Document ID: EPA-HQ-OPP-2006-0986-0012
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-09-26T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

June 27, 2007

SUBJECT:	Allethrins:  Revised HED Chapter of Reregistration Eligibility
Decision Document (RED).  for Bioallethrin (0040003),  Esbiol (004004), 
Esbiothrin (004007), and Pynamin Forte (004005) and Section 3
Registration Action for Use in Food Handling Establishments:  Esbiothrin
and Esbiol.   DP Barcode: D337992

FROM:	Kit Farwell, D.V.M., Toxicologist/Risk Assessor

		Timothy Dole, C.I.H., Occupational Residential Exposure Assessor

		Toiya Goodlow, Chemist

		Reregistration Branch 1

		Health Effects Division (7509P)

THROUGH:	Michael Metzger, Branch Chief

		Reregistration Branch 1

		Health Effects Division (7509P)

TO:	Molly Clayton, Chemical Review Manager

		Reregistration Branch 3

		Special Review and Reregistration Division (7508P)

		and

		Ann Sibold, Chemical Reviewer

Insecticide Branch

Registration Branch (7505P)

This document is the human health risk assessment for the allethrin
series of pyrethroid insecticides, Bioallethrin (004003), Esbiol
(004004), Esbiothrin (004007, formerly 004003/004004), and Pynamin Forte
(004005).  This risk assessment evaluates existing uses for the above
allethrins as well as a proposed Section 3 registration action for the
use of Esbiothrin and Esbiol in food handling establishments (FHE). 
This assessment has been revised to incorporate risk assessment and risk
mitigation changes that have occurred since the end of the public
comment period.

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc170786843"  1.0	EXECUTIVE
SUMMARY	  PAGEREF _Toc170786843 \h  4  

  HYPERLINK \l "_Toc170786844"  2.0	INGREDIENT PROFILE	  PAGEREF
_Toc170786844 \h  8  

  HYPERLINK \l "_Toc170786845"  2.1	Summary of Registered/Proposed Uses	
 PAGEREF _Toc170786845 \h  8  

  HYPERLINK \l "_Toc170786846"  2.2	Structure and Nomenclature	  PAGEREF
_Toc170786846 \h  11  

  HYPERLINK \l "_Toc170786847"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc170786847 \h  12  

  HYPERLINK \l "_Toc170786848"  3.0	Hazard Characterization/Assessment	 
PAGEREF _Toc170786848 \h  13  

  HYPERLINK \l "_Toc170786849"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc170786849 \h  13  

  HYPERLINK \l "_Toc170786850"  3.2	Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc170786850 \h  14  

  HYPERLINK \l "_Toc170786851"  3.3	FQPA Considerations	  PAGEREF
_Toc170786851 \h  14  

  HYPERLINK \l "_Toc170786852"  3.3.1	Toxicity Database	  PAGEREF
_Toc170786852 \h  14  

  HYPERLINK \l "_Toc170786853"  3.3.2	Developmental and Reproductive
Toxicity Studies	  PAGEREF _Toc170786853 \h  15  

  HYPERLINK \l "_Toc170786854"  3.3.3	Additional Information from
Literature Sources	  PAGEREF _Toc170786854 \h  21  

  HYPERLINK \l "_Toc170786855"  3.3.4	Pre-and/or Postnatal Toxicity	 
PAGEREF _Toc170786855 \h  21  

  HYPERLINK \l "_Toc170786856"  3.3.5	Recommendation for a DNT or
Comparative Neurotoxicity Study	  PAGEREF _Toc170786856 \h  21  

  HYPERLINK \l "_Toc170786857"  3.4	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc170786857 \h  22  

  HYPERLINK \l "_Toc170786858"  3.4.1	Acute Reference Dose - Females age
13-49	  PAGEREF _Toc170786858 \h  22  

  HYPERLINK \l "_Toc170786859"  3.4.2	Acute Reference Dose - General
Population	  PAGEREF _Toc170786859 \h  22  

  HYPERLINK \l "_Toc170786860"  3.4.3	Chronic Reference Dose (cRfD)	 
PAGEREF _Toc170786860 \h  23  

  HYPERLINK \l "_Toc170786861"  3.4.4	Incidental Oral Exposure
(Short-Term)	  PAGEREF _Toc170786861 \h  24  

  HYPERLINK \l "_Toc170786862"  3.4.5	Incidental Oral Exposure
(Intermediate-Term)	  PAGEREF _Toc170786862 \h  25  

  HYPERLINK \l "_Toc170786863"  3.4.6	Dermal Absorption	  PAGEREF
_Toc170786863 \h  26  

  HYPERLINK \l "_Toc170786864"  3.4.7	Dermal Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc170786864 \h  26  

  HYPERLINK \l "_Toc170786865"  3.4.8	Inhalation Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc170786865 \h  27  

  HYPERLINK \l "_Toc170786866"  3.4.9	Level of Concern for Margin of
Exposure	  PAGEREF _Toc170786866 \h  28  

  HYPERLINK \l "_Toc170786867"  3.4.10    Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc170786867 \h  28  

  HYPERLINK \l "_Toc170786868"  3.4.11     Classification of
Carcinogenic Potential	  PAGEREF _Toc170786868 \h  29  

  HYPERLINK \l "_Toc170786869"  3.5	Endocrine disruption	  PAGEREF
_Toc170786869 \h  31  

  HYPERLINK \l "_Toc170786870"  4.0	Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc170786870 \h  31  

  HYPERLINK \l "_Toc170786871"  5.0	Dietary Exposure/Risk
Characterization	  PAGEREF _Toc170786871 \h  32  

  HYPERLINK \l "_Toc170786872"  5.1	Pesticide Metabolism and Drinking
Water Profile	  PAGEREF _Toc170786872 \h  32  

  HYPERLINK \l "_Toc170786873"  5.2	Dietary Exposure and Risk	  PAGEREF
_Toc170786873 \h  32  

  HYPERLINK \l "_Toc170786874"  5.2.1	Acute Dietary Exposure/Risk	 
PAGEREF _Toc170786874 \h  34  

  HYPERLINK \l "_Toc170786875"  5.2.2	Chronic Dietary Exposure/Risk	 
PAGEREF _Toc170786875 \h  34  

  HYPERLINK \l "_Toc170786876"  5.3	Anticipated Residues	  PAGEREF
_Toc170786876 \h  35  

  HYPERLINK \l "_Toc170786877"  5.4	Dietary Risk Characterization	 
PAGEREF _Toc170786877 \h  37  

  HYPERLINK \l "_Toc170786878"  6.0	Residential Exposure/Risk
Characterization	  PAGEREF _Toc170786878 \h  38  

  HYPERLINK \l "_Toc170786879"  6.1	Residential Handler Exposure	 
PAGEREF _Toc170786879 \h  38  

  HYPERLINK \l "_Toc170786880"  6.2.	Residential Post Application
Exposure	  PAGEREF _Toc170786880 \h  38  

  HYPERLINK \l "_Toc170786881"  6.2.1	Residential Post Application
Exposure Data	  PAGEREF _Toc170786881 \h  39  

  HYPERLINK \l "_Toc170786882"  6.2.2	Residential Post Application
Exposure Assumptions	  PAGEREF _Toc170786882 \h  39  

  HYPERLINK \l "_Toc170786883"  6.2.3	Residential Post Application Risk
Estimates	  PAGEREF _Toc170786883 \h  42  

  HYPERLINK \l "_Toc170786884"  6.3 Residential Risk Characterization	 
PAGEREF _Toc170786884 \h  42  

  HYPERLINK \l "_Toc170786885"  7.0	Aggregate Risk Assessments	  PAGEREF
_Toc170786885 \h  44  

  HYPERLINK \l "_Toc170786886"  8.0	Cumulative Risk Assessment	  PAGEREF
_Toc170786886 \h  45  

  HYPERLINK \l "_Toc170786887"  9.0	Occupational Exposures and Risk	 
PAGEREF _Toc170786887 \h  45  

  HYPERLINK \l "_Toc170786888"  9.1	Occupational Handler Risk	  PAGEREF
_Toc170786888 \h  45  

  HYPERLINK \l "_Toc170786889"  9.2	Occupational Post Application Risk	 
PAGEREF _Toc170786889 \h  47  

  HYPERLINK \l "_Toc170786890"  10.0	 Data Needs and Label Requirements	
 PAGEREF _Toc170786890 \h  49  

  HYPERLINK \l "_Toc170786891"  REFERENCES:	  PAGEREF _Toc170786891 \h 
51  

  HYPERLINK \l "_Toc170786892"  Appendix A:	Toxicology Assessment	 
PAGEREF _Toc170786892 \h  52  

  HYPERLINK \l "_Toc170786893"  A.1	Toxicology Data Requirements	 
PAGEREF _Toc170786893 \h  52  

  HYPERLINK \l "_Toc170786894"  A.2	Toxicity Profiles	  PAGEREF
_Toc170786894 \h  53  

  HYPERLINK \l "_Toc170786895"  Appendix B:	Tolerance Reassessment
Summary and Table	  PAGEREF _Toc170786895 \h  59  

 1.0	EXECUTIVE SUMMARY

  SEQ CHAPTER \h \r 1 This human health risk assessment is being
conducted as part of EPA’s human health risk assessment for the
Allethrins Reregistration Eligibility Decision (RED) and a proposed
Section 3 registration action for the use of Esbiothrin and Esbiol in
food handling establishments (FHE).   This document addresses the human
health risks associated with allethrins based on label prescribed uses. 
This document has been revised to include the following risk assessment
and risk mitigation changes.

Risk Assessment Changes

1.	The POD for chronic dietary and intermediate term incidental oral
exposures has been changed from 6.0 mg/kg/day to 8.0 mg/kg/day based
upon a benchmark dose analysis.

2.   A developmental neurotoxicity (DNT) study is required for the
allethrins.   However, the Agency is currently evaluating whether a DNT
or another comparative toxicity study measuring different endpoints
would be best suited for addressing the concern for sensitivity to young
animals.

Risk Mitigation Changes (To be included in the Allethrin RED)

1.   The residential PCO product labels will be limited to a 0.1 percent
spray dilution rate, and language to labeling will be added reducing the
volume from 1 gallon per 1000 ft2 to 0.5 gallon per 1000 ft2. 

2.	The maximum spray dilution for indoor fogging applications will be
reduced from 3.0 percent (as listed on the Esbiol 300 Insect label
#432-870) to 1.5 percent.

3.	The consumer surface and space sprays, which currently range from
0.05 percent to 0.5 percent ai in products, will be limited to 0.25
percent ai.

4.	The consumer product labels will be changed to require spot treatment
only.  The broadcast surface applications to rugs and carpets will be
eliminated.   

5.	The use of the 6 ounce outdoor total release fogger will be deleted
from the Raid Yard Guard label (4822-394).

6.	The pet uses (aerosols sprays and shampoos) will be cancelled.  The
pet bedding uses will remain as spot treatments.

Allethrins:  The allethrin series of pyrethroid insecticides assessed in
this document include Bioallethrin (004003), Esbiol (004004), Esbiothrin
(004007, formerly 004003/004004), and Pynamin Forte (004005).  This risk
assessment evaluates existing uses for the above allethrins as well as a
proposed Section 3 registration action for the use of Esbiothrin and
Esbiol in food handling establishments (FHE).  

The allethrins all have the same chemical structure but have several
isomers which are "mirror images" of each other.  The allethrins differ
only in the percentage of isomers present in each pesticide (see Table
2.2b).  

Allethrin was the very first pyrethroid to be developed in 1949 and is
structurally very similar to cinerin I in naturally occurring pyrethrum.
 The allethrins cause immediate but temporary paralysis of insects
("knockdown" action), but are not "kill" agents for insects, so they are
usually formulated with a synergist and/or with other pyrethroids to
prevent recovery by insects.  The allethrins are classified as type I
pyrethroids because they lack an α-cyano substituent.  They degrade
rapidly in sunlight.  

Uses:  Allethrins are used to control flying and crawling insects in a
number of commercial, horticultural and residential applications. 
Commercial applications include space, broadcast and crack and crevice
treatment in a variety of commercial, industrial and institutional
sites.  Horticultural applications include foliar and fogger treatment
on non-food plants.  Residential uses include pest control in homes and
outdoor domestic structures, and on gardens.  There are also proposed
uses of Esbiothrin and Esbiol in food handling establishments as space
or general spray, spot and/or crack and crevice treatment.  Allethrins
are formulated as liquid concentrates, ready to use aerosol sprays, pet
shampoos and dips, mosquito coils and mosquito mats.

Hazard:  A number of new toxicity studies have been received since the
allethrins were last evaluated by the Hazard Identification Assessment
Review Committee in 1997.  The toxicity database is most complete for
Esbiothrin and Pynamin Forte.  The d-trans d- isomer, which is present
in the greatest concentration in Esbiol (see Table 2.2b), is reportedly
more insecticidally active than the other 3 main isomers.  

Similar types of toxicity (neurotoxicity and liver toxicity) occurred at
generally similar doses with the different allethrins and data from all
four chemicals were used to select endpoints and assess potential
sensitivity for FQPA considerations.  Clinical signs of neurotoxicity
were seen in rat and dog studies, and occurred at lower doses after
gavage or capsule dosing than after exposure in the feed.  Liver
toxicity in subchronic and chronic rat, mouse, and dog studies included
microscopic liver changes, elevated liver enzymes, and increased liver
weight.  

Genetic toxicity studies with Esbiol, Esbiothrin, Bioallethrin, and
Pynamin Forte were negative for mutagenicity.  Carcinogenicity studies
were conducted with Esbiothrin and Pynamin Forte.  The only evidence of
carcinogenicity was the appearance of rare benign kidney tumors in male
rats treated with Esbiothrin.  Doses in the mouse carcinogenicity study
were considered inadequate and Esbiothrin is classified as having
"suggestive evidence of carcinogenicity, but not sufficient to assess
human carcinogenic potential".  

Developmental toxicity included rib/rib-vertebral anomalies in a rabbit
developmental study with Pynamin Forte.  No developmental toxicity was
noted in rats treated with Esbiol, Esbiothrin, or Pynamin Forte or in
rabbits treated with Esbiol or Esbiothrin.  In a reproductive study with
Esbiothrin, decreased viability and a marginal increase in delayed
developmental milestones occurred.  Decreased pup body weights occurred
in a reproduction study with Pynamin Forte.  

Endpoints:   The endpoints for risk assessment were based on
neurotoxicity and liver toxicity.  Because endpoints for risk assessment
were at the same or lower dose at which developmental and reproductive
toxicity occurred, there were no concerns for sensitivity of offspring. 
The allethrins are neurotoxicants and a DNT or comparative neurotoxicity
study in adults and offspring is required.  A database uncertainty
factor of 10x was applied to the points of departure used in dietary and
residential assessments to account for the lack of this study.  

No systemic toxicity was noted in dermal exposure studies with Esbiol,
Esbiothrin, or Pynamin Forte and risk assessments by the dermal route of
exposure were not required.  Clinical signs of neurotoxicity occurred in
an inhalation study with Esbiol.  

Drinking water:  The registered uses of the allethrins are not expected
to adversely impact groundwater or surface water; therefore, a
qualitative drinking water assessment was not performed. 

Food exposure:   Although acute dietary exposure analyses are not
ordinarily required for food handling uses, the application of
allethrins as a space spray produced relatively high residues, and an
acute dietary assessment was therefore conducted.  The acute analysis
assumed that 100% of food handling establishments and all foods were
treated with allethrins.  DEEM default processing factors were
incorporated.  Anticipated residues were determined based on the
magnitude of residue study for food handling establishment uses, which
analyzed milk, butter, cooked and uncooked meat, flour, rice, bread,
lettuce, cooked and uncooked apples, candy and sugar.  The highest
residue values from each commodity were translated to other foods when
appropriate.  For foods forms that could not be translated, the highest
residue value of 0.93 ppm was used.  Dietary risk estimates were
determined considering exposures from food only; no exposure to drinking
water is expected as a result of allethrins application.  

For dietary assessments, HED is concerned if dietary risk exceeds 100%
of the Population Adjusted Dose (PAD).  For the allethrins, acute
dietary risk estimates were below the Agency’s level of concern.  The
highest exposure and risk estimates were for children 1-2 years old.  At
the 95th percentile, the exposure for children 1-2 years of age was
0.027 mg/kg/day, which utilized 90% of the acute population adjusted
dose (aPAD).  

A partially refined chronic dietary exposure assessment was also
performed.  The assessment included average residue values from the FHE
magnitude of residue study.  It was also assumed that all foods and 20%
of all food handling facilities were treated with allethrins based on an
estimate by the Biological Effects and Analysis Division (BEAD). 
Default DEEM processing factors were incorporated.  Chronic dietary risk
estimates were below the Agency’s level of concern.  The highest
exposure and risk estimates were for children 1-2 years old:  exposure
was 0.0024 mg/kg/day, which utilized 31% of the chronic population
adjusted dose (cPAD).  

Residential handlers:  An assessment was conducted for handlers who mix,
load, and apply allethrins in a residential setting.  Only inhalation
exposures were assessed for the residential handler scenarios.  Dermal
exposures were not assessed because no systemic toxicity occurred at the
limit dose in dermal toxicity studies.  Data from the Pesticide Handlers
Exposure Database were used because chemical-specific monitoring data
were not available.  Residential handler exposures were assessed for
aerosol can application to a variety of use sites.  This application is
protective of risks from trigger sprayer applications because the unit
exposure values are lower for trigger sprayer application.     SEQ
CHAPTER \h \r 1 All of the handler MOEs exceed the target MOE of 1000
and are not of concern at baseline.   

Residential post application:  The term “post application” describes
individuals who are exposed to pesticides after entering areas
previously treated with pesticides.  Allethrin post application
incidental oral exposures may occur after surface applications of
allethrin are made to residential areas such as carpets and vinyl
flooring.  Inhalation exposures may occur after space spray and outdoor
fogger applications.  Incidental oral exposures were assessed for
toddlers and inhalation exposures were assessed for adults and toddlers.
 The MOEs were all greater than the target MOE of 1000 except for
inhalation exposures from yard and patio total release fogger
application where the MOE is 650.

Residential Risk Characterization:  The yard and patio fogger scenario
is only of concern when the product is in the form of a total release
fogger.   The yard and patio scenario is not of concern when the product
is in the form of a hand held fogger.   Although both product forms are
on the same label (4822-394) the hand held form is more typically found
on retail shelves and likely represents the majority of usage.  This is
supported by the Residential Exposure Joint Venture (REJV) survey which
indicated that most of the Allethrin containing Yard and Patio Fogger
products in the house hold inventory were hand held foggers.  The hand
held fogger contains approximately 454 grams of product which is enough
for approximately 9 sprays based upon the nozzle discharge rate of 6
grams per second and a spray duration of 9 seconds   By contrast, the
total release foggers can only be used once because they discharge their
entire contents upon activation.  It should also be noted that the NOAEL
of 1.3 mg/kg/day observed in the inhalation study may be an artifact of
dose spacing because it is five times lower than the LOAEL of 6.5
mg/kg/day.   Given that the MOE is 650 with a NOAEL of 1.3 mg/kg/day,
only a slightly higher NOAEL of 2.0 mg/kg/day would yield an MOE of
1000.  Considering this, HED has minimal concern with an MOE of 650 for
this scenario.

Aggregate exposure:  Aggregate assessments were conducted for incidental
oral exposure scenarios because the same study is used for the dietary
and incidental oral exposure endpoints based on liver toxicity in dog
studies.  Inhalation exposure was not aggregated because the endpoint
for inhalation exposure was based on a different effect (neurotoxicity).
 Aggregate risk was calculated for combined food and residential
exposure for children 1-2 years old because this age group had the
highest dietary exposure and could be expected to receive incidental
oral exposure.  No endpoints were identified for dermal exposure and the
allethrins are not expected to adversely impact ground water, so
exposure by these routes was not aggregated.  The short term aggregate
MOEs are not of concern for any of the scenarios because they exceed the
LOC of 1000   An intermediate term aggregate MOE of 750 was estimated
for one scenario (PCO Broadcast – Carpet).  There is minimal concern
for this estimated risk, however, since the intermediate term
(continuous exposure over a one to six month period) exposures of
toddlers to day zero carpet surface residues is highly unlikely due to
dissipation.  The MOE of 750 is expected to be protective for this
exposure scenario. 

Occupational handlers:  Although the term “handler” applies to
individuals who mix, load, and apply the pesticide product, most
allethrin products are packaged in aerosol cans, so most of the
allethrin uses involve only application.  There are a few products
packaged as ready to use liquids or liquid concentrates, which are
applied with mechanical sprayers, compressed air sprayers or foggers. 
These products are used in commercial/industrial/ institutional areas,
non-food greenhouses and non-food animal premises.   

Only inhalation exposures were assessed.   Most of the inhalation MOEs
are above the target MOE of 100 without respirators and therefore the
inhalation risks are not of concern.   The high pressure handwand
scenario is of concern without respirators and requires a dust mask to
achieve the target MOE.  The space spray fogger scenario is also of
concern and requires a PF50 full face respirator with appropriate
cartridges to achieve the target MOE.

Occupational post application:   Occupational post application
inhalation exposure was assessed for a metered release scenario.  The
MOE is 850, which exceeds the target MOE of 100 and is not of concern.  

2.0	INGREDIENT PROFILE

Summary of Registered/Proposed Uses

Target Pests and Use Sites:

  SEQ CHAPTER \h \r 1 Insecticides containing allethrins are used to
control flying and crawling insects at a variety of occupational and
residential use sites as listed below:

Domestic (household):   Crawling and flying insect killers for use
indoors as space, general surface, spot and crack & crevice
applications; on house plants and residential greenhouses.

Crawling and flying insect killers for use outdoors as localized space
and contact spray, perimeter treatments (sidewalks, decks, patios,
outside surfaces of buildings, etc.), and application to ornamental
plants.

Commercial/Industrial/Institutional:   Crawling and flying insect
killers for use indoors as space, general surface, spot and crack &
crevice applications.  Also for use on indoor plants.

Crawling and flying insect killers for use outdoors as localized space
and contact sprays and perimeter treatments (sidewalks. entranceways,
outside surfaces of buildings, etc.). Also for use on ornamental plants
in landscaped areas.

Greenhouses:  Use in commercial greenhouses to control various plant
pests on ornamentals as a space and/or contact spray.

Food Handling Establishments:  There are proposed uses of Esbiothrin and
Esbiol in food handling establishments as space or general spray, spot
and/or crack and crevice treatment.  A food handling establishment is
any place other than a residential kitchen in which food is held,
processed, prepared, and/or served.  

Formulations

  SEQ CHAPTER \h \r 1 Allethrins are formulated as emulsifiable
concentrates, liquid concentrates, pressurized liquids, ready to use
liquid sprays, pet shampoos and dips, mosquito coils and mosquito mats. 
The registered products are formulated and used as listed in Table 2.1a.

Table 2.1a.  Allethrin Formulations and Use Categories

Formulation	Number of LabelsA	Domestic Household	Commercial

Industrial

Institutional	Greenhouse	Animal TreatmentB

Pressurized Liquid	136	YES	YES	YES	YES

RTU Liquids 	31	YES	YES	YES	YES

Emulsifiable Concentrates	3	NO	YES	YES	YES

Liquid Concentrates	6	NO	YES	YES	YES

Shampoos and Dips	22	NO	NO	NO	YES

Mosquito Coils and MatsC	15	YES	NO	NO	NO

A. As listed in the Use Closure Memo.

B. Primarily includes cats, dogs and horses.   Excludes animals used for
food.

C. Listed as impregnated materials in OPPIN.

Smart Meeting Information

A summary of information about application of allethrins obtained from
Smart meetings with registrants is included in Table 2.1b.  

Table 2.1b.  Allethrin Smart Meeting Information 

Use 	Indoor/

Outdoor	Percent ai	Comments

Crawling Insect Killer Aerosols

(Surface Spray)	Both	0.05 to 0.25	Spray until wet (20 to 50 ml/m2). 
Droplet size is 50 to 80 micron.

Wasp and Hornet Aerosols	Outdoor 	0.05 to 0.1 (water or solvent based)
Spray nest for to 2 – 3 seconds.  Discharge rate is 20 grams per
second in a jet stream with a range of 15 to 20 feet.

Yard and Patio Foggers 

(i.e. hand held foggers)	Outdoor 	0.1 to 0.15 (water based)	Spray for 2
to 3 sec. at bushes, grass etc.  Typical discharge rate is 5-6 gram
product per sec.  Application rate is 1 to 3 seconds per square meter.
Droplet size is 50 to 100 micron.  

Flying Insect Killer Aerosols 

(Space Spray)	Both	0.1 to 0.25 (usually water based)	Spray room for 3-5
sec. Keep room closed for 15 minutes and ventilate (i.e. open windows)
prior to re-entry.  Discharge rate 1 gram per second.  Droplet size is
10 to 25 micron.  Not very effective outdoors.  Very common overseas. 
Not common in the U.S.

Total Release Aerosols 

(i.e. stationary foggers)	Indoor	1.2 to 3.0 (usually water based)	6
ounce can treats 5000 to 6000 ft3 room. Droplet size is 40 to 50 micron.
Vacate room for several hours.  Ventilate for 30 minutes.

Mosquito and Fly Repellent Mats	Outdoor	Mosquito 7%

Fly         24%	Mats weigh 0.93 grams and last 10 hours.  Protect an
average patio (15 x 15 ft).  Aerosol size is very small (<2 microns).

Mosquito Repellent Coils	Outdoor	0.25 to 0.3 %	Coils weigh 12 grams and
burn for 6 to 7 hours.

Pet Spray Aerosols *

	Indoor	0.2% water based	Apply directly to animal until hair is moist. 
Can also be used to treat bedding rugs and carpets.  Largely replaced by
spot-ons and pills (Frontline, Advantage, Program)

Pet shampoos*	Indoor	0.12%	For use on dogs. Largely replaced by spot-ons
and pills.

* Note - the pet spray and shampoo uses will be cancelled. 

Proposed Uses

A summary of use directions for the proposed uses of Esbiol and
Esbiothrin in food-handling establishments are shown in Table 2.1c.



Table 2.1c.  Summary of Use Directions for Esbiol and Esbiothrin in Food
Handling Establishments.

Application 

Type	

Formulation

	

Application Rate 

	

Max. No. Application per Season	

Max. Seasonal Application Rate	Use Directions and Limitations

Esbiol

General spray	

VBC Esbiol® 90 Insecticide	

1.43 % final dilution spray, 1.0 fluid oz. per 1000 ft3	Not Specified
Not Specified	

Note 1

Space Spray

	Note 2

Spot Treatment

0.32% final dilution spray, 0.45 fluid oz. per 1000 ft2

	Note 3, 4

Crack and Crevice Treatment

1.43 % final dilution spray, 1.0 fluid oz. per 1000 ft3

	Note 5

Esbiothrin

General spray	

VBC Esbiothrin® 90 Insecticide	1.70 % final dilution spray, 1.0 fluid
oz. per 1000 ft3	Not Specified	Not Specified	

Note 1

Space Spray

	Note 2

Spot Treatment

0.39% final dilution spray, 0.55 fluid oz. per 1000 ft2

	Note 6,4

Crack and Crevice Treatment

1.70 % final dilution spray, 1.0 fluid oz. per 1000 ft3

	Note 5

Notes

1. Do not apply directly to food/feed. Do not apply as a space spray
while food processing is underway.  Cover or remove all food and food
processing surfaces. Wash all food processing surfaces before reuse.
After spraying, wash all surfaces where food will be handled and rinse
with potable water rinse prior to use. Except in federally-inspected
meat and poultry plants, food/feed processing operations do not have to
be stopped.  

2. Cover or remove exposed food/feed and cover food handling surfaces. 
Close rooms and shut ventilating equipment.  Apply at application rate
of 1.0 oz/1000 ft3, filling the room with mist. Vacate treated area and
ventilate before reoccupying. Keep area closed for at least 1 hour.
Repeat treatment if reinfestation occurs. Do not apply while food
processing is underway.  In animal quarters (unoccupied cattle and horse
barns, poultry and swine houses, kennels): Cover exposed water, drinking
fountains and animal feed before application. Direct spray towards upper
portions of the enclosure filling the room with mist. Vacate area and
ventilate before reoccupying.

3. Mix 0.45 oz. of concentrate with sufficient oil to equal 1 gallon of
diluted spray. 

4.  Apply as a coarse droplet spray using 1 gallon to 1000 ft2. Spray
walls, floors and other surfaces of bins, storage and handling areas.
Treat unloading, handling and processing areas. Also treat inside
conveying, processing and handling equipment. Spray around the base of
heavy machinery and equipment. Spray insects directly when possible.

5. Treat wall voids, insect tunnels, boxed beams and other hollow
elements of construction. Inject voids for 5-10 seconds followed by
sufficient air to move particles throughout the void.

6. Mix 0.55 oz. of concentrate with sufficient oil to equal 1 gallon of
diluted spray. 

2.2	Structure and Nomenclature  TC \l2 "2.2	Structure and Nomenclature 

The allethrin series of pyrethroid insecticides assessed in this risk
assessment include Bioallethrin (0040003),  Esbiol (004004),  Esbiothrin
(004007, formerly 004003/004004), and Pynamin Forte (004005).  

The different allethrin pyrethroids differ only in the percentage of
stereoisomers present.  There are three asymmetric carbons and thus
eight potential isomers, although 4 isomers are present in the greatest
concentration for these products.  The allethrins are structurally very
similar to cinerin I in naturally occurring pyrethrum.  

Allethrin (004001, no longer registered) was the very first pyrethroid
to be developed in 1949.  The allethrins cause immediate but temporary
paralysis of insects ("knockdown" action), but are not "kill" agents for
insects, so they are usually formulated with a synergist and/or with
other pyrethroids to prevent recovery by insects.  The allethrins are
classified as type I pyrethroids because they lack an α-cyano
substituent.  They degrade rapidly in sunlight.  

Table 2.2a.  Test Compound Nomenclature

Chemical Structure for the Allethrins	

Empirical Formula	C19H26O3

Molecular Weight	302.4

Chemical Class	type I pyrethroid

Known Impurities of Concern	None



Table 2.2b.  Percentage of Isomers for Each Technical Product in the
Allethrin Family

Isomer	

Esbiol

(S-Bioallethrin)	

Esbiothrin	

Bio-allethrin	

Pynamin Forte

(d-allethrin)

PC Code	

004004	

004007 a	

004003	

004005

CAS #	

28434-00-6	

584-79-2	

584-79-2	

584-79-2

d-trans chrysanthemic acid of  d-allethrolone b	

> 90%	

72%	

( 46%	

36%

d-trans chrysanthemic acid of l-allethrolone	

5%	

21%	

( 46%	

36%

d-cis chrysanthemic acid of d-allethrolone	

- - - c	

- - - 	

- - - 	

9%

d-cis chrysanthemic acid of l-allethrolone	

- - - 	

- - - 	

- - - 	

9%

a  PC code for Esbiothrin formerly 004003/004004

b The d-trans d- isomer is reportedly the most insecticidally active;
isomer used in plant metabolism study.	

c  - - - indicates < 2%

 Adapted from 1/23/97 William O. Smith memo (D222638).

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

Table 2.3.  Physical and Chemical Properties

Parameter	Esbiol a

S-Bioallethrin	Esbiothrin b

	Bioallethrin c

	Pynamin Forte d

d-allethrin

Physical state	viscous liquid	viscous liquid	viscous liquid a	liquid

Boiling point	165-1700 C	1650 C	1650 C	281.50 C

pH	4.9	4.5	4.3	4.08

Density	1.010	1.010	1.012	1.009

Water solubility 	4.6 mg/L	4.6 mg/L	4.6 mg/L	5.0 mg/L

Vapor pressure mm Hg	3.3 x 10-4	3.3 x 10-4 	3.3 x 10-4	1.24 x 10-6

Dissociation constant	N/A	N/A	N/A	N/A

Octanol/water partition 	KOW = 48000	log Pow > 5	log Pow > 5	POW = 8.94
x104

UV/visible absorption 	not reported	not reported	not reported	not
reported

a 2/2/06 Product Chemistry Review, D326386	b 2/27/97 Product Chemistry
Review, D226959	   

c 2/27/97 Product Chemistry Review, D226950   	d 12/27/05 Product
Chemistry Review, D324618

3.0	Hazard 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 

Esbiothrin, Esbiol, and Bioallethrin were evaluated together by the
Hazard Identification Assessment Review Committee (HIARC) in 1997. 
Although bridging of toxicity data between the chemicals had previously
been done, the HIARC decided not to allow bridging between those three
allethrins because of the limited database, especially for developmental
and reproductive toxicity studies.  Since that time, a number of new
studies have been submitted and reviewed which provide a sufficient
database for bridging.  

New studies with Esbiol include developmental toxicity in rats and
rabbits, acute and subchronic neurotoxicity studies, subchronic dermal
toxicity in rats, and a subchronic inhalation toxicity study.  New
studies with Pynamin Forte include a 2- generation reproductive toxicity
study in rats, a 21-day dermal toxicity in rabbits, an Ames study, and
an inhalation study.  There is also a new micronucleus study with
Bioallethrin.  The inhalation study with Pynamin Forte was recently
submitted and classified unacceptable although this study had a higher
NOAEL than that from the only other allethrin inhalation study (Esbiol).
 

The new and old studies with Esbiothrin evaluated for this assessment
include developmental studies in rats and rabbits, a 2-generation
reproduction study in rats, chronic toxicity studies in dogs and rats,
carcinogenicity studies in rats and mice, subchronic studies in mice and
dogs, a 21-day dermal study in rabbits, and a battery of mutagenicity
studies.  

The new and old studies with Pynamin Forte include developmental rat and
rabbit studies, a 2-generation reproduction study in rats, chronic
toxicity studies in dogs and rats, carcinogenicity studies in rats and
mice, a subchronic dermal toxicity study in rabbits, an inhalation study
in rats, and a subchronic feeding study in mice. 

The new and old studies with Esbiol include developmental studies in
rats and rabbits, acute and subchronic neurotoxicity studies in rats,
subchronic feeding studies in rats and dogs, subchronic dermal and
inhalation studies, and mutagenicity studies.  

Bioallethrin studies include a developmental rat study, subchronic
studies with rats and dogs, metabolism studies, and mutagenicity
studies.  

The registrants report that the d-trans d- isomer is more insecticidally
active than the other 3 main isomers (d-trans l-,  d-cis d-,  and d-cis
l-).  No side-by-side comparisons of the 4 main isomers are available;
however, if the d-trans d- isomer is more insecticidally active, then
this isomer could cause neurotoxicity at a lower dose than the other
isomers.  This is not always evident from the toxicity studies which
used different doses for the different chemicals and were conducted by
different labs in different years.  

Clinical signs of neurotoxicity, such as muscle tremors, hunched
posture, salivation, were seen in the rat studies which used gavage
dosing.  Muscle tremors and other signs of neurotoxicity were noted in
dog subchronic and chronic studies and occurred at a lower dose in a
capsule study than in feeding studies.  

Liver toxicity in subchronic and chronic rat, mouse, and dog studies
included increased liver weight, microscopic liver changes, and elevated
liver enzymes.  Microscopic changes in the thyroid were noted in a
subchronic rat study with Esbiol.  

Genetic toxicity studies with Esbiol, Esbiothrin, Bioallethrin, and
Pynamin Forte were negative for mutagenicity.  Carcinogenicity studies
were conducted with Esbiothrin and Pynamin Forte.  The only evidence of
carcinogenicity was rare benign kidney tumors in male rats treated with
Esbiothrin.  Doses in the mouse carcinogenicity study were considered
inadequate and the cancer classification for Esbiothrin is "suggestive
evidence of carcinogenicity, but not sufficient to assess human
carcinogenic potential".  

Developmental toxicity included rib/rib-vertebral anomalies in a rabbit
developmental study with Pynamin Forte.  No developmental toxicity was
noted in rats treated with Bioallethrin, Esbiol, Esbiothrin, or Pynamin
Forte or in rabbits treated with Esbiol or Esbiothrin.  

In a reproductive study with Esbiothrin, decreased viability and a
marginal increase in delayed developmental milestones occurred. 
Decreased pup body weights occurred in a reproduction study with Pynamin
Forte.  

No systemic toxicity was noted in dermal exposure studies with Esbiol,
Esbiothrin, or Pynamin Forte.  Clinical signs of neurotoxicity occurred
in an inhalation study with Esbiol.  

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

Two metabolism studies with Bioallethrin were available.  There were no
major differences between sexes, between low and high dose groups, nor
between single-dose groups and repeated-dose groups.  The majority of
radioactivity was eliminated within 3 days.  Urinary elimination ranged
from approximately 25 – 50% and fecal elimination ranged from 50 –
70%.  There was no bioaccumulation of residue in tissues.  Metabolism
was mainly by oxidation of double bonds and isobutenyl methyl groups, by
ester cleavage, and by conjugation.  Principal metabolites included
esters and conjugates of allethrolone and dihydroxy allethrolone, epoxy
allethrin, and allethrolone.  

3.3	FQPA Considerations  TC \l2 "3.3	FQPA Considerations 

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

There are developmental toxicity studies in rats with Bioallethrin,
Esbiothrin, Esbiol, Pynamin Forte; developmental rabbit studies with
Esbiothrin, Esbiol, Pynamin Forte; 2-generation reproduction studies
with Esbiothrin and Pynamin Forte; and acute and subchronic
neurotoxicity studies with Esbiol.  Comparative neurotoxicity studies in
adults and offspring are not available for any of the allethrins. 

se they lack an α-cyano substituent, in contrast to the type II
pyrethroids which have an α-cyano substituent.  Neurotoxicity of type I
pyrethroids is characterized as tremor, prostration, enhanced startle
response, and aggressive behavior (Casarett and Doull's Toxicology, 6th
edition).  Similar signs were observed in the guideline studies in which
clinical signs of neurotoxicity were noted. 

3.3.2	Developmental and Reproductive Toxicity Studies  TC \l3 "3.3.3
Developmental Toxicity Studies 

Developmental Toxicity with Esbiothrin (rats):   In a developmental
toxicity study (MRID 41632201), 24 pregnant Crl:CD®BR rats per group
were administered Esbiothrin (95.2% a.i.) by gavage at doses of 0, 5,
25, or 125 mg/kg/day on gestation days (GD) 6-15, inclusive.  On GD 20,
all dams were sacrificed, subjected to gross necropsy, and all fetuses
examined externally.  

No clinical signs of toxicity or mortalities were observed in the 0, 5,
or 25 mg/kg/day groups.  One rat died at 125 mg/kg/day (HDT, day 10 of
gestation).  A significantly (p ( 0.01) increased incidence of tremors
(21/25), body jerks (20/25), and hypersensitivity to sound (20/25) were
observed in high-dose dams.  These observations generally occurred for
approximately 4 hours after intubation on days 10 through 15 of
gestation and did not persist overnight.  Excessive salivation was
observed in 0/25, 1/25, 2/25, and 1/25 animals in the 0, 5, 25, and 125
mg/kg/day groups, respectively, and may have been related to treatment. 
No treatment-related effects were observed on maternal body weight, food
consumption, or gross necropsy.

The maternal toxicity LOAEL is 125 mg/kg/day based on clinical signs of
toxicity and the maternal toxicity NOAEL is 25 mg/kg/day.

Pregnancy incidences; the average number of corpora lutea,
implantations, resorptions and fetuses per litter; the number of dams
with viable fetuses; and the litter averages for fetal sex ratios, body
weights and percent resorbed conceptuses were comparable with the
control group for all treated groups.  No treatment-related gross
external, soft tissue, or skeletal malformations/variations were
observed in fetuses from any dose group.

The developmental toxicity NOAEL is >125 mg/kg/day and the developmental
toxicity LOAEL was not identified.

This developmental toxicity study in the rat is classified acceptable
(guideline) and satisfies the guideline requirement for a developmental
toxicity study (OPPTS 870.3700) in the rat.

Developmental Toxicity with Esbiol (rats):   In a developmental toxicity
study (MRID 44666301), Esbiol (96.9%) was administered to 22 female CD
(SD) rats/dose by gavage at dose levels of 0, 5, 20, or 80 mg/kg bw/day
on days 6 through 15 of gestation, inclusive.  On GD 20, all surviving
dams were sacrificed and examined grossly.  

A total of four high-dose dams died prior to scheduled termination.  One
animal was found dead on GD 7; three others were killed moribund on GDs
7, 9, and 14, respectively.  Among high-dose animals that survived to
termination, 100% showed tremors and piloerection between GDs 11-15. 
Clinical signs were absent by about 2 hours post-dosing.  All control,
low-, and mid-dose animals survived to scheduled termination with no
treatment-related clinical signs of toxicity.  No treatment-related
effects on absolute body weight were observed in any group during the
study.  

The maternal toxicity LOAEL for Esbiol in Sprague-Dawley rats is 80
mg/kg/day based on mortality and clinical signs of toxicity.  The
maternal toxicity NOAEL is 20 mg/kg/day.

No treatment-related differences were noted between the treated and
control groups for numbers of corpora lutea and implantations, placental
and gravid uterine weights, live fetuses per dam, resorptions, fetal sex
ratios, and pre- or post-implantation losses.  Fetal body weights were
similar between the treated and control groups.  Developmental toxicity
was not identified; there were no treatment-related external, visceral,
or skeletal malformations/variations observed in any group.

The developmental toxicity LOAEL for Esbiol in Sprague-Dawley rats is
not identified and the developmental toxicity NOAEL is (80 mg/kg/day. 
This developmental toxicity study in the rat is classified
Acceptable/Guideline and satisfies the guideline requirements for a
developmental toxicity study in rats.

Developmental Toxicity with Pynamin Forte (rats):   In a developmental
toxicity study (MRID 41225803), Pynamin Forte (93.4) was administered to
25 pregnant Crl:CD(SD)BR rats per dose by gavage from gestation days 6 -
15.  Doses were 0, 10, 30, or 100 mg/kg/day.  

Maternal toxicity at 100 mg/kg/day included clinical signs (excessive
salivation, tremors, body jerks, chromodacryorrhea), and decreased body
weight gain.  The maternal NOAEL was 30 mg/kg/day.  The maternal LOAEL
was 100 mg/kg/day based on clinical signs and decreased body weight
gain. 

No developmental toxicity occurred in this study.  Treatment had no
effect on pregnancy incidences, number of corpora lutea, implantations,
implantation efficiencies, litter sizes, live and dead fetuses, early
and late resorptions, fetal body weights, fetal sex ratios, or fetal
viability.  No teratogenic effects were noted.  The developmental NOAEL
was 100 mg/kg/day, the highest dose tested.  The developmental LOAEL was
not determined.  

In a rangefinding study, the maternal LOAEL was 50 mg/kg/day, the lowest
dose tested, based on clinical signs (salivation) and the developmental
NOAEL was 300 mg/kg/day, the highest dose tested.  

This developmental toxicity study in rats is classified
acceptable/guideline and satisfies guideline requirements for a
developmental toxicity study in rats.  

Developmental Toxicity with Bioallethrin (rats):   In a developmental
toxicity study (MRID 00078624), at least 28 pregnant Sprague-Dawley rats
per group were administered Bioallethrin (92.5%) by gavage at doses of
0, 50, 125, or 195 mg/kg/day on gestation days (GD) 6-15, inclusive.  

No clinical signs of toxicity were observed in animals from the 0, 50,
or 125 mg/kg/day groups.  An increase in the incidence of maternal
mortality occurred in the high-dose group: 0/28, 0/33, 1/33, and 6/34 (p
( 0.05) dams in the 0, 50, 125, and 195 mg/kg/day groups, respectively. 

The maternal toxicity LOAEL is 195 mg/kg/day based on increased
mortality and the maternal toxicity NOAEL is 125 mg/kg/day.

There were no differences between treated groups and controls for
pregnancy rate, numbers of corpora lutea, implantations, live or dead
fetuses, or resorptions per dam, and fetal body weights.  No
treatment-related external or visceral malformations/variations were
observed in any fetuses.  Rudimentary ribs were increased in all treated
groups, however, this was not considered a treatment-related effect. 
The developmental toxicity NOAEL is 195 mg/kg/day. 

There were several major deficiencies in the conduct of this study:
dosing solutions were not analyzed for concentration, homogeneity, or
stability; food consumption was not measured; gross necropsies were not
performed on the dams; individual maternal and fetal data were not
included; and number of corpora lutea were not calculated on the summary
table.  This study is classified Acceptable (nonguideline) and does not
satisfy the guideline requirements for a developmental toxicity study in
rats.

Developmental Toxicity with Esbiothrin (rabbits):   In a developmental
toxicity study (MRID 41632202), 20 pregnant New Zealand white rabbits
per group were administered Esbiothrin (95.2%) by gavage at doses of 0,
30, 100, and 300 mg/kg/day on gestation days (GD) 6-18, inclusive. 
Cesarean section was performed on all surviving does on GD 29 followed
by teratological examination of all fetuses.

No treatment-related mortalities or clinical signs of toxicity were
observed in does in the 0, 30, or 100 mg/kg/day groups.  In the 300
mg/kg/day dose group, four does died during the treatment period (3 on
GD 9 and 1 on GD 10).  A significantly (p ( 0.01) increased incidence of
clinical signs of toxicity at the high-dose included tremors (7/20),
decreased motor activity (7/20), ataxia (6/20), and impaired righting
reflex (4/20).  These signs generally occurred about 4 hours postdosing
on GD 7-12 and did not persist more than one day.

There were no statistically significant differences attributed to
treatment in body weights, body weight gains, or food consumption values
between the 30 or 100 mg/kg/day groups and the controls.  In the
high-dose group, all of the does that died had reduced body weight prior
to death.  If these animals are excluded from the group means, there
were no significant differences in body weights or body weight gains
between the high dose group and the controls at any time period.  No
gross lesions attributable to the test substance were observed in any of
the does, including those that died.

The maternal toxicity LOAEL is 300 mg/kg/day based on mortality and
clinical signs of toxicity (tremors, decreased motor activity, ataxia,
and impaired righting reflex) and the maternal toxicity NOAEL is 100
mg/kg/day.

There were no statistically significant differences between the treated
and control groups in pregnancy indices, averages for corpora lutea,
implantations, live litter sizes, resorptions, fetal sex ratios, fetal
body weights, percent resorbed conceptuses, or the numbers of does with
any resorptions or with viable fetuses.  There were no fetal gross,
external, soft tissue, or skeletal malformations/variations that were
considered to be related to treatment.

The NOAEL for developmental toxicity is 300 mg/kg/day (HDT) and the
LOAEL was not identified.  This developmental toxicity study in the
rabbit is classified acceptable (guideline) and satisfies the guideline
requirement for a developmental toxicity study in rabbits.

Developmental Toxicity with Esbiol (rabbits):   In a developmental
toxicity study (MRID 44657801), Esbiol (96.9) was administered to 16
female New Zealand white rabbits/dose by gavage at dose levels of 0, 5,
50, or 200 mg/kg bw/day from gestation days (GD) 6 through 19,
inclusive.  On GD 29, all surviving does were sacrificed and examined
grossly.  

No treatment-related deaths occurred in any animal and gross necropsy
was unremarkable.  One low-dose doe aborted on GD 21 and was sacrificed.
 Clinical signs of toxicity were limited to tremors in one high-dose
animal on GD 19 approximately 30 minutes after dosing.  No
treatment-related effects on absolute body weight were observed in any
group during the study.  The high-dose animals had transient decreases
in body weight gain after the initiation of dosing.  Food consumption by
the high-dose group was 86% of the control group level for GD 6-12.  A
compensatory increase in food consumption occurred in the high-dose
group during the post-dosing interval.  

The maternal toxicity LOAEL is 200 mg/kg/day based on decreased body
weight gain and tremors.  The maternal toxicity NOAEL is 50 mg/kg/day.

Treatment had no effect on numbers of corpora lutea, implantations,
gravid uterine weights, live fetuses, resorptions, fetal sex ratios,
pre- or post-implantation losses, fetal body weights, or external or
visceral malformations/variations.  The high-dose group had an increased
number of litters with incomplete metacarpal(tarsal)/phalangeal
ossification (6 litters vs 2 in controls) and an increased number of
litters with unossified epiphyses (7 litters vs 4 in controls).  There
was also an increased number of fetuses with 13 ribs (77 vs 56 in
controls) and an increased number of fetuses with 20 thoracolumbar
vertebrae (46 vs 36 in controls); litter data for these effects were not
available.  

The developmental toxicity LOAEL for Esbiol in New Zealand white rabbits
is 200 mg/kg/day based on decreased ossification.  The developmental
toxicity NOAEL is 50 mg/kg/day.  This developmental toxicity study in
the rabbit is classified Acceptable/Guideline and satisfies guideline
requirements for a developmental toxicity study in rabbits. 

Developmental Toxicity with Pynamin Forte (rabbits):   In a
developmental toxicity study (MRID 41225806), Pynamin Forte (93.4) was
administered to 20 pregnant NZW rabbits per dose by gavage from
gestation days 7 - 19.  Doses were 0, 30, 100, or 350 mg/kg/day.  

The death of one doe in the high-dose group on day 10 of gestation was
attributed to treatment.  Body weight gains in the high-dose group were
significantly less than controls from gestation days 7 - 10 (-30 g vs
+20 g in controls), but were comparable to controls for the entire
dosing period (+110 g vs +130 g in controls).  Two does in the high-dose
group had gastric inflammation or ulceration.  The maternal NOAEL is 100
mg/kg/day.  The maternal LOAEL is 350 mg/kg/day based on mortality and
decreased body weight gain.  

Treatment had no effect upon the number of corpora lutea, implantations,
resorptions and live fetuses; implantation efficiencies; percentages of
live male fetuses; fetal body weights or litter sizes. 
Rib/rib-vertebral malformations were increased in the high-dose group.  

The developmental NOAEL is 100 mg/kg/day.  The developmental LOAEL is
350 mg/kg/day based upon increased rib/rib-vertebral malformations. 
This developmental toxicity study in rabbits is classified
acceptable/guideline and satisfies guideline requirements for a
developmental toxicity study in rabbits.

Reproduction Study with Esbiothrin:   Esbiothrin was tested in a
2-generation reproduction study in rats at 0, 70, 200, 600 or 1800 ppm
(0, 5.8, 16.8, 50.4 or 150.0 mg/kg/day for males and 0, 7.4, 22.5, 67.1
or 207.0 mg/kg/day for females).  

No treatment-related effects were observed on mortality or clinical
signs of toxicity in F0 or F1 male or female parents.  No
treatment-related effects were observed on body weights in treated F0
males or females.  Body weights at 1800-ppm were slightly decreased
throughout treatment in F1 males (92-95% of the control values, p<0.05)
and on premating days 1, 15, 50, and 99, gestation day 21, and lactation
days 1 and 4 in F1 females (92-93% of control values).  There were no
treatment-related effects on gross or microscopic findings.

The parental NOAEL is 600 ppm (50.4 mg/kg/day for males and 67.1
mg/kg/day for females) and the LOAEL is 1800 ppm based on decreases in
body weights in male and female F1 parents (150.0 mg/kg/day for males
and 207.0 mg/kg/day for females).  

There were no treatment-related effects on reproductive performance of
either generation.  The day 21 viability index for high-dose F1 pups was
significantly decreased.  No statistically significant decreases in
viability indices were observed for F2 pups.  

F1 and F2 pups in the 1800-ppm group showed evidence of delayed
development (eye opening, auricular duct opening, and air righting).  
Body weights of F1 pups in the 1800-ppm group were significantly less
than control values throughout lactation (range: 76% at day 7 to 94% at
day 1). F2 pups in the 1800-ppm group weighed 91 to 93% of control
weights throughout lactation.  Body weight gain in F1 pups was reduced
by 42% at 1800 ppm during the first 7 days of lactation.  

The LOAEL for developmental effects is 1800 ppm (150.0 mg/kg/day for
males and 207.0 mg/kg/day for females) based on decreased viability,
decreased body weight gain, and delayed developmental milestones of the
pups.  The corresponding NOAEL is 600 ppm (50.4 mg/kg/day for males and
67.1 mg/kg/day for females).

This two-generation reproduction study in rats is classified acceptable
(guideline) and satisfies guideline requirements for a two-generation
reproduction study in rats.

Reproduction Study with Pynamin Forte:   In a 2-generation reproduction
study (MRID 41246801) Pynamin Forte (d-allethrin, 91.9% a.i.) was
administered to 30 Crl:COBS® CD®(SD)BR rats/sex/dose in the diet at 0,
200, 2,000, or 6,000 ppm (equivalent to doses of 0, 12.8, 130.0, or
386.7 mg/kg/day for P1 males; 0, 13.3, 137.0, or 430.5 mg/kg/day for F1
males; 0, 14.7, 144.6, or 440.1 mg/kg/day for P1 females; 0, 14.6,
152.4, or 476.9 mg/kg/day for F1 females).  

There was no effect upon reproductive indices.  At the 2,000 ppm dose
level, treatment-related reductions in body weights and body weight
gains were noted in the F1 females and reductions in  body weight gains
were noted in the P1 and F1 males.  For both generations, absolute and
relative liver weights were increased and treatment-related
hepatocellular hypertrophy was noted (P1 males only and in both sexes of
the F1 generation).

Parental toxicity at 6,000 ppm for both generations and sexes included
reductions in body weights, body weight gains, and feed consumption
values; increases in absolute and relative (to body weight) liver
weights; and histopathology of the liver described as hepatocellular
hypertrophy.

The parental NOAEL = 200 ppm (12.8 mg/kg/day in males and 14.7 mg/kg/day
in females) and the parental LOAEL = 2000 ppm (130 mg/kg/day in males
and 145 mg/kg/day in females) based on reductions in body weights, body
weight gains, increases in absolute and relative liver weights, and
hepatocellular hypertrophy. 

At 6,000 ppm, treatment-related decreases in mean pup body weights were
noted in both the F1 and F2 generations.  For the F1 generation litters
dosed at the high-dose, the severity of the reductions in body weight
increased over time as the pups began to supplement their nutrient
intake (milk) with the treated diet ((9% on day 4, p(0.05 and (21% on
day 21, p(0.01).  For the high-dose F2 litters, mean pup body weights
were also decreased throughout lactation ((3-18%), however, the
differences from the controls were not statistically significant.

The offspring NOAEL is 200 ppm (14.7 mg/kg/day) and the LOAEL for
offspring toxicity is 2,000 ppm (145 mg/kg/day) based on reductions in
pup body weights of the F2 generation.  

The reproductive study in the rat is classified Acceptable/Guideline and
satisfies the guideline requirement for a 2-generation reproductive
study (OPPTS 870.3800, §83-4) in rats.

3.3.3	Additional Information from Literature Sources  TC \l3 "3.3.5
Additional Information from Literature Sources 

No relevant information from the open literature was found in a PubMed
search.  

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

Developmental:   There was no evidence of prenatal susceptibility in
developmental rat studies with Bioallethrin, Esbiol, Esbiothrin, or
Pynamin Forte;  or in a developmental rabbit study with Esbiothrin
because no treatment-related developmental toxicity occurred in these
studies.  There was no evidence of prenatal susceptibility in the
developmental rabbit study with Pynamin Forte because rib and vertebral
malformations occurred at the same dose as maternal mortality.  There
was no evidence of prenatal susceptibility in the developmental rabbit
study with Esbiol because decreased ossification occurred at the same
dose as did maternal neurotoxicity.  

Reproductive:   There was evidence of postnatal qualitative
susceptibility in the 2-generation reproduction study with Esbiothrin: 
decreased pup viability and delayed developmental milestones occurred at
a dose that only caused decreased parental body weight.  

There was no evidence of postnatal susceptibility in the 2-generation
reproduction study with Pynamin Forte.  Decreased pup body weights
occurred at the same dose which caused decreases in parental body weight
and liver effects.  

Degree of Concern Analysis for Pre- and/or Postnatal Susceptibility:  
There was evidence of susceptibility in the Esbiothrin 2-generation
reproduction study.  However, there are no residual uncertainties
because the NOAELs for dietary exposure (30 and 8 mg/kg/day), incidental
oral exposure (20 and 8 mg/kg/day), and inhalation exposure (1.3
mg/kg/day) are all lower than the offspring NOAEL from the reproductive
study (50 mg/kg/day).

3.3.5	Recommendation for a DNT or Comparative Neurotoxicity Study  TC
\l3 "3.3.7	Recommendation for a Developmental Neurotoxicity Study 

As described above, the allethrins are neurotoxicants which act by
prolonging the opening of the sodium channel in nervous tissue,
resulting in a hyperexcitable state.  Neurotoxicity was observed in a
number of dog and rat studies, tremors being the most common sign. 
Neurotoxicity in the Esbiol acute neurotoxicity study also included
hunched posture, abnormal gait, and decreased grip strength. A
developmental neurotoxicity (DNT) study is required for the allethrins. 
 However, the Agency is currently evaluating whether a DNT or
comparative toxicity study in adults and offspring would be best suited
for addressing the concern for sensitivity to young animals.

 

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

3.4.1	Acute Reference Dose - Females age 13-49  TC \l3 "3.5.1	Acute
Reference Dose (aRfD) - Females age 13-49 

Study Selected:   Not applicable

MRID Number:  None

Dose and Endpoint for Establishing aRfD:   None

Comments about Study/Endpoint/Uncertainty Factor:   Rib/rib-vertebral
malformations were noted in the Pynamin Forte rabbit developmental study
and decreased ossification occurred in the Esbiol rabbit developmental
study.  These endpoints were not selected because the NOAELs (100
mg/kg/day and 50 mg/kg/day, respectively) were significantly higher than
the NOAEL based on neurotoxicity selected for the general population
acute reference dose (aRfD).  Therefore, the acute dietary assessment
based on neurotoxic effects will be protective of developmental effects
as well.  

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

Study Selected:   Acute neurotoxicity in rats (Esbiol)

MRID Number:   44517801

Dose and Endpoint for Establishing aRfD:   

NOAEL = 30 mg/kg/day

LOAEL = 90 mg/kg/day based on FOB findings (tremors, hunched posture,
abnormal gait, decreased grip strength) 

Uncertainty Factor(s):   1000x (10x for interspecies extrapolation, 10x
for intraspecies variability, and 10x for lack of a comparative
neurotoxicity study)

Comments:   The FOB changes are characteristic of the allethrins. 

Acute RfD =   30 mg/kg/day  =  0.03 mg/kg/day

          1000

Executive Summary:   In an acute oral neurotoxicity study (MRID
44517801), Esbiol (S-Bioallethrin; 96.9% w/w a.i., Batch/lot # 6N 0248B)
in 1% (w/v) methylcellulose in purified water was administered in a
single dose by gavage (10 mL/kg) to fasted Sprague-Dawley CD rats
(10/sex/dose) at doses of 0, 5, 30, or 90 mg/kg.  All animals were
observed for up to 14 days post-dosing.  Functional observational
battery (FOB) and motor activity were evaluated pretreatment and on Days
1 (at the time of peak effect, approximately 30-60 minutes post-dosing),
and days 7 and 14.  At termination, 5 rats/sex/group were perfused in
situ for neurohistological examination.  Positive pathology control data
were not provided.

At 90 mg/kg, the following transient FOB effects were noted in females
on Day 1: increased incidence of slight to moderately hunched posture,
slight to moderate body twitches, and severe tremor during homecage
observations; slight to moderately abnormal gait, slight to severe
tremor, and slight head or body twitches during open-field observations;
and increased (p<=0.01) body temperature (incr 0.9(C), and decreased
hindlimb (decr 22%, p<=0.05) and forelimb (decr 12%, NS) grip strength.

No compound-related effects on mortality, clinical signs, body weight,
body weight gain, food consumption, motor activity, or gross and
histopathology were observed at any dose.  No adverse treatment-related
FOB effects were noted at Days 7 and 14.

The NOAEL is 30 mg/kg.   The LOAEL is 90 mg/kg based on FOB effects
(hunched posture, head and/or body twitches, tremor, abnormal gait,
increased body temperature, and decreased hindlimb and forelimb grip
strength) which occurred on day 1 in females. 

Although positive control data demonstrated the ability to detect major
neurotoxic endpoints and changes in motor activity, pathology positive
control data were not submitted.  However, neuropathology has not been
noted with other pyrethroids.  This study is classified
acceptable/non-guideline and satisfies the guideline requirements (OPPTS
870.6200a; OECD 424) for an acute neurotoxicity screening battery in
rats. 

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

Study Selected:   6-Month dog feeding study (Bioallethrin)

MRID Number:  00151447

Dose and Endpoint for Establishing cRfD:  

BMDL10 = 8.0 mg/kg/day based on microscopic liver changes
(hepatocellular degeneration) for males and females occurring at the mid
and high doses.  

Uncertainty Factor(s):   1000x (10x for interspecies extrapolation, 10x
for intraspecies variability, and 10x for lack of a comparative
neurotoxicity study)

Comments about Study/Endpoint/Uncertainty Factor:   Liver toxicity
occurs in other studies with the allethrins.  A BMDL10 was used rather
than the NOAEL from this study because of the 6x difference between the
NOAEL (6 mg/kg/day) and the LOAEL (36 mg/kg/day).  A 10% response for
the BMDL was selected because of the mild nature of the lesions,
characterized as "acute swelling of hepatocytes", which did not progress
in severity at the high dose.  The lesions were accompanied by increased
relative liver weight and moderate increases in alkaline phosphatase in
males.  The selected BMDL10 value was 267 ppm (D339909).  This dietary
concentration was converted to a mg/kg/day dose by using the dose in
males, which was lower than that in females:  267 ppm/200 ppm x 6.1
mg/kg/day = 8 mg/kg/day.  

Chronic RfD  =   8 mg/kg/day  =  0.008 mg/kg/day

          1000

Executive Summary:   In an oral toxicity study (MRID 00151447),
Bioallethrin (92.5% a.i.) was administered to 6 beagle dogs/sex/dose in
the diet at levels of 0, 200, 1000, or 5000 ppm for 6 months.  These
concentrations resulted in approximate dose levels of 0, 6.1, 36.3, or
162 mg/kg/day for males and 0, 7.2, 36.4, or 172 mg/kg/day for females.

Clinical observations included slight irregular heart rhythms and
general body trembling in high-dose males and females and excessive
salivation in high-dose males only.  The onset of body tremors ranged
from weeks 1 to 4 and were last observed between weeks 1 and 27. 
Decreases in mean body weight gain were observed in mid-dose males and
in high-dose males and females, and food consumption was consistently
decreased in high-dose males and females.  No treatment-related effects
on ophthalmology, hematology, urinalysis, or gross pathology were
observed.  

Increases in mean alkaline phosphatase enzyme activity was observed in
mid-dose males (+196%) and high-dose males (+493%) and high-dose females
(+382%) compared to controls; this increase is considered
toxicologically significant at the high dose.  SGPT enzyme activity was
increased in high-dose animals males (+367%) and females (+452%)
compared to control values.  GGTP enzyme activity was increased in
high-dose animals but there was considerable variation in control
animals and this was not considered toxicologically significant. 
Increased relative liver weights were observed in mid- and high-dose
animals of both sexes.  A dose-related hepatocellular degeneration of
the liver was observed in mid- and high-dose males and females.  

The NOAEL for this study is 200 ppm (6.1 mg/kg/day for males; 7.2
mg/kg/day for females) and the LOAEL is 1000 ppm (36.3 mg/kg/day for
males; 36.4 mg/kg/day for females), based on hepatocellular degeneration
in both sexes at 1000 ppm and above.  Toxicity at the high dose (5000
ppm) also included slight irregular heart rhythms and general body
trembling (both sexes), salivation (males), decreases in body weight
gain and food consumption (both sexes), and increases in liver enzymes. 

This toxicity study is classified acceptable (nonguideline) for a
chronic feeding study and acceptable (guideline) for a subchronic
feeding study in the dog.  It is a well conducted study and was
conducted during the time when six month dog studies were considered
acceptable as chronic studies.

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

Study Selected:   30-day dog feeding study (Esbiothrin)

MRID Number:   43293401

Dose and Endpoint:  

NOAEL = 20 mg/kg/day

LOAEL = 63 mg/kg/day based on liver toxicity

Uncertainty Factor(s):  1000x (10x for interspecies extrapolation, 10x
for intraspecies variability, 10x for lack of a comparative
neurotoxicity study)

Comments about Study/Endpoint/Uncertainty Factor:  The duration of
exposure was appropriate for this endpoint.  Although this was a
rangefinding study, it was considered an acceptable study for endpoint
selection.  

Executive Summary:   In a 4-week rangefinding study in dogs (MRID
43293401), Esbiothrin (94.7 to 98.8 %) was administered to two Beagle
dogs/sex in the feed at concentrations of 0, 50, 200, 800, 3200 or 6400
ppm (males: 0, 1.3, 4.5, 19.5, 63.2 or 153.2 mg/kg/day;  females: 0,
1.5, 5.9, 22.1, 74.8, or 174.0 mg/kg/day. 

One male in the high-dose group had clinical signs which began on day 8
and became more pronounced until day 29, when the dog was found dead. 
Clinical signs usually began 3 hours after eating, lasted about 6 hours
and included marked tremors, restlessness and uncoordinated movements. 
Several days before death, the signs intensified to loss of balance,
lateral recumbency, stereotypes of the mouth, clonic convulsions and
epileptic seizures.  No clinical signs were observed in any other dogs. 
Body weights in treated animals were generally comparable to controls,
although there was a larger overall body weight loss in 6400 ppm males
(-1.5 kg) compared to controls (-0.1 kg).  

Liver enzymes were elevated in 3200 and 6400 ppm males and females
although there was a lot of variability because there were only two
dogs/sex/group.  Alkaline phosphatase was elevated in 3200 ppm males
(184% of controls), in one 3200 ppm female (458%), in 6400 ppm males
(312%), and in 6400 females (354%).   ALT was elevated in one 3200 ppm
male (1317%) and in the 6400 ppm males (312%).  Absolute liver weights
were elevated in 3200 ppm males (123%) and females (146%), and in the
surviving 6400 ppm male (135%) and the 6400 ppm females (200%). 
Relative liver weights were increased in 3200 ppm males (146%) and
females (163%), and in the surviving 6400 ppm male (156%) and the 6400
ppm females (203%).  Brown pigments in the hepatocytes and bile
canaliculi was seen microscopically in the high-dose dogs, but no
toxicologically significant lesions were observed.  

The NOAEL is 800 ppm (19.5 mg/kg/day in males and 22.1 mg/kg/day in
females).  The LOAEL is 3200 ppm ( 63.2 mg/kg/day in males and 74.8
mg/kg/day in females), based on elevated liver enzymes and increased
liver weight.  This 4-week rangefinding study in dogs is classified
acceptable/non-guideline.  It was used for dose selection for the
chronic study in dogs. 

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

Study Selected:   6-Month dog feeding study (Bioallethrin)

MRID Number:  00151447

Dose and Endpoint:  BMDL10 = 8.0 mg/kg/day based on microscopic liver
changes (hepatocellular degeneration) for males and females occurring at
the mid and high doses.  

Uncertainty Factor(s):   1000x (10x for interspecies extrapolation, 10x
for intraspecies variability, and 10x for lack of a comparative
neurotoxicity study)

Comments about Study/Endpoint/Uncertainty Factor:   Liver toxicity
occurs in other studies with the allethrins.  A BMDL10 was used rather
than the NOAEL from this study because of the 6x difference between the
NOAEL (6 mg/kg/day) and the LOAEL (36 mg/kg/day).  A 10% response for
the BMDL was selected because of the mild nature of the lesions,
characterized as "acute swelling of hepatocytes", which did not progress
in severity at the high dose.  The lesions were accompanied by increased
relative liver weight and moderate increases in alkaline phosphatase in
males.  The selected BMDL10 value was 267 ppm.  This dietary
concentration was converted to a mg/kg/day dose by using the dose in
males, which was lower than that in females:  267 ppm/200 ppm x 6.1
mg/kg/day = 8 mg/kg/day.  

Executive Summary:   See chronic dietary section, above, for the
executive summary.  

 3.4.6	Dermal Absorption  TC \l3 "3.5.5	Dermal Absorption 

There is not an acceptable dermal absorption study with any of the
allethrins.   

See Comments section for Dermal Exposure section, below.  

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

Study Selected:   N/A

MRID Number:  N/A

Dose and Endpoint for Establishing cRfD:   N/A

Uncertainty Factor(s):   N/A

Comments about Study/Endpoint/Uncertainty Factor:  Dermal risk
assessments are not required because no systemic toxicity occurred in a
dermal rat study at 1000 mg/kg/day with Esbiol; or at 1000 mg/kg/day in
rabbits with Esbiothrin; or at 300 mg/kg/day (highest dose tested) in
rabbits with Pynamin Forte.  In addition, there was negligible dermal
absorption with the closely related pyrethrin isomers (0.22%).   There
were no developmental concerns from the Pynamin Forte or Esbiol rabbit
developmental studies:  rib malformations or decreased ossification
occurred at a maternally lethal dose or at a dose causing maternal
neurotoxicity.  

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

Study Selected:   28-Day inhalation study in rats (Esbiol)

MRID Number:  MRID 44517802

Dose and Endpoint:   

NOAEL = 1.3 mg/kg/day

LOAEL = 6.5 mg/kg/day based on clinical signs in females (limb tremors,
hunched posture, vocalization during handling)

Uncertainty Factor(s):  100x for occupational exposure (10x for
interspecies extrapolation and 10x for intraspecies variability).  1000x
for residential exposure (included 10x database uncertainty factor for
lack of a comparative neurotoxicity study.  

Comments about Study/Endpoint/Uncertainty Factor:   The route of
exposure is appropriate for this exposure scenario.  An acute inhalation
assessment using an endpoint from the acute neurotoxicity study was not
performed because the NOAEL from that study (30 mg/kg/day) was much
greater than the NOAEL from the inhalation study (1.3 mg/kg/day).  An
inhalation study with Pynamin Forte is currently classified
unacceptable/guideline.  

Executive Summary:   In a 28-day inhalation toxicity study (MRID
44517802), Esbiol (S-Bioallethrin; 96.9% w/w a.i.; Lot/batch # 6N 0248B)
was administered via snout-only inhalation to CD Sprague-Dawley rats
(5/sex/concentration) for 6 hours/day, 5 days/week for 4 weeks at
analytical concentrations of 0, 0.0051, 0.025, or 0.073 mg/L.  Doses
were equivalent to 0, 1.3, 6.5, or 19.0 mg/kg/day.  

There were no effects of treatment on survival, body weights, body
weight gains, food consumption, clinical chemistry, organ weights, gross
pathology, or histopathology.

Clinical signs of toxicity in mid- and high-dose females included
intermittent tremors in the limbs, hunched posture, and vocalization
when handled.  Additionally at 0.073 mg/L in these animals, walking on
tiptoes and aggressive behavior were observed.   Intermittent tremors in
the limbs were also noted in the high-dose males.

Additional clinical observations indicated a compromised ability of the
rats to maintain a clean, groomed appearance and included increased
incidences over controls of:  wet and/or matted fur in high-dose males
and mid- and high-dose females; brown staining on head in mid- and
high-dose females; hair loss on body in the high-dose males; and brown
staining around snout in the all male and female treatment groups.  At
necropsy, badly groomed fur on the dorsum was observed in 3/5 females in
the high-dose group.  

The LOAEL is 0.025 mg/L (6.5 mg/kg/day) based on increased incidences of
clinical signs of toxicity (intermittent tremors in the limbs, hunched
posture, vocalization during handling, ungroomed appearance) in females.
 The NOAEL is 0.0051 mg/L (1.3 mg/kg/day).  The submitted study is
classified as acceptable/non-guideline (only 5 animals per group) and
satisfies the requirements for which it was intended as a 28-day
inhalation toxicity study in the rat.

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

The target Margins of Exposure (MOEs) for residential and occupational
exposure and risk assessment are as follows:

Table 3.4.9   Summary of Levels of Concern for Risk Assessment.

Route of Exposure	

	Duration of Exposure

	

Short-Term 

(1-30 Days)	

Intermediate-Term

(1-6 Months)	

Long-Term

(>6 Months)

Occupational Exposure

Dermal (all populations)	

N/A	

N/A	

N/A

Inhalation (all populations)	

100	

100	

100

Residential Exposure

Incidental Oral	

1000	

1000	

1000

Dermal (all populations)	

N/A	

N/A	

N/A

Inhalation (all populations)	

1000	

1000	

1000

Incidental oral and inhalation MOEs for residential exposure include a
10x database uncertainty factor for lack of a comparative neurotoxicity
study.  

A dermal risk assessment was not required because there was no systemic
toxicity in dermal toxicity studies at 1000 mg/kg/day and because of
negligible dermal absorption with pyrethrin (0.22%).  

3.4.10    Recommendation for Aggregate Exposure Risk Assessments  TC \l3
"3.5.9	Recommendation for Aggregate Exposure Risk Assessments 

An aggregate exposure considers exposure from three major routes:  oral,
dermal, and inhalation.  No endpoints were identified for dermal
exposure, so dermal exposure need not be assessed in an aggregate
assessment of the allethrins.  Because the allethrins are not expected
to adversely impact ground water, drinking water will not be included in
an aggregate assessment.  

A short-term aggregate exposure assessment can be conducted for post
application exposure which will include dietary exposure and incidental
oral exposure using the endpoint for short-term incidental oral
exposure.  The NOAEL is 20 mg/kg/day based on liver toxicity in the
30-day dog study with Esbiothrin.  Inhalation exposure will not be
included because inhalation exposure has a different endpoint
(neurotoxicity), however, liver toxicity is the most sensitive endpoint.
 An intermediate-term aggregate exposure assessment can be conducted for
post application exposure which will include dietary exposure and
incidental oral exposure.  The endpoint uses a BMDL10 of 8 mg/kg/day
based on liver toxicity in a 6-month dog study with Bioallethrin.  As
mentioned above, inhalation exposure will not be included because
inhalation exposure has a different endpoint (neurotoxicity).  

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

Genetic toxicity studies with Esbiol, Esbiothrin, Bioallethrin, and
Pynamin Forte were negative for mutagenicity.  Carcinogenicity studies
were conducted with Esbiothrin and Pynamin Forte.  The only evidence of
carcinogenicity was rare benign kidney tumors in male rats treated with
Esbiothrin.  Doses in the mouse carcinogenicity study were considered
inadequate and the cancer classification for Esbiothrin is "suggestive
evidence of carcinogenicity, but not sufficient to assess human
carcinogenic potential".  

3.4.12	Summary of Toxicological Doses and Endpoints

Table 3.4.a  Toxicological Doses and Endpoints for Dietary and
Residential Exposure

Exposure/

Scenario	Point of Departure	Uncertainty/

FQPA Safety Factors	RfD, PAD, Level of Concern	Study and Toxicological
Effects

Acute Dietary (General Population, including infants and children)	NOAEL
=  30 mg/kg

	UFA = 10x

UFH = 10x

FQPA SF= 10x

[UFDB]	aRfD = 0.03 mg/kg 

aPAD = 0.03 mg/kg	Acute neurotoxicity in rats (Esbiol).  LOAEL = 90
mg/kg based on functional observational battery (tremors, hunched
posture, abnormal gait, decr. grip strength)

Chronic Dietary (All Populations)	BMDL10 = 8 mg/kg/day

	UFA = 10x

UFH = 10x

FQPA SF = 10x

[UFDB]	cRfD = 0.008 mg/kg/day

cPAD = 0.008  mg/kg/day	6-month dog (Bioallethrin).  

BMDL10 based on based on microscopic liver changes (hepatocellular
degeneration)

Incidental Oral Short-Term 

(1-30 days)	NOAEL = 20 mg/kg/day	UFA = 10x

UFH = 10x

FQPA SF = 10x

[UFDB]	Residential LOC for MOE = [1000]	30-day dog  (Esbiothrin).  

LOAEL = 63 mg/kg/day based on elevated liver enzymes and increased liver
weight

Incidental Oral Intermediate-Term 

(1-6 months)	BMDL10 = 8 mg/kg/day

	UFA =  10x

UFH = 10x

FQPA SF = 10x

[UFDB]	Residential LOC for MOE = 1000	6-month dog (Bioallethrin).  

BMDL10 based on based on microscopic liver changes (hepatocellular
degeneration)

Dermal 

(all durations)	N/A	N/A	N/A	No systemic toxicity at 1000 mg/kg/day with
Esbiothrin or Esbiol and negligible dermal absorption with pyrethrins
(0.22%)

Inhalation

(all durations)	NOAEL = 1.3 mg/kg/day	UFA = 10x

UFH = 10x

FQPA SF = 10x

[UFDB]	Residential LOC for MOE = 1000	28-day inhalation study in rats
with Esbiol.  LOAEL = 6.5 mg/kg/day based on clinical signs in females
(limb tremors, hunched posture, vocalization during handling)

Cancer 

(all routes)	Classification:    Esbiothrin:  suggestive evidence of
carcinogenicity, but not sufficient to assess human carcinogenic
potential.  

The FQPA Safety Factor (FQPA SF) is a database uncertainty factor (UFDB)
to account for the lack of comparative neurotoxicity data with the
allethrins.  

Point of Departure (POD) = A data point or an estimated point derived
from dose-response data which is used to mark the beginning of
extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (intraspecies).  UFH =
potential variation in sensitivity among members of the human population
(interspecies).  UFDB = to account for the absence of key data.  FQPA SF
= FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c =
chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level
of concern.  N/A = not applicable.



Table 3.4b  Toxicological Doses and Endpoints for Occupational Exposure

Exposure/

Scenario	Point of Departure	Uncertainty/

FQPA Safety Factors	RfD, PAD, Level of Concern	Study and Toxicological
Effects

Dermal 

(all durations)	N/A	N/A	N/A	No systemic toxicity at 1000 mg/kg/day with
Esbiothrin or Esbiol and negligible dermal absorption with pyrethrins
(0.22%)

Inhalation

(all durations)	NOAEL = 1.3 mg/kg/day	UFA = 10x

UFH = 10x	Occupational LOC for MOE = 100 	28-day inhalation study in
rats with Esbiol.  LOAEL = 6.5 mg/kg/day based on clinical signs in
females (limb tremors, hunched posture, vocalization during handling)

Cancer 

(all routes)	Classification:    Esbiothrin:  suggestive evidence of
carcinogenicity, but not sufficient to assess human carcinogenic
potential. 

Point of Departure (POD) = A data point or an estimated point derived
from dose-response data which is used to mark the beginning of
extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (intraspecies).  UFH =
potential variation in sensitivity among members of the human population
(interspecies).  MOE = margin of exposure.  LOC = level of concern.  N/A
= not applicable.

3.5	Endocrine disruption  TC \l2 "3.6	Endocrine disruption 	

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

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

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

An incident report is being prepared.  

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

5.1	Pesticide Metabolism and Drinking Water Profile   TC \l2 "5.1 
Pesticide Metabolism and Environmental Degradation 

The nature of the residue in plants is adequately understood for the
purposes of the food handling use petition.  Metabolism in three
different scenarios was studied: applications were made to field grown
crops, Petri dishes to investigate photolysis in vitro, and stored
foods.  Allethrin and several photoproducts were identified in the field
metabolism portion of the study.  Allethrin comprised between 11-75% of
the TRR (total radioactive residues) for field grown crops.  The in
vitro photolysis portion of the study was primarily conducted to aid in
the identification of possible photodegradates detected.  Allethrin was
not detected after 24 hours when exposed to direct sunlight.  For the
2-, 5- and 7-day samples the primary residues extracted were a
combination of photoproducts, illustrating that allethrin is rapidly
degraded in sunlight.  

The stored food scenario of the metabolism study is applicable to the
proposed use and was performed to simulate the environment of a food
handling establishment and study the fate in/on foods in these
environments.  Allethrin was the principal residue extracted from stored
food samples, accounting for approximately 84-94% of the TRR. Trace
amounts of various photoproducts were detected in the analyses.  A
metabolite that consisted of 13.8% of the TRR in lettuce was not
identified.  The results of the stored food portion of the study show
that the parent compound is not significantly degraded producing only
trace amounts of epoxides and no allethrolone.  Allethrolone, which was
found in field grown crops, was the only product identified for which
cleaving had occurred; all other photoproducts retained the ester
linkage.  Based on the submitted study, the residue of concern is the
parent compound, allethrin, for tolerance expression and risk assessment
purposes.

No livestock metabolism data were submitted with the food handling
establishment petition.  A nature of the residue study for livestock is
required due to the inclusion of granaries, feed processing plants and
unoccupied animal quarters as possible application sites on the current
VBC Esbiol® 90 Insecticide labels for Esbiothrin and Esbiol.  The need
for a meat, milk, poultry and eggs magnitude of the residue study will
be determined when the required livestock nature of the residue study
has been received and reviewed.  Alternatively, HED recommends that the
petitioner remove any application sites that could result in Esbiol or
Esbiothrin residues in/on livestock feed items.

The Environmental Fate and Effects Division concluded that the use of
allethrins at food handling establishments (FHEs) would not adversely
impact ground or surface water; therefore, a drinking water assessment
was not performed and residues of concern for water were not determined
(2/28/06 memo, Cheryl Sutton, D323355).  

5.2	Dietary Exposure and Risk TC \l2 "5.2  Dietary Exposure and Risk 

were conducted using the Dietary Exposure Evaluation Model software with
the Food Commodity Intake Database (DEEM-FCID™, Version 2.03), which
incorporates consumption data from USDA’s Continuing Surveys of Food
Intakes by Individuals (CSFII), 1994-1996 and 1998.  The 1994-96, 98
data are based on the reported consumption of more than 20,000
individuals over two non-consecutive survey days.  Foods “as
consumed” (e.g., apple pie) are linked to EPA-defined food commodities
(e.g. apples, peeled fruit - cooked; fresh or N/S; baked; or wheat flour
- cooked; fresh or N/S, baked) using publicly available recipe
translation files developed jointly by USDA/ARS and EPA.  For chronic
exposure assessment, consumption data are averaged for the entire U.S.
population and within population subgroups, but for acute exposure
assessment are retained as individual consumption events.  Based on
analysis of the 1994-96, 98 CSFII consumption data, which took into
account dietary patterns and survey respondents, HED concluded that it
is most appropriate to report risk for the following population
subgroups: the general U.S. population, all infants (<1 year old),
children 1-2, children 3-5, children 6-12, youth 13-19, adults 20-49,
females 13-49, and adults 50+ years old.

HED policy does not require an acute dietary exposure analysis for food
handling uses.  However, the application of allethrins as a space spray
produced residues as high as 0.93 ppm for covered food commodities at
the lower application rate.  For this reason, an acute dietary
assessment was conducted.  

For acute exposure assessments, individual one-day food consumption data
are used on an individual-by-individual basis.  The reported consumption
amounts of each food item can be multiplied by a residue point estimate
and summed to obtain a total daily pesticide exposure for a
deterministic exposure assessment, or “matched” in multiple random
pairings with residue values and then summed in a probabilistic
assessment.  The resulting distribution of exposures is expressed as a
percentage of the aPAD on both a user (i.e., only those who reported
eating relevant commodities/food forms) and a per-capita (i.e., those
who reported eating the relevant commodities as well as those who did
not) basis.  In accordance with HED policy, per capita exposure and risk
are reported for all tiers of analysis.  However, for tiers 1 and 2, any
significant differences in user vs. per capita exposure and risk are
specifically identified and noted in the risk assessment.

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

5.2.1	Acute Dietary Exposure/Risk  TC \l3 "5.2.1  Acute Dietary
Exposure/Risk 

DEEM-FCID™ when appropriate.  For foods forms that could not be
translated, the highest residue value of 0.93 ppm was used.  

HED is concerned when dietary risk exceeds 100% of the PAD.  The acute
dietary exposure analyses were below the Agency’s level of concern. 
For the U.S. population the exposure was 0.014 mg/kg/day, which utilized
46% of the aPAD.  The highest exposure and risk estimates were for
children 1-2 years old.  At the 95th percentile, the exposure for
children 1-2 was 0.027 mg/kg/day, which utilized 90% of the aPAD (see
Table 5.2.2).  

5.2.2	Chronic Dietary Exposure/Risk  TC \l3 "5.2.2  Chronic Dietary
Exposure/Risk 

DEEM-FCID™ when appropriate.  For foods forms that could not be
translated, the highest average residue value of 0.88 ppm was used.  

HED is concerned when dietary risk exceeds 100% of the PAD.  The dietary
exposure analysis results in chronic dietary risk estimates that are
below the Agency’s level of concern.  For the U.S. population the
exposure was 0.0010 mg/kg/day, which utilized 13% of the cPAD.  The
highest exposure and risk estimates were for children 1-2 years old. 
The exposure for food only was 0.0024 mg/kg/day, which utilized 31% of
the cPAD (see Table 5.2.2).  

Esbiothrin is classified as having "suggestive evidence of
carcinogenicity, but not sufficient to assess human carcinogenic
potential".  Therefore, a cancer dietary assessment was not performed. 



Table 5.2.2.  Dietary Exposure and Risk for Allethrins

Population Subgroup	Acute Dietary

95th  Percentile	Refined Chronic Dietary

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

(mg/kg/day)	% cPAD

General U.S. Population	0.03

	0.0139	46	0.008	0.00101	13

All Infants (< 1 year old)

0.0206	69

0.00134	17

Children 1-2 years old

0.0270	90

0.00244	31

Children 3-5 years old

0.0233	78

0.00212	26

Children 6-12 years old

0.0165	55

0.00142	18

Youth 13-19 years old

0.0115	38

0.000925	12

Adults 20-49 years old

0.00984	33

0.000832	10

Adults 50+ years old

0.00881	29

0.000775	9.7

Females 13-49 years old

0.00937	31

0.000793	9.9

5.3	Anticipated Residues 

FCID™ when appropriate.  For food forms that could not be translated,
the highest residue value of 0.93 ppm was used for the acute assessment
and the highest average residue value of 0.88 ppm was used for the
chronic assessment.  See “Allethrins: Petition for the Establishment
of a Tolerance for Esbiol and Esbiothrin for Use in Food/Feed Handling
Establishments.  Summary of Analytical Chemistry and Residue Data, DP
Barcode 324039” by Toiya Goodlow for additional information. 



Table 5.3. Anticipated Residues and Translations Based on Food Handling
Establishment Residue Studies with Esbiol.

Commodity	Acute AR 	Chronic AR1 	DEEM-FCIDTM Translation

Milk	0.028	0.027	Dairy products, all other milks [coconut, soybean]

Butter	0.26	0.255	Crops groups 14 & 20: tree nuts and oilseeds; milk
fat; peanuts; pine nut; all other oils [citrus, coconut, corn field,
cottonseed, olive, palm, peppermint, sesame, soybean, spearmint]

Cooked meat 	None	0.152	Not used for acute assessment, the higher
uncooked meat value used  instead

Uncooked meat	0.19	0.152	All meats; poultry; eggs

Flour	0.44	0.32	All flours [arrowroot, barley, buckwheat, chickpea,
cornfield, oat, potato, rice, rye, soybean, triticale, wheat]; all grain
byproducts [barley bran, corn field meal & bran, oat bran, rice bran,
wheat bran & germ]

Rice	0.23	0.19	Rice[white, brown & wild];  all whole grains [amaranth,
barley pearled, buckwheat, corn (pop & sweet), millet, oat groats,
quinoa, rye, sorghum, wheat]

Bread	None	None	Not used

Lettuce	0.93	0.88	Crop groups 2,4, 5 & 19: leaves of root & tuber, leafy
and Brassica leafy vegetables, herbs and spices; ginger; teas;
asparagus; belguim endive; peppermint; spearmint 

Cooked Apples	0.061	0.06883	All juices [apple, apricot, blackberry,
carrot, celery, cherry, cranberry, grape, grapefruit, lemon, lime,
mango, orange, papaya, passion fruit, peach, pear, pineapple, prune,
raspberry, strawberry, tangerine, tomato, watermelon]

Raw apples	0.096	0.06883	Crop groups 1A,8,9,10,11,12,13: root, fruiting,
and cucurbit vegetables, squash/cucumbers, citrus, pome, and stone
fruits, all berries; all other fruits [acerola, banana, breadfruit,
cherimoya, coconut, cranberry, date, feijoa, fig, canistel, grape,
guava, joboticaba, jackfruit, kiwifruit, longan, lychee, mamey apple,
mango, mulberry, papaya, passion fruit, pawpaw, persimmon, pineapple,
plantain, pomegranate, sapote, Spanish lime, soursop, starfruit, sugar
apple, tamarind, tomato tree] 

Candy	None	None	Not used

Sugar	0.48	0.295	Beet sugar; corn field syrup & starch; honey; maple
sugar & syrup; sugarcane molasses & sugar; sorghum syrup

Default value- highest residue: lettuce	0.93	0.88	Crop groups 3 & 6:
bulb and legume vegetables; All other commodities that did not translate
[alfalfa seed, artichoke, avocado, bamboo shoots, cactus, carob,
cassava, cocoa bean chocolate & powder, coffee, dasheen corm, fish, hop,
mushroom, olive, palm heart, potato, psyllium seed, seaweed, sesame
seed, sweet potato, tanier corm, tumeric, vinegar, water chestnut,
watercress, yam  

1 Chronic AR does not include 20% facilities treated factor.  Factor
added under Adjustment Factor 2 in DEEM-FCID TM. 

2 Meat average used for the chronic AR is the average of cooked and
uncooked meat residues.

3 Apple average used for the chronic AR is the average of cooked and
uncooked apples.

The Biological Economics and Analysis Division provided HED with a
projected estimate of the percentage of FHE facilities that may use
allethrins to treat pests.  BEAD determined that 20% of all food
handling establishments may be treated with allethrins based on the
available data from registered pesticides currently used in food
handling establishments.  This value was incorporated into the chronic
assessment only; no percent treated value was used in the acute
analysis.  



     Dietary Risk Characterization

n DEEM-FCID™ such as percent crop treated and processing factors,
sensitivity analyses, and a variety of other issues which may be
chemical- or crop-specific. Characterization of the allethrin dietary
assessment and associated uncertainties include: 

Anticipated residues based on the MOR study for food handling
establishments were used in the acute and chronic assessment.  The
residue study was performed using space spray applications, which is the
most rigorous type of application (space > general > spot >crack and
crevice) for food handling establishment treatments.   According to
OPPTS Guideline 860.1460 the space spray study can be submitted as a
conservative/worst case scenario for all four treatment types, since it
is likely to produce the highest residue levels.  Therefore, using the
highest residue values for the acute analysis and average residue values
for the chronic analysis from the space spray study is conservative and
may result in an overestimate of dietary risks for less rigorous
applications of allethrins. 

DEEM-FCID™ were included in these analyses).  This is an extremely
conservative assumption that is necessary since it is not possible to
determine which foods will be present at the time of application in each
food handling establishment.

BEAD provided HED with a projected estimate of the percentage of FHE
facilities that may use allethrins to treat pests.  BEAD determined that
20% of all food handling establishments may be treated with allethrins
based on the available data from registered pesticides currently used in
food handling establishments.  This value was incorporated into the
chronic assessment only.  The acute assessment assumed that 100% of food
handling establishments will be treated with allethrins. 

6.0	Residential Exposure/Risk Characterization  TC \l1 "6.0	Residential
(Non-Occupational) Exposure/Risk Characterization 

6.1	Residential Handler Exposure TC \l2 "6.1	Residential Handler
Exposure 

The term “handler” applies to individuals who mix, load, and apply
the pesticide product.  Only inhalation exposures have been assessed for
the residential handler scenarios.  Dermal exposures were not assessed
because no dose or endpoints were selected for dermal exposure. 
Residential handler exposures were assessed for aerosol can application
to a variety of use sites.  Some allethrin products are packaged as
ready to use trigger sprayer bottles.  The handler risks calculated from
aerosol can application are protective of risks from trigger sprayer
applications because the unit exposure values are lower for trigger
sprayer application.     SEQ CHAPTER \h \r 1 PHED unit exposure data
were used to assess exposures because chemical-specific monitoring data
were not available.  

The following assumptions were used in estimating risks from residential
handler exposure to allethrins:

The body weight of an adult handler is 70 kg.

One aerosol can is used per day.  This assumption is based upon the HED
Science HED Science Advisory Committee on Exposure SOP 12:
“Recommended Revisions to the Standard Operating Procedures for
Residential Exposure Assessment” (2/22/2001).	

Each aerosol can contains 15 to 16 ounces by weight of product based
upon the labels included in the Use Closure Memo. 

The percent ai in the products ranges from 0.10 to 0.25 percent by
weight based upon the limitations to be included in the RED.

All of the handler MOEs exceed the target MOE of 1000, therefore, the
handler risks are not of concern.   

Table 6.1  Residential Handler Risks for Allethrin

Use Scenario	Percent ai in Product	Amount of Product Used per Day	Amount
of ai used per day 	Inhalation MOE*

Handler Exposures – Aerosol Can Application

Indoor Surface or Space Spray 

Hand Held Yard and Patio Fogger	

Wasp and Hornet Nests	0.25

0.15

0.10	One 15 ounce can

One 16 ounce can

One 16 ounce can	0.0047 lb

0.0015 lb

0.0010 lb	29,000  46,000

70,000

*All of the MOEs exceed the target MOE of 1000 and therefore the risks
are not of concern.

6.2.	Residential Post Application Exposure TC \l2 "6.2.	Residential 
Postapplication Exposure 

The term “post-application” describes individuals who are exposed to
pesticides after entering areas previously treated with pesticides. 
Allethrin post application incidental oral exposures may occur after
surface applications of allethrin are made to residential areas such as
carpets and vinyl flooring.  Inhalation exposures may occur after space
spray application.  Incidental oral exposures were assessed for toddlers
and inhalation exposures were assessed for adults and toddlers.  Dermal
exposures were not assessed because no systemic effects were observed at
the limit dose in the dermal toxicity studies in test animals and no
toxicity endpoint was selected for dermal exposure.  The following
scenarios were assessed:

Toddler incidental oral ingestion of residues on indoor surfaces after
fogger treatment.

Toddler incidental oral ingestion of residues on indoor surfaces after
PCO broadcast surface treatment.

Toddler incidental oral ingestion of residues on indoor surfaces after
Consumer spot surface treatment.

4)	Inhalation exposures from space spray application

5)	Inhalation exposures from mosquito coils and fly mats

6)	Inhalation exposures from yard and patio foggers

In the previous version of the ORE assessment (D334788), incidental oral
exposures from PCO broadcast surface sprays were assessed at spray
dilutions that ranged from 0.25 to 3.0 percent with a spray volume of 1
gallon per 1000 ft2 and risks of concern were identified.  In response
to these concerns, the registrants have agreed to limit the spray
dilution to 0.05 percent when the spray volume is 1 gallon per 1000 ft2
or 0.10 percent when the spray volume is 0.50 gallons per 1000 ft2. 

Because many of the consumer applied products contain greater than 0.05
percent allethrins, the residential applications of consumer products
will be limited to spot treatments in accordance with the allethrin RED
and broadcast surface applications to areas such as rugs and carpets
will be eliminated.   Some of the existing labels already require spot
treatments, for example, the Real Kill label#9688-86 states: “FOR SPOT
TREATMENT ONLY - Direct spray into cracks and crevices in walls, dark
corners of rooms, cabinets, closets, along and behind baseboards,
beneath and behind sinks, stoves, refrigerators and cabinets, around
plumbing and other utility installations and wherever else these pests
may find entrance”.  Given that the typical consumer  product is an
aerosol can which contains approximately 16 ounces by weight, which is
roughly equivalent to 16 ounces by volume, and given that spray volume
is 1 gallon per 1000 ft2 as stated in the Allethrin Smart Meeting, the
area that could be treated with one can is 125 ft2 or approximately 10
percent of a typical 1250 ft2 house.

6.2.1	Residential Post Application Exposure Data

Exposure data for assessing post-application exposures from the use of
foggers and aerosols in indoor residential settings were based upon
pyrethrin studies conducted by the Non-Dietary Exposure Task Force
(NDETF).  The pyrethrin study data are considered applicable for
allethrin because of the structural similarity between pyrethrin and
allethrin.   

	

6.2.2	Residential Post Application Exposure Assumptions

The following assumptions were used in estimating risks from residential
post application exposure to allethrins:



General Assumptions

The body weight of an adult is 70 kg

The body weight of a toddler is 15 kg

The breathing rates are 1.0 m3/hr for adults and 0.7 m3/hr for children.
 These values are from SOP #12 and are recommended for scenarios of a
few hours in duration.  

Exposure is assessed on day of application (i.e., day zero) 

The application rates were generally taken from the product labels, the
Allethrin Smart Meeting or the limits to be established in the RED. 

Indoor Fogger Surface Treatment Post Application Exposure Assumptions

The application rate is 3.6 mg/m3 based upon the Speer 4X Indoor Fogger
(formerly 11715-96, transferred to 2724-552) which is a 1.5 ounce fogger
containing 1.2 percent allethrin.  It is assumed that one fogger will
treat a 5000 ft3 (141.5 m3) room as stated on the label.

 The indoor surface residue is 0.65 µg/cm2 based on NDETF study data
for pyrethrin and the above application rate.  

The hand transfer efficiency is 8% for carpet and 11% for vinyl based on
NDETF data

The saliva extraction factor is 50 percent.

The surface portion of hand put in mouth is 20 cm2

The hand-to-mouth (HMT) exposure frequency is 20 times per hour for
short term exposures as listed in SOP #12.  This is a 90th percentile
value from a video observation study of 30 preschool children.

The HTM exposure frequency is 9.5 times per hour for intermediate term
exposures as listed in SOP 12. This is the mean value from the video
observation study.

The exposure duration is 4 hours for hard surface floors and 8 hours for
carpeted floors.

PCO Broadcast Indoor Surface Treatment Post Application Exposure
Assumptions 

The spray dilution is 0.05 percent when the spray volume is 1 gallon per
1000 square feet.

The spray dilution is 0.10 percent when the spray volume is 0.5 gallon
per 1000 square feet.

The hand transfer efficiency is 8% for carpet and 11% for vinyl based on
NDETF data

The saliva extraction factor is 50 percent.

The surface portion of hand put in mouth is 20 cm2

The HTM exposure frequency is 20 times per hour for short term
exposures.  

The HTM exposure frequency is 9.5 times per hour for intermediate term
exposures.

The exposure duration is 4 hours for hard surface floors and 8 hours for
carpeted floors.

Consumer Spot Indoor Surface Treatment Post Application Exposure
Assumptions

The spray dilution ranges from 0.05 to 0.25 percent based upon the
consumer product labels and RED limitations.

One 16 ounce aerosol can is applied based upon the residential SOPs.

The application will made as a spot treatment as required by the
Allethrin RED.

The spray volume is 1 gallon/1000 ft2 based on the Allethrin Smart
Meeting.

One can treats 125 ft2 which is 10 percent of the area of a typical 1250
ft2 house.

The exposure duration is 0.4 hours for hard surface floors and 0.8 hours
for carpeted floors based upon the Residential SOP values of 4 hours for
hard surface floor and 8 hours for carpeted floors for broadcast
application times a correction factor of 0.1 to account for the smaller
area treated during spot treatments.  

The hand transfer efficiency is 8% for carpet and 11% for vinyl based on
NDETF data

The saliva extraction factor is 50 percent.

The surface portion of hand put in mouth is 20 cm2

The HTM exposure frequency is 20 times per hour for short term
exposures.  

The HTM exposure frequency is 9.5 times per hour for intermediate term
exposures.

Space Spray Application Exposure Assumptions

The products contain 0.1 or 0.2 percent based upon existing labels and
the Allethrin RED. 

Two application rates were considered with the lowest rate based upon
the amount of spray applied during the NDETF study and the highest rate
based upon the Raid label.

The air concentration of 0.022 mg/m3 from the NDETF study was adjusted
to reflect the above rates.

The exposure duration is 2 hours because air monitoring, which was
conducted for two hours after application, indicated that the air
concentrations dropped from an initial value of 0.12 mg/m3 to 0.014
mg/m3.

Mosquito Coil and Fly Mat Exposure Assumptions 

The percent a.i. is 0.3 percent for mosquito coils and 24 percent for
fly mats based upon the product labels.

The weight of the mosquito coils and mats is 12 grams and 0.93 grams,
respectively, based upon the allethrin smart meetings.

The duration of emission is 6 hours for a coil and 10 hours for a mat
based upon the allethrin smart meetings.

The number of mats or coils used is two per treatment based upon the
residential SOPs.

The space treated is 90.62 m3 based upon the a 20 foot by 20 foot patio
with a “ceiling height” of 8 feet as specified in the residential
SOPs.  (3200 ft3 = 90.62 m3) 

The initial concentration is calculated as an instant release where all
of the material is thrown up into the space as stated in the residential
SOPs.

The time weighted average (TWA) concentration is 100 times less than the
initial concentration based upon the residential SOPs.

The exposure duration is 5 hours for adults and 3 hours for children
based upon the Residential SOPs. 

Hand Held Yard and Patio Fogger Assumptions

The percent a.i. is 0.15 based upon the product labels.

The spray discharge rate is 6 grams of product per second based upon the
Allethrin Smart Meeting.

The spray duration is 3 seconds based upon the Allethrin Smart Meeting.

The space treated is 90.62 m3.

The initial concentration is calculated as an instant release.

The TWA concentration is 100 times less than the initial concentration.

The exposure duration is 5 hours for adults and 3 hours for children. 



Total Release Yard and Patio Fogger Assumptions

The percent a.i. is 0.15 based upon the product labels.

The container size is 1.5 ounces based upon the Raid Yard Guard label
4822-394. The 6.0 ounce size will be eliminated from this label in
accordance with the RED.

The space treated is 90.62 m3.

Two containers are used as specified in the Residential SOPs.

The initial concentration is calculated as an instant release.

The TWA concentration is 100 times less than the initial concentration.

The exposure duration is 5 hours for adults and 3 hours for children.

6.2.3	Residential Post Application Risk Estimates

The exposure and risk estimates for the residential post application
scenarios are summarized in Table 6.2 and the calculations are included
in Appendix A of the Allethrin ORE Assessment.  Most of the scenarios
are not of concern because the MOEs approach or exceed the target MOE of
1000.   The outdoor fogger scenario is of concern for inhalation
exposures because the inhalation MOE of 650 does not exceed the target
MOE of 1000.   

6.3 Residential Risk Characterization

Handler Risks

All of the handler MOEs exceed the target MOE of 1000, therefore, the
handler risks are not of concern.   The handler risks are conservative
because it was assumed that one entire can would be used per day.   

Post Application Risks

The yard and patio fogger scenario is only of concern when the product
is in the form of a total release fogger.   The yard and patio scenario
is not of concern when the product is in the form of a hand held fogger.
  Although both product forms are on the same label (4822-394) the hand
held form is more typically found on retail shelves and likely
represents the majority of usage.  This is supported by the Residential
Exposure Joint Venture (REJV) survey which indicated that most of the
Allethrin containing Yard and Patio Fogger products in the house hold
inventory were hand held foggers.  The hand held fogger contains
approximately 454 grams of product which is enough for approximately 9
sprays based upon the nozzle discharge rate of 6 grams per second and a
spray duration of 9 seconds   By contrast, the total release foggers can
only be used once because they discharge their entire contents upon
activation.  It should also be noted that the POD, which is a NOAEL of
1.3 mg/kg/day observed in the inhalation study, may be an artifact of
dose spacing because it is five times lower than the LOAEL of 6.5
mg/kg/day.   Given that the MOE is 650 with a NOAEL of 1.3 mg/kg/day,
only a slightly higher NOAEL of 2.0 mg/kg/day would yield an MOE of
1000.  Considering this, HED has minimal concern with an MOE of 650 for
this scenario.

Table 6.2 – Allethrin Residential Post Application Risk Summary

Source of Exposure	Application Rate	Exposed Population	MOE*

Incidental Oral Exposures (Short Term)

Fogger Treatment - Carpet Floors  

Fogger Treatment - Vinyl Floors 	3.6 mg/m3

	Children	3600

5200

PCO Surface Treatment - Carpet Floors  

PCO Surface Treatment - Vinyl Floors 	0.0042 lb ai/1000 ft2	Children
1200

1700

Consumer Spot Treatment - Carpet Floors  

Consumer Spot Treatment - Vinyl Floors 	0.25% Spray	Children	2200

3400

Consumer Spot Treatment - Carpet Floors  

Consumer Spot Treatment - Vinyl Floors 	0.05% Spray	Children	11000

17000

Incidental Oral Exposures (Intermediate Term)

Fogger Treatment - Carpet Floors  

Fogger Treatment - Vinyl Floors 	3.6 mg/m3	Children	3000

4400

PCO Surface Treatment - Carpet Floors  

PCO Surface Treatment - Vinyl Floors 	0.0042 lb ai/1000 ft2	Children	960

1400

Consumer Spot Treatment - Carpet Floors  

Consumer Spot Treatment - Vinyl Floors 	0.25% Spray	Children	1900

2800

Consumer Spot Treatment - Carpet Floors  

Consumer Spot Treatment - Vinyl Floors 	0.05% Spray	Children	9600

14000

Inhalation Exposures (Short/Intermediate Term)

Space Spray – 0.25 Percent Product 	0.40 mg/m3

(based upon the NDETF study)	Children

Adults	         1300

4200

Space Spray – 0.10 Percent Product 	0.16 mg/m3

(based upon the NDETF study)	Children

Adults	3050

10000

	0.35 mg/m3

(Based upon Raid label 4822-513)	Children

Adults	1400

4800

Mosquito Coils	2 coils per  patio	Children

Adults	7000

14000

Fly Mats	2 mats per patio	Children

Adults	1800

3600

Hand Held Yard and Patio Fogger 	3 second spray per patio

(based on the Smart Meeting)	Children

Adults	3100

6200

Hand Held Yard and Patio Fogger 	9  second spray per patio

(Back calculated)	Children

Adults	1000

2200

Total Release Yard and Patio Fogger	Two 1.5 ounce foggers per patio
Children

Adults	650

1300

*MOEs in bold font do not approach or exceed the target MOE of 1000 and
indicate risks of concern.

7.0	Aggregate Risk Assessments 

Aggregate assessments were conducted for incidental oral exposure
scenarios because the same study is used for the dietary and incidental
oral exposure endpoints based on liver toxicity in dog studies. 
Inhalation exposure could not be included in the aggregate assessment
because the endpoint for inhalation exposure was based on neurotoxicity.
 Aggregate risk was calculated for combined food and residential
exposure for children 1-2 years old.  This population was assessed
because this age group had the highest dietary exposure and could be
expected to receive incidental oral exposure.  No endpoints were
identified for dermal exposure and the allethrins are not expected to
adversely impact ground water, so exposure by these routes was not
assessed.  As shown below, the short term aggregate MOEs are not of
concern for any of the scenarios because they exceed the LOC.  An
intermediate term aggregate MOE of 750 was estimated for one scenario
(PCO Broadcast – Carpet).  There is minimal concern for this estimated
risk, however, since the intermediate term (continuous exposure over a
one to six month period) exposures of toddlers to day zero carpet
surface residues is highly unlikely due to dissipation.  The MOE of 750
is expected to be protective for this exposure scenario. 

Table 7.0.   Allethrin Aggregate Risk for Children 1-2 Years Old.  

Exposure Scenario	POD

mg/kg/day	LOC1	Food

Exposure2

mg/kg/day	Residential Exposure3

mg/kg/day	Aggregate Exposure4

mg/kg/day	Aggregate MOE5

Short-term Exposure

Fogger – carpet

Fogger – vinyl floor	20 (NOAEL)	1000	0.0024	0.0056

0.0039	0.0080

0.0063	2500

3200

PCO Broadcast – carpet

PCO Broadcast – vinyl

0.017

0.012	0.019

0.014	1100

1400

Consumer Spot Treatment - carpet

Consumer Spot Treatment - carpet

0.0090

0.0060	0.011

0.0084	1800

2400

Intermediate-term Exposure

Fogger – carpet

Fogger – vinyl floor	 8 

(BMDL10)	1000	0.0024	0.0027

0.0018	0.0051

0.0042	1600

1900

PCO Broadcast – carpet

PCO Broadcast - vinyl

0.0083

0.0057	0.0107

0.0081	750

990

Consumer Spot Treatment - carpet

Consumer Spot Treatment - carpet

0.0042

0.0029	0.0066

0.0053	1200

1500

1Level of Concern (LOC) based on 10x uncertainty factor for interspecies
extrapolation, 10x for intraspecies variability, and 10x for lack of a
developmental neurotoxicity study.

2 Refined chronic dietary exposure for children 1-2 years old (Table
5.2.2)

3 Residential Exposure = Incidental oral exposure from the Allethrin ORE
Assessment.

4Aggregate Exposure = Food Exposure + Residential Exposure

5Aggregate MOE = POD / Aggregate Exposure



8.0	Cumulative Risk Assessment  TC \l1 "8.0	Cumulative Risk
Characterization/Assessment 

Section 408 of the FFDCA states that the Agency consider "available
information” concerning the cumulative effects of a particular
pesticide's residues and "other substances that have a common mechanism
of toxicity."  EPA has not made a common mechanism of toxicity finding
as to the allethrins and any other substances.  For the purposes of this
tolerance action, therefore, EPA has not assumed that allethrins have a
common mechanism of toxicity with other substances.  For information
regarding EPA’s efforts to determine which chemicals have a common
mechanism of toxicity and to evaluate the cumulative effects of such
chemicals, see the policy statements released by EPA’s Office of
Pesticide Programs concerning common mechanism determinations and
procedures for cumulating effects from substances found to have a common
mechanism on EPA’s website at
http://www.epa.gov/pesticides/cumulative/.

9.0	Occupational Exposures and Risk   TC \l1 "9.0	Occupational
Exposure/Risk Pathway 

9.1	Occupational Handler Risk  TC \l2 "9.1
Short-/Intermediate-/Long-Term/Cancer (if needed) Handler Risk 

The term “handler” applies to individuals who mix, load, and apply
the pesticide product.  Because most allethrin products are packaged in
aerosol cans, most of the allethrin uses involve only application. 
There are a few products packaged as ready to use liquids or liquid
concentrates, which are applied with mechanical sprayers, compressed air
sprayers or foggers.  These products are used in commercial/
industrial/institutional areas, non-food greenhouses and non-food animal
premises.   

PHED Exposure Data  SEQ CHAPTER \h \r 1 

It is the policy of the HED to use data from the Pesticide Handlers
Exposure Database (PHED) when chemical-specific monitoring data or other
handler-specific data are not available.  PHED was designed by a task
force of representatives from the US. EPA, Health Canada, the California
Department of Pesticide Regulation, and members of the American Crop
Protection Association.  The PHED exposure data were used for the low
pressure handwand/back sprayer, aerosol can and HP handwand scenarios.  
The low pressure handwand and back sprayer scenarios were combined
because they have the same inhalation unit exposures.

Fogger Exposure Data 

In the previous assessment, data from two studies were used to estimate
worker exposures during fogging applications.  These studies include a
University of Florida study on greenhouse applicators (Nigg et. al.,
1987) and an MGK study that monitored applicator exposure to prallethrin
during ULV cold fogging (Bergman, 2002).  Both the Nigg study and MGK
study have data quality concerns because only one worker was monitored. 
The MGK study also has ethics concerns because proper informed consent
procedures were not followed.   Based upon these concerns, the OPP
Ethics Reviewer and HED Management decided that neither study should be
used for risk assessment. (EPA, 2007).  These studies have thus been
deleted from this assessment.

The following assumptions were used in estimating risks to occupational
handlers from exposure to allethrins:

The body weight of an adult handler is 70 kg.

The exposure duration ranges from short to long term. (Note – The
endpoint for inhalation exposures is the same for all durations of
exposure)

Respiratory protection either not worn (No Resp.) or consists of a
filtering facepiece dustmask (PF5 Resp.) or a full face piece respirator
(PF50).

The application rates for low pressure handwand/backpack sprayer and
high pressure handwand are from the PCO product labels and are expressed
in terms of product dilution rather than area treated.  

The application rate for PCO aerosol can application is from label
5602-192. 

Undiluted products could be used for space sprays, contact sprays,
surface sprays and crack and crevice treatments at a wide variety of
commercial, industrial and institution sites as listed on the labels.

Dilute sprays could be used for foliar applications in greenhouses.

A greenhouse applicator could apply 1000 gallons of a dilute spray
solution per day using a high-pressure hand-wand based upon ExpoSAC
Policy #9.   

For standard surface spray applications, a PCO could apply 40 gallons of
undiluted pesticide solution per day using a low pressure hand-wand or
backpack sprayer.  This assumption is from ExpoSAC Policy #9.  

The application rate concentration for space sprays (i.e. fogging)  is
based upon the application of 1.0 ounce of spray per 1000 cubic feet
based upon product labels.

The space spray fogging applicator would be exposed to the average of
the initial concentration and the application rate concentration during
hand held fogging.

The fogging applicator will be exposed to average concentration for 240
minutes per 480 minute work day with the unexposed time being spent in
transportation and setup.  If an Actisol Commercial Unit is used as is
specified on the labels, the applicator could treat 134,000 cubic feet
in 240 minutes.   This is based upon the spray output of the Actisol
unit (0.56 ounces per minute @ 15 PSI).

Occupational Handler Risk Summary: 

Only inhalation exposures have been assessed.   Dermal exposures were
not assessed because no dose or endpoints were selected for dermal
exposure.   The target MOE is 100 for short, intermediate and long term
inhalation exposures.  Risk estimates for the surface spray scenarios
are summarized in Table 9.1 and the risk estimated for the space spray
scenario is summarized in Table 9.2.  The calculations are detailed in
Appendix A of the ORE Assessment. 	

Most of the surface spray inhalation MOEs are above the target MOE of
100 without respirators (i.e. No Resp.) and therefore the inhalation
risks are not of concern.   The high pressure handwand scenario is of
concern without respirators and requires a PF5 filtering facepiece
respirator (i.e. a dust mask) to achieve the target MOE.  



Table 9.1 – Occupational Handler Risks from Surface Spray
Applications

Exposure Scenario	Dilution	Spray Dilution

(Percent ai)	Amount Sprayed per Day	lb ai  handled per day	Inhalation
MOE

M/L/A liquids with LP hand-wand or backpack sprayer	Undiluted	1.5	40
gallons	5	600 – No Resp.

M/L/A liquids with LP hand-wand or backpack sprayer	Diluted in water
0.11	40 gallons	0.37	8100 – No Resp.

M/L/A liquids with HP hand-wand (Greenhouse Use)	 Diluted in water	0.11
1000 gallons	9.2	81 – No Resp.

400 – PF5 Resp. 

Aerosol Can application	Undiluted	0.54	6 cans

 (16 oz ea)	0.032	2300 – No Resp.

 MOEs highlighted in bold font indicate risks of concern because they do
not exceed the target MOE of 100.

The MOEs for space spray applications are of concern when respirators
are not worn.  The MOEs are not of concern if PF50 Full Face Respirators
with appropriate cartridges are worn.

Table 9.2 – Occupational Handler Risks from Space Spray Applications 

Label #	Spray Dilution	Application Rate 

(lb ai/1000 ft3)	Average Concentration

(mg/m3)	Respirator Worn	Inhalation MOE

1021-1478	1.5	0.0010	8.0	None	2.8

1021-1453	1.0	0.00067	5.4

4.2

1021-1478	1.5	0.0010	8.0	PF50 Full Face	140

1021-1453	1.0	0.00067	5.4

210

MOEs highlighted in bold font indicate risks of concern because they do
not exceed the target MOE of 100.

Occupational Handler Risk Characterization: 

It is likely that space spray applications to larger spaces are done
using automatic equipment which reduces operator exposure.   Additional
exposure data and information regarding space spray application methods
could be used to refine the risks. 

9.2	Occupational Post Application Risk  TC \l2 "9.2
Short-/Intermediate-/Long-Term/Cancer (if needed) Postapplication Risk 

Allethrins are used as space sprays in a wide variety of indoor areas
such as barns, greenhouses, and residences.   For many of the
applications there are restrictions such as “Do not apply when people
are present” or “Do not allow unprotected persons to enter until
treated area has been thoroughly ventilated” which minimize post
application exposures.   There is one product (Misty Mizer Insecticide
III, 10807-69) which is applied from a time metered device; however, the
label requires that the device be set to operate only 12 hours per day
during off hours.  

Given the above use characteristics, occupational post application
inhalation exposures are anticipated primarily from time metered device
applications.  To assess these exposures, a scenario that involves the
metered release into an industrial work area was evaluated based upon
the Misty Mizer label #10807-69.  No exposure data was available to
assess post application exposures.  

The inhalation MOE is 850, which exceeds the target MOE of 100 and is
not of concern.   This MOE is representative of a space that is
ventilated at the rate of 0.20 air changes per hour at night and 1.0 air
changes per hour during the day.

The risk for the metered release scenario is conservative because it was
assumed that the aerosols would remain airborne until they were removed
by ventilation and the effects of aerosol settling were not considered. 
Aerosol settling could be a major factor depending upon the aerosol size
and rate of evaporation.  Information regarding the aerosol size and
evaporation rate could be used to refine the risks.

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

Toxicology 

Developmental Neurotoxicity Study

A developmental neurotoxicity (DNT) study is required for the
allethrins.   However, the Agency is currently evaluating whether a DNT
or another comparative toxicity study measuring different endpoints
would be best suited for addressing the concern for sensitivity to young
animals.  The registrants should consult with EPA before beginning this
study.

Residue Chemistry

860.1200 Directions for Use

HED recommends the removal of granaries, feed processing plants,
unoccupied animal quarters and any other FHEs that store livestock feeds
as possible application sites from the current VBC Esbiol® 90
Insecticide labels.  Alternatively, the Agency must require the
submission of a nature of the residue study for livestock (Guideline
860.1300) and reserve the right to require a meat, milk, poultry and
eggs magnitude of the residue study (Guideline 860.1480) if necessary.

Clarification is requested for the use directions for each of the four
proposed treatment applications (space and general spray, spot and crack
and crevice treatments).  Use directions should be explicitly stated for
each proposed FHE treatment type.  

HED recommends that the VBS Esbiol® and Esbiothrin® 90 Insecticide
labels be revised to 

restrict any FHE applications while food processing is underway for all
types of food/feed processing plants.

The submitted labels should also be revised to include food restrictions
for the spot and crack and crevice treatment applications (e.g. cover or
remove foods before treatment or ventilate treated area).  Currently,
there are no limitations specified for these two types of FHE
applications.

860.1300 Nature of the Residue – Livestock

A nature of the residue study for livestock is required due to the
inclusion of granaries, feed processing plants, unoccupied animal
quarters and any other FHEs that store livestock feeds as possible
application sites on the current VBC Esbiol® 90 Insecticide labels for
Esbiothrin and Esbiol.  Provided the labels are revised to remove these
use sites, a livestock metabolism study will not be required.

860.1480 Meat, Milk, Poultry, and Eggs

The requirement of a meat, milk, poultry and eggs study is reserved
until the livestock nature of the residue study has been received and
reviewed.  

860.1520 Processed Food and Feed

Pilot processing studies are required demonstrating the
concentration/reduction of residue 

levels in/on the raw agricultural commodities potato tubers and wheat.  
Food handling establishment treatments can potentially be applied at
multiple stages of processing.  If there is not significant reduction of
total allethrin residues in/on food commodities, residue levels may
exceed the recommended 1 ppm tolerance for FHE uses.  The petitioner is
required to submit processing data for potato flakes only for potato
tubers, and all wheat processed commodities which includes wheat bran,
flour, middlings, shorts and germ.  Additional processing studies may be
required if residue levels are not reduced by 50% or more in the
processed fractions of potato tubers and wheat.

860.1550 Proposed Tolerances

  SEQ CHAPTER \h \r 1 

The petitioner is required to submit a revised Section F to specify a
tolerance level of 

1.0 ppm for total allethrin residues including d-trans chrysanthemic
acid of d-allethrolone, d- trans chrysanthemic acid of l-allethrolone,
d-cis chrysanthemic acid of d-allethrolone, and d-cis chrysanthemic acid
of l-allethrolone in/on all foods in food handling establishments. 
Since the analytical method submitted is not capable of distinguishing
between allethrin isomers and reports total allethrin, the tolerance
should also be expressed as total allethrin.  

860.1650 Submittal of Analytical Reference Standards

Analytical reference standards for the complete allethrin series of
pyrethroids are not currently available in the National Pesticide
Standards Repository.  Standards for Bioallethrin (004003) and Pynamin
Forte (004005) are expired, and no reference standard is available for
Esbiothrin (004007).  The reference standards should be sent to the
Analytical Chemistry Lab, which is located at Fort Meade, to the
attention of Theresa Cole or Frederic Siegelman at the following
address:

USEPA

National Pesticide Standards Repository/Analytical Chemistry Branch/OPP

	701 Mapes Road

	Fort George G. Meade, MD  20755-5350

Note:  Mail will be returned if the extended zip code is not used.

Occupational and Residential Exposure

875.1400 Inhalation Exposure Indoor

A inhalation exposure study is required for the occupational handler
fogger scenario (Mix/Load/Apply liquids with fogger) due to lack of
adequate data.  

REFERENCES:  TC \l1 "References: 

Allethrins: Acute and Chronic Dietary Exposure and Risk Assessments for
the Section 3 Registration Action for the Use of Esbiothrin and Esbiol
in Food Handling Establishments.  Toiya Goodlow. DP Barcode 294724. 

Allethrins: Petition for the Establishment of a Tolerance for Esbiothrin
and Esbiol for Use in Food/Feed Handling Establishments.  Summary of
Analytical Chemistry and Residue Data.  Petition Number: 6H5743. DP
Barcode 324039.

Allethrins: Revised Occupational and Residential Exposure Assessment and
Recommendations for the Reregistration Eligibility Decision (RED). 
Timothy Dole.  DP Barcode D340744.  

Esbiothrin: Report of the Cancer Assessment Review Committee.  Jessica
Kidwell.  TXR 0051399.  12/2/03.  

EPA, 2007.  “Re: Use of the Prallethrin and/or Nigg Studies”, Email
from John Carley to Molly Clayton, March 1, 2007

Benchmark Dose Analysis of 6-Month Dose Feeding Study of Bioallethrin in
Dogs, Philip Villanueva and Kit Farwell.  DP Barcode D339909. 

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

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

The requirements (40 CFR 158.340) for food use for the allethrins are
listed below. Use of the new guideline numbers does not imply that the
new (1998) guideline protocols were used.  

Test 

	Technical

	Required	Satisfied

870.1100    Acute Oral Toxicity	

870.1200    Acute Dermal Toxicity	

870.1300    Acute Inhalation Toxicity	

870.2400    Primary Eye Irritation	

870.2500    Primary Dermal Irritation	

870.2600    Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100    Oral Subchronic (rodent)	

870.3150    Oral Subchronic (nonrodent)	

870.3200    21-Day Dermal	

870.3250    90-Day Dermal	

870.3465    90-Day Inhalation		yes

yes

yes

no

yes 	yes

yes

yes

-

yes a 

870.3700a  Developmental Toxicity (rodent)	

870.3700b  Developmental Toxicity (nonrodent)	

870.3800    Reproduction		yes

yes

yes	yes

yes

yes

870.4100a  Chronic Toxicity (rodent)	

870.4100b  Chronic Toxicity (nonrodent)	

870.4200a  Oncogenicity (rat)	

870.4200b  Oncogenicity (mouse)	

870.4300    Chronic/Oncogenicity		yes

yes

yes

yes

yes	yes b

yes

yes

yes

yes

870.5100    Mutagenicity—Gene Mutation - bacterial	

870.5300    Mutagenicity—Gene Mutation - mammalian	

870.5xxx    Mutagenicity—Structural Chromosomal Aberrations	

870.5xxx    Mutagenicity—Other Genotoxic Effects		yes

yes

yes

yes	yes

yes

yes

yes

870.6100a  Acute Delayed Neurotox. (hen)	

870.6100b  90-Day Neurotoxicity (hen)	

870.6200a  Acute Neurotox. Screening Battery (rat)	

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

870.6300    Developmental Neurotoxicity		no

no

no

yes

yesC	-

-

yes

yes

no

870.7485    General Metabolism	

870.7600    Dermal Penetration		yes

no	yes

-

Special Studies for Ocular Effects

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)		

no

no

no	

-

-

-

a Requirement for 90-day inhalation study satisfied by 28-day inhalation
study.

b Requirement for chronic toxicity study satisfied by combined
chronic/oncogenicity study

c May be satisfied with a comparative neurotoxicity study.

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

Acute Toxicity of Bioallethrin

Guideline	Study Type	MRID	Results	Tox Category

870.1100	Acute Oral	00151444	LD50 709 mg/kg (M)

1042 mg/kg (F)           	III

870.1200	Acute Dermal	41155801	LD50 > 3000 mg/kg (M&F)           	III

870.1300	Acute Inhalation	42906902	LC50 : 2.51 mg/L          	IV

870.2400	Primary Eye Irritation	41155803	Slight to moderate irritant	III

870.2500	Primary Skin Irritation	41155805	Very slight dermal irritant	IV

870.2600	Dermal Sensitization	41155807	negative	N/A

Acute Toxicity of Esbiol

Guideline	Study Type	MRID	Results	Tox Category

870.1100	Acute Oral	00151460	LD50 : 574.5 mg/kg (M)

412.9 mg/kg (F)           	II

870.1200	Acute Dermal	41155802	LD50 > 2000 mg/kg 	III

870.1300	Acute Inhalation	41670801	LC50 : 1.32 mg/L (M)

1.23 mg/L (F)          	III

870.2400	Primary Eye Irritation	41155804	Moderate ocular irritant	III

870.2500	Primary Skin Irritation	41155806	Not a dermal irritant.	IV

870.2600	Dermal Sensitization	41155808	Not a sensitizer	N/A

Acute Toxicity of Esbiothrin

Guideline	Study Type	MRID	Results	Tox Category

870.1100	Acute Oral	00151449	LD50 432 mg/kg (M)

378.0 mg/kg (F)           	

II

870.1200	Acute Dermal	00151451	LD50 > 2000 mg/kg	III

870.1300	Acute Inhalation	00151452	LC50 : 2.63 g/m3 - unacceptable 	III

870.2400	Primary Eye Irritation	00151454	Minimally 	IV

870.2500	Primary Skin Irritation	00151453	Slightly 	III

870.2600	Dermal Sensitization	42907001	negative	n/a



Acute Toxicity of Pynamin Forte

Guideline	Study Type	MRID	Results	Tox Category

870.1100	Acute Oral	41017101	M:  2150 mg/kg

F:  900 mg/kg	III

870.1200	Acute Dermal	41017102	M:  2660 mg/kg 

F:  4390 mg/kg 	III

870.1300	Acute Inhalation	41017103	LC50 > 3.875 mg/L

	870.2400	Primary Eye Irritation	41017104	slight irritant	III

870.2500	Primary Skin Irritation	41017104	negative	IV

870.2600	Dermal Sensitization	41017105	negative	N/A

Summary of Allethrin Toxicity Database

	

Esbiol  (S-Bioallethrin)

>90% d- trans d-	

Esbiothrin

72% d- trans d-	

Bioallethrin

46% d- trans d-	

Pynamin Forte  (d-allethrin)

36% d- trans d-

Acute Neurotoxicity gavage	

NOAEL = 30 mkd

LOAEL = 90 mkd: FOB (hunched posture, tremors, abnormal gait, (grip
strength)  1997.  5, 30, 90 mkd	

	

	

Subchronic Neurotoxicity	

NOAEL = 144 mg/kg/day

LOAEL = 452 mkd:  (BW, no neurotox observed.  Unacceptable (no positive
control data) 2000.

75, 250, 2000, 6000 ppm 

5, 6.5, 18, 144, 452 mkd	

	

	

90-day rat	

NOAEL = 18 mkd

LOAEL = 37 mkd: micro pituitary 

changes (M)

149 mkd: (BW; (liver/ thyroid wt, thyroid micro changes

594 mkd:  micro liver changes. 

1996.   

250, 500, 2000, 8000 ppm

18,   37,   149,    594 mkd	

	

NOAEL = 75 mkd

LOAEL = 250 mkd:   (BW gain; ( liver enzymes; (abs/rel liver wt

1972. Unacceptable (no supporting tables)

500, 1500, 5000, 10000 ppm

25,   75,    250,    500  mkd	

Chronic/Cancer rat	

	

NOAEL = 27 mkd

LOAEL = 83 mkd:   (BW (F);  

( liver enzymes, liver micro.  

renal tubular adenomas: HDT males

1990.   

100, 500, 1500,4500 ppm

5.5,  27,   83,    259   mkd	

	

NOAEL =  29 mkd 

LOAEL = 120 mkd:   (BW (F), (liver wt (M)

Negative for tumor response

1985.   

125, 500, 2000 ppm

6,     24,   102   mkd



Subchronic mouse	

	

NOAEL =  229 mkd

LOAEL = 420 mkd:   (liver wt and alkaline phosphatase (115%)

1621 mkd, piloerection and hunched posture during weeks 3/4.  

1986.   8- week study.  

100, 1000, 2000, 4000, 8000 ppm

22,    229,  420,   843,   1621 mkd	

	

NOAEL = 14 mkd

LOAEL = 43 mkd - enlarged hepatocytes

1986.  5-week study.  

423 mkd: ( liver wt

1522 mkd: (BW (83%/92%(PCV (43% vs 48%), (SGPT (45 vs 31)

1986.   

100, 300, 1000, 3000, 10000 ppm

14,   43,   144,   423,   1550   mkd

Cancer mouse	

	

NOAEL = 214 mkd, HDT

No treatment-related tumors.  

1990.   

50, 250, 1250 ppm

8,   42,   214   mkd	

	

NOAEL = 72 mkd, HDT

LOAEL = 350 mkd:  (rel liver wt, microscopic liver changes.  No incr in
tumors. 

1989 

200, 600, 3000 ppm

14,   72,   350   mkd

Developmental rats	

Maternal NOAEL = 20 mkd

   LOAEL = 80 mkd:   clinical signs, mortality

Devel NOAEL = 80 mkd, HDT

   LOAEL > 80 mkd

1998.   

5, 20, 80 mkd	

Maternal NOAEL = 25 mkd

   LOAEL = 125 mkd: clinical signs,  mortality 

Develop NOAEL = 125 mkd, HDT

   LOAEL > 125 mkd

1990.   

5, 25, 125 mkd 	

Maternal NOAEL = 125 mkd

   LOAEL = 195 mkd (mortality)

Devel NOAEL = 195 mkd

1979.   50, 125, 195 mkd

Note:  Not a reliable study for endpoint selection.  	

Maternal NOAEL = 30 mkd

   LOAEL = 100 mkd:   tremors,(wt gain

Develop NOAEL = 100 mkd  HDT

1989.   

10, 30, 100 mkd

Developmental rabbit	

Maternal NOAEL = 50 mkd

   LOAEL = 200 mkd:   (BW gain,  tremors

Devel NOAEL = 50 mkd, 

   Devel LOAEL = 200 mkd:  (ossification.  

1998.   5, 50, 200 mkd	

Maternal NOAEL = 100 mkd

   LOAEL = 300 mkd: mortality and clinical signs

Develop NOAEL = 300 mkd, HDT

   LOAEL > 300 mkd

1990.   

30, 100, 300 mkd.	

	

Maternal NOAEL = 100 mkd

   LOAEL = 350 mkd :   mortality, (BW gain

Developmental NOAEL = 100 mkd

   LOAEL = 350 mkd:   rib/rib-vertebral malformations

1989.   30, 100, 350 mkd

Reproduction	

	

Parental NOAEL = 50 mkd

   LOAEL = 150 mkd: (body weight

Offspring NOAEL = 50 mkd

   LOAEL = 150 mkd: (viability, BW gain, marginal increase in delayed
developmental milestones (eye opening, auricular duct opening)

1988.   

70, 200, 600, 1800 ppm

6,   17,   50,   150   mkd	

	

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ሀparental NOAEL =  13 mkd

  LOAEL = 130 mkd:  (BW,(liver wt, and microscopic liver changes 

offspring NOAEL = 15 mkd

  LOAEL = 145 mkd:(pup wt in F2 generation

1989.  

 200, 2000, 6000 ppm

13,    130,   387   mkd

Subchronic dog feeding	

NOAEL = 38 mkd

LOAEL = 90 mkd: (BW, clinical signs, ( liver wt

1996.   90-day feeding study. 

400, 1000, 2250 ppm

16,   38,    90      mkd	

NOAEL = 20 mkd

LOAEL = 63 mkd: (liver wt, enzymes.  

153 mkd:  clinical signs and death 

1986.  4-week feeding study.    

50, 200, 800, 3200, 6400 ppm

1,   4.5,  20,   63,    153   mkd	

	

Chronic dog feeding	

	

NOAEL = 70 mkd HDT

LOAEL > 70 mkd

70 mkd:    alkaline phosphatase ( 240% relative to controls, brown/
black livers, ( liver/thyroid wt.   

1987.   1-year feeding study. 

80, 400, 2000 ppm

3,   14,  70      mkd	

NOAEL = 6 mkd

LOAEL = 36 mkd: microscopic liver changes.  

162 mkd:  (liver enzymes, cardiac arrhythmias, trembling, (wt gain

1982.   6- month feeding study. 

200, 1000, 5000 ppm

6,     36,    162    mkd	

Chronic dog capsule	

	

	

	

NOAEL = 6 mkd

LOAEL = 20 mkd: clinical signs 1989.   

 6, 20, 60, 100 mkd (capsule)

21-day dermal rabbit	

	

systemic NOAEL = 1000 mkd, HDT

1990.   

40, 200, 1000 mkd

	

	

systemic NOAEL = 300 mkd, HDT

1990.   

3, 10, 30, 300 mkd

28-day dermal rat	

systemic NOAEL = 1000 mkd, highest dose tested

dermal NOAEL = 1000 mkd, highest dose tested

1998.   

10, 100, 1000 mkd	

	

	

28-day inhalation - rat	

NOAEL = 1.3 mkd

LOAEL = 6.5 mkd based on clinical signs in females (limb tremors,
hunched posture, vocalization during handling)

1997.   

0.0051,  0.025,  0.073  mg/L

1.3,        6.5,     19        mkd	

Unacceptable study

Metabolism / PK	

	

	

Urinary elimination ~ 25-50%; fecal elimination ~ 50-60% in different
groups.  Several metabolites identified.  	

Dermal Absorption	

Unacceptable study, not upgradeable	

	

	

NOTE:  For feeding studies,  doses in mg/kg/day are reported for males. 

HDT = highest dose tested

Appendix B:	Tolerance Reassessment Summary and Table TC \l1 "Appendix
C:  Tolerance Reassessment Summary and Table 

For the purposes of petition 6H5743, HED has determined that the residue
of concern is the parent compound, allethrin.  No Codex, Canadian, or
Mexican MRLs have been established for the allethrins.  Adequate residue
data for food handling establishment uses are available.  

VBS proposed the establishment of a 1.0 ppm tolerance for Esbiothrin and
Esbiol use in food FHE for all foods and feeds.  A revised section F
must be submitted reflecting the recommended tolerance for total
allethrin and the correct commodity definition as specified in appendix
Table C.1.  Since the analytical method submitted is not capable of
distinguishing between allethrin isomers and reports total allethrin,
the tolerance should also be expressed as total allethrin.  

Provided that the residue chemistry deficiencies outlined in this
document are fulfilled, the available data will support a 1.0 ppm
tolerance for residues of total allethrin on all foods treated in food
handling establishments. 

TABLE C.1.       Tolerance Summary for Esbiol and Esbiothrin 

Commodity	

Established/Proposed Tolerance (ppm)	

Recommended Tolerance (ppm)	

Comments; Correct Commodity Definition

All food items in food handling establishments	1.0	1.0	A tolerance of
1.0 ppm is established for total allethrin residues including d-trans
chrysanthemic acid of d-allethrolone, d-trans chrysanthemic acid of
l-allethrolone, d-cis chrysanthemic acid of d-allethrolone, and d-cis
chrysanthemic acid of l-allethrolone in or on all food items in food
handling establishments.

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