Page 2 of 15

Executive Summary

Attached is t h e Health Effects Division’s (HED) human health risk assessment status update for d

- P henothrin (phenothrin) conducted as part of the Registration Review process

. The HED Phenothrin Registration Review Team has evaluated the most recent human health
assessment s and database for the insecticide phenothrin to determine the scope of work necessary to support the Registration Review. The risk assessment supporting the Reregistration Eligibility Decision document (RED) issued in September , 200 8, a refined residenti al exposure
assessment conducted in August, 2008 and an updated aggregate exposure assessment conducted in June, 200 9 are the primary sources for this evaluation. Phenothrin, is a pyrethroid insecticide. Pyrethroids are synthetic esters derived from natur ally occurring pyrethrins

. Phenothrin is not currently registered for direct application to agricultural crops and there are no tolerances for specific raw agricultural commodities

. However, use of phenothrin over agricultural lands is considered a food use and a single tolerance is established in/on all crops for this use. Phenothrin is used to control adult mosquitoes indoors and outdoors in residential and commercial areas. Pheno thrin is also used directly on pets.

T he liver is the principal target organ for exposure to phenothrin. Phenothrin is classified as ―not likely to be carcinogenic to humans ,‖ based on r at liver tumors, which occurred only at

exce ssively toxic doses a nd absence of a statistically significant occurrence of hepatocelluar adenomas in mice. No risks of concern have been identified for dietary, occupational, residential, and aggregate exposures, and all risk estimates are below Agency levels of concern.

HED’s Registration Review Scoping Document conclusions are as follows : 1) The dietary exposure assessment is adequate based on current methodologies. However, a n updated dietary risk assessment may be required for R egistration R eview to incorporate any r evised points of departure (P O Ds) or uncertainty factors. 2) The drinking water exposure assessment is adequate based on current methodologies but may need to be revised to incorporate any newly submitted data and / or updated modeling practices

. 3) The residential exposure assessment needs to be updated according to current standard operating procedures. 4 ) The occupational exposure assessment need s to be updated to reflect current standard operating procedures

. 5 ) The aggregate assessment needs to be reevaluated and may need to be revised based on current standard operating procedures. 6 ) I mmunotoxicity and subchronic neurotoxicity stud ies are required under 40 CFR Part 158 as a part of the new data requirements for registration of a pesticide (fo od and non

- food uses)

.Page 3 of 15

Introduction

HED has evaluated the existing human health risk assessments for phenothrin to determine whether sufficient data are available and whether a new human health risk assessment is needed to support Registration Review. HED has considered the most recent risk assessment s for phenothrin

, updates to its toxicity, exposure and usage da tabases, and current Agency science policies and risk assessment methods.

Use Profile

Phenothrin is a T ype I pyrethroid insecticide. Pyrethroids are synthetic esters derived from naturally occurring pyrethrins (which are extract s of chrysanthemum fl owers)

. Type I pyrethroids act on axons in the peripheral and central nervous system by interacting with sodium channels in mammals and/or insects. Phenothrin and other pyrethroids are usually combined with synergists which enhance insecticidal activity by preventing enzymatic break down of the pyrethroid

. Phenothrin is not currently registered for direct application to agricultural crops and there are currently no tolerances for specific raw agricultural commodities

. However, use of phenothrin as a mos quitocide over agricultural lands is considered a food use and a tolerance of 0.01 ppm is established on all crops (40 CFR 180.647)

. Phenothrin is used to control adult mosquitoes outdoors in residential yards and public recreational areas. It is also used indoors as an insecticide and miticide in commercial, industrial, and institutional non

- food areas, transport vehicles such as aircraft, ships, railroad cars and truck trailers, homes and gardens, greenhouses and pet qua rters . It is applied directly to pets. Phenothrin is applied as a wide area mosquitocide either by aircraft or truck

- mounted ultra

- low volume (ULV) sprayers. It is applied by both professional pest control operators and homeowners to indoor and outdoor areas. It is applied indoors with surface, space, and directed crack and crevice sprayers, aerosol generators, and foggers , and hand applied carpet powders

. For outdoor sites, liquid formulations are applied as surface sprays or directed perimeter treatm ent around buildings and structures. Phenothrin is applied directly to pets as a pour

- on, shampoo, and pet collar.

Hazard Identification/Toxicology

B ased on subchronic and chronic oral studies in rodents and dogs

, the liver is the principal target organ for exposure to phenothrin

. Effects on the liver include increased liver weight, hepatocellular vacuolization and hypertrophy and, at higher doses, increased liver serum
enzymes. Based on a subchronic inhalation study in rats, the primary inhalati on exposure effects

are histopathologic changes in the nasal turbinates . Phenothrin showed no systemic toxicity up to the limit dose of 1000 mg/kg/day in a 3

- week dermal toxicity study in rats. The results of the
two

- generation reproduction study in rats indicate that phenothrin is not a reproductive toxicant. Phenothrin demonstrated qualitative and quantitative susceptibility in the acceptable rabbit developmental study based on an observation of spina bifida in one fetus at doses lower than those at wh ich maternal effects were seen. S ignificant maternal (increased abortions) and developmental toxicity (spina bifida and hydrocephalus ) i n fetuses were observed in the rabbit developmental study. In a rat developmental study, minimal effects were observed at the highest dose tested. The spina bifida effect in rabbits was considered significant as it is an indicator ofPage 4 of 15

neurotoxic effects and because the use of methylcellulose as a vehicle may have resulted in an underestimation of toxicity.

A cute, subchronic and developmental neurotoxicity studies were not available in 2008

. The only neurotoxicity study available at that time was unacceptable/non

- guideline 5

- day study in rats which demonstrated clinical signs of piloerection but no axonal damage. Potential for developmental neurotoxicity was identified based on the co

- occurrence of spina bifida, microphthalmia and treatment

- related incidence of hydrocephaly in the rabbit developmental study. The 10X FQPA safety factor was retained as a data base u ncertainty factor to account for lack of acceptable neurotoxicity studies. Acute and subchronic neurotoxicity studies were identified as data deficiencies in the 2008 risk assessment (D326939, 7/2/08) . A developmental neurotoxicity stud y was also req uire d pending the study results of the acute and subchronic neurotoxicity studies.

Phenothrin is classified by the HED C ancer Assessment Review Committee as ―not likely to be carcinogenic to humans

. ‖ Rat liver tumors occurred only at excessively toxic dose s (limit dose) and mouse hepatocellular adenomas, which are common, did not achieve statistical significance . A cceptable mutagenicity studies were negative for mutagenic potential.

Phenothrin has a low acute toxicity by oral (category III), dermal (categ ory III), and inhalation (category IV) routes of exposure. It is a mild eye irritant (Category III) but is not a skin irritant or a skin sensitizer.

For the 200 8 phenothrin risk assessment, toxicity endpoints or points of departure ( PODs ) were selected for dietary, drinking water, residential, and occupational exposure scenarios

. Acute and chronic population adjusted doses (PADs) were selected for assessment of food and drinking water exposures. An acute PAD for females 13

- 49 was selected from a devel opmental toxicity study in rabbits based on the presence of spina bifida

. An aPAD for the general population was not selected because no effect attributable to a single day oral exposure was observed in animal studies. A chronic PAD was selected from a 5 2

- week feeding study in dogs based on liver and adrenal effects . A POD from a 13 week inhalation study in rats was selected for assessment of inhalation exposure pathway for workers and residential handlers/occupants based on histopathological changes in the nasal turbinates

. A POD for incidental oral exposures was selected from a 2

- generation rat reproduction study based on body weight, kidney and liver effects. The incidental oral endpoint was refined based on a benchmark dose analysis (BMD) submitted by the registrant and reviewed by HED. A POD for dermal exposure was not selected based on dermal absorption studies which indicate low dermal absorption and a dermal toxicity study in which dermal effects were not observed at the limit dose. An uncertai nty factor of 1000 was applied for all exposure routes (10x for interspecies extrapolation, 10x for intraspecies variation, and 10x for database uncertainty factor for the inadequate toxicology database i.e., absence of acceptable neurotoxicity studies).

The Office of Pesticide Programs has re

- evaluated the need of a 10X FQPA Safety Factor for human health risk assessments for pyrethroid pesticides. Based on a review of the available guideline and literature studies, the Agency is reducing the FQPA Safety Factor to 1X for adults, including women of child

- bearing age, and children greater than 6 years of age. However, thePage 5 of 15

Agency is retaining a 3X FQPA Safety Factor for children from birth to 6 years of age. The 3X is based on age

- dependent

- pharmacokinetic s and is further supported by physiologically

- based pharmacokinetic (PK) model predictions of a 3

- fold increase of pyrethroid concentration in juvenile target tissue compared to adults. In addition, there is sufficient evidence that the pharmacodynamic (P D) responses are similar in adults and juveniles and therefore a full 10X safety factor is not warranted (D381210, 6/7/11)

. The Agency is expecting additional in vitro and in vivo data . P esticide registrants and product formulators (Council for the Advan cement of Pyrethroid Human Risk Assessment (CAPHRA) are i) conducting in vitro studies demonstrating the interaction of pyrethroids e x ogenously expressed rat and human VGSCs in Xenopus oocytes; ii) conducting in vitro studies demonstrating interaction of p yrethroids in rat neurolemma cells; iii) developing rat and human PBPK models, including additional pharmacokinetic data; and iv) conducting in vivo behavioral testing using auditory startle testing in rats. As more data for individual pyrethroids become available, the Agency will determine whether re

- evaluation of the
age

- related sensitivity of pyrethroids is appropriate.

Data Requirement s

OPP conducted a review of available developmental neurotoxicity studies (DNTs) for six pyrethroids in 2010 (D371723, 1/20/10) . Based on that review , the Agency has determined that the six available DNT’s, when considered together, provide sufficient information to determine that the conclusions drawn from the studies are applicable to all pyrethroids, includi ng phenothrin. The effects seen in the available rabbit developmental study were considered in applying this determination to phenothrin . The p r imary effects of concern in the phenothrin rabbit study (spina bifida seen at 100 mg/kg/day and microphthalmia seen at 300 mg/kg/day) were observed on ly in a single fetus each. Based on the weight of the evidence from pyrethroid DNT review

, the absence of a clear dose

- response for the malformations observed in the phenothrin developmental rabbit study, and the ab sence of evidence of neurotoxicity in the phenothrin rat developmental study, OPP concluded that a DNT for phenothrin would provide little additional information. Since the Agency has determined that there is little value added in conducting DNTs for addi tional pyrethroids, the registrant may apply for a waiver from the requirement of a DNT for phenothrin citing OPP’s review of the six available DNTs. An acute neurotoxicity study in rats submitted by the registrant in 2009 was reviewed and classified as

a cceptabl e/guideline. The submitted study satisfies the guideline requirement for an acute neurotoxicity study (870.6200a). I mmunotoxic ity and subchronic neurotoxicity studies are required under 40 CFR Part 158 as a part of the new data requirements for r egistration of a pesticide for food and non

- food uses

. The registrant submitted a protocol for the subchronic neurotoxicity study for HED’s review in July, 2009. HED determined that a subchronic neurotoxicity study conduct ed in accordance with the submitted protocol would satisfy the guideline data requirement of a 90

- day neurotoxicity battery in rats.

Conclusions

Based on HED’s re

- evaluation of the toxicity analysis conducted for the 2009 phenothrin risk assessment

, immu notoxicity and subchronic neurotoxicity studies are required. PODs for oral (i.e., dietary

, drinking water and incidental oral) exposure are adequate but need to be reevaluated to incorporate information from the pyrethroid DNT study evaluation and toxici tyPage 6 of 15

data submitted to satisfy new data requirements and to reflect OPP’s reevaluation of the safety factor for pyrethroid pesticides. PODs for inhalation and dermal exposures are adequate.

Dietary and Drinking Water Exposure

The residue of concern for dietary exposure in plants is phenothrin per se

. HED conducted screening level acute and chronic dietary and drinking water exposure assessment for application of phenothrin as a wide

- area mosquito adulticide over agricultural lands ( D 326931

, 8/ 19/08)

. Acute and chronic dietary assessment s w ere conducted for all commodities . T he Environmental Fate and Effects Division’s (EFED’s) estimated upper

- bound drinking water concentration s were incorporated directly into the dietary assessments. The acute and chronic
assessment s assumed tolerance level residues in plant commodities and 100% crop treated. Results of the acute dietary assessment indicate that exposure and risk estimates for the population subgroup of concern, females 13

- 49 years, are b elow HED’s level of concern

. Results of the c hronic dietary exposure assessment indicate that estimate d risks are not of concern for the general population and all population subgroups.

The OPP Antimicrobials Division (AD) evaluated the labeled produ ct in which phenothrin is formulated with three other active ingredients (ADBAC, DDAC, and isopropyl alcohol) and used indoors by homeowners as a disinfectant, sanitizer and deodorizer product. AD will conduct a Tier I indirect dietary screening

- level an alysis of these uses to assess residue transfer to food placed on treated countertops

. AD anticipates that the contribution of this use will be minimal compared to the dietary exposures for the conventional insecticidal uses. The Agency will determine wh ether the antimicrobial use dietary contribution is significant enough to be included in the dietary assessment of conventional uses pending results of the AD
assessment. The need for a drinking water assessment is not anticipated for antimicrobial uses. (D90800).

Data Requirements

The data base for the dietary and drinking water assessment is complete.

Conclusions

The dietary and drinking water exposure assessment s are adequate based on current methodologies. However, an updated dietary risk assessment may be required for Registration Review to incorporate any revised points of departure (PODs) or uncertainty factors. The dietary exposure assessment may also need to be revised to include exposures associated with antimicrobial uses. In addition, if new fate data is submitted to the Agency (e.g., adsorption/desorption data, metabolism data, etc.), or if modeling practices or guidance is updated before the risk assessment phase an updated drinking water assessm ent may be required for Registration Review. The revised assessments should be conducted using the newest version of DEEM

- FCID which includes updated consumption information.Page 7 of 15

Tolerances and International Harmonization

A tolerance of 0.01 parts per million is established for residues of phenothrin in or on all food/feed crops following wide

- area mosquito adulticide applications. There are no Codex or Canadian maximum residue limits (MRLs) for phenothrin. The tolerance expression for phenothrin need s to be reviewed and updated as necessary based on HED’s Interim Guidance on Tolerance Expressions (S. Knizner, 5/27/09). Where possible, EPA encourages the harmonization of U.S. tolerances and MRLs in key export markets. The Agency will work to harmoniz e tolerances/MRLs, where possible, during registration review.

Residential Exposure

Numerous phenothrin products are registered for residential use

. The residential exposure assessment conducted in July, 2008 (D326945, 7/2/08) includes handler and post

- application residential exposure scenarios. Based on a review of active labels and information provided by the registrant, twelve residential scenarios were assessed for exposure via inhalation and incidental ingestion pathways. Dermal exposure was not assessed because PODs for dermal exposure were not selected based on dermal toxicity studies

. Short and intermediate

- term exposures were assessed for residential handler and post

- application exposure scenarios based on registered use s and expected exposure patterns.

Residential handler exposure scenarios

, assessed us ing HED OPP’ standard deterministic risk assessment methodology

, showed that estimated risks were not of concern. The results of the deterministic residential post

- application exposure assessment indicate d estimated risks of concern (i.e., MOEs < 1000) for the following residential scenarios : incidental ingestion risks to toddlers playing on vinyl floor and carpet after treatment with fogger formulation, p ost

ap plication incidental ingestion risks to toddlers playing on carpet after treatment with carpet powder, and incidental ingestion of residues on pets via hand

- to

- mouth after pet treatment. All other residential handler and post

- application exposure scenario assessments conducted using deterministic modeling result in estimated MOEs that are not of concern (MOEs > 1000). The registrant submitted a probabilistic assessment using the Cumulative and Aggregate Risk Evaluation System (CARES ® Versio n 3.0; http://cares.ilsi.org/ ), a publicly available software program, for those res idential post

- application exposure scenarios that presented risks of concern based on the deterministic assessment. Probabilistic exposure assessment is recognized as a refinement over deterministic assessment because it incorporates the full range of expo sures and their associated probabilities. HED conducted a revised CARES assessment based on the registrant’s submission to generate refined estimate s of incidental oral risk to children from application of phenothrin to carpet and pets. Based on HED’s pr obabilistic assessment, MOEs were below 1000 at the 99.9 th and 99.5 th percentiles for the pet care spot

- on scenarios. All other post

- application exposure scenario assessments conducted using probabilistic modeling result in estimated MOEs that are not of c oncern (MOEs > 1000).

In an August, 2008 addendum to the July, 2008 risk assessment, HED provided a refined assessment of residential exposure from use of p henothrin as a spot on treatment for pets

. The refined residential assessment was conducted in response to the submission of a benchmark dose (BMD) analysis of the toxicity endpoint for incidental oral exposure. As noted above, t hePage 8 of 15

probabilistic assessment for this scenario conducted for the July, 2008 assessment indicated risk estimates of concern to toddlers from incidental ingestion of residues on pets via hand

- to

- mouth activity. Th e refined residential exposure assessment addendum incorporate d an incidental oral toxicity endpoint which was der ived using BMD analysis. Based on this refined analysis, this pet treatment scenario does not present risks of concern.

AD evaluated the phenothrin product registered for indoor use by homeowners as a disinfectant, sanitizer and deodorizer product. T he only product with this use (EPA Reg 397

- 13) is also used as an insecticide and used as a surface, space, and directed crack and crevice spray. The product is applied indoors in homes on floors, carpets, upholstered furniture, and countertops. AD verifi ed that the application rates and uses on the label were similar to the insectici d al use patterns previously assessed in the HED risk assessment (D326945, 7/2/08). Therefore, AD does not anticipate additional residential risk assessments are needed (D39080 0).

Conclusions

The residential exposure assessment need s to be updated to reflect current standard operating procedures. It should be noted that HED does not, as a matter of policy, conduct probabilistic residential exposure analyses using CARES . Howe ver, the registrant may again choose to submit a CARES analysis if necessary based on the results of the assessment conducted for Registration Review. As previously, HED will review the registrant ’ s submission for possible inclusion in the Registration Review assessment.

Aggregate Exposure

The aggregate risk assessment integrates the assessments conducted for dietary/drinking water and residential exposure. Since there is potential for concurrent exposure via the food, water and residential pathways for registered uses of phenothrin , all routes of exposure were considered for the aggregate assessment. In a June, 2009 addendum to the July, 2008 risk
assessment
, HED conducted a screening level aggregate assessment of risks from exposure to d

p henothrin residues from food, drinking water, and indoor pesticide uses. S hort

- and intermediate

- term exposures were assess ed for postapplication exposures to children 1

- 2 years old from hand

- to

- mouth exposure. Dietary and drinking water exposure estimates were average values from the screening level chronic food and drinking water exposure assessment. Residential exposure estimates for outdoor uses were based on deterministic screening level estimates of post

- ap plication incidental ingestion risks to toddlers reentering treated lawns. Residential exposure estimates for indoor uses were 99

. 9 th percentile values from the CARES assessment. Based on this assessment aggregate exposures do not present risks of concer n.

Conclusions

The aggregate assessment is adequate but may need to be revised to incorporate changes to the dietary and/or residential exposure assessment based on new toxicological or dietary exposure data and/or to reflect current standard operating p rocedures for dietary, drinking water, and/or residential risk assessment.Page 9 of 15

Occupational Exposure

Risk assessments were conducted for occupational handler exposure scenarios based on registered uses

. Occupational post

- application scenarios were not ass essed because there is no dermal endpoint and post

- application inhalation exposures are not expected for non

- volatile compounds such as phenothrin. Occupational handler exposure s and risk s were estimated for pesticide control operators, wide area mosquito abatement, and pet application scenarios. Occupational exposure and risk estimates indicate MOEs of concern (MOEs < 1000) at the maximum use rate for only one of the worker scenarios assessed: mixing, loading and applying liquids with high pressure hand w and for non

- food greenhouse use . MOEs for this greenhouse use are not of concern at maximum application rates with use of a PF5 respirator. All other occupational exposure scenarios do not present risks of concern (i.e., MOEs > 1000).

AD evaluated the phenothrin product registered for use indoors by homeowners as a disinfectant, sanitizer and deodorizer product. The only product with this use (EPA Reg 397

- 13) is also used as an insecticide and used as a surface, space, and directed cra ck and crevice spray. The product is applied indoors in homes on floors, carpets, upholstered furniture, and countertops. AD verified that the application rates and uses on the label were similar to the insectici d al use patterns previously assessed in the HED risk assessment (D326945, 7/2/08). Therefore, AD does not anticipate additional occupatio nal risk assessments are needed.

Conclusions

The occupational exposure assessment is adequate but needs to be updated to reflect
current standard operating pro cedures. Recommended unit exposures for occupational handler assessments have generally been derived only from PHED. However, recently both the ORETF and AHETF have produced pesticide handler exposure monitoring data that the Agency is using in place of PHED ( http://www.epa.gov/pesticides/science/handler

- exposure

- data.html ). As more reliable data become available (such as that from the AHETF and ORETF), the Agency will continue to replace existing data. Reviewers should incorporate new exposure monitoring data, as necessary, during Registration Review."

Incident Report

An updated incident report was conducted for phenothrin for Registration Review (K. Oo, D390605, 8/11/11 )

. Based on the low frequency and severity of incident cases, there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident information and if a concern is triggered, additiona l analysis will be included in the risk assessment.

Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpointsPage 10 of 15

which may be susceptible to endocrine influence, including effects on endocrine ta rget organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its reregistration decision

, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. How ever, as required by FFDCA section 408(p), phenothrin is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and oth er ingredients) may have an effect in humans or wildlife similar to an effect produced by a ―naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.‖ The EDSP employs a two

- tiered approach to making the statutoril y required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and establish a dose

- response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Phenothrin is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Accordingly, as part of registration review, EPA will issue future EDSP orders/data call

ins, requiring the submission of EDSP screening assays for Phenothrin. For further information on the status of the EDSP, the pol icies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.

C umulative

The Food Quality Protection Act (FQPA) requires the Agency to consider the cumulative risks of chemicals sharing a common mechanism of toxicity. Phenothrin is a member of the pyrethroid/pyrethrin common mechanism group ( http://www.regulations.go v ; 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 Nov. 9, 2011 and is available at http://www.regulations.gov ; EPA

- HQ

- OPP

- 2011

- 0746. No cumulative risks of concern were identified allowing the Agency to consider new uses for pyrethroid actives. For information regarding EPA’s ef

forts to evaluate the risk of exposure to pyrethroids, refer to http://www.epa.gov/oppsrrd1/reevaluation/pyrethroids

- pyrethrins.html

.Page 11 of 15

Human Studies

The residential ex posure assessment for phenothrin relied in part on data in the residential exposure SOPs from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. Many such studies, involving exposure to many different pestic ides, comprise generic pesticide exposure databases such as the Outdoor Residential Exposure Task Force (ORETF) Database

. EPA has reviewed all the studies supporting these multi

- pesticide generic exposure databases, and has found no clear and convincing e vidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevailing at the time the research was conducted. A ll applicable requirements of EPA’s Rule for the Protection of Huma n Subjects of Research (40 CFR Part 26) have been satisfied , and t here is no regulatory barrier to continued reliance on these studies.

The occupational exposure assessment for phenothrin rel ied in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure

. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as the Pesticide Ha ndlers Exposure Database (PHED) and the Agricultural Reentry Task Force (ARTF) Database

. However, recently both the ORETF and AHETF have produced pesticide handler exposure monitoring data that the Agency is using in place of PHED ( http://www.epa.gov/pesticides/science/handler

- exposure

- data.html ). As more reliable data become available, the Agency will continue to replace existing data and new exposure monitoring data will be incorporated into HED’s R egistration Review assessments as necessary. EPA has reviewed all the studies supporting these multi

- pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevailing at the time the research was conducted. A ll applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied , and t here is no regulatory barrier to continued reliance on these studies

.

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in the 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.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf). The OPP typically considers the highest potential exposures from the legal use of a pesticide when conducting human

- health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diets within the U.S., and people who might be exposed when harvesti ng crops. Should these highest exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure that the risk estimates are based on the best available information.Page 12 of 15

Conclusions/Future Actions Needed

T he actions needed in the future Registration Review for phenothrin are listed below

.
Hazard Identification and Endpoint Selection Immunotoxicity and subchronic neurotoxicity studies are required under 40 CFR Part 158 as a part of the new data requirements for registration of a pesticide for food and non

- food uses

.
Dietary and Drinking Water Exposure and Risk The data base for the dietary and drinking water assessment is complete. The dietary and drinking water exposure assessment s are adequate based on current methodologies. However, a n updated assessment may be required during the registration review process to include any revised points of departure (P O Ds) or uncertainty factors. The dietary exposure assessment may also need to be revised to include exposures associated with antimicrobial uses. In addition, if new fate data is submitted or if modeling practices or guidance is updated before the risk assessment phase, a revised drinking water assessment may be required. The revised assessments should be conducted using the newest version of DEEM

- FCID which includes updated consumption information. The revised assessments should be conducted using the newest version of DEEM

- FCID which include s updated consumption informat ion

.

Residential Exposure and Risk The residential r isk assessment needs to be updated to reflect current policies and SOPs

.
Aggregate Exposure and Risk The aggregate assessment is adequate but may need to be revised to incorporate changes to the die tary and/or residential exposure assessment based on new toxicological data and/or to reflect current standard operating procedures for residential risk assessment.

Occupation al Exposure and Risk The occupational exposure assessment needs to be updated t o reflect current SOPs.

Incident Report Based on the low frequency and severity of incident cases, there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the risk
assessment.

Data Requirements

Toxicity Data Requirements

- Immunotoxicity study (GLN (870.7800)

- Subchronic Neurotoxicity

– Rat (870.6200b)Page 13 of 15

References

d

- Phenothrin (Sumithrin®) Risk Assessment for Reregistration Eligibility Decision ( RED) and Associated Section 3 Registration Action

, B

. Daiss D 326939

, 7 / 2 /0 8

d

- Phenothrin ( Sumithrin ®) : Occupational and Resident ial Exposure Assessment for the Reregistration Eligibility Decision (RED) , B. Daiss, D 326945 , 7/ 2/08

d

- Phenothrin (Sumithrin ®) Acute and Chronic Dietary and Drinking Water Exposure and Risk Assessment for the Reregistration Eligibility Decision ( RED), B. Daiss, D364965, 2/6/08 d

- Phenothrin (Sumithrin ®) : Addendum to the Residential Exposure Assessment

, B. Daiss, D 326931 , 8/ 19/08

d

- Phenothrin (Sumithrin ®) : Benchmark Dose Analysis of Toxicity Endpoint for Incidental Oral Exposure

, B. Daiss, D 326934 , 8/ 19/08

Phenothrin

– Reques t to Expand Mosquitocide Use to Permit Application over Agricultural Lands. Residue Chemistry Issues

– Enforcement Method and Retreatment Interval, R. Loranger, D 327509 , 2/21/07)

Pyrethroids: Evaluation of Data from Developmental Neurotoxicity Studies and Consideration of Comparative Sensitivity , E. Scollon, D37 1723, 1/20/10

d

- Phenothrin (Sumithrin®): Addendum

— Aggregate Exposure Assessment for the Reregistration Eligibility Decision (RED) and Errata, B. Daiss, D366211, 6/16/09

Tier II Drinking Wa ter Assessment for RED for d

- Phenothrin , J. Meléndez, D340776 , 9/11/07

AGDISP Modeling of Phenothrin for Residential Exposure

, J. Meléndez, D34 2403, 10/22/07

Sumithrin (D

- Phenothrin): Report of the Cancer Assessment Review Committee, J. Kidwell, TXR 0054 233, 5/30/06

Sumithrin ( Phenothrin ) : Review of Human Incidents. K. Oo ( D390605 7 /1 4 /11 ) DRAFT

Antimicrobials Division (AD) Summary of Human Health Effects Data for the Phenothrin (Sumitrin) Registration Review Decision Document, N. Mottl, D 390800

Registration Review: Preliminary Problem Formulation for Environmental Fate and Ecological Risk, Endangered Species, and Drinking Water Assessments for D

- phenothrin (Case 0426 ) , B. Keirnan, D 390606, 8/31/11 (DRAFT)

Re

- Evaluation of the FQPA Safety Factor for Pyrethroid Pesticides , E. Scollon, A. Lowit, D381210, 6/27/11Page 14 of 15

Attachments

Chemical Identity

Table 1. Phenothrin Nomenclature
Chemical structure

Common name d

- Phenothrin; Phenothrin
IUPAC name 3

- phenoxybenzyl (1 RS ,3 RS ;1 RS ,3 SR )

- 2,2

- dimethyl

- 3

- (2

- methylprop

- 1

- enyl)cyclopropanecarboxylate or 3

- phenoxybenzyl (1 RS )

- cis

- trans

- 2,2

- dimethyl

- 3

- (2

- methylprop

- 1

- enyl)cyclopropanecarboxylate or 3

- phenoxybenzyl (±)

- cis

- trans

- chrysanthemate
CAS name (3

- phenoxyphenyl)methyl 2,2

- dimethyl

- 3

- (2

- methyl

- 1

- propenyl) cyclopropanecarboxylate CAS registry number 026022

- 80

- 2

Points of Departure Tables

Summary of Toxicological Doses and Endpoints for d

- Phenothrin for Use in Dietary and Non

- Occupational Human Health Risk Assessments
Exposure/ Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD,

LOC for Risk Assessment Study and Toxicological Effects

Acute Dietary (General Population, including Infants and Children) An acute RfD for the general population or any population subgroups was not selected because no

effect attributable to a single (or few) day(s) oral exposure was observed in animal studies.

Acute Dietary (Females 13

- 49 years of age) NOAEL =

30 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 10x UF DB Acute RfD =

0.030 mg/kg/day aPAD = 0.030 mg/kg/day Developmental Toxicity Study

– rabbit

Developmental LOAEL = 100 mg/kg/day

based on spina bifida

Chronic Dietary (All Populations) NOAEL= 7.1 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 10x UF DB Chronic RfD =

0.007 mg/kg/day cPAD = 0.007 mg/kg/day Chronic Toxicity study in dogs

Chronic toxicity LOAEL = 26.8 mg/kg/day based on hepatocellular enlargement in the liver and focal degeneration in the adrenal

cortex in both sexes.Page 15 of 15

Summary of Toxicological Doses and Endpoints for d

- Phenothrin for Use in Dietary and Non

- Occupational Human Health Risk Assessments
Exposure/ Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD,

LOC for Risk Assessment Study and Toxicological Effects

Incidental Oral Short

- Term (1

- 30 days) and Intermediate

Term (1

- 6 months) BMDL 10 =

100 mg/kg/day UF A = 10 x

UF H = 10 x FQPA SF= 10 x UF DB Residential

LOC for MOE = 1000 2

- generation rat reproduction study

. The

NOAEL is 1000 ppm (50 mg/kg/day). The LOAEL is 3000 ppm ( 150 mg/kg/day ) based on decreased body weight (4

- 6%) and increased liver weight in F0 and F1 parental animals, and an increase in absolute and relative spleen weight, and decreased absolute uterine weight in F1 adults and on decreased body weight gain during lactation

o f F2b pups, and decreased litter size of F1b litters at day 1, decreased absolute heart and kidney weight in F2b males, increased relative liver weight in male and female F2b

pups.

Dermal All Durations Dermal toxicity systemic LOAEL = not established

21/2 8 Dermal toxicity study in rats dermal toxicity systemic LOAEL not established up to 1000 mg/kg/day (HDT) Inhalation Short

Term (1

- 30 days) and Intermediate

Term (1

- 6 months) NOAEL=

0.104 mg/L (26.6 mg/kg/day) UF A = 10 x

UF H = 10 x FQPA SF= 10 x UF DB Residential

LOC for MOE = 1000 90 Day inhalation toxicity study LOAEL =

0.291 mg/L (74.4 mg/kg/day) based on histopathological changes in the nasal

turbinates.

Cancer (oral, dermal, inhalation) Classification: ―Not likely to be Carcinogenic to Humans‖ ba sed on the absence of significant tumor increases in two adequate rodent carcinogenicity studies.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolati on to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies ). UF H = potential variation in sensitivity among members of the human population (intraspecies). . UF DB = to account for the absence of key dat a (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Summary of Toxicological Doses and Endpoints for [Chemical] for Use in Occupational Human Health Risk Assessments
Exposure/ Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk Assessment Study and Toxicological Effects

Dermal All Durations Dermal toxicity systemic LOAEL = not established

21/28 Dermal toxicity study in rats dermal toxicity systemic LOAEL not established up to 1000 mg/kg/day (HDT) Inhalation Short

Term (1

- 30 days) and Intermediate

- Term (1

- 6 months) NOAEL=

0.104 mg/L (26.6 mg/kg/day) UF A = 10 x

UF H = 10 x UF DB = 10 x Occupational LOC

for MOE = 1000 90 Day inhalation toxicity study LOAEL =

0.291 mg/L (74.4 mg/kg/day) based on histopathological changes in the nasal turbinates.

Cancer (oral, dermal, inhalation) Classification: ―Not likely to be Carcinogenic to Humans‖ based on the absence of signific ant

tumor increases in two adequate rodent carcinogenicity studies.