Tetraconazole Human

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

 

MEMORANDUM

Date: 14-APRIL-2011

SUBJECT: Tetraconazole: Human

Vine Climbing Subgroup 13

Corn and Popcorn.

PC Code: 120603

Decision Nos.: 435873, 436333

Petition Nos.: 0E7735, 0F7737

Risk Assessment Type: Single Chemical

Aggregate

TXR No.: NA

MRID No.: NA

FROM: Allison A. Nowotarski, Biologist

Thomas Bloem, Chemist

Anwar Y. Dunbar, Ph.D., Pharmacologist

Risk Assessment Branch 1 (RAB1)

Health Effects Division (HED

THROUGH: George F. Kramer, Ph.D., Branch Senior Chemist

Dana M. Vogel, Branch Chief 

RAB1/HED (7509P)

TO: Barbara Madden,

Fungicide Branch

Registration Division (

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human 

health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and 

exposure data and conduct dietary, occupational, residential, and aggregate exposure 

assessments, as needed, to estimate the risk to human health that will result from all registered 

and proposed uses of tetraconazole

1H-1,2,4-triazole). A summary of the findings and an assessment of human risk resulting from the 

registered and proposed uses for 

assessment and occupational/residential exposur

Nowotarski (RAB1), the dietary risk assessment

Bloem (RAB1), the hazard characterization was provided by Anwar Dunbar

Human-Health Risk Assessment 

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND

 POLLUTION PREVENTION

Human-Health Risk Assessment for Proposed Uses on Small Fruit 

Vine Climbing Subgroup 13-07F, Low-Growing Berry Subgroup 12

DP Barcodes: D380618, D38144

Registration Nos.: 80289-7, 80289

Regulatory Action: Section 3

Single Chemical/ Case No.: 7043

CAS No.: 112281-77-3

40 CFR: §180.557

Nowotarski, Biologist

Thomas Bloem, Chemist

Dunbar, Ph.D., Pharmacologist

Risk Assessment Branch 1 (RAB1)

Health Effects Division (HED; 7509P)

George F. Kramer, Ph.D., Branch Senior Chemist

Vogel, Branch Chief 

RAB1/HED (7509P)

RM 05

Fungicide Branch

Registration Division (RD; 7505P)

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human 

health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and 

osure data and conduct dietary, occupational, residential, and aggregate exposure 

assessments, as needed, to estimate the risk to human health that will result from all registered 

tetraconazole (1-[2-(2,4-dichlorophenyl)-3-(1,1,2,2-tetrafluoroethoxy)propyl]

. A summary of the findings and an assessment of human risk resulting from the 

registered and proposed uses for tetraconazole are provided in this document. The risk 

assessment and occupational/residential exposure assessment were provided by Allison 

Nowotarski (RAB1), the dietary risk assessment and residue chemistry data review by 

(RAB1), the hazard characterization was provided by Anwar Dunbar (RAB1), and the 

 DP#: 380618 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION

Health Risk Assessment for Proposed Uses on Small Fruit 

Growing Berry Subgroup 12-07G, and Field 

448

7, 80289-8

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human 

health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and 

osure data and conduct dietary, occupational, residential, and aggregate exposure 

assessments, as needed, to estimate the risk to human health that will result from all registered 

rafluoroethoxy)propyl]-

. A summary of the findings and an assessment of human risk resulting from the 

are provided in this document. The risk 

e assessment were provided by Allison 

and residue chemistry data review by Thomas 

(RAB1), and the 
Tetraconazole Human-Health Risk Assessment DP#: 380618 

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drinking water assessment by Chris Koper of the Environmental Fate and Effects Division 

(EFED).

Table of Contents

1.0 Executive Summary ........................................................................................................... 4

2.0 HED Recommendations..................................................................................................... 9

2.1 Data Deficiencies/Conditions of Registration............................................................. 9

2.2 Tolerance Considerations........................................................................................... 10

2.2.1 Enforcement Analytical Method ........................................................................... 10

2.2.2 International Harmonization................................................................................. 10

2.2.3 Recommended Tolerances...................................................................................... 10

2.2.4 Revisions to Petitioned-For Tolerances ................................................................ 11

3.0 Introduction ...................................................................................................................... 11

3.1 Chemical Identity........................................................................................................ 11

3.2 Physical/Chemical Characteristics............................................................................ 12

3.3 Proposed Use Pattern ................................................................................................. 12

3.4 Anticipated Exposure Pathways................................................................................ 12

3.5 Consideration of Environmental Justice .................................................................. 13

4.0 Hazard Characterization and Dose-Response Assessment .......................................... 13

4.1 Toxicology Studies Available for Analysis................................................................ 13

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)............................ 14

4.2.1 Dermal Absorption ................................................................................................. 14

4.3 Toxicological Effects................................................................................................... 14

4.4 Safety factor for Infants and Children (FQPA Safety Factor)............................... 17

4.4.1 Completeness of the Toxicology Database............................................................ 17

4.4.2 Evidence of Neurotoxicity ...................................................................................... 17

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ...... 18

4.4.4 Residual Uncertainty in the Exposure Database.................................................. 18

4.5 Toxicity Endpoint and Point of Departure Selections............................................. 18

4.5.1 Dose-Response Assessment .................................................................................... 18

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment... 20

4.5.3 Cancer Classification and Risk Assessment Recommendation .......................... 20

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment............................................................................................................................... 21

4.6 Endocrine Disruption ................................................................................................. 22

5.0 Dietary Exposure and Risk Assessment......................................................................... 23

5.1 Metabolite/Degradate Residue Profile ...................................................................... 23

5.1.1 Summary of Plant and Animal Metabolism Studies ........................................... 23

5.1.2 Summary of Environmental Degradation ............................................................ 24

5.1.3 Residues of Concern Summary and Rationale..................................................... 25

5.2 Food Residue Profile................................................................................................... 26

5.3 Water Residue Profile................................................................................................. 27

5.4 Dietary Risk Assessment ............................................................................................ 27

5.4.1 Description of Residue Data Used in Dietary Assessment .................................. 27

5.4.2 Percent Crop Treated Used in Dietary Assessment............................................. 28

6.0 Residential (Non-Occupational) Exposure/Risk Characterization.............................. 28

6.1 Residential Bystander Postapplication Inhalation Exposure ................................. 28

6.2 Spray Drift................................................................................................................... 28
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7.0 Aggregate Exposure/Risk Characterization .................................................................. 29

8.0 Cumulative Exposure/Risk Characterization................................................................ 30

9.0 Occupational Exposure/Risk Characterization............................................................. 30

9.1 Short-/Intermediate-/Long-Term/Cancer (if needed) Handler Risk ..................... 30

9.2 Short-/Intermediate-/Long-Term/Cancer (if needed) Post-Application Risk....... 34

9.2.1 Dermal Postapplication Risk ................................................................................. 34

9.2.2 Inhalation Postapplication Risk............................................................................. 37

Appendix A. Toxicology Profile and Executive Summaries .................................................. 38

A.1 Toxicity Profiles .......................................................................................................... 37

A.2 HEC Inhalation Calculations .................................................................................... 44
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1.0 Executive Summary

Interregional Research Project No. 4 (IR-4) has proposed a Section 3 Registration (PP# 0E7735) 

for application of tetraconazole to the small fruit vine climbing (except fuzzy kiwifruit) subgroup 

13-07F and low-growing berry subgroup 13-07G (except cranberry). Additionally Isagro has 

proposed a Section 3 Registration (PP# 0F7737) for application of tetraconazole to field corn and 

popcorn. This memorandum serves as HED’s assessment of exposure and risk to occupational 

and residential pesticide handlers from contact with tetraconazole as used on fruit, berries, and 

corn. 

Tetraconazole is a systemic fungicide and is a member of the conazole/triazole class of 

pesticides. Tetraconazole acts by inhibiting the metabolic pathway leading to fungal sterol 

production (sterol-demethylation inhibitor (DMI)) and is currently registered for application to 

sugar beet, grape, peanut, pecan, and soybean with tolerances ranging from 0.03-1.0 ppm (40 

CFR 180.557). Tolerances as a result of secondary residues are also established in/on hog, 

poultry, and ruminant commodities at 0.01-0.25 ppm. 

The proposed end use products are MettleTM, a 1 lb ai/gallon micro-emulsion (ME), and Domark®

230ME, a 1.9 lb ai/gallon ME. Application is proposed at a maximum rate of 0.039 lb ai/acre to 

the small fruit vine climbing and low-growing berry groups, and at a maximum rate of 0.09 lb 

ai/acre to field corn and popcorn. 

Hazard Assessment: The toxicology database for tetraconazole is considered adequate for 

purposes of risk assessment. Tetraconazole has low acute toxicity via the oral, dermal, and 

inhalation routes (Categories III and IV). It is a slight eye irritant (Category III), but is not a 

dermal irritant or a dermal sensitizer (Category IV). The liver and kidney are the primary target 

organs of tetraconazole in mice, rats, and dogs. Toxicity in these organs occurred following 28-

day, 90-day, and 1-2 year oral exposures.

For chronic durations, the dog was the most sensitive species, followed by the mouse, and then 

the rat. Chronic toxicity in the dog included increased absolute and relative kidney weights and 

histopathological changes in the male kidney (cortical tubular hypertrophy) which were observed 

at the mid-dose (2.95 mg/kg/day). At the high dose (12.97 mg/kg/day), liver effects were 

observed in both sexes. In the mouse, effects included increased liver weights, hepatocellular 

vacuolization in both sexes, and increased kidney weights in males (12 mg/kg/day). In rats, 

several effects not related to liver and kidney toxicity were observed at the dose of 27.7 

mg/kg/day. These included histopathological changes of the bone, pale and thickened incisors, 

decreased absolute and relative adrenal and pituitary weights in males, and finally decreased 

body weight (at terminal sacrifice) in females. Centrilobular hepatocyte hypertrophy was 

observed in the high-dose groups for both sexes in this study. 

Oral rat and rabbit prenatal developmental studies showed no increased quantitative 

susceptibility of the fetus to tetraconazole exposure in utero. In the developmental toxicity study

in rats, the maternal toxicity was manifested as decreased body weight gain, food consumption, 

increased water intake, increased liver and kidney weights (100 mg/kg/day). There were 

developmental effects in rats that suggested qualitative susceptibility. They consisted of 

increased incidences of supernumerary ribs, and increased incidences of hydroureter and 

hydronephrosis (100 mg/kg/day), which exceeded the high-end value of the historical control 

range. No developmental toxicity was seen in the rabbit study. The sole maternal effect in this 
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rabbit study was decreased body weight gain which occurred at the highest dose tested (30 

mg/kg/day). 

A two-generation rat reproduction study also revealed no increased quantitative susceptibility in 

offspring. Parental toxicity resulted in increased mortality in females of the P and F1 generations 

at the mid dose of 5.9 mg/kg/day. This increase in mortality had a higher incidence at the 

highest dose tested (40.6 mg/kg/day in females). Effects in parental animals that survived the 

duration of the study were consistent with other studies in the database including decreased 

body-weight gain and food consumption during pre-mating, increased relative liver and kidney

weights, and hepatocellular hypertrophy in males and females at the lowest-observed adverseeffect levels (LOAELs) of 35.5 mg/kg/day (males) and 40.6 mg/kg/day (females).

There were signs of neurotoxicity in the acute neurotoxicity study. There were no systemic 

effects observed in the 21-day dermal toxicity study up to the highest dose used (241 mg/kg 

ai/day, 1000 mg/kg/day total formulation). Dermal irritation resulted from treatment with 30 

mg/kg ai/day of the low dose formulation of tetraconazole. This study was classified as 

acceptable/guideline, but because it did not test up the limit dose for the technical grade active 

ingredient, it was deemed inappropriate for risk assessment (TXR No. 0052657, Guruva B. 

Reddy et al., 6/29/04).

In the 28-day inhalation study in rats, toxicity was observed at the lowest concentration/dose 

tested (0.0538 mg/L/14.3 mg/kg/day). At the highest concentration tested, there were treatmentrelated increases in absolute lung weights in both sexes. There were also treatment-related 

increases in absolute and relative liver weights in males (0.520 mg/L) and females (0.159 and 

0.520 mg/L). In the kidney, there were treatment-related increases in absolute and relative 

kidney and adrenal gland weights in females (0.520 mg/L). In females, there was a treatmentrelated statistically significant increase in circulating globulins at the mid and high 

concentrations. Finally, in the kidney, at the highest concentration tested, there was a 50% 

increase in the incidence of tubular hyaline droplets with features characteristic of α-2 

microglobulin. This was observed only in males, and this effect is not considered relevant to 

humans. 

Tetraconazole did not show evidence of mutagenicity in in vitro or in vivo studies. 

Carcinogenicity studies with tetraconazole resulted in an increased incidence of combined 

benign and malignant liver tumors in mice of both sexes (118 and 217 mg/kg/day for males, 140 

and 224 mg/kg/day in females). The levels of the doses tested were adequate. In contrast to 

mice, no tumors were noted in male or female rats after long-term dietary administration of 

tetraconazole. The HED Cancer Assessment Review Committee (CARC; HED DOC. NO. 

013948, David Nixon et al., 11/10/99) classified tetraconazole as "likely to be carcinogenic to 

humans" by the oral route based on the occurrence of liver tumors in male and female mice, in 

accordance with the EPA Draft Guidelines for Carcinogen Risk Assessment (July, 1999). 

Human cancer risk is based upon the oral slope factor (Q1*) of 2.3 x 10-2 mg/kg/day derived 

from the male mouse liver tumors combined (benign and malignant).

Dose-Response Assessment 

The acute neurotoxicity study in rats was selected for the acute dietary endpoint for the 

generation population. An UF of 100 (10-fold for interspecies extrapolation and 10-fold for 

intraspecies variability) was applied to the NOAEL of 50 mg/kg/day to generate the aRfD of 0.5 

mg/kg/day for the general population. The LOAEL is 200 mg/kg/day due to decreased motor 
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activity on day 0 in both sexes, and clinical signs in females including hunched posture, 

decreased defecation, and/or red or yellow material on various body surfaces. 

The rat prenatal developmental toxicity study was selected for the acute dietary endpoint for 

females 13-49 years of age. An UF of 100 (10-fold for interspecies extrapolation and 10-fold for 

intraspecies variability) was applied to the developmental NOAEL of 22.5 mg/kg/day to generate 

the aRfD of 0.225 mg/kg/day for females 13-49 years of age. The developmental was LOAEL is 

100 mg/kg/day based upon increased incidence of supernumerary ribs, and increased incidences 

of hydroureter and hydronephrosis.

The chronic dog toxicity study was selected for the chronic dietary endpoint for the general 

population. An UF of 100 (10-fold for interspecies extrapolation and 10-fold for intraspecies 

variability) was applied to the NOAEL of 0.73 mg/kg/day to generate the cRfD of 0.0073 

mg/kg/day for the general population. The LOAEL is 2.95 mg/kg/day based upon increased 

absolute and relative kidney weights and histopathological changes in the male kidney. 

The 2-generation reproduction toxicity study in rats was selected for the short-term dermal 

endpoint. The parental NOAEL is 0.7 mg/kg/day. The LOAEL is 4.9 mg/kg/day based upon 

increased mortality of adult females in the P and F1 generations. The chronic oral toxicity

(feeding)/dog study was selected for the intermediate dermal endpoint. The NOAEL is 0.73 

mg/kg/day. The LOAEL is 2.95 mg/kg/day based upon increased kidney weights. A 12% 

dermal-absorption factor should be used in route-to-route extrapolation.

The 28-day inhalation toxicity study was selected for the short- and intermediate-term inhalation 

exposure scenarios. There was no NOAEL observed in this study. The LOAEL is 0.0548 mg/L 

based upon squamous cell metaplasia of the laryngeal mucous, mono-nuclear cell infiltration, 

goblet cell hyperplasia, hypertrophy of the nasal cavity and nasopharyngeal duct, and follicular 

hypertrophy of the thyroid in males. This route specific study is protective of the portal of entry 

effects described above. It is the most appropriate study for the short term duration of exposure. 

Since an oral NOAEL was selected for inhalation exposure assessment, an inhalation-absorption 

factor of 100% should be used. 

The 2009 Field Volatilization SAP suggested that the Agency use route specific inhalation 

studies instead of relying on oral studies in risk assessment. The oral studies may be less 

conservative than route specific studies. Because this HEC and the dose derived from it were 

calculated from a LOAEL, an extra 10X (UFL) will be added to the standard 10X intraspecies 

and 3X interspecies uncertainty factors for calculation of HECs for a total level of concern of 

300.

Food Quality Protection Act (FQPA) Decision: The tetraconazole risk assessment team 

recommends that the 10X FQPA SF for the protection of infants and children be reduced to 1X 

since there is a complete toxicity database for tetraconazole and exposure data are complete or 

are estimated based on data that reasonably account for potential exposures. The 

recommendation is based on the following: 1) There are no residual uncertainties for pre- and 

post-natal toxicity. 2) There were effects indicative of neurotoxicity in the acute neurotoxicity

study in rats; however, the LOC is low since a clear NOAEL was established which is being used 

in endpoint selection. 3) The toxicology database for tetraconazole does not show any evidence 

of treatment-related effects on the immune system.
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Dietary Risk Estimates (Food + Water): Acute, chronic and cancer aggregate dietary (food and 

drinking water) exposure and risk assessments were conducted using the Dietary Exposure 

Evaluation Model-Food Commodity Intake Database (DEEM-FCID; ver. 2.03) which use food 

consumption data from the U.S. Department of Agriculture’s (USDA’s) Continuing Surveys of 

Food Intakes by Individuals (CSFII) from 1994-1996 and 1998. The following paragraphs are 

summaries of the acute, chronic, and cancer analyses. For information concerning exposure to 

the metabolites of concern that HED has determined to be toxicologically different from 

tetraconazole, see the Aggregate Section. 

The unrefined acute analysis resulted in exposure estimates less than HED’s level of concern 

(children 1-2 years old were the most highly exposed population subgroup at 1.8% aPAD). 

The chronic analysis (food and water) was refined through the incorporation of empirical 

processing factors, average field trial residues, average residues from the feeding studies, and 

projected percent crop treated estimates. The resulting exposure estimates are less than HED's 

LOC (all infants <1 year old were the most highly exposed population subgroup at 5% cPAD; 

see Table 5.4.1). 

The cancer analysis (food and water) was refined through the incorporation of empirical 

processing factors, average field trial residues, average residues from the feeding studies, and

projected percent crop treated estimates. The resulting exposures estimates yielded a cancer risk 

for the U.S. population of 3 x 10-6 which is less than HED's LOC (see Table 5.6.2). A critical 

commodity analysis for the cancer run (U.S. population) indicated that the major contributors 

were water (63% of total exposure), strawberry (11% of total exposure), dairy products (5% of 

total exposure), and soybean oil (4% of total exposure). 

Residential (Non-Occupational) Exposure and Risk Assessment: There are no residential uses 

proposed or currently registered for tetraconazole. Therefore, residential handler and postapplication exposure/risk were not assessed. 

Aggregate-Risk Estimates: In accordance with the FQPA, HED must consider and aggregate 

(add) pesticide exposures and risks from three major sources: food, drinking water, and 

residential exposures. Because there are no residential uses for tetraconazole, only food and 

water were included in aggregate assessments. Since the dietary exposure analysis included the 

drinking water estimates, the discussion and exposure estimates presented above represent acute, 

chronic, and cancer aggregate exposure. All aggregate risk estimates to tetraconazole are not of 

concern to HED.

It is noted that application of tetraconazole also results in exposure to 1,2,4-triazole (T) and its 

conjugated metabolites which are considered to be toxicologically different from tetraconazole 

as well as to metabolites which HED determined are toxicologically identical to propiconazole 

(M14360-ketone, M14360-CP(C-1)-alcohol, and M14360(C-1)-alcohol). As part of a separate 

document, HED conducted an aggregate exposure analysis for T and its conjugated metabolites; 

all aggregate exposure were less than HED’s level of concern (D388544, T. Bloem, 14-Apr2011). In addition, HED concludes that the most recent propiconazole risk assessment 

(D375282, B. Daiss et al., 3-Nov-2010) which yielded exposures less than HED’s level of 

concern does not require revision as the residue estimates incorporated into this analysis are 

protective of the potential residues resulting from the application of tetraconazole. 
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Occupational Exposure and Risk Assessment: It is anticipated that there will be occupational 

handler and post-application short- and intermediate-term exposure from the proposed uses. 

Chronic exposure is not expected for the proposed uses. A cancer assessment was conducted.

No chemical-specific handler exposure data were submitted in support of this Section 3 

registration. It is the policy of the HED to use data from the Pesticide Handlers Exposure 

Database (PHED) Version 1.1 as presented in PHED Surrogate Exposure Guide (8/98) to assess 

handler exposures for regulatory actions when chemical-specific monitoring data are not 

available. All inhalation risks for occupational handlers are above the target MOE of 300 with 

baseline protection (i.e., no respirator), and, therefore, do not exceed the LOC. All dermal risks 

for occupational handlers are above the target MOE of 100 with baseline protection or the 

addition of gloves (recommended by the label); therefore, the proposed uses are not of concern 

for HED. Estimated cancer risks are below 10-6 with the use of gloves as recommended by the 

label.

HED expects that post-application dermal exposure will occur since tetraconazole is applied 

postemergence as a foliar spray. Since no post-application data were submitted in support of this 

registration action, exposures during post-application activities were estimated using dermal 

transfer coefficients from HED’s Science Advisory Council for Exposure (ExpoSAC) Policy

Number 3.1 “Agricultural Transfer Coefficients” (August 2000). HED has determined that 

short- and intermediate-term risk estimates are not of concern (i.e., MOEs ≥100) on the day of 

treatment (i.e., Day 0) for most post-application exposure activities. For high contact activities 

(TC=10,000 for grapes and TC=17,000 for field corn and popcorn) the MOEs are <100 on the 

day of treatment. The high contact activities for grapes (girdling, cane tying, and cane turning) 

are only expected to occur for cultivation of table grapes. The high contact activity for corn 

(detasseling) is only expected to occur for field corn or popcorn grown for seed. Estimated 

cancer risks, based on the average residue over 30 days, for all post-application activities, except 

for detasseling corn grown for seed, are below 10-6. Estimated cancer risks for detasseling corn 

grown for seed are greater than 10-6using the average residue over 30 days. The cancer risk is 

below 10-6on day 20.

Environmental Justice Considerations: Potential areas of environmental justice concerns, to 

the extent possible, were considered in this human-health risk assessment, in accordance with 

U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority

Populations and Low-Income Populations,”

(http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf).

Review of Human Research: This risk assessment relies in part on data from studies in which 

adult human subjects were intentionally exposed to a pesticide to determine their dermal and 

inhalation exposure. Many such studies, involving exposure to many different pesticides, 

comprise generic pesticide exposure databases such as the PHED and the Agricultural Reentry

Task Force (ARTF) Database. EPA has reviewed all the studies in these multi-pesticide generic 

exposure databases, and based on available evidence has found them to have been neither 

fundamentally unethical nor significantly deficient relative to standards of ethical research 

conduct prevailing when they were conducted. There is no regulatory barrier to continued 

reliance on these studies, and all applicable requirements of EPA’s Rule for the Protection of 

Human Subjects of Research (40 CFR Part 26) have been satisfied.
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Recommendations for Tolerances: A revised Section F is requested specifying the correct 

tolerance expression (see Table 2.2.3), commodity definition, and/or tolerance levels. HED 

recommends that the tetraconazole tolerance expression be changed to the following (40 CFR 

180.557(a)): 

180.557(a): Tolerances are established for residues of the fungicide tetraconazole, including its 

metabolites and degradates, in or on the commodities listed below. Compliance with the following 

tolerance levels is to be determined by measuring only tetraconazole (1-[2-(2,4-dichlorophenyl)-3-

(1,1,2,2-tetrafluoroethoxy)propyl]-1H-1,2,4-triazole).

2.0 HED Recommendations

Provided revised Sections B and/or F are submitted, HED can recommend for a conditional 

registration and permanent tolerances for the use of tetraconazole on small fruit vine climbing 

(except fuzzy kiwifruit) subgroup 13-07F, low-growing berry subgroup 12-07G (except 

cranberry) popcorn, and field corn. Additional data are needed as a condition of registration as 

outlined in section 2.1 below. The specific tolerance recommendations are discussed in section 

2.2, and label modifications are discussed in section 2.1.

2.1 Data Deficiencies/Conditions of Registration

Residue Chemistry

 The following storage stability data are needed to validate the magnitude of the residue 

data: T, TA, and TAA in strawberry (516 days), grape (236 days), grape juice (64 days), 

and raisin (91 days); tetraconazole in corn grain, forage, and stover (266 days; grain data 

will be translated to all processed commodities excluding refined oil); T in corn forage 

and stover (263 days); tetraconazole, T, TA, and TAA in refined corn oil (198 days).

 Revised Section B with the application instructions for cranberry removed and with 

language prohibiting the addition of adjuvants to the spray solutions for subgroup 13-

07F and subgroup 13-07G crops. 

 Revised Section F specifying the correct tolerance expression (see below), commodity

definition, and/or tolerance levels. HED recommends that the tetraconazole tolerance 

expression be changed to the following (40 CFR 180.557(a)): Tolerances are established 

for residues of the fungicide tetraconazole, including its metabolites and degradates, in or 

on the commodities listed below. Compliance with the following tolerance levels is to be 

determined by measuring only tetraconazole (1-[2-(2,4-dichlorophenyl)-3-(1,1,2,2-

tetrafluoroethoxy)propyl]-1H-1,2,4-triazole).

Occupational and Residential Exposure

 Dislodgeable foliar residues (DFR) data for corn grown for seed.

 Short- and intermediate-term post-application risks were a concern until day 7 for table 

grape post-application activities and until day 20 for detasseling corn grown for seed. 

RD should ensure the appropriate REI is presented on the label. A revised Section B 

should be submitted.
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2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate analytical methods are available to enforce the currently established tetraconazole per 

se plant and livestock tolerances (D280006, W. Donovan, 10-Jan-2002, D267481, 12-Oct-2000; 

D278236, W. Donovan, 22-Oct-2001). As part of the corn petition, Isagro submitted adequate 

method validation and independent laboratory validation (ILV) data which indicates that the 

QuEChERS multi-residue method L 00.00-115 (48135104.der.docx) is capable of quantifying 

tetraconazole residues in/on a variety of fruit, cereal grain, root, oilseed, and livestock 

commodities (note that mean recoveries in/on wheat straw were 50-70%;). Based on these data 

and since the extraction solvent employed in the QuEChERS method (acetonitrile) is similar to 

the extraction solvent employed in the radiovalidated enforcement methods (acetone), HED 

concludes that the QuEChERS method is adequate for enforcement of the tolerances 

recommended in the current document and forwarded the method to the Food and Drug 

Administration (FDA; D386650, T. Bloem, 14-April-2011).

2.2.2 International Harmonization

HED notes that there are no Canadian or Codex maximum residue limits for tetraconazole; 

therefore, harmonization is not an issue. 

2.2.3 Recommended Tolerances

Table 2.2.3 is a summary the proposed and HED-recommended tolerances for residues of 

tetraconazole per se (40 CFR 180.557). A revised Section F is requested specifying the correct 

tolerance expression (see Table 2.2.3), commodity definition, and/or tolerance levels. HED 

recommends that the tetraconazole tolerance expression be changed to the following (40 CFR 

180.557(a)): 

180.557(a): Tolerances are established for residues of the fungicide tetraconazole, including its 

metabolites and degradates, in or on the commodities listed below. Compliance with the following 

tolerance levels is to be determined by measuring only tetraconazole (1-[2-(2,4-dichlorophenyl)-3-

(1,1,2,2-tetrafluoroethoxy)propyl]-1H-1,2,4-triazole).

Table 2.2.3. Tolerance Summary.

Commodity Proposed 

Tolerance (ppm)

HED-Recommended 

Tolerance (ppm) Comments

Small fruit vine climbing, except fuzzy kiwifruit, subgroup 13-07F 0.20 0.20

--

Low growing berry subgroup 13-07G (except cranberry) 0.25 0.25

Corn, field, forage 1.0 1.1

A revised 

Section F is 

requested. 

Corn, field, grain 0.01 0.01

Corn, field, stover 1.5 1.7

Corn, pop, grain 0.01 0.01

Corn, pop, stover 1.5 1.7

Milk Not proposed 0.03

Milk, fat Not proposed 0.75

Fat (cattle, goat, horse, sheep) Not proposed 0.15

Liver (cattle, goat, horse, sheep) Not proposed 1.5

Meat byproducts, except liver (cattle, goat, horse, sheep) Not proposed 0.15

Poultry, meat byproducts Not proposed 0.05
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2.2.4 Revisions to Petitioned-For Tolerances

Based on the magnitude of the residue data, the tolerance spreadsheet as specified by the 

Guidance for Setting Pesticide Tolerances Based on Field Trial Data, and/or guidance 

concerning the appropriate language to be used when writing tolerance expressions (S. Knizner, 

27-May-2009), HED determined that the tolerance expression and levels specified in Section 

2.2.3 are appropriate.

3.0 Introduction

3.1 Chemical Identity

Table 3.1. Test Compound Nomenclature.

Chemical Structure

N

N

N

OCF2CF2H

Cl

Cl

Common name Tetraconazole

Company experimental name None Specified in Submission

IUPAC name (±)-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propyl-1,1,2,2-tetrafluoroethyl ether

CAS name 1-[2-(2,4-dichlorophenyl)-3-(1,1,2,2-tetrafluoroethoxy) propyl]-1H-1,2,4-triazole

CAS # 112281-77-3

3.2 Physical/Chemical Characteristics

Table 3.2. Physicochemical Properties of the Technical Grade Tetraconazole.

Melting point/range Not applicable - test is a viscous liquid 

MRID 44268104; D259842, 

B. Kitchens, 11-Apr-2000.

pH 5.48 in DI H2O

5.47 for saturated solution at 20°C

Density 1.4382 g/ml at 20°C

1.4252 g/ml at 30°C 

Water solubility (PAI >94.16%) 159.31 mg/L at 25°C

Solvent solubility not available

Vapor pressure (PAI >99.65%)

0.13 x 102Pa at 35.5°C

0.58 x 102Pa at 46.5°C

2.985 x 102Pa at 60°C

MRID 44305301; D259842, 

B. Kitchens, 11-Apr-2000.

Dissociation constant (Ka) 0.158 - 0.316 MRID 46055603; D294198, 

B. Kitchens, 26-Jan-2004.

Octanol/water partition coefficient (PAI >99.65%) log Pow = 3.53 at 25°C MRID 44305301; D259842, 

B. Kitchens, 11-Apr-2000.

UV/visible absorption spectrum not available

3.3 Proposed Use Pattern

IR-4 has proposed a Section 3 Registration (PP# 0E7735) for application of tetraconazole to the 

small fruit vine climbing (except fuzzy kiwifruit) subgroup 13-07F and low-growing berry

subgroup 13-07G (except cranberry). Additionally Isagro has proposed a Section 3 Registration 

(PP# 0F7737) for application of tetraconazole to field corn and popcorn. The proposed use 

patterns are detailed in Table 3.3. See Section 2.1 for recommended modifications to the 

proposed label. 
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Table 3.3. Summary of Proposed Directions for Use of Tetraconazole.

Commodity

Trade Name 

(EPA Reg. 

No.)

Application 

Timing, 

Type, 

Equipment

Application 

Rate

(lb ai/A)

Maximum Seasonal 

Application Rate

(lb ai/A)

PHI1

(days)

Maximum 

Number 

Applications

Small fruit 

vine 

climbing 

(except 

fuzzy 

kiwifruit) 

subgroup 12-

07F

MettleTM

(80289-0)

Ground, 

aerial, 

chemigation

0.023-0.039 0.08 14 2

Lowgrowing 

berry 

subgroup 13-

07G

0.16 0 4

Field corn 

and Popcorn

Domark®

230 ME

(80289-7)

0.045-0.090

0.09 Not specified 2

1. PHI = pre-harvest interval 

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the 

proposed new uses of tetraconazole on small fruit vine climbing (except fuzzy kiwifruit) 

subgroup 12-07F, low-growing berry subgroup 13-07G, and corn. Humans may be exposed to 

tetraconazole in food and drinking water, since tetraconazole may be applied directly to growing 

crops and application may result in tetraconazole reaching surface and ground water sources of 

drinking water. There are no residential uses of tetraconazole, so there is not likely to be 

exposure in residential or non-occupational settings. In an occupational setting, applicators may

be exposed while handling the pesticide prior to application, as well as during application. There 

is a potential for post-application exposure for workers re-entering treated fields. 

Risk assessments have been previously prepared for the existing uses of tetraconazole. This risk 

assessment considers all of the aforementioned exposure pathways based on the proposed new 

uses of tetraconazole, but also considers the existing uses as well, particularly for the dietary

exposure assessment. 

3.5 Consideration of Environmental Justice

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

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf). As a part of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to 

well-established procedures. In line with OPP policy, HED estimates risks to population 

subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water 

consumption, and activities in and around the home that involve pesticide use in a residential 

setting. Extensive data on food consumption patterns are compiled by the USDA under the 

CSFII and are used in pesticide risk assessments for all registered food uses of a pesticide. These 
Tetraconazole Human-Health Risk Assessment DP#: 380618 

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data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, 

and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, 

specialized subgroups and exposure assessments are performed when conditions or 

circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of 

pesticide products and associated risks for adult applicators and for toddlers, youths, and adults 

entering or playing on treated areas post-application are evaluated. Further considerations are 

currently in development as OPP has committed resources and expertise to the development of 

specialized software and models that consider exposure to bystanders and farm workers as well 

as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis 

Tetraconazole has been evaluated extensively for its toxicity and mode of action. Its toxicity

database is adequate to support registration. In the last risk assessment (D347084/ M. ClockRust et al., 10/03/2008), three toxicology data requirements were identified including the lack of 

a guideline immunotoxicity study, as well as acute and subchronic neurotoxicity studies. All 

three of these studies are now required under the 40 CFR Part 158 for conventional pesticide 

registration. Since then, the acute neurotoxicity study has been submitted and reviewed by the 

Agency. In addition, a 28-day inhalation study toxicity study was submitted and reviewed. The 

evaluation of the acute neurotoxicity and the 28-day inhalation toxicity studies are included in 

this hazard assessment. Finally, the subchronic neurotoxicity and immunotoxicity studies were 

recently submitted and have undergone preliminary review. No effects of concern were 

observed in either study, and neither have affected the selection of endpoints.

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

Rat metabolism data indicate that tetraconazole was well absorbed from the gastro-intestinal tract 

based upon the high recovery levels in the urine (52-76%) and feces (12-36%). Less than 6% 

(2.8-5.8%) of the administered dose remained in the carcass/tissues within 72 hours post-dosing 

indicating negligible bioaccumulation. There was no major difference in absorption and 

elimination of tetraconazole between sexes and dose levels. Males had slightly higher peak 

levels in the blood than females. Metabolic identification revealed the moiety triazole ring as the 

major urinary and fecal metabolite. 

4.2.1 Dermal Absorption

A dermal-absorption study on tetraconazole is not available. A dermal-absorption factor of 12% 

was extrapolated by the ratio of the LOAEL of 30 mg/kg/day established in an oral 

developmental toxicity study in rabbits and the NOAEL of 241 mg ai/kg/day established in the 

21-day dermal toxicity study in rabbits (HIARC report TXR NO. 0052657). The dermalabsorption data for compounds structurally related to tetraconazole range from 2-40%. Dividing 

the NOAEL of 241 mg ai/kg/day from the 21-day dermal toxicity study into the LOAEL of 30 

mg/kg/day from the oral developmental toxicity study in results in a dermal-absorption factor of 

12%: 

30 mg/kg/day ÷ 241 mg/kg/day × 100 = 12% dermal-absorption factor
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4.3 Toxicological Effects

Tetraconazole is a systemic fungicide and a member of the conazole/triazole class of pesticides. 

As with similar chemicals in this class (Cyproconazole), tetraconazole inhibits fungal sterol 

production by inhibiting the enzyme lanosterol 14 α-demethylase, a cytochrome P450 enzyme 

(family 51, subfamily A, polypeptide 1). Its inhibitory action in fungi causes an accumulation of 

irregular methylated sterols, and a corresponding reduction of ergosterol. This badly affects 

fungal cell membranes making them no longer functional. With humans also expressing a 

myriad of cytochrome P450s both hepatic and extra-hepatic, there is potential for toxicity, due to 

exposure to these chemicals. This class of anti-fungal compounds has also been shown to 

interact with members of the cytochrome P450-like nitric oxide synthase (NOS) family of 

enzymes. Over or under production of nitric oxide (NO), an important signaling molecule, can 

have numerous harmful effects in mammalian systems, and can thus potentially lead to toxicities 

in humans. 

Tetraconazole has low acute toxicity via the oral, dermal, and inhalation routes (Categories III 

and IV). It is a slight eye irritant (Category III), but is not a dermal irritant or a dermal sensitizer 

(Category IV). 

The liver and kidney are the primary target organs of tetraconazole in mice, rats, and dogs. 

Toxicity in these organs occurred following 28-day, 90-day, and 1-2 year oral exposures. With 

regards to the doses at which toxicity was observed, mice and rats were equally sensitive for 90-

day oral exposures (LOAELs were ~16-29 mg/kg/day). A subchronic dog study was not 

available review and this study requirement was satisfied by the chronic dog study (D347084/ M. 

Clock-Rust et al., 10/03/2008).

 

For chronic durations, the dog was the most sensitive species, followed by the mouse, and then 

the rat. Chronic toxicity in the dog included increased absolute and relative kidney weights and 

histopathological changes in the male kidney (cortical tubular hypertrophy) which were observed 

at the mid dose (2.95 mg/kg/day). At the high dose (12.97 mg/kg/day), liver effects were 

observed including increased liver enzyme release in both sexes, increased absolute and relative 

liver and kidney weights for both sexes, and histopathological changes in both organs. In the 

mouse, effects included increased liver weights, hepatocellular vacuolization in both sexes, and 

increased kidney weights in males (12 mg/kg/day). In rats, several effects not related to liver and 

kidney toxicity were observed at the dose of 27.7 mg/kg/day. These included histopathological 

changes of the bone, pale and thickened incisors, decreased absolute and relative adrenal and 

pituitary weights in males, and finally decreased body weight (at terminal sacrifice) in females. 

Centrilobular hepatocyte hypertrophy was observed in the high dose groups for both sexes in this 

study. 

Oral rat and rabbit prenatal developmental studies showed no increased quantitative 

susceptibility of the fetus to tetraconazole exposure in utero. In the developmental toxicity study

in rats, the maternal toxicity was manifested as decreased body weight gain, food consumption, 

increased water intake, increased liver and kidney weights (100 mg/kg/day). There were 

developmental effects in rats that suggested qualitative susceptibility. They consisted of 

increased incidences of supernumerary ribs, and increased incidences of hydroureter and 

hydronephrosis (100 mg/kg/day), which exceeded the high-end value of the historical control 

range. No developmental toxicity was seen in the rabbit study. The sole maternal effect in this 
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rabbit study was decreased body weight gain which occurred at the highest dose tested (30 

mg/kg/day). 

A two-generation rat reproduction study also revealed no increased quantitative susceptibility in 

offspring. Decreased litter weight and mean pup weight and increased liver weight were noted at 

a dose of 35.5 mg/kg/day in males and 40.6 mg/kg/day in females. Parental toxicity resulted in 

increased mortality in females of the P and F1 generations at the mid dose of 5.9 mg/kg/day. 

This increase in mortality had a higher incidence at the highest dose tested (40.6 mg/kg/day in 

females). Effects in parental animals that survived the duration of the study were consistent with 

other studies in the database including decreased body weight gain and food consumption during 

pre-mating, increased relative liver and kidney weights, and hepatocellular hypertrophy in males 

and females at the LOAEL of 35.5 mg/kg/day (males) and 40.6 mg/kg/day (females).

There were signs of neurotoxicity in the acute neurotoxicity study. At the mid dose of 200 

mg/kg/day, effects included a loss of motor activity in both sexes, and clinical signs including 

hunched posture, decreased defecation, and/or red or yellow material on various body surfaces in 

females. 

There were no systemic effects observed in the 21-day dermal toxicity study up to the highest 

dose used (241 mg/kg ai/day, 1000 mg/kg/day total formulation). Dermal irritation resulted from 

treatment with 30 mg/kg ai/day of the low dose formulation of tetraconazole. This study was 

classified as acceptable/guideline, but because it did not test up the limit dose for the technical 

grade active ingredient, it was deemed inappropriate for risk assessment (TXR No. 0052657, 

Guruva B. Reddy et al., 6/29/04).

In the 28-day inhalation study in rats, toxicity was observed at the lowest concentration/ dose 

tested (0.0538 mg/L/14.3 mg/kg/day). Effects included squamous cell metaplasia of the 

laryngeal mucous, mono-nuclear cell infiltration, goblet cell hyperplasia, hypertrophy of the 

nasal cavity and nasopharyngeal duct, and follicular hypertrophy of the thyroid in males. At the 

highest concentration tested, there were treatment-related increases in absolute lung weights in 

both sexes. There were also treatment-related increases in absolute and relative liver weights in 

males (0.520 mg/L) and females (0.159 and 0.520 mg/L). In the kidney, there were treatmentrelated increases in absolute and relative kidney and adrenal gland weights in females (0.520 

mg/L). In females, there was a treatment-related statistically significant increase in circulating 

globulins at the mid and high concentrations. Finally, in the kidney, at the highest concentration 

tested, there was a 50% increase in the incidence of tubular hyaline droplets with features 

characteristic of α-2 microglobulin. This was observed only in males, and this effect is not 

considered relevant to humans. 

Tetraconazole did not show evidence of mutagenicity in in vitro or in vivo studies. 

Toxicity of Tetraconazole Metabolites

Free triazole metabolites (includes T, TA, TAA, triazolyl hydroxypropionic acid (THP), and/or 

all labile conjugates of these compounds):

HED has previously addressed the toxicity of T, TA and TAA in D322215 (HED Risk 

Assessment Document; M. Doherty et al., 7-Feb-2006). Please refer to this document for 

information concerning the toxicity of these free triazole metabolites. 

The free triazole risk assessment mentioned above pertains to exposure to T, TA, and TAA from 

the conazole/triazole fungicides. Tetraconazole results in the formation of these compounds as 
Tetraconazole Human-Health Risk Assessment DP#: 380618 

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well as THP. THP is a residue of concern in rotational crops and livestock (included as a residue 

of concern in livestock based on the identification in rotational crops and therefore as a potential

residue in feed). Based on the proposed application rates and the results of the confined 

rotational crop studies, HED has concluded that residues in rotational crops will be negligible; 

therefore, risk due to residues of THP are expected to be negligible and the previous free-triazole 

risk assessment is adequate to address risk resulting from all tetraconazole metabolites. 

Metabolites in common with propiconazole (M14360-ketone, M14360-CP(C-1)-alcohol, and 

M14360(C-1)-alcohol):

The tetraconazole plant metabolism, livestock metabolism, and/or confined rotational crop 

studies resulted in the identification of M14360-ketone, M14360(C-1)-alcohol, and M14360-

CP(C-1)-alcohol (structurally similar to M14360(C-1)-alcohol); these compounds are also 

metabolites/degradates of propiconazole (identified as CGA-91304 and CGA-91305 in the 

propiconazole risk assessment). These common metabolites/degradates will be referred to as 

CGA-91304/CGA-91305 from here on. HED concluded that the toxicity of these 

metabolites/degradates are accounted for in the propiconazole toxicity database (because they are 

identified in the propiconazole mouse and rat metabolism studies); whereas they were not 

identified in the tetraconazole rat metabolism study, and are therefore not accounted for in the 

tetraconazole toxicity database.

Although the identification of common metabolites/degradates often triggers the need for an 

aggregate risk assessment, this is not necessary at this time for the following reasons:

Residues of CGA-91304/CGA-91305 in/on plant and livestock commodities resulting from 

application of tetraconazole are expected to be at negligible levels in comparison to the 

magnitude of these residues following application of propiconazole.

Since exposure to these compounds resulting from tetraconazole is insignificant, the 

propiconazole risk assessment can act as a 'worst-case' risk assessment for CGA91304/CGA-91305, since they were included in the residues of concern for the 

propiconazole risk assessment.

However, if and when application of tetraconazole results in significant exposure to CGA91304/CGA-91305, at that time it will be necessary to include the magnitude of these 

compounds resulting from application of tetraconazole in the propiconazole risk assessment. 

4.4 Safety Factor for Infants and Children (FQPA SF)

HED’s RAB1 risk assessment team concluded that based on toxicological considerations and the 

residue assumptions used in the dietary and residential exposure analyses, the FQPA SF may be 

reduced to 1X. 

4.4.1 Completeness of the Toxicology Database

The toxicology database for tetraconazole is adequate for FQPA consideration. The following 

acceptable studies are available:

Developmental toxicity study in rats and rabbits (2) 

Two-generation reproduction study in rats (1) 

Acute and Subchronic neurotoxicity studies in rats (2)

Immunotoxicity Study (1)
Tetraconazole Human-Health Risk Assessment DP#: 380618 

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The toxicity database for tetraconazole is complete. An acute neurotoxicity study was submitted 

and exhibited indications of neurotoxicity but the LOC is low for reasons described below. A 

subchronic neurotoxicity study was recently submitted, and after preliminary review, there were 

no signs of neurotoxicity. There is no evidence of neurotoxicity in any of the other studies in the 

toxicity database for tetraconazole. An immunotoxicity study was also recently submitted and 

has also undergone preliminary review. There was no evidence of immunotoxicity in this study. 

The EPA believes the existing data are sufficient for endpoint selection for exposure/risk 

assessment scenarios and for evaluation of the requirements under the FQPA, and an additional 

UFDB does not need to be applied.

4.4.2 Evidence of Neurotoxicity 

There were effects indicative of neurotoxicity in the acute neurotoxicity study in rats. However, 

the LOC is low since a clear NOAEL was established which is being used in endpoint selection. 

Furthermore, the dose at which these neurotoxic effects were observed is 2 to 100-fold higher 

than the primary effects seen in the other studies in the database (liver and kidney). After 

preliminary review, a subchronic neurotoxicity study has shown no evidence for neurotoxicity.

Finally, there are no other signs of neurotoxicity in any of the other studies in the database. 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There are no residual uncertainties for pre- and post-natal toxicity. There is no evidence of 

increased quantitative susceptibility of rat or rabbit fetuses to in utero exposure to tetraconazole. 

There is evidence of increased qualitative susceptibility to fetuses in the rat prenatal 

developmental toxicity (increased incidences of supernumary ribs, and hydroureter and 

hydronephrosis). The LOC is low however because 1) the fetal effects were seen at the same 

dose as the maternal effects, 2) a clear NOAEL was established, 3) the developmental NOAEL 

from study in rats is being used as the POD for the acute dietary endpoint (females 13-49 years 

of age), and 4) there were no developmental effects in the rabbit study. There is also no evidence 

of increased quantitative or qualitative susceptibility to offspring in the 2-generation 

reproduction study.

4.4.4 Residual Uncertainty in the Exposure Database

Tolerance-level residues, 100% crop treated, and modeled water estimates were incorporated 

into the acute dietary exposure analysis. Therefore, the acute analysis is highly conservative. 

The chronic and cancer dietary exposure analyses utilized empirical processing factors, average 

field trial residues, average residues from the feeding studies, percent crop treated estimates, and 

modeled drinking water estimates. A critical commodity analysis for the chronic/cancer runs 

indicated that more than half of the exposure was derived from water. The models upon which 

the water estimates were based incorporate conservative (protective) assumptions with actual 

concentrations likely to be significantly lower. As a result, it can be concluded that the 

chronic/cancer risk estimates provided in this document do not underestimate the risks posed by 

tetraconazole. 
Tetraconazole Human-Health Risk Assessment DP#: 380618 

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4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

In the previous risk assessment for tetraconazole (D347084/ M. Clock-Rust et al., 10/03/2008), 

the short-term dermal and inhalation endpoints were based upon the offspring NOAEL and 

LOAEL from the 2 generation reproduction study. The intermediate-term inhalation endpoint 

was based upon the NOAEL and LOAEL from the chronic dog study. In the current risk 

assessment, the endpoint for the short-term dermal scenario was changed to the parental NOAEL 

and LOAEL from the 2-generation reproduction study. The parental NOAEL is being used 

because it is more sensitive for toxicity, and is thus more protective for this endpoint. The routespecific inhalation study was used for the short- and intermediate-term inhalation endpoints, and 

human equivalent concentrations were calculated for both durations using the rfc methodology. 

There are also no expected exposures through the incidental oral, long-term dermal or inhalation 

scenarios, so these scenarios were not evaluated. 

Acute Dietary Endpoint (General Population): The acute neurotoxicity study in rats was 

selected for the acute dietary endpoint for the generation population. An UF of 100 (10-fold for 

interspecies extrapolation and 10-fold for intraspecies variability) was applied to the NOAEL of 

50 mg/kg/day to generate the aRfD of 0.5 mg/kg/day for the general population. The LOAEL is 

200 mg/kg/day due to decreased motor activity on day 0 in both sexes, and clinical signs in 

females including hunched posture, decreased defecation, and/or red or yellow material on 

various body surfaces. This study is appropriate for the expected duration of exposure, and is 

protective for potential neurotoxic effects due to acute exposure to Tetraconazole. No other 

studies were considered for this endpoint. 

Acute Reference Dietary Endpoint (Females 13-49): The rat prenatal developmental toxicity

study was selected for the acute dietary endpoint for females 13-49 years of age. An UF of 100 

(10-fold for interspecies extrapolation and 10-fold for intraspecies variability) was applied to the 

developmental NOAEL of 22.5 mg/kg/day to generate the aRfD of 0.225 mg/kg/day for females 

13-49 years of age. The developmental was LOAEL is 100 mg/kg/day based upon increased 

incidence of supernumerary ribs, and increased incidences of hydroureter and hydronephrosis. 

The endpoint chosen, supernumerary ribs, was presumed to occur following a single exposure 

during the period of organogenesis. This study is appropriate for the expected duration of 

exposure and is protective for the population of concern. The developmental rabbit toxicity

study was also considered for this endpoint but it was not used because the maternal decreased 

body-weight gain was observed only at the high dose, and no fetal effects were observed. No 

other studies were considered for this endpoint. 

Chronic Dietary Endpoint (RfD): The chronic dog toxicity study was selected for the chronic 

dietary endpoint for the general population. An UF of 100 (10-fold for interspecies extrapolation 

and 10-fold for intraspecies variability) was applied to the NOAEL of 0.73 mg/kg/day to 

generate the cRfD of 0.0073 mg/kg/day for the general population. The LOAEL is 2.95 

mg/kg/day based upon increased absolute and relative kidney weights and histopathological 

changes in the male kidney. Other studies considered for this endpoint were the 

chronic/carcinogenicity studies in mice and rats, as well as the 2-generation reproduction study 

in rats. This study was chosen because it has one of the two lowest NOAELs in the database (in 

addition to the 2-generation reproduction) and has the lowest LOAEL of any study in the 

database where there are effects in one of the target organs (kidney). Since it is a 1-year feeding 
Tetraconazole Human-Health Risk Assessment DP#: 380618 

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study, it is the most appropriate study to assess chronic dietary exposure. Finally it is protective 

for the effects observed at higher doses (12-40 mg/kg/day) observed in the subchronic oral 

toxicity studies (liver and kidney), chronic studies in mice and rats (liver, kidney and others), and 

the effects observed in both parents (mortality, liver and kidney) and offspring (decreased litter 

weights and increased liver weights) in the 2-generation reproduction study. 

Short- and Intermediate-Term Incidental Oral Endpoint: Not warranted since residential uses 

are not expected.

Dermal-absorption Factor: A dermal-absorption study on tetraconazole is not available. A 

dermal-absorption factor of 12% was extrapolated by the ratio of the LOAEL of 30 mg/kg/day

established in an oral developmental toxicity study in rabbits and the NOAEL of 241 mg 

ai/kg/day established in the 21-day dermal toxicity study in rabbits (TXR No. 0052657, Guruva 

B. Reddy et al., 6/29/04). The dermal-absorption data for compounds structurally related to 

tetraconazole range from 2-40%. Dividing the NOAEL of 241 mg ai/kg/day from the 21-day

dermal toxicity study into the LOAEL of 30 mg/kg/day from the oral developmental toxicity

study in results in a dermal-absorption factor of 12%: 

30 mg/kg/day/ 241 mg ai/kg/day x 100 = 12% dermal-absorption factor 

Short-Term Dermal Endpoint: The 2-generation reproduction toxicity study in rats was 

selected for the short-term dermal endpoint. The parental NOAEL is 0.7 mg/kg/day. The 

LOAEL is 4.9 mg/kg/day based upon increased mortality of adult females in the P and F1

generations. The subchronic rat toxicity and prenatal developmental rat toxicity studies were 

also considered for this endpoint. This study was chosen because it is appropriate for the 

duration of exposure and is protective of the effects observed the developmental toxicity studies. 

No systemic toxicity was seen at the high dose of 2000 mg/kg/day with the formulation product 

in the 21-day dermal toxicity study with rabbits. This study was not used as the basis for shortterm dermal risk assessment because the test material was a formulation product. A 12% 

dermal-absorption factor should be used in route-to-route extrapolation. In the previous risk 

assessment, the offspring NOAEL (4.5 mg/kg/day) was used as the point of departure for this 

endpoint. The parental NOAEL (0.7 mg/kg/day) which is the most sensitive endpoint for the 

short-term duration is now selected to best protect adults in occupational settings, who are the 

population of concern for this endpoint.

Intermediate-Term Dermal Endpoints: The chronic oral toxicity (feeding)/dog study was 

selected for the intermediate-term dermal endpoint. The NOAEL is 0.73 mg/kg/day. The 

LOAEL is 2.95 mg/kg/day based upon increased absolute and relative kidney weights and 

histopathological changes in the male kidney. The subchronic rat toxicity and prenatal 

developmental rat toxicity studies were also considered for this endpoint. This study is 

appropriate for the duration of exposure, and this dose/end-point was selected due to the concern 

for nephrotoxicity seen in dogs. It is also protective for the mortality observed in parental 

females in the 2-generation reproduction study seen and higher doses. A 12% dermal-absorption 

factor should be used in route-to-route extrapolation.

Short- and Intermediate-Term Inhalation Exposure: The 28-day inhalation toxicity study was 

selected for the short- and intermediate-term inhalation exposure scenarios. There was no 

NOAEL observed in this study. The LOAEL is 0.0548 mg/L based upon squamous cell 
Tetraconazole Human-Health Risk Assessment DP#: 380618 

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metaplasia of the laryngeal mucous, mono-nuclear cell infiltration, goblet cell hyperplasia, 

hypertrophy of the nasal cavity and nasopharyngeal duct, and follicular hypertrophy of the 

thyroid in males. This route-specific study is protective of the portal of entry effects described 

above. It is the most appropriate study for the short-term duration of exposure. It is also the 

most protective study in the database for the above-mentioned effects in the respiratory tract for 

the intermediate-term duration. To better predict human exposure, the rat LOAEL was 

converted to a HEC (methods described in the appendix). The HEC for the LOAEL of 0.0548 

mg/L is 0.00484 mg/L, and the actual dose conversion to be used for occupational assessment is 

1.3 mg/kg/day. 

Comments about Study/Endpoint/ Uncertainty Factor: The 2009 Field Volatilization SAP 

suggested that the Agency use route specific inhalation studies instead of relying on oral studies 

in risk assessment. The oral studies may be less conservative than route specific studies. 

Because this HEC and the dose derived from it were calculated from a LOAEL, an extra 10X 

(UFL) will be added to the standard 10X intraspecies and 3X interspecies uncertainty factors for 

calculation of HECs for a total level of concern of 300.

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

Since short- and intermediate-term dermal endpoints are based on oral studies, dietary exposure 

will be aggregated to dermal exposures for all populations/durations. Dermal and inhalation 

exposures cannot be combined due to different effects. 

 

4.5.3 Cancer Classification and Risk Assessment Recommendation

Carcinogenicity studies with tetraconazole resulted in an increased incidence of combined 

benign and malignant liver tumors in mice of both sexes (118 and 217 mg/kg/day for males, 140 

and 224 mg/kg/day in females). The levels of the doses tested were adequate. In contrast to 

mice, no tumors were noted in male or female rats after long-term dietary administration of 

tetraconazole. The HED CARC (HED DOC. NO. 013948, David Nixon et al., 11/10/99) 

classified tetraconazole as "likely to be carcinogenic to humans" by the oral route based on the 

occurrence of liver tumors in male and female mice, in accordance with the EPA Draft 

Guidelines for Carcinogen Risk Assessment (July, 1999). Human cancer risk is based upon the 

oral slope factor (Q1*) of 2.3 x 10-2 mg/kg/day derived from the male mouse liver tumors 

combined (benign and malignant).

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

The PODs, uncertainty factors, and toxicity endpoints are presented in Table 4.5.4a and Table 

4.5.4b.
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Table 4.5.4.a. Summary of Toxicological Doses and Endpoints for Tetraconazole for Use in Dietary and NonOccupational Human-Health Risk Assessments.

Exposure/

Scenario POD Uncertainty/FQPA Safety Factors

RfD, PAD, 

LOC for Risk 

Assessment

Study and Toxicological Effects

Acute Dietary

General 

Population

NOAEL = 

50 

mg/kg/day

UFA = 10x 

UFH = 10x 

SFFQPA = 1

aRfD = 0.5 

mg/kg/day

aPAD = 0.5 

mg/kg/day

Acute neurotoxicity (rat)

LOAEL = 200 mg/kg/day due to 

decreased motor activity on day 0 in both 

sexes, and clinical signs in females 

including hunched posture, decreased 

defecation, and/or red or yellow material 

on various body surfaces. 

Acute Dietary

Females 13-49 

years of age

NOAEL =

22.5 

mg/kg/day

UFA = 10x 

UFH = 10x 

SFFQPA = 1 

aRfD = 0.225 

mg/kg/day

aPAD = 0.225 

mg/kg/day

Developmental toxicity study in rats 

Developmental LOAEL = 100 mg/kg/day 

based on increased incidence of small 

fetuses, supernumerary ribs, and 

hydroureter and hydronephrosis.

Chronic 

Dietary (All 

Populations)

NOAEL = 

0.73 

mg/kg/day

UFA = 10x 

UFH = 10x 

SFFQPA = 1

cRfD = 

0.0073 

mg/kg/day

cPAD = 

0.0073 

mg/kg/day

Chronic oral toxicity – dog

LOAEL = 2.95/3.33 (M/F) mg/kg/day, 

based on absolute and relative kidney 

weights and histopathological changes in 

the male kidney.

Cancer (oral, 

dermal, 

inhalation)

Classification: “Likely to be Carcinogenic to Humans.” Q1

* = 2.3 x 10-2

(mg/kg/day)-1based 

on male mouse liver benign and/or malignant combined tumor rates.

Point of Departure (POD) = A data point or an estimated point that is derived from observed doseresponse data and used to mark the beginning of extrapolation to determine risk associated with lower 

environmentally relevant human exposures. NOAEL = no-observed adverse-effect level. LOAEL = 

lowest-observed adverse-effect level. UF = uncertainty factor. UFA = extrapolation from animal to 

human (interspecies). UFH = potential variation in sensitivity among members of the human population 

(intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. UFS = use of a short-term study for 

long-term risk assessment. UFDB = to account for the absence of key date (i.e., lack of a critical study). 

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

reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. 

Table 4.5.4.b. Summary of Toxicological Doses and Endpoints Tetraconazole for Use in Occupational 

Human-Health Risk Assessments.

Exposure/

Scenario POD Uncertainty Factors

LOC for Risk 

Assessment Study and Toxicological Effects

Short-Term (1-

30 days) 

Dermal 

Oral study 

Parental 

NOAEL = 0.7 

mg/kg/day 

(dermalabsorption rate = 

12%1)

UFA = 10x

UFH = 10x

SFFQPA = 1

LOC = 100 

(occupational)

Reproductive toxicity – rat

Parental LOAEL = 4.9/5.9 mg/kg/day 

(M/F), based on increased mortality of 

adult females in the P and F1

generations.

IntermediateTerm (1-6 

months) 

Dermal 

Oral study 

NOAEL = 0.73 

mg/kg/day

(dermalabsorption rate = 

12%1)

UFA = 10x

UFH = 10x 

LOC = 100 

(occupational)

Chronic oral toxicity – dog

LOAEL = 2.95/3.33 (M/F) mg/kg/day, 

based on absolute and relative kidney 

weights and histopathological changes 

in the male kidney.
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Table 4.5.4.b. Summary of Toxicological Doses and Endpoints Tetraconazole for Use in Occupational 

Human-Health Risk Assessments.

Exposure/

Scenario POD Uncertainty Factors

LOC for Risk 

Assessment Study and Toxicological Effects

Short (1-30 

days) and 

Intermediateterm (1-6 

months) 

Inhalation 

Occupational1.3 

mg/kg/day; HEC

= 0.0048 mg/L; 

4.84 mg/m3; 

0.0548 mg/L 

(rat)

UFA = 3x

UFH = 10x

UFL = 10x

LOC = 300 

(occupational)

28-Day Inhalation toxicity – rat

LOEAL = 1.3 mg/kg/day (0.0048 

mg/kg/L, 0.0548 mg/L (rat)) for males 

and females, based on squamous cell 

metaplasia of laryngeal mucous, 

mononuclear cell infiltration, goblet 

hyperplasia and hypertrophy of nasal 

cavity and nasopharyngeal duct and 

follicular hypertrophy of thyroid in 

males. 

*NOEAL not established 

Cancer (oral, 

dermal, 

inhalation)

Classification: “Likely to be Carcinogenic to Humans.” Q1

* = 2.3 x 10-2

(mg/kg/day)-1based 

on male mouse liver benign and/or malignant combined tumor rates.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response 

data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally 

relevant human exposures. NOAEL = no-observed adverse-effect level. LOAEL = lowest-observed adverseeffect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = 

potential variation in sensitivity among members of the human population (intraspecies). UFL = use of a 

LOAEL to extrapolate a NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to 

account for the absence of key date (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of 

concern. N/A = not applicable. 112% dermal-absorption factor – Derived from HIARC report TXR NO. 

0052657.

4.6 Endocrine Disruption

As required under Federal Food, Drug, and Cosmetic Act (FFDCA) section 408(p), EPA has 

developed the Endocrine Disruptor Screening Program (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.

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. 

This list of chemicals was selected based on the potential for human exposure through pathways 

such as food and water, residential activity, and certain post-application agricultural scenarios. 

This list should not be construed as a list of known or likely endocrine disruptors.

Tetraconazole was not among the group of 58 pesticide active ingredients on the initial list to be 

screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide 
Tetraconazole Human-Health Risk Assessment DP#: 380618 

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chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all 

pesticide active ingredients.

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

Nature of the Residue - Plants: The HED Metabolism Assessment Review Committee 

(MARC) reviewed the sugar beet (triazole ring labeled study), grape (triazole and phenyl ring 

labeled studies), and wheat (triazole and phenyl ring labeled studies) metabolism studies 

(D264157, W. Donovan, 19-Apr-2000). The MARC tentatively concluded that the residue of 

concern in banana, peanut, and sugar beet was tetraconazole per se. This decision was not 

finalized due to uncertainty concerning the toxicity of the free triazole metabolites, incomplete 

identification of residues in wheat straw, and the lack of a phenyl-labeled sugar beet metabolism 

study. HED has subsequently determined that the free triazole metabolites are of toxicological 

concern (TXR No. 0052011) and received/reviewed the requested metabolism studies. Since the 

MARC was disbanded prior to the submission/review of the requested data and prior to the 

submission of the triazole-labeled soybean metabolism study, a final conclusion pertaining to the 

residues of concern in plants was not made by the MARC. 

Based on the tentative conclusions made by the MARC, the results of the metabolism studies, 

and toxicological considerations, HED concludes that the residue of concern for tolerance 

enforcement in all crops is tetraconazole per se and the residues of concern for risk assessment 

are as follows: (1) shelled pea and bean (succulent and dried): tetraconazole and T, TA, TAA, 

and all labile conjugates of these compounds and (2) all remaining crops: tetraconazole, 

M14360-alcohol (free and conjugated), M14360-acid, M14360-DFA, M14360-

hydroxydetriazolyl-O-malonyldiglucoside, and T, TA, TAA and all labile conjugates of these 

compounds. HED notes that Syngenta developed a common moiety method for propiconazole 

which employs base hydrolysis followed by oxidation and that a similar method would be 

appropriate for determination of the tetraconazole non-free-triazole metabolites (non-freetriazole metabolites hydrolyzed/oxidized to 2,4-dichlorobenzoic acid). For a full discussion 

pertaining to the residues of concern in plants see the HED risk assessment document D321751 

(M. Clock-Rust et al., 26-Jan-2007).

Nature of the Residue – Livestock: The MARC reviewed the goat metabolism studies and 

tentatively determined that the residues of concern in livestock were tetraconazole and T 

(D264157, W. Donovan, 19-Apr-2000). This decision was not finalized due to uncertainty 

concerning the toxicity of T and due to the lack of a poultry metabolism study. HED has 

subsequently determined that the free triazole metabolites are of toxicological concern (TXR No. 

0052011) and received/reviewed a poultry metabolism study (D282558, W. Donovan, 17-May2002). Since the MARC was disbanded prior to the submission and/or review of these data, a 

final conclusion pertaining to the residues of concern in livestock was not made by the MARC. 

Based on the tentative conclusions made by the MARC, the results of the metabolism studies, 

and toxicological considerations, HED concludes that the residue of concern in livestock for 

tolerance enforcement is tetraconazole per se and the residues of concern for risk assessment are 

tetraconazole, M14360-alcohol (free and conjugated), M14360-acid, M14360-DFA, M14360(C-
Tetraconazole Human-Health Risk Assessment DP#: 380618 

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1)-alcohol (free and conjugated), M14360-hydroxydetriazolyl-O-malonyldiglucoside, and T, TA, 

THP, and TAA and all labile conjugates of these compounds. HED included as residues of 

concern the free triazole metabolites (excluding T) and non-free-triazole metabolites as these 

were identified as significant residues in plants; T was included as it was a significant metabolite 

in the livestock and plant metabolism studies. For a full discussion pertaining to the residues of 

concern in livestock see the HED risk assessment document D321751 (M. Clock-Rust et al., 26-

Jan-2007).

Nature of the Residue - Rotational Crops: The MARC reviewed the [triazole14C]-

tetraconazole confined rotational crop study and tentatively determined that the residue of 

concern in rotational crops is tetraconazole per se (D264157, W. Donovan, 19-Apr-2000). This 

decision was not finalized due to uncertainty concerning the toxicity of the free triazole 

metabolites and due to the lack of a [phenyl14C]-tetraconazole confined rotational crop study. 

HED has subsequently determined that the free triazole metabolites are of toxicological concern 

(TXR No. 0052011) and received/reviewed the [phenyl14C]-tetraconazole confined rotational 

crop study. Since the MARC was disbanded prior to the submission and/or review of these data,

a final conclusion pertaining to the residues of concern in rotational crops was not made by the 

MARC. 

Based on the tentative conclusions made by the MARC, the results of the confined rotational 

crop studies, and toxicological considerations, HED concludes that the residue of concern in 

rotational crops for tolerance enforcement is tetraconazole per se and the residues of concern for 

risk assessment are tetraconazole, M14360-acid, M14360-DFA, M14360(C-1)-alcohol (free and 

conjugated), and TA, THP, and TAA and all labile conjugates of these compounds. 

HED notes that the triazole- and phenyl-labeled confined rotational crop studies indicated that 

majority of the residues in rotational crops following application of tetraconazole are the free 

triazole metabolites. Since the toxicity of the free triazole; M14360(C-1)-alcohol (free and 

conjugated); and tetraconazole, M14360-acid, and M14360-DFA are different (see section 5.1.3) 

and based on the magnitude of M14360(C-1)-alcohol (free and conjugated; <1-23% TRR) and 

tetraconazole (15-81% TRR), M14360-DFA (<1-11% TRR), and M14360-acid (<1-23% TRR) 

in the phenyl-labeled confined rotational crops study, HED concluded that the non-free triazole 

metabolites should be included as residues of concern in rotational crops. 

5.1.2 Summary of Environmental Degradation

Tetraconazole is persistent in the environment and has moderate to slight mobility in soils. 

Laboratory and field half-lives ranged from 107 days to more than 1 year; however, the 

dissipation of tetraconazole applied directly to foliage is much more rapid. Foliar-dissipation 

studies suggest that tetraconazole is taken up quickly and extensively metabolized in plants 

yielding tetraconazole acid, tetraconazole alcohol, TA, and TAA as metabolites. Successive 

applications of tetraconazole are expected to result in year-to-year soil accumulation. 

Tetraconazole has potential to reach surface water via runoff and spray drift, but its tendency to 

reach ground water is expected to be reduced due to its lack of mobility in soil.

5.1.3 Residues of Concern Summary and Rationale

Based on sugar beet, grape, wheat, soybean, ruminant, and poultry metabolism studies, and a 

confined rotational crop study, HED determined that the residues of concern in primary crops, 
Tetraconazole Human-Health Risk Assessment DP#: 380618 

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livestock, and rotational crops are as defined in Table 5.1.3. HED determined that the 

toxicological effects resulting from exposure to T, TA, TAA, THP, and all labile conjugates of 

these compounds and M14360(C-1)-alcohol are different from that resulting from exposure to 

tetraconazole. The toxicity of the remaining residues of concern is considered to be identical to 

that of tetraconazole. For a full discussion concerning these conclusions, see HED’s 2007 risk 

assessment (D321751, M Clock-Rust et al., 26-Jan-2007). 

HED notes that M14360-ketone, M14360-CP(C-1)-alcohol, and M14360(C-1)-alcohol were 

indentified in the plant, livestock, and/or confined rotational crop studies and, as indicated 

section 5.1.1, HED concluded that the toxicity of these compounds is accounted for in the 

propiconazole toxicity database. Based on the magnitude of these residues relative to the other 

identified residues in the tetraconazole metabolism and rotational crop studies, HED concluded 

that only M14360(C-1)-alcohol is a residues of concern and in only rotational crops. However, 

when performing a tetraconazole risk assessment, the reviewer should determine if the 

magnitude of M14360-ketone, M14360-CP(C-1)-alcohol, and/or M14360(C-1)-alcohol residues 

following the application of tetraconazole are such that a revised propiconazole risk assessment 

is required. 

Table 5.1.3. Residues for Tolerance Expression and Risk Assessment.

Matrix Residues included in Risk Assessment Residues included in Tolerance 

Expression

Shelled Pea 

and Bean

tetraconazole and T, TA, TAA, and all labile conjugates of 

these compounds Tetraconazole

Remaining 

Plants

tetraconazole, M14360-alcohol (free and conjugated), M14360-

acid, M14360-DFA, M14360-hydroxydetriazolyl-Omalonyldiglucoside, and T, TA, TAA, and all labile conjugates 

of these compounds

Tetraconazole

Livestock

tetraconazole, M14360-alcohol (free and conjugated), M14360-

acid, M14360-DFA, M14360(C-1)-alcohol (free and 

conjugated), M14360-hydroxydetriazolyl-Omalonyldiglucoside, and T, TA, THP, and TAA and all labile 

conjugates of these compounds

Tetraconazole

Rotational 

Crops

tetraconazole, M14360-acid, M14360-DFA, M14360(C-1)-

alcohol (free and conjugated), and TA, THP, and TAA and all 

labile conjugates of these compounds

Tetraconazole

Drinking 

Water Tetraconazole Not Applicable

5.2 Food Residue Profile

D382300, T. Bloem, 14-Apr-2011

Magnitude of the Residue – Proposed Primary Crops: Adequate grape (representative crop for 

13-07F subgroup), strawberry (representative crop for 13-07G subgroup), and field corn 

magnitude of the residue data were submitted. The field trials were geographically distributed as 

suggested in Table 5 of 860.1500, were conducted with the proposed formulation, and employed 

the proposed application scenario. Adequate grape and field corn processing studies were also 

submitted and these studies indicate that separate tolerances in/on the grape and field corn 

processed commodities are unnecessary. The following storage stability data are needed to 

validate the magnitude of the residue data: T, TA, and TAA in strawberry (516 days), grape 

(236 days), grape juice (64 days), and raisin (91 days); tetraconazole in corn grain, forage, and 

stover (266 days; grain data will be translated to all processed commodities excluding refined 
Tetraconazole Human-Health Risk Assessment DP#: 380618 

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oil); T in corn forage and stover (263 days); tetraconazole, T, TA, and TAA in refined corn oil 

(198 days).

Provided a revised Section B is submitted which eliminates the cranberry application instructions 

and prohibits the addition of adjuvants to the spray solutions for 13-07F and 13-07G crops, HED 

concludes that the plant tolerances listed in Table 5.4.1 for residues of tetraconazole per se are 

appropriate (the currently established grape tolerance should be deleted). A revised Section F is 

requested.

Magnitude of the Residue - Livestock: Tolerances for residues of tetraconazole per se are 

currently established in/on ruminant (cattle, goat, horse, and sheep) fat (0.02 ppm), liver (0.20 

ppm), meat (0.01 ppm), and meat byproducts (except liver; 0.01 ppm) and milk (0.01 ppm), and 

milk fat (0.25 ppm). Tolerances are also established in/on hog fat (0.01 ppm), hog liver (0.05 

ppm), and hog meat (0.01 ppm) and in/on poultry fat (0.05 ppm), meat (0.01 ppm), meat 

byproducts (0.01 ppm), and egg (0.02 ppm). 

Based on the livestock maximum reasonably balanced dietary burdens (MRBDBs) and the 

previously submitted and reviewed dairy cattle (D254411, W. Donovan, 18-May-2000) and 

poultry (46614307.der.doc; D329379, T. Bloem, 23-Jan-2007) feeding studies, HED concludes 

that the livestock tolerances listed in Section 2.2.3 are appropriate (the currently established hog, 

egg, poultry meat and fat, and ruminant meat tolerances remain appropriate). A revised Section 

F is requested. 

Magnitude of the Residue – Rotational Crops: The field rotational crop studies resulted in 

tetraconazole per se residues of <0.02 ppm in/on all studied rotational crops (wheat grain, pea, 

potato, canola seed, sugar beet (top and root)), excluding wheat straw, planted 7-9 days after a 

bare soil application at 1.4-17x the proposed seasonal rates (D278236, W. Donovan, 22-Oct2001). Residues of tetraconazole per se were <0.02-0.05 ppm in/on wheat straw when planted 7-

9 days after a bare soil treatment at 4.2-17x. Based on these data, the proposed plant-back 

intervals, and proposed application rates, HED concludes that residues of tetraconazole and its 

metabolites of concern will be insignificant in rotational crops. 

Multiresidue Methods (MRMs) Testing: HED has previously reviewed information concerning 

the MRMs testing of tetraconazole and forwarded these data to the FDA (D278236, W. 

Donovan, 22-Oct-2001; D332231, T. Bloem, 13-Sep-2006). Tetraconazole was not recovered 

through the MRM Protocols. 

5.3 Water Residue Profile

EFED provided modeled ground water (Screening Concentration In Ground Water (SCIGROW); 

ver. 2.3) and surface water (Pesticide Root Zone Model (PRZM ver. 3.12.2) and Exposure 

Analysis Modeling System (EXAMS ver. 2.98.04.06)) estimated drinking water concentrations 

(EDWCs) for tetraconazole per se resulting from the proposed application scenarios (EFED 

memorandum - D380619, C. Koper, 12-Oct-2010). However, previously provided EDWCs were 

greater and were therefore incorporated in the current dietary analyses (see bolded numbers in 

Table 5.3; PRZM/EXAMS estimates). For derivation of these EDWCs, see EFED memorandum 

D347805 (I. Maher, 1-Jul-2008). The water models and their description are available at the 

EPA internet site: http://www.epa.gov/oppefed1/models/water/. 
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Table 5.3. Summary of Estimated Surface Water and Groundwater Concentrations for Tetraconazole.

Scenario Tetraconazole per se (μg/L; ppb)

Peak Yearly 30-Year-Annual Average

Minnesota - sugar beets aerial spray16.68 4.68 3.29

Georgia - pecans aerial spray2

10.45 3.48 2.84

1

 EDWCs assumed 0.87 of the basin cropped (assumes 100% of the crop treated).

2

 EDWCs assumed 0.85 to account for percent of basin cropped (assumes 100% of the crop treated).

5.4 Dietary Risk Assessment

D381912, T. Bloem, 14-Apr-2011

5.4.1 Description of Residue Data Used in Dietary Assessment

Acute, chronic, and cancer dietary risk assessments were conducted using the DEEM-FCIDTM

(ver. 2.03) which incorporates the food consumption data from the USDA’s CSFII (1994-1996 

and 1998). These analyses incorporated all the proposed/registered uses. The following 

paragraphs are summaries of the acute, chronic, and cancer analyses. For information 

concerning exposure to the metabolites of concern that HED has determined to be 

toxicologically different from tetraconazole, see Section 7.0. 

Acute: The unrefined acute analysis resulted in exposure estimates less than HED’s level of concern 

(children 1-2 years old were the most highly exposed population subgroup at 1.8% aPAD; see Table 

5.4.1). 

Chronic: The chronic analysis (food and water) was refined through the incorporation of 

empirical processing factors, average field trial residues, average residues from the feeding 

studies, and projected percent crop treated estimates. The resulting exposure estimates are less 

than HED's LOC (all infants <1 year old were the most highly exposed population subgroup at 

5% cPAD; see Table 5.4.1). 

Cancer: The cancer analysis (food and water) was refined through the incorporation of empirical 

processing factors, average field trial residues, average residues from the feeding studies, and 

projected percent crop treated estimates. The resulting exposures estimates yielded a cancer risk 

for the U.S. population of 3 x 10-6 which is less than HED's LOC (see Table 5.4.1). A critical 

commodity analysis for the cancer run (U.S. population) indicated that the major contributors 

were water (63% of total exposure), strawberry (11% of total exposure), dairy products (5% of 

total exposure), and soybean oil (4% of total exposure). 

Table 5.4.1. Summary of Dietary (Food and Drinking Water) Exposure and Risk.

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% aPAD*

Dietary 

Exposure

(mg/kg/day)

% cPAD*

Dietary 

Exposure

(mg/kg/day)

Risk

General U.S. Population 0.003570 <1 0.000140 1.9 0.000111 2.5 x 10-6

All Infants (< 1 year old) 0.006518 1.3 0.000360 4.9

not applicable

Children 1-2 years old 0.009120 1.8 0.000274 3.8

Children 3-5 years old 0.006743 1.4 0.000247 3.4

Children 6-12 years old 0.004167 <1 0.000159 2.2

Youth 13-19 years old 0.002460 <1 0.000102 1.4

Adults 20-49 years old 0.002102 <1 0.000122 1.7

Adults 50+ years old 0.001807 <1 0.000129 1.8

Females 13-49 years old 0.002140 <1 0.000124 1.7
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5.4.2 Percent Crop Treated Used in Dietary Assessment

The acute analysis assumed 100% crop treated and the chronic and cancer analyses incorporated 

the following percent crop treated new use estimates provided by the Biological and Economic 

Analysis Division (BEAD; D332043, J. Alsadek, 13-Dec-2006; D382470, L. Yourman 16-Mar2011): sugar beet - 70%; peanut - 77%; field corn - 9%; and soybean - 5%. 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no residential uses proposed or currently registered for tetraconazole. Therefore, 

residential handler and post-application exposure/risk were not assessed.

6.1 Residential Bystander Post-application Inhalation Language

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for tetraconazole at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV), low vapor pressure (0.58 x 102Pa at 46.5°C), and the 

low proposed use rates (0.035 and 0.09 lb ai/A). However, volatilization of pesticides may be a 

source of post-application inhalation exposure to individuals nearby pesticide applications. The 

Agency sought expert advice and input on issues related to volatilization of pesticides from its 

Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in 

December 2009, and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, develop policies and procedures to 

identify the need for and, subsequently, the way to incorporate post-application inhalation 

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

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

for tetraconazole.

6.2 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for tetraconazole. 

The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical-by-chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT®computer model 

to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic 

methods. After the policy is in place, the Agency may impose further refinements in spray drift 

management practices to reduce off-target drift with specific products with significant risks 

associated with drift.

Although a quantitative residential post-application inhalation exposure assessment was not 

performed because of pesticide drift from neighboring treated agricultural fields, an inhalation 
Tetraconazole Human-Health Risk Assessment DP#: 380618 

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exposure assessment was performed for flaggers. This exposure scenario is representative of a 

worse case inhalation (drift) exposure and may be considered protective of most outdoor 

agricultural and commercial post-application inhalation exposure scenarios. 

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. Because there 

are no residential uses for tetraconazole, only food and water were included in aggregate 

assessments. Since the dietary exposure analysis included the drinking water estimates, the 

discussion and exposure estimates presented in Section 5.4 represent aggregate acute, chronic, 

and cancer aggregate exposures. All aggregate tetraconazole risk estimates are not of concern to 

HED.

It is noted that application of tetraconazole also results in exposure to 1,2,4-triazole (T) and its 

conjugated metabolite which are considered to be toxicologically different from tetraconazole as 

well as to metabolites which HED determined are toxicologically identical to propiconazole 

(M14360-ketone, M14360-CP(C-1)-alcohol, and M14360(C-1)-alcohol). As part of a separate 

document, HED conducted an aggregate exposure analysis for T and its conjugated metabolites; 

all aggregate exposure were less than HED’s level of concern (D388544, T. Bloem, 14-Apr2011). In addition, HED concludes that the most recent propiconazole risk assessment 

(D375282, B. Daiss et al., 3-Nov-2010) which yielded exposures less than HED’s level of 

concern does not require revision for the following reasons: (1) for the commodities which 

tetraconazole and propiconazole have in common (plant and livestock), the propiconazole 

tolerances are higher than the tetraconazole tolerances indicating that the conclusion which led to 

the elimination M14360-ketone, M14360-CP(C-1)-alcohol, and/or M14360(C-1)-alcohol as 

residues of concern following application of tetraconazole, namely insignificant residues, would 

also be applicable to propiconazole; (2) M14360-ketone and M14360(C-1)-alcohol were 

significant residues in the propiconazole livestock metabolism studies (ruminants = 31% TRR; 

poultry = 79% TRR) but were insignificant residues in the tetraconazole livestock metabolism 

studies (M14360-ketone was identified in livestock tissue at ≤4.5% TRR; M14360-CP(C-1)-

alcohol and M14360(C-1)-alcohol were not identified); and (3) based on the tetraconazole field 

rotational crop study, the proposed/registered application rates and plantback intervals, and the 

M14360(C-1)-alcohol to tetraconazole residue ration from the confined rotational crop study, 

HED concludes that residues of M14360(C-1)-alcohol will be insignificant in rotational crops 

planted in fields treated with tetraconazole. 

8.0 Cumulative Exposure/Risk Characterization

Tetraconazole 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 (EPA, 2002). In conazoles, however, a variable pattern of toxicological 

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

tumors in rats. Some induce developmental, reproductive, and neurological effects in rodents. 

Furthermore, the conazoles produce a diverse range of biochemical events including altered 

cholesterol levels, stress responses, and altered DNA methylation. It is not clearly understood 
Tetraconazole Human-Health Risk Assessment DP#: 380618 

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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 following a cumulative risk approach based on a common mechanism of toxicity

for the conazoles. For information regarding EPA’s procedures for cumulating effects from 

substances found to have a common mechanism of toxicity, see EPA’s website at 

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

Tetraconazole is a triazole-derived pesticide. This class of compounds can form the common 

metabolite T and two triazole conjugates (TA and TAA). To support existing tolerances and to 

establish new tolerances for triazole-derivative pesticides, including tetraconazole, U.S. EPA 

conducted a human-health risk assessment for exposure to T, TA, and TAA resulting from the 

use of all current and pending uses of any triazole-derived fungicide. The risk assessment is a 

highly conservative, screening-level evaluation in terms of hazards 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 10X FQPA SF for the protection of infants and 

children. The assessment includes evaluations 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 http://www.regulations.gov, Docket Identification (ID) 

Number EPA-HQ-OPP-2005-0497.

9.0 Occupational Exposure/Risk Characterization

9.1 Short- and Intermediate-Term/Cancer Handler Risk

The proposed use sites are small fruit vine climbing (except fuzzy kiwifruit) subgroup 12-07F, lowgrowing berry subgroup 13-07G, field corn and popcorn. The proposed application methods are 

groundboom, aerial, and chemigation. Potential occupational handler exposure scenarios include:

1) mixer/loader using open pouring of liquids in support of aerial, groundboom, and chemigation 

operations; 2) aerial applicators; 3) applicators using open-cab ground boom equipment; and 4) 

flaggers.

HED completed both short- and intermediate-term assessments for occupational scenarios in all 

cases because these kinds of exposures are likely and acceptable use/usage data are not available 

to justify deleting intermediate-term scenarios. Based on use data and label instructions, HED 

believes that occupational exposures may occur over a single day or up to weeks at a time for 

many use-patterns and that intermittent exposure over several weeks may also occur. Some 

applicators may apply the product over a period of weeks, because they are commercial 

applicators who are completing multiple applications for multiple clients. The average adult 

body weight of 60 kg was used for estimating dermal and inhalation dose because the endpoint is 

from a developmental study and was observed in offspring. Long-term exposures are not 

expected; therefore, a long-term assessment was not conducted.

No chemical-specific data are available with which to assess potential exposure to pesticide 

handlers. The estimates of exposure to pesticide handlers are based upon surrogate study data 

available in PHED (August, 1998). For pesticide handlers, it is HED standard practice to present 

estimates of dermal exposure for “baseline”; that is, for workers wearing a single layer of work 

clothing consisting of a long-sleeved shirt, long pants, shoes plus socks, and no protective 

gloves, as well as for “baseline” and the use of protective gloves or other personal-protective 

equipment (PPE) as might be necessary. The proposed product label involved in this assessment 
Tetraconazole Human-Health Risk Assessment DP#: 380618 

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directs applicators and other handlers to wear protective eyewear, long-sleeved shirt, long pants, 

socks, shoes, and chemical-resistant gloves. 

Table 9.1a provides a summary of the estimated exposures and risks to occupational pesticide 

handlers. An MOE ≥100 is adequate to protect occupational pesticide handlers from dermal 

exposures and an MOE ≥300 is adequate to protect occupational pesticide handlers from 

inhalation exposures. Since all the estimated dermal MOEs are >100 with baseline protection or 

the addition of gloves (as already required by the label), and all inhalation MOEs >300, the 

proposed uses are not of concern for HED.
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Table 9.1a. Occupational Dermal and Inhalation Exposures and Risks.

Crop or 

Target

App. Rate (lb 

ai/A)

Area 

Treated 

Daily or 

Amount 

Handled 

(Acres or 

gallons 

per day)

Dermal and Inhalation 

Unit Exposures (mg/lb 

ai)

Short- and Intermediateterm Doses (mg/kg/day)e

MOEsf

Short- and 

intermediate- term 

Mixer/Loader for Aerial Applications

Small 

fruit vine 

climbing 

subgroup 

12-07F 0.039 350

Dermal

Baselinec: 2.9

PPE-G: 0.023

Inhal.

Baselined: 0.0012

Dermal

Baseline: 0.079

PPE-G

g

: 0.00063

Inhal.

Baseline: 0.00054

Dermal

Baseline: 8.8

PPE-G: 1,100

Inhal.

Baseline: 2,400 Lowgrowing 

berry

Field 

corn and 

Popcorn

0.090 1200

Dermal

Baseline: 2.9

PPE-G: 0.023

Inhal.

Baseline: 0.0012

Dermal

Baseline: 0.63

PPE-G: 0.005

Inhal.

Baseline: 0.00019

Dermal

Baseline: 1.1

PPE-G: 140

Inhal.

Baseline: 700

Mixer/Loader for Chemigation Applications

Small 

fruit vine 

climbing 

subgroup 

12-07F

0.039 350

Dermal

Baseline: 2.9

PPE-G: 0.023

Inhal.

Baseline: 0.0012

Dermal

Baseline: 0.079

PPE-G: 0.00063

Inhal.

Baseline: 0.00023

Dermal

Baseline: 8.8

PPE-G: 1,100

Inhal.

Baseline: 5,600 Lowgrowing 

berry

Field 

corn and 

Popcorn

0.090 1200

Dermal

Baseline: 2.9

PPE-G: 0.023

Inhal.

Baseline: 0.0012

Dermal

Baseline: 0.63

PPE-G: 0.005

Inhal.

Baseline: 0.0019

Dermal

Baseline: 1.1

PPE-G: 140

Inhal.

Baseline: 700

Mixer/Loader for Groundboom Applications

Small 

fruit vine 

climbing 

subgroup 

12-07F 0.039 80

Dermal

Baseline: 2.9

PPE-G: 0.023

Inhal.

Baseline: 0.0012

Dermal

Baseline: 0.018

PPE-G: 0.00014

Inhal.

Baseline: 0.000053

Dermal

Baseline: 39

PPE-G: 4,900

Inhal.

Baseline: 24,000 Lowgrowing 

berry

Field 

corn and 

Popcorn

0.090 200

Dermal

Baseline: 2.9

PPE-G: 0.023

Inhal.

Baseline: 0.0012

Dermal

Baseline: 0.1

PPE-G: 0.00083

Inhal.

Baseline: 0.00031

Dermal

Baseline: 6.7

PPE-G: 850

Inhal.

Baseline: 4,200

Applying Sprays via Aerial Application
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a Application rates are the maximum application rates determined from proposed labels for tetraconazole.

b Amount handled per day values are HED estimates of acres treated per day or gallons handled per day based on ExpoSAC SOP #9 

“Standard Values for Daily Acres Treated in Agriculture,” industry sources, and HED estimates.

c Baseline Dermal: Long-sleeve shirt, long pants, and no gloves.

d Baseline Inhalation: no respirator.

e Dose (mg/kg/day) = Unit exposure(mg/lb ai) x App Rate (0.039 or 0.09 ai/acre) x Area Treated ( acres/day) or Amount 

Handled (gallons) x Absorption (12% for dermal and 100% for inhalation) / Body weight (70 or 60 kg). 

f MOE = NOAEL/Dose; where the short- and intermediate-term dermal NOAEL = 0.7 mg/kg/day; short- and intermediate-term 

inhalation NOAEL = 1.3 mg/kg/day.

g PPE-G = long-sleeve shirt, long pants, and gloves.

h Engineering control = enclosed cockpit and baseline attire (long-sleeve shirt, long pants, shoes, and socks).

Cancer risk estimates resulting from exposures to tetraconazole were calculated using a linear 

low-dose extrapolation approach in which a Lifetime Average Daily Dose (LADD) is first 

calculated and then compared with a Q1* that has been calculated for tetraconazole based on dose 

response data (Q1* = 2.3 x 10-2(mg/kg/day)-1). Absorbed average daily dose (ADD) levels were 

used as the basis for calculating the LADD values. These values also serve as the basis for the 

cancer risk estimates. Dermal and inhalation ADD values were first added together to obtain 

combined ADD values. LADD values were then calculated and multiplied by the Q1* to obtain 

cancer risk estimates.

Small 

fruit vine 

climbing 

subgroup 

12-07F 0.039 350

Dermal

Eng. controlh: 0.005

Inhal.

Baseline:0.000068

Dermal

Eng. control: 0.00014

Inhal.

Baseline: 0.000013

Dermal

Eng. Control: 5,100

Inhal.

Low- Baseline: 98,000

growing 

berry

Field 

corn and 

Popcorn

0.090 1200

Dermal

Eng. control: 0.005

Inhal.

Baseline: 0.000068

Dermal

Eng. control: 0.00032

Inhal.

Baseline: 0.000031

Dermal

Eng. control: 2,200

Inhal.

Baseline: 42,000

Applying Sprays via Groundboom Application

Small 

fruit vine 

climbing 

subgroup 

12-07F 0.039 80

Dermal

Baseline: 0.014

Inhal.

Baseline: 0.00074

Dermal

Baseline: 0.000087

Inhal.

Baseline: 0.000033

Dermal

Baseline: 8,000

Inhal.

Low- Baseline: 39,000

growing 

berry

Field 

corn and 

Popcorn

0.090 200

Dermal

Baseline: 0.014

Inhal.

Baseline: 0.00074

Dermal

Baseline: 0.0002

Inhal.

Baseline: 0.000076

Dermal

Baseline: 3,500

Inhal.

Baseline: 17,000

Flagger

Small 

fruit vine 

climbing 

subgroup 

12-07F 0.039

350

Dermal

Baseline: 0.011

Inhal.

Baseline: 0.00035

Dermal

Baseline: 0.0003

Inhal.

Baseline: 0.000068

Dermal

Baseline: 2,300

Inhal.

Low- Baseline: 19,000

growing 

berry

Field 

corn and 

Popcorn

0.090

Dermal

Baseline: 0.011

Inhal.

Baseline: 0.00035

Dermal

Baseline: 0.00069

Inhal.

Baseline: 0.00016

Dermal

Baseline: 1,000

Inhal.

Baseline: 8,300
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To estimate the carcinogenic risk from the absorbed ADD, the values must be amortized over the 

working lifetime of occupational handlers. Based on use scenario and use patterns, it is 

anticipated that commercial applicators would apply tetraconazole less than 30 days per year. 

Finally, a 35-year career and a 70-year lifespan were used to complete the calculations. 

HED conducted an assessment of the carcinogenic risk estimates associated with tetraconazole 

following exposures to occupational handlers. The minimum level of PPE for handlers is based

on acute toxicity for the end-use product. RD is responsible for ensuring that PPE listed on the 

label is in compliance with the Worker Protection Standard (WPS) for Agricultural Pesticides. 

The Agency generally considers occupational cancer risk estimates within the range of 10-6or 

less to be negligible, but may accept risk estimates as high as 1x10-4 when all mitigation 

measures that are feasible and practical have been applied, particularly when there are critical 

pest management needs associated with the use of the pesticide. 

Estimated tetraconazole cancer risks for handlers are summarized below in Table 9.1b. 

Estimated cancer risks are below 10-6 with the use of gloves as recommended by the label.

Table 9.1b. Handler Cancer Risk Estimates for Commercial Tetraconazole Handlers.

Scenario Mitigation Dermal Dosea

(mg/kg/day)

Inhalation Dosea

(mg/kg/day)

Combined 

ADDb

(mg/kg/day)

Commercial

LADDc

(mg/kg/day)

Commercial

Cancer

Riskd

Mixer/Loader

Mixing/Loading 

Liquids for 

Aerial 

Applications

Baseline Dermal 

and Inhalation 0.63 0.0022 0.63 2.6E-02 5.9E-04

Single layer 

w/gloves + 

Baseline 

Inhalation

0.005 0.0022 0.0071 2.9E-04 6.7E-06

Mixing/Loading 

Liquids for 

Chemigation

Baseline Dermal 

and Inhalation 0.63 0.0022 0.63 2.6E-02 5.9E-04

Single layer 

w/gloves + 

Baseline 

Inhalation

0.005 0.0022 0.0071 2.9E-04 6.7E-06

Mixing/Loading 

Liquids for 

Groundboom 

Applications 

Baseline Dermal 

and Inhalation 0.10 0.00036 0.10 4.3E-03 9.9E-05

Single layer 

w/gloves + 

Baseline 

Inhalation

0.00083 0.00036 0.0012 1.1E-06 9.18E-07

Applicator

Applying Sprays 

via Aerial 

Equipment

Eng Control 0.0011 0.00012 0.0012 4.9E-05 1.1E-06

Applying Sprays 

via Groundboom 

Equipment

Baseline Dermal 

and Inhalation 0.00050 0.00022 0.00073 3.0E-05 6.9E-07

a. Dermal Dose and Inhalation Doses (mg/kg/day) = See Table 9.1a.

b. Combined ADD (mg/kg/day) = Dermal Dose (mg/kg/day) + Inhalation Dose (mg/kg/day).

c. Commercial Applicator LADD (mg/kg/day) = ADD x [(30 days/yr)/ (365 days/yr)] x (35 yrs/70yrs).

d Commercial Applicator Cancer Risk = Commercial LADD x Q1* [2.3 x 10-2(mg/kg/day)-1]. 
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9.2 Short- and Intermediate-Term/Cancer Post-Application Risk

9.2.1 Dermal Post-Application Risk

HED expects that post-application dermal exposure will occur since tetraconazole is applied 

post-emergence as a foliar spray. 

Since no post-application data were submitted in support of this registration action, exposures 

during post-application activities were estimated using dermal transfer coefficients from HED’s 

ExpoSAC Policy Number 3.1 “Agricultural Transfer Coefficients” (August 2000). Table 9.2.1a 

summarizes the scenarios assessed.

Table 9.2.1a. Anticipated Post-application Activities and Dermal Transfer Coefficients.

Proposed 

Crops

Policy Crop 

Group Category

Application Rate

(lb ai/acre)

Transfer Coefficients 

(cm2/hr) Activities

Small fruit 

vine climbing 

subgroup 12-

07F

Vine/trellis 0.039

500 Weeding (hand), hedging, 

irrigation

1,000 Scouting

1,100 Harvesting, pruning

5,000

Thinning, training, tying, 

pruning, leaf pulling, 

harvest (hand)

10,000

Girdling, tying (cane 

turning), turning (cane 

turning)

Low-growing 

berry Berry, low 0.039

400 Irrigation, mulching, 

scouting, weeding

1,500 Harvest (hand), pruning 

(pinching), training

Field Corn and 

Popcorn

Field/row crop, 

tall 0.090 1,000 Scouting, irrigation, 

17,000 Detasseling 

Once daily exposures are calculated, the calculation of daily-absorbed dose and the resulting 

MOEs use the same algorithms that are described above for the handler exposures. These 

calculations are completed for each day or appropriate block of time after application.

HED has determined that short- and intermediate-term risk estimates are not of concern (i.e., 

MOEs ≥100) on the day of treatment (i.e., Day 0) for most post-application exposure activities. 

For high contact activities (TC=10,000 for grapes and TC=17,000 for field corn and popcorn) the 

MOEs are < 100 on the day of treatment. The high contact activities for grapes (girdling, cane

tying, and cane turning) are only expected to occur for cultivation of table grapes. MOEs are 

>100 on day 7 after treatment. The high contact activity for corn (detasseling) is only expected 

to occur for field corn or popcorn grown for seed. MOEs are >100 on day 20 after treatment. 

Table 9.2.1b presents a summary of occupational post-application risks associated with use of 

tetraconazole. 
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Table 9.2.1b. Post-application Risk Estimates for Tetraconazole.

Crop

Application 

Rate

(lb ai/A)

Transfer Coefficient

(cm2/hr)

DFR1

(ug/cm2)

Days After 

Treatment

Daily Dose2

(mg/kg/day) MOE3 

Small fruit vine 

climbing 

subgroup 12-

07F

0.039

500 0.09

0 (12 hours)

0.001 1,000

1,000 0.09 0.001 500

1,100 0.09 0.002 450

5,000 0.09 0.007 100

10,000

0.09 0 (12 hours) 0.014 50

0.08 1 0.013 56

0.07 2 0.011 62

0.06 3 0.010 69

0.06 4 0.009 76

0.05 5 0.008 85

0.05 6 0.007 94

0.04 7 0.007 100

Low growing 

berry 0.039 400 0.09 0 (12 hours) 0.001 1,300

1,500 0.09 0.002 330

Field and 

Popcorn

0.090

1,000 0.09 0 (12 hours) 0.001 500

17,000

0.09 0 (12 hours) 0.024 29

0.08 1 0.021 33

0.07 2 0.019 36

0.06 3 0.017 40

0.06 4 0.016 45

0.05 5 0.014 50

0.05 6 0.013 55

0.04 7 0.011 62

0.04 8 0.010 68

0.03 9 0.009 76

0.03 10 0.008 84

0.03 11 0.008 94

0.02 20 0.007 100

1: DFR (μg/cm2) = Application Rate (lb ai/A) x (1- Daily Dissipation Rate)tx CF (4.54E+8 μg/lb) x CF (2.47E-8 A/cm2) x 20% 

DFR after initial treatment.

2: Daily Dose = [DFR (ug/cm2) x TC (cm2/hr) x 0.001 mg/μg x Dermal Absorption (12%) x 8 hrs/day] ÷ Body Weight (60 kg).

3: MOE = NOAEL (Short- and Intermediate-term NOAEL = 0.7 mg/kg/day)/Daily Dose (LOC = 100).

The occupational exposure and cancer risk calculations for post-application workers are 

presented in this section. The use of dissipation data and the manner in which daily postapplication dermal exposures were calculated are inherently different than with handler 

exposures. However, once daily exposures are calculated, the calculation of the LADD and the 

resulting cancer risk estimates use the same algorithms that are described above for the handler 

exposures. As stated above, the Agency generally considers occupational cancer risks in the 

general range of10-6to be negligible, but may accept risks as high as 1x10-4 when all mitigation 

measures that are feasible and practical have been applied. 

Cancer risk estimates are summarized in Table 9.2.1c below. Occupational post-application 

exposure scenarios were assessed for individuals employed by multiple establishments (i.e., 

commercial or migratory farmworkers) and were assumed to be exposed 30 days per year. 

Dislodgeable foliar residues were estimated using the method described above in the non-cancer 

post-application section (assuming 20% of the active ingredient is available initially and 

dissipation of 10% per day thereafter). HED used the average residue over 30 days to estimate 

cancer risk. Estimated cancer risks, based on the average residue over 30 days, for all postapplication activities, except for detasseling corn grown for seed, are below 10-6

. Estimated 
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cancer risks for detasseling corn grown for seed are greater than 10-6using the average residue 

over 30 days. The cancer risk is below 10-6on day 20.

Table 9.2.1c. Cancer Exposure/Risk Estimates for Tetraconazole Post-application Workers.

Crop DATa DFRb

(ug/cm2)

Transfer 

Coefficientc 

(cm2/hr)

Daily Dosed 

(mg/kg/day) LADDe Cancer Riskf

Small fruit 

vine climbing

1 - 30

0.03

500 0.00024 9.9E-06 2.27E-07

5,000 0.0024 9.9E-05 2.27E-06

10,000 0.0048 9.9E-05 4.54E-06

Low-growing 

berry 0.03 400 0.00019 7.9E-06 1.8E-07

1,500 0.00072 3.0E-05 6.81E-07

Field/row crop, 

tall

0.06 1,000 0.00096 3.9E-05 9.07E-07

17,000 0.016 6.7E-04 1.54E-05

20 0.02 17,000 0.007 2.2E-04 5.14e-06

a. DAT= days after treatment; 1-30 = average of residues from day of application through Day 30

b. DFR (μg/cm2) = Application Rate (lb ai/A) x (1- Daily Dissipation Rate)tx CF (4.54E+8 μg/lb) x CF (2.47E-8 A/cm2) x 20% DFR 

after initial treatment. Transfer Coefficients selected in accordance with ExpoSAC Policy 3.1 (August 2000).

c. Transfer Coefficients selected in accordance with ExpoSAC Policy 3.1 (August 2000).

d. Daily Dose (mg/kg/day) = DFR (μg/cm2) x 0.001 mg/ug x Tc (cm2/hr) x DA (12%) x ET (8 hr/day)/60 kg.

e. LADD (mg/kg/day) = DD x [(30 days/yr)/ (365 days/yr)] x (35 yrs/70yrs).

f. Cancer Risk = LADD x Q1* [2.3 x 10-2(mg/kg/day)-1].

9.2.2 Inhalation Post-Application Risk

Based on the Agency's current practices, a quantitative occupational post-application inhalation 

exposure assessment was not performed for tetraconazole at this time. However, there are 

multiple potential sources of post-application inhalation exposure to individuals performing postapplication activities in previously treated fields. These potential sources include volatilization 

of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency

sought expert advice and input on issues related to volatilization of pesticides from its FIFRA

SAP in December 2009. The Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for tetraconazole. 

REI

Short- and intermediate-term post-application risks were not a concern on day 0 (12 hours 

following application) for all post-application activities, except for 1) girdling, tying, and turning 

table grapes, and 2) detasseling corn grown for seed. For all other applications, the REI is based 

on the acute toxicity of tetraconazole. Tetraconazole has low acute toxicity via the oral, dermal, 

and inhalation routes (Categories III and IV). It is a slight eye irritant (Category III), but is not a 

dermal irritant or a dermal sensitizer (Category IV). Acute Toxicity Category III and IV 

chemicals via these routes are supported by a 12-hour REI under the WPS. 

Short- and intermediate-term post-application risks were a concern until day 7 for table grape 

post-application activities and until day 20 for detasseling corn grown for seed. RD should 

ensure the appropriate REI is presented on the label. A revised Section B should be submitted, if 

RD deems appropriate.
Tetraconazole Human-Health Risk Assessment DP#: 380618 

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Appendix 1. Toxicity Profile Tables

Table A.1. Acute Toxicity of Tetraconazole.

Guideline

No.

Study Type MRID #(s) Results Toxicity Category

870.1100 

(81-1)

Acute Oral (rat) 44268112 LD50 = 1031 mg/kg III

870.1200 

(81-2)

Acute Dermal 44335501 LD50 > 2000 mg/kg III

870.1300 

(81-3)

Acute Inhalation 44305302 LC50 > 3.66 mg/L IV

870.2400 

(81-4)

Primary Eye Irritation 44335502 Slight eye irritant III

870.2500 

(81-5 )

Primary Skin Irritation 44335503 Not a dermal irritant IV

87.2600 

(81-6)

Dermal Sensitization 44268113 Not a dermal sensitizer NA

Table A.2. Subchronic, Chronic, and Other Toxicity.

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.3100 

4-Week Oral toxicity 

rodents (rat)

44751304 (1988) 

Acceptable/non-guideline 

0, 70, 200, or 500 

mg/kg/day via gavage

NOAEL was not established. 

LOAEL = 70 mg/kg/day, based on decreased body weight gains in 

and increased liver weights both sexes, and increased kidney 

weights in males and ovary weights in females. 

870.31004-Week Oral 

toxicity rodents (rat)

44751305 (1988) 

Acceptable/nonguideline 

0, 40, 160, 640, 2500 or 

10000 ppm 

M: 0, 4.4, 17.5, 68.4, 229 

mg/kg/day; F: 0, 3.8, 16.1, 

62.3, 217 mg/kg/day

NOAEL = not established (M), 3.8 (F) mg/kg/day.

LOAEL = 4.4/15.3 (M/F) mg/kg/day, based on increased liver 

weights, enlarged livers and enlarged centrilobular hepataocytes.

870.3100 

4-Week Oral toxicity 

rodents (rat)

44751306 (1989) 

Acceptable/nonguideline 

0, 2, 5, 15 or 40 ppm 

M: 0, 0.21, 0.52, 1.57 or 

4.19 mg/kg/day

NOAEL = 4.19 mg/kg/day (M).

LOAEL was not established.

870.3100 

90-Day oral toxicity 

rodents (rat)

44335504 (1988) 

Acceptable/guideline 

0, 10, 60, or 360 ppm 

M : 0, 0.7, 4.1, or 23.9 

mg/kg/day 

F: 0, 0.9, 5.5, or 28.7 

mg/kg/day

NOAEL = 4.1/5.5 mg/kg/day (M/F).

LOAEL = 23.9/28.7 (M/F) mg/kg/day, was based upon increased 

body weight gains in males, decreased body weight gains in 

females, increased absolute and liver weights in both sexes, 

enlarged livers in males, enlarged centrilobular hepatocytes in 

males and females.
Tetraconazole Human-Health Risk Assessment DP#: 380618 

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Table A.2. Subchronic, Chronic, and Other Toxicity.

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.3100 

90-Day oral toxicity 

rodents (mice)

44778701 (1989) 

Acceptable/non-guideline 

0, 5, 25, 125, or 625 ppm 

M : 0, 1, 4, 16, or 85 

mg/kg/day 

F: 0, 1, 4, 20, or 103 

mg/kg/day

NOAEL = 4 mg/kg/day (M/F).

LOAEL = 16/20 mg/kg/day, based on single liver cell 

degeneration in males, and increased serum glutamic pyruvic 

transaminase (SGPT) and serum glutamic oxaloacetic 

transaminase (SGOT), decreased BUN levels, increased absolute 

and relative liver weights and presence hepatocellular single cell 

necrosis in females.

870.3150

90-Day oral toxicity in 

non-rodents (dog)

NA1 NA

870.3200 

21-Day dermal toxicity 

(rabbit)

44751307 (1992) 

Acceptable/guideline 

0, 250, 100 or 2000 

(formulation) mg/kg/day 

Actual a.i 0, 30.1, 120.4 or 

241 mg/kg/day

Systemic Toxicity

NOAEL = 241 (a.i) mg ai/kg/day.

LOAEL was not established.

Dermal Toxicity

NOAEL = not established.

LOAEL = 30 (a.i) mg/kg/day, based on dermal irritation.

870.3465 

28-Day Inhalation 

toxicity (rat)

46990301 (2006) 

Acceptable/non-guideline 

0, 0.0548, 0.159, or 0.520 

mg/L 

(0, 14.3, 43.15, or 141.15 

mg/kg/day)

NOAEL = Not established.

LOEAL = 0.0548 mg/L (14.3 mg/kg/day) for males and females, 

based on squamous cell metaplasia of laryngeal mucosa, 

mononuclear cell infiltration, goblet hyperplasia and hypertrophy 

of nasal cavity and nasopharyngeal duct and follicular 

hypertrophy of thyroid in males.

870.3700a 

Prenatal developmental 

in rodents (rat)

44335505 (1990) 

Acceptable/guideline 

F: 0, 5, 22.5, or 100 

mg/kg/day (GD 2-15)

Maternal NOAEL = 22.5 mg/kg/day.

LOAEL = 100 mg/kg/day, based on decreased body weight gain, 

and food consumption and increased water intake, and increased 

liver and kidney weights.

Developmental NOAEL = 22.5 mg/kg/day.

LOAEL = 100 mg/kg/day, based on increased incidence of small 

fetuses, supranumerary ribs and hydroureter and hydronephrosis.

870.3700b 

Prenatal developmental 

in nonrodents (rabbit)

44335506 (1990) 

Acceptable/guideline 

F: 0, 7.5, 15, or 30 

mg/kg/day

Maternal NOAEL = 15 mg/kg/day.

LOAEL = 30 mg/kg/day, based upon decreased body weight gain. 

Developmental NOAEL = 30 mg/kg/day.

LOAEL was not established.

870.3800 

Reproduction and 

fertility effects (rats)

44305306 (1991) 

Acceptable/guideline 

0, 10, 70, and 490 ppm 

M: 0, 0.7, 4.9, and 35.5 

mg/kg/day 

F: 0, 0.8, 5.9, and 40.6 

mg/kg/day

Parental/Systemic NOAEL = 0.7/0.8 mg/kg/day (M/F).

Parental LOAEL = 4.9/5.9 mg/kg/day (M/F), based on increased 

mortality of adult females in the P and F1 generations.

Reproductive NOAEL = 35.5/40.6 mg/kg/day (M/F).

LOAEL = Not established.

Offspring NOAEL = 4.9/5.9 mg/kg/day.

LOAEL = 35.5/40.6 mg/kg/day (M/F), based on decreased litter 

weight and mean pup weight in litters of all generations before 

weaning and increased relative liver weights at weaning in both 

sexes of all litters.
Tetraconazole Human-Health Risk Assessment DP#: 380618 

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Table A.2. Subchronic, Chronic, and Other Toxicity.

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.4300

Combined chronic 

toxicity/carcinogenicity 

rodents (rat)

44305304 (1992) 

Acceptable/guideline 

M: 0, 10, 80, 640 or 1280 

ppm 

F: 0, 10, 80, 640 ppm 

M: 0, 0.4, 3.4, 27.7, or 59 

mg/kg/day 

F: 0, 0.6, 4.4, or 39.4 

mg/kg/day

NOAEL = 3.4/4.4 mg/kg/day (M/F) 

LOAEL = 27.7/39.4 (M/F), based upon histopathology of the 

bone (osseous hypertrophy of the cranium/parietal bone), pale and 

thickened incisors, and decreased absolute and relative adrenal 

and pituitary weights in males; decreased body weight (at terminal 

sacrifice) in females. 

Dosing was considered adequate. 

No treatment-related increases in tumor incidence was observed.

870.4100b 

Chronic toxicity dogs

44305303 (1990) 

Acceptable/guideline 

M & F: 0, 22.5, 90 or 360 

ppm. 

M: 0, 0.73, 2.95 or 12.97 

mg/kg/day 

F: 0, 0.82, 3.33, or 14.5 

mg/kg/day

NOAEL = 0.73/0.82 (M/F) mg/kg/day.

LOAEL = 2.95/3.33 (M/F), based upon increased absolute and 

relative kidney weights and histopathological changes in the male 

kidney.

At the high dose of 12.97 mg/kg/day, liver effects were observed

including increased serum levels of alkaline phosphatase, γglutamyltransferase, alanine aminotransferase and ornithine 

carbamoyl transferase in both sexes from study week 13 to 52, 

increased absolute and relative liver and kidney weights for both 

sexes, and histopathological changes in both organs.

870.4300 

Carcinogenicity mice

44305305 (1998) 

Acceptable/guideline 

0, 10, 90, 800, or 1250 ppm 

M: 0, 1.4, 12, 118, or 217 

mg/kg/day 

F: 0, 1.6, 14.8, 140, or 224 

mg/kg/day

NOAEL = 1.4/1.6 (M/F) mg/kg/day.

LOAEL = 12/14.5 (M/F), based upon increased liver weights and 

hepatocellular vacuolization in both sexes and increased kidney 

weights in males. 

Dosing was considered adequate based on above findings. 

Treatment-related increased incidence of combined benign and 

malignant liver tumors in both sexes.

Gene Mutation

870.5265

reverse gene mutation 

assay in bacteria

44335511 (1987)

Acceptable/guideline125-

2000 μg/plate ± S9 

activation.

Cytotoxicity was evident for the majority of strains at ≥1000 

μg/plate -S9 and at 2000 μg/plate +S9. There was no evidence of 

induced mutant colonies over background.

Gene Mutation 

870.5300 

forward gene mutation 

assay in mammalian 

cells

44335508 (1988) 

Acceptable/guideline 

5-125 μg/mL ± S9 

activation.

Cytotoxicity was observed in all trials at ≥100 μg/mL +/-S9. 

There was no indication that M 14360 induced a mutagenic

response, either in the presence of absence of S9 activation.

Cytogenetics 

870.5375 

in vitro mammalian 

cytogenetic assay

44335507 (1989) 

Acceptable/guideline 

0.5-250 μg/mL ± S9 

activation.

Cytotoxicity was observed at ≥31.3 μg/mL -S9 (6-hr. treatment 

and 24-hr. cell harvest or 24 hrs. of continuous treatment before 

sampling); ≥15 μg/mL -S9 (48 hrs of continuous treatment before 

sampling) and at ≥15.6 μg/mL +S9 (6-hr. treatment and a 24-hr. 

cell harvest). Not clastogenic with or without S9 activation, at 

any dose tested. 

Other Effects 

870.5395 

in vivo mammalian 

cytogenetic assay

44335509 (1989) 

Acceptable/guideline 

0, 185, 370 or 740 mg/kg

Did not induce micronucleated polychromatic erythrocytes 

(MPEs) in bone marrow at any dose. The test material was not 

cytotoxic to the target tissue. 
Tetraconazole Human-Health Risk Assessment DP#: 380618 

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Table A.2. Subchronic, Chronic, and Other Toxicity.

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses Results

Other Genotoxic 

Effects 

870.5550 

UDS synthesis in 

mammalian cell culture

44335510 (1989) 

Acceptable/guideline 

0.25-512 μg/mL ± S9 

activation

Cytotoxicity was evident in all trials at ≥64 μg/mL +/-S9. The 

positive controls induced significant and dose-related increases in 

UDS. No evidence of genotoxic effect under any test condition.

870.6200a 

Acute neurotoxicity 

(rat)

48049401 (2010) 

Acceptable/guideline 

0, 50, 200, or 800 

mg/kg/day

NOAEL = 50 mg/kg/day.

LOAEL = 200 mg/kg/day due to decreased motor activity on day 

0 in both sexes, and clinical signs in females including hunched 

posture, decreased defecation, and/or red or yellow material on 

various body surfaces. 

870.6200b 

Subchronic

neurotoxicity (rat)

48049402 (2010) 

Classification: Pending

0, 40, 120 and 640 ppm 

(0, 2.89/3.13, 8.69/9.46, or 

45.92/ 50.67 mg/kg/day

[M/F])

Preliminary NOAEL = 8.69/9.46 mg/kg/day.

Preliminary LOAEL = 45.92/ 50.67 mg/kg/day based upon 

decreased mean body weight gains.

870.7485

Metabolism and 

pharmacokinetics (rat)

44305307 (1993)

Acceptable/guideline

M & F: 14Cphenyl]tetraconazole or 

[

14C-triazole]tetraconazole 

were given single gavage 

dose of 5 or 60 mg/kg. 

About 92.0-100.7% of the administered dose was recovered in 

urine, feces, and tissues within 72 hours of dosing. Absorption of 

[

14C]tetraconazole from the G.I. tract of rats was evident in both 

low- and high-dose animals based on the high level of urinary 

excretion, which ranged from 50.7-71.0% by 48 hours post-dose. 

Only minor differences were noted in the pattern of excretion 

between the sexes, labels, and dose levels. About 3-6% of the 

dose was recovered in the carcass/tissues. Differences were noted 

maximum blood concentrations between the doses, sexes, and 

label. No differences were noted in the half-life.
Tetraconazole Human-Health Risk Assessment DP#: 380618 

Page 42 of 47

Table A.2. Subchronic, Chronic, and Other Toxicity.

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.7485 

Metabolism and 

pharmacokinetics (rat)

45068403 (1992) 

Acceptable/guideline for 

excretion, distribution and 

metabolic identification 

portion of the study.

Single oral doses of [14C] 

triazole ring labeled M14360 administered at dose 

levels of 5 or 60 mg/kg, 

urine and feces were 

collected from five 

rats/sex/dose for 168 hours 

at which time these animals 

were killed and their tissues 

and organs were harvested. 

The remaining five 

animals/sex/group were 

killed at peak blood levels 

of radioactivity occurring at 

8-28 hours of post dosing 

and their tissues and organs 

were harvested. 

Radioactivity was measured 

in urine, feces, blood, 

tissues, organs, carcasses 

and cage washes from all 

animals. 

Total recovery of radioactivity ranged from 95% to 102% of the 

administered dose. Most of the dose (75%) was recovered in the 

urine after 7 days. Feces accounted for 15 to 18% of the 

administered dose. Triazole was the major metabolite identified 

in the urine and feces. In the urine M-14360 acid along with 

minor metabolite of M-14360 alcohol and its glucuronide 

conjugate (M3) were isolated. In the feces, minor amounts of 

parent M-14360, the acid and alcohol were isolated. Data suggest 

M-14360 or its metabolites do not accumulate in the tissues 

following single oral administration. 95-98% of the urinary and 

fecal metabolites were identified.

There is a qualitative and quantitative difference in the 

metabolites in the males and females and the dose levels. Male 

rats produced more triazole than females (65-67% of the AD vs. 

48% in females) in the urine, while urine of females had more of 

M-14360 acid. The same pattern was also seen in the multiple 

dosing studies, although the differences were not pronounced. In 

the multiple dosing studies, triazole (3.2-3.9% of the AD for 

males and females at the low dose vs. 6.5-6.8% for the high dose), 

M-14360 acid, M-14360 alcohol, M-14360, M6 and others were 

reported while in the single dosing only triazole (5.6-10.4% of the 

administered low and high doses in both sexes), M-14360 acid 

and M-14360 were reported. Based on the results, the study 

authors postulated that cleavage of M-14360 to yield triazole 

appears to be a major step through glutathione mediated path. A 

metabolic pathway was proposed where the initial step is the 

formation of an aldehyde intermediate of M-14360 following 

dealkylation of the fluoro-alkyl group of the molecule. 

870.7485 

Metabolism and 

pharmacokinetics (rat)

44268114 (1990) 

Acceptable/guideline for 

single dose excretion and 

distribution

Single oral doses of 14CTetraconazole phenyl 

labeled or triazole ring 

labeled were administered 

at dose levels of 5 or 60 

mg/kg, urine, feces and 

expired air were collected 

for 168 hours and 

radioactivity in blood, 

tissues, organs, carcass and 

cage washes were 

determined.

Total recovered radioactivity ranged from 99% to 114% for the 

phenyl label and 96% to 109% for the triazole label of the 

administered dose (AD). Most of the radioactivity was recovered 

in the urine, particularly the triazole label. In the triazole study, 

males excreted the radiolabel into the urine more and faster than 

in the females. Compared to the phenyl label, more of the triazole 

label was excreted at both doses in the urine. Radioactivity in the 

tissues was minimal and accounted for less than 1% in the phenyl 

label. For the triazole label 0.9% to 1.4% radioactivity was 

recovered in tissues. In the feces, more phenyl label (21-32%) 

than in the triazole label (12-16% of the AD) radioactivity was 

excreted. Male rats generally excreted the radiolabel into the 

feces faster than in the females for both labels. 
Tetraconazole Human-Health Risk Assessment DP#: 380618 

Page 43 of 47

Table A.2. Subchronic, Chronic, and Other Toxicity.

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.7485 

Metabolism and 

pharmacokinetics (rat)

44268119 (1994) 

Acceptable/guideline for 

excretion and distribution of 

triazole labeled M-14360 

following repeated oral 

administration.

Groups of rats received 

single oral dose of nonradiolabeled M 14360 at 5 

or 60 mg/kg for 14 days 

followed by single oral dose 

of [14C] triazole ring 

labeled M 41360; animals 

were placed metabolism 

cages where urine and feces 

were collected and 

radioactivity in blood, 

tissues, organs, carcass and 

cage washes were 

determined upon sacrifice.

The test material was readily absorbed and distributed in the body 

within 8 hours after dosing and about 100.9 ± 4.0% of the 

administered dose was recovered. Urine was the major route of 

excretion accounting for nearly 87% of the AD after 7 days of 

exposure. Most of the urinary radioactivity was excreted during 

the first 48 hours. Fecal elimination of the radioactivity was the 

next major route accounting for 12-16% of the AD after 7 days of 

exposure. Less than 1% of the AD was recovered in tissues. Sex 

has no effect on excretion and distribution.

Non-guideline – rats 

Liver enzyme induction

44751310 (1998) 

Acceptable/nonguideline 

In diet at doses of 0, 10, 80, 

640 ppm; the positive 

control was Phenobarbital 

(Na) salt, 75 mg/kg/day for 

4 weeks.

Dietary administration of tetraconazole for 4 weeks results in liver 

enzyme induction at dose levels of 80 and 640 ppm. Induction at 

the 640-ppm dose level was similar to that induced by 

phenobarbital at 75 mg/kg/day.

Non-guideline – mice 

Liver enzyme induction

44751309 (1996) 

Acceptable/nonguideline 

In diet at doses of 0, 20, 

800, 1250 ppm in the diet; 

the positive control was 

Phenobarbital (Na) salt, 75 

mg/kg/day for 4 weeks.

Tetraconazole administration for 4 weeks results in liver enzyme 

induction. At doses ≥ 20 ppm in females an apparent increases in 

microsomal protein, cytochrome P450, and ethylmorphine Ndemethylase were observed. At all dose levels in males and 

females, 7-pentoxyresorufin O-depentylase values were 

statistically elevated. At 800 and 1250 ppm, statistically 

significant findings were typically noted. However, doseresponse increases were not apparent in these findings at the 1250 

ppm level as compared to the lower 800 ppm level. 

870.7800

Immunotoxicity (Rats)

48439401 (2011)

Classification: Pending

0, 20, 125, 1000 ppm

(0, 2/2, 10/10, 82/77 [AFC 

Group/ NK Group])

Preliminary NOAEL = 88/77 mg/kg/day

Preliminary LOAEL = Not established
Tetraconazole Human-Health Risk Assessment DP#: 380618 

Page 44 of 47

Appendix 2. HEC Inhalation Calculations

Table A.3. HEC Array for Occupational Risk Assessment.

Relevant

Study

LOAEL

mg/L

NOAEL

mg/L Da Dh Wa Wh RDDR HEC(mg/L) inter intra UFL

Acute Exposure

28-days 

inhalation 

rat 

(0015784)

Systemic NA NA NA NA NA NA NA NA NA NA NA

Port-of

entry

0.0548 NA 6 8 1 1 0.165 0.00678 3 10 10

Short- & Intermediate-Term Exposure

28-days 

inhalation 

rat 

(0015784)

Systemic NA NA NA NA NA NA NA NA NA NA NA

Port-of

entry

0.0548 NA 6 8 5 5 0.165 0.00484 3 10 10

Key for Array Table

LOAEL: Lowest-observed adverse-effect level

NOAEL: No-observed adverse-effect level

Da: Daily animal exposure (hrs/day)

Wa: Weekly animal exposure (days/week)

RDDR: Regional gas dose ratio

inter: interspecies extrapolation UF

Dh: Anticipated daily human exposure (hrs/day)

Wh: Anticipated weekly human exposure (days/week)

HEC: Human-equivalent concentration

intra: intraspecies variation UF

UL: UF due to lack of NOAEL

UD: UF for extrapolation to longer exposures

Using the HEC calculated (based on the portal of entry effects of squamous cell metaplasia of the 

laryngeal mucous, mono-nuclear cell infiltration, goblet cell hyperplasia, hypertrophy of the 

nasal cavity and nasopharyngeal duct, and follicular hypertrophy of the thyroid in males and the 

resulting LOAELvalue from the inhalation study), a conversion of the inhalation concentration 

to a dose (mg/L to mg/kg/day) was conducted as follows: 

dose (systemic HEC value) mg/L x A x CF (L/hr/kg) x D (hours) x AF = mg/kg;

Occupational: (0.00484 mg/L) x 1 x 45.2 x 6 x 1 = 1.3 mg/kg/day

 

Where: 

A absorption: ratio of deposition and absorption in respiratory tract compared to absorption 

by the oral route.

CF Conversion Factor: A L/hr/kg factor which accounts for respiratory volume and body 

weight for a given species and strain (Table 1 of guidance document).

D Duration: Duration of daily animal or human exposure (hours).

AF Activity Factor: Animal default is 1.

When conducting inhalation risk assessments, the magnitude of the UFs applied is dependent on 

the methodology used to calculate risk. For studies in this risk assessment with inhalation animal 

data, UFs are based on the RfC methodology developed by the Office of Research and 

Development (ORD) for the derivation of inhalation reference concentration s (RfCs) and human 

equivalent concentrations (HECs) for use MOE calculations. Since the RfC methodology takes 

into consideration the pharmacokinetic (PK) differences but not pharmacodynamic (PD) 

differences, the UF for interspecies extrapolation may be reduced to 3X (to account for the PD 

differences) while the UF for intraspecies variation is retained at 10X1. Thus, the UF when using 

the RfC methodology is customarily 30X.

 

1 A 3X UF for interspecies extrapolation is retained to account for the PD differences between animals and humans 

which are not accounted for in the RfC methodology. 
Tetraconazole Human-Health Risk Assessment DP#: 380618 

Page 45 of 47

Based on current Tetraconazole Labels, HED believes exposures can be short- (1-30 days) or 

intermediate- (1 to 6 months) term in duration. Long-term exposures are not anticipated for 

Tetraconazole based on proposed labeled uses. Acute exposures are not expected but were 

calculated. 

For the acute, short- and intermediate-term scenarios, inhalation data from the 28- day inhalation 

rodent study was most appropriate for determining HECs. In the RfC methodology, different 

HECs may be calculated for the same experimental NOAEL due to:

1. Different algorithms are used to derive HECs for systemic versus port-of-entry

effects. Typically, HECs are calculated separately for systemic versus port-ofentry effect. For Tetraconazole, port-of-entry irritation was observed and 

therefore, only port-of-entry HECs were derived. For additional information on 

the methodologies used in this risk assessment and HEC arrays, please refer to 

Appendix.

2. Time adjustments are traditionally needed for non-occupational (bystander) 

versus occupational exposure scenarios. Traditionally, HECs for nonoccupational exposure are based on the number of hours an individual may be at 

home. Therefore, the most conservative estimate of hours spent at home would 

be 24 hours/day and 7 days/week. In comparison, the average work week for an 

occupational worker is 8 hours/day and 5 days/week. The HEC array table 

reflects the time adjustment in the calculations (Table A.3.5B).

METHODOLOGIES FOR INHALATION RISK CALCULATIONS

The RfC methodology applies a dosimetric adjustment that takes into consideration not only the 

differences in ventilation rate (MV) but also the physicochemical properties of the inhaled 

compound, the type of toxicity observed (e.g., systemic vs. port of entry) and the PK but not PD 

differences between animals and humans. Based on the RfC guidance (1994), the methodology

for RfCs derivation is an estimate of the quantitative dose-response assessment of chronic noncancer toxicity for individual inhaled chemicals and includes dosimetric adjustment to account 

for the species-specific relationships of exposure concentration to deposited/delivered dose. This 

adjustment is influenced by the physicochemical properties of the inhaled compound as well as 

the type of toxicity observed (e.g., systemic vs. port of entry), and takes into consideration the 

PK differences between animals and humans. Though the RfC methodology was developed to 

estimate toxicity of inhaled chemicals over a lifetime, it can be used for other inhalation 

exposures (e.g., acute and short-term exposures) since the dosimetric adjustment incorporates 

mechanistic determinants of disposition that can be applied to shorter duration of exposures 

provided the assumptions underlying the methodology are still valid. These assumptions, in turn, 

vary depending on the type of toxicity observed and will be discussed later on in this document. 

Thus, the derivation of a HEC for inhaled gases is described by the following equation:

Where:

PODstudy: Point of departure identified in the critical toxicology study

Danimal exposure: Duration of animal exposure (hrs/day; days/wk)

HEC = POD *

D 

D 

*

W

W

study * RGDR animal exposure (hrs/ day)

human exposure (hrs/ day)

animal exposure (days / wk)

human exposure (days/ wk)
Tetraconazole Human-Health Risk Assessment DP#: 380618 

Page 46 of 47

Danticipated exposure: Anticipated human duration of exposure (hrs/day; days/wk)

RGDR: Regional Gas Dose Ratio

For gases eliciting both port of entry and systemic effects, calculations to estimate the inhalation 

risk to humans are dependent on the regional gas dose ratio (RGDR). In the case of systemic 

effects, the RGDR is defined as the ratio of the blood:gas partition coefficient of the chemical for 

the test species to humans (Hb/g animal/Hb/g human). When this ratio is unknown or when the Hb/g 

animal > Hb/g human a default value of 1.0 is used as the RGDR. This default is based on the 

observation that for chemicals where partition coefficient data are available in both rats and 

humans the RGDR value has usually been comparable or slightly higher than 1. Thus, the use of 

an RGDR of 1 results in a protective calculation of the inhalation risk. Some of the key

assumptions fundamental to the use of the RfC methodology to derive a HEC based on systemic 

effects include:

1) all the concentrations of inhaled gas within the animal’s body are periodic with respect to 

time (i.e. periodic steady state - the concentration vs. time profile is the same for every

week). Periodicity must be attained for at least 90% of the exposure.

2) in the respiratory tract, the air, tissue, capillary blood concentration are in equilibrium 

with respect to each other.

3) systemically, the blood and tissue concentrations are in equilibrium with respect to each 

other.

In the case of chloropicrin, the physicochemical properties and metabolism data for the 

compound indicate that these conditions (i.e., periodicity and equilibrium between different 

compartments) will be achieved in a very short period of time. Under these conditions, 

therefore, the use of the RfC methodology to estimate acute inhalation risk is appropriate. 

When the critical toxic effect in a study occurs in the respiratory tract (i.e., port-of-entry effects), 

the RGDR is not related to the blood:gas partition coefficient of the compound but rather the 

ratio of the minute volume (MV) to the surface area (SA) of the affected region. In these 

instances, attaining periodicity or equilibrium between the compartments is not critical (since the 

effect is a function of the direct interaction between the inhaled compound and the affected 

region in the respiratory tract) and the RGDR may be calculated using the following equation:

Where:

MV animal: Minute volume for the test species (varies depending on body weight)

SA animal: Surface area of the affected region in animals

MV human: Minute volume for humans (default value is 13.8 l/min)

SA human: Surface area of the affected region in humans

The MV animal is calculated using the allometric scaling provided in USEPA (1988a). The 

equation for calculation of the MV animal is:

lnMVanimal = b0 + b1ln(BW)

RGDR =

MV 

SA 

MV 

SA 

animal

animal

human

human
Tetraconazole Human-Health Risk Assessment DP#: 380618 

Page 47 of 47

Where:

ln MVanimal : natural logarithm of the minute volume

b0 : species specific intercept used in the algorithm to calculate minute volumes based on body 

weight

b1: species-specific coefficient used in the algorithm to calculate minute volumes based on body

weight

ln BW: natural logarithm of the body weight (expressed in kg)

The values for the species-specific parameters used to calculate the MV animal based on body 

weight and the values for the surface areas of various regions of the respiratory tract 

(extrathoracic, thoracic, and pulmonary) are provided in the EPA document “Methods for 

Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry” 

(1994).

Calculations used to estimate the inhalation risk to humans from aerosols are dependent not on 

the RGDR as for gases, but on the regional deposited dose ratio (RDDR). Inhalation studies 

using aerosols characterize particulate exposure by defining the particulate diameter (mass 

median aerodynamic diameter [MMAD]) and the geometric standard deviation (σg), which is 

then used to determine the RDDR. The RDDR is a multiplicative factor used to adjust an 

observed inhalation particulate exposure concentration of an animal (A) to the predicted 

inhalation particulate exposure concentration for a human (H) that would be associated with the 

same dose delivered to the rth region or target tissue.

RDDRr = (RDDr/Normalizing Factor)A

 (RDDr/Normalizing Factor)H 

As with calculations for gases, the r regions and potential target tissues are the three respiratory

regions (ET, TB, PU). The RDDR is easily calculated by using a software program designed 

specifically for computing the RDDR from the MMAD and σg defined from an aerosol 

inhalation study. The values for the species-specific parameters used to calculate the RDDR are 

provided in the EPA document “Methods for Derivation of Inhalation Reference Concentrations 

and Application of Inhalation Dosimetry.” 

The magnitude of the UFs applied is dependent on the methodology used to calculate risk. The 

RfC methodology takes into consideration the PK differences but not the PD differences. 

Consequently, the UF for interspecies extrapolation may be reduced to 3X (to account for the PD 

differences) while the UF for intraspecies variation is retained at 10X. Thus, the UF when using 

the RfC methodology is customarily 30X.