Document ID: EPA-HQ-OPP-2009-0636-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-01-06T05:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: 

Jim Tompkins, 703-305-5697 and Beth Benbow, 703-347-8072

Bayer CropScience LP

PP#: 9F7589

	EPA has received a pesticide petition (9F7589) from Bayer CropScience
LP, [2 T. W. Alexander Drive, Research Triangle Park, NC 27709]
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 indaziflam N-[(1R,
2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl-1,3,5-triazine-2,4-diamine]-6
-(1-fluoroethyl)] and its fluoroethyl-indaziflam metabolite in or on raw
agricultural commodities fruit, pome, group, fruit, citrus, group,
fruit, stone, group, nut, tree, group, pistachios, grapes, olives all at
[0.01] parts per million (ppm), and almond, hulls at [0.2] ppm, and the
import tolerance for refined sugar at [0.01] 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 nature of the indaziflam residues in plants and
livestock is adequately understood. The plant residues of concern for
tolerance enforcement are the combined residues of indaziflam (N-[(1R,
2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl-1,3,5-triazine-2,4-diamine]-6
-(1-fluoroethyl)-] and its fluoroethyl-indaziflam metabolite
[1,3,5-triazine-2,4-diamine]-6-(1-fluoroethyl)-].

	2. Analytical method. Indaziflam residues are quantified in raw
agricultural commodities by high pressure liquid chromatography/triple
stage quadrupole mass spectrometry (LC/MS/MS) using the stable
isotopically labeled analytes as internal standards. The limit of
quantification (LOQ) for each analyte was 0.005 ppm for all commodities.

	3. Magnitude of residues. Residue trials were conducted to support the
tolerances requested above including the following: 

Citrus: A total of 23 field trials were conducted evaluating residues at
target harvest intervals of 14, 45 and 240 days after application. 

Pome Fruit: A total of 18 field trials were conducted evaluating
residues at target harvest intervals of 14, 45 and 210 target days after
application.

Stone Fruit: A total of 21 field trials were conducted evaluating
residues at target harvest intervals of 14, 45 and 150/210 days after
application.

Tree Nuts: A total of 10 field trials were conducted evaluating residues
at target harvest intervals of 14 days after application.

Grapes: A total of 12 field trials were conducted evaluating residues at
target harvest intervals of 14, 45 and 140-240 days after application.

Olives: A total of 6 field trials were conducted evaluating residues at
target harvest intervals of 14, 45 and 300 days after application.

Sugarcane: A sugarcane processing trial was conducted to measure the
magnitude of total indaziflam residues in sugarcane and sugarcane
processed commodities following an exaggerated rate application to
ratooned sugarcane.

B. Toxicological Profile

1. Acute toxicity.  Indaziflam has a low acute oral (LD50 > 2,000 mg/kg
bw; Category III), dermal (LD50: > 2,000 mg/kg bw; Category III) and
inhalative toxicity (LC50: > 2.30 mg/L air; Category IV) in male and
female rats.  It is not an eye or skin irritant (both Category IV) nor
is it a skin sensitizer.

	2. Genotoxicty. Indaziflam was negative for mutagenicity and
clastogenicity in all the standard in vivo and in vitro assays.

	3. Reproductive and developmental toxicity. The reproductive and
developmental studies conducted with indaziflam showed that the test
substance was not a reproductive toxicant.  Parental and offspring body
weight and/or body weight change were decreased at high concentrations,
however there was no effect on reproductive ability of adults.  The
findings observed in rat fetuses (decreased body weights) were minor and
were secondary to maternal toxicity.  There was no indication of a
teratogenic effect of indaziflam in either the rat or the rabbit.

4. Neurotoxicity. Acute, subchronic and developmental neurotoxicity of
indaziflam was assessed in the rat.  Compound-related effects following
a single oral dose of the test substance were limited to 500 mg/kg and
2000 mg/kg in males and 100 mg/kg and up in females.    SEQ CHAPTER \h
\r 1 Effects in males and/or females consisted of decreased motor and
locomotor activity on the day of treatment (with recovery by the next
test occasion), urine, oral and perianal stains (generally resolved one
to five days after treatment), tremors, increased reactivity and
decreased activity (generally resolved the following day after
treatment), salivation, cool to touch, clonic convulsions, ventrum
wet/staining and death in three females (2000 mg/kg only).   Lastly,
compound-related microscopic lesions in high-dose males described as
focal to multi-focal individual nerve fiber degeneration observed in the
gasserian ganglion and peripheral nerves (sciatic and tibial) were
evident.   Slight decreases in measures of motor and locomotor activity
were evident in females treated at 100 mg/kg, with no effect at the next
lower dose of 50 mg/kg.  Based on these results, doses of 100 and 50 mg
BCS-AA10717/kg body weight are the overall NOAELs for males and females,
respectively. In the subchronic study, there were no mortalities. 
However, similar effects in motor and locomotor activity, as well as
clinical signs of neurotoxicity were only noted at the top dose, 10000
ppm (580.9 and 585.7 mg/kg/day for males and females, respectively). 
These results establish a NOAEL for neurotoxicity endpoints of 8000 ppm
(243.6 mg/kg/day in males and 306.9 mg/kg/day in females).  In the
developmental neurotoxicity study, the dam and offspring NOAEL was 1000
ppm (83.8 mg/kg bw/day), based on clinical signs of toxicity in dams
(tremor, dilated pupils, nasal stains, and repetitive chewing
movements), marked decrease in body weight and body weight gain, and
decreased food consumption in dams and offspring. There were no effects
on neuropathology in this study.

	5. Subchronic toxicity. Short and Intermediate-term exposures to
indaziflam were assessed in the mouse, rat and dog.  The only treatment
related effect noted in the mouse, following a 90-day exposure, was
reduced body weights at the highest dose tested. The common target
organs in rats and dogs were the liver, thyroid, and nervous system. 
Liver findings seen in rats and dogs were restricted to increased liver
weight, hepatocellular hypertrophy, and increased cholesterol.  Kidneys
were enlarged in the rat, but without corresponding weight change or
pathology.  Neurobehavioral and neuropathological changes were noted in
both rats and dogs following acute, short-term and chronic exposure to
indaziflam.  Effects noted included tremors, salivation and decreased
motor activity in rats, and uncoordinated gait and convulsions in dogs. 
Neuropathological lesions included axonal swelling and degeneration, as
well as individual nerve fiber degeneration.  These findings were found
in the brain, spinal cord and peripheral (sciatic and tibial) nerve
tracts.  Indaziflam is not toxic by the dermal route, as there was no
toxicity noted at the highest dose tested (1000 mg/kg/day) in a 28-day
dermal toxicity study in rats.  The dog was the most sensitive species
overall after sub-acute to sub-chronic administration of indaziflam with
the lowest NOAEL at 7.5 mg/kg bw/day in males and females in the 90-day
oral gavage study.

	6. Chronic toxicity. Chronic toxicity of indaziflam was evaluated in
the rat, mouse and dog.  Target organs were liver, kidney, thyroid and
nervous system.  In the chronic rat, top dose females (10000 ppm)
demonstrated similar signs as that seen in the acute and subchronic
neurotoxicity studies (e.g. dilated pupil, reduced motor activity,
limited use of limbs, uncoordinated movements, tremors, hindlimbs
splayed, low alertness). The incidence of treatment-related clinical
signs in females decreased significantly after the change of dose level
from 10000 to 6000 ppm.  Clinical signs were not evident in the chronic
dog at any dose level.  Organ effects noted in these studies included
increased liver, kidney and thyroid weights, with centrilobular
hepatocellular hypertrophy in the liver, tubular hyperplasia (male mouse
only) and brown pigment in the kidney, and follicular cell hypertrophy
in the thyroid (male rat only), histopathological changes to the central
and peripheral nerve tracts were noted only in the dog. The dog was the
most sensitive species overall after chronic administration of
indaziflam with the lowest NOAEL at 2.0 mg/kg bw/day in males and
females in the 1-year oral feeding study.  There were no
treatment-related neoplasms in the rat or mouse.  Therefore, following
chronic exposure, there is no indication of oncogenic potential relevant
for the human health risk assessment of indaziflam.

	7. Animal metabolism. A metabolism study for indaziflam, in which male
rats were given single oral doses of [indane-3-14C] AE 1170437 or
[triazine-2,4-14C] AE 1170437, showed that the uptake and excretion of
AE 1170437 was rapid.  Following oral administration, greater than 87%
of the administered dose was excreted within 24 hours.  In general, the
majority of the radioactivity was excreted in the feces with fecal:
renal excretion ratios ranging from approximately 1:1 for the low dose
experiments to approximately 10:1 for the high dose experiments.  No
volatile residues were detected, and no mineralization was observed. 
Residue levels in tissues were highest in GIT and liver.  Higher residue
levels were found in the residual carcass of animals in the bile
cannulation experiments.

Both uptake and clearance of indaziflam from the blood was rapid. 
Females appeared to absorb slightly more material compared to for males.
 Blood residues smoothly fell off in all dose groups indicating an
absence of reuptake.

Once absorbed, the metabolism of AE 1170437 was rapid, occurring mainly
through oxidative pathways.  That portion of the administered dose
recovered as unmetabolized parent in the feces, particularly in the high
dose experiments, was likely not absorbed.

	8. Metabolite toxicology. The two major metabolites of indaziflam are
AE 2158969 (BCS-AA10717-carboxylic acid) and BCS-AA10365
(BCS-AA10717-fluoroethyldiaminotriazine, FDAT).  As both major
metabolites are common in the rat, as well as the environment, toxicity
studies conducted with the TGAS are adequate to assess any potential
toxicity from these metabolites.  Primary mutagenicity screening tests
which were conducted on the metabolites of indaziflam showed them not to
be genotoxic.

	9. Endocrine disruption. The toxicology database for Indaziflam
(BCS-AA10717) is current and complete.  Studies in this database include
evaluation of the potential effects on reproduction and development and
an evaluation of the pathology of the endocrine organs following short-
or long-term exposure.

Bayer CropScience will conduct additional testing if and when required
under the Agency’s Endocrine Disruptor Screening Program (EDSP). 

C. Aggregate Exposure

Aggregate risk assessments were conducted for indaziflam including an
acute aggregate for food and drinking water exposure, a chronic
aggregate for food and drinking water exposure and a short term
aggregate assessment which includes food, drinking water and residential
exposure.  The assessments were conducted using the CARES® Version 3.0
software. Results of the short term aggregate assessment gave an MOE of
8700 for Children 1-2, the most sensitive subpopulation. The Level of
Concern for aggregate assessment of indaziflam is 100.

Dietary exposure. 

	i. Food and Water. 

Assessments were conducted to evaluate potential risks due to acute and
chronic dietary exposure of the U.S. population and selected population
subgroups to residues of indaziflam.  The dietary (food only) assessment
includes all proposed crops: Crop Group 10 Citrus Fruit; Crop Group 11
Pome Fruit; Crop Group 12 Stone Fruit; Crop Subgroup 13-07-F Small Fruit
Vine Climbing (except Kiwi); Crop Group 14 Tree Nuts; and olives.  The
drinking water assessment is based on conservative modeled acute and
chronic estimated drinking water concentrations for the US.  Exposure
from food and water together based on all the proposed uses of
indaziflam consumed only 1.9% of the acute RfD/PAD and 2.4% of the
chronic RfD/PAD for the most sensitive subpopulation of infants.

	2. Non-dietary exposure. 

The short term residential assessment includes application exposure by
homeowners applying indaziflam on lawns or ornamental plants, as well as
post-application exposure estimates for adults and children playing on
lawns and golf courses. Residential post-application exposure from
contact with indaziflam treated turf or ornamentals on the day of
application resulted in MOEs in excess of 600 for toddlers, and in
excess of 1,000 for adults, well above the Level of Concern of 100 for
indaziflam.

 

D. Cumulative Effects

	The toxicological properties of indaziflam indicate that it does not
have a common mechanism of toxicity with any other compounds. Although
it contains a triazine ring it does not exhibit the toxicological
properties of the chlorotriazine common mechanism group. Therefore it is
not necessary to cumulate its exposure with any other compounds. 

E. Safety Determination

	1. U.S. population Using the conservative exposure assumptions
described above and based on the completeness of the toxicity data, it
can be concluded that aggregate exposure to residues of indaziflam
present a reasonable certainty of no harm.  Exposure from residues in
crops and drinking water utilizes 1.9% of the aPAD and 2.4% of the cPAD
for the most sensitive population of infants.  EPA generally has no
concerns for exposures below 100% of the Population Adjusted Doses. 
Therefore, the aggregate assessment for all proposed uses for indaziflam
demonstrates that there is a reasonable certainty that no harm will
result to the US Population and subpoppulations from the use of
indaziflam noted here.

	2. Infants and children. The developmental and reproductive toxicity of
indaziflam were evaluated in developmental toxicity studies in the rat
and rabbit, a 2-generation reproduction study in the rat and a
developmental neurotoxicity study in the rat. These studies are
discussed under Section B (Toxicology Profile) above.  The developmental
toxicity data demonstrated no increased sensitivity of rats or rabbits
to in utero exposure to indaziflam. In addition, the multi-generation
reproductive toxicity study did not identify any increased sensitivity
of rats to in utero or post-natal exposure. The developmental toxicity
studies are designed to evaluate adverse effects on the developing
organism resulting from maternal pesticide exposure during gestation.
Reproduction studies provide information relating to effects from
exposure to the pesticide on the reproductive capability of mating
animals and data on systemic toxicity.

FFDCA section 408 provides that EPA shall apply an additional tenfold
margin of safety for infants and children in the case of threshold
effects to account for pre-and post-natal toxicity and the completeness
of the data base unless EPA determines that a different margin of safety
will be safe for infants and children. The indaziflam database is
complete for FQPA purposes and there are no residual uncertainties for
pre-/post-natal toxicity for indaziflam.  Therefore, the Special FQPA
Safety Factor can be reduced to 1x.  

Based on the exposure assessments described above and on the
completeness and reliability of the toxicity data, it can be concluded
that the dietary exposure from all proposed uses of indaziflam consumes
1.9% of the aRfD/aPAD at the 99.9th percentile and 2.4% of the cRfD/cPAD
for the most sensitive population subgroup of infants.  Short term
aggregate risk assessment of indaziflam which includes food, drinking
water and residential pathways gives an MOE of 8,700 for Children 1-2,
the most sensitive subpopulation for this scenario.  This is well above
the Level of Concern of 100 for indaziflam.  Thus, it can be concluded
that there is a reasonable certainty that no harm will result from
aggregate exposure to indaziflam residues.

F. International Tolerances

There currently are no international (CODEX) tolerances/MRLs for
indaziflam.

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