                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                         WASHINGTON, D.C. 20460      

                                                 	OFFICE OF CHEMICAL SAFETY AND
                                                                                               POLLUTION PREVENTION
	



MEMORANDUM

Date:		14-APRIL-2011

SUBJECT:  Tetraconazole:  Human-Health Risk Assessment for Proposed Uses on Small Fruit Vine Climbing Subgroup 13-07F, Low-Growing Berry Subgroup 12-07G, and Field Corn and Popcorn.

PC Code:  120603
DP Barcodes:  D380618, D381448
Decision Nos.:  435873, 436333
Registration Nos.:  80289-7, 80289-8
Petition Nos.:  0E7735, 0F7737
Regulatory Action:  Section 3
Risk Assessment Type:  Single Chemical/
Aggregate
Case No.:  7043
TXR No.:  NA
CAS No.:  112281-77-3
MRID No.:  NA
40 CFR:  §180.557

FROM:	Allison A. Nowotarski, Biologist
      Thomas Bloem, Chemist 
      Anwar Y. Dunbar, Ph.D., Pharmacologist
      Risk Assessment Branch 1 (RAB1)
            Health Effects Division (HED; 7509P)

THROUGH:	George F. Kramer, Ph.D., Branch Senior Chemist
	Dana M. Vogel, Branch Chief 
            RAB1/HED (7509P)

TO:		Barbara Madden, 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 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 (1-[2-(2,4-dichlorophenyl)-3-(1,1,2,2-tetrafluoroethoxy)propyl]-1H-1,2,4-triazole).  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 Thomas Bloem (RAB1), the hazard characterization was provided by Anwar Dunbar (RAB1), and the 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
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


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 Mettle[(TM)], a 1 lb ai/gallon micro-emulsion (ME), and Domark[(R)] 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 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 adverse-effect 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 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 treatment-related 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.  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 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. 

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 post-application 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-Apr-2011).  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.  

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[-6] using the average residue over 30 days.  The cancer risk is below 10[-6] on 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.

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.



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
                                       

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
                                       
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 10[2] Pa at 35.5°C
0.58 x 10[2] Pa at 46.5°C
2.985 x 10[2] Pa 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. 


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)
                                    PHI[1]
                                    (days)
                                       
                          Maximum Number Applications
Small fruit vine climbing (except fuzzy kiwifruit) subgroup 12-07F
                             Mettle[(TM)] (80289-0)
                          Ground, aerial, chemigation
                                  0.023-0.039
                                     0.08
                                      14
                                       2
Low-growing berry subgroup 13-07G
                                       
                                       
                                       
                                     0.16
                                       0
                                       4
Field corn and Popcorn
                               Domark[(R)] 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 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. Clock-Rust 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 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/kg/day x 100 = 12% dermal-absorption factor 
                                       

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 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 treatment-related 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 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 CGA-91304/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 CGA-91304/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) 
      
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.  

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 route-specific 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 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 short-term 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 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.

Table 4.5.4.a.  Summary of Toxicological Doses and Endpoints for Tetraconazole for Use in Dietary and Non-Occupational 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)[-1] based 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 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 (dermal-absorption 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. 
Intermediate-Term (1-6 months) Dermal 

Oral study NOAEL = 0.73 mg/kg/day
(dermal-absorption 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.
Short (1-30 days) and Intermediate-term (1-6 months) Inhalation   
Occupational1.3 mg/kg/day; HEC = 0.0048 mg/L; 4.84 mg/m[3]; 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)[-1] based 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 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).  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable.  [1] 12% 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 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-free-triazole 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-May-2002).  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-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 [triazole-[14]C]-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 [phenyl-[14]C]-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 [phenyl-[14]C]-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, 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-O-malonyldiglucoside, 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-O-malonyldiglucoside, 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 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-Oct-2001).  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/.  


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 spray[1]
                                     6.68
                                     4.68
                                     3.29
Georgia - pecans aerial spray[2]
                                     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-FCID[(TM)] (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
                              (95[th] 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
                                        

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-Mar-2011):  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 10[2] Pa 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[(R)] 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 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-Apr-2011).  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 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, low-growing 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 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.





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 Intermediate-term Doses (mg/kg/day)[e]
                                    MOEs[f]
                                       
                                       
                                       
                                       
                                       
                                       
                        Short- and intermediate- term 
                     Mixer/Loader for Aerial Applications
                  Small fruit vine climbing  subgroup 12-07F
                                     0.039
                                      350
                                    Dermal
                               Baseline[c]: 2.9
                                 PPE-G: 0.023
                                    Inhal.
                              Baseline[d]: 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
                               Low-growing 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
                               Low-growing 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
                               Low-growing 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
Small fruit vine climbing  subgroup 12-07F
                                     0.039
                                      350
                                    Dermal
                            Eng. control[h]: 0.005
                                    Inhal.
                               Baseline:0.000068
                                       
                                    Dermal
                             Eng. control: 0.00014
                                    Inhal.
                              Baseline: 0.000013
                                    Dermal
                              Eng. Control: 5,100
                                    Inhal.
                               Baseline: 98,000
Low-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.
                               Baseline: 39,000
Low-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.
                               Baseline: 19,000
Low-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
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.
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[-6]or 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 Dose[a] (mg/kg/day)
                        Inhalation Dose[a] (mg/kg/day)
                          Combined ADD[b] (mg/kg/day)
                                  Commercial
                                    LADD[c]
                                  (mg/kg/day)
                                  Commercial
                                    Cancer
                                    Risk[d]
                                 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]].   

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 (cm[2]/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. 

Table 9.2.1b.  Post-application Risk Estimates for Tetraconazole.
                                     Crop
                               Application Rate
                                   (lb ai/A)
                             Transfer Coefficient
                                  (cm[2]/hr)
                               DFR[1] (ug/cm[2])
                             Days After Treatment
                                 Daily Dose[2]
                                  (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 (ug/cm[2]) = Application Rate (lb ai/A) x (1- Daily Dissipation Rate)[t] x CF (4.54E+8 ug/lb) x CF (2.47E-8 A/cm[2]) x 20% DFR after initial treatment.
2:  Daily Dose = [DFR (ug/cm[2]) x TC (cm[2]/hr) x 0.001 mg/ug 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 post-application 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[-6] to 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 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[-6] using the average residue over 30 days.  The cancer risk is below 10[-6] on day 20.

 Table 9.2.1c.  Cancer Exposure/Risk Estimates for Tetraconazole Post-application Workers.
                                      Crop
                                     DAT[a]
                                     DFR[b]
                                   (ug/cm[2])
                        Transfer Coefficientc (cm[2]/hr)
                            Daily Dosed (mg/kg/day)
                                    LADD[e]
                                 Cancer Risk[f]
                           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 (ug/cm[2]) = Application Rate (lb ai/A) x (1- Daily Dissipation Rate)[t] x CF (4.54E+8 ug/lb) x CF (2.47E-8 A/cm[2]) 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 (ug/cm[2]) x 0.001 mg/ug x Tc (cm[2]/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 post-application 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.
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.
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)
NA[1]
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.
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, γ-glutamyltransferase, 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 ug/plate -S9 and at 2000 ug/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.  
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: 14C-phenyl]tetraconazole or [[14]C-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 [[14]C]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.
870.7485     Metabolism and pharmacokinetics (rat)
45068403 (1992) Acceptable/guideline for excretion, distribution and metabolic identification portion of the study.
Single oral doses of [[14]C] triazole ring labeled M-14360 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 14C-Tetraconazole 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.  
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 non-radiolabeled 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 N-demethylase 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, dose-response 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  

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 LOAEL value 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 10X.  Thus, the UF when using the RfC methodology is customarily 30X.

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-of-entry 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 non-occupational 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 non-cancer 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)
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)

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.
