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 results were similar across the six submitted 

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

DNTs on pyrethroids, when considered together, 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 supporting 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 Comparative Sensitivity

EPA has evaluated the data and information provided 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 literature. This evaluation was initiated, in part, by 

EPA’s preparation for registration 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 pyrethroids including their mode of action (MOA); the in vivo toxicity 

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

effect(s) used in OPP’s single chemical risk assessments; the results reported for the available 

pyrethroid DNT studies; and information from 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 that the conclusions drawn from the DNTs are 

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

Agency’s conclusion1

. 

Mode of Action & Toxicity Syndromes: 

 

Pyrethroids, the synthetic derivatives of the pyrethrins, have evolved 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 increased 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 voltage-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 rats. The T-syndrome has been historically 

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

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

characterized by initial pawing and burrowing, salivation, and choreoathetosis and is typically 

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

supported by the Pyrethroid Working Group2

, the T-syndrome was associated with elevated 

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

temperature, excessive salivation, and impaired mobility. A few pyrethroids, including 

esfenvalerate and fenpropathrin, elicit symptoms that are a combination of the T- and CSsyndromes3

. 

 

1 This document is not an exhaustive review of pyrethroid toxicity. For readers interested in more 

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

(1990), Narahashi (1992), Clark (1995), Soderlund (1995), Bloomquist (1996), Narahashi (1996), 

Shafer et al. (2005), Wolansky and 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 currently reviewing the SAP report and may consider additional 

pyrethroids as showing mixed syndromes 
 January 20, 2010 

Page 5 of 36 

Figure 1. Typical structure of a pyrethroid pesticide including acid and alcohol moieties and 

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

It has been suggested that the neurotoxicity 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 enter the cell; this typically results in membrane 

depolarization. In neurons, this results in initiation 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 depolarized. 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 resulting in long trains of action potentials. Type II 

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

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

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

and the resulting behavioral syndrome are not completely understood. 

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

pharmacokinetic and pharmacodynamic properties. The 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 shown in Figure 2, levels of deltamethrin, a Type II 

pyrethroid, in brain tissue clearly peak 2-3 hours 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 concentrations 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 tissue 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 motor activity as measured during the time-to-peakeffect. The pharmacokinetics that determine specific 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 the results of the DNT studies will be discussed 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 pyrethroids; one Type I (bifenthrin), four Type II’s 

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

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

Generally, the toxic effects to offspring observed 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 studies 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 where frank toxicity was noted. For example, 

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

studies are 18, 10, and 19 mg/kg/day, respectively. 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 resistance 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, for 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 guideline DNT studies do not show effects on 

behaviors or parameters that are only measured 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 combination with decreased body weight and 

absolute brain weight. Changes in brain morphometry were only observed for lambda-
 January 20, 2010 

Page 7 of 36 

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

weight decreases were also noted. At the mid-dose (4.3 mg/kg/day) in the lambdacyhalothrin study, no effects were noted in pups for any of these measures. The lambdacyhalothrin study is lacking measures of brain 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. Furthermore, 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 typically associated with acute pyrethroid 

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

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

(23 out of 25 animals) studies at the maternal 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 bifenthrin. 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 examined (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 tremors were observed at the mid- or lowdoses. The tremors in pups were graded 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 exhibited 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. However, this reported increase in grooming 

counts showed a weak dose-response and high variability in all dose groups. 

Specifically, in the control and low-dose groups, 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 quantifiable measurements of learning and memory, 

acoustic startle response, and brain morphometrics. 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 DNTs 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 the DNT are not consistent with pyrethroid 

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

guideline studies (reproduction, acute neurotoxicity, special FOB, subchronic 

neurotoxicity, etc.) at similar 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 evidence 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-cyhalothrin), 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 sensitivity 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 the 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 the 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 reproduction 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 multigeneration 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 same 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, the 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 susceptibility, are actually very similar. 

In this instance, the DNT did not provide 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 offspring based on body weight changes, similar 

effects were also observed in multigeneration reproduction studies for these two 

pyrethroids. Moreover, the reproductive toxicity 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 discussed in detail in Shafer et al. (2005) and 

are summarized briefly below. 
 January 20, 2010 

Page 9 of 36 

Critical Effects Selected for Risk Assessment: 

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

are provided in Table 1. Neurotoxicity consistent 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 provide the most sensitive endpoints 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 selection 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 neurotoxicity in rats and/or dog studies, administer 

pyrethroids in a bolus dose. Acute neurotoxicity 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 meals quickly over a few minutes, the chemical is 

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

over several hours, resulting in a much longer period 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 rapidly absorbed, distributed and 

cleared from the body and neurotoxicity is correlated with peak concentrations. 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 literature 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 properties, potential sensitivity of young animals is likely 

attributable to incomplete maturation of the enzyme 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 compared to the PND 72 rats suggesting a possible 

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

LD50 was lowest in the PND 11 rats (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 that age-dependent pharmacokinetics plays a major 

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

Similarly, Cantalamessa (1993) treated juvenile (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, pretreatment with TOTP caused a significant increase in 

cypermethrin and permethrin mortality while pretreatment 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 detoxification pathway in young animals. 

The data from Sheets et al. (1994) and Cantalamessa (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 pyrethroids 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 deltamethrin physiologically-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 isoforms 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 isoforms since the isoform of the sodium channel 

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

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

that one rodent VGSC isoform that is highly expressed 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 VGSCs 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, additional studies with the other isoforms widely 

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

species-specific pharmacodynamic differences. More 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 there is sufficient evidence to assume increased 

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

mechanisms. The currently available DNT studies 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 neurotoxicity. 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-syndrome/Type I pyrethroids) or choreoathetosis and 

salivation (CS-syndrome/Type II pyrethroids), although 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 lead 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 several 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 sensitive 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. This 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 investigators 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 compared 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 (effective dose 50%) of 4 mg/kg based on auditory 

startle response. The no-effect level in the deltamethrin 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 literature direct-dosing 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 of pharmacokinetics, and the lack of a chemicalspecific time-to-peak-effect window in the DNT study, the DNT is not likely to be able to identify or 

characterize increased juvenile susceptibility. 

 

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

degree of variability commonly observed in DNT studies. It is not unusual for standard deviations 
 January 20, 2010 

Page 12 of 36 

to exceed the mean value for many measurements 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 possible 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 determining the points of departure for use in risk 

assessment for these pesticides. Instead, clinical 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 assessment, since EPA believes the available data will appropriately characterize 

potential relevant results of conducting 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 (animal use, laboratory time, EPA 

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

scientific evidence does indicate a continued concern 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 comparative 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 deltamethrin 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 evaluating what additional experimentation on pyrethroid-specific effects 

related to the MOA and pharmacokinetic characteristics and comparative sensitivity between 

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

pyrethroid registrants and other stake-holders as additional action is needed. 
 January 20, 2010 

Page 13 of 36 

Table 1. Points of Departure (PODs) for Pyrethroid and Pyrethrin Single Chemical Aggregate R

Pyrethroid 

name 

(PC Code) 

(Type I/II/mixed) 

Acute RfD* Chronic RfD* Incidental Oral* Dermal* Inhalation* 

Allethrin; SBioallethrin 

(004003, 

004004) 

(Type I) 

Acute Dietary, general population=0.03 (Acute Neurotoxicity study rats (30/90)#

based on tremors, hunched posture, abnormal gait, decreased grip strength. 

Chronic Dietary=0.008 6-Month dog (BMDL10 = 8) 

based on hepatocellular degeneration 

 Short-term Range-finding dog (20/63) based on elevated liver enzymes and increased liver weights. Intermediate-term 6-month dog (BMDL10 = 8) 

based on hepatocellular degeneration

Short-and intermediateterm, general population not required. 

Short-, intermediate-, and long-term 28 day inhalation rat: (1.3/6.5) bason limb tremors, hunched posturevocalizations during handling. Residential and Occupational exposure. 
 January 20, 2010 

Page 14 of 36 

Table 1. Points of Departure (PODs) for Pyrethroid and Pyrethrin Single Chemical Aggregate R

Pyrethroid 

name 

(PC Code) 

(Type I/II/mixed) 

Acute RfD* Chronic RfD* Incidental Oral* Dermal* Inhalation* 

Bifenthrin 

(128825) 

(Type I) 

Acute Dietary, general population=0.33Acute neurotoxicity in rats (32.8/70.3) based on observations of mortality (females only), clinical and FOB findings and differences in motor activity 

Chronic Dietary=0.013 1-year dog (1.3/2.7) based on observations of increased incidence of tremors in both sexes 

 Short-and intermediate-term90-day dog (2.2/4.4) based increased incidence of tremors in both sexes 

 Short-, intermediate-, and long-term 21-day dermal rat (47/93) based on staggered gait and exaggerated hind limb flexion Residential and Occupational exposure.

 Short-and intermediate-te90-day dog (2.2/4.4) based increased incidence of tremors in both sexes Long-term 1-year dog (1.3/2.7) based oincreased incidence of tremors in both sexes Residential and Occupational exposure.
 January 20, 2010 

Page 15 of 36 

Table 1. Points of Departure (PODs) for Pyrethroid and Pyrethrin Single Chemical Aggregate R

Pyrethroid 

name 

(PC Code) 

(Type I/II/mixed) 

Acute RfD* Chronic RfD* Incidental Oral* Dermal* Inhalation* 

Cyfluthrin 

(128831) 

(Type II) 

Acute Dietary, general population=0.02 

Acute neurotoxicity in rats (2/10) based on gait incoordination, decreased activity, writhing, salivation and decreased motor activity 

Chronic Dietary=0.024 1-year dog (2.4/10.64) based on clinical signs, gait abnormalities, abnormal posture 

 Short-, intermediate-, and long-term 90-day dog (2.4/13.9) based on vomiting, gait abnormalities, decreased body weight gain

 Short-, intermediate-term90 day dog (2.4/13.9) based on vomiting, gait abnormalities, decreased body weight gain 

Long-term

1-year dog (2.4/10.64) based on clinical signs, gait abnormalities, abnormal posture 

Residential and 

Occupational exposure.

 Short-term 28-day rat (0.07/0.73) baseon decreases in body weight and decreased urinapH in males Intermediate-anlong-term (90-dinhalation rat (0.02/0.16) baseon decreases in body weight in males and clinicasigns in females 

Residential and 

Occupational exposure.

Cyfluthrin, 

beta- 

(118831) 

(Type II) 

Same as cyfluthrin Same as cyfluthrin Same as cyfluthrin Same as cyfluthrin Same as cyfluth
 January 20, 2010 

Page 16 of 36 

Table 1. Points of Departure (PODs) for Pyrethroid and Pyrethrin Single Chemical Aggregate R

Pyrethroid 

name 

(PC Code) 

(Type I/II/mixed) 

Acute RfD* Chronic RfD* Incidental Oral* Dermal* Inhalation* 

Cyhalothrin 

(128867) 

(Type II) 

Acute Dietary, general population=0.005 1-year dog; lambda cyhalothrin (0.5/ 3.5) based on ataxia observed from day 2.

Chronic Dietary=0.001 1-year dog; lambda cyhalothrin (0.1/0.5) based on gait abnormalities.

 Short- and intermediate-term 1-year dog; lambda cyhalothrin (0.1/0.5) based on gait abnormalities.

Short-, 

intermediate-, and long-term21-day dermal rat; lambda cyhalothrin (10/50) based on neurotoxicity (reduced splay reflex and stability, and splayed gait), decreases in body weight gain. Residential and Occupational exposure. 

 Short-, intermediate-, and long-term 21-day inhalation rat; lambda cyhalothrin (0.08/0.90) baseon neurotoxicity (salivation, lacrymation, and splayed gait), decreases in bodweight gain, punctuate foci in the cornea, changes in urinalysis, and decrease in cholesterol. Residential and Occupational exposure.
 January 20, 2010 

Page 17 of 36 

Table 1. Points of Departure (PODs) for Pyrethroid and Pyrethrin Single Chemical Aggregate R

Pyrethroid 

name 

(PC Code) 

(Type I/II/mixed) 

Acute RfD* Chronic RfD* Incidental Oral* Dermal* Inhalation* 

Cyhalothrin, 

lambda- 

(128897) 

(Type II) 

Same as 

cyhalothrin 

Same as 

cyhalothrin 

Same as 

cyhalothrin 

Same as 

cyhalothrin 

Same as 

cyhalothrin 

Cyhalothrin, 

gamma- 

(128807) 

(Type II) 

Acute Dietary, general population=0.002 1-year dog; lambda cyhalothrin (0.25/3.5) based on ataxia observed from day 2.

Same as 

cyhalothrin 

Same as 

cyhalothrin 

Same as 

cyhalothrin 

Same as 

cyhalothrin 
 January 20, 2010 

Page 18 of 36 

Table 1. Points of Departure (PODs) for Pyrethroid and Pyrethrin Single Chemical Aggregate R

Pyrethroid 

name 

(PC Code) 

(Type I/II/mixed) 

Acute RfD* Chronic RfD* Incidental Oral* Dermal* Inhalation* 

Cypermethrin 

(109702) 

(Type II) 

Acute Dietary, general population=0.1 Acute neurotoxicity in rats (10/50) based on soiled fur, abnormal posture, splayed hindlimbs, impaired gait, and convulsions. 

Chronic Dietary=0.06 1-year dog (6/18.1) based on decreased BW/BWG in females; mortality, tremors, irregular gait, and salivation in males. 

 Short- and intermediate-termDevelopmental Neurotoxicity (7.40/17.30) based on decreased BW.

Short-and intermediateterm, general population not required

Long-term, 

general population 1-year dog (6/18.1) based on decreased BW/BWG in females; mortality, tremors, irregular gait, and salivation in males. Short- and intermediate-term childrenDevelopmental Neurotoxicity (7.40/17.30) based on decreased BW. 

 Short-, intermediate anlong-term 21-day rat inhalation (0.01/0.05 mg/L) based on decreases in BW and salivation. Residential and Occupational exposure.
 January 20, 2010 

Page 19 of 36 

Table 1. Points of Departure (PODs) for Pyrethroid and Pyrethrin Single Chemical Aggregate R

Pyrethroid 

name 

(PC Code) 

(Type I/II/mixed) 

Acute RfD* Chronic RfD* Incidental Oral* Dermal* Inhalation* 

Cypermethrin, 

zeta- 

(129064) 

(Type II) 

Same as 

cypermethrin 

Same as 

cypermethrin 

Same as 

cypermethrin 

Same as 

cypermethrin 

Same as 

cypermethrin 

Cyphenothrin 

(129013) 

(Type II) 

N/A N/A 

 Short- and intermediate-term90-day dog (10/30) based emesis, tremors, and reddish/pale mucosa

 Short- and intermediate-term 90-day dog (10/30) based emesis, tremors, and reddish/pale mucosa Residential and Occupational

 Short- and intermediate-te90-day dog (10/3based emesis, tremors, and reddish/pale mucosa Residential and Occupational

Deltamethrin 

(097805) 

(Type II) 

Acute Dietary, All populations=0.01 Wolansky et al., 2006: (1/3) based on reduced motor activity.

Chronic Dietary=0.01 Wolansky et al., 2006: (1/3) based on reduced motor activity.

Short-, intermediateterm, all populations Wolansky et al., 2006: (1/3) based on reduced motor activity.

Short-, intermediate- and long-term, all populations Wolansky et al., 2006: (1/3) based on reduced motor activity. Residential and Occupational exposure.

Short-, intermediate- anlong-term, all populations Wolansky et al., 2006: (1/3) baseon reduced motoactivity. Residential and Occupational exposure.
 January 20, 2010 

Page 20 of 36 

Table 1. Points of Departure (PODs) for Pyrethroid and Pyrethrin Single Chemical Aggregate R

Pyrethroid 

name 

(PC Code) 

(Type I/II/mixed) 

Acute RfD* Chronic RfD* Incidental Oral* Dermal* Inhalation* 

Esfenvalerate 

(109303) 

(mixed) 

Acute Dietary, general population=0.002 Acute neurotoxicity study in rats (1.75/1.90) based on tremors.

Chronic Dietary=0.002 Acute neurotoxicity study in rats (1.75/1.90) based on tremors.

Short-, intermediate-termAcute neurotoxicity study in rats (1.75/1.90) based on tremors.

Short-, intermediate- and long-term, 21-day dermal (25/125) based on abnormal hindlimb gait. Residential and Occupational exposure.

Short-, intermediate, anlong-termAcute neurotoxicstudy in rats (1.75/1.90) baseon tremors. 

Residential and 

Occupational exposure.
 January 20, 2010 

Page 21 of 36 

Table 1. Points of Departure (PODs) for Pyrethroid and Pyrethrin Single Chemical Aggregate R

Pyrethroid 

name 

(PC Code) 

(Type I/II/mixed) 

Acute RfD* Chronic RfD* Incidental Oral* Dermal* Inhalation* 

Fenpropathrin 

(127901) 

(mixed) 

Acute Dietary, general population=0.06 Developmental rat (6/10) based on ataxia, sensitivity to extreme stimuli, spastic jumping and tremors.

Chronic Dietary=0.025 1-year dog (2.5/6.25) based on tremors and ataxia.

N/A 

 Short-, intermediate-, and long term Reproduction rat (3/8.9) based on clinical signs and mortality. Occupational exposure only.

 Short-, intermediate-, and long term Reproduction rat (3/8.9) based on clinical signs and mortality. Occupational exposure only.

Fenvalerate 

(109301) 

(Type II) 

same as 

esfenvalerate 

same as 

esfenvalerate 

same as 

esfenvalerate 

same as 

esfenvalerate 

same as 

esfenvalerate 
 January 20, 2010 

Page 22 of 36 

Table 1. Points of Departure (PODs) for Pyrethroid and Pyrethrin Single Chemical Aggregate R

Pyrethroid 

name 

(PC Code) 

(Type I/II/mixed) 

Acute RfD* Chronic RfD* Incidental Oral* Dermal* Inhalation* 

Tau-fluvalinate 

(109302) 

(Type II) 

Acute Dietary, general population=0.005 Chronic rat and subchronic neurotoxicity (0.5/1) based on excessive salivation, lacrimation, pawing, hyper/hypo activity, abnormal stance, and ruffling.

Chronic Dietary, general population=0.005 Chronic rat and subchronic neurotoxicity (0.5/1) based on excessive salivation, lacrimation, pawing, hyper/hypo activity, abnormal stance, and ruffling.

N/A N/A 

 Short-, intermediate-, and long term Chronic rat and subchronic neurotoxicity (0.5/1) based on excessive salivation, lacrimation, pawing, hyper/hypo activity, abnormastance, and ruffling. Occupational exposure only.
 January 20, 2010 

Page 23 of 36 

Table 1. Points of Departure (PODs) for Pyrethroid and Pyrethrin Single Chemical Aggregate R

Pyrethroid 

name 

(PC Code) 

(Type I/II/mixed) 

Acute RfD* Chronic RfD* Incidental Oral* Dermal* Inhalation* 

Imiprothrin 

(004006) 

(Type II) 

N/A N/A N/A N/A 

 Short-, intermediate-, and long-term 28 day inhalation rat (0.022/0.186 mg/L) based on increased incidence of clinical signs indicating effects on the nervous system, decreasin BWG, hemolyanemia, increase in relative liver weights, dark liveincrease in absolute and relative salivary gland weights anhyperplasia of acinous cells.
 January 20, 2010 

Page 24 of 36 

Table 1. Points of Departure (PODs) for Pyrethroid and Pyrethrin Single Chemical Aggregate R

Pyrethroid 

name 

(PC Code) 

(Type I/II/mixed) 

Acute RfD* Chronic RfD* Incidental Oral* Dermal* Inhalation* 

Metofluthrin 

(109709) 

(Type I) 

N/A N/A 

Short-term Developmental rat (15/30) based on tremors in adults. 

N/A 

Short-term 28 day inhalation rat (0.099/0.196 mg/L) based on mortality, tremorataxia, hypersensitivity, gait changes, lateral position, convulsions, and hypothermia in both sexes. Occupational exposure only.

Permethrin 

(109701) 

(Type I) 

Acute Dietary, general population=0.025 Acute neurotoxicity in rats (25/75) based on aggression, abnormal/decreased movement and increased body temperature. 

Chronic Dietary=0.025 Acute neurotoxicity in rats (25/75) based on aggression, abnormal/decreased movement and increased body temperature.

Short- and intermediate-termAcute neurotoxicity in rats (25/75) based on aggression, abnormal/decreased movement and increased body temperature.

Short-, intermediate- and long-term 21-day dermal (500/ND) 

Residential and 

Occupational exposure.

Short-, intermediate- anlong-term 15 day inhalation rat (0.042/ 0.583 mg/L) based on tremors and hypersensitivity. 

Residential and 

Occupational exposure.
 January 20, 2010 

Page 25 of 36 

Table 1. Points of Departure (PODs) for Pyrethroid and Pyrethrin Single Chemical Aggregate R

Pyrethroid 

name 

(PC Code) 

(Type I/II/mixed) 

Acute RfD* Chronic RfD* Incidental Oral* Dermal* Inhalation* 

Prallethrin 

(128722) 

(Type II) 

Acute Dietary, general population=0.05  1-year dog (5/10) based on tremors week 1.

Chronic dietary=0.05 1-year dog (5/10) based on trembling, rapid eye, blinking, and hunched posture. 

Short- and intermediate-term 1-year dog (5/10) based on trembling, rapid eye, blinking, and hunched posture.

Short-, intermediate- and long-term 21-day dermal (30/150) based on fixation, abnormal gait, tremors, sensitivity to external stimuli, vocalization, twitching and writhing, and spasms. Residential and Occupational exposure.

Short-, intermediate- anlong-term 28 day inhalation rat (0.0010/0.004mg/L) based on irregular respiration, decreased spontaneous activity, nasal discharge, salivation, and incontinence. Residential and Occupational exposure.
 January 20, 2010 

Page 26 of 36 

Table 1. Points of Departure (PODs) for Pyrethroid and Pyrethrin Single Chemical Aggregate R

Pyrethroid 

name 

(PC Code) 

(Type I/II/mixed) 

Acute RfD* Chronic RfD* Incidental Oral* Dermal* Inhalation* 

Pyrethrins 

(069001, 

069004, 069006, 

069012, 

869001) 

(not synthetic) 

Acute Dietary, general population=0.07 Acute neurotoxicity in rats (20/63) based on tremors. 

Chronic Dietary=0.04 Chronic rat (4.37/43.9) based on an increased incidence of thyroid follicular cell hyperplasia in males. 

Short-termAcute neurotoxicity in rats (20/63) based on tremors.in females. Intermediate-termReproduction in rat (6.4/65) based on decreased F1b pup weights during lactation.

Short-and intermediateterm, general population not required. 

Short-, intermediate- anlong-term 90-day inhalation rat (0.03/0.1 mg/based on tremorlabored breathinhyperactivity, secretory signs, matted coat, and decreased BW/BWG.

Resmethrin 

(097801) 

(Type I) 

N/A 

Chronic dietary=0.35 Reproduction rat (35/ 70.8) based on decreased mating index, decreased viability index, and decreased pup weight.

Short- and intermediate-termDevelopmental rat (40/ 80) based on decreased body weight gain and food consumption.

Short-, intermediateterm, and longterm

Developmental rabbit (30/100) based on skeletal variations, possible marginal increase in resorbed litters. Residential and Occupational exposure.

Short-, intermediate-, and long-term 90-day inhalation rat (ND/ 0.1 mg/Lbased on decreased glucolevels in males, decreased body weight gain, and increased BUN. Residential and Occupational exposure.
 January 20, 2010 

Page 27 of 36 

Table 1. Points of Departure (PODs) for Pyrethroid and Pyrethrin Single Chemical Aggregate R

Pyrethroid 

name 

(PC Code) 

(Type I/II/mixed) 

Acute RfD* Chronic RfD* Incidental Oral* Dermal* Inhalation* 

Sumithrin (dphenothrin) 

(069005) 

(Type II) 

Acute Dietary, females 13-49=0.03 Dev Rabbit (30/100) based on spina bifida

Chronic Dietary=0.007 1-year dog (7.1/26.8) based on hepatocellular enlargement in the liver and focal degeneration in the adrenal cortex in both sexes 

 Short- and intermediate-termReproduction rat (50/ 150) based decreased body weight, increased liver weight in parental animals, and an increase in spleen weight, decreased uterine weight in F1 adults, decreased body weight gain during lactation of F2b pups, decreased litter size of F1b litters at day 1, decreased absolute heart and kidney weight in F2b males, increased liver weight in male and female F2b pups.

Short-and intermediateterm, general population not required. 

Short-, intermediateterm, all populations 90-day inhalation rat (26.6/75) bason nasal histopathology. Residential and Occupational exposure.
 January 20, 2010 

Page 28 of 36 

Table 1. Points of Departure (PODs) for Pyrethroid and Pyrethrin Single Chemical Aggregate R

Pyrethroid 

name 

(PC Code) 

(Type I/II/mixed) 

Acute RfD* Chronic RfD* Incidental Oral* Dermal* Inhalation* 

Tefluthrin 

(128912) 

(Type I) 

Acute Dietary, general population=0.005 1-year dog (0.5/2) based on tremors 

Chronic Dietary=0.005 1-year dog (0.5/2) based on tremors 

N/A 

Short-, intermediateterm, and longterm 1-year dog (0.5/2) based on tremors 

Short-and intermediate, anlong-term not required. 

Tetramethrin 

(069003) 

(Type I) 

N/A N/A 

Short-term Reproduction rat (25/150) based on decreased body weight and food consumption, bile duct hyperplasia in F1 males

Short-and intermediateterm, general population not required. 

Short-, intermediate-te90-day inhalation rat (3.5/23.5) based on increased clinicasigns, kidney anliver weights, decreased body weight, changes hematology and urinalysis, liver hypertrophy and gross necropsy findings, hyaline droplets in kidne

Occupational 

exposure only.
 January 20, 2010 

Page 29 of 36 

Table 1. Points of Departure (PODs) for Pyrethroid and Pyrethrin Single Chemical Aggregate R

Pyrethroid 

name 

(PC Code) 

(Type I/II/mixed) 

Acute RfD* Chronic RfD* Incidental Oral* Dermal* Inhalation* 

Tralomethrin 

(121501) 

(Type II) 

Acute Dietary, general population=0.01 1-year dog (0.75/3) based on decreased BW, tremors, ptyalism. [0.75 raised to 1.0 at 14 weeks with no effects 

Chronic Dietary=0.01 1-year dog (0.75/3) based on decreased BW, tremors, ptyalism. [0.75 raised to 1.0 at 14 weeks with no effects 

N/A 

Short-and intermediateterm, general population not required. 

Not available 

NOAEL – No Observed Adverse Effect Level; LOAEL – Lowest Observed Adverse Effect Level; BMDL 10 – Benchmark Dose Lower Confidence Level 10%; BW/BW

Gain; ND – Not Determined; N/A – Not Available *Values in mg/kg/day unless otherwise noted # NOAEL/LOAEL 
 January 20, 2010 

Page 30 of 36 

References: 

Anand, S. S., J. V. Bruckner, W. T. Haines, S. Muralidhara, J. W. Fisher and S. Padilla (2006). 

Characterization of deltamethrin metabolism by rat plasma and liver microsomes. Toxicology and 

Applied Pharmacology 212(2): 156-166. 

Bloomquist, J. R. (1996). Ion channels as targets for insecticides. Annual Review of Entomology 

41: 163-90. 

Cantalamessa F. Acute toxicity of two pyrethroids, permethrin, and cypermethrin in neonatal and 

adult rats (1993). Archives of Toxicology. 1993; 67(7): 510-3. 

Clark, J. M. (1995). Effects and mechanisms of action of pyrethrin and pyrethroid insecticides. 

Handbook of Neurotoxicology. L. W. Chang and R. S. Dyer. New York, Marcel Dekker, Inc.: 511-

46. 

Godin, S. J., M. J. DeVito, M. F. Hughes, D. G. Ross, E. J. Scollon, J. M. Starr, R. W. Setzer, R. 

B. Conolly, R. Tornero-Velez. Physiologically based pharmacokinetic modeling of deltamethrin: 

development of a rat and human diffusion-limited model. Toxicological Sciences (submitted, note 

accepted with minor revisions). 

Gray, A. J., Conners, T. A., Hoellinger, H., and Nguyen-Hoang-Nam (1980). The relationship 

between the pharmacokinetics of intravenous cismethrin and bioresmethrin and their mammalian 

toxicity. Pesticide Biochemistry and Physiology. 13, 281-293. 

Kim, K.-B., S. S. Anand, H. J. Kim, C. A. White and J. V. Bruckner (2008). Toxicokinetics and 

tissue distribution of Deltamethrin in Adult Sprague Dawley Rats. Toxicological Sciences. 101(2): 

197-205. 

Meacham, C. A., P. D. Brodfuehrer, J. A. Watkins and T. J. Shafer (2008). Developmentallyregulated sodium channel subunits are differentially sensitive to [alpha]-cyano containing 

pyrethroids. Toxicology and Applied Pharmacology 231: 273-81. 

Narahashi, T. (1992). Nerve membrane Na channels as targets of insecticides. Trends 

Pharmacol. Sci. 13(6): 236-41. 

Narahashi, T. (1996). Neuronal ion channels as the target sites of insecticides. Pharmacology 

and Toxicology 79: 1-14. 

Nemec. 2006. An acute functional observational battery comparison study in rats. PWG Study 

number 02-PWG-001. 

Shafer, T. J., D. Meyer and K. M. Crofton (2005). Developmental neurotoxicity of pyrethroid 

insecticides: critical review and future needs. Environmental Health Perspectives 113(2): 123-36. 

Sheets, L. P., J. D. Doherty, M. W. Law, L. W. Reiter and K. M. Crofton (1994). Age-Dependent 

differences in the susceptibility of rats to deltamethrin. Toxicology and Applied Pharmacology 

126(1): 186-190. 

Sheets LP. (2000). A consideration of age-dependent differences in susceptibility to 

organophosphorus and pyrethroid insecticides. Neurotoxicology 21:57-63. 

Soderlund, D. M. and J. R. Bloomquist (1989). Neurotoxic actions of pyrethroid insecticides. 

Annual Review of Entomology 34: 77-96. 
 January 20, 2010 

Page 31 of 36 

Soderlund, D. M. (1995). Mode of action of pyrethrins and pyrethroids. Pyrethrum Flowers: 

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 working group on neurodevelopmental endpoints. 

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

U.S. Environmental Protection Agency. Proposed Common Mechanism Grouping for the 

pyrethrins and synthetic pyrethroids, 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). Neurotoxicological 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 bioresmethrin 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. Neurotoxicology 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 Chemical Aggregate Risk Assessments”. 

870.3100 Subchronic Rat 

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

study received Oct 24, 1955 under PP0050; CDL:090101-C) 

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

Dietary Repeat Dose Study: Lab Project Number: 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-week Subchronic Oral Toxicity Study in Dogs 

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

Hazleton Laboratories America, Inc. 285 p. 

41267801 Von Keutz, E. (1987) FCR 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). Unpublished 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 Subchronic (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-Day Dermal Toxicity to the Rat: (Final 

Report): Lab Project Number: CTL/P/2532: LR0526. Unpublished study prepared by ICI Central 

Toxicology Lab. 330 p. 

45275401 Delker, D. (2000) Esfenvalerate Technical: 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) Bifenthrin 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. (Unpublished study received Mar 17, 1982 under 59-200; 

prepared by Huntingdon Research Centre, England, submitted by Burroughs Wellcome Co., 

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

00157793 Pauluhn, J. (1984) Study for Subchronic 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 Technical): SBP 6/84997. Unpublished 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: Cyfluthrin: Addendum to Bayer Report No. 12436, 

Dated Feb. 1, 1984: Study No. T9015085. Unpublished 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 Project 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 Project Number: 146: 100571. Unpublished study 

prepared by Bayer AG. 949 p. 

42012101 Kawaguchi, S. (1991) Three-Month Inhalation 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 Exposures: Final Report: Lab Project Number: 91-

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

43750730 Kawaguchi, S. (1992) A 4-Week Inhalation 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) ESBIOL: 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 Repeated Inhalation Toxicity Study of S-1264 in 

Rats: Final Report. Project Number: 3704, QAT/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) Teratologic 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 Laboratory No. 6288. (Unpublished 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- pared 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 Hazleton 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 Orally to Rats. Project Number: QAT/0003, 

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

870.3800 Reproduction and 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 prepared by Huntingdon Research Centre. 468 p. 

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

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

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

Research. 1449 p. 

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

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

and Development Corp. 547 p. 

43189101 Hoberman, A. (1994) Reproductive Effects of SBP-1382 (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 Effects 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 study 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 prepared by Hazleton Laboratories 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 Imperial Chemical Industries PLC, Central 

Toxicology Laboratory. 336 p. 

40141308 Stonard, M. (1986) Tefluthrin: 1 Year 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 Dog: Lab Project Number: 94-276-ZR: 8365: 108007. 

Unpublished study prepared by Bayer Corp. 1151 p. 

44536801 Daly, I. (1995) A Chronic (12-Month) Oral 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 Project No. 556-011. Unpublished study prepared 

by International Research and Development Corp. 2002 p. 

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

00150111 and Related MRIDs 00128335. Fluvalinate 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 54800 Technical Acute Neurotoxicity Screen in Rats: Lab 

Project Number: A97-4643: P-3281: 182TST97375. 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 Number: 7618-98-0114-TX-001: 2504. Unpublished study 

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

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

Project Number: DUPONT-3874: 3874. Unpublished study 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 Neurotoxicity Screen in Rats: Lab 

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

336 p. 

870.6300 Developmental Neurotoxicity Study 

46054101 Sheets, L.; Lake, S. (2003) A Developmental 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-Cyhalothrin: 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 Developmental Neurotoxicity Study of ZetaCypermethrin Technical in Rats: Final Report. Project Number: A2004/5809, WIL/105018. 

Unpublished study prepared by WIL Research Laboratories, Inc. 2260 p. 

46750501 Nemec, M. (2006) A Dietary Developmental 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 Developmental Neurotoxicity Study of Fenpropathrin 

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

prepared by WIL Research Laboratories, Inc. 2346 p.