

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

              OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION


MEMORANDUM     			

July 1, 2015		 

SUBJECT:	Cyprodinil.  Human Health Risk Assessment for the Expansion of Existing Crop Group/Representative Commodity Uses to Stone Fruit Group 12-12, and Adding New Uses on the Artichoke, Guava, Pomegranate, Passionfruit, Feijoa, Jaboticaba, Wax Jambu, Starfruit, and Acerola and Amended Uses on Greenhouse Cucumbers and Small Tomatoes. 

PC Code:  288202
DP Barcode:  D425998
Decision No.:  490951
Registration Nos.:  100-811, 100-828, 100-953, and 100-1317
Petition No.:  4E8273
Regulatory Action:  Section 3
Risk Assessment Type:  NA
Case No.: 7025
TXR No.:  NA
CAS No.:  121552-61-2
MRID No.:  49346901  -  05
40 CFR:  180.532


FROM:	Thurston Morton, Risk Assessor
            Abdallah Khasawinah, PhD., Toxicologist
            Ivan Nieves, Chemist
            Risk Assessment Branch IV
	Health Effects Division (7509P)

THROUGH:	Charles Smith, Acting Branch Chief
		Risk Assessment Branch 4
            Health Effects Division (7509P)
            
TO:			Laura Nollen/Barbara Madden, RM20
            Risk Integration, Minor Use & Emergency Response Branch                    Registration Division (RD) (7505P)

	

This document provides the Health Effects Division's (HED's) risk assessment of the proposed use of cyprodinil on globe artichoke, guava, passionfruit, feijoa, jaboticaba, wax jambu, starfruit, acerola, post-harvest use on pomegranate, and amended uses on greenhouse cucumbers and small tomatoes.   



1.0 	EXECUTIVE SUMMARY	5
2.0	HED RECOMMENDATIONS	9
2.1	Data Deficiencies/Conditions of Registration	9
2.2	Tolerance Considerations	10
2.2.1	Enforcement Analytical Method	10
2.2.2	International Harmonization	10
2.2.3	Recommended Tolerances	10
2.2.4	Revisions to Petitioned-For Tolerances	11
2.3	Label Recommendations	11
3.0	INGREDIENT PROFILE	11
3.1	Chemical Identity	11
3.2	Physical/Chemical Characteristics	12
3.3	Pesticide Use Pattern	12
3.4 	Anticipated Exposure Pathways	14
3.5	Considerations of Environmental Justice	14
4.0	HAZARD CHARACTERIZATION/ASSESSMENT	15
4.1	Toxicology Studies Available for Analysis	15
4.2	Absorption, Distribution, Metabolism and Excretion	15
4.3	Toxicological Effects	16
4.4	Safety Factor for Infants and Children (FQPA Safety Factor)	17
4.4.1	Completeness of the Toxicology Database	17
4.4.2	Evidence of Neurotoxicity	17
4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal	18
4.4.4	Residual Uncertainty in the Exposure Database	18
4.5	Toxicity Endpoint and Point of Departure	18
4.5.1	Dose-Response Assessment	18
4.5.2	Recommendations for Combining Exposure Routes	19
4.5.3	Classification of Carcinogenic Potential	19
4.5.4	Summary of Points of Departure Used in Risk Assessment	19
5.0	DIETARY AND DRINKING WATER EXPOSURE AND RISK ASSESSMENT	21
5.1 	Metabolite/Degradate Residue Profile	21
5.1.1	Summary of Plant and Livestock Metabolism Studies	21
5.1.2 	Comparison of Metabolic Pathways	21
5.1.3 	Environmental Fate and Transport	21
5.1.4 	Residues of Concern Summary and Rationale	22
5.2	Food Residue Profile	22
5.2.1	Residues in Crops	22
5.3 	Water Residue Profile	23
5.3.1	Estimated Drinking Water Concentrations	23
5.4 	Dietary and Drinking Water Exposure and Risk	24
5.4.1	Acute Dietary and Drinking Water Analysis	24
5.4.2	Chronic Dietary and Drinking Water Analysis	25
6.0 	RESIDENTIAL EXPOSURE AND RISK ASSESSMENT	25
6.1	Residential Bystander Postapplication Inhalation Exposure	26
6.2	Spray Drift	26
7.0 	AGGREGATE EXPOSURE AND RISK ASSESSMENT	27
7.1	Acute & Chronic Aggregate Risk	27
7.2	Short- and Intermediate-Term Aggregate Risk	27
7.3	Intermediate-Term Aggregate Risk	28
8.0	CUMULATIVE RISK	28
9.0	OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION	28
9.1	 Exposure Scenarios	28
9.2	Handler Exposure	29
9.2.1 	Handler Exposure Scenarios	29
9.2.2	Handler Exposure Data	29
9.2.3 	Handler Exposure Assumptions	29
9.2.4 	Handler Exposure and Risk Estimates	30
9.3	Post Application Exposure	30
9.3.1	Post Application Exposure Scenarios	32
9.3.2	Post Application Exposure Assumptions	33
9.3.3 	Post-Application Exposure and Risk Estimates	33
9.3.4 	Restricted Entry Interval	35
10.	REFERENCES	35
A 	TOXICOLOGY DATA SUMMARY	36
A.1 	Guideline Data Requirements	36
A.3	Toxicological Endpoints	36
APPENDIX B.  Chemical Names And Structures Of Metabolites	52
B.1 	Chemical Names And Structures	52
APPENDIX C. Physical/Chemical Properties	54
APPENDIX D.  Studies Reviewed for Ethical Conduct	54











































1.0 	EXECUTIVE SUMMARY

This assessment provides information to support a Section 3 registration for the use of cyprodinil on globe artichoke, guava, passionfruit, feijoa, jaboticaba, wax jambu, starfruit, acerola, and post-harvest use on pomegranate, along with expansion of the fruit, stone, group 12 to fruit, stone, group 12-12.  This document addresses the dietary, drinking water, residential and occupational exposure and risk associated with currently registered uses and proposed new uses of cyprodinil.  It provides a reassessment of tolerances (pesticide residue limits in food) to ensure that they meet the safety standard established by the Food Quality Protection Act (FQPA) of 1996.    

Use Profile

Cyprodinil (4-cyclopropyl-6-methyl-N-phenyl-2-pyrimidinamine) is a systemic 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 and ground application equipment.  Cyprodinil is used on ornamental landscapes on golf courses and around residential, institutional, public, commercial and industrial buildings, parks, recreational areas and athletic fields.  It is applied to non-food areas with ground-boom and handheld spray equipment.  Since the label does not limit use to "professional" or certified applicators, there is potential for residential "handlers" to obtain and to apply the product.  Residential exposures are limited to residential applicators; however, since cyprodinil is only used on ornamentals and there is no dermal POD, only inhalation exposure was assessed.
		 
Proposed New/Amended Uses

In conjunction with PP#1E7854, IR-4 is requesting a Section 3 registration for Vanguard(TM) WG (EPA Reg. No. 100-828), a 75% water dispersible granule (WDG) formulation for use on globe artichoke, acerola, feijoa, guava, jaboticaba, passionfruit, starfruit, and wax jambu; Switch(R) 62.5 WG Fungicide (EPA Reg. No. 100-953), a 37.5% water dispersible granule (WDG) formulation of cyprodinil for use on guava, passionfruit, starfruit, and pomegranate (post-harvest); and Inspire Super (TM) Fungicide (EPA Reg. No. 100-1317), a 2.09 lb ai/gallon  emulsion oil in water (EW) formulation to artichoke.  In support of these new uses, IR-4 has submitted new magnitude of the residue data for cyprodinil using the WDG formulation of cyprodinil at the proposed use rate.

In addition, IR-4 is requesting amendments for the Section 3 registrations for Vanguard(TM) WG (EPA Reg. No. 100-828) and Inspire Super (TM) Fungicide (EPA Reg. No. 100-1317) to expand currently registered foliar uses for stone fruit group 12 to include the additional commodities specified under the following new crop group:  Fruit, stone, group 12-12  No amendments to the use patterns (i.e., maximum use rates, retreatment intervals, preharvest intervals, use of adjuvants, etc.) on the subject crops have been proposed.  No new residue chemistry data were submitted to support these uses.  Instead the petitioner wishes to rely on previously submitted residue chemistry data to support the currently registered uses of cyprodinil.

In addition, IR-4 is proposing to remove the restriction against using Vanguard(TM) WG (EPA Reg. No. 100-828) and Switch(R) 62.5 WG Fungicide (EPA Reg. No. 100-953) on small tomatoes along with removing the restriction against using Inspire Super (TM) Fungicide (EPA Reg. No. 100-1317) on greenhouse cucumbers.

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

The major target organs of cyprodinil are the liver in both rats and mice and the kidney in rats.  Liver effects observed consistently in subchronic and chronic studies in rats and mice include increased liver weights, increases in serum clinical chemistry parameters associated with adverse effects on liver function, hepatocyte hypertrophy, and hepatocellular necrosis.  Adverse kidney effects include tubular lesions and inflammation following subchronic exposure of male rats.  The hematopoietic system also appeared to be a target of cyprodinil, causing mild anemia in rats exposed subchronically.  Chronic effects in dogs were limited to decreased body-weight gain, decreased food consumption and decreased food efficiency.  There was no evidence of increased susceptibility in the developmental rat or rabbit study following in utero exposure or in the 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 highest dose in a 21 day dermal toxicity study in rabbits.  There was no evidence of carcinogenic potential in either the rat chronic toxicity/carcinogenicity or mouse carcinogenicity studies.   

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

Dose Response Assessment

Toxicological points of departure (PODs) were selected for dietary, occupational, and residential exposure scenarios.  A POD (NOAEL = 200 mg/kg/day) for acute dietary exposure was selected for the general population and all population subgroups from an acute neurotoxicity study in rats based on clinical signs (hunched posture, pilorection, and reduced responsiveness to sensory stimuli, reduced motor activity and hypothermia).  The POD (NOAEL = 2.7 mg/kg/day) for chronic dietary exposure was selected from a chronic/carcinogenicity feeding study in rats based on degenerative liver lesions (spongiosis hepatitis) in males.  A dermal exposure endpoint was not selected as no systemic toxicity was seen at the highest dose test in a 21 day dermal toxicity study in rabbits.   A short-and intermediate term inhalation exposure POD of 62 mg/kg/day (No Observable Adverse Effect Level; NOAEL) was selected from a 28-day feeding study in rats based on decreased body-weight gain, increased cholesterol and phospholipid levels, microcytosis, and hepatocyte hypertrophy seen at the Lowest Observed Adverse Effect Level (LOAEL) of 299 mg/kg/day. The POD of 62 mg/kg/day is appropriate and protective for the longer-term intermediate exposure scenario since there is no progression of toxicity observed in the 90-day SCN study where the NOAEL is 54 mg/kg/day based on decreased body weight gain, hepatocyte hypertrophy, kidney tubular casts, thyroid follicular cell hypertrophy at the LOAEL of 600 mg/kg/day.  An uncertainty factor of 100x was applied to PODs for both acute and chronic dietary exposure (10x for interspecies extrapolation, 10x for intraspecies variation). A recent HASPOC decision (TXR 0054812), based on a weight of evidence approach is requiring a 90-day inhalation toxicity study to reduce uncertainty associated with the use of an oral POD for assessing risk via the inhalation route.  Therefore, in the absence of a route-specific inhalation study, a 10X database uncertainty factor for occupational workers and a 10x FQPA SF factor for residential scenarios should be applied specifically to the inhalation assessment.  

Exposure/Risk Assessment and Risk Characterization

Risk assessments were conducted for dietary (food and water) and occupational exposure based on registered uses and requests for new or expanded use of cyprodinil on a number of commodities.  The proposed uses will not result in residential exposure; however, there is a currently registered ornamental use that has been previously evaluated to reflect updates to HED's 2012 Residential Standard Operating Procedures (SOPs) (D398361, I. Nieves, 5/3/12).  No residential risks of concern were identified.  Conservative acute and moderately refined chronic dietary and drinking water risk assessments for cyprodinil conclude that dietary and drinking water exposure estimates are below HED's level of concern for the general population and all population subgroups.  Dermal risks to agricultural workers following treatments were not assessed since no short- or intermediate-term dermal endpoint of concern was identified.  The majority of the proposed uses have been previously assessed in association with evaluation for similar use patterns (D398361, I. Nieves, 5/3/12), and no risk estimates of concern were identified.  The proposed use on cucumbers grown in greenhouses was re-assessed based on a change in formulation (previously assessed as a dry flowable; proposed as a liquid) (D362494, I. Nieves, 8/4/09) and recent updates to unit exposures and body weight assumptions.  Occupational handler risk estimates resulted above HED's LOC of 1,000 and therefore not of concern.  At baseline, the occupational handler inhalation MOEs range from 1,300 to 1,100,000, depending on the scenario.   The proposed use on post-harvest pomegranates resulted in inhalation exposure risk estimates above HED's LOC of 1,000 at baseline.  MOEs resulted in 4,900 and 11,000.  Exposure and risk estimates from post-application inhalation exposure for sorter and packers for the proposed use on pomegranates results in no risk estimates of concern.  MOEs resulted in 15,000 for direct inhalation exposure, and 320,000 for indirect inhalation exposure.

 
Use of Human Studies

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These studies, listed in Appendix D have been determined to require a review of their ethical conduct.  Some of these studies are also subject to review by the Human Studies Review Board.  All of the studies used have received the appropriate review.

Environmental Justice

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

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

Tolerance Recommendation

Pending submission of a minor revision to Section F (see requirements under Section 2.2.3 Recommended Tolerances), there are no residue chemistry issues that would preclude granting the proposed use or establishment of the following tolerance for residues of cyprodinil.  
      
          Artichoke, globe.....	4.0 ppm
          Guava	1.5 ppm
          Passionfruit.............................................................1.5 ppm
          Feijoa....................................................................1.5 ppm Jaboticaba...............................................................1.5 ppm 
          Wax Jambu.............................................................1.5 ppm
          Starfruit 	1.5 ppm
          Acerola	1.5 ppm
          Pomegranate	.10 ppm
          Fruit, stone, group 12-12..................	2.0 ppm
      


Table 1. 	Tolerance Summary for Cyprodinil
Commodity
                     Established/Proposed Tolerance (ppm)
                          Recommended Tolerance (ppm)
Comments; Correct Commodity Definition
                      Tolerances Proposed Under PP#1E7854
Artichoke
                                      4.0
                                      4.0
Artichoke, globe
Guava
                                      1.5
                                      1.5
---
Passionfruit
                                      1.5
                                      1.5
---
Feijoa
                                      1.5
                                      1.5
---
Jaboticaba
                                      1.5
                                      1.5
---
Wax Jambu
                                      1.5
                                      1.5
---
Starfruit
                                      1.5
                                      1.5
---
Acerola
                                      1.5
                                      1.5
---
Pomegranate
                                      7.0
                                      10
---
Fruit, stone, group 12-12
                                      2.0
                                      2.0
---

No Codex MRLs are established in/on globe artichoke, acerola, feijoa, guava, jaboticaba, passionfruit, starfruit, wax jambu, and pomegranate.  A Mexican MRL has not been established for the requested crops.  The Agency with be harmonized with Codex on the fruit, stone, group 12-12 MRL of 2.0 ppm.  

2.0	HED RECOMMENDATIONS

2.1	Data Deficiencies/Conditions of Registration 

There are no deficiencies in the residue chemistry or exposure data requirements for the proposed actions.  Tolerances should be revised, as specified in Table 1 Section 2.2.3.  Revised Sections B and F are required for the IR-4 Petition PP#4E8273.  The HASPOC concluded (TXR 0054812), based on a weight of evidence (WOE) approach, that a 90-day inhalation toxicity study is required at this time to reduce uncertainty associated with the use of an oral POD for assessing risk via the inhalation route.  This determination considered all of the available hazard and exposure information for cyprodinil, including: (1) the use of an oral POD results in MOEs as low as 150 for risk via the inhalation route for intermediate-term exposure from occupational uses; and (2) the toxicological profile of cyprodinil indicates that toxicity increases with increased exposure from short-term to intermediate durations.  Therefore, in the absence of a route-specific inhalation study, a 10X database uncertainty factor for occupational workers and a 10x FQPA SF factor for residential scenarios should be applied specifically to the inhalation assessment.  

Note to PM:

      Revised Sections B & F required.
      
      
      
2.2	Tolerance Considerations

	2.2.1	Enforcement Analytical Method

Adequate HPLC/UV methods (AG-631 and AG-631B) are available for enforcing tolerances of cyprodinil on plant commodities.  The limits of quantitation (LOQ) for the plant methods range from 0.005 to 0.065 ppm depending on the commodity.  An adequate LC/MS method (GRM010.01A) is also available for enforcing tolerances of cyprodinil residues in livestock commodities.  The method LOQ for this method is 0.02 ppm for the combined residues of cyprodinil and its metabolite CGA-304075 (free and conjugated), expressed as parent.

	2.2.2	International Harmonization

No Codex MRLs are established in/on globe artichoke, acerola, feijoa, guava, jaboticaba, passionfruit, starfruit, wax jambu, and pomegranate.  A Mexican MRL has not been established for the requested crops.  The Agency with be harmonized with Codex on the fruit, stone, group 12-12 MRL of 2.0 ppm.  There are no tolerances established in Mexico.  

	2.2.3	Recommended Tolerances
      
HED has examined the residue chemistry database for cyprodinil and recommends in favor of the establishment of a tolerance for residues of cyprodinil in/on the following:

          Artichoke, globe.....	4.0 ppm
          Guava	1.5 ppm
          Passionfruit.............................................................1.5 ppm
          Feijoa....................................................................1.5 ppm Jaboticaba...............................................................1.5 ppm 
          Wax Jambu.............................................................1.5 ppm
          Starfruit 	1.5 ppm
          Acerola	1.5 ppm
          Pomegranate	10 ppm
          Fruit, stone, group 12-12..................	2.0 ppm
      


Table 2.2.3. 	Tolerance Summary for Cyprodinil
Commodity
                     Established/Proposed Tolerance (ppm)
                          Recommended Tolerance (ppm)
Comments; Correct Commodity Definition
                               40 CFR §180.532
Artichoke
                                      4.0
                                      4.0
Artichoke, globe
Guava
                                      1.5
                                      1.5
---
Passionfruit
                                      1.5
                                      1.5
---
Feijoa
                                      1.5
                                      1.5
---
Jaboticaba
                                      1.5
                                      1.5
---
Wax Jambu
                                      1.5
                                      1.5
---
Starfruit
                                      1.5
                                      1.5
---
Acerola
                                      1.5
                                      1.5
---
Pomegranate
                                      7.0
                                      10
---
Fruit, stone, group 12-12
                                      2.0
                                      2.0
---

      
Adequate crop field trial data reflecting the proposed use patterns were submitted in support of the proposed use and tolerance.  The Organization for Economic Cooperation and Development tolerance calculation procedures were utilized in determining the appropriate tolerance level for the proposed use.  The proposed and recommended tolerance for residues of cyprodinil as a result of the subject action are presented in Table 2.2.3.

	2.2.4	Revisions to Petitioned-For Tolerances

No significant changes to the petitioned-for tolerance are required.  However, the proposed Artichoke tolerance must be corrected to artichoke, globe.  In addition, the pomegranate tolerance level should be revised to 10 ppm.  This is because different field trial use patterns should not be mixed in the OECD MRL calculator.

2.3	Label Recommendations

The label instructions for Artichoke should be revised to specify Globe Artichoke.  The proposed use directions are adequate.  Directions on the proposed supplemental label to Inspire(TM) Fungicide (EPA Reg. No. 100-1262) coupled with the spray volume and confined rotational crop restrictions on the current Inspire[R] Fungicide Label (EPA Reg. No. 100-1262 are adequate.

3.0	INGREDIENT PROFILE 

3.1	Chemical Identity

Structure and nomenclature are reported in Table 3.1.

Table 3.1.	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 products (EP)
75% water-dispersible granule (WDG) formulation (Vangard(TM) Fungicide; EPA Reg. No. 100-828); a multiple active ingredient (MAI) end-use product (Inspire Super (TM) Fungicide; EPA Reg. No. 100-1317) formulated as an emulsion [oil] in water (EW), containing 8.4% difenoconazole and 24.1% cyprodinil

3.2	Physical/Chemical Characteristics 

The physicochemical properties of cyprodinil are reported in Appendix C.  
      
3.3	Pesticide Use Pattern

Proposed cyprodinil use patterns taken from submitted supplemental labels (Table 3.3).  


















Table 3.3.  Summary of Proposed Directions for Use 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
                                 Artichoke[1]
                               Broadcast foliar
                           Ground/Aerial/Chemigation
                                  Vangard WG
                                    75% WDG
                                   [100-828]
                                     0.33
                                   4 implied
                                      1.3
                                       3
A minimum retreatment interval (RTI) of 14 days is proposed.  
                               Broadcast foliar
                                  Ground Only
                                 Inspire Super
                                2.09 lb/gal EW
                                  [100-1317]
                                     0.33
                                   4 implied
                                     1.3 
                                       3
A minimum retreatment interval (RTI) of 7-10 days is proposed.
    Acerola, feijoa, guava, jaboticaba, passionfruit, starfruit, wax jambu
                               Broadcast foliar
                           Ground/Aerial/Chemigation
Vangard WG
                                    75% WDG
                                   [100-828]
                                     0.33
                                  2 by aerial
                                   4 implied
                                      1.3
                                       0
A minimum retreatment interval (RTI) of 7-10 days is proposed.
                               Broadcast foliar
                                  Ground Only
                                 Switch 62.5WG
                                   37.5% WDG
                                   [100-953]
                                     0.33
                                  1 by aerial
                                   4 implied
                                      1.3
                                       0
A minimum retreatment interval (RTI) of 7-10 days is proposed.  Aerial application in California only.
                         Stone fruits Crop Group 12-12
                               Broadcast foliar
                                 Ground/Aerial
Vangard WG
                                    75% WDG
                                   [100-828]
                                     0.47
                                  2 by aerial
                                   4 implied
                                      1.4
                                       2
Apply maximum of 2 applications during the pre-harvest period through 2 days prior to harvest needed. California only
                                       
                                 Inspire Super
                                2.09 lb/gal EW
                                  [100-1317]
                                     0.33
                                  2 by aerial
                                   4 implied
                                      1.4
                                       
A minimum retreatment interval (RTI) of 7 is proposed.
                         Cucumber Grown in Greenhouses
                               Broadcast foliar
                                  Ground Only
                                 Inspire Super
                                2.09 lb/gal EW
                                  [100-1317]
                            0.0075 lb ai/1000 ft[2]
                                      NS
                                      NS 
                                       7
A minimum retreatment interval (RTI) of 7-10 days is proposed.
                     Pomegranate (Post-harvest dip/drench)
                              In-Line Dip/Drench
                                 Switch 62.5WG
                                   37.5% WDG
                                   [100-953]
                                       
0.45 lb ai/100 gal of water, wax/emulsion, or aqueous dilution of wax/oil emulsion
                                       2
0.45-0.90 lb ai/100 gal of water, wax/emulsion, or aqueous dilution of wax/oil emulsion
                                       0
For maximum decay control, treat fruit once before storage and once after storage, prior to marketing.
[1] Although not specified in the use direction, the use of artichoke is intended to be for globe artichoke consistent with the supporting data.
  
3.4 	Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new uses of cyprodinil on globe artichoke, guava (along with other tropical fruits) and post-harvest use on pomegranate.  For domestic uses, humans may be exposed to cyprodinil in food and drinking water, since cyprodinil may be applied directly to growing crops and application may result in cyprodinil reaching surface and ground water sources of drinking water.  There are also residential uses of cyprodinil, so there is exposure in residential or non-occupational settings.  In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application.  There is a potential for post-application exposure for workers re-entering treated fields.  

Risk assessments have been previously prepared for the existing uses of cyprodinil.  This risk assessment considers all of the aforementioned exposure pathways based on the proposed use of cyprodinil, but also considers the existing uses as well, particularly for the dietary exposure assessment.

3.5	Considerations of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture's (USDA's) National Health and Nutrition Examination Survey/What We Eat in America, (NHANES/WWEIA), are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post-application are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0	HAZARD CHARACTERIZATION/ASSESSMENT

4.1	Toxicology Studies Available for Analysis

The toxicology database for cyprodinil is adequate for evaluating and characterizing cyprodinil toxicity and selecting endpoints for purposes of this risk assessment.  Acute neurotoxicity (MRID 48304202) and immunotoxicity studies (MRIDs 48304203, 4829350) required under revised 40 CFR Part 158 Toxicology Data Requirements have been submitted and determined to be acceptable.  Based on a weight of evidence (WOE) approach a 90-day inhalation toxicity study is required at this time to reduce uncertainty associated with the use of an oral POD for assessing risk via the inhalation route (HASPOC, TXR 0054812).  
      
4.2	Absorption, Distribution, Metabolism and Excretion

Absorption, distribution, metabolism, and excretion of cyprodinil were studied in rats.  In an initial study, single oral doses (0.5 or 100 mg/kg bw) of phenyl or pyrimidyl-radiolabelled cyprodinil were administered with one low-dose group receiving unlabeled cyprodinil for 2 weeks prior to treatment with radiolabelled compound.  Absorption was very rapid (peak concentration at 0.3 hours) with rapid clearance (half-life of < 2 hrs).  A minimum of 75% of the administered dose was absorbed.  Excretion was rapid and almost complete, with urine as the principle route of excretion (48-68%), and >90% of the administered dose detected in the urine and feces within 48 hours.  Tissue residues declined rapidly, with the highest concentrations (< 1.8 ppm) found in kidneys, liver, lungs, spleen, thyroid, whole blood, and carcass.  The urine, fecal, and bile metabolite patterns were complex, with 8, 8 and 9 defined metabolite fractions, respectively.  Unchanged parent compound was detected in feces extract only.  Excretion, distribution and metabolite profiles were independent of dose level, pretreatment, and type of label, although there were some quantitative differences sex-dependent qualitative differences in two urinary metabolite fractions.
      
In a follow-up study, excreta and bile from radiolabelled rats from the previous study were used to characterize, isolate and identify the metabolites detected in that study.  Eleven metabolites were isolated from urine, feces and bile, and the metabolic pathways in the rat were proposed.   All urinary and biliary metabolites but one were conjugated with glucuronic acid or sulfonated, and excreted.   Cyprodinil was almost completely metabolized by hydroxylation of the phenyl ring or pyrimidine ring, followed by conjugation.  An alternative pathway involved oxidation of the phenyl ring followed by glucuronic acid conjugation.  The major metabolic pathways of cyprodinil were not significantly influenced by the dose, treatment regimen, or sex of the animal.

4.3	Toxicological Effects

The major target organs of cyprodinil are the liver and the kidney.  Liver effects were consistent among male and female rats and mice in both subchronic and chronic studies and typically included increased liver weights along with increases in serum clinical chemistry parameters associated with adverse effects on liver function (i.e., increased cholesterol and phospholipid levels).  Microscopic lesions in rats and mice included hepatocyte hypertrophy and hepatocellular necrosis.  In the kidneys, adverse effects were seen as chronic tubular lesions and chronic kidney inflammation following subchronic exposure of male rats.  Chronically, cyprodinil caused increased kidney weights and progressive nephropathy in male rats.  Chronic effects in dogs were limited to decreased body-weight gain, decreased food consumption and decreased food efficiency; liver toxicity was not seen in the dog.  The hematopoietic system also appeared to be a target of cyprodinil as mild anemia was seen in rats exposed subchronically (reductions in hematocrit and hemoglobin and microcytosis).  Although increases in thyroid weight and/or hypertrophy of thyroid follicular cells were observed at higher doses in the rat 28-day oral-toxicity studies (both feeding and oral gavage) and in the 90-day oral-toxicity study in rats, treatment related changes in thyroid weights or gross/microscopic observations were not observed in the chronic rat study or in other studies (thyroid hormones were not evaluated in any study).  A 28-day dietary immunotoxicity study in mice resulted in no apparent suppression of the humoral component of the immune system.  The only effect attributed to cyprodinil treatment was higher mean absolute, relative (to body weight), and adjusted liver weights for the 5000 ppm group.  There were no treatment-related effects on absolute, adjusted, or relative spleen or thymus weights; no effects on specific activity or total activity of splenic IgM antibody-forming cells to the T cell-dependent antigens RBC.  No dermal or systemic toxicity was seen following repeated dermal application at the highest dose in a 21 day dermal toxicity study in rabbits.

An acute neurotoxicity study indicated systemic toxicity with signs of induced hunched posture, pilorection, and reduced responsiveness to sensory stimuli and reduced motor activity.  Females were slightly more affected than males per daily clinical observations, which disappeared by day 3 to 4.  A dose-related reduction in body temperature was seen in all treated animals, thus hypothermia is considered a compound-related effect in the HDT and was found to be statistically significant, whereas the lower dosed animals was not or only marginally significant and was fully reversible in all groups.  Clinical signs, hypothermia, and changes in motor activity were found to all be reversible by day 8 and 15 investigations.  There were no histopathological findings to support evidence of damage to the central nervous system, eyes, optic nerves, or skeletal muscles. A subchronic neurotoxicity study showed no treatment related effects on mortality, clinical signs, or gross or histological neuropathology.  FOB and motor activity testing revealed no treatment related effects up to the highest dose tested.  No clinical signs suggestive of neurobehavioral alterations or evidence of neuropathological effects were observed in the available oral-toxicity studies.  There was also no evidence of a neurodevelopmental effect in the rat or rabbit developmental-toxicity studies or in the rat two generation reproductive-toxicity study.  

There was no evidence of increased susceptibility in the developmental rat or rabbit study following in utero exposure or in the two-generation reproduction study following pre- and post-natal exposure.  Fetal toxicity, manifested as significantly lower fetal weights and an increased incidence of delayed ossification in the rat and a slight increase in litters showing extra ribs (13[th]) in the rabbit, was reported in developmental toxicity studies.  In a rat two generation reproduction study, significantly lower pup weights for F1 and F2 offspring were observed.  However, each of these fetal/neonatal effects occurred at the same dose levels at which maternal toxicity (decreased body weight gain) was observed and were considered to be secondary to maternal toxicity. 
      
Cyprodinil has low acute toxicity via the oral, dermal, and inhalation routes (Toxicity Category III).  Cyprodinil is mildly irritating to the eyes (Toxicity Category III) and negligibly irritating to the skin (Toxicity Category IV).  It is a dermal sensitizer.  

The complete toxicity profile for cyprodinil is provided in Appendix A. 
      
4.4	Safety Factor for Infants and Children (FQPA Safety Factor)	

For non-inhalation routes of exposure, the FQPA factor for potential susceptibility to infants and children is reduced to 1x based on the following considerations.  Further discussion may be found in the following sections.

   oo The toxicology data base for cyprodinil is complete and adequate for assessing susceptibility under FQPA.
   oo There is no indication of susceptibility of rats or rabbit fetuses to in utero and/or postnatal exposure in the developmental and reproductive toxicity data.
   oo There are no residual uncertainties in the exposure database.
   oo The dietary and residential exposure and risk assessments are conservative and will not underestimate exposure to cyprodinil.
For inhalation exposure scenarios for all population groups, EPA is retaining a 10X FQPA safety factor for the lack of a route specific inhalation study.
      
	4.4.1	Completeness of the Toxicology Database

The toxicity database for cyprodinil is sufficient for a full hazard evaluation and is considered adequate to evaluate risks to infants and children.  Acceptable studies have been submitted for developmental toxicity, reproductive toxicity, acute and subchronic neurotoxicity and immunotoxicity.  However, in the absence of a route-specific inhalation study, a 10X database uncertainty factor for occupational workers and a 10x FQPA SF factor for residential scenarios should be applied specifically to the inhalation assessment.  

	4.4.2	Evidence of Neurotoxicity

In a subchronic neurotoxicity study in rats, there were no treatment related effects on mortality, clinical signs, or gross or histological neuropathology.  Functional Observational Battery (FOB) and motor activity testing revealed no treatment related effects up to the highest dose tested.   In an acute neurotoxicity study in mice, clinical signs, hypothermia, and changes in motor activity were all found to be reversible and no longer seen at day 8 and 15 investigations.  There were no treatment related effects on mortality, gross or histological neuropathology.  Reduced motor activity, induced hunched posture, pilorection and reduced responsiveness to sensory stimuli were observed and disappeared in all animals by day 3 to 4.

	4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal
      
The available acceptable guideline studies indicated no increased susceptibility of rats or rabbits to in utero and/or from postnatal exposure to cyprodinil.  In the prenatal developmental toxicity studies in rats and rabbits and the two-generation reproduction study in rats, toxicity to the fetuses/offspring, when observed, occurred at the same doses at which effects were observed in maternal/parental animals.  

In a rat developmental toxicity study, there were significantly lower mean fetal weights in the high-dose group compared to controls as well as a significant increase in skeletal anomalies in the high-dose group due to abnormal ossification. The skeletal anomalies/variations were considered to be a transient developmental delay that occurs secondary to the maternal toxicity noted in the high-dose group.  In the rabbit study, the only treatment related developmental effect was indication of an increased incidence of a 13th rib at maternally toxic doses.  Signs of fetal effects in the reproductive toxicity study included significantly lower F1 and F2 pup weights in the high-dose group during lactation, which continued to be lower than controls post-weaning and after the pre-mating period (examination in F1 generation only).  Reproductive effects were seen only at doses that also caused parental toxicity.
      
	4.4.4	Residual Uncertainty in the Exposure Database 	

There are no residual uncertainties in the exposure database.  The residue data base is adequate.  The dietary risk assessment is conservative and will not underestimate dietary exposure to cyprodinil.  The residential exposure estimates included in the aggregate risk assessment are conservative based on maximum use rates and will not underestimate non-dietary risks to homeowners.   
4.5	Toxicity Endpoint and Point of Departure

	4.5.1	Dose-Response Assessment

An acute POD of 200 mg/kg was selected from an acute neurotoxicity study in rats based on LOAEL of 600 mg/kg showing clinical signs (hunched posture, pilorection, and reduced responsiveness to sensory stimuli, reduced motor activity and hypothermia).  An uncertainty factor (UF) of 100x (10x to account for interspecies extrapolation and 10x for intraspecies variation) was applied to the NOAEL to obtain an acute reference dose (aRfD) of 2.0 mg/kg/day.  Since the FQPA factor has been reduced to 1X, the acute population adjusted dose (aPAD) is equivalent to the aRfD.   The selected endpoint is considered appropriate for acute dietary exposure because effects were seen after a single dose.  
      
A chronic POD of 2.7 mg/kg/day (NOAEL) was selected from a chronic/carcinogenicity oral study in rats based on the histopathological alterations in the liver (spongiosis hepatis) in males at 35.6 mg/kg/day (LOAEL). The selected NOAEL is the lowest NOAEL observed in the most sensitive species following long-term exposure.  A UF 100x (10x to account for interspecies extrapolation and 10x for intraspecies variation) was applied to the dose to obtain a chronic reference dose (cRfD/cPAD) of 0.027 mg/kg/day.  
      
A POD for dermal exposure was not selected because no dermal or systemic toxicity was seen following repeated dermal application at the highest dose tested in a 21 day dermal toxicity study in rabbits. 
      
A short-and intermediate term inhalation exposure POD of 62 mg/kg/day (No Observable Adverse Effect Level; NOAEL) was selected from a 28-day feeding study in rats based on decreased body-weight gain, increased cholesterol and phospholipid levels, microcytosis, and hepatocyte hypertrophy seen at the Lowest Observed Adverse Effect Level (LOAEL) of 299 mg/kg/day. This POD of 62 mg/kg/day is appropriate and protective for the longer-term intermediate exposure scenario since there is no progression of toxicity observed in the 90-day SCN study where the NOAEL is 54 mg/kg/day based on decreased body weight gain, hepatocyte hypertrophy, kidney tubular casts, thyroid follicular cell hypertrophy at the LOAEL of 600 mg/kg/day.  The toxicological profile of cyprodinil indicates that toxicity increases with increased durations, specifically between short-term (28-day) and long-term exposures (2-year).  Therefore, based on the weight of evidence regarding cyprodinil, a 90-day inhalation toxicity study is required to reduce uncertainties associated with the use of an oral POD for assessing risk via the inhalation route.  

	4.5.2	Recommendations for Combining Exposure Routes

When there are potential residential exposures to the pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures.  There are no residential incidental oral (i.e., hand to mouth) exposures to cyprodinil, therefore, aggregate exposure from food and incidental oral exposures is not required.  However, an aggregate risk assessment of combined short-term inhalation and background dietary exposure is required for residential handlers because PODs selected for these exposure routes are based on common toxicological effects (i.e., liver effects).
	
      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) (TXR number 0051401) as "not likely to be carcinogenic to humans."
 
	4.5.4	Summary of Points of Departure Used in Risk Assessment

Toxicological doses/endpoints selected for the cyprodinil risk assessment are provided in Table 4.5.4.1 and 4.5.4.2.

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Cyprodinil  for Use in Dietary Human Health Risk Assessments
                               Exposure/Scenario
                              Point of Departure
                        Uncertainty/FQPA Safety Factors
                       RfD, PAD, LOC for Risk Assessment
                                       
                        Study and Toxicological Effects
                                       
Acute Dietary
(All Populations) 
NOAEL = 200 mg/kg
UFA= 10x
UFH=10x
FQPA SF= 1x
Acute RfD = 2.0 mg/kg           aPAD = 2.0 mg/kg/day    
Acute Neurotoxicity - Rat
LOAEL = 600 mg/kg based on clinical signs of toxicity (hunched posture, pilorection, and reduced responsiveness to sensory stimuli, reduced motor activity and hypothermia) 
Chronic Dietary 
(All Populations)
NOAEL= 2.7 mg/kg/day
UFA= 10x
UFH=10x
FQPA SF= 1x
Chronic RfD = 0.027
mg/kg/day
cPAD = 0.027mg/kg/day
2-Year Chronic Toxicity/ Carcinogenicity- rat
LOAEL = 35.6 mg/kg/day based on degenerative liver lesions (spongiosis hepatitis) in males.
Cancer (all routes)
Classification: "Not likely to be carcinogenic to humans" (TXR 0051401)
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  
NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  
UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies). SF = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  



Table 4.5.4.2.  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-/ Intermediate Term 
(1-30 days) 

Oral NOAEL=  62 mg/kg/day
(inhalation absorption rate = 100%)
Residential: UFA = 10x
UFH = 10x
FQPA SF = 10X*

Occupational: UFA = 10x
UFH = 10x
UFDB = 10X
Residential LOC for MOE = 1,000 




Occupational LOC for MOE = 1,000
28-Day Feeding/Range-Finding - Rat
LOAEL = 299 mg/kg/day based on decreased body-weight gain, increased cholesterol and phospholipid levels, microcytosis, and hepatocyte hypertrophy.

The POD of 62 mg/kg/day is appropriate and protective for the longer-term intermediate exposure scenario since there is no progression of toxicity observed in the 90-day SCN study where the NOAEL is 54 mg/kg/day based on decreased body weight gain, hepatocyte hypertrophy, kidney tubular casts, thyroid follicular cell hypertrophy at the LOAEL of 600 mg/kg/day.
Cancer (all routes)
Not likely human carcinogen
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  
NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  
UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies). UFDB = lack of inhalation study. SF = FQPA Safety Factor MOE = margin of exposure.  LOC = level of concern.  * FQPA SF is composed of the 10X factor for the inhalation study data gap.   

5.0	DIETARY AND DRINKING WATER EXPOSURE AND RISK ASSESSMENT

5.1 	Metabolite/Degradate Residue Profile

	5.1.1	Summary of Plant and Livestock Metabolism Studies

The nature of the residue in plants is adequately understood based on acceptable metabolism studies on apple, peach, potato, tomato, and wheat. The nature of the residue in ruminants is adequately understood based on acceptable lactating goat metabolism studies.  A poultry metabolism study is not available but is not required for this action since there are no poultry feed stuffs associated with the proposed new use of cyprodinil on leafy petiole group 4B.  The nature of the residue in confined rotational crops is understood.

	5.1.2 	Comparison of Metabolic Pathways
 
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 ruminant 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 metabolism 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 oxidation of the phenyl ring followed by glucuronic acid conjugation.  In the rat study, eleven metabolites were isolated from urine, feces and bile, and the metabolic pathways in the rat were proposed.   All urinary and biliary metabolites but one were conjugated with glucuronic acid or sulfonated, and excreted.  CGA 304075 was not separately identified as an isolated metabolite in the rat study.
     
	5.1.3 	Environmental Fate and Transport

The environmental fate data base for cyprodinil is substantially complete.  Cyprodinil has a relatively low solubility in water.  Based on its octanol/water partition coefficient, it is likely to partition with organic tissues and other organic media.  It is alkaline in water. It is not likely to volatilize substantially based on its low vapor pressure and Henry's Law constant.  Cyprodinil appears to bind strongly to particulate and sediment, showing relatively low soil mobility.   It appears to be a persistent compound under most conditions, except aerobic soil metabolism, as demonstrated in laboratory studies.  Its potential for groundwater contamination appears to be low.  However, due to its high persistence under aquatic conditions, aquifers that lie below areas that have low organic content and coarse textured soils or shallow leaky aquifers could be prone to contamination.  Even though buffer zones can ameliorate moderately the level of spray drift, the potential for runoff still exists for long periods of time.  Cyprodinil has a high affinity to sorb to soil and particulate suggests the potential for runoff in eroded particles.  This stability and binding to particulate and organic matter (aerobic and anaerobic conditions) suggests that cyprodinil residues in sediments could contribute to a possible resuspension of the compound through mixing and mass balance for an extended period.  Degradates of cyprodinil include 4-cyclopropyl-6-methyl-2-amine-pyrimidine, CGA-275535 (slightly mobile), CGA-321915 (mobile to moderately mobile), and CGA-249287 (moderately mobile) (degradate identified of concern in this assessment; 11.7% at 28 days in the aerobic soil metabolism study, and 14.2% in the aerobic aquatic metabolism study).  The water residues of concern are the parent and CGA 249287 (4-cyclopropyl-6-methylpyrimidin-2-amine) (D292557, 6/8/03).

	5.1.4 	Residues of Concern Summary and Rationale

Residues of concern for dietary and drinking water risk assessment and tolerance expression for cyprodinil are provided in Table 5.1.4.  HED has concluded that the residues of concern for livestock for both risk assessment and the tolerance definition should include the combined residues of cyprodinil and free and conjugated CGA-304075 (4-[(4-cyclopropyl-6-methylpyrimidin-2-yl)amino]-phenol, expressed in parent equivalents (D345970 and D345182, G. Kramer, 6/4/08).  The water residues of concern are the parent and CGA 249287 (4-cyclopropyl-6-methylpyrimidin-2-amine) (D292557, 6/8/03).

Table 5.1.4.  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

Following four applications of a 2.09 lb ai/gal EW formulation at a total application rate of 1.30 - 1.33 lbs ai/A, individual sample (and per-trial average) residues of cyprodinil were 0.08 - 0.62 ppm (0.11 - 0.58 ppm) in/on cucumber fruit collected at a PHI of 0 days.  There were no significant differences between the residues in the large variety cucumbers vs. the small variety cucumbers.  

Following four or five applications of a 2.09 lb ai/gal EW formulation at a total application rate of 1.300 - 1.655 lbs ai/A, individual sample (and per-trial average) residues of cyprodinil were 0.825 - 1.52 ppm (0.932 - 1.33 ppm) in/on mature globe artichoke flower buds collected at a PHI of 3 days.  There were no significant differences between the residues in the perennial globe artichokes vs. the annual globe artichokes.  



Following four applications of Switch(R) 62.5WG at a total application rate of 1.31 - 1.43 lbs ai/A, individual sample (and per-trial average) residues of cyprodinil were 0.345 - 0.626 ppm (0.353 - 0.522 ppm) in/on guava fruit collected at a PHI of 0 days.  

Data reflect three different post-harvest treatment scenarios/techniques of 1 or 2 applications using a water dispersible granule (WDG) formulation of cyprodinil (Switch(R) 62.5WG.  Each of these post-harvest scenarios/techniques are considered separate/discrete datasets for tolerance determination.  Following one application as a dip with wax at 0.45 lb ai/100 gal, individual sample (and per-trial average) residues of cyprodinil were 0.24-1.60 ppm (0.93-1.52 ppm) in/on pomegranate collected on the day of treatment.  Following a total of two applications, one application as a dip with wax at 0.45 lb ai/100 gal and a second application as a dip with no wax at 0.45-0.46 lb ai/100 gal, individual sample (and per-trial average) residues of cyprodinil were 2.22-3.60 ppm (2.56-3.42 ppm) in/on pomegranate treated and collected on the same day.  Following a total of two applications, one application as a dip with wax at 0.45-0.46 lb ai/100 gal and then a drench application with no wax at 0.45-0.46 lb ai/100 gal, individual sample (and per-trial average) residues of cyprodinil were 0.38-2.69 ppm (0.53-2.25 ppm) in/on pomegranate treated and collected on the same day.  

Side-by-side field trial data on lettuce, mustard greens and tomatoes comparing residues of cyprodinil resulting from multiple late season uses of the EW formulation with a WDG formulation of cyprodinil are available (DP# 354013, 3/20/09, B. Cropp-Kohlligian).  Cyprodinil residues were similar for the EW and WDG formulations on all three crops.  

The previously submitted stone fruit field trial data and processing data are adequate to support the proposed expansion of those uses to stone fruit group 12-12.  No additional data are required.  The recommended tolerance for residues of cyprodinil in/on fruit, stone, group 12-12 (2.0 ppm) is the same as the petitioned-for tolerance.

5.3 	Water Residue Profile
    
	5.3.1	Estimated Drinking Water Concentrations 

Drinking water residues were incorporated directly into the acute and chronic dietary analyses as "water, direct, all sources" and "water, indirect, all sources" and were provided by the Environmental Fate and Effects Division (EFED) (D421158, J Melendez 1/12/15).  The tier 2 aquatic models PRZM (Pesticide Root Zone Model)-EXAMS (Exposure Analysis Modeling System), and the models Screening Concentration in Ground Water (SCI-GROW) and Pesticide Root Zone Model for Groundwater (PRZM-GW) were used to obtain estimated drinking water concentrations (EDWCs) in surface water and groundwater, respectively.  The acute EDWC in surface water is 34.8 ug/L for the total residues of cyprodinil plus CGA-249287.  The chronic EDWC in surface waters is 24.7 ug/L for the total residues of cyprodinil and CGA-249287.  The cancer/chronic EDWC in surface waters is 16.4 ug/L for the total residues of cyprodinil and CGA-249287.  All surface waters EDWCs were obtained using the New York grapes PRZM scenario.  The PRZM-GW generated EDWC for the use on grapes, using the FL citrus surrogate scenario were 2.05 ug/L for the total residues of cyprodinil and CGA-249287 (acute) and 1.80 ug/L for the total residues (chronic).  For details on methods, characterization of results, uncertainties, etc., please, refer to the previous DWAs. Table 5.3.1 provides a summary of the Tier 2 modeled drinking water concentrations.

Table 5.3.1.  Maximum Estimated Drinking Water Concentrations for the Use of Cyprodinil (expressed as total residues of cyprodinil plus its degradate CGA-249287)
DRINKING WATER SOURCE (MODEL USED) 
USE (rate modeled per year)
MAXIMUM ESTIMATED DRINKING WATER CONCENTRATION  (EDWC)  ( ppb) 
Groundwater (PRZM-GW)
FL citrus[1] (1.4 lb a.i.)
Acute
                                     2.05


Chronic
                                     1.80
Surface water
(PRZM/EXAMS)
NY grapes (1.4 lb a.i.)
Acute
                                     34.8


Chronic
                                     24.7


Cancer/Chronic
                                     16.4
1 Scenario was used as a surrogate and run with the maximum application rate for grapes.

5.4 	Dietary and Drinking Water Exposure and Risk

Screening level acute and refined chronic dietary and drinking water exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database DEEM-FCID(TM), Version 3.16, which incorporates consumption data from USDA's National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA).  This dietary survey was conducted from 2003 to 2008.  Dietary risk assessment incorporates both exposure and toxicity of a given pesticide.  For acute and chronic dietary assessments, the risk is expressed as a percentage of a maximum acceptable dose (i.e., the dose which HED has concluded will result in no unreasonable adverse health effects).  This dose is referred to as the population adjusted dose (PAD).  The PAD is equivalent to the reference dose (RfD) divided by the additional Safety Factor, if applied. For acute and non-cancer chronic exposures, HED is concerned when estimated dietary risk exceeds 100% of the PAD.  

	5.4.1	Acute Dietary and Drinking Water Analysis

A new dietary assessment was conducted for the proposed new uses.  The proposed uses results dietary risk estimates below HED's level of concern; see Table 5.4.1.1. The highest is children 1-2 years resulting in 8.6% of the aPAD. 












Table 5.4.1.1.  Summary of Acute Dietary (Food plus Water) Exposure and Risk for Cyprodinil at the 95[th] Percentile. 

Population Subgroup

                                 aPAD (mg/kg)

                               Exposure (mg/kg)

                                     %aPAD

General U.S. Population






                                      2.0
                                   0.095198
                                      4.8

All Infants (< 1 year old)

                                   0.101588
                                      5.1

Children 1-2 years old

                                   0.172629
                                      8.6

Children 3-5 years old

                                   0.158663
                                      7.9

Children 6-12 years old

                                   0.083374
                                      4.2

Youth 13-19 years old

                                   0.071553
                                      3.6

Adults 20-49 years old 

                                   0.091866
                                      4.6

Adults 50-99 years old 

                                   0.091595
                                      4.6

Females 13-49 years old 

                                   0.096706
                                      4.8
The bolded %aPAD is the highest.

	5.4.2	Chronic Dietary and Drinking Water Analysis

A new dietary assessment was conducted for the proposed new uses of cyprodinil and results in dietary risk estimates below HED's level of concern; see Table 5.4.2.


Table 5.4.2.  Summary of Chronic Dietary (Food plus Water) Exposure and Risk for cyprodinil. 

Population Subgroup

                               cPAD (mg/kg/day)

                             Exposure (mg/kg/day)

                                     %cPAD

General U.S. Population






                                     0.027
                                   0.007794
                                      29

All Infants (< 1 year old)

                                   0.013042
                                      48

Children 1-2 years old

                                   0.023045
                                      85

Children 3-5 years old

                                   0.016592
                                      62

Children 6-12 years old

                                   0.008522
                                      32

Youth 13-19 years old

                                   0.004665
                                      17

Adults 20-49 years old 

                                   0.006327
                                      23

Adults 50-99 years old 

                                   0.007772
                                      29

Females 13-49 years old 

                                   0.006706
                                      25
The bolded %cPAD is the highest.

6.0 	RESIDENTIAL EXPOSURE AND RISK ASSESSMENT

The proposed uses will not result in residential exposure; however, there is a currently registered ornamental use that has been previously evaluated to reflect updates to HED's 2012 Residential Standard Operating Procedures (SOPs) (D398361, I. Nieves, 5/3/12).  No risk estimates of concern were identified.  The updated results for the residential use impacting the aggregate are presented below in table 6.0 for reference purposes. Post-application exposure was not quantified since no dermal endpoint was identified for cyprodinil.



Table 6.0. Residential Handler Inhalation Exposure and Risk Estimates for Cyprodinil.
                               Application Site
                             Application Equipment
                            Max Application Rate[a]
                             Amount AI Handled [b]
                         Unit Exposures[c] (mg/lb ai)
                      Absorbed Daily Dose[d] (mg/kg-day)
                                    MOE[e]
                                   LOC=1000
                                       
                                       
                            (lb ai/gallon solution)
                               (gallons solution)
                                       
                                       
                                       
                                  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
   a.  Application Rate based on proposed use on label for PalladiumTM Fungicide (EPA Reg. No. 100-1328).
   b.  Based on 2012 Residential SOPs.
   c.  Unit Exposures based on 2012 Residential SOPs.
   d.  Inhalation Dose (mg/kg/day) = daily unit exposure (mg/ - lb ai) * application rate (lb ai/gallon) * amount handled (gallons) /  - body weight (80 kg);  
   e.  Inhalation MOE = PoD (NOAEL of 62 mg/kg/day) / Daily inhalation dose (mg/kg/day). Level of concern = 1000. 

6.1	Residential Bystander Postapplication Inhalation Exposure

Volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications.  The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219).  
During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is required for cyprodinil.

6.2	Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications.  This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for cyprodinil.  The agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call-In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the agency's Spray Drift website for more information).  The agency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk assessments for pesticides.  The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently.  The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs) - Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift.  This document outlines the quantification of indirect non-occupational exposure to drift.  
 
7.0 	AGGREGATE EXPOSURE AND RISK ASSESSMENT 

In accordance with the FQPA, when there are potential residential exposures to a pesticide, aggregate risk assessment must consider exposures from three major routes: oral, dermal, and inhalation.  There are three sources for these types of exposures: food, drinking water, and residential uses.  In an aggregate assessment, exposures from relevant sources are risks themselves and can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.  Since there are no residential incidental oral (i.e., hand to mouth) exposures to cyprodinil based on existing registered products and use patterns, aggregate exposure from food and incidental oral exposures is not required.  Short-term residential handler exposures are expected based on current use patterns.  Intermediate-term residential exposures are not anticipated.  An aggregate risk assessment of combined short-term inhalation and oral (dietary and drinking water) exposure is required for residential handlers because PODs selected for these exposure routes are based on common toxicological effects (i.e., liver effects).   The acute and chronic exposure estimates from the dietary exposure analyses represent aggregate risk for acute and chronic exposures and are not of concern.  

7.1	Acute & Chronic Aggregate Risk	

Acute and chronic aggregate exposures include food plus drinking water exposures.  As demonstrated under Section 5.4, acute and chronic aggregate risks are not of concern.

7.2	Short-Term Aggregate Risk	

Short term aggregate exposure takes into account residential exposure plus average exposure levels to food and water (considered to be a background exposure level).   The short term aggregate risk for residential handlers is the estimated risk associated with combined risks from average food and drinking water exposures and inhalation exposures to adult applicators.   Short term aggregate risk estimates for residential handlers are provided in Table 7.2. Aggregate margins of exposure (MOEs) are not of concern.  
	
Table 7.2.  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
                                    0.0078
                                   0.000098
                                     7900
                               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)



7.3	Intermediate-Term Aggregate Risk 

There are no residential use scenarios that will result in potential intermediate term exposure to cyprodinil.  Therefore, an intermediate-term aggregate was not performed.

8.0	CUMULATIVE RISK

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

EPA does not have, at this time, available data to determine whether cyprodinil has a common mechanism of toxicity with other substances.  Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to cyprodinil and any other substances and, cyprodinil does not appear to produce a toxic metabolite produced by other substances which have tolerances in the U. S.  For the purposes of this tolerance reassessment action, therefore, EPA has not assumed that cyprodinil has a common mechanism of toxicity with other substances.  For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's OPP concerning common mechanism determinations and 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 exposure scenarios on artichoke, guava, passionfruit, feijoa, jaboticaba, wax jambu, starfruit, acerola, tomato (small), and stone fruit, group 12-12 have been previously evaluated at the same rate (i.e., 0.33 lb ai/A) for the same registered end-use products than currently proposed (D398361, I. Nieves, 5/3/12).  No estimated risks of concern were identified at label required PPE (i.e., filtering piece respirator).  MOEs were above the Agency's LOC (MOEs >LOC=1000) and ranged from 1,500 to 990,000 for short- and intermediate-term durations.
	
Occupational exposure risk potential scenarios for uses on cucumber grown in greenhouses have also been assessed on a previous memo (D362494, I. Nieves, 8/4/09), at the same application rate (i.e., 0.33 lb ai/A) but to account for a difference in formulation (i.e., liquid instead of the dry flowable previously assessed) and recent updates to unit exposures and body weight assumptions, an updated quantification of risks for the proposed use is presented below.

The post-harvest use on pomegranates have never been assessed before therefore an occupational assessment for this use was performed and presented below.

9.2	Handler Exposure 

The term "handler" applies to individuals who mix, load, and apply the pesticide product. 
There is a potential for exposure to cyprodinil during mixing, loading, and application activities through the inhalation route.  Cyprodinil products are applied using groundboom and chemigation equipment. 

	9.2.1 	Handler Exposure Scenarios

HED uses the term handlers to describe those individuals who are involved in the pesticide application process.  HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each task.  Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.  

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses on cucumber grown in greenhouses and post-harvest use on pomegranates.  For the proposed post-harvest use on pomegranates, the quantitative exposure/risk assessment developed for occupational handlers is based on the mixing/loading water dispersable granules (WDG) or a dry flowable formulation (DF) for automated system exposure scenario and a mechanically pressured handgun.  A separate applicator assessment was not conducted as the application of cyprodinil is mechanically automated for the in-line dip/drench wash tanks.  A mixer/loader assessment was performed and is considered to result in a conservative estimate of handler risk.  

	9.2.2	Handler Exposure Data

A series of assumptions and exposure factors served as the basis for completing the occupational handler risk assessments.  Each assumption and factor is detailed below on an individual basis.

	9.2.3 	Handler Exposure Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational handler risk assessments.  Each assumption and factor is detailed below on an individual basis.

Application Rate:  The application rate is the maximum rate identified on the proposed Inspire Super[(R)] and Switch(R) 62.5WG labels (See Section 4.0) for cucumbers grown in greenhouses and post-harvest pomegranates, accordingly.
 
Unit Exposures:  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 PHED 1.1, the AHETF database, the ExpoSAC "Assessment of Occupational Exposure for Post-Harvest Commodity Pesticide Treatments" (M. Crowley, 3/23/2012), or other registrant-submitted occupational exposure studies.  Some of these data are proprietary (e.g., AHETF data), 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", which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website.  

Amount Handled:  Information on amount handled per day was taken from HED ExpoSAC Policy/Guidance "Assessment of Occupational Exposure for Post-Harvest Commodity Pesticide Treatments" (M. Crowley, 3/23/2012).  Since the label specifies the application rate as a % solution and does not provide information on the amount of commodity to be treated, a default estimate of 25,000 gallons was used.
  
Exposure Duration: HED classifies exposures from 1 to 30 days as short-term and exposures 30 days to six months as intermediate-term.  Exposure duration is determined by many things, including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the cultural practices surrounding that use site.  For most agricultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for more than a one-month time frame; however, there may be a large agribusiness and/or commercial applicators who may apply a product over a period of weeks (e.g., completing multiple applications for multiple clients within a region).  For cyprodinil, based on the proposed use pattern, short- and intermediate-term exposures are expected.

Mitigation/Personal Protective Equipment:  Estimates of dermal and inhalation exposure were calculated for various levels of PPE.  Results are presented for "baseline," defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator. 

Occupational Handler Non-Cancer Exposure and Risk Estimate Equations
The algorithms used to estimate non-cancer exposure and dose for occupational handlers can be found in Appendix A.

	9.2.4 	Handler Exposure and Risk Estimates
 			
Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates
Table 9.2.4.1 provides a summary of the estimated exposures and risks to occupational pesticide handlers for the proposed use on cucumbers grown in greenhouses.  An MOE >= 1000 was selected to protect occupational pesticide handlers from inhalation exposure (TXR# 0054812, K. Rury, 3/29/12).  Occupational handler risk estimates resulted above HED's LOC of 1,000 and therefore not of concern.  At baseline, the occupational handler inhalation MOEs range from 1,300 to 1,100,000, depending on the scenario.  

Table 9.2.4.1. Occupational Exposure Risk Estimates for Cyprodinil Use on Cucumbers Grown in Greenhouses.
                             Application Equipment
                                      Max
                                  Application
                                    Rate[1]
                                Area Treated[2]
                          Inhalation Unit Exposure[3]
                                  (ug/lb ai)
                   Short-& Intermediate-Term Inhalation
                                       
                                       
                                       
                               Mitigation Level
                                    Dose[4]
                                  (mg/kg-day)
                                    MOE[5]
                                   LOC=1,000
                                 Mixer/Loader
                                 Chemigation/
                                  Groundboom
                                     0.33
                                  lb ai/acre
                                      60
                                     acres
                                     0.219
                                   0.000054
                                   1,100,000
                                  Applicator
                                  Groundboom
                                     0.33
                                  lb ai/acre
                                      60
                                     acres
                                     0.34
                                   0.000084
                                    740,000
                            Mixer/Loader/Applicator
                                   Backpack
                                     0.033
                                 lb ai/gallon
                                      40
                                    gallons
                                      140
                                    0.0023
                                    27,000
                             Manually-pressurized
                                   Handwand
                                       
                                       
                                      30
                                   0.000495
                                    130,000
                           Mechanically-pressurized
                                    Handgun
                                       
                                     1000
                                    gallons
                                      120
                                    0.0495
                                     1,300
  1	Based on registered or proposed label (Reg. No.100-1317).
  2	Exposure Science Advisory Council Policy #9.1.
  3	Based on the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (May 2013);  Level of mitigation: Baseline = Long-sleeved shirt, long pants, shoes plus socks and no respirator.  PF10 R = filtering facepiece respirator
  4	Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/gal) x Amount Handled (gal/day) / BW (80 kg).
  5	ST& IT Inhalation MOE = Inhalation NOAEL (62 mg/kg/day) / Inhalation Dose (mg/kg/day).


Table 9.2.4.2 provides a summary of the estimated exposures and risks to occupational pesticide handlers for the proposed use on post-harvest pomegranates.  An MOE >= 1000 is considered protective to occupational pesticide handlers from inhalation exposure (TXR# 0054812, K. Rury, 3/29/12).  Inhalation exposure risk estimates scenarios for this proposed use resulted above HED's LOC of 1,000 at baseline.  MOEs resulted in 4,900 and 11,000.










Table 9.2.4.2.  Occupational Handler Non-Cancer Exposure and Risk Estimates for Post-harvest Use on Pomegranates.
                                   Exposure 
                                   Scenario
                           Inhalation Unit Exposure
                                (μg/lb ai)[1]
                                Max. App. Rate
                            (lb ai/gal solution)[2]
                             Amount Handled Daily 
                                 (gal/day)[3]
                                 Short- &
                               Intermediate-Term
                                  Inhalation
                                       
                               Mitigation Level:
                                   Baseline
                                       
                                       
                              Dose (mg/kg/day)[4]
                                    MOE[5]
                                   LOC=1000
                                 Mixer/Loader
                           WDG for Automated System
                                     8.96
                                    0.0045
                                    25,000
                                     0.013
                                     4,900
                            Mixer/Loader/Applicator
                      WDG for Mechanical Pressure Handgun
                                      3.9
                                    0.0045
                                    25,000
                                    0.0055
                                    11,000
1	Based on the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (May 2013);  Level of mitigation: Baseline = Long-sleeved shirt, long pants, shoes plus socks and no respirator.  PF10 R = Long-sleeved shirt, long pants, shoes plus socks and a filtering facepiece respirator
2	Based on registered or proposed label (Reg. No.100-953).
3	HED ExpoSAC Policy/Guidance "Assessment of Occupational Exposure for Post-Harvest Commodity Pesticide Treatments."
4	Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/gal) x Amount Handled (gal/day) / BW (80 kg).
5	ST & IT Inhalation MOE = Inhalation NOAEL (62 mg/kg/day) / Inhalation Dose (mg/kg/day).

9.3	Post Application Exposure 
      
HED uses the term post-application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re-entry exposure).  Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting; or in the case of post-harvest applications, sorting and packing fruit after it has been treated.  Post-application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical's degradation properties.  In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post-application exposure.
 
	9.3.1	Post Application Exposure Scenarios

For the proposed use on cucumbers grown in greenhouses, although a quantitative occupational post-application 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 post-application exposure.  Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post-application inhalation exposure scenarios.

The Worker Protection Standard for Agricultural Pesticides contains requirements for protecting workers from inhalation exposures during and after greenhouse applications through the use of ventilation requirements.[40 CFR 170.110, (3) (Restrictions associated with pesticide applications)]

During automated treatments, for the proposed use on post-harvest pomegranates, inhalation exposure is anticipated for workers performing sorting and packing tasks.  Since the workers experience exposure following the treatment, this is technically "post-application" exposure; however, unlike other post-application activities (e.g., harvesting, scouting, etc.), this treatment is not governed by the Worker Protection Standard (WPS) and potential re-entry intervals (REIs).  Additionally, for workers in the warehouse or packaging facility not directly involved in the automated treatment process, there is potential for indirect inhalation exposure.  Exposures for these various scenarios are assessed using HED ExpoSAC Policy/Guidance "Assessment of Occupational Exposure for Post-Harvest Commodity Pesticide Treatments" (M. Crowley, 23-MAR-2012).
 
	9.3.2	Post Application Exposure Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational post-application risk assessments.  Each assumption and factor is detailed below on an individual basis.

Exposure Duration:  HED classifies exposures from 1 to 30 days as short-term and exposures 30 days to six months as intermediate-term.  For cyprodinil, based on the proposed use pattern, short- and intermediate-term exposures are expected.  

Application Rate: The application rate is the maximum rate identified on the proposed Switch(R) 62.5WG label (See Section 4.0).

Exposure Time:  The average occupational workday is assumed to be 8 hours. 

	9.3.3 	Post-Application Exposure and Risk Estimates
 
Occupational Post-application Non-Cancer Risk Estimates:
Table 9.3.3.1 summarizes exposure and risk estimates from post-application inhalation exposure for sorter and packers.  Table 9.3.3.2 provides a summary for post-application indirect inhalation exposure risk estimates. No risk estimates of concern (MOEs > LOC of 1,000) were identified at baseline for short-and intermediate-term durations for all scenarios.  MOEs resulted in 15,000 for direct inhalation exposure, and 320,000 for indirect inhalation exposure.

Table 9.3.3.1.  Occupational Post-application Inhalation Exposure and Risk Estimates for Cyprodinil on Pomegranates.
                                   Activity
                                   Max App. 
                                    Rate[1]
                              (% ai in solution)
                                     Unit 
                                 Exposure[2] 
                                   (ug/% ai)
                                  Short-&
                               Intermediate-term
                                  Inhalation 
                                       
                                       
                               Mitigation Level
                                     Dose 
                                (mg/kg-day)[3]
                                    MOE[4]
                                   LOC=1,000
                                    Sorter
                                     0.05
                                     6720
                                    0.0042
                                    15,000
                                    Packer
                                       
                                     6760
                                    0.0042
                                    15,000
1. Percent cyprodinil in solution: (19.2 oz/100 gal) x (1 lb/16oz) x (37.5% cyprodinil formulation) x (H2O density: 8.329 lb/gal) x 100 = 0.05%
2.  Based on Table 2 in ExpoSAC Policy/Guidance "Assessment of Occupational Exposure for Post-Harvest Commodity Pesticide Treatments" (M. Crowley, 3/23/2012); Level of mitigation: T-shirt and NR = no respirator; PF10 Respirator = filtering facepiece respirator.
3.  Inhalation Dose = [Unit Exposure (ug/% ai) * Application Rate (% ai in solution) * Adjustment Factor (0.001 μg/mg)]/ Body Weight (80 kg).
4.  Inhalation MOE = Inhalation POD (62 mg/kg/day)/Inhalation Dose.

Table 9.3.3.2.  Occupational Post-application Indirect Inhalation Exposure and Risk Estimates for Cyprodinil.
                                   Crop/Site
                                 Max App. Rate
                              (% ai in solution)
                                 Short-& 
                         Intermediate-Term Inhalation
                                       
                                       
                                Unit Exposure 
                                 (μg/% ai)[1]
                                     Dose
                                (mg/kg/day)[2]
                                    MOE[3]
                                       
                                       
                               Mitigation Level
                                       
                                       
                                 Pomegranates
                                     0.05
                                      307
                                    0.0002
                                    320,000
1.  Based on Table 2 in ExpoSAC Policy/Guidance "Assessment of Occupational Exposure for Post-Harvest Commodity Pesticide Treatments" (M. Crowley, 3/23/2012); Level of mitigation: T-shirt and NR = no respirator.
2.  Inhalation Dose = [Unit Exposure (ug/% ai) * Application Rate (% ai in solution) * Adjustment Factor (0.001 μg/mg)]/ Body Weight (80 kg).
3.  Inhalation MOE = Inhalation POD (62 mg/kg/day)/Inhalation Dose.

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 and a dermal assessment was not quantified.

	9.3.4 	Restricted Entry Interval

Cyprodinil is classified as Toxicity Category III for acute dermal and eye irritation, and Toxicity Category IV for skin irritation potential.  Under 40 CFR 156.208 (c) (2) (iii), active ingredients classified as Acute III or IV for acute dermal, eye irritation and primary skin irritation are assigned a 12-hour REI.  Therefore, the REI of 12 hours required in the registered labels is adequate to protect agricultural workers from post-application exposures to cyprodinil.   

10.	REFERENCES

Cyprodinil.  Expansions of Existing Crop Group/Representative Commodity Uses to Stone Fruit Group 12-12, and Adding New Uses on the Artichoke, Guava, Pomegranate, Passionfruit, Feijoa, Jaboticaba, Wax Jambu, Starfruit, and Acerola.  Summary of Analytical Chemistry and Residue Data., T. Morton, D421157, 04/23/2015

Cyprodinil  -  Acute and Chronic Dietary and Drinking Water Exposure and Risk Assessment.  T. Morton, D425997, 07/01/2015

Cyprodinil.  Occupational and Residential Exposure Assessment for a Proposed Uses on Cucumber (greenhouse), Artichoke, Guava, Passion fruit, Feijoa, Jaboticaba, Wax Jambu, Starfruit, Acerola, Pomegranate (post-harvest), Tomato (small), and Stone Fruit, Group 12-12.  I. Nieves, D425999, 05/05/2015

Estimated Drinking Water Concentrations for Cyprodinil and its Metabolite CGA-249287 for the New Uses of the Chemical on Certain Stone Fruits (Crop Group 12-12), Certain Tropical Fruits, Artichoke, Cucumber (Greenhouse Use), and Pomegranate (Postharvest Dip) J. Melendez, D421158, 1/12/15

























APPENDICES

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
                                   43709027 
                                   43709026
                                   43709028
                                   43709029
                                   47526801
870.3700a
870.3700b
870.3800
                  Prenatal Developmental Toxicity - Rodent	
                  Prenatal Developmental Toxicity - Non-Rodent	
                  Reproduction and Fertility Effects	
                                       Y
                                       Y
                                       Y
                                       Y
                                       Y
                                       Y
                                   43709033
                                   43709032
                                   43709034
870.4100a
870.4100b
870.4200a
870.4200b
870.4300
                  Chronic (Oral) Toxicity - Rodent	
                  Chronic (Oral) Toxicity - Non-Rodent (Dog)	
                  Carcinogenicity - Rat..................		
                  Carcinogenicity - Mouse	
                  Combined Chronic Toxicity /Carcinogenicity
                                       Y
                                       Y
                                       Y
                                       Y
                                       Y
                                       Y
                                       Y
                                       Y
                                       Y
                                       Y
                                   43737602
                                   43709030
                                   43737602
                                   42710006
                                   43737602
870.6100a
870.6100b
870.6200a
870.6200b
870.6300
870.7800
                  Neurotoxicity - Acute Delayed Neurotox.- Hen	
                  Neurotoxicity  - Subchronic - Hen	
                  Neurotoxicity - Acute - Rat	
                  Neurotoxicity -Subchronic - Rat	
                  Developmental Neurotoxicity..................
                  Immunotoxicity.............................	
                                       N
                                       N
                                       Y
                                       Y
                                       N
                                       Y
                                       N
                                       N
                                       Y
                                       Y
                                       N
                                       Y
                                      ---
                                      ---
48304202
45906101
                                      ---
                                   48304203
                                   48293501
1 Based on WOE by HASPOC (TXR 0054812)


A.2	Toxicity Profiles 

Table 1  Acute Toxicity of Cyprodinil.
                                 Guideline No.
                                  Study Type
                                    MRIDs #
                                    Results
                               Toxicity Category
                                   870.1100
Acute Oral
                                   43709014
LD50 = 2796 mg/kg
                                      III
                                   870.1200
Acute Dermal
                                   43709016
LD50 > 2000 mg/kg
                                      III
                                   870.1300
Acute Inhalation
                                   43709018
LC50 = 1.2 mg/L
                                      III
                                   870.2400
Primary Eye Irritation
                                   43709021
mild/mod irritant
                                      III
                                   870.2500
Primary Skin Irritation
                                   43709022
very slight irritant
                                      IV
                                   870.2600
Dermal Sensitization
                                   43709024
                                   44392102
positive
                                      NA

Table 2.  Toxicity Profile of Cyprodinil Technical. 

                           Guideline No./ Study Type

                    MRID No. (year)/ Classification /Doses

                                    Results

870.3100
90-Day oral toxicity (mouse)

43709027 (1991)
Acceptable/guideline
0, 500, 2000, 6000 ppm
M: 0, 73.3, 257, 849 mg/kg/day
F: 0, 103, 349, 1121 mg/kg/day

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

870.3100
90-Day oral toxicity (rat)

43709026 (1991)
Acceptable/guideline
0, 50, 300, 2000, 12,000 ppm
M: 0, 3.14, 19, 134, 810 mg/kg/day
F: 0, 3.24, 19.3, 137, 803 mg/kg/day

NOAEL =3.14 mg/kg/day
LOAEL = 19 mg/kg/day based on increased tubular kidney lesions in males

Non-guideline
28-Day Feeding/ Range Finding 
(rat)

43866301 (1989)
Acceptable/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 levels, 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, 559.66 mg/kg/day
F: 0, 6.79, 52.75, 231.93, 580.95 mg/kg/day

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 sexes

870.3200
21/28-Day dermal-toxicity
(rat)

 47526801 (008)
Acceptable/
Guideline
0, 5, 25, 125, 1000 mg/kg/day

NOAEL = 1000 mg/kg/day 
LOAEL = Not established

870.3700a
Prenatal developmental
(rat) 

43709033 (1991)
Acceptable/Guideline
0, 20, 200, 1000 mg/kg/day

Maternal NOAEL = 200 mg/kg/day
LOAEL = 1000 mg/kg/day based on lower 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 efficiency

870.4200
Carcinogenicity - (mouse)

43709031, 44417902
Acceptable/Guideline
0, 10, 150, 2000, 5000 ppm
M: 0, 1.15, 16.1, 212.4, 630 mg/kg/day
F: 0, 1.08, 14.7, 196.3, 558.1 mg/kg/day

NOAEL = 16.1 mg/kg/day
LOAEL = 212.4 mg/kg/day based on a dose-related increase in the incidence of focal and multifocal hyperplasia of the exocrine pancreas in males

No evidence of carcinogenicity
870.7800
Immunotoxicity  (mouse)
48304203
Acceptable/Guideline
0, 500, 2000, 5000 ppm
0, 103.8, 468.3, 1245.3 mg/kg/day
NOAEL > 1245.3 mg/kg/day
LOAEL > 1245.3 mg/kg/day 
There were no cyprodinil-related effects on absolute, adjusted, or relative spleen or thymus weights; no effects on specific activity or total activity of splenic IgM 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.
870.6200a
Acute Neurotoxicity
48304202
Acceptable/Guideline
0,200, 600, 2000 mg/kg 
/day

NOAEL = 200 mg/kg/day
LOAEL = 600 mg/kg/day
Based on clinical signs of toxicity and low motor activity and reversible hypothermia, no neuropathic changes were noted at any dose level. 
870.6200b
Subchronic Neurotoxicity
45906101
Acceptable/Guideline
0,80, 800, 8000 ppm 
M: 0, 5.8, 54.5, 601
F: 0, 6.3, 58.7, 631 mg/kg/day

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

870.5100
Gene Mutation - Bacteria

43709037 (1990)
Acceptable/Guideline


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

870.5300
Gene Mutation - 
In vitro mammalian cell

43709036 (1990)
Acceptable/Guideline

In a Chinese hamster V79 cell HGPRT forward gene mutation assay, cyprodinil was negative up to cytotoxic concentrations (96.0 ug/mL  with S9) (24 ug/mL without S9).

870.5375
Cytogenetics/
In vitro Chromosomal Aberration

43709038 (1991)
Acceptable/Guideline

In an in vitro assay for chromosome aberrations in Chinese hamster ovary (CHO) cells, cyprodinil gave negative results up to cytotoxic concentrations (50 ug/mL without S9, 18- or 42-hour cell harvest or 25 ug/mL with S9, 18- hour cell harvest) or to the highest sub-cytotoxic concentration (50 ug/mL with S9, 42-hour cell harvest).

870.5395
Cytogenetics/
In vivo bone marrow micronucleus

43709039 (1990)
Acceptable/Guideline


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

870.5550 
UDS

43709035 (1991)
Acceptable/Guideline

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

870.7485
Metabolism and pharmacokinetics

43709040 (1992)
Acceptable/Guideline

Single oral doses (0.5 or 100 mg/kg bw) of phenyl or pyrimidyl-radiolabelled CGA 219417 (purity  98%) were administered to Tif:RAIf(SPF) rats, with one low-dose group receiving unlabeled CGA 219417 (purity  99%) for 2 weeks prior to treatment with radiolabelled compound.  Absorption was very rapid (tcmax= 0.3 hours) with rapid clearance (tcmax/2=1.2 hours).  A minimum of 75% of the administered dose was absorbed.  Excretion was rapid and almost complete, with urine as the principle route of excretion (48-68%), and >90% of the administered dose detected in the urine and feces within 48 hours.  Excretion, distribution and metabolite profiles were essentially independent of dose level, pretreatment, and type of label, although there were some quantitative differences sex-dependent qualitative differences in two urinary metabolite fractions.

870.7485
Metabolism and pharmacokinetics

43709041 (1992)
Acceptable/guideline

Must be considered with MRID 43709040.

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

870.7600
Dermal Absorption (rat)

45906102 (1999)
In review
6 ug/cm[2] or 870 ug/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.

      
      
      


      A.3	Toxicological Endpoints


A.3.1	Acute Reference Dose (aRfD)  -  All Populations
      
Selected Study: Acute Neurotoxicity Rat; MRID 48304202

Dose and Endpoint for Establishing a POD:  NOAEL = 200 mg/kg from an acute neurotoxicity study based on LOAEL of 600 mg/kg showing clinical signs (hunched posture, pilorection, and reduced responsiveness to sensory stimuli, reduced motor activity and hypothermia).  

Uncertainty Factor (UF): 1000x (10x for interspecies and 10x for intraspecies variation; and 10X for lack of 90-day inhalation study)

              Acute RfD  =     200 mg/kg (NOAEL) =     0.20 mg/kg
                                                                         1000 (UF)

[Note: The acute RfD has been revised from previous risk assessments based on receipt and review of an acute neurotoxicity study and subsequent reevaluation of available data.]

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

Selected Study: Combined Chronic Toxicity/Carcinogenicity-Rat; MRIDs  43737602, 44429401 and 44417902

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

Uncertainty Factor (UF): 100x (10x for interspecies and 10x for intraspecies variation, and 10X for lack of 90-day inhalation study)

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

            Chronic RfD  =     2.7 mg/kg (NOAEL) =     0.0027 mg/kg
                                                                         1000 (UF)
      
A.3.3	Inhalation Exposure (Short to Intermediate Term)

A No Observable Adverse Effect Level (NOAEL) of 62 mg/kg/day was identified for short to intermediate-term inhalation risk assessments.  The 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.  
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 weekrecovery period. 

At 50 ppm and above there were - increased cholesterol and phospholipid levels in females (18% for both) which increased with increasing dose [cholesterol - 300 ppm (20%), and male and female 2000(37-48%) and 12000 (85-105%) ppm groups; phospholipid -300 ppm (23%) group, and male and female 2000 (36%) and 12000(71-90%) ppm groups.]

At 300 ppm and above there was - increased alkaline phosphatase in the male with females affected at 12000 ppm.  Liver abnormalities at 300 ppm included hepatocyte hypertrophy and hepatocyte necrosis observed in male rats, with females affected at 2000 and 12000 ppm. Kidney abnormalities included a low incidence (0, 0, 10, 10, 20% for males only, control to high dose) vacuolization of the epithelium of the proximal convoluted tubules, and chronic tubular lesions (0, 0, 30, 50, 80% for males and 20, 20, 0, 50, 80% for females, control to high dose), in male and/or female rats at 300 ppm. The tubular lesions were more frequent at 2000 and 12000 ppm. Enlarged (hypertrophic) pituitary cells in the adenohypophysis were observed in males in the 300 ppm group, and males and females in the 2000 and 12000 ppm groups. "Minimal" to "moderate" hypertrophy of the follicular epithelia of the thyroid was noted in males in the 300, 2000, and 12000 ppm groups. 

At 2000 ppm and above there were additional hepatic lesions consisting of "sharply demarcated membranous structures containing a vacuolated eosinophilic material" ("cytoplasmic inclusion bodies") and renal chronic tubular lesions in 50 % of the males and females. There was an increase in protein and globulin levels in the males. Relative liver weights were higher for male and female rats in the 2000 and 12000 ppm groups. Relative thyroid weights were higher for male rats in the 2000 ppm group, and male and female rats in the 12000 ppm groups.

At 12000 ppm there was - a decrease in body weight gains of female and male rats (20-26% lower than controls at the termination of the study). Hemoglobin and hematocrit values were lower, albumin levels higher and glucose levels lower in the males. Leukocyte counts and gamma glutamyl transpeptidase activity levels were higher in the male and female groups. Additional renal lesions included nephrocalcinosos (0, 0, 10, 0, 50%, control to high dose in males only). Relative kidney weights were also higher for high dose males. The relative weights of the adrenals in males were greater than the controls, with "minimal" increases in the amount of fat vesicles in the adrenal cortex noted in a majority of these animals.  

Following a 4-week post treatment recovery period (using 0 and 12000 ppm rats only), all hematological and blood chemistry differences lost significance, with the exception of cholesterol and phospholipid concentrations in females. The relative weights of the liver and thyroid glands of males in the 12000 ppm groups remained greater than those of the control group, but with the exception of chronic tubular kidney lesions, the prevalence of all microscopic abnormalities was reduced. 

Most changes at 50 were not adequate to establish an LOAEL therefore the LOAEL is 300 ppm (19 mg/kg body weight/day) for rats, based on increased chronic tubular kidney lesions in males. The NOAEL is 50 ppm (3.14 mg/kg/day).

This subchronic toxicity study is classified acceptable (guideline), and satisfies the guideline requirement for a subchronic oral study (82-1) for rodents.

	870.3100	90-Day Oral Toxicity  -  Mouse MRID 43709027

A 3-month study (MRID 43709027) was carried out in Tif:MAGf(SPF) albino mice where animals (10 mice/sex/dose) were fed diets containing 0, 500,2000 or 6000 ppm (actual concentrations: males - 0, 73.3, 257 or 849 mg/kg/day; females - 0, 103, 349 or 1121 mg/kg/day) of CGA 219417 technical (99.5% a.i., Batch No- P 912004).  There was no effect on mortality, or hematology parameters, and no clinical sighs of toxicity. Treatment-related effects included increased absolute and relative liver weights (112-118 %) in 6000 ppm males, and hepatic changes in mid- and high dose males and females that consisted of multifocal hepatocyte necrosis in 2000 and 6000 ppm males (30 % as compared to 0 in the control and low dose groups) and glycogen depletion in 2000 and 6000 ppm females (10, 10, 70 and 100% from controls to high dose). The LOAEL is 2000 ppm based on histopathological changes in the liver. The NOAEL is 500 ppm (malts - 73.3; females - 103 mg/kg/day).  This study is acceptable (guideline) even though it is listed as a range-finding study. It satisfies the guideline requirement for a subchronic study in the rodent (82-1(a)).

	870.3100	90-Day Oral Toxicity  -  Dog MRID 43709028

A 3-month study was carried out in Beagle dogs where animals (4/sex/dose) were fed diets containing 0, 200, 1500, 7000 or 20000 ppm (actual concentrations: males - 0, 6.07, 45.87, 210.33 or 559.66 mg/kg/day; females - 0, 6.79, 52.75, 231.93 or 580.95 mg/kg/day) CGA 219417. There was no effect on mortality, or clinical chemistry parameters. Vomiting was observed in all high-dose females during the first week of treatment, and an increase in mean platelet count was noted in high-dose females at weeks 7 and 13. Lower bodyweight gains (64-76%) and decreased food consumption were apparent in high-dose males and females throughout the study period. There was a transient decrease in bodyweight gain and food consumption in 7000 ppm females, which was noted after the first week of treatment only, and this was considered non-adverse. The LOAEL is 20,000 ppm (males -560, females -581 mg/kg/day) based on lower bodyweight gains and decreased food consumption in both sexes. The NOAEL is 7000 ppm (males -210, females - 232 mg/kg/day).

      870.3200  28 Day Dermal Toxicity  -  Rat MRID 47526801

In a 28-day dermal toxicity study (MRID 47526801), Cyprodinil (99%, P012011) was applied to the shaved skin of 50 HanRCC Wistar Rats/sex/dose at dose levels of 0 (vehicle control), 5, 25, 125 and 1000 mg/kg bw/day, 6 hours/day for 5 days/week during a 28-day period, for a total treatment of 20 days.

The following parameters were measured: general clinical observations, detailed behavioral observations. Body weight and food consumption, functional observational battery including grip strength and locomotor activity. Ophthalmoscopic examination, hematology and clinical chemistry. Organ weights, macroscopic and histopathological examination of selected organs.
No treatment related effects were seen at any concentration when measuring body weight gain, food consumption, hematological parameters, clinical chemical parameters, organ weights, gross or histopathology. 

Skin lesions characterized by fissures, scabs, erythema, hair loss, sores, were common in all experimental groups and the control group, probably resulting from shaving the skin to apply the test article or vehicle.  

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

This 28-day dermal toxicity study in the HanRCC Wistar rats is acceptable guideline and satisfies the guideline requirement for a 28-day dermal toxicity study (OPPTS 870.3200; OECD 410) in rats. 

A.4.2	Prenatal Developmental Toxicity - Rat

	870.3700a Prenatal Developmental Toxicity Study  -  Rat MRID 43709033

In a developmental toxicity study (MRID No. 43709033), CGA 219417 technical (99.5% a.i., Batch No. P912004) was administered in 3% aqueous corn starch suspension by oral gavage to 20-23 Tif:RAIf(SPF) females albino rats per dose of 0, 20, 200 or 1000 mg/kg/day or gestation days 6-15.  Treatment related findings included reduced locomotor activity (one high dose female), significantly lower mean body weight (16%), body weight gain (65%), gravid uterine weight (18%), and mean carcass weight (10%), and significantly decreased food consumption (32-42%) in high-dose females. The LOAEL for maternal toxicity is 1000 mg/kg/day based on lower body weight/body weight gain and reduced food consumption. The NOAEL was 200 mg/kg/day.  There were significantly lower mean fetal weights (11%) in the high-dose group compared to controls as well as a significant increase in skeletal anomalies in the high-dose group relative to the control, which was due to abnormal ossification (4/20 litters in the high dose group compared to 0 in any other group), primarily as absent or reduced metacarpal 5 ossification. The skeletal anomalies/variations were considered to represent a transient developmental delay that occurs secondary to the maternal toxicity noted in the high-dose group. The LOAEL for developmental toxicity is 1000 mg/kg/day based on lower mean fetal weights and an increased incidence of delayed ossification. The NOAEL for developmental toxicity is 200 mg/kg/day. This study is classified acceptable (guideline) and satisfies the guideline requirement for a developmental study in the rat [(OPPTS 870.3700 (83-3a)].

	870.3700b Prenatal Developmental Toxicity Study  -  Rabbit  MRID 43709032

In a developmental toxicity (MRID No. 43709032), CGA 219417 technical (99 5%a.i., Lot# P9t2004) was administered in 3% aqueous corn starch suspension to 19 inseminated female rabbits (Russian Chbb:HM, SPF)/dose by gavage at dose levels of 0,5; 30; 150, or 400 mg/kg/day from days 7 through 19 of gestation. Mean maternal body weight gain (p <0.01) and food consumption (not significant) decreased, mainly during the first week of treatment in the 400 mg/kg/day group. Mean body weight gain was 622% less than controls (p <0.01) in this group between days 7 and 13 of gestation. The maternal LOAEL is 400 mg/kg/day, based on decreased body weight gain. The maternal NOAEL is 150 mg/kg/day. Fetuses at the 400 mg/kg/day dose exhibited indications of an increased incidence of a 13th rib (not significant). Although there were indications of developmental delays in fetal skeletons, such as poor or absent ossification of the sternebrae and metacarpals at all dose levels, only the extra rib is likely to be compound related. Uni- or bilateral hyperflexion of the carpal joint at the 400 and 150 mg/kg/day doses (not significant) was not associated with the skeletal changes. The fetal developmental LOAEL is 400 mg/kg/day based on a slight increase of litters showing extra (13th) ribs. The fetal developmental NOAEL is 150 mg/kg/day.  The developmental toxicity study in the rabbit is classified acceptable (guideline) and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; §83-3 (b)) in rabbit.

A.4.3	Reproductive Toxicity

	870.3800 Reproduction and Fertility Effects  -  Rat MRID 43709034

In a two-generation reproduction study (MRID No. 43709034), Tif:RAIf rats (30 rats/sex/dose), with one litter per generation received CGA219417 (99.5 % a.i., Batch No. P912004) in the diet at doses of 0, 10, 100, 1000 or 4000 ppm (actual intake, males: 0, 0.7, 6.7, 68 or 273; females: 0, 0.8, 8.2, 81 or 326 mg/kg/day) for a 10 week pre-mating period.  Signs of toxicity at 4000 ppm consisted of lower body weights (12.5%) in the F0 females after the pre-mating period. Increased liver weight in 1000 (marginal) and 4000 ppm males and females was not supported by histopathological findings. Although these were considered treatment related, they were considered to be non-adverse. The LOAEL for maternal systemic toxicity is 4000 ppm (about 326 mg/kg/day) based on lower body weights in the F0 females during the pre-mating period. The NOAEL for maternal systemic toxicity was 1000 ppm (about 81 mg/kg/day). HIARC determined that premating body weight gain (not absolute body weight) should be used as the basis of the NOAEL.  Signs of reproductive toxicity included significantly lower F1 and F2 pup weights in the high-dose group during lactation, which continued to be lower than controls post-weaning and after the pre-mating period (examination in F1 generation only). The LOAEL for reproductive/developmental toxicity is 4000 ppm (about 326 mg/kg/day) based on decreased pup weights (F1 and F2). The NOAEL for reproductive toxicity is 1000 ppm (about 81 mg/kg/day).
The two-generation reproduction study in the rat is classified acceptable (guideline) and satisfies the guideline requirement for a two-generation reproduction study (OPPTS 870.3800; §83-4) in rat.

A.4.4	Chronic Toxicity

        870.4100a (870.4300) Combined Chronic Toxicity/Carcinogenicity  -  Rat MRIDs 43737602, 44429401, 44417902

In a 24-month chronic toxicity/oncogenicity study (MRID No: 43737602, 44429401,44417902), Tif:RAIf rats (50 rats/sex/dose - carcinogenicity portion, plus 20/sex/dose laboratory investigations) were fed diets containing 0, 5, 75, 1000 or 2000 ppm (actual concentrations: males 0, 0.177, 2.7, 35.6 or 73.6 mg/kg/day; females  0, 0.204, 3.22, 41.2 or 87.1 mg/kg/day) CGA 219417(99.2-99.6% a.i. Batch No. P 912006). An additional 10/sex/dose were fed test diets for 12 months (interim sacrifice). Survival was slightly lower in males at 2000 ppm relative to control and other dose groups (54, 50, 50, 49, and 44%, from controls to high dose). Toxicologically significant findings included increased liver weights in high-dose males (10.7%) and a dose-related increase in the incidence of spongiosis hepatis in the liver of 1000 and 2000 ppm males (5, 5, 3, 17 and 23 %, controls to high dose). For chronic toxicity, the NOAEL was 75 ppm (2.7 mg/kg/day) and the LOAEL was 1000 ppm (35.6 mg/kg/day) based on degenerative liver lesions (spongiosis hepatis) in males. This chronic carcinogenicity study in the rat is acceptable (guideline).

      870.4100b Chronic Toxicity - Dog  MRID 43709030
      
A 1-year study (MRID 43709030) was carried out in Beagle dogs where animals (4/sex/dose) were fed diets containing 0,25,250,2500 or 15,000 ppm (actual concentrations: males -0, 0.72, 6.87, 65.63 or 449.25; females -0, 0.76, 6.80, 67.99 or 446.37 mg/kg/day) CGA 219417 (99.6% a.i., Batch No. P 912006).
      
There was no effect on mortality, hematological, or clinical chemistry parameters, and no clinical signs of systemic toxicity. Throughout the first half of the study, lower bodyweight gains (31-38% less) (attributable primarily to 2/4 of each sex) and decreased food consumption were apparent in high-dose males and females; with reduced food efficiency in high dose males and females in the latter part of the study. The LOEL is 15,000 ppm (males - 449.25, females 446.37 mg/kg/day) based on lower bodyweight gains and decreased food consumption and food efficiency. The NOAEL is 2500 ppm (males - 65.63, females - 67.99 mg/kg/day).  This study is classified as acceptable (guideline) and satisfied the guideline requirement for a chronic oral dog study (870.4100b).

A.4.5	Carcinogenicity

870.4200a Carcinogenicity/Chronic Study  -  Mice MRID 43709031

An 18-month oncogenicity study was carried out in Tif:MAGf(SPF) albino mice where animals (50 mice/sex/dose - carcinogenicity portion, plus 10/sex/dose - hematology) were fed diets containing 0, 10, 150, 2000 or 5000 ppm (actual concentrations: males - 0, 1.15, 16.1, 212.4 or 630; females - 0, 1.08, 14.7, 196.3 or 558.1 mg/kg/day) of CGA 219417 (99.0-99.5% a.i., Batch No. P912006). There was no effect on mortality, or hematology parameters, and no clinical signs of toxicity. Treatment-related effects included lower bodyweight and bodyweight gain (males - 10%, females - 27%) at 5000 ppm, reduced food efficiency and increased relative liver weights (16%) in high-dose males and females, and a dose-related, increase in minimal to marked pancreatic acinar cell hyperplasia in 2000 and 5000 ppm males (8, 8, 10, 16, 28% incidence, from control to high dose). The LOAEL is 2000 ppm (males - 212.4 mg/kg/day) based on a dose-related increase in the incidence of focal, and multifocal hyperplasia of the exocrine pancreas in. males. The NOAEL was 150 ppm (males - 16.1 mg/kg/day). This study was tested to adequate levels based on signs of toxicity in males at 2000 ppm and female at 5000 ppm. This chronic carcinogenicity study in the mouse is acceptable/guideline.

A.4.6	Mutagenicity

	Gene Mutation
Guideline # 870.5100 Bacterial assay
MRID 43709037 
Acceptable/Guideline
Guideline #870.5300, In vitro mammalian cell gene mutation test
MRID 43709036
Acceptable Guideline

Not mutagenic


Not mutagenic in the presence or absence of S9-activation up to cytotoxic concentrations (96.0 ug/mL with S9) (24 ug/mL without S9).


	Cytogenetics
Guideline # 870.5375, 
Cytogenetics/In vitro Chromosomal Aberration 
MRID 43709038
Acceptable Guideline

Guideline #870.5395 
Cytogenetics/In vivo bone marrow micronucleus MRID 43709039
Acceptable Guideline
cyprodinil gave negative results up to cytotoxic concentrations 



negative



A.4.7	Neurotoxicity

	870.6100 Delayed Neurotoxicity Study  -  Hen - NA

	870.6200a  Acute Neurotoxicity Screening Battery MRID 48304202

In an acute neurotoxicity study in mice (MRID 48304202) CGA 219417 technical (batch #: P.012011 a light beige powder with a purity of 99.2%) was administered to rats to assess the potential acute neurotoxicity and to estimate the NOAEL of exposure of the test compound, a fungicide, when administered by gavage.  The test article was administered by gavage as single oral dose of 0, 200, 600, and 2000 mg/kg to a total of 80 Sprague-Dawley-derived rats (10 males, and 10 females, per dose group).  Mortality, clinical signs, body weight, and food consumption were monitored throughout the study. A 'Functional Observational Battery'
(FOB) was performed pretest, at the time of peak effect (2 hours post-dose, and on test days 8 and 15. At necropsy, animals were sacrificed by in situ perfusion. The brain, spinal cord, peripheral nerves and eyes were collected, prepared for histological evaluation and 5 animals per sex each of the control and top-dose group (experimental group I) examined microscopically.  Two animals of group 3 died spontaneously. The male, found dead on test day 2, was most likely miss-intubated. For the female, which was found dead on test day 18, the cause of death could not be identified. Body weight gain and food consumption were not affected by treatment. Observations and functional tests conducted as part of the FOB showed relevant changes at the time of peak effect only. In females of group 3 and 4 reduced activity, hunched posture, piloerection, and increased responsiveness to sensory stimuli were observed with hunched posture seen also in few group 2 females. In females of group 3 and 4, signs lasted up to test day 4 and were considered to indicate toxicity. A dose related decrease in body temperature was observed, being minimal in animals of group 2.  Changes in motor activity parameters were limited to the time of peak effect. In group 4 males and in females of group 3 and 4 horizontal and vertical activity parameters were reduced.  Macroscopic and microscopic examination of the multiple areas of the central and peripheral nervous system, the eyes, optic nerves, and skeletal muscle of the male and female, control and high-dose animals of experimental group I didn't reveal any treatment-related neuropathic changes.  Based on these data it was concluded that CGA 219417 tech., when administered to rats at a single oral dose of 200, 600 or 2000 mg/kg, induced a dose-related hypothermia. Due to its full reversibility in all dose groups, the slightly reduced body temperature in low-dose animals was not considered as adverse.  A dose of 200 mg/kg thus represented the NOAEL for this study. The LOAEL was deemed to be 600 mg/kg and greater induced signs of toxicity at the time of peak effect which disappeared within a few days as well.  In the absence of any permanent or delayed functional changes and of neuropathic changes in the central and peripheral nervous system, CGA 219417 tech was considered not to be neurotoxic up to the near lethal dose of 2000 mg/kg.

	870.6200b Subchronic Neurotoxicity Screening Battery MRID 45906101

In a subchronic neurotoxicity study (MRID 45906101) CGA 219417 technical (99.2% a.i., batch #: P. 012011) was administered to 10 Tif: RAIf Sprague-Dawley derived albino rats/sex/group at dose levels of 0, 80, 800, or 8000 ppm (equivalent to 0, 5.8, 54.5, and 601 mg/kg bw/day in males and 0, 6.3, 58.7, and 631 mg/kg bw/day in females) for 90 consecutive days.  Neurobehavioral assessment (functional observational battery and motor activity testing) was performed in 10 animals/sex/group pre-exposure and at weeks 4, 8, and 13. At study termination, 10 animals/sex/group were euthanized and perfused in situ for neuropathological examination.  Of the perfused animals, 5/sex/group of the control and high-dose groups were subjected to histopathological evaluation of brain and peripheral nervous system tissues.  In addition, the liver, kidneys, thyroid gland, and pituitary were collected from all animals and examined microscopically. 


There were no treatment related effects on mortality, clinical signs, or gross or histological neuropathology.  FOB and motor activity testing revealed no treatment related effects up to the highest dose tested (8000 ppm).  In high-dose animals, absolute body weight was significantly or slightly less than the controls throughout the study due to reduced weight gain by the treated animals.  Cumulative weight gain by the high-dose groups was significantly less than that of the control groups during weeks 1-6 and 8 for males and weeks 1, 4, and 11-13 for females.  The most pronounced effect on weight gain was during the first week of the study when high-dose males and females gained 59% and 38%, respectively, of the control levels.  Overall weight gain by the high-dose males and females was 87% and 79%, respectively, of the controls.  Food consumption by the high-dose animals was reduced only at week 1 to 89% and 77% of controls for males and females, respectively.  In the high-dose group, absolute and relative liver weights were increased in both sexes (126-138% and 121-125% of controls for males and females, respectively).  Absolute and relative kidney weights were elevated in high-dose females (112-118% of controls).

Microscopic examination revealed an increase in the incidence, but not in severity, at the high dose of lesions in the liver, kidney, and thyroid.  Hepatocellular hypertrophy in the liver was observed in 5/10 high-dose males compared with 1/10 controls and in 5/10 high-dose females compared with 0/10 controls; this is an adaptive response.  Tubular lesions or tubular casts were seen in the kidneys of 4/10 high-dose males and 5-7/10 high-dose females vs 0-2/10 animals in the control groups.  Hypertrophy of the follicular epithelial cells in the thyroid gland occurred in 5/10 high-dose males and 4/10 high-dose females compared with only 1/10 control males.

Based on the results of this 90-day subchronic oral neurotoxicity study, the neurotoxicity LOAEL for CGA 219417 technical in male and female rats was not identified, while the NOAEL is 8000 ppm (601 mg/kg bw/d in males; 631 mg/kg bw/d in females).

The systemic toxicity LOAEL for CGA 219417 technical in male and female rats is 8000 ppm (601 mg/kg bw/d in males and 631 mg/kg bw/d in females) based on decreased body weight gain, tubular casts in the kidneys, and thyroid follicular cell hypertrophy.  The NOAEL is 800 ppm (54.5 mg/kg bw/d in males and 58.7 mg/kg bw/d in females).

The study is classified as Acceptable/Guideline and satisfies the guideline requirement for a subchronic neurotoxicity study in rats (870.6200b).  










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 unlabeled CGA 219417 (purity  99%) for 2 weeks prior to treatment with radiolabelled compound.  Absorption was very rapid (tcmax= 0.3 hours) with rapid clearance (tcmax/2=1.2 hours).  A minimum of 75% of the administered dose was absorbed.  A biphasic first order kinetics was observed for radioactivity depletion, with a duration of 0.3-1.2 hours for the first phase, and 27-65 hours for the second phase.  Excretion was rapid and almost complete, with urine as the principle route of excretion (48-68%), and >90% of the administered dose detected in the urine and feces within 48 hours.  Tissue residues declined rapidly, with the highest concentrations ( 1.8 ppm) found in kidneys, liver, lungs, spleen, thyroid, whole blood, and carcass.  The urine, fecal, and bile metabolite patterns were complex, with 8, 8 and 9 defined metabolite fractions, respectively.  Unchanged parent compound was detected in feces extract only.  Excretion, distribution and metabolite profiles were essentially independent of dose level, pretreatment, and type of label, although there were some quantitative differences sex-dependent qualitative differences in two urinary metabolite fractions.

This study is classified as acceptable (guideline) and when taken together with study (MRID 43709041) satisfies the guideline requirement for a metabolism study in rats (85-1).

Study 2

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

This study is classified as acceptable (guideline) and when taken together with study (MRID 43709040) satisfies the guideline requirement for a metabolism study in rats (85-1).

A.4.9	Immunotoxicity

	870.7800	Immunotoxicity  -  Mice  MRID 48304203

In an immunotoxicity study (MRID 48304203), the test substance cyprodinil was offered ad libitum in the diet of Crl:DC1 (ICR) female mice, for 28 consecutive days to three groups (Groups 2-4) at dietary concentrations of 500, 2000, and 5000 ppm, respectively.  Mice in Group 5 were administered the positive control substance, cyclophosphamide (CPS), via IP (50 mg/kg/day) for four consecutive days (study days 24-27).  The vehicle and positive control groups (Groups 1 and 5, respectively) were offered a basal diet on a comparable regimen as the cyprodinil-treated groups.  In addition, all mice were immunized with sheep red blood cells (sRBC) on study day 24.  All animals were euthanized on day 28.  Mortality and morbidity were observed twice daily in all animals, while clinical exams were performed once a day.  More detailed physical exams were performed once a week and the day of necropsy.  Single animal body weights were recorded two times a week and food consumption was recorded weekly.  Complete necropsies were conducted on all animals.  Organs (liver, spleen, and thymus) were collected and weighed at scheduled necropsy.  Spleens were analyzed by ImmunoTox(R),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-treated group were consistent with previous studies assessing cyprodinil at similar exposure levels.  Noted for the positive control (CPS) were lower mean absolute and adjusted spleen and thymus weights when compared to vehicle control group.  All effects seen with the CPS were consistent with the known immunosuppressant effects and also validated the appropriateness of the AFC assay.  No mention of a NK cell activity assay was performed.  It is unclear why this test was not performed and no justification was noted in the study write-up.

Based on the study, treatment of female Crl:CD-1(ICR) mice with cyprodinil given on a continued basis in the diet for 28 sequential days resulted in no apparent suppression of the humoral component of the immune system.  The NOEL for the suppression of the immune response in female CD-1 mice given cyprodinil was 5000ppm (1245.3mg/kg/day).  The only effect attributed to cyprodinil treatment was higher mean absolute, relative to body weight, and adjusted liver weights also for the 5000ppm group.  



APPENDIX B.  Chemical Names And Structures Of Metabolites

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


                               \s \* MERGEFORMAT
                                       
CGA-232449


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


                               \s \* MERGEFORMAT
                                       
CGA-304075


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


                               \s \* MERGEFORMAT
                                       
CGA-304076



                               \s \* MERGEFORMAT
                                       
NOA-413167



                               \s \* MERGEFORMAT
                                       
CGA-249287


4-cyclopropyl-6-methyl-2-pyrimidinamine


                               \s \* MERGEFORMAT
                                       
NOA-422054


4-cyclopropyl-6-hydroxymethyl-2-pyrimidinamine

                               \s \* MERGEFORMAT
                                       
CGA-263208


phenylguanidine



                               \s \* MERGEFORMAT
                                       









APPENDIX C. Physical/Chemical Properties


Table C.1 Physicochemical Properties of Technical Grade of Cyprodinil.
Parameter
                                     Value
Reference
Melting point/range
75.9 [0]C
                        DP# 345970, W. Cutchin, 6/4/08
pH
9.5 at 25 [0]C (1% aqueous dispersion)

Density
1.21 g/cm[3] at 20[0]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 [0]C

Dissociation constant, pKa
4.44 at 20 [0]C

Octanol/water partition coefficient, Log(KOW) at 25 C
3.9 at pH 5, 4.0 at pH 7,  4.0 at pH 9

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



APPENDIX D.  Studies Reviewed for Ethical Conduct

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

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

