UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: 23 March 2016 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Triadimefon and Triadimenol. Human Health Assessment Scoping Document in Support 

of Registration Review. 

PC Codes: I 0990 I (triadimefon), 12720 I (triadimenol) 

Decision No.: 5 11057 

Petition No.: NA 

Risk Assessment Type: Single Chemical, Aggregate 

TXR No.: NA 

MRJD No.: NA 

DP Barcode: 0430121 

Registration Nos.: Multiple 

Regulatory Action: Registration Review 

Case No.: 2700 

CAS No.: 43121-43-3 (triadimefon), 

55219-65-3 (triadimenol) 

40 CFR: 180.410 (triadimefon), 

180.450 (triad imenol) 

FROM: 

Kar

Michael 

lyn Middleton, 

A. Doherty

M.S., 

, Ph.D.

To

, 

x

Chem

icologi

ist 

st 

~~~ ,?, 

Zaida I. Figueroa, DrPH, Industrial Hygienist· ·' 

Health Effects Division (7509P) +.A μ 

Nathan Mott!, Biologist -\-::: ~=--,__,..?-""---. Jonathan Leshin, PhD, Toxicologist 

Risk Assessment Science Support Bra 

Antimicrobials Division (AD, 75 lOP) 

THRU: Jess Rowland, Deputy Director 

Jeff Dawson, Deputy Director (acti 0 r-; ~ 

Health Effects Division (7509P) r _ ,,..- -" --k-- \'- s w 

Steven Weiss, Branch Chief 1 - ~~ Timothy Leighton, Senior Scientist I - KJ. -... 

RAS SB/ AD (75 1 OP) 

TO: Christina Motilall/Tom Moriarty/Neil Anderson 

Risk Management and Implementation Branch I 

Pesticide Re-Evaluation Division (7508P) 

Rachel Ricciardi, Chemical Review Manager 

Antimicrobials Division (AD, 751 OP) 

Page I of34 
The Health Effects Division (HED) and Antimicrobials Division (AD) have jointly prepared a human 

health risk assessment scoping document for triadimefon and triadimenol to support registration review. 

HED reviewed the conventional uses and AD reviewed the antimicrobial uses of these pesticides. This 

document summarizes the evaluation of the data available for assessing human health risk from exposure 

to triadimefon and triadimenol, as well as any data needed to support registration review. 

Executive Summary 

Triadirnefon and triadirnenol are triazole-derivative fungicides. Triadimenol is a metabolite of 

triadimefon and is also a registered active ingredient. Triadimefon is registered for use as a wood 

preservative. which is considered an antimicrobial use, and as a conventional fungicide for use 

on pine seeds/seedlings, Christmas trees, ornamental plantings and landscapes (exterior/interior), 

and turf in commercial and residential settings. Triadimenol is registered as a fungicide for seed 

treatment on barley. corn, cotton, oats. rye, sorghum, and wheat. In addition, there is a tolerance 

without a US registration for residues in/on banana. 

The toxicology database for triadimefon is complete with the exception of the subchronic 

inhalation toxicity study. The study is required based on high inhalation risk estimates for several 

exposure scenarios (TXR#0057320). The inhalation risk estimates are still of concern for some 

conventional-use scenarios even with the use of additional personal protection equipment (PPE; 

such as PFS or PF IO respirators) and engineering controls. In the absence of the inhalation 

study, a l OX database uncertainty factor should be retained for inhalation exposure only. The 

toxicology database for triadimenol, a metabolite of triadimefon is complete and no additional 

studies are required (TXR#0077332). 

The residue chemistry database for triadimefon and triadimenol is not complete. The Agency had 

previously required studies reflecting metabolism in cereal and cotton following seed treatment, 

and a number of additional studies were being reserved pending the outcome of the required 

metabolism study (triadimenol Tolerance Reassessment Eligibility Decision (TRED); 0314891 , 

17 November 2005). Although the metabolism studies were submitted, they were found to be 

unacceptable by HED. Upon further consideration of the available data, HED will use the results 

from confined rotational crop studies along with the available metabolism studies to elucidate 

metabolism in cereals and cotton following seed treatment. Nevertheless, the residue chemistry 

database remains incomplete due to the need for limited field accumulation in rotational crop 

residue studies (OCSPP Guideline 860.1900) which were also required in the triadimenol TRED. 

Extensive field rotational crop residues studies may also be required, depending on the results 

from the limited studies. 

ln April, 2009 (D351282), AD evaluated the potential risk from exposure to triadimefon alone; 

no risk estimates of concern were identified. In August, HED (035 1080) evaluated the potential 

risk from the combined exposure to triadimefon and triadimenol. In that assessment, aggregate 

margins of exposure (MOEs) were of concern (i.e., the MOEs were below the level of concern, 

or LOC); however, the risk estimates were characterized as being not of concern due to the 

conservative assumptions used in the assessment. 

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Page 3 of 34

In evaluating the data available for triadimefon and triadimenol, HED and AD have identified 

the following data needs for triadimefon (which will be bridged, as needed, to triadimenol), 

noting that analysis of both triadimefon and triadimenol should be included in any studies 

involving residue analysis:

HED Data Needs for Triadimefon:

 A 90-day inhalation toxicity study (OCSPP Guideline 870.3465)

 A limited field rotational crop study (OCSPP Guideline 860.1900) and potentially an 

extensive field rotational crop study.

 A dislodgeable foliar residue study (OCSPP Guideline 875.2100) may be required 

pending a determination of the registration status of the use on pineapple.

AD Data Needs for Triadimefon:

 Dermal (Guideline 875.1200) and inhalation (Guideline 875.1400) surrogate applicator 

exposure studies (mixing/loading wettable powders, dip/spray sapstain, and wood 

pressure treatment).

 Product use data (Guideline 875.1700) to clarify uses, application rates (wood retentions), 

and application equipment.

 Wipe studies (Guideline 875.2300) for treated decks at the highest wood retention rate.

To date, OPP has not conducted an aggregate assessment for triadimefon/triadimenol that 

considers both the antimicrobial and conventional pesticide uses. During registration review, 

HED/AD will conduct new dietary, residential, aggregate, and occupational risk assessments

incorporating all registered uses of these compounds (both antimicrobial and conventional), 

using the existing data and the newly required toxicity and exposure studies.

Introduction

The triazole-derivative fungicides triadimefon and triadimenol are scheduled for registration 

review by the Office of Pesticide Programs. This scoping document identifies the current state of 

the hazard and exposure databases for these compounds, any studies that are necessary to bring 

those databases up to current standards, and the anticipated work to be done by the Health 

Effects and the Antimicrobials Divisions in order complete a human health risk assessment under 

registration review.

In addition to being an active ingredient, triadimenol is a major metabolite of triadimefon, and 

the toxicological effects associated with these compounds are the same. As a result, triadimefon 

and triadimenol are assessed together by combining exposure estimates from each compound. 

The last comprehensive risk assessment was conducted in conjunction with reregistration in 2006 

(D331455, 1 August 2006), following the triadimefon Reregistration Eligibility Decision 

(RED)/triadimenol TRED, in response to mitigation measures resulting from the triadimefon 

RED. Subsequent to that assessment, HED conducted an abbreviated assessment to evaluate 

reinstating the use on residential turf (D351080, 3 August 2009).

At the time of the last assessment, triadimefon was registered for use as a fungicide on pine 

seed/seedlings, Christmas trees, ornamental plantings, landscapes (exterior/interior), and 

residential and commercial turf, and pineapple (post-harvest dip and seed-piece treatment), and 

triadimenol was registered for use as a seed treatment on barley, corn, cotton, oats, rye, sorghum, 
Page 4 of 34

and wheat, resulting in tolerances for residues in/on commodities of those crops. In addition, 

there is a tolerance for residues in/on banana without a US registration (i.e., an “import 

tolerance”). It is HED’s understanding that since the last risk assessment the uses of triadimefon 

on pineapple have been cancelled by the registrant. If the pineapple uses of triadimefon have 

not been cancelled, then a dislodgeable foliar residue study (OCSPP 875.2100) is required.

In April 2009, triadimefon was assessed by the Antimicrobials Division for use as a wood 

preservative, and there are currently three registered products that contain approximately 45-49% 

triadimefon. These products are formulated as a wettable powder, a ready-to-use solution, and a 

soluble concentrate.

In developing this scoping document, the most recent human health risk assessments have been 

relied on along with the existing toxicology, residue chemistry, and occupational/residential 

exposure databases for triadimefon and triadimenol.

Hazard Identification/Toxicology

The toxicology database for triadimefon is complete with the exception of the subchronic 

inhalation toxicity study. Inhalation risk estimates of concern were identified using the oral point 

of departure (POD) currently selected for risk assessment at baseline level clothing (i.e., longsleeves shirt, long pants, shoes plus socks) with no respiratory protection which is consistent 

with the current labels. Additional PPE is needed to obtain acceptable risk estimates (i.e., PF 5 

or PF 10 respirators, or engineering controls). However, inhalation risks of concern still exist 

with the use of additional PPE for granules applied aerially (applicator MOE=220 with 

engineering controls, with an LOC of 1,000) and for wettable powders using a mechanicallypressurized handgun in greenhouses (mixer/loader/applicator MOE=570 with a PF10 respirator). 

Therefore, the Hazard Science Policy Council (HASPOC) determined that an inhalation toxicity 

study is needed for triadimefon. In the absence of the inhalation toxicity study, a 10X database 

uncertainty factor should be retained only for inhalation exposure. An immunotoxicity study is 

also not available for triadimefon; however, the HASPOC determined that the study is not 

required, based on a weight of evidence approach, considering the available hazard and exposure 

information (TXR#0057320). The HASPOC also determined that missing studies for triadimenol 

(a metabolite of triadimefon), including acute and subchronic neurotoxicity, inhalation, and 

metabolism studies are not needed because these data gaps are satisfied by studies with 

triadimefon (TXR#0077322). Therefore, the toxicology database for triadimenol is complete and 

no additional studies are required. 

For both triadimefon and triadimenol, neurotoxicity and liver effects were consistently observed 

in oral and dermal toxicity studies. For triadimefon, several neurobehavioral findings (FOB, 

hyperactivity, increased auditory startle reflex, changes in body temperature and motor activity) 

were observed after oral and dermal exposure in guideline studies. Effects on the liver were seen 

in toxicity studies in rats and mice including changes in liver enzymes, increased organ weights, 

hypertrophy, and histopathology. Long-term exposure to triadimefon led to an increased 

incidence of hepatocellular adenomas in mice and thyroid adenomas in rats. Consequently, 

triadimefon is classified as a "possible human carcinogen." A nonlinear approach was considered 

appropriate for assessing cancer risk to triadimefon since the thyroid adenomas seen were 

borderline in terms of statistical significance and, despite the presence of hepatocellular 
Page 5 of 34

adenomas in both sexes of mice, all of the tumors associated with the active ingredient were 

benign. Finally, there is no mutagenicity concern for triadimefon.

For triadimenol, neurotoxic effects including changes to behavioral characteristics, motor 

activity, and spontaneous activity were observed in a special acute neurotoxicity study with rats 

and mice. Limited neurotoxicity was observed in the guideline neurotoxicity studies for 

triadimenol. However, there are data from the literature that highlight a neurotoxic concern for 

triadimenol after repeated exposure. Effects on the liver in rats, mice and dogs included 

increased organ weights, elevated enzymes, hypertrophy, and/or histopathology changes. Longterm exposure led to an increased incidence of hepatocellular adenomas in females only. 

Triadimenol is classified as Group C, “possible human carcinogen,” based on an increased 

incidence of hepatocellular adenomas in female mice only. A nonlinear approach was considered 

appropriate for assessing cancer risk to triadimenol since the tumors observed were benign and 

only seen in one sex. Additionally, there is no mutagenicity concern for triadimenol.

There was evidence of quantitative and/or qualitative susceptibility seen in developmental and 

reproduction studies for both triadimefon and triadimenol. For triadimefon, skeletal effects 

(incomplete ossification of pelvis pubes, phalanges, and irregular spinous process on the scapula) 

were seen in the rabbit developmental study and abnormal ribs and distended urinary bladder 

were observed in one of two rat developmental studies. The effects in rat and rabbit fetuses were 

seen in the absence of treatment related maternal effects. Additionally, decreased pup weight, 

deviated snout, and clinical signs (increased auditory startle, and # trials to criterion in pass 

avoidance test) were observed in offspring animals in the presence of less severe maternal 

toxicity (decreased body weight) in the reproduction study. For triadimenol, extra ribs were 

observed in fetuses in a rat developmental study in the presence of non-treatment related effects 

on body weight (decreased <10%). 

There is low concern for the susceptibility observed in the triadimefon/triadimenol studies since 

clear NOAELs were determined for the effects seen and because the current points of departure

are protective of the effects. Therefore, the FQPA factor has been reduced to 1x for both 

chemicals. 

Both triadimefon and triadimenol have low toxicity in acute lethality studies via the oral, dermal, 

and inhalation routes of exposure (Toxicity Category III and IV). They are not dermal irritants 

(Category IV) or sensitizers. Triadimefon is slightly irritating to the eye (Category IV), while 

triadimenol is an eye irritant (Category II). 

Endpoints and PODs for both triadimefon and triadimenol dietary assessments are based on 

triadimefon data since the chemicals have a similar structure, toxicity profile, and mode of 

action. For acute and chronic dietary exposure, the triadimefon subchronic neurotoxicity (SCN) 

study was used with a NOAEL of 3.4 mg/kg/day, based on hyperactivity observed at the LOAEL 

of 54.6 mg/kg/day. Although an acute neurotoxicity study is also available for triadimefon, the 

SCN study was considered appropriate for assessing both acute and chronic dietary scenarios 

since the NOAELs were similar in the studies and there was no progression in toxicity with 

increased duration (similar LOAELs). The oral SCN study was also used for assessing risks 

associated with triadimefon inhalation exposure. For dermal exposure, a dermal toxicity study 
Page 6 of 34

was used with a NOAEL of 300 mg/kg/day, based on neurotoxic effects (increased reactivity and 

activity) observed at the limit dose of 1000 mg/kg/day. For triadimenol, previous risk 

assessments did not address worker exposure. Therefore, endpoints and PODs for these scenarios 

will be selected during registration review. No residential exposure is expected for triadimenol; 

long-term exposures are not anticipated for triadimefon or triadimenol based on the registered 

use patterns. 

Since the last risk assessment for triadimefon, food uses for the active ingredient have been 

cancelled. Therefore, dietary exposure is no longer anticipated for triadimefon and this should be 

reflected in future risk assessments. For triadimenol, future risk assessments should use the acute 

neurotoxicity (ACN) study with a slightly lower POD (as compared to the SCN) to assess acute 

dietary exposure to protect for effects observed in the special acute CNS study. The SCN study is 

still appropriate for assessing chronic dietary exposure. 

Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and 

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and 

sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic 

studies that assess growth, developmental and reproductive effects in different taxonomic groups. 

As part of the most recent registration decision for triadimenol and triadimefon, EPA reviewed 

these data and selected the most sensitive endpoints for relevant risk assessment scenarios from 

the existing hazard database. However, as required by FFDCA section 408(p), triadimenol and 

triadimefon are subject to the endocrine screening part of the Endocrine Disruptor Screening 

Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide

active and other ingredients) may have an effect in humans or wildlife similar to an effect

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator

may designate.” The EDSP employs a two-tiered approach to making the statutorily required

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal

systems. Chemicals that go through Tier 1 screening and are found to have the potential to

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2

testing is designed to identify any adverse endocrine-related effects caused by the substance, and

establish a dose-response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list
Page 7 of 34

of chemicals identified for EDSP screening was published on June 14, 20131and includes some

pesticides scheduled for registration review and chemicals found in water. Neither of these lists

should be construed as a list of known or likely endocrine disruptors.

Triadimefon is on List 1 for which EPA has received all of the required Tier 1 assay data. The 

Agency has reviewed all of the assay data received for the appropriate List 1 chemicals and the 

conclusions of those reviews are available in the chemical-specific public dockets (see Docket 

No. EPA-HQ-OPP-2005-0258) for triadimefon. Triadimenol was not included on either the first 

or second list. 

Conclusions for Hazard Identification/Toxicology

An inhalation toxicity study is needed for triadimefon, based on unacceptable inhalation risk 

estimates for several scenarios. Unacceptable risk estimates still exist for some scenarios with 

additional PPE (i.e., PF 10 respirator) and/or engineering controls; current labels don’t require 

respiratory protection. In the absence of the study, a 10X database uncertainty factor should be 

retained for inhalation exposure only.

The toxicology database for triadimenol is complete, and no new data are needed. However, 

endpoints and PODs for worker scenarios should be selected for triadimenol during registration 

review. Also, the triadimefon ACN study (instead of the SCN) should be used to assess acute 

dietary exposure for triadimenol to protect for effects observed in the special acute CNS study. 

The endpoints, points of departure and safety factors used for risk assessment should also be 

reexamined based on current HED policy, as well as any new data received.

Dietary Exposure

Conventional Uses

Adequate studies are available depicting the metabolism of triadimefon in crops and livestock, a 

suitable method is available to assess compliance with tolerances, and the available residue data 

(field trials, processing studies, feeding studies) are acceptable and are supported by appropriate 

analytical method and storage stability studies. The residue chemistry database for triadimefon is 

complete.

Adequate metabolism data for triadimenol, extrapolated from triadimefon, are available to 

understand the nature of the residue in plants following foliar application, in livestock, and in 

rotational crops; however, suitable studies depicting the metabolism of triadimenol in cereal 

grains and cotton following seed treatment are not available. The need for these studies was 

identified in the TRED for triadimenol (D314891, 17 November 2005). The studies were 

submitted and reviewed by HED in 2009 (D349015, 4 August 2009). The submitted studies (in 

winter wheat, spring wheat, and spring barley) were determined to be unacceptable. However, 

upon further evaluation of the available data, HED has determined that metabolism studies 

conducted as seed treatment are no longer needed. 

 

1 http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074
Page 8 of 34

The confined rotational crop study conducted with triadimefon included wheat as a rotational 

crop. That study was found to be suitable for extrapolation to satisfy the requirement for a 

confined rotational crop study with triadimenol. Since the environmental conditions in a 

confined rotational crop study mimic those that would be encountered in a seed-treatment 

metabolism study, and the results from the foliar crop metabolism and confined rotational crop 

studies result in a similar profile of residues, HED concludes that the metabolism in crops is 

adequately understood for foliar as well as seed-treatment applications of triadimefon and 

triadimenol.

With that determination, the studies being reserved (storage stability for field corn, sweet corn, 

cotton, and wheat forage, hay, straw, and processed commodities; and analytical methods) are 

also no longer needed. However, the residue chemistry database for triadimenol is still not 

complete. The confined rotational crop study demonstrated that residues persist to a degree that 

tolerances for inadvertent residues may be required. Therefore, limited and possibly extensive 

rotational crop studies, conducted according to OCSPP Guideline 860.1900, are required.

Dietary risk estimates in the last risk assessment (D351080, 3 August 2009), reflecting 

conventional uses of triadimefon and triadimenol, were not of concern (<10% aPAD and <5% 

cPAD).

HED notes that uses of triadimenol on pineapple appear to have been cancelled; however, 

language still exists on the labels of three technical products (EPA Reg. Nos. 264-736, 264-740, 

and 81964-4) indicating that the product can be used to formulate end-use products intended for 

use on pineapple. Such references on the technical product label should be deleted.

Antimicrobial Uses

EPA has not established tolerances or tolerance exemptions for residues for the antimicrobial 

uses of triadimefon and triadimenol. Triadimefon and triadimenol have not been cleared as food 

additives by the US Food and Drug Administration (US FDA) under the Federal Food, Drug, and 

Cosmetic Act (FFDCA) Section 409. The only antimicrobial FIFRA-registered uses of 

triadimefon and triadimenol are as wood preservatives (wood-base composite products; wood 

products for above ground and in-ground contact; reconstituted wood-based composite products; 

and veneer-based wood products). These uses are not expected to result in direct or indirect 

dietary (food) exposure; therefore, a dietary exposure assessment is not necessary for the 

antimicrobial uses of triadimefon and triadimenol.

A qualitative drinking water risk assessment was conducted in 2009 (D351279) for the wood 

preservative use. The drinking water assessment concluded that drinking water concentrations 

are negligible and that a drinking water assessment is not necessary for wood preservative uses.

Conclusions for Dietary Assessment

During registration review, HED will complete a new dietary risk assessment in order to address 

results from the required rotational crop study and to update the assessment to the most recent 
Page 9 of 34

dietary consumption database. That dietary assessment will likely necessitate new estimates for 

residues in drinking water from the Environmental Fate and Effects Division.

Residential Exposure

There is potential for residential exposure to triadimefon associated with handler activities from 

the registered residential uses on turf (lawns) and garden/trees (ornamentals); residential handler 

exposures are not expected from uses as a wood preservative. Post-application exposures may 

occur from the lawn, ornamental, and wood-preservative uses of triadimefon, and that exposure 

may be to the parent compound and/or to triadimenol.

Although triadimenol is not registered for any use sites that will result in residential exposure 

from the direct application of triadimenol, residential post-application exposure to triadimenol 

may occur via application of triadimefon. Since triadimefon and triadimenol share the same 

toxicological points of departure, the post-application assessment for triadimefon addresses any 

exposures that may occur to triadimenol as well.

Residential Handlers

Triadimefon

Homeowners might be exposed to triadimefon when they handle turf and garden/trees products 

for the control of fungal diseases in residential settings. Triadimefon may be applied as waterdispersible granules (WDG), water-soluble packets (WSP), and/or granular (G) formulations in 

residential settings using handheld equipment (i.e., backpack sprayer and manually-pressurized 

handwand), hose-end sprayer or granule spreaders (e.g., belly grinder, shaker can, rotary pushtype spreader, etc.). Based on the registered use pattern, the duration of exposure for residential

handlers is expected to be short- term (i.e., 1 to 30 days) in duration. Intermediate-term (i.e., 1 to 

6 months) and long-term exposures (i.e., greater than 6 months) are not anticipated. Residential 

handler exposures were previously assessed as part of the 2006 RED (D314814, D315040, S. 

Recore, 06/30/2006). In 2009, the Agency conducted a revised residential assessment for the use 

of triadimefon on residential lawns/turf and determined that the turf use could be reinstated 

(D351080, Z. Figueroa, 08/03/2009). Residential handler risk estimates are not of concern.

In conjunction with determining data needs during registration review, triadimefon was reviewed 

by HASPOC to evaluate the need for a route-specific inhalation study, as previous assessments 

were conducted using data from an oral study. As noted above, the HASPOC recommended that 

inhalation toxicity study is needed based on occupational handler risk estimates. In preparation 

for the HASPOC meeting, inhalation risk estimates were also calculated for residential handlers 

using current SOPs and exposure assumptions. Residential handler inhalation risk estimates were 

not of concern (MOEs>2,100).

The most recent residential handler exposure assessments do not reflect the policies of the 

HED’s 2012 Residential Standard Operating Procedures (SOPs), but did not identify risks of 

concern. For registration review, HED anticipates that the handler exposure assessment will need 

to be updated to reflect current exposure assumptions and procedures for residential assessment 
Page 10 of 34

(e.g., HED’s 2012 Residential SOPs for Treated Turf and Gardens and Trees). However, no risks 

of concern are expected.

Triadimenol

There are no residential use sites registered for triadimenol; therefore, an assessment of 

residential handler exposure is not necessary.

Residential Post-Application 

Turf and Ornamental Uses

Adults and children can be exposed to post-application residues of triadimefon on treated turf. In 

assessing post-application exposures to triadimefon, HED has assumed such exposures occur on 

the day of treatment. Post-application exposures to adults and children from treated turf (i.e., 

dermal, and hand-to-mouth, objects-to-mouth, and ingestion of contaminated soil for children 

only) were previously assessed using chemical-specific transferable turf residue (TTR) data and 

the SOPs For Residential Exposure Assessment. The results of the previous residential postapplication exposure assessment indicated that risks are not of concern (MOE > 100) (D351080, 

Z. Figueroa, 08/03/2009). 

In addition, post-application exposure can result from conducting activities in previously treated 

areas (e.g., gardening). The 2006 RED considered post-application exposure to adults and 

children from treated areas such as gardens and trees (D314814, D315040, S. Recore, 

06/30/2006). This assessment indicated that there were no risk estimates of concern associated 

with residential post-application garden/trees scenarios. In conjunction with determining data 

needs for registration review, revised dermal post-application risk estimates were calculated for 

occupational handlers conducting post-application activities using current policies and exposure 

assumptions. Since the estimated residential post-application exposure for residential 

garden/trees using default DFR values for triadimefon is minimal in comparison to the level of 

concern (i.e., the calculated MOE is greater than 2 times higher than the level of concern, MOE 

= 470 compared to the LOC of 100); the 40CFR DFR data requirement is not needed for 

triadimefon. In this instance, it is unlikely that chemical-specific DFR data would be needed to 

further refine exposure assessments or would add appreciably to our overall understanding of the 

availability of dislodgeable foliar pesticide residues for triadimefon. 

The most recent residential post-application exposure assessments do not reflect the policies of 

the HED’s 2012 Residential Standard Operating Procedures (SOPs), but did not identify risks of 

concern. For registration review, HED anticipates that the post-application exposure assessment 

will need to be updated to reflect current exposure assumptions and procedures for residential 

assessment (e.g., HED’s 2012 Residential SOPs for Treated Turf and Gardens/Trees).

Wood-Preservative Uses

AD has determined that a residential post-application assessment is needed to determine risk for 

children playing on pressure treated playsets and decks. Compared to adults, children are more 
Page 11 of 34

likely to display higher contact activities with wood surfaces (e.g., pressure treated wood playset 

structures), and have a higher surface area to body weight ratio. The potential outdoor residential 

post-application exposure pathways are outlined below:

• Dermal contact with triadimefon-treated wood products (e.g., residential 

playground equipment and decks); and,

• Incidental ingestion due to hand-to-mouth contact with triadimefon-treated wood 

products.

A deterministic screening-level assessment was developed by EPA in 2009 to assess children’s 

exposure using a surrogate assumption that the wood residue concentration would be 1 μg/cm2

(D351282). A confirmatory wood wipe study (GDLN 875.2300) was required as a condition of 

registration to determine the surface residues of triadimefon over time, to provide adequate 

residue data to verify the bounding estimate and to refine the risk assessment. The Agency has 

not received these data. OPP will conduct a more refined assessment, based on the measured 

surface residues of triadimefon and triadimenol, during registration review.

For the wood-preservative uses, residential inhalation exposure is considered negligible based on 

the low vapor pressure of triadimefon (less than 1 x 10-6 mm Hg).

Spray Drift and Volatilization – Conventional Uses

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

volatilization) may occur as a result of the conventional applications of triadimefon. The 

potential for spray drift will be quantitatively evaluated for each pesticide during the Registration 

Review process which ensures that all uses for that pesticide will be considered concurrently. 

The approach is outlined in the revised (2012) Standard Operating Procedures for Residential 

Risk Assessment (SOPs) – Residential Exposure Assessment Standard Operating Procedures 

Addenda 1: Consideration of Spray Drift. This document outlines the quantification of indirect 

non-occupational exposure to drift. In terms of volatilization, the agency has developed a 

Volatilization Screening Tool and a subsequent Volatilization Screening Analysis2. 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 triadimefon.

Conclusions for Residential Assessments

The residential exposure database is adequate to support the existing triadimefon registrations. 

HED previously conducted residential handler and post-application assessments for the uses on 

turf and gardens/trees. The risk estimates were not of concern. However, during registration 

review, HED will update these assessments as needed based on revised toxicity endpoints, 

updated exposure assumptions, and the revised 2012 Residential SOPs. The need for spray drift 

 

2 Volatilization Screening Tool Analysis available at: http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP2014-0219.
Page 12 of 34

and volatilization risk assessments for triadimefon will be also be examined during registration 

review.

AD requires a wood wipe study (GDLN 875.2300) for pressure treated decks for registration 

review for triadimefon and triadimenol. Upon receipt of the requested wood wipe data, AD will 

conduct a refined residential post-application risk assessment for children for 

triadimefon/triadimenol, in support of the wood preservative uses.

Aggregate Risk Assessment

Aggregate risk estimates for acute and chronic exposure to triadimefon and triadimenol are 

equivalent to the dietary risk estimates and are not of concern. Short-term aggregate risk 

estimates were provided in the most recent risk assessment (D351080, 3 August 2009). Margins 

of exposure for adults were not of concern. The MOEs for infants, children 1-2 years old, and 

children 3-5 years old ranged from 92 to 94. Although these MOEs were less than the level of 

concern of 100, they were characterized as being not of concern due to the conservatisms in the 

endpoint selection, including the weight of evidence for doses eliciting the neurotoxic effect 

selected for the risk assessment endpoint. HED notes that the past aggregate assessments for 

triadimefon/triadimenol do not include sources of exposure from the use of triadimefon as a 

wood preservative.

During registration review, HED and AD will provide an updated aggregate risk assessment 

which takes into account the conventional and antimicrobial uses of both compounds.

Occupational Exposure

Triadimefon

In occupational settings for conventional uses, triadimefon may be applied by aerial equipment 

(sod grass only), airblast (tree nursery/Christmas tree farms), groundboom, tractor spreader, 

handheld equipment (e.g., backpack sprayer, mechanically-pressurized handgun, manuallypressurized handwand), or a ready-to-use microinjection. There is potential for occupational 

exposure associated with handler activities (i.e., mixing, loading, and applying) as well as with 

post-application activities (i.e., re-entering treated areas). Occupational exposures are also 

expected for handlers working in commercial/nursery seed treatment operations (e.g., 

loader/applicator, sewer, bagger, multiple activities workers, and planters) treating pine seeds. It 

is HED’s understanding that all food uses for triadimefon have been cancelled. Based on the 

conventional use sites and use patterns, the durations of exposure are expected to be short- and 

intermediate-term. Long-term exposures (i.e., more than 6 months of continuous exposure) are 

not expected to occur.

For uses as a wood preservative, occupational scenarios included mixing and loading wettable 

powders; and pressure and sapstain (dip and spray) applications. Under these scenarios, short-, 

intermediate-, and long-term exposures are expected to occur.
Page 13 of 34

Occupational Handlers

Conventional Uses

The 2006 RED evaluated a number of occupational handler scenarios that represented the major 

triadimefon occupational handler exposures based on application equipment and formulation 

type using the Pesticide Handler Exposure Database (PHED); D314814, D315040, S. Recore, 

06/30/2006). That assessment indicated that occupational handler non-cancer scenarios resulted 

in risk estimates that were not of concern assuming baseline clothing and/or some level of 

mitigation (i.e., additional personal protective equipment (PPE)) for a number of occupational 

handler scenarios. 

For occupational handlers working in commercial seed treatment operations (D326678, R. 

Griffin, 02/09/2006), the dermal risk estimates were not of concern for all registered uses at 

some level of risk mitigation (i.e., chemical-resistant gloves or apron). For commercial seed 

treatment, inhalation MOEs were of concern for two scenarios even with maximum inhalation 

risk mitigation of engineering controls or a 90% protection factor half-face respirator.

In conjunction with determining data needs for registration review, triadimefon was reviewed by 

HED’s HASPOC to evaluate the need for a route-specific inhalation study because previous 

assessments were conducted using data from an oral study. Revised inhalation risk estimates 

were calculated for occupational handlers using current policies, commercial seed treatment 

methodologies and exposure assumptions. Short- and intermediate-term occupational handler 

inhalation MOEs ranged from 11 –570,000; a number of occupational handler scenarios have 

inhalation risk estimates of concern (MOEs< 1,000) at baseline the level of mitigation (i.e., no 

respirator). None of the registered labels currently require any inhalation PPE (i.e., respirator).

Additional personal protective equipment (PPE) is necessary to obtain risk estimates above the 

LOC (i.e., PF 5 or PF 10 respirators, or engineering controls for a number of scenarios). 

However, even with additional PPE, inhalation risk estimates were still of concern for handlers 

applying granules aerially (applicator MOE=220 with engineering controls) and for handlers 

applying wettable powders using a mechanically-pressurized handgun in greenhouses 

(mixer/loader/applicator MOE=570 with a PF10 respirator). All the MOEs for seed treatment 

handlers wearing label-required PPE (i.e., single layer + gloves for loader/applicator and 

multiple activities worker; single layer + no gloves for sewer and bagger) are greater than 1,100 

and are not of concern.

Based on existing registrations, previous risk assessments identified most of the anticipated 

occupational handler exposure scenarios, and estimated risks were not of concern. However, 

since the 2006 RED new exposure data and updated commercial seed treatment methodologies 

are available to assess exposure to occupational handlers. Because of these changes, HED will 

likely conduct an updated occupational handler assessment for triadimefon. Additionally, all 

occupational handler scenarios will need to be reassessed to address updates to HED’s exposure 
Page 14 of 34

policies, including updates to default exposure data used for handler scenarios and assumptions 

for body weights, as well as any revised toxicity endpoints and PODs.

Wood-Preservative Uses

For registration review, the Agency will need new surrogate data to assess handler exposures of 

wood preservatives (mixing/loading wettable powders for composite wood, dip and spray 

sapstain treatments and pressure treatments). Surrogate dermal and inhalation proprietary unit 

exposure data generated by the Antimicrobial Exposure Assessment Task Force II (AETF) and 

Sapstain Industry Group (SIG) would fulfill the data requirement for these assessments. AD no 

longer accepts Chemical Manufacturers Association (CMA) data for registration review. Both 

the AEATF and SIG require compensation for the proprietary use of their unit exposure data.

Upon receipt of the data, AD will conduct new risk assessments. In registration review, 

applicator product use data (875.1700) are needed to clarify uses, application rates (wood 

retentions), and application equipment (verify composite, sapstain and wood pressure 

treatments). The durations of exposure for the occupational uses for workers at wood treatment 

plants are considered to be short (1 to 30 days), intermediate (30 days to 6 months), and longterm (> 6 months).

Occupational Post-Application

Conventional Uses

The 2006 RED evaluated a number of occupational post-application scenarios that represented 

the major triadimefon occupational post-application exposure scenarios based on the registered 

uses. That assessment relied on default assumptions and the Agricultural Reentry Task Force 

(ARTF) since no chemical-specific dislodgeable foliar residue (DFR) data were available. All 

occupational post-application exposure scenarios were not of concern at day 0 (i.e., 12 hours 

after application) for all post-application activities.

Chemical-specific transferable turf residue (TTR) data is available to evaluate post-application 

exposures from treated turf/sod.

In conjunction with determining data needs for registration review, revised dermal postapplication risk estimates were calculated for occupational handlers conducting post-application 

activities using current policies and exposure assumptions. In accordance with 40CFR158, DFR 

data are required for all occupational (e.g., crop, nursery, greenhouse use sites) uses that could 

result in post-application exposure to foliage. In the absence of chemical-specific DFR data, EPA 

uses default values. The 2012 Standard Operating Procedures for Residential Pesticide 

Exposure Assessment includes an analysis of a number of DFR studies, which resulted in the 

selection of a revised default values for the fraction of the application rate available for transfer 

after a foliar application (FAR). These values are based on an analysis of 19 DFR studies. Since 

that time, the Agricultural Re-entry Task Force (ARTF) has submitted information (MRID 

49299201) that corrects an application rate error made in the original submission of “ARF039 –

Determination of Dermal and Inhalation Exposure to Reentry Workers During Chrysanthemum 

Pinching in a Greenhouse” (MRID 45344501). As a result, the range of FAR values was revised 
Page 15 of 34

from 2% - 89% to 2% - 47%. In the data, a large range of transferability is observed and this 

variability can potentially be attributable to many factors such as active ingredient; formulation; 

field conditions in the studies; weather conditions (e.g., humidity); or many other difficult to 

quantify factors. Although witnessed across multiple chemicals, this range in FAR values is not 

expected when considering DFR data for a single chemical. At this time, the ARTF submission 

did not alter the selection of 25% as the reasonable, high-end default value. Because DFR data 

are not available for triadimefon, EPA is using the default value of 25%. Although there may be 

a small degree of uncertainty in the use of the default DFR value for triadimefon (i.e., there is a 

small chance that the FAR value may exceed the applicable default value), it is likely that the 

health-protective aspects of EPA’s occupational post-application assessment methodology will 

more than compensate for this potential uncertainty. For example, when assessing residential and 

occupational post-application exposure to gardens and ornamentals, EPA assumes the following: 

exposures occur to zero-day (i.e., day of application ) residues every day of the assessed 

exposure duration (i.e., EPA assumes that no dissipation or degradation occurs, it doesn’t rain, 

etc); individuals perform the same post-application activities performed in the transfer 

coefficient study day after day (e.g., weeding, harvesting, pruning, etc.); and individuals engage 

in these post-application activities for a high-end amount of time every day (represented by data 

reflecting time spent gardening based on survey data). Given the conservatisms discussed above 

and the potential compounding nature of these conservatisms, EPA is able to rely upon the 

calculated exposure estimates with confidence that exposure is not being underestimated.

Since the highest estimated occupational post-application exposure using default DFR values for 

triadimefon is minimal in comparison to the level of concern (i.e., the calculated MOE is greater 

than 2 times higher than the level of concern, MOE = 430 compared to the LOC of 100); HED 

determined that the 40CFR DFR data requirement is not needed for triadimefon. In this instance, 

it is unlikely that chemical-specific DFR data would be needed to further refine exposure 

assessments or would add appreciably to our overall understanding of the availability of 

dislodgeable foliar pesticide residues for triadimefon.

Since the previous review, there have been several updates to HED’s exposure policies, 

including updates to post-application transfer coefficients, transferable residue assumptions and 

assumptions for body weights. Thus, these post-application scenarios will need to be updated in 

the Registration Review risk assessment to reflect current policies and updated exposure data.

Wood-Preservative Uses

AD does not anticipate the need to conduct an occupational post-application exposure 

assessment. Data from AEATF and SIG cover all worker exposures (i.e., combines both handler 

and post-application exposures). If new policies or procedures arise, the Agency may revisit the 

need for a quantitative occupational post-application inhalation exposure assessment for 

triadimefon.
Page 16 of 34

Triadimenol

Occupational Handlers

Triadimenol is registered for use in the United States for seed treatment (only) in barley, corn, 

cotton, oats, rye, sorghum, and wheat. Formulations registered include emulsifiable concentrate 

(EC), wettable powder (WP), flowable concentrate (FlC), and soluble concentrate (SC). As there 

are no other registered uses for triadimenol, occupational assessment by AD during registration 

review is not necessary.

Occupational exposures are expected for handlers working in commercial seed treatment 

operations (e.g., primary handlers such as loader/applicator, sewer, bagger and multiple activities 

workers) as well as secondary handlers such as planters). Occupational post-application 

occupational exposures are not of concern for any of the registered uses of triadimenol. Based on 

the use pattern, occupational short- and intermediate-term dermal and inhalation exposures are 

anticipated. Long-term exposures (i.e., more than 6 months of continuous exposure) are not 

expected to occur. 

There is the potential for dermal and inhalation exposure to occupational handlers from the 

currently registered use pattern of triadimenol. The most recent assessment (D326716, R. Griffin, 

02/09/2006) conducted in conjunction with the Tolerance Reassessment Eligibility Decision 

(TRED) document for triadimenol, did not address worker exposures to triadimenol. However, 

quantitative dermal and inhalation exposures were previously assessed as part of reregistration 

for occupational handlers working in commercial seed treatment operations for triadimefon (e.g., 

primary handlers such as loader/applicator, sewer, bagger and multiple activities workers) as 

well as secondary handlers such as planters; D326678, R. Griffin, 02/09/2006). All the 

appropriate scenarios were assessed. The dermal risk estimates were not of concern for all 

registered uses at some level of risk mitigation (i.e., chemical-resistant gloves or apron). For 

commercial seed treatment, inhalation MOEs were of concern for two scenarios (even with 

maximum inhalation risk mitigation of engineering controls or a 90% protection factor half-face 

respirator).

Since an inhalation study is not available for triadimenol, HED’s HASPOC evaluated the need 

for a route-specific inhalation study. Using an oral study, inhalation risk estimates were 

calculated for occupational handlers using current policies, commercial seed treatment 

methodologies and exposure assumptions. Short- and intermediate-term occupational handler 

inhalation MOEs were not of concern (> 1,000). The lowest MOE was 1,200 for workers 

conducting multiple activities for the registered seed treatment uses on corn and cotton with no 

respirator.

Although no risks of concern were identified for occupational handler scenarios previously 

assessed for triadimefon, a quantitative occupational handler exposure assessment is anticipated

under registration review. The risk assessment will include both triadimefon and triadimenol, and 

will incorporate revisions to the Agency’s scenario-specific surrogate handler exposure data, 

updated exposure methodologies related to commercial seed treatment, any potential updates to 

points of departure and to body-weight assumptions. 
Page 17 of 34

Occupational Post-Application

As the only registered uses of triadimenol are for seed treatment, occupational post-application 

exposures are not expected.

Conclusions for Occupational Exposure and Risks

Updated occupational handler exposure assessments will be conducted during registration review

for both triadimefon and triadimenol based upon revisions to the Agency’s scenario-specific 

surrogate handler exposure data, revised surrogate unit exposure values, and updated exposure 

methodologies related to commercial seed treatment and policies related to secondary handlers 

for seed treatment. An updated occupational post-application assessment will be conducted 

during registration review to: 1) assess foliar applications of triadimefon to ornamentals (cut 

flowers) based on revisions to transfer coefficients, transferable residue and body weight 

assumptions; 2) incorporate the TTR data based on existing and anticipated occupational postapplication risk estimates for treated turf/sod; and 3) incorporate revised toxicity endpoints.

Public Health and Pesticide Epidemiology Data

D431445, E. Evans and S. Recore, 2 February 2016

D431446, E, Evans and S. Recore, 2 February 2016

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

triadimenol in both the Incident Data System (IDS) and the Sentinel Event Notification System 

for Occupational Risk-Pesticides (SENSOR) 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.

Tolerance Assessment and International Harmonization

Triadimefon: A permanent tolerance for residues of triadimefon (as triadimefon plus triadimenol, 

expressed as triadimefon) in/on pineapple is currently listed in 40 CFR 180.410. It is HED’s 

understanding that the use on pineapple has been cancelled and that this entry can be deleted; 

furthermore, the labels for three technical products (EPA Reg. Nos. 264-736, 264-740, and 

81964-4) should be revised to remove the reference to products for treatment of pineapple. If the 

entry is retained, the tolerance expression will need to be updated to the current format in order 

to address coverage and compliance.

Triadimenol: Permanent tolerances for residues of triadimenol (as triadimenol plus its butanediol 

metabolite calculated as triadimenol) are listed in 40 CFR 180.450. Listings address barley, corn, 

oat, rye, wheat, and cotton commodities. In addition, there is a listing without a U.S. registration 

for residues in/on banana. During registration review, the tolerance expression will need to be 

updated to the current format in order to address coverage and compliance. In addition, HED will 

likely recommend that the entry itself be revised to be in terms of “Triadimenol” rather than by 

its chemical name.
Page 18 of 34

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in the 

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,” 

(https://www3.epa.gov/environmentaljustice/resources/policy/exec_order_12898.pdf). The OPP 

typically considers the highest potential exposures from the legal use of a pesticide when 

conducting human-health risk assessments, including, but not limited to, people who obtain 

drinking water from sources near agricultural areas, the variability of diets within the U.S., and 

people who might be exposed when harvesting crops. Should these highest exposures indicate 

potential risks of concern, OPP further refines the risk assessments to ensure that the risk 

estimates are based on the best available information.

Cumulative Risk Assessments

Triadimefon and triadimenol are both members of the triazole class of fungicides. EPA is not 

currently following a cumulative risk approach for the triazole fungicides. However, this class of 

compounds does produce common metabolites: 1,2,4-triazole, triazolylalanine, triazolylacetic 

acid, and/or triazolylpyruvic acid. These compounds are assessed separately from their parent 

compounds, in an aggregates strategy that takes into account the multiple active ingredients 

involved in their formation and the various sources of exposure.

Human Studies

The previous triadimefon/triadimenol risk assessments relied 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 the Pesticide Handlers Exposure 1.1 (PHED) Database, 

Outdoor Residential Exposure Task Force (ORETF) database, Agricultural Handler Exposure 

Task Force (AHETF) database, 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 

website3. 

Risk Assessment Updates, Data Requirements, and Label Revisions 

Risk Assessment Updates

During registration review, HED and AD anticipate conducting new risk assessments for 

triadimefon/triadimenol in order to evaluate oral, dermal, and inhalation routes of exposure, 

including dietary, residential, and occupational sources of exposure. HED and AD will 

consider both the conventional uses and the antimicrobial uses when evaluating aggregate 

exposure.

 

3 Available at: http://www.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupational-pesticide-handlerexposure-data and http://www.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupational-pesticide-postapplication-exposure.
Page 19 of 34

Data Requirements

OCSPP Guideline 860.1900: Field Accumulation in Rotational Crops (HED)

OCSPP Guideline 870.3465: 90-Day Inhalation Toxicity (HED)

OCSPP Guideline 875.2100: Dislodgeable Foliar Residue Dissipation (HED; only if the uses 

of triadimefon on pineapple are still registered)

OCSPP Guideline 875.1200: Dermal Exposure-Indoor (AD)

OCSPP Guideline 875.1400: Inhalation Exposure-Indoor (AD)

OCSPP Guideline 875.1700: Product Use Information (AD)

OCSPP Guideline 875.2300: Indoor Surface Residue Dissipation (wood preservative) (AD)

Label Revisions

Assuming that the uses of triadimefon on pineapple have been cancelled, the technical labels 

for triadimefon should be revised to delete references to formulations of product intended for 

treatment of pineapple

References

D314742. 23 November 2005. Ary, S. Triadimefon – Summary of Analytical Chemistry and 

Residue Data for the Reregistration Eligibility Decision (RED) Document.

D314891. 17 November 2005. Ary, S. Triadimenol – Summary of Analytical Chemistry and 

Residue Data for the Tolerance Reassessment Eligibility Decision (TRED) 

Document.

D331455. 1 August 2006. Barnes, Y and Piper, S. Triadimefon & Triadimenol: Aggregate 

Acute, Chronic, and Short-Term Risk Assessments Reflecting July, 2006 Risk 

Mitigation in Response to the Phase 4 Triadimefon RED.

D349015. 4 August 2009. Barnes, P. Triadimefon & Triadimenol. Submission of Plant 

Metabolism Studies and a Confined Rotational Crop Study in Response to the 

Triadimenol TRED Dated August 2006.

D351080. 3 August 2009. Figueroa, Z. and Scollon, E. Triadimefon: Human Health Risk 

Assessment to Support Reinstatement of Use on Residential Turf.

TXR# 0057320. 2 February 2016. Triadimefon: Summary of the Hazard and Science Policy 

Council (HASPOC) Meeting of November 12th, 2015: Recommendations on a 

Waiver Request for Immunotoxicity and Subchronic Inhalation Studies.

TXR# 0077322. 22 March 2016. Triadimenol: Summary of the Hazard and Science Policy 

Council (HASPOC) Meeting of November 12th, 2015: Recommendations on 

Waiver Requests for Subchronic Inhalation, Acute and Subchronic Neurotoxicity, 

and Metabolism Studies.

D431445. 2 February 2016. Evans, E and Recore, S. Triadimefon: Tier I (Scoping) Review of 

Human Incidents and Epidemiology.

D431446. 2 February 2016. Evans, E and Recore, S. Triadimenol: Tier I (Scoping) Review of 

Human Incidents and Epidemiology
Page 20 of 34

D351279. 10 March 2009. Lindheimer, T. Acute and Chronic Drinking Water Exposure and 

Risk Assessments to the Registration Action of Preventol® A20 Preservative (EPA 

Reg # 39967-TN).

D351282. 21 April 2009. Mottl, N. Preventol® A20 and Preventol ®A20 Preservative: 

Occupational and Residential Exposure Assessment for New Antimicrobial Uses 

(wood and wood composites) of Triadimefon for Proposed Products (39967-AO 

and 39967-TN).

Attachments

Attachment 1. Triadimefon Toxicity Profile Tables
Page 21 of 34

Attachment 1. Triadimefon Toxicity Profile Tables 

Table 1a. Acute Toxicity Profile for Triadimefon.

New 

Guideline 

No. 

Study Type MRID #(s) Results 

Toxicity Category 

870.1100 Acute Oral - rat 

264276 

LD50 = 1,470 mg/kg (Males) 

LD50 = 1,090 mg/kg 

(Females) 

III 

870.1200 Acute Dermal -

Rabbit 264276 LD50 > 2,000 mg/kg III 

870.1300 Acute Inhalation -

rat 41616002 

LC50 > 3.570 mg/L IV 

870.2400 

Acute (Primary) 

Eye Irritation -

rabbit 

41782501 Slightly irritating IV 

870.2500 Acute (Primary) 

Dermal (Skin) 

Irritation - rabbit 

41616004 

Not an irritant IV 

870.2600 Skin (Dermal) 

Sensitization –

guinea pig 

41554001 

Sensitizer 

Not Applicable 
Page 22 of 34

Table 1b. Subchronic, Chronic, and Other Toxicology Profile for Triadimefon

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.3100a

90-Day oral toxicity (rats)

00048624

Acceptable/guideline

0, 50, 200, 800 and 2000 

ppm

(0, 2.5, 10, 40 and 100 

mg/kg/day)

NOAEL >2000 ppm (100 mg/kg/day) (HDT). Decreased 

body weight gain and food consumption at 2000 ppm (100 

mg/kg/day) was attributed to palatability. 

The LOAEL was not observed.

870.3100

30-Day oral toxicity (rats)

00048627

Acceptable/guideline

0, 3, 10, or 30 mg/kg/day

NOAEL is 10 mg/kg/day. The LOAEL is 30 mg/kg/day 

based on increased liver weights.

870.3100b

90-Day oral toxicity (dogs)

00048625 & 00060226 

(1974)

Acceptable/guideline

0, 150, 600 and 2400 ppm

(0, 3.75, 15, and 

60mg/kg/day)

NOAEL > 2400 ppm (60mg/kg/day) (HDT). Decreased 

body weight gain and food consumption at 2400 ppm 

(60mg/kg/day) was attributed to palatability.

The LOAEL was not observed.

870.3200

21-Day dermal toxicity 

(rats)

42341501 (1992)

Acceptable/guideline

0, 100, 300, or 1000 mg/kg 

bw/day

NOAEL is 300 mg/kg/day. The LOAEL was 1000 

mg/kg/day based on increased reactivity and activity in the 

females. 

870.3700a 

Prenatal developmental in 

(rats)

00089023 (1981)

Acceptable/guideline

0, 10, 25, 50, or 100 mg/kg 

bw/day

Maternal NOAEL is 10 mg/kg/day and the LOAEL is 25 

mg/kg/day based on dose- related increase in both degree 

and duration of motor activity and/ or depression of 

maternal weight.

Developmental NOAEL is 50 mg/kg/day and the LOAEL 

is 100 mg/kg/day based on increased incidences of cleft 

palates; two fetuses from two different litters were found 

to have cleft palate.

870.3700a

Prenatal developmental in 

(rats)

00149336 & 92188018 

(1990)

Acceptable/guideline

0, 10, 30, or 90 mg/kg 

bw/day

Maternal NOAEL is 30 mg/kg/day and the LOAEL is 90 

mg/kg/day based on decreased body weight gains. 

Developmental NOAEL is 30 mg/kg/day. The LOAEL is 

90 mg/kg/day based on increased incidences of distended 

urinary bladders and abnormal ribs (extra ribs and rib 

buds). 

870.3700b

Prenatal developmental in 

(rabbits)

41446201 & 42089601 

(1990)

Acceptable/guideline

0, 20, 50, or 120mg/kg 

bw/day

Maternal NOAEL is 50 mg/kg/day and the LOAEL is 120 

mg/kg/day based on minor decreases in initial body 

weight gains, placental weights, and fetal weights and on 

initial decreased food consumption. 

Developmental NOAEL is 20 mg/kg/day. The LOAEL is 

50 mg/kg/day based on dose-related increases in the 

incidences of incomplete ossification of the pelvis pubes 

and anterior and posterior phalanges and irregular spinous 

processes on the scapula.
Page 23 of 34

870.3800

Reproduction and fertility 

effects

(rats)

00155075, 92188019 & 

92188320 (1984)

Acceptable/nonguideline

0, 50, or 1800 ppm (0, 2.5, 

90 mg/kg/day)

The reproductive study in 

the rat is acceptable/ 

nonguideline in conjunction 

with the 3-generation study 

(MRID 00032541).

Parental/Systemic/ Reproductive toxicity NOAEL was not 

established because of the equivocal findings on body 

weights in the F1 dams and ovary weights in the P dams at 

2.5 mg/kg/day.

Offspring NOAEL is 2.5 mg/kg/day and the LOAEL is 90 

mg/kg/day based on decreased pup weights and viability 

in the F1 and F2 generations and decreased litter size in the 

F2 generation. 

Based on the combined two studies the Parental 

systemic/Reproductive toxicity NOAEL is 15 

mg/kg/day and the LOAEL is 90 mg/kg/day.

The Offspring NOAEL is 15 mg/kg/day and the 

LOAEL is 90 mg/kg/day.

870.3800

Reproduction and fertility 

effects

(3 -Gen)

(rats)

00032541 (1979)

Acceptable/nonguideline

0, 50, 300, or 1800 ppm (0, 

2.5, 15, and 90 mg/kg/day)

The reproductive study in 

the rat is acceptable/ 

nonguideline in conjunction 

with the multi generation 

reproduction study (MRID 

00155075)

Parental systemic/Reproductive toxicity NOAEL is 15 

mg/kg/day and the LOAEL is 90 mg/kg/day based on 

decreased fertility, body weights, body weight gains, and 

litter size. 

Offspring NOAEL and LOAEL is equivocal due to severe 

reproductive effects (In the F1 pups, at 90 mg/kg/day, the 

number of offspring per dam was decreased (p<0.05) in 

the F1a and F1b litters (decr. 20-31%) at post-natal day 

(PND) 5. At PND 28, viability was decreased (p<0.01) in 

the F1a (90.7% treated vs 97.8% controls) and F1b (56.4% 

treated vs 84.2% controls) pups. Additionally, body 

weight gains of the F1a pups were decreased (decr. 10%; 

p<0.05) during lactation).

Based on the combined two studies the Parental 

systemic/Reproductive toxicity NOAEL is 15 

mg/kg/day and the LOAEL is 90 mg/kg/day.

The Offspring NOAEL is 15 mg/kg/day and the 

LOAEL is 90 mg/kg/day.

870.4100b

Chronic toxicity

(dogs)

00032539 & 00126261 

(1978)

Acceptable/guideline

0, 100, or 330, or 1000 

ppm (wk 1–54), or 2000 

ppm (wk 55-104) 

M: 0, 3.03, 11.42, 34.70 

(wk 1-54) or 68.80 (wk 55-

104) mg/kg bw/day

F: 0, 3.49, 11.96, 33.67 (wk 

1-54) or 60.42 (wk 55-104) 

mg/kg bw/day

NOAEL is 330 ppm (equivalent to 11.42/11.96 mg/kg/day 

in males/females). 

LOAEL is 1000 ppm (equivalent to 34.70/33.67 

mg/kg/day in males/females), based on increased alkaline 

phosphatase levels in both sexes; and decreased food 

consumption and increased cholesterol in females. 
Page 24 of 34

870.4200b

Carcinogenicity

(mice)

40752101& 40865101 

(1986)

Acceptable/guideline

0, 50, 300, or 1800 ppm

M: 13.5, 76.0, or 550.1 

mg/kg/day

F: 0, 19.6, 119.4 or 765 

mg/kg/day

NOAEL is 50 ppm (equivalent to 13.5/19.6 mg/kg/day in 

males/females).

LOAEL is 300 ppm (equivalent to 76.0/119.4 mg/kg/day 

in males/females) based on hepatocellular hypertrophy in 

both sexes; increased liver weights in males; and Kupffer 

cell proliferation, single cell necrosis and pigment 

accumulation in the liver of females. 

At the doses tested, the carcinogenic potential of MEB 

6447 in mice is positive. There was a treatment-related 

increase (p<=0.05, study authors) in hepatocellular 

adenomas. The incidence at the high dose (22% in males 

and 18% in females) exceeded the concurrent controls (4-

6%) and the historical controls (0-18.4% [mean=5.9%] in 

males and 0-2% [mean=0.3%] in females). A positive 

trend (p<0.01, Agency reviewers, TXR # 007294) in 

combined liver nodules and hepatocellular adenoma was 

observed. Furthermore, an increased incidence (p<0.01, 

Agency reviewers, TXR # 007294) of combined liver 

nodules and hepatocellular adenomas was observed at the 

high dose in both sexes. Dosing was considered adequate 

based on hepatotoxicity in both sexes at >=300 ppm; and 

decreased body weights and body weight gain and 

increased overall food and water consumption in males at 

1800 ppm.

870.4300

Combined Chronic/ 

Carcinogenicity

(rats)

42153901 (1991)

Acceptable/guideline

0, 50, 300, or 1800 ppm

M: 0, 2.7, 16.4, or 114.0 

mg/kg/day

F: 0, 3.6, 22.5, or 199.0 

mg/kg/day

NOAEL = 16.4/22.5 mg/kg/day in males/females.

LOAEL = 114.0/199.0 mg/kg/day in males/females based 

on increased food consumption in both sexes, incidence of 

fat in the hepatocytes in both sexes, alanine 

aminotransferase levels in males, cholesterol levels in 

females, and absolute and relative (to body) liver weights 

in females, and decreased body weight and body weight 

gains in females. 

At the doses tested, the carcinogenic potential of MEB 

6447 is equivocal based on the incidence of thyroid 

adenomas and cystic hyperplasia in both sexes.

870.5100

Bacterial system

099412 7 099413

acceptable/ guideline

negative

870.5395

Micronucleus assay

00048637 (1977)

acceptable/ guideline

negative

870.5450

Cytogenetics dominant 

lethal assay

00048628 (1976)

acceptable/ guideline

negative

870.5550 

DNA damage/ Repair

00159343 (1985) negative
Page 25 of 34

870.6200a

acute neurotoxicity 

screening battery

(rats

43495509 (1992)

unacceptable/non-guideline

0, 30, 100, 300 mg/kg/day

No definitive NOAEL or LOAEL could be established

870.6200a

acute neurotoxicity 

screening battery

(rats)

43936101 (1996)

Acceptable/guideline

0, 2, 31.2, 424.4 (females 

only) and 587.4 (males 

only)

The NOAEL is 2 mg/kg. 

The LOAEL for systemic/neurobehavioral findings is 31.2 

mg/kg based on clinical signs, FOB, rearing, body 

temperature, MA, habituation, and spatial distribution in 

males and females. 

870.6200b

Subchronic neurotoxicity 

screening battery

(rats)

44153501 (1996)

Acceptable/guideline

0,50,800,or 2200 ppm

M: 0, 3.4, 54.6 or 149.8 

mg/kg/day

F: 0,4.3, 68.7, or 189.7 

mg/kg/day

NOAEL is 50 ppm (3.4 and 4.3 mg/kg/day, 

males/females, respectively).

LOAEL for neurotoxicity is 800 ppm (54.6 and 68.7 

mg/kg/day males/females respectively) based largely on 

hyperactivity.

870.6300

Developmental 

Neurotoxicity Study in 

Rats

47377101 (2008)

Acceptable/Non-guideline

0, 100, 300, or 800 ppm

0, 8.0, 23.9, 71.3 mg/kg/day

Parental NOAEL is 23.9 mg/kg/day and the LOAEL is 

71.3 mg/kg/day based on decreases in body weight on GD 

13 and LD 0 and body weight gain during GD 0-20.

Offspring NOAEL is 23.9 mg/kg/day and the LOAEL is 

71.3 mg/kg/day based on post-weaning clinical signs 

(deviated snout); decreases in pre-weaning body weight 

(PND 11, 17, and 21) in both sexes, pre-weaning body 

weight gain in both sexes; increased peak amplitude 

during auditory startle reflex testing in females; and 

increased number of trials to criterion during the retention 

phase of the avoidance test in females.

870.7485

Metabolism and 

pharmacokinetics

(rats)

42409101(1992)

Acceptable/guideline

5 or 50 mg/kg

Radioactivity was not detected in the expired air. The 

overall recovery of radioactivity was 97-112%. The 

compound was predominantly excreted (90-98% dose) 

within 4 days. The excretion profile of the repeated lowdose group was similar to the single low-dose group; 

however, the excretion profiles were sex-dependent. Over 

a 4 day-period, recovery in the urine was 24-28% dose in 

males and 57-66% in females, and recovery in feces was 

63-66% in males and 32-40% in females. Thus, based on 

urinary excretion, absorption was at least 24% dose in 

males and 57% in females. Less than 1% dose remained in 

the body 4 days after treatment. 
Page 26 of 34

870.7485

Metabolism and 

pharmacokinetics

(rats)

00033057(1979)

Acceptable/guideline

24.5-25.0 mg/kg

Radioactivity was not detected in the expired air of 

animals. Over a 7 day-period, recovery in the urine was 

29.8% dose in males and 39.9% in females, and recovery 

in feces was 52.7% in males and 34.5% in females. Thus, 

based on urinary excretion, absorption was at least 29.8% 

dose in all animals.

Plasma levels of radioactivity were highest 1-2 hours postdose (2.5-3.2 ppm), and the half-life (calculated by the 

reviewer) was about 4 hours. Tissue concentrations in 

males were generally similar to females. The highest 

concentrations of radioactivity were found in the fat (43.5-

45.0 ppm) at 4-8 hours post-dose. Approximately 50% of 

the radiolabeled compound in the fat of males was 

unchanged Bayleton and 50% was isomeric forms of the 

2-butanol derivative KWG 0519 (triadimenol); over 90% 

was Bayleton in females. In addition, relatively high 

concentrations of radioactivity were observed in the liver 

(26.2-28.4 ppm) and skin (21-22 ppm) at 2 hours postdose. Tissue concentrations were <0.14 ppm at 7 days 

post-dose. 

In the urine, the major component of the acidified extract 

was KWG 0519 acid (6.1-7.7% dose). In the direct extract 

of urine, 3 minor metabolites were identified: pchlorophenol, KWG 1323, and KWG 1342 (two isomers). 

In the direct extract of the feces, KWG 1323, KWG 1342, 

and KWG 0519 acid (5.7-20.0% dose) were identified. 

KWG 1323 was the predominant metabolite in the feces 

of females (12.7% dose), and KWG 0519 acid was the 

predominant metabolite in the feces of males (20.0% 

dose). Thus, the major metabolites were the alcohol and 

acid of Bayleton, which were formed by the sequential 

hydroxylation and oxidation of the methyl group of the 

t-butyl chain.
Page 27 of 34

Attachment 2. Triadimefon Toxicology Endpoint Tables.

Table 2a. Summary of Toxicological Doses and Endpoints for Triadimefon in Dietary and NonOccupational Human Health Risk Assessments.

Exposure

Scenario

Dose Used in Risk 

Assessment, UF

FQPA SF and Level of 

Concern (LOC) for Risk 

Assessment

Study and Toxicological Effects

Acute Dietary

(all populations)

NOAEL = 3.4 

mg/kg/day

UF = 100

Acute RfD = 0.034 

mg/kg/day

FQPA SF = 1X

aPAD = acute RfD

FQPA SF

aPAD = 0.034 mg/kg/day

Subchronic neurotoxicity study in rats.

LOAEL = 54.6/68.7 mg/kg/day based 

largely on hyperactivity.

Chronic Dietary

(all populations)

NOAEL = 3.4 

mg/kg/day

UF = 100

Chronic RfD = 0.034 

mg/kg/day

FQPA SF = 1X

PAD = chronic RfD

FQPA SF

cPAD = 0.034 mg/kg/day

Subchronic neurotoxicity study in rats.

LOAEL = 54.6/68.7 mg/kg/day based 

largely on hyperactivity.

Incidental Oral 

Short-Term and 

Intermediate-Term

(1 - 30 days)

(1-month – 6 months)

NOAEL = 3.4 

mg/kg/day Residential

MOE = 100

Subchronic neurotoxicity study in rats.

LOAEL = 54.6/68.7 mg/kg/day based 

largely on hyperactivity.

Dermal

Short-Term and 

Intermediate-Term

(1 - 30 days)

(1-month – 6 months)

Dermal NOAEL = 

300 mg/kg/day

Residential

MOE = 100

21 Day Dermal Toxicity in rabbits.

The LOAEL= 1000 mg/kg/day based on 

increased reactivity and activity in the 

females.

Inhalation

Short-Term and 

Intermediate-Term

(1 - 30 days)

(1-month – 6 months)

NOAEL = 3.4 

mg/kg/day

Residential

MOE = 100 Subchronic neurotoxicity study in rats.

LOAEL = 54.6/68.7 mg/kg/day based 

largely on hyperactivity.

Cancer (oral, dermal, 

inhalation)

Classification: Category C “possible human carcinogen” based on statistically significant 

increase in thyroid adenomas in male Wistar rats and statistically significant increases in 

hepatocellular adenomas in both sexes of the NMRI mouse.

NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty 

factor. FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference 

dose. MOE = margin of exposure. LOC = level of concern. 
Page 28 of 34

Table 2b. Summary of Toxicological Doses and Endpoints for Triadimefon in Occupational Human 

Health Risk Assessments.

Exposure

Scenario

Dose Used in Risk 

Assessment, UF

Level of Concern (LOC) 

for Risk Assessment Study and Toxicological Effects

Dermal

Short-Term and 

Intermediate-Term

(1 - 30 days)

(1-month – 6 months)

Dermal NOAEL = 

300 mg/kg/day Occupational

MOE = 100

21 Day Dermal Toxicity in rabbits.

The LOAEL= 1000 mg/kg/day based on 

increased reactivity and activity in the 

females.

Inhalation

Short-Term and 

Intermediate-Term

(1 - 30 days)

(1-month – 6 months)

NOAEL = 3.4 

mg/kg/day Occupational

MOE = 100

Subchronic neurotoxicity study in rats.

LOAEL = 54.6/68.7 mg/kg/day based 

largely on hyperactivity.

Cancer (oral, dermal, 

inhalation)

Classification: Category C “possible human carcinogen” based on statistically significant 

increase in thyroid adenomas in male Wistar rats and statistically significant increases in

hepatocellular adenomas in both sexes of the NMRI mouse.

NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty 

factor. MOE = margin of exposure. LOC = level of concern.

Attachment 3. Triadimenol Toxicity Profile Tables.

Table 3a: Acute Toxicity Profile - Triadimenol Technical

Guideline No. Study Type MRID(s) Results Toxicity 

Category

870.1100 Acute oral -rat 00125411 LD50 = 689 mg/kg (males)

LD50 = 752 mg/kg (females)

III

870.1200 Acute dermal - rabbit 00145086 LD50 > 2000 mg/kg III

870.1300 Acute inhalation - rat 00145087 LC50 > 2.58 mg/L (Limit Dose) IV

870.2400 Acute eye irritation - rabbit 00145088 eye irritant (irritation cleared in 

21 days or longer). II

870.2500 Acute dermal irritation - rabbit 00145088 mild skin dermal irritation IV

870.2600 Skin sensitization- guinea pig 00125413 Not a skin sensitizer Not 

Applicable

Table 3b: Subchronic, Chronic, and Other Toxicity Profile - Triadimenol Technical

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.3100

90-Day oral toxicity 

rodents (rats)

00127769 (1977)

Acceptable/guideline

0, 150, 600, or 2400 ppm

M: 0, 12.16, 49.23, 203.07

mg/kg/day

NOAEL is 600 ppm (equivalent to 49.23/71.33 

mg/kg/day [M/F]). The LOAEL is 2400 ppm 

(equivalent to 203.07/236.60 mg/kg/day [M/F]) 

based on initial body weight decreases in both 

sexes.
Page 29 of 34

Table 3b: Subchronic, Chronic, and Other Toxicity Profile - Triadimenol Technical

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

F: 0, 17.07, 71.33, 236.60

mg/kg/day

42192701 (1983)

Acceptable/guideline

0, 120, 600, or 3000 ppm

M: 0, 8.0, 39.6, 208.5 

mg/kg/day

F: 0, 9.4, 46.4, 221.1 

mg/kg/day

NOAEL is 120 ppm (equivalent to 8.0/9.4 

mg/kg/day in the males/females). The LOAEL for 

this study is 600 ppm (equivalent to 39.6/46.4 

mg/kg/day in the males/females) based on increased 

liver weights and incidences of liver hypertrophy in 

the males and females and on fatty changes in the 

liver in the females. 

870.3150

90-Day oral toxicity (nonrodents- dogs)

00125420 (1977)

Acceptable/guideline

0, 150, 600, or 2400 ppm

M: 0, 44.2, 178.5, or 717.0 

mg/kg/day

F: 0, 44.8, 179.0 or 702.1 

mg/kg/day

NOAEL is 600 ppm (equivalent to 44.2/44.8 

mg/kg/day in the males/females). The LOAEL for 

this study is 2400 ppm (equivalent to 717.0/702.1 

mg/kg/day in the males/females) based on decreased 

body weights and body weight gains in the females, 

increased alkaline phosphatase, cholesterol, absolute 

kidney weights, and renal cysts in the males, and 

increased N-demethylase and relative liver weights 

in the males and females. 

870.3150

6 months oral toxicity 

(non- rodents- dogs)

00151247 (1984)

Acceptable/guideline

0, 10, 30, or 100 ppm

0, 0.25, 0.75, or 2.5 

mg/kg/day

NOAEL is 100 ppm (approximately equivalent to 

2.5 mg/kg/day). The LOAEL was not observed. 

870.3200

15-Day dermal toxicity 

(rabbits)

00151246 (1984)

Acceptable/guideline

0, 50, or 250 mg/kg/day

NOAEL is 250 mg/kg/day for males and females. 

The LOAEL was not observed.

870.3465

21-Day inhalation toxicity 

(rats)

00125421 (1976)

Unacceptable/not 

ungradable

0, 30, 68, or 230 mg/m3

0, 0.030, 0.068, or 0.230 

mg/L

NOAEL is 0.230 mg/L/day, the highest dose tested.

The LOAEL was not observed.

870.3700a 41498401 (1990)

Acceptable/guideline

Maternal NOAEL is 5 mg/kg/day and the LOAEL is 

15 mg/kg/day based on decreased body weights and 
Page 30 of 34

Table 3b: Subchronic, Chronic, and Other Toxicity Profile - Triadimenol Technical

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

Prenatal developmental in 

(rats)

0, 5, 15, 25, or 60 

mg/kg/day

40307804 & 40887702 

(1987)

Acceptable/guideline

0, 30, 60, or 120 mg/kg/day

adjusted (for gravid uterine weight) body weight 

gains.

Developmental NOAEL is 25 mg/kg/day and the 

LOAEL is 60 mg/kg/day based on increased 

incidences of extra ribs, a variation. 

Maternal NOAEL is 30 mg/kg/day and the LOAEL 

is 60 mg/kg/day based on decreased body weights, 

body weight gains, and food consumption. 

Developmental NOAEL is 30 mg/kg/day and the 

LOAEL is 60 mg/kg/day based on increased 

incidences of supernumerary ribs. 

870.3700b

Prenatal developmental in 

(rabbits)

42365001 (1992)

Acceptable/guideline

0, 5, 25, or 125 mg/kg/day

40307805 & 40887703 

(1987)

Acceptable/guideline

0, 8, 40, or 200 mg/kg/day

Maternal NOAEL is 25 mg/kg/day and the LOAEL 

is 125 mg/kg/day based on decreased body weights, 

body weight gains, and food consumption.

Developmental NOAEL is 125 mg/kg/day (HDT). 

The developmental LOAEL was not observed. 

Maternal NOAEL is 40 mg/kg/day and the LOAEL 

is 200 mg/kg/day based on clinical signs of toxicity, 

decreased body weights and food consumption, and 

increased post-implantation loss and early 

resorptions.

Developmental NOAEL is 40 mg/kg/day and the 

LOAEL is 200 mg/kg based on skeletal 

abnormalities. 

870.3800

Reproduction and fertility 

effects

(rats)

00151248 (1984)

Acceptable/ guideline 

0, 20, 100, or 500 ppm

(0, 1, 5 or 25 mg/kg/day)

Parental/Systemic toxicity NOAEL is 5 mg/kg/day 

and the LOAEL is 25 mg/kg/day based on 

decreased body weights and body weight gains in 

the F1b generation. 

Offspring toxicity NOAEL is 5 mg/kg/day and the 

LOAEL is 5 mg/kg/day based on decreased pup 

weight.

Reproductive toxicity NOAEL appears to be 5 

mg/kg/day

The LOAEL for reproductive performance was not 

observed. 

870.4100b 00150484 & 00159012 

(1984)
Page 31 of 34

Table 3b: Subchronic, Chronic, and Other Toxicity Profile - Triadimenol Technical

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

Chronic toxicity (dog) Acceptable/non-guideline

0, 150, 600, or 2400 ppm

0, 3.8, 15.0, or 60.0 

mg/kg/day

The NOAEL is 3.8 mg/kg/day and the LOAEL is 15 

mg/kg/day based on changes in enzyme levels.

870.4200

Carcinogenicity

(mice)

44740901 (1998)

Unacceptable/guideline

0, 80, 400, or 2000 ppm

M: 0, 11.3, 60.2, or 340.3 

mg/kg/day

F: 0, 17.2, 91.3 or 472 

mg/kg/day

NOAEL in males is 80 ppm (equivalent to 11.3 

mg/kg/day) and in females is 400 ppm (equivalent 

to 91.3). 

LOAEL in males is 400 ppm (equivalent to 60.2 

mg/kg/day) based on hepatic changes and increased 

relative food consumption. The chronic LOAEL in 

females is 2000 ppm (equivalent to 472.0 

mg/kg/day) based on decreased body weights and 

body weight gains, increased relative food 

consumption, and hepatic changes. 

No evidence of carcinogenicity 

870.4200

Carcinogenicity

(mice)

00126259 (1982)

Acceptable/guideline

0, 125, 500, or 2000 ppm

0, 19, 75, or 300 mg/kg/day

The NOAEL is 125 ppm (equivalent to 19 

mg/kg/day).

The LOAEL is 500 ppm (equivalent to 75 

mg/kg/day), based on increased alanine 

aminotransferase levels in both sexes and aspartate 

aminotransferase in females. 

At the doses tested, the carcinogenic potential of 

KWG 0519 is positive at 500 ppm. Hepatic 

neoplastic lesions occurred in females due to 

treatment. The incidence of adenomas increased 

dose-dependently (2-10% treated vs 0% concurrent 

controls and 4% historical controls). The incidence 

of hepatic carcinoma was increased at 500 and 2000 

ppm (4-6% treated vs 2% concurrent controls). The 

incidence of combined hepatic adenomas and 

carcinomas was also increased at 500 and 2000 ppm 

(10-16% treated vs 2% controls). The Toxicology 

Branch Peer Review Committee (TXR #006772, 

dated July 6, 1988) concluded that KWG 0519 

should be classified as a Group C carcinogen. 

Dosing was considered adequate based on decreased 

body weights, and increased blood levels of hepatic 

enzymes and liver weights, and increased incidences 

of gross and microscopic abnormalities.

870.4300

Combined 

Chronic/Carcinogenicity

(rats)

00126260 (1982)

Acceptable/guideline

0, 125, 500, or 2000 ppm

The NOAEL is 125 ppm (approximately equivalent 

to 6.25 mg/kg/day). 

The LOAEL is 500 ppm (approximately equivalent 

to 25 mg/kg/day), based on increased glutamate 

dehydrogenase and liver bile duct vacuolization in 
Page 32 of 34

Table 3b: Subchronic, Chronic, and Other Toxicity Profile - Triadimenol Technical

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

0, 6.25, 25, or 100 

mg/kg/day

males; and aspartate and alanine aminotransferase 

levels in females.

no evidence of carcinogenicity

870.5100

Bacterial system, 

mammalian activation 

gene mutation

00126264 (1979)

Unacceptable/ guideline

0, 4, 20, 100, 500, or 2500 

μg/plate (+S9) and 2500 

μg/plate (-S9)

Negative

870.5300

In Vitro Mammalian Cell 

Gene Mutation

00126269 (1982)

Acceptable/ guideline

7.8, 15.6, 31.3, 62.5, or 

125.0 μg/mL (-S9)

3.91, 7.81, 15.6, 31.3, or 

62.5 μg/mL (+S9)

Negative

870.5450

Cytogenetics 

dominant lethal assay

00126266 (1978)

Unacceptable/up- gradable

0 or 500 mg/kg

Negative

870.5500

Other Genotoxicity

DNA damage

00126271 (1981)

Acceptable/guideline

0, 62.5, 125, 250, 500, or 

1000 μg/plate

Negative

no evidence that DNA damage was induced

870.5550

Other Genotoxicity

Unscheduled DNA 

Synthesis

00126271 (1982)

Acceptable/guideline

0, 0.25, 0.5, 1, 2.5, 5, 10, 

25, 50, 100, or 250 μg/mL.

Negative

no evidence that unscheduled DNA synthesis

870. 5900

Other Effects 

In vitro Sister Chromatid 

Exchange Assay

40815901 (1987)

Acceptable/guideline

0, 100, 125, 150, 175, or 

200 μg/mL (+S9)

0, 38, 75, 150, 225, or 300 

μg/mL (-S9)

Negative

Other Studies

Central Nervous Effects

(mouse)

00145083 (1983)

3.75 to 60 mg/kg

In mice, KWG 0519 (3.75 to 60 mg/kg) stimulated 

the spontaneous motility, increased their irritability 

and escape response and augmented certain 

reflexes; dose of 15 and 60 mg/kg potentiated the 

effect of amphetamine; and doses of 12 to 48 mg/kg 

antagonized that of reserpin. The substance 

prolonged the hexobartital sleeping time at 15 and 

60 mg/kg. In rats, the dose of 48 mg/kg had an 

excitatory effect.

A comparison with caffeine showed that the effect 

of the dose of 2.5 mg caffeine/ kg corresponded 

approximately to that of 12 to 15 mg/ KWG 0519/ 
Page 33 of 34

Table 3b: Subchronic, Chronic, and Other Toxicity Profile - Triadimenol Technical

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

kg, in the amphetamine potentiation test that of 4 

mg KWG 0519/ kg, in the antagonism of ptosis 10 

mg caffeine/ kg and 12 mg KWG 0519/ kg were 

comparable. The no-effect dose was ca. 1 mg/kg.

Attachment 4. Triadimenol Toxicology Endpoint Tables.

Table 4a. Summary of Toxicological Doses and Endpoints for Triadimenol Dietary and NonOccupational Human Health Risk Assessments.

Exposure

Scenario

Dose Used in Risk 

Assessment, UF

FQPA SF and Level of 

Concern (LOC) for Risk 

Assessment

Study and Toxicological Effects

Acute Dietary

(all populations)

NOAEL = 3.4 

mg/kg/day

UF = 100

Acute RfD = 0.034 

mg/kg/day 

FQPA SF = 1X

aPAD = acute RfD

FQPA SF

aPAD = 0.034 mg/kg/day

Subchronic neurotoxicity study in rats.

LOAEL = 54.6/68.7 mg/kg/day based 

largely on hyperactivity.

Chronic Dietary

(all populations)

NOAEL = 3.4 

mg/kg/day

UF = 100

chronic RfD = 0.034 

mg/kg/day 

FQPA SF = 1X

PAD = chronic RfD

FQPA SF

cPAD = 0.034 mg/kg/day

Subchronic neurotoxicity study in rats.

LOAEL = 54.6/68.7 mg/kg/day based 

largely on hyperactivity.

Cancer (oral, dermal, 

inhalation)

Classification: Category C “possible human carcinogen” based on increases in 

hepatocellular adenomas in female mice.

OCCUPATIONAL ENDPOINT/PODS SELECTED FOR SCREENING PURPOSES:

Table 4b. Summary of Toxicological Doses and Endpoints for Triadimenol in Occupational Human 

Health Risk Assessments

Exposure

Scenario

Dose Used in Risk 

Assessment, UF

Level of Concern (LOC) 

for Risk Assessment Study and Toxicological Effects

Dermal

Short-Term and 

Intermediate-Term

(1 - 30 days)

(1-month – 6 months)

NOAEL = 30 

mg/kg/day

DAF=50%*

Occupational

MOE = 100

Rabbit Developmental

Developmental LOAEL is 60 mg/kg/day 

based on increased incidences of 

supernumerary ribs in the absence of 

treatment related maternal toxicity. 
Page 34 of 34

Table 4b. Summary of Toxicological Doses and Endpoints for Triadimenol in Occupational Human 

Health Risk Assessments

Exposure

Scenario

Dose Used in Risk 

Assessment, UF

Level of Concern (LOC) 

for Risk Assessment Study and Toxicological Effects

Inhalation

Short-Term

Intermediate-Term

(1 - 30 days; 1 - 6 months )

NOAEL = 5 

mg/kg/day Occupational

MOE = 100

Rat Developmental

LOAEL=15 mg/kg/day, based on 

decreased body weights.

Cancer (oral, dermal, 

inhalation)

Classification: Category C “possible human carcinogen” based on increases in 

hepatocellular adenomas in female mice.

*Estimated dermal absorption factor calculated by comparing the ratio of the oral rabbit developmental LOAEL and the rabbit 

dermal NOAEL (oral LOAEL/dermal NOAELx100)