Document ID: EPA-HQ-OPP-2006-0986-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-12-27T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

December 20, 2006  

SUBJECT:	Allethrins:  HED Chapter of Reregistration Eligibility Decision
Document (RED).  Phase 2, Error Correction Reregistration Action 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: D334789.

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

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

		Toiya Goodlow, Chemist

		Reregistration Branch 1

		Health Effects Division (7509P)

THROUGH:	Jeff Dawson

		Reregistration Branch 1 (7509P)

		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) and
incorporates phase 1 error correction comments from Valent BioSciences
Corporation.  The per cent active ingredient for pet spray treatments
was corrected in this risk assessment.  

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc147291444"  1.0	Executive
Summary	  PAGEREF _Toc147291444 \h  4  

  HYPERLINK \l "_Toc147291445"  2.0	Ingredient Profile	  PAGEREF
_Toc147291445 \h  7  

  HYPERLINK \l "_Toc147291446"  2.1	Summary of Registered/Proposed Uses	
 PAGEREF _Toc147291446 \h  7  

  HYPERLINK \l "_Toc147291447"  2.2	Structure and Nomenclature	  PAGEREF
_Toc147291447 \h  11  

  HYPERLINK \l "_Toc147291448"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc147291448 \h  12  

  HYPERLINK \l "_Toc147291449"  3.0	Hazard Characterization/Assessment	 
PAGEREF _Toc147291449 \h  13  

  HYPERLINK \l "_Toc147291450"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc147291450 \h  13  

  HYPERLINK \l "_Toc147291451"  3.2	Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc147291451 \h  14  

  HYPERLINK \l "_Toc147291452"  3.3	FQPA Considerations	  PAGEREF
_Toc147291452 \h  14  

  HYPERLINK \l "_Toc147291453"  3.3.1	Toxicity Database	  PAGEREF
_Toc147291453 \h  14  

  HYPERLINK \l "_Toc147291454"  3.3.2	Developmental and Reproductive
Toxicity Studies	  PAGEREF _Toc147291454 \h  15  

  HYPERLINK \l "_Toc147291455"  3.3.3	Additional Information from
Literature Sources	  PAGEREF _Toc147291455 \h  20  

  HYPERLINK \l "_Toc147291456"  3.3.4	Pre-and/or Postnatal Toxicity	 
PAGEREF _Toc147291456 \h  20  

  HYPERLINK \l "_Toc147291457"  3.3.5	Recommendation for a Developmental
Neurotoxicity Study	  PAGEREF _Toc147291457 \h  20  

  HYPERLINK \l "_Toc147291458"  3.4	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc147291458 \h  22  

  HYPERLINK \l "_Toc147291459"  3.4.1	Acute Reference Dose - Females age
13-49	  PAGEREF _Toc147291459 \h  22  

  HYPERLINK \l "_Toc147291460"  3.4.2	Acute Reference Dose - General
Population	  PAGEREF _Toc147291460 \h  22  

  HYPERLINK \l "_Toc147291461"  3.4.3	Chronic Reference Dose (cRfD)	 
PAGEREF _Toc147291461 \h  23  

  HYPERLINK \l "_Toc147291462"  3.4.4	Incidental Oral Exposure
(Short-Term)	  PAGEREF _Toc147291462 \h  24  

  HYPERLINK \l "_Toc147291463"  3.4.5	Incidental Oral Exposure
(Intermediate-Term)	  PAGEREF _Toc147291463 \h  25  

  HYPERLINK \l "_Toc147291464"  3.4.6	Dermal Absorption	  PAGEREF
_Toc147291464 \h  26  

  HYPERLINK \l "_Toc147291465"  3.4.7	Dermal Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc147291465 \h  26  

  HYPERLINK \l "_Toc147291466"  3.4.8	Inhalation Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc147291466 \h  26  

  HYPERLINK \l "_Toc147291467"  3.4.9	Level of Concern for Margin of
Exposure	  PAGEREF _Toc147291467 \h  28  

  HYPERLINK \l "_Toc147291468"  3.4.10    Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc147291468 \h  28  

  HYPERLINK \l "_Toc147291469"  3.4.11     Classification of
Carcinogenic Potential	  PAGEREF _Toc147291469 \h  29  

  HYPERLINK \l "_Toc147291470"  Table 3.4.a  Toxicological Doses and
Endpoints for Dietary and Non-Occupational Exposure	  PAGEREF
_Toc147291470 \h  30  

  HYPERLINK \l "_Toc147291471"  Table 3.4b  Toxicological Doses and
Endpoints for Occupational Exposure	  PAGEREF _Toc147291471 \h  31  

  HYPERLINK \l "_Toc147291472"  3.5	Endocrine disruption	  PAGEREF
_Toc147291472 \h  31  

  HYPERLINK \l "_Toc147291473"  4.0	Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc147291473 \h  31  

  HYPERLINK \l "_Toc147291474"  5.1	Pesticide Metabolism and Drinking
Water Profile	  PAGEREF _Toc147291474 \h  32  

  HYPERLINK \l "_Toc147291475"  5.2	Dietary Exposure and Risk	  PAGEREF
_Toc147291475 \h  32  

  HYPERLINK \l "_Toc147291476"  5.2.1	Acute Dietary Exposure/Risk	 
PAGEREF _Toc147291476 \h  34  

  HYPERLINK \l "_Toc147291477"  5.2.2	Chronic Dietary Exposure/Risk	 
PAGEREF _Toc147291477 \h  34  

  HYPERLINK \l "_Toc147291478"  Table 5.2.2.  Dietary Exposure and Risk
for Allethrins	  PAGEREF _Toc147291478 \h  35  

  HYPERLINK \l "_Toc147291479"  5.3	Anticipated Residues	  PAGEREF
_Toc147291479 \h  35  

  HYPERLINK \l "_Toc147291480"  5.4	Characterization of Acute and
Chronic Dietary Assessments	  PAGEREF _Toc147291480 \h  37  

  HYPERLINK \l "_Toc147291481"  6.1	Residential Handler Exposure	 
PAGEREF _Toc147291481 \h  38  

  HYPERLINK \l "_Toc147291482"  Table 6.1  Residential Handler Risks for
Allethrin	  PAGEREF _Toc147291482 \h  38  

  HYPERLINK \l "_Toc147291483"  6.2.	Residential Post Application
Exposure	  PAGEREF _Toc147291483 \h  38  

  HYPERLINK \l "_Toc147291484"  Table 6.2  Allethrin Residential Post
Application Risk	  PAGEREF _Toc147291484 \h  43  

  HYPERLINK \l "_Toc147291485"  7.0	Aggregate Risk Assessments and Risk
Characterization	  PAGEREF _Toc147291485 \h  44  

  HYPERLINK \l "_Toc147291486"  Table 7.0.   Aggregate Risk for Children
1-2 Years Old.	  PAGEREF _Toc147291486 \h  44  

  HYPERLINK \l "_Toc147291487"  8.0	Cumulative Risk Assessment	  PAGEREF
_Toc147291487 \h  45  

  HYPERLINK \l "_Toc147291488"  9.0	Occupational Exposure/Risk Pathway	 
PAGEREF _Toc147291488 \h  45  

  HYPERLINK \l "_Toc147291489"  9.1	Occupational Handler Risk	  PAGEREF
_Toc147291489 \h  45  

  HYPERLINK \l "_Toc147291490"  Table 9.1   Allethrin Occupational
Handler Risks	  PAGEREF _Toc147291490 \h  47  

  HYPERLINK \l "_Toc147291491"  9.2	Occupational Post Application Risk	 
PAGEREF _Toc147291491 \h  48  

  HYPERLINK \l "_Toc147291492"  10.0	Data Needs and Label Requirements	 
PAGEREF _Toc147291492 \h  49  

  HYPERLINK \l "_Toc147291493"  REFERENCES:	  PAGEREF _Toc147291493 \h 
51  

  HYPERLINK \l "_Toc147291494"  Appendix A:	Toxicology Assessment	 
PAGEREF _Toc147291494 \h  52  

  HYPERLINK \l "_Toc147291495"  A.1	Toxicology Data Requirements	 
PAGEREF _Toc147291495 \h  52  

  HYPERLINK \l "_Toc147291496"  A.2	Toxicity Profiles	  PAGEREF
_Toc147291496 \h  53  

  HYPERLINK \l "_Toc147291497"  Appendix B:  Tolerance Reassessment
Summary and Table	  PAGEREF _Toc147291497 \h  59  

 1.0	Executive Summary

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, on gardens and direct application to cats,
dogs and horses.  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 developmental neurotoxicity
study is required.  A database uncertainty factor of 10x was applied to
endpoints 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 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
0.026956 mg/kg/day, which utilized 90% of the acute population adjusted
dose (aPAD).  

A 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 0.002443
mg/kg/day, which utilized 41% 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, vinyl flooring
and pets.  Inhalation exposures may occur after space spray application.
 Incidental oral exposures were assessed for toddlers and inhalation
exposures were assessed for adults and toddlers.  Again, 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 dermal exposure.  Some of the scenarios
are of concern because the MOEs do not exceed the target MOE of 1000. 
These include incidental oral exposures from surface sprays and pet
treatments and inhalation exposures from space spray and outdoor fogger
applications.  The remaining scenarios are not of concern because the
MOEs exceed 1000.

Aggregate exposure:  Aggregate assessments were only conducted for
exposure scenarios which did not exceed a level of concern.  Incidental
oral exposures from surface spray uses were not aggregated because the
incidental oral risks exceeded the level of concern by themselves. 
Aggregate exposure did not exceed a level of concern for short- and
intermediate-term exposure for foggers on carpets and vinyl floors. 
Aggregate exposure for short-term exposure after pet treatment also did
not exceed a level of concern.  

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.  As before, dermal exposures
were not assessed because no systemic effects were observed at the limit
dose in the dermal toxicity studies in test animals.   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 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  TC \l1 "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; on pets
(dogs, cats, horses) and pet premises (bedding, dog houses, etc.).

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.

Animal Treatments:   Treatments of animals not intended for food (pets,
horses) as a direct spray, wipe-on, dust-on or dip. Use in and around
pet premises (kennels, pet bedding. stalls, etc.). Use in livestock
structures (dairies, barns, etc.) as a space spray and/or a premise
treatment as a general surface, spot and/or crack & crevice treatment
when food/feed animals are not present.

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.

Application

A summary of information about application of allethrins obtained from
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.



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

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

Application Timing, Type, and Equipment	

Formulation

[EPA Reg. No.]	

Application Rate 

	

Max. No. Application per Season	

Max. Seasonal Application Rate	Use Directions and Limitations

Food Handling Establishments

General spray	

VBC Esbiol® 90 Insecticide	

1.43 % final dilution spray, 1.0 fluid oz. per 1000 ft3	NS1	NS	

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.  

Space Spray

	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.

Spot Treatment

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

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

Crack and Crevice Treatment

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

	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.

1 NS= Not specified

Table 2.1d.       Summary of Directions for Use of Esbiothrin in Food
Handling Establishments.

Application Timing, Type, and Equipment	

Formulation

[EPA Reg. No.]	

Application Rate 

	

Max. No. Application per Season	

Max. Seasonal Application Rate	Use Directions and Limitations

Food Handling Establishments

General spray	

VBC Esbiothrin® 90 Insecticide	

1.70 % final dilution spray, 1.0 fluid oz. per 1000 ft3	NS1	NS	

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.  

Space Spray

	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.

Spot Treatment

0.39% final dilution spray, 0.45 fluid oz. per 1000 ft2

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

Crack and Crevice Treatment

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

	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.

1 NS= Not specified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	

Bioallethrin	

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, and an Ames study. 
There is also a new micronucleus study with Bioallethrin.  An inhalation
study with Pynamin Forte was recently submitted and is presently under
review.  This study has 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, 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.  A developmental neurotoxicity study
is not available for any of the allethrins. 

use 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 6 mg/kg/day) and
incidental oral exposure (20 and 6 mg/kg/day) are all lower than the
offspring NOAEL from the reproductive study (50 mg/kg/day).  

3.3.5	Recommendation for a Developmental 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 study is therefore required and a 10x
database uncertainty factor is required for the lack of this study.  



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 developmental
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:  

NOAEL = 6 mg/kg/day

LOAEL = 36 mg/kg/day based on microscopic liver changes (hepatocellular
degeneration)

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

Comments about Study/Endpoint/Uncertainty Factor:   Liver toxicity is
seen in other studies with the allethrins.  

Chronic RfD  =   6 mg/kg/day  =  0.006 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 activity was observed in
mid-dose males and high-dose males and females.  Alanine
aminotransferase activity was increased (p<0.01) in high-dose animals of
both sexes when compared to control values. Statistically significant
(p<0.05) increases were also observed in gamma glutamyl transpeptidase
(GGTP) and aspartate amino transferase (SGOT) activities in high-dose
males and females; however, GGTP values were only marginally increased
over pretreatment values and SGOT values were decreased in both sexes
when compared to the respective pretreatment values.  Increased liver
weights were observed in mid- and high-dose animals of both sexes but
are considered possibly treatment-related but of questionable
toxicological significance.  A dose-related hepatocellular degeneration
of the liver was observed in mid- and high-dose males and females. 
Acute cellular centrilobular swelling and brown granular liver
pigmentation were also observed.

	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 and slight irregular heart rhythms
and general body trembling (both sexes), salivation (males), decreases
in body weight gain and food consumption (both sexes), increases in
alanine aminotransferase activity (both sexes) and slight increases in
GGTP activity in both sexes at 5000 ppm.

	This toxicity study is classified as 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 developmental
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) 

MRID Number:  00151447

Dose and Endpoint:  

NOAEL = 6 mg/kg/day

LOAEL = 36 mg/kg/day based on microscopic liver changes (hepatocellular
degeneration)

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

Comments about Study/Endpoint/Uncertainty Factor:   Liver toxicity is
seen in other studies with the allethrins.  

Executive Summary:   see chronic dietary section, above

 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 developmental 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).  

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 developmental
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 NOAEL of 6 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
Non-Occupational 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)	NOAEL= 6 mg/kg/day	UFA = 10x

UFH = 10x

FQPA SF = 10x

[UFDB]	cRfD = 0.006 mg/kg/day

cPAD = 0.006  mg/kg/day	6-month dog (Bioallethrin).  

LOAEL = 36 mg/kg/day 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)	NOAEL = 6 mg/kg/day	UFA =  10x

UFH = 10x

FQPA SF = 10x

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

LOAEL = 36 mg/kg/day 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 (oral, dermal, inhalation)	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 developmental 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 (oral, dermal, inhalation)	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 

Acute and chronic dietary exposure assessments for the allethrins 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 

An acute dietary exposure assessment was conducted for allethrins.  The
acute analysis assumed that 100% of food handling establishments and all
foods are treated with allethrins.  Default DEEM 7.81 processing factors
were applied.  The highest residue values from each commodity
represented in the FHE magnitude of residue study were translated to
other food forms within 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 0.013877 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 0.026956 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 0.001006 mg/kg/day, which utilized 17% of the cPAD.  The
highest exposure and risk estimates were for children 1-2 years old. 
The exposure for food only was 0.002443 mg/kg/day, which utilized 41% 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

	0.013877	46	0.006	0.001006	17

All Infants (< 1 year old)

0.020619	69

0.001336	22

Children 1-2 years old

0.026956	90

0.002443	41

Children 3-5 years old

0.023259	78

0.002116	35

Children 6-12 years old

0.016523	55

0.001418	24

Youth 13-19 years old

0.011537	38

0.000925	15

Adults 20-49 years old

0.009835	33

0.000832	14

Adults 50+ years old

0.008811	29

0.000775	13

Females 13-49 years old

0.009374	31

0.000793	13

5.3	Anticipated Residues 

 food forms within DEEM-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.  

     Characterization of Acute and Chronic Dietary Assessments

rporated in 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: 

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 (Non-Occupational) 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 9 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 0.50 percent by
weight based upon the labels.

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 

Pet and Bedding Spray

Hand Held Yard and Patio Fogger	

Wasp and Hornet Nests	0.50

0.32

0.15

0.10	One 15 ounce can

One   9 ounce can

One 16 ounce can

One 16 ounce can	0.0047 lb

0.0018 lb

0.0015 lb

0.0010 lb	15,000

39,000

  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. 
Inhalation exposures may occur after space spray application. 
Incidental oral exposures may occur after surface applications of
allethrin are made to residential areas such as carpets, vinyl flooring
and pets.  Incidental oral exposures were assessed for toddlers and
inhalation exposures were assessed for adults and toddlers.  Dermal
exposures were not assessed because no dose or endpoint was selected for
dermal exposure.  

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. 

Indoor Fogger Surface Treatment Post Application Exposure Assumptions

The application rate is 0.000225 lb ai/1000 ft3 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 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 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
exposures as listed in SOP #12.  This is the mean value from the video
observation study.  

Indoor Surface Treatment Post Application Exposure Assumptions

One 1 gallon of spray applied per 1000 square feet. 

The spray dilution ranges from 0.25 percent to 3.0 percent. 

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

Pet Treatment Post Application Assumptions

The product contains 0.32 percent allethrin based upon the Chemsico Dual
Flea Control label (#9688-41, accepted 4/24/1991).

One half of a 9 oz spray container is used to treat each animal. 

The transferable residue from a treated pet is assumed to be 20% of the
application rate.

The surface area of a treated (30 lb) dog is 6000 cm2 (EPA 1993 Wildlife
Exposure Factors Handbook - carbaryl)

The saliva extraction factor is 50 percent.

The surface portion of hand put in mouth is 20 cm2.

The frequency of hand-to-mouth events is one per day (frequency modified
to reflect transferable residue assumption which is based on a 5 minute
heavy rubbing/petting technique that would lead to significantly higher
hand concentrations than would result from a single contact)

Space Spray Application Exposure Assumptions

Three application rates were considered with the lowest rate based upon
the amount of spray applied during the NDETF study, the medium rate
based upon the Raid label 4822-139 and the highest rate based upon SOP
assumptions.

The air concentration of 0.019 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 0.10 mg/m3 to 0.012
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 or 6 ounces based upon the Raid Yard Guard
label 4822-394.

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.

Risk Characterization for Post Application Exposure:

Residential post application incidental oral exposures were assessed for
indoor fogger and surface spray deposition onto floor surfaces. 
Residential post application inhalation exposures were assessed for
space sprays, yard and patio foggers, mosquito coils and fly mats. Some
of the scenarios are of concern because the MOEs do not exceed the
target MOE of 1000, including incidental oral exposures from surface
sprays and pet treatments and inhalation exposures from space sprays and
outdoor fogger application (Table 6.2).  The remaining scenarios are not
of concern because the MOEs exceed the target MOE of 1000 for incidental
oral and inhalation exposures.  

The surface spray dilutions range from 0.15 to 3.0 percent with one
gallon of spray applied per 1000 square feet.   These rates are listed
on a variety of RTU labels that appear to be intended primarily for PCO
applications to commercial and institutional sites.  Information
regarding the use of these products at residential sites could be used
to refine incidental oral risks.

The space spray application rates and resultant exposures are variable
depending upon the label considered and user adherence to label
instructions.  Although the Raid label is fairly specific (apply 4
second spray per 1000 ft3) other labels contain statements such as
“fill room with mist” which are less specific.  Many of the labels
also require that the room be kept closed for 15 minutes and ventilated
thoroughly prior to entry.

Inhalation following release of a total release aerosol fogger used
indoors was not modeled separately because the fogger labels typically
require actions that reduce exposure.   The Speer  4X Indoor Fogger
label, for example, has the following statement “DO-NOT RE-ENTER
BUILDING FOR FOUR HOURS; then open exterior doors and windows and allow
to air for 60 minutes before reoccupying area”.   This label has the
highest concentration of allethrin (1.20% a.i.) and the most recent
approval date (5/20/2003).   The other fogger labels have lower
concentrations of allethrin and are much older with approval dates that
range from 1981 to 1992.

Incidental oral exposures were not assessed for outdoor fogger
applications because it was assumed that the aerosols would disperse
before settling.  

The incidental oral risks calculated for spray application to pets are
protective of dip or shampoo applications because the shampoos and dips
are used at lower dilution rates than the spray formulations.  

The incidental oral risks calculated for spray application to pets are
based upon the Chemsico Dual Flea Control label (9688-41) which has the
highest concentration of allethrin (0.32%).  The next highest
concentration of allethrin (0.30%) is in Esbiothrin Flea and Tick Mist
(270-352), while the remaining labels contain 0.050% to 0.16% allethrin.

Table 6.2  Allethrin Residential Post Application Risk

Source of Exposure	Application Rate	Exposed Population	MOE*

Incidental Oral Exposures – Short Term

Fogger Treatment - Carpet Floors  

Fogger Treatment - Vinyl Floors 	0.00225 lb ai/1000 ft3	Children

	3600

5200

Surface Spray - Carpet Floors  

	3.0% spray (1 GA per 1000 ft2)

0.15% spray (1 GA per 1000 ft2)	Children

	20

230

Surface Spray – Vinyl Floors	3.0% spray (1 GA per 1000 ft2)

0.15% spray (1 GA per 1000 ft2)	Children

	28

330 

Treated Pets – Spray Formulations	0.32 percent a.i.	Children	2,100

Incidental Oral Exposures – Intermediate Term

Fogger Treatment - Carpet Floors  

Fogger Treatment - Vinyl Floors 	0.00225 lb ai/1000 ft3	Children

	2200

3300

Surface Spray - Carpet Floors  

	3.0% spray (1 GA per 1000 ft2)

0.25% spray (1 GA per 1000 ft2)	Children

	12

140

Surface Spray – Vinyl Floors	3.0% spray (1 GA per 1000 ft2)

0.25% spray (1 GA per 1000 ft2)	Children

	18

210

Treated Pets – Spray Formulations	0.32 percent a.i.	Children	650

Inhalation Exposures – Short/Intermediate Term

Space Spray 	0.000050 lb ai/1000 ft3

(based upon the NDETF study)	Children

Adults	720

2400

	0.000044 lb ai/1000 ft3

(Based upon the Raid label)	Children

Adults	810

2700

	0.000033 lb ai/1000 ft3

(based upon the SOP)	Children

Adults	110

360

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	Children

Adults	3100

6200

Total Release Yard and Patio Fogger	Two 6 ounce foggers per patio
Children

Adults	160

310

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

Adults	650

1300

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

7.0	Aggregate Risk Assessments and Risk Characterization  TC \l1 "7.0
Aggregate Risk Assessments and Risk Characterization 

Aggregate assessments were only conducted for exposure scenarios which
did not exceed a level of concern.  Incidental oral exposures from
surface spray uses were not aggregated because the incidental oral risks
exceeded the level of concern by themselves.  

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.  

Because the same study is used for the dietary and incidental oral
exposure endpoints based on liver toxicity in dog studies, these two
exposures could be combined.  Inhalation exposure could not be included
in the aggregate assessment because the endpoint for inhalation exposure
was based on neurotoxicity.  

As shown below, aggregate exposure did not exceed a level of concern for
short- and intermediate-term exposure for foggers on carpets and vinyl
floors.  Aggregate exposure for short-term exposure after pet treatment
also did not exceed a level of concern.  

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

Exposure Scenario	NOAEL

mg/kg/day	LOC1	Max Allowable

Exposure2

mg/kg/day	Food

Exposure

mg/kg/day	Residential Exposure3

mg/kg/day	Food + Residential Exposure

mg/kg/day	Aggregate MOE

(food +

residential)4

Short-term Exposure

Fogger – carpet	

20	

1000	

0.02	

0.0024	0.0056	0.0080	2500

Fogger – vinyl floor

	0.0039	0.0063	3200

Treated pets

	0.0093	0.0117	1700

Intermediate-term Exposure

Fogger – carpet	6	1000	0.006	0.0024	0.0027	0.0051	1200

Fogger – vinyl floor

	0.0018	0.0042	1400

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

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = Incidental oral exposure from Table A4 or
Occupational and Residential Exposure Assessment, Timothy Dole.

 4Aggregate MOE = [NOAEL / (Food + Residential 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 Exposure/Risk Pathway  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.   

The occupational handler exposure assessment used data from the
Pesticide Handlers Exposure Database (PHED) because chemical-specific
monitoring data were not available.  The PHED exposure data were used
for the low pressure handwand/back sprayer, aerosol can (surface spray
and pet spray) and HP handwand scenarios.   The low pressure handwand
and back sprayer scenarios were combined because they have the same
inhalation unit exposures.  Both Nigg and MGK fogger exposure data were
used.  The Nigg unit exposure data for fogging were taken from a
University of Florida study on greenhouse applicators applying
insecticides using a Dramm Pulsfog K-6005 pulse fogger (reviewed in
D289191 memo, January 27, 2005).  The MGK Fogger exposure data are from
a MGK study that monitored applicator exposure during ULV cold fogging
(Bergman, 2002).   See the Occupational and Residential Exposure
Assessment for more details (8/20/06,  Tim Dole, D294723).  

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, high
pressure handwand and fogger application are from the PCO product labels
and are listed in Table 5 above.  The application rates are expressed in
terms of product dilution rather than area treated.  

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

The application rate for animal care technician application to pets is
0.32% ai based upon the label #9688-41.

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

Dilute sprays could be used for foliar applications in greenhouses.

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.  

For the fogging scenario that is based upon the Nigg data, a PCO could
apply 134 ounces of spray solution per day.   This is based upon spray
output (0.56 ounce per minute @ 15 PSI) of an Actisol Commercial Unit,
which is listed on several of the PCO labels, times a daily spray
duration of 240 minutes.  The daily spray duration is based upon the
assumption that one half of an eight hour workday would be spent
spraying while the other half would be used for set up.

 

For the fogging scenario that is based upon the MGK data, a PCO could
apply two gallons per day.  This is based upon spray output of a
Whitmire Microgen E-2 fogger (1.0 ounce per minute) times a daily spray
duration of 240 minutes.  

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.   

An animal groomer or veterinary technician could treat 8 animals per day
and could use one half of a 16 oz spray container for each animal.  This
assumption is based upon professional judgment and has been used for
other chemicals such as carbaryl and cyfluthrin.

Risk Characterization for Occupational Handler Exposure: 

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 handler scenarios are
summarized in Table 9.1 and the calculations are detailed in Appendix A
of the ORE Assessment.	

Most of the 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.  The fogger scenario is also of
concern when evaluated with the MGK data and requires a PF50 full face
respirator with appropriate cartridges to achieve the target MOE.

The MOEs for the fogger scenario are either 930 or 2 depending upon the
data source used.  The MOE of 930 is based upon the Nigg data which has
serious deficiencies and likely underestimates exposure.  The MOE of 2
is based upon the MGK data which probably overestimates exposure because
of extrapolation from a relatively small area (5500 ft3) treated during
the study to the larger area (240,000 ft3) assumed in this assessment.  
It is unlikely that the exposures would increase in a linear fashion
because larger areas would tend to have higher ceilings and because the
operator could back away from the fog as it is being applied.   
Therefore, the actual MOE is probably greater than 2 and less than 930. 
It is also likely that fogging of larger spaces is done using automatic
equipment which reduces operator exposure.   Additional exposure data
and information regarding fogging application methods could be used to
refine the risks.  MOEs for surface spray and pet spray are 2200 and
5400, respectively, and are not of concern.  

Table 9.1   Allethrin Occupational Handler Risks

Exposure Scenario	Use	Spray Dilution

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

PCO Application to Residential, Industrial or Institutional Sites

M/L/A liquids with LP hand-wand or backpack sprayer	Surface Spray
Undiluted	3	40 gallons	10	300 – No Resp.

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

M/L/A liquids with fogger (Based upon Nigg data)	ULV Space Spray	3	1
gallon	0.25	930 - No Resp.

M/L/A liquids with fogger (Based upon MGK data)	ULV Space Spray	3	2
gallons	0.50	2 - No Resp.

100 – PF50

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

400 – PF5 Resp. 

Aerosol Can application	Surface Spray	0.54	6 cans (16 oz ea)	0.032	2200
– No Resp.

Aerosol can application	Pet Spray	0.32	4 cans (16 oz ea)	0.013	5400 –
No Resp.

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

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 

870.6300 Developmental Neurotoxicity Study

There is a datagap for a developmental neurotoxicity study.  This study
should preferentially be conducted with Esbiol because it contains the
highest percentage of the d-trans d- isomer, which is reportedly the
most insecticidally active isomer.  

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 the
uncertainties associated with the currently available data from the Nigg
and MGK studies.  The Nigg data, which consists of only three usable
replicates, also has other serious deficiencies and likely
underestimates exposure.  The MGK data consists of 25 useable
replicates, however, the same operator using the same fogger in the same
room performed all 25 replicates. 

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: Occupational and Residential Exposure Assessment and
Recommendations for The Reregistration Eligibility Decision (RED). 
Timothy Dole.  DP Barcode D334788.  12/11/06.  

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

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    Develop. Neuro		no

no

no

yes

yes	-

-

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

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

	

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



	

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	

	

parental 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
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ఀ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	

	

	

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.

Allethrins Human Health Risk Assessment    December 20, 2006            
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Allethrins Human Health Risk Assessment    September 28, 2006           
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