 

<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:>

<  SEQ CHAPTER \h \r 1 <  SEQ CHAPTER \h \r 1 ISK Biosciences
Corporation>>

<3F8142>

β-D-glucopyranosyloxy-2-methylphenyl)-2-oxoethyl]-3-methyl-2-thiophenec
arboxamide, 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.   SEQ CHAPTER \h \r 1 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
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.   SEQ CHAPTER \h \r 1 >

<	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. 

  SEQ CHAPTER \h \r 1 >

<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.    SEQ CHAPTER \h \r 1 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.   SEQ CHAPTER \h \r 1 A battery of four tests has been
conducted to assess the genotoxic potential of technical isofetamid. 
Assays conducted included in vitro 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.   SEQ CHAPTER \h \r 1 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).  

  SEQ CHAPTER \h \r 1 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 in males and 30.0 mg/kg/day in females).  

  SEQ CHAPTER \h \r 1 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.   SEQ CHAPTER \h \r 1 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.   SEQ CHAPTER \h \r 1 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.   SEQ CHAPTER \h \r 1 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.   SEQ CHAPTER \h \r 1  Potential dietary
exposures from food were estimated for all proposed tolerances for the
crops listed below, using the Dietary Exposure 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.   SEQ CHAPTER \h \r 1 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 +   SEQ CHAPTER \h \r 1 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.   SEQ CHAPTER \h \r 1 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. 

  SEQ CHAPTER \h \r 1 Isofetamid can only be commercially applied to
residential turf.  Therefore, non-occupational 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 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>

<  SEQ CHAPTER \h \r 1 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.   SEQ CHAPTER \h \r 1 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.   SEQ CHAPTER \h \r 1 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. 

>

<F. International Tolerances>

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ఀܪ栕䫟

 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,   SEQ CHAPTER \h \r 1 similar crop tolerances are being
requested in Canada.   In addition, submissions are being made to the EU
and Japan for the similar crops.>

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