### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

MEMORANDUM

Date: 1/22/13 OFF I CE OF
CH EM ICAL SA FETY AND
POLLUTION PREVENTION

SUBJECT: Triforine. Human Health Risk Assessment to Support Petition for the

Es tablishment of Permanent To le rance s without U.S. Registration for Blueberries

and Toma to es.

PC Code : I 0790 I

Decision No.: 453199

Petition No.: I E7911

Risk Assessment Type: S ingl e Chemical Aggregate

TXRNo .: NA

MRIDNo. : NA DP Barcode: 039804 I Registration No. : NA Regulatory Action: Import Tolerance

CaseNo.: NA

CAS No.: 37273-84-0

40CFR: TBD

FROM: DonnaS. Davis, Senior Chemist**~** Lind a Taylor

, Toxicolo gist

### ~**~** Matt Lloyd, CIH, ORE ssor In ' .N,

- 

### Dt1**~.M** RAB VII 

## I**~V"** 'v

· ' 

### 1-J.;S-1

.. Heal t h E ffects Division (7509P)

1 

# W**~**

THROUGH: William H. Donovan, Ph.D., t/; f n i.<fr

# em**~** Michael S. Metzger, Chief

### rJ~**.,** -k-.,.1.

. 

### :..--r::- -r

-- -
RAB VNII

Health Effects Division (7509P)

TO: Heather Garvie, Risk Manager Mary Waller, Team Le ader Cynthia Giles-Parker, Chief Fungicide-Herbicide Branch Registration Division (7505P)

Attached please find the human health risk assessment to s upport the requested tolerances

without U.S. registration for triforine on blueberry and tomato.

Page 1 of29Triforine Human Health Risk Assessment D39804 1

Tab l e of Contents

1.0 Executive Summary

. .............................................. .. ...... . ... . .. .. .. . ... . ... . .. . ............................... 4

2.0 HED Recommendations

........................ . ........................ . .. .. .. . . . . . ... . ... . .. .. .. . .............. . ............ 5

2.1

2.2

2.2.1

2.2.2

2.2.3

2.2.4

2.2.5

2.3 Data Deficiencies

.......... . ....... . .. . ...... . ... . ........................................................ . .... . ... . . . . . .. .. .. 5

Tolerance Considerations

............................... . ... . .. . ... .. .. .. . . . ... . .. .. .. .. .. .. .............................. 5

Enforcement Analytical Method

.. ......................................................................... . ...... 5 Analytical Reference Standard

............................................................ .. ... . ... . ... . ... .. .. . ... 5

Recommended Tolerances

...................... . ..... .. ... . .. . ... . ... . ... . ........... . ............................... 5

Revisions to Petitioned-For Tolerances

. . .. .. ... . ... . .. . ....................................................... 6

International Harmonization

............ . .................................... . ... . .. . ... . ... . ... . ... . ... . ... . ... .. .. . 6

Label Recommendations

. . ...... . ... . ... . .. . ... . ........................................... . ... . ....... . .................. 6

3.0 Introduction

.......................................... . ... . ... . ... . ... . ............................................................... 6

3

. 1 Chemical Identity

............................... . ... . ................................... . .... . . . .... . . . . . ... .. .. . ... .. .. .. .. .. 6

3.2 Physical/Chemical Characteristics

....... . .......... . ... . .. .. ... . ...... . ... . .. . ... .. ... . .. . .......................... 7

3

. 3 Pesticide Use Pattern

.. . .. .. .. . .. .. .......................................................................................... 7

3.4 Anticipated Exposure Pathways

........................................................................ . ... . ....... .. . 7

3.5 Consideration of Environmental Justice

. ... . ... . ... . ... . .. .. ... . .. . . . . . ... . .. .. ...... . ... .. ....... . ...... . ....... 8

4.0 Hazard Characterization and Dose

- Response Assessment

........... . ... . .. .. . .... .. .. .. ... . ... . ... .. .. .. .. 8

4.1 Summary of Toxicological Effects

. ... .. . .. .. .. .. . ... .. .. . ... . ... . .. . ... .. .. . ........... . ........................... 8

4.2 Safety Factor for Infants and Chi l dren (FQPA Safety Factor)

................................. . . . . . ... 9

4.2.1 Completeness of the Toxicology Database

.. .. .. . ... .. .. . ... . ... . ... . .. .. .. .. .. . ... .. .. .. .. .. .. .. .. .. ..... 10

4.2.2 Evidence of Neurotoxicity

........................... . .......... . ................................................... 10

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal..

.. .. .. . . .. . 10

4.2.4 Residual Uncertainty in the Exposure Database

............................ . .. . .......................... 10

4.3 Toxicity Endpoint and Point of Departure Selections

. . ... . ... . ... . ... . ...... . . ...... .. .. .. .. .. . . . . ... . .. 11

4.3.1 Dose

- Response Assessment

........ . ................................................... . .......................... 11

4.3.2 Recommendation for Combining Routes of Exposures for Risk Assessment

... . . . . .. . . 11

4.3.3 Cancer Classification and Risk Assessment Recommendation

....... . .......................... 11

4.3.4 Summary ofPoints of Departure and Toxicity Endpoints Used in Human Risk

Assessment.

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

5.0 Dietary Exposure and Risk Assessment

.......................... . ................................................. 14

5.1

5.2

5

. 3

5.4

5.4.1

5.4.2

5.4

. 3

5.4.4

5.4.5

5.4.6 Residues of Concern Summary and Rationale

..... . ......................................................... 14

Food Residue Profile

.. . ... . ................. . ..... . ... . ... . .............. . ... . ... . ... .. .. . .. .. .. . ....... .. .. .. ... . .. .. .. .. 14

Water Residue Profile

.................................................................................................... 14 Dietary Risk Assessmen t.

............................................................. . .... . . ... . . . . . . .... . ....... . ... . . 15 Description of Residue Data Used in Dietary Assessment..

................ . .............. . ....... 15

Percent Crop Treated Used in Dietary Assessment..

....................... . ....................... . .. 15

Acute Dietary Risk Assessment

. ... .. .. . ... . .. .. .. . ... . ... . ... . .. .. .. .. .. . .. .. ... . .. .. ... . .. .. .. .. .. .. ... . ... . . . 15

Chronic Dietary Risk Assessment

................................................... . .......................... 15

Cancer Dietary Risk Assessment

... . ... . .. .. .. .. .. . ... . .. .. ... . .. . ... . .. .. .. .. .. .. .. .. .. . ... .. .. .. . . . ... .. .. .. .. 16 Summary Table

.... . ...... . ......... . ..................................................................................... 16

Page 2 of29

### Triforine Human Health Risk Assessment D398041

Page 3 of 29 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ .... 16

6.1 Residential Handler Exposure

................................ ................................ ........................ 16

6.2 Residential Post

- Application Exposure

................................ ................................ .......... 17

6.3 Residential Risk Estimates for Use in Aggregate Assessment

................................ ...... 18

6.4 Residential Bystander Post

- application Inhalation Exposure

................................ ........ 18

6.5 Spray Drift

................................ ................................ ................................ ...................... 19

7.0 Aggregate Exposure/Risk Characterization

................................ ................................ ....... 19

7.1 Acute Aggregate Risk

................................ ................................ ................................ .... 19

7.2 Short

- Term Aggregate Risk

................................ ................................ ........................... 19

7.3 Intermediate

- Term Aggregate Risk

................................ ................................ ................ 20

7.4 Chronic Aggregate Risk

................................ ................................ ................................ . 20

7.5 Cancer Aggregate Risk

................................ ................................ ................................ ... 20

8.0 Cumulative Exposure/Risk Characterization

................................ ................................ ..... 20

9.0 Occupational Exposure/Risk Characterization

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

10.0 References

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

Appendix A. To xicology Assessment

................................ ................................ .......................... 22

A.1 Toxicology Data Requirements

................................ ................................ ...................... 22

A.2 Toxicity Profiles

................................ ................................ ................................ ............. 23

Appendix B. Physical/Chemical Properties

................................ ................................ ................. 28

Appendix C. Review of Human Research

................................ ................................ ................... 29

### Triforine Human Health Risk Assessment D398041

Page 4 of 29 1.0 Executive Summary

Triforine is a systemic amide fungicide with protectant, eradicant, and curative characteristics.

All U.S. food uses of triforine were voluntarily cancelled in 199 6

, and the associated tolerances

were revoked in 2004. Triforine is currently registered for use on ornamentals including roses, trees, herbaceous plants, and woody shrubs and vines.

Landis International, on behalf of Summit Agro North America Holding Corporation, has petitioned to establish tolerances without U.S. registration (import tolerances) for residues of triforine in/on blueberries at 0.02 ppm and tomatoes at 0.5 ppm. HED is recommending that the tolerance for blueberry be increased to 1.0 ppm and recommending a tolerance of 0.5 ppm for tomato. These recommended tolerances are harmonized with Codex, and an acceptable GC/ECD analytical method is available to enforce the propos ed tolerances. An analytical reference standard for triforine is available in the U.S. EPA repository.

The principal toxic effects of triforine are changes in the liver and hematopoietic system following repeated oral dosing, and t he dog i s the most sens itive species for the hematopoietic effects. Liver effects include increased liver weights, cholesterol and alkaline phosphatase levels. Toxicity was not observed in a rat 21

- day dermal toxicity study at dose levels greater

than the limit dose. Triforin e is not acutely toxic via the oral, dermal, and inhalation routes. No developmental or reproductive toxicity was observed at doses below the limit dose. Triforine

does not demonstrate neurotoxic or immunotoxic potential.

Triforine is classified as “Suggestive Evidence of Carcinogenicity”; however, there is insufficient evidence to require quantification of cancer risk. Quantification of dermal risk is not required, based on lack of toxicity in the rat dermal toxicity study at a dose level greater t han the

limit dose , and the lack of pertinent effects in other toxicity studies not measured in the dermal toxicity study. A dermal absorption factor is not required. The FQPA safety factor can be reduced to 1X based on completeness of the database, lack of susceptibility or sensitivity to pre

or post

- natal exposure to triforine, the absence of neurotoxicity, and lack of uncertainty in the exposure database.

The residue chemistry database for triforine is complete. The nature of the residue in blue berry and tomato is adequately understood. Blueberry and tomato field trials have been submi tted that are adequate in number and geographic representation, were generated by a validated analytical method, and are supported by adequate storage stability da ta. An acceptable processi ng study has been provided that shows residues of triforine do not concentrate in tomato paste or puree.

Since this petition requests tolerances without U.S. registration, establishing the requested tolerances will have no impac t on domestic drinking water. For the purpose of th is risk

assessment, modeled drinking water concentrations from the currently registered uses on ornamentals were included. Triforine does not pose an acute dietary risk. HED conducted a highly conserva tive chronic dietary (food and water) risk assessment that used tolerance level residues, assumed 100 percent crop treated, included empirical or default processing factor s , and modeled drinking water estimates. Chronic dietary (food and water) risks were not of concern as

### Triforine Human Health Risk Assessment D398041

Page 5 of 29 risks were <1% of the chronic adjusted population dose (cPAD) for the U.S. general population and all population subgroups.

There are no new residential uses associated with this petition. For the purpose of this risk assessment, residential exposure values from the currently registered uses of ornamentals were included in the aggregate assessment. There are no aggregate risks of concern for triforine.

There are no domestic uses associated with this action ; therefore , discussion of occupational exposure and risk is not pertinent.

2.0 HED Recommendations

HED has no objection to the establishment of tolerances without U.S. registrations for residues of triforine in/on blueberry and tomato.

2.1 Data Deficiencies

The toxicology, residue chemistry and occupational/residential exposure databases are complete and support the requested tolerance s for blueberry and tomato. There are no data deficiencies identified for this petition.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The Pesticide Analytical Manual, Volume II gas chromatography with electron capture detection analytical method titled “Determination of Triforine Residues” is adequate to enforce the proposed tolerances without U.S. registration on blueberries and tomatoe s.

2.2.2 Analytical Reference Standard

A reference standard is available at the EPA National Pesticide Standards Repository with an expiration date of April 2014 (D393943, D. Davis, 12/13/12).

2.2. 3 Recommended Tolerances

Currently there are no tole rances established for residues of triforine. Based on the HED Interim Guidance on Tolerance Expressions (S. Knizner, 5/27/09), the following tolerance expression is

recommended.

Tolerances are established for residues of triforine, including its metabolites and degradates , in or on the commodites in the table below. Compliance with the tolerance levels specified below is be determined by measuring only triforine

, (N,N ́

- [1,2

- piperazinediylbis(2,2,2

- trichloroethylidene)]bis[formamide]) , in or on th e commodity

.

### Triforine Human Health Risk Assessment D398041

Page 6 of 29 Table 2.2.3 . Tolerance Summary for Triforine

. Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments

( correct commodity definition )

blueberry 0.02 1.0 blueberry

tomato 0.5 0.5 tomato



### The tolerance listing should note that there is no U.S. registration for either blueberry or tomato.

2.2. 4 Revisions to Petitioned

- For Tolerances

No change is proposed to the petitioned

- for tomato tolerance. However, HED recommends increasing the petitioned

- for tolerance for blueberry from 0.02 ppm to 1.0 ppm to harmonize

with the established Codex MRL.

2.2. 5 International Harmonization

Establishment of the recommended tolerances for blueberry at 1.0 ppm and for tomato at 0.5 ppm for residues of triforine will allow for full har monization of both the residue definition and

the tolerance level between the U.S. and Codex.

2.3 Label Recommendations

This request is for tolerances without U.S. registration; therefore, there are no U.S. labels associated with this petition, a nd a discussion of label recommendations is not pertinent.

3.0 In troduction

Triforine is a systemic amide fungicide with protectant, eradicant, and curative characteristics.

All U.S. food uses of triforine were voluntarily cancelled in 1996

, and the associated tolerances were revoked in a final rule published on July 23, 2004 (69 FR 43918) (FRL

- 7358

- 6). Triforine is currently registered for use on ornamentals including roses, trees, herbaceous plants, and woody shrubs and vines. Landis Inte rnational, on behalf of Summit Agro North America Holding Corporation, has petitioned to establish tolerances without U.S. registration (import tolerances) for residues of triforine in/on blueberries and tomatoes.

3.1 Chemical Identity

Table 3.1. Trifor ine Nomenclature

Chemical Structure

### Triforine Human Health Risk Assessment D398041

Page 7 of 29 Table 3.1. Trifor ine Nomenclature

Common Name Triforine

IUPAC name [piperazine

- 1,4

- diylbis(2,2,2

- trichloroethane

- 1,1

- diyl)]diformamide

CAS Name N,N’

- [1,4

- piperazinediylbis(2,2,2

- trichloroethylidene)]bis [ formamide ]

CAS Registry Number 26644

- 46

- 2

End

- use product (EP) 195 g ai/L (1.63 lb ai/gal) dispersible concentrate (DC) formulation (Saprol ® 190 DC or Funginex ® DC, containing 18.2% triforine)



### 3.2 Physical/Chemical Characteristics

Triforine has low water solubility. Its octanol/water partition coefficient suggests that it is a hydrophobic compound that is more fat soluble than water soluble, exhibiting a tendency to dissolve in fats, oils, lipids, and non

- polar solvents, more readi ly than in water. Further, triforine has a low vapor pressure. The full complement of physiochemical properties for this active ingredient is shown in Attachment 1.

3.3 Pesticide Use Pattern

There are no U.S. registrations sought in connection with t he establishment of the requested tolerances; therefore the registrant has provided a summary of the international uses of triforine on blueberries and tomatoes. That information is included in Table 3.3, below.

Table 3.3. Summary of Proposed Directions for Use of Triforine Applic. Timing, Type, and Equip. Formulation Applic.

Rate (lb ai/A) Max. No.

Applic. per

Season Max. Seasonal

Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations

Blueberries (Canada) Early season foliar ground

and aerial application Funginex®

DC Fungicide 190 g ai/L 0.51 3 1.52 60 10

- 14 day RTI; ground spray volume is 1000 L/ha; aerial spray

volume is 50

– 60 L/ha;
Tomatoes (Mexico)

Late season foliar ground application Saprol 200

C.E. 190 g ai/L 0.34 4 1.36 3 7 day RTI



### In addition, triforine is currently registered in the U.S. for use on ornamentals, including roses, trees, herbaceous plants, and woody shrubs and vines. Products containing triforine are applied by aerosol spray, hose

- end sprayer, and tank

- type sprayer to control black spot, rust, and powdery mildew. As a general use pesticide, triforine may be applied around the home by individuals or professional applicators.

3.4 Anticipated Exposure Pathways

T he Registration Division has requested an assessment of human health risk to support the proposed new tolerances for triforine on blueberries and potatoes. Humans may be exposed to triforine in food and drinking water, since triforine residues may be foun d in imported blueberries and tomatoes, and since application of triforine in residential settings may result in

### Triforine Human Health Risk Assessment D398041

Page 8 of 29 triforine reaching surface and ground water sources of drinking water. Additionally, humans may be exposed to triforine in residential or non

- occupational settings since the active ingredient is currently registered for use on ornamentals. Lastly, in an occupational setting, applicators may be exposed while handling triforine for ornamental application.

3.5 Consideration of Environmental Jus tice

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 in volve 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) and are used i n 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 todd lers, 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 consi der exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

4.1 Summary of Toxicological Effects

The principal toxic effects of tri forine are changes in the liver and hematopoietic system following repeated oral dosing, and t he dog i s the most sensitive species for the hematopoietic effects. The effects observed in subchronic and chronic oral toxicity studies generally are not

severe and include a mild, hemolytic anemia in which the bone marrow compensates by increasing pro duction of red blood cells. This effect is ch aracterized by decreased hematocrit/hemoglobin with hemosiderin deposition in several organs, no evidence of bone

marrow depression, and entry of increased numbers of immature cells into the peripheral

circulation. The anemia is reversible with cessation of exposure . Liver effects include increased liver weights, cholesterol and alkaline phosphatase levels. Toxicity was not observed in a rat 21

- day dermal toxicity study at dose levels greater than the limit dose. Triforine is not acutely toxic

via the o ral, dermal, and inhalation routes.

### Triforine Human Health Risk Assessment D398041

Page 9 of 29 No maternal or developmental toxicity was observed in the rat in the developmental toxicity study at dose levels up to the limit dose (actual 840 mg/kg/day). In the rabbit, decreased maternal body weight and food consum ption and decreased fetal body weight were observed at the limit dose. In the rat reproductive toxicity study, there was a slight decrease in testes weight in F1 males and a decrease in the fertility index in the F1 males at a dose greater than the limit dose.

Triforine does not demonstrate neurotoxic potential. At dose levels greater than the limit dose, no clinical signs were observed in the rat chronic toxicity/carcinogenicity study; in either the rat or rabbit developmental toxicity study; or in the rat 2

- generation reproduction study. In a subchronic neurotoxicity (SCN) study in rats , there were no adverse effects on any functional operational battery ( FOB ) parameter monitored; motor activity was comparable among the

groups and there were no neurop athological effects observed in either sex at dose levels greater

than the limit dose. Although an acute neurotoxicity study (ACN) is not available for triforine,

the Hazard and Science Policy Council (HASPOC) determined that an ACN was not required ( TXR No. 0056502, J. VanAlstine, 1/22/13 ). Triforine does not show any immunotoxic potential following exposure to rats and mice at dose levels above the limit dose.

There was a treatment

- related increase in lung tumors (females) and liver tumors (males)

foll owing long

- term exposure to mice at the limit dose. T here is sufficient evidence that triforine reaches the target organ, and mutagenicity is not a concern. Triforine is classified as “Suggestive Evidence of Carcinogenicity”; however, there is insufficient evidence to support quantification

of human carcinogenic risk.

In rats, triforine was rapidly absorbed and eliminated via the urine (78%) and feces (18%), with 94% being excreted within 48 hours post dose. The majority of a single low oral dose and repeated low oral doses were absorbed, whereas only 10%

- 20% of a single high dose was

absorbed. The major target organs following repeated oral exposure to triforine are the liver and hematopoietic syst em. Radiolabeled test material was found i n the bone marrow, spleen, and whole blood, which is consistent with the effects observed in dogs and rats (hematology changes, increased erythropoiesis, and hemosiderin deposition in the liver and bone marrow). The absorbed dose is completely metabolized and excreted in the urine mainly as metabolite W1069 (N

- [piperazine

- 1

- yl

- (trichloromethyl) methylene] formamide hydrochloride, which is formed by cleavage of one of two identical side

- chains. The cleaved side

- chain is further metabolized prior

to excreti on, mainly to trichloroethanol, which is excreted in urine as its glucuronic acid conjugate.

No dermal ab sorption studies are available. Quantification of dermal risk is not required, based on lack of toxicity in the rat dermal toxicity study at a dose level greater than the limit dose , and

the lack of pertinent effects in other toxicity studies not measured in the dermal toxicity study. A dermal absorption factor is not required.

4. 2 Safety F actor for Infants and Children (FQPA Safety Factor)

The FQP A SF for triforine can be reduced to 1X based on considerations summarized in Sections 4.2.1 through 4.2.4, below.

### Triforine Human Health Risk Assessment D398041

Page 10 of 29 4.2.1 Completeness o f the Toxicology Database

The toxicology database for triforine is complete. Acceptable rat and rabbit developmental toxicity studies, a rat 2

- generation reproduction study, a subchronic neurotoxicity study in rats, and immunotoxicity studies in rats and mice are available. The H ASPOC determined that the acute neurotoxicity study may be waived.

4.2.2 Evidence of N eurotoxicity

There is no evidence of neurotoxicity or neuropathology in the available studies. The body/head

tremors observed in male mice that died on test in the ca rcinogenicity study were attributed to agonal death ; the salivation, mild trembling, and moderate ataxia observed in the chronic toxicity study in one dog on day 723 only was not considered treatment

- related

. At dose levels greater than the limit dose, no clinical signs were observed in the rat chronic toxicity/carcinogenicity study; in either the rat or rabbit developmental toxicity study; or in the rat 2

- generation reproduction study. In a subchronic neurotoxicity (SCN) study, there were no adverse effe cts on

any functional operational battery ( FOB ) parameter monitored; motor activity was comparable among the groups and there were no neuropathological effects observed in either sex at dose levels greater than the limit dose. There is not a concern for d evelopmental neurotoxicity.

4.2.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

There is no evidence of increased susceptibility following in utero exposure to triforine in either the rat or rabbit developmental toxicity study at dose levels up to the limit dose, and there is no evidence of increased susceptibility following in utero and/or pre

- /post

- natal exposure in the 2

- generation reproduction st udy in rats at dose levels greater than the limit dose.

Triforine has been evaluated for potential developmental effects in the rat and rabbit (gavage administration). Maternal toxicity included decreased body weight and food consumption in

rabbits at the limit dose, and maternal toxicity was not observed in rats at dose levels up to the limit dose. Decreased fetal body weight was observed in the rabbit at the limit dose, whereas there were no developmental effects in the rat at the limit dose (actual 840 mg/kg/day). Decreased fertility index and decreased testes weight was observed in F1 males in the 2

- generation reproduction study only at a dose level greater than the limit dose.

4.2.4 Residual Uncertainty in the Exposure Datab ase

There is no residual uncertainty in the exposure database. All the required exposure information has been submitted. Dietary (food and water) exposure assessments included tolerance level residues, assumed 100% crop treated, included empirical or default processing factors, and used modeled water numbers. The dietary risk assessment is highly conservative and unlikely to

underestimate risk.

### Triforine Human Health Risk Assessment D398041

Page 11 of 29 4. 3 Toxicity Endpoint and Point of D eparture Selections

4.3.1 Dose

- Response Assessment

A detailed description of the toxicit y studies used for selecting toxicity endpoints and points of departure for various exposure scenarios is presented in A ppendix A

.

No hazard or appropriate acute endpoint attributable to a single exposure was identified from the available oral toxicity da tabase; therefore

, no acute dietary risk is expected following acute exposure to triforine.

The chronic dietary endpoint was selected from the combined subchronic/chronic toxicity feeding studies in the dog with a NOAEL of 22 mg/kg/day. At the study LOAEL of 120 mg/kg/day, decreased RBC, hematocrit, hemoglobin values and siderosis in the liver, spleen, and

bone marrow were observed. A 100X uncertainty factor was applied to account for inter

- and

intra

- species variability resulting in a c hronic reference dose (cRfD) of 0.22 mg/kg/day. Since the FQPA factor is reduced to 1X, the RfD is equivalent to the chronic population adjusted dose (cPAD).

An oral study was used to determine points of departure for the inhalation risk assessment. The HASPOC concluded, based on a weight of evidence (WOE) approach, that a 28

- day inhalation toxicity study is not required at this time ( TXR No. 0056502, J. VanAlstine, 1/22/13 ).

Incidental oral, s hort

- term and intermediate

- term inhalation endpoints for risk assessment were selected from the combined subchronic/chronic toxicity feeding studies in the dog with a NOAEL of 22 mg/kg/day. At the study LOAEL of 120 mg/kg/day, decreased RBC, hematocrit,

h emoglobin values and siderosis in the liver, spleen, and bone marrow were observed. Inhalation hazard is assumed to be equivalent to oral hazard.

Th ere was no potential hazard via the dermal route because of the lack of systemic toxicity following 21 d ays of dermal exposure to rats at dose levels up to 1100 mg/kg/day, which is greater than the limit dose. The endpoints of concern were all assessed in this study, and there is no developmental or reproductive concern at dose levels that do not exceed the limit dose.

4.3 .2 Recommendation for Combining Routes of Exposures for Risk Assessment

Oral and inhalation exposure should be combined , as the same endpoints are used for both routes of exposure. There is no hazard posed by triforine via the dermal route.

4.3 .3 Cancer Classification and Risk Assessment Recommendation

The Cancer Assessment Review Committee (CARC) classified triforine as “ Suggest ive Evidence of Carcinogenicity” based on tumors seen in both sexes of one species (mouse) onl y at the limit dose (liver tumors in male mice a nd lung tumors in female mice). T here is sufficient evidence that triforine reaches the target organ, and mutagenicity is not of concern ; however, there is insufficient evidence to support quantification of human carcinogenic risk. Since the effects seen

### Triforine Human Health Risk Assessment D398041

Page 12 of 29 in the study that serves as the basis for the chronic RfD occurred at doses substantially below the lowest dose that induced tumors, the chronic RfD is considered protective of all chronic effects including potential carcinogenicity (TXR #0052658, J. Kidwell, 6/29/04)

.

4.3 .4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk

Assessment.

Table 4.3 .4.1 Summary of Toxicological Doses and Endpoints for Triforine for Use in Dietary and Non

Occupational Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Acute Dietary (All populations) No hazard or appropriate acute endpoint was identified in the database. There are no

developmental concerns. HASPOC determined that an ACN is not required (10/25/12).

Chronic Dietary (All Populations) NOAEL =

22 mg/kg/day UF A 10x

UF H 10x

FQPA SF = 1X cRfD = 0.22

mg/kg/day

cPAD = 0.22 mg/kg/day Subchronic/Chronic oral toxicity (dog)

MRID 00122575

MRID 42380410/43222102 LOAEL = 120 mg/kg/day, based on decreased RBC, hematocrit, hemoglobin values and siderosis in the liver, spleen,

and bone marrow

Incidental Oral

Short

- Term (1

- 30 days) NOAEL =

22 mg/kg/day UF A 10x

UF H 10x

FQPA SF = 1x Residential

LOC for

MOE < 100 Subchronic/chronic oral toxicity (dog)

MRID 00122575

MRID 42380410/43222102 LOAEL = 120 mg/kg, based on decreased RBC, hematocrit, and h emoglobin values, increased spleen weight, and siderosis in the liver, spleen, and bone marrow.

Incidental Oral

Intermediate

Term (1

- 6 months) NOAEL =

22 mg/kg/day UF A 10x

UF H 10x

FQPA SF = 1x Residential

LOC for

MOE < 100 Subchronic/chronic oral toxicity (dog)

MRID 00122575

MRID 42380410/43222102 LOAEL = 120 mg/kg, based on decreased RBC, hematocrit, and hemoglobin values, increased spleen weight, and siderosis in the liver, spleen, and bone marrow.

Dermal (All durations) No potential hazard via the dermal route, based on the lack of systemic effects following repeat

dermal exposure of rats at dose levels up to 1100 mg/kg/day, which is greater than the limit dose. The endpoints of concern were all assessed in this study, and there is no developmen tal or reproductive concern at dose levels that do not exceed the limit dose.

Inhalation

Short

- Term (1

- 30 days) NOAEL =

22 mg/kg/day UF A 10x

UF H 10x

FQPA SF = 1x Residential

LOC for

MOE < 100 Subchronic/chronic oral toxicity (dog)

MRID 00122575

MRID 423 80410/43222102 LOAEL = 120 mg/kg, based on decreased RBC, hematocrit, and hemoglobin values, increased spleen weight, and siderosis in the liver, spleen, and bone marrow.

### Triforine Human Health Risk Assessment D398041

Page 13 of 29 Table 4.3 .4.1 Summary of Toxicological Doses and Endpoints for Triforine for Use in Dietary and Non

Occupational Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Inhalation

Intermediate

Term (1

- 6 months) NOAEL =

22 mg/kg/day UF A 10x

UF H 10x

FQPA SF = 1x Residential

LOC for

MOE < 100 Subchronic/chronic oral toxicity (dog)

MRID 00122575

MRID 42380410/43222102 LOAEL = 120 mg/kg, based on decreased RBC, hematocrit, and hemoglobin values, increased spleen weight, and siderosis in the liver, spleen, an d bone marrow.

Cancer (oral, dermal, inhalation) Classification: Suggestive Evidence of Carcinogenicity; insufficient evidence to support

q uantification of human carcinogenic risk. Since the effects seen in the study that serves as the

basis for the chronic RfD occurred at doses substantially below the lowest dose that induced tumors, the chronic RfD is considered protective of all chronic effects including potential carcinogenicity.

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 adver se effect level.

LOAEL = lowest observed adverse effec t level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Table 4.3 .4.2 Summary of Toxicological Doses and Endpoints for Triforine for Use in Occupational Human

Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk

Assessment Study and Toxicological Effects

Dermal (All durations) No potential hazard via the dermal route, based on the lack of systemic effects following repeat

dermal e xposure of rats at dose levels up to 1100 mg/kg/day, which is greater than the limit dose. The endpoints of concern were all assessed in this study, and there is no developmental or reproductive concern at dose levels that do not exceed the limit dose.

Inhalation (All

durations NOAEL=22

mg/kg/day UF A =10x

UF H =10x Occupational

LOC for MOE =

100 Subchronic/chronic oral toxicity (dog)

MRID 00122575

MRID 42380410/43222102 LOAEL = 120 mg/kg, based on decreased RBC, hematocrit, and hemoglobin values,

increased spleen weight, and siderosis in the liver, spleen, and bone marrow.

Cancer (oral, dermal, inhalation) Classification: Suggestive Evidence of Carcinogenicity; insufficient evidence to support

q uantification of human carcinogenic risk. Since the effects seen in the study that serves as the basis for the chronic RfD occurred at doses substantially below the lowest dose that induced tumors, the chronic RfD is considered protective of all chronic effects including potential carcinogenicity.

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 ad verse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern.

### Triforine Human Health Risk Assessment D398041

Page 14 of 29 5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary and Rationale

For the purpose of this import tolerance on blueberries and tomatoes, the nature of the residue in plants is adequately understood. Since no degradation of triforine was seen in apple, cucumber, and tomato metabolism studies, the residue of concern in pla nts is triforine per se for both tolerance setting and risk assessment purposes.

Since there are no uses on animal feed items, a determination on the residues of concern in animals is not required. Further, since there are no domestic uses of triforine in agricultural settings, a determination on the residues of concern in rotational crops is not required at this

time.

5 .2 Food Residue Profile

Blueberry and tomato field trials have been submitted that are adequate in number and geographic representation. An acceptable processing study has been provided. These data were generated by a validated analytical method, and are supported by adequate st orage stability data (D393943, D. Davis, 12/13/12).

Field trial data demonstrates that quantifiable residues of triforine are not found in blueberries

treated 60

- days before harvest. However, quantifiable residues are found in tomatoes treated 3

- days be fore harvest. The residue is expected to be a surface residue consisting of primarily parent compound, as metabolism data in plants shows that triforine undergoes limited translocation or degradation. Tomato processing data show no concentration of resid ues in puree

or paste.

There are no animal feed items associated with the petitioned

- for tolerances; therefore a discussion of residues in livestock feed items and the potential for secondary residues in livestock commodities for human consumption is not pertinent to this action.

5.3 Water Residue Profile

Since this petition requests tolerances without U.S. registration, establishing the requested tolerances will have no impact on domestic drinking water residues. For the purpose of this risk

assessment , the most recent drinking wa ter assessment (D339605, K. Moo re, 3/5/08), which estimated residues resulting from the residential uses of triforine was consulted. Modeled estimated drinking water concentrations from those uses are included in this risk ass essment.

Surface water estimated drinking water concentrations (EDWCs) are based on FIRST modeling

and represent untreated surface water concentrations. For surface water, the modeled EDWCs for peak and annual average exposure are 85.1 ppb and 0.84 ppb , respectively. The one

- in

- 10

- year peak day concentration is used for acute endpoints and the one

- in

- 10

- year annual average

concentration is used for chronic endpoints. Groundwater EDWCs are based on SCIGROW modeling and represent the concentration that might be expected in shallow unconfined aquifers

### Triforine Human Health Risk Assessment D398041

Page 15 of 29 under sandy soils. For groundwater, both peak and average exposure estimates are 0.43 ppb

. Model o utput is used for both acute and chronic endpoints. The drinking water models and their descriptions are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/

.

As there is no acute dietary hazard posed by triforine, only a chr onic dietary risk assessment was

conducted. The highest annual average EDWC from the surface water model of 0.84 ppb was included in the chronic dietary risk assessment.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Ass essment

There are currently no food uses or tolerances listed in the 40 CFR for triforine. The petitioner has requested the establishment of tolerances without U.S. registration in/on blueberry and tomato. HED is recommending that the tolerances be set at 1.0 ppm for blueberry and 0.5 ppm for tomato. The tolerance level residues were included in the dietary assessment for these raw agricultural commodities (RACs). A processing study for tomatoes was submitted that showed

no concentration of triforine r esidues in tomato paste and puree; therefore the RAC tolerance was used and the concentration factor were set to a value of “1” for all processed tomato products, with the exception of dried tomatoes. Empirical data are not available for this processed

co mmodity, so the DEEM 7.81 default processing factor for dried tomatoes of 14.3 was included in the dietary risk assessment.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The dietary assessment assumes that 100% of the blueberry, tomato, and tom ato processed commodities consumed in the U.S. are imported, and further that all of the imports have been treated with triforine, effectively assuming 100% crop treated for the two crops that are included in the dietary risk assessment.

5.4.3 Acute Dietary Risk Assessment

Triforine does not pose an acute dietary hazard.

5.4.4 Chronic Dietary Risk Assessment

A high ly conservative chronic aggregate dietary ( food and drinking water ) exposure and risk

assessment was c onducted using the Dietary Exposur e Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID) Version 3.16 . This software uses 2003

- 2008 food consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). Triforine chronic dietary risks are not of concern. Estimated risks were <1% of the chronic population adjusted dose (cPAD) for the general U.S. population and all p opulation subgroups. Detailed

results are shown in Table 5.4.6.

### Triforine Human Health Risk Assessment D398041

Page 16 of 29 5.4.5 Cancer Dietary Risk Assessment

While triforine has been classified as “Suggestive Evidence of Carcinogenicity”, there is insufficient evidence to support the conduct of a quantitativ e cancer risk assessment. Since the effects seen in the study that serves as the basis for the chronic RfD occurred at doses substantially below the lowest dose that induced tumors, the chronic RfD is considered protective of all chronic effects including potential carcinogenicity. As noted in Section 5.4.4, there are no chronic dietary risks of concern.

5.4.6 Summary Table

A summary of the dietary (food and water) exposure and risk assessments for triforine is shown

in Table 5.4.6.

Table 5.4.6

. Summar y of Dietary (Food and Water) Exposure and Risk for Triforine

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

cPAD*

General U.S. Population 0.000452 <1

All Infants (<1 year old) 0.000293 <1

Children 1

- 2 years old 0.000898 <1

Children 3

- 5 years old 0.000914 <1

Children 6

- 12 years old 0.000586 <1

Youth 13

- 19 years old 0.000387 <1

Adults 20

- 49 years old 0.000410 <1

Adults 50

- 99 years old 0.000393 <1

Females 13

- 49 years old 0.000386 <1



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no new residential uses with this petition; however, in order to complete the aggregate risk assessment, HED has updated the residential exposure assessment (D408358, M. Lloyd,

1/22/13 ) to reflect currently registe red uses. Triforine is registered for use on ornamentals including roses, trees, herbaceous plants, and woody shrubs and vines. Products containing triforine are applied by aerosol spray, hose

- end sprayer, and tank

- type sprayer to control black

spot, rus t, and powdery mildew. As a general use pesticide, triforine may be applied around the home by individuals.

6.1 Residential Handler Exposure

HED uses the term “handlers” to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct tasks related to applications and that exposures can vary depending on the specifics of each task. Resi dential handlers are addressed

### Triforine Human Health Risk Assessment D398041

Page 17 of 29 somewhat differently by HED as homeowners are assumed to complete all elements of an application without use of any protective equipment.

Since triforine does not pose a hazard by the dermal route of exposure, the residentia l handler assessment includes only inhalation exposure. The quantitative exposure/risk assessment developed for residential handlers is based on the following scenarios:

(1) Mixing/loading/ a pplying liquid concentrates with hose

- end sprayer; (2) Mixing/loading/applying liquid concentrates with a manually pressurized handwand

sprayer ; (3) Mixing/loading/ a pplying liquid concentrates with garden backpack sprayer (4) Mixing/loading/applying liquid concentrates with sprinkler can (5) Applying with aerosol can, a nd (6) Applying ready to use sprays with a hose

- end sprayer A series of assumptions and exposure factors served as the basis for completing the residential handler risk assessments. These assumptions include use of the single maximum application rate

of 0.002 1 lbs ai/gallon, u nit exposure values and estimates for area treated or amount handled

based on HED’s 2012 Residential SOPs , a body weight of 80 kg, that t oxicity by the inhalation route is considered to be equivalent to toxicity by the oral route of expos ure , and that exposures are expected to be short

- term in duration. No residential handler risks of concern were identified. The results of the handler exposure and risk assessment are shown in table 6.1, below.

Table 6.1. Residential Handler Non

- cancer Exposure and Risk Estimates for Triforine.

Exposure Scenario Level of

Concern Inhalation Unit

Exposure
(ug/lb ai) Maximum

Application

Rate 1 Area Treated or

Amount
Handled Daily 2 Inhalation

Dose (mg/kg/day) 3 MOE s 4

(no respiratory protection)

Mixer/Loader/Applicator Manually

pressurized

handwand 100 0.018 0.0021 5 gallons 0.0000024 9,700,000

Hose

- end Sprayer 100 0.0014 0.0021 11 gallons 0.0000004 5,700,000
Backpack 100 0.14 0.0021 5 gallons 0.000018 1,300,000
Sprinkler can 100 0.0014 0.00 21 5 gallons 0.00000018 130,000,000

Aerosol can 100 3 0.000875 2 cans 0.000066 350,000

Hose

- end Sprayer 100 0.034 0.0021 11 gallons 0.0000098 2,300,000

1 Based on registered use pattern (D339610)

. 2 2012 Residential SOPs

. 3 Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal ) x Area Treated or Amount Handled (A or gallons/day) / BW (kg).

4 Inhalation MOE = Inhalation NOAEL (mg/kg/day) / Inhalation Dose (mg/kg/day).



### 6.2 Residential Post

- Application Exposure

The Agency uses a set of pre

- defined scenarios to address exposures in the residential environment. All types of exposures are considered that can result from the application of a pesticide chemical in and around the home as well as in other areas where exposures in the

gener al population can occur such as parks and playgrounds. For triforine, no dermal endpoints

### Triforine Human Health Risk Assessment D398041

Page 18 of 29 of concern were identified so there is no concern for post

- application dermal exposures. Additionally, the mouthing behaviors of children are also commonly addresse d in post

application assessments as well as possible inhalation exposures. For triforine, a quantitative

post

- application exposure assessment was not conducted because (1) the primary uses of triforine

are for disease control on roses and other ornament al plants where children would not be expected to routinely contact treated plants and engage in mouthing behaviors which is described in the Agency’s Standard Operating Procedures For Residential Exposure Assessment (SOPs); and (2) triforine is relatively non

- volatile which, coupled with the dilution expected outdoors and the small amounts of active ingredient used diminish the possibility of post

- applica tion inhalation exposure ( also described in Agency’s SOPs). Therefore, there is no concern for post

ap plication exposures to triforine.

6.3 Residential Risk Estimates for Use in Aggregate Assessment

For the purpose of the triforine aggregate human health risk assessment, a summary of the most
health

- protective residential exposure estimates for all reg istered residential uses are provided in

Table 6.1

. Based on the residential use profile and the 2012 Revised Residential SOPs, only

short

- term inhalation residential handler (for adults) should be included in the aggregate risk

assessment. The residenti al contribution to the aggregate is the handler aerosol scenario, reflecting an individual using 2 cans of aerosol spray a day over the short

- term exposure duration (up to 30 days).

6.4 Residential Bystander Post

- application Inhalation Exposure

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for triforine at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure ( 6.0 x 10 - 4 

### mm Hg ) , and the low proposed use rate (0.46 lbs ai/A). However, 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 vo latilization 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 1 

### . The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may

re visit the need for a quantitative post

- application inhalation exposure assessment for triforine.

Although a quantitative residential post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for han dlers (i.e., applicators of

consumer

- oriented liquid and aerosol triforine products). These exposure scenarios do not represent risk concerns, are representative of worse case inhalation exposures, and should be considered protective of most post

- applicat ion inhalation exposure scenarios.

1 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

### Triforine Human Health Risk Assessment D398041

Page 19 of 29 6.5 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application s , but, to a lesser extent, could also be a potentia l source of exposure from ground application method s employed for triforine . The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray dri ft management practices (see the Agency’s Spray Drift website for more information ; http://www.epa.gov/opp00001/factsheets/spraydrift.htm ) . On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registra nts, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target drift with specific products with significant risk

estimates associated with drift.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g. , a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

7.1 Acute Aggregate Risk

Triforine does not pose an acute aggregate risk.

7.2 Sh ort

- Term Aggregate Risk

HED conducted short

- term aggregate risk assessment s for adult males and adult females. There are no residential exposure scenarios for children; therefore aggreg ate risks for children include exposures from food and water. Those risks are addressed in Section 5.4.4 of this review and no

risks of concern were identified.

Short

- term aggregate exposure and risk assessments included short

- term residential inhalation exposure and average food and water residues ; there are no oral res idential exposures for adults and triforine does not pose a dermal hazard, so only residential inhalation exposure is included in the aggregate assessment . No short

- term aggregate risks of concern were identified. The results

are shown in Table 7.2.

### Triforine Human Health Risk Assessment D398041

Page 20 of 29 Tab le 7.2 Short

- Term Aggregate Risk Calculations

Population Short

- Term Scenario

NOAEL mg/kg/day LOC 1 Max

Allowable Exposure 2
mg/kg/day Average

Food and

Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Tota l

Exposure mg/kg/day 4 Aggregate

MOE (food, water, and residential) 5

Adult Male 22 100 0.22 0.000 410 0.000066 0.000476 46 ,000

Adult Female 0.00 0410 0.000066 0.000476 46 ,000

1 LOC of 100 includes the standard inter

- and intra

- species uncertainty factors totaling 100

. 2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC ; NOAEL and LOC taken from Table 4.3.4.2.

3 Residential Exposure = ( Oral exposure + Dermal ex posure + Inhalation Exposure); however, there is no hazard posed by triforine via the dermal route of exposure and there are no oral residential exposures; therefore for this assessment the residential exposure is limi ted to inhalation exposure. Residue values taken from Table 6.1.

4 Total Exposure = ( Avg Food & Water Exposure + Res idential Exposure) . Average food residues from Table 5.4.6.

5



### 7.3 Intermediate

- Term Aggregate Risk

Residential intermediate

- term exposure is not anticipated; therefore, an intermediate

- term aggregate risk assessment is not pertinent to this petition.

7.4 Chronic Aggregate Risk

There are no chronic aggregate residential exposure scenarios; therefore, chronic aggregate risk includes exposures from food and water only. As discussed in Section 5.4.4, there are no chronic dietary risks of concern.

7.5 Cancer Aggregate Risk

While triforine has been classified as “Suggestive Evidence of Carcinogenicity”, there is insufficient evidence to support quantification of human carcinogenic risk. Since the effects seen in the study that serves as the basis for the chronic RfD occurred at doses substantially below the lowest dose that induced tumors, the chronic RfD is considered protective of all chronic effects including potential carcinogenicity. As discussed in Section 7.4, there are no chronic aggregate

risks of concern.

8.0 Cumulat ive Exposure/Risk Characterization

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 toxicit y finding as

to triforine and any othe r substances and triforine does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not
assumed that triforine has a common mechanism of toxicity with other substances. For information regardi ng 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 Office of Pesticide Programs 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/pesticides/cumulative/.

### Triforine Human Health Risk Assessment D398041

Page 21 of 29 9.0 Occupational Exposure/Risk Characterization

This petition is limited to tolerances without U.S. registra tion for triforine. Since this action does not involve domestic application of triforine, an occupational exposure and risk assessment is not required.

10.0 References

Author: Jessica Kidwell

Date: 6/29/04

TXR Number: 0052658

Title: TRIFORINE : Report of the Cancer Assessment Review Committee. P.C. Code

107901

Author: Julie VanAlstine

Date: 1/22/13

TXR Number: 0056502

Title: Triforine: Summary of Hazard and Science Policy Council (HASPOC) Meetings

of October 25, 2012: Recommendations on the Requirement of a Subchronic Inhalation Study and the Acute Neurotoxicity Study for Triforine.

Author: Donna S. Davis

Date: 12/13/12

DP Number: D 393943

Title: Triforine

. Petition for the Establishment of Permanent Tolerances without U.S.

Registration for Blueberries and Tomatoes

. S ummary of Analytical Chemistry

and Residue Data.

Author: Donna S. Davis

Date: 12/13/12

DP Number: D407480

Title: Triforine. Chronic Aggregate Dietary (Food and Drinking Water) Exposure and

Risk Assessmen t to Support Request for Tolerances without U.S. Registration for Blueberry and Tomato.

Author: Matthew Lloyd

Date: 1/22/13

DP Number: D 408358

Title: Triforine. Occupational and Updated Residential Exposure Assessment for a

Proposed Import Tolerance Use on Blueberries and Tomatoes

### Triforine Human Health Risk Assessment D398041

Page 22 of 29 A ppendix A

. Toxicology Assessment

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food uses for triforine are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity

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

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

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

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

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

................................ ...................... yes

yes

yes

yes

yes

yes Yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

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

................................ ......... 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

................................ .......................... yes

yes

yes CR

CR Yes

yes

yes

no waived

870.3700a Developmental Toxicity (rodent)

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

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

................................ ................................ . yes

yes

yes Yes

yes

yes

870.4100a Chronic Toxicity (rodent)

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

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

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

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

................................ .................... yes

yes

yes

yes

yes Yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

................ 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

... 870.5395 Mutagenicity

— Other Genotoxic Effects

....................... yes

yes

yes

yes Yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen)

................................ ..... 870.6100b 90

- Day Neurotoxicity (hen)

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

....................... 870.6200b 90

- Day Neuro. Screening Battery (rat)

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

................................ .............................. no

no

yes

yes CR -

- waived

waived

-

870.7485 General Metabolism

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

................................ ........................ 870.7 8 00 Immunotoxicity

................................ ............................. CR

CR

yes Yes

no

yes

Special Studies for Ocular Effects

Acute Oral (rat)

................................ ........................... Subchronic Oral (rat)

................................ .................. Six

- month Oral (dog)

................................ .................. no

no

no no

no

no CR conditionally required

### Triforine Human Health Risk Assessment D398041

Page 23 of 29 A.2 Toxicity Profile s

Table A.2.1 Acute Toxicity Profile

- Triforine

Guideline

No. Guideline No. Guideline

No. Guideline No. Guideline

No.

870.1100 Acute oral [ rat] 42172701 LD 50 > 5000 mg/kg IV

870.1200 Acute dermal [rabbit] 42172702 LD 50 = >2000 mg/kg III

870.1300 Acute inhalation [rat] 42172703 LC 50 = > 5.12 mg/L IV

870.2400 Acute eye irritation [rabbit] 42380407 conjunctival redness in 1 rabbit at 24 hrs. [score 1]; cleared by 48 hrs. III

870.2500 Acute dermal irritation

[rabbit] 42380408 not an irritant IV

870.2600 Skin sensitization [guinea

pig] 42380409

43396901 not a dermal sensitizer N/A

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Triforine

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

Classification /Doses Results

870.3100

90

- Day oral toxicity [Wistar

FW

- 49 rat; 73 days old at start] MRID 00091341

technical [W524, Lot III] 0 ppm, 100 ppm, 500 ppm unacceptable/non

- guideline [2 doses] [0, 5, 25 mg/kg/day, std con] NOAEL = 500 ppm [25 mg/kg/day]

LOAEL = no effects no ted

870.3150

13

- week oral toxicity in 8 month old beagle dogs MRID 00068936 (1971 )

technical [W524, Lot III] 0, 3500, 10000, 30000 ppm

, plus 6

- week recovery 30000 ppm group) males 0, 83, 230, 690/710 mg/kg/day females 0, 85, 240, 730/720 mg/kg/day

( no revised Executive Summary; see

MRID 00122575 below ) NOAEL = not attained LOAEL = 3500 ppm [males 83/females 85 mg/kg/day], based on decreased RBC at 6 weeks, hematocrit, hemoglobin; increased reticulocyte counts; increased alkaline phosphatase and bilirubin at week 13; hemosiderin deposition in liver and bone marrow; siderosis of Kupffer

= s cells; increased spleen weight

effects reversible following 6

- week recovery period at 30000 ppm

870.3150

13

- week oral toxicity in

nonrodents [8

- 10 months old beagle dogs] MRID 00122575 (1971)

technical [W524] 0, 100, 600, or 3500 ppm diet 0, 3.6, 22, 120 mg/kg/day NOAEL = 600 ppm [22 mg/kg/day] LOAEL = 3500 ppm [120 mg/kg/day], based on decreased RBC, hematocrit, hemoglobin values and

sideros is in the liver, spleen, and bone marrow.

effects reversible (see MRID 00068936 above)

### Triforine Human Health Risk Assessment D398041

Page 24 of 29 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Triforine

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

Classification /Doses Results

870.3150

13

- week oral toxicity in nonrodents [8

- 10 months old beagle dogs] MRID 00122575 (1971)

technical [W524] 0, 100, 600, or 3500 ppm diet 0, 3.6, 22, 120 mg/kg/day

(see MRID 00068936 above) NOAEL = 3500 ppm [120 mg/kg/day], highest dose

tested LOAEL = 10000 ppm [230 mg/kg/day], based on decreased RBC at 6 weeks, hematocrit, hemoglobin; increased reticulocyte counts; increased alkaline phosphatase and bilirubin at week 13; hemosiderin deposition in liver and bone marrow; siderosis of Kupffer

= s cells; increased spleen weight observed in

another 13

- week study.

effects reversible

870.3200

21

- Day dermal toxicity (SD rat) 10/sex; topical application shaved intact, occluded skin (4 hours/day) MRID 00091338/00122576

0, 0.5% and 1.5% aqueous dilution of 20% triforine emulsion, equivalent to 0, 10, or 30 mg/kg (triforine)

acceptable/non

- guideline NOAEL (systemic) > 1.5% [30 mg/kg/day] NOAEL (dermal) > 1.5% [30 mg/kg/day]

870.3200

21/28

- Day dermal toxicity (Fischer 344 rat) 7/sex; MRID 42395201 (1992)

0, 110, 350, or 1100 mg/kg/day, 5 days/week, 3 weeks

acceptable/non

- guideline NOAEL = 1100 mg/kg/day

870.3250

90

- Day dermal toxicity no study located/not required

870.3465 90

- day inhalation toxicity Waived

870.3700a

Prenatal developmental in rodent [Sprague

Dawley Crl:CD(SD)BR
rat] MRID 42889201/43222101 (1993)

acceptable/guideline

99.8% 0, 200, 500, 1000 mg/kg/day gestation days 6

- 15 Maternal NOAEL = 1000 mg/kg/day [actual 840 mg/kg/day ]; HDT

LOAEL = no effects Developmental NOAEL = 1000 mg/kg/day; [actual 840 mg/kg/day ]; HDT

LOAEL = no effects

870.3700b

Prenatal developmental in nonrodent (rabbit) MRID 43664901 (1995)

unacceptable (alone)/guideline 0, 6, 30, or 150 mg/kg/day gestation days 6

- 18 Materna l toxicity NOAEL >150 mg/kg/day [HDT] Maternal toxicity LOAEL = see below Developmenta l toxicity NOAEL = 150 mg/kg/day [HDT] Developmental toxicity LOAEL = see below

870.3700b

Prenatal developmental in nonrodent (rabbit MRID 43664902 (range

- finding)

acceptable/non

- guideline

99.6% 0, 250, 500, 1000 mg/kg/day gestation days 6

- 18 Materna l toxicity NOAEL 500 mg/kg/day [HDT] Maternal toxicity LOAEL = 1000 mg/kg/day,

based on decreas ed body

- weight gain and food consumption Developmenta l toxicity NOAEL = 500 mg/kg/day Developmental toxicity LOAEL = 1000 mg/kg/day, based on decreased fetal body weights

### Triforine Human Health Risk Assessment D398041

Page 25 of 29 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Triforine

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

Classification /Doses Results

870.3700b

Prenatal developmental in nonrodent (rabbit) MRID 42889202 (1993)

98.9% acceptable/non

- guideline 1000 mg/kg/day gestation days 6

- 18 maternal toxicity NOAEL = 500 mg/kg/day maternal toxicity LOAEL = 1000 mg/kg/day, based on decreased maternal body

- weight gain (51% of control during dosing period) and food consumption developmental toxicity NOAEL = 500 mg/kg/day developmental toxicity LOAEL = 1000 mg/kg/day, based on decreased fetal body weights

W hen the 3 rabbit studies are considered together, there is a reasonable body of information with which

to establish maternal NOAEL/LOAEL; developmental NOAEL can be established at 500 mg/kg/day; although fetal examinations were not performed at this dose level, since no visceral or

skeletal alterations were observed at 1000 mg/kg/day.

870.3800 Reproduction and fertility effects (Crl:CD (SD)BR rats) MRID 42371801/43323301

(1990/1994) acceptable/guideline

0, 500, 3000, 20000 ppm males: 38 mg/kg/day, 226 mg/kg/day, and 1525 mg/kg/day; females: 48 mg/kg/day, 288 mg/kg/day, and 1924 mg/kg/day. Parental toxicity NOAEL = 500 ppm [males 38/females 48 mg/kg/day; Parental toxicity LOAEL = 3000 ppm [males 226/females 288 mg/kg/day], based on decreased body

- weight gain and organ weight changes.

Reproductive NOAEL =3000 ppm [males 226/females 288 mg/kg/day Reproductive LOAE L = 20000 ppm [males 1525 mg/kg/day; females 1924 mg/kg/day], based on a slight decrease in testes weight [high

- dose F1 males] and a decrease in the fertility index in the high

- dose

F1 males.

Offspring NOAEL = 3000 ppm [males 226/females 288 mg/kg/day], Offspring LOAEL = 20000 ppm [males 1525 mg/kg/day; females 1924 mg/kg/day, based on a slight decrease in testes weight [high

- dose F1 males] and decreased pup body weights in both generations [both sexes].

870.4100a Chronic toxicity rodents (SD rat) MRID 42412001 (1991)

98.9% [batch # 2764] acceptable/guideline 0, 200, 2000, 20000 ppm M 0, 10, 101, 1038 mg/kg/day F 0, 13, 136, 1436 mg/kg/day Systemic toxicity NOAEL = 2000 ppm [males 101 mg/kg/day; females 136 mg/kg/day] Systemic toxicity LOAEL = 20000 ppm [males 1038 mg/kg/day; females 1436 mg/kg/day]. based on increased adrenal, kidney, liver, and spleen weights in females and increased hemosiderin deposits in the spleens of both sexes

870.4100b Chronic toxicity nonrodent (dogs) MRID 42380410/43222102 ( 1973 )

0, 10, 40, 100, 1000 ppm [males 0.23, 0.93, 2.39, 22.5mg/kg/day; females 0, 0.25, 0.99, 2.56, 23.6 mg/kg/day] Systemic toxicity NOAEL = 1000 ppm [males 22.5/ females 23.6 mg/kg/day], highest dose tested.

### Triforine Human Health Risk Assessment D398041

Page 26 of 29 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Triforine

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

Classification /Doses Results

870.4200 Carcinogenicity Sprague

- Dawley

rats MRID 42412001 (1991)

98.9% [batch # 2764] acceptable/guideline 0, 200, 2000, 20000 ppm M 0, 10, 101, 1038 mg/kg/day F 0, 13, 136, 1436 mg/kg/day see above under 870.4100a

slight [not statistically significant] increase in hepatocellular adenomas/car cinomas [high

- dose males]; slight [not statistically significant] increase in islet adenomas of the pancreas [high

- dose females]; the increase in pancreatic tumors incidence occurred at a dose greater [1436 mg/kg/day] than the limit dose [1000 mg/kg/day].

dose levels adequate [limit dose tested]

870.4300 Carcinogenicity mice[105 week]

Crl:CD

- 1 (ICR)BR mouse MRID 42454001 (1991) 98.9% [Lot # 2764] acceptable/guideline 0, 70, 700, 7000 ppm males 0, 11.4, 117, 1204 mg/kg/day females 0, 15.9, 161, 1570 mg/kg/day Systemic toxicity NOAEL = 70 ppm [11.4 males mg/kg/day; 15.9 females mg/kg/day] Systemic toxicity LOAEL = 700 ppm [117 males mg/kg/day; 161 females mg/kg/day], based on increased mortality in males, increased clinical signs [subdued, pale extre mities, body/head tremors, cyanosis, firm/swollen abdomen, hunched/ emaciated/thin appearance in males], decreased body

- weight gain in males, increased histopathologic lesions in the liver, lung, and colon/rectum. increased incidence of hepatocellular ade nomas, carcinomas, and combined adenomas and/or carcinomas in the high

- dose males and an increased incidence of lung alveolar/bronchiolar adenomas, carcinomas, and/or combined ALB adenomas and/or carcinomas in the high

- dose

females.

Gene Mutation

- Ames assay 870.5265 see Table A.2.3

Micronucleus

assay mouse 870.5385 see Table A.2.3

Other Effects

- rat hepatocyte/DNA repair test

- UDS

870.5550 see Table A.2.3

870.6200a

Acute neurotoxicity screening battery Study requirement waived

870.6200b

Subchronic neurotoxicity screening battery Study requirement waived

### Triforine Human Health Risk Assessment D398041

Page 27 of 29 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Triforine

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

Classification /Doses Results

870.6300 Developmental neurotoxicity Not required

870.7485

Metabolism and pharmacokinetics MRID 00071991/00071992

(1971/74 )

3 H (not specifically labeled, but mostly in ring) Oral dosing; 94% of 3 H excreted after 48 hours; 96%

of 3 H excreted after 168 hours; 18% fecal excretion and 78% by renal excretion; two metabolites found in urine; one identified as chloralformamide

870.7485

Metabolism and pharmacokinetics MRID 123000/123001 (1974/75)

14 C (side chain) labeled compound excreted similarly to 3 H tritiated compound but

blood levels of 14 C are about twice as high; major

metabolite is triforine from which one side chain has been removed; other metabolite is designated as

A side chain @ metabolite

870.7485

Metabolism and pharmacokinetics MRID 42428402 ( 1992) single or repeated low dose (10 mg/kg), most of the triforine is absorbed, while after a single high dose (1000 mg/kg), 10

- 20% of the dose is absorbed. The absorbed dose is completely metabolized and excreted in urine mainly as metabolite W1069, which is formed by cleavage of one of 2 i dentical

side

- chains. The cleaved side

- chain is further metabolized prior to excretion, mainly to trichloroethanol, which is excreted in urine a s its glucuronic acid conjugate; radiolabeled material was found in the bone marrow, spleen and whole

blood.

870.7600

Dermal penetration no study available

870.7800 Immunotoxicity MRID 48638401/ 48638402 (2011) Negative in both rats and mice at dose above limit

dose

### Triforine Human Health Risk Assessment D398041

Page 28 of 29 Appendix B

. Physical/Chemical Properties

Table B.1. Physiochemical Properties

Parameter Value Reference

Molecular Weight 434.98 MRIDs 42019601,

- 02, and 42172704, DP Barcodes 170396 and 174772, P. Deschamp, 11/17/82 Melting point/range 151.3

- 154.1 C, color change from white to light brown at 148.6 C

pH at 20 C An aqueous dispersion varied from pH

5.57

- 8.33

Density (g/mL at 20

- 26 C) 1.554

Water solubility (g/L at 20°C) Distilled water

- 12.5 x 10

- 3
Water, pH 5

- 11.3 x 10
- 3

Water, pH 7

- 9.0 x 10
- 3
Water, pH 9

- 8.7 x 10
- 3

Solvent solubility (g/100 mL at 19.5 °C) Methanol

- 4.69

Toluene

- 0.011 Tetrahydrofuran

- 16.8 Hexane, flask

- <0.47 x 10
- 3

Hexane, colum n

- 0.26

Vapor pressure (25°C) 8.0 x 10
- 2 Pa (6.0 x 10
- 4 mm Hg)

Dissociation constant, pKa (20 °C) 2.4 x 10
- 11 (pKa = 10.6 ± 0.2)

Octanol/water partition coefficient, logP OW (25°C) 1.6 x 10 2 , log P

ow = 2.2 in MeOH[HPLC ratio of equilibrium

concentrations in a 2

- phase system] MRIDs 42795801,

- 02, DP Barcode 192209, F. Toghrol, 9/17/93

UV/visible absorption spectrum Not Available

### Triforine Human Health Risk Assessment D398041

Page 29 of 29 Appendix C

. Review of Human Research

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 data, which include studies from PHED 1.1; the Outdoor Residential Exposure Task Force (ORETF) databa se; the
Residential SOPs

, are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studie s Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website at the following urls. ( http://www.epa.gov/pesticides/scienc e/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

.