UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

 PREVENTION, PESTICIDES,

AND TOXIC SUBSTANCES

MEMORANDUM

Date:		23-FEB-2010

SUBJECT:	Novaluron:  Human-Health Risk Assessment for Proposed Section 3
Use on Grain Sorghum. 

PC Code:  124002	DP Barcode:  D364307  

Decision No.:  407899  	Registration No.:  66222-35

Petition No.:  9F7547	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

Robert Mitkus, Ph.D., DABT, 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:		John Hebert (RM 07)/ Jennifer Gaines

		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 (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 fruiting
vegetables group 8, cucurbit vegetable group 9, low growing berry
subgroup 13-07G, miscellaneous fruiting vegetables, snap bean, dry bean
seed, and Swiss chard (Memo, J. Van Alstine, et al., 04-DEC-2009;
D363988).  A detailed hazard characterization for novaluron is presented
in a previous HED risk assessment (Memo, S. Levy, et al., 03-NOV-2005;
D313322).  The following information from the 25-FEB-2008 risk
assessment for the use of novaluron on tomato and sugarcane (Memo, G.
Kramer, 25-FEB-2008; D347661) 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
grain sorghum.    

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc254682210"  1.0	Executive
Summary	  PAGEREF _Toc254682210 \h  4  

  HYPERLINK \l "_Toc254682211"  2.0	PROPOSED USE PATTERN	  PAGEREF
_Toc254682211 \h  9  

  HYPERLINK \l "_Toc254682212"  3.0	HAZARD CHARACTERIZATION/FQPA
CONSIDERATIONS	  PAGEREF _Toc254682212 \h  10  

  HYPERLINK \l "_Toc254682213"  3.1	FQPA Considerations	  PAGEREF
_Toc254682213 \h  11  

  HYPERLINK \l "_Toc254682214"  3.2	Endocrine Disruption	  PAGEREF
_Toc254682214 \h  13  

  HYPERLINK \l "_Toc254682215"  4.0	DIETARY EXPOSURE/RISK
CHARACTERIZATION	  PAGEREF _Toc254682215 \h  13  

  HYPERLINK \l "_Toc254682216"  4.1	Food Residue Profile	  PAGEREF
_Toc254682216 \h  13  

  HYPERLINK \l "_Toc254682217"  4.2	Drinking Water Residue Profile	 
PAGEREF _Toc254682217 \h  17  

  HYPERLINK \l "_Toc254682218"  4.3	Dietary Exposure and Risk	  PAGEREF
_Toc254682218 \h  18  

  HYPERLINK \l "_Toc254682219"  4.4	Anticipated Residue and %CT
Information	  PAGEREF _Toc254682219 \h  19  

  HYPERLINK \l "_Toc254682220"  5.0	Residential (Non-Occupational)
Exposure/Risk Characterization	  PAGEREF _Toc254682220 \h  19  

  HYPERLINK \l "_Toc254682221"  5.1	Spray Drift	  PAGEREF _Toc254682221
\h  19  

  HYPERLINK \l "_Toc254682222"  6.0	AGGREGATE RISK ASSESSMENTS AND RISK
CHARACTERIZATION	  PAGEREF _Toc254682222 \h  20  

  HYPERLINK \l "_Toc254682223"  7.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY	 
PAGEREF _Toc254682223 \h  20  

  HYPERLINK \l "_Toc254682224"  7.1	Occupational Pesticide Handler
Exposure and Risk	  PAGEREF _Toc254682224 \h  20  

  HYPERLINK \l "_Toc254682225"  7.2	Occupational Post-Application Worker
Exposure and Risk	  PAGEREF _Toc254682225 \h  23  

  HYPERLINK \l "_Toc254682226"  8.0	DATA NEEDS AND LABEL RECOMMENDATIONS
  PAGEREF _Toc254682226 \h  25  

  HYPERLINK \l "_Toc254682227"  8.1	Toxicology	  PAGEREF _Toc254682227
\h  25  

  HYPERLINK \l "_Toc254682228"  8.2	Residue Chemistry	  PAGEREF
_Toc254682228 \h  25  

  HYPERLINK \l "_Toc254682229"  Appendix A:  TOXICOLOGY ASSESSMENT	 
PAGEREF _Toc254682229 \h  27  

  HYPERLINK \l "_Toc254682230"  A.1.	Acute Toxicity Profile	  PAGEREF
_Toc254682230 \h  27  

  HYPERLINK \l "_Toc254682231"  A.2	Toxicity Profiles	  PAGEREF
_Toc254682231 \h  27  

 

1.0	Executive Summary

Under Section 3 of the Federal Insecticide, Fungicide and Rodenticide
Act (FIFRA), as amended, Makhteshim-Agan of North America (MANA) has
submitted a petition (PP# 9F7547) 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 grain sorghum.  To
support the submission for permanent tolerances for residues of
novaluron in/on grain sorghum grain, forage, stover, and aspirated grain
fractions (AGF), MANA proposes tolerance increases for residues of
novaluron in/on the following livestock commodities:  hog and poultry
meat, liver, kidney, and fat; and eggs.  End-use products containing
novaluron as the ai are formulated as an EC, a suspension concentrate
(SC), or a water-dispersible granular (WDG).

Novaluron, a benzoylphenyl urea compound, is a pesticide chemical
belonging to the class of insecticides called insect-growth regulators
(IGRs).  Tolerances for residues of novaluron are established in/on
cotton, Brassica head and stem vegetables (subgroup 5A), pome fruit
(group 11), tuberous and corm vegetables (subgroup 1C), tomatoes,
sugarcane, bushberry subgroup 13-07B, Brassica, leafy greens (subgroup
5B), turnip greens, and stone fruit (crop group 12) at levels ranging
from 0.05 to 30 ppm.  Tolerances for residues of novaluron are also
established in/on the following livestock commodities:  eggs, milk, milk
fat, the meat, fat, kidney, liver, and meat byproducts (except kidney
and liver) of cattle, goat, horse, and sheep, and the meat, fat, and
meat byproducts of poultry and hog.  A time-limited tolerance, with an
expiration date of 31-DEC-2011, is established in association with a
Section 18 Emergency Exemption for strawberries at 0.50 ppm.  Tolerances
are pending for fruiting vegetables group 8, cucurbit vegetables group
9, low growing berry subgroup 13-07G (except lowbush blueberry),
miscellaneous fruiting vegetables, snap bean, dry bean seed, and Swiss
chard (Memo, J. Van Alstine et al., 04-DEC-2009; D363988).

All uses for novaluron, either proposed or existing, are agricultural or
commercial in nature.  No residential uses are proposed, nor are any
registered or proposed uses expected to result in residential exposure. 


Hazard Characterization

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 (toxicity to blood) such as methemoglobinemia,
decreased hemoglobin, decreased hematocrit, and decreased red blood
corpuscles (RBCs or erythrocytes) that were associated with compensatory
erythropoiesis.  No maternal and/or developmental toxicity was observed
in animals tested up to the limit dose in either the rat or rabbit
developmental toxicity studies.  In the two-generation reproductive
toxicity study, increased spleen weights were observed in parents and
offspring at the same dose, and reproductive toxicity was observed in
males only at a higher dose.  Neurotoxic effects, including clinical
signs, changes in functional-observation battery (FOB) parameters, and
neuropathology were observed following a single dose at the limit dose
only (2000 mg/kg/day) in the acute neurotoxicity study in rats. 
However, no signs of neurotoxicity or neuropathology were observed
following repeated dosing in the subchronic neurotoxicity study in rats
at similar doses, no evidence of neuropathology was observed in
subchronic and chronic toxicity studies in rats, mice, or dogs, and
novaluron is not considered acutely toxic (LD50>5000 mg/kg).  Therefore,
RAB1 toxicologists reaffirmed the HED Hazard Identification Assessment
Review Committee (HIARC) conclusion that there is not a concern for
neurotoxicity resulting from exposure to novaluron.  There was no
evidence of either carcinogenic or genotoxic potential with novaluron.  
 

Dose Response and Endpoint Selection

The RAB1 toxicologists reevaluated the novaluron database and reaffirmed
the previous conclusion of the HIARC (16-DEC-2003, TXR# 0052361) 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
developmental toxicity studies at levels up to the limit dose in the rat
or rabbit or in the two-generation reproduction study in rats.  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 risk assessments, 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).

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 toxicity/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 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.

Based on the toxicological database, a short-term dermal endpoint was
not selected; therefore, only intermediate-term dermal exposure was
assessed.  Short- and intermediate-term inhalation toxicological
endpoints have been selected and 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	LOC for MOEs <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



	

Dietary Exposure Estimate

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 (food and drinking water) exposure and risk assessment
was conducted for the proposed new use on grain sorghum, all established
uses, and drinking water.  A partially refined assessment was conducted.
 EFED provided the estimated drinking water concentrations (EDWCs) which
were incorporated into the analysis.  A Screening Level Usage Analysis
(SLUA) memorandum for existing uses and a percent crop treated for new
use (PCTn) memorandum for sorghum were provided by the Biological and
Economic Analysis Division (BEAD).  The chronic analysis incorporated
average percent crop treated (%CT) data for apples, cabbage, cotton,
pears, and potatoes and PCTn data for grain sorghum.  100% CT was
assumed for the remaining food commodities.  Anticipated residues (ARs)
for meat, milk, hog, and poultry commodities were calculated using PCTn
for grain sorghum, average %CT for apple and cotton, and assumed 100% CT
for sugarcane.  The chronic analysis also incorporated average field
trial residues for some commodities; average greenhouse trial residues
for tomatoes; empirical processing factors for apple juice (translated
to pear and stone fruit juice) and tomato paste and purée; and Dietary
Exposure Evaluation Model (DEEM™, ver. 7.81) default processing
factors for the remaining processed commodities.  In accordance with HED
Standard Operating Procedure (SOP) 2000.1, average field trial residues
were translated from representative commodities in the crop group to
other commodities in that crop group as needed.   

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 exposure results in a
risk estimate that is 11% of the cPAD for the general U.S. population
and 32% of the cPAD for children 1-2 years old, the most highly exposed
population subgroup.  

Residential Exposure/Risk

There are no residential uses proposed or currently registered for
novaluron.  Therefore, a residential risk assessment is not required.

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 not of concern.  

Occupational Exposure Estimates

Occupational handler and post-application exposure from the proposed
uses of novaluron are anticipated.  Based on label information, exposure
is expected to occur for short- and intermediate-term exposure
durations.  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 the PHED Surrogate Exposure Guide (AUG-1998) to assess
handler exposures for regulatory actions when chemical-specific
monitoring data are not available [HED Science Advisory Council for
Exposure (ExpoSAC) Draft SOP #7, dated 28-JAN-1999].  

 ≥100), provided workers wear chemical-resistant gloves as recommended
on the label.  No short-term point of departure was selected for the
dermal route of exposure; therefore, the risks presented for handlers
are representative of intermediate-term exposures and would be
considered protective of short-term exposures.

The MOEs for occupational post-application exposure are all greater than
the target MOE of 100 on day 0 (12 hours after application) for all
crops and activities and are not of concern.  Post-application dermal
risks were calculated based on an intermediate-term point of departure
and are considered highly conservative for the included activities.

Since the post-application assessment is not a concern on Day 0 (12
hours following application), the restricted-entry interval (REI) is
based on the acute toxicity of novaluron technical material.  The
proposed label for Rimon® has a 12-hour REI.  The technical material
has a Toxicity Category III for acute dermal and a Toxicity Category IV
for acute oral and inhalation and primary eye and skin irritation.  It
is not a dermal sensitizer.  Per the Worker Protection Standard (WPS), a
12-hour REI is required for chemicals classified under Toxicity
Categories III and IV and is adequate for the proposed use patterns.  

Environmental Justice Considerations

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human-health risk assessment, in
accordance with U.S. Executive Order 12898, “Federal Actions to
Address Environmental Justice in Minority Populations and Low-Income
Populations,” (  HYPERLINK
"http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pd
f" 
http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf
).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the U.S. Department of Agriculture
(USDA) under the Continuing Surveys of Food Intakes by Individuals
(CSFII) and are used in pesticide risk assessments for all registered
food uses of a pesticide.  These data are analyzed and categorized by
subgroups based on age, season of the year, ethnic group, and region of
the country.  Additionally, OPP is able to assess dietary exposure to
smaller, specialized subgroups and exposure assessments are performed
when conditions or circumstances warrant.  Whenever appropriate,
non-dietary exposures based on home use of pesticide products and
associated risks for adult applicators and for toddlers, youths, and
adults entering or playing on treated areas post-application are
evaluated.  Further considerations are currently in development as OPP
has committed resources and expertise to the development of specialized
software and models that consider exposure to bystanders and farm
workers as well as lifestyle and traditional dietary patterns among
specific subgroups.

Review of Human Research

This risk assessment relies in part on data from the PHED and the
Agricultural Reentry Task Force (ARTF) studies in which adult human
subjects were intentionally exposed to a pesticide or other chemical. 
These studies have been reviewed and have been determined to be ethical.

Recommendation for Tolerances and Registration

Pending submission of revised Sections B and F (see requirements under
Directions for Use and Proposed Tolerances), there are no residue
chemistry issues that would preclude granting a conditional registration
for the use of novaluron on grain sorghum.  

The proposed uses and the submitted data support the permanent
tolerances for residues of the insecticide novaluron, including its
metabolites and degradates, in or on the commodities listed 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 (RACs):

Grain, aspirated fractions	25 ppm

	Poultry, fat	7.0 ppm

Sorghum, grain, grain	3.0 ppm

	Egg	1.5 ppm

Sorghum, grain, forage	6.0 ppm

	Hog, meat	0.07 ppm

Sorghum, grain, stover	40 ppm

	Hog, liver	0.10 ppm

Poultry, meat	0.40 ppm

	Hog, kidney	0.10 ppm

Poultry, liver	0.80 ppm

	Hog, meat byproducts	0.10 ppm

Poultry, kidney	0.80 ppm

	Hog, fat		1.5 ppm

Poultry, meat byproducts	0.80 ppm







Data Needs and Label Recommendations

The residue chemistry, toxicology, and occupational and residential
databases will support unconditional registration upon submission of
data/information which adequately addresses the following issues:  

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 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 for petition number 9F7547 should be submitted
which:

Specifies that the use of adjuvants/surfactants on grain sorghum is
prohibited;

Specifies that the label is for “grain sorghum” as opposed to
“sorghum;” 

Specifies separate preharvest interval (PHIs) for grain sorghum forage
(7 days), grain (14 days), and stover (14 days); and

States that the use of novaluron on crops grown for food in greenhouses,
except tomatoes, is prohibited.  

860.1380 Storage Stability Data

Storage stability data on grain sorghum forage, grain, AGF, and stover
for up to 275, 253, 237, and 245 days, respectively, are required.  

860.1550 Proposed Tolerances

A revised Section F for petition number 9F7547 should be submitted which
cites 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:”

A revised Section F is requested which reflects the recommended
tolerances and commodity definitions presented in Table 4.1.  

Occupational and Residential Exposure

None.  

2.0	PROPOSED USE PATTERN

MANA submitted a draft label for Rimon® 0.83EC Insecticide (EPA Reg.
No. 66222-35) to include the proposed new use (see Table 2.0) on grain
sorghum.



Table 2.0.  Summary of Proposed Use Pattern for Novaluron on Grain
Sorghum.

Application Equipment	Formulation

[EPA Reg. No.]	Applic. Rate 

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

(lb ai/A)	PHI

(days)	Use Directions and Limitations

Grain Sorghum

Aerial/ Groundboom	0.83 lb/gal EC

[66222-35]	0.058-0.078	3	0.23	14	A 7 to 14 day retreatment interval
(RTI) is specified to protect new growth.  For the most effective
control, fields should be scouted twice weekly.  REI = 12 hours.



Conclusions:  The proposed label is adequate to allow evaluation of the
residue data relative to the proposed new use on grain sorghum; however,
a revised Section B is requested which:  

specifies that the use of adjuvants/surfactants on grain sorghum is
prohibited;

specifies that the label is for “grain sorghum” as opposed to
“sorghum;” 

specifies separate PHIs for grain sorghum forage (7 days), grain (14
days), and stover (14 days); and

states that the use of novaluron on crops grown for food in greenhouses,
except tomatoes, is prohibited.  

3.0	HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS

A detailed hazard characterization for novaluron is presented in a
previous HED risk assessment (Memo, S. Levy, et al., 03-NOV-2005;
D313322).  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 (toxicity to blood) such as
methemoglobinemia, decreased hemoglobin, decreased hematocrit, and
decreased RBCs (or erythrocytes) that were associated with compensatory
erythropoiesis.

No maternal and/or developmental toxicity was observed in animals tested
up to the limit dose in either the rat or rabbit developmental toxicity
studies.  In the two-generation reproductive toxicity study, increased
spleen weights were observed in parents and offspring at the same dose,
and reproductive toxicity (decreases in epididymal sperm counts and
increased age at preputial separation in the F1 generation) was observed
in males only at a higher dose.  Neurotoxic effects, including clinical
signs (piloerection, fast/irregular breathing), FOB parameters (head
swaying, abnormal gait), and neuropathology (sciatic and tibial nerve
degeneration) were observed following a single dose at the limit dose
only (2000 mg/kg/day) in the acute neurotoxicity study in rats. 
However, no signs of neurotoxicity or neuropathology were observed
following repeated dosing in the subchronic neurotoxicity study in rats
at similar doses (1752 mg/kg/day in males and 2000 mg/kg/day in
females).  In addition, novaluron is not considered acutely toxic
(LD50>5000 mg/kg).  Therefore, RAB1 toxicologists reaffirmed the HED
HIARC conclusion that there is not a concern for neurotoxicity resulting
from exposure to novaluron.  There was no evidence of carcinogenic
potential in either the rat or mouse carcinogenicity studies, and there
was no evidence of mutagenic potential in several genotoxicity studies,
including the bacterial (Salmonella, E. coli) reverse-mutation assay,
the in vitro mammalian chromosomal aberration assay, the in vivo mouse
bone-marrow micronucleus assay, and the bacterial DNA damage/repair
assay.    

3.1	FQPA Considerations

The RAB1 risk assessment team concluded that the FQPA SF can be reduced
to 1X based on the following:

There is no evidence of increased susceptibility in the rat or rabbit
developmental toxicity studies up to the limit dose or in the
two-generation reproduction study in rats.

There are no concerns or residual uncertainties for pre- and/or
postnatal toxicity.

Acute and subchronic neurotoxicity screening batteries were performed
with novaluron in rats.  Novaluron is not considered neurotoxic, since
effects observed in the acute neurotoxicity study were observed at the
limit dose only and were not reproduced at similar, repeated doses in
the subchronic neurotoxicity study.  In addition, no evidence of
neuropathology was observed in subchronic and chronic toxicity studies
in rats, mice, or dogs, and novaluron is not considered acutely toxic
(LD50>5000 mg/kg).

A developmental-neurotoxicity (DNT) study is not required.

Histopathological examination of the organs of the immune system (i.e.,
thymus, spleen, lymph nodes) showed an increase in spleen weight and
increased incidence and severity of hemosiderosis in the spleen in the
chronic studies in rats and mice and in the reproduction study in rats. 
These findings were associated with the primary hematotoxicity of
novaluron, which caused secondary accumulation of damaged erythrocytes
in the spleen following removal from the blood.  Therefore, these are
not considered immunotoxic effects.  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.

The conservative residue assumptions used in the dietary exposure risk
assessment.

The completeness of the residue chemistry database and conservative
drinking water assessment.

The doses and toxicological endpoints selected for human health risk
assessment are summarized in Table 3.1.

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.

3.2	Endocrine Disruption

As required under Federal Food, Drug, and Cosmetic Act (FFDCA) section
408(p), EPA has developed the Endocrine Disruptor Screening Program
(EDSP) to determine whether certain substances (including pesticide
active and other ingredients) may have an effect in humans or wildlife
similar to an effect produced by a “naturally occurring estrogen, or
other such endocrine effects as the Administrator may designate.”  The
EDSP employs a two-tiered approach to making the statutorily required
determinations.  Tier 1 consists of a battery of 11 screening assays to
identify the potential of a chemical substance to interact with the
estrogen, androgen, or thyroid (E, A, or T) hormonal systems.  Chemicals
that go through Tier 1 screening and are found to have the potential to
interact with E, A, or T hormonal systems will proceed to the next stage
of the EDSP where EPA will determine which, if any, of the Tier 2 tests
are necessary based on the available data.  Tier 2 testing is designed
to identify any adverse endocrine related effects caused by the
substance, and establish a dose-response relationship between the dose
and the E, A, or T effect.

Between October 2009 and February 2010, EPA is issuing test orders/data
call-ins for the first group of 67 chemicals, which contains 58
pesticide active ingredients and 9 inert ingredients.  This list of
chemicals was selected based on the potential for human exposure through
pathways such as food and water, residential activity, and certain
post-application agricultural scenarios.  This list should not be
construed as a list of known or likely endocrine disruptors.

Novaluron is not among the group of 58 pesticide active ingredients on
the initial list to be screened under the EDSP.  Under FFDCA sec. 408(p)
the Agency must screen all pesticide chemicals.  Accordingly, EPA
anticipates issuing future EDSP test orders/data call-ins for all
pesticide active ingredients. 

For further information on the status of the EDSP, the policies and
procedures, the list of 67 chemicals, the test guidelines and the Tier 1
screening battery, please visit our website:  http://www.epa.gov/endo/.

4.0	DIETARY EXPOSURE/RISK CHARACTERIZATION

The residue chemistry data submitted in support of the proposed uses are
summarized in the pending HED memorandum by J. L. Van Alstine (D374420).
 The chronic dietary exposure assessment is summarized in the pending
HED memorandum by J. L. Van Alstine (D374419).

4.1	Food Residue Profile

Nature of the Residue - Plants:  HED previously 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 (Memo, G. Kramer,
22-MAR-2004; D285474).  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 only
(Memo, G. Kramer et al., 03-FEB-2004; D297646).  

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 hen metabolism studies (Memo, G. Kramer,
22-MAR-2004; D285474).  The HED MARC determined that the residue of
concern in livestock for purposes of tolerance enforcement and risk
assessment is novaluron only (Memo, G. Kramer et al., 03-FEB-2004;
D297646).

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.  A second method,
high-performance liquid chromatography/ultraviolet (HPLC/UV), was
submitted for the analysis of novaluron residues only in/on cotton
commodities.  Both methods were 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;
Memo, G. Kramer, 05-DEC-2003; D296264).

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 (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).

Multiresidue Methods:    SEQ CHAPTER \h \r 1 Novaluron was tested
through the FDA MRM Test guidelines in PAM I, Appendix II (JAN-1994). 
The results indicate that novaluron is not adequately recovered by any
of the MRMs.  This study was forwarded to FDA for further evaluation and
updating of PAM Vol. I, Appendix I (Memo, S. Levy, 19-OCT-2005;
D322359).

Magnitude of the Residue - Plants:  MANA has submitted field trial data
to support the proposed use of novaluron on grain sorghum.  Twelve grain
sorghum field trials were conducted in the U.S. during the 2007 growing
season in North American Free Trade Agreement (NAFTA) Growing Zones 2
(NC; 1 trial), 4 (AR; 1 trial), 5 (IL, KS, and NE; 4 trials), 6 (OK and
TX; 1 trial each), 7 (NE, 1 trial), and 8 (KS, OK, and TX; 1 trial
each).

Each trial site consisted of one untreated plot and one treated plot. 
The treated plots received three broadcast spray applications of a 0.83
lb/gal EC formulation of novaluron (EPA Reg. No. 66222-35) at
0.076-0.081 lb ai/A per application, with 7- to 15-day RTIs, for a total
rate of 0.232-0.239 lb ai/A; forage samples were harvested after only
two applications, for a total rate of 0.156-0.160 lb ai/A.  Applications
were made using ground equipment in approximately 20-34 GPA spray
volumes, without an adjuvant.  Samples of grain sorghum forage, grain,
and stover were taken at normal harvest times, 6 to 7 days after the
second application for forage and 13 to 14 days after the last
application for grain and stover.  To evaluate residue decline,
additional treated samples were also collected at one trial 1, 3, 10,
and 14 days after the second application (forage) and 10, 14, 17, and 21
days after the last application (grain and stover).

Residues of novaluron ranged from 0.620 to 4.82 ppm in/on 24 samples of
treated sorghum forage harvested 6-7 days following foliar treatments
with the 0.83 lb/gal EC formulation at a total rate of 0.156-0.160 lb
ai/A.  Novaluron residues ranged from 0.586 to 1.96 ppm in/on 22 samples
of treated sorghum grain, and from 3.62 to 26.0 ppm in/on 22 samples of
treated sorghum stover (adjusted to 88% dry matter) harvested 13-14 days
following foliar treatments at a total rate of 0.232-0.239 lb ai/A.

In the residue decline trial, average residues of novaluron generally
decreased in/on forage, from 4.0 ppm at the 1-day PHI to 2.0 ppm at the
14-day PHI, and stover, from 6.7 ppm at the 7-day PHI to 3.8 ppm at the
21-day PHI; average residues in/on grain were approximately the same at
all sampling intervals.

Conclusions:  The submitted field trial data for grain sorghum
commodities are classified as scientifically acceptable and will support
the establishment of residue tolerances for novaluron in/on grain
sorghum forage (6.0 ppm), grain (3.0 ppm), and stover (40 ppm), pending
submission of freezer storage stability data for residues of novaluron
in/on grain sorghum forage, grain, and stover for up to 275, 253, and
245 days, respectively.  Although this is a deficiency, HED recommends a
conditional registration for the use of novaluron on grain sorghum. 
This decision is based on previously submitted storage stability data
for various commodities which demonstrates the stability of novaluron
in/on food commodities for up to 15.3 months, which exceeds the longest
storage time (9.0 months for grain sorghum forage) of the grain sorghum
commodities in the field trials.  The residue chemistry database will
support an unconditional registration upon submission of adequate
storage stability data along with revised Sections B and F.  

Processed Food and Feed:  A processing study on grain sorghum AGF and
flour was submitted which indicated that residues of novaluron
concentrate in AGF (13X) but do not concentrate in flour (processing
factor of 0.66X).  Sorghum flour is not considered to be a human food
item in the U.S.  A tolerance value of 25 ppm [i.e., 1.84 ppm
(highest-average field trial (HAFT)) x 13 = 24 ppm] was calculated for
AGF.  For grain sorghum AGF, the processed food data are classified as
scientifically acceptable and will support the establishment of residue
tolerances for novaluron in/on AGF (25 ppm) pending submission of
freezer storage stability data for grain sorghum grain and AGF.

Confined/Field Accumulation in Rotational Crops:  Based on the results
of the submitted 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, which is appropriate for this petition.  Future uses that
have significantly higher application rates will require confined
rotational crop studies at higher rates using chlorophenyl-labeled
novaluron.  The HED MARC has determined that for tolerance assessment
and risk assessment, parent only is the residue of concern in rotational
crops (Memo, G. Kramer et al., 03-FEB-2004; D297646).

   

Magnitude of the Residue - Livestock:  The potential for secondary
transfer of novaluron residues of concern in meat, milk, and eggs exists
because there are livestock feedstuffs associated with the
proposed/registered novaluron uses.  Livestock dietary burdens of
novaluron were calculated, which incorporate the proposed/registered
uses of novaluron.  The calculations reflected the most recent guidance
from HED (OPPTS 860.1000 Supplement, Table 1 Feedstuffs, 30-JUN-2008)
concerning revisions of feedstuff percentages and constructing
reasonably balanced dietary burdens (RBDBs).  

The currently established livestock tolerances are based on the
following RBDBs for novaluron:  5.9 ppm for beef cattle, 2.3 ppm for
dairy cattle, 0.12 for poultry, and 0.09 for swine (Memo G. Kramer,
07-FEB-2008; D340137).  Based on the proposed/registered uses, the
revised RBDBs for novaluron are 9.6 ppm for beef cattle, 12.4 ppm for
dairy cattle, 2.4 for poultry, and 2.5 for swine.  This increase in the
RBDBs necessitates an increase in the tolerances for secondary residues
in/on poultry and hog commodities; however, no changes are necessary for
the tolerances for secondary residues in/on cattle, goat, horse, and
sheep.  The revised tolerances for residues of novaluron in hog and
poultry are as follows:  0.07 ppm in hog meat; 0.10 ppm in hog liver,
kidney, and meat byproducts; 1.5 ppm in hog fat; 1.5 ppm in eggs; 0.40
ppm in poultry meat; 0.80 ppm in poultry liver, kidney, and meat
byproducts; and 7.0 ppm in poultry fat.  The petitioner is requested to
submit a revised Section F reflecting these tolerances.

Tolerance Summary:  Permanent tolerances for novaluron have been
established for a variety of commodities under 40 CFR §180.598.  The
HED MARC determined that the residue of concern in plants (primary and
rotational crops) and livestock for purposes of tolerance enforcement
and risk assessment is novaluron only (Memo, G. Kramer et al.,
03-FEB-2004; D297646).  A revised Section F for petition number 9F7547
should be submitted which cites 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:”

A revised Section F is requested which reflects the HED-recommended
tolerances and commodity definitions presented in Table 4.1.  

No Codex, Canadian, or Mexican MRLs have been established for novaluron
in/on grain sorghum.  

The Agency’s Guidance for Setting Pesticide Tolerances Based on Field
Trial Data was utilized for determining appropriate tolerance levels.



Table 4.1.  Tolerance Summary for Novaluron.

Commodity	Proposed Tolerance (ppm)	HED-Recommended Tolerance (ppm)
Comments; 

Correct Commodity Definition

Grain sorghum, grain	3	3.0  	Sorghum, grain, grain

Grain sorghum, aspirated grain fractions	25	25	Grain, aspirated
fractions

Grain sorghum, forage	6	6.0	Sorghum, grain, forage

Grain sorghum, stover	40	40	Sorghum, grain, stover

Poultry, fat	7.0	7.0

	Poultry, muscle	0.4	0.40	Poultry, meat

Poultry, liver	0.8	0.80

	Poultry, kidney	0.8	0.80

	--	--	0.80	Poultry, meat byproducts

Hog, fat	1.5	1.5

	Hog, muscle	0.07	0.07	Hog, meat

Hog, liver	0.15	0.10

	Hog, kidney	0.15	0.10

	--	--	0.10	Hog, meat byproducts

Eggs	1.5	1.5	Egg



4.2	Drinking Water Residue Profile

The drinking water residues used in the dietary risk assessment were
provided by EFED (Memo, I. Maher, 16-JUL-09; D363989).  Since the
application rates for the proposed new uses are significantly lower than
the use rates for pome fruits and stone fruits, the EDWCs provided in
the previous drinking water assessments dated 10-MAR-2009 (D357061) and
11-FEB-2004 (D285477) are applicable for the proposed uses.  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 Pesticide Root Zone Model/Exposure Analysis Modeling System
(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 FQPA Index Reservoir Screening Tool
(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 Screening Concentration in Ground Water (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 chloroaniline metabolite 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 USDA’s
CSFII from 1994-1996 and 1998.  The analysis was performed to support
the request for use of novaluron on grain sorghum.

The chronic analysis incorporated average %CT data for apples, cabbage,
cotton, pears, and potatoes and PCTn data for grain sorghum.  100% CT
was assumed for the remaining food commodities.  ARs for meat, milk,
hog, and poultry commodities which were calculated using PCTn for grain
sorghum, average %CT for apple and cotton, and 100% CT for sugarcane
were incorporated into the analysis.  The chronic analysis also
incorporated average field trial residues for some commodities (pome
fruit, sugarcane, bushberries, Brassica leafy greens, stone fruit, bell
pepper, non-bell pepper, cucumber, summer squash, cantaloupe,
strawberry, succulent snap bean, dry bean seed, and Swiss chard);
average greenhouse trial residues for tomatoes; empirical processing
factors for apple juice (translated to pear and stone fruit juice) and
tomato paste and purée; and DEEM( (ver. 7.81) default processing
factors for the remaining processed commodities.  In accordance with HED
SOP 2000.1, average field trial residues were translated from
representative commodities in the crop group to other commodities in
that crop group as needed.   

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 results in a risk estimate that
is 11% of the cPAD for the general U.S. population and 32% 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 Novaluron1,2.

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	0.001206	11	N/A	N/A

All Infants (<1 year old)

	0.001955	18



Children 1-2 years old

	0.003537	32



Children 3-5 years old

	0.002771	25



Children 6-12 years old

	0.001700	16



Youth 13-19 years old

	0.001021	9



Adults 20-49 years old

	0.000884	8



Adults 50+ years old

	0.001027	9



Females 13-49 years old

	0.000874	8



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

2 The highest dietary exposure is bolded.  

4.4	Anticipated Residue and %CT Information

A SLUA memorandum and PCTn memorandum were provided by BEAD (A. Grube,
17-NOV-2009, D371221; C. Doucoure et al., 29-DEC-2009, D371615).  The
SLUA memo included %CT data for apples, cabbage, cotton, pears, and
potatoes.  The market leader approach was used by BEAD to determine the
PCTn for sorghum.  

The chronic dietary analysis incorporated average %CT data for apples
(15%), cabbage (10%), cotton (2.5%), pears (10%), and potatoes (2.5%)
and PCTn data for grain sorghum (5%).  100% CT was assumed for the
remaining food commodities.  Livestock dietary burdens of novaluron were
calculated based on the proposed/registered uses, tolerance-level
residues, and PCTn data for grain sorghum (5%), average %CT data for
apple (15%) and cotton (2.5%), and 100% CT for sugarcane.  These
livestock dietary burdens were used, along with average transfer
coefficients, to calculate anticipated secondary residues for meat,
milk, hog, and poultry commodities which were incorporated into the
chronic dietary assessment.  

5.0	Residential (Non-Occupational) Exposure/Risk Characterization

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.

5.1	Spray Drift 

Spray drift is always a potential source of exposure to residents nearby
to spraying operations.  This is particularly the case with aerial
application but, to a lesser extent, could also be a potential source of
exposure from the ground application method additionally employed for
novaluron.  The Agency has been working with the Spray Drift Task Force,
EPA Regional Offices and State Lead Agencies for pesticide regulation
and other parties to develop the best spray drift management practices. 
The Agency is now requiring interim mitigation measures for aerial
applications that must be placed on product labels/labeling.  The Agency
has completed its evaluation of the new database submitted by the Spray
Drift Task Force, a membership of U.S. pesticide registrants, and is
developing a policy on how to appropriately apply the data and the
AgDRIFT® computer model to its risk assessments for pesticides applied
by air, orchard airblast, and ground hydraulic methods.  After the
policy is in place, the Agency may impose further refinements in spray
drift management practices to reduce off-target drift and risks
associated with aerial as well as other application types where
appropriate.

6.0	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 LOC.  

7.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY

An occupational exposure assessment for novaluron was prepared in a
pending HED memorandum (L. Venkateshwara; D374418).  See Table 2.0 for a
summary of the proposed use patterns.  

7.1	Occupational Pesticide Handler Exposure and Risk

There is potential for occupational handler exposure from the proposed
use on grain sorghum.  Handler’s exposure and risk were estimated for
the following scenarios: 

Mixer/Loader:

(1) 	Mixing/loading liquids for aerial application;

(2)	Mixing/loading liquids for groundboom application;

Applicator:

(3) 	Applying sprays via aerial applications;

(4) 	Applying sprays via groundboom 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 the 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 on the proposed labels.  There is no short-term
dermal point of departure; therefore, only intermediate-term dermal
exposure has been assessed and is anticipated to be protective of
short-term dermal exposure.  Short- and intermediate-term inhalation
exposures have been assessed.  The short- and intermediate-term
inhalation toxicological points of departure 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 dose.  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 (lb 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).

Non-cancer dermal and inhalation risks for each applicable handler
scenario are calculated using an 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 7.1 presents the estimated risks for workers based on the
intermediate-term dermal and short- and intermediate-term inhalation
exposures at baseline and with PPE.  HED has determined that risks are
not of concern (i.e., MOEs ≥100), provided workers wear
chemical-resistant gloves as recommended on the label.  No short-term
point of departure was selected for dermal exposure; therefore, the
risks presented for handlers are representative of 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 7.1.  Occupational Handler Dermal and Inhalation Exposures and
Risks.

Dermal and

Inhalation Unit Exposures

(mg/lb ai)	Application rate

(lb ai/A)1	Area Treated Daily (A)2	Short- and Intermediate-term Doses
(mg/kg/day)3	Total Dose4	Short- and Intermediate-term MOE	Total MOEs 5

(1) Mixer/Loader – Groundboom Application

Dermal

Baseline: 2.9 

Single layer w/gloves:  0.023

Inhalation

Baseline: 0.0012 	0.078	80	Dermal

Baseline6: 0.026

Single layer w/gloves8 : 0.00021	Baseline Dermal + Inhalation

0.026

Single layer w/gloves + Inhalation

0.00032	Dermal

Baseline6: 

170

Single layer w/gloves8 : 21,000	Baseline Dermal + Inhalation

170

Single layer w/gloves + Baseline Inhalation

14,000



	Inhalation 

Baseline7:  0.00011

Inhalation Baseline7:  41,000

	(2) Mixer/Loader – Aerial Application

Dermal

Baseline: 2.9

Single layer w/gloves:  0.023

Inhalation

Baseline: 0.0012 	0.078	350	Dermal

Baseline:  0.11

Single layer w/gloves:

0.00090	 Baseline Dermal + Inhalation

0.11

Single layer w/gloves + Inhalation

0.0014	Dermal

Baseline:  39

Single layer w/gloves:

13,000	Baseline Dermal + Inhalation

39

Single layer w/gloves + Baseline Inhalation

3,200



	Inhalation

Baseline: 0.00047

Inhalation

Baseline: 9,400

	(3) Applicator –Groundboom Application

Dermal

Baseline: 0.014

Inhalation

Baseline: 0.00074	0.078	80	Dermal

Baseline: 0.00012	Baseline Dermal + Inhalation

0.0002	Dermal

Baseline: 35,000	Baseline Dermal + Inhalation

23,000



	Inhalation

Baseline: 0.000066

Inhalation

Baseline: 66,000

	(4) Applicator –Aerial Application

Dermal

Engineering Control: 0.0050

Inhalation

Engineering Control: 0.000068 	0.078	350	Dermal

Engineering control:

0.0002	Combined Engineering Control

0.00023	Dermal

Engineering control:

22,000	Combined Engineering Control

20,000



	Inhalation

Engineering control:  0.000027

Inhalation

Engineering control:  170,000

	(5) Flagger –Aerial  Application

Dermal

Baseline: 0.011

Inhalation

Baseline: 0.00035 	0.078	350	Dermal

Baseline: 0.00043

	Baseline Dermal + Inhalation

0.0006 	Dermal

Baseline: 10,000

	Baseline Dermal + Inhalation

7,700



	Inhalation

Baseline:  0.00014 

Inhalation

Baseline:  32,000

	1 Application rates are the maximum recommended rates provided on the
novaluron product label.

2 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.

3 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. 

4 Total Dose = Dermal + Inhalation Dose.

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

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

7 Baseline Inhalation:  no respirator.

8 Single layer with gloves:  single layer baseline attire plus
chemical-resistant gloves.

7.2	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 at 22º C), a quantitative post-application
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
post-application data were submitted in support of this registration
action, dermal exposures during post-application activities were
estimated using dermal transfer coefficients from the ExpoSAC Policy
Number 3.1:  Agricultural Transfer Coefficients, August 2000, summarized
in Table 7.2.1 below and the following assumptions:

Application Rate		=	0.078 lb ai/A;  

Exposure Duration	=	8 hours per day;

Body Weight		=	70 kg for adult male;

Dermal Absorption	=	10%; and

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 7.2.1.  Anticipated Post-application Activities and Dermal
Transfer Coefficients.

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

Grain Sorghum	Field/row crop tall	100	Scouting and hand weeding



1000	Irrigation and scouting



The following equations were used to calculate risks for workers
performing post-application 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 post-application exposures associated with the proposed new use are
summarized in Table 7.2.2.  The resulting MOEs are greater than 100 on
day 0 (12 hours after application) for all crops and activities. 
Post-application dermal risks were calculated based on an
intermediate-term endpoint and are considered highly conservative for
the included activities.

Table 7.2.2.  Post-application Risks for Novaluron.

Crop	Application  Rate

(lb ai/A)	Transfer Coefficient

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

(mg/kg/ay)	MOE2

Grain Sorghum	0.078

	100	0.18	12 hours (0 days)	0.0002	21,900



1,000

	0.002	2,200

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).

Since the post-application assessment is not a concern on Day 0 (12
hours following application), the REI is based on the acute toxicity of
novaluron technical material.  The proposed label for Rimon® has a
12-hour REI.  The technical material has a Toxicity Category III for
acute dermal and a Toxicity Category IV for acute oral and inhalation
and primary eye and skin irritation.  It is not a dermal sensitizer. 
Per the WPS, a 12-hour REI is required for chemicals classified under
Toxicity Category III and IV.  

8.0	DATA NEEDS AND LABEL RECOMMENDATIONS

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.

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

8.2	Residue Chemistry

860.1200 Directions for Use

		A revised Section B for petition number 9F7547 should be submitted
which:

Specifies that the use of adjuvants/surfactants on grain sorghum is
prohibited;

Specifies that the label is for “grain sorghum” as opposed to
“sorghum;” 

Specifies separate PHIs for grain sorghum forage (7 days), grain (14
days), and stover (14 days); and

States that the use of novaluron on crops grown for food in greenhouses,
except tomatoes, is prohibited.  

860.1380 Storage Stability Data

Storage stability data on grain sorghum forage, grain, AGF, and stover
for up to 275, 253, 237, and 245 days, respectively, are required.  

860.1550 Proposed Tolerances

A revised Section F for petition number 9F7547 should be submitted which
cites 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:”

A revised Section F is requested which reflects the recommended
tolerances and commodity definitions presented in Table 4.1.

8.3	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, R. Mitkus

RDI: RAB1 Branch (02/17/10); G. Kramer (02/5/10); D. Vogel (02/23/10)

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)/Doses/Classification	

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.

870.3200

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.

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

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

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

Developmental NOAEL = 1000 mg/kg/day; LOAEL = not established.

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

(1997,1998);

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

Acceptable/Guideline

	Maternal NOAEL = 1000 mg/kg/day; LOAEL = not established.

Developmental NOAEL = 1000 mg/kg/day; LOAEL = not established.



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 (M) = 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.

870.4100

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.

870.4300 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.

870.5100

Salmonella typhimurium and  Escherichia coli Reverse Mutation Assay
44961㄰″ㄨ㤹⤷഻

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.

870.5375

In vitro mammalian chromosome aberration test	44961015 (1992);

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.

870.5395

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.

870.5500

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.

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.

870.6200

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).

870.6200

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46086204 (2002);

0, 17.5/20.5, 174/207, 1752/2000 mg/kg/day

(M/F)

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.



Novaluron	                       Human-Health Risk Assessment	          
    DP#:  364307

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