
                 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
                                     Large
                                     0.030
                                      270
                                      140
                                       
                                       
                                Incidental Oral
                                       
                                       
                                     0.028
                                      280
                                       
                                   67517-82:
                                      Cat
                                     Adult
                                    Dermal
                                      130
                                    Small 
                                    0.0053
                                     1,500
                                       X
                                       
                                       
                                       
                                      310
                                    Medium 
                                    0.0076
                                     1,100
                                       
                                       
                                       
                                       
                                      460
                                     Large
                                    0.0071
                                     1,100
                                       
                                       
                                   Children
                                    1 < 2
                                    Dermal 
                                      130
                                    Small 
                                     0.014
                                      590
                                      300
                                       
                                       
                                Incidental Oral
                                       
                                       
                                     0.013
                                      610
                                       
                                       
                                       
                                    Dermal 
                                      310
                                    Medium
                                     0.020
                                      410
                                      210
                                       
                                       
                                Incidental Oral
                                       
                                       
                                     0.019
                                      430
                                       
                                       
                                       
                                    Dermal 
                                      460
                                     Large
                                     0.018
                                      440
                                      220
                                       
                                       
                                Incidental Oral
                                       
                                       
                                     0.018
                                      450
                                       
                              Pump/Trigger Spray
                              2596-126, 140: Cat
                                   (Trigger)
                                     Adult
                                    Dermal
                                      250
                                    Small 
                                    0.0065
                                     1,200
                                       X
                                       
                                       
                                       
                                      350
                                        
                                     Large
                                    0.0034
                                     2,300
                                       
                                       
                                   Children
                                    1 < 2
                                    Dermal 
                                      250
                                    Small 
                                     0.017
                                      480
                                      440
                                       
                                       
                                Incidental Oral
                                       
                                       
                                    0.0017
                                     4,700
                                       
                                       
                                       
                                    Dermal 
                                      350
                                        
                                     Large
                                    0.0087
                                      920
                                      830
                                       
                                       
                                Incidental Oral
                                       
                                       
                                    0.00090
                                     8,900
                                       
                                 2596-140: Cat
                                    (Pump)
                                     Adult
                                    Dermal
                                      51
                                    Small 
                                    0.0013
                                     6,000
                                       X
                                       
                                       
                                       
                                      71
                                     Large
                                    0.00070
                                    12,000
                                       
                                       
                                   Children
                                    1 < 2
                                    Dermal 
                                      51
                                    Small 
                                    0.0034
                                     2,400
                                     2,200
                                       
                                       
                                Incidental Oral
                                       
                                       
                                    0.00035
                                    23,000
                                       
                                       
                                       
                                    Dermal 
                                      71
                                     Large
                                    0.0018
                                     4,500
                                     4,100
                                       
                                       
                                Incidental Oral
                                       
                                       
                                    0.00018
                                    43,000
                                       
                                2596-125, -140:
                                      Dog
                                   (Trigger)
                                     Adult
                                    Dermal
                                      350
                                    Small 
                                    0.0045
                                     1,800
                                       X
                                       
                                       
                                       
                                      400
                                    Medium 
                                    0.0022
                                     3,600
                                       
                                       
                                       
                                       
                                      700
                                     Large
                                    0.0025
                                     3,200
                                       
                                       
                                   Children
                                    1 < 2
                                    Dermal 
                                      350
                                    Small 
                                     0.012
                                      690
                                      620
                                       
                                       
                                Incidental Oral
                                       
                                       
                                    0.0012
                                     6,600
                                       
                                       
                                       
                                    Dermal 
                                      400
                                    Medium
                                    0.0057
                                     1,400
                                     1,300
                                       
                                       
                                Incidental Oral
                                       
                                       
                                    0.00059
                                    14,000
                                       
                                       
                                       
                                    Dermal 
                                      700
                                     Large
                                    0.0063
                                     1,300
                                     1,200
                                       
                                       
                                Incidental Oral
                                       
                                       
                                    0.00066
                                    12,000
                                       
1	Based on registered TCVP pet products as detailed in Table 4.0.
2	Dose (mg/kg/day) equations provided in Appendix A.
3	MOE = PoD (8.0 mg/kg/day) / Dose (mg/kg/day).
4  Total MOE = 1 / (1 / Dermal MOE) + (1 / Incidental Oral MOE), where applicable.

Residential Post-application Cancer Exposure and Risk Estimate Equations
As was done for residential handlers, post-application cancer risk estimates for adults were calculated using a linear low-dose extrapolation approach in which a 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]).  The algorithms used to estimate the LADD and cancer risk for residential post-application exposure can be found in Appendix A.  

It should be noted that in the past, cancer risk assessments have assumed that children are no more sensitive than adults to carcinogens (i.e., no adjustment was made to children's exposure estimates in calculating a cumulative lifetime exposure).  More recently, the Agency's "Guidelines for Carcinogen Risk Assessment" (USEPA, 2005) and "Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens" (USEPA, 2005) proposed age-dependent adjustment factors to be applied to children's exposure.  These age-dependent factors are applied only to carcinogens shown to have a mutagenic mode of action.  In general, most carcinogenic pesticides have not been shown to act through a mutagenic mode of action, and thus separate assessment of children and adults is not warranted.  Any pesticide found to be a carcinogen acting through a mutagenic mode of action should be dealt with on a case by case basis, and such an assessment should follow the Agency's 2005 guidance.  The mutagenicity database for TCVP suggests that this chemical is not mutagenic in both the gene mutation assay and primary rat hepatocyte unscheduled DNA synthesis assay and, therefore, only adult cancer risk estimates have been estimated.  

Days per Year of Exposure: 
For purpose of estimating adult dermal cancer risks, exposure was assumed for 180 of 365 total days per year.  This factor is used as a health protective estimate of the number of days that an individual could be exposed to a treated animal per year of product use.  The recommendation of 6 months exposure is conservative, particularly when paired with the assumption that this exposure duration is repeated for 50 years during an adult's lifetime. 
 

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

Lifetime Expectancy: Life expectancy values are from the Exposure Factors Handbook 2011 Edition Table 18-1 (U.S. EPA, 2011).  The table shows that the overall life expectancy is 78 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. 

Summary of Residential Post-application Cancer Exposure and Risk Estimates
Adult residential post-application dermal cancer risk estimates range from 10[-8] to 10[-6] (detailed below in Table 5.2.3).

Table 5.2.3.   Residential Post-Application Cancer Exposure and Risk Estimates from TCVP Pet Products
                                  Animal Type
                                  Animal Size
                                   Lifestage
                                   LADD[1,2]
                            Cancer Risk Estimate[3]
                                    Collar
                                 2596-49: Cat
                                     Small
                                     Adult
                                    2.2E-04
                                    4.0E-07

                                    Medium

                                    1.3E-04
                                    2.4E-07

                                     Large

                                    8.1E-05
                                    1.5E-07
                                2596-50,62: Dog
                                     Small

                                    1.8E-04
                                    3.3E-07

                                     Large

                                    8.4E-05
                                    1.5E-07
                                 2596-83: Cat
                                     Small

                                    2.3E-04
                                    4.2E-07

                                     Large

                                    1.8E-04
                                    3.3E-07
                                 2596-139: Cat
                                     Small

                                    1.9E-04
                                    3.5E-07

                                    Medium

                                    1.2E-04
                                    2.1E-07

                                     Large

                                    7.2E-05
                                    1.3E-07
                                11556-164: Dog
                                     Small

                                    2.2E-04
                                    4.0E-07

                                    Medium

                                    9.3E-05
                                    1.7E-07

                                     Large

                                    5.9E-05
                                    1.1E-07
                                11556-165: Cat
                                     Small

                                    2.7E-04
                                    5.0E-07

                                    Medium

                                    1.6E-04
                                    3.0E-07

                                     Large

                                    1.0E-04
                                    1.9E-07
                                 2596-84: Dog
                                     Small

                                    1.8E-04
                                    3.3E-07

                                     Large

                                    8.4E-05
                                    1.5E-07
                                 2596-139: Dog
                                     Small

                                    4.8E-04
                                    8.8E-07

                                    Medium

                                    2.1E-04
                                    3.8E-07

                                     Large

                                    1.3E-04
                                    2.4E-07
                                 2596-63: Cat
                                     Small

                                    2.9E-04
                                    5.3E-07

                                     Large

                                    1.2E-04
                                    2.2E-07
                                  Dust/Powder
                                47000-123: Dog
                                     Small
                                     Adult
                                    5.1E-04
                                    9.3E-07

                                    Medium

                                    5.5E-04
                                    1.0E-06

                                     Large

                                    5.6E-04
                                    1.0E-06
                                47000-123: Cat
                                     Small

                                    2.5E-04
                                    4.7E-07

                                    Medium

                                    3.7E-04
                                    6.7E-07

                                     Large

                                    3.4E-04
                                    6.3E-07
                                 2596-78: Cat
                                     Small

                                    1.7E-03
                                    3.1E-06

                                     Large

                                    1.1E-03
                                    1.9E-06
                                 2596-79: Dog
                                     Small

                                    1.4E-03
                                    2.6E-06
                                       
                                    Medium

                                    1.2E-03
                                    2.2E-06
                                       
                                     Large

                                    9.6E-04
                                    1.8E-06
                                 67517-82: Dog
                                     Small

                                    1.5E-03
                                    2.8E-06

                                    Medium

                                    1.6E-03
                                    3.0E-06

                                     Large

                                    1.7E-03
                                    3.1E-06
                                 67517-82: Cat
                                     Small

                                    7.6E-04
                                    1.4E-06

                                    Medium

                                    1.1E-03
                                    2.0E-06

                                     Large

                                    1.0E-03
                                    1.9E-06
                              Pump/Trigger Spray
                              2596-126, 140: Cat
                                   (Trigger)
                                     Small
                                     Adult
                                    4.6E-04
                                    8.3E-07

                                     Large

                                    2.4E-04
                                    4.4E-07
                                 2596-140: Cat
                                    (Pump)
                                     Small

                                    9.3E-05
                                    1.7E-07

                                     Large

                                    4.9E-05
                                    8.9E-08
                              2596-125, -140: Dog
                                   (Trigger)
                                     Small

                                    3.2E-04
                                    5.8E-07

                                    Medium

                                    1.6E-04
                                    2.9E-07

                                     Large

                                    1.7E-04
                                    3.2E-07
1	Total 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

	5.3 	Residential Risk Characterization

The evaluation of the potential residential post-application health risks from exposures to cats/dogs treated with TCVP pet products is conservative.  The risk estimates calculated are based upon protective assumptions of TCVP hazard, product application rates, durations of exposure, and contact with the treated animal, and they make use of the best available post-application exposure data.

Application Rate:  The application rates used in the assessment of pet products represent the maximum amount of TCVP that could be applied by weight of the treated animal (small, medium, and large) for TCVP collars, dusts/powders, and pump/trigger sprays.  

For TCVP collars, the applicator is directed to cut off and dispose of any excess length once the product is fit and buckled into place.  As described in the Treated Pet SOP, because the exact length cannot be determined, the corresponding TCVP loss cannot be quantified and, therefore, exposure is assessed assuming the full collar length.  While this approach may result in an overestimate of collar application rate, it ensures protection of users who may contact dogs wearing an uncut TCVP collar.  
 
For TCVP dusts/powders, all products identify a specific amount to use per animal weight that allows for determination of the maximum application rate.  For TCVP pump/trigger sprays, all registered products direct the user to apply a specific number of "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 was not recommended.  The maximum number was considered in the risk assessment for cats and dogs and based on animal size.

Exposure Data:  It is HED policy to use the best available data to assess exposure. Where chemical- or formulation-specific exposure data were available, these data were used to conduct the assessment of residential handler and post-application exposures or integrated with other data as appropriate.  The exposure estimates based on the use of these data are the most accurate representation of exposures anticipated from use of TCVP pet products and are not expected to underestimate residential risks. 

All residential handler exposure estimates are based on the values recommended in the 2012 SOPs for Residential Exposure Assessment (SOPs).  For the application of TCVP dust/powder formulation exposure scenario, chemical-specific exposure monitoring data are available (MRID 45519601).  These data were previously reviewed by the Agency and determined to be acceptable for use in risk assessment.  In fact, these data have been incorporated into the calculation of the unit exposure value associated with this scenario in the 2012 Residential SOPs.  A carbaryl dust/powder exposure study is also included in the SOP unit exposure recommendation for the dust/powder exposure scenario as described in the Residential SOPs.  For purpose of the residential handler dust/powder assessment, only the TCVP unit exposure data were used.  For further information regarding how the exposure estimates were determined, please refer to the 2012 Residential SOPs where the process is explained in detail. 

For the assessment of residential post-application exposures from registered TCVP products, surrogate and chemical-specific transferable residue transfer studies were used which are believed to best represent the potential exposures from TCVP use.  These residue data were collected from treated dogs after treatment with 1) TCVP aerosol, powders, and pump spray formulations (MRID 45485501) and 2) a pet collar containing the active ingredient propoxur (MRID 48589901).  HED previously completed a review of the TCVP aerosol, powder, and pump spray formulation residue transfer study for (MRID 45485501) in 2001.  That study was reevaluated based on current standards of conduct for pet residue transfer studies.  This reevaluation of the TCVP transferable residue study resulted in a number of changes from the 2001 review.  These differences are illustrated in Table 5.2.1 of this document.

The 2012 Residential SOPs: Treated Pets recommends that the fraction of applied residues which come off of a companion animal on the day of application (i.e., Day 0) should serve as the basis for assessment of post-application exposures.  This input is defined as fraction application rate (FAR) in the 2012 SOPs.  The day of application percent residue transfer values resulting from the above referenced studies used for exposure/risk quantification are as follows:  pet collars, 0.072% (arithmetic mean); dusts/powders, 0.048% (maximum observed); and pump/trigger sprays, 0.81% (maximum observed).  

The TCVP powder and pump spray post-application exposure study was not conducted in a manner reflective of current standards that require a defined stroking procedure and greater number of petting simulations.  That is, the pet (cat/dog) should be stroked in a single motion with the grain of the fur starting with both sides (along the ribcage) of the animal and followed by the same motion along the back (dorsally) from the base of the neck to the tail.  The two sides and back, in this order, account for one petting simulation.  A total of 20 petting simulations (or 60 stroking motions) are currently required.  In the TCVP post-application exposure study, the dogs were stroked only one side of treated dog's back from head to rump five times.  It is also notable that the dogs were stroked with a bare hand, rather than with the currently required transferable collection method, cotton gloves worn over a mannequin hand.  Transferable residues were collected for analysis in the TCVP post-application exposure study from the bare hand using a methanol wipe.  In the current method, the cotton gloves are removed from the mannequin hand for analysis.  The mannequin hand is not analyzed, but acts only as a residue collection tool to avoid direct contact with the treated animal.  Despite these differences, the TCVP powder and pump spray post-application exposure study was reflective of current policy regarding pet residue transfer studies at the time that it was conducted.  

For the reasons described in Section 5.2 of this document, HED used the maximum observed percent residue transfer on the day of product application (Day 0), as opposed to the average, for both formulations for exposure/risk quantification.  This approach results in residue transfer for pump/trigger sprays comparable to the arithmetic mean percent residue transfer observed from the analysis of all liquid formulated product data sets presented in the 2012 Residential SOPs; 0.81% and 0.96%, respectively.  The TCVP dust/powder study is the only data available for this pet product formulation and, thus, HED has no basis of comparison; however, the data are acceptable for risk quantitation and are the best available for the product type.  

No exposure data are available for assessment of post-application exposures from the use of TCVP pet collars.  Two post-application exposure studies have been submitted to the Agency in support of residential pet collar uses, the aforementioned propoxur pet collar study and a recently submitted deltamethrin pet collar residue transfer study (MRID 49350101).   Both studies were conducted in a manner consistent with current standards and are recommended for use in risk quantitation.  The propoxur pet collar study resulted in mean percent residue transfer on Day 0 in excess of that of the deltamethrin study; 0.072% and 0.003%, respectively.  The more conservative mean percent residue transfer resulting from the propoxur study was selected for use as a surrogate for estimation of TCVP post-application risks.   

In comparison to other formulations used for pet pest control (e.g., dusts, spot-ons, sprays), the pet collar formulation is unique and results in considerably lower percent residue transfer values.  When other pet product formulations are applied to a treated pet, it can be reasonably assumed that the entire amount of that applied (i.e., the application rate) is available on the hair coat of the animal for transfer to the exposed individual.  For example, the labeled amount of the TCVP pump/trigger spray product can be used directly in the assessment of exposure/risk because it is assumed this amount is available on the surface for contact.  Pet collar formulations operate by slowly releasing the ai from the collar medium, making them efficacious for pest treatment over longer periods of time.  Due to this activity, it can be difficult for the risk assessor to determine the amount which is initially available on the animal because the majority is retained within the collar.  Accordingly, the propoxur and deltamethrin pet collar study results in residue transfer much less than that from other, liquid formulated products.

For residential handler exposure assessment for TCVP collar products, exposure data for spot-on applications was used as a surrogate to estimate handler exposures.  For the reasons described in the preceding paragraph, the use of the spot-on applicator exposure data is highly conservative.   

For purpose of quantification of estimated TCVP post-application cancer exposures/risks, HED used the mean percent residue transfer of all days sampled in the propoxur collar and TCVP dust/powder and pump spray studies.  For the TCVP collar, 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.  

While the use of the maximum observed percent residue transfer on Day 0 is not typically undertaken for non-cancer or cancer residential exposure assessment, it allows for use data best representative of the exposure potential from TVCP pet products while ensuring a conservative, health protective assessment of residential risks.

Pet Contact:  For the purpose of determining exposure to treated pets, the 2012 Residential SOPs make use of transfer coefficients (TCs).  TC is an exposure rate for a selected activity which involves contact with a source, such as children playing with treated pets or on treated turf.  The TC concept is a long-standing established approach used to estimate residential, as well as occupational exposures, and is the basis for the Agency's post-application exposure guidelines.  A TC is derived by taking the ratio of study volunteer dermal exposure per unit time (mg/hr), and the concurrent measure of residue transfer.  Ideally, dermal exposure is based on an activities representative of the use pattern and residue transfer is determined by use of an established method specific to the use pattern.  For pet exposures, TCs can be defined as animal surface area contact per unit time (cm[2]/hr).  

Currently, there is no exposure study available using representative, or typical adult and child activities with pets and a concurrent transferable residue (TR) measure.  In the absence of direct exposure data for residential activities with pets, the Agency concluded that studies conducted to monitor pet grooming activities are likely to result in a highly protective estimate of pet contact relative to contact associated with petting, hugging, or sleeping with a pesticide-treated pet. These data were gathered while human volunteers applied dust/powders and shampoo products to various dogs of differing sizes and fur lengths.  Since these individuals extensively handled the dogs, it is expected that their resulting exposures are higher than would be reasonably anticipated from routine contact with treated pets.  The volunteers in the shampoo study, who were professional groomers, shampooed 8 dogs for 5 minutes each, rinsed, and lifted them to counters for drying and combing resulting in very high exposures.  In the dust study, volunteers applied dust via shaker can to 8 dogs each and then rubbed the dusts into the dogs' coats.  The applicator studies were not conducted in a manner which measured TR, or active ingredient per surface area. Therefore, the residue available on the animal for transfer was predicted by multiplying the arithmetic mean fraction of application rate from the analysis of all liquid formulated product data sets presented in the 2012 Residential SOPs, 0.96%.  This approach has the effect of increasing TC estimates, thus resulting in TC values which are more protective of human health.  Furthermore, the selection of the mean value, in lieu of the screening level FAR value, 2%, further increases the TC estimates with use of the dust and shampoo studies.  

Exposure Time:  The exposure time (ET) assumption used to assess residential post-application exposure to TCVP pet products is derived from a study which sought to evaluate the times that individuals spend performing different activities around the home.  Based upon the 2012 Residential SOPs: Treated Pet SOP, the point estimates recommended for adult and child ET with pets are 0.77 and 1 hours, respectively.  In the study, animal care is defined as "care of household pets including activities with pets, playing with the dog, walking the dog and caring for pets of relatives, and friends."  The data identified the time spent with an animal while performing household activities as recorded in 24 hour diaries by study volunteers.  While the activities defined do not necessarily represent the time volunteers were actively engaged in constant contact with the animal as is implicit in the post-application dermal and incidental oral algorithms, the data are the most accurate representation of time spent with pets available and, therefore, it is assumed that contact is continual throughout the timed activity.  HED assumes the ET value reflects a reasonable high end estimate of time spent in contact with a dog treated with TCVP pet products.  

When use of the study data are coupled with high end assumptions of pet contact, the result is an exposure assessment that inherently implies vigorous, continual contact for the entire duration of contact.  While it is possible that an adult or child may be in close contact with a pet intermittently throughout the day, they would not be actively engaged in the highly vigorous contact implied by use of the TCs based on the applicator exposure data for the full exposure duration assumed.  Further, it is possible that adults or children may be exposed from sleeping with a treated pet; however, they are not actively engaged in a high level of contact, or the repeated mouthing behaviors exhibited by children during waking hours, which are inherently assumed in the assessment conducted.    

Hazard:  The toxicology database for TCVP is complete and adequate to support the residential assessment from TCVP pet product use.  For TCVP, AChE inhibition is the most sensitive endpoint in the toxicology database in multiple species, durations, lifestages, and routes.  TCVP has low acute (lethality) toxicity by the oral, dermal, and inhalation routes of exposure.  It is classified as a Group C possible human carcinogen by the Agency with a linear low-dose approach for quantification of risk using the oral slope factor (Q1*) of 1.83 x 10[-3] (mg/kg/day)[-1].  TCVP is not mutagenic and immunotoxicity was not observed at levels that exceed the limit dose.  The FQPA SF was reduced to 1X since there is no evidence of sensitivity of the young animal in the pre- and post-natal studies compared to the adult, and there are no data gaps.  

Consistent with risk assessments for other AChE-inhibiting compounds, HED conducted a BMD analysis for TCVP using a benchmark response (BMR) level of 10%, and has thus calculated BMD10 and BMDL10 values.  The use of the 10% BMR is derived from a combination of statistical and biological considerations.  A power analysis was conducted by the Office of Research and Development (ORD) on over 100 brain AChE datasets across more than 25 OPs as part of the OP cumulative risk assessment (CRA) (USEPA, 2002).  This analysis demonstrated that 10% is a level that can be reliably measured in the majority of rat toxicity studies.  In addition, the 10% level is generally at or near the limit of sensitivity for discerning a statistically significant decrease in ChE activity in the brain compartment and is a response level close to the background brain ChE level.  With respect to biological considerations, a change in 10% brain AChE inhibition is protective for downstream clinical signs and apical neurotoxic outcomes.  Based on a robust BMD analysis evaluating a broad representation of the TCVP toxicity database, points of departure were selected for the assessment of the major residential routes of exposure; dermal (handler and post-application), incidental oral (post-application only), and inhalation (handler only).  

For the dermal risk assessment, a steady state PoD was selected from the subchronic oral toxicity study in rats.  Since an oral study was selected, a DAF of 9.57% was used for the route-to-route extrapolation. The DAF is based on the results of a dermal penetration study in rats. The use of the rat dermal absorption data is considered conservative because rats tend to have more permeable skin that humans (3  -  10X).  Therefore, the use of the rat DAF based on the rat dermal penetration study likely leads to an overestimation of residential dermal exposures.  

Indirect Incidental Oral Exposures: An assessment of indirect incidental oral exposures resulting from children putting objects or other toys in their mouth that potentially have residue from contact with treated pets (i.e., object-to-mouth exposures) was not conducted.  The 2012 residential SOPs state that hand-to-mouth and object-to-mouth incidental oral exposures assessments should be conducted for treatments to indoor environments and lawns/turf only.  For these exposure scenarios, children's hand-to-mouth exposures are expected from direct contact with treated surfaces (i.e., treated turf and carpets/hard floors) and object-to-mouth exposures are expected due to the potential for secondary exposures from mouthing objects that may have been in contact with the treated surface.  With use of the methods described in the indoor environments and lawn/turf SOPs, the quantification of hand-to-mouth exposures following direct contact with the treated surface always results in exposures of a greater magnitude and, as a result, a more health protective assessment of risk (i.e., a lower MOE) than from indirect object-to-mouth exposures.  

When the dermal and incidental oral exposure routes share a common toxicological endpoint, as is the case for TCVP, risk estimates are combined for these routes.  The incidental oral exposure scenarios (i.e., hand-to-mouth and object-to-mouth) are considered inter-related and it is likely that they occur interspersed amongst each other across time.  Accordingly, choosing the highest of the incidental oral exposure scenarios is protective of both.  Further, combining both of the incidental oral exposure scenarios with the dermal exposure scenario would be unrealistic because of the highly conservative nature of each individual assessment.  Therefore, the hand-to-mouth exposure scenario, which has the highest estimated incidental oral risk, is combined with the dermal post-application exposure and is considered a protective estimate of children's exposures following pesticide usage.  This approach is consistent with that used for assessment of post-application exposures from TCVP pet product usage. 

	5.4	Residential Risk Estimates for Use in Aggregate Assessment

Tables 5.1.1, 5.2.2 and 5.2.3 reflect the residential risk estimates that are recommended for use in the aggregate assessment that will be conducted as part of the Preliminary Risk Assessment during Registration Review for TCVP.
 The recommended residential exposure for use in the adult aggregate non-cancer risk assessment is combined (dermal and inhalation) exposures from applications to large dogs with a dust/powder product (EPA Reg. No. 65717-82). 
 The recommended residential exposure for use in the children 1<2 years old non-cancer aggregate assessment is combined (dermal and hand-to-mouth exposures) from post-application exposure to either small cats or large dogs from EPA Reg. Nos. 2596-78 and 67517-82, respectively. 
 The recommended residential exposure for use in the adult aggregate cancer assessment is dermal exposure from the post-application exposure to large dogs from EPA Reg. No. 67517-82 (dose is 1.7E-03 mg/kg/day).






Table 5.4.  Recommendations for the Residential Exposures for the TCVP Aggregate Risk Assessment[1]
                                   Lifestage
                                  (Scenario)
                               Dose (mg/kg/day)
                                Risk Estimates
                                       
                                    Dermal
                                  Inhalation
                                     Oral
                                   Total[2]
                                    Dermal
                                  Inhalation
                                     Oral
                                 Total MOE[3]
                                    ARI[4]
                              Residential Handler
                                     Adult
                                     0.018
                                    0.00035
                                      N/A
                                     0.018
                                      440
                                     4,700
                                      N/A
                                      N/A
                                      4.2
                         Residential Post-application
                                     Child
                                     0.030
                                      N/A
                                     0.029
                                     0.059
                                      270
                                      N/A
                                      280
                                      140
                                      N/A
                                Cancer Exposure
                                     Adult
                                    1.7E-03
                                      N/A
                                      N/A
                                    1.7E-03
                                      N/A
                                      N/A
                                      N/A
                                      N/A
                                      N/A
1 Bolded worst-case risk estimates should contribute to the residential exposure portion of the aggregate assessment. 
2 Total Dose (mg/kg/day) = Dermal Dose + Inhalation Dose + Incidental Oral Dose (where applicable).
3 Total MOE = 1 / (1 / Dermal MOE) + (1 / Incidental Oral MOE).
4 ARI = 1/ [(Dermal LOC (100) / Dermal MOE) + (Inhalation LOC (30) / Inhalation MOE)].

	5.5	Spray Drift

This assessment has not been conducted for the TCVP pet use products that are unlikely to result in spray drift.  Further, spray drift is not anticipated from the occupational use of TCVP for direct application to livestock or livestock premises. 

	5.6	Residential Bystander Post-Application Inhalation Exposure

Residential post-application inhalation exposure is expected to be negligible from TCVP pet products and, thus, a quantitative assessment was not performed.  Per the Residential SOPs, the combination of low vapor pressure (2.6 x10[-7] mmHg at 25°C) and the small amounts of pesticide applied to pets is expected to result in negligible levels of chemical in the air, and therefore negligible inhalation exposures.  












Appendix A:  Algorithms Used to Calculate Residential Non-Cancer and Cancer Risk Estimates

Dermal and Inhalation Handler Exposure Algorithm

Daily dermal and inhalation exposure (mg/day) for residential pesticide handlers, for a given formulation-application method combination, is estimated by multiplying the formulation-application method-specific unit exposure by an estimate of the amount of active ingredient handled in a day, using the equation below:

                                E = UE * AR * A

where:

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

Post-application Dermal Exposure Algorithm

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

	E = TC * TR * ET	

where:

      E	   = exposure (mg/day);
      TC	= transfer coefficient (cm[2]/hr);
      TR	= transferable residue (mg/cm[2]); and
      ET	= exposure time (hours/day).


	TR= AR * FARSA	
	
where:

      TR	= transferable residue (mg/cm[2]);
      AR	= application rate or amount applied to animal (mg);
      FAR	= fraction of the application rate available as transferable residue; and
      SA	= surface area of the pet (cm[2]).
      
Absorbed dermal dose, normalized to body weight, is calculated as:

	D = E * AF 	BW		

where:
      D	= dose (mg/kg-day);
      E	= exposure (mg/day); 
      AF	= absorption factor (dermal); and
      BW	= body weight (kg). 
      

Table A.1.  Treated Pets  -  Inputs for Residential Post-application Dermal Exposure 
                              Algorithm Notation
                                Exposure Factor
                                     Units
                                Point Estimates
                                      AR
                               Application rate
                                     (mg) 
                            Unique for each product
                                      SA
                            Surface Area of Animal 
                                    (cm[2])
                                Small Cat, Dog
                                 Cat  -  1,500
                                 Dog  -  3,000
                                       
                                       
                                Medium Cat, Dog
                                 Cat  -  2,500
                                 Dog  -  7,000
                                       
                                       
                               Large Cat, Dog  
                                 Cat  -  4,000
                                Dog  -  11,000
                                      FAR
                    Fraction of AR Available for Transfer 
                         (recommended point estimate)
                                  Non-Cancer
                       Collar (Propoxur Study): 0.00072
                          Dust/Powder (TCVP): 0.00048
                           Pump Spray (TCVP): 0.0081
                                       
                                    Cancer
                       Collar (Propoxur Study): 0.00013
                          Dust/Powder (TCVP): 0.00022
                           Pump Spray (TCVP): 0.0018
                                      TC
                       Transfer Coefficient  -  Liquids 
                                   (cm2/hr)
                                     Adult
                                     5,200
                                       
                                       
                          Children 1 < 2 years old
                                     1,400
                                       
                        Transfer Coefficient  -  Solids
                                   (cm2/hr)
                                     Adult
                                    140,000
                                       
                                       
                          Children 1 < 2 years old
                                    38,000
                                      ET
                                 Exposure Time
                                (hours per day)
                                     Adult
                                     0.77
                                       
                                       
                          Children 1 < 2 years old
                                      1.0
                                      BW
                                  Body weight
                                     (kg)
                                     Adult
                                      80
                                       
                                       
                          Children 1 < 2 years old
                                      11

Post-application Hand-to-Mouth Exposure Algorithm

Exposure from hand-to-mouth activity is calculated as follows (based on algorithm utilized in SHEDS-Multimedia):

	E = [HR * (FM * SAH ) * (ET * N_Replen) * (1- (1- SE) (Freq_HtM/N-Replen))] 	

where:

      E	= exposure (mg/day);
      HR	= hand residue loading (mg/cm[2]);
      SAH	= surface area of one child hand (cm[2]);
      FM	= fraction hand surface area mouthed /event (fraction/event);
      ET	= exposure time (hr/day);
      N_Replen  	= number of replenishment intervals per hour (intervals/hour);
      SE	= saliva extraction factor (i.e., mouthing removal efficiency); and
      Freq_HtM   	= number of hand-to-mouth contacts events per hour (events/hour).

and

	HR = E * Faihands
	          2 * SAH 	
where:
      HR	= hand residue loading (mg/cm[2]);
      E		= dermal exposure (mg);
      Faihands	= fraction of a.i. on hands compared to total residue from dermal transfer coefficient study (unitless); and
      SAH		= surface area of one child hand (cm[2]).

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

	D = E 
	         BW	
where:
      D	= dose (mg/kg-day);
      E	= exposure (mg/day); and
      BW	= body weight (kg).
      
      
Table A.2.  Treated Pets  -  Inputs for Residential Post-application Hand-to-Mouth Exposure
                              Algorithm Notation
                                Exposure Factor
                                    (units)
                               Point Estimate(s)
                                   Fai hands
    Fraction of a.i. on hands from transfer coefficient studies (unitless)
                                 Solid = 0.37
                                Liquid = 0.040
                                      FM
          Fraction hand surface area mouthed /event (fraction/event)
                                     0.13
                                   N_Replen
                       Replenishment intervals per hour
                                (intervals/hr)
                                       4
                                      ET
                                 Exposure time
                                  (hours/day)
                          Children 1 < 2 years old
                                      1.0
                                      SE
                           Saliva extraction factor
                                     0.48
                                   Freq_HtM
                         Hand-to-mouth events per hour
                                  (events/hr)
                          Children 1 < 2 years old
                                      20
                                      SAH
                    Typical surface area of one child hand
                                    (cm[2])
                          Children 1 < 2 years old
                                      150
                                      BW
                                  Body Weight
                                     (kg)
                          Children 1 < 2 years old
                                      11

Cancer Exposure Algorithm

Exposure/Dose Amortization:

An accurate estimate of exposure over the course of weeks, years or a lifetime is difficult to predict as exposure likely differs from one day to the next due to product-specific application regimens, residue dissipation, human behavior and activity patterns, and the extent to which an individual's exposure varies due to behavior changes.  Approaches for amortizing dose over various exposure durations are explained in more detail in Section 1.3 of the 2012 Residential SOPs; however an example would be amortization of an individual's daily dose over their lifetime necessary for calculating exposures for cancer risk assessments.  This amortized dose is known as the lifetime average daily dose (LADD) and it can be calculated as follows:

			 LADD =        D * EF * ET
					  AT * CF

where:

      LADD	 = lifetime average daily dose (dermal + inhalation, mg/kg-day);
      D	 = dose (mg/kg-day);
      EF	 = exposure frequency (i.e., frequency of product use) (days/year);
      ET	 = exposure time (years);
      AT	 = averaging time (i.e., life expectancy) (years); and
      CF	 = conversion factor (365 days/year). 
      
      
Table A.3.  Treated Pets  -  Inputs for Cancer Exposure/Risk
                              Algorithm Notation
                                Exposure Factor
                                    (units)
                               Point Estimate(s)
                                      EF
                        Exposure Frequency (days/year)
Handlers: Collars, 4;  Dusts/Powders and Pump/Trigger Sprays, 6

Post-application (all formulations): 180  
                                      ET
                             Exposure Time (years)
                                      50
                                      AT
                            Averaging Time (years)
                                      78
                                      CF
                         Conversion Factor (days/year)
                                      365


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

OPP's ChE policy (USEPA, 2000) describes the manner in which ChE data are used in human health risk assessment.  The following text provides a brief summary of that document to provide context to points of departure selected.  

AChE can be inhibited in the central or peripheral nervous tissue.  Measurements of AChE or cholinesterase (ChE) inhibition in peripheral tissues (e.g., liver, diaphragm, heart, lung etc.) are rare.  As such, experimental laboratory studies generally measure brain (central) and blood (plasma and red blood cell [RBC]) ChE.  Blood measures do not represent the target tissue, per se, but are instead used as surrogate measures for peripheral toxicity in studies with laboratory animals or for peripheral and/or central toxicity in humans.  In addition, RBC measures represent AChE, whereas plasma measures are predominately butyryl-ChE (BuChE).  Thus, RBC AChE data may provide a better representation of the inhibition in target tissues.  As part of the dose response assessment, evaluations of neurobehavior and clinical signs are performed to consider the dose response linkage between AChE inhibition and apical outcomes.

Refinements to OPP's use of ChE data have come in the implementation of BMD approaches in dose response assessment.  Beginning with the OP cumulative risk assessment (CRA), OPP has increased its use of BMD modeling to derive PoDs for AChE inhibiting compounds.  Most often the decreasing exponential empirical model has been used.   

OPP does not have a defined benchmark response (BMR) for OPs.  However, the 10% level has been used in the majority of dose response analyses conducted to date.  This 10% level represents a 10% reduction in AChE activity (i.e., inhibition) compared to background (i.e., controls).  Specifically, the BMD10 is the estimated dose where ChE is inhibited by 10% compared to background.  The BMDL10 is the lower confidence bound on the BMD10.  

The use of the 10% BMR is derived from a combination of statistical and biological considerations.  A power analysis was conducted by the ORD on over 100 brain AChE datasets across more than 25 OPs as part of the OP CRA (USEPA, 2002).  This analysis demonstrated that 10% is a level that can be reliably measured in the majority of rat toxicity studies.  In addition, the 10% level is generally at or near the limit of sensitivity for discerning a statistically significant decrease in ChE activity in the brain compartment and is a response level close to the background brain ChE level.  With respect to biological considerations, a change in 10% brain AChE inhibition is protective for downstream clinical signs and apical neurotoxic outcomes.  RBC AChE inhibition data tend to be more variable than brain AChE data.  OPP begins its BMD analyses using the 10% BMR for RBC AChE inhibition. However, BMRs up to 20% could be considered on a case by case basis, as long as such PoDs are protective for brain AChE inhibition, potential peripheral inhibition, and clinical signs of neurotoxicity.


Appendix C:  Results for BMD/BMDL modeling for TCVP 

BMD analyses were performed with EPA's Benchmark Dose Software (Version 2.4) using an exponential model for continuous data.  The Hill model was also performed for some data sets, but did not result in the best fit for the data.  The data selected for evaluation consisted of decreased brain and red blood cell (RBC) cholinesterase (ChE) activities.  Data were analyzed from a 21-day oral toxicity study (MRID 45570601), a 13-week subchronic oral toxicity study (MRID 43371201), and a 2 year chronic oral toxicity study (MRID 42980901); a gestational comparative cholinesterase assay (CCA; MRID 48291101); and a 28-day inhalation toxicity study (MRID 48803501).  All data from these studies were considered; however, some data were not amenable to BMD analysis.   

OPP has used the exponential model for modeling AChE activity for the OP and N-methyl carbamate cumulative risk assessments and with multiple single chemical risk assessments of ChE-inhibiting pesticides.  Model runs for ChE activity were conducted with an appropriate benchmark response level (10%).  As such the BMD10 (estimated dose to result in 10% change from background levels) and BMDL10 (the lower 95% confidence level on the BMD10) are provided in the output.  Statistical (e.g., goodness of fit values) and graphical results were used in model evaluation. 
         
The results of the repeated oral and inhalation dosing BMD analyses are summarized below in Table C.1.  Good model fit (p>0.1) was obtained for the majority of the analyses, with any exceptions being noted.  

For exposure to repeated doses the BMDL10 for ChE inhibition in the adult female RBCs were similar in the 13-week subchronic study and the 21-day oral toxicity study (8.0 mg/kg/day vs 6.7 mg/kg/day, respectively).  Although data from the shorter duration study resulted in a slightly lower BMDL, visual examination of the modeled data provided greater confidence in the 13-week study.  For inhalation exposure, the adult male was about twice as sensitive as the adult female (0.023 mg/L in males vs 0.050 mg/L in females).


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

TCVP Study
                                       
                                    Age/Sex
                                       
                                  Compartment
                                  BMD Results

                                       
                                       
                                     BMD10
                                    BMDL10
MRID 43371201
13W Oral  -  13 Weeks
                                  Adult Male
                                     Brain
                   No dose response (analysis not performed)

                                 Adult Female
                                     Brain
                               No dose response

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

                                 Adult Female
                                      RBC
                                10.5 mg/kg/day
                                 8.0 mg/kg/day
MRID 42980901
Chronic Oral Tox  -  364, 539, and 721 Days
                                 Adult Female
                                      RBC
        No dose-response effect was observed at 364,  539, or 721 days
MRID 45570601
21D Oral Tox  -  21 Days
                                 Adult Female
                                     Brain
                                14.7 mg/kg/day
                                12.2 mg/kg/day

                                       
                                      RBC
                                 9.9 mg/kg/day
                                 6.7 mg/kg/day
MRID 48803501
28D Inhalation  -  28 Days
                                  Adult Male
                                      RBC
                                  0.122 mg/L
                                  0.023 mg/L

                                 Adult Female
                                      RBC
                                  0.394 mg/L
                                  0.050 mg/L

      
