UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

 OFFICE OF PREVENTION, PESTICIDE 

 AND TOXIC SUBSTANCES 

MEMORANDUM 

October 7, 2009 

SUBJECT: Cyprodinil Human Health Risk Assessment for Proposed New Use of Cyprodinil 

on Imported Canola Seed 

PC Code: 288202 DP Barcode: D368812 

Decision No.: 404256 Registration No.: 100-953 

Petition No.: PP8E7502 Regulatory Action: Section 3 Registration 

Risk Assessment Type: Single Chemical Aggregate Case No.: NA 

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

MRID No.: NA 40 CFR: 180.532

FROM: Becky Daiss, Biologist 

Jerry Stokes, 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 Division’s (HED’s) risk assessment of proposed 

new use of cyprodinil on canola seed imported from Canada. Supporting documents are listed 

below. 

Residue Chemistry Assessment – J. Stokes, D362486, 9/15/09 

Dietary and Drinking Water Exposure Assessment – B. Daiss, D368813 10/6/2009 

Drinking Water Exposure Assessment – J. Menendez, D342973, 5/2/08 

Occupational and Residential Exposure Assessment – M. Dow, D362494, 8/4/09 

TABLE OF CONTENTS 

Page 1 of 36 
Page 2 of 36 

 pg. 

1.0 EXECUTIVE SUMMARY .................................................................................................4 

2.0 INGREDIENT PROFILE ....................................................................................................6 

2.1 Registered Products .............................................................................................................6 

2.2 Registered and Proposed New Uses ....................................................................................7 

2.3 Structure, Nomenclature and Physical/Chemical Properties ...............................................7 

3.0 HAZARD CHARACTERIZATION/ASSESSMENT ........................................................8 

3.1 Hazard Characterization .....................................................................................................8 

3.2 FQPA Hazard Considerations .............................................................................................9 

3.2.1 Developmental Toxicity ......................................................................................10 

3.2.2 Reproductive Toxicity ..........................................................................................11 

3.2.3 Pre-and/or Postnatal Toxicity ................................................................................11 

 3.2.4 Immunotoxicity......................................................................................................11 

 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 .......................................................12 

3.3.3 Chronic Reference Dose – All Populations ...........................................................12 

3.3.4 Classification of Carcinogenic Potential................................................................13 

3.4 Recommendation for Aggregate Exposure........................................................................13 

3.5 Summary of Endpoints Selected for Risk Assessment......................................................14 

3.6 Endocrine Disruption.........................................................................................................14 

4.0 DIETARY AND DRINKING WATER EXPOSURE ASSESSMENT ............................15 

4.1 Residue Chemistry Profile .................................................................................................15 

4.1.1 Metabolism in Primary Crops................................................................................15 

4.1.2 Metabolism in Livestock .......................................................................................15 

4.1.3 Residue Analytical Method ...................................................................................16 

4.1.4 Storage Stability.....................................................................................................16

4.1.5 Residues in Crops ..................................................................................................17 

 4.1.6 Residues in Livestock ............................................................................................17 

 4.1.7 Residues in Processed Commodities .....................................................................17 

4.2 Drinking Water Profile ......................................................................................................18 

4.2.1 Environmental Fate and Transport ........................................................................18 

4.2.2 Estimated Drinking Water Concentrations ............................................................18 

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 

6.0 CUMULATIVE RISK.......................................................................................................21 
Page 3 of 36 

8.0 DATA NEEDS...................................................................................................................22 

8.1 Toxicity Data .....................................................................................................................22 

8.2 Chemistry Data ..................................................................................................................22 

APPENDICES 

1.0 GUIDELINE TOXICOLOGY DATA SUMMARY .........................................................23 

 1.1 Guideline Data Requirements................................................................................23 

 1.2 Toxicity Profiles ....................................................................................................24 

2.0 METABOLIC PROFILE...................................................................................................28 

3.0 ADDITIONAL TOXICITY STUDIES .............................................................................30 

4.0 REFERENCES FOR TOXICITY STUDIES ....................................................................33 

 
Page 4 of 36 

1.0 EXECUTIVE SUMMARY

This assessment provides information to support an amended Section 3 registration for 

the use of cyprodinil on canola grown in Canada and imported into the U.S. 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 (CA 

only) and ground application equipment. Cyprodinil is used 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 New Uses

 Syngenta is supporting the use of cyprodinil on canola grown in Canada and imported 

into the U.S. The formulation being proposed for use in Canada is the 62.5% WDG MAI, 

marketed under the trade name SWITCHTM 62.5 WG (EPA Reg. No. 100-953). The proposed 

use on canola is for a single broadcast foliar application at 20-30% flowering (BBCH 62-63) at 

rates of 290-366 g ai/ha (0.26-0.33 lb ai/A) using ground equipment. The proposed PHI is 35 

days. Ground or aerial application equipment is permitted. 

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 
Page 5 of 36 

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 inflamation 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. No neurotoxicity 

studies with cyprodinil are available. However, there was no evidence of neuropathological 

effects in the available oral-toxicity studies. There was no evidence of carcinogenic potential in 

either the rat chronic toxicity/carcinogenicity or mouse carcinogenicity studies and no concern 

for mutagenicity. 

 A neurotoxicity battery (870.6200 a and b) and an immunotoxicity study (870.7800) are 

required in accordance with the revised 40 CFR Part 158 Toxicology Data Requirements. 

Dose Response Assessment

 Toxicological points of departure (PODs) were 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 feeding 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

 Risk assessments were conducted for dietary (food and water) based on registered uses 

and requests for new uses of cyprodinil on canola seed. Screening level 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. Occupational and residential exposures for the proposed new use of cyprodinil on 

ornamentals are assessed in a separate risk assessment (M. Dow, D362494, 8/4/09). Worker 

exposures were assessed for handler and post-application activities and residential exposures 

were assessed for handler activities. Based on that assessment, occupational and residential 

exposures are not of concern at the maximum allowable application rates for the proposed new 

uses. 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. 
Page 6 of 36 

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. 

Tolerance Recommendation 

There are no residue chemistry issues that would preclude establishing a tolerance and 

granting a registration for the requested use of cyprodinil or establishment of the following 

tolerances for residues of cyprodinil: 

 Canola, seed .....................................................................................0.03 ppm 

HED continues to recommend that the current tolerance expression for animal 

commodities be changed to reflect both parent and metabolite CGA-304075 (4-[(4-cyclopropyl6-methyl-2-2-pyrimidinyl)amino]-phenol). 

2.0 INGREDIENT PROFILE 

2.1 Registered Products 

There are currently 5 active Section 3 cyprodinil registrations according to the OPPIN 

data base. 

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 an oil emulsion in water (EW) MAI containing 2.09 lb/gal 

cyprodinil and 0.73 lb/gal of difenoconazole. The current application proposes use on canola 

grown in Canada and imported into the U.S. The formulation being proposed for use in Canada 

is the 62.5% WDG MAI, marketed under the trade name SWITCHTM 62.5 WG (EPA Reg. No. 

100-953). The proposed use on canola is for a single broadcast foliar application at 20-30% 

flowering at rates of 290-366 g ai/ha (0.26-0.33 lb ai/A) using ground equipment. The proposed 

PHI is 35 days. Maximum application rates for existing and proposed uses are provided in Table 

2. Maximum rates are based on a review of active and proposed labels. 

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

CH3

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) 62.5% WDG (SwitchTM 62.5WG Fungicide; EPA Reg. No. 100-953), which contains 25% 

fludioxonil and 37.5% cyprodinil 

Page 7 of 36 
Page 8 of 36 

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/cm3 at 20 C 

Water solubility (mg/L at 25 C) pH 7.6 16 

pH 5 20 

pH 7 13 

pH 9 15 

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, pKa 4.44 at 20 C 

Octanol/water partition coefficient, Log(KOW) 

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 

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 
Page 9 of 36 

weight and/or hypertrophy of thyroid follicular cells 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 weights or gross/microscopic observations were not 

observed in the chronic rat study or in other studies (thyroid hormones were not evaluated in any 

study). 

 No neurotoxicity studies have been submitted for cyprodinil. However, the available 

data do not indicate a need for neurotoxicological testing. No clinical signs suggestive of 

neurobehavioral alterations or evidence of neuropathological 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 principle route of excretion (48-68%), and >90% of the administered dose detected 

in the urine and feces within 48 hours. 

 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 

(13th) in the rabbit, was reported in developmental toxicity studies. In a rat two-generation 

reproduction study, significantly lower pup weights for F1 and F2 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. 

Based on the results of the available toxicity studies, there is no evidence for 

neurotoxicity or immunotoxicity. However, in accordance with the revised 40 CFR Part 158 

Toxicology Data Requirements, a Neurotoxicity Battery (870.6200a and b) and an 

Immunotoxicity study (870.7800) are required (Appendix A and B). 

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 and acceptable multi- and single generation reproduction studies in 

the rat have been submitted. 

3.2.1 Developmental Toxicity 
Page 10 of 36 

3.2.1.1 Rat Developmental Study 

In a developmental toxicity study (MRID 43709033), cyprodinil technical (99.5%) was 

administered in 3% aqueous corn starch suspension 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), 

significantly lower mean body weight (16%), body weight 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 food 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 were 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. 

3.2.1.2Rabbit 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 indications 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 significant) 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. 

 3.2.2 Reproductive Toxicity 

In a two-generation reproduction study (MRID No. 43709034), Tif:RAIf rats (30 
Page 11 of 36 

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 females was not supported by histopathological 

findings. 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 

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/day). Reviewers determined that pre-mating 

body weight gain (not absolute body weight) should be used as the basis of the NOAEL. Signs 

of reproductive toxicity 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) based on decreased pup 

weights (F1 and F2). The NOAEL for reproductive toxicity is 1000 ppm (about 81 mg/kg/day). 

3.2.3 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 the prenatal 

developmental toxicity studies in either rats or rabbits. 

3.2.4 Immunotoxicity 

There are no indications in the available studies that organs associated with immune 

function, such as the thymus and spleen, are affected by cyprodinil. There are no effects seen on 

the developing immune system in the existing studies. An immunotoxicity study is required, 

however, under 40 CFR Part 158 as a part of the new data requirements for registration of a 

pesticide (food and non-food uses). 

 3.2.5 FQPA Factor 

 Since there are adequate developmental studies in rats and rabbits and an adequate multigeneration study in rats, and no residual uncertainties that indicate the need for a factor, the 

FQPA factor has been reduced to 1X. 
Page 12 of 36 

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 (13th) ribs, which is presumed to occur after a single exposure. 

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

variation) 

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 additional 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 significant 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 
Page 13 of 36 

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)

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 exposures 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. 
Page 14 of 36 

Table 6. Summary of Toxicological Doses and Endpoints for Cyprodinil for Use in Dietary Human 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 (13th).

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 hepatis) 

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 dose-response data and used to 

mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. 

NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. 

UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity 

among members of the human population (intraspecies). 

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 7. Summary of Toxicological Doses and Endpoints for 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 

UFA= 10x 

UFH=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 

UFA= 10x 

UFH=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

EPA is required under the FFDCA, as amended by FQPA, to develop a screening 

program to determine whether certain substances (including all pesticide active and other 

ingredients) “may have an effect in humans that is similar to an effect produced by a 

naturally occurring estrogen, or other such endocrine effects as the Administrator may 

designate.” Following recommendations of its Endocrine Disruptor and Testing Advisory 
Page 15 of 36 

Committee (EDSTAC), EPA determined that there was a scientific basis for including, as 

part of the program, the androgen and thyroid hormone systems, in addition to the estrogen 

hormone system. EPA also adopted EDSTAC’s recommendation that the Program include 

evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA 

and, to the extent that effects in wildlife may help determine whether a substance may have 

an effect in humans, FFDCA authority to require the wildlife evaluations. As the science 

develops and resources allow, screening of additional hormone systems may be added to the 

Endocrine Disruptor Screening Program (EDSP). 

When additional appropriate screening and/or testing protocols being considered under 

the Agency’s EDSP have been developed, cyprodinil may be subjected to further screening 

and/or testing to better characterize effects related to endocrine disruption. 

4.0 DIETARY AND DRINKING WATER EXPOSURE ASSESSMENT

4.1 Residue Chemistry Profile 

4.1.1 Metabolism in Primary Crops 

 The metabolism of cyprodinil has been studied in apple, peach, potato, tomato, and 

wheat. The residue of concern in plants is the parent compound cyprodinil as determined by the 

HED Metabolism Assessment Review Committee (MARC) (D243198, G. Kramer, 3/11/98). 

The metabolism of cyprodinil in plants is adequately understood and additional plant metabolism 

data are not required for this proposed use on canola. 

 4.1.2 Metabolism in Livestock 

The nature of the residue in ruminants is adequately understood based on acceptable 

lactating goat metabolism studies. HED has 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, expressed in parent equivalents (D345970 and D345182, G. 

Kramer, 6/4/08). Therefore, HED recommends that the current tolerance expression for animal 

commodities be changed to reflect both parent and metabolite CGA-304075 (4-[(4-cyclopropyl6-methyl-2-2-pyrimidinyl)amino]-phenol). 

A poultry metabolism for cyprodinil has not been previously submitted as none of the 

registered uses included poultry feedstuffs. However, with this petition for tolerances on canola 

seed, there is now the potential for dietary exposure of poultry to cyprodinil residues through the 

consumption of canola meal containing cyprodinil residues. Based on the proposed tolerance 

level for canola seed, the potential dietary exposure of poultry to cyprodinil residues is extremely 

low (0.005 ppm). Therefore, for purposes of this petition, HED will waive the requirement for a 

poultry metabolism study. 

Residues of concern for dietary and drinking water risk assessment and tolerance 
Page 16 of 36 

expression for cyprodinil are provided in Table 8. 

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. 

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 0.50 ppm using Protocol D. These data were 

forwarded to FDA (G. Kramer, 11/28/1995). 

 

4.1.4 Storage Stability 

No storage stability data are available on an oil seed crop. However, in conjugation with 

the canola field trials and processing studies, Syngenta has initiated a storage stability study 

using control samples of canola seeds, meal and oil fortified with cyprodinil at 0.2 ppm. Data 

from this on-going storage stability study should be submitted. Once these data are available, 

the stability of cyprodinil in canola seeds, meal and oil will be assessed. In the interim, the 

stability data on avocadoes can be used to support the residue data on canola seeds and meal, as 

avocadoes are a neutral fruit that contain 15-30% oil by weight. 

4.1.5 Residues in Crops 
Page 17 of 36 

 Sixteen canola field trials were conducted in Canada in Zones 5, 7, and 14 during 2007 

using a WDG formulation containing 37.5% cyprodinil and 25% fludioxonil. The WDG 

formulation was applied to canola as a single broadcast foliar application at flowering at a 

cyprodinil rate of 0.31-0.35 lb ai/A (1x rate) using ground equipment. Single control and 

duplicate treated samples of canola seed were harvested (cut) from each test at 35-53 days after 

treatment (DAT), and samples were field-dried for 2-32 days prior to collection. Additional 

samples were harvested from two sites at 44, 48, 53, and 57 DAT or 35, 42, 49, and 56 DAT to 

assess residue decline. Samples were stored frozen from collection to analysis for up to 200 

days. Following a single broadcast foliar application residues were non-detectable (<0.006 ppm) 

in/on 29 out of 32 samples. Residues were above the LOQ in only one sample (0.021) and were 

detectable in two more samples (0.007 and 0.017 ppm). Average residues were 0.02 ppm in/on 

canola seeds, and the HAFT residues were <0.02 ppm. No pattern of residue decline could be 

determined as residues were ND in/on all seed samples from the two residue decline tests. 

Provided that adequate supporting storage stability data are submitted for cyprodinil in frozen 

canola seed, the submitted canola field trial data are adequate and fulfill the field trial 

requirements for imported canola. 

4.1.6 Residues in Livestock 

 Adequate cattle feeding studies are available for cyprodinil. As canola meal is a 

significant feedstuff for livestock, the maximum dietary burden of (MDB) was recalculated for 

this petition. Using the Agency’s most recent guidance on constructing reasonably balanced 

livestock diets, MDB for livestock to cyprodinil was recalculated to be 0.88 ppm for beef cattle, 

0.89 ppm for dairy cattle, and 0.005 ppm for swine and poultry. The lower MDB levels for 

poultry and swine resulted from removing cowpeas from their diet. Although cowpeas are 

covered by the existing 0.6 ppm tolerance for dry beans, they were not included in the poultry 

and swine diets because the use directions for beans on cyprodinil labels specifically exclude 

applications to cowpeas. As the proposed uses will not increase the dietary exposure of livestock 

to cyprodinil residues, reassessment of animal tolerances is not required for this petition. The 

current 0.02 ppm tolerances for meat byproducts of cattle, goats, horses, and sheep are adequate. 

 Although the addition of a tolerance on canola seed will result in the potential dietary exposure 

of poultry to cyprodinil residues, HED has determined that a poultry feeding study is not 

required for the current petition as the potential dietary exposure of poultry is extremely low. 

4.1.7 Residues in Processed Foods 

Syngenta has submitted processing studies on canola in support of the proposed use for 

cyprodinil (WDG) on canola grown in Canada. In two field trials conducted in Canada in Zones 

14 during 2007, a WDG formulation containing 37.5% cyprodinil was applied to canola as a 

single broadcast foliar application at rates of 1120-1127 g ai/ha (3x rate; 1.0 lb ai/A). 

Applications were made using ground equipment in volumes of ~200 L/ha and included the use 

of a crop oil concentrate at 1.0% v/v. Single bulk control and treated samples of canola seed 

were harvested from each test at 38 or 52 DAT. The canola seed were then processed into meal 

and refined oil using simulated commercial practices. Canola seed, meal, and oil samples were 
Page 18 of 36 

stored at ≤-10°C for up to 191 days prior to analysis. Residues were ND in samples of canola 

seed (<0.006 ppm), meal (<0.006 ppm) and refined oil (<0.003 ppm) from both field trials. 

Therefore, processing factors could not be calculated. The theoretical processing factors for 

canola are 1.9x for meal and 3.0x for refined oil. Provided that adequate supported storage 

stability data are submitted for canola seed, meal and oil, the canola processing studies are 

adequate. The data indicate that quantifiable residues of cyprodinil are unlikely to occur in 

canola meal and refined oil following an application at up 3x the proposed maximum use rate; 

therefore, separate tolerances are not required for canola meal and refined oil. 

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-m3

/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 (KOC

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 

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 directly into the chronic dietary analysis 

(“water, direct, all sources” and “water, indirect, all sources”) and were provided by EFED 

(D342973, J Melendez 5/2/08). 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 
Page 19 of 36 

Concentrations (EDWCs) for cyprodinil and its metabolite CGA-249287 were derived based on 

a maximum application rate of 0.469 lb a.i./A (applied 3 times/season) on grapes assuming 

minimum intervals between application. The concentrations have been adjusted with the 

Percent Crop Area (PCA) of 0.87 for a national assessment. 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 Cyprodinil Human Health Risk Assessment 

Drinking Water Source Peak (μg/L) Annual Mean (μg/L)

Surface Water 35 20 

Ground Water 0.11 0.11 

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: Summary of Acute Dietary Exposure and Risk for Cyprodinil

Acute (95th Percentile) Population Subgroup aPAD (mg/kg/day) Exposure (mg/kg/day) %aPAD 

Females 13-49 years old 1.5 0.0550 4 

 4.3.2 Chronic Dietary and Drinking Water Analysis 

 A conservative chronic dietary exposure analysis was performed for the general U.S. 

population and various population subgroups. Tolerance level residues and 100 crop treated 
Page 20 of 36 

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. Chronic 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 70%. The cPAD for the general U.S. 

population was 41%. 

Table 11: Summary of Chronic Dietary Exposure and Risk for Cyprodinil

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

General U.S. Population 0.0123 41 

All Infants (< 1 year old) 0.0095 32 

Children 1-2 years old 0.0211 70 

Children 3-5 years old 0.0189 63 

Children 6-12 years old 0.0134 45 

Youth 13-19 years old 0.0104 35 

Adults 20-49 years old 0.0118 39 

Adults 50+ years old 0.0114 38 

Females 13-49 years old

0.027 

0.0122 41 

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 - Dermal LOC/MOE = 100; 

Inhalation LOC/MOE = 100; 

Exposure 

Scenario1

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

Inhalation 

MOE6

Dermal 

Dose 

(m/k/d) 7

Dermal 

MOE8

Aggreg 

MOE9

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 exposure 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. 
Page 21 of 36 

3

 Application rates are based on maximum values based on proposed label presented as lb ai/gallon). 4

 Amount treated is based on the area or gallons that can be reasonably applied in a single day for each exposure scenario of concern based on the 

application method and formulation/packaging type. (Standard EPA/OPP/HED values). 5

 Inhalation dose (mg/kg/day) = [unit exposure (ug/lb ai) * 0.001 mg/ug unit conversion * Inhalation absorption (100%) * Application 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 inhalation (NOAEL 62 mkd)/ Daily Inhalation Dose. 7

 Dermal Dose (mg/kg/day) = [unit exposure (mg/lb ai) * Application rate (lb ai/acre or lb ai/gallon) * Daily area treated/amount 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 Short-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 

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) 
Page 22 of 36 

 - Acute Neurotoxicity Study (GLN 870. 6200a) 

 - Subchronic Neurotoxicity Study (GLN 870.6200b) 

 - 28-day dermal toxicity study in rats (GLN 870.3200) (required in prior assessment) 

 - 28-day inhalation toxicity study in rats (GLN 870.3465) (required in prior 

assessment) 

7.2 Chemistry 

 - The petitioner must submit the results from the storage stability study on canola seed, 

meal and oil to support sample storage conditions and durations from the canola field 

trials and processing studies. 

 - Based on the expected low dietary exposure of poultry to cyprodinil resulting from 

this use, HED has waived the requirement for a poultry metabolism study for this 

petition. The addition of any other uses on crops that include poultry feedstuffs will 

trigger the requirement for a poultry metabolism study. 
Page 23 of 36 

APPENDICES 

1.0 TOXICOLOGY DATA SUMMARY 

1.1 Guideline Data Requirements 

Table 1. Guideline Data Requirements 

Technical

Test

Required Satisfied

870.1100 Acute Oral Toxicity ....................................................... 

870.1200 Acute Dermal Toxicity .................................................. 

870.1300 Acute Inhalation Toxicity .............................................. 

870.2400 Primary Eye Irritation .................................................... 

870.2500 Primary Dermal Irritation .............................................. 

870.2600 Dermal Sensitization...................................................... 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.3100 Oral Subchronic (rodent) ............................................... 

870.3150 Oral Subchronic (nonrodent) ......................................... 

870.3200 21-Day Dermal .............................................................. 

870.3250 90-Day Dermal .............................................................. 

870.3465 90-Day Inhalation .......................................................... 

yes 

yes 

yes 

no 

yes 

yes 

yes 

no 

- 

no 

870.3700a Developmental Toxicity (rodent)................................... 

870.3700b Developmental Toxicity (nonrodent)............................. 

870.3800 Reproduction ................................................................. 

yes 

yes 

yes 

yes 

yes 

yes 

870.4100a Chronic Toxicity (rodent) .............................................. 

870.4100b Chronic Toxicity (nonrodent) ........................................ 

870.4200a Oncogenicity (rat) .......................................................... 

870.4200b Oncogenicity (mouse).................................................... 

870.4300 Chronic/Oncogenicity.................................................... 

yesa 

yes 

yesa

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.5100 Mutagenicity—Gene Mutation - bacterial ..................... 

870.5300 Mutagenicity—Gene Mutation - mammalian ................ 

870.5375 Mutagenicity—Structural Chromosomal Aberrations ... 

870.5900 Mutagenicity—Other Genotoxic Effects ....................... 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.6100a Acute Delayed Neurotox. (hen) ..................................... 

870.6100b 90-Day Neurotoxicity (hen)........................................... 

870.6200a Acute Neurotox. Screening Battery (rat)........................ 

870.6200b 90-Day Neuro. Screening Battery (rat).......................... 

870.6300 Develop. Neuro.............................................................. 

no 

no 

yes 

yes 

no 

- 

- 

no

no 

- 

870.7485 General Metabolism....................................................... 

870.7600 Dermal Penetration ........................................................ 

870.7800 Immunotoxicity.............................................................. 

yes 

no 

yes 

yes 

yes 

no 

a Guideline 870.4300 satisfies guideline 870.4100a and 870.4200a. 
Page 24 of 36 

1.2 Toxicity Profiles 

Table 1 Acute Toxicity of Cyprodinil. 

Guideline No. Study Type MRIDs # Results Toxicity Category 

870.1100 Acute Oral 43709014 LD50 = 2796 mg/kg III 

870.1200 Acute Dermal 43709016 LD50 > 2000 mg/kg III 

870.1300 Acute Inhalation 43709018 LC50 = 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/F 

LOAEL = 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 36 

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 

870.3200 

21/28-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/day 

LOAEL = 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 (13th) 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 36 

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 

870.5100 

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 μg/plate +/-S9) that produced 

reproducible cytotoxicity for the majority of strains. 

Compound insolubility was reported at ≥313 μg/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 μg/mL with S9) (≥24 μg/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 μg/mL without S9, 18- 

or 42-hour cell harvest or ≥25 μg/mL with S9, 18- hour cell 

harvest) or to the highest sub-cytotoxic concentration (50 

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

870.5395 

Cytogenetics/ 

In vivo bone marrow 

micronucleus 

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 

overt toxicity or clear evidence 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 μg/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 (tcmax= 0.3 hours) with rapid 

clearance (tcmax/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, 
Page 27 of 36 

Table 2.. Toxicity Profile of Cyprodinil Technical. 

Guideline No./ 

Study Type 

MRID No. (year)/ 

Classification /Doses 

Results 

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 

sex of the animal. 

870.7600 

Dermal Absorption 

(rat) 

45906102 (1999) 

In review 

6 μg/cm2

 or 870 μg/cm2 

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. 
2.0 – METABOLIC PROFILE 

Chemical Name/Code Chemical Structure 

Cyprodinil (CGA-219417) 

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

pyrimidinamine

N

N

CH3

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

CH3

N

H

OH

CGA-304076

N

N N

H

CH3

OH

NOA-413167

N

N N

H

OH

CH3

Page 28 of 36 
Page 29 of 36 

Chemical Name/Code Chemical Structure 

CGA-249287

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

N

CH3

2

NH

NOA-422054

4-cyclopropyl-6-hydroxymethyl-2-pyrimidinamine N

N

OH

2NH

CGA-263208

phenylguanidine 

N

H

NH

NH2
Page 30 of 36 

3.0 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 (LD50 >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 acute, 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 toxicity study (MRID 43866301), CGA-219417 

(cyprodinil; >95% ai; Batch No. HE 15083) was administered 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 hypertrophy 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 36 

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 36 

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 ($96.0 :g/mL with S9) ($24 :g/mL without S9) 

(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 ($50 :g/mL without S9, 

18- or 42-hour cell harvest or $25 :g/mL with S9, 18- hour cell harvest) or to the highest 

sub-cytotoxic concentration (50 :g/mL with S9, 42-hour cell harvest) (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). 
4.0 TOXICOLOGY 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 Neurotoxicity 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 

prepared by Ciba-Geigy Ltd. 455 p. 

Page 33 of 36 
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 Carcinogenicity 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 Carcinogenicity 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 Carcinogenicity 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: (Dose 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: 

Amended (Final Report): Lab Project Number: 891328. Unpublished study prepared by 

Ciba-Geigy Ltd. 1409 p. 

Page 34 of 36 
83-5 Dietary: Combined Chronic 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--Microsome 

Test: 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 

43709040 Thanei, P. (1992) Absorption, Distribution, 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. 

Page 35 of 36 
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 36 of 36