
                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                               
                                                                               
                                                      OFFICE OF CHEMICAL SAFETY
\* MERGEFORMAT
                                                       AND POLLUTION PREVENTION


MEMORANDUM

Date:  		8/30/2012

SUBJECT:	Fenpropathrin.  Human Health Risk Assessment for Section 3 Registration on Tropical Fruit and a Request for a Tolerance Without U.S. Registration on Tea  

 
PC Code:  127901
DP Barcode:  D368175  
Decision No.:  417627 
Registration No.:  59639-35 
Petition No.:  9E7594 
Regulatory Action:  Section 3 Registration 
Risk Assessment Type:  Single Chemical
                                         Aggregate
Case No.:  NA 
TXR No.:  NA 
CAS No.: 39515-41-8
MRID No.: NA
40 CFR:  §180.466


FROM:	Douglas A. Dotson, Ph.D., Chemist
		Edward Scollon, Ph.D., Toxicologist
		Suku Oonnithan, Ph.D., Biologist
		Registration Action Branch II
		Health Effects Division (7509P)

THROUGH:	Karlyn Middleton, Toxicologist
		Dennis McNeilly, Chemist
		Zaida Figueroa, Industrial Hygienist
		Christina Swartz, Branch Chief
		Registration Action Branch II
			and
		Dana Vogel, Acting Associate Division Director
		Deborah Smegal, MPH, Toxicologist
		Health Effects Division
		
TO:		Laura Nollen/Barbara Madden, RM Team 5 
      RIMUERB
      Registration Division (7505P)


The Registration Division (RD) requested that the Health Effects Division (HED) conduct a human health risk assessment for the proposed use of the insecticide fenpropathrin on tropical fruit, and for a tolerance for residues in tea (without U.S. registration).  This document contains the human health risk assessment associated with these actions and incorporates updated endpoints for risk assessment, updated residue monitoring data and percent crop treated assumptions, as well as the most recent data and assumptions for conducting occupational exposure assessments.  No risks of concern were identified for the proposed registration action.


1.0	Executive Summary	5
2.0	HED Recommendations	8
2.1	Data Deficiencies/Conditions of Registration	8
2.2	Tolerance Considerations	8
2.2.1	Enforcement Analytical Method	8
2.2.2	International Harmonization	8
2.2.3	Recommended Tolerances	9
2.2.4	Revisions to Petitioned-For Tolerances	9
2.3	    Label Recommendations	10
3.0	Introduction	10
3.1	Chemical Identity	10
3.2	Physical/Chemical Characteristics	10
3.3	Pesticide Use Pattern	10
3.4	Anticipated Exposure Pathways	11
3.5	Consideration of Environmental Justice	11
4.0	Hazard Characterization and Dose-Response Assessment	12
4.1	Toxicology Studies Available for Analysis	12
4.2	Toxicological Profile	13
4.3	Pyrethroid Pharmacokinetic and Pharmacodynamic Profile	15
4.3.1	Pharmacokinetics	15
4.3.2	Pharmacodynamics	16
4.3.3	Critical Duration of Exposure	18
4.4	Safety Factor for Infants and Children (FQPA Safety Factor)	19
4.4.1	Completeness of the Toxicology Database	20
4.4.2	Evidence of Neurotoxicity	21
4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal	21
4.4.4	Residual Uncertainty in the Exposure Database	22
4.5	Toxicity Endpoint and Point of Departure Selections	22
4.5.1	Dose-Response Assessment	22
4.5.2	Recommendation for Combining Routes of Exposure for Risk Assessment	24
4.5.3	Cancer Classification and Risk Assessment Recommendation	24
4.5.4	Summary of Points of Departure and Toxicity Endpoints 	24
5.0	Dietary Exposure and Risk Assessment	25
5.1	Metabolite/Degradate Residue Profile	25
5.1.1	Summary of Plant and Animal Metabolism Studies	25
5.1.2	Summary of Environmental Degradation	26
5.1.3	Comparison of Metabolic Pathways	26
5.1.4	Residues of Concern Summary and Rationale	26
5.2	Food Residue Profile	27
5.3	Water Residue Profile	28
5.4	Dietary Risk Assessment	28
5.4.1	Description of Residue Data Used in Dietary Assessment	28
5.4.2	Percent Crop Treated Used in Dietary Assessment	29
5.4.3	Acute Dietary Risk Assessment	29
5.4.4	Summary Table	30
6.0	Residential (Non-Occupational) Exposure/Risk Characterization	30
6.1	Residential Handler and Post-Application Exposure and Risk Estimates	30
6.2	Spray Drift	31
7.0	Aggregate Exposure/Risk Characterization	31
8.0	Cumulative Exposure/Risk Characterization	31
9.0	Occupational Exposure/Risk Characterization	32
9.1	Short-/Intermediate-Term Handler Risk	32
9.2	Occupational/Commercial Post-application	34
10.0	References	35
Appendix A.  Toxicology Profile and Executive Summaries	39
A.1	Toxicology Data Available for Penthiopyrad	39
A.2	Toxicity Profile Tables	40
A.3	Hazard Identification and Endpoint Selection	46
A.4	Human Equivalent Analysis	50
A.5	Pyrethroid Cumulative Screen	50
Appendix B.  Physical/Chemical Properties	51
Appendix C.  Review of Human Research	52


1.0	Executive Summary

Fenpropathrin (alpha-cyano-3-phenoxy-benzyl 2,2,3,3-tetramethylcyclopropanecarboxylate) is an ingestion and contact pyrethroid insecticide and acaricide currently registered for use on fruits, vegetables, field crops, and ornamental plants for the control of various insect pests and mites.  

Fenpropathrin is currently registered for use on a variety of tropical fruits.  The Interregional Research Project Number 4 (IR-4) proposed tolerances for residues of fenpropathrin in/on numerous additional tropical fruits.  IR-4 has also proposed a tolerance without U.S. registration on tea.  The end use product proposed for use on the tropical fruits is Danitol[(R)] 2.4 EC Spray (EPA Registration Number 59639-35).

Pyrethroids have historically been classified into two groups, Type I and Type II, based on chemical structure and toxicological effects.  Fenpropathrin is a mixed-type pyrethroid having intermediate effects between the Type I and Type II pyrethroids in in vitro and in vivo studies.  Behavioral changes such as muscle tremors were observed in most of the fenpropathrin experimental toxicology studies.  Although the database of fenpropathrin experimental toxicology studies is not complete, it provides a robust characterization of the hazard potential for children and adults.  In addition to the standard guideline studies, numerous studies from the scientific literature that describe the pharmacodynamic and pharmacokinetic profile of the pyrethroids in general have been considered in this assessment.  The only missing information is that needed to fully characterize sensitivity of juveniles following exposure to fenpropathrin.  There are on-going efforts to develop methods to inform the possibility of increased sensitivity of juvenile rats to pyrethroids as a class at doses near the LOAEL values.  Pending receipt of the additional data, HED has conducted a conservative and health-protective assessment using the available guideline and literature studies.

Pyrethroids disrupt the voltage-gated sodium channels in the nervous system, resulting in neurotoxicity.  In the fenpropathrin toxicity database, tremors were the most commonly observed effect and also the most sensitive relative to dose.  Other neurotoxic effects observed included ataxia, increased sensitivity (e.g., heightened response) to external stimuli, convulsions, and increased auditory startle response.

Fenpropathrin is rapidly absorbed following an oral dose.  As a class, pyrethroids are also rapidly metabolized in vivo and, therefore, effects are typically observed shortly after dosing.  In addition, the severities of effects do not increase with duration.  As the NOAELs for the acute and chronic studies are similar, the acute endpoint is protective of the endpoints from repeat dosing studies, which represent longer-term exposures.  Thus, for purposes of endpoint selection and exposure assessment, only single-day risk assessments need to be conducted.

Evidence of increased qualitative or quantitative susceptibility of the offspring was not observed in any of the available animal testing guideline toxicity studies, including the developmental neurotoxicity study (DNT).  However, the Agency will retain a 3x uncertainty factor to protect for exposures to children < 6 years of age based on the following:  1) age-dependent pharmacokinetics, supported by rat Physiologically Based Pharmacokinetic (PBPK) model predictions of a 3-fold increase of pyrethroid concentration in juvenile brain compared to adults; 2) in vitro pharmacodynamic (PD) data and in vivo data indicating similar responses between adult and juvenile rats at low doses; and 3) data indicating that the rat is a conservative model compared to the human, based on species-specific pharmacodynamics of homologous sodium channel isoforms.  

The dose and endpoint for acute dietary risk assessment were selected from the Wolansky et al. (2006) acute oral study, in which decreased motor activity was observed.  The dose used for risk assessment was determined using a benchmark dose (BMD) analysis conducted in accordance with standard Agency assumptions with respect to the benchmark response (BMR).  The same study, endpoint, and dose were used for the inhalation risk assessment for workers, along with standard assumptions for extrapolation from the oral route.  Based on the available data for fenpropathrin, the use of the acute endpoint and dose for risk assessment is protective for repeated dose exposure and risk.  A dermal risk assessment was not conducted based on the lack of effects in a 21-day dermal study and absence of qualitative or quantitative susceptibility in the toxicity database.  As there are no existing or proposed uses that would result in non-dietary exposure to children or adults in residential settings, these exposures were not considered for endpoint selection.

HED has characterized fenpropathrin as "not likely to be carcinogenic to humans" in accordance with the EPA Final Guidance for Carcinogen Risk Assessment (3/29/05).

Adequate residue data are available for the purpose of evaluating the proposed uses and associated tolerances, including adequate plant and livestock metabolism data, field residue and rotational crop studies, as well as appropriate supporting analytical methods and storage stability data.  The recommended tolerances are based on the potential for detectable residues in the treated commodities.

The acute dietary risk estimates for fenpropathrin are below HED's level of concern for all population subgroups, including those comprised of infants and children.  The acute risk estimate for the general U.S. population is 19% of the acute population adjusted dose (aPAD).  The population subgroup with the highest acute dietary risk estimate is Children 3-5, which uses 97% of the aPAD.  The assessment was refined by incorporating distributions of residues from field trial and monitoring data, and through use of estimated percent crop treated information.  Both empirical and default processing factors were used.  For drinking water, a very conservative modeled surface water estimated drinking water concentration was used.  As a result of the fact that many conservative assumptions were made for this assessment, in particular, the use of field trial data (as opposed to monitoring data) for many commodities, HED is confident that the acute dietary exposure assessment significantly overestimates risk to the general U.S. population and all population subgroups.
 
 The acute aggregate risk estimates are equivalent to the corresponding dietary (food plus water) risk estimates, which are not of concern.
  
Fenpropathrin may be applied to fruit trees by ground equipment (airblast).  In addition, aerial application may be used for avocado trees.  Fenpropathrin is intended for use by commercial and professional applicators.  There is potential for short- and intermediate-term occupational handler and post-application exposure via the inhalation and dermal pathways.  No long-term exposure (> 6 months) is expected.  As fenpropathrin does not increase in potency with repeated dosing, only single-day occupational exposures are being assessed.  As there is no dermal hazard associated with this chemical, inhalation risk only is being assessed quantitatively.  
It is HED policy to use the best available data to assess handler exposure.  Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), and the Agricultural Handler Exposure Task Force (AHETF) database.  Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA.  Default assumptions established by the HED's Exposure Science Advisory Council (ExpoSAC) were used for parameters such as body weight and acres treated per day.

Occupational handler assessments are based on inhalation exposures only because a dermal endpoint and dose were not selected.  As noted previously, an acute POD is considered to be protective of repeated inhalation exposures (i.e., short- and intermediate-term durations), and thus only a single POD was used to assess workers.  The estimated short-term inhalation margins of exposure (MOEs) for occupational handlers are all above HED's level of concern (LOC) of an MOE of 100 (the lowest MOE was 5,300), assuming the baseline level of personal protective equipment (PPE), and with the use of engineering controls (i.e., enclosed cockpit) for aerial applications.

There is a potential for post-application dermal and inhalation exposures to workers who enter fenpropathrin-treated fields to do irrigation, fruit thinning, scouting, and harvesting.  However, HED did not quantitatively estimate post-application dermal exposure because of the lack of toxicity via the dermal route of exposure.  Based on the Agency's current practices, a quantitative non-cancer occupational post-application inhalation exposure assessment is not being conducted at this time.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for fenpropathrin.  However, HED notes that inhalation exposure for aerial flaggers is considered to be protective of potential post-application inhalation exposure, and the associated inhalation risk estimates for flaggers are not of concern.

Fenpropathrin was included in a recent cumulative risk assessment for pyrethrins and pyrethroids.  The proposed new uses will contribute minimal risk to the overall cumulative assessment.  In the cumulative assessment, residential exposure was the greatest contributor to the total exposure.  As there are no residential uses for fenpropathrin, the proposed new uses will have no impact on the residential component of the cumulative risk estimates.  Dietary exposures make a minor contribution to total pyrethroid exposure in the 2011 cumulative risk assessment.  The dietary exposure assessment performed in support of the pyrethroid cumulative was much more highly refined than that performed for the single chemical.  In addition, for the fenpropathrin risk assessment, the most sensitive apical endpoint in the fenpropathrin database was selected to derive the POD.  Additionally, the POD selected for fenpropathrin is specific to fenpropathrin, whereas the POD selected for the cumulative assessment was based on common mechanism of action data that are appropriate for all 20 pyrethroids included in the cumulative assessment.
Review of Human Research:  This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These studies (listed in Appendix C) have been determined to require a review of their ethical conduct, and all of the studies utilized in this assessment have received the appropriate review.

2.0	HED Recommendations

HED does not object to the granting of the requested registration or the recommended tolerances for fenpropathrin in/on the proposed new uses on tropical fruits.  In addition, HED does not object to the granting of the recommended tolerance without U.S. registration for fenpropathrin in/on tea.   

2.1	Data Deficiencies/Conditions of Registration

None

2.2	Tolerance Considerations

2.2.1	Enforcement Analytical Method

An adequate method, Residue Method Number RM-22-4, is available for the enforcement of tolerances of fenpropathrin in plants.  Residues in crops are extracted with acetone/hexane, partitioned into hexane, cleaned up by silica gel and C18 Sep Pak chromatography, and analyzed by GC/ECD.  The LOD is 0.01 ppm.

There is also an adequate GC/ECD enforcement method for the determination of fenpropathrin residues in livestock commodities (RM-22A-1).  The lowest limit of method validation was 0.05 ppm in milk and 0.5 ppm in fat and meat.

The FDA PESTDATA database (dated 6/2005) indicates that fenpropathrin is completely recovered by multiresidue methods Section 302 (Protocol D).  Recovery was variable using Section 303 (Protocol E; 43-71% recovery) and Section 304 (Protocol F; 58-114% recovery).  

2.2.2	International Harmonization

No Codex, Canadian, or Mexican MRLs are established for fenpropathrin on the proposed tropical fruits.  As a result, harmonization of tolerances is not an issue for these commodities.  A Codex MRL is established for residues of fenpropathrin in/on tea, green, black at 2 ppm.  Using the Organization for Economic Cooperation and Development (OECD) MRL calculation procedures, the recommended tolerance for dried tea would be 3.0 ppm.  For the purposes of harmonization of the U.S. tolerance with the established Codex MRL, HED is recommending in favor of a tolerance of 2.0 ppm for dried tea.  HED considers this tolerance level to be adequate because the highest field trial value was 1.38 ppm.  In the U.S., the residue definition is parent fenpropathrin.  The Codex residue definition is fenpropathrin, the residue is fat soluble.


2.2.3	Recommended Tolerances

HED recommends that 40CFR §180.466 be amended by establishing tolerances for the commodities listed in Table 2.2.3, below.

Currently, tolerances are established for residues of the pesticide chemical fenpropathrin (alpha-cyano-3-phenoxy-benzyl 2,2,3,3-tetramethylcyclopropanecarboxylate) in or on the commodities in 40CFR §180.466.  This tolerance expression needs to be revised as follows:   "Tolerances are established for residues of fenpropathrin including its metabolites and degradates, in or on the commodities in the table below.  Compliance with the tolerance levels specified below is to be determined by measuring only fenpropathrin (alpha-cyano-3-phenoxy-benzyl 2,2,3,3-tetramethylcyclopropanecarboxylate)."

Table 2.2.3.  Tolerance Summary for Fenpropathrin
Commodity as Proposed by Registrant
                           Proposed Tolerance (ppm)
                          Recommended Tolerance (ppm)
Comments; Correct Commodity Definition
Guava
                                      1.5
                                      3.0
                                       
Acerola
                                      1.5
                                      3.0
                                       
Feijoa
                                      1.5
                                      3.0
                                       
Jaboticaba
                                      1.5
                                      3.0
                                       
Passionfruit
                                      1.5
                                      3.0
                                       
Starfruit
                                      1.5
                                      3.0
                                       
Wax jambu
                                      1.5
                                      3.0
                                       
Lychee
                                      3.0
                                      7.0
                                       
Longan
                                      3.0
                                      7.0
                                       
Spanish lime
                                      3.0
                                      7.0
                                       
Pulasan
                                      3.0
                                      7.0
                                       
Rambutan
                                      3.0
                                      7.0
                                       
Sugar apple
                                      1.0
                                      1.5
                                       
Atemoya
                                      1.0
                                      1.5
                                       
Biriba
                                      1.0
                                      1.5
                                       
Cherimoya
                                      1.0
                                      1.5
                                       
Custard apple
                                      1.0
                                      1.5
                                       
Ilama
                                      1.0
                                      1.5
                                       
Soursop
                                      1.0
                                      1.5
                                       
Tea
                                      2.0
                                      2.0
Tea, dried
Tolerance should include a footnote stating "There is no U.S. registration on tea, dried, as of (date of FR notice)."


2.2.4	Revisions to Petitioned-For Tolerances

The proposed tolerances for residues in tropical fruits are different from the tolerances being recommended by HED.  The reason for the differences is that the proposed tolerances were determined using the NAFTA tolerance calculator, whereas HED used the OECD MRL calculation procedures to determine the recommended tolerances.  A revised Section F should be submitted to reflect the tolerances recommended by HED.

2.3	Label Recommendations

None


3.0	Introduction

3.1	Chemical Identity

Table 3.1.  Fenpropathrin Nomenclature
Chemical structure
                                       
Common name
Fenpropathrin
Company experimental name
WC-4741706 (Shell); S-5206 (Sumitomo)
IUPAC name
(RS)-α-cyano-3-phenoxybenzyl 2,2,3,3-tetramethylcyclopropanecarboxylate
CAS name
Cyano(3-phenoxyphenyl)methylester 2,2,3,3-tetramethyl-cyclopropanecarboxylic acid
CAS registry number
39515-41-8
End-use product (EP)
2.4 lb/gal EC formulation (Danitol[(R)] 2.4 EC Spray; EPA Reg. No. 59639-35)


3.2	Physical/Chemical Characteristics

Fenpropathrin has very low water solubility (0.33 ppm at 25ºC) and a relatively high octanol/water partition coefficient (log KOW = 5.1).  These values account for the low surface and groundwater concentrations determined by EFED's drinking water models.  The chemical has a vapor pressure of 5.5 x 10[-][6] mm Hg at 25ºC.  See Appendix B for a listing of additional physical and chemical properties.     

3.3	Pesticide Use Pattern

The petitioner submitted a draft label for the 2.4 lb/gal EC formulation of fenpropathrin (Danitol[(R)] 2.4 EC Spray; EPA Reg. No. 59639-35).  The label includes use directions for a number of fruit, vegetable, and field crops that are already registered.  Danitol[(R)] is currently registered for use on avocado, canistel, mango, papaya, salal, sapodilla, black sapote, mamey sapote, and star apple.  The use directions for both the registered and proposed tropical and subtropical fruits are presented in Table 3.3.  No directions were proposed for the domestic use of fenpropathrin on tea because only an import tolerance was proposed. 

Table 3.3.  Summary of Directions for Use of Fenpropathrin
Applic. Timing, Type, and Equip.
                                  Formulation
                                [EPA Reg. No.]
                           Max. Single Applic. Rate 
                                   (lb ai/A)
                          Max. No. Applic. per Season
                          Max. Seasonal Applic. Rate
                                   (lb ai/A)
                                      PHI
                                    (days)
                        Use Directions and Limitations
Tropical and Subtropical Fruit:  Acerola, Atemoya, Avocado, Biriba, Canistel, Cherimoya, Custard Apple, Feijoa, Guava, Ilama, Jaboticaba, Longan, Lychee, Mango, Papaya, Passion Fruit, Pulasan, Rambutan, Sapodilla, Sapote (Black, Mamey), Soursop, Spanish Lime, Star Apple, Star Fruit, Sugar Apple, and Wax Jambu
Foliar
Ground (all crops)

Aerial (avocado only)
                                 2.4 lb/gal EC
                                  [59639-35]
                                    0.3-0.4
                                  1 (avocado)
                                       
                                      or
                                       
                              2 (all other crops)
                                      0.8
                                       1
Begin applications when first pest activity is noticed.  A 14-day retreatment interval is specified.  Ground applications are to be made in >=75 gal/A; aerial applications to avocado may be made in >=50 gal/A.
PHI= Preharvest interval

The use directions for the proposed tropical and subtropical fruits are identical to those for the registered tropical and subtropical fruits except that the minimum spray volume for ground applications for all tropical fruits has been reduced from 100 gal/A to 75 gal/A.  The personal protective equipment (PPE) on the proposed label includes a long-sleeved shirt, long pants, shoes with socks, chemical resistant gloves, and protective eyewear.

3.4	Anticipated Exposure Pathways

Humans could be exposed to fenpropathrin in food because fenpropathrin may be applied directly to growing crops.  In addition, these applications can result in fenpropathrin reaching surface and groundwater, both of which can serve as sources of drinking water.  However, the low water solubility of the chemical and its affinity to bind to soil organic matter would cause the chemical to be present at very low concentrations in drinking water sources.  The domestic uses on tropical fruits result in the potential for occupational exposures.  Because of the agricultural uses, applicators might be exposed while handling the pesticide prior to application, mixing/loading the pesticide, and during application.  Also, there is a potential for post-application exposure for workers re-entering treated fields.  There are no registered or proposed residential uses for fenpropathrin; as a result, residential exposure is not an anticipated exposure pathway.

3.5	Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for children, youths, and adults entering or playing on treated areas post-application are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.



4.0   Hazard Characterization and Dose-Response Assessment

Fenpropathrin is a member of the pyrethroid class of insecticides.  Pyrethroids have historically been classified into two groups, Type I and Type II, based on chemical structure and toxicological effects.  Type I pyrethroids, which lack an alpha-cyano moiety, induce in rats a syndrome consisting of aggressive sparring, altered sensitivity to external stimuli, hyperthermia, and fine tremor progressing to whole-body tremor and prostration (T-syndrome).  Type II pyrethroids, which contain an alpha-cyano moiety, in rats produce a syndrome that includes pawing, burrowing, salivation, hypothermia, and coarse tremors leading to choreoathetosis (CS-syndrome) (Verschoyle and Aldridge 1980; Lawrence and Casida 1982).  Fenpropathrin is a Mixed Type pyrethroid because the biochemical responses and resulting clinical signs of neurotoxicity are intermediate between those of Type I and Type II pyrethroids.  The adverse outcome pathway (AOP, based on the Bradford-Hill criteria) shared by pyrethroids involves the ability to interact with voltage-gated sodium channels (VGSCs) in the central and peripheral nervous systems, leading to changes in neuron firing and, ultimately, neurotoxicity (Figure 4.0).  

Target Tissue DoseVGSC AlterationsIn Vivo Clinical SignsAltered NeuronalExcitability

             Figure 4.0.  Adverse outcome pathway for pyrethroids
                                       
                                       
4.1 Toxicology Studies Available for Analysis

The database of experimental toxicology studies available for fenpropathrin provides a robust characterization of the hazard potential for children 6 years old and older as well as for adults.  A 90-day inhalation study is not available for consideration as required under the Part 158 toxicology data requirements.  However, HED has waived this study requirement for the current assessment (HASPOC memo, TXR# 0053978, 4/10/12).  In addition, there are ongoing efforts to develop data in juvenile rats at doses near the LOAEL values (see Section 4.4) to inform the potential sensitivity of infants and young children to pyrethroids as a class.  Despite these scientific efforts, HED is confident that it has chosen points of departure and uncertainty factors in this risk assessment that are health protective and have a strong scientific foundation.

Data from the following studies were used to evaluate the hazard potential of fenpropathrin:

      -Wolansky Acute Oral Study in the Rat
      -WIL Laboratory Acute Oral Study in the Rat 
      -21 Day Dermal Studies in the Rat and Rabbit
      -90 Day Oral Studies in the Rat and Dog
      -Chronic/Carcinogenicity Studies in the Rat, Mouse, and Dog 
      -Developmental Studies in the Rat and Rabbit
      -Reproduction Study in the Rat 
      -Acute, Subchronic, and Developmental Neurotoxicity (DNT) Studies in the Rat
      - Immunotoxicity Study in the Rat 
      -Mutagenicity Battery of Studies

These studies are available for consideration of fenpropathrin toxicity and provide a comprehensive database.  The Wolansky and WIL studies are acute oral non-guideline studies that measure locomotor and functional observational battery (FOB) activity, respectively, and provide robust data to evaluate the hazard potential of fenpropathrin.

In addition, numerous studies from the scientific literature conducted over several decades describe the pharmacodynamic and pharmacokinetic profile of the pyrethroids in general.  This scientific literature has recently been reviewed by several groups (Soderlund et. al. 2002; Shafer et. al. 2005; Wolansky and Harrill 2008). 

4.2 Toxicological Profile

Fenpropathrin has been evaluated for a variety of toxicological effects in guideline experimental toxicity studies.  Behavioral changes characteristic of Type I pyrethroids such as muscle tremors were seen in most of the experimental toxicology studies including the acute, subchronic, and developmental neurotoxicity studies, subchronic studies in the rat and dog, the chronic carcinogenicity study in the rat, the developmental studies in the rat and rabbit, and in the 3-generation reproduction study in the rat.  Tremors were the most common indication of neurotoxicity; however, ataxia, increased sensitivity (e.g., heightened response) to external stimuli, convulsions, and increased auditory startle response were also observed.

Fenpropathrin has been evaluated for potential developmental effects in the rat and rabbit.  Maternal toxicity included neurological effects such as ataxia, sensitivity to external stimuli, tremors in rat, and flicking of forepaws in the rabbit.  Developmental effects were limited to incomplete or asymmetrical ossification of sternebrae at the maternally toxic dose in the rat.  There were no developmental effects in the rabbit.  Furthermore, there were no indications of immunotoxicity in any of the guideline studies, including the immunotoxicity study in rats.  

The potential reproductive toxicity of fenpropathrin was examined in a 3-generation reproduction study in the rat.  Maternal effects at the high dose included increased deaths and clinical signs of toxicity.  Eighteen of the 24 dams in the high-dose group (32 mg/kg/day) died.  Ten of these deaths occurred during lactation of the F1B dams (i.e., 2[nd] litter of 2[nd] generation).  Clinical signs including tremors, muscle twitches, and increased sensitivity were observed in all high-dose females in all generations and were most intense during the 2[nd] or 3[rd] week of lactation.  At the mid-dose, 10.1 mg/kg/day, clinical signs of toxicity were observed in a single dam.  No treatment-related effects in the males at any dose were noted; however, it is not clear from the study if males were evaluated.  It should be noted that the effects in the maternal rats occurred during lactation.  During lactation, the dietary intake of nursing dams increases dramatically, resulting in a greater consumption of fenpropathrin.  In the offspring, there was mortality at the high dose (32 mg/kg/day) in the F2A and F2B litters (3[rd] generation, 1[st] and 2[nd] litters) although litter size was only significantly decreased at lactation day 21 in the F2B litters.  At the mid-dose (10 mg/kg/day), tremors were observed in 3 pups from the F2B litter, 2 of which died.  There were no reports of clinical signs of toxicity (i.e., tremors) in any other pups.  Therefore, minimal signs of treatment-related effects were observed at the mid-dose for both adults and pups, reducing concern for quantitative or qualitative sensitivity. 

The registrant submitted a DNT study which established a clear NOAEL for adult and offspring toxicity.  Similar NOAELs and LOAELs were observed in adults and offspring.  Effects in the dams were tremors and convulsions, while offspring effects consisted of decreased body weights.  In the fenpropathrin DNT study there was no evidence of increased sensitivity in rat pups.  However, the Agency has reviewed existing pyrethroid data, including a number of DNT studies, and has concluded that the DNT is not a particularly sensitive study for comparing the sensitivity of young and adult animals to pyrethroids (E. Scollon, D381210, 6/27/11).  Some literature studies did indicate susceptibility for other pyrethroids, but in context these studies were conducted at relatively high doses that might not reflect environmental exposures.  Overall, there is no indication of increased juvenile sensitivity specifically to fenpropathrin.

There was no evidence of carcinogenicity in either the rat or mouse long-term dietary studies, nor was there any mutagenic activity in bacteria or cultured mammalian cells.  Fenpropathrin is classified as "not likely to be carcinogenic to humans" in accordance with the EPA Final Guidance for Carcinogen Risk Assessment (3/29/05).  With respect to acute lethality studies, fenpropathrin exhibits high acute toxicity via the oral route and dermal route (Categories I and II, respectively).  Conversely, toxicity via inhalation is Category IV.  Fenpropathrin is a mild eye irritant (Category III), but does not cause dermal irritation in rabbits or skin sensitization in guinea pigs.

The resulting pharmacokinetics for fenpropathrin is similar to the pharmacokinetics of other pyrethroids, i.e., rapid absorption and clearance.  Following a single oral dose of 2.5 or 25 mg/kg radiolabeled fenpropathrin in corn oil, 99% of the radioactivity was excreted via the urinary and fecal pathways by 7 days.  A greater proportion was eliminated via the fecal route following a single dose (1:2 urine:feces) compared to repeated dosing (1:1 urine:feces).  No differences were observed between sexes.  By 168 hours, only minor traces of radioactivity remained in the carcass, primarily in the adipose tissue.  As pyrethroid metabolites are not active, radiolabeled fenpropathrin studies that do not consider metabolism are likely to overestimate the amount of active pesticide present in vivo.  As previously described, pyrethroids are susceptible to ester hydrolysis in the plasma and oxidative metabolism by cytochrome P450 enzymes.  Major biotransformation products from single and repeated dose rat metabolism studies included oxidation of the methyl group on the acid moiety, hydroxylation at the 4'-position of the alcohol moiety, cleavage of the ester linkage, and conjugation with sulfuric and glucuronic acid.   

4.3 Pyrethroid Pharmacokinetic and Pharmacodynamic Profile
      
The extensive body of scientific literature on the pyrethroids provides insight into the contributions of pharmacokinetics (PK) and pharmacodynamics (PD) to the general toxicity profile of this class of chemicals.  This information also provides valuable insight into the potential age-related differences in toxicity for the pyrethroids.  The following sections discuss the specific issues related to pyrethroid pharmacokinetics, pyrethroid pharmacodynamics, and age-related differences in pyrethroid toxicity.
4.3.1	Pharmacokinetics

Pharmacokinetics can be defined as what the body does to the chemical; in this case, how pyrethroids are distributed and eliminated following exposure.  Specific to pyrethroids, PK refers to the process(es) that determine(s) the concentration of the pyrethroids reaching sodium channels.  The underlying pharmacokinetics of pyrethroids is an important determinant of their toxicity because the concentration of pyrethroid at the sodium channel relates to the extent of toxicity.  Greater pyrethroid concentration results in increased neurotoxicity.  Physiological processes that significantly contribute to the PK include metabolism, protein binding, and partitioning.  Carboxylesterases and cytochrome P450 enzymes are the two major enzyme families responsible for the metabolism of pyrethroids.  It is the ontogeny of these enzymes that accounts for the age-related sensitivity observed after pyrethroid exposures.  With respect to the partitioning of pyrethroids within the body, pyrethroids are highly lipophilic and preferentially deposit in fatty tissue such as adipose compared to leaner tissues such as muscle.  Pyrethroid residues in fatty tissue are not available to interact with the voltage-gated sodium channels (VGSCs) in vital tissues and, therefore, do not contribute to overall toxicity.  

Physiologically-based pharmacokinetic (PBPK) models, designed to predict pyrethroid concentration in tissues following in vivo exposure, have recently been developed by the Agency.  The Agency has determined that the important PK properties relevant for the metabolism and distribution of pyrethroids in the body are sufficiently similar for members of this class such that using a `generic' or family model structure for this class is scientifically appropriate.  In other words, because of the similarities in the PK profiles of pyrethroids, a single model structure is able to predict the tissue dose based on the pharmacokinetics of every member of the class.  The family modeling approach was presented to and supported by the FIFRA SAP (USEPA 2007).

In 2011 the Agency conducted an analysis of the toxicokinetic profile of pyrethroids as a class.  Several studies in this analysis indicate that there are age-dependent pharmacokinetic differences for the pyrethroids (i.e., there are differences in the ability of adults and juveniles to metabolize pyrethroids).  The enzymes that metabolize and detoxify the pyrethroids are present in rats and humans at birth (Koukouritaki et. al. 2004; Yang et. al. 2009).  As a result, both juveniles and adults are able to tolerate low doses of pyrethroids when the internal dose, or the amount of pyrethroid at the sodium channel, is low.  However, the activity of these enzymes increases with age, conveying in adults a greater capacity to detoxify pyrethroids compared to juveniles (Anand et. al. 2006; de Zwart et. al. 2008; Yang et. al. 2009).  For example, the rate of in vitro metabolism of deltamethrin by plasma carboxylesterases, plus hepatic carboxylesterases and cytochrome P450s (microsomes) are at least 6 times higher for post-natal day 90 (PND 90) rats compared to PND 10 rats (Anand et. al. 2006).  As a consequence, higher internal doses (i.e., those associated with high doses in experimental toxicology studies) overwhelm the clearance mechanisms in juveniles, but because adults have greater enzyme activity, they are able to tolerate higher doses prior to the onset of toxicity.  As a matter of perspective, the anticipated exposures from typical dietary or residential activities are not expected to overwhelm the premature metabolic systems in juveniles.  

Predictive PBPK models have recently been developed to describe the PK of a few pyrethroids (Mirfazaelian et. al. 2006; Godin et. al. 2010).  Among these is an age-dependent model developed by the Agency which is capable of predicting the concentration of deltamethrin in the brains of rats at multiple ages (Tornero-Velez et. al. 2010).  The brain is considered to be the primary target organ for pyrethroids, and increased pyrethroid concentrations are correlated with increasing systemic toxicity.  This model predicts that, compared to adult rats (i.e., 90-days old), equivalent brain concentrations of deltamethrin would be achieved with a 3.8x fold lower oral dose in 10-day old rats and 2.5x lower dose in 21-day old rats (Tornero-Velez et. al. 2010).  For example, a 1 mg/kg dose in the adult is equivalent to a 0.26 mg/kg dose (≈1 mg/kg/3.8mg/kg) in the 10-day old rats and to a 0.4 mg/kg (≈1 mg/kg/2.5mg/kg) dose in a 21-day old rat.  The difference between a 3.8- and a 2.5-fold dose is within background variability of the model.  As these age groups bracket the developmental stage of greatest concern in humans (i.e., children <= 6), the Agency concludes that juvenile rats are 3 times as sensitive as adults with respect to pyrethroid pharmacokinetics.
4.3.2	Pharmacodynamics

Pharmacodynamics can be defined as the changes that chemicals cause to the body, in this case, how pyrethroids interact with the sodium channels.  Substantial evidence from in vitro and in vivo studies support the adverse outcome pathway (AOP) illustrated in Figure 4.3 and the disruption of sodium channels by pyrethroids as an early key event (Lund and Narahashi 1982; Salgado et. al. 1989; Song and Narahashi 1996; Tabarean and Narahashi 1998; Soderlund et. al. 2002).  There are several recent studies that provide specific information for fenpropathrin.  Choi and Soderlund (2006) examined interactions of several pyrethroids, including fenpropathrin, with mammalian VGSCs expressed in Xenopus oocytes (i.e., frog oocytes).  Fenpropathrin produced modifications of sodium channel kinetics intermediate between Type I and Type II compounds (Figure 4.3).  With respect to altered neuronal excitability, Type I pyrethroids cause slight prolongations of the sodium current tails (e.g. ~20 ms), often resulting in long trains of action potentials.  In contrast, Type II pyrethroids significantly prolong sodium current tails (e.g. 200 ms to minutes) typically resulting in increased resting membrane potential and ultimately causing depolarization dependent action potential block.  Cao et. al. (2011a) measured sodium influx in primary cultures of mammalian (mouse) neurons and demonstrated that fenpropathrin caused increases in sodium influx in this model; this confirms the ability of fenpropathrin to interact with VGSC in intact mammalian neurons.  An additional study by Cao et. al. (2011b) demonstrated that the interaction of fenpropathrin with VGSC caused changes in neuronal excitability that resulted in calcium influx into intact mouse neurons.  As this effect of fenpropathrin was entirely blocked by the VGSC blocker tetrodotoxin, it provides evidence that the changes in sodium channel function lead to changes in neuronal excitability, as illustrated in Figure 4.3.

                                       

Figure 4.3  Resting modification of rat Nav1.8 sodium channels by fenpropathrin expressed in Xenopus oocytes. Channel current vs time traces from individual representative oocytes in the absence or presence (*) of 100 uM fenpropathrin were obtained during and after 40-ms depolarizations from 100 mV to 10 mV. Calibration bars: 20 ms for the x-axis and 500 nAmp on the y-axis.  Figure extracted from Figure 3 in Choi and Soderlund (2006).  

HED would prefer to use an early key event in the AOP for pyrethroids in selection of points of departure, such as sodium channel modification.  However, in vivo techniques used to detect VGSC alteration and altered neuronal excitability are not practical for use in risk assessment at this time, and approaches for extrapolating in vitro findings to in vivo measures are not yet developed.  As such, the Agency is focusing its efforts for all pyrethroids in hazard characterization and identification on the apical endpoint (i.e., changes in neurobehavior in laboratory animals).  Neurotoxicity resulting from pyrethroids is generally characterized by tremors, hyper- or hypothermia, heightened response to stimuli, salivation, reduced locomotor activity or convulsions (Soderlund et. al. 2002; Wolansky and Harrill 2008; Weiner et. al. 2009).   

In contrast to the age-related PK differences identified in the 2011 analysis, PD contributions to pyrethroid toxicity are not age-dependent, even though there are several variations of sodium channels, called isoforms, which are differentially expressed by tissue and age.  Because of the nature of the interaction of pyrethroids with sodium channels, it is difficult to obtain dynamic information in vivo.  To date, a readily useable biomarker of in vivo pyrethroid interaction with sodium channels has not been identified, making it impractical to determine the isoform combinations that are present and being acted upon by pyrethroids.  Therefore, much of the information available to the Agency to characterize the PD relationship between pyrethroids and sodium channels has been derived from in vitro studies using frog oocytes or neuronal cells cultured in defined media.  These in vitro techniques do not provide direct quantitative measure of in vivo pyrethroid activity.  However, these techniques consistently and qualitatively demonstrate that channel isoforms expressed in juveniles are not more sensitive to pyrethroid perturbation compared to isoforms expressed in adults and that, pharmacodynamically, the rat is a conservative model for humans.  For example, Meacham et al. (2008), expressed adult and juvenile isoforms of rat sodium channels in frog oocytes and compared their sensitivity following exposure to deltamethrin.  The isoforms had comparable responses at environmentally relevant concentrations (<500 nM) of deltamethrin, suggesting a lack of PD difference between juveniles and adults at low exposure levels.  In addition, in a direct comparison of a homologous rat and human VGSC isoform NaV1.3, the rat isoform was 4-fold more sensitive than the equivalent human sodium channel to the pyrethroid tefluthrin (Tan and Soderlund 2009).  This observation suggests that the rat is a highly-sensitive model, and extrapolations from the rat would be protective of human health.  The occurrence and ontogeny of voltage-gated sodium channels in humans is not well characterized compared to those of the rat.  However, based on the comparable function and distribution of sodium channels between the species, the rat is an appropriate surrogate for the evaluation of human PD (Goldin et. al. 2000; Goldin 2002).  As a result, the Agency concludes that juvenile rats are not more sensitive than adults with respect to pyrethroid pharmacodynamics.  Therefore, the pharmacodynamic contribution to the FQPA factor will be 1x.

4.3.3	Critical Duration of Exposure

One of the key elements in risk assessment is the appropriate integration of temporality between the exposure and hazard assessments.  Following a single oral gavage dose, fenpropathrin is absorbed quickly in rats displaying decreased motor activity and increased tremors.  Effects such as tremors and ataxia were observed within 2 and 3 hours following dosing in the rat developmental and acute neurotoxicity studies, respectively.  Rats typically recover within 24 hours without any persisting neurotoxic effects at doses near the LOAEL value.  This observation is consistent with the toxicity profiles for other pyrethroids which are marked by rapid absorption, metabolism, and time-to-peak effect.  The NOAELs and LOAELs for tremors established from results of experimental toxicity studies with fenpropathrin are remarkably consistent across durations of exposure, ranging from a single dose up to 2-years of dosing (Table 4.3.3). 

Table 4.3.3.  Fenpropathrin NOAEL and LOAEL Values versus Treatment Time
                                     Study
                                   Duration
                                Study findings

                                       
                                     NOAEL
                                  (mg/kg/day)
                               LOAEL (mg/kg/day)
Wolansky (2006)
                            Acute, single exposure
                               [A]BMDL1SD = 5.0
                                 BMD1SD = 6.4
WIL
                            Acute, single exposure
                               [B]BMDL20 = 26.7
                                 BMD20 = 28.9
Acute neurotoxicity 
                            Acute, single exposure
                                      15
                                      30
Developmental Rat
                                    10 days
                                       3
                                       6
Developmental Rabbit[2]
                                    10 days
                                       4
                                      12
Subchronic neurotoxicity
                                    90 days
                                      13
                                      38
DNT
                                    86 days
                                       8
                                      19
Sub-chronic dog
                                    90 days
                                    <6.2
                                      6.2
Sub-chronic rat
                                    90 days
                                      15
                                      30
Reproductive toxicity
                                   120 days
                                      3.0
                                     10.1
Chronic-carcinogenicity
                                    2-years
                                      7.2
                                     19.5
[A] BMD1SD  is the central estimate of the dose that results in decreased motor activity compared to control animals based upon a 1 standard deviation using Benchmark Dose Analysis.  BMDL1SD is the 95% lower confidence limit of the central estimate.  Data extrapolated for Wolansky (2006), MRID 47885701.
[B] BMD20  is the central estimate of the dose that results in a 20% difference in FOB scores compared to control animals using Benchmark Dose Analysis.  BMDL is the 95% lower confidence limit of the central estimate.  Data and analysis can be found in MRID 48714301.


Comparing the NOAELs and LOAELs established from fenpropathrin single dose and repeat dosing studies, it is apparent that repeat exposures do not result in lower NOAELs.  This observation is consistent with the general kinetic profile for pyrethroids.  The BMDL1SD from the acute Wolansky study at 5.0 mg/kg is lower than that from the chronic two-year cancer study NOAEL= 7.2 mg/kg/day (LOAEL of 19.5 mg/kg/day).  Therefore, the endpoint from the acute study is protective of the endpoints from the repeat dosing studies.  Thus, for purposes of endpoint selection and exposure assessment, only single-day risk assessments need to be conducted.

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

Exposure of children under 6 years old to fenpropathrin is expected, and it must be considered in the context of the pyrethroids as a class.  The Agency is retaining a 3x uncertainty factor to protect for exposures to children less than 6 years of age based on the increased quantitative susceptibility seen in the scientific literature related to pyrethroid pharmacokinetics.  This decision is consistent with the Agency's 2011 analysis, and is supported by rat PBPK model predictions of a 3-fold increase of deltamethrin concentrations in the juvenile brain compared to adult brains (see Section 4.3.1).  The PK of pyrethroids as a group is sufficiently similar that significant deviations from the 3-fold increase of deltamethrin concentrations are not expected for other pyrethroids.  As noted in Section 4.3.2, juveniles are not more sensitive than adults with respect to pyrethroid pharmacodynamics and, thus, no uncertainty factor is needed for PD considerations.

There was no evidence of increased qualitative or quantitative susceptibility in developmental toxicity studies in the rat and rabbit, and a three-generation reproductive toxicity study in the rat.  This lack of susceptibility is consistent with the results of the guideline pre- and post-natal testing for other pyrethroid pesticides.  There are, however, high-dose LD50 studies (i.e., those that determine the dose that results in lethality to 50 percent of the tested population) in the scientific literature indicating that pyrethroids can result in increased quantitative sensitivity in the young.  Examination of pharmacokinetic and pharmacodynamic data indicates that the sensitivity observed at high doses is related to pyrethroid age-dependent pharmacokinetics - the activity of enzymes associated with the metabolism of pyrethroids.  With otherwise equivalent administered doses for adults and juveniles, predictive pharmacokinetic models indicate that the differential adult-juvenile pharmacokinetics will result in a 3x greater dose at the target organ in juveniles compared to adults.  No evidence of increased quantitative or qualitative susceptibility was seen in the pyrethroid scientific literature related to pharmacodynamics (the effect of pyrethroids at the target tissue) both with regard to inter-species differences between rats and humans and to differences between juveniles and adults.  Specifically, there are in vitro pharmacodynamic data and in vivo data indicating similar responses between adult and juvenile rats at low doses and data indicating that the rat is a conservative model compared to the human based on species-specific pharmacodynamics of homologous sodium channel isoforms in rats and humans.

In light of the high-dose literature studies showing juvenile sensitivity to pyrethroids, and the absence of the requested data on juvenile sensitivity to pyrethroids, EPA is retaining a 3x safety factor as estimated by pharmacokinetic modeling.  For several reasons, EPA concludes there are reliable data showing that a 3x factor is protective for the safety of infants and children.  First, the high doses that produced juvenile sensitivity in the literature studies are well above normal dietary or residential exposure levels of pyrethroids to juveniles, and these lower levels of exposure are not expected to overwhelm the ability to metabolize pyrethroids as occurred with the high doses used in the literature studies.  This conclusion is confirmed by the lack of a finding of increased sensitivity in pre- and post-natal guideline studies in any pyrethroid, including fenpropathrin, despite the relatively high doses used in those studies.  Second, the portions of  the uncertainty factors that account for potential pharmacodynamic differences are likely to overstate the risk of inter- and intraspecies pharmacodynamic differences, given the data showing similarities in pharmacodynamics between juveniles and adults and between humans and rats.  For both the inter-species and intra-species uncertainty factors, the pharmacodynamic portions are generally considered to be 3x; however, for pyrethroids the factor is reduced to 1x because no differences among the various groups are observed.  Finally, as indicated, pharmacokinetic modeling only predicts a 3x difference between juveniles and adults.

The information described above is summarized in Re-Evaluation of the FQPA Safety Factor for Pyrethroid Pesticides (D381210, E. Scollon, A. Lowit, 6/27/2011).  

4.4.1	Completeness of the Toxicology Database

The toxicology database for fenpropathrin is not complete. Acceptable fenpropathrin developmental toxicity studies in rats and rabbits are available, as well as an acceptable reproduction study in rats.  The main toxic effect associated with dosing was tremors, a common sign for a pyrethroid.  This effect was seen in most toxicology studies with fenpropathrin, and was observed during in the ACN, SCN and developmental neurotoxicity (DNT) studies.  While the database is considered to be complete with respect to the guideline toxicity studies, EPA lacks additional data to address the potential for juvenile sensitivity to all pyrethroids, including fenpropathrin.

In light of the literature studies indicating a possibility of increased sensitivity to fenpropathrin in juvenile rats at high doses, EPA has requested proposals for study protocols which could identify and quantify potential juvenile sensitivity associated with exposure to fenpropathrin.  For the reasons discussed in Section 4.4, the uncertainty regarding the protectiveness of the intraspecies uncertainty factor raised by the literature studies and the absence of the requested data warrant application of an additional 3x for risk assessments for infants and children < 6 years of age.

Although a repeated dose inhalation toxicity study is not available, HED's HASPOC discussed the inhalation data requirements and concluded that an inhalation study is not required at this time (HASPOC memo, TXR 0053978, 4/10/2012).  In making this determination, the HASPOC considered the following:  (1) There are no residential uses; (2) the MOEs from the most recent risk assessment (occupational inhalation MOEs > 1,000), (3) the physical and chemical properties, and (4) the toxicological profile of fenpropathrin that shows neurotoxicity is the most sensitive effect and occurs at similar dose levels following both acute inhalation and oral exposures.  

4.4.2	Evidence of Neurotoxicity

There are no residual uncertainties with regard to evidence of neurotoxicity for fenpropathrin.  As with other pyrethroids, fenpropathrin causes neurotoxicity from interaction with sodium channels leading to clinical signs of neurotoxicity.  These effects are well characterized and adequately assessed by the available guideline and non-guideline studies.

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

Based on the fenpropathrin-specific data from the guideline toxicity studies, there is no indication of increased juvenile sensitivity.  Fenpropathrin is neither a developmental nor a reproductive toxicant.  Fenpropathrin has been evaluated for potential developmental effects in the rat (following gavage or dietary administration) and in the rabbit (gavage administration).  Maternal toxicity included neurological effects (i.e., tremors).  There were no developmental effects of biological significance in either species.  The potential reproductive toxicity of fenpropathrin was examined in a three-generation reproduction study in the rat.  Tremors were noted only in females of both generations, while one parental generation rat had clonic convulsions.  

After reviewing the extensive body of peer-reviewed literature on pyrethroids, the Agency has reached a number of conclusions regarding juvenile sensitivity for pyrethroids including the following considerations:  the Agency has no residual uncertainties regarding age-related sensitivity for women of child bearing age as well as for all adult populations and children > 6 years of age, based on the absence of pre-natal sensitivity observed in 76 guideline studies for 24 pyrethroids and the scientific literature.  Additionally, no evidence of increased quantitative or qualitative susceptibility was seen in the pyrethroid scientific literature related to pharmacodynamics.  The Agency is retaining a 3x uncertainty factor to protect for exposures of children <6 years of age based on the increased quantitative susceptibility seen in the scientific literature related to pyrethroid pharmacokinetics.

Furthermore, high-dose studies in the scientific literature indicated that younger animals were more susceptible to the toxicity of pyrethroids.  For example, Sheets et al (1994) found increased brain deltamethrin levels in young rats (PND 11 and 21) relative to adult rats (PND 72).  These age-related differences in toxicity are principally due to age-dependent pharmacokinetics; the activity of enzymes associated with the metabolism of pyrethroids increase with age (Anand et al, 2006).  However, in context, normal dietary or residential exposures of juveniles are not expected to overwhelm their ability to metabolize pyrethroids.  In support, at a dose of 4.0 mg/kg deltamethrin (near the Wolansky study LOAEL value of 3.0 mg/kg for deltamethrin), the change in the acoustic startle response was similar between adult and young rats (Sheets, 1994).  In addition, ORD has recently developed an age-dependent PBPK model for deltamethrin (Tornero-Velez et al, 2010) that predicts a 3 - fold increase of pyrethroid in neuronal tissue in younger animals compared to adults.  There are several studies (in vitro and in vivo) that indicate that pharmacodynamic contributions to pyrethroid toxicity are not age-dependent.  Examination of specific VGSCs has demonstrated that there is a lack of increased sensitivity in either juvenile specific isoforms (Meacham et al, 2008) or in human isoforms compared to rat variants (Tan and Soderlund, 2009).  
Additional in vitro and in vivo studies are currently being conducted that could potentially inform a number of issues related to pyrethroid toxicity as a class.  In 2010, the Agency requested proposals for study protocols which could identify and quantify potential juvenile sensitivity.  The Agency received a single, coordinated response from the Pyrethrin and Pyrethroids Working Group (PPTWG), a conglomerate of pyrethroid registrants.  The PPTWG protocol was reviewed during a July 2010 FIFRA SAP meeting.  Based on comments from the SAP, the initial study proposal was refined.  At the present time, pesticide registrants and product formulators have come together as the Council for the Advancement of Pyrethroid Human Risk Assessment (CAPHRA).  The Council plans to:  1) conduct in vitro studies demonstrating the interaction of pyrethroids in rat and human VGSCs expressed in Xenopus oocytes, 2) conduct in vitro studies demonstrating interaction of pyrethroids in rat neurolemma cells, 3) develop rat and human PBPK models, including additional pharmacokinetic data, and 4) conduct in vivo behavioral testing using auditory startle testing in rats.  As these data become available, the Agency will determine whether re-evaluation of the age-related sensitivity of pyrethroids is appropriate.
 
4.4.4	Residual Uncertainty in the Exposure Database

There is no residual uncertainty in the exposure database because adequate residue data are available.  Although the risk estimates for children under 6 years of age are high, many conservative assumptions were made in the dietary exposure assessment.  Risk estimates are based on partially refined estimates of residues in foods and the percentage of the crop that will be treated.  In addition, for drinking water, a very conservative surface water estimated drinking water concentration was used. 

4.5	Toxicity Endpoint and Point of Departure Selections

4.5.1	Dose-Response Assessment

The details for selecting toxicity endpoints and points of departure (PODs) are presented in Appendix A3.  Based on the existing and proposed use patterns for fenpropathrin, the expected exposure profile will be for dietary, dermal, and inhalation exposures. 

As previously indicated, the toxicity endpoints in the fenpropathrin database are consistently based on clinical signs of neurotoxicity and, more specifically, tremors.  These studies include multiple species, study designs, and durations (Table 4.3.3).  Moreover, the acute exposure or bolus dosing studies generally result in lower NOAELs compared to longer term dietary administration studies, consistent with other pyrethroids in this class.  Because uncertainty associated with the POD is propagated throughout the risk assessment, one of the key factors in POD selection is the robustness of the dose-response data.  The guideline experimental toxicology studies available for fenpropathrin are generally high quality and were considered in the POD selection process (Appendix A.2) and in the weight of the evidence evaluation.  In addition to the typical guideline studies, data from two special studies (Wolansky study on motor activity and WIL FOB study) evaluating neurobehavioral outcomes are available for fenpropathrin (Wolansky et. al. 2006; Weiner et. al. 2009).  Wolansky et al. (2006) measured motor activity at the time of peak effect after exposure to 11 pyrethroids, including fenpropathrin.  Dose-response relationships were determined using 6-11 doses per pyrethroid (8 doses used for fenpropathrin) and 3-18 rats per dose group (7-12 animals/group used for fenpropathrin), minimizing variability and increasing the confidence in the BMD estimates determined from this study.  Moreover, each pyrethroid was evaluated by the same scientist, thus decreasing some of the variability associated with neurobehavioral measures.  In the WIL study, 17 pyrethroids were evaluated using a specially designed FOB study focused on the outcomes associated with pyrethroid toxicity syndromes.  The fenpropathrin data from the WIL study were not considered as part of POD selection.  The fenpropathrin dose selection was poor (i.e., 2 doses out of the 3 administered resulted in no activity), resulting in low confidence of the calculated BMDL (MRID 48714301).

Observation of tremors is the most prominent finding in the guideline experimental toxicology studies and was considered in the POD determination.  Guideline studies typically have only three treatment groups and often do not evaluate clinical signs at the time of peak effect.  Moreover, scoring metrics of tremors varies widely among guideline studies.  Given the multiple strengths associated with study design of Wolansky, et al. (2006) and the resulting well-defined dose-response curve, Wolansky, et al. (2006) provides the most robust data set for extrapolating risk from fenpropathrin.  

A BMD analysis was conducted by the Agency for all the pyrethroids included in the Wolansky study (MRID 48714301).  Overall, because of the large number of doses and high quality measurements, the BMD analysis yielded high confidence results.  In performing BMD analysis, a benchmark response (BMR) must be selected.  As a general approach, it is preferred to use a combination of biological and statistical factors in the BMR selection.  In the case of motor activity data, there is no specific level of change established by the scientific community as being considered adverse.  Therefore, OPP has elected to use one standard deviation (1SD) from the control group, as suggested, for continuous endpoints in the Agency's BMD guidance (USEPA 2012) as the BMR.  OPP has estimated both the BMD1SD and the BMDL1SD (where the BMDL1SD is the lower 95% confidence limit of the BMD1SD).   The BMD1SD and the BMDL1SD for fenpropathrin are 6.4 mg/kg and 5.0 mg/kg, respectively.  As a matter of science policy, EPA uses the BMDL, not the BMD, for deriving PODs.  Therefore, the BMDL1SD of 5.0 mg/kg is being used as the dose for acute dietary risk assessment.  

A route-specific inhalation study is not available for fenpropathrin; however, HED has waived the study.  As a result, the oral BMDL1SD of 5.0 mg/kg is being used to extrapolate inhalation risk.  Dermal toxicity studies are available for fenpropathrin in the rat and rabbit.  However, no treatment-related findings were observed in either species at the limit dose and, therefore, a dermal assessment is not being conducted.

Acute Dietary (All Age Groups):  Quantitation of the dietary risks was performed using the acute oral Wolansky study, with a BMDL1SD value of 5.0 mg/kg and a BMDL1SD value of 6.4 mg/kg based on decreased locomotor activity. 

Short-term Dermal:  A dermal assessment was not conducted for fenpropathrin.  Although the acute dermal toxicity of fenpropathrin is Category II, and a dermal penetration study indicates that up to 33% of a dermally applied dose is absorbed, HED's residual concern for potential dermal toxicity is reduced because:  1) in the acute study there was no indication of toxicity below the 250 mg/kg dose (which is 50-fold greater than the proposed oral POD of 5 mg/kg), and 2) the majority of residue in the dermal penetration study was bound to the upper dermal layers and was not available for systemic circulation.

Furthermore, there is no indication of increased susceptibility.  As dermal studies do not assess developmental and reproductive parameters, there is the potential that such effects would be overlooked in a dermal study.  As neurotoxicity is observed at the same or lower doses than reproductive and developmental effects were observed and neurotoxicity would be apparent in a dermal study, there is reduced concern that developmental effects would be missed.    

Short-term Inhalation:  In the absence of an inhalation study, an oral study is being used.  A POD of 5.0 mg/kg is selected from the Wolansky acute rat study for this endpoint because of the overall robust nature of the study.  Toxicity via the inhalation route is assumed to be equal to toxicity via the oral route.

See Appendix A.3 for a more detailed description of endpoint selection.

4.5.2	Recommendation for Combining Routes of Exposure for Risk Assessment

Only the acute dietary and inhalation routes of exposure are being assessed.  There are no other routes of exposure to be combined.

4.5.3	Cancer Classification and Risk Assessment Recommendation

There was no evidence of carcinogenicity in either the rat or mouse long-term dietary studies nor was there any mutagenic activity in bacteria or cultured mammalian cells.  Fenpropathrin is classified as "not likely to be carcinogenic to humans" in accordance with the EPA Final Guidance for Carcinogen Risk Assessment (3/29/2005). 

4.5.4	Summary of Points of Departure and Toxicity Endpoints

Table 4.5.  Summary of Fenpropathrin Toxicological Doses and Endpoints for Use in Human Health Risk Assessment

                               Exposure Scenario
                              Point of Departure
                       Uncertainty/FQPA Safety Factors 
                RfD, PAD, Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Acute Dietary-
(>= 6 years old)
Wolansky BMDL1SD = 5.0 mg/kg

UFA = 10x
UFH = 10x
FQPA SF = 1x
Acute RfD = 0.05 mg/kg

aPAD =0.05 mg/kg/day
Wolansky BMD1SD = 6.4 mg/kg
based on decreased motor activity
Acute Dietary-
(< 6 years old)

Wolansky BMDL1SD = 5.0 mg/kg

UFA = 10x
UFH = 10x
FQPA SF = 3x 

Acute RfD = 0.05 mg/kg

aPAD =0.017 mg/kg/day
Wolansky BMD1SD = 6.4 mg/kg
based on decreased motor activity
Short-Term 
(1-30 days) 
Dermal
There was no systemic toxicity via the dermal route; therefore, no endpoint was selected.

Short-Term 
(1-30 days)
Inhalation
Wolansky BMDL1SD = 5.0 mg/kg[1]

UFA = 10x
UFH = 10x
FQPA SF = 1x 
Occupational LOC for MOE = 100
Wolansky BMD1SD = 6.4 mg/kg
based on decreased motor activity

Cancer (oral, dermal, inhalation)
Classification:    "not likely to be carcinogenic to humans" in accordance with the EPA Final Guidance for Carcinogen Risk Assessment (3/29/05)  
[1] Toxicity via the inhalation route is assumed to be equal to toxicity via the oral route.
Abbreviations:  BMD1SD  is the central estimate of the dose that results in decreased motor activity compared to control animals based upon a 1 standard deviation using Benchmark Dose Analysis; BMDL is the 95% lower confidence limit of the central estimate.  Data extrapolated for Wolansky (2006), MRID 47885701; UF = uncertainty factor.  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.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  FQPA SF = FQPA Safety Factor.  aPAD = acute population adjusted dose, RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.


5.0	Dietary Exposure and Risk Assessment 

5.1	Metabolite/Degradate Residue Profile

5.1.1	Summary of Plant and Animal Metabolism Studies

HED has determined that the nature of the residue in primary crops is adequately understood.  Metabolism studies were conducted on apples, cotton, pinto beans, and tomatoes.  In these crops, parent fenpropathrin was the predominant residue identified.  Conjugated metabolites were also present, but at very low levels.  In the cotton metabolism study, there was extensive metabolism of the parent compound.  HED determined that the residue of concern in primary crops is the parent compound.

The nature of the residue in rotational crops is also adequately understood.  In a confined rotational crop study, the predominant residues in rotated crops were 2,2,3,3-tetramethylcyclo-propanecarboxylic acid (TMPA) and 3-phenoxybenzoic acid (3-PBA).  Fenpropathrin was also found in rotated crops, but at less than 10% of the total radioactive residues.

Metabolism studies with goats and poultry have been submitted and reviewed.  The majority of the residue in muscle, fat, milk, and eggs was found to be the parent compound.  The residues in kidney and liver consisted mainly of low levels of various metabolites.  HED previously stated that the livestock metabolites, with the possible exception of TMPA lactone, have also been identified in rat metabolism studies and their contributions to the overall toxicity of fenpropathrin have been considered (Memo, J. Whalen, 9/16/1989).
5.1.2	Summary of Environmental Degradation
      
Fenpropathrin appears to be resistant to degradation in biotic processes and is relatively stable to abiotic processes.  The chemical is expected to have little mobility in soil surfaces, and leaching into groundwater is not expected to be an important transport process.  Volatilization is not expected to be an important transport process.  Fenpropathrin is stable to hydrolysis at both pH 5 and 7, and shows moderate hydrolysis at pH 9 (half-lives on the order of 15 days).  The chemical is light-stable under aqueous photolysis and soil photodegradation.  Under both aerobic and anaerobic soil metabolism conditions, fenpropathrin degrades slowly, with half-lives of 152 and 186 days, respectively.  If released to water, fenpropathrin partitions with the sediment and organic matter, where it might persist.  In the field, fenpropathrin shows a wide range of half-lives (8-144 days).  This variability might be due to the wide range of conditions observed in different parts of the U.S.  Except for COOH-fenpropathrin (observed in the anaerobic soil metabolism study), other degradates observed in the laboratory result from the cleavage of the ester moiety of fenpropathrin.  TMPA and 3-PBA were among the observed degradates in the hydrolysis study.  CONH2-fenpropathrin, monitored in the field, was observed only in the upper layers of soil and appeared to be immobile.

5.1.3	Comparison of Metabolic Pathways

Adequate studies are available depicting the metabolism of fenpropathrin in rats, primary crops (apples, cotton, pinto beans, tomatoes), rotational crops (carrots, lettuce, wheat), and livestock (lactating goats, laying hens) (D222174, L. Cheng, 10/23/97).  Fenpropathrin is susceptible to metabolism in plants and animals.  In rats, the major biotransformation products from single and repeated dose rat metabolism studies included oxidation of the methyl group on the acid moiety, hydroxylation at the 4'-position of the alcohol moiety, cleavage of the ester linkage, and conjugation with sulfuric and glucuronic acid.  Major metabolites (i.e., >10% of applied total radioactive residue (TRR)) were phenoxybenzoic acid and TMPA-glucuronic acid.  Parent was the only major compound identified in the feces.  The primary metabolites found in the confined rotational crop study were hydrolysis products of parent compound.  Because of the similarity of the metabolites between the animal and plant studies, the rat toxicity studies account for the metabolites found in plants and livestock commodities.

5.1.4	Residues of Concern Summary and Rationale

The nature of the fenpropathrin residue is adequately understood in plants, rotational crops, livestock commodities, surface water, and groundwater.  Parent fenpropathrin is the major residue in plant and livestock studies.  Furthermore, the plant, animal, and environmental degradates identified are unlikely to be more toxic than the parent.  Therefore, parent fenpropathrin is the residue of concern for both tolerance enforcement and risk assessment in plants, livestock commodities, and drinking water.     

Table 5.1.4  Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression
Matrix
Residues included in Risk Assessment
Residues included in Tolerance Expression
Plants
Primary Crop
Fenpropathrin
Fenpropathrin

Rotational Crop
Not Applicable
Not Applicable
Livestock
Ruminant
Fenpropathrin
Fenpropathrin

Poultry
Fenpropathrin
Fenpropathrin
Drinking Water
Fenpropathrin
Not Applicable


5.2	Food Residue Profile

The registrant submitted adequate use directions for the proposed tropical fruits.  In addition, the registrant submitted adequate field trial data for guava, lychee, sugar apple, and atemoya to support the proposed uses on tropical fruits.  HED's Chemistry Science Advisory Council (ChemSAC) approved a revision of 40 CFR §180.1(g) to permit the extension of tolerances for guava, lychee, and sugar apple to tolerances for the other tropical fruits in this petition.  The submitted crop field trial data for guava, lychee, and sugar apple may be translated to support the proposed uses on the corresponding specific commodities; however, a separate tolerance must be established for each commodity.  ChemSAC approved the following revisions:  (1) a tolerance for guava also applies to feijoa, jaboticaba, wax jambu, starfruit, passionfruit, and acerola; (2) a tolerance for lychee also applies to longan, Spanish lime, rambutan, and pulasan; and (3) a tolerance for sugar apple also applies to cherimoya, ilama, soursop, and biriba.  A tolerance for sugar apple already applies to atemoya and custard apple.  The submitted crop field trial data will support the proposed tolerances of 3.0 ppm for guava, acerola, feijoa, jaboticaba, passionfruit, starfruit, and wax jambu; 7.0 ppm for lychee, longan, Spanish lime, pulasan, and rambutan; and 1.5 ppm for sugar apple, atemoya, biriba, cherimoya, custard apple, ilama, and soursop.
Table 5.2 provides a summary of the field trials that were performed for fenpropathrin.

Table 5.2.  Summary of Residue Data from Crop Field Trials with Fenpropathrin.
Crop matrix
                              Total Applic. Rate
                                   (lb ai/A)
                                  PHI (days)
                             Residue Levels (ppm)



                                       n
                                     Min.
                                     Max.
                                    HAFT[1]
                                    Median
                                     Mean
                                   Std. Dev.
                        TROPICAL AND SUBTROPICAL FRUITS
        (proposed use = 0.8 lb ai/A total application rate, 1-day PHI)
Guava
                                   0.78-0.82
                                       1
                                       6
                                     0.48
                                      1.1
                                      1.0
                                     0.59
                                     0.71
                                     0.25
Lychee
                                   0.80-0.84
                                       1
                                       6
                                      2.1
                                      2.6
                                      2.5
                                      2.4
                                      2.3
                                     0.20
Sugar apple/atemoya
                                   0.81-0.82
                                       1
                                       6
                                     0.25
                                     0.70
                                     0.48
                                     0.40
                                     0.45
                                     0.16
[1]  HAFT = Highest average field trial result.


Adequate field trial data reflecting use of fenpropathrin on tea grown in India are available for establishing an import tolerance on dried tea.  The OECD MRL calculation procedures recommend that the tolerance be established at 3.0 ppm.  However, there is a Codex MRL of 2.0 ppm for dried tea.  HED considers this tolerance level to be adequate because the highest field trial value was 1.38 ppm.  As a result, HED recommends in favor of a tolerance of 2.0 ppm for tea, dried in order to harmonize with the Codex MRL.  

HED does not require residue data for any processed commodities associated with this tolerance petition.  As a result, no processing studies were submitted and none are needed.

There are no livestock feedstuffs associated with the proposed use on tropical fruits or tea.  As a result, the current tolerances for livestock commodities are adequate.

Information is available concerning the potential of fenpropathrin to bioconcentrate in fish.  The chemical has a relatively high octanol/water partition coefficient and depurates from fish at a moderate rate.  EFED's registration review problem formulation (D371483, J. Melendez, 6/16/2010) states that "...fenpropathrin appears to have a potential to bioconcentrate in aquatic organisms & biomagnify in aquatic and terrestrial organisms."  However, the moderate depuration rate reduces the concern for residues in fish for subsistence and recreational fishers. 

5.3	Water Residue Profile

The Environmental Fate and Effects Division (EFED) provided the results of a drinking water assessment that was performed for fenpropathrin (D368174, Jose Melendez, 4/26/2010).  In this memo, EFED stated that the results of a previous assessment (D313331, J. Melendez, 9/3/2008) should be used in the current dietary exposure and risk assessment.  Water numbers were based on parent only.  The EFED memo of 9/3/2008 provided Tier 1 estimated environmental concentrations (EDWCs) for fenpropathrin that were calculated using the FIRST Model for surface water and the SCIGROW Model for groundwater.  For surface water, the acute (peak) water concentration is 10.3 ppb.  The groundwater screening concentration is 0.005 ppb.  These values generally represent upper-bound estimates of the concentrations that might be found in surface water and groundwater resulting from the use of fenpropathrin on grapes, because this is the scenario that results in the highest EDWCs.  For the acute dietary exposure assessment, the peak water concentration value of 10.3 ppb was used.  The model and its description are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/.  

5.4	Dietary Risk Assessment

5.4.1	Description of Residue Data Used in Dietary Assessment

An acute aggregate dietary (food and drinking water) exposure and risk assessment was conducted using the Dietary Exposure Evaluation Model DEEM-FCID(TM), Version 2.03, which uses food consumption data from the U.S. Department of Agriculture's Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998.

A chronic dietary exposure assessment was not performed because repeated exposure to fenpropathrin does not result in a point of departure lower than that resulting from acute exposure, and a chronic dietary endpoint was not selected.  The acute dietary risk assessment is considered to be protective of chronic dietary risk.  An assessment for cancer was not performed because fenpropathrin was classified as "not likely to be carcinogenic to humans."  As a result, an acute assessment was the only dietary exposure assessment performed for fenpropathrin.   

The acute assessment was based on tolerance level residues, distributions of field trial values, and distributions of Pesticide Data Program (PDP) monitoring data.  Residue distributions were used for the commodities that made the most significant contributions to the risk estimates (i.e., the "risk drivers").  Monitoring data were used for risk drivers when they were available; however, field trial data were used for the remaining risk drivers.  Distributions of monitoring data values were used for broccoli, Chinese mustard cabbage, cauliflower, watermelon, squash, oranges, tangerines, apples, apple juice, pears, blueberries, huckleberries, grapes, grape juice, and strawberries.  Monitoring data from the years 2007 through 2010, inclusive, were used.  Broccoli PDP data were translated to Chinese mustard cabbage and cauliflower.  Orange PDP data were translated to tangerines.  Finally, blueberry PDP data were translated to huckleberries.  Distributions of field trial data were used for cherries, peaches, plums, grapefruit, raspberries, blackberries, apricots, cabbage, papaya, olives, tomatoes, cucumbers, Brussels sprouts, and guava.  For most processed commodities, DEEM default processing factors were used for those commodities for which they were available.  In some cases, empirical processing factors were used.  For drinking water, a very conservative surface water EDWC generated with the FIRST Model was used.  As a result of the fact that many conservative assumptions were made for this assessment, in particular, the use of field trial data (as opposed to monitoring data) for many commodities, HED is confident that the acute dietary exposure assessment significantly overestimates risk to the general U.S. population and all population subgroups.

5.4.2	Percent Crop Treated Used in Dietary Assessment

The Biological and Economic Analysis Division (BEAD) provided a Screening Level Usage Analysis (SLUA) for fenpropathrin (D402054, S. Haddad, 5/25/2012).  The SLUA provided maximum percent crop treated estimates for commodities with established tolerances.  Percent crop treated estimates were not used for any of the proposed commodities.  
The following maximum percent crop treated estimates were used in the acute dietary risk assessment for the following crops that are currently registered:  apples (15%), apricots (2.5%), blueberries (2.5%), broccoli (2.5%), Brussels sprouts (10%), cabbage (2.5%), cauliflower (2.5%), cherries (5%), cotton (2.5%), cucumbers (2.5%), grapefruit (35%), grapes (10%), nectarines (2.5%), oranges (35%), peaches (2.5%), pears (10%), plums (2.5%), prune plums (2.5%), squash (2.5%), strawberries (50%), tangerines (15%), tomatoes (10%), and watermelons (2.5%).

5.4.3	Acute Dietary Risk Assessment

The acute risk estimates are below HED's level of concern for all population subgroups, including those comprised of infants and children.  Generally, HED is concerned when risk estimates exceed 100% of the PAD.  The acute risk estimate for the general U.S. population is 19% of the aPAD.  The population subgroup with the highest acute dietary risk estimate is Children 3-5, which uses 97% of the aPAD.  As percent crop treated estimates were incorporated into the acute assessment, the risk estimates are being reported at the 99.9[th] percentile of exposure.  The acute dietary risk estimates are given in Table 5.4.4.

HED considers the acute assessment to be partially refined, but at the same time, very health-protective.  Refinements were made to the risk drivers in the assessment; however, for many of the risk drivers, these refinements consisted of the incorporation of field trial data (See Section 5.4.1, above).  For pyrethroids, monitoring data are almost always significantly lower than field trial data.  Monitoring data more accurately represent the residue levels to which people will actually be exposed to pesticide residues in their diets.  For many commodities, the assumption was made that 100% of the crop would be treated.  For other commodities, maximum percent crop treated estimates were incorporated.  These estimates are based on past usage data and are considered to be reliable.  Percent crop treated estimates were not available for two of the risk drivers for children 1-6 years of age, raspberries and blackberries.  As a result, 100% crop treated was used for these commodities.  If usage estimates were available and had been used, the risk estimates for the population subgroups, Children 1-2 and Children 3-5, would have been lower.  As all risk estimates are not of concern, it is not necessary to make any further refinements to the dietary exposure assessment at this time.

Residues in drinking water made a negligible contribution to the risk estimates.  

5.4.4	Summary Table
 
 
 Table 5.4.4.   Summary of the Acute Exposure and Risk Estimates for Fenpropathrin
 
 Population Subgroup
                     Acute Assessment (99.9[th] Percentile)
                               Chronic Assessment
 
                                  aPAD, mg/day
                           Exposure Estimate, mg/day
                                     % aPAD
                                  cPAD, mg/day
                           Exposure Estimate, mg/day
                                     % cPAD
U.S. Population
                                     0.05
0.009489
19
                                      NA
                                       
                                       
                                       
                                       
                                       
                                       
                                      NA





                                       
                                      NA






All infants
                                     0.017
0.011457
67
                                       


Children 1-2 yrs
                                     0.017
0.015343
90
                                       


Children 3-5 yrs*
                                     0.017
0.016488
97
                                       


Children 6-12 yrs
                                     0.05
0.013489
27
                                       


Youth 13-19 yrs
                                     0.05
0.009290
19
                                       


Adults 20-49 yrs
                                     0.05
0.007920
16
                                       


Adults 50+ yrs
                                     0.05
0.008093
16
                                       


Females 13-49 yrs
                                     0.05
0.008476
17
                                       


 *Most highly exposed population subgroup
 
 
 
 6.0 Residential (Non-Occupational) Exposure/Risk Characterization
 
6.1	Residential Handler and Post-application Exposure and Risk Estimates 

There are no registered or proposed residential uses for fenpropathrin.  As a result, residential handler and post-application risk is not of concern. 




6.2	Spray Drift

Spray drift is always a potential source of exposure to residents nearby spraying operations.  This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for fenpropathrin.  The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency's Spray Drift website for more information at: http://www.epa.gov/opp00001/factsheets/spraydrift.htm).  On a chemical-by-chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling.  The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods.    After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift with specific products with significant risks associated with drift.

Although a quantitative post-application inhalation exposure assessment was not performed for fenpropathrin to address pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers who assist aerial applicators.  This exposure scenario is representative of a worst-case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post-application inhalation exposure scenarios.

 7.0 Aggregate Exposure/Risk Characterization
In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risk estimates from three major sources: food, drinking water, and residential exposures.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risk estimates themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.  The only applicable aggregate scenario for fenpropathrin is acute aggregate risk which results from exposure to residues in food and drinking water alone.  The acute dietary exposure analysis included both food and drinking water.  Therefore, acute aggregate risk estimates are equivalent to the acute dietary risk estimates, as discussed in Section 5.4.3, above.  Acute aggregate risk is not of concern for the general U.S. population or any population subgroup. 

 8.0 Cumulative Exposure/Risk Characterization
The Agency is required to consider the cumulative risks of chemicals sharing a common mechanism of toxicity.  The Agency has determined that the pyrethroids and pyrethrins share a common mechanism of toxicity (http://www.regulations.gov; EPA-HQ-OPP-2008-0489-0006). The members of this group share the ability to interact with voltage-gated sodium channels ultimately leading to neurotoxicity.  The cumulative risk assessment for the pyrethroids/ pyrethrins was published on 11/9/2011 and is available at http://www.regulations.gov; EPA-HQ-OPP-2011-0746.  No cumulative risks of concern were identified, allowing the Agency to consider new uses for pyrethroids.  For information regarding EPA's efforts to evaluate the risk of exposure to this class of chemicals, refer to http://www.epa.gov/oppsrrd1/reevaluation/pyrethroids-pyrethrins.html.

Fenpropathrin is included in the pyrethroid/pyrethrin cumulative risk assessment.  The new uses that have been proposed have an insignificant impact on the cumulative risk assessment.  No dietary, residential, or aggregate risk estimates of concern have been identified in the single chemical assessment.  In the cumulative assessment, residential exposure was the greatest contributor to the total exposure.  As there are no residential uses for fenpropathrin, the proposed new uses will have no impact on the residential component of the cumulative risk estimates.

Dietary exposures make a minor contribution to the total pyrethroid exposure.  The dietary exposure assessment performed in support of the pyrethroid cumulative was much more highly refined than that performed for the single chemical.  In addition, for the fenpropathrin risk assessment, the most sensitive apical endpoint in the fenpropathrin database was selected to derive the POD.  Additionally, the POD selected for fenpropathrin is specific to fenpropathrin, whereas the POD selected for the cumulative assessment was based on common mechanism of action data that are appropriate for all 20 pyrethroids included in the cumulative assessment.  Dietary exposure to fenpropathrin residues in the proposed tropical fruits and tea will contribute very little to the dietary exposure to fenpropathrin alone.  As a result, the proposed uses will make an insignificant contribution to dietary risk to the pyrethroids as a whole.   


 9.0 Occupational Exposure/Risk Characterization
Fenpropathrin may be applied to fruit trees by ground equipment (airblast).  In addition, aerial application may be used for avocado trees.  Fenpropathrin is intended for use by commercial and professional applicators.  Therefore, there is potential for short- and intermediate-term occupational handler and post-application exposure via the inhalation and dermal pathways.  No long-term exposure (> 6 months) is expected.  However, as noted previously, fenpropathrin does not increase in potency with repeated dosing, and therefore only single-day occupational exposures are being assessed.  These single-day risk estimates are protective for repeated exposures.  As there is no dermal hazard associated with this chemical, only inhalation risk is being assessed quantitatively.  

9.1	Short-/Intermediate-Term Handler Risk

Exposure scenarios describe the handler activities (mixer, loader, applicator, and flagger) and type of application equipment.  Based on the proposed use pattern, the following scenarios were identified for the application of fenpropathrin to tropical fruits:  

::	Mixing/loading liquid formulation for aerial application,
::	Mixing/ loading liquid formulation for airblast equipment,
::	Applying the spray using air equipment (enclosed cockpit),
::	Applying the spray using airblast equipment, and
::	Flagging for aerial spray application
There are no chemical-specific exposure data for fenpropathrin to develop unit exposures required for estimating handler exposure.  It is HED policy to use the best available data to assess handler exposure.  Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, include the PHED (Version 1.1) database, and the Agricultural Handler Exposure Task Force (AHETF) database.  Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA.  The standard values recommended for use in predicting handler exposure that are used in this assessment, known as "unit exposures," are outlined in the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at: http://www.epa.gov/pesticides/science/handler-exposure-data.html.

The Danitol[(R)] label directs applicators and other handlers to wear long-sleeved shirt, long pants, chemical-resistant gloves, shoes, socks, and protective eyewear. 

Table 9.1 summarizes the short-term inhalation risk estimates for handlers resulting from the proposed use of fenpropathrin on tropical fruits, applied as a foliar treatment.  There is no toxicity associated with dermal exposure to fenpropathrin and, therefore, there is no dermal risk for handlers.  The acute inhalation endpoint and dose are protective of repeated exposures as discussed previously.  The results of HED's assessment indicate that the short-term inhalation risk estimates (MOE >= 5,300) are above HED's LOC of an MOE of 100 at the baseline level of PPE (i.e., no respirator), and with the use of engineering controls for aerial applications.  These risk estimates are not of concern.

Furthermore, the Agency has evaluated scenarios that might be limited in nature such as flagging during aerial applications because engineering controls (i.e., Global Positioning Satellite technology) are now predominantly used as indicated by the 1998 National Agricultural Aviation Association (NAAA) survey of their membership.  It appears, however, flaggers are still used in approximately 10 to 15 percent of aerial application operations.  In cases like these, the Agency strongly encourages the use of the engineering control system but will continue to evaluate risks for flaggers and any other population where a clear exposure pathway exists until the potential for exposure is eliminated.  The Agency is aware that NAAA is conducting another survey on exposure issues and will consider those results at such time as it is appropriate to do so.


 Table 9.1.  Fenpropathrin Occupational Handler Exposure and Risk Estimates  
                                   Exposure
                                   Scenario
                                    PPE [1]
                                  Max. Single
                                  Appl. Rate
                                   (lb ai/A)
                                     Area
                                    Treated
                                    (Acres)
                                Inhalation Unit
                             Exposure & Source
                                  (ug/lb ai)
                                Inhalation Dose
                                    (mg/kg/
                                    day) 2
                                  Short-term
                               Inhalation MOE 3
                                MIXER / LOADER
Liquids (EC) for aerial equipment
Baseline  
(no respirator)
                                      0.4
                                      350
                                     0.219
                                    (AHETF)
                                    0.00038
                                    13,000
Liquids (EC) for airblast equipment 
Baseline

(no respirator)
                                      0.4
                                      40
                                     0.219
                                    (AHETF)
                                   0.000044
                                    110,000
                            APPLICATOR and FLAGGER
Spray for aerial equipment
Closed cockpit
                                      0.4
                                      350
                                     0.068
                                    (PHED)
                                    0.00012
                                    42,000
Spray for airblast equipment
Baseline
(open cab and no respirator)
                                      0.4
                                      40
                                     4.71
                                    (AHETF)
                                    0.00094
                                     5,300
 Flagger: Aerial Applications
Baseline 
(no respirator) 
                                      0.4
                                      350
                                     0.35
                                    (PHED)
                                    0.00061
                                     8,200
MOE = margin of exposure, AHETF=Agricultural Handler Exposure Task Force, PHED=Pesticide Handlers Exposure Database. 
1. Baseline PPE includes long-sleeved shirt, long pants and shoes with socks and engineering controls.  The submitted label recommends baseline PPE plus chemical-resistant gloves and protective eyewear. 
2. Inhalation Dose (mg/kg/day) = [Appl. Rate (lb ai/A) * Acres Treated/Day * Inhalation Unit Exposure (ug/lb ai handled/day /1000)] / Body wt (80 kg).
3. Short-term Inhalation MOE = Short-term Inhalation POD (5.0 mg/kg/day) / Inhalation dose (mg/kg/day).  


9.2	Occupational/Commercial Post-application Exposure 

Post-application workers might be exposed to residues of fenpropathrin through dermal and inhalation routes when they enter treated tropical fruit orchards to perform post-application activities, such as thinning, irrigation, scouting, harvesting, etc.  Dermal post-application exposure was not quantitatively estimated for use of fenpropathrin on tropical fruits because of the absence of a dermal endpoint.

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment is not being performed for fenpropathrin at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV) and the low use rate (0.4 lb ai/A).  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields.  These potential sources include volatilization of pesticides and re-suspension of dusts and/or particulates that contain pesticides.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for fenpropathrin.

Although a quantitative post-application inhalation exposure assessment was not performed, HED has assessed inhalation exposure and risk for occupational/commercial flaggers for aerial applications of fenpropathrin on tropical fruits, and the risk estimates are not of concern.  Inhalation exposure for flaggers is likely to be higher than inhalation exposure associated with post-application activities.  Therefore, the flagger inhalation risk estimates are considered to be protective of all potential post-application activities performed in treated tropical fruit orchards, and these risks are not of concern.

Restricted Entry Interval

The registered Danitol[(R)] 2.4 EC Spray has a 24-hour restricted entry interval (REI) and is in compliance with the Worker Protection Standard because fenpropathrin is Toxicity Category II via the dermal route.  It is not an eye or skin irritant, and it is not a skin sensitizer.


10.0	References

OPP Memoranda

D. Dotson, et al., 11/26/2008, D313330, Fenpropathrin.  Human Health Risk Assessment for the Proposed Uses on Barley, Stone Fruit (Crop Group 12), Tree Nuts (Crop Group 14), Pistachio, Caneberries (Crop Subgroup 13-07A), Olive, Avocado, Black Sapote, Canistel, Mamey Sapote, Mango, Papaya, Sapodilla, and Star Apple  

D. Smegal, 4/10/2012, TXR# 0053978, Summary of Hazard and Science Policy Council (HASPOC) Meeting of January 19, 2012:  Recommendations on waiver requests for a 90-day inhalation study for fenpropathrin 

J. Kidwell, 7/24/2012, Fenpropathrin - Summary of Toxicology Science Advisory Council (ToxSAC) E-Meeting

E. Scollon, A. Lowit, 6/27/2011, D381210, Re-Evaluation of the FQPA Safety Factor for Pyrethroid Pesticides

D. Dotson, 7/24/2012, D368340, Fenpropathrin.  Request for Tolerances in Support of New Uses on the Tropical Fruits Guava, Acerola, Feijoa, Jaboticaba, Passionfruit, Starfruit, Wax Jambu, Lychee, Longan, Spanish Lime, Pulasan, Rambutan, Sugar Apple, Atemoya, Biriba, Cherimoya, Custard Apple, Ilama, and Soursop.  Request for a Tolerance Without U.S. Registration on Tea.  Summary of Analytical Chemistry and Residue Data.

D. Dotson, 7/24/2012, D402246, Fenpropathrin.  Acute Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Action on the Tropical Fruits Guava, Acerola, Feijoa, Jaboticaba, Passionfruit, Starfruit, Wax Jambu, Lychee, Longan, Spanish Lime, Pulasan, Rambutan, Sugar Apple, Atemoya, Biriba, Cherimoya, Custard Apple, Ilama, and Soursop, and a Tolerance Without U.S. Registration on Tea

Suku Oonnithan, 6/11/2012, D372847, Fenpropathrin:  Occupational and Residential Exposure Assessment for the Proposed New Use on Additional Tropical Fruits.
M. Shamim, 7/6/1993, D180582, Review of Hydrolysis, Photolysis in Water, Photolysis on Soil, Anaerobic Soil Metabolism, Mobility and Adsorption/ Desorption, and Terrestrial Field Dissipation Studies; Proposed New Uses on Tomatoes and Strawberries; Label Amendment.

J. Melendez, 4/26/2010, D368174, Tier I Estimated Drinking Water Concentrations of Fenpropathrin: IR-4 Petition for the Use of Fenpropathrin on Additional Tropical and Sub Tropical Fruits and for Tolerance for Tea.


Toxicology References

Anand, S. S., J. V. Bruckner, W. T. Haines, S. Muralidhara, J. W. Fisher and S. Padilla (2006). "Characterization of deltamethrin metabolism by rat plasma and liver microsomes." Toxicology and Applied Pharmacology 212(2): 156-166.

Cao, Z., T. J. Shafer, K. M. Crofton, C. Gennings and T. F. Murray (2011a). "Additivity of Pyrethroid Actions on Sodium Influx in Cerebrocortical Neurons in Primary Culture." Environ Health Perspect.

Cao, Z., T. J. Shafer and T. F. Murry (2011b). "Mechanisms of Pyrethroid Insecticide-Induced Stimulation of Calcium Influx in Neocortical Neurons." J Pharmacology and Experimental Therapy 336(1): 197-205.

Choi, J.-S. and D. M. Soderlund (2006). "Structure-activity relationships for the action of 11 pyrethroid insecticides on rat Nav1.8 sodium channels expressed in Xenopus oocytes." Toxicology and Applied Pharmacology 211(3): 233-244.

de Zwart, L., M. Scholten, J. G. Monbaliu, P. P. Annaert, J. M. Van Houdt, I. Van den Wyngaert, L. M. De Schaepdrijver, G. P. Bailey, T. P. Coogan, W. C. Coussement and G. S. Mannens (2008). "The ontogeny of drug metabolizing enzymes and transporters in the rat."  Reproductive Toxicology 26(3-4): 220-230.

Godin, S. J., M. J. DeVito, M. F. Hughes, D. G. Ross, E. J. Scollon, J. M. Starr, R. W. Setzer, R. B. Conolly and R. Tornero-Velez (2010). "Physiologically Based Pharmacokinetic Modeling of Deltamethrin: Development of a Rat and Human Diffusion-Limited Model." Toxicol. Sci. 115(2): 330-343.

Goldin, A., R. Barchi, J. Caldwell, F. Hofmann, J. Howe, J. Hunter, R. Kallen, G. Mandel, M. Meisler, YBNetter, M. Noda, M. Tamkun, S. Waxman, J. Wood and W. Catterall (2000). "Nomenclature of voltage-gated sodium channels." Neuron 28(2): 365-368.

Goldin, A. L. (2002). "Evolution of Voltage-Gated Na+ Channels." J Exp Biol 205(5): 575-584.

Koukouritaki, S. B., J. R. Manro, S. A. Marsh, J. C. Stevens, A. E. Rettie, D. G. McCarver and R. N. Hines (2004). "Developmental Expression of Human Hepatic CYP2C9 and CYP2C19." Journal of Pharmacology and Experimental Therapeutics 308(3): 965-974.

Lawrence, L. and J. Casida (1982). "Pyrethroid toxicology: Mouse intracerebral sturcture-toxicity relationships." Pesticide Biochemistry and Physiology 18: 9-14.

Lund, A. and T. Narahashi (1982). "Dose-dependent interaction of the pyrethroid isomers with sodium channels of squid axon membranes." Neurotoxicology 3(1): 11-24.

Meacham, C. A., P. D. Brodfuehrer, J. A. Watkins and T. J. Shafer (2008). "Developmentally-regulated sodium channel subunits are differentially sensitive to [alpha]-cyano containing pyrethroids." Toxicology and Applied Pharmacology 231: 273-281.

Mirfazaelian, A., K. Kim, S. Anand, H. Kim, R. Tornero-Velez, J. Bruckner and J. Fisher (2006). "Development of a physiologically based pharmacokinetic model for deltamethrin in the adult male Sprague-Dawley rat." Toxicol Sci 93(2): 432 - 442.

Salgado, V., M. Herman and T. Narahashi (1989). "Interactions of the pyrethroid fenvalerate with nerve membrane sodium channels: Temperature dependence and mechanism of depolarization." Neurotoxicology 10(1): 1-14.

Shafer, T. J., D. Meyer and K. M. Crofton (2005). "Developmental neurotoxicity of pyrethroid insecticides: critical review and future needs." Environmental Health Perspectives 113(2): 123-136.

Soderlund, D., J. Clark, L. Sheets, L. Mullin, V. Piccirillo, D. Sargent, J. Stevens and M. Weiner (2002). "Mechanisms of pyrethroid neurotoxicity: implications for cumulative risk assessment." Toxicology 171(1): 3 - 59.

Song, J. H. and T. Narahashi (1996). "Modulation of sodium channels of rat cerebellar purkinje neurons by the pyrethroid tetramethrin." Journal of Pharmacology and Experimental Therapeutics 277: 445-453.

Tabarean, I. V. and T. Narahashi (1998). "Potent Modulation of Tetrodotoxin-Sensitive and Tetrodotoxin-Resistant Sodium Channels by the Type II Pyrethroid Deltamethrin." J Pharmacol Exp Ther 284(3): 958-965.

Tan, J. and D. M. Soderlund (2009). "Human and rat Nav1.3 voltage-gated sodium channels differ in inactivation properties and sensitivity to the pyrethroid insecticide tefluthrin." NeuroToxicology 30(1): 81-89.

Tornero-Velez, R., A. Mirfazaelian, K.-B. Kim, S. S. Anand, H. J. Kim, W. T. Haines, B. James V and J. W. Fisher (2010). "Evaluation of deltamethrin kinetics and dosimetry in the maturing rat using a PBPK model." Toxicol Appl Pharmacol 244: 208-217.

USEPA (2012). "Benchmark Dose Technical Guidance.  Risk Assessment Forum, Office of Research and Development, U.S. Environmental Protection Agency.  Washington, DC.  EPA/100/R-12/001."

USEPA (2007). Meeting Minutes:  FIFRA SAP Meeting on Assessing Approaches for the Development of PBPK Models of Pyrethroid Pesticides. Document ID:  EPA-HQ-OPP-2007-0388-0049.  www.regulations.gov.

USEPA (2010). "Pyrethroids: Evaluation of Data from Developmental Neurotoxicity Studies and Consideration of Comparative Sensitivity," D31723 Jan 20, 2010.  Document ID:  EPA-HQ-OPP-2008-0331-0028

Verschoyle, R. D. and W. N. Aldridge (1980). "Structure-activity relationships of some pyrethroids in rats." Arch Toxicol 45(4): 325-329.

Weiner, M. L., M. Nemec, L. Sheets, D. Sargent and C. Breckenridge (2009). "Comparative functional observational battery study of twelve commercial pyrethroid insecticides in male rats following acute oral exposure." Neurotoxicology 30 Suppl 1: S1-16.

Wolansky, M., C. Gennings and K. Crofton (2006). "Relative potencies for acute effects of pyrethroids on motor function in rats." Toxicol Sci 89(1): 271 - 277.

Wolansky, M. J. and J. A. Harrill (2008). "Neurobehavioral toxicology of pyrethroid insecticides in adult animals: A critical review." Neurotoxicology and Teratology 30(2): 55-78.

Yang, D., R. E. Pearce, X. Wang, R. Gaedigk, Y.-J. Y. Wan and B. Yan (2009). "Human carboxylesterases HCE1 and HCE2: Ontogenic expression, inter-individual variability and differential hydrolysis of oseltamivir, aspirin, deltamethrin and permethrin." Biochemical Pharmacology 77(2): 238-247.


  

                                  Appendices
                                       
                        Appendix A:  Toxicology Profile

                  Appendix A.1.  Toxicology Data Requirements


Toxicology Requirements for Fenpropathrin 

Guideline Number and Toxicity Study

                                   Required

                                   Satisfied

870.1100	Acute Oral Toxicity	
870.1200	Acute Dermal Toxicity	
870.1300	Acute Inhalation Toxicity	
870.2400	Primary Eye Irritation	
870.2500	Primary Dermal Irritation	
870.2600	Dermal Sensitization	

                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes

                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes

870.3100	Oral Sub-chronic (Rodent)	
870.3150	Oral Sub-chronic (Non-Rodent)	
870.3200	21-Day Dermal	
870.3250	90-Day Dermal	
870.3465	90/28-Day Inhalation	

                                      yes
                                      yes
                                      yes
                                      yes
                                      yes

                                      yes
                                      yes
                                      yes
                                      yes
                                    yes[1]

870.3700	Developmental Toxicity  (Rodent)	
870.3700	Developmental Toxicity (Non-rodent)	
870.3800	Reproduction	

                                      yes
                                      yes
                                      yes

                                      yes
                                      yes
                                      yes

870.4100	Chronic Toxicity (Rodent)	
870.4100	Chronic Toxicity (Non-rodent)	
870.4200	Oncogenicity (Rat)	
870.4200	Oncogenicity (Mouse)	
870.4300	Chronic/Oncogenicity	

                                      yes
                                      yes
                                      yes
                                      yes
                                      yes

                                      yes
                                      yes
                                      yes
                                      yes
                                      yes

870.5100	Mutagenicity: Gene Mutation - bacterial	
870.5300	Mutagenicity: Gene Mutation - mammalian	
870.5375	Mutagenicity: Structural Chromosomal Aberrations	
870.5385	Mutagenicity: Structural Chromosomal Aberrations	
870.5500	Mutagenicity: Other Genotoxic Effects	
870.5550	Mutagenicity: Other Genotoxic Effects	

                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes

                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes

870.6100	Acute Delayed Neurotoxicity (Hen)	
870.6100	90-Day Neurotoxicity (Hen)	
870.6200	Acute Neurotoxicity Screening Battery (Rat)	
870.6200	90 Day Neuro. Screening Battery (Rat)	
870.6300	Developmental Neurotoxicity	

                                      no
                                      no
                                      yes
                                      yes
                                      yes

                                       -
                                       -
                                      yes
                                      yes
                                      yes

870.7485	General Metabolism	
870.7600	Dermal Penetration	
870.7800      Immunotoxicity.......................................................................

                                      yes
                                      yes
                                      yes

                                      yes
                                      yes
                                      yes
           --Not Applicable

[1]The required 28-day inhalation study was waived by the HED HASPOC.
                    Appendix A2.	  Toxicity Profile Tables

Acute Toxicity of Fenpropathrin
Guideline No./Study Type
                                     MRID
             Results
                          Toxicity           Category
870.1100 Acute oral toxicity (rat)
     00127343
LD50  =M:54 mg/kg
             F:48.5 mg/kg
                                       I
870.1200 Acute dermal toxicity (rat)
     00127352       
LD50 = M:1600 mg/kg
              F:870 mg/kg
                                      II
870.1200b Acute dermal toxicity (rabbit)
     00127355
LD50 = M: >2000 mg/kg bw
              F: >2000 mg/kg bw
                                      III
870.1300 Acute inhalation toxicity (rat)
     00163812
LC50 = ND
                                      IV
870.2400 Acute eye irritation (rabbit)
     00127357
Mild eye irritant
                                      III
870.2500 Acute dermal irritation (rabbit)
     00127357
Not a dermal irritant
                                      IV
870.2600 Skin sensitization (guinea pig)
     00127358
Not a dermal sensitizer
                                      NA
ND = Not Determined

Subchronic, Chronic, and Other Toxicity Studies for Fenpropathrin  
                           Guideline No./ Study Type
                    MRID No. (year)/ Classification /Doses
                                    Results
Subchronic Studies
870.3100
90-Day oral toxicity rats
(unreported strain)

00127363 (1979)
Acceptable/guideline
M&F: 0, 3, 30, 100, 300, 600 ppm
(0, 0.15, 1.5, 5, 15, 30 mg/kg/day), in diet
NOAEL = 15 mg/kg/day
LOAEL = 30 mg/kg/day based on clinical signs of tremors, body weight reductions, decreased blood clotting time in females, and possibly increased alkaline phosphatase levels (both sexes).
870.3150
90-Day oral toxicity
(Beagle dog)
00127364 (1980)
Acceptable/guideline
M&F: 0, 250, 500, 750 ppm
(0, 6.25, 12.5, 18.8 mg/kg/day)
NOAEL = <6.2 mg/kg/day
LOAEL = 6.2 mg/kg/day based on effects on the gastrointestinal system, tremors, and body weight changes.
870.3200
21-Day dermal toxicity (Sprague-Dawley rat)
47325602 (2006)
Acceptable/guideline
0, 20, 200, or 1000 mg/kg/day for 6 hrs/day, 21 days
Systemic NOAEL = 1000 mg/kg/day
Systemic LOAEL = not observed

Dermal NOAEL = 1000 mg/kg/day
Dermal LOAEL = not observed
870.3200
21-Day dermal toxicity
(NZW rabbit)
00127366 (1982)
Acceptable/guideline
M&F: 0, 500, 1200, 3000 mg/kg/day
NOAEL = >3000 mg/kg/day

Only local irritation was seen.  There were no systemic effects, thus the LOAEL was not determined.
Developmental and Reproduction Studies
870.3700a
Prenatal developmental
[CDF(R) (F-344)/CrLBR rats)
41525903 (1990)
Acceptable/guideline
0, 0.4, 1.5, 2.0, 3.0, 6.0, 10.0 mg/kg/day (gavage)

LOAEL = 10 mg/kg/day based on increased incidence of asymmetrical ossification of sternebrae and incomplete ossification of the 5[th] and 6[th] sternebrae
Maternal NOAEL = 3 mg/kg/day
LOAEL = 6 mg/kg/day based on decreased food consumption and body weight gains.

At 10 mg/kg/day, 6 dams died between days 7 and 13, and one dam was sacrificed moribund on day 8.   The remaining 23 dams survived through the end of gestation.
Also in the high dose group, many clinical signs were observed in the dams including ataxia, sensitivity to external stimuli, spastic jumping, and tremors.  These signs were most severe 2 hours post-dosing and during the first days of dosing. 

Developmental
NOAEL = 6 mg/kg/day  
LOAEL = 10 mg/kg/day based on increased incidence of asymmetrical ossification of sternebrae and incomplete ossification of the 5[th] and 6[th] sternebrae
870.3700b
Prenatal developmental
(NZW rabbit)
00163816 (1985)
Acceptable/guideline
0, 4, 12, 36 mg/kg/day (gavage)
Maternal NOAEL = 4 mg/kg/day
LOAEL = 12 mg/kg/day based on flicking of the forepaws.
Developmental NOAEL = >36 mg/kg/day
No dose related effects were seen, thus the LOAEL was not determined.
870.3800
Reproduction and fertility effects
(Sprague-Dawley rats)
00163817 (1986)
Acceptable/guideline
0, 40, 120, 360 ppm
(M: 0, 3.0, 8.9, 26.9 mg/kg/day
F: 0, 3.4, 10.1, 32.0 mg/kg/day), in diet, premating determinations
Parental/Systemic NOAEL = M:3.0; F: 3.0 mg/kg/day
LOAEL = M: 8.9; F: 10.1 mg/kg/day based on death and clinical signs of neurotoxicity in females.

Offspring NOAEL = M:3.0; F:3.4 mg/kg/day
LOAEL = M: 8.9; F: 10.1 mg/kg/day based on increased mortality and body tremors.
Chronic Toxicity Studies		
870.4100b
Chronic toxicity (Beagle dog)
00143130 (1984)
Acceptable/guideline
0, 100, 250, 750 ppm
(0, 2.5, 6.25, 18.75 mg/kg/day)

NOAEL = 2.5 mg/kg/day
LOAEL = 6.25 mg/kg/day based on tremors and ataxia in both sexes.
Chronic/Carcinogenicity Studies
870.4200b
Carcinogenicity (CD-1 mouse)
00163814 (1985)
Acceptable/guideline
0, 40, 150, 600 ppm
(M: 0, 3.9, 13.7, 56.0 mg/kg/day
F: 0, 4.2, 16.2, 65.2 mg/kg/day), in diet
NOAEL = Not established
LOAEL = M: >56.0; F: >65.2 mg/kg/day
There was an overall lack of toxic response.  However the aborted mouse carcinogenicity study (MRID No. 00163815) demonstrated that at a slightly higher maximum tolerated dose (MTD) of 1000 ppm, the test article was lethal to 15% of the mice after only 13 weeks.  Thus the maximum dose used in this completed study (600 ppm) was very close to the MTD.  A repeat study is not justified.
no evidence of carcinogenicity
870.4300
Chronic/
Carcinogenicity - (CD rat)
00163813 (1986)
Acceptable/guideline
0, 50, 150, 450, 600 ppm
(M: 0, 1.93, 5.71, 17.06, 22.8 mg/kg/day
F: 0, 2.43, 7.23, 19.45, 23.98 mg/kg/day), in diet
NOAEL = M:17.06; F: 7.23 mg/kg/day
LOAEL = 19.45 mg/kg/day based on increase mortality and body tremors in the females

no evidence of carcinogenicity
Mutagenicity Studies
Gene Mutation
870.5100
Bacterial Reverse Mutation Test
00163818 (1984)
Acceptable/guideline
0, 50, 10, 500, 100, or 5000 ug/plate +/- S9
Negative in Salmonella typhimurium TA 1535, TA1537, TA1538, TA98, and TA100 and Escerichia coli Wp2 uvrA up to the limit concentration with evidence of compound insolubility.
Gene Mutation
870.5300
In vitro mammalian cell gene mutation test
00126832 (1982)
Acceptable/guideline
0, 50.3, 84.5 141.9, 238.2, 400 ug/mL in the absence of mammalian metabolic activation
0, 30, 47.5, 75.3, 119.4, 189.2, 300 mg/mL in the presence of mammalian metabolic activation
There was no clear evidence (or a concentration related positive response) of induced mutant colonies over background.
870.5375
Cytogenetics 
In vitro mammalian cell chromosomal aberration assay
41281601 (1989)
Acceptable/guideline
10-30 ug/mL -S9 and 250-1000 ug/mL +S9
Negative in Chinese hamster ovary (CHO) cells (cytotoxicity observed at >=30 ug/mL -S9 and compound precipitation at 1000 ug/mL +S9).
870.5500 
Other Genotoxic Effects Bacterial DNA damage or repair test
00126831 (1980)
Acceptable/nonguideline
10-5000 ug/disc -S9 only 
Negative in Bacillus subtilis H17 (DNA repair proficient) and M45 (DNA repair deficient).
870.5900 
Other Genotoxic Effects
In vitro sister chromatid exchange assay   

00163821 (1984)
Acceptable/guideline
3x10[-6]-1x10[-4] M (solubility limit) +/-S9
Negative in CHO cells up to the solubility limit.
Neurotoxicity Studies

870.6200a Acute Neurotoxicity Screening Battery (Sprague-Dawley rats)
47345605 (2006)
Acceptable/guideline
0, 3, 6, 15, or 30 mg/kg
NOAEL = 15 mg/kg 
LOAEL = 30 mg/kg, based on slight tremors and clonic convulsions in both sexes at the time of peak effect
870.6200b Subchronic Neurotoxicity Study (Sprague-Dawley rats)
47345607 (2007)
Acceptable/guideline
0, 60, 190, or 570 ppm
M: 0, 4, 13, or 38 mg/kg/day
F: 0, 5, 15, or 50 mg/kg/day
NOAEL = 13/15 mg/kg/day
LOAEL = 38/50 mg/kg/day, based on tremors, convulsions, impaired gait, and related findings in the FOB predominantly in the females
870.6300 Developmental Neurotoxicity Study (Sprague-Dawley rats)
47345609 (2008)
Acceptable/guideline
0, 40, 100, or 250 ppm
0/0, 3/7, 8/16, or 19/40 mg/kg/day gestation/lactation, respectively
Maternal NOAEL = 8/16 mg/kg/day
Maternal LOAEL = 19/40 mg/kg/day, based on tremors during lactation

Offspring NOAEL = 8/16 mg/kg/day
Offspring LOAEL = 19/40 mg/kg/day, based on small pup size and decreased body weights and body weight gains during the pre-weaning period

Neurotoxicity NOAEL = 8/16 mg/kg/day
Neurotoxicity LOAEL = 19/40 mg/kg/day, based on increased mean overall maximum auditory startle response amplitude and average response amplitude in the females (PND60) and decreased absolute brain weights in the males
Other Studies

870.7485
Metabolism and pharmacokinetics (Sprague-Dawley rat)
43476801 (1994)
Acceptable/guideline
0, 2.5, 25 mg/kg/day
radiolabeled S-3206 on either the alcohol or acid portion of the molecule by gavage.  In experiment I, rats received 14 daily doses of 2.5 mg/kg followed on the 15[th] day by radiolabeled S-3206.  In experiments II and III, rats received a single dose of radiolabeled S-3206 at either 2.5 or 25 mg/kg.
Greater than 99% of the administered dose was excreted within 168 hours with  28%-56% excreted in the urine and the remainder in the fecs, following both a single and 14 day repeated doses.  Major biotransformations of the absorbed compound included the oxidation of the methyl group of the acid moiety, hydroxylation at the 4'-position of the alcohol moiety, cleavage of the ester linkage, and conjugation with sulfuric acid or glucuronic acid.
870.7600
Dermal penetration
43433801 (1991)
Acceptable/guideline
0, 0.03, 1.5, 30 mg/rat
(0, 0.0013, 0.0663, 1.26 mg/cm[2] - radiolabeled) 
EC Formulation (31.9% a.i.)
Exposure times of 1.5, 1.2, 4, 10, and 24 hours
Dermal absorption increased with dose but not proportionally.  The percentage of the dose absorbed decreased with the increasing administered dose.  The total body burden could be expected to rapidly decrease due to excretion via urine and feces.  Mean dermal absorption for the 10-hour interval was 33.3, 20.1, and 17.6% in the low, mid, and high dose groups, respectively.
870.7800
Immunotoxicity
(Sprague-Dawley rat)
48536804 (2011)
Acceptable/guideline
0, 150, 300, or 450 ppm
(0, 14, 26, or 42 mg/kg/day)
Humoral NOAEL = 42 mg/kg/day
Humoral LOAEL = not determined

Systemic NOAEL = 26 mg/kg/day
Systemic LOAEL = 42 mg/kg/day based on decreased body weights, body weight gain and clinical signs including hyperactivity, hyper-reactivity to touch, and twitching.
Non-Guideline Studies
Wolansky et. al. (2006)

47885701(Draft) 
Acceptable-Non-Guideline 
Acute Oral Toxicity in Rats - Motor Activity
0, 0.01, 0.1, 1.0, 4.0, 8.0, 12.0, 16.0, 24.0 mg/kg via gavage in corn oil (1 mL/kg)

BMDL1SD = 5.0 mg/kg
BMD = 6.4 mg/kg based on decreased locomotor activity

WIL Study 
47050504 (2006)  
Acceptable-Non-Guideline 
Acute Oral Toxicity in Rats  -  FOB

0, 15, 30 mg/kg via gavage in corn oil (5 mL/kg)

BMDL20 = 26.7 mg/kg
BMD20 = 28.9 mg/kg based on  multiple FOB changes




          Appendix A3.  Hazard Identification and Endpoint Selection

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

Wolansky data:  BMDL1SD =  5.0 mg/kg8 doses, well-defined Dose-Response CurveBMD analysis instead of N/L approachMotor activity data high quality, objective, time of peak effectLong-Evans, sensitive strain1 ml/kg of corn oil, greater response comparedCompare available acute studies to other durations/species/effectsOther acute studies more appropriate PODs?ACN: NOAEL = 15 mg/kgWIL:  Low confidence due to poor dose selectionand BMDL ( 26.7 mg/kg) exceeds proposed PODConsider other toxicological effects providing lower PODsRepeated dosing studies?Other species?1 yr dog: small N, fewer doses than WolanskyNOAEL = 6.2Allometric scaling  -  Human equivalent doseRat Wolansky  -  1.46 mg/kgDog  -  1.54 mg/kg/day1 yr dog: NOAEL = 2.5 mg/kg/day90-day dog: NOAEL = <6.2 mg/kg/dayDNT: Maternal & Offspring NOAEL = 8 mg/kg/dayReproductive: NOAEL = 3 mg/kg/dayChronic rat: NOAEL =7.23 mg/kg/day90-day rat: NOAEL = 15 mg/kg/dayConsider other toxicological endpoints:Decreased food consumption and body weight gain in the reproduction study at LOAEL of 3 mg/kg/day and body weight reductions in 90-day dog at LOAEL of 15 mg/kg/day-not seen with other pyrethroidsInconsistent with remainder of database-occurs at doses similar to or greater than PODFenpropathrin


Acute Reference Dose (aRfD) and Acute Population Adjusted Dose

The information used in the POD determination for acute oral endpoints is listed here.  Figure A3 provides a visual picture of this evaluation.  

   1.  The Wolansky acute rat study with a POD of 5.0 mg/kg is selected for this endpoint due to the overall robust nature of the study with 8 doses, producing an excellent dose response curve. The Wolansky study was considerably conservative, gavage dosing using 1 ml/kg corn oil a vehicle and volume.
   2. The WIL study also provided a uniform study design with all pyrethroids tested. However, the WIL study evalutated FOB parameters based on the common mode of action (i.e., interaction with voltage gated sodium channels resulting in neurotoxicity).  These FOB parameters provided a higher LOAEL than the Wolansky study and therefore was not used for endpoint selection. 
   3. The Agency notes that the lowest NOAELs were observed in bolus/gavage studies, including the subchronic and chronic dog studies (dietary administration) and the prenatal developmental studies in the rat and rabbit (gavage dose).  The dog studies are considered to be a bolus dose because dogs will typically consume their meals over a very short period, as opposed to rats which feed continuously over several hours.  By consuming more fenpropathrin-treated food over a shorter period of time, the dog is more likely to have greater maximal plasma concentrations immediately after feeding compared to the rat.
  
As rats feed continuously, and fenpropathrin is metabolized and excreted from the system relatively quickly, the overall systemic concentration in the rat remains low.  The higher plasma concentration in the dog will likely result in a more conservative LOAEL.  The overall result of the dog's feeding pattern is similar to gavage or capsule dosing as stated previously.  The LOAELs for these studies were all based, at least in part, on neurotoxicity.

         a. Dog Studies:
            
                 i. Subchronic dog  -  The 90-day dog study LOAEL was the lowest dose tested, 6.2 mg/kg, and was based on effects on the gastrointestinal system, tremors, and body weight changes.
                 ii. Chronic dog  -  The LOAEL for the chronic dog study was 6.25 mg/kg/day and was based on tremors and ataxia.  The NOAEL was 2.5 mg/kg/day.
                 iii. The dog studies were conducted by dietary administration.  Although there was toxicity at doses slightly greater than the proposed POD of 5.0 mg/kg, the human equivalent dose based on allometric scaling indicates that the NOAELs from the Wolansky rat study and the dog studies are equivalent. 
            
        Human equivalent Doses of Fenpropathrin 
Rat (Wolansky)
Human Equiv. Dose *
Dog 
Human Equiv. Dose*
BMD
BMDL1SD
BMD
BMDL1SD
NOAEL
LOAEL
NOAEL
LOAEL
6.4
5.0
1.87
1.46
2.5
6.2
1.54
3.81
        *Human Equivalent based on allometric scaling: Scaling Factor 0.75; Default weights: rat = 0.5 kg, dog = 10 kg, Human = 70 kg; NOAELH=NOAELD (BWD/BWH)^1-0.75; Sample and Arenal, Bull Environ Contam Toxicol (1999) 62:653-63 
        
         b. Developmental Studies

                 i.  In the rat developmental study, effects including deaths (7/30) and neurotoxicity (ataxia, sensitivity to external stimuli, spastic jumping, and tremors) were observed at 10 mg/kg/day in dams.  However, at the study LOAEL of 6 mg/kg/day, maternal toxicity was limited to decreased food consumption and body weight gains.  The developmental LOAEL was 10 mg/kg/day based on asymmetrical ossification of sternebrae and incomplete ossification of the 5[th] and 6[th] vertebrae.  The developmental NOAEL was 6 mg/kg/day and the maternal NOAEL is 3 mg/kg/day.  The POD is lower, and therefore protective, of these effects.
                  
The BMDL1SD from the Wolansky study is more appropriate for risk assessment based on the following:
                     1. The BMDL1SD is captured between the maternal NOAEL of 3 mg/kg/day and LOAEL of 6 mg/kg/day and is below the developmental NOAEL of 6 mg/kg/day
                     2. The BMD is a more accurate estimate of toxicity compared to the NOAEL/LOAEL approach
                     3. The observed effects at the maternal LOAEL are not quantitatively or qualitatively more severe compared to the decrease in motor activity observed in the Wolansky study
                        
                 ii. In the rabbit developmental study, the maternal LOAEL was 12 mg/kg/day based on flicking of the forepaws.  The NOAEL was 4 mg/kg/day.  No developmental effects were observed.  Although the NOAEL of 4 mg/kg/day is slightly lower than the proposed POD of 5.0 mg/kg; 1) the effects observed in the rabbit study are not qualitatively more severe than the decreased motor activity observed in the Wolansky study; and 2) the Wolansky is a more robust study containing more dose levels and is based on a BMD analysis which is a more estimate of toxicity compared to NOAEL/LOAEL levels.
                  
   4. In the 3-generation study, the maternal LOAEL is 10 mg/kg/day based on increased mortality and tremors in females.  The NOAEL is 3 mg/kg/day.  Maternal effects at the high dose of 32 mg/kg/day included increased deaths and clinical signs of toxicity.  Eighteen of the 24 high-dose dams died, 10 of which occurred during lactation of the F1B dams (i.e., 2[nd] litter of 2[nd] generation).  Clinical signs including tremors, muscle twitches, and increased sensitivity were observed in all high-dose females in all generations and were most intense during the 2[nd] or 3[rd] week of lactation.  At the maternal LOAEL of 10 mg/kg/day, clinical signs of toxicity were observed in a single dam.  No treatment-related effects in the males at any dose, however, it is not clear from the study if males were observed.  There was mortality in pups at the high dose (32 mg/kg/day) in the F2A and F2B litters (3[rd] generation, 1[st] and 2[nd] litters) although it appears there was an effect on litter size by lactation day 21 in the F2B litters.  At the mid-dose (10 mg/kg/day), tremors were observed in 3 pups from the F2B litter, 2 of which died.  There were no reports of clinical signs of toxicity (i.e., tremors) in any other pups.  Therefore, minimal signs of treatment-related were observed at the mid-dose for both adults and pups, reducing any concern for quantitative or qualitative sensitivity for this study.  

Although this study resulted in a lower NOAEL (3 mg/kg/day) compared to the proposed POD, the most severe maternal and offspring effects were limited to the high dose group (32 mg/kg/day).  At the LOAEL (10 mg/kg/day), effects were limited to tremors in a single dam (in the 2[nd] generation) and 3 offspring from the 3[rd] generation (2 of which subsequently died).  Because these effects occurred in subsequent generations, were only observed in relatively few animals, were less severe compared to the high dose, and the BMD estimate is a more accurate estimate of toxicity compared to NOAELs and LOAELs (which are limited by dose-spacing, the proposed POD of 5.0 mg/kg is protective of the effects observed in this study.

   5. The FQPA Factor for children <6 years of age is 3X based on evidence of juvenile sensitivity in the literature.  This information described above is summarized in Re-Evaluation of the FQPA Safety Factor for pyrethroid pesticides (D381210, E. Scollon, 6/27/2011).  
      Based on an evaluation of over 70 guideline toxicity studies submitted to the Agency, including prenatal developmental toxicity studies in rats and rabbits, and multi-generation reproduction toxicity studies and DNTs in rats in support of pyrethroid registrations, there is no evidence that pyrethroids directly impact developing fetuses (USEPA 2010; Table 1)).  None of the studies show any indications of fetal/offspring toxicity at doses that do not cause maternal toxicity.  Therefore the Agency is reducing the FQPA safety factor to 1X for women of child-bearing age.
Appendix A4.  Human Equivalent Analysis (Dog study vs. acute rat motor activity)
                             RAT  Study (Wolansky)
                            DOG Study (Sub-chronic)
chemical 
 rat dose (mg/kg)
human dose (mg/kg)
dog dose (mg/kg)
human dose (mg/kg)

BMD
BMDL
BMD
BMDL
NOAEL
LOAEL
LOAEL
NOAEL
beta-cyfluthrin
                                                                           1.42
                                                                           1.17
                                                                           0.41
                                                                           0.34
                                                                            2.4
                                                                           13.9
                                                                           8.54
                                                                           1.48
bifenthrin
                                                                            4.1
                                                                            3.1
                                                                           1.19
                                                                           0.90
                                                                            2.2
                                                                            4.2
                                                                           2.58
                                                                           1.35
bioallethrin
                                                                           65.6
                                                                           42.2
                                                                          19.07
                                                                          12.27
                                                                            20
                                                                             63
                                                                          38.73
                                                                          12.30
cyhalothrin
                                                                           0.92
                                                                           0.64
                                                                           0.27
                                                                           0.19
                                                                              1
                                                                            2.5
                                                                           1.54
                                                                           0.61
cyphenothrin
                                                                              -
                                                                              -
                                                                              -
                                                                              -
                                                                           12.5
                                                                           37.5
                                                                          23.05
                                                                           7.68
cypermethrin
                                                                          11.19
                                                                           7.16
                                                                           3.25
                                                                           2.08
                                                                           12.5
                                                                           37.5
                                                                          23.05
                                                                           7.68
deltamethrin
                                                                           2.48
                                                                           1.49
                                                                           0.72
                                                                           0.43
                                                                              1
                                                                            2.5
                                                                           1.54
                                                                           0.61
esfenvalerate
                                                                           1.19
                                                                           0.65
                                                                           0.34
                                                                           0.19
                                                                              5
                                                                            7.5
                                                                           4.61
                                                                           3.07
fenpropathrin
                                                                           6.44
                                                                           5.01
                                                                           1.87
                                                                           1.46
                                                                           2.5
                                                                            6.2
                                                                           3.81
                                                                           1.54
permethrin
                                                                           63.1
                                                                           44.4
                                                                          18.34
                                                                          12.91
                                                                             50
                                                                            500
                                                                         307.39
                                                                          30.74
resmethrin
                                                                         162.32
                                                                          75.89
                                                                          47.19
                                                                          22.06
                                                                           300
                                                                              -
                                                                              -
                                                                          184.4
tefluthrin
                                                                           3.67
                                                                            2.8
                                                                          1.067
                                                                           0.81
                                                                           0.5
                                                                            1.5
                                                                           0.92
                                                                           0.31



                  Appendix A5.  Pyrethroid Cumulative Screen

The Agency is required to consider the cumulative risks of chemicals sharing a common mechanism of toxicity.  The Agency has determined that the pyrethroids and pyrethrins share a common mechanism group (http://www.regulations.gov; EPA-HQ-OPP-2008-0489-0006).  The members of this group share the ability to interact with voltage-gated sodium channels ultimately leading to neurotoxicity.  The cumulative risk assessment (CRA) for the pyrethroids/pyrethrins was published on Nov. 9, 2011 (USEPA, 2011a) and is available at http://www.regulations.gov; EPA-HQ-OPP-2011-0746.  Fenpropathrin was included in this cumulative risk assessment.  No cumulative risk estimates of concern were identified, allowing the Agency to consider new uses for pyrethroid actives.  For information regarding EPA's efforts to evaluate the risk of exposure to pyrethroids, refer to http://www.epa.gov/oppsrrd1/reevaluation/pyrethroids-pyrethrins.html.


                   Appendix B.  Physical/Chemical Properties


Physicochemical Properties of Fenpropathrin
                                   Parameter
                                     Value
                                   Reference
Melting point/range
                             45-50ºC (113-122ºF)
DP# 315918, 9/20/05,
W. Cutchin
pH
                               4-5 (1% emulsion)

Density g/cm[3]
                                     1.103

Water solubility (25ºC)
                                   0.33 ppm

Solvent solubility (mg/L at 25ºC)
                         Xylene, cyclohexanone:  1,000
                                Methanol:  337

Vapor pressure at 25ºC
                           5.5 x 10[-6] (0.730 mPa)

Dissociation constant, pKa
                                      NA

Octanol/water partition coefficient, Log(KOW)
                                      5.1

UV/visible absorption spectrum
                                 Not available





                     Appendix C.  Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These data are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements.  For certain studies that review may have included review by the Human Studies Review Board.  Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html and http://www.epa.gov/pesticides/science/post-app-exposure-data.html.
