Document ID: EPA-HQ-OPP-2008-0769-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-12-09T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

 PREVENTION, PESTICIDES,

AND TOXIC SUBSTANCES

MEMORANDUM

Date:		09-SEP-2009

SUBJECT:	Novaluron:  Human-Health Risk Assessment for Proposed Section 3
Uses on Bushberry Crop Subgroup 13-07B; Brassica, Leafy Greens, Crop
Subgroup 5B; Turnip, Greens; and Fruit, Stone, Crop Group 12.  

PC Code:  124002	DP Barcode:  D357078

Decision No.:  399480 	Registration No.:  66222-35

Petition No.:  8E7426	Regulatory Action:  Section 3 Registration

Risk Assessment Type:  Single Chemical Aggregate	Case No.:  NA

TXR No.:  NA	CAS No.:  116714-46-6

MRID No.:  NA 	40 CFR:  §180.598

FROM:	Julie L. Van Alstine, MPH, Environmental Health Scientist

Lata Venkateshwara, Environmental Scientist

Kelly M. Lowe, Environmental Scientist

Robert Mitkus, Ph.D., Toxicologist

		Risk Assessment Branch 1 (RAB1)

		Health Effects Division (HED; 7509P)

THROUGH:  Dana M. Vogel, Branch Chief 

		George F. Kramer, Ph.D., Branch Senior Chemist 

		RAB1/HED (7509P)

TO:		Daniel Rosenblatt/Laura Nollen (RM 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 Julie Van Alstine (RAB1), the hazard characterization
by Robert Mitkus (RAB1), the occupational/residential exposure
assessment by Lata Venkateshwara and Kelly Lowe (RAB1), and the drinking
water assessment by Iwona Maher of the Environmental Fate and Effects
Division (EFED).

The most recent human-health risk assessment was conducted in
conjunction with a request for the use of novaluron on sugarcane and
tomato (Memo, G. Kramer, 25-FEB-2008; D347661).  A human-health risk
assessment was also recently conducted for a Section 18 Emergency
Exemption request for the use of novaluron on strawberries in Florida
(Memo, W. Cutchin, 03-DEC-2008; D358003).  A detailed hazard
characterization for novaluron is presented in a previous HED risk
assessment (Memo, S. Levy, et al., 03-NOV-2005; DP# 313322).  The
following information from the 25-FEB-2008 risk assessment can be
applied directly to this action:

Physical/Chemical Properties Characterization (Section 2.0; pg. 8-9);
and

Cumulative Risk (Section 6.0 pg 18-19).

This document contains only those aspects of the risk assessment which
are affected by the proposed Section 3 requests for use of novaluron on
bushberry subgroup 13-07B; Brassica, leafy greens, subgroup 5B; turnip,
greens; and fruit, stone, group 12.  

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc240275803"  1.0	Executive
Summary	  PAGEREF _Toc240275803 \h  4  

  HYPERLINK \l "_Toc240275804"  2.0	PROPOSED USE PATTERN	  PAGEREF
_Toc240275804 \h  9  

  HYPERLINK \l "_Toc240275805"  3.0	HAZARD CHARACTERIZATION/FQPA
CONSIDERATIONS	  PAGEREF _Toc240275805 \h  11  

  HYPERLINK \l "_Toc240275806"  3.1	FQPA Considerations	  PAGEREF
_Toc240275806 \h  12  

  HYPERLINK \l "_Toc240275807"  3.2	Endocrine Disruption	  PAGEREF
_Toc240275807 \h  14  

  HYPERLINK \l "_Toc240275808"  4.0	DIETARY EXPOSURE/RISK
CHARACTERIZATION	  PAGEREF _Toc240275808 \h  14  

  HYPERLINK \l "_Toc240275809"  4.1	Food Residue Profile	  PAGEREF
_Toc240275809 \h  14  

  HYPERLINK \l "_Toc240275810"  4.2	Drinking Water Residue Profile	 
PAGEREF _Toc240275810 \h  17  

  HYPERLINK \l "_Toc240275811"  4.3	Dietary Exposure and Risk	  PAGEREF
_Toc240275811 \h  18  

  HYPERLINK \l "_Toc240275812"  4.4	Residential Exposure and Risk
Pathway	  PAGEREF _Toc240275812 \h  19  

  HYPERLINK \l "_Toc240275813"  5.0	AGGREGATE RISK ASSESSMENTS AND RISK
CHARACTERIZATION	  PAGEREF _Toc240275813 \h  19  

  HYPERLINK \l "_Toc240275814"  6.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY	 
PAGEREF _Toc240275814 \h  19  

  HYPERLINK \l "_Toc240275815"  6.1	Occupational Pesticide Handler
Exposure and Risk	  PAGEREF _Toc240275815 \h  19  

  HYPERLINK \l "_Toc240275816"  6.2	Occupational Post-Application Worker
Exposure and Risk	  PAGEREF _Toc240275816 \h  23  

  HYPERLINK \l "_Toc240275817"  7.0	DATA NEEDS AND LABEL RECOMMENDATIONS
  PAGEREF _Toc240275817 \h  26  

  HYPERLINK \l "_Toc240275818"  7.1	Toxicology	  PAGEREF _Toc240275818
\h  26  

  HYPERLINK \l "_Toc240275819"  7.2	Residue Chemistry	  PAGEREF
_Toc240275819 \h  26  

  HYPERLINK \l "_Toc240275820"  7.3	Occupational and Residential
Exposure	  PAGEREF _Toc240275820 \h  27  

  HYPERLINK \l "_Toc240275821"  Appendix A:  TOXICOLOGY ASSESSMENT	 
PAGEREF _Toc240275821 \h  28  

  HYPERLINK \l "_Toc240275822"  A.1.	Acute Toxicity Profile	  PAGEREF
_Toc240275822 \h  28  

  HYPERLINK \l "_Toc240275823"  A.2	Toxicity Profiles	  PAGEREF
_Toc240275823 \h  28  

 

1.0	Executive Summary

Under Section 3 of the Federal Insecticide, Fungicide and Rodenticide
Act (FIFRA), as amended, the Interregional Research Project No. 4 (IR-4)
has submitted petitions (PP#s 8E7425 and 8E7426) to register the end-use
product Rimon® 0.83 Emulsifiable Concentrate (EC) Insecticide (EPA Reg.
No. 66222-35), a 0.83 pound (lb) active ingredient (ai)/gallon (gal) EC
formulation of novaluron
(N-[[[3-chloro-4-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy]
phenyl]amino]carbonyl]-2,6-difluorobenzamide) on bushberry subgroup
13-07B; Brassica, leafy greens, subgroup 5B; turnip, greens; and fruit,
stone, group 12.  The basic producer of novaluron is Makhteshim-Agan of
North America (MANA).  End-use products containing novaluron as the ai
are formulated as EC, suspension concentrate (SC), or water-dispersible
granular (WDG).

IR-4 submitted the bushberry petition on behalf of the Agricultural
Experiment Stations of FL, ME, MI, NJ, OR, PA, and WA.  The petition for
uses on Brassica leafy greens, turnip greens, and stone fruit was
submitted by IR-4 on behalf of the Agricultural Experiment Stations of
CA, DE, FL, GA, MI, MS, NJ, NC, OK, OR, PA, SC, TN, UT, and WA.  IR-4
requests the establishment of tolerances for residues of novaluron only
in/on bushberry subgroup 13-07B (7.0 ppm); Brassica, leafy greens,
subgroup 5B (25 ppm); turnip, greens (25 ppm); and fruit, stone, group
12 (8.0 ppm).  

Novaluron, a benzoylphenyl urea compound, is a pesticide chemical
belonging to the class of insecticides called insect-growth regulators
(IGRs).  IGRs slowly kill insects over a period of a few days by
disrupting the normal growth and development of immature insects. 
Novaluron acts as an insecticide mainly by ingestion, but has some
contact activity.  It is currently registered for uses on pome fruits,
Brassica head and stem vegetables, tuberous and corm vegetables, cotton,
tomatoes, and sugarcane.  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.  

Hazard Characterization

Under the revised 40 CFR Part 158 guidelines, an immunotoxicity study is
now required for novaluron; however, the Agency does not believe that
conducting a functional immunotoxicity study will result in a lower
no-observed-adverse-effect level (NOAEL) than the regulatory dose for
risk assessment.  Apart from the immunotoxicity study requirement, the
toxicological database for novaluron is complete and 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, and
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 did not produce maternal and/or developmental toxicity.
 In the two-generation reproductive toxicity study, both maternal and
offspring toxicity were evidenced by splenomegaly, 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 and subchronic neurotoxicity screening batteries were performed
using novaluron in rats.  Neurotoxic effects of novaluron following a
single dose 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) at the limit dose only (2000 mg/kg/day). 
No signs of neurotoxicity or neuropathology were observed following
repeated dosing 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 Hazard Identification Assessment Review Committee (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 RAB1 toxicologists reevaluated the novaluron database and concluded
that the Food Quality Protection Act (FQPA) Safety Factor (SF) for
increased susceptibility of infants and children can be reduced to 1X. 
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 that the FQPA SF 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, the completeness of the residue chemistry database, and
conservative drinking water assessment.  RAB1 toxicologists reaffirmed
the endpoints previously selected by the HIARC (16-DEC-2003; TXR#
0052361).

An 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 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 RBC damage and turnover
resulting in a regenerative anemia.  The FQPA SF of 1X is applicable for
chronic dietary risk assessment.  Therefore, the chronic
population-adjusted dose (cPAD) is 0.011 mg/kg/day.

There is no short-term dermal endpoint; therefore, only
intermediate-term dermal exposure was assessed.  Short- and
intermediate- term inhalation exposures have been assessed.  In
addition, the short- and intermediate-term inhalation toxicological
endpoints are the same; therefore, the estimates of risk for short-term
duration inhalation exposures are protective of those for
intermediate-term inhalation duration exposures.  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 occupational dermal
and inhalation exposures are for margins of exposure (MOEs) <100.  

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.

Endpoints applicable to risk assessments performed for novaluron in this
document are summarized 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 current chronic dietary
analysis assumed 100% crop-treated for all commodities and was refined
through the use of empirical processing factors, some average field
trial residues (pome fruit, sugarcane, bushberries, Brassica leafy
greens, turnip greens, and stone fruit), average greenhouse trial
residues for tomatoes, anticipated residues (ARs) for meat and milk
commodities, and HED-recommended tolerances for poultry commodities. 
Empirical processing factors for apple juice were translated to pear and
other pome fruit juice and all stone fruit juice.  In accordance with
HED Standard Operating Procedure (SOP) 2000.1, average field-trial
residues for apple and pear were translated to the remaining pome fruit
crops and average field-trial residues for peaches were translated to
nectarines and apricots.  An empirical processing factor was also used
for dried plums.  Estimated drinking water concentrations (EDWCs),
provided by EFED, were included in this assessment as well.  For this
action, the chronic dietary (food and drinking water) exposure to
novaluron is below HED’s LOC for the general U.S. population and all
population subgroups.  The chronic dietary risk estimates were 25% of
the cPAD for the general U.S. population and 83% of the cPAD for
children 1-2 years old, 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 drinking water models.  Tier II 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 I 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 (2.6 ppb).  Therefore, the EDWC value for the chloroaniline
degradate was used to assess chronic aggregate risk. 

Aggregate Exposure Scenarios and Risk Conclusions

Including all existing and proposed uses, an aggregate human-health risk
assessment was conducted for chronic aggregate exposure (food + water)
only.  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.  The chronic aggregate
exposure and risk estimates are below HED’s LOC.  

Occupational Exposure Estimates

It is anticipated that there will be occupational handler and
post-application exposure for the proposed uses of novaluron.  No
chemical-specific handler exposure data were submitted in support of
this Section 3 registration.  It is the policy of HED to use data from
the Pesticide Handlers Exposure Database (PHED) Version 1.1 as presented
in PHED Surrogate Exposure Guide (AUG-1998) to assess handler exposures
for regulatory actions when chemical-specific monitoring data are not
available.  All risks for occupational handlers are above the level of
concern (i.e., MOEs ≥100) with either baseline clothing protection or
with the addition of gloves.  No short-term endpoint was selected for
dermal exposure; therefore, the risks presented for handlers are
representative of intermediate-term exposures, but would be considered
protective of short-term exposures.

The MOEs for occupational postapplication exposure are greater than the
target MOE of 100 on day 0 (12 hours after application) for all crops
and activities.  Postapplication dermal risks were calculated based on
an intermediate-term endpoint and are considered highly conservative for
the included activities.

Recommendation for Tolerances and Registration

Pending submission of revised Sections B and F, there are no residue
chemistry issues that would preclude granting an unconditional
registration for the requested use of novaluron on bushberries,
Brassica, leafy greens, and turnip greens, or the establishment of the
tolerances for novaluron residues listed below:    SEQ CHAPTER \h \r 1 

Bushberry subgroup 13-07B	7.0 ppm

Brassica, leafy greens, subgroup 5B	25 ppm

Turnip, greens	25 ppm

Fruit, stone, group 12, except cherry	1.9 ppm

Cherry	8.0 ppm

Plum, prune, dried	2.6 ppm

Additional storage stability data needs to be submitted before the
residue chemistry database will support an unconditional registration
for the requested use of novaluron on stone fruit.  

Data Needs and Label Recommendations

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 (Toxicity Category IV) of novaluron and inhalation
MOEs >1000 (highest inhalation dose = 0.0019, corresponding to a MOE of
2300) 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.

An immunotoxicity study is required as specified in the new 40 CFR Part
158 data requirements.

Residue Chemistry

860.1200 Directions for Use

A revised section B should be submitted which:

specifies a preharvest interval (PHI) for the use of novaluron on
“Peach Twig Borers”;

updates “chines (bok choy)” to “Chinese (bok choy)” in the
foliar feeding insects controlled by Rimon on “Leafy Brassica
Greens” section; 

prohibits the use of novaluron on turnips harvested for the root and
prohibits the feeding of turnip tops to livestock; and

includes a statement in the “Stone Fruit,” “Bushberries,”
“Leafy Brassica Greens,” and “Turnip Greens” sections which
states that the use of adjuvants on these commodities is prohibited.

860.1380 Storage Stability Data

Storage stability data on dried plums for up to 243 days (~8 months) are
required.

  

860.1550 Proposed Tolerances

A revised Section F should be submitted to remove the word combined and
cite the appropriate CAS name for novaluron:

“Tolerances are established for residues of the insecticide novaluron,
including its metabolites and degradates, in or on the commodities in
the table below.  Compliance with the tolerance levels specified below
is to be determined by measuring only novaluron
(N-[[[3-chloro-4-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy]phenyl]amin
o]carbonyl]-2,6-difluorobenzamide) in or on the following raw
agricultural commodities:”

In addition, the proposed tolerance should be revised to reflect the
correct commodity definitions and the recommend tolerances as specified
in Table 4.1.

Note to RD:  40 CFR 180.598 should also be amended to correct the
commodity “Vegetables, tuberous and corn, subgroup 1C” to
“Vegetable, tuberous and corm, subgroup 1C.”  Also, the existing
tolerance for residues of novaluron in/on eggs should be increased from
0.05 ppm to 0.07 ppm (Memo, S. Levy, 31-JAN-08; DP# 340137).

Occupational and Residential Exposure

None.  

2.0	PROPOSED USE PATTERN

IR-4 has submitted a draft label, dated 19-AUG-2008, for Rimon® 0.83 EC
Insecticide (EPA Reg. No. 66222-35) to include the proposed new uses
(see Table 2.0) on bushberry crop subgroup 13-07B; Brassica, leafy
greens, subgroup 5B; turnip, greens; and stone fruit, group 12.



Table 2.0.  Summary of Proposed Use Pattern for Novaluron. 

Crop Type/ Use Site	Max. Application Rate	Application Equipment
Application Interval	Max. lb ai per Crop, Season or Year	Max.
Applications per Crop or Year or Season	PHI (days)	Additional Notes

RIMON® 0.83EC Insecticide  [EPA Reg # (66222-35):  9.3% ai, 0.83 lbs
ai/gal; liquid; REI = 12 hours]

Brassica, leafy greens, subgroup 5B	0.078 lb ai/A	Aerial, groundboom	7
to 14 days	0.23 lb ai /A/season	3 applications per crop per season	7
days of harvest	Do not make more than 2 applications against whiteflies
per season.

Turnip greens	0.078 lb ai/A	Aerial, groundboom	7 to 14 days	0.23 lb ai
/A/season	3 applications per crop per season	7 days of harvest	Do not
make more than 2 applications against whiteflies per season.

Stone fruit, group 121	0.32 lb ai/A	Aerial, airblast	14 to 17 days for
oriental fruit moth	0.97 lb ai /A/season	3 applications per season	14
days of harvest for oriental fruit moth	Do not use RIMON® in alternate
row middle application patterns since this method will result in
off-timing application and poor performance.

	10 to 14 days for oliquebanded leafroller, fruittree leafroller,
omnivorus leafroller

	8 days of harvest for oliquebanded leafroller, fruittree leafroller,
omnivorus leafroller

	Bushberry Subgroup1	0.19 lb ai/A	Aerial, groundboom	10 to 14 days	0.58
lb ai/A/season	3 applications per crop per season	8 days of harvest	Do
not make more than 2 applications against whiteflies per season.

1 Do not apply by ground equipment within 75 feet of bodies of water
such as lakes, reservoirs, rivers, permanent streams, natural ponds,
marshes, or estuaries.  All applications must include a 25 foot
vegetative buffer strip within the buffer zone to decrease runoff.

2 PHI = preharvest interval; REI = restricted-entry interval.  HED
Conclusions:  The proposed label is adequate to allow evaluation of the
residue data relative to the proposed new uses on bushberry subgroup
13-07B; Brassica, leafy greens, subgroup 5B; turnip, greens; and fruit,
stone, group 12 provided a revised section B is submitted which:

specifies a PHI for the use of novaluron on Peach Twig Borers;

updates “Chines (bok choy)” to “Chinese (bok choy)” in the
foliar feeding insects controlled by Rimon® on Leafy Brassica Greens
section; 

prohibits the use of novaluron on turnips harvested for the root and
prohibits the feeding of turnip tops to livestock; and

includes a statement in the Stone Fruit, Bushberries, Leafy Brassica
Greens, and Turnip Greens sections which states that the use of
adjuvants on these commodities is prohibited.

3.0	HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS

Under the revised 40 CFR Part 158 guidelines, an immunotoxicity study is
now required for novaluron; however, the Agency does not believe that
conducting a functional immunotoxicity study will result in a lower
NOAEL than the regulatory dose for risk assessment.  Apart from the
immunotoxicity study requirement, 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, and decreased 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 splenomegaly, 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 and subchronic neurotoxicity screening batteries were performed
using novaluron in rats.  Neurotoxic effects of novaluron following a
single dose were evidenced by clinical signs (piloerection,
fast/irregular breathing), FOB parameters (head swaying, abnormal gait),
and neuropathology (sciatic and tibial nerve degeneration) at the limit
dose only (2000 mg/kg/day).  No signs of neurotoxicity or neuropathology
were observed following repeated dosing 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.

Novaluron primarily produced hematoxic effects which are associated with
increased erythropoiesis.  Histopathological examination of organs
associated with the immune system (i.e., thymus, spleen, lymph nodes)
showed an increase in absolute spleen weight and increased incidence and
severity of hemosiderosis in the spleen of the chronic studies in rats
and mice and the reproduction study in rats at high doses.  These
findings were associated with the hematotoxic effect which caused
removal and accumulation of abnormal erythrocytes.  The overall weight
of evidence suggests that novaluron does not directly target the immune
system.  An immunotoxicity study is required as part of the revised 40
CFR Part 158 toxicology data requirements for novaluron; however, HED
does not believe that conducting a functional immunotoxicity study will
result in a lower NOAEL than the regulatory dose being used for risk
assessment, and an additional UF for database uncertainty (UFDB) is not
needed to account for the lack of the required immunotoxicity study.

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.  

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 3.1.

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 with novaluron in rats.  Novaluron does not
appear to be a neurotoxicant since the effects observed in the acute
neurotoxicity study were not severe, were only noticed at the limit
dose, and were not reproduced at similar doses in the subchronic
neurotoxicity study.  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 SF(s): 

Based upon the above-described data, the FQPA SF 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.  Apart from the
immunotoxicity study requirement, 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	FQPA SF and LOC for Risk
Assessment	Study and Toxicological Effects

Acute Dietary 

(all populations)

	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

	FQPA SF = 1X

cRfD = cPAD = 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	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	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 was
observed at the limit dose in the 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/ 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/ 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/ 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/ 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/ 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 = 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

EPA is required under the 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 were
scientific bases for including, as part of the program, 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.  When the appropriate
screening and/or testing protocols being considered under the Agency’s
Endocrine Disrupter Screening Program (EDSP) have been developed and
vetted, novaluron may be subjected to additional screening and/or
testing to better characterize effects related to endocrine disruption.

4.0	DIETARY EXPOSURE/RISK CHARACTERIZATION

The residue chemistry data submitted in support of the proposed uses
were summarized in the HED memorandum by J. L. Van Alstine (Memo,
09-SEP-2009; D357060).  The chronic dietary exposure assessment was
completed in a HED memorandum by J. L. Van Alstine (Memo, 09-SEP-2009;
D359460).

4.1	Food Residue Profile

Nature of the Residue - Plants:  HED previously (PP#2F6430) concluded
that the nature of the residue in plants is adequately understood based
on acceptable metabolism studies conducted on apples, cabbage, cotton,
and potatoes using [difluorophenyl-U-14C]novaluron and
[chlorophenyl-U-14C]novaluron as the test substances.  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 that 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; D285474).  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; D297646).  

Nature of the Residue - Livestock:  Based on the most recent Table 1 of
OPPTS 860.1000 [Memo, Chemistry Science Advisory Council (ChemSAC),
30-JUN-2008], and provided that a revised Section B is submitted, which
prohibits the use of novaluron on turnips harvested for the root and
prohibits the feeding of turnip tops to livestock, there are no feed
commodities associated with the current petition.  Therefore, a
discussion of the nature of the residue in livestock is unnecessary.    

Residue Analytical Enforcement Method - Plant:  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 for the GC/ECD method have been
submitted and reviewed in a previous HED memorandum (Memo, S. Levy,
23-AUG-2006; D325183) and both methods were forwarded to the EPA
Analytical Chemistry Branch (ACB)/Biological and Economics Analysis
Division (BEAD) for petition method validation (PMV).  

ACB concluded that based upon review of the submitted method validation
data, without laboratory validation, that the GC/ECD and
high-performance liquid chromatography/ultraviolet (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 (Memo, S. Levy,
15-SEPT-2004; D306998).  Both methods have been forwarded to the Food
and Drug Administration (FDA) for inclusion in the Pesticide Analytical
Manual, Volume II (PAM II) as a Letter Method (S. Levy, 15-SEPT-2004;
D307595).  An interference study was requested and a specific
single-analyte confirmatory method was submitted and considered
acceptable (Memo, J. Langsdale, 21-OCT-2008; D355574).

Magnitude of the Residue - Plants:  The submitted field trial data for
blueberries and mustard greens are adequate and will support the
establishment of residue tolerances for novaluron in/on the bushberry
crop subgroup 13-07B (7.0 ppm) and the Brassica, leafy greens, crop
subgroup 5B (25 ppm).  The submitted field trial data for peaches,
plums, and cherries are adequate to support the establishment of residue
tolerances for novaluron in/on fruit, stone, group 12, except cherry at
1.9 ppm and in/on cherry at 8.0 ppm.  However, additional storage
stability data need to be submitted before the residue chemistry
database will support an unconditional registration for the requested
use of novaluron on stone fruit.  

Processed Food and Feed:  For dried plums, the processed food data are
classified as scientifically acceptable pending submission of freezer
storage stability data for dried plums for up to 243 days (~8 months). 
The submitted processing study indicated a concentration factor of 3.39x
for dried plums.  The available data support a tolerance of 2.6 ppm for
residues of novaluron in/on dried plums.    

Confined/Field Accumulation in Rotational Crops:  Bushberries and stone
fruit are typically not rotated; however, Brassica leafy greens and
turnip greens may be rotated.  The available confined rotational crop
study is adequate.  The HED MARC has determined that for tolerance
assessment and risk assessment, parent only is the residue of concern. 
Based on the results of a previously submitted confined rotational crop
study (PP#2F6430), 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, which is appropriate for this
petition.  

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 blueberries, mustard greens, peaches,
plums, and cherries 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 7.0 ppm for bushberry crop subgroup 13-07B; 25 ppm for
Brassica, leafy greens, crop subgroup 5B; 1.9 ppm for fruit, stone,
group 12, except cherry; and 8.0 ppm for cherry.  The tolerance for
dried plums (prunes) was calculated to be 2.6 ppm.  A revised Section F
is required to update the proposed tolerance of 8.0 ppm for residues
in/on fruit, stone, group 12 to 1.9 ppm for fruit, stone, group 12,
except cherry, 8.0 ppm for cherry, and 2.6 ppm for plume, prune, dried. 
The word combined should be removed from the revised Section F and the
appropriate CAS name for novaluron,
“N-[[[3-chloro-4-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy]phenyl]am
ino]carbonyl]-2,6-difluorobenzamide” should be cited.      

There are no feed commodities associated with the current petition
provided a revised Section B is submitted which prohibits the use of
novaluron on turnips harvested for the root and prohibits the feeding of
turnip tops to livestock.

No Codex, Canadian, or Mexican MRLs have been established for novaluron
on bushberries, Brassica, leafy greens, turnip greens, and stone fruit. 
Canada is currently in the process of reviewing the use of novaluron on
Brassica, leafy greens, subgroup 5B and fruit, stone, group 12.  EPA and
PMRA tolerance recommendations have been harmonized at 7.0 ppn for
Brassica, leafy greens, subgroup 5B, 1.9 ppm for fruit, stone, group 12,
except cherry, 8.0 ppm for cherry, and 2.6 ppm for dried plums (personal
communication with Monica Le of PMRA, 28-AUG-2009).  

A summary of HED’s recommended tolerances for the current petition is
presented in Table 4.1.  A revised Section B should be submitted which
reflects the correct commodity definitions and tolerances as specified
in Table 4.1.  

Table 4.1.  Tolerance Summary for Novaluron.

Commodity	IR-4 Proposed Tolerance (ppm)	HED-Recommended Tolerance (ppm)
Correct Commodity Definition

Bushberry subgroup 13-07B	7.0	7.0

	Brassica, leafy greens, subgroup 5B	25	25	Brassica, leafy greens,
subgroup 5B

Turnip, greens	25	25

	Fruit, stone, group 12	8.0	1.9	Fruit, stone, group 12, except cherry

Cherry	-	8.0	Cherry

Plum, prune, dried	-	2.6	Plum, prune, dried

4.2	Drinking Water Residue Profile

The following information concerning the environmental fate and drinking
water assessment of novaluron was provided by EFED (Memo, I. Maher,
10-MAR-09; D357061).  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.  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
standard EFED drinking water models.

Tier II PRZM/EXAMS modeling was performed to estimate drinking water
concentrations for surface water for the parent novaluron.  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 aerial applications to
apples grown in PA at the maximum annual application rate of 0.96 lb
ai/acre, applied three times at 0.32 lb ai/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 0.76 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.  For surface water, the annual average EDWC for
chlorophenyl urea is 0.89 ppb and the annual average EDWC for
chloroaniline is 2.6 ppb.  The chlorophenyl urea estimate is based upon
the maximum application rate in peaches [0.32 lb ai/A applied 3 times
per season every 7 days (0.96 lb ai/year)] and the chloroaniline
estimate is based upon the maximum application rate in apples [0.32 lb
ai/A applied 3 times per season every 10 days (0.96 lb ai/year)].

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
ai/acre (i.e., three applications of 0.32 lb ai/acre).  The estimate for
the parent novaluron is 0.0056 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.

4.3	Dietary Exposure and Risk

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.”

A chronic dietary exposure and risk assessment was conducted using the
DEEM-FCID(, Version 2.03, which uses food consumption data from the U.S.
Department of Agriculture’s (USDA’s) Continuing Surveys of Food
Intakes by Individuals (CSFII) from 1994-1996 and 1998.  The analysis
was performed to support the request for use of novaluron on bushberry
subgroup 13-07B; Brassica, leafy greens, subgroup 5B; turnip greens; and
fruit, stone, group 12.  

The 1994-96 and 1998 CSFII data are based on the reported consumption of
more than 20,000 individuals over two non-consecutive survey days. 
Foods “as consumed” (e.g., apple pie) are linked to EPA-defined food
commodities (e.g., apples, peeled fruit - cooked; fresh or N/S; baked;
or wheat flour - cooked; fresh or N/S, baked) using publicly available
recipe translation files developed jointly by USDA/ARS and EPA.  For
chronic exposure assessment, consumption data are averaged for the
entire U.S. population and within population subgroups, but for acute
exposure assessment are retained as individual consumption events. 
Based on analysis of the 1994-96 and 1998 CSFII consumption data, which
took into account dietary patterns and survey respondents, HED concluded
that it is most appropriate to report risk for the following population
subgroups: the general U.S. population, all infants (<1 year old),
children 1-2, children 3-5, children 6-12, youth 13-19, adults 20-49,
females 13-49, and adults 50+ years old.

For chronic dietary exposure assessment, an estimate of the residue
level in each food or food-form (e.g., orange or orange juice) on the
food commodity residue list is multiplied by the average daily
consumption estimate for that food/food form to produce a residue intake
estimate.  The resulting residue intake estimate for each food/food form
is summed with the residue intake estimates for all other food/food
forms on the commodity residue list to arrive at the total average
estimated exposure.  Exposure is expressed in mg/kg body weight/day and
as a percent of the cPAD.  This procedure is performed for each
population subgroup.

The chronic dietary (food and drinking water) exposure and risk
assessment was conducted for the proposed use on bushberries, Brassica
leafy greens, turnip greens, stone fruit, all established uses, and
drinking water.  A partially refined assessment was conducted.  EDWCs
were provided by EFED.  The chronic analysis assumed 100% crop treated
for all commodities; incorporated average field trial residues for some
commodities (pome fruit, sugarcane, bushberries, Brassica leafy greens,
and stone fruit); average greenhouse trial residues for tomatoes;
empirical processing factors for apple juice (translated to pear and
stone fruit juice), tomato paste and purée, and dried plums; 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 chronic dietary (food and drinking water) exposure to novaluron is
below HED’s LOC for the general U.S. population and all population
subgroups.  The chronic dietary exposure estimates are 25% of the cPAD
for the general U.S. population and 83% of the cPAD for children 1-2
years old, the most highly exposed population subgroup.  



Table 4.3.  Summary of Chronic Dietary Exposure (Food and Drinking
Water) and Risk for Novaluron.

Population Subgroup	Acute Dietary	Chronic Dietary	Cancer

	Dietary Exposure (mg/kg/day)	% aPAD	Dietary Exposure

(mg/kg/day)	% cPAD	Dietary Exposure

(mg/kg/day)	Risk

General U.S. Population	N/A	N/A	0.002710	25	N/A	N/A

All Infants (< 1 year old)

	0.004645	42

Children 1-2 years old

	0.009150	83

Children 3-5 years old

	0.007120	65

Children 6-12 years old

	0.004293	39

Youth 13-19 years old

	0.002346	21

Adults 20-49 years old

	0.001905	17

Adults 50+ years old

	0.001908	17

Females 13-49 years old

	0.001824	17

1 The chronic RfD (cRfd= cPAD = 0.011 mg/kg/day).

4.4	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

Including all existing and proposed uses, a human-health aggregate risk
assessment has been conducted for the following exposure scenario: 
chronic aggregate exposure (food + water only).  An acute aggregate
assessment was not conducted for novaluron because an endpoint of
concern attributable to a single dose was not identified.  A cancer
aggregate 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 4.3.  The chronic aggregate exposure and risk estimate is
below HED’s level of concern.  

6.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY

An occupational exposure assessment for novaluron was prepared in an HED
memorandum dated 17-FEB-2009 (L. Venkateshwara et al.; D359459).  See
Table 2.0 for a summary of the proposed use patterns.  

6.1	Occupational Pesticide Handler Exposure and Risk

There is potential for occupational handler exposure from the proposed
uses on agricultural crops.  Handler’s exposure and risk were
estimated for the following scenarios: 

	

Mixer/Loader:

(1a) 	Mixing/loading liquids for aerial application;

(1b)	Mixing/loading liquids for groundboom application;

(1c)	Mixing/loading liquids for airblast applications;

 

Applicator:

(2) 	Applying sprays via aerial applications;

(3) 	Applying sprays via groundboom applications;

(4)	Applying sprays via airblast applications; and

Flagger:

(5) 	Flagging to support aerial applications.

No chemical-specific data were available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure to pesticide
handlers are based upon surrogate study data available in PHED (August,
1998).  For pesticide handlers, HED presents estimates of dermal
exposure for “baseline” (i.e., workers wearing a single layer of
work clothing consisting of a long-sleeved shirt, long pants, shoes plus
socks, and no protective gloves), as well as for “baseline” and the
use of protective gloves or other personal-protective equipment (PPE),
as might be necessary.  The novaluron product labels direct applicators
and other handlers to wear a long-sleeved shirt, long pants, protective
eyewear, chemical-resistant gloves, and shoes plus socks. 

Handler exposure is expected to be short- and intermediate-term based on
information provided in the proposed labels.  There is no short-term
dermal endpoint; therefore, only intermediate-term dermal exposure has
been assessed.  Short- and intermediate- term inhalation exposures have
been assessed.  In addition, the short- and intermediate-term inhalation
toxicological endpoints are the same; therefore, the estimates of risk
for short-term duration inhalation exposures are protective of those for
intermediate-term inhalation duration exposures.  The average adult body
weight of 70 kg was used for estimating inhalation and dermal doses. 
Long-term exposures are not expected, therefore, a long-term assessment
was not conducted.

Daily dermal or inhalation handler exposures are estimated for each
applicable handler task with the application rate, the area treated in a
day, and the applicable dermal or inhalation unit exposure using the
following formula:

Daily Exposure (mg ai/day) = Unit Exposure (mg ai/lb ai handled) x
Application Rate (lbs ai/area) x Daily Area Treated (area/day)

Where:  

Daily Exposure		=	Amount (mg ai/day) deposited on the surface of the
skin that is 

available for dermal absorption or amount inhaled that is available for
inhalation absorption;

Unit Exposure 		=	Unit exposure value (mg ai/lb ai) derived from August
1998 PHED 

data;

Application Rate		=	Normalized application rate based on a logical unit
treatment, such as 

acres; and

Daily Area Treated 	=	Normalized application area based on a logical
unit treatment such as 

acres (A/day).

The daily dermal or inhalation dose is calculated by normalizing the
daily exposure by body weight and adjusting, if necessary, with an
appropriate dermal or inhalation-absorption factor using the following
formula:

Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day) x
(Absorption Factor (%/100)) / Body Weight (kg)

Where:

Average Daily Dose 	=	Absorbed dose received from exposure to a
pesticide in a given scenario (mg ai/kg body weight/day);

Daily Exposure 		=	Amount (mg ai/day) deposited on the surface of the
skin that 

is available for dermal absorption or amount inhaled that is available
for inhalation absorption;

Absorption Factor 	=	A measure of the amount of chemical that crosses a
biological 

boundary such as the skin or lungs (% of the total available absorbed);
and

Body Weight 		=	Body weight determined to represent the population of
interest in a risk assessment (kg).  An average adult body weight of 70
kg was used for estimating inhalation and dermal doses.

Non-cancer dermal and inhalation risks for each applicable handler
scenario are calculated using a MOE, which is a ratio of the NOAEL to
the daily dose.  All MOE values were calculated using the formula below:

MOE= NOAEL or LOAEL (mg/kg/day) / Average Daily Dose (mg/kg/day)

Dermal and inhalation risks were combined in this assessment, since the
toxicological effects for these exposure routes were similar.  Dermal
and inhalation risks were combined using the following formula:

  SEQ CHAPTER \h \r 1 Total MOE = NOAEL / (Dermal + Inhalation Dose)

Table 6.1 presents the estimated risks for workers based on the short-
and intermediate-term dermal and inhalation exposures at baseline and
with personal protective equipment.  HED has determined that risks are
not of concern (i.e., MOEs >100), provided workers wear protective
gloves as recommended on the label.  No short-term endpoint was selected
for dermal exposure, therefore, the risks presented for handlers are
representative of only intermediate-term exposures and would be
considered protective of short-term exposures.

It should be noted that only engineering control data are available to
assess dermal and inhalation risks to handlers operating aircraft
(enclosed cockpit).  The risks are not of concern for pilots using
enclosed cockpits.



Table 6.1.  Occupational Handler Dermal and Inhalation Exposures and
Risks.

Dermal and

Inhalation Unit Exposures

(mg/lb ai)	Application rate

(lb ai/A)a	Area Treated Daily (A)b	Short- and Intermediate-term Doses
(mg/kg/day)c	Total Dose d	Total MOEs e

Mixer/Loader – Airblast Application

Dermal

Baseline f:  2.9 (HC) i

Single layer w/glovesh:  0.023 (LC)

Inhalation

Baseline g:  0.0012 (HC)	0.32	40	Dermal

Baseline:  0.053

Single layer w/gloves:  0.00042	Baseline Dermal + Inhalation

0.053

Single layer w/gloves + Inhalation

0.00064	Baseline Dermal + Inhalation

82

Single layer w/gloves + Baseline Inhalation

6800

	Inhalation

Baseline:  0.00022

Mixer/Loader – Groundboom Application

Dermal

Baseline:  2.9 (HC) 

Single layer w/gloves: 0.023 (LC)

Inhalation

Baseline:  0.0012 (HC)	0.19	80	Dermal

Baseline:  0.062

Single layer w/gloves:  0.000499	Baseline Dermal + Inhalation

0.062

Single layer w/gloves + Inhalation

0.00076 	Baseline Dermal + Inhalation

70

Single layer w/gloves + Baseline Inhalation

5800

	Inhalation

Baseline:  0.00026

Mixer/Loader – Aerial Application

Dermal

Baseline:  2.9 (HC)

Single layer w/gloves: 0.023 (LC)

Inhalation

Baseline:  0.0012 (HC)	0.32	350	Dermal

Baseline:  0.464

Single layer w/gloves:

0.00368	 Baseline Dermal + Inhalation

0.47

Single layer w/gloves + Inhalation

0.0056	Baseline Dermal + Inhalation

9

Single layer w/gloves + Baseline Inhalation

790

	Inhalation

Baseline:  0.0019

Applicator –Airblast Application

Dermal

Baseline:  0.36 (HC)

Inhalation

Baseline:  0.0045 (HC)	0.32	40	Dermal

Baseline:  0.0066	Baseline Dermal + Inhalation

0.0074

	 Baseline Dermal + Inhalation

590

	Inhalation 

Baseline:  0.00082

Applicator –Groundboom Application

Dermal

Baseline:  0.014 (HC)

Inhalation

Baseline:  0.00074 (HC)	0.19	80	Dermal

Baseline:  0.000304

	

Baseline Dermal + Inhalation

0.00046

	Baseline Dermal + Inhalation

9400

	Inhalation

Baseline:  0.00016

Applicator –Aerial Application

Dermal

Engineering Control: 0.0050 (HC)

Inhalation

Baseline:  0.000068 (HC)	0.32	350	Dermal

Baseline:  0.0008	Baseline Dermal + Inhalation

0.00091	Baseline Dermal + Inhalation

4800

	Inhalation

Baseline:  0.00011

Flagger –Aerial  Application

Dermal

Baseline:  0.011

Inhalation

Baseline:  0.00035 (LC)	0.32	350	Dermal

Baseline:  0.00176

Inhalation

Baseline:  0.00056  	Baseline Dermal + Inhalation

0.0023 	Baseline Dermal + Inhalation

1900

a  Application rates are the maximum recommended rates provided on the
novaluron product labels.

b  Area treated per day values are HED estimates based on ExpoSAC Policy
#9 “Standard Values for Daily Acres Treated in Agriculture,”
industry sources, and HED estimates.

c  Dose (mg/kg/day) = Unit exposure(mg/lb ai) x App Rate (lb ai/acre) x
Area Treated (acres/day) x %Absorption (10% dermal and 100% inhalation
assumed) / Body weight.  The body weight is 70 kg for the inhalation and
dermal dose. 

d  Total Dose = Dermal + Inhalation Dose.

e  Total MOE = NOAEL(4.38 mg/kg/day) / Total Dose.

f  Baseline Dermal:  Long-sleeved shirt, long pants, no gloves.

g  Baseline Inhalation:  no respirator.

h  Single layer w/gloves:  Single layer baseline attire plus
chemical-resistant gloves.

i  Data Confidence for PHED unit exposures:  LC = Low Confidence, MC =
Medium Confidence, HC = High Confidence.

6.2	Occupational Post-Application Worker Exposure and Risk

HED assumes that inhalation exposures are minimal following outdoor
applications of an active ingredient with low vapor pressure.  Since
novaluron is applied only in outdoor settings and has a low vapor
pressure (1.2 x 10-7 mm Hg), a quantitative postapplication inhalation
exposure and risk assessment was not conducted. 

The proposed use is for a postemergent application; therefore, a dermal
post application exposure assessment was conducted.  Since no
postapplication data were submitted in support of this registration
action, dermal exposures during postapplication activities were
estimated using dermal transfer coefficients from the Science Advisory
Council for Exposure (ExpoSAC) Policy Number 3.1: Agricultural Transfer
Coefficients, August 2000, summarized in Table 6.2 below and the
following assumptions:

Application Rate		= 	0.078 lb ai/A for Brassica, leafy greens, subgroup 

5B and turnip greens 

0.32 lb ai/A for stone fruit, group 12

0.19 lb ai/A for bushberry subgroup 13-07B

Exposure Duration	=	8 hours per day

Body Weight		=	70 kg for adult male		

Dermal Absorption	= 	10%

Fraction of ai retained on foliage is assumed to be 20% (0.2) on day
zero (= % dislodgeable foliar residue (DFR), after initial treatment)
for agricultural crops.  This fraction is assumed to further dissipate
at the rate of 10% (0.1) per day on following days.  These are default
values established by HED’s ExpoSAC.

Table 6.2.  Anticipated Postapplication Activities and Dermal Transfer
Coefficients.

Proposed Crops	Policy Crop Group Category	Exposure Potential	Transfer
Coefficients (cm2/hr)	Activities

Brassica, leafy greens, subgroup	Vegetable, head and stem Brassica	Low
2000	Irrigation, scouting, thinning, hand weeding

Medium	4000	Scouting

High	5000	Hand harvest, irrigation, hand pruning, topping, thinning,
tying

Turnip greens	Vegetable, root	Low	300	Irrigation, scouting, thinning,
hand weeding

High	2500	Hand harvest

Stone fruit, group 12	Tree “fruit,” deciduous	Low	1000	Scouting,
irrigation, hand weeding

High	1500	Hand harvest, hand pruning, tying

Very High	3000	Thinning

Bushberry	Berry, low	Low	400	Scouting, hand weeding, irrigation, hand
pruning, thinning

High	1500	Hand harvest, hand pruning

The information in Table 6.2 is based on proprietary and non-proprietary
data.

The following equations were used to calculate risks for workers
performing postapplication activities:

DFRt (µg/cm2) = AR (lb ai/acre) x F x (1-D)t x 4.54E8 µg/lb x 2.47E-8
acre/cm2

Where:	

	DFRt	=	dislodgeable foliage residue on day "t" (µg/cm2);

	AR	=	application rate (lb ai/acre);

	F	=	fraction of ai retained on foliage (unitless);

	D	=	fraction of residue that dissipates daily (unitless);

and

Daily dermal dose t (mg/kg-day) = [DFRt (µg/cm2) x 1E-3 mg/µg x Tc
(cm2/hr) x DA x ET (hrs)] / BW (kg)

Where:

	t	=	number of days after application day (days);

	DFRt	=	dislodgeable foliage residue on day "t" (µg/cm2);

	Tc	=	transfer coefficient (cm2/hr);

	DA	=	dermal absorption factor (unitless);

	ET	=	exposure time (hr/day);

	BW	=	body weight (kg);

and

MOE = NOAEL (mg/kg/day) / Daily Dermal Dose (mg/kg/day).

The postapplication exposures associated with the proposed new uses are
summarized in Table 6.3.  The resulting MOEs are greater than 100 on day
0 (12 hours after application) for all crops and activities. 
Postapplication dermal risks were calculated based on an
intermediate-term endpoint and are considered highly conservative for
the included activities.

Table 6.3.  Postapplication Risks for Novaluron.

Crop	Application Rate

(lb ai/A)	Contact Potential	Transfer Coefficient

(cm2/hr)	DFR (ug/cm2)	Days After Treatment	Daily Dose1

(mg/kg/ay)	MOE2

Brassica, leafy greens, subgroup  5B	0.078	Low	Irrigation, scouting,
thinning, hand weeding (2000)	0.18	12 hours (0 days)	0.004	1100

Medium	Scouting (4000)

	0.008	550

0.01	440

High	Hand harvest, irrigation, hand pruning, topping, thinning, tying
(5000)

Turnip, greens	0.078	Low	Irrigation, scouting, thinning, hand weeding
(300)	0.18	12 hours (0 days)	0.0006	7,300

High	Hand harvest (2500)

	0.005	880

Stone fruit, group 12	0.32	Low	Scouting, irrigation, hand weeding (1000)
0.72	12 hours (0 days)	0.008	530

High	Hand harvest, hand pruning, tying (1500)

	0.012	370

Very High	Thinning (3000) 

	0.025

	180

Bushberry Subgroup 13-07B	0.19	Low	Scouting, hand weeding, irrigation,
hand pruning, thinning (400)	0.43	12 hours (0 days)	0.002	2200

High	Hand harvest, hand pruning (1500)

	0.007	600

The information in the table is based on proprietary and non-proprietary
data.

1 Daily Dose = [DFR (ug/cm2) x Tc (cm2/hr) x 0.001 mg/µg x Dermal
Absorption (10%) x 8 hrs/day] ÷ Body Weight (70 kg).

2 NOAEL/Daily Dose (Intermediate-term NOAEL = 4.38 mg/kg/day).

7.0	DATA NEEDS AND LABEL RECOMMENDATIONS

7.1	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.

An immunotoxicity study is required as specified in the new 40 CFR Part
158 data requirements.

7.2	Residue Chemistry

860.1200 Directions for Use

A revised section B should be submitted which:

specifies a PHI for the use of novaluron on Peach Twig Borers;

updates “Chines (bok choy)” to “Chinese (bok choy)” in the
foliar feeding insects controlled by Rimon on Leafy Brassica Greens
section; and

prohibits the use of novaluron on turnips harvested for the root and
prohibits the feeding of turnip tops to livestock; and

includes a statement in the Stone Fruit, Bushberries, Leafy Brassica
Greens, and Turnip Greens section which states that the use of adjuvants
on these commodities is prohibited.

860.1380 Storage Stability Data

Storage stability data on dried plums for up to 243 days (~8 months) is
required.  

860.1550 Proposed Tolerances

A revised Section F should be submitted to remove the word combined and
cite the appropriate CAS name for novaluron:

”Tolerances are established for residues of the insecticide novaluron,
including its metabolites and degradates, in or on the commodities in
the table below.  Compliance with the tolerance levels specified below
is to be determined by measuring only novaluron
(N-[[[3-chloro-4-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy]phenyl]amin
o]carbonyl]-2,6-difluorobenzamide) in or on the following raw
agricultural commodities:”

In addition, the proposed tolerance should also be revised to reflect
the correct commodity definitions and the recommend tolerances as
specified in Table 4.1.

Notes to RD:  40 CFR 180.598 should be amended to correct the commodity
“Vegetables, tuberous and corn, subgroup 1C” to “Vegetable,
tuberous and corm, subgroup 1C.”  Also, the existing tolerance for
residues of novaluron in/on eggs should be increased from 0.05 ppm to
0.07 ppm (Memo, S. Levy, 31-JAN-08; DP# 340137).

7.3	Occupational and Residential Exposure

None.  

Attachments:

Appendix A:  TOXICOLOGY ASSESSMENT

A.1	Acute Toxicity Profile.

A.2	Toxicity Profiles.

cc: J. Van Alstine, L. Venkateshwara, K. Lowe, R. Mitkus

RDI: RAB1 Chemists (6/24/09); RAB1 Branch (6/24/09); G. Kramer (9/9/09);
D. Vogel (9/9/09)

J. Van Alstine: S-10954: Potomac Yard 1 (PY1): (703)603-8866: 7509P:
RAB1

Appendix A:  TOXICOLOGY ASSESSMENT

A.1.	Acute Toxicity Profile

Table A.1.  Acute Toxicity of Novaluron.

Guideline No.	Study Type	MRID #(s)	Results	Toxicity Category

870.1100

(81-1)	Acute Oral (rat)	44961001	LD50 > 5000 mg/kg	IV

870.1200

(81-2)	Acute Dermal (rat)	 45003201	LD50 > 2000 mg/kg	III

870.1300

(81-3)	Acute Inhalation (rat)	45003202	LC50 > 5.15 mg/L	IV

870.2400

(81-4)	Primary Eye Irritation (rabbit)	45003203 	Not an eye irritant	IV

870.2500

(81-5 )	Primary Skin Irritation (rabbit)	45003204	Not a dermal irritant
IV

87.2600

(81-6)	Dermal Sensitization (guinea pig)	45084001 	Not a dermal
sensitizer	N/A

A.2	Toxicity Profiles

Table A.2.  Toxicity Profile of Novaluron.

Guideline No/ 

Study type	

MRID No.(year)/ classification/Doses	

Results

870.3100

90-Day oral toxicity rodents	45651504/45651503 (1993/1990);

Acceptable/guideline

Study I: 0, 50, 100, 200, or 400 ppm (equivalent to 0, 3.52, 6.93,
13.03, and

27.77 mg/kg bw/day, respectively in males and 0, 4.38, 8.64, 17.54, and
34.39 mg/kg bw/day, respectively in females)

Study II: 0, 10, 320, or 10,000

ppm (equivalent to 0, 0.7, 22.2, and 713 mg/kg bw/day, respectively in
males and 0, 0.8, 24.3, and 754 mg/kg bw/day, respectively in females)
NOAEL = 320 ppm (22.2 mg/kg/day) in males and 50 ppm (4.38 mg/kg/day) in
females.

LOAEL = 400 ppm (27.77 mg/kg/day) in males based on increased occurrence
of extramedullary hematopoiesis and hemosiderosis in spleen; and 100 ppm
(8.64 mg/kg/day) in females based on reduction in hemoglobin,
hematocrit,

and RBC count; increased occurrence of extramedullary hematopoiesis in
the

spleen and hemosiderosis in the spleen and liver.

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 novaluron (Lot no. 970211/4, 99.3% chemical purity)
followed by a single dose of radiolabeled novaluron.

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]novaluron or [difluorophenyl-14C]novaluron,
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.

Acceptable/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

Acceptable/Guideline	There was no statistically significant increase in
the frequency of micronucleated polychromatic erythrocytes in mouse bone
marrow at any dose or harvest time.

870.5375

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	40, 200, and 1000 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)

Acceptable/Guideline	Novaluron was considered not to show any evidence
of causing DNA damage to HeLa S3 epithelioid cells in this unscheduled
DNA synthesis 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)

Acceptable/Guideline	Novaluron was equivocal for bacterial DNA damage in
the absence of S9 activation, and negative for bacterial DNA damage in
the presence of S9 activation.

Novaluron	                       Human-Health Risk Assessment	          
         DP# 357078 

________________________________________________________________________
________________________________________________________________________
___________________________________________

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