UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460

OFFICE OF 

CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

Date: 11/15/11 

SUBJECT: Penflufen. Human Health Risk Assessment to Support New Uses on Potato 

(Crop Subgroup 1C), Legume Vegetables (Crop Group 6 and Crop Group 7), 

Cereal Grains (Crop Group 15 and Crop Group 16), Oilseeds (Crop Group 20), 

and Alfalfa. 

 

PC Code: 100249 DP Barcode: D387450 

Decision No.: 431556 Registration No.: 264-RRRI, 264-RRRO, 264-RREN, 

264-RREL, 264-RREU, 264-RRER, 263-RREE, 264-

RREG

Petition No.: PP# 0F7711 Regulatory Action: New Active Ingredient; Section 3 

Registration

Risk Assessment Type: Single Chemical Aggregate Case No.: NA

TXR No.: NA CAS No.: 494793-67-8

MRID No.: NA 40 CFR: TBD

FROM: Donna S. Davis, Chemist 

 Alexandra LaMay, Biologist 

 Linda Taylor, Toxicologist

 Risk Assessment Branch VII 

 Health Effects Division (7509P) 

THROUGH: Christine L. Olinger, Senior Chemist, RAB VII 

 Michael S. Metzger, Chief, RAB V & VII 

 Steven Knizner/Ray Kent, RARC Designated Reviewers 

 Health Effects Division (7509P) 

TO: Marianne Lewis, Risk Manager 

 Venus Eagle, Product Manager 01 

 Meredith Laws, Chief 

 Insecticide-Rodenticide Branch 

 Registration Division (7505P) 

Attached please find the human health risk assessment for the new Bayer CropScience fungicide, 

penflufen. This assessment addresses in-furrow and seed treatment use on potatoes and seed 

treatment use on legume vegetables, cereal grains, oilseeds, and alfalfa for the active ingredient, 

penflufen only, with one exception. In reviewing end use product labels, rotational crop 

language recommendations are based on consideration of all active ingredients in the 

formulation. All other human health risk assessment considerations for co-formulants will be 

addressed in separate residue chemistry summary documents as appropriate. 

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Penflufen Human Health Risk Assessment D387450 

Table of Contents

1.0 Executive Summary ............................................................................................................. 4 

2.0 HED Recommendations....................................................................................................... 6 

2.1 Data Deficiencies/Conditions of Registration .................................................................. 6 

2.2 Tolerance Considerations ................................................................................................. 6 

2.2.1 Enforcement Analytical Method ............................................................................... 6 

2.2.2 International Harmonization ..................................................................................... 7 

2.2.3 Recommended Tolerances ........................................................................................ 7 

2.2.4 Revisions to Petitioned-For Tolerances .................................................................... 8 

2.3 Label Recommendations .................................................................................................. 8 

2.3.1 Recommendations from Residue Reviews ............................................................... 8 

2.3.2 Recommendations from Occupational Assessment ................................................ 10 

3.0 Introduction ........................................................................................................................ 10 

3.1 Chemical Identity ........................................................................................................... 10 

3.2 Physical/Chemical Characteristics ................................................................................. 11 

3.3 Pesticide Use Pattern ...................................................................................................... 11 

3.4 Anticipated Exposure Pathways ..................................................................................... 13 

3.5 Consideration of Environmental Justice ........................................................................ 13 

4.0 Hazard Characterization and Dose-Response Assessment ................................................ 14 

4.1 Toxicology Studies Available for Analysis ................................................................... 14 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME) ................................... 14 

4.2.1 Dermal Absorption ..................................................................................................... 15 

4.3 Toxicological Effects ..................................................................................................... 15 

4.4 Safety factor for Infants and Children (FQPA Safety Factor) ....................................... 16 

4.4.1 Completeness of the Toxicology Database ................................................................ 16 

4.4.2 Evidence of Neurotoxicity .......................................................................................... 16 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ............. 17 

4.4.4 Residual Uncertainty in the Exposure Database ......................................................... 17 

4.5 Toxicity Endpoint and Point of Departure Selections .................................................... 18 

4.5.1 Dose-Response Assessment ....................................................................................... 18 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment ........... 19 

4.5.3 Cancer Classification and Risk Assessment Recommendation .................................. 20 

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment ................................................................................................................................ 20 

5.0 Dietary Exposure and Risk Assessment ............................................................................ 22 

5.1 Metabolite/Degradate Residue Profile ........................................................................... 22 

5.1.1 Summary of Plant and Livestock Metabolism Studies ........................................... 22 

5.1.2 Summary of Environmental Degradation ............................................................... 23 

5.1.3 Comparison of Metabolic Pathways ....................................................................... 24 

5.1.4 Residues of Concern Summary and Rationale ........................................................ 24 

5.2 Food Residue Profile ...................................................................................................... 26 

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Penflufen Human Health Risk Assessment D387450 

5.3 Water Residue Profile .................................................................................................... 27 

5.4 Dietary Risk Assessment ................................................................................................ 27 

5.4.1 Description of Residue Data Used in Dietary Assessment ..................................... 27 

5.4.2 Percent Crop Treated Used in Dietary Assessment ................................................ 28 

5.4.3 Acute Dietary Risk Assessment .............................................................................. 28 

5.4.4 Chronic Dietary Risk Assessment .......................................................................... 28 

5.4.5 Cancer Dietary Risk Assessment ............................................................................ 28 

5.4.6 Summary Table ....................................................................................................... 28 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization .................................... 29 

6.1 Spray Drift ...................................................................................................................... 29 

7.0 Aggregate Exposure/Risk Characterization ....................................................................... 29 

8.0 Cumulative Exposure/Risk Characterization ..................................................................... 30 

9.0 Occupational Exposure/Risk Characterization .................................................................. 30 

9.1 Short-/Intermediate-Term Handler Risk ........................................................................ 30 

9.2 Short-/Intermediate-Term Post-Application Risk .......................................................... 34 

9.2.1 Dermal Postapplication Risk................................................................................... 34 

9.2.2 Inhalation Postapplication Risk .............................................................................. 36 

10.0 References .......................................................................................................................... 36 

Appendix A. Toxicology Profile and Executive Summaries ....................................................... 38 

A.1 Toxicology Data Requirements ...................................................................................... 38 

A.2 Toxicity Profiles ............................................................................................................. 39 

A.3 Hazard Identification and Endpoint Selection ............................................................... 49 

A.4 Executive Summaries ..................................................................................................... 64 

Appendix B. Metabolism Data ..................................................................................................... 92 

B1. Structures and Identify of Metabolites of Penflufen ......................................................... 92 

B2. Plant Metabolism Study Summaries ................................................................................. 99 

B3. Livestock Metabolism Studies ........................................................................................ 101 

Appendix C. Physical/Chemical Properties ............................................................................... 103 

Appendix D. End Use Products and Detailed Label Restrictions .............................................. 104 

Appendix E. Review of Human Research ................................................................................. 106 

 

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Penflufen Human Health Risk Assessment D387450 

1.0 Executive Summary 

Penflufen is a new carboxamide fungicide proposed for use primarily as a seed treatment in 

alfalfa, potatoes (tuberous and corm crop subgroup 1C), legume vegetables including soybeans 

(crop group 6 and crop group 7), cereal grains (crop group 15 and crop group 16), and oilseeds 

(crop group 20). An in-furrow application to potatoes is also proposed. The reported pesticidal 

mode of action is as an inhibitor of mitochondrial respiration by inhibiting succinate 

dehyrogenase, an enzyme in the electron transport system. Bayer CropScience has requested 

registration of the uses listed above and the establishment of tolerances to support those uses. 

Penflufen is being reviewed as part of a global work-sharing project with Australia (APVMA) 

and Canada (PMRA). 

The toxicology database is considered complete for penflufen. The liver and thyroid are target 

organs for penflufen. Additionally, increased incidence of thyroid follicular cell 

hypertrophy/hyperplasia was observed across studies and species. Reproductive toxicity was 

observed in the 2-generation reproduction study in rats. Delayed sexual maturation was 

observed in females in both generations, and the magnitude of the associated decline in body 

weight was not considered a factor in the delay in sexual maturation. Developmental toxicity 

was not observed in the rat or rabbit, although the dose levels in both studies were not considered 

adequate to assess developmental toxicity potential of penflufen. However, there is little concern 

that new studies would identify a developmental endpoint with a NOAEL lower than the 

NOAEL selected for risk assessment. Decreased motor/locomotor activity was observed in both 

sexes of rats following acute and in female rats following subchronic oral exposure, although 

neuropathological lesions were not observed in either study. There are no mutagenicity concerns 

for penflufen. The animal data on penflufen are suggestive of carcinogenicity, which raises a 

concern for carcinogenic effects but are judged not sufficient for quantification of cancer risk in 

humans. 

For the acute dietary risk assessment, an acute reference dose (aRfD) of 0.50 mg/kg/day was 

selected for assessment of all populations, based on a NOAEL of 50 mg/kg/day in the rat acute 

neurotoxicity study with decreased motor and locomotor activities in females observed at 100 

mg/kg/day. Since the FQPA 10X factor is being reduced to 1X (see discussion below), the acute 

population adjusted dose (aPAD) is equal to the aRfD. For the chronic dietary risk assessment, a 

chronic reference dose (cRfD) of 0.32 mg/kg/day was selected for assessments of all 

populations, based on a NOAEL of 38 mg/kg/day from the chronic dog study. The LOAEL of 

357 mg/kg/day is based on decreased terminal body weight and body weight gain (females), 

increased prothrombin time (males), increased alkaline phosphate activity (both sexes), 

decreased cholesterol (both sexes), increased GGT levels (both sexes), decreased albumin and 

albumin/globulin ratio (both sexes), decreased calcium and phosphorus (both sexes), increased 

liver weights (both sexes), increased incidence of focal hepatocellular brown pigment and 

hepatocellular hypertrophy (both sexes), increased incidence of zona glomerulosa vacuolation of 

the adrenal gland (females), and an increased incidence of thyroid follicular cell hypertrophy 

(both sexes). No dermal hazard was identified for penflufen. Since the FQPA 10X factor is 

being reduced to 1X, the chronic PAD is equal to the cRfD. For short-term occupational 

exposure scenarios involving inhalation exposure, the NOAEL of 55.7 mg/kg/day was selected 

from the dog oral subchronic toxicity study. The LOAEL of 532 mg/kg/day was based on 

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Penflufen Human Health Risk Assessment D387450 

decreased body weight/body weight gain in females, increased alkaline phosphatase activity in 

both sexes, increased GGT activity in both sexes, decreased albumin in males, increased liver 

weights in both sexes, increased adrenal weights in males, increased incidence of hepatocellular 

hypertrophy in both sexes, and an increased incidence of slight diffuse cortical 

hypertrophy/hyperplasia in the adrenal in males. For the intermediate-term occupational 

exposure scenarios involving inhalation exposure, the NOAEL of 38 mg/kg/day was selected 

from the chronic dog oral toxicity study discussed above. Penflufen has been classed as 

“suggestive” with respect to carcinogenicity and the Agency has determined that the chronic 

population adjusted dose is protective of all long-term effects, including potential 

carcinogenicity. 

The risk assessments conducted for penflufen were based on the most sensitive endpoints in the 

toxicity database, and the NOAELs selected for risk assessment are considered protective of 

potential developmental, neurotoxic, and immunotoxic effects for infants and children. Further, 

highly conservative exposure estimates were incorporated into the risk assessment; therefore, 

reduction of the 10X FQPA safety factor to 1X is considered appropriate. 

The residue chemistry database is considered complete for penflufen. The nature and magnitude 

of the residue in plants has been adequately delineated. The nature and magnitude of residues in 

rotational crops has also been adequately delineated and residues are not expected in 

commodities planted in the same fields no less than 30 days after treated seeds have been 

planted. The residue of concern in plants and rotational crops is the parent compound only. 

Residues in livestock commodities are not expected since quantifiable residues are not likely in 

any livestock feedstuff. Adequate storage stability, method validation data and processing 

studies have been submitted. An adequate LC/MS/MS (liquid chromatography/tandem mass 

spectrometry) analytical method is available to enforce the proposed tolerances. There are no 

issues with respect to international harmonization raised by this action. 

Environmentally, penflufen is a moderately mobile chemical that is expected to be persistent in 

the environment in aerobic and anaerobic conditions. Based on the environmental fate 

parameters, there is the potential for penflufen to reach water resources. As this is a new 

chemical, there is no monitoring data available, thus drinking water concentrations were 

estimated using models. 

Highly conservative acute and chronic dietary (food and water) assessments using tolerance level 

residues, assuming 100% crop treated and incorporating modeled water exposure estimates 

demonstrated that estimated risks were <1% of the acute population adjusted dose (aPAD) at the 

95th percentile exposure and <1% of the chronic population adjusted dose (cPAD) for the U.S. 

population and all modeled populations. There are no residential uses for penflufen; therefore, 

the aggregate risk estimate for this chemical is equivalent to the dietary risk estimate and there 

are no concerns for acute or chronic aggregate risk estimates for penflufen. 

No dermal hazard has been identified for penflufen; therefore occupational handler and 

postapplication risks were assessed for the inhalation route of exposure only. All estimated 

short- and intermediate-term handler inhalation risks greatly exceeded the Agency’s level of 

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Penflufen Human Health Risk Assessment D387450 

concern. Postapplication inhalation exposure is expected to be negligible; therefore a 

quantitative assessment was not required. 

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 the 

Pesticide Handlers Exposure Database (PHED), the Agricultural Handler Exposure Task Force 

(AHETF), the Outdoor Residential Exposure Task Force (ORETF), and Seed Treatment SOPs 

and study MRID 47054702 have been determined to require a review of their ethical conduct, 

have received that review, and have been determined to be ethical. 

2.0 HED Recommendations 

2.1 Data Deficiencies/Conditions of Registration 

Provided the end use product labels are revised as noted in Section 2.3.1, below, there are no 

data gaps with respect to toxicology, residue chemistry or occupational exposure assessment for 

penflufen. 

2.2 Tolerance Considerations 

2.2.1 Enforcement Analytical Method 

An adequate analytical method is available to enforce the proposed tolerances for penflufen in 

plant commodities. The LC/MS/MS method, EL-002-P09-03, has been adequately validated, 

has undergone a successful ILV (independent laboratory validation), is considered adequately 

radiovalidated and has been reviewed by the Agency for appropriateness as an enforcement 

method. 

Bayer method EL-002-P09-03 is described briefly as follows. Samples are homogenized and 

extracted with 4:1 acetonitrile (ACN)/water repeatedly. The extracts are combined, cleaned up 

using solid phase extraction; a stable, isotopically labeled internal standard is added, and taken to 

dryness. Hydrochloric acid is added to the dried extract and the solution is heated to hydrolyze 

any conjugates. The sample is then neutralized with sodium hydroxide and diluted with formic 

acid in water. An aliquot of the extract is analyzed for residues of penflufen by LC/MS/MS. 

Penflufen has also been subjected to analysis by the FDA multi-residue method protocols. 

Penflufen is not recovered by the FDA multi-residue methods. 

BayerCrop Science provided a stable, isotopically labeled reference standard for the parent 

compound, penflufen to the EPA National Standard Repository (email communication from T. 

Cole to D. Davis 11/15/11). 

 

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Penflufen Human Health Risk Assessment D387450 

2.2.2 International Harmonization 

Penflufen is part of a global review project with Canada and Australia. During the course of the 

review, the Agencies reached agreement on both the tolerance expression for plant commodities 

and the tolerance levels for commodities common to the three countries. At this time no 

tolerances are required in the U.S. for livestock commodities; therefore, a discussion of 

international harmonization with respect to livestock commodities is not germane to this 

assessment. 

There are no Codex or Mexican MRLs for penflufen and U.S. and Canadian tolerances are fully 

harmonized; therefore, there are no issues with respect to international harmonization associated 

with the tolerances recommended in this action. 

2.2.3 Recommended Tolerances 

Table 2.2.3 summarizes the registrant’s proposed tolerances and the Agency’s final tolerance 

recommendations. The tolerance expression for penflufen should read as follows: 

Tolerances are established for residues of the fungicide penflufen, including its 

metabolites and degradates, in or on the commodities in the table below. Compliance 

with the tolerance levels for the penflufen is to be determined by measuring only 

penflufen (N-[2-(1,3-dimethylbutyl)phenyl]-5-fluoro-1,3-dimethyl-1H-pyrazole-4-

carboxamide). 

Table 2.2.3. Tolerance Summary for Penflufen 

Commodity Proposed Tolerance 

(ppm) 

Recommended 

Tolerance (ppm) 

Comments 

Correct Commodity Definition

Alfalfa, Forage 0.01 0.01 Alfalfa, forage 

Alfalfa, Hay 0.01 0.01 Alfalfa, hay 

Tuberous and Corm 

Vegetable (Crop Subgroup 1C) 

0.01 0.01 Vegetable, tuberous and corm, 

subgroup 1C 

Legume Vegetables, 

succulent or dried (Crop 

Group 6) 

0.01 0.01 Vegetable, legume, group 6 

Foliage of Legume 

Vegetables, including 

soybeans (Crop Group 

7) 

0.01 0.01 Vegetable, foliage of legume, group 7 

Soybean, seed 0.01 - Not required, soybean seed is 

included in crop group 6. 

Cereal grains (Crop 

Group 15) 

0.01 0.01 Grain, cereal, group 15 

Forage, fodder and straw 

of Cereal grains (Crop 

Group 16) 

0.01 0.01 Grain, cereal, forage, fodder and 

straw, group 16 

Oilseeds (Crop Group 

20) 

0.01 0.01 Oilseed, group 20 

Cotton, gin by-products 0.01 0.01 Cotton, gin by-products 

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Penflufen Human Health Risk Assessment D387450 

2.2.4 Revisions to Petitioned-For Tolerances 

The Agency is recommending that tolerances be set for the commodities requested by the 

registrant at the levels requested. However, minor modifications to some commodity definitions 

are recommended to be consistent with Agency naming-conventions for commodities. 

2.3 Label Recommendations 

2.3.1 Recommendations from Residue Reviews 

HED is aware of the issue regarding the use of treated seeds (primarily corn) being used for 

ethanol production and the potential of pesticide residues occurring in the byproducts that can be 

used for livestock feed or fertilizer. The standard restriction with wording such as that on the 

proposed penflufen labels ("Do not use for feed, food or oil purposes") is not adequate to 

preclude this use of treated seeds. Since OPP is actively working with Bayer to develop a more 

appropriate label statement to address this concern, HED recommends that the wording to be 

developed through this process be used on the labels of all the penflufen products. 

Additional label-specific revisions are as follows. Note that the suggested rotational crop 

language includes consideration of rotational crop restrictions for penflufen as well as any coformulant(s) in the end-use product. 

PENPROME 177FS (264-RREE)

• The “rate per seed” for soybeans needs to be corrected to reflect the appropriate rate and 

AOSA (Association of Official Seed Analysts) recommendation of 4000 soybean seeds 

per pound. 

• The crop rotation restriction should be revised to specify the following. “Crops for which 

there are registered use of penflufen, which includes alfalfa, potatoes (Crop Subgroup 

1C), legume vegetables (Crop Group 6/7), cereal grains (Crop Group 15/16), and oil 

seeds (Crop Group 20) may be replanted at any time. All other crops may be planted no 

less than 30 days after planting treated seeds.” 

PEN 240FS (264-RRRO)

• The rate per seed for soybeans, cotton and field corn should be corrected to reflect the 

AOSA recommendation of 4000 seeds per pound for soybean, 3600 seeds per pound for 

cotton and 1360 seeds per pound for field corn. 

• Under the potato instructions for in-furrow treatment in combination with seed piece 

treatment the application rate column in the table should be revised to read as follows. 

“Apply a minimum of 0.4 fl oz per 1,000 row feet (4 ml per 100 row meters) up to a 

maximum in-furrow application of 9.2 fl oz per acre.” 

• The crop rotation restriction should be revised to specify the following. “Crops for which 

there are registered use of penflufen, which includes alfalfa, potatoes (Crop Subgroup 

1C), legume vegetables (Crop Group 6/7), cereal grains (Crop Group 15/16), and oil 

seeds (Crop Group 20) may be replanted at any time. All other crops may be planted no 

less than 30 days after planting treated seeds.” 

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Penflufen Human Health Risk Assessment D387450 

PENPRO 118FS (264-RREG)

• The crop rotation restriction should be revised to specify the following. “Crops for which 

there are registered use of penflufen, which includes alfalfa, potatoes (Crop Subgroup 

1C), legume vegetables (Crop Group 6/7), cereal grains (Crop Group 15/16), and oil 

seeds (Crop Group 20) may be replanted at any time. All other crops may be planted no 

less than 30 days after planting treated seeds.” 

PENCLO 273.5FS (264-RREL)

• The crop rotation restriction should be revised to specify the following. “Crops for which 

there are registered uses of both clothianidin and penflufen, which includes canola, 

cotton, cereal grains except rice, mustard seed, potato (Crop Subgroup 1C) and soybeans 

may be replanted at any time. Grasses, non-grass livestock feeds, dried beans and dried 

peas may be planted no less than 30 days after planting treated seeds. Do not plant any 

other crop in the treated area for at least twelve months after treated seeds are planted.”

PENRED 240FS (264-RREN)

• The rate per seed for soybeans, cotton and field corn should be corrected to reflect the 

AOSA recommendation of 4000 seeds per pound for soybean, 3600 seeds per pound for 

cotton and 1360 seeds per pound for field corn. 

• Under the potato instructions for in-furrow treatment in combination with seed piece 

treatment the application rate column in the table should be revised to read as follows. 

“Apply a minimum of 0.4 fl oz per 1,000 row feet (4 ml per 100 row meters) up to a 

maximum in-furrow application of 9.2 fl oz per acre.” 

• The crop rotation restriction should be revised to specify the following. “Crops for which 

there are registered use of penflufen, which includes alfalfa, potatoes (Crop Subgroup 

1C), legume vegetables (Crop Group 6/7), cereal grains (Crop Group 15/16), and oil 

seeds (Crop Group 20) may be replanted at any time. All other crops may be planted no 

less than 30 days after planting treated seeds.” 

PENCLOTRIME 310.68FS

• The crop rotation restriction should be revised to specify the following. “Areas planted 

with treated seed may be replanted immediately with canola, cotton, corn (field, pop and 

sweet), cereal grains except rice, mustard, rapeseed, sorghum, soybean, and potatoes 

(tuberous and corm subgroup 1C). These areas may also be replanted no less than 30 

days after planting treated seeds with grasses, non-grass livestock feeds, dried beans, 

fruiting vegetables (including cucurbits), leafy vegetables (including brassica vegetables) 

and sugar beets. Do not plant any other crop in the treated area for at least twelve months 

after treated seeds are planted. 

PENTRI 308FS

• The rate per seed for soybeans needs to be corrected to reflect the appropriate rate and 

AOSA recommendation of 4000 soybean seeds per pound. 

• The rate per 100 lbs of seed and rate per seed for field corn should reflect the same 

application rate. Further, the AOSA recommendation of 1260 seeds per pound for field 

corn should be incorporated into the rate per seed calculation. 

• The rate per 100 lbs of seed and rate per seed for cotton should reflect the same 

application rate. Further, the seeds per pound on the label should be revised to reflect 

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Penflufen Human Health Risk Assessment D387450 

3600 cotton seeds per pound. 

• The crop rotation restriction should be revised to specify the following. “Crops for which 

there are registered uses of both trifloxystrobin and penflufen, which includes barley, 

corn, oats, potato, rice, soybean and wheat may be replanted at any time. All other crops 

may be planted no less than 30 days after planting treated seeds.” 

2.3.2 Recommendations from Occupational Assessment 

The following label revisions are recommended based on the occupational assessment. Note that 

the suggested revisions include consideration of restrictions for penflufen as well as any coformulant(s) in the end-use product. 

 

PENRED 240FS, PEN240FS, PENCLO 273.5FS, PENTRI 308FS, PENPRO 118FS

The labeling should state: Bags containing treated seeds shall be labeled with the following 

information: “After the seeds have been planted, do not enter or allow worker entry into treated 

areas during the restricted-entry interval (REI) of 12 hours. Exception: Once the seeds are 

planted in soil or other planting media, the Worker Protection Standard allows workers to enter 

the treated area without restriction if there will be no worker contact with the treated seeds in the 

soil or planting media.” 

PENPROME 177FS

The labeling should state: Bags containing treated seeds shall be labeled with the following 

information: “After the seeds have been planted, do not enter or allow worker entry into treated 

areas during the restricted-entry interval (REI) of 24 hours. Exception: Once the seeds are 

planted in soil or other planting media, the Worker Protection Standard allows workers to enter 

the treated area without restriction if there will be no worker contact with the treated seeds in the 

soil or planting media.” 

3.0 Introduction 

3.1 Chemical Identity

The structure and chemical identify for penflufen are shown in Table 3.1. The structures for all 

metabolites discussed in this risk assessment are shown in Appendix B. 

Table 3.1 Test Compound Nomenclature 

Chemical Structure 

N N H

N

O

F

3CH

3CH

3CH CH3

3CH

Empirical Formula C18H24FN3O 

Common Name Penflufen 

Company experimental name BYF 14182 

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Penflufen Human Health Risk Assessment D387450 

Table 3.1 Test Compound Nomenclature 

IUPAC name N-[2-(1,3-dimethylbutyl)phenyl]-5-fluoro-1,3-dimethyl-1H-pyrazole-4-

carboxamide 

CAS Name 1H-Pyrazole-4-carboxamide, N-[2-(1,3-dimethylbutyl)phenyl]-5-fluoro-1,3-

dimethylCAS Registry Number 494793-67-8 

End-use product/EP PEN 240FS, PENRED 240FS, PENCLO 273.5FS), PENTRI 308FS), 

PENCLOTRIME 310.68FS, PENPROME 177FS 

Chemical Class Carboxamide 

Known Impurities of Concern None 

3.2 Physical/Chemical Characteristics

The physical and chemical properties, as well as a summary of relevant environmental fate 

parameters are detailed in Appendix C. 

Penflufen has a low vapor pressure (10-9 torr) and is; therefore, not a volatile pesticide. This 

active ingredient has an octanol water partition coefficient that would suggest it might have a 

slight bioaccumulation potential in lipophilic matrices. Penflufen has low water solubility and 

does not dissociate; however, environmentally, penflufen is a moderately mobile chemical that is 

expected to be persistent in the environment in aerobic and anaerobic conditions. Based on the 

environmental fate parameters, there is the potential for penflufen to reach water resources. 

3.3 Pesticide Use Pattern 

The proposed use pattern for penflufen on the various crops for which registration is sought are 

summarized in Table 3.3. 

Table 3. 3. Summary of Directions for Use of Penflufen 

Application 

Timing, Type, 

and 

Equipment Formulation Use Rates 

PHI 

(days) 

Use Directions and 

Limitations 

Alfalfa 

Slurry or misttype seed 

treatment 

PENRED 240FS 

PENTRI 308FS 

PENPROME 

177FS 

PEN 240FS 

0.015 lb ai/100 lbs seed 

(15 g ai/100 kg seed) 

NS Do not use for feed, 

food or oil purposes. 

Store away from feeds 

and foodstuffs. 

Rotational crop 

restrictions as detailed 

in Appendix D. 

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Table 3. 3. Summary of Directions for Use of Penflufen 

Application 

Timing, Type, 

and PHI Use Directions and 

Equipment Formulation Use Rates (days) Limitations 

Potato (Tuberous and Corm Crop Subgroup 1C)

Apply as a 

dilute spray to 

seed pieces 

PENRED 240FS 

PENCLO 273.5FS 

PENPRO 118FS 

PEN 240FS 

0.002 lb ai/100 lbs seed 

(2 g ai/100kg seed) 

may be combined with in-furrow 

application on PENRED 240FS and 

PEN 240 FS labels 

NS Do not use for feed, 

food or oil purposes. 

Store away from feeds 

and foodstuffs. 

Rotational crop 

restrictions as detailed 

in Appendix D. 

Ground 

application as 

in-furrow 

spray 

PENRED 240FS 

PEN 240 FS 

0.12 lb ai/A 

may be combined with seed piece 

treatment application 

NS Do not use for feed, 

food or oil purposes. 

Store away from feeds 

and foodstuffs. 

Rotational crop 

restrictions as detailed 

in Appendix D.

Legume Vegetables Including Soybean (Crop Group 6C) 

Slurry or misttype seed 

treatment 

PENRED 240FS 

PENTRI 308FS 

PENPROME 118 

FS (dried only) 

PEN 240 FS 

0.005 lbs ai/100 lbs seed 

(5 g ai/100 kg seed) 

NS Do not use for feed, 

food or oil purposes. 

Store away from feeds 

and foodstuffs. 

Rotational crop 

restrictions as detailed 

in Appendix D. 

Cereal Grains (Crop Group 15) 

Slurry or misttype seed 

treatment 

PENRED 240FS 

PENTRI 308FS 

(wheat, corn, rice 

only) 

PENPRO 118FS 

(wheat only) 

PENPROME 

177FS 

(barley, wheat, 

triticale and rice 

only) 

PEN 240FS 

Cereal grains, except corn, and 

sorghum 

0.005 lbs ai/100 lbs seed 

(5 g ai/100 kg seed) 

Corn, sorghum 0.010 lbs ai/100 lbs 

seed 

(10 g ai/100 kg/seed) 

NS Do not use for feed, 

food or oil purposes. 

Store away from feeds 

and foodstuffs. 

Rotational crop 

restrictions as detailed 

in Appendix D. 

Oilseeds (Crop Group 20) 

Slurry or misttype seed 

treatment 

PENRED 240FS 

PENTRI 308FS 

(cotton only) 

PENCLOTRIME 

310.68FS (canola, 

rape, mustard only) 

PENCLO 273.5FS 

(cotton only) 

PEN 240FS (cotton, 

0.015 lb ai/100 lbs seed 

(15 g ai/100kg seed) 

NS Do not use for feed, 

food or oil purposes. 

Store away from feeds 

and foodstuffs. 

Rotational crop 

restrictions as detailed 

in Appendix D. 

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Table 3. 3. Summary of Directions for Use of Penflufen 

Application 

Timing, Type, 

and PHI Use Directions and 

Equipment Formulation Use Rates (days) Limitations 

sunflower, 

safflower only) 

3.4 Anticipated Exposure Pathways 

The Registration Division has requested an assessment of human health risk to support the 

proposed new use of penflufen on alfalfa, potatoes, legume vegetables including soybeans, cereal 

grains, and oilseeds. Humans may be exposed to penflufen in their diet resulting from residues 

present in foods grown from penflufen treated seeds. Further, given the environmental fate 

parameters of penflufen and the proposed use outdoors in agricultural settings, the potential 

exists for penflufen to reach water resources resulting in potential residues in drinking water. 

There are no residential uses of penflufen, so exposure in residential and non-occupational 

settings is not likely. In an occupational setting, applicators may be exposed while handling the 

pesticide prior to application, as well as during application. There is also potential for exposure 

to planters who are handling treated seeds. The potential for postapplication exposures following 

the planting of penflufen-treated seeds is unlikely because sustained levels of contact with 

treated seed after it has been planted in the soil or other planting media would not be expected. 

These are the first registrations proposed for penflufen; therefore, this is the first risk assessment 

prepared by the Agency to address potential risks associated with the use of this new fungicide. 

This assessment will consider the dietary and worker risks aforementioned for all newly 

proposed uses of penflufen. 

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the USDA under the Continuing 

Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to 

assess dietary exposure to smaller, specialized subgroups and exposure assessments are 

performed when conditions or circumstances warrant. Whenever appropriate, non-dietary 

exposures based on home use of pesticide products and associated risks for adult applicators and 

for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. 

Further considerations are currently in development as OPP has committed resources and 

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Penflufen Human Health Risk Assessment D387450 

expertise to the development of specialized software and models that consider exposure to 

bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups. 

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis 

Based on the proposed use pattern, all required studies for penflufen have been submitted. The 

available toxicology database is sufficient for assessing the toxicity and characterizing the hazard 

of the chemical. The available toxicology studies for penflufen are listed in Table A.1 in 

Appendix A. 

• Acute lethality studies (oral, dermal, inhalation, primary eye and dermal irritation, 

and dermal sensitization) 

• Subchronic oral toxicity studies (rat, mouse, and dog) 

• Developmental (rat and rabbit) and reproductive toxicity (rat) studies 

• Dermal toxicity and dermal penetration studies (28-day dermal toxicity, in vivo 

dermal penetration, comparative in vitro dermal penetration (rat vs human skin) 

• Neurotoxicity (acute and subchronic) and immunotoxicity studies (rat and mouse) 

• Chronic oral toxicity studies (rat, mouse, dog) 

• Carcinogenicity studies [rat (chronic combined) and mouse] 

• Metabolism studies (rat) 

• Mutagenicity battery (parent and metabolites) 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME) 

The absorption, distribution, metabolism and excretion of penflufen in rats were investigated 

with both [phenyl-UL-13C6/

14C] - and [pyrazole-3-14C]-labeled test compounds. The absorption, 

distribution, metabolism, and excretion of the metabolite penflufen-3-hydroxy-butyl were also 

investigated. 

Absorption: The absorption of the radioactivity from the gastrointestinal tract (GIT) was rapid 

(within 40 to 90 minutes) and almost complete (94%). 

Distribution: The results from the whole body autoradiography showed that the radioactivity 

was distributed among all tissues, and tissue concentrations were in the same order of magnitude 

irrespective of the position of the radiolabel. Highest residues were observed in the blood, liver, 

and kidney. Generally, concentrations in the tissues/organs were proportional to the dose. 

Elimination: No significant differences in the excretion pattern of radioactivity were observed 

between the two positions of radiolabel or between sexes. More than 93% of the administered 

radioactivity was excreted at study termination for both radiolabels. The plasma concentration 

curves showed a fast elimination phase, and the t1/2 elim 1 was 20-24 hours. The radioactivity 

Page 14 of 106 
Penflufen Human Health Risk Assessment D387450 

concentration in the plasma declined to ≈1%- ≈3.6% of the maximum value within 72 hours post 

dose. Both sexes showed one terminal elimination phase at the low dose, whereas a second 

maximum plasma concentration value was exhibited after 48 hours at the high dose, possibly due 

to enterohepatic circulation. 

Metabolism: Penflufen was very extensively metabolized in the rat, and numerous metabolites 

were identified. Unchanged parent compound was found only in low percentages of the 

administered radioactivity. Metabolic reactions were detected in at least 10 different positions of 

the molecule, and a large number of metabolites were identified. Most of the metabolites were 

demethylated in the pyrazole ring. Hydroxylation was another major metabolic reaction leading 

to trihydroxy and dihydroxy compounds, with only a minor part of the metabolites hydroxylated 

in only a single position. Further oxidation of hydroxy groups yielded ketones or carboxylic 

acids. A prominent hydroxylation reaction occurred in the 3 position of the alkyl side chain, and 

the single metabolite, penflufen-3-hydroxy-butyl, was detected in very low amounts. However, 

many metabolites originating from penflufen-3-hydroxy-butyl were identified, and this 

metabolite was considered a key intermediate in the rat metabolism. This assumption was 

supported by the findings of a separate rat ADME study with penflufen-3-hydroxy-butyl, which 

showed the same metabolic pattern as in the metabolism studies with the parent compound, 

demonstrating that the rat is systemically exposed to penflufen-3-hydroxy-butyl after 

administration of penflufen. 

4.2.1 Dermal Absorption 

Dermal absorption is minimal (<1%), based on the findings from two dermal penetration studies 

available for penflufen; an in vivo single 8-hour application to rats and an in vitro dermal 

absorption study (human and rat skin). 

4.3 Toxicological Effects 

Penflufen is an alkylamide fungicide belonging to the chemical class of carboxamides. The 

reported pesticidal mode of action is as an inhibitor of mitochondrial respiration by inhibiting 

succinate dehydrogenase, an enzyme in the electron transport system. 

The liver and thyroid are target organs for penflufen. Increased liver weight, alterations in 

clinical chemistry parameters relevant to effects on the liver, and an increase in the incidence of 

hepatocellular hypertrophy were consistent findings across species and duration of exposure (28-

day, 90-day, and 1- to 2-year exposure periods). The hepatic total cytochrome P-450 content, 

and benzoxyresorufin (BROD) and pentoxyresorufin (PROD) enzyme activities, were shown to 

be increased in rats of both sexes following subchronic oral exposure. Additionally, increased 

incidence of thyroid follicular cell hypertrophy/hyperplasia was observed across studies and 

species (no data provided on thyroid hormone levels). The liver and thyroid findings were 

mostly reversible after a 3-month recovery period in the rat. In the rat and mouse, following 104 

week/78 week exposure periods at dose levels up to and/or greater than the limit dose, there was 

no increase in the incidence of liver or thyroid tumors. 

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Penflufen Human Health Risk Assessment D387450 

Reproductive toxicity was observed in the 2-generation reproduction study in rats. Delayed 

sexual maturation was observed in females in both generations, and magnitude of the associated 

decline in body weight was not considered to be a factor in the delay in sexual maturation.

Developmental toxicity was not observed in the rat or rabbit, although the dose levels in both 

studies were not considered adequate to assess developmental toxicity potential of penflufen. 

However, there is little concern that new studies would identify a developmental endpoint with a 

NOAEL lower than the NOAEL selected for risk assessment. 

Decreased motor/locomotor activity was observed in both sexes of rats following acute and in 

female rats following subchronic oral exposure, although neuropathological lesions were not 

observed in either study. 

There are no mutagenicity concerns. The animal toxicity data on penflufen are suggestive of 

carcinogenicity, which raises a concern for carcinogenic effects but are judged not sufficient for 

quantification of cancer risk in humans. The classification is based on the presence of a 

statistically significant increase in histiocytic sarcomas in male rats, a marginal increase in brain 

astrocytomas, a fatal tumor, in male rats at the high dose, and ovarian adenomas in female rats at 

the high dose. There was no evidence of carcinogenicity in male or female mice 

4.4 Safety factor for Infants and Children (FQPA Safety Factor) 

The Agency recommends that the 10X FQPA safety factor for the protection of infants and 

children, be reduced to 1X. The risk assessments conducted for penflufen were based on the 

most sensitive endpoints in the toxicity database, and the NOAELs selected for risk assessment 

are considered protective of potential developmental, neurotoxic, and immunotoxic effects for 

infants and children. Highly conservative exposure estimates were incorporated into the risk 

assessment for penflufen. There are no residual uncertainties with regard to pre- and/or postnatal 

toxicity or neurotoxicity, and exposure; therefore, reduction of the 10X FQPA safety factor to 1X 

is appropriate as described in the following sections. 

4.4.1 Completeness of the Toxicology Database 

As discussed in Sections 4.1 and 4.4, above, the toxicology database for penflufen is complete 

for consideration of estimated risks for all populations of concern, particularly with respect to 

studies that address the sensitivity of infants and children. 

4.4.2 Evidence of Neurotoxicity 

In the acute neurotoxicity study in rats for penflufen, clinical signs including urine stain in both 

sexes, an increased incidence of stiff-legged hind limbs, locomotor in-coordination, decreased 

activity, and clear lacrimation (production and shedding of tears) in females were observed, and 

there was a dose-related decrease in motor activity and locomotor activity in both sexes. 

Habituation was not affected at any dose level in either sex. In the FOB, females showed a 

decrease in body temperature compared to the control. Body weights and body weight gains 

were comparable among the groups (both sexes). All signs of toxicity resolved by day 7. Brain 

weight was not affected, and there were no compound-related gross or microscopic lesions. 

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Penflufen Human Health Risk Assessment D387450 

 In the subchronic neurotoxicity study in rats, there were no consistent findings during the FOB 

(other than body weight effects), and no treatment-related neuropathological lesions were 

observed in either sex that could be attributed to treatment. Motor activity was slightly reduced 

in females, which is consistent with the findings following acute exposure. 

There is no other evidence in the toxicology database on penflufen that demonstrates any 

potential for penflufen to cause any permanent or long-term peripheral or central nervous system 

toxicity. The clinical findings observed in the acute study followed a gavage dose and resolved 

within 7 days. 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal 

In the 2-generation reproduction study in rats, a slight decrease in litter size (both generations), 

decreased pup body weight and pup body-weight gain, delayed vaginal patency (both 

generations), and decreased brain, spleen, and thymus weights were observed in the offspring at 

the same dose level where decreased body weight, decreased body weight gain, alterations in 

food consumption, decreased thymus weight in both genders, and decreased spleen weights in 

females (both generations) were observed in the adult rat. 

In the rat developmental toxicity study, the maternal findings at the highest dose tested are 

considered minimal. Although there was a significant reduction in maternal body weight gain at 

the high dose, which correlated with a decrease in food consumption, body weights were 

comparable to those of the control, and the liver changes are considered adaptive and not 

adverse. No adverse effects were observed on the foetuses. The dose levels tested are not 

considered adequate for assessing the developmental toxicity potential of penflufen. 

In the developmental toxicity study in rabbits, the maternal findings at the highest dose tested are 

considered minimal. Although there was a significant reduction in maternal body weight gain at 

the high dose, which correlated with a decrease in food consumption, body weights were 

comparable to those of the control. No other effects were observed. No adverse effects were 

observed at the highest dose tested. The dose levels do not appear adequate for assessing the 

developmental toxicity potential of penflufen in the rabbit.

 Although there is some evidence of qualitative sensitivity of the young (delayed sexual 

maturation and decreased little size), the effects are well characterized, and there is a clear 

NOAEL. The dose level where offspring effects were identified in the reproduction study is 

comparable to the high dose used in the rat developmental toxicity study where no effects were 

identified in either the maternal or fetal rat. Since minimal/no effects were observed in the 

developmental toxicity studies following exposure of the maternal animals to dose levels equal 

to and greater than those tested in the studies used for risk assessment, there is little concern that 

new studies would identify a developmental endpoint with a NOAEL lower than the NOAELs 

selected for risk assessment. 

4.4.4 Residual Uncertainty in the Exposure Database 

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There is no residual uncertainty in the exposure database for penflufen with respect to dietary 

(food and water) exposure. 

A complete database with respect to both the nature and magnitude of residues expected in food 

has been provided. The dietary food exposure assessment is based on tolerance level residues, 

assumes 100% crop treated for all commodities, and incorporates processing factors as 

appropriate which results in very high-end estimates of dietary food exposure. Further, highly 

conservative, modeled drinking estimates of exposure were included in the assessments. Actual 

exposures and risks from penflufen in food and drinking water are likely to be far lower than 

estimated in this risk assessment. 

4.5 Toxicity Endpoint and Point of Departure Selections 

4.5.1 Dose-Response Assessment 

A detailed description of the toxicity studies used for selecting toxicity endpoints and points of 

departure for various exposure scenarios, as well as a detailed rationale for selection of the 

toxicity endpoints are presented in Appendix A. 

For the acute dietary risk assessment, the aPAD of 0.50 mg/kg/day was selected for assessment 

of all populations, based on a NOAEL of 50 mg/kg/day in the rat acute neurotoxicity study with 

decreased motor and locomotor activities in females observed at 100 mg/kg/day. This endpoint 

is a single-dose effect and is appropriate for the populations of concern. Neither the rat nor the 

rabbit developmental toxicity study provides an alternate endpoint since no adverse effects were 

observed at the highest dose levels tested (300 mg/kg/day and 600 mg/kg/day) in those studies. 

The endpoint selected for the acute risk assessment is considered protective of potential 

developmental effects that might occur at higher dose levels. 

For the chronic dietary risk assessment, the cPAD of 0.38 mg/kg/day was selected for 

assessments of all populations, based on a NOAEL of 38 mg/kg/day from the chronic dog study. 

The LOAEL of 357 mg/kg/day is based on decreased terminal body weight and body weight 

gain (females), increased prothrombin time (males), increased alkaline phosphate activity, 

decreased cholesterol, increased GGT levels, decreased albumin and albumin/globulin ratio, 

decreased calcium and phosphorus, increased liver weights, increased incidence of focal 

hepatocellular brown pigment and hepatocellular hypertrophy, and an increased incidence of 

thyroid follicular cell hypertrophy in both sexes and an increased incidence of vacuolations of 

the adrenal glands (females). This study provided the most sensitive endpoint available and is 

appropriate for chronic dietary exposure due to the route (oral) and duration (chronic) of dosing. 

For the repeat dose studies available, the dose spread is large in all cases (LOAEL of 250-532 

mg/kg/day), and the NOAELs are similar (males: 32-64 mg/kg/day/females: 38-76 mg/kg/day). 

The chronic dog study provides the only NOAEL that is lower than the acute NOAEL. 

For occupational exposure scenarios involving dermal exposure, no hazard was identified. This 

is based on the lack of dermal irritation or systemic effects at the limit dose (1000 mg/kg/day) in 

a 28-day dermal toxicity study in rats, and the fact that dermal absorption is minimal (<1%). 

This is a route-specific study that also assessed all of the endpoints used in the other exposure 

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Penflufen Human Health Risk Assessment D387450 

scenarios and durations of exposure (e.g. neurological endpoints, thyroid and liver 

histopathology). Additionally, the endpoints assessed in the maternal animals are also assessed 

in the dermal studies. No increased susceptibility was seen between offspring and adult animals 

in the developmental toxicity studies in rats and rabbits and in the 2-generation reproduction 

study in rats. Reproductive toxicity was observed in the 2-generation reproduction study, based 

on delayed sexual maturation in the females in both generations. Given a dermal absorption 

factor of 1%, which was calculated using data from a rat in vivo study and a human:rat in vitro

study (see Appendix A.3. for details), the dermal equivalent dose NOAEL for the delays in 

sexual maturation would be approximately 5800 mg/kg/day, well above the limit dose for the 

dermal toxicity study. Therefore, the quantification of dermal risk is not required since no hazard 

was identified. 

For short-term occupational exposure scenarios involving inhalation exposure, the NOAEL of 

55.7 mg/kg/day was selected from the dog oral subchronic toxicity study. The LOAEL of 532 

mg/kg/day was based on decreased body weight/body weight gain in females, increased alkaline 

phosphatase activity in both sexes, increased GGT activity in both sexes, decreased albumin in 

males, increased liver weights in both sexes, increased adrenal weights in males, increased 

incidence of hepatocellular hypertrophy in both sexes, and an increased incidence of slight 

diffuse cortical hypertrophy/hyperplasia in the adrenal in males. No inhalation studies are 

available for penflufen. Although a repeat dose inhalation study is a data requirement, based on 

the magnitude of the inhalation MOEs and the Toxicity Category IV classification for acute 

inhalation exposure, this requirement can be waived. For all of the repeat oral dose studies 

considered for this exposure scenario, the dose spread is large in all cases (LOAEL of 250-532 

mg/kg/day), and the NOAELs are similar (males: 32-64 mg/kg/day; females: 38-76 mg/kg/day). 

The subchronic dog study is appropriate for this duration of exposure. In the rat repeat dose 

subchronic oral toxicity studies at dose levels up to the limit dose and NOAELs > 200 

mg/kg/day, the effects on the liver are considered mostly adaptive. In the dog studies, the 

duration of the study relative to the lifespan of the dog is short compared to rat studies, which 

encompass a greater proportion of the rat’s life; therefore, it is not known whether the liver 

effects in the dog studies are adaptive. Although the liver findings in the dog study at the 

LOAEL may not be adverse, because the dog studies encompass a small proportion of the dog’s 

lifespan, they are considered appropriate as the basis for the LOAEL. The dog study provides the 

lowest NOAEL for this duration of exposure.

For the intermediate-term occupational exposure scenarios involving inhalation exposure, the 

NOAEL of 38 mg/kg/day was selected from the chronic dog oral toxicity study. The LOAEL of 

357 mg/kg/day was based on decreased terminal body weight and body weight gain (females), 

increased prothrombin time (males), increased alkaline phosphate activity, decreased cholesterol, 

increased GGT levels, decreased albumin and albumin/globulin ratio, decreased calcium and 

phosphorus, increased liver weights, increased incidence of focal hepatocellular brown pigment 

and hepatocellular hypertrophy, and an increased incidence of thyroid follicular cell hypertrophy 

in both sexes, and an increased incidence of vacuolation of the adrenal gland in females. The 

chronic oral toxicity study in dogs is appropriate for this duration of exposure. The selected 

endpoint is the most sensitive endpoint in the data base. 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment 

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Penflufen Human Health Risk Assessment D387450 

As part of conducting a human health risk assessment process, the Agency considers risks from 

individual routes of exposure (oral, dermal, and inhalation). Additionally, the Agency must 

assess aggregate risks from dietary and residential exposures. In order to conduct an aggregate 

risk assessment a determination is made if it is appropriate to combine across routes of exposure 

and aggregate dietary risks with residential (non-occupational) risks. At this time, there are no 

residential uses for penflufen, so a discussion of combining routes of exposure is not pertinent to 

this assessment. 

4.5.3 Cancer Classification and Risk Assessment Recommendation 

The CARC concluded that penflufen exhibits “Suggestive Evidence of Carcinogenic Potential” 

based on the presence of statistically significant increase in histiocytic sarcomas with a positive 

trend in male rats only (but in the absence of a dose response and lack of pre-neoplastic lesions). 

A marginal increase in brain astrocytomas was also observed in males at the high dose; however, 

this effect was not dose-related, did not reach statistical significance, and there was no overall 

trend. In addition, there were no pre-neoplastic lesions, such as glial proliferations, which are a 

good indicator of chemical tumor induction (i.e., there will be changes in the cells prior to 

transformation to a neoplasm). The ovarian adenomas observed at the high dose also showed no 

dose response, no pair-wise significance, no decrease in latency, and there were no preneoplastic lesions such as hyperplasia of the epithelial cells of the endometrium. Additionally, 

there was no evidence of carcinogenicity in male or female mice (at doses that were judged to be 

adequate to assess the carcinogenic potential), no concern for mutagenicity (in vivo or in vitro)

for the parent molecule or the two metabolites, and there were no other lines of evidence (such as 

structure-activity relationship). Therefore based on the single line of limited evidence for 

carcinogenicity (histiocytic sarcomas in male rats), a stronger conclusion for carcinogenic 

potential could not be supported and thus, the weight of evidence is suggestive of carcinogenic 

potential for penflufen. Also, according the Guidelines, when there is a “Suggestive” 

classification, the Agency does not attempt a dose-response assessment, as the nature of the data 

generally would not support one. Therefore, the Agency has determined that quantification of 

risk using a non-linear approach (i.e., RfD) will adequately account for all chronic toxicity, 

including carcinogenicity, which could result from exposure to penflufen. The NOAEL (38 

mg/kg/day) used for establishing the Chronic RfD is approximately 10-fold lower than the dose 

(approximately 300 mg/kg/day) that induced a marginal non-significant increase in brain tumors 

in male rats. 

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment 

Table 4.5.3 summarizes the toxicological doses and endpoints selected for the acute and chronic 

dietary risk assessments and non-occupational inhalation exposure scenarios for penflufen. Table 

4.5.4 summarizes the toxicological doses and endpoints selected for the short- and intermediateterm occupational inhalation exposure scenarios for penflufen. 

 

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Table 4.5.3 Summary of Toxicological Doses and Endpoints for Penflufen for Use in Dietary and Residential 

(Non-Occupational) Human Health Risk Assessments 

Exposure/ 

Scenario 

Point of 

Departure 

Uncertainty/FQPA 

Safety Factors 

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment Study and Toxicological Effects 

Acute Dietary 

(All 

populations, 

including 

children and 

women 13-49 

years of age) 

NOAEL= 

50 

mg/kg/day 

UFA= 10 x 

UFH=10 x 

FQPA SF = 1x 

Acute RfD = 

0.50 mg/kg/day 

aPAD =0.5 

mg/kg/day 

Acute neurotoxicity study in rats 

(MRID 48023829) 

LOAEL = 100 mg/kg, based on decreased 

motor and locomotor activity (39-81% 

on day of treatment) in females 

Chronic 

Dietary (All 

Populations) 

NOAEL= 

38 

mg/kg/day 

UFA= 10 x 

UFH=10 x 

FQPA SF = 1x 

Chronic RfD = 

0.38 

mg/kg/day 

cPAD = 0.38 

mg/kg/day 

Chronic toxicity study in dogs 

(MRID 48023813) 

LOAEL = 357/425 mg/kg/day, based on 

decreased terminal body weight and body 

weight gain (females), increased 

prothrombin time (males), increased 

alkaline phosphate activity, decreased 

cholesterol , increased GGT levels, 

decreased albumin and albumin/globulin 

ratio, decreased calcium and phosphorus , 

increased liver weights , increased 

incidence of focal hepatocellular brown 

pigment and hepatocellular hypertrophy, 

and an increased incidence of thyroid 

follicular cell hypertrophy in both sexes, 

and in increased incidence of zona 

glomerulosa vacuolation of the adrenal 

gland in females. 

Inhalation 

Short- Term 

(1-30 days) 

NOAEL= 

55.7 

mg/kg/day 

UFA= 10 x 

UFH=10 x 

FQPA SF = 1x 

Nonoccupational 

LOC for MOE 

= 100 

Subchronic oral toxicity study in dogs 

 (MRID 48023808) 

LOAEL = 532/568 mg/kg/day, based on 

decreased body weight/body weight gain 

(females), clinical chemistry changes, 

increased liver weights, and increased 

incidence of hepatocellular hypertrophy 

in both sexes, and an increased incidence 

of slight diffuse cortical 

hypertrophy/hyperplasia in the adrenal in 

males. 

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Penflufen Human Health Risk Assessment D387450 

Table 4.5.3 Summary of Toxicological Doses and Endpoints for Penflufen for Use in Dietary and Residential 

(Non-Occupational) Human Health Risk Assessments 

Exposure/ 

Scenario 

Point of 

Departure 

RfD, PAD, 

Level of 

Concern for 

Uncertainty/FQPA Risk 

Safety Factors Assessment Study and Toxicological Effects 

Inhalation 

IntermediateTerm (1-6 

months) 

NOAEL= 

38 

mg/kg/day 

Assume 

inhalation 

toxicity 

equivalent 

to oral 

toxicity 

UFA= 10 x 

UFH=10 x 

FQPA SF= 1 x 

Residential 

LOC for MOE 

= 100 

Chronic toxicity study in dogs 

(MRID 48023813) 

LOAEL = 357/425 mg/kg/day, based on 

decreased terminal body weight and body 

weight gain (females), increased 

prothrombin time (males), increased 

alkaline phosphate activity, decreased 

cholesterol, increased GGT levels, 

decreased albumin and albumin/globulin 

ratio, decreased calcium and phosphorus, 

increased liver weights, increased 

incidence of focal hepatocellular brown 

pigment and hepatocellular hypertrophy, 

and an increased incidence of thyroid 

follicular cell hypertrophy in both sexes, 

and increased incidence of zona 

glomerulosa vacuolation of the adrenal 

gland in females. 

Cancer (oral, 

dermal, 

inhalation) 

Classification: “Suggestive”. Quantification of risk using a non-linear approach (i.e., RfD) will 

adequately account for all chronic toxicity, including carcinogenicity that could result from 

exposure to penflufen. 

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning 

of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. 

LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = 

potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population 

adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern.

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile 

5.1.1 Summary of Plant and Livestock Metabolism Studies 

5.1.1.1 Plant Metabolism Studies 

Plant metabolism data were submitted for potato (seed treatment and in-furrow applications), 

wheat (seed treatment), soybean (seed treatment), and rice (at transplant) to support the requested 

new uses of penflufen. Studies for all commodities reflected labeling in both the phenyl and 

pyrazole rings, application rates were equal to, or exaggerations of the currently proposed use 

rates and application techniques reflect the request application patterns. 

The metabolic pathway in potatoes, wheat, soybeans and rice is substantially similar. Following 

seed treatment or in-furrow use of penflufen in potatoes, wheat, soybeans and rice, degradation 

appears to follow three major pathways: 1) substitution of glutathione for fluorine on the 

pyrazole ring followed by hydrolysis of the glutathione moiety to cysteine; 2) hydroxylation of 

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the third or fourth carbon on the butyl substituent, followed by conjugation with glucose and 

malonic acid; and 3) cleavage of the N-phenyl linkage. 

While the proposed metabolic pathways for these crops are similar, in the absence of data on a 

fruiting vegetable, this data set is not considered adequate to define the nature of the residue in 

all plants. Further, since the application techniques were limited to seed treatment, in-furrow or 

at transplant (rice), these data will not support foliar uses of penflufen on agricultural crops. 

However, the submitted metabolism data are considered adequate to support the requested seed 

treatment uses on alfalfa, legume vegetables, cereal grains, oils seeds and the use on potatoes as 

a seed piece treatment and a single in-furrow application. 

A summary of the major findings from each of the plant metabolism studies are included in 

Appendix B. 

5.1.1.2 Livestock Metabolism Studies 

Livestock metabolism studies were submitted for the hen (poultry) and lactating goat (ruminant) 

for penflufen to support the requested new uses. Studies in both animals reflected labeling in 

both the phenyl and pyrazole rings. 

Penflufen is extensively metabolized in the hen and lactating goat. The metabolic pathways in 

poultry and ruminants appear similar. No difference in metabolic profile was noted between the 

pyrazole and phenyl ring labeled studies. The main metabolic pathways in livestock involve Ndemethylation in the pyrazole ring, hydroxylation at various positions in the molecule, oxidation 

to keto and to carboxylic acid groups, conjugations with glucuronic acid and cleavage of the Nphenyl and carboxamide bond. 

The submitted livestock metabolism studies adequately address the requirement to elucidate the 

nature of the residue in livestock for penflufen. The Agency has determined that the newly 

proposed uses of penflufen are classified as 180.6 (a) (3), no reasonable expectation of finite 

residues with respect to residues in a livestock commodities since quantifiable residues are not 

likely to be present in the livestock feedstuffs associated with this petition. 

A summary of the major findings from the laying hen and goat metabolism studies are included 

in Appendix B. 

5.1.2 Summary of Environmental Degradation 

Drinking Water Memo, D386698, R. Baris, 8/25/10 

Penflufen is persistent in aerobic and anaerobic conditions, and is moderately mobile based on 

the FAO Soil mobility classifications (mean Koc = 365; MRID 48023546) (USEPA, 2006). 

Penflufen is persistent in soil with half-lives ranging from 115 to 433 days in aerobic soil from 

two studies conducted in six soils (MRID 48023552, 48023553). It degrades very slowly in 

anaerobic soil with an extrapolated half-life of 886 days (combined label; MRID 48023555). 

There is no evidence of degradation via hydrolysis, which was studied across environmental pHs 

(pH 5, 7, and 9 at 50oC; MRID 48023547). Penflufen degraded slowly by aerobic aquatic 

metabolism with half-lives ranging from 267 to 301 days (MRID 48023556); there is no 

Page 23 of 106 
Penflufen Human Health Risk Assessment D387450 

evidence of degradation in anaerobic aquatic systems (MRID 48023557). The primary route of 

degradation is via aqueous photolysis (17 days, corrected environmental half-life of 83.2 days; 

MRID 48023548); however photolysis only plays a significant role in shallow clear waters. 

Penflufen and its residues of concern (Pen-3HB, and AAP) are expected to persist in both the 

terrestrial and aquatic environments. Pen-3HB is much more mobile than the parent, but the AAP 

degradate is comparatively immobile. Under aerobic conditions, the compound can be slowly 

metabolized, but it is stable to anaerobic metabolism. AAP will persist with half-lives ranging 

from 116-260 days (there is no metabolism data for the Pen-3HB degradate). Penflufen was 

detected in the submitted terrestrial field dissipation studies above the level of quantitation 

(LOQ) up to 60cm depth, however the majority of the detections were only reported in the upper 

soil layers (0-15 cm). 

5.1.3 Comparison of Metabolic Pathways 

The metabolism of penflufen in the rat is detailed in Section 4.2 and the metabolism in plants and 

livestock is discussed in Section 5.1.1. Based on the submitted data, the metabolic profile in 

plants is similar in potatoes, cereal grains, oilseeds and legumes. Metabolism in the rat and 

livestock (ruminants and poultry) is similar and, in animals, penflufen is extensively metabolized 

and conjugated. The metabolites identified in the plant metabolism studies are either found as 

metabolites in the animal studies, or are intermediaries in the metabolic pathways elucidated in 

animals; therefore, there are no residues of concern in plant studies, nor are there any unique 

metabolic pathways in the plant, that are not represented in the rat metabolism study. 

5.1.4 Residues of Concern Summary and Rationale 

ROCKS Memo, D387299, W. Irwin, 6/15/2011 

The HED Residues of Concern Knowledgebase Sub-committee (ROCKS) considered the 

available data on the nature and magnitude of residues in penflufen and has concluded that for 

plants, the parent compound only be included for tolerance enforcement and dietary risk 

assessment. At this time, there is no reasonable expectation of finite residues in livestock so the 

committee had no recommendation on residues of concern in livestock. For drinking water, the 

ROCKS recommended including the parent, penflufen-3-hydroxybutyl (Pen-3HB), and 

penflufen-pyrazolyl-AAP. The reasoning behind these recommendations is as follows: 

 

• Hazard Considerations: Technical penflufen displayed low acute toxicity via the oral, 

dermal and inhalation routes of exposure (Toxicity Categories III and IV). Increased 

liver weight, hepatocellular hypertrophy, and thyroid hypertrophy were observed in 

several animal studies throughout the penflufen toxicity database. Reproductive toxicity 

(delayed sexual maturation) was observed in females in both generations in the rat 

reproduction study. There are no neurotoxicity or mutagenicity concerns. Mutagenicity 

studies with penflufen-pyrazolyl-AAP and Pen-3HB were also negative for mutagenic 

activity. However, penflufen is “suggestive” for carcinogenicity but not sufficient for 

quantitation of cancer risk in humans. A structure activity analysis of penflufen and its 

major metabolites using DEREK v.12 did not raise any concerns for toxic effects that 

were not already observed in the toxicity database. 

• Drinking Water: Parent penflufen, and the metabolites Pen-3HB and penflufenPage 24 of 106 
Penflufen Human Health Risk Assessment D387450 

pyrazolyl-AAP (AAP) were identified as potential major degradates in drinking water. 

Penflufen is relatively stable in soil degradation studies (t1⁄2 > 100 days) and is not 

susceptible to hydrolysis. Concentrations of the degradates were increasing at the end of 

the degradation studies precluding accurate measures of half-lives. Therefore, there is a 

reasonable expectation of exposure to these compounds. Since the structures of the 

metabolites are similar to the parent, they are assumed to have similar toxicities. 

Therefore, ROCKS recommended that parent penflufen, Pen-3HB and AAP be included 

as residues of concern for drinking water. In addition, since penflufen is susceptible to 

photolysis, the ROCKS committee recommended that the metabolites M60 (fluoro acid) 

and M64 (bis-desmethyl-3-carboxylic acid) be reassessed should there be any uses 

proposed where aqueous photolysis may be a significant route of environmental 

dissipation. 

• Primary/Rotational crops: The proposed use for penflufen is seed treatment or in-furrow 

treatment (potatoes only) so the ROCKS recommendation is based on these uses only. 

Since the metabolic and degradation pathways for primary/rotational crops are similar, all 

crops will be discussed together. 

Residues identified in the plant metabolism and confined rotational studies included 

parent, Pen-3HB, Pen-HGT, Pen-PCX, and Pen-D3C. Total residues in the plant are low 

in the primary crop metabolism studies, which reflect the proposed seed treatment uses. 

In confined rotational crop studies at 3X application rates, some metabolites were in the 

ppb range (i.e., Pen-3HB); at exaggerated application rates of up to 10X, only low levels 

of parent were measured in forage materials. Similarly, residues were low or nondetectable in field trials. Of those that were identified, they were largely conjugated and 

most likely to be found in livestock feedstuffs and are a lesser concern. Based on 

structure and SAR analysis, the metabolites identified in the plant studies are not likely to 

be more toxic than the parent penflufen. 

Therefore, due to the low quantities identified, the conjugated nature of the residues that 

were identified, and likelihood that the residues will be found in livestock feedstuff at 

minimal levels, the ROCKS recommended parent only be included for risk assessment 

and tolerance. If there is gross misuse, there is likely to be parent residues that would be 

an adequate indicator of misuse. 

The residues of concern for penflufen are summarized in table 5.1.4, below. 

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Penflufen Human Health Risk Assessment D387450 

Table 5.1.4. Penflufen Residues to be Included in the Risk Assessment and Tolerance Expression.

Matrix Residues included in Risk Assessment 

Residues included in Tolerance 

Expression for Compliance 

Monitoring 

Plants Primary Crop Penflufen Penflufen 

Rotational Crop Penflufen Penflufen 

Livestock Ruminant Not applicable; no expectation of finite 

residues in livestock commodities. 

Not applicable; no expectation of 

finite residues in livestock 

commodities. 

Poultry Not applicable; no expectation of finite 

residues in livestock commodities. 

Not applicable; no expectation of 

finite residues in livestock 

commodities. 

Drinking Water Penflufen plus metabolites penflufenhydroxybutyl and penflufen-pyrazolylAAP 

 N/A 

Penflufen Parent: N-[2-(1,3-dimethylbutyl)phenyl]-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide 

Penflufen-hydroxybutyl: Pen-3HB, 5-fluoro-N-[2-(3-hydroxy-1,3-dimethylbutyl)phenyl]-1,3-dimethyl-1H-pyrazole-4-

carboxamide 

Penflufen-pyrazolyl-AAP: N-(2-acetylphenyl)-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide 

5.2 Food Residue Profile 

The submitted data on the metabolism of penflufen in potatoes (seed treatment and in-furrow), 

wheat (seed treatment), soybeans (seed treatment) and rice (in soil at transplant) demonstrate that 

residues are generally low, but do translocate throughout the plants. The highest residues are 

generally found in the foliage or forage portions of plants (feed items), and not in the tubers, 

seeds or grains of these commodities (food items). The registrant has provided studies on 

sunflower, cotton, canola, beans, peas and alfalfa that demonstrate there is no uptake of 

radioactivity into any aerial portion of those plants; indicating that penflufen is not taken up by 

these plants and that there is little likelihood of exposure to penflufen from consuming the edible 

portion of these commodities. Field trial data submitted for the remaining commodities showed 

no quantifiable residues of penflufen in any of the food or feedstuff associated with those 

commodities. 

Adequate residue chemistry data have been provided for penflufen. Field trials are of adequate 

number and geographic representation, were generated using adequate analytical methods and 

are supported by adequate storage stability data. Adequate studies were submitted for corn, 

wheat, soybean and potato to elucidate the fate of penflufen in processed commodities derived 

from these crops. The Agency has determined that the newly proposed uses of penflufen are 

classified as 180.6 (a) (3), no reasonable expectation of finite residues with respect to residues in 

livestock commodities since quantifiable residues are not likely to be present in the livestock 

feedstuffs associated with this petition. Confined rotational crops studies show that the 

metabolism of penflufen in rotated crops is similar to that in primary crops. Limited field trials 

generated using validated analytical methods and supported by adequate storage stability data are 

of adequate number and geographic representation to demonstrate that residues are not likely in 

any commodity planted 30-days after initially planting penflufen-treated seeds. 

Page 26 of 106 
Penflufen Human Health Risk Assessment D387450 

5.3 Water Residue Profile 

Drinking Water Memo, D386698, R. Baris, 8/25/10 

Penflufen is a new chemical; therefore, there are no monitoring data currently available for this 

active ingredient or its residues of concern in drinking water. Estimated drinking water 

concentrations (EDWCs) were generated using OPP’s standard suite of models. The screening 

model FIRST (FQPA Index Reservoir Screening Tool, version 1.1, 01/01/07) was used to 

calculate the surface water EDWCs. Estimated groundwater EDWCs were calculated using the 

screening model SCI-GROW (Screening Concentrations in Ground Water, version 2.3, 

07/29/03). 

Maximum application rates for penflufen as a high-end estimate of exposure in drinking water 

were modeled based on the proposed labels. Chemical specific and model input values were 

chosen in accordance with current input parameter guidance (USEPA, 2009). The two major 

degradates of penflufen (pen-3HB and AAP) were included in this exposure assessment. Total 

toxic residue half-lives were calculated for parent + pen-3HB + AAP. The degradation studies 

were characterized by large amount of un-extracted and uncharacterized material; thus there is 

considerable uncertainty regarding the degradation of penflufen residues in the environment. To 

characterize this uncertainty, model simulations were completed using high-end conservative 

estimates which used half-lives that included un-extracted residues. However, supplemental data 

submitted by the applicant show that a large portion of the un-extracted residues are potentially 

biologically mediated and may be irreversibly bound; EDWCs excluding un-extracted residues 

would be lower than the estimates provided in Table 5.3 (MRID 48652501). Standard default 

percent cropped areas (PCA) were used for all agricultural uses as estimates of the extent of 

watershed on which crops is grown (Effland et al., 1999); the default agricultural PCA of 0.87 

was applied. The use of penflufen as both a seed piece treatment and in-furrow banded 

application to potatoes generated the highest EDWCs for both ground and surface water. The 

maximum surface and ground water EDWCs for use in the human health risk assessment for 

penflufen are shown in Table 5.3. 

 

Table 5.3 Maximum Estimated Surface Water and Groundwater Drinking Water Concentrations for 

Penflufen and Major Degradates1.

Scenario Surface Water Conc., ppb 2 Groundwater Conc., ppb 3

Acute 11.4 16.6 

Chronic (non-cancer) 1.8 16.6 

1

 EDWCs are the total of penflufen, Pen-3HB and AAP, the residues of concern in drinking water. 2

 From the Tier I FQPA Index Reservoir Screening Tool, version 1.1; potato (seed treatment and in-furrow total application 

0.28 lbs ai/A) scenario. 

3

 From the SCI-GROW model; potato scenario. 

Highest value for use in risk assessment is shown in bold.

5.4 Dietary Risk Assessment 

5.4.1 Description of Residue Data Used in Dietary Assessment 

The acute and chronic dietary risk assessment used tolerance level residues for all commodities 

included in the assessment. 

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Penflufen Human Health Risk Assessment D387450 

5.4.2 Percent Crop Treated Used in Dietary Assessment 

The acute and chronic dietary risk assessment assumed 100% crop treated for all commodities 

included in the assessment. 

5.4.3 Acute Dietary Risk Assessment 

A highly conservative acute dietary risk assessment was conducted which used tolerance level 

residues, assumed 100 percent crop treated (% CT) for all commodities, incorporated a DEEMTM 

default processing factor for dried potatoes and included Tier I modeled drinking water 

estimates. The estimated exposure (food and water) to the U.S. population and all modeled 

populations from the proposed new uses of penflufen resulted in an estimated risk equivalent to 

<1% of the acute population adjusted dose (aPAD) at the 95th percentile. 

5.4.4 Chronic Dietary Risk Assessment 

A highly conservative chronic dietary risk assessment was conducted which used tolerance level 

residues, assumed 100 percent crop treated (% CT) for all commodities, incorporated a DEEMTM 

default processing factor for dried potatoes and included Tier I modeled drinking water 

estimates. The estimated exposure (food and water) to the U.S. population and all modeled 

populations from the proposed new uses of penflufen resulted in an estimated risk equivalent to 

<1% of the chronic population adjusted dose. 

5.4.5 Cancer Dietary Risk Assessment 

The Agency has classified penflufen as “suggestive of carcinogenicity” and has concluded that 

the chronic population adjusted dose is protective of all chronic effects, including potential 

carcinogenicity. The results of the chronic dietary risk assessment are discussed in Section 5.4.4. 

5.4.6 Summary Table 

Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and 

Risk for Penflufen 

Population Subgroup 

Acute Dietary 

(95th Percentile) Chronic Dietary 

Dietary 

Exposure 

(mg/kg/day) % aPAD* 

Dietary 

Exposure 

(mg/kg/day) % cPAD* 

General U.S. Population 0.000949 <1% 0.000407 <1% 

All Infants (< 1 year old) 0.003364 <1% 0.001231 <1% 

Children 1-2 years old 0.001546 <1% 0.000650 <1% 

Children 3-5 years old 0.001404 <1% 0.000613 <1% 

Page 28 of 106 
Penflufen Human Health Risk Assessment D387450 

Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and 

Risk for Penflufen 

Acute Dietary Chronic Dietary (95th Percentile) 

Population Subgroup 

Dietary Dietary 

Exposure Exposure 

(mg/kg/day) % aPAD* (mg/kg/day) % cPAD* 

Children 6-12 years old 0.000975 <1% 0.000424 <1% 

Youth 13-19 years old 0.000777 <1% 0.000312 <1% 

Adults 20-49 years old 0.000857 <1% 0.000373 <1% 

Adults 50+ years old 0.000773 <1% 0.000381 <1% 

Females 13-49 years old 0.000856 <1% 0.000369 <1% 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization 

Residential exposures and risk are not assessed because the proposed uses of penflufen do not 

involve applications by homeowners or commercial applicators in residential settings at this time 

and there are no existing or proposed residential uses. 

6.1 Spray Drift 

A postapplication inhalation exposure assessment is not required as exposure is expected to be 

negligible. Seed treatment assessments provide quantitative inhalation exposure assessments for 

seed treaters and secondary handlers (i.e. planters). It is expected that these exposure estimates 

would be protective of most postapplication inhalation exposure scenarios. 

In-furrow potato piece treatment can be applied by spray; however, the pathway from furrow to 

drift is likely to be negligible due to the spray being applied as a soil-directed spray that is then 

immediately covered as part of the planting process. 

7.0 Aggregate Exposure/Risk Characterization 

There are no residential uses for penflufen; therefore the aggregate exposure and risk 

assessments include acute and chronic dietary (food and water) only and are shown in Section 

5.4.3 and 5.4.4. There are no aggregate risk estimates of concern for the proposed new uses of 

penflufen.

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Penflufen Human Health Risk Assessment D387450 

8.0 Cumulative Exposure/Risk Characterization 

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to penflufen and any other substances and penflufen does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that penflufen has a common mechanism of toxicity with other substances. 

For information regarding EPA’s efforts to determine which chemicals have a common 

mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy 

statements released by EPA’s Office of Pesticide Programs concerning common mechanism 

determinations and procedures for cumulating effects from substances found to have a common 

mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. 

9.0 Occupational Exposure/Risk Characterization 

9.1 Short-/Intermediate-Term Handler Risk 

Occupational handler exposure to penflufen is expected for individuals involved in commercial 

seed treatment and on-farm seed treatment. Exposure during in-furrow potato piece treatment is 

also expected. Occupational seed treatment primary handlers may experience short- and 

intermediate-term exposure to penflufen while performing seed treatment activities in 

commercial settings. In addition, occupational secondary handlers may experience short- and 

intermediate-term exposure while planting penflufen-treated seeds. No chemical-specific 

handler exposure data were submitted in support of this use pattern. For assessing commercial 

seed treatment and seed planting activities, unit exposure data were taken from HED ExpoSAC 

Policy 14: SOPs for Seed Treatment and MRID 47054702 (Study Review of “Determination of 

Dermal and Inhalation Exposure of Workers during On-Farm Seed Piece Treatment of Potatoes”. 

MRID 47054702. Bayer CropScience. D378750, S. Tadayon, 6/23/10). The amount of active 

ingredient handled depends on the application rate (lb ai/lb seed) and the pounds of seed treated 

in a day (or the pounds of seed that can be planted in a day), all of which vary depending upon 

the seed type. Values for the amount of seed treated and planted per day were obtained from 

HED ExpoSAC Policy 15. For the potato seed piece treatment exposure assessment, unit 

exposures were also used from the Occupational Pesticide Handler Unit Exposure Surrogate 

Reference Table. 

Quantification of dermal exposure and risk is not required since a dermal hazard has not been 

identified for penflufen. Only inhalation exposure and risks were quantified. The occupational 

inhalation exposure assessment was completed for commercial seed treatments. On-farm seed 

treatment utilizes similar machinery as commercial seed treatment; the only difference being the 

size of the equipment. With the specific labels restricting direct product use in hopper-boxes, 

planter-boxes, and slurry-boxes, the assessed commercial seed treatment exposure and risk is 

protective of on-farm seed treatment scenarios. The proposed personal protective equipment 

(PPE) for penflufen on all proposed labels requires that all mixers, loaders, applicators and other 

Page 30 of 106 
Penflufen Human Health Risk Assessment D387450 

handlers to wear long sleeved shirt and long pants, socks plus shoes, and chemical resistant 

gloves (except when bagging or sewing bags of treated seeds). 

Short- and intermediate-term handler exposures and risk estimates for seed treatment activities 

are shown in Tables 9.1.1, 9.1.2, 9.1.3 and 9.1.4, below. All inhalation risk estimates greatly 

exceed HED’s level of concern and; therefore, are not of concern. 

Table 9.1.1. Summary of Short- and Intermediate-Term Handler Exposures and Risks for Penflufen (Seed 

Treatment Only). 

Seed Type 

Inhalation 

UEa Max App Rateb Amt Treatedc Inhalatopm Dosed

Short-Term 

Inhal MOEe

IntermediateTerm Inhal 

MOEf

mg/lb lb ai/lb seed lb seed/day mg/kg/day LOC = 100 LOC = 100 

LOADER/APPLICATOR (no respirator) 

Alfalfa 0.00034 0.00015 718,000 0.00052 110,000 73,000 

Beans and Peas 0.00034 0.00005 194,000 0.000047 1,200,000 810,000 

Soybean 0.00034 0.00005 718,000 0.00017 320,000 220,000 

Cereal Grains, 

incl. Rice 0.00034 0.00005 718,000 0.00017 320,000 220,000 

Canola 0.00034 0.00015 104,000 0.000076 740,000 500,000 

Field Corn 0.00034 0.0001 550,000 0.00027 210,000 140,000 

Sweet Corn 0.00034 0.0001 194,000 0.000094 590,000 400,000 

Cotton 0.00034 0.0001 160,000 0.000078 720,000 490,000 

Sunflower and 

safflower 0.00034 0.00015 718,000 0.00052 110,000 73,000 

Sorghum 0.00034 0.0001 718,000 0.00035 160,000 110,000 

SEWER (no respirator) 

Alfalfa 0.00023 0.00015 718,000 0.00035 160,000 110,000 

Beans and Peas 0.00023 0.00005 194,000 0.000032 1,700,000 1,200,000 

Soybean 0.00023 0.00005 718,000 0.00012 470,000 320,000 

Cereal Grains, 

incl. Rice 0.00023 0.00005 718,000 0.00012 470,000 320,000 

Canola 0.00023 0.00015 104,000 0.000051 1,100,000 740,000 

Field Corn 0.00023 0.0001 550,000 0.00018 310,000 210,000 

Sweet Corn 0.00023 0.0001 194,000 0.000064 870,000 600,000 

Cotton 0.00023 0.0001 160,000 0.000053 1,100,000 720,000 

Sunflower and 

safflower 0.00023 0.00015 718,000 0.00035 160,000 110,000 

Sorghum 0.00023 0.0001 718,000 0.00024 240,000 160,000 

BAGGER (no respirator) 

Alfalfa 0.00016 0.00015 718,000 0.00025 230,000 150,000 

Beans and Peas 0.00016 0.00005 194,000 0.000022 2,500,000 1,700,000 

Soybean 0.00016 0.00005 718,000 0.000082 680,000 460,000 

Cereal Grains, 

incl. Rice 0.00016 0.00005 718,000 0.000082 680,000 460,000 

Canola 0.00016 0.00015 104,000 0.000036 1,600,000 1,100,000 

Field Corn 0.00016 0.0001 550,000 0.00013 440,000 300,000 

Sweet Corn 0.00016 0.0001 194,000 0.000044 1,300,000 860,000 

Cotton 0.00016 0.0001 160,000 0.000037 1,500,000 1,000,000 

Sunflower and 0.00016 0.00015 718,000 0.00025 230,000 150,000 

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Penflufen Human Health Risk Assessment D387450 

Table 9.1.1. Summary of Short- and Intermediate-Term Handler Exposures and Risks for Penflufen (Seed 

Treatment Only). 

Seed Type 

Inhalation 

UEa Max App Rateb Amt Treatedc Inhalatopm Dosed

Intermediate- Short-Term Term Inhal Inhal MOEe

MOEf

mg/lb lb ai/lb seed lb seed/day mg/kg/day LOC = 100 LOC = 100 

safflower 

Sorghum 0.00016 0.0001 718,000 0.00016 340,000 230,000 

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Penflufen Human Health Risk Assessment D387450 

Table 9.1.1. Summary of Short- and Intermediate-Term Handler Exposures and Risks for Penflufen (Seed 

Treatment Only). 

Seed Type 

Inhalation 

UEa Max App Rateb Amt Treatedc Inhalatopm Dosed

Intermediate- Short-Term Term Inhal Inhal MOEe

MOEf

mg/lb lb ai/lb seed lb seed/day mg/kg/day LOC = 100 LOC = 100 

MULTIPLE ACTIVITIES (no respirator) 

Alfalfa 0.0016 0.00015 718,000 0.0025 23,000 15,000 

Beans and Peas 0.0016 0.00005 194,000 0.00022 250,000 170,000 

Soybean 0.0016 0.00005 718,000 0.00082 68,000 46,000 

Cereal Grains, 

incl. Rice 0.0016 0.00005 718,000 0.00082 68,000 46,000 

Canola 0.0016 0.00015 104,000 0.00036 160,000 110,000 

Field Corn 0.0016 0.0001 550,000 0.0013 44,000 30,000 

Sweet Corn 0.0016 0.0001 194,000 0.00044 130,000 86,000 

Cotton 0.0016 0.0001 160,000 0.00037 150,000 100,000 

Sunflower and 

safflower 0.0016 0.00015 718,000 0.0025 23,000 15,000 

Sorghum 0.0016 0.0001 718,000 0.0016 34,000 23,000 

a Unit Exposures from HED Exposure Science Advisory Council Policy 14 (baseline inhalation = no respirator). 

b Application Rates based on proposed label uses for penflufen. 

c HED default for lb seed treated per day from HED Exposure Science Advisory Council Policy 15; wheat used as surrogate for alfalfa. 

d Daily Inhalation Dose (mg/kg/day) = daily inhalation unit exposure (mg/lb ai) x application rate (lb ai/lb seed) x amount treated (lb seed/day) x 

absorption factor (100%) / body weight (70 kg adult). 

e Short-term Inhalation MOE = NOAEL (55.7 mg/kg/day for short-term exposure) / Inhalation Dose (mg/kg/day). Level of concern = 100. 

f Intermediate-term Inhalation MOE = Intermediate-term NOAEL (38 mg/kg/day for intermediate-term exposure) / Inhalation Dose (mg/kg/day). 

Level of concern = 100. 

Table 9.1.2. Short- and Intermediate-Term Occupational Handler Exposures and Risks for In-Furrow 

and Potato Seed Piece Treatment. 

Application 

Ratea 

Amount 

Treated 

Per Dayc 

Unit Exposuresb Dosed

mg/kg/day 

MOEs 

LOC = 100 

Baseline Inhalation Baseline Inhalation e 

Short-term 

Baseline 

Inhalationf

IntermediateTerm Baseline 

Inhalationg lb ai/A Acres/day μg/lb ai 

Mixer/Loader

0.12 200 0.219 0.000075 740,000 510,000 

Groundboom Applicator- Surrogate for In-furrow potato treatment 

0.12 200 0.34 0.000117 480,000 330,000 

a Application Rates based on proposed uses on label. 

b Acres treated per day from ExpoSAC Policy 9. 

c Baseline inhalation unit exposures represent no respirator protection. All values are reported in the Occupational Pesticide Handler Unit 

Exposure Surrogate Reference Table dated September 2011, using PHED, AHETF, and ORETF data. 

d Baseline Inhalation: no respirator. 

e Inhalation Dose (mg/kg/day) = daily unit exposure (μg/lb ai) x application rate (lb ai/A) x amount treated /day (acres/day) x conversion 

factor (1 mg/1,000 μg) x inhalation absorption factor (100%) / body weight (70 kg adult). 

f Inhalation MOE = short-term NOAEL (55.7 mg/kg/day) / inhalation daily dose (mg/kg/day). Level of concern = 100. 

g Inhalation MOE = intermediate-term NOAEL (38 mg/kg/day) / inhalation daily dose (mg/kg/day). Level of concern = 100. 

 

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Penflufen Human Health Risk Assessment D387450 

Table 9.1.3. Summary of Handler (on-farm liquid seed piece treatment to potatoes) Exposures and Risks for 

Penflufen. (Data from MRID 47054702)

Seed Type* Inhal UEa Max App 

Rateb 

Amt of Seed 

Planted/Dayc

Inhalation 

Dosed

Short-term 

Inhalation 

MOEe

Intermediateterm Inhalation 

MOEf 

mg/lb lb ai/lb seed lb seed/day mg/kg/day LOC = 100 LOC = 100 

Potato Pieces 0.0064 0.00002 480,000 0.000878 63,000 43,000 

a Unit Exposures from data from MRID 47054702. 

b Application Rates based on proposed label uses for penflufen. 

c Information on amount of potato pieces treated per day from the National Potato Council. 

d Daily Inhalation Dose (mg/kg/day) = daily inhalation unit exposure (mg/lb ai) x application rate (lb ai/lb seed) x amount planted (lb seed/day) 

x absorption factor (100%) / body weight (70 kg adult). 

e Short-term Inhalation MOE = NOAEL (55.7 mg/kg/day for short-term exposure) / Inhalation Dose (mg/kg/day). Level of concern = 100. 

f Intermediate-term Inhalation MOE = NOAEL (38 mg/kg/day for intermediate-term exposure) / Inhalation Dose (mg/kg/day). Level of concern 

= 100. 

Table 9.1.4. Summary of Secondary Handler (Planter) Exposures and Risks for Penflufen (with no respiratory 

protection).

Seed Type* Inhal UEa Max App 

Rateb 

Amt of Seed 

Planted/Dayc

Inhalation 

Dosed

Short-term 

Inhalation 

MOEe

Intermediateterm Inhalation 

MOEf 

mg/lb lb ai/lb seed lb seed/day mg/kg/day LOC = 100 LOC = 100 

Alfalfa 0.0034 0.00015 4,000 0.000029 1,900,000 1,300,000 

Beans and PeasSoybean and Garden 

pea* 

0.0034 0.00005 12,000 0.000029 1,900,000 1,300,000 

Cereal Grains- Rice and 

Wheat* 0.0034 0.00005 30,000 0.000073 760,000 520,000 

Corn 0.0034 0.0001 3,000 0.000015 3,800,000 2,600,000 

Cotton 0.0034 0.0001 3,600 0.000017 3,200,000 2,200,000 

Oilseeds- Safflower* 0.0034 0.00015 8,000 0.000058 960,000 650,000 

Sorghum 0.0034 0.0001 800 0.0000039 14,000,000 9,800,000 

Potato Pieces 0.0034 0.00002 480,000 0.000466 120,000 82,000 

a Unit Exposures from HED Exposure Science Advisory Council Policy 14: Standard Operating Procedures for Seed Treatment. 

b Application Rates based on proposed label uses for penflufen. 

c HED default for lb seed planted per day from HED Exposure Science Advisory Council Policy 15, except for potato pieces; Information on 

amount of potato pieces treated per day from the National Potato Council. 

d Daily Inhalation Dose (mg/kg/day) = daily inhalation unit exposure (mg/lb ai) x application rate (lb ai/lb seed) x amount planted (lb seed/day) 

x absorption factor (100%) / body weight (70 kg adult). 

e Short-term Inhalation MOE = NOAEL (55.7 mg/kg/day for short-term exposure) / Inhalation Dose (mg/kg/day). Level of concern = 100. 

f Intermediate-term Inhalation MOE = NOAEL (38 mg/kg/day for intermediate-term exposure) / Inhalation Dose (mg/kg/day). Level of concern 

= 100. 

* In the case where there are several crops in the crop group assessed with the same application rate, the crop with the highest amount of seeds 

planted per day was assessed as representative of that crop group (i.e., beans and peas, cereal grains other than corn and sorghum, oilseeds other 

than cotton) 

9.2 Short-/Intermediate-Term Post-Application Risk 

9.2.1 Dermal Postapplication Risk 

The potential for post-application exposures following the planting of penflufen-treated seeds is 

unlikely because sustained levels of contact with treated seed after it has been placed in the soil 

or other planting media would not be expected because no routine cultural practice required for 

the production of agricultural commodities involves such an activity as defined in the no/low 

contact criteria in the Worker Protection Standard (WPS). Also, as no dermal hazard has been 

Page 34 of 106 
Penflufen Human Health Risk Assessment D387450 

identified, no quantitative post-application assessment is required for exposure to treated seeds 

that have already been planted. 

The proposed labels require that workers wear long-sleeved shirt, long pants, shoes, socks and 

chemical-resistant gloves when opening bags of treated seed or loading/pouring the treated seed. 

No additional PPE requirements are necessary for labeling of treated seed. 

The Worker Protection Standard (WPS) allows workers to enter treated areas without restriction 

if there will be no worker contact with the treated seeds in the soil or planting media. Certain 

tasks, even though they are not routine, may involve contact with the soil subsurface (e.g. repair 

of certain irrigation equipment) and they are covered by the REI. Therefore, the REI is based on 

the acute toxicity of the active ingredients. Note that REI recommendations include 

consideration of penflufen as well as any co-formulant(s) in the end-use product. A 12-hour REI 

is appropriate for seeds that have been planted that were treated with penflufen, clothianidin, 

prothioconazole, and/or trifloxystrobin. For products containing metalaxyl, a 24-hour REI is 

appropriate. 

PENRED 240FS, PEN240FS, PENCLO 273.5FS, PENTRI 308FS, PENPRO 118FS

The labeling should state: Bags containing treated seeds shall be labeled with the following 

information: 

“After the seeds have been planted, do not enter or allow worker entry into treated areas during 

the restricted-entry interval (REI) of 12 hours. Exception: Once the seeds are planted in soil or 

other planting media, the Worker Protection Standard allows workers to enter the treated area 

without restriction if there will be no worker contact with the treated seeds in the soil or planting 

media.” This label requirement is not currently on the proposed labels. 

PENCLOTRIME 310.68FS

The proposed label requires bags containing treated seeds be labeled to require an REI of 24 

hours after seeds have been planted, with the exception that once the seeds are planted in soil or 

other planting media, the Worker Protection Standard allows workers to enter the treated area 

without restriction if there will be no worker contact with the treated seeds in the soil or planting 

media. This requirement is on the proposed label for PENCLOTRIME 310.68FS; no change is 

required. 

For PENPROME 177FS

The labeling should state: Bags containing treated seeds shall be labeled with the following 

information: 

“After the seeds have been planted, do not enter or allow worker entry into treated areas during 

the restricted-entry interval (REI) of 24 hours. Exception: Once the seeds are planted in soil or 

other planting media, the Worker Protection Standard allows workers to enter the treated area 

without restriction if there will be no worker contact with the treated seeds in the soil or planting 

media.” This label requirement is not currently on the proposed label. 

Page 35 of 106 
Penflufen Human Health Risk Assessment D387450 

9.2.2 Inhalation Postapplication Risk 

A postapplication inhalation exposure assessment is not required as exposure is expected to be 

negligible. Seed treatment assessments provide quantitative inhalation exposure assessments for 

seed treaters and secondary handlers (i.e. planters). It is expected that these exposure estimates 

would be protective of most postapplication inhalation exposure scenarios. 

10.0 References

Toxicology References

Author: Jessica Kidwell 

Date: March 28, 2011 

TXR No.: 0051558 

Title: Penflufen: Report of the Cancer Assessment Review Committee 

Residue Chemistry References

Author: William Irwin 

Date: June 15, 2011 

DP Number: D287299 

Title: Penflufen: Report of the Residues of Concern Knowledgebase Sub-committee 

(ROCKS) 

Author: Donna Davis 

Date: November 15, 2011 

DP Number: D395192 

Title: Penflufen. New Active Ingredient - New Uses on Alfalfa, Potato (Crop 

Subgroup 1C), Legume Vegetables (Crop Group 6 and Crop Group 7), Cereal 

Grains (Crop Group 15 and Crop Group 16), and Oilseeds (Crop Group 20). 

Residue Chemistry Summary Document. 

Author: Reuben Baris 

Date: August 25, 2011 

DP Number: D386698 

Title: Tier I Drinking Water Exposure Assessment for the Section 3 New Chemical 

Registration of Penflufen. 

 

Page 36 of 106 
Penflufen Human Health Risk Assessment D387450 

Author: Donna Davis 

Date: November 15, 2011 

DP Number: D395193 

Title: Penflufen. Acute and Chronic Aggregate Dietary (Food and Drinking Water) 

Exposure and Risk Assessments for Section 3 Registration Actions for New Uses 

on Alfalfa, Potato (Crop Subgroup 1C), Legume Vegetables (Crop Group 6 and 

Crop Group 7), Cereal Grains (Crop Group 15 and Crop Group 16), and Oilseeds 

(Crop Group 20). 

Occupational Assessment References

Author: Alexandra LaMay 

Date: November 15, 2011 

DP Number: D392917 

Title: Penflufen; Occupational Exposure Assessment for Seed Treatment Use and InFurrow Potato Piece Treatment. 

Science Advisory Council for Exposure (ExpoSAC) Policy 14: Standard Operating Procedures 

(SOPs) for Seed Treatment (May 1, 2003). 

ExpoSAC Policy 15: Amount of Seed Treated or Planted per Day (March 2, 2004). 

Study Review of “Determination of Dermal and Inhalation Exposure of Workers during OnFarm Seed Piece Treatment of Potatoes”. MRID 47054702. Bayer CropScience. D378750, S. 

Tadayon, 6/23/10. 

Occupational Pesticide Handler Unit Exposure Surrogate Reference Table, US Environmental 

Protection Agency Office of Pesticide Programs, June 21, 2011. 

Page 37 of 106 
Penflufen Human Health Risk Assessment D387450 

Appendix A. Toxicology Profile and Executive Summaries 

A.1 Toxicology Data Requirements 

The toxicological data requirements (40 CFR 158.340) for food uses for penflufen are in Table 

A1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols 

were used. 

Table A.1 Test Technical 

Required Satisfied 

870.1100 Acute Oral Toxicity 

870.1200 Acute Dermal Toxicity 

870.1300 Acute Inhalation Toxicity 

870.2400 Primary Eye Irritation 

870.2500 Primary Dermal Irritation 

870.2600 Dermal Sensitization 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.3100 Oral Subchronic (rat and mouse) 

870.3150 Oral Subchronic (dog) 

870.3200 21/28-Day Dermal (rat) 

870.3250 90-Day Dermal 

870.3465 28-Day Inhalation 

yes 

yes 

yes 

CR 

CR 

yes 

yes 

yes 

--- 

no 

870.3700a Developmental Toxicity (rat) 

870.3700b Developmental Toxicity (rabbit) 

870.3800 Reproduction (rat) 

yes 

yes 

yes 

yesa 

yesa 

yes 

870.4100a Chronic Toxicity (rat) 

870.4100b Chronic Toxicity (dog) 

870.4200a Carcinogenicity (rat) 

870.4200b Carcinogenicity (mouse) 

870.4300 Chronic/Carcinogenicity (rat) 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.5100 Mutagenicity—Gene Mutation - bacterial 

870.5300 Mutagenicity—Gene Mutation - mammalian 

870.5375 Mutagenicity—Structural Chromosomal 

Aberrations 

870.5395 Mutagenicity—Mammalian Erythrocyte 

Micronucleus 

870.5500 Mutagenicity— Bacterial DNA Damage or Repair Test 

870.5550 Mutagenicity—Unscheduled DNA Synthesis 

yes 

yes 

yes 

yes 

no 

no 

yes 

yes 

yes 

yes 

--- 

--- 

870.6100a Acute Delayed Neurotoxicity. (hen) 

870.6100b 90-Day Neurotoxicity (hen) 

870.6200a Acute Neurotoxicity Screening Battery (rat) 

870.6200b 90 Day Neurotoxicity Screening Battery (rat)

 

870.6300 Developmental Neurotoxicity (rat) 

no 

no 

yes 

yes 

CR 

--- 

--- 

yes 

yes 

no 

870.7485 General Metabolism (rat) 

870.7600 Dermal Penetration (8-hour), in vivo (male rat)

 

yes 

CR 

yes 

yes 

Page 38 of 106 
Penflufen Human Health Risk Assessment D387450 

870.7800 Immunotoxicity (rat and mouse)...........................

 

yes yes 

Non-Guideline: Comparative dermal absorption, in vitro (rat 

 and human skin) 

Non-Guideline: 28-day oral toxicity (rat) 

Non-Guideline: 28-day oral toxicity (mouse) 

Non-Guideline: 8-hour dermal penetration, in vivo (male rat)

no 

no 

no 

no 

yes 

yes 

yes 

yes 

a

 ---study acceptable (non-guideline) ); study is non-guideline since the highest dose tested was not high enough to 

produce a dose response, which is a criteria for a guideline study; additional studies are not required since the 

endpoints selected are protective of any developmental effects that may be seen at higher doses. 

A.2 Toxicity Profiles 

Table A.2. Subchronic, Chronic and Other Toxicity Profile for Penflufen

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

NA 28-Day oral toxicity 

(rat) 

48023838 (2004) 

Acceptable/non-guideline 

0, 150, 2000, 7000 ppm 

(diet) 

M: 12, 154, 560 mg/kg 

bw/day 

F: 13, 169, 648 mg/kg 

bw/day 

NOAEL = 560 mg/kg bw/day (males)/648 

mg/kg bw/day (females). 

LOAEL = not identified; the liver was 

identified as a major target organ for BYF 

14182 (dose-related increase total P-450, 

BROD, and PROD activities in both sexes, 

increased cholesterol levels in females, 

increased liver weight in both sexes, increased 

incidence of hepatocellular hypertrophy in both 

sexes). The liver effects are considered 

adaptive and not adverse. 

NA 28-Day oral toxicity 

(mouse) 

48023839 (2005) 

Acceptable/non-guideline 

0, 150, 3500, 7000 ppm 

(diet) 

M: 0, 26, 632, 1274 

mg/kg bw/day 

F: 0, 31, 741, 1585 mg/kg 

bw/day 

NOAEL = 1274 mg/kg bw/day (males)/1585 

mg/kg bw/day (females). 

LOAEL = not identified. The liver effects 

(increased liver weights associated with 

centrilobular hepatocellular hypertrophy; 

associated clinical chemistry findings at 7000 

ppm) are considered adaptive and not adverse. 

NA 28-Day oral toxicity 

(dog) 

48023840 (2005) 

Acceptable/non-guideline 

0, 1300, 6500, 26000 ppm 

M: 0, 49, 244, and 759 

mg/kg bw/day 

F: 0, 52, 246, and 895 

mg/kg bw/day 

NOAEL = 759 mg/kg bw/day (males)/895 

mg/kg/day (females). 

LOAEL = not identified. 

No adverse effects (2 Beagle dogs/sex) 

administered BYF 14182 via the diet (28 days); 

the liver and thyroid were identified as target 

organs, as evidenced by increased alkaline 

phosphatase and GGT activities in both sexes, 

increased liver weight and increased incidences 

of hepatocellular hypertrophy, thyroid follicular 

cell hypertrophy, and decreased follicular 

diameter in the thyroid in both sexes. 

Page 39 of 106 
Penflufen Human Health Risk Assessment D387450 

Table A.2. Subchronic, Chronic and Other Toxicity Profile for Penflufen

Guideline 

No. 

Study Type MRID No. (year)/ Results

Classification /Doses

870.3100 90-Day oral toxicity 

(rat) 

48023805(2006) 

Acceptable/guideline 

(definitive 90-day rat 

study, together with the 

findings of MRID 

48023806) 

0, 150, 7000, 14000 ppm 

(diet) 

M: 0, 9.5, 457 and 

949 mg/kg/day 

F: 0, 11.4, 492 and 

1009 mg/kg/day 

NOAEL = 949 mg/kg bw/day (males)/1009 

mg/kg bw/day (females). 

LOAEL = not identified. The findings at 14000 

ppm included an increase in total cholesterol 

concentration and gamma-glutamyltransferase 

activity in both sexes, an increase in the 

incidence of centrilobular hepatocellular hypertrophy, which was correlated with higher liver 

weights and macroscopically enlarged livers in 

both sexes, an increased incidence of thyroid 

follicular cell hypertrophy in both sexes, and 

altered colloid in males. These effects are 

considered an adaptive response and not 

adverse. 

870.3100 90-Day oral toxicity 

(rat) 

48023806 (2006) 

Acceptable/guideline 

(when considered together 

with the findings of 

MRID 48023805) 

 

0, 50, 150, 3500 ppm 

(diet) 

M: 0, 3.2, 9.3 and 228 

mg/kg bw/day 

F: 0, 3.7, 11.4 and 

260 mg/kg bw/day 

NOAEL = 228 mg/kg bw/day 

(males)/260 mg/kg bw/day (females). 

LOAEL not identified; increased liver weights 

and an increased incidence of centrilobular 

hepatocellular hypertrophy were observed, 

which were not accompanied by alterations in 

relevant clinical chemistry parameters or 

adverse liver lesions. The effects observed are 

considered adaptive and not adverse over this 

time frame. 

870.3100 90-Day oral toxicity 

(mouse) 

48023807 (2006) 

Acceptable/guideline 

0, 150, 3500, 7000 ppm 

(diet) 

M: 0, 26.9, 638, 1238 

mg/kg bw/day 

F: 0, 31.5, 757 and 1600 

mg/kg bw/day 

NOAEL = 1238 mg/kg bw/day (males)/1600 

mg/kg bw/day (females). 

LOAEL = not identified; liver effects are 

considered adaptive and not adverse. 

Page 40 of 106 
Penflufen Human Health Risk Assessment D387450 

Table A.2. Subchronic, Chronic and Other Toxicity Profile for Penflufen

Guideline 

No. 

Study Type MRID No. (year)/ Results

Classification /Doses

870.3150 90-Day oral toxicity 

(dog) 

48023808 (2008) 

Acceptable/guideline 

(gavage) 

M: 0, 5.6, 55.7 and 

532 mg/kg bw/day 

F: 0, 6.1, 63.1 and 568 

mg/kg bw/day 

NOAEL = 55.7 mg/kg bw/day (males)/63.1 

mg/kg bw/day (females), based on the minimal 

liver effects (increased liver weight and 

hepatocellular hypertrophy), which were not 

accompanied by significant alterations in 

relevant clinical chemistry parameters or 

adverse liver lesions in both sexes. The effects 

observed are considered adaptive and not 

adverse over this time frame. 

LOAEL = 532 mg/kg bw/day (males)/568 

mg/kg bw/day (females), based on decreased 

body weight/body weight gain in females, 

increased alkaline phosphatase activity in both 

sexes, increased GGT activity in both sexes, 

decreased albumin in males, increased liver 

weights in both sexes, increased adrenal 

weights in males, increased incidence of 

hepatocellular hypertrophy in both sexes, and 

an increased incidence of slight diffuse cortical 

hypertrophy/hyperplasia in the adrenal in 

males. 

870.3200 28-Day dermal 

toxicity (rat) 

48023809 (2009) 

Acceptable/guideline 

0, 100, 300, or 1000 

mg/kg bw/day 

NOAEL = 1000 mg/kg bw/day 

LOAEL = not identified. 

Increased lymphocyte debris within the thymic 

cortex (♂/♀; 7/10 each); lesion characterized 

by the increased presence of fragmented thymic 

cortical lymphocytes noted within tingible body 

macrophages; finding not accompanied by a 

decrease in the size or weight of the thymus or 

changes in lymphocyte counts. The significance 

of the finding at the limit dose is not known. 

870.3250 90-Day dermal 

toxicity (species) 

870.3465 90-Day inhalation 

toxicity (species) 

Page 41 of 106 
Penflufen Human Health Risk Assessment D387450 

Table A.2. Subchronic, Chronic and Other Toxicity Profile for Penflufen

Guideline 

No. 

Study Type MRID No. (year)/ Results

Classification /Doses

870.3700a Prenatal 

developmental in 

(rats) 

48023810 (2008) 

Acceptable/non-guideline 

0, 30, 100, or 300 mg/kg 

bw/day 

GD 6-20 

Maternal toxicity NOAEL = 300 mg/kg 

bw/day; findings at the 300 mg/kg/day dose 

level are considered minimal. The dose levels 

do not appear adequate for assessing the 

developmental toxicity potential of BYF 14182. 

Although there was a significant reduction in 

maternal body weight gain at 300 mg/kg/day, 

which correlated with a decrease in food 

consumption, body weights were comparable to 

those of the control, and the liver changes are 

considered adaptive and not adverse. 

Maternal toxicity LOAEL was not identified. 

Developmental toxicity NOAEL = 300 mg/kg 

bw/day. At 300 mg/kg/day, the highest dose 

tested, no adverse effects were observed. 

However, this dose was a no adverse effect 

dose level in the range-finding study also. The 

dose levels are not considered adequate for 

assessing the developmental toxicity potential 

of BYF 14182. 

Developmental toxicity LOAEL was not 

identified. 

Little concern that new studies would identify a 

developmental endpoint with a NOAEL lower 

than the NOAELs selected for risk assessment.

870.3700b Prenatal 

developmental in 

(rabbit) 

48023811(2008) 

Acceptable/non-guideline 

0, 30, 100, or 600 mg/kg 

bw/day 

GD 6-28 

Maternal NOAEL = 600 mg/kg/day 

The maternal findings at the 600 mg/kg 

bw/day dose level are considered minimal. 

The dose levels do not appear adequate for 

assessing the developmental toxicity 

potential of BYF 14182 in the rabbit. 

Although there was a significant reduction in 

maternal body weight gain at 600 

mg/kg/day, which correlated with a decrease 

in food consumption, body weights were 

comparable to those of the control. No other 

effects were observed. 

Maternal LOAEL was not identified. 

Developmental NOAEL = 600 mg/kg bw/day. 

Developmental toxicity LOAEL was not 

identified. 

Little concern that new studies would identify a 

developmental endpoint with a NOAEL lower 

than the NOAELs selected for risk assessment.

Page 42 of 106 
Penflufen Human Health Risk Assessment D387450 

Table A.2. Subchronic, Chronic and Other Toxicity Profile for Penflufen

Guideline 

No. 

Study Type MRID No. (year)/ Results

Classification /Doses

870.3800 Reproduction and 

fertility effects 

(rat) 

48023812 (2009) 

acceptable/guideline 

0, 200, 1000, or 4000 ppm 

(diet) 

M: 0, 12.8, 64.1, 252.2 

mg/kg bw/day 

F: 0, 15, 75.9, 294.5 

mg/kg bw/day 

Parental/Systemic NOAEL = 64 mg/kg 

bw/day (males)/76 mg/kg bw/day (females) 

LOAEL = 252.2 mg/kg bw/day (males)/294.5 

mg/kg bw/day (females), based on decreased 

body weight, decreased body weight gain, 

alterations in food consumption, decreased 

thymus weight in both genders, and decreased 

spleen weights in females (both generations). 

The increased liver weights and hepatocellular 

hypertrophy are considered adaptive and not 

adverse. 

Reproductive NOAEL = 73 mg/kg bw/day 

LOAEL = 291 mg/kg bw/day, based on delayed 

sexual maturation in females in both 

generations. 

Offspring NOAEL = 73 mg/kg bw/day 

LOAEL = 291 mg/kg bw/day, based on a slight 

decrease in litter size in both generations, 

decreased pup body weight and pup bodyweight gain, delayed vaginal patency in both 

generations, and decreased brain, spleen, and 

thymus weights. 

870.4100a Chronic toxicity 

(rat) 

48023815 (2009) 

Acceptable/guideline 

0, 100, 2000 or 7000 ppm 

(diet) 

 M: 0, 4.0, 79 and 288 

mg/kg bw/day 

F: 0, 5.6, 113 or 399 

mg/kg bw/day 

NOAEL = 2000 ppm (79/113 mg/kg bw/day) 

LOAEL = 7000 ppm (288/399 mg/kg bw/day), 

based on decreased body weight/body weight 

gain in females, increased liver weight in both 

sexes, increased incidence of centrilobular to 

panlobular hepatocellular hypertrophy and 

centrilobular hepatocellular macrovacuolation 

in both sexes, increased incidence of 

hepatocellular brown pigment in females, 

hepatocellular necrosis, colloid alteration in the 

thyroid in females, and increased cholesterol in 

females. These effects are considered mainly 

adaptive in nature. 

Page 43 of 106 
Penflufen Human Health Risk Assessment D387450 

Table A.2. Subchronic, Chronic and Other Toxicity Profile for Penflufen

Guideline 

No. 

Study Type MRID No. (year)/ Results

Classification /Doses

870.4100b Chronic toxicity 

(dog) 

48023813 (2009) 

Acceptable/guideline 

0, 200, 1000, 10000 ppm 

(diet) 

M: 0, 6.8, 32.0 and 

357 mg/kg bw/day 

F: 0, 7.7, 37.9 and 425 

mg/kg bw/day 

NOAEL = 38 mg/kg bw/day. NOAEL is based 

on the minimal changes in the liver (increased 

liver weight and hepatocellular hypertrophy, 

which were not accompanied by relevant 

changes in clinical chemistry parameters and 

adverse liver lesions) that are not considered 

adverse. 

LOAEL = 357 mg/kg bw/day, based on 

decreased body weight and body weight gain in 

females, increased prothrombin time in males, 

increased alkaline phosphatase activity in both 

sexes, increased GGT levels in both sexes, 

increased liver weights in both sexes, increased 

hepatocellular hypertrophy in both sexes, and 

an increased incidence of thyroid follicular cell 

hypertrophy in both sexes. 

870.4200 Carcinogenicity 

(rat) 

48023815 (2009) 

Acceptable/guideline 

0, 100, 2000 or 7000 ppm 

(diet) 

 M: 0, 4.0, 79 and 288 

mg/kg bw/day 

F: 0, 5.6, 113 or 399 

mg/kg bw/day 

See above under 870.4100a. 

There are three tumor types (brain astrocytomas 

in males, ovarian tubulostromal neoplasms in 

females, and histiocytic sarcoma in males). 

Penflufen was evaluated by the EPA HED 

Cancer Assessment Review Committee 

(CARC) on February 16, 2011, and it was 

concluded that penflufen should be classified 

Suggestive, quantification not required. All 3 

tumor types were considered treatment-related. 

Dosing was considered adequate based on the 

presence of tumors. 

870.4300 Carcinogenicity 

(mouse) 

48023814 (2009) 

0, 100, 1000, 6000 ppm 

M: 0, 14.3, 146, or 

880 mg/kg bw/day 

F: 0, 18.4, 182, and 

1101 mg/kg bw/day 

NOAEL = 6000 ppm (880/1101 mg/kg bw/day) 

LOAEL = LOAEL not identified (included a 

dose level that exceeded the limit dose in 

females and one that was close to the limit dose 

in males. 

The liver effects and associated effects on the 

thyroid are considered adaptive and not 

adverse. 

no evidence of carcinogenicity

Gene 

Mutation 

870.5100 

Ames assay 

Salmonella 

typhimurium 

TA98, TA100, 

TA1535, Ta1537, 

Ta1538 

48023816 (2007) 

Acceptable/guideline 

16 to 5000 μg/plate 

BYF 14182 

Negative with and without metabolic activation 

Gene 

Mutation 

870.5100 

Ames assay 

Salmonella 

typhimurium 

TA98, TA100, 

TA1535, Ta1537, 

Ta1538 

48023817 (2009) 

Acceptable/guideline 

3 to 5000 μg/plate 

BYF 14182 

Negative with and without metabolic activation 

Page 44 of 106 
Penflufen Human Health Risk Assessment D387450 

Table A.2. Subchronic, Chronic and Other Toxicity Profile for Penflufen

Guideline 

No. 

Study Type MRID No. (year)/ Results

Classification /Doses

Gene 

Mutation 

870.5100 

Ames assay 

Salmonella 

typhimurium 

TA98, TA100, 

TA1535, Ta1537, 

Ta1538 

48023818 (2008) 

Acceptable/guideline 

16 to 5000 μg/plate 

Negative with and without metabolic activation 

Gene 

Mutation 

870.5100 

Ames assay 

Salmonella 

typhimurium 

TA98, TA100, 

TA1535, Ta1537, 

Ta1538 

48023819 (2009) 

Acceptable/guideline 

16 to 5000 μg/plate 

BYF 14182-pyrazolylAAP 

Negative with and without metabolic activation 

870.5300 In vitro V79/HPRT 

test – forward 

mutation 

(BYF 14182) 

48023820 (2007) 

Acceptable/guideline 

Experiment 1: without S9: 

0, 25, 50, 75, 100, 125, 

150 or 175 μg/mL; with 

S9: 0, 50, 75, 100, 125, 

150, 175 or 200 μg/mL 

Experiment 2: without S9: 

0, 12.5, 25, 50, 75, 100 or 

125 μg/mL; with S9: 0, 

25, 50, 75, 100, 125 or 

150 μg/mL 

Negative with and without metabolic activation 

870.5300 In vitro V79/HPRT 

test – forward 

mutation 

(BYF 14182) 

48023821 (2009) 

Acceptable/guideline 

E1&E2: without S9: 0, 

4.5, 9, 18, 27, or 36 

μg/mL 

E1:with S9: 0, 4.7, 9.4, 

18.8, 37.5, or 75 μg/mL 

E2: with S9: 0, 18.8, 37.5, 

75, 100, or 125 μg/mL 

Negative with and without metabolic activation 

870.5300 In vitro V79/HPRT 

test – forward 

mutation 

(BYF 14182-3- 

hydroxy-butyl) 

48023822 (2008) 

Acceptable/guideline 

0, 75, 150, 300, 600, 900, 

or 1200 μg/mL (+/-S9) 

Negative with and without metabolic activation 

870.5300 In vitro V79/HPRT 

test – forward 

mutation 

(BYF 14182-3- 

pyrazolyl-AAP) 

48023823 (2009) 

Acceptable/guideline 

0, 3, 6, 12, 24, 36, 48, or 

60 μg/mL (+/-S9) 

Negative with and without metabolic activation 

Page 45 of 106 
Penflufen Human Health Risk Assessment D387450 

Table A.2. Subchronic, Chronic and Other Toxicity Profile for Penflufen

Guideline 

No. 

Study Type MRID No. (year)/ Results

Classification /Doses

870.5375 Chinese Hamster 

V79 cells –

chromosome 

aberrations 

(BYF 14182) 

48023824 (2007) 

Acceptable/guideline 

4-hour: 0, 10, 20, 40, 70, 

and 100 μg/mL (-S9) 

18-hour: 0, 3, 6, 12, 24, 36 

μg/mL (-S9) 

 4-hour: 0, 15, 30, 60 and 

90 μg/mL (+ S9) 

4-hour: 0, 40, 70, and 100 

μg/mL (-S9) and 0, 60, 

75, and 90 μg/mL (+S9) 

(harvested 30 hours after 

treatment) 

Negative with and without metabolic activation 

870.5375 Chinese Hamster 

V79 cells –

chromosome 

aberrations 

(BYF 14182) 

48023825 (2009) 

Acceptable/guideline 

-S9: 0, 9.4, 18.8 and 37.5 

g/mL (4-hour treatment) 

–S9: 0, 4.7, 9.4 and 18.8 

μg/mL (18-hour treatment) 

+S9: 0, 18.8, 37.5 and 

75.0 μg/mL (4-hour 

treatment) 

+S9: 0, 100, 150 and 300 

μg/mL were harvested at 

28 hours 

cytotoxicity determination 

4.7-1200 μg/mL (±S9) 

2.3-300 μg/mL (±S9).

Negative with and without metabolic activation 

870.5375 Chinese Hamster 

V79 cells –

chromosome 

aberrations 

(BYF 14182-3-

hydroxy-butyl) 

48023826 (2008) 

Acceptable/guideline 

-S9: 0, 150, 300, 600, 900, 

and 1200 μg/mL (4-hour 

treatment), and 0, 75, 150, 

300, 450, and 600 μg/mL 

(18-hour treatment) 

 +S9: 0, 75, 150, 300, 600, 

and 900 μg/mL (4-hour 

treatment); harvested 

18 hours after treatment. 

600, 900, and 1200 μg/mL 

(-S9) and 300, 600, and 

900 μg/mL (+S9); 

harvested 30 hours after 

treatment (4-hour 

treatment). 

Negative with and without metabolic activation 

Page 46 of 106 
Penflufen Human Health Risk Assessment D387450 

Table A.2. Subchronic, Chronic and Other Toxicity Profile for Penflufen

Guideline 

No. 

Study Type MRID No. (year)/ Results

Classification /Doses

870.5375 Chinese Hamster 

V79 cells –

chromosome 

aberrations 

(BYF 14182-

pyrazolyl-AAP) 

48023827 (2009) 

Acceptable/guideline 

-S9: 0, 15, 30 and 60 

μg/mL (4-hour and 18-

hour treatments) 

+S9: 0, 15, 30 and 60 

μg/mL (18-hour harvest 

after treatment) 

Negative with and without metabolic activation 

870.5395 Mouse 

Micronucleus 

48023828 (2007) 

Acceptable/guideline 

250, 500, 1000 mg/kg 

(male) 

Negative 

870.6200a Acute neurotoxicity 

screening battery 

48023829 (2009) 

Acceptable/guideline 

(gavage) 

 0, 100, 500, or 2000 

mg/kg bw 

NOAEL = 50 mg/kg/day 

LOAEL = 100 mg/kg/day based on decreased 

motor activity and locomotor activity in 

females. 

870.6200b Subchronic 

neurotoxicity 

screening battery 

48023830 (2009) NOAEL = 2000 ppm (126/156 mg/kg bw/day 

LOAEL = 8000 ppm (516/609 mg/kg bw/day 

based on a slight decrease in motor activity in 

females, which is consistent with a similar 

finding of decreased motor activity in females 

in the acute neurotoxicity study. 

870.6300 Developmental 

neurotoxicity 

Not required 

870.7485 Metabolism and 

pharmacokinetics 

(species) 

48023831 

48023832 

48023833 

48023834 

48023835 

48023836 

(2009) 

Single dose: elimination pharmacokinetics; 

rapid absorption & elimination; no apparent 

effect of increasing dose on absorption or 

elimination, although differences between 

sexes in amount in feces/urine. 

Metabolism, single dose: most excreted in 

feces (males)/urine (females); widely 

distributed with highest concentration in liver 

and kidneys; biotransformation characterized as 

very fast; complex mixture of metabolites. 

Metabolic pathway, single dose: 94-97% 

excreted; numerous metabolites identified; 

almost complete absorption 

Multiple dosing: not performed 

870.7600 Dermal penetration 

(rat, male) 

48024009 (2009) 

Acceptable/guideline 

 1, 50, or 240 g/L for 8 

hours (achieved doses 

ranged from 0.010 to 

0.011 mg/cm2

, 0.50 to 

0.53 mg/cm2

, and 2.63 to 

2.73 mg/cm2

) 

maximum % absorbed was 1.442%, 4.152%, 

and 5.350% for high, mid, and low dose 

formulations, respectively 

Page 47 of 106 
Penflufen Human Health Risk Assessment D387450 

Page 48 of 106 

Table A.2. Subchronic, Chronic and Other Toxicity Profile for Penflufen

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

OECD 

428 

In vitro dermal 

absorption 

(human/rat) 

48024011 (2009) 

Acceptable/non-guideline 

Doses: 50 g/L, 10 g/L, 

and 1 g/L 

mean total amounts of [14C] considered to be 

potentially absorbable (directly absorbed + 

total remaining at dose site) at doses of 50 g/L, 

10 g/L, and 1 g/L were 4.115%, 5.754%, and 

6.516%, respectively, for rat skin and 0.172%, 

1.449%, and 1.457%, respectively, for human 

skin; mean % of the applied dose potentially 

absorbable was 24-fold, 4-fold, and 4.5-fold 

greater in the rat skin than in the human skin, 

respectively. 

870.7800 Immunotoxicity 48023837 (2008) 

Acceptable/guideline 

0, 200, 1000 or 7000 ppm 

M: 0, 17.9, 82.6 or 

755.6 mg/kg bw/day 

F: 0, 20.4, 104.5 or 960.5 

mg/kg bw/day 

NOAEL = 755.6 mg/kg bw/day for males and 

960.5 mg/kg bw/day for females 

LOAEL = not established. 

 
Penflufen Human Health Risk Assessment 

A.3 Hazard Identification and Endpoint SelectionTable A.3. Toxicology Endpoint Selection Worksheet: Penflufen Exposure Scenario Study Candidates Rationale for Selection of Dose/Endpoint/Study Acute Dietary, All populations (including females 13+) Acute Dietary, Females 13+ 

Acute Neurotoxicity (rat) MRID 48023829 Developmental Toxicity (rat) MRID 48023810 

The developmental toxicity studies in rats and rabbits aneurotoxicity study in rats were all considered for acute assessment. Effects noted in the acute neurotoxicity study were attriand are appropriate for endpoint selection. The NOAEestablished are protective of any potential acute systemeffects. Selected. In the acute neurotoxicity study in Wistar rat

activity and locomotor activity were observed in femaletreatment at the LOAEL of 100 mg/kg (NOAEL = 50 mNo significant effects were observed in the developmenrats (300 mg/kg/day) or rabbits (600 mg/kg/day) at the Since neither study had toxic effects that could be attribexposure, neither is considered appropriate for endpoinfor the acute dietary risk assessment for females 13+. Bclassified acceptable/non-guideline, since the highest dstudies is considered inadequate, based on range-findineffects in the definitive studies. However, the ACN stuselected for all populations since the NOAEL and LOAhighest doses tested in the developmental toxicity studiconsidered protective of potential developmental effectadequately high dose levels. Not Selected: In the developmental toxicity study in Sp

maternal findings at the 300 mg/kg/day dose level are cAlthough there was a significant reduction in maternal mg/kg/day (↓13%), which correlated with a decrease in 

body weights were comparable to those of the control, 

Page 49 of 106 
Penflufen Human Health Risk Assessment 

Table A.3. Toxicology Endpoint Selection Worksheet: Penflufen Exposure Scenario Study Candidates Rationale for Selection of Dose/Endpoint/Study 

Developmental Toxicity (rabbit) MRID 48023811 

are considered adaptive and not adverse. A maternal toxadverse-effect-level (LOAEL) was not identified. No treatment-related effects were observed on litter par

and post implantation loss, early or late resorptions, fetmale and female fetuses, fetal body weights, or on the imalformations/variations at the external, visceral or skeat any dose level tested. Not selected: In the developmental toxicity study in rab

at the 600 mg/kg/day dose level are considered minimasignificant reduction in maternal body weight gain at 6which correlated with a decrease in food consumption, comparable to those of the control. No other effects wematernal toxicity lowest-observed-adverse-effect-level identified. No adverse effects were observed at 600 mg/kg/day, thMinimal fetal rabbit toxicity was observed at this dose the slight decrease in mean fetal body weights (7%-8%

Chronic Dietary, General Population 

Chronic/Carcinogenicity (rat) MRID 48023815 

The chronic toxicity study in dogs, chronic toxicity studchronic/carcinogenicity in rats, carcinogenicity study in generation reproduction study in rats were all considererisk assessment. Not selected: This study was not selected because there 

endpoint on which to regulate (LOAEL was not identif7000 ppm (males: 288 mg/kg/day weight/day; females: weight/day) included decreased body weight/body weigincreased liver weight in both sexes, increased incidencpanlobular hepatocellular hypertrophy and of centrilobumacrovacuolation in both sexes, increased incidence of pigment in females, colloid alteration in the thyroid in f

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Penflufen Human Health Risk Assessment 

Table A.3. Toxicology Endpoint Selection Worksheet: Penflufen Exposure Scenario Study Candidates Rationale for Selection of Dose/Endpoint/Study 

Carcinogenicity (mouse) MRID 48023814 Chronic toxicity (dog) MRID 48023813 

cholesterol in females. These effects are considered an 

not adverse. Because of the presence of tumors, the dosadequate. Not selected: This study was not selected because there 

endpoint on which to regulate (LOAEL was not identiftested exceeded the limit dose in females and was close males. The liver effects and associated effects on the thadaptive and not adverse. In the subchronic oral toxicity somewhat higher dose level (7000 ppm; males: 1238 m1600 mg/kg/day), a similar liver response was observedcontinued exposure does not result in additional/more sExposure of mice to BYF 14182 at dose levels greater tdose for a period of 78 weeks did not result in an increaany tumor type in either sex. Candidates NOAEL = 32 mg/kg/day (males)/37.9 mg/kg/day (femaminimal changes in the liver (increased liver weight anhypertrophy, which were not accompanied by relevant chemistry parameters and adverse liver lesions) that are adverse. The LOAEL = 357 mg/kg/day (males)/425 mgbased on decreased terminal body weight and body weiincreased prothrombin time (males), increased alkaline (both sexes), decreased cholesterol (both sexes), increasexes), decreased albumin and albumin/globulin ratio (bcalcium and phosphorus (both sexes), increased liver wincreased incidence of focal hepatocellular brown pigmhypertrophy (both sexes), increased incidence of zona gof the adrenal gland (females), and an increased incidencell hypertrophy (both sexes). 

Page 51 of 106 
Penflufen Human Health Risk Assessment 

Table A.3. Toxicology Endpoint Selection Worksheet: Penflufen Exposure Scenario Study Candidates Rationale for Selection of Dose/Endpoint/Study 

2-Generation Reproduction (rat) (adult) MRID 48023812 2-Generation Reproduction (rat)  (offspring) MRID 48023812 Subchronic Oral Toxicity (dog) MRID 48023808 Discussion: For the repeat dose studies (table at right), the dose spread is large in all cases, and the NOAELs are similar (males: 32-64 mkd/females: 38-76 mkd). In order not to break Burnam’s law, the chronic dog study provides the only NOAEL that is lower 

Parental systemic NOAEL = 1000 ppm [64 mg/kg/day (females)]. Parental LOAEL = 4000 ppm (252.2 mg/kgmg/kg/day (females), based on decreased body weight, gain, alterations in food consumption, decreased thymu

genders, and decreased spleen weights in females (both Offspring NOAEL = 1000 ppm [58.4 mg/kg/day (male(females)]. Offspring LOAEL = 4000 ppm (256.5 mg/kmg/kg/day (females), based on a slight decrease in littegenerations, decreased pup body weight and pup body-vaginal patency and balanopreputial separation, and deand thymus weights. NOAEL = 1800 ppm [55.7 mg/kg/day (males)/63.1 mgminimal liver effects (increased liver weight and hepatowhich were not accompanied by significant alterations chemistry parameters or adverse liver lesions, were obsconsidered adaptive and not adverse over this time framppm (532 mg/kg/day (males)/568 mg/kg/day (females)weight/ body weight gain in females, increased alkaline both sexes, increased GGT activity in both sexes, decreincreased liver weights in both sexes, increased adrenal increased incidence of hepatocellular hypertrophy in bo

increased incidence of slight diffuse cortical hypertrophadrenal in males were observed. 

Comparison of NOAELs and LOAELs Study NOAEL LOAEL Effects Acute Acute neurotoxicity 

50 100 Decreased mot

females 

Repeat Reproduction (parental) 

♂ 64 ♀ 76 

♂252 ♀ 295 

↓BW/BWG/FC

wt (♀) 

Page 52 of 106 
Penflufen Human Health Risk Assessment 

Table A.3. Toxicology Endpoint Selection Worksheet: Penflufen Exposure Scenario Study Candidates Rationale for Selection of Dose/Endpoint/Study 

than the acute NOAEL. However, looking at the LOAELs, the magnitude of the NOAEL for each repeat dose study could be the same. In the rat repeat oral dose studies at dose levels up to the limit dose, the effects on the liver are considered adaptive and not adverse. In the dog studies, the duration of the study relative to the lifespan of the dog is short. The selection is conservative but protective of other findings and the lack of adequate studies to detect potential developmental effects 

Reproduction (offspring) 

♂ 58 

♀71 

♂257 ♀ 293 

↓ little size botBW/BWG, del(♀/♂), ↓ brain, 

Subchronic (dog) ♂ 56 

♀ 63 

♂532 ♀ 568 

↓ BW/BWG (♀

(♀/♂), ↓ album

(♀/♂), ↑ adren

of hepatocellul

incidence of slihypertrophy/ h((♂). 

Chronic (dog) ♂ 32 

♀ 38 

♂357 ♀425 

At NOAEL, m(↑liver weight hypertrophy, wby relevant chaparameters or aare not consideAt LOAEL, ↓ tprothrombin tim

cholesterol (♀/

albumin and al

↓ calcium and p

weights (♀/♂), 

hepatocellular bhepatocellular incidence of zoof the adrenal gincidence of thhypertrophy (♀

Incidental Oral, Short-term (1-30 days) and Intermediate-term (1 – 6 months) 

2-Generation Reproduction (rats) (offspring) 

The reproduction study in rats, the 90-day oral toxicity day oral toxicity study in rats, the subchronic neurotoxiall considered for incidental exposure risk assessment. No residential exposure is anticipated due to a proposed only. Therefore, there is no potential for oral non-dietaringestion exposure to infants and children. Offspring effects (population of concern) were noted in 

in rats (delayed sexual maturation, both sexes), and the 

Page 53 of 106 
Penflufen Human Health Risk Assessment 

Table A.3. Toxicology Endpoint Selection Worksheet: Penflufen Exposure Scenario Study Candidates Rationale for Selection of Dose/Endpoint/Study 

MRID 48023812 Subchronic Oral Toxicity (dog) MRID 48023808 

[58.4 mg/kg/day (males)/71.2 mg/kg/day (females)]. NOAEL = 55.7 mg/kg/day (males)/63.1 mg/kg/day (femliver effects (increased liver weight and hepatocellular 

were not accompanied by significant alterations in relevparameters or adverse liver lesions, were observed. The adaptive and not adverse over this time frame. The NOAELs are similar, and the LOAELs are lower thtested in the developmental toxicity studies in rats and 

selected endpoint is protective of effects that might be odevelopmental toxicity studies at adequate dose levels a

potential developmental effects. Selected: 90-day dog and 2-generation reproduction stu

In the reproduction toxicity study in rats, a slight decreagenerations, decreased pup body weight and pup body-vaginal patency and balanopreputial separation, and deand thymus weights were observed at the LOAEL of 4mg/kg/day (males)/293.4 mg/kg/day (females)]. The N[58.4 mg/kg/day (males)/71.2 mg/kg/day (females)]. In a subchronic oral toxicity study in dogs, decreased bgain in females, increased alkaline phosphatase activity increased GGT activity in both sexes, decreased albumliver weights in both sexes, increased adrenal weights iincidence of hepatocellular hypertrophy in both sexes, incidence of slight diffuse cortical hypertrophy/hyperplmales were observed at the LOAEL of 18000 ppm (532 (males)/568 mg/kg/day (females). At the NOAEL 1800 (males)/63.1 mg/kg/day (females)], the minimal liver eweight and hepatocellular hypertrophy), which were nosignificant alterations in relevant clinical chemistry par

Page 54 of 106 
Penflufen Human Health Risk Assessment 

Table A.3. Toxicology Endpoint Selection Worksheet: Penflufen Exposure Scenario Study Candidates Rationale for Selection of Dose/Endpoint/Study 

Subchronic Neurotoxicity (rat) MRID 48023830 

lesions, were observed. The effects are considered adapover this time frame. Not selected: A NOAEL for neurotoxicology endpoints 

ppm (126 mg/kg/day (males)/156 mg/kg/day (females)ppm [516 mg/kg/day (males)/609 mg/kg/day (females)decrease in motor activity in females, which is consisteof decreased motor activity in females in the acute neur48023829). 

Dermal Absorption In Vivo Repeat Exposure Dermal 

penetration (rat) MRID 48023809 In Vivo Single 8-hour application Dermal penetration (rat) MRID 48024009 In Vitro Dermal Absorption (human and rat skin) MRID 48024009 

LOAEL was not identified. There was an increased inc(minimal severity) in both sexes at the limit dose [1000 both sexes)]. This lesion was characterized by the increfragmented thymic cortical lymphocytes noted within tmacrophages. This finding was not accompanied by a dweight of the thymus or changes in lymphocyte counts. finding at the limit dose is not known. Following single 8-hour dermal application, the amoun

potentially absorbable (sum of direct absorption and amskin) ranged from 0.775% and 1.442% for the neat prod2.743% and 5.152% for the intermediate dose (50 g/L) 5.350% for the low dose (1 g/L) formulation. Direct dermal absorption seemed to increase over time 0.277% at 8 hours post dose to 0.960% at 168hours pos1.584% at 8 hours post dose to 2.388% at 168 hours pofrom 1.624% at 8 hours post dose to 4.948% and 3.770post dose (1 g/L). For the Penflufen FS 240 red formulation (neat formulaabsorbable dose at 24 hours post-dose was 23.9-fold gr(4.115%) than human skin (0.172%). For a 10 g/L dilutformulation, the total absorbable dose was 3.97-fold gr

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Table A.3. Toxicology Endpoint Selection Worksheet: Penflufen Exposure Scenario Study Candidates Rationale for Selection of Dose/Endpoint/Study 

Estimated human in vivo DAF using the 

above 2 studies 

Comparison of the 28 day oral toxicity study in rats (MRID 48023838) and the 28-day dermal toxicity study in rats (MRIF 48023809) Structure Activity Relationship (SAR) and Physiochemical properties 

(3.754%) than human skin (1.449%). For the 1 g/L diluformulation, the total absorbable dose was 4.47-fold gr(6.516%) than human skin (1.457%). 

Parameter Penflufen (g

1 

Human/in vitro 1.457 Rat/in vitro 6.516 Rat/in vivo (24 hours) 4.004 Estimated human/in vivo (24 hours) 0.89 

For risk assessment purposes, an upper bound dermal acan be calculated by comparing the 28-day oral and derHowever, no significant effects were observed at the hieither study. NOAEL (1000mg/kg/day) from a 28-day dermal toxicitoxic effects noted; thymic debris) and the HDT (560/628-day oral toxicity study in rats (adaptive liver effects DAF of 56% (DAF= (560/1000) x 100%=56%). The e10-fold higher than the highest DAF observed in rats (6comparative in vitro dermal absorption studies (rat and following in vivo 8-hour exposure in the rat. The in vitthat dermal absorption in rat skin was at least four timeabsorption in human skin (0.17-1.45%). No appropriate structure activity relationships were ideof chemical-specific or structural analog data, physiochtest material could be considered when determining an absorption factor. It has been traditionally accepted thaabsorption may be assumed where the molecular weigh

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Penflufen Human Health Risk Assessment 

Table A.3. Toxicology Endpoint Selection Worksheet: Penflufen Exposure Scenario Study Candidates Rationale for Selection of Dose/Endpoint/Study 

100% Dermal Absorption Factor (DAF) 

and log octane-water (Pow) is smaller than -1 or higher 

100% dermal absorption is used. The molecular weigh(<500) and the Pow is 3.33 (less than 4). Therefore, a appropriate. A 100% default DAF is used when there are no other oDAF, when there are no valid in vivo dermal absorption physicochemical properties do not support reduction to and oral to dermal extrapolation is not appropriate. The appear appropriate.

Dermal 

Dermal toxicity (rat) MRID 48023809 

The repeat dose dermal toxicity study in rats, the 2-genstudy in rats, the 90-day oral toxicity study in dogs, chrin dogs, the subchronic neurotoxicity study in rats were short-and/or intermediate-term dermal risk assessment. In a 28 day dermal toxicity study in rats, no dermal irrit

effects were observed up to the limit dose of 1000 mg/kThere are no adequate developmental toxicity studies offspring effects. The highest doses tested (300 and 60and rabbit, respectively) are greater than the NOAELs schronic oral exposure. Offspring effects were noted in the reproduction study maturation, both sexes), and the NOAEL is 1000 ppm [(males)/71.2 mg/kg/day (females)]. In the dog studies at the NOAELs [55.7 mg/kg/day (ma(females) and 32 mg/kg/day (males)/37.9 mg/kg/day (f

liver effects (increased liver weight and hepatocellular were not accompanied by significant alterations in relevparameters or adverse liver lesions, were observed. The adaptive and not adverse over both time frames. 

Page 57 of 106 
Penflufen Human Health Risk Assessment 

Table A.3. Toxicology Endpoint Selection Worksheet: Penflufen Exposure Scenario Study Candidates Rationale for Selection of Dose/Endpoint/Study Dermal, Short-term, (1-30 days) Dermal, Intermediate-term (1-6 months) 

2-Generation Reproduction (rats) (offspring) MRID 48023812 Subchronic Oral Toxicity (dog) MRID 48023808 Chronic toxicity (dog) MRID 48023813 

The NOAELs are similar, and the LOAELs are lower thtested in the developmental toxicity studies in rats and selected endpoint is protective of effects that might be odevelopmental toxicity studies at adequate dose levels a

potential developmental effects. Selected: 90-day and chronic dog and 2-generation rep

In the reproduction toxicity study in rats, a slight decreagenerations, decreased pup body weight and pup body-vaginal patency and balanopreputial separation, and deand thymus weights were observed at the LOAEL of 40mg/kg/day (males)/293.4 mg/kg/day (females)]. The N[58.4 mg/kg/day (males)/71.2 mg/kg/day (females)]. In a subchronic oral toxicity study in dogs, decreased bgain in females, increased alkaline phosphatase activity increased GGT activity in both sexes, decreased albumliver weights in both sexes, increased adrenal weights iincidence of hepatocellular hypertrophy in both sexes, incidence of slight diffuse cortical hypertrophy/hyperplmales were observed at the LOAEL of 18000 ppm (532 (males)/568 mg/kg/day (females). At the NOAEL 1800 (males)/63.1 mg/kg/day (females)], the minimal liver eweight and hepatocellular hypertrophy), which were nosignificant alterations in relevant clinical chemistry parlesions, were observed. The effects are considered adapover this time frame. NOAEL = 32 mg/kg/day (males)/37.9 mg/kg/day (femaminimal changes in the liver (increased liver weight anhypertrophy, which were not accompanied by relevant chemistry parameters and adverse liver lesions) that are adverse. The LOAEL = 357 mg/kg/day (males)/425 mg

Page 58 of 106 
Penflufen Human Health Risk Assessment 

Table A.3. Toxicology Endpoint Selection Worksheet: Penflufen Exposure Scenario Study Candidates Rationale for Selection of Dose/Endpoint/Study 

Subchronic Neurotoxicity (rat) MRID 48023830 

based on decreased terminal body weight and body wei

increased prothrombin time (males), increased alkaline (both sexes), decreased cholesterol (both sexes), increasexes), decreased albumin and albumin/globulin ratio (bcalcium and phosphorus (both sexes), increased liver wincreased incidence of focal hepatocellular brown pigm

hypertrophy (both sexes), increased incidence of zona gof the adrenal gland (females), and an increased incidencell hypertrophy (both sexes). Not selected: A NOAEL for neurotoxicology endpoints 

ppm (126 mg/kg/day (males)/156 mg/kg/day (females)ppm [516 mg/kg/day (males)/609 mg/kg/day (females)decrease in motor activity in females, which is consisteof decreased motor activity in females in the acute neur48023829). 

Inhalation 

2-Generation Reproduction (rats) (offspring) MRID 48023812 2-Generation Reproduction (rats) 

The 2-generation reproduction study in rats, the 90-day rats and dogs, the chronic oral toxicity study in dogs, thneurotoxicity study in rats, and the chronic study in dogfor short-and/or intermediate-term inhalation risk assesNo repeat exposure inhalation studies are available, so for risk assessment, with an assumed absorption factor Offspring NOAEL = 1000 ppm [58.4 mg/kg/day (male(females)]. Offspring LOAEL = 4000 ppm [(256.5 mg/mg/kg/day (females)], based on a slight decrease in littegenerations, decreased pup body weight and pup body-

vaginal patency and balanopreputial separation, and deand thymus weights. Parental systemic NOAEL = 1000 ppm [64 mg/kg/day 

Page 59 of 106 
Penflufen Human Health Risk Assessment 

Table A.3. Toxicology Endpoint Selection Worksheet: Penflufen Exposure Scenario Study Candidates Rationale for Selection of Dose/Endpoint/Study Inhalation, ShortTerm (1-30 days) Inhalation, Intermediate-Term (1-6 months) 

(adult) MRID 48023812 Subchronic Oral Toxicity (dog) MRID 48023808 Chronic toxicity (dog) MRID 48023813 

(females)]. Parental LOAEL = 4000 ppm (252.2 mg/kgmg/kg/day (females), based on decreased body weight, gain, alterations in food consumption, decreased thymugenders, and decreased spleen weights in females (both In a subchronic oral toxicity study in dogs, decreased bgain in females, increased alkaline phosphatase activity increased GGT activity in both sexes, decreased albumliver weights in both sexes, increased adrenal weights iincidence of hepatocellular hypertrophy in both sexes, 

incidence of slight diffuse cortical hypertrophy/hyperpl

males were observed at the LOAEL of 18000 ppm (532 (males)/568 mg/kg/day (females). At the NOAEL 1800 (males)/63.1 mg/kg/day (females)], the minimal liver eweight and hepatocellular hypertrophy), which were nosignificant alterations in relevant clinical chemistry parlesions, were observed. The effects are considered adapover this time frame. NOAEL = 32 mg/kg/day (males)/37.9 mg/kg/day (femaminimal changes in the liver (increased liver weight anhypertrophy, which were not accompanied by relevant chemistry parameters and adverse liver lesions) that are adverse. The LOAEL = 357 mg/kg/day (males)/425 mgbased on decreased terminal body weight and body weiincreased prothrombin time (males), increased alkaline (both sexes), decreased cholesterol (both sexes), increasexes), decreased albumin and albumin/globulin ratio (bcalcium and phosphorus (both sexes), increased liver wincreased incidence of focal hepatocellular brown pigmhypertrophy (both sexes), increased incidence of zona gof the adrenal gland (females), and an increased incidencell hypertrophy (both sexes). 

Page 60 of 106 
Penflufen Human Health Risk Assessment 

Page 61 of 106 

Table A.3. Toxicology Endpoint Selection Worksheet: Penflufen Exposure Scenario Study Candidates Rationale for Selection of Dose/Endpoint/Study 

Subchronic Neurotoxicity (rat) MRID 48023830 

Not selected: A NOAEL for neurotoxicology endpoints 

ppm (126 mg/kg/day (males)/156 mg/kg/day (females)ppm [516 mg/kg/day (males)/609 mg/kg/day (females)decrease in motor activity in females, which is consisteof decreased motor activity in females in the acute neur48023829). 
Penflufen Human Health Risk Assessment D387450 

A.3.1 Acute Reference Dose (aRfD) - General Population, including infants, children, and 

females age 13-49 

Study Selected: Acute Neurotoxicity Study in Rats 

MRID No.: 48023829 

Executive Summary: See Appendix A, Guideline [§ 870.6200] 

Dose and Endpoint for Risk Assessment: NOAEL = 50 mg/kg bw, based on decreased motor 

and locomotor activity (39-81% on day of treatment) in females seen at LOAEL = 100 mg/kg 

bw. 

Comments about Study/Endpoint/Uncertainty Factors: The study is appropriate for acute 

dietary exposure due to the route (oral) and duration (acute) of dosing. The effects are clearly 

adverse and result from a single exposure. The NOAEL and LOAEL established are protective 

of any potential acute systemic or developmental effects. Endpoints from the developmental rat 

and rabbit studies as well as the 2-generation reproduction study were not selected since there 

were no effects seen that were attributable to a single exposure. Therefore, the dose and 

endpoint from the ACN study were selected and are considered protective of potential acute 

toxicity for all populations (i.e., the general population, including infants and children and 

females ages 13 to 49 years old) since the NOAEL/LOAEL from the ACN were lower than the 

highest dose tested in the developmental toxicity studies 

A.3.2 Chronic Reference Dose (cRfD) `

Study Selected: Chronic Toxicity Study in Dogs 

MRID No.: 48023813 

Executive Summary: See Appendix A, Guideline [§ 870.4100] 

Dose and Endpoint for Risk Assessment: NOAEL = 38 mg/kg bw/day based on decreased 

terminal body weight and body weight gain (females), increased prothrombin time (males), 

increased alkaline phosphate activity (both sexes), decreased cholesterol (both sexes), increased 

GGT levels (both sexes), decreased albumin and albumin/globulin ratio (both sexes), decreased 

calcium and phosphorus (both sexes), increased liver weights (both sexes), increased incidence 

of focal hepatocellular brown pigment and hepatocellular hypertrophy (both sexes), increased 

incidence of zona glomerulosa vacuolation of the adrenal gland (females), and an increased 

incidence of thyroid follicular cell hypertrophy (both sexes)at the LOAEL = 357 mg/kg/day 

(males)/425 mg/kg/day (females). 

Comments about Study/Endpoint/Uncertainty Factors: The study is appropriate for chronic 

dietary exposure due to the route (oral) and duration (chronic) of dosing. This is a conservative 

endpoint. For the repeat dose studies available, the dose spread is large in all cases (LOAEL of 

250-532 mg/kg/day), and the NOAELs are similar (males: 32-64 mg/kg/day/females: 38-76 

mg/kg/day). The chronic dog study provides the only NOAEL that is lower than the acute 

NOAEL. In the rat repeat dose studies at dose levels up to the limit dose, the effects on the liver 

are considered mostly adaptive. In the dog studies, the duration of the study relative to the 

lifespan of the dog is short. The selection is conservative but protective of other findings and the 

lack of adequate studies to detect potential developmental effects. 

A.3.3 Dermal Exposure (Short-, Intermediate- and Long-Term) 

In a 28-day dermal toxicity study in rats, no dermal irritation or systemic effects were observed 

up to the limit dose of 1000 mg/kg/day. Dermal absorption is minimal (<1%). This is a routespecific study that also assessed all of the endpoints used in the other exposure scenarios and 

Page 62 of 106 
 

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durations of exposure (e.g. neurological endpoints, thyroid and liver histopathology). In addition, 

no increased susceptibility was seen between offspring and adult animals in the developmental 

toxicity studies in rats and rabbits and in the 2-generation reproduction study in rats. Therefore, 

the quantification of dermal risk is not required since no hazard was identified. 

A.3.4 Inhalation Exposure (Short-Term) 

Study Selected: Subchronic Toxicity Study in Dogs 

MRID No.: 48023808 

Executive Summary: See Appendix A, Guideline [§ 870.3150] 

Dose and Endpoint for Risk Assessment: NOAEL = 55.7 mg/kg/day (1800 ppm) in males, 

based on decreased body weight/ body weight gain in females, increased alkaline phosphatase 

activity in both sexes, increased GGT activity in both sexes, decreased albumin in males, 

increased liver weights in both sexes, increased adrenal weights in males, increased incidence of 

hepatocellular hypertrophy in both sexes, and an increased incidence of slight diffuse cortical 

hypertrophy/hyperplasia in the adrenal in males seen at LOAEL = 18000 ppm (532 mg/kg/day 

(males)/568 mg/kg/day (females). 

Comments about Study/Endpoint/Uncertainty Factors: No inhalation studies are available 

for penflufen; therefore, a 90-day oral toxicity study in dogs was used for inhalation risk 

assessment. The selected endpoint is the most sensitive endpoint for this duration of exposure. 

For the repeat dose studies available, the dose spread is large in all cases (LOAEL of 250-532 

mg/kg/day), and the NOAELs are similar (males: 32-64 mg/kg/day/females: 38-76 mg/kg/day). 

The subchronic dog study is appropriate for this duration of exposure. In the rat repeat dose 

subchronic oral toxicity studies at dose levels up to the limit dose, the effects on the liver are 

considered mostly adaptive. In the dog studies, the duration of the study relative to the lifespan 

of the dog is short; therefore, the liver effects are considered adverse in the dog. 

A.3.4 Inhalation Exposure (Intermediate-Term) 

Study Selected: Chronic Toxicity Study in Dogs 

MRID No.: 48023813 

Executive Summary: See Appendix A, Guideline [§ 870.4100] 

Dose and Endpoint for Risk Assessment: NOAEL = 38 mg/kg/day based on decreased 

terminal body weight and body weight gain (females), increased prothrombin time (males), 

increased alkaline phosphate activity (both sexes), decreased cholesterol (both sexes), increased 

GGT levels (both sexes), decreased albumin and albumin/globulin ratio (both sexes), decreased 

calcium and phosphorus (both sexes), increased liver weights (both sexes), increased incidence 

of focal hepatocellular brown pigment and hepatocellular hypertrophy (both sexes), increased 

incidence of zona glomerulosa vacuolation of the adrenal gland (females), and an increased 

incidence of thyroid follicular cell hypertrophy (both sexes) seen at LOAEL = 357 mg/kg/day 

(males)/425 mg/kg/day (females). 

Comments about Study/Endpoint/Uncertainty Factors: No inhalation studies are available 

for penflufen; therefore, a chronic oral toxicity study in dogs was used for inhalation risk 

assessment. In the rat repeat dose oral toxicity studies, the effects on the liver occur following 

exposure that includes most of the rats’ lifespan. In the dog studies, the duration of the study 

relative to the lifespan of the dog is short. Therefore, the selected endpoint is the most sensitive 

endpoint and most sensitive species for this duration of exposure. 
 

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A.4 Executive Summaries 

A.4.1 Subchronic Toxicity

 870.3100 90-Day Oral Toxicity - Rat

Executive Summary: In a subchronic oral toxicity study (MRID 48023805), BYF 14182 

(batch number NLL 7306-18, 98.6% purity) was administered continuously via dietary 

administration to groups of Wistar rats (10/sex/group) at concentrations of 0, 150, 7000, or 

14000 ppm (equivalent to 0, 9.5, 457 and 949 mg/kg bw/day in males and 0, 11.4, 492 and 

1009 mg/kg bw/day in females) for at least 90 days. This study is a companion study to MRID 

48023806 (SA 05148, M-273186-01-2), which is a 90-day dietary study in Wistar rats that was 

performed using dose levels of 0, 50, 150, or 3500 ppm (equivalent to 0, 3.2, 9.3 or 228 mg/kg 

bw/day in males and 0, 3.7, 11.4 or 260 mg/kg bw/day in females). 

No treatment-related mortalities or clinical signs of toxicity (including the neurotoxicological 

assessment) were observed during the study in either sex. Body weight was comparable among 

the male groups throughout the study, although body weight gain was significantly reduced by 

24% in males at 14000 ppm during the first week of treatment. Thereafter, body weight changes 

were similar to controls. In females, body weight was slightly reduced over the entire treatment 

period (5% to 7%) at 7000 ppm and 14000 ppm. During the first week of treatment, body weight 

gain was reduced in females by 36% at 7000 ppm and 55% at 14000 ppm. With continued 

exposure, the weekly body weight gain was comparable among the groups through 7 weeks. On 

Day 90, the overall mean reduction in body weight gain was 17% at 7000 ppm and 12% at 14000 

ppm, when compared to controls, but there was no dose response. Mean food consumption was 

reduced over the entire treatment period at 7000 ppm (8% to 17%) and 14000 ppm (5% to 14%) 

compared to controls. 

Higher total cholesterol concentration, globulin concentration, and gamma-glutamyltransferase 

activity and lower albumin/globulin ratio were observed in both sexes at 7000 ppm and 14000 

ppm. Higher total protein concentration (7000 ppm and 14000 ppm) and albumin concentration 

(14000 ppm) were observed in males. Lower mean alanine aminotransferase and/or asparate 

aminotransferase activities were observed in both sexes at 14000 ppm. In females at 7000 ppm 

and 14000 ppm, lower total bilirubin concentrations were observed. 

At necropsy, mean absolute and relative liver weights were increased in males and females at 

14000 ppm and to a lesser extent at 7000 ppm. Enlarged livers were observed in all rats at 14000 

ppm and in 8/10 males and 7/10 females at 7000 ppm. 

Centrilobular hepatocellular hypertrophy was observed in all rats of both sexes at 7000 ppm and 

in 9/10 males and all females at 14000 ppm, compared to none in either sex in the control and 

150 ppm groups. In the thyroid, 8/10 males at both the 7000 ppm and 14000 ppm dose levels, 

and 6/10 females at 14000 ppm had thyroid follicular cell hypertrophy, and 3/10 males at both 

the 7000 ppm and 14000 ppm dose levels had altered colloid. In the kidney, an increased 

incidence of hyaline droplet accumulation was noted in 6/10 males at 14000 ppm and in 5/10 

males at 7000 ppm. 

In this definitive 90-day rat study (MRID 48023805), together with the findings of MRID 

48023806 (point KIIA 5.3.2/02), it was concluded that the Lowest Observed Adverse Effect 
 

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Level (LOAEL) was not identified. The findings at 14000 ppm (equivalent to 949 mg/kg bw/day 

in males and 1009 mg/kg bw/day in females) included an increase in total cholesterol 

concentration and gamma-glutamyltransferase activity in both sexes, an increase in the incidence 

of centrilobular hepatocellular hypertrophy, which was correlated with higher liver weights and 

macroscopically enlarged livers in both sexes, an increased incidence of thyroid follicular cell 

hypertrophy in both sexes, and altered colloid in males. These effects are considered an adaptive 

response and not adverse. 

This study is classified as totally reliable (acceptable/guideline), and it satisfies the guideline 

requirement for a subchronic oral toxicity study (OPPTS 870.3100; OECD 408) in rats. 

Executive summary: In a subchronic oral toxicity study (MRID 48023806), BYF 14182 

(batch number NLL 7306-18, 98.2 to 98.8% purity) was administered via the diet to groups of 

Wistar rats (10/sex/group) at concentrations of 0, 50, 150, and 3500 ppm (equivalent to 0, 3.2, 

9.3 and 228 mg/kg bw/day in males and 0, 3.7, 11.4 and 260 mg/kg bw/day in females) for at 

least 90 days. In this study, only the kidney, liver, pancreas, pituitary and thyroid glands were 

examined at microscopy, and no hematology, urinalysis, ophthalmological, or neurotoxicological 

examinations were performed. This study was performed to provide additional information on 

the potential toxic effects of BYF 14182 observed in a similar subchronic oral toxicity study in 

Wistar rats (MRID 48023805). Both studies were performed to provide information for selection 

of dose levels for future toxicity studies in the rat. 

No treatment-related mortalities or clinical signs of toxicity were observed during the study. No 

treatment-related body weight or food consumption changes were observed at any dose level 

throughout the study. Clinical chemistry parameters were not affected. 

At necropsy, mean terminal body weight in females at 3500 ppm was decreased by 6% when 

compared to control rats. Mean absolute and relative liver weights were increased by 13% to 

15% in males and 8% to 16% in females. Enlarged livers were observed in 4/10 females at 3500 

ppm. 

Increased liver weights were observed in both sexes at 3500 ppm, which is consistent with the 

minimal centrilobular hepatocellular hypertrophy observed in both sexes at 3500 ppm. This 

finding was considered to be an adaptative response and not an adverse effect, based on a lack of 

accompanying alterations in relevant clinical chemistry parameters and adverse lesions. There 

was an increase in thyroid weight in both sexes, mainly at the3500 ppm dose level, but these 

changes were not accompanied by any microscopic findings. In the kidney, minimal tubular 

hyaline droplets were observed in males at 3500 ppm. 

A Lowest Observed Adverse Effect Level (LOAEL) was not identified in this study. At the 

highest dose tested (3500 ppm, equivalent to 228 mg/kg bw/day in males and 260 mg/kg 

bw/day in females), increased liver weights and an increased incidence of centrilobular 

hepatocellular hypertrophy were observed, which were not accompanied by alterations in 

relevant clinical chemistry parameters or adverse liver lesions. The effects observed are 

considered adaptive and not adverse over this time frame. 

This subchronic oral toxicity study is classified acceptable/non-guideline and alone does not 

satisfy the guideline requirement for a subchronic oral toxicity study in the rat. It is nonguideline because only the kidney, liver, pancreas, pituitary and thyroid glands were examined 
 

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microscopically, and hematology, urinalysis, or ophthalmological examinations were not 

performed. When considered together with MRID 48023805 (Report No. SA04199), this 

guideline requirement (OPPTS 870.3100; OECD 408) is satisfied.

 870.3100 90-Day Oral Toxicity - Mouse

Executive Summary: In a subchronic oral toxicity study (MRID 48023807), BYF 14182 

(batch number NLL 7306-18, 98.8% purity) was administered continuously via dietary 

administration to groups of C57BL/6J mice (10/sex/group) at concentrations of 0, 150, 3500 and 

7000 ppm (equivalent to 0, 26.9, 638 and 1238 mg/kg bw/day in males and 0, 31.5, 757 and 1600 

mg/kg bw/day in females) for at least 90 days. 

No mortalities or treatment-related clinical signs of toxicity were observed during the study. 

Body weight and food consumption parameters were comparable among the groups for both 

sexes throughout the study. There was a dose-related decrease in total cholesterol concentration 

in males and females at the 3500 ppm and 7000 ppm dose levels. Alanine aminotransferase was 

increased in both sexes at 7000 ppm (males ↑35%/females ↑48%), although statistical 

significance was not attained in the males. 

At necropsy, there was a dose-related increase in mean absolute and relative liver weights in both 

sexes at 3500 ppm and 7000 ppm. Enlarged livers were observed in 9/10 males and 8/10 females 

at 7000 ppm and 5/10 males and 1/10 females at 3500 ppm. Consistent with these findings was 

the increased incidence of minimal to mild diffuse centrilobular hepatocellular hypertrophy 

observed in 9/10 males and 7/10 females at 7000 ppm and 4/10 males and 4/10 females at 3500 

ppm. 

A Lowest Observed Adverse Effect Level (LOAEL) was not identified in this study, which 

included a dose level that exceeded the limit dose in both sexes (7000 ppm; equivalent to 1238 

mg/kg bw/day in males and 1600 mg/kg bw/day in females). The liver effects are considered 

adaptive and not adverse. 

This subchronic oral toxicity study is classified acceptable/non-guideline, and it does not satisfy 

the guideline requirement (OPPTS 870.3100; OECD 408) for a subchronic oral toxicity study in 

the rodent. The study is considered non-guideline because there were no ophthalmoscopic or 

hematological examinations, ovaries were not weighed, and several clinical chemistry 

parameters (sodium, potassium, glucose, and creatinine levels) were not measured. 

 870.3150 90-Day Oral Toxicity – Dog 

Executive Summary: In a subchronic oral toxicity study (MRID 48023807), BYF 14182 

(batch number 2005-004498, 95.6% purity) was administered to 4 Beagle dogs/sex/group via the 

diet at doses of 0, 180, 1800 or 18000 ppm (equivalent to 0, 5.6, 55.7 and 532 mg/kg bw/day in 

males and 0, 6.1, 63.1 and 568 mg/kg bw/day in females) for at least 13 weeks. 

There were no mortalities or treatment-related clinical signs of toxicity or changes at the physical 

and ophthalmological examinations and urinalysis in either sex. During the first week of 

exposure, a mean body weight loss of 0.1 kg was observed in males at 18000 ppm compared to a 

mean body weight gain of 0.1 kg in controls. Thereafter, mean body weights in males at 18000 
 

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ppm were similar to controls. Overall body weight gain was reduced (↓25%) in males at 18000 

ppm. In females at 18000 ppm, the mean body weight gain was reduced by 50% during the first 

week of dosing, by 89% during weeks 1-7, and by 82% overall. Final body weights were reduced 

by ↓21% in females at 18000 ppm compared to the controls. The overall mean body weight gain 

in females at 18000 ppm was reduced by 82% in high dose females compared to the controls. 

Mean food consumption was reduced by 39% in males and 35% in females during the first week 

of treatment compared to controls. This initial decrease in food consumption was most likely 

attributable to adaptation to the treated diet. Thereafter, mean food consumption in males was 

comparable to controls, whereas food intake was lower in females at 18000 ppm throughout the 

study. 

Both sexes at 18000 ppm displayed an increase in prothrombin time throughout the study 

(compared to the pre-test and control values) at 18000 ppm. Increased platelet counts were 

observed in females and decreased total protein was observed in males at 18000 ppm. Increased 

alkaline phosphatase activity was observed in both sexes at 18000 ppm throughout the study, and 

the magnitude of the change increased with time on test. Gamma-glutamyltransferase activities 

were slightly increased in males and significantly increased in females at 18000 ppm, and the 

magnitude of the change increased with time on test. Lower total cholesterol concentrations 

(relative to pre-test values) were observed in males throughout the study and in females at the 

end of the study at 18000 ppm. Mean albumin concentrations were decreased in both sexes at 

18000 ppm throughout the study (relative to pre-test value), and the albumin/globulin ratio was 

decreased also. 

There was a dose-related increase in adrenal weight in males, which was associated with a slight 

diffuse cortical hypertrophy/hyperplasia in 2/4 males at 18000 ppm. There was a dose-related 

increase in liver weight in both sexes, which correlated with the microscopic lesions observed at 

1800 ppm and 18000 ppm. A minimal to slight diffuse panlobular hepatocellular hypertrophy 

was seen in all males and females at 18000 ppm, together with the multifocal presence of a 

minimal amount of intrahepatocellular eosinophilic material in 2/4 males and 1/4 females and 

minimal hepatocellular single cell death in 2/4 males and 1/4 females. At 1800 ppm, the liver 

changes were associated with a minimal diffuse panlobular hepatocellular hypertrophy in 1/4 

males and 3/4 females. 

A dietary level of 1800 ppm (equivalent to 55.7 mg/kg bw/day in males and 63.1 mg/kg bw/day 

in females) was established as the NOAEL in both sexes based on the minimal liver effects 

(increased liver weight and hepatocellular hypertrophy), which were not accompanied by 

significant alterations in relevant clinical chemistry parameters or adverse liver lesions. The 

effects observed are considered adaptive and not adverse over this time frame. The LOAEL is 

established at 18000 ppm (equivalent to 532 mg/kg bw/day in males and 568 mg/kg bw/day in 

females), based on decreased body weight/body weight gain in females, increased alkaline 

phosphatase activity in both sexes, increased GGT activity in both sexes, decreased albumin in 

males, increased liver weights in both sexes, increased adrenal weights in males, increased 

incidence of hepatocellular hypertrophy in both sexes, and an increased incidence of slight 

diffuse cortical hypertrophy/hyperplasia in the adrenal in males. 

This study is classified as totally reliable (acceptable/guideline), and it satisfies the guideline 

requirement for a subchronic oral toxicity study (OPPTS 870.3150; OECD 409) in dogs. 
 

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 870.3200 21/28-Day Dermal Toxicity – Rat 

Executive Summary: In a subacute dermal toxicity study (MRID 48023809), Technical grade 

BYF 14182 (Batch No. 2005-004498; 95.6% purity) was administered by topical (dermal) 

application to 10 Wistar Hanover IGS [CRL:WI (Han)] rats/sex/dose at dose levels of 0 (control 

group), 100, 300, and 1000 mg/kg bw/day for 6 hours/day, 5 days/week for 4 weeks, for a total 

of 21 doses. The test substance was applied to a 3-inch by 3-inch two-ply gauze pad that had 

been moistened with deionized water. 

There were no treatment-related deaths or clinical signs of toxicity. Body weights, food 

consumption, hematology, clinical chemistry, organ weights, and macroscopic examination of 

tissues were comparable among the groups for both sexes. There was an increased incidence of 

thymic debris (minimal severity) in both sexes at 1000 mg/kg bw/day (7 of 10 in both sexes). 

This lesion was characterized by the increased presence of fragmented thymic cortical 

lymphocytes noted within tingible body macrophages. This finding was not accompanied by a 

decrease in the size or weight of the thymus or changes in lymphocyte counts. The significance 

of the finding at the limit dose is not known. 

The No-Observed-Adverse-Effect Level (NOAEL) for dermal application over 28 days is 

established at 1000 mg/kg bw/day in males and females. A LOAEL was not identified. 

This dermal toxicity study is classified acceptable/guideline, and it satisfies the guideline 

requirement (870.3200; OECD 410) for a repeated dose dermal toxicity study in rats. 

 870.3465 90-Day Inhalation – Rat

A.4.2 Prenatal Developmental Toxicity

 870.3700a Prenatal Developmental Toxicity Study – Rat 

Executive Summary: In a developmental toxicity study (MRID 48023810), groups of 

sperm-positive female Sprague-Dawley rats (23/dose level) were exposed via oral gavage to 

BYF 14182 (batch number 2005-004498, 95.6% purity) at doses of 0 (vehicle, aqueous solution 

of 0.5% methylcellulose 400), 30, 100 or 300 mg/kg bw/day from gestation day (GD) 6 to GD 

20. 

There were no mortalities or treatment-related clinical signs of toxicity in the maternal rats. 

Initially (GD 6-8), maternal rats at 300 mg/kg bw/day displayed a mean body weight loss, and 

thereafter, gained weight at a lower rate than controls. Overall body weight gain (GD 6-21) at 

300 mg/kg bw/day was 13% lower than control, and the corrected body weight gain was 19% 

lower than control. Body weight of the 300 mg/kg bw/day-dams on GD 21 was comparable to 

(↓3%) the control. Similarly at 100 mg/kg bw/day, maternal rats displayed lower mean body 

weight gains initially (↓32%) but the gains were comparable to control from GD 10 on. Maternal 

body weight of the 100 mg/kg bw/day-dams was slightly greater than the control on GD 21, and 

maternal corrected body weight change was comparable to the control. Mean food consumption 

was reduced slightly at all intervals between GD 6 and 12 at 300 mg/kg bw/day. Thereafter, 

mean food consumption was unaffected by treatment. 
 

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At necropsy, treatment-related findings consisted of prominent lobulation of the liver in 4/23 

females at 300 mg/kg bw/day and in 3/23 females at 100 mg/kg bw/day. Mean liver weight was 

increased at 300 mg/kg/day (14%) compared to controls. 

No treatment-related effects were observed on litter parameters, including pre and post 

implantation loss, early or late resorptions, fetal death, percentage of male and female fetuses, 

fetal body weights, or on the incidence of malformations/variations at the external, visceral or 

skeletal fetal examination, at any dose level tested. 

The maternal findings at the 300 mg/kg bw/day dose level are considered minimal. The 

dose levels do not appear adequate for assessing the developmental toxicity potential of 

BYF 14182. Although there was a significant reduction in maternal body weight gain at 300 

mg/kg bw/day, which correlated with a decrease in food consumption, body weights were 

comparable to those of the control, and the liver changes are considered adaptive and not 

adverse. A maternal toxicity lowest-observed-adverse-effect-level (LOAEL) was not 

identified. 

A developmental toxicity lowest-observed-adverse-effect-level (LOAEL) was not identified. 

At 300 mg/kg bw/day, the highest dose tested, no adverse effects were observed. However, 

this dose was a no adverse effect dose level in the range-finding study also. The dose levels 

are not considered adequate for assessing the developmental toxicity potential of BYF 

14182. 

This study is classified as acceptable/non-guideline, and it does not satisfy the guideline 

requirement (OPPTS 870.3700; OECD 414) for a developmental toxicity study in rats. It is nonguideline because dose levels were not adequate to assess developmental toxicity potential, but 

there is nothing to gain by repeating the study. 

 870.3700b Prenatal Developmental Toxicity Study – Rabbit 

Executive Summary: In a developmental toxicity study (MRID 48023811), 23 time-mated 

pregnant female New Zealand White rabbits/dose level were administered BYF 14182 

(batch number 2005-004498, 95.6% purity) via oral gavage from gestation day (GD) 6 to 28, the 

day of mating being designated GD 0. The doses given were 0 (vehicle, aqueous solution of 

0.5% methylcellulose 400), 30, 100 and 600 mg/kg bw/day. 

One female rabbit at 600 mg/kg bw/day was sacrificed for humane reasons on GD 25. This 

rabbit had no or few feces between GD 17 and 25 and lost 640 g in body weight from GD 6 to 

25. No abnormality was identified at necropsy. In the surviving dams, no treatment-related 

clinical signs were observed. The females at 600 mg/kg bw/day showed a mean body weight loss 

of 0.01 kg initially (GD 6 to GD 8) compared to a mean maternal body weight gain of 0.02 kg in 

the controls. Thereafter, mean maternal body weight gain was reduced (↓60% to ↓71%) at 

several time intervals between GD 8 and 22 and overall (GD 6 to 29; ↓26%). All groups 

displayed a negative corrected body weight change, but the mean maternal corrected body 

weight change at 600 ppm was larger (-0.29 kg) than that of the control (-0.20 kg). Consistent 

with the reduced body weight gain, mean maternal food consumption was reduced at 600 mg/kg 
 

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bw/day (18% to 27%) throughout most of the study (GD 6 to GD22). However, body weights 

were comparable among all groups 

At sacrifice, no treatment-related macroscopic findings were observed in the maternal rabbit, and 

mean liver weights were similar to the controls. Mean fetal body weights for the combined sexes 

and for the individual sexes at 600 mg/kg bw/day were 7% to 8% lower than the controls. Other 

litter parameters were unaffected by treatment. 

There were no toxicologically relevant external, visceral or skeletal observations at any dose 

tested. However, a treatment-related increased incidence of incomplete ossification of the 5 and 

6 sternebrae was noted in the 600 mg/kg bw/day pups. 

At the highest dose tested (600 mg/kg bw/day), minimal maternal toxicity was observed, as 

evidenced by the slight decrease (1%-4%) in body weight throughout the dosing period (GD 6-

29) and a lack of any other effects. Minimal fetal toxicity was observed at this dose level, as 

evidenced by the slight decrease in mean fetal body weights (7%-8%). 

The maternal findings at the 600 mg/kg bw/day dose level are considered minimal. The 

dose levels do not appear adequate for assessing the developmental toxicity potential of 

BYF 14182 in the rabbit. Although there was a significant reduction in maternal body 

weight gain at 600 mg/kg bw/day, which correlated with a decrease in food consumption, 

body weights were comparable to those of the control. No other effects were observed. A 

maternal toxicity lowest-observed-adverse-effect-level (LOAEL) was not identified. 

A developmental toxicity lowest-observed-adverse-effect-level (LOAEL) was not identified. 

No adverse effects were observed at 600 mg/kg bw/day, the highest dose tested. However, 

this dose was a no adverse effect dose level in the range-finding study also. The dose levels 

do not appear adequate for assessing the developmental toxicity potential of BYF 14182. 

This study is classified as acceptable/non-guideline, and it does not satisfy the guideline 

requirement (OPPTS 870.3700; OECD 414) for a developmental toxicity study in rabbits. The 

study is classified as non-guideline because the highest dose is not considered adequate for 

assessment developmental toxicity. However, there is no need to repeat the study, as the 

endpoints selected (32-56 mg/kg bw/day) for risk assessment are protective of any effects that 

might occur at higher dose levels (>600 mg/kg bw/day). 

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects - Rat

Executive Summary: In a two-generation reproduction study (MRID 48023812), BYF 14182 

(95.6%; Batch No. 2005-004498) was administered to 30 Wistar Han CRL: WI (HAN) 

rats/sex/dose via the diet at nominal dietary concentrations of 0, 200, 1000, or 4000 ppm 

[equivalent to 0, 12.8, 64.1, or 252.2 mg/kg bw/day (males)/ 0, 15, 75.9, or 294.5 mg/kg bw/day 

(females)] throughout the 10-week pre-mating period and to the dams through gestation and 

lactation. There was one set of litters per generation. 
 

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Parental rats: No treatment-related effects on survival or clinical signs of toxicity were observed 

in adult rats of either gender or generation. Reductions in body weight (males 5%-8%/females 

7%-8%) and body weight gain (P1 males ↓14%/P1 females ↓36%/F1 adult female ↓15%) were 

accompanied by decreases in food consumption in both generations during the pre-mating 

periods at 4000 ppm. Throughout gestation, females showed declines in body weight (↓8%-10%) 

and body weight gain (days 0-20 14%-15%) in both generations at 4000 ppm. During lactation, 

females at 4000 ppm showed lower body weights (↓6%-11%) than the controls, but body-weight 

gains were slightly greater than the controls in both generations. Increased liver weights 

(absolute and relative) were observed in both genders and both generations at the 4000 ppm dose 

level and were accompanied by an increased incidence of hypertrophy (centrilobular and/or 

midzonal). These liver findings are considered an adaptive response and not an adverse effect. 

Decreased thymus weight (absolute and relative) was observed in both genders in both 

generations at 4000 ppm, and decreased absolute spleen weight was observed in females in both 

generations at 4000 ppm. These latter organ weights were not accompanied by micropathology 

findings. The parental systemic LOAEL is 4000 ppm (252.2 mg /kg bw/day in males, 294.5 

mg /kg bw/day in females), based on decreased body weight, decreased body weight gain, 

alterations in food consumption, decreased thymus weight in both genders, and decreased 

spleen weights in females (both generations). The parental systemic NOAEL is 1000 ppm 

(64 mg /kg bw/day in males and 75.9 mg /kg bw/day in females). 

Offspring: Pups exhibited a decrease in body weight and a decrease in overall body weight gain 

throughout lactation at the 4000 ppm dose level. Litter size was decreased in both generations 

and was outside the historical control range. There were delays in vaginal opening and preputial 

separation at the 4000 ppm dose level in both generations. The magnitude of the associated 

decline in body weight was not considered to be a factor in the delay in female sexual 

maturation. The time of occurrence of both landmarks was outside the testing facility's historical 

control range, but the one-day delay in balanopreputial separation is not considered biologically 

significant. There was a decrease in absolute and relative spleen weights in both genders in both 

generations. Brain weight was slightly lower at 4000 ppm in both genders and both generations.

The offspring LOAEL is 4000 ppm (256.5 mg/kg bw/day in males, 293.4 mg/kg bw/day in 

females). The LOAEL is based on a slight decrease in litter size in both generations, 

decreased pup body weight and pup body-weight gain, delayed vaginal patency, and 

decreased spleen weights. The offspring NOAEL is 1000 ppm (58.4 mg/kg bw/day in males, 

71.2 mg /kg bw/day in females). 

Reproductive Performance (P1 and F1): Reproductive toxicity was observed in both 

generations in females, as evidenced by the delay in vaginal opening. The reproductive toxicity 

LOAEL is 4000 ppm (294.5 mg /kg bw/day), based on delayed sexual maturation in females in 

both generations. The reproductive toxicity NOAEL is 1000 ppm (71.2 mg /kg bw/day). 

This study is classified as totally reliable (acceptable/guideline), and it satisfies the guideline 

requirement for a 2-generation reproductive study (OPPTS 870.3800; OECD 416) in rats. 

 
 

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A.4.4 Chronic Toxicity

 870.4100a (870.4300) Chronic Toxicity/Carcinogenicity – Rat 

Executive Summary: In a chronic toxicity/carcinogenicity study (MRID 48023815), BYF 

14182, (Batch N° 2005-004498, 95.6% purity) was administered via the diet to groups of 

Wistar rats at 0, 100, 2000 and 7000 ppm, corresponding to 0, 4.0, 79 and 288 mg/kg bw/day in 

males and 0, 5.6, 113 and 399 mg/kg bw/day in females over a 24-month treatment period 

(10 rats/sex/group designated for the interim sacrifice after 52 weeks, 10 rats/sex/group 

designated for the recovery group sacrificed after 65 weeks following 52 week of treated diet, 

and 13 weeks of untreated diet, and 60 rats/sex/group designated for the final sacrifice after 104 

weeks). 

No treatment-related mortality or clinical signs of toxicity were observed in either sex at any 

dose level. Body weights and body weight gains were comparable among the male groups 

throughout the study. Treatment-related decreases in body weights and body weight gains were 

observed in females at 2000 ppm and 7000 ppm, and the body weight deficits increased with 

time of exposure. During the first week of exposure, a dose-related reduction in body weight 

gain was observed in females at 2000 ppm (↓25%) and 7000 ppm (↓58%), whereas the reduction 

over the first 90 days was ↓10% and ↓20%, respectively. At study termination, a 12% decrease in 

body weight was observed in females at 7000 ppm, and overall body weight gain was decreased 

by 18% compared to the control. Food consumption was consistent with the lower body weight 

observed. No differences on body weight, body weight gain, or food consumption were observed 

at the end of the recovery period. 

There was a dose-related increase in mean total cholesterol concentrations in females during the 

first year of treatment only, whereas treated males displayed lower cholesterol values compared 

to the controls but there was no dose-response. Decreases in alkaline phosphatase activity, 

aspartate aminotransferase activity, and alanine aminotransferase activity were observed in both 

sexes at 7000 ppm throughout the study. 

At the end of the chronic phase (12 months), there was a dose-related increase in liver weight in 

both sexes when compared to controls. In females at 2000 ppm and both sexes at 7000 ppm, 

there was an increased incidence of enlarged livers. At 7000 ppm, a higher incidence of 

centrilobular to panlobular hepatocellular hypertrophy and centrilobular hepatocellular 

macrovacuolation was observed in both sexes, and a higher incidence of hepatocellular brown 

pigments was observed in females only. In the thyroid gland, a higher incidence of enlarged 

thyroid glands was observed at 7000 ppm, which correlated with a higher incidence of follicular 

cell hypertrophy observed in both sexes and a higher incidence of colloid alteration was observed 

in females. The liver and the thyroid gland microscopic findings were mostly reversible as liver 

hypertrophy was not observed after the 3-month recovery period and only one male rat presented 

a minimal follicular cell hypertrophy at the end of the recovery period. 

At the end of the carcinogenicity phase (24 months), females at 7000 ppm showed increased 

thymus weights, although statistical significance was not attained. Both sexes at 7000 ppm 

displayed increased liver weights (absolute and/or relative) compared to controls. Treatment-
 

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related macroscopic findings consisted of enlarged livers and dark livers in the both sexes, white 

focus in the liver in females only, and dark thyroid glands in both sexes. 

There was a dose-related increase in the incidence of centrilobular to panlobular hepatocellular 

hypertrophy and of centrilobular hepatocellular macrovacuolation in both sexes, and females 

displayed a higher incidence of hepatocellular brown pigments. In the thyroid gland, a higher 

incidence of follicular cell hypertrophy and colloid alteration was observed in both sexes. A 

higher incidence of follicular brown pigments was observed in females at 7000 ppm. 

There was evidence of an increase in the incidence of neoplastic findings in both sexes. There 

was an increased incidence of brain astrocytomas in males at 7000 ppm, which are considered 

rare tumors. The increase in astrocytomas was marginal and not dose-related, and the increased 

incidence at the high dose did not reach statistical significance when compared to controls. 

Additionally, there were no pre-neoplastic lesions, such as glial proliferation, which is a good 

indicator of chemical tumor induction; i.e.,there will be changes in the cells prior to 

transformation to a neoplasm. A higher incidence of ovarian tubulostromal neoplasms (adenoma 

and combined adenoma plus adenocarcinoma) was observed, The ovarian adenomas observed at 

the high dose also showed no dose response, no pair-wise significance, no decrease in 

latency,and there were no pre-neoplastic lesions such as hyperplasia of the epithelial cells of the 

endometrium. Histiocytic sarcoma was observed in males at all dose levels compared to none in 

the control males but there was an absence of a dose response and a lack of pre-neoplastic 

lesions.

The NOAEL is 2000 ppm (males 79 mg/kg/day/females 113 mg/kg/day). The LOAEL is 7000 

ppm ( 288 mg/kg bw/day weight/day in males and 399 mg/kg bw/day in females), based on 

decreased body weight/body weight gain in females, increased liver weight in both sexes, 

increased incidence of centrilobular to panlobular hepatocellular hypertrophy and centrilobular 

hepatocellular macrovacuolation in both sexes, increased incidence of hepatocellular brown 

pigment in females, hepatocellular necrosis, colloid alteration in the thyroid in females, and 

increased cholesterol in females.

This chronic toxicity/carcinogenicity study is classified as acceptable/guideline, and it satisfies 

the guideline requirement (OPPTS 870.4300; OECD 453) for a chronic toxicity/carcinogenicity 

study in the rat. 

 870.4100b Chronic Toxicity - Dog

Executive Summary: In a one-year oral toxicity study (MRID 48023813), BYF 14182 

(batch number 2005-004498, 95.6% purity) was administered to 4 Beagle dogs/sex/group via the 

diet at doses of 0, 200, 1000, or 10000 ppm (equivalent to 0, 6.8, 32.0 and 357 mg/kg body 

weight/day in males and 0, 7.7, 37.9 and 425 mg/kg body weight/day in females) for at least 

52 weeks. 

There were no mortalities, and no treatment-related clinical signs of toxicity or changes in 

ophthalmological examinations, hematology evaluation, or urinalysis were observed. t 10000 

ppm, body weights and body weight gains were comparable among the male groups, but females 

showed lower body weights (↓18% at termination) and body weight gains (↓54% overall). Mean 

food consumption was reduced by 33% in high dose males and by 21% in high dose females 
 

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during the first week of treatment. This initial decrease was most likely attributable to adaptation 

to the treated diet. Thereafter, mean food consumption was comparable to the controls in both 

sexes. 

Prothrombin time was significantly increased in males at 10000 ppm. Mean alkaline phosphatase 

activities were markedly increased (↑215 to ↑389%, relative to pre-test values) in both sexes at 

10000 ppm throughout the study. A slight increase in alkaline phosphatase activities was 

observed throughout the study in 1/4 males at 1000 ppm. In high dose dogs, mean albumin, 

albumin/globulin ratio, phosphorus, and calcium concentrations were decreased in both sexes 

relative to pre-test values and when compared to controls. GGT levels were increased at 10000 

ppm in both sexes at termination compared to the controls. Liver weights were increased in both 

sexes at all dose levels compared to controls. At necropsy, an enlarged liver was observed in 1/4 

males and a dark thyroid gland was observed in 1/4 males and 1/4 females at 10000 ppm. In the 

liver, panlobular hepatocellular hypertrophy was observed in 3/4 males and 4/4 females at 10000 

ppm and in 1/4 females at 1000 ppm. Focal hepatocellular brown pigment was observed in 2/4 

males and 3/4 females at 10000 ppm and 1/4 males at 1000 ppm. In the thyroid gland, minimal to 

slight follicular cell hypertrophy was observed in 1/4 males and 3/4 females at 10000 ppm. In the 

adrenal gland, an increased incidence of zona glomerulosa vacuolation was observed in females 

at 10000 ppm. 

The No Observed Adverse Effect Level (NOAEL) is established at 1000 ppm (equivalent to 32 

mg/kg body weight/day in males and 37.9 mg/kg body weight/day in females), based on the 

minimal changes in the liver (increased liver weight and hepatocellular hypertrophy, which were 

not accompanied by relevant changes in clinical chemistry parameters and adverse liver lesions) 

that are not considered adverse. The Lowest Observed Adverse Effect Level is established at 

10000 ppm (equivalent to 357 mg/kg/day in males and 425 mg/kg/day in females), based on 

decreased terminal body weight and body weight gain in females, increased prothrombin time in 

males, increased alkaline phosphate activity in both sexes, decreased cholesterol in both sexes, 

increased GGT levels in both sexes, decreased albumin and albumin/globulin ratio in both sexes, 

decreased calcium and phosphorus in both sexes, increased liver weights in both sexes, increased 

incidence of focal hepatocellular brown pigment and hepatocellular hypertrophy in both sexes, 

increased incidence of zona glomerulosa vacuolation of the adrenal gland in females, and an 

increased incidence of thyroid follicular cell hypertrophy in both sexes. 

This study is classified as totally reliable (acceptable/guideline), and it satisfies the guideline 

requirement for a chronic oral toxicity study (OPPTS 870.4100; OECD 452) in dogs. 

A.4.5 Carcinogenicity

 870.4200a Carcinogenicity Study – rat (see above)

 870.4200b Carcinogenicity (feeding) – Mouse 

Executive Summary: In a carcinogenicity study (MRID 48023814), BYF 14182 (Batch No. 

2005-004498, 95.6% purity) was administered via the diet to C57BL/6J mice (60/sex/group) at 

dose levels of 0, 100, 1000 or 6000 ppm (equivalent to 0, 14.3, 146, and 880 mg/kg bw/day in 

males and 0, 18.4, 182, and 1101 mg/kg bw/day in females) for 52 weeks. After 52 weeks 
 

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(chronic phase), 10 mice/sex/group were sacrificed (interim sacrifice). The remaining 

50 mice/sex/group continued treatment until the scheduled final sacrifice following at least 

78 weeks of treatment (carcinogenicity phase). 

There were no treatment-related effects on mortality or clinical signs of toxicity in either sex. 

Slight decreases (↓6%-7%) in overall body weight gains were observed in both sexes at 6000 

ppm, but terminal body weights were comparable to the control for both sexes. Initial body 

weight gain was significantly decreased (↓27%) in females at 6000 ppm, and males at 6000 ppm 

displayed a reduced body weight gain (↓18%) over the first 6 weeks. 

There was a dose-related decrease in mean total leukocyte (↓30% and ↓36%) and absolute 

lymphocyte (↓26% and ↓37%) counts in males at 1000 ppm and 6000 ppm, respectively, at 13 

months. Females at 6000 ppm also showed decreases in mean total leukocyte (↓24%) and 

absolute lymphocyte (↓23%) counts at 13 months, but statistical significance was not attained. 

At the 12-month sacrifice, increased liver weights were observed in both sexes at 6000 ppm 

compared to the controls. Enlarged liver was observed in 2/10 males and 6/9 females. Pale liver 

was observed in 1/10 males and 3/9 females. Histopathological examinations were not performed 

at this time point. 

At the 18-month terminal sacrifice, increased absolute and relative liver weights were observed 

in both sexes at 6000 ppm. Enlarged livers were observed in 2/45 males and 33/45 females. In 

addition, enlarged thyroid glands were found in 9/45 females. These findings were correlated 

with treatment-related microscopic changes in the liver and the thyroid gland. There was a doserelated increase in the incidence and/or severity of diffuse centrilobular hepatocellular 

hypertrophy in both sexes. An increased incidence of hepatocellular vacuolation was observed in 

males at 6000 ppm, whereas a higher severity of hepatocellular vacuolation was observed in all 

female groups compared to the control. Additionally, females showed a higher incidence and 

severity of diffuse, mainly periportal, hepatocellular macrovacuolation at 6000 ppm. In the 

thyroid, a higher incidence and severity of follicular cell hyperplasia was observed in 38/50 

females at 6000 ppm compared to 23/50 females in the control group. 

There was no increase in the incidence of any tumor type following dietary administration of 

BYF 14182 to C57BL/6J mouse over an 18-month period at dose levels up to 6000 ppm 

(equivalent to 880 and 1101 mg/kg body weight/day in males and females, respectively). 

Treatment-related increased liver weights associated with histopathological findings were 

observed in the liver in both sexes at all dose levels. These liver effects were associated with 

thyroid effects and are considered an adaptive response and not adverse. 

A Lowest Observed Adverse Effect Level (LOAEL) was not identified in this study, which 

included a dose level that exceeded the limit dose in females and one that was close to the limit 

dose in males. The liver effects and associated effects on the thyroid are considered adaptive and 

not adverse. In the subchronic oral toxicity study in mice at a somewhat higher dose level (7000 

ppm; 1238 mg/kg bw/day and 1600 mg/kg bw/day), a similar liver response was observed, 

indicating that continued exposure does not result in additional/more severe toxicity. Exposure of 
 

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mice to BYF 14182 at dose levels greater than or near the limit dose for a period of 78 weeks did 

not result in an increase in the incidence of any tumor type in either sex. 

This carcinogenicity study is classified acceptable/guideline, and it satisfies the guideline 

requirement (870.4200; OECD 451) for a carcinogenicity study in the mouse. 

A.4.6 Mutagenicity

Gene Mutation

Guideline 870.5100, Ames assay 

MRID 48023816 

Classification: acceptable/guideline 

BYF 14182 did not induce gene mutation, either with or without 

metabolic activation, in any of the S. typhimurium TA strains up to 

concentrations that inhibited cell growth in the plate incorporation and 

pre-incubation modification of the Salmonella/microsome test. Doses: 16 

to 5000 μg/plate, diluted in dimethyl sulfoxide (DMSO). Growth 

inhibition due to the test substance observed in all S. typhimurium TA 

strains ±S9 at 1581 and 5000 μg per plate. Precipitation of the test 

substance occurred at ≥ 500 μg per plate ±S9 . 

Guideline 870.5100, Ames assay 

MRID 48023817 

Classification: acceptable/guideline 

BYF 14182 did not induce gene mutation, either with or without metabolic 

activation, in any of the Salmonella typhimurium TA strains at 

concentrations up to 5000 μg/plate in the plate incorporation and in the preincubation modification of the S. typhimurium reverse mutation assay. 

Doses: 3 to 5000 μg/plate, diluted in dimethyl sulfoxide (DMSO). 

Guideline 870.5100, Ames assay 

MRID 48023818 

Classification: acceptable/guideline 

BYF 14182-3-hydroxy-butyl did not induce gene mutation, either with or 

without metabolic activation, in any of the Salmonella typhimurium TA 

strains at concentrations up to 5000 μg/plate in the plate incorporation and 

in the pre-incubation modification of the S. typhimurium reverse mutation 

assay. 

8 concentrations ranging from 16 to 5000 μg/plate, diluted in dimethyl 

sulfoxide (DMSO). 

Guideline 870.5100, Ames assay 

MRID 48023819 

Classification: acceptable/guideline 

BYF 14182-pyrozolyl-AAP did not induce gene mutation, either with or 

without metabolic activation, in any of the Salmonella typhimurium TA 

strains at concentrations up to 5000 μg/plate in the plate incorporation and 

in the pre-incubation modification of the S. typhimurium reverse mutation 

assay. 

Doses: 6 concentrations ranging from 16 to 5000 μg/plate, diluted in 

dimethyl sulfoxide (DMSO). 
 

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Guideline 870.5300, mammalian cell 

forward gene mutation 

MRID 48023820 

Classification: acceptable/guideline 

Chinese hamster V79 cells: BYF 14182 did not induce increases in 

mutant frequency at concentrations up to 150 μg/mL (+S9)/100 μg/mL (-

S9) in the V79/HPRT forward mutation assay. 

Significant concentration-related cytotoxicity was observed –S9 (≥125 

μg/mL) and +S9 (≥150 μg/mL), as evidenced by decreases in survival to 

treatment and decreases in relative population growth following exposure. 

Doses: -S9: 0, 25, 50, 75, 100, 125, 150 or 175 μg/mL (Experiment 1) and 

at 0, 12.5, 25, 50, 75, 100 or 125 μg/mL (Experiment 2) ; +S9: 0, 50, 75, 

100, 125, 150, 175 or 200 μg/mL and 0, 25, 50, 75, 100, 125 or 150 

μg/mL for Experiments 1 and 2, respectively. 

Guideline 870.5300, mammalian cell 

forward gene mutation 

MRID 48023821 

Classification: acceptable/guideline 

Chinese hamster V79 cells: 

Doses: 0, 4.5, 9, 18, 27, or 36 μg/mL (-S9) both Experiments 1 and 2, and 

at 0, 4.7, 9.4, 18.8, 37.5, or 75 μg/mL (+S9) Experiment 1 and 0, 18.8, 

37.5, 75, 100, or 125 μg/mL +S9 in Experiment 2. The treatment period 

in both experiments was 4 hours. BYF 14182 did not induce increases in 

mutant frequency at concentrations up to 100 μg/mL (+S9)/36 μg/mL (-

S9) in the V79/HPRT forward mutation assay. 

Compound precipitation was noted at ≥100 μg/mL (+S9). BYF 14182 

was tested up to cytotoxic concentrations in the absence (36 μg/mL) and 

presence (100 μg/mL) of S9 activation. There were no reproducible 

treatment-related increases in the mutant frequency with or without 

metabolic activation at concentrations ranging from 4.5 μg/mL to 125 

μg/mL. 

Guideline 870.5300, mammalian cell 

forward gene mutation 

MRID 48023822 

Classification: acceptable/guideline 

Chinese hamster V79 cells: BYF 14182-3-hydroxy-butyl did not induce 

increases in mutant frequency (±S9), at concentration up to 1200 μg/mL 

(at or above the limit of solubility in the culture medium) in the 

V79/HPRT forward mutation assay. 

BYF 14182-3-hydroxy-butyl concentrations of 75, 150, 300, 600, 900, or 

1200 μg/mL ±S9. 

Guideline 870.5300, mammalian cell 

forward gene mutation 

MRID 4802382 

Classification: acceptable/guideline 

Chinese hamster V79 cells were exposed to BYF 14182-pyrazolyl-AAP 

at concentrations of 0, 3, 6, 12, 24, 36, 48, or 60 g/ml both ±S9. 

BYF 14182- pyrazolyl-AAP did not induce increases in mutant frequency 

at concentrations up to 60 μg/mL (with and without metabolic activation) 

in the V79/HPRT forward mutation assay. 

 
 

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Cytogenetics 

Guideline 870.5375 In vitro

genotoxicity (clastogenicity in 

mammalian cells) 

MRID 48023824 

Classification: acceptable/guideline 

Chinese Hamster V79 cells: BYF 14182 did not induce increases in the 

numbers of aberrant metaphases at concentrations up to and including 

cytotoxic levels. Therefore, under the conditions of the study, BYF 14182 

is considered not to be clastogenic for mammalian cells in vitro with and 

without metabolic activation. 

Doses: BYF 14182 at 0, 10, 20, 40, 70, and 100 g/mL (4-hour 

treatment) and 0, 3, 6, 12, 24, 36 μg/mL (18-hour treatment) –S9; at 0, 15, 

30, 60 and 90 μg/mL (+ S9 mix; 4-hour treatment); harvested 18 hours 

after treatment start; cultures exposed (4-hour treatment) at 0, 40, 70, and 

100 μg/mL (-S9) and 0, 60, 75, and 90 μg/mL (+S9) were harvested 30 

hours 

Guideline 870.5375 In vitro

genotoxicity (clastogenicity in 

mammalian cells) 

MRID 48023825 

Classification: acceptable/guideline 

Chinese Hamster V79 cells: BYF 14182 did not induce chromosomal 

aberrations in mammalian cells at concentrations that caused clear 

cytotoxicity (reduced cell numbers/mitotic indices below 

50%/precipitation). BYF 14182 is not clastogenic for mammalian cells in 

vitro. 

Doses: 0, 9.4, 18.8 and 37.5 g/mL (4-hour treatment, Experiment I), and 

0, 4.7, 9.4 and 18.8 μg/mL (18-hour treatment, Experiment II) -S9 mix and 

at 0, 18.8, 37.5 and 75.0 μg/mL (+ S9 mix; 4-hour treatment, Experiment 

I); harvested 18 hours after treatment start; concentrations of 0, 100, 150 

and 300 μg/mL (+S9 mix) were harvested at 28 hours after the beginning 

of treatment (Experiment II). The concentrations used for cytotoxicity 

determination ranged from 4.7-1200 μg/mL for Experiment I (±S9) and 

from 2.3-300 μg/mL for Experiment II (±S9). 

Guideline 870.5375 In vitro

genotoxicity (clastogenicity in 

mammalian cells) 

MRID 48023826 

Classification: acceptable/guideline 

Chinese Hamster V79 cells: BYF 14182-hydroxy-butyl did not induce 

increases in the numbers of aberrant metaphases at concentrations up to 

cytotoxic levels ( ≥ 900 μg/mL) in both the presence and absence of 

metabolic activation. 

Doses of BYF 14182-3-hydroxy-butyl: 0, 150, 300, 600, 900, and 1200 

g/mL (4-hour treatment), and 0, 75, 150, 300, 450, and 600 μg/mL (18-

hour treatment) -S9 mix) and 0, 75, 150, 300, 600, and 900 μg/mL (4-hour 

treatment) +S9 mix. Harvested 18 hours after treatment start; cultures 

treated with 600, 900, and 1200 μg/mL (-S9) and 300, 600, and 900 

μg/mL (+S9) were harvested 30 hours after the beginning of the treatment 

(4-hour treatment). 
 

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Guideline 870.5375 In vitro

genotoxicity (clastogenicity in 

mammalian cells) 

MRID 48023827 

Classification: acceptable/guideline 

Chinese Hamster V79 cells: BYF 14182-pyrazolyl-AAP did not induce 

increases in the numbers of aberrant metaphases at concentrations up to 

cytotoxic levels (60 μg/mL) in mammalian cells in vitro. Based on this 

test, BYF 14182-pyrazolyl-AAP is considered not to be clastogenic for 

mammalian cells in vitro. 

Doses of BYF 14182-pyrazolyl-AAP: 0, 15, 30 and 60 g/mL (4-hour 

and 18-hour treatments; -S9 mix) and at 0, 15, 30 and 60 μg/mL (+ S9 

mix). Cultures harvested 18 hours after treatment start; cultures treated 

with 60 μg/mL were harvested 30 hours after treatment. 

Other Genotoxicity

Guideline 870.5395 In vivo

genotoxicity (somatic cells) – 

micronucleus 

MRID 48023828 

Classification: acceptable/guideline 

male Crl:NMRI BR mice were administered BYF 14182 twice via the 

intraperitoneal (i.p.) route at doses of 0 (0.5% aqueous Cremophor 

emulsion), 250, 500 and 1000 mg/kg bw, separated by 24 hours. There 

was no indication of a clastogenic effect of intraperitoneally administered 

BYF 14182 in the micronucleus test on the male mouse at dose levels up 

to those producing clear evidence of an effect on the target population. 

A.4.7 Neurotoxicity

870.6200 Acute Neurotoxicity Screening Battery

Executive Summary: In an acute neurotoxicity study (MRID 48023829), groups of non-fasted, 

>9-week old Wistar HAN CRL:WI (HAN) rats (12/sex/dose) were administered a single oral 

dose (gavage) of BYF 14182 (technical grade, 95.6%; Lot/Batch # 2005-004498) in 0.5% (w/v) 

methylcellulose/0.4% (w/v) Tween 80 in deionized water (dosing volume of 10 ml/kg) at 

nominal doses of 0 (vehicle), 100, 500, or 2000 mg/kg bw and observed for 14 days. Since there 

were compound-related effects on measures of motor and locomotor activity at the low dose (100 

mg/kg bw) in females, a follow-up study was conducted with additional females (12/dose) under 

the same conditions at nominal doses of 0 (vehicle), 25, or 50 mg/kg bw. 

In the initial study, all rats (12/sex/dose level) were used for neurobehavioral evaluation, with 

6/sex/dose used for micropathology. Observations for moribundity and mortality were performed 

at least once daily for 14 days, detailed clinical observations for each animal were performed 

daily throughout the study and body weight measurements (measured weekly as a component of 

the functional observational battery) were performed. Neurobehavioral assessments (functional 

observational battery (FOB) and motor activity testing) were conducted in the 12 rats/sex/group 

during the week prior to treatment and on days 0 (day of treatment, ≈1 hour post dose; the time 

of peak effect), 7 days (initial group only) and 14 days (initial group only) post dose. At study 

termination, 6 rats/sex/group were euthanized and perfused for neuropathological examination. 

Of the perfused rats, all of the controls and 2000 mg/kg bw dose group were subjected to 

histopathological evaluation of brain and peripheral nervous system tissues. All rats from the 

initial study were subjected to a gross necropsy. Selected rats (six/sex/dose level) were perfused, 

the brain was weighed, and skeletal muscle, peripheral nerves, eyes (with optic nerves), and 

tissues from the central nervous system were examined microscopically. 
 

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In the follow-up study, conducted to establish a NOAEL for measures of activity in females, the 

rats were handled and otherwise treated the same as rats from the initial study for consistency; 

i.e., observations for moribundity and mortality were performed at least once daily, detailed 

clinical observations performed daily throughout the study, and body weight measurements 

(component of the FOB). An FOB and automated measurements of activity (figure-eight maze) 

were conducted during the week prior to treatment and on day 0 (day of treatment, at the time of 

peak effect). These rats were sacrificed when all signs of toxicity were no longer evident. 

There were no deaths. On the day of treatment, clinical signs were observed at 500 mg/kg bw 

and 2000 mg/kg bw, which included urine stains in both sexes and an increased incidence of 

stiff-legged hind limbs, locomotor incoordination, decreased activity, and clear lacrimation in 

females. A dose-related decrease in motor activity and locomotor activity was observed on the 

day of treatment in females at all dose levels and in males at 500 mg/kg bw and 2000 mg/kg bw. 

Habituation was not affected at any dose level in either sex. In the FOB, females at 500 mg/kg 

bw and 2000 mg/kg bw showed a similar decrease (↓0.8°C) in body temperature compared to the 

control. Body weights and body weight gains were comparable among the groups (both sexes). 

All signs of toxicity resolved by day 7. Brain weight was not affected. There were no compoundrelated gross or microscopic lesions at 2000 mg/kg bw. The follow-up study established a 

NOAEL for measures of motor and locomotor activity in females, with no compound-related 

effects at 25 mg/kg bw and 50 mg/kg bw. 

The NOAEL in females is established at 50 mg/kg bw. The LOAEL is established at 100 mg/kg 

bw, based on decreased motor activity and locomotor activity in females. The NOAEL in males 

is established at 100 mg/kg bw. The LOAEL is established at 500 mg/kg bw, based on decreased 

motor activity and locomotor activity in females and urine staining. 

This acute neurotoxicity study is classified as acceptable/guideline, and it satisfies the guideline 

requirement (OPPTS 870.6200; OECD 424) for an acute neurotoxicity study in rats. 

 870.6200 Subchronic Neurotoxicity Screening Battery

Executive Summary: In a subchronic neurotoxicity study (MRID 48023830), technical grade 

BYF 14182 (Lot/Batch # 2005-004498, 95.6%) was administered in the diet to young-adult 

Wistar Han Crl:WI (HAN) rats (11-12/sex/dietary level), using nominal concentrations of 0, 250, 

2000 and 8000 ppm (equivalent to 16, 126, and 516 mg/kg bw/day in males and 19.9, 155.9, and 

608.8 mg/kg bw/day in females). 

There were no deaths or clinical signs of toxicity in either sex at any dose level. Decreased body 

weights (males 6%-7%/females 5%-11%) and body weight gains (males 11%/females 29%) 

were observed in both sexes at 8000 ppm and were accompanied by decreased food 

consumption. There were no consistent findings during the FOB (other than bodyweight effects), 

and no treatment-related neuropathological lesions were observed in either sex that could be 

attributed to treatment. Motor activity was slightly reduced in females at 8000 ppm, which is 

consistent with the findings following acute exposure. 
 

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A NOAEL for neurotoxicology endpoints is established at 2000 ppm (equivalent to 126 mg/kg 

bw/day in males and 156 mg/kg bw/day in females). The LOAEL is 8000 ppm (equivalent to 

516 mg/kg bw/day in males and 609 mg/kg bw/day in females), based on a slight decrease in 

motor activity in females, which is consistent with a similar finding of decreased motor activity 

in females in the acute neurotoxicity study (MRID 48023829). 

This subchronic neurotoxicity study is classified acceptable/guideline, and it satisfies the 

guideline requirement (OPPTS 870.6200; OECD 424) for a subchronic neurotoxicity study in the 

rat. 

A.4.8 Metabolism

870.7485 Metabolism - Rat

Executive Summary: In a rat metabolism study (MRID 48023831), four male Wistar Unilever 

Hsd/Cpb:WU rats were gavaged with a single oral dose of [phenyl-UL-13C6/

14C] BYF 14182 

[batch nos. BECH 2034, 2137, 2155; 98%-99.5%] in 0.5% aqueous Tragacanth solution at doses 

of 2 mg/kg bw or 200 mg/kg bw. Four female Wistar Unilever Hsd/Cpb:WU rats were dosed 

only at the 2 mg/kg bw dose level. All rats were sacrificed at 72 hours after dosing to obtain 

blood, organs and tissues. Additionally, in a bile-duct cannulation experiment, 4 male rats were 

gavaged with a single dose of [phenyl-UL-13C6/

14C] BYF 14182 at 2 mg/kg bw and were 

sacrificed at 48 hours after dosing. For analysis and quantification of the parent compound and 

metabolites in urine, bile, and faeces, respective samples from all rats in each test group were 

pooled, and samples from these pools were used for characterization, identification, and 

quantification. Urine, faeces, and bile samples were analyzed and quantified by radio-HPLC. 

In all four experiments, 94% to 97% of the administered dose was recovered in urine, bile, and 

faeces, organs, and tissues at sacrifice. The absorption of [phenyl-UL-13C6/

14C] BYF 14182 

commenced immediately after oral administration, with the maximum equivalent concentration 

(Cmax) in plasma being reached between 40 minutes and 1.5 hours (tmax) after dosing [Test 1 

(male): Peak reached at 40 minutes (0.7380 μg/mL), Test 2 (female): peak reached at 1.0 hour 

(0.7508 μg/mL), and Test 3 (male): Peak reached at 1.5 hours (19.190 μg/mL)]. The percent 

absorption of [phenyl-UL-13C6/

14C] BYF 14182 based on recoveries of radioactivity in the bile, 

urine and body, excluding GIT, was 91.23% of the administered dose. 

In males at both dose levels, the majority of the dose (> 61%) was excreted via faeces. The renal 

excretion of male rats was ≈28% at 2 mg/kg, ≈34% at 200 mg/kg, and ≈21% in the bile duct 

cannulated male rats at 2 mg/kg. For the females, there was no significant difference between the 

excretion via urine and faeces (both ≈46% of the dose) at 2 mg/kg. Bile duct cannulated male 

rats showed a high excretion via bile (≈72% of the recovered radioactivity), and there was no 

significant radioactivity present in the body at the time of sacrifice (48 hours after 

administration). 

The radioactivity concentration in the plasma declined to ≈1% of the maximum value for both 

sexes at 2 mg/kg bw and to ≈3.6% for males at 200 mg/kg bw within 72 hours post 

administration. The plasma concentration curves at the 2 mg/kg bw dose level showed a fast 

elimination phase at the beginning of the test, and the t1/2 elim 1 was 23.6 hours for males and 20.4 

hours for females. Plasma concentrations of both sexes at 2 mg/kg bw showed one terminal 
 

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elimination phase. The plasma concentration curve of the 200 mg/kg bw group exhibited a 

second maximum after 48 hours possibly due to enterohepatic circulation. 

At 2 mg/kg bw, the elimination of the test substance was somewhat faster for males than for 

females. The AUC0 - ∞-value for females (3.6 mg/L-hour) is approximately 1.4 times higher than 

for males (2.5 mg/L-hour). This indicates a slightly higher systemic exposure for female rats. 

The mean residence time (MRTtot) of the radioactivity was short at 2 mg/kg bw (13.5 hours for 

males and 14.2 hours for females). Low amounts of radioactivity were determined in organs and 

tissues at sacrifice, 72 h after oral administration. Negligible amounts of radioactivity were found 

in the GIT, demonstrating an almost complete elimination of the radioactivity. Generally, 

concentrations in organs at 200 mg/kg bw were ≈100-times higher as compared to the 

concentrations at 2 mg/kg bw, reflecting the dose ratio. The highest equivalent concentrations 

were detected in the liver (0.02 to 0.06 μg/g at 2 mg/kg bw and ≈6.15 μg/g at 200 mg/kg bw) and 

kidney (≈0.02 μg/g at 2 mg/kg bw and ≈3.14 μg/g at 200 mg/kg bw). Concentrations between 

0.04 μg/g (at 2 mg/kg bw) and 6.74 μg/g (at 200 mg/kg bw) were found in erythrocytes. 

Residues were very low (in the range of 0.001 to 0.011 μg/g) in the other organs of both sexes at 

2 mg/kg bw. In most cases, residues in the organs and tissues of female rats were slightly higher 

than in male rats. 

[Phenyl-UL-13C6/

14C] BYF 14182 was extensively metabolized in the rat. Metabolic reactions 

were detected in 10 different positions of the molecule. By combination of the transformations at 

multiple sites, a large number of metabolites (up to 38 metabolites) were formed. The majority of 

metabolites (62.7% and 79.4% of the administered dose) were identified. The other metabolites 

were characterized by their extraction and chromatographic behavior. There were no different 

metabolites found in males and females, but the amount of some metabolites was different with 

regard to sex (e.g., BYF 14182-desmethyl-dihydroxy-ketone: males ≈5%/females 17% of the 

administered dose). 

The most important metabolic reactions are the demethylation in the pyrazole ring and 

hydroxylation followed by further oxidation in different positions of the molecule. BYF 14182-

3-hydroxy-butyl is a prominent metabolite in plants, and this metabolite and its conjugate were 

identified in very low amounts only in the bile in the current study. A separate rat ADME study 

with BYF 14182-3-hydroxy-butyl (MRID 48023836) as the test compound was performed (KIIA 

5.1/06). 

An overview of the main metabolic reactions of [phenyl-UL-13C6/

14C] BYF 14182 in rats is 

presented below: 

N-demethylation in the pyrazole ring 

hydroxylation at the following positions of the molecule: 

in the alkyl side chain of the phenyl ring, the position 4’ of the phenyl ring and the methyl group 

in position 3 of the pyrazole ring 

further oxidation of the hydroxy group in the position 2 of the alkyl side chain forming a keto 

group 

further oxidation of the hydroxy group in the position 4 of the alkyl side chain forming a 

carboxylic acid 

oxidative cleavages of the alkyl side chain forming an acetyl group or a carboxylic acid group 
 

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conjugation of the hydroxy group in the position 4’ of the phenyl ring and in the position 2 of the 

alkyl side chain with glucuronic acid 

further oxidation of the hydroxymethyl group of the pyrazole ring forming a carboxylic acid 

group 

conjugation of a dihydroxy, trihydroxy and dihydroxy-keto compound with cysteine 

All results correspond well with the findings in the ADME study with the pyrazole label 

(IIA 5.1. 02). 

This metabolism study in the rat is classified acceptable/guideline, and it satisfies the guideline 

requirement for a metabolism study [OPPTS 870.7485, OECD 417] in rats when considered in 

conjunction with the metabolism study in rats (MRID 48023832) using the [pyrazole-3-14C] 

labeled BYF 14182. 

Executive Summary: In a rat metabolism study (MRID 48023832), four male Wistar Unilever 

Hsd/Cpb:WU rats were administered (via gavage) a single dose of [Pyrazole-3-14C] BYF 14182 

[batch no. BECH 2136; 99% purity; radiochemical purity >98%] in 0.5% aqueous Tragacanth 

solution at a dose of 2 mg/kg bw and sacrificed 3 days after dosing. Plasma, urine and faeces 

were monitored throughout the study. The total radioactivity was determined in plasma, urine, 

and faeces and in organs and tissues at sacrifice. The metabolism was investigated by HPLC with 

radioactivity detection and spectroscopic methods in selected urine samples and faeces extracts. 

At sacrifice, 94.6% of the administered radioactivity was recovered in plasma, urine, faeces and 

in organs and tissues. 

The absorption of [pyrazole-3-14C] BYF 14182 started immediately after administration as 

shown by the plasma concentration curve. The renal excretion was 27.61% of the administered 

dose. The majority of the radioactivity (66.59% of administered dose) was excreted with the 

faeces. 

The maximum equivalent concentration in plasma (Cmax) was 0.59μg/mL. The maximum (tmax) 

was reached approximately 0.67 hour after dosing. The radioactivity in the plasma declined to 

≈0.5% of the maximum concentration (Cmax) within 72 hours post dose. 

The plasma concentration curve showed a very fast elimination phase at the beginning of the test 

(= t1/2 elim 1) followed by a single terminal elimination phase. Elimination half-lives were 

calculated based on a two-compartment model. The calculated AUC0 - ∞- was 2.4 mg/L*hour. A 

mean residence time (MRTtot) of the total radioactivity was determined to be 13 hours. 

Low amounts of radioactivity were determined in organs and tissues at sacrifice 72 hours after 

oral administration. Negligible amounts of radioactivity were found in the GIT. 

The highest equivalent concentration was detected in liver (≈0.044 μg/g). Lower concentrations 

were detected in erythrocytes (≈0.037 μg/g), thyroid gland (≈0.019 μg/g), and in kidneys (≈0.017 

μg/g). The concentrations in the other organs and tissues ranged from ≈0.002 to 0.007μg/g. 

[Pyrazole-3-14C] BYF 14182 was extensively metabolized, and the majority of metabolites (68.7 

% of the administered dose) were identified. Other metabolites (≈20.1% of the administered 

dose) were characterized. Most of the metabolites were demethylated in the pyrazole ring. 

Hydroxylation was another prominent metabolic reaction. 

The main metabolic transformations detected were: 

 N-demethylation in the pyrazole ring 
 

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hydroxylation at the following positions of the molecule: the alkyl side chain of the phenyl ring, 

the position 4’ of the phenyl ring, and the methyl group in position 3 of the pyrazole ring 

further oxidation of the hydroxy group in the position 2 of the alkyl side chain forming a keto 

group 

further oxidation of the hydroxy group in the position 4 of the alkyl side chain forming a 

carboxylic acid 

oxidative cleavages of the alkyl side chain forming an acetyl group or a carboxylic acid group 

conjugation of the hydroxy group in the position 4’ of the phenyl ring and in the position 2 of the 

alkyl side chain with glucuronic acid 

further oxidation of the hydroxymethyl group of the pyrazole ring forming a carboxylic acid 

group 

conjugation of a trihydroxy compound with cysteine 

cleavage of the carboxamide bond forming carboxylic acid, which was further metabolized via 

conjugation with glucuronic acid 

cleavage of the N-phenyl bond forming the carboxamide 

The results in this ADME study with the pyrazole label are in good agreement with the results of 

the ADME study conducted with the phenyl label (IIA 5.1 /01) and with the results of the whole 

body autoradiography studies performed with BYF 14182 (IIA 5.1/03 and IIA 5.1/04). The main 

metabolic routes observed in the studies employing the phenyl and the pyrazole labels are 

identical, except for a few that are specific for the pyrazole label metabolites. 

This metabolism study in the rat is classified acceptable/guideline, and it satisfies the guideline 

requirement for a metabolism study [OPPTS 870.7485, OECD 417] in rats when considered in 

conjunction with the metabolism study in rats (MRID 48023831) using the [phenyl-UL-13C6/

14C] 

labeled BYF 14182. 

Executive Summary: In a metabolism study (MRID 48023833), Wistar Hsd/Cpb:WU rats (8 

males and 9 females) were administered (via gavage) a single dose of [phenyl-UL-13C6/

14C] BYF 

14182 [batch no. NLL7306-16 and NLL7306-17, 99% purity; radiochemical batch no. BECH 

1682 and BECH 2137, purity 98%-99%] in 0.5% aqueous Tragacanth solution at a dose level of 

3.7 mg/kg bw (males) or 5.1 mg/kg bw (females). The distribution of the total radioactivity to 

and elimination from the blood, organs and tissues were analyzed qualitatively and quantitatively 

by whole-body autoradioluminography (WBAL). The kinetic behavior of BYF 14182, uniformly 

labeled with 14C and 13C in the phenyl ring of the molecule, was investigated over a period of 

seven days. One rat/sex was sacrificed at 1, 4, 8, 24, 48 (female only), 72, 120, and 168 hours 

after dose for cryosectioning. The amounts of radioactivity in the excreta (urine and faeces) and 

exhaled air were determined also. 

BYF 14182 was readily absorbed from the gastrointestinal tract and quickly distributed 

throughout the body. The excretion of radioactivity via urine and faeces was almost complete 

after 2 (females) to 3 (males) days. During the test period of 7 days, male rats showed a higher 

faecal (up to ≈68%) than urinary (up to ≈33%) excretion, and female rats showed a higher 

urinary excretion (up to ≈61%) than faecal (up to ≈41%) excretion. Less than 0.1% of the 

administered radioactivity was exhaled as 14CO2 or other volatiles during a sampling period of 

48 hours (both sexes). 

In male rats, maximum total radioactive residues (TRR) values were reached for all organs and 

tissues (except nasal mucosa) at one hour after administration (tmax). The values for liver, kidney, 
 

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myocardium and adrenals were higher than in the blood. A similar distribution was observed 

throughout the experimental period. 

In female rats, maximum TRR-values were also reached for all organs and tissues at one hour 

after administration. The values for liver, kidney, brown fat, myocardium, pancreas, most 

glandular organs, and the ovary and uterus were higher than in blood. 

From peak values, a biphasic decline of radioactivity concentrations was observed for all organs 

and tissues over the 7-day period. At termination, very low but still quantifiable radioactive 

residues (<0.05 μg active substance-equiv./g) were measured in some organs. 

This metabolism study in the rat is classified acceptable/guideline and it satisfies the guideline 

requirement for a metabolism study [OPPTS 870.7485, OECD 417] in rats when considered in 

conjunction with the ADME metabolism studies in rats (MRID 48023831 using the [phenyl-UL13C6/14C] labeled BYF 14182 and MRID 48023832 using the [pyrazole-3-14C] labeled BYF 

14182. 

Executive Summary: In a metabolism study (MRID 48023834), Wistar Hsd/Cpb:WU rats (8 

males and 8 females) were administered (via gavage) a single dose of [pyrazole-3-14C] 

BYF 14182 (BECH 2136: Test 1 males; KATH 6012; Test 2 females; chemical/radiochemical 

purity >98%; chemical purity 99.5%) in 0.5% aqueous Tragacanth solution at a dose of 5.3 

mg/kg bw (males) or 5.4 mg/kg bw (females). The distribution of the total radioactivity to and 

elimination from the blood, organs and tissues were analyzed qualitatively and quantitatively by 

whole-body autoradioluminography (WBAL). The kinetic behavior of BYF 14182, labeled with 

14C in the 3-position of the pyrazole ring of the molecule, was investigated over a period of seven 

days. One rat/sex was sacrificed at 1, 4, 8, 24, 48, 72, 120, or 168 hours after dose for 

cryosectioning. The amount of radioactivity in the excreta (urine and faeces) and exhaled air 

were determined also. 

BYF 14182 was readily absorbed from the gastrointestinal tract and quickly distributed 

throughout the body. For both sexes, the excretion of radioactivity via urine and faeces was 

almost complete after 3 days. During the test period of 7 days, male rats showed higher faecal 

(up to ≈65%) than urinary (up to ≈34%) excretion, whereas urinary (up to ≈57%) and faecal (up 

to ≈61%) excretion were similar in the female rats. Less than 0.1% of the administered 

radioactivity was exhaled as 14CO2 or other volatiles during a sampling period of 48 hours (both 

sexes). 

In male rats, maximum total radioactive residue (TRR) values were reached for all organs and 

tissues at one hour after administration (tmax). The values for liver, kidney, myocardium, 

adrenals, and Harderian gland were higher than in the blood. A similar distribution was observed 

throughout the study period of seven days. 

In female rats, maximum TRR values were also reached for all organs and tissues at one hour 

after administration, and the values for liver, kidney, brown fat, myocardium, pancreas, most 

glandular organs, ovary, and uterus were higher than in the blood. 

From peak values, a biphasic decline of radioactivity concentrations was observed for all organs 

and tissues over the 7-day period. Seven days after administration, low but still quantifiable 

radioactive residues (<0.05 μg active substance-equiv./g) were measured in some organs. 

This metabolism study in the rat is classified acceptable/guideline and it satisfies the guideline 

requirement for a metabolism study [OPPTS 870.7485, OECD 417] in rats when considered in 

conjunction with the ADME metabolism studies in rats (MRID 48023831 using the [phenyl-UL13C6/14C] labeled BYF 14182 and MRID 48023832 using the [pyrazole-3-14C] labeled BYF 
 

Penflufen Human Health Risk Assessment D387450 

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14182) and the quantitative whole body autoradiography study in rats (MRID 48023833 using 

the [phenyl-UL-13C6/14C] labeled BYF 14182). 

Executive Summary: In a metabolism study (MRID 48023835), 3 groups of Wistar 

Hsd/Cpb:WU rats (4 rats/sex/time point) were orally administered by gavage with a single dose 

of [Phenyl-UL-13C6/

14C] BYF 14182 [Batch # KATH 6038 (males: Tests 1-3) and KATH 6616 

(females: Tests 4-6); >99% purity; radiochemical purity >98%-99%] in 0.5% aqueous 

Tragacanth solution at a dose level of 5 mg/kg bw. The rats were sacrificed 1, 4, or 24 hours after 

dosing. At each sampling interval, urine, blood, liver and kidney samples, and gastrointestinal 

tract (GIT) and residual carcass were taken. The depletion of radioactive residues from organs 

and tissues (plasma, liver and kidney), the excretion with urine, and the metabolism of 

BYF 14182 were investigated. 

The overall recovery ranged from 90.4% to 102.3% of the administered dose in male rats and 

from 96.8% to 99.8% in female rats. 

The renal excretion started immediately (1 hour) after administration and increased until 24 

hours to 32.3% and to 49.2% of the administered dose in male and female rats, respectively. At 

the earlier time intervals, a similar % of the dose was noted between the sexes [8.2%/9.0% (M/F) 

at 1 hour and 20.7%/20.5% (M/F) at 4 hours]. 

The maximum total radioactive residue (TRR) levels were detected in organs and tissues, as well 

as in the combined GIT plus faeces at one hour after administration (tmax). The distribution of the 

radioactivity within blood, liver and kidney was rapid. A significant decline of radioactivity 

concentrations was observed for all organs and tissues over the 24-hour test period. 

BYF 14182 was metabolized extensively. Metabolic reactions were detected at ≥10 different 

structural positions of the molecule. The majority of metabolites (58% to 94%) were 

identified. Other unknown metabolites were characterized by their extraction and 

chromatographic behavior. 

The metabolism was qualitatively similar in male and female rats. Differences occurred only in 

terms of quantity with respect to individual metabolites in urine, plasma, liver and kidney of 

males and females. 

The major biotransformation reactions of [phenyl-UL-13C6/

14C] BYF 14182 in male and female 

rats were demethylation (in the pyrazole ring) and hydroxylation reactions followed by further 

oxidation in different positions of the molecule. The C3-position of the alkyl side chain was a 

preferred hydroxylation site. Many metabolites originating from BYF 14182-3-hydroxy-butyl 

were identified. The principal metabolic reactions in the rat were: 

N-demethylation in the pyrazole ring 

hydroxylation at the following positions of the molecule: 

the alkyl side chain of the phenyl ring, the position 4’ of the phenyl ring and the methyl group in 

position 3 of the pyrazole ring 

further oxidation of the hydroxyl group in position 2 of the alkyl side chain to form a keto 

metabolite 

further oxidation of the hydroxyl group in the position 4 of the alkyl side chain to form a 

carboxylic acid metabolite 

oxidative cleavages of the alkyl side chain forming an acetyl- or a carboxylic acid moiety 

conjugation of the hydroxyl group in the position 4’ of the phenyl ring and in the 

position 2 of the alkyl side chain with glucuronic acid 
 

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further oxidation of the hydroxymethyl group of the pyrazole ring to form a carboxylic acid 

metabolite 

The metabolism results are in good agreement with those obtained from the ADME rat study 

conducted with the phenyl radiolabel led test substance (MRID 48023831; IIA 5.1 /01). A 

proposed metabolic pathway was identified. 

This metabolism study is classified acceptable/guideline, and it satisfies the guideline 

requirement for a metabolism study [OPPTS 870.7485, OECD 417] in rats when considered in 

conjunction with the ADME metabolism studies in rats (MRID 48023831 using the [phenyl-UL13C6/

14C] BYF 14182 and MRID 48023832 using the [pyrazole-3-14C] labeled BYF 14182) and 

the quantitative whole body autoradiography studies in rats (MRID 48023833 using the [phenylUL-13C6/

14C] BYF 14182 and MRID 48023834 using the [pyrazole-3-14C] labeled BYF 14182). 

Executive Summary: In a rat metabolism study (MRID 48023836), four male Wistar Unilever 

Hsd/Cpb:WU rats were administered a single oral dose (gavage) of [Pyrazole-3-14C] 

BYF 14182-3-hydroxy-butyl [batch nos. BECH 2173; >99%] in 0.5% aqueous Tragacanth 

solution at a dose of 2 mg/kg bw and sacrificed after 72 hours. The total radioactivity was 

determined in plasma, urine, faeces, and in organs and tissues at sacrifice. The metabolism was 

investigated by HPLC with radioactivity detection and spectroscopic methods in selected urine 

samples and faeces extracts. 

 

The absorption of BYF 14182-3-hydroxy-butyl began immediately after administration. The 

maximum equivalent concentration in plasma (Cmax ≈0.57μg/mL) was reached 40 minutes (0.67 

hours) after dosing (tmax). The radioactivity in the plasma declined to ≈0.4% of the maximum 

within 72 hours post administration. All of the administered-radioactivity (100.7%) was 

recovered in plasma, urine, faeces, organs, and tissues at sacrifice. 

The renal excretion accounted for 25% of the administered dose, with the majority of the 

radioactivity (75%) being excreted with the faeces of the male rats. 

Low amounts (0.34% of administered dose) of residue were found in organs and tissues at 

sacrifice 72 hours after administration. Negligible amounts (0.05% of administered dose) of 

radioactivity were found in the gastrointestinal tract (GIT). The highest equivalent concentration 

was detected in the liver (≈ 0.044 μg/g), with lower concentrations in erythrocytes (≈ 0.039μg/g) 

and in kidneys (≈ 0.013 μg/g). The concentrations in the other organs and tissues were low and 

ranged from 0.001μg/g to 0.007μg/g. 

Based on these observations, the biokinetic behavior of BYF 14182-3-hydroxy-butyl and 

BYF 14182 was very similar. 

BYF 14182-3-hydroxy-butyl was extensively metabolized in the rat. Metabolic reactions 

were observed in the same structural positions as detected for BYF 14182. The majority of 

metabolites (≈60% of the administered dose) were identified. Another 15% of metabolites 

were characterized by their extraction and chromatographic behavior. Only low amounts 

of the unchanged parent compound were detected in the urine and faeces extracts. 

The majority of the metabolites were demethylated in the pyrazole ring. Further hydroxylation of 

BYF 14182-3-hydroxy-butyl is another major metabolic reaction yielding di- and trihydroxy 

compounds. Further oxidation of one of the hydroxy groups to keto compounds or carboxylic 

acids was also observed. Metabolites, originating from cleavage in the alkyl side chain with 
 

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further oxidation, were detected. Low amounts of pyrazole label specific metabolites originating 

from the cleavage of the carboxamide bond or N-phenyl bond, were detected in urine and faeces 

extracts. 

All metabolites that were postulated to be formed from the intermediate BYF 14182-3-

hydroxy-butyl in the metabolism study with BYF 14182 (IIA 5.1 /01 and IIA 5.1 /02) were 

detected after administration of BYF 14182-3-hydroxy-butyl also. 

The main metabolic reactions of [pyrazole-3-14C] BYF 14182-3-hydroxy-butyl in rats detected 

were: 

N-demethylation in the pyrazole ring 

further hydroxylation at the following positions of the molecule: the alkyl side chain of the 

phenyl ring, the position 4’ of the phenyl ring and the methyl group in position 3 of the pyrazole 

ring 

further oxidation of the hydroxy group in the position 2 of the alkyl side chain forming a keto 

group 

further oxidation of the hydroxy group in the position 4 of the alkyl side chain forming a 

carboxylic acid 

oxidative cleavages of the alkyl side chain forming an acetyl group or a carboxylic acid group 

conjugation of the hydroxy group in the position 4’ of the phenyl ring and in the 

position 2 of the alkyl side chain with glucuronic acid 

further oxidation of the hydroxymethyl group of the pyrazole ring forming a carboxylic acid 

group 

conjugation of a trihydroxy compound with cysteine 

cleavage of the carboxamide bond forming carboxylic acid, which was further metabolized via 

conjugation with glucuronic acid 

cleavage of the N-phenyl bond forming the carboxamide 

The very similar biokinetic and metabolic behavior of BYF 14182-3-hydroxy-butyl and 

BYF 14182 in 2 mg/kg-dosed male rats shows that the metabolism of BYF 14182 proceeds via

BYF 14182-3-hydroxy-butyl as a key systemic intermediate. 

This metabolism study in male rats is classified acceptable/guideline, and it satisfies the 

guideline requirement for a metabolism study [OPPTS 870.7485, OECD 417] in rats when 

considered in conjunction with the related metabolism studies in rats (MRID 48023832) using 

the [pyrazole-3-14C] labeled BYF 14182; (MRID 48023831). 

 870.7600 Dermal Absorption - Rat

Executive Summary: In an in vivo dermal penetration study (MRID 48024009), [14C]-BYF 

14182 in a FS 240 red formulation (99.5%, Lot/batch No NLL7306-17) was applied to the dorsal 

surface of 16 male Wistar Rj: WI (IOPS HAN) rats/group at concentrations of 1, 50, or 240 g/L 

for 8 hours. The achieved doses ranged from 0.010 to 0.011 mg/cm2

, 0.50 to 0.53 mg/cm2, and 

2.63 to 2.73 mg/cm2

, respectively. Following the 8-hour exposure period, the remaining test 

material was washed off the skin, and a skin tape stripping procedure was performed. Four rats in 

each group were sacrificed at 8, 24, 72, or 168 hours after dermal application. The amount of 

radioactivity absorbed, excreted, and present on or in the skin was quantified. 

 
 

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Summary Table. Dermal Absorption Rate 

Dose level (g/L) Mean % of applied dose absorbed and in/on skin 

Termination timeC 8 hours 24 hours 72 hours 168 hours 

(n=4 rats/group) absorbedA skinB absorbed skin absorbed skin absorbed skin 

240 0.277 0.942 0.306 1.136 0.520 0.255 0.960 0.274 

50 1.584 2.030 0.699 2.199 1.830 3.322 2.388 0.355 

1 1.624 2.738 3.035 0.970 4.948 0.401 3.770 0.297 A % of applied dose directly absorbed 

B % of applied dose at dose site 

C

 Following a single 8-hour exposure period 

The overall recovery of radiolabel was acceptable, with the mean recoveries ranging from 90.4% 

to 93.3% (240 g/L dose), 96.9% to 102.6% (50 g/L dose), and 93.7% to 96.1% (1 g/L dose) of 

the applied dose. At all dose levels, the majority of the radiolabel was not absorbed and was 

recovered from the skin by swabbing. The total amount non-absorbed ranged from 89%-92%, 

92%-99%, and 89%-92% of the applied dose at 240 g/L, 50 g/l, and 1 g/L, respectively. The total 

% of the applied dose at the dose site ranged from 0.26% to 1.14% (240 g/L dose), 0.36% to 

3.32% (50 g/L dose), and 0.30 to 2.74% (1 g/L dose). The total % of the applied dose directly 

absorbed ranged from 0.28% to 0.96% (240 g/L dose), 0.70% to 2.39% (50 g/L dose), and 1.62% 

to 4.95% (1 g/L dose) over the 168-hour observation period. Following an 8-hour exposure 

period, the amount of [14C]-BYF 14182 potentially absorbable (sum of direct absorption and 

amount detected in the skin) ranged from 0.78% to 1.44% for the neat product, from 2.74% to 

5.15% for the 50 g/L dose, and from 4.00% to 5.35% for the 1 g/L dose.

This study is classified as totally reliable (acceptable/guideline), and it satisfies the guideline 

requirements (OCSPP 870.7600; OECD 427) for a dermal penetration study in rats. 

Executive Summary: In an in vitro dermal penetration study (MRID 48024011), unlabeled BYF 

14182 (purity 99.5%; Lot/Batch No. NLL7306-17) spiked with radiolabeled [phenyl-13C6/

14C]-

BYF 14182 (purity>98%; Batch No. KATH 6292) was applied at a rate of 10 μL/cm2 to excised 

Wistar Rj: WI (IOPS HAN) male rat and female human dermatomed skin mounted in flowthrough diffusion cells. The single application was applied at three concentrations corresponding 

to the neat product (SYP13405, nominal value of 50 g BYF 14182/L formulation) and two 

dilutions (SYP13405, nominal value of 10 g BYF 14182/L formulation and SYP13407, nominal 

value of 1 g BYF 14182/L formulation). The amount of compound applied ranged from 0.416 to 

0.518 mg/cm2

, 0.101 to 0.112 mg/cm2, and 0.0098 to 0.0105 mg/cm2, respectively. Receptor 

fluid samples were collected at hourly intervals for the duration of the study (24 hours). Eight 

hours post-application, the remaining test material on the skin membranes was washed off the 

skin using sponge swabs. At 24 hours post application, the skin samples were swabbed again and 

tape-stripped to remove residual dose and the stratum corneum. The skin samples were removed 

from the diffusion cells and analysed. 

The overall recovery of radioactivity was acceptable for all experiments using rat (>93%) and 

human (>95%) dermatomed skin membranes. The amount of radioactivity in the receptor fluid 

(0-24 hours), receptor fluid at termination, and receptor chamber (considered as directly 

absorbed) was always greater for rat skin (0.352%, 1.309%, and 3.394% of the applied dose for 

the 50 g/L, 10 g/L, and 1 g/L dose formulations, respectively) than human skin (0.067%, 

0.323%, and 0.780% of the applied dose for the 50 g/L, 10 g/L, and 1 g/L dose formulations, 
 

Penflufen Human Health Risk Assessment D387450 

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respectively) under identical experimental conditions. The amount of radioactivity in the skin 

and stratum corneum (total % of applied dose at dose site) was 3.763%, 4.445%, and 3.122% 

(rat) and 0.105%, 1.126%, and 0.678% (human), respectively. The mean total amounts of 

radioactivity considered to be potentially absorbable (directly absorbed + total remaining at 

dose site) at doses of 50 g/L, 10 g/L, and 1 g/L were 4.115%, 5.754%, and 6.516%, respectively, 

for rat skin and 0.172%, 1.449%, and 1.457%, respectively, for human skin. The mean % of the 

applied dose potentially absorbable was 24-fold, 4-fold, and 4.5-fold greater in the rat skin than 

in the human skin for the 50 g/L, 10 g/L, and 1 g/L dose formulations, respectively. 

 

This study is classified as totally reliable (acceptable/guideline). There is no OCSPP guideline, 

but the study was performed according to the OECD 428 guideline for an in vitro dermal 

penetration study in the rat. 

A.4.9 Immunotoxicity 

 870.7800 Immunotoxicity 

Executive Summary: In an immunotoxicity study (MRID 48023837), BYF 14182 (Lot/Batch 

2005-004498; 95.6%) was administered via the diet to 8 male and 8 female Wistar (Hsd 

Cpb:WU) rats per group, at concentrations of 0, 200, 1000 or 7000 ppm (equivalent to 17.9, 82.6 

or 755.6 mg/kg bw/day in males and 20.4, 104.5 or 960.5 mg/kg bw/day in females) for a period 

of 29 (males) or 30 (females) days to investigate potential immunotoxic effects of BYF 14182. A 

Plaque Forming Cell (PFC) assay was performed using the spleen. The thymus and spleen were 

weighed, and cell counts in the spleen were determined. 

No treatment-related mortalities or clinical signs of toxicity were observed during the study in 

either sex. A slight reduction in body weight was observed in both sexes at 7000 ppm at 

termination (↓7% in males and ↓9% in females). 

There were no treatment-related effects on spleen or thymus weights or total spleen cell counts. 

The plaque-forming assay showed no evidence of treatment-related effects. A high interindividual variability was noted in all the treatment groups as well as in the control group. It is 

acknowledged that high inter-individual variability is a normal distribution of the immune 

response of out-bred strains. Evaluation of individual animal data did not show any trend or 

distribution that would demonstrate significant suppression of anti-SRBC PFC response. 

This study did not perform a Natural Killer (NK) cells activity assay. Evaluation of the available 

toxicity database on penflufen revealed that decreased thymus weights in males were observed at 

7000 and 14000 ppm in a rat 90-day oral toxicity study. Decreased thymus and spleen weights 

were observed at 4000 ppm of parental and offspring of both sexes in a rat reproduction study. 

However, the decrease in thymus weight was considered a secondary effect due to decreased 

body weight; the relative thymus weight was not significantly different from the control. In 

addition, the toxicology database of penflufen indicates that the target organs are the liver and 

thyroid. The overall weight of evidence suggests that this chemical does not directly target the 

immune system. Therefore, NK cell activity assay is not required at this time. 
 

Penflufen Human Health Risk Assessment D387450 

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The immunotoxicity NOAEL is 7000 ppm (755.6 mg/kg bw/day for males and 960.5 mg/kg 

bw/day for females); the LOAEL was not established. 

This immunotoxicity study is classified as acceptable/guideline, and it satisfies the guideline 

requirement for an immunotoxicity study (OPPTS 870.7800). 

 
 

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Appendix B. Metabolism Data 

B1. Structures and Identify of Metabolites of Penflufen 

Table B1. Chemical structure, codes and chemical names of penflufen metabolites. 

Common Names / 

Code IUPAC Name Chemical Structure 

Penflufen 

BYF 14182 

N-[2-(1,3-Dimethylbutyl)phenyl] 5-fluoro-1,3-

dimethyl-1H-pyrazole-4-carboxamide 

BYF 14182-3-

hydroxy-butyl 

Pen-3HB 

BCS-AA10006 

5-fluoro-N-[2-(3-hydroxy-1,3-

dimethylbutyl)phenyl]-1,3-dimethyl-1Hpyrazole-4-carboxamide 

BYF 14182-3-

hydroxy-butylglucoside 

BCS-AA10006-

glucoside 

5-fluoro-N-{2-[3-(beta-D-glucopyranosyloxy)-

1,3-dimethylbutyl]phenyl}-1,3-dimethyl1H-pyrazole-4-carboxamide 

BYF 14182-3-

hydroxy-butylmalonyl-glucoside 

BCS-AA10006-

malonyl-glucoside 

3-(2-{[(5-fluoro-1,3-dimethyl-1H-pyrazol4-yl)carbonyl]amino}phenyl)-1,1- 

dimethylbutyl 6-O- 

(carboxyacetyl)-beta-D-glucopyranoside

BYF 14182-4-

hydroxy-butylmalonyl-glucoside 

4-(2-{[(5-fluoro-1,3-dimethyl-1H-pyrazol4-yl)carbonyl]amino}phenyl)-2- 

methylpentyl 6-O- 

(carboxyacetyl)-beta-D-glucopyranoside

N

N

CH3

C

O

N

H

H3C F

CH

H3C CH2

H

CH

H3C C 3

N

N

CH3

C

O

N

H

H3C F

CH

H3C CH2

C

H3C CH3

OH

N

N

CH3

C

O

N

H

H3C F

CH

H3C CH2

C

H3C CH3 O

O

OH

HO

HO OH

N

N

CH3

C

O

N

H

H3C F

CH

H3C CH2

C

H3C CH3 O

O

OH

O

HO

O

O HO OH

N

N

CH3

C

O

N

H

H3C F

CH

H3C CH2

CH

H3C C 2

O O

HO OH

O

O O

HO

H

OH
 

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Table B1. Chemical structure, codes and chemical names of penflufen metabolites. 

Common Names / IUPAC Name Code Chemical Structure 

BYF 14182- 

pyrazolyl-AAP 

AE 2300037 

N-(2-acetylphenyl)-5-fluoro-1,3-dimethyl-1Hpyrazole-4-carboxamide

N N H

N

O

F O

3CH

3CH

3CH

BYF 14182-

homoglutathione 

Pen-HGT 

BCS-AA10790 

Gamma-glutamyl-S-(4-{[2-(1,3-

dimethylbutyl)phenyl]carbamoyl}-1,3-dimethyl1H-pyrazol-5-yl)cysteinyl-beta-alanine 

BYF 14182-

glutathione 

gamma-glutamyl-S-(4-{[2-(1,3-

dimethylbutyl)phenyl]carbamoyl}-1,3-dimethyl1H-pyrazol-5-yl)cysteinyl-glycine 

BYF 14182-

cysteine 

S-(4-{[2-(1,3-dimethylbutyl)phenyl]carbamoyl}-

1,3-dimethyl-1H-pyrazol-5-yl)cysteine 

BYF 14182-

succinyl-cysteine 

4-({1-carboxy-2-[(4-{[2-(1,3-

dimethylbutyl)phenyl]carbamoyl}-1,3-dimethyl1H-pyrazol-5-yl)thio]ethyl}amino)-4-

oxobutanoic acid 

BYF 14182-

succinyl-cysteinylglycine 

N-(3-carboxypropanoyl)-S- 

(1,3-dimethyl-4-{[2-(4- 

methylpentan-2-yl)phenyl]carbamoyl}-1Hpyrazol-5-yl)cysteinylglycine 

N

N

CH3

C

O

N

H

CH

H

H3

H3C S H3C C 2

CH

H3C C

H

N

O NH

O

NH2

O

HO

O

OH

N

N

CH3

C

O

N

H

CH

H3C CH2

CH

H3C CH3

OH

O

H3C S

H

N

O NH

O

NH2

O

HO

N

N

CH3

C

O

N

H

CH

H3C S H3C CH2

CH

H3C CH3

H2N

O OH

N

N

CH3

C

O

N

H

CH

H3C S H3C CH2

CH

H3C CH3

H

N

O OH

O

O

HO

N

N

CH3

C

O

N

H

H3C S

CH

H3C CH2

H CH

N

O

H3C CH3

O NH

O

HO

O

OH
 

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Table B1. Chemical structure, codes and chemical names of penflufen metabolites. 

Common Names / IUPAC Name Code Chemical Structure 

BYF 14182-

cysteinyl 

succinimide 

3-[(1,3-dimethyl-4-{[2-(4- 

methylpentan-2-yl)phenyl]carbamoyl}-1Hpyrazol-5-yl)sulfanyl]-2-(2,5- 

dioxopyrrolidin-1-yl)propanoic acid 

BYF 14182-

sulfonic acid 

1,3-dimethyl-4-{[2-(4-methylpentan-2- 

yl)phenyl]carbamoyl}-1H-pyrazole5-sulfonic acid 

BYF 14182-

hydroxy-sulfonic 

acid 

Structure not specified 

BYF 14182-

hydroxy-acetylcysteine Structure not specified 

BYF 14182-

pyrazole-4-

carboxamide 

Pen-PCX 

BCS-AA10791 

5-Fluoro-1,3-dimethyl-1H-pyrazole-4-

carboxamide 

BYF 14182-bis –

desmethyl-3-

carboxylic acid 

Pen-D3C 

BCS-CM41431 

5-Fluoro-1H-pyrazole-3-carboxylic acid 

N

N

CH3

C

O

N

H

H3C S

CH

H3C CH2 OH

CH

H3C CH3

O N O

O

N

N N

H

H3C SO3H

CH

H3C CH2

CH

H3C CH3

CH3

C

O

N

H

H3C SO3H

CH

H3C CH2

CH

H3C CH3 +O

N

CH3

C

O

N

N

N

CH3

C

O

N

H

CH

H3C CH2

CH

H3C CH3

H

+O

H3C S

H

N

O O

O

H3C

N

N NH

H3C F

CH3

C

O

2

N

HN

C

O

OH

F
 

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Table B1. Chemical structure, codes and chemical names of penflufen metabolites. 

Common Names / IUPAC Name Code Chemical Structure 

BYF 14182-

hydroxy-mercaptolactic acid Structure not specified 

BYF 14182-

desmethyldicarboxylic acid 5-fluoro-1H-pyrazole-3,4-dicarboxylic acid 

BYF 14182-

desmethylpyrazole-4-

carboxamide 

5-fluoro-3-methyl-1H-pyrazole4-carboxamide 

BYF 14182-bisdesmethyl-3-

carbonyl-serine 

Structure not completely specified 

BYF 14182 – 

fluoro acid 

5-fluoro-1,3-dimethyl-1H-pyrazole-4- carboxylic 

acid 

BYF 14182-

desmethyl-2,3-

dihydroxy 

N-[2-(2,3-dihydroxy-1,3- dimethylbutyl)phenyl]-

5-fluoro-3-methyl-1H-pyrazole-4-carboxamide 

BYF 14182-

desmethyl-3-

hydroxy-ketone 

5-fluoro-N-[2-(3-hydroxy-1,3-dimethyl-2-

oxobutyl)phenyl]-3-methyl-1H-pyrazole-4-

carboxamide 

N

N

CH3

C

O

N

H

CH

C CH2

CH

3C CH3+O

H3C S H3

H HO

O OH

HN

N

C

OH

F

C O

O OH

HN

N

C

F

CH3 O

NH2

HN

N

F

C

O serine

N

N

C

OH

H3C F

CH3 O

N

H F

CH

H3C

C

H3C C

OH

OH

N

CH3

C

O

N

H

H3

N

CH3

C

O

N

H

N

H F

CH

H3C

C

H3C CH3

O

OH
 

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Table B1. Chemical structure, codes and chemical names of penflufen metabolites. 

Common Names / IUPAC Name Code Chemical Structure 

BYF 14182-

desmethylhydroxymethyl-2,3-

dihydroxy 

N-[2-(2,3-dihydroxy-1,3- dimethylbutyl)phenyl]-

5-fluoro-3-(hydroxymethyl)-1H-pyrazole-4-

carboxamide 

BYF 14182-

desmethyl-acetylcarboxylic acid 

4-[(2-acetylphenyl)carbamoyl]-5-fluoro-1Hpyrazole-3-carboxylic acid 

BYF 14182-

hydroxy-ketocarboxylic acid Structure not completely specified 

BYF 14182-

dihydroxy (isomer 

1 and 2) 

Structure not completely specified 

BYF 14182-1,3,4’-

trihydroxy 

N-[2-(1,3-dihydroxy-1,3-dimethylbutyl)-4-

hydroxyphenyl]-5-fluoro-1,3-dimethyl)-1Hpyrazole-4-carboxamide 

BYF 14182-3,4’-

dihydroxy 

5-fluoro-N-[4-hydroxy-2-(3-hydroxy-1,3-

dimethylbutyl)phenyl]-1,3-dimethyl-1Hpyrazole-4-carboxamide 

N

H F

CH

H3C

H3

N

CH2

C

O

N

H

C

C CH3

OH

OH

HO

N

N

C

O

N

H

H F

C

H3C O

C

HO O

+2O

-2H

N

C

C

O

N

H

HO O

N

H3C F

CH

H3C CH2

H3C CH3

+2O

N

CH3

C

O

N

H

H

H3

N

H3C F

CH

H3C C 2

H3C C

N

H

H3C F

C

H3C CH2

H3C C

OH

OH

N

CH3

C

O

N

H3

OH

N

CH3

C

O

N

H

OH

N

H F

CH

H3C

C

H3C CH3

OH
 

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Table B1. Chemical structure, codes and chemical names of penflufen metabolites. 

Common Names / IUPAC Name Code Chemical Structure 

BYF 14182-3,4’-

dihydroxyglucuronide 

4-{[(5-fluoro-1,3-dimethyl-1H-pyrazol-4-

yl)carbonyl]amino}-3-(4-hydroxy-4-

methylpentan-2-yl)phenyl beta-Dglucopyranosiduronic acid 

BYF 14182 - 

2,3,4’-trihydroxy 

N-[2-(2,3-dihydroxy-1,3-dimethylbutyl)-4-

hydroxyphenyl]-5-fluoro-1,3-dimethyl-1Hpyrazole-4-carboxamide 

BYF 14182-3,4’-

dihydroxy-ketone 

5-fluoro-N-[4-hydroxy-2-(3-hydroxy-1,3-

dimethyl-2-oxobutyl)phenyl]-1,3-dimethyl-1Hpyrazole-4-carboxamide 

BYF 14182-3,4’-

dihydroxy-ketoglucuronide 

4-{[(5-fluoro-1,3-dimethyl-1H-pyrazol-4-

yl)carbonyl]amino}-3-(3-hydroxy-1,3-dimethyl2-oxobutyl)phenyl beta-D-glucopyranosiduronic 

acid 

BYF 14182- 3-

hydroxy-pentanoic 

acid 

4-(2-{[(5-fluoro-1,3-dimethyl-1H-pyrazol-4-

yl)carbonyl]amino}phenyl-2-hydroxy-2-

methylpentanoic acid

BYF 14182-4’-

hydroxy – 

glucuronide 

(isomer 1 and 2) 

3-(1,3-dimethylbutyl)-4-{[(5-fluoro-1,3,dimethyl1H-pyrazol-4-yl)carbonyl]amino}phenylbeta-Dglucopyranosiduronic acid 

N

H F

CH

H3C

C

H3C C 3

OH

N

CH3

C

O

N

H

H

O

O

OH

O OH

OH

OH

N

H

H3C F

CH

H3C CH

H3C C 3

OH

OH

N

CH3

C

O

N

H

OH

N

H

H F

CH

H3C

C

H3C CH3

OH

O

N

CH3

C

O

N

OH

N

H F

CH

H3C

C

H3C CH3

O

OH

O

N

CH3

C

O

N

H

O

O

OH

OH

OH

OH

N

H3C F

CH

H3C CH2

H3C C

OH

O

OH

N

CH3

C

O

N

H

N

H F

CH

H3C

CH

H3C CH3

O OH

N

CH3

C

O

N

H

O

O

OH

OH

OH
 

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Table B1. Chemical structure, codes and chemical names of penflufen metabolites. 

Common Names / IUPAC Name Code Chemical Structure 

BYF 14182-

desmethyl-4-

carboxylic acidglucuronide 

Structure not completely specified 

BYF 14182-

pentanoic acid, 

isomer 1 and 2 

4-(2-{[(5-fluoro-1,3-dimethyl-1H-pyrazol-4-

yl)carbonyl]amino}phenyl)-2-methylpentanoic 

acid 

BYF 14182-

desmethylpentanoic acid 

4-(2-{[(5-fluoro-3-methyl-1H-pyrazol-4-

yl)carbonyl]amino}phenyl)-2-methylpentanoic 

acid

BYF 14182-3,4,4’-

trihydroxy 

N-[2-(3,4-dihydroxy-1,3-dimethylbutyl)-4-

hydroxyphenyl]-5-fluoro-1,3-dimethyl-1Hpyrazole-4-carboxamide 

BYF 14182- 

desmethyldihydroxy-ketone 

5-fluoro-N-{2-[3-hydroxy-1-(hydroxymethyl)-3-

methyl-2-oxobutyl]phenyl}-3-methyl-1Hpyrazole-4-carboxamide 

BYF 14182-

desmethylhydroxymethylpentanoic acid* 

4-[2-({[5-fluoro-3-(hydroxymethyl)-1H-pyrazol4-yl]carbonyl}amino)phenyl]-2-methylpentanoic 

acid 

BYF 14182-

desmethyl-3-

hydroxy-ketocarboxylic acid* 

5-fluoro-4-{[2-(3-hydroxy-1,3-dimethyl-2-

oxobutylyl]phenyl]carbamoyl}-1H-pyrazole]-3-

carboxylic acid 

N

N

C

OH

H F

glucuronic 

acid

CH3 O + 

N

H

H3C F

CH

H3C CH2

H3C C

O

N

CH3

C

O

N

OH

N

N N

H

H F

CH

H3C CH2

H3C C

O

OH

CH3

C

O

N

H3C F

CH

H3C CH2

H3C C 2

OH

OH

N

CH3

C

O

N

H

H

OH

N

H

H F

CH

C

H2

C

H3C CH3

OH

HO O

N

CH3

C

O

N

N

H F

CH

H3C CH2

H3C C

OH

O

N

CH2

C

O

N

H

HO

N

H F

CH

H3C C

H3C CH3

O

OH

N

C

C

O

N

H

HO O
 

Penflufen Human Health Risk Assessment D387450 

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Table B1. Chemical structure, codes and chemical names of penflufen metabolites. 

Common Names / IUPAC Name Code Chemical Structure 

BYF 14182-2,3,4-

trihydroxy 

1,2-dideoxy-2-(2-{[(5-fluoro-1,3-dimethyl-1Hpyrazol-4-yl)carbonyl]amino}phenyl)-4-Cmethylpentitol 

BYF 14182-

desmethyl-4-

carboxylic acid 5-fluoro-3-methyl-1H-pyrazole-4-carboxylic acid 

N

H3C F H3

N

CH3

C

O

N

H

CH

C CH

H3C CH2

OH

OH

OH

N

N

C

OH

H F

CH3 O

*Identification was not unambiguous. 

B2. Plant Metabolism Study Summaries 

Potato metabolism studies 

The metabolism of penflufen was investigated in potatoes treated with penflufen labeled in the 

phenyl and pyrazole rings. Additionally, studies for each label were conducted reflecting both 

seed treatment (~0.005 lb ai/100 lbs seed) and in-furrow (~0.5 lbs ai/A) applications at rates 

approximately twice the currently proposed use pattern. Mature tubers were harvested from all 

four applications and potato leaves were harvested from the pyrazole label in-furrow application. 

No significant differences were noted either based on label position or on application technique. 

Total radioactive residue (TRR) was low in all tuber samples with the in-furrow tubers having 

higher residues likely due to a higher application rate. The major residue in tubers was the 

parent compound at ~20 - 30% of the TRR; minor amounts of penflufen-3-hydroxybutyl (Pen3HB) were found from the in-furrow application of phenyl labeled penflufen at 12% of the TRR. 

Other metabolites identified were all < 10% of the TRR. In pyrazole treated potato leaves from 

the in-furrow application, the TRR was significantly higher in the leaves than in the tubers from 

the same study, though the TRR in the leaves was still at low levels. The major residue in the 

leaves was Pen-3HB at 19% of the TRR and penflufen-3-hydroxybutyl glucoside at 11% of the 

TRR. All other identified metabolites were <10% of the TRR. Extractability of the residues in 

these studies was high and the identification acceptable. Two routes of degradation are 

postulated for penflufen in potatoes: 1) substitution of glutathione for fluorine in the pyrazole 

ring followed by hydrolysis of the glutathione moiety to cysteine; and 2) hydroxylation of the 

third carbon on the butyl substituent, followed by conjugation with glucose and malonic acid. 

Wheat metabolism studies

The metabolism of penflufen was investigated in spring wheat treated with penflufen labeled in 

the phenyl and pyrazole rings. Studies for each label were conducted reflecting seed treatment at 

0.05 lbs ai/100 lbs seed (1x the currently proposed rate) and 0.5 lbs ai/100 lbs seed (10x the 
 

Penflufen Human Health Risk Assessment D387450 

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currently proposed rate). Forage, hay, grain and straw samples were collected and analyzed. 

The TRR in grain from both application rates and labels was very low precluding attempts at 

identification. Higher TRR values were observed in forage, hay and straw with residues being 

highest in straw, followed by hay and forage. The major residue in forage, hay and straw was 

penflufen-3-hydroxybutyl-malonyl-glucoside at ~20-35% of the TRR and 4-hydroxybutylmalonyl-glucoside at ~10–20% of the TRR. The parent compound and other minor metabolites 

were identified and all were < 10% of the TRR. Of note, in the pyrazole ring labeled study, very 

minor amounts of the cleavage product, penfulufen-pyrazole-4-carboxamide (Pen-PCX) were 

noted in hay and straw. In the phenyl ring labeled study no metabolites specific to the phenyl 

ring were detected. Extractability of the residues in these studies was high and the identification 

acceptable. Three routes of degradation are postulated for penflufen in wheat: 1) substitution of 

glutathione for fluorine on the pyrazole ring followed by hydrolysis of the glutathione moiety to 

cysteine; 2) hydroxylation of the third or fourth carbon on the butyl substituent, followed by 

conjugation with glucose and malonic acid; and 3) cleavage of the N-phenyl linkage to yield 

Pen-PCX. 

Soybean metabolism studies

The metabolism of penflufen was investigated in soybeans treated with penflufen labeled in the 

phenyl and pyrazole rings. Studies for each label were conducted reflecting both seed treatment 

at 0.05 lbs ai/100 lbs seed (1x the currently proposed rate) and 0.5 lbs ai/100 lbs seed (10x the 

currently proposed rate). Soybean forage, hay and seed were collected and analyzed. The TRR 

in soybean seed was low with the highest TRR in forage followed by hay. The major residue in 

seed included penflufen-homoglutathione (Pen-HGT) at 22–77% of the TRR and penflufendesmethyl-dicarboxylic acid (pyrazole ring only) at 65% of the TRR. In forage the major 

residues were Pen-HGT at 56-60% of the TRR and cysteine at 10–13% of the TRR. In hay the 

major metabolites included Pen-HGT at 21–46% of the TRR, penflufen-3-hydroxybutylmalonyl-glucoside at 37–38% of the TRR and parent compound (phenyl ring label study only) at 

14% of the TRR. Other minor metabolites were identified and all were <10% of the TRR. 

Extractability of the residues in these studies was high and the identification acceptable. Three 

routes of degradation are postulated for penflufen in wheat: 1) hydrolysis of the fluorine 

substituent on the pyrazole ring, followed by glutathione conjugations and subsequent hydrolysis 

of the glutathione moiety; 2) hydroxylation of the third carbon on the butyl substituent, followed 

by conjugation with glucose and malonic acid; and 3) cleavage of the N-phenyl linkage followed 

by hydrolysis of the resulting amide to carboxylic acid, oxidation of the C3-methyl substituent, 

and loss of the N-methyl substituent to yield penflufen-desmethyl-dicarboxylic acid. 

Rice metabolism studies

The metabolism of penflufen was investigated in dry-seeded rice treated with penflufen labeled 

in the phenyl and pyrazole rings. Studies for each label were conducted reflecting soil treatment 

at transplant at 0.45 lbs ai/A. Rice kernels, husks and straw were collected and analyzed. The 

TRR in kernels was low with high levels of TRR found in straw and moderate residues found in 

husks. The major residue in seed included the parent compound at 20-31% of the TRR and Pen3HB at 20-23% of the TRR. In rice husks the major residue was parent at 15-27% of the TRR 

and Pen-3HB at 23-24% of the TRR. Other minor metabolites were identified in kernels and 

husks and all were <10% of the TRR. In rice straw multiple metabolites were identified, with 

no metabolite present at levels greater than 6% of the TRR. Extractability of the residues in 
 

Penflufen Human Health Risk Assessment D387450 

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these studies was high and the identification acceptable. Three routes of degradation are 

postulated for penflufen in wheat: 1) hydrolysis of the fluorine substituent on the pyrazole ring, 

followed by glutathione conjugations and subsequent hydrolysis of the glutathione moiety; 2) 

hydroxylation of the third carbon on the butyl substituent, followed by conjugation with glucose 

and malonic acid; and 3) cleavage of the N-phenyl linkage followed by hydrolysis of the 

resulting amide to carboxylic acid, oxidation of the C3-methyl substituent, and loss of the Nmethyl substituent to yield penflufen-desmethyl-dicarboxylic acid. 

B3. Livestock Metabolism Studies 

Poultry metabolism studies

The metabolism of penflufen in poultry was investigated using laying hens orally dosed at a rate 

equivalent to 25 - 27 ppm in the feed of pyrazole or phenyl ring labeled penflufen. Twelve hens, 

six dosed with pyrazole ring labeled penflufen and six dosed with phenyl ring labeled penflufen 

were dosed 14 times at 24 hour intervals and sacrificed about six hours after the last dose. Total 

radioactivity was measured in the excreta and eggs daily, as well as in the poultry muscle, fat, 

liver and skin at sacrifice. The majority of the administered dose was recovered in the excreta. 

Residues in eggs increased linearly reaching a plateau between day 6 and 8. The highest tissue 

TRR values were measured in the liver and kidney, with lower levels in the skin, fat and muscle. 

The major residue in eggs was the parent compound at 12% with multiple minor metabolites 

detected, all at <10% of the TRR. The major residue in fat was parent, which was the only 

compound identified at 74- 8% of the TRR. In muscle, the only metabolite identified at over 

10% of the TRR was 3,4’-dihydroxy-keto-glucuronide at 10% of the TRR, no parent was 

detected in muscle. Low levels of various minor metabolites were identified in muscle, all below 

10% of the TRR. In liver, no metabolite greater than 10% was identified and parent was not 

detected even as a minor metabolite. 

No significant difference in metabolic profile was seen between the pyrazole and phenyl ring 

labeled studies. Parent was the major metabolite in fat and seen at 10% of the TRR in eggs, 

however penflufen is extensively metabolized in the laying hen with over 50 metabolites 

identified or characterized in the different tissues. The main metabolic pathways in the hen are 

N-demethylation in the pyrazole ring, hydroxylation at the various positions of the molecule, 

further oxidation of hydroxyl groups forming keto and carboxylic acid groups, oxidative 

cleavage of the alkyl side chain forming an acetyl compound and conjugations of the hydroxyl 

group in the 4’-position of the phenyl ring with glucuronic acid. 

Ruminant metabolism studies

The metabolism of penflufen in ruminants was investigated using lactating goats orally dosed at 

a rate equivalent to 48 ppm in the feed. Two goats, one dosed with pyrazole ring labeled 

penflufen and one dosed with phenyl ring labeled penflufen were dosed 5 times at 24 hour 

intervals and sacrificed about twenty four hours after the last dose. Total radioactivity was 

measured in the milk and excreta at timed intervals as well as in liver, kidney, muscle and fat at 

sacrifice. The majority of the administered dose was recovered in the excreta. The highest tissue 

TRR values were measured in liver, followed by kidney, fat and muscle. In milk, the major 

residues were 2,3,4’-trihydroxy (isomer 1) at 17-24% of the TRR, 3,4’-dihydroxy at 14-16 % of 

the TRR, and 2,3,4’-trihydroxy (isomer 2) at 10% of the TRR. Additional minor metabolites 
 

Penflufen Human Health Risk Assessment D387450 

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were identified at <10% of the TRR. In muscle, multiple minor metabolites were identified with 

3,4’-dihydroxy as the only metabolite >10% of the TRR at 15-18%. In fat, 3,4’-dihydroxyglucuronide and 3,4’-dihydroxy were identified at 15 and 14% of the TRR, respectively. 

Multiple minor metabolites were identified in fat, all <10% of the TRR. In liver multiple 

metabolites were identified with 3,4’-dihydroxy-glucuronide being the only metabolite >10% of 

the TRR at 10 - 15%. Likewise in kidney, multiple metabolites were identified with pentanoic 

acid (isomer 2) and 3,4’-dihydroxy-glucuronide being the only metabolites >10% of the TRR at 

16–17% and 10 - 13%, respectively. 

No substantive difference in metabolic profile was seen between the pyrazole and phenyl ring 

labeled studies. Penflufen is extensively metabolized in the ruminant as demonstrated by the 

high level of identified metabolites present at low levels (<10% of the TRR). The main 

metabolic pathways in the ruminant are N-demethylation in the pyrazole ring, hydroxylation at 

the various positions of the molecule, further oxidation of the hydroxyl group in the 2-position of 

the alkyl side chain forming a keto group, oxidation of a terminal methyl group of the alkyl side 

chain to a carboxylic acid group, and conjugation of the hydroxyl group in the 4’-position of the 

phenyl ring with glucuronic acid. 

 
 

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Appendix C. Physical/Chemical Properties 

Table C1. Physical/Chemical Properties of Penflufen 

Parameter Value Reference 

Molecular Weight 317.41 g/mol MRID No. 48023535 

pH 6.7 (1% suspension in distilled water 

@ 22°C) 

MRID No. 48023525 

Water solubility (20°C) @ pH 4 = 11.0 mg/L 

@ pH 7 = 10.9 mg/L 

@ pH 9 = 11.2 mg/L 

MRID No. 48023535 

Solvent solubility (20°C ) Solvent g/L

methanol 126 

n-heptane 1.6 

toluene 62 

dichloromethane >250 

acetone 139 

ethylacetate 96 

dimethyl sulfoxide 162 

MRID No. 48023536 

Vapor pressure (25°C) 9.0 x 10-9 torr MRID No. 48023537 

Dissociation constant, pKa No dissociation constant (pKa) was 

found in aqueous solution of penflufen 

in the range of 1<pH<12. The 

molecule has no structural moieties 

which are prone to dissociate. 

MRID No. 48023532 

Henry’s law constant 1.04 x 10-10 atm·m3/mol MRID No. 48023539 

Octanol/water partition coefficient, log KOW

(25°C) 

@pH 7 = 3.3 MRID No. 48023534 

Hydrolysis t1/2 at 50°C Stable MRID No. 48023547 

Aqueous photolysis t1/2 at 25°C 83.2 days MRID No. 48023548 

Aerobic soil metabolism t1/2 at 25°C (combined 

radio-label half-life) 

249 days (silt loam) 

433 days (sandy loam)* 

MRID No. 48023553 

Aerobic soil metabolism t1/2 at 20oC 117 days (silt loam) 

165 days (sandy loam)* 

243 days (loam)* 

129 (loam)* 

MRID No. 48023552, 

AAP (degradate)

257 days (sandy loam)* 

116 days (silt loam) 

231 days (loam)* 

128 days (clay loam)* 

MRID No. 48023554 

Anaerobic Soil Metabolism t1⁄2 at 20°C 866 days* MRID No. 48023555 

Aerobic aquatic metabolism t1/2 at 20°C (sandy 

loam:sediment system, 2 radio-labels) 

301 days* 

267 days 

MRID No. 48023556 

Anaerobic aquatic metabolism t1/2 at 20°C 

(combined labels) 

Stable MRID No. 48023557 

* Extrapolated beyond the study duration. 

 
 

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Appendix D. End Use Products and Detailed Label Restrictions 

Table D.1. Penflufen End Use Products 

EPA Reg 

No. 

Product Composition Labeled crops Proposed Restrictions Co-Formulants 

264-RRRO PEN 240FS 22.7% penflufen 

2 lbs 

penflufen/gal 

Alfalfa, dried and 

succulent legume 

vegetables including 

soybeans, cereal 

grains, cotton, 

sunflower, safflower, 

and potato (seed piece 

treatment and infurrow) 

Do not use for feed, food or oil 

purposes. Store away from feeds and 

foodstuffs. 

Registered seed treatment crops and 

potatoes may be replanted at any 

time. All other crops may be planted 

after 30 days. 

None 

264-RREE PENPROME 

177FS 

3.59% penflufen 

0.32 lb 

penflufen/gal 

Alfalfa, dried legume 

vegetables including 

soybeans, barley, 

wheat, triticale, and 

rice. 

Do not use for feed, food or oil 

purposes. Store away from feeds and 

foodstuffs. 

Crops on this label or for which 

tolerances exist for penflufen may be 

replanted at any time. All other 

crops may be planted after 30 days. 

Prothioconazole and 

Metalaxyl 

264-RREG PENPRO 118FS 9.35% penflufen 

0.83 lb 

penflufen/gal 

Wheat, potato seed 

piece treatment 

Do not use for feed, food or oil 

purposes. Store away from feeds and 

foodstuffs. 

Crops on this label and other crops 

for which tolerances exist for 

penflufen may be replanted at any 

time. All other crops may be planted 

after 30 days. 

Prothioconazole 

264-RREL PENCLO 

273.5FS 

6.0% penflufen 

0.56 lb 

penflufen/gal 

Cotton, potato seed 

piece treatment 

Do not use for feed, food or oil 

purposes. Store away from feeds and 

foodstuffs. 

Crops on this label and other crops 

for which tolerances exist for 

clothianidan and penflufen may be 

replanted at any time. Grasses, nongrass animal feeds, dried beans and 

dried peas may be planted after 30 

days. Do not plant any other crop in 

the treated area for at least twelve 

months after treated seeds are 

planted. 

Clothianidin 

264-RREN PENRED 240FS 22.4% penflufen 

2 lbs 

penflufen/gal 

Alfalfa, dried and 

succulent legume 

vegetables including 

soybean, cereal grains, 

and oilseeds, potatoes 

(seed piece treatment 

and in-furrow) 

Do not use for feed, food or oil 

purposes. Store away from feeds and 

foodstuffs. 

Registered seed treatment crops and 

potatoes may be replanted at any 

time. All other crops may be planted 

after 30 days. 

None 
 

Penflufen Human Health Risk Assessment D387450 

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Table D.1. Penflufen End Use Products 

EPA Reg 

No. 

Product Composition Labeled crops Proposed Restrictions Co-Formulants 

264-RRER PENCLOTRIME 

310.68FS 

0.82% penflufen 

0.09 lb 

penflufen/gal 

Canola, rapeseed and 

mustard seed 

Do not use for feed, food or oil 

purposes. Store away from feeds and 

foodstuffs. 

Areas planted with treated seed may 

be replanted immediately with 

canola, cotton, corn (field, pop and 

sweet), cereal grains except rice, 

fruiting vegetables (including 

cucurbits), leafy vegetables 

(including brassica vegetables), 

mustard, rapeseed, sorghum, 

soybean, sugar beet, tuberous and 

corm vegetables. These areas may 

also be replanted after 30 days with 

grasses, non-grass animal feeds, and 

dried beans. Do not plant any other 

crop in the treated area for at least 

four months after treated seeds are 

planted. 

Clothianidin, 

trifloxystrobin, 

metalaxyl 

264-RREU PENTRI 308FS 13.3% penflufen 

1.28 lb 

penflufen/gal 

Alfalfa, legume 

vegetables including 

soybeans, wheat, corn, 

sorghum, cotton and 

rice 

Do not use for feed, food or oil 

purposes. Store away from feeds and 

foodstuffs. 

Crops on this label and other crops 

for which tolerances exist for 

trifloxystrobin and penflufen may be 

replanted at any time. All other 

crops may be planted after 30 days. 

Trifloxystrobin 
 

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Appendix E. 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 the 

Pesticide Handlers Exposure Database (PHED), the Agricultural Handler Exposure Task Force 

(AHETF), the Outdoor Residential Exposure Task Force (ORETF), and Seed Treatment SOPs 

and study MRID 47054702 have been determined to require a review of their ethical conduct, 

have received that review, and have been determined to be ethical.