Document ID: EPA-HQ-OPP-2007-0446-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-07-25T04:00Z

UNITED STAES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

 PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

DATE:		APRIL 16, 2007 

SUBJECT:	Diflubenzuron.  Human Health Risk Assessment for the Proposed 	
Establishment of an Emergency Exemption Tolerance for Use in/on 	
Lemons.

Petition #	07CA04	

PC Code:	108201

DP #:	336813	

Class:	Insecticide

Decision #:	374651	40 CFR:	§180.377

FROM:	Breann Hanson, Biologist 

		Alternative Risk Integration and Assessment (ARIA) Team

		Risk Integration Minor Use and Emergency Response Branch 		
(RIMUERB)/Registration Division (RD) (7505P)

THROUGH:	William Cutchin, Acting Senior Scientist 

		ARIA Team

		RIMUERB/RD (7505P)

		AND

		P.V. Shah Ph.D., Acting Branch Chief

		Registration Action Branch 1 (RAB 1)

		Health Effects Division (HED) (7509P)

TO:		Libby Pemberton/Dan Rosenblatt, RM Team 05

		RIMUERB/RD (7505P)

Under provisions in Section 18 of the Federal Insecticide, Fungicide and
Rodenticide Act (FIFRA), as amended, the State of California has
requested the quarantine use of diflubenzuron to eradicate Diaprepes
weevils over a 42 acre outbreak site on commercial and residential
plantings (including containerized nursery stock) of citrus fruits
including grapefruit (pummelos and related cultivars or hybrids),
avocados (including black sapote, canistel, mamey sapote, mango, papaya,
sapodilla and star apple), guavas (including feijoa, jaboticaba, wax
jambu, starfruit, passion fruit and acerola), lychee (including longan,
Spanish lime, rambutan, and pulasan) that have been quarantined. 
Although diflubenzuron will be used at the above mentioned crop sites,
for purposes of this risk assessment, only lemon residues will be
addressed.  According to the applicant, lemons are the only proposed
commodity undergoing treatment that has the potential to enter into
inter-state commerce.  The remaining sites will be confined to
residential areas and none of these food items will enter commerce.  The
California Department of Food and Agriculture (CDFA) is leading this
eradication program and will be stripping the fruit off the tropical and
sub-tropical plants post-application.  However, due to the nature of the
plant, residential plantings of avocados are too prolific for stripping.
 A residue value of 0.8 ppm will be applied in this assessment for
avocados for those potential residues.  The EPA strongly urges stripping
of all fruit but lemons and avocados from the treated areas.  Homeowner
consumption, and therefore residues, of treated avocados is not
regulated by the Federal Food, Drug and Cosmetic Act.

  TC \l1 "1.0 EXECUTIVE SUMMARY 

TABLE OF CONTENTS

  TOC \o "1-4" \h \z \u    HYPERLINK \l "_Toc164483301"  1.0	EXECUTIVE
SUMMARY	  PAGEREF _Toc164483301 \h  5  

  HYPERLINK \l "_Toc164483302"  2.0	INGREDIENT PROFILE	  PAGEREF
_Toc164483302 \h  10  

  HYPERLINK \l "_Toc164483303"  2.1	Proposed Use	  PAGEREF _Toc164483303
\h  10  

  HYPERLINK \l "_Toc164483304"  2.2	Identification of Active Ingredient	
 PAGEREF _Toc164483304 \h  11  

  HYPERLINK \l "_Toc164483305"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc164483305 \h  12  

  HYPERLINK \l "_Toc164483306"  3.0	HAZARD CHARACTERIZATION	  PAGEREF
_Toc164483306 \h  12  

  HYPERLINK \l "_Toc164483307"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc164483307 \h  12  

  HYPERLINK \l "_Toc164483308"  3.1.1	Database Summary	  PAGEREF
_Toc164483308 \h  13  

  HYPERLINK \l "_Toc164483309"  3.1.1.1	Studies Available and Considered
  PAGEREF _Toc164483309 \h  13  

  HYPERLINK \l "_Toc164483310"  3.1.1.2	Mode of action, metabolism,
toxicokinetic data	  PAGEREF _Toc164483310 \h  13  

  HYPERLINK \l "_Toc164483311"  3.1.3	FQPA	  PAGEREF _Toc164483311 \h 
14  

  HYPERLINK \l "_Toc164483312"  3.2	Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc164483312 \h  14  

  HYPERLINK \l "_Toc164483313"  3.3	FQPA Considerations	  PAGEREF
_Toc164483313 \h  15  

  HYPERLINK \l "_Toc164483314"  3.3.1	Adequacy of the Toxicity Database	
 PAGEREF _Toc164483314 \h  15  

  HYPERLINK \l "_Toc164483315"  3.3.2	Evidence of Neurotoxicity	 
PAGEREF _Toc164483315 \h  15  

  HYPERLINK \l "_Toc164483316"  3.3.3	Developmental/Reproductive
Toxicity Studies	  PAGEREF _Toc164483316 \h  15  

  HYPERLINK \l "_Toc164483317"  3.3.4	Pre-and/or Postnatal Toxicity	 
PAGEREF _Toc164483317 \h  15  

  HYPERLINK \l "_Toc164483318"  3.3.4.1	Determination of Susceptibility	
 PAGEREF _Toc164483318 \h  15  

  HYPERLINK \l "_Toc164483319"  3.3.4.2	Degree of Concern Analysis and
Residual Uncertainties for Pre- and/or Postnatal Susceptibility	 
PAGEREF _Toc164483319 \h  15  

  HYPERLINK \l "_Toc164483320"  3.3.5	Recommendation for a Developmental
Neurotoxicity Study	  PAGEREF _Toc164483320 \h  15  

  HYPERLINK \l "_Toc164483321"  3.4	FQPA Safety Factor for Infants and
Children	  PAGEREF _Toc164483321 \h  16  

  HYPERLINK \l "_Toc164483322"  3.5	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc164483322 \h  16  

  HYPERLINK \l "_Toc164483323"  3.5.1	Acute Reference Dose (aRfD)	 
PAGEREF _Toc164483323 \h  16  

  HYPERLINK \l "_Toc164483324"  3.5.2	Chronic Reference Dose (cRfD)	 
PAGEREF _Toc164483324 \h  16  

  HYPERLINK \l "_Toc164483325"  3.5.4	Dermal Absorption	  PAGEREF
_Toc164483325 \h  16  

  HYPERLINK \l "_Toc164483326"  3.5.5	Short-Term Dermal Exposure	 
PAGEREF _Toc164483326 \h  16  

  HYPERLINK \l "_Toc164483327"  3.5.8	Short-/Intermediate-Term
Inhalation Exposure	  PAGEREF _Toc164483327 \h  17  

  HYPERLINK \l "_Toc164483328"  3.5.10	Level of Concern for Margin of
Exposure	  PAGEREF _Toc164483328 \h  17  

  HYPERLINK \l "_Toc164483329"  3.5.11	Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc164483329 \h  17  

  HYPERLINK \l "_Toc164483330"  3.5.12	Classification of Carcinogenic
Potential	  PAGEREF _Toc164483330 \h  17  

  HYPERLINK \l "_Toc164483331"  4.0	PUBLIC HEALTH AND PESTICIDE
EPIDEMIOLOGY DATA	  PAGEREF _Toc164483331 \h  19  

  HYPERLINK \l "_Toc164483332"  5.0	DIETARY EXPOSURE/RISK
CHARACTERIZATION	  PAGEREF _Toc164483332 \h  20  

  HYPERLINK \l "_Toc164483333"  5.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc164483333 \h  20  

  HYPERLINK \l "_Toc164483334"  5.1.1	Metabolism in Primary Crops	 
PAGEREF _Toc164483334 \h  20  

  HYPERLINK \l "_Toc164483335"  5.1.2	Metabolism in Rotational Crops	 
PAGEREF _Toc164483335 \h  20  

  HYPERLINK \l "_Toc164483336"  5.1.3	Metabolism in Livestock	  PAGEREF
_Toc164483336 \h  20  

  HYPERLINK \l "_Toc164483337"  5.1.4	Analytical Methodology	  PAGEREF
_Toc164483337 \h  20  

  HYPERLINK \l "_Toc164483338"  5.1.5	Environmental Degradation	 
PAGEREF _Toc164483338 \h  20  

  HYPERLINK \l "_Toc164483339"  5.1.6	  Drinking Water Residue Profile	 
PAGEREF _Toc164483339 \h  21  

  HYPERLINK \l "_Toc164483340"  5.1.7	Food Residue Profile	  PAGEREF
_Toc164483340 \h  21  

  HYPERLINK \l "_Toc164483341"  5.1.8	International Residue Limits	 
PAGEREF _Toc164483341 \h  22  

  HYPERLINK \l "_Toc164483342"  5.2	Dietary Exposure and Risk	  PAGEREF
_Toc164483342 \h  22  

  HYPERLINK \l "_Toc164483343"  5.2.1	Acute Dietary Exposure/Risk	 
PAGEREF _Toc164483343 \h  22  

  HYPERLINK \l "_Toc164483344"  5.2.2	Chronic Dietary Exposure/Risk	 
PAGEREF _Toc164483344 \h  23  

  HYPERLINK \l "_Toc164483345"  5.2.3	Cancer Dietary Risk	  PAGEREF
_Toc164483345 \h  23  

  HYPERLINK \l "_Toc164483346"  5.3	Anticipated Residue and Percent Crop
Treated (%CT) Information	  PAGEREF _Toc164483346 \h  23  

  HYPERLINK \l "_Toc164483347"  6.0	RESIDENTIAL (NON-OCCUPATIONAL)
EXPOSURE/RISK CHARACTERIZATION	  PAGEREF _Toc164483347 \h  24  

  HYPERLINK \l "_Toc164483348"  7.0	AGGREGATE RISK ASSESSMENTS AND RISK
CHARACTERIZATION	  PAGEREF _Toc164483348 \h  24  

  HYPERLINK \l "_Toc164483349"  7.1	Acute Aggregate Risk	  PAGEREF
_Toc164483349 \h  24  

  HYPERLINK \l "_Toc164483350"  7.2	Short/Intermediate-Term Aggregate
Risk	  PAGEREF _Toc164483350 \h  24  

  HYPERLINK \l "_Toc164483351"  7.3	Chronic Aggregate Risk	  PAGEREF
_Toc164483351 \h  25  

  HYPERLINK \l "_Toc164483352"  7.4	Cancer Aggregate Risk	  PAGEREF
_Toc164483352 \h  25  

  HYPERLINK \l "_Toc164483353"  8.0	CUMULATIVE RISK
CHARACTERIZATION/ASSESSMENT	  PAGEREF _Toc164483353 \h  25  

  HYPERLINK \l "_Toc164483354"  9.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY	 
PAGEREF _Toc164483354 \h  25  

  HYPERLINK \l "_Toc164483355"  10.0	DATA NEEDS AND LABEL
RECOMMENDATIONS	  PAGEREF _Toc164483355 \h  30  

  HYPERLINK \l "_Toc164483356"  Appendix A:  TOXICOLOGY ASSSESSMENT	 
PAGEREF _Toc164483356 \h  32  

  HYPERLINK \l "_Toc164483357"  A.1	Toxicology Data Requirements	 
PAGEREF _Toc164483357 \h  32  

  HYPERLINK \l "_Toc164483358"  A.2	Toxicity Profiles	  PAGEREF
_Toc164483358 \h  33  

  HYPERLINK \l "_Toc164483359"  A.3	Executive Summaries	  PAGEREF
_Toc164483359 \h  33  

  HYPERLINK \l "_Toc164483360"  A.4	References (in MRID order)	  PAGEREF
_Toc164483360 \h  45  

 

1.0	EXECUTIVE SUMMARY

A petition has been submitted by the State of California, with support
from Chemtura USA Corporation, for the establishment of a Section 18
Emergency Exemption tolerance for the insecticide/acaricide
diflubenzuron (N-[((4-chlorophenyl)amino)
carbonyl]-2,6-difluorobenzimide) in/on lemons (PP# 07CA04). 
Diflubenzuron acts as a chitin inhibitor to suppress the growth of many
leaf-eating larvae, mosquito larvae, aquatic midges, rust mite, boll
weevil, and flies.  The proposed end-use product for this risk
assessment is Dimilin® 2L, EPA Reg. No. 400-461.  The product is to be
tank mixed with spray oils which are exempt from tolerances but not
specifically labeled for the proposed use.   These proposed spray oils
are: Superior 415 Spray Oil, EPA Reg. No. 2935-542; Britz 415 Supreme
Spray Oil, EPA Reg. No. 10951-15; and Spray Oil 415, EPA Reg. No.
34704-727.  According to California’s request, efficacy data indicates
that the addition of the spray oil can enhance the efficacy of the
diflubenzuron.  Eggs laid on oil treated leaves can fall off, further
enhancing the efficacy of the treatment.   

Tolerances for residues of diflubenzuron are established under 40CFR
§180.377.  Tolerances listed in 40 CFR §180.377(a)(1) are expressed in
terms of diflubenzuron per se.  Under this section, current tolerances
range from 0.05 ppm in/on eggs; milk; fat and meat of cattle, goat, hog,
horse, poultry, and sheep; poultry meat byproducts to 6.0 ppm in globe
artichoke.

Tolerances listed in 40 CFR §180.377(a)(2) are expressed in terms of
the combined residues of diflubenzuron and its metabolites
4-chlorophenylurea (CPU) and 4-chloroaniline (PCA).  Under this section,
current tolerances range from 0.02 ppm in/on rice grain to 55 ppm in
peanut hay.

Time-limited tolerances listed in 40 CFR §180.377(b) are expressed in
terms of the combined residues of diflubenzuron and its metabolites CPU
and PCA, expressed as the parent diflubenzuron, in connection with use
of the pesticide under Section 18 Emergency Exemptions granted by EPA. 
Under this section, current tolerances range from 0.10 ppm in/on wheat
milled byproducts to 30 ppm in wheat aspirated grain fractions

The most recent human health risk assessment for diflubenzuron was
conducted in conjunction with an Interregional Research Project No. 4
(IR-4) request for the establishment of permanent tolerances for
residues of diflubenzuron in/on barley, oats, wheat, Brassica leafy
greens (Crop Subgroup 5B), turnip greens, eggplant, okra, peanut, and
pummelo (G. Kramer, DP #s: 321152, 321155, & 321158, 09/14/2006).  

Under PP#07CA4, the State of California requests the establishment of
tolerances for the combined residues of diflubenzuron and its
metabolites CPU and PCA in/on the following raw agricultural commodities
(RACs):

	Lemons…………..0.8 ppm

Also, due to the nature of the plant, residential plantings of avocados
are too prolific for stripping.  A residue value of 0.8 ppm will be
applied in this assessment for avocados for those potential residues.  

Human Health Risk Assessment

Toxicology/Hazard

The acute oral, dermal and inhalation toxicity of diflubenzuron is low. 
It is a mild eye irritant and not a skin irritant in laboratory animals.
 It is negative for sensitization in the guinea pig.  In subchronic and
chronic feeding studies, the primary endpoint of concern, produced most
likely by PCA, was methemoglobinemia and/or sulfhemoglobinemia.  These
effects were evident in both sexes of mice, rats, and dogs and were
produced by more than one route of administration in rats [i.e., oral,
dermal and inhalation].  The general consequence of methemoglobinemia
and/or sulfhemoglobinemia is the impairment of the oxygen transportation
capacity of the blood, which is generally known to be caused by aromatic
amines in both humans and animals.

The overall toxicology database is sufficient for a determination of
potential hazard to infants and children.  The data provide no
indication of an increased susceptibility to rats or to rabbits from in
utero or post-natal exposure to diflubenzuron.  

Dose Response Assessment

On April 21, 1998 HED’s Hazard Identification Assessment Review
Committee (HIARC) evaluated the toxicology database, selected doses and
endpoints for chronic dietary exposures as well as occupational and
residential exposure scenarios [short-, intermediate-, and long-term
exposure (dermal and inhalation)], assessed the carcinogenic potential
and addressed the sensitivity of infants and children from exposure to
diflubenzuron as required by the Food Quality Protection Act (FQPA) of
1996.  On August 14, 2001, the HIARC revisited diflubenzuron and
selected the 21-day dermal toxicity study in rats for short-term dermal
exposure to be consistent with the current policy for 1- to 30-day
duration.  On February 12, 2002, the HIARC revisited diflubenzuron and
selected the 28-day inhalation toxicity study in rats for short-, and
intermediate-term inhalation exposure and reduced the uncertainty factor
(UF) from 3x to 1x, since the selected study has a
no-observed-adverse-effect level (NOAEL).

FQPA Assessment

The FQPA Safety Factor Committee (SFC) recommended that the FQPA safety
factor used in human health risk assessments (as required by FQPA of
August 3, 1996) be reduced to 1x in assessing the risk posed by this
chemical (B. Tarplee, HED Document Number 012630, 06/14/1998). 
Consequently, the current chronic reference dose (cRfD) and chronic
population adjusted dose (cPAD) values are equivalent (0.02 mg/kg/day).
This decision was based on the following:  1) there is no indication of
increased susceptibility of rats or rabbits to in utero or postnatal
exposure; 2) a developmental neurotoxicity study (DNT) with
diflubenzuron is not required; 3) food and drinking water exposure
assessments will not underestimate the potential exposure for infants
and children; and 4) there are currently no registered or proposed
residential (non-occupational) uses of diflubenzuron. 

Dietary Exposure (Food/Water)

Residue Chemistry and Risk

Treatment will be limited to an area of 42 acres in Los Angeles, Orange
and San Diego counties in California.  The product will be applied as a
foliar spray at the rate of 0.275 lb ai. per acre (in 50-1000 gallons
per acre with 0.5% oil added) by ground or air and not expected to
exceed a total of 158 lbs. of product (34.7 lbs. ai.) for the first year
of treatment.  

A residue study (MRID 45333601) was submitted but not formally reviewed
for this action.  The results from the field trials show that residues
of diflubenzuron in lime samples were 0.151-0.172 ppm while residues in
lemons were 0.245-0.551 ppm in samples harvested 21 days following the
last application of a total rate of 15 oz. ai./A.  

Below are the summarized findings from the previous 2006 risk
assessment. 

The qualitative nature of the residue in plants and fungi is adequately
understood based on data from citrus, mushroom, rice, and soybean
metabolism studies.  The metabolism of diflubenzuron in crops tested is
similar, and the radioactive components are also similar to those found
in soil.  The nature of the residue in livestock is also adequately
understood based on acceptable poultry and ruminant metabolism studies
reflecting oral dosing.  The HED Metabolism Assessment Review Committee
(MARC) has concluded that the residues of concern in plants, livestock,
and fungi, for the purpose of tolerance expression, are diflubenzuron
and its metabolites PCA and CPU.

There are adequate enforcement methods, published in the Pesticide
Analytical Manual (PAM, Vol. II), for determining diflubenzuron residues
of concern.  In addition, a new analytical methodology for plant
commodities was successfully validated by an independent laboratory as
well as by Agency chemists at the Analytical Chemistry Branch
(ACB)/Biological and Economics Analysis Division (BEAD) in conjunction
with the approved rice petition.  T  SEQ CHAPTER \h \r 1 hese methods
can separately determine residues of diflubenzuron by gas
chromatography/electron-capture detection (GC/ECD), CPU by GC/ECD, and
PCA by GC/mass spectrometry (MS).  

Water Exposure and Risk

The Environmental Fate and Effects Division (EFED) previously provided a
drinking water assessment (A. Al-Mudallal, DP #: 321156, 08/25/2006). 
Because monitoring data were unavailable, estimates of diflubenzuron and
the major degradate CPU concentrations were made only with mathematical
models.  The Pesticide Root Zone Model/Exposure Analysis Modeling System
(PRZM/EXAMS) models with IR scenarios and percent crop area adjustment
factors were used to conduct surface water exposure assessments. 
Screening Concentration in Ground Water (SCIGROW) was used for
groundwater.  Estimated Drinking Water Concentrations (EDWCs) were
generated for the total toxic residue which includes parent
diflubenzuron and the major degradate CPU.  The highest estimated
surface water concentrations occurred with the PA pear scenario.  For
chronic assessments the EDWC is 2.76 ppb; this was the value used in
this assessment.  The groundwater estimate from SCIGROW is 0.208 ppb. 
This scenario presents the most conservative surface water concentration
due to use of diflubenzuron, including the proposed lemon use.  

Acute and Chronic Dietary Exposure Results and Characterization

No toxic effects attributable to a single (i.e., acute) exposure to
diflubenzuron have been identified; therefore, an acute reference dose
(aRfD) has not been established for diflubenzuron and an acute dietary
exposure assessment has not been conducted.  

(DEEM-FCID™, Version 2.03).  The highest chronic drinking water
concentration of 2.76 ppb was used in this analysis.  The assessment was
based on the assumption of recommended tolerance-level residues, 100%
crop treated (%CT) and that DEEM default processing factors were used
for some commodities.  The results of the analysis indicate that chronic
risk from the dietary (food + drinking water) exposure to diflubenzuron
will not exceed HED’s level of concern for the general U.S. population
and all population subgroups.

Residential Exposure/Risks

Although there are no registered homeowner uses, there are registered
uses for professional applications to outdoor residential and
recreational areas to control mosquitoes, moths, and other insects. 
However, the potential for post-application residential exposure is
expected to be limited.  Due to the low dermal absorption rate (0.5%) of
diflubenzuron and since the state is conducting a substantial homeowner
outreach/education program, minimal bystander contact is expected.

Aggregate Exposure/Risks

Short-, intermediate-, and long-term aggregate-risk assessments were not
performed because there are no registered or proposed uses of
diflubenzuron which result in residential exposures.  Acute and cancer
aggregate-risk assessments were not performed because no appropriate
endpoint was available to determine the aRfD for the general population
or any population subgroup and diflubenzuron is not carcinogenic.  

Chronic aggregate risk estimates do not exceed HED's level of concern. 
Since the chronic aggregate risk exposure includes only food and water,
and the chronic dietary analysis included both, no further calculations
are necessary.  Since the chronic dietary risk does not exceed HED’s
level of concern, the chronic aggregate risk does not exceed HED’s
level of concern.

Occupational Exposure/Risks

Based upon the proposed new use patterns, RD believes the most highly
exposed occupational pesticide handlers will be mixer/loaders using open
pour loading of liquids, applicators using open-cab ground-boom sprayer,
applicators using open-cab airblast sprayer, applicators using
fixed-wing aircraft, applicators using high-pressure hand-wand and
mixer/loader/applicators using backpack sprayer with open pour loading
of liquids.  The toxicological endpoints for short-term dermal and
short-term inhalation effects were derived from two different studies;
however, both studies indicate similar toxicological effects (i.e.,
methemoglobinemia).  The level of concern is for Margins of Exposure
(MOEs) < 100.  

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 Pesticide
Handler Exposure Database (PHED) (v. 1.1, 1998).   For pesticide
handlers, it is HED standard practice to present estimates of dermal
exposure for “baseline” that is, for 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 PPE as might be necessary. 

Environmental Justice Consideration

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.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
http://www.eh.doe.gov/oepa/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 USDA under the Continuing
Survey of Food Intake 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 does not rely on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.

Additional Data Needs

None are required for this petition.

Recommendations for Tolerances/Registration

ARIA concludes that there are no residue chemistry or toxicology data
requirements that would precluded the establishment of the ARIA
recommended time-limited tolerance of 0.80 ppm for diflubenzuron in/on
lemons.  ARIA also recommends for exempting the tank mixing spray oils
from the requirement of a tolerance for this use.

2.0	INGREDIENT PROFILE

2.1	Proposed Use

The product suggested for use is Dimilin® 2L (Reg. No. 400 - 461).  The
request is for use in the Counties of Los Angeles, Orange and San Diego.
 The rate of application is 0.275 lb ai/A in 50 - 1000 gallons of
spray/A depending upon tree size.  Spray should be mixed with 0.5 %
Superior 415 Spray Oil.  Applications may be made by ground or aerially.
 There is a maximum of 3 applications/yr/site.  The reapplication
interval is 90 days.  There is a 21 day preharvest interval (PHI).  

Table 2.1 Summary of Proposed Use Pattern for Diflubenzuron

Crop/Site	Citrus, avocados, guavas and other tropical fruit

Pest	Diaprepes root weevil

Method of Applic.	air, ground (backpack, highpressure handwand,
airblast)

Max. Applic. Rate	0.275 lb ai/A

Max. No. Applications	3/site/yr

Applic. Interval	90 days

Max. Amount Applied	35 lb ai for first year

Acres treated	estimated 42 acres

Preharvest Interval	21 days

Restricted Entry Interval	12 hours

Manufacturer	Crompton Crop Protection

2.2	Identification of Active Ingredient

Common Name	Diflubenzuron

Trade and other Names	Dimilin, Vigilante, Micromite, Adept

IUPAC Name	1-(4-chlorophenyl)-3-(2,6-difluorobenzoyl)urea

CAS Name	N-[[(4-chlorophenyl)amino]carbonyl]-2,6-difluorobenzamide

CAS Registry Number	35367-38-5

End-Use Products (EP)	2 lb/gal FlC formulation; DIMILIN® 2L (EPA Reg.
No. 400-461);

25% WP formulation; DIMILIN® 25W (EPA Reg. No. 400-465);

Common Name	4-chloroaniline (PCA)

2.3	Physical and Chemical Properties

TABLE 2.3  Physicochemical Properties of Diflubenzuron.

Parameter	Value	Reference

Melting range	230-232 °C	  HYPERLINK
"http://www.arsusda.gov/acsl/services/ppdb/textfiles/DIFLUBENZURON" 
http://www.arsusda.gov/acsl/services/ppdb/textfiles/DIFLUBENZURON 

pH	Not available

	Density	Not available

	Water solubility (25 °C)	0.08 ppm

	Solvent solubility (25 °C) (ppm)	6.5 x 103     Acetone             

2 x 103        Acetonitrile        

2.4 x 104     Dioxane             

1.04 x 105   Dimethylformamide    

1.2 x 105     Dimethylsulfoxide   

1 x 103        Methanol            

6 x 102        Dichloromethane     

	Vapor pressure (25 °C)	1.2 x 10- 4 mPa

	Dissociation constant, pKa	Not available

	Octanol/water partition coefficient, Log(KOW)	3.89

	

3.0	HAZARD CHARACTERIZATION  TC \l1 "3.0  HAZARD CHARACTERIZATION 

A complete hazard characterization is presented in the Section 3 risk
assessment for the use of diflubenzuron on rice (Memo, G. Kramer et al.,
DP #: 254693, 03/30/1999).  For purposes of clarity, the dose-response
assessment is summarized below.

3.1	Hazard and Dose-Response Characterization

In subchronic and chronic feeding studies, the primary endpoint of
concern, produced most likely by PCA, was methemoglobinemia and/or
sulfhemoglobinemia, which was evident in both sexes of mice, rats, and
dogs and which was produced by more than one route of administration in
rats [i.e., oral and inhalation].  The general consequence of
methemoglobinemia and/or sulfhemoglobinemia is the impairment of the
oxygen transportation capacity of the blood, which is generally known to
be caused by aromatic amines in both man and animals.  Additionally, the
aromatic amine most likely responsible for the methemoglobinemia and/or
sulfhemoglobinemia, PCA, is also the agent suspected in the production
of tumors in carcinogenic studies in rodents.

The overall toxicology database is sufficient for a determination of
potential hazard to infants and children. The data provide no indication
of an increased susceptibility to rats or to rabbits from in utero or
post-natal exposure to diflubenzuron.  Developmental and reproduction
studies in rats and rabbits indicate a very low or possibly non-existent
hazard potential for adverse effects.  Developmental studies were tested
at the limit dose of 1000 mg/kg/day without apparent effects in both
dams and the fetuses.  The reproduction study indicated that effects in
offspring occurred at doses that were higher than the doses producing
effects in parents.  There was no indication of abnormalities in the
development of the fetal nervous system in the prenatal developmental
toxicity studies in either rats or rabbits at the maternal limit doses
of 1000 mg/kg/day nor was there evidence of effects on the nervous
system following pre- and/or post-natal exposure in a two generation
reproduction study in rats.  There were no reports of

treatment-related clinical observations indicative of central nervous
system involvement or histopathological changes in the central nervous
system [non-perfused tissues] in the subchronic or the chronic studies.

3.1.1	Database Summary  TC \l3 "3.1.1	Database Summary 

3.1.1.1	Studies Available and Considered 

The overall toxicology database is sufficient for a determination of
potential hazard to infants and children.  The data provide no
indication of an increased susceptibility to rats or to rabbits from in
utero or post-natal exposure to diflubenzuron.  Developmental and
reproduction studies in rats and rabbits indicate a very low hazard
potential for adverse effects.  Developmental studies were tested at the
limit dose of 1000 mg/kg/day without apparent effects in both dams and
the fetuses.  The reproduction study indicated that effects in offspring
occurred at doses that were higher than the doses producing effects in
parents.  There was no indication of abnormalities in the development of
the fetal nervous system in the prenatal developmental toxicity studies
in either rats or rabbits at the maternal limit doses of 1000 mg/kg/day.
 In addition, there was no evidence of effects on the nervous system
following pre- and/or post-natal exposure in a two-generation
reproduction study in rats.  There were no reports of treatment-related
clinical observations indicative of central nervous system toxicity or
histopathological changes in the central nervous system [non-perfused
tissues] in the subchronic or the chronic studies.

3.1.1.2	Mode of action, metabolism, toxicokinetic data

Diflubenzuron belongs to the benzoylphenylurea class of pesticides.  It
is a chitin synthesis inhibitor, a compound which disrupts the normal
development of insects by blocking production of chitin, an important
componet of the exoskeleton of insects, preventing insects from molting.
 

 3.1.2	Toxicological Effects

The hemopoietic system is the target site with effects including
increased sulfhemoglobin and/or methemoglobin levels in rat and dog
studies.  No appropriate acute endpoint was identified in the hazard
database to quantitate the risk to the general population or to females
13-50 years old from single dose administration of diflubenzuron. 
Therefore, there is no aRfD or acute population-adjusted dose (aPAD). 
The short-term dermal endpoint was selected from a 21-day rat dermal
study with a NOAEL of 500 mg/kg/day based on a significant increase in
methemoglobinemia observed at the lowest-observed-adverse-effect level
(LOAEL) of 1000 mg/kg/day.  The intermediate-term dermal endpoint was
selected from a 13-week oral (capsule) study in the dog with a NOAEL of
2 mg/kg/day based on increased methemoglobinemia observed at the LOAEL
6.24 mg/kg/day.  The short-, and intermediate-term inhalation endpoints
were selected from a 28-day rat inhalation toxicity study with a NOAEL
of 0.109 mg/L (highest dose tested, HDT), based on a statistically
significant increase in methemoglobin levels observed at 0.12 mg/L
(LOAEL) in a 21-day rat inhalation toxicity study.  The chronic dietary,
long-term dermal and long-term inhalation endpoints were selected from a
chronic dog study with a NOAEL of 2 mg/kg/day based on increased
methemoglobin levels observed at 10 mg/kg/day (LOAEL).  The cRfD is 0.02
mg/kg/day and the cPAD is 0.02 mg/kg/day.  The HED RfD/Peer Review
Committee classified diflubenzuron as “Group E,” evidence of
non-carcinogenicity for humans, based on lack of evidence of
carcinogenicity in rats and mice (04/27/1995).  PCA, a metabolite of
diflubenzuron, tested positive for splenic tumors in male rats and
hepatocellular adenomas/carcinomas in male mice in a National Toxicology
Program (NTP) study.  Therefore, the RfD/Peer Review Committee
classified PCA as a “Group B2" probable human carcinogen.  However,
recently submitted acceptable rat metabolism studies show that
diflubenzuron was not metabolized to either PCA or CPU.  On May 8, 2001,
the MARC reviewed the recently submitted metabolism studies, accepted
the study findings, and concluded that cancer risks for CPU and PCA
should be assessed individually.  The non-carcinogenic risk assessment
should include diflubenzuron, CPU and CPA.

3.1.3	FQPA

The FQPA SFC recommended that the FQPA safety factor used in human
health risk assessments be reduced to 1x in assessing the risk posed by
this chemical (B. Tarplee, HED Document Number 012630, 06/14/1998). 
Consequently, the current cRfD and cPAD values are equivalent (0.02
mg/kg/day). This decision was based on the following:  1) there is no
indication of increased susceptibility of rats or rabbits to in utero or
postnatal exposure; 2) a DNT with diflubenzuron is not required; 3) food
and drinking water exposure assessments will not underestimate the
potential exposure for infants and children; and 4) there are currently
no registered or proposed residential (non-occupational) uses of
diflubenzuron. 

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)

Recently submitted rat metabolism data (MRID#s 44875501 and 44875502)
indicate that diflubenzuron does not metabolize to PCA or CPU nor is CPU
converted to PCA.  The HED MARC met several times (02/20/2001 and
05/8/2001), concurred with the study findings, and concluded that a 2%
in vivo conversion factor for diflubenzuron to PCA or CPU should be
dropped (MARC memo, 05/31/2001).  In conclusion, the MARC recommended
that non-carcinogenic risk assessment should include parent, CPU and
PCA.

3.3	FQPA Considerations

3.3.1	Adequacy of the Toxicity Database  TC \l3 "3.3.1	Adequacy of the
Toxicity Database 

Acceptable neurotoxicity, developmental and reproductive toxicity
studies conducted with diflubenzuron are available in rats and rabbits. 
The toxicology database is considered complete for the purposes of FQPA
assessment.  

3.3.2	Evidence of Neurotoxicity

The data provide no indication of an increased susceptibility to rats or
to rabbits from in utero or post-natal exposure to diflubenzuron.  In
addition, there was no evidence of effects on the nervous system
following pre- and/or post-natal exposure in a two-generation
reproduction study in rats.  There were no reports of treatment-related
clinical observations indicative of central nervous system toxicity or
histopathological changes in the central nervous system [non-perfused
tissues] in the subchronic or the chronic studies.

   TC \l3 "3.3.2	Evidence of Neurotoxicity 

3.3.3	Developmental/Reproductive Toxicity Studies

Developmental and reproduction studies in rats and rabbits indicate a
very low hazard potential for adverse effects.  Developmental studies
were tested at the limit dose of 1000 mg/kg/day without apparent effects
in both dams and the fetuses.  The reproduction study indicated that
effects in offspring occurred at doses that were higher than the doses
producing effects in parents. 

  TC \l3 "3.3.5	Additional Information from Literature Sources 

3.3.4	Pre-and/or Postnatal Toxicity  TC \l3 "3.3.6	Pre-and/or Postnatal
Toxicity 

3.3.4.1	Determination of Susceptibility

Based on the available developmental toxicity studies in rats and
rabbits, there is no increased susceptibility to fetuses exposed in
utero.    TC \l4 "3.3.6.1	Determination of Susceptibility 

3.3.4.2	Degree of Concern Analysis and Residual Uncertainties  TC \l4
"3.3.6.2	Degree of Concern Analysis and Residual Uncertainties  for Pre-
and/or Postnatal Susceptibility

	

Based on the available reproduction toxicity studies, there is no
evidence of increased susceptibility in rat fetuses following
pre-/post-natal exposure.  

3.3.5	Recommendation for a Developmental Neurotoxicity Study  

A DNT study with diflubenzuron is not required.  The HIARC recommended a
dermal-absorption factor of 0.5% based on a 1- to 10-hour exposure from
a rat study.  TC \l3 "3.3.7	Recommendation for a Developmental
Neurotoxicity Study 

3.4	FQPA Safety Factor for Infants and Children

The FQPA safety factor for diflubenzuron has been reduced to 1X, see
section 3.1.3 above.   

3.5	Hazard Identification and Toxicity Endpoint Selection

3.5.1	Acute Reference Dose (aRfD) 

No appropriate toxicological endpoint attributable to a single exposure
was identified in the hazard database, including oral developmental
toxicity studies in rats and rabbits.

  TC \l3 "3.5.2	Acute Reference Dose (aRfD) - General Population 

3.5.2	Chronic Reference Dose (cRfD) 

The chronic dog study was used to select the endpoint for establishing
the cRfD of 0.02 mg/kg/day.  The standard 100x UF was applied to account
for interspecies extrapolation and intraspecies variation.  The NOAEL of
2.0 mg/kg/day was based on methemoglobinemia and sulfhemoglobinemia seen
at 10 mg/kg/day (LOAEL).  The FQPA SFC determined that a FQPA safety
factor of 1x is applicable for chronic dietary risk assessment. Thus,
the cPAD is 0.02 mg/kg/day.

3.5.3	Incidental Oral Exposure (Short- and Intermediate-Term)

These endpoints were not evaluated.  There are no registered or proposed
uses of diflubenzuron which result in significant residential exposure.

3.5.4	Dermal Absorption  TC \l3 "3.5.5	Dermal Absorption 

The HIARC recommended a dermal-absorption factor of 0.5% based on a 1-
to 10-hour exposure from a rat study.

3.5.5	Short-Term Dermal Exposure 

A short-term dermal endpoint was selected from a 21-day rat dermal
toxicity study.  The NOAEL of 500 mg/kg/day was based on the significant
increase in methemoglobinemia observed at 1000 mg/kg/day (limit dose). 
This study is route-specific, is of appropriate duration and measures
the effects of concern; i.e., methemoglobin and/or sulfhemoglobin.

3.5.6	Intermediate-Term Dermal Exposure

An intermediate-term dermal endpoint was selected from a subchronic oral
toxicity dog study.  The NOAEL of 2.0 mg/kg/day was based on increased
methemoglobinemia at 6.24 mg/kg/day.  This endpoint (methemoglobinemia/
sulfhemoglobinemia) was seen consistently in the 90-day dog study and
chronic toxicity studies in rats, mice and dogs at about similar ranges
and it is appropriate for this exposure period of concern.  Since an
oral NOAEL was selected for a dermal-exposure scenario, a
dermal-absorption factor of 0.5% should be used for this risk assessment
when converting dermal exposure to oral equivalents.

3.5.7	Long-Term Dermal Exposure

A long-term dermal endpoint was selected from a chronic oral toxicity
study in the dog, see section 3.5.2, above.  An oral study was selected
since no appropriate long-term dermal study is available in the
database.  A 0.5% dermal-absorption factor should be used to convert to
oral equivalents.

3.5.8	Short-/Intermediate-Term Inhalation Exposure

Inhalation endpoints were selected from a 28-day rat inhalation toxicity
study.  The NOAEL of 0.109 mg/L (HDT) in the study was based on
significant increase in methemoglobinemia seen in a 21-day inhalation
toxicity study at 0.12 mg/L (LOAEL at LDT).

3.5.9	Long-Term Inhalation Exposure

A long-term inhalation endpoint was selected from a chronic oral
toxicity dog study, see section 3.5.2, above.  An oral study was
selected since no appropriate long-term inhalation study is available in
the database.  A 100% inhalation-absorption factor should be used to
convert to oral equivalents.

  TC \l3 "3.5.7	Inhalation Exposure (Short-, Intermediate- and
Long-Term) 

3.5.10	Level of Concern for Margin of Exposure

A MOE of 100 is adequate for occupational exposure.  TC \l3 "3.5.8	Level
of Concern for Margin of Exposure 

3.5.11	Recommendation for Aggregate Exposure Risk Assessments

Aggregate exposure risk assessments were assessed by incorporating the
drinking water directly into the dietary-exposure assessment for the
following scenario: chronic aggregate exposure (food + drinking water). 
Short-, intermediate-, and long-term aggregate-risk assessments were not
performed because there are no registered or proposed uses of
diflubenzuron which result in residential exposures.  Acute and cancer
aggregate-risk assessments were not performed because no appropriate
endpoint was available to determine the aRfD for the general population
or any population subgroup and diflubenzuron is not carcinogenic.  

3.5.12	Classification of Carcinogenic Potential 

Based on the available evidence, which included adequate carcinogenicity
studies in rats and mice, and battery of negative mutagenicity studies,
diflubenzuron was classified as “Group E,” evidence of
non-carcinogenicity for humans, by the RfD Peer Review Committee
(04/27/1995).  Rat metabolism data generated at this time also indicated
that diflubenzuron was metabolized to PCA and CPU and estimated to be
about 2% of in vivo conversion.

 

3.5.13	Summary of Toxicological Doses and Endpoints for Diflubenzuron
for Use in Human Risk Assessments

Table 3.5.13.  Summary of Toxicological Dose and Endpoints for
Diflubenzuron for Use in Human Risk Assessment1.

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	Not Applicable	No appropriate endpoint
attributable to single exposure was available in oral studies. 
Therefore, a risk assessment is not required.

Chronic Dietary

all populations	NOAEL= 2 mg/kg/day

UF = 100

Chronic RfD = 

0.02 mg/kg/day	FQPA SF = 1x

cPAD = 

chronic RfD

 FQPA SF

= 0.02 mg/kg/day	Chronic Toxicity Study - Dog

LOAEL = 10 mg/kg/day based on methemoglobinemia and sulfhemoglobinemia

Short- and Intermediate-Term Incidental Oral

(1 day - 6 months)

(Residential)	Not applicable	Not applicable	These endpoints were not
evaluated.    There are no registered uses of diflubenzuron which result
in significant residential exposure.

Short-Term Dermal (1 - 30 days)

(Occupational)	NOAEL = 500 mg/kg/day	LOC for MOE = 100	21-Day dermal rat

LOAEL = 1000 mg/kg/day based on methemoglobinemia

Intermediate-Term Dermal (1 - 6 months)

(Occupational)	NOAEL = 2 mg/kg/day	LOC for MOE = 100	13 - week oral dog 
                                   LOAEL = 6.4 mg/kg/day based on       
   methemoglobinemia 

Long-Term Dermal (Longer than 6 months)

(Occupational)	NOAEL = 2 mg/kg/day	LOC for MOE = 100	Chronic Toxicity
Study - Dog

LOAEL = 10 mg/kg/day based on methemoglobinemia and sulfhemoglobinemia

Short-Term Inhalation (1 - 30 days)

(Occupational)	NOAEL = 20.302 mg/kg/day	LOC for MOE = 100	28-day
Inhalation Toxicity Study - Rat/

21-day Inhalation Toxicity Study - Rat

LOAEL = 0.12 mg/L based on methemoglobinemia (21-day study)

Intermediate-Term Inhalation (1 - 6 months)

(Occupational)	NOAEL = 20.302 mg/kg/day	LOC for MOE = 100	28-day
Inhalation Toxicity Study - Rat/

21-day Inhalation Toxicity Study - Rat

LOAEL = 0.12 mg/L based on methemoglobinemia (21-day study)

Long -Term Inhalation (Longer than 6 months)

(Occupational)	NOAEL = 2  mg/kg/day	LOC for MOE = 100 (Occupational)
Chronic Toxicity Study - Dog

LOAEL = 10 mg/kg/day based on methemoglobinemia and sulfhemoglobinemia

Cancer (oral, dermal, inhalation)	Diflubenzuron

Not Required	Not Applicable	Acceptable oral rat and mouse
carcinogenicity studies; no evidence of carcinogenic or mutagenic
potential. “Group E” evidence of non- carcinogenicity for humans.

	1.  UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL =
no-observed-adverse-	effect level, LOAEL =
lowest-observed-adverse-effect level, cPAD = chronic population-
adjusted dose, RfD = reference dose, MOE = margin of exposure, LOC =
level of concern.

	2.  Conversion from mg/L to oral dose (mg/kg/day)

3.6	Endocrine disruption

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

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

4.0	PUBLIC HEALTH AND PESTICIDE EPIDEMIOLOGY DATA

No public health/epidemiology data were used in developing this risk
assessment.

5.0	DIETARY EXPOSURE/RISK CHARACTERIZATION  TC \l1 "5.0	Dietary
Exposure/Risk Characterization 

5.1	Pesticide Metabolism and Environmental Degradation

5.1.1	Metabolism in Primary Crops

The qualitative nature of the residue in plants and fungi is adequately
understood based on data from citrus, mushroom, rice, and soybean
metabolism studies.  The metabolism of diflubenzuron in crops tested is
similar, and the radioactive components are also similar to those found
in soil.  The nature of the residue in livestock is also adequately
understood based on acceptable poultry and ruminant metabolism studies
reflecting oral dosing.  

5.1.2	Metabolism in Rotational Crops

  SEQ CHAPTER \h \r 1 The nature of the residue in rotational crops is
adequately understood for purposes of reregistration (Residue Chemistry
Chapters for the Reregistration Eligibility Decision (RED) document,
03/15/1995).  Lemons though are not a rotational crop.

5.1.3	Metabolism in Livestock

	

There are ruminant and/or poultry feed items associated with the uses of
diflubenzuron on barley, oats, wheat, and peanuts.  The calculated
maximum theoretical dietary burdens resulting from the registered uses
are supported by previously submitted livestock feeding studies.  

5.1.4	Analytical Methodology		

	

There are adequate enforcement methods, published in the Pesticide
Analytical Manual (PAM, Vol. II), for determining diflubenzuron residues
of concern.  In addition, a new analytical methodology for plant
commodities was successfully validated by an independent laboratory as
well as by Agency chemists at the Analytical Chemistry Branch
(ACB)/Biological and Economics Analysis Division (BEAD) in conjunction
with the approved rice petition.  The new methods were forwarded to the
Food and Drug Administration (FDA) for publication in PAM Vol. II as
Roman Numeral Methods.  T  SEQ CHAPTER \h \r 1 hese methods can
separately determine residues of diflubenzuron by gas
chromatography/electron-capture detection (GC/ECD), CPU by GC/ECD, and
PCA by GC/mass spectrometry (MS).  

  TC \l3 "5.1.4	Analytical Methodology 

5.1.5	Environmental Degradation

Diflubenzuron appears to be relatively non-persistent and immobile under
normal use conditions. The major route of dissipation appears to be
biotic processes (half-life of approximately 2 days for aerobic soil
metabolism). Diflubenzuron is stable to hydrolysis and photolysis. 
Available data indicate that it is unlikely that diflubenzuron will
contaminate ground water or surface water.

  TC \l3 "5.1.5	Environmental Degradation 

5.1.6	  Drinking Water Residue Profile

The drinking water residues used in the dietary risk assessment were
previously provided by the Environmental Fate and Effects Division and
summarized in the following memorandum: “IR-4/Section 3-Local and New
Uses Registration for Diflubenzuron Use on Peanuts, Okra, Small grains
(Winter, Spring, Durum, Barley, and Oats), Pummelo, Mustard Greens,
Broccoli, Raab, Cabbafe (bok choy), Collards, Kale, Mizuna, Mustard
spinach, Rape, Greens and Turnip greens,” (A. Al-Mudallal, DP #:
321156, 08/25/2006) and incorporated directly into this dietary
assessment.  Water residues were incorporated in the DEEM-FCID into the
food categories “water, direct, all sources” and “water, indirect,
all sources.”   

Because monitoring data are unavailable, estimates of diflubenzuron and
the major degradate CPU concentrations were made only with mathematical
models.  The PRZM/EXAMS models with IR scenarios and percent crop area
adjustment factors were used to conduct surface water exposure
assessments.  SCIGROW was used for groundwater.  EDWCs were generated
for the total toxic residue which includes parent diflubenzuron and the
major degradate CPU.  The highest estimated surface water concentrations
occurred with the PA pear scenario.  For chronic assessments the EDWC is
2.76 ppb; this was the value used in this assessment.  The groundwater
estimate from SCIGROW is 0.208 ppb.  This scenario presents the most
conservative surface water concentration due to use of diflubenzuron.  

5.1.7	Food Residue Profile

No new residue chemistry data was reviewed with this petition. 
Treatment will be limited to an area of 42 acres in Los Angeles, Orange
and San Diego counties in California.  The product will be applied as a
foliar spray at the rate of 0.275 lb ai. per acre (in 50-1000 gallons
per acre with 0.5% oil added) by ground or air and not expected to
exceed a total of 158 lbs. of product (34.7 lbs. ai.) for the first year
of treatment.  

A residue study (Micromite®4L and Micromite® 25W in Lemons and Limes:
Magnitude of the Residue Study, Gaydosh, K., Entocon, Inc., Study No.:
RP-96028, 10/08/1999, MRID 45333601) was submitted but not formally
reviewed for this action.  The results from the field trials show that
residues of diflubenzuron in lime samples were 0.151-0.172 ppm while
residues in lemons were 0.245-0.551 ppm in samples harvested 21 days
following the last application of a total rate of 15 oz. ai./A.  The
mean validation recovery for diflubenzuron was 82%, with a standard
deviation of 11%.   The proposed tolerance of 0.8 ppm is adequate to
support the proposed use.

5.1.8	International Residue Limits

The Codex Alimentarius has established maximum residue limits (MRL),
expressed in terms of diflubenzuron per se, for many commodities
including:  apple (5 ppm), citrus fruits (0.5 ppm), edible offal
(mammalian) (0.1 ppm), eggs (0.05 ppm), meat (from mammals other than
marine mammals) (0.1 ppm), milks (0.02 ppm), mushrooms (0.3 ppm), pear
(5 ppm), pome fruits (5 ppm), poultry meat (0.05 ppm), rice (0.01 ppm),
and rice straw and fodder (dry) 0.7 ppm).  As the U.S. residue
definition includes CPU and PCA, compatibility is not possible with the
proposed tolerances. 

5.2	Dietary Exposure and Risk

™ Version 2.03, which incorporates consumption data from USDA’s
CSFII, 1994-1996 and 1998.  The 1994-96, 98 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, 98
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 assessments, 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 dietary exposure analysis was performed by ARIA (B. Hanson, DP #:
337826, 04/16/2007).

 TC \l2 "5.2  Dietary Exposure and Risk 

5.2.1	Acute Dietary Exposure/Risk

An acute dietary-exposure assessment was not performed because there
were no toxic effects attributable to a single dose.  Thus, an endpoint
of concern was not identified to quantitate acute dietary risk to the
general population or to any population subgroup.

5.2.2	Chronic Dietary Exposure/Risk

A chronic dietary assessment assuming tolerance level residues,
including a 0.8 ppm avocado residue value, and 100% crop treated was
conducted.  The highest estimate of chronic surface water exposure (2.76
ppb) was used for drinking water in this analysis.  The chronic dietary
risk assessment shows that for all included commodities, the chronic
dietary risk estimates are below HED’s level of concern (i.e. <100%
chronic population adjusted doses (cPAD).  For the U.S. population the
exposure for food and water utilized 12% of the cPAD.  The chronic
dietary risk estimate for the highest reported exposed population
subgroup, children 1-2 years old, is 38% of the cPAD.

Table 5.2.2  Summary of Chronic Dietary (Food and Drinking Water)
Exposure Risk for Diflubenzuron

Population Subgroup	Chronic Dietary

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

General U.S. Population	0.002363	12

All Infants (< 1 year old)	0.002317	12

Children 1-2 years old	0.007533	38

Children 3-5 years old	0.005880	29

Children 6-12 years old	0.003530	18

Youth 13-19 years old	0.002340	12

Adults 20-49 years old	0.001671	8

Adults 50+ years old	0.001833	9

Females 13-49 years old	0.001747	9

5.2.3	Cancer Dietary Risk

Based on the previously submitted metabolism studies, there are two
possible sources for dietary exposure to PCA and CPU- residues in fungi
(mushrooms) and residues in livestock commodities (milk and liver).  As
human exposure to PCA and CPU is not affected by these uses, the cancer
dietary risk from PCA and CPU will not be addressed in this document.

5.3	Anticipated Residue and Percent Crop Treated (%CT) Information

No anticipated residue or %CT information was considered in the chronic
dietary analysis.  

6.0	RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK CHARACTERIZATION

Although there are no registered homeowner uses, there are registered
uses for professional applications to outdoor residential and
recreational areas to control mosquitoes, moths, and other insects. 
However, the potential for post-application residential exposure is
expected to be limited.  Due to the low dermal absorption rate (0.5%) of
diflubenzuron and since the state is conducting a substantial homeowner
outreach/education program informing residents on how to avoid pesticide
exposure, minimal bystander contact is expected.

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 groundboom application methods.  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 data base 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. 

7.0	AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

In accordance with the FQPA, ARIA must consider and aggregate pesticide
exposures and risks from non-occupational sources, including; food,
drinking water, and residential pathways.  In an aggregate assessment,
exposures from relevant sources are added together and compared to
quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks
themselves can be aggregated.  When aggregating exposures and risks from
various sources, ARIA considers both the route and duration of exposure.

7.1	Acute Aggregate Risk

An acute aggregate-risk assessment was not performed because no
appropriate endpoint was available to determine the aRfD for the general
population or any population subgroup.   

7.2	Short/Intermediate-Term Aggregate Risk  TC \l2 "5.2  Short-Term
Aggregate Risk  

There are no residential uses associated with diflubenzuron; therefore,
short and intermediate-term aggregate risk assessments were not
performed.

7.3	Chronic Aggregate Risk  TC \l2 "5.4  Chronic Aggregate Risk 

Since the chronic aggregate risk exposure includes only food and water
and the chronic dietary analysis included both, no further calculations
are necessary.  Since the chronic dietary risk does not exceed HED’s
level of concern, the chronic aggregate risk does not exceed HED’s
level of concern.

7.4	Cancer Aggregate Risk  TC \l2 "5.5  Cancer Aggregate Risk 

A cancer aggregate-risk assessment was not performed because
diflubenzuron is not carcinogenic.

8.0	CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to diflubenzuron and any other
substances and diflubenzuron does not appear to produce a toxic
metabolite produced by other substances. For the purposes of this
tolerance action, therefore, EPA has not assumed that diflubenzuron has
a common mechanism of toxicity with other substances.

For information regarding EPA’s efforts to determine which chemicals
have a common mechanism of toxicity and to evaluate the cumulative
effects of such chemicals, see the policy statements released by EPA’s
Office of Pesticide Programs concerning common mechanism determinations
and procedures for cumulating effects from substances found to have a
common mechanism on EPA’s website at   HYPERLINK
http://www.epa.gov/pesticides/cumulative/.
http://www.epa.gov/pesticides/cumulative/. 

9.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY

ARIA provided an assessment for the use of diflubenzuron on citrus,
avocados, guavas and other tropical fruit (M. Dow, DP #: 337825,
03/08/2007).  

Occupational Pesticide Handler Exposure

Based upon the proposed new use patterns, RD believes the most highly
exposed occupational pesticide handlers will be mixer/loaders using open
pour loading of liquids, applicators using open-cab ground-boom sprayer,
applicators using open-cab airblast sprayer, applicators using
fixed-wing aircraft, applicators using high-pressure hand-wand and
mixer/loader/applicators using backpack sprayer with open-pour loading
of liquids

The total area expected to be treated the first year is about 45 acres. 
Most treatment blocks are expected to be rather small.  Information on
the size of a "typical" treatment block is not available to RD.  For
purposes of a screening level, conservative estimate of exposure and
risk, RD will assume each method of application could be used to treat
all estimated acres treated (i.e., 45 A) except for backpack in which RD
assumes 5 acres are treated.  

Particularly for ground applications, private (i.e., grower) applicators
may perform all functions, that is, mix, load and apply the material. 
The HED ExpoSAC SOP Number 12 (03/29/2000) directs that although the
same individual may perform all those tasks, they shall be assessed
separately.  The available exposure data for combined
mixer/loader/applicator scenarios are limited in comparison to the
monitoring of these two activities separately.  These exposure scenarios
are outlined in the PHED Surrogate Exposure Guide (August 1998).   HED
has adopted a methodology to present the exposure and risk estimates
separately for the job functions in some scenarios and to present them
as combined in other cases.  Most exposure scenarios for hand-held
equipment (such as hand wands, backpack sprayers, and push-type granular
spreaders) are assessed as a combined job function.  With these types of
hand-held operations, all handling activities are assumed to be
conducted by the same individual.  The available monitoring data support
this and HED presents them in this way.  Conversely, for equipment types
such as fixed-wing aircraft, groundboom tractors, or air-blast sprayers,
the applicator exposures are assessed and presented separately from
those of the mixers and loaders.  By separating the two job functions,
HED determines the most appropriate levels of personal protective
equipment (PPE) for each aspect of the job without requiring an
applicator to wear unnecessary PPE that might be required for a
mixer/loader (e.g., chemical-resistant gloves may only be necessary
during the pouring of a liquid formulation).  

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 (v.
1.1, 1998).   For pesticide handlers, it is HED standard practice to
present estimates of dermal exposure for “baseline” that is, for
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 PPE as might be necessary.   

The Dimilin® 2L label instructs applicators and other handlers to wear
long-sleeved shirt, long pants, chemical resistant gloves and shoes plus
socks.  Mixers and loaders supporting fixed wing aircraft must wear
long-sleeved shirt, long pants, chemical resistant gloves, shoes plus
socks and dust/mist filtering respirator with MSHA/NIOSH approval number
prefix TC21C or a NIOSH approved respirator with R,P or HE filter.

HED’s HIARC met to discuss the adequacy of the toxicological database
relative to diflubenzuron (Memo, G. Reddy, HED DOC. NO. 0050503,
“DIFLUBENZURON – 3rd Report of the Hazard Identification Assessment
Review Committee, 03/06/2002).  Diflubenzuron was classified in Acute
Toxicity Category III for acute dermal toxicity and primary eye
irritation.  It was classified in Toxicity Category IV for acute
inhalation and primary skin irritation and it is not a dermal
sensitizer.  Relative to this assessment of handler exposure and risk,
the HIARC identified a short-term (1 – 30 days) dermal toxicological
endpoint (methemoglobinemia) with a NOAEL of 500 mg/kg bw/day.   The
dermal endpoint was identified from a 21 day dermal study in the rat. 
The HIARC also identified a short-term inhalation endpoint
(methemoglobinemia) with a NOAEL of 20.3 mg/kg bw/day.  The endpoint was
identified from a 28-day inhalation study in the rat.  See Table 9.0 for
a summary of exposure and risk to occupational pesticide handlers.  The
level of concern is for MOEs < 100.  

Table 9.0 Estimated Handler Exposure and Risk from the Use of
Diflubenzuron on the California Section 18 Use Sites

Unit Exposure1

mg a.i./lb handled	

Applic. Rate2	

Units Treated3

Per Day	

Average Daily

Dose4

mg a.i./kg bw/day	

MOE5	

COMBINED

MOE6

Mixer/Loader - Liquid - Open Pour

Dermal:

SLNG       2.9    HC

SLWG      0.023 HC	

Inhal         0.0012 HC	

0.275 lb a.i./A	

45 A	

Dermal:

No Gloves      0.51

With Gloves   0.0041

Inhal               0.00021	No Glove           980

With Glove 121,950

Inhal             96,666	

NG

970

WG

54,054

Applicator - Aerial (Pilots not required to wear gloves)

Dermal:

SLNG       0.0050 HC

Inhal         0.000068 MC	

0.275 lb a.i./A	

45 A	

Dermal:

No Gloves      0.00088

Inhal               0.000012	

No Glove     7,812

Inhal       1,691,666     	

NG

425,326

Applicator - Air-blast - Open-cab

Dermal:

SLNG       0.36 HC

SLWG      0.24 HC

Inhal         0.0045 HC	

0.275 lb a.i./A	

45 A	

Dermal:

No Gloves      0.064

With Gloves   0.042

Inhal               0.00079	

No Glove     7,812

With Glove  11,904

Inhal             25,696	

NG	

5,991

WG

8,135

Applicator - Ground-boom - Open-cab

Dermal:

SLNG       0.014 HC

SLWG      0.014 MC

Inhal         0.00074 HC	

0.275 lb a.i./A	

45 A	

Dermal:

No Gloves      0.0025

With Gloves   0.0025

Inhal               0.00079	

No Gloves    200,000

With Gloves 200,000

Inhal             156,154	

NG 

87,689

WG

87,689

Applicator - High-Pressure Hand-wand

Dermal

SLNG      1.8 LC

SLWG     0.64 LC

Inhal        0.079 LC	

0.275 lb a.i./A	

45 A	

Dermal:

No Gloves      0.318

With Gloves   0.113

Inhal               0.00155	

No Gloves       1,572

With Gloves    4,424

Inhal               13,096	

NG 

1,403

WG

3,306

Mixer/Loader/Applicator - Backpack - Open Pour Liquid

Dermal

SLWG     2.5 LC

Inhal        0.03 LC	

0.275 lb a.i./A	

5 A	

Dermal:

With Gloves   0.113

Inhal               0.00059	With Gloves   10,204

Inhal               34,406	

WG

7,870

1.  Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”,
Estimates of Worker Exposure from The Pesticide Handler Exposure
Database Version 1.1, August 1998.   SLNG = Dermal Single Layer Work
Clothing No Gloves; SLWG = Dermal Single Layer  Work Clothing With
Gloves;  Inhal. = Inhalation.  Units = mg a.i./lb ai handled.  Data
Confidence: LC = Low Confidence, MC = Medium Confidence, HC = High
Confidence.

2.  Applic. Rate. = Taken from California Section 18 Quarantine request

3.  Units Treated are assumed as most conservative from California
Section 18 Quarantine request

4.  Average Daily Dose = Unit Exposure * Applic. Rate * Units Treated  (
Body Weight (70 kg).  

5.  MOE = Margin of Exposure = NOAEL  ( ADD.  Dermal NOAEL = 500 mg
a.i./kg bw/day; Inhalation NOAEL = 20.3 mg a.i./kg bw/day

6.    The toxicological endpoints for short-term dermal effects and
short-term inhalation effects were derived from two different studies
however both  studies indicate similar toxicological effects (i.e.,
methemoglobinemia).   Since the results of the two studies indicate
similar toxicological effects, the Margins of Exposure (MOEs) are shown
as Combined MOEs.   Combined MOEs are expressed as:

                                   1                             (HED
SOP 97.2; 26 NOV 97).

1/MOEDermal + 1/MOEInhalation  

Post-Application Agricultural Worker Exposure

Typically there is the possibility for agricultural workers to
experience post-application exposures to dislodgeable pesticide
residues; in this case through the stripping of fruits from treated
trees.  There were no chemical-specific data with which to estimate
post-application exposure of agricultural workers to dislodgeable
residues of diflubenzuron.  Therefore, theoretical estimates of
exposure, based on surrogate studies, have been conducted.  The ExpoSAC
(SOP 003.1, Rev. 7 Aug. 2000, Regarding Agricultural Transfer
Coefficients; Amended ExpoSAC Meeting notes - 13 Sept 01) lists a number
of possible post-application agricultural activities relative to the
subject crops that might result in pesticide exposure to agricultural
workers.  Transfer Coefficients (TC) expressed as cm²/hr are identified
for each of the post-application, agricultural activities.  The TCs are
derived from data in surrogate exposure studies conducted during the
various activities listed.

The highest (i.e., most conservative) TCs relative to the subject crops
are for hand harvesting with a TC of 3,000 cm²/hr.   For risk
assessment purposes, a TC of 3,000 cm²/hr is used in conjunction with
the maximum rate of application (0.275 lb a.i./A).  

The TCs used in this assessment are from an interim TC SOP developed by
HED’s ExpoSAC using proprietary data from the Agricultural Re-Entry
Task Force (ARTF) database (SOP # 3.1).  It is the intention of HED’s
ExpoSAC that this SOP will be periodically updated to incorporate
additional information about agricultural practices in crops and new
data on transfer coefficients.  Much of this information will originate
from exposure studies currently being conducted by the ARTF, from
further analysis of studies already submitted to the Agency, and from
studies in the published scientific literature.

Lacking compound specific dislodgeable foliar residue (DFR) data, HED
assumes 20 % of the application rate is available as DFR on day zero
after application.  This is adapted from the ExpoSAC SOP No. 003
(05/07/1998 - Revised 08/07/2000).  

The following convention is used to estimate post-application exposure. 

Average Daily Dose (ADD) (mg a.i./kg bw/day) = DFR µg/cm2 * TC cm2/hr *
hr/day * 0.001 mg/µg * 1/70 kg bw 

 and where:

Surrogate DFR = application rate * 20% available as dislodgeable residue
* (1-D)t * 4.54 x 108 µg/lb * 2.47 x 10-8 A/cm2 .  

0.275 lb a.i./A * 0.20 * (1-0)0 * 4.54 x 108 µg/lb *  2.47 x10-8 A/cm²
= 0.617 µg/cm2 , therefore,

0.617 µg/cm2 * 3,000 cm2/hr * 8 hr/day * 0.001 mg/µg ( 70 kg bw =
0.212 mg/kg bw/day.

MOE = NOAEL ( ADD then 500.0 mg/kg bw/day ( 0.212 mg/kg bw/day = 2,358.

A MOE of 100 is adequate to protect agricultural workers from
post-application exposures.  Since the estimated MOEs are > 100, the
proposed uses do not exceed RD’s level of concern.

The interim worker protection standard REI of 12 hours is adequate to
protect agricultural workers from post-application exposures.  

10.0	DATA NEEDS AND LABEL RECOMMENDATIONS

None.

REFERENCES:

Dietary Exposure Memorandum

	AMENDED Diflubenzuron  Chronic Dietary Exposure Assessment for the
Section 18 Use on Lemons.  PP# 07CA04., B. Hanson, DP#: 337826,
04/16/2007.

Drinking Water Memorandum

	IR-4/Section 3-Local and New Uses Registration for Diflubenzuron Use on
Peanuts, Okra, Small grains (Winter, Spring, Durum, Barley, and Oats),
Pummelo, Mustard Greens, Broccoli, Raab, Cabbafe (bok choy), Collards,
Kale, Mizuna, Mustard spinach, Rape, Greens and Turnip greens.; A.
Al-mudallal; DP #: 321156; 08/25/2006.  

Residue Chemistry Data Review Memorandum

		Diflubenzuron.  IR-4’s Request To Register New Food/Feed Uses on
Barley, Oats, Wheat, Brassica Leafy Greens (Crop Subgroup 5B), Turnip
Greens, Eggplant, Okra, Peanut, and Pummelo.  Summary of Analytical
Chemistry and Residue Data.  G. Kramer; DP #s: 321623, 321625, and
321627; 09/14/2006.

Occupational and Residential Exposure Memorandum

	Diflubenzuron - Human, Non-Dietary Exposure/Risk Assessment for the
California Section 18 Quarantine Use Request on Commercial and
Residential Plantings of Citrus, Avocados, Guavas and Lychee.; M. Dow;
DP #: 337825; 03/08/2007.

Risk Assessment Document

	Diflubenzuron on Barley, Oats, Wheat, Brassica Leafy Greens (Crop
Subgroup 5B), Turnip Greens, Eggplant, Okra, Peanut, and Pummelo (PP#s
5E6965, 5E6966, and 5E6967).; G. Kramer, DP #s: 321152, 321155, &
321158; 09/14/2006.  

	

Appendix A:  TOXICOLOGY ASSSESSMENT

A.1	Toxicology Data Requirements

The requirements (40 CFR 158.377) for food use of diflubenzuron are in
Table A.1. Use of the new guideline numbers does not imply that the new
(1998) guideline protocols were used.

 TC \l2 "A.1  Toxicology Data Requirements  

Table A.1  Toxicology Data Requirements for Prosulfuron

Test 

	Technical

	Required	Satisfied

870.1100    Acute Oral Toxicity	

870.1200    Acute Dermal Toxicity	

870.1300    Acute Inhalation Toxicity	

870.2400    Primary Eye Irritation	

870.2500    Primary Dermal Irritation	

870.2600    Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100    Oral Subchronic (rodent)	

870.3150    Oral Subchronic (nonrodent)	

870.3200    21-Day Dermal	

870.3250    90-Day Dermal	

870.3465    90-Day Inhalation		yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

870.3700a  Developmental Toxicity (rodent)	

870.3700b  Developmental Toxicity (nonrodent)	

870.3800    Reproduction		yes

yes

yes	yes

yes

yes

870.4100a  Chronic Toxicity (rodent)	

870.4100b  Chronic Toxicity (nonrodent)	

870.4200a  Oncogenicity (rat)	

870.4200b  Oncogenicity (mouse)	

870.4300    Chronic/Oncogenicity		yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

870.5100    Mutagenicity—Gene Mutation - bacterial	

870.5xxx    Mutagenicity—Structural Chromosomal Aberrations	

870.5xxx    Mutagenicity—Other Genotoxic Effects		yes

yes

yes	yes

yes

yes

870.6100a  Acute Delayed Neurotox. (hen)	

870.6100b  90-Day Neurotoxicity (hen)	

870.6200a  Acute Neurotox. Screening Battery (rat)	

870.6200b  90-Day Neuro. Screening Battery (rat)	

870.6300    Develop. Neuro		no

no

no

no

no	-

-

-

-

-

870.7485    General Metabolism	

870.7600    Dermal Penetration		yes

no	yes

-

Special Studies for Ocular Effects

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)		no

no

no

no	-

-

-

-

A.2	Toxicity Profiles

Table A.2  Acute Toxicity of Diflubenzuron

Guideline

 No.	

Study Type	

MRID #(S).	

Results	

Toxicity Category

81-1	

Acute Oral	

00157103	

LD50 =>5,000 mg/kg	

IV

81-2	

Acute Dermal	

00157104	

LD50 =>2000 mg/kg	

III

81-3	

Acute Inhalation 	

00163311	

LC50 =>2.49 mg/L	

IV

81-4	

Primary Eye  Irritation	

00157105	

mild irritant	

III

81-5

 	

Primary Skin Irritation	

00157106	

no irritation	

IV

81-6	

Dermal Sensitization	

42251101	

negative	

n/a

A.3	Executive Summaries

Non-Guideline   Short-Term Inhalation Exposure (1 - 30 Days) 

Study Selected: Twenty-eight day rat inhalation 

MRID No.: 44950601

Executive Summary:  In a subchronic inhalation toxicity study (MRID
44950601), dimilin technical (96.5% a.i., Batch FUX021000-FUN91A10A) was
administered to groups of 10 male and 10 female Sprague-Dawley albino
rats/concentration.  Exposure was by nose-only inhalation at
concentrations of 0, 12, 34, or 109 mg/m3 (0. 0.012, 0.034, or 0.109
mg/L) for 6 hours/day, 5 days/week, for approximately 4 weeks (22-23
consecutive exposures, excluding weekends, over a 30-31 day calendar
period).

There was no test material-related effect on mortality, body weight or
weight gain, food consumption, clinical signs, ophthalmoscopy,
urinalysis, organ weights, and gross or microscopic pathology.  Slight
but statistically significant decreases were seen in erythrocyte counts,
hemoglobin, and hematocrit in both sexes (93-95% of controls) and in
serum bilirubin in males (increased from 0.1 to 0.2 mg/dL) administered
100 mg/m3.  It is unclear whether these alterations were induced by
treatment, however, they were too small to be biologically significant
and lacked microscopic correlates, and were thus considered
toxicologically unimportant.  Under the conditions of this study,
therefore, a LOAEL was not established and the NOAEL is the highest dose
tested, i.e., 109 mg/m3 (0.109 mg/L).

This subchronic inhalation toxicity study in the rat is
Acceptable/Non-Guideline.  The study satisfies the guideline requirement
for a subchronic inhalation toxicity study in rats as requested by the
HIARC. 

Dose and Endpoint for Risk Assessment: NOAEL = 20.30 mg/kg/d1 (0.109
mg/L; HDT).

Comments about Study/Endpoint: The study is of appropriate for route and
duration of exposure.  The concentration selected for risk assessment
did not elicit any adverse effect following 28 days of inhalation
exposure.  The HIARC, however, selected this dose based on
methemoglobinemia which was consistently observed across species and
studies even though it was not seen in the critical study.

Non-Guideline   Intermediate-Term Inhalation Exposure (1 - 6 months) 

Study Selected: Twenty-eight day rat inhalation 

							

MRID No.: 44950601

Executive Summary:  see Short-Term Inhalation

Dose and Endpoint for Risk Assessment: NOAEL = 20.30 mg/kg/d (0.109
mg/L; HDT).

Comments about Study/Endpoint: The study is of appropriate for route and
duration of exposure.  The concentration selected for risk assessment
did not elicit any adverse effect following 28 days of inhalation
exposure.  The HIARC, however, selected this dose based on
methemoglobinemia which was consistently observed across species and
studies even though it was not seen in the critical study.

A.3.1	Subchronic Toxicity

870.3100		Oral Subchronic Toxicity - Rodent 

Study Selected: 14 day subchronic oral toxicity study in mice.

MRID No.: 00099713

Executive Summary: In a 14-day subchronic oral toxicity study, technical
grade diflubenzuron was administered each day by gavage to 10 Swiss
strain male mice at a dose level of 8, 40, 200, 1000 or 5000 mg/kg/day.
The mice were fasted for 16 hours prior to the first dose of test
material. The test material was administered as a

suspension in 1% tragacanth. Twenty control animals were treated
similarly with a blank suspension. Blood was drawn from all animals at
15 days after the first dose and analyzed for methemoglobin,
sulfhemoglobin and Heinz bodies in the erythrocytes. At day 15, the
animals were sacrificed and those of the control and highest dose groups
were autopsied. Significantly increased (p < 0.05) levels of
methemoglobin were

observed at 1000 and 5000 mg/kg/day. Significantly increased (p < 0.05)
levels of sulfhemoglobinemia were observed at 200, 1000 and 5000
mg/kg/day. The

percentage of erythrocytes containing Heinz bodies was highly increased
at 1000 and 5000 mg/kg/day. No effect on body weights or on organs and
tissues examined at

autopsy was observed.

Dose and Endpoint for Risk Assessment: NOEL = 40 mg/kg/day based on
increased sulfhemoglobin at 200 mg/kg/day.

870.31050	Oral Subchronic Toxicity - Nonrodent 

Study Selected: 13 week oral [subchronic] feeding study in dogs. 

MRID No.: 00038706

Executive Summary: In a subchronic feeding study, technical grade
diflubenzuron (batch # P7227) was administered in the diet to beagle
dogs at dose levels of 0 (control), 10, 20, 40 and 160 ppm (equal to 0,
0.42, 0.84, 1.64 and 6.24 mg/kg/day). Groups of 3 male and 3 female dogs
were used for each treated and control group. Hematology and blood
chemistries were performed at 2, 4, 6 and 12 weeks: methemoglobin,
sulfhemoglobin and urinalyses were performed at 6 and 12 weeks.
Ophthalmoscopic examinations were conducted at 6 and 12 weeks. Gross
necropsies were performed on all dogs. Organ weights were determined and
histopathological examinations were performed at the terminal sacrifice
at 13 weeks. Mortality, clinical

signs, body weights and food consumption were not affected by treatment
with diflubenzuron.  Ophthalmoscopic examinations were negative. 
Methemoglobinemia was observed in the dogs at 160 ppm (after 6 weeks).
No gross necropsy, organ weight or histopathological changes were
reported at any level that could be related to treatment with
diflubenzuron. 

Endpoint and dose for use in risk assessment:  Calculated NOEL 2.0
mg/kg/day based on increased methemoglobinemia at 6.24 mg/kg/day. 

Comments about studies and/or endpoint: In this 13-week feeding study in
dogs, a steady state for methemoglobinemia was observed to occur after 6
weeks.

In both the rat study and the mouse study, a NOEL of about 2 mg/kg/day
was calculated by regression analysis. Considering all the available
data (including

data from chronic feeding studies in rats, dogs and mice in which the
NOEL for methemoglobinemia/sulfhemoglobinemia to be used to calculate
the RfD also

was 2 mg/kg/day), it was concluded that the NOEL for intermediate term
risk assessments should be 2 mg/kg/day (rather than the slightly lower
NOEL of 1.64

mg/kg/day determined in the dog study above).  

870.3200   	21-Day Dermal Toxicity – Rat

Study Selected: 21-Day dermal toxicity study in rat

				 				

MRID No.: 43954101

Executive Summary: In a subchronic, 21-day dermal toxicity study,
Dimilin (diflubenzuron tech. 96.7% a.i.) was administered to 10/sex/dose
in 0.25% gum tragacanth in distilled, deionized water to the dorsal skin
on the backs of the test animals at 0, 20, 500, or 1,000 mg/kg/day for 6
hour period each day.

Dermal treatment for 21 days did not affect mortality, clinical signs,
body weight changes, food consumption and/or organ weight changes.  At
1,000 mg/kg/day, slight dermal irritation and traces of acanthosis and
hyperkeratosis were noted in males and females.  Liver and kidney
histopathology was remarkable.  Males exhibited slight elevations in the
white cell count in the mid and high dose groups.  Males also had small
reductions in hemoglobin and hematocrit at 1000 mg/kg dose group.  In
females at the top two doses there were statistically significant (P <
0.05) decreases in RBC count, hemoglobin levels and hematocrit values. 
Hematological changes in males and females were within in the historical
ranges for this species and age of rat, and therefore, considered not
biologically significant.   Methemoglobin levels increased significantly
(P < 0.05 & 0.01) in males and females at 1000 mg/kg dose.  There was
increased incidence of anisocytosis, hypochromasia and polychromasia in
males and females at the top dose.  On August 14, 2001, the HED HIARC
re-evaluated the study and concluded that the increased
methemoglobinemia in males and females at 1000 mg/kg should be
considered as toxicity-induced change.  Therefore, the NOAEL is 500
mg/kg and LOAEL is 1000 mg/kg based on methemoglobinemia.

Dose and Endpoint for Risk Assessment:  NOAEL = 500 mg/kg/day based on
increased methemoglobinemia at 1000 mg/kg/day. 

Comments about Study/Endpoint: This dermal toxicity study in rats is
route- specific, is of appropriate duration and measures the effects of
concern, i.e., methemoglobin and/or sulfhemoglobin.  Previously, the
end-points for short-term exposure were based on a 14- day mouse feeding
study. The HIARC re-evaluated the 21-day dermal study in rat and revised
the NOAEL from 20 mg/kg/day to 500 mg/kg/day, since the
methemoglobinemia seen at 500 mg/kg/day was within normal physiological
parameters, but occurred at adverse levels at 1000 mg/kg/day.

870.3250 	Intermediate-Term Dermal Toxicity – Dog

Study Selected:  Chronic Toxicity - Dog.				 

				

MRID No.:  00146174

Executive Summary:	See 870.4100b Chronic Toxicity – Nonrodent, below. 

Dose and Endpoint for Risk Assessment: NOAEL = 2 mg/kg/day based on
methemoglobinemia and sulfhemoglobinemia at 10 mg/kg/day (LOAEL). 
Corrected for 0.5% dermal absorption.

Comments about Study/Endpoint: Long term dermal studies are not
available for diflubenzuron therefore a chronic feeding study was
chosen. However, since an oral NOAEL was selected for a dermal endpoint
a dermal absorption factor of 0.5% should be used for this risk
assessment when converting dermal exposure to oral equivalents. 
Therefore the dermal equivalent dose producing a NOAEL by the oral route
is 400.0 mg/kg/day [i.e. 2.0 mg/kg/day ÷ 0.005 = 400.0 mg/kg/day.]

870.3465		90-Day Inhalation – Rat

Study Selected: Chronic Toxicity - Dog 

MRID No.: 00146174

Executive Summary:  See 870.4100b Chronic Toxicity – Nonrodent, below 

Dose and Endpoint for Risk Assessment:  NOAEL = 2.0 mg/kg/d based on
methemoglobinemia and sulfhemoglobinemia at 10 mg/kg/day (LOAEL).

Comments about Study/Endpoint/Uncertainty Factor:  An oral study was
selected since no appropriate inhalation study is available in the
database.  This study is of appropriate duration of exposure.  Assume
that inhalation absorption is equivalent to oral absorption.

A.3.2	Prenatal Developmental Toxicity

870.3700a 	Prenatal Developmental Toxicity Study – Rodent

Study Selected:  Developmental Toxicity – Rat

MRID No.: 41703504

Executive Summary:  In a developmental toxicity in rats, Technical grade
diflubenzuron [97.6% pure] was administered in 1.0% gum tragacanth
solution by oral gavage to 2 groups of 24 Sprague Dawley rats on days
6-15 of gestation at dose levels of either 0 or 1000 mg/kg/day [the
limit dose]. No maternal or developmental toxicity was observed. For
maternal and developmental toxicity, the NOAEL was 1000 mg/kg/day
(Limit-Dose); a LOAEL was not achieved.

870.3700b 	Prenatal Developmental Toxicity Study – Nonrodent 

Study Selected:  Developmental Toxicity – Rabbit

MRID No.: 41703505

Executive Summary:  In a developmental toxicity study with rabbits,
Technical grade diflubenzuron [97.6% pure] was administered in 1.0% gum
tragacanth solution by oral gavage to 2 groups of  New Zealand White
rabbits on days 7-19 of gestation at dose levels of either 0 or 1000
mg/kg/day [the limit dose]. No maternal or developmental toxicity was
observed.  For maternal and developmental toxicity, the NOAEL was 1000
mg/kg/day (Limit-Dose); a LOAEL was not achieved.

A.3.3	Reproductive Toxicity

870.3800 	Reproduction and Fertility Effects – Rat

Study Selected:   2-Generation Reproduction Study - Rats

MRID No.: 42700002

Executive Summary:  In a 2-generation reproduction study in rats
(Sprague-Dawley) complete in 1992, 30 rats/sex/dose received either 0,
10, 200, 2000, or 4000 ppm (0, 0.67, 13.3, 136, and 278 mg/kg/day for P0
males and 0, 0.76, 15.3, 152, and 3l1 mg/kg/day for P0 females during
the premating growth periods, respectively) of CGA-152005 (99.1% a.i.)
mixed in the feed. Note that organ weights were not obtained in this
study.

The study is classified as Core Minimum Data and satisfies the guideline

requirement for a reproduction study.

A.3.4	Chronic Toxicity

870.4100a

Study Selected:  Carcinogenicity/Oncogenicity Study - Rat

MRID No. 00145467

Executive Summary:  See 870.4300 Carcinogenicity - Rat, below.

The combined chronic oral toxicity/oncogenicity study in the rat is
classified Acceptable/guideline and satisfies the guideline requirements
for a chronic toxicity and oncogenicity study in rats.

Adequacy of Dose Levels Tested:  Dosing was considered adequate since
the highest dose level tested, 500 mg/kg/day, approached the limit dose
of 1000 mg/kg/day for cacinogenicity studies and significant toxicity
(particulary methemoglobinemia, sulfhemoglobinemia, erythrocyte
destruction, compensatory regeneration of erythrocytes and hemolytic
anemia) was observed at this dose level.

870.4100b 	Chronic Toxicity – Nonrodent

Study Selected:   Chronic Toxicity - Dog

MRID No.: 00146174

Executive Summary:  In a 52-week chronic oral study, technical grade
diflubenzuron was administered in gelatin capsules to beagle dogs once
each day (7 days/week) at dose levels of 0 (control), 2, 10, 50 or 250
mg/kg/day.  Groups of 6 male and 6 female dogs were used for each
treated group and 12 male and 12 female dogs were used for the control
group.  Mortality, clinical signs, food consumption and water
consumption were not affected by treatment with diflubenzuron.  Except
for a slight decrease in mean body weight gain observed in female dogs
at 250 mg/kg/day, body weights were also not affected.  Ophthalmoscopic
examinations, clinical chemistries and urinalyses were negative. 
Statistically significant increases in methemoglobin and sulfhemoglobin
were observed in male and female dogs at dose levels of ³10 mg/kg/day. 
Heinz bodies were also observed in the erythrocytes of male dogs at 250
mg/kg/day and in those of female dogs at ³50 mg/kg/day.  At dose levels
of 50 mg/kg/day and higher, signs of hemolytic anemia, destruction of
erythrocytes and of compensatory regeneration of erythrocytes were
observed.  Increased platelet counts were also noted in females at ³50
mg/kg/day.  Absolute spleen and liver weights, but not relative organ
body weight ratios, were increased in male dogs at 50 and 250 mg/kg/day.
 Organ weights were not increased in female dogs.  The NOAEL in this
study is 2 mg/kg/day and the LOAEL is 10 mg/kg/day, based on
methemoglobinemia and sulfhemoglobinemia.

Dose and Endpoint for Establishing RFD: 	NOAEL = 2.0 mg/kg/day based on
methemoglobinemia and sulfhemoglobinemia at 10 mg/kg/day (LOAEL).

Uncertainty Factor(s):

Chronic RfD =      2.0  mg/kg/day (NOAEL) = 0.02  mg/kg/day			

			100 (UF)

Comments about Study/Endpoint/Uncertainty Factor:  The HIARC concurred
with the dose, end point, and the uncertainty factor selected by the RFD
Committee in 1986.

A.3.5	Carcinogenicity

870.4200a 	Carcinogenicity – Rat

Study Selected:   Oncogenicity Study - Rat

MRID No.: NTP Report No. 351, July 1989

Executive Summary:  In a carcinogenicity study, p-choloroaniline (> 99%
purity) was dissolved in equimolar equivalents of hydrochloric acid and
administered by gavage (5 days/week) to F344/N rats at dose levels of 0,
2, 6, or 18 mg/kg/day for 24-months.  Groups of 50 male and 50 female
rats were used for each treated groups and the control group. 
Hematology examinations and mehtemoglobin measurements were conducted on
15 rats/sex/group at 6, 12, 18, and 24 months.  Increased survival was
observed in male rats at 2 and 6 mg/kg/day and in female rats at 2, 6,
and 18 mg/kg/day relative to control rats.  The authors of the study
attributed the increased survival in these treatment groups to a
decreased incidence of mononuclear cell leukemia in the same groups. 
Mean body weights for treated male and female groups generally remained
within 5% of the control male and female weights throughout the study. 
Results of hematology examinations and methemoglobin measurements showed
mild hemolytic anemia and dose-related increases in methemoglobin at
dose levels of 6 and 18 mg/kg/day.  Male rats at 6 and 18 mg/kg/day and
female rats at 18 mg/kg/day had blue extremities indicative of cyanosis.
 Histopathological examinations indicated nonneoplastic
treatment-related effects in spleen, liver, bone marrow and adrenal
gland.  Treatment-related increased incidence of uncommon sarcomas of
the spleen was observed in male rats in this study.  These sarcomas
included fibrosarcomas, hemangiosarcomas, and osteosarcomas, many of
which metastasized to other sites.  The combined incidence of these
sarcomas in male rats was 0/49, 3/50, and 38/50 at dose levels of 0, 2,
6 and 18 mg/kg/day, respectively.  In addition, in female rats, 1
fibrosarcoma was observed at a 6 mg/kg/day and 1 osteosarcoma at 18
mg/kg/day.  No additional uncommon sarcomas of the spleen were observed
in female rats in this study.  A marginally increased incidence of
pheochromocytomas was also observed in the adrenal gland of male and
female rats at 18 mg/kg/day.  For male rats, the incidence was 13/49,
14/48, 15/48 and 26/49 and for female rats was 2/50, 3/50, 1/50, and
6/50 at dose levels of 0, 2, 6 and 18 mg/kg/day, respectively. 
Decreased incidences of mononuclear cell leukemias and of malignant
lymphomas were also noted in the treated male and female rats in this
study.

Systemic toxicity NOAEL was 2 mg/kg/day based on mild hemolytic anemia,
dose- related increased in methemoglobin levels in males and females,
cyanosis in females observed at 6 mg/kg/day (LOAEL).

This oncogenicity study in the rat is classified
Acceptable/non-guideline and does not satisfy the guideline requirements
for a oncogenicity study in rats.

Discussion of Tumor Data:  Treatment-related increased incidence of
uncommon sarcomas of the spleen was observed in male rats in this study.
 These sarcomas included fibrosarcomas, hemangiosarcomas, and
osteosarcomas, many of which metastasized to other sites.  The combined
incidence of these sarcomas in male rats was 0/49, 3/50, and 38/50 at
dose levels of 0, 2, 6 and 18 mg/kg/day, respectively.  In addition, in
female rats, 1 fibrosarcoma was observed at a 6 mg/kg/day and 1
osteosarcoma at 18 mg/kg/day.  No additional uncommon sarcomas of the
spleen were observed in female rats in this study.  A marginally
increased incidence of pheochromocytomas was also observed in the
adrenal gland of male and female rats at 18 mg/kg/day.  For male rats,
the incidence was 13/49, 14/48, 15/48 and 26/49 and for female rats was
2/50, 3/50, 1/50, and 6/50 at dose levels of 0, 2, 6 and 18 mg/kg/day,
respectively.  Decreased incidences of mononuclear cell leukemias and of
malignant lymphomas were also noted in the treated male and female rats
in this study. There was no increased incidence neoplastic lesions in
either male or female mice.

Adequacy of Dose Levels Tested:  Dosing was considered adequate to test
the carcinogenic potential of p-chloroaniline.  Systemic toxicity
(LOAEL) was observed in males and females at 6 mg/kg/day as evidenced by
mild hemolytic anemia, dose-related increased in methemoglobin levels,
and cyanosis in females.  The NOAEL was 2 mg/kg/day.

870.4200b 	Carcinogenicity – Mouse

1)  Study Selected:  Oncogenicity Study - Mouse

MRID No.  00142490

Executive Summary: In a 91-week carcinogenicity study, technical grade
diflubenzuron was administered in the diet to HC/CFLP strain mice at
dose levels of 0, 16, 80, 400, 2000, or 10000 ppm (equivalent to 0, 2.4,
12, 60, 300, or 1500 mg/kg/day).  Groups of 52 male and 52 female mice
were used for each treated group and 104 male and 104 female mice were
used for the control group.  Mortality, body weights and food
consumption were not affected by treatment with diflubenzuron. 
Increases in methemoglobin and sulfhemoglobin were consistently observed
in male and female mice throughout the study at dose levels of 12
mg/kg/day and higher.  A blue/gray discoloration of the skin and
extremities and dark eyes accompanied the increased methemoglobin and
sulfhemoglobin.  At higher dose levels (particularly > 300 mg/kg/day),
signs of hemolytic anemia, erythrocyte destruction and compensatory
regeneration were observed as were histopathological effects in the
liver.  Treatment with diflubenzuron was not associated with an
increased incidence of neoplastic lesions in either male or female mice.
 Dosing was considered adequate since the highest dose tested, 1500
mg/kg/day, exceeded the limit dose of 1000 mg/kg/day for carcinogenicity
studies.

The systemic toxicity NOAEL is determined to be 2.4 mg/kg/day.  The
systemic toxicity LOAEL is 12 mg/kg/day based on increased methemoglobin
and sulfhemoglobin levels consistently observed in male and female mice
throughout the study.

The study is classified Acceptable/guideline and it satisfies the
guideline requirements for a carcinogenicity study in mice.

Discussion of Tumor Data:  There was no increased incidence of
neoplastic lesions in either male or female mice.

Adequacy of Dose Levels Tested:  Dosing was considered adequate since
the highest dose level tested, 1500 mg/kg/day, exceeded the limit dose
of 1000 mg/kg/day.

2) Study Selected: 	Oncogenicity Study - Mouse

MRID No.: NTP Study, Report No. 351, July 1989.

Executive Summary:  In a carcinogenicity study, p-choloroaniline (> 99%
purity) was dissolved in equimolar equivalents of hydrochloric acid and
administered by gavage (5 days/week) to B6C3F1 mice at dose levels of 0,
3, 10, or 30 mg/kg/day for 24-months.  Groups of 50 male and 50 female
mice were used for each treated group and the control group.  Increased
mortality was observed in male mice at 10 mg/kg/day after 99 weeks, but
not at 30 mg/kg/day.  Treatment did not affect mortality in female mice.
 Mean body weights for treated male and female groups were not affected
by treatment with the test material.  At 24 months, hemosiderin was
observed in the kupffer cells of the livers of male and female mice and
in the renal tubules of female mice at 30 mg/kg/day.  Proliferation of
hematopoietic cells was noted in the livers of female mice at all
treatment levels.  Increased incidence of combined hepatocellular
adenomas/carcinomas were observed in the male mice in this study. 
Incidences were 11/50, 21/49, 20/50 and 21/50 at dose levels of 0, 3,
10, and 30 mg/kg/day, respectively.  The increase in combined tumors
were primarily due to a dose-related increase in hepatocellular
carcinomas as follows: 3/50, 7/49, 11/50, and 17/50 at 0, 3, 10, and 30
mg/kg/day, respectively.  Many of these carcinomas metastasized to the
lungs (1/50, 1/49, 2/50, and 9/50 at 0, 3, 10, and 30 mg/kg/day,
respectively).  Increased incidence of hemangiosarcomas in the spleen
and/or liver were also observed in the male mice in this study at 30
mg/kg/day.  Incidences were 4/50, 4/49, 1/50, and 10/50 at dose levels
of 0, 3, 10, and 30 mg/kg/day, respectively.  Incidences of malignant
lymphomas were decreased in the treated male and female mice.  No
evidence of carcinogenicity was observed in the female mice in this
study.

Systemic toxicity NOAEL was 10 mg/kg/day based on hemosiderin
accumulation in kupffer cells of the liver in male and female mice at 30
mg/kg/day (LOAEL).

This oncogenicity study in mice is classified Acceptable/non-guideline
and does not satisfy the guideline requirements for a oncogenicity study
in mice.

Discussion of Tumor Data:  Increased incidence of combined
hepatocellular adenomas/carcinomas were observed in the male mice in
this study.  Incidences were 11/50, 21/49, 20/50 and 21/50 at dose
levels of 0, 3, 10, and 30 mg/kg/day, respectively.  The increase in
combined tumors were primarily due to a dose-related increase in
hepatocellular carcinomas as follows: 3/50, 7/49, 11/50, and 17/50 at 0,
3, 10, and 30 mg/kg/day, respectively.  Many of these carcinomas
metastasized to the lungs (1/50, 1/49, 2/50, and 9/50 at 0, 3, 10, and
30 mg/kg/day, respectively).  Increased incidence of hemangiosarcomas in
the spleen and/or liver were also observed in the male mice in this
study at 30 mg/kg/day.  Incidences were 4/50, 4/49, 1/50, and 10/50 at
dose levels of 0, 3, 10, and 30 mg/kg/day, respectively.

Adequacy of Dose Levels Tested:  Dosing was considered adequate to test
the carcinogenic potential of p-chloroaniline.  Systemic toxicity
(LOAEL) was observed in male and female mice at 30 mg/kg/day as
evidenced by hemosiderin accumulation in kupffer cells of the liver. 
The NOAEL was 10 mg/kg/day.

870.4300		Chronic/Oncogenicity

Study Selected:  Carcinogenicity Study - Rat

MRID No. 00145467

Executive Summary:  In a 104-week carcinogenicity study, technical grade
diflubenzuron was administered in the diet to Sprague-Dawley strain rats
at dose levels of 0, 156, 625, 2500 or 10,000 ppm (equivalent to 0, 7.8,
31, 125 or 500 mg/kg/day).  Groups of 50 male and 50 female rats were
used for each treated group and 100 male and 100 female rats were used
for the control group.  Mortality, clinical signs, body weights and food
consumption were not affected by treatment with diflubenzuron. 
Increases in methemoglobin and sulfhemoglobin were observed at all
treatment levels.  Histopathological signs of erythrocyte destruction
and compensatory regeneration were observed at levels of >7.8 mg/kg/day.
 Signs of hemolytic anemia, increased resticulocytes and increased
spleen and liver weights were noted at >125 mg/kg/day.  Treatment with
diflubenzuron was not associated with increased incidence of neoplastic
lesions in either males or females.  Dosing was considered adequate
since the highest dose level tested, 500 mg/kg/day, approached the limit
dose of 1000 mg/kg/day for cacinogenicity studies and significant
toxicity (particulary methemoglobinemia, sulfhemoglobinemia, erythrocyte
destruction, compensatory regeneration of erythrocytes and hemolytic
anemia) was observed at this dose level.  Systemic Toxicity NOAEL was
not establised.  The LOAEL is the lowest dose tested 7.8 mg/kg/day based
on signs of erythrocyte destruction and compensatory regeneration.   	

This combined chronic oral toxicity/oncogenicity study in the rat is
classified Acceptable/guideline and satisfies the guideline requirements
for a chronic toxicity and oncogenicity study in rats.

Discussion of Tumor Data: There was no increased incidence of neoplastic
lesions in either male or female rats.

Adequacy of Dose Levels Tested:  Dosing was considered adequate since
the highest dose level tested, 500 mg/kg/day, approached the limit dose
of 1000 mg/kg/day for cacinogenicity studies and significant toxicity
(particulary methemoglobinemia, sulfhemoglobinemia, erythrocyte
destruction, compensatory regeneration of erythrocytes and hemolytic
anemia) was observed at this dose level.

A.3.6	Mutagenicity

870.5100 	Mutagenicty – Bacterial

MRID No.:  41703503

Executive Summary: In a Salmonella/mammalian microsome plate
incorporation assay, strains TA98, TA100, TA1535, TA1537 and TA1538 were
exposed to technical grade diflubenzuron with and without S9 metabolic
activation at concentrations of 0, 8, 40, 200, or 1000 ·g/plate.  The
high dose was selected on the basis of slight compound precipitation at
1000 ·g/plaste.  Preparations for metabolic S9 activation were made
from Aroclor induced rat liver.  The solvent used was DMSO. 
Diflubenzuron was not cytotoxic with or without S9 activation in any of
the Salmonella strains in this assay.  There was no evidence of induced
mutant colonies over background levels at any of the evaluated
concentrations.

870.5xxx 	Mutagenicty – Structural Chromosomal Aberrations

MRID No.:  41703502

Executive Summary:  In an in vitro chromosome damage assay, cultures of
Chinese hamster ovary (CHO) cells were exposed to technical grade
diflubenzuron with and without S9 metabolic activation.  The test
material was tested at concentrations up to cytotoxic/precipitating
levels of 200 - 250 ·g/ml.  Preparations for S9 metabolic activation
were made from Aroclor 1254 induced rat liver.  The solvent used was
DMSO.  The test material did not induce an increase in structural
chromosome aberrations over background levels at any of the evaluated
concentrations.

870.5xxx 	Mutagenicty – Other

MRID No.:  41703501

Executive Summary:  In an unscheduled DNA synthesis (UDS) assay,
cultures of primary rat hepatocytes were exposed to technical grade
diflubenzuron at concentrations ranging from 0.1 to 333 ·g/ml.  At the
high dose of 333 ·g/ml, cytotoxicity was oserved (36% cell survival in
an initial assay and 8% cell survival in a confirmatory assay).  The
solvent used was DMSO.  Positive controls were adequate.  The test
material did not cause an appreciable increase in net nuclear grain
counts compared to the solvent control at any of the evaluated
concentrations.  Diflubenzuron did not induce a gentoxic effect in this
assay system.

A.3.7	Neurotoxicity

Acute and subchronic neurotoxicity studies are not required. There is no
evidence in the available studies that dimilin targets the nervous
system [RFD Committee Report of 03/16/1995].

A.3.8	Metabolism

870.7485		Metabolism – Rat

Study Selected:  Metabolism Study - Rat

MRID No.:  44875501, 44875502

Recently submitted rat metabolism data indicate that diflubenzuron does
not metabolize to PCA or CPU nor is CPU converted to PCA. The HEDMARC
met several times (2/20/01 and 5/8/01), concurred with the findings and
concluded that a 2% in vivo conversion factor for diflubenzuron to PCA
or CPU should be dropped (MARC memo dated May 31, 2001). In conclusion,
the MARC recommended that non-carcinogenic risk assessment should
include parent, CPU and PCA; and cancer risk for CPU and PCA should be
assessed individually.

870.7600		Dermal Absorption – Rat

Dermal Absorption Factor:   0.5 percent. 

Twenty four male Sprague-Dawley rats were divided into two groups of 12
males each and given either 0.005 or 0.05 mg/cm.sq. of C-14
diflubenzuron technical in gum tragacanth [0.25%]. Four 4 animals per
dose group were sacrificed after either 1, 4, or 10 hours of exposure.
The control group consisted of 3 males with 1 animal sacrificed at the
end of 1, 4, or 10 hours of exposure. Systemic absorption was less than
0.5% at each time interval regardless of the dose. Approximately 4.7 -
6.2% diflubenzuron was bound to the skin at the application site.

A.4	References (in MRID order)

00038706	Chesterman, H.; Heywood, R.; Barker, M.H.; et al. (1974) Du
112307: Toxicity in Repeated Dietary Administration to Beagle Dogs (Re-
peated Administration for 13 	Weeks): PDR169/74157. (Unpub- lished study
received Feb 10, 1976 under 6G1744; prepared by Huntingdon Research
Centre, submitted by Thompson-Hayward Chem- ical Co., Kansas City,
Kans.; CDL:094963-G)

00099713 	Keet, M.; Boschman, A.; Saxena, S.; et al. (1977) The Effect
of Du 112307 (Technical) in Male Mice after Daily Oral Administration,
for a Period of 14 Days, on Bodyweight, Methaemoglobin, Sulph-
haemoglobin and Heinz Body Formation and Gross Pathology: Re- port No.
56645/33/77. (Unpublished study received Feb 6, 1978 under 148-1259;
prepared by Philips-Duphar, B.V., the Nether- lands, submitted by
Thompson-Hayward Chemical Co., Kansas City, KS; CDL:096787-C)

00142490	Colley, J.; Heywood, R.; Street, A. (1984) The Effect of Diflu-
benzuron Given by Oral Administration with the Feed on Toxicity and
Tumour Development in Male and Female HC/CFLP Mice: Final Report: PDR
360/831096/B. Unpublished study prepared by Hunt- ingdon Research
Centre. 2716 p.

00145467	Burdock, G. (1984) Oncogenicity Study in Rats: Final Report:
Pro- ject No. 553-122. Unpublished study prepared by Hazleton Lab-
oratories America, Inc. 4230 p.

00146174	Greenough, R.; Goburdhun, R.; Hudson, P. et. al. (1985)
Diflubenzu- ron 52 Week Oral Toxicity Study in Dogs: Project No. 630146.
Unpublished study prepared by Inveresk Research International. 353 p.

00157103	Koopman, T. (1985) Acute Oral Toxicity Study with Diflubenzuron
VC-90 in Rats: Int. Doc. No. 56645/30/84. Unpublished study prepared by
Duphar B.V. 11 p.

00157104	Koopman, T. (1985) Acute Dermal Toxicity Study with
Diflubenzuron VC-90 in Rats: Int. Doc. No. 56645/31/84. Unpublished
study prepared by Duphar B.V. 12 p.

00163311	Greenough, R.; McDonald, P. (1986) Acute Inhalation Toxicity
Study in Rats (Limit Test): Diflubenzuron VC 90: IRI Project No. 635296:
Report No. 3545. Unpublished study prepared by Inveresk Research
International. 23 p.

00157105	Koopman, T. (1985) Primary Irritation of Diflubenzuron VC-90 to
the Rabbit Eye: Int. Doc. No. 56645/29/84: Report No. H.133.401.
Unpublished study prepared by Duphar B.V. 11 p.

00157106	Koopman, T. (1985) Primary Irritation of Diflubenzuron VC-90 to
the Rabbit Skin: Int. Doc. No. 56645/44/84. Unpublished study prepared
by Duphar B.V. 9 p.

41703501	Enninga, I. (1990) Evaluation of DNA Repair Inducing Ability of
Diflubenzuron in a Primary Culture of Rat Hepatocytes (with Independent
Repeat): Lab Project Number: 002418: C.303.40.026: 56645/114/90.
Unpublished study prepared by RCC Notox B.V. 34 p.

41703502	Taalman, R.; Hoorn, A. (1986) Mutagenicity Evaluation of
Difluben- zuron Technical in an in vitro Cytogenetic Assay Measuring
Chromosome Aberration Frequencies in Chinese Hamster Ovary (CHO) Cells:
Final Report: Lab Project Number: 56645/36/1986. Unpub- lished study
prepared by Hazleton Biotechnologies Corp. 25 p.

41703503	Koorn, J. (1990) Study to Examine the Possible Mutagenic
Activity of Diflubenzuron in the Ames Salmonella/Microsome Assay: Lab
Project Number: DT 90/27: 56645/74/90. Unpublished study pre- pared by
Duphar B.V. 23 p.

41703504	Kavanagh, P. (1988) Diflubenzuron: Oral (Gavage) Rat Teratology
Limit Study: Lab Project Number: PHD/11/87: 56645/68/87. Unpub- lished
study prepared by Toxicol Laboratories Ltd. 91 p.

41703505	Kavanagh, P. (1988) Diflubenzuron: Oral (Gavage) Rabbit
Teratology Limit Study: Lab Project Number: PHD/12/87: 56645/79/87.
Unpub- lished study prepared by Toxicol Laboratories Ltd. 78 p.

42251101	Prinsen, M. (1992) Sensitization Study with Diflubenzuron
Technical in Guinea Pigs: Lab Project Number: B 91-0063/04. Unpublished
study prepared by TNO Tox. and Nutrition Institute. 24 p.

42685238	Minor, J. (1991) A Rangefinding Teratology Probe in Rabbits
with CGA-152005 Technical: Final Report: Lab Project Number: F-00076.
Unpublished study prepared by Ciba-Geigy Corp. 119 p.

42685239	Minor, J. (1992) Teratology Study in Rabbits: CGA-152005
Technical: Lab Project Number: F-00077. Unpublished study prepared by
Ciba-Geigy Corp. 192 p.

42700001	Meyer, L. (1991) A Rangefinding Teratology Probe in CD Rats
with CGA-152005 Technical: Volume 1: Final Report: Lab Project Number:
F-00074. Unpublished study prepared by Ciba-Geigy Corp. 123 p.

42700002	Greci, L.; Turnier, J. (1992) A Two-Generation Reproduction
Study in Rats with CGA-152005 Technical: Interim Report: Lab Project
Number: F-00082. Unpublished study prepared by Ciba-Geigy Corp. 430 p.

43159317	Gilles, P. (1994) Addendum 1 to Final Report: A Teratology
Study in CD Rats with CGA-152005 Technical: Lab Project Number: F-00075.
Unpublished study prepared by Environmental Health Center. 44 p.

43159318	Gilles, P. (1994) Addendum 2 to Final Report: A Teratology
Study in Rabbits with CGA-152005 Technical: Lab Project Number: F-00077.
Unpublished study prepared by Environmental Health Center. 50 p.

43159326	Doweyko, A. (1993) Metabolism of (phenyl-(carbon 14))
CGA-152005 in the Rat: Lab Project Number: F-00112. Unpublished study
prepared by Environmental Health Center. 123 p.

43578301	Brooker, A. (1995) Diflubenzuron Technical: The Effect on
Reproductive Function of Two Generations in the Rat: Lab Project Number:
PDR 569: 56345/83/94: PDR 569/932539. Unpublished study prepared by
Huntingdon Research Centre Ltd. 416 p.

43954101	Goldenthal, E. (1996) 21-Day Dermal Toxicity Study in Rats:
Dimilin Technical (Diflubenzuron): Lab Project Number: 399-186.
Unpublished study prepared by MPI Research. 164 p.

44871304	Story, D. (1999) Comparison of Methemoglobin Formation and
Splenic Tumor Incidence in Rats Fed para-chloroaniline or Diflubenzuron.
Unpublished study prepared by Uniroyal Chemical Company. 5 p.

44875501	Gay, M.; Wang, R.; Long, S. (1999) Metabolism of
(U-(carbon-14)-Phenyl)-4-Chlorophenylurea by Male Fisher (sic) Rats: Lab
Project Number: 98203P. Unpublished study prepared by Uniroyal Chemical
Co., Inc. 133 p. {OPPTS 870.7485}

摧北ñ

摧北ñ

摧北ñ



 

 

 

=

>

?

C

D

b

d

n

q

{

€

„

…

Ž

>

?

o

„

…

†

‡

ˆ

‰

Š

‹

Œ

Ž

j¡

hÚ

hÚ

hÚ

h—

옍)

hÚ

h/

hÚ

h—

옍)

hÚ

hÚ

hÚ

h—

옍)

@

将

将

将

将

将

将

将

将

将

¶

hž

hØ

h¢-

옍)

hŸ

hŸ

h

옍)

&

&

š

&

š

š

š

š

š

š

š

š

耀騆

	@

€

옍)

¶

·

1

愀Ĥ摧北ñ܀Q

R

b

c

h

i

q

…

š

¶

Í

à

ù

ú

ý

愀Ĥ摧北ñ਀‹

‘

™

®

Â

Þ

ß

à

ó

h

h/

h/

옍)

옍)

 hH	

h/

h/

h/

옍)

옍)

옍)

@

@

$

@

$

@

@

$

@

$

@

$

@

$

@

@

$

@

h/

$

@

@

$

@

$

@

$

@

$

@

$

@

$

@

옍)

h/

옍)

	㜀$␸䠀$摧㇐º

@

@

hD

hD

@

h

h

h

h

h

h

h

h

h

h

h

h

h

@

h

h

h

h

h/

h/

@

@

	Gay, M.; Wang, R. (1999) Metabolism of (U-(carbon-14)-Anilino)-
Diflubenzuron by Male Fisher (sic) Rats: Lab Project Number: 98246P.
Unpublished study prepared by Uniroyal Chemical Co., Inc. 112 p. {OPPTS
870.7485}

44950601	Newton, P. (1999) A 4-Week Inhalation Toxicity Study of Dimilin
Technical in Rats: Lab Project Number: 399-205. Unpublished study
prepared by MPI Research, Inc. 	357 p.

Page   PAGE  2  of 48

Page   PAGE  1  of 48