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

                                                  OFFICE OF CHEMICAL SAFETY AND
                                                                                POLLUTION PREVENTION

MEMORANDUM

DATE:		November 5, 2014

SUBJECT:	Residential Exposure Assessment in Response to the Natural Resources Defense Council Petition to Cancel All Pet Uses for Tetrachlorvinphos

PC Code:  083701
DP Barcode: D420283
Petition No.:  NA
Registration Nos.: NA
Risk Assessment Type:  Single Chemical, Residential Exposure Assessment
Regulatory Action: Petition Response
TXR No.:  NA
Case No.:  NA
MRID No.:  45485501, 45519601, 48589901
CAS No.:  22248-79-9

FROM:		Wade Britton, MPH, Industrial Hygienist
		Risk Assessment Branch V (RABV)
		Health Effects Division (HED; 7509P)
		Office of Pesticide Programs

THROUGH:	Michael Metzger, Chief
		RABV and RABVII/HED (7509P)
		And
		Kristin Rury, Biologist
		Nancy J. Tsaur, Chemist
		Exposure Science Advisory Committee (ExpoSAC) / HED

TO:		Neil Anderson, Branch Chief
            Kelly Ballard, Chemical Review Manager
			Risk Management and Implementation Branch I (RMIBI)
			Pesticide Re-evaluation Division (PRD; 7508P)
			Office of Pesticide Programs

The purpose of this document is to provide a residential exposure assessment for all pet uses of the active ingredient, tetrachlorvinphos (TCVP).  On April 23, 2009, the Natural Resources Defense Council (NRDC) petitioned the Agency to cancel all pet uses of TCVP.  This assessment was conducted as a response to NRDC's petition and characterizes the potential risks associated with the use of TCVP pet products.  An earlier exposure assessment was also conducted 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 assessment of human health exposures from residential pesticide 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 previously 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-2009-0356).

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 study (MRID 48589901).   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 Residential 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.

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 Assessment	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	39

1.0	Executive Summary

Tetrachlorvinphos (TCVP) is a member of the organophosphate (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 issues raised in the 2009 NRDC petition regarding the potential exposures resulting from residential 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 accumulation 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 suggests 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 developmental 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 of exposure for both red blood cell (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.

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 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 weeks but this can vary among OPs.  Based on the robust dataset from the OP 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 assessment 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 assessments, a steady state PoD was selected, a benchmark dose lower confidence limit for 10% RBC AChE inhibition (BMDL10) 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 benchmark dose modeling (BMD) techniques to be consistent with the current methods 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 results of a dermal penetration study in rats.

For the inhalation risk assessment, a steady state PoD was selected, a BMDL10 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, and 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 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 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.

Residential Exposure 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, steady 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 the 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 health 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 (EPA 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 defines 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 use 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 application 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 children 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 exposure 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 from 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 study (MRID 45519601), and TCVP dust and pump spray study (MRID 45485501) and propoxur collar pet residue transfer studies (MRID 48589901) 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.
2.0	Risk Assessment Conclusions and Recommendations

      2.1	Summary of Risk Estimates

All residential handler and post-application TCVP pet product non-cancer exposure scenarios assessed resulted in risk estimates that are not of concern to the Agency.  For adults, 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].

      2.2	Label Recommendations from Residential Assessment

As currently written, label language for the trigger spray products (EPA Reg. No. 2596-125 and 2596-126) states that "more 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 prescribed 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 identified 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 OPs, 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 toxicology database in multiple species, durations, 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.

                                    Target
                                  Tissue Dose
                  Phosphorylation of the active site of AChE
                                 Neurotoxicity
                         Accumulation of acetylcholine
                                    Target
                                  Tissue Dose
                  Phosphorylation of the active site of AChE
                                 Neurotoxicity
                         Accumulation of acetylcholine
                  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 chronic oral toxicity study in dogs, cholinesterase inhibition and increased liver and 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 synthesis 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 presence of metabolic activation.  TCVP is classified as a possible human carcinogen.  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 developmental 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 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.

Table 3.0.  Acute Toxicity of Tetrachlorvinphos Technical

                                 Guideline No.

                                  Study Type

                                   MRID No.

                                    Results

                               Toxicity Category

870.1100

Acute Oral  -  Rat

                                   41222504

LD50 =
1480 mg/kg (M)
465-965 mg/kg (F)

                                      III

870.1200

Acute Dermal  -  Rabbit

                                   41222505

LD50 > 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 PoDs 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 weeks, but this can vary among OPs.  Based on the robust dataset from the OP 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 assessment is scientifically supportable 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 result in only small changes in AChE inhibition.  This shallow dose response leads to variability in the AChE data and a relatively broad range of BMD10/BMDL10 values from 6.8 to 61.6 mg/kg/day/3.6 to 26.3 mg/kg/day.  Moreover, when evaluating the data across 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 inhibition 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.

Consistent with risk assessments for other AChE-inhibiting compounds, OPP has conducted a BMD analysis using a benchmark response (BMR) level of 10%, and has thus calculated BMD10 and BMDL10 values.  The BMD10 is the estimated dose where ChE is inhibited by 10% compared to background.  The BMDL10 is the lower confidence bound on the BMD10.  As a matter of science policy, the agency uses the BMDL, not the BMD, for use as the PoD (USEPA, 2012).  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 modeling, 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.

BMD assessment of the 90-day subchronic oral study provides a BMD10 of 10.4 mg/kg/day and a BMDL10 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 BMDL10 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-response data for deriving PoDs.  There are BMDL10 values in Table C.1 in Appendix C that provide lower BMDL10 values (comparative cholinesterase assays), but due to high variability in the AChE data and the fact that no cholinesterase inhibition was observed at dose levels equal to and greater than these lower BMD10/BMDL10 values, they were not considered appropriate for deriving PoDs.

For the inhalation risk assessment, a steady state PoD was selected, BMDL10 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, 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 (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 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 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.

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 dermal penetration study in rats.  Since the inhalation PoD 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 Toxicological 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

BMDL10  = 8.0 mg/kg/day

UFA= 10x
UFH=10x
FQPA SF = 1x

Residential LOC for MOE = 100
Subchronic Oral Toxicity Study  -  Rat
LOAEL was 142 mg/kg/day based on RBC ChE inhibition

BMD10 = 10.49 mg/kg/day, based on female RBC ChE inhibition
Dermal  (steady state)
NOAEL= 6.7 mg/kg/day

BMDL10  = 8.0 mg/kg/day

Dermal Absorption
=  9.57% a
UFA= 10x
UFH=10x
FQPA SF = 1x
Residential LOC for MOE = 100
Subchronic Oral Toxicity Study  -  Rat
LOAEL was 142 mg/kg/day based on RBC ChE inhibition

BMD10 = 10.49 mg/kg/day, based on female RBC ChE inhibition
Inhalation (steady state)
NOAEL=
0.05 mg/L/day

BMDL10=0.02 mg/L/day (males)

HEC=0.058 mg/L/dayb

HED=1.653c mg/kg/day
UFA= 3x
UFH=10x
FQPA SF = 1x
Residential LOC for MOE = 30
Subchronic Inhalation Toxicity Study - Rat
LOAEL = 0.5 mg/L, based on RBC ChE inhibition in males and females

BMD10 = 0.12 mg/L/day, based on RBC ChE inhibition in both sexes
Cancer
(oral, dermal, inhalation)
Classification: A possible human (Group C) carcinogen.  Q1* = 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 lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies); MOE = margin of exposure.  LOC = level of concern.  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 (MRID 41862401/ MRID 42111501).
b Human Equivalent Concentration (HEC) = 0.058 mg/L; PoD (BMDL10 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 pump 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 every 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 infestation.
                                    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 infestation.
                                    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.
                                    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 severe 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 infestation.
                                 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:
                               43 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, medium
                                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).  Previously, 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 expected for adults who apply TCVP products to their pets and from post-application exposures to adults and children who may 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 equipment.

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 for 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 application 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 animal (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 described 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 fit and buckled into 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 assumed 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 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 were not recommended.

Unit Exposures and Area Treated or Amount Handled:  Chemical-specific unit exposure data were provided in support of residential handler risk assessment for the dust/powder formulations only (MRID 45519601).  The study, "Determination of Dermal and Inhalation Exposures to Tetrachlorovinphos (TCVP) During the Application of an Insecticide Powder to a Dog," was previously reviewed by the Agency 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 dogs 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 applications 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. Steady 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 Year of Exposure: For the purpose 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 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 years 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.

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.

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 Residential 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).

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
                                    0.0010
                                     7,600
                                  Negligible
                                      NA

                                 2596-50, 62:
                                      Dog

                                   0.0061:
                                19 gram collar

                                     0.018
                                     4,500

                                    0.010:
                                32 gram collar

                                    0.0030
                                     2,700

                                   2596-63:
                                      Cat

                                    0.0048:
                                15 gram collar

                                    0.0014
                                     5,800

                                    0.0055:
                                17 gram collar

                                    0.0016
                                     5,100

                                   2596-83:
                                      Cat

                                    0.0039:
                                12 gram collar

                                    0.0011
                                     7,200

                                    0.0080:
                                25 gram collar

                                    0.0023
                                     3,500

                                   2596-84:
                                      Dog

                                    0.0061:
                                19 gram collar

                                    0.0018
                                     4,500

                                    0.010:
                                32 gram collar

                                    0.0030
                                     2,700

                                   2596-139:
                                      Cat

                                    0.0032:
                                10 gram collar

                                    0.00093
                                     8,600

                                   2596-139:
                                      Dog

                                    0.016:
                                50 gram collar

                                    0.0046
                                     1,700

                                  11556-164:
                                      Dog

                                    0.0072:
                                24 gram collar

                                    0.0021
                                     3,800

                                  11556-165:
                                      Cat

                                   0.0045:
                                15 gram collar

                                    0.0013
                                     6,100

                       Application of TCVP Dusts/Powders
                                   2596-78:
                                      Cat
                                  Dermal: 100
                                Inhalation: 30
                                     1,700
                                      3.1
                                   0.00062:
                                     small

                                    0.0025
                                     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

                                   0.000094:
                                     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:
                                     large

                                     0.018
                                      440
                                    0.00035
                                     4,700
                                      4.2
                    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) x Application Rate (lb ai/pet) x Area Treated or Amount Handled (pets/day) x Dermal Absorption 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) x Application Rate (lb ai/pet) x 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))

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 Q1* that has been calculated for TCVP based on dose response data in the appropriate toxicology study (Q1* = 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 Q1* to obtain cancer risk estimates.  The algorithms 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-08

                                     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 Lifetime Average Daily Dose (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 x Q1[*], where Q1[*] = 1.83 x 10[-3] (mg/kg/day)[-1]

	5.2	Residential 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 products.  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, the 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.

Residential Post-Application Exposure Data and Assumptions
A series of assumptions and exposure factors served as the basis for completing the residential post-application 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 data include the following residue transfer studies:  propoxur collar (MRID 48589901); and TCVP powder and pump spray (MRID 45485501).

HED previously conducted a data evaluation record (DER) of the TCVP exposure study for aerosols, powders, and pump sprays 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.  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 ug/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 ug/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 stroking 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 from container in grams x actual percent active ingredient in test product).
Regression analyses were conducted using the residue data in ug/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 to be stroked in a single motion with the grain of the fur starting with both sides (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 simulations (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 studies 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 transfer 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 to 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 (FAR) in the 2012 SOPs. Day of application (Day 0) percent residue transfer values (as referenced from the above studies) used for exposure/risk quantification are as follows:  pet collars, 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 and TCVP dust/powder and pump spray studies.  For the TCVP collar, HED used an average FAR (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 average of the maximum observed percent residue transfer for each day tested for calculation of cancer exposures/risks resulting in an FAR 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 number 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) meta-analysis of child hand mouthing frequency.  The indoor data were selected, even though 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 health 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 Residential SOPs.

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 AChE inhibition, exists for dermal and incidental oral routes of exposure to TCVP; thus, exposures should be combined for all routes of exposure.

Summary of Residential Post-Application Non-Cancer Exposure and Risk Estimates
Residential post-application steady state adult dermal exposure and children 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 (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
                                    0.0038
                                     2,100
                                       X

                                    Medium
                                    0.0023
                                     3,500

                                     Large
                                    0.0014
                                     5,600

                                   Children
                                   1 < 2
                                    Dermal

                                    Small
                                    0.0097
                                      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
                                     2,770
                                    Small
                                    0.0032
                                     2,500
                                       X

                                     4,670
                                     Large
                                    0.0015
                                     5,400

                                   Children
                                   1 < 2
                                    Dermal
                                     2,770
                                    Small
                                    0.0081
                                      980
                                      890

                                Incidental Oral

                                    0.00085
                                     9,400

                                    Dermal
                                     4,670
                                     Large
                                    0.0037
                                     2,100
                                     1,900

                                Incidental Oral

                                    0.00039
                                    21,000

                                 2596-63: Cat
                                     Adult
                                    Dermal
                                     2,190
                                    Small
                                    0.0051
                                     1,600
                                       X

                                     2,480
                                     Large
                                    0.0021
                                     3,700

                                   Children
                                   1 < 2
                                    Dermal
                                     2,190
                                    Small
                                     0.013
                                      620
                                      560

                                Incidental Oral

                                    0.0013
                                     6,000

                                    Dermal
                                     2,480
                                     Large
                                    0.0055
                                     1,500
                                     1,400

                                Incidental Oral

                                    0.00057
                                    14,000

                                 2596-83: Cat
                                     Adult
                                    Dermal
                                     1,750
                                    Small
                                    0.0040
                                     2,000
                                       X

                                     3,650
                                     Large
                                    0.0032
                                     2,500

                                   Children
                                   1 < 2
                                    Dermal
                                     1,750
                                    Small
                                     0.010
                                      780
                                      710

                                Incidental Oral

                                    0.0011
                                     7,500

                                    Dermal
                                     3,650
                                     Large
                                    0.0080
                                     1,000
                                      910

                                Incidental Oral

                                    0.00084
                                     9,600

                                 2596-84: Dog
                                     Adult
                                    Dermal
                                     2,770
                                    Small
                                    0.0032
                                     2,500
                                       X

                                     4,670
                                     Large
                                    0.0015
                                     5,400

                                   Children
                                    1 < 2
                                    Dermal
                                     2,770
                                    Small
                                    0.0081
                                      980
                                      890

                                Incidental Oral

                                    0.00085
                                     9,400

                                    Dermal
                                     4,670
                                     Large
                                    0.0037
                                     2,100
                                     1,900

                                Incidental Oral

                                    0.00039
                                    21,000

                                 2596-139: Cat
                                     Adult
                                    Dermal
                                     1,460
                                    Small
                                    0.0034
                                     2,400
                                       X

                                    Medium
                                    0.0020
                                     4,000

                                     Large
                                    0.0013
                                     6,300

                                   Children
                                    1 < 2
                                    Dermal

                                    Small
                                    0.0086
                                      930
                                      840

                                Incidental Oral

                                    0.00089
                                     9,000

                                    Dermal

                                    Medium
                                    0.0051
                                     1,600
                                     1,400

                                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
                                    0.0023
                                     3,500

                                   Children
                                    1 < 2
                                    Dermal

                                    Small
                                     0.021
                                      370
                                      340

                                Incidental Oral

                                    0.0022
                                     3,600

                                    Dermal

                                    Medium
                                    0.0092
                                      870
                                      790

                                Incidental Oral

                                    0.00096
                                     8,400

                                    Dermal

                                     Large
                                    0.0058
                                     1,400
                                     1,300

                                Incidental Oral

                                    0.00061
                                    13,000

                                  11556-164:
                                      Dog
                                     Adult
                                    Dermal
                                     3,290
                                    Small
                                    0.0038
                                     2,100
                                       X

                                    Medium
                                    0.0016
                                     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
                                     1,700

                                Incidental Oral

                                    0.00043
                                    19,000

                                    Dermal

                                     Large
                                    0.0026
                                     3,000
                                     2,700

                                Incidental Oral

                                    0.00027
                                    29,000

                                  11556-165:
                                      Cat
                                     Adult
                                    Dermal
                                     2,060
                                    Small
                                    0.0047
                                     1,700
                                       X

                                    Medium
                                    0.0028
                                     2,800

                                     Large
                                    0.0018
                                     4,500

                                   Children
                                    1 < 2
                                    Dermal

                                    Small
                                     0.012
                                      660
                                      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
                                     1,800
                                     1,600

                                Incidental Oral

                                    0.00047
                                    17,000

                                 Dusts/Powders
                                  47000-123:
                                     Dog
                                     Adult
                                    Dermal
                                      170
                                    Small
                                    0.0035
                                     2,300
                                       X

                                      430
                                    Medium
                                    0.0038
                                     2,100

                                      680
                                     Large
                                    0.0038
                                     2,100

                                   Children
                                    1 < 2
                                    Dermal
                                      170
                                    Small
                                    0.0090
                                      890
                                      450

                                Incidental Oral

                                    0.0087
                                      920

                                    Dermal
                                      430
                                    Medium
                                    0.0097
                                      830
                                      420

                                Incidental Oral

                                    0.0093
                                      860

                                    Dermal
                                      680
                                     Large
                                    0.0098
                                      810
                                      410

                                Incidental Oral

                                    0.0095
                                      840

                                  47000-123:
                                      Cat
                                     Adult
                                    Dermal
                                      43
                                    Small
                                    0.0018
                                     4,500
                                       X

                                      100
                                    Medium
                                    0.0025
                                     3,200

                                      150
                                     Large
                                    0.0024
                                     3,400

                                   Children
                                    1 < 2
                                    Dermal
                                      43
                                    Small
                                    0.0045
                                     1,800
                                      900

                                Incidental Oral

                                    0.0043
                                     1,800

                                    Dermal
                                      100
                                    Medium
                                    0.0065
                                     1,200
                                      620

                                Incidental Oral

                                    0.0063
                                     1,300

                                    Dermal
                                      150
                                     Large
                                    0.0061
                                     1,300
                                      670

                                Incidental Oral

                                    0.0059
                                     1,400

                                   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
                                     1,200

                                   Children
                                    1 < 2
                                    Dermal
                                      470
                                    Small
                                     0.025
                                      320
                                      160

                                Incidental Oral

                                     0.024
                                      330

                                    Dermal
                                      940
                                    Medium
                                     0.021
                                      380
                                      190

                                Incidental Oral

                                     0.021
                                      390

                                    Dermal
                                     1,200
                                     Large
                                     0.017
                                      470
                                      240

                                Incidental Oral

                                     0.016
                                      490

                                   67517-82:
                                      Dog
                                     Adult
                                    Dermal
                                      510
                                    Small
                                     0.011
                                      760
                                       X

                                     1,300
                                    Medium
                                     0.011
                                      710

                                     2,000
                                     Large
                                     0.012
                                      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