Page 3 of 53

5. 2.4 Estimated Drinking Water Concentrations

................................ ............................ 21

5.3 Dietary and Drinking Water Exposure and Risk

................................ ............................... 2 2

5. 3 .1 Acute Dietary and Drinking Water Analysis

................................ ......................... 2 2

5. 3 .2 Chronic Dietary and Drinking Water Analysis

................................ ...................... 2 2

6.0 RESIDENTIAL EXPOSURE AND RISK

................................ ................................ ........ 2 3

7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT

................................ ............... 2 3

7.1 Short

- Term Aggregate Risk to Residential Applicators

................................ .................... 2 4

8.0 CUMU LATIVE RISK

................................ ................................ ................................ ....... 2 4

9.0 OCCUPATIONAL EXPOSURE AND RISK

................................ ................................ ... 2 5
9.1 Exposure Scenarios

................................ ................................ ................................ ............ 2 5
9.2 Handler Exposure and Risk Assessment

................................ ................................ ............ 2 5

9

. 2 .1 Handler Exposure Scenarios

................................ ................................ .................. 2 5

9

. 2 .2 Handler Exposure Data

................................ ................................ .......................... 2 5
9.2.3 Handler Exposure Assumptions

................................ ................................ ............. 2 6
9.2.4 Handler Exposure and Risk Estimates

................................ ................................ ... 2 6
9.3 Post

- application Exposure and Risk Assessment

................................ .............................. 3 2

9

. 3 .1 Post

- application Dermal Exposure

................................ ................................ ........ 3 2

9

. 3 .2 Post

- application Inhalation Exposure

................................ ................................ .... 32

10.0 REFERENCES

................................ ................................ ................................ .................. 32

Appendix A. Toxicity Profile and Executive Summaries

................................ .............................. 3 4

A.1 Toxicity Data Requirements

................................ ................................ .................. 3 4

A.2 Toxicity Profiles

................................ ................................ ................................ ..... 3 5

A.3 Hazard Identification and Endpoint Selection

................................ ....................... 40

A.4 Executive Summaries

................................ ................................ ............................. 4 1 Appendix B. Metabolism

................................ ................................ ................................ .............. 5 1 Appendix C. Physical/Chemical Properties

................................ ................................ ................... 5 3 Appendix D. Review of Human Research

................................ ................................ ..................... 5 3Page 4 of 53

1.0 EXECUTIVE SUMMARY

This assessment provides information to support an amend ed Section 3 registration for the use of cyprodinil on a number of crops and crop groups. T his document addresses the dietary

, drinking

water , residential and occupational exposure and risk associated with cu rrently registered uses

and proposed new use s 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 anilino

pyrimidine 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 a nd ground application equipment. Cyprodinil is used on ornamental landscape s 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 res idential applicators ; however, since cyprodin i l is only used on ornamentals and there is no dermal POD, only i nhalation exposure was assessed.

Proposed New/ Amended Use s

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 WG TM Fungicide (EPA Reg. No. 100

- 953), a 37.5% water dispersible granule (WDG) formulation of cyprodinil ; Vanguard TM 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 Vanguard TM WG

, Switch

62.5 WG TM Fungicide , and Inspire Super TM F ungicide 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 foll owing 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 Fung icide and Switch 62.5 WG TM Fungicide on the leafy petiole subgroup 04B

.Page 5 of 53

Hazard Identification

T he 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 in clude increased liver weights

, increases in serum clinical chemistry parameters associated with adverse
effects on liver function

, hepatocyte hypertrophy

, and hepatocellular necrosis. A dverse 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

su sceptibility in the developmental rat or rabbit study following in utero exposure or in the two

generation reproduction study following pre

- or post

- natal exposure. There was no evidence of neuropathological or other 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 high est 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 inh alation 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

expo sure scenarios

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

and all population subgroup s from a n 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/carcinogen icity feeding study in rats based on degenerative live r 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 s ubchronic 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/carcinogen icity fee ding study in rats

. A n uncertainty factor of 100 x 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 . T herefore, in

the absence of a route

- specific inhalation study, a 10X database uncertainty f actor for occupational workers and a 10x FQPA SF factor for residential scenarios should be appliedPage 6 of 53

specifically to the inhalation assessment

.

Exposure/Risk Assessment and Risk Characterization

Risk assessments were conducted for dietary (food and wate r) and occupational exposure based on registered uses and request s 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 endpo int of concern was identified. Short

- term inhalation risk

estimate s to occupational handlers are not of concern for any scenario (i.e., MOE s ≥ 1 ,0 00) at baseline (i.e., no respirator). However, intermediate

- term exposure risk estimates at bas eline 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 Equi pment (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 as sociated 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 ha ndler 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 shor t

- 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. O ccup ational exposures may occur over a single day or up to weeks at a time ; s ome applicators may apply these products over a period of weeks because they are commercial applicators who are completing multiple pesticide applications for multiple clients. Infor mation 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 w hich 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 . S ome 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 action s

. Tolerances s hould 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# 1E78 54. 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 re sults 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 d urations . 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 Tol erance 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 t o 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 an d 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 Co dex 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 wit h 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 to lerances 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 Vanguard TM WG (EPA Reg. No. 100

- 828), Switch 62.5 WG TM 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, p ome 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

, S mall 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 es tablishm ent 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 4BPage 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. T hese tolerance levels are different than those proposed by the registrant.

This is due to harmonization with propose d 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

- phenyl

CAS registry number 121552

- 61

- 2

Molecular weight 225.29

End

- use product s (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 Phys ical/Chemical Characteristics

A detailed description of the physiciochemical properties of cyprodinil is provided in Appendix C. Cyprodinil has a rel atively 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 indicate s that cyprodin i l

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

residu es 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.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 W G 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 WG TM Fungicide, Vanguard TM 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 use s of cyprodinil. Syngenta Crop Protection, Inc. is requesting a Section 3 registration for the use of Vangard®WG Fungicide and
Switch 62.5 WG TM 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 Use s 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% W DG [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% W DG [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% W DG [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% W DG [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% W DG [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% W DG [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 d ietary (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 sho rt

- 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 Environme ntal 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 pat terns 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 ad ult 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 so ftware 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

T he toxicology database for cyprodinil is adequate for evaluating and characterizing cyprodinil toxicity and selecting endpoints for purposes of this risk assessment. A cute neurotoxicity (MRID 48304202) and immunotoxicity studies (MRIDs 48304203, 4829350) required under revised 40 CFR Part 158 Toxicology Data Requirements have been submitted and determin ed 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 associa ted with the use of an oral POD for assessing risk via the inhalation route (HASPOC, TXR 0054812)

.

4.2 Absorption, Distribution, Metabolism and Excretion

A bsorption, distribution, metabolism, and excretion of cyprodinil were studied in rats. In an ini tial 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 f or 2 weeks prior to treatment with radiolabelled compound. Absorption was very r apid ( 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, pretrea tment, 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

, e xcreta and bile from radiolabelled rats from the previous study were used

to char acterize, 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 metabolite s but one were conjugated with glu curonic 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 a cid 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 fo od efficiency; liver toxicity was not seen in the dog. The hematopoietic system also appeared to be a target of cyprodinil as m ild anemia was seen in rats exposed subchronically (reductions in hematocrit and hemoglobin and microcytosis). Although increas es 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 wei ghts 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 com ponent 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 rela tive 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 sl ightly 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 fou nd 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 i nvestigations. There were no histopathological findings to support evidence of damage to the central nervous system, eyes, optic nerves, or skeletal muscles. A subchronic neurotoxic ity stud y showed no treatment relatedPage 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

obser ved 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 susce ptibility in the developmental rat or rabbit study following in utero exposure or in the two

- generation reproduction study following pre

- and post

natal exposure. Fetal toxicity, manifested as significantly lower fetal weights and an increased

incidence o f delayed ossification in the rat and a slight increase in litters showing extra ribs (13 th ) in the rabbit, was reported in developmental toxicity studies. In a rat two generation reproduction study, significantly lower pup weights for F 1 and F 2 offspring were observed. However, each of these fetal/neonatal effects occurred at the same dose levels at which maternal toxicity (decreased body weight gain) was observed and were considered to be secondary to maternal toxicity.

Cyprodinil has low ac ute 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 in fants 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.

- Ther e 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 ex posure and risk assessment s 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 toxicit y, 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

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

4.4.2 Evidence of Neurotoxicity

In a subchronic neurotoxicity study in rats, t here 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

w ere 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 respons iveness 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 r abbits 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 d oses 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 anomalie s 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 treat ment 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 underesti mate dietary exposure to

cypr odinil. 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 Endpoint s 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). A n uncertainty factor (UF) of 10 0 x (10x to account for interspecies extrapolation and 10x for intraspecies variation) was applied to the NOAEL to obtain an ac ute reference dose (aRfD) of

2.0 mg/kg/day. Since the FQPA factor has been reduced to 1X, the acute population adjusted dose ( a PAD) is equivalent to the a RfD. The selected e ndpoint is considered appropriate for acute dietary exposure because effects were seen after a single dose. [No te: T he 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/ carcinogenicit y 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 (10 x 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. 0 27 mg/kg/day.

A POD for dermal exposure was not selected because n o 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 i nhalation 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, microcyto sis, and hepatocyte hypertrophy seen at the LOAEL of 299 mg/kg/day. A n intermediate

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

selected from the chronic/ car cinogenicity oral study in rats. The toxicological profile of cyprodinil indicates that toxicity increases with increased durations, specifically between short

term (28

- day) and intermediate exposures (2

- year) . Therefore , based on the weight of evidence

r egarding 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 cyprodin il , aggregate exposure from food and incidental oral exposures is not required

. However, a n 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 t o 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 UF A = 10x

UF H =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 UF A = 10x

UF H =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 hepat it is) 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 o bserved adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose.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 Short

Term (1

- 30 days) Oral NOAEL= 62 mg/kg/day (inhalation absorption rate = 100%) Residential:

UF A = 10x

UF H = 10x FQPA SF =

10X*

Occupational:

UF A = 10x

UF H = 10x

UF DB = 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) O ral NOAEL = 2.7 mg/kg/day (inhalation absorption rate = 100%) Residential:

UF A = 10x

UF H = 10x FQPA SF =

10X*

Occupational:

UF A = 10x

UF H = 10x

UF DB = 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 o bserved adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies)

. UF DB = 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 lacta ting goat metabolism studies. A poultry metabolism study is not available but is not required for this action since there are no pou ltry 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 s ubstantially 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 i s 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 c onditions, except aerobic soil metabolism, as demonstrated in laboratory studies. I ts 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 or ganic 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 co ntribute 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 residue s 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 [ 14 C

- pyrimidinyl] cyprodinil. Free and conjugated CGA

- 304075 was a major residue in muscle, liver, kidney, and milk based on acceptable lactating goat metabolis m studies using [ 14 C

- phenyl] and [ 14 C

- 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

ox idation of the phenyl ring followed by glucuronic acid conjugation

. In the rat study, e leven metabolites were isolated from urine, feces and bile, and the metabolic pathways in the rat were proposed. All urinary and biliary metabolite s but one were conj ugated 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 p rovided in Table 7

. HED has concluded that the residues of concern for livestock

for both risk assessment and the tolerance definition should include the c ombined 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)

. T he water residue s of concern are the parent and CGA 24928 7 (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 tolerance s

. Field trial study data were submitted for spinach, pepper, and lemon commodities. The trials were conducted with Switch 62.5WG to support the requested tolerance s 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. LAFT 2 HAFT 2 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. T he stability

of cyprodinil has been demonstrated in a variety of other crops, including mustar d 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 rotati onal 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 . T olerances 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 M R DBs, to lerances 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 t he current ly

established 0.0 2 ppm tolerance levels for meat byproducts of cat tle, 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 concentra te 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 analys e s 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 T ier 2 aquatic models. G round 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 s urface water EDWCs

for cyprodinil and CGA

- 249287 used in t he 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

A cute and chronic dietary and drinking water exposure and risk assessment s w ere 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

u nreasonable 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

f rom application of cyprodinil to grapes

. The resulting 9 5 th percentile acute exposure estimate s

are not of concern for the general U.S. population or any of the oth er population subgroups. The subgroup with the highest risk estimate i s children 1

- 2 years old with a % acute population adjusted dose (a PAD ) of 8%. The% a PAD for the general U.S. population i s 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 f ruit, 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 incorporatedPage 23 of 53

the 10 year average surface drinking wate r 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 i s children 1

- 2 years
old with a % chronic PAD ( cPAD ) of 75%. The % cPAD for the general U.S. population i s 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 po st application exposures using these new procedures and data.

R isks 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
, 0 0 0

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
residen tial 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 resid ential incidentalPage 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

. S hort

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

- term residential exposures are not anticipated

. A n 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)

. T he 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 w ith 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

. A ggregate margins of exposure ( MOE s ) are not of concer n.

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 d ata 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 tox icity 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 ha s 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 andPage 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 /expande d use s on number of commodities. Based on the product labels short

- term exposure is expected. There is also potential for intermediate

- term exposure. Therefore short

and intermediate

- term exposure is assessed for occupational handlers and post

- application
activities. Dermal risk to agricultural w orkers 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 flowable s or liquids to support groundboom ground application Mixing/loading dry flowable s or liquids to support airblast ground application Mixing/loading dry flowable s or liquids to support aerial applications Mixing/loading dry flowab le s 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 reg istrant

- 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 withPage 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

- exposure

data.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 weig ht of an adult handler is 8 0 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 v olumes 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 pa rticular 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 pu rposes 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 10 0 0 is considered adequate for inhalation and dermal exposure. All worker exposures are assessed as short

- and intermediate

- term based on lab el prescribed uses and expected or potential exposure durations. For this action, the proposed labels include resistance management language indicating to al ternate 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 no t available to justify eliminating consideration of potential intermediate

- term exposures, both durations were assessed. O ccupational exposures may occur over a single day or up to
weeks at a time ; s ome applicators may apply these products over a period o f weeks because they are commercial applicators who are completing multiple pesticide applications for multiplePage 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 endpo int of concern was identified. Short

- term inhalation risk

estimate s to occupational handlers are not of concern for any scenario (i.e., MOE s ≥ 1 ,0 00) 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 1 4. 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

Exposure c,d (mg/lb ai) Daily Dose e

(mg/kg/day) ST MOE f

LOC=1,000 IT MOE g

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 =

1,800Page 28 of 53 Table 1 4. 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

Exposure c,d (mg/lb ai) Daily Dose e

(mg/kg/day) ST MOE f

LOC=1,000 IT MOE g

LOC=1,000

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

Dip applications Strawberry transplants 0.0019 lb ai/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 half

face cartridge or canister respirator or a powered air

- purifying respirator (PAPR). e. Inhalation Dose (mg/kg/day) daily unit exposure ( m g/ 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 = 100 0 g. Intermediate

- term Inhalation MOE = NOAEL (2.7 mg/kg/day) / inhalation daily dose (mg/ kg/ day). LOC = 100 0Page 29 of 53 Table 1 5. 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

Exposure c,d (mg/lb ai) Daily Dose e

(mg/kg/day) ST MOE f

LOC=1,00
0 IT MOE g

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 =

28,000Page 30 of 53 Table 1 5. 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

Exposure c,d (mg/lb ai) Daily Dose e

(mg/kg/day) ST MOE f

LOC=1,00
0 IT MOE g

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

- appr oved half

- face cartridge or canister respirator or a powered air

- purifying respirator (PAPR). e. Inhalation Dose (mg/kg/day) daily unit exposure ( m g/ 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 = 100 0 g. Intermediate

- term Inhalation MOE = NOAEL (2.7 mg/kg/day) / inhalation daily dose (mg/ kg/ day). LOC = 100 0Page 31 of 53 Table 1 6. Inspire Super Fungicide Risk of Exposure

Expo sure Scenario Crop Name Application

Rate (lbs a.i./A) a Area

Treated Daily (A) b Unit

Exposure c,d (mg/lb ai) ST Daily

Dose e (mg/kg/day) ST MOE f

LOC=1,000 IT MOE g

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 0.33

40 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 ( m g/ 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 = 100 0 g.Intermediate

- term Inhalation MOE = NOAEL (2.7 mg/kg/day) / inhalation daily dose (mg/ kg/ day). LOC = 100 0Page 32 of 53

9.3 Post

- application Exposure and Risk

9.3.1 Post

- app lication 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 rate s

. 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 re ceived 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 Agr icultural 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 ex posure 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 exp ected 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 Nu merous 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, D 398 361

, D 390232 5 / 3 /12Page 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 /12Page 34 of 53

APPENDI CES

A. TOXICOLOGY DATA SUMMARY

A.1 Guideline Data Requirements

Guideline

No. Study Type Technical MRID

No. Required Submitted

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 4 37090 27
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

4 5906101

--- 48304203
48293501

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

A.2 Toxic ity Profiles

Table 1 Acute Toxicity of Cyprodinil.

Guideline No. Study Type MRIDs # Results Toxicity Category

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

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

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

870.2400 Primary Eye Irritation 43709021 mild/mod irritant III

870.2500 Primary Skin Irritation 43709022 very slight irritant IV

870.2600 Dermal Sensitization 43709024
44392102 positive NA

Table 2. Toxicity Profile of Cyprodinil Technical.

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3100
90

- Day oral toxicity (mouse) 43709027 (1991)

Acceptable/guideline 0, 500, 2000, 6000 ppm M: 0, 73.3, 257, 849 mg/kg/day

F: 0, 103, 349, 1121 mg/kg/day NOAEL = 73.3/103 mg/kg/day, M/F LOAEL = 257/349 mg/kg/day, M/F, based on histopathological changes in the liver

870.3100
90

- Day oral toxicity (rat) 43709026 (1991)

Acceptable/guideline 0, 50, 300, 2000, 12,000

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

lesions in males

Non

- guideline

28

- Day Feeding/ Range Finding (rat) 43866301 (1989)

Acceptable/Non

guideline 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 body

weight gains, microcytosis, increase cholesterol and phospholipid l evels, and hepatocyte hypertrophy

Non

- guideline

28

- Day Gavage/ Range Finding (rat) 43737601 (1991)

Acceptable/Non

guideline 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 body

weight gains and decreased food consumption in both sexesPage 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 dermal

toxicity (rat) 47526801 ( 008 )

A cceptable /
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 body

weight/body

- weight gain and reduced food consumption Developmental NOAEL = 200 mg/kg/day LOAEL = 1000 mg/kg/day based on lower mean fetal weights and increased incidence of delayed ossification

870.3700b
Prenatal developmental (rabbit) 43709032 (1991)

Acceptable/Guideline 0, 5, 30, 150, 400 mg/kg/day Maternal NOAEL = 150 mg/kg/day LOAEL = 400 mg/kg/day based on decreased body

- weight gain Developmental NOAEL = 150 mg/kg/day LOAEL = 400 mg/kg/day based on slight increase of litters showing extra (13 th ) ribs

870.3800 Reproduction and fertility effects (rat) 43709034 (1993)

Acceptable/Guideline 0, 10, 100, 1000, 4000

ppm M: 0, 0.7, 6.7, 68, 273 mg/kg/day F: 0, 0.8, 8.2, 81, 326 mg/kg/day Maternal/Systemic NOAEL = 81 mg/kg/day LOAEL = 326 mg/kg/day based on decreased body weight gain in the F0 females during the pre

- mating period. Reproductive/Developmental NOAEL = 81 mg/kg/day LOAEL = 326 mg/kg/day based on decreased pup weights (F1 and F2)

870.4300 Chronic toxicity/ Carcinogenicity (feeding) (rat) 43737602 (1994)

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

No evidence of carcinogenicity

870.4100b Chronic toxicity (dog) 43709030 (1991)

0, 25, 250, 2500, 15000 M: 0, 0.72, 6.87, 65.35, 449.25 mg/kg/day F: 0, 0.76, 6.80, 67.99, 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 efficiencyPage 37 of 53

Table 2. Toxicity Profile of Cyprodinil Technical.

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870. 4 200 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 antibody

forming 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.

8 70.6200a 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 s ub

- 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 sacr ifice time.

870.5550

UDS 43709035 (1991)

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

870.7485

Metabolism and pharmacokinetics 43709040 (1992)

Acceptable/Guideline Single oral doses (0.5 or 100 mg/kg bw) of phenyl or pyrimidyl

administered to Tif:RAIf(SPF) rats, with one low

- dose

2 weeks prior t o treatment with radiolabelled compound. Absorption was very rapid (t

cmax = 0.3 hours) with rapid clearance (t cmax/2 =1.2 hours). A minimum of 75% of the administered dose was absorbed. Excretion was rapid and almost complete, with urine as the principle route of excretion (48

- 68%), and >90% of the administered dose detected in the urine and feces within 48 hours. Excretion, distribution and metabolite profiles were essentially independent of dose level, pretreatment, and type of label, although there wer e some quantitative differences sex

dependent 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, fece s 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 hydroxylatio n 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

s ulfonation 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 notPage 39 of 53

Table 2. Toxicity Profile of Cyprodinil Technical.

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

significantly infl uenced by the dose, treatment regimen, or

sex of the animal.

870.7600 Dermal Absorption (rat) 45906102 (1999)

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

remained on the treated skin at 24 hours.Page 40 of 53

A.3 HAZARD IDENTIFICATION AND ENDPOINT SELECTION

A .3.1 Acute Reference Dose (aRfD)

– A ll Populations

Selected Study : Acute Neurotoxicity Rat ; MRID 4 8304202

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).

U ncertainty Factor (UF) : 100 0 x (10x for interspecies and 10x for intraspecies variation ; and 10X
for lack of 90

- day inhalation study )

Acute RfD = 200 mg/kg (NOAEL) = 0.2 0 mg/kg

100 0 (UF)

[Note: T he 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 ; MRID s 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. 0 0 27 mg/kg

100 0 (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 Chroni c Toxicity/Carcinogenicity on r ats 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 cholester ol 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 1 2000(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 f emales 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 addi tional 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 prot ein and globulin levels in the males. Relative liver weights were higher for malePage 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. Leukoc yte 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 th e 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 gu ideline 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/ k g / 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 consist ed 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, 2 00

, 1500, 7000 or 20000 ppm (actual concentrations: males

- 0, 6.07, 45.87,Page 43 of 53

2 10.33 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 incre ase 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 bodyweig ht 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 c onsumption 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 observation s, detailed behavio ral 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 histopath ological 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 histo pathology.

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

- R at

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 consumptionPage 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 consum ption. 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 t o 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 oc curs 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 m g/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 develop mental 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 (n ot 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 hy perflexion 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 deve lopmental 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 Tox icity

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 histopathologic al 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

Th e 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 significantl y lower F1 and F2 pup weights in the. high

- dose group during lactation, which continued to be lower than controls post

weaning and after the pre

- mating period (examination in F1 generation only). The LOAEL for reproductive/developmental toxicity is 4000 ppm (about 32 6 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 co ncentrations: 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 slight ly 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 t he 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 le sions (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) (attr ibutable 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 NO A EL is 2500 ppm (males

- 65.63, females

- 67.99 mg/kg/day). This study is classified as acceptable (guideline) and satisfied the guideline require ment 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., B atch 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 20 00 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 wa s tested to adequate levels based on si gns 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

negativePage 47 of 53

A.4.7 Neurotoxicity

870.6100 Delayed Neurotoxicity Study

– Hen

- NA

870.6200 a 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 adm inistered 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 brai n, 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 ma le, 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

par ameters 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 ad ministered 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 20 0 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

cha nges 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.

870.6200 b 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, a nd 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 wee ks 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 b ody 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 h igh

- 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 increa se 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 thyr oid 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 o n 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 guideli ne 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%) f or 2 weeks prior to treatment with radiolabelled compound. Absorption was very rapid (t
cmax = 0.3 hours) with rapid clearance (t cmax/2 =1.2 hours). A minimum of 75% of the administered dose was absorbed. A biphasic first order kinetics was observed for ra dioactivity 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, althou gh 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 requiremen t 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 monosulf ate 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 deco njugated 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.

Th is 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) fo r 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 blo od 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. Sp leens 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 cell

dependent antigen sRBC. Effects did include higher mean absolute, relative to body weight, and adjusted liver weights noted in the 5000ppm cyprodinil

- tr eated 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 se en 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 t he 5000ppm group.Page 51 of 53

B. METABOLI SM

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

CGA

- 232449

6

- cyclopropyl

- 2

- (phenylamino)

- 4

- pyrimidinemethanol

CGA

- 304075

4

- [(4

- cyclopropyl

- 6

- methyl

- 2

- 2

- pyrimidinyl)amino]

- phenol

CGA

- 304076

NOA

- 413167Page 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

CGA

- 263208

phenylguanidinePage 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/cm 3 at 20 C Water solubility (mg/L at 25 C) 16 at pH 7.6, 20 at pH 5, 13 at pH 7, 5 at pH 9 Solvent solubility (g/L at 25 C) ethanol

- 160, acetone

- 610, toluene

- 460,

n

- octanol

- 160, n

- hexane

- 30 Vapor pressure 3.8 x 10 - 6 mm Hg at 25 C Dissociation constant, pK

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

UV/visible absorption spectrum (molar absorption coefficients for the absorbance maximum) 29,200 L/mol∙cm at 270.8 nm (neutral) 29,200 L/mol∙cm at 251.6 nm (acidic) 29,200 L/mol∙cm at 316.8 nm (acidic) 28,400 L/mol∙cm at 270.8 nm (basic)

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 ba se (SOP #3.1)