Date: 

Subject: 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

September 03, 2014 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

Allethrins. Revised Registration Review Preliminary Risk Assessment. 0422619 

PC Code: 004003, 004004, 004005, 004007 DP Barcode: D422619 

Decision No.: 49/{f!q3 Registration No.: 

Petition No.: Regulatory Action: PRA 

Risk Assessment Type: Risk Assessment Case No.: NA 

TXR No.: NA CAS No.: multiple 

MRID No.: NA 40 CFR: NA 

From: Matthew Lloyd, Industrial Hygienist ~M_ Ronnie Bever, Ph.D.; Toxicologist ;"\L ' ' ~ .. :t. Bt~ 

Risk Assessment Branch VII 

Health Effects Division (7509P)~ ~ ~ 1 ;J( 

Through: Michael Metzger, Chief .1( V { Risk Assessment Branch VII 

To: 

Introduction 

Health Effects Division (7509P) 

Molly Clayton, Risk Manager 

Tracy Perry, Team Leader 

Patricia Parrott, Chief 

Risk Management and Implementation Branch III 

Pesticide Re-Evaluation Division (7508P) 

The Pesticide Reevaluation Division (PRD) requested the Health Effects Division (HED) 

conduct a preliminary human health risk assessment for existing uses of allethrins under 

registration review. The allethrins series of pyrethroid insecticides are used to repel flying pests, 

including mosquitoes. There are no occupational or food uses registered for allethrins at this 

time; therefore, this risk assessment only addresses the potential residential exposures associated 

with the existing uses. 

Page I of 13 
Table of Contents 

1.0 Executive Summary ............................. ................... .... .... .... .... .... ................... .... .... .............. 3 

2.0 Risk Assessment Conclusions and Recommendations ........................................................ 4 

2.1 Summary of Risk Estimates ............................................................................................. 4 

3.0 Hazard Characterization ....................................................................................................... 4 

4.0 Use Profile ........................................................................................................................... 6 

5.0 Residential Exposure and Risk Estimates ............................................................................ 7 

6.0 Aggregate Risk Assessment.. .... ...................................... ........................................ ............. 8 

7.0 Occupational Exposure and Risk Estimates ...................................................... .... .... ......... 8 

7 .l Occupational Handler Exposure/Risk Estimates .... ................................ .......................... 8 

Appendix A. Acute Toxicity Profile of Allethrins ................................................. ................ ....... I 0 

Appendix B. Summary of Residential Non-cancer Algorithms .................................................. 12 

Page 2 of 13 
Page 3 of 13

1.0 Executive Summary

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. 

HED completed the allethrins scoping document in support of registration review in March of 

2010. At the time, the scoping document identified a number of toxicological updates that were 

necessary based on the registered use profile at the time. Since the March, 2010 scoping 

document, the proposed tolerance for food handling establishments has been withdrawn. There 

are no food uses for the allethrins; a Federal Register final rule revoking all food tolerances was 

published on September 29, 2004. The only remaining registered use is for various allethrin 

impregnated mosquito mats that repel mosquitoes and other flying insects. The remaining 

registered use is based on d-allethrin (also known as pynamin forte). Based on the currently 

registered use pattern, there is no occupational risk assessment necessary. Therefore, this risk 

assessment only addresses the potential residential exposures associated with the existing uses. 

Hazard Profile and Points of Departure (POD)

Pyrethroids are neurotoxicants which act by prolonging the opening of the sodium channel in 

nerves and causing neurotoxicity. The toxicology database for allethrins is complete and 

adequate to assess the residential exposures associated with the existing uses. The only current 

use of allethrin is as a volatilized agent, and the primary route of exposure is through inhalation. 

A 28-day inhalation study in rats was conducted and clinical signs of neurotoxicity were

observed (limb tremors, hunched posture, and vocalization during handling). The Point of 

Departure (POD) from this study is protective for all adverse effects in the hazard database for 

allethrins, including those effects observed in developmental and reproductive toxicity studies as 

well as through all routes of exposure. Dermal and incidental oral exposures were not 

quantitatively assessed in this document because of their negligible contribution to overall 

exposure compared to the inhalation route of exposure. Additionally, no dermal endpoint/POD 

was identified for allethrins based on the available toxicity database. The cancer classification is 

“suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic 

potential,” and quantification of cancer risk is not required. 

Allethrins have moderate acute toxicity (II/III) and low dermal toxicity (IV) via the oral and 

dermal routes. They are slightly irritating to the eye (Category III), and very slightly to the skin 

(Category IV), and are negative for skin sensitization.

For adults, the level of concern (LOC) for residential inhalation risk assessments is a margin of 

exposure (MOE) of 30, based on the combined interspecies (3X) and intraspecies (10X) 

uncertainty factors. For children, the level of concern (LOC) for residential inhalation risk 

assessments is a margin of exposure (MOE) of 100, based on the combined interspecies (3X), 3X 

database uncertainty factor for children <6 years of age, and the intraspecies (10X) uncertainty

factors.
Page 4 of 13

Residential Exposure:

There are no residential risks of concern for allethrins for the registered uses of allethrins. The 

residential post-application inhalation risk estimate for adults and children was an MOE of 1,400 

(with an LOC of 30 for adults and 100 for children <6 years of age).

2.0 Risk Assessment Conclusions and Recommendations

2.1 Summary of Risk Estimates

HED has identified no residential risk estimates of concern for the registered uses of allethrins to 

control mosquitoes and other flying pests.

3.0 Hazard Characterization

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. 

Acute Toxicity

Allethrins have moderate acute toxicity (II/III) and low dermal toxicity (IV) via the oral and 

dermal routes. They are slightly irritating to the eye (Category III), and very slightly to the skin 

(Category IV), and are negative for skin sensitization. Additional information on the acute 

toxicity profile for allethrins is available in Appendix A.

Toxicological PODs Used for Risk Assessment

The toxicology database for allethrins is adequate to assess the residential exposures associated 

with the existing uses. The only current use of allethrin is as a volatilized agent, and the primary 

route of exposure is through inhalation. A 28-day inhalation study in rats is available for 

endpoint selection. The NOAEL was 0.0051 mg/L (HEC = 0.0154 mg/L = 15.4 mg/m3), and the 

LOAEL was 0.025 mg/L based on clinical signs of neurotoxicity in females (limb tremors, 

hunched posture, and vocalization during handling). This POD is protective for all adverse 

effects in the hazard database, including those effects observed in developmental and 

reproductive toxicity studies as well as through all routes of exposure. 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.

Food Quality Protection Act (FQPA) considerations do not apply to allethrins for the existing use 

patterns described in this risk assessment. However, since the allethrins are pyrethroids and 

exposure to children under <6 years old is expected, allethrins must be considered in the greater 

context of the pyrethroids as a class. 
Page 5 of 13

The LOC for residential inhalation risk assessments is a MOE of 30 (for adults), based on the 

combined interspecies (3X) and intraspecies (10X) uncertainty factors. 

The population of greatest concern to the Agency for pyrethroid exposure is children from birth 

to <6 years of age. For exposures from birth to <6 years of age, the Agency further will retain an 

additional 3X safety factor based on 1) age-dependent pharmacokinetics, supported by rat PBPK 

model predictions of a 3-fold increase of pyrethroid concentration in juvenile brain compared to 

adults; 2) in vitro pharmacodynamic data and in vivo data indicating similar responses between 

adult and juvenile rats at low doses; 3) data indicating that the rat is a conservative model 

compared to the human based on species-specific pharmacodynamics of homologous sodium 

channel isoforms. When the Pyrethroid and Pyrethrin Technical Working Group1data become 

available, the Agency will determine, on an individual basis, whether re-evaluation of the 

database uncertainty factor safety factor is warranted. Therefore, the LOC for residential 

inhalation risk assessments is a MOE of 100 (for children), based on the combined interspecies 

(3X), database uncertainty factor (3X) and intraspecies (10X) uncertainty factors. 

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 summary of the toxicological doses and endpoints for allethrins is provided in Table 3.2.

Table 3.2. Summary of Toxicological Doses and Endpoints for Allethrins for Use in Occupational Human Health Risk 

Assessments.

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Dermal ShortTerm (1-30 

days) and 

IntermediateTerm (1-6 

months)

Negligible exposure from the dermal route is expected; therefore, no risk is expected from this exposure 

scenario. 

Incidental Oral 

(Short-term)

Negligible exposure from the incidental oral route is expected; therefore, no risk is expected from this 

exposure scenario. 

Inhalation 

Short-Term (1-

30 days) 

HEC = 15.4

mg/m3

UFA=3x

UFH=10x

UFDB=3x

Residential LOC for 

MOE (adult) = 30

Residential LOC for 

MOE (children <6 

years of age) = 100

MRID 44517802

NOAEL = 0.0051 mg/L (HEC = 0.0154 mg/L 

= 15.4 mg/m3)

LOAEL = 0.025 mg/L based on clinical signs 

in females (limb tremors, hunched posture,

and vocalization during handling)

Cancer (oral, 

dermal, 

inhalation)

Classification: suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic 

potential. 

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 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 (interspecies). UFH = potential variation in sensitivity among members of the human 

population (intraspecies). MOE = margin of exposure. LOC = level of concern. cRfD = chronic reference dose.

 

1

Since the submission of the study proposal, the PPTWG has evolved and is now recognized as the Council for the Advancement of Pyrethroid 

Risk Assessment (CAPHRA). 
Page 6 of 13

4.0 Use Profile 

The currently registered Allethrins products are intended as ambient air repellents for flying 

pests like mosquitoes in non-occupational settings (backyards, camping, etc.). The allethrins 

products are formulated and sold as impregnated mats that are heated by either a candle or 

butane cartridge. The products are designed for outdoor yard/patio use, and are restricted from 

indoor/enclosed space use (i.e., tents and enclosed porches).

The impregnated mats weigh 0.8 oz (2268 mg) and are 21% active ingredient. 

A summary of the use directions is provided in Table 4.1.

Based on the anticipated use patterns, the duration of exposure for the registered uses is expected 

to be short-term (1 to 30 days). Intermediate- and long-term exposures are not anticipated for this 

product or generally assessed for non-occupational uses. Because the products are marketed 

towards consumers and have no occupational uses, there is no PPE identified on the product 

labels.

Table 4.1 – Allethrins Use Profile (Mosquito Mat Applicators)

Target

Product

Formulation

% A.I.

Method of 

Application 

Equipment†

Application 

Rates

Additional 

Information

Mosquitoes 

and flying 

insects

71910-3 21 Vaporization 

through butane 

cartridge 

applicator or 

candle

0.8 oz mats 

last ~4 hours

Product 

activation 

occurs through 

heat of 

applicator; 

treats 15’x15’ 

area

71910-4 21
Page 7 of 13

5.0 Residential Exposure and Risk Estimates

Residential Handler Exposure 

Based on the use pattern and product activation of the registered allethrins products, there is no 

residential handler exposure per se. 

Handler exposure, both dermal and inhalation, is expected to be negligible as the application activity 

(i.e., product activation) does not involve application (e.g., spraying liquids or spreading granules) in 

the typical sense. 

Residential Post-application Exposure

Based on the use pattern and product activation of the registered allethrins products, there is 

potential for post-application inhalation exposure for adults and children. Based on HED’s 2012 

Residential SOPs, post-application dermal and incidental oral exposures are not assessed because 

of their negligible contribution to overall exposure compared to the inhalation route of exposure.

Additionally, no dermal endpoint/POD was identified for allethrins based on the available 

toxicity database.

A series of assumptions and exposure factors served as the basis for completing the residential 

post-application inhalation risk assessments. 

Application Rate: The impregnated allethrins mats consist of 113.4 mg of active ingredient and 

it is assumed that the active ingredient is volatilized at an even rate over the course of the 

exposure duration. 

The remainder of the exposure factors relevant to the allethrins assessment are detailed in HED’s 

2012 SOPs (Section 5.2 “Candles, Coils, Torches, and Mats and the associated Residential SOP 

Appendix D.3.2). The default exposure factors are consistent with these allethrins products, 

including the default area treated in the SOP. The available product labels indicate that the 

product is effective in a 15’ x 15’ area, consistent with the exposure scenario identified in the 

SOP.

Residential Post-Application Non-Cancer Exposure and Risk Estimate Equations

The algorithms used to estimate non-cancer exposures and doses for residential exposure can be 

found in Appendix B.

Summary of Residential Post-application Non-Cancer Exposure and Risk Estimates

Based on information provided on the product label and the “Candles, Coils, Torches, and Mats 

exposure scenario laid out in the 2012 Residential SOPs, Table 5 summarizes the inhalation risk 

estimates for adults and children based on outdoor use of the allethrin impregnated mosquito 

mats. The LOC for adults is 30 and for children is 100. The risk estimates are not of concern for 

adults or children (MOE of 1,400 is greater than the LOCs for adults and children).
Page 8 of 13

Table 5 – Allethrins Residential Post-Application Inhalation Exposure

Inhalation 

Exposure/Risk:

Lifestage Emission rate1

(mg ai/hr)

Airflow Q 

(m3/hr)

Exposure 

Time 

(hrs/day)

Volume 

of 

Treated 

space 

(m3)

Time Weighted 

Average 

Exposure (mg 

ai/m3)

Inhalation 

MOE 

2

(rounded)

Adults & 

Children (1 

<2 years)

113.4 4000 2.3 51 0.0108 1,400

1 – complete vaporization of the active ingredient from impregnated matrix assumed

2 – LOC = 30 for adults and 100 for children

6.0 Aggregate Risk Assessment

No aggregate assessment is required for allethrins as there are currently no registered food uses 

and exposure to residues in drinking water is not expected from the registered area repellent 

uses; therefore, an aggregate risk assessment is not needed. The only allethrins exposure is the 

potential for inhalation exposure via use of the mosquito mats addressed above in Section 5.0. 

7.0 Occupational Exposure and Risk Estimates

7.1 Occupational Handler Exposure/Risk Estimates

Based on the registered uses for the allethrins products, there are no occupational exposure 

scenarios (handler or post-application) to consider. The allethrins products are geared towards 

the consumer market and are assessed using HED’s 2012 residential SOPs (See above: Section 

5).

8.0 Cumulative

The Agency is required to consider the cumulative risks of chemicals sharing a common 

mechanism of toxicity. The Agency has determined that the pyrethroids and pyrethrins, 

including allethrins, share a common mechanism of toxicity (http://www.regulations.gov; EPAHQ-OPP-2008-0489-0006). The members of this group share the ability to interact with voltagegated sodium channels ultimately leading to neurotoxicity. The cumulative risk assessment for 

the pyrethroids/pyrethrins was published on Nov. 9, 2011 (USEPA, 2011a) and is available at 

http://www.regulations.gov; EPA-HQ-OPP-2011-0746. Further information about the 

determination that pyrethroids and pyrethrins share a common mechanism of toxicity may be 

found in document ID: EPA-HQ- OPP-2008-0489-0006.

While allethrins has been included as an active ingredient in the pyrethroid cumulative 

assessment, the exposure scenarios covered in this assessment (i.e., outdoor repellent uses) were 

not exposure scenarios addressed in the 2011 pyrethroid cumulative risk assessment. For that 

effort, the Agency focused on the four main (i.e., high potential exposure) pyrethroid residential 

use scenarios – turf, pets, gardens, and indoors (e.g., fogger and crack and crevice applications). 

In calculating cumulative risks to pyrethroids, the Agency would not combine exposures from 

multiple unrelated use scenarios because (1) the common toxic effect is acute neurotoxicity, and 
Page 9 of 13

(2) the likelihood of being exposed acutely from multiple use scenarios is insignificant. Since 

other use scenarios are likely to lead to higher risks than those resulting from use of allethrin 

products, the Agency has determined that consideration of allethrin use will not change the 

overall findings presented in the pyrethroid cumulative risk assessment. For information 

regarding EPA’s efforts to evaluate the risk of exposure to pyrethroids, refer to 

http://www.epa.gov/oppsrrd1/reevaluation/pyrethroids-pyrethrins.html.
Page 10 of 13

Appendix A. Acute Toxicity Profile of Allethrins

Acute Toxicity of Bioallethrin

Guideline Study Type MRID Results Tox Category

870.1100

Acute Oral 00151444

LD50 : 709 mg/kg (M)

 1042 mg/kg (F) III

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

870.1300 Acute Inhalation 42906902 LC50 : 2.51 mg/L IV

870.2400 Primary Eye Irritation 41155803 Slight to moderate irritant III

870.2500 Primary Skin Irritation 41155805 Very slight dermal irritant IV

870.2600 Dermal Sensitization 41155807 negative N/A

Acute Toxicity of Esbiol

Guideline Study Type MRID Results Tox Category

870.1100

Acute Oral 00151460

LD50 : 574.5 mg/kg (M)

 412.9 mg/kg (F) II

870.1200 Acute Dermal 41155802 LD50 > 2000 mg/kg III

870.1300

Acute Inhalation 41670801

LC50 : 1.32 mg/L (M)

 1.23 mg/L (F) III

870.2400 Primary Eye Irritation 41155804 Moderate ocular irritant III

870.2500 Primary Skin Irritation 41155806 Not a dermal irritant. IV

870.2600 Dermal Sensitization 41155808 Not a sensitizer N/A

Acute Toxicity of Esbiothrin

Guideline Study Type MRID Results Tox Category

870.1100

Acute Oral 00151449

LD50 : 432 mg/kg (M)

 378.0 mg/kg (F) II

870.1200 Acute Dermal 00151451 LD50 > 2000 mg/kg III

870.1300 Acute Inhalation 00151452

LC50 : 2.63 g/m3-

unacceptable III

870.2400 Primary Eye Irritation 00151454 Minimally IV

870.2500 Primary Skin Irritation 00151453 Slightly III

870.2600 Dermal Sensitization 42907001 negative N/A
Page 11 of 13

Acute Toxicity of Pynamin Forte

Guideline Study Type MRID Results Tox Category

870.1100 Acute Oral 41017101 LD50 : 2150 mg/kg (M)

 900 mg/kg (F) III

870.1200 Acute Dermal 41017102 LD50 : 2660 mg/kg (M)

 4390 mg/kg (F) III

870.1300 Acute Inhalation 41017103 LC50 > 3.875 mg/L IV

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
Page 12 of 13

Appendix B. Summary of Residential Non-cancer Algorithms

Residential Non-cancer Post-Application Exposure Algorithms

Post-application Inhalation Exposure Algorithm

The following algorithm is used to determine post-application inhalation exposure to CCTM

(modified to account for incorporating the TWA air concentration):

TWA = [(VE * ET)/Q * (ET-(V/Q)]/T

where:

TWA = TWA air concentration (mg ai/m3 / day);

VE = vaporization efficiency (%);

ER = emission rate (mg ai/hr);

ET = exposure time (hr/day);

V = volume of treated space (m3); and

Q = airflow (m3/hr)

T = time of animal exposure based on inhalation study (6 hours)

The airflow through the treated space can be calculated as follows:

Q = AV *CF1* CF2 * Across-section

where:

Q = airflow through treated space (m3/hr);

AV = air velocity (m/s);

CF1 = time unit conversion factor (60 seconds/1 minute);

CF2 = time unit conversion factor (60 minutes / hour); and

Across-section = cross-section of outdoor space treated (m2).

The emission rate from a CCTM product can be calculated as follows:

UL

A * N

ER P

where:

ER = emission rate (mg ai/hr);

A = amount of mg ai in CCTM product (mg ai/product);

NP = number of products used (products); and

UL = useful life of product (hours).
Page 13 of 13

Table A-X: CCTM – Inputs for Residential Post-Application Inhalation Exposure

Algorithm 

Notation

Exposure Factor

(units) Point Estimate(s)

VE

Vaporization efficiency

(percent)

100% assumed unless registrant provides data 

for product

A

Amount of ai in the product

(mg) 113.4

ER Emission rate

(mg ai/hr) Calculated

UL Useful life

(hours)

Candles/Coils/Torches 4 

Mats 4 

ET Exposure time

(hours)

Adults 2.3

Children 1 < 2 years old 2.3

V

Volume of treated space

(m3)

51

Q

Airflow through treated area

(m3/hr) 4,000

AV Air velocity

(m/s) 0.1

NP

Number of products used

(# products) 1 product per treated area

Acrosssection

Cross sectional area of area treated

(m2)

11

Margin of Exposure: Non-cancer risk estimates for the relevant post-application scenario are 

calculated using a MOE, which is a ratio of the toxicological Point of Departure (POD) to the 

time weighted average air concentration of concern. All MOE values are calculated using the 

following formula:

MOE= 

HEC

TWA

where:

MOE = margin of exposure: value used by HED to represent risk estimates (unitless),

HEC = point of departure expressed an HEC (mg/m3), and

TWA = time weighted average air concentration (in mg/m3).