Document ID: EPA-HQ-OPP-2007-0438-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-12-10T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF                  

PREVENTION, PESTICIDES AND 

TOXIC SUBSTANCES        

MEMORANDUM

DATE:		25-FEB-2008

SUBJECT:	PP#7E7199.  Novaluron in/on Sugarcane and Tomato.  Health
Effects Division (HED) Risk Assessment.  DP#: 347661.  PC Code: 124002. 
Decision#: 379033.

FROM:	George F. Kramer, Ph.D., Senior Chemist

Mary Clock-Rust, Biologist

P.V. Shah, Ph.D., Branch Senior Scientist

Registration Action Branch 1 (RAB1)/HED (7509P)

THROUGH:	Dana M. Vogel, Branch Chief

RAB1/HED (7509P)

TO:		Daniel Rosenblatt (PM Team 05)

Registration Division (RD; 7505P)

The HED of the Office of Pesticide Programs (OPP) is charged with
estimating the risk to human health from exposure to pesticides.  The RD
of OPP has requested that HED evaluate hazard and exposure data and
conduct dietary, occupational, residential, and aggregate exposure
assessments, as needed, to estimate the risk to human health that will
result from all registered and proposed uses of novaluron
(N-[[[3-chloro-4-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy]
phenyl]amino]carbonyl]-2,6-difluorobenzamide).  A summary of the
findings and an assessment of human risk resulting from the registered
and proposed uses for novaluron are provided in this document.  The risk
assessment, residue chemistry data review, and dietary risk assessment
were provided by George Kramer (RAB1), the hazard characterization by
P.V. Shah (RAB1), the occupational/residential exposure assessment by
Mary Clock-Rust (RAB1), and the drinking water assessment by Iwona Maher
of the Environmental Fate and Effects Division (EFED).

NOTE:  HED completed a Section 3 risk assessment for the use of
novaluron in/on Brassica, head and stem, subgroup 5A (Memo, S. Levy, et
al., 03-NOV-2005; DP# 313322).  This document contains only those
aspects of the risk assessment which are affected by the addition of the
proposed novaluron uses.

Recommendation for Tolerances and Registration 

The HED Hazard Identification Assessment Review Committee (HIARC)
requested a 28-day inhalation toxicity study as a condition of
registration.  However, based on the low volatility and low inhalation
toxicity (Toxicity Category IV) of novaluron and inhalation margins of
exposure (MOEs) >1000 for the proposed uses in this risk assessment,
novaluron qualifies for a waiver of the 28-day inhalation toxicity study
for the proposed uses [HED Standard Operating Procedure (SOP) 2002.01:
Guidance: Waiver Criteria for Multiple-Exposure Inhalation Toxicity
Studies, 15-AUG-2002].  The requirement for the 28-day inhalation
toxicity study is waived for this action only.  If in the future,
requests for new uses or formulations are submitted that may result in a
significant change in either the toxicity profile or exposure scenarios,
HED will reconsider this data requirement.

Provided revised Sections B and F are submitted, HED concludes that the
toxicological and residue chemistry databases, as well as the aggregate
and occupational risk assessments, support conditional registration of
the requested new uses and establishment of the following permanent
tolerances for residues of novaluron per se as follows:

Sugarcane, cane	0.50 ppm

Tomato	1.0 ppm

HED recommends that conversion of conditional registration to
unconditional registration may be considered upon submission of the
following residue chemistry data:

860.1340 Residue Analytical Methods

As initially requested in PP#4E6834 (DP# 325183, 8/23/06, S. Levy), an
interference study for the plant method is required to determine whether
other pesticides registered on the same commodities interfere with the
determination of novaluron; an interference study may be waived if a
specific single-analyte confirmatory method is submitted.  

860.1520 Processed Food and Feed

A sugarcane processing study conducted at an exaggerated rate (up to 5x)
is required in attempts to achieve quantifiable residues in the raw
agricultural commodity (RAC) and to demonstrate the possible potential
for concentration with processing.

Note to RD:  The preferred chemical name for novaluron is
N-[[[3-chloro-4-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy]phenyl]amino
]carbonyl]-2,6-difluorobenzamide.  40 CFR §180.598 should be revised
accordingly.  It is also noted that 40 CFR 180.598 should be amended to
correct the commodity “Vegetables, tuberous and corn, subgroup 1C”
to “Vegetable, tuberous and corm, subgroup 1C.”

Table of Contents

  TOC \f  1.0  EXECUTIVE SUMMARY	  PAGEREF _Toc191697350 \h  4 

2.0  PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION	  PAGEREF
_Toc191697351 \h  8 

3.0  HAZARD CHARACTERIZATION	  PAGEREF _Toc191697352 \h  9 

3.1	FQPA Considerations	  PAGEREF _Toc191697353 \h  9 

3.2	Endocrine Disruption	  PAGEREF _Toc191697354 \h  11 

4.0  EXPOSURE ASSESSMENT	  PAGEREF _Toc191697355 \h  12 

4.1	Summary of Proposed Uses	  PAGEREF _Toc191697356 \h  12 

4.2	Dietary Exposure/Risk Pathway	  PAGEREF _Toc191697357 \h  13 

4.3	Water Exposure and Risk Pathway	  PAGEREF _Toc191697358 \h  16 

4.4	Dietary-Exposure Analysis	  PAGEREF _Toc191697359 \h  17 

4.5	Residential Exposure and Risk Pathway	  PAGEREF _Toc191697360 \h  18

5.0  AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION	  PAGEREF
_Toc191697361 \h  18 

6.0  CUMULATIVE RISK	  PAGEREF _Toc191697362 \h  18 

7.0  OCCUPATIONAL EXPOSURE	  PAGEREF _Toc191697363 \h  19 

7.1	Occupational Handler	  PAGEREF _Toc191697364 \h  19 

7.2	Occupational Postapplication	  PAGEREF _Toc191697365 \h  21 

7.3	Incident Data	  PAGEREF _Toc191697366 \h  22 

8.0  DATA NEEDS/LABEL REQUIREMENTS	  PAGEREF _Toc191697367 \h  22 

8.1	Toxicology	  PAGEREF _Toc191697368 \h  22 

8.2	Residue Chemistry	  PAGEREF _Toc191697369 \h  23 

8.3	Occupational/Residential Exposure	  PAGEREF _Toc191697370 \h  23 

Attachment:  Toxicity Profile of Novaluron	  PAGEREF _Toc191697371 \h 
24 

 1.0	EXECUTIVE SUMMARY tc \l1 "1.0	EXECUTIVE SUMMARY 

Under Section 3 of the Federal Insecticide, Fungicide and Rodenticide
Act (FIFRA), as amended, Interregional Research Project No. 4 (IR-4) has
applied for registration of the active insecticidal ingredient novaluron
for use on tomato and sugarcane.  Novaluron is currently registered for
use on cotton; pome fruit; vegetables, tuberous and corm, group 1C; and
greenhouse/shadehouse grown ornamental plants.  Novaluron tolerances
have been established in 40 CFR §180.598 for plant and livestock
commodities and are expressed in terms of novaluron per se.  All uses
for novaluron, either proposed or existing, are agricultural or
commercial in nature.  No residential uses are registered or proposed,
nor are any of the uses expected to result in residential exposure.

Novaluron, a benzoylphenyl urea compound, is a pesticide chemical
belonging to the class of insecticides called insect growth regulators. 
Novaluron slowly kills the insects over a period of a few days by
disrupting cuticle formation and deposition causing insect mortality
during molting.  This memorandum serves as HED’s estimate of exposure
and risk resulting from the proposed uses.

Hazard Characterization

The toxicological database for novaluron is adequate to support Section
3 registration and permanent tolerances.

Novaluron has low acute toxicity via the oral (Toxicity Category IV),
dermal (Toxicity Category III) and inhalation routes (Toxicity Category
IV).  No ocular (Toxicity Category IV) or dermal irritation (Toxicity
Category IV) was noted.  Novaluron is not a dermal sensitizer. 

In subchronic and chronic toxicity studies, novaluron primarily produced
hematotoxic effects such as methemoglobinemia, decreased hemoglobin,
decreased hematocrit, decreased red blood corpuscles (RBCs or
erythrocytes) associated with increased erythropoiesis.

The rat and rabbit developmental toxicity studies were tested up to the
limit doses that produced no maternal and/or developmental toxicity.  In
the two-generation reproductive toxicity study, both maternal and
offspring toxicity were evidenced by spleenomegaly, whereas reproductive
toxicity was observed only in males as evidenced by decreases in
epididymal sperm counts and increased age at preputial separation in the
F1 generation.

Acute/subchronic neurotoxicity screening batteries were performed using
novaluron in rats.  Neurotoxic effects of novaluron were evidenced by
clinical signs (piloerection, fast/irregular breathing), functional
observation battery (FOB) parameters (head swaying, abnormal gait) and
neuropathology (sciatic and tibial nerve degeneration only at limit dose
(2000 mg/kg/day).  No signs of neurotoxicity or neuropathology were
observed in the subchronic neurotoxicity study in rats at doses up to
1752 mg/kg/day in males and 2000 mg/kg/day in females.  Therefore, the
HED HIARC concluded that there is not a concern for neurotoxicity
resulting from exposure to novaluron.

There was no concern for mutagenic activity as indicated by several
mutagenicity studies such as a bacterial (Salmonella, E. coli) reverse
mutation assay, an in vitro mammalian chromosomal aberration assay, an
in vivo mouse bone-marrow micronucleus assay and bacterial DNA damage or
repair assay.  There was no evidence of carcinogenic potential in either
the rat or mouse carcinogenicity studies.  

Dose Response and Endpoint Selection

The oral acute reference dose (aRfD) for the general population,
including infants and children, was not established since an endpoint of
concern attributable to a single dose was not identified.  

The chronic reference dose (cRfD) of 0.011 mg/kg/day was determined on
the basis of the chronic carcinogenicity study in the rat.  An
uncertainty factor (UF) of 100 (10-fold for interspecies extrapolation
and 10-fold for intraspecies variability) was applied to the
no-observed-adverse-effect-level (NOAEL) of 1.1 mg/kg/day to derive the
cRfD.  The lowest-observed-adverse-effect- level (LOAEL) of 30.6
mg/kg/day was based on evidence of red blood corpuscle (RBC) damage and
turnover resulting in a regenerative anemia.  The Food Quality
Protection Act (FQPA) Safety Factor (SF) of 1X is applicable for chronic
dietary risk assessment. Therefore, the chronic population-adjusted dose
(cPAD) is 0.011 mg/kg/day.

In accordance with the EPA Draft Guidelines for Carcinogen Risk
Assessment (JUL-1999), novaluron is classified as “not likely to be
carcinogenic to humans” based on the lack of evidence for
carcinogenicity in mice and rats.

The RAB1 toxicologists reevaluated the novaluron database and concluded
that the FQPA safety factor for increased susceptibility of infants and
children can be reduced to 1X since there are no residual uncertainties
for pre- and/or post-natal toxicity.  The decision was based on a lack
of increased susceptibility in the rat and/or rabbit developmental
toxicity studies at levels up to the limit dose.  Also, no increased
qualitative and/or quantitative evidence of increased susceptibility was
found following pre/post-natal exposure in a 2-generation reproduction
study in rats.  This conclusion was in agreement with the previous
conclusions by the HIARC (16-Dec-2003, TXR # 0052361).  The risk
assessment team concluded the FQPA safety factor for increased
susceptibility of infants and children can be reduced to 1X based on
toxicological considerations (above), the conservative residue
assumptions used in the dietary and residential exposure risk
assessments, and the completeness of the residue chemistry database and
conservative drinking water assessment.  RAB1 toxicologists also
reaffirmed the endpoints previously selected by the HIARC (16-DEC-2003;
TXR # 0052361).

A 10% dermal-absorption factor was based on an acceptable
dermal-absorption study in rats in which the maximum total absorbed dose
(expressed as percent of administered dose) ranged from approximately
0.5% to 10% of the applied dose.  The level of concern (LOC) for
residential dermal exposures and occupational dermal and inhalation
exposures are for MOEs <100.  Endpoints applicable to risk assessments
performed for novaluron in this document are summarized in the table
below.



Exposure Scenario	

Dose	

Endpoint	

Study/Effect

Chronic dietary	

NOAEL = 1.1 mg/kg/day	

cRfD and cPAD = 0.011 mg/kg/day	

Combined chronic toxicity/carcinogenicity feeding study-rat-Erythrocyte
damage and turnover resulting in a regenerative anemia at the LOAEL of
30.6 mg/kg/day. 

Intermediate-term dermal

(10% absorption rate)	

NOAEL = 4.38 mg/kg/day	

Target MOE = 100 (occupational)	90-day feeding study-rat-clinical
chemistry and histopathology at the LOAEL of 8.64 mg/kg/day.

Short-term inhalation

	

Intermediate-term inhalation

	

Chronic Dietary Exposure Estimate

A chronic dietary risk assessment was conducted using the Dietary
Exposure Evaluation Model software with the Food Commodity Intake
Database (DEEM-FCID(, Version 2.03).  The chronic dietary assessment
conducted, was an update of the previous dietary assessment conducted in
2005; i.e., average field trial residue values for the commodities
associated with this action and empirical processing factors for tomato
purée and paste were added to the last dietary assessment.  Estimated
drinking water concentrations (EDWCs), provided by EFED, were included
in this assessment as well.  In the last dietary assessment, the chronic
analysis assumed 100% crop treated for all commodities; incorporated
average field trial residues; empirical processing factors for apple
juice (translated to pear juice); and DEEM( (ver 7.76) default
processing factors for the remaining processed commodities. 
Furthermore, anticipated residues (ARs) were calculated for meat and
milk commodities and HED-recommended tolerances were used for poultry
commodities (partially refined, Tier 2 analysis).  For this action, the
resulting food risk estimates were not of concern to HED ((74% cPAD);
children 1-2 years old were the most highly exposed population subgroup.
 

Drinking Water Estimates

Concentrations of novaluron and its chlorophenyl urea and chloroaniline
degradates in surface water and ground water were estimated by EFED
using modeling.  Tier 2 Pesticide Root Zone Model/Exposure Analysis
Modeling System (PRZM/EXAMS) modeling was performed to estimate drinking
water concentrations for novaluron (parent) in surface water.  Tier 1
modeling (FQPA Index Reservoir Screening Tool (FIRST)) was used to
estimate concentrations of the chlorophenyl urea and chloroaniline
degradates in surface water.  For ground water, the Screening
Concentration in Ground Water (SCI-GROW) model was used to predict
ground water concentrations for novaluron and the chlorophenyl urea and
chloroaniline degradates.  Drinking water estimates from EFED are meant
to represent upper-bound estimates of the concentrations that might be
found in surface water and ground water based upon existing and proposed
uses.  Chronic estimates for the terminal degradate, chloroaniline, are
the highest (2.61 ppb).  This is consistent with the expected
degradation pattern for novaluron.  Therefore, the EDWC value for
chloroaniline was used to assess chronic aggregate risk. 

Aggregate Exposure Scenarios and Risk Conclusions

Including all existing and proposed uses, human-health risk assessments
have been conducted for the following exposure scenario only:  chronic
dietary exposures (food + water).  The chronic aggregate exposure and
risk estimate is below HED’s level of concern.  Because there are no
uses of novaluron that could result in residential exposures, this
aggregate risk assessment takes into consideration dietary food + water
exposure only.

Occupational Exposure Estimates

Handler:  Based on the proposed use patterns, HED expects the most
highly-exposed occupational pesticide handlers are likely to be
mixer/loaders using open-pour of liquids for aerial and groundboom
application and applicators using open-cab groundboom or aerial spray
equipment.  HED performed an assessment of these exposure scenarios. 
All occupational handler risk estimates are not of concern to HED
(MOE>100) provided workers wear protective gloves when handling
novaluron.  

Post-Application:  There is a potential for post-application exposure to
workers from pesticides during the course of typical agricultural
activities.  For the current action, intermediate-term post-application
dermal exposure was assessed using conservative assumptions for the
proposed uses. The resulting intermediate-term dermal MOE of 1,100 is
not of concern to HED.

Recommendation for Tolerances and Registration

The HED Hazard Identification Assessment Review Committee (HIARC)
requested a 28-day inhalation toxicity study as a condition of
registration.  However, based on the low volatility and low inhalation
toxicity (Toxicity Category IV) of novaluron and inhalation margins of
exposure (MOEs) >1000 for the proposed uses in this risk assessment,
novaluron qualifies for a waiver of the 28-day inhalation toxicity study
for the proposed uses [HED Standard Operating Procedure (SOP) 2002.01:
Guidance: Waiver Criteria for Multiple-Exposure Inhalation Toxicity
Studies, 15-AUG-2002].  The requirement for the 28-day inhalation
toxicity study is waived for this action only.  If in the future,
requests for new uses or formulations are submitted that may result in a
significant change in either the toxicity profile or exposure scenarios,
HED will reconsider this data requirement.

Provided revised Sections B and F are submitted, HED concludes that the
toxicological and residue chemistry databases, as well as the aggregate
and occupational risk assessments, support conditional registration of
the requested new uses and establishment of the following permanent
tolerances for residues of novaluron per se as follows:

Sugarcane, cane	0.50 ppm

Tomato	1.0 ppm

HED recommends that conversion of conditional registration to
unconditional registration may be considered upon submission of the
following residue chemistry data:

860.1340 Residue Analytical Methods

As initially requested in PP#4E6834 (DP# 325183, 8/23/06, S. Levy), an
interference study for the plant method is required to determine whether
other pesticides registered on the same commodities interfere with the
determination of novaluron; an interference study may be waived if a
specific single-analyte confirmatory method is submitted.  

860.1520 Processed Food and Feed

A sugarcane processing study conducted at an exaggerated rate (up to 5x)
is required in attempts to achieve quantifiable residues in the RAC and
to demonstrate the possible potential for concentration with processing.

Note to RD:  The preferred chemical name for novaluron is
N-[[[3-chloro-4-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy]phenyl]amino
]carbonyl]-2,6-difluorobenzamide.  40 CFR §180.598 should be revised
accordingly.  It is also noted that 40 CFR 180.598 should be amended to
correct the commodity “Vegetables, tuberous and corn, subgroup 1C”
to “Vegetable, tuberous and corm, subgroup 1C.”

2.0	PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION

 tc \l1 "2.0	PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION 

Table 2.0.1.  Novaluron Nomenclature.

Chemical structure	

Common name	Novaluron

IUPAC name
1-[3-chloro-4-(1,1,2-trifluoro-2-trifluoromethoxyethoxy)phenyl]-3-[2,6-d
ifluorobenzoyl]urea

CAS name
N-[[[3-chloro-4-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy]phenyl]amino
]carbonyl]-2,6-difluorobenzamide

CAS registry number	116714-46-6

End-use products (EPs)	Rimon® 10SC Insecticide (0.83 lb/gal FlC; EPA
Reg. No. 66222-40)

Rimon® 0.83 EC Insecticide (0.83 lb/gal EC; EPA Reg. No. 66222-35)

3 μg/L at 20(C

	Solvent solubility (at 25(C)	8.39 mg/L in n-heptane

1.88 g/L in xylene

14.5 g/L in methanol

198 g/L in acetone

113 g/L in ethyl acetate

0.98 g/L in n-octanol

	Vapor pressure (mm Hg)	1.2 x 10-7

	Dissociation constant, pKa	Not determined due to low water solubility

	Octanol/water partition coefficient, Log(KOW)	4.3 at 25(C

	UV/visible absorption spectrum	Molar absorption coefficients of at 3
maximum absorbances:

15,400 L/mol ( cm at 253 nm (neutral)

9,780 L/mol ( cm at 253 nm (acidic)

20,500 L/mol ( cm at 263 nm (basic)

	

3.0	HAZARD CHARACTERIZATION

 tc \l1 "3.0	HAZARD CHARACTERIZATION 

A detailed hazard characterization for novaluron is presented in HED’s
previous risk assessment (Memo, S. Levy, et al., 03-NOV-2005; DP#
313322).  The doses and toxicological endpoints selected for various
exposure scenarios applicable to this risk assessment are summarized in
Table 3.

3.1	FQPA Considerations

 tc \l2 "3.1	FQPA Considerations  

Pre-and/or Postnatal Toxicity

The HIARC (2003) concluded that there is not a concern for pre- and/or
postnatal toxicity resulting from exposure to novaluron.  

A. Determination of Susceptibility

There is no evidence of increased susceptibility in the rat and/or
rabbit developmental toxicity studies up to the limit dose.  There is no
evidence of increased qualitative and/or quantitative susceptibility to
novaluron following pre/post-natal exposure in a 2-generation
reproduction study in rats.

B. Degree of Concern Analysis and Residual Uncertainties 

There are no concerns or residual uncertainties for pre and/or
post-natal toxicity.  Acute and subchronic neurotoxicity screening
batteries were performed using novaluron in rats.  Novaluron does not
appear to be a potent neurotoxicant since the effects observed were not
severe and noticed only at high doses.  Neuropathologic effects were
also observed in a few control animals. No evidence of neuropathology
was observed in chronic and subchronic toxicity studies in rats, mice
and/or dogs.  Therefore, the HIARC concluded that there is not a concern
for developmental neurotoxicity resulting from exposure to novaluron.

C. FQPA Safety Factor(s): 

Based upon the above-described data, the FQPA safety factor for
increased susceptibility of infants and children can be reduced to 1X
since there are no residual uncertainties for pre and/or postnatal
toxicity.  A developmental-neurotoxicity (DNT) study is not required. 
The novaluron toxicological database is complete.  The RAB1 risk
assessment team concluded that the FQPA SF can be reduced to 1X based on
toxicological considerations, the conservative residue assumptions used
in the dietary and residential exposure risk assessments, and the
completeness of the residue chemistry database and conservative drinking
water assessment.

Table 3.1.  Summary of Toxicological Dose and Endpoints for Novaluron.

Exposure

Scenario	

Dose Used in Risk Assessment, UF 	Special FQPA SF* and LOC for Risk
Assessment	

Study and Toxicological Effects

Acute Dietary

	Not applicable	None	An endpoint of concern attributable to a single
dose was not identified.  An acute RfD was not established.

Chronic Dietary

(all populations)	NOAEL= 1.1 mg/kg/day

UF = 100

Chronic RfD = 

0.011 mg/kg/day	FQPA SF =  1X

cPAD = 

chronic RfD

 FQPA SF

= 0.011 mg/kg/day	Combined chronic toxicity/carcinogenicity feeding in
rat

LOAEL = 30.6 mg/kg/day based on erythrocyte damage and turnover
resulting in a regenerative anemia.

Short-Term 

Incidental Oral 

(1-30 days)

	NOAEL= 4.38 mg/kg/day	Residential LOC for MOE = 100

Occupational LOC for MOE = 100	90-day feeding study in rat

LOAEL = 8.64 mg/kg/day based on clinical chemistry (decreased
hemoglobin, hematocrit and RBC counts) and histopathology (increased
hematopoiesis and hemosiderosis in spleen and liver).

Intermediate-Term 

Incidental Oral 

(1-6 months)

	NOAEL= 4.38 mg/kg/day	Residential LOC for MOE = 100

Occupational LOC for MOE = 100	90-day feeding study in rat

LOAEL = 8.64 mg/kg/day based on clinical chemistry (decreased
hemoglobin, hematocrit and RBC counts) and histopathology (increased
hematopoiesis and hemosiderosis in spleen and liver).

Short-Term Dermal (1-30 days)	Not applicable	None	No toxicity observed
at the limit dose in dermal study and there were no developmental
toxicity concerns at the limit-dose; therefore, quantification of
short-term dermal risk is not necessary.

Intermediate-Term

Dermal 

(1-6 months)	Oral NOAEL = 4.38 mg/kg/day

(dermal-absorption rate = 10%)	Residential LOC for MOE = 100

Occupational LOC for MOE = 100 	90-day feeding study in rat

LOAEL = 8.64 mg/kg/day based on clinical chemistry (decreased
hemoglobin, hematocrit and RBC counts) and histopathology (increased
hematopoiesis and hemosiderosis in spleen and liver).

Long-Term Dermal 

(>6 months)

	Oral NOAEL= 1.1 mg/kg/day

(dermal-absorption rate = 10 %)	Residential LOC for MOE = 100

Occupational LOC for MOE = 100 	Combined chronic
toxicity/carcinogenicity feeding in rat LOAEL = 30.6 mg/kg/day based on
erythrocyte damage and turnover resulting in a regenerative anemia.

Short-Term Inhalation 

(1-30 days)	Oral NOAEL = 4.38 mg/kg/day

(inhalation absorption rate = 100%)	Residential LOC for MOE = 100

Occupational LOC for MOE = 100 	90-day feeding study in rat

LOAEL = 8.64 mg/kg/day based on clinical chemistry (decreased
hemoglobin, hematocrit and RBC counts) and histopathology (increased
hematopoiesis and hemosiderosis in spleen and liver).

Intermediate-Term Inhalation 

(1-6 months)

	Oral NOAEL = 4.38 mg/kg/day

(inhalation absorption rate = 100%)	Residential LOC for MOE = 100

Occupational LOC for MOE = 100	90-day feeding study in rat

LOAEL = 8.64 mg/kg/day based on clinical chemistry (decreased
hemoglobin, hematocrit and RBC counts) and histopathology (increased
hematopoiesis and hemosiderosis in spleen and liver).

Long-Term Inhalation 

(>6 months)

	Oral NOAEL= 1.1 mg/kg/day

(inhalation absorption rate = 100%)	Residential LOC for MOE = 100

Occupational LOC for MOE = 100 	Combined chronic
toxicity/carcinogenicity feeding in rat

LOAEL = 30.6 mg/kg/day based on erythrocyte damage and turnover
resulting in a regenerative anemia.

Cancer	Not likely to be carcinogenic to humans.

UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL =
no-observed adverse-effect level, LOAEL = lowest-observed adverse-effect
level, PAD = population-adjusted dose (a = acute, c = chronic) RfD =
reference dose, MOE = margin of exposure, LOC = level of concern, NA =
Not Applicable

3.2	Endocrine Disruption

 tc \l2 "3.2	Endocrine Disruption 

EPA is required under the Federal Food Drug and Cosmetic Act (FFDCA), as
amended by FQPA, to develop a screening program to determine whether
certain substances (including all pesticide active and other
ingredients) "may have an effect in humans that is similar to an effect
produced by a naturally occurring estrogen, or other such endocrine
effects as the Administrator may designate."  Following the
recommendations of its Endocrine Disruptor Screening and Testing
Advisory Committee (EDSTAC), EPA determined that there was scientific
basis for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system.  EPA also
adopted EDSTAC’s recommendation that the Program include evaluations
of potential effects in wildlife.  For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA has authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).

When the appropriate screening and/or testing protocols being considered
under the Agency’s EDSP have been developed, novaluron may be
subjected to additional screening and/or testing to better characterize
effects related to endocrine disruption.

4.0	EXPOSURE ASSESSMENT tc \l1 "4.0	EXPOSURE ASSESSMENT 

References:	Residue chemistry summary - Memo, G. Kramer, 07-FEB-2008;
D340137

Dietary exposure and risk analysis - Memo, G. Kramer, 07-FEB-2008;
D347657

Drinking water summary - Memo, I. Maher, 13-DEC-2007; D340579

4.1	Summary of Proposed Uses tc \l2 "4.1	Summary of Proposed Uses 

IR-4 has submitted the proposed labels for Rimon® 0.83 EC (emulsifiable
concentrate) Insecticide (0.83 lb/gal EC; EPA Reg. No. 66222-35), adding
new uses on tomato (field and greenhouse) and sugarcane; and Rimon® 10
SC (soluble concentrate) Insecticide (0.83 lb/gal flowable concentrate
(FlC); EPA Reg. No. 66222-40), adding uses on greenhouse tomato.  A
summary of the proposed uses of novaluron on tomato and sugarcane is
presented in Table 4.1.

Table 4.1.  Summary of Directions for Use of Novaluron.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate 

(lb a.i./A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb a.i./A)	PHI

(days)	Use Directions and Limitations

Sugarcane

Foliar;

Ground/aerial	0.83 lb/gal EC

[66222-35]	0.058-0.078	5	0.39	14	Apply in a minimum of 10 GPA using
ground equipment or 2 GPA using aerial equipment.  Repeat applications
when threshold levels are again exceeded.  Use of a non-ionic surfactant
is recommended.  No reapplication interval is specified.  

Tomato (field and greenhouse)

Foliar;

Ground/aerial	0.83 lb/gal EC

[66222-35]	0.058-0.078	3	0.23	2	Apply in a minimum of 10 GPA using
ground equipment or 2 GPA using aerial equipment.  Reapplication may be
made with a minimum 7-day interval.  

For greenhouses, use 9-12 oz (0.058-0.078 lb a.i.) in 100 gal/water. 

Tomato (greenhouse)

Foliar;

Ground	0.83 lb/gal FlC

[66222-40]	0.058-0.078	3	0.23	2	Direct to foliage using uniform spray
coverage (consult local agricultural specialist for spray volumes). 
Reapplication may be made with a minimum 7-day interval.  

The accepted (master) label for Rimon® 0.83 EC Insecticide states that
only registered crops may be rotated in a treated field within 30 days
of application.  Rimon® may be applied alone, as a tankmix, or in
rotation with other registered insecticides.

Conclusions.  Provided a reapplication interval of at least 8 days is
specified for sugarcane, the proposed labels are adequate to allow
evaluation of the residue data relative to the proposed new uses on
sugarcane and tomatoes.  However, the requested use for greenhouse-grown
tomatoes on the EC formulation label should be removed until additional
residue data are provided to support this use.  

4.2	Dietary Exposure/Risk Pathway tc \l2 "4.2	Dietary Exposure/Risk
Pathway 

Nature of the Residue - Plants:  Adequate metabolism studies for
novaluron are available on apples, cabbage, cotton, and potatoes.  These
studies indicate that novaluron is not extensively metabolized in these
crops.  The parent compound, novaluron, was either the only residue
component identified or was the predominant residue component in all
analyzed plant matrices.  The reviewed studies also indicate novaluron,
when foliarly applied during the vegetative growth stage, is not readily
translocated to mature apple fruit, potato tubers or cottonseed (Memo,
G. Kramer, 22-MAR-2004; DP# 285474).  Based on these studies, the
Metabolism Assessment and Review Committee (MARC) determined that the
residue of concern in crops for purposes of tolerance enforcement and
risk assessment is novaluron per se (Memo, G. Kramer et al.,
03-FEB-2004; DP# 297646).  

Nature of the Residue - Livestock:  HED also previously concluded that
the nature of the residue in livestock is adequately understood based on
the submitted goat and poultry metabolism studies (Memo, G. Kramer,
22-MAR-2004; DP# 285474).  The HED MARC determined that the residue of
concern in livestock for purposes of tolerance enforcement and risk
assessment is novaluron per se (Memo, G. Kramer et al., 03-FEB-2004; DP#
297646).

Residue Analytical Enforcement Method - Plant:  Makhteshim-Agan of North
America (MANA) previously submitted a gas
chromatography/electron-capture detection (GC/ECD) residue analytical
method for the analysis of novaluron residues in/on pome fruit, cabbage,
and potato commodities; HED concluded that the method was adequate for
gathering data on novaluron.  The method was adequately validated by the
petitioner and by an independent laboratory.  Acceptable radiovalidation
data have been submitted and reviewed in DP# 325183 for the GC/ECD
method, and both methods were forwarded to the EPA Analytical Chemistry
Branch (ACB)/Biological and Economics Analysis Division (BEAD) for
petition method validation (PMV).  An interference study was required.

ACB concluded that based upon review of the submitted method validation
data, without laboratory validation, that the GC/ECD and HPLC/UV methods
appear suitable for food tolerance enforcement in plants (apples,
cabbage, potatoes) and cotton.  ACB recommended that the analytical
methods do not need to be laboratory validated by EPA (DP# 306998). 
Both methods have been forwarded to FDA for inclusion in the PAM II as a
Letter Method (DP# 307595).  An interference study is still required to
determine whether other pesticides registered on the same commodities
interfere with the determination of novaluron; an interference study may
be waived if a specific single-analyte confirmatory method is submitted.
 Pending submission of the requested validation data, HED concludes that
the current enforcement methods are adequate to enforce the tolerances
associated with the current petition.

Magnitude of the Residue - Plants:  The submitted field trial data for
sugarcane are adequate and will support the establishment of a tolerance
of 0.50 ppm for residues of novaluron in/on sugarcane.  The submitted
residue data for tomatoes are adequate to support the requested use of
the EC formulation on field-grown tomatoes and of the FlC formulation on
greenhouse-grown tomatoes.  However, additional data are required to
support the requested use of the EC formulation on greenhouse-grown
tomatoes.  The submitted data show that maximum residues of novaluron
from the outdoor field trials in which tomatoes were harvested 1-2 days
following foliar treatments were 0.126 ppm in/on large-fruit variety
tomatoes and 0.275 ppm in/on small-fruit variety tomatoes.  Maximum
residues of novaluron from the greenhouse trials in which tomatoes were
harvested 1-2 days following foliar treatments at 1x were 0.200 ppm
in/on large-fruit variety tomatoes and 0.470 ppm in/on small-fruit
variety tomatoes.  The available data will support the establishment of
a tolerance of 1.0 ppm for residues of novaluron in/on tomato.

Processed Food and Feed:  The submitted sugarcane processing data are
inadequate because the study has not demonstrated that residues of
novaluron will not concentrate in the processed commodities of sugarcane
following processing of the RAC treated at an appropriate exaggerated
rate or at the theoretical maximum concentration factors (11.8x for
refined sugar or 20x for molasses).  In the submitted processing study,
residues of novaluron were below the method limit of quantitation (LOQ)
in/on the RAC treated at 2x; residues in samples of molasses and refined
sugar, which were processed from 2x-treated sugarcane, were also below
the LOQ.  A new sugarcane processing study is required using a minimum
exaggerated application rate of 5x.  It is noted that quantifiable
residues of novaluron were obtained in several of the respective field
trials conducted at the 1x nominal field rate (0.39 lb a.i./A).

The submitted tomato processing data are adequate to satisfy data
requirements.  These data indicate that residues of novaluron are not
likely to concentrate above the LOQ in purée, but may concentrate
slightly in paste.  The expected residues of novaluron resulting in
tomato paste with processing do not exceed the recommended tolerance for
tomato; therefore, no tolerances for tomato processed commodities are
needed.  

Confined/Field Accumulation in Rotational Crops:  Based on the results
of the confined rotational crop study, the appropriate plantback
interval (PBI) for all non-labeled crops is 30 days.  The current and
proposed labels include a restriction that only registered crops may be
rotated to a treated field within 30 days of the final application.

Tolerance Summary:  Permanent tolerances for novaluron have been
established for a variety of commodities under 40 CFR §180.598.  The
available field trial data for sugarcane and tomato were entered into
the Agency’s tolerance spreadsheet (using maximum likelihood
estimation (MLE) procedures to impute censored values) as specified by
the Guidance for Setting Pesticide Tolerances Based on Field Trial Data
SOP to determine appropriate tolerance levels.  The tolerance
spreadsheet recommends tolerances of 0.50 ppm for sugarcane, 0.45 ppm
for field-grown tomatoes and 1.0 ppm for greenhouse-grown tomatoes; the
higher tolerance of 1.0 ppm will be appropriate as the interim tolerance
for tomato.  A revised Section F is required to increase the proposed
tolerance for tomato from 0.40 ppm to 1.0 ppm.  In addition, HED has
recently recommended that the existing egg tolerance should be increased
to 0.07 ppm (Memo, S. Levy, 31-JAN-2008; D340137).

The existing livestock tolerances for novaluron are adequate to support
the new uses on sugarcane.  Sugarcane molasses is the only livestock
feedstuff associated with this petition, and the dietary burdens are not
expected to significantly increase with the addition of this commodity.

No Canadian or Mexican maximum residue limits (MRLs) have been
established for novaluron on the requested crops.  A Codex (step 8/CXL)
is established for novaluron (fat soluble) on tomato at 0.02 ppm.  

A summary of the recommended tolerances for the current petition is
presented in Table 4.2.  The proposed tolerances should be revised to
reflect the recommended tolerance levels and correct commodity
definitions as specified in Table 4.2.  



Table 4.2.  Tolerance Summary for Novaluron.

Commodity	Established

Tolerance 

(ppm)	Proposed

Tolerance

(ppm)	HED-Recommended 

Tolerance (ppm)	Comments; 

Correct Commodity Definition

Tomato	--	0.40	1.0

	Tomato, paste	--	0.80	Remove	Not needed; residues will be covered by
the RAC tolerance

Sugarcane, cane	0.15

(Section 18)	0.50	0.50

	

4.3	Water Exposure and Risk Pathway tc \l2 "4.3	Water Exposure and Risk
Pathway 

The following information concerning the environmental fate and drinking
water assessment of novaluron was provided by EFED (Memo, I. Maher,
13-DEC-2007; D340579).  At the present time, surface and ground water
monitoring data are not available for novaluron.

The HED MARC concluded that parent and the chlorophenyl urea and
chloroaniline degradates are residues of potential concern to be
included in the drinking water assessment.

Modeling and Drinking Water Estimates

Monitoring data for novaluron, chlorophenyl urea and chloroaniline in
surface water and ground water were not found.  Novaluron is not
included in the USGS National Water-Quality Assessment (NAWQA) Program,
the Pesticides in Ground Water Database (USEPA, 1992), and it was not an
analyte in the National Pesticide Survey (USEPA, 1990).  Monitoring data
are not available for novaluron or its chlorophenyl urea and
chloroaniline degradates, in surface water or ground water. 
Concentrations in surface water and ground water were estimated using
modeling.

Tier 2 PRZM/EXAMS modeling was performed to estimate drinking water
concentrations for surface water for novaluron per se.  The scenarios
were selected to provide high-end drinking water concentrations for each
crop and represent the geographic locations where the specific crops are
grown in large quantities.

The most-conservative estimates were obtained for airblast applications
to apples grown in Pennsylvania at the maximum annual application rate
of 0.96 lb a.i./acre, applied three times at 0.32 lb a.i./acre with an
interval between applications of ten days.

For surface water, the 1-in-10-year annual mean EDWC for the parent
novaluron is 1.8 ppb.  

A Tier I drinking water analysis was performed for the chlorophenyl urea
and chloroaniline degradates.  The FIRST model was used to obtain
surface water estimates.  As a conservative assumption, the model
assumed chlorophenyl urea was directly applied, i.e., as granular, to
the field, assuming no spray drift and no foliar interception.  The
FIRST model estimates a peak and an annual average value based on the
Index Reservoir scenario.

For surface water, the annual average EDWC for chlorophenyl urea is 0.86
ppb and the annual average EDWC for chloroaniline is 2.6 ppb.  Both of
these estimates are based upon the maximum application rate in apples.

For ground water, the SCI-GROW model was used to predict a ground water
concentration for novaluron at the annual application rate of 0.96 lb
a.i./acre (i.e., three applications of 0.32 lb a.i./acre).  The estimate
for the parent novaluron is 0.0055 ppb in drinking water from shallow
ground water sources.  For the chlorophenyl urea degradate, the
predicted ground water concentration is 0.0045 ppb, and for the
chloroaniline degradate the concentration is 

0.0090 ppb.  These concentrations were estimated with the same
assumptions used for surface water modeling, and may be considered as
both the peak and annual average upper bound exposures.

These EDWC values are meant to represent upper-bound estimates of the
concentrations that might be found in surface water and ground water
based upon existing and proposed uses.  Of the three EDWC values,
chronic estimates for the terminal metabolite, chloroaniline are the
highest (100% conversion from parent to aniline was assumed).  This is
consistent with the expected degradation pattern for novaluron. 
Therefore, the EDWC value for the chloroaniline degradate (2.6 ppb) was
used to assess chronic aggregate risk.

4.4	Dietary-Exposure Analysis tc \l2 "4.4	Dietary-Exposure Analysis 

A chronic dietary risk assessment was conducted using the DEEM-FCID(
(ver. 2.03) model which uses food consumption data from the USDA’s
Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996
and 1998.  An acute dietary assessment was not conducted for novaluron
because an endpoint of concern attributable to a single dose was not
identified.  A cancer dietary assessment was not conducted because
novaluron was classified as “not likely to be carcinogenic to
humans.”

The current chronic dietary assessment is an update of the previous
dietary assessment conducted in 2005 (i.e., average field trial residue
values for the commodities associated with this action and empirical
processing factors for tomato purée and paste were added to the last
dietary assessment).  In addition, HED has recently recommended that the
existing egg tolerance should be increased to 0.07 ppm (Memo, S. Levy,
31-JAN-2008; D340137).  EDWCs, provided by EFED, were included in this
assessment as well.  In the last dietary assessment, the chronic
analysis assumed 100% crop treated for all commodities; incorporated
average field trial residues for some commodities; empirical processing
factors for apple juice (translated to pear juice); and DEEM( (ver 7.81)
default processing factors for the remaining processed commodities. 
Furthermore, ARs were used for meat and milk commodities and recommended
tolerances were used for poultry commodities.  The resulting chronic
dietary risk estimate (food + water) was not of concern to HED (<100%
cPAD; see Table 4.4).



Table 4.4.  Summary of Chronic Dietary Exposure and Risk for Novaluron. 

Population Subgroup	

cPAD (mg/kg/day)	

Exposure (mg/kg/day)	

%cPAD

General U.S. Population	

0.011	

0.002332	

21

All Infants (< 1 year old)

0.003766	

34

Children 1-2 years old

0.008146	

74

Children 3-5 years old

0.006306	

57

Children 6-12 years old

0.003837	

35

Youth 13-19 years old

0.002033	

18

Females 13-49 years old

0.001560	

14

Adults 20-49 years old

0.001662	

15

Adults 50+ years old

0.001486	

13

4.5	Residential Exposure and Risk Pathway tc \l2 "4.5	Residential
Exposure and Risk Pathway 

All uses for novaluron, either proposed or existing, are agricultural or
commercial in nature.  No residential uses are proposed, nor are any of
the uses expected to result in residential exposure.  Therefore, a
residential exposure assessment was not performed for this action.

5.0	AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION tc \l1 "5.0
AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION 

Including all existing and proposed uses, human-health risk assessments
have been conducted for the following exposure scenario:  chronic
dietary exposures (food + water only).  The chronic dietary exposure and
risk estimate is below HED’s level of concern.  An acute dietary
assessment was not conducted for novaluron because an endpoint of
concern attributable to a single dose was not identified.  A cancer
dietary assessment was not conducted because novaluron was classified as
“not likely to be carcinogenic to humans.”

Because there are no uses of novaluron that could result in residential
exposures, this aggregate risk assessment takes into consideration
dietary food + water exposure only; therefore, the chronic aggregate
estimates would be the same as the chronic dietary exposure results
shown in Table 4.4.

6.0	CUMULATIVE RISK tc \l1 "6.0	CUMULATIVE RISK 

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to novaluron and any other
substances and novaluron does not appear to produce a toxic metabolite
produced by other substances. For the purposes of this tolerance action,
therefore, EPA has not assumed that novaluron has a common mechanism of
toxicity with other substances.  For information regarding EPA’s
efforts to determine which chemicals have a common mechanism of toxicity
and to evaluate the cumulative effects of such chemicals, see the policy
statements released by EPA’s Office of Pesticide Programs concerning
common mechanism determinations and procedures for cumulating effects
from substances found to have a common mechanism on EPA’s website at
http://www.epa.gov/pesticides/cumulative/.

7.0	OCCUPATIONAL EXPOSURE tc \l1 "7.0	OCCUPATIONAL EXPOSURE 

Reference:	Occupational and residential exposure/risk assessment - Memo,
M. Clock-Rust. DP# 315780.

Occupational exposure and risks were assessed based on the proposed uses
on sugarcane and tomatoes, including greenhouse-grown tomatoes.  Use
rates and label statements can be found in Table 4.1 of this document.  

For handlers, intermediate-term dermal and inhalation risks were
assessed.  For post-application workers, intermediate-term dermal risk
was assessed (post-application inhalation exposure is considered to be
negligible).  An appropriate endpoint for quantification of short-term
dermal risk assessment was not identified by HIARC since no adverse
effects were observed at the limit dose in a 21-day dermal toxicity
study in rats, and there were no developmental toxicity concerns at the
limit-dose.  Therefore, a corresponding dermal risk assessment for the
short-term duration is not required.  

7.1	Occupational Handler tc \l2 "7.1	Occupational Handler 

Based upon the proposed use patterns, HED assessed risks to occupational
pesticide handlers based on the following scenarios:

Field-grown Tomatoes and Sugarcane

mixing/loading liquid concentrates to support aerial applications
(Pesticide Handler's Exposure Database (PHED)),

mixing/loading liquid concentrates to support groundboom applications
(PHED),

applying sprays with aircraft (PHED),

applying sprays with groundboom equipment (PHED),

flagging to support aerial spray applications (PHED),

Greenhouse-grown Tomatoes

mixing/loading/applying liquid concentrates with low-pressure hand-wand
equipment Outdoor Residential Exposure Task Force (ORETF), 

mixing/loading/applying liquid concentrates with handgun equipment
(ORETF), and

mixing/loading/applying liquid concentrates with high-pressure hand-wand
equipment (PHED).

No chemical-specific data were available with which to assess potential
exposure to occupational pesticide handlers.  The estimates of exposure
to pesticide handlers are based upon surrogate study data available in
PHED (v. 1.1, 1998) and the ORETF data.

Since a single endpoint of concern (clinical chemistry observed in the
90-day rat study with a NOAEL of 4.38 mg/kg/day) was identified for both
dermal and inhalation intermediate risk assessment, exposures were
combined (summed) and compared to the NOAEL.

In Table 7.1 below, occupational exposure was summarized.  Instead of
presenting exposure and risk for all possible exposure patterns, only
those that result in the highest exposure were included.  Field-grown
tomatoes were excluded since the exposure pattern for mixer/loaders and
applicators treating sugarcane is expected to result in higher exposure
than that for field-grown tomatoes.  This is due to the higher acreage
treated for sugarcane.  In all cases, handlers treating sugarcane have a
higher level of exposure than that for handlers treating field-grown
tomatoes.  See the ORE assessment cited above for full details on all
exposure scenarios. 

An MOE (100 is adequate to protect occupational pesticide handlers.  All
occupational handler MOEs are estimated to be >100 with baseline
personal-protective equipment (PPE, single layer of clothing) or with
baseline PPE and protective gloves.  According to the proposed labels,
applicators and other handlers must wear long-sleeved shirt and long
pants, chemical-resistant gloves, shoes plus socks and protective
eyewear.  The intermediate-term dermal risk assessment is protective of
any short-term dermal risks.

Table 7.1.  Estimated Intermediate-Term Handler Exposure and Risk from
the Use of Novaluron.

Unit Exposure1

(mg a.i./lb handled)	Application Rate2 (lb a.i./A)	Units Treated3

Per Day (Acres)	Average Daily Dose4

mg a.i./kg bw/day	MOE5

Mixer/Loader - Liquid - Open Pour - Supporting Aerial Operations for
Sugarcane

Dermal:

SLNG       2.9    HC

SLWG      0.023 HC

Inhal:        0.0012 HC	0.078 	1200	Dermal:

SLNG     0.39  

SLWG    0.0031

Inhal:       0.0016	NG 11

WG 930

Applicator - Groundboom - Open Cab for Sugarcane

Dermal:

SLNG       0.014 HC

SLWG      0.014 MC

Inhal:       0.00074 HC	0.078	200	Dermal:  

SLNG/WG  0.00031 

Inhal:  0.00016	

SLNG  9,300

SLWG 9,300

Applicator – Aerial Application to Sugarcane (Gloves not worn)

Dermal:

SLNG       0.0050 HC

SLWG      N/A

Inhal:        0.000068 MC	

0.078	

1200	

Dermal:  

SLNG 0.00067

SLWG N/A

Inhal: 0.000091	

SLNG 5,800

Mixer/Loader/Applicator – Low-Pressure Handwand to Greenhouse Tomatoes

Dermal:

SLNG      30 

SLWG      N/A

Inhal:         0.0038	

0.078	

5	Dermal:

SLNG 0.017

Inhal: 0.000021	SLNG 260

Mixer/Loader/Applicator – Handgun to Greenhouse Tomatoes

Dermal:

SLNG      N/A 

SLWG      0.45

Inhal:         0.0018	

0.078	

5	Dermal:

SLWG 0.00025

Inhal: 0.000002	SLWG 17,000

Mixer/Loader/Applicator – High-Pressure Handwand to Greenhouse
Tomatoes

Dermal:

SLNG      N/A 

SLWG      2.5

Inhal:         0.12	

0.078	

5	Dermal: 

SLWG 0.00028

Inhal: 0.00067	SLWG 11,000

1.  Unit Exposures are taken from the PHED Surrogate Exposure Guide. HC
= high data confidence.

2.  Application Rate = from proposed RimOn® labels for 10 % EC and 7.5%
WG.

3.  Units Treated from SOP No. 9.1.  ExpoSAC;  Revised 5 July 2000.

4.  Average Daily Dose (ADD) = Unit Exposure * Applic. Rate * Units
Treated * absorption factor  ( Body Weight (70 kg). (Assumes 10% dermal
absorption and 100 % inhalation absorption.).

5.  MOE = NOAEL ( ADD.  No short-term dermal endpoint was identified
therefore only short-term inhalation risk is presented (NOAEL = 4.38 mg
a.i./kg bw/day).  The intermediate-term dermal and inhalation endpoints
are the same (NOAELs = 4.38 mg a.i./kg bw/day respectively) and are
identified from the same study.  Therefore, dermal exposure is summed
with inhalation exposure and risk is presented for “baseline” work
clothing and NO gloves (NG) as well as “baseline” work clothing WITH
the use of protective gloves (WG).

7.2	Occupational Postapplication tc \l2 "7.2	Occupational
Postapplication 

There is a potential for post-application exposure to workers from
pesticides during the course of typical agricultural activities.

There were no chemical-specific dislodgeable foliar residue data to
assess postapplication risks to workers while performing tasks related
to crops treated with novaluron.  Occupational postapplication exposures
and risks were assessed using HED’s default assumptions that 20% of
the initial application is available for transfer on day 0 (i.e., 12
hours after application) and that the residue dissipates at a rate of
10% per day.

HED assumes an 8 hour workday for postapplication workers and assumes 70
kilograms for an adult (average adult weight).

For novaluron, the exposure durations for noncancer postapplication risk
assessment were short-term (30 days) and intermediate-term (greater
than 30 days up to several months).  However, since there is no dermal
toxicological endpoint of concern for short-term exposures,
postapplication risks are presented only for intermediate-term dermal
exposures. 

Inhalation exposures are thought to be negligible for outdoor
postapplication scenarios, since novaluron has low vapor pressure and
the dilution factor outdoors is considered infinite. 

Daily dermal exposures were calculated on each postapplication day after
application using the following equation:

DE(t) (mg/day) = (DFR(t) (µg/cm2) x TC (cm2/hr) x Hr/Day)/1,000
(µg/mg)

Where:

DE(t)	=	Daily exposure or amount deposited on the surface of the skin at
time (t) attributable for activity in a previously treated area;

	DFR(t)	=	Dislodgeable foliar residue at time “t” (µg/cm2);

	TC	=	Transfer Coefficient (cm2/hour); and

	Hr/day	=	Exposure duration meant to represent a typical workday (8
hours).

Where:

	Default DFR (µg/cm2) = AR (lb a.i./A) x F x (1- D)t x CF1 x CF2

	AR = Maximum application rate

	F = Fraction of a.i. retained on the foliage

	D = Fraction of residue that dissipates daily

	t = Postapplication day

	CF1 = 4.54E+8 µug/lb

	CF2 = 2.47E-8 A/cm2

The default DFR value on day 0 was calculated based on the application
rate and default assumption regarding the fraction of ai that is
retained on foliage after application (20%).  Table 7.2 presents the
results of the occupational postapplication risk assessment when HED
default assumptions are used.  Using surrogate data DFR data, risks are
not of concern to HED for any postapplication occupational scenario on
day 0 (12 hours following application).

Table 7.2.  Summary of Occupational Postapplication Risks with HED
Default Assumptions.

Crop Grouping	Application rate

(lb a.i./acre)	Default DFR 

(μg/cm2) (lb a.i./acre)	Transfer Coefficient (µg/cm2)	Day after
Application	MOE

(Level of Concern = 100)

Tomatoes, Greenhouse Tomatoes	0.078	0.175	1,000 (hand harvest hand
pruning, staking, thinning, training, tying)	0 (12 hours)	2,200

Sugarcane

	2,000 (scouting)	0 (12 hours)	1,100

Novaluron is classified in acute toxicity category III for acute dermal
toxicity and category IV for primary eye irritation and primary skin
irritation.  It is not a dermal sensitizer.  A restricted entry interval
(REI) of 12 hours is appropriate and meets the requirements of the
Worker Protection Standard (WPS) for Agricultural Pesticides.  

7.3	Incident Data tc \l2 "7.3	Incident Data 

OPP’s Incident Data System (IDS) (29-DEC-2003) indicates “no
incident data” are recorded for novaluron.

8.0	DATA NEEDS/LABEL REQUIREMENTS tc \l1 "8.0	DATA NEEDS/LABEL
REQUIREMENTS 

8.1	Toxicology tc \l2 "8.1	Toxicology 

The HED HIARC requested a 28-day inhalation toxicity study as a
condition of registration.  However, based on the low volatility and low
inhalation toxicity (Category IV) of novaluron and inhalation MOEs >1000
for the proposed uses in this risk assessment, novaluron qualifies for a
waiver of the 28-day inhalation toxicity study for the proposed uses
[HED SOP 2002.01: Guidance: Waiver Criteria for Multiple-Exposure
Inhalation Toxicity Studies, 15-AUG-2002].  The requirement for the
28-day inhalation toxicity study is waived for this action only.  If in
the future, requests for new uses or formulations are submitted that may
result in a significant change in either the toxicity profile or
exposure scenarios, HED will reconsider this data requirement.

8.2	Residue Chemistry tc \l2 "8.2	Residue Chemistry 

860.1200 Directions for Use (tomato and sugarcane)

The requested use for greenhouse-grown tomatoes on the EC formulation
label should be removed until additional residue data are provided to
support this use.  Also, a reapplication interval of at least 8 days
should be specified for sugarcane.

860.1340 Residue Analytical Methods

As initially requested in PP#4E6834 (DP# 325183, 8/23/06, S. Levy), an
interference study for the plant method is required to determine whether
other pesticides registered on the same commodities interfere with the
determination of novaluron; an interference study may be waived if a
specific single-analyte confirmatory method is submitted.  

860.1520 Processed Food and Feed

A sugarcane processing study conducted at an exaggerated (up to 5x) is
required in attempts to achieve quantifiable residues in the RAC and to
demonstrate the possible potential for concentration with processing.

860.1550 Proposed Tolerances

The proposed tolerance for tomato should be revised from 0.40 ppm to 1.0
ppm.

The proposed tolerance for tomato paste should be removed.

8.3	Occupational/Residential Exposure tc \l2 "8.3
Occupational/Residential Exposure 

None.

Attachment:  Toxicity Profile of Novaluron.

cc:  G. Kramer (RAB1), M. Clock-Rust (RAB1)

RDI:  RAB1 Chemists (2/6/08), RAB1 Branch (2/6/08)

G.F. Kramer:S10781:PY-S:(703)305-5079:7509P:RAB1

Attachment:  Toxicity Profile of Novaluron.  tc \l1 " Attachment: 
Toxicity Profile of Novaluron  

 Guideline No/ 

Study type	

MRID No.(year)/ classification/Doses	

Results

870.4300 Chronic/Carcinogenicity-rat	45651506 (1995);

0, 25, 700, or 20,000 ppm  test material;

M: 0, 1.1, 30.6, and 884.2 mg/kg/day 

F:  0, 1.4, 39.5, and 1113.5 mg/kg/day

Acceptable/Guideline	NOAEL (M/F) =1.1/1.4 mg/kg/day

LOAEL (M/F)=30.6/39.5 mg/kg/day based on Erythrocyte damage and turnover
resulting in a regenerative mild anemia

870.4300 Chronic/Carcinogenicity-mouse	45651507/45877901 (2000/2003);

0, 30, 450, or 7000 ppm test material;

M: 0, 3.6, 53.4, or 800.0 mg/kg/day 

F: 0, 4.3, 63.3, or 913.4 mg/kg/day

Acceptable/Guideline	NOAEL (M/F)=3.6/4.3 mg/kg/day

LOAEL (M/F)=53.4/63.3 mg/kg/day based on increased erythrocyte turnover
due to hemoglobin oxidation and resulting in a mild anemia

870.4100b Chronic toxicity - dog	45638320 (1999);

0, 10, 100, 1000  mg/kg/day 

Acceptable/Guideline	NOAEL= 10 mg/kg/day

LOAEL=100 mg/kg/day based on hematologic changes associated with
histopathological changes in liver and spleen

870.3800 Reproduction  and fertility- rat	 45651505 (Main Study, 1999),
45638319 (Preliminary Study, 1998) 

0, 1000, 4000 or 12,000 ppm ;

M: 0, 74.2, 297.5 or 894.9 mg/kg/day 

F: 0, 84.0, 336.7 or 1009.8 mg/kg/day

Acceptable/Guideline	Parental NOAEL= Not established; LOAEL (M/F)=
74.2/84.0 mg/kg/day based on increased absolute and relative spleen
weights.

Offspring NOAEL= Not established; LOAEL (M/F)= 74.2/84.0 mg/kg/day based
on increased absolute and relative spleen weights.

Reproductive NOAEL (M/F)= 74.2/( 1009.8 mg/kg/day; LOAEL= 297.5
mg/kg/day based on decreased epididymal sperm counts and increased age
of preputial separation in the F1 generation, reproductive LOAEL for
females was not established.

870.3200

28-day Dermal Toxicity - rat	45288501 (1998);

0, 75, 400, 1000  mg/kg/day 

Acceptable/Guideline	Systemic NOAEL= 1000 mg/kg/day; LOAEL= not
established

Dermal NOAEL= 1000 mg/kg/day; LOAEL= not established

870.6200

Acute Neurotoxicity screening battery- rat	45082601 (1999);

0, 200, 650, 2000 mg novaluron/kg

Acceptable/Guideline	NOAEL= 650 mg/kg/day; LOAEL=2000 mg/kg/day based on
clinical signs (piloerection, irregular breathing), FOB parameters
(increased head swaying, abnormal gait) and neuropathology (sciatic and
tibial nerve degeneration).

870.6200b Subchronic Neurotoxicity screening battery- rat	

46086204 (2002);

0, 17.5, 174, 1752 mg/kg/day

Acceptable/Guideline	NOAEL (M/F)=> 1752/> 2000 mg/kg/day; LOAEL= not
established

870.7485

Metabolism-rat	45638401(2000), 45638323(1998);

single dose of 2 mg/kg or 1000 mg/kg, or 14 multiple 2 mg/kg/day doses
of unlabeled RIMON (Lot no. 970211/4, 99.3% chemical purity) followed by
a single dose of radiolabeled RIMON.

Acceptable/Guideline	Novaluron exhibited marginal absorption (16-18%),
relatively rapid and complete excretion within 48 hours primarily via
the feces and to  a lesser extent via urine in rat.  Biliary
contribution for fecal excretion appears to be insignificant. 
Absorption appeared to be approaching saturation at high doses. Peak
plasma concentration occurred at 2-5 hours. Urinary metabolite profiles
revealed 15 components and 8 components following administration of
[chlorophenyl-14C]RIMON or [difluorophenyl-14C]RIMON, respectively.  The
most prevalent urinary metabolite was 2,6-difluorobenzoic acid
represented the majority of the urinary radioactivity.  Other components
individually represented no more than 5.9% of the dose and most
represented considerably less than 1%. Parent compound was the most
prevalent contributor in the feces. The fecal metabolite profile
revealed two metabolites;
3-chloro-4-(1,1,2-trifluoro-2-trifluoromethoxyethoxy)aniline, and
1-[3-chloro-4-(1,1,2-trifluoro-2-trifluoromethoxyethoxy)phenyl]urea. 
Quantitatively, these were minor components accounting for <2% of the
dose.  In the repeated dose group some tissues such as fat contained
measurable radioactivity at 168 hours post dose but did not appear to
suggest significant potential for bioaccumulation or sequestration at
the doses tested.

870.7600

Rat Dermal Penetration	45638415

(2000);

1.0, 0.067, 0.0048, or 0.0003 mg/cm2 

Acceptable/Guideline 	Recovery of administered radioactivity was an
acceptable 90.19-105.26%.   The maximum total absorbed dose (expressed
as per cent of administered dose and determined as the sum of
radioactivity in excreta, cage wash, untreated skin, fat, blood, and
residual carcass) ranged from about 0.5% to 10% of that administered.

870.3700a Prenatal Developmental in rodents-Rat	45082602 (1997); 

0, 250, 500, 1000 mg/kg/day

Acceptable/Guideline	Maternal NOAEL: > 1000; LOAEL: not established 

Developmental NOAEL: > 1000; LOAEL: not established

870.3700b Prenatal Developmental in nonrodents-Rabbit	45638316,
45638318, 45638317

(1997,1998);

0, 100, 300, 1000 mg/kg/day 

Acceptable/Guideline	Maternal NOAEL: > 1000; LOAEL: not established 

Developmental NOAEL: > 1000; LOAEL: not established

870.5100

Salmonella typhimurium and  Escherichia coli Reverse Mutation Assay
44961013 (1997)

0, 312.5, 625, 1250, 2500, or 5000 μg/plate in the presence and absence
of metabolic activation (±S9)

Acceptable/Guideline	Novaluron, tested up to the limit of solubility
(2500 μg/plate) and the limit dose (5000 μg/plate), was not cytotoxic
with or without S9 activation in four S. typhimurium strains and one
strain of E. coli, and did not induce a genotoxic response in any strain

870.5100

Salmonella typhimurium- bacterial reverse gene mutation assay	45030003
(1986)

0, 10, 33, 100, 333, 1000, or 3333 μg/plate in the presence and absence
of mammalian metabolic activation (±S9)

Acceptable/Guideline	Novaluron, tested up to the limit of solubility
(3333 μg/plate), was not cytotoxic with or without S9 activation in
five S. typhimurium strains, and did not induce a genotoxic response in
any strain.

870.5300

Gene Mutation	45638321(1989);

0, 50, 100, 125, 150, 175 or 200 μg/mL with and without metabolic
activation (S9-mix) in two independent assays.

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	ble/Guideline 	There was no evidence of biologically significant
induction of mutant colonies over background

870.5395

Mammalian erythrocyte micronucleus test in mice	45638322(1989);

0, 1250, 2500 or 5000 mg/kg body weight

μg/mL, with and without metabolic activation (±S9)

Acceptable/Guideline	Novaluron produced no evidence of clastogenic
activity in primary human lymphocytes, in the presence or absence of S9
activation

870.5550

Unscheduled DNA Synthesis in HeLa S3 Human Epitheliod cells	45030002
(1988)

0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64, 128, or 256 μg/mL (±S9)

	test for mutagenic potential

870.5500

Mutagenicity–Rec assay with Bacillus subtilis	44961014 (1998)

50, 150, 500, 1,500, or 5,000 μg/plate, with and without mammalian
metabolic activation (±S9)

	DNA damage in the absence of S9 activation, and negative for bacterial
DNA damage in the presence of S9 activation

M - Male; F - Female

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