Date:

Subject: UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

September 03, 2014 OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

Allethrins. Re v ised Regis trat ion 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.; Toxicolo g is t ;"\L ' '**~** .. 

### :t.**Bt~** Risk Assessment Branch VII

Health Effec t s 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, Tea m Leader

Patricia P arrott, Chief

Risk Management and Implementation Branch III

Pesticide Re-Evaluation Division (7508P)

The Pesticide Reevaluation Division (PRD) requested th e Health Effec t s Division (HED)

conduct a preliminary human health risk assessment for existing uses of a llethrins under registration review. T he allethrins series of pyrethroid insecticides are used to repel flying pests, including mosquitoes. There are no occupational or food uses re g i stered for allethrins at this time; therefo re
, this risk assessment only addresses th e potential residential exposures associated

with the existing uses.

P age I of 13

### Tab l e of Cont ent s

1. 0 Exec u t i ve 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 Occ u pat i ona l Hand l er Exp o sure/Risk Estimates

.. .. .............................. .. .......................... 8 Append i x A. Acute Toxicity P r ofile of A ll ethrins

.......... .. .. .. .. .. .. .. ...................... . .. .. .. ........ .. .. .. .. .. . I 0 Appendix B

. Summary of Residential Non-cancer Algorithms

........................ . ......................... 12

Page 2 of 13Page 3 of 13



### 1.0 Executive Summary

The allethrin series of p yrethroid 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 updat es 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. T herefore, this risk assessment only addresses the potential residential exposures associated with the existing uses.

Haza rd 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 residenti al 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 re productive 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 ha ve 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 (Cate gory IV), and are negative for skin sensitization.

For adults, t he level of concern (LOC) for residential inhalation risk assessments is a margin of exposure (MOE) of 3 0

, based on the combined interspecies ( 3 X) and intraspec ies (10X) uncertainty factors

. For children, t he level of concern (LOC) for residential inhalation risk assessments is a margin of exposure (MOE) of 100

, based on the combined interspecies ( 3 X) , 3X database uncertainty factor for children <6 years of age, and the intraspecies (10X) unc ertainty

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 estimate s 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 ha ve 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 fo r 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 inhalati on. 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/m 3 

### ) , and the

LOAEL was 0.025 mg/L based on clinical signs of neurotoxicity in females (limb tremors, hunched posture, and vo calization 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

qua ntitatively 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) con siderations do not apply to allethrins for the existing use patterns described in this risk assessment. However, s ince 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 ( 3 X ) and intraspecies (10X) uncertainty factors.

The populati on 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 a n 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 Group 1 

### data become available, the Agency will determine, on an individual basis, whether re

- evaluation of the database uncertainty factor safety factor is warranted. Therefore, t he LOC for residential

inhalation risk assessments is a MOE of 100 (for children), based on the combined interspecies ( 3 X) , 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

Departur e Uncertainty

Factors Level of Concern

for Risk

Assessment Study and Toxicological Effects

Dermal Short

Term (1

- 30 days) and

Intermediate

Term (1

- 6 months) N egligible exposure from the dermal route is expected ; therefore, no risk is expected from this exposure

scenario.

Incidental Oral (Short

- term) N egligible 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 /m 3 UF A = 3 x

UF H =10x

UF DB = 3 x 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/m 3 )

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. UF A = extrapolation from animal to human (interspecies). UF H = 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 (back yards, 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 2 1 % 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, ther e 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 21Page 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 a nd 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 data base.

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 as sumed 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, a nd Mats and the associated Residential SOP

A ppendix 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 i s 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 rate 1 (mg ai/hr) Airflow Q

(m 3 /hr) Exposure

Time (hrs/day) Volume

of

Treated

space (m 3 ) Time Weighted

Average Exposure ( mg ai/m 3 ) Inhalation

MOE

2 (rounded)

Adults & Children (1 <2 years) 113.4 4000 2.3 51 0.0108 1, 4 00

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 inh alation 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 require d 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 ; EPA

HQ

- OPP

- 2008

- 0489

- 0006). The members of this group share the ability to interact with voltage

gated sodium channels ultimately leading to neurotoxicity. The cumulative risk assessment for the pyrethroids/pyrethrins was publ ished 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, andPage 9 of 13



### (2) the likelihood of being expos ed 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 , t he Agency has determined that consideration of allethrin use will not change the

ove rall findings presented in the pyrethroid cumulative risk assessment. For information regarding EPA’s efforts to evaluate the risk of exposure to pyrethroids, refer to

h ttp://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 LD 50 : 709 mg/kg (M) 1042 mg/kg (F) III

870.1200 Acute Dermal 41155801 LD 50 > 3000 mg/kg (M&F) III

870.1300 Acute Inhalation 42906902 LC 50 : 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 LD 50 : 574.5 mg/kg (M) 412.9 mg/kg (F) II

870.1200 Acute Dermal 41155802 LD 50 > 2000 mg/kg III

870.1300

Acute Inhalation 41670801 LC 50 : 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 LD 50 : 432 mg/kg (M) 378.0 mg/kg (F) II

870.1200 Acute Dermal 00151451 LD 50 > 2000 mg/kg III

870.1300 Acute Inhalation 00151452 LC 50 : 2.63 g/m 3

- 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/APage 11 of 13 Acute Toxicity of Pynamin Forte

Guideline Study Type MRID Results Tox Category

870.1100 Acute Oral 41017101 LD 50 : 2150 mg/kg (M)

90 0 mg/kg (F) I I I

870.1200 Acute Dermal 41017102 LD 50 : 2660 mg/kg (M)

4390 mg/kg (F) III

870.1300 Acute Inhalation 41017103 LC 50 > 3.875 mg/L I V

870.2400 Primary Eye Irritation 41017104 Slight irritant I II

870.2500 Primary Skin Irritation 41017104 Negative IV

870.2600 Dermal Sensitization 41017105 N egative N/APage 12 of 13



### Appendix B . Summary of Residential Non

- cancer Algorithms

Residential Non

- cancer Post

- A pplication 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 );

V E 

### = vaporization efficiency (%);

ER = emission rate (mg ai/hr);

ET = exposure time (hr/day);

V = volume of treated space (m 3 

### ); and Q = airflow (m 3 

### /hr)

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

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

Q = AV *CF1* CF2 * A
cross

- section



### where : Q = airflow through treated space (m 3 

### /hr);

AV = air velocity (m/s);

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

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

A cross

- section 

### = cross

- section of outdoor space treated (m 2 

### ).

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

where :
ER = emission rate (mg ai/hr);

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

N P 

### = number of products used (products); and

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

Table A

- X : CCTM

– Inputs for Residential Post

- A pplication Inhalation Exposure Algorithm

Notation Exposure Factor (units) Point Estimate(s)



### V E 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 (m 3 ) 51

Q Airflow through treated area (m 3 /hr) 4,000

AV Air velocity (m/s) 0.1

N P Number of products used (# products) 1 product per treated area



### A cross

section Cross sectional area of area treated (m 2 ) 11



### Margin of Exposure: Non

- cancer risk estimates for the relevant post

- application s cenario 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 a re calculated using the following formula:

MOE= HEC

TWA

where:

MOE = m argin of e xposure: value used by HED to represent risk estimates (unitless),

HEC = p oint of d eparture expressed an HEC ( mg/m 3 

### )

, and

TWA = time weighted average air concentration (in mg/m 3 

### )

.