EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Dominic Schuler, (703) 347-0260

INSTRUCTIONS: Please utilize this outline in preparing the pesticide petition. In 

cases where the outline element does not apply, please insert “NA-Remove” and 

maintain the outline. Please do not change the margins, font, or format in your 

pesticide petition. Simply replace the instructions that appear in green, i.e., “[insert 

company name],” with the information specific to your action.

TEMPLATE:

ISK Biosciences Corporation

3F8142

EPA has received a pesticide petition (3F8142) from ISK Biosciences 

Corporation, 7470 Auburn Road, Suite A, Concord, Ohio, 44077, 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 by establishing a tolerance for residues of the 

fungicide isofetamid, N-[ 1,1 -dimethyl-2-[2-methyl-4-(l-methylethoxy)phenyl]-2-

oxoethyl]-3-methyl-2-thiophenecarboxamide (CA) and its metabolite GPTC, N-[1,ldimethyl-2-(4-β-D-glucopyranosyloxy-2-methylphenyl)-2-oxoethyl]-3-methyl-2-

thiophenecarboxamide, expressed as isofetamid in or on the following raw agricultural 

commodities: almond, at 0.02 parts per million (ppm); almond hulls at 0.2 ppm; 

lettuce, head, at 6.0 ppm; lettuce, leaf, at 7.0 ppm; fruit, small vine climbing, except 

fuzzy kiwifruit, subgroup 13-07F at 3.0 ppm; berry, low growing, subgroup 13-07G

at 4.0 ppm; and rapeseed subgroup 20A at 0.04 ppm. 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 plant metabolism of isofetamid is understood for the 

purposes of this petition. The residue of concern was defined on the basis plant 

metabolism studies conducted in grapes, lettuce and beans and in rotational crops, 

as the sum of IKF-5411 and its metabolite, GPTC, expressed as IKF-5411. The 

metabolic pathway was similar for all crops and the predominant metabolic 

pathway involved O-dealkylation of IKF-5411 to form 4HP followed by subsequent 
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conjugation to form GPTC (glucose conjugate) in primary crops and GPTC and 

malonyl-GPTC in rotational crops. Separation of the ring system also occurred in 

both primary and rotational crop but was a very minor route of metabolism in 

comparison to the formation of GPTC. The nature of the residue studies showed 

that isofetamid was the major identifiable residue with low levels of GPTC in some 

crops. The tolerance expression for the proposed crops will include parent, 

isofetamid, and the metabolite GPTC. 

2. Analytical method. The LC-MS/MS method proposed for residue analysis of plants 

and plant products determines the residues of parent IKF-5411 and its metabolite, 

GPTC. The method involves extraction of samples with acetone or with acetonitrile: 

water (80:20 v/v) mixture. Extracts are then subjected to SPE clean-up, with 

subsequent quantification of residues by liquid chromatography with tandem mass 

spectrometric determination (LC-MS/MS). The method has been shown to provide 

satisfactory recoveries and has a limit of quantification of 0.01 mg/kg. 

3. Magnitude of residues. The results from five (5) field trials conducted on almonds

during the 2011 growing season show that the maximum total residue (isofetamid + 

GPTC) after four applications of isofetamid at the target rate of ~0.446 lb a.i./A at 

10 (±1) day intervals applied at pink bud to petal fall was 0.04 ppm on hulls and 

were non-detectable (less than 0.005 ppm) on nutmeats. 

The results from 15 field trials conducted on grape vineyards during the 2011 

growing season show that the maximum total residue (isofetamid + GPTC) after 

three applications of isofetamid at the target rate of ~0.581 lb a.i./A at 10 (±1) day 

intervals applied up to 14 days before harvest was 2.6 ppm. 

The results from 13 field trials conducted on head lettuce and 13 field trials 

conducted on leaf lettuce during the 2011 growing season show that the maximum 

total residue (isofetamid + GPTC) after two applications of isofetamid at the target 

rate of ~0.322 lb a.i./A at 10 (±1) day intervals applied up to 14 days before harvest

was 4.76 ppm on head lettuce with wrapper leaves, 0.98 ppm on head lettuce 

without wrapper leaves and 5.29 ppm on leaf lettuce. 

The results from 17 field trials conducted on canola during the 2011 growing season 

show that the maximum total residue (isofetamid + GPTC) after two applications of 

isofetamid at the target rate of ~0.268 lb a.i./A at 6 to 29 day intervals applied at 20 

– 40% flowering (BBCH 62-64) to end of flowering (BBCH 67-69) was 0.01 ppm. 

B. Toxicological Profile

1. Acute toxicity. Results from a battery of acute toxicity studies place 

technical isofetamid in Toxicity Category III for oral LD50 and dermal LD50, and 

Category IV for inhalation LC50, dermal irritation, and eye irritation. Technical 

isofetamid was not a dermal sensitizer. In an acute neurotoxicity study, no 

treatment related effects were observed at any dose. The NOAEL was 2,000 mg/kg 

bw, the highest rate tested.

2. Genotoxicty. A battery of four tests has been conducted to assess the 

genotoxic potential of technical isofetamid. Assays conducted included in vitro
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reverse gene mutation tests in bacteria, in vitro gene mutation test in a mouse 

lymphoma cells, a chromosomal damage test in mammalian cells, and an in vivo

micronucleus test in mice. Isofetamid did not elicit a genotoxic response in any of 

the studies conducted.

3. Reproductive and developmental toxicity. In a two-generation reproductive 

toxicity study, general toxicity effects were observed on body weights, liver weights 

and thyroid weights at 10,000 ppm (594 mg/kg bw/day) in dams during gestation 

and lactation and in weanling pups. No reproductive effects were observed. The 

NOAEL for reproductive effects was 10,000 ppm (594 mg/kg bw/day males; 906 

mg/kg bw/day females). The NOAEL for general toxicity was 1,000 ppm (57.1 

mg/kg bw/day males; 90.5 mg/kg bw/day females).

In a rat developmental study, pregnant rats were dosed by gavage with isofetamid

from Days 6 to 19 of gestation. There were no treatment-related effects observed in 

the study. The NOAEL for maternal toxicity and embryo fetal toxicity was 1,000

mg/kg bw/day. 

In a rabbit developmental study, pregnant rabbits were dosed with isofetamid on 

Days 6 to 27 of gestation. There were maternal rabbit body weight changes in the 

high dose (1000 mg/kg/day) group. No treatment-related teratogenicity effects were

observed in the study. The NOAEL for developmental effects on fetuses was the 

highest dose tested, 1000 mg/kg/day. The maternal general toxicity NOAEL was 300

mg/kg bw/day.

The developmental studies (prenatal developmental studies in rat and rabbit and 

the two generation reproduction study in rat) provided no indication of increased 

sensitivity of rats or rabbits from in utero or post-natal exposure to isofetamid. 

Thus, isofetamid is not considered a developmental or reproductive toxicant.

4. Subchronic toxicity. The oral toxicity of isofetamid was investigated in mice, 

rats, and dogs in 13-week studies. In mice, changes in the liver and adrenal gland 

occurred at the highest dose of 8000 ppm (1067 mg/kg bw/day males; 1306 mg/kg 

bw/day females). The NOAEL was 1000 ppm (129 mg/kg/day in males and 161 

mg/kg/day in females). 

In rats, changes in the liver, thyroid, and adrenal gland occurred at the 1000 and 

10,000 ppm rates. The NOAEL was 100 ppm which was equivalent to a dosage of 

6.65 mg/kg bw/day to males and 7.83 mg/kg bw/day to females. 

In the 90-day dog study, body weight and blood chemistry effects were observed at 

the 10,000 rate in both males and females and at the 1000 ppm rate (32.7 mg/kg 

bw/day) in females only. The NOAEL was 1000 ppm in males (29.3 mg/kg/day) and 

100 ppm in females (3.07 mg/kg/day).

5. Chronic toxicity. In a long-term feeding study, mice were fed isofetamid in 

the diet for 78 weeks. There was no evidence of carcinogenicity at any dose, up to 

the maximum dose of 4000 ppm (502 mg/kg bw/day) for males and 3000 ppm (431 

mg/kg bw/day) for females. Based on bodyweight changes, the NOAEL was 100 

ppm for males (12 mg/kg/day) and 800 ppm for females (118 mg/kg/day).

In a 1-year chronic toxicity study in rats, treatment related effects were only seen at 

the 5000 ppm level. The NOAEL for chronic effects was 500 ppm (22.7 mg/kg/day
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in males and 30.0 mg/kg/day in females). 

An oncogenicity study was conducted where isofetamid was administered 

continuously for a period of 104 weeks to male and female Wistar Hannover rats. It 

was concluded that isofetamid was not carcinogenic in this study at levels up to 5000 

ppm. The general toxicity NOAELs were 500 ppm (20.3 mg/kg bw/day) for males 

and 100 ppm (5.02 mg/kg bw/day) in females. 

In a chronic dog study, three groups of four dogs/sex/group received isofetamid for 

52 weeks. Blood chemistry and liver effects were observed in the high dose group of 

6000 ppm. The NOAEL was determined to be 200 ppm (5.34 mg/kg/day for males 

and 5.58 mg/kg/day for females).

6. Animal metabolism. A study on the metabolism of isofetamid in animals 

using radioactive test material has been conducted with isofetamid, labeled with 14C

in two positions, the phenyl [

14C-Ph]- or thiophene [14C-Th] ring at the dose levels of 

5 and 200 mg/kg. IKF-5411 was readily excreted by the rat with biliary excretion 

being the major route of elimination with evidence of re-absorption of biliary 

excreted metabolites and subsequent preferential excretion in urine. Biliary and 

urinary excretion and the residues in tissues and carcass showed that absorption 

was greater than 93% of the administered dose at both dose levels. There was no 

evidence of retention of IKF-5411 or its metabolites as tissue and blood levels were 

negligible apart from the liver with no individual tissue containing greater than 

0.5% of the administered dose.

IKF-5411 was shown to undergo extensive metabolism via O-dealkylation, 

hydroxylation with subsequent glucuronidation. There were quantitative, but not 

qualitative, differences in metabolism due to position of the radiolabel in the 

metabolism of IKF-5411 and a quantitative sex difference related to the difference 

in excretion patterns between males and females. Cleavage between the benzene and 

thiophene ring structures was only a minor metabolic route in the rat. 

7. Metabolite toxicology. Comparison of the metabolism of isofetamid by 

plants and in animals indicates a pathway common to both plants and animals. The 

data indicate that the final products of the metabolism of isofetamid in animals and 

plants represent differences in the extent of metabolism. Several of the metabolites 

resulting from isofetamid are similar in plants and animals and, therefore, have 

already been evaluated toxicologically.

8. Endocrine disruption. An evaluation of the potential effects on the 

endocrine systems of mammals has not been determined; however, no evidence of 

such effects was reported in subchronic, chronic or reproductive toxicology. There 

was no observed pathological finding of the endocrine organs in these studies, and 

there were no reproductive effects at the maximum dose tested of 20,000 ppm. 

There is no evidence at this time that isofetamid causes endocrine effects.

C. Aggregate Exposure

1. Dietary exposure. Potential dietary exposures from food were estimated for 

all proposed tolerances for the crops listed below, using the Dietary Exposure 
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Evaluation Model-Food Consumption Intake Database (DEEM-FCIDTM) version 

3.12, and percent crop treated of 100%. The following raw agricultural 

commodities were included: almonds; lettuce, head and leaf; grapes (subgroup 13-

07F); low growing berries (subgroup 13-07G); and rapeseed (subgroup 20A).

For chronic dietary exposure, a conservative chronic reference dose (RfD) of 0.05

mg/kg bw/day was used, based on the NOAEL from the rat carcinogenicity study 

(5.02 mg/kg bw/day for females) and dividing by an uncertainty factor of 100. The 

chronic population adjusted dose (cPAD) is also 0.05 mg/kg bw/day since the FQPA 

safety factor should be 1 for isofetamid.

Acute dietary exposure analysis was not warranted based on the low order of acute 

toxicity.

i. Food. Tier 1 chronic dietary exposure analyses were conducted for 

isofetamid in/on the crops noted above to determine the exposure contribution of 

these commodities to the diet and to ascertain the chronic risk potential. The 

estimates were based on proposed tolerance level residues for all crops, a grape 

processing study, conservative market share assumptions of 100% crop treated, and 

consumption data from the USDA’s NHANES/WWEIA dietary survey of food 

intake conducted in 2003-2008. 

Even using all of the worst case exposure scenarios listed above, the Tier 1 chronic 

dietary (food + drinking water) exposure estimates resulted in an estimated 

exposure for the general U.S. population of 0.003360 mg/kg bw/day. This exposure 

corresponds to 6.7% of the cPAD of 0.05 mg/kg bw/day. The highest exposure 

estimate calculated was for the subgroup, children 1-2 years old. This exposure was 

determined to be 0.008808 mg/kg bw/day (17.6% of the cPAD).

It can be concluded that the long-term dietary exposure to isofetamid through 

residues on treated almonds, grapes (subgroup 13-07F), leaf and head lettuce, 

rapeseed, (subgroup 20A); and low growing berries (subgroup 13-07G) should not 

be cause for concern.

ii. Drinking water. Since isofetamid is intended for application outdoors to 

turf and field grown crops, the potential exists for parent and or metabolites to 

reach ground or surface water that may be used for drinking water. The drinking 

water component for the chronic risk assessment was directly entered into the 

dietary exposure model and is included in the exposure values noted above.

2. Non-dietary exposure. 

Isofetamid can only be commercially applied to residential turf. Therefore, nonoccupational exposure of isofetamid to the general population is not expected, 

however, postapplication exposure is possible. For Dermal Short-Term exposure, 

no toxicity was found at 1000 mg/kg in a 28-day rat dermal toxicity study. In 

addition, in vitro rat skin, in vitro human skin, and in vivo rat studies were 

conducted that suggest about 0.4% of isofetamid from the formulation and up to 

10% of it from dilute spray tank would be absorbed through human skin.

Therefore, in the absence of any hazard identified for dermal exposure, a dermal 
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post-application risk assessment was not conducted for children or adults. 

However, there is potential for post-application exposures to children resulting from 

lawn treatment that need to be assessed based on the potential for non-dietary 

incidental oral ingestion. Potential inhalation exposure was not considered since it 

is negligible when assessing re-entry risks. The post application exposure to 

children from incidental oral exposures from residential lawn use results in a MOE

of 963, which is greater than 100 and therefore is not of concern.

D. Cumulative Effects

Isofetamid is an SDHI type fungicide. We do not believe that isofetamid has a 

common mechanism of toxicity with any other pesticide, but it is unknown at this 

time.

E. Safety Determination

1. U.S. population. Dietary and occupational exposure will be the major 

routes of exposure to the U.S. population. Ample margins of safety have been 

demonstrated for both situations. For the general U.S. population, the chronic 

dietary exposure to isofetamid is 0.003360 mg/kg bw/day, which utilizes less than 

6.7% of the RfD for the overall U.S. population, assuming 100% of the crops are 

treated. A cancer dietary assessment was not conducted because this product did 

not show any potential to be carcinogenic to animals. Since there is no dermal point 

of concern, dermal post-application risk assessments were not conducted and only 

inhalation exposure was determined for handlers. Using the pesticide handlers 

exposure data base (PHED) updated by EPA in March 2010, the margins of 

exposure (MOE) for occupational exposure were greater than 98,000 to 124,000 for 

use on turf and 5,000 to 172,000 for use on crops. Based on the completeness and 

reliability of the toxicity data and the conservative exposure assessments, there is a 

reasonable certainty that no harm will result from the aggregate exposure of 

residues of isofetamid including all anticipated dietary exposure, occupational 

exposure and all other non-occupational exposures.

2. Infants and children. As noted above, chronic dietary exposure of the most 

highly exposed subgroup in the population, children, 1-2 years old, is 0.008808

mg/kg bw/day or 17.6% of the RfD. Thus, it can be concluded that there is 

reasonable certainty that no harm will result to infants and children from acute or 

chronic exposure to Isofetamid.

Based on the completeness and reliability of the toxicity data, the lack of 

toxicological endpoints of special concern, the lack of any indication of greater 

sensitivity of children, and the conservative exposure assessment, there is a 

reasonable certainty that no harm will result to infants and children from the 

aggregate exposure to residues of isofetamid from all anticipated sources of dietary 

and non-occupational exposure. 
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F. International Tolerances

Presently, there is no Codex maximum residue levels (MRLs) established for 

residues of isofetamid on any crop. Since this is being submitted as a Joint Review 

with PMRA, similar crop tolerances are being requested in Canada. In addition,

submissions are being made to the EU and Japan for the similar crops.