UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460      

	OFFICE OF PREVENTION, PESTICIDES

                                                                        
                   AND TOXIC SUBSTANCES

	

  SEQ CHAPTER \h \r 1 MEMORANDUM

Date:		March 5, 2010

SUBJECT:	Allethrins: Human Health Assessment Scoping Document in Support
of Registration Review.  

PC Codes: 004003, 004004, 004005, 004007 	DP Barcode:  371342 

Decision No.: 422724	Registration No.: NA

Petition No.: None	Regulatory Action: Registration Review Scoping
Document

Risk Assessment Type: NA 	Case No.: 0437

TXR No.: None	CAS No.: 28434-00-6; 584-79-2

MRID No.: None	40 CFR: NA



FROM:	Toiya Goodlow, Risk Assessor/Chemist			

		Kit Farwell, D.V.M., Toxicologist

		Matthew Lloyd, CIH, Industrial Hygienist 

		Risk Assessment Branch VII

		Health Effects Division (7509P)

		Office of Pesticide Programs

THRU:	Michael S. Metzger, Branch Chief

		Risk Assessment Branch VII

		Health Effects Division (7509P)

		Office of Pesticide Programs

TO:		Molly Clayton

		Pesticide Re-evaluation Division (7508P)

		Office of Pesticide Programs

Executive Summary

The HED Allethrins Registration Review Team evaluated the most recent
human health assessments and database for the allethrins to determine
the scope of work necessary to support Registration Review. In this
evaluation, HED considered the most recent risk assessments and the
Reregistration Eligibility Decision (RED) document for allethrins.  

The allethrin series of pyrethroid insecticides include bioallethrin,
esbiol, esbiothrin, and pynamin forte.  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.  Allethrins are used as space sprays in a
wide variety of indoor areas such as greenhouses, commercial
institutions, and residences. There are no food uses for the allethrins;
however, there is a pending food use for esbiothrin and esbiol to be
used in food handling establishments (FHEs).

Pyrethroids are neurotoxicants which act by prolonging the opening of
the sodium channel in nerves and causing neurotoxicity.  All four
allethrins caused similar types of neurotoxicity and liver toxicity at
generally similar doses.  No risks of concern have been identified for
dietary, residential, aggregate and occupational exposure.  

The toxicity database is incomplete.  Immunotoxicity, subchronic mouse
toxicity, and a micronucleus assay are required to support continued
registration.  A new carcinogenicity study in mice may be required for
esbiothrin pending the results of the requested subchronic mouse
toxicity study.  A developmental neurotoxicity (DNT) study was
previously required for allethrins.  However, EPA has recently
determined that, as an alternative to the generation and submission of a
new DNT study for the allethrins, registrants may instead choose to cite
the six previously submitted DNT studies for pyrethroid pesticides.  The
six chemicals with acceptable DNTs include bifenthrin, cyfluthrin,
cyhalothrin, cypermethrin (zeta), fenpropathrin, and deltamethrin.  A
decision regarding the need for a Food Quality Protection Act (FQPA) or
other database uncertainty/safety factor required to assure protection
of infants and children will be made following receipt of remaining
required toxicity data, and following a final determination of the
potential for increased susceptibility of these subpopulations to
pyrethroid pesticides based on the results of these data.  The allethrin
risk assessment may need to be revised to incorporate these decisions.  

The residue chemistry database for the allethrins is incomplete for the
pending FHE use; these data gaps were identified in the 2007 risk
assessment.  In response to these requirements, label and tolerance
amendments for the FHE petition have been submitted to the Agency and
are currently under review.  

No new data are required for occupational and residential exposure. 

Introduction

The allethrin series of pyrethroid insecticides include bioallethrin
(004003), esbiol (004004), esbiothrin (004007, formerly 004003/004004),
and pynamin forte (004005).  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 Tables 2 and 3 attached to the document for the
structure, chemical names, and other identifiers of the allethrin
pesticides.

HED evaluated the most recent risk assessments (2006-07), the RED
documents (2007 and 2009), data received since the RED, and conducted an
open literature search to determine if additional studies and/or risk
assessments are needed to support the Registration Review of allethrins.
 

Allethrins are used as space sprays in a wide variety of indoor areas
such as greenhouses, commercial institutions, and residences. There are
no food uses for the allethrins; a Federal Register final rule revoking
all food tolerances was published on September 29, 2004.  There is a
pending petition for the establishment of a permanent food handling
establishment tolerance set at 1.0 ppm.   A food handling establishment
is any place other than a residential kitchen in which food is held,
processed, prepared, and/or served.  

Hazard Identification/Toxicology

The allethrins are members of the pyrethroid chemical class of
compounds.  Pyrethroids are neurotoxicants which act by prolonging the
opening of the sodium channel in nerves and causing neurotoxicity.  

The database for the allethrins is extensive and was evaluated in a
recent risk assessment (7/27/07, D337992).  Because the allethrins are
structurally similar differing only in the relative proportions of
stereoisomers and caused similar types of neurotoxicity and liver
toxicity at generally similar doses, one set of risk assessment
endpoints covering all four chemicals was selected from the combined
database. Endpoints were based on neurotoxicity and liver toxicity. 
Clinical signs of neurotoxicity included muscle tremors, hunched
posture, and salivation in rat studies and muscle tremors, hunched
posture, and seizures in dogs.  

No developmental abnormalities occurred in rat developmental studies
with any of the four allethrins.  Bone anomalies were noted in
developmental toxicity studies in rabbits with esbiol and pynamin forte.
 Decreased viability and delayed maturation were noted in a reproduction
study with esbiothrin and decreased offspring weight occurred in a
reproduction study with pynamin forte.  

Benign kidney tumors occurred in male rats in the esbiothrin rat study. 
No tumors were found in rat and mice studies with pynamin forte, and
genetic toxicity studies were negative for all four allethrins.  The
cancer classification is "suggestive evidence of carcinogenicity, but
not sufficient to assess human carcinogenic potential", and
quantification of cancer risk is not required.  

A literature review with PubMed was conducted to determine if new
toxicity studies in the open literature were available since the last
risk assessment.  No new toxicity studies were found in the literature
search that would result in changes to the current risk assessment.  

Several recent toxicity studies have been submitted by the registrant
since the last allethrins risk assessment and are currently under
review.  They include acute and subchronic neurotoxicity studies with
pynamin forte and a reproduction study with esbiol.  Preliminary review
found that these studies may include endpoints that are slightly more
sensitive than those currently being used to quantify risks, but which
are not likely to lead to unacceptable risk estimates.  

There was no evidence of prenatal or offspring susceptibility in
developmental rat studies with bioallethrin, esbiol, esbiothrin, or
pynamin forte; in developmental rabbit studies with esbiothrin, pynamin
forte, or esbiol; or in a 2-generation reproduction study with pynamin
forte.  There was evidence of offspring susceptibility in the
2-generation reproduction study with esbiothrin, however there were no
residual uncertainties because the points of departure for risk
assessment were all lower than the offspring no observed adverse effect
level (NOAEL) from the reproductive study.

Because the allethrins are neurotoxicants, as noted above, a
developmental neurotoxicity study was required and the FQPA safety
factor of 10X was retained in the risk assessment to account for this
datagap.  However, EPA has recently determined that, as an alternative
to the generation and submission of a new DNT study, registrants may
instead choose to cite the six previously submitted DNT studies for
pyrethroid pesticides.  The six chemicals with acceptable DNTs include:
bifenthrin, cyfluthrin, cyhalothrin, cypermethrin (zeta), fenpropathrin,
and deltamethrin.  Given the similarity of certain results across all
these studies, EPA has concluded that, when considered together, they
provide sufficient information for EPA to determine that the conclusions
are applicable to all pyrethroids.  EPA will therefore consider citation
of all of the six studies as a substitute for generating a single new
study for allethrins.  The Agency is investigating whether other data
may be necessary to evaluate the potential for increased susceptibility
of the young.  A decision regarding the need for an FQPA or other
database uncertainty/safety factor required to assure protection of
infants and children will be made following receipt of the remaining
required toxicity data, and following a final determination of the
potential for increased susceptibility of these subpopulations to
pyrethroid pesticides based on the results of these data.  The allethrin
risk assessment may need to be revised to incorporate these decisions.  
 

Toxicological data deficiencies were identified for allethrins during
the scoping process.  Dosing in the mouse carcinogenicity study with
esbiothrin (MRID 41519804) was considered inadequate and was not
supported by the 8-week range finding study.  A 90-day subchronic oral
toxicity study for esbiothrin is required to determine if doses in the
mouse carcinogenicity study were adequate.  If the 90-day subchronic
study does not demonstrate adequate dosing, then a new mouse
carcinogenicity study will be required for esbiothrin.  This will be
determined once the requested subchronic study has been received and
reviewed by the Agency.  A micronucleus assay with esbiothrin (MRID
00151456) was classified as unacceptable and should also be repeated. 
An immunotoxicity study is now required as a part of 40 CFR Part 158 for
conventional pesticide registration.  The immunotoxicity requirement was
included in the allethrins reregistration generic data call-in (GDCI)
issued in December 2009.   

Once all data have been received and reviewed, allethrins endpoints and
safety factors used for risk assessment will be reexamined.  

Dietary Exposure

Although all food tolerances were cancelled in 2004, a dietary
assessment was performed in 2007 to support the pending Section 3
request to use esbiothrin and esbiol, stereoisomers of allethrin, in
food handling establishments.  Refined acute and chronic dietary risk
assessments were conducted using the Dietary Exposure Evaluation Model
(DEEM-FCID™, Version 2.03) which used food consumption data from the
U.S. Department of Agriculture’s Continuing Surveys of Food Intakes by
Individuals (CSFII) from 1994-1996 and 1998.  Dietary risk estimates
were determined considering exposures from food only; no exposure to
drinking water is expected as a result of the allethrins FHE
application.  The Environmental Fate and Effect Division (EFED) has not
previously conducted a drinking water assessment for the allethrins
because the chemical's use was limited primarily to indoor non-food
uses, and was labeled for only limited outdoor uses (e.g., spot
treatments, foggers).  Because there are currently no food uses for
allethrins and FHE applications are generally applied indoors, residues
in drinking water are not expected and a drinking water assessment will
not be conducted to support a human dietary risk assessment.  

Acute dietary exposure analyses are not ordinarily required for food
handling uses; however, 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 included in DEEM-FCID™ were
treated with allethrins.  The chronic analysis assumed that all foods
included in DEEM-FCID™ and 20% of all food handling facilities were
treated with allethrins based on an estimate by the Biological Effects
and Analysis Division (BEAD).  Anticipated residues, based on a
magnitude of residue study for food handling establishment use submitted
by the registrant, were used for both the acute and chronic assessments.
 Acute and chronic risk estimates were below the Agency’s level of
concern.          

There are existing residue chemistry deficiencies associated with the
pending FHE use including requirements for OPP Test Guidelines 860.1200,
860.1300, 860.1480, 860.1520, 860.1550, 860.1650.  These data gaps were
identified in the 2007 risk assessment.  In response to these
requirements, label and tolerance amendments pertaining to several
guideline studies for the FHE petition have been submitted to the Agency
and are currently under review.  See the Data Requirements section of
this document for further details.  Protective assumptions were used in
the previous dietary assessment to account for the lack of these data. 
No additional data gaps were identified during the Registration Review
scoping process.  An updated dietary assessment for the pending FHE use
may be required in Registration Review to incorporate any changes to the
toxicological endpoints and uncertainty factors; this will be determined
once the required toxicology data have been received and reviewed by the
Agency.  

Residential Exposure 

Non-dietary risk assessments for the allethrins are included in the
revised occupational and residential exposure/risk assessment and
supporting documents (D340744, Dole / D359479, Lloyd).  The results of
this analysis have been summarized and are included in the allethrins
RED.

Residential Handlers

Residential handlers may be exposed to allethrins as a result of space
sprays, surface sprays, crack and crevice treatments, residential
greenhouse sprays, application to pets, and ornamental plant treatment
in landscaped areas around the home.  Dermal exposure was not
quantitatively assessed because there was no systemic toxicity at the
limit dose in dermal toxicity studies and negligible dermal absorption
was observed in the closely related pyrethrin isomers in the hazard
database. Residential handler inhalation risk estimates assessed to date
are below the Agency’s level of concern. 

Residential Post-application 

Residential post-application exposure may occur as a result of indoor
and outdoor surface (“spot”) applications, space sprays, pet
treatments, and the use of hand held yard and patio foggers, greenhouse
sprays, mosquito coils, and automated misting systems. Dermal exposure
was not quantitatively assessed because there was no systemic toxicity
at the limit dose in dermal toxicity studies and negligible dermal
absorption derived from the hazard database.  Incidental oral and
inhalation exposures for the short- and intermediate-term exposure
durations were assessed and are below the Agency’s level of concern,
except for inhalation exposures from yard and patio total release
foggers.  However, the Agency does not anticipate a risk of concern from
this use because Residential Exposure Joint Venture survey information
indicates the yard and patio total release fogger formulation is used
infrequently compared to the handheld aerosol spray formulation (which
yielded risk estimates below our concern). Also, the inhalation endpoint
is derived from a study where the NOAEL is five times lower than the
lowest observed adverse effect level (LOAEL). The Agency recognizes the
large dose spacing in the inhalation exposure endpoint selection; even a
small change in the selected point of departure would yield risk
estimates below the Agency’s level of concern. Based on these
considerations, HED has minimal concern for this exposure scenario.  

No residential data gaps were identified during the Registration Review
scoping process.  Adequate data were available to assess all of the
residential exposure scenarios for the registered uses of allethrins. 
An updated residential assessment may be required in Registration Review
to incorporate any changes to the toxicological endpoints and
uncertainty factors; this will be determined once the required
toxicology data have been received and reviewed by the Agency.  It
should also be noted that likely upcoming policy revisions such as
anticipated modifications in the Standard Operating Procedures (SOPs)
for residential exposure assessment could also cause elements of the
current exposure assessments to be revised (e.g., post-application
exposure for automated misting systems and the calculation of dose from
hand-to-mouth behaviors in young children).  

Aggregate Risk Assessment

An aggregate exposure assessment considers food, drinking water, and
residential exposures from three major routes: oral, dermal, and
inhalation.  Incidental oral and dietary exposures were aggregated
because the same endpoint (liver effects from a 30-day dog study) was
used for both.  Inhalation exposure was not aggregated because a
different endpoint was chosen for assessing inhalation risks
(neurotoxicity).  No endpoints were identified for dermal exposure. 
Residues of the allethrins are not expected in groundwater or surface
water because outdoor residential uses are limited to spot use only and
the sole food use is for FHEs (indoor treatments).  Therefore, aggregate
risk was calculated for combined food and residential exposure. The
estimated allethrin aggregate risks are below the Agency’s level of
concern.   

The upcoming policy revisions in the SOPs for residential exposure
assessment may require revisions to the residential assessment, in which
case a new aggregate assessment may be required.  Additionally,
revisions to the aggregate assessment may be required in Registration
Review to incorporate any changes to the toxicological endpoints and
uncertainty factors; this will be determined once the required
toxicology data have been received and reviewed by the Agency.  

Occupational Exposure 

The Occupational risk assessment for the allethrins is described in
detail in the revised occupational and residential exposure/risk
assessment and supporting documents (D340744, Dole / D359479, Lloyd). 
The results of this analysis have been summarized and are included in
the allethrins RED.

Occupational Handlers

Occupational handlers are likely to be exposed to allethrins using
handheld application equipment, mixing and loading allethrin
formulations for outdoor area spray foggers, and using aerosol sprays.
Currently, the majority of allethrin products are packaged in
ready-to-use aerosol cans. Occupational handler inhalation risk
estimates were conducted for the short- and intermediate-term exposure
durations.  Based on current policy, greenhouse uses result in long-term
exposure triggering the use of a long-term point of departure (PoD) for
worker risk. However, since the allethrin occupational inhalation PoD is
identical for the short-, 

intermediate-, and long-term exposure durations, and because the
screening-level long-term exposure assessment is based on peak air
concentrations as for the shorter-term assessments, occupational risk
estimates for all durations of exposure will be identical given the
current hazard database.  All occupational handler risk estimates are
below the Agency’s level of concern.

Occupational Post-application

Occupational post-application inhalation exposures are primarily
anticipated from automatic misting systems used in commercial/industrial
horse barns, dog kennels and zoo animal quarters. Occupational
post-application inhalation risk estimates are below the Agency’s
level of concern.  

No occupational exposure data gaps were identified during the
Registration Review scoping process. An updated occupational assessment
may be required in Registration Review to incorporate any changes to the
toxicological endpoints and uncertainty factors; this will be determined
once the required toxicology data have been received and reviewed by the
Agency.  

Public Health and Pesticide Epidemiology Data 

EPA consulted the following two incident databases to prepare incident
reports for the four allethrins active ingredients (ais) in preparation
of the registration review docket opening: OPP Incident Data System
(IDS) and the Centers for Disease Control and Prevention/National
Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event
Notification System for Occupational Risk (SENSOR).  

In IDS, 26 single chemical incidents were reported between 2002 and
2009, i.e., there were 26 incidents in which the end-use product
associated with the incident contained only one of the four allethrins
ais and was not a product co-formulated with another ai.  An IDS query
was also conducted for incidents involving multi-ai products containing
allethrins, which identified a moderately large number of incidents.  
Since these incidents involve more than one active ingredient, there is
considerable uncertainty as to whether the incidents reported are a
direct result of exposure to an allethrin ai or another ai.

In NIOSH SENSOR, 177 cases were reported between 1998 and 2005 involving
esbiol or pynamin forte.  Cases reported for esbiol or pynamin forte
alone and where exposure was determined to be definite, probable, or
possible were reviewed in detail, as these cases provide more reliable
information about the potential effects of exposure to allethrins. 
Using these selection criteria, 2 cases were identified.  The symptoms
in these 2 cases included neurotoxic, dermal, and ocular effects.  Both
cases were classified as low severity.  NIOSH SENSOR was not searched
for bioallethrin or esbiothrin; however, this search will be conducted
during the development of the Final Work Plan (FWP).  Of the 175 NIOSH
SENSOR cases in which esbiol or pynamin forte are not the only ai, there
were 144 cases classified as low severity, 25 cases classified as
moderate severity, 2 cases classified as high severity, 3 cases were
considered unlikely to be related to the pesticide product, and 3 cases
were fatal.  All of the high and fatal severity cases were cases of
misuse; 4 were ingestion of the product and the fifth was a case of
dermal contact.

In general, both the IDS and NIOSH SENSOR queries resulted in moderately
large numbers of case reports.  However, most of these incidents were of
low severity and no patterns or trends were discerned among the reported
cases.  Subsequently, it is not clear human incident data warrant
further analysis for the risk assessment and/or risk management of
allethrins.  The Agency will continue to monitor the incident
information and if a concern is triggered, additional analysis will be
included in the risk assessment.

Tolerance Assessment and International Harmonization

All U.S. food tolerances were voluntarily cancelled for the allethrins. 
A Federal Register final rule revoking all tolerances was published on
September 29, 2004.  There is a pending petition for the establishment
of a permanent food handling establishment tolerance set at 1.0 ppm.  No
Codex, Canadian, or Mexican maximum residue limits (MRLs) have been
established for allethrins. 

Environmental Justice

Potential areas of environmental justice concerns, to the extent
possible, were considered in the human health risk assessment, in
accordance with U.S. Executive Order 12898, "Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,"   HYPERLINK
"http://www.eh.doe.gov/nepa/tools/guidance/Volume1/2-6-EO_12898envjustic
e.pdf" 
http://www.eh.doe.gov/nepa/tools/guidance/Volume1/2-6-EO_12898envjustice
.pdf ).  The Office of Pesticide Programs (OPP) typically considers the
highest potential exposures from the legal use of a pesticide when
conducting human health risk assessments, including, but not limited to,
people who obtain drinking water from sources near agricultural areas,
the variability of diets within the U.S., and people who may be exposed
when harvesting crops.  Should these highest exposures indicate
potential risks of concern, OPP further refines the risk assessments to
ensure that the risk estimates are based on the best available
information.

Cumulative  

The allethrins are a member of the pyrethroid class of insecticides. 
This class also includes permethrin, cypermethrin, cyfluthrin,
tau-fluvalinate, bifenthrin, fenpropathrin, and lambda-cyhalothrin,
among others.  EPA developed a draft science policy document on the
proposed common mechanism of toxicity for naturally-occurring pyrethrins
and synethric pyrethroids (Proposed common mechanism grouping for the
pyrethrins and pyrethroids, draft, May 19, 2009;   HYPERLINK
"http://www.regulations.gov/search/Regs/home.html?R=09000064809a62df" 
http://www.regulations.gov/search/Regs/home.html#documentDetail?R=090000
64809a62df  ).  This document was supported by the Federal Insecticide,
Fungicide, and Rodenticide Act Scientific Advisory Panel (FIFRA SAP) and
EPA will finalize the policy document on the pyrethroid common mechanism
of toxicity taking into account the SAP comments.  Pesticides with a
common mechanism of toxicity are subject to cumulative risk assessment
under the FQPA. Research is on-going by EPA’s Office of Research and
Development (ORD) to make improvements to the Stochastic Human Exposure
and Dose Simulation (SHEDS) probabilistic exposure model, which are
important for the pyrethroid cumulative risk assessment.  EPA ORD is
also developing physiologically-based pharmacokinetic models for several
pyrethroids.  The status of both of these research modeling efforts will
be reviewed by the FIFRA SAP in July, 2010.  For information regarding
EPA’s efforts to evaluate the risk to pyrethroids see   HYPERLINK
"http://www.epa.gov/oppsrrd1/reevaluation/pyrethroids-pyrethrins.html" 
http://www.epa.gov/oppsrrd1/reevaluation/pyrethroids-pyrethrins.html . 

Human Studies

Past allethrins risk assessments rely in part on data in generic
databases from studies in which adult human subjects were intentionally
exposed to a pesticide to determine their dermal and inhalation
exposure.  Many such studies, involving exposure to many different
pesticides, comprise generic pesticide exposure databases such as the
Non-dietary Exposure Database and the Pesticide Handler Exposure
Database.  EPA has reviewed all the studies supporting these
multi-pesticide generic exposure databases, and has found no clear and
convincing evidence that any of them were either fundamentally unethical
or significantly deficient relative to standards of ethical research
conduct prevailing when they were conducted.  There is no regulatory
barrier to continued reliance on these studies, and all applicable
requirements of EPA’s Rule for the Protection of Human Subjects of
Research (40 CFR Part 26) have been satisfied.

Data Requirements

No new data are required for occupational and residential exposure. 
Residue chemistry and toxicology data deficiencies include the
following:

Residue Chemistry

Guideline 860.1200 Directions for Use

Guideline 860.1300 Nature of the Residue – Livestock

Guideline 860.1480 Meat, Milk, Poultry, and Eggs

Guideline 860.1520 Processed Food and Feed

Guideline 860.1550 Proposed Tolerances  SEQ CHAPTER \h \r 1 

Guideline 860.1650 Submittal of Analytical Reference Standards

All chemistry data gaps are associated with the pending FHE use and have
been previously required in the allethrins 2007 risk assessment. 
Information pertaining to guidelines 860.1200, 860.1300, 860.1480 and
860.1550 has been submitted to the Agency and is under review.

Toxicology

Guideline 870.6300 Developmental Neurotoxicity Study- Previously
required

Guideline 870.7800 Immunotoxicity- 40 CFR Part 158 data requirement,
previously required

Guideline 870.5395 In Vivo Cytogenetics- New data requirement

Guideline 870.3100 90-Day Oral Toxicity in Mice- New data requirement

Guideline 870.4200 Carcinogenicity Study in Mice- New data requirement,
pending the outcome of the 90-day Oral Toxicity Study

References

Table 1. Memoranda Relevant to Registration Review

Author	Barcode/MRID	Date	Title

T. Dole	D340744	6/27/07	Allethrins: Revised Occupational and Residential
Exposure Assessment and Recommendations for The Reregistration
Eligibility Decision (RED).

M. Lloyd	D359479	2/17/09	Allethrins: Addendum to the Revised
Occupational and Residential Exposure Assessment for The Reregistration
Eligibility Decision (RED). [PC Codes 004003; DP Barcode D359479]

NDETF	46188618

NDETF Study Volume 18: Measurement of Air Concentration, Dermal Exposure
and Deposition of Pyrethrin and Piperonyl Butoxide Following the Use of
an Aerosol Spray

NDETF	46188613

NDETF Study Volume 13: Measurement of Transfer of pyrethrin and
Piperonyl Butoxide Residues from vinyl and Carpet Flooring Treated with
a Fogger Formulation to DSS Wetted Hands Following a Single Hand Press. 



NDETF	46188602

NDETF Study Volume 2: Post Application Deposition Measurements for
Pyrethrins & Piperonyl Butoxide Following Use of a Total Release Fogger

Herb Nigg	40350501

Nigg et al., 1987. Pesticide Exposure to Florida Greenhouse Applicators,
Nigg, H.N., Stamper,

J.H. and Mahon, W.D., University of Florida, 1987

J.Breman	45869301

Bergman, 2003. Applicator Exposure and Air Sampling Following
Application of ETOC Fogging Concentrate 2764 by ULV Fogging, Bergman,
John T., McLaughlin Gormley King Company, 2003

J. Kidwell	None	12/2/03	Esbiothrin: Report of the Cancer Assessment
Review Committee. TXR 0051399.

K. Farwell

P. Villanueva	D339909	6/28/07	Benchmark Dose Analysis of 6-Month Dose
Feeding Study of Bioallethrin in Dogs.

K. Farwell	D337992	6/27/07	Allethrins:  Revised HED Chapter of
Reregistration Eligibility Decision Document (RED) for Bioallethrin
(0040003),  Esbiol (004004),  Esbiothrin (004007), and Pynamin Forte
(004005) and Section 3 Registration Action for Use in Food Handling
Establishments:  Esbiothrin and Esbiol.  

T. Goodlow	D324039	9/26/06	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.

T. Goodlow	D341272	7/10/07	Allethrins: Revised 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.

P. Caulkins	None	6/29/07	Reregistration Eligibility Decision (RED) for
Allethrins

R. Keigwin	None	5/27/09	Reregistration Eligibility Decision for
Allethrins Revised May 2009

M. Hawkins	D371343	11/24/09	Updated Review of Allethrin Incident
Reports. PC codes 004004, 004005

J. Cordova	D373201	2/23/10	Updated Review of the Allethrin (bioallethrin
and esbiothrin) Incidents Reports. PC codes 004003, 004007  



Attachments

Chemical Identity Tables

Table 2.  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 3.  Percentage of Isomers for Each Technical Product in the
Allethrin Family



Isomer	

Esbiol

(S-Bioallethrin)	

Esbiothrin	

Bio-allethrin	

Pynamin Forte

(d-allethrin)



PC Code	

004004	

004007 a	

004003	

004005



CAS #	

28434-00-6	

584-79-2	

584-79-2	

584-79-2



d-trans chrysanthemic acid of  d-allethrolone b	

> 90%	

72%	

( 46%	

36%



d-trans chrysanthemic acid of l-allethrolone	

5%	

21%	

( 46%	

36%



d-cis chrysanthemic acid of d-allethrolone	

- - - c	

- - - 	

- - - 	

9%



d-cis chrysanthemic acid of l-allethrolone	

- - - 	

- - - 	

- - - 	

9%

a  PC code for Esbiothrin formerly 004003/004004

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

c  - - - indicates < 2%

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

Toxicology Table

Table 4.  Toxicological Doses and Endpoints for the Allethrins

Exposure/

Scenario	Point of Departure	Uncertainty/

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

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

	UFA = 10x

UFH = 10x

FQPA SF= 10x

[UFDB]	aRfD = 0.03 mg/kg 

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



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

	UFA = 10x

UFH = 10x

FQPA SF = 10x

[UFDB]	cRfD = 0.008 mg/kg/day

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

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

Incidental Oral Short-Term 

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

UFH = 10x

FQPA SF = 10x

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

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

Incidental Oral Intermediate-Term 

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

	UFA =  10x

UFH = 10x

FQPA SF = 10x

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

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

Dermal 

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

Inhalation

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

UFH = 10x

FQPA SF = 10x

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

Cancer 

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

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
= Food Quality Protection Act 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.

Tolerance/MRL Table

Table 5. Summary of US and International Tolerances and Maximum Residue
Limits 

US	Canada1	Mexico	Codex

Residue Definition: 

None	None	None	None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

Commodity	US	Canada	Mexico	Codex

None	None	None	None	None

1 Numerous registrations as a house and garden insecticide.

DCI Justifications

Guideline Number: 870.3100

Study Title:  90-Day Oral Toxicity in Mice

Rationale for Requiring the Data

The Cancer Assessment Review Committee reported that dosing in the mouse
carcinogenicity study with esbiothrin was inadequate and was not
supported by toxicity occurring in the 8-week rangefinding study.   

Practical Utility of the Data

How will the data be used?  The 90-day oral toxicity study in mice will
be used to justify doses used in the mouse carcinogenicity study with
esbiothrin.  Results from the 90-day study may show that doses selected
in the mouse carcinogenicity study were close to a maximum tolerated
dose.  

If the data show that dosing in the mouse carcinogenicity study was
close to a maximum tolerated dose, then the testing requirement for a
mouse carcinogenicity study will be satisfied.  If toxicity in the
90-day study show that dosing was inadequate, then a new mouse
carcinogenicity study with esbiothrin may be required.

How could the data impact the Agency's future decision-making?  If
testing shows that dosing in the carcinogenicity study was adequate,
there will be no change in the Agency's assessment of risk.  If testing
was shown to be inadequate, then a new mouse carcinogenicity study may
be required which would require an assessment of potential carcinogenic
risk.  



Guideline Number: 870.5395

Study Title:  In Vivo Cytogenetics

Rationale for Requiring the Data

The carcinogenicity of esbiothrin was evaluated by the Cancer Assessment
Review Committee because of an increase in number of benign kidney
tumors in a carcinogenicity study in rats.  The mutagenic potential of
esbiothrin (MRID 00151456) was a critical part of this evaluation.  The
micronucleus study with esbiothrin was negative; however, it was
classified unacceptable because the chemical was not tested to a maximum
tolerated dose.  

Practical Utility of the Data

How will the data be used?  The data can be used to better characterize
the carcinogenic potential of esbiothrin.  

How could the data impact the Agency's future decision-making? A
negative result from the required study would result in decreased
carcinogenic concern but is not expected to result a change to the risk
assessment because quantitation of carcinogenic risk is not presently
required.  A positive result from this assay could result in a
reassessment of esbiothrin's carcinogenic potential.  This could
possibly result in a need to quantify the carcinogenic potential of
esbiothrin although this is not expected to occur because micronucleus
assays with esbiol and pynamin forte were negative.  



Guideline Number: 870.4200

Study Title:  Carcinogenicity Study in Mice

Rationale for Requiring the Data

The carcinogenicity of esbiothrin was evaluated by the Cancer Assessment
Review Committee because of an increase in number of benign kidney
tumors in a carcinogenicity study in rats.  The mouse carcinogenicity
study (MRID 41519804) was negative for tumorigenicity, however, this
study was classified unacceptable because no significant toxicity was
noted and the dose levels were not supported by the 8-week rangefinding
study.  A 90-day study in mice is now required.  If toxicity found in
the 90-day study supports dose selection in the mouse carcinogenicity
study, then a carcinogenicity study will not be required.  If dose
selection is not supported, then a new carcinogenicity study will be
required.  

Practical Utility of the Data

How will the data be used?  The data could be used to better
characterize the carcinogenic potential of esbiothrin.  The cancer
assessment is presently incomplete due to the lack of an acceptable
mouse carcinogenicity study.  

萎ﱼ葝ﱼ摧盜

됂逃$愂Ĥ摧盜

‡

ˆ

Ž

®

¯

F

Y

 hž

 hž

)

F

h

‡

ˆ

¯

Ì

î

×

Ø

ᔀY

^

Š

’

¤

Ô

Ø

ñ

h:|

h:|

h N

h

h N

m

h

m

摧窴¢

m

m

옍)

h’

h’

h’

옍)

옍)

옍)

옍)

옍)

옍)

옍)

옍)

h’

옍)

옍)

kdm

$	\

kdó

$	\

옍)

h’

h’

$	\

옍)

$	\

옍)

¥欀蕤

옍)

kd

$	\

옍)

$	\

옍)

옍)

옍)

옍)

$	\

옍)

옍)

옍)

gd’

$	\

q

q

q

q

”ÿ 

혈\鐄ᗿ븍렔䴚%脆

hîi

  A negative result from this study will not result in any changes to
the risk assessment because quantitation of carcinogenic potential is
not presently required.  A positive result from this study would result
in reassessment by the Cancer Assessment Review Committee.  This could
result in a requirement for quantitation of carcinogenic potential which
could result in increased risk concerns.  



Page   PAGE  14  of   NUMPAGES  14 

