Document ID: EPA-HQ-OPP-2008-0768-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-12-03T05:00Z

EPA Registration Division contact: Laura Nollen, (703) 305-7390

Interregional Research Project Number 4 (IR-4)

	

	Petition Numbers (PP#) 8E7425, 8E7426

EPA has received pesticide petitions (PP #) 8E7425 and 8E7426 from IR-4,
500 College Road East, Suite 201W, Princeton, NJ 08540,  proposing,
pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act,
21 U.S.C. 346a(d), to amend 40 CFR 180.598 by establishing a tolerance
for residues of novaluron
N-[[[3-chloro-4-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy]phenyl]amino
]carbonyl]-2,6-difluorobenzamide in or on Stone Fruit (Crop Group 12) at
8 parts per million (ppm) (PP# 8E7426), Bushberries (Subgroup 13-07B) at
7 ppm (PP# 8E7425), Leafy Brassica (Subgroup 5B) at 25 ppm (PP# 8E7426),
Turnip Greens at 25 ppm (PP# 8E7426), and by increasing a tolerance for
residues of novaluron on egg from 0.05 to 0.07 parts per million (ppm)
(PP# 8E7426). Makhteshim-Agan of North America, Inc., 4515 Falls of
Neuse Road, Raleigh, NC 27609, is the manufacturer and basic registrant
of novaluron. Makhteshim-Agan of North America, Inc., prepared and
summarized the following information in support of the subject pesticide
petition for novaluron. EPA has determined that the petition contains
data or information regarding the elements set forth in section
408(d)(2) of the FFDCA. 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 qualitative nature of the residue of novaluron in plants is
adequately understood based on acceptable plant metabolism studies
reflecting its uses on apples, cabbage, cotton, and potatoes. These
plant metabolism studies have demonstrated that novaluron does not
metabolize and is non-systemic (does not translocate within the plant).
The results observed in the plant and livestock metabolism studies show
similar metabolic pathways. The residue of concern, which should be
regulated, is the parent compound, novaluron, only. 			

		

2.	Analytical Method

	An adequate analytical method, gas chromatography/electron capture
detector (GC/ECD), as published in the Federal Register of April 5, 2006
(Volume 71, Number 65; FRL-7756-8), is available for enforcing
tolerances of novaluron residues in or on stone fruit, bushberries,
leafy brassica and turnip greens. The method verification trial supports
a limit of quantitation (LOQ) of 0.05 ppm, and the limit of detection
(LOD) is 0.005 ppm for the different matrices. The limit of quantitation
(LOQ = 0.05 ppm) was taken as the lowest level validated by this method.
   

		3. 	Magnitude of Residues

i.     Stone Fruit:  A total of 32 residue trials were conducted in
cherries, peaches and plums during the 2005 and 2006 season covering the
major growing areas in the NAFTA Regions. The supported use pattern on
all stone fruit crops is a maximum of three foliar applications at a
maximum rate of  50 fl. oz product/A, or 0.32 lb ai/A, for a total
seasonal application of approximately 0.96 lb ai/A , and a pre-harvest
interval (PHI) of 7 days.  The proposed tolerance for the stone fruit
crop group (#12) is 8 ppm.  Additional crop-specific details are as
follows:

Cherries:  Seven field trials were conducted at the supported use
pattern covering NAFTA Regions I (1 trial), V (3 trials), X (1 trial),
and XII (1 trial).  Measured novaluron residues range from 0.74 ppm to
4.08 ppm, with an average residue of 2.17 ppm.  The estimated tolerance
for cherries only is 8 ppm using the MRL calculator.

Peaches:  Fifteen field trials were conducted at the supported use
pattern covering NAFTA Regions I (1 trial), II (5 trials), V (4 trials),
VI (1 trial), X (4 trials), and XI (1 trial). Measured novaluron
residues range from 0.18 ppm to 2.10 ppm, with an average residue of
0.61 ppm.  The estimated tolerance for peaches only is 1.8 ppm using the
MRL calculator.

Plums:  Ten field trials were conducted at the supported use pattern
covering NAFTA Regions I (1 trial), V (3 trials), X (5 trials), XI (1
trial), and XII (1 trial).  Measured novaluron residues range from 0.08
ppm to 0.80 ppm, with an average residue of 0.40 ppm.  The estimated
tolerance for plums only is 1.9 ppm using the MRL calculator.  Dried
plums from one trial in California had an estimated, maximum
concentration factor for novaluron residues of 3.39.

Bushberries:  A total of nine field trials were conducted with
blueberries covering NAFTA Growing Regions I (1 trial), II (4 trials), V
(3 trials), and XII (1 trial) during the 2005 season. The supported use
pattern consists of three applications, at a maximum rate of  30 fl. oz
product/A, or 0.194 lb ai/A, for a total seasonal rate of 0.58 lb ai/A,
and a PHI of 7 days.  Measured novaluron residues range from 0.61 ppm to
3.81 ppm, with an average residue of 1.97 ppm. The proposed tolerance
for the bushberry crop group (#13B) is 7 ppm.

Leafy Brassica and Turnip Greens:  A total of eleven field trials were
conducted with mustard greens in support of the proposed tolerance for
the leafy brassica crop group (5B) and turnip greens. The field trials
were conducted during the 2005 season covering NAFTA Regions II (3
trials), III (1 trial), IV (1 trial), V (2 trials), VI (1 trial), X (2
trial) , XII (1 trial) at the supported use pattern of three foliar
applications at a maximum rate of  12 fl. oz product/A, or  0.078 lb
ai/A, for a total seasonal rate of 0.23 lb ai/A, and a PHI of 3 days. 
Measured novaluron residues range from 1.39 ppm to 18.54 ppm, with an
average residue of 5.41 ppm. The proposed tolerance for the leafy
brassica crop group (5B) and turnip greens is 25 ppm.  

B.	 Toxicological Profile

	1.   	Acute Toxicity

In an acute oral toxicity study in rats, novaluron had an LD50 >5,000
mg/kg.  A dermal toxicity study in rats resulted in an LD50 greater than
2,000 mg/kg.  The LC50 for acute inhalation in rats was greater than
5.15 mg/l.  In rabbits, novaluron is not a skin irritant, but it is a
mild eye irritant.  Novaluron is not a sensitizer in guinea pigs.

		2.	  Genotoxicity

The mutagenic potential of Novaluron was investigated in several in vivo
and in vitro studies.  Results in two Ames assays, an in vivo mouse
micronucleus assay, an in vitro unscheduled DNA synthesis (UDS) assay,
an in vitro cell mutation assay, and an in vitro human lymphocyte
clastogenicity test were negative.  Novaluron is therefore considered to
have no potential to induce mutagenicity.

		3.     Reproductive and Developmental Toxicity

	i.   A two generation rat reproduction study was conducted with dose
levels of 1,000, 4,000, and 12,000 ppm (74.2, 297.5, 894.9 mg/kg/day,
and 84, 336.7, 1,009.8 mg/kg/day for males and females, respectively). 
Maternal and offspring toxicity was evidenced by increased absolute and
relative spleen weights, whereas reproductive toxicity was observed only
in males at 297.5 mg/kg/day (LOAEL) based on decreased epididymal sperm
counts and increased age at preputial separation in the F1 generation.
The no observed adverse effect level (NOAEL) in males was 1,000 ppm
(74.2 mg/kg/day) and in females it was $12,000 ppm (1,009.8 mg/kg/day).

	ii.    Teratology studies were conducted in the rat and rabbit.  No
treatment-related mortalities were observed in either study.  No effect
on survival, development or growth of fetuses was noted in either
species in either study.  No maternal or developmental toxicity was
observed up to and including the limit dose of 1,000 mg/kg/day (NOAEL).
These two studies demonstrate that novaluron was not teratogenic in
either rats or rabbits. 

		4.	Subchronic Toxicity

Rats, mice and dogs all show the same toxicologic response.  Generally, 
 novaluron induces small increases in methemoglobin; red cells are   
sequestered; and, compensatory hematopoiesis occurs.  The severity of
these changes is well within the physiological capacity of the animals
and is judged   not adverse.

Rats treated topically with novaluron in a 28-day study at 0, 75, 400
and 1,000 mg/kg/day did not show signs of systemic toxicity.  Small
treatment-related increases in methemoglobin were seen in both sexes at
1,000 mg/kg/day and in females at 400 mg/kg/day.  The highest
methemoglobin value seen in females was 1.28% compared with 0.86% in
controls.  Organ weights, macroscopic and microscopic examination of
organs and tissues did not reveal any treatment-related changes.

	

Two 13-week rat studies were conducted.  In one study, doses were
administered at 50, 100, 200, 400 ppm (3.52, 6.93, 13.83, 27.77
mg/kg/day and 4.38, 8.64, 17.54 and 34.39 mg/kg/day for males and
females, respectively). The LOAELs from the combined results were 27.77
mg/kg/day in males based on increased occurrence of extramedullary
hematopoiesis and hemosiderosis in spleen; and 8.64 mg/kg/day in females
based on reduction in hemoglobin, hematocrit and RBC count; increased
occurrence of extramedullary hematopoiesis and hemosiderosis in spleen
and liver.  The NOAEL was determined to be 4.38 mg/kg/day.  

A 13-week mouse study was conducted with dose levels of 30, 100, 1,000,
10,000 ppm (4.2, 12.8, 135.9, 1,391.9 and 4.7, 15.2, 135.6, 1,493.1
mg/kg/day, for males and females, respectively).  The NOAEL was
determined to be 100 ppm (12.8 and 15.2 mg/kg/day, male and females,
respectively).  The LOAEL was 1,000 ppm (135.9 and 135.6 mg/kg/day,
males and females, respectively) based on increased body weight gain,
low erythrocyte counts, and secondary splenic changes.  There were no
clinical treatment-related signs noted.

Two 13-week dog studies were conducted.   One study resulted in an NOAEL
of 100 mg/kg/day and a LOAEL of 300 mg/kg/day based on low erythrocyte
counts and secondary splenic and liver changes.  No clinical
treatment-related signs were noted.  Another study, was conducted using
only one dose level of 10 mg/kg/day.  There were no clinical or
histopathological treatment-related signs and the NOEL was determined to
be 10 mg/kg/day.

		5.	Chronic Toxicity

	i.    Chronic toxicity and oncogenicity was evaluated in the rat, mouse
and dog.  The rat chronic toxicity and oncogenicity was conducted with
dose levels of 25, 700, 20,000 ppm (1.1, 30.6, 884.2 and 1.4, 39.5,
1,113.5 mg/kg/day for males and females, respectively).  The LOAEL in
male and female rats was 30.6 and 39.5 mg/kg/day, respectively, based on
evidence of erythrocyte damage and turnover resulting in a regenerative
anemia in both sexes. The corresponding NOAEL was 25 ppm (1.1 and 1.4
mg/kg/day for male and female rats, respectively). There was no evidence
of carcinogenicity in this study.  A mouse chronic toxicity study was
conducted with dose levels of 30, 450, 7,000 ppm (3.6, 53.4, 800.0 and
4.3, 63.3, 913.4 mg/kg/day for males and females, respectively).  The
LOAEL in male and female mice was 53.4 and 63.3 mg/kg/day, respectively,
based on erythrocyte turnover due to hemoglobin oxidation and resulting
in a compensated anemia. The corresponding NOAEL was 30 ppm (3.6 and 4.3
mg/kg/day for male and female mice, respectively). There was also no
evidence of carcinogenicity in this study.  Chronic toxicity was
investigated in dogs using dose levels of 10, 100, 1,000 mg/kg/day.  The
NOAEL of 100 mg/kg/day was based on methemoglobin.

		ii.  	The chronic reference dose (cRfD) of 0.011 mg/kg/day has been
established on the basis of the chronic carcinogenicity study in rats.
An uncertainty factor (UF) of 100 was applied to the NOAEL of 1.1
mg/kg/day for male rats deriving to the cRfD. 

 		iii. 	 In accordance with the EPA Draft Guidelines for Carcinogen
Risk Assessment (July 1999), novaluron is classified as not likely to be
carcinogenic to humans due to results of oncogenicity studies that show
no evidence of carcinogenicity in rats and mice.  

		6.	Animal Metabolism

Metabolism studies in rats and goats were conducted with the parent
material labeled in both the difluorophenyl and chlorophenyl moieties.
Rats absorb little novaluron when it is administered orally.  More than
90% of the dietary administered [chlorophenyl 14C(U)] novaluron is
recovered in the feces.  When the diflurophenyl ring of the molecule is
labeled, the recovered 14C activity in the feces is lower but still
above 75%.  The difference is thought to reflect intestinal metabolism
by microbial flora and the higher absorption of the diflurophenyl
metabolites.

The parent molecule as well as its degradates are absorbed from the
gastrointestinal tract.  All parent material is metabolized either upon
initial entry into the systemic circulation or, if sequestered to the
fat, upon its depuration back to the systemic circulation.  There is no
intact novaluron found in the urine. Novaluron=s high octanol-water
partition coefficient is responsible for its preferential movement to
fat.  The half-life in fat calculated from the rat metabolism study is
approximately 55 hours.

Two groups of metabolites are formed after oral administration of
novaluron.  One group is typified by the aniline metabolite
3-chloro-4-(1,1,2-trifluoro-2-trifluoromethoxyethoxy) aniline, referred
to as 3-TFA.  The other group of metabolites is typified by
2,6-difluorobenzoic acid is from the diflurophenyl moiety of the
molecule.  Nearly all the metabolites are formed at a level of 1% or
less of the applied dose.  They are rapidly excreted.

The metabolism in goats and hens mimics that seen in rats.

	7.     Metabolite Toxicology

   

Makhteshim-Agan of North America Inc., has determined that there are no
metabolites of toxicological concern and therefore, no metabolites need
to be included in the tolerance expression and require regulation. For
drinking water assessment the soil degradates, chlorophenyl urea and
chloroaniline will be included besides the parent, novaluron. 

 		

8.      Endocrine Disruption

   	

No special studies investigating potential estrogenic or other endocrine
effects of novaluron have been conducted.  However, inspection of
in-life data from toxicology studies does not indicate that novaluron is
an endocrine disruptor.  Specifically, endocrine organ weights (e.g.,
thyroid, testes, ovaries, pituitary from the two-generation study) were
not adversely affected by novaluron.  Milestones of sexual development
were not affected by novaluron; and, reproduction was not adversely
affected.  Based on these observations, there is no evidence to suggest
that novaluron has an adverse effect on the endocrine system. 

C.   Aggregate Exposure

	1.	Dietary Exposure

Tolerances have been established (40 CFR 180.598) for the residues of
novaluron, in or on the following raw agricultural commodities: Apple,
wet pomace at 8.0; cattle, fat at 11 ppm; cattle, kidney at 1.0 ppm;
cattle, liver at 1.0 ppm; cattle, meat at 0.60 ppm; cattle, meat
byproducts, except liver and kidney at 0.60 ppm; cotton, gin byproducts
at 30 ppm; cotton, undelinted seed at 0.60 ppm; eggs at 0.05 ppm; fruit,
pome, group 11 at 2.0 ppm; goat, fat at 11 ppm; goat, kidney at 1.0 ppm;
goat, liver at 1.0 ppm; goat, meat at 0.60 ppm; goat, meat byproducts
except liver and kidney at 0.60 ppm; hog, fat at 0.05 ppm; hog, meat at
0.01 ppm; hog, meat byproducts at 0.01 ppm; horse, fat at 11 ppm; horse,
kidney at 1.0 ppm; horse, liver at 1.0 ppm; horse, meat at 0.60 ppm;
horse, meat byproducts, except liver and kidney at 0.60 ppm; milk at 1.0
ppm; milk, fat at 20 ppm; poultry, fat at 0.40 ppm; poultry, meat at
0.03 ppm; poultry, meat byproducts at 0.04 ppm; sheep, fat at 11 ppm;
sheep, kidney at 1.0 ppm; sheep, liver at 1.0 ppm; sheep, meat at 0.60
ppm; sheep, meat byproducts, except liver and kidney at 0.60 ppm, and
vegetables, tuberous and corn, subgroup 1C at 0.05 ppm, as published in
the Federal Register of April 5, 2006 (Volume 71, Number 65;
FRL-7756-8).

EPA is presently reviewing the petition PP#7E7199 concerning the pending
tolerances of novaluron on sugarcane and tomatoes.  The average residues
in sugarcane are 0.125 ppm, and in molasses 0.24 ppm.  Residues in
refined sugar are below the LOD (0.005 ppm).  Assuming residues present
at the LOD, the average processing factor for refined sugar is 0.15.  As
for the pending use on tomatoes, EPA has calculated processing factors
of <0.7 for tomato puree, and 1.1 for tomato paste.  The information
from the EPA petition for sugarcane and tomatoes was incorporated into
this dietary assessment.

In addition to the existing tolerances, this Notice of Filing includes
exposure assessments for potential residues of novaluron in or on
tomatoes, sugarcane, stone fruit, bushberries, leafy brassica and turnip
greens. Average residues from field trials were assumed in the dietary
exposure assessment (see previous section).  An empirical processing
factor of 3.39 was calculated using data from a processing trial for
dried plums.  Otherwise, all DEEM default processing factors were used
for juices, dried fruit, etc. among stone fruit and bushberries.

		i. 	Food

		a.   Acute Dietary Exposure. No toxicological endpoint attributable to
a single exposure was identified in the available toxicology studies,
including the rat and rabbit developmental studies.  Therefore, the
acute aggregate risk is negligible.

	

b.     Chronic Dietary Exposure.  A chronic dietary risk assessment was
conducted using the Dietary Exposure Evaluation Model (DEEM) software
with the Food Commodity Intake Database (DEEM-FCIDTM Version 2.16),
which incorporates consumption data derived from the 1994 - 1998 USDA
Continuing Surveys of Food Intake by Individuals (CSFII). The assessment
included all uses (existing, pending and proposed), assuming provided
percent crop treated estimates at market maturity [apples (30%), pears
(50%), head and stem brassica (30%), tuberous and corm vegetables (18%),
cotton (12%), tomatoes (15%), sugarcane (28%), stone fruit (20%),
bushberries (15%), leafy brassica (20%), turnip greens (15%)] average
field residues, anticipated residues for meat and milk products with the
exception for cotton seed commodities and poultry, for which
tolerance-level residues were assumed. An empirical processing factor of
3.39 was calculated using data from a processing trial for dried plums. 
Otherwise, all DEEM default processing factors were used for juices,
dried fruit, etc. among stone fruit and bushberries.

The appropriate cRfD value for novaluron is 0.011 mg/kg/day, based upon
the NOAEL of 1.1 mg/kg/day from the chronic carcinogenicity study in
rats, and an UF of 100. The chronic dietary exposures account for 7.0%
to 24.4% of the cPAD. The most highly exposed subpopulation, children
aged 1-2 years, has an estimated total novaluron exposure of 0.00268
mg/kg/day), equal to 24.4% of the cPAD. The estimated novaluron exposure
for the general U.S. population (0.000766 mg/kg/day) is equivalent to
7.0% of the cPAD. 

c.     Novaluron was classified as “not likely to be carcinogenic to
humans.''. Therefore, a quantitative cancer risk assessment was not
conducted. 

	

ii.     Drinking Water

		a. 	Acute Exposure. Since no acute dietary endpoint was determined,
Makhteshim-Agan of North America, Inc., concludes there is reasonable
certainty of no harm from acute drinking water exposure.

   

b.    Chronic Exposure. 

There are no monitoring data for novaluron to complete a comprehensive
risk assessment for novaluron in drinking water. Therefore, the
Pesticide Root Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS,
Tier 2 model) was used for the concentration of novaluron (parent) in
surface water, the Food Quality Protection Act (FQPA) Index Reservoir
Screening Tool (FIRST, Tier I model) was used to estimate surface water
concentrations of the chlorophenyl urea and chloroaniline degradates. 
For “Screening Concentrations In Ground Water” the SCI-GROW model
was used, assuming that novaluron may reach the surface or the ground
water via the parent compound or via the its degradates. The modeling
represents upper-bound estimates based on the environmental
characteristics and associated modeling parameters, which are designed
to provide conservative, health protective, high-end estimates of water
concentrations, which will not likely be exceeded. Chronic estimates for
the terminal degradate, chloroaniline, represent the worst case,
assuming 100% conversion of the parent compound. Based on the use of
novaluron on apples (highest application rate among all uses), the
calculated EECs of novaluron derived from these models are 2.61 parts
per billion (ppb) for surface water and 0.009 ppb for ground water. The
chronic dietary exposure assessment includes as the worst case the
annual average concentration of 2.61 ppb in surface water.

		2.	Non-Dietary Exposure

	Presently and in the future, novaluron is not considered for
residential uses. Novaluron is not registered for use on any sites that
would result in residential exposure. The term “residential exposure''
refers to non-occupational, non-dietary exposure (e.g., for lawn and
garden pest control, indoor pest control, termiticides, and flea and
tick control on pets). Therefore, there is no non-dietary exposure
(acute, short-term, intermediate-term or chronic).

   

D.	Cumulative Effects

To Makhteshim-Agan of North America’s Inc., knowledge, there are
currently no available data or other reliable information indicating
that any toxic effects produced by novaluron would be cumulative with
those of other chemical compounds; thus only the potential risks of
novaluron have been considered in this assessment of its aggregate
exposure.

	

E.	 Safety Determination

   	1.     U.S. Population

No acute aggregate risk assessment was conducted because there is no
toxicological endpoint attributable to a single exposure.  Short- and
intermediate-term aggregate risk assessments were not performed because
of no current or future residential uses. No cancer aggregate risk
assessment was conducted because novaluron has not been shown to be
carcinogenic.  Therefore, only a chronic aggregate risk assessment was
performed based on potential exposure from food and drinking water,
considering all existing and proposed uses.  The chronic exposure of the
U.S. population utilizes 7% of the cRfD, and the most sensitive
population subgroup (children 1 to 2 years old) utilizes 24.4% of the
cRfD.  In view of these assessments, Makhteshim-Agan of North America
Inc., concludes that there is reasonable certainty that no harm will
result from the proposed uses of novaluron.		

		2.	 Infants and Children

Section 408 of FFDCA provides that EPA may apply an additional safety
factor for infants and children to account for prenatal and postnatal
toxicity and the completeness of the database. The toxicology database
for novaluron is complete including acceptable data from rat and rabbit
developmental toxicity studies and a two generation rat reproduction
study that have been used to assess the potential for increased
sensitivity of infants and children. The data provided no quantitative
or qualitative evidence of increased susceptibility of rats or rabbits
to in utero and/or postnatal exposure to novaluron. In addition there is
no concern for developmental neurotoxicity resulting from exposure to
novaluron, and a developmental neurotoxicity study is not required.
Therefore, the Agency determined in its recent review to reduce the FQPA
Safety Factor to 1X (Federal Register of June 2, 2004; 69 FR 31013;
FRL-7359-2). Thus, the chronic population adjusted dose (cPAD) is
considered 0.011 mg/kg/day. The DEEM analysis regarding the aggregate
chronic exposure calculations utilizes less than 24.4% of the cPAD for
the most sensitive subgroup, children 1 to 2 years old. Therefore,
Makhteshim-Agan of North America Inc., concludes that there is
reasonable certainty that no harm will result to infants and children
from aggregate exposure to novaluron residues.

	

F.	International Residue Limits

At present, there are no Canadian, Mexican, or Codex maximum residue
limits (MRLs) established for novaluron on tomato, tomato paste, and
sugarcane. Therefore, international harmonization is not an issue at
this time.