Metconazole Tolerance Petition, June 29, 2010 

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Section 1 

Informative Summary 

Notice of Filing 
Metconazole Tolerance Petition, June 29, 2010 

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EPA Registration Division contact: Andrew Ertman, (703)308-9367 

Interregional Research Project Number 4 (IR-4) 

PP #0E7743 

 EPA has received a pesticide petition (PP #0E7743) from Interregional Research 

Project Number 4 (IR-4), IR-4 Project Headquarters, Rutgers, The State University of 

New Jersey, 500 College Road East, Suite 201 W, Princeton, NJ 08450 proposing, 

pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 

U.S.C. 346a(d), to amend 40 CFR part 180.617 by establishing a tolerance for residues 

of metconazole, 5-[(4-chlorophenyl)-methyl]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-

ylmethyl)cyclopentanol, measured as the sum of cis- and trans- isomers in or on the raw 

agricultural commodities Bushberry subgroup 13-07B at 0.35 parts per million (ppm) and 

Tuberous and corm vegetable subgroup 1C at 0.02 ppm. 

EPA has determined that the petitions contain data or information regarding the 

elements set forth in section 408(d)(2) of the FFDCA; however, EPA has not fully 

evaluated the sufficiency of the submitted data at this time or whether the data supports 

granting of the petitions. Additional data may be needed before EPA rules on the 

petitions. 

A. Residue Chemistry

 1. Plant metabolism. The metabolism of Metconazole is adequately understood 

for the purpose of granting the proposed tolerances. Nature of the residue studies 

(OPPTS Harmonized Guideline 860.1300) were conducted in wheat, canola, banana, 

peas, and mandarin oranges as representative crops in order to characterize the fate of 

metconazole in all crop matrices. Two radiocarbon labeling positions were studied in 

each crop. In all crops triazole ring labeling was used, and the other label was positioned 

either in the p-chlorophenyl or the cyclopentyl rings. In all five crops the metconazole, 

Residue of Concern was identified as parent metconazole. 

 2. Analytical method. Independently validated analytical methods have been 

submitted for analyzing parent metconazole residues with appropriate sensitivity for 

crops and processed commodities for which a tolerance is being requested. 

 3. Magnitude of residues. Field trials were carried out with blueberry and potato 

to determine the magnitude of the residue. A total of 17 trials representing NAFTA 

growing regions were conducted for potato. A total of 11 trials representing NAFTA 

growing regions were conducted for blueberry.
Metconazole Tolerance Petition, June 29, 2010 

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B. Toxicological Profile 

EPA has evaluated the available toxicity data and considered its validity, completeness, 

and reliability as well as the relationship of the results of the studies to human risk. 

1. Acute Toxicity. Metconazole technical is considered to be slightly toxic (Toxicity 

Category III) to the rat by the oral route of exposure. In an acute oral study in rats, the 

LD50 value of metconazole technical was 727 milligrams per kilogram of body weight 

(mg/kg b.w.) for males and 595 mg/kg b.w. for females. The oral LD50 for combined 

sexes was 660 mg/kg b.w. Metconazole technical demonstrates no acute toxicity via the 

dermal route of exposure [LD50 value >2000 mg/kg (highest dose tested)] (Toxicity 

Category III) or inhalation route of exposure [LC50 >5.6 mg/L] (Toxicity Category IV). 

The material is mildly irritating to the eye (Toxicity Category III) and is not irritating to the 

skin (Toxicity Category IV), nor is it a skin sensitizer. 

2. Genotoxicity. Both metconazole technical and WL 136184 technical (greater than 

95% cis isomer) have been tested in an extensive battery of in vitro and in vivo 

genotoxicity assays measuring several different endpoints of potential genotoxicity. 

Collective results from these studies indicate that metconazole does not pose a 

genotoxic risk, and therefore, is not likely to be a genotoxic carcinogen. 

3. Reproductive and developmental toxicity. Several developmental toxicity studies in 

rats conducted with metconazole technical and WL 136184 showed no evidence of 

teratogenic effects in fetuses, and no evidence of developmental toxicity in the absence 

of maternal toxicity. Thus, metconazole is neither a selective developmental toxicant nor 

a teratogen in the rat. Two rat developmental toxicity studies have been conducted with 

metconazole technical. In the first study, the no-observable-adverse-effect-level 

(NOAEL) for maternal toxicity was 12 mg/kg b.w./ day, based on decreased body weight 

gain at 30 mg/kg b.w./day, the next highest dose tested, and the NOAEL for 

developmental toxicity was also 12 mg/kg b.w./day, based on decreased fetal body 

weights and an increased incidence of skeletal ossification variations at 30 mg/kg 

b.w./day. In the second study, the maternal and fetal NOAEL was 16 mg/kg/day based 

on findings similar to the first study at the next higher dose level of 65 mg/kg/day. In the 

rat developmental toxicity study conducted with WL 136184 technical, the NOAEL for 

maternal toxicity was 24 mg/kg b.w./day based on decreased body weight gain at 60 

mg/kg b.w./day, the highest dose tested, and the NOAEL for developmental toxicity was 

also 24 mg/kg b.w./day, based on an increase in the total number of resorptions, 

reductions in fetal body weights and an increased incidence of skeletal ossification 

variations at 60 mg/kg b.w./day. 

Results from a developmental toxicity study in rabbit’s metconazole technical also 

indicated no evidence of teratogenicity or developmental toxicity in the absence of 

maternal toxicity. Thus, metconazole technical is neither a selective developmental 

toxicant nor a teratogen in the rabbit. In this rabbit developmental study, the NOAEL for 

maternal toxicity was 20 mg/kg b.w./day based on decreased food consumption and 

body weight gain, reductions in hemoglobin, hematocrit and corpuscular volume, 

increases in platelet counts and alkaline phosphatase activity, and increased absolute 

and relative liver weights at 40 mg/kg b.w./day (the highest dose tested). The NOAEL for 

developmental toxicity was also 20 mg/ kg b.w./day, based on an increase in the total 
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number and mean number of resorptions and decreased fetal body weight at 40 mg/kg 

b.w./day. 

Two multi-generation reproduction studies were conducted with Metconazole Technical -

- one with the >95% cis form and one with the 85/15 cis/trans form. Dose levels and 

results in both studies were similar, although the 95% cis study diet was adjusted to 

maintain a constant dose. Dose levels in the >95% cis study were 0, 2, 8, 32 and 48 

mg/kg/day and in the 85/15 cis study were 0, 30, 150 and 750 ppm (approximately 0, 

2.1, 10.6 and 52.8 mg/kg/day for pre-mating growth period). For the >95% cis study, the 

results support a NOAEL for parental toxicity of 8 mg/kg/day based on increased ovarian 

weight and increased gestation length at the next highest dose tested (32 mg/kg/day). 

The NOAEL for growth and development of the offspring is also 8 mg/kg/day, based on 

reductions in live litter size for F2 litters at 32 mg/kg/day. The NOAEL for reproductive 

performance and fertility was 48 mg/kg/day (the highest dose tested). In the 85/15 

cis/trans study, the NOAEL identified for parental toxicity, offspring growth and 

development and reproductive toxicity was 10.8 mg/kg/day (150 ppm) based on effects 

observed at the highest dose tested of 52.8 mg/kg/day (750 ppm). 

Results of reproduction and developmental toxicity studies conducted with metconazole 

technical show no increased sensitivity to developing offspring as compared to parental 

animals. 

4. Subchronic toxicity. Subchronic (90-day) dietary studies in rats were conducted with 

metconazole technical. In the study the NOAEL was 100 ppm (approximately 6.8 mg/kg 

b.w./day) based on hepatic fatty vacuolation in males at 300 ppm, the next highest 

concentration tested. 

In a 90-day dietary study in mice conducted with metconazole technical, the NOAEL was 

30 ppm (approximately 5.5 mg/kg b.w./day), based on increased aspartate and alanine 

aminotransferase activities in males, increased absolute and relative weights of the liver 

and spleen of females, and increased incidences of hepatocellular vacuolation and 

hypertrophy for males and females at 300 ppm, the next highest concentration tested. 

In a 90-day dietary study in beagle dogs with metconazole technical the NOAEL was 60 

ppm (approximately 2.5 mg/kg b.w./day) based on decreased body weight gain and food 

consumption for females, and a slight increase in reticulocyte count for males at 600 

ppm, the next highest concentration tested. 

5. Chronic toxicity. Findings similar to those observed in the short-term and subchronic 

studies were apparent in the long-term dietary toxicity studies conducted in rats, dogs 

and mice. 

In a chronic toxicity study, long-term (104-weeks) administration of metconazole 

technical to rats supported a NOAEL for systemic toxicity of 100 ppm (approximately 4.8 

mg/kg b.w./day), based on increased adjusted liver weight, clinical chemistry changes, 

and increased incidences of hepatocellular lipid vacuolation and centrilobular 

hypertrophy at interim sacrifice for males at 300 ppm, the next highest concentration 

tested. 

In a 104-week carcinogenicity study in rats fed diets containing 0, 100, 300 or 1000 ppm 

metconazole technical, the NOAEL for carcinogenicity was 1000 ppm (50 mg/kg/day) the 
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highest dose tested. The NOAEL for chronic systemic toxicity was 100 ppm (5.6 

mg/kg/day) based on increased incidences of centrilobular hypertrophy and pigment 

disposition in the liver and increased incidences of cortical vacuolation in the adrenal at 

300 ppm. 

In a one-year dietary study in beagle dogs, the NOAEL was 300 ppm (approximately 

11.1 mg/ kg b.w./day), based on decreased body weight gain for males during weeks 1 

to 13 and increased alkaline phosphatase activity for males and females at 1,000 ppm, 

the next highest concentration tested. 

A 91-week carcinogenicity study in mice with metconazole technical supports a NOAEL 

for non-neoplastic effects of 30 ppm (approximately 4.8 mg/kg b.w./ day), based on 

increased white blood cell count for males, increased aspartate and alanine 

aminotransferase activities and increased absolute and adjusted liver weight for females, 

and microscopic changes in the liver, spleen and adrenal gland for males and females at 

300 ppm (the next highest concentration tested). The NOAEL for carcinogenicity was 

300 ppm (approximately 48.3 mg/kg b.w./day) based on increased incidences of 

hepatocellular adenomas in males and females and hepatocellular carcinomas in 

females at 1,000 ppm, the highest concentration tested. The increased incidences of 

hepatic adenomas and carcinomas at the highest concentration tested are considered to 

occur through promotional and non-genotoxic secondary mechanisms following toxicity 

and induction of mixed function oxidase in mice. Consequently, metconazole is not likely 

to be oncogenic in humans at the low levels of exposure that will result from its use as a 

fungicide.

6. Animal metabolism. The rat metabolism studies show that the qualitative nature of the 

fate of metconazole in animals is adequately understood. In studies conducted with 

radiolabeled metconazole (85:15 isomer mixture) or radiolabeled WL 136184 

radioactivity was rapidly eliminated in urine and feces within 48 hours of dosing. Biliary 

excretion was shown to be a prominent route of elimination. At both high and low doses 

of metconazole, male rats generally excreted lower amounts of radioactivity in the urine, 

and greater amounts of radioactivity in the feces as compared to females. The pattern of 

metabolites detected in males and females was similar at high and low doses, and little 

or no parent compound was found in either feces or urine. Five days following oral 

dosing of metconazole at the highest dose, low levels of radioactivity were detected in 

the majority of tissues analyzed; however higher concentrations of radioactivity were 

found in the adrenal glands, gastro-intestinal tract and liver. A comparison of 

radioactivity levels in the adrenal glands following oral administration of low and high 

doses indicates that uptake in the adrenal may be saturable. No differences in tissue 

levels were noted between males and females. 

7. Metabolite toxicology. The metabolism of metconazole is similar in plants and 

mammals with extensive hydroxylation being the predominate reactions. Due to the 

similar structural nature of most metabolites, the toxicity of the plant metabolites is 

adequately estimated from the results of studies performed with the technical in various 

animals. EPA concern for unique plant metabolites common to most triazole fungicides 

has been addressed with research conducted by the U.S. Triazole Task Force. 

8. Endocrine disruption The toxicology database for metconazole technical is current 

and complete. This includes a thorough evaluation of the potential effects on 

reproduction and development, and the pathology of the endocrine organs following 
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short-term and long-term exposures. The battery of tests included as part of this petition 

fully characterizes potential endocrine-related in vivo effects, clearly defines 

NOAEL/LOAEL values, and indicates no increased sensitivity to developing offspring. 

C. Aggregate Exposure

1. Dietary exposure and risk 

 Food: Dietary exposure estimates were based on established tolerance values, 

default processing factors with the exception of a determined process factor for sugar 

beet molasses, and 100% of all crops treated. The consumption data was from the 

USDA Continuing Survey of Food Intake by Individuals (CSFII 1994 - 1996, 1998). 

Residues (proposed tolerances) from use of Metconazole on Bushberries (Subgroup 13-

07B) and Tuberous and Corm Vegetable (Subgroup 1 C) were not included in the 

assessment because the contribution to the overall aggregate exposure is considered 

negligible. These minor crop residues will be included in the aggregate exposure 

assessment at a later date

 Drinking water: The Agency used screening level water exposure models in the 

dietary exposure analysis and risk assessment for metconazole in drinking water. These 

simulation models take into account data on the physical, chemical, and fate/transport 

characteristics of metconazole. Based on the Pesticide Root Zone Model/Exposure 

Analysis Modeling System (PRZM/EXAMS) and Screening Concentration in Ground 

Water (SCI- GROW) models, the estimated environmental concentrations (EECs) of 

metconazole for acute exposures are estimated to be 45 parts per billion (ppb) for 

surface water and 0.38 ppb for ground water. The EECs for chronic exposures for noncancer assessments are estimated to be 22 ppb for surface water and 0.38 ppb for 

ground water. 

Exposure assessments have been conducted to evaluate the potential risk due to acute 

and chronic dietary exposure of the U.S. population and various subgroups to residue of 

metconazole. The latest assessment included all the existing tolerance values for 

canola, soybean, sugar beet, barley, wheat, oats, rye, triticale, cotton, corn (field, pop, 

sweet) stone fruit (crop group 12), tree nuts (crop group 14), peanuts, bananas, milk, 

meat, and eggs. 

 a. Acute Dietary Exposure 

The acute dietary exposure from food and water to the residues of metconazole, 

including its metabolites and degradates, occupies 3.7% of the aPAD for the population 

group (females 13-49 years old) receiving the greatest exposure. The estimated 

exposure is well below the Agency's level of concern. 

 b. Chronic Dietary Exposure 

The chronic dietary exposure to the residues of metconazole, including its metabolites 

and degradates, from food and water will utilize 5.6% of the cPAD for the U.S. 

population and 12% of the cPAD for the most highly exposed population group (children 

1-2 years old). The estimated exposure is well below the Agency's level of concern. 
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2. Non-dietary exposure and risk. Metconazole use is registered on residential and 

recreational turf. The following post-application exposure scenarios were evaluated: 1) 

adults and toddler (< 1 year old) post-application dermal exposure; 2) toddlers’ incidental 

ingestion of pesticide residues on lawns from hand-to-mouth transfer; 3) toddlers’ objectto-mouth transfer from mouthing pesticide-treated turf grass; and 4) toddlers’ incidental 

ingestion of soil from pesticide-treated residential areas. The post-application exposure 

assessment was based on generic assumptions specified in the Recommended 

Revisions to the Residential Standard Operating Procedures and recommended 

approaches by an EPA science advisory council. A dermal absorption value of 3 % was 

used in the assessment of metconazole. The amount of metconazole available for 

transfer following the application of metconazole at the rate of 0.6 lb ai/A was 

determined from turf transferable residue studies conducted by Valent U.S.A 

Corporation (MRID No. 468051-07, 468051-08). The regression equations provided in 

the reports were used to determine the turf dislodgeable foliar residue, 0.044 μg/cm2

, 

present immediately after the spray treatment has dried (Time 0). The exposure and risk 

estimates for the residential exposure scenarios are assessed for the day of application 

because adults and toddlers could contact treated turf immediately after application. All 

short-/intermediate-term MOE were greater than 100 which indicates that exposure from 

all residential scenarios result in exposures well below a level of concern. 

3. Short-term risk. Short-term risk takes into account residential exposure plus chronic 

exposure to food and water (considered to be a back ground exposure level). 

Metconazole is currently registered for uses that could result in short-term residential 

exposure and the Agency has determined that it is appropriate to aggregate chronic 

food, water, and short-term exposures for the residues of metconazole, including its 

metabolites and degradates. EPA has concluded that short-term aggregate MOE from 

dietary exposure (food + drinking water) and non-occupational/ residential handler 

exposure (inhalation) for adults is 1,900. The short-term aggregate MOE from dietary 

exposure (food + drinking water) and non-occupational/residential exposure (incidental 

oral) for children 1-2 years old is 430. These MOEs are not of concern to the Agency 

since they are greater than the LOC of 100. 

4. Intermediate-term risk. Intermediate-term risk takes into account residential exposure 

plus chronic exposure to food and water (considered to be a background exposure 

level). Metconazole is currently registered for uses that could result in intermediate-term 

residential exposure and the Agency has determined that it is appropriate to aggregate 

chronic food, water, and intermediate-term exposures for the residues of metconazole, 

including its metabolites and degradates. EPA has concluded that intermediate-term 

aggregate MOEs from dietary exposure (food + drinking water) and nonoccupational/residential handler exposure (inhalation) for adults is1, 400. The 

intermediate-term aggregate MOE from dietary exposure (food + drinking water) and 

non-occupational/residential exposure (incidental oral) for children 1-2 years old is 480. 

These MOEs are not of concern to the Agency since they are greater than the LOC of 

100. 

5. Aggregate cancer risk for U.S. population. Metconazole is classified as ``not likely to 

be carcinogenic to humans'' at levels that do not cause mitogenesis. The cPAD is 

protective of mitogenesis and because the chronic risk assessment for metconazole 

shows exposure to be below the cPAD, there is no cancer concern. 

D. Cumulative Effects 
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Metconazole is a member of the triazole-containing class of pesticides. In Oct 2008, the 

HED issued an updated dietary exposure and risk analysis for the common triazole 

metabolites 1,2,4-triazole (T), triazolylalanine (TA), triazolylacetic acid (TAA), and 

triazolylpyruvic acid (TP). 

The assessment covers the new uses of the triazole-derivative fungicides metconazole 

(canola, corn, cotton, and sugarcane; PP#s 7F7221, 7F7292, 08FL03), propiconazole 

(beets, parsley, and pineapple; PP# 7F7300), prothioconazole (wheat, barley; PP# 

7F7279), and tetraconazole (grapes; PP# 7E7273). Acute and chronic aggregate 

dietary (food and drinking water) exposure and risk assessments were conducted using 

the Dietary Exposure Evaluation Model DEEM-FCIDTM, Version 2.03 which use food 

consumption data from the U.S. Department of Agriculture’s Continuing Surveys of Food 

Intakes by Individuals (CSFII) from 1994-1996 and 1998. Four assessments were 

conducted: acute and chronic durations for T, and acute and chronic durations for 

combined residues of TA, TAA, and TP. Residue chemistry databases for most of the 

subject-listed parent compounds do not include residue measurements for the triazole 

metabolites; therefore, metabolite residues have been estimated based on metabolism 

studies and parent compound tolerances. As with the previous triazole metabolite 

assessments, this assessment includes exposure estimates resulting from direct 

consumption of T, TA, TAA, and/or TP as well as indirect exposure resulting from 

consumption of parent fungicides followed by in vivo conversion to the metabolites. For 

each food form in the acute assessment, the residue used is the maximum estimate 

from the various food/triazole fungicide combinations combined with the average indirect 

residue estimate. For the chronic assessments, the residue estimates are the average 

residue from the food-specific food/triazole combinations combined with the average 

indirect residue estimates. All four assessments assume 100% crop treated and include 

conservative estimates for residues of the metabolites in drinking water. The resulting 

exposure and risk estimates are based on health-protective assumptions and should be 

characterized as conservative. For all four analyses, risk estimates are below HED’s 

level of concern for all population subgroups. 

E. Safety Determination

Based on the above risk assessment, IR-4 concludes that there is a reasonable certainty 

that no harm will result to the general population or to infants and children from the 

aggregate exposure to metconazole from the pending and proposed use on Bushberries 

(Subgroup 13-07B) and Tuberous and Corm Vegetable (Subgroup 1 C).

F. International Tolerances

There are no CODEX maximum residue levels established or proposed for 

residues of metconazole.