Document ID: EPA-HQ-OPP-2014-0230-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-05-23T04:00Z

Interregional Research Project Number 4 (IR-4)

Valent U.S.A. Corporation

Pesticide Petition, PP# 4E8244

	EPA has received a pesticide petition, 4E8244, 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 tolerances 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 following raw
agricultural commodities: Fruit, stone, group 12-12 at 0.2 parts per
million (ppm); Nut, tree, group 14-12 at 0.04 ppm; Pea and bean, dried
shelled, except soybean, subgroup 6C at 0.15 ppm; Rapeseed subgroup 20A
at 0.08 ppm; and Sunflower subgroup 20B at 0.9 ppm. Upon establishment
of the above tolerances, the petition additionally requests to amend 40
CFR part 180.617 by deleting  the tolerances for residues tolerances 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 commodities: Canola seed at 0.04 ppm; Fruit, stone, group 12 at 0.2
ppm; Pistachio at 0.04 ppm; and Nut, Tree, Group 14 at 0.04 ppm. These
previously established tolerances will be superseded by inclusion in
crop group or subgroup tolerances established by this action.

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 dry bean,
dry pea and sunflower to determine the magnitude of the residue. A total
of 13 trials representing NAFTA growing regions were conducted for dry
bean. A total of 6 trials representing NAFTA growing regions were
conducted for dry pea.  A total of 11 trials representing NAFTA growing
regions were conducted for sunflower.

No additional residue data is needed to support the updated crop
groupings of stone fruit group (12-12) , tree nut group (14-12) and the
expansion of  canola to rapeseed subgroup 20A since the proposed
tolerance levels remain the same as the established tolerances for stone
fruits (CG12), tree nuts (CG14) and canola.   



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 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 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 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 Dried Shelled
Pea and Bean (Except Soybean), Subgroup 6C and Sunflower Subgroup 20B
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. The additional exposure resulting from the crop expansion of
stone fruit group (CG 12-12), tree nut group (CG 14-12) and rapeseed
subgroup 20A is anticipated to be negligible as well.  

              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 45.48 parts per
billion (ppb) for surface water and 0.38 ppb for ground water. The EECs
for chronic exposures for non-cancer assessments are estimated to be
38.16 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), tuberous
and corm vegetables (subgroup 1C), bushberries subgroup (13-07B),
sugarcane, 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 3.8% 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 12.6 %
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.  

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’
object-to-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 1700. 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 420 .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 non- occupational/residential handler
exposure (inhalation) for adults is 1700.. 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 460. 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	

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). 

ter) exposure and risk assessments were conducted using the Dietary
Exposure Evaluation Model DEEM-FCID™, 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 proposed uses on dried shelled pea and bean (except soybean),
subgroup 6C, sunflower subgroup 20B and the updated crop groupings of
stone fruit group (12-12) and tree nut group (14-12) and rapeseed
subgroup 20A  

 

F. International Tolerances

	There are no CODEX maximum residue levels established or proposed for
residues of metconazole.

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azole Tolerance Petition, September 20 , 2013                           
                                                                        

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