Page 3 of 53

5.2.4 Estimated Drinking Water Concentrations............................................................21

5.3 Dietary and Drinking Water Exposure and Risk ...............................................................22

5.3.1 Acute Dietary and Drinking Water Analysis.........................................................22

5.3.2 Chronic Dietary and Drinking Water Analysis......................................................22

6.0 RESIDENTIAL EXPOSURE AND RISK ........................................................................23

7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT...............................................23

7.1 Short-Term Aggregate Risk to Residential Applicators....................................................24

8.0 CUMULATIVE RISK.......................................................................................................24

9.0 OCCUPATIONAL EXPOSURE AND RISK...................................................................25

9.1 Exposure Scenarios............................................................................................................25

9.2 Handler Exposure and Risk Assessment............................................................................25

9.2.1 Handler Exposure Scenarios..................................................................................25

9.2.2 Handler Exposure Data ..........................................................................................25

9.2.3 Handler Exposure Assumptions.............................................................................26

9.2.4 Handler Exposure and Risk Estimates...................................................................26

9.3 Post-application Exposure and Risk Assessment ..............................................................32

9.3.1 Post-application Dermal Exposure ........................................................................32

9.3.2 Post-application Inhalation Exposure ....................................................................32

10.0 REFERENCES ..................................................................................................................32

Appendix A. Toxicity Profile and Executive Summaries..............................................................34

A.1 Toxicity Data Requirements..................................................................................34

A.2 Toxicity Profiles.....................................................................................................35

A.3 Hazard Identification and Endpoint Selection .......................................................40

A.4 Executive Summaries.............................................................................................41

Appendix B. Metabolism ..............................................................................................................51

Appendix C. Physical/Chemical Properties...................................................................................53

Appendix D. Review of Human Research.....................................................................................53
Page 4 of 53

1.0 EXECUTIVE SUMMARY

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

cyprodinil on a number of crops and crop groups. This document addresses the dietary, drinking 

water, residential and occupational exposure and risk associated with currently registered uses 

and proposed new uses 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 at 40 CFR §180.532 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 used on ornamental landscapes 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, there is 

potential for residential “handlers” to obtain and to apply the product. Residential exposures are 

limited to residential applicators; however, since cyprodinil is only used on ornamentals and 

there is no dermal POD, only inhalation exposure was assessed.

Proposed New/Amended Uses

Interregional Research Project No. 4 (IR-4), is requesting an amended Section 3 use the of the 

following registered products on all fruiting vegetable crops and leafy vegetables Crop Group 

4A: Switch 62.5 WGTM Fungicide (EPA Reg. No. 100-953), a 37.5% water dispersible granule 

(WDG) formulation of cyprodinil; VanguardTM WG (EPA Reg. No. 100-828), a 75% water 

dispersible granule (WDG) formulation; and Inspire Super TM Fungicide (EPA Reg. No. 100-

1317), a 2.09 lb ai/gallon emulsifiable concentrate.

IR-4 is also requesting amendments for the Section 3 registrations for VanguardTM WG, Switch

62.5 WGTM Fungicide, and Inspire Super TM Fungicide to expand currently registered foliar uses 

for bulb vegetables, fruiting vegetables, berry and small fruits, dragon fruit, pome fruits, and 

leafy vegetables to include the additional commodities specified under the following new crop 

groups/subgroups: Onion, bulb subgroup 3-07A; Onion, green subgroup 3-07B; Caneberry 

subgroup 13-07A; Bushberry subgroup 13-07B; Small fruit vine climbing subgroup 13-07F, 

except fuzzy kiwifruit; Dragon fruit; Vegetable, fruiting, group 8-10; Vegetable, leafy, except 

brassica, subgroup 04A; Pome Fruits Group 11-10; and Low growing Berry Subgroup 13-07G, 

Except Cranberry. 

Syngenta Crop Protection, Inc. is requesting a Section 3 registration for the use of Vangard®WG 

Fungicide and Switch 62.5 WGTM Fungicide on the leafy petiole subgroup 04B. 
Page 5 of 53

Hazard Identification

The toxicology database for cyprodinil is adequate for evaluating and characterizing toxicity and 

selecting endpoints for purposes of this risk assessment. 

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 inflammation 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 twogeneration reproduction study following pre- or post-natal exposure. There was no evidence of 

neuropathological or other neurological effects in the available acute or subchronic neurotoxicity 

study. The submitted 28-day immunotoxicity study concluded no apparent suppression of the 

humoral component of the immune system. No dermal or systemic toxicity was seen following 

repeated dermal application at the highest dose in a 21 day dermal toxicity study in rabbits. 

There was no evidence of carcinogenic potential in either the rat chronic toxicity/carcinogenicity 

or mouse carcinogenicity studies. 

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. 

Dose Response Assessment

Toxicological points of departure (PODs) were selected for dietary, occupational, and residential 

exposure scenarios. A POD for acute dietary exposure was selected for the general population 

and all population subgroups from an acute neurotoxicity study in rats based on clinical signs 

(hunched posture, pilorection, and reduced responsiveness to sensory stimuli, reduced motor 

activity and hypothermia). The POD for chronic dietary exposure was selected from a 

chronic/carcinogenicity feeding study in rats based on degenerative liver lesions (spongiosis 

hepatitis) in males. A dermal exposure endpoint was not selected as no systemic toxicity was 

seen at the highest dose test in a 21 day dermal toxicity study in rabbits. A POD for short-term 

inhalation exposure was selected from a subchronic feeding study in rats based on decreased 

body-weight gain, increased cholesterol and phospholipid levels, microcytosis, and hepatocyte 

hypertrophy. A POD for intermediate term inhalation exposure was selected from the 

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). A recent HASPOC decision (TXR 0054812), based on a weight of 

evidence approach is requiring a 90-day inhalation toxicity study to reduce uncertainty 

associated with the use of an oral POD for assessing risk via the inhalation route. Therefore, in 

the absence of a route-specific inhalation study, a 10X database uncertainty factor for 

occupational workers and a 10x FQPA SF factor for residential scenarios should be applied 
Page 6 of 53

specifically to the inhalation assessment. 

Exposure/Risk Assessment and Risk Characterization

Risk assessments were conducted for dietary (food and water) and occupational exposure based 

on registered uses and requests for new or expanded use of cyprodinil on a number of 

commodities. Conservative acute and moderately refined 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. Dermal 

risks to agricultural workers following treatments were not assessed since no short- or 

intermediate-term dermal endpoint of concern was identified. Short-term inhalation risk

estimates to occupational handlers are not of concern for any scenario (i.e., MOEs ≥ 1,000) at 

baseline (i.e., no respirator). However, intermediate-term exposure risk estimates at baseline for 

mixing/loading dry flowables for aerial, chemigation, and groundboom applications were of 

concern (i.e., MOE < 1,000). MOEs for these scenarios ranged from 150 to 920. These concerns 

were mitigated by applying additional Protective Personal Equipment (PPE) (i.e., PF5 or PF 10 

respirators). The scenario with the lowest MOE (mixing/loading a dry flowable formulation for 

aerial application; MOE = 150) reached an MOE of 1,500 after adding a PF 10 respirator.

Although there are no residential uses associated with the proposed new uses, an updated 

residential exposure assessment was conducted to incorporate updated exposure assumptions. 

The updated residential exposure assessment showed no risk concerns. Aggregate risks from 

dietary and residential handler exposures are not of concern.

For this action, the proposed labels include resistance management language indicating to 

alternate fungicides and mode of action after 2 applications with cyprodinil. Based on this 

language, it is possible that a short-term (1-30 days) exposure assessment would be healthprotective for occupational handlers; however, since use/usage data are not available to justify 

eliminating consideration of potential intermediate-term exposures, both durations were 

assessed. Occupational exposures may occur over a single day or up to weeks at a time; some 

applicators may apply these products over a period of weeks because they are commercial 

applicators who are completing multiple pesticide applications for multiple clients. Information 

on the commercial use of fungicides could help to refine the assessment. Long-term exposures 

are not expected; therefore, a long-term assessment was not conducted.

Use of Human Studies

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies, listed in Appendix D have 

been determined to require a review of their ethical conduct. Some of these studies are also 

subject to review by the Human Studies Review Board. All of the studies used have received the 

appropriate review.
Page 7 of 53

2.0 HED RECOMMENDATIONS

2.1 Data Deficiencies

There are no deficiencies in the residue chemistry or exposure data requirements for the 

proposed actions. Tolerances should be revised, as needed, for purposes of international 

harmonization and to reflect the correct commodity definitions as specified in Table 1 Section 

2.2.3. Revised Sections B and F are required for the IR-4 Petition PP#1E7854. A revised 

Section F is required for the Syngenta Petition PP#1E7869. The HASPOC concluded (TXR 

0054812), based on a weight of evidence (WOE) approach, that a 90-day inhalation toxicity 

study is required at this time to reduce uncertainty associated with the use of an oral POD for 

assessing risk via the inhalation route. This determination considered all of the available hazard 

and exposure information for cyprodinil, including: (1) the use of an oral POD results in MOEs 

as low as 150 for risk via the inhalation route for intermediate-term exposure from occupational 

uses; and (2) the toxicological profile of cyprodinil indicates that toxicity increases with 

increased exposure from short-term to intermediate durations. Therefore, in the absence of a 

route-specific inhalation study, a 10X database uncertainty factor for occupational workers and a 

10x FQPA SF factor for residential scenarios should be applied specifically to the inhalation 

assessment. 

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate HPLC/UV methods (AG-631 and AG-631B) are available for enforcing tolerances of 

cyprodinil on plant commodities. The limits of quantitation (LOQ) for the plant methods range 

from 0.01 to 0.05 ppm depending on the commodity. An adequate LC/MS method 

(GRM010.01A) is also available for enforcing tolerances of cyprodinil residues in livestock 

commodities. The method LOQ for this method is 0.02 ppm for the combined residues of 

cyprodinil and its metabolite CGA-304075 (free and conjugated), expressed as parent.

2.2.2 International Harmonization

Codex maximum residue limits (MRLs) are currently established for eggplant, pepper and 

tomato commodities. It is not possible to harmonize with Codex MRLs for residues of 

cyprodinil these subgroup 8-10B commodities because the US is recommending the 

establishment of a fruiting vegetable group 8 tolerance at 1.5 ppm, and removal of the existing 

0.45 ppm tolerance in/on tomato and tomatillo, along with the 1.0 ppm tolerance on tomato 

paste. Canada is proposing a fruiting vegetable crop group 8-10 MRL and an MRL for the 

Vegetable, leafy, except brassica, subgroup 4A. Neither Codex nor Canada has MRLs for the 

leafy petioles crop group. There are no tolerances established in Mexico. 

2.2.3 Recommended Tolerances

HED has examined the residue chemistry database for cyprodinil. Based on that review, there 

are no residue chemistry issues that would preclude granting amended registrations for

VanguardTM WG (EPA Reg. No. 100-828), Switch 62.5 WGTM Fungicide (EPA Reg. No. 100-
Page 8 of 53

953), and Inspire Super TM Fungicide (EPA Reg. No. 100-1317) to expand currently registered 

foliar uses for bulb vegetables, fruiting vegetables, berry and small fruits, dragon fruit, pome 

fruits, and leafy vegetables to include the additional commodities specified under the following 

new crop groups/subgroups, respectively: Onion, bulb subgroup 3-07A, Onion, green subgroup 

3-07B, Caneberry subgroup 13-07A, Bushberry subgroup 13-07B, Small fruit vine climbing 

subgroup 13-07F, except fuzzy kiwifruit, Dragon fruit, Vegetable, fruiting, group 8-10, 

Vegetable, leafy, except brassica, subgroup 04A, Pome Fruits Group 11-10, and Low growing 

Berry Subgroup 13-07G, Except Cranberry or establishment of tolerances for residues of 

cyprodinil only in/on the commodities listed in Table1. 

Table 1. Tolerance Summary for Cyprodinil

Commodity Established/Proposed 

Tolerance (ppm)

Recommended Tolerance 

(ppm)

Comments; Correct 

Commodity Definition

Tolerances Proposed Under PP#1E7854

Onion, bulb subgroup 3-

07A

0.6 0.6 Onion, bulb, subgroup 3-

07A

Onion, bulb subgroup 3-

07B

4.0 4.0 Onion, green, subgroup 3-

07B

Caneberry subgroup 13-

07A

10.0 10 ---

Bushberry subgroup 13-

07B

3.0 3.0 ---

Small fruit vine climbing 

subgroup 13-07F, except 

fuzzy kiwifruit

2.0 2.0 Fruit, small vine climbing, 

except fuzzy kiwifruit, 

subgroup 13-07F

Low growing berry 

subgroup 13-07G, except 

cranberry

5.0 5.0 Berry, low growing, 

subgroup 13-07G

Vegetable, fruiting, group 

8-10

1.3 1.5 ---

Vegetable, leafy, except 

Brassica, subgroup 04A

40 50 Vegetable, leafy, except 

brassica, subgroup 4A

Fruit, pome, group 11-10 1.7 1.7 ---

Dragonfruit 2.0 2.0 Dragon fruit

Tolerances That Need Amended Under PP#1E7854

Citrus, oil 100 ppm Section F

60 ppm NOF

60 ---

Tolerances That Need Removed Under PP#1E7854

Onion, bulb 0.60

Onion, green 4.0

Caneberry subgroup 13A 10

Bushberry subgroup 13B 3.0

Grape 2.0

Strawberry 5.0

Tomato 0.45

Tolerances Proposed Under PP#1E7869

Leafy petioles subgroup 

04B

30 30 Leaf petiole subgroup 4B
Page 9 of 53

2.2.4 Revisions to Petitioned-For Tolerances

The Organization for Economic Cooperation and Development tolerance calculation procedures 

were utilized in determining the appropriate tolerance level for the requested new uses. A 

tolerance level of 50 ppm for Vegetable, leafy, except brassica, subgroup 4A and a tolerance of 

1.5 ppm for the Vegetable, fruiting, group 8-10 are appropriate to cover the proposed amended 

uses of cyprodinil. These tolerance levels are different than those proposed by the registrant. 

This is due to harmonization with proposed Canadian MRLs and use of the OECD tolerance 

calculation procedures to determine MRLs.

3.0 INGREDIENT PROFILE 

3.1 Chemical Identity 

Table 2. Cyprodinil Nomenclature.

Chemical structure

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 (WDG) formulation (VangardTM Fungicide; EPA Reg. No. 100-

828); a multiple active ingredient (MAI) end-use product (Inspire Super TM Fungicide; EPA 

Reg. No. 100-1317) formulated as an emulsion [oil] in water (EW), containing 8.4% 

difenoconazole and 24.1% cyprodinil

3.2 Physical/Chemical Characteristics

A detailed description of the physiciochemical properties of cyprodinil is provided in Appendix 

C. Cyprodinil has a relatively low solubility in water. Based on its octanol/water partition 

coefficient (Log KoW = 3.9 at pH of 5 and 4.0 at pH of 7 and 9), it is likely to partition with 

organic tissues and other organic media. However, the rat metabolism indicates that cyprodinil 

does not bioaccumulate in mammals (i.e., tissue residues declined rapidly and total tissue 

residues accounted for 0.2-0.6% of the administered dose). Cyprodinil has a low vapor pressure 

and is not likely to volatilize substantially. 

3.3 Pesticide Use Pattern

3.3.1 Registered Products 

There are currently 5 active Section 3 cyprodinil registrations in the Office of Pesticides 

Programs Information Network (OPPIN) data base.

N

N

CH3

N

H
Page 10 of 53

Table 3. Registered Cyprodinil Products

Reg # Name % ai Company Name

100-811 Cyprodinil Technical 99

Syngenta Crop Protection, Inc.

100-828 Vangard WG Fungicide 75

100-953 Switch 62.5 WG 37.5

100-1317 Inspire Super 24.1

100-1328 Palladium (Fungicide) 37.5

3.3.2 Registered and Proposed New Uses 

Cyprodinil is a systemic anilino-pyrimidine fungicide registered to Syngenta Crop Protection 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. 

IR-4 is requesting amended Section 3 use of Switch 62.5 WGTM Fungicide, VanguardTM WG and 

Inspire Super TM Fungicide on all fruiting vegetable crops and all leafy vegetables Crop Group 

4A. In support of this new use, IR-4 has submitted new pepper and spinach magnitude of the 

residue data for cyprodinil using the WDG formulation of cyprodinil. IR-4 is also requesting 

Section 3 amendments to expand currently registered foliar uses of these products to include bulb 

vegetables, berry and small fruits, dragon fruit, and pome fruit to include the additional 

commodities specified under the new crop groups/subgroups for these commodities. No new 

data were submitted for this action. Instead, IR-4 wished to rely on previously submitted residue 

chemistry data which support the currently registered uses of cyprodinil. Syngenta Crop 

Protection, Inc. is requesting a Section 3 registration for the use of Vangard®WG Fungicide and 

Switch 62.5 WGTM Fungicide on the leafy petiole subgroup 4B. In support of this new use, 

Syngenta has submitted celery magnitude of the residue data for cyprodinil using the WDG 

formulation of cyprodinil at the proposed use rate. Proposed new or amended use patterns and 

for these products are provided in Table 4. 
Page 11 of 53

Table 4. Summary of Proposed New Uses of Cyprodinil

Applic. 

Timing, Type, 

and Equip.

Formulation

[EPA Reg. No.]

Applic. 

Rate 

(lb ai/A)

Max. No. 

Applic. 

per 

Season

Max. Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations

Spinach

Broadcast foliar

Ground/Aerial/

Chemigation

 Vangard WG

75% WDG

[100-828]

0.114 4 0.34 0

A minimum retreatment 

interval (RTI) of 7 days is 

proposed. 

Broadcast foliar

Ground Only

Switch 62.5WG

37.5% WDG

[100-953]

0.33 4 implied 1.31 0

A minimum retreatment 

interval (RTI) of 7-10 

days is proposed.

Celery

Broadcast foliar

Ground/Aerial/

Chemigation

Vangard WG

75% WDG

[100-828]

0.33 2 by aerial

4 implied 1.3 0

A minimum retreatment 

interval (RTI) of 7-10 

days is proposed.

Broadcast foliar

Ground Only

Switch 62.5WG

37.5% WDG

[100-953]

0.33 4 implied 1.31 0

A minimum retreatment 

interval (RTI) of 7-10 

days is proposed.

Pepper

Broadcast foliar

Ground/Aerial/

Chemigation

Vangard WG

75% WDG

[100-828]

0.33 2 by aerial

4 implied 1.3 0

A minimum retreatment 

interval (RTI) of 7-10 

days is proposed.

Broadcast foliar

Ground Only

Switch 62.5WG

37.5% WDG

[100-953] 

0.33 4 implied 1.31 0

A minimum retreatment 

interval (RTI) of 7-10 

days is proposed.

Broadcast foliar

Ground/Aerial/

Chemigation

Inspire Super

2.09 lb/gal EW

[100-1317]

0.33 2 by aerial

4 implied 1.3 0

A minimum retreatment 

interval (RTI) of 7-10 

days is proposed.

3.4 Anticipated Exposure Pathways

Exposure via dietary (food and water), occupational, and residential pathways are expected based 

on existing and proposed new/expanded uses of cyprodinil. Although there are no residential 

uses associated with the proposed new uses, an updated residential exposure assessment was 

conducted to incorporate recently updated exposure assumptions. Short-term exposures to 

residential handlers are expected from application to ornamental plants. Residential handler 

exposure scenarios are considered to be short-term only, due to the infrequent use patterns 

associated with homeowner products. An aggregate risk assessment of combined short-term 

inhalation exposure from existing residential uses and new dietary exposure estimates is required 

for residential handlers because PODs selected for these exposure routes are based on common 

toxicological effects (i.e., liver effects). 
Page 12 of 53

3.5 Considerations of Environmental Justice 

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

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED estimates 

risks to population subgroups from pesticide exposures that are based on patterns of that 

subgroup’s food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Whenever appropriate, non-dietary exposures based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas postapplication are evaluated. Further 

considerations are currently in development, as OPP has committed resources and expertise to 

the development of specialized software and models that consider exposure to bystanders and 

farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. 

4.0 HAZARD CHARACTERIZATION/ASSESSMENT

4.1 Toxicology Studies Available for Analysis

The toxicology database for cyprodinil is adequate for evaluating and characterizing cyprodinil

toxicity and selecting endpoints for purposes of this risk assessment. Acute neurotoxicity 

(MRID 48304202) and immunotoxicity studies (MRIDs 48304203, 4829350) required under 

revised 40 CFR Part 158 Toxicology Data Requirements have been submitted and determined to 

be acceptable. Based on a weight of evidence (WOE) approach a 90-day inhalation toxicity 

study is required at this time to reduce uncertainty associated with the use of an oral POD for 

assessing risk via the inhalation route (HASPOC, TXR 0054812). 

4.2 Absorption, Distribution, Metabolism and Excretion

Absorption, distribution, metabolism, and excretion of cyprodinil were studied in rats. In an 

initial study, single oral doses (0.5 or 100 mg/kg bw) of phenyl or pyrimidyl-radiolabelled 

cyprodinil were administered with one low-dose group receiving unlabelled cyprodinil for 2 

weeks prior to treatment with radiolabelled compound. Absorption was very rapid (peak 

concentration at 0.3 hours) with rapid clearance (half life of < 2 hrs). 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. Tissue residues declined rapidly, with the highest concentrations (<

1.8 ppm) found in kidneys, liver, lungs, spleen, thyroid, whole blood, and carcass. The urine, 

fecal, and bile metabolite patterns were complex, with 8, 8 and 9 defined metabolite fractions, 

respectively. Unchanged parent compound was detected in feces extract only. Excretion, 

distribution and metabolite profiles were independent of dose level, pretreatment, and type of 

label, although there were some quantitative differences sex-dependent qualitative differences in 

two urinary metabolite fractions.
Page 13 of 53

In a follow-up study, excreta and bile from radiolabelled rats from the previous study were used 

to characterize, isolate and identify the metabolites detected in that study. Eleven metabolites 

were isolated from urine, feces and bile, and the metabolic pathways in the rat were proposed. 

All urinary and biliary metabolites but one were conjugated with glucuronic acid or sulfonated, 

and excreted. Cyprodinil was almost completely metabolized by hydroxylation of the phenyl 

ring or pyrimidine ring, followed by conjugation. An alternative pathway involved oxidation of 

the phenyl ring followed by glucuronic acid conjugation. The major metabolic pathways of 

cyprodinil were not significantly influenced by the dose, treatment regimen, or sex of the animal.

4.3 Toxicological Effects

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 seen as chronic tubular lesions and 

chronic kidney inflammation 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 as mild anemia was seen in rats exposed subchronically 

(reductions in hematocrit and hemoglobin and microcytosis). Although increases in thyroid 

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). A 28-day dietary immunotoxicity study in mice resulted in no apparent suppression of 

the humoral component of the immune system. The only effect attributed to cyprodinil treatment 

was higher mean absolute, relative (to body weight), and adjusted liver weights for the 5000 ppm 

group. There were 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 antigens RBC. No dermal or systemic toxicity was seen following 

repeated dermal application at the highest dose in a 21 day dermal toxicity study in rabbits.

An acute neurotoxicity study indicated potential systemic toxicity with signs of induced hunched 

posture, pilorection, and reduced responsiveness to sensory stimuli and reduced motor activity. 

Females were slightly more affected than males per daily clinical observations, which 

disappeared by day 3 to 4. A dose-related reduction in body temperature was seen in all treated 

animals, thus hypothermia is considered a compound-related effect in the HDT and was found to 

be statistically significant, whereas the lower dosed animals was not or only marginally 

significant and was fully reversible in all groups. Clinical signs, hypothermia, and changes in 

motor activity were found to all be reversible by day 8 and 15 investigations. There were no 

histopathological findings to support evidence of damage to the central nervous system, eyes, 

optic nerves, or skeletal muscles. A subchronic neurotoxicity study showed no treatment related 
Page 14 of 53

effects on mortality, clinical signs, or gross or histological neuropathology. 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 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. 

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. 

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 complete toxicity profile for cyprodinil is provided in Appendix A. 

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

For non-inhalation routes of exposure, the FQPA factor for increased susceptibility to infants and 

children is reduced to 1x based on the following considerations. Further discussion may be 

found in the following sections.

- The toxicology data base for cyprodinil is complete and adequate for assessing increased 

susceptibility under FQPA.

- There is no indication of increased susceptibility of rats or rabbit fetuses to in utero 

and/or postnatal exposure in the developmental and reproductive toxicity data.

- There are no residual uncertainties in the exposure database.

- The dietary and residential exposure and risk assessments are conservative and will not 

underestimate exposure to cyprodinil.

For inhalation exposure scenarios for all population groups, EPA is retaining a 10X FQPA safety 

factor for the lack of a route specific study.

4.4.1 Completeness of the Toxicology Database

The toxicity database for cyprodinil is sufficient for a full hazard evaluation and is considered 

adequate to evaluate risks to infants and children. Acceptable studies have been submitted for 

developmental toxicity, reproductive toxicity, acute and subchronic neurotoxicity and 

immunotoxicity. However, in the absence of a route-specific inhalation study, a 10X database 

uncertainty factor for occupational workers and a 10x FQPA SF factor for residential scenarios 

should be applied specifically to the inhalation assessment. 
Page 15 of 53

4.4.2 Evidence of Neurotoxicity

In a subchronic neurotoxicity study in rats, there were no treatment related effects on mortality, 

clinical signs, or gross or histological neuropathology. Functional Observational Battery (FOB) 

and motor activity testing revealed no treatment related effects up to the highest dose tested. In 

an acute neurotoxicity study in mice, clinical signs, hypothermia, and changes in motor activity 

were all found to be reversible and no longer seen at day 8 and 15 investigations. There were no 

treatment related effects on mortality, gross or histological neuropathology. Reduced motor 

activity, induced hunched posture, pilorection and reduced responsiveness to sensory stimuli 

were observed and disappeared in all animals by day 3 to 4.

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

The available acceptable guideline studies indicated no increased susceptibility of rats or rabbits 

to in utero and/or from postnatal exposure to cyprodinil. In the prenatal developmental toxicity 

studies in rats and rabbits and the two-generation reproduction study in rats, toxicity to the 

fetuses/offspring, when observed, occurred at the same doses at which effects were observed in

maternal/parental animals. 

In a rat developmental toxicity study, there were significantly lower mean fetal weights in the 

high-dose group compared to controls as well as a significant increase in skeletal anomalies in 

the high-dose group due to abnormal 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. In the rabbit study, the only treatment related developmental effect 

was indication of an increased incidence of a 13th rib at maternally toxic doses. Signs of fetal 

effects in the reproductive toxicity study 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). Reproductive effects were 

seen only at doses that also caused parental toxicity.

4.4.4 Residual Uncertainty in the Exposure Database 

There are no residual uncertainties in the exposure database. The residue data base is adequate. 

The dietary risk assessment is conservative and will not underestimate dietary exposure to 

cyprodinil. The residential exposure estimates included in the aggregate risk assessment are 

conservative based on maximum use rates and will not underestimate non-dietary risks to 

homeowners. 

4.5 Toxicity Endpoints and Points of Departure

Toxicity endpoints and points of departure (PODs) for dietary (food and water) and exposure 

scenarios are summarized below. A detailed description of the studies used as a basis for the 

selected endpoints are presented in Appendix A. 
Page 16 of 53

4.5.1 Dose-Response Assessment

An acute POD of 200 mg/kg/day day was selected from an acute neurotoxicity study in rats 

based on LOAEL of 600 mg/kg/day showing clinical signs (hunched posture, pilorection, and 

reduced responsiveness to sensory stimuli, reduced motor activity and hypothermia). An 

uncertainty factor (UF) of 100x (10x to account for interspecies extrapolation and 10x for 

intraspecies variation) was applied to the NOAEL to obtain an acute reference dose (aRfD) of 

2.0 mg/kg/day. Since the FQPA factor has been reduced to 1X, the acute population adjusted 

dose (aPAD) is equivalent to the aRfD. The selected endpoint is considered appropriate for 

acute dietary exposure because effects were seen after a single dose. [Note: The acute RfD has 

been revised from previous risk assessments based on receipt and review of an acute 

neurotoxicity study and subsequent reevaluation of available data.]

A chronic POD of 2.7 mg/kg/day (NOAEL) was selected from a chronic/carcinogenicity oral 

study in rats based on the histopathological alterations in the liver (spongiosis hepatis) in males 

at 35.6 mg/kg/day (LOAEL). The selected NOAEL is the lowest NOAEL observed in the most 

sensitive species following long-term exposure. A UF 100x (10x to account for interspecies 

extrapolation and 10x for intraspecies variation) was applied to the dose to obtain a chronic 

reference dose (cRfD/cPAD) of 0.027 mg/kg/day. 

A POD for dermal exposure was not selected because no dermal or systemic toxicity was seen 

following repeated dermal application at the highest dose tested in a 21 day dermal toxicity study 

in rabbits. 

A short-term inhalation exposure POD of 62 mg/kg/day (NOAEL) was selected from a 28-day 

feeding study in rats based on based on decreased body-weight gain, increased cholesterol and 

phospholipid levels, microcytosis, and hepatocyte hypertrophy seen at the LOAEL of 299 

mg/kg/day. An intermediate-term inhalation exposure POD of 2.7 mg/kg/day (NOAEL) was 

selected from the chronic/carcinogenicity oral study in rats. The toxicological profile of 

cyprodinil indicates that toxicity increases with increased durations, specifically between shortterm (28-day) and intermediate exposures (2-year). Therefore, based on the weight of evidence

regarding cyprodinil, a 90-day inhalation toxicity study is required to reduce uncertainties

associated with the use of an oral POD for assessing risk via the inhalation route. 

4.5.2 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 (i.e., hand to mouth) exposures to cyprodinil, aggregate 

exposure from food and incidental oral exposures is not required. However, an aggregate risk 

assessment of combined short-term 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).
Page 17 of 53

4.5.3 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 by the HED Hazard 

Identification Assessment Review Committee (HIARC) as “not likely to be carcinogenic to 

humans.”

4.5.4 Summary of Endpoints Selected for Risk Assessment

Toxicological doses/endpoints selected for the cyprodinil risk assessment are provided in Table 5

and 6.

Table 5. 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

(All Populations)

NOAEL = 200

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Acute RfD = 2.0

mg/kg/day 

aPAD = 2.0

mg/kg/day 

Acute Neurotoxicity - Rat

LOAEL = 600 mg/kg/day based on clinical 

signs of toxicity (hunched posture, 

pilorection, and reduced responsiveness to 

sensory stimuli, reduced motor activity and 

hypothermia)

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 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. 
Page 18 of 53

Table 6. Summary of Toxicological Doses and Endpoints for Cyprodinil for Use in Non-Dietary 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)

No dermal or systemic toxicity was seen following repeated dermal application at the highest dose tested 

for 21 days to rabbits. Therefore a POD for dermal exposure was not selected.

Inhalation ShortTerm 

(1-30 days) 

Oral NOAEL= 62 

mg/kg/day

(inhalation 

absorption rate = 

100%)

Residential: 

UFA = 10x

UFH = 10x

FQPA SF = 

10X*

Occupational: 

UFA = 10x

UFH = 10x

UFDB = 10X

Residential LOC 

for MOE = 1,000 

Occupational LOC 

for MOE = 1,000

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

Intermediate-Term

(1-6 months)

Oral NOAEL = 

2.7 mg/kg/day

(inhalation

absorption rate = 

100%)

Residential: 

UFA = 10x

UFH = 10x

FQPA SF = 

10X*

Occupational: 

UFA = 10x

UFH = 10x

UFDB = 10X

Residential LOC 

for MOE = 1,000 

Occupational LOC 

for MOE = 1,000

2-Year Chronic Toxicity/ Carcinogenicity in 

Rats

LOAEL = 35.6 mg/kg/day based on 

degenerative liver lesions (spongiosis hepatis) 

in males.

Cancer (all routes) Not likely human carcinogen

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to 

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

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

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

among members of the human population (intraspecies). UFDB = lack of inhalation study. SF = FQPA Safety Factor MOE = 

margin of exposure. LOC = level of concern. * FQPA SF is composed of the 1X factor for increased quantitative susceptibility 

and the 10X factor for the inhalation study data gap. 

5.0 DIETARY AND DRINKING WATER EXPOSURE ASSESSMENT

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

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

studies on apple, peach, potato, tomato, and wheat. The nature of the residue in ruminants is 

adequately understood based on acceptable lactating goat metabolism studies. A poultry 

metabolism study is not available but is not required for this action since there are no poultry 

feed stuffs associated with the proposed new use of cyprodinil on leafy petiole group 4B. The 

nature of the residue in confined rotational crops is understood.

 
Page 19 of 53

5.1.2 Summary of Environmental Degradation

The environmental fate data base for cyprodinil is substantially complete. Cyprodinil has a 

relatively low solubility in water. Based on its octanol/ water partition coefficient, it is likely to 

partition with organic tissues and other organic media. It is alkaline in water. It is not likely to 

volatilize substantially based on its low vapor pressure and Henry’s Law constant. Cyprodinil 

appears to bind strongly to particulate and sediment, showing relatively low soil mobility. It

appears to be a persistent compound under most conditions, except aerobic soil metabolism, as 

demonstrated in laboratory studies. 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 has a 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 are the parent and CGA 

249287 (4-cyclopropyl-6-methylpyrimidin-2-amine) (D292557, 6/8/03).

5.1.3 Comparison of Metabolic Profile

Based on acceptable metabolism studies on apple, peach, potato, tomato, and wheat, 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. The metabolism of cyprodinil in ruminants 

proceeds predominantly via hydroxylation followed by conjugation with sulfuric and glucuronic 

acid. Breakdown of the pyrimidinyl ring was seen only in the liver and resulted in Metabolite 

L1. Cleavage of the amino bridge between the phenyl and the pyrimidinyl rings was only a 

minor reaction as indicated by the small amounts of CGA 249287 found in the liver and kidneys 

of goats dosed with [14C-pyrimidinyl] cyprodinil. Free and conjugated CGA-304075 was a major 

residue in muscle, liver, kidney, and milk based on acceptable lactating goat metabolism studies 

using [14C-phenyl] and [14C-pyrimidinyl]cyprodinil. 

In metabolism studies in rats, cyprodinil was almost completely metabolized by hydroxylation of 

the phenyl ring or pyrimidine ring, followed by conjugation. An alternative pathway involved 

oxidation of the phenyl ring followed by glucuronic acid conjugation. In the rat study, eleven 

metabolites were isolated from urine, feces and bile, and the metabolic pathways in the rat were 

proposed. All urinary and biliary metabolites but one were conjugated with glucuronic acid or 

sulfonated, and excreted. CGA 304075 was not separately identified as an isolated metabolite in 

the rat study. Metabolite structures are provided in Appendix B.
Page 20 of 53

5.1.4 Residues of Concern Summary and Rationale

Residues of concern for dietary and drinking water risk assessment and tolerance expression for 

cyprodinil are provided in Table 7. HED has concluded that the residues of concern for livestock 

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 water residues of concern are the parent and CGA 249287 (4-cyclopropyl-6-

methylpyrimidin-2-amine) (D292557, 6/8/03).

Table 7. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance 

Expression for Cyprodinil

Matrix Risk Assessment Tolerance Expression

Plants cyprodinil cyprodinil

Livestock cyprodinil and CGA-304075 cyprodinil and CGA-304075

Water cyprodinil and CGA 249287 NA

5.2 Food Residue Profile

5.2.1 Residues in Crops

There are an adequate number of field trials from representative geographical locations to 

support the requested commodity and crop group tolerances. Field trial study data were 

submitted for spinach, pepper, and lemon commodities. The trials were conducted with Switch 

62.5WG to support the requested tolerances for a 0-day PHI. Results of submitted studies are 

provided in Table 8. Residue decline data show that cyprodinil decreases in bell peppers, 

spinach, and celery with increasing pre-harvest intervals.

TABLE 8. Summary of Residue Data from Field and Greenhouse Trials with Cyprodinil.

Commodity Total App. 

Rate (lb ai/A)

[g a.i./ha]

PHI 

(days)

Residue Levels (ppm)1

n Sample

Min.

Sample

Max.

LAFT2 HAFT2 Median Mean Std. Dev.

Field Trials

Bell Pepper 1.302-1.417

[1459.0-

1588.3]

0 18 0.023 0.697 0.036 0.682 0.149 0.201 0.191

Nonbell 

Pepper

1.308-1.339

[1466.1-

1500.8]

0 10 0.119 0.818 0.169 0.668 0.225 0.318 0.209

Spinach 1.300-1.367

[1457.1-

1532.2]

0 22 4.58 36.9 5.64 32.1 10.3 11.8 7.36

Celery 2.16-2.23 0 8 3.2 17 3.5 17 8.5 8.7 4.5

Greenhouse Trials

Bell Pepper 1.304-1.315

[1461.6-

1473.9]

0 8 0.04 0.32 0.08 0.27 0.21 0.20 0.09

Nonbell 

Pepper

1.327

[1487.4] 0 2 0.58 0.60 0.59 0.59 0.59 0.59 --
Page 21 of 53

The submitted field trial data are supported by acceptable storage stability data. Demonstrated 

storage stability for the submitted field trial samples include 9 months for peppers, 5.8 months 

for dried lemon pulp, 5.9 months for lemon juice, and 10.6 months for lemon oil. The stability 

of cyprodinil has been demonstrated in a variety of other crops, including mustard greens for 20 

months and grape, wine, apple, wheat (ear and stalk), strawberry, and potato for up to 2 years. 

Adequate confined and limited field rotational crop studies are available for the registered and 

proposed new uses. As residues of parent and each metabolite were <LOQ in/on all lettuce, 

garden beet and wheat raw agricultural commodity samples, HED concluded that rotational crop 

tolerances are not currently required.

5.2.2 Residues in Meat, Milk, Poultry, and Eggs

Adequate cattle feeding studies are available for cyprodinil. Tolerances for cyprodinil residues 

in livestock commodities were previously assessed in conjunction with petitions for tolerances 

on various plant commodities. Using the Agency’s most recent guidance on constructing 

reasonably balanced livestock diets the maximum reasonably dietary burdens (MRDBs) of 

livestock for cyprodinil residues were calculated to be 0.88 ppm for beef cattle, 1.2 ppm for dairy 

cattle, and 0.005 ppm for poultry and swine. Based on these MRDBs, tolerances for residues of 

cyprodinil and free and conjugated CGA-304075, expressed in parent equivalents, were required 

on meat byproducts of cattle, goats, horses, and sheep at 0.02 ppm (LOQ). The proposed new 

uses do not contain any livestock feed stuffs, therefore, HED has determined that the currently 

established 0.02 ppm tolerance levels for meat byproducts of cattle, goats, horses, and sheep are 

adequate. Adequate storage stability data are available to support the submitted livestock 

feeding studies.

5.2.3 Residues in Processed Commodities 

A lemon processing study was submitted in support of proposed new uses. The submitted lemon 

processing study is adequate. Residues of cyprodinil concentrated in dried lemon pulp and oil, 

but did not concentrate in lemon juice. The tolerance for citrus oil can be decreased to 60 ppm 

(0.34 ppm x 171= 58 ppm).

5.2.4 Estimated Drinking Water Concentrations 

Drinking water residues were incorporated directly into the acute and chronic dietary analyses as

“water, direct, all sources” and “water, indirect, all sources.” Estimated Drinking Water 

Concentrations (EDWCs) for cyprodinil 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. EDWCs for cyprodinil and its metabolite 

CGA-249287 were derived based on a maximum application rate of 0.47 lb a.i./A applied 3 

times/year, or 1.4 lb a.i./A/year, on grapes. 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 CGA-249287 used in the exposure assessment, as well as the ground water 

estimates, are provided in Table 9. 
Page 22 of 53

Table 9. EDWCs for the Cyprodinil Human Health Risk Assessment 

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

Surface Water 34.79 24.65

Ground Water 0.0861 0.0861

5.3 Dietary and Drinking Water Exposure and Risk

Acute and chronic dietary and drinking water exposure and risk assessments were 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. 

5.3.1 Acute Dietary and Drinking Water Analysis

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

and various 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 estimates 

are not of concern for the general U.S. population or any of the other population subgroups. The 

subgroup with the highest risk estimate is children 1-2 years old with a % acute population 

adjusted dose (aPAD) of 8%. The% aPAD for the general U.S. population is 5%.

Table 10. Summary of Acute Dietary Exposure and Risk for Cyprodinil

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

Exposure (mg/kg/day) %aPAD

General U.S. Population

2.0

0.095794 4.8

All Infants (< 1 year old) 0.102882 5.1

Children 1-2 years old 0.151445 7.6

Children 3-5 years old 0.131883 6.6

Children 6-12 years old 0.098193 4.9

Youth 13-19 years old 0.080270 4.0

Adults 20-49 years old 0.092162 4.6

Adults 50+ years old 0.085400 4.3

Females 13-49 years old 0.099465 5.0

5.3.2 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. For the chronic dietary analysis, tolerance level 

residues for most commodities; average field trial residues for pome fruit, head lettuce, leaf 

lettuce, and grapes; and 100% crop treated assumptions were used. DEEM default and empirical 

processing factors were used to modify the tolerance values. The chronic analysis incorporated 
Page 23 of 53

the 10 year average surface drinking water estimate from application of cyprodinil to grapes. 

Chronic dietary risk estimates are not of concern for the general U.S. population or any of the 

other population subgroups. The subgroup with the highest risk estimate is children 1-2 years 

old with a % chronic PAD (cPAD) of 75%. The % cPAD for the general U.S. population is 

28%.

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

Population Subgroup cPAD (mg/kg/day) Chronic

Exposure (mg/kg/day) % cPAD

General U.S. Population

0.027

0.007421 28

All Infants (< 1 year old) 0.014099 52

Children 1-2 years old 0.020269 75

Children 3-5 years old 0.015148 56

Children 6-12 years old 0.008552 32

Youth 13-19 years old 0.005195 19

Adults 20-49 years old 0.005818 22

Adults 50+ years old 0.007260 27

Females 13-49 years old 0.006066 23

6.0 RESIDENTIAL EXPOSURE AND RISK

This existing residential use pattern has previously been assessed and the resulting exposures and 

risk estimates did not exceed HED’s level of concern. However, HED has recently updated the 

residential standard operating procedures (SOPs) and body weights to be used in all human 

health assessments. Therefore, all of the existing residential use patterns have been reassessed 

for residential handler and post application exposures using these new procedures and data.

Risks for existing residential applications do not present risks of concern (Table 12). 

Table 12. Residential Handler Inhalation Exposure and Risk Estimates for Cyprodinil.

Application 

Site Application Equipment

Max 

Application 

Rate

(lb ai/gallon 

solution)

Amount AI 

Handled 

Factor

(gallons 

solution)

Unit 

Exposures 

(mg/lb ai)

Absorbed 

Daily Dose 

(mg/kg-day)

MOE

LOC=1,000

Ornamentals

Manually-pressurized 

Handwand

0.00141

5 1.1 0.000098 640,000

Hose-end Sprayer 11 0.0014 0.00000027 230,000,000

Backpack 5 1.1 0.000098 640,000

7.0 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 risks 

themselves and can be aggregated. When aggregating exposures and risks from various sources, 

HED considers both the route and duration of exposure. Since there are no residential incidental 
Page 24 of 53

oral (i.e., hand to mouth) exposures to cyprodinil based on existing registered products and use 

patterns, aggregate exposure from food and incidental oral exposures is not required. Short-term 

residential handler exposures are expected based on current use patterns. Intermediate-term 

residential exposures are not anticipated. An aggregate risk assessment of combined short-term 

inhalation and oral (dietary and drinking water) exposure is required for residential handlers 

because PODs selected for these exposure routes are based on common toxicological effects (i.e., 

liver effects). The acute and chronic exposure estimates from the dietary exposure analyses 

represent aggregate risk for acute and chronic exposures and are not of concern. 

7.1 Short-Term Aggregate Risk to Residential Applicators

Short term aggregate exposure takes into account residential exposure plus average exposure 

levels to food and water (considered to be a background exposure level). The short term 

aggregate risk for residential handlers is the estimated risk associated with combined risks from 

average food and drinking water exposures and inhalation exposures to adult applicators. Short 

term aggregate risk estimates for residential handlers are provided in Table 13. Aggregate 

margins of exposure (MOEs) are not of concern. 

Table 13. Short-Term Aggregate Risk Assessment for Cyprodinil

Residential Handler

Exposure Scenario

Food + Water Exposure

(mg/kg/day) 1

Short-Term Residential 

Exposure, (mg/kg/day) 2

MOE

Food + Water + Residential 3

Mixing/Loading/Applying WDG – Ornamentals

Manually-pressurized 

Handwand

0.007

0.000098

9000 Hose-end Sprayer 0.00000027

Backpack 0.000098

1 Chronic Dietary/Drinking Water Exposure (mkd) (Adults 50+ years old)

2 Residential Exposure = Inhalation Daily Dose (mkd)

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

Exposure (mkd)

8.0 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 
Page 25 of 53

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/.

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION

9.1 Exposure Scenarios

Occupational handler and post-application exposure scenarios were assessed for existing and 

proposed new/expanded uses on number of commodities. Based on the product labels short-term

exposure is expected. There is also potential for intermediate-term exposure. Therefore shortand intermediate-term exposure is assessed for occupational handlers and post-application 

activities. Dermal risk to agricultural workers following treatments was not assessed since no 

short- or intermediate-term dermal endpoint of concern was identified. 

9.2 Handler Exposure and Risk Assessment

The term “handler” applies to individuals who mix, load, and apply the pesticide product. The 

following handler exposure scenarios were assessed for proposed new uses of cyprodinil.

9.2.1 Handler Exposure Scenarios

Mixer/Loaders

Mixing/loading dry flowables or liquids to support groundboom ground application

Mixing/loading dry flowables or liquids to support airblast ground application

Mixing/loading dry flowables or liquids to support aerial applications

Mixing/loading dry flowables or liquids to support chemigation application

Mixing/loading dry flowables to support dip applications

Applicators

Applying sprays with open cab groundboom equipment

Applying sprays with open cab airblast equipment

Applying sprays with aerial, fixed-wing, enclosed cockpit equipment

Flagger 

Flagging for aerial equipment spray applications

9.2.2 Handler Exposure Data

No chemical-specific handler exposure data were submitted in support of this registration. It is 

the policy of HED to use the best available data to assess handler exposure. Sources of generic 

handler data, used as surrogate data in the absence of chemical-specific data, include the PHED 

1.1, the AHETF database, the ORETF database, or other registrant-submitted occupational 

exposure studies. Some of these data are proprietary and subject to the data protection 

provisions of FIFRA. The standard values recommended for use in predicting handler exposure 

that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational 

Pesticide Handler Unit Exposure Surrogate Reference Table” 

(http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), which, along with 
Page 26 of 53

additional information on HED policy on use of surrogate data, including descriptions of the 

various sources, can be found at http://www.epa.gov/pesticides/science/handler-exposuredata.html.

9.2.3 Handler Exposure Assumptions

The following standard exposure assumptions were used in estimating risks to workers from 

exposure to cyprodinil for the existing and proposed new/expanded uses. The daily areas treated 

were defined for each handler scenario by determining the amount that can be reasonable treated 

in a single day. When possible, the assumptions for daily areas treated are taken from HED’s 

ExpoSAC Policy #9 (: “Standard Values for Daily Acres Treated in Agriculture”, which was 

revised on July 5, 2000.

• Average body weight of an adult handler is 80 kg.

• Exposure duration short-term and potentially intermediate-term for all workers 

assessed. 

• Maximum application rates as determined by label review were used for all types and 

methods of application.

• SOP daily volumes handled and/or area treated used for the scenarios assessed are: 

- 80 acres treated per day for groundboom applications

- 350 acres treated per day for aerial applications 

- 40 acres treated per day for airblast applications

HED does not possess information to indicate how much dip solution might typically be required 

for the proposed pre-plant use. For a typical mixer/loader situation, there are HED default values 

available with which to assess exposure and risk. However, in this particular case of a 

mixer/loader preparing a batch dip solution for dipping strawberry transplants; it is not known 

how much stock solution is typically needed per day. For other use patterns such as 

mechanically-pressurized handgun spraying, HED typically assumes 1,000 gallons of solution 

are prepared and sprayed per day. HED believes it is unlikely that volumes of dip solution 

greater than 1,000 gallons per day would be necessary; however, there is no documentation to 

support that assumption. For the purposes of this assessment, estimates of exposure and risk are 

presented for assumed uses of 100 gallons/day and for 1,000 gallons per day. 

9.2.4 Handler Exposure and Risk Estimates

A target LOC or MOE of 1000 is considered adequate for inhalation and dermal exposure. All 

worker exposures are assessed as short-and intermediate-term based on label prescribed uses and 

expected or potential exposure durations. For this action, the proposed labels include resistance 

management language indicating to alternate fungicides and mode of action after 2 applications 

with cyprodinil. Based on this language, it is possible that a short-term (1-30 days) exposure 

assessment would be health-protective for occupational handlers; however, since use/usage data 

are not available to justify eliminating consideration of potential intermediate-term exposures, 

both durations were assessed. Occupational exposures may occur over a single day or up to 

weeks at a time; some applicators may apply these products over a period of weeks because they 

are commercial applicators who are completing multiple pesticide applications for multiple 
Page 27 of 53

clients. Information on the commercial use of fungicides could help to refine the assessment. 

Long-term exposures are not expected; therefore, a long-term assessment was not conducted. 

Dermal risks to agricultural workers following treatments were not assessed since no short- or 

intermediate-term dermal endpoint of concern was identified. Short-term inhalation risk

estimates to occupational handlers are not of concern for any scenario (i.e., MOEs ≥ 1,000) at 

baseline (i.e., no respirator). However, intermediate-term exposure risk estimates at baseline for 

mixing/loading dry flowables for aerial, chemigation, and groundboom applications were of 

concern (i.e., MOE < 1,000). MOEs for these scenarios ranged from 150 to 920. These concerns 

were mitigated by applying additional Protective Personal Equipment (PPE) (i.e., PF5 or PF 10 

respirators). The scenario with the lowest MOE (mixing/loading a dry flowable formulation for 

aerial application; MOE = 150) reached an MOE of 1,500 after adding a PF 10 respirator. A 

summary of occupational handler exposure and risk calculations, assumptions, and results is 

provided in Tables 14-16.

Table 14. Switch® 62.5WG Fungicide Risk of Exposure

Exposure 

Scenario Crop Name

Applicati

on

Rate 

(lbs 

a.i./A)a

Area 

Treat

ed 

Daily

(A)b

Unit 

Exposurec,d

(mg/lb ai)

Daily Dosee

(mg/kg/day)

ST MOEf

LOC=1,000

IT MOEg

LOC=1,000

Mitigation Level (Baseline, PF 5 and/or PF 10)

Dry Flowable Mixer/Loader

Chemigation

Berries, Bushberries, 

Caneberries, Grapes; 

Strawberries; Tropical 

Fruits, Dragon Fruit; 

Leafy Vegetables 

(except Brassica); 

Onions, Bulb Onions, 

Green Onions, Onions 

grown for seed; 

Strawberries; 

Tomatoes, Peppers, 

Eggplant and Other 

Fruiting Vegetables

0.33

350

Baseline = 

0.00896

PF 5=0.0017

PF 

10=0.00090

Baseline = 

0.013

PF5=0.0026

PF10=0.0013

Baseline = 

4,800

Baseline = 

210

PF5=1,000

PF10=2,100

Aerial (Only 

California)

Berries, Bushberries, 

Caneberries, Grapes; 

Strawberries; Tropical 

Fruits, Dragon Fruit

350

Baseline = 

0.00896

PF 5=0.0017

PF 

10=0.00090

Baseline = 

0.013

PF5=0.0026

PF10=0.0013

Baseline = 

4,800

Baseline = 

210

PF5=1,000

PF10=2,100

Groundboo

m

Leafy Vegetables 

(except Brassica); 

Onions, Bulb Onions, 

Green Onions, Onions 

grown for seed; 

Strawberries; 

Tomatoes, Peppers, 

Eggplant and Other 

Fruiting Vegetables; 

Bushberries; 

Caneberries; Leafy 

Petioles Subgroup 

04B

80

Baseline = 

0.00896

PF5=0.001792

Baseline = 

0.0029

PF5=0.00059

Baseline = 

21,000

Baseline = 

920

PF5=4,600

Airblast

Berries Grapes; 

Tropical Fruits, 

Dragon Fruit

40 Baseline = 

0.00896

Baseline = 

0.0015

Baseline = 

42,000

Baseline = 

1,800
Page 28 of 53

Table 14. Switch® 62.5WG Fungicide Risk of Exposure

Exposure 

Scenario Crop Name

Applicati

on

Rate 

(lbs 

a.i./A)a

Area 

Treat

ed 

Daily

(A)b

Unit 

Exposurec,d

(mg/lb ai)

Daily Dosee

(mg/kg/day)

ST MOEf

LOC=1,000

IT MOEg

LOC=1,000

Mitigation Level (Baseline, PF 5 and/or PF 10)

Dip 

applications Strawberry transplants 0.0019 lbai/gal

100 

gallon

s Baseline = 

0.0266

Baseline = 

0.000062

Baseline = 

990,000

Baseline = 

43,000

1,000 

gallon

s

Baseline = 

0.00062

Baseline = 

99,000

Baseline = 

4,300

Liquid Spray Applicator

Aerial, 

Fixed-Wing 

(Only 

California)

Berries, Bushberries, 

Caneberries, Grapes; 

Strawberries; Tropical 

Fruits, Dragon Fruit

0.33

350 Baseline = 

0.000068

Baseline = 

0.00010

Baseline = 

640,000

Baseline = 

28,000

Open Cab 

Groundboo

m

Leafy Vegetables 

(except Brassica); 

Leafy Petioles 

Subgroup 04B;

Onions, Bulb Onions, 

Green Onions, Onions 

grown for seed; 

Strawberries; 

Bushberries; 

Caneberries; 

Tomatoes, Peppers, 

Eggplant and Other 

Fruiting Vegetables

80 Baseline = 

0.00034

Baseline = 

0.00011

Baseline = 

560,000

Baseline = 

24,000

Open Cab 

Airblast

Berries; Grapes; 

Tropical Fruits, 

Dragon Fruit

40 Baseline = 

0.00471

Baseline = 

0.00077

Baseline = 

80,000

Baseline = 

3,500

Aerial Flagger

Flagger

Berries, Bushberries, 

Caneberries, Grapes; 

Strawberries; Tropical 

Fruits, Dragon Fruit

0.33 350 Baseline = 

0.00035

Baseline = 

0.00050

Baseline = 

120,000

Baseline = 

5,400

a. Application Rates based on Syngenta’s Switch® 62.5WG Fungicide proposed label

b. Science Advisory Council Policy No. 9.1

c. Unit Exposures based on March, 2012 “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”

d. PHED/ORETF (level of mitigation: Baseline, PPE, PF 5 = 80% protection factor provided by a NIOSH-approved quarter-face, cup-style 

respirator (it is similar to the paint masks painters often wear), PF 10 = a 90% protection factor is provided by a NIOSH-approved halfface cartridge or canister respirator or a powered air-purifying respirator (PAPR).

e. Inhalation Dose (mg/kg/day) daily unit exposure (mg/lb ai) x application rate (lb ai/acre) x acres treated daily (A) / body weight (80 kg) 

f. Short-term Inhalation MOE = NOAEL (62 mg/kg/day) / inhalation daily dose (mg/kg/day). LOC = 1000

g. Intermediate-term Inhalation MOE = NOAEL (2.7 mg/kg/day) / inhalation daily dose (mg/kg/day). LOC = 1000
Page 29 of 53

Table 15. Vangard® WG Fungicide Risk of Exposure

Exposure 

Scenario Crop Name

Applicatio

n

Rate 

(lbs a.i./A)a

Area 

Treate

d Daily

(A)b

Unit 

Exposurec,d

(mg/lb ai)

Daily Dosee

(mg/kg/day)

ST MOEf

LOC=1,00

0

IT MOEg

LOC=1,00

0

Mitigation Level (Baseline, PF 5 and/or PF 10)

Dry Flowable Mixer/Loader

Aerial (Only 

California)/

Chemigation

Pome Fruits 0.23

350

Baseline = 

0.00896

PF5=0.001792

Baseline = 

0.0092

PF5=0.0018

Baseline = 

6,700

Baseline = 

290

PF5=1,500

Berries, Bushberries, 

Caneberries; Leafy 

Vegetables (except 

brassica); Leafy 

Petioles Subgroup 

04B; Tropical Fruits, 

Dragon Fruit; 

Tomatoes, Peppers, 

Eggplant and Other 

Fruiting Vegetables; 

Tropical Fruits, 

Dragon Fruit

0.33

Baseline = 

0.00896

PF5=0.001792

PF10=0.00089

6

Baseline = 

0.013

PF5=0.0026

PF10=0.001

3

Baseline = 

4,800

Baseline = 

210

PF5=1,000

PF10=2,10

0

Grapes; Onions, Bulb 

Onions, Green 

Onions, Onions 

grown for seed; 

Strawberries

0.47

Baseline = 

0.00896

PF5=0.001792

PF10=0.00089

6

Baseline = 

0.018

PF5=0.0037

PF10=0.001

8

Baseline = 

3,400

Baseline = 

150

PF5=730

PF10=1,50

0

Groundboo

m

Onions, Bulb Onions, 

Green Onions, Onions 

grown for seed; 

Strawberries

0.47

80

Baseline = 

0.00896

PF5=0.001792

Baseline = 

0.0042

PF5=0.0008

4

Baseline = 

15,000

Baseline = 

640

PF5=3,200

Leafy Vegetables 

(except Brassica); 

Leafy Petioles 

Subgroup 04B; 

Bushberries; 

Caneberries;Tomatoe

s, Peppers, Eggplant 

and Other Fruiting 

Vegetables 

0.33

Baseline = 

0.00896

PF5=0.001792

Baseline = 

0.0029

PF5=0.0004

2

Baseline = 

21,000

Baseline = 

920

PF5=6,400

Airblast

Grapes 0.47

40 Baseline = 

0.00896

Baseline = 

0.0021

Baseline = 

30,000

Baseline = 

1,300

Berries;Tropical 

Fruits, Dragon Fruit 0.33 Baseline = 0.0015

Baseline = 

42,000

Baseline = 

1,800

Pome Fruits 0.23 Baseline = 0.0010

Baseline = 

59,000

Baseline = 

2,600

Dip 

applications

Strawberry 

transplants

0.0019 lb 

ai/gal

100 

gallons Baseline = 

0.0266

Baseline = 

0.000062

Baseline = 

990,000

Baseline = 

44,000

1,000 

gallons

Baseline = 

0.000623

Baseline = 

99,000

Baseline = 

4,300

Liquid Spray Applicator

Aerial, 

Fixed Wing 

(Only 

California)

Pome Fruits 0.23

350

Baseline = 

0.000068

Baseline = 

0.00007

Baseline = 

890,000

Baseline = 

39,000

Berries, Bushberries, 

Caneberries; Leafy 

Vegetables (except 

brassica); Leafy 

Petioles Subgroup 

04B; Tropical Fruits, 

Dragon Fruit; 

Tomatoes, Peppers, 

0.33 Baseline = 

0.000068

Baseline =

0.00010

Baseline = 

640,000

Baseline = 

28,000
Page 30 of 53

Table 15. Vangard® WG Fungicide Risk of Exposure

Exposure 

Scenario Crop Name

Applicatio

n

Rate 

(lbs a.i./A)a

Area 

Treate

d Daily

(A)b

Unit 

Exposurec,d

(mg/lb ai)

Daily Dosee

(mg/kg/day)

ST MOEf

LOC=1,00

0

IT MOEg

LOC=1,00

0

Eggplant and Other 

Fruiting Vegetables; 

Tropical Fruits, 

Dragon Fruit

Grapes; Onions, Bulb 

Onions, Green 

Onions, Onions 

grown for seed; 

Strawberries

0.47 Baseline = 

0.00014

Baseline = 

440,000

Baseline = 

19,000

Open Cab 

Groundboo

m

Onions, Bulb Onions, 

Green Onions, Onions 

grown for seed; 

Strawberries

0.47

80 Baseline = 

0.00034

Baseline = 

0.00016

Baseline = 

390,000

Baseline = 

17,000

Leafy Vegetables 

(except Brassica); 

Leafy Petioles 

Subgroup 04B; 

Bushberries; 

Caneberries;Tomatoe

s, Peppers, Eggplant 

and Other Fruiting 

Vegetables 

0.33 Baseline = 

0.00011

Baseline = 

560,000

Baseline = 

24,000

Open Cab 

Airblast

Grapes 0.47

40 Baseline = 

0.00471

Baseline = 

0.0011

Baseline = 

56,000

Baseline = 

2,400

Berries; Tropical 

Fruits, Dragon Fruit 0.33 Baseline = 0.00077

Baseline = 

80,000

Baseline = 

3,500

Pome Fruits 0.23 Baseline = 0.00055

Baseline = 

110,000

Baseline = 

4,900

Aerial Flagger

Flagger

Pome Fruits 0.23

350 Baseline = 

0.00035

Baseline = 

0.00036

Baseline = 

170,000

Baseline = 

7,500

Berries, Bushberries, 

Caneberries; Leafy 

Vegetables (except 

brassica); Tropical 

Fruits, Dragon Fruit; 

Tomatoes, Peppers, 

Eggplant and Other 

Fruiting Vegetables; 

Tropical Fruits, 

Dragon Fruit

0.33 Baseline = 

0.00050

Baseline = 

120,000

Baseline = 

5,400

Grapes; Onions, Bulb 

Onions, Green 

Onions, Onions 

grown for seed; 

Strawberries

0.47 Baseline = 

0.00072

Baseline = 

86,000

Baseline = 

3,800

a. Application Rates based on Syngenta’s Vangard® WG Fungicide proposed label

b. Science Advisory Council Policy No. 9.1

c. Unit Exposures based on March, 2012 “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”

d. PHED/ORETF (level of mitigation: Baseline, PPE, PF 5 = 80% protection factor provided by a NIOSH-approved quarter-face, cup-style 

respirator (it is similar to the paint masks painters often wear), PF 10 = a 90% protection factor is provided by a NIOSH-approved half-face 

cartridge or canister respirator or a powered air-purifying respirator (PAPR).

e. Inhalation Dose (mg/kg/day) daily unit exposure (mg/lb ai) x application rate (lb ai/acre) x acres treated daily (A) / body weight (80 kg) 

f. Short-term Inhalation MOE = NOAEL (62 mg/kg/day) / inhalation daily dose (mg/kg/day). LOC = 1000

g. Intermediate-term Inhalation MOE = NOAEL (2.7 mg/kg/day) / inhalation daily dose (mg/kg/day). LOC = 1000
Page 31 of 53

Table 16. Inspire Super Fungicide Risk of Exposure

Exposure 

Scenario Crop Name

Application

Rate 

(lbs a.i./A)a

Area 

Treated 

Daily

(A)b

Unit 

Exposurec,d

(mg/lb ai)

ST Daily 

Dosee

(mg/kg/day)

ST MOEf

LOC=1,000

IT MOEg

LOC=1,000

Liquid Mixer/Loader

Aerial (Only 

California)/

Chemigation

Fruiting Vegetable 

Group; Grapes; 

Strawberry and other 

low growing berry 

subgroup (except 

cranberry)

0.33

350

Baseline = 

0.000219

Baseline = 

0.00031

Baseline = 

200,000

Baseline = 

8,600

Pome Fruit Group 0.20 Baseline = 0.00019

Baseline = 

330,000

Baseline = 

14,000

Groundboom

Fruiting Vegetable 

Group; Strawberry 

and other low 

growing berry 

subgroup (except 

cranberry)

0.33 80 Baseline = 

0.000072

Baseline = 

870,000

Baseline = 

38,000

Airblast Grapes 0.3340

Baseline = 

0.000036

Baseline = 

1,700,000

Baseline = 

76,000

Pome Fruit Group 0.20 Baseline = 0.000021

Baseline = 

2,900,000

Baseline = 

130,000

Liquid Applicator

Aerial, Fixed 

Wing (Only 

California)

Fruiting Vegetable 

Group; Grapes; 

Strawberry and other 

low growing berry 

subgroup (except 

cranberry)

0.33

350 Baseline = 

0.000068

Baseline = 

0.00010

Baseline = 

640,000

Baseline = 

28,000

Pome Fruit Group 0.20 Baseline = 0.000058

Baseline = 

1,100,000

Baseline = 

46,000

Open Cab 

Groundboom

Fruiting Vegetable 

Group; Strawberry 

and other low 

growing berry 

subgroup (except 

cranberry)

0.33 80 Baseline = 

0.00034

Baseline = 

0.00011

Baseline = 

560,000

Baseline = 

24,000

Open Cab 

Airblast

Grapes 0.33

40 Baseline = 

0.00471

Baseline = 

0.00077

Baseline = 

81,000

Baseline = 

3,500

Pome Fruit Group 0.20 Baseline = 0.00046

Baseline =

130,000

Baseline = 

5,900

Aerial Flagger

Flagger

Fruiting Vegetable 

Group; Grapes; 

Strawberry and other 

low growing berry 

subgroup (except 

cranberry)

0.33

350 Baseline = 

0.00035

Baseline = 

0.00050

Baseline = 

120,000

Baseline = 

5,400

Pome Fruit Group 0.20 Baseline = 0.00030

Baseline = 

210,000

Baseline = 

9,000

a. Application Rates based on Syngenta’s Inspire Super Fungicide proposed label

b. Science Advisory Council Policy No. 9.1

c. Unit Exposures based on March, 2012 “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”

d. PHED/ORETF (level of mitigation: Baseline.

e. Inhalation Dose (mg/kg/day) daily unit exposure (mg/lb ai) x application rate (lb ai/acre) x acres treated daily (A) / body weight (80 kg) 

f. Short-term Inhalation MOE = NOAEL (62 mg/kg/day) / inhalation daily dose (mg/kg/day). LOC = 1000

g.Intermediate-term Inhalation MOE = NOAEL (2.7 mg/kg/day) / inhalation daily dose (mg/kg/day). LOC = 1000
Page 32 of 53

9.3 Post-application Exposure and Risk

9.3.1 Post-application Dermal Exposure

Since there are no dermal endpoints of concern, post-application dermal exposure was not 

examined for occupational uses.

9.3.2 Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for cyprodinil at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category III and IV), low vapor pressure (3.8 x 10-6 mm HG), and 

the low proposed use rates. However, there are multiple potential sources of post-application 

inhalation exposure to individuals performing post-application activities in previously treated 

fields. These potential sources include volatilization of pesticides and resuspension of dusts

and/or particulates that contain pesticides. The Agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on 

March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

Agency is in the process of evaluating the SAP report as well as available post-application 

inhalation exposure data generated by the Agricultural Reentry Task Force and may, as 

appropriate, develop policies and procedures, to identify the need for and, subsequently, the way 

to incorporate occupational post-application inhalation exposure into the Agency's risk 

assessments. If new policies or procedures are put into place, the Agency may revisit the need 

for a quantitative occupational post-application inhalation exposure assessment for cyprodinil.

Although a quantitative occupational postapplication inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than postapplication exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational postapplication

inhalation exposure scenarios.

10.0 REFERENCES

Cyprodinil. Amended Use. Expansions of Existing Crop Group/Representative Commodity Uses to Numerous Crop 

Subgroups, Adding Use on Leafy Petiole Subgroup 4B, and Adding Use on the Remaining Crops in Fruiting 

Vegetables Group 8-10. Summary of Analytical Chemistry and Residue Data, T. Morton, 389554, 391680, 5/3/12

Cyprodinil – Acute and Chronic Dietary and Drinking Water Exposure and Risk Assessment. 

T. Morton, D390233, D398362, 5/3/12

Drinking Water Exposure Assessment – J. Melendez, D385884, 6/30/11

Cyprodinil: Occupational and residential exposure and risk assessment for a section 3 registration on onion 

subgroups 3-07A and B; berry and small fruit subgroups 13-07A, B, F, and G; fruiting vegetable group 8-10; leafy 

greens subgroup 4A; leafy petioles subgroup 4B; pome fruit group 11-10; and dragon fruit, I. Nieves, D398361,

D390232 5/3/12
Page 33 of 53

Cyprodinil - Fourth Report of the Hazard Identification Assessment Review Committee, J. Kidwell, TXR 0051401,

11/19/02 

Cyprodinil – Hazard and Science Policy Council (HASPOC) Summary, K. Rury, TXR 0054812, 03/29/12
Page 34 of 53

APPENDICES

A. TOXICOLOGY DATA SUMMARY

A.1 Guideline Data Requirements

Guideline 

No. Study Type Technical MRID 

Required Submitted No.

870.3100

870.3150

870.3200

870.3250

870.3465

Subchronic (Oral) Toxicity - Rodent....................................................

Subchronic (Oral) Toxicity - Non-Rodent ...........................................

21/28-Day Dermal Toxicity .................................................................

90-Day Dermal Toxicity ......................................................................

90-Day Inhalation Toxicity .................................................................

Y

Y

N

N

Y

1

Y

N

Y

N

N

43709027

43709026

43709028

43709029

47526801

870.3700a

870.3700b

870.3800

Prenatal Developmental Toxicity - Rodent ..........................................

Prenatal Developmental Toxicity - Non-Rodent..................................

Reproduction and Fertility Effects.......................................................

Y

Y

Y

Y

Y

Y

43709033

43709032

43709034

870.4100a

870.4100b

870.4200a

870.4200b

870.4300

Chronic (Oral) Toxicity - Rodent.........................................................

Chronic (Oral) Toxicity - Non-Rodent (Dog) ......................................

Carcinogenicity - Rat......................................................................

Carcinogenicity - Mouse ......................................................................

Combined Chronic Toxicity /Carcinogenicity

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

43737602

43709030

43737602

42710006

43737602

870.6100a

870.6100b

870.6200a

870.6200b

870.6300

870.7800

Neurotoxicity - Acute Delayed Neurotox.- Hen...................................

Neurotoxicity - Subchronic - Hen .......................................................

Neurotoxicity - Acute - Rat..................................................................

Neurotoxicity -Subchronic - Rat ..........................................................

Developmental Neurotoxicity..................

Immunotoxicity............................. ..............................................

N

N

Y

Y

N

Y

N

N

Y

Y

N

Y

---

---

48304202

45906101

---

48304203

48293501

1 Based on WOE by HASPOC (TXR 0054812)
Page 35 of 53

A.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 

(dog)

43709028 (1991)

Acceptable/Guideline

0, 200, 1500, 7000, 20000

ppm

M: 0, 6.07, 45.85, 210.33, 

NOAEL =210/232 mg/kg/day, M/F

LOAEL = 560/581 mg/kg/day, M/F, based on lower bodyweight gains and decreased food consumption in both sexes
Page 36 of 53

Table 2. Toxicity Profile of Cyprodinil Technical.

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

559.66 mg/kg/day

F: 0, 6.79, 52.75, 231.93, 

580.95 mg/kg/day

870.3200

21/28-Day dermaltoxicity

(rat)

47526801 (008)

Acceptable/

Guideline

0, 5, 25, 125, 1000 

mg/kg/day

NOAEL = 1000 mg/kg/day

LOAEL = Not established

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, 

446.37 mg/kg/day

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 37 of 53

Table 2. Toxicity Profile of Cyprodinil Technical.

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

870.4200

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)

48304203

Acceptable/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 on 

specific activity or total activity of splenic IgM antibodyforming cells to the T cell-dependent antigen sRBC. 

Cyprodinil attributed effects was higher mean absolute, 

relative (to body weight), and adjusted liver weights at 

HDT.

870.6200a

Acute Neurotoxicity

48304202

Acceptable/Guideline

0,200, 600, 2000 mg/kg

/day

NOAEL = 200 mg/kg/day

LOAEL = 600 mg/kg/day

Based on clinical signs of toxicity and low motor activity 

and reversible hypothermia, no neuropathic changes were 

noted at any dose level.

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 ( -S9) that produced 

reproducible cytotoxicity for the majority of strains. 

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 

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 

-

or 42- - hour cell 

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

μg/mL with S9, 42-hour cell harvest).
Page 38 of 53

Table 2. Toxicity Profile of Cyprodinil Technical.

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

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 

pyrimidyladministered to Tif:RAIf(SPF) rats, with one low-dose 

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, 

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 
Page 39 of 53

Table 2. Toxicity Profile of Cyprodinil Technical.

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

significantly influenced by the dose, treatment regimen, or 

sex of the animal.

870.7600

Dermal Absorption 

(rat)

45906102 (1999)

In review

6 μg/cm2or 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.
Page 40 of 53

A.3 HAZARD IDENTIFICATION AND ENDPOINT SELECTION

A.3.1 Acute Reference Dose (aRfD) – All Populations

Selected Study: Acute Neurotoxicity Rat; MRID 48304202

Dose and Endpoint for Establishing a POD: NOAEL = 200 mg/kg/day day from an acute 

neurotoxicity study based on LOAEL of 600 mg/kg/day showing clinical signs (hunched posture, 

pilorection, and reduced responsiveness to sensory stimuli, reduced motor activity and 

hypothermia). 

Uncertainty Factor (UF): 1000x (10x for interspecies and 10x for intraspecies variation; and 10X 

for lack of 90-day inhalation study)

Acute RfD = 200 mg/kg (NOAEL) = 0.20 mg/kg

 1000 (UF)

[Note: The acute RfD has been revised from previous risk assessments based on receipt and 

review of an acute neurotoxicity study and subsequent reevaluation of available data.]

A.3.2 Chronic Reference Dose (cRfD) - All Populations

Selected Study: Combined Chronic Toxicity/Carcinogenicity-Rat; MRIDs 43737602, 44429401 

and 44417902

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 and 10x for intraspecies variation, and 10X 

for lack of 90-day inhalation study)

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) = 0.0027 mg/kg

 1000 (UF)

A.3.3 Inhalation Exposure (Short-Term)

A No Observable Adverse Effect Level (NOAEL) of 62 mg/kg/day was identified for short-term 

inhalation risk assessments. The short-term NOAEL is based on decreased body weight gains, 

microcytosis, increased cholesterol and phospholipid levels, and hepatocyte hypertrophy seen at 

the Lowest Observable Adverse Effect Level (LOAEL) of 299 mg/kg/day from a 28-Day 

Feeding/Range-finding study on rats with cyprodinil. 
Page 41 of 53

A.3.4 Inhalation Exposure (Intermediate-Term)

A NOAEL of 2.7 mg/kg/day was identified for intermediate-term inhalation risk assessments. 

The intermediate-term NOAEL is based on degenerative liver lesions (spongiosis hepatis) in 

male rats seen at the Lowest Observable Adverse Effect Level (LOAEL) of 35.6 mg/kg/day from 

a 2-Year Chronic Toxicity/Carcinogenicity on rats with cyprodinil. The HASPOC concluded, 

based on a weight of evidence (WOE) approach, that a 90-day inhalation toxicity study is 

required at this time to reduce uncertainty associated with the use of an oral POD for assessing 

risk via the inhalation route. 

A.4 EXECUTIVE SUMMARIES FOR SUPPORTING TOXICITY STUDIES

A.4.1 Subchronic Toxicity

870.3100 90-Day Oral Toxicity – Rat MRID 43709026

In a subchronic toxicity study (MRID 43709026), CGA 219417 (cyprodinil; 99.5% ai; Lot No. P

912004) was administered in the diet to 20 rats/sex/dose at dose levels of 0 or 12000 ppm (0 or

810 mg/kg/day, respectively, for males; 0 or 803 mg/kg/day, respectively, for females), and to 10

rats/sex/dose at dose levels of 50, 300, or 2000 ppm (3.14, 19.0, or 134 mg/kg/day, respectively,

for males; 3.24, 19.3, or 137 mg/kg/day for females) for 90 days. All animals were sacrificed at

90 days except for 10 control and 10 2000 ppm rats/sex which were sacrificed after a 4 week

recovery period. 

At 50 ppm and above there were - increased cholesterol and phospholipid levels in females (18% 

for both) which increased with increasing dose [cholesterol - 300 ppm (20%), and male and 

female 2000(37-48%) and 12000 (85-105%) ppm groups; phospholipid -300 ppm (23%) group, 

and male and female 2000 (36%) and 12000(71-90%) ppm groups.]

At 300 ppm and above there was - increased alkaline phosphatase in the male with females 

affected at 12000 ppm. Liver abnormalities at 300 ppm included hepatocyte hypertrophy and 

hepatocyte necrosis observed in male rats, with females affected at 2000 and 12000 ppm. Kidney 

abnormalities included a low incidence (0, 0, 10, 10, 20% for males only, control to high dose) 

vacuolization of the epithelium of the proximal convoluted tubules, and chronic tubular lesions 

(0, 0, 30, 50, 80% for males and 20, 20, 0, 50, 80% for females, control to high dose), in male 

and/or female rats at 300 ppm. The tubular lesions were more frequent at 2000 and 12000 ppm. 

Enlarged (hypertrophic) pituitary cells in the adenohypophysis were observed in males in the 300 

ppm group, and males and females in the 2000 and 12000 ppm groups. “Minimal” to “moderate” 

hypertrophy of the follicular epithelia of the thyroid was noted in males in the 300, 2000, and 

12000 ppm groups. 

At 2000 ppm and above there were additional hepatic lesions consisting of “sharply demarcated 

membranous structures containing a vacuolated eosinophilic material” (“cytoplasmic inclusion 

bodies”) and renal chronic tubular lesions in 50 % of the males and females. There was an 

increase in protein and globulin levels in the males. Relative liver weights were higher for male 
Page 42 of 53

and female rats in the 2000 and 12000 ppm groups. Relative thyroid weights were higher for 

male rats in the 2000 ppm group, and male and female rats in the 12000 ppm groups.

At 12000 ppm there was - a decrease in body weight gains of female and male rats (20-26% 

lower than controls at the termination of the study). Hemoglobin and hematocrit values were 

lower, albumin levels higher and glucose levels lower in the males. Leukocyte counts and 

gamma glutamyl transpeptidase activity levels were higher in the male and female groups. 

Additional renal lesions included nephrocalcinosos (0, 0, 10, 0, 50%, control to high dose in 

males only). Relative kidney weights were also higher for high dose males. The relative weights 

of the adrenals in males were greater than the controls, with “minimal” increases in the amount 

of fat vesicles in the adrenal cortex noted in a majority of these animals. 

Following a 4-week post treatment recovery period (using 0 and 12000 ppm rats only), all 

hematological and blood chemistry differences lost significance, with the exception of 

cholesterol and phospholipid concentrations in females. The relative weights of the liver and 

thyroid glands of males in the 12000 ppm groups remained greater than those of the control 

group, but with the exception of chronic tubular kidney lesions, the prevalence of all microscopic 

abnormalities was reduced. 

Most changes at 50 were not adequate to establish an LOAEL therefore the LOAEL is 300 ppm 

(19 mg/kg body weight/day) for rats, based on increased chronic tubular kidney lesions in males. 

The NOAEL is 50 ppm (3.14 mg/kg/day).

This subchronic toxicity study is classified acceptable (guideline), and satisfies the guideline 

requirement for a subchronic oral study (82-1) for rodents.

870.3100 90-Day Oral Toxicity – Mouse MRID 43709027

A 3-month study (MRID 43709027) was carried out in Tif:MAGf(SPF) albino mice where 

animals (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/kg/day) 

of CGA 219417 technical (99.5% a.i., Batch No- P 912004). There was no effect on mortality, 

or hematology 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). This study is acceptable 

(guideline) even though it is listed as a range-finding study. It satisfies the guideline requirement 

for a subchronic study in the rodent (82-1(a)).

870.3100 90-Day Oral Toxicity – 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, 
Page 43 of 53

210.33 or 559.66 mg/kg/day; females - 0, 6.79, 52.75, 231.93 or 580.95 mg/kg/day) 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).

870.3200 28 Day Dermal Toxicity – Rat MRID 47526801

In a 28-day dermal toxicity study (MRID 47526801), Cyprodinil (99%, P012011) was applied to 

the shaved skin of 50 HanRCC Wistar Rats/sex/dose at dose levels of 0 (vehicle control), 5, 25,

125 and 1000 mg/kg bw/day, 6 hours/day for 5 days/week during a 28-day period, for a total 

treatment of 20 days.

The following parameters were measured: general clinical observations, detailed behavioral 

observations. Body weight and food consumption, functional observational battery including grip 

strength and locomotor activity. Ophthalmoscopic examination, hematology and clinical 

chemistry. Organ weights, macroscopic and histopathological examination of selected organs.

No treatment related effects were seen at any concentration when measuring body weight gain, 

food consumption, hematological parameters, clinical chemical parameters, organ weights, gross 

or histopathology. 

Skin lesions characterized by fissures, scabs, erythema, hair loss, sores, were common in all 

experimental groups and the control group, probably resulting from shaving the skin to apply the 

test article or vehicle.

The NOAEL is 1000 mg/kg/day. The LOAEL is not established.

This 28-day dermal toxicity study in the HanRCC Wistar rats is acceptable guideline and 

satisfies the guideline requirement for a 28-day dermal toxicity study (OPPTS 870.3200; OECD 

410) in rats. 

A.4.2 Prenatal Developmental Toxicity - Rat

870.3700a Prenatal Developmental Toxicity Study – Rat MRID 43709033

In a developmental toxicity study (MRID No. 43709033), CGA 219417 technical (99.5% a.i., 

Batch No. P912004) 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 
Page 44 of 53

(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 represent 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. This study is classified acceptable (guideline) and satisfies the guideline 

requirement for a developmental study in the rat [(OPPTS 870.3700 (83-3a)].

870.3700b Prenatal Developmental Toxicity Study – Rabbit MRID 43709032

In a developmental toxicity (MRID No. 43709032), CGA 219417 technical (99 5%a.i., Lot# 

P9t2004) 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. The developmental toxicity 

study in the rabbit is classified acceptable (guideline) and satisfies the guideline requirement for 

a developmental toxicity study (OPPTS 870.3700; §83-3 (b)) in rabbit.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat MRID 43709034

In a two-generation reproduction study (MRID No. 43709034), Tif:RAIf rats (30 rats/sex/dose), 

with one litter per generation received CGA219417 (99.5 % a.i., Batch No. P912004) in the diet 

at doses of 0, 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 non-adverse. 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. 
Page 45 of 53

The NOAEL for maternal systemic toxicity was 1000 ppm (about 81 mg/kg/day). HIARC 

determined that premating 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 postweaning 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).

The two-generation reproduction study in the rat is classified acceptable (guideline) and satisfies 

the guideline requirement for a two-generation reproduction study (OPPTS 870.3800; §83-4) in 

rat.

A.4.4 Chronic Toxicity

870.4100a (870.4300) Combined Chronic Toxicity/Carcinogenicity – Rat MRIDs 

43737602, 44429401,44417902

In a 24-month chronic toxicity/oncogenicity study (MRID No: 43737602, 44429401,44417902), 

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 (actual concentrations: 

males 0, 0.177, 2.7, 35.6 or 73.6 mg/kg/day; females 0, 0.204, 3.22, 41.2 or 87.1 mg/kg/day) 

CGA 219417(99.2-99.6% a.i. Batch No. P 912006). 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 (54, 50, 50, 49, and 44%, from controls to high dose). 

Toxicologically significant findings included increased liver weights in high-dose males (10.7%) 

and a dose-related increase in the incidence of spongiosis hepatis3 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. This chronic carcinogenicity study in the rat is 

acceptable (guideline).

870.4100b Chronic Toxicity - Dog MRID 43709030

A 1-year study (MRID 43709030) was carried out in Beagle dogs where animals (4/sex/dose) 

were fed diets containing 0,25,250,2500 or 15,000 ppm (actual concentrations: males -0, 0.72, 

6.87, 65.63 or 449.25; females -0, 0.76, 6.80, 67.99 or 446.37 mg/kg/day) CGA 219417 (99.6% 

a.i., Batch No. P 912006).

There was no effect on mortality, hematological, or clinical chemistry parameters, and no clinical 

signs of systemic toxicity. Throughout the first half of the study, lower bodyweight gains (31-

38% less) (attributable primarily to 2/4 of each sex) and decreased food consumption were 

apparent in high-dose males and females; with reduced food efficiency in high dose males and 

females in the latter part of the study. The LOEL is 15,000 ppm (males - 449.25, females 446.37 

mg/kg/day) based on lower bodyweight gains and decreased food consumption and food 

efficiency. The NOAEL is 2500 ppm (males - 65.63, females - 67.99 mg/kg/day). This study is 

classified as acceptable (guideline) and satisfied the guideline requirement for a chronic oral dog 

study (870.4100b).
Page 46 of 53

A.4.5 Carcinogenicity

870.4200a Carcinogenicity/Chronic Study – 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. P912006). There was no effect on mortality, or hematology parameters, and no clinical signs 

of toxicity. Treatment-related effects included lower bodyweight and bodyweight 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 LOAEL is 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 female at 5000 ppm. This 

chronic carcinogenicity study in the mouse is acceptable/guideline.

A.4.6 Mutagenicity

Gene Mutation

Guideline # 870.5100 Bacterial assay

MRID 43709037 

Acceptable/Guideline

Guideline #870.5300, In vitro 

mammalian cell gene mutation test

MRID 43709036

Acceptable Guideline

Not mutagenic

Not mutagenic in the presence or absence of S9-activation up to 

S9).

Cytogenetics

Guideline # 870.5375, 

Cytogenetics/In vitro Chromosomal 

Aberration

MRID 43709038

Acceptable Guideline

Guideline #870.5395 

Cytogenetics/In vivo bone marrow 

micronucleus MRID 43709039

Acceptable Guideline

cyprodinil gave negative results up to cytotoxic concentrations 

negative
Page 47 of 53

A.4.7 Neurotoxicity

870.6100 Delayed Neurotoxicity Study – Hen - NA

870.6200a Acute Neurotoxicity Screening Battery MRID 48304202

In an acute neurotoxicity study in mice (MRID 48304202) CGA 219417 technical (batch #: 

P.012011 a light beige powder with a purity of 99.2%) was administered to rats to assess the 

potential acute neurotoxicity and to estimate the NOAEL of exposure of the test compound, a 

fungicide, when administered by gavage. The test article was administered by gavage as single 

oral dose of 0, 200, 600, and 2000 mg/kg to a total of 80 Sprague-Dawley-derived rats (10 males, 

and 10 females, per dose group). Mortality, clinical signs, body weight, and food consumption 

were monitored throughout the study. A 'Functional Observational Battery'

(FOB) was performed pretest, at the time of peak effect (2 hours post-dose, and on test days 8 

and 15. At necropsy, animals were sacrificed by in situ perfusion. The brain, spinal cord, 

peripheral nerves and eyes were collected, prepared for histological evaluation and 5 animals per 

sex each of the control and top-dose group (experimental group I) examined microscopically. 

Two animals of group 3 died spontaneously. The male, found dead on

test day 2, was most likely missintubated. For the female, which was found dead on test day 18, 

the cause of death could not be identified. Body weight gain and food consumption were not 

affected by treatment. Observations and functional tests conducted as part of the FOB showed 

relevant changes at the time of peak effect only. In females of group 3 and 4 reduced activity, 

hunched posture, piloerection, and increased responsiveness to sensory stimuli were observed 

with hunched posture seen also in few group 2 females. In females of group 3 and 4, signs lasted 

up to test day 4 and were considered to indicate toxicity. A dose related decrease in body 

temperature was observed, being minimal in animals of group 2. Changes in motor activity 

parameters were limited to the time of peak effect. In group 4 males and in females of group 3 

and 4 horizontal and vertical activity parameters were reduced. Macroscopic and microscopic 

examination of the multiple areas of the central and peripheral nervous system, the eyes, optic 

nerves, and skeletal muscle of the male and female, control and high-dose animals of 

experimental group I didn’t reveal any treatment-related neuropathic changes. Based on these 

data it was concluded that CGA 219417 tech., when administered to rats at a single oral dose of 

200, 600 or 2000 mg/kg, induced a dose-related hypothermia. Due to its full reversibility in all 

dose groups, the slightly reduced body temperature in low-dose animals was not considered as 

adverse. A dose of 200 mg/kg thus represented the NOAEL for this study. The LOAEL was 

deemed to be 600 mg/kg and greater induced signs of toxicity at the time of peak effect which 

disappeared within a few days as well. In the absence of any permanent or delayed functional 

changes and of neuropathic changes in the central and peripheral nervous system, CGA 219417 

tech was considered not to be neurotoxic up to the near lethal dose of 2000 mg/kg.

870.6200b Subchronic Neurotoxicity Screening Battery MRID 45906101

In a subchronic neurotoxicity study (MRID 45906101) CGA 219417 technical (99.2% a.i., batch 

#: P. 012011) was administered to 10 Tif: RAIf Sprague-Dawley derived albino rats/sex/group at 

dose levels of 0, 80, 800, or 8000 ppm (equivalent to 0, 5.8, 54.5, and 601 mg/kg bw/day in 

males and 0, 6.3, 58.7, and 631 mg/kg bw/day in females) for 90 consecutive days. 
Page 48 of 53

Neurobehavioral assessment (functional observational battery and motor activity testing) was 

performed in 10 animals/sex/group pre-exposure and at weeks 4, 8, and 13. At study termination, 

10 animals/sex/group were euthanized and perfused in situ for neuropathological examination. 

Of the perfused animals, 5/sex/group of the control and high-dose groups were subjected to 

histopathological evaluation of brain and peripheral nervous system tissues. In addition, the 

liver, kidneys, thyroid gland, and pituitary were collected from all animals and examined 

microscopically. 

There were no treatment related effects on mortality, clinical signs, or gross or histological

neuropathology. FOB and motor activity testing revealed no treatment related effects up to the 

highest dose tested (8000 ppm). In high-dose animals, absolute body weight was significantly or 

slightly less than the controls throughout the study due to reduced weight gain by the treated 

animals. Cumulative weight gain by the high-dose groups was significantly less than that of the 

control groups during weeks 1-6 and 8 for males and weeks 1, 4, and 11-13 for females. The 

most pronounced effect on weight gain was during the first week of the study when high-dose 

males and females gained 59% and 38%, respectively, of the control levels. Overall weight gain 

by the high-dose males and females was 87% and 79%, respectively, of the controls. Food 

consumption by the high-dose animals was reduced only at week 1 to 89% and 77% of controls 

for males and females, respectively. In the high-dose group, absolute and relative liver weights 

were increased in both sexes (126-138% and 121-125% of controls for males and females, 

respectively). Absolute and relative kidney weights were elevated in high-dose females (112-

118% of controls).

Microscopic examination revealed an increase in the incidence, but not in severity, at the high 

dose of lesions in the liver, kidney, and thyroid. Hepatocellular hypertrophy in the liver was 

observed in 5/10 high-dose males compared with 1/10 controls and in 5/10 high-dose females 

compared with 0/10 controls; this is an adaptive response. Tubular lesions or tubular casts were 

seen in the kidneys of 4/10 high-dose males and 5-7/10 high-dose females vs 0-2/10 animals in 

the control groups. Hypertrophy of the follicular epithelial cells in the thyroid gland occurred in 

5/10 high-dose males and 4/10 high-dose females compared with only 1/10 control males.

Based on the results of this 90-day subchronic oral neurotoxicity study, the neurotoxicity 

LOAEL for CGA 219417 technical in male and female rats was not identified, while the NOAEL 

is 8000 ppm (601 mg/kg bw/d in males; 631 mg/kg bw/d in females).

The systemic toxicity LOAEL for CGA 219417 technical in male and female rats is 8000 ppm 

(601 mg/kg bw/d in males and 631 mg/kg bw/d in females) based on decreased body weight 

gain, tubular casts in the kidneys, and thyroid follicular cell hypertrophy. The NOAEL is 800 

ppm (54.5 mg/kg bw/d in males and 58.7 mg/kg bw/d in females).

The study is classified as Acceptable/Guideline and satisfies the guideline requirement for a 

subchronic neurotoxicity study in rats (870.6200b). 
Page 49 of 53

A.4.8 Metabolism

870.7485 Metabolism – Rat 

Study 1

In a metabolism study ( MRID 43709040), 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. A 

biphasic first order kinetics was observed for radioactivity depletion, with a duration 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. Tissue residues declined rapidly, with the 

highest concentrations ( 1.8 ppm) found in kidneys, liver, lungs, spleen, thyroid, whole blood, 

and carcass. The urine, fecal, and bile metabolite patterns were complex, with 8, 8 and 9 defined 

metabolite fractions, respectively. Unchanged parent compound was detected in feces extract 

only. Excretion, distribution and metabolite profiles were essentially independent of dose level, 

pretreatment, and type of label, although there were some quantitative differences sex-dependent 

qualitative differences in two urinary metabolite fractions.

This study is classified as acceptable (guideline) and when taken together with study (MRID 

43709041) satisfies the guideline requirement for a metabolism study in rats(85-1).

Study 2

Excreta (Group D1 and D2) and bile (Group G1) from radiolabelled CGA 219417-treated 

Tif:RAIf(SPF) rats of a previous ACME 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.

This study is classified as acceptable (guideline) and when taken together with study (MRID 

43709040) satisfies the guideline requirement for a metabolism study in rats (85-1).
Page 50 of 53

A.4.9 Immunotoxicity

870.7800 Immunotoxicity – Mice MRID 48304203

In an immunotoxicity study (MRID 48304203), the test substance cyprodinil was offered ad 

libitum in the diet of Crl:DC1 (ICR) female mice, for 28 consecutive days to three groups 

(Groups 2-4) at dietary concentrations of 500, 2000, and 5000 ppm, respectively. Mice in Group 

5 were administered the positive control substance, cyclophosphamide (CPS), via IP (50 

mg/kg/day) for four consecutive days (study days 24-27). The vehicle and positive control 

groups (Groups 1 and 5, respectively) were offered a basal diet on a comparable regimen as the 

cyprodinil-treated groups. In addition, all mice were immunized with sheep red blood cells 

(sRBC) on study day 24. All animals were euthanized on day 28. Mortality and morbidity were 

observed twice daily in all animals, while clinical exams were performed once a day. More 

detailed physical exams were performed once a week and the day of necropsy. Single animal 

body weights were recorded two times a week and food consumption was recorded weekly. 

Complete necropsies were conducted on all animals. Organs (liver, spleen, and thymus) were 

collected and weighed at scheduled necropsy. Spleens were analyzed by ImmunoTox®,Inc . for 

IgM antibody forming cells directed towards the sRBC determination. Test substances were 0, 

103.8, 468.3, and 1245.3mg/kg/day or 0, 500, 2000, and 5000ppm, respectively, for the entire 4-

week study. All animals survived to necropsy. There were no test substance-related clinical 

observations, no effects on body-weight, food consumption, no macroscopic findings. There 

were no cyprodinil-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 celldependent antigen sRBC. Effects did include higher mean absolute, relative to body weight, and 

adjusted liver weights noted in the 5000ppm cyprodinil-treated group were consistent with 

previous studies assessing cyprodinil at similar exposure levels. Noted for the positive control 

(CPS) were lower mean absolute and adjusted spleen and thymus weights when compared to 

vehicle control group. All effects seen with the CPS were consistent with the known 

immunosuppressant effects and also validated the appropriateness of the AFC assay. No 

mention of a NK cell activity assay was performed. It is unclear why this test was not performed 

and no justification was noted in the study write-up.

Based on the study, treatment of female Crl:CD-1(ICR) mice with cyprodinil given on a 

continued basis in the diet for 28 sequential days resulted in no apparent suppression of the 

humoral component of the immune system. The NOEL for the suppression of the immune 

response in female CD-1 mice given cyprodinil was 5000ppm (1245.3mg/kg/day). The only 

effect attributed to cyprodinil treatment was higher mean absolute, relative to body weight, and 

adjusted liver weights also for the 5000ppm group. 
Page 51 of 53

B. METABOLISM

B.1 Chemical Names And Structures

Table B.1 Cyprodinil and Metabolites Names and Structures

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

CGA-304075

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

phenol

CGA-304076

N

N N

H

CH3

OH

NOA-413167

N

N N

H

OH

CH3
Page 52 of 53

Table B.1 Cyprodinil and Metabolites Names and Structures

Chemical Name/Code Chemical Structure

CGA-249287

4-cyclopropyl-6-methyl-2-pyrimidinamine

NOA-422054

4-cyclopropyl-6-hydroxymethyl-2-pyrimidinamine

N

N

OH

H2N

CGA-263208

phenylguanidine
Page 53 of 53

C. PHYSICAL/CHEMICAL PROPERTIES

Table C.1 Physicochemical Properties of Technical Grade of Cyprodinil.

Parameter Value Reference

Melting point/range 75.9 C

DP# 345970, W. Cutchin, 

6/4/08

pH 9.5 at 25 C (1% aqueous dispersion)

Density 1.21 g/cm3at 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, 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)

D. REVIEW OF HUMAN RESEARCH

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)