# January 20, 2010

Page 2 of 36 

# registration review. It has been determined that, for pyrethroid pesticides, DNTs do not

provide sensitive endpoints for risk assessment or provide sufficient information related

to the susceptibility of infants and children; furthermore, the effects they do show can be

found in other guideline studies. Certain re sults were similar across the six submitted

pyrethroid DNT studies. As a result the Agen cy has concluded that the six available

DNTs on pyrethroids, when considered toge ther, provide sufficient information to

determine that the conclusions drawn from DNTs are applicable to all pyrethroids

(Memo, R. Keigwin, Director, PRD/OPP, 9/ 4/2009). The attached document provides

the major scientific evidence s upporting the Agency’s conclusion.

# January 20, 2010

Page 3 of 36 

# Chemical PC Code CAS No.

Allethrin Stereoisomers 004001 584-79-2

Bifenthrin 128825 82657-04-3

Bioallethrin 004003 28057-48-9

Cyclethrin 004052 97-11-0

Cyfluthrin 128831 68359-37-5

Cyfluthrin, beta- 118831 68359-37-5

Cyhalothrin, lambda- 128897 91465-08-6

Cyhalothrin 128867 68085-85-8

Cyhalothrin, gamma- 128807 76703-62-3

Cypermethrin 109702 52315-07-8

Cypermethrin, beta- 109702 65731-84-2

Cypermethrin, zeta- 129064 52315-07-8

Cyphenothrin 129013 39515-40-7

D-Allethrin 004005 84030-86-4



# Deltamethrin 097805 52918-63-5

Esbiothrin 004007 84030-86-4



# Esfenvalerate 109303 66230-04-4

Etofenprox 128965 80844-07-1

Fenfluthrin 109705 69409-94-5

Fenpropathrin 127901 39515-41-8

Fenvalerate 109301 51630-58-1

Imiprothrin 004006 72963-72-5

Metofluthrin 109709 240494-70-6

Permethrin 109701 52645-53-1

Phenothrin 069005 26002-80-2

Prallethrin 128722 23031-36-9

Pyrethrins (not synthetic) 069001 8003-34-7

Resmethrin 097801 10453-86-8

S-Bioallethrin 004004 28434-00-6



# Sumithrin (D-phenothrin) 069005 26046-85-5

Tau-fluvalinate 109302 102851-06-9

Tefluthrin 128912 79538-32-2

Tetramethrin 069003 7696-12-0

Tralomethrin 121501 66841-25-6

# January 20, 2010

Page 4 of 36 

# Pyrethroids: Evaluation of Data from DNTs & Consideration of Co mparative Sensitivity

EPA has evaluated the data and information provid ed by the available guideline developmental

neurotoxicity studies (DNTs) for pyrethroids, as well as data pertaining to the effects of

pyrethroids on juveniles from the scientific literat ure. This evaluation was initiated, in part, by

EPA’s preparation for regist ration review and also for the anticipated cumulative risk assessment

of pyrethroids. In addition, EPA has received requests from some stakeholders to re-consider the

utility of the DNT studies for pyrethroids and/or to consider bridging proposals where the DNT

study for one pyrethroid satisfies the requirement for another. EPA has evaluated multiple lines

of scientific information about pyrethroid s including their mode of action (MOA); the in vivo toxicity

syndromes typical for Type I and II pyrethroids; thei r pharmacokinetic (PK) properties, the critical

effect(s) used in OPP’s single chemical risk as sessments; the results r eported for the available

pyrethroid DNT studies; and information fr om the open scientific literature.

In a September 4, 2009 letter from Richard Keigwin, Director of the Pesticide Review Division, the

Agency noted that the six available DNT studies on pyrethroids, when considered together,

provide sufficient information to determine t hat the conclusions drawn from the DNTs are

applicable to all pyrethroids. This document provi des the major scientific evidence supporting the

Agency’s conclusion 1



# .

Mode of Action & Toxicity Syndromes:

Pyrethroids, the synthetic derivat ives of the pyrethrins, have evol ved structurally over the past

several decades. However, the basic components of pyrethrins, a chrysanthamic acid linked to

an aromatic alcohol through an ester linkage have been conserved (Fig. 1). Structural

modifications such as the addition of halogens to the chrysthanthamic acid and aromatic alcohol

moieties and the addition of the α -cyano group have incr eased photostability, insecticidal

potency, and in some incidences, stereoisomerism of the pyrethroids. As a point of reference,

pyrethroids lacking the α -cyano group are referred to as Type I and those with the α -cyano group

are referred to as Type II pyrethroids.

The naturally occurring pyrethrins and synthetic pyrethroids share the same mode of action

(USEPA, 2009): interaction with vo ltage-gated sodium channels (VGSCs ). The interaction results

in disruption of membrane excitability in the nervous system, leading to neurotoxicity that is

generally characterized by two different toxicity syndromes, T- (fine tremors) and CS-syndromes

(choreoathetosis and salivation) observed in ra ts. The T-syndrome has been historically

characterized by aggressive sparring, increased se nsitivity to external stimuli and fine whole body

tremors and is associated with Type I pyrethro ids. The CS-syndrome has been historically

characterized by initial pawing and burrowing, sa livation, and choreoathetosis and is typically

associated with Type II pyrethroids. In a modi fied functional observational battery (FOB) study

supported by the Pyrethroid Working Group 2 

# , the T-syndrome was associated with elevated

temperature, tremors, and myoclonus. The CS- behaviors were associated with lower

temperature, excessive salivation, and impair ed mobility. A few pyrethroids, including

esfenvalerate and fenpropathrin, elicit symptom s that are a combination of the T- and CSsyndromes 3



# .

1 

# This document is not an exhaustive review of pyre throid toxicity. For readers interested in more

detailed information, see Soderlund and Bloom quist (1989), Vijverberg and van den Berken

(1990), Narahashi (1992), Clark (1995), Soderl und (1995), Bloomquist (1996), Narahashi (1996),

Shafer et al. (2005), Wolansky an d Harrill (2008), and Nemec (2006).

2 

# The Pyrethroid Working Group (PWG) is a consortium of registrants including Bayer

CropScience, DuPont Crop Protection, FMC Corporation, Pytech Chemicals (including

Cheminova and Dow AgroSciences), Syngenta Crop Protection, and Valent USA Corporation.

3 

# Note: The Agency is cu rrently reviewing the SAP repor t and may consider additional

pyrethroids as showing mixed syndromes

# January 20, 2010

Page 5 of 36 

# Figure 1. Typical structure of a pyrethroid pesticid e including acid and alcohol moieties and

location of the alpha-cynao group when present. Cyper methrin is illustrated below.

It has been suggested that the neurotox icity syndromes are attributed to the nature of interaction

between the specific pyrethroids and the VGSCs. Sodium channel activation (opening) allows

sodium ions to cross the plasma membrane and ent er the cell; this typically results in membrane

depolarization. In neurons, this results in initia tion of an action potential if sufficient numbers of

sodium channels are activated. Sodium channels normally inactivate, or close, after a very brief

time, limiting the time that the membrane is dep olarized. Pyrethroids modify VGSCs such that

they remain open for longer periods of time than under normal conditions. Type I pyrethroids

modify the channels such that there is a slight prolongation of the open time (i.e. sodium tail

currents of approximately 20 ms), often resultin g in long trains of action potentials. Type II

pyrethroids significantly prolong channel open ti me (sodium tail currents 200ms to minutes)

typically resulting in increased resting memb rane potential and often inducing depolarizationdependent block of action potentials. While this mode of action (MOA) clearly contributes to

pyrethroid neurotoxicity, all the steps between t hese changes in excitability at the cellular level

and the resulting behavioral syndrom e are not completely understood.

The pattern of toxicity is somewhat unique to th is class of pesticides and can be attributed to the

pharmacokinetic and pharmacodynamic properties. T he parent pyrethroid is the toxicologically

active compound. As such, no metabolic activation is required; instead, metabolism results in

detoxification. As evidenced by the rapid onset of toxicity, these pesticides are rapidly absorbed,

distributed, and cleared from the body. As show n in Figure 2, levels of deltamethrin, a Type II

pyrethroid, in brain tissue clearly peak 2-3 hour s post-dosing followed by a rapid decrease in

concentration (Godin et al., In Press ). In general, time course typifies the progression of signs in

mammalian species, which appear within 1 hour of sub-lethal oral exposure, peak within 4-8

hours, and recover in 12–48 hours (Wolansky and Harrill, 2008).

Pyrethroid neurotoxicity is correlated to peak conc entrations of pyrethroid. Research on a limited

number of them (i.e., deltamethrin, cismethrin , and bioresemethrin) has shown a direct link

between the concentration of pyrethroid in tissu e and neurotoxicity (Gray et al. 1980, White et al.,

1976). More recently, Wolansky et al. (2006) have demonstrated a dose-response relationship

for 11 pyrethroids (including Type I and Type II chemicals) following acute gavage dosing.

Increasing dose levels resulted in decreased moto r activity as measured during the time-to-peakeffect. The pharmacokinetics that determine spec ific tissue concentrations are critical and can

be greatly influenced by the manner of feeding (e .g., gavage vs. dietary feeding). The details of

how pharmacokinetics influence t he results of the DNT studies will be discus sed throughout this

document.

# January 20, 2010

Page 6 of 36 

# 0 4 8 12 16 20 24 0.001

0.01

0.1 

# Model Simulation

po 3mg/Kg

Time (h)Deltamethrin (ug/g)



# Figure 2. Model simulation and time course of brain concentration of deltamethrin after an oral dose.

Dashed line represents the simulation of the optimized diffusion-limited model. ▲ represents individual

data points after an oral dose (3 mg/kg) of deltamethrin (N=4). Adapted from Godin et al, in press.

Results of DNT Studies :

Clinical Effects and Neurotoxicity

Six DNTs are currently available for pyrethro ids; one Type I (bifenthrin), four Type II’s

(cyfluthrin, lambda-cyhalothrin, zeta-c ypermethrin, deltamethrin) and one mixed

syndrome pyrethroid (fenpropathrin). Thes e studies are summarized in Table 1.

Generally, the toxic effects to offspring obse rved in DNTs are decreases in pup weight,

pup weight gain, and/or brain weight. The Health Effects Division typically uses pup

weight decrements greater than 5% in DNT studi es as a response level of concern. In

five of six DNT studies, decreased pup weight and/or pup weight gain were noted at the

LOAEL. These decreases in pup weight measures were seen in combination with

indications of neurotoxicity in only two of the six studies (deltamethrin—vocalizations;

fenpropathrin—auditory startle), indicative that weight changes are a more sensitive

indicator of toxicity in the pups than are neurological effects.

Brain weight decrements of 6-7% were noted in three of six studies at the LOAEL (betacyfluthrin, lambda-cyhalothrin, fenpropathrin). For all three, the pup LOAELs from the

DNTs are similar to doses in other studies wh ere frank toxicity was noted. For example,

the pup LOAELs in the beta-cyfluthrin, la mbda-cyhalothrin, and fenpropathrin DNT

studies are 18, 10, and 19 mg/kg/day, respective ly. In a special FOB study conducted by

the Pyrethroid Working Group (PWG), at 12. 5 mg/kg, beta-cyfluthrin produced clonic

convulsions, abnormal posture, biting, and re sistance to handling; at 10 mg/kg, lambdacyhalothrin produced abnormal posture, resistance to removal, salivation, and abnormal

gait; and at 15 mg/kg, fenpropathrin resulted in tremors, abnormal posture, salivation,

and resistance to removal. Furthermore, fo r all three chemicals, the NOAELs from the

DNT studies were 1.5-10X greater than the NOAELs used to determine the RfD/PAD.

With some exceptions, the available guide line DNT studies do not show effects on

behaviors or parameters that are only meas ured in the DNT (e.g. learning, memory,

auditory startle, and brain morphometrics). For example, none showed changes in

learning or memory at any dose. Changes in auditory response were only observed in

fenpropathrin at the study LOAEL and in co mbination with decreased body weight and

absolute brain weight. Changes in brain mo rphometry were only observed for lambda-

# January 20, 2010

Page 7 of 36 

# cyhalothrin at a dose (10 mg/kg/day) wher e decreased pup survival and brain and body

weight decreases were also noted. At t he mid-dose (4.3 mg/kg/day) in the lambdacyhalothrin study, no effects were noted in pup s for any of these measures. The lambdacyhalothrin study is lacking measures of br ain morphometrics at the low- and mid-doses

and is deficient in motor activity measures . However, these parameters were not

affected at the low- or mid-dose in any of the other five DNT studies, decreasing our

concern for the missing measurements. Furthe rmore, the LOAEL of 10 mg/kg/day in the

lambda-cyhalothrin study is almost 10-fold higher than the dose at which neurotoxic

effects were reported by Wolansky et al. ( 2006), and is 100-fold higher than the NOAEL

used to derive the acute reference dose (RfD) and population adjusted dose (PAD).

Salivation, choreoathetosis, and tremors are ty pically associated with acute pyrethroid

toxicity. Salivation and choreoathetosis were not observed in any DNT study; however

tremors were observed in adults in the fenpro pathrin (24 out of 25 animals) and bifenthrin

(23 out of 25 animals) studies at the mater nal LOAELs. Tremors also occurred in the

pups for bifenthrin (6 out of 40). Unlike the adults, tremors were not seen in pups at the

LOAEL in any DNT study.

The results of the bifenthrin DNT study show a different pattern than the other studies.

For example, unlike the other pyrethroids, no decrements in body weight, body weight

gain, or brain weight were noted in pups for bi fenthrin. Furthermore, the bifenthrin DNT is

the only study to show tremors in pups and only at a dose above the LOAEL. Tremors

were observed in 6 pups out of 40 exami ned (4 males on post-natal day (PND) 10 and 2

females on PND 28) at the highest dose (9 mg/kg/day); the LOAEL was 7.2 mg/kg/day

based on increased grooming counts. No trem ors were observed at the mid- or lowdoses. The tremors in pups were gra ded as slight and only occurred on single

occasions. At 9 mg/kg/day, 23 out of 25 dams experienced tremors ranging from a few

incidents to multiple days. Therefore, it is not surprising that the pups which displayed

tremors were from litters whose dams also ex hibited tremors. On the other hand, there

was no correlation between the severity of tremors in the dams and the presence of

tremors in the pups.

Bifenthrin is the only pyrethroid DNT study with reported clinical signs (increased

grooming counts) in pups at the LOAEL. Howe ver, this reported increase in grooming

counts showed a weak do se-response and high variab ility in all dose groups.

Specifically, in the control and low-dose group s, mean counts were 0.4±0.8 and in the

mid- and high-dose groups, counts were 1.8±1.4 and 1.6±1.6, respectively. As such, the

standard deviations for each dose group were equal or greater than the respective

means and the incidence of counts shows a weak gradation in response.

The DNT is unique in that it provides quant ifiable measurements of learning and memory,

acoustic startle response, and brain mor phometrics. However, EPA’s review of the

available DNTs indicates that these parameters are not sensitive indicators of pyrethroid

toxicity. Rather, the offspring LOAELs in five of six studies were based on decreased

body weight and body weight gain. Some DN Ts do demonstrate occasional neurotoxic

effects (grooming counts, vocalizations, and tremors) but these effects do not

consistently appear for the pyrethroids tested. Furthermore, with the exception of

bifenthrin, the adverse effects observed in t he DNT are not consistent with pyrethroid

neurotoxicity. Additionally, t he effects noted in the DNTs were also observed in other

guideline studies (reproduction, acute n eurotoxicity, special FOB, subchronic

neurotoxicity, etc.) at simila r or lower doses compared to the DNTs. Thus, these DNT

studies provide little unique information on the hazard potential of these pesticides.

# January 20, 2010

Page 8 of 36 

# Sensitivity

As discussed briefly below, sufficient eviden ce exists to suggest pups may be more

susceptible to pyrethroid toxicity than adults (i.e . sensitivity). However, this sensitivity is

not consistently evident in the available DNTs. In four DNT studies (bifenthrin,

deltamethrin, fenpropathrin, and lambda-cyhalot hrin), adverse effects were observed in

pups at doses that were equal to or greater than doses which caused adverse effects in

dams (i.e., there was no evidence of increased se nsitivity in the offspring for these four).

In two of the six studies (beta-cyfluthrin and zeta-cypermethrin), effects in pups were

noted at lower doses than in the dams.

• For beta-cyfluthrin , there are four multigeneration reproduction studies available.

Similar to the results of t he beta-cyfluthrin DNT, three of the studies indicate pups

are more sensitive than the dams based on body weight changes. In the fourth

study, there were no toxic effects in th e parents or offspring. In addition,

decreased brain weight was observed at the pup LOAEL in the DNT, despite the

absence of maternal toxicity at this dose. The brain and body weight changes in

the DNT were observed at similar doses causing body weight changes in the

reproduction studies. Furthermore, tremors were not observed in the DNT but

were noted in the pups in two of the repr oduction studies at the LOAELs. Thus,

the DNT did not provide new information on the toxic potential of beta-cyfluthrin

when compared to the other guideline studies.

• For zeta-cypermethrin , there are three multigenera tion reproduction studies

available. In these studies, pup weight effects were seen at doses comparable to

dams; whereas, pup weight effects seen in the DNT study were observed at

lower doses than those that caused the sa me effect in the dams, and therefore

were considered evidence of increased susceptibility. Decreases in pup weight

gains were observed at 25, 27, and 37.5 mg /kg/day in the reproduction studies.

Pup weights were reduced in the DNT study at 17.3 mg/kg/day, a dose similar to

the dose at which these effects were seen in the reproduction studies. Maternal

weights were also decreased in all of the studies at these same doses. Maternal

weight effects were typically <10% different from respective controls, while pup

weight effects varied from 5 to 21% below control values among all studies,

including the DNT. The effect on maternal weight was not considered adverse in

the DNT, and therefore, t he decreased pup weight was categorized as increased

sensitivity. While the DNT is the only zeta-cypermethrin study to indicate

increased sensitivity in the pups, the results from the DNT and reproduction

studies, which did not indicate increased su sceptibility, are actually very similar.

In this instance, the DNT did not provi de new information on the toxic potential of

zeta-cypermethrin when compared to the other guideline studies.

Therefore, while the beta-cyfluthrin and zeta -cypermethrin DNT studies did indicate some

potential increased sensitivity in the offspr ing based on body weight changes, similar

effects were also observed in multigeneration reproduction studies for these two

pyrethroids. Moreover, the reproductive toxi city studies for beta-cyfluthrin noted tremors

in pups that were not observed in the DNT. When taken together, the results of all six

DNT studies provided no new information on the hazard of these pyrethroids or the

potential for sensitivity in pups beyond what was already understood from other guideline

toxicity studies. It is also important to note that the findings of the DNTs are not

consistent with literature studies suggesting that juveniles may indeed be more sensitive

than adults. These literature studies are discus sed in detail in Shafer et al. (2005) and

are summarized briefly below.

# January 20, 2010

Page 9 of 36 

# Critical Effects Select ed for Risk Assessment:

Points of departure and critical effects used in ri sk assessments for the pyrethrins and pyrethroids

are provided in Table 1. Neurotoxicity consis tent with the pyrethroid MOA is more commonly

observed in acute neurotoxicity studies in rats and/or acute and chronic studies in dogs and

therefore these studies frequently pr ovide the most sensitive endpoint s for this class. Neurotoxic

effects have been selected by OPP as regulatory endpoints to derive reference doses (RfDs) or

population adjusted doses (PADs) for use in single chemical risk assessments. None of the six

DNTs have been used for endpoint and dose selectio n for dietary risk assessments. Only one

DNT study was used to identify a point of departure (PoD) for the short- and intermediate-term

incidental oral and dermal endpoint (children only ) (i.e. zeta-cypermethrin) based on decreased

body weight and body weight gain in pups.

The studies used for selection of PoDs, acute neurot oxicity in rats and/or dog studies, administer

pyrethroids in a bolus dose. Acute neurotoxicit y studies are administered via oral gavage and the

dog studies may either be administered via capsule or in the food. Although mixing the pyrethroid

with food in the chronic dog studies may appear similar to subchronic or chronic rat feeding

studies, because dogs tend to consume their meal s quickly over a few minutes, the chemical is

ingested over a very shor t period of time. In contrast, during dietary administration, rats will eat

over several hours, resulting in a much longer pe riod of feeding. Therefore, the dose span for the

acute neurotoxicity study in rats and dog studies covers only a few seconds to minutes, while the

dose is consumed over several hours in rat feeding studies.

As discussed in the Mode of Action section, pyrethroids are ra pidly absorbed, distributed and

cleared from the body and neurotox icity is correlated with peak co ncentrations. Therefore, the

gavage and bolus feeding patterns result in greater internal doses (i.e., amount of pyrethroid

reaching the target site) compared to rodent dietary administration, resulting in lower PoDs. For

risk assessment, PoDs were based on neurotoxic endpoints from acute and bolus studies and

are protective of neurotoxic effects observed in the dietary administration DNT studies.

Key Literature Studies on Juvenile Sensitivity:

Data from studies published in the open literatur e suggest that juveniles may be more sensitive

than adults to direct administration of pyrethroids. Possible sources of the increased sensitivity in

pups include age-related pharmacokinetic (PK) and pharmacodynamic (PD) differences. With

respect to differences in pharmacokinetic properti es, potential sensitivity of young animals is likely

attributable to incomplete maturation of the enzym e systems that detoxify pyrethroids, particularly

the carboxylesterases and cytochrome P450s. Consequently, pyrethroid concentrations in the

target tissue (e.g., brain) may be higher in young animals than in adults given the same

administered dose. Sheets et al. (1994) examined the effects of deltamethrin on auditory startle

response in PND 21 and PND 72 rats. At 4 mg/kg, there was no difference in the startle

response between these two age groups. However, deltamethrin brain concentrations were

approximately 2-fold higher in the PND 21 compar ed to the PND 72 rats suggesting a possible

functional difference. In examining the letha lity of deltamethrin on PND 11, 21, and 72 rats, the

LD50 was lowest in the PND 11 ra ts (5.1 mg/kg) and increased as the rats aged; in PND 21 rats

the LD50 (median lethal dose) was 11 mg/kg, and in PND 72 rats it was 81 mg/kg. The

deltamethrin brain concentrations were similar between weanlings receiving an LD50 dose of 11

mg/kg and adults receiving an LD50 dose of 81 mg/kg. Therefore, although the younger pups

received a much lower dose of deltamethrin compared to the adults, brain concentrations were

similar between the two age groups. The comparable brain concentrations despite large

differences in dose supports the conclusion t hat age-dependent pharmacokinetics plays a major

role in increased pup sensitivity to acute deltamethrin toxicity (Sheets et al., 1994).

Similarly, Cantalamessa (1993) treated juven ile (PND 8, 16 and 21) and adult rats with

cypermethrin and permethrin and found an inverse relationship between toxicity and age; the

# January 20, 2010

Page 10 of 36 

# pyrethroids were most toxic to the youngest animals. Furthermore, Cantalamessa (1993)

pretreated juvenile and adult rats with either tri- o-tolyl phosphate (TOTP), an esterase inhibitor, or

piperonyl butoxide (PB), a monooxygenase inhibitor. Pretreatment with either TOTP or PB had

no effect on juvenile mortality. In adults, pretreat ment with TOTP caused a significant increase in

cypermethrin and permethrin mortality while pret reatment with PB had no effect. Cantalamessa

(1993) concluded that lack of response in the pretreated neonate rat is likely due to incomplete

development of the ester hydrolysis det oxification pathway in young animals.

The data from Sheets et al. (1994) and Cantalames sa (1993) are consistent with more recent in

vitro data. Anand et al. (2006) demonstrated the in vitro metabolism of deltamethrin by plasma

carboxyesterases, hepatic carboxyesterases, and hepatic microsomes were 6, 35, and 7 times

higher for PND 90 rats than PND 10 rats. However, the Sheets et al. (1994, 2000) and

Cantalamessa (1993) studies used high doses, often at or near lethality. It is unknown whether

such sensitivity would occur at lower doses more relevant for human health risk assessment. For

example, following a single dose with deltamethrin at 0.4, 2, or 10 mg/kg in adult rats, brain

concentrations were 5-fold greater in the 2 and 10 mg/kg groups compared to the 0.4 mg/kg

group after 2 hours (Kim et al., 2008). Furthermore, while half-life values for tissues were very

similar for the 2 and 10 mg/kg doses, ranging from 10 hours in the blood to 200 hours in the fat,

half-life values were not generated for any tissue in 0.4 mg/kg dose due to the rapid metabolism

and elimination. Therefore, exposure to pyrethro ids at lower environmental concentrations is not

likely to lead to accumulation and is more similar to a series of acute exposures than to a chronic

exposure. EPA is currently developing a delta methrin physiol ogically-based pharmacokinetic

(PBPK) model to evaluate differences in tissue dosimetry for rats ranging from PND 10 to PND 90

based on available time course data of doses that ranged from 0.4 to 10 mg/kg. This model

predicts an approximately 3-fold increase in deltamethrin brain concentration in juvenile rats

compared to adults.

With respect to pharmacodynamics, disruption of voltage-gated sodium channel (VGSC) is a key

event in pyrethroid neurotoxicity. Multiple is oforms of the VGSC exist and are expressed in a

tissue, region and developmentally specific fashion. Evidence is unclear about whether there are

differences in sensitivity between the VGSC isof orms since the isoform of the sodium channel

differs between fetal and post-natal rats. The dev elopmentally expressed isoforms of the VGSC

transition to the adult isoforms between birth and PN D 6-10 in rodents. Recent studies indicate

that one rodent VGSC isoform that is highly ex pressed primarily during embryonic periods may

be more sensitive than one isoform that is highly expressed in the adult nervous system, but this

sensitivity may be concentration dependant (Meacham et al., 2008). In addition, the

developmentally expressed isoform of human VGSC s may be less sensitive than are the VGSCs

expressed in adult or juvenile rats (Tan and Soderlund, 2009). The data in Tan and Soderlund

(2009) suggest that one human VGSC isoform is less sensitive than its analog in rats with respect

to pharmacodynamic characteristics. However, addi tional studies with the other isoforms widely

expressed in nervous tissue are necessary bef ore a general conclusion can be made regarding

species-specific pharmacodynamic differences. Mo re information is available in a review by

Shafer et al. (2005) on developmental neurotoxicity and sensitivity in juveniles to pyrethroids.

Based on this information, the Agency finds t here is sufficient evidence to assume increased

susceptibility of juveniles to pyrethroid toxicity due to age-dependent pharmacokinetic

mechanisms. The currently available DNT stud ies do not provide any additional information

beyond the standard reproductive guideline studies in this regard, and none of DNT studies

include direct dosing to the young prior to weaning, for which there is greater evidence of

sensitivity differences.

# January 20, 2010

Page 11 of 36 

# Weight of the Evidence:

It has been established that pyrethroids share a common mechanism of action: interaction with

the voltage-gated sodium channels leading to neuroto xicity. As previously discussed, differences

between Type I and II compounds in their interactions with VGSC produce different effects on

membrane excitability (repetitive firing for Type Is and depolarization-dependent action potential

block for Type IIs). These differences in action at the cellular level are the basis for acute toxicity

characterized by either fine tremors (T-syndr ome/Type I pyrethroids) or choreoathetosis and

salivation (CS-syndrome/Type II pyrethroids), alth ough not all steps between cellular changes in

excitability and behavior are well understood.

The ability to evaluate this mechanism of toxicity using Agency Guideline studies is paramount to

producing an effective and relevant risk assessment. Several factors weigh into the ability of the

DNT to effectively contribute to this decision, including the pharmacokinetics of pyrethroids and

implications for toxicity and potential juvenile sensitivity to acute pyrethroid toxicity.

The pharmacokinetic properties of pyrethroids le ad to rapid absorption and elimination. Since

neurotoxicity is correlated to peak concentrations in tissue, signs of acute neurotoxicity progress

rapidly. A general time course typifying the progression in mammalian species includes signs of

toxicity appearing within 1 hour of sub-lethal oral exposure, peaking within 4-8 hours, and

recovering in 12–48 hours.

Consistent with this pattern of toxicity, studies that administer the pyrethroids in a bolus dose

more frequently provide the most sensitive endpoints. In dietary administration studies like the

DNT study, rats are exposed to the pesticide over seve ral hours of feeding. This is in contrast to

a bolus dose in gavage studies where the entire dose is given at one time. In the dietary studies,

the total administered dose of the pyrethroid consumed may be equal to or even higher than the

gavage dose. However, it is the internal dose at the target tissues which is related to the

magnitude of toxicity. Due to the rapid metabolism and clearance in the dietary studies,

pyrethroids do not reach a peak level at the target tissues as high as in gavage studies and thus

the degree of toxicity in dietary studies is far less than that for gavage studies. As a result, acute

gavage studies tend to be far more sensitiv e than dietary studies for pyrethroids.

Chemicals with a small window of time-to-peak-effect such as the pyrethroids are difficult to

evaluate using dietary studies such as the DNT. Th is difficulty stems from the following: 1) the

DNT does not consider a time-to-peak-effect and therefore may miss the window of peak toxicity,

and 2) the dietary administration results in lower internal doses compared to gavage studies. In

the more robust studies the Agency has to evaluate pyrethroid toxicity, the Wolansky et al. (2006)

acute motor activity study and the Pyrethroid Working Group (PWG) modified Functional

Observational Battery (FOB) study, the investigat ors carefully determined the time-to-peak-effect

following an acute dose. While the PWG FOB study was not designed to determine threshold

effects, studies that were, such as the Wolansky et al. (2006) motor activity study and Sheets et

al. (1994), resulted in lower effective doses co mpared to guideline studies. For example, the

Wolansky et al. (2006) study indicated a no-effect level of 1 mg/kg for deltamethrin and the

Sheets et al. (1994) study produced an ED50 (effe ctive dose 50%) of 4 mg/kg based on auditory

startle response. The no-effect level in the del tamethrin DNT is higher, at 6.8 mg/kg/day.

Until more evidence becomes available, the Agency currently assumes juveniles have an

increased susceptibility to acute pyrethroid toxicity based on lit erature direct-dos ing studies such

as Sheets et al. (1994), Cantalamessa (1993), and Anand et al. (2006). Based on the Agency’s

analysis of available DNT studies, the role ofpharmacokinetics, and the lack of a chemicalspecific time-to-peak-effect window in the DNT st udy, the DNT is not likely to be able to identify or

characterize increased juv enile susceptibility.

In addition to the pharmacokinetic issues relat ed to the feeding study design, there is a high

degree of variability commonly observed in DNT studi es. It is not unusual for standard deviations

# January 20, 2010

Page 12 of 36 

# to exceed the mean value for many measuremen ts in the DNT. This variability has been

described in Tyl et al. (2008) and complicates the review and interpretation of these studies.

The six DNTs are valuable in that they allow the Agency to better focus our inquiry regarding

neurotoxic effects of pyrethroids in juveniles on effects relevant to the mechanism of action and

pharmacokinetics. This focus would not be possibl e in the absence of the six DNT results.

Although they are useful in terms of weight-of- evidence considerations, the pyrethroid DNT

studies have not made a significant impact in det ermining the points of depa rture for use in risk

assessment for these pesticides. Instead, clinic al signs of neurotoxicity and body weight effects

observed in other guideline studies provide the critical endpoints.

Conclusions

Based on the scientific evidence summarized in this document, the Agency believes that

conducting additional DNT studies on pyrethroids will not contribute new information which is

relevant for risk assessme nt, since EPA believes the available data will appropriately characterize

potential relevant results of c onducting a DNT for any pyrethroid. Thus, EPA is hopeful that the

registrants with DNT requirements will choose to cite the existing database to satisfy the DNT

requirement rather than devoting new substantial resources (ani mal use, laboratory time, EPA

review resources, etc.) associated with conduct ing and evaluating new DNT studies. However,

scientific evidence does indicate a continued conc ern for possible differential sensitivity with

direct dosing in juveniles compared with adults. Thus, there is a need for additional information to

inform these concerns.

As observed with organophosphates and N -methyl carbamate pesticides, the DNT is not a

particularly sensitive study for evaluating compar ative sensitivity of young animals to adults for

pyrethroids. This is further evidenced by the Sheets et al. (1994) study which demonstrates a

greater sensitivity of pups compared to adults for lethal doses of deltamethrin; sensitivity which

was not observed in the deltam ethrin DNT. The importance of focused experimentation on

pyrethroid-specific effects related to the MOA and pharmacokinetic characteristics of pyrethroids

has also been shown in the modified FOB study supported by the Pyrethroid Working Group.

The Agency is currently evaluat ing what additional experimentation on pyrethroid-specific effects

related to the MOA and pharmacokinetic charac teristics and comparative sensitivity between

juveniles and adults may be necessary. The A gency will continue to communicate with the

pyrethroid registrants and other stake- holders as additional action is needed.January 20, 2010Page 13 of 36Table 1. Points of Departure (PODs)for Pyrethroid and Pyrethrin SingleChemical Aggregate Risk AssessmentsPyrethroidname(PC Code)(Type I/II/mixed)Acute RfD*Chronic RfD*Incidental Oral*Dermal*Inhalation*DevelopmentalNeurotoxicityStudy (DNT)*Allethrin; SBioallethrin(004003,004004)(Type I)Acute Dietary,generalpopulation=0.03(AcuteNeurotoxicity studyrats (30/90)#based on tremors,hunched posture,abnormal gait,decreased gripstrength.ChronicDietary=0.0086-Month dog(BMDL10= 8)based onhepatocellulardegenerationShort-termRange-finding dog(20/63) based onelevated liverenzymes andincreased liverweights.Intermediate-term6-month dog(BMDL10= 8)based onhepatocellulardegenerationShort-andintermediateterm, generalpopulation notrequired.Short-,intermediate-,and long-term28 day inhalationrat: (1.3/6.5) basedon limb tremors,hunched posture,vocalizationsduring handling.Residential andOccupationalexposure.N/AJanuary 20, 2010Page 14 of 36Table 1. Points of Departure (PODs)for Pyrethroid and Pyrethrin SingleChemical Aggregate Risk AssessmentsPyrethroidname(PC Code)(Type I/II/mixed)Acute RfD*Chronic RfD*Incidental Oral*Dermal*Inhalation*DevelopmentalNeurotoxicityStudy (DNT)*Bifenthrin(128825)(Type I)Acute Dietary,generalpopulation=0.33Acute neurotoxicityin rats (32.8/70.3)based onobservations ofmortality (femalesonly), clinical andFOB findings anddifferences inmotor activityChronicDietary=0.0131-year dog(1.3/2.7) based onobservations ofincreasedincidence oftremors in bothsexesShort-andintermediate-term90-day dog(2.2/4.4) basedincreasedincidence oftremors in bothsexesShort-,intermediate-,and long-term21-day dermal rat(47/93) based onstaggered gait andexaggerated hindlimb flexionResidential andOccupationalexposure.Short-andintermediate-term90-day dog(2.2/4.4) basedincreasedincidence oftremors in bothsexesLong-term1-year dog(1.3/2.7) based onincreasedincidence oftremors in bothsexesResidential andOccupationalexposure.Maternal(3.6/7.2) based ontremors,convulsions,increasedgrooming counts;Offspring(3.6/7.2) based onincreasedgrooming countsJanuary 20, 2010Page 15 of 36Table 1. Points of Departure (PODs)for Pyrethroid and Pyrethrin SingleChemical Aggregate Risk AssessmentsPyrethroidname(PC Code)(Type I/II/mixed)Acute RfD*Chronic RfD*Incidental Oral*Dermal*Inhalation*DevelopmentalNeurotoxicityStudy (DNT)*Cyfluthrin(128831)(Type II)Acute Dietary,generalpopulation=0.02Acute neurotoxicityin rats (2/10)based on gaitincoordination,decreased activity,writhing, salivationand decreasedmotor activityChronicDietary=0.0241-year dog(2.4/10.64) basedon clinical signs,gait abnormalities,abnormal postureShort-,intermediate-,and long-term90-day dog(2.4/13.9) basedon vomiting, gaitabnormalities,decreased bodyweight gainShort-,intermediate-term90 day dog(2.4/13.9) basedon vomiting, gaitabnormalities,decreased bodyweight gainLong-term1-year dog(2.4/10.64) basedon clinical signs,gait abnormalities,abnormal postureResidential andOccupationalexposure.Short-term28-day rat(0.07/0.73) basedon decreases inbody weight anddecreased urinarypH in malesIntermediate-andlong-term(90-dayinhalation rat(0.02/0.16) basedon decreases inbody weight inmales and clinicalsigns in femalesResidential andOccupationalexposure.N/ACyfluthrin,beta-(118831)(Type II)Same as cyfluthrin Same as cyfluthrin Same as cyfluthrin Same as cyfluthrin Same as cyfluthrinMaternal(17.8/ND)Offspring(11/17.8) based ondecreasedBW/BWG & brainweight in femalesJanuary 20, 2010Page 16 of 36Table 1. Points of Departure (PODs)for Pyrethroid and Pyrethrin SingleChemical Aggregate Risk AssessmentsPyrethroidname(PC Code)(Type I/II/mixed)Acute RfD*Chronic RfD*Incidental Oral*Dermal*Inhalation*DevelopmentalNeurotoxicityStudy (DNT)*Cyhalothrin(128867)(Type II)Acute Dietary,generalpopulation=0.0051-year dog;lambda cyhalothrin(0.5/ 3.5) based onataxia observedfrom day 2.ChronicDietary=0.0011-year dog;lambda cyhalothrin(0.1/0.5) based ongait abnormalities.Short- andintermediate-term1-year dog;lambda cyhalothrin(0.1/0.5) based ongait abnormalities.Short-,intermediate-,and long-term21-day dermal rat;lambda cyhalothrin(10/50) based onneurotoxicity(reduced splayreflex and stability,and splayed gait),decreases in bodyweight gain.Residential andOccupationalexposure.Short-,intermediate-,and long-term21-day inhalationrat; lambdacyhalothrin(0.08/0.90) basedon neurotoxicity(salivation,lacrymation, andsplayed gait),decreases in bodyweight gain,punctuate foci inthe cornea,changes inurinalysis, anddecrease incholesterol.Residential andOccupationalexposure.N/AJanuary 20, 2010Page 17 of 36Table 1. Points of Departure (PODs)for Pyrethroid and Pyrethrin SingleChemical Aggregate Risk AssessmentsPyrethroidname(PC Code)(Type I/II/mixed)Acute RfD*Chronic RfD*Incidental Oral*Dermal*Inhalation*DevelopmentalNeurotoxicityStudy (DNT)*Cyhalothrin,lambda-(128897)(Type II)Same ascyhalothrinSame ascyhalothrinSame ascyhalothrinSame ascyhalothrinSame ascyhalothrinMaternal(4.3/10) based ondecreasedBW/BWG & FC;OffspringAlthough toxicityseen at 10mg/kg/day,definitiveNOAEL/LOAELnot determineddue todeficiencies.Cyhalothrin,gamma-(128807)(Type II)Acute Dietary,generalpopulation=0.0021-year dog;lambda cyhalothrin(0.25/3.5) basedon ataxia observedfrom day 2.Same ascyhalothrinSame ascyhalothrinSame ascyhalothrinSame ascyhalothrinN/AJanuary 20, 2010Page 18 of 36Table 1. Points of Departure (PODs)for Pyrethroid and Pyrethrin SingleChemical Aggregate Risk AssessmentsPyrethroidname(PC Code)(Type I/II/mixed)Acute RfD*Chronic RfD*Incidental Oral*Dermal*Inhalation*DevelopmentalNeurotoxicityStudy (DNT)*Cypermethrin(109702)(Type II)Acute Dietary,generalpopulation=0.1Acute neurotoxicityin rats (10/50)based on soiledfur, abnormalposture, splayedhindlimbs,impaired gait, andconvulsions.ChronicDietary=0.061-year dog(6/18.1) based ondecreasedBW/BWG infemales; mortality,tremors, irregulargait, and salivationin males.Short- andintermediate-termDevelopmentalNeurotoxicity(7.40/17.30) basedon decreased BW.Short-andintermediateterm, generalpopulation notrequiredLong-term,generalpopulation1-year dog(6/18.1) based ondecreasedBW/BWG infemales; mortality,tremors, irregulargait, and salivationin males.Short- andintermediate-termchildrenDevelopmentalNeurotoxicity(7.40/17.30) basedon decreased BW.Short-,intermediate andlong-term21-day ratinhalation(0.01/0.05 mg/L)based ondecreases in BWand salivation.Residential andOccupationalexposure.N/AJanuary 20, 2010Page 19 of 36Table 1. Points of Departure (PODs)for Pyrethroid and Pyrethrin SingleChemical Aggregate Risk AssessmentsPyrethroidname(PC Code)(Type I/II/mixed)Acute RfD*Chronic RfD*Incidental Oral*Dermal*Inhalation*DevelopmentalNeurotoxicityStudy (DNT)*Cypermethrin,zeta-(129064)(Type II)Same ascypermethrinSame ascypermethrinSame ascypermethrinSame ascypermethrinSame ascypermethrinMaternal(7.3/ND);Offspring(7.4/17.3) basedon decreasedBW/BWG.Cyphenothrin(129013)(Type II)N/A N/AShort- andintermediate-term90-day dog (10/30)based emesis,tremors, andreddish/palemucosaShort- andintermediate-term90-day dog (10/30)based emesis,tremors, andreddish/palemucosaResidential andOccupationalShort- andintermediate-term90-day dog (10/30)based emesis,tremors, andreddish/palemucosaResidential andOccupationalN/ADeltamethrin(097805)(Type II)Acute Dietary, Allpopulations=0.01Wolansky et al.,2006: (1/3) basedon reduced motoractivity.ChronicDietary=0.01Wolansky et al.,2006: (1/3) basedon reduced motoractivity.Short-,intermediateterm, allpopulationsWolansky et al.,2006: (1/3) basedon reduced motoractivity.Short-,intermediate- andlong-term, allpopulationsWolansky et al.,2006: (1/3) basedon reduced motoractivity.Residential andOccupationalexposure.Short-,intermediate- andlong-term, allpopulationsWolansky et al.,2006: (1/3) basedon reduced motoractivity.Residential andOccupationalexposure.Maternal(6.8/16.1) basedon decreasedBW/BWG and FC;Offspring(6.8/16.1) basedon decreasedBW/BWG,vocalizations, anddecreased fixedbrain weight.January 20, 2010Page 20 of 36Table 1. Points of Departure (PODs)for Pyrethroid and Pyrethrin SingleChemical Aggregate Risk AssessmentsPyrethroidname(PC Code)(Type I/II/mixed)Acute RfD*Chronic RfD*Incidental Oral*Dermal*Inhalation*DevelopmentalNeurotoxicityStudy (DNT)*Esfenvalerate(109303)(mixed)Acute Dietary,generalpopulation=0.002Acute neurotoxicitystudy in rats(1.75/1.90) basedon tremors.ChronicDietary=0.002Acute neurotoxicitystudy in rats(1.75/1.90) basedon tremors.Short-,intermediate-termAcute neurotoxicitystudy in rats(1.75/1.90) basedon tremors.Short-,intermediate- andlong-term,21-day dermal(25/125) based onabnormal hindlimbgait.Residential andOccupationalexposure.Short-,intermediate, andlong-termAcute neurotoxicitystudy in rats(1.75/1.90) basedon tremors.Residential andOccupationalexposure.N/AJanuary 20, 2010Page 21 of 36Table 1. Points of Departure (PODs)for Pyrethroid and Pyrethrin SingleChemical Aggregate Risk AssessmentsPyrethroidname(PC Code)(Type I/II/mixed)Acute RfD*Chronic RfD*Incidental Oral*Dermal*Inhalation*DevelopmentalNeurotoxicityStudy (DNT)*Fenpropathrin(127901)(mixed)Acute Dietary,generalpopulation=0.06Developmental rat(6/10) based onataxia, sensitivityto extreme stimuli,spastic jumpingand tremors.ChronicDietary=0.0251-year dog(2.5/6.25) basedon tremors andataxia.N/AShort-,intermediate-,and long termReproduction rat(3/8.9) based onclinical signs andmortality.Occupationalexposure only.Short-,intermediate-,and long termReproduction rat(3/8.9) based onclinical signs andmortality.Occupationalexposure only.Maternal(8-16/19-40) (gestationlactation) based ontremors;OffspringNOAEL/LOAEL=(8-16/19-40)(gestationlactation) based onsmall pup size,decreasedBW/BWG,increasedmaximum &average startleresponseamplitude(females), anddecreased brainweight (males).Fenvalerate(109301)(Type II)same asesfenvaleratesame asesfenvaleratesame asesfenvaleratesame asesfenvaleratesame asesfenvalerateN/AJanuary 20, 2010Page 22 of 36Table 1. Points of Departure (PODs)for Pyrethroid and Pyrethrin SingleChemical Aggregate Risk AssessmentsPyrethroidname(PC Code)(Type I/II/mixed)Acute RfD*Chronic RfD*Incidental Oral*Dermal*Inhalation*DevelopmentalNeurotoxicityStudy (DNT)*Tau-fluvalinate(109302)(Type II)Acute Dietary,generalpopulation=0.005Chronic rat andsubchronicneurotoxicity(0.5/1) based onexcessivesalivation,lacrimation,pawing,hyper/hypoactivity, abnormalstance, andruffling.Chronic Dietary,generalpopulation=0.005Chronic rat andsubchronicneurotoxicity(0.5/1) based onexcessivesalivation,lacrimation,pawing,hyper/hypoactivity, abnormalstance, andruffling.N/A N/AShort-,intermediate-,and long termChronic rat andsubchronicneurotoxicity(0.5/1) based onexcessivesalivation,lacrimation,pawing,hyper/hypoactivity, abnormalstance, andruffling.Occupationalexposure only.N/AJanuary 20, 2010Page 23 of 36Table 1. Points of Departure (PODs)for Pyrethroid and Pyrethrin SingleChemical Aggregate Risk AssessmentsPyrethroidname(PC Code)(Type I/II/mixed)Acute RfD*Chronic RfD*Incidental Oral*Dermal*Inhalation*DevelopmentalNeurotoxicityStudy (DNT)*Imiprothrin(004006)(Type II)N/A N/A N/A N/AShort-,intermediate-,and long-term28 day inhalationrat (0.022/0.186mg/L) based onincreasedincidence ofclinical signsindicating effectson the nervoussystem, decreasesin BWG, hemolyticanemia, increasein relative liverweights, dark liver,increase inabsolute andrelative salivarygland weights andhyperplasia ofacinous cells.N/AJanuary 20, 2010Page 24 of 36Table 1. Points of Departure (PODs)for Pyrethroid and Pyrethrin SingleChemical Aggregate Risk AssessmentsPyrethroidname(PC Code)(Type I/II/mixed)Acute RfD*Chronic RfD*Incidental Oral*Dermal*Inhalation*DevelopmentalNeurotoxicityStudy (DNT)*Metofluthrin(109709)(Type I)N/A N/AShort-termDevelopmental rat(15/30) based ontremors in adults.N/AShort-term28 day inhalationrat (0.099/0.196mg/L) based onmortality, tremors,ataxia,hypersensitivity,gait changes,lateral position,convulsions, andhypothermia inboth sexes.Occupationalexposure only.N/APermethrin(109701)(Type I)Acute Dietary,generalpopulation=0.025Acute neurotoxicityin rats (25/75)based onaggression,abnormal/decreased movement andincreased bodytemperature.ChronicDietary=0.025Acute neurotoxicityin rats (25/75)based onaggression,abnormal/decreased movement andincreased bodytemperature.Short- andintermediate-termAcute neurotoxicityin rats (25/75)based onaggression,abnormal/decreased movement andincreased bodytemperature.Short-,intermediate- andlong-term21-day dermal(500/ND)Residential andOccupationalexposure.Short-,intermediate- andlong-term15 day inhalationrat (0.042/ 0.583mg/L) based ontremors andhypersensitivity.Residential andOccupationalexposure.N/AJanuary 20, 2010Page 25 of 36Table 1. Points of Departure (PODs)for Pyrethroid and Pyrethrin SingleChemical Aggregate Risk AssessmentsPyrethroidname(PC Code)(Type I/II/mixed)Acute RfD*Chronic RfD*Incidental Oral*Dermal*Inhalation*DevelopmentalNeurotoxicityStudy (DNT)*Prallethrin(128722)(Type II)Acute Dietary,generalpopulation=0.051-year dog (5/10)based on tremorsweek 1.Chronicdietary=0.051-year dog (5/10)based ontrembling, rapideye, blinking, andhunched posture.Short- andintermediate-term1-year dog (5/10)based ontrembling, rapideye, blinking, andhunched posture.Short-,intermediate- andlong-term21-day dermal(30/150) based onfixation, abnormalgait, tremors,sensitivity toexternal stimuli,vocalization,twitching andwrithing, andspasms.Residential andOccupationalexposure.Short-,intermediate- andlong-term28 day inhalationrat (0.0010/0.0044mg/L) based onirregularrespiration,decreasedspontaneousactivity, nasaldischarge,salivation, andincontinence.Residential andOccupationalexposure.Range findingcompleted.January 20, 2010Page 26 of 36Table 1. Points of Departure (PODs)for Pyrethroid and Pyrethrin SingleChemical Aggregate Risk AssessmentsPyrethroidname(PC Code)(Type I/II/mixed)Acute RfD*Chronic RfD*Incidental Oral*Dermal*Inhalation*DevelopmentalNeurotoxicityStudy (DNT)*Pyrethrins(069001,069004, 069006,069012,869001)(not synthetic)Acute Dietary,generalpopulation=0.07Acute neurotoxicityin rats (20/63)based on tremors.ChronicDietary=0.04Chronic rat(4.37/43.9) basedon an increasedincidence ofthyroid follicularcell hyperplasia inmales.Short-termAcute neurotoxicityin rats (20/63)based ontremors.infemales.Intermediate-termReproduction in rat(6.4/65) based ondecreased F1bpup weights duringlactation.Short-andintermediateterm, generalpopulation notrequired.Short-,intermediate- andlong-term90-day inhalationrat (0.03/0.1 mg/L)based on tremors,labored breathing,hyperactivity,secretory signs,matted coat, anddecreasedBW/BWG.N/AResmethrin(097801)(Type I)N/AChronicdietary=0.35Reproduction rat(35/ 70.8) basedon decreasedmating index,decreased viabilityindex, anddecreased pupweight.Short- andintermediate-termDevelopmental rat(40/ 80) based ondecreased bodyweight gain andfood consumption.Short-,intermediateterm, and longtermDevelopmentalrabbit (30/100)based on skeletalvariations,possible marginalincrease inresorbed litters.Residential andOccupationalexposure.Short-,intermediate-,and long-term90-day inhalationrat (ND/ 0.1 mg/L)based ondecreased glucoselevels in males,decreased bodyweight gain, andincreased BUN.Residential andOccupationalexposure.N/AJanuary 20, 2010Page 27 of 36Table 1. Points of Departure (PODs)for Pyrethroid and Pyrethrin SingleChemical Aggregate Risk AssessmentsPyrethroidname(PC Code)(Type I/II/mixed)Acute RfD*Chronic RfD*Incidental Oral*Dermal*Inhalation*DevelopmentalNeurotoxicityStudy (DNT)*Sumithrin (dphenothrin)(069005)(Type II)Acute Dietary,females 13-49=0.03Dev Rabbit(30/100) based onspina bifidaChronicDietary=0.0071-year dog(7.1/26.8) basedon hepatocellularenlargement in theliver and focaldegeneration inthe adrenal cortexin both sexesShort- andintermediate-termReproduction rat(50/ 150) baseddecreased bodyweight, increasedliver weight inparental animals,and an increase inspleen weight,decreased uterineweight in F1adults, decreasedbody weight gainduring lactation ofF2b pups,decreased littersize of F1b littersat day 1,decreasedabsolute heart andkidney weight inF2b males,increased liverweight in male andfemale F2b pups.Short-andintermediateterm, generalpopulation notrequired.Short-,intermediateterm, allpopulations90-day inhalationrat (26.6/75) basedon nasalhistopathology.Residential andOccupationalexposure.N/AJanuary 20, 2010Page 28 of 36Table 1. Points of Departure (PODs)for Pyrethroid and Pyrethrin SingleChemical Aggregate Risk AssessmentsPyrethroidname(PC Code)(Type I/II/mixed)Acute RfD*Chronic RfD*Incidental Oral*Dermal*Inhalation*DevelopmentalNeurotoxicityStudy (DNT)*Tefluthrin(128912)(Type I)Acute Dietary,generalpopulation=0.0051-year dog (0.5/2)based on tremorsChronicDietary=0.0051-year dog (0.5/2)based on tremorsN/AShort-,intermediateterm, and longterm1-year dog (0.5/2)based on tremorsShort-andintermediate, andlong-term notrequired.N/ATetramethrin(069003)(Type I)N/A N/AShort-termReproduction rat(25/150) based ondecreased bodyweight and foodconsumption, bileduct hyperplasia inF1 malesShort-andintermediateterm, generalpopulation notrequired.Short-,intermediate-term90-day inhalationrat (3.5/23.5)based onincreased clinicalsigns, kidney andliver weights,decreased bodyweight, changes inhematology andurinalysis, liverhypertrophy andgross necropsyfindings, hyalinedroplets in kidneyOccupationalexposure only.N/AJanuary 20, 2010Page 29 of 36Table 1. Points of Departure (PODs)for Pyrethroid and Pyrethrin SingleChemical Aggregate Risk AssessmentsPyrethroidname(PC Code)(Type I/II/mixed)Acute RfD*Chronic RfD*Incidental Oral*Dermal*Inhalation*DevelopmentalNeurotoxicityStudy (DNT)*Tralomethrin(121501)(Type II)Acute Dietary,generalpopulation=0.011-year dog(0.75/3) based ondecreased BW,tremors, ptyalism.[0.75 raised to 1.0at 14 weeks withno effectsChronicDietary=0.011-year dog(0.75/3) based ondecreased BW,tremors, ptyalism.[0.75 raised to 1.0at 14 weeks withno effectsN/AShort-andintermediateterm, generalpopulation notrequired.Not available N/ANOAEL – No Observed Adverse Effect Level; LOAEL– Lowest Observed Adverse Effect Level; BMDL10– Benchmark Dose Lower Confidence Level 10%; BW/BWG – Body Weight/Body WeightGain; ND – Not Determined; N/A – Not Available*Values in mg/kg/dayunless otherwise noted# NOAEL/LOAEL

# January 20, 2010

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Production, Chemistry, Toxicology, and Uses. J. E. Casida and G. B. Quistad. New York, Oxford

University Press: 217-233.

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.

Tyl, R. W., K. Crofton, A. Moretto, V. Moser, L. P. Sheets and T. J. Sobotka (2008). Identification

and interpretation of developmental neurotoxicity effects: A report from the ILSI Research

Foundation/Risk Science Institute expert wo rking group on neurodevelopmental endpoints.

Neurotoxicology and Teratology 30(4): 349-381.

U.S. Environmental Protection Agency. Pr oposed Common Mechanism Grouping for the

pyrethrins and synthetic pyre throids, draft. May 19, 2009.

http://www.regulations.gov/search/Regs/ home.html#documentDetail?R=09000064809a62df

Vijverberg, H. P. and B. J. v. d. Bercken (1990). Neurotoxicolog ical effects and the mode of action

of pyrethroid insecticides. Critical Reviews in Toxicology 21: 105-26.

White, N. H., Verschoyle, R. D., Moradian, M. H., and Barnes, J. M. (1976). The relationship

between brain levels of cismethrin and bioresme thrin in female rats and neurotoxic effects.

Pesticide Biochemistry and Physiology

. 6: 491-500.

Wolansky, M. J., Gennings, C., and Crofton, K. M. (2006). Relative potencies for acute effects of

pyrethroids on motor function in rats. Toxicological Sciences. 89: 271-77.

Wolansky, M. J. and J. A. Harrill (2008). Neurobehavioral toxicology of pyrethroid insecticides in

adult animals: A critical review. Neurot oxicology and Teratology 30(2): 55-78.

# January 20, 2010

Page 32 of 36 

# Appendix 1.

List of MRIDs and citations for studies named in Table 1 “Points of Departure (PODs) for

Pyrethroid and Pyrethrin Single Ch emical Aggregate Risk Assessments”.

870.3100 Subchronic Rat

00072114 Dow Chemical Company (1944) Semichr onic Oral Toxicity of p-Chlorophenyl pChlorobenzenesulfonate (K6451) to Female Rats: 130-day Dietary Feeding Study. (Unpublished

study received Oct 24, 195 5 under PP0050; CDL:090101-C)

44047101 McFarlane, M. (1996) S-Bioallethrin (Esbiol) Code: RU 16121: Rat 90-Day

Dietary Repeat Dose Study: Lab Project Numb er: TOX 94423: TOX/95/254-5. Unpublished study

prepared by AgrEvo UK Ltd. 354 p.

870.3150 Subchronic Dog

00141200 Serota, D.; Kundzins, W. (1984) 13-wee k Subchronic Oral Toxicity Study in Dogs

with FMC 54800, Technical: Final Report: Proj ect No. 104-217. Unpublished study prepared by

Hazleton Laboratories America, Inc. 285 p.

41267801 Von Keutz, E. (1987) FC R 4545: Study of Subchronic Oral Toxicity to Dogs (13-

Week Feeding Study): Project ID 98348. Unpublished study prepared by Bayer Ag. 259 p.

42717503 Nagata, R. (1987) Subacute (13-week) Oral Toxicity Study of S-2703F in

Beagles: Final Report (EET-71-0074). Unpublishe d study prepared by Shin Nippon Biomedical

Labs, Ltd. 522 p.

870.3200 21/28 Dermal Toxicity

41143801 Milburn, G. (1989) Permethrin: 21 Day Dermal Study in Rats: Report No.

CTL/P/2445: Study No. LR0533. Unpublished study prepared by ICI Central Toxicology

Laboratory. 305 p.

42653301 Milburn, G. (1989) Permethrin: 21 Day Dermal Study in Rats: Individual Animal

Data Supplement: An Addendum: Lab Project Number: CTL/P/2445: LR0533. Unpublished study

prepared by Zeneca Central Toxicology Lab. 249 p.

42999101 Bernier, L. (1993) A Study of the S ubchronic (21-Day) Dermal Toxicity of S4068SF in Albino Rats: Lab Project Number: 85131: FFT-31-0176. Unpublished study prepared

by Bio-Research Laboratories, Ltd. 342 p.

44333802 Leah, A. (1989) Lambda-Cyhalothrin: 21-D ay Dermal Toxicity to the Rat: (Final

Report): Lab Project Number: CTL/P/2532: LR0 526. Unpublished study prepared by ICI Central

Toxicology Lab. 330 p.

45275401 Delker, D. (2000) Esfenvalerate Techni cal: Repeat Dose Dermal Toxicity: 21-Day

Study in Rats: Lab Project Number: 12737: 1012: THA000428. Unpublished study prepared by

E.I. du Pont de Nemours and Company. 570 p. {OPPTS 870.3200}

45280501 Watt, B.; Freeman, C. (2000) Bifent hrin Technical: 21-Day Repeated-Dose

Dermal Toxicity Study in Rats: Lab Project Number: A2000-5162: P-3455: 182TSST00436.

Unpublished study prepared by FMC Corp. 344 p. {OPPTS 870.3200}

# January 20, 2010

Page 33 of 36 

# 870.3465 Subchronic Inhalation

00096713 Alexander, D.J.; Clark, G. C.; Jackson, G.C.; et al. (1980) Permethrin Technical:

Inhalation Study in Rats: 15 X 6 Hour Exposures over a 3 Week Period: WLC 34/80323. Includes

method CAL 1173 dated Sep 21, 1979. (Unpublis hed study received Mar 17, 1982 under 59-200;

prepared by Huntingdon Research Centre, Engl and, submitted by Burroughs Wellcome Co.,

Research Triangle Park, N.C.; CDL:247019-G)

00157793 Pauluhn, J. (1984) Study for Subchroni c Inhalative Toxicity to the Rat for 13

Weeks: FCR 1272 (Cyfluthrin): Rept. No. 12436. Un- published Mobay study no. 86443 prepared

by Bayer AG Institute of Toxicology and Hanover Medical University. 170 p.

00158476 Coombs, D.; Hardy, C.; Clark, G.; et al. (1985) 90-Day Inhalation Toxicity Study

in the Rat: Resmethrin: (SBP - 1382 Technica l): SBP 6/84997. Unpublis hed study prepared by

Huntingdon Research Centre. 333 p.

40082901 Pauluhn, J. (1987) Study of the Subchronic Inhalation Toxicity in Accordance

with OECD Guideline No. 413: FCR 1272: Cy fluthrin: Addendum to Bayer Report No. 12436,

Dated Feb. 1, 1984: Study No. T9015085. Unpu blished Mobay Report No. 86443 prepared by

Bayer AG. 157 p.

40239301 Pauluhn, J. (1983) Study of the Subchronic Inhalation Toxicity in Accordance

with OECD Guideline No. 413: Baythroid: Supplemental Submission: Second Addendum to Bayer

No. 12436. Unpublished study prepared by Bayer AG. 24 p.

41289201 Kenny, T.; Coombs, D.; Hardy, C. (1989) Sumithrin T.G.: 90-Day Inhalation

Toxicity Study in the Rat (ET-91-0122) (Amended Version): Lab Project Number:

SMO/314/89644. Unpublished study prepared by Huntingdon Research Centre Ltd. 273 p.

41321818 Kohda, H. (1986) Subacute Inhalation Toxicity of S-4068SF in Rats: (ETOC): Lab

Study Nos. 380001; IH-84-09; Ref. No. FFT-60- 0078. Unpublished study prepared by Sumitomo

Chemical Co., Ltd. 329 p.

41387702 Hext, P. (1990) Lambda-Cyhalothrin Production Material: 21-day Sub- acute

Inhalation Toxicity Study in the Rat: Lab Proj ect Number: CTL/P/2772: MR0135. Unpublished

study prepared by ICI Central Toxicology Laboratory. 102 p.

41783001 Pauluhn, J. (1989) FCR 4545 (C. N. Betacyfluthrin, Proposed) Sub- acute

Inhalation Toxicity Study in the Rat: Lab Proj ect Number: 146: 100571. Unpublished study

prepared by Bayer AG. 949 p.

42012101 Kawaguchi, S. (1991) Three-Month Inhal ation Toxicity Study of Neo- Pynamin in

Rats: Lab Project Number: 2189. Unpublished study prepared by Sumitomo Chem. Co. 1055 p.

42030907 Kohda, H. (1986) Subacute Inhalation Toxicity of S-4068SF in Rats: Lab Project

Number: IH-84-09. Unpublished study prepared by Sumitomo Chemical Co., Inc. 334 p.

42478201 Newton, P. (1992) A Subchronic (3 -Month) Inhalation Toxicity Study of

Pyrethrum Extract in the Rat Via Whole-body Ex posures: Final Report: Lab Project Number: 91-

8335. Unpublished study prepared by Bio/dynamics Inc. 870 p.

43750730 Kawaguchi, S. (1992) A 4-Week Inhal ation Toxicity Study of S-41311 in Rats:

Lab Project Number: 2485: SGT-20-0056: 200056. Unpublished study prepared by Sumitomo

Chemical Co., Ltd. 459 p.

# January 20, 2010

Page 34 of 36 

# 44517802 Coombs, D. (1997) ESBI OL: Rat 28-Day Repeat Dose Inhalation Toxicity Study:

Lab Project Number: AGV 141/971017: TOX 96221. Unpublished study prepared by Huntingdon

Life Sciences, Ltd. 145 p.

46406736 Deguchi, Y. (2002) Four-Week Repeat ed Inhalation Toxicity Study of S-1264 in

Rats: Final Report. Project Number: 3704, QA T/0031, P02027. Unpublished study prepared by

Sumitomo Chemical Co. Ltd., Envr. Health. 413 p.

870.3700 Developmental Toxicity

00028453 Machi, R.A.; Kam, C.; Gallo, M.A.; et al. (1979) Teratol ogic Evaluation of SBP1382 Technical in the Albino Rat: Snell Project # 2054-066. (Unpublished study received Jan 23,

1980 under 432- 487; prepared by Booz, Allen & Hamilton, Inc., submitted by Penick Corp.,

Lyndhurst, N.J.; CDL:241765-A; 241766; 241768; 241769; 241770)

0029002 Becci, P.J.; Knickerbocker, M.; Parent, R.A. (1979) Teratologic Evaluation of

SBP-1382 Technical in Albino Rabbits: FDRL Laborat ory No. 6288. (Unpublis hed study including

letter dated Jan 14, 1980 from R.W. Fogleman to Maarten L. deVries, received Jan 23, 1980

under 432-487; prepared by Food and Drug Research Laboratories, Inc., submitted by Penick

Corp., Lyndhurst, N.J.; CDL: 241800-A)

41230003 Nemec, M. (1989) A Teratology Study in Rabbits with Sumithrin: Final Report:

Project No. WIL-118003. Unpublished study pre- pa red by WIL Research Laboratories, Inc. 348

p.

41525903 Morseth, S. (1990) Rat Teratology Study with S-3206: Lab Project No.: 343-216.

Unpublished study prepared by Hazlet on Laboratories America, Inc. 304 p.

46454111 Hara, H.; Suyami, S.; Ushimaru, T. et. al. (2002) Study for Effects on EmbryoFetal Developmental of S-1264 Administered Or ally to Rats. Project Number: QAT/0003,

ST01085. Unpublished study prepared by Ina Research Inc. 106 p.

870.3800 Reproduction a nd Fertility Effects

00163817 Cozens, D.; Barton, S.; Offer, J.; et al. (1986) Effect of S-3206 on Multigeneration

of the Rat: SMO 164/85707. Unpublished study pr epared by Huntingdon Research Centre. 468 p.

40276404 Tesh, J.; Willoughby, C.; Fowler, J. (1986) Sumithrin: Effects upon Reproductive

Performance of Rats Treated Continuously th roughout Two Successive Generations: (ET-61-

0101): Laboratory Project ID: 85/SUM009/331. U npublished study prepared by Life Science

Research. 1449 p.

41327501 Schardein, J. (1989) Two Generation Re production Study in Rats with Pyrethrum

Extract: Lab Project Number: 556/005. Unpub- lish ed study prepared by International Research

and Development Corp. 547 p.

43189101 Hoberman, A. (1994) Re productive Effects of SBP-13 82 (Resmethrin) Technical

Administered Orally via the Diet to Crl:CD BR VAF/Plus Rats for Two Generations with Two

Litters per Generation: Lab Project Number: 718 -004: RBT-92-102. Unpublished study prepared

by Argus Research Laboratories. 1533 p.

44082201 Hoberman, A. (1995) Reproductive Effe cts of Sumithrin Administered Orally via

the Diet to Crl:CD VAF/Plus Rats for Two Generations: Final Report: Lab Project Number: 1119-

# January 20, 2010

Page 35 of 36 

# 025: ET-51-0160: ARGUS 1119-025. Unpublished stud y prepared by Argus Research Labs, Inc.

1151 p.

870.4100 Chronic Toxicity (Dog)

00143130 Pence, D. (1984) Chronic Toxicity Study in Dogs: Project No. 343- 153.

Unpublished study prepared by Hazleton Laboratories Ameri- ca, Inc. 514 p.

163065 Serota, D. (1985) 52-Week Chronic Oral Toxicity Study in Dogs: FMC 54800 Technical:

Final Rept.: Project No. 104-219. Unpublished study pr epared by Hazleton Lab oratories America,

Inc. 306 p.

40027902 Hext, P.; Brammer, A.; Chalmers, D .; et al. (1986) PP321: 1 Year Oral Dosing

Study in Dogs: Report No. CTL/P/1316: [Includes Individual Animal Data Supplement of Report

No. CTL/P.1316S]. Unpublished study prepared by Im perial Chemical Industries PLC, Central

Toxicology Laboratory. 336 p.

40141308 Stonard, M. (1986) Tefluthrin: 1 Y ear Oral Dosing Study in Dogs: Laboratory

Project ID: CTL/P/1575. Unpublished study prepared by ICI Central Toxicology Laboratory. 88 p.

40276401 Cox, R. (1987) Chronic Toxicity Study in Dogs with Sumithrin, T.G.: Final Report:

HLA Study No. 343-173. Unpublished study prepared by Hazleton Laboratories America, Inc. 408

p.

42077002 Horner, S.; Buist, D.; Crook, D. et al . (1991) S-4068SF: Oral Toxicity Study in

Beagle Dogs: Lab Project Number: SMO 292/ 89531. Unpublished study prepared by Huntingdon

Research Centre Ltd. 315 p.

44435401 Jones, R.; Hastings, T. (1997) Technical Grade Cyfluthrin (FCR 1272): A Chronic

Toxicity Feeding Study in the Beagle Do g: Lab Project Number: 94-276-ZR: 8365: 108007.

Unpublished study prepared by Bayer Corp. 1151 p.

44536801 Daly, I. (1995) A Chronic (12-Month) Or al Toxicity Study of FMC 30980 Technical

in the Dog via Dietary Administration: Final Report: Lab Project Number: 92-3115: A93-3821: 92-

8123. Unpublished study prepared by Pharmaco LSR, Inc. 876 p.

870.4300 Combined Chronic Toxicity/Carcinogenicity

41559501 Goldenthal, E. (1990) Evaluation of Pyrethrum Extract in a Two Year Dietary

Toxicity and Oncogenicity Study in Rats: Lab Pr oject No. 556-011. Unpublished study prepared

by International Research and Development Corp. 2002 p.

92069048 Levin, A. (1990) Sandoz Crop Protecti on Corporation Phase 3 Summary of MRID

00150111 and Related MRIDs 00128335. Fl uvalinate Half Resolved: Chronic

Feeding/Oncogenicity (sic): Rat: Project 322-053.: 12 p.

870.6200 Neurotoxicity Screening Battery

44401101 Sheets, L.; Gilmore, R.; Hamilton, B. (1997) An Acute Oral Neurotoxicity

Screening Study with Technical Grade FCR 4545 in Fischer 344 Rats: Lab Project Number: 96-

412-GO: 107755. Unpublished study prepared by Bayer Corp. 382 p.

# January 20, 2010

Page 36 of 36 

# 44517801 Broadmeadow, A. (1997) ESBIOL: Rat Acute Oral Neurotoxicity Study: Lab

Project Number: AGV133/970021: 96226: 970021. Unpublished study prepared by Huntingdon

Life Sciences, Ltd. 327 p.

44862102 Watt, B. (1998) FMC 5480 0 Technical Acute Neurotox icity Screen in Rats: Lab

Project Number: A97-4643: P-3281: 182TST9737 5. Unpublished study prepared by FMC

Corporation. 994 p.

44900601 Yoshida, M.; Watson, M. (1999) A 90-Day Subchronic Neurotoxicity Study in

Rats with Tau-Fluvalinate: Lab Project Numb er: 7618-98-0114-TX-001: 2504. Unpublished study

prepared by Ricerca, Inc. 632 p. {OPPTS 870.6200}

45228301 Malley, L. (2000) Esfenvalerate: Ac ute Oral Neurotoxicity Study in Rats: Lab

Project Number: DUPONT-3874: 3874. Unpublished st udy prepared by E.I. du Pont de Nemours

and Co. 301 p. {OPPTS 870.6200}

45657401 McDaniel, K.; Moser, V. (1993) Utility of a Neurobehavioral Screening Battery for

Differentiating the Effects of Two Pyrethroids, Permethrin and Cypermethrin. Neurotoxicology and

Teratology 15:71-83. Non-guideline.

44962201 Watt, B. (1998) FMC 56701 Technical: Acute Neurotoxic ity Screen in Rats: Lab

Project Number: A97-4642: P97-0141: P-3261. Un published study prepared by FMC Corporation.

336 p.

870.6300 Developmental Neurotoxicity Study

46054101 Sheets, L.; Lake, S. (2003) A Devel opmental Neurotoxicity Screening Study with

Technical Grade Beta-Cyfluthrin in Wistar Rats . Project Number: 02/D72/IS, 200620, CY521801.

Unpublished study prepared by Bayer Corp. 1134 p.

46449102 Milburn, G. (2004) Lambda-Cyhalothr in: Developmental NeuroToxicity Study in

Rats. Project Number: RR0969. Unpublished study prepared by Syngenta Crop Protection, Inc.

2385 p. Relates to L0000986.

46670402 Nemec, M. (2005) A Dietary Devel opmental Neurotoxicity Study of ZetaCypermethrin Technical in Rats: Final R eport. Project Number: A2004/5809, WIL/105018.

Unpublished study prepared by WIL Re search Laboratories, Inc. 2260 p.

46750501 Nemec, M. (2006) A Dietary Developm ental Neurotoxicity Study of Bifenthrin

Technical in Rats: Final Report. Project Number: A2004/5860, WIL/105021. Unpublished study

prepared by WIL Research Laboratories, Inc. 2335 p.

46814301 Gilmore, R.; Sheets, L.; Hoss, H. (2006) A Developmental Neurotoxicity

Screening Study With Technical Grade Deltamethrin in Wistar Rats. Project Number:

04/D72/WO, 201469. Unpublished study prepared by Bayer Corp. 1074 p.

47345609 Stump, D. (2008) A Dietary Developmen tal Neurotoxicity Study of Fenpropathrin

Technical in Rats. Project Number: WIL/ 194029, VP/30179, 200800018A. Unpublished study

prepared by WIL Research Laboratories, Inc. 2346 p.