 

Amended Notice of Filing: IR-4 PP#7E7258

<EPA Registration Division contact: Susan Stanton, 703-305-5218>

 

<Interregional Research Project Number 4 (IR-4) PP#7E7258>

<	EPA has received an amended pesticide petition (PP#7E7258) from
Interregional Research Project Number 4 (IR-4), 500 College Rd., East,
Suite 201 W, Princeton, NJ  08540 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 180.476 by establishing tolerances  for residues of
triflumizole, 1-[1-((4-chloro-2-(trifluoromethyl)
phenyl)imino)-2propoxyethyl]-1H-imidazole, and its metabolites
containing the 4-chloro-2-trifluoromethylaniline moiety, in or on the
raw agricultural commodities leafy greens subgroup 4A, except spinach
and cilantro at 35 ppm parts per million (ppm); turnip, greens at 40
ppm; Swiss chard at 18 ppm; Pineapple at 4.0 ppm; Papaya; Sapote, black;
Canistel; Sapote, mamey; Mango; Sapodilla; and Star apple at 2.5 ppm;
and Hop,dried cones at 50.0 ppm.  EPA has determined that the petition
contains data or information regarding the elements set forth in section
408 (d)(2) of the 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. In crops, the metabolism of [14C]-Phenyl]
triflumizole was investigated in cucumber, pears, grapes and apples. The
major metabolites were:
N-(4chloro-2trifluoromethylphenyl)-n-propoxyacetamidine  (FM-6-1),
N-(4-chloro-2-trifluoromethylphenyl)-n-propoxyacetanilide  (FD-1-1) and
the free or conjugated products of
N-(4-chloro-2-trifluoromethylphenyl)-hydroxyacetamidine (the
0-dealkylation product of FM-6-1),
N-(4-chloro-2-trifluoromethylphenyl)-hydroxyacetanilide (FD-2-1) and the
triflumizole aniline (FA-1-1).

	2. Animal metabolism. In livestock, oral administration of
[14C]-triflumizole was conducted twice daily for 5 days at 14 mg/kg/day
(equivalent to 280 ppm in feed for the cow) and 144 mg/kg/day
(equivalent to 50 ppm in feed for chicken). On the sixth day the animals
were sacrificed and meat, milk and egg samples were analyzed.  Cow’s
liver, kidney, fat and muscle contained 11.26, 3.36, 0.66, and 0.30 ppm
of [14C]-triflumizole equivalent, respectively. Residues in milk reached
a plateau of about 0.7 ppm after 24 hours. Chicken liver, kidney, fat,
and muscle contained 1.10, 0.74, 0.17 and 0.05 ppm of [14C]-triflumizole
equivalent, respectively.  Residues in eggs reach a maximum of 0.30 ppm
level. Metabolites identified in these tissues were mainly triflumizole
aniline (FA-1-1) and the sulfate/glucuronide conjugates of the 6-hydroxy
derivative of triflumizole aniline (FA-1-5). The latter was the major
metabolite in milk. Unchanged triflumizole was present in trace amounts
in the whole egg.>

<	3. Analytical method. The analytical method is suitable for analyzing
crops for residues of triflumizole and its aniline containing
metabolites at the proposed tolerance levels. The analytical method has
been independently validated. Residue levels of triflumizole are
converted to FA-1-1 by acidic and alkaline reflux, followed by
distillation. Residues are then extracted and subjected to SPE
purification. Detection and quantitation are conducted by gas
chromatograph equipped with nitrogen phosphorus detector, electron
capture detector or mass spectrometry detection. The limit of
quantitation of the method has been determined in the range of 0.01 ppm
to 0.05 ppm for the combined residues of triflumizole and FA-1-1. The
enforcement methodology has been submitted to the Food & Drug
Administration for publication in the Pesticide Analytical Manual, Vol.
II (PAM II).>

<	4. Magnitude of residues. Section 3 registrations for triflumizole is
currently exist for several commodities (e.g., apple, cherry, filbert,
grape, pear, strawberry, cucurbits, and meat, milk, poultry and eggs)
and feed items. The proposed group tolerance for leafy brassica
vegetables (subgroup 5B) at 20 ppm is pending (PP#7E7183). The subject
of the August 23, 2006 Federal Register notice regarding triflumizole
was the establishment and/or extension of emergency exemption tolerances
on several crops in Texas (i.e., parsley leaves, dandelion leaves, Swiss
chard, collard, kale, kohlrabi, mustard greens, Chinese napa cabbage,
broccoli, coriander leaves and turnips greens). Many of these crops are
in subgroup 4A leafy greens and 5A head and stem brassica, so the
purpose of this dietary exposure assessment is to expand the uses of
triflumizole to all crops in subgroup 4A , 5A and 5B to Swiss chard,
hops, papaya (which includes black sapote, canistel, mamey sapote,
mango, sapodilla and star apple), and pineapple.>

<B. Toxicological Profile>

<	1. Acute toxicity.  The database includes the following studies for
triflumizole technical: a rat acute oral study with a LD50 of 1.42 g/kg;
a rabbit acute dermal study with a LD50 >5 g/kg; a rat acute inhalation
study with LC50  >3.2 mg/l; a rabbit primary ocular irritation study
which showed mild irritation; a rabbit primary dermal irritation study
which showed no irritation; a guinea pig dermal sensitization study
which showed slight dermal sensitization potential. The database also
includes the following studies for Procure 480SC: a rat acute oral study
with a LD50 >2 g/kg; a rabbit acute dermal study with a LD50 >5 g/kg; a
rat acute inhalation study with a LC50 >3.3 mg/l; a rabbit primary
ocular irritation study which showed slight irritation; a rabbit primary
dermal irritation study which showed no irritation; a guinea pig dermal
sensitization study which was negative for skin sensitization. Acute
neurotoxicity study of triflumizole in rats. Male and female rats were
administered a single dose of triflumizole by oral gavage at levels of
0, 25, 100, 200 (female) and 400 (male) mg/kg and observed for 15 days.
Decreased motor activity was noted 3 to 6 hours post exposure in male
and female rats at 100 mg/kg and above. Functional Observational Battery
(FOB) effects included a decrease rearing counts in females, decreases
in forelimb and hind limb grip strength in males and forelimb grip
strength in females at 100 mg/kg and above. The NOEL was considered to
be 25 mg/kg based on clinical findings and functional observational
battery evaluations at 100 mg/kg.>

<	2. Genotoxicty. Triflumizole was negative in all genotoxicity assays
including: Ames assay in S. typhimurium, gene conversion assay in yeast
strain D4, REC assay in B. subtilis, unscheduled DNA synthesis (UDS)
assay in cultured rat hepatocytes, chromosome aberration assay in
cultured Chinese hamster lung (CHL) cells and a mouse micronucleus
assay.>

<	3. Reproductive and developmental toxicity. In a developmental
toxicity study, triflumizole was administered by oral gavage to
pregnant, female Sprague Dawley rats at dosage levels of 0, 10, 35 or
120 mg/kg/day. Maternal toxicity, as evidenced by a substantial
reduction in body weight gain, was seen at 35 and 120 mg/kg/day. At
these dosage levels there was a decrease in fetal viability in the form
of late resorptions. There were no teratogenic effects. The no observed
effect level (NOEL) for maternal and developmental toxicity was 10
mg/kg/day. 

Triflumizole was also administered by oral gavage to pregnant, female
New Zealand White rabbits at dosage levels of 0, 5, 25, or 50 mg/kg/day.
Maternal toxicity was observed at a dose level of 50 mg/kg/day as
demonstrated by a reduction in body weight gain. There were no
developmental or teratogenic effects. The NOEL for maternal toxicity was
25/mg/kg/day and the NOEL for developmental toxicity was greater than 50
mg/kg/day. 

The reproductive toxicity of triflumizole was evaluated in rat
reproduction study, conducted on three generations, at dietary
concentrations of 0, 30, 70 and 170 ppm. Fertility was not affected by
treatment. There was an increase in placental weight in the Flb, F2b and
F3b litters and a statistically significant increase in gestation length
in the high dose group at the F1a interval and at all three dose levels
at the F3a interval. Critical review of the gestation length data
demonstrated that theNOEL for reproductive effects in this study is 70
ppm (MRID # 47136402), which was the original conclusion of the study
director at Life Science Research. This is based on the increase in
gestation length seen at 170 ppm in two of six matings. In addition, the
NOEL for systemic parental toxicity was greater than 170 ppm and the
NOEL for developmental toxicity was 70 ppm (3.5 mg/kg/day) based upon
increased incidences of hydroureter and space between the body wall and
organs.>

<	4. Subchronic toxicity. To assess sub-acute dermal toxicity,
triflumizole was applied to the backs of male and female Sprague Dawley
rats for 6 hours per day for three weeks at dose levels of 10, 100 and
1000 mg/kg/day.  Female rats exposed to 1000 mg/kg/day exhibited mild
fatty vacuolation in the liver, which was within the range of normal
biological variation.  Therefore, the no-observed effect level (NOEL)
for subchronic dermal toxicity in rats was considered to be greater than
1000 mg/kg/day.

90 Day Neurotoxicity Study of Triflumizole in Rats. Male and female rats
were administered triflumizole in the diet at levels of 70, 700 or 2000
ppm (4.1, 40.9, 117.3 mg/kg/day male and 4.9, 47.8, and 133.3 mg/kg/day
females) for a period of 90 days. The NOEL for general toxicity was 70
ppm based on body weight (significantly higher in males at 700 ppm and
significantly lower in females at 2000 ppm), food consumption (lower in
females at 2000 ppm), hematology (values were slightly lower in males
and females at 2000 ppm and at week 4 in the 700 ppm dose group) and
pathology evaluations (higher in mean and relative liver weights in
males an females at 700 and 2000 ppm, hepatocellular hypertrophy in
males and females at 700 and 2000 ppm). The NOEL for neurotoxicity was
2000 ppm.>

<	5. Chronic toxicity. Triflumizole was fed to male and female beagle
dogs for one year at dietary concentrations of 0, 100, 300 and 1,000 ppm
to assess chronic toxicity. At a dosage level of 1,000 ppm there was an
increase in serum liver enzymes and a decrease in RBC concentration. The
NOEL for chronic toxicity in dogs was 300 ppm (7.5 mg/kg/day). 

Triflumizole was fed to male and female Sprague Dawley rats for two
years at dietary concentrations of 0, 100, 400 and 1,600 ppm to assess
chronic toxicity. At the high dose level there was a substantial
reduction in body weight gain in males and females. At the mid and high
dose levels there was an increase in liver weight. Fatty vacuolization
of the liver was seen at all dose levels and hepatocytic hypertrophy was
seen in high and mid-dose males and females. Female rats given 400 or
1,600 ppm were confined to hepatocytic fatty vacuolation and hypertrophy
in females. These changes were less severe than those seen in rats given
400 or 1,600 ppm and were considered by the laboratory to be indicative
of adaptive metabolic change.   No evidence of oncogenic effects were
demonstrated in rats.  The dietary level of 100 ppm (5 mg/kg/day) is
considered to be a NOEL. >

<	6. Animal metabolism. Triflumizole, [14C-Phenyl]
1-(1-((4-chloro-2-trifluoromethylphenyl)imino)-2-propoxyethyl)-1H-imidaz
ole, was found to be rapidly absorbed and excreted in rats. Two days
after oral dosing, 78% was found to be excreted in the urine and 20% in
the feces. No sex difference was noted. It appears that the loss of the
imidazole ring was the basic step in the metabolic pathway of the
fungicide in mammals.  The elimination of the imidazole ring yielded
initially N-(4-chloro-2-trifluoromethylphenyl)-n-propoxyacetamidine
(FM-6-1), and N-(4-chloro-2trifluoromethyphenyl-n-propoxyacetanilide 
(FD-1-1). Other hydroxylated  metabolites identified (free, or as
sulfate/glucuronide conjugates) included, amoung others,
N-(4-chloro-2-trifluoromethylphenyl)-hydroxyacetamidine (FM-8-1);
4-chloro-2-trifluoromethyl-hydroxyacetanilide (FD-2-1); and
4-chloro-2-trifluoromethyl-6-hydroxyaniline (FA-1-5). >

<	7. Metabolite toxicology. Both plant and animals produce the same
metabolites that were identified in the metabolism studies; therefore,
the toxicity of the metabolites has essentially been evaluated in the
rat toxicology studies.>

<	8. Endocrine disruption.[In the rat reproduction study there was an
increase in placental weight in females at the high dose level of 170
ppm. There was also a biologically significant increase in gestation
length in high dose F0 and F2 females (Fla and F3a intervals). The NOEL
for endocrine effects is 70 ppm (3.5 mg/kg/day).>

<C. Aggregate Exposure>

<	1. Dietary exposure. [\Based on dietary, drinking water and
non-occupational exposure assessments, there is reasonable certainty of
no harm to the US population, any population subgroup, or infants and
children from acute or chronic exposure to triflumizole.>

<	i. Food. Chronic dietary exposures were estimated utilizing Dietary
Exposure Evaluation Model software with Food Commodity Intake Database
(DEEM-FCID), version 2.16. EPA’s most recent estimate of chronic
estimated dietary exposures for triflumizole are reported in the August
23, 2006, Federal Register notice which established emergency exemption
tolerances on a variety of crops. In the assessment, EPA used a mixture
of anticipated residues (i.e., mean residues from field trials) and
tolerances for the different crops. EPA included percent crop treated
information from Biological and Economic Analysis Division (BEAD) for
apples, grapes and pears, while all others were assumed to be 100%
treated. EPA used modified processing factors for apples and grapes
based on previously submitted studies, while default processing factors
were used for all other foods. EPA also included an estimated
concentration in drinking water of 40 ppb, which is the chronic (annual
average) concentration in surface water generated by the FIRST model in
the residue file. In the August 23, 2006, Federal Register notice, EPA
used a cPAD of 0.015 mg/kg/day.  Since that time Chemtura has
resubmitted documentation supporting a revised cPAD for triflumizole of
0.035 mg/kg/day (MRID # 47136402).  The revised cPAD will be used in
this assessment.  The total chronic dietary exposures are estimated to
be 37.3% of the cPAD for the general US population, 16.1% for all
infants, 42.0% for children aged 1-2 years old, and 43.9% for children
aged 3-5 years old.  Chronic dietary exposures below 100% of the cPAD
are reasonably anticipated to result in no harm to exposed populations. 

For the acute assessment, EPA’s August 23, 2006, assessment assumed
tolerance-level residues, and 100% crop treated for all crops. EPA used
modified processing factors for apples and grapes based on previously
submitted studies, while default processing factors were used for all
other foods. Drinking water was included directly into the dietary
assessment using the acute (peak) concentration for surface water (191
ppb) estimated by the FIRST model. For this updated assessment, an acute
residue file was created using all the information and assumptions from
the EPA assessment and then adding the proposed crops assuming
tolerance-level residues, 100% crop treated and default processing
factors. Acute exposures were calculated using DEEM-FCID version 2.16.
The acute population adjusted dose (aPAD) for triflumizole is 0.25
mg/kg/day for the general population and 0.1 mg/kg/day for females aged
13-49. At the 95th percentile, which is the appropriate point of
comparison for this conservative Tier 1 acute dietary assessment, the
estimated acute exposures range from 23.39% of the aPAD for all infants
to 41.49% of the aPAD for children aged 1-2 years old. For females aged
13-49 years old, the 95th percentile acute dietary exposure is 70.56% of
the subpopulation-specific aPAD (0.1 mg/kg/day). Acute dietary exposures
below 100% of the aPAD are reasonably anticipated to result in no harm
to exposed populations.>

<	ii. Drinking Water. Tier I screen models FIRST (First Index Reservoir
Screening Tool) and SCI-GRO (Screening Concentrations in Ground Water)
were used to predict estimates of triflumizole concentrations in surface
and groundwater, respectively. Drinking water levels of comparison
(DWLOCs) were estimated and compared to drinking water estimated
concentrations (DWECs) using EPA standard operating procedures. DWECs
were obtained from the August 23, 2006, acute exposures. The chronic
DWLOCs are 98 ppb for toddlers, 324 ppb for adult females and 369 ppb
for all adults. The chronic and acute DWECs are below the chronic and
acute DWLOCs, respectively, for all population groups and exposure
durations.>

<	2. Non-dietary exposure. There are no registered or proposed uses for
application by homeowners. For the proposed residential uses, only
professional handlers would apply triflumizole to woody ornamentals
(trees, shrubs, vines). Triflumizole is not used or proposed for use on
lawns or turf. Therefore, residential exposure is not likely.>

<D. Cumulative Effects>

<	The potential for cumulative effects of triflumizole, an imidazole,
and other substances that have a common mechanism of toxicity was
considered. The mammalian toxicity of triflumizole is well defined. No
reliable information exists to indicate that toxic effects produced by
triflumizole would be cumulative with those of any other chemical
compounds. Therefore, consideration of a common mechanism of toxicity
with other compounds is not appropriate. Thus, only the potential risks
of triflumizole are considered in the aggregate exposure assessment.   >

<E. Safety Determination>

<	U.S. population. i. Short-Term Risk.  The acute population adjusted
dose (aPAD) for triflumizole is 0.25 mg/kg/day for the general
population and 0.1 mg/kg/day for females aged 13-49.   Acute dietary
exposure to children (1-2 yrs) was 0.1037 mg/kg/day and was 41.49% of
the aPAD. Acute dietary exposure to females 13-49 yrs was 0.0706
mg/kg/day, and was 70.56% of the aPAD. The acute drinking water level of
concern (DWLOC) was calculated to be 658 ppb, and the model-predicted
acute EECs of 191 ppb for surface water and 0.12 ppb for groundwater are
less than this DWLOC. Therefore, acute aggregate exposure from
triflumizole is not expected to exceed the aPAD.

ii. Chronic Risk. In the August 23, 2006, Federal Register Notice, EPA
used a cPAD of 0.015 mg/kg/day. Since that time, Chemtura has
resubmitted documentation supporting a revised cPAD for Triflumizole of
0.035 mg/kg/day (MRID# 47136402). The chronic Population Adjusted Dose
(cPAD) of 0.035 mg/kg bw/day was based on the NOEL of 3.5 mg/kg/day from
the rat reproduction study, a 100x uncertainty factor, and a 1x FQPA
safety factor. The chronic dietary exposure to the general U.S.
population was 0.0130 mg/kg/day and was 37.3% of the cPAD. The chronic
dietary exposure to children (1-2 yrs) was 0.0147 mg/kg/day and 42.0% of
the cPAD. The chronic DWLOC was calculated to be 160 ppb, and the
model-predicted chronic EECs of 40 ppb for surface water and 0.12 ppb
for groundwater are less than this DWLOC. Therefore, chronic aggregate
exposure from triflumizole is not expected to exceed the cPAD.>

<	2. Infants and children. Acute dietary exposure to children (1-2 yrs)
was 0.1006 mg/kg/day and was 40.23% of the aPAD. The chronic dietary
exposure to children (3-5 yrs) was 0.0144 mg/kg/day and 41% of the
cPAD.>

<F. International Tolerances>

<	Maximum Residue Limits have been established for Chinese cabbage, kale
turnip greens and leafy greens in Japan at 1.0 ppm.>

