UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

DATE: September 17, 2015 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: Triticonazole. Human Health Assessment Scoping Document in Support of 

Registration Review. 

PC Code: 125620 DJ> Barcode: 0425626 

Decision No.: 499940 Registration No.: NA 

Petition No.: 1\A Regulatory Action: Registration Review 

Risk Assessment Type: Single Chemical/Aggregate Case No.: 7036-2 

TXR No.: NA CAS No.: 131983-72-7 

MRID No.: NA ~0 CFR: § 180.583 

FROM: Nancy Keller, Chemist 6 ~ ;~ 

Nancy 

Risk 

Vincent 

Assessment 

Dodd, 

Chen, 

Chem

Toxicologis

Branch 

st~ 

3 

t 

(i(AB3) 

~ 

~ 

Health Effects Division (7509P) 

THROUGH: Christine Olinger, Branch Chief /JiJ / c.// ..... Risk 

Health 

Assessment 

Effects Division 

Branch 

(7509

3 (RAB3

P) 

(){ ~ 

TO: Miguel Zavala. Chemical Review Manager 

Risk Management and Implementation Branch 3 

Pesticide Reevaluation Division (7508P) 

As part of Registration Review, the Pesticide Reevaluation Division (PRD) has requested that the 

Health Effects Division (HED) provide a human health risk assessment scoping document for the 

fungicide triticonazole to support Registration Review. To evaluate the scope of work necessary 

to support Registration Review, HED has considered recent risk assessments for triticonazole, 

updates to its toxicity. exposure, and usage databases, and the latest Agency science policy and 

risk assessment methodologies. The most recent risk assessment for triticonazole was conducted 

in 2013 for a new use on greenhouse/outdoor ornamentals, and a fully updated residential risk 

assessment of all existing residential uses, including lawns/turf, gardens, and trees, was included 

(0402683, N. Tsaur, 05/30/2013). 

Page I of26 
Executive Summa ry 

Triticonazole is a fungicide in the triazole chemical family that acts by inhibiting the synthesis of 

ergosterol (specifically C-1 4 demethylation). otherwise known as a sterol demethylation 

inhibition (OMI). 

Triticonazole is currently registered and formulated for use as a seed treatment for the cereal 

grain crop groups ( 15 and 16). and for use on golf courses. sod fam1s. outdoor and greenhouse 

ornamentals. residential ntrf, residential ornamentals. and indoor houseplants. 

The toxicology database for triticonazole is complete and adequate for risk assessment of the 

currently registered uses. Based on a weight of evidence approach considering all the available 

hazard and exposure information. liED granted a waiver for the subchronic inhalation toxicity 

study (TXR0056649. K. Rury. 05/06/20 13). At the time of Registration Review or the next risk 

assessment. the Agency may update PODs and toxicological endpoints since they are considered 

conservative based on updated policies for endpoint selection. Additionally, the uncertainty 

fac tors will be reassessed in the context of the updated PODs and endpoints. 

The li ver was the main target organ of toxicity. In the rat. mouse. and dog repeat dose oral 

toxicity studies. the adverse effects were manifested by fatty vacuolation in the li ver and adrenal 

glands: li ver effects were also observed in other triazole pesticides. Triticonazole is classified as 

.. not likely to be carcinogenic to humans·· based on the lack of evidence of carcinogenicity in 

both the rat and the mouse studies. The 1 OX rood Quality Protection Act (FQPA) Safety Factor 

was reduced to I X because there are no residual uncertainties for pre- and post-natal toxicity and 

there are no residual uncertainties in the exposure database. 

The residue chemistry database is sufficient to support the current registrations of triticonazole. 

The nature of the residue in cereal grains and livestock has been adequately defined. Adequate 

field trial/processing data. rotational crop data. storage stability data, and enforcement methods 

are available. 

ew dietary exposure and aggregate risk assessments are not anticipated during Registration 

Review. unless there are significant increases to the drinking water exposure estimates that need 

to be incorporated. An updated triazole risk assessment is also not anticipated. 

~ew residential handler and post-application exposure and risk assessments are not anticipated to 

be needed during Registration Review since they have already been updated previously with 

updated SOPs. However. occupational handler and post-application exposure and risk 

assessments are needed during Registration Review to account for recent changes in exposure 

assessment assumptions. including body weight. amount treated. and transfer coefficients. 

The Agency will examine the need for spray drift and volatilization assessments during 

Registration Review for triticonazole based on the potential for exposure to bystanders from 

agricultural applications. However, it is likely that the existi ng residential turf usc will protect 

for any potential spray drift applications. 

Page 2 of26 
Introduction 

Triticonazole is a fu ngicide in the triazolc chemical family that blocks growth by disrupting cell 

membrane formation through inhibition of ergosterol biosynthesis in fungi. It is currently 

registered and fonnulated for use as a seed treatment for the cereal grain crop groups ( 15 and 

I 6). and for use on golf courses. sod tarms, outdoor and greenhouse ornamentals. residential turf, 

residential ornamentals. and indoor houseplants. 

The most recent human health risk assessment for triticonazole was finalized in 2013 for new 

uses on outdoor and greenhouse ornamentals (0402683, N. Tsaur, 05/30/2013). Triticonazole is 

currently registered and formulated for usc as a seed treatment tor the cereal grain crop groups 

( 15 and 16), and for use on golf courses, sod farms, outdoor and greenhouse ornamentals, 

residential turf, residential ornamentaJs. and indoor houseplants. Homeowners may apply 

triticonazole to residential turf and ornamental plants. Triticonazole end use products are 

forn1Ulated as soluble concentrates (SC), water dispersible granules (WG), granules (G), and 

liquids for seed treatment ( L). Applications can be made with ground. aerial. chemigation, and 

handheld spray equipment. as well as commercial seed treatment equipment. Refer to 

At1achment I for the chemical identity oftriticonazolc. 

Hazard Idcntificationffoxicology 

Triticonazole, a triazole fungicide, blocks growth by disrupting cell membrane formation 

through inhibition of ergosterol biosynthesis in fungi. There are no mammalian molecular data 

to specifically demonstrate this mode of action in test animals. 

The toxicology daLabase for triticonazolc is complete and adequate for risk assessment of the 

cwTently registered uses. The studies available for risk assessment include an acute toxicity · 

battery: subchronic oral toxicity studies in rats: a subchronic dermal toxicity study in rats; 

chronic toxicity studies in mice. rats. and dogs; carcinogenicity studies in rats and mice; prenatal 

developmental toxicity studies in rats and rabbits: a reproduction and fertility effects study in 

rats; a banery of mutagenicity studies; metabolism and pharmacokinctic studies in rats; acute and 

subchronic neurotoxicity studies in rats: a dermal penetration study in rats: and an 

immunotoxicity study in rats. A detailed description of all of the available studies can be found 

in Attachment 6. 

The available absorption, distribution, metabolism, and elimination (ADME) study in rats · 

indicated that orally-administered radiolabeled triticonazole is rapidly absorbed, widely 

distributed, partially metabolized. and clears the body quickly. There was no evidence of 

bioaccumulation. 

In the rat, mouse, and dog repeat dose oral toxiciry studies. the adverse effects were manifested 

by fatty vacuolation in the liver and adrenal glands: liver effects were also observed in other 

triazolc pesticides. Increased motor activity was observed at the limit dose in an acute 

neurotoxicity study. but there were no indications of neurotoxicity in the subchronic study. 

There was no indication of increased immunotoxic potential in the T-cell dependent antibody 

response (TOAR) assay. 

Page 3 of26 
The database contains prenatal developmental toxicity studies in rats and rabbits and a 

reproduction and fertility study in rats. In the rat prenatal developmental toxicity study. there 

was no evidence for increased susceptibility: developmental efTects (e.g. supernume rary ribs) 

occurred at the same dose as the dose that caused maternal toxicity (i.e. decreased body weight). 

In the rabbit prenatal developmental toxicity study. there were no indications of increased 

susceptibility in utero. In the rat reproduction and fertility study. there was no evidence of 

increased susceptibility: offspring toxicity (i.e. decreased pup survival and decreased pup body 

weights) occurred at the same dose as parental toxicity (i.e. mortality. microscopic lesions in 

adrenals. and decreased body weight). and reproducti ve toxicity (i.e. decreased fertility). 

Overall. there is no residual uncertainty for pre/post-natal toxicity; there is no concern for 

increased susceptibility in the prenatal developmental toxicity studies in rats and rabbits and 

reproduction and ferti lity study in rats. The developmental neurotoxicity (DNT) study was 

waived. The I OX Food Quality Protection Act (FQPA) Safety Factor was reduced to 1 X because 

there are no residual uncertainties for pre- and post-natal toxicity and there are no residual 

uncertainties in the exposure database. 

Tritieonazole has been classified as "not li kely to be carcinogenic in humans'· based on the 

results of a carcinogenicity study in mice and the combined chronic toxicity and carcinogenicity 

study in rats (TXR0054249. J. Kidwell. 06/ 15/2006); the mutagenicity studies do not indicate 

increased mutagenic potential in the bat1ery of in dtro and in vivo assays. 

The subchronic inhalation toxicity study has been waived because the inhalation margin of 

exposure (MOE) is greater than the Agency"s level of concern for inhalation waivers(> 1 000) 

(TXR0056649. K. Rury. 05/06/20 13). 

Triticonazole has low toxicity via the oral (Toxicity Category IIJ). dermal (Toxicity Category 

Ill). and inhalation (Toxicity Category IV) routes: is not an eye irritant (Toxicity Category IV) or 

a dermal irritant (Toxicity Category IV): and is not a dermal sensitizer. 

Please refer to Attachment 4 for a summary of the toxicity endpoints and points of departure 

(PODs) and Attachment 6 for the complete toxicity profile table. 

Conclusions: The toxicology database for triticonazole is adequate fo r risk assessment of the 

current uses. At the time of Registration Review or the next risk assessment. the Agency may 

update PODs and toxicological endpoints since they arc considered conservative based on 

updated policies for endpoint selection. Additionally. the uncertainty factors will be reassessed in 

the context of the updated PODs and endpoints. 

Page 4 of26 
Dietary Exposure 

The nature of the residue in plants and livestock commodities has been adequately defined. 

Adequate metabolism studies on barley, wheat, dairy cattle, and laying hens are available to 

support the registered uses on cereal grains. The residue of concern for cereal grains and 

livestock for the dietary risk assessment and the tolerance expression is the parent compound. 

The most recent dietary risk assessment that addresses the triazole deri vatives [I ,2,4-triazole, 

triazolylalanine. and triazolylacetic acid] includes consideration of the contribution of triazole 

deri vatives from the use of triticonazole on barley and wheat (0426492. T. Morton, 04/09/20 15). 

Adequate enforcement methods are available. An adequate liquid chromatography/mass 

spectrometry (LC/MS) and LC/tandem mass spectrometry (LC/MS/MS) method (Method 

148.02) is available for the enforcement of the proposed tolerances for triticonazole in cereal 

grain matrices. The validated limit of quantitation (LOQ) is 0.0 1 ppm tor triticonazo le inion all 

cereal grain crop matrices. A livestock enforcement method is not needed since no livestock 

tolerances are established. 

The data requirements for testing with multiresidue methods have been fulfilled. Based on the 

results of the testing. the multiresidue methods are not appropriate for determining tritieonazole 

residues. 

Adequate field trial, processing, and storage stability data are available to support the established 

tolerances. 

Adequate rotational crop data are available. A contined rotational crop study indicated that it is 

unlikely that quantifiable residues oftriticonazole (>0.0 1 ppm) will be found in rotated crop 

commodities at plant-back intervals of30 days or greater when triticonazole is used as a seed 

treatment at the registered label rates. Based on the confined rotational crop study, a field 

acc umulation in rotational crops study is not required and rotational crop tolerances are not 

needed. 

The registered uses fall under 40 CFR § 180.6(a)(3) for livestock commodities, i.e. although it is 

not possible to establish with certainty whether tinite residues will be incurred. there is no 

reasonable expectation of finite residues in livestock commodities. This conclusion is based on 

dairy cattle and laying hen metabolism studies and low calculated dietary burdens. 

Acute and chronic dietary (food and dri nking water) exposure risk assessments were conducted 

in 2013. The acute and chronic analyses were both unrefined, using tolerance-level residues. 

I 00% crop treated (CT), and conservati ve estimated drinking water concentrations (EDWCs) tor 

ground water sources provided by the Environmental Fate and Effects Division (EFED). 

For the acute dietary analysis, the incorporated EDWC value of 520 ppb giL) is the primary 

risk driver. The EDWC value was generated by the Pesticide Root Zone Model for Ground 

Water (PRZM-GW). The acute dietary risk assessment shows that for all included commodities, 

Page 5 of 26 
the acute dietary risk estimates at the 95111 percentile arc not of concern to l-I ED (i.e. <1 00% of 

the acute population-adj usted dose (aPAD)). 

For the chronic dietary analysis, the incorporated EDWC value of 163 ppb (from PRZM-G W) is 

the primary risk driver. The non-cancer chronic dietary risk assessment shows that for all 

included commodities. the chronic dietary risk estimates are not of concern to HED [i.e. < I 00% 

o f the chronic population-adjusted dose (cPAD)l. 

Triticonazole is classified as ··not likely to be carcinogenic to humans:·· therefore. cancer risk 

was not assessed. 

Conclusions: A new dietary exposure assessment is not anticipated to be needed during 

Registration Review unless there are significant increases to the drinking water exposure 

estimates. 

Residential Exposure 

Triticonazole is currently registered for use in residential settings on turf and ornamental plants. 

There is potential for short-term residential exposure to triticonazole during handling (mixing, 

loading. and applying) and post-application activities. 

Residential Handlers 

Various triticonazolc labels of varying formulations indicate that triticonazole is registered for 

usc on residential turf and ornamentals. Previous residential exposure and risk assessments for 

triticonazole were conducted at the maximum registered application rate and incorporated the 

revised 20 12 Residential SOPs (D409743. N. Tsaur. 03/07/2013). Applications can be made to 

turf and ornamentals via handheld spray equipment for liquids and via hand for granules. 

Residential handler (inhalation only) margins of exposure (MOEs) ranged from II 0.000 to 

6.600.000.000. and are not of concern. Dermal risk estimates were not conducted because a 

dermal hazard was not identified for triticonazole. 

Residential Post-Application 

Short-term incidental oral exposure and risk estimates were previously reassessed using the 2012 

Residential SOPs (0409743. N. Tsaur. 03/07/20 13). Dermal risk estimates for adults and 

children were not conducted because a dermal ha7_ard was not identified for triticonazole. Postapplication MOEs were not of concern for any of the registered residential uses oftriticonazole. 

The short-term incidental oral MOEs for children I to <2 years old range from 1.400 to 

1.300.000. 

Spray Drift or Volatilization 

Residential bystander exposures resulting from off-site transport (e.g. spray drift or 

volatilization) may occur as a result of applications of triticonazole. The potential for spray drift 

will be evaluated for each pesticide during the Registration Review process which ensures that 

all uses for that pesticide will be considered concurrently. The approach is outlined in the 

revised (2012) Standard Operating Procedures for Residential Risk Assessment (SOPs) -

Residential Exposure Assessment Standard Operating Procedures Addenda I: Consideration of 

Page 6 of26 
Spray Drift. This document outlines the quantification of indirect non-occupational exposure to 

drift. In terms of volatilization. the agency has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(h ttp://\v"\-\W.rC!.!ulations.gov/#!docketDetail:D=EP 1\-IIQ-OPP-20 14-0219). During Registration 

Review. the agency will utilize this analysis to determine if data (i.e. flux studies. route-specific 

inhalation toxicological studies) or further analysis is required for triticonazole. 

Conclusions: There are registered residential uses of triticonazole that have been assessed using 

the maximum application rates and revised 20 12 Residential SOPs. Therefore. a residential 

handler and post-application assessment is not required during Registration Review. The 

Agency will examine the need for a volatilization assessment, as well as evaluate the potential 

triticonazole exposure from spray drift during Registration Review. However, it is likely that the 

existing residential turf usc will protect for any potential spray drift applications. 

Aggregate Risk Assessment 

Aggregate assessments consider exposures from food, drinking water, and residential uses. 

Since there are residential uses of triticonazole. aggregate risk considers residential handler and 

post-application exposures. food. and drinking water. 

In the most recent human health risk assessment (0402683, N. Tsaur, 05/30/2013), an acute 

aggregate risk assessment, which is equivalent to the acute dietary risk assessment, was not of 

concern to H ED. Only females 13-49 years old were assessed, since an acute endpoint of 

concern was not identified for the general population. 

A shon-tem1 aggregate risk assessment was conducted for adults and children. for adults, the 

pathways leading to aggregate exposure include oral dietary (background) and inhalation 

(primary) routes. For children, the pathways leading to aggregate exposure include oral dietary 

(background) and incidental oral (primary) routes. The adult and children short-term aggregate 

dietary and residential MOEs are I 00.000 and 1.400. respectively (LOC = I 00). 

Chronic exposure from the residential pathway is not anticipated based on the current 

triticonazole use pattern. Therefore. the chronic aggregate risk (food and drinking water) is 

equivalent to the chronic dietary (food and drinking water) exposure estimate, which was not of 

concern to HED. 

Conclusions: Aggregate exposure to triticonazole is currently not of concern to HED. New 

aggregate assessments arc not anticipated to be needed during Registration Review, unless 

changes in uses. procedures. or estimated drinking water concentrations occur. 

Page 7 of26 
Occupationa l Exposure 

T riticonazole is registered for use as a seed treatment on cereal grains (crop groups 15 and 16): 

industrial/commercial turf grass (including golf course turf, sod farms. seed farms. college and 

professional sports fields. and residential and commercial lawns): and on ornamentals in 

greenhouses and fields. There is potential for short- and intermediate-term occupational 

exposure to triticonazole during handling (mixing. loading, and applying) and post-application 

activities. 

Occupational Handlers 

The registered triticonazole labels require occupational handlers to wear long sleeved shirts. long 

pants, shoes. socks. and chemical resistant gloves. Applications can be made using ground. 

aerial. chemigation. and handheld spray equipment. as well as commercial seed treatment 

equipment. Although some of the updated occupational exposure assessment policies and body 

weight assumptions were incorporated into previous triticonazolc exposure assessments. updated 

occupational handler and post-application assessments will be needed for some occupational 

scenarios. All current occupational handler MOEs are not of concern (MOE > I 00). 

Occupational Post-Application 

A dermal endpoint was not identified for triticonazole: therefore. an assessment of occupational 

defiT!al post-application exposure to triticonazole was not conducted. Based on the Agency's 

current practices. a quantitative post-application inhalation exposure assessment was not 

performed for triticonazole at this time. If nevl policies or procedures are put into place. the 

Agency may revisit the need for a quantitative occupational post-application inhalation exposure 

assessment for triticonazolc. 

Conclusions: There is sufficient information available to assess occupational handler and postapplication exposures. Updated occupational handler and post-application exposure assessments 

will be conducted during Registration Review for the fu ll registered use profile of triticonazole. 

Page 8 of26 
Public Health a nd Pesticide Epidemiology Data 

OPP 

Based on the low frequency and severity of incident cases reponed for triticonazolc in both the 

Incident Data System (IDS) and the Centers for Disease Control and Prevention/National 

Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System 

for Occupational Risk-Pesticides (SENSOR), there does not appear to be a concern at this time 

that would warrant further investigation. For the Main IDS, from January I, 20 I 0 to February 4. 

2015. there were no incidents reponed involving triticonazole. In Aggregate IDS, from January 

I. 2010 to February 4, 20 15, there were three incidents reponed invol ving triticonazole. These 

incidents were classified as minor severity. Overall. there are few incidents reponed to IDS 

involving triticonazole. 

A query of the Sentinel Event Notification System for Occupational Risk (SENSOR)-Pesticides 

database for 1998-2010 identified no cases involving triticonazole. 

The Agricultural Health Study (AI-IS) is a high quality, prospective epidemiology study 

evaluating the link between pesticide use and various health outcomes including cancer. The 

AI-IS includes private and commercial pesticide applicators and their spouses. If there are AHS 

findings relevant to a particular pesticide going through registration review, the Agency will 

ensure they are considered in the problem formulation!scoping phase of the process and. if 

appropriate, fully reviewed in the risk assessment phase of the process. The AI-IS includes 

information on use of 50 di ITerent pesticide active ingredients commonly used in agriculture. 

Triticonazole is not included in the Ai lS. and therefore. this study does not provide information 

for this report. 

The Agency will continue to monitor the incident information and if a concern is triggered. 

add itional analysis will be included in the risk assessment. 

Conclusions: Based on the low frequency and low severity of incident cases reported for 

triticonazole in both IDS and SENSOR-Pesticides databases. there does not appear to be a 

concern at this time that would warrant further investigation. The Agency will continue to 

monitor the incident information and if a concern is triggered, additional analysis will be 

included in the risk assessment. 

Page 9 of26 
Tolerance Assessment and International Harmonization 

Tolerances are established for plant commodities under 40 CfR § 180.583(a) for residues of the 

fungicide triticonazole, (I RS)-(E)-5-[( 4-chlorophenyl)methylene ]-2.2-dimethyl-1-( 1 H-1.2.4-

triazol-1-ylmethyl)cyclopentanol. on cereal grains (grains. forage. fodder. and straw) from the 

treatment of seed prior to planting. The crop group tolerances are established for .. grain. cereal. 

forage. fodder, and straw. group 16. except rice .. at 0.10 ppm and for grain. cereal. group 15. 

except rice .. at 0.0 1 ppm. No tolerances are established on livestock commodities. No 

tolerances are established for Section 18s. regional registrations. or indirect/inadvertent residues. 

The tolerance expression in 40 CfR § 180.583 should be modified to add a compliance statement 

as fo llows: 

"Tolerances are established for residues of the fungicide triticonazole. including its metabolites 

and degradates, from the treatment of seed prior to planting. in or on the commodities in the table 

below. Compliance with the tolerance levels specified below is to be determined by measuring 

only (5£)-5-[( 4-chlorophenyl)methylene ]-2.2-dimethyl-1 -( I H-1.2.4-triazol-1-

ylrnethyl)cyclopentanol.·· 

As shown in Attachment 3. there are no Codex ma.ximum residue limits (MRLs) established for 

triticonazole: therefore. there is no harmonization issue with Codex at this time. 

Environmental Justice 

Potential areas of environmental justice concerns, to the extent possible. "viii be considered in the 

registration review. in accordance with US Executive Order 12898. "Federal Actions to Address 

Environmental Justice in Minority Populations and Low-Income Populations." 

http://www.eh.doc.gov/oepa/guidance/justicc/eo 12898.pdt). As a part of every pesticide risk 

assessment. OPP considers a large variety of consumer subgroups accordi ng 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 under the 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 and ethnic group. Additionally. OPP is 

able to assess dietary exposure to smaller. specialized subgroups and exposure assessments arc 

performed when conditions or circumstances warrant. Whenever appropriate. non-dietary 

exposures based on home usc 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. 

Page 10 of26 
Cumulative 

Triticonazole is a member of the triazole-containing class of pesticides. Although conazoles act 

similarly in plants (fungi) by inhibiting ergosterol biosynthesis, there is not necessarily a 

relationship between their pesticidal activity and their mechanism of toxicity in mammals. 

Structural similarities do not constitute a common mechanism of toxicity. Evidence is needed to 

establish that the chemicals operate by the same. or essentially the same, sequence of major 

biochemical events. In conazoles. however. a variable pattem of toxicological responses is 

found. Some are hepatotoxic and hepatocarcinogenic in mice; some induce thyroid tumors in 

rats: and some induce developmental. reproductive, and neurological effects in rodents. 

Furthermore. the conazolcs produce a diverse range of biochemical events including altered 

cholesterol levels. stress responses, and altered DNA methylation. It is not clearly understood 

whether these biochemical events are directly connected to their toxicological outcomes. Thus. 

there is currently no evidence to indicate that conazoles share common mechanisms of toxicity 

and EPA is not fol lowing a cumulative risk approach based on a common mechanism of toxicity 

for the conazoles. For infom1ation regarding EPA· s procedures for cumulating efTects from 

substances found to have a common mechanism of toxicity. sec EPA·s website at 

http://www.epa.gov/pesticidcs/cumulative. 

Triticonazole and other triazole-containing pesticides can form the common metabolite I ,2,4-

triazole and two triazole conjugates (triazolylalanine and triazolylacetic acid). To support 

existing tolerances and to establish new tolerances tor triazole-derivative pesticides, including 

triticonazole. U.S. EPA conducted a human health risk assessment for exposure to I ,2.4-triazole. 

triazolylalanine, and triazolylacetic acid resulting from the use of all current and pending uses of 

any triazolc-derived fungicide. The risk assessment is a highly conservative, screening-level 

evaluation in tem1s ofhazards associated with common metabolites (e.g., use of a maximum . 

combination of uncertainty factors) and potential dietary and non-dietary exposures (i.e .. high 

end estimates of both dietary and non-dietary exposures). In addition, the Agency retained the 

additional I OX FQPA safety factor for the protection of infants and children. The assessment 

includes eval uations of risks for various subgroups, including those comprised of infants and 

children. The Agency's complete risk assessment is found in the propiconazole reregistration 

docket at hnp://wv,rw.regulations.gov, Docket Identification (ID) Number EPA-HQ-OPP-2005-

0497. 

The registered uses of triticonazole do not result in increases in dietary exposure estimates for 

free triazolc or conjugated triazoles and thus, no updated risk assessments are needed for the 

triazolc derivatives (0426492. T. Morton, 04/09/20 15). 

Human Studies 

The risk assessments which have been previously conducted for triticonazole relied in part on 

data from studies in which adult human subjects were intentionally exposed to a pesticide to 

detenninc their dermal and inhalation exposure. Many such studies. involving exposure to many 

different pesticides. comprise generic pesticide exposure databases such as the Pesticide 

Handl ers Exposure Database (PHED), the Outdoor Residenti al Exposure Task Force (ORETF). 

the Agricultural Reentry Task Force (ARTF) Database; and ExpoSAC Policy 14. 15. and 15.1 

(SOPs for Seed Treatment). EPA has reviewed all the studies supporting these multi-pesticide 

Page II of26 
generic exposure databases. and has found no clear and convincing evidence that the conduct of 

any of them was either fundamentally unethi cal or significantly deficient relative to the e thical 

standards prevailing at the time the research was conducted. All applicable requirements of 

EPA·s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been 

satisfied. and there is no regulatory barrier to continued reliance on these studies. 

tta Deficiencies 

No toxicologicaL residue chemistry. or occupational and residential exposure data are needed to 

support the registered uses of triticonazolc at this time. 

Page 12 of26 
References 

Recent Memoranda Relevant to Registration Review ofTriticonazole 

Author DP!fXR # Date Title 

Risk Assessment 

W. Wassell D27327S 09/04/2002 PP#9F06051; HED Risk Assessment: Human Health Risk 

Assessment for First Food Usc ofTriticonazole for Seed Treatment 

Uses on Wheat and Barley. 

M. Doherty D322215 02/07/2006 1.2.4-Triazole, Triazole Alanine. Triazole Acetic Acid: Human 

Health Aggregate Risk Assessment in Support of Reregisrration 

and Registration Actions for Triazole-derivative Fungicide 

1 Comp_ounds. 

S. Winfield 031661 2/ 12/20/2006 Triticonazole: liED Human Health Risk Assessment for Proposed 

0313844 Use on Turf. PC Code: 125620. Reg Nos. 264-ANR, 432-REAI. 

DP Numbers 316612 and 3138-l.t. 

N. Tsaur D35861.t 08/07/2009 Triticonazole. Human Health Risk Assessment for Proposed Seed 

Treatment Use on Cereal Gntins (Crop Group 15) Including Barley, 

Field Corn. Oats. Popcorn. Rye. Sorghum Grain. Sweet Com. 

Triticale. and Wheat (Excluding Rice): and forage. Fodder, and 

Straw of Cereal Grains (Crop Group 16), Excluding Rice. 

N. Tsaur D372454 08/30/2010 Triticonazole. Human Health Risk Assessment for Proposed 

Residential Handler Use on Turf. Omantcntals. and Indoor 

Houseplants. 

N. Tsaur 0402683 05130!20 13 Triticonazole. Aggregate Human Health Risk Assessment for 

Proposed Use on Ornamentals (Outdoor nnd Greenhouse) with 

Updated Residential Risk Estimates of All Existing Residential 

Uses (Lawns/Turf: Gardens and Trees). 

Residue Chemistry 

N. Dodd 0262566 06/06/2001 PP#9f06051. Triticonazolc Seed Treatment on Barley and Wheat. 

Review of Analytical Methods and Residue Data. First Food Usc 

Review. 

N. Dodd 0281088 05111 /2002 PP#9F06051. Triticonazole Seed Treatment on Barley and Wheat. 

harter ~'' brand PB Fungicide Label. Revised ChartcrT'' brand 

Triticonazole Fun~icide label. 

A. Acierto 0325956 06/ 12/2009 Triticonazole. Application for New Seed Treatment Uses on Cereal 

Grains (Except Rice) (PP#8F7420). Summary of Analytical 

. Chemist!) and Residue Data. 

S. Funk D370705 10/30/2009 Triticonazole. Application for New Seed Treannent Uses on Cereal 

Grains (Except Rice) (PP#8F7420). Amendment to Label and 

Request for Removal of Plant Back Interval Restrictions 

Requ iremcnt. 

D. Drew 0363016 06/ 12/2012 Storage Stability of 1 ,2.4-Triazole. Triazolylalanine and 

Triazolylacetic Acid in Various Crop Matrices and Processed 

Commodities (up to four years under frozen storage). 

Dietarv Exposure Assessment 

N. Tsaur 0409744 04/ 10/2013 Triticonazole. Acute and Chronic Aggregate Dietary (Food and 

Drinking Water) Exposure and Risk Assessment for the Section 3 

Registration Action to Add New Uses on Outdoor and Greenhouse 

Ornamentals. 

Occupational and Residential Exposure Assessment 

N. Tsaur 0409743 03/07/2013 Triticonazole. Occupational and Residential Exposure Assessment 

for a Proposed Usc on Oman1entals with An Upd<I!Cd Residential 

Exposure Assessment of All Existing Residential Uses 

(Lawnsfrurf: Gardens and Trees). 

Page 13 of26 
Recent Memoranda Relevant to Registration Review ofTriticonazole 

Author I DPffXR # I Date I Title 

Incident Report 

S. Recore l 0428796 I 04t0112015 I Triticonazole: Tier I Review of Human Incidents 

Attachments 

I. Chemical Identity Table 

2. Physicochemical Properties ofTeclmical Grade Triticonazole Table 

3. Tolerance/MRL Summary Table 

4. Endpoint Selection Tables 

5. Toxicology Data Requirements 

6. Toxicity Profile Tables 

Page 14 of26 
Attnchmcnt I 

Chemical Identity Table 

Triticonazole Nomenclature 

Chemical structure 

~~I N 

0 11 

H3

C 

H3

C :;:;.----

I 

~ 

hCl 

Common name Triticonazole 

Company experimental name BAS 595 F (fomterl>' RPA 4000717) 

IUPAC name (RS)-(£)-5-( 4-chlorobenzylidene)-2.2-dimethyl-1-( 1//-1.2.4-triazol-1-

ylmethyl)cyclopentanol 

CAS name (5£)-5-[( 4-chlorophenyl)methylene ]-2.2-dimethyl-1-( I /-/-1 .2.4-triazol-1-

ylmethyl)cyclopentanol 

CAS regisrry number 13 1983-72-7 

Chemical structure ofT 

metabolite N~ 

I 

N~ 

1.2.-t-triazol.: 

Chemical structure ofTA 1

metabolite H ~ N~ I 

HO~N-__§N 

0 

triazole alanine or triazolylalanim: 

Chemical structure ofTAA 

metabolite 0 N~ 

N~ 

I I 

HO 

triazole acetic acid or triatnlylac.:tic acid 

Page 15 of26 
Attachment 2 

Physicochemical Properties of Technical Grade Triticooazole Table 

Physicochemical Properties of the Technical Grade Triticonazolc 

Parameter Value Reference 

Melting poim (0C} 

140 °C: PAl displays two crystalline 

fomls meltingarl37 and 14 1 oc 

pll Not available 

Density at 20 °C (glmL) 1.21 g/mL (PAl) 

Water solubility (at 20 °C) 8.4 mg/L at 20 oc 

Solvent Solubility (giL) 

Hexane 0.12 giL 

Methanol 18.2 giL 

Solvent solubility (at 2 1.2°C) Acetone 74.5 giL BASF document number 

Toluene 12.6 giL 2002110 I 6091" 

Dich loromcthanc 191 giL 

Ethyl acetate 48.6 giL 

n-Octanol 6.2 giL 

Vapor pressure at 25°C <0.1 X IQ•S PA at 50 °C 

Dissociation constant (pK.) Docs not dissociate 

Octanollwater pan it ion coefficient Log P = 3.29 at 20 °( 

UV/visible absorption spectrum Not available 

~ 

a As referenced m MRID 4747020.>. 

Page 16 of26 
Athlchment 3 

Tolcrance/MRL Tables 

nuconazo e _) - , ate o fR equest - ) 

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definirion 

' 

us Canada Mexico3 Codex 

-10 CrR *180.583 

( 5 [; )· 5-l ( -1-ch luroph.:ny l)mcthy knc J-2.2 • Triticonazolc. (I RS)-(E)-5·((4-

ch oroph.:n~ l)m..:thyl.:n.:J-2.2-dim..:th) 1-1-( I H- dim.:th) I· I·( 111-1.2.-l-tri:vol-1- None 

1.2.4-trinzol-1-vlm.:tlwl)cylop.:ntanol ylmo.:thyl)cyclopcntanol 

Commodity 

Tolerance {ppm} /Maximum Residue Limil (mglkg) 

us Canada Mexico3 Codex 

Grain. cereal, forage, fodder and 

straw. group 16. 0.10 except rice 

Grain

0.0 I barley. field com. oats. popcorn 

. cereal, group 15, except rice 0.01 grain. rye, sweet com kernels plus cob 

with husks removed. Lriticalc. wheat 

Completed: M. cgussie: 07/27/2015 

a Mcxtco adopts US tolerances and/or Codex MRLs for tiS cxpon purposes. 

Page 17 of26 
Attachment 4 

Endpoint Selection Tables 

Summa ry of T oxicological Doses and Endpoints for use in Dietary and Non-Occupationa l Huma n Health 

Risk Assessments 

Exposure Point of 

Uncertainty I RfD. PAD. Level 

FQPA Safety ofConcern for Study and Toxicological Effects 

Scena rio Departure (POD) Factors Risk Assessment 

Acute Dietary NOAEL = UF" = lOx aRfD = Acute Neurotoxicitv Studv - Rat 

General 400 mglkg UFu = lOx 4 mglkglday LOAEL = 2000 mg/kg 

population FQPA SF = IX Based on increased motor activity 

(including infants aPAD = in both sexes. 

and children) 4 mglkg/day 

Acute Dietary Developmental UF,, - lOx aRfD - Prenatal DeveloRmental Toxicitv 

Females ( 13-49 NOAEL = UFH = lOx 0.5 rngfkg/day - Rabbit 

years old) 50 rng!kg/day FQPA SF = IX Developmental LOAEL = 75 

aPAD = mgfkg/day 

0.5 mglkg/day Based on cranial variations, 

abortion, and increased pre- and 

post-implantation losses assumed 

to occur following a single dose. 

Chronic Dietary NOAEL = UF,, - lOx cRfD = Carcinogenicitv - Mouse 

17.4 mglkg/day UFu = lOx 0. 17 mglkg/day LOAEL = 202.2 mg!kg/day 

FQPA SF = IX Based on decreased body weight 

cJ>AD = gain and liver toxicity (e.g. 

0. 17 mglkglday hepatocytic large fatty 

vacuolation). 

Incidental Oral Maternal UF , = IOx Residential LOC Prenatal DeveloRmental Toxicirv 

Short Term NOAEL = 25 ur .. = lOx for MOE = 100 - Rabbit 

( 1-30 days) mg/kg/day FQPA SF = IX Maternal LOAEL = 50 mglkg/day 

Based on decreased body weight 

gain. reduced food consumption. 

and mortality. 

lnciaental Oral NOAEL = UF" "' lOx Residential LOC Carcinogenicitv - Mouse 

Intermediate Term 17.4 mglkg/day UFu = lOx for MOE = 100 LOAEL = 202.2 mglkglday 

( 1-6 months) FQPA SF IX Based on decreased body weight 

gain ::md liver toxicity (e.g. 

hepatocytic large latty 

vacuolation). 

Dermal Quantification of dern1al risk was not conducted. Dennal absorption is minimal (<2% of the 

Short Tenn total administered dose) regardless of dose. and rats treated by dermal occlusion for 6-7 

( 1-30 days) hours/day for 23 days at doses up to I 000 mglkg/day (Limit-Dose) did not exhibit any signs 

Intermediate Term of systemic toxicity or dermal irritation. and no treatment-related histopathology findings 

( 1-6 months) were noted. 

Long Tcnn 

(>6 months 

Inhalation Maternal UF" = lOx Residential LOC Prenatal DevciOU!llCntal Toxicit\' 

Short Term NOAEL ~ 25 UFu - lOx for MOE = 100 - Rabbit 

( 1-30 days) mglkglday FQPA SF = IX Maternal LOAEL = 50 mgfkglday 

Oased on decreased body weight 

gain. reduced food consumption. 

and monality. 

Page 18 of26 
i 

Summary of Toxicological Doses and Endpoints for usc in Dietary and Non-Occupational Human Health 

Risk Assessments 

Exposure Point of Uncertainty I RfD. PAD, Level 

Scenario Departure FQPA Safety of Concern for Study and Toxicological Effects (POD) Factors Risk Assessment 

Inhalation NOAEL = UF,, = lOx Residential LOC Carcinogcnicitv- Mouse 

Intermediate fenn 17.4 mglkglday UFu = lOx for MOE = 100 LOAEL = 202.2 mglkg/day 

( 1-6 months) FQPA SF = IX Based on decreased body weight 

gain and liver toxicity (e.g. 

hepatocytic large fatty 

vacuolation). 

Cancer (oral, Classification: "Not likely to be Carcinogenic to Humans·• based on the absence of sign ificant 

dermal. and tumor increases in two adequate rodent carcinogenicity studies (TXR0054249, J. Kidwell, 

inhalation) 06/ 15/2006). 

Pomt of Departure (POD) = A data pomt or an estmwted pomt thatss denved from observed dose-response data and used to mark 

the beginning of extrapolation to detem1ine risk associat.:d 11 ith lmn:r .:m iromm:ntally r.:lcvant human exposures. NOAEL = no 

observed adverse dli.'Ctlcvd. LOAEL lo11c:;t ob~ened ad1·erse cfTectlen:l. UF = uncertainty factor. UF" = extrapolation t'rom 

animal to human (intcrspccies). UFu = potcntial variation in scnsitivity among mcmbers ofth.: hum;m population (intrnspccics). 

fQJ>A SF = FQPA Salt:ty Factor. l'viOE = margin of exposure. LOC = kvel of conccm. N/A = not applicnble. 

Summary of Toxicological Doses a nd Endpoi nts for usc in Occupational Human Health Risk Assessments 

Exposure Point of Uncertainty I IUD, PAD, Level 

Scenario Dcpanure (PoD) FQPA Safety of Concern for Study and Toxicological Effects 

Factors Risk Assessment 

Dermal Quantification of dennal risk was not conducted. Dermal absorption is minimal (<2% of the 

Short Term total administered dose) regardless of dose. and rats treated by dem1al occlusion for 6-7 

( 1-30 days) hours/day for 23 days at doses up to 1000 mglkglday (Limit-Dose) did not exhibit any signs 

lntem1ediate Term of systemic toxicity or dennal irritation, and no treauncnt-rclmcd histopathology findings 

( 1-6 months) were noted. 

Long Term 

(>6 months 

Inhalation Matcmal UF" - lOx Occupational Prenatal cveloQm ntal To it ~ Short Tcm1 NOAEL = 25 UFu - lOx LOC for MOE = - Rabbit 

( 1-30 days) mglkg!day 100 Maternal LOAEL = 50 mglkglday 

Based on decreased body weight 

gain, reduced food consumption, 

and mortality. 

Inha lation NOAEL - UF"- lOx Occupational Carcinogenicitv - Mouse 

lntenncdiate Tcrn1 I 7.4 mg/kglday UFH- lOx LOC for MOE = LOAEL - 202.2 mglkg!day 

( 1-6 monlhs) FQPA SF = 100 Oased on decreased body weight 

IX gain and liver toxicity (e.g. 

hcpatocytic large fatty 

vacuolation). 

Cancer (dermal Classification: "Not likely to be Carcinogenic to Humans'' based on the absence of 

and inhalation) significant tumor increases in two adequate rodent carcinogenicity studies (TXR0054249. J. 

Kidwell. 06/ 15/2006). 

Posnt of Dcpartun: (PoD) = A data pomt or an estimated pomt that 1s dcnved from observed dose-response data :usd used to·mnrk 

the beginning of extrapolation to detcnninc risk associutcd with IOI\Cr cnvironmcntally relevant human cxposurcs. NOAEL "" no observed adverse effect lcvcl. I.Ot\EL - lcmcst ohscrl'cd adverse c!Tect lcvcl. F = uncertainty factor. UF" = cxtr:tpolmion from 

:mimalto human (intcrspccics). UFu = posential variation in scnsiti\ it~ among mcmb~rs of the hum;m population (intraspccics). 

FQPA SF = FQJ>A Safcty Factor. 1\•IOE - margin or exposurc. LOC = lcvcl nf concern. N/,\ = not applicable. 

Page 19 of26 
Attachment 5 

Toxicology Data Requirements 

The requirements (40 CFR 158.500) for food uses are in the table below. Use of the new 

guideline numbers does not imply that the new (1998) guideline protocols were used. 

Toxicology Da ta Requirements 

Guideline Study Type Required Submitted 

870.1100 Acute Oral Toxicity Yes Yes 

870.1200 Acute Dennal Toxicity Yes Yes 

870.1300 Acute Inhalation Toxicity Yes Yes 

870.2400 Acute Eye Irritation Yes Yes 

870.2500 Acute Dennal Irritation Yes Yes 

870.2600 Skin Sensitization Yes Yes 

870.3100 90-Day Oral Toxicity in Rodents Yes Yes 

870.3150 90-Day Oral Toxicity in Non-Rodents Yes No 

870.3200 21 /28-Day Dennal Toxicity Yes Yes 

870.3250 90-Day Dem1al Toxicity CR No 

870.3465 90-Day Inhalation Toxicity CR No 

Prenatal Developmental Toxicity Study (Rat) Yes Yes 

870.3700 Prenatal Developmental Toxicity Study (Rabbit) Yes Yes 

870.3800 Reproduction and Ferti lity Effects Yes Yes 

870.4100 Chronic Toxicity (Rodent) Yes Yes 

870.4200 

Carcinogenicity (Rat) Yes Yes 

Carcinogenicity (Mouse) Yes Yes 

870.5100 Bacterial Reverse Mutation Test Yes Yes 

870.5300 in vitro Mammalian Cell Gene Mutation Test Yes• Yes 

870.5375 in vitro Mammalian Chromosome Aberration Test Yes 

870.5385 Mammalian Bone Marrow Chromosomal Aberration Test Yes• No 

870.5395 Mammalian Ervthrocyte Micronucleus Test Yes 

Delayed Neurotoxicity of Organophosphoms Substances (Acute. I len) CR No 

870.6 100 Delayed Neurotoxicity of Organophosphorus Substances (28-Day. Hen) CR No 

Neurotoxicity Screening Banery (Acute. Rat) Yes I Yes 870.6200 Neurotoxicity Screening Battery (90-Day. Rat) Yes Yes 

870.6300 Developmental Neurotoxicity Study CR No 

870.7200 Companion Animal Safety CR No 

870.7485 Metabolism and Pham1acokinetics Yes Yes 

870.7600 Dermal Penetration CR Yes 

870.7800 lmmunotoxicity Yes Yes .. CR - Cond111onally ReqUired. NA = Not Applicable. 

a Either guideline study type may be used to satisfy the data requirement (e.g. 870.5300 or 870.5375). 

b Study requirement waived (TXR0056649. K. Rury. 05/0612013). 

c Study requirement waived (TXR0053424. S. Dapson. 11 113/2006). 

Page 20 of26 

Satisfied 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

NA 

Yesb 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

NA 

NA 

Yes 

Yes 

Yes' 

NA 

Yes 

NA 

Yes 
Attachment 6 

Toxicity Profile for Triticonazolc 

Acute Toxicity ofTriticonazole Technical 

Guideline Study Type MRIDNo. Results No. 

Toxicity 

Category 

870.1 100 Acute Oral Toxicity 44802028 LD~o;::: 2000 mg/ kg 

44802029 Ill LDso > 2000 mg!kg 

870.1200 Acute Dennal Tox iciry 44802030 LDso:::: 2000 mg!kg Il l 

870.1300 Acute Inhalation 

Tox icity 44802031 LCso > 2.63 rng/L IV 

Non-irritant 

Acute Ocular Irritation Index: 2.7 

Mean Ocular Irritation Index: 0 

870.2-WO Acute Eye Irritation 44802032 Transient redness to the conjunctivae at IV 

one hour after administration in all 

animals; redness disappeared after 24 

hours 

870.2500 Acute Dcm1al 

Irritation 44802033 Not an irritant IV 

870.2600 Dermal Sensitization ·168 1730 1 Not a sensitizer in the 13uehler test in N/A guinea pigs 

Page 21 of26 
Tox.ieity Profile ofTritieonazole Technical 

Guideline Study Type 

MRID (year) I Doses I Results Classification 

870.3100 90-Day Oral 44802 102 (199 1) NOAEL (mglkglday): M = 2.0 F = 

Toxicity in 44802101 ( 199 1) 22.3 

Rodents Dietary Concentration (ppm): LOAEL (mglkg/day): M = 19.8 F= (Rat) 0. 25. 250. 12500. 25000 1183.5 

Dietary Dose (mglkg/day): M: Based on a statistically significant 

M: 0. 2.0. 19.8. 1117.0.2309.3 increase in the incidence of adrenocortical 

F: 0. 2.2. 22.3. 1183.5. 2368.8 fatly vacuolation. 

Acceptable I Guideline F: Based on hair loss. decreased food 

efficiencies. adrenocortical fatly vacuolation. 

zona rcticularis degeneration. ccntrincinar 

hcpatocytic fatty vacuolation. and more 

severe anisocytosis and spherocytosis. 

870.3150 90-Day Oral NA Refer to MR I D 448021 03 - the Chronic 

Toxicity in Non- Toxicity Study in Dogs (870.4 1 00) 

Rodents 

870.3200 21128-Da)' 4493360 I ( 1997) Dermal Irritation 

Dermal Toxicity Dermal Dose (mglkgtday): NOAEL (mg./kg/day): M = 1000 F "' 

(Rat) M: 0, 100.300. 1000 1000 

F: 0. I 00. 300. 1000 LOAEL (mgl kgfday): M > 1000 F > 

Acceptable I Guideline 1000 

Svsternic 

NOAEL (mglkg/day): M = 1000 F = 

1000 

LOAEL (mgfkg/day): M > 1000 F > 

1000 

870.3465 90-Day NA Study requirement waived (TX R0056649. 06 

Inhalation May 2013) 

ToxicitY 

870.3700 Prenntal 44802105 ( 1991 ) Maternal 

Developmental 4480210-1 ( 1990) OAEL (mglkg/dny) "" 200 

Toxicity Study Gavage Dose (rnglkg/day): LOAEL {mg./kg/day) = 1000 

(Rat) F: 0. 40. 200.1000 Based on reduction in mean body weight 

Acceptable I Guideline gain during GD 12-16. 

DeveloJ2mental 

NOAEL (mglkgfday) = 200 

LOAEL (mglkgfday) = 1000 

Based on a treatment-relnted increases in 

unilnteral and bilateral supemumerarv ribs. 

Page 22 of26 
Toxicity Profile ofTriticonazole Technical 

Guideline Study Type 

Prenatal 

Developmental 

Toxicity Study 

(Rabbit) 

870.3800 Reproduction and 

Fertility Effects 

(Rat) 

870.4100 Chronic Toxicity 

(Dog) 

MRID (year) I Doses I 

Classificarion 

44802106 (1991) 

Gavage Dose (mglkg/day): 

F: 0. 5. 25. 50. 75 

Acceptable I Guideline 

44933604 ( 1993) 

Dietary Concentration (ppm): 

0, 5. 25. 750.5000 

Dietary Dose (mglkg/day): 

Mo: 0, 0.25. 1.25. 37.5, 250 

Fo: 0. 0.25, 1.25. 37.5, 250 

M1: 0. 0.25. 1.25. 37.5. 250 

F1: 0. 0.25, 1.25. 37.5. 250 

Acceptable I Guideline 

44802103 ( 1993) 

Dietary Concentration (ppm): 

0, l 00, 200. 400 

Dietary Dose (rnglkglday): 

M: 0, 2.5, 25, !50 

F: 0. 2.5. 25. 150 

Acceptable I Guideline 

Page 23 o1'26 

Results 

Maternal 

NOAEL (mglkg!day) = 25 

LOAEL (mglkg/day) = 50 

Based on decreased body weight gain afler 

dosing initiation. reduced food conswnption. 

and mortality, and the maternal toxicity. 

Developmental 

NOAEL (rnglkg/day) - 50 

LOAEL (mglkglday) ; 75 

Based on cranial variations. abortion. and 

increased pre- and post-implantation losses. 

Parental 

NOAEL (mg!kg/day): M = 37.5 F = 

37.5 

LOAEL (mg/kg!day): M "' 250 F = 250 

Based on reduced body weights of the Fo 

females and the F. males and females and 

microscopic lesions in the adrenal glands of 

Fo and F1 males and females. 

Reproductive 

NOAEL (mglkg/day): M = 37.5 F = 

37.5 

LOAEL (mg/kglday): M - 250 F ~ 250 

Based on Fo perinatal mortality, decreased 

fertility of the F1 animals. 

Offspring 

NOAEL (mglkg/day): M = 37.5 F "' 

37.5 

LOA EL (mglkg/day): M "' 250 F = 250 

Based on reduced F1 ;md F2 pup survival. and 

reduced F1 and ~ pup body wei!!,ht 

NOAEL (mglkg/day): M = 25 F = 25 

LOAEL (mglkglday): M = 150 F "' 150 

Based on decreased absolute body weights of 

female dogs. decreased weight gain by male 

and female dogs. and treatment-related 

toxicity to the eye. liver. and adrenals: in 

addition to transient neurological signs 

(tremors, h) peroctivit) or hypoactivity. 

convulsions, and ataxia). 
Toxicity Profile of Triticonazole Technical 

Guideline Study Type 

870.4200 Carcinogenicity 

(Mouse) 

870.4300 Combined 

870.5 100 

870.5300 

870.5375 

Chronic Toxicity 

1 Carcinogenicity 

(Rat) 

Bacterial Reverse 

Mutation Test 

(Salmonella 

1_1 phimurium) 

in l'itro 

Mammalian Cell 

Gene Mutation 

Test 

(Chinese 

Hamster V79 

Cells) 

in vitro 

Mammalian 

Chromosome 

Aberration Test 

(Human 

Lymphocytes) 

MRID (year) I Doses I 

Classification 

44802108 ( 1994) 

Dietary Concentration (ppm): 

0. 15. 150. 1500 

Dietary Dose (mglkglday): 

M: 0. 1.8. 17.4. 202.2 

F: 0. 2.1. 20. 1. 209.5 

Acceptable I Guideline 

44802107 (1994) 

Dietary Concentration (ppm): 

0.5.25. 75.5000 

Dietary Dose (rnglkglday): 

M: 0. 0.2. 1.0. 29.4. 203.6 

F: 0. 0.3. 1.3. 38.3. 286.6 

Acceptable I Guideline 

44802109 (1991) 

Applied Dose ()Jg/plate): 

±S9: 25. 79.250.790.2500 

Acceptable I Guideline 

44802 11 0 (1999) 

Applied Dose ()Jglplate): 

±S9: I 0.0. 33.3. I 0. 333 

Acceptable I Guideline 

44807113 (1991) 

Applied Dose (mg/mL): 

±S9: 62.5. 125.250. 500 

Acceptable I Guideline 

44802111 ( 1997) 

Applied Dose (ppm): 

±S9: 274.4. 392. 560 

-S9: 337.5. 450. 600 

-'-$9: 253.1. 337.5. 450 

Acceptable I Guideline 

Page 24 of26 

Results 

NOAEL (mglkglday): M - 17.4 F -

20. 1 

LOAEL (mglkglday): M == 202.2 F = 

209.5 

Based on decreased body weight gain and 

liver toxicity (e.g. hepatocytic large fatty 

vacuolation). 

Treatment for up to 78 weeks with 

RPA400727 did not result in a significant 

increase in the incidence of neoplastic lesions 

in this study. 

NOAEL (mglkg/day): M = 203.6 F -

38.3 

LOAEL (mg/kg/day): M > 203.6 F = 

286.6 

F: Based on decreased body weight and body 

weight gain and adrenal conical and liver 

toxicity (e.g. fatty vacuolation). 

RPA400727 showed no carcinogenic activity 

in either male or female rats after 

administration for up to I 00 weeks. 

No evidence of compound-induced 

carcinogenicity as per CARC repon June 15. 

2006). 

-±-S9: Negative up to 2500 ~tg/plate. 

TI1erc was no evidence of treatment-induced 

mutant colonies above background levels. 

:::S9: Negative up to 2500 ~t g/plate. 

There was no evidence of treatment-induced 

mutant colonies above background levels. 

There was no consistent evidence of induced 

mutant colonies over background. 

A It hough there was suggestive evidence of a 

possible increase in the frequency of aberrant 

cells at cytotoxic doses in the absence of 59-

mix. the positive results were not 

n:produciblc: therefore there was no 

consistent evidence of chromosomal 

aberrations induced over background. 
Toxicity Profile ofTriticooazole Technical 

Guideline Study Type MRID (year) I Doses I 

Classificatio Results n 

870.5395 Mammalian 44802114 ( 1992) There was no significant increase in the 

Erythrocyte Gavage Dose (mgtl:g): frequency of m icronucleated polychromatic 

Micronucleus M: 0, 25, 125, 625 erythrocytes in bone marrow after any tested 

Test (Mouse) F: 0.25,125.625 RPA 400727 dose at an) harvest time. 

Acceptable I Guideline 

870.5550 Unscheduled 44802112 ( 1992) There was no evidence that unscheduled 

DNA Synthesis Dose (J.lg/rnL): DNA synthesis. as determined by radioactive 

in Mammalian 7.81, 15.6, 31.3.62.5 tracer procedures [nuclear silver grain 

Cells in Culture Acceptable I Guideline counts] was induced. 

(Rat 

Hepntocytcs) 

870.6200 Acute 44802036 ( 1997) Neurotoxicity 

Neurotoxicity 44933602 ( 1997) NOAEL (mg/kg): M = 400 F- 400 

Screening Battery Gavage Dose (mglkg): LOAEL (mg/kg): M = 2000 F = 

(Rat) M: 0. 80, 400. 2000 2000 

F: 0, 80,400.2000 Based on increased motor activity in both 

Acceptable I Guideline males and females. 

Svstemic 

NOAEL (mglkg/day): M = 1000 F = 

1000 

LOAEL (mglkg/day): M > 1000 F > 

1000 

90-Day 44933603 ( 1997) Neurotoxicitv/Svstemic 

Neurotoxicity Dietary Concentration (ppm): NOAEL (mglkglday): M - 695.1 ~ 

Screening Bancry 0. 500, 2500. I 0000 820.3 

(Rat) Dietary Dose (mglkg/day): LOA EL (mglkg/day): M > 695.1 F > 

M: 0, 32.5, 169.9. 695. 1 820.3 

F: 0. 38.5. 199.4. 820.3 

Acceptable I Guideline 

870.6300 Developmental 4655050 I (2005) Study requirement waived (TXR0053424. 13 

I Neurotoxicity Waiver Request November 2006) 

Study 

Page 25 of26 
Toxicity Profile ofTriticooazole Technical 

Guideline Study Type 

870.7485 Metabolism and 

Pham1acokinetic 

s (Rat) 

870.7600 Dermal 

Penetration 

(Rat) 

870.7800 lmmunotoxicity 

(Rat) 

MRrD (year) I Doses I 

Classification 

4650340 I ( 1993) 

Gavage Dose (mg/kg): 

Single: 5. 500 

Repeated: 5 ( 14 Days) 

Acceptable I Guideline 

47 15890 1 (2000) 

Biliary Excretion 

Gavage Dose (mglkg): 

Single: 5. 500 

Acceptable I Guideline 

44802115 (1996) 

Dermal Dose (mg/cm2): 

M: 0.15.3 

Acceptable I Guideline 

48733901 (20 11 ) 

Dietary Concentration (ppm): 

0.500.1500.5000 

Dietary Dose (mglkglday): 

F: 0. 53. 162. 462 

Acceptable I Guideline 

Results 

Absorption of an oral dose oftriticonazole 

was rapid and reached its peak blood 

concentration between 1 and 2 hours after 

dosing. 

In the high dose (500 mglkg). RPA 

triticonazolc was found in the greatest 

concentration in the liver. kidneys. lungs. fat. 

Gl tract. skin/fur. blood and plasma. Also. it 

was found in male heans and in female uteri. 

TI1e test compound was metabolized rapidly. 

since levels of parent compound (0.1 7 -1.44% 

AD) were significantly lower than 

metabolites ( 14-4 I% A D) after 24 hours. TI1c 

most abundant metabolite in the urine was 

RPA 406972 (45-65% AD) in the 500 mg./kg 

dose and a hydroxylated RPA 406972 (29-

33% AD) in the 5 mg/kg dose. The most 

abundant components found in the feces were 

RPA 406972 and RPA 405826/404886. 

RPA 400727 is primarily eliminated through 

biliary excretion. Excretion was rapid. most 

of the radiolabel being excreted in the urine 

and feces within 48 hours of treatment 

(>90% for the single-dose groups: >67% for 

the repeat-dose groups). 

Dermal Absorption Factor = 2% 

Based on the data presented in the reviewed 

study dermal absorption of the test material is 

minimal (<2% of the administered dose) at 

the low and hi~h dose. 

lmmunotoxicitv 

NOAEL (mg/kglday): M = NA 

LOAEL (mg.lkg.lday): M = NA 

Svstemic 

F = 462 

F > -162 

NOAEL (mglkglday): M = NA F = 162 

LOAEL (mglkg/day): M = 1 A F - -162 

Based on reduced body weights and body 

.._ _ _ _ ......._ _ _ _ ___ _,_ _ _ _ ___ ___ _ _ ___.__ve igh t gains. and increased liver weichts. 

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