Page 2 of 18 

Table of Contents 

1. Executive Summary 3 

2. Proposed Use Profile 6 

3. Hazard Characterization 7 

4. Residential Exposure and Risk 9 

5. Occupational Exposure and Risk 9 

5.1 Handler 9 

5.2 Postapplication 14 

6. Data Needs and Labels Recommendations 17 
Page 3 of 18 

1.0 Executive Summary 

The registrant, Nichino, has submitted a request for a Section 3 registration for a proposed use of the 

new active ingredient (ai) tolfenpyrad to control thrips, aphids and scales on ornamental plants grown 

in greenhouses. Tolfenpyrad is a pyrazole insecticide that inhibits respiration of target pests through 

the inhibition of the respiratory electron transport chain. Inhibition results in very rapid insecticidal 

responses, including cessation of movement and feeding, lack of fecundity, and eventual death of the 

pest. 

The end-use product (EP), Tolfenpyrad 15EC Insecticide is formulated as an emulsifiable concentrate 

(EC) and contains 15% of the ai, tolfenpyrad. It is applied by backpack sprayer, high pressure 

handwand, and low pressure handwand. Since the product is only applied commercially in 

greenhouses, there are no food or residential uses associated with this ai. The proposed maximum 

single application rate is 0.003 lb ai/gallon of water. The total application rates (AR) range from 0.003 

– 0.006 lb ai per gallon, per crop cycle, or growing season. In addition, two separate spray volumes 

are specified on the label, resulting in a range of application rates from 0.68 to 1.36 lb ai/A. Based on 

the number of seasonal applications (2 applications per crop cycle, with a minimum re-treatment 

interval, RTI, of 10 days) indicated on product labels and information provided by the registrant, nondietary exposures are expected to be of short-, intermediate and long-term durations for occupational 

handlers and for workers conducting postapplication activities in greenhouses. No chemical specific 

data were submitted in support of the occupational exposure assessments for tolfenpyrad, so HED used 

default assumptions with respect to handler unit exposure, as well as for assessing postapplication 

exposure and risk (i.e., dissipation on ornamental plants, and standard transfer coefficients, TCs, for 

postapplication activities). 

Hazard Profile and Points of Departure (POD)

The toxicology database for tolfenpyrad is adequate for risk assessment. The current toxicity database 

for tolfenpyrad indicates moderate toxicity (Category II) via the acute oral route of exposure and mild 

toxicity (Category III) via the dermal and inhalation routes of exposure. Tolfenpyrad is mildly 

irritating (Category III) to the eye and slightly irritating (Category IV) to the skin. It is not a skin 

sensitizer. 

A variety of toxic effects were noted in the toxicology database for tolfenpyrad. The most consistent 

finding across species and studies was effects on body weight and body weight gain. Decreases in 

body weight and/or body weight gain were observed in adults of all species (rat, mice, rabbit, and dog) 

in the majority of the subchronic oral and dermal toxicity studies, and all chronic toxicity studies. The 

rat species is most sensitive to body weight changes, with effects observed at much lower doses than in 

other species. In rats, significant decreases in body weight and body weight gain were observed in 

subchronic oral, and acute and subchronic neurotoxicity studies. 

The body weight changes observed in the database were most often seen in the presence of decreased 

food consumption and in some studies, additional toxicity including liver/kidney effects and clinical 

signs. Moribundity and/or mortality were also noted in at least one study in all species. However, this 

was observed in the presence of body weight changes and mainly observed at the highest dose tested 

(HDT). 

 
Page 4 of 18 

 

Although a possible increase in qualitative susceptibility was observed in a developmental 

immunotoxicity study, there was no evidence of increased quantitative susceptibility. Additionally, 

there was no evidence of increased quantitative or qualitative susceptibility in developmental toxicity 

or reproduction studies. Therefore, there is no residual concern for increased susceptibility and no 

concern for immunotoxicity or neurotoxicity. Tolfenpyrad is classified as “not likely to be 

carcinogenic to humans.”

For purposes of the current risk assessment, endpoints were selected for occupational short- and 

intermediate-term inhalation exposures and short-, intermediate-, and long-term dermal exposures. For 

dermal exposures, a route-specific 21-day dermal toxicity study in rats was used for endpoint selection. 

However, an extra 3x uncertainty factor (UF, subchronic to chronic) was applied to long-term dermal 

risk assessments since the short-term dermal study was used to assess long-term dermal exposure. 

For short-and intermediate-term inhalation exposures, a 4-week inhalation study was used for endpoint 

selection. No toxic effects were observed up to the no observed adverse effect level (NOAEL) of 10 

mg/m3 (EPA calculated dose = 2.6 mg/kg/day) and the lowest observed adverse effect level (LOAEL) 

was not determined. However, it was stated in the inhalation study that mortality was observed in a 

range-finding study at 26 mg/m3 (6.8 mg/kg/day). HED used the NOAEL of 2.6 mg/kg/day from the 

4-week inhalation study for risk assessment; regardless, the range-finding study should be submitted to 

the Agency for review as a condition of registration. 

For short-, and intermediate-term dermal and inhalation assessments, a combined UF of 100x served as 

the basis for the level of concern (LOC) for occupational risk, or margins of exposure (MOEs). For the 

long-term dermal assessment, a combined UF of 300x served as the basis for the LOC. Therefore, for 

short-, and intermediate term dermal and inhalation risk assessments, MOEs greater than 100 are not of 

concern. For long-term dermal risk assessments, MOEs greater than 300 are not of concern. 

 

Occupational Handlers Exposure

No chemical-specific handler exposure data were submitted in support of this registration. Therefore, 

data from the Pesticide Handlers Exposure Database (PHED) Version 1.1 were used to assess handler 

exposures (HED Science Advisory Council for Exposure (ExpoSAC), SOP No. 7, January 1999). 

A summary of the risks for occupational handlers is included in Table 4. The maximum application 

rate for each exposure scenario was assessed (i.e., 0.003 lb ai/gal). All handler short- and 

intermediate-term scenarios resulted in MOEs greater than the level of concern (MOEs > 100) with 

risk mitigation (e.g., chemical-resistant gloves). Long-term handler risks were also not of concern 

(MOEs > 300). HED recommends all handlers wear a long-sleeved shirt, long pants, socks, 

chemical-resistant gloves, and footwear as stated in the proposed label. 

Occupational Postapplication Exposure

Dermal 

No chemical-specific data, such as dislodgeable foliar residue (DFR) studies, were submitted for the 

purpose of conducting a postapplication exposure assessment. Therefore, HED used default 

assumptions with respect to dissipation on ornamental plants, standard TCs for various postapplication 
Page 5 of 18 

activities, and “day 0” foliar residue values (i.e., residues after initial treatment). The two spray 

volumes specified on the label were used to determine the application rate on a per acre basis, in order 

to determine the potential exposure from contacting treated foliage; these per acre application rates 

were 0.68-1.36 lb ai/A. The same study (as well as dose and endpoint) was selected for assessing 

short- and intermediate-term dermal exposure. Similarly, the same study was selected for short-and 

intermediate-term inhalation exposure. Therefore, short-term exposure and risk calculations were 

considered representative/protective of intermediate-term exposure and risk. Long-term exposure and 

risk were also calculated. 

The short- and intermediate-term postapplication risks for ornamental crops were not of concern. 

Long-term postapplication MOEs are not of concern for low-medium contact activities (i.e., pruning, 

tying, hand pinching, and nursery activities). For long-term postapplication high contact activities 

(i.e., cutting flowers), a REI of 4 days would be needed to reach the target MOE of 300 at the 

maximum spray volume/A (AR=1.36 lb ai/A). However, it should be noted that long-term (≥ 6 

months-1 year) dermal postapplication exposure was estimated assuming the same residue calculated 

on the day of initial treatment. HED believes the residue available for exposure after 6 months or 

longer is likely to be lower than the residue value estimated on day of initial treatment. Considering 

the nature of the residues used for risk assessment, the MOE = 210 (on day 0) for high contact 

postapplication activities (AR=1.36 lb ai/A) is recognized as a conservative risk estimate. Submission 

of a chemical-specific DFR study for greenhouses is recommended to refine the residue values and 

reduce this uncertainty for high contact scenarios. 

Inhalation 

The Worker Protection Standard (WPS) for Agricultural Pesticides contains requirements for 

protecting workers from inhalation exposures during and after greenhouse applications through the use 

of ventilation requirements. Tolfenpyrad has a vapor pressure of 3.0 x 10-8 mm Hg. Although there is 

potential for postapplication inhalation exposure resulting from the use of tolfenpyrad in greenhouses, 

with proper use of ventilation, tolfenpyrad inhalation exposure is expected to be negligible. Therefore, 

a quantitative postapplication inhalation exposure assessment was not performed. This approach may 

be revisited in the future with potential changes in the Agency’s approach for assessing inhalation 

exposure and risk. 

Restricted Entry Interval

The REI specified on the proposed label is based on the acute toxicity of the tolfenpyrad technical 

material. Based on the acute toxicity profile of tolfenpyrad, the 24 hour REI appearing on the 

proposed label is appropriate for low, medium, and high contact postapplication activities. 

Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies, which comprise PHED and the 

Agricultural Reentry Task Force (ARTF), have been determined to require a review of their ethical 

conduct, have received that review, and have been determined to be ethically conducted. 
Page 6 of 18 

Conclusions and Recommendations

Risks for occupational handlers who apply Tolfenpyrad 15EC Insecticide on ornamental plants in 

greenhouses are not of concern to HED. Risks from short- and intermediate-term postapplication 

activities are also not of concern. Risks from long-term postapplication activities have been assessed 

in a conservative manner and are detailed above. 

Based on the current risk assessment, HED recommends: 

• All handlers should wear a long-sleeved shirt, long pants, socks, chemical-resistant gloves and 

footwear as stated in the proposed label. 

• The proposed label personal protective equipment (PPE) language should be revised to state the 

use of: “Chemical-resistant gloves made of materials such as barrier laminate or polyvinyl 

chloride.” 

• The default dislodgeable foliar residue (DFR) values and assumptions used in the assessment may 

be under or overestimated. Therefore, submission of a chemical-specific DFR study for 

greenhouses is recommended to reduce this uncertainty, and could potentially result in reduced 

exposure and risk estimates for all scenarios. 

• To determine the exposure duration that needs to be assessed for future registration actions, the 

applicant could provide the Agency with information to characterize the use pattern for the end-use 

product (EP) containing tolfenpyrad. Such information might include specific seasonal 

information about the use to be assessed, major regions on which the product is applied and how 

the product fits with other active ingredients in pest resistance management programs. 

• The Registration Division (RD) should ensure that the appropriate restricted reentry interval (REI) 

is included on the proposed label. 

• Proprietary data from the Agricultural Reentry Task Force (ARTF) have been used in this 

assessment. The chemical review manager (CRM) is encouraged to pursue data compensation in 

the event the registrant is not a member of this respective task force.

2.0 Proposed Use Profile 

The proposed use pattern and formulation specified in the EP containing tolfenpyrad for this 

registration request is summarized in Table 1. Applications of Tolfenpyrad 15EC Insecticide are to be 

made using foliar spray equipment. The proposed label has a PPE requirement that applicators and 

other handlers wear a long-sleeved shirt, long pants, socks, chemical-resistant gloves, and footwear. 
Page 7 of 18 

Table 1. Summary of Proposed Use Patterns and Formulations for Tolfenpyrad.

Formulation Method of 

Application 

Use Sites Application Rate Timing of Application

Tolfenpyrad 15EC 

Insecticide 

- emulsifiable 

concentrate 

(15% a.i.) 

For Commercial use 

EPA Reg #71711-XX 

(1.25 lb ai/gal) 

foliar spray by 

low and high 

pressure 

handwand, 

backpack 

sprayer 

greenhouse-grown 

ornamental plants 

(ash, yew, rose, 

evening primrose, 

gladiolus, cherry, 

arrowood, marigold, 

moss rose, new guinea 

impatiens, petunia, 

gerbera, 

chrysanthemum, 

coleus, poinsettia, 

schefflera, lantana) 

Max single appl. rate = 

0.00313 lb ai/gal 

(0.68 - 1.36 lb ai/A)‡ 

2 apps per crop cycle (0.006 lbs 

ai/gal); 

24-hour REI; 

10-day interval between apps; 

Apply uniformly. 

Do not apply more than 100 gallons 

per 20,000 ft2

 (218 gal/A) up to 10 

gallons per 1,000 ft2 (436 gal/A). 

 

‡ Lower Spray Volume = 0.68 lb ai/A (at 100 gal/20,000 ft2 = 218 gal/A) 

0.00313 lb ai/gal * 218 gal/A = 0.68 lb ai/A 

Higher Spray Volume = 1.36 lb ai/A (at 10 gal/1000 ft2

 = 436 gal/A) 

0.00313 lb ai/gal * 436 gal/A = 1.36 lb ai/A 

3.0 Hazard Characterization 

The toxicology database for tolfenpyrad is adequate for risk assessment. The current toxicity database 

for tolfenpyrad indicates moderate toxicity (Category II) via the acute oral route of exposure and mild 

toxicity (Category III) via the dermal and inhalation routes of exposure. Tolfenpyrad is mildly 

irritating (Category III) to the eye and slightly irritating (Category IV) to the skin. It is not a skin 

sensitizer. 

Decreases in body weight and body weight gain were also seen in chronic rat studies but at lower doses 

than observed in the other rat studies. Although these effects were seen at lower doses, the body 

weight decrements noted in the chronic study were not as pronounced as they were in the subchronic 

study or in the neurotoxicity studies. Decreases in body weight and body weight gain were also 

observed in the reproduction study, the developmental toxicity, and the developmental immunotoxicity 

studies at doses comparable to the chronic study. Decreases in body weight gain were also seen in a 

21-day dermal toxicity study, but in the absence of any other systemic toxicity. The body weight 

changes observed in the database were most often seen in the presence of decreased food consumption 

and in some studies, additional toxic effects (liver/kidney effects, clinical signs, etc). 

Body weight changes observed in other species were similar in magnitude to those in rats, but were 

observed at higher doses. Significant decreases in body weight and body weight gain were seen in 

both mice and dogs after subchronic exposure; these effects were also noted in rabbits in a 

developmental study. Chronic exposure resulted in body weight and body weight gain decreases in 

mice and dogs at lower doses. The severity of body weight changes increased with dose in mice while 

body weight effects in dogs were seen only at the highest dose tested (HDT). 
Page 8 of 18 

Moribundity and/or mortality were noted in at least one study in all species and mainly observed at the 

HDT. In all cases, effects were observed in the presence of body weight changes, as well as other 

toxic effects in mice and dogs (liver/kidney effects and clinical signs). 

Other toxic effects noted in the database included effects on the liver and kidney in rats and dogs. 

Additionally, effects on the harderian gland and lymph nodes were seen in rats and testicular atrophy 

and clinical signs were seen in dogs. No treatment-related effects were noted in the liver or kidney in 

mice; however, rough coats, hunched posture, ataxia, hypoactivity, and clinical signs including missing 

ears and ear lesions (scabs, sores, ulceration, and inflammation) were noted. 

A possible increase in qualitative susceptibility was seen in a developmental immunotoxicity study; 

however, there was no evidence of increased quantitative susceptibility. Additionally, there was no 

evidence of increased quantitative or qualitative susceptibility in developmental toxicity and 

reproduction studies. As a result, there is no concern for increased quantitative and/or qualitative 

susceptibility of young animals to tolfenpyrad. There is also no concern for neurotoxicity or 

immunotoxicity. 

There was no evidence of carcinogenicity in cancer studies with mice and rats. Therefore, in 

accordance with EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), tolfenpyrad 

is classified as “not likely to be carcinogenic to humans.” 

For short-, intermediate-, and long-term dermal exposures, a route-specific 21-day dermal toxicity 

study in rats was used for endpoint selection. However, an extra 3x UF (subchronic to chronic) was 

applied to long-term dermal risk assessments since the short-term dermal study was used to assess 

long-term dermal exposure. 

For short-and intermediate-term inhalation exposures, a 4-week inhalation study was used for endpoint 

selection. No toxic effects were observed up to the NOAEL of 10 mg/m3 (EPA calculated dose = 2.6 

mg/kg/day) and the LOAEL was not determined. However, it was stated in the inhalation study that 

mortality was observed in a range-finding study at 26 mg/m3

 (6.8 mg/kg/day). HED used the NOAEL 

of 2.6 mg/kg/day from the 4-week inhalation study for risk assessment; regardless, the range-finding 

study should be submitted to the Agency for review as a condition of registration. 

Table 2. Acute Toxicity Profile –Tolfenpyrad (Technical Ingredient). 

Guideline 

No.

Study Type MRID(s) Results Toxicity 

Category

870.1100 Acute oral –Rat 47457501 LD50 Females => 386 mg/kg bw 

LD50 Females =>150 mg/kg bw 

LD50 Combined =>239 mg/kg bw 

II 

870.1200 Acute dermal-Rat 47457503 LD50 Males > 2000 mg/kg bw 

LD50 Females > 3000 mg/kg bw 

LD50 Combined > 2500 mg/kg bw 

III 

870.1300 Acute inhalation-Rat 47447734 LC50 Males >2.21 mg/L 

LC50 Females >1.50 mg/L 

LC50 Combined >1.82 mg/L 

III 

870.2400 Acute eye irritation-Rabbit 47457505 Mildly irritating III 
Page 9 of 18 

870.2500 Acute dermal irritation-Rabbit 47457507 Slightly irritating IV 

870.2600 Skin sensitization-Guinea Pig 47447740 Not Sensitizing - 

Table 3. Summary of Toxicological Doses and Endpoints for Tolfenpyrad for Use in Occupational Human 

Health Risk Assessments. 

Exposure/ 

Scenario 

Point of 

Departure 

Uncertainty 

Factors 

Level of Concern 

for Risk 

Assessment 

Study and Toxicological Effects 

Dermal 

Short-Term 

And 

IntermediateTerm 

(Up to 6 months 

of Exposure) 

NOAEL= 

200 

mg/kg/day 

UFA= 10 x 

UFH=10 x 

Occupational LOC 

for MOE = 100 

No LOAEL determined in 21-day dermal 

study in rats; not tested up to the limit dose of 

1000 mg/kg/day. 

Only minimal changes in body weight gain 

(no absolute body weight changes) and food 

consumption were observed in the study and 

not considered adverse 

Dermal LongTerm (>6 

months) 

NOAEL= 

200 

mg/kg/day 

UFA= 10 x 

UFH=10 x 

UFS=3 x Occupational LOC 

for MOE = 300 

No LOAEL determined in 21-day dermal 

study in rats; not tested up to the limit dose of 

1000 mg/kg/day. 

Only minimal changes in body weight gain 

(no absolute body weight changes) and food 

consumption were observed in the study and 

not considered adverse 

Inhalation 

Short-Term 

And 

IntermediateTerm 

(Up to 6 months 

of Exposure) 

NOAEL= 2.6 

mg/kg/day 

IAF = 100% 

UFA= 10 x 

UFH=10 x Occupational LOC 

for MOE = 100 

No LOAEL determined 

4 week inhalation study in rats. No effects 

observed up to 2.6 mg/kg/day in main study. 

Mortality observed at 6.8 mg/kg/day in a 

range-finding study (not available). 

Cancer (oral, 

dermal, 

inhalation) 

Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant tumor 

increases in two adequate rodent carcinogenicity studies. 

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

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

population (intraspecies). UFS = use of a short-term study for long-term risk assessment. MOE = margin of exposure. LOC 

= level of concern. 

4.0 Residential Exposure and Risk 

Tolfenpyrad has no residential uses, and no occupational uses at residential sites are being requested at 

this time; therefore, no residential risk assessment has been conducted. Furthermore, no bystander 

exposure is expected since applications are only anticipated to be made in greenhouses settings. 

5.0 Occupational Exposure and Risk 

5.1 Handlers 

Tolfenpyrad 15EC Insecticide is formulated as an emulsifiable concentrate (EC) and contains 15% of 

the ai, tolfenpyrad. The product is to be applied by backpack sprayer, high pressure handwand, and 

low pressure handwand equipment. The proposed maximum single application rate is 0.003 lb ai per 
Page 10 of 18 

gallon. The application rates range from 0.003 – 0.006 lb ai per gallon per crop cycle. In addition, two 

separate spray volumes are specified on the label, resulting in a range of application rates of 0.68 to 

1.36 lb ai/A. Based on the number of seasonal applications (2 applications per crop cycle, with a 

minimum 10-day RTI) indicated on product labels and information provided by the registrant, nondietary exposures are expected to be of short-, intermediate- and long-term durations for occupational 

handlers. 

However, based on integrated pest management practices and chemical rotations, long-term handler 

exposures are considered to be less likely and any assessments of such exposures are likely to be 

conservative. No handler activities are expected for more than 6 consecutive months. Since doses 

selected for short-, intermediate- and long-term assessments are the same, the short-term exposure and 

risk assessment is protective of long-term exposures. 

The following handler exposures result from dermal and inhalation routes for the proposed greenhouse 

uses: 

• Mixing/Loading/Applying Liquid Formulation for High Pressure Handwand 

• Mixing/Loading/Applying Liquid Formulation for Low Pressure Handwand 

• Mixing/Loading/Applying Liquid Formulation for Backpack Sprayer 

5.1.1. Data and Assumptions for Handler Exposure Scenarios 

The assumptions, parameters and factors used for the exposure calculations include: 

 

• Application rates were based on the proposed label. Maximum application rate on proposed 

 label = 32 oz/100 gal . Product contains 1.25 lb ai/gal (0.0098 lb ai/fl oz). 

Maximum Single Application Rate = 32 oz/100 gal * 0.0098 lb ai/fl oz = 0.00313 lb ai/gal 

 

• Unit Exposures: Chemical-specific data for assessing exposure during pesticide handling activities 

were not submitted to the Agency in support of this Section 3 application. It is HED policy to use 

data from PHED to assess handler exposures for regulatory actions when chemical-specific data 

are not available (HED ExpoSAC, SOP No. 7, January 1999). 

 

The baseline clothing level was used as a starting point to calculate handler exposures, even though 

the proposed label recommends the use of baseline clothing plus chemical-resistant gloves. 

Depending upon the need for additional dermal protection, additional PPE is added to obtain an 

MOE higher than the LOC. The baseline clothing level for occupational exposure scenarios 

generally represents an individual wearing long pants, a long-sleeved shirt, shoes, socks, no 

chemical-resistant gloves, and no respirator. As reflected in the calculations included herein, PPE 

may involve the addition of chemical-resistant gloves. For handlers mixing/loading and applying 

liquids with high and low pressure handwand and backpack sprayer, no data are available to assess 

risks at baseline attire. Therefore, those handler scenarios were assessed at baseline plus chemicalresistant gloves. 

The proposed label has PPE recommendations which include: 
Page 11 of 18 

• Applicators and other handlers must wear a long-sleeved shirt, long pants, socks, chemicalresistant gloves and footwear. 

 

• Area Treated: Based on HED’s Exposure Science Advisory Committee SOP Number 9.1, the 

following gallons per day were assumed: 

 

• 40 gallons/day for mixing/loading/applying liquids using low-pressure handwand, and 

backpack sprayer. 

 

• 1000 gallons/day for mixing/loading/applying liquids using high pressure handwand. 

 

• Body Weight: The average adult body weight of 70 kg was used for all calculations, since the 

endpoints selected for risk assessment were not sex-specific. 

Equations and Calculations: 

Daily Exposure: Daily handler exposures are estimated for each applicable handler task with the 

application rate, the amount of acres treated or gallons applied in a day, and the applicable unit 

exposure using the following formula: 

Daily Exposure (mg ai/day) = Unit Exposure (μg ai/lb ai handled) * Application Rate (lbs ai/A or gal) * Daily Amount 

Handled (A or gal/day) * Conversion Factor (mg/1,000 μg) 

Where: 

Daily Exposure = Amount (mg ai/day) deposited on the surface of the skin that is available for dermal 

absorption or amount inhaled that is available for inhalation absorption, 

Unit Exposure = Unit exposure value (μg ai/day), 

Application Rate = Normalized application rate based on a logical unit treatment (lb ai/acre), and 

Daily Amount Handled = Normalized application area based on a logical unit treatment such as acres or gallons (A/day 

or gal/day). 

Daily Dose: Daily dose (inhalation or dermal) was calculated by normalizing the daily dermal or 

inhalation exposure value by body weight. 

Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day)/Body Weight (kg) 

Where: 

Average Daily Dose = Absorbed dose received from exposure to a pesticide in a given scenario (mg pesticide active 

ingredient/kg body weight/day), 

Daily Exposure = Amount (mg ai/day) deposited on the surface of the skin that is available for dermal absorption or 

amount inhaled that is available for inhalation absorption, and 

Body Weight = Body weight determined to represent the population of interest in a risk assessment. 

Margin of Exposure (MOE): The daily dermal dose and daily inhalation dose received by occupational 

handlers were compared to the appropriate POD (i.e., NOAEL) to assess the risk to occupational 

handlers for each exposure route. All MOE values were calculated separately for dermal and 

inhalation exposure levels using the following formula: 
Page 12 of 18 

MOE = NOAEL (mg/kg/day)/Average Daily Dose (mg/kg/day) 

Where: 

MOE = Margin of exposure value used by HED to represent risk or how close a chemical exposure is to being a 

concern (unitless), 

ADD = Average daily dose (ADD) is absorbed dose received from exposure to pesticide, and 

NOAEL = Dose level in a toxicity study, where no observed adverse effects occurred in the study. 

5.1.2. Exposure and Risk 

Summaries of the short-term risks (MOEs) at baseline (a long-sleeved shirt, long pants, shoes, and 

socks), and at baseline plus chemical-resistant gloves for handlers, are included in Table 4. The results 

indicate that dermal and inhalation risks do not exceed HED’s LOC, with MOEs greater than 100 at 

the baseline clothing scenario with the addition of chemical-resistant gloves, which are already 

specified on the proposed label. 

HED recommends that the proposed label PPE language be amended from: 

“Chemical-resistant gloves made of any waterproof material such as barrier laminate or 

polyvinyl chloride” to “Chemical-resistant gloves made of materials such as barrier laminate or 

polyvinyl chloride.” 
Page 13 of 18 

Table 4. Short- and Intermediate-Term Handler Exposure for Tolfenpyrad.Exposure Scenario 

Mitigation Levela

Dermal Unit Exposureb(mg/lb ai)

Inhalation Unit Exposure b (mg/lb ai)

Crop Application 

Ratec

Amount Treatedd

Dermal Dosee(mg/kg/day)

Dermal MOEf

Inhalation Doseg(mg/kg/day)

Short- and Intermediate-Term 

Mixing/Loading and Applying liquids for high pressure handwand application (PHED data) 

Single layer, Gloves 

2.5 0.120 mg/lb 

ai

Ornamentals 0.00313 lb 

ai/gal 

1,000 gallons/day 

0.11179 1,800 0.00537 

Mixing/Loading and Applying liquids for low pressure handwand (PHED data) 

Single layer, Gloves 

0.43 0.03 mg/lb 

ai

Ornamentals 0.00313 lb 

ai/gal 

40 gallons/day 

0.00077 260,000 0.00005 

Mixing/Loading and Applying liquids for backpack sprayer application (PHED data) 

Single layer, Gloves 

2.50 0.03 mg/lb 

ai

Ornamentals 0.00313 lb 

ai/gal 

40 gallons/day 

0.00447 45,000 0.00005 

a. Baseline Dermal: Long-sleeve shirt, long pants, and no gloves. Baseline plus Gloves Dermal: Baseline plus chemical-resistant gloves. 

b. Unit Exposures based on PHED Version 1.1. c. Application Rates based on proposed use on label for tolfenpyrad. d. Exposure Science Advisory Council Policy No. 9.1. e. Dermal Dose (mg/kg/day) = Daily Unit Exposure (mg/lb ai) x Application Rate (lb ai/gal) x Gallons Treated / Body Weight (70 kg). 

f. Dermal MOE = NOAEL (200 mg/kg/day) / Dermal Daily Dose (mg/kg/day). Short- and Intermediate-Term LOC = 100; Long-term LOC = 300. 

g. Inhalation Dose (mg/kg/day) = Daily Unit Exposure (μg/lb ai) x Application Rate (lb ai/acre) x Acres Treated / Body Weight (70 kg). 

h. Inhalation MOE = NOAEL (2.6 mg/kg/day) / Inhalation Daily Dose (mg/kg/day). Level of concern = 100. 
Page 14 of 18 

5.2 Postapplication 

Based on the number of seasonal applications indicated on these product labels, the proposed 

greenhouse use pattern, and information provided by the registrant, postapplication exposures are 

expected to be short- (1-30 days), intermediate- (1-6 months), and long-term (≥ 6 months-1 year) 

in duration. However, only short-term and long-term exposures were quantitatively assessed. 

Since doses selected for short- and intermediate-term assessments are the same, the short-term 

exposure and risk assessment is therefore protective of intermediate-term exposures. Since 

tolfenpyrad is going to be used on multiple rotational ornamental crops, workers are expected to 

conduct nursery postapplication activities and will potentially be exposed to foliar residues more 

than 6 consecutive months per year. 

Since no chemical-specific data such as DFR studies were submitted to estimate postapplication 

exposure, postapplication activities were assessed using dermal TCs from ExpoSAC: ARTF 

Ornamental Plants Transfer Coefficients, April 2002, summarized in Table 5. In addition, 

default assumptions with respect to the fraction available for transfer and residue dissipation (as 

described below) were used, along with the following: 

• Application Rate = 0.68 – 1.36 lb ai/A, representing the lower and higher spray volumes 

specified on the label and shown in Table 1. 

• Exposure Duration = 8 hours per day 

• Body Weight = 70 kg 

The fraction of ai retained on foliage surfaces is assumed to be 20% (0.2) of the application rate 

on the day of initial treatment. This fraction is assumed to further dissipate at the rate of 10% 

(0.1) per day. These are standard values established by HED ExpoSAC when no information is 

known about possible bonding to soil and foliar surfaces and dissipation of the active ingredient 

over time.

HED generally assesses exposure at “day 0” (i.e., on the day of treatment), and if MOEs are 

below the LOC, HED determines how many days would be needed in order to achieve an MOE 

>100. These calculations take into consideration the type of reentry activities likely to occur for 

a given scenario. Higher contact activities (such as hand harvesting or harvesting cut flowers) 

result in higher exposures, and may require longer reentry intervals to be specified on the label. 

Table 5. Anticipated Postapplication Activities and Dermal Transfer Coefficients for Greenhouse Use of 

Tolfenpyrad. 

Proposed Crops Policy Crop/Group 

Category 

Transfer 

Coefficients 

(cm2/hr) 

Activity Reference† 

110 outdoor ornamental 

pruning, tying 

MRID 454695-01; 

ARTF Study No. 

ART043 

Ornamentals ash, yew, rose, evening 

primrose, gladiolus, 

cherry, arrowood, 

marigold, moss rose, new 

guinea impatiens, 

petunia, gerbera, 

175 greenhouse hand 

pinching ornamentals; 

nurseries activities 

MRID 453445-01; 

ARTF Study No. 

ART039 
Page 15 of 18 

chrysanthemum, coleus, 

poinsettia, schefflera, 

lantana 

400 harvest (workers moved 

plants to trucks and 

reorganized the gallon 

pots or containers) 

MRID 454695-02; 

ARTF Study No. 

ART044 

Cut flowers 5100 (short-term) 

2700 

(intermediateand long term) 

hand-harvesting MRID 465139-01 

† The information in the table is based on proprietary and non-proprietary data. 

5.2.1. Exposure and Risk 

Inhalation 

The WPS for Agricultural Pesticides contains requirements for protecting workers from 

inhalation exposures during and after greenhouse applications through the use of ventilation 

requirements. Tolfenpyrad has a vapor pressure of 3.0 x 10-8 mm Hg. Although there is 

potential for postapplication inhalation exposure resulting from the use of tolfenpyrad in 

greenhouses, with proper use of ventilation, tolfenpyrad inhalation exposure is expected to be 

negligible. Therefore, a quantitative postapplication inhalation exposure assessment was not 

performed. This approach may be revisited in the future with potential changes in the Agency’s 

approach for assessing inhalation exposure and risk. 

Dermal 

A summary of the postapplication MOEs and respective reentry intervals is provided in Table 6. 

Based on the number of seasonal applications indicated on the proposed product labels, and 

information provided by the registrant, postapplication exposures are expected to be shortintermediate- and long-term in duration for all ornamentals plants. Standard assumptions with 

respect to body weight, area treated, and TCs were used to calculate the MOEs for occupational 

reentry. Since the same endpoint was selected for short- and intermediate-term exposure, shortterm exposure and risk are representative/protective of intermediate-term exposures. For longterm exposures, HED provided a comparison of the estimated number of days required before an 

MOE reached the LOC. 

Two spray volumes were assessed with application rates ranging from 0.68-1.36 lb ai/A; the 

default approach was used for estimating REIs, since no DFR data were submitted. 

The short- and intermediate-term postapplication assessments for ornamental crops resulted in 

MOEs of 100 or greater on “day 0” (immediately after application) for low, medium and high 

contact exposure activities (i.e., pruning, tying, hand pinching, nursery activities, and cutting 

flowers) and were not of concern. 

Long-term postapplication MOEs are not of concern for low-medium contact activities (i.e., 

pruning, tying, hand pinching, and nursery activities). For long-term postapplication high 

contact activities (i.e., cutting flowers), a REI of 4 days would be needed to reach the target 

MOE of 300 at the maximum spray volume/A (AR=1.36 lb ai/A). However, it should be noted 

that long-term (≥ 6 months-1 year) dermal postapplication exposure was estimated assuming the 
Page 16 of 18 

same residue calculated on day of initial treatment (i.e., day “0” residue value). HED believes the 

residue available for exposure after 6 months or longer is likely to be lower than the residue 

value estimated on the day of initial treatment. The day “0” residue value used for long-term 

postapplication dermal assessment represents a high-end assumption. Considering the nature of 

the residues used for the long-term postapplication risk assessment, the MOE = 210 (on day 0) 

for high contact activities at the maximum spray volume/A (1.36 lb ai/A) is recognized as a 

conservative risk estimate. 

Submission of a chemical-specific DFR study for greenhouses is recommended to refine the 

residue values and reduce the uncertainty for high contact scenarios. 

Table 6. Short-, Intermediate- and Long-Term Postapplication Exposure and Risk for Tolfenpyrad.

Crops Activity Application 

Rate 

(lb ai/A) 

DATa 

(TC - cm2/hr) 

DFRb (ug/cm2) Daily Dosec

(mg/kg/day) 

MOEd

Short- and Intermediate-term

0.68 0 

(110 cm2/hr) 

pruning, 1.523 0.0191 10,000 

tying 

1.36 0 

(110 cm2/hr) 

3.046 0.0383 5,200 

0.68 0 

(175 cm2/hr) 

hand 1.523 0.0305 6600 

pinching, 

nursery 

activities 1.36 0 

(175 cm2/hr) 

3.046 0.0609 3,300 

0.68 0 

(400 cm2/hr) 

harvesting 1.523 0.0696 2,900 

(workers 

moved plants 

to trucks and 

reorganized 

the gallon 

pots or 

containers) 

1.36 0 

(400 cm2/hr) 

3.046 0.1393 1,400 

0.68 0 

(5100 cm2/hr) 

1.523 0.8878 230 

Ornamentals 

hand 

harvesting; 

cutting 

flowers 1.36 0 

(5100 cm2/hr) 

3.046 1.7756 110 

Long-Term 

0.68 0 

(110 cm2/hr) 

Ornamentals pruning, 1.523 0.0191 10,000 

tying 

1.36 0 

(110 cm2/hr)

3.046 0.0383 5,200 
Page 17 of 18 

0.68 0 

(175 cm2/hr) 

hand 1.523 0.0305 6,600 

pinching, 

nurseries 

activities 1.36 0 

(175 cm2/hr) 

3.046 0.0609 3,300 

0.68 0 

(400 cm2/hr) 

harvesting 1.523 0.0696 2,900 

(workers 

moved plants 

to trucks and 

reorganized 

the gallon 

pots or 

containers) 

1.36 0 

(400 cm2/hr) 

3.046 0.1393 1,400 

0.68 0 

(2700 cm2/hr) 

1.523 0.4700 430 

0 

(2700 cm2/hr)

3.046 0.9400 210 

handharvesting 

1.36 

4 

(2700 cm2/hr) 

1.999 0.6168 320 

Note: 

a. DAT = Days After Treatment. TC = Transfer Coefficient. 

b. Dislodgeable Foliar Residue (DFR) = Application Rate (lb ai/A) x (1- Daily Dissipation Rate)t

 x 4.54E8 ug/lb x 2.47E-8 

A/cm2

 x 0.2 

c. Short- and Intermediate-term Daily Dose = [DFR (ug/cm2

) x TC (cm2/hr) x 0.001 mg/ug x 8 hrs/day] ÷ Body Weight (70 kg); 

 Long-term Daily Dose = [DFR (ug/cm2

) x TC (cm2/hr) x 0.001 mg/ug x 8 hrs/day] ÷ Body Weight (70 kg) 

d. Short- and Intermediate-term MOE = NOAEL/Daily Dose (NOAEL = 200 mg/kg/day; LOC = 100). 

e. Long-term MOE = NOAEL/Daily Dose (NOAEL = 200 mg/kg/day; LOC = 300). 

 

5.2.2 Restricted Entry Interval 

The REI specified on the proposed label is based on the acute toxicity of tolfenpyrad technical 

material which is classified as Category III for acute dermal and inhalation toxicity, Category IV 

for dermal and eye irritation, and Category II for acute oral toxicity. Based on the acute toxicity 

profile of tolfenpyrad, the 24 hour REI appearing on the proposed label is appropriate for low, 

medium, and high contact postapplication activities. 

6.0 Data Needs and Label Recommendations 

Based on the current risk assessment: 

• All handlers should wear a long-sleeved shirt, long pants, socks, chemical-resistant gloves 

and footwear as stated in the proposed label. 

• The proposed label personal protective equipment (PPE) language should be revised to state 

the use of: “Chemical-resistant gloves made of materials such as barrier laminate or 

polyvinyl chloride.” 

• The default dislodgeable foliar residue (DFR) values and assumptions used in the assessment 

may be under or overestimated. Therefore, submission of a chemical-specific DFR study for 

greenhouses is recommended to reduce this uncertainty, and could potentially result in 

reduced exposure and risk estimates for all scenarios. 
Page 18 of 18 

• To determine the exposure duration that needs to be assessed for future registration actions, 

the applicant could provide the Agency with information to characterize the use pattern for 

the end-use product (EP) containing tolfenpyrad. Such information might include specific 

seasonal information about the use to be assessed, major regions on which the product is 

applied and how the product fits with other active ingredients in pest resistance management 

programs. 

• The Registration Division (RD) should ensure that the appropriate restricted reentry interval 

(REI) is included on the proposed label.