UNITED STATES ENVIRONM ENTA L PROTEC TI ON AGENCY

WASHINGTON, D.C

. 20460



### MEMORANDUM

DATE: 2/24/2015 OFFICE OF CHEMICAL SAFETY
AND POLLUTION PRE VENT ION



### SUBJECT: Deltamethr in

. Human H ealth Risk Assessment for the Proposed Use of
Deltamethrin as a Mosquito Adu l t i c ide over Agricultura l Crop s.

PC Code: 097805
Decision No.: 484277
Petition No.: 3F82 1 0 DP B arc ode: 0417556 Registration No.: 432

- RLGU Regulatory Action: S e c ti on 3 R egist ration
Cas e No.: 7414 Risk Assessment Type: S in gle Chemical Aggregate
TXRNo.: NA
MRIDNo.:NA CAS No

. : 52918-63-5
40 CFR: § 180.435



### FROM:

THROUGH:

TO: Doug l as A. Dotson, Ph.D., Chemist 

# J.**f)~** Jaime D' Agostino, Ph.D

.,**Toxicologis~_A.** 

# 4--

Margarita Collantes, M.S.,

### Biologist~~ 

# Jv

Risk Assessment Branch II
Health Effects Division (7509P)

Chr istina Swartz, Branch Chief

# ~ Risk Assessment Branch II
Healt h Effects Division (7509 P )

Olga Odiott!Richard Gebken, PM Team 1 0
Invertebrat eN ertebrate Branch (IVB2) Registratio n Division (7505P)

The Registration Division (RD) requested that the Health Effects Division (HED) conduct a human health risk assessment for the proposed use of deltamethrin as a wide-area mosquito
adulticide in the airspace over agricultural crops.

This document contains th e human health risk assessment associated wi th thi s action and incorporates updated endpoints for risk assessment as well as the most recent data and assumptions for conducting residential and occupat ional exposure assessments. No risks of

concern were identified.Deltamethrin Human Health Risk Assessment D P No. D417556

Table of Contents

1.0 Executive Summary

. .. .. . .. .. .................... ..... .. ... . .. .. .. .. .. .. .. .. .. .. .. ...... ........... .. .... .. ... .. .. .. .. .. ... . ... 4

2.0 HED Recommendations

........... . .. .. .. . ... . ...... .. .......................................... . .. .. .. ... . .. .. .. ... . ........ 7

2.1
2.2
2.2.1

2

. 2.2
2.2.3

2.2.4
2.3 Data Deficiencies

.. .. .. . ... . ............................ .. ...... .. .. . ... . .. .. ... . .. .. .. ... . . .... .. ... ..... .................. . 7

Tolerance Considerations

.... . ... .. .. . ... . ... . .. .. .. .. .. . ................................................... .. .. .. .. .. .. . 8
Enforcement Analytical Method

.................... .. . ... . . ... .. .. .. .. .. .. .. .. .. . ... . .. ... .. .. ... ... . ..... ...... 8

International Harmon ization

.... .. . .. .. .. .. .. .. .. .. ... . .. .. .......................... . ........................ .. . .. 8
Recommended Tolerances

........................ . ............... . ... . .. .. ... . .. .. .. .. .. .. .. .. .. .. ... . ............. 8
Revisions to Petitioned-For Tolerances

. .......................................... . ....... . ... .. ...... .. ... . . 9

Label Recommendations

.......................................... .. .. .. . ... . ... . ... . .. . . ... . ... . ....... . ....... ... . . 9

3.0
3.1

3.2
3.3

3.4

3.5 In troduct ion

..... . ..................... .. . ... . .......... . ... . ... . .. ... . ... . .. ... . ... . ........... ................... ..... ......... .. 10
Chemical Identity

. .. . ... . .................................................... ... . .. ...... .. .. .. .. .. . ... .. .. .. .. .. .. .. .. .. .. 1 0 Physica l /Che mical Characteristics

. . ... . .. .. .. .. .. .. .. .. .. .. . ... . ... .. .. . ... . ................... . ................. 1 0
Pesticide Use Pattern

. .. .. .. . ... .......................................................................................... 10 Anticipated Exposure Pathways

....... . ................................................ . ................ .. . .. ..... 13

Consideration of Environmental Justice

.... .. .. ... .. ......... .. .. . ... . ... . ... . ...... .. ... . ... . ... .. .. .. .. .. .. . 1 4

4 .0 Hazard Characterization and Dose-Response Assessment..

........................ . .................... 1 4
4.1

4.2
4.3
4.3.1

4.3.2
4.3.3

4 .4

4.4.1

4.4.2
4.4.3

4.4.4
4.5

4

. 5.1
4.5.2
4.5.3

4.5.4

5.0
5.1

5

. 1.1
5.1.2

5

. 1.3

5.1.4
5.2

5.3
5.4

5.4

. 1

5.4.2

5.4.3 Toxicology Studies Available for Analysis

....... . ... .. .. .. ...... .. . ... . ... . .. ... .. . .. .. .. .. .. ... .. .. .. .. ... 15
Toxico l ogica l Profile

................................................... . .................... . ............ . .............. 1 6 Pyrethroid Pharmacokinetic and Pharmacodynamic Profi l e

..... . .. .. .. ... . .. .. ... .. .. ............. 1 7
Pharmacokine tics

........................................................ ...... ... ......... ........... ....... . ......... 1 7 Pharmacodynamics

......... .. .. ..... . ....... . .......... .. .. .. .. ... . .. .. .. .. . ... .. .. .. . ... .. . ... .. .. .. .. .. .. .. ... .. .. . 19
Critica l Duration of Exposure

.. .. ................. ....... . .. .. .. .. .. . ... . ................................... . ... 20 Safety Fac tor for Infan ts and Children (FQPA Safety Factor )

..................................... 22 Completeness of the Toxicology Database

.. .. ....... ..... .. .. .. .......... .. .. .. .. .. .. .. .. .. . .... .. . .. .. . 22

E vidence ofNeurotoxicity

............... . ................ . .. .. ... . .. . ... .. ..... ... .. . ... .. .. .. . ... . ....... .. .. .. . 23
Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

..... .. .... 23

Residual Uncertainty in the Exposure Database

... . . ... . ... . ... .. .. ......... . ......................... 24 Toxicity Endpoint and Point of Departure Selections

. .. .. .. . .. .. .. ...... .. .. .. .. .. ... . ... . .. ... ... . . .. 25 Dose-Response and Hazard Assessment

... .. .. .. .. .. .. ... . .. .. .. .. ................... . ...... . ........... . 25
Recommendation for Combining Routes of Exposure for Risk Assessment

.. .. . ... . .. 27

Cancer C l assification and Ris k Assessment Recommendation

... . .. . ... . ... . ................. 27 Summary of Points of Departure and Toxici ty Endpoin ts

.......... . . .. .. .. ... .. . . .. .. .. .. .. .. .. 27 Dietary Exposure and Risk Assessment

.. . ........................................................................ 28 Metabolite/Degradate Residue Profi l e

............ . ... .. .. . .. .. .. ....... . .......... .. . ... . ... ... ... . ...... ...... 28 Summary of Plant and Animal Metabolism Studies

...................... . ....... .. .. ...... .. .. .. .. . 28 Summary of Environmenta l Degradat i on

. .. .. .. .. . ... .. . .. .. .. ... . .. .. ....... . .. . ... .. .. ...... ... ...... 289 Comparison of Metabolic · Pathways

......... .. .. ......... . ........ . .. .. .. .. .. .. .. . ... .. .. .. .. ... .. .. . .. .. ... 29

Residues of Concern Summary and Rationale

....................................... . ... .. .. .. .. .. .. ... 30

Food Resid ue Profile

.. . ...... . ... .. . .. .. . ... . .. . ............... . ... . ..................................................... 30

Water Residue Profile

.................................................... .. .. .. .. .. . ... . ... .. .. .. . .. .. ... . ... . ... . ...... 31 Dietary Risk Assessment

.. . .. .. .................................................................... . ... . ... .. . ... .. .. . 31 Description of Residue Data Used in Dietary Assessment..

.............. ..... . ................. 31

Percent Crop Treated Used in Dietary Assessment..

.. . .. .. .. .. .. .. .. . .. . . .. .. ... .. .. .. . ....... ..... 33

Acute Dietary Risk Assessment..

.. ... . .. . .............. . ............................................... .. .. .. . 34

Page 2 of67Deltamethrin Human Health Risk Assessment DP No. D417556

Page 3 of 67 5.4.4 Chronic Dietary Exposure Assessment

................................ ................................ ..... 3 4
5.4.5 Summary Table

................................ ................................ ................................ ......... 3 5
6.0 Residential Exposure and Risk Estimates

................................ ................................ ......... 3 5
6.1 Proposed Use: Wide

- Area Mosquito Control

................................ .............................. 3 5

6. 2 Residential Handler Exposure / Risk Estimates for Registered Uses

............................. 37

6. 3 Residential Post

- Application Exposure /Risk Estimates for Registered Uses

............... 39

6. 4 Residential Risk Estimates for Use in Aggregate Assessment

................................ ..... 4 1

6. 5 Spray Drift

................................ ................................ ................................ .................... 4 1
7.0 Aggr egate Exposure/Risk Characterization

................................ ................................ ...... 42
7.1 Acute Aggregate Risk

................................ ................................ ................................ ... 4 2
7.2 Short

- Term Aggregate Risk Estimates

................................ ................................ ......... 4 2
8.0 Cumulative Exposu re/Risk Characterization

................................ ................................ .... 43
9.0 Occupational Exposure/Risk Characterization

................................ ................................ . 44
9

. 1 Occupational Handler Exposure/Risk Estimates

................................ .......................... 44
9.2 Occupational Post

- application Risk Estimates

................................ ............................. 46
9.2 .1 Occupational Post

- application Inhalation Risk Estimates

................................ ........ 4 6
9.2 .2 Occupational Post

- application Dermal Risk Estimates

................................ ............ 46
10.0 References

................................ ................................ ................................ ......................... 4 6 Appendix A. Toxicology Profile

................................ ................................ ................................ .. 50
A.1 Toxicology Data Requirements

................................ ................................ .................... 50
A.2 Toxicity Profile Table s

................................ ................................ ................................ . 51
A.3 Toxicological Doses and Endpoint s for Use in Human Risk Assessments

.................. 5 7
A.4 Pyrethroid Cumulative Screen

................................ ................................ ...................... 61 Appendix B . Physical/Chemical Properties

................................ ................................ ................. 6 6 Appendix C . Review of Human Research

................................ ................................ ................... 6 7Deltamethrin Human Health Risk Assessment DP No. D417556

Page 4 of 67 1.0 Executive Summary

Deltamethrin (1R,3R)

- R

- cyano(3

- phenoxyphenyl)methyl 3

- (2,2

- dibromoethenyl)

- 2,2

- dimethylcyclopropanecarboxylate) is a broad

- spectrum pyrethroid insecticide that is registered in
the U

. S

. for direct application to a wide var iety of food/feed crops, for use on stored grains, and for use in food/feed handling establishments (FHEs)

. Numerous formulations of deltamethrin are also registered for use in commercial and residential outdoor and indoor sites, as well as in paint addit ive and pet products. The registrant, Bayer Environmental Science, petitioned the Agency to amend 40CFR §180.435(a)(2) to include the use of deltamethrin as a wide

- area mosquito adulticide in the airspace over agricultural crops

. Bayer further proposed that the 0.05 ppm tolerance established for residues of deltamethrin in commodities resulting from the FHE

use apply to the adulticide use as well. There are no new residential uses associated with this regulatory action; however, a revised asse ssment of the registered residential uses is provided for the purpose of updating the aggregate risk assessment.

Pyrethroids have historically been classified into two groups, Type I and Type II, based on chemical structure and toxicological effects. Pyr ethroids disrupt the voltage

- gated sodium channels in the nervous system, resulting in neurotoxicity. Deltamethrin is a Type II pyrethroid. Neurotoxicity was observed throughout the database and clinical signs characteristic of Type II pyrethroids, such a s increased salivation, altered mobility/gait, and tremors

, were the most
common effects observed. Other observed neurotoxic effects included increased sensitivity to external stimuli, abnormal vocalization, and decreased fore

- and hind

- limb grip strength

.

The database of deltamethrin experimental toxicology studies is largely complete and provides a robust characterization profile for children 6 years old and older, as well as for adults. In addition to the standard guideline studies, numerous studies f rom the scientific literature that describe the pharmacodynamic and pharmacokinetic profile of the pyrethroids in general have
been considered in this assessment. Many of these studies were conducted with deltamethrin. A
28

- or 90

- day inhalation study wa s not available

, but the requirement for this study was waived by HED’s Hazard and Science Policy Council (HASPOC). In addition, there are ongoing efforts to develop data in juvenile rats to gain more i nform ation concerning the potential sensitivity of
in fants and young children to pyrethroids as a class. Despite the missing studies and the ongoing scientific efforts, HED is confident that it has chosen endpoints, points of departure

, and uncertainty factors that are protective for all populations, includ ing infants and children

.

Deltamethrin is rapidly absorbed following an oral dose, and effects are typically observed within two to five hours after dosing. For pyrethroids, as a class, the combination of rapid absorption, metabolism, and elimination precludes accumulation and increased potency following repeated dosing. This is also true of deltamethrin. No observed adverse effect levels (NOAELs) for the acute and chronic studies are similar, and the acute endpoint is protective of the endpoints fro m repeat dosing studies. Thus, for purposes of endpoint selection and exposure assessment, only single

- day risk assessments need to be conducted.

There were no indications of fetal toxicity in any of the guideline studies. Evidence of increased juvenile qualitative sensitivity was observed in the developmental neurotoxicity and 2

- generation reproduction studies. These observations are consistent with the findings of juvenile sensitivityDeltamethrin Human Health Risk Assessment DP No. D417556

Page 5 of 67 in the literature for deltamethrin. However, the observations of i ncreased sensitivity were at doses that were considered to be relatively high (i.e., near lethal doses)

, whereas at doses near the point of departure

, no effects on parental animals or offspring were observed in either the developmental neurotoxicity ( DNT ) or 2

- generation reproduction study and

, therefore

, there is no susceptibility at these doses. The Agency has retain ed a 3 X uncertainty factor to protect for exposures of children <6 years of age based on increased quantitative susceptibility seen in
stud ies on pyrethroid pharmacokinetics (primarily conducted with deltamethrin) and the increased quantitative juvenile susceptibility observed in high dose guideline and literature studies with deltamethrin and other pyrethroids.

The Wolansky et al. acute ora l study (2006), in which decreased motor activity was observed, provides the most robust data set for extrapolating risk from exposure to deltamethrin. The dose used for risk assessment was determined using a benchmark dose (BMD) analysis using 1
standard deviation from the control group as the benchmark response (BMR) as suggested for continuous endpoints in the Agency’s BMD guidance (USEPA 2012). The Wolansky acute study, endpoint, and dose were used for all dietary (acute), non

- occupational (incidental oral and inhalation), and occupational exposure (inhalation) scenarios because it was the most robust data set for extrapolating risk from deltamethrin

, and there is a lack of increased hazard from repeated/chronic exposure to deltamethrin . A dermal risk assessment was not conducted based
on the lack of effects in a 21

- day dermal study and low potential for dermal absorption for deltamethrin. These findings are consistent with the toxicology profile of many pyrethroids.

HED has charact erized deltamethrin as “not likely to be carcinogenic to humans” in accordance with the EPA Final Guidance for Carcinogen Risk Assessment (3/29/ 20 05).

Adequate residue data are available for the purpose of establishing a tolerance and for evaluating
risk from the u se of deltam ethrin as a wide

- area mosquito adulticide

. Bayer submitted the results of residue trials that were performed on alfalfa, grass, and lettuce.

The toxicological kinetic data for deltamethrin demonstrate that it is not appropriate to a ssess chronic dietary risk for this insecticide because of a lack of increased toxicity with increased duration of exposure . However, the residential use sites for deltam ethrin and the patterns for exposure require estimates of chronic dietary exposure (i .e. background from food and water) in order to estimate aggregate risk.

A cute and chronic dietary exposure estimates were derived using the Dietary Exposure
Evaluation Model (DEEM) with consumption data from the 2003

- 2008 National Health and
Nutrition Examination Surveys (NHANES)

. The acute risk estimates are below HED’s level of concern for all population subgroups, including those comprised of infants and children. As percent crop treated estimates were used for some commodities, the risk estimates are being reported at the 99.9 th percentile of exposure. A lthough a chronic dietary endpoint wa s not required for deltamethrin

, a chronic dietary exposure assessment was performed to provide background exposure for aggregation with residential exposure.

There are no residential handler exposure scenarios associated with the new proposed mosquito
control use because applications are to be made by f ederal, s tate, t ribal

, or local g overnmentDeltamethrin Human Health Risk Assessment DP No. D417556

Page 6 of 67 o fficials as well as the U.S. m ilitary. However, there is potent ial for residential post

- application exposure resulting from mosquito control use. This document also includes handler and post

application exposure assessment s for existing residential uses (i.e., indoor, outdoor, pet, and paint additive) that reflect u pdates to HED’s 2012 Residential SOPs, along with policy changes for body weight assumptions, and updated inhalation and incidental oral toxicological endpoints
and uncertainty factors ( UFs )

.

All post

- application inhalation and incidental oral exposure estimates resulting from the proposed mosquito and fly control scenarios were assessed using the single maximum application rate of 0.0018 lb ai/acre and resulted in MOEs greater than their respective LOCs and
are not of concern.

All registered resident ial handler scenarios resulted in inhalation risk estimates greater than the LOC and are not of concern (i.e., margins of exposure (MOEs) are ≥ 100). Post

- application inhalation exposure for adults and children is anticipated to be negligible for represen tative residential registered uses; therefore, a quantitative post

- application inhalation exposure assessment was not performed. All the representative indoor/outdoor and pet residential use scenarios resulted in incidental oral (hand

- to

- mouth) post

- appli cation risk estimates for children ranging from an MOE of 630 to 400,000 and are not of concern.

The acute aggregate risk estimates are equivalent to the corresponding dietary (food plus water) risk estimates, which are not of concern. The short

- term a ggregate risk assessment is based on residues in background dietary exposure (food + drinking water) a nd residues resulting from residential exposure. For adults, residential exposure consist s of post

- application inhalation exposure and for children, residential exposure consist s of incidental oral ( hand

- to

- mouth )
transfer. The short

- term aggregate risk estimates are not of concern for adults or children

.

Deltamethrin was included in a cumulative risk assessment (CRA) for pyrethrins and pyrethroids ( D394576, K. Whitby, 10/4/2011). Typically, proposed new residential uses of pyrethroid chemicals are evaluated to determine whether they would contribute signi ficantly to or change the overall findings of the CRA.

Since the 2011 CRA, no new residential uses have been proposed for deltamethrin. Therefore,
the current tolerance evaluation and the currently registered residential uses for deltamethrin will
have n o impact on the residential component of the cumulative risk estimates. The revised point s of departure ( PODs ) selected for deltamethrin are specific to deltamethrin, whereas the
PODs selected for the cumulative assessment were based on common mechanism o f action data that are appropriate for all 20 pyrethroids included in the cumulative assessment.

Systemic toxicity via the dermal route of exposure is not anticipated. Therefore, a dermal POD
was not selected

, and a quantitative dermal handler and post

- application exposure assessment was not performed. Occupational assessments are based on inhalation exposures only. Occupational handler scenarios resulted in inhalation MOEs greater than the LOC (inhalation
MO E ≥ 100) at baseline (i.e., no respirator) and are not of concern.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 7 of 67 The proposed BES0668 Insecticide label specifies the use of portable, motorized backpack equipment adjusted to deliver U ltra L ow V olume (ULV) particles of less than 100 microns.
HED do es not have unit exposure handler data for hand held fogging equipment. Therefore,
chemical

- specific data are needed to support this scenario, and constitute a data gap for
deltamethrin. These data need to be submitted in accordance with the 40 CFR Part 158 data requirements

.

Based on the Agency’s current practices, a quantitative non

- cancer occupational post

- application inhalation exposure assessment i s not being performed for deltamethrin at this time. If new policies or procedures are put into place, the Agency m ight revisit the need for a quantitative residential post

- application inhalation exposure assessment for deltamethrin.

There are no human health risk concerns associated with the proposed use. HED does not object
to the establish ment of a to lerance of 0.0 5 ppm for residues of deltamethrin in or on all commodities as a result of the mosquito adulticide use

.

Potential areas of environmental justice concerns were considered in this human health risk assessment to the extent possible. The asses sment resulted in no risks of concern

.

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from
the Residential SOPs (Turf/Lawn, Indoor Environments, and Pets, Impregnated Materials and Treated Paints and Preservative), are: (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For c ertain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency
website.

2.0 HED Recommendations

HED has no object ion to the esta blishment of a tolerance of 0.05 ppm for the use of deltamethrin

as a wide

- area mosquito adulticide over all crops

.

2.1 Data Deficiencies

There are no data deficiencies associated with the proposed tolerance for use of deltamethrin as a mosquito adulticide

. However, HED has identified the need for a turf transferable residue (TTR) study to support the existing uses of deltamethrin. This deficiency was not identified in the 2010 human health assessment scoping document in support of r egistration r eview and

, therefore

, the
Data Call

- In for deltamethrin did not include the required TTR study.

Since the estimated residential turf post

- application exposure for residential turf using default TTR values for deltamethrin is not minimal in comparison to the level of concern (i.e., the calculated MOE is not greater than 10 times higher than the level of concern, MOE = 750 compared to the LOC of 300), future refinements of this post

- application exposure forDeltamethrin Human Health Risk Assessment DP No. D417556

Page 8 of 67 deltamethrin may be necessary due to increased use of deltamethrin or advances in EPA risk assessments. Therefore, EPA is requiring the 40 CFR TTR data requirement to facilitate any necessary exposure assessments refinements and to further EPA’s general understanding of the availability of turf transfera ble pesticide residues.

HED does not have unit exposure handler data for hand held fogging equipment. Therefore,
chemical

- specific data are needed to support this scenario for occupational workers , and constitute a data gap for deltamethrin. These data need to be submitted in accordance with the
40 CFR Part 158 data requirements

.

2. 2 Tolerance Considerations

2. 2 .1 Enforcement Analytical Method

Adequate methods, utilizing gas chromatograph y with electron capture detection (GC/ECD), are
available for en forcing tolerances for residues of deltamethrin in plant commodities, as described
in Pesticide Analytical Manual ( PAM ) Volume II, Section 180.422. Another GC/ECD method (Method HRAV

- 22) is available for enforcing tolerances in livestock commodities. Adequate confirmatory method validation data have been submitted for these methods, along with adequate independent laboratory valid ation (ILV) trials.

Multiresidue methods data for cis

- deltamethrin and trans

- deltamethrin were pre viously sent to FDA. Cis

- deltamethrin is completely recovered through Methods 302 and 303, and partially recovered through Method 30 4. Trans

- Deltamethrin is partially recovered through Method 303, but not recovered through Method 304.

2. 2 .2 International Harmonization

Harmonization of MRLs is not an issue for th e proposed use of deltamethrin as a wide

- area mosquito alulti cide, as established tolerance levels are not changing. Harmonization of existing tolerances will be addressed during registration review

.

2. 2 .3 Recommended Tolerances

Currently, a tolerance of 0.05 ppm is established for residues of the insecticide deltamethrin (1 R ,3 R )

- 3

- (2,2

- dibromovinyl)

- 2,2

- dimethylcyclopropanecarboxylic acid ( S )

- alpha

- cyano

- 3

- phenoxybenzyl ester and its major metabolites, trans deltamethrin ( S )

- alpha

- cyano

- m

phenoxybenzyl

- (1 R ,3 R )

- 3

- (2,2

- dibromovinyl)

- 2,2

- dimethylcyclopropanecarboxylate and a lpha

R

- deltamethrin[( R )

- alpha

- cyano

- m

- phenoxybenzyl

- (1 R ,3 R )

- 3

- (2,2

- dibromovinyl)

- 2,2

- dimethylcyclopropanecarboxylate] in or on all food/feed items (other than those covered by a higher tolerance as a result of use on growing crops) in food/feed handling es tablishments. The
tolerance level does not need to be increased for the proposed use as a mosquito adulticide; however, the tolerance expression needs to be modified as discussed below.

HED recommends that the tolerance expression for deltam ethrin, cited under 40CFR §180.435[a][2], be amended to read as follows:Deltamethrin Human Health Risk Assessment DP No. D417556

Page 9 of 67 A tolerance of 0.05 ppm is established for residues of the insecticide deltamethrin (1 R ,3 R )

- 3

- (2,2

- dibromovinyl)

- 2,2

- dimethylcyclopropanecarboxylic acid ( S )

- alpha

- cyano

- 3

- phenoxyben zyl ester and its major metabolites, trans

- deltamethrin ( S )

- alpha

- cyano

- m

- phenoxybenzyl

- (1 R ,3 R )

- 3

- (2,2

- dibromovinyl)

- 2,2

- dimethylcyclopropanecarboxylate and alpha

- R

- deltamethrin[( R )

- alpha

- cyano

- m

phenoxybenzyl

- (1 R ,3 R )

- 3

- (2,2

- dibromovinyl)

- 2,2

- dimethylcyclopropanecarboxylate] as follows :

(i) In or on all food/feed items (other than those covered by a higher tolerance as a result of use on growing crops) in food/feed handling establishments or as a wide

area mosquito a dulticide.

(ii) The insecticide may be present as a residue from application of deltamethrin in food handling establishments, including food service, manufacturing and processing establishments, such as restaurants, cafeterias, supermarkets, bakeries,
bre weries, dairies, meat slaughtering and packing plants, and canneries, feed handling establishments including feed manufacturing and processing establishments, in accordance with the following prescribed conditions:

Compliance with the tolerance levels spe cified is to be determined by measuring only deltamethrin, (1 R, 3 R )

- 3

- (2,2

- dibromovinyl)

- 2,2

- dimethylcyclopropanecarboxylic acid ( S )

- alpha

- cyano

- 3

- phenoxybenzyl ester, and its major metabolites, trans

- deltamethrin, ( S )

- alpha

- cyano

- m

phenoxybenzyl(1 R, 3 S )

- 3

- ( 2,2

- dibromovinyl)

- 2,2

- dimethylcyclopropanecarboxylate, and alpha

- R

- deltamethrin, ( R )

- alpha

- cyano

- m

phenoxybenzyl

- (1 R, 3 R )

- 3

- (2,2

- dibromovinyl)

- 2,2

- dimethylcyclopropanecarboxylate, in or on the commodity.

2. 2 .4 Revisions to Petitioned

- For Tolerances

None

2. 3 Label Recommendations

The proposed label contains the following statement: “Apply at a rate not to exceed 0.0014 pounds of deltamethrin per acre in any given 24

- hour period.” The adulticide residue trials were performed at a 3

- day retreatment inte rval, however. As a result, the registrant should revise the label to state that the maximum single application rate is 0.00134 lb ai/A

, and the minimum re

treatment interval is 3 days.

The label also states: “Do not make more than 25 applications per s ite per year.” In the residue trials that were performed, only 10 applications were made . As a result, the registrant should revise the label to state that no more than 10 applications per year may be made at the maximum application rate of 0.00134 lb ai /A.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 10 of 67 The proposed label also states: “Do not exceed 0.036 pounds of AI per acre per year to any site.” This maximum value of 0.036 lb ai/A is based on 25 applications per year, rather than 10. As a result, the registrant should revise the label to state that 0.0134 lb ai/A is the maximum seasonal application rate.

3.0 In troduction

3.1 Chemical Identity

T able 3.1

. Test Compound Nomenclature.

Compound Chemical Structure

Common Name Cis

- d eltamethrin

Molecular Formula C 22 H 19 Br 2 NO 3 Molecular Weight 505.24 Company Experimental Name AEF108569

IUPAC Name (S)

- α

- cyano

- 3

- phenoxybenzyl (1R,3R)

- 3

- (2,2

- dibromovinyl)

- 2,2

- dimethylcyclopropanecarboxylate

CAS Name (1R,3R)

- R

- cyano(3

- phenoxyphenyl)methyl 3

- (2,2

- dibromoethenyl)

- 2,2

- dimethylcyclopropanecarboxylate

CAS Number 52918

- 63

- 5

End

- use Products (EPs) BES0668 Insecticide (EPA File Symbol 432

- RLGU)

3.2 Physical/Chemical Characteristics

Deltamethrin is a solid under ambient conditions. The compound has a ve r y low solubility in water, and low to high solubility in organic solvents. Its octanol/water partition coefficient suggests that accumulation of deltamethrin in fatty tissues is possible. See Appendix B for a listing of additional p hysical and c hemical properties.

3.3 Pesticide Use Pattern

Bayer Environmental Science submitted a proposed label for the mosquito adulticide formulation, BES0668 Insecticide , a liquid contain ing 2.0% active ingred ient. It may be applied by ULV truck mounted fogger and portable backpack or hand

- carried equipment at a single maximum application rate of 0.00134 lb ai/acre in residential, industrial, urban, recreational, municipal, agricultural and other areas where a dult mosquitoes and flies are found. BES0668 is also to be applied in indoor/outdoor livestock and poultry facilities. This product is to be applied by f ederal, s tate, t ribal, or local government officials responsible for public health or vector control, or by persons certified in the appropriate category, authorized by the state or tribal lead pesticide regulatory agency to perform adult mosquito control applications, or by persons underDeltamethrin Human Health Risk Assessment DP No. D417556

Page 11 of 67 their direct supervision, or as allowed by state regulations for pe rsons treating private property. BES0668 is also to be applied at a single maximum application rate of 0.0018 lb ai/acre for control of sand flies by the United States military by ULV ground applications. A summary of the proposed use pattern is presente d in Table 3.3. a.

The proposed label contains the following statement: “Apply at a rate not to exceed 0.0014 pounds of deltamethrin per acre in any given 24

- hour period.” The adulticide residue trials were performed at a 3

- day retreatment interval, however. As a result, the label sho uld be revise d t o state that the maximum single application rate is 0.00134 lb ai/A and the minimum re

- treatment interval is 3 days.

The label also states: “Do not make more than 25 applications per site per year.” In the
submitted residue trials, only 10 applications were made . As a result, the registrant should revise the label to state that no more than 10 applications per year may be made at the maximum application rate of 0.00134 lb ai/A.

The proposed label also states: “Do not exceed 0.036 pounds of AI per acre per year to any site.” This maximum value of 0.036 lb ai/A is based on 25 applications per year, rather than 10. As a result, the registrant should revise the label to state that 0.0134 lb ai/A is the maximum seasonal application ra te.

D eltamethrin is registered to control a variety of indoor and outdoor pests found on turf, in homes, and in commercial settings, including food handling establishments; as well as in pet and Table 3.3. a. Summary of Directions for Proposed Mosquito Vector Control Use of Deltamethrin

. Method of Application Product and

Formulation (Reg. No.) Application

Rate (lb ai/A) Maximum

No. Applications per Season Maximum

Seasonal Application

Rate (lb ai/A) RTI

(days) Use Directions,

Application Timing, Type and Limitations

Truck mounted ULV fogger,
Ground

, and
Hand Held Equipment BES0668

Insecticide Reg. No. 432

- RLGU (0.17 lb ai/gal) 0.00134
lb ai/A

over crops 25 0.036
lb ai/A in

one year over
crops 3 More frequent applications may be made to prevent or
control a threat to public/animal health determined by a state,
tribal or local health or vector control agency.

0.0018

lb ai/A 20 0.036 lb ai/a

per year NA To be applied by U.S. military personal under U.S. military supervision for control
of sand fliesDeltamethrin Human Health Risk Assessment DP No. D417556

Page 12 of 67 paint additive products. For the purpose of updating the ag gregate human health risk assessment, previously assessed representative residential uses have been re

- evaluated using the 2012
Residential SOPs

. A more comprehensive assessment m ight be completed during r egistration

r eview. A summary of the representati ve registered residential uses is provided in Table 3.3.b

.

Table 3.3.b . Summary of Registered Residential Uses for Deltamethrin.

Method of Application Product and

Formulation ( EPA Reg. No.) Application
Rate Maximum

No. Application s per Season Maximum

Seasonal Application
Rate (lb ai/A) Use Directions,

Application Timing, Type and Limitations

Aerosol Spray D

- Force

Insecticide

0.06% ai

(279

- 9554) 0.00075

lb ai/can NA Continues killing insects up to
8 weeks For indoor and outdoor

use as a spot or crack and
crevice application . Also

treat mattress es , especially tufts, folds

, and edges for control of bed bugs. Spray surface until slightly wet.

Low pressure
hand held equipment for
indoor uses and hand pressur ized

or power operated sprayers for
outdoor use sites K

- Othrine® SC

Insecticide

4.75% ai

(432

- 763)

(contains 0.42 lb ai/gal) Indoor use

–

0.005 lb ai/gal

Outdoor perimeter

- 0.214 lb ai/A or
0.005 lb ai/gal

Turf

–
0.13 lb ai/A

Ornamentals

0.00026

lb ai/gal NA NA Indoor treatment s are to be made as spot or crack and crevice applications. Do not apply as a space

spray , and do not treat entire floor, carpet

, or coverings.

Outdoor treatments are to be made as building perimeter treatments or broadcast to lawns, recreational grounds

, and
ornamentals.

Delta Wettable
Powder 5% ai

(432

- 832) 0.005 lb ai/gal NA NA Indoor applications are to be made as spot or crack and crevice applications.

Do not apply as a space

spray , and do not treat entire floor, carpet

, or coverings.

Outdoor applications are
to be made as broadcast to lawns, recreational grounds

, and ornamentals as a general surface spray.

Hose

- end Sprayer or hand held pressurized

spray er RUC

- 415

Insecticide

4.75% ai

(432

- 805) Lawn

–

0.005 lb ai/gal

Perimeter

– 0.0023 lb ai/gal Repeat as

needed for
lawns and every 7 to 10 days for
ornamentals

, if needed. NA For use by homeowners on lawns, ornamentals, decks, foundations, patios

, and other outdoor areas.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 13 of 67 Table 3.3.b . Summary of Registered Residential Uses for Deltamethrin.

Method of Application Product and

Formulation ( EPA Reg. No.) Application
Rate Maximum

No. Application s per Season Maximum

Seasonal Application
Rate (lb ai/A) Use Directions,

Application Timing, Type and Limitations

Ready

- to

- Use Container, hand duster, or
bulbous duster Green Light

Many Purpose
Dust

0.05% ai

(73327

- 14) Crack and

crevice

0.00000025

lb ai/ft 2

Home vegetable garden

– 0.00000066
lb ai/ft 2 Repeat at 7

-

day intervals

as necessary. NA Apply indoors to crack
and crevices. Do not apply as a broadcast application or to

mattresses. For
ornamental and home garden use

, apply thin layer of dust on upper and lower sides of leaves,

stems

, and flowers

.

Granular Spreader Delta Gra nules

0.1% ai

(4

- 422) 0.000003

lb ai/ft 2 or

0.13 lb ai/A Repeat as

needed NA Apply to home lawns, under shrubbery

, and
other ornamental recreational turf grass

areas.

Ready

- to

- Use Deltamethrin 4%

Pet Collar for Dogs

4% ai

(68451

- 1) 0.0024 lb ai/pet Reapply new collar every
six months NA Use only on dogs to
control fleas and ticks. Do not use on puppies
under 12 weeks old.

Brush, roller or
conventional
airless equipment Bug Juice

Insecticide
Additive

4.75% ai

(47332

- 11)
0.42 lb ai/gal 0.005

lb ai/g al/can NA NA Add 1 2⁄3 or 8 1⁄3 fluid
ounces to either 1 or 5 gallons of latex coating, oil base coating, stains

, or sealers

, then mix well to proper dilution. Apply product in and on
residential and non

residential buildings and structures including
residential kitchens and all types of food handling
establishments. Do not apply as a broadcast interior application.

3.4 Anti cipated Exposure Pathways

Humans could be exposed to deltame thrin from consuming food with residues resulting from agricultural applications (both pre

- harvest and stored grains), and from consuming food treated
in FHEs

. Furthermore, agricultural applications c ould result in deltame thrin reaching surface and groundwater, both of which can serve as sources of drinking water. However, because of the low water solubility of the chemical and its affinity to bind to soil organic matter

, drinking water concentrations will be very low

. T here is also the potential for exposure to o ccupational applicators while handling the pesticide prior to application as well as during application

. InDeltamethrin Human Health Risk Assessment DP No. D417556

Page 14 of 67 addition there is the potential for residential post

- application ex posure to the mosquito adulticide
via the inhalation route. T he potential exposure and risk for h omeowners exposed via inhalation during mixing, loading, and applying non

- restricted end

- use products in residential settings , as well as residential post

- app lication incidental oral exposure for children have been reassessed for the purpose of completing an aggregate risk assessment. Although there is the potential for dermal exposure, there is no dermal endpoint and

, therefore

, this exposure route has not been
assessed.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Orde r 12898, “ Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations, ” ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture under the National Health and Nutrition Examination Survey, What We E at in America, (NHANES/WWEIA). These food consumption patterns are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups

, and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, no n

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for children , youths, and adults entering or playing on treated areas
post

- application are evaluated. Exposure risk estimates were not of concern. Further considerations are currently in development

, as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patte rns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

Deltamethrin is a member of the pyrethroid class of insecticides. Pyrethroids have historically been classified into two groups, Type I and Type II, based on chemical structure and toxicological effects. Type I pyrethroids, which lack an alpha

- cyano moiety, induce in rats a syndrome consisting of aggressive sparring, altered sensitivity to external stimuli, hyperthermia, and fine tremor progressing to whole

- body tremo r and prostration (T

- syndrome). Type II pyrethroids, which contain an alpha

- cyano moiety, produce in rats a syndrome that includes pawing, burrowing, salivation, hypothermia, and coarse tremors leading to choreoathetosis (CS

syndrome) ( Verschoyle and Aldridge 1980 ; Lawrence and Casida 1982 ) . Deltamethrin is a T ype II pyrethroid. The adverse outcome pathway (AOP, identified using a weight

- of

- evidence approach based on the Bradford

- Hill criteria) shared by pyrethroids involves the ability to
interact wi th voltage

- gated sodium channels (VGSCs) in the central and peripheral nervous systems, leading to changes in neuron firing and, ultimately, neurotoxicity (Figure 4.0).Deltamethrin Human Health Risk Assessment DP No. D417556

Page 15 of 67 Figure 4.0. Adverse outcome pathway for pyrethroids

4.1 Toxicology Studies Available for Analysis

The database of experimental toxicology studies available for deltamethrin provides a robust characterization of the hazard profile for children 6 years old and older

, as well as for adults. A
28

- or 90

- day inhalation study is not available for consideration as required under the Part 158 toxicology data requirements ; however, HED’s HASPOC determined that a subchronic
inhalation stud y in the rat is not required for deltamethrin ( TXR# 0056944 , K. Rury, 4/29/2014 ). In addition, there are ongoing efforts to develop data in juvenile rats (see Section 4.4) to inform the potential sensitivity of infants and young children to pyrethroids as a class. Despite the missing studies and the ongoing scientific efforts, HED is confident that it has chosen points of departure and uncertainty factors in this risk assessment that are health protective and have a strong scientific foundation. The data from the following studies were used to evaluate the hazard potential of deltamethrin:

- Wolansky Acute Oral Study in the Rat

- WIL Laboratory Acute Oral Study in the Rat

- 21

- Day Dermal Study in the Rat

- 90

- Day Oral Stud ies in the Rat and Dog

- Chronic/Carcinogenicity Studies in the Rat, Mouse, and Dog

- Developmental Studies in the Rat and Rabbit

- Reproduction Study in the Rat

- Acute (ACN) , Subchronic (SCN) , and Developmental Neurotoxicity (DNT) Studies in
the Rat

- Immunotoxicity Study in the Rat

- Mutagenicity Battery of Studies

The studies available for consideration of deltamethrin toxicity provide a comprehensive database. The Wolansky and WIL studies are acute oral non

- guideline studies that measure
locomotor and functional observational battery (FOB) activity, respectively, and provide robust data to evaluate the hazard potential of deltamethrin. In addition, numerous studies from the
scientific literature conducted over several decades describe the pharmacodynamic and pharmacokinetic p rofile of deltamethrin and of the pyrethroids in general. This scientific literature has been recently reviewed by several groups ( Soderlund et al. 2002 ; Shafer et al.,
2005 ; Wolansky and Harrill 2008 )

.

Target Tissue

Dose VGSC

Alterations In Vivo
Clinical Signs Altered
Neuronal ExcitabilityDeltamethrin Human Health Risk Assessment DP No. D417556

Page 16 of 67 4.2 Toxicological Profile

Deltamethrin has been evaluated for a variety of toxic effects in experimental toxicity studies. Deltamethrin targets the nervous system. Neurotoxicity was observed throughout the database

, and effects were seen across species, sexes, exposure duration

, and routes of administration. Clinical signs characteristic of Type II pyrethroids, such as increased salivation, altered mobility /gait , and tremors were seen in experimental toxicology studies including neurotoxicity
studies (acute and subchronic) in r ats , subchronic and chronic studies in dogs and rats, and developmental and reproduction studies in rats. In addition to the clinical signs noted above, increased sensitivity to external stimuli, abnormal vocalization, and decreased fore

- and hind

limb gr ip strength were commonly observed in the database

.

Deltamethrin did not result in any systemic toxicity following dermal exposure for 21 days up to
the limit dose. N o toxicity was observed following acute dermal exposure to deltamethrin up to
a dose of 2000 mg/kg /day

. This finding is consistent with the toxicology profile of many pyrethroids, including fenpropathrin, zeta

- cypermethrin, and allethrin. Typically

, pyrethroids have a low absorption value of ≤ 5% and a high rate of metabolism. D eltamethrin had a slightly higher absorption value of 11.3%

, although the majority of the radioactivity measured was at the skin site (10.6%). This is typical of the p yrethroids

, as they are lipophilic

, and much of the radioactivity measured in the skin o f dermal penetra tion studies with pyrethroids is captured in the upper dermal layers an d not available for absorption or systemic circulation.

Deltamethrin ha d no adverse effects on fetuses or offspring in the prenatal developmental studies
in rats and ra bbits. However, potential qualitative susceptibility was observed at high doses in
the DNT and 2

- generation reproduction study

. In the DNT study, an increased incidence of vocalization when handled was observed during FOB observations on PND 4 for male p ups , and decreased pre

- and post

- weaning body weight was observed in pups of both sex es at 16.1 mg/kg/day. In maternal animals, only decreased body weight and body weight gain were observed despite undergoing the same neurological measurements as the pups , including FOB analysis.

In the 2

- generation reproduction study, t reatment

- related effects in the parental animals at the high dose (21.2/23.5 mg/kg/day, M/F) were limited to lesions on head, neck

, or forelimbs

, and alopecia in the males and ataxia and hypersensitivity in the females during gestation. In the F 1 generation, there were increased pup mortalities (PND 8

- 14) and clinical findings that were observed early in the post

- weaning period (i.e.

, impaired righting reflexes, hyperactivity, splayed
lim bs, vocalization, and excessive salivation) at the high dose (24.9/27.2 mg/kg/day, M/F)

. There was no increase in mortality or clinical signs in the F 2 generation. Decreased body weight
was observed in the adult P and F 1 generations

, and decreased pup weight was observed in both
the F 1 and F 2 pups. It is notable that the dose (24.9/27.2 mg/kg/day) and age of pups (PND 8

- 14) where mortality was observed i s consistent with the LD 50 in PND 11 pups for deltamethrin (11 mg/kg; Sheets et a l. 1994) observed in the literature

.

The increased qualitative susceptibility in the DNT and 2

- generation reproduction study were observed at doses 10

- to 20

- fold higher than the PODs selected for risk assessment. Therefore,

t he current PODs are protecti ve of the observed sensitivity.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 17 of 67 There w as no evidence of immunotoxicity in an immunotoxicity study in rats or in any other study in the toxicology database

. Deltamethrin is classified as “ n ot like ly to be carcinogenic to
humans. ” There was no evidence of carcinogenicity in the combined chronic/carcinogenicity study in rats or the carcinogenicity study in mice. In a battery of mutagenicity studies there was no evidence of a mutagenic effect.

Deltamethrin has either moderate (Toxicity Category II, MRID 00 070734) or minimal (Toxicity Category IV, MRID 41651019) toxicity via the oral route of exposure in acute lethality studies (LD 50 ) in rats

. The acute oral study

, which co ncluded that deltamethrin was of Toxicity Category IV

, used aqueous methyl cellulose as the vehicle, while an other study used both PEG 200 and sesame oil as the vehicles. It has been reported that deltamethrin is less toxic when dissolved in aqueous vehicles such as methyl cellulose

, and this m ight explain the considerable
difference in results between the two studies (Crofton et al., 1995)

. Deltamethrin has moderate acute toxicity via the inhalation (Toxicity Category II/III) route of exposure and minimal toxicity via the dermal (Toxicity Category III) route. It is minimally irritating to the eye (Toxicity Category III) and non

- irritating to the skin (Toxicity Category IV). It is not a skin sensitizer.

4.3 Pyrethroid Pharmacokinetic and Pharmacodynamic Profile

OPP is making best use of the e xtensive scientific knowledge about the mode of action/adverse outcome pathway ( MOA/AOP ) on pyrethroids in the risk assessments for this class of pesticides. In this way, information on a subset of pyrethroids can be used to help interpret and understand the toxicological profile for other members of the class. It is notable that a significant portion of the scientific literature on pyrethroids utilizes deltamethrin as the test chemical. In the on

- going work by the Council for the Advancement of Pyrethro id Human Risk Assessment (CAPHRA), deltamethrin is one of two sentinel pyrethroids being used to develop the initial, extensive
database of in vitro and in vivo toxicology studies and highly refined p hysiologically

- based pharmacokinetic (PBPK) models. As such, in the near future, extensive new data will become
available to further refine the deltamethrin hazard assessment.

The following sections discuss the specific issues related to pyrethroid pharmacokinetics, pyrethroid pharmacodynamics, and age

- relate d differences in pyrethroid toxicity.

4.3.1 Pharmacokinetics

Pharmacokinetics (PK) can be defined as what the body does to the chemical; in this case, how pyrethroids are distributed and eliminated following exposure. Specific to pyrethroids, PK refers to the process(es) that determine the concentration of the pyrethroids reaching sodium channels. The underlying PK of pyrethroids is an important determination of their toxicity because the concentration of pyrethroid at the sodium channel relates to the extent of toxicity; greater pyrethroid concentration translates as increased neurotoxicity. Physiological processes that significantly contribute to the PK include metabolism, protein binding, and partitioning. Carboxylesterases and cytochrome P450 enzym es are the two major enzyme families responsible for the metabolism of pyrethroids. It is the ontogeny of these enzymes that accounts for the age

related sensitivity observed after pyrethroid exposures. However, pyrethroid residues in fattyDeltamethrin Human Health Risk Assessment DP No. D417556

Page 18 of 67 tissue are no t available to interact with the voltage

- gated sodium channels (VGSCs) in vital tissues and, therefore, do not contribute to overall toxicity.

A ge

- dependent pharmacokinetic differences have been identified for several pyrethroids (i.e.,
there are differen ces in the ability of adults and juveniles to metabolize pyrethroids). The

enzymes that metabolize and detoxify pyrethroids are present in rats and humans at birth ( Koukouritaki et al. 2004 ; Yang et al. 2009 )

. As a result, both juveniles and adults are able to tolerate low doses of pyrethroids when the internal dose, or the a mount of pyrethroid at the sodium channel, is low. However, the activity of these enzymes increases with age, conveying in adults a greater capacity to detoxify pyrethroids compared to juveniles ( Anand et al. 2006 ; de
Zwart et al. 2008 ; Yang et al. 2009 ) . For example, the rate of in vitro metabolism of deltamethrin by plasma carboxy l esterases , plus hepatic carboxy l esterases and cytochrome P450s (microsomes) is at least 6 times higher for PND 90 rats compared to PND 10 rats ( Anand et al.
2006 ) . As a consequence, higher internal doses (i.e., those associated with high doses in

ex perimental toxicology studies) overwhelm the clearance mechanisms in juveniles

, but because adults have greater enzyme activity, they are able to tolerate higher doses prior to the onset of toxicity. As a matter of perspective, the anticipated exposures f rom typical dietary or residential activities are not expected to overwhelm the premature metabolic systems in juveniles. To better understand the role of pharmacokinetics and reduce uncertainty associated with extrapolating across species (i.e., rat to human) and life stages, PBPK models, designed to predict pyrethroid concentration in tissues following in vivo exposure, have recently been developed by the Agency. The Agency has determined that the important PK properties relevant
for the metabolism and distribution of pyrethroids in the body are sufficiently similar for members of this class such that using a ‘generic’ or family model structure for this class is scientifically appropriate. In other words, because of the similarities in the PK profiles of pyrethroids, a single model structure is able to predict the tissue dose based on the pharmacokinetics of every member of the class. The family modeling approach was primarily developed based on PBPK modeling performed with deltamethrin and was present ed to and supported by the F ederal Insecticide, Fungicide, and Rodenticide Scientific Advisory Panel (FIFRA SAP ), ( USEPA 2007 )

.

The initial deltamethrin PBPK model presented to the SAP was developed in the adult male SD rat (Mirfazaelian et al. 2006). The deltamethrin PBPK model was further refined b ased on oral bioavailability and disposition studies in rats and included estimates for target tissue concentrations in humans (Godin et al. 2010). The initial PBPK model was also extended by accounting for age

- dependent changes in physiological and bioch emical parameters (Tornero

Velez et al. 2010) to address juvenile sensitivity in rats. Currently, the CAPHRA, a group of pesticide registrants and product formulators, is collecting metabolism and tissue dosimetry data
from rats and human tissues across d ifferent life stages. Th ese data will be used to inform the development of PBPK models for additional pyrethroids. The code for the models for the initial
model is expected to be submitted to the Agency in 2015. Because of the evolving nature of the

PBP K model for deltamethrin, the A gency has decided not to use the existing model for conducting animal to human extrapolation. However, the A gency expects that in future risk

assessments

, PBPK modeling will be used to perform interspecies extrapolation.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 19 of 67 4 .3.2 Pharmacodynamics

Pharmacodynamics can be defined as the changes that chemicals cause to the body, in this case, how pyrethroids interact with the sodium channels. Substantial evidence from in vitro and in
vivo studies support the AOP illustrated in Figure 4. 0 and the disruption of sodium channels by pyrethroids as an early key event ( Lund and Narahashi 1982 ; Salgado et al. 1989 ; Song and
Narahashi 1996 ; Tabarean and Narahashi 1998 ; Soderlund et al. 2002 )

. Choi and Soderlund ( 2006 ) examined interactions of several pyrethroids , including deltamethrin, with mammalian VGSCs expressed in Xenopus (frog) oocytes. Deltamethrin produce d modifications of sodium channel kinetics consistent with other Type II compounds (Figure 4.3 .2 ). With respect to altered neuronal excitability, Type II pyrethroids significantly prolong sodium current tails (e.g. 200 ms to minutes) typically resulting i n increased resting membrane potential and ultimately causing depolarization dependent action potential block. Cao et al. (2011a) measured sodium influx in primary cultures of mammalian (mouse) neurons and demonstrated that deltamethrin caused
increases i n sodium influx in this model . T his observation confirms the ability of deltamethrin to
interact with VGSC in intact mammalian neurons. An additional study by Cao et al

. (2011b) demonstrated that the interaction of deltamethrin with VGSC caused changes i n neuronal excitability that resulted in calcium influx into intact mouse neurons. As this effect was entirely blocked by the VGSC blocker tetrodotoxin, it provides evidence that the changes in sodium channel function lead to changes in neuronal excitabil ity, as illustrated in Figure 4.3. 2.

Figure 4.3 .2

. Resting modification of rat Nav1.8 sodium channels by deltamethrin expressed in Xenopus oocytes. Channel current vs

. time traces from individual representative oocytes in th e absence or presence (*) of 10 μM
deltamethrin were obtained during and after 40

- ms depolarizations from 100 mV to 10 mV. Calibration bars: 20 ms
for the x

- axis and 500 nAmp on the y

- axis. Figure e xtracted from Figure 3 in Choi and Soderlund ( 2006 )

.

HED would prefer t o use an early key event in the AOP for pyrethroids in selection of PODs. However, in vivo measures of VGSC alteration and altered neuronal excitability are not readily available for use in risk assessment at this time, and approaches for extrapolating in vitro findings like those discussed here to in vivo measures are not yet developed. Therefore, the Agency is focusing its efforts in hazard characterization and identification on the apical endpoint (i.e., changes in neurobehavior in laboratory animals). Neurotoxicity resulting from pyrethroids is generally characterized by tremors, hyper

- or hypothermia, heightened response to stimuli, salivation, and convulsions ( Soderlund et al. 2002 ; Wolansky and Harrill 2008 ; Weiner et al.
2009 )

.

In contrast to the age

- related PK differences ide ntified in the 2011 analysis, pharmacodynamic ( PD ) contributions to pyrethroid toxicity are not age

- dependent

, even though there are several variations of sodium channels, called isoforms, that are differentially expressed by tissue andDeltamethrin Human Health Risk Assessment DP No. D417556

Page 20 of 67 age. Because of th e nature of the interaction of pyrethroids with sodium channels, it is difficult to obtain dynamic information in vivo. To date, a readily useable biomarker of in vivo pyrethroid interaction with sodium channels has not been identified, making it impracti cal to determine the isoform combinations that are present and being acted upon by pyrethroids. Therefore, much of the information available to the Agency to characterize the PD relationship between pyrethroids
and sodium channels has been derived from in vitro studies using frog oocytes or neuronal cells
cultured in defined media. These in vitro techniques do not provide a direct quantitative measure
of in vivo pyrethroid activity. However, these techniques consistently and qualitatively
demonstrate tha t channel isoforms expressed in juveniles are not more sensitive to pyrethroid perturbation compared to isoforms expressed in adults and that, pharmacodynamically, the rat is a conservative model for humans. For example, Meacham et al. ( 2008 ) , compared the sensitivity of an adult isoform and a juvenile isoform expressed in frog oocytes to deltamethrin. The isoforms had comparable responses at environmentally relevant concentrations (<500 nM) of deltamethrin, suggesting a lack of PD difference between ju veniles and adults at low exposure levels. In addition, a study directly comparing a homologous rat and human VGSC isoform,
NaV 1.3 , revealed that the rat isoform was 4

- fold more sensitive than the equivalent human sodium channel to the pyrethroid tefluthr in ( Tan and Soderlun d 2009 ) . These data suggest that the rat is a highly sensitive model

, and extrapolations from the rat would be protective of human health. The occurrence and ontogeny of voltage

- gated sodium channels in humans is not well characterized compared to tho se in the rat. However, based on the comparable function and distribution of sodium channels between the species, the rat is an appropriate surrogate for the
evaluation of human PD ( Goldin et al. 2000 ; Goldin 2002 ) . As a result, the Agency concludes that juvenile rats are not more sensitive than adults with respect to pyrethroid pharmaco

dynamics. Therefore, the pharmacodynamic contribution to the FQPA Safety F actor will be 1 X

.

4.3.3 Critical Duration of Exposure

One o f the key elements in risk assessment is the appropriate integration of temporality between the exposure and hazard assessments. Following a single oral gavage dose, deltamethrin is absorbed quickly in rats. Effects such as tremors, salivation, and impai red mobility were observed within 3 hours following oral gavage dosing in the deltamethrin acute neurotoxicity study. In addition, effects on motor activity in the W olansky acute study, FOB observations in the WIL acute study , and abnormalities in gait in the chronic dog toxicity study were observed
within 2

, 4 , and 5 hours, respectively, of administration of deltamethrin. These observations are consistent with the toxicity profiles for other pyrethroids t h at are marked by rapid absorption, metabolism, an d elimination, with a time to peak effect for neurobehavioral effects ranging from
4 to 8 hours ( Wolansky and Harrill 2008 ; Weiner et al. 2009 ; Scollon et al. 2011 )

.

The combination of rapid absorption, metabolism, and elimination precludes accumulation and increased potency following repeated dosing. Therefore, for most pyrethroids, the acute toxicity
studies t ypically result in neurotoxicity at lower doses. In the case of deltamethrin, the chronic dog study (NOAEL =1 mg/kg/day) and Wolansky study (BMDL 1SD = 1.49 mg/kg) have very similar PODs and are the lowest amongst the available studies. The h uman e quivalent d oses (HED) based on allometric scaling (Table 4.3.3) indicate that the BMDL 1SD from the Wolansky study is lower than the NOAEL from the chronic dog study. T he other two acute studies (WIL acute study and the acute neurotoxicity study) have PODs that are approximately 2 0

- 30 foldDeltamethrin Human Health Risk Assessment DP No. D417556

Page 21 of 67 higher than the POD from the Wolansky acute study (Table 4.3.3). It is notable that both the WIL acute study and the acute neurotoxicity study used relatively high vehicle volumes of 5

m L /kg, compared to a vehicle volume of 1 m L /kg in the Wolansky acute study , which may account for the differences observed. For deltamethrin, the gavage volume can play an important role in potency becaus e the volume impacts the absorption characteristics (e.g., timing and

amount ; Crofton et al, 1995). In the WIL and acute neurotoxicity studies, it is likely that the relatively high corn oil volume caused a reduction in the peak level of deltamethrin in the brain

, resulting in lower toxicity, thereby increasing the POD.

In general, rat di etary studies tend to have higher NOAELs/LOAELs for pyrethroids becaus e , as rats feed continuously

, pyrethroids are metabolized and excreted from the system relatively quickly

, and the overall systemic concentration in the rat remains low. In contrast, bo lus/gavage dosing results in greater maximal plasma concentrations immediately after dosing. The results from the deltamethrin studies are similar in this respect

, with the dietary studies having higher NOAELs than the bolus/gavage studies. Comparing the POD s established from the Wolansky acute study and repeat dosing studies, it is apparent that repeat exposures do not result in lower
POD s (Table 4.3.3)

. This observation is consistent with the general kinetic profile for pyrethroids. Therefore, the end point from the Wolansky acute study is protective of the endpoints from the repeat dosing studies and

, for the purposes of endpoint selection and exposure assessment, only single

- day risk assessments need to be conducted.

Table 4.3.3. Deltamethrin Point of Departure V alues versus Treatment Time for

Signs of Neurotoxicity

. Study Duration Study findings
NOAEL (mg/kg/day) or BMDL LOAEL

(mg/kg/day)

or BMD 3⁄4 Body Weight

Adjustment for

HED Comparison C Wolansky acute rat (Gavage

- 1 m L /kg corn oil) Acute, single

exposure A BMDL 1SD = 1.49 BMD 1SD = 2.48 0.43

WIL acute rat (Gavage

- 5 m L /kg corn oil) Acute, single

exposure B BMDL 20 = 10.5 BMD 20 = 14.5 3.05

Acute neurotoxicity rat (Gavage

- 5 m L /kg corn oil) Acute, single

exposure 15 50 4.36

Developmental Rat ( Gavage

- 1 m L /kg corn oil) 10 days 3.3 7 0.96

Subchronic neurotoxicity rat (Dietary) 90 days 14 54 4.07
Sub

- chronic rat (Gavage

- 2.5 m L /kg corn oil) 90 days 2.5 10 0.73

Reproductive toxicity (Dietary) 120 days 5.4 21.2 1.57 Chronic dog (Capsule) 1

- year 1 10 0.61 Chronic/carcinogenicity rat (Dietary) 2

- years 22.2 35.9 6.40

A BMD 1SD is the central estimate of the dose that results in decreased motor activity compared to control animals based upon 1 standard deviation using Benchmark Dose Analysis. BMDL 1SD is the 95% lower confidence limit of the central estimate. Data and analysis can be found in MRID 47885701.

B BMD 20 is the central estimate of the dose that results in a 20% difference in FOB scores compared to control animals using Benchmark Dose Analys is. BMDL is the 95% lower confidence limit of the central estimate. Data and analysis can be found in

MRID 48714301

. C Human Equivalent Doses based on allometric scaling: Scaling Factor 0.75; Default weights: rat = 0.5 kg, dog = 10 kg, Human = 70 kg; NOA EL H =NOAEL D (BW D /BW H )^1

- 0.75; Sample and Arenal, 1999.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 22 of 67 4.4 Safety F actor for Infants and Children (FQPA Safety Factor)

There were no indications of fetal toxicity in any of the guideline studies, including developmental studies in the rat and rabbit, a de velopmental neurotoxicity study in rats, and a 2

- generation reproduction study in rats. There was evidence of increased juvenile qualitative susceptibility at high doses observed in both the DNT and 2

- generation reproduction studies. However, these high

- dose effects are only at doses 10

- to 20

- fold higher than the deltamethrin
POD. The observations of increased qualitative juvenile sensitivity in the guideline studies are consistent with the findings of juvenile sensitivity in the literature for deltamet hrin

, which are also high

- dose effects.

After reviewing the extensive body of peer

- reviewed literature on pyrethroids, the Agency has no residual uncertainties regarding age

- related sensitivity for women of child bearing age as well as
for all adult populations and children >6 years of age, based on the absence of pre

- natal sensitivity observed in 76 guideline studies for 24 pyrethroids and the scientific literature. Additionally, no evidence of increased quantitative or qualitative susceptibility wa s seen in the pyrethroid scientific literature related to pharmacodynamics. The Agency is retaining a 3X uncertainty factor to protect for exposures of children <6 years of age based on the increased quantitative susceptibility seen in studies on pyrethro id pharmacokinetics and the increased quantitative juvenile susceptibility observed in high dose studies, such as the deltamethrin guideline DNT and 2

- generation reproduction studies.

4.4.1 Completeness of the Toxicology Database

The toxicology database for deltamethrin is largely complete including developmental toxicity studies in rats and rabbits, a reproduction study in rats, and acute neurotoxicity ( A CN)

, subchronic neurotoxicity ( SCN ) , and developmental neurotoxicity (DNT) studies. HED’s
HAS POC det ermined that a subchronic inhalation study in the rat is not required for deltamethrin ( TXR# 0056944 ). At this time, EPA lacks additional data to address the potential for juvenile sensitivity to many pyrethroids, including deltamethrin.

The Agency is ex pecting additional in vitro and in vivo data . In 2010, the Agency requested proposals for study protocols that could identify and quantify potential juvenile sensitivity and received a single response from the Pyrethrin and Pyrethroids Technical Working Group (PPTWG), a conglomerate of pyrethroid registrants. The PPTWG protocol was reviewed during a July 2010 FIFRA SAP meeting. Based on comments from the SAP, the initial study proposal
was refined. At the present time, the CAPHRA is 1 ) conducti ng in vitro studies demonstrating the interaction of pyrethroids with exogenously expressed rat and human VGSCs in Xenopus oocytes; 2 ) conducting in vitro studies demonstrating interaction of pyrethroids with VG S Cs in rat neurolemma cells; 3 ) developing ra t and human PBPK models, including additional pharmacokinetic data; and 4 ) conducting in vivo behavioral testing using auditory startle testing
in rats. As more data for deltamethrin and other individual pyrethroids become available, the Agency will deter mine whether re

- evaluation of the age

- related sensitivity of pyrethroids is appropriate.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 23 of 67 For the reasons discussed in Section 4.4, the uncertainty regarding the protectiveness of the intraspecies uncertainty factor raised by the literature studies and th e absence of the requested data warrant application of an additional 3X for risk assessment for infants and children <6 years of age.

4.4.2 Evidence of Neurotoxicity

As with other pyrethroids, deltamethrin causes neurotoxicity from interaction with sodium channels leading to clinical signs of neurotoxicity. These effects are well characterized and adequately assessed by the available guideline and non

- guideline studies.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

H igh

- dose studies in the scientific literature indicate that younger animals are more susceptible to the toxicity of pyrethroids. For example, Sheets et al

. (1994) found increased brain deltamethrin levels in young rats (PND 11 and 21) relative to adult rats (PND 72). These age

related differences in toxicity are principally due to age

- dependent pharmacokinetics . T he activity of enzymes associated with the metabolism of pyrethroids increase with age (Anand et
al

. , 2006). However, in context, normal die tary or residential exposures of juveniles are not expected to overwhelm their ability to metabolize pyrethroids. In support, at a dose of 4.0 mg/kg deltamethrin (near the Wolansky study LOAEL value of 3.0 mg/kg for deltamethrin), the change in the acoust ic startle response was similar between adult and young rats (Sheets et al, 1994). In addition, EPA’s Office of Research and Development ( ORD ) recently developed an

age

- dependent PBPK model for deltamethrin (Tornero

- Velez et al, 2010) that predicts a 3

– fo ld increase of pyrethroid in neuronal tissue in younger animals compared to adults. There are several studies ( in vitro and in vivo ) that indicate that PD contributions to pyrethroid toxicity are
not age

- dependent. Examination of specific VGSCs has demon strated that there is a lack of increased sensitivity in either juvenile specific isoforms (Meacham et al

. , 2008) or in human isoforms compared to rat variants (Tan and Soderlund, 2009).

There were no indications of fetal toxicity in any of the guideline s tudies, including developmental studies in the rat and rabbit, a developmental neurotoxicity study in rats, and a 2

- generation reproduction study in rats. There was evidence of increased juvenile qualitative susceptibility at high doses observed in both t he DNT and 2

- generation reproduction studies. In the DNT study, increased vocalization was observed during FOB handling of pups on PND 4 at the same dose where decreased body weight and body weight gain were observed in maternal animals (16.1 mg/kg/day)

. No findings were observed in the maternal animals during FOB handling in the DNT. In the 2

- generation reproduction study, the P generation showed limited clinical signs of neurotoxicity and decreased body weights at the highest dose tested (21.2/23.5 mg/kg/day, M/F). Effects observed in the F 1 generation at the same dose included decreased pup weight, increased pup mortality between PND 8

- 14, increased pup mortality within the first 8 days post

- weaning, and additional clinical signs of neurotoxicity not observed in the parental generation. The increased mortality and additional clinical signs were considered to be evidence of qualitative sensitivity in juveniles.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 24 of 67 The observations of increased qualitative juvenile sensitivity in the guideline studies ar e consistent with the findings of juvenile sensitivity in the literature for deltamethrin

. The increased sensitivity in the DNT and 2

- generation reproduction study w as observed in animals of a similar life stage (PND 4 and PND 8

- 14, respectively) as the animals in the Sheets study (Sheets et al., 1994). Furthermore, the dose at which increased pup death was observed in the 2

- generation reproduction study (~25 mg/kg/day) is similar to the LD 50 value in the Sheets study for pups on PND 11 and 21 (11 mg/kg /day). T he qualitative sensitivity observed in the DNT and
2

- generation reproduction studies w as seen at the highest doses tested . These doses are considered to be relatively high (i.e., near the lethal doses) and are ~30

- to 50

- fold greater than the poi nt of departure selected for the acute and chronic dietary reference dose ( 1.49 mg/kg ) ; therefore, the current risk assessment is protective of the observed sensitivity

. At doses near the Wolansky POD, no effects on parental animals or offspring were obse rved in either the DNT or
2

- generation reproduction study and

, therefore

, there is no susceptibility at these doses.

After reviewing the extensive body of peer

- reviewed literature on pyrethroids, the Agency has no residual uncertainties regarding age

- related sensitivity for women of child bearing age as well as for all adult populations and children >6 years of age, base d on the absence of pre

- natal sensitivity observed in 76 guideline studies for 24 pyrethroids and the scientific literature. Additionally, no evidence of increased quantitative or qualitative susceptibility was seen in the pyrethroid scientific literature related to pharmacodynamics. The Agency is retaining a 3X uncertainty factor to protect for exposures of children <6 years of age based on the increased quantitative susceptibility seen in studies on pyrethroid PK and the increased quantitative juvenile susceptibility observed in high doses studies, such as the deltamethrin guideline DNT
and 2

- generation reproduction studies.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties with regard to dietary exposure . The die tary exposure assessments are based on high

- end health protective residue levels that account for parent and metabolites of concern, processing factors, and percent crop treated assumptions. Furthermore, conservative, upper

- bound assumptions were used to determine exposure through drinking water and residential sources, such that these exposures have not been underestimated.

Although EPA has required additional data on transferable residues from treated turf for
deltam ethrin, EPA is confident that it has not underestimated turf exposure because of the conservativeness of the default turf transfer value and conservative assumptions in the short

- term turf assessment procedures (e.g., assuming residues do not degrade over the thirty

- day assessment period and assuming high

- end activities on turf for every day of the assessment period). The additional data on turf transferable residues have been required in case refinement of exposure assessments is needed in the future and to further EPA’s general understandin g of the availability of pesticide residues on turf.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 25 of 67 4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose

- Response and Hazard Assessment

Endpoint selection is discussed in Appendix A.3. Based on the existing and proposed use patterns for deltamethrin, the expected exposure profile will be for acute dietary, as well as short

term incidental oral, dermal

, and inhalation exposures. Based on the toxicity profile, HED is not conducting dermal (all durations) or intermediate

- and long

- term inhalation exposure

assessments for adults or children. A chronic dietary risk assessment is not being conducted because there is no apparent increase in haz ard from repeated/chronic exposures to deltamethrin. Therefore, the acute endpoint is protective of the endpoints from repeat dosing studies. A chronic dietary exposure assessment is being performed in order to generate background exposure estimates to a ggregate with residential exposure estimates for the short

- term aggregate risk assessment.

As previously indicated, the toxicity endpoints in the deltamethrin database are consistently based on clinical signs of neurotoxicity. The studies include multipl e species, study designs, and durations (Table 4.3.3). Because uncertainty associated with the POD is propagated throughout the risk assessment, one of the key factors in POD selection is the robustness of the dose

response data. In addition to the typic al guideline studies, data from two special studies (Wolansky study on motor activity and WIL FOB study) evaluating neurobehavioral outcomes
are available for deltamethrin ( Wolansky et. al. 2006 ; Weiner et. al. 2009 ) . Wolansky et al.

m easured motor activity at the time of peak effect after exposure to 11 pyrethroids, including deltamethrin, although other neurobehavioral parameters were not asses sed. Dose

- response relationships were determined using 6

- 11 doses per pyrethroid (6 doses used for deltamethrin)
and 8

- 18 rats per dose group, minimizing variability and increasing the confidence in the BMD estimates determined from this study. Moreover, each pyrethroid was evaluated by the same scientist, thus decreasing some of the variability associated with neurobehavioral measures. In the WIL study, 17 pyrethroids including deltamethrin were evaluated using a specially designed FOB study focused on the outcomes associated with pyrethroid toxicity syndromes at the time to peak effect. Dose

- response relationships were determined using 2

- 3 doses per pyrethroid (3 doses used for deltamethrin) and 10 male rats per dose group. However, as discussed in Se ction
4.3.3

, the WIL FOB study and the ACN study both used high vehicle volumes that likely impacted absorption characteristics of deltamethrin

, thereby increasing the POD.

Observations of salivation, effects on mobility /gait , and tremors were the most pr ominent findings in the guideline experimental toxicology studies and were considered in the POD determination. Given the multiple strengths associated with the study design of Wolansky, et al. ( 2006 ) and the resulting well

- defined dose

- response curve, the Wolansky study provides the most robust data set for extrapolating risk from deltamethrin. Although the guideline studies typically have only three treatment groups

, they often do not evaluate clini cal signs at the time of peak effect, and the scoring metrics for neurotoxicity parameters vary widely among guideline
studies . T he NOAELs/LOAELs from the guideline studies, in general, are consistent with

, and
support

, the findings of the Wolansky study.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 26 of 67 A BMD analysis was conducted by the Agency for all the pyrethroids included in the Wolansky study (MRID 4 7885701 ) . Overall, because of the large number of doses and high quality measurements, the BMD analysis yielded high

- confidence results. In perfo rming BMD analys e s, a benchmark response (BMR) must be selected. As a general approach, it is prefer able to use a combination of biological and statistical factors in the BMR selection. In the case of motor activity data, the scientific community has not established a specific level of change that would be considered to be adverse. Therefore, OPP has elected to use one standard deviation (1SD) from the control group, as suggested, for continuous endpoints in the Agency’s BMD guidance ( USEPA 20 12 ) as the BMR. OPP has estimated both the BMD 1SD and the BMDL 1SD (where the

BMDL 1SD is the lower 95% confidence limit of the BMD 1SD ). The BMD 1SD and the BMDL 1SD for deltamethrin are 2.48 mg/kg and 1.49 mg/kg, respectively. As a matter of science policy, EPA uses the BMDL, not the BMD, for deriving PODs. Therefore, the BMDL 1SD of 1.49 mg/kg is being used as the dose for risk assessment.

As described in section 4.3.1, PBPK models are currently available for species extrapolation
from rats to humans. T he use of PBPK models to predict human equivalent concentrations is not

necessary for the current action

.

Acute Dietary (All Age Groups) : Quantitation of the dietary risks was performed using the acute oral Wolansky study, with a BMDL 1SD value of 1.49 m g/kg and a BMD 1SD value of 2.48 mg/kg based on decreased locomotor activity. The acute neurotoxicity, chronic dog, and WIL acute
studies were all considered for risk assessment because they all had effects that were observed within hours of dosing. Howev er, the Wolansky study had the lowest POD among all studies and is considered the most robust study in the database. The chronic dog study had a slightly lower NOAEL (1 mg/kg/day); however, the human equivalent dose based on allometric scaling
was actuall y higher for the chronic dog study (0.61 mg/kg/day) compared to the Wolansky study (0.43 mg/kg) (Table 4.3.3). As there is no apparent increase in hazard from repeated/chronic exposures to deltamethrin, the acute dietary exposure assessment is protective of chronic dietary

exposures. Accordingly, a chronic dietary assessment was no t conducted.

Incidental oral short

- term : Quantitation of the incidental oral risks was performed using the acute oral Wolansky study, with a BMDL 1SD value of 1.49 mg/kg and a BMD 1SD value of 2

. 48 mg/kg based on decreased locomotor activity. The BMDL 1SD value of 1

. 49 mg/kg is pr otective of potential offspring effects observed in the DNT and 2

- generation reproduction study.

Short

- term Dermal : A 21

- day dermal study in rat for deltamethrin is available for consideration. However, no treatment

- related findings were observed at the limit dose . There was also no toxicity observed following acute dermal exposure to deltamethrin up to a dose of 2000 mg/kg

. T herefore, a dermal hazard was not identified for deltamethrin

, and no dermal risk assessment
will be conducted

. This finding is consistent with the toxicology profile of many pyrethroids. No dermal hazard has been identified for fenpropathrin, zeta

- cyper methrin, or allethrin. Typically

, pyrethroids have a low dermal absorption value of ≤ 5% and a high rate of
metabolism

. D eltamethrin had a slightly higher dermal absorption value of 11.3%

, although the majority of the radioactivity measured was at the ski n site (10.6%). This is typical of the pyrethroids

, as they are lipophilic

, and much of the radioactivity measured in the skin of dermalDeltamethrin Human Health Risk Assessment DP No. D417556

Page 27 of 67 penetration studies with pyrethroids is captured in the upper dermal layers an d not available for absorption or system ic circulation.

Short

- term Inhalation : A route

- specific inhalation study is not available for deltamethrin ; however, H ASPOC waived the requirement for this study (TXR# 0056944 ) . As a result, the oral

BMDL 1SD of 1

. 49 mg/kg from the Wolansky acute rat study is being used for this endpoint to extrapolate inhalation risk because of the overall robust nature of the study and the lack of increased hazard from repeated/chronic exposures to deltamethrin

. Absorption and t oxi city via
the inhalation route are assumed to be equal to toxicity via the oral route.

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

When there are potential occupational and residential exposures to a pesticide, the risk

asses sment must address exposures from three major ro u t es : oral, dermal

, and inhalation, and determine whether the individual exposures can be combined if they have the same toxicological effects. For deltamethrin, there are no routes to combine despite all e xposure scenarios being based on the same endpoint : decreased motor activity. No dermal hazard was identified for
deltamethrin

, and the inhalation route of exposure only applies to occupational and residential
handlers

. Furthermore, i nhalation post

- appl ication exposure is expected to be minimal

. T herefore

, incidental oral is the only potential route of exposure for children.

4.5.3 Cancer Classification and Risk Assessment Recommendation

There was no evidence of carcinogenicity in either the rat or mouse long

- term dietary studies up to the highest dose tested

, nor was there any mutagenic activity in bacteria or cultured mammalian cells. Deltamethrin is classified as “not likely to be carcinogenic to humans” in
accordance with the EPA Final Guidance for Carcinogen Risk Assessment (3/29/2005).

4.5.4 Summary of Points of Departure and Toxicity Endpoints

Table 4.5.4.1

. Summary of Deltamethrin Toxicological Doses and Endpoints for Use in Dietary and Non

Occupational Human Health Risk Assessment

. Exposure
Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD, Level of

Concern for Risk
Assessment Study and

Toxicological Effects

Acute Dietary

- (≥ 6 years old) Wolansky

BMDL 1SD = 1.49 mg/kg UF A = 10X

UF H = 10X FQPA SF = 1 X Acute RfD = 0.0 15 mg/kg

aPAD =0.0 1 5 mg/kg/day Wolansky BMD 1SD = 2.48 mg/kg
based on decreased motor activity

Acute Dietary

- (< 6 years old) Wolansky

BMDL 1SD = 1.49 mg/kg UF A = 10X

UF H = 10X FQPA SF = 3X Acute RfD = 0.0 1 5 mg/kg

aPAD =0.00 5 mg/kg/day Wolansky BMD 1SD = 2.48 mg/kg
based on decreased motor activity

Incidental Oral (Short

term) Wolansky

BMDL 1SD = 1.49 mg/kg UF A = 10X

UF H = 10X FQPA SF = 3X Residential LOC for
MOE = 300 Wolansky BMD 1SD = 2.48 mg/kg
based on decreased motor activityDeltamethrin Human Health Risk Assessment DP No. D417556

Page 28 of 67 Table 4.5.4.1

. Summary of Deltamethrin Toxicological Doses and Endpoints for Use in Dietary and Non

Occupational Human Health Risk Assessment

. Exposure
Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD, Level of

Concern for Risk
Assessment Study and

Toxicological Effects

Dermal (short

- term; all populations) A dermal assessment was not conducted based on the lack of effects in a 21

- day dermal study

and low potential for dermal absorption for deltamethrin.

* Inhalation (Short

- term; ≥ 6 years old) Wolansky

BMDL 1SD = 1.49 mg/kg UF A = 10X

UF H = 10X FQPA SF = 1 X Residential LOC for
MOE = 100

Occupational LOC for
MOE = 100 Wolansky BMD 1SD = 2.48 mg/kg
based on decreased motor activity

* Inhalation (Short

- term; < 6 years old) Wolansky

BMDL 1SD = 1.49 mg/kg UF A = 10X

UF H = 10X FQPA SF = 3X Residential LOC for
MOE = 300 Wolansky BMD 1SD = 2.48 mg/kg
based on decreased motor activity Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of treatment

related tumor s in two adequa te rodent carcinogenicity studies.

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). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. * Inhalation absorption is assumed to be equivalent to oral absorption.

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

Based on acceptable metabolism data in pla nts and animals, HED has concluded that the nature of the residue in plants and animals is adequately understood. In both plants and animals, the
residues of concern for both tolerance enforcement and risk assessment are the cis

- , trans

- and alpha

- R

- isom ers of deltamethrin.

In acceptable tomato, cotton, apple

, and corn metabolism studies

, the three deltamethrin isomers ( cis

- , trans

- , and alpha

- R

- ) were the major [ 14 C]

- residues. All other metabolites were present at
<10% of the total radioactive residue ( TRR ) , or accounted for <0.01 ppm. In plants, the main component of the active ingredient, cis

- deltamethrin, undergoes isomerization to form trans

- and alpha

- R

- deltamethrin. Each of these isomers can also undergo cleavage at the ester linkage to yield 3

- phenoxybenzaldehyde, and cis

- or trans

- Br 2 CA metabolites that can be further oxidized,
reduced

, and/or conjugated. Deltamethrin is also directly hydroxylated to 4’

- hydroxydeltamethrin, or the nitrile group can be hydrolyzed to form an amide metabolite.

Acceptable cattle and poultry metabolism studies were conducted using [ 14 C]

- tralomethrin , a closely related pyrethroid that breaks down into deltamethrin via debromination. In theseDeltamethrin Human Health Risk Assessment DP No. D417556

Page 29 of 67 studies, d eltamethrin was the major residue in c attle fat, muscle

, and milk (48

- 96% TRR), and was detected in kidneys at 1

- 2% of the TRR. In the poultry metabolism studies, deltamethrin was also the major residue identified in fat, muscle

, and egg yolks (32

- 85% TRR), and was
detected in liver at 14% of the TRR. In both the cattle and poultry studies, deltamethrin was further metabolized by cleavage at the ester linkage to yield 3

- phenoxybenzaldehyde and Br 2 CA metabolites, which were further oxidized, reduced

, and/or conjugated. Free and conjugated

res idues of Br 2 CA and 3

- phenoxybenzaldehyde were major components detected in liver, kidney

, and muscle of both cattle and poultry. In poultry, minor amounts of 4’

- hydroxydeltamethrin were also detected in liver.

5.1.2 Summary of Environmental Degradation

When applied to the field, deltamethrin is likely to partition in to the soil and organic matter in the

crops . It appears to bind strongly to soil and organic matter, though binding is not instantaneous (K OC >> 100,000, immobile). It is not expected to leach into sub

- surfaces. It m ight reach aquatic environments via spray drift or in runoff events accompanied by erosion. Deltamethrin appears to be moderately to highly persistent in terrestrial environments. I t has the potential to persist in

aq uatic environments, where it might partition with the sediment. Because of its low Henry’s Law
Constant , deltamethrin is unlikely to volatilize substantially.

Deltamethrin is relatively stable at pH 5 and 7 ; h owever, it rapidly degrade s (half

- life of 2.5 days) at an alkaline pH of 9 to form Br 2 CA and 3

- phenoxybenzaldehyde. It does not appear to photodegrade substantially in aqueous solutions.

Based on acceptable aerobic soil metabolism data, deltamethrin d egrade s rapidly (half

- life 11

- 19 days) to form DBVA or Br 2 CA (<10%) and CO 2 . The proposed routes of degradation are ester hydrolysis and microbial

- mediated mineralization to CO 2

. In an anaerobic soil metabolism study, deltamethrin degraded in an Arizona sandy l oam (pH 8.1) with a half

- life of 32

- 36 days for the benzyl and gem inal labels, respectively. For the gem inal label experiment, only 1 metabolite,

Br 2 CA or decamethrinic acid, was found at 49% of the applied radioactivity by D ay 30, and
remained at about t

his level on D ays 59 (52%) and 90 (48%). For the benzyl label, the only
metabolite identified was 3

- phenoxybenzoic acid, which was only detected in a D ay

- 30 sample, accounting for only 3% of the applied radioactivity. In an aerobic aquatic metabolism stu dy, consisting of loam or sandy loam test systems from the Netherlands, the half

- lives for the whole systems were 26 and 120 days

, respectively. The major transformation product was the alpha

- R

isomer of deltamethrin, at up to 24% in the sandy loam.

In a fish bioconcentration study, deltamethrin had bio

- concentration factors of 1 89 x and 3630 x in edible and visceral fish tissues, respectively. The whole body BCF of 698 x was calculated from edible and visceral fish tissue results. The majority of the radioactive residue found in fish was parent, accounting for 78 and 83% of the TRR in edible and viscer al fish tissues, respectively.

5.1.3 Comparison of Metabolic Pathways

In the rat metabolism studies, deltamethrin was relatively well absorbed after oral dosing, with rapid excretion via the urine and feces. Fecal extracts contained mostly unabsorbed, unchangedDeltamethrin Human Health Risk Assessment DP No. D417556

Page 30 of 67 deltamethrin. Absorbed deltamethrin was cleaved at the ester site, and the cleaved products were rapidly conjugated into 4’SO 4

- m

- phenoxybenzo ic acid and dibromocyclopropanecarboxylic
acid

- glucuronide, and then excreted in the urine

.

In plants and animals, parent cis

- deltamethrin can form the trans and alpha

- R isomers, which can then undergo hydrolysis at the ester linkage.

5.1.4 Residues of Concern Summary and Rationale

The residues of concern in plants and livestock for both risk assessment and tolerance
enforcement are cis

- , trans

- , and alpha

- R deltamethrin. These same three isomers are the
residues of concern for risk assessment in drinking water.

T able 5 .1

. 4. Summary of Deltamethrin Metabolites and Degradates to be Included in Risk

Assessment and the Tolerance Expression.

Matrix Residues in Risk Assessment Residues in the Tolerance Expression

Plants Primary crops Cis

- , trans

- and alpha

- R

- deltamethrin Cis

- , trans

- and alpha

- R

- deltamethrin

Rotational crops Not Applicable Not A pplicable

Livestock Ruminants Cis

- , trans

- and alpha

- R

- deltamethrin Cis

- , trans

- and alpha

- R

- deltamethrin

Poultry Drinking water Cis

- , trans

- and alpha

- R

- deltamethrin Not A pplicable

5 .2 Food Residue Profile

Bayer conducted mosquito adulticide residue trials in accordance with a protocol that was previously approved by HED’s Chemistry Science Advisory Council (ChemSAC) and submitted a report of the results (MRID 49114112). Residue results are supported by adequate storage

st ability and analytical method data. Residues were below 0.05 ppm in all samples of leaf lettuce treated at both the 1x and 1⁄2x rate. In grass forage, residues ranged up to 0.087 ppm in samples treated at a 1x rate. In alfalfa forage, residues ranged up t o 0.070 ppm in samples treated at a 1x rate. Residues in alfalfa hay and grass hay are not being considered for tolerance

- setting purposes for crops because hay is a dried commodity. In all trials, residues increased with an
increase in the number of tre atments.

HED notes that the residue trials were conducted using grass, alfalfa

, and lettuce as representative crops reflecting the potential for residues if crops are directly treated with the mosquito adulticide ; however, in general, r esidential areas ar e the areas being intentionally treated, and the potential for drift onto growing crops is fairly low based on the Biological and Economic Analysis Division’s (BEAD) estimate of 1% crop treated for all crops for the mosquito adulti cide use. Therefore

, alt hough there were some residues slightly above the recommended tolerance of 0.05 ppm, HED considers this tolerance to be protective of residues that will be found when the mosquito adulti cide is used in accordance with the label recommendations (e.g., maxim um single application rate, a maximum of 10 applications, and a
3

- day re

- treatment interval).Deltamethrin Human Health Risk Assessment DP No. D417556

Page 31 of 67 5.3 Water Residue Profile

EFED assess ed the proposed adulticide use of deltamethrin (D417559, J. Melendez, 10/9/2014)

, and determined that the previous drinkin g water assessment, dated April 24, 2007 could be used to cover the proposed use because the surface water estimated drinking water concentrations ( EDWCs ) calculated for the adulticide use using the Surface Water Concentration Calculator (SWCC), were lower than the values previously determined (D335136, J. Melendez, 4/24/2007). Furthermore, the groundwater values are at the limit of solubility of 0.2 ppb. EFED determined
that there was no need to conduct a PRZM

- GW assessment.

For the 2007 assessment, E FED calculated the EDWCs based on a maximum application rate of 0.45 lb a.i./A/season. EFED determined the groundwater concentrations using the Screening Concentration in Groundwater (SCIGROW) Model and the surface water concentrations using the FQPA Inde x Reservoir Screening Tool (FIRST) Model. The acute drinking water concentration in surface water is 0.20 ppb. It was based on applications of the chemical to sweet corn. The cancer/chronic EDWC is 0.0771 ppb (based on applications to sweet corn, with t he highest application rate). The SCIGROW Model for groundwater generated an EDWC of 0.200 ppb. This value is the same as the surface water value and was recommended for use both for acute and chronic exposures. Both the acute surface drinking water con centration and the ground drinking water concentration were limited by the solubility of deltamethrin.

5.4 Dietary Risk Assessment

Acute and chronic dietary (food and drinking water) exposure assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID) Version 3.16 . This software uses 2003

- 2008 food consumption da ta from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey,
What We E at in America, (NHANES/WWEIA). The chronic assessment was conducted solely for the purpose of obtaining estimates of background levels of diet ary exposure for estimating aggregate risk.

Overall, because of the low estimate of 1% of all crops treated (PCT) for the wide

- area mosquito
adulti cide, as well as the low residue level of 0.05 ppm (i.e., the same as the food handling
establishment tolera nce), the dietary exposure estimates did not increase significantly compared to those recently provided in conjunction with the tolerance established for residues in fish (without a US registration)

.

5.4.1 Description of Residue Data Used in Dietary Asses sment

The acute and chronic dietary exposure assessments are partially refined. In the acute assessment, residues could result from two different sources: agricultural uses and adulticide uses. In the chronic assessment, residues could result from thre e different sources: agricultural uses, FHE uses, and adulticide uses. In the assessments, residue inputs consisted of a combination of tolerance level residues, monitoring data, mosquito adulticide residue values, and
FHE residue values. The residue in put files included both plant and livestock commodities.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 32 of 67 Detailed discussions of the residue values can be found in the dietary exposure memo prepared in support of this risk assessment (D423638, D. Dotson, 12 / 4 /2014 ). Conservative inputs were
used in bo th the acute and chronic assessments , including the assumption that drinking water residues would be present at the limit of solubility of deltamethrin . As a result, HED has not underestimate d exposure.

Acute Assessment

In the acute assessment, tolerance level residues were used for most commodities. Distributions of monitoring data were used for a number of commodities including carrots, carrot babyfood, soybeans, tomatoes, cantaloupes, watermelons, cucumbers, apples, a pple juice, apple sauce babyfood, pears, pear babyfood, cereal grains, and milk. To account for the adulticide use, a
distribution of the residue values from the adulticide trial was used. The residue values were modified by maximum %CT estimates provide d by BEAD (for blended commodities) or were included in a distribution considering the %CT estimate

. Additional information regarding %CT estimates is provided below. The data for the various commodities in the assessment were
entered into the residue in put file as indicated in T able 5.4.1

. a

. That is, if the commodity would only have a residue as a r esult of the adulticide use, then a n adulti cide residue value was used; however if the commodity could have residues from both agricultural uses and the adul t icide, this possibility was addressed in the analysis. Essentially, for the situation in which residues could occur from both sources, the DEEM M odel sampled the agricultural distribution 99% of the time, and the adulti cide distribution only 1% of the ti me. The limit of solubility of
deltamethrin in water w as used as a point estimate for drinking water. DEEM

- FCID Version 7.81 default processing factors were used for some processed commodities and empirical factors
were used for others.

Table 5.4.1.a

. Summary of Treatment of Data Used in Acute Assessment

. Type of Commodity Established

Tolerance/No
Tolerance Tolerance/PDP

Used Blending

Classification Data Used

Plant Tolerance Tolerance

- Tol + Mosq
Plant Tolerance PDP NB/PB PDP + Mosq
Plant Tolerance PDP Blended Avg PDP + Mosq
Plant Tolerance PDP for RAC Blended Avg PDP for RAC based on Max %CT + Mosq
Plant No Tolerance

- - Mosq
Livestock Tolerance Tolerance

- Tol
Livestock (Milk Only ) No Tolerance PDP

- PDP

Chronic Assessment

In the chronic assessment, tolerance level residues were used for most commodities. The average PDP value was used for cereal grains and milk. The average mosquito adulticide residue
value was used to account for the adulticide uses and 1⁄2 the FHE toleran ce was used to account for the FHE uses. The residue values were modified by %CT estimates provided by BEAD, as
discussed in the %CT information section below. The data for the various commodities in theDeltamethrin Human Health Risk Assessment DP No. D417556

Page 33 of 67 assessment were entered into the residue input fil e using the approach described in Table 5.4.1

. b

. The limit of solubility in water for deltamethrin was used in the dietary assessment . T his value is
considered to be conservative. DEEM

- FCID Version 7.81 default processing factors were used for some proc essed commodities and empirical factors were used for others.

Table 5.4.1.b . Summary of Treatment of Data Used in Chronic Assessment

. Type of Commodity Established

Tolerance/No
Tolerance Tolerance/PDP

Used %CT

Estimate Used Data Used

Plant Tolerance Tolerance 100% Tol + Mosq
Plant Tolerance Tolerance Estimate (Tol x %CT) + Mosq.
Plant Tolerance PDP

- Avg PDP + Mosq
Plant No Tolerance

- - FHE + Mosq
Livestock Tolerance Tolerance

- Tolerance
Livestock (Milk Only ) Tolerance PDP

- Avg PDP

Livestock No Tolerance

- - FHE + Mosq

Cancer Assessment

C ancer risk is not of concern for deltam ethrin because the compound is classified as “not likely to be carcinogenic to humans. ”

5.4.2 Percent Crop Treated Used in Dietary Assessment

As noted above, i n the acute and chronic assessments, the mosquito adulticide %CT estimate of
1% was used. Residues from the adulticide use were included for all commodities with the exception of livestock commodities. Additional %CT information is as follows:

Acute Asses sment

The following maximum percent crop treated estimates (SLUA, 5/5/2014, BEAD Usage and Label Use Team) were used in the acute dietary risk assessment for crops that are currently registered for deltamethrin:

Crops with an assumption of 2.5% CT: apples

, cantaloupes

, carrots

, soybeans

, tomatoes , and
watermelons

.

Crops with an assumption of 5% CT: cucumbers and pears.

Chronic Assessment

The following average percent crop treated estimates were used in the chronic dietary risk
assessment for cr ops that are currently registered for deltamethrin:

Crops with an assumption of 1% CT: apples

, cantaloupes

, carrots

, cotton

, potatoes (some food forms), pumpkins

, radishes

, squash

, tomatoes

, turnips

, and watermelon s

.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 34 of 67 Crops with an assumption of 2.5% CT: cucumbers

, leeks

, onions

, pears , and sunflowers.

Crops with an assumption of 4.65% CT (i.e., with residues resulting only from the FHE use) : almonds, pistachios, potatoes (some food forms), soybeans, sweet corn, and walnuts.

Crops with an assumpti on of 5% CT: canola and peppers.

Finally, BEAD estimated 40% CT for globe artichokes

.

BEAD provided an estimate of a 4.65% probability that a food a person consumes contains residues as a result of treatment in an FHE at some point with any pesticide (i.e., i t is not specific

to deltam ethrin )

. In the chronic assessment, for the commodities for which 1⁄2 the FHE tolerance was used, the assumption was made that there was a 4.65% chance that a food item consumed by a person contained deltamethrin residues as a result of treatment at some point in an FHE.

5.4.3 Acute Dietary Risk Assessment

The acute dietary risk estimates are below HED’s LOC for all population subgroups, including those comprised of infants and children. Generally, HED is concerned when risk estimates exceed 100% of the population

- adjusted dose (PAD). The acute dietary risk estimate for the general U.S. population is 1 8 % of the aPAD. The population subgroup with the highest acute dietary risk estimate is Children 3

- 5 years old , which uses 8 1 % of the aPAD. As percent crop treated estimates were used for some commodities, the risk estimates are being reported at the
99.9 th percentile of exposure. The dietary assessment is conservative, even though monitoring
data were used, because it is based on the use of (1) some tolerance level data, (2) a conservative approach to estimating residues that coul d result from FHE uses

, (3) the use of upper bound %CT estimates, and (4) the limit of solubility as an estimate of deltamethrin residues in d rinking

water

.

The acute dietary exposure estimates increased slightly for all population subgroups as a result of the inclusion of residues from the adulticide applications. Residues in the adulticide trials were low and the %CT estimate was also low (1%). For these r easons, the results demonstrated that the use of deltamethrin as a mosquito adulticide will make a n in significant contribution to the

acute dietary risk associated with the chemical.

5.4.4 Chronic Dietary Exposure Assessment

The chronic dietary exposure estimate for the general U.S. population is 0.000 25 9 mg/kg/day. The population subgroup with the highest chronic dietary exposure estimate is Children 1

- 2 years old , which has a dietary exposure estimate of 0.000 8 46 mg/kg/day.

As with the acute dietary exposure estimates, the chronic dietary exposure estimates increased slightly for all population subgroups as a result of the inclusion of residues from the adulticide applications. Again, the results demonstrated that the use of deltamethrin as a mosquit o adulticide will make a n in significant contribution to the dietary risk associated with the chemical.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 35 of 67 5.4. 5 Summary Table

Table 5.4. 5. Summary of the Acute and Chronic Dietary Exposure and Risk Estimates for

Deltamethrin

. Population Subgroup Acute Assessment (99.9 th Percentile) Chronic Assessment aPAD, mg/kg/day Exposure Estimate,

mg/kg/day % aPAD cPAD Exposure Estimate, mg/kg/day % cPAD

U.S. Population 0.0149 0.00 2614 18 NA 0.000259

NA All infants 0.005 0. 003421 68 NA 0.000308
Children 1

- 2 yrs* 0.005 0.004071 81 NA 0.000846
Children 3

- 5 yrs 0.005 0.003998 80 NA 0.000618
Children 6

- 12 yrs 0.0149 0.00 2372 16 NA 0.000386
Youth 13

- 19 yrs 0.0149 0.00 1701 11 NA 0.000211
Adults 20

- 49 yrs 0.0149 0.0 02210 15 NA 0.000198
Adults 50

- 99 yrs 0.0149 0.00 1719 12 NA 0.000214
Females 13

- 49 yrs 0.0149 0.00 2669 18 NA 0.000195 *Most highly exposed population subgroup s

6.0 Residential Exposure and R isk Estimates

There are no residential handler exposure scenarios associated with the proposed mosquito control use as applications are to be made by f ederal, s tate, t ribal or local g overnment o fficials as
well as the U.S. m ilitary. However, there is potential for resi dential post

- application exposure
associated with the proposed wide

- area mosquito and fly control use

. This document provides residential handler and post

- application exposure assessment s for existing residential indoor, outdoor, pet, and paint preservative uses for the purpose of updating the aggregate human health
risk assessment. This assessment reflects updates to HED’s 2012 Residential SOPs 1 , along with policy changes for body weigh t assumptions, updated inhalation and incidental oral toxicological endpoints and doses, and reduced FQPA Safety Factors for adult and children’s populations.

6.1. Proposed Use: Wide

- Area Mosquito Control

There are residential post

- application exposure scenarios associated with the proposed mosquito and fly control use

, as applications are to be made in residential, urban, recreational, and other areas where adult mosquitoes and flies are found. Since the proposed label did not specify where
the militar y would be applying this product for control of sand flies, all post

- application risk estimates were based on the highest application rate of 0.0018 lb ai/acre to be protective of all potential scenarios for adults and children.

To calculate post

- application exposure from ULV truck fogger applications, HED used the 2012 Residential SOPs for Outdoor Fogging/Misting Systems, with minimal modification to the well

mixed box (WMB) model. The WMB model allows for the estimation of inhalation exposu re in the breathing zones of adults and children residing in areas being treated by ground application

1 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.htmlDeltamethrin Human Health Risk Assessment DP No. D417556

Page 36 of 67 of deltamethrin. This methodology is a modification of the previous method used in assessing
post

- application inhalation exposure resulting from a truck mounted mosquito fogger. The revised methodology more accurately accounts for dilution using the WMB model. The quantitative risk assessment for residential post

- application exposures is based on the following
scenarios:

 Post

- application inhalation e xposure resulting from ULV truck fogger mosquito and fly applications

, and

,

 Incidental oral (hand

- to

- mouth) contact with residues deposited on lawn/turf resulting from liquid formulations from ULV truck fogger mosquito and fly applications.

The lifestages selected for each post

- application scenario are based on an analysis provided as an Appendix in the 2012 Residential SOPs 2 . The assessment of the lifestages provided in this document is protective for the exposure and risk estimates of all other lifestag es with potential

exposure.

The data and assumptions, as well as detailed algorithms/calculations used to derive post

application exposure from use of a truck fogger are described in detail in the occupational and residential exposure assessment for the p roposed mosquito adulti cide use ( D417525

, M. Collantes, 12/18/2014 ).

All post

- application inhalation and incidental oral exposure estimates f o r the mosquito control scenarios resulted in MOEs greater than their respective LOCs and are not of concern. Tab le

6 .1.a provides a summary of the post

- application inhalation risk estimates and Table 6 .1.b provides a summary of the incidental oral risk estimates resulting from ground ( truck fogger) applications of deltamethrin.

Table 6 .1.a. Post

- application Inhalation Exposure & Risk Estimates from Wide

- area Mosquito

Adulticide Use.
Life Stage Application

Rate 1 Inhalation

Rate 2 (m 3 /hr) Q 3

(m 3 /hr) Exposure 4

(mg/day) Dose 5

(mg/kg/day) Inhalation

MOE 6

Adult 7.5

mg ai/day 0.64 5400 0.00089 0.000011 130,000
Child 0.33 0.00046 0.0000417 36,000

1. Application Rate scaled to WMB (see Appendix E of M. Collantes, D417525 ) = (0.0018 lb ai/A x 454 g/lb x 1000mg/g)/(43,560 ft 2 /400 ft 2 ) = 7.5 mg ai/day.
2. Inhalation Rate = Residential SOPs.
3. Q = Airflow through treated area (5400 m 3 /hr).
4. Exposure (mg/day) = AR (mg ai/day) x IR (m 3 /hr)/ Q (m 3 /hr).
5. Inhalation Dose (mg/kg/day) = Exposure (mg/day)/BW (kg).

6. Inhalation MOE = BMDL (1.49 mg/kg/day) /Inhalation Dose (mg/kg/day); Adults and childr en > 6 yrs LOC = 100; Children < 6 yrs LOC = 300.

2 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.htmlDeltamethrin Human Health Risk Assessment DP No. D417556

Page 37 of 67 Table 6 .1.b. Incidental Oral Exposure Estimates Resulting from BES0668 Insecticide.

Use/Scenario Application Rate (lb ai/A) Hand Residue a

(mg/ m 2 ) Incidental Oral

Dose b (mg/kg/day) Incidental

Oral MOE c

Truck mounted ULV fogger,
Ground and Hand Held Equipment 0.0018 0.0000001 0.000001 2,700,000

a. Hand Residue = ( See Appendix B of M. Collantes, D417525 ).

b. Incidental Oral Dose (mg/kg/day) = [HR * ( F M * SA H ) * (ET * N_Replen) * (1

- (1

- SE ) (Freq_HtM/N

- Replen) )].

c. Incidental Oral MOE = NOAEL (1.49 mg/kg/day)/Incidental Oral Dose (mg/kg/day) ; LOC = MOE ≥ 300.

6. 2 Residential Handler Exposure/Risk Estimates for Registered Uses

A residential handler exposure assessment was previousl y performed for existing residential indoor, outdoor, turf, pet, and paint uses (D418867, M. Collantes, 6/11/2014) , and the resulting scenarios and MOEs are still considered appropriate for the purpose of conducting an aggregate
risk assessment.

Summary o f Registered Residential Handler Exposure and Risk Estimates

Representative (worst case) registered residential uses were previously assessed using the 2012 Residential SOPs and revised inhalation endpoints and doses. All residential handler scenarios

re sulted in inhalation risk estimates greater than the LOC (MOEs ≥ 100) and are not of concern. The lowest MOE of 4,300 was associated with the use of a backpack sprayer to treat lawns with a wettable powder formulation. The exposure estimates are summariz ed for the worst

- case representative residential handler exposure scenario for each registered product in Table 6

. 2

.

Table 6 .2. Residential Handler Exposure and Risk Estimates for Deltamethrin Registered

Uses

.

Exposure Scenario Level of
Concern Inhalation

Unit Exposure (mg/lb ai) Maximum

Application
Rate 1 Area Treated or

Amount Handled Daily 2 Inhalation

Dose (mg/kg/day) 3 MOE 4

Mix/Load/Apply
Manually Pressurized
Handwand for Indoor Crack &
Crevice and Mattress
Treatment

K

- Othrine SC Insecticide (4.75% ai) Reg. No.432

- 763 100 1.1 0.005 lb ai/gal 0.5 gals 0.000034 43,000

Hose

- end Sprayer

– Turf

K

- Othrine SC Insecticide (4.75% ai) Reg. No.432

- 763 0.022 0.13 lb ai /A 0.5 A 0.000018 83,000Deltamethrin Human Health Risk Assessment DP No. D417556

Page 38 of 67 Table 6 .2. Residential Handler Exposure and Risk Estimates for Deltamethrin Registered

Uses

.

Exposure Scenario Level of
Concern Inhalation

Unit Exposure (mg/lb ai) Maximum

Application
Rate 1 Area Treated or

Amount Handled Daily 2 Inhalation

Dose (mg/kg/day) 3 MOE 4

Back Pack

- Garden and Trees

K

- Othrine SC Insecticide (4.75% ai) Reg. No.432

- 763 0.14 0.005 lb ai/gal 5 gals 0.000044 34,000

Manually Pressurized Handwand and Backpack

– Lawn/Turf and Gardens/Trees

Delta Wettable Powder
(5% ai) Reg. No. 432

- 832 1.1 0.005 lb ai/gal 5 gals 0.00034 4,300

Airless Sprayer Bug Juice Insecticidal Additive (4.75% ai) Reg. No. 47332

- 11 0.56 0.005 lb ai/gal/can 5 one gal cans 0.00018 8,500

Load/Apply Belly Grinder
Delta Granules (0.1% ai) Reg. No. 4

- 422 100 0.039 0.000003

lb ai/ft 2 1200 ft 2 0.0000018 850,000

Apply

Shaker Can

– Garden/Trees
Many Purpose Dust RTU (0.05% ai) Reg. No. 73327

- 14

100 18 0.00000066

lb ai/ft 2 1200 ft 2 0.00018 8,400

Aerosol Spray

– Garden/Trees

D

- Force Insecticide
(0.06% ai) Reg. No. 279

- 9554

3 0.00075

lb ai/can 2 cans 0.000056 26,000

Aerosol Spray

– Indoor Crack & Crevice and
Mattress

D

- Force Insecticide
(0.06% ai) Reg. No. 279

- 9554 0.5 can 0.000014 110,000

Ready

- to

- Use Pet Collar
(4% ai) Reg. No. 4

- 422 negligible 0.0024 lb ai/pet 2 pet s NA

1 Based on registered labels.
2 Based on HED’s 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html ).
3 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Applic ation Rate × Area Treated or Amount Handled ÷ Body Weight (80 kg).
4 Inhalation MOE = Inhalation NOAEL (1.49 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).Deltamethrin Human Health Risk Assessment DP No. D417556

Page 39 of 67 6. 3 Residential Post

- application Exposure/Risk Estimates for Registered Uses

A residential post

- appl ication exposure assessment was previously performed for existing residential indoor, outdoor, lawn, pet

, and paint uses (D418867, M. Collantes, 6/11/2014). Risk estimates for these registered residential scenarios have been revised to reflect updates to HED’s
2012 Residential SOPs 3 , along with policy changes for body weight assumptions and updated toxicological endpoints.

Summary of Residential Post

- application Non

- Cancer Exposure and Risk Estimates

Systemic toxicity via the dermal route of exposure i s not anticipated. No treatment

- related findings were observed at the limit dose; therefore, a dermal point of departure (POD) was not selected and a post

- application dermal exposure assessment is not required. Furthermore, post

application inhalation ex posure for adults and children is anticipated to be negligible for representative residential registered uses; therefore, a quantitative post

- application inhalation exposure assessment was not performed. All the representative indoor/outdoor and pet
incid ental oral (hand

- to

- mouth) post

- application scenarios resulted in risk estimates ranging from
an MOE of 630 (for incidental oral exposure following treatment of mattresses for bedbugs) to 24,000 and are not of concern. A summary of the registered resident ial post

- application exposure and risk estimates for deltamethrin is provided in Table 6

. 3

.

Table 6

. 3 . Registered Residential Post

- application Non

- cancer Exposure and Risk

Estimates for Deltamethrin.

Lifestage Post

- application Exposure Scenario Application
Rate 1 Dose

(mg/kg/day) 2 MOEs 3 Combined MOEs Use Site Route of

Exposure

Adult Indoor C&C

K

- Othrine SC
Insecticide Reg. No.432

- 763 (0.06% ai) Dermal

0.005 lb ai/ gal NA NA

NA Inhalation

Child Dermal NA NA Inhalation

HTM 0.0000614 24,000

OTM 0.000039 38,000

Adult

Indoor C&C and

Mattress

D

- Force Ready

- to

- Use Aerosol Spray Reg. No.
279

- 9554 Dermal

0.00075 lb
ai/can NA NA Dermal Mattress

Inhalation

Child Dermal

NA NA Dermal Mattress

Inhalation

HTM 0.0023 630

OTM 0.00031 4700

Adult

Lawn/Turf Delta

Granules Reg. No.

4

- 422 Dermal

0.13 lb ai/A

or 0.000003 lb
ai/ft 2 NA NA

NA Inhalation

Child Dermal NA NA Inhalation

HTM 0.0002 7,600

OTM 0.00001 120,000 Soil Ingestion 0.000044 340,000

3 Available: http://www.ep a.gov/pesticides/science/residential

- exposure

- sop.htmlDeltamethrin Human Health Risk Assessment DP No. D417556

Page 40 of 67 Table 6

. 3 . Registered Residential Post

- application Non

- cancer Exposure and Risk

Estimates for Deltamethrin.

Lifestage Post

- application Exposure Scenario Application
Rate 1 Dose

(mg/kg/day) 2 MOEs 3 Combined MOEs Use Site Route of

Exposure Episodic Ingestion 0.0127 120

Adult

Lawn/Turf

K

- Othrine SC
Insecticide Reg. No.432

- 763 (0.06% ai) (using default TTR value) Dermal

0.13 lb ai/A NA NA

Inhalation

Child Dermal NA NA

Inhalation

HTM 0.0020 750

OTM 0.00006 25,000 Soil Ingestion 0.000034 340,000

Adult

4% Deltamethrin

Pet Collar (Reg. No. 68451

- 1) Dermal

0.0024 lb ai/pet NA NA Inhalation

Child Dermal NA NA Inhalation

HTM (small dog) 0.000014 11,000

HTM (medium size dog) 0.0000058 26,000

HTM (large dog) 0.0000037 400,000

1 Based on registered label.
2 Dose (mg/kg/day) equations: see Appendixes B

- D for specific equations used by exposure scenario.
3 MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day).
4. HTM = Hand

- to

- Mouth ; OTM = Object

- to

- Mouth

Turf Transferable Residue (TTR) Data

T he estimated residential turf post

- application exposure using the default TTR value for deltamethrin is not minimal in comparison to the level of concern (i.e., the calculated MOE is not greater than 10 times the level of concern, MOE = 750 compared to the LOC of 300). F uture refinements of this post

- application exposure for deltamethrin may be necessary due to increased
use of deltame thrin or advances in EPA risk assessments. Therefore, EPA is requiring TTR data
in accordance with 40CFR Part 158 to facilitate any necessary exposure assessment refinement s and to further EPA’s general understanding of the availability of turf transferable pesticide
residues.

Episodic Granular Ingestion

The default granular ingestion rate of 0.3 grams/day was adjusted to 0.14 grams/day (1/10 of the product) to reflect the amount of product applied on a per area basis (3 lb/1000ft 2 ) as explained in the Residential SOP for Turf and Lawns. The reduction in ingestion rate resulted in an estimated dose of 0.0127 mg/kg/day and a n MOE of 120

, which is below the LOC for incidentalDeltamethrin Human Health Risk Assessment DP No. D417556

Page 41 of 67 ingestion of granules. In order to achieve an MOE greater than the LOC (MOE ≥ 300) based on amount of product applied per area, the application rate would need to be reduced from the
current rate of 0.000003 lb ai/ft 2 to 0.000001 lb ai/ft 2 . However, ing estion of granules is considered an episodic (or acute) event and not a routine behavior for children. Since HED does not believe that this would occur on a regular basis, the scenario is considered to be an acute poisoning rather than a short

- term exposu re typically assessed in HED’s human health risk assessments. Furthermore, the registered label instructs the user to thoroughly water treated areas after application so that both granules and lawns are moistened to ensure granules dissolve properly.

6. 4 Residential Risk Estimates for Use in Aggregate Assessment

The recommended residential exposure for the use in the adult aggregate assessment reflects the inhalation handler exposure resulting from the flea control scenario (i.e., treatment of lawns/tu rf and gardens/trees by manually pressurized handgun and backpack). This scenario resulted in a n MOE of 4,300 and is not of concern.

The incidental oral (hand

- to

- mouth) post

- application exposure resulting from control of bed bugs
scenario was selected to estimate aggregate exposure for child ren . This scenario resulted in a n MOE of 630 and is not of concern. A summary of the residential risk estimates for use in the
aggregate assessment is provided in Table 6

. 4

.

Table 6

. 4. Recommendation for the Resi dential Exposure to be U sed in the Deltamethrin

Aggregate Assessment.

Lifestage Exposure

Scenario Dose (mg/kg/day) 1 MOE 2

Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Adult
Male Back Pack

– Garden
and Trees NA 0.00034 N/A NA NA 4,300 N/A NA

Child Bed Bug

Scenario (Indoor) NA 0.0023 NA NA NA 630 NA

1 Dose = the highest dose for each applicable lifestage of all residential scenarios assessed. Total = dermal + inhalation + i ncidental oral (where applicable).
2 MOE = the MOEs associated with the highest residential doses. Total = 1 ÷ (1/Dermal MOE) + (1/Inhalation MOE) + (1/Incidental Oral MOE), where applicable.

6. 5 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for deltamethrin

. The A gency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data
Call

- In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray dri ft management practices (see the A gency’s SprayDeltamethrin Human Health Risk Assessment DP No. D417556

Page 42 of 67 Drift website for more information) 4

. The A gency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk assessments for pesticides.

This product may be applied over any and all crops or agricultural areas, (including row, tree, fruit, citrus, pasture, rangeland, and other areas where agricultural enterprises take place) for the control of adult mosquitoes within or adjacent to the treatment areas, or to areas where drift over cropland could occur.

The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently. T he approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs)

- Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantifi cation
of indirect non

- occupational exposure to drift.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risk
estimate s from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risk estimate s themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

7.1 Acute Aggregate Risk

A cute aggregate risk for deltam ethrin r esult s from exposure to residues in food and drinking water alone. The acute dietary exposure analysis included both food and drinking water ;

t herefore, acute aggregate risk estimates are equivalent to the acute dietary risk estimates

, as discussed in Section 5.4.3, above. Acute aggregate risk is not of concern for the general U.S. population or any popul ation subgroup

.

7.2 Short

- Term Aggregate Risk Estimates

S hort

- term aggregate risk assessments are needed for adults and children

. For the short

- term aggregate assessment for adults, residential handler inhalation exposure needs to be combined with background exposure from food and water. For the short

- term aggregate assessment for
children

, post

- application incidental oral exposure (i.e., hand to mouth transfer ) need s to be combined with background exposure from food and w ater. The chronic dietary exposure estimates serve as the background dietary exposure. Of the population subgroups comprised of adults, the U.S. population has the highest dietary exposure estimate. Of the population subgroups comprised of infants and c hildren, the subgroup with the highest dietary exposure
estimate is Children 1

- 2 years old. As the oral and inhalation endpoints and points of departure are the same, the exposures for both adults and children can be added to determine the total

4 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmDeltamethrin Human Health Risk Assessment DP No. D417556

Page 43 of 67 exposure. The LOC for adult populations is 100. The MOE s for the general U.S. population and
Females 13

- 49 are 2, 5 00 and 2, 8 00

, respectively . These MOEs are not of concern. The LOC for
children < 6 years old is 300. The MOE for Children 1

- 2 years old is 5 3 0 an d is not of concern. A summary of the aggregate risk estimates is provided in Table 7.2.

Table 7.2

. Short

- Term Aggregate Risk Calculations

.

Population Short

- Term Scenario

BMDL 1SD mg/kg/day LOC 1 Max
Allowable Exposure 2 mg/kg/day Average Food

and Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Tota l

Exposure mg/kg/day 4 Aggregate

MOE (food, water, and residential) 5 U.S. Population 1.49 100 0.0149 0.000 25 9 0.00034 0.000 59 9 2, 5 00
Females 13

- 49 1.49 100 0.0149 0.000 19 5 0.00034 0.000 53 5 2, 8 00
Child ren 1

- 2 1.49 300 0.005 0.000 8 46 0.002 0.002 822 5 2 0

1 An UF of 100x was applied to adults to account for interspecies extrapolation (10x) and intraspecies variation (10x). No additional uncertainty factors/safety factors are required for adults.
An F QPA Safety Factor of 3 x was applied to children <6 years of age

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

. 3 Residential Exposure = Oral exposure (children) or Inhalation Exposure (adults)

. See Table 6.3 for residential exposure estimates.

4 Total Exposure = Avg Food & Water Exposure + Residential Exposure

. 5 Aggregate MOE = BMDL 1SD (1.49 mg/kg/day) ÷ (Avg Food & Water Exposure + Residential Exposure)

.

8. 0 Cumulative Exposure/Risk Characterization

The Agency is required to consider the cum ulative risks of chemicals sharing a common mechanism of toxicity. The Agency has determined that the pyrethroids and pyrethrins 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 published on 11/9/2011 and is available at http://www.regulations.gov ; EPA

- HQ

OPP

- 2011

- 0746. No cumulative risks of concern were identified

, allowing the Agency to consider new uses for pyrethroid s . For information regarding EPA’s efforts to evaluate the risk of exposure to this class of chemicals , refer to : http://www.epa.gov/oppsrrd1/reevaluation/pyrethroids

- pyre thrins.html

.

Deltam e thrin is included in the pyrethroid/pyrethrin cumulative risk assessment (CRA) . The proposed use of deltamethrin as a mosquito adulticide ha s an insignificant impact on the CRA

. No dietary, residential, or aggregate risk estimates of concern have been identified in the single chemical assessment. In the cumulative assessment, residential exposure was the greatest contributor to the total exposure . A lthough there are residential uses for deltam ethrin

, the proposed wide

- a rea mosquito adulticide use will have no impact on the residential component of
the cumulative risk estimates

. In order to determine if the registered deltamethrin indoor and turf

uses will significantly contribute to or change the overall findings in the pyrethroid CRA

, the Agency performed a quantitative exposure and risk assessment. This assessment used the
deltamethrin relative potency factor ( RPF ) as well as the same exposure algo rithms and inputs that were used in the 2011 pyrethroid CRA.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 44 of 67 MOEs calculated and presented in Appendix Table A .2 of the 2011 pyrethroid CRA were compared with the MOEs currently driving turf and indoor crack and crevice exposures and risks
in Table 6.4.7a from the pyrethroid CRA

. Adult handler exposures and risk estimates are currently driven by cyfluthrin turf use (i.e. mixing/loading/applying via hose

- end sprayer) with a dermal MOE of 9,200 and combined (dermal + inhalation) MOE of 8,900, which are lower than the estimated deltamethrin dermal MOE of 15,000 and combined MOE of 500,000. Adult and child dermal post

- application exposure and risk s are also currently driven by cyfluthrin turf use with an MOE of 4,500 and 3,000 respectively. For children < 6 ye ar s old, hand

- to

- mouth post

application exposure and risk estimates are currently driven by the cy halothrin indoor crack and
crevice use with an MOE of 9,7 00, which is lower than the estimated deltamethrin MOE o f 16,0 00. A summary of these MOEs is present ed in Appendix Table A .2

, while the detailed
calculations for deltamethrin are presented in Appendix Table A .3. In all cases, the estimated
deltamethrin MOEs using the RPF method were higher (i.e., less of a risk concern) than those used in the 2011 pyret hroid CRA. Thus

, the Agency continues to support the previous

assessment

, and concludes that the registered deltamethrin use s will not significantly contribute to the overall findings in the 2011 pyrethroid CRA.

D ietary exposures make a minor contribution to the total pyrethroid exposure. The dietary exposure assessment performed in support of the pyrethroid cumulative was much more highly refined than that performed for the single chemical. In addition, f or the deltam e thrin risk
assessment, the most sensitive apical endpoint in the deltam e thrin database was selected to derive the POD. Additionally, the POD selected for deltam e thrin is specific to deltame thrin

, whereas the POD selected for the cumulative assessment was based on common mechani sm of action data that are appropriate for all 20 pyrethroids included in the cumulative assessment. Dietary exposure to deltame thrin residues resulting from the proposed wide

- area mosquito
adulticide use will contribute very little to the dietary exposur e to deltame thrin alone. As a result, the proposed tolerance will make an insignificant contribution to dietary risk to the pyrethroids as a whole.

9.0 Occupational Exposure/Risk Characterization

9 .1 Occupational Handler Exposure/Risk Estimates

Based on the anticipated use patterns and current labeling, types of equipment

, and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for occupational h andlers is based on the following scenarios:

 Mixer/loader ULV mosquito and fly control via groundboom (surrogate for truck mounted fogger) for residential, agricultural, industrial, poultry and livestock facilities,

 Mixer/loader ULV mosquito and fly con trol via airblast (surrogate for truck mounted fogger), for residential, agricultural, industrial, poultry and livestock facilities , and

 Applying ULV mosquito and fly control via airblast (surrogate for truck mounted fogger) for residential, agricultural, industrial, poultry and livestock facilities.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 45 of 67 Summary of Occupational Handler Exposure and Risk Estimates Occupational handler scenarios associated with truck mounted fogger applications resulted in inhalation MOEs greater than the LOC (inhalation MOE ≥ 1 00) at baseline (single layer clothing, no gloves or respirator) and are not of concern. A summary of the occupational handler risk estimates is provided in Table 9 .1.

Table 9.1

. Occupational Handler Exposure Risk Estimates for Deltamethrin.

Exposure
Scenario Crop or

Target Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Applica

tion Rate 2 (lb ai/A) Area

Treated or
Amount
Handled Daily 3 Inhalation

Mitigation
Level Dose (mg/kg/day) 4 MOE 5

Mixer/Loader Airlbast (surrogate
for Truck Mounted Ground fogger) Mosquito and

Fly Control in Residential,
Industrial and Agricultural
Areas 0.219

Baseline 0.0018

3

, 000 A 0.0000148 100,000 Groundboom (surrogate for Truck
Mounted Ground fogger) Airblast(surrogate
for Truck Mounted Ground fogger) Poultry and

Livestock
Facilities 0.219

Baseline 0.00134 0.000011 140,000 Groundboom (surrogate for Truck
Mounted Ground fogger) Applicator

Airblast (surrogate
for Truck Mounted Ground fogger) Mosquito and

Fly Control in Residential,
Industrial and Agricultural
Areas 4.71 Baseline 0.0018

3

, 000 A 0.000318 4,700

Groundboom (surrogate for Truck
Mounted Ground fogger) Poultry and

Livestock
Facilities 0.34

Baseline

0.00134 0.000017 87,000

Airblast (surrogate for Truck
Mounted Ground fogger) 4.71
Baseline 0.000236 6,300

Mixer/Loader/Applicator Manually
Pressurized
Handwand Poultry and

Livestock Facility 30
0.000045 lb ai/gal 40 gals 0.00000067 2

, 200,000

Mechanically
Pressurized
Handwand 3.9 1

, 000 gals 0.0000022 680,000

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”; Level of mitigation: Baseline, PPE, Eng ineering Controls.
2 Based on the proposed use.
3 Exposure Science Advisory Council Policy #9.1.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 46 of 67 4 Inhalation Dose = Inhalation Unit Exposures (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (0.0018 lb ai/acre) × Area Treated or Amount Handled (A) ÷ BW (80 kg).
5 Inhalation MOE = Inhalation BMDL (1.49 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

9 .2 Occupational Post

- app lication Risk Estimates

9 .2.1 Occupational Post

- application Inhalation Risk Estimates

There are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The A gency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, F ungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The A gency has evaluated the SAP report and has develop ed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

OPP

- 2014

- 0219 ). During Registra tion Review, the A gency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis are required for deltamethrin. In addition, the Agency is continuing to evaluate the availabl e post

application inhalation exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exp osure into the A gency ’ s risk

assessments.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational handlers. Handler exposure resulting from a pplication of pesticides outdoors is likely to result in higher exposure than post

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation

exposu re scenarios.

9 .2.2 Occupational Post

- application Dermal Risk Estimates

Systemic toxicity via the dermal route of exposure is not anticipated. No treatment

- related findings were observed at the limit dose; therefore, a quantitative dermal exposure asses sment is not required.

10.0 References

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Page 47 of 67 MRID 49 114112. M. Krolski (201 3 ) Magnitude of the Residue in/on Alfalfa, Leaf Lettuce, and Grass Following Ultra Low Volume (ULV) Spray for Mosquito Control. Study Number:
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D42 3638 , Deltamethrin. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Proposed Use of Deltamethrin as a Wide

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, D. Dotson, 12 /4 /201 4

D41 7 525

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D417559, Tiers I and II Estimated Drinking Waters Concentrations for Deltamethrin for the New
Use as an Adulticide for the Product BES0668 Insecticide , J. Melendez, 10/9/2014

D335136, J. Melendez

, Tier I Estimated Drinking Water Concentrations of Deltamethrin for the
Use in the Human Health Risk Assessment: IR

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on Flax

, 4/ 2 4 /20 07

K. Whitby, D394576, Pyrethroid Cumulative Risk Assessment , 10/4/2011

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, K. Rury, 4/29/2014

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Cao, Z., T. J. Shafer and T. F. Murry (2011b). “ M echanisms of pyrethroid insecticide

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regulated sodium channel subunits are differentially sensitive to [alpha]

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- Velez, J. V. Bruckner, and J. W. Fisher (2006). “ Development of a physiologically based pharmacokinetic model for deltamethrin in the adult male Sprague

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Scollon, E. J., J. M. Starr, K. M. Crofton, M. J. Wolansky, M. J. DeVito, and M. F. Hughes (2011). “ Correlation of tissue concentrations of the pyrethroid bifenthrin with neurotoxicity in
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- 230Deltamethrin Human Health Risk Assessment DP No. D417556

Page 50 of 67 Appendices

Appendix A: Toxicology Profile

Appendix A.1. Toxicology Data Requirements

Toxicology Requirements for Deltamethrin

Guideline Number and Toxicity Study 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 Sub

- chronic (Rodent)

................................ ..................... 870.3150 Oral Sub

- chronic (Non

- Rodent)

................................ ............. 870.3200 21

- Day Dermal

................................ ................................ ...... 870.3250 90

- Day Dermal

................................ ................................ ...... 870.3465 90/28

- Day Inhalation

................................ ............................. yes yes yes

no

no yes

yes yes

-

-

870.3700 Developmental Toxicity (Rodent)

................................ ........ 870.3700 Developmental Toxicity (Non

- rodent)

................................ ... 870.3800 Reproduction

................................ ................................ ......... yes yes yes yes

yes yes

870.4100 Chronic Toxicity (Rodent)

................................ ..................... 870.4100 Chronic Toxicity (Non

- rodent)

................................ .............. 870.4200 Oncogenicity (Rat)

................................ ................................ . 870.4200 Oncogenicity (Mouse)

................................ ........................... 870.4300 Chronic/Oncogenicity (Rat)

................................ ................... yes yes yes yes yes yes

yes yes yes yes

870.5100 Mutagenicity: Gene Mutation

- bacterial

............................... 870.5300 Mutagenicity: Gene Mutation

- mammalian

.......................... 870.5375 Mutagenicity: Structural Chromosomal Aberrations

............. 870.5385 Mutagenicity: Structural Chromosomal Aberrations

............. 870.5500 Mutagenicity: Other Genotoxic Effects

................................ . 870.5550 Mutagenicity: Other Genotoxic Effects

................................ . yes yes yes yes yes yes yes

yes yes yes yes yes

870.6100 Acute Delayed Neurotoxicity (Hen)

................................ ...... 870.6100 90

- Day Neurotoxicity (Hen)

................................ .................. 870.6200 Acute Neurotoxicity Screening Battery (Rat)

........................ 870.6200 90 Day Neuro. Screening Battery (Rat)

................................ . 870.6300 Developmental Neurotoxicity

................................ ................ no

no yes yes yes -

- yes yes yes

870.7485 General Metabolism

................................ ............................... 870.7600 Dermal Penetration

................................ ................................ 870.7800 Immunotoxicity....................................................................... yes yes

yes yes

yes

yesDeltamethrin Human Health Risk Assessment DP No. D417556

Page 51 of 67 Appendix A

. 2. Toxicity Profile Tables

Table A

. 2.1 Acute Toxicity of Deltamethrin

Guideline No./Study Type MRID Results Toxicity Category

870.1100 Acute oral toxicity (rat) 41651019

00070734 LD 50 = > 5000 mk/kg (1% aqueous

methyl cellulose)

LD 50 = 66.7 mg/kg (M), 86 mg/kg (F) (polyethylene glycol)

LD 50 = 128.5 mg/kg (M), 138.7 mg/kg (F) (sesame oil) IV

II

870.1200 Acute dermal toxicity (rat) 41651020 LD 50 = >2000 mg/kg III

870.1300 Acute inhalation toxicity (rat) 41651021

00070734 LC 50 = 2.2 mg/L

LC 50 = 0.6 mg/L III

II

870.2400 Acute eye irritation (rabbit) 41651022 Mild/moderate eye irritant III

870.2500 Acute dermal irritation (rabbit) 41651023 Not a dermal irritant IV

870.2600 Skin sensitization (guinea pig) 41651024 Not a dermal sensitizer NA

Table A

. 2.2 Subchronic, Chronic, and Other Toxicity Studies

Guideline No./ Study Type MRID No. (year)/Classification
/Doses Results

870.3100
90

- Day oral toxicity

rat 00098103 (1977) Acceptable /non

- guideline (stability and purity data absent)

M / F: 0, 0.1, 1.0, 2.5, 10.0 mg/kg/day NOAEL = 2.5 mg/kg/day LOAEL = 10 mg/kg/day based on increased hypersensitivity to sound in males and
females at week 6.

870.3150
90

- Day oral toxicity

dog 00098104 (1977) Acceptable /non

- guideline (agent purity not listed, too few animals (n=3 per sex/group), number of required observations were absent)
M/ F: 0, 0.1, 1.0, 2.5, 10 mg/kg/day NOAEL = 1 mg/kg/day LOAEL = 2.5 mg/kg/day based on pupil dilation, depressed patellar reflex, and an increased incidence of diarrhea and vomiting.

870.3200
21

- Day dermal toxicity

- rat 42773901 (1993) Acceptable/guideline
M/ F: 0, 100, 300, 1000 mg/kg/day Systemic NOAEL = > 1000 mg/kg/day (limit dose)
The dermal NOAEL was not established: signs of local irritation (paresthesia) seen at
all doses.
LOAEL = not identified.

870.3250
90

- Day dermal toxicity NA NADeltamethrin Human Health Risk Assessment DP No. D417556

Page 52 of 67 Table A

. 2.2 Subchronic, Chronic, and Other Toxicity Studies

Guideline No./ Study Type MRID No. (year)/Classification
/Doses Results

21

- Day inhalation toxicity

- rat 00098089 (1978) Unacceptable/non

- guideline (Concerns over the distribution of deltamethrin inside the exposure chamber, particle size (no MMAD or GSD reported), and lack of incidence data reported for clinical findings).
M/ F: 0, 0.003, 0.0096, 0.0563 mg/L for 6 h/day for 5 days/week NOAEL = 0.003 mg/L (0.783 mg/kg /day) LOAEL = 0.0096 mg/L (2.5 mg/kg/day) based on excessive salivation, hunched posture, peripheral vasodilation, aggressive behavior, hypersensitivity to noise, and scarring of the ears.

870.3700a
Prenatal developmental

- rat 41651025 (1990) Acceptable/guideline F: 1.0, 3.3, 7, 11 mg/kg/day Maternal NOAEL = 3.3 mg/kg/day LOAEL = 7 mg/kg/day based on increased
salivation in 11/25 animals and convulsions in one animal (9 animals had convulsions at the next highest dose). Developmental NOAEL > 11 mg/kg/day
LOAEL was not observed

.

00098092 (1976) Unacceptable/ guideline (not noted if increased in delayed ossification
were noted in fetal and/or litter incidences; neither route of administration or vehicle noted) F: 0, 0.1, 1.0, 10 mg/kg/day Maternal NOAEL = 1.0 mg/kg/day LOAEL = 10 mg/kg/day based on slightly reduced body weight. Developmental NOAEL = 1.0 mg/kg/day LOAEL = 10 mg/kg/day based on delayed ossification of the sternebrae; fetal losses increased from controls (2.2, 2.6, 2.7, and
4 %), though not statistically different.

870.3700b
Prenatal developmental

- mouse 00098092 (1976) Unacceptable/ guideline (not noted if increased in delayed ossification
were noted in fetal and/or litter incidences) F: 0, 0.1, 1.0, 10 mg/kg/day Maternal NOAEL =  10 mg/kg/day
LOAEL was not observed. Developmental NOAEL = 0.1 mg/kg/day LOAEL = 1.0 mg/kg/day based on decreased fetal weight, and delayed ossification of the sternebrae and paws

.

870.3700b
Prenatal developmental

- rabbit 45881901 (2001) Acceptable/ non

- guideline F: 0, 3, 10, 32 mg/kg/day in corn oil Maternal NOAEL = 32 mg/kg/day
LOAEL = not established. Developmental NOAEL  32 mg/kg/day
LOAEL = not established.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 53 of 67 Table A

. 2.2 Subchronic, Chronic, and Other Toxicity Studies

Guideline No./ Study Type MRID No. (year)/Classification
/Doses Results

00098092 (1976) Unacceptable /guideline (neither
route of administration or vehicle noted; details of teratogenic parameters examined not given) F: 0, 1, 4, 16 mg/kg/day Maternal NOAEL =  16 mg/kg/day
LOAEL was not observed Developmental NOAEL = 4 mg/kg/day LOAEL = 16 mg/kg/day based on decreased fetal weights and increased fetal loss (6.6, 18.5, 15.5, 10.2, 27.4%)

41651026 (1990) Unacceptable /guideline F: 0, 10, 25, 100 mg/kg/day in carboxymethylcellulose (deltametrhin dissolved in aqueous vehicles is reported to be less toxic) Maternal NOAEL = 100 mg/kg/day
LOAEL = was not established. Developmental NOAEL = 25 mg/kg/day LOAEL = 100 mg/kg/day based on increases in delayed ossification and skeletal variations

.

870.3800 Reproduction and fertility effects

- rats 44398101 (1992) Acceptable/guideline M&F: 0, 5, 20, 80, 320 ppm
Parental animals M: 0, 0.3, 1.3, 5.4, 21.2 mg/kg/day F: 0, 0.4, 1.5, 6.1, 23.5 mg/kg/day

F 1 animals M: 0, 0.4, 1.4, 5.8, 24.9 mg/kg/day F: 0, 0.4, 1.7, 6.7, 27.2 mg/kg/day Parental/Systemic NOAEL = M: 5.4; F: 6.1 mg/kg/day LOAEL = M: 21.2; F: 23.5 mg/kg/day based on clinical signs in P generation (lesions on head, neck, and forearms in males and ataxia and hypersensitivity in females), decreased body weights in both the P and F 1 generation, and gross pathological findings in the F 1 generation. Offspring NOAEL = M: 5.8; F: 6.7 mg/kg/day LOAEL = M: 24.9; F: 27.2 mg/kg/day based on increased pup mortality (PND 8

- 14) in the

F 1 generation, increased mortality during the first 8 days post weaning in the F 1 generation, clinical signs that were observed early in the post weaning period in the F 1 generation (impaired righting reflex, urine stained fur, hyperactivity, splayed limbs, vocalization, and salivation) and decreased pup weights in
the F 1 (PND 4

- 21) and F 2 generation (PND 7

- 21). Rep roductive NOAEL = M:  24.9; F: 27.2 mg/kg/day

LOAEL = M:  21.2; F: 23.5 mg/kg/day

.

870.4100a Chronic toxicity

- rat Same as Chronic Toxicity/Carcinogenicity

- rat see below (870.4300) See below (870.4300)Deltamethrin Human Health Risk Assessment DP No. D417556

Page 54 of 67 Table A

. 2.2 Subchronic, Chronic, and Other Toxicity Studies

Guideline No./ Study Type MRID No. (year)/Classification
/Doses Results

870.4100b Chronic toxicity

- dog 44372601 (1993) Acceptable/guideline
M/ F: 0, 1, 10, 50 mg/kg/day (gelatin capsule)

- 52 weeks NOAEL = 1 mg/kg/day LOAEL = 10 mg/kg/day based on chewing and scratching of extremities, abnormal gait with body tremors, and liquid feces.

870.4200b Carcinogenicity

- mouse 44372602 (1995) Acceptable/guideline
M/ F: 0, 10, 100, 1000, 2000 ppm M: 0, 1.5, 15.7, 155.4, 314.8 mg/kg/day F: 0, 2.0, 19.6, 189.3, 395.1 mg/kg/day NOAEL = 314.8/395.1 mg/kg/day ( M/F,HDT)
LOAEL = 603.4/738.8 mg/kg/day (M/F) based on decreased body weight observed in
the 12

- week range finding study.

No evidence of carcinogenicity, HDT assumed to be adequate to characterize the carcinogenic potential based on a 12

- week

range finding study in mice showing decreased body weight at 603.4/738.8 mg/kg/day (M/F).

870.4300
Chronic/ Carcinogenicity

- rat 44398102 (1995) Acceptable/guideline
M/ F: 0, 25, 125, 500, 800 ppm M: 0, 1.1 5.4, 22.2, 35.9 mg/kg/day F: 0, 1.5, 7.3, 29.5, 47.1 mg/kg/day NOAEL = 22.2/29.5 mg/kg/day (M/F) LOAEL = 35.9/47.1 based on unsteady gait and splayed hindlimbs observed in the first few weeks of the study in male rats. No evidence of carcinogenicity, HDT assumed to be adequate to characterize the carcinogenic potential based on a 13

- week toxicity stu dy in rats showing death, reduced body weight gains and marked neurological disturbances at  1000 ppm

.

00098105 (1980) Unacceptable /guideline (inadequate dosing) M&F: 0, 2, 20, 50 ppm M&F: 0, 0.1, 1.0, 2.5 mg/kg/day NOAEL = >50 ppm (HDT)
LOAEL was not determined

No evidence of carcinogenicity

.

870.5100
Bacterial reverse
mutation test

S. typhimurium 42475902 (1980) Acceptable/guideline 0, 2, 10, 50, 200, 1000, 5000 μg/plate +/

- S9 There was no evidence of an induced mutagenic effect at concentrations up to the limit dose (5000 μg/plate +/

- S9). Compound precipitation seen at  200 μg/plate.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 55 of 67 Table A

. 2.2 Subchronic, Chronic, and Other Toxicity Studies

Guideline No./ Study Type MRID No. (year)/Classification
/Doses Results

870.5375
In vitro mammalian
chromosome
aberration test

Chinese hamster ovary (CHO) cells 4 1651027 (1989) Acceptable/guideline 0, 19, 38, 75, 150 μg/mL +/

- S9 There was no evidence of an induced mutagenic effect up to cytotoxic concentrations (  38 μg/mL

- S9; 150 μg/mL +S9). Levels  75 μg/mL were insoluble.

Other Genotoxicity
870.5550
Bacterial DNA damage/repair

E. coli 42475902 (1980) Acceptable/guideline 0, 1250, 2500, 5000 μg/well +/

- S9 There was no evidence of DNA repair/damage up to the limit dose (5000 μg/well +/

- S9). Compound precipitation seen

at  200 μg/well.

Other Genotoxicity
870.5550 Unscheduled DNA synthesis in primary rat hepatocytes 41651028 (1989) Acceptable/guideline 0, 0.13, 4.2, 13, 42, 130, 420, 1300, 4200 μg/mL There was no evidence that unscheduled DNA synthesis was induced up to insoluble

conce ntrations (  130 μg/mL).

870.6200a Acute neurotoxicity screening battery

- rats 44557901 (1998) Acceptable/guideline M&F: 0, 5, 15, 50 mg/kg Neurotoxic NOAEL= 15 mg/kg/day LOAEL = 50 mg/kg/day based on clinical signs during handling, open field, and sensory observations including, convulsions and tremors, increased salivation, soiled fur, impaired mobility, low arousal, decreased rearing, decreased fore

- and hind

- limb grip strength, and decreased body temperature.

870.6200b
Subchronic neurotoxicity screening battery 44557902 (1998) Acceptable/guideline M&F: 0, 50, 200, 800 ppm M: 0, 4, 14, 54 mg/kg/day F: 0, 4, 16, 58 mg/kg/day Neurotoxic NOAEL= M: 14; F: 16 mg/kg/day LOAEL = M: 54; F: 58 mg/kg/day based on mortality, clinical signs, FOB findings, and decreased body weights, body weight gains, and food consumption

.

870.6300 Developmental neurotoxicity 46814301 (2006) Acceptable/Non

- Guideline (pending review of positive

- control data) 0, 20, 80, 200 ppm 0, 1.6, 6.8, 16.1 mg/kg/day (gesta tion and lactation) Maternal NOAEL = 6.8 mg/kg/day.
Maternal LOAEL = 16.1 mg/kg/day based on decreased body weight (6

- 7% on GD 13 and GD 20). Offspring NOAEL = 6.8 mg/kg/day Offspring LOAEL = 16.1 mg/kg/day based on decreased pre

- and post

- weaning body weight and increased incidence of vocalizations (males) during FOB.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 56 of 67 Table A

. 2.2 Subchronic, Chronic, and Other Toxicity Studies

Guideline No./ Study Type MRID No. (year)/Classification
/Doses Results

870.7485
Metabolism and pharmacokinetics

- rats 41677401 (1990) Acceptable/guideline
M/ F: 0.55, 5.5 mg/kg The test material was relatively well absorbed. Excretion was almost complete within 48 hours. Approximately 36

- 59% of
the dose was found in feces and an approximately equal amount in urine. Absorbed deltamethrin was cleaved by hydrolysis at the ester site follo wed by rapid sulfate and glucuronide conjugation.

870.7600 Dermal penetration NA NA

870.7800 Immunotoxicity 48988205 (2012) Acceptable/guideline F: 0, 8.3, 23.5, 48.3 mg/kg/day NOAEL = 48.3 mg/kg/day
LOAEL = not established. No evidence of systemic toxicity or immunotoxicity was observed in the study up to the highest dose tested.

Literature studies

Wolansky et al.

- Acute Oral Toxicity in Rats

Motor Activity 47885701 (2006) Acceptable/non

- guideline 0, 0.03, 0.1, 0.3, 1, 3, and 10 mg/kg
Vehicle: Corn oil Volume: 1 ml/kg BMDL 1SD = 1.49 mg/kg

BMD 1SD = 2.48 mg/kg based on decreased motor activity.

WIL Study

- Acute Oral Toxicity in Rats

FOB 47050504 (2006) Acceptable/Non

- Guideline 0, 12.5, 25, and 35 mg/kg via gavage in corn oil (5 mL/kg) BMDL 20 = 10.5 mg/kg

BMD 20 = 14.5 mg/kg based on multiple FOB changes.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 57 of 67 A.3 Toxicological Doses and Endpoints for Use in Human Risk Assessments

Figure A3. 1 Decision tree for evaluating potential toxicity studies for endpoint selection

Hazard

Identification and Endpoint Selection A.3.1 Acute Reference Dose (aRfD)

– All Populations Including Infants and Children and Females Age 13

- 49

Study Selected : Acute M otor Activity (Wolansky et al., 2006)

MRID # : 47885701

Dose and Endpoint for Risk Assessment : BMDL 1SD = 1.49 mg/kg, based on decreased motor activity seen at 3 mg/kg.

Uncertainty Factor : Adults and Children ≥ 6 years old: 100X (1X FQPA, 10X interspecies extrapolation, 10X intraspecies variability)

Acute RfD = = 0.0 15 mg/kg

Children < 6 years old: 300X (3X FQPA, 10X interspecies extrapolation, 10X intraspecies variability)Deltamethrin Human Health Risk Assessment DP No. D417556

Page 58 of 67 Comments about Study/Endpoint : The Wolansky study was selected based on decreased motor activity observed within 3 hours following an acute exposure. BMD analysis was
conducted and a BMDL 1SD value of 1.49 mg/kg was determined. Endpoints for risk assessment are not typically selected from literature studies. However, the Wolansky et al. (2006) study is uniquely appropriate based on: 1) the large number of dose levels (6); 2) the large number of animals (8

- 18 per group); 3) neurotoxicity was determined at the time to peak effect (2 hours post dosing); and 4) motor activity is recognized as one of the most common techniques for determining pyrethroid neurotoxicity in laboratory animal studies (Wolansky and Harrill 2008)

. Furthermore, the selection of the BMDL 1SD from the Wolansky study is supported by multiple guideline and literature studies. The ACN, chronic dog, and WIL studies were all considered for risk assessment since they all had effects that were observed within hours following dosing. However, these studies all had higher NOAELs and were not selected for risk assessment. The chronic dog study had a slightly lower NOAEL (1 mg/kg/d ay); however, the human equivalent dose based on allometric scaling was actually higher for the chronic dog study (0.61 mg/kg/day) compared to the Wolansky study (0.43 mg/kg). The WIL study and the ACN study both used relatively high vehicle volumes (5 ml /kg vs. 1 ml/kg in Wolansky) which likely impacted the absorption characteristics of deltamethrin, thereby increasing the POD. Since there is no apparent increase in hazard from repeated/chronic exposures to deltamethrin , the acute dietary exposure

assessm ent is protective of chronic dietary exposures since acute exposure levels are higher than chronic exposure levels. Accordingly, a chronic dietary risk assessment was not conducted.

A.3.2 Incidental Oral Exposure (Short

- Term)

Study Selected : Acute Mot or Activity (Wolansky et al., 2006)

MRID # : 47885701

Dose and Endpoint for Risk Assessment : BMDL 1SD = 1.49 mg/kg, based on decreased motor activity seen at 3 mg/kg.

Uncertainty Factor : Adults and Children < 6 years old: 300X (3X FQPA, 10X interspecies extrapolation, 10X intraspecies variability)

Comments about Study/Endpoint : The Wolansky study was selected based on decreased motor activity observed within 3 hours following an acute exposure. BMD analysis was
conducted and a BMDL 1SD value of 0 1.49 mg/kg was determined. Endpoints for risk assessment are not typically selected from literature studies. However, the Wolansky et al. (2006) study is uniquely appropriate based on: 1) the large number of dose levels (6); 2) the large number of animals (8

- 18 per group); 3) neurotoxicity was determin ed at the time to peak effect (2 hours post dosing); and 4) motor activity is recognized as one of the most common Acute RfD = = 0.00 5 m g/kgDeltamethrin Human Health Risk Assessment DP No. D417556

Page 59 of 67 techniques for determining pyrethroid neurotoxicity in laboratory animal studies (Wolansky and Harrill 2008) . Furthermore, the selection of the BMDL 1SD from the Wolansky study is supported by multiple guideline and literature studies. The short

- term oral stu dies, developmental and reproduction studies, and the chronic oral studies were all considered for risk assessment. However, the Wolansky study provided the most appropriate NOAEL that is protective of potential developmental/offspring effects, as well as other systemic effects observed in the toxicology database.

A.3.3 Dermal Exposure (Short

- Term)

A 21

- day dermal study in rat for deltamethrin is available for consideration. However, no

treatment

- related findings were observed at the limit dose . There was also no toxicity observed following acute dermal exposure to deltamethrin up to a dose of 2000 mg/kg . T herefore, a
dermal hazard was not identified for deltamethrin and no dermal risk assessment will be
conducted

. This finding is consistent with the toxicology profile of many pyrethroids. No dermal hazard has been identified for fenpropathrin, zeta

- cypermethrin, allethrin, and prallethrin. Typically pyrethroids have a low absorption value of ≤ 5% and a high rate o f metabolism

. D eltamethrin had a slightly higher absorption value of 11.3%

, although the majority of the radioactivity measured was at the skin site (10.6%). This is typical of the pyrethroids

, as they are lipophilic and much of the radioactivity measured in the skin of dermal penetration studies with pyrethroids is captured in the upper dermal layers an d not available for absorption or systemic
circulation.

A.3.4 Inhalation Exposure (Short

- Term)

Study Selected : Acute Motor Activity (Wolansky et al., 2006)

MRID # : 47885701

Dose and Endpoint for Risk Assessment : BMDL 1SD = 1.49 mg/kg, based on decreased motor activity seen at 3 mg/kg.

Uncertainty Factor :

Adults and Children ≥ 6 years old: 100X (1X FQPA, 3X interspecies extrapolation, 10X intraspec ies variability)

Children < 6 years old: 300X (3X FQPA, 10X interspecies extrapolation, 10X intraspecies variability)

Comments about Study/Endpoint : An acceptable inhalation study was not available for
deltamethrin. The HASPOC waived the requirement for a subchronic inhalation study (TXR# 0056944)

. In the absence of an inhalation study an oral study is being used. T he Wolansky study was selected based on decreased motor activity observed within 3 hours following an
acute exposure. BMD analysis was c onducted and a BMDL 1SD value of 1.49 mg/kg was
determined. Endpoints for risk assessment are not typically selected from literature studies.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 60 of 67 However, the Wolansky et al. (2006) study is uniquely appropriate based on: 1) the large number of dose levels (6); 2) the large number of animals (8

- 18 per group); 3) neurotoxicity was determined at the time to peak effect (2 hours post dosing); and 4) motor activity is recognized as one of the most common techniques for determining pyrethroid neurotoxicity in laboratory animal studies (Wolansky and Harrill 2008) . Furthermore, the selection of the

BMDL 1SD from the Wolansky study is supported by multiple guideline and litera ture studies.
The short

- term oral studies, developmental and reproduction studies, and the chronic oral studies were all considered for risk assessment. However, the Wolansky study provided the most appropriate NOAEL that is protective of potential develo pmental/offspring effects, as well as other systemic effects observed in the toxicology database. Absorption and toxicity via the inhalation route are assumed to be equal to toxicity via the oral route.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 61 of 67 Appendix A

. 4

. Pyrethroid Cumulative Screen

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 share a common mechanism group (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 (CRA) for the pyrethroids/pyrethrins was published on Nov. 9, 2011 (USEPA, 2011a) an d is available at http://www.regulations.gov;
EPA

- HQ

- OPP

- 2011

- 0746. No cumulative risk estimates of concern were identified allowing the Agency to consider new uses for pyrethroid actives. For information regarding EPA’s efforts to
evaluate the risk of e xposure to pyrethroids, refer to http://www.epa.gov/oppsrrd1/reevaluation/pyrethroids

- pyrethrins.html

.

The active ingredient, deltamethrin

, was assessed in the November 2 011 pyrethroid cumulative
risk assessment. T he Agency has determined based on its chemical structure and based on the observation of neurobehavioral effects consistent with Type II pyrethroids, that deltamethrin
should be included in the CMG for this clas s of pesticides. As such, the Agency must consider the potential contribution of deltamethrin to the cumulative risk assessment. No new residential use scenarios have been proposed or registered since the 2011 pyrethroid CRA. Therefore, there
has been n o change to the overall findings in the pyrethroid CRA due to contribution of
deltamethrin uses.

A

. 4

. 1. Cumulative Hazard Assessment: Relative Potency Estimation for Deltamethrin

The 2011 pyrethroid CRA relies on the relative potency factor (RPF) approach using administered dose as the metric for quantifying chemical potency. In the RPF approach, the toxic potency of each chemical in the common assessment group (CAG) is determined. One
member of the CAG is selected as the index chemical which is used as the point of reference for standardizing neurobehavioral potency of the other members of the CAG. In order to develop such potency estimates, EPA prefers to use a uniform measure of toxicity. In other words, the Agency prefers to use data which a re from the same endpoint and same duration and to the extent possible any other factors which effect potency (e.g., time to peak effect, sex, etc). In the pyrethroid CRA, the Agency used the two special WIL Functional Observational Battery (FOB) studies for estimating relative potency. Th ese studies were was selected because the y examined many behaviors, including key ones for evaluating neurotoxicity specific to pyrethroids. Specifically, the studies looked at a number of key parameters that are direct ly relevant to the Type I (e.g., hyperthermia tremors and clonus) and Type II (e.g., hypothermia, salivation, and mobility) syndromes. In addition to the WIL FOB studies, there is another study (Wolansky et al, 2006) that provides a high quality data set for estimating relative potency. Whereas the WIL FOB studies focus on endpoints specific to pyrethroid toxicity syndromes, the Wolansky study measured motor activity. Motor activity is considered an apical endpoint
because it measures alterations in the activity level of an intact rat. Although the Wolansky study provides a potential data source for a uniform measure of potency, it was not utilized in the CRA because of the lack of specific relevance to the common mechanism of action for the pyrethroids.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 62 of 67 In the CRA, deltamethrin was used as the index chemical. Deltamethrin stands out as having one of the most robust databases of guideline and literature studies. For example, multiple studies on deltamethrin have been identified examining in vivo neuro toxicity, in vitro sodium channel interaction, metabolism, pharmacokinetics following multiple routes of administration (oral, dermal, intravenous, intercerebral, etc.) and PBPK modeling. Furthermore, t he deltamethrin
PoD derived from the FOB data is of s ufficiently high quality to minimize error or uncertainty in
the cumulative risk estimates. The RPFs used for the CAG in the pyrethroid screening level cumulative were determined by dividing the chemical

- specific BMD 20 by the BMD 20 of the index chemical ( deltamethrin). Therefore, for deltamethrin the RPF is 1.00.

T able A. 4 .1

. Pyrethroid RPF Comparison FOB vs. Motor Activity
Pyrethroid FOB Motor Activity

lambda

- cyhalothrin 1.63 1.90 a

tefluthrin 1.36 1.11 a

cyfluthrin 1.15 1.14 a

bifenthrin 1.01 1.96 a

deltamethrin 1.00 1.00 a

fenpropathrin 0.50 0.33 a

metofluthrin 0.48

--

esfenvalerate 0.36 2.09 a

cypermethrin 0.19 0.23 a

tau

- fluvalinate 1.00

-- cyphenothrin 0.15

--
d

- allethrin 0.11

--
allethrin 0.11 0.03 a
prallethrin 0.10

-- permethrin 0.09 0.15 a

resmethrin 0.05 0.02 a

pyrethrins 0.02

-- imiprothrin 0.02

--

flumethrin

-- 5.02 b
a Represents motor activity data from the Wolansky study b Represents motor activity data from the flumethrin A CN studyDeltamethrin Human Health Risk Assessment DP No. D417556

Page 63 of 67 A

. 4

. 2. Cumulative Exposure and Risk Issues

In order to determine if the registered deltamethrin indoor and turf uses will significantly contribute to or change the overall findings in the pyrethroid CRA

, the Agency performed a quantitative exposure and risk assessment. This assessment used the deltamethrin RPF as well as the same exposure algorithms and inputs that were used in the 2011 pyrethroid CRA.

MOEs calculated and presented in Appendix Table A

. 4

. 2 .a were compared with the MOEs currently driving turf and indoor crack and crevice exposures and risks in Table 6.4.7a from the 2011 pyrethroid CRA

. Adult handler exposures and risks estimates are currently driven by cyfluthrin turf use (i.e. mixing/loading/applying via hose

- end sprayer) with a dermal MOE of 9,200 and combined (dermal + inhalation) MOE of 8,900, which are lower than the estimated deltamethrin dermal MOE of 15,000 and combined MOE of 500,000. Adult and child dermal
post

- application exposure and risk are also currently driven by cyfluthrin turf use with an MOE of 4,500 and 3,000 respectively. For children < 6 year s old, hand

- to

- mouth post

- application exposure and risk estimates are currently driven by the cy halothrin indoor crack and crevice use
with an MOE of 9,7 00, which is lower than the estimated deltamethrin MOE o f 16,0 00. A summary of these MOEs is presented in Appendix Table A

. 4. 2 .a while the detailed calculatio ns for deltamethrin are presented in Appendix Table A

. 4.2.b . In all cases, the estimated
deltamethrin MOEs using the RPF method were higher (i.e., less of a risk concern) than those used in the 2011 pyrethroid CRA. Thus the Agency continues to support th e previous
assessment and concludes that the registered deltamethrin use will not significantly contribute to the overall findings in the 2011 pyrethroid CRA.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 64 of 67 Table A. 4

. 2. a. Comparison of Deltamethrin MOEs with Pyrethroid Cumulative MOEs

Chemical Exposure
Scenario Route of Exposure Population MOE Combined
MOE

Registered Use Deltamethrin

Turf (EC)

– M/L/A
Hose

- end Sprayer Handler Dermal

Adult 15,000 500,000

Handler Inhalation 420,000

Post

- application Dermal 7,700 NA

Post

- application Dermal Child 5,300 4,600 Post

- application HTM 36,000

CRA C yfluthrin Handler Dermal

Adult 9,200 8,900 Handler Inhalation 280,000

Post

- application D ermal 4,500 NA

Post

- application Dermal Child 3,000 2,700 Post

- application HTM 21,000

Registered Use Deltamethrin

Indoor

– M/L/A
crack & crevice Handler Dermal

Adult 87,000 66,000

Handler Inhalation 270,000

Post

- application Dermal 70,000 NA

Post

- application Dermal
Child 58,000 12,000 Post

- application HTM 16,000

CRA C yfluthrin Handler Dermal 43,000 33,000 Handler Inhalation 140,00

Cyhalothrin Post

- application Dermal 43,000 NA

Post

- application Dermal 36,000 7,600 Post

- application HTM 9,700Deltamethrin Human Health Risk Assessment DP No. D417556

Page 65 of 67 Table A. 4 .2.b. Deltamethrin Screening Level “Cumulative” MOEs

Handler Exposure

Exposure
Scenario Application

Rate Amount

Treated Daily (animals) Baseline

Dermal
Unit Exposure (mg/lb ai) Baseline

Inhalation
Unit Exposure (mg/lb ai) Baseline Dermal

Unit Exposure (mg/lb ai) Baseline

Inhalation
Unit Exposure (mg/lb ai) Baseline

Dermal Dose Adjusted

Baseline
Dermal Dose (mg/kg/day) a Adjusted

Baseline
Dermal
MOE b Base line

Inhalation
Dose Adjusted

Baseline
Inhalation
Dose (mg/kg/day) Baseline Inhalation MOE

Adult

- Turf 0.13

lb ai/A 0.5 15 0.024 0.98 0.3 0.0007 0.00068 15,000 2.23E

- 5 2.2E

- 5 470,000

Adult

– Indoor
C&C 0.0005

lb ai/gal 0.5 69 1.1 0.17 0.00275 0.0001 0.00012 87,000 3.8E

- 5 3.8E

- 5 270,000

Post

- app lication Hand

- to

- Mouth Exposure

Exposure
Scenario Fai hands 1

- 2 yr old
Dermal Exposure SA H

(cm 2 ) HR t

(mg/cm 2 ) F M

Exposure
Time (hours/day) N_Replen SE Freq_HtM

BW Average Daily Dose (mg/kg/day) Adjusted

Dose (mg/kg/day) a Adjusted

MOE b Fraction of Hand
Surface Area
Mouthed/Event Number of replenishment intervals per hr (intervals/hr) Extraction by

Saliva H

- t

- M

events per hour

Child

- Turf ( 6 > year s old) 0.03 4 0. 45 150 5.15 E

- 5 0.13 0.9 4 0.5 13.9 11.4 0.0002 8 0.000 28 36 ,000

Chil d

– C&C ( 6 > year s old) 0.15 0.04 150 2E

- 5 0.13 5 4 0.5 20 11.4 0.00066 0.00066 16,000

Post

- application Dermal Exposure

Exposure
Scenario Application Rate Body Weight (kg) Hours of

Exposure Conversion

Factor (mg/ug) DFR/TTR

(ug/cm 2 DAT 0) Transfer

Coefficient (cm 2 /hr) Absorbed Dermal Dose

(mg/kg/day) Adjusted Dose (mg/kg/day) a Adjusted

MOE b

Child

- Turf ( 6> year s old) 0.13 lb ai/A 11.4 0.9 0.001 0.0 105 37, 500 0.00 2 0.00 19 35 ,000

Adult

- Turf 0.13 lb ai/A 71.8 1

. 1 0.001 0.0 1 0 5 130

, 0 00 0.0014 0.00 1 35 77 ,000

Exposure
Scenario Surrogate Deposition

(ug/cm 2 ) Conversion Factor 1 (ug/lb) Conversion

Factor 2 (ft 2 to cm2) Surface

Residue (ug/cm 2 ) Fraction

Transferred Transfer

Coefficient (cm 2 /hr) Exposure

Time (hr/day) CF3

(mg/ug) Adjusted Dose

(mg/kg/day) Adjusted

MOE

Child

– C&C 0.2 4.5E+8 1.08E

- 3 0.2 0.02 2,000 5 1E

- 3 0.00018 58,000

Adult

– C&C 0.2 4.5E+8 1.08E

- 3 0.2 0.02 6,800 8 1E

- 3 0.00015 70,000 a Doses were adjusted based on an estimated deltam ethrin RPF of 5.02 b MOEs were calculated by comparing the adjusted dose to the oral BMD 20 from the WIL FOB data for the index chemical, deltamethrin (14.5 mg/kg/day) c Handler inhalation exposure is expected to be negligible from deltam ethrin pet collars and

, thus

, a quantitative assessment was not performed.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 66 of 67 Appendix B

. Physical/Chemical Properties

T able B.1. Physicochemical Properties of Technical Grade Deltamethrin.*

Parameter Value Melting Point/Range (°C) 100

- 102 pH Not available. Density (g/cm 3 at 25°C) 0.550 Water Solubility (ug/L at 25°C) <0.2 Solvent Solubility (% by w eight at 20oC) Acetone 33
Alcohol 0.6 Isopropanol 0.2 Ethyl acetate 25

n

- Hexane 0.2
Toluene 23

DMF 38
Dioxane 39 Vapor Pressure (mm Hg at 25oC) [mPa at 25°C] 1.5 x 10

- 8 [1.24 x 10

- 5 ]
Dissociation C onstant, pK a Does not dissociate

. Octanol/ Water Partition C oefficient, K OW ( at 25oC ) 2.7 x 10 5

UV/ V isible A bsorption S pectrum Not available

. * Reference: MARC Briefing Memorandum; D284320; D. Dotson; 5 November 2002.Deltamethrin Human Health Risk Assessment DP No. D417556

Page 67 of 67 Appendix C

. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data are subject to ethics review pursuant to 40 C FR 26, have received that review, and are compliant with applicable ethics requirements. For certain studies

, that review may have included review by the Human Studies Review Board. Descriptions of data sources as well as guidance on their use can be fou nd at http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

.