UNITED STATES ENV IRO NMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460



### MEMORANDUM

DATE: November 5, 20 14 OFFICE OF CHEM I CAL SAFETY AND

POLLUTION PREVENTION

SUBJECT: 

### Residential Exposure Assessment in Response to the Natural Resources

Defense Council Petition to Cancel All Pet Uses for Tetrach lorvinphos

PC Code: 083701


### Petition No.: NA


### Risk Assessment Type: Single Chemical,

Residential Expos ur e Assessment



### TXRNo.: NA



### MRID No.: 45485501,45519601,48589901 

### DP Barcode: D420283 

### Registration Nos.: NA 

### Regulatory Action: Petition Response



### Case No.: NA


### CAS No.: 22248-79-9

FROM: Wade Britton, MPH, Indust ri a l Hygienist 

# /UJj

Risk Assessment Branch V (RABV) 

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Health Effects Division (HED; 7509P)

Office of Pesticide Programs**~** 

### I**~**

THROUGH: Michael Metzger, Chief 

# D 

# 0 /(

RABV and RABVIIJHED (75

# . And 

# n

. Kristin Rury

, Bio logi st \(

, 

### :l.- .JI'l

- ,....,...**---..~.** Nancy J. Tsaur

, Chemist \1 J Exposure Sc i ence Adv i sory tlo

TO: Nei l A nderson

, Branch C hief Kelly Ballard

, Chemical Review Manage r Risk Management and Implementation Branch I (RMIBI)

Pesticide R e-eva luation D ivision (PRD; 7508P)

Office of Pesticide P rograms

The purpose of this document is to provide a residential exposure assessment for all pet u ses of

the active in gredien t

, tetrachlorvinphos (TCVP). On April 23

, 2009, the Na tur a l Resources

Defense Counc il (N RDC) petitioned the Agency to cance l all pet uses of TCVP. This

assessment was conducted as a response to NRDC's petition and characterizes the potential

risks associated with t he u se of TCVP p et products. An earlier ex po sure assessme nt was a l so

Page 1 of 45Page 2 of 45

conducted 1 in response to the petition that identified no human health risks of concern from residential use of TCVP pet products. This current exposure assessment makes use of the 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment (2012 Residential SOPs) , the Agency’s most current guidance for the a ssessment of human health exposures from residential pestici de usage

. This assessment also incorporates changes that have occurred since the prior assessment including the following: updates to toxicological points of departure (PoDs ) and uncertainty factors (UFs); voluntary product cancellations ; label

amendments ; a re

- evaluation of pre viously submitted exposure data; and use of a recently

submitted pet collar pet residue transfer study . This current exposure assessment supersedes the prior exposure assessment and is posted to the public docket (EPA

- HQ

- OPP

- 2009

- 03 56 ).

It is HED policy to use the best available data to assess exposure. Several sources of generic data were used in this assessment as surrogate data in the absence of chemical

- specific data, including the 2012 Residential SOPs (Treated Pets SOP) , and a propoxur collar pet residue

transfer stud y (MRID 4858990 1 )

. A TCVP dust/powder applicator exposure study ( MRID 45519601), and TCVP dust and pump spray study ( MRID 45485501) were also used. Both TCVP studies were included as a part of the 2012 Residen tial SOPs. Some of these data are proprietary, and subject to the data protection provisions of the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA).

Note: This memorandum was reviewed by the Exposure Science Advisory Committee (ExpoSAC) May 8, 2014.

1 J. Dawson. Tetrachlorovinphos : Summary of Pet Collar Risk Estimates. 2/22/10. D346880.Page 3 of 45



## Table of Contents

1.0 Executive Summary

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

2.0 Risk Assessment Conclusions and Recommendations

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

2.1 Summary of Risk Estimates

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

2.2 Label Recommendations from Residential Assessment

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

2.3 Data Deficiencies and Requirements

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

3.0 Hazard Characterization and Dose

- Response Assessment

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

4.0 Use Profile

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

5.0 Residential Exposure and Risk Estimates

................................ ................................ .......... 14

5.1 Residential Handler Exposures

................................ ................................ ...................... 15

5.2 Residential Post

- application Exposure/Risk Estimates

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

5.3 Residential Risk Characterization

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

5.4 Residential Risk Estimates for Use in Aggregate Assessme nt

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

5.5 Spray Drift

................................ ................................ ................................ ...................... 38

5.6 Residential Bystander Post

- Application Inhalation Exposure

................................ ....... 38

Appendix A: Algorithms Used to Calculate Residential Non

- Cancer and Cancer Risk Estimates

................................ ................................ ................................ ................................ ....................... 39Page 4 of 45

1.0 Executive Summary

Tetrachlorvinphos (TCVP) is a member of the organophosp hate (OP) class of pesticides. TCVP is used as a direct animal treatment to livestock and their premises, outdoors in recreational

areas , and as a flea treatment on cats and dogs

. Currently registered TCVP pet products include collar, dust/powder, and pump and trigger spray formulations. This assessment is intended to

address only those issue s raised in the 2009 NRDC petition regarding the potential exposures resulting fro m residen tial TCVP pet product usage . Residential exposures are anticipated for adults who apply TCVP products to pets and for adults and children contacting previously treated pets.

Hazard

Like other OPs

, the initiating event in the adverse outcome pathway (AOP)/mode of action (MOA) for TCVP involves inhibition of the enzyme acetylcholinesterase (AChE) via phosphorylation of the serine residue at the active site of the enzyme. This inhibition leads to

accu mulation of acetylcholine and ultimately to neurotoxicity in the central and/or peripheral

nervous system

. For TCVP , AChE inhibition is the most sensitive endpoint in the toxicology database in multiple species, durations, lifestages, and routes

.

The toxicology database for TCVP is complete. TCVP has low acute (lethality) toxicity by the oral, dermal, and inhalation routes of exposure. It is a slight dermal irritant, a moderate eye irritant, and a dermal sensitizer. TCVP is classified as a possible human (Group C) carcinogen based on statistically significant increases in combined hepatocellular adenoma/carcinomas in mice, and suggestive evidence of thyroid c

- cell adenomas and adrenal pheochromocytomas in

rats. The mutagenicity database for TCVP su ggests that this chemical was not mutagenic in both the gene mutation assay and primary rat hepatocyte unscheduled DNA synthesis assay. However, this chemical was positive for inducing chromosomal aberrations in Chinese hamster ovary cells in the absence of metabolic activation, but was negative in the presence of metabolic

activation. Immunotoxicity was not observed at dose levels that exceed the limit dose.

Developmental toxicity was observed in the rabbit developmental toxicity study, as evidenced by an increase in abortions and early resorptions, with an increase in post

- implantation loss and a decrease in live fetuses at the same dose level where mortality, abortions, and red vaginal fluid were observed in the maternal rabbit. Developmental toxicity was not observed in the rat developmental toxicity study. No reproductive toxicity was observed in the 2

- generation reproductive study in rats, but increased adrenal weights were observed in the parental rats.

Transient clinical signs characteristic of cholinergic toxicity were observed in the acute and subchronic neurotoxicity studies in rats, but no clinical signs were observed in the maternal rats or in the offspring in the dev elopmental neurotoxicity study. However, cholinesterase activity

was not measured in any of these neurotoxicity studies

. There are comparative cholinesterase

studies as well as subchronic and chronic oral toxicity studies on TCVP that provide cholinesterase dose response data across multiple lifestages , durations, and routes o f exposure

for both red blood cell ( RBC ) and brai n cholinesterase inhibition. No clinical signs characteristic of cholinergic toxicity were ob served in any of these assays. Many of thesePage 5 of 45

studies have been evaluated using benchmark dose modeling techniques.

Endpoints and Uncertainty Factors for Risk Assessment

Like other OPs, TCVP exhibits a phenomenon known as steady state AChE inhibition. After repeated dosing at the same dose level, the degree of inhibition comes into equilibrium with the

pr oduction of new, uninhibited enzyme. At this point, the amount of AChE inhibition at a given

dose remains consistent across duration. In general, OPs reach steady state within 2

- 3 wee ks but this can vary among OPs. Based on the robust dataset from the O P cumulative risk assessment across the OPs, exposure assessments of 21 days and longer will be conducted for all routes of exposure; i.e., oral, dermal, and inhalation, for all single chemical OP assessments. Given this,

the 21

- day and longer exposure as sessment is scientifically supportable and also provides consistency with the OP cumulative risk assessment and across the OP registration review risk

assessments.

For the dermal and incidental oral risk assessment s , a steady state PoD was selected, a

be nchmark dose lower confidence limit for 10% RBC AChE inhibition ( BMDL 10 ) of 8.01 mg/kg/day, from the subchronic oral toxicity study in rats based on the endpoint (RBC AChE inhibition). The RBC cholinesterase data from this study were evaluated using benchm ark dose modeling (BMD) techniques to be consistent with the current meth ods being used for the OPs. Since an oral study was selected, a dermal absorption factor (DAF) of 9.57% should be used in

the route

- to

- route extrapolation. The DAF is based on the re sults of a derm al penetration study in

rats.

For the inhalation risk assessment, a steady state PoD was selected, a BMDL 10 of 0.02 mg/L/day,

based on a route

- specific endpoint from the subchronic inhalation toxicity study in rats. Using the Agency’s Reference concentration (RfC) methodology, a human equivalent concentration (HEC) was calculated. The HEC is 0.058 mg/L/day, an d the Human Equivalent Dose is 1.65 mg/kg/day.

TCVP is classified as a Group C possible human carcinogen by the Agency with a linear low

dose approach for quantification of risk using the oral slope factor (Q1*) of 1.83 x 10

- 3
(mg/kg/day)

- 1

.

The Food Quality Protection Act (FQPA) safety factor (SF) was reduced to 1X since there is no evidence of sensitivity of the young animal compared to the adult and there are no data gaps. A total UF of 100X is appropriate for dermal and incidental oral routes of e xposure (10X for interspecies extrapolation, 10X for intraspecies variation, and 1X FQPA SF). For the inhalation route of exposure, a total SF of 30X (3X for interspecies extrapolation, 10X for intraspecies variation, and 1X FQPA SF) is appropriate. The interspecies extrapolation is reduced from 10X to 3X because the reference concentration RfC methodology for inhalation is used to determine an HEC and takes into consideration the pharmacokinetic differences between animals and

humans

.Page 6 of 45

Residential Expo sure and Risk

Residential exposures are anticipated from the use of TCVP pet products. Residential TCVP handler and post

- application exposures are anticipated to be short

- (1 to 30 days) to

intermediate

- term (1 to 6 months) in duration . However, because of the steady state AChE

inhibition exhibited by the OPs, s teady state exposures (21 days and longer) were assessed and presented for residential exposures to TCVP pet products.

As mentioned previously, this residential exposure assessment supersedes t he 2010 assessment of exposures from TCVP pet products. It reflects the use of the 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment (2012 Residential SOPs), the Agency’s most current guidance for the assessment of human hea lth exposures from residential pesticide usage. This assessment also incorporates the following changes:

 the assumption of steady state exposures for TCVP exposure assessment;

 updated PoDs following reevaluation of the TCVP toxicity database using the BMD techniques consistent with the methods currently used for other OPs;

 reduction of the total UF for inhalation exposures from 100X to 30X due to use of the Agency’s RfC/HEC methodology;

 voluntary cancellation of TCVP trigger pump spray pet products (EP A Reg. Nos. 2596

- 122, 2596

- 123, and 2596

- 136);

 data submitted by the product registrant Hartz Mountain Corporation regarding the amount of TCVP dispensed per stroke of a pump or trigger spray pet product;

 a master label amendment change for pump and trigger spray products ( EPA Reg. No.

2596

- 140 ) that define s the number of strokes per pet based on animal size;

 the re

- evaluation of a previously submitted and reviewed pet residue transfer study for TCVP dust/powder and pump spray formulations; and

 the u se of a pet residue transfer study data specific to collar formulations.

Residential handler (adults) combined steady state (dermal and inhalation) exposures are not of concern to the Agency (i.e., all aggregate risk indexes (ARIs) are ≥ 1) from applica tion of any registered TCVP pet product

. The ARI approach was required to combine the dermal and inhalation routes of exposure because of the different levels of concern (LOCs).

Residential post

- application steady state adult dermal (only) exposure and c hildren 1 to < 2 years old combined ( dermal and incidental oral exposures ) are not of concern to the Agency (i.e, all MOEs are ≥ 100) for all TCVP pet products assessed. The combined MOE approach

was used because the dermal and incidental oral routes of e xposure have the same LOC.

Estimated residential handler cancer risk estimates range from 10

- 9 to 10

- 7 , and residential post

application cancer risk estimates range from 10

- 8 to 10

- 6

.

Human Studies Review

This risk assessment relies in part on data fr om studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include the 2012 Residential SOPs (Treated Pets SOP)

, as well as a TCVP dust/powder applicator exposure studyPage 7 of 45

( MRID 45519601), and TCVP dust and pump spray study ( MRID 45485501) and propoxur collar pet residue transfer studies (MRID 4858990 1 ) are (1) subject to ethics review pursuant to

40 CFR Part 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain 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

2.0 Risk Assessment Conclusion s and Recommendations

2.1 Summary of Risk Estimates

All residential handler and post

- application TCVP pet product non

- cancer exposure scenarios

assessed resu lted in risk estimates that are not of concern to the Agency. For adults, e stimated

r esidential handler cancer risk estimates range from 10

- 9 to 10

- 7 , and residential post

- application

cancer risk estimates range from 10

- 8 to 10

- 6

.

2. 2 Label Recommendations from Residential Assessment

As currently written, l abel language for the trigger spray product s (EPA Reg. No. 2596

- 125 and

2596

- 126 ) state s that “ m ore spray may be needed for longhaired [cats/ dogs ] .” HED recommends that this language should be removed from the product labels as it could potentially allow for more than the pres cribed number of strokes from a trigger spray to be applied to an animal.

2. 3 Data Deficiencies and Requirements

There are no data deficiencies or requirements identif ied for TCVP at this time.

3.0 Hazard Characterization and Dose

- Response Assessment

TCVP is a member of the organophosphate class of pesticides. Like other O Ps, the initiating

event in the adverse outcome pathway/mode of action ( AOP / MOA ) for TCVP involves inhibition of the enzyme AChE via phosphorylation of the serine residue at the active site of the

enzyme. This inhibition leads to accumulation of acetylcholine and ultimately to neurotoxicity in the central and/or peripheral nervous system (see Figure 1). For TCVP , AChE inhibition is the most sensitive endpoint in the toxicolo gy database in multiple species, dura tions, lifestages,

and routes. AChE inhibition is the focus of this hazard characterization; the availability of reliable AChE inhibition dose response data is one of the key determinants in evaluating this toxicology database.

2 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.htmlPage 8 of 45 Figure 1. Adverse outcome pathway for OPs

In subchronic and chronic toxicity/carcinogenicity studies in rats, effects observed in addition to cholinesterase inhibition were microscopic lesions in the liver, kidney, thyroid, and adrenal gland. In the carcinogenicity study in mice, increases were observed in the hepatocellular

adenomas and carcinomas in males. In the chro nic oral toxicity study in dogs, cholinesterase

inhibition and increased liver an d kidney weights were observed. The mutagenicity database suggests that TCVP was not mutagenic in both gene mutation assays and the primary rat hepatocyte unscheduled DNA syn thesis assay. However, TCVP was positive for inducing chromosomal aberrations in Chinese hamster ovary cells in the absence of metabolic activation and was negative in the pre sence of metabolic activation. TCVP is classified as a possible human carcinoge n. Immunotoxicity was not observed at dose levels that exceed the limit dose.

Developmental toxicity was observed in the rabbit developmental toxicity study, as evidenced by an increase in abortions and early resorptions, with an increase in post

- implant ation loss and a decrease in live fetuses at the same dose level where mortality, abortions, and red vaginal fluid

were o bserved in the maternal rabbit. Developmental toxicity was not observed in the rat developmental toxicity study. No reproductive toxi city was observed in the 2

- generation reproductive study in rats, but increased adrenal weights were observed in the parental rats.

Transient clinical signs characteristic of cholinergic toxicity were observed in the acute and subchronic neurotoxicity st udies in rats, but no clinical signs were observed in the maternal rats or in the offspring in the developmental neurotoxicity study. However, cholinesterase activity was not measured in any of these neurotoxicity studies

. There are comparative cholinest erase studies as well as subchronic and chronic oral toxicity studies on TCVP that provide cholinesterase dose response data across multiple lifestages , durations, and routes of exposure for

both RBC and brain cholinesterase inhibition. No clinical signs characteristic of cholinergic toxicity were observed in any of these assays. Many of these studies have been evaluated using benchmark dose modeling techniques. For all three components of the comparative cholinesterase assays (i.e, acute, repeated, and gestational ) for TCVP, the dose response data are not robust enough for BMD analysis due to high variability in the AChE data. However, these studies do support a conclusion that there is no lifestage sensitivity observed for TCVP. Further

support comes from time course study in pups and adults which provides high quality data and shows no age

- dependent sensitivity.

Acute Toxicity

TCVP has low acute toxicity by the oral, dermal, and inhalation routes of exposure. It is a slight dermal irritant, a moderate eye irritant, and a dermal sensitizer. Target

Tissue Dose Phosphorylation

of the active site

of AChE Neurotoxicity

Accumulation

of acetylcholinePage 9 of 45

Table 3.0. Acute Toxicity of Tetrachlorvinphos Technical

Guideline

No. Study Type MRID

No. Results Toxicity Category

870.1100 Acute Oral

– Rat 41222504 LD 50 = 1480 mg/kg (M)

465

- 965 mg/kg (F) III

870.1200 Acute Dermal

– Rabbit 41222505 LD 50 > 2000 mg/kg III

870.1300 Acute Inhalation

- Rat 00138933 LC50 > 3.61mg/L IV

870.2400 Acute Eye Irritation

- Rabbit 41222506 moderate III

870.2500 Acute Dermal Irritation

- Rabbit 41222507 slight IV

870.2600 Skin Sensitization

- Guinea Pig 41377902

42981001 sensitizer N/A

870.6100 Acute Delayed Neurotoxicity 41905901 No clinical signs of neurotoxicity observed (NTE not measured) N/A

Toxicological Po Ds Used for Risk Assessment

Like other OPs, TCVP exhibits a phenomenon known as steady state AChE inhibition. After repeated dosing at the same dose level, the degree of inhibition comes into equilibrium with the production of new, uninhibited enzyme. At this point, the amount of AChE inhibition at a given

dose remains consistent across duration. In general, OPs reach steady state within 2

- 3 wee ks

, but this can vary among OPs. Based on the robust dataset from the OP cumulative risk assessment

across t he OPs, exposure assessments of 21 days and longer will be conducted for all routes of exposure; i.e., oral, dermal, and inhalation, for all single chemical OP assessments. Given this,

the 21

- day and longer exposure assessment is scientifically supportabl e and also provides consistency with the OP cumulative risk assessment and across the OP registration review risk

assessments

.

TCVP shows a shallow dose

- response curve for cholinesterase inhibition; in other words, large

increases in administered dose re sult in only sm all changes in AChE inhibition. This shallow dose response leads to variability in the AChE data and a relatively broad range of

BMD 10 /BMDL 10 values from 6.8 to 61.6 mg/kg/day/3.6 to 26.3 mg/kg/day. Moreover, when evaluating the data acros s the database, the magnitude of AChE inhibition varies across different studies at comparable dose levels. For example, in the chronic rat toxicity study, increasing the dose from 5.9 mg/kg/day to 62.7 mg/kg/day only leads to changes in female RBC AChE

i nhibition of 10% or less. In the same study at a dose of 125 mg/kg/day, females displayed 17%

- 25% RBC cholinesterase inhibition, whereas males displayed no RBC cholinesterase inhibition at 88 mg/kg/day. Similarly

, in the gestational study, pregnant dams did not exhibit any inhibition up to a dose of 75 mg/kg/day

, whereas in the 21

- day subchronic study, female rats showed approximately 40% RBC AChE inhibition at a dose of 50 mg/kg/day.Page 10 of 45

C onsistent with risk assessment s for other AChE

- inhibiting compounds

, OPP has conducted a BMD analysis using a benchmark response (BMR) level of 10%

, and has thus calculated BMD 10 and BMDL 10 values. The BMD 10 is the estimated dose where ChE is inhibited by 10% compared to background. The BMDL 10 is the lower confidence bo und on the BMD 10

. As a matter of science policy, the a gency uses the BMDL, not the BMD, for use as the PoD (USEPA,

2012 3 )

. All BMD/BMDL modeling was completed using USEPA BMD Software, version 2.2; an exponential model was used to fit the data, with the assumption of constant variance across each dataset. A summary of OPP’s cholinesterase ( ChE ) policy and use of BMD modelin g, and

the results of the TCVP BMD analyses

, can be found in Appendices B and C of this document

, respectively. The technical details of the analysis can be found in a separate BMD

memorandum

. 4

BMD assessment of the 90

- day subchronic oral study provides a BMD 10 of 10.4 mg/kg/day and a

BMDL 10 of 8.01 mg/kg/day. The previous risk assessment used the no

- observed

- adverse

- effect level ( NOAEL ) of 6.7 mg/kg/day from this same study. This BMDL 10 of 8.01 mg/kg/day was selected for the dermal and incidental oral risk assessments. This study was selected because it

has the most robust dose

- re sponse data for deriving PoDs. There are BMDL 10 values in Table C.1 in Appendix C that provide lower BMDL 10 values (comparative cholinesterase assays), but due to high varia bility in the AChE data and the fact that no cholinesterase inhibition was observed at dose levels equal to and greater than these lower BMD 10 /BMDL 10 values, they were not considered appropriate for deriving PoDs.

For the inhalation risk assessment, a s teady state PoD was selected, BMDL 10 of 0.02 mg/L/day,

based on a route

- specific endpoint from the subchronic inhalation toxicity study in rats. Using the Agency’s Reference concentration (RfC) methodology, a human equivalent concentration (HEC) was calcu lated. The HEC is 0.058 mg/L/day, and the Human Equivalent Dose is 1.653 mg/kg/day.

TCVP is classified as a Group C possible human carcinogen by the Agency with a linear low

dose approach for quantification of risk using the oral slope factor (Q 1 *) of 1.83 x 10

- 3
(mg/kg/day)

- 1

.

The Food Quality Protection Act (FQPA) safety factor (SF) was reduced to 1X since there is no evidence of sensitivity of the young animal compared to the adult and there are no data gaps. A total uncertainty factor (UF) of 100X is appropriate for dermal and incidental oral routes of exposure (10X for interspecies extrapolation, 10X for intraspecies variation, and 1X FQPA SF). For the inhalation route of exposure, a total SF of 30X (3X for interspecies extrapolation, 10X

for int raspecies variation, and 1X FQPA SF) is appropriate. The interspecies extrapolation is reduced from 10X to 3X because the reference concentration RfC methodology for inhalation is used to determine an HEC and takes into consideration the pharmacokinetic d ifferences

between animals and humans

.

3 USEPA Benchmark Dose Guidance: http://www.epa.gov/raf/publications/pdfs/benchmark_dose_guidance.pdf

4 J. Bever. Tetrachlorvinphos: Benchmark Dose Analysis of Subchronic and Chronic Studies to Support Derivation of Points of Departure. 5/20/2014. TXR # 0056970. D420286.Page 11 of 45

Absorption

Because an oral study was selected for dermal exposure assessment, a dermal absorption factor (DAF) of 9.57% should be used in the route

- to

- route extrapolation. The DAF is based on the

results of a derm al penetration study in rats. Since the inhalation Po D was based on a route

specific toxicity study, no absorption factor was necessary to estimate exposure. Body Weight

The standard body weight for the general adult population, 80 kg, was used for all exposure scenarios covered in this risk assessment since the endpoints selected were not based on developmental and/or fetal effects. A body weight of 11kg was assumed for children 1 to < 2 years old.

Table 3.1. Summary of Toxicologic al Doses and Endpoints for TCVP for Use in Residential

Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty

Factors Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Incidental

Oral ( steady state ) NOAEL= 6.7

mg/kg/day

BMDL 10 = 8.0 mg/kg/day UF A = 10x

UF H =10x FQPA SF =

1x Residential LOC

for MOE = 100 Subchronic Oral Toxicity Study

– Ra t

LOAEL was 142 mg/kg/day based on

RBC ChE i nhibition

BMD 10 = 10.49 mg/kg/day, based on

female RBC ChE inhibition

Dermal (steady state) NOAEL= 6.7

mg/kg/day

BMDL 10 = 8.0 mg/kg/day

Dermal

Abs orption

= 9.57% a UF A = 10x

UF H =10x FQPA SF =

1x Residential LOC

for MOE = 1 00 Subchronic Oral Toxicity Study

– Ra t

LOAEL was 142 mg/kg/day based on

RBC ChE i nhibition

BMD 10 = 10.49 mg/kg/day, based on

female RBC ChE inhibition

Inhalation ( steady state ) NOAEL=

0.05 mg/ L /day

BMDL 10 =0.02 mg/L/day (males)

HEC=0.058 mg/L/day b

HED=1.653 c mg/kg/day UF A = 3 x

UF H =10x FQPA SF =

1x Residential LOC

for MOE = 30 Subchronic Inhalation Toxicity Study

-

Ra t LOAEL = 0.5 mg/L, based on RBC ChE

i nhibition in males and females

BMD 10 = 0.12 mg/L/day, based on RBC

ChE inhibition in both sexes

Cancer (oral, dermal, inhalation) Classification: A possible human (Group C) carcinogen

. Q 1 * = 1.83 x 10

- 3

(mg/kg/day)

- 1

1 Explanation of Abbreviations: 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 lowe r environmentallyPage 12 of 45

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 (inters pecies). UF H = potential variation in sensitiv ity among

membe rs of the human population (int r a species ); MOE = margin of exposure. LOC = level of concern. N/A = not applicable. a = Since an oral NOAEL was selected, a dermal absorption factor of 9.57% should be used in route

- to

- route extrapolation (MR ID 41862401/ MRID 42111501). b Human Equivalent Conc entration (HEC) = 0.058 mg/L; Po D (BMDL 10 0.022867 mg/L) x (RDDR 2.525) c Human Equivalent Dose (HED) = 1.65 mg/kg/day

.

4.0 Use Profile

TCVP is used as a direct animal treatment to livestock and their premises, outdoors in recreational areas, and as a flea treatment on cats and dogs. Table 4.0 below presents the current residential pet uses of TCVP that include collar, dust/powder, and pu mp and trigger spray

formulations.

Table 4.0. Summary of Registered TCVP Pet Products EPA Reg.

No. Use Site Application Rate Use Restrictions

Collars

2596

- 49 Cats 1,650 mg ai 11.3 gram collar (14.6% ai) Do not use in kittens under 12 weeks of age.

Place the collar around the cat’s neck, adjust for proper fit, and buckle in place. Leave 2 or 3 inches on the collar for extra adjustment and cut off and dispose of the extra length. Replace the collar ev ery 3 months, every 2 months for severe

infestation.

2596

- 50

Dogs 2,770 mg ai 19 gram collar (14.6 % ai)

4,670 mg ai 32 gram collar (14.6% ai) Do not use on puppies less than 6 weeks of age.

Place the collar around the dog’s neck, adjust for proper fit, and buckle in place. Leave 2 or 3 inches on the collar for extra adjustment and cut off and dispose of the extra length. Replace the collar every 3 months, every 2 months for severe

infesta tion.

2596

- 62 Do not use on puppies less than 12 weeks of age. Place the collar around the dog’s neck, adjust for proper fit, and buckle in place. Leave 2 or 3 inches on the collar for extra adjustment and cut off and dispose of the extra length. Replace the collar every 5 months, every 4 months for severe

infestation.

2596

- 63 Cats 2,190 mg ai 15 gram collar (14.6% ai)

2,480 mg ai 17 gram collar (14.6% ai) Do not use on kittens less than 12 weeks of age.

Place the collar around the cat’s neck, adjust for proper fit, and buckle in place. Leave 2 or 3 inches on the collar for extra adjustment and cut off and dispose of the extra length. Replace the collar every 5 months, every 4 months for severe

infesta tion.

2596

- 83 Cats 1,750 mg ai 12 gram collar (14.6% ai)

3,650 mg ai 25 gram collar (14.6% ai) Do not use on kittens less than 12 weeks of age.

Place the collar around the cat’s neck, adjust for proper fit, and buckle in place. Leave 2 or 3 inches on the collar for extra adjustment and cut off and dispose of the extra length. Replace the collar every 7 months, every 5 months for severe

infestation.Page 13 of 45

Table 4.0. Summary of Registered TCVP Pet Products EPA Reg.

No. Use Site Application Rate Use Restrictions

2596

- 84 Dogs 2,770 mg ai 19 gram collar (14.6% ai)

4,670 mg ai 32 gram collar (14.6% ai) Do not use on puppies under 6 weeks of age.

Place the collar around the dog’s neck, adjust for proper fit, and buckle in place. Leave 2 or 3 inches on the collar for extra adjustment and cut off and dispose of the extra length. Replace the collar every 7 months, every 5 months for severe

infestation.

2596

- 139 Cats/

Dogs 1,460 mg ai

10 gram collar (14.6% ai)

7,300 mg ai 50 gram collar (14.6% ai) Do not use on puppies under 6 weeks old/ kittens under 12 weeks

old. Place the collar around the cat’s/dog’s neck, adjust for proper fit, and buckle in place. Leave 2 or 3 inches on the collar for extra adjustment and cut off and dispose of the extra length. Replace the collar every 7 months, or more frequently for seve re infestation.

11556

- 164 Dogs 3,290 mg ai 24 gram collar (13.7% ai) Do not use on puppies under 6 weeks.

Place the collar around the dog’s neck, adjust for proper fit, and buckle in place. Leave 2 or 3 inches on the collar for extra adjustment and cut off and dispose of the extra length. Replace the collar every 5 months, every 4 months for severe

infestation.

11556

- 165 Cats 2,060 mg ai 15 gram collar (13.7% ai) Do not use on kittens less than 12 weeks of age.

Place the collar around the cat’s neck, adjust for proper fit, and buckle in place. Leave 2 or 3 inches on the collar for extra adjustment and cut off and dispose of the extra length. Replace the collar every 5 months, every 4 months for severe

infesta tion.

Dusts/Powders

2596

- 78 Cats 280 mg ai (3.3% ai) 0.30 ounce per small cat

470 mg ai (3.3% ai) 0.5 ounce per large cat Not for use on kittens less than 12 weeks of age. Dust entire cat beginning at head and working back. Use approximately 1/3 ounce of powder for a small cat or 1⁄2 ounce for a large cat. Repeat at weekly intervals if necessary.

2596

- 79 Dogs 470 mg ai (3.3% ai) 1⁄2 ounce per small dog

940 mg ai 1 ounce per medium dog

1,200 mg ai 1 1⁄4 ounce per large dog Not for use on puppies less than 12 weeks of age. Dust entire dog beginning at the head and working back. Make sure powder gets down to the skin. Lightly dust the dog’s bedding with approximately the same amount of powder. Repeat treatment of dog and bedding at weekly intervals if

necessary. Use 1⁄2 ounce of powder for a small dog; 1 oz for a medium dog; and 1 1⁄4 oz for large dogs.

47000

- 123 Cats Estimated Range:

4 3 mg ai, small 100 mg ai, medium

150 mg ai , large (1.0% ai) Do not apply to kittens or puppies under 12 weeks old.

Dust powder evenly over the animal and rub thoroughly through

the hair coat to skin. Use 1/3 oz of powder per every 10 pounds of body weight of your cat or dog. Do not reapply product for 30 days. Dogs Estimated Range:

170 mg ai, small 430 mg ai, mediumPage 14 of 45

Table 4.0. Summary of Registered TCVP Pet Products EPA Reg.

No. Use Site Application Rate Use Restrictions

680 mg ai, large

67517

- 82 Cats Estimated Range:

130 mg ai, small 310 mg ai, medium

460 mg ai, large (3% ai) Do not use on puppies under 12 weeks of age.

Dust powder liberally over the animal and rub thoroughly through

hair coat to skin. Use 1/3 oz of powder per every 10 pounds of body weight of your cat or dog. To control fleas, reapply every 16 days. To control brown dog ticks, reapply every 7 days. Dogs Estimated Range:

510 mg ai, small 1,300 mg ai, medium 2,000 mg ai, large Pump/Trigger Sprays

2596

- 125 Dogs 300 mg ai , small 400 mg ai, medium 700 mg ai, large (1.1% ai) Do not apply to pets (puppies) less than 6 weeks old.

Hold bottle upright about 6 inches from pet. Spray lightly until the tips of the pet’s hair are moist. Rub spray into animal’s coat. Repeat once per week. Recommended dosage: Spray 25

- 30 strokes for a small dog. Spray

30

- 40 strokes for a medium dog. Spray 40

- 70 strokes for a large dog. More spray may be needed for longhaired dogs. 1

2596

- 126 Cats 250 mg ai , small 350 mg ai, large (1.1% ai) Do not apply to pets (kittens) less than 6 weeks old.

Hold bottle upright about 6 inches from pet. Spray lightly until the tips of the pet’s hair are moist. Rub spray into animal’s coat. Repeat once per week. Recommended dosage: Spray 15

- 25 strokes for a small cat. Spray

25

- 35 strokes for a large cat. More spray may be needed for longhaired cats. 1

2596

- 140 Cats 3

(Pump) 51 mg ai , small

71 mg ai, large (1.1% ai) Do not use on puppies or kittens less than 12 weeks old.

Hold bottle upright about 6 inches from pet. Spray lightly until the tips of the pet’s hair are moist. Rub spray into animal’s coat. Repeat once per week. Recommended dosage: Spray 15

- 25 strokes for a small cat. Spray

25

- 35 strokes for a large cat. 2 Recommended dosage: Spray 25

- 35 strokes for a small dog. Spray

30

- 40 strokes for a medium dog. Spray 40

- 70 strokes for a large dog. 2 Cats 3 (Trigger) 250 mg ai, small

350 mg ai, large (1.1% ai)

Dogs (Trigger) 350 mg ai, small

400 mg ai, medium 700 mg ai, large (1.1% ai)

2596

- 136 A “Cancellation Order for Section 3 Pesticide Product Registration(s)” was finalized on July 31, 2013

pertaining to EPA Reg. No. 2596

- 136, Hartz 2 in 1 Flea and Tick Spray for Cats and Dogs.

2596

- 122,

- 123 EPA Reg. Nos. 2596

- 122 and

- 123 have been voluntarily cancelled.

1. Current label language (EPA Reg. No. 2596

- 125 and 2596

- 126) allows for more than a prescribed amount of strokes per cat/dog. Assessment is based on the amount labelled for each weight range . Any such label language allowing for an

exceedance should be removed. 2. The recommended number of strokes as presented for EPA Reg. No. 2596

- 140 is based on master label amendments proposed by the registrant and granted by EPA (March 2014) . Pre viously, a number of strokes per cat/dog was not recommended. The maximum number of strokes was considered in the risk assessment for cats and dogs based on animal size. 3. EPA Reg. No. 2596

- 140 registered as both a pump spray and trigger spray for cats.

5.0 Residential Exposure and Risk Estimates

Residential exposures are anticipated from use of TCVP pet products. Exposures are expectedPage 15 of 45

for adults who apply TCVP products to their pets and from post

- application exposures to adults

and children who ma y contact previously treated pets. Residential TCVP handler and post

application exposures are anticipated to be short

- (1 to 30 days) to intermediate

- term (1 to 6 months). However, because of the steady state AChE inhibition exhibited by the OPs, steady state exposures (21 days and longer) were assessed and presented for residential exposures to TCVP pet products

.

5.1 Residential Handler Exposures

HED uses the term “handlers” to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct tasks related to applications and that exposures can vary depending on the specifics of each task. Residential handlers are assumed to complete all elements of an application without use of any protective equ ipment.

Residential handler exposures to TCVP pet products may occur via the dermal or inhalation routes while the product is placed on a cat or dog. A steady state residential handler exposure

assessment ( combined dermal and inhalation) was performed fo r homeowners applying TCVP products to cats/dogs. In addition, a residential handler cancer assessment was conducted.

The quantitative exposure/risk assessment developed for residential handlers is based on the following exposure scenarios: the applicat ion of TCVP pet collars, dusts/powders, and pump/trigger sprays to cats and dogs.

Residential Handler Exposure Data and Assumptions

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

handler risk assessments. Each assumption and factor is detailed below.

Application Rate: The application rates used in the assessment of pet products typically represent the maximum amount of active ingredient ( ai ) that could be applied by weight of the

treated anim al (small, medium, and large). However, this is only possible when the product is manufactured for use, or is labeled specifically for different animal weight ranges. If this information is not provided, a number of assumptions are used which are describ ed in HED’s 2012 Residential SOPs ( Treated Pets SOP )

. Application rates for all TCVP pet products are presented in Table 4.0.

For TCVP collars, the applicator is directed to cut off and dispose of any excess length once the product is f

it and buckled in to place. As described in the Treated Pet SOP, because the exact length cannot be determined, the corresponding ai loss cannot be quantified and , therefore, exposure is assessed assuming the full collar length.

Per the 2012 Treated Pet SOP, it is assum ed that residential handlers of pet treatment products will treat 2 animals per application. For TCVP dusts/powders, all products identify a specific amount to use per animal weight that allows for determination of the maximum application rate.

For TCVP pump sprays, all registered products direct the user to apply a specific number of “strokes” per animal size. In order to determine the amount of ai applied per treatment asPage 16 of 45

specified by number of strokes, HED requested additional informati on from the pro duct registrant. Hartz Mountain Corporation provided information regarding the volume of product released per stroke for pump and trigger spray products; 0.19 and 0.93 grams, respectively. Only trigger spray products are registered for dogs; however, bot h pump and trigger spray products are registered for cats. Additionally, per request of HED, in March 2014 Hartz Mountain Corporation amended the master label of EPA Reg. No. 2596

- 140 to recommend a number of strokes per animal size. Previously, a number of strokes per cat/dog were not recommended.

Unit Exposures and Area Treated or Amount Handled : C hemical

- specific unit exposure data were provided in support of residential handler risk assessment for the dust/powder formulations only (MRID 455196 01). The study, “Determination of Dermal and Inhalation Exposures to Tetrachlorovinphos (TCVP) During the Application of an Insecticide Powder to a Dog,” was

pr eviously reviewed by the Agency 5 and determined to be acceptable. This exposure data was

used as a surrogate to estimate handler exposures from the TCVP dust/powder products. The study resulted in average unit exposures for the dermal and inhalation routes of exposure of 1,700 mg/lb ai and 3 .1 mg / lb ai, respectively.

In the absence of exposure data for residential handling of pet collars and pump/trigger sprays, HED used exposure values from the 2012 Residential SOPs: Treated Pets as a surrogate to estimate handler exposures. Surrogate exposure data for a groomer trigger pump spray application to do gs was used to estimate handler exposures from TCVP pump spray products. No exposure data are available for assessment of handler exposures from the application of

collars. In the absence of formulation

- specific data, exposure data for spot

- on applicatio ns was used to estimate handler exposures from the TCVP collar products.

Exposure Duration: Residential handler exposure is expected to be short

- term in duration.

Intermediate

- and long

- term exposures are not likely because of the intermittent nature of applications by homeowners. S teady state exposures (21 days and longer) were assessed and presented for residential exposures to TCVP pet products because of the steady state AChE

inhibition exhibited by the OPs.

Days per Y

ear of Exposure: For the p urpose of assessing residential handler cancer exposure /risk from TCVP product application, HED has assumed 4 days per year for collars , and 6 days per year for dusts/powders and pump sprays. The collar is based on a worst

- case assumption of a single application every 3 months. Collar re

- treatment intervals range from 3 to 7 months. HED

assumed a bi

- monthly retreatment interval for dusts/powders and pump sprays.

Years per Lifetime of Exposure: It is assumed that residential handlers would b e exposed for 50 years out of a 78 year lifespan. This factor is routinely used as a conservative estimate of the number of years an individual could continually use a single pesticide product.

Lifetime Expectancy: Life expectancy values are from the Exposure Factors Handbook 2011

Edition Table 18

- 1 (U.S. EPA, 2011). The table shows that the overall life expectancy is 78 years based on life expectancy data from 2007. In 2007, the average life expectancy for males

5 S. Hanley. HED’s Review of Determination of Dermal and Inhalation Exposures to T etrachlorvinphos (TCVP) During the Application of an Insecticide Powder to a Dog. 1/9/02. D278626.Page 17 of 45

was 75 years and 80 years for females . Based on the available data, the recommended value for use in cancer risk assessments is 78 years.

Residential Handler Non

- Cancer Exposure and Risk Estimate Equations The algorithms used to estimate non

- cancer exposure and dose for residential handlers can be found in Appendix A and/or the 2012 Residential SOPs

. 6

Combining Exposure/Risk Estimates

A total ARI approach was required to combine the dermal and inhalation routes of exposure because of the different levels of concern (LOCs) ; dermal exposure (100) and inhalation exposure (30 )

. ARIs of less than 1 are risk estimates of concern. The ARI was calculated as

follows.

Aggregate Risk Index (ARI) = 1÷ [ ( Dermal LOC ÷ Dermal MOE ) + ( Inhalation LOC ÷ Inhalation MOE ) ]

Summary of Residen tial Handler Non

- Cancer Exposure and Risk Estimates Residential handler (adults) combined steady state dermal and inhalation exposures are not of concern to the Agency (i.e., all ARIs are ≥ 1) from application of any registered TCVP pet product (Table 5.1

. 1 ).

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

- exposure

- sop.htmlPage 18 of 45 Table 5.1

. 1. Residential Handler Non

- cancer Exposure and Risk Estimates from Use of TCVP Pet Products

Exposure Scenario Reg. No. Level of

Concern Dermal Unit

Exposure (mg/lb ai) Inhalation

Unit Exposure (mg/lb ai) Maximum

Application

Rate 1

(lb ai/pet) Amount

Handled Daily 2 Dermal Inhalation Total

Dose (mg/kg/day) 3 MOE 4 Dose (mg/kg/day) 5 MOE 6 ARI 7

Application of TCVP

Collars 2596

- 49:

Cat

Dermal: 100 120 Negligible 0.0036:
11 gram collar

2

animals treated per day 0.0 0 1 0 7,600

Negligible NA 2596

- 50, 62: Dog 0.0061:
19 gram collar 0.018 4,500

0.010:
32 gram collar 0.0 0 3 0 2,700

2596

- 63:

Cat 0.0048:
15 gram collar 0.0 0 14 5,800

0.0055:
17 gram collar 0.0 0 16 5,100

2596

- 83:

Cat 0.0039:
12 gram collar 0.0 0 1 1 7,200

0.0080:
25 gram collar 0.0 023 3,500

2596

- 84: Dog 0.0061:
19 gram collar 0. 0 01 8 4,500

0.010:
32 gram collar 0.0 030 2,700

2596

- 139:

Cat 0.0032:
10 gram collar 0.00 093 8,600

2596

- 139: Dog 0.016:
50 gram collar 0.0 046 1,700

11556

- 164: Dog 0.0072:
24 gram collar 0.0021 3,800

11556

- 165:

Cat 0.0045:
15 gram collar 0.0 013 6,100Page 19 of 45 Table 5.1

. 1. Residential Handler Non

- cancer Exposure and Risk Estimates from Use of TCVP Pet Products

Exposure Scenario Reg. No. Level of

Concern Dermal Unit

Exposure (mg/lb ai) Inhalation

Unit Exposure (mg/lb ai) Maximum

Application

Rate 1

(lb ai/pet) Amount

Handled Daily 2 Dermal Inhalation Total

Dose (mg/kg/day) 3 MOE 4 Dose (mg/kg/day) 5 MOE 6 ARI 7

Application of TCVP

Dusts/Powders 2596

- 78:

Cat

Dermal: 100

Inhalation:

30 1,700 3.1 0.00062:

small 0.0 025 3,200 0.000048 34,000 31

0.0010 : large 0. 0042 1,900 0.000080 21,000 18

2596

- 79; Dog 0.0010:

small 0.0042 1,900 0.000080 21,000 18

0.0021:

medium 0.0084 950 0.00016 10,000 9.2

0.0026: large 0.011 760 0.00020 8,300 7.4

47000

- 123:

Cat 0.000 0 94:

small 0.00038 21,000 0.0000073 230,000 200

0.00023 : medium 0.00092 8,700 0.000017 95,000 85

0.00034 : large 0.0014 5,800 0.000026 63,000 57

47000

- 123:
Dog 0.00037 : small 0.0015 5,200 0.000029 57,000 51

0.00094 : medium 0.0038 2,100 0.000073 23,000 20

0.0015 : large 0.0061 1,300 0.00012 14,000 13

67517

- 82:

Cat 0.00028 : small 0.0011 7,000 0.000022 76,000 68

0.00067 : medium 0.0028 2,900 0.000052 32,000 28

0.0010 : large 0.0041 1,900 0.000078 21,000 19

67517

- 82:
Dog 0.0011 : small 0.0046 1,700 0.000087 19,000 17

0.0028 : medium 0.011 700 0.00022 7,600 6.8

0.0045 : 0.018 440 0.00035 4,700 4.2Page 20 of 45 Table 5.1

. 1. Residential Handler Non

- cancer Exposure and Risk Estimates from Use of TCVP Pet Products

Exposure Scenario Reg. No. Level of

Concern Dermal Unit

Exposure (mg/lb ai) Inhalation

Unit Exposure (mg/lb ai) Maximum

Application

Rate 1

(lb ai/pet) Amount

Handled Daily 2 Dermal Inhalation Total

Dose (mg/kg/day) 3 MOE 4 Dose (mg/kg/day) 5 MOE 6 ARI 7

large

Application of TCVP Pump /Trigger Sprays 2596

- 126,

- 140:

Cat (Trigger)

820 3.3 0.00055:

small 0.0011 7,400 0.000045 36,000 70

0.00077:

medium 0.0015 5,300 0.000064 26,000 50

2596

- 140

Cat
(Pump) 0.00011:

small 0.00022 36,000 0.0000093 180,000 340

0.00016:
large 0.00031 26,000 0.000013 130,000 240

2596

- 125

, - 140 : Dog (Trigger) 0.00077:

small 0.0015 5,300 0.000064 26,000 50

0.00088:

medium 0.0017 4,600 0.000073 23,000 43

0.0015:
large 0.0030 2,600 0.00013 13,000 25

1 Based on registered TCVP pet product labels.

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

- exposure

- sop.html ).

3 Dermal Dose = Dermal Unit Exposure (mg/lb ai) × Application Rate (lb ai/pet) × Area Treated or Amount Handled (pets/day) × Dermal Absorptio n Factor (9.6 %) ÷ Body Weight (80 kg).

4 Dermal MOE = Dermal NOAEL ( 8.0 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

5 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/pet) × Area Treated or Amount Handled (pets/day) ÷ Body Weight (80 kg).

6 Inhalation MOE = Inhalation NOAEL ( 1.65 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

7 Aggregate Risk Index (ARI) = 1/ ((1 / (Dermal MOE/ Dermal LOC ; 100 )) + (1/ ( Inhalation MOE/ Inhalation LOC ; 30 ))Page 21 of 45

Residential Handler Cancer Exposure and Risk Estimate Equations Cancer risk estimates were calculated using a linear low

- dose extrapolation approach in which a Lifetime Average Daily Dose (LADD) is first calculated and then compared with a Q 1 * that has

been calculated for TCVP based on dose response data in the appropriate toxicology study (Q 1 *

= 1.83 x 10

- 3 (mg/kg/day)

- 1 ). Absorbed average daily dose (ADD) levels were used as the basis for calculating the LADD values. Dermal and inhalation ADD values were first added together to obtain combined ADD values. LADD values were then calculated and compared to the Q 1 * to obtain cancer risk estimates. The algori thms used to estimate the LADD and cancer risk for residential handlers can be found in Appendix A

.

Summary of Residential Handler Cancer Exposure and Risk Estimates Estimated residential handler cancer risk estimates range from 10

- 9 to 10

- 7 (Table 5.1.2 )

.

Table 5.1 .2

. Residential Handler Cancer Exposure and Risk Estimates from TCVP Pet

Products

Reg No./ Animal Type Animal Size Lifestage LADD 1,2 Cancer Risk

Estimate 3

Pet Collars

2596

- 49: Cat Any

Adult 7.4E

- 06 1.3E

- 08

2596

- 50, 62: Dog Small 1.2E

- 05 2.3E

- 08

Medium, Large 2.1E

- 05 3.8E

- 08

2596

- 63: Cat Small 9.8E

- 06 1.8E

- 08

Medium, Large 1.1E

- 05 2.0E

- 08

2596

- 83: Cat Small 7.8E

- 06 1.4E

- 08

Medium, Large 1.6E

- 05 3.0E

- 08

2596

- 84: Dog Small 1.2E

- 05 2.3E

- 08

Medium, Large 2.1E

- 05 3.8E

- 08

2596

- 139: Cat Any 6.5E

- 06 1.2E

- 08

2596

- 139: Dog Any 3.3E

- 05 6.0E

- 08

11556

- 164: Dog Any 1.5E

- 05 2.7E

- 08

11556

- 165: Cat Any 9.2E

- 06 1.7E

- 08

Dust/Powder

2596

- 78: Cat Small

Adult 2.7E

- 05 5.0E

- 08

Medium 4.5E

- 05 8.3E

- 08

2596

- 79: Dog Small 4.5E

- 05 8.3E

- 08

Medium 9.0E

- 05 1.7E

- 07

Large 1.1E

- 04 2.1E

- 07

47000

- 123: Cat Small 4.1E

- 06 7.5E

- 09

Medium 9.8E

- 06 1.8E

- 08

Large 1.5E

- 05 2.7E

- 08

47000

- 123: Dog Small 1.6E

- 05 3.0E

- 08

Medium 4.1E

- 05 7.5E

- 08Page 22 of 45

Table 5.1 .2

. Residential Handler Cancer Exposure and Risk Estimates from TCVP Pet

Products

Reg No./ Animal Type Animal Size Lifestage LADD 1,2 Cancer Risk

Estimate 3

Large 6.6E

- 05 1.2E

- 07

67517

- 82: Cat Small 1.2E

- 05 2.3E

- 08

Medium 3.0E

- 05 5.4E

- 08

Large 4.4E

- 05 8.1E

- 08

67517

- 82: Dog Small 4.9E

- 05 9.0E

- 08

Medium 1.2E

- 04 2.3E

- 07

Large 2.0E

- 04 3.6E

- 07

Pump/Trigger Sprays

2596

- 126:

- 140: Cat (Trigger) Small

Adult 1.2E

- 05 2.2E

- 08

Large 1.7E

- 05 3.0E

- 08

2596

- 140:
Cat (Pump) Small 2.4E

- 06 4.4E

- 09

Large 3.4E

- 06 6.2E

- 09

2596

- 125,

- 140: Dog (Trigger) Small 1.7E

- 05 3.0E

- 08

Medium 1.9E

- 05 3.5E

- 08 Large 3.3E

- 05 6.1E

- 08

1 Total L ifetime A verage D aily D ose (mg/kg/day) = Dermal LADD (mg/kg/day) + Inhalation LADD (mg/kg/day). 2 Dermal and Inhalation LADD equations provided in Appendix A.

3 Cancer risk estimates = Total LADD × Q 1 * , where Q 1 * = 1.83 x 10

- 3 (mg/kg/day)

- 1

5.2 Residen tial Post

- application Exposure/Risk Estimates

There is the potential for post

- application exposure for individuals exposed as a result of contacting a cat/ dog previously treated with TCVP pet product s

. The quantitative exposure/risk

assessment for residential post

- application exposures is based on the following scenarios:

1) Post

- application dermal (adults and children 1 to < 2 years old) exposure from contacting cats and dogs treated with TCVP; and 2) Post

- application incidental oral (hand

- to

- mouth) exposure (children 1 to < 2 years olds only) from contacting cats and dogs treated with TCVP.

Residential post

- application inhalation exposure is expected to be negligible from TCVP pet products and, thus, a quantitative assessment was not performed. Per the 2012 Residential SOPs,

t he combination of low vapor pressure (2.6 x 10

- 7 mmHg at 25°C) and the small amounts of pesticide applied to pets is expected to result in negligible inhalation exposures.

The lifestages selected for each post

- application scenario (i.e., adults and children 1 to < 2 years old) are based on an analysis provided in the 2012 Residential SOPs. While not the only lifestage potentially exposed for these post

- application scenarios, the lifestage that is included in the quantitative assessment is health protective for the exposures and risk estimates for all who

are potentially exposed.Page 23 of 45

Residential Post

- Application Exposure Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the residential

post

- applicati on risk assessment. Each assumption and factor is detailed in the 2012 Residential

SOPs. Surrogate and chemical

- specific residue transfer studies were used for assessment of

post

- application exposures from registered TCVP pet products. These exposure da ta include the

followi ng residue transfer studies: propoxur collar (MRID 4858990 1 ); and TCVP pow der and pump spray (MRID 454855 01).

HED previous ly conducted a data evaluation record (DER) of the TCVP exposure study for aerosols, powder s, and pump sprays 7 in 2001

. In support of the Agency’s response to the NRDC petition, the study has been reevaluated based on current standards of conduct for pet residue

transfer studies

. 8 The reevaluation of the TCVP residue transfer study resulted in a number of changes from the 2001 DER. Table 5.2.1 below presents a comparison of the methods used to evaluate the study data.

Table 5.2.1. Comparison of 2001 and Current TCVP Pet Residue Transfer Study Reviews

2001 Review Current Review

Hand wipe residue data were corrected for average field fortification recoveries <90%. Hand wipe residue data were corrected for average field fortification recoveries <120%.

TCVP residues on hands in μg/cm 2 were calculated using the surface area of the stroking area (defined as length of dog x length of study participant’s hand). TCVP residues are calculated in μg/cm 2 using the surface area of the entire dog, based on the weight

of the test animal.

The percent of applied TCVP dislodged by the hand following treatment was calculated based on the amount of TCVP residue on the stroking area, which was determined from extrapolating residues detected in fur samples from a shaved area to the

area of the st roking area. The percent of applied TCVP transferred to the

hand was calculated based on the total amount of active ingredient applied to the dog (calculated as

the amount removed fr om container in grams x actual percent active ingredient in test produc t).

Regression analyses were conducted using the residue data in μg/cm 2

. The revised regression analyses were conducted using the percent of applied dose transferred to

the hand.

It should be noted that the TCVP powder and pump spray post

- application exposure study was not conducted in a manner reflective of current standards that require a defined stroking procedure and greater number of petting simulations. That is, the pet is t o be stroked in a single motion with the grain of the fur starting with both side s (along the ribcage) of the [cat/dog] and followed by the same motion along the back (dorsally) from the base of the neck to the tail . The two sides and back, in this order

, account for one petting simulation. A total of 20 petting

7 S. Hanley. Re

- evaluation of Determination of the Dislodgeability of Tetrachlorvinphos (TCVP) from the Fur of Dogs Following the Application of an Insecticide Powder, Pump Spray or Aerosol. 3/25/02. D277543.

8 W. Britton. Tetrachlorvinphos: Re evaluation of “HED’s Review of Determination of the Dislodgeability of Tetrachlorvinphos (TCVP) from the Fur of Dogs Following the Application of an Insecticide Powder, Pump Spray

or Aerosol ; MRID 45485501. 5/16/14. D420285

.Page 24 of 45

simulat ions (or 60 stroking motions) are currently required. In the TCVP post

- application exposure study

, the dogs were stroked only one side of treated dog’s back from head to rump

five times. However, the study was reflective of current policy regarding pet residue transfer

stud ies at the time that it was conducted. In order to account for the differences between the TCVP post

- application exposure study and the currently recommended standard, the Agency used the maximum observed percent residue transfer on the day of product application (Day 0) for both formulations for exposure and risk quantification. Typically, the Agency assesses post

application risk with use of the mean percent residue tr ansfer measured on Day 0; the use of the maximum value results in a more health protective risk assessment. Even though the post

application exposure study methods have evolved, the TCVP study employed a rigorous

collection method and is not anticipated t o underestimate exposure.

The 2012 Residential SOPs: Treated Pets recommends assessment of post

- application exposures using day of application (i.e., Day 0) residue transfer

-- defined as fraction application rate ( F AR )

in the 2012 SOPs . Day of applicati on (Day 0) percent residue transfer values (as referenced from the above studies) used for exposure/risk quantification are as follows: pet co llars, 0.072 %; dusts/powders, 0.048% (maximum observed) ; and pump sprays, 0.81 % (maximum observed)

.

For purpose of quantification of estimated TCVP post

- application cancer exposures/risks, HED recommends use the average percent residue transfer of all days sampled in the propoxur collar 9
and TCVP dust/powder and pump spray studies. For the TCVP collar, HED used an average F AR (of 28 days sampling in the propoxur collar study) of 0.013% to represent 180 days exposure per year. Due to the reasons described above with use of the TCVP dust/powder and pump spray exposure data, HED used an a verage of the maximum observed percent residue transfer for each day tested for calculation of cancer exposures/risks resulting in an F AR of 0.022% and 0.18 % for dusts/powders and pump sprays, respectively.

Exposure Duration : Residential post

- application exposure is expected to be short

- and

intermediate

- term for dust/powders and pump/trigger sprays. For pet collars, post

- application exposures is expected to be long

- term (greater than 6 months) due to the potential for extended usage in more temperate parts of the country, and the longer active lifetime of pet collar products. Again, because of the steady state AChE inhibition exhibited by the OPs, steady state exposures (21 days and longer) were assessed and presented for residential post

- application exposures to TCVP pet products

.

Hand

- to

- Mouth Event Frequency : The 2012 Residential SOPs recommend a frequency estimate

of 20 as the modeled number of hand

- to

- mouth events per hour for children 1

- 2 years old. There are currently no data available that specifically address the numbe r of hand

- to

- mouth events that occur relative to the amount of time that a child spends with a pet. As a result, the estimate for frequency of hand

- to

- mouth events in indoor environments is based on the Xue et al. (2007) 10

meta

- analysis of child hand mouthing frequency. The indoor data were selected, even though

9 S. Shelat. Propoxur: Data Evaluation Record for the Study “Determination of Transferable Residues of Propoxur from the Hair of Dogs Wearing collars Impregnated with Propoxur

– Final Report

. ” 10/12/12. D393899.

10 Xue, J., Zartarian, V., Moya, J., Freeman, N., Beamer, P., Black, K., Tulve, N., Shalat, S. (2007), A Meta

Analysis of Children's Hand

- to

- Mouth Frequency Data for Estimating Nondietary Ingestion Exposure. Risk Analysis, 27(2):411

- 420.Page 25 of 45

child exposure to treated pets can occur either indoors or outdoors, because the indoor data result in a greater frequency of contacts and, therefore, a more healt h protective risk assessment.

Residential Post

- application Non

- Cancer Exposure and Risk Equations The algorithms used to estimate cancer and non

- cancer exposure and dose for residential post

application can be found in Appendix A and/or the 2012 Residen tial SOPs

. 11

Combining Exposure and Risk Estimates HED combines risk values resulting from separate routes of exposure when it is likely they can occur simultaneously based on the use pattern and the behavior associated with the exposed population, and if the hazard associated with the points of departure is similar across routes. A common toxicological endpoint, RBC A ChE inhibition , exists for dermal and incidental oral routes of exposure to TCVP ; thus, exposures should be combined for all routes of expos ure.

Summary of Residential Post

- Application Non

- Cancer Exposure and Risk Estimates Residential post

- application s teady state adult dermal exposure and children 1 to < 2 years old combined dermal and incidental oral exposures are not of concern to the Ag ency (i.e, all MOEs are ≥ 100) for all TCVP pe t products assessed (Table 5.2.2 ).

Table 5.2. 2

. Residential Post

- Application Non

- Cancer Exposure and Risk Estimates from TCVP

Products
EPA Reg.

No./

Animal Lifestage Post

- application

Exposure Scenario Application

Rate (mg ai) 1 Animal

Size Dose (mg/kg/day) 2 MOEs 3 Total

MOE 4 Route of Exposure

Pet Collars

2596

- 49:

Cat Adult Dermal

1

, 650 Small 0.0 038 2,100

X Medium 0.0 023 3,500
Large 0.0 0 14 5,600

Children

1 < 2 Dermal Small 0.0 097 830 750

Incidental Oral 0.0010 7,900

Dermal Medium 0.0058 1, 400 1,300 Incidental Oral 0.00061 13 ,000

Dermal Large 0.0036 2,200 2,000 Incidental Oral 0.00038 21 ,000

2596

- 50,

62: Dog Adult Dermal 2

, 77 0 Small 0.0032 2, 500 X 4

, 67 0 Large 0.00 15 5,400

Children

1 < 2 Dermal 2

, 77 0 Small 0.0081 980 890

Incidental Oral 0.00085 9,400

Dermal 4

, 67 0 Large 0.00 37 2,100 1,9 00 Incidental Oral 0.000 39 21 ,000

2596

- 63:

Cat Adult Dermal 2

, 190 Small 0.00 51 1, 600

X 2

, 48 0 Large 0.00 2 1 3, 700

Children Dermal 2

, 190 Small 0.013 620 560

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

- exposure

- sop.htmlPage 26 of 45

Table 5.2. 2

. Residential Post

- Application Non

- Cancer Exposure and Risk Estimates from TCVP

Products
EPA Reg.

No./

Animal Lifestage Post

- application

Exposure Scenario Application

Rate (mg ai) 1 Animal

Size Dose (mg/kg/day) 2 MOEs 3 Total

MOE 4 Route of Exposure

1 < 2 Incidental Oral 0.0013 6 ,000

Dermal 2

, 48 0 Large 0.00 55 1, 500 1,4 00 Incidental Oral 0.000 57 14 ,000

2596

- 83:

Cat Adult Dermal 1

, 75 0 Small 0.00 40 2,000 X 3

, 650 Large 0.00 32 2, 500

Children

1 < 2 Dermal 1

, 75 0 Small 0.010 780 710

Incidental Oral 0.0011 7,500

Dermal 3

, 650 Large 0.0 080 1,000 910 Incidental Oral 0.00 084 9,600

2596

- 84: Dog Adult Dermal 2

, 77 0 Small 0.0032 2

, 500 X 4

, 67 0 Large 0.00 15 5,400

Children

1 < 2 Dermal 2

, 77 0 Small 0.0081 980 890

Incidental Oral 0.00085 9,400

Dermal 4

, 67 0 Large 0.0 0 37 2,100 1,9 00 Incidental Oral 0.00039 21,000

2596

- 139:

Cat Adult Dermal

1

, 460 Small 0.00 34 2

, 400

X Medium 0.00 20 4,000
Large 0.00 13 6,300

Children

1 < 2 Dermal Small 0.0086 930 840

Incidental Oral 0.00089 9,000

Dermal Medium 0.0051 1,6 00 1,4 00 Incidental Oral 0.00054 15 ,000

Dermal Large 0.0032 2, 500 2,300 Incidental Oral 0.00033 24 ,000

2596

- 139: Dog Adult Dermal

7

, 300 Small 0.0084 950

X Medium 0.0036 2,200
Large 0.00 23 3,500

Children

1 < 2 Dermal Small 0.021 3 70 340

Incidental Oral 0.0022 3,6 00

Dermal Medium 0.0092 870 790 Incidental Oral 0.00096 8,400

Dermal Large 0.0058 1,4 00 1,3 00 Incidental Oral 0.00061 13 ,000

11556

- 164: Dog Adult Dermal

3,290 Small 0.0038 2,100

X Medium 0.00 16 4

, 900
Large 0.0010 7,700

Children

1 < 2 Dermal Small 0.0096 830 750

Incidental Oral 0.0010 8,000

Dermal Medium 0.0041 1, 900 1,7 00 Incidental Oral 0.00043 19 ,000Page 27 of 45

Table 5.2. 2

. Residential Post

- Application Non

- Cancer Exposure and Risk Estimates from TCVP

Products
EPA Reg.

No./

Animal Lifestage Post

- application

Exposure Scenario Application

Rate (mg ai) 1 Animal

Size Dose (mg/kg/day) 2 MOEs 3 Total

MOE 4 Route of Exposure

Dermal Large 0.0026 3,000 2,7 00 Incidental Oral 0.00027 29 ,000

11556

- 165:

Cat Adult Dermal

2,060 Small 0.00 47 1,7 00

X Medium 0.00 28 2,8 00
Large 0.00 18 4,500

Children

1 < 2 Dermal Small 0.012 6 60 600

Incidental Oral 0.0013 6,400

Dermal Medium 0.0072 1,100 1,000 Incidental Oral 0.00075 11,000

Dermal Large 0.0045 1,8 00 1,6 00 Incidental Oral 0.00047 17 ,000

Dusts/Powders

47000

- 123: Dog Adult Dermal 170 Small 0.0 0 35 2,300

X 4 30 Medium 0.0 0 38 2,1 0 0

680 Large 0.0 0 38 2,100

Children

1 < 2 Dermal 170 Small 0.0 0 90 890 450

Incidental Oral 0.0 0 87 920

Dermal 4 30 Medium 0.0 0 97 830 420 Incidental Oral 0.0 0 93 860

Dermal 680 Large 0.0 0 98 810 410 Incidental Oral 0.0 0 95 840

47000

- 123 :
Cat Adult Dermal 4 3 Small 0.0 0 18 4,500

X 10 0 Medium 0.0 0 25 3,200

15 0 Large 0.0 0 24 3,400

Children

1 < 2 Dermal 4 3 Small 0.0 0 45 1

, 8 0 0 900

Incidental Oral 0.0 0 4 3 1

, 8 0 0

Dermal 10 0 Medium 0.0 0 65 1

, 2 0 0 620 Incidental Oral 0.0 0 63 1

, 3 0 0

Dermal 15 0 Large 0.0 0 61 1

, 3 0 0 670 Incidental Oral 0.0 0 59 1

, 4 0 0

2596

- 78:

Cat Adult Dermal 280 Small 0.012 690 X 470 Large 0.0073 1,100

Children

1 < 2 Dermal 280 Small 0.030 270 140

Incidental Oral 0.029 280

Dermal 470 Large 0.019 430 220 Incidental Oral 0.018 450

2596

- 79: Dog Adult Dermal 470 Small 0.0097 820

X 940 Medium 0.0083 960
1,200 Large 0.0066 1,2 00

Children Dermal 470 Small 0.025 320 160Page 28 of 45

Table 5.2. 2

. Residential Post

- Application Non

- Cancer Exposure and Risk Estimates from TCVP

Products
EPA Reg.

No./

Animal Lifestage Post

- application

Exposure Scenario Application

Rate (mg ai) 1 Animal

Size Dose (mg/kg/day) 2 MOEs 3 Total

MOE 4 Route of Exposure

1 < 2 Incidental Oral 0.024 330

Dermal 940 Medium 0.021 380 1 90 Incidental Oral 0.021 390

Dermal 1,200 Large 0.017 4 70 240 Incidental Oral 0.0 16 490

67517

- 82: Dog Adult Dermal 510 Small 0.0 11 760

X 1,300 Medium 0.0 11 710
2,000 Large 0.0 12 690

Children

1 < 2 Dermal 510 Small 0.027 300 150

Incidental Oral 0.026 310

Dermal 1,300 Medium 0.029 280 140 Incidental Oral 0.028 290

Dermal 2,000 Large 0.030 270 140 Incidental Oral 0.028 2 80

67517

- 82:

Cat Adult Dermal 130 Small 0.005 3 1,5 00

X 310 Medium 0.0076 1,100

460 Large 0.0071 1,100

Children

1 < 2 Dermal 130 Small 0.014 590 300

Incidental Oral 0.013 610

Dermal 310 Medium 0.0 20 410 210 Incidental Oral 0.019 430

Dermal 460 Large 0.018 440 220 Incidental Oral 0.018 450

Pump/Trigger Spray

2596

- 126,

140: Cat (Trigger) Adult Dermal 250 Small 0.0065 1,2 00

X 350 Large 0.0034 2,3 00

Children

1 < 2 Dermal 250 Small 0.017 4 80 440

Incidental Oral 0.0017 4,700

Dermal 350 Large 0.0087 920 830 Incidental Oral 0.00090 8,900

2596

- 140:

Cat (Pump) Adult Dermal 51 Small 0.0013 6,000 X 71 Large 0.00070 12,000

Children

1 < 2 Dermal 51 Small 0.0034 2,4 00 2,200

Incidental Oral 0.000 35 23 ,00 0

Dermal 71 Large 0.0018 4,500 4,100 Incidental Oral 0.000 18 43 ,000

2596

- 125,

- 140: Adult Dermal 350 Small 0.0045 1,8 00 X 400 Medium 0.0022 3,6 00Page 29 of 45

Table 5.2. 2

. Residential Post

- Application Non

- Cancer Exposure and Risk Estimates from TCVP

Products
EPA Reg.

No./

Animal Lifestage Post

- application

Exposure Scenario Application

Rate (mg ai) 1 Animal

Size Dose (mg/kg/day) 2 MOEs 3 Total

MOE 4 Route of Exposure
Dog (Trigger) 700 Large 0.0025 3,200

Children

1 < 2 Dermal 350 Small 0.012 690 620

Incidental Oral 0.0012 6,600

Dermal 400 Medium 0.0057 1,4 00 1,3 00 Incidental Oral 0.00059 14 ,000

Dermal 700 Large 0.0063 1,3 00 1,200 Incidental Oral 0.00066 12 ,000

1 Based on registered TCVP pet products as detailed in Table 4.0.

2 Dose (mg/kg/day) equations provided in Appendix A.

3 MOE = Po D ( 8.0 mg/kg/day) ÷ Dose (mg/kg/day).

4 Total MOE = 1 ÷ (1 ÷ Dermal MOE) + (1 ÷ Incidental Oral MOE), where applicable.

Residential Post

- application Cancer Exposure and Risk Estimate Equations As was done for residential handlers, p ost

- application cancer risk estimates for adults were calculated using a li near low

- dose extrapolation approach in which a LADD is first calculated and then compared with a Q 1 * that has been calculated for TCVP based on dose response data in the appropriate toxicology study (Q 1 * = 1.83 x 10

- 3 (mg/kg/day)

- 1 ). The algorithms used to estimate the LADD and cancer risk for residential post

- application exposure can be found in Appendix A.

It should be noted that in the past, cancer risk assessments have assumed that children are no

more sensitive than adults to carcinogens (i.e., no adjustment was made to children's exposure estimates in calculating a cumulative lifetime exposure). More recently, the Agency's "Guidelines for Carcinogen Risk Assessment" (USEPA, 2005) and “Supplemental Guidance for Assessing Su sceptibility from Early

- Life Exposure to Carcinogens” (USEPA, 2005) proposed

age

- dependent adjustment factors to be applied to children's exposure. These age

- dependent factors are applied only to carcinogens shown to have a mutagenic mode of action. In g eneral, most carcinogenic pesticides have not been shown to act through a mutagenic mode of action

, and thus separate assessment of children and adults is not warranted. Any pesticide found to be a carcinogen acting through a mutagenic mode of action shou ld be dealt with on a case by case

basis

, and such an assessment should follow the Agency’s 2005 guidance. The mutagenicity

database for TCVP suggests that this chemical is not mutagenic in both the gene mutation assay and primary rat hepatocyte unschedul ed DNA synthesis ass ay and, therefore , only adult cancer

risk estimates have been estimated.

Days per Year of Exposure: For purpose of estimating adult dermal cancer risks, exposure was assumed for 180 of 365 total days per year. This factor is used a s a health protective estimate of the number of days that an individual could be exposed to a treated animal per year of product use. The recommendation of 6 months exposure is conservative, particularly when paired with the assumption that this

exposure duration is repeated for 50 years during a n adult’s lifetime.Page 30 of 45

Years per Lifetime of Exposure:

It is assumed that adults would be exposed for 50 years out of a 78 year lifespan. This factor is routinely used as a conservative estimate of the number of years an individual could continually use a single pesticide product.

Lifetime Expectancy: Life expectancy values are from the Exposure Factors Handbook 2011

Edition Table 18

- 1 (U.S. EPA, 2011). The table shows that the overall life expectancy is 78

ye ars based on life expectancy data from 2007. In 2007, the average life expectancy for males was 75 years and 80 years for females. Based on the available data, the recommended value for use in cancer risk assessments is 78 years.

Summary of Residential Post

- application Cancer Exposure and Risk Estimates

Adult residential post

- application dermal cancer risk estimates range from 10

- 8 to 10

- 6 ( detailed

below in Table 5.2.3 ).

Table 5.2.3

. Residential Post

- Application Cancer Exposure and Risk Estimates from

TCVP Pet Products

Animal Type Animal

Size Lifestage LADD 1,2 Cancer Risk Estimate 3

Collar

2596

- 49: Cat Small

Adult 2.2E

- 04 4.0E

- 07

Medium 1.3E

- 04 2.4E

- 07

Large 8.1E

- 05 1.5E

- 07

2596

- 50,62: Dog Small 1.8E

- 04 3.3E

- 07

Large 8.4E

- 05 1.5E

- 07

2596

- 83: Cat Small 2.3E

- 04 4.2E

- 07

Large 1.8E

- 04 3.3E

- 07

2596

- 139: Cat Small 1.9E

- 04 3.5E

- 07

Medium 1.2E

- 04 2.1E

- 07

Large 7.2E

- 05 1.3E

- 07

11556

- 164: Dog Small 2.2E

- 04 4.0E

- 07

Medium 9.3E

- 05 1.7E

- 07

Large 5.9E

- 05 1.1E

- 07

11556

- 165: Cat Small 2.7E

- 04 5.0E

- 07

Medium 1.6E

- 04 3.0E

- 07

Large 1.0E

- 04 1.9E

- 07

2596

- 84: Dog Small 1.8E

- 04 3.3E

- 07

Large 8.4E

- 05 1.5E

- 07

2596

- 139: Dog Small 4.8E

- 04 8.8E

- 07

Medium 2.1E

- 04 3.8E

- 07

Large 1.3E

- 04 2.4E

- 07

2596

- 63: Cat Small 2.9E

- 04 5.3E

- 07Page 31 of 45

Table 5.2.3

. Residential Post

- Application Cancer Exposure and Risk Estimates from

TCVP Pet Products

Animal Type Animal

Size Lifestage LADD 1,2 Cancer Risk Estimate 3

Large 1.2E

- 04 2.2E

- 07

Dust/Powder

47000

- 123: Dog Small

Adult 5.1E

- 04 9.3E

- 07

Medium 5.5E

- 04 1.0E

- 06

Large 5.6E

- 04 1.0E

- 06

47000

- 123: Cat Small 2.5E

- 04 4.7E

- 07

Medium 3.7E

- 04 6.7E

- 07

Large 3.4E

- 04 6.3E

- 07

2596

- 78: Cat Small 1.7E

- 03 3.1E

- 06

Large 1.1E

- 03 1.9E

- 06

2596

- 79: Dog Small 1.4E

- 03 2.6E

- 06

Medium 1.2E

- 03 2.2E

- 06

Large 9.6E

- 04 1.8E

- 06

67517

- 82: Dog Small 1.5E

- 03 2.8E

- 06

Medium 1.6E

- 03 3.0E

- 06

Large 1.7E

- 03 3.1E

- 06

67517

- 82: Cat Small 7.6E

- 04 1.4E

- 06

Medium 1.1E

- 03 2.0E

- 06

Large 1.0E

- 03 1.9E

- 06

Pump /Trigger Spray

2596

- 126, 140: Cat (Trigger) Small

Adult 4.6E

- 04 8.3E

- 07

Large 2.4E

- 04 4.4E

- 07

2596

- 140: Cat (Pump) Small 9.3E

- 05 1.7E

- 07

Large 4.9E

- 05 8.9E

- 08

2596

- 125,

- 140: Dog (Trigger) Small 3.2E

- 04 5.8E

- 07

Medium 1.6E

- 04 2.9E

- 07

Large 1.7E

- 04 3.2E

- 07

1 Total L ifetime A verage D aily D ose (mg/kg/day) = Dermal LADD (mg/kg/day) + Inhalation LADD (mg/kg/day). 2 Dermal and Inhalation LADD equations provided in Appendix A.

3 Cancer risk estimates = Total LADD × Q1*, where Q1* = 1.83 x 10

- 3 (mg/kg/day)

- 1

5.3 Residential Risk Characterization

The evaluation of the potential residential post

- application health risks from exposures to cats/dogs treated with TCVP pet products is conservative. The risk estimates calculated are based upon protective assumptions of TCVP hazard, product application rate s , duration s of

exposure, and contact with the treated animal, and they make use of the best available post

-Page 32 of 45

application exposure data

.

Application Rate: The application rates used in the assessment of pet products represent the

maximum amount of TCVP that could be applied by weight of the treated animal (small, medium, and large) for T C VP collars, dusts/powders, and pump/trigger spray s.

For TCVP collars, the applicator is directed to cut off and dispose of any excess length once the product is fit and buckled into place. As described in the Treated Pet SOP, because the exact length cannot be determined, the corresponding TCVP loss cannot be quantified and, therefore, exposure is assessed assuming the full collar length. While this approach may result in an overestimate of collar application rate, it ensures protection of users who may contact dogs wearing an uncut TCVP collar.

For TCVP dusts/powders, all products identify a specific amount to use per animal weight that allows for determination of the maximum application rate. For TCVP pump/trigger sprays, all registered products direct the user to apply a specific number of “st rokes” per animal size. In order to determine the amount of ai applied per treatment as specified by number of strokes, HED requested additional information from the product registrant. Hartz Mountain Corporation provided information regarding the volume of product released per stroke for pump and trigger spray products; 0.19 and 0.93 grams, respectively. Only trigger spray products are registered for dogs; however, both pump and trigger spray products are registered for cats. Additionally, per

request of HED, in March 2014 Hartz Mountain Corporation amended the master label of EPA Reg. No. 2596

- 140 to recommend a number of strokes per animal size. Previously, a number of strokes per cat/dog was not recommended. The maximum number was considered in the risk assessment for cats and dogs and based on animal size.

Exposure Data : It is HED policy to use the best available data to assess exposure . Where

chemical

- or formulation

- specific exposure data were available, these data were used to conduct

the asse ssment of residential handler and post

- application exposures or integrated with other data as appropriate . The exposure estimates based on the use of these data are the most accurate representation of exposures anticipated from use of TCVP pet products an d are not expected to

underestimate residential risks.

All residential handler exposure estimates are based on the values recommended in the 2012 SOPs for Residential Exposure Assessment (SOPs). For the application of TCVP dust/powder

formulation exposure scenario, c hemical

- specific exposure monitoring data a re available (MRID 45519601). These data were previously reviewed by the Agency and d etermined to be acceptable for use in risk assessment

. In fact, t he se data have been incorporated into the calculation of the unit exposure value associated with this scenario in the 2012 Residential SOPs

. A carbaryl dust/powder exposure study is also included in th e SOP unit exposure

recommendation for th e dust/powder exposure scenario as described in the Re sidential SOPs.

For purpose of the residential handler dust/powder assessment, only the TCVP unit exposure

data were used. For further information regarding how the exposure estimates were determined, please refer to the 2012 Residential SOPs where the p rocess is explained in detail.

For the assessment of residential post

- application exposures from registered TCVP products,Page 33 of 45

s urrogate and chemical

- specific transferable residue transfer studies were used which are believed to best represent the potential exposures from TCVP use . These residue data were collected from treated dogs after treatment with 1) TCVP aerosol 12

, powders , and pump spray formulations (MRID 45485501) and 2) a pet collar containing the active ingredient propoxur (MRID 48589901 )

. HED previously completed a review of the TCVP aerosol, powder, and pump spray formulation residue transfer study for (MRID 45485501 ) in 2001. Tha t study was reevaluated based on current standards of conduct for pet residue transfer studies

. Th is

reevalua tion of the TCVP transferable residue study resulted in a number of changes from the

2001 review

. These differences are illustrated in Table 5.2.1 of this document.

The 2012 Residential SOPs: Treated Pets recommends that the fraction of applied residues which come off of a companion animal on the day of application (i.e., Day 0) should serve as the basis

for assessment of post

- application exposures

. This input is defined as fraction application rate ( F AR ) in the 2012 SOPs

. The day of application percent residue transfer values resulting from the above referenced studies used for exposure/risk quantification are as follows: pet collars,

0.072% (arithmetic mean) ; dusts/powders, 0.048% (maximum observed); and pump /trigger sprays, 0.81% (maximum observed).

The TCVP powder and pump spray post

- application exposure study was not conducted in a manner reflective of current standards that require a defined stroking procedure and greater number of petting simulations. That is, the pet (cat/dog) should be strok ed in a single motion with the grain of the fur starting with both side s (along the ribcage) of the animal and followed by the same motion along the back (dorsally) from the base of the neck to the tail . The two sides and back, in this order , account for one petting simulation. A total of 20 petting simulations (or 60 stroking motions) are currently required. In the TCVP post

- application exposure study

, the dogs were strok ed only one side of treated dog’ s back from head to rump five times. It is also

no table that the dogs were stroked with a bare hand

, rather than with the currently required transferable collection method, cotton gloves worn over a mannequin hand. Transferable

residues were collected for analysis in the TCVP post

- application exposure st udy from the bare hand using a methanol wipe. In the current method, the cotton gloves are removed from the mannequin hand for analysis

. The mannequin hand is not analyzed, but acts only as a residue

collection tool to avoid direct contact with the treat ed animal

. Despite these differences , the TCVP powder and pump spray post

- application exposure study was reflective of current policy regarding pet residue transfer studies at the time that it was conducted.

For the reasons described in Section 5.2 of this document, HED used the maximum observed

percent residue transfer on the day of product application (Day 0) , as opposed to the average, for both formulations for exposure/risk quantification. This approach results in residue transfer for pump/trigger sprays comparable to the arithmetic mean percent residue transfer observed from the analysis of all liquid formulated product data sets presented in the 2012 Residential SOPs;

0.81 % and 0.96%, respectively. The TCVP dust /powder study is the only data available for this pet product formulation and, thus, HED has no basis of comparison; however, the data are acceptable for risk quantitation and are the best available for the product type.

No exposure data are available f or assessment of post

- application exposures from the use of

12 Note: The TCVP aerosol per product formulation is no longer a registered use.Page 34 of 45

TCVP pet collars. Two post

- application exposure studies have been submitted to the Agency in support of residential pet collar uses, the aforementioned propoxur pet collar study and a recently

su bmitted deltamethrin pet collar residue transfer study (MRID 49350101)

. 13 Both studies were

conducted in a manner consistent with current standards and are recommended for use in risk quantitation. The propoxur pet collar study resulted in mean percent r esidue transfer on Day 0 in excess of that of the deltamethrin study; 0.072% and 0.003%, respectively. The more conservative mean percent residue transfer result ing from the propoxur study was selected for use as a surrogate for estimation of TCVP post

- ap plication risks.

In comparison to other formulations used for pet pest control (e.g., dusts, spot

- ons, sprays), the pet collar formulation is unique and result s in considerably lower percent residue transfer values. When other pet product formulations are applied to a treated pet, it can be reasonably assumed that the entire amount of that applied (i.e., the application rate) is available on the hair coat of the

animal for transfer to the exposed individual. For example, the labeled amount of the TCVP pump/trigger spray product can be used directly in the assessment of exposure/risk because it is

assumed this amount is available on the surface for contact . Pet collar formulations operate by slowly releasing the ai from the collar medium, making them efficacious for pest treatment over longer periods of time. Due to this activity , it can be difficult for the risk assessor to determine

the amount which is initial ly available on the animal because the majority is retained within the collar. Accordingly, the propoxur and deltamethrin pet collar study results in residue transfer much less than that from other, liquid formulated products.

For residential handler exp osure assessment for TCVP collar products, exposure data for spot

- on applications was used as a surrogate to estimate handler exposures. For the reasons described in the preceding paragraph , the use of the spot

- on applicator exposure data is highly conser vative.

For purpose of quantification of estimated TCVP post

- application cancer exposures/risks, HED

used the mean percent residue transfer of all days sampled in the propoxur collar and TCVP dust/powder and pump spray studies. For the TCVP collar, HE D used an average F AR (of 28 days sampling in the propoxur collar study) of 0.013% to represent 180 days exposure per year.

Due to the reasons described above with use of the TCVP dust/powder and pump spray exposure data, HED used an a verage of the maximu m observed percent residue transfer for each day tested

for calculation of cancer exposures/risks resulting in an F AR of 0.022% and 0.18% for dusts/powders and pump sprays, respectively.

While t he use of the maximum observed percent residue transfer on Day 0 is not typically

undertaken for non

- cancer or cancer residential exposure assessment, it allows for use data best representative of the exposure potential from TVCP pet products while ensuring a conservative, health protective assessment of residenti al risks.

Pet Contact: For the purpose of determining exposure to treated pets, the 2012 Residential SOPs

make use of transfer coefficients (TCs) . TC is an exposure rate for a selected activity which involves contact with a source, such as children playing with treated pets or on treated turf. The TC concept is a long

- standing established approach used to estimate residential, as well as

13 M. Collantes. Deltamethr in: Data Evaluation Record for the Study “ Deltamethrin: two

- month dislodgeable residue study of deltamethrin in beagle dogs treated with Scalibor ® Protector Band .” 6/4/14. D420043.Page 35 of 45

occupati onal exposures, and is the basis for the Agency’s post

- application exposure guidelines

. 14

A TC is derived by taking the ratio of study volunteer dermal exposure per unit time (mg/hr), and the concurrent measure of residue transfer. Ideally, dermal exposur e is based on an activities representative of the use pattern and residue transfer is determined by use of an established method specific to the use pattern. For pet exposures, TC s can be defined as animal surface area contact per unit time (cm 2 /hr).

C urrently, there is no exposure study available using representative, or typical adult and child activities with pets and a concurrent transferable residue ( TR ) measure

. In the absence of direct exposure data for residential activit ies with pets , the Agenc y conclude d that studies conducted to

monitor pet grooming activities are likely to result in a highly protective estimate of pet contact relative to contact associated with petting, hugging , or sleeping with a pesticide

- treated pet

. These data were gather ed while hu man volunteers applied dust/powder s and shampoo product s to various dogs of differing sizes and fur lengths. Since these individuals extensively handled the dogs, it is expected that their resulting exposures are higher than would be reasonably anticipated from routine contact with treated pets. The volunteers in the shampoo study, who were professional groomers, shampooed 8 dogs for 5 minutes each, rinsed, and lifted them to counters for drying and combing result ing in very high exposures. In the dust study, volunteers applied dust via shaker can to 8 dogs each and then rubbed the dusts into the dogs’ coats. The applicator studies were not conducted in a manner which measured TR, or active ingredient per

surface area. Therefore, the residue available on the animal for transfer was predicted by multiplying the arithmetic mean fraction of application rate from the analysis of all liquid formulated product data sets presented in the 2012 Residential SOPs, 0.96%. Th is approach has the effect of increasing TC estimates, thus resulting in TC values which are more protective of human health. Furthermore, the selection of the mean value, in lieu of the screening level F AR value, 2%, further increases the TC estimates wi th use of the dust and shampoo studies.

Exposure Time : The exposure time (ET) assumption used to assess residential post

- application

exposure to TCVP pet products is derived from a study which sought to evaluate the times that individuals spen d perform ing different activities around the home. Based upon the 2012

Residential SOPs: Treated Pet SOP, the point estimates recommended for adult and child ET with pets are 0.7 7 and 1 hours, respectively. In the study, animal care is defined as “care of

househo ld pets including activities with pets, playing with the dog, walking the dog and caring for pe ts of relatives, and friends.” The data identified the time spent with an animal while performing household activities as recorded in 24 hour diaries by study v olunteers. While the activities defined do not necessarily represent the time volunteers were actively engaged in constant contact with the animal as is implicit in the post

- application dermal and incidental oral algorithms, the data are the most accurate representation of time spent with pets available and, therefore, it is assumed that contact is continual throughout the timed activity. HED assumes the ET value reflects a reasonable high end estimate of time spent in contact with a dog treated with

TCVP pet products

.

When use of the study data are couple d with high end assumptions of pet contact, the result is an exposure assessment that inherently implies vigorous, continual contact for the entire duration of

14 http://www.ecfr.gov/cgi

- bin/text

idx?SID=6bfd4539761be8d5b20dfbf6bc19b9d0&node=40:25.0.1.1.9.9&rgn=div6Page 36 of 45

contact. While it is possible that an ad ult or child may be in close contact with a pet intermittently throughout the day, they would not be actively engaged in the highly vigorous contact implied by use of the TCs based on the applicator exposure data for the full exposure

duration assumed. Fu rther, it is possible that adults or children may be exposed from sleeping with a treated pet; however, they are not actively engaged in a high level of contact, or the repeated mouthing behaviors exhibited by children during waking hours, which are inhere ntly

assumed in the assessment conducted.

Hazard : The toxicology database for TCVP is complete and adequate to support the residential

assess ment from TCVP pet product use. For TCVP , AChE inhibition is the most sensitive endpoint in the toxicology database in multiple species, durations, lifestages, and routes

. TCVP has low acute (lethality) toxicity by the oral, dermal, and inhalation routes of exposure. It is classified as a Group C possible human carcinogen by the Agency with a linear low

- dose approach for quantification of risk using the oral slope factor (Q1*) of 1.83 x 10

- 3 (mg/kg/day)

- 1

. TCVP is not mutagenic and immunotoxicity was not observed at levels that exceed the limit

dose. The FQPA SF was reduced to 1X since there is no evidence o f sensitivity of the young

animal in the pre

- and post

- natal studies compared to the adult

, and there are no data gaps.

C onsistent with risk assessment s for other AChE

- inhibiting compounds

, HED conducted a BMD analysis for TCVP using a benchmark respons e (BMR) level of 10%

, and has thus calculated

BMD 10 and BMDL 10 values

. The use of the 10% BMR is derived from a combination of statistical and biological considerations. A power analysis was conducted by the Office of Research and Development (ORD) on ov er 100 brain AChE datasets across more than 25 OPs as part of the OP cumulative risk assessment ( CRA ) (USEPA, 2002). This analysis demonstrated that 10% is a level that can be reliably measured in the majority of rat toxicity studies. In addition, the 10 % level is generally at or near the limit of sensitivity for discerning a statistically significant decrease in ChE activity in the brain compartment and is a response level close to the background brain ChE level. With respect to biological consideration s, a change in 10% brain AChE inhibition is protective for downstream clinical signs and apical neurotoxic outcomes. Based on a robust BMD analysis evaluating a broad representation of the TCVP toxicity database, points of departure were selected for the assessment of the major residential routes of exposure; dermal (handler and post

- application) , incidental oral (post

- application only) , and

inhalation (handler only)

.

For the dermal risk assessment, a steady state PoD was selected from the subchronic oral toxicity study in rats. Since an oral study was selected, a DAF of 9.57% was used for the route

- to

- route extrapolation. The DAF is based on the results of a derm al penetration study in rats. The use of the rat dermal absorption da ta is considered conservative because rats tend to have more permeable skin that humans (3

– 10X). Therefore, the use of the rat DAF based on the rat dermal penetration study likely leads to an overestimation of residential dermal exposures.

Indirect I ncidental Oral Exposures : An assessment of indirect incidental oral exposures resulting from children putting objects or other toys in their mouth that potentially have residue from

contact with treated pets (i.e., object

- to

- mouth exposures) was not conduc ted. The 2012

residential SOPs state that hand

- to

- mouth and object

- to

- mouth incidental oral exposures

assessm ents should be conducted for treatments to indoor environments and lawns/turf only. ForPage 37 of 45

these exposure scenarios, children’s hand

- to

- mouth exposu res are expected from direct contact with treated surfaces (i.e., treated turf and carpets/hard floors) and object

- to

- mouth exposures are expected due to the potential for secondary exposures from mouthing objects that may have been

in contact with the tre ated surface. With use of the methods described in the indoor environments and lawn/turf SOPs, the quantification of hand

- to

- mouth exposures following direct contact with the treated surface always results in exposures of a greater magnitude and, as

a res ult, a more health protective assessment of risk (i.e., a lower MOE) than from indirect object

- to

- mouth exposures.

When the dermal and incidental oral exposure routes share a common toxicological en dpoint, as

is the case for TCVP , risk estimates are combined for these routes. The incidental oral exposure scenarios (i.e., hand

- to

- mouth and object

- to

- mouth) are considered inter

- related and it is likely that they occur interspersed amongst each other across time. Accordingly, choos ing the highest of the incidental oral exposure scenarios is protective of both. Further, combining both of the incidental oral exposure scenarios with the dermal exposure scenario would be unrealistic because of the highly conservative nature of each ind ividual assessment. Therefore, the hand

- to

mouth exposure scenario, which has the highest estimated incidental oral risk, is combined with the dermal post

- application exposure and is considered a protective estimate of children’s exposures following pesti cide usage. This approach is consistent with that used for assessment of post

- application exposures from TCVP pet product usage.

5.4 Residential Risk Estimates for Use in Aggregate Assessment

Table s 5. 1 .1 , 5.2.2 and 5.2.3 reflect the residential risk estimates that are recommended for use in the aggregate assessment that will be conducted as part of the Preliminary Risk Assessment during Registration Review for TCVP

.

 The recommended residential exposure for use in the adult aggregate no n

- cancer risk

assessment is combined ( dermal and inhalation ) exposures from applications to large dogs with a dust/powder product (EPA Reg. No. 65717

- 82).

 The recommended residential exposure for use in the children 1<2 years old n on

- cancer aggregate assessment is comb ined ( dermal and hand

- to

- mouth exposures ) from post

application exposure to either small cats or large dogs from EPA Reg. Nos. 2596

- 78 and

67517

- 82, respectively.

 The recommended residential exposure for use in the adult aggr egate cancer assessment
is der mal exposure from the post

- application exposure to large dogs from EPA Reg. No.

67517

- 82 (dose is 1.7E

- 03 mg/kg/day).Page 38 of 45 Table 5.4 . Recommendations for the Residential Exposures for the TCVP Aggregate Risk

Assessment 1

Lifestage (Scenario) Dose (mg/kg/day) Risk Estimates

Dermal Inhalation Oral Total 2 Dermal Inhalation Oral Total

MOE 3 ARI 4

Residential Handler

Adult 0.018 0.00035 N/A 0.018 440 4,700 N/A N/A 4.2

Residential Post

- application

Child 0.030 N/A 0.029 0.059 270 N/A 280 140 N/A

Cancer Exposure

Adult 1.7E

- 03 N/A N/A 1.7E

- 03 N/A N/A N/A N/A N/A

1 Bolded worst

- case risk estimates should contribute to the residential exposure portion of the aggregate assessment. 2 Total Dose (mg/kg/day) = Dermal D ose + Inhalation Dose + Incidental Oral D ose (where applicable).

3 Total MOE = 1 ÷ (1 ÷ Dermal MO E) + (1 ÷ Incidental Oral MOE).

4 ARI = 1÷ [(Dermal LOC (100) ÷ Dermal MOE) + (Inhalation LOC (30) ÷ Inhalation MOE)].

5.5 Spray Drift

This assessment has not been conducted for the TCVP pet use products that are un likely to result in spray drift

. Further, spray drift is not anticipated from the occupational use of TCVP for direct application to livestock or livestock premises.

5.6 Residential Bystander Post

- App lication Inhalation Exposure

Residential post

- application inhalation exposure is expected to be negligible from TCVP pet products and, thus, a quantitative assessment was not performed. Per the Residential SOPs, the combination of low vapor pressure (2.6 x10

- 7 mmHg at 25°C) and the small amounts of pesticide applied to pets is expected to result in negligible levels of chemical in the air, and therefore negligible inhalation exposures.Page 39 of 45

Appendix A : Algorithms Used to Calculate Residential No n

- Cancer and Cancer Risk

Estimates

Dermal and Inhalation Handler Exposure Algorithm

Daily dermal and inhalation exposure (mg/day) for residential pesticide handlers, for a given

formulation

- application method combination, is estimated by multiplying the formulation

application method

- specific unit exposure by an estimate of the amount of active ingredient handled in a day, using the equation below:

E = UE * AR * A

where:

E = exposure (mg/day); UE = unit exposure (mg/lb ai); AR = application rate (e.g., lb ai/ft 2 , lb ai/gal); and A = number of animals treated per day.

Post

- application Dermal Exposure Algorithm

The following method is used to calculate dermal exposures that are attributable to an adult or child contacting a treated companion pet:

E = TC * TR * ET

where:

E = exposure (mg/day);

TC = transfer coefficient (cm 2 /hr);

TR = transferable residue (mg/cm 2 ); and

ET = exposure time (hours/day).

TR = AR ∗ F AR

SA

where:

TR = transferable residue (mg/cm 2 );

AR = application rate or amount applied to animal (mg);

F AR = fraction of the application rate available as transferable residue; and

SA = surface area of the pet (cm 2 ).

Absorbed dermal dose, normalized to body weight, is calculated as:Page 40 of 45 D = E * AF

BW

where:

D = dose (mg/kg

- day);

E = exposure (mg/day);

AF = absorption factor (dermal); and

BW = body weight (kg).

Table A.1. Treated Pets

– Inputs for Residential Post

- application Dermal Exposure Algorithm

Notation Exposure Factor

Units Point Estimates

AR Application rate (mg) Unique for each product

SA Surface Area of

Animal (cm 2 ) Small Cat, Dog Cat

– 1,500 Dog

– 3,000

Medium Cat, Dog Cat

– 2,500 Dog

– 7,000

Large Cat, Dog Cat

– 4,000 Dog

– 11,000

F AR Fracti on of AR Available for Transfer

(recommended point estimate) Non

- Cancer Collar (Propoxur Study): 0.00072 Dust/Powder (TCVP): 0.00048 Pump Spray (TCVP): 0.0 081

Cancer Collar (Propoxur Study): 0.00013 Dust/Powder (TCVP): 0.00022 Pump Spray (TCVP): 0.0018

TC Transfer Coefficient

– Liquids (cm 2 /hr) Adult 5,200

Children 1 < 2 years old 1,400

Transfer Coefficient

– Solids (cm 2 /hr) Adult 140,000

Children 1 < 2 years old 38,000

ET Exposure Time

(hours per day) Adult 0.77

Children 1 < 2 years old 1.0

BW Body weight

(kg) Adult 80

Children 1 < 2 years old 11

Post

- application Hand

- to

- Mouth Exposure Algorithm

Exposure from hand

- to

- mouth activity is calculated as follows (based on algorithm utilized in

SHEDS

- Multimedia):Page 41 of 45 E = [HR * (F

M * SA H ) * (ET * N_Replen) * (1

- (1

- SE) (Freq_HtM/N

- Replen) )]

where:

E = exposure (mg/day);

HR = hand residue loading (mg/cm 2 );

SA H = surface area of one child hand (cm 2 );

F M = fraction hand surface area mouthed /event (fraction/event);

ET = exposure time (h r/day); N_Replen = number of replenishment intervals per hour (intervals/hour);

SE = saliva extraction factor (i.e., mouthing removal efficiency); and Freq_HtM = number of hand

- to

- mouth contacts events per hour (events/hour).

and

HR = E * Fai hands 2 * SA H where:

HR = hand residue loading (mg/cm 2 );

E = dermal exposure (mg);

Fai hands = fraction of a.i. on hands compared to total residue from dermal transfer

coefficient study (unitless); and

SA H = surface area of one child hand (cm 2 ).

Oral dose, normalized to body weight, is calculated as:

D = E

BW

where:

D = dose (mg/kg

- day);

E = exposure (mg/day); and

BW = body weight (kg).

Table A.2. Treated Pets

– Inputs for Residential Post

- application Hand

- to

- Mouth Exposure Algorithm

Notation Exposure Factor (units) Point Estimate(s)

Fai hands Fraction of a.i. on hands from transfer coefficient studies (unitless) Solid = 0.37 Liquid = 0.040

F M Fraction hand surface area mouthed /event (fraction/event) 0.13

N_Replen Replenishment intervals per hour (intervals/hr) 4

ET Exposure time

(hours/day) Children 1 < 2 years

old 1.0

SE Saliva extraction factor 0.48 Freq_HtM Hand

- to

- mouth events per Children 1 < 2 years 20Page 42 of 45

Table A.2. Treated Pets

– Inputs for Residential Post

- application Hand

- to

- Mouth Exposure Algorithm

Notation Exposure Factor (units) Point Estimate(s)

hour (events/hr) old

SA H Typical surface area of

one child hand (cm 2 ) Children 1 < 2 years

old 150

BW Body Weight (kg) Children 1 < 2 years

old 11

Cancer Exposure Algorithm

Exposure/Dose Amortization :

An accurate estimate of exposure over the course of weeks, years or a lifetime is difficult to predict as exposure likely differs from one day to the next due to product

- specific application regimens, residue dissipation, human behavior and activity patterns, and the extent to which an individual’s exposure varies due to behavior changes. Approaches for am ortizing dose over various exposure durations are explained in more detail in S ection 1.3 of the 2012 Residential SOPs; however an example would be amortization of an individual’s daily dose over their

life time necessary for calculating exposures for cance r risk assessments. This amortized dose is known as the lifetime average daily dose (LADD) and it can be calculated as follows:

LADD = D * EF * ET

AT * CF

where:

LADD = lifetime average daily dose ( dermal + inhalation, mg/kg

- day);

D = dose (mg/kg

- day);

EF = exposure frequency (i.e., frequency of product use) (days/year);

ET = exposure time (years);

AT = averaging time (i.e., life expectancy) (years); and

CF = conversion factor (365 days/year).

Table A.3. Treated Pets

– Inputs for Cancer Exposure/Risk Algorithm

Notation Exposure Factor (units) Point Estimate(s)

EF Exposure Frequency (days/year) Handlers : Collars, 4; Dusts/Powders and Pump/Trigger Sprays, 6

Post

- application (all formulations): 180

ET Exposure Time (years) 50

AT Averaging Time (years) 78

CF Conversion Factor (days/year) 365Page 43 of 45

Appendix B : Summary of OPP’s ChE Policy & Use of BMD Modeling

OPP’s ChE policy (USEPA, 2000 15 ) describes the manner in which ChE data are used in human

health risk assessment. The following text provides a brief summary of that document to provide context to points of departure selected.

AChE can be inhibited in the central or peripheral nervous tissue. Measurements of AChE or cholinesterase ( ChE) inhibition in peripheral tissues (e.g., liver, diaphragm, heart, lung etc.) are rare. As such, experimental laboratory studies generally measure brain (central) and blood (plasma and red blood cell [RBC]) ChE. Blood measures do not represent the tar get tissue, per se, but are instead used as surrogate measures for peripheral toxicity in studies with laboratory animals or for peripheral and/or central toxicity in humans. In addition, RBC measures represent AChE, whereas plasma measures are predominat ely butyryl

- ChE (BuChE). Thus, RBC AChE data may provide a better representation of the inhibition in target tissues. As part of the dose response assessment, evaluations of neurobehavior and clinical signs are performed to consider the dose response lin kage between AChE inhibition and apical outcomes.

Refinements to OPP’s use of ChE data have come in the implementation of BMD approaches in dose response assessment. Beginning with the OP cumulative risk assessment ( CRA ) , OPP has

increased its use of BMD modeling to derive PoDs for AChE inhibiting compounds. Most often the decreasing exponential empirical model has been used.

OPP does not have a defined benchmark response (BMR) for OPs. However, the 10% level has been used in the majority of dose re spon se analyses conducted to date. This 10% level represents a 10% reduction in AChE activity (i.e., inhibition) compared to background (i.e., controls). Specifically, the BMD 10 is the estimated dose where ChE is inhibited by 10% compared to background. The BMDL 10 is the lower confidence bound on the BMD 10

.

The use of the 10% BMR is derived from a combination of statistical and biological considerations. A power analysis was conducted by the ORD on over 100 brain AChE datasets

across more than 25 OPs as part of the OP CRA (USEPA, 2002). This analysis demonstrated that 10% is a level that can be reliably measured in the majority of rat toxicity studies. In addition, the 10% level is generally at or near the limit of sensitivity for discerning a stati stically significant decrease in ChE activity in the brain compartment and is a response level close to the background brain ChE level. With respect to biological considerations, a change in 10% brain AChE inhibition is protective for downstream clinical signs and apical neurotoxic outcomes. RBC AChE inhibition data tend to be more variable than brain AChE data. OPP begins its BMD analyses using the 10% BMR for RBC AChE inhibition. However, BMRs up to 20% could be considered on a case by case basis, as l ong as such PoDs are protective for brain AChE inhibition, potential peripheral inhibition, and clinical signs of neurotoxicity.

15 USEPA (2000) Office of Pesticide Programs, US Environmental Protection Agency, Washington DC 20460. August 18, 2000 Office of Pesticide Programs Science Policy of The Use of Data on Cholinesterase Inhibition for Risk Assessments of Organophosphorous and Carbamate Pesticides. http://www.epa.gov/oppfead1/trac/science/cholin.pdfPage 44 of 45

Appendix C : R esults for BMD/BMDL modeling for TCVP

BMD analyses were performed with EPA’s Benchmark Dose Software (Version 2. 4 ) using an exponential model for continuous data 16

. The Hill model was also performed for some data set s
, but did not result in the best fit for the data. The data selected for evaluation consisted of decreased brain and red blood cell (RBC) cholinest erase (ChE) activities. Data were analyzed

from a 21

- day oral toxicity study (MRID 45570601), a 13

- week subchronic oral toxicity study (MRID 43371201), and a 2 year chronic oral toxicity study (MRID 42980901); a gestational comparative cholinesterase assa y (CCA; MRID 48291101); and a 28

- day inhalation toxicity study (MRID 48803501). All data from these studies were considered; however, some data were not amenable to BMD analysis.

OPP has used the exponential model for modeling AChE activity for the OP and N

- methyl

carbamate cumulative risk assessments and with multiple single chemical risk assessments of

ChE

- inhibiting pesticides. Model runs for ChE activity were conducted with an appropriate benchmark response level (10%). As such the BMD 10 (estimated dose to result in 10% change from background levels) and BMDL 10 (the lower 95% confidence level on the BMD 10 ) are provided in the output. Statistical (e.g., goodness of fit values) and graphical results were used in

model evaluation.

The results of the repeated oral and inhalation dosing BMD analyses are summarized below in

Table C. 1

. Good model fit (p> 0.1) was obtained for the majority of the analyses, with any exceptions being noted.

For exposure to repeated doses the BMDL 10 for ChE inhibition in the adult female RBCs were

similar in the 13

- week subchronic study and the 21

- day oral toxicity study (8 .0 mg/kg/day vs 6.7 mg/kg/day, respectively). Although data from the shorter duration study resulted in a slightly lower BMDL, visual examination of the modeled data provided greater confidence in the

13

- week study. For inhalation exposure, the adult mal e was about twice as sensitive as the adult female (0.023 mg/L in males vs 0.050 mg/L in females).

Table C .1. Results of BMD Exponential Modeling for Brain and RBC ChE Data on TCVP, Repeated Oral Dosing Studies in Rats, Ranging in Duration from 21 days to 2 years.

TCVP Study Age/Sex Compartment BMD Results

BMD 10 BMDL 10

MRID 43371201

13W Oral

– 13

Weeks Adult Male Brain No dose response (analysis not performed)

Adult

Female Brain No dose response

Adult Male RBC 61.6 mg/kg/day 26.3 mg/kg/day

Adult

Female RBC 10.5 mg/kg/day 8.0 mg/kg/day

16 J. Bever. Tetrachlorvinphos: Benchmark Dose Analysis of Subchronic and Chronic Studies to Support Derivation of Points of Departure. 5/20/2014. TXR # 0056970. D420286.Page 45 of 45

Table C .1. Results of BMD Exponential Modeling for Brain and RBC ChE Data on TCVP, Repeated Oral Dosing Studies in Rats, Ranging in Duration from 21 days to 2 years.

TCVP Study Age/Sex Compartment BMD Results

BMD 10 BMDL 10 MRID 42980901

Chronic Oral

Tox

– 364, 539, and 721 Days Adult

Female RBC No dose

- response effect was observed at 364, 539, or 721 days

MRID 45570601

21D Oral Tox

– 21 Days Adult

Female Brain 14.7 mg/kg/day 12.2 mg/kg/day

RBC 9.9 mg/kg/day 6.7 mg/kg/day

MRID 48803501

28D Inhalation

– 28 Days Adult Male RBC 0.122 mg/L 0.023 mg/L

Adult

Female RBC 0.394 mg/L 0.050 mg/L