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Executive Summary

Attached is the Health Effects Division’s (HED) human health risk assessment status 

update for d-Phenothrin (phenothrin) conducted as part of the Registration Review process. The 

HED Phenothrin Registration Review Team has evaluated the most recent human health 

assessments 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, 2008, a refined residential exposure 

assessment conducted in August, 2008 and an updated aggregate exposure assessment conducted 

in June, 2009 are the primary sources for this evaluation. Phenothrin, is a pyrethroid insecticide. 

Pyrethroids are synthetic esters derived from naturally 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. Phenothrin is also used directly on pets. 

The liver is the principal target organ for exposure to phenothrin. Phenothrin is classified 

as ―not likely to be carcinogenic to humans,‖ based on rat liver tumors, which occurred only at 

excessively toxic doses and 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, an updated 

dietary risk assessment may be required for Registration Review to incorporate any revised 

points of departure (PODs) 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 needs 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) 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 (food and non-food uses). 
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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 assessments

for phenothrin, updates to its toxicity, exposure and usage databases, and current Agency science 

policies and risk assessment methods. 

Use Profile 

Phenothrin is a Type I pyrethroid insecticide. Pyrethroids are synthetic esters derived 

from naturally occurring pyrethrins (which are extracts of chrysanthemum flowers). 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 mosquitocide 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 quarters. 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 treatment around buildings and structures. Phenothrin is 

applied directly to pets as a pour-on, shampoo, and pet collar.

Hazard Identification/Toxicology

Based 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 inhalation 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 which maternal effects were seen. Significant maternal (increased abortions) and 

developmental toxicity (spina bifida and hydrocephalus) in 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 of 
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neurotoxic effects and because the use of methylcellulose as a vehicle may have resulted in an 

underestimation of toxicity.

Acute, 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 uncertainty 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 study was also required pending the study results of the acute and subchronic 

neurotoxicity studies. 

Phenothrin is classified by the HED Cancer Assessment Review Committee as ―not likely 

to be carcinogenic to humans.‖ Rat liver tumors occurred only at excessively toxic doses (limit 

dose) and mouse hepatocellular adenomas, which are common, did not achieve statistical 

significance. Acceptable mutagenicity studies were negative for mutagenic potential.

Phenothrin has a low acute toxicity by oral (category III), dermal (category 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 2008 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 

developmental 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 52-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 uncertainty 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, the 
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Agency is retaining a 3X FQPA Safety Factor for children from birth to 6 years of age. The 3X 

is based on age-dependent-pharmacokinetics 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 (PD) 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. Pesticide registrants and product formulators (Council for the Advancement of 

Pyrethroid Human Risk Assessment (CAPHRA) are i) conducting in vitro studies demonstrating 

the interaction of pyrethroids exogenously expressed rat and human VGSCs in Xenopus oocytes; 

ii) conducting in vitro studies demonstrating interaction of pyrethroids 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 Requirements

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, including 

phenothrin. The effects seen in the available rabbit developmental study were considered in 

applying this determination to phenothrin. The primary 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 only 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 absence 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 additional 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 

acceptable/guideline. The submitted study satisfies the guideline requirement for an acute 

neurotoxicity study (870.6200a). 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. The registrant submitted a protocol for the subchronic 

neurotoxicity study for HED’s review in July, 2009. HED determined that a subchronic 

neurotoxicity study conducted 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, immunotoxicity 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 toxicity 
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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 (D326931, 

8/19/08). Acute and chronic dietary assessments were conducted for all commodities. The 

Environmental Fate and Effects Division’s (EFED’s) estimated upper-bound drinking water

concentrations were incorporated directly into the dietary assessments. The acute and chronic 

assessments 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 below HED’s level of concern. 

Results of the chronic dietary exposure assessment indicate that estimated risks are not of 

concern for the general population and all population subgroups. 

The OPP Antimicrobials Division (AD) evaluated the labeled product 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 analysis 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 whether 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 assessments 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 assessment may be required 

for Registration Review. The revised assessments should be conducted using the newest version 

of DEEM-FCID which includes updated consumption information. 
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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 needs 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 

harmonize 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 uses and expected exposure patterns. 

Residential handler exposure scenarios, assessed using 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 indicated 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, postapplication 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® Version 3.0; http://cares.ilsi.org/), a publicly available software 

program, for those residential 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 exposures and 

their associated probabilities. HED conducted a revised CARES assessment based on the 

registrant’s submission to generate refined estimates of incidental oral risk to children from 

application of phenothrin to carpet and pets. Based on HED’s probabilistic assessment, MOEs 

were below 1000 at the 99.9th and 99.5th 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 concern (MOEs > 1000). 

In an August, 2008 addendum to the July, 2008 risk assessment, HED provided a refined 

assessment of residential exposure from use of phenothrin 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, the 
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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. The refined residential exposure assessment addendum incorporated an incidental oral 

toxicity endpoint which was derived 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. The 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 verified that the application rates and uses on the label were similar to the 

insecticidal use patterns previously assessed in the HED risk assessment (D326945, 7/2/08). 

Therefore, AD does not anticipate additional residential risk assessments are needed (D390800).

Conclusions

The residential exposure assessment needs 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. However, 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 dphenothrin residues from food, drinking water, and indoor pesticide uses. Short- and 

intermediate-term exposures were assessed 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-application 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 concern.

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 procedures for dietary, 

drinking water, and/or residential risk assessment.
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Occupational Exposure 

Risk assessments were conducted for occupational handler exposure scenarios based on 

registered uses. Occupational post-application scenarios were not assessed because there is no 

dermal endpoint and post-application inhalation exposures are not expected for non-volatile 

compounds such as phenothrin. Occupational handler exposures and risks 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 wand 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 crack 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 

insecticidal use patterns previously assessed in the HED risk assessment (D326945, 7/2/08). 

Therefore, AD does not anticipate additional occupational risk assessments are needed.

Conclusions

The occupational exposure assessment is adequate but needs to be updated to reflect 

current standard operating procedures. 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, additional 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 endpoints 
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which may be susceptible to endocrine influence, including effects on endocrine target 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. However, 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 other 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 

statutorily 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 callins, requiring the submission of EDSP screening assays for Phenothrin. For further information 

on the status of the EDSP, the policies 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/.

Cumulative

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.gov; EPA-HQ-OPP2008-0489-0006). 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 efforts 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 exposure 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 pesticides, 

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 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. All applicable requirements of 

EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been 

satisfied, and there is no regulatory barrier to continued reliance on these studies.

The occupational exposure assessment for phenothrin relied 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 Handlers 

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 Registration 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. All applicable requirements of EPA’s Rule for the 

Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there 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 harvesting 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.
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Conclusions/Future Actions Needed

The 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 assessments are adequate based on current methodologies. However, an 

updated assessment may be required during the registration review process to include 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 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 includes updated consumption information. 

Residential Exposure and Risk

The residential risk 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 

dietary and/or residential exposure assessment based on new toxicological data and/or to reflect 

current standard operating procedures for residential risk assessment. 

Occupational Exposure and Risk

The occupational exposure assessment needs to be updated to 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)
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References

d-Phenothrin (Sumithrin®) Risk Assessment for Reregistration Eligibility Decision (RED) and 

Associated Section 3 Registration Action, B. Daiss D326939, 7/2/08

d-Phenothrin (Sumithrin®): Occupational and Residential Exposure Assessment for the 

Reregistration Eligibility Decision (RED), B. Daiss, D326945, 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, 

D326931, 8/19/08

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

Exposure, B. Daiss, D326934, 8/19/08

Phenothrin – Request to Expand Mosquitocide Use to Permit Application over Agricultural Lands. Residue Che

Method and Retreatment Interval, R. Loranger, D327509, 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 Water Assessment for RED for d-Phenothrin, J. Meléndez, D340776, 9/11/07

AGDISP Modeling of Phenothrin for Residential Exposure, J. Meléndez, D342403, 10/22/07

Sumithrin (D-Phenothrin): Report of the Cancer Assessment Review Committee, J. Kidwell, 

TXR 0054233, 5/30/06

Sumithrin (Phenothrin): Review of Human Incidents. K. Oo (D390605 7/14/11) DRAFT

Antimicrobials Division (AD) Summary of Human Health Effects Data for the Phenothrin 

(Sumitrin) Registration Review Decision Document, N. Mottl, D390800

Registration Review: Preliminary Problem Formulation for Environmental Fate and Ecological 

Risk, Endangered Species, and Drinking Water Assessments for D-phenothrin (Case 0426), B. 

Keirnan, D390606, 8/31/11 (DRAFT)

Re-Evaluation of the FQPA Safety Factor for Pyrethroid Pesticides, E. Scollon, A. Lowit, 

D381210, 6/27/11
Page 14 of 15

Attachments

Chemical Identity

Table 1. Phenothrin Nomenclature

Chemical structure

Common name d-Phenothrin; Phenothrin

IUPAC name 3-phenoxybenzyl (1RS,3RS;1RS,3SR)-2,2-dimethyl-3-(2-methylprop-1-

enyl)cyclopropanecarboxylate or

3-phenoxybenzyl (1RS)-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

UFA= 10x

UFH=10x

FQPA SF= 10x

UFDB

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

UFA= 10x

UFH= 10x

FQPA SF= 10x

UFDB

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.

H3C

CH3

H3C CH3

O

O

O
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

IntermediateTerm

(1-6 months)

BMDL10 = 

100 

mg/kg/day

UFA= 10 x

UFH= 10 x

FQPA SF= 10 x

UFDB

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 

of 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

21/28 Dermal toxicity study in rats dermal toxicity systemic LOAEL not established up to 1000 

mg/kg/day (HDT)

Inhalation ShortTerm (1-30 days) 

and

IntermediateTerm (1-6 

months)

NOAEL= 

0.104 mg/L 

(26.6 

mg/kg/day)

UFA= 10 x

UFH= 10 x

FQPA SF= 10 x

UFDB

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‖ based 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 extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL 

= no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = 

extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human 

population (intraspecies). . UFDB = to account for the absence of key data (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 ShortTerm (1-30 days) 

and

Intermediate-Term 

(1-6 months)

NOAEL= 

0.104 mg/L 

(26.6 

mg/kg/day)

UFA= 10 x

UFH = 10 x

UFDB = 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 significant 

tumor increases in two adequate rodent carcinogenicity studies.