UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: 1/22/13 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

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

Establishment of Permanent Tolerances without U.S. Registration for Blueberries 

and Tomatoes. 

PC Code: I 0790 I 

Decision No.: 453199 

Petition No.: IE7911 

Risk Assessment Type: Single 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: 

Lind

DonnaS. 

Matt 

a 

Lloyd, 

Taylor

Davis, 

CIH, 

, Toxicolo

Senior 

ORE 

gist 

Chemist 

ssor 

~ 

In

~ 

' .N, - Dt1 ~ ~.M RAB VII I ~V" 'v ·' 1-J.;S-1 .. 

Health Effects Division (7509P) 1 W ~ 

THROUGH: 

Michael 

William 

S. 

H. 

Metzger, 

Donovan, 

Chief 

Ph.D.,t/; f n

rJ~

i.<fr em~ ., -k-.,.1. . :..--r::--r---

RAB VNII 

Health Effects Division (7509P) 

TO: Heather Garvie, Risk Manager 

Mary Waller, Team Leader 

Cynthia Giles-Parker, Chief 

Fungicide-Herbicide Branch 

Registration Division (7505P) 

Attached please find the human health risk assessment to support the requested tolerances 

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

Page 1 of29 
Triforine Human Health Risk Assessment D398041 

Table 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 Children (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 Assessment. ............................................................................................... 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. Toxicology 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 1996, 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 proposed 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 the dog is the most sensitive 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. Triforine 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 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. The FQPA safety factor can be 

reduced to 1X based on completeness of the database, lack of susceptibility or sensitivity to preor 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 blueberry 

and tomato is adequately understood. Blueberry and tomato field trials have been submitted that

are adequate in number and geographic representation, were generated by a validated analytical 

method, and are supported by adequate storage stability data. An acceptable processing 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 impact on domestic drinking water. For the purpose of this 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 conservative chronic dietary (food and water) risk assessment that used tolerance level 

residues, assumed 100 percent crop treated, included empirical or default processing factors, 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 tolerances 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 tomatoes. 

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 tolerances 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 the 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 harmonization 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, and a discussion of label recommendations is not pertinent.

3.0 Introduction

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 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 and tomatoes.

3.1 Chemical Identity

Table 3.1. Triforine Nomenclature 

Chemical Structure

N

N

N

H

N

H

H

O

H

O

Cl3C

Cl3C
Triforine Human Health Risk Assessment D398041

Page 7 of 29

Table 3.1. Triforine 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 readily 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 the 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

The 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 found 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 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) and 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 and Dose-Response Assessment

4.1 Summary of Toxicological Effects

The principal toxic effects of triforine are changes in the liver and hematopoietic system 

following repeated oral dosing, and the dog is 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 production of red blood cells. This effect is characterized by decreased 

hematocrit/hemoglobin with hemosiderin deposition in several organs, no evidence of bonemarrow 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 oral, 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 consumption 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 neuropathological 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) 

following long-term exposure to mice at the limit dose. There 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 system. Radiolabeled test material was found in 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 excretion, mainly to trichloroethanol, which is excreted in urine as its glucuronic acid 

conjugate.

No dermal absorption 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 Factor for Infants and Children (FQPA Safety Factor)

The FQPA 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 of 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 HASPOC determined that the 

acute neurotoxicity study may be waived. 

4.2.2 Evidence of Neurotoxicity

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 carcinogenicity 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 effects 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 developmental neurotoxicity.

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or 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 study 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 Database

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 Departure Selections

4.3.1 Dose-Response Assessment

A detailed description of the toxicity studies used for selecting toxicity endpoints and points of 

departure for various exposure scenarios is presented in Appendix A.

No hazard or appropriate acute endpoint attributable to a single exposure was identified from the 

available oral toxicity database; 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 chronic 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, short-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, 

hemoglobin values and siderosis in the liver, spleen, and bone marrow were observed. 

Inhalation hazard is assumed to be equivalent to oral hazard. 

There was no potential hazard via the dermal route because of the lack of systemic toxicity 

following 21 days 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 “Suggestive Evidence 

of Carcinogenicity” based on tumors seen in both sexes of one species (mouse) only at the limit 

dose (liver tumors in male mice and lung tumors in female mice). There 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 NonOccupational 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

UFA 10x

UFH 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

UFA 10x

UFH 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.

Incidental Oral 

IntermediateTerm (1-6 

months)

NOAEL = 

22 

mg/kg/day

UFA 10x

UFH 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 developmental or 

reproductive concern at dose levels that do not exceed the limit dose.

Inhalation 

Short- Term 

(1-30 days)

NOAEL = 

22 

mg/kg/day

UFA 10x

UFH 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.
Triforine Human Health Risk Assessment D398041

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Table 4.3.4.1 Summary of Toxicological Doses and Endpoints for Triforine for Use in Dietary and NonOccupational 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 

IntermediateTerm (1-6 

months)

NOAEL = 

22 

mg/kg/day

UFA 10x

UFH 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.

Cancer (oral, 

dermal, 

inhalation)

Classification: Suggestive Evidence of Carcinogenicity; 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.

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). 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 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 developmental or 

reproductive concern at dose levels that do not exceed the limit dose.

Inhalation (All 

durations

NOAEL=22 

mg/kg/day

UFA=10x

UFH=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 

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.

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). MOE = margin of exposure. LOC = level of concern. 
Triforine Human Health Risk Assessment D398041

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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 plants 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 storage 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 before 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 residues 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 water assessment (D339605, K. Moore, 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 assessment. 

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

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

Model output 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 chronic 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 Assessment

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 residues 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 

commodity, 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 tomato 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 highly conservative chronic aggregate dietary (food and drinking water) exposure and risk 

assessment was conducted using the Dietary Exposure 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 population subgroups. Detailed 

results are shown in Table 5.4.6.
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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 quantitative 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. Summary 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 registered 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, rust, 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. Residential handlers are addressed 
Triforine Human Health Risk Assessment D398041

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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 residential handler 

assessment includes only inhalation exposure. The quantitative exposure/risk assessment 

developed for residential handlers is based on the following scenarios: 

(1) Mixing/loading/applying liquid concentrates with hose-end sprayer;

(2) Mixing/loading/applying liquid concentrates with a manually pressurized handwand 

sprayer;

(3) Mixing/loading/applying liquid concentrates with garden backpack sprayer 

(4) Mixing/loading/applying liquid concentrates with sprinkler can

(5) Applying with aerosol can, and

(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 0.0021 lbs ai/gallon, unit exposure values and estimates for area treated or amount handled 

based on HED’s 2012 Residential SOPs, a body weight of 80 kg, that toxicity by the inhalation 

route is considered to be equivalent to toxicity by the oral route of exposure, 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 

Rate1

Area Treated or 

Amount 

Handled Daily2

Inhalation

Dose

(mg/kg/day)3

MOEs

4

(no respiratory 

protection)

Mixer/Loader/Applicator

Manuallypressurized 

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 0.0021 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 

general 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 addressed in postapplication 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 ornamental 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-application 

inhalation exposure (also described in Agency’s SOPs). Therefore, there is no concern for postapplication 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 registered 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 residential 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 postapplication 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, 20101. 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 

revisit 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 handlers (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-application inhalation exposure scenarios.

 

1 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
Triforine Human Health Risk Assessment D398041

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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 applications, but, to a lesser extent, could also be a 

potential source of exposure from ground application methods 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 drift 

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 registrants, 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 Short-Term Aggregate Risk

HED conducted short-term aggregate risk assessments for adult males and adult females. There 

are no residential exposure scenarios for children; therefore aggregate 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 residential 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

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Table 7.2 Short-Term Aggregate Risk Calculations

Population

Short -Term Scenario

NOAEL 

mg/kg/day LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day

Residential 

Exposure 

mg/kg/day3

Total 

Exposure 

mg/kg/day4

Aggregate 

MOE (food, 

water, and 

residential)5

Adult Male 22 100 0.22 0.000410 0.000066 0.000476 46,000

Adult Female 0.000410 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.

3Residential Exposure = (Oral exposure + Dermal exposure + 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 limited to inhalation 

exposure. Residue values taken from Table 6.1. 

4 Total Exposure = (Avg Food & Water Exposure + Residential 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 Cumulative 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 toxicity finding as 

to triforine and any other 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 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 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

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9.0 Occupational Exposure/Risk Characterization

This petition is limited to tolerances without U.S. registration 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: D393943

Title: Triforine. Petition for the Establishment of Permanent Tolerances without U.S. 

Registration for Blueberries and Tomatoes. Summary 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 Assessment to Support Request for Tolerances without U.S. Registration for 

Blueberry and Tomato.

Author: Matthew Lloyd

Date: 1/22/13

DP Number: D408358

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

Proposed Import Tolerance Use on Blueberries and Tomatoes
Triforine Human Health Risk Assessment D398041

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Appendix 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 ........................................................

870.7800 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

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A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile - Triforine

Guideline 

No. Guideline No.

Guideline 

No. Guideline No.

Guideline 

No.

870.1100 Acute oral [rat] 42172701 LD50 > 5000 mg/kg IV

870.1200 Acute dermal [rabbit] 42172702 LD50 = >2000 mg/kg III

870.1300 Acute inhalation [rat] 42172703 LC50 = > 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 noted

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 

siderosis 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 [SpragueDawley 

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

Maternal toxicity NOAEL >150 mg/kg/day [HDT]

Maternal toxicity LOAEL = see below

Developmental 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

Maternal toxicity NOAEL 500 mg/kg/day [HDT]

Maternal toxicity LOAEL = 1000 mg/kg/day, 

based on decreased body-weight gain and food 

consumption

Developmental 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

When 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 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 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/carcinomas [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 extremities, 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 adenomas, 

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

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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)

3H (not specifically 

labeled, but mostly in ring)

Oral dosing; 94% of 3H excreted after 48 hours; 96% 

of 3H 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)

14C (side chain) labeled compound

excreted similarly to 3H tritiated compound but 

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

metabolite is triforine from which one side chain has 

been removed; other metabolite is designated as 

Aside 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 identical 

side-chains. The cleaved side-chain is further 

metabolized prior to excretion, mainly to 

trichloroethanol, which is excreted in urine as 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, column- 0.26

Vapor pressure (25°C) 8.0 x 10-2Pa 

(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, logPOW

(25°C)

1.6 x 102, log Pow= 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) database; 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 Studies 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/science/handler-exposure-data.html and 

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