated crops (1.3 lb ai/A) are

available.

4.1.2 Residues of Concern

Residues of concern for dietary and drinking water risk assessment and tolerance expression for cyprodinil are provided in Table 8. HED recommends that the current toleranceexpression for animal commodities be changed to reflect both parent and metabolite CGA304075 (4-[(4-cyclopropyl-6-methyl-2-2-pyrimidinyl)amino]-phenol).

Table 8: Summary of MARC Decisions for Cyprodinil

Residues of Concern 1 Matrix For Risk Assessment 2 For Tolerance Expression

Plants cyprodinil cyprodinil

Livestock cyprodinil and CGA-304075 cyprodinil and CGA-304075

Water cyprodinil and CGA 249287 cyprodinil



### 4.1.3 Residue Analytical Methods

4.1.3.1 Enforcement Methods

Adequate HPLC/UV methods with column switching (Syngenta Methods AG-631 and AG-631B) are available for enforcing tolerances of cyprodinil on plant commodities. The LOQs for these methods range from 0.01 to 0.05 ppm depending on the plant commodities. Method AG-631B also contains procedures for confirmatory analysis by GC/NPD.

### Page 17 of 38 An adequate HPLC/MS method (GRM010.01A) is also available for enforcing tolerances in livestock commodities. This method determines residues of both parent and the metabolite CGA-304075 (free and conjugated), expressed as parent. The LOQ is 0.01 ppm for each analyte for a combined LOQ of 0.02 ppm.

4.1.3.2 Multiresidue Methods

Data are available depicting the recovery of cyprodinil and its metabolite CGA-232449 through FDA Multiresidue method testing protocols (C through E). Acceptable recoveries were obtained for cyprodinil in apples fortified at 0.40 ppm using Protocol D. These data were forwarded to FDA (G. Kramer, 11/28/1995).

4.1.4 Residues in Crops

There is adequate number and geographic location of apple and pear field trials conducted with a WDG formulation of cyprodinil to support the proposed amended uses on pome fruit. Syngenta Crop Protection submitted residue data from 12 apple field trials conducted in the U.S. in Zones 1, 2, 5, 9, 10, and 11 and from 6 pear field trials conducted in the U.S. in Zones 1, 10, and 11 using a water-dispers ible granular (WDG) formulation containing 75% cyprodinil. Residues of cyprodinil in/on apples and pears harvested at 0 days after the last application (DALA) following five broadcast folia r applications of a 75% WDG formulation of cyprodinil at a rate of 0.2286-0.263 lb ai/A/application with a retreatment interval of 6-9 days were 0.17-1.4 ppm and 0.11-0.73 ppm, respectively. The data support a reduction of PHI to 0- days for the amended use of the WDG formulation on pome fruit. The data also support an increased maximum use rate of 0.20 lb ai/A/application (1.0 lb ai/A/season of cyprodinil) and a reduced PHI of 14-days for the EW formulation of cyprodinil/difenoconazole.

4.1.5 Residues in Livestock

Adequate cattle feeding studies are available for cyprodinil. Since, apple wet pomace may be fed locally to dairy cattle, the maximum daily burdens (MDBs) were recalculated for this action. The MDB for livestock to cyprodinil was recalculated to be 0.88 ppm for beef cattle, 1.2 ppm for dairy cattle, and 0.005 ppm for swine and poultry. Based on the proposed amended uses of cyprodinil on pome fruit, the currently established 0.02 ppm tolerance levels for meat byproducts of cattle, goats, horses, and sheep are adequate but the currently established tolerance expression for livestock commodities should be changed to reflect measurement of both parent and metabolite CGA-304075. Separate tolerances should be established for residues of cyprodinil and free and conjugated CGA-304075, expr essed in parent equivalents, on meat byproducts of cattle, goats, horses, and sheep at 0.02 ppm (LOQ).

4.1.6 Residues in Processed Commodities

### Page 18 of 38 Based on the submitted apple field trial and available apple processing data (MRID 44186417; DP# D233182, PP# 6F4656, G. Kramer, 2/20/98), the currently established tolerance for residues of cyprodinil in apple wet pomace will need to be increased from 0.15 ppm to 4.6 ppm to cover the proposed amended uses of cyprodinil on pome fruit.

4.1.7 Residues in Rotational Crops

An adequate field accumulation study with mustard greens as the primary crop and rotational crops of wheat, lettuce and garden beets planted at plant back intervals (PBIs) of 27 to 32 days showed residues of parent and each metabolite <LOQ in/on all lettuce, garden beet and wheat RAC samples. This study supports the label specified 30-day PBI and indicates that rotational crop tolerances are not currently required.

4.1.8 Storage Stability

In the submitted field trial study, apple and pear samples were stored frozen (-20°C ± 10°C) for up to 11.7 months prior to analysis. No storage stability data were submitted with the field trials. Adequate data are available indicati ng that cyprodinil is stable in/on peaches, apples, and apple pomace for at least 12 months when stored frozen (DP# D233182, G. Kramer, 2/20/98); these data are adequate to support the submitted apple and pear field trial data.

4.2 Drinking Water Profile

4.2.1 Environmental Fate and Transport

The environmental fate data base for cyprodinil is considered substantially complete. Cyprodinil has a relatively low solubility in water (13 ppm at pH 7). Based on its octanol/ water partition coefficient, it is likely to partition with organic tissues and other organic media. It is alkaline in water (pH 9.5 and pKa = 4.44). It is not likely to volatilize substantially, with a vapor pressure of 3.80x10 -6 

### mmHg and a Henry’s Law constant of 7.04x10 -8 

### Atm-m 3 

### /mol at 20°C. Cyprodinil binds to sediment and particulate. It appears to be a persistent compound under most conditions, except aerobic soil metabolism, as demonstrated in laboratory studies. Cyprodinil appears to bind strongly to particulate and sediment, showing relatively low soil mobility (K OC 

### range 1550 to 2030); its potential for groundwater contamination appears to be low. However, due to its high persistence under aquatic conditions, aquifers that lie below areas that have low organic content and coarse textured soils or shallow leaky aquifers could be prone to contamination. Even though buffer zones can ameliorate moderately the level of spray drift, the potential for runoff still exists for long periods of time. Cyprodinil’s high affinity to sorb to soil and particulate suggests the potential for runoff in eroded particles. This stability and binding to particulate and organic matter (aerobic and anaerobic conditions) suggests that cyprodinil residues in sediments could contribute to a possible resuspension of the compound through mixing and mass balance for an extended period. Degradates of cyprodinil include 4- cyclopropyl-6-methyl-2-amine-pyrimidine, CGA-275535 (slightly mobile), CGA-321915 (mobile to moderately mobile), and CGA-249287 (moderately mobile) (the degradate identified

### Page 19 of 38 of concern in this assessment; 11.7% at 28 days in the aerobic soil metabolism study, and 14.2% in the aerobic aquatic metabolism study). The water residues of concern as determined by MARC are the parent and CGA 249287 (4-cyclopropyl-6-methylpyrimidin-2-amine) (D292557, 6/8/03).

4.2.2 Estimated Drinking Water Concentrations

Drinking water residues were incorporated di rectly into the chronic dietary analysis (“water, direct, all sources” and “water, indirect, all sources”) and were provided by the Environmental Fate and Effects Division (EFED). EFED generated the surface water estimates using the linked PRZM and EXAMS tier 2 aquatic models. Ground water estimates were calculated using the Tier 1 Screening Concentration in Ground Water model. Estimated Drinking Water Concentrations (EDWCs) for cyprodinil and its metabolite CGA-249287 were derived based on a maximum application rate of 1.4 lb a.i./A on grapes. Combined surface water EDWCs for cyprodinil and the CGA-249287 metabolite used in the exposure assessment, are provided in Table 9.

Table 9. EDWCs for the Cyprodin il Human Health Risk Assessment Drinking Water Source Peak ( μ g/L) Annual Mean ( μ g/L)

Surface Water 34.79 24.65

Ground Water 0.0861 0.0861



### 4.3 Dietary and Drinking Water Exposure and Risk

Screening-level acute and chronic dietary and drinking water exposure and risk assessment was conducted using the Dietary Exposure Evaluation Model with the Food Commodity Intake Database (DEEM-FCIDTM). Dietary risk assessment incorporates both exposure and toxicity of a given pesticide. For acute and chronic dietary assessments, the risk is expressed as a percentage of a maximum acceptable dose (i.e., the dose which HED has concluded will result in no unreasonable adverse health effects). This dose is referred to as the population adjusted dose (PAD). The PAD is equivalent to the reference dose (RfD) divided by the additional Safety Factor, if applied. For acute and non-cancer chronic exposures, HED is concerned when estimated dietary risk exceeds 100% of the PAD.

4.3.1 Acute Dietary and Drinking Water Analysis

A screening level acute dietary exposure analysis was performed for the population subgroup females 13-49 only. No acute endpoint was identified for the remaining population subgroups. Tolerance level residues and 100 crop treated assumptions were used. DEEM default and empirical processing factors were used to modify the tolerance values. The acute analysis incorporated the 1 in 10 year peak surface drinking water estimate from application of cyprodinil to grapes. The resulting 95th percentile acute exposure estimate for females 13-49 years old is not of concern to HED (4% acute population adjusted dose (aPAD)).

Table 10: Summar y of Acute Dietar y Ex p osure and Risk for C yp rodinil

### Page 20 of 38 Acute ( 95th Percentile ) Population Subgroup aPAD (mg/kg/day) Exposure (mg/kg/day) %aPAD

Females 13-49 y ears ol d 1.5 0.0554 4



### 4.3.2 Chronic Dietary and Drinking Water Analysis

A moderately refined chronic dietary exposure analysis was performed for the general U.S. population and various population subgroups. Average field trial residues for pome fruit, tolerance level residues for the remaining commodities, and 100 % crop treated assumptions were used. DEEM default and empirical processing factors were used to modify the tolerance values. The chronic analysis incorporated the 10 year average surface drinking water estimate from application of cyprodinil to grapes. Chroni c dietary risk estimates are not of concern for general population or other population subgroups. The subgroup with the highest risk estimate was children 1-2 years old with a cPAD of 86%. The cPAD for the general U.S. population was

43%.

Table 11: Summar y of Chronic Dietar y Ex p osure and Risk for C yp rodinil

Chronic Population Subgroup cPAD (mg/kg/day) Exposure (mg/kg/day) % cPAD

General U.S. Po p ulation 0.0129 43

All Infants ( < 1 y ear old ) 0.0131 44

Children 1-2 y ears ol d 0.0257 86

Children 3-5 y ears ol d 0.0216 72

Children 6-12 y ears ol d 0.0143 48

Youth 13-19 y ears ol d 0.0107 36

Adults 20-49 y ears ol d 0.0121 40

Adults 50+ y ears ol d 0.0117 39

Females 13-49 y ears ol d 0.027

0.0125 42



### 5.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT

In accordance with the FQPA, when there are potential residential exposures to a pesticide, aggregate risk assessment must consider exposures from three major routes: oral, dermal, and inhalation. There are three sources for these types of exposures: food, drinking water, and residential uses. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. An aggregate risk assessment of combined short-term dermal, inhalation and oral exposure is required for residential handlers because PODs selected for these exposure routes are based on common toxicological effects (i.e., liver effects). MOEs for residential exposure are provided in Table 12. Aggregate MOEs for food, water and residential exposure are provided in Table 13.

Table 12. Estimated Cyprodinil Exposure & MOEs for Short-Term Residential Handler Exposure - LOC/MOE = 100;

### Page 21 of 38 Exposure

Scenario 1 Inhalation

Unit Exposure (ug/lb ai) 2 Dermal Unit Exp (mg/lb ai) 2 App

Rate (lbai/G) 3 Area

Treated (G/day) 4 Inhalation

Dose (m/k/d) 5 Inhalatio

n MOE 6 Dermal

Dose (m/k/d) 7 Dermal

MOE 8 Agg

MOE 9

Mixing/Loading/Applying WDG – Ornmentals Handheld Pump Sprayer 3.8 56 0.0000004 > 1000000 0.0017 37000 37000

Backpack Spray 30 5.1 0.000003 > 1000000 0.0002 410000 400000
Hose-end Spray 1.5 39 0.0014 5

0.0000002 > 1000000 0.0012 53000 53000

1 Use patterns are from the proposed labels.

2 Baseline unit exposures are assumed for all residential exposur e senarios. Unit exposures for and-held pump sprayer and hose- end sprayer are from the ORETF study OMA-005 MRID 445185-01 Unit exposures for backpack sprayer are reported in the PHED Surrogate Exposure Guide dated August 1998.

3 Application rates are based on maximum values base d on proposed label presented as lb ai/gallon).

4 Amount treated is based on the area or gallons that can be r easonably applied in a single day for each exposure scenario of co ncern based on the application method and formulation/packagi ng type. (Standard EPA/OPP/HED values).

5 Inhalation dose (mg/kg/day) = [unit exposure (ug/lb ai) * 0. 001 mg/ug unit conversion * Inhala tion absorption (100%) * Applica tion rate (lb ai/acre or lb ai/gallon) * Daily area treated/amount handled (acres or gallons)] / Body weight (60 kg).

6 Inhalation MOE = short-term endpoint for i nhalation (NOAEL 62 mkd)/ Daily Inhalation Dose.

7 Dermal Dose (mg/kg/day) = [unit exposure (mg/lb ai) * Applica tion rate (lb ai/acre or lb ai/gallon) * Daily area treated/amoun t handled (acres or gallons) * Dermal Absorption Factor (30%)] / Body weight (60 kg).

8 Dermal MOE = short-term endpoint for dermal (NOAEL 62 mkd)/Daily Dermal Dose.

9 Aggregate MOE = Inhalation/Dermal short-term endpoint (NOAEL (62 mkd)/Daily Inhalation Dose + Daily Dermal Dose

Table 13. Short-Term Aggregate Risk Assessment for Cyprodinil

Residential Handler Exposure Scenario Food + Water Exposure (mg/kg/day) 1 Residential Exposure, (mg/kg/day) 2 MOE

Food + Water + Residential 3

Mixing/Loading/Applying WDG – Ornmentals
Handheld Pump Spray 0.0017 4400

Backpack Spray 0.0002 5200

Hose-end Spray 0.012

0.0012 4400

1 Chronic Dietary/Drinking Water Exposure (mkd) (Adults 20-49 years old)

2 Residential Exposure = Inhalation Daily Dose + Dermal Daily Dose (mkd)

3 Aggregate Food/Water/Residential MOE = Inhalation/Dermal S hort-term endpoint (NOAEL 62 mkd)/Food & Water Exposure (mkd) + Residential Exposure (mkd)



### 6.0 CUMULATIVE RISK

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider “available information” concerning the cumulative effects of a particular pesticide's residues and “other substances that have a common mechanism of toxicity.”

EPA does not have, at this time, available data to determine whether cyprodinil has a common mechanism of toxicity with other substances. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to cyprodinil and any other substances and, cyprodinil does not appear to produce a toxic metabolite produced by other substances which have tolerances in the U. S. For the purposes of this tolerance reassessment action, therefore, EPA has not assumed that cyprodinil has a common mechanism of toxicity with other

### Page 22 of 38 substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s OPP concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on

EPA’s website at http://www.epa.gov/fedrgstr/EPA_PEST/2002/January/Day_16/

.



### 7.0 DATA NEEDS

7.1 Toxicity

- Immunotoxicity Study (GLN 870.7800) (The available preliminary immunotoxicity study is considered Upgradeable/Guideline due to the omission of a NK cell activity assay. The registrant needs to either submit the assay or provide justification for why it is not needed.) - Acute Neurotoxicity Study (GLN 870. 6200a) - 28-day dermal toxicity study in rats (GLN 870.3200) (required in prior assessment)

### Page 23 of 38 APPENDICES

A. TOXICOLOGY DATA SUMMARY

A.1 Guideline Data Requirements

Table 1. Guideline Data Requirements

Technical Test Required Satisfied

870.1100 Acute Or al Toxi city .......................................................

870.1200 Acute De rmal Toxi city ..................................................

870.1300 Acute Inha lation Toxi city .............................................. 870.2400 Primary Eye Irrita tion .................................................... 870.2500 Primary De rmal Irrita tion ..............................................

870.2600 Dermal Sensitiza tion...................................................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subc hronic (rode nt) ...............................................

870.3150 Oral Subc hronic (nonr odent) .........................................

870.3200 21-Da y Dermal ..............................................................

870.3250 90-Da y Dermal .............................................................. 870.3465 90-Day Inhalatio n .......................................................... yes

yes

yes

no

yes yes

yes

no

-

no

870.3700a Developmental Toxicity (r odent)................................... 870.3700b Developmental T oxicity (nonr odent).............................

870.3800 Re productio n ................................................................. yes

yes

yes yes

yes

yes

870.4100a Chronic Toxi city (rode nt) ..............................................

870.4100b Chronic Toxic ity (nonrode nt) ........................................ 870.4200a Oncogeni city (ra t) .......................................................... 870.4200b Oncogenic ity (mous e)....................................................

870.4300 Chronic/ Oncogeni city.................................................... yes a

yes

yes a

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gen e Mutation - b acterial ..................... 870.5300 Mutagenicity—Gen e Mutation - mammalian ................ 870.5375 Mutagenicity—Structural Chromosomal Aberrations ... 870.5900 Mutagenicity—Other Genotoxic Effects ....................... yes

yes

yes

yes yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen) ..................................... 870.6100b 90-Day Neurot oxicity (h en)...........................................

870.6200a Acute Neurotox. Sc reening Batte ry (rat)........................ 870.6200b 90-Day Neuro. Scr eening Battery (rat)..........................

870.6300 Devel op. Neuro.............................................................. no

no

yes

yes

no -

-

no

yes

-

870.7485 Genera l Metabo lism.......................................................

870.7600 Dermal Penetra tion ........................................................

870.7800 Imm unotoxic ity.............................................................. yes

no

yes yes

yes

no

a Guideline 870.4300 satisfies guideline 870.4100a and 870.4200a.

### Page 24 of 38 A.2 Toxicity Profiles

Table 1 Acute Toxicity of Cyprodinil.

Guideline No. Study Type MRIDs # Results Toxicity Category

870.1100 Acute Oral 43709014 LD 50 = 2796 mg/kg III

870.1200 Acute Dermal 43709016 LD 50 > 2000 mg/kg III

870.1300 Acute Inhalation 43709018 LC 50 = 1.2 mg/L III

870.2400 Primary Eye Irritation 43709021 mild/mod irritant III

870.2500 Primary Skin Irritation 43709022 very slight irritant IV

870.2600 Dermal Sensitization 43709024

44392102 positive NA

Table 2.. Toxicity Profile of Cyprodinil Technical.

Guideline No./

Study Type MRID No. (year)/

Classification /Doses Results

870.3100 90-Day oral toxicity (mouse) 43709027 (1991) Acceptable/guideline 0, 500, 2000, 6000 ppm M: 0, 73.3, 257, 849 mg/kg/day F: 0, 103, 349, 1121 mg/kg/day NOAEL = 73.3/103 mg/kg/day, M/F LOAEL = 257/349 mg/kg/day, M/F, based on histopathological changes in the liver

870.3100 90-Day oral toxicity (rat) 43709026 (1991) Acceptable/guideline 0, 50, 300, 2000, 12,000

ppm M: 0, 3.14, 19, 134, 810 mg/kg/day F: 0, 3.24, 19.3, 137, 803 mg/kg/day NOAEL =3.14 mg/kg/day LOAEL = 19 mg/kg/day based on increased tubular kidney

lesions in males

Non-guideline 28-Day Feeding/ Range Finding (rat) 43866301 (1989)Acceptable/Nonguideline 0, 100, 600, 3000, 15000

ppm M: 10.3, 64.8, 316, 1460 mg/kg/day F: 0, 10.1, 62.2, 299, 1390 mg/kg/day NOAEL = 64.8/62.2 mg/kg/day, M/FLOAEL = 316/299 mg/kg/day, M/F, based on lower bodyweight gains, microcytosis, increase cholesterol and phospholipid levels, and hepatocyte hypertrophy

Non-guideline 28-Day Gavage/ Range Finding (rat) 43737601 (1991)Acceptable/Nonguideline 0, 10, 100 1000 mg/kg/day NOAEL = 10 mg/kg/day LOAEL = 100 mg/kg/day based on increased liver weights and abnormalities in liver morphology

870.3150 90-Day oral toxicity 43709028 (1991) Acceptable/Guideline NOAEL =210/232 mg/kg/day, M/F LOAEL = 560/581 mg/kg/day, M/F, based on lower body-

### Page 25 of 38 Table 2.. Toxicity Profile of Cyprodinil Technical.

Guideline No./

Study Type MRID No. (year)/

Classification /Doses Results

(dog) 0, 200, 1500, 7000, 20000

ppm M: 0, 6.07, 45.85, 210.33, 559.66 mg/kg/day F: 0, 6.79, 52.75, 231.93, 580.95 mg/kg/day weight gains and decreased food consumption in both sexes

870.320021/28-Day dermaltoxicity (rat) 43709029 (1991) Unacceptable/

Guideline 0, 5, 25, 125, 1000 mg/kg/day NOAEL = 25/125 mg/kg/day, F/M LOAEL = 125/1000 mg/kg/day, F/M, based on clinical signs (hunched posture and/or piloerection).

870.3700a

Prenatal developmental (rat) 43709033 (1991) Acceptable/Guideline 0, 20, 200, 1000 mg/kg/day Maternal NOAEL = 200 mg/kg/dayLOAEL = 1000 mg/kg/day based on lower bodyweight/body-weight gain and reduced food consumption Developmental NOAEL = 200 mg/kg/day LOAEL = 1000 mg/kg/day based on lower mean fetal weights and increased incidence of delayed ossification

870.3700b

Prenatal developmental (rabbit) 43709032 (1991) Acceptable/Guideline 0, 5, 30, 150, 400 mg/kg/day Maternal NOAEL = 150 mg/kg/day LOAEL = 400 mg/kg/day based on decreased body-weight gain Developmental NOAEL = 150 mg/kg/day LOAEL = 400 mg/kg/day based on slight increase of litters showing extra (13 th ) ribs

870.3800 Reproduction and fertility effects (rat) 43709034 (1993) Acceptable/Guideline 0, 10, 100, 1000, 4000

ppm M: 0, 0.7, 6.7, 68, 273 mg/kg/day F: 0, 0.8, 8.2, 81, 326 mg/kg/day Maternal/Systemic NOAEL = 81 mg/kg/day LOAEL = 326 mg/kg/day based on decreased body weight gain in the F0 females during the pre-mating period. Reproductive/Developmental NOAEL = 81 mg/kg/day LOAEL = 326 mg/kg/day based on decreased pup weights (F1 and F2)

870.4300 Chronic toxicity/ Carcinogenicity (feeding) (rat) 43737602 (1994) Acceptable/Guideline 0, 5, 75, 1000, 2000 ppm M: 0, 0.177, 2.7, 35.6, 73.6 mg/kg/day F: 0, 0.204, 3.22, 41.2, 87.1 mg/kg/day NOAEL = 2.7 mg/kg/day LOAEL = 35.6 mg/kg/day based on degenerative liver lesions (spongiosis hepatis) in males

No evidence of carcinogenicity

870.4100b Chronic toxicity (dog) 43709030 (1991) 0, 25, 250, 2500, 15000 M: 0, 0.72, 6.87, 65.35, 449.25 mg/kg/day F: 0, 0.76, 6.80, 67.99, NOAEL = 65.63/67.99 mg/kg/day, M/F LOAEL = 449.25/446.3, M/F, mg/kg/day based on lower body-weight gains and decreased food consumption and food efficiency

### Page 26 of 38 Table 2.. Toxicity Profile of Cyprodinil Technical.

Guideline No./

Study Type MRID No. (year)/

Classification /Doses Results

446.37 mg/kg/day

870.3200 Carcinogenicity - (mouse) 43709031, 44417902 Acceptable/Guideline 0, 10, 150, 2000, 5000

ppm M: 0, 1.15, 16.1, 212.4, 630 mg/kg/day F: 0, 1.08, 14.7, 196.3, 558.1 mg/kg/day NOAEL = 16.1 mg/kg/day LOAEL = 212.4 mg/kg/day based on a dose-related increase in the incidence of focal and multifocal hyperplasia of the exocrine pancreas in males

No evidence of carcinogenicity

870.7800 Immunotoxicity (mouse) 48293501 Upgradeable/Guideline 0, 500, 2000, 5000 ppm 0, 103.8, 468.3, 1245.3 mg/kg/day NOAEL > 1245.3 mg/kg/day LOAEL > 1245.3 mg/kg/day There were no cyprodinil-related effects on absolute, adjusted, or relative spleen or thymus weights; no effects onspecific activity or total activity of splenic IgM antibodyforming cells to the T cell-dependent antigen sRBC.

870.6200b

Subchronic Neurotoxicity 45906101 Acceptable/Guideline 0,80, 800, 8000 ppm M: 0, 5.8, 54.5, 601 F: 0, 6.3, 58.7, 631 mg/kg/day Neurotoxicity NOAEL > 601 mg/kg/day M; 631 mg/kg/day

F Neurotoxicity LOAEL > 601 mg/kg/day M; 631 mg/kg/day

F Systemic toxicity NOAEL = 54.5 mg/kg/day M; 58.7 mg/kg/day F Systemic LOAEL = 601 mg/kg/day M; 631 mg/kg/day F based on decreased body weight gain and microscopic lesions in the liver (hepatocellular hypertrophy), kidney (tubular casts) and thyroid gland (follicular cell hypertrophy)

870.5100

Gene Mutation -

Bacteria 43709037 (1990) Acceptable/Guideline In a reverse gene mutation assay with Salmonella typhimurium/Escherichia coli , cyprodinil was negative up to concentrations ( ≥ 1250 μ g/plate +/-S9) that produced reproducible cytotoxicity for the majority of strains. Compound insolubility was reported at ≥ 313 μ g/plate.

870.5300

Gene Mutation -

In vitro mammalian

cell 43709036 (1990) Acceptable/Guideline In a Chinese hamster V79 cell HGPRT forward gene mutation assay, cyprodinil was negative up to cytotoxic concentrations ( ≥ 96.0 μ g/mL with S9) ( ≥ 24 μ g/mL without S9).

870.5375 Cytogenetics/

In vitro

Chromosomal

Aberration 43709038 (1991) Acceptable/Guideline In an in vitro assay for chromosome aberrations in Chinese hamster ovary (CHO) cells, cyprodinil gave negative results up to cytotoxic concentrations ( ≥ 50 μ g/mL without S9, 18-

or 42-hour cell harvest or ≥ 25 μ g/mL with S9, 18- hour cell harvest) or to the highest sub-cytotoxic concentration (50

μ g/mL with S9, 42-hour cell harvest).

870.5395 Cytogenetics/

In vivo bone marrow 43709039 (1990) Acceptable/Guideline In an in vivo bone marrow micronucleus assay, cyprodinil was negative when administered orally (gavage) at 5000 mg/kg (HDT) to both sexes of Tif:MAGF mice. No signs of

### Page 27 of 38 Table 2.. Toxicity Profile of Cyprodinil Technical.

Guideline No./

Study Type MRID No. (year)/

Classification /Doses Results

micronucleus overt toxicity or clear ev idence of cytotoxicity for the target organ were noted at any dose or sacrifice time.

870.5550

UDS 43709035 (1991) Acceptable/Guideline In an UDS assay in primary rat hepatocytes, cyprodinil was negative up to a cytotoxic concentration (80 μ g/mL)

870.7485

Metabolism and pharmacokinetics 43709040 (1992) Acceptable/Guideline Single oral doses (0.5 or 100 mg/kg bw) of phenyl or pyrimidyl-radiolabelled CGA 219417 (purity ≥ 98%) were administered to Tif:RAIf(SPF) rats, with one low-dose group receiving unlabelled CGA 219417 (purity ≥ 99%) for 2 weeks prior to treatment with radiolabelled compound. Absorption was very rapid (t

cmax = 0.3 hours) with rapid clearance (t cmax/2 =1.2 hours). A minimum of 75% of the administered dose was absorbed. Excretion was rapid and almost complete, with urine as the principle route of excretion (48-68%), and >90% of the administered dose detected in the urine and feces within 48 hours. Excretion, distribution and metabolite profiles were essentially independent of dose level, pretreatment, and type of label,although there were some quantitative differences sexdependent qualitative differences in two urinary metabolite

fractions.

870.7485

Metabolism and pharmacokinetics 43709041 (1992) Acceptable/guideline Must be considered with MRID 43709040.

Excreta (Group D1 and D2) and bile (Group G1) from radiolabelled CGA 219417-treated Tif:RAIf(SPF) rats of a previous ADME study (MRID 43709040) were used to characterize, isolate and identify CGA 219417 metabolites (MRID 43709041). Eleven metabolites were isolated from urine, feces and bile, and the metabolic pathways in the rat were proposed. All urinary and biliary metabolites (with the exception of 7U) were conjugated with glucuronic acid or sulfonated, and excreted. CGA 219417 was almost completely metabolized by hydroxylation of the phenyl ring (position 4) or pyrimidine ring (position 5), followed by conjugation. An alternative pathway involved oxidation of the phenyl ring followed by glucuronic acid conjugation. A quantitative sex difference was observed with respect to sulfonation of the major metabolite that formed 6U. The monosulfate metabolite (1U) was predominant in females, whereas equal amounts of mono- and disulfate (6U) conjugates were noted in males. Most of the significant metabolites in feces were exocons of biliary metabolites (2U, 3U, 1G). These were assumed to be deconjugated in the intestines, partially reabsorbed into the general circulation, conjugated again, and eliminated renally. The major metabolic pathways of CGA 219417 were not significantly influenced by the dose, treatment regimen, or

### Page 28 of 38 Table 2.. Toxicity Profile of Cyprodinil Technical.

Guideline No./

Study Type MRID No. (year)/

Classification /Doses Results

sex of the animal.

870.7600 Dermal Absorption (rat) 45906102 (1999)

In review 6 μg/cm 2 or 870 μg/cm 2 In a dermal absorption study with CGA 219417 formulated as SWITCH 62.5 WG in the rat, the maximum systemic absorption was 21.71% (at 24 hours). An additional 12% of the applied dose (that is potentially available for absorption)

remained on the treated skin at 24 hours.

### Page 29 of 38 B. STUDIES REVIEWED FOR ETHICAL CONDUCT

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task Force members Health Canada, U.S. Environmental Protection Agency, and the National Agricultural Chemicals Association, released February, 1995.

Agricultural Re-entry Task Force (ARTF) data base (SOP #3.1)

### Page 30 of 38 B. ADDITIONAL TOXICOLOGY STUDIES

Dermal Toxicity – Rat (MRID 43709029)

The HIARC downgraded the 28-day dermal-toxicity study in the rat (MRID 43709029)to Unacceptable/Guideline and recommended the submission of an acceptable 28-day dermaltoxicity study. This study was reclassified as Unacceptable by the July 9, 2002 HIARC because: 1) Cyprodinil has marginal toxicity via the dermal route (LD 50 

### >2000 mg/kg); 2) The chemical structure does not suggest dermal absorption; 3) There is no pattern of toxicity that is consistent with the other toxicity studies. For example, there is a questionable sex specificity ( i.e. , a 40- fold difference was noted between the original LOAEL for females (25 mg/kg/day) and males (1000 mg/kg/day) that has not been observed in acu te, subchronic or chronic studies in rat, rabbit or dog test species. Similarly, clinical signs used to set the LOAEL for females (piloerection and/or hunched posture) are suggestive of a neurotoxic effect. However, there is no evidence of neurotoxicity in repeated dose studies throughout the cyprodinil database. The HIARC also recommended that the LOAEL/NOAEL for females be increased to 125/25 mg/kg/day based on both hunched posture and piloerection due to the questionable biological significance of the piloerection seen in females at 25 mg/kg/day in the absence of other signs at the same dose level in this study. Based on all these considerations, HIARC concluded that there was a lack confidence in this study.

Subchronic Oral Toxicity – Rat (MRID 43866301)

In a range finding subchronic t oxicity study (MRID 43866301), CGA-219417 (cyprodinil; >95% ai; Batch No. HE 15083) was ad ministered in the diet to Tif:RAIf(SPF) albino rats, 5 rats/sex/dose level at 0, 100, 600, 3000 or 15000 ppm (males - 0, 10.3, 64.8, 316 or 1460 mg/kg/day; females - 0, 10.1, 62.2, 299 or 1390 mg/kg/day) for 28 days. There was no effect on mortality and no clinical signs of toxicity. Treatment-related effects included lower body weight gains in 15000 ppm males (30 %) and slight decreases in 3000 (9%) and 15000 ppm (10%) females; decreased food consumption in high-dose animals (8-15% lower); decreased water consumption (10-40 % depending on week), decreased erythrocyte, haemoglobin, and haematocrit levels, and significantly increased cholesterol and phospholipid levels in 3000 and 15000 ppm animals; increased absolute and relative liver weights in 3000 and 15000 ppm females; microcytosis, hepatocyte hypertr ophy and thyroid follicular hypertrophy in 3000 and 15000 ppm males, hypochromasia in 15000 ppm males, and glycogen depletion in 15000 ppm

males and females. The slight increases in platelets, cholesterol and phospholipid levels at 600 ppm were not considered to be adverse in this study, as there were no associated histopathological findings at this dose. The LOAEL is 3000 ppm (316 and 299 mg/kg/day for males and females, respectively) based on lower body weight gains, microcytosis, increased cholesterol and phospholipid levels and hepatocyte hypertrophy. The NOAEL is 600 ppm (64.8 and 62.2 mg/kg/day for males and females, respectively).

### Page 31 of 38 Subchronic Feeding Study – Dog (MRID 43709028)

A 3-month study was carried out in Beagle dogs where animals (4/sex/dose) were fed diets containing 0,200! 1500, 7000 or 20000 ppm ( actual concentrations: males - 0, 6.07, 45.87, 210.33 or 559.66 mg/kg/day; females- 0, 6.79, 52.75, 231.93 or 580.95 mg/kgfday) CGA

219417. There was no effect on mortality, or clinical chemistry parameters. Vomiting was observed in all high-dose females during the first week of treatment , and an increase in mean platelet count was noted in high-dose females at weeks 7 and 13. Lower bodyweight gains (64-76%) and decreased food consumption were apparent in high-dose males and females throughout the study period. There was a transient decrease in bodyweight gain and food consumption in 7000 ppm females, which was noted after the first week of treatment only, and this was considered non-adverse. The LOAEL is 20,000 ppm (males -560, females -581 mg/kg/day) based on lower bodyweight gains and decreased food consumption in both sexes. The NOAEL is 7000 ppm (males -210, females - 232 mg/kg/day).

Subchronic Feeding Study – Mice (MRID 43709027)

A 3-month study (MRID 43709027) was carried out in Tif:MAGf(SPF) albino mice where animais (10 mice/sex/dose) were fed diets containing 0, 500,2000 or 6000 ppm (actual concentrations: males - 0, 73.3, 257 or 849 mg/kg/day; females -0, 103, 349 or 1121 mg/g’day) of CGA 2i19417 technical (99.5% a.i., Batch No - P 912004). There was no effect on mortality, or haematology parameters, and no clinical sighs of toxicity. Treatment-related effects included increased absolute and relative liver weights (112-118 %) in 6000 ppm males, and hepatic changes in mid- and high dose males and females that consisted of multifocal hepatocyte necrosis in 2000 and 6000 ppm males (30 % as compared to 0 in the control and low dose groups) and glycogen depletion in 2000 and 6000 ppm females (10, 10, 70 and 100% from controls to high dose). The LOAEL is 2000 ppm based on histopathological changes in the liver. The NOAEL is 500 ppm (malts - 73.3; females - 103 mg/kg/day).

Carcinogenicity Study in Mice (MRID 43709031)

An 18-month oncogenicity study was carried out in Tif:MAGf(SPF) albino mice where animals (50 mice/sex/dose - carcinogenicity portion, plus 10/sex/dose - hematology) were fed diets containing 0, 10, 150, 2000 or 5000 ppm (actual concentrations: males - 0, 1.15, 16.1, 212.4 or 630; females - 0, 1.08, 14.7, 196.3 or 558.1 mg/kg/day) of CGA 219417 (99.0-99.5% a.i., Batch No. P 912006). There was no effect on mortality, or hematology parameters, and no clinical signs of toxicity. Treatment-related effects included lower body weight and body weight gain (males - 10%, females - 27%) at 5000 ppm, reduced food efficiency and increased relative liver weights (16%) in high-dose males and females, and a dose-related increase in minimal to marked pancreatic acinar cell hyperplasia in 2000 and 5000 ppm males (8, 8, 10, 16, 28% incidence, from control to high dose). The

### Page 32 of 38 LOAEL was 2000 ppm (males - 212.4 mg/kg/day) based on a dose-related increase in the incidence of focal and multifocal hyperplasia of the exocrine pancreas in males. The NOAEL was 150 ppm (males - 16.1 mg/kg/day). This study was tested to adequate levels based on signs of toxicity in males at 2000 ppm and females at 5000 ppm.

Mutagenicity

(i) Gene Mutation

In a reverse gene mutation assay with Salmonella typhimurium/Escherichia coli

, cyprodinil was negative up to concentrations ($1250 :g/plate +/-S9) that produced reproducible cytotoxicity for the majority of strains. Compound insolubility was reported at $313 :g/plate (MRID No. 43709037).

In a Chinese hamster V79 cell HGPRT forward gene mutation assay, cyprodinil was negative up to cytotoxic concentrations (MRID No. 43709036).

(ii). Chromosome Aberrations

In an in vitro assay for chromosome aberrations in Chinese hamster ovary (CHO) cells, cyprodinil gave negative results up to cytotoxic concentrations) (MRID No. 43709038).

In an in vivo bone marrow micronucleus assay, cyprodinil was negative when administered orally (gavage) at 5000 mg/kg (HDT ) to both sexes of Tif:MAGF mice. No signs of overt toxicity or clear evidence of cytotoxicity for the target organ were noted at any dose or sacrifice time (MRID No. 43709039).

(iii) Other Mutagenic Mechanisms

In an unscheduled DNA synthesis assay in primary rat hepatocytes, cyprodinil was negative up to a cytotoxic concentration (80 :g/mL) (MRID No. 43709035).

### D. METABOLIC PROFILE

Chemical Name/Code Chemical Structure

Cyprodinil (CGA-219417)

4-cyclopropyl-6-methyl-N-phenyl-2- pyrimidinamine N N

CH 3 N H



### CGA-232449

6-cyclopropyl-2-(phenylamino)-4- pyrimidinemethanol N N

OH N H



### CGA-304075

4-[(4-cyclopropyl-6-methyl-2-2- pyrimidinyl)amino]-phenol N N

CH 3 N H

OH



### CGA-304076

N N N H

CH 3 OH



### NOA-413167

N N N H OH

CH 3



### Page 33 of 38

### Page 34 of 38 Chemical Name/Code Chemical Structure

CGA-249287

4-cyclopropyl-6-methyl-2-pyrimidinamine 

### N N

CH 3 

### NH

2



### NOA-422054

4-cyclopropyl-6-hydroxymethyl-2-pyrimidinamine 

### N N

OH NH

2



### CGA-263208

phenylguanidine N H NH

NH 2

### E. TOXICITY STUDY REFERENCES

82-1 Subchronic Oral Toxicity: 90-Day Study

MRID Citation Reference

43709026 Frankhauser, H. (1991) CGA-219417 Technical: 3-Month Oral Toxicity Study in Rats (Administration in Food): Amended: Lab Project Number: 891321. Unpublished study prepared by Ciba-Geigy Ltd. 436 p.

43709027 Frankhauser, H. (1991) CGA-219417 Technical: 3-Month Range Finding Toxicity Study in Mice: (Final Report): Lab Project Number: 891320. Unpublished study prepared by Ciba-Geigy Ltd. 219 p.

43709028 Altmann, B. (1991) CGA-219417 Technical: 3-Month Subchronic Oral Toxicity Study in Beagle Dogs: Amended (Final Report): Lab Project Number: 891323. Unpublished study prepared by Ciba-Geigy Ltd. 323 p.

43737601 Frankhauser, H. (1991) CGA-219417 Technical: 28-Day Oral Cumulative Toxicity Study in Rats: Amended (Final Report): Lab Project Number: 891322. Unpublished study prepared by Ciba-Geigy Ltd. 264 p.

43866301 Bachman, M. (1989) CGA-219417: 28-Days Range Finding Study in Rats: (Administration in Food): Lab Project Number: 891050. Unpublished study prepared by Ciba-Geigy Ltd. 263 p.

45614706 Altmann, B. (2002) 90-Day Oral Toxicity Study in Rat (Administration in Food): CA1139 A: Final Report: Lab Project Number: 20013024: 2692-01. Unpublished study prepared by RCC Ltd. 599 p. {OPPTS 870.3100}

82-2 21-day dermal-rabbit/rat

MRID Citation Reference

43709029 Hagemann, C. (1991) CGA-219417 Technical: 28-Day Repeated Dose Dermal Toxicity Study in the Rat: Amended (Final Report): Lab Project Number: 901078. Unpublished study prepared by Ciba-Geigy Ltd. 230 p.

82-7 Subchronic Neurotoxicity

MRID Citation Reference

45906101 Classen, W. (1997) 90-Day Subchronic Neur otoxicity Study in Rats: Final Report: Lab Project Number: 963031. Unpublished study prepared by Novartis Crop Protection AG. 367 p. {OPPTS 870.6200}

83-1 Chronic Toxicity

MRID Citation Reference

43709030 Altmann, B. (1992) CGA-219417 Technical: 12-Month Chronic Dietary Toxicity Study in Beagle Dogs: Amended (Final Report): Lab Project Number: 891324. Unpublished study



### Page 35 of 38prepared by Ciba-Geigy Ltd. 455 p.

43737602 Frankhauser, H. (1994) CGA-219417 Technical: 24-Month Carcinogenicity and Chronic Toxicity Study in Rats: Lab Project Number: 891326. Unpublished study prepared by Ciba-Geigy Ltd. 1255 p.

44417902 Fankhauser, H. (1994) 24-Months Carcinogenici ty and Chronic Toxicity Study in Rats: Cyprodinil Technical (CGA-219417): Addendum: Lab Project Number: 891326. Unpublished study prepared by Novartis Crop Protection, Inc. 374 p.

83-2 Oncogenicity

MRID Citation Reference

43709031 Frankhauser, H. (1994) CGA-219417 Technical: 18-Month Carcinogenicity Study in Mice: Amended (Final Report): Lab Project Number: 891325. Unpublished study prepared by Ciba-Geigy Ltd. 828 p.

43737602 Frankhauser, H. (1994) CGA-219417 Technical: 24-Month Carcinogenicity and Chronic Toxicity Study in Rats: Lab Project Number: 891326. Unpublished study prepared by Ciba-Geigy Ltd. 1255 p.

44417901 Fankhauser, H. (1994) 18-Month Carcinogenici ty Study in Mice: Cyprodinil Technical (CGA-219417): Addendum: Lab Project Number: 891325. Unpublished study prepared by Novartis Crop Protection, Inc. 348 p.

44417902 Fankhauser, H. (1994) 24-Months Carcinogenici ty and Chronic Toxicity Study in Rats: Cyprodinil Technical (CGA-219417): Addendum: Lab Project Number: 891326. Unpublished study prepared by Novartis Crop Protection, Inc. 374 p.

83-3 Teratogenicity -- 2 Species

MRID Citation Reference

43709032 Marty, J. (1991) CGA-219417 Technical: Developmental Toxicity Study in Rats: Amended (Final Report): Lab Project Number: 891327. Unpublished study prepared by Ciba-Geigy Ltd. 299 p.

43709033 Marty, J. (1991) CGA-219417 Technical: Developmental Toxicity (Teratogenicity Study in Rabbits): Amended (Final Report): Lab Project Number: 891329. Unpublished study prepared by Ciba-Geigy Ltd. 238 p.

43886301 Marty, J. (1990) CGA-219417 Technical: Preliminary Oral Toxicity Study with CGA219417 Technical in Pregnant Rabbits: (D ose Rangefinding Study): Lab Project Number: 891331. Unpublished study prepared by Ciba-Geigy Ltd. 25 p.

45614707 Khalil, S. (2002) Prenatal Developmental Toxicity Study in the Rat: CGA-263208 Technical: Final Report: Lab Project Number: 20013025: 2693-01. Unpublished study prepared by RCC Ltd. 474 p. {OPPTS 870.3700}

83-4 2-generation repro.-rat

MRID Citation Reference

43709034 Khalil, S. (1993) CGA-219417 Technical: Two-Generation Reproduction Study in Rats:



### Page 36 of 38Amended (Final Report): Lab Project Number: 891328. Unpublished study prepared by Ciba-Geigy Ltd. 1409 p.

83-5 Dietary: Combined Ch ronic Toxicity/Oncogenicity Studies

MRID Citation Reference

44429401 Chow, E. (1997) Cyprodinil Technical: 24-Months Carcinogenicity and Chronic Toxicity Study in Rats: Supplement: Lab Project Number: CGA 219417: 891326. Unpublished study prepared by Novartis Crop Protection, Inc. 86 p.

84-2 Interaction with Gonadal DNA

MRID Citation Reference

43709035 Geleick, D. (1991) CGA-219417 Technical: Authoradiographic (sic) DNA Repair Test on Rat Hepatocytes in vitro: Amended: Lab Project Number: 901083. Unpublished study prepared by Ciba-Geigy Ltd. 101 p.

43709036 Geleick, D. (1990) CGA-219417 Technical: Gene Mutation Test with Chinese Hamster Cells V79: Amended: Lab Project Number: 901086. Unpublished study prepared by Ciba-Geigy Ltd. 51 p.

43709037 Ogorek, B. (1990) CGA-219417 Technical: Salmonella and Escerichia/Liver--MicrosomeTest: Amended: Lab Project Number: 901084. Unpublished study prepared by CibaGeigy Ltd. 49 p.

43709038 Strasser, F. (1991) CGA-219417 Technical: Structural Chromosomal Aberration Test: Cytogenic Test on Chinese Hamster Cells in vitro: Amended: Lab Project Number: 901085. Unpublished study prepared by Ciba-Geigy Ltd. 43 p.

43709039 Ceresa, C. (1990) CGA-219417 Technical: Structural Chromosomal Aberration Test: Micronucleus Test, Mouse in vivo Study: Amended: Lab Project Number: 901082. Unpublished study prepared by Ciba-Geigy Ltd. 45 p.

45353505 Hertner, T. (1992) Salmonella and Escherichia/Liver-Microsome Test: CGA-249287 Technical: Final Report: Lab Project Number: 923089: 530-92. Unpublished study prepared by Novartis Crop Protection AG. 71 p. {OPPTS 870.5100}

45353506 Hertner, T. (1994) Salmonella and Escherichia/Mammalian-Microsome Mutagenicity Test: CGA-263208 Technical: Final Report: Lab Project Number: 943052: 530-94. Unpublished study prepared by Novartis Crop Protection AG. 72 p. {OPPTS 870.5100}

45353507 Hertner, T. (1994) Salmonella and Escherichia/Mammalian-Microsome Mutagenicity Test: CGA-232449 Technical: Final Report: Lab Project Number: 943108: 531-94. Unpublished study prepared by Novartis Crop Protection AG. 80 p. {OPPTS 870.5100}

45353508 Deparade, E. (2000) Salmonella and Escherichia/Mammalian-Microsome Mutagenicity Test: NOA 422054 Technical: Final Report: Lab Project Number: 20003021: 946-00. Unpublished study prepared by Novartis Crop Protection AG. 65 p. {OPPTS 870.5100}

85-1 General metabolism

MRID Citation Reference



### Page 37 of 3843709040 Thanei, P. (1992) Absorption, Distributi on, Metabolism, and Excretion of (U-(carbon 14))Phenyl and (2-(carbon 14))Pyrimidyl CGA-219417 in the Rat: Lab Project Number: 08PT01: 08PT02: 08PT/03. Unpublished study prepared by Ciba-Geigy Ltd. 154 p.

43709041 Mueller, T. (1992) The Metabolism of (U-(carbon 14))Phenyl CGA-219417 and (2- (carbon 14))Pyrimidyl CGA-219417 in the Rat: Lab Project Number: 13/92: 03TM01: PR 13/92. Unpublished study prepared by Ciba-Geigy Ltd. 68 p.

44867315 Allen, J.; East, P.; Francis, R. et al. (1975) Metabolism of Debrisoquine Sulfate: Identification of Some Urinary Metabolites in Rat and Man. Drug Metabolism and Disposition 3(5):332-337.

85-3 Dermal Penetration/Absorption

MRID Citation Reference

45906102 Mewes, K. (1999) Dermal Absorption of (Phenyl-U-(Carbon 14)) CGA 219417 Formulated as Switch 62.5 WG (A-9219 B) in the Rat: Final Report: Lab Project Number: 028AM04. Unpublished study prepared by Novartis Crop Protection AG. 53 p. {OPPTS 870.7600}

45906103 Mewes, K. (1999) The In Vitro Percutaneous Absorption of (Phenyl-U-(Carbon 14)) CGA 219417 Formulated as Switch 62.5 WG (A-9219 B) Through Rat and Human Epidermis: Final Report: Lab Project Number: 028AM05. Unpublished study prepared by Novartis Crop Protection AG. 47 p.



### Page 38 of 38