Study Title PRIVATE  

Publicly Releasable Summary of the Petition

for Establishment of a Tolerance for Novaluron in or on

Tomato, Tomato Paste, and Sugarcane

EPA Registration Action References

IR-4 Tolerance Petition

PP# 7E7199

Authors

Robert Everich, Ph.D

Bert Volger, Ph.D.

Document Date

March 19, 2007

Prepared by

Makhteshim-Agan of North America Inc.

4515 Falls of Neuse Road, 

Raleigh, NC 27609

Submitted by

IR-4 Project Headquarters

Rutgers, the State University of New Jersey

500 College Road East, Suite 201W

Princeton, NJ 08540



Interregional Research Project Number 4 (IR-4)

	

PP #7E7199

EPA has received a pesticide petition (PP # 7E7199) 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
(1-[3-chloro-4-(1,1,2-trifluoro-2-trifluoromethoxyethoxy)phenyl]-3-[2,6-
difluorobenzoyl]urea) in or on tomato at 0.40 parts per million (ppm);
tomato, paste at 0.80 ppm; and in or on sugarcane, cane at 0.50 ppm.
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 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 apple, cabbage, cotton, and
potato metabolism studies. 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), is available for enforcing tolerances of novaluron
residues in or on tomatoes, sugarcane and its processed commodities, as
published in the Federal Register of April 5, 2006 (Volume 71, Number
65; FRL-7756-8). Based on the sample size and dilution factors, the
limit of quantitation in matrix was equal to the lowest concentration
level for the validation analyses.  The method verification trial
supports a limit of quantitation (LOQ) of 0.05 ppm in the different
tomato and sugarcane matrices. The limit of quantitation (LOQ = 0.05
ppm) was taken as the lowest level validated by this method.

		3. 	Magnitude of Residues

	A total of 19 residue trials were conducted in tomatoes (including 4
greenhouse trials) during the 2004 season covering the major growing
areas in the NAFTA Regions. Novaluron was applied three times, following
a 6 to 9 day spray interval, using a maximum application rate of 0.086
lb active ingredient per acre (total of 0.254 lb a.i./A per season).
Whole fruit samples were harvested 1 to 2 days after the last
application. The average novaluron residues from these samples ranged
from less than 0.05 ppm (LOQ) to 0.365 ppm. The mean residue from all
treated whole fruit tomato trials was 0.107 ppm. The mean residue from
treated small-fruited variety trials was 0.255 ppm. Overall, the average
residues from field trials were similar to those from greenhouse trials,
with the exception of one greenhouse trial (average 0.365 ppm). Two
trials were conducted for the processing of whole tomatoes into tomato
puree and paste. Processed puree samples had significantly lower
residues than unprocessed samples, indicating that no concentration of
residues occurs. However, treated samples that were processed into
tomato paste resulted in higher residues than whole fruit tomatoes with
a maximum concentration factor of 1.9. 

	Concerning sugarcane, eight field residue trials were conducted
covering EPA Regions III (3 trials), IV (3 trials), VI (1 trial), and
XIII (1 trials) during the 2004 season. These locations are
representative of the major sugarcane production areas of the United
States. The application regime consisted of five applications at 8 to
12-day intervals, using a maximum of 0.078 lb active ingredient per acre
(total of 0.39 lb ai/A), and a pre-harvest interval of 10 to 14 days. 
One trial site was treated with 2X of the intended application rate
(0.157 lb ai/A), and sugarcane samples were collected for processing
into fractions of molasses and refined sugar. The treated sugarcane
samples were found to have average novaluron residues ranging from less
than 0.05 ppm to 0.293 ppm. There were no residues above the LOQ (0.05
ppm) in sugarcane molasses or refined sugar prepared from sugarcane
treated at the 1X or the 2X rate and harvested at 14 days after last
application. 

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 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 recently
published in the Federal Register of April 5, 2006 (Volume 71, Number
65; FRL-7756-8).  In addition to the existing tolerances, this Notice of
Filing includes exposure assessments for potential residues of novaluron
in or on tomatoes, tomato paste, and sugarcane. 

		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 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% and sugarcane =28%), 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. 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 4.0% to 22.8% of the cPAD. The most highly exposed
subpopulation, children aged 1-2 years, has an estimated total novaluron
exposure (0.002505 mg/kg/day) that is equal to 22.8% of the cPAD. The
estimated novaluron exposure for the general U.S. population (0.000700
mg/kg/day) is equivalent to 6.4% 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 6.4% of the cRfD, and the most sensitive
population subgroup (children 1 to 2 years old) utilizes 22.8% 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 22.8% 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, cane. Therefore, international harmonization is not an issue
at this time.

 

 

