Document ID: EPA-HQ-OPP-2006-0874-0007
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-11-01T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF	

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: July 10, 2006 

MEMORANDUM

SUBJECT:	Chlorflurenol Methyl Ester.  HED Chapter of the Reregistration
Eligibility Decision Document (RED).  

PC Code:			098801

Decision #: 			362457

DP Barcode:			D323832.

			Risk Assessment Type: 		Single Chemical Aggregate

FROM:	David G Anderson, Risk Assessor and Toxicologist

		Shanna Recore, Occupational/Residential Risk Assessor

		Yvonne Barnes, Product Chemist

		Reregistration Branch II

		Health Effects Division (7509P)

THROUGH:	Alan Nielsen, Branch Senior Scientist

		William Hazel, Chief

		Reregistration Branch II 

		Health Effects Division (7509P)

TO:		Tawanda Spears, Chemical Review Manager

		Reregistration Branch III

		Special Review and Reregistration Division

		

	Attached is the HED risk assessment for chlorflurenol methyl ester.  



Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc139705740"  1.0 EXECUTIVE
SUMMARY	  PAGEREF _Toc139705740 \h  5  

  HYPERLINK \l "_Toc139705741"  2.0	Ingredient Profile	  PAGEREF
_Toc139705741 \h  8  

  HYPERLINK \l "_Toc139705742"  2.1	Summary of Registered/Proposed Uses	
 PAGEREF _Toc139705742 \h  8  

  HYPERLINK \l "_Toc139705743"  2.2	Registered Use Categories and Use
Sites	  PAGEREF _Toc139705743 \h  8  

  HYPERLINK \l "_Toc139705744"  2.3	Application Methods	  PAGEREF
_Toc139705744 \h  11  

  HYPERLINK \l "_Toc139705745"  2.4	Structure and Nomenclature	  PAGEREF
_Toc139705745 \h  11  

  HYPERLINK \l "_Toc139705746"  2.5	Physical and Chemical Properties	 
PAGEREF _Toc139705746 \h  12  

  HYPERLINK \l "_Toc139705747"  3.0	Hazard/Dose-Response
Characterization/Assessment	  PAGEREF _Toc139705747 \h  12  

  HYPERLINK \l "_Toc139705748"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc139705748 \h  12  

  HYPERLINK \l "_Toc139705749"  3.1.1	Database Summary:	  PAGEREF
_Toc139705749 \h  12  

  HYPERLINK \l "_Toc139705750"  3.1.2	Studies available and considered
(animal, human, general literature)				  PAGEREF _Toc139705750 \h  13  

  HYPERLINK \l "_Toc139705751"  3.1.3	Mode of action, metabolism,
toxicokinetic data	  PAGEREF _Toc139705751 \h  14  

  HYPERLINK \l "_Toc139705752"  3.1.4	Sufficiency of studies/data	 
PAGEREF _Toc139705752 \h  14  

  HYPERLINK \l "_Toc139705753"  3.1.5	Toxicological Effects	  PAGEREF
_Toc139705753 \h  14  

  HYPERLINK \l "_Toc139705754"  3.1.6	Dose-response	  PAGEREF
_Toc139705754 \h  14  

  HYPERLINK \l "_Toc139705755"  3.2	Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc139705755 \h  15  

  HYPERLINK \l "_Toc139705756"  3.3	FQPA Considerations	  PAGEREF
_Toc139705756 \h  15  

  HYPERLINK \l "_Toc139705757"  3.4	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc139705757 \h  15  

  HYPERLINK \l "_Toc139705758"  3.4.1	Acute Reference Dose (aRfD) -
Females age 13-49, Children of the General Population.	  PAGEREF
_Toc139705758 \h  15  

  HYPERLINK \l "_Toc139705759"  3.4.3	Chronic Reference Dose (cRfD)	 
PAGEREF _Toc139705759 \h  15  

  HYPERLINK \l "_Toc139705760"  3.4.4	Incidental Oral Exposure (Short-
and Intermediate-Term)	  PAGEREF _Toc139705760 \h  17  

  HYPERLINK \l "_Toc139705761"  3.4.5	Dermal Absorption	  PAGEREF
_Toc139705761 \h  17  

  HYPERLINK \l "_Toc139705762"  3.4.6	Dermal Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc139705762 \h  17  

  HYPERLINK \l "_Toc139705763"  3.4.7	Inhalation Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc139705763 \h  18  

  HYPERLINK \l "_Toc139705764"  3.4.8	Level of Concern for Margin of
Exposure	  PAGEREF _Toc139705764 \h  18  

  HYPERLINK \l "_Toc139705765"  3.4.9	Recommendation for Combining
Exposure Risk Assessments	  PAGEREF _Toc139705765 \h  18  

  HYPERLINK \l "_Toc139705766"  3.4.10	Classification of Carcinogenic
Potential	  PAGEREF _Toc139705766 \h  19  

  HYPERLINK \l "_Toc139705767"  3.4.11	Mutagenicity Studies	  PAGEREF
_Toc139705767 \h  19  

  HYPERLINK \l "_Toc139705768"  3.4.12	Summary of Toxicological Doses
and Endpoints for chlorflurenol methyl ester for Use in Human Risk
Assessments	  PAGEREF _Toc139705768 \h  19  

  HYPERLINK \l "_Toc139705769"  4.0	Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc139705769 \h  20  

  HYPERLINK \l "_Toc139705770"  5.0	Dietary Exposure/Risk
Characterization	  PAGEREF _Toc139705770 \h  20  

  HYPERLINK \l "_Toc139705771"  5.1	Drinking Water Residue Profile	 
PAGEREF _Toc139705771 \h  20  

  HYPERLINK \l "_Toc139705772"  5.2	Food Residue Profile	  PAGEREF
_Toc139705772 \h  22  

  HYPERLINK \l "_Toc139705773"  6.0	Residential Exposure and Risks	 
PAGEREF _Toc139705773 \h  22  

  HYPERLINK \l "_Toc139705774"  6.1	Residential Handler Exposures and
Non-cancer Risk Estimates	  PAGEREF _Toc139705774 \h  23  

  HYPERLINK \l "_Toc139705775"  6.1.1	Residential Handler Exposures and
Risks	  PAGEREF _Toc139705775 \h  23  

  HYPERLINK \l "_Toc139705776"  6.1.2	Handler Exposure Scenarios	 
PAGEREF _Toc139705776 \h  23  

  HYPERLINK \l "_Toc139705777"  6.1.3	Data and Assumptions for Handler
Exposure Scenarios	  PAGEREF _Toc139705777 \h  24  

  HYPERLINK \l "_Toc139705778"  6.1.4	Residential Handler Exposure and
Non-Cancer Risk Estimates	  PAGEREF _Toc139705778 \h  25  

  HYPERLINK \l "_Toc139705779"  6.1.5	Residential Handler Exposure and
Risk Estimates for Cancer	  PAGEREF _Toc139705779 \h  26  

  HYPERLINK \l "_Toc139705780"  6.1.6 	Summary of Risk Concerns and Data
Gaps for Handlers	  PAGEREF _Toc139705780 \h  26  

  HYPERLINK \l "_Toc139705781"  6.1.7	Recommendations for Refining
Residential Handler Risk Assessment				  PAGEREF _Toc139705781 \h  26  

  HYPERLINK \l "_Toc139705782"  6.2	Residential Postapplication
Exposures and Assumptions	  PAGEREF _Toc139705782 \h  26  

  HYPERLINK \l "_Toc139705783"  6.2.1	Residential Postapplication
Exposure Scenarios	  PAGEREF _Toc139705783 \h  27  

  HYPERLINK \l "_Toc139705784"  6.2.2	Data and Assumptions for
Residential Postapplication Exposure Scenarios	  PAGEREF _Toc139705784
\h  29  

  HYPERLINK \l "_Toc139705785"  6.2.3	Residential Postapplication
Exposure and Non-cancer Risk Estimates				  PAGEREF _Toc139705785 \h  30
 

  HYPERLINK \l "_Toc139705786"  6.2.4	Residential Postapplication
Exposure and Risk Estimates for Cancer				  PAGEREF _Toc139705786 \h  36
 

  HYPERLINK \l "_Toc139705787"  6.2.5	Summary of Residential
Postapplication Risk Concerns and Data Gaps		  PAGEREF _Toc139705787 \h 
36  

  HYPERLINK \l "_Toc139705788"  6.2.6	Recommendations for Refining
Residential Postapplication Risk Assessments	  PAGEREF _Toc139705788 \h 
37  

  HYPERLINK \l "_Toc139705789"  6.3	Residential Risk Characterization	 
PAGEREF _Toc139705789 \h  37  

  HYPERLINK \l "_Toc139705790"  6.3.1	Characterization of Residential
Handler Risks	  PAGEREF _Toc139705790 \h  37  

  HYPERLINK \l "_Toc139705791"  6.3.2	Characterization of Residential
Postapplication Risks	  PAGEREF _Toc139705791 \h  37  

  HYPERLINK \l "_Toc139705792"  7.0	OCCUPATIONAL EXPOSURE AND RISKS	 
PAGEREF _Toc139705792 \h  38  

  HYPERLINK \l "_Toc139705793"  7.1	Occupational Handler Exposures and
Risk Estimates	  PAGEREF _Toc139705793 \h  38  

  HYPERLINK \l "_Toc139705794"  7.1.1	Data and Assumptions for Handler
Exposure Scenarios	  PAGEREF _Toc139705794 \h  39  

  HYPERLINK \l "_Toc139705795"  7.1.2	Occupational Handler Exposure
Scenarios	  PAGEREF _Toc139705795 \h  45  

  HYPERLINK \l "_Toc139705796"  7.1.3	Non-cancer Occupational Handler
Exposure and Assessment	  PAGEREF _Toc139705796 \h  46  

  HYPERLINK \l "_Toc139705797"  7.1.4 	Cancer Occupational Handler
Exposure and Risk Assessment	  PAGEREF _Toc139705797 \h  58  

  HYPERLINK \l "_Toc139705798"  7.1.5 	Summary of Risk Concerns and Data
Gaps for Occupational Handlers	  PAGEREF _Toc139705798 \h  58  

  HYPERLINK \l "_Toc139705799"  7.1.6	Recommendations for Refining
Occupational Handler Risk Assessment	  PAGEREF _Toc139705799 \h  60  

  HYPERLINK \l "_Toc139705800"  7.2	Occupational Postapplication
Exposures and Non-Cancer Risk Estimates	  PAGEREF _Toc139705800 \h  60  

  HYPERLINK \l "_Toc139705801"  7.2.1	Occupational Postapplication
Exposure Scenarios	  PAGEREF _Toc139705801 \h  60  

  HYPERLINK \l "_Toc139705802"  7.2.2	Data/Assumptions for
Postapplication Exposure Scenarios	  PAGEREF _Toc139705802 \h  63  

  HYPERLINK \l "_Toc139705803"  7.2.3	Occupational Postapplication
Exposure and Non-cancer Risk Estimates	  PAGEREF _Toc139705803 \h  63  

  HYPERLINK \l "_Toc139705804"  7.2.4	Occupational Postapplication
Exposure and Risk Estimates for Cancer	  PAGEREF _Toc139705804 \h  65  

  HYPERLINK \l "_Toc139705805"  7.2.5	Summary of Occupational
Postapplication Risk Concerns and Data Gaps		  PAGEREF _Toc139705805 \h 
65  

  HYPERLINK \l "_Toc139705806"  7.2.6	Recommendations for Refining
Occupational Postapplication Risk Assessment	  PAGEREF _Toc139705806 \h 
66  

  HYPERLINK \l "_Toc139705807"  8.0	Data Needs and Label Requirements	 
PAGEREF _Toc139705807 \h  66  

  HYPERLINK \l "_Toc139705808"  8.1	Toxicology	  PAGEREF _Toc139705808
\h  66  

  HYPERLINK \l "_Toc139705809"  8.2	Residue Chemistry	  PAGEREF
_Toc139705809 \h  66  

  HYPERLINK \l "_Toc139705810"  8.3	Occupational and Residential
Exposure	  PAGEREF _Toc139705810 \h  66  

  HYPERLINK \l "_Toc139705811"  References:	  PAGEREF _Toc139705811 \h 
67  

  HYPERLINK \l "_Toc139705812"  A.1	Toxicology Data Requirements	 
PAGEREF _Toc139705812 \h  68  

  HYPERLINK \l "_Toc139705813"  A.2  Toxicity Profiles	  PAGEREF
_Toc139705813 \h  69  

  HYPERLINK \l "_Toc139705814"  A.3  Executive Summaries	  PAGEREF
_Toc139705814 \h  72  

  HYPERLINK \l "_Toc139705815"  A.3.1	Subchronic Toxicity	  PAGEREF
_Toc139705815 \h  72  

  HYPERLINK \l "_Toc139705816"  A.3.2	Prenatal Developmental Toxicity	 
PAGEREF _Toc139705816 \h  73  

  HYPERLINK \l "_Toc139705817"  A.3.3	Reproductive Toxicity	  PAGEREF
_Toc139705817 \h  75  

  HYPERLINK \l "_Toc139705818"  A.3.4	Chronic Toxicity	  PAGEREF
_Toc139705818 \h  78  

  HYPERLINK \l "_Toc139705819"  A.3.5	Carcinogenicity	  PAGEREF
_Toc139705819 \h  79  

  HYPERLINK \l "_Toc139705820"  A.3.6	Mutagenicity	  PAGEREF
_Toc139705820 \h  80  

  HYPERLINK \l "_Toc139705821"  A.3.7	Neurotoxicity	  PAGEREF
_Toc139705821 \h  80  

  HYPERLINK \l "_Toc139705822"  A.3.8	Metabolism	  PAGEREF _Toc139705822
\h  80  

  HYPERLINK \l "_Toc139705823"  A.3.9	Dermal Absorption	  PAGEREF
_Toc139705823 \h  81  

  HYPERLINK \l "_Toc139705824"  A.4	References	  PAGEREF _Toc139705824
\h  81  

 

	

1.0 EXECUTIVE SUMMARY   

	This assessment provides the evidence for reregistration of
chlorflurenol methyl ester.  The reregistration process provides
re-review of previously registered pesticides under the Federal
Insecticide, Fungicide and Rodenticide Act [FIFRA] to assure scientific
reliability and conformity to the data standards established under the
Food Quality Protection Act [FQPA] of 1996. 

	Chlorflurenol methyl ester is a nonfood use herbicide, plant growth
retardant and plant growth regulator.  As a herbicide and plant growth
retardant it is used for the postemergent control of annual grasses,
broadleaf weeds, trees, shrubs and vines.  As a plant growth regulator,
chlorflurenol is used to produce pineapple planting material [sliplets]
well over one year before the pineapples are harvested.  As this use is
not expected to result in finite residues in pineapples, this is
considered to be a nonfood use and no tolerances are necessary in
pineapples.

	Chlorflurenol methyl ester [technical] is greater than 96% total ester
and is composed of three related chemicals chlorflurenol methyl ester
[65% to70%], dichlorflurenol methyl ester [10% to 15%] and
deschlorflurenol methyl ester [15% to 20%].  

	Chlorflurenol methyl ester shows low acute toxicity by the oral, dermal
and inhalation routes [toxicity is category IV].  Clorflurenol methyl
ester was essentially non-irritating to the eye and skin, respectively
[toxicity category III and IV].  It is not a skin sensitizer in a Guinea
pig study.  

	The acceptable and unacceptable studies with chlorflurenol methyl ester
show no severe toxicity.  The most sensitive species is the dog showing
slight red blood cell destruction at 4 weeks after the start of the
study and only at the highest dose tested.  A 13-week subchronic study
in rats showed toxicity, but did not confirm the hematological effects. 
The female body weight decrement was seen in rats at higher dose levels
than in the dog study at month 13 or the effects on hematology at week
4.  A 21-day dermal study in rabbits with a formulation of chlorflurenol
methyl ester showed no systemic effects, but showed destruction of the
hair follicles and edema in the treated skin.  The skin effects were
dose related.  These effects were considered due to skin irritation from
the formulation containing 87.5% inerts, most of which are known skin
irritants.  Potential systemic effects of the technical grade could not
be definitively evaluated due to these inerts; however, systemic effects
are not likely to be seen at lower dose levels than those of the active
ingredient tested in the 21-day dermal study in rabbits.  Potential
reproductive effects were not tested in the 21-day dermal study. 

	A carcinogenicity study in mice showed no evidence of carcinogenicity
at lower doses or above a limit dose of 1 g/kg/day.  A battery of
mutagenicity studies was all negative.

	Unacceptable kinetic/distribution studies suggest that each of the
three radiolabeled components comprising chlorflurenol methyl ester were
barely detectable in the rat mammary glands or in nursing pups.  Since
the studies used only one female/treatment, the findings could not be
verified.  However, this study showed that each of the three components
in chlorflurenol methyl ester is probably rapidly excreted mostly in the
urine within 24 hours.  Radiolabel in the mammary gland and the nursing
pups was not quantified in the treated animals. 

	Prenatal studies in the rat and rabbit show no increased fetal
susceptibility.  At the highest dose tested, rats showed delayed
ossification at higher incidence than control incidence.  Maternal
toxicity in the form of body weight decrement was seen at mid- and
highest dose tested.  The rabbit showed no effects in fetuses or mothers
at the highest dose tested.  Post-natal studies were not required, but a
1973 three-generation reproduction study previously submitted for other
purposes showed equivocal litter size and pup weight decrement at birth
and subfertility in adult offspring, but showed a poor dose response.

	Due to these ambiguous findings in the reproduction study, an
additional uncertainty factor of 3X was used when calculating human oral
risk.  The additional 3X factor may be removed by another acceptable
reproduction study showing a more definitive NOAEL for effects on the
litters and fertility.

	Exposures to the pesticide were calculated assuming maximum application
rates from both labels and from a March 14, 2006 memorandum from the
Biological and Economic Analysis Division [BEAD] of the USEPA [BEAD
memo].  No dermal absorption studies are available.  This resulted in
the assumption of 100% dermal absorption from an oral study endpoint for
dermal exposure.  

	When levels of exposure were above the Level of Concern [LOC],
suggesting an unacceptable exposure, the exposures to granular
formulations were recalculated using 10% dermal absorption for
comparison. 

	There is opportunity for adult residential handler exposure from the
application to lawns and ornamentals. A Margin of Exposure [MOE] less
than 100 exceeds OPP’s LOC and suggests unacceptable risk.  All
residential handler activities showed MOE greater than 100, suggesting
acceptable risk.  Attire for residential handlers is assumed to be
short-sleeved shirts, short pants, shoes and socks. 

	Several  residential postapplication scenarios were identified for
chlorflurenol methyl ester, including dermal exposure from residue on
lawns and turf (adult, youth and toddler), hand-to-mouth transfer of
residues on lawns (toddler), ingestion of pesticide residue on treated
grass (toddler), and incidental ingestion of soil from pesticide-treated
residential areas (toddler).

	For the adult populations, all postapplication risks were below HED’s
level of concern, except for the 3.0 lb ai/A (BEAD) application rates
where MOEs are 44 on day 0.  For the youth populations, all
postapplication noncancer risks were below HED’s level of concern. 
For toddlers, postapplication noncancer risks are not of concern for the
oral route.  For the dermal route, risks to toddlers from high contact
activity on lawns exceed HED’s level of concern at the 1.0/1.1 lb ai/A
(Label) and 3.0 lb ai/A (BEAD) application rates, except when 10% dermal
absorption is assumed for the granular formulations.  Calculated
combined risks to toddlers (i.e., dermal high contact activity plus hand
to mouth activity plus object to mouth activity on treated turf plus
incidental soil ingestion of pesticide residue from treated turf areas)
are therefore, also of concern, except when 10 percent dermal absorption
is assumed for the granular formulations.  

	There are potential exposures to occupational mixers, loaders,
applicators, and other handlers during the usual use-patterns associated
with chlorflurenol methyl ester. These risks were calculated assuming
maximum application rates from both the product labels and from the BEAD
memo. For all occupational scenarios, the inhalation risks were below
HED’s level of concern at the baseline level.  

	The dermal risks were below HED's level of concern at some level of
mitigation for all occupational scenarios, except applying liquid sprays
using rights-of-way equipment: 

to turf growing in culverts, rights of way, median strips, ditches,
and/or under security fences at the 3 lb ai/A rate (Label & BEAD);

to non-agricultural rights-of-ways/fence rows and hedge rows at the 3 lb
ai/A rate (Label & BEAD);

to gymnosperms and hardwoods at the 5 lb ai/A rate;

to shrubs, shade trees and vines at the 4.5 lb ai/A rate (BEAD); and

to high density forestry management at the 4.0 lb ai/A rate (BEAD).

Risks remain a concern at maximum personal protective equipment and no
engineering controls are available for rights-of-way application
equipment.

	Using ORETF data, the dermal risks were a concern at baseline for
handlers mixing/loading/applying liquids with an overhead directed low
pressure handwand equipment for the scenarios where BEAD application
rates are assessed.  No ORETF data currently are available to assess the
corresponding personal protective equipment exposures for these
scenarios.  However, using PHED data, the dermal risks were not a
concern with the addition of chemical-resistant gloves to baseline
attire.

	There are potential postapplication exposures to occupational workers
during the usual use-patterns associated with chlorflurenol. 
Specifically, there is concerned about postapplication exposures from
treatment of pineapples and golf course turf. In agricultural crop
settings, a Restricted Entry Interval or REI – is used to mitigate
postapplication risks following applications to crops.  The REI is time
period following a pesticide application during which entry into the
treated area is restricted.  To establish REIs, EPA considers
postapplication risks on varying days after application. For pineapple
applications, the MOEs are greater than 100 on day 0 (REI = 12 hours)
for all of the exposure levels.	

	For the golf course turf using the 1.0 and 1.1 lb ai/A (Label) rates
for sprays and granular applications respectively and assuming hand
weeding and transplanting tasks are performed and assuming 100% dermal
absorption, risks are not a concern at day 4 for liquid formulations and
at day 5 for granular formulations.  Assuming golf course mowing tasks
are performed, risks are not a concern on day 0 (12 hours following
application) for liquid or granular applications using these application
rates and assuming 100 percent absorption. Risks are not a concern at
day 0 (12 hours following application) for granular applications for any
postapplication tasks using the 1.1 lb ai/A application rate and
assuming 10% dermal absorption.  

	For the golf course turf using the 3.0 lb ai/A (BEAD) rates for sprays
and granular applications and assuming 100% dermal absorption, risks are
not a concern for hand weeding and transplanting tasks at day 14 and for
mowing at day 8.  For the golf course turf using the 3.0 lb ai/A (BEAD)
rates for granular applications and assuming 10% dermal absorption,
risks are not a concern for any tasks at day 0 (REI = 12 hours).  

	See Sections 6.0 through 7.2.6 for Residential Exposure and
Occupational Exposure for mixed exposure scenarios of concern.

	Potential contamination of surface water and ground water were modeled
by Tier II PRZM/EXAMS and Tier I SCIGROW.  Risk was assessed by DEEM for
chronic exposure to drinking water using modeled surface water estimated
concentrations and modeled groundwater estimated concentrations.  Using
surface water estimates, exposures to all groups were below the chronic
RfD and OPP’s LOC.  The highest exposure groups were non-nursing
infants at 20% of the chronic oral RfD and all infants (< one year) at
16% of the chronic oral RfD.  However, using ground water estimated
concentrations two groups were above the chronic RfD and above OPP’s
LOC.  The assessment by DEEM for ground water showed that the highest
estimated exposure was 176% of the chronic RfD for non-nursing infants
and 142% of the chronic RfD for all infants (< 1 year).  The next
highest estimated exposure was to children 1-2 years at 64% of the
chronic RfD.    These exposures were not combined  with infants and
children exposured to lawns treated with sprays or granulated
cholorflurenol.  It should be noted that since toddler exposure from
treated lawns was above OPP’s LOC, and any additional exposure from
drinking water would result in additional concern. 

2.0	Ingredient Profile  

Summary of Registered/Proposed Uses 

	At this time, there are four products containing chlorflurenol that are
intended for occupational and/or residential uses.  All products are
registered by Repar Corporation. Two of the products (Maintain CF 125
and Reap Thru Herbicide) are emulsifiable concentrates and contain 12.5
and 15.9 percent active ingredient, respectively.  Maintain CF 125 is
also registered as a special local needs product under EPA SLN No.
HI-980007.  The other two products (Repar Broad Spectrum Weed and Feed
and Repar Weed and Feed 28-3-3) are granulars and contain 0.17 and 0.70
percent active ingredient, respectively.

2.2	Registered Use Categories and Use Sites  

An analysis of the current labeling and available use information was
incomplete, in that frequency of application and number of applications
per season is not stated.  Chlorflurenol is registered for use in a
variety of agricultural, commercial, and residential scenarios and thus
these populations are potentially exposed while performing handling
tasks, including mixing/loading, applying, and flagging tasks.  It is
also possible for these populations to be exposed to chlorflurenol
during postapplication time periods.  Tables 1a, 1b, and 1c provided the
maximum application rates for the registered scenarios based on
information from the product labels.  Table 2 provides the maximum
application rates from a March 14, 2006 memo from the Biological and
Economic Analysis Division (BEAD) of USEPA (BEAD memo). 



  SEQ CHAPTER \h \r 1 Table 1a: Summary of Maximum Application Rates
for Registered Chlorflurenol Methyl Ester Agricultural Uses – Label

Crop Site	Target of Application	Maximum Application Rate	Application
Equipment	Area Treated or Amount Handled Per Day

Liquid Formulations

Pineapple plants:

for plant material production (non food use)	Plant growth regulator	1 lb
a.i./A (Label)	Groundboom	80 acres

	Airblast	40 acres

 

  SEQ CHAPTER \h \r 1 Table 1b: Summary of Maximum Application Rates for
Registered Chlorflurenol Methyl Ester Commercial Uses – Label

Crop Site	Target of Application	Maximum Application Rate	Application
Equipment	Area Treated or Amount Handled Per Day

Liquid Formulations

Turf:  Lawns and Ornamental Turf  (including golf course and parks)
Broadleaf weeds and plant growth retardant	1.0 lb a.i./A	low pressure
handwand	40 gallons

	Handgun	5 acres for A and M/L/A

100 acres for M/L (for 20 LCOs)

	Groundboom	40 acres

Gymnosperms	Plant growth retardant	0.25 lb ai/100 gallons	low pressure
handwand	40 gallons

	Handgun	1,000 gallons

	rights-of-way sprayer	1,000 gallons

Hardwoods:

growing under utility lines, as screens or ground cover, adjacent to
highways	Plant growth retardant	1.0 lb ai/100 gallons	handgun	1,000
gallons

	rights-of-way sprayer	1,000 gallons

	low-pressure handwand	40 gallons

Hedges:

growing under utility lines, as screen	Plant growth retardant	1.0 lb
ai/100 gallons	handgun	1,000 gallons

	rights-of-way sprayer	1,000 gallons

	low-pressure handwand	40 gallons

Vines

growing under utility lines, as screens or ground cover, rights-of-way,
hedgerows	Plant growth retardant	1.0 lb ai/100 gal	handgun	1,000 gallons

	rights-of-way sprayer	1,000 gallons

	low-pressure handwand	40 gallons

Turf:

growing in culverts, rights-of-way, median strips, ditches, under
security fences	Plant growth regulator	3.0 lb a.i./acre	rights-of-way
sprayer	80 acres

	handgun	5 acres

	low-pressure handwand	5 acres

Trees:

bark banding	Plant growth retardant	0.083 lb a.i./gal	low-pressure
handwand	40 gallons

Granular Formulations

Turf:  Lawns and Ornamental Turf  (including golf course and parks)
Broadleaf weeds	1.1 lb a.i./acre	tractor-drawn spreader	40 acres

	push-type spreader	5 acres

	belly grinder	1 acre

  SEQ CHAPTER \h \r 1 Table 1c: Summary of Maximum Application Rates
for Registered Chlorflurenol Methyl Ester Residential Uses – Label

Crop Site	Target of Application	Maximum Application Rate	Application
Equipment	Area Treated or Amount Handled Per Day

Granular Formulations

Turf:  lawns	Broadleaf weeds	0.25 lb a.i./A	push-type spreader	0.5 acre

	belly grinder	1,000 ft2



Table 2.  Summary of Maximum Application Rates for Registered
Chlorflurenol Methyl Ester Uses – BEAD

Use Site	Treatment Type	Maximum Application Rate

(a.i. lb/acre)

Pineapple	Growth regulator	1.0

Ornamental trees	Growth regulator	2.5

Non-agricultural rights-of-ways/fence rows and hedge rows	Weed control &
growth retardant	

3 .0

Established turf	Weed control & turf growth retardant	3.0

High density forestry vegetation management (plant density >1500 stems
per acre; plant height > 8 ft)	Weed control	4.0

Shrubs, shade trees and vines	Growth regulator	4.5

Hardwood and gymnosperm trees	Height control	5.0

2  SEQ CHAPTER \h \r 1 .3	Application Methods 

	Chlorflurenol is applied with several types of application equipment,
including airblast sprayers, ground boom sprayers, low pressure handwand
sprayers, handgun sprayers, rights-of-way sprayers, tractor-drawn
spreaders, push-type spreaders, and belly grinders.  For information on
the Occupational Handler assumptions and variables used in the
calculation of exposure, see [Section 7.1  Occupational Handler
Exposures and Risk Estimates].

2.4	Structure and Nomenclature 

  TC \l2 "2.2	Structure and Nomenclature 

  SEQ CHAPTER \h \r 1 Table 3.   Nomenclature for Chlorflurenol Methyl
Ester

Chemical structure	Major product

Hydrolysis product

 

Common name	chlorflurenol-methyl, flurenol

Molecular formula	C15H11ClO3

Molecular weight	274.07 g/mol

IUPAC name	Methyl (RS)-2-chloro-9-hydroxyfluorene-9-carboxylate

CAS name	Methyl 2-chloro-9-hydroxy-9H-fluorene-9-carboxylate

CAS number	2536-31-4

PC Code	098801

2.5	Physical and Chemical Properties   TC \l2 "2.3	Physical and Chemical
Properties 

Table 4  Physicochemical Properties of Chlorflurenol Methyl Ester

Parameter	

Value	

Reference

Melting point/range	136-142 degrees Celsius	MRID 434549-03

pH	 Not Applicable, Crystalline material	MRID 43154901

Density 	-1.5	MRID 431549-03

Water solubility 	18mg/L	MRID 431549-03

Solvent solubility at:

25 degrees Celsius	Cyclohexane 0.24 g/ 100 ml

Isopropanol 2.4 g/100 ml

Benzene 7.0 g/100 ml

Ethanol 8.0 g/100 ml

Methanol 15 g/100 ml

Acetone 26 g/100 ml

	MRID 431549-02

Vapor pressure 	5 - 10-5 Torr at 25 degrees Celsius	MRID 431549-03

Dissociation constant, pKa	None	MRID 431549-03

Octanol/water partition coefficient	Estimated Log P 2.86

Estimate from fate data on water 65 or log P=1.81	MRID 433554-01

MRID 43496202

UV/visible absorption spectrum	None provided	Data Gap

3.0	Hazard/Dose-Response Characterization/Assessment   TC \l1 "3.0
Hazard Characterization/Assessment 

3.1	Hazard and Dose-Response Characterization   TC \l2 "3.1	Hazard and
Dose-Response Characterization    

3.1.1	Database Summary:    TC \l3 "3.1.1	Database Summary 

	Chlorflurenol methyl ester shows low acute toxicity by the oral, dermal
and inhalation routes [toxicity is category IV].  Eye and skin
irritation were mild and essentially non-irritating, respectively
[toxicity category III and IV].  It is not a skin sensitizer in a Guinea
pig study.  

	The acceptable and unacceptable studies with chlorflurenol methyl ester
show no severe toxicity.  The most sensitive species is the dog showing
slight red blood cell destruction at 4 weeks after the start of the
study and only at the highest dose tested [NOAEL/LOAEL = 31/94
mg/kg/day].  This red blood cell destruction was supported by
hemosiderin deposits in the liver at the 2-year termination.  No studies
were seen that confirmed the hematological findings in the chronic dog
study.  At month 13, the study showed decreased body weight in males and
females, but not in females at termination.  An unacceptable 13 week
study in 3 dogs/sex/group at comparable dose levels showed inconsistent
nominally decreased red blood cells, but no hemosiderin deposits at
termination.  A 13-week subchronic study in rats showed a dose related
decreased body weight in females accompanied by decreased food
efficiency and at the mid dose tested and at the highest dose tested
decreased male body weight gain .  The female body weight decrement was
seen in rats at higher dose levels than in the dog study at month 13 or
the effects on hematology at week 4.  A 21-day dermal study in rabbits
with a formulation of chlorflurenol methyl ester showed no systemic
effects, but showed destruction of the hair follicles and edema in the
treated skin.  The skin effects were dose related.  These effects were
considered due to skin irritation from the formulation containing 87.5%
inerts, most of which are known skin irritants.  Potential systemic
effects of the technical grade could not be definitively evaluated due
to these inerts; however, systemic effects are not likely to be seen at
lower dose levels than those of the active ingredient tested in the
21-day dermal study in rabbits.  Potential reproductive effects were not
tested in the 21-day dermal study. 

	A carcinogenicity study in mice showed no evidence of carcinogenicity
at lower doses or above a limit dose of 1 g/kg/day.  A battery of
mutagenicity studies was all negative.

	Unacceptable kinetic/distribution studies showed that each of  the
three radiolabeled components comprising chlorflurenol methyl ester were
barely detectable in the rat mammary glands or in nursing pups.  Since
the studies used only one female/treatment, the findings could not be
verified.  However, this study showed that each of the three components
in chlorflurenol methyl ester is probably rapidly excreted mostly in the
urine within 24 hours.  Radiolabel in the mammary gland and the nursing
pups was not quantified. 

	Prenatal studies in the rat and rabbit show no increased fetal
susceptibility.  The rat showed delayed ossification at higher incidence
than control values.  This delayed ossification was shown at the highest
dose tested and maternal toxicity was seen at the mid- and highest dose
tested.  The rabbit showed no effects in fetuses or mothers at the
highest dose tested.  Postnatal studies were not required, but a 1973
three-generation reproduction study previously submitted for other
purposes showed equivocal litter size and pup weight decrement at birth
and subfertility in adult offspring.  The potential effects were more
variable than usual for a study on reproduction.  The reproducibility of
these effects can be questioned.  In addition, the study showed an
excessive number of  pregnancies in female rats that showed no sperm
during the period of cohabitation, i.e., no evidence that mating had
occurred.  Although, this finding could raise questions about the
conduct of the study, there was no suggestion in the data of a dose
related response among the generations of females that showed no sperm. 
However, when all these females from all 6 groups of matings among the 3
generations in the study were added together, there was a suggestion of
a treatment related response.  Due to these ambiguous findings in the
reproduction study, an additional uncertainty factor of 3X was used when
calculating human oral risk.  The additional 3X factor may be removed by
another acceptable reproduction study showing a more definitive NOAEL
for effects on the litters and fertility.

3.1.2	Studies available and considered (animal, human, general
literature)   TC \l4 "3.1.1.1	Studies available and considered (animal,
human, general literature) 

	No animal or human toxicity studies with chlorflurenol methyl ester
were found in the literature.  The toxicity studies available and
considered in the assessment of chlorflurenol methyl ester were:

1.  Acute – 		Oral LD50, Dermal LD50, Inhalation LC50, Eye and skin
irritation and dermal sensitization

2.  Subchronic -	An acceptable/nonguideline 21-day dermal study in
rabbits.  An acceptable 90-day subchronic study in rats

3. Chronic - 		An acceptable chronic 2-year feeding study in dogs  A
carcinogenicity study in mice.

4.  Developmental - 	An acceptable developmental toxicity study in rats
and an unacceptable developmental toxicity study in rabbits

5.  Reproduction -	An unacceptable 3-generation reproduction study in
rats

6  Mutagenicity - 	A study on reverse mutation in S. typhimurium;  A
study on chromosomal aberration in CHO cells;  An in vitro study for rat
hepatocyte unscheduled DNA synthesis;  An in vitro mammalian cell HGPRT
test.  The battery of guideline mutagenicity studies was acceptable.

7.  Kinetics/distribution -	An unacceptable/non-guideline study of
kinetics and distribution, including radiolabel in rat milk. 

3.1.3	Mode of action, metabolism, toxicokinetic data   TC \l4 "3.1.1.2
Mode of action, metabolism, toxicokinetic data   

	There was no data on a mode of action.  However, general information
about suggested distribution and kinetic data has been submitted.  The
data suggest that chlorflurenol methyl ester is circulated
enterohepatically and excreted in the feces and mostly in urine all
within 24 hours, resulting in no accumulation.  

3.1.4	Sufficiency of studies/data   TC \l4 "3.1.1.3	Sufficiency of
studies/data   

	The toxicity data base for chlorflurenol methyl ester is adequate for
risk assessment.  The toxicity data requirements for a nonfood use
pesticide depend on exposure and toxicity.  In the case of chlorflurenol
methyl ester which shows both low toxicity and moderate exposure, the
requirements are the 6 acute studies, a subchronic study, a
developmental toxicity study and a battery of mutagenicity studies. 
These data requirements have been satisfied by acceptable studies. 
However, a 1973 reproduction study submitted for other purposes shows
equivocal effects that add uncertainty to the data base.

3.1.5	Toxicological Effects   TC \l3 "3.1.2	Toxicological Effects   

	Toxicological effects of concern are found in a chronic study in dogs
at 4 weeks.  Chlorflurenol methyl ester administered to dogs resulted in
treatment-related red blood cell destruction at the highest dose tested
within 4 weeks with a NOAEL/LOAEL of 31/94 mg/kg/day.  No other study
showed a lower NOAEL. 

3.1.6	Dose-response   TC \l3 "3.1.3	Dose-response 

	The acceptable and unacceptable subchronic studies in the rat and dog
showed treatment related effects at the highest dose tested [HDT] in the
dog..  The chronic dog study showed marginal hematological effects
within 4 weeks at the HDT.  The only studies showing a dose related
response were the rat subchronic and developmental toxicity studies in
the form of a body weight decrement in female rats and maternal rats,
respectively at the middle and high dose.

	An old reproduction study (1973)[See section A.3.3 in Appendix A], that
 was not required showed possible, but inconsistent subfertility in
rats.  This unacceptable reproduction study may have shown equivocal
effects on fertility, litter size at birth and pup weight decrement at
the HDT.  The fertility of P0 parents was unaffected; the next
generation apparently showed effects at all dose levels, but showed no
dose-related response and in the last generation there was statistically
significant dose-related decrease in fertility at the two top dose
levels.  The study also showed a peculiar effect at mating.  An unusual
number of pregnant females showed no sperm during cohabitation.  This
effect is rarely seen in studies on reproduction.  However, the method
for identification of sperm at mating was not described and may have
been inadequate.  Older studies show more variation in fertility than
current studies, raising the question that the potential decreased
fertility may not be reproducible. The study was unacceptable largely
due the variable fertility.  For these reasons an extra 3X database
uncertainty factor will be used in the Risk assessment for chlorflurenol
methyl ester, unless another study on reproduction is submitted that
shows a more definitive NOAEL for reproductive effects.

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)   TC \l2 "3.2
Absorption, Distribution, Metabolism, Excretion (ADME) 

	Chlorflurenol methyl ester is rapidly absorbed and excreted mostly in
the urine within 24 hours, with minor additional excretion between 24
and 72 hours.  In the study in one female rat/treatment, the report
authors claimed that very small amounts of radiolabel were retained in
the mammary gland and barely detectable amounts in nursing pups.  The
amount of label retained in the mammary gland and nursing pups was not
quantified, and is thus unknown. 

The kinetic data submitted suggest that chlorflurenol in the rat was
circulated enterohepaticaly. Although the data also suggested that
chlorflurenol was not secreted in rat milk, these data were not
replicated or quantified and the sensitivity of the
radio-autography/radiological methods used were not described, the
absence in the milk supply was not proven. 

3.3	FQPA Considerations   TC \l2 "3.3	FQPA Considerations 

	As there are no uses of chlorflurenol methyl ester that qualify as food
uses, no tolerance has been established and the requirements of FQPA are
not applicable.

3.4	Hazard Identification and Toxicity Endpoint Selection   TC \l2 "3.5
Hazard Identification and Toxicity Endpoint Selection 

3.4.1	Acute Reference Dose (aRfD) - Females age 13-49, Children of the
General Population.    TC \l3 "3.5.1	Acute Reference Dose (aRfD) -
Females age 13-49   

	There is no study with a single dose suitable. 

Comment:  An acute RfD is used to assess acute food exposure.  Since
exposure to chlorflurenol methyl ester does not occur through food,
addressing this endpoint is unnecessary.

3.4.3	Chronic Reference Dose (cRfD)   TC \l3 "3.5.3	Chronic Reference
Dose (cRfD) 

	Selected Study:  Chronic Feeding study in Dogs [MRID# 0082863]     GDL
870.4100

EXECUTIVE SUMMARY:  In a chronic toxicity study (MRID 00082863) IT 3456
[Chlorflurenol, technical (96% a.i., batch/lot # 5/69)] was administered
to 4 Beagle dogs/sex/group in the diet at dose levels of 0, 300, 1000 or
3000 ppm ( for male/female equivalent to 0, 8.7/8.8, 30.6/29.9 or
94.0/94.4 mg/kg bw/day, calculated from test material consumption) for
104 weeks.  One extra dog/sex/group was treated with test material for
104 weeks, after which the dogs were untreated for 8 weeks.  Hematology
and clinical chemistry evaluation was performed at 6 intervals during
the study.  Animals were subjected to gross pathology and microscopic
examination.  

	Body weight appeared to be slightly reduced by month 13 at the highest
dose tested [HDT].  Dogs showed this body weight decrement at month 13
when compared with initial body weights for males [the HDT gained 0% vs.
22.3% for control weight] and for females [the HDT gained 6.6% vs. 20.3%
for control body weight].  Male body weight gain appeared to be reduced
for the remainder of the study.  Male body weight gain was decreased at
104 weeks [body weight gain was 0.8 kg at the HDT and 2.5 kg for
controls].  At the end of the study female body weight gain was the same
as control weight gain.  Food consumption was unaffected in both sexes. 

Erythrocytes [ERY], hemoglobin concentration [Hb] and hematocrit [Ht]
values appeared to be slightly decreased at the HDT in males and females
starting at week 4 [the first time period evaluated] and male dogs
maintained a decrease through out the study.   Some of the values in the
HDT were statistically significantly reduced, but were still within the
normal range for dogs.    The (ERY, (Hb and (Ht values [difference
between measured values and week -2 values] appeared to decrease in
males and females at the HDT starting at week 4 and male dogs maintained
the decrease through out the study.  This decrease is consistent with
the slightly higher incidence and/or severity of siderous in the spleen,
liver and Kupffer cells at the HDT.    Hemosiderin in the 1000 ppm group
was not considered sufficiently consistent to show that the mid dose
group was affected.  In addition the values for ERY, Hb and Ht from the
1000 ppm group of animals did not show consistent effects.  From week
26-52 to termination, the values for ERY, Hb and Ht for treated female
dogs did not appear to differ from control.       

Clinical chemistry values showed no consistent treatment related
effects.  Organ weights were unchanged from control values.  

On microscopic examination increased hemosiderin in liver and liver
Kupffer cells and possibly in the spleen at the HDT seemed to confirm
the hematological effects.  In addition, the highest dose group showed
higher incidence of gastritis and possible stomach lymphatic
hyperplasia.  

A single dog/sex was allowed to recover for 2 months and although the
hemosiderin appeared to decrease, effects in one dog are difficult to
interpret.

The NOAEL was 30.6/29.9 mg/kg/day for males/females.  The LOAEL was
94.0/94.4 mg/kg/day for male/females based on decreased erythrocytes,
hemoglobin and hematocrit by week 4 in males and females, supported by
hemosiderin deposits in liver and increased incidence of gastritis and
possible decreased body weight in males and females by month 13 of the
study, but not in females by study termination at 24 months.

This study is ACCEPTABLE/GUIDELINE and satisfies the guideline
requirement [870.4100b] for a dog chronic study.   This DER takes
precedence over previous conclusions.

	Dose and Endpoint for Establishing cRfD:  NOAEL is 31 mg/kg/day.  The
LOAEL is 94 mg/kg/day based on male and females decreased erythrocyte,
hemoglobin and hematocrit by week 4 of the study and supported by
hemosiderin deposits in the liver at termination.  At this same dose
body weight decrement was seen in male and females at month 13, but not
in females by the end of the study. 

	Uncertainty Factor:  300x [10 for interspecies extrapolation, 10 for
intraspecies variation and 3X for database uncertainty in the NOAEL in a
reproduction study].

	Comments about the Study/Endpoint/Uncertainty Factor:  The
hematological effects occurred at 4 weeks and remained until termination
where hemosiderin deposits confirmed the red blood cell destruction. 
This endpoint will be unnecessary for current uses, since there are no
food uses.  However, this endpoint may be necessary at a later date
and/or handler exposures.

3.4.4	Incidental Oral Exposure (Short- and Intermediate-Term)   TC \l3
"3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term) 

	Selected Study:  Chronic Feeding study in Dogs [MRID 00082863]     GDL
870.4100

	[See Section 3.5.3  for the executive Summary of MRID 00082863]

	Dose for Establishing an Endpoint:  NOAEL is 31 mg/kg/day.  The LOAEL
is 94 mg/kg/day based on male and females decreased erythrocyte,
hemoglobin and hematocrit by week 4 of the study and supported by
hemosiderin deposits in the liver at termination.  At this same dose
body weight decrement was seen in male and females at month 13, but not
in females by the end of the study. 

	Uncertainty Factor:  300x [10 for interspecies extrapolation, 10 for
intraspecies variation and 	3X for database uncertainty in the NOAEL in
a reproduction study].

	Comments about the Study/Endpoint/Uncertainty Factor:  The
hematological effects occurred at 4 weeks and remained until termination
with hemosiderin deposits confirming the red blood cell destruction.  

3.4.5	Dermal Absorption  TC \l3 "3.5.5	Dermal Absorption 

	There are no dermal absorption studies.  Therefore, 100% dermal
absorption will be assumed; exposure will also be calculated assuming
10% dermal absorption for comparitive purposes

3.4.6	Dermal Exposure (Short-, Intermediate- and Long-Term)   TC \l3
"3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term) 

	Selected Study:  Chronic Feeding study in Dogs [MRID 00082863]     GDL
870.4100

	[See Section 3.5.3  for the executive Summary of  MRID 00082863]

	Dose for Establishing an Endpoint:  NOAEL is 31 mg/kg/day.  The LOAEL
is 94 mg/kg/day based on male and females decreased erythrocyte,
hemoglobin and hematocrit by week 4 of the study and supported by
hemosiderin deposits in the liver at termination.  At this same dose
body weight decrement was seen in males and females at month 13, but not
in females by the end of the study. 

	Uncertainty Factor:  100x [10 for interspecies extrapolation, 10 for
intraspecies variation].

	Comments about the Study/Endpoint/Uncertainty Factor:  The
hematological effects occurred at 4 weeks and remained until termination
with hemosiderin deposits confirming the red blood cell destruction. 
The 3x uncertainty factor is dropped for dermal exposure, since an
endpoint from an oral study is used.  In addition, since there is no
dermal absorption study, the default assumption is 100% dermal
absorption, which is excessive.  This built in extra safety factor is
adequate, especially since a non-guideline 21-day dermal study on a
formulation showed no systemic toxicity. 

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

	Selected Study:  Chronic Feeding study in Dogs [MRID 00082863]     GDL
870.4100

	[See Section 3.5.3  for the executive Summary of MRID 00082863]

	Dose for Establishing an Endpoint:  NOAEL is 31 mg/kg/day.  The LOAEL
is 94 mg/kg/day based on male and females decreased erythrocyte,
hemoglobin and hematocrit by week 4 of the study and supported by
hemosiderin deposits in the liver at termination.  At this same dose
body weight decrement was seen in male and females at month 13, but not
in females by the end of the study. 

	Uncertainty Factor:  100x [10 for interspecies extraploationvariation,
10 for intraspecies variation].

	Comments about the Study/Endpoint/Uncertainty Factor:  The
hematological effects occurred at 4 weeks and remained until termination
with hemosiderin deposits confirming the red blood cell destruction. 
This endpoint maybe unnecessary for current uses, since chlorflurenol
methyl ester is not irritating and shows low toxicity by the oral route
and effects from inhalation exposure are unlikely.

3.4.8	Level of Concern for Margin of Exposure  TC \l3 "3.5.8	Level of
Concern for Margin of Exposure 

Table 5   Summary of Levels of Concern for Risk Assessment.

Route	Short-Term

(1 - 30 Days)	Intermediate-Term

(1 - 6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	100	100	NA

Inhalation	100	100	NA

Residential Exposure

Dermal	100	100	NA

Inhalation	NA	NA	NA

Incidental Oral	300	300	300

	Occupational exposure:  Since oral studies are used for dermal and
inhalation endpoints, there is a built in safety factor associated with
absorption which is assumed to be 100%, but may be much lower.   

	Residential exposure:  Since the potential exists for incidental oral
exposure to infants and children, a 3X database factor is applied when
infants or children are exposed.

3.4.9	Recommendation for Combining Exposure Risk Assessments  TC \l3
"3.5.9	Recommendation for Combined Aggregate Exposure Risk Assessments  

	Since all endpoints are oral, all routes of exposure may be combined,
including incidental oral, dermal and inhalation.  However, a combined
risk index must be used when combining dermal and oral risk because the
uncertainty factors associated with the two types of exposures differ.  

3.4.10	Classification of Carcinogenic Potential  TC \l3 "3.5.10
Classification of Carcinogenic Potential  

 

	There is no indication of dose related or treatment related
carcinogenic effects in males or

 females in an acceptable carcinogenicity study in mice below or above
the limit dose of 

1 g/kg/day [MRID 00082865].

	

3.4.11	Mutagenicity Studies 

	A battery of acceptable mutagenicity studies were all negative.

3.4.12	Summary of Toxicological Doses and Endpoints for chlorflurenol
methyl ester for Use in Human Risk Assessments  TC \l3 "3.5.11	Summary
of Toxicological Doses and Endpoints for [Chemical] for Use in Human
Risk Assessments 

	No studies in humans have been submitted.

Table 6.	Summary of Toxicological Doses and Endpoints for Chlorflurenol
methyl ester for Use in                           Human Health Risk 
Assessments.

Exposure/

Scenario	Dose Used in Risk Assessment	Level of Concern [LOC] for Risk
Assessment and contributing factors	Study and Toxicological Effects

Acute Dietary

(Females 13-49 years of age)	No studies reflecting a single dose are
appropriate or available from which to select this endpoint.

Acute Dietary

(General population including infants and children)	No studies
reflecting a single dose are appropriate or available from which to
select this endpoint.

Chronic Dietary

(All populations)	NOAEL = [31] mg/kg/day

Chronic RfD = 0.10 mg/kg/day	LOC = 100% of the cRfD.  Total UF=300 

Interspecies10X

Intraspecies 10X

Database 3X  	Chronic 2-year feeding study in dogs 

LOAEL = 94 mg/kg/day based on decreased erythrocyte, hemoglobin and
hematocrit at 4 weeks.  

Incidental Oral Short-Term

(1 - 30 days) and Intermediate-Term (1-6 moths)	NOAEL = 31 mg/kg/day

	LOC for MOE = 300	Chronic 2-year feeding study in dogs 

LOAEL = 94 mg/kg/day based on decreased erythrocyte, hemoglobin and
hematocrit at 4 weeks. 

Dermal 

Short-Term

(1 - 30 days), intermediate-Term (1-6 months) and Long-Term (>6moths)
NOAEL = 31 mg/kg/day	LOC for MOE = 100

Residential

LOC for MOE = 100

Occupational	Chronic 2-year feeding study in dogs 

LOAEL = 94 mg/kg/day based on decreased erythrocyte, hemoglobin and
hematocrit at 4 weeks.

Inhalation 

Short-Term

(1 - 30 days), Intermediate-Term (1-6 months) and Log-Term (>6 months)
NOAEL = 31 mg/kg/day	LOC for MOE = 100

Residential

LOC for MOE = 100

Occupational	Chronic 2-year feeding study in dogs 

LOAEL = 94 mg/kg/day based on decreased erythrocyte, hemoglobin and
hematocrit at 4 weeks.

Cancer (oral, dermal, inhalation)	Classification: Chlorflurenol methyl
ester is unlikely to be a human carcinogen

UF = uncertainty factor, FQPA SF = Any additional safety factor retained
due to concerns unique to the FQPA, NOAEL = no observed adverse effect
level, LOAEL = lowest observed adverse effect level, PAD = population
adjusted dose (a = acute, c = chronic) RfD = reference dose, MOE =
margin of exposure, LOC = level of concern, NA = not applicable

4.0	Public Health and Pesticide Epidemiology Data    TC \l1 "4.0	Public
Health and Pesticide Epidemiology Data 

	Incidence reports /epidemiology data are not available at this time. 
However, given the minimal nature of acute toxicity (Toxicity Categories
III for eye and IV for other acute studies, large numbers of incidence
are not expected.

5.0	Dietary Exposure/Risk Characterization    TC \l1 "5.0	Dietary
Exposure/Risk Characterization 

	Chlorflurenol methyl ester is a nonfood use pesticide having no
tolerances to reassess.  Consequently, there are no residue chemistry
data requirements and thus, dietary exposure or risk assessments are not
applicable.  Chlorflurenol methyl ester is used on pineapple after fruit
harvest to stimulate production of vegetative planting material (slips).
 The time between pesticide treatment and the first harvest of pineapple
fruit would be 1.5 to 2 years.  No residues are expected in the fruit
according to a HED Greyberad Committee decision in 1995 [TXR# 012504]. 
HED upholds this decision in this RED chapter. 

5.1	Drinking Water Residue Profile TC \l3 "5.1.9	Drinking Water Residue
Profile 

	It should be noted that drinking water exposure to chlorflurenol methyl
ester is very limited.  Due to the limited number of pound per year
used, this water contamination is likely limited to use areas only.  It
follows that expanded use, would result in additional contamination.

	Chronic drinking water exposure were modeled by DEEM software using
surface water concentration, which showed all groups were exposed to
levels below the chronic oral endpoint of 0.1 mg/kg/day.  Non-nursing
infants and all infants (< one year) were exposed to highest percentage
of the RfD at 20% and 16 % respectively.  All other groups were exposed
to drinking water at 7.4% to 4.7% of the oral chronic RfD of 0.1
mg/kg/day.  These levels are below EPA LOC.  Selected levels for the
highest exposure within a group are given in Table 7a  

	However, it should be noted that toddlers exposed to spray and granular
treated lawns are above HED’s LOC.  Any additional exposure from water
would exacerbate this concern.  

Table 7a Selected population exposures (selected for highest surface
water exposures within a group) 

Population subgroup	Mg/kg/day a	Margin of exposure	% of the endpoint of
0.10 mg/kg/day

US population (summer season)	0.005343	5,802	5.3%

Western region	0.005699	5,439	5.7%

Hispanics	0.005646	5,490	5.6%

Non-hispanic blacks	0.004722	6,565	4.7%

Non-hispanic/non-white/non-black	0.006098	5084	6.1%

All infants (1<year)]	0.016308	1,901	16.3%

Nursing infants	0.006049	5,125	6.0%

Non-nursing infants 	0.020201	1,535	20.2%

Females 20+ (not pregnant or nursing)	0.004965	6.243	5.0%

Females 13-50 years	0.004812	6,442	4.8%

Females 13+ nursing	0.006891	4,498	6.9%

Males 20+ yrs	0.004457	6,955	4.5%

Seniors 55+	0.004883	6,348	4.9%

Children 1-2 years	0.007387	4.197	7.4%

Children 3-5 years	0.006915	4,483	6.9%

Children 6-12 years	0.004770	6,499	4.8%

Youths 13-19 yrs	0.003596	8,622	3.6%

a   For drinking water, Deem software was modeled using surface water
concentration at 236 ppb.

	Chronic drinking water exposures were also modeled by DEEM software
using estimated ground water concentration, where only two groups were
exposed to levels above the LOC.  Non-nursing infants and all infants (<
one year) were exposed to highest percentage of the RfD at 176% and 142%
respectively.  All other groups were exposed to drinking water at 31% to
60% of the oral chronic RfD of 0.1 mg/kg/day.  The 176% and 142%  are
above  OPP’s LOC.  Selected levels for the highest exposure within a
group are given in Table 7b   

Table 7b Selected population exposures (selected for highest ground
water exposures within a group)

Population subgroup	Mg/kg/day a	% of the endpoint of 0.10 mg/kg/day

US population (summer season)	0.046414	46.2%

Western region	0.049506	49.5%

Hispanics	0.049046	49.0%

Non-hispanic blacks	0.041015	41.0%

Non-hispanic/non-white/non-black	0.052870	53.0%

All infants (1<year)]	0.141662	141.7%

Nursing infants	0.052540	52.5%

Non-nursing infants 	0.175478	175.5%

Females 20+ (not pregnant or nursing)	0.043131	43.1%

Females 13-50 years	0.041801	41.8%

Females 13+ nursing	0.059862	59.9%

Males 20+ yrs	0.038717	38.7%

Seniors 55+	0.042420	42.4%

Children 1-2 years	0.064165	64.2%

Children 3-5 years	0.060069	60.1%

Children 6-12 years	0.041432	41.4%

Youths 13-19 yrs	0.031233	31.2%

For drinking water, Deem software was modeled using ground water
concentration at 2050 ppb.

	Potential drinking water residues were estimated for groundwater from
Tier I SCIGROW and surface water from Tier II PRZM and EXAMS models. 
The environmental fate information is incomplete.  Due to this
incomplete information, conservative default values have been
substituted for missing data in order to proceed with this assessment. 
The OPP/EFED Florida turf scenario was selected for this assessment as a
worst case based on the available usage and environmental fate
information.  It is likely that a more complete database for this
chemical would lead to reduced estimates of chlorflurenol methyl ester
concentrations in drinking water.  For this assessment, it was assumed
that 8 applications of chlorflurenol methyl ester were applied to turf
grass at a rate of 3.0 pounds active ingredient per acre with a 28 day
interval between applications and the pesticide is stable in the
environment.  The acute and chronic groundwater concentration of 2050
ppb is the highest estimated values.  This would represent a maximum
concentration in a shallow, private well in a high usage area.  Surface
water concentrations are for acute concentration: 386 ppb; for chronic
non-cancer: 236 ppb and for ground water concentration 2050 pbb. [Table
8].

Table 8  	Summary of Estimated Surface Water and Groundwater
Concentrations for [Chemical].

	[Chemical]

	Surface Water Conc., ppb a	Groundwater Conc., ppb b

Acute	386	2050

Chronic (non-cancer)	236	2050

a From the Tier II PRZM-EXAMS – Index Reservoir model.  Input
parameters are based on OPP/EFED Florida Turf scenario.

b From the SCI-GROW model assuming a maximum seasonal use rate of 3 lb
a.i./A, 8 applications/year spaced at 28 day intervals; a Koc of  65
L/mg and stable ½ life. 

5.2	Food Residue Profile  TC \l3 "5.1.10	Food Residue Profile 

	There are no residues in food.

6.0	Residential Exposure and Risks 

		Chlorflurenol methyl ester is an herbicide, plant growth retardant,
and plant growth regulator that is used in agricultural, commercial, and
residential settings.  As an herbicide and/or plant growth retardant,
chlorflurenol is used for the postemergent control of annual grasses,
broadleaf weeds, trees, shrubs, and vines. As a plant growth regulator,
chlorflurenol is used in the production of pineapple planting material
(sliplets). Chlorflurenol is registered as emulsifiable concentrate and
granular formulations. The emulsifiable concentrate formulations are
applied using groundboom sprayer, rights-of-way sprayer, handgun
sprayer, low pressure handwand sprayer, and airblast sprayer. Granular
formulations are applied using a bellygrinder, push-type spreader, and
tractor-drawn spreader.  

Hazard Concerns

  SEQ CHAPTER \h \r 1 Adverse effects were identified at durations of
exposure ranging from short-term (up to 30 days) to long-term (> 6
months).  The short- and intermediate-term dermal, inhalation, and
incidental oral endpoints are based on a NOAEL of 31 mg/kg/day from a
chronic 2-year feeding study in dogs where the LOAEL is 94 mg/kg/day. 
The LOAEL is based on decreased erythrocyte, hemoglobin and hematocrit
at 4 weeks. Long-term exposures to chlorflurenol (i.e., greater than 6
months) are not expected for current registered uses.  Additionally, no
cancer endpoint was identified; therefore cancer risks are not assessed.

	HED’s level of concern (LOC) for chlorflurenol methyl ester
occupational and residential dermal and inhalation exposures is 100
(i.e., a margin of exposure (MOE) less than 100 exceeds HED’s level of
concern).  The dermal and inhalation margins of exposure were combined
for the occupational and residential handler risk assessments because
the toxicity endpoints for the dermal and inhalation routes of exposure
are based on the same toxicological effects.  For incidental oral
exposures, HED’s level of concern is 300 (i.e., a margin of exposure
(MOE) less than 300 exceeds HED’s level of concern). The dermal and
incidental oral ingestion margins of exposure for the residential
postapplication risk assessments for toddlers were also combined because
the toxicity endpoints for the dermal and oral routes of exposure are
based on the same toxicological effects.  

6.1	Residential Handler Exposures and Non-cancer Risk Estimates

	

It has been determined there is a potential for exposure in residential
settings during the application process for homeowners who use granular
products containing chlorflurenol.  There is also a potential for
exposure from entering chlorflurenol-treated areas, such as lawns and
golf courses.  Risk assessments have been completed for both residential
handler and postapplication scenarios.

	

	In addition to homeowner uses in residential settings, chlorflurenol
products are labeled for weed control at residential settings, which is
applied by occupational applicators, but may result in postapplication
exposures in residential settings.  These potential postapplication
exposures to homeowners also have been considered in this assessment.

6.1.1	Residential Handler Exposures and Risks  tc "3.1	Residential
Handler Exposures and Risks " \l 2 

	HED uses the term “handlers” to describe those individuals who are
involved in the pesticide application process.  HED believes that there
are distinct tasks related to applications and that exposures can vary
depending on the specifics of each task as was described under
occupational handlers.

	

6.1.2	Handler Exposure Scenarios  tc "3.1.1	Handler Exposure Scenarios "
\l 3 

	Scenarios are used to define risks based on the U.S. EPA Guidelines for
Exposure Assessment (U.S. EPA; Federal Register Volume 57, Number 104;
May 29, 1992).  Assessing exposures and risks resulting from residential
uses is very similar to assessing occupational exposures and risks, with
the following exceptions:

Residential handler exposure scenarios are considered to be short-term
only, due to the infrequent use patterns associated with homeowner
products.

A tiered approach for personal protection using increasing levels of PPE
is not used in residential handler risk assessments.  Homeowner handler
assessments are based on the assumption that individuals are wearing
shorts, short-sleeved shirts, socks, and shoes.

Homeowner handlers are expected to complete all tasks associated with
the use of a pesticide product including mixing/loading if needed as
well as the application.

Label use-rates and use-information specific to residential products
serve as the basis for the risk calculations.

Area/volumes of spray or chemical used in the risk assessment are based
on HED’s guidance specific to residential use-patterns.

	HED has determined that there is potential exposure to residential
mixer, loader, and applicators during the usual use-patterns associated
with chlorflurenol.  Based on the use patterns, two major residential
exposures were identified.

	Mixers/Loaders/Applicators

	(1) Mixing/loading/applying granular with push-type spreader (ORETF);
and

	(2) Mixing/loading/applying gra  nular with a belly grinder (PHED).

6.1.3	Data and Assumptions for Handler Exposure Scenarios  tc "3.1.2
Data and Assumptions For Handler Exposure Scenarios " \l 3 

	A series of assumptions and exposure factors served as the basis for
completing the residential handler risk assessments.  Each assumption
and factor is detailed below. In addition to these factors, unit
exposure values were used to calculate risk estimates.  These unit
exposure values were taken from the Outdoor Residential Exposure Task
Force (ORETF) studies.  Both PHED and ORETF studies are presented below.

	Assumptions and Factors:  The assumptions and factors used in the risk
calculations include:

Exposure factors used to calculate daily exposures to handlers were
based on applicable data, if available.  When appropriate data is
unavailable, values from a scenario deemed similar might be used. 

HED always considers the maximum application rates allowed by labels in
its risk assessments.  If additional information such as average or
typical rates is available, these values also may be used to allow risk
managers to make a more informed risk management decision. 
Average/typical application rates were not available for residential
scenarios.

Residential risk assessments are based on estimates of what homeowners
would typically treat, such as the size of a lawn or the size of a
garden.  The factors used for the chlorflurenol assessment were from the
Health Effects Division Science Advisory Committee Policy 12:
Recommended Revisions to the Standard Operating Procedures for
Residential Exposure Assessment which was completed on February 22,
2001, and on professional judgment.  The daily volumes handled and area
treated used in each residential scenario are provided in Table 2 of
that policy recommendation.  

Residential Handler Exposure Studies:  The unit exposure values that
were used in this assessment were based on the Outdoor Residential
Exposure Task Force studies and the Pesticide Handler Exposure Database
(PHED, Version 1.1 August 1998).  The ORETF data used in the residential
assessment is described below.

ORETF Handler Studies -- OMA001-OMA004 (MRID 449722-01)

A report was submitted by the ORETF (Outdoor Residential Exposure Task
Force) that

presented data in which the application of various products used on turf
by homeowners and lawncare operators (LCOs) was monitored.  All of the
data submitted in this report were completed in a series of studies.

OMA003: Homeowner Granular Applications with a Rotary (Push-type)
Spreader tc "OMA003\: Homeowner Granular Applications with a Rotary
(Push-type) Spreader"  (MRID 449722-01): A mixer/loader/applicator study
was performed by the Outdoor Residential Exposure Task Force (ORETF)
using Dacthal (active ingredient DCPA, dimethyl
tetrachloroterephthalate) as a surrogate compound to determine
“generic” exposures of individuals applying a granular pesticide
formulation to residential lawns.  A total of 30 volunteers were
monitored using passive dosimetry (inner and outer whole body
dosimeters, hand washes, face/neck wipes, and personal inhalation
monitors).  Each volunteer carried, loaded, and applied two 25-lb bags
of fertilizer (0.89% active ingredient) with a rotary type spreader to a
lawn covering 10,000 ft2.  The target application rate was 2 lb
a.i./acre (actual rate achieved was about 1.9 lbs a.i./acre).   The
average application time was 22 minutes, including loading the rotary
push spreader and disposing of the empty bags.  Each replicate handled
approximately 0.45 lbs a.i.  Dermal exposure was measured using inner
and outer whole body dosimeters, hand washes, face/neck washes, and
personal air monitoring devices with OVS tubes. The results for the
rotary (push-type) spreader are summarized in Table 9 below.  

Table 9: Unit Exposure Values for Homeowner Granular Applications with a
Rotary (Push-type) Spreader Obtained From ORETF Study (MRID 449722-01)

Scenario Monitored	Unit Exposures

	Dermal

(mg a.i./lb handled)	Inhalation

(µg a.i./lb handled)

	Short Pants, Short Sleeves	Long Pants, Short Sleeves	Long Pants, Long
Sleeves

	Homeowner Granular Applications with a Push-type Spreader	0.67	0.09
0.07	0.88

	1 All unit exposure values are geometric means.

 	6.1.4	Residential Handler Exposure and Non-Cancer Risk Estimates  tc
"3.1.3	Residential Handler Exposure and Non-Cancer Risk Estimates " \l 3

	Non-cancer risks were calculated using the Margin of Exposure (MOE) as
described in Section 7.1.3.  Assessing exposures and risks resulting
from residential uses is very similar to assessing occupational
exposures and risks, except as described in Section 7.1.1.  The other
major difference with residential risk assessments is that the
uncertainty factor which defines the level of risk concern has the
additional FQPA safety factor applied.  In the case of chlorflurenol, it
was decided by HED that the factor for handler risk assessments is 100,
which is based on the FQPA safety factor of 1X along with the 10X for
inter-species extrapolation and 10X for intra-species sensitivity.  

	The residential exposure and risk estimates associated with the use of
chlorflurenol are presented in Table 10.  The risk calculations for
residential chlorflurenol handlers are included in Appendix D of the
June  30, 2006 Chlorflurenol Methyl Ester:  Occupational and Residential
Exposure Assessment for the RED.

Table 10:  Residential Handler Short- and Intermediate-term Dermal,
Inhalation and Total Exposure and Risks

Exposure Scenario1	Crop or Target	Application Rate	Area Treated Daily
(acres)	Baseline Unit Exposures	Baseline MOEs

(Level of Concern = 100)

Dermal (mg/lb a.i.)	Inhalation (µg/lb a.i.)	Dermal	Inhalation	Total

Mixer/Loader/Applicator

1) Mixing/loading/ applying granular with push-type spreader (ORETF OMA
003)	Turf	0.25 lb. a.i./acre

(Label - 100% DA)	0.5 acres	0.67	0.88	26,000	2,000,000	26,000

0.25 lb. a.i./acre (Label – 10% DA)

260,000	20,000,000	260,000

2) Mixing/loading/ applying with a belly grinder (PHED)	Turf	0.25 lb.
a.i./acre

(Label - 100% DA)	0.023	110	62	3,400	6,100,000	3,400

0.25 lb ai/acre (Label – 10% DA)

34,000	61,000,000	34,000

		6.1.5	Residential Handler Exposure and Risk Estimates for Cancer

	No cancer endpoints of concern for chlorflurenol were identified;
therefore cancer risks to residential handlers were not assessed. 

		6.1.6 	Summary of Risk Concerns and Data Gaps for Handlers  tc "3.1.5 
Summary of Risk Concerns and  Data Gaps for Handlers " \l 3 

	All non-cancer risks (i.e., MOEs) to handlers associated with the
scenarios are not of concern, because they exceed HED’s uncertainty
factor of 100.

		6.1.7	Recommendations for Refining Residential Handler Risk Assessment
 tc "3.1.6	Recommendations For Refining Residential Handler Risk
Assessment " \l 3 

	In order to refine this residential risk assessment, more data on
actual use patterns including rates, timing, and areas treated would
better characterize chlorflurenol risks.  Exposure studies for many
equipment types that lack data or that are not well represented in PHED
(e.g., because of low replicate numbers or data quality) should also be
considered based on the data gaps identified above and based on a review
of the quality of the data used in this assessment.  

	6.2	Residential Postapplication Exposures and Assumptions

 	 tc "3.2	Residential Postapplication Exposures and Risks " \l 2 

	HED uses the term “postapplication” to describe exposures to
individuals that occur as a result of being in an environment that has
been previously treated with a pesticide.  Chlorflurenol can be used in
many areas that can be frequented by the general population including
residential areas (e.g., home lawns and gardens).  As a result,
individuals can be exposed by entering these areas if they have been
previously treated.

	

		6.2.1	Residential Postapplication Exposure Scenarios  tc "3.2.1
Residential Postapplication Exposure Scenarios " \l 3 

	A wide array of individuals of varying ages can potentially be exposed
to chlorflurenol when they are in areas that have been previously
treated.  Postapplication exposure scenarios were developed for each
residential setting where chlorflurenol can be used.  The scenarios
likely to result in postapplication exposures are as follows: 

Dermal exposure from residue on lawns and turf (adult, youth and
toddler);

Hand-to-mouth transfer of residues on lawns (toddler);

Ingestion of pesticide treated grass (toddler); and

Incidental ingestion of soil from pesticide-treated residential areas
(toddler).

	Incidental ingestion of chlorflurenol granules from pesticide-treated
residential areas was not assessed because there an acute dietary
endpoint was not identified.

HED relies on a standardized approach for completing residential risk
assessments that is based on current labels and guidance contained in
the following four documents:

Series 875, Residential and Residential Exposure Test Guidelines: Group
B - Postapplication Exposure Monitoring Test Guidelines (V 5.4, Feb.
1998) This document provides general risk assessment guidance and
criteria for analysis of residue dissipation data.

Standard Operating Procedures for Residential Exposure Assessment (Dec.
1997) This document provides the overarching guidance for developing
residential risk assessments including scenario development, algorithms,
and values for inputs.

Science Advisory Council For Exposure Policy 12 (Feb. 2001): Recommended
Revisions To The Standard Operating Procedures (SOPs) For Residential
Exposure Assessment This document provides additional, revised guidance
for completing residential exposure assessments.

Overview of Issues Related To The Standard Operating Procedures For
Residential Exposure Assessment (August 1999 Presentation To The FIFRA
SAP) This document provides rationale for Agency changes in SOPs.

		

	When the guidance in current labels and these documents is considered,
it is clear that HED should consider children of differing ages as well
as adults in its assessments.  It is also clear that different age
groups should be considered in different situations.  The populations
that were considered in the assessment include:

Residential Adults: these individuals are members of the general
population that are exposed to chemicals by engaging in activities at
their residences (e.g., in their lawns or gardens) and also in areas not
limited to their residence (e.g., golf courses or parks) previously
treated with a pesticide.  These kinds of exposures are attributable to
a variety of activities and are usually addressed by HED in risk
assessments by considering a representative activity as the basis for
the exposure calculation.

Residential Children: children are members of the general population
that can also be exposed in their residences (e.g., on lawns and other
residential turf grass areas). These kinds of exposures are attributable
to a variety of activities such as playing outside. Toddlers have been
selected as the sentinel (representative) population for the turf
assessment. Youth-aged children (ages 10 to 12) are considered the
sentinel population for a golfing assessment, because it is likely that
children of this age would be playing golf.  Children are addressed by
HED in risk assessments by considering representative activities for
each age group in an exposure calculation.

	The SOPs for Residential Exposure Assessment defines several scenarios
that apply to uses specified in current labels.  These scenarios served
as the basis for the residential postapplication assessment along with
the modifications to them and the additional data and approaches
described above.  HED used this guidance to define the exposure
scenarios that essentially include dermal and nondietary ingestion
exposure to toddlers on treated lawns and dermal exposure to adults and
youth on treated lawns.  The SOPs and the associated scenarios are
presented below:

Dose from dermal exposure on treated turf:  Postapplication dermal dose
calculations for toddlers from playing on treated turf, for youth and
adults playing golf on treated turf, and for adults mowing and
exercising on treated turf

Dose from hand-to-mouth activity from treated turf:  Postapplication
dose calculations for toddlers from incidental nondietary ingestion of
pesticide residues on treated turf from hand-to-mouth transfer (i.e.,
those residues that are swallowed when toddlers get pesticide residues
on their hands from touching treated turf and then put their hands in
their mouth);

Dose from object-to-mouth activity from treated turf:  Postapplication
dose calculations for toddlers from incidental nondietary ingestion of
pesticide residues on treated turf from object-to-mouth transfer (i.e.,
those residues that are swallowed when toddlers put treated turf in
their mouths);

Dose from soil ingestion activity from treated turf:  Postapplication
dose calculations for toddlers from incidental nondietary ingestion of
pesticide residues from ingesting soil in a treated turf area (i.e.,
those soil residues that are swallowed when toddlers get pesticide
residues on their hands from touching treated soil and then put their
hands in their mouth); and

	

The detailed residential postapplication calculations are presented in
Appendix E of this document.



		6.2.2	Data and Assumptions for Residential Postapplication Exposure
Scenarios  tc "3.2.2	Data and Assumptions for Residential
Postapplication Exposure Scenarios " \l 3 

	Assumptions and Exposure Factors

	A series of assumptions and exposure factors served as the basis for
completing the residential postapplication risk assessments.  The
assumptions and factors used in the risk calculations are consistent
with current Agency policy for completing residential exposure
assessments (i.e., SOPs for Residential Exposure Assessment).  The
values used in this assessment include:

There are many factors that are common to the occupational and
residential postapplication risk assessments, such as body weights for
adults, and analysis of residue dissipation data.  Please refer to the
assumptions and factors in Section 7.1.2 for further information
concerning these common values.

HED combines risks resulting from exposures to individual applications
when it is likely they can occur simultaneously based on the use pattern
and the behavior associated with the exposed population.  The
toxicological endpoints used in assessing risks must have the same
toxicological effect in order for the risks to be combined.  HED has
combined risks using the aggregated risk index (ARI) for different kinds
of exposures for the following scenario: toddlers on turf – dermal
(high contact lawn activity) plus hand-to-mouth plus object-to-mouth
plus soil ingestion. 

Exposures to adults and children on treated turf have been addressed
using the latest HED  standard operating procedures for this scenario
including:

the transfer coefficients used are those presented during the 1999
Agency presentation before the FIFRA Science Advisory Panel that have
been adopted in routine practice by HED;

3 year old toddlers are expected to weigh 15 kilograms (representing an
average weight from years one to six);	

hand-to-mouth exposures are based on a frequency of 20 events/hour and a
surface area per event of 20 cm2, representing the palmar surfaces of
three fingers;

saliva extraction efficiency is 50 percent meaning that every time the
hand goes in the mouth approximately ½ of the residues on the hand are
removed;

object-to-mouth exposures are based on a 25 cm2 surface area;

ingestion rate of soil is 100 mg/day;

exposure durations for turfgrass scenarios are estimated to be 2 hours
and exposure durations for home gardening (ornamental) scenarios are
estimated to be 0.67 hours for adults and 0.33 hours for youth - based
on information in HED’s Exposure Factors Handbook;

soil residues are contained in the top centimeter and soil density is
0.67 mL/gram; and 

dermal, hand- and object-to-mouth, and soil ingestion are combined to
represent an overall risk from exposure to turf.

Postapplication residential risks are based on maximum application rates
or values specified in the SOPs for Residential Exposure Assessment.

The Jazzercize approach is the basis for the dermal transfer
coefficients as described in HED’s Series 875 guidelines, SOPs for
Residential Exposure Assessment, and the 1999 FIFRA SAP Overview
document.

		6.2.3	Residential Postapplication Exposure and Non-cancer Risk
Estimates  tc "3.2.3	Residential Postapplication Exposure and Non-cancer
Risk Estimates " \l 3 

	Non-cancer risks were calculated using the Margin of Exposure (MOE)
approach, which is a ratio of the body burden to the toxicological
endpoint of concern. Exposures were calculated by considering the
potential sources of exposure (i.e., TTRs on lawns), then calculating
dermal and nondietary ingestion exposures. 

	Dermal exposures and risks from lawn uses were calculated in the same
manner as described above in Section 7.2.3.  Along with calculating
these dermal exposures, other aspects of the turf exposure scenarios
were calculated such as the dose from nondietary ingestion.  The
algorithms used for each type of calculation are presented below which
have not been previously addressed in Section 7.2.3. 

	Nondietary Ingestion Exposure from Treated Turf:  Nondietary ingestion
exposure from treated turf was calculated using the following equations.
 These values were then used to calculate MOEs.

	Dermal Exposure from Treated Lawns (adult and toddler)

The approach used to calculate the dermal doses that are attributable to
exposure from contacting treated lawns is:

ADD = (TTR0 * ET * TC * DA * CF1) / BW

Where:	

ADD	=	average daily dose (mg/kg/day);

TTRt	=	turf transferable residue on day "0" (µg/cm2).  TTR =
application rate (µg/cm2) * fraction of a.i. retained on foliage (5%
for turf activities, 20% for gardening activities) ;

	ET	=	exposure time (2 hr/day);

 	TC	=	transfer coefficient (14,500 cm2/hr for adults and 5,200 cm2/hr
for toddlers);

	DA	=	dermal absorption factor;

CF1	=	weight unit conversion factor to convert µg units to mg for the
daily exposure (0.001 mg/µg); and

	BW	=	body weight (70 kg for adults and 15 kg for toddlers).

	Hand-to-mouth Transfer of Pesticide Residues on Lawns (toddler)

The approach used to calculate the nondietary ingestion exposures that
are attributable to hand-to-mouth behavior on treated turf is:

ADD = (TTR0 * SA * FQ * ET * SE * CF1) / BW

Where:	

ADD	=	average daily dose (mg/kg/day);

TTRt	=	turf transferable residue on day "0" (µg/cm2); TTR = application
rate (µg/cm2) * fraction of a.i. retained on foliage (5%) ;

	SA	=	surface area of the hands (20 cm2/event);

	FQ	=	frequency of hand-to-mouth activity (20 events/hr);

ET	=	exposure time (2 hr/day);

 	SE	=	extraction by saliva (50%);

CF1	=	weight unit conversion factor to convert µg units in the TTR
value to mg for the daily exposure (0.001 mg/µg); and

	BW	=	body weight (15 kg).

	Object-to-mouth Transfer of Pesticide Residues on Lawns (toddler)

The approach used to calculate doses that are attributable to
object-to-mouth behavior on treated turf that is represented by a child
mouthing on a handful of turf is:

ADD = (TTR0 * IgR* CF1) / BW

Where:	

ADD	=	average daily dose (mg/kg/day);

TTRt	=	turf transferable residue on day "0" (µg/cm2); TTR = application
rate (µg/cm2) * fraction of a.i. retained on foliage (20%)

IgR	=	ingestion rate of grass (25 cm2/day);

CF1	=	weight unit conversion factor to convert the µg of residues on
the grass to mg to provide units of mg/day (1E-3 mg/µg); and

	BW	=	body weight (15 kg).

Incidental Ingestion of Soil from Pesticide-Treated Residential Areas
(toddler)

The approach used to calculate doses that are attributable to soil
ingestion is:

ADD = (SR0 * IgR * CF1) / BW

Where:	

ADD	=	average daily dose (mg/kg/day);

SR0t	=	soil residue on day "0" (0.0022 µg/g);

IgR	=	ingestion rate of soil (100 mg/day);

CF1	=	weight unit conversion factor to convert the µg of residues on
the soil to grams to provide units of mg/day (1E-6 g/µg); and

	BW	=	body weight (15 kg).

		

And

SRt = AR * F * CF2 * CF3 * CF4

Where:

AR	=	application rate (lb a.i./acre);

F	=	fraction of a.i. available in uppermost cm of soil (1 fraction/cm)
(100%); 

CF2	=	volume to weight unit conversion factor to convert the volume
units (cm3) to weight units for the SR value (U.S. EPA, 1992) (0.67
cm3/g soil);

CF3	=	area unit conversion factor to convert the surface are units
(acres) in the application rate to cm2 (2.47E-8 acre/cm2); and

CF4	=	weight unit conversion factor to convert the lbs a.i. in the
application rate to µg (4.54E8 µg/lb).

	Non-cancer Risk Summary  tc "Non-cancer Risk Summary\: " \l 4  

	Adults

	Table 11 presents the postapplication MOE values calculated for adults
after lawn, turf and home garden applications chlorflurenol.  All
postapplication non-cancer risks were below HED’s level of concern,
except for high contact activities on residential turf assuming the 3.0
lb a.i./A (BEAD) application rates where MOEs are 44 on day 0.  

Table 11: Adult Residential Risk Estimates (Dermal) for Postapplication
Exposure

Exposure Scenario	Dermal Transfer Coefficient (µg/cm2)	Application Rate

(lb a.i./acre)	MOE at Day 0 (Level of Concern = 100)

Spray

Residential Turf (High Contact Activities)	14,500	1.0 (Label)	130

3.0 (BEAD)	44

Residential Turf (Mowing)	3,400	1.0 (Label)	570

3.0 (BEAD)	190

Golfer	500	1.0 (Label)	1,900

3.0 (BEAD)	650

Granular

Residential Turf  (High Contact Activities)	14,500	1.1 (Label – 100%
DA)	120

1.1 (Label – 10% DA)	1,200

3.0 (BEAD - 100% DA)	44

3.0 (BEAD - 10% DA)	440

Residential Turf (Mowing)	3,400	1.1 (Label – 100% DA)	520

1.1 (Label – 10% DA)	5,200

3.0 (BEAD - 100% DA)	190

3.0 (BEAD - 10% DA)	1,900

Golfer	500	1.1 (Label – 100% DA)	1,800

1.1 (Label – 10% DA)	18,000

3.0 (BEAD - 100% DA)	650

3.0 (BEAD - 10% DA)	6,500

Youths (11-12 years old)

	Table 12 summarizes the risk assessment for youths [10 to 12 years
old].  Short-term MOEs for chlorflurenol for these youths were >100 for
all scenarios considered. 

Table 12: Youth Residential Risk Estimates (Dermal) for Postapplication
Exposure

Exposure Scenario	Dermal Transfer Coefficient (µg/cm2)	Application Rate

(lb a.i./acre)	MOE at Day 0 (Level of Concern = 100)

Spray

Residential Turf (Mowing)	3,400	1.0 (Label)	320

3.0 (BEAD)	110

Golfer	500	1.0 (Label)	1,100

3.0 (BEAD)	360

Granular

Residential Turf (Mowing)	3,400	1.1 (Label- 100% DA)	290

1.1 (Label- 10% DA)	2,900

3.0 (BEAD - 100% DA)	110

3.0 (BEAD - 10% DA)	1,100

Golfer	500	1.1 (Label- 100% DA)	980

1.1 (Label- 10% DA)	9,800

3.0 (BEAD - 100% DA)	360

3.0 (BEAD - 10% DA)	3,600

	Toddler (3 year old) 



	Table 13 summarizes the risk assessment for toddlers.  The
postapplication non-cancer risks are not of concern for the oral route
(MOE’s >300).  For the dermal route, risks to toddlers from high
contact activity on lawns exceed HED’s level of concern (MOE’s <100)
at the 1.0/1.1 lb a.i./A (Label) and 3.0 lb a.i./A (BEAD) application
rates, except when 10% dermal absorption is assumed for the granular
formulations.  Calculated combined risks to toddlers (i.e., dermal high
contact activity plus hand to mouth activity plus object to mouth
activity on treated turf plus incidental soil ingestion of pesticide
residue from treated turf areas) are therefore, also of concern, except
when 10 percent dermal absorption is assumed for the granular
formulations.  

Table 13: Toddler Residential Risk Estimates for Postapplication
Exposure

Exposure Scenario	Route of Exposure	Dermal Transfer Coefficient
(µg/cm2)	Application Rate

(lb a.i./acre)	MOE at Day 0 (Level of Concern = 100 for dermal and 300
for oral)

Spray

Residential Turf  (High Contact Activities)	Dermal	5,200	1.0 (Label)	80

	3.0 (BEAD)	27

Hand to Mouth Activity on Turf	Oral	NA	1.0 (Label)	2,100

	3.0 (BEAD)	690

Object to Mouth Activity on Turf

NA	1.0	8,300

	3.0 (BEAD)	2,800

Incidental Soil Ingestion

NA	1.0	620,000

	3.0 (BEAD)	210,000

Granular

Residential Turf  (High Contact Activities)	Dermal	5,200	1.1 (Label

100% DA)	72

	1.1 (Label 10% DA)	720

	3.0 (BEAD – 100% DA)	27

	3.0 (BEAD - 10% DA)	270

Hand to Mouth Activity on Turf	Oral	NA	1.1	1,900

	3.0 (BEAD)	690

Object to Mouth Activity on Turf

NA	1.1	7,500

	3.0 (BEAD)	2,800

Incidental Soil Ingestion

NA	1.1	560,000

	3.0(BEAD)	210,000

Combined Risk Assessment for Residential Scenarios

	

	HED combines risk values resulting from separate postapplication
exposure scenarios when it is likely they can occur simultaneously based
on the use-pattern and the behavior associated with the exposed
population.  In the case of the chlorflurenol, the dermal and incidental
oral ingestion toxicological endpoints have the same toxicological
effect, therefore dermal and oral doses were combined. 

A total aggregated risk index (ARI) was used since the target MOE values
for dermal exposure (100) and incidental oral exposure (300) are
different. The target ARI is 1; therefore, ARIs of less than 1 are risks
of concern.  The combined risk index was calculated from the aggregate
risk index (ARI) as follows.

Aggregate Risk Index (ARI) = 1/(1/RIhigh contact activity) +
(1/RIhand-to-mouth) + (1/RIobject-to-mouth) + (1/RIincidental soil
ingestion)

Where:

	Risk Index (RI) = MOE/Uncertainty Factor

	Table 14 summarizes the combined risk assessment for toddlers. 
Calculated combined risks to toddlers (i.e., dermal high contact
activity, hand-to-mouth activity, object-to-mouth activity on treated
turf plus incidental soil ingestion of pesticide residue from treated
turf areas) are of concern for applications of chlorflurenol at:

1.0 lb a.i./A (label) for spray applications assuming 100% dermal
absorption (ARI = 0.70); 

1.1 lb a.i./A (label and 100% dermal absorption) for granular
applications (ARI = 0.63)

3.0 lb a.i./A (BEAD) for spray applications assuming 100% dermal
absorption (ARI = 0.23); and

3.0 lb a.i./A (BEAD) for granular applications assuming 100% dermal
absorption (ARI = 0.23.

	The ARIs are greater than 1 for the 1.1 and 3.0 lb a.i./A (label and
BEAD respectively) for granular applications if 10% dermal absorption is
assumed.  The ARI for the 1.1 lb a.i./A scenario is 3 and the ARI for
the 3 lb a.i./A scenario is 1.1.

Table 14: Residential Scenarios for Short-Term Risk Estimates - Toddlers

Postapplication Exposure Scenario	Risk Index (RI)	Combined Risk Index
(ARI)

Toddler	Turf - Spray Application

(1.0 lb a.i./acre - Label)	Dermal – High Contact Activity	0.80

	0.70

Hand to Mouth	6.9

	Object to Mouth	27

	Incidental Soil Ingestion	2100

Turf - Spray Application

(3.0 lb a.i./acre – BEAD)	Dermal – High Contact Activity	0.27	0.23

Hand to Mouth	2.3

	Object to Mouth	9.2

	Incidental Soil Ingestion	688

Turf – Granular Application

(1.1 lb a.i./acre – Label - 100% DA)	Dermal – High Contact Activity
0.72	0.63

Hand to Mouth	6.3

	Object to Mouth	25

	Incidental Soil Ingestion	1800

Turf – Granular Application

(1.1 lb a.i./acre – Label - 10% DA)	Dermal – High Contact Activity
7.3	3

Hand to Mouth	6.3

	Object to Mouth	25

	Incidental Soil Ingestion	1800

Turf – Granular Application

(3.0 lb a.i./ acre – BEAD - 100% DA)	Dermal – High Contact Activity
0.27	0.23

Hand to Mouth	2.3

	Object to Mouth	9.2

	Incidental Soil Ingestion	688

Turf – Granular Application

(3.0 lb a.i./acre – BEAD - 10% DA)	Dermal – High Contact Activity
2.7	1.1

Hand to Mouth	2.3

	Object to Mouth	9.2

	Incidental Soil Ingestion	688

	

		6.2.4	Residential Postapplication Exposure and Risk Estimates for
Cancer

	Residential postapplication cancer risks were not assessed for
chlorflurenol because no cancer endpoints of concern were identified.  

		6.2.5	Summary of Residential Postapplication Risk Concerns and Data
Gaps    tc "3.2.5	Summary of Residential Postapplication Risk Concerns
and Data Gaps " \l 3 

	HED considered a number of exposure scenarios for products that can be
used in the residential environment representing different segments of
the population including toddlers, youth-aged children, and adults. 
Short-term non-cancer MOEs were calculated for all scenarios.  Cancer
risks were not calculated, since no toxicological endpoint for cancer
was selected.  In residential settings, HED does not use
restricted-entry intervals or other mitigation approaches to limit
postapplication exposures, because they are viewed as impractical and
not enforceable.  As such, risk estimates on the day of application are
the key concern.  

For the adult populations, all postapplication non-cancer risks were
below HED’s level of concern, except for the 3.0 lb a.i./A (BEAD)
application rate where MOEs are 44 on day 0.  For the youth populations,
all postapplication non-cancer risks were below HED’s level of
concern.  For toddlers, postapplication non-cancer risks are not of
concern for the oral route.  For the dermal route, risks to toddlers
from high contact activity on lawns exceed HED’s level of concern at
the 1.0/1.1 lb a.i./A (Label) and 3.0 lb a.i./A (BEAD) application
rates, except when 10% dermal absorption is assumed for the granular
formulations.  Calculated aggregated risks to toddlers (i.e., dermal
high contact activity plus hand to mouth activity plus object to mouth
activity on treated turf plus incidental soil ingestion of pesticide
residue from treated turf areas) are therefore, also of concern, except
when 10 percent dermal absorption is assumed for the granular
formulations.  

		6.2.6	Recommendations for Refining Residential Postapplication Risk
Assessments    tc "3.2.6	Recommendations For Refining Residential
Postapplication Risk Assessments " \l 3 

	In order to refine this residential assessment, data on actual use
patterns including rates, timing, and the kinds of tasks performed are
required to better characterize chlorflurenol risks. 

6.3	Residential Risk Characterization    tc "3.3	Residential Risk
Characterization " \l 2 

	Characterization of the residential risks included in this document
must consider each of the approaches used to calculate risks as well as
the information that could be forthcoming in any probabilistic
assessment that is submitted for chlorflurenol methyl ester. 

		6.3.1	Characterization of Residential Handler Risks

   tc "3.3.1  Characterization Of Residential Handler Risks " \l 3 

	The data that were used in the chlorflurenol residential handler
assessment represent the best data and approaches that are currently
available.  The inputs for application rate and other use/usage
information (e.g., area treated and frequency of use) used by the Agency
were supported by the proposed chlorflurenol labels.  There are also
many uncertainties in the assessment that are common with the
occupational assessment as well.  These factors and their impacts on the
results should be considered as well in the interpretation of the
results for residential handlers.  Section 2.3.1 provides a summary of
these issues.  

	In summary, with respect to residential handler risks, the Agency
believes that the values presented in this assessment represent the
highest quality results that could be produced given the exposure, use,
and toxicology data that are available. 

		6.3.2	Characterization of Residential Postapplication Risks    tc
"3.3.2  Characterization Of Residential Postapplication Risks " \l 3 

	The general population can be exposed through many different pathways
that result from uses on lawns and from indoor surface treatments.  To
represent the wide array of possible exposures, the Agency relies on the
scenarios that have been defined in the SOPs for Residential Exposure
Assessment and accompanying documents such as the overview presented to
the FIFRA Science Advisory Panel.  For turf uses, the Agency considered
only toddlers (3 year olds) in the assessments.  Toddler MOEs were
calculated for nondietary ingestion (hand-/object-to-mouth, soil
ingestion and granules ingestion).  MOEs from treated indoor surfaces
were also evaluated for toddlers for whom exposures may occur from
hand-to-mouth behavior. 

	The data that were used in the chlorflurenol residential
postapplication assessment represent the best data and approaches that
are currently available.  To the extent possible, the Agency has
attempted to use chlorflurenol methyl ester specific data.  When
chemical-specific data were unavailable, the Agency used the current
approaches for residential assessment, many of which include recent
upgrades to the SOPs.  For example, for the toddler hand-to-mouth
calculations, no TTR data were available but a 5 percent transferability
factor was applied to calculate residue levels appropriate for this
exposure pathway.

	Finally, the Agency believes that the values presented in this
assessment represent the highest quality results that could be produced
based on the currently available postapplication exposure data.  The
Agency believes that the risks represent reasonable worse-case estimates
of exposure because maximum application rates are used to define residue
levels upon which the calculations are based. 

7.0	OCCUPATIONAL EXPOSURE AND RISKS

	7.1	Occupational Handler Exposures and Risk Estimates

	HED uses the term “handlers” to describe those individuals who are
involved in the pesticide application process.  HED believes that there
are distinct job functions or tasks related to applications and that
exposures can vary depending on the specifics of each task.  Job
requirements (e.g., amount of chemical to be used in an application),
the kinds of equipment used, the target being treated, and the level of
protection used by a handler can cause exposure levels to differ in a
manner specific to each application event. 

	HED uses exposure scenarios to describe the various types of handler
exposures that may occur for a specific active ingredient. The use of
scenarios as a basis for exposure assessment is very common as described
in the U.S. EPA Guidelines for Exposure Assessment (U.S. EPA; Federal
Register Volume 57, Number 104; May 29, 1992).  Information from the
current labels, use and usage information, toxicology data, and exposure
data were all key components in the development of the exposure
scenarios.  HED has developed a series of general descriptions for tasks
that are associated with pesticide applications.  Tasks associated with
occupational pesticide handlers are categorized using one of the
following terms:

●	Mixers and/or Loaders:  these individuals perform tasks in
preparation for an application.  For example, prior to application,
mixer/loaders would mix the chemical and load it into the holding tank
of the airplane or groundboom... 

●	Applicators: these individuals operate application equipment during
the release of a pesticide product into the environment.  These
individuals can make applications using equipment such as airplanes or
groundboom.

●	Mixer/Loader/Applicators and or Loader/Applicators: these
individuals are involved in the entire pesticide application process
(i.e., they do all job functions related to a pesticide application
event).  These individuals would transfer the chemical into the
application equipment and then also apply it.

  SEQ CHAPTER \h \r 1 A chemical can produce different effects based on
how long a person is exposed, how frequently exposures occur, and the
level of exposure.  HED classifies exposures up to 30 days as short-term
and exposures greater than 30 days up to several months as
intermediate-term.  HED completes both short- and intermediate-term
assessments for occupational scenarios in essentially all cases, because
these kinds of exposures are likely and acceptable use/usage data are
not available to justify deleting intermediate-term scenarios. Based on
use data and label instructions, HED believes that occupational
chlorflurenol exposures may occur over a single day or up to weeks at a
time for many use-patterns and that intermittent exposures over several
weeks also may occur.  Some applicators may apply chlorflurenol over a
period of weeks, because they are custom or commercial applicators who
are completing a number of applications for a number of different
clients. Long-term handler exposures are not expected to occur for
chlorflurenol.

	Other parameters are also defined from use and usage data such as
application rates and application frequency.  HED always completes
non-cancer risk assessments using maximum application rates for each in
order to ensure there are no concerns for each specific use.

  

	Occupational handler exposure assessments are completed by HED using
different levels of risk mitigation.  Typically, HED uses a tiered
approach.  The lowest tier is designated as the baseline exposure
scenario (i.e., long-sleeve shirt, long pants, shoes, socks, and no
respirator).  If risks are of concern at baseline attire, then
increasing levels of personal protective equipment or PPE (e.g., gloves,
double-layer body protection, and respirators) are evaluated.  If risks
remain a concern with maximum PPE, then engineering controls (e.g.,
enclosed cabs or cockpits, water-soluble packaging, and closed
mixing/loading systems) are evaluated.  This approach is used to ensure
that the lowest level of risk mitigation that provides adequate
protection is selected, since the addition of PPE and engineering
controls involves an additional expense to the user and – in the case
of PPE – also involves an additional burden to the user due to
decreased comfort and dexterity and increased heat stress and
respiratory stress.

		7.1.1	Data and Assumptions for Handler Exposure Scenarios

 tc "2.1.1	Data and Assumptions For Handler Exposure Scenarios " \l 3 

		7.1.1.1	Assumptions for Handler Exposure Scenarios tc "2.1.1.1
Assumptions for Handler Exposure Scenarios " \l 4 

	A series of assumptions and exposure factors served as the basis for
completing the occupational handler risk assessments.  Each assumption
and factor is detailed below on an individual basis. The assumptions and
factors used in the risk calculations include:  

Occupational handler exposure estimates were based on surrogate data
from: (1) the Pesticide Handlers Exposure Database (PHED) and (2) the
Outdoor Residential Exposure Task Force (ORETF).

●	The toxicological endpoint of concern for dermal and inhalation
risks are from studies where the effects were observed in males and
females, therefore, the average body weight of an adult male handler
(i.e., 70 kg) is used to complete the handler dermal and inhalation
non-cancer risk assessment.

●	 The dermal absorption for liquid concentrate formulations was
assumed to be 100 percent, since no dermal absorption data are
available.  Certain solvents in liquid formulations can result in a high
percent of dermal absorption.  The dermal absorption for granular
formulation was assessed assuming both 100 percent and 10 percent, since
although there are no dermal absorption data available, it is rare for
dermal absorption of a granular formulation to exceed 10 percent.

●	Generic protection factors (PFs) were used to calculate exposures
when data were not available.  For example, a 50 percent protection
factor was assumed for the use of a double layer body protection. 

●	  For non-cancer assessments, HED assumes the maximum application
rates allowed by the master labels in its risk assessments (see Tables
1a, 1b, 1c and 2). 

●	The average occupational workday is assumed to be 8 hours.  

	The daily areas treated were defined for each handler scenario (in
appropriate units) by determining the amount that can be reasonably
treated in a single day (e.g., acres, square feet, or gallons per day). 
When possible, the assumptions for daily areas treated are taken from
the Health Effects Division Science Advisory Committee on Exposure SOP
#9: Standard Values for Daily Acres Treated in Agriculture, which was
completed on July 5, 2000.  However, no standard values are available
for numerous scenarios.  Assumptions for these scenarios are based on
HED estimates and could be further refined from input from affected
sectors (see Tables 1a, 1b, and 1c)

7.1.1.2	Exposure Data for Handler Exposure Scenarios

	HED uses unit exposure to assess handler exposures to pesticides.  Unit
exposures are estimates of the amount of exposure to an active
ingredient a handler receives while performing various handler tasks and
are expressed in terms of micrograms or milligrams of active ingredient
per pound of active ingredient handled.  HED has developed a series of
unit exposures that are unique for each scenario typically considered in
our assessments (i.e., there are different unit exposures for different
types of application equipment, job functions, and levels of
protection).  The unit exposure concept has been established in the
scientific literature and also through various exposure monitoring
guidelines published by the U.S. EPA and international organizations
such as Health Canada and OECD (Organization for Economic Cooperation
and Development).  Unit exposures were based on surrogate data from PHED
and ORETF, which are described below.

	Pesticide Handler Exposure Database (PHED) Version 1.1 (August 1998):
PHED was designed by a task force of representatives from the U.S. EPA,
Health Canada, the California Department of Pesticide regulation, and
member companies of the American Crop Protection Association.  PHED is a
software system consisting of two parts – a database of measured
exposures for workers involved in the handling of pesticides under
actual field conditions and a set of computer algorithms used to subset
and statistically summarize the selected data.  Currently, the database
contains values for over 1,700 monitored individuals (i.e., replicates).

	Users select criteria to subset the PHED database to reflect the
exposure scenario being evaluated.   The subsetting algorithms in PHED
are based on the central assumption that the magnitude of handler
exposures to pesticides are primarily a function of activity (e.g.,
mixing/loading, applying), formulation type (e.g., liquids, granulars),
application method (e.g., aerial, groundboom), and clothing scenarios
(e.g., gloves, double layer clothing).

	Once the data for a given exposure scenario have been selected, the
data are normalized (i.e., divided by) by the amount of pesticide
handled resulting in standard unit exposures (milligrams of exposure per
pound of active ingredient handled).  Following normalization, the data
are statistically summarized.  The distribution of exposure for each
body part (e.g., chest, upper arm) is categorized as normal, lognormal,
or “other” (i.e., neither normal nor lognormal).  A central tendency
value is then selected from the distribution of the exposure for each
body part.  These values are the arithmetic mean for normal
distributions, the geometric mean for lognormal distributions, and the
median for all “other” distributions.  Once selected, the central
tendency values for each body part are composited into a “best fit”
exposure value representing the entire body. 

	The unit exposures calculated by PHED generally range from the
geometric mean to the median of the selected data set.  To add
consistency and quality control to the values produced from this system,
the PHED Task Force has evaluated all data within the system and has
developed a set of grading criteria to characterize the quality of the
original study data.  The assessment of data quality is based on the
number of observations and the available quality control data. These
evaluation criteria and the caveats specific to each exposure scenario
are summarized in Appendix A, Table A1 of the June 30, 2006
Chlorflurenol Occupational and Residential Exposure RED.  While data
from PHED provide the best available information on handler exposures,
it should be noted that some aspects of the included studies (e.g.,
duration, acres treated, pounds of active ingredient handled) may not
accurately represent labeled uses in all cases.  HED has developed a
series of tables of standard unit exposure for many occupational
scenarios that can be utilized to ensure consistency in exposure
assessments.  Unit exposures are used which represent different levels
of personal protection as described above.  Protection factors were used
to calculate unit exposures for varying levels of personal protection if
data were not available.

	ORETF Handler Studies (MRID 449722-01):  A report was submitted by the
ORETF (Outdoor Residential Exposure Task Force) that presented data in
which the application of various products used on turf by homeowners and
lawncare operators (LCOs) was monitored.  All of the data submitted in
this report were completed in a series of studies.  The studies relevant
to the scenarios used for the chlorflurenol assessment are described
below and are summarized in Appendix A, Table A1 in the June 30, 2006,
Chlorflurenol Occupational and Residential Exposure Assessment for the
RED .

  SEQ CHAPTER \h \r 1 OMA001: LCO Granular Applications with a Rotary
Spreader (MRID 449722-01):  A loader/applicator study was performed by
the Outdoor Residential Exposure Task Force (ORETF) using Dacthal
(active ingredient DCPA, dimethyl tetrachloroterephthalate) as a
surrogate compound to determine “generic” exposures of lawn care
operators (LCOs) applying a granular pesticide formulation to
residential lawns. Surrogate chemicals were chosen by the Task Force for
their representativeness based on physical chemical properties and other
factors.  Dacthal, which was the surrogate chemical used for the
granular spreader studies, has a molecular weight of 331.97 and a vapor
pressure of 1.6 x 10-6, and is believed to be an appropriate surrogate
for many relatively nonvolatile pesticides. 

	The study was designed to simulate a typical work day for a LCO
applying granular pesticide formulation to home lawns.  Each LCO
replicate involved loading and applying approximately 3.3 lb a.i. (360
lb formulated product) over a period of about 4 hours to 15 simulated
residential lawns (6480 ft2 each) with a rotary type spreader.  The
average industry application rate of 2 lb a.i./acre was simulated
(actual rate achieved was about 1.9 lb a.i./acre).  The monitoring
period included driving, placing the spreader onto and off of the truck,
carrying and loading the formulation in the spreader, and the actual
application.  Incidental activities such as repairs, cleaning up spills,
and disposing of empty bags were monitored.  A total of 40 replicates
(individual application events) were monitored using passive dosimetry
(inner and outer whole body dosimeters, hand washes, face/neck wipes,
and personal inhalation monitors with OVS tubes).  The inner samples
represent a single layer of clothing.  Inhalation exposure was
calculated using an assumed respiratory rate of 17 Lpm for light work
(NAFTA, 1999), the actual sampling time for each individual, and the
pump flow rate.  In 20 of the replicates, the subjects wore
chemical-resistant gloves while in the remaining replicates, no gloves
were worn.  No gloves were worn in any replicate while driving.  

	All results were normalized for the amount of active ingredient
handled.  Nearly all samples (for every body part and for inhalation)
were above the level of quantitation (LOQ) for dacthal.  Where results
were less than the reported LOQ, ½ LOQ value was used for calculations,
and no recovery corrections were applied.  The overall laboratory
recoveries ranged from 83 to 101% and the field recoveries ranged from
73 to 98%.  The unit exposure values are presented in Table 15 below.
[Note the inhalation exposure value is a median because the data were
found to be neither normally nor lognormally distributed.  All dermal
values are geometric means as the data were lognormally distributed.]

Table 15: Unit Exposure Values for LCO Granular Applications with a
Rotary Spreader Obtained From ORETF Studies (MRID 449722-01)

Type	Unit Exposure1 (mg exp./lb a.i. handled)

	Dermal	Inhalation

	Single Layer,

No Gloves	Single Layer,

Gloves	Double Layer2,

Gloves

	LCO Granular Applications with a Rotary Spreader	0.35	0.22	0.11	0.0073

1 All dermal unit exposure values are geometric means. The inhalation
value is a median.  2  Double layer value calculated using a 50%
protection factor. 

OMA002:  MA002: LCO Spray Applications with a Low Pressure Handgun (MRID
449722-01):  

A mixer/loader/applicator study was performed by the Outdoor Residential
Exposure Task Force (ORETF) using Dacthal as a surrogate compound to
determine “generic” exposures to individuals applying a pesticide to
turf with a low-pressure “nozzle gun” or “handgun” sprayer. 
Dermal and inhalation exposures were estimated using whole-body passive
dosimeters and breathing-zone air samples on OVS tubes. Inhalation
exposure was calculated using an assumed respiratory rate of 17 liters
per minute for light work (NAFTA, 1999), the actual sampling time for
each individual, and the pump flow rate.   All results were normalized
for pounds active ingredient handled.   

A total of 90 replicates were monitored using 17 different subjects. 
Four different formulations of dacthal [75% wettable powder (packaged in
4 and 24 pound bags), 75% wettable powder in water soluble bags (3 pound
bag), 75% water dispersible granules (2 pound bag) and 55% liquid
flowable (2.5 gallon container)] were applied by five different LCOs to
actual residential lawns at each site in three different locations
(Ohio, Maryland, and Georgia) for a total of fifteen replicates per
formulation.  An additional ten replicates at each site were monitored
while they performed spray application only using the 75 percent
wettable powder formulation.  A target application rate of 2 pounds
active ingredient was used for all replicates (actual rate achieved was
about 2.2 pounds active ingredient per acre). Each replicate treated a
varying number of actual client lawns to attain a representative target
of 2.5 acres (1 hectare) of turf.   The exposure periods averaged five
hours twenty-one minutes, five hours thirty-nine minutes, and six hours
twenty-four minutes, in Ohio, Maryland and Georgia, respectively. 
Average time spent spraying at all sites was about two hours.  All
mixing, loading, application, adjusting, calibrating, and spill clean up
procedures were monitored, except for typical end-of-day clean-up
activities, e.g. rinsing of spray tank, etc.  Dermal exposure was
measured using inner and outer whole body dosimeters, hand washes,
face/neck washes, and personal air monitoring devices.  All test
subjects wore one-piece, 100 percent cotton inner dosimeters beneath 100
percent cotton long-sleeved shirt and long pants, rubber boots and
nitrile gloves.  Gloves are typically worn by most LCOs, and required by
many pesticide labels for mixing and loading.  

	Overall, residues were highest on the upper and lower leg portions of
the dosimeters.  In general, concurrent lab spikes produced mean
recoveries in the range of 78-120 percent, with the exception of OVS
sorbent tube sections which produced mean recoveries as low as 65.8
percent.  Adjustment for recoveries from field fortifications were
performed on each dosimeter section or sample matrix for each study
participant, using the mean recovery for the closest field spike level
for each matrix and correcting the value to 100 percent.  The unit
exposure values are presented below in Table 16.  [Note the data were
found to be lognormally distributed.  As a result, all exposure values
are geometric means.]

Table 16: Unit Exposure Values Obtained for LCO Spray Applications with
a Low Pressure Handgun from ORETF Handgun Studies (MRID 449722-01)

Application Method4	Total Dermal Unit Exposure1 (mg/lb a.i.)	Inhalation
Unit Exposure1,2 

(µg/lb a.i.)

	Single Layer, No Gloves	Single Layer, Gloves	Double Layer, Gloves 3

	LCO Handgun Spray Mixer/Loader/Applicator

Liquid Flowable	No Data	0.45	0.245	1.8

1 Unit exposure values reported are geometric means.  2 Air
concentration (mg/m3/lb a.i.) calculated using NAFTA ‘99 standard
breathing rate of 17 lpm (1 m3/hr).

3 Exposure calculated using OPP/HED 50% protection factor (PF) for
cotton coveralls on torso, arms, and legs.

4 All commercial handlers wore long pants, long-sleeved shirt, nitrile
gloves and shoes.

  SEQ CHAPTER \h \r 1 OMA005: Homeowner Liquid Applications to Fruit
Trees and Ornamental Plants with a Hose-end Sprayer and a Low Pressure
Handwand (MRID 445185-01): 

	Applications of Sevin Liquid® Carbaryl insecticide [RP-2 liquid (21%)]
were made by volunteers to two young citrus trees and two shrubs in each
replicate that was monitored in the study.  The test field was located
only in Florida.  Twenty (20) replicates were monitored using hose-end
sprayer (Ortho® DIAL or Spray® hose end sprayer), and 20 replicates
were monitored using hand held pump sprayers (low pressure handwands).

	Each replicate opened the end-use product, added it to the hose-end
sprayer or hand held pump and then applied it to the trees and shrubs. 
After application to two trees and two shrubs dosimeters were collected.
 Inhalation exposure was monitored with personal air sampling pumps with
OVS tubes attached to the shirt collar in the breathing zone.  Dermal
exposure was assessed by extraction of carbaryl from inner and outer 100
percent cotton dosimeters. The inner and outer dosimeters were segmented
into: lower and upper arms, lower and upper legs, front and back torso. 
No gloves were worn therefore hand exposure was assessed with 400 ml
handwash with 0.01 percent Aerosol OT-75 sodium dioctyl sulfosuccinate
(OTS).  One hundred percent cotton handkerchiefs wetted with 25 ml OTS
were used to wipe face and neck to determine exposure.  

	Field fortification recoveries for passive dosimeters averaged 88.3
percent for inner and 76.2 percent for outer dosimeters.  Face and neck
wipe fortifications average 82.5 percent.  Handwash and inhalation OVS
tube field fortification averaged >90 percent.  Inner and outer
dosimeter and face and neck wipe residues were adjusted for field
fortification results.  Handwash and inhalation residues were not
adjusted. 

	Laboratory method validation for each matrix fell within the acceptable
range of 70 to 120 percent.   The limit of quantitation (LOQ) was 1.0
µg/sample for all media except the inhalation monitors where the LOQ
was 0.01 µg/sample.  The limit of detection (LOD) was 0.5 µg/sample
for all media except the inhalation monitors where the LOQ was 0.005
µg/sample.

	For use in reregistration documents, the dermal exposure was calculated
by adding the values from the hand rinses, face/neck wipes to the outer
dosimeter lower legs and lower arms plus the inner dosimeter front and
rear torso, upper legs and upper arms.  This accounts for the
residential handler wearing short-sleeved shirt and short pants.  The
results for the low pressure handwand are summarized in Table 17 below. 

	

	The distribution of the unit exposure values is categorized as normal,
lognormal, or “other” (i.e., neither normal nor lognormal).  A
central tendency value is selected from the distribution of the exposure
values.  These values are the arithmetic mean for normal distributions,
the geometric mean for lognormal distributions, and the median for all
“other” distributions.   The dermal exposure had a lognormal
distribution so the geometric mean value was used to determine dermal
exposure.  The inhalation exposure had neither a normal or lognormal
distribution so the median was used to determine inhalation exposure. 

Table 17: Unit Exposure Values for Homeowner Liquid Applications to
Fruit Trees and Ornamental Plants with a Low Pressure Handwand Obtained
From ORETF Study (MRID 445185-01)

Scenario Monitored	Total Dermal Unit Exposure1 (mg/lb a.i.)	Inhalation
Unit Exposure2

(µg/lb a.i.)

	Short Pants, Short Sleeves	Long Pants, Short Sleeves	Long Pants, Long
Sleeves

	Homeowner Liquid Applications with a Hand Held Sprayer (Low Pressure
Handwand)	56	36	30	2.6

	1 Dermal unit exposure values reported are the geometric means.

	2 Inhalation unit exposure values reported are the median values.

  SEQ CHAPTER \h \r 1 OMA006: Homeowner Liquid Application to Garden
with a Dial type Sprayer, a Low Pressure Handwand and a Ready-to-use
Bottle (MRID 444598-01):    SEQ CHAPTER \h \r 1 The study was designed
to quantify dermal and inhalation exposure of homeowners as they mixed,
loaded and applied liquid formulations of a carbaryl end-use product to
home garden vegetables.  A hose end sprayer and a hand held pump sprayer
(low pressure handwand) were used to apply Sevin Liquid® Brand Carbaryl
Insecticide.  A ready-to-use sprayer was used to apply Sevin® Ready to
Use Insect Spray. For each application method, twenty replicates were
conducted with gloves and 20 replicates were conducted without gloves.
Inhalation exposure was monitored using personal air samplers (average
flow rate of 1.5 liter/minute) and dermal exposure was monitored by
using inner and outer dosimeters, facial/neck wipes, and hand washes. 
The overall mean field fortification recovery of each matrix ranged from
77.6 ± 13.6% (outer dosimeters) to 98.4 ± 3.8% (OVS tubes). Laboratory
fortified recovery samples were analyzed with each set of samples
analyzed on a particular day; however, the results of the laboratory
recoveries were not provided in the Study Report. The results for the
low pressure handwand are summarized in Table 18 below.  



  SEQ CHAPTER \h \r 1 Table 18.  Unit Exposure Values for Homeowner
Liquid Application to Garden with a Low Pressure Handwand Obtained From
ORETF Study (MRID 444598-01)

Scenario Monitored	Total Dermal Unit Exposure1 (mg/lb a.i.)	Inhalation
Unit Exposure1

(µg/lb a.i.)

	Short Pants, Short Sleeves	Long Pants, Short Sleeves	Long Pants, Long
Sleeves

Gloves	No Gloves	Gloves	No Gloves	Gloves	No Gloves

	Homeowner Liquid Applications with a Low Pressure Handwand Sprayer	10.5
38	0.78	17	0.33	15	2.7

1 Unit exposure values reported are geometric means.

		7.1.2	Occupational Handler Exposure Scenarios  tc "2.1.2	CAMA Handler
Exposure Scenarios " \l 3 

	 It has been determined that exposure to pesticide handlers is likely
during the occupational use of chlorflurenol on agricultural crops,
non-crop areas, and on turfgrass. The anticipated use patterns and
current labeling indicate occupational exposure scenarios based on the
types of equipment and techniques that can potentially be used for
chlorflurenol applications.  The quantitative exposure/risk assessment
developed for occupational handlers is based on the following scenarios.

	Mixer/Loaders:

	(1a) Mixing/loading liquids for airblast application (PHED);

 	(1b) Mixing/loading liquids for ground application (PHED); 

(1c) Mixing/loading liquids to support LCO handgun applications (PHED);

(1d) Mixing/loading liquids for rights-of-way application (PHED); and

(2) Mixing/loading granules for tractor drawn spreader application
(PHED).  

	Applicators:

	(3) Applying sprays with airblast sprayer (PHED);

(4) Applying sprays with groundboom sprayer (PHED); 

(5) Applying sprays with a handgun sprayer (PHED);

(6) Applying sprays with rights-of-way sprayer (PHED); and

(7) Applying granules with tractor drawn spreader (PHED).

			

	Mixer/Loader/Applicators:

(8) Mixing/loading/applying liquids with low pressure handwand sprayer
(PHED);

(9) Mixing/loading/applying liquids with low pressure handwand sprayer
(ground

directed) (ORETF);

(10) Mixing/loading/applying liquids with low pressure handwand sprayer

(overhead directed) (ORETF);

	(11) Mixing/loading/applying liquids with a handgun sprayer (LCO
ORETF);

	(12) Mixing/loading/applying granules with a bellygrinder (PHED); and

	(13) Mixing/loading/applying granules with a push-type spreader (LCO
ORETF).

			

	7.1.3	Non-cancer Occupational Handler Exposure and Assessment  tc
"2.1.3	Non-cancer CAMA Handler Exposure and Assessment " \l 3 

7.1.3.1	Non-cancer Occupational Handler Exposure and Risk Calculations 
tc "2.1.3.1	Non-cancer CAMA Handler Exposure and Risk Calculations " \l
4 

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

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

Where:  

Daily Exposure		=	Amount (mg or µg a.i./day) deposited on the surface
of the skin that is available for dermal absorption or amount inhaled
that is available for inhalation absorption;

Unit Exposure 		=	Unit exposure value (mg or µg a.i./lb a.i.) derived
from August 1998 PHED data or from ORETF data;

Application Rate		=	Normalized application rate based on a logical unit
treatment, such as acres, square feet, or gallons. Maximum values are
generally used (lb a.i./A, lb a.i./sq ft, lb a.i./gal); and

	Daily Area Treated 	=	Normalized application area based on a logical
unit treatment such as acres (A/day), square feet  (sq ft/day), gallons
per day (gal/day). 

	Daily Dose:  The daily dermal or inhalation dose is calculated by
normalizing the daily exposure by body weight and adjusting, if
necessary, with an appropriate dermal or inhalation absorption factor. 
For all dermal and inhalation exposure, an average male and female body
weight of 70 kilograms was used, since the toxicological endpoint is not
sex-specific.  100% absorption was used for inhalation exposures. 
Dermal exposure was assessed assuming 100% dermal absorption for liquid
formulations and both 100% and 10% dermal absorption for granular
formulations.  Daily dose was calculated using the following formula:

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

Where:

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

Daily Exposure 			=	Amount (mg a.i./day) deposited on the surface of the
skin that is available for dermal absorption or amount inhaled that is
available for inhalation absorption;

Absorption Factor 		= 	A measure of the amount of chemical that crosses
a biological boundary such as the skin or lungs (% of the total
available absorbed); and

Body Weight 			= 	Body weight determined to represent the population of
interest in a risk assessment (kg).

	Margins of Exposure:  Non-cancer dermal and inhalation risks for each
applicable handler scenario are calculated using a Margin of Exposure
(MOE), which is a ratio of the toxicological endpoint of concern to the
daily dose.  All MOE values were calculated separately for dermal and
inhalation exposure levels using the formula below:

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

Where:

MOE 			= 	Margin of Exposure, value used by HED to represent risk or how
close a chemical exposure is to being a concern (unitless);

ADD 			= 	Average Daily Dose or the absorbed dose received from exposure
to a pesticide in a given scenario (mg pesticide active ingredient/kg
body weight/day); and

NOAEL or LOAEL	= 	Dose level in a toxicity study, where no observed
adverse effects (NOAEL) or where the lowest observed adverse effects
(LOAEL) occurred in the study

	Risk values are presented for each route of exposure (i.e., dermal or
inhalation) in each scenario, because risk mitigation measures are
specific to the route of exposure.  A total MOE was also calculated
because the dermal and inhalation toxicological endpoints of concern are
based on the same adverse effects.  The total MOE values were calculated
using the formula below:

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

			

			7.1.3.2	Occupational Non-cancer Risk Summary (using PHED and ORETF
data)  tc "2.1.3.2	CAMA Non-cancer Risk Summary (using PHED and ORETF
data) " \l 4 

	Table 19 presents the risk assessments for short and intermediate-term
dermal and inhalation exposures at baseline, with additional personal
protective equipment, and with engineering controls.  All of the risk
calculations for occupational chlorflurenol handlers completed in this
assessment are included in Appendix B of the May13, 2006 Chlorflurenol
Occupational and Residential Exposure RED..





Table  19. Occupational Handler Short-and Intermediate-term Dermal,
Inhalation and Total Exposure and Risks

Exposure Scenario	Crop or Target	App Rate	Area Treated Daily	MOEs (Level
of Concern = 100)

Dermal	Inhalation	Total

Baseline (unless indicated otherwise)	PPE-G, SL: Single layer w/gloves
PPE-G, DL: Double layer w/ gloves	Baseline (unless indicated otherwise)
Baseline Dermal + Baseline Inh. (unless indicated otherwise)	PPE-G, SL
Dermal + Baseline Inh.	PPE-G, DL Dermal + Baseline Inh.

Mixer/Loader

1a) Mixing/

Loading Liquids Concentrates for Airblast Applications (PHED)	Pineapple
1.0 lb a.i./A (Label & BEAD)	40 acres	19	2,400	3,200	45,000	19	2,200
3,000

1b) Mixing/

Loading Liquids Concentrates for Groundboom Applications (PHED)
Pineapple	1.0 lb a.i./A (Label & BEAD)	80 acres	9.4	1,200	1,600	23,000
9.3	1,100	1,500

	Turf: Golf Course	1.0 lb a.i./A (Label)	40 acres	19	2,400	3,200	45,000
19	2,200	3,000

3.0 lb a.i./A (BEAD)	40 acres	6.2	790	1,100	15,000	6.2	750	990

1c) Mixing/

Loading Liquid Concentrates to Support LCO Handgun Applications
(mixing/loading supports 20 LCOs) (PHED)

	Lawn and Ornamental Turf (including golf course)	1.0 lb a.i./A (Label)
100 acres	7.5	940	1,300	18,000	7.5	900	1,200

3.0 lb a.i./A (BEAD)	100 acres	2.5	310	430	6000	2.5	300	400

1d)  Mixing/

Loading Liquid Concentrates to Support Rights of Way (PHED)	Gymnosperms
0.0025 lb a.i./gal (Label)	1,000 gal	300	38,000	51,000	720,000	300
36,000	48,000

5 lb a.i./acre (BEAD)	80 acres	1.9	240	320	4,500	1.9	220	300

	Hardwoods, Hedges, Vines	0.01 lb a.i./gal (Label)	1,000 gal	75	9,400
13,000	180,000	75	9,000	12,000

5 lb a.i./acre (BEAD)	80 acres	1.9	240	320	4,500	1.9	220	300

	Non-agricultural rights-of-ways/fence rows and hedge rows	3.0 lb a.i./A
(Label & BEAD)	80 acres	3.1	390	530	7,500	3.1	370	500

	Turf:  growing in culverts, ROW, median strip, ditches	3.0 lb a.i./A
(Label & BEAD)	80 acres	3.1	390	530	7,500	3.1	370	500

	Shrubs, Shade Trees, and Vines	4.5 lb a.i./A (BEAD)	80 acres	2.1	260
350	5,000	2.1	250	330

	Hedges, Vines	0.01 lb a.i./gallon (Label)	80 acres	75	9,400	13,000
180,000	75	9,000	12,000

	High density Forestry Vegetation	4.0 lb a.i./A (BEAD)	80 acres	2.3	290
400	5,700	2.3	280	370

2) Mixing/ Loading Granules for Tractor Drawn Spreader Application
(PHED)	Lawns and Ornamental Turf (including golf course)

Lawns and Ornamental Turf (including golf course)	1.1 lb a.i./A

(Label -100% DA)	40 acres	5,900	7,100	15,000	29,000	4,900	5,700	9,700

1.1 lb a.i./A (Label - 10% DA)	40 acres	59,000	71,000	150,000	29,000
19,000	21,000	24,000

3.0 lb a.i./A (BEAD - 100% DA)	40 acres	2,200	2,600	5,300	11,000	1,800
2,100	3,500

3.0 lb a.i./A (BEAD - 10% DA)	40 acres	22,000	26,000	53,000	11,000	7,100
7,600	8,900

Applying

3) Applying Sprays via Airblast Equipment (PHED)	Pineapple	1.0 lb a.i./A
(Label & BEAD)	40 acres	  SEQ CHAPTER \h \r 1 150	230	250	12,000	150	220
240

4) Applying Sprays via Groundboom Equipment (PHED)	Pineapple	1.0 lb
a.i./A (Label & BEAD)	80 acres	1,900	1,900	2,500	37,000	1,800	1,800
2,300

	Turf: Golf Course	1.0 lb a.i./A (Label)	40 acres	3,900	3,900	4,900
73,000	3,700	3,700	4,600

3.0 lb a.i./A   (BEAD)	40 acres	1,300	1,300	1,600	24,000	1,200	1,200
1,500

5) Applying Sprays via Handgun Equipment (PHED)

	Lawn and Ornamental Turf (including golf course)	1.0 lb a.i./A (Label)
5 acres	No Data	1,300	2,300	310,000	No Data	1,300	2,300

3.0 lb a.i./ A   (BEAD)	5 acres	No Data	430	760	100,000	No Data	420	760

6) Applying Sprays via Rights of Way Equipment (PHED)	Gymnosperms
0.0025 lb a.i./gal (Label)	1,000 gal	670	2,200	3,000	220,000	670	2,200
3,000

5 lb a.i./A (BEAD)	80 acres	4.2	14	19	1,400	4.2	14	18

	Hardwoods	0.01 lb a.i./gal (Label)	40 gal	170	560	750	56,000	170	550
740

5.0 lb a.i./A (BEAD)	80 acres	4.2	14	19	1,400	4.2	14	18

	Non-agricultural rights-of-ways/fence rows and hedge rows	3.0 lb a.i./A
(Label  & BEAD)	80 acres	7.0	23	31	2,300	6.9	23	31

	Turf:  growing in culverts, ROW, median strip, ditches	3.0 lb a.i./A
(Label  & BEAD)	80 acres	7.0	23	31	2,300	6.9	23	31

	Shrubs, Shade Trees and Vines	4.5 lb a.i./A (BEAD)	80 acres	4.6	15	21
1,500	4.6	15	21

	Hedges and Vines	0.01 lb a.i./gallon (Label)	1000 gal	170	560	750
56,000	170	550	740

	High Density Forestry Management	4 lb a.i./A (BEAD)	80 acres	5.2	17	23
1,700	5.2	17	23

7) Applying granules with tractor drawn (PHED)	Lawns and Ornamental Turf
(including golf course)	1.1 lb a.i./A (Label - 100% DA)	40 acres	5,000
6,800	12,000	41,000	4,400	5,900	9,100

1.1 lb a.i./A (Label - 10% DA)	40 acres	50,000	68,000	120,000	41,000
4,400	26,000	30,000

3.0 lb a.i./A (BEAD - 100% DA)	40 acres	1,800	2,500	4,300	15,000	1,600
2,200	3,300

3.0 lb a.i./A (BEAD - 10% DA)	40 acres	18,000	25,000	43,000	15,000	8,300
9,400	11,000

Mixing/Loading/Applying

8) Mixing/

Loading/

Applying Liquid Concentrates with Low Pressure Handwand (PHED)	Lawns and
Ornamental Turf (including golf course)	1.0 lb a.i./A (Label)	5 acres
4.3	1,000	1,200	14,000	4.3	940	1,100

3.0 lb a.i./A (BEAD)	5 acres	1.4	340	390	4,800	1.4	310	360

	Gymnosperms	0.0025 lb a.i./gal (Label)	40 gal	220	50,000	59,000	720,000
220	47,000	54,000

5.0 lb a/A (BEAD)	5 acres	0.87	200	230	2,900	0.87	190	220

	Hardwoods, Hedges, Vines	0.01 lb a.i./gal	40 gal	54	13,000	15,000
180,000	54	12,000	14,000

5.0 lb a/A (BEAD)	5 acres	0.87	200	230	2,900	0.87	190	220

	Non-agricultural rights-of-ways/fence rows and hedge rows	3.0 lb a.i./A
(Label & BEAD)	5 acres	1.4	340	390	4,800	1.4	310	360

	Turf:  growing in culverts, ROW, median strip, ditches	3.0 lb a.i./A
(Label & BEAD)	5 acres	1.4	340	390	4,800	1.4	310	360

	Shrubs, Shade Trees and Vines	4.5 lb a.i./A (Label & BEAD)	5 acres	0.96
220	260	3,200	0.96	210	240

	Hedges, Vines	0.01 lb a.i./gallon (Label)	40 gal	54	13,000	15,000
180,000	54	12,000	14.000

	Trees- bark banding	0.083 lb a.i./gal (Label)	40 gal	6.5	1,500	1,800
22,000	6.5	1,400	1,600

	Ornamental Trees	2.5 lb a.i./A (BEAD)	5 acres	1.7	400	470	5,800	1.7	380
430

	High Density Forestry Vegetation	4.0 lb a.i./A (BEAD)	5 acres	1.1	250
290	3,600	1.1	240	270

9) Mixing/

Loading/

Applying Liquid Concentrates with Low Pressure Handwand – Ground
Directed (ORETF OMA 006)	Lawns and Ornamental Turf (including golf
course)	1.0 lb a.i./A (Label)	5 acres	29	1,300	No Data	160,000	29	1,300
No Data

3.0 lb a.i./A (BEAD)	5 acres	9.6	440	No Data	54,000	9.6	430	No Data

	Non-agricultural rights-of-ways/fence rows and hedge rows	3.0 lb a.i./A
(BEAD)	5 acres	9.6	440	No Data	54,000	9.6	430	No Data

	Turf:  growing in culverts, ROW, median strip, ditches	3.0 lb a.i./A
(BEAD)	5 acres	9.6	440	No Data	54,000	9.6	430	No Data

	Shrubs, Shade Trees, and Vines	4.5 lb a.i./A (BEAD)	5 acres	6.4	290	No
Data	36,000	6.4	290	No Data

	Hedges	0.01 lb a.i./gal (Label)	40 gal	360	16,000	No Data	2,000,000	360
16,000	No Data

	Trees- bark banding	0.083 lb a.i./gal (Label)	40 gal	44	2,000	No Data
240,000	44	2,000	No Data

10) Mixing/

Loading/

Applying Liquid Concentrates with Low Pressure Handwand –

Overhead Directed (ORETF OMA 005)	Gymnosperms	0.0025 lb a.i./gal (Label)
40 gal	720	No Data	No Data	5,700,000	720	No data	No data

5 lb a.i./A (BEAD)	5 acres	2.9	No Data	No Data	33,000	2.9	No Data	No
Data

	Hardwoods	0.01 lb a.i./gal (Label)	40 gal	180	No Data	No Data	2,100,000
180	No Data	No Data

5.0 lb a.i./A (BEAD)	5 acres	2.9	No Data	No Data	33,000	2.9	No Data	No
Data

	Vines	0.01 lb a.i./gallon (Label)	40 gal	180	No Data	No Data	2,100,000
180	No Data	No Data

	Shade Trees and Vines	4.5 lb a.i./A (BEAD)	5 acres	3.2	No Data	No Data
37,000	3.2	No Data	No Data

	Ornamental Trees	2.5 lb a.i./A (BEAD)	5 acres	5.8	No Data	No Data
67,000	5.8	No Data	No Data

	High Density Forestry Vegetation	4 lb a.i./A (BEAD)	5 acres	3.6	No Data
No Data	42,000	3.6	No Data	No Data

11) Mixing/

Loading/

Applying Liquid Concentrates with a Handgun Sprayer (LCO ORETF data OMA
002)	Lawn and Ornamental Turf	1.0 lb a.i./A (Label)	5 acres	No Data	960
1,800	240,000	No Data	960	1,800

3.0 lb a.i./A  (BEAD)	5 acres	No Data	320	590	80,000	No Data	320	590

	Gymnosperms	0.0025 lb a.i./gal (Label)	1,000 gal	No Data	1,900	3,500
480,000	No Data	1,900	3,500

5.0 lb a.i./A (BEAD)	5 acres	No Data	190	350	48,000	No Data	190	350

	Hardwoods	0.01 lb a.i./gal (Label)	1,000 gal	No Data	480	890	120,000	No
Data	480	880

5.0 lb a.i./A (BEAD)	5 acres	No Data	190	350	48,000	No Data	190	350

11) Mixing/

Loading/

Applying Liquid Concentrates with a Handgun Sprayer (LCO ORETF data OMA
002) (cont.)	Non-agricultural rights-of-ways/fence rows and hedge rows
3.0 lb a.i./A (Label & BEAD)	5 acres	No Data	320	590	80,000	No Data	320
590

	Turf:  growing in culverts, ROW, median strip, ditches	3.0 lb a.i./A
(Label & BEAD)	5 acres	No Data	320	590	80,000	No Data	320	590

	Shrubs, Shade Trees, Vines	4.5 lb a.i./A (BEAD)	5 acres	No Data	210	390
54,000	No Data	210	390

	Hedges, Vines	0.01 lb a.i./gallon (Label)	5 acres	No Data	480	890
120,000	No Data	480	880

	Ornamental Trees	2.5 lb a.i./A (BEAD)	5 acres	No Data	390	710	96,000	No
Data	380	700

	High density Forestry Vegetation	4.0 lb a.i./A (BEAD)	5 acres	No Data
240	440	60,000	No Data	240	440

12) Mixing/ loading/applying granules with a bellygrinder (PHED)	Lawns
and Ornamental Turf (including golf course)	1.1 lb a.i./A (Label –
100% DA)	1 acre	200	210	350	32,000	200	210	340

1.1 lb a.i./A (Label – 10% DA)	1 acre	2,000	2,100	3,500	32,000	1,900
2,000	3,100

3.0 lb a.i./A (BEAD – 100% DA)	5 acres	72	78	130	12,000	72	77	130

12) Mixing/ loading/applying granules with a bellygrinder (PHED) (cont.)
Lawns and Ornamental Turf (including golf course)	3.0 lb a.i./A (BEAD
– 10% DA)	5 acres	720	780	1,300	12,000	680	730	1,100

13) Mixing/ loading/applying granules with a push-type spreader (LCO
ORETF OMA 001)	Lawns and Ornamental Turf (including golf course)	1.1 lb
a.i./A (Label – 100% DA)	5 acres	1,100	1,800	3,600	54,000	1,100	1,700
3,400

1.1 lb a.i./A (Label – 10% DA)	5 acres	110,000	180,000	36,000	54,000
9,300	13,000	22,000

3.0 lb a.i./A (BEAD – 100% DA)	5 acres	410	660	1,300	20,000	400	640
1,200

3.0 lb a.i./A (BEAD – 10% DA)	5 acres	41,000	66,000	13,000	20,000
3,400	4,900	7,900

		7.1.4 	Cancer Occupational Handler Exposure and Risk Assessment

	

	No cancer endpoints of concern for chlorflurenol were identified;
therefore cancer risks to handlers were not assessed.

	7.1.5 	Summary of Risk Concerns and Data Gaps for Occupational Handlers
 tc "2.1.5 	Summary of Risk Concerns and Data Gaps for Occupational
Handlers " \l 3 

			7.1.5.1	Summary of Risk Concerns  tc "2.1.5.1	Summary of Risk
Concerns " \l 3 

	For dermal and inhalation exposures (short- and intermediate-term), the
level of concern or target MOE is 100.  The calculated dermal and
inhalation risks were combined for short-term and for intermediate-term
because the dermal and inhalation endpoints were based on the same
toxicological effects.  

	For all occupational scenarios, the inhalation risks were below HED’s
level of concern at the baseline level.  

	For all occupational scenarios, the dermal risks were below HED's level
of concern at some level of mitigation for all occupational scenarios
except applying liquid sprays using rights-of-way equipment: 

to turf growing in culverts, rights of way, median strips, ditches,
and/or under security fences at the 3 lb a.i./A rate (Label & BEAD) and
80 acres per day  -- the baseline dermal MOE was 7.0 and with the
highest dermal mitigation level (double layer clothing with gloves), the
dermal MOE and the total MOE (dermal plus inhalation) is 31;

to non-agricultural rights-of-ways/fence rows and hedge rows at the 3 lb
a.i./A rate (Label & BEAD) and 80 acres per day  -- the baseline dermal
MOE was 7.0 and with the highest dermal mitigation level (double layer
clothing with gloves), the dermal MOE and the total MOE (dermal plus
inhalation) is 31;

to gymnosperms at the 5 lb a.i./A rate (BEAD) and 80 acres per day  --
the baseline dermal MOE was 4.2 and with the highest dermal mitigation
level (double layer clothing with gloves), the dermal MOE and the total
MOE (dermal plus inhalation) is 18;

to shrubs, shade trees, and vines at the 4.5 lb a.i./A rate (BEAD) and
80 acres per day  -- the baseline dermal MOE was 4.6 and with the
highest dermal mitigation level (double layer clothing with gloves), the
dermal MOE and the total MOE (dermal plus inhalation) is 21; and

to high density forestry management at the 4.0 lb a.i./A rate (BEAD) and
80 acres per day  -- the baseline dermal MOE was 5.2 and with the
highest dermal mitigation level (double layer clothing with gloves), the
dermal MOE and the total MOE (dermal plus inhalation) is 23.

For the following scenarios, the dermal and total risks were of concern
at baseline level of mitigation, but were not a concern with single
layer clothing plus gloves):

 

mixing/loading liquid concentrates for all scenarios, except
mixing/loading liquid concentrates to support rights-of-way applications
to gymnosperms at the 0.0025 lb a.i./gal (label) application rate –
these dermal risks were not of concern at baseline;

mixing/loading/applying liquid concentrates with low pressure handwand
(PHED data) for all scenarios, except applications to gymnosperms at the
0.0025 lb a.i./gal (label) application rate – these dermal risks were
not of concern at baseline;

mixing/loading/applying liquid concentrates with low pressure handwand
(ground directed ORETF data), for all scenarios except applications to
hedges at the 0.01 lb a.i./gal (Label) application rate – these dermal
risks were not of concern at baseline; and

mixing/loading/applying liquid concentrates with low pressure handwand
(upward directed ORETF data), for all scenarios except applications to
hardwoods and vines at the 0.01 lb a.i./gal (Label) application rate and
applications to gymnosperms at the 0.0025 lb a.i./gal (label)
application rate – these dermal risks were not of concern at baseline.

	For the following scenario, the dermal and total risks were of concern
at baseline and single layer plus gloves levels of mitigation, but were
not a concern with double layer body protection plus chemical-resistant
gloves:   loading/applying granular formulations with a bellygrinder
(PHED data) for the 3.0 lb a.i./A (BEAD) application rate and assuming
100% dermal absorption

	There are no data to assess baseline dermal risks for application via
handgun equipment and mixing/loading/applying via handgun equipment.
Dermal risks are below HED’s level of concern for handlers of these
scenarios when personal protective equipment (i.e., single layer
clothing plus gloves) is considered.

	7.1.5.2	Summary of Data Gaps  tc "2.1.5.2	Summary of Data Gaps " \l 4 

	There are no data gaps associated with the occupational handler
scenarios.

		7.1.6	Recommendations for Refining Occupational Handler Risk
Assessment  tc "2.1.6	Recommendations For Refining Occupational Handler
Risk Assessment " \l 3 

	In order to refine this occupational risk assessment, data on actual
use patterns including rates, timing, and areas treated would better
characterize chlorflurenol methyl ester risks.  Exposure studies for
many equipment types that lack data or that are not well represented in
PHED or ORETF (e.g., because of low replicate numbers or data quality)
should also be considered based on the data gaps identified above and
based on a review of the quality of the data used in this assessment.

	7.2	Occupational Postapplication Exposures and Non-Cancer Risk
Estimates

HED uses the term “postapplication” to describe exposures to
individuals that occur as a result of being in an environment that has
been previously treated with a pesticide (also referred to as reentry
exposure).  HED believes that there are distinct job functions or tasks
related to the kinds of activities that occur in previously treated
areas.  Job requirements (e.g., the kinds of jobs to cultivate a crop),
the nature of the crop or target that was treated, and how the chemical
residues degrade in the environment can cause exposure levels to differ
over time.  Each factor has been considered in this assessment.

		7.2.1	Occupational Postapplication Exposure Scenarios

Currently, chlorflurenol uses are varied as it can be used on
agricultural crops (i.e. pineapple) and in a variety of other outdoor
occupational settings (i.e., rights-of-way, golf course turf).   As a
result, a wide array of individuals can potentially be exposed by
working in areas that have been previously treated.  HED is concerned
about the kinds of exposures one could receive in the workplace. 

	HED uses a concept known as the transfer coefficient to numerically
represent the postapplication exposures one would receive (generally
presented as cm2/hour).  The transfer coefficient concept has been
established in the scientific literature and through various exposure
monitoring guidelines published by the U.S. EPA and international
organizations such as Health Canada and the Organization for Economic
Cooperation and Development.  The establishment of transfer coefficients
also forms the basis of the work of the Agricultural Reentry Task Force.
 A transfer coefficient is a measure of the residue transferred from a
treated surface to a person who is doing a task or activity in a treated
area.  These values are the ratio of an exposure for a given task or
activity to the amount of pesticide residue on treated surfaces
available for transfer. HED has developed a series of standard transfer
coefficients that are unique for variety of job tasks or activities that
are used in lieu of chemical- and scenario-specific data.

	To develop a postapplication assessment, HED considers the types of
tasks and activities that individuals are likely to be doing in areas
recently treated with a pesticide. For consistency within
postapplication assessments, HED has developed a list of tasks commonly
associated with specific crops or use-patterns, which are likely to
result in postapplication exposures.  Postapplication pesticide
exposures that result from an individual’s employment are considered
occupational exposures. Common examples include: crop maintenance tasks
(e.g., irrigating, weeding, and mowing) and crop advisor tasks (e.g.,
scouting).

	HED considers how and when a pesticide is applied to estimate the level
of transferable residues to which individuals could be exposed over
time.  Label directions and other use data are considered to determine
application rates and application frequency.  HED completes non-cancer
postapplication risk assessments using maximum application rates for
each scenario. When postapplication non-cancer risks are a concern using
maximum application rates, HED may also consider typical application
rates or application frequency, to further evaluate the overall risks
associated with the use of the pesticide.  To estimate the amount of
transferable residues on a treated surface, HED uses, when possible,
chemical- and crop-specific studies as described in HED guidelines for
exposure data collection (Series 875, Occupational and Residential
Exposure Test Guidelines: Group B - Postapplication Exposure Monitoring
Test Guidelines).  For postapplication exposures, unique techniques are
used to measure the amount of pesticide residue on a treated surface
available for possible transfer.  These techniques are distinct from
those which measure total pesticide residue on a treated surface and
absorbed into a treated entity. When appropriate chemical- and
crop-specific transferable residue data are unavailable, HED also has
developed a standard modeling approach to predict transferable residues
over time (best described in HED’s SOPs for Residential Exposure
Assessment).  All agricultural occupational postapplication scenarios
(i.e. pineapple) were evaluated using HED’s default assumptions that
20 percent of the initial application is available for transfer on day 0
(i.e., 12 hours after application) and that the residue dissipates at a
rate of 10 percent per day.  All commercial occupational postapplication
scenarios (i.e. lawn and turf) were evaluated using HED’s default
assumptions that 5 percent of the initial application is available for
transfer on day 0 (i.e., 12 hours after application) and that the
residue dissipates at a rate of 10 percent per day.   

renol.  Short-term (30 days) always are considered in these
assessments.  Intermediate-term (greater than 30 days to several months)
exposure durations are appropriate for postapplication occupational
exposures scenarios where the pesticide is reapplied several times over
a growing season, or the pesticide residues persist for relatively long
periods of time, or the crop or use-pattern is such that occupational
postapplication workers may be exposed to several different treated
areas in the course of their work.  For example, migrant and seasonal
workers may move from farm to farm and be exposed several weeks to
several months or different fields or greenhouses on an individual
establishment may be treated over a period of weeks due to differing
levels of infestation or staggered crop cycles.  For chlorflurenol, the
exposure durations for non-cancer postapplication risk assessment were
short-term (30 days) and intermediate-term (greater than 30 days up
to several months).  However, since the dermal toxicological endpoint of
concern is the same for short- and intermediate-term exposures, the
short- and intermediate-term postapplication risks are numerically
identical.

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

	HED has used the basic approach described above since the mid 1980s for
calculating postapplication risks to pesticides.  From that time to the
present, several revisions and modifications were made to Agency
policies as data, which warranted such changes, became available.  In
1995, the Agency issued a Data Call-In for postapplication agricultural
data that prompted the formation of the Agricultural Reentry Task Force
(ARTF).  This task force has generated a number of exposure studies and
associated documents that are currently under review.  The work of the
ARTF is not yet complete; however, sufficient data were available from
the group that warranted a significant interim change in Agency policy
related to the data which were already available as the efforts of the
ARTF paralleled a push for tolerance reassessment stipulated by the
timelines established by FQPA.  As a result of the need for the revision
and using the latest data, the Agency developed a revised policy on
August 7, 2000 entitled Policy 003.1 Science Advisory Council for
Exposure Policy Regarding Agricultural Transfer Coefficients.  The
revision to this policy entailed linking worker activities to more
specific crop/agronomic groupings and making better use of the available
occupational postapplication exposure data.  In the new policy, transfer
coefficients were selected to represent the activities associated with
18 distinct crop/agronomic groupings based on different types of
vegetables, trees, berries, vine/trellis crops, turf, field crops, and
bunch/bundle crops (e.g., tobacco). 

Within each agronomic group, a variety of cultural practices are
required to maintain the included crops.  These practices are varied and
typically involve light to heavy contact with immature plants as well as
with more mature plants.  HED selected transfer coefficient values in
its revision of Policy 003 to represent this range of exposures within
each agronomic group.  In the policy, transfer coefficients were placed
in 1 of 5 generic categories based on the exposures relative to that
group.  These 5 categories include: very low exposure, low exposure,
medium exposure, high exposure, and very high exposure.  Numerical
values were not necessarily assigned to each category for each crop
group.  Selections depended upon the actual agronomic practices that
were identified for each group (i.e., some groups had 2 assigned
transfer coefficients while others had 5).  The transfer coefficient
values which have been used for pineapple are excerpted directly from
Agency Policy 003.1 for the vegetable, stem/stalk category.  The ARTF
Scoping Survey does not specifically include pineapple; therefore, all
exposure levels (low, medium, and high) for the vegetable, stem/stalk
category were used. For lawn and turf activities, transfer coefficient
values from Agricultural Reentry Task Force (ARTF) study were used. 

	In addition to transfer coefficients, occupational postapplication
exposures to workers are estimated, in general, using transferable turf
residue, dislodgeable foliar residue or soil transferable residue
values. Transferable turf residues (TTRs) are the amounts of pesticide
available on the turf surface that can potentially be transferred to the
skin of workers who contact treated turf.  Dislodgeable foliar residues
(DFRs) are the amounts of pesticide available on the surface of crops
(other than turf) that can potentially be transferred to the skin of
workers who contact treated crop. DFRs and TTRs are measured using
techniques that specifically determine the amount of residues on the
surface treated leaves or other plant surfaces.  In order to define the
amount of transferable residues to which individuals can be exposed,
whenever possible HED relies on chemical- and crop-specific studies as
described in HED guidelines for exposure data collection (Series 875,
Occupational and Residential Exposure Test Guidelines: Group B -
Postapplication Exposure Monitoring Test Guidelines).  However, when no
chemical- and crop-specific TTR or DFR studies are available, HED uses a
standard modeling approach to predict transferable residues over time
(best described in HED’s SOPs for Residential Exposure Assessment).  



		7.2.2	Data/Assumptions for Postapplication Exposure Scenarios  tc
"2.2.2	Data/Assumptions for Postapplication Exposure Scenarios " \l 3 

	A series of assumptions and exposure factors served as the basis for
completing the occupational postapplication worker risk assessments. 
Each assumption and factor is detailed below on an individual basis. In
addition to these values, transfer coefficient values were used to
calculate risk estimates.  The transfer coefficients for pineapple were
taken from HED’s revised policy entitled Policy 003.1 Science Advisory
Council for Exposure Policy Regarding Agricultural Transfer Coefficients
(August 7, 2000).  The transfer coefficients for turf were taken a more
recent study by the Agricultural Reentry Task Force. The assumptions and
factors used in the risk calculations are presented below:

There are many factors that are common to handler and postapplication
risk assessments such as body weights, duration, and application rates. 
See Section 2.1.1.1 for these values. In the postapplication risk
assessment, maximum application rates were considered.  

Levels of Concern: HED has established levels of concern (LOC) for
occupational postapplication risks – margins of exposure of less than
100 for occupational non-cancer dermal and inhalation risks are a
concern.

Dislodgeable Foliar Residues: No chlorflurenol-specific dislodgeable
foliar residue (DFR) data were available for pineapple.  Therefore, this
assessment uses HED’s default assumption that 20 percent of the
application rate is available on day 0 (i.e., 12 hours after
application) and the residue dissipates at a rate of 10 percent per day.

Transferable Turf Residues: No chlorflurenol-specific transferable turf
residue (TTR) data were available.  Therefore, this assessment uses
HED’s default assumption that 5 percent of the application rate is
available on day 0 (i.e., 12 hours after application) and the residue
dissipates at a rate of 10 percent per day.

Exposures were calculated to reflect default DFR and TTR values over
time coupled with surrogate transfer coefficients.

		7.2.3	Occupational Postapplication Exposure and Non-cancer Risk
Estimates

	Occupational non-cancer risks were calculated using a Margin of
Exposure (MOE), which is a ratio of the daily dose to the toxicological
endpoint of concern.

	Daily Exposure: Daily dermal exposures were calculated on each
postapplication day after application using the following equation (see
equation D2-20 from Series 875-Occupational and Residential Test
Guidelines: Group B-Postapplication Exposure Monitoring Test Guidelines
and Residential SOP 3.2: Postapplication Dermal Potential Doses from
Pesticide Residues on Gardens):

DE(t) (mg/day) = (TR(t) (µg/cm2) x TC (cm2/hr) x Hr/Day)/1000 (µg/mg)

Where:

DE(t)	=	Daily exposure or amount deposited on the surface of the skin at
time (t) attributable for activity in a previously treated area, also
referred to as potential dose (mg a.i./day);

	TR(t)	=	Transferable residues that can either be dislodgeable foliar or
turf transferable residue at time “t” (µg/cm2);

	TC	=	Transfer Coefficient (cm2/hour); and

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

Note that the (TR(t)) input may represent levels on the day of
application in the case of short-term risk calculations.

	Daily Dose and Margins of Exposure:  The manner in which daily
postapplication dermal exposures were calculated is inherently different
than with handler exposures.  However, once daily exposures are
calculated, the calculation of daily absorbed dose and the resulting
Margin of Exposures use the same algorithms that are described above for
the handler exposures (See Section 2.1.3).  These calculations are
completed for each day or appropriate block of time after application.

		Non-cancer Risk Summary  tc "2.2.3	Non-cancer Risk Summary " \l 3  

For pineapple applications, the MOEs are greater than 100 on day 0 (REI
= 12 hours) for all of the exposure levels.	

For the golf course turf using the 1.0 and 1.1 lb a.i./A (Label) rates
for sprays and granular applications respectively, the calculated MOE on
day 0 (12 hours following application) is 71 for liquid applications and
65 for granular applications (assuming 100% dermal absorption) at the
highest exposure level (hand weeding and transplanting). For these
postapplication scenarios, the target MOE is not reached until the 4th
day after application (MOE =110) for liquid formulations, and the target
MOE is not reached until the 5th day after application (MOE = 110) for
granular formulations.  All other postapplication turf scenarios using
the 1.0 and 1.1 lb a.i./A (Label) rates have risks below HED’s level
of concern on day 0 (12 hours following application).  

For the golf course turf using the 3.0 lb a.i./A (BEAD) rates for sprays
and granular applications, the calculated MOE on day 0 (12 hours
following application):

for liquid and granular applications (assuming 100% dermal absorption)
is 24 at the higher exposure level (hand weeding and transplanting) and
the target MOE is not reached until day 14 (MOE=100);

for liquid and granular applications (assuming 100% dermal absorption)
is 47 at the lower exposure level (mowing) and the target MOE is not
reached until day 8 (MOE=110);

for granular applications (assuming 10% dermal absorption) is 240 at the
higher exposure level (hand weeding and transplanting);

for granular applications (assuming 10% dermal absorption) is 470 at the
lower exposure level (mowing). 

	Table 20 presents a summary of occupational postapplication risks
associated with use of chlorflurenol. The risk calculations for
occupational chlorflurenol handlers are included in Appendix C.



Table 20.  Summary of Occupational Postapplication Risks

Crop Grouping	Application rate

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

(Level of Concern = 100)

Pineapple	1.0 (Label & BEAD)	300 (irrigation, scouting, thinning, hand
weeding)	0 (12 hours)	400

500 (irrigation, scouting)	0 (12 hours)	240

1,000 (hand harvesting, hand pruning)	0 (12 hours)	120

Turf	1.0 – liquid (Label)	3,400 (mowing)	0 (12 hours)	140

6,800 (hand weeding, transplanting)	4	110

	3.0 – liquid (BEAD)	3,400 (mowing)	8	110

6,800 (hand weeding, transplanting)	14	100

	1.1 – granular (LABEL)

100% dermal absorption	3,400 (mowing)	0 (12 hours)	130

6,800 (hand weeding, transplanting)	5	110

	1.1 – granular (LABEL)

10% dermal absorption	3,400 (mowing)	0 (12 hours)	1,300

6,800 (hand weeding, transplanting)	0 (12 hours)	650

	3.0 – granular (BEAD)

100% dermal absorption	3,400 (mowing)	8	110

6,800 (hand weeding, transplanting)	14	100

	3.0 – granular (BEAD)

10% dermal absorption	3,400 (mowing)	0 (12 hours)	470

6,800 (hand weeding, transplanting)	0 (12 hours)	240

7.2.4	Occupational Postapplication Exposure and Risk Estimates for
Cancer  tc "2.2.4	Occupational Postapplication Exposure and Risk
Estimates for Cancer " \l 3 

	Since no toxicological endpoint of concern was identified for cancer,
cancer risks from occupational postapplication exposures were not
assessed.  

7.2.5	Summary of Occupational Postapplication Risk Concerns and Data
Gaps  tc "2.2.5	Summary of Occupational Postapplication Risk Concerns
and Data Gaps " \l 3 

	There are several occupational postapplication scenarios that have
risks above HED’s level of concern for non-cancer risk assessments. 
For hand weeding and transplanting of golf course turfgrass treated at
1.0/1.1 lb a.i./A, the target MOE is not reached until the 4th day after
application (MOE =110) for liquid formulations, and the target MOE is
not reached until the 5th day after application (MOE = 110) for granular
formulations.  For the golf course turf using the 3.0 lb a.i./A (BEAD)
rates for sprays and granular applications, the calculated MOE on day 0
(12 hours following application):

for liquid and granular applications (assuming 100% dermal absorption)
is 24 at the higher exposure level (hand weeding and transplanting) and
the target MOE is not reached until day 14 (MOE=100);

for liquid and granular applications (assuming 100% dermal absorption)
is 47 at the lower exposure level (mowing) and the target MOE is not
reached until day 8 (MOE=110);

for granular applications (assuming 10% dermal absorption) is 240 at the
higher exposure level (hand weeding and transplanting);

for granular applications (assuming 10% dermal absorption) is 470 at the
lower exposure level (mowing). 

  SEQ CHAPTER \h \r 1 HED has used the most up-to-date information
available to complete this postapplication risk assessment for
chlorflurenol. Several data gaps exist, such as a lack of
chlorflurenol-specific postapplication studies. Additionally, the ARTF
Scoping Survey does not include pineapple, though pineapple was assigned
to the vegetable stem/stalk transfer coefficient category in Policy
003.1. 

7.2.6	Recommendations for Refining Occupational Postapplication Risk
Assessment  tc "2.2.6	Recommendations For Refining Occupational
Postapplication Risk Assessment " \l 3 

	To refine this occupational risk assessment, data on actual use
patterns including rates, timing, and the kinds of tasks that are
required to produce agricultural commodities and other products would
better characterize chlorflurenol risks.  Exposure studies for many
cultural practices that lack data or that are not well represented in
the revised transfer coefficient policy should also be considered based
on the data gaps identified above.

8.0	Data Needs and Label Requirements    TC \l1 "10.0	Data Needs and
Label Requirements 

8.1	Toxicology    TC \l2 "10.1	Toxicology 	

	Toxicology data requirements are acceptable and satisfied.  However,
another study on reproduction with a more definitive NOAEL for effects
on pups and fertility will be necessary to remove the 3X uncertainty
factor.

8.2	Residue Chemistry    TC \l2 "10.2	Residue Chemistry 

	A study on the UV/visible spectra is necessary.

8.3	Occupational and Residential Exposure    TC \l2 "10.3	Occupational
and Residential Exposure 

	No studies are required at this time.

References:    TC \l1 "References: 

	Memorandum from Shana Recore to David G Anderson , dated June 30, 2006,
Subject: Chlorflurenol: Occupational and Residential Exposure Assessment
for the Reregistration Eligibility/Decision [RED].

Appendix A:  Toxicology Assessment  TC \l1 "Appendix A:  Toxicology
Assessment 

A.1	Toxicology Data Requirements TC \l2 "A.1  Toxicology Data
Requirements  

	A confirmatory study on reproduction [guideline 870.300] is necessary
to remove the extra 3X uncertainty factor and establish a NOAEL for pup
effects and fertility effects in adult offspring. 

The requirements (40 CFR 158.340) for Non food use for CHLORFLURENOL
METHYL ESTER are in Table 1. Use of the new guideline numbers does not
imply that the new (1998) guideline protocols were used.

Table A.1:  Data Requirements for a non-food use pesticide, such as
chlorflurenol methyl ester.

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

no

no

no

no	yes

no

no A

no

no

870.3700a  Developmental Toxicity (rodent)	

870.3700b  Developmental Toxicity (nonrodent)	

870.3800    Reproduction		yes

no

no	Yes

no B

no B

870.4100a  Chronic Toxicity (rodent)	

870.4100b  Chronic Toxicity (nonrodent)	

870.4200a  Oncogenicity (rat)	

870.4200b  Oncogenicity (mouse)	

870.4300    Chronic/Oncogenicity		no

no

               no

no

no	No

yes C

no

yes D

no

870.5100    Mutagenicity—Gene Mutation - bacterial	

870.5300    Mutagenicity—Gene Mutation - mammalian	

870.5300    Mutagenicity—Structural Chromosomal Aberrations	

870.5550    Mutagenicity—Other Genotoxic Effects		yes

yes

yes

yes	yes

yes

yes

yes

870.6100a  Acute Delayed Neurotox. (hen) E	

870.6100b  90-Day Neurotoxicity (hen) E	

870.6200a  Acute Neurotox. Screening Battery (rat) F	

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

870.6300    Develop. Neuro F		no

no

no

no

no	-

-

-

-

-

870.7485    General Metabolism	

870.7600    Dermal Penetration		no

no	no G

no

Special Studies for Ocular Effects H

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)	

See next page for explanation for superscripts A to H.

Footnotes for Table A.1:  A  A formulation rather than the technical
grade of chlorflurenol was studied [technical grade is required].  B 
The unacceptable developmental rabbit study and unacceptable
reproduction studies submitted were not required.  C The acceptable
chronic dog study submitted was not required.  D The acceptable
carcinogenicity study in the mouse was not required.  E  Required only
for organophosphate pesticides.  F  Required if the pesticide shows
evidence of neurotoxicity.  G  Not required for pesticides with this use
pattern.  H  Reserved

A.2  Toxicity Profiles TC \l2 "A.2  Toxicity Profiles 

Table A.2.1	Acute Toxicity Profile – Chlorflurenol methyl ester 

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

870.1100	Acute oral [rat]	43355402 	LD50 > 5000 mg/kg	IV

870.1200	Acute dermal [rabbit]	43355403	LD50 > 5000 mg/kg	IV

870.1300	Acute inhalation [rat]	45147201	LC50 > 5.07 mg a.i./L	IV

870.2400	Acute eye irritation [rabbit]	43355404	Mild irritation, cleared
in 72 hours	III

870.2500	Acute dermal irritation [rabbit]	43355405	Practically non
irritating	IV

870.2600	Skin sensitization [Guinea pig]	43361701	Not a sensitizer
Negative

Table A.2.2:	Subchronic, Chronic, Developmental, Reproduction ,
mutagenicity and other toxicity profile of  chlorflurenol methyl ester.

Guideline/

Study type/

Acceptability	

MRID#/Date/

Doses	

Results

870.3100

90-Day oral/SD rat

Acceptable

Lot# 45, 99.9%	

45441001 [2001]

Acceptable

0,1000,5000,10000 ppm [M: 0,74,361, 697; F: 0,87,390,750 mg/kg/day] 	

NOAEL = M/F 697/87 mg/kg/day

LOAEL = M/F None/390 mg/kg/day based decreased body weight gain in
females [Female BWt accompanied by decreased food efficiency].  Males
showed a possible treatment related nominal decreased body weight gain
of 11% at 697 mg/kg/day.  

870.3100

90-Day oral/Wistar rat

Unacceptable	

00120854 & 00120867 [1968] 0, 1000, 5000, 10000 ppm [0, 50, 250, 500
mg/kg/day] 	

NOAEL = 250 mg/kg/day 

LOAEL = 500 mg/kg/day based on body weight decrement in females.

Unacceptable: lacking hematology clinical chemistry & some histology  

870.3150

90-Day oral/dog

Unacceptable	

00120868 [1968]

Unacceptable

0,300,1000,3000 ppm

0, 8.95, 29.9, 89.5 mg/kg/day	

NOAEL = >89.5 mg/kg/day

LOAEL = None.  No treatment related decreases in hematological
parameters, which showed only random fluctuation from control animals
and from pre-dosing conditions in males and female up to 8 weeks. 
Although, some parameters at the HDT were slightly numerically less than
control values, they were not consistently less or consistently
numerically less than the initial values for the group.  The 90-day dog
was not entirely inconsistent with the 2-year dog study.  

Unacceptable; only 3 dogs/sex/group and dose levels were not verified.

870.3150NG

21-Day dermal toxicity/

rabbit, Proj# 1385

Lot# 759-78

Acceptable/NG	

00120883 [1970]

Acceptable/NG

Test material CF-125 [12.5% a.i.] Doses  0, 0.5, 1.0 ml/kg/day or (0,
62.5, 125 mg a.i./kg

	

NOAEL = None 

LOAEL = 62.5 mg a.i./kg/day based on dose related  local degeneration of
hair follicles and epithelial thickening at the 2 dose levels used.  No
systemic effects reported.  Since the test material was applied as a
neat formulation, the dermal effects may have been due to the dispersing
agent in CF-125.  CF-125 is 12.5% active ingredient with 87.5% being 
inert ingredients of which most were known skin irritants in the context
of this study. 

Acceptable as a non-guideline study.  The toxicity of the technical
grade of the pesticide could not be evaluated.   

870.4100b

Chronic toxicity

Dog

Acceptable	

00082863 [1975]

0, 300, 1000, 3000 ppm or [M/F: 0/0, 8.7/8.8, 30.6/29.9, 94.0/94.4
mg/kg/day	

NOAEL = 30.6/29.9 mg/kg/day for males/females. LOAEL = 94.0/94.4
mg/kg/day for male/females based on decreased erythrocytes, hemoglobin
and hematocrit by week 4 in males and females, supported by hemosiderin
deposits in liver and incidence of gastritis and possible decreased body
weight in males and females by month 13 of the study, but not in females
by study termination at 24 months.  Transient alkaline phos. and
elevated SGPT was seen at the HDT. 

870.4100a

Chronic toxicity rats 

Unacceptable	

00082864 [1971]

0, 300, 1000, 3000 ppm or 0, 15, 50, 150 mg/kg/day	

52 week interim report.

Tentative NOAEL = 50 mg/kg/day

                LOAEL = 150 mg/kg/day based on one male with elevated
SGPT and alkaline phos. 

Unacceptable: Inadequate number of rats were studied histologically for
too short a period.

870.4200b

Carcinogenicity Mouse

Acceptable	

00082865 [1976]

0, 1000, 3000, 10000 ppm or 0, 150, 450, 1500 mg/kg/day  	

NOAEL = 1500 mg/kg/day

LOAEL = None, no dose related carcinogenic response was noted. 

Acceptable

Non GDL

Carcinogenicity Rats

Unacceptable 	

0082866 [1969]

subcutaneous 0, 30  mg/kg/week, and feeding about 92 mg/kg/day or about
700 mg/kg/week. 	

Subcutaneous dose:

NOAEL = 30 mg/kg/week

LOAEL= None

Feeding study:

NOAEL = 92 mg/kg/day 

LOAEL= None

Unacceptable because studied for 1-year only 

870.3700a

Developmental toxicity/ SD rat

Acceptable	

4510901 [2000]

Acceptable

0, 250, 750, 1000 mg/g/day 

	Maternal: NOAEL = 250 mg/kg/day

                  LOAEL = 750 mg/kg/day based on statistically
significant and treatment related reduced body weight gain during the
treatment period, GD 6-16. 

Devel: NOAEL = 250 mg/kg/day

            LOAEL = 750 mg/kg/day based on treatment related increased
incompletely ossified anterior skull bones [nasal and frontal bones
about doubled that of controls].   In addition a cleft palate was seen
in each of two litters and one diaphragmatic hernia at 1000 mg/kg/day
and one cleft palate at 750 mg/kg/day [cleft palate is rare in rats,
historical incidence not given].   

870.3700b 

Developmental toxicity/NZW rabbit

Unacceptable	

00120862 [1969]

Unacceptable

Proj# 1624-97

0, 25, 50, 100 mg/kg/day	

Maternal NOAEL = 100 mg/kg/day

               LOAEL = None

Devel NOAEL = 100 mg/kg/day

           LOAEL = None, although a wide variation in skeletal variants
were seen among the groups.

Unacceptable due to no demonstrated toxicity and lack of individual
animal data and no indication that fetal soft tissue was evaluated.

870.3800

3-Generation reproduction/Charles River rat

Unacceptable	

00082867 [1973]

0, 300, 1000, 3000 ppm or 0, 15, 50, 150 mg/kg/day

	

Parental, systemic NOAEL = 50 mg/kg/day.

              Systemic LOAEL = 150 mg/kg/day for nominal decreased body
weight. 

Offspring NOAEL = 15 or 50 mg/kg/day

                LOAEL = 50 or150 mg/kg/day based on decreased pup weight
at birth and/or litter size from the P0b, F1a and F1b generations. 
Decreased absolute thymus and testes weights in the F3b generation
weanling pups [The only group from which organ weight were collected].

Reproduction NOAEL = Unknown.

                       LOAEL = Unknown.  Appears to be considerable
variation in results generation to generation such that NOAEL/LOAEL was
not definitive.  Reviewer could not assign a NOAEL.  Decreased variable
pregnancy rate  in the F1a, F1b, F2a and F2b generation [only F2a shows
a dose relationship], decreased absolute thymus in F3b weanlings [The
only group from which organ weight were collected].  Female F0 and F2
body weight gain was lower than controls premating in the 150 mg/kg/day
group.  

Unacceptable due to uncertainty and variability in pregnancy rates in
control and all doses.    

870.5100

Ames, S typhimurium	

43562802 [1995]

Acceptable	

In a reverse mutation assay with S tryphimurim [TA1535, TA 1537, TA1538,
TA98 and TA100] was exposed with and without S9 activation at 250, 500,
750, 1000 or 2500 µg/plate.  Cytotoxicity was seen in all strains at
2500 µg/plate.  

There were no signs of a mutagenic response with or without S9.    

870.5300

In vitro cell (CHO) Chromosomal Aberration 	

43562801 [1995]

Acceptable	

In this Chinese hamster ovary cell in vitro assay, cells were exposed to
non-activated doses of 5.0-75 µg/mL and activated doses of 50-200
µg/mL.  Treated cultures were scored for structural aberrations.  
Cytotoxicity was indicated by approximately 40% reduction in mitotic
index at the highest dose in the non-activated and activated systems.

There was no indication of clastogenic effects in the non-activated or
activated systems.   

870.5550

In vitro rat hepatocyte UDS  	

45137404 [1988]

Acceptable

	

Chlorflurenol was studied for unscheduled DNA synthesis in rat
hepatocytes at 0, 1.5, 5, 15, 50 or 150 µg/mL.  Cytotoxicity was seen
at 150 µg /mL indicated by decrease [3H] thymidine incorporation. 
Since there was no evidence UDS with or without S9 activation, the study
was considered negative for mutagenic evidence.   

870.5300

In vitro mammalian cell HGPRT test	

45137405 [1988]

Acceptable	

In two independently performed mammalian cell gene mutation assays at
the HPRT locus (MRID 45137405), V79 cells cultured in vitro were exposed
to Chlorflurenol-methyl ester in ethanol at  0, 6, 20, 40, or 60 μg/mL
with and without S9 to the solubility limit.   There was no evidence
that Chlorflurenol-methyl ester induced mutant colonies over background
in the presence or absence of S9-activation.  

NG

Metabolism & Pharmacokinetics

Unacceptable/NG	

00082868 [1972]

Unacceptable/NG	

Majority eliminated via the rat kidney and about 1/20 in the feces.  The
small amounts detected in the mammary gland suggested that the test
material was  not secreted in milk.  Recovered test material from the
feces and urine within 72 hours after administration were 64% IT-3456,
75% of IT-5733 and 83% of IT-3294.  Biliary recyclization was indicated.
  Small amounts were detected in the mammary gland of lactating females,
but not in their pups. Identification of potential  metabolites was not
investigated. 

Unacceptable due to inadequate replication, distribution not
quantitated, test material inadequately identified.    

A.3  Executive Summaries   TC \l2 "A.3  Executive Summaries   

	Summaries included are acceptable and unacceptable studies considered,
but not necessarily used to assess risk.

A.3.1	Subchronic Toxicity

90-Day Oral Toxicity – Rat [MRID# 45441001]

EXECUTIVE SUMMARY:  In a 90-day dietary study (MRID 45441001),
chlorflurenol methyl ester (Lot# 45, 99.9% pure) was administered to 10
Sprague Dawley rats/sex/group at dietary levels of 0, 1000, 5000 or
10000 ppm (males: 0.0, 74, 361 or 697 mg/kg/day; females: 0.0, 87, 390
or 750 mg/kg/day).  Body weights, food consumption, and clinical
observations  were recorded.  Ophthalmoscopic examinations were
conducted.  At study termination, rats were sacrificed and blood
collected for hematology and clinical chemistry studies.  Organ weights
were recorded and gross and microscopic examinations were conducted. 

	All rats survived to terminal sacrifice.  There were no clinical signs
of toxicity and there were treatment related effects on hematology or
clinical chemistry parameters, organ weights or necropsy findings.  All
treated groups of female rats had dose-related lower final body weight
than control group (not significant) and dose-related lower body weight
gains (reduced in Groups 2, 3 and 4 by 15, 21 and 24%, respectively)
which were statistically significant in the 5000 ppm and 10000 ppm
groups (p<0.01).  The food consumption and food efficiency were also
lower in all treated groups compared with the control group. 

	Under the conditions of this study, a NOAEL for females was established
at 1000 ppm (87 mg/kg/day) and a LOAEL at 5000 ppm (390 mg/kg/day) based
on dose-related decrease in body weight gain.  For males the NOAEL was
10000 ppm 697 mg/kg/day and a LOAEL was not established.

	This study is considered to be ACCEPTABLE/GUIDELINE as a 90-day study
and fulfills FIRA Guideline requirements for a subchronic oral toxicity
study in the rat [870.3100 (82-1a)].

COMPLIANCE:  Signed and dated GLP, Quality Assurance and Data
confidentiality statements were provided.

	870.3100	90-Day Oral Toxicity – Mouse  

	Not required and none was submitted. 

90-Day Oral Toxicity – Dog [MRID# 00120868]

	Not required and unacceptable because only 3 dogs/sex/group were used
and no toxicity was demonstrated 

	870.3200	21/28-Day Dermal Toxicity – Rat [MRID# 00120883]

EXECUTIVE SUMMARY:  In a 21-day dermal toxicity study (MRID 00120883),
formulated chlorflurenol methyl ester [Lot# 759-78 (12.5% a.i.,
batch/lot # 759-78)] was applied to the shaved skin of 5 New Zealand
rabbits/sex/group at dose levels of 0, 0.5 or 1.0 ml/kg bw/day
[equivalent to 0, (62.5 mg a.i./kg/day or (125 mg a.i./kg/day, assuming
a density of 1.0 g/ml for CF 125] 24 hours/day for 5 days/week during a
21-day period.  Equal numbers of rabbits and dose levels were evaluated
with abraded and intact skin.  

	The only treatment related effects seen were in the treated skin.
Drying and slight fissuring of the skin midway through the study was
noted, which at termination resulted in epithelial thickening and
varying amounts of keratonization with varying destruction of hair
follicles.  Although the varying degrees of destruction of hair
follicles was shown in most dosed animals, the damage was observed to be
less severe among the lowest dosed animals.  The treated skin effects
were believed to be due to the 87.5% of the CF 125 formulation that were
skin reactive inerts.  Only mild skin effects were noted at mid study.

No treatment related changes were noted in body weight, weight gain,
hematology, clinical chemistry, organ weights, or systemic toxicity in
treated animals.  Histological findings were consistent with random
effects in controls and treated animals. 

There were no systemic effects.  The LOAEL is 62.5 mg/kg/day, based on
epithelial thickening, keratinization and destruction of hair follicles.
 A NOAEL was not seen for skin effects.

This 21-day dermal toxicity study in the (rabbit) is an
ACCEPTABLE/NON-GUIDELINE study and does not satisfy the guideline
requirement for a 21/28-day dermal toxicity study (OPPTS 870.3200 ; OECD
410) in the rabbit.  The technical grade of the test material was not
studied.  It is not upgradeable because some of the recommended
parameters were not studied, including some hematology, clinical
chemistry and histopathology parameters, but the major parameters were
studied.  The study is useful in that it shows no systemic toxicity at
125 mg/kg/day with a reasonable degree of certainty. 

COMPLIANCE:  Signed and dated GLP, Quality Assurance, and Data
Confidentiality statements were (not) provided.  The study was conducted
prior to publication of these regulatory requirements.

	870.3465	90-Day Inhalation – Rat

A.3.2	Prenatal Developmental Toxicity

	870.3700a Prenatal Developmental Toxicity Study – Rat

EXECUTIVE SUMMARY:  In a developmental toxicity study (MRID 45190901)
with chlorflurenol-methyl ester [calculated as 99.1% a.i.; batch/lot# UT
047843] was administered to 31 female, Crl:CD(SD):BR strain of Sprague
Dawley rats/group by gavage at dose levels of 0, 250, 750 or 1000 mg
a.i./kg bw/day from days 6 through 15 of gestation.  Doses were
administered in 1% carboxymethyl cellulose/water in a volume of 5
mL/kg/day.  Maternal toxicity was evaluated and fetal evaluations were
conducted one-half the fetuses viscerally or skeletally.  

	Maternal toxicity was seen as a statistically significant decrement in
body weight gain gestational days 6 to 16 at 750 and 1000 mg/kg/day and
at 1000 mg/kg/day gestational day 6-9. Supporting this body weight
decrement was nominally decreased food efficiency at 750 and 1000
mg/kg/day.  

The maternal NOAEL was 250 mg/kg/day.  The maternal LOAEL is 750 mg/kg
bw/day based on body weight gain decrement and nominally decreased food
efficiency.  Delayed ossification was seen in skull bones.  The
incidence of incompletely ossified nasal bones and frontal bone were
increased at 750 and 1000 mg/kg/day (60.9-63.0% vs. 28.6% in control]
and 55.6%-60.9% vs. 33.3% in control], respectively.  Intrauterine death
was borderline statistically significant [p = 0.0529] at 1000 mg/kg/day
[1.7 vs. 0.3 in control].  The post-implantation loss and early
resorptions, which were nominally increased at 1000 mg/kg/day supported
the intrauterine death at 1000 mg/kg/day.

The developmental NOAEL is 250 mg/kg/day. The developmental LOAEL is 750
mg/kg bw/day, based on treatment related delayed ossification in skull
bones [nasal and frontal] in fetuses and litters.

The developmental toxicity study in the rat is classified ACCEPTABLE
[guideline]; and satisfies the guideline requirement for a developmental
toxicity study (OPPTS 870.3700; OECD 414) in the rat.

COMPLIANCE:  Signed and dated GLP, Quality Assurance, and Data
Confidentiality statements were provided.   Historical control data was
submitted for fetuses, but not for litters.   

	870.3700b Prenatal Developmental Toxicity Study – Rabbit

	Study not required and unacceptable [MRID# 00120862] due to failure to
submit data on fetal soft tissue and study showed no toxicity in dams or
fetuses.

EXECUTIVE SUMMARY: In a developmental toxicity Study (MRID#s 00120862,
00069980 and 00073536), IT 3456 (chlorflurenol methyl ester, 98% a.i.)
was administered by gastric intubation to 13-14 New Zealand female
rabbits/group at dose levels of 0, 25, 50 or 100 mg/kg/day from days 6
through 18 of gestation.  The submitted study consists of a summary of
the data that was previously submitted to the Agency prior to
implementation of GLP standards as well as copies of the original MRIDs.
 

There were no treatment related effects in mortality, clinical signs of
toxicity, body weight, or cesarean parameters.   Equivocal reductions in
body weight gain were noted at the mid dose (50 mg/kg/day).  A maternal
LOAEL was not observed.  The maternal NOAEL under the conditions of the
study is => 100 mg/kg/day.  

There were no treatment related effects in developmental parameters
including mortality, body weight, abnormalities or skeletal parameters. 
A developmental LOAEL was not observed.  The developmental NOAEL under
the conditions of the study is => 100 mg/kg/day.  

The study is classified UNACCEPTABLE/GUIDELINE (870.3500 OR 83-3b) and
does not satisfy the guideline requirements for a developmental study in
rabbits and a new study must be conducted.  No maternal or developmental
toxicity was observed.  It appears that the animals could have tolerated
a higher dose level, however, the dose rationale was not provided.  In
addition the following acceptance criteria were not met: individual
fetal soft tissue and skeletal examinations were not performed; at least
12 pregnant animals/dose group were not available because 3 pregnant
rabbits died during the study; and food consumption was not reported. 
Moreover, this study should have been properly reformatted as per EPA
requirements.  It therefore seems unlikely this study can be upgraded. .
 

A.3.3	Reproductive Toxicity

	Not required for a non-food use pesticide, but may show subfertility in
offspring. 

	870.3800 Reproduction and Fertility Effects – Rat [MRID# 0008267]

EXECUTIVE SUMMARY:   In a three-generation study on reproduction [MRID#
00082867], Charles River rats [20 females/group and 10 males/group] were
administered chlorflurenol methyl ester at 0, 300, 1000 or 3000 ppm
[Standard table equivalent for P0  males and females: 0, 15, 50 or 150
mg a.i./kg/day] in the diet continuously for 3 generations.  
Twenty-one-day old pups [10/sex/group] from only the 3rd generation were
subjected to necropsy; organs were weighted and microscopically
examined.   

	Female body weight was consistently lower in the 1000 and 3000 ppm
group than in controls in all generations, P0 [96% and 89% of control,
respectively], F1 [93% and 87% of control, respectively] and F2 [93% and
91% of control, respectively]; none of the reductions in weight were
statistically significant.  Male body weight was unchanged.  

	Pup weight was statistically significantly decreased at 1000 and 3000
ppm in the P0, first litter  [91% and 89% of control, respectively] at
day 4, but not at birth and only at 3000 ppm in the second litter at
birth (96% of control)and day 4 (91% of control).  Again for the F2
generation at 1000 and 3000 ppm, the first litter weight was
statistically significantly reduced [91% and 92% of control,
respectively] at day 4, but not at birth of for the second litter at
either dose.  Litter size appeared to be sporadically decreased at 3000
ppm in the P0 second litter at birth and at day 4, and the F1 for both
litters, but not for the F2 for both litters. 

	Litter size at birth was statistically significantly reduced at 3000
ppm in 3 of the 6 sets of litters produced during the study [P0 second
litter, F1 first and second litter, but not in the F2 first or second
litter].

	Body weight of the F3, 21-day old pups was significantly reduced at
3000 ppm.  Absolute and relative brain weight was statistically
significantly reduced [90% of control].  Absolute gonad weight was
reduced at 1000 and 3000 ppm [85.1% and 84.6% of control, respectively],
but the relative weight did not differ from control.  Microscopic
examination showed no histopathology.  The only comment about the gonads
was that all animals showed immaturity as may be expected from 21-day
old gonads. 

	There was a problematic apparent decrease in fertility at all dose
levels in this 1973 study, which showed a statistically significant dose
relationship only in the first mating of the F2 generation at 1000 [50%]
and 3000 ppm [40%] compared with control at 90% and the 300 ppm group at
80%.  The other matings showed lower fertility than control, but little
to no dose response was shown [See accompanying table in the Appendix]. 
The P0 first and second matings showed no dose related effects on
fertility, while the F1 first and second matings were lower than control
and for the F2 second matings, control and high dose groups were equally
low.  The suggestion of subfertility in these rats may have been shown,
but unproven. Another study on reproduction is needed  to confirm or
reject the potential effects on fertility and pups.   

	Out of 479 matings, 145 showed sperm negative vaginal smears of which
29 of these females produced litters.  This appears to be a high number
of pregnancies for which no vaginal sperm were shown.  When all pregnant
females showing no sperm during cohabitation were added together for the
6 total matings, a treatment related increased response was seen in the
data [last four rows of the table of matings, pregnancies, and
pregnancies with out demonstrated sperm during cohabitation in the
Appendix]. {The method used in determining the presence of vaginal sperm
was not stated and may have been inadequate or the sperm count for some
rats was extremely low.} In addition, if estrous cycles were noted they
were not recorded.  Only the time to pregnancy was recorded.  Historical
control levels were not presented for vaginal sperm negative females
producing litters.  It is the experience of this reviewer that out of
145 sperm negative vaginal spears, no more than 2-3 of these rats would
produce pregnancies and none would be expected to produce pregnancies.

	The study raises unanswered questions about possible effects of
chlorflurenol on fertility in rats.  Histopathology on 21 day old F3
pups showed no histological effects on testes or ovaries [the only pups
studied for these effects]. No gonadal effects were noted in the 2-year
chronic dog study or the 90-day study in rats.   The study on
reproduction should be repeated to clarify the questionable results in
MRID# 00082867.

	Neither the NOAEL nor the LOAEL can be determined due to the
variability from generation to generation.  However, litter size at
birth and pup weight decrement were statistically significantly reduced
at the HDT of 3000 ppm..   

	The study is UNACCEPTABLE/GUIDELINE and is not satisfactory for a study
on reproduction in rats [870.3800] .  The data in the study was too
variable for adequate interpretation. 

Table of Response of litters in the 3-generation study on reproduction
[MRID# 00082867]

Generation	Parameter	Control	15 mg/kg/day	50 mg/kg/day	150 mg/kg/day

P0 1st mating	Pup wt at birth	6.3	6.1	6.0	6.0

	At day 4	11.1	10.4	10.1*	9.9*

	At day 12	29.0	27.1	25.3**	24.9**

	At day21	58.2	50.8	49.9*	47.2**

	Litter size at birth	12.0	12.2	13.1	12.0

	At day 4 	12.1	11.2	12.1	11.4

	At day12	12.0	11.2	11.8	11.4

	At day 21	12.0	11.2	11.8	11.4

P0 2nd mating 	Pup wt at birth	6.5	6.6	6.4	6.2*

	At day 4	11.6	11.7	11.0	10.6*

	At day 12	31.2	30.5	29.9	28.5**

	At day21	58.7	55.5	55.4	52.8

	Litter size at birth	12.4	11.8	11.91	10.7*

	At day 4 	12.0	10.9	11.2	9.8**

	At day12	11.9	10.9	11.1	9.8**

	At day 21	11.9	10.9	11.1	9.7**

F1 1st mating	Pup wt at birth	6.2	6.7	6.6*	6.6

	At day 4	10.2	10.8	9.4	10.1

	At day 12	27.1	28.2	23.7	26.9

	At day21	54.7	53.2	47.1**	50.8

	Litter size at birth	13.1	11.3	11.2	8.8**

	At day 4 	12.2	9.9	10.4	8.1***

	At day12	11.9	9.7	10.0	7.9***

	At day 21	11.8	9.7	10.0	7.9***

F1 2nd  mating	Pup wt at birth	6.7	6.6	6.8	6.7

	At day 4	11.4	10.9	11.1	11.0

	At day 12	28.9	26.2	26.0	26.8

	At day21	55.0	48.5	50.6	49.8

	Litter size at birth	12.9	12.5	11.6	9.8*

	At day 4 	12.3	12.2	12.0	9.3**

	At day12	12.1	11.9	10.7	9.2**

	At day 21	11.9	11.8	11.9	9.2*

F2 1st mating	Pup wt at birth	6.2	6.3	6.2	6.1

	At day 4	10.5	10.5	9.6*	9.7*

	At day 12	27.7	26.9	24.8*	25.6

	At day21	53.4	51.5	48.4*	49.7

	Litter size at birth	12.3	12.9	12.8	10.5

	At day 4 	11.6	12.1	12.2	10.0

	At day12	11.4	11.9	12.0	9.8

	At day 21	11.4	11.9	12.0	9.6

F2 2nd  mating	Pup wt at birth	6.2	6.6	6.4	6.0

	At day 4	10.4	10.7	10.3	10.3

	At day 12	26.0	26.2	24.6	23.9

	At day21	51.0	51.9	50.4	46.1

	Litter size at birth	12.1	13.8	12.2	11.4

	At day 4 	11.0	13.0*	11.5	11.0

	At day12	10.7	12.7	11.3	11.0

	At day 21	10.5	12.2	11.2	11.0

* , **, *** = p < 0.05. <0.01 or 0.001

Table of matings, pregnancies and pregnancies without apparent sperm for
P0, F1 and F2 generations [MRID# 00082867]  Data taken from page 42 -
46.  

Dose group [mg/kg/day]	Total mating with  positive sperm smears a	Total
pregnancies

[with positive & negative sperm]	Not pregnant

[with positive & negative sperm]	# rats without sperm positive smears
Pregnancy rate [%]

Total	Pregnant	Not pregnant

	1st P0 Mating with 20 females/group

0	19	20	0	1	1	0	100

300	14	13	7	6	2	4	65**

1000	19	18	2	1	1	0	90

3000	16	18	2	4	2	2	90

2nd P0 mating with 20 females/group

0	18	18	2	2	0	2	90

300	14	15	5	6	2	4	75*

1000	20	20	0	0	0	0	100

3000	18	20	0	2	2	0	100

1st F1 mating with 20 females/group

0	13	14	6	7	2	5	70

300	14	11	9	6	2	4	55

1000	11	12	8	9	1	8	60

3000	9	11	9	11	4	7	55

2nd F1 mating with females/group

0	16	14	6	4	0	4	70

300	12	11	9	8	1	7	55

1000	11	10	10	9	2	7	50

3000	10	12	8	10	2	8	60

1st F2 mating with 20 females/group

0	19	18	2	1	0	1	90

300	15	16	4	5	1	4	80

1000	9	10	10	11	1	10	50*

3000	7	8	12	13	2	11	40**

2nd F2 mating with 19 females in control and 20 females/.dose group

0	12/19	12/19	7/19	7/19	0/19	7/19	63

300	12	11	9	8	1	7	55

1000	7	6	14	13	0	13	30

3000	9	7	13	11	0	11	35

Summary results of total P0, F1 and F2 matings, including controls 

Total	324/479	325/479	154/479	155/479	29/479	126/479	68

Summary data from the first and second matings of the PO, F1 and F2
generations 

0	97/119	97/119	21/119	22/119	3/119	19/119	80.7

300	81/120	77/120	43/120	39/120	9/120	30/120	64.2

1000	77/120	76/120	44/120	43/120	5/120	38/120	63.3

3000	69/120	76/120	44/120	51/120	12/120	39/120	63.3

a = # females mated with positive sperm smears. * = p > 0.05, **  = p >
0.01. 

A.3.4	Chronic Toxicity 

	870.4100a (870.4300) Chronic Toxicity – Rat [MRID# 00082864]

	Unacceptable as a chronic study due to several factors, especially
microscopic examination was conducted on only 3 rats/sex 

	870.4100b Chronic Toxicity – Dog {MRID# 00082863]

EXECUTIVE SUMMARY:   In a chronic toxicity study (MRID 00082863) IT 3456
[Chlorflurenol, technical (96% a.i., batch/lot # 5/69)] was administered
to 4 Beagle dogs/sex/group in the diet at dose levels of 0, 300, 1000 or
3000 ppm ( for male/female equivalent to 0, 8.7/8.8, 30.6/29.9 or
94.0/94.4 mg/kg bw/day, calculated from test material consumption) for
104 weeks.  One extra dog/sex/group was treated with test material for
104 weeks, after which the dogs were untreated for 8 weeks.  Hematology
and clinical chemistry evaluation was performed at 6 intervals during
the study.  Animals were subjected to gross pathology and microscopic
examination.  

Body weight appeared to be slightly reduced by month 13 at the highest
dose tested [HDT].  Dogs showed this body weight decrement at month 13
when compared with initial body weights for males [the HDT gained 0% vs.
22.3% for control weight] and for females [the HDT gained 6.6% vs. 20.3%
for control body weight].  Male body weight gain appeared to be reduced
for the remainder of the study.  Male body weight gain was decreased at
104 weeks [body weight gain was 0.8 kg at the HDT and 2.5 kg for
controls].  At the end of the study female body weight gain was the same
as control weight gain.  Food consumption was unaffected in both sexes. 

Erythrocytes [ERY], hemoglobin concentration [Hb] and hematocrit [Ht]
values appeared to be slightly decreased at the HDT in males and females
starting at week 4 [the first time period evaluated] and male dogs
maintained a decrease through out the study.   Some of the values in the
HDT were statistically significantly reduced, but were still within the
normal range for dogs.    The (ERY, (Hb and (Ht values [difference
between measured values and week -2 values] appeared to decrease in
males and females at the HDT starting at week 4 and male dogs maintained
the decrease through out the study.  This decrease is consistent with
the slightly higher incidence and/or severity of siderous in the spleen,
liver and Kupffer cells at the HDT.    Hemosiderin in the 1000 ppm group
was not considered sufficiently consistent to show that the mid dose
group was affected.  In addition the values for ERY, Hb and Ht from the
1000 ppm group of animals did not show consistent effects.  From week
26-52 to termination, the values for ERY, Hb and Ht for treated female
dogs did not appear to differ from control.       

Clinical chemistry values showed no consistent treatment related
effects.  Organ weights were unchanged from control values.  

On microscopic examination increased hemosiderin in liver and liver
Kupffer cells and possibly in the spleen at the HDT seemed to confirm
the hematological effects.  In addition, the highest dose group showed
higher incidence of gastritis and possible stomach lymphatic
hyperplasia.  

A single dog/sex was allowed to recover for 2 months and although the
hemosiderin appeared to decrease, effects in one dog are difficult to
interpret.

The NOAEL was 30.6/29.9 mg/kg/day for males/females.  The LOAEL was
94.0/94.4 mg/kg/day for male/females based on decreased erythrocytes,
hemoglobin and hematocrit by week 4 in males and females, supported by
hemosiderin deposits in liver and increased incidence of gastritis and
possible decreased body weight in males and females by month 13 of the
study, but not in females by study termination at 24 months.

This study is ACCEPTABLE/GUIDELINE and satisfies the guideline
requirement [870.4100b] for a dog chronic study.   This DER takes
precedence over previous conclusions.

A.3.5	Carcinogenicity  

	870.4200a Carcinogenicity Study – rat [MRID# 00082866]

	Unacceptable due to only1-year interim report of a 2-year study was
submitted. and other factors   Not required.

	870.4200b Carcinogenicity (feeding) – Mouse [MRID# 00082865]

SUMMARY: In a carcinogenicity study in mice [MRID 00082865], 50
NMBI-FMD-SPF mice/sex were administered IT 3456 [chlorflurenol methyl
ester] in the feed at 0, 1000, 3000 or10000 ppm  [equivalent to Males:
0, 136, 397 or 1538 mg/kg/day; Females: 0,158, 504 or 1905 mg/kg/day]
for 18 months.  Weekly body weights were determined up to week 12 and
every two weeks to termination.  Weekly food consumption was determined
up to week 12 and every two weeks to termination.  Necropsy and
microscopic examination of the tissue were performed at termination. 

No dose related or treatment related effects were noted in any parameter
studied.  Mortality, body weight, and food consumption were unchanged. 
Random tumors were seen after microscopic examination, but a dose or
treatment relationship was absent.   Neoplasms of the reticular tissue
were 8.25%, 15.96, 15.63 and 14.13%, respectively  in control, 1000 ppm,
3000 ppm and 10000 ppm.  Since historical control data for this neoplasm
ranges from 5% to 28%, control appear to be low compared with dosed
groups.  In addition, although over a 10 fold dose range, no dose
response was seen.   The highest incidence of tumors were pulmonary
adenomas.  Total pulmonary adenomas [benign and malignant] were 15.5%,
9.6%, 12.5% and 9.8%, respectively in control, 1000 ppm, 3000 ppm and
10000 ppm.              

No dose related toxic or carcinogenic effects were noted in mice above
the limit dose level of 1 g/kg/day.  

The NOAEL was the highest dose tested of 1538/1905 mg/kg/day in male and
female mice.  A LOAEL was not seen. 

The study is ACCEPTABLE/GUIDELINE and satisfies the requirements for a
carcinogenicity study in mice [870.4200].  The study was done prior to
GLPs.   Organ weights were not determined and some summary table were
not presented, but the study results appeared to be adequate to show
that there were no carcinogenic response in mice to chlorflurenol
administration. 

A.3.6	Mutagenicity 

	See Table A.2.2 for summary of the mutagenicity studies.

A.3.7	Neurotoxicity 

	These studies are not required.  Chlorflurenol methyl ester is neither
an organic phosphate nor shows evidence of neurotoxicity. 

	870.6100 Delayed Neurotoxicity Study - Hen

	870.6200 Acute Neurotoxicity Screening Battery

	870.6200 Subchronic Neurotoxicity Screening Battery

	870.6300 Developmental Neurotoxicity Study

A.3.8	Metabolism 

	870.7485	Metabolism – Rat

	Not required, but an unacceptable study was submitted   Study showed
some information, but study was inadequately replicated since most of
the tests were conducted in only one female rat.

EXECUTIVE SUMMARY: Kinetics and distribution of radiolabeled IT 3456, IT
3294 and IT 5733 [3 components of chlorflurenol methyl ester] were each
assessed [MRID 0082868].  The kinetic were conducted in 3 experiments. 
Experiment 1: One female Wistar rat each was administered a single dose
of 5 mg of IT 3456, IT 3294 or IT 5733/kg and the amount excreted n the
urine and feces collected at 24 hours.  Another set of 3 females were
dosed similarly and urine and feces collected at 72 hours and whole body
radio-autography conducted to located residual radiolabel.  Experiment
2: One lactating female/ test material was dosed with 10 mg/kg and 3
days later radio-autography conducted to locate residual radiolabel. 
Experiment 3: One nursing dam with 10 pups/dam was dosed with 5 mg/kg
and 3 days later radiolabel was counted in 2 pups/time period of 1, 2, 4
8 and 24 hours.  Doses were administered in 0.5 mL DMSO/kg by
intravenously into the caudal vein in Experiment 1 and 3 and by gavage
in 0.5 ml DMSO/kg in Experiment 2.  

	Each of all 3 test materials were excreted almost completely within 24
hours primarily in the urine with lesser amounts in the feces; small
amounts were excreted between 24 and 72 hours.  Enterohepatic
circulation was noted.  Most of the radiolabel detected were in the
lungs and kidney with small amounts of radiolabel detected in the
mammary gland in Experiment 2.  Pups from Experiment 3 showed no
measurable radiolabeled test material.   

	Thus, each of all three test materials were rapidly excreted in the
urine and feces, with small amounts being seen in the mammary gland and
none in the milk.    

The study is UNACCEPTABLE/NG for a metabolism study in rodents.  The
study results were no replicated and some of the data was not presented
and/or readable and thus conclusions were not verifiable.  Test
materials were inadequately identified.  Distribution of the radiolabel
in the rats was not adequately quantified.  The study may have been a
range-finding study.  

COMPLIANCE: These studies were conducted in 1972 prior to GLP Guideline
requirements.  No quality Assurance or Data Confidentiality Claim
statements were provided.

A.3.9	Dermal Absorption

	870.7600	Dermal Absorption – Rat

	A dermal absorption was not submitted. 

A.4	References 

00082863 	Frohberg, H.; Metallinos, A.; Pies, H.; et al. (1975) Chronic
Toxicity Test with IT 3456 in Beagle Dogs: Administration with the Food
over a Period of Two Years.  (Translation; unpublished study received
Apr 25, 1978 under 21137-EX-3; prepared by E. Merck, West Germany,
submitted by EM Laboratories, Inc., Elms- ford, N.Y.; CDL:097056-A). 

00082865	Hofmann, A.; Weisse, G.; Kovac, W.; et al. (1976) IT 3456:
18-month Carcinogenicity Study in Mice, Substance Administered in the
Food: Document No. CF 41 E/76.  (Unpublished study received Apr 25, 1978
under 21137-EX-3; prepared by E. Merck, West Germany, submitted by EM
Laboratories, Inc., Elmsford, N.Y.; CDL: 097058-A) 

00082868	Wenzl, H.; Garbe, A.; Nowak, H. (1972) EMD-IT 3294; EMD-IT
5733; EMD-IT 3456: Investigations of the Kinetics and Distribution in
Rats: Document No. CF 6/72.  (Translation; unpublished study received
Apr 25, 1978 under 21137-EX-3; prepared by E. Merck, West Germany,
submitted by EM Laboratories, Inc., Elmsford, N.Y.; CDL:097058-E) 

00120883	Kohn, F.; Stahoviak, E.; Vega, S.; et al. (1970) Report to
United States Borax Research Corporation: 21-day Subacute Dermal
Toxicity Study of Maintain CF-125: Lifestream Laboratories Project No.
1385.  (Unpublished study received Jan 7, 1970 under 1624-8; prepared by
Lifestream Corp., submitted by United States Borax & Chemical Corp., Los
Angeles, CA; CDL:108523-A) 

43355402	Wnorowski, G. (1994) Acute Oral Toxicity Limit Test:
(Chlorflurenol Methyl): Lab Project Number: 3170.  Unpublished study
prepared by Product Safety Labs.  16 p. 

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␱䀀Ħ摧熟¨ༀ355403	Wnorowski, G. (1994) Acute Dermal Toxicity
Limit Test: (Chlorflurenol Methyl): Lab Project Number: 2958. 
Unpublished study prepared by Product Safety Labs.  15 p. 

43355404	Wnorowski, G. (1994) Primary Eye Irritation: (Chlorflurenol
Methyl): Lab Project Number: 2605.  Unpublished study prepared by
Product Safety Labs.  21 p. 

43355405	Wnorowski, G. (1994) Primary Skin Irritation: (Chlorflurenol
Methyl): Lab Project Number: 2864.  Unpublished study prepared by
Product Safety Labs.  16 p.

43361701	Wnorowski, G. (1994) Dermal Sensitization Test--Buehler Method:
(Chlorflurenol Methyl): Lab Project Number: 3035.  Unpublished study
prepared by Product Safety Labs.  24 p. 43595402	Pant, K. (1995)
Evaluation of a Test Article in the Salmonella typhimurium Plate
Incorporation Mutation Assay in the Presence and Absence of
Aroclor-Induced Rat Liver S-9: Chlorflurenol-Methyl: Lab Project Number:
0336-2110: CFM-NITA-842A.  Unpublished study prepared by SITEK Research
Labs.  49 p.

43562801	Thilagar, A. (1995) Test for Chemical Induction of Chromosome
Aberration in Cultured Chinese Hamster Ovary (CHO) Cells With and
Without Metabolic Activation: Final Report: Lab Project Number:
0336-3110: CFM-NITA-842B.  Unpublished study prepared by Sitek Research
Labs.  59 p. 

45137404	Timm, A. (1988) Unscheduled DNA Synthesis in Hepatocytes of
Male Rates in Vitro (UDS Test) with Chlorflurenol-Methyl, Technical: Lab
Project Number: 117033.  Unpublished study prepared by CCR Cytotest Cell
Research GmbH & Co. KG.  30 p. {OPPTS 870.5550} 

45137405	Heidemann, A. (1988) Detection of Gene Mutations in Mammalian
Cells in Vitro HGPRT Test with Chlorflurenol-Methyl, Technical: Lab
Project Number: 117022.  Unpublished study prepared by CCR Cytotest Cell
Research GmbH & Co. KG.  34 p. {OPPTS 870.5300} 

45147201	Moore, G. (2000) Acute Inhalation Toxicity Study in Rats-Limit
Test: Chlorflurenol-Methyl (ICA-MECFOL): Lab Project Number: 9125: P330.
 Unpublished study prepared by Product Safety Labs. 24 p. {OPPTS
870.1300}

45190901	Muller, W. (2000) Chlorflurenol-Methyl, Technical Oral (Gavage)
Teratogenicity Study in the Rat: Lab Project Number: 926-460-028:
460-028.  Unpublished study prepared by Hazleton Laboratories
Deutschland GmbH.  222 p. 

45441001	Kuhn, J. (2001) 90-Day Oral Toxicity Study in Rats (Diet):
Chlorflurenol Methyl Ester: Final Report: Lab Project Number: 5472-99. 
Unpublished study prepared by Stillmeadow, Inc. 136 p. {OPPTS 870.3100}

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