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[Dow AgroSciences LLC]

[Insert petition number]

EPA has received a pesticide petition ([insert petition number]) from [Dow

AgroSciences LLC], [9330 Zionsville Road – Indianapolis, IN  46268] 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.
   

(Options (pick one)

1. by establishing proposed tolerances for residues of

2. to establish an exemption from the requirement of a tolerance for

[myclobutanil alpha‐butyl‐alpha‐(4‐chlorophenyl)‐1 H ‐1,2,4‐triazole‐1‐propanenitrile,

including its metabolites and degradates, in or on commodities.  Compliance with the

tolerance levels specified is to be determined by measuring only myclobutanil alpha‐butyl‐

alpha‐(4‐chlorophenyl)‐1 H ‐1,2,4‐triazole‐1‐propanenitrile and its alcohol metabolite (alpha‐

(3‐hydroxybutyl)‐alpha‐(4‐chlorophenyl)‐1 H ‐1,2,4‐triazole‐1‐propanenitrile (free and bound),

in or on the commodity] in or on the raw agricultural commodity [Grass, hay] at [5 ppm] parts

per million (ppm); [Grass, forage] at [1.5 ppm].  [Proposed tolerances are in association with a

use pattern of grasses grown for seed with a 45 day PHI for hay harvest and a 45‐day PGI for

grazing.  This petition supports expansion of the current State Local Need (SLN) uses for

grasses grown for seed to a full national Section 3 use.] EPA has determined that the petition

contains data or information regarding the elements set forth in section 408 (d)(2) of  FDDCA;

however, EPA has not fully evaluated the sufficiency of the submitted data at this time or

whether the data supports granting of the petition. Additional data may be needed before EPA

rules on the petition.

A. Residue Chemistry

1. Plant metabolism. [The nature of the myclobutanil residues in crops is adequately

understood.  Information on plant metabolism was summarized in the Agency decision

document on soybeans (Acute and Chronic Dietary Exposure and Risk Assessments for

Section3 Use on Soybeans, DP 332917, October 25, 2006):  EPA stated Plant metabolism

studies on wheat, grapes, and apples have previously been submitted, and were reviewed

(PP#2F4155,   DP Num: 183273, D. Davis, 2/8/93) . . . The residues of concern in plants are the

parent myclobutanil and its RH‐9090 metabolite (free and bound).]
   

2. Analytical method. [An adequate enforcement method is available for enforcement

of tolerances in plants.  A review of Rohm and Haas Method 34S‐88‐10, MRID# 40803302 was

summarized by EPA in 2007 (Human‐Health Risk Assessment for Proposed Use on Section 3

Requests for Use on Snap Bean, Mint, Papaya, Gooseberry, Currant, Caneberry, Bell and non‐

Bell pepper, Head and Leaf Lettuce, and Artichoke, DP 341689, November 1, 2007) as: An

adequate enforcement method (Rohm and Haas Method 34S‐88‐10) is available to enforce the

proposed tolerances.  Quantitation is by gas chromatography using a GC/NPD for

myclobutanil and a GC/ECD for residues measured as the alcohol metabolite.  HED has

conducted a successful method validation of Method 34S‐88‐10, and the method has been

forwarded to the Food and Drug Administration (FDA) for inclusion in Pesticide Analytical

Method Volume II (PAM) Vol. II (PP#7F3476 and FAP#7H5524, M. J. Nelson, 4/14/88 and

7/18/89).]

3. Magnitude of residues. [To support existing State Local Need uses, as well as expand

the use in grasses grown for seed and remove some of the labeling restrictions, Dow

AgroSciences conducted an US Magnitude of Residue study in grasses grown for seed.  An

emulsifiable concentrate formulation containing myclobutanil was applied four times at

approximately 14‐day intervals at the nominal rate of 0.188 lb a.i./A per application for a

seasonal total nominal rate of 0.752 lb a.i./A to grass which was being grown for seed

production.  Trials were conducted at a total of eight sites with three trials in Oregon, two

trials each in Washington and Michigan and one trial in Nebraska.  Predominate grass species

at the trial sites included Kentucky Bluegrass, Fescue, Orchard grass, Ryegrass, and Brome

grass.  At 14‐15 days after the final application of myclobutanil, the grass was cut for harvest

of seed.  Seed was collected and grass seed screenings were separated from the seed.  After

cutting the grass for harvest of seed, the grass was allowed to re‐grow and cuttings of the re‐

growth grass were harvested as grass forage and hay at 42‐46, 57‐61 and 74‐79 days after the

last application and samples were collected for residue analysis.

Samples of grass seed screenings, grass straw, re‐growth grass forage and hay were analyzed

for residues of total myclobutanil defined as myclobutanil and its alcohol metabolite (RH‐

9090).  Residues of myclobutanil and RH‐9090 were extracted, hydrolyzed to release the

conjugated RH‐9090, purified by on‐line solid phase extraction and analyzed by high

performance liquid chromatography with positive‐ion atmospheric pressure chemical

ionization tandem mass spectrometry (LC/MS/MS).  The validated limit of quantitation (LOQ)

of the method for both myclobutanil and RH‐9090 was 0.010 μg/g for all matrices.

At the 45‐day PGI, residues for total myclobutanil in grass forage ranged from 0.06 to 0.95

ppm.  For grass hay at the 45‐day PHI, the residues ranged from 0.31 to 2.61 ppm.  Residues in
   

the grass seed screenings and grass straw were significantly higher, but grass straw and grass

seed screenings are of minimal overall economic value as animal feeds; it is proposed to

disallow the use of seed screenings and grass straw for livestock feed on the label.   

Based on this study, proposed tolerances for grass hay and grass forage are similar, but lower

than existing tolerances for soybean hay and forage.  Because the proposed grass uses do not

increase the calculated livestock dietary burden to levels above the previously employed

Maximum Theoretical Dietary Burden value, a reassessment of livestock meat and milk

tolerances is not required.]

B. Toxicological Profile [Per the 2007 EPA Human‐Health Risk Assessment (for Proposed Use

on Section 3 Requests for Use on Snap Bean, Mint, Papaya, Gooseberry, Currant, Caneberry,

Bell and non‐Bell pepper, Head and Leaf Lettuce, and Artichoke, DP 341689), the toxicology

database for myclobutanil is adequate and endpoints for risk assessments have been

established.]

1. Acute toxicity.  [Per the 2007 EPA Human‐Health Risk Assessment D341689:  

myclobutanil has low acute toxicity with the exception for ocular irritation.  It is Toxicity

Category III for oral acute toxicity, and Category IV for dermal and inhalation acute toxicity

and dermal irritation.  Myclobutanil is Category I for ocular irritation and the technical is a

dermal sensitizer.

2. Genotoxicty. [Per the 2007 EPA Human‐Health Risk Assessment: There is no concern

for mutagenic activity.]

3. Reproductive and developmental toxicity. [Per the EPA 2007 Human‐Health Risk

Assessment D341689:  there is no evidence of increased susceptibility in either of the

developmental toxicity studies or the reproduction study.  In the rat developmental toxicity

study, maternal toxicity, which included rough hair coat and salivation, occurs at the same

dose level as increases in incidences of 14th rudimentary and 7th cervical ribs in the fetuses.  

At the next higher dose there is also alopecia, desquamation and red exudate around the

mouth in the dams.  In the rabbit developmental toxicity study there is reduced body weight

and body weight gain during the dosing period, clinical signs of toxicity and a possible increase

in abortions in the does at the same dose level that there are increased resorptions, decreased

litter size and decreased viability index.  The maternal toxicity in the rat reproduction study
   

includes increased liver weights and hepatocellular hypertrophy.  Reproductive effects occur at

the same dose and include increased incidences in the number of still born pups and atrophy of

the testes, epididymides and prostate.  Developmental effects occurring at the same dose in

the reproduction study include decreased pup body weight gain during lactation.  EPA has

applied an acute dietary reference dose of 0.60 mg/kg/day to females 13 to 50 years of age,

based on the developmental toxicity study in rabbit.  EPA determined that an additional

safety factor was not needed for the protection of infants and children (FQPA SF = 1x).]

4. Subchronic toxicity. [As reviewed in the 2007 EPA Human‐Health Risk Assessment

D341689, in rat subchronic studies, the primary target organ is the liver.  EPA states:  Liver

effects, following subchronic exposure, include hypertrophy, hepatocellular necrosis and

increased liver weight.  In the subchronic dog, there are hepatocellular hypertrophy, increased

relative and absolute liver weight and increased alkaline phosphatase.  Subchronic exposures

in the mouse result in a toxicity profile similar to the rat.  Signs of toxicity observed in the rat

28‐day dermal studies are limited to dermal irritation; there is no evidence of systemic

toxicity.]

5. Chronic toxicity. [Per the 2007 EPA Human‐Health Risk Assessment D341689: chronic

exposure to the rat also results in hepatocellular vacuolization and additional testicular

effects, which include bilateral aspermatogenesis, increased incidences of hypospermia and

cellular debris in the epididymides and increased incidences of arteritis/periarteritis in the

testes.  The mouse, following chronic exposure, has, in addition, increased Kupffer cell

pigmentation, periportal punctate vacuolation, and individual cell necrosis of the liver.  There

is no evidence of carcinogenic potential in either the rat or mouse.  In the chronic dog study,

liver toxicity is similar with the addition of “ballooned” hepatocytes and increases in serum

glutamic pyruvic transaminase and gamma glutamyl transferase. . . .  Myclobutanil was

determined to be not carcinogenic in two acceptable animal studies.  Therefore, it was

classified as a “Group E” chemical (evidence of noncarcinogenicity for humans).]

6. Animal metabolism. [Per the 2007 EPA Human‐Health Risk Assessment D341689:

Myclobutanil is rapidly absorbed and excreted with complete elimination by 96 hours.  There is

extensive metabolism prior to excretion with elimination of radiolabeled material evenly

distributed between urine and feces.  There is no evidence of tissue accumulation.]

7. Metabolite toxicology. [Common metabolic pathways for myclobutanil have been

identified in both plants (grapes, apples, wheat) and animals (rat, goat, hen).  The metabolic
   

pathway common to both plants and animals involves oxidation of the –butyl alkyl side chain

in the 3‐ and 4‐ positions, oxidation of the cyano‐group, and subsequent conjugation.  

Extensive degradation and elimination of polar metabolites occurs in animals such that

residues are unlikely to accumulate in humans or animals exposed to these residues through

the diet. The RH‐9090 alcohol metabolite is already included in residue definition for crops.  In

addition, data on the three common  metabolites of the broader triazole class of chemistry is

available through the US Triazole Task Force, of which DAS in a member.]

8. Endocrine disruption. [Myclobutanil is on the 2009 EPA Final List of Initial Pesticide

Active Ingredients to be Screened under the FFDCA Endocrine Disruption Screening Program

and test orders were received on Dec 17, 2009.  The tier I EDSP screening studies have been

completed and are being submitted in December 2011 for Agency review within the two year

period allowed for completion of the test orders.]

C. Aggregate Exposure

1. Dietary exposure. [The proposed use in grass grown for seed does not require a new

human dietary assessment, because no changes to the meat or milk tolerances are needed.  

The 2007 EPA Human‐Health Risk Assessment (D341689) remains applicable: Acute (females

13‐49 years old) and chronic dietary exposure (general U.S. population and all population

subgroups) assessments were conducted using the Dietary Exposure Evaluation Model ‐ Food

Commodity Intake DatabaseTM (DEEM‐FCIDTM; ver. 2.03) program which incorporates

consumption data from USDA’s Continuing Surveys of Food Intakes by Individuals (CSFII),

1994‐1996 and 1998. DEEM contains food consumption data as reported by respondents in

the USDA Continuing Surveys of Food Intake by Individuals (CSFII) conducted in 1994‐1996 and

1998 and food translation to RACs, as indicated by EPA/USDA FCID recipe sets.]

i. Food. [Per the 2007 EPA Human‐Health Risk Assessment, D341689: An acute dietary

exposure assessment was performed for females 13‐49 years old  . . . using tolerance‐level

residues and 100% CT information for all registered and proposed uses. Drinking water was

incorporated directly in the dietary assessment using the acute (peak) concentration for

surface water generated by the PRZM‐EXAMS model. These assessments conclude that the

acute dietary exposure estimates (95th percentile) are below HED’s level of concern (<100% of

the aPAD) for females 13‐49 years old at 4% of the aPAD  . . . A refined, chronic dietary

exposure assessment was performed for the general U.S. population and various population

subgroups using USDA PDP monitoring data for apple juice, bananas (not plantains) and milk,
   

registered and proposed tolerance for all other commodities; average % CT information for

apple (except juice), apricots, artichokes, asparagus, green beans, blackberry, broccoli,

cantaloupe, cauliflower, cherry, cucumber, grape, hops, mint, nectarine, peach, peppers, plum,

pumpkin, raspberry, soybeans, squash, strawberry, tomato, and watermelon; and 100% CT

information for all other registered and proposed uses. Drinking water was incorporated

directly into the dietary assessment using the chronic concentration for surface water

generated by the PRZM‐EXAMS model. This assessment concludes that the chronic dietary

exposure estimates are below HED’s level of concern (<100% of the cPAD) for the general U.S.

population (20% of the cPAD) and all population subgroups. The most highly exposed

population subgroup is children 1‐2 years old at 30% of the cPAD.]

ii. Drinking Water. [The proposed use in grass grown for seed does not require a new

drinking water assessment.  Per the 2007 EPA Human‐Health Risk Assessment, D341689, EPA

EFED has previously provided estimated Drinking Water Concentrations (EDWCs) of

myclobutanil in surface and ground water using PRZM‐EXAMS and Screening Concentration in

Ground Water (SCIGROW), respectively. The assessment was based on tropical fruit, which has

the highest use rate among all existing uses. EFED calculated the 1‐ in 10‐year peak acute and

1‐ in 10‐year estimated annual mean non‐cancer chronic EDWCs for myclobutanil in surface

water to be 120.1 ppb and 46.3 ppb, respectively. The ground water EDWC for both acute and

chronic exposures is estimated as 2.83 ppb.  These drinking water values have been directly

incorporated into the dietary analysis discussed above.]

2. Non‐dietary exposure. [The proposed use in grasses grown for seed does not change

the previous aggregate assessments within the 2007 Human Health Assessment, D341689 in

which the EPA previously concluded the following:

The acute aggregate risk assessment takes into account exposure estimates from dietary

consumption of myclobutanil (food and drinking water). Dermal, inhalation, and incidental

oral exposures resulting from short‐term residential applications are assessed separately. The

acute dietary exposure estimates are below HED’s level of concern (<100% aPAD) at the 95th

exposure percentile for females 13‐49 years old (4% of the aPAD). . .Therefore, the acute

aggregate risk associated with the proposed uses of myclobutanil are not of concern to HED

for females 13‐49 years old.

The short‐term aggregate risk assessments estimate risks likely to result from 1‐30 days of

exposure to myclobutanil residues in food, drinking water, and residential pesticide uses. In
   

aggregating short‐term risk, HED considered background chronic dietary exposure (food and

drinking water . . .) and short‐term, non‐dietary oral and/or dermal exposures . . . For the

general U.S. population and all population subgroup, including infants and children, all short‐

term MOEs are greater than 100; and, therefore, are not of concern to HED (MOE <100).

The intermediate‐term aggregate risk assessment estimates risks likely to result from 1 to 6

months exposure to myclobutanil residues in food, drinking water, and residential pesticide

scenarios. In aggregating intermediate‐term risk, HED considered background chronic dietary

exposure (food and drinking water . . .) and intermediate‐term, non‐dietary oral and/or

dermal exposures . . . For the general U.S. population and all population subgroup, including

infants and children, all intermediate‐term MOEs are greater than 100; and, therefore, are not

of concern to HED (MOE <100).

The chronic aggregate risk assessment takes into account average exposure estimates from

dietary consumption of myclobutanil (food and drinking water) and residential uses.  . . . no

chronic residential exposures are expected. Therefore, the chronic aggregate risk assessment

includes exposure from food and drinking water only. The chronic dietary exposure estimates

are below HED’s level of concern (<100% cPAD) for the general U.S. population (20% of the

cPAD) and all population subgroups. The most highly exposed population subgroup is children

1‐2 years old at 30% of the cPAD. Therefore, the chronic aggregate risk associated with the

proposed uses of myclobutanil are not of concern to HED for the general U.S. population or

any population subgroups.]

D. Cumulative Effects

[For the purpose of this assessment, it is assumed that myclobutanil does not have a

mechanism of toxicity common with other substances and no cumulative risk assessment is

required.  It is also noted that EPA has previously conducted separate acute and chronic

aggregate (food + water) dietary risk assessments for three common metabolites of triazole‐

based fungicides in 2006 and has since updated those assessments as necessary to cover new

uses.  However, for this new use in grasses grown for seed, no update is anticipated.  Exposure

estimates of residues of these metabolites in water should not change as a result of this new

use, because myclobutanil use rates are lower than those previously assessed.  The impact of

this new use on the metabolites in food should also be negligible, because no net increase to

the animal burden is calculated for myclobutanil.]
   

E. Safety Determination

1. U.S. population. [Based on the exposure assumptions in the 2007 EPA Human‐Health

Risk Assessment, D341689, it is concluded that there is a reasonable certainty that no harm

will result to US‐general population from exposure to myclobutanil residues.  Moreover this

petition does not increase the animal burden and therefore no new human assessments are

needed.]

2. Infants and children. [Based on the exposure assumptions in the 2007 EPA Human‐

Health Risk Assessment, D341689, EPA has previously determined that an additional safety

factor was not needed for the protection of infants and children (FQPA SF = 1x) and that there

is a reasonable certainty that no harm will result to infants and children from aggregate

exposure to myclobutanil. Moreover this petition does not increase the animal burden and

therefore no new human assessments are needed. ]

F. International Tolerances

[Several governing bodies have established Maximum Residue Levels (MRLs) for

myclobutanil in a variety of crops.  The limited international MRLs for forages are found in the

following table based on a MRLs compiled by searches in Homologa

(http://www.homologa.com/).  Homologa is a third party database; Dow AgroSciences makes

no claim regarding the verification of these values relative to the individual national

authoritative sources.  The proposed tolerances are higher than those in other international

animal feeds with other international MRL values.

Country Crop Amount Unit

Japan Ginkgo‐Nut Forage crops   0.05 PPM

EU Harmonized Animal Feed 0.01 PPM

]