UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: November 9, 2015 

SUBJECT: Pronamide. Human Health Risk Assessment for Registration Review and to 

Support New Section 3 Use on Leaf Lettuce (Revised). 

PC Code: 101701 

Decision No.: 0493477 

Petition No.: 4F8301 

DP Barcode: 0422207, 0410291 

Registration No.: 62719-578 

Regulatory Action: Registration Review/Section 3 

Risk Assessment Type: Single Chemical/Aggregate Case No.: 0082 

TXR No.: NA CAS No.: 23950-58-5 

MRID No.: see References 40 CFR: 40 CFR § 180.3 17 

FROM: 

THROUGH: 

TO: 

Ray Kent, Ph.D., Senior Scientisf 1 ~ ~ -

Ideliz Negr6n-Encarnaci6n, D fi"Ct#ist . .9Jt.& .._I ---

Seyed Tadayon, Chemist- /'10:-~<J__-.. ~;; 

Risk Assessment Branch V and Yll / 

Health Effects Division (7509Pkft· / /} 

Mike Metzger, Branch Chief J ,..,P) Risk Assessment Branch V an V I 

Health Effects Division (7509P) 

Office of Pesticide Programs .-.£.JL dO'" 

Anna Lowit, RARC Detailed Reviewer ~(tl ~ 

Charles Smith, RARC Detailed Reviewer , (\ .n 1 

- ~ 

William Irwin, ToxSAC Detailed Reviewer lu <J' 11'-u-vri 

Chris Schlosser, ToxSAC Detailed Reviewer 

Wilhelmena Livingston, Chemical Review Manager 

Kevin Costello, Branch Chief 

Risk Management and Implementation Branch IV 

Pesticide Re-evaluation Division (7508P) 

Reuben Baris, Risk Manager 

Daniel Kenny, Branch Chief 

Herbicide Branch 

Registration Division (7505P) 

Page 1 of72 
Pronamide Human Health Risk Assessment DP No. 0422207 

Table of Contents 

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

2.0 HED Recommendations ............................................................ ........................................ 7 

2.1 Data Deficiencies ............................................................................................................ 7 

2.2 Tolerance Considerations .............................................................................................. 7 

2.2.1 Enforcement Analytical Method ................................................................ ............... 8 

2.2.2 Recommended Tolerances ......................................................................................... 8 

2.2.3 Revisions to Petitioned-For Tolerances .............................................................. l o+G 

2.2.4 lnternational Harmonization ............................................................................... UH 

2.3 Label Recommendations .......................................................................................... UH 

2.3.1 Recommendations from Residue Reviews .......................................................... UH 

2.3.2 Recommendations from Occupational Assessment ........................................... UH 

2.3.3 Recommendations from Residential Assessment.. ............................................. 11-l+ 

3.0 Introduction .................................................................................................................. UH 

3.1 Chemical Identity ..................................................................................................... JlH 

3.2 Physical/Chemical Characteristics ......................................................................... JlH 

3.3 Pesticide Use Pattern .................................................................... ........... ................. 12H 

3.4 Anticipated Exposure Pathways ............................................................................. 11-H 

3.5 Consideration of Environmental Justice ................................................................ 14+4 

4.0 Hazard Characterization and Dose-Response Assessment ...................................... 14+4 

4.1 Toxicology Studies Available for Analysis ............................................................. 14+4 

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

4.2.1 Dermal Absorption ............................................................................................... 16+6 

4.3 Toxicological Effects ................................................................................................ 11+6 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ........................... ~+8 

4.4.1 Completeness of the Toxicology Database .......................................................... ~+8 

4.4.2 Evidence of Neurotoxicity .................................................................................... ~+9 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal.. .. 1.2+9 

4.4.4 Residual Uncertainty in the Exposure Database ............................................... 19+9 

4.5 Toxicity Endpoint and Point of Departure Selections .......................................... 1.2+9 

4.5.1 Dose-Response Assessment .................................................................................. 1.2+9 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment. £1.U 

4.5.3 Cancer Classification and Risk Assessment Recommendation ........................ £1.U 

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

Assessment ........................................................................................................................... 23~ 

5.0 Dietary Exposure and Risk Assessment ..................................................................... 2~ 

5.1 Metabolite/Degradate Residue Profile ................................................................... 2~ 

5.1.2 Summary of Environmental Degradation .......................................................... 282'8 

5.1.3 Comparison of Metabolic Pathways ................................................................... 282'8 

5.1.4 Residues of Concern Summary and Rationale .................................................. 29~ 

5.2 Food Residue Profile ................................................................................................ 29~ 

5.4 Dietary Risk Assessment .......................................................................................... 11;.i. 

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5.4.1 Description of Residue Data Used in Dietary Assessment.................................... 31

5.4.2 Percent Crop Treated Used in Dietary Assessment .............................................. 31

5.4.3 Acute Dietary Risk Assessment............................................................................... 31

5.4.4 Chronic Dietary Risk Assessment........................................................................... 31

5.4.5 Cancer Dietary Risk Assessment............................................................................. 32

5.4.6 Summary Table......................................................................................................... 32

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 33

6.1 Residential Handler Exposure .................................................................................... 33

6.2 Post-Application Exposure .......................................................................................... 33

6.4 Residential Risk Estimates for Use in Aggregate Assessment.................................. 34

6.6 Spray Drift.................................................................................................................... 35

7.0 Aggregate Exposure/Risk Characterization.................................................................. 35

7.2 Short-Term Aggregate Risk ........................................................................................ 36

8.0 Cumulative Exposure/Risk Characterization ............................................................... 36

9.0 Occupational Exposure/Risk Characterization ............................................................ 37

9.1 Occupational Handler Exposure/Risk Estimates...................................................... 37

9.2 Occupational Post-application Exposure/Risk Estimates ........................................ 39

9.2.1 Occupational Post-application Inhalation Exposure/Risk Estimates.................. 39

9.2.2 Occupational Post-application Dermal Exposure/Risk Estimates....................... 39

10.0 References......................................................................................................................... 42

Appendix A. Toxicology Profile and Executive Summaries .................................................. 48

A.1 Toxicology Data Requirements................................................................................... 48

A.2 Toxicity Profiles............................................................................................................ 49

A.3 Hazard Identification and Endpoint Selection .......................................................... 58

Appendix B. Metabolites and Metabolic Pathways for Pronamide ...................................... 63

The following are rat metabolites found in the urine and feces................................................ 63

Appendix C. Physical/Chemical Properties............................................................................. 66

Appendix D. Summary of Registered and Proposed Uses for Pronamide ........................... 67

Appendix E. Occupational Exposure/Risk Summary Tables................................................ 68

Appendix F. International Residue Limits Table ................................................................... 68
Pronamide Human Health Risk Assessment DP No. D422207

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1.0 Executive Summary

Background

Pronamide, also called propyzamide, [3,5-dichloro-N-(1,1-dimethyl-2-propynyl)benzamide], is a 

selective, systemic, pre-and post-emergence herbicide registered for the control of grasses and 

broadleaf weeds in several food and feed crops as well as woody ornamentals, Christmas trees, 

grasses grown for seed or turf (sod), golf course turf, recreational area turf, and fallow land. This 

assessment has been conducted for the purpose of addressing two separate regulatory actions: 

(1) Section 3 registration for leaf lettuce, and (2) reassessment of all currently registered uses to 

support the Draft Risk Assessment (DRA) for Registration Review. 

Exposure and Use Profile

There are five end-use products registered with pronamide as the active ingredient. These 

include liquid and wettable powder in Water Soluble Package (WSP) formulations. The 

registered use sites include various agricultural sites, Christmas tree farms, golf courses, 

seedling nurseries, landscape ornamentals, non-crop use sites (such as railroad, highway, 

roadside, pipeline and utility rights-of-way, and industrial areas), residential/commercial turf, 

and sod farms. Most of the uses are soil-directed, and are applied either via aerial, chemigation, 

groundboom, or handheld equipment. The application rates for all uses range from 0.5 to 4 lb 

ai/A. The re-entry interval (REI) for the registered uses is 24 hours. All of the pronamide 

registered labels require handlers to wear a double layer of clothing (long sleeved shirt and long 

pants) with either waterproof or chemical-resistant gloves.

There is a proposed new Section 3 use on leaf lettuce. The liquid formulation (EPA REG # 

62719-578) may be applied via aerial, chemigation, and groundboom equipment. The proposed 

single maximum application rates and PHIs range from 0.5 lbs ai/A (25 days) to 2.0 lbs ai/A (55 

days). Two broadcast applications can be made per year. 

Hazard Assessment

The primary target organ for pronamide is the liver. Effects include elevated levels of enzymes 

associated with liver damage and histopathology of liver cells. There are other target organs as 

well, including the thyroid, testes and pituitary, but effects to these organs are typically 

secondary to primary effects on the liver. The liver is affected in all species tested.

Pronamide is a carcinogen in rats and mice, causing liver tumors in mice, thyroid tumors in male 

rats and testicular tumors in rats. Mode of action (MOA) data have been submitted to the 

Agency and accepted for all three tumor types. All of the cancer modes of action focus on the 

liver as the site of the molecular initiating events for carcinogenicity. 
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Neurotoxicity was observed in the acute neurotoxicity study (ACN) at a lowest observed effect 

level (LOAEL) of 40 mg/kg, and is the basis for the point of departure (POD) of 4 mg/kg/day to 

assess acute dietary risk. Since there are no effects observed in any of the pronamide toxicity 

studies below 4 mg/kg/day, this point of departure from the ACN study also serves as a 

convenient reference point to assess chronic dietary risk, inhalation risk and short and 

intermediate incidental oral risk to young children. 

Residue Chemistry

Several residue chemistry data deficiencies were identified in the scoping document of 

pronamide (D363904, 06/17/2009). New data has been submitted and evaluated in support of 

Registration Review and there is a proposed new use on leaf lettuce. The chemistry database of 

pronamide is adequate to support Registration Review and the proposed new use in leaf lettuce 

provided that data needs, recommended tolerances and label modifications described in Section 

2.0 are considered. The nature of the residue is adequately understood for alfalfa and lettuce, 

rotational crops, livestock, and drinking water. The terminal residues of concern in plants,

livestock commodities, and drinking water, are pronamide and its metabolites containing the 3,5-

dichlorobenzoyl moiety. Adequate enforcement methods for residues of pronamide on plants

and livestock are available. To support the use on peas, field trial data from two additional field 

trials for pea vines and hay and four additional field trials for pea seed are required.

 

Dietary Exposure and Risk

Unrefined acute and chronic dietary assessments were performed. Tolerance level residues of 

pronamide were used for the registered uses and proposed new use on leaf lettuce. Default 

processing factors and 100% crop treated (CT) assumptions were utilized. Drinking water was 

incorporated directly in the dietary assessment using the Tier II acute and chronic estimated 

drinking water concentrations (EDWC) for surface water generated by the Surface Water 

Concentration Calculator (SWCC). Acute and chronic dietary (food and water) risks from the 

existing and proposed use of pronamide are ≤ 46% of the aPAD and ≤ 11% of the cPAD, 

respectively. These are not of concern for the general population and the regulated population 

subgroups, i.e. < 100% of the aPAD and cPAD.

Residential (Non-Occupational) Exposure and Risk

Residential handler exposures are not expected as pronamide is a Restricted Use Pesticide and as 

such can only be applied by Certified Applicators. However, there is the potential for postapplication exposure from currently registered turf uses (e.g., residential turf, golf courses) and 

these uses have been reassessed to reflect updates to HED’s 2012 Residential SOPs. 

All dermal and incidental oral risk estimates for post-application exposure are not of concern 

(i.e., dermal MOEs ≥ 100 and all incidental oral MOEs ≥ 1000). 

Aggregate Exposure and Risk
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There was a single scenario assessing aggregate risk to children from post application exposure 

to pronamide from treated turf. Aggregate hand-to-mouth and chronic food and water exposure 

is not of concern since the aggregate MOE of 1700 is greater than the LOC of 1000.

Spray Drift

A quantitative spray drift assessment for pronamide is not required because the turf postapplication MOEs are protective for any potential exposures related to spray drift.

Occupational Exposure and Risk

Occupational handler exposure and risk estimates indicate that short- and intermediate-term 

dermal MOEs are not of concern to HED (i.e., MOEs >100) for any of the end-use products as 

long as label-required personal protective equipment (PPE) of double layer clothing and gloves 

are worn during mixing/loading of liquid formulation for aerial application to high-acreage crops

(corn, soybeans and wheat).

To assess inhalation risk an inhalation study is normally required, or, in the absence of an 

inhalation study, an appropriate oral study may be used as a surrogate for risk assessment 

provided the MOEs are >1000 for inhalation exposure. In 2003 a waiver of the requirement to 

perform an inhalation study was granted because the MOEs based on an oral study exceeded 

1000. Unit exposures and exposure assessment procedures have evolved since 2003 based on 

new data, nevertheless at this time, all short and intermediate-term scenarios have adequate 

MOEs in excess of 3000 (see Appendix E). Accordingly the requirement to perform an 

inhalation study continues to be waived.

Occupational post-application dermal exposure and risk estimates were assessed for the 

registered uses that are not soil-directed (e.g., turf), and resulted in acceptable MOE’s >100 on 

the day of application, ranging from 100 to 79,000. Based on quantitative post-application 

assessment, the labeled REI of 24 hours is required to protect workers from exposures to 

pronamide. 
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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://www3.epa.gov/environmentaljustice/resources/policy/exec_order_12898.pdf

Human Studies Review

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 data, which include studies from 

the PHED 1.1, the AHETF database, and the ARTF database are (1) subject to ethics review 

pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable 

ethics requirements. For certain studies, the ethics review may have included review by the 

Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, 

can be found at the Agency website1. 

2.0 HED Recommendations

2.1 Data Deficiencies

Dislodgeable Foliar Residue (DFR): Since the MOE associated with the highest estimated 

occupational post-application exposure using default DFR values for pronamide is equal to the 

level of concern (i.e., the calculated MOE is not greater than 2 times higher than the level of 

concern, MOE = 100 compared to the LOC of 100); the DFR data under 40 CFR is needed.

Residue Chemistry. Additional field trials for pea vines and hay and pea seed are needed. 

Storage stability data will be required if samples to be collected from the requested field pea field 

trials are stored frozen longer than the intervals for which residues have been demonstrated to be 

stable (I. Negrón-Encarnación, D383372).

The standards of pronamide and methyl-3,5-dichlorobenzoate will expire in September 2015. In 

addition, the standard of 3,5-dichlorobenzoic acid is needed to support the residue measured in 

the new enforcement method for livestock commodities. The registrant should submit these 

standards to the EPA National Pesticide Standards Repository. 

2.2 Tolerance Considerations

Tolerances have been previously established in 40 CFR §180.317 for the combined residues of 

pronamide and its metabolites (containing the 3,5-dichlorobenzoyl moiety and calculated as 3,5-

dichloro-N-(1,1-dimethyl-2-propynyl)benzamide). The terminal residues of concern in plants and 

 

1 http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html
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livestock commodities, and in drinking water, are pronamide and its metabolites containing the 

3,5-dichlorobenzoyl moiety.

2.2.1 Enforcement Analytical Method

Plant: An adequate residue analytical method is available for tolerance enforcement of residues 

in/on plant commodities. The PAM II lists a GLC/ECD method, designated as Method I, which 

converts residues of pronamide and its metabolites to methyl 3,5-dichlorobenzoate (MDCB). 

Method I was successfully radiovalidated using aged samples from the alfalfa and lettuce 

metabolism studies.

Livestock: Modifications to the livestock enforcement method were required previously 

(02/28/2002; D275536). An Independent Laboratory Validation (ILV) of a new method was

submitted and considered acceptable. Based on this a gas chromatography method with 

negative-ion chemical ionization mass spectrometry detection (GC/MS), Method GRM 02.21, 

for the determination of residues of pronamide and metabolites containing the 3,5-

dichlorobenzoyl moiety converted to 3,5-dichlorobenzoic acid (3,5-DCBA) in milk, bovine liver, 

kidney, muscle, and fat, and eggs and poultry muscle and fat is available for enforcement of 

tolerances for livestock commodities.

2.2.2 Recommended Tolerances

The current tolerance expression for pronamide (40CFR §180.317) is adequate for plant 

commodities, and includes both coverage and compliance statements for enforcement purposes. 

HED recommends a tolerance of 1 ppm to support the use of pronamide on leaf lettuce in order 

to harmonize with the Canadian MRL for lettuce (I. Negrón-Encarnación, D424598, 01/15/2015, 

I. Negrón-Encarnación, D429782, 10/26/2015 and discussion below). Moreover, based on 

limited field trial data to support the use of pronamide on field pea, HED recommends increasing 

the tolerance for field pea seed from 0.05 ppm to 0.10 ppm, and establishing tolerances of 1.5 

ppm and 3.0 ppm for field pea vines and dry pea hay, respectively (I. Negrón-Encarnación, 

D383372, 09/17/2015). 

The current tolerance expression is not adequate to enforce tolerances in livestock commodities 

as the tolerance enforcement method converts residues of pronamide to 3,5-dichlorobenzoic acid 

instead of methyl-3,5-dichlorobenzoate. Based on this, HED recommends modification of 40 

CFR § 180.317 (a) General in two sections, (1) and (2). The first section may include the current 

tolerance expression for plants followed by a table with the tolerances for plant commodities 

while the second section may contain the tolerance expression below followed with a table with 

the tolerances for livestock commodities. 

The recommended tolerance expression for section (2) is: “Tolerances are established for 

residues of the herbicide propyzamide, including its metabolites and degradates, in or on the 

commodities in the following table. Compliance with the tolerance levels specified in the table 

below is to be determined by measuring only those propyzamide residues convertible to 3,5-
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dichlorobenzoic acid, expressed as the stoichiometric equivalent of propyzamide, 3,5-dichloroN-(1,1-dimethyl-2-propynyl)benzamide, in or on the commodity.”

Table 2.2.2. Tolerance Reassessment Summary for Pronamide

Commodity Established / Proposed* 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Tolerance to be Listed Under 40 CFR §180.317(a)(1)

Alfalfa, seed 10.0 10.0

Animal feed, nongrass, 

group 18

10.0 10.0

Apple 0.1 0.1

Artichoke, globe 0.01 0.01

Blackberry 0.05 0.05

Blueberry 0.05 0.05

Boysenberry 0.05 0.05

Endive 1.0 1.0

Fruit, stone, group 12 0.1 0.1

Grape 0.1 0.1

Lettuce, head 1.0 1.0

Lettuce, leaf 1.0 1

Pear 0.1 0.1

Radicchio 2.0 2.0

Raspberry 0.05 0.05

Tolerance to be Listed Under 40 CFR §180.317(a)(2)

Cattle, fat 0.2 0.2

Cattle, kidney 0.4 0.4

Cattle, liver 0.4 0.4

Cattle, meat 0.02 0.02

Cattle, meat byproducts, 

except kidney and liver

0.02 0.02

Egg 0.02 0.02

Goat, fat 0.2 0.2

Goat, kidney 0.4 0.4

Goat, liver 0.4 0.4

Goat, meat 0.02 0.02

Goat, meat byproducts, 

except kidney and liver

0.02 0.02

Hog, fat 0.2 0.2

Hog, kidney 0.4 0.4

Hog, liver 0.4 0.4

Hog, meat 0.02 0.02

Hog, meat byproducts, 

except kidney and liver

0.02 0.02
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Horse, fat 0.2 0.2

Horse, kidney 0.4 0.4

Horse, liver 0.4 0.4

Horse, meat 0.02 0.02

Horse, meat byproducts, 

except kidney and liver

0.02 0.02

Milk 0.02 0.02

Poultry, fat 0.02 0.02

Poultry, liver 0.2 0.2

Poultry, meat 0.02 0.02

Poultry, meat byproducts, 

except liver

0.02 0.02

Sheep, fat 0.2 0.2

Sheep, kidney 0.4 0.4

Sheep, liver 0.4 0.4

Sheep, meat 0.02 0.02

Sheep, meat byproducts, 

except kidney and liver

0.02 0.02

Tolerance Listed Under 40 CFR §180.317(c)

Pea, field, seed 0.05 0.101

Tolerances To Be Listed Under 40 CFR §180.317(c)

Pea, field, hay -- 3.01

Pea, field, vines -- 1.51

1 To be re-evaluated upon submission of adequate magnitude of residue studies.

2.2.3 Revisions to Petitioned-For Tolerances

The registrant had proposed a tolerance of 1.0 ppm for leaf lettuce. The recommended US 

tolerance was estimated following the Organisation for Economic Co-operation and 

Development (OECD) calculation procedures using field trial data that supports the intended use 

pattern. The data of the 2009 decline trials was organized in the following four sets: 0.5 lb ai/A 

(25 day-PHI), 1.0 lb ai/A (35-day PHI), 1.5 lb ai/A (45-day PHI), and 2.0 lb ai/A (55-day PHI). 

All data sets result in a rounded MRL of 2 ppm with the exception of the 0.5 lb ai/A which 

results in a rounded MRL of 1.5 ppm. Based on these calculations, the tolerance suggested by 

the OECD calculation procedures is 2 ppm. Canada has an MRL of 1 ppm for residues of

pronamide on lettuce. The highest residue obtained from the crop field trial data with leaf lettuce 

was 1.0 ppm which is at the tolerance level. Because substantial data is available for pronamide 

on leaf lettuce (18 crop field trials in the US; 8 of those with 4 different use patterns), residues 

decline significantly within days (e.g. mean residues observed in the 2009 decline trials decrease 

by a factor of 0.6 in comparison to those from samples harvested 10 days before), and MRLs 

established by most countries are at 1 ppm or below, HED recommends in favor of a tolerance of 

1 ppm for leaf lettuce.
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2.2.4 International Harmonization

Where possible, EPA encourages the harmonization of US Tolerances and Maximum Residue 

Limits (MRLs) in key export markets. A table with US tolerances, and Canadian and Codex 

MRLs for pronamide is provided in Appendix G. Currently, Mexican or Codex MRLs for 

pronamide have not been established. The US and Canadian tolerance expressions are 

harmonized for measurement of pronamide, including metabolites containing the 3,5-

dichlorobenzoate moiety. Canadian MRLs for apple, blueberry and pear are harmonized with 

US tolerances. The Canadian MRL for lettuce is 1 ppm. In order to harmonize with the 

Canadian MRL for lettuce, HED recommends that the US tolerance for leaf lettuce be

established at 1 ppm.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

The current labels for pronamide include plant back intervals for other crops than those 

recommended in the 2002 TRED. Rotation to crops other than leafy vegetables (crop group 4), 

root and tuber vegetables (crop group 1), and cereal grains is allowed by following a 365-day 

plant-back interval (PBI), refer to Section 3.3. 

Feeding/grazing restrictions on the labels can be removed as potential residues of pronamide 

in/on field pea feedstuff and livestock commodities have been evaluated, and these restrictions 

are generally considered impractical and/or unenforceable.

For the new use on leaf lettuce, it is recommended that detailed instructions for split applications 

be included in the supplemental label. The maximum allowable total rates and corresponding 

PHIs for split applications should follow the recommendations currently proposed for regular 

applications. 

2.3.2 Recommendations from Occupational Assessment

The current PPE for registered uses and the proposed use are coveralls over short-sleeved shirt 

and short pants, waterproof gloves and chemical-resistant footwear plus socks. The PPE are 

adequate and no extra PPE is required. 

2.3.3 Recommendations from Residential Assessment

None at this time.

3.0 Introduction
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Pronamide is a selective, systemic, pre-and post-emergence herbicide registered for the control 

of grasses and broadleaf weeds in several food and feed crops as well as woody ornamentals, 

Christmas trees, nursery stocks, lawns, turf, and fallow land. 

3.1 Chemical Identity

Table 3.1 Pronamide Nomenclature.

Compound

Empirical Formula C12H11Cl2NO

Molecular weight 256.13

Common name pronamide or propyzamide 

Company experimental name Not applicable

IUPAC name 3,5-dichloro-N-(1,1-dimethylpropynyl)benzamide

CAS name 3,5-dichloro-N-(1,1-dimethyl-2-propynyl)benzamide

CAS registry number 23950-58-5

Chemical Class Amide herbicide (Pesticide Manual, 11th edition)

3.2 Physical/Chemical Characteristics

Pronamide is slightly soluble in water (15 mg/L) and is not expected to volatilize significantly 

due to the compound’s relatively low vapor pressure of 8.5x10-5torr. The log Kow for 

pronamide is 3.43. A table of physico-chemical properties for pronamide may be found in 

Appendix C.

3.3 Pesticide Use Pattern

There are five end-use product labels registered with pronamide as the active ingredient. These 

include liquid, and wettable powder formulations. Pronamide, may be applied using ground 

spray equipment, by soil incorporation, or by aircraft. The single application rates for 

agricultural uses range from 0.5 to 4 lb ai/A, and the maximum application rate per year range 

from 1 to 6 lbs ai/A. The 2002 residue chemistry chapter in support of the Tolerance 

Reassessment Eligibility Decision (TRED) recommended plant back intervals of 30-day for leafy 

vegetables (except Brassica vegetables) (Crop Group 4); 90-day for root and tuber vegetables 

(Crop Group 1); 360-day for cereal grains (Crop Group 15) and the forage, fodder, and straw of 

cereal grains (Crop Group 16) (D275536, 02/28/2002). Currently, extensive rotational crop 

restrictions, dependent on application rates, are established on the product labels. The restrictions 

for root and tuber vegetables, leafy vegetables crop group 4, and cereal grains are considered 

Cl

Cl

O

N

H

CH3

CH3 CH
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adequate. However, restrictions for other crops such as legume vegetables and cotton (90 to 

150-day PBI), and brassica leafy vegetables, cucurbit vegetables, fruiting vegetables, and bulb 

vegetables (90 to 210-day PBIs) are included in the labels. As indicated in the 2002 TRED, 

these rotational crop restrictions are inappropriate based on the results of the reviewed confined 

and limited rotational field studies.

Conclusions: Several label modifications are recommended with respect to the established plant 

back intervals, split applications for leaf lettuce, and feeding/grazing restrictions for pea feedstuff 

commodities. 

(1) Appropriate plant back intervals are established for leafy vegetables crop group 4, root 

and tuber vegetables crop group 1, and cereal grains in the Dow labels for Kerb® (EPA 

Reg. Nos. 62719-578, and 62719-397) and those from Willowood (EPA Reg. Nos. 

87290-22, 87290-9 and 87290-3). However, rotation to other crops than those was not 

recommended in the 2002 TRED. Rotation to other crops is allowed by following a 365-

day PBI. Based on this, the rotation instructions for legume vegetables and cotton (90 to 

150-day PBI), and brassica leafy vegetables, cucurbit vegetables, fruiting vegetables, and 

bulb vegetables (90 to 210-day PBIs) currently included in the labels should be deleted.

(2) For the new use on leaf lettuce, it is recommended that detailed instructions for split 

applications are included in the supplemental label, e.g. for split applications part of the 

maximum allowable application rate can be initially applied and the balance of the 

maximum allowable application rate can be made up to 10 days later. The maximum 

allowable total rates and corresponding PHIs for split applications for leaf lettuce should 

be 0.5, 0.75, 1.5, and 2.0 lbs ai/A with corresponding PHIs of 25, 35, 45, and 55 days, 

respectively. 

(3) For the established use on field pea, the registrant may delete the existing feeding/grazing 

restrictions on the label since they are impractical and/or unenforceable. 

3.4 Anticipated Exposure Pathways

The Registration Division and Pesticide Re-evaluation Division have requested an assessment of 

human health risk to support the proposed new use of pronamide for a Section 3 registration for 

leaf lettuce, and assessment of all currently registered uses to support the Preliminary Risk 

Assessment (PRA) for Registration Review. Humans may be exposed to pronamide in food and 

drinking water, since pronamide may be applied directly to growing crops and application may 

result in pronamide reaching surface and ground water sources of drinking water. There are 

residential uses of pronamide, so there is likely to be exposure in residential or non-occupational 

settings. In an occupational setting, applicators may be exposed while handling the pronamide

prior to application, as well as during application. There is a potential for post-application 

exposure for workers re-entering treated fields to dislodgeable pesticide residues from treated 

surfaces. The proposed use pattern is for preemergence or early postemergence application. As

a result, there are few, if any, agricultural activities that might be necessary in the days closely 
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following application. The most likely activity is scouting for herbicide efficacy. Unlike 

scouting for insects or mites, there is little expected foliar contact, other than possibly walking in 

a treated field several days after application.

Risk assessments have been previously prepared for the existing uses of pronamide. This risk 

assessment considers all of the aforementioned exposure pathways based on the proposed new 

uses of pronamide, but also considers the existing uses as well, particularly for the dietary 

exposure assessment. 

Based on the proposed and registered use patterns, it has been determined that the potential 

exposure scenarios that will need to be assessed include short- and intermediate-term 

occupational (handler and post-application) and residential exposures (post-application only). 

 

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://www3.epa.gov/environmentaljustice/resources/policy/exec_order_12898.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 National Health and Nutrition Survey/What We Eat in America (NHANES/WWEIA) 

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 and ethnic group. 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 

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, the database for pronamide is complete. The data from the

following acceptable studies were used to evaluate the hazard potential of pronamide:

 Oral subchronic toxicity study in the rat
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 Dermal subchronic toxicity study in the rat

 Prenatal developmental toxicity study in the rabbit

 Multi-generation reproduction study in the rat

 Chronic toxicity studies in the rat and dog

 Carcinogenicity studies in the rat and mouse

 Mutagenicity battery 

 Acute and subchronic neurotoxicity screening batteries in the rat

 Metabolism with pharmacokinetic studies in the rat

 Dermal absorption studies in vivo and in vitro

 Immunotoxicity study in the mouse

 Carcinogenicity MOA studies, including

o a study designed to determine the induction pattern of hepatic metabolizing 

enzymes (CYPs) in male mice,

o a study designed to determine molecular, cellular, and biochemical changes in the 

livers of male rats related to Leydig cell tumor formation, 

o a thyroid function and hepatic clearance study in male rats

o Bromodeoxyuridine (BrdU) labeling index to explore patterns of hepatic cell 

proliferation in mice

o a 90-day study to evaluate the MOA of pronamide-induced Leydig tumors in 

older male rats, 

o a study to determine if there is a surge in LH (luteinizing hormone) levels in the 

blood of rats after administration of pronamide in male rats.

The Hazard and Science Policy Council (HASPOC) determined that a new rat developmental 

toxicity study is not required since rabbits are the most sensitive species for developmental 

toxicity and a repeat developmental toxicity study in rats will not impact the risk assessment 

(TXR# 0056955). Also, the HASPOC granted a waiver to the comparative thyroid assay since 

the available mode of action studies show no direct interaction with the thyroid pathway and the 

thyroid effects are mediated through alterations in liver enzymes (TXR#0057211).

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

Orally administered pronamide is quickly absorbed from the g.i. tract and rapidly eliminated. In 

an ADME study with 14C-pronamide (MRIDs 41801801, 41929901 and 42858001) radiolabel

was recovered (total = 93-103%) in the urine (40-61%), feces (40-60%), tissues and carcass 

(0.08-2.4%) over a 7 day period. No bioaccumulation was apparent. The half-life of elimination 

of radioactivity from plasma of low dose (2 mg/kg) rats was biphasic with a rapid phase = 13 hrs 

(males and females) and a slow phase of 37 hours in males and 45 hours in females; and that of 

high dose (100 mg/kg) rats was monophasic with a half-life of 24hrs (males and females). 

Very little pronamide per se was recovered in the urine and no significant difference in urinary 

metabolite profile was observed between doses or sexes. In the urine, there were 27 unidentified 
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metabolites and none exceeded 3.3% of the dose. Few metabolites were identified in the feces, 

and nearly all of them were less than 1% of the dose. 

Data from dermal absorption studies discussed below (MRIDs 41117201 and 40256701) are also 

relevant to oral absorption. One satellite group of rats in the dermal studies was dosed i.v. with 

1.3 mg/kg a.i. and urine and feces were collected over a 7-day period. Nearly 100% of the 

administered dose was recovered with 63% of the label in the urine and 36% in the feces. Fecal 

excretion of an i.v. dose indicates biliary clearance and the same pattern of urinary and fecal 

excretion is seen in the oral studies discussed above, suggesting that nearly all orally 

administered pronamide (at least up to 100 mg/kg) is absorbed from the g.i. tract. 

Pronamide is an amide of 3,5-dichlorobenzoic acid. In metabolic studies in rats no alteration of 

the halogenated benzene ring took place, but the alkyl (1,1-dimethyl-2-propynyl) group was 

extensively metabolized. The methyl groups and the triple bond were readily oxidized to 

hydroxyl and carboxyl groups and these were in turn conjugated with glucose and malonic acid. 

Appendix B contains structures of rat metabolites and a proposed metabolic pathway for 

pronamide in rats. 

4.2.1 Dermal Absorption 

Two formulations of radiolabeled pronamide (14C-Kerb 50W and 14C-Kerb 3.3F) were evaluated 

for dermal absorption in the rat (MRIDs 41117201 and 40256701). Each formulation was tested 

at a low dose of 1.2 mg ai/kg (0.08 mg ai/cm2

) or a high dose of 66 mg ai/kg (4.4 mg ai/cm2). 

After 6 hours of exposure the treated areas of the rats were wiped with a soap solution followed 

by water. Dermal absorption was compared with oral uptake of 68 mg/kg 14C- pronamide 

administered by gavage in corn oil, or an i.v. dose of 1.3 mg/kg of 14C- pronamide in DMSO. 

Quantitation of uptake was based primarily on radiolabel recovered from excreta. 

A total of 19% and 17% of recovered 14C-pronamide was eliminated in the excreta following the 

low and high dose of 14C-Kerb 50W, respectively. A total of 15% and 5% of the recovered 14C1abel was eliminated in the excreta following the low and high dose of 14C- Kerb 3.3F, 

respectively. Based on the available data, the low dose of the 50W formulation was selected for 

risk assessment as it represents the highest dermal absorption potential. However, a low total 

mass balance recovery was obtained at this dose (78%), compared to the high dose (122%). 

Therefore, the data were normalized to give a dermal absorption factor of 23%. Furthermore, the 

Cl

Cl

O

N

H

CH3

CH3 CH
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total absorbed dose reported in the study did not include the radioactivity remaining in the 

carcass. At this dose level 2 of the 4 carcasses were analyzed and found that 1.2 and 0.7% of the 

dose remained. Therefore, a 1% correction factor was applied to yield a final DAF of 24% for 

pronamide.

4.3 Toxicological Effects

Pronamide is a selective, systemic, pre-and post-emergence herbicide, that inhibits root and 

shoot growth from seedlings. Its mode of action in plants is to interfere with cell division in the 

root systems of a select group of annual grasses and broadleaf weeds.

In mammals, pronamide is primarily a liver toxicant. Liver-related effects included increases in 

absolute and relative liver weight, hypertrophy, and increases in serum enzymes associated with 

liver toxicity such as alkaline phosphatase and alanine aminotransferase, and/or histopathology. 

Adverse liver findings were consistently observed in every animal species studied with 

progression towards more severe effects over time ultimately leading to tumorigenesis in rats and 

mice. Based on the studies submitted, the rat is the most sensitive species. In most studies there 

is no gender sensitivity in response to pronamide.

Pronamide causes liver tumors in mice and thyroid tumors and testicular Leydig cell tumors in 

rats. In mice, cancer mode of action data clearly show rapid induction of CYP2B1 associated 

with the constitutive androstane nuclear receptor (CAR), as well as induction of peroxisomes and 

peroxisomal enzymes associated with a second nuclear receptor, PPAR-α. Induction of the 

nuclear receptors is followed by hepatocellular proliferation and eventually, liver tumors.

In rats tumor precursor effects such as decreases in T4 levels, increases in liver weight, liver 

hypertrophy, and elevated testosterone metabolism have been shown to occur at pronamide doses 

below or equivalent to the tumorigenic dose. For example, in rat pubertal studies submitted to 

fulfill EDSP testing requirements, there were effects on blood T4 levels at doses 2- to 4-fold 

lower than doses resulting in thyroid tumors. Based on mode of action studies, tumorigenesis for 

all three tumor types has been shown to be mediated by liver enzymes induced in response to 

treatment with pronamide. In rats, pronamide induces CYP2B1 200 fold over background levels, 

but has no effect on other CYPs commonly associated with carcinogenic modes of action. 

CYP2B1 is a biological marker for the constitutive androstane nuclear receptor (CAR) which

interacts with pronamide to produce thyroid tumors in male rats and Leydig cell tumors of the 

testes. The CAR pathway is associated with the activation of uridine diphosphate glucuronyl 

transferase (UGT) which catalyzes the condensation of glucuronic acid with thyroxine (T4), 

leading to enhanced biliary excretion of T4. In male rats, the tumorigenic dose of pronamide for 

both thyroid tumors and Leydig cell tumors is 1000 ppm in the diet (34-75 mg/kg/day based on 

age of the rats) (12/02/2014, TXR 0057037).

There was no evidence of quantitative or qualitative increased susceptibility in the fetuses or the 

offspring of rats or rabbits following pre- and/or postnatal exposure to pronamide. In the 

prenatal developmental toxicity study in rabbits and the multi-generation reproduction study in 
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rats, any observed toxicity to the fetuses or offspring occurred at equivalent or higher doses than 

effects to parental animals.

In nearly every oral repeated dose study of pronamide there are dose-related decreases of body 

weight, body weight gain and food consumption also seen in the 28-day dermal toxicity study in 

rats. Typically, these effects on body weight occur at or above effects on the liver such as 

hypertrophy or increases in liver weight. The only exceptions to the co-occurrence of negative 

effects on body weight and increased liver weight and hypertrophy were in the subchronic 

neurotoxicity (SCN) and dermal toxicity studies where there were no effects at all on the liver. It 

should be noted, however, that the liver is not one the tissues examined within the SCN study 

design. 

In contrast with the SCN where only body weight effects were reported at the LOAEL, in the 

acute neurotoxicity (ACN) study the LOAEL was based on an increase in landing foot splay in 

female rats and a decrease in motor activity seen in both genders on Day 1. The NOAEL was not 

determined in this study.

In the immunotoxicity study with pronamide in mice, there was no evidence of immunotoxicity 

nor significant systemic toxicity.

Pronamide has a low order of acute toxicity via the oral, dermal, and inhalation routes of 

exposure (Toxicity Category III or IV), produces mild irritation to the eyes and skin (Toxicity 

Category IV), and is not a dermal sensitizer. 

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

The toxicology and exposure data bases for pronamide are complete and the toxicology studies 

are adequate for assessing increased susceptibility under FQPA. There was no evidence of 

quantitative or qualitative susceptibility in the developing organism and evidence for 

neurotoxicity was limited to effects seen following a single gavage dosing in the acute 

neurotoxicity study. There was no evidence of neurotoxicity in the subchronic neurotoxicity 

study. Therefore, there is no concern for developmental neurotoxicity. 

4.4.1 Completeness of the Toxicology Database

The toxicity database for pronamide is complete. 

4.4.2 Evidence of Neurotoxicity

In the acute neurotoxicity study following oral (gavage) administration, there was an increase in 

landing foot splay in female rats and a decrease in motor activity seen in both genders on Day 1. 

There was no evidence of neurotoxicity in the subchronic neurotoxicity study following dietary 

administration. There was no evidence of neurotoxicity in the rest of the toxicology database 

across other species or other strains of rat. 
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4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There was no evidence of quantitative or qualitative increased susceptibility in developing

fetuses or in offspring of rats or rabbits following pre- and/or postnatal exposure to pronamide. 

4.4.4 Residual Uncertainty in the Exposure Database

Non-dietary exposure. The residential post-application exposure assessments are based upon the 

2012 Residential Standard Operating Procedures (SOPs). These assessments of exposure are not 

likely to underestimate the resulting estimates of risk from exposure to pronamide.

Dietary exposure. There is no residual uncertainty in the exposure database for pronamide with 

respect to dietary exposure. An adequate database with respect to both the nature and magnitude 

of residues expected in food and water has been provided.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

Toxicity endpoints and points of departure (PoDs) for assessment of risks from exposure to 

pronamide are summarized below. Detailed descriptions of the studies used as a basis for the 

selected endpoints are presented in Appendix A. Toxicological endpoints were established for 

all relevant exposure scenarios.

Acute Dietary Endpoint (General Population): The acute neurotoxicity study in rats (MRID 

48599202) was selected for this exposure scenario. The LOAEL of 40 mg/kg is the Point of 

Departure (POD) and is based on the increase in landing foot splay in female rats and the 

decrease in motor activity seen in both genders on Day 1. This endpoint is appropriate for both 

the exposure duration (acute/single dose) and the population of concern (general population). 

An acute RfD of 0.04 mg/kg/day is derived using the LOAEL of 40 mg/kg/day and 1000X 

Uncertainty Factor which included 10X for inter-species extrapolation, 10X for intra-species 

variation and a 10X for the use of a LOAEL (UFL).

Acute Dietary Endpoint (Females 13-49 years old and infants and children): An endpoint of 

concern attributable to a single exposure was not identified from the database. In the 

developmental rabbit study, abortions were noted and could possibly be a result of fetal toxicity; 

however, as the abortions occurred very late (on or after GD 22), this finding was not considered 

to be a result of single dose of pronamide.

Chronic Dietary Endpoint, Incidental Oral (short and intermediate term), and Inhalation 

Endpoint (short and intermediate term): The database for pronamide contains subchronic and 
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chronic toxicity, carcinogenicity and reproductive toxicity studies conducted in CD rats and 

neurotoxicity studies (acute and subchronic) conducted in Fischer 344 rats. 

In CD rats, the target organs were liver, thyroid and the testes. In the chronic 

toxicity/carcinogenicity study with CD rats, pronamide caused increased relative liver weight 

and histopathological lesions in the liver, thyroid, and ovaries at 43 mg/kg/day, the same dose 

that induced thyroid and testicular tumors in rats. The registrant has submitted mode of action 

studies for each of the tumor types and the available MOA studies clearly identify the sequence 

of key events, dose-response concordance and temporal relationship to effects seen in these 

target organs. For example, absolute and relative liver weights of rats dosed with 43 mg/kg/day 

were increased 29% and 36% after 4 weeks of treatment, and pronamide effects on T4 levels 

occurred at doses as low as 10 mg/kg/day after 4 weeks of dosing.

In Fischer 344 rats, minimal neurotoxicity was seen after a single gavage dose of 40 mg/kg in the 

ACN study but no neurotoxicity was evident following dietary administration in F344 rats in the 

90-day SCN study in which systemic toxicity was manifested as decreases in body weight, body 

weight gain, and food consumption) at 12 mg/kg/day. There was no evidence of neurotoxicity in 

the rest of the toxicology database across other species or other strains of rat.

The LOAEL of 40 mg/kg in the ACN study in Fischer rats is also appropriate for assessing risk 

from chronic dietary and non-dietary (short/intermediate term incidental oral and inhalation 

exposures). The lowest LOAEL in the conventional toxicity database for pronamide is 12 

mg/kg/day from the SCN, also carried out in Fischer rats. The NOAEL for the study was 2.4 

mg/kg/day. The Fischer rat may therefore be a more sensitive model for human toxicity than the 

CD rat used in most other pronamide studies. The lowest LOAEL in the studies cited in the 

cancer mode of action analysis is 10 mg/kg/day from the male pubertal assay in CD(SD) rats 

submitted under the EDSP program. The NOAEL for the study is 2.5 mg/kg/day. Application of 

a 10x UFL factor to the LOAEL of 40 mg/kg/day established in the ACN results in an

extrapolated NOAEL of 4.0 mg/kg/day. The lower NOAEL of 2.5 mg/kg/day in the male 

pubertal assay is an artifact of dose selection; therefore, the higher extrapolated NOAEL is 

protective of the concern for the adverse effects observed at 10 mg/kg/day and higher doses in 

the toxicity database.

A chronic RfD of 0.04 mg/kg/day is derived using the POD of 4.0 mg/kg/day and an Uncertainty 

Factor of 100 which includes 10X for inter-species extrapolation, 10X for intra-species variation 

and a 1x FQPA SF. 

Short and Intermediate Term Incidental Oral Exposure: The LOAEL of 40 mg/kg/day based on 

motor activity and food splay in the acute neurotoxicity study. The Level of Concern (LOC) is a 

target Margin of Exposure (MOE) of 1000 which includes 10X for inter-species extrapolation, 

10X for intra-species variation and a 10X UFL). 

Dermal (Short and Intermediate-Term) Endpoints for Occupational and Non-Occupational 

Exposure Scenarios: The dermal endpoint was selected from a 28-day dermal toxicity study in 

rats. Although no target organ was identified, the significant (p<0.05) decreases in absolute body 
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weight (10%) and food consumption (7-8% during the final two week of the study) were seen in 

males at 500 mg/kg/day. These effects were slightly enhanced at the next highest dose (1000 

mg/kg/day); 12% decrease in body weight and 8-13% decrease in food consumption. The 

NOAEL of 100 mg/kg/day was selected as the POD for dermal risk assessments. 

The endpoint is appropriate for the route and duration of exposure as well as the population of 

concern. The occupational and residential LOC is a MOE of100 (includes UFA=10x and 

UFH=10x).

Inhalation (Short and Intermediate-term Endpoints for Occupational Exposure Scenarios:

In 2003 a request to waive the inhalation study for pronamide was granted based on use and 

exposure data available at the time. Since then, additional data on unit exposures and on 

pronamide usage have become available, however MOEs have not changed appreciably. 

Accordingly the waiver of the requirement to conduct an inhalation study remains in effect. The 

MOEs associated with occupational inhalation exposure all exceed 3,000.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

Since the same endpoint/study is selected for incidental oral and inhalation exposure scenarios, 

these routes can be combined. The dermal POD for pronamide is based on a study that measures

body weight decreases and decreased food consumption. No other effects were observed. 

Decreased body weight is also observed in most oral studies with pronamide, however the body 

weight effects in oral studies are associated with liver effects such as increased liver weights, 

hypertrophy and decreased T4 levels. 

In the dermal study with pronamide there was no effect at all on the liver, and no other systemic 

effects to suggest that meaningful dermal absorption had occurred, and in addition there were 

local effects at the sight of application that could have had an effect on food consumption and 

body weight. For these reasons, HED recommends that dermal exposure not be combined with 

any other route of exposure.

4.5.3 Cancer Classification and Risk Assessment Recommendation

In accordance with the Agency’s 2005 Guideline for Carcinogen Risk Assessment, pronamide is 

classified as “Not Likely to be Carcinogenic to Humans” at doses that do not result in 

induction of hepatic cell proliferation or metabolic enzymes leading to disruption of thyroid or 

gonadal endocrine axes (TXR 0057037). These decisions are based on the following 

considerations:

Pronamide induced liver tumors in male and female CD-1 mice and thyroid follicular tumors and 

testicular tumors in male Crl:CD rats. Mechanistic data to support the hypothesized MOAs were 

submitted for each tumor type and evaluated against the criteria established in the 2006 IPCS 

Human Relevance Framework. The MOAs were adequately supported by studies that clearly 
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identified the sequence of key events, dose-response concordance and temporal relationship to 

the particular tumor type. 

Quantification of carcinogenic risk is not required. The chronic Reference Dose (RfD) would be 

protective of non-carcinogenic and carcinogenic effects observed in the mouse and rat 

carcinogenicity study or MOA studies conducted at higher doses. 
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4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Pronamide for Use in Dietary and NonOccupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure 

(POD)

Uncertainty/ 

FQPA Safety 

Factors

RfD, PAD, Level 

of Concern for 

Risk Assessment Study and Toxicological Effects

Acute Dietary 

(All 

Populations)

LOAEL = 40

mg/kg/day

UFA=10X

UFH=10X

UFL= 10X

FQPA SF =1X

aRfD=aPAD=

0.04 mg/kg/day

Acute neurotoxicity in rat: NOAEL was 

not established; LOAEL = 40 mg/kg (the 

lowest dose tested) based on the increase 

in landing foot splay in female rats and the 

decrease in motor activity seen in both 

genders on Day 1.

Acute Dietary 

Females 13-

49 years of 

age

An endpoint attributable to a single exposure was not available in the database including the 

developmental toxicity studies in rats and rabbits.

Chronic Dietary 

(All 

Populations)

LOAEL = 40

mg/kg/day

UFA=10X

UFH=10X

UFL= 10X

FQPA SF =1X

cRfD=cPAD=

0.04 mg/kg/day

The POD of 40 mg/kg/day was selected based 

on a weight of evidence approach using the 

results from the 4 studies in rats listed below. 

Subchronic neurotoxicity (SCN): NOAEL of 

2.38 mg/kg/day is based on the significant 

decreases in body weight, body weight gain, 

and food consumption seen at 11.28 mg/kg/day 

(LOAEL) in males.

Acute neurotoxicity (ACN): NOAEL was not 

established. The LOAEL of 40 mg/kg/day with 

a 10X LOAEL to NOAEL uncertainty factor 

(UFL) yields a derived POD of 4 mg/kg/day 

(40÷10).

Combined chronic toxicity/ carcinogenicity

NOAEL of 8.46/10.69 mg/kg/day is based on 

increased relative liver weight and 

histopathological lesions in the liver, thyroid, 

and ovaries at 42.59/55.09 mg/kg/day 

(LOAEL).

Male pubertal study. NOAEL of 2.5 

mg/kg/day. The LOAEL is 10 mg/kg/day 

based on decreased serum T4.

Incidental 

Oral ShortTerm (1-30 

days)

LOAEL = 40

mg/kg/day

UFA=10X

UFH=10X

UFL= 10X

FQPA SF =1X

Residential LOC 

for MOE = 1000

See Chronic RfD
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Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Pronamide for Use in Dietary and NonOccupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure 

(POD)

Uncertainty/ 

FQPA Safety 

Factors

RfD, PAD, Level 

of Concern for 

Risk Assessment Study and Toxicological Effects

Dermal ShortTerm (1-30 

days) and 

IntermediateTerm (1-6 

months)

NOAEL= 

100 

mg/kg/day

UFA=10X

UFH=10X

FQPA SF=1X

Residential LOC 

for MOE = 100 

28-day dermal toxicity study in rat:

LOAEL = 500 mg/kg/day based on 

decreases in body weight and food 

consumption in males. No target organ 

(liver) toxicity was seen following 

repeated dermal dosing, and no effect in 

females.

Inhalation 

Short-Term 

(1-30 days) 

and 

IntermediateTerm (1-6 

months)

LOAEL = 40

mg/kg/day

UFA=10X

UFH=10X

UFL= 10X

FQPA SF =1X

Residential LOC 

for MOE = 1000

See chronic RfD.

Cancer (oral, 

dermal, 

inhalation)

Classification: “Not Likely to be Carcinogenic to Humans” at doses that do not result in induction 

of hepatic cell proliferation or metabolic enzymes leading to disruption of thyroid or gonadal 

endocrine axes.

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). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c 

= chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Pronamide for Use in Occupational 

Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment Study and Toxicological Effects

Dermal ShortTerm (1-30 

days) and 

IntermediateTerm (1-6 

months)

NOAEL= 

100 

mg/kg/day

UFA=10X

UFH=10X

Occupational 

LOC for MOE = 

100 

28-day dermal toxicity study in rat:

LOAEL = 500 mg/kg/day based on 

decreases in body weight and food 

consumption in males. No target organ 

(liver) toxicity was seen following 

repeated dermal dosing
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Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Pronamide for Use in Occupational 

Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment Study and Toxicological Effects

Inhalation 

Short-Term (1-

30 days) and 

IntermediateTerm (1-6 

months)

LOAEL = 40

mg/kg/day

UFA=10X

UFH=10X

UFL= 10X

Occupational 

LOC for MOE = 

1000

See chronic RfD.

Cancer (oral, 

dermal, 

inhalation)

Classification: “Not Likely to be Carcinogenic to Humans” at doses that do not result in 

induction of hepatic cell proliferation or metabolic enzymes leading to disruption of thyroid or 

gonadal endocrine axes.

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). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

data (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

4.6 Endocrine Disruption

As required by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal 

Food, Drug, and Cosmetic Act (FFDCA), EPA reviews numerous studies to assess potential 

adverse outcomes from exposure to chemicals. Collectively, these studies include acute, 

subchronic, and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, 

developmental, reproductive, and general or systemic toxicity. These studies include endpoints 

that may be susceptible to endocrine influence, including effects on endocrine target organ 

histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, 

reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates 

acute tests and chronic studies that assess growth, developmental and reproductive effects in 

different taxonomic groups. As part of its reregistration decision for pronamide, EPA reviewed 

these data and selected the most sensitive endpoints for relevant risk assessment scenarios from 

the existing hazard database. However, as required by FFDCA section 408(p), pronamide is 

subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 
Pronamide Human Health Risk Assessment DP No. D422207

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systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list 

of chemicals identified for EDSP screening was published on June 14, 20132and includes some 

pesticides scheduled for Registration Review and chemicals found in water. Neither of these 

lists should be construed as a list of known or likely endocrine disruptors.

Pronamide is on List 1 for which EPA has received all of the required Tier 1 assay data. The 

Agency has reviewed all of the assay data received for the appropriate List 1 chemicals and the 

conclusions of those reviews are available in the chemical-specific public dockets (see EPA-HQOPP-2009-0326 for propyzamide (pronamide)).

For further information on the status of the EDSP, the policies and procedures, the lists of 

chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our 

website.

3

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

Primary Crops: The qualitative nature of the residue in plants is adequately understood on 

alfalfa, lettuce and similar crops (D275536, 02/28/2002). Soil applied pronamide is readily 

absorbed through the root system, translocated upward, and distributed into the entire plant. 

Conversely translocation from leaf absorption is not appreciable. Metabolism occurs primarily 

via oxidation of the aliphatic half of the pronamide molecule followed by conjugation to 

(malonyl) glucose. The terminal residues in alfalfa and lettuce consist mainly of pronamide per 

se, glucose conjugates, and glucose-malonyl conjugates, all containing the intact 3,5-

dichlorobenzoyl moiety. 

 

2 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of 

chemicals.

3 http://www.epa.gov/endo/
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Pronamide 

No evidence of fragmentation of the benzene ring or loss of the chlorine substituents was 

observed. The terminal residues of concern are pronamide and its metabolites containing the 

3,5-dichlorobenzoyl moiety. 

Rotational Crops: The qualitative nature of the residue in rotational crops is adequately 

understood based on an acceptable confined rotational crop study (MRID 41462001 and 

41913506). In this study, uniformly ring labeled [14C]pronamide was applied at a rate of 4.0 lb 

ai/A to bare ground plots, and crops were planted in the treated areas after 30 days, 6 months, 

and 1 year. The subplots representing each plantback interval (PBI) were allowed to remain 

fallow until such time that lettuce (a leafy vegetable), carrots (a root crop), and wheat (a small 

grain) were planted. The terminal residues of concern in rotated crops following treatment of 

primary crops with pronamide consist of the parent pronamide and its metabolites bearing the 

3,5-dichlorobenzoyl moiety. 

Livestock: The qualitative nature of the residue in livestock is adequately understood (D275536, 

02/28/2002). Studies involving lactating goats and laying hens indicate that the primary route of 

elimination is by excretion (urine and feces). Minimal residues were distributed to goat and 

poultry muscle. The major metabolites in the eggs, liver, and fat of poultry are pronamide and 

3,5-dichlorobenzoic acid. The major metabolites in the milk, fat, muscle, and liver of goats are 

pronamide, 3,5-dichlorobenzoic acid, and compounds containing the 3,5-dichlorobenzoyl 

moiety. The metabolic pathway involves modification of the aliphatic portion of pronamide. 

The terminal residues of concern in livestock commodities are pronamide and its metabolites 

containing the 3,5-dichlorobenzoyl moiety.

The residues of concern for pronamide are summarized in Table 5.3.

Table 5.3. Summary of Pronamide Metabolites and Degradates to be included in the Risk Assessment and 

Tolerance Expression

Matrix Residues included in Risk 

Assessment

Residues included in 

Tolerance Expression

Plants Primary Crop

pronamide and its metabolites 

containing the 3,5-

dichlorobenzoyl moiety

pronamide and its metabolites 

containing the 3,5-

dichlorobenzoyl moiety

Rotational Crop

Livestock Ruminant

Poultry

Drinking Water Not Applicable

Conclusions. For purposes of Registration Review, no additional plant metabolism studies are 

required; however, because the available metabolism studies were conducted only on alfalfa and 
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lettuce, HED may request additional metabolism studies in the future should the petitioner seek 

for additional uses on other crop groups.

5.1.2 Summary of Environmental Degradation

The major routes of degradation of pronamide appear to be aerobic microbial degradation in soil

and photolysis in water. Four major degradates of pronamide have been identified with a maximum

applied radioactivity of 31.9%, 27.3%, 32.2%, and 15.0%, respectively. 

 

 RH-24644 RH-24655 RH-24580 RH-26059 

HED determined that all degradates of pronamide that contain the 3,5-dichlorobenzoyl moiety are

of risk concern, assuming that their toxicity is similar to that of pronamide parent (USEPA, 2002). 

A total toxic residues (TTR) approach was therefore used to generate EDWCs that reflect residues,

in drinking water, of the parent compound plus all such degradates of concern.

Pronamide has relatively low vapor pressure (8.5x10-5torr) and is soluble in water up to 15 mg/L. 

The compound is stable to hydrolysis, relatively resistant to soil photolysis and moderately 

susceptible to aquatic photolysis. Pronamide degrades relatively readily in aerobic soil 

environments, but is more persistent in anaerobic environments and aquatic environments. 

Sorption to soils is a function of organic carbon and also correlates with cation exchange capacity. 

Nonetheless the compound is mobile in soil, and thus presents a potential groundwater concern in 

some areas, e.g., those with sandy soils and high water tables. Pronamide has been detected in both 

surface water and groundwater.

EDWCs based on total toxic residues for pronamide likely exceed actual concentrations in most 

drinking water supplies due to the conservative nature of the exposure models, use of national

PCA (1.0), and limited acceptable environmental fate data. 

5.1.3 Comparison of Metabolic Pathways

There is a common theme to pronamide metabolism whether in primary crops, rotational crops, 

livestock or rats. The 3,5-dichlorobenzoic acid moiety of pronamide is not altered whereas the 

aliphatic hydrocarbon moiety is extensively oxidized followed by conjugation of the oxidized 

fragments. In plants, glucose and malonyl conjugates are formed, whereas in livestock and rats, 

conjugates have not been identified.

Cl

Cl

N

O

Cl

Cl

N

O

Cl

Cl

N

O O

Cl

Cl

N

O

O

O
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The terminal residues of concern in plants and livestock commodities, and in drinking water, are 

pronamide and its metabolites containing the 3,5-dichlorobenzoyl moiety.

5.1.4 Residues of Concern Summary and Rationale

The residues of concern in agricultural commodities, livestock and drinking water from use of 

pronamide consist of all residues convertible to 3,5-dichlorobenzoic acid. All such residues are 

assumed to be equipotent to parent pronamide based on the similarity of structure to the parent 

compound, pronamide.

5.2 Food Residue Profile

Tolerances are established in the 40 CFR § 180.317 for the use of pronamide on alfalfa, apple, 

artichoke, berries, endive, stone fruits, grape, head lettuce, pear, radicchio, field pea, and 

rhubarb. In addition, tolerances are established for livestock commodities, and several feed 

commodities. Generally, residues below 0.4 ppm are expected in most food commodities with 

the exception of head lettuce (1.0 ppm), endive (1.0 ppm) and radicchio (2.0 ppm). A tolerance 

of 1 ppm is recommended to support a proposed new use on leaf lettuce. This tolerance is 

supported by adequate residue data. Interim tolerances of 0.10 ppm, 1.5 ppm and 3.0 ppm are 

recommended for field pea seed, vines and hay, respectively. Additional crop field trial data is 

required to support the use on field pea. Adequate rotational crop field trials are available to 

support the use of pronamide. Label modifications recommended in Section 3.3 need to be 

addressed. 

5.3 Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by the 

Environmental Fate and Effects Division (EFED) in the following memorandum: “Propyzamide 

(Pronamide): Tier II Drinking Water Exposure Assessment in support of the Proposed Use of 

Propyzamide on Leaf Lettuce” (D414467, K. Milians, 04/21/2015) and incorporated directly into 

this dietary assessment. Water residues were incorporated in the DEEM-FCID into the food 

categories “water, direct, all sources” and “water, indirect, all sources.” 

Besides modeling the use of leaf lettuce, EFED modeled the use of artichoke because this use 

allows the maximum application rate (for any crop) of 8 lbs a.i./acre (i.e., 4 lbs a.i./acre x 2 

assumed applications/yr). Table 5.3 shows the estimated drinking water concentrations in surface 

water and ground water (including values using Sci-Grow and PRZM-GW for ground water). 

Surface water EDWCs based on total toxic residues and maximum annual application rates were 

highest for leaf lettuce (102, 47.0 and 33.6 ppb, for peak concentration and chronic values, 

respectively). The EDWCs recommended by EFED are 102 ppb for the acute dietary assessment 

and 47.0 ppb for the chronic and cancer dietary assessments.

Table 5.3. Tier II Total Residue of Concern EDWCs in Surface Water and Ground Water from Propyzamide 

Uses on New Uses (Maximum EDWCs in Bold).
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Drinking Water Source (Model, 

Use, Modeled rate) Scenario

EDWCs

Acute (μg/L) Chronic (μg/L) Cancer (μg/L)

Surface Water (SWCC, Artichokes,

4 lb a.i./A x 2 applic.; total of 8 

lb/A/yr)

CA row crop 

RLF (aerial 

application)

61.4 33.4 26.0

Surface Water (SWCC, Leaf 

Lettuce, 2 lb a.i./A x 2 applic.; total 

of 4 lb/A/yr)

CA lettuce 

(aerial 

application)

102 47.0 33.6

Ground Water (PRZM-GW, 

Artichokes, 

4 lb a.i./A x 2 applic.; total of 4 

lb/A/yr)

WI sands 21 18.6 18.6

Ground Water (SCI-GROW, 

Artichokes,

4 lb a.i./A x 2 applic.; total of 8 

lb/A/yr)

N/A 0.802 0.802 0.802

Ground Water (SCI-GROW, Leaf 

Lettuce, 2 lb a.i./A x 2 applic.; total 

of 4 lb/A/yr)

N/A 0.401 0.401 0.401

N/A= Not Applicable 

Values in bold show the EDWCs recommended for HED’s acute (102 ppb) and chronic (47.0 ppb) and cancer (33.6 

ppb) dietary risk assessment as they are considered protective of all the registered uses of pronamide.
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5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Unrefined acute and chronic dietary assessments were performed. Tolerance level residues of 

pronamide (residues convertible to methyl 3,5-dichlorobenzoate) were used for the registered 

uses and proposed new use on leaf lettuce. Default processing factors and 100% of crop treated 

(CT) assumptions were incorporated. Drinking water was incorporated directly in the dietary 

assessment using the Tier II acute and chronic estimated drinking water concentration (EDWC) 

for surface water generated by the Surface Water Concentration Calculator (SWCC).

The EDWCs reported here are based on artichoke (CA) and leaf lettuce uses and represent the

most conservative (highest) EDWCs for surface and groundwater, which are recommended for

use in HED’s dietary assessment. The leaf lettuce use generated the highest surface water and 

groundwater EDWCs. The total toxic residues of pronamide include pronamide parent and all 

degradates with the 3,5-dichlorobenzoyl moiety, which are assumed to have toxicity similar to 

that of pronamide parent. The recommended estimated drinking water concentrations (EDWCs) 

for the dietary assessment is 102 ppb for the acute dietary assessment and 47.0 ppb for chronic 

and cancer dietary assessments.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The acute and chronic assessments were performed by assuming that 100% of the crop was 

treated for all food commodities. 

5.4.3 Acute Dietary Risk Assessment

The resulting acute dietary exposure estimates using the DEEM-FCIDTM model were less than 

100% of the acute population adjusted dose (aPAD) at the 95th percentile of exposure for the 

general U.S. population and all population subgroups. Pronamide acute dietary exposure (food + 

drinking water) was estimated at 0.007144 mg/kg/day for the general U.S. population (18% of 

the aPAD) and 0.018539 mg/kg/day (46% of the aPAD) for the most highly exposed population 

subgroup (All Infants < 1 year old). The results per user and per capita are similar.

5.4.4 Chronic Dietary Risk Assessment

The resulting chronic dietary exposure estimates using the DEEM-FCIDTM model were less than 

100% of the chronic population adjusted dose (cPAD) for the general U.S. population and all 

population subgroups. Pronamide chronic dietary exposure (food + drinking water) was 

estimated at 0.001706 mg/kg/day for the general U.S. population (4.3% of the cPAD) and 

0.004410 mg/kg/day (11 % of the cPAD) for the most highly exposed population subgroup 

(Children 1-2 years old).
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5.4.5 Cancer Dietary Risk Assessment

Pronamide was classified as "Not Likely to be Carcinogenic to Humans" at doses that do not 

result in induction of hepatic cell proliferation or metabolic enzymes leading to disruption of 

thyroid or gonadal endocrine axes; therefore, a cancer risk assessment is not needed.

5.4.6 Summary Table

As stated previously, for acute and chronic assessments, HED is concerned when dietary risk 

exceeds 100% of the PAD. The DEEM-FCID analyses estimate the dietary exposure of the U.S. 

population and various population subgroups. The results reported in Table 4 are for the general 

U.S. Population, all infants (<1 year old), children 1-2, children 3-5, children 6-12, youth 13-19, 

females 13-49, adults 20-49, and adults 50-99 years.

Table 4. Summary of Dietary (Food and Drinking Water) Exposure and Risk for 

Pronamide.

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary

Dietary Exposure 

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

General U.S. Population 0.007144 18 0.001706 4.3

All Infants (<1 year old) 0.018539 46 0.003854 9.6

Children 1-2 years old 0.013317 33 0.004410 11

Children 3-5 years old 0.010013 25 0.003083 7.7

Children 6-12 years old 0.006963 17 0.001804 4.5

Youth 13-19 years old 0.005480 14 0.001241 3.1

Adults 20-49 years old 0.006570 16 0.001534 3.8

Adults 50-99 years old 0.005893 15 0.001526 3.8

Females 13-49 years old 0.006753 17 0.001558 3.9
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6.0 Residential (Non-Occupational) Exposure/Risk Characterization

The proposed use on leaf lettuce is not expected to result in residential exposure. In this 

assessment pronamide is assessed for the currently registered residential uses on turf grass and 

golf courses using the 2012 Residential SOPs. Residential post-application scenarios were 

assessed at a maximum application rate of 1.44 lb ai/A for liquid and 1.5 lb ai/A for wettable 

powder in Water Soluble Package (WSP) formulations. There were no residential risk estimates 

of concern identified.

6.1 Residential Handler Exposure

Residential handler exposures are not expected as pronamide is a Restricted Use Pesticide and as 

such can only be applied by Certified Applicator. 

6.2 Post-Application Exposure

There is the potential for post-application exposure for individuals exposed as a result of being in 

an environment that has been previously treated with pronamide. The quantitative exposure/risk 

assessment for residential post-application exposures is based on the following scenarios: 

 Physical activities on turf: adults (dermal) and children 1 to < 2 years old (dermal and 

incidental oral);

 Mowing: adults (dermal) and children 11 to < 16 years old (dermal); and

 Golfing: adults (dermal), children 11 to < 16 years old (dermal), and children 6 to< 11 

years old (dermal).

The lifestages selected for each post-application scenario are based on an analysis provided as an 

Appendix in the 2012 Residential SOPs4. While not the only lifestage potentially exposed for 

these post-application scenarios, the lifestage that is included in the quantitative assessment is 

health protective for the exposures and risk estimates for any other potentially exposed lifestage.

Residential Post-application Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the residential 

post-application risk assessment. Each assumption and factor is detailed in the 2012 Residential 

SOPs4.

Application Rate: The application rates used in this assessment are provided in Table 4.1. 

Exposure Duration: Residential post-application exposure is expected to be short-term in 

duration. While multiple applications may be possible, it is anticipated that these applications 

will be intermittent in nature and dissipation due to rainfall/irrigation, grass growth, and grass 

mowing is expected. There is the potential for intermediate-term exposure to pronamide, 

 

4 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
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however, since the maximum yearly application rate is the same as the maximum single 

application rate, the short-term assessment is protective of intermediate-term soil ingestion 

exposure. 

TTR Data: The parameters for estimation of post-application risk are based on a regression 

analysis of chemical specific TTR data in MRID 44952501 “Turf Transferrable Residues for 

Pronamide Applied to Turf” (D422661; September 20, 2015).

Combining Exposures/Risk Estimates

Dermal and incidental oral (hand-to-mouth) risk estimates were not combined in this assessment

because the dermal and oral endpoints are not based on the same effect.

Combining Incidental Oral Exposure and Risk Estimates

The incidental oral scenarios (i.e., hand-to-mouth and object-to-mouth) should be considered 

inter-related and it is likely that they occur interspersed amongst each other across time. 

Combining these scenarios would be overly-conservative because of the conservative nature of 

each individual assessment. Therefore, these scenarios have not been combined.

Summary of Residential Post-application Non-Cancer Exposure and Risk Estimates

Table 6.2.1 provides a summary of the residential post-application exposures and risk estimates 

for pronamide. All dermal and incidental oral risk estimates for post-application exposure are 

not of concern (i.e., MOEs ≥ 100 for dermal estimates and ≥1000 for incidental oral estimates).

Table 6.2.1. Short-Term Residential Post-application Exposure and Risk Estimates for Pronamide

Lifestage Post-application Exposure Scenario Dose (mg/kg/day)1 MOEs2 Combined 

MOEs

Liquid formulation and wettable powder(WSP)**

Adult

Turf

Liquid 

formulation

1.5 lb ai/A

Dermal

Physical Activities on Turf 0.50 200

N/A

Mowing 0.01 9,800

Golfing 0.039 2,500

Child 11 to < 16 

years old Dermal Mowing 0.012 8,600

Golfing 0.046 2,200

Child 6 to < 11 

years old Dermal Golfing 0.054 1,900

Child 1 to < 2 

year old

Dermal Physical Activities on Turf 0.99 100

Hand to Mouth 0.020 2000

Object to Mouth 0.00062 65,000

Short- and Intermediate-term Incidental Soil 

Ingestion 0.000051 790,000

1 Dose (mg/kg/day) equations provided in Appendix [A].

2 MOE = POD (Dermal = 100 mg/kg/day and Incidental oral = 40 mg/kg/day LOAEL from ACN) ÷ Dose (mg/kg/day). LOC = 100 for 

dermal and 1000 for incidental oral exposure.

6.3 Residential Bystander Post-Application Inhalation Exposure

Volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby pesticide applications. The Agency sought expert advice and input on issues 
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related to volatilization of pesticides from its FIFRA Scientific Advisory Panel (SAP) in 

December 2009, and received the SAP’s final report on March 2, 2010.5 The Agency has 

evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent 

Volatilization Screening Analysis.6 During Registration Review, the Agency will utilize this 

analysis to determine if data (i.e., flux studies) or further analyses are required for pronamide.

6.4 Residential Risk Estimates for Use in Aggregate Assessment 

Table 6.4.1 reflects the residential risk estimates that are recommended for use in the aggregate 

assessment for pronamide

 The only residential scenario appropriate for aggregation is for children 1 to <2 years old 

short-term exposure associated with hand/object to mouth exposure from post-application 

exposure to turf .

Table 6.4.1. Recommendations for the Residential Exposures for the Pronamide Aggregate Assessment.

Lifestage Exposure Scenario

Dose (mg/kg/day) MOE

Dermal Inhalation Oral Dermal Inhalation Oral

Short-term

Child to 1 < 2 year old

Post-application exposure 

from activities on turf (liquid 

formulation) 

NA NA 0.020 NA NA 2000

6.5 Spray Drift

Off-target movement of pesticides can occur via many types of pathways and it is governed by a 

variety of factors. Sprays that are released and do not deposit in the application area end up offtarget and can lead to exposures to those it may directly contact. They can also deposit on 

surfaces where contact with residues can eventually lead to exposures (e.g., children playing on 

lawns where residues have deposited next to treated fields). The potential risk estimates from 

these residues can be calculated using drift modeling coupled with methods employed for 

residential risk assessments for turf products.

A quantitative spray drift assessment for pronamide is not required because the maximum 

application rate for a crop/target site (4 lb ai/A) multiplied by the adjustment factor for drift of 

0.26 is less than the maximum direct spray residential turf application rate (also 4 lb ai/A)7for 

any pronamide products. The turf post-application MOEs are protective for any potential 

exposures related to spray drift for pronamide and have previously been discussed in Section 6.2. 

 

7.0 Aggregate Exposure/Risk Characterization

 

5 http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

6 http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219

7 4.0 lb ai/A x 0.26 ≤ 4.0 lb ai/A
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In accordance with FQPA, HED must consider and aggregate (add) pesticide exposures and risks 

from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure.

For pronamide acute and chronic aggregate exposures are the same as dietary exposures that 

include food and drinking water. Oral and dermal exposure estimates were not combined in this 

assessment since the toxicological effects for these exposure routes were not the same. 

7.2 Short-Term Aggregate Risk

The only scenario to be aggregated is children’s short-term hand-to-mouth exposure following 

application of pronamide to turf. The short-term exposure is aggregated with the average 

chronic dietary exposure for children (1 to 2 years old from Table 4)

Table 7.2 Short-Term Aggregate Risk Calculations

Population

Short-Term Scenario

LOAEL 

mg/kg/day LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day

Residential 

Exposure 

mg/kg/day3

Total 

Exposure 

mg/kg/day4

Aggregate 

MOE (food, 

water, and 

residential)5

Child 40 1000 0.04 0.004410 0.02 0.024 1700

1 Based on a POD of 40 mg/kg from the LOAEL of an ACN study. The traditional inter- and intraspecies factors are 

applied as well as a UFL of 10 for a total LOC of 1000.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = Oral exposure (hand-to-mouth) - Table 5.3.1.

4 Total Exposure = Average Food & Water Exposure + Residential Exposure

5 Aggregate MOE = NOAEL / (Average Food & Water Exposure + Residential Exposure)

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 pronamide and any other substances and pronamide 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 pronamide 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/.
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9.0 Occupational Exposure/Risk Characterization

The most recent exposure assessment for pronamide was conducted in 2007 (M. Dow, 

D329436). At the maximum rate of 4 lb ai/A identified for most agricultural crops, including the 

proposed use on leaf lettuce, there were no occupational handler risks of concern. 

Based on review of currently registered pronamide labels, uses on Christmas tree farms and 

landscape ornamentals were not covered by the previous assessment. These use patterns have

been assessed in this document to complete the Registration Review for pronamide. Updated 

risk estimate tables have also been included for occupational handlers for all registered uses 

since the inhalation point of departure and LOC for pronamide have changed since the previous 

assessment.

Based on the Agency's current practices, a quantitative non-cancer occupational post-application 

inhalation exposure assessment was not performed for pronamide at this time. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for pronamide

9.1 Occupational Handler Exposure/Risk Estimates

The quantitative exposure/risk assessment developed for occupational handlers is based on the 

following scenarios which covers all the registered and proposed uses of pronamide: 

 Mixing/loading liquids to support aerial applications,

 Mixing/loading liquids to support chemigation applications,

 Mixing/loading liquids to support groundboom applications, 

 Mixing/loading wettable powder in Water Soluble Package (WSP) to support aerial 

applications,

 Mixing/loading wettable powder in Water Soluble Package (WSP) to support 

chemigation applications,

 Mixing/loading wettable powder in Water Soluble Package (WSP) to support 

groundboom applications,

 Mixing/loading wettable powder in Water Soluble Package (WSP) for groundboom 

applications,

 Applying sprays with aircraft,

 Applying sprays with groundboom equipment,

 Mixing/loading/applying wettable powder in Water Soluble Package (WSP) or liquids 

via backpack,

 Mixing/loading/applying wettable powder in Water Soluble Package (WSP) or liquids 

via mechanically-pressurized handgun, and
Pronamide Human Health Risk Assessment DP No. D422207

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 Mixing/loading/applying wettable powder in Water Soluble Package (WSP), or liquids 

via manually-pressurized hand wand



Occupational Handler Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational 

handler risk assessments. Each assumption and factor is detailed below on an individual basis.

Application Rate: The application rates used in this assessment are provided in Appendix E. For 

similar crop/application method scenarios, the highest application rate was assessed assuming 

this would be protective of lower application rates. 

Unit Exposures: The standard values recommended for use in predicting handler exposure that 

are used in this assessment, known as “unit exposures”, are outlined in the “Occupational 

Pesticide Handler Unit Exposure Surrogate Reference Table8”, which, along with additional 

information on HED policy on use of surrogate data, including descriptions of the various 

sources, can be found at the Agency website9. 

Area Treated or Amount Handled: The inputs for area treated were primarily based on 

information in Expo SAC Policy 9.1. 

 

Exposure Duration: 

For the proposed use pattern, short- and intermediate-term exposures are anticipated for the 

following reasons: (1) up to two applications can be made 60 days apart; and (2) commercial 

applicators may apply this product at various locations within a region over a period of weeks. 

The same exposure durations are anticipated for all registered pronamide uses, and it should be 

noted that the short- and intermediate-term PODs are the same; therefore, short-term risk 

estimates are protective of longer-term exposures.

Mitigation/Personal Protective Equipment: Estimates of dermal and inhalation exposure were 

calculated for various levels of personal protective equipment (PPE). Results are presented for 

“baseline,” defined as a single layer of clothing consisting of a long sleeved shirt, long pants, 

shoes plus socks, no protective gloves, and no respirator, as well as baseline with various levels 

of PPE as necessary (e.g., gloves, respirator, etc). All of the pronamide registered labels require 

handlers to wear a double layer of clothing (long sleeved shirt and long pants) with either 

waterproof or chemical-resistant gloves.

Combining Exposures/Risk Estimates

Dermal and inhalation risk estimates were not combined in this assessment, since the 

toxicological effects for these exposure routes were not the same.

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates

 

8 Available: http://www.epa.gov/opp00001/science/handler-exposure-table.pdf

9 Available: http://www.epa.gov/pesticides/science/handler-exposure-data.html
Pronamide Human Health Risk Assessment DP No. D422207

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The occupational handler exposure and risk estimates indicate that the short- and intermediateterm dermal and inhalation MOEs are not of concern to HED (i.e., MOEs > 100 for dermal and 

>1000 for inhalation) for the wettable powder formulation (WSP). For the liquid formulation, the 

short- and intermediate-term dermal and inhalation MOEs are not of concern to HED (i.e., 

MOEs > 100 for dermal and >1000 inhalation, as long as double layer and gloves are worn for 

aerial application to high-acreage crops).

HED has no data to assess exposures to pilots using open cockpits. The only data available is for 

exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the 

engineering control (enclosed cockpits) and baseline attire (long-sleeve shirt, long pants, shoes, 

and socks); per the Agency’s Worker Protection Standard stipulations for engineering controls, 

pilots are not required to wear protective gloves for the duration of the application. With this 

level of protection, there are no risk estimates of concern for applicators.

Flaggers. HED has assessed the exposure potential to human flaggers. The Agency is mindful 

that the use of human flaggers has declined sharply in recent years and will continue to monitor 

all available information sources to best assess and characterize the exposure potential for human 

flaggers in agricultural aerial applications.

(See Appendix E for detailed occupational handler exposures.)

9.2 Occupational Post-application Exposure/Risk Estimates

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). The majority of pronamide usage occurs preemergence or when the plants are 

dormant. The only crop with post-application activities is lettuce.

9.2.1 Occupational Post-application Inhalation Exposure/Risk Estimates

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed for pronamide, an inhalation exposure assessment was performed for 

occupational/commercial handlers. Exposure resulting from application of pesticides outdoors is 

likely to result in higher inhalation exposure than post-application exposure. Since no inhalation 

risks were identified for handlers of pronamide end use products, the handler inhalation exposure 

estimates are considered protective of most occupational post-application inhalation exposure 

scenarios.

9.2.2 Occupational Post-application Dermal Exposure/Risk Estimates

Most of the registered uses (with exception of lettuce), for pronamide are soil-directed preplant 

or pre-emergent uses where no crop foliage is present. In general, such exposures are considered 

to be negligible and therefore were not assessed. 
Pronamide Human Health Risk Assessment DP No. D422207

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The registered and proposed uses lettuce, turf (golf courses and sod farms) and nursery crops 

(ornamentals, and non-bearing plants)are not specifically soil-directed and, therefore, could 

result in potential post-application exposures. These exposures have been assessed in this risk 

assessment.

Occupational Post-application Dermal Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational 

post-application risk assessments. Each assumption and factor is detailed below on an individual 

basis. 

Exposure Duration: For the proposed pronamide use pattern, short- and intermediate-term 

exposures are anticipated for the following reasons: (1) up to two applications can be made 60 

days apart; and (2) commercial applicators may apply this product at various locations within a 

region over a period of weeks. The same exposure durations are anticipated for all registered 

pronamide uses, and it should be noted that the short- and intermediate-term PODs are the same; 

therefore, short-term risk estimates are protective of longer-term exposures.

Transfer Coefficients: Sources of generic post-application data, used as surrogate data in the 

absence of chemical-specific data, are derived from Agricultural Reentry Task Force, L.L.C.

(ARTF) exposure monitoring studies, and, as proprietary data, are subject to the data protection 

provisions of FIFRA. The standard values recommended for use in predicting post-application 

exposure that are used in this assessment, known as “transfer coefficients”, are presented in the 

ExpoSAC Policy 310” which, along with additional information about the ARTF data, can be 

found at the Agency website11. 

Table 9.2.2.1. Summary of Post-Application Activities and Dermal Transfer Coefficients.

Crop Policy Crop 

Group Category

Crop 

Height

Foliage 

Density

Transfer 

Coefficients 

(cm2/hr)

Activities

Landscape 

ornamentals 

(Container, Field 

grown Ornamental 

plantings)

Nursery Crop 

(Ornamentals, 

Non-bearing 

Plants)

Low Min

230

Grafting, Propagating, Transplanting

Low Full

Hand Harvesting, Hand Pruning, Scouting, 

Hand Weeding, Transplanting, Pinching, 

Tying/Training

High Min Hand Harvesting, Hand Pruning, 

Transplanting

High Full

Hand Harvesting, Hand Pruning, Scouting, 

Container Moving, Hand Weeding, 

Transplanting, Pinching

Low/High Full 1,900 Handset Irrigation

Golf Courses

Turf/Sod

Low Full 2,500 Maintenance, greens only

3,700 Maintenance

Sod Low Full 6,700 Maintenance, Slab Harvesting, 

Transplanting/Planting

Lettuce 4 Low Full 1,900 Handset Irrigation

 

10 Available: http://www.epa.gov/pesticides/science/exposac_policy3.pdf

11 Available: http://www.epa.gov/pesticides/science/post-app-exposure-data.html
Pronamide Human Health Risk Assessment DP No. D422207

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Application Rate: The application rates used in this assessment are provided in Appendix E. 

Exposure Time: The average occupational workday is assumed to be 8 hours. 

Dislodgeable Foliar Residue (DFR): In accordance with the updated Part 158 data requirements 

(2007), one or more DFR studies are required when a pesticide has residential or occupational 

uses that could result in post-application dermal exposure. As part of the recent revision to the 

Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide 

Exposure Assessment, HED analyzed a number of DFR studies and selected a new default value 

for the fraction of the application rate available to be dislodged after a foliar application (FAR). 

This default value is 25% and is based on an analysis of 19 DFR studies where the FAR value 

ranged from 2% to 89%. This value is recommended for use in both residential and occupational 

post-application assessments. Of the analyzed DFR studies, the maximum FAR value seen was 

89% or 3.6 times higher than the default residue transfer value. Therefore, HED has decided that 

a calculated MOE of approximately 2 times higher than the LOC (e.g., an MOE > 200 if the 

LOC =100) using the default dislodged residue values would provide an adequate margin of 

safety for any potentially higher residues seen in a chemical-specific DFR study (Guidance for 

Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) 

Studies. 12/12/2012, Exposure Science Advisory Council). 

Since the highest estimated occupational post-application exposure using default DFR values for 

pronamide is not minimal in comparison to the level of concern (i.e., the calculated MOE is not 

greater than 2 times higher than the level of concern, MOE = 100 on day 1 compared to the LOC 

of 100; EPA is requiring the 40CFR DFR data. Therefore, EPA is requiring the 40CFR DFR 

data requirement to facilitate any necessary exposure assessments refinements and to further 

EPA’s general understanding of the availability of dislodgeable foliar pesticide residues. 

Occupational Post-application Non-Cancer Dermal Exposure and Risk Estimate Equations

The algorithms used to estimate non-cancer exposure and dose for occupational post-application 

workers can be found in Tadayon, DXXXXXX .

Occupational Post-application Non-Cancer Dermal Risk Estimates

The short- and intermediate-term post-application exposure scenarios associated with the 

registered uses of pronamide are summarized in Table 9.2.2.2. All scenarios resulted in adequate 

MOEs at or greater than the LOC of 100 (ranging from 100 to 2,600) on day 1 (24 hours after 

application); and, therefore, are not of concern to HED.
Pronamide Human Health Risk Assessment DP No. D422207

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Table 9.2.2.2. Occupational Post-application Non-Cancer Exposure and Risk Estimates for Pronamide

Crop/Site Activities

Transfer 

Coefficient 

(cm2/hr)

Application

Rate (lb ai/A)

DFR or

TTR 1

Dermal Dose

(mg/kg/day)2

MOE3

(LOC = 100)

Short- and Intermediate-term

Landscape 

ornamentals 

(Container, Field 

grown 

Ornamental 

plantings)

Hand Harvesting, Hand Pruning, 

Transplanting, Hand Harvesting, Hand 

Pruning, Scouting, Container Moving, 

Hand Weeding, Transplanting, 

Pinching

230

2

5.61 0.129 780

Handset Irrigation 1,900 1.066 94 (day0)

5.05 0.959 100 (day1)

Golf Courses Maintenance, greens only 2,500

1.5 0.148

0.038 2600

Maintenance 3,700 0.055 1800

Sod Maintenance, Slab Harvesting, 

Transplanting/Planting 6,700 0.099 1,000

Lettuce Handset Irrigation 1900 2

5.61 1.066 94 (day0)

5.05 0.959 100 (day1)

1 DFR = Application Rate × F × (1-D)t × 4.54E8 μg/lb × 2.47E-8 acre/cm2; where F = 0.25 and D = 0.10 per day. 

TTR= obtained from pronamide TTR study MRID # 449525-01

2 Daily Dermal Dose = [DFR (μg/cm2) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day]  BW (80 kg).

3 MOE = POD (100 mg/kg/day) / Daily Dermal Dose. 

Restricted Entry Interval. Based on the quantitative post-application assessment, the labeled 

REI of 24 hours is required to protect workers from exposures to pronamide 

10.0 References

Internal memos

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Committee (MTARC) Evaluation of the Available Mechanistic Information for the Active 

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Pronamide (Propyzamide). Human Health Assessment Scoping Document in Support of 

Registration Review. D363904, June 17, 2009

Pronamide (Propyzamide): Report of the Cancer Assessment Review Committee: December 2, 

2014; TXR 0057037.

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2014: Recommendations on Data Requirement for a Developmental Toxicity Rat Study: TXR 

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Pronamide: Summary of Hazard and Science Policy Council (HASPOC) Meeting of November 

5, 2015: Recommendations on the Need for Comparative Thyroid Toxicity Study; TXR 

0057211.

Pronamide (Propyzamide). Petition for the Establishment of Permanent Tolerances and 

Registration for Use on Leaf Lettuce. Summary of Analytical Chemistry and Residue Data.; DP 

Barcode: 424598; 01/15/2015.

Pronamide. Comparative Thyroid Assay Waiver Request; February 25, 2015, TXR#0057124.

Propyzamide (Pronamide): Tier II Drinking Water Exposure Assessment in support of the

Proposed Use of Propyzamide on Leaf Lettuce; DP Barcode: 414467; April 21, 2015.

BEAD Review of Pronamide (101701) Use Summary Table Submitted by Dow Agrosciences, 

DP Barcode: 425407, 05/20/2015.

Pronamide. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and 

Risk Assessment in Support of Registration Review and the Section (3) Registration Action for 

Leaf Lettuce. DP Barcode: 427082; 09/16/2015.

Pronamide (Propyzamide). Summary of Analytical Chemistry and Residue Data to Support 

Registration Review; DP Barcode: 427081; 09/17/2015.

Pronamide. IR-4’s Response to Pronamide RED/TRED Data Requirements. Summary of 

Analytical and Residue Chemistry Data for Dried Winter Pea Commodities; DP Barcode: 

383372; 09/17/2015.

Pronamide (Propyzamide). Occupational and Residential Exposure Assessment for the 

Registration Review Draft Risk Assessment and to Support the Section 3 Proposed Use on Leaf 

Lettuce. DP Barcode: D422661; September 20, 2015.

MRIDs

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Philadelphia, Pa.; CDL:233726-C)

MRID 00085505. Powers, M.B. (1966) Acute Oral Administration--Rats; Acute Eye Irritation--

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MRID 00085506. Larson, P.S.; Borzelleca, J.F. (1967) Toxicologic Study on the Effect of 

Adding RH-315 to the Diet of Rats for a Period of Three Months. (Unpublished study received 

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MRID 00148065. Costlow, R.; Kane, W. (1985) Teratology Study with Kerb Technical (No inert 

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MRID 41462001. Nelson, S.; NIcholls, R. (1990) Confined Rotation Crop Study for Carbon 14 

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Report Final: Lab Project Number: 94P-179: 94R-179. Unpublished study prepared by Rohm 

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MRID 46885701. Yano, B.; Dryzga, M. (2005) Pronamide Technical: 28-Day Dermal Toxicity 

Study in F344/DuCrl Rats. Project Number: 051127. Unpublished study prepared by Dow 

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Male CD-1 Mice: Final Report. Project Number: WIL/410031, 100086. Unpublished study 

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F344/DuCrl Rats. Project Number: 101164. Unpublished study prepared by The Dow Chemical 

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Probe Study in F344/DuCrl Rats. Project Number: 101180. Unpublished study prepared by The 

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Subchronic Neurotoxicity Study in F344/DuCrl Rats. Project Number: 111003. Unpublished 

study prepared by The Dow Chemical Co. 577p.

MRID 48673402. Marty, M.; Zablotny, C.; Stebbins, K. (2012) Pronamide: Pubertal 

Development and Thyroid Function In Intact Juvenile/Peripubertal Female Crl:CD(SD) Rats. 

Project Number: 111080/OCR WIL/410051. Unpublished study prepared by The Dow Chemical 

Co. 224 p. Relates to L0001472.

MRID 48688001. Marty, M.; Andrus, A.; Thomas, J. (2012) Pubertal Development and Thyroid 

Function In Intact Juvenile Peripubertal Male Crl:CD(SD) Rats: Pronamide. Project Number: 

111081, 10001909, 111081A. Unpublished study prepared by The Dow Chemical Company. 

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Leydig Cell Tumor Mode of Action Study in Aged Crl:CD(SD) Rats. Project Number: 111057 

WIL/410065, 368/010. Unpublished study prepared by Dow Chemical Co., The. 450p.
Pronamide Human Health Risk Assessment DP No. D422207

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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food uses of pronamide are in Table 1. Use of the new guideline numbers 

does not imply that the new (1998) guideline protocols were used.

Study

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 (rodent)...............................................

870.3150 Oral Subchronic (nonrodent).........................................

870.3200 28-Day Dermal..............................................................

870.3250 90-Day Dermal..............................................................

870.3465 90-Day Inhalation..........................................................

yes

yes

yes

no

yes

yes

yes a

yes

-

no

870.3700 Developmental Toxicity (rodent) ...................................

870.3700 Developmental Toxicity (nonrodent) .............................

870.3800 Reproduction .................................................................

yes

yes

yes

yes c

yes

yes

870.4100 Chronic Toxicity (rodent)...............................................

870.4100 Chronic Toxicity (nonrodent).........................................

870.4200 Oncogenicity (rat) ..........................................................

870.4200 Oncogenicity (mouse) ....................................................

yes

no

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Bacterial reverse mutation assay ....................

870.5300 Mutagenicity—In vitro mammalian cell gene mutation test.......

870.5375 Mutagenicity—In vitro mammalian chromosome aberration test

870.5395 Mutagenicity—Mammalian erythrocyte micronucleus test........

yes

yes

yes

yes

yes

yes

yes

yes

870.6100 Acute Delayed Neurotoxicity (hen)................................

870.6100 90-Day Neurotoxicity (hen) ...........................................

870.6200 Acute Neurotoxicity Screening Battery (rat)..................

870.6200 90-Day Neurotoxicity Screening Battery (rat) ...............

870.6300 Developmental Neurotoxicity .......................................

no

no

yes

yes

CR

-

-

yes

yes

yesd

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration........................................................

870.7800 Immunotoxicity .............................................................

yes

CR

yes

yes

yes

yes

a Test was not submitted; however, a chronic dog study was submitted instead.

c An acceptable, non-guideline study was submitted in rat which did not demonstrate an adverse effect at the highest dose tested, but did

prove the rabbit to be the more sensitive species. Therefore this study requirement was considered to be satisfied.

d This study was waived by the HIARC 12/10/2001
Pronamide Human Health Risk Assessment DP No. D422207

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A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile – Pronamide

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [Rat] 00085505 LD50 > 5000 mg/kg IV

870.1100 Acute oral [Rat] 43583901 LD50 > 5000 mg/kg IV

870.1200 Acute dermal [Rabbit] 43583902 LD50 > 2000 mg/kg III

870.1300 Acute inhalation [Rat] 44034201 LC50 > 2.1 mg/L IV

870.2400 Acute eye irritation [Rabbit] 43583904 Non-Irritating IV

870.2500 Acute dermal irritation [Rabbit] 43583903 Non-Irritating IV

870.2600 Skin sensitization [Guinea Pig] 00062605 Negative Non-Sensitizing

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Pronamide

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

870.3050 28-Day oral 

toxicity (rat)

42669402 (1987)

Acceptable-non-guideline

0, 500, 1000 ppm

♂: 0, 37, 74 mg/kg/day 

♀: 0, 44, 88 mg/kg/day

NOAEL = 74 mg/kg/day

LOAEL was not observed 

All parameters required to be evaluated under 

the appropriate guideline (OCSPP 870.3050; 

OECD 407) for a 28-day oral toxicity study in 

the rat were not evaluated. Additionally, the 

animals could have tolerated a higher dose.

870.3050 28-Day oral 

toxicity (mouse)

45919801 (2002)

Acceptable-guideline

♂: 0, 16, 81, 408, 892 

mg/kg/day 

♀: 0, 18, 84, 434, 1040 

mg/kg/day

NOAEL = 81 mg/kg/day

LOAEL = 408 mg/kg/day based on 

histopathology of the liver; and increased 

serum alkaline phosphatase, alanine 

aminotransferase, and aspartate 

aminotransferase

Additionally at the high dose, the following 

findings were noted: decreased body weights in 

males, decreased food consumption in both 

sexes, increased serum total bilirubin, total 

protein, and creatinine in both sexes, decreased 

serum glucose in both sexes, gross and 

histological liver lesions, decreased thymus 

size with atrophy in males, and decrease fat in 

males.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Pronamide

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

870.3100 90-Day oral 

toxicity (rat)

00085506 (1967)

Acceptable-non-guideline

♂♀: 0, 50, 150, 450, 

1350, 4050 ppm

♂♀: approximately 

equivalent to 2.5, 7.5, 22, 

68, and 202 mg/kg/day, 

assuming 1 ppm = 0.05 

mg/kg/day

NOAEL = 68 mg/kg/day

LOAEL = 202 mg/kg/day based on decreased 

body weights in females

All parameters currently required to be 

evaluated under the appropriate guideline 

(OCSPP 870.3050; OECD 407) for a 28-day 

oral toxicity study in the rat were not evaluated. 

Additionally, the animals could have tolerated 

a higher dose.

870.3100 90-Day oral 

toxicity (rat)

42669403 (1989)

Acceptable-guideline

♂♀: 0, 40, 200, 1000, 

4000 ppm

♂: 0, 2.5, 12, 60, 254 

mg/kg/day

♀: 0, 3.1, 15, 75, 289 

mg/kg/day

NOAEL = 60 mg/kg/day

LOAEL = 254 mg/kg/day based on decreases 

in body weight and food consumption in both 

sexes and liver findings (increased weight, 

hypertrophy, and cholesterol in both sexes, and 

increased serum alkaline phosphatase (males) 

and triglycerides (females))

870.3100 90-Day oral 

toxicity (mouse)

Not submitted

870.3150 90-Day oral 

toxicity (dog)

Not submitted; however, a 

chronic dog toxicity study 

was submitted.

This guideline is satisfied by the chronic dog

870.3200 28-Day dermal 

toxicity (F344 rat)

46885701 (2005)

Acceptable-guideline

♂♀: 0, 100, 500, 1000 

mg/kg/day

NOAEL = 100 mg/kg/day

LOAEL = 500 mg/kg/day based on decreases 

in body weight (10%) and food consumption 

(8%) in males – minimal toxicity, animals 

could have tolerated higher dosages.

No additional findings were noted at the high 

dose, and body weight and food consumption 

were only marginally more affected (decrease 

of 12% in body weight and 13% in food 

consumption). Females were not affected at 

any dose.

870.3250 90-Day dermal 

toxicity (species)

Not submitted 28-Day dermal study submitted and dermal 

absorption value is available

870.3465 90-Day inhalation 

toxicity (species)

Not submitted Waiver granted in 2003. (TXR# 0051730)
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Pronamide

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

870.3700 Prenatal 

developmental 

(rat)

00125789 (1971)

Unacceptable-guideline

0, 7.5, 15 mg/kg/day

An evaluation of the potential teratogenic 

effects could not be made due to the absence of 

data on external, visceral, and intracranial 

variations and malformations in fetuses. In 

addition, information on the test material's 

purity and stability of dosage mixtures, and 

individual animal data such as age, weight, or 

reproductive history were not available. The 

study was conducted with only two groups 

dosed with pronamide (instead of three) and 

one control.

870.3700 Prenatal 

developmental 

(rat)

40334501 (1987)

Acceptable-non-guideline

0, 5, 20, 80, 160 

mg/kg/day

Maternal NOAEL = 160 mg/kg/day

LOAEL was not observed

Developmental NOAEL = 160 mg/kg/day

A LOAEL was not observed

This was a scientifically sound study, which 

did not demonstrate an adverse effect at the 

highest dose tested. An adequate doseselection rationale was not provided.

870.3700 Prenatal 

developmental 

(rabbit)

00148065 (1985)

Acceptable-guideline

0, 5, 20, 80 mg/kg/day

Maternal NOAEL = 20 mg/kg/day; LOAEL = 

80 mg/kg/day based on the following (#/18 

treated vs #/18controls): abortions, mortality (1 

vs 0), anorexia (10 vs 1), red urinary precipitate 

(7 vs 0), abortions (5 vs 0), hepatic necrosis (5 

vs 0), eosinophilic hepatocytes (8 vs 1), 

swelling of hepatocytes (9 vs 0), pigmentation 

of Kupffer cells (6 vs 0), and punctate 

vacuolation of midzonal and centrilobular 

hepatocytes (13 vs 3). Mottled liver was 

commonly observed in the animals that aborted 

or died. It was also noted that a hunched 

appearance was more commonly observed in 

the treated animals. 

Developmental NOAEL = 20 mg/kg/day

LOAEL = 80 mg/kg/day based on abortions 
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Pronamide

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

870.3800 Reproduction and 

fertility effects

(rat)

41540301 (1990)

Acceptable-guideline

♂♀: 0, 40, 200 or 1500 

ppm 

F0: ♂ = 0, 3.5, 17.5 and 

123.2

♀ = 0, 3.0, 15.4 and 114.0 

mg/kg/day

through 2 generations 

(one mating period per 

generation).

Parental/Systemic Toxicity

NOAEL = 200 ppm (17.5 mg/kg/day-females 

and 15.4 mg/kg/day-males); LOAEL = 1500

ppm (123.2 mg/kg/day-females and 114.0 

mg/kg/day-males), based upon decreases in 

body weight and feed consumption in both 

sexes, increased incidences of histopathology 

in the liver, adrenal glands, thyroid gland, and 

anterior pituitary gland in P1 and P2 

generations, and increased incidences of uterine 

gross pathology in P2 females.

Reproductive Toxicity

NOAEL/LOAEL  1500 ppm

Developmental/Offspring Toxicity

NOAEL = 200 ppm (17.5 mg/kg/day-females 

and 15.4 mg/kg/day-males)

LOAEL = 1500 ppm (123.2 mg/kg/dayfemales and 114.0 mg/kg/day-males) based 

upon decreases in combined male/female pup 

weight/litter.

870.4100 Chronic toxicity

(CD rat)

See under 

870.4200

00133111 (1970)

Acceptable-non-guideline

0, 30, 100, 300 ppm

0, 1.5, 5, 15 mg/kg/day

(using standard 

conversion factor of 0.05)

Systemic Toxicity NOAEL = 15 mg/kg/day

Systemic Toxicity LOAEL = not identified. 

870.4100 Chronic toxicity 

(dog) 

Beagle

41807601/42130301 

(1991) Acceptableguideline

0, 300, 875, or 1750 ppm

0, 11.9, 33.1, or 67.7 

mg/kg/day (males)

0, 11.9, 36.1, or 69.0 

mg/kg/day (females)

NOAEL = 300 ppm [11.9 (males/females)]

LOAEL = 875 ppm [33.1 (males); 36.1 

(females)] based upon increased serum alkaline 

phosphatase activity (males), increases thyroid 

and liver weights and liver histopathology 

(hypertrophy, hyperplasia, and granular brown 

pigmentation and mononuclear infiltration of 

Kupffer cells).
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Pronamide

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

870.4200 Carcinogenicity

(Crl:CD(BR) 

VAF/Plus rat)

41714001/41714002 

(1990)

41799601 (1990) 

supplemental histopath

Acceptable-guideline

0, 40, 200, 1000 ppm*

♂: 0, 1.73, 8.46, 42.59 

mg/kg/day

♀: 0, 2.13, 10.69, 55.09 

mg/kg/day

*25, 100, 400 ppm for 2 

weeks; then 35, 140, 560 

ppm for 3 weeks; then 40, 

200, 1000 ppm thereafter

Systemic Toxicity NOAEL = 8.46/10.69 

mg/kg/day

Systemic Toxicity LOAEL = 42.59/55.09 

mg/kg/day, based on increased relative liver 

weight and increased non-neoplastic histologic 

changes in the liver (centrilobular hypertrophy, 

eosinophilic cell alteration; both sexes), thyroid 

(follicular cell hypertrophy; both sexes), and 

ovaries (sertoliform tubular hyperplasia).

evidence of carcinogenicity: thyroid follicular 

cell adenomas (both sexes); benign testicular 

interstitial cell tumors in males.

870.4200 Carcinogenicity

(CD-1 mouse)

46424801 (2004)

Acceptable-guideline

Pronamide (95.9% a.i.; 

Lot No. F0031-166) was 

administered in the diet to 

CD1 mice (50/sex/dose) 

for up to 78 weeks at 

doses of 0, 5, 50, or 250 

mg/kg bw/day.

NOAEL = 50 mg/kg/day

LOAEL = 250 mg/kg/day, based on 

cardiotoxicity (increased incidences of 

thrombus in the heart and multifocal 

myocardial degeneration) in females and 

hepatotoxicity (bile stasis, focus of eosinophilic 

cellular alteration, bile duct hyperplasia, 

panlobular hepatocyte hypertrophy, and 

pigment-laden macrophages (bile) in both 

sexes; focus of basophilic cellular alteration, 

focus of vacuolated cellular alteration, 

multifocal necrosis, centrilobular-midzonal 

vacuolation, and individual hepatocyte 

vacuolation in males; and centrilobular 

hepatocyte hypertrophy in females) in both 

sexes. 

evidence of carcinogenicity: increased 

incidence of hepatocellular adenomas and 

carcinomas in both sexes at 250 mg/kg/day.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Pronamide

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

870.4200 Carcinogenicity

(male B6C3F1 

mouse)

00114114 (1982)

Acceptable-non-guideline, 

when used in conjunction 

with MRID 00107968

0, 0, 20, 100, 500, or 2500 

ppm 

0, 0, 3, 15, 75, or 375 

mg/kg/day

(standard conversion 

factor of 0.15 used)

NOAEL = 15 mg/kg/day

LOAEL = 75 mg/kg/day, based on gross 

findings (increased incidences of hepatic 

nodules/masses and liver enlargement) 

observed in male mice after 24 months of 

treatment.

At 375 mg/kg/day, decreased body weight, 

increased liver weights, and an increased 

incidence of parenchymal necrosis and 

cholestasis was observed in the liver. 

evidence of carcinogenicity: increased 

incidence of hepatocellular carcinomas and 

hepatocellular adenomas at 75 and 375 

mg/kg/day.

870.4200 Carcinogenicity

(C57BL/6 x 

C3H/anf F1

mouse)

00107968 (1974)

Acceptable-non-guideline, 

acceptable when used in 

conjunction with MRID 

00114114

0, 1000 or 2000 ppm 

0, 150 or 300 mg/kg/day

(standard conversion 

factor of 0.15 used)

NOAEL = not identified

LOAEL = not identified. This is a 2-dose nonGLP study.

Females at 2000 ppm displayed decreased body 

weight (↓17% at week 78); increased liver 

weights reported in both sexes at week 30 

(interim sacrifice); liver weight not reported at 

18-month sacrifice. At terminal sacrifice, 

cholestasis in hepatocytes and/or Kupffer’s 

cells in 28/99 males at 2000 ppm. Cholestasis 

was not accompanied by hepatocellular 

carcinoma.

evidence of carcinogenicity: increased 

incidence of hepatocellular carcinomas at both 

dose levels (dose-related) in males.

870.5100 Reverse gene 

mutation assay in 

bacteria, S. 

typhimurium

strains TA98, 

TA100, TA1535, 

and TA1537 and 

E. coli strain WP2 

uvrA

49167402 (2008)

Acceptable, guideline

0, 1.5, 5.0, 15, 50, 150, 

500, 1500, and 5000 

μg/plate, without and with 

activation, 

There was no evidence of induced mutant 

colonies over background.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Pronamide

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

870.5100 Genotoxicity

Ames bacterial 

gene mutation 

assay

Salmonella 

typhimurium

strains TA1535, 

TA1537, TA1538, 

TA98 and TA100 

and in Escherichia 

coli WP2 hcr

40090602 (1978)

Acceptable, guideline

Salmonella typhimurium

±S9: 10 to 5000 μg/plate 

Bacillus subtilis H17 

(rec+) and M45 (rec-)

±S9: 20 to 2000 μg/disc 

No evidence of mutagenic activity was seen at 

any dose level tested in the presence or absence 

of S-9 mix in either mutation test.

870.5300 Genotoxicity

In vitro 

mammalian cell 

gene mutation 

(HGPRT locus in 

CHO) test

40211106 (1984)

Acceptable, guideline

2.5 to 40 μg/mL with or 

without S9 activation. 

no evidence of mutagenic activity.

slightly cytotoxic at 40 μg/mL+/-S9

870.5375 Cytogenetics 

in vitro

mammalian cell 

assay in Chinese 

hamster ovary 

(CHO) cells

40211108 (1987)

Acceptable, guideline

dose range 25-400μg/mL 

±S9

no evidence of a clastogenic response either in 

the presence or the absence of S9 activation. 

doses 250 μg/mL insoluble; cytotoxicity was 

not seen. 

870.6200 Acute 

neurotoxicity 

screening battery

F344/DuCrl rats

48599202 (2011)

Acceptable-guideline

0, 40, 200 or 600 mg/kg

NOAEL for acute neurotoxicity was not 

determined. LOAEL is 40 mg/kg (the LDT), 

based on the increase in landing foot splay in 

female rats and the decrease in motor activity 

seen in both genders on Day 1.

870.6200 Subchronic 

neurotoxicity 

screening battery

F344/DuCrl rats

48599204 (2011)

Acceptable-guideline

0, 40, 200, or 1000 ppm 

(time-weighted average 

dosages of 0, 2.4, 11.8, or 

59.5 mg/kg/day in males, 

and 0, 2.7, 13.3, or 65.2 

mg/kg/day in females)

NOAEL is 40 ppm (equivalent to 2.38/2.67 

mg/kg/day in M/F).

LOAEL for this study is 200 ppm (equivalent 

to 11.8/13.3 mg/kg/day in M/F), based on 

decreased body weights, body weight gains, 

and food consumption in males. 

870.6300 Developmental 

neurotoxicity

Not submitted Waived by the HIARC 12/10/2001
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Pronamide

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

870.7485 Metabolism and 

pharmacokinetics

(rat)

41801801 (1991)

41929901 (1991)

42858001 (1993)

14C-phenyl-Pronamide for

14 days

Pronamide is rapidly absorbed and completely 

and rapidly eliminated; radioactivity was 

recovered (93-103%) in the urine (40-61 %), 

feces (40-60%) and tissues and carcass (0.08-

2.43%). No bioaccumulation was apparent. The 

elimination of radioactivity from the plasma of 

low dose rats was biphasic [rapid phase = 12.6 

hrs (males) and 12.7 hrs (females); slow phase 

= 36.6 hrs (males) and 45.3 (females) and that 

of the high dose rats was monophasic [t/z = 

24.1 hrs (males) and 24.8 hrs (females)]. Very 

little unchanged pronamide was recovered in 

the urine and no significant difference in 

urinary metabolite profile was observed 

between the doses or the sexes. The two major 

urinary metabolites were SS47-70 (3.0-5.9%) 

of the dose and metabolite 10 (12.7-18.9%). In 

the urine, 27 metabolites were found and none 

exceeded 3.3% of the dose, whereas, almost all 

of the unknowns in the feces were less than 1 

% of the dose.

870.7600 Dermal 

penetration (rat)

41117201 (1989)

40256701 (1987)

Acceptable, non-guideline

Pronamide 99%a.i.

14C-Pronamide [check –

unintelligible]

The recoveries with the 50W formulation were 

78% at the low dose and 122% at the high 

dose. Normalization of the low-dose data 

(worst-case scenario) for the 50W formulation 

to adjust for recover, and further adjustment for 

carcass residue, results in a dermal absorption 

factor (DAF) of 24%. 

870.7800 Immunotoxicity 

(CD-1 mouse)

48599201 (2010)

Acceptable, guideline

0, 15, 75, 250 mg/kg/day 

Achieved: 0, 14, 74, 244 

mg/kg/day

Immunotoxicity NOAEL = 244 mg/kg/day

Immunotoxicity LOAEL was not established.

Systemic NOAEL = 15 mg/kg/day

Systemic LOAEL = 75 mg/kg/day, based on 

increased liver weights.

890.1450 Female pubertal 

study (~3 weeks) 

(Crl:CD(SD) rats)

48673402 (2012). 0, 

25,100,300 mg/kg/day 

(gavage)

LOAEL for decreased T4 (-25%) in serum is 

25 mg/kg/day. There was no NOAEL

890.1500 Male pubertal 

study (~4 weeks) 

(Crl:CD(SD) rats)

48688001 (2012). 0, 2.5, 

10, 25 mg/kg/day 

(gavage)

NOAEL = 2.5 mg/kg/day. The LOAEL is 10 

mg/kg/day based on decreased serum T4 

(-13%)

870.6200 Subchronic 

neurotox probe 

(4 weeks) 

F344/DuCrl rats

48599203 (2011) 0, 500, 

1000, 2500 ppm

LOAEL = 500 ppm (40.5 mg/kg/day – males) 

based on increased relative liver weight (12% 

male & 9% female)
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Pronamide

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

MOA 13-week oral 

toxicity (CD rat –

males only)

49167410 (2013) 0, 200, 

1000, 2000 ppm

NOAEL = 200 ppm (15 mg/kg/day) based on 

200-fold increase over background in CYP2B1 
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A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) - Females age 13-49

No single dose endpoint suitable for this exposure scenario could be identified in the database. In 

the developmental rabbit study, abortions were noted and could possibly be a result of fetal 

toxicity; however, as the abortions occurred very late (on or after GD 22), this finding was not 

considered to be a result of single dose of pronamide.

A.3.2 Acute Reference Dose (aRfD) - General Population

Study Selected: Acute Neurotoxicity in Rats

MRID No.: 48599202

Executive Summary: In an acute neurotoxicity study (MRID 48599202), groups of fasted 7 

week old F344/DuCrl rats (10/sex/dose) were given a single oral dose of pronamide (96.2% 

purity, Lot # XG1088R301, TSN003588-0004) in 0.5% METHOCELTM (10 ml/kg) at doses of 

0, 40, 200 or 600 mg/kg bw on Day 1 and observed for 15 days. Neurobehavioral assessment 

(functional observational battery and motor activity testing) was performed in 10 

animals/sex/group at pre-dosing and Days 1, 8, and 15. Hand-held clinical observations were 

performed on Days 2, 3 and 4. Body weights were determined pre-dosing and on Days 1, 2, 8, 

and 15. Cholinesterase activity was not determined. At study termination, all surviving animals 

in the control and high dose groups were euthanized and perfused in situ for neuropathological 

examination, as well as five animals from the low dose group and seven males and nine females 

from the mid-dose group. Of the perfused animals, all of the control and high-dose group were 

subjected to histopathological evaluation of brain and peripheral nervous system tissues. 

No treatment-related findings were observed in any dose group on Days 8 and 15. No adverse, 

treatment-related findings were noted on body weight, body weight gain, gross pathology, or 

neuropathology.

One 600 mg/kg female was sacrificed moribund on Day 2; all other animals were sacrificed on 

schedule. Although the cause of death was not provided, this death was considered treatmentrelated considering the profound effects observed in the 600 mg/kg females. Treatment-related 

clinical signs were present in the 600 mg/kg dose group on Day 2 and consisted primarily of 

decreased activity, decreased or absent feces, uncoordinated gait, and red periocular soiling. 

Other clinical signs on Day 2 were present only in females of the 600 mg/kg dose group and 

included slow or labored respiration and animals that were cold to touch. All of these clinical 

signs were resolved by Day 3 with the exception of 1 female with decreased activity and absent 

feces, which was resolved by Day 4, and 1 or 2 males and/or females with red periocular soiling 

on Days 3 or 4. 

On Day 1 in the 200 and 600 mg/kg females, dose-related decreases were observed in resistance 

to removal, muscle tone, extensor thrust (NS at 200 mg/kg), reactivity to handling, level of 

activity (NS), response to noise, response to touch, and response to pinch; an increase in 
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incoordination was noted, and 5/10 females at 600 mg/kg were unable to walk. Additional 

effects noted in the 600 mg/kg females included decreases in palpebral closure, lacrimation, 

pupil size, and salivation; increased urination was also observed. Decreased rectal temperatures 

were noted in the 200 and 600 mg/kg females. Hindlimb and forelimb grip strengths were 

decreased in the 200 and 600 mg/kg females, with the effect being greater on forelimb grip. 

Landing foot splay increased at 200 and 600 mg/kg in males (increased 59%, 63%; 600 mg/kg 

not evaluated statistically) and the 40, 200, and 600 mg/kg females (increased 21%, 31% and 

53%). FOB findings were most severe in the females.

In the 600 mg/kg males, decreases were observed in resistance to removal, muscle tone (NS), 

reactivity to handling, level of activity response to noise, response to touch, and response to 

pinch; increased incoordination was also noted. In the 200 mg/kg males, decreases in level of 

activity and response to noise were observed.

Repeated measure analysis on the square root of the motor activity indicated the following: (i) 

treatment effects were different between males and females at one or more intervals; (ii) 

treatment did not affect the within-session distribution of counts at any time interval; (iii) there 

were no differences between control and 40 mg/kg group at any time interval on the square root 

transformed data (p=0.0534); and (iv) there were differences between the 200 and 600 mg/kg 

groups and the control. However on day 1, there were large dose-dependent decreases in the 

untransformed total motor activity counts at 40, 200, and 600 mg/kg in males (-42%, -70%, and -

79%) -and females (-41%, -83% and -91%) which are considered adverse and statistically 

significant at all doses.

The LOAEL (lowest-observed-adverse effect level) is 40 mg/kg (the LDT), based on the 

increase in landing foot splay in female rats and the decrease in motor activity seen in both 

genders on Day 1. The NOAEL (the no-observed-effect level) for acute neurotoxicity was 

not determined.

This study is classified as acceptable/guideline and satisfies the guideline requirement for an acute 

neurotoxicity study in rats (870.6200; OECD 424).

Dose and Endpoint for Risk Assessment: POD = 40 mg/kg/day based on increase in landing foot 

splay in female rats and the decrease in motor activity seen in both genders on Day 1 at the LOAEL 

= 40. 

Comments about Study/Endpoint/Uncertainty Factors: Acute Dietary Endpoint (General 

Population): The acute neurotoxicity study in rats was selected for the acute dietary endpoint for 

the general population. The LOAEL is 40 mg/kg/day (lowest dose tested) which was based on 

the increase in landing foot splay in female rats and the decrease in motor activity seen in both 

genders on Day 1. This endpoint is appropriate for both the exposure duration (acute/single dose) 

and the population of concern (general population). 

The point of departure (POD) is the LOAEL of 40 mg/kg/day. The POD is divided by a 

combined 1000X uncertainty factor (UF), consisting of the usual 10x interspecies uncertainty 

factor for extrapolation from animal to human (UFA); the usual 10x intraspecies factor for 
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Page 60 of 72

variation in human response (UFH); and a 10x factor for LOAEL to NOAEL extrapolation

(UFL). The acute reference dose (aRfD) is 0.04 mg/kg/day for the general population. Therefore, 

the aRfD is equivalent to the acute population adjusted dose (aPAD).

POD = LOAEL of 40 mg/kg/day

aRfd= aPaD= 40 mg/kg/day = 0.04 mg/kg/day

1000 (UF)

Where 1000 (UF) = 10 (UFA) x 10 (UFH) x 10 (UFL)

A.3.3 Chronic Reference Dose (cRfD), A.3.4 Incidental Oral Exposure (Short and 

Intermediate Term), Inhalation Exposure (short and intermediate term)

Study Selected: Acute Neurotoxicity in Rats

MRID No.: 48599202

Executive Summary: See Section A.3.2 above

Dose and Endpoint for Risk Assessment: POD = 4 mg/kg/day based on increase in landing foot 

splay in female rats and the decrease in motor activity seen in both genders on Day 1 at the LOAEL 

= 40. The POD = LOAEL ÷10 =4 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors: The study selected is the ACN, the 

same study selected for acute risk assessment. Ordinarily an acute study is not used for longer 

term exposure scenarios, but in this risk assessment a POD based on the LOAEL of 40 mg/kg 

from the ACN study and dividing by an uncertainty factor of 10 for use of a LOAEL (UFL) is 

considered appropriate to assess longer term assessments. The derived POD of 4 mg/kg/was 

selected for the chronic dietary, incidental oral (short-term), and inhalation (short- and 

intermediate-term) endpoints based on a weight of evidence approach using the results from 3 

studies. The studies include the acute and subchronic neurotoxicity rat studies and the combined 

chronic toxicity/carcinogenicity rat study. The NOAELs/LOAELs from each study are listed 

below.

1) Subchronic neurotoxicity (SCN) in F344 rats: NOAEL of 2.38 mg/kg/day is based on 

the significant decreases in body weight, food consumption, and food efficiency seen at 

11.28 mg/kg/day (LOAEL) in males.

2) Acute neurotoxicity (ACN) in F344 rats: NOAEL was not established. The LOAEL of 

40 mg/kg/day with a 10X LOAEL to NOAEL uncertainty factor (UFL) yields a derived 

POD of 4 mg/kg/day (40÷10).

3) Combined chronic toxicity/carcinogenicity in CD rats: NOAEL of 8.46 mg/kg/day is 

based on increased relative liver weight and histopathological lesions in the liver, thyroid, 

and ovaries at 43 mg/kg/day (LOAEL).

The lowest LOAEL of the three studies is 11.28 mg/kg/day from the SCN study. The highest 

NOAEL (8.6 mg/kg/day) in the combined rat study is not appropriate for a POD since that value 

is very close to the LOAEL of 11.28 mg/kg/day. The next highest value to consider is 4.0 

mg/kg/day, the derived POD which is a factor of 3x lower than the LOAEL from the SCN. HED 
Pronamide Human Health Risk Assessment DP No. D422207

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considers 4.0 mg/kg/day to be the appropriate value for use as the POD as it will be protective of 

the suite of effects seen at the LOAELs of 11.28 mg/kg/day (SCN) and 42.6 mg/kg/day 

(chronic/carcinogenicity rat) and also 40 mg/kg/day (ACN). This POD is appropriate for use 

across all exposure durations.

Application of a 100-fold uncertainty factor has been determined to be appropriate (10X 

interspecies and 10X intraspecies). 

For the chronic dietary risk assessment, the cRfD of 0.04 mg/kg/day is equivalent to the cPAD. 

Extrapolated POD = (LOAEL 40 mg/kg/day) = 4 mg/kg/day

10 (UFL)

cRfd= cPaD= 4 mg/kg/day = 0.04 mg/kg/day

100 (UF)

A.3.5 Dermal Exposure (Short-, Intermediate- and Long-Term)

Study Selected: 28-Day Dermal Toxicity Study in the Rat

MRID No.: 46885701

Executive Summary: In a 28-day dermal toxicity study (MRID 46885701), Pronamide (95.9% 

a.i., Lot No. F0031-166) in 0.5% aqueous methycellulose was applied as a paste suspension to 

the shaved skin of ten Fischer 344 rats/sex/dose at concentrations of 0, 100, 500, or 1000 mg/kg 

bw/day, six hours/day, seven days/week for at least 28 days. 

No adverse, treatment-related effects were observed on mortality, clinical signs (including a 

limited functional observational battery), ophthalmoscopic findings, hematology, clinical 

chemistry, organ weights, or gross pathology.

Terminal body weight was decreased (p≤0.05) by 10% and 12% at 500 and 1000 mg/kg/day, 

respectively. Overall (Days 1-28) body weight gains of 500 and 1000 mg/kg/day male rats were

decreased by 40% and 45%, respectively, while food consumption was decreased (p≤0.05) by 

7-13% for 2 or 3 weeks in these groups. No treatment-related effects were found in female rats. 

Treatment-related effects at the application site were limited to slight scaling in one 1000 

mg/k/day male observed on Days 22-29 and increased incidences of very slight to slight 

epidermal hyperplasia and slight multifocal inflammation. These effects were considered to be 

adaptive responses to the irritant properties of the test material. No other treatment-related 

effects were found.

The LOAEL is 500 mg Pronamide/kg/day based on decreases in body weight, body weight 

gain, and food consumption in males. The NOAEL is 100 mg/kg/day. Dermal toxicity was 

not observed, and no effects were noted in females.
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This 28-day dermal toxicity study in the Fischer 344 rat is acceptable, guideline and satisfies the 

guideline requirement for a 28-day dermal toxicity study (OPPTS 870.3200; OECD 410) in the 

rat.

Dose and Endpoint for Risk Assessment: NOAEL = 100 mg/kg/day. The LOAEL = 500 

mg/kg/day in males based on decreases in body weight (10%) and food consumption (8%) in 

males – minimal toxicity, animals could have tolerated higher dosages. Females were not 

affected.

Comments about Study/Endpoint/Uncertainty Factors: The dermal endpoint was selected 

from a 28-day dermal toxicity study in rats. The POD was a NOAEL of 100 mg/kg/day. The 

LOAEL was 500 mg/kg/day based on decreases in body weight and food consumption in males. 

No target organ (liver) toxicity was seen following repeated dermal dosing. This is considered a 

conservative endpoint since the animals could have tolerated a higher dose. The endpoint is 

appropriate for the route and duration of exposure as well as the population of concern.

The occupational and residential levels of concern for the margin of exposure is 100 (includes 

UFA=10x and UFH=10x).
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Appendix B. Metabolites and Metabolic Pathways for Pronamide

The following are rat metabolites found in the urine and feces.
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The following is the proposed metabolic pathway in the rat supplied by the registrant. 
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Appendix C. Physical/Chemical Properties

Table C1. Physico-Chemical Properties (Stillmeadow Technical)

Parameter Value Reference

Molecular Weight 256.13

pH N/A

Tomlin, C.D.S. (ed.). The 

Pesticide Manual - World 

Compendium. 11th ed. Surrey, 

UK: The British Crop 

Protection Council, 1994, p. 

862]

Water solubility (20°C) 15 mg/L

Solvent solubility (g/L)(20°C to 25°C)

Methanol, isopropanol 150 

Cyclohexanone, MEK 200 

DMSO 330 

Vapor pressure (25°C) 0.058 mPa ( 4.4x10-7torr)

Dissociation constant, pKa Not applicable

Octanol/water partition coefficient, log KOW

(25°C) 3.43

Aerobic Soil Metabolism Half-life (days) 165 MRID 46413407 cited in 

Milians, D414467 (2015)
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Appendix D. Summary of Registered and Proposed Uses for Pronamide

Crop/Use Site Application Timing and Type of Application Registered 

Formulations

Maximum 

Application 

Rate

Personal Protective 

Equipment (PPE) and 

Restricted Entry Interval 

(REI)

Agricultural Fallow/Idleland

Agricultural Uncultivated Areas September/December/Broadcast Aerial L/WP(WSP) 0.5 24 hrs REI 

Alfalfa Spring/Fall/Winter/ Broadcast/ Aerial Chemigation/ 

Groundboom L/WP(WSP) 2 24 hrs REI 50 days PHI

Apple Fall/Postharvest direct spray L/WP(WSP) 4 24 hrs REI 

Apricot Fall/Postharvest direct spray L/WP(WSP) 4 24 hrs REI

Artichoke Ratoon/ Broadcast/Aerial Chemigation/ Groundboom L/WP(WSP) 4 24 hrs REI 60 days PHI

Blackberry Fall/Winter/ Broadcast/ Chemigation/ Groundboom L/WP(WSP) 3 24 hrs REI 

Blueberry Fall/Winter/ Broadcast/ Chemigation/ Groundboom, L/WP(WSP) 3 24 hrs REI 

Boysenberry Fall/Winter/ Broadcast/ Chemigation/ Groundboom L/WP(WSP) 3 24 hrs REI 

Cherry Fall/Postharvest direct spray L/WP(WSP) 4 24 hrs REI

Christmas Tree Plantations Early winter/Fall/ direct spray/Aerial L/WP(WSP) 4 24 hrs REI 365 days PHI

Clover Fall/Winter/ Broadcast/Chemigation/ Groundboom L/WP(WSP) 2 24 hrs REI 120 days PHI

Commercial/Industrial Lawns Spring/Broadcast/Aerial/Chemigation/ Groundboom L 1.44 24 hrs REI

Crown Vetch Fall/Winter/ Broadcast/Chemigation/ Groundboom L/WP(WSP) 2 24 hrs REI 120 days PHI

Endive Postplant/Broadcast/Aerial /Chemigation/ Groundboom L/WP(WSP) 2 24 hrs REI 55 days PHI

Golf Course Turf Spring/Broadcast/Aerial/Chemigation/ Groundboom L/WP(WSP) 1.44 24 hrs REI

Grapes Fall/Postharvest direct spray L/WP(WSP) 4 24 hrs REI

Grasses Grown For Seed Fall/Preemergence/Early Winter WP(WSP) 0.375 24 hrs REI

Leafy Greens Postemergence/ Chemigation/ Groundboom L 224 hrs REI 55 days PHI WP(WSP) 1.5

Lettuce Postplant/Broadcast/Aerial / Chemigation/ Groundboom L/WP(WSP) 2 24 hrs REI 55 days PHI

Leaf Lettuce (Section 3) Postplant/Broadcast/Aerial / Chemigation/ Groundboom/

Hand held sprayer L 1 24 hrs REI 45 days PHI

Nectarine Fall/Postharvest direct spray L/WP(WSP) 4 24 hrs REI

Ornamental And/or Shade Trees Fall/ direct spray/ Hand held sprayer L/WP(WSP) 2 24 hrs REI

Ornamental Grasses Broadcast/Aerial/ Chemigation/ Groundboom/Hand held 

sprayer

WP(WSP) 1.5 24 hrs REI

Ornamental Herbaceous Plants Fall/ direct spray/ Hand held sprayer L/WP(WSP) 2 24 hrs REI

Ornamental Lawns And Turf Spring/Broadcast/Aerial/Chemigation/ Groundboom/ 

Hand held sprayer L/WP(WSP) 1.44 24 hrs REI

Ornamental Nonflowering Plants Fall/ direct spray/ Hand held sprayer L/WP(WSP) 2 24 hrs REI

Ornamental Sod Farm (Turf) Spring/Broadcast/Aerial/Chemigation/ Groundboom /

Hand held sprayer L 1.44 24 hrs REI

Ornamental Woody Shrubs And 

Vines Fall/ direct spray/ Hand held sprayer L/WP(WSP) 2 24 hrs REI

Peach Fall/Postharvest direct spray L/WP(WSP) 4 24 hrs REI 

Pear Fall/Postharvest direct spray L/WP(WSP) 4 24 hrs REI 

Peas Broadcast/Early winter/ Chemigation/ Groundboom L/WP(WSP) 1.5 24 hrs REI

Plum Fall/Postharvest direct spray L/WP(WSP) 4 24 hrs REI 

Prune Fall/Postharvest direct spray L/WP(WSP) 4 24 hrs REI 

Raspberry (Black - Red) Fall/Winter/ Broadcast/ Chemigation/ Groundboom L/WP(WSP) 3 24 hrs REI 

Rhubarb Fall/Broadcast/ Chemigation/ Groundboom L/WP(WSP) 2 24 hrs REI 38 days PHI

Sainfoin Fall/Winter/ Broadcast/Chemigation/Groundboom L/WP(WSP) 2 24 hrs REI 120 days PHI

Sugar Beet Fall/Winter/ Broadcast/Chemigation/ Groundboom L/WP(WSP) 1 24 hrs REI 

Trefoil Fall/Winter/ Broadcast/ Chemigation/ Groundboom L/WP(WSP) 2 24 hrs REI 120 days PHI
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Appendix E. Occupational Exposure/Risk Summary Tables

Occupational Handler Non-Cancer Exposure and Risk Estimates for Pronamide

Exposure Scenario Crop or Target

Dermal Unit 

Exposure 

(μg/lb ai)1

Inhalation 

Unit Exposure 

(μg/lb ai)1

Maximum 

Application 

Rate (lb 

ai/A)2

Area 

Treated 

(acres)3

Dermal

(LOC = 100)

Inhalation

(LOC = 1000)

Mitigation Level = baseline 

unless indicated otherwise

Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7

Mixer/Loader

Aerial application of 

Wettable powder in 

Water Soluble Package

(WSP)

Nursery (ornamentals, vegetables, trees, container stock) 8.6

(Engineering

Control)

0.083

(Engineering

Control )

1.5 60 0.011 9,100 0.00027 150,000

Sod 1.5 350 0.0644 1,600 0.00158 25,000

Field crop, typical acreage8and Orchard10 4 0.171 580 0.0042 9,500

Field crop, high-acreage9 2 1200 0.294 340 0.0072 5,600

Chemigation 

application of Wettable 

powder in Water 

Soluble Package

(WSP)

Sod 1.5

350

0.0644 1,600 0.00158 25,000

Field crop, typical acreage 8

and Orchard10 4 0.171 580 0.0042 9,500

Field crop, high-acreage9 2 0.0585 1,200 0.0021 19,000

Nursery (ornamentals, vegetables, trees, container stock) 1.5 60 0.011 9,100 0.00027 150,000

Groundboom 

application of Wettable 

powder in Water 

Soluble Package

(WSP)

Golf course (fairways, tees, greens) 1.5 40 0.00735 14,000 0.00018 220,000 Field-grown ornamental crops

Nursery (ornamentals, vegetables, trees, container stock) 1.5 60 0.011 9,100 0.00027 150,000

Sod 1.5 80 0.0148 8,800 0.00036 110,000

Field crop, typical acreage8and Orchard10 4 0.0393 2,500 0.00096 42,000

Field crop, high-acreage9 2 200 0.049 2,000 0.0012 33,000

Aerial application of 

liquid formulation

Nursery (ornamentals, vegetables, trees, container stock) 37.6

(Single 

layer/Glove)

0.219 2 60 0.0564 1,800 0.000329 120,000

Sod 1.44

350

0.238 420 0.00138 29,000

Field crop, typical acreage8and Orchard10 4 0.658 150 0.00384 10,000

Field crop, high-acreage9 29.1 (DL/G) 0.219 2 1200 0.873 110 0.00658 6,100

Chemigation 

application of a liquid 

formulation

Nursery (ornamentals, vegetables, trees, container stock) 37.6

(Single 

layer/Glove)

0.219 2 60 0.0564 1,800 0.000329 120,000

Sod 1.44

350

0.238 420 0.00138 29,000

Field crop, typical acreage8and Orchard10 4 0.658 150 0.00384 10,000

Field crop, high-acreage9 2 0.329 300 0.00768 20,000

Groundboom 

application of liquid 

formulation

Nursery (ornamentals, vegetables, trees, container stock) 2 60 0.0564 1,800 0.000329 120,000

Sod 1.44 80 0.0541 1,800 0.000315 130,000

Golf course (fairways, tees, greens) 40 0.0271 3,700 0.000158 250,000

Field crop, typical acreage8 4 80 0.15 670 0.000876 46,000

Field crop, high-acreage9 2 200 0.188 530 0.0011 36,000
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Occupational Handler Non-Cancer Exposure and Risk Estimates for Pronamide

Exposure Scenario Crop or Target

Dermal Unit 

Exposure 

(μg/lb ai)1

Inhalation 

Unit Exposure 

(μg/lb ai)1

Maximum 

Application 

Rate (lb 

ai/A)2

Area 

Treated 

(acres)3

Dermal

(LOC = 100)

Inhalation

(LOC = 1000)

Mitigation Level = baseline 

unless indicated otherwise

Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7

Applicator

Aerial spray 

application

Nursery (ornamentals, vegetables, trees, container stock) 2.08

(Engineering

Control)

0.0049

(Engineering

Control)

2 60 0.00313 32,000 0.00000735 5,400,000

Sod 1.5 350 0.0136 7,400 0.0000321 1,200,000

Field crop, typical acreage8and Orchard10 4 0.0364 2,700 0.0000858 470,000

Field crop, high-acreage9 2 1200 0.0624 1,600 0.000148 270,000

Groundboom spray 

application

Golf course (fairways, tees, greens) 78.6 0.34 1.5 40 0.059 1,700 0.000255 160,000 Field-grown ornamental crops

Nursery (ornamentals, vegetables, trees, container stock) 2 60 0.118 850 0.00051 78,000

Sod 1.5 80 0.118 850 0.00051 78,000

Field crop, typical acreage8 and Orchard10 4 0.315 320 0.00136 29,000

Field crop, high-acreage9 2 200 0.393 250 0.0017 24,000

Flagger

Flagger for aerial spray 

application

Nursery (ornamentals, vegetables, trees, container stock) 11 0.35 2 60 0.0165 6,100 0.00525 76,000

Sod 1.5

350

0.0723 1,400 0.0023 17,000

Field crop, typical acreage8and Orchard10 4 0.193 520 0.00613 6,500

Field crop, typical and high-acreage9 2 0.0963 1,000 0.00306 13,000
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Occupational Handler Non-Cancer Exposure and Risk Estimates for Pronamide

Exposure Scenario Crop or Target

Dermal Unit 

Exposure 

(μg/lb ai)1

Inhalation 

Unit Exposure 

(μg/lb ai)1

Maximum 

Application 

Rate (lb 

ai/A)2

Area 

Treated 

(acres)3

Dermal

(LOC = 100)

Inhalation

(LOC = 1000)

Mitigation Level = baseline 

unless indicated otherwise

Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7

Mixer/Loader/Applicator

Wettable powder in 

Water Soluble Package

(WSP) via Backpack

Orchard10 crops (ground soil directed) 8260 2.58 0.1 lb ai/gal

40 gallons

0.413 240 0.000129 310,000

Wettable powder in 

Water Soluble Package

(WSP) via Backpack

Landscaping, turf (lawns, athletic fields, parks, etc.) 8,260 2.58

0.075

0.31 320 0.0000968 410,000

Wettable powder in 

Water Soluble Package

(WSP)via ManuallyPressurized Handwand

Landscaping, turf (lawns, athletic fields, parks, etc.)

430

(Single 

layer/Glove)

30 0.0161 6,200 0.00113 35,000

Wettable powder in 

Water Soluble Package

(WSP) via 

Mechanicallypressurized Handgun

Golf course (fairways, tees, greens)

1350 18 1.5 5 0.126 790 0.00169 24,000 Landscaping, turf (lawns, athletic fields, parks, etc.)

Liquids via Backpack Orchard10 crops (ground soil directed) 8,260 2.58 0.2

40 gallons

0.826 120 0.000258 160,000

Nursery (ornamentals, vegetables, trees, container stock)

0.072

0.298 340 0.0000929 430,000

Liquids via Manuallypressurized Handwand Landscaping, turf (lawns, athletic fields, parks, etc.)

430

(Single 

layer/Glove)

30 0.0155 6,500 0.00108 37,000

Liquids via 

Mechanicallypressurized Handgun

Golf course (fairways, tees, greens) 1,140 1.9 1.44 5 0.103 970 0.000171 230,000 Landscaping, turf (lawns, athletic fields, parks, etc.)

Orchard10 crops (ground soil directed) 390

(Single 

layer/Glove)

3.9

0.2 1000 

gallons

0.971 100 0.00975 4,100

Nursery (ornamentals, vegetables, trees, container stock) 0.072 0.351 280 0.00351 11,000

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013); 

2 Based on registered and proposed labels.

3 Exposure Science Advisory Council Policy #9.1 and Registrant information.

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Area Treated (A/day) ÷ BW (80 kg).

5 Dermal MOE = Dermal NOAEL (100 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Area Treated (A/day) ÷ BW (80 kg).

7 Inhalation MOE = ACN LOAEL (40 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

8 Field crops, typical acreage category covers the following crops: asparagus, Brassica, head and stem, Brassica, leafy greens, cabbage, berries, edamame, fallow cropping systems, flax, fruiting 

vegetables, okra, horseradish, lima beans, melons, rhubarb, strawberry, succulent peas, tobacco, turnips, Christmas tree farms, mint, peanuts, peppermint, spearmint, potato sugarcane, dry shelled peas 

and beans and sunflower @ a maximum of 2lb ai/A and for berries @ 3 lb ai/A 

9 Field crops, high acreage crops category covers the following crops: corn, soybeans and wheat @2 lb ai/A.

10 Orchard crops, apples, apricot, artichoke, cherry, peach, pear, peach, pear, plum, nectarine, citrus fruits, tree nuts, grapes, Christmas tree plantations @4 lb ai/A 
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Appendix F. International Residue Limits Table

Pronamide (aka Propyzamide; PC Code 101701)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex

40 CFR 180.317:

(a) General. (1) propyzamide residues 

convertible to methyl 3,5-dichlorobenzoate, 

expressed as the stoichiometric equivalent of 

propyzamide, 3,5-dichloro-N-(1,1-dimethyl-2-

propynyl)benzamide

3,5-dichloro-N-(1,1-

dimethyl-2-propyn-1-

yl)benzamide, including 

metabolites containing 

the 3,5-dichlorobenzoate 

moiety

None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico1 Codex

Alfalfa, seed 10.0

Animal feed, nongrass, group 18 10.0

Apple 0.1 0.1

Artichoke, globe 0.01

Blackberry 0.05

Blueberry 0.05 0.05 lowbush blueberries

Boysenberry 0.05

Cattle, fat 0.2

Cattle, kidney 0.4

Cattle, liver 0.4

Cattle, meat 0.02

Cattle, meat byproducts, except 

kidney and liver

0.02

Egg 0.02

Endive 1.0

Fruit, stone, group 12 0.1

Goat, fat 0.2

Goat, kidney 0.4

Goat, liver 0.4

Goat, meat 0.02

Goat, meat byproducts, except 

kidney and liver

0.02

Grape 0.1

Hog, fat 0.2

Hog, kidney 0.4

Hog, liver 0.4

Hog, meat 0.02

Hog, meat byproducts, except 

kidney and liver

0.02

Horse, fat 0.2

Horse, kidney 0.4

Horse, liver 0.4

Horse, meat 0.02

Horse, meat byproducts, except 

kidney and liver

0.02

Lettuce, head 1.0 1 lettuce

Milk 0.02
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Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex

Pear 0.1 0.1

Poultry, fat 0.02

Poultry, liver 0.2

Poultry, meat 0.02

Poultry, meat byproducts, except 

liver

0.02

Radicchio 2.0

Raspberry 0.05

Sheep, fat 0.2

Sheep, kidney 0.4

Sheep, liver 0.4

Sheep, meat 0.02

Sheep, meat byproducts, except 

kidney and liver

0.02

Completed: M. Negussie; 05/07/15

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

(c) Tolerances with regional registrations. Tolerances with regional registration, as defined in §180.1(l), are 

established for residues of the herbicide propyzamide, including its metabolites and degradates, in or on the 

commodities in the table in this paragraph. Compliance with the tolerance levels specified in this paragraph is to be 

determined by measuring only those propyzamide residues convertible to methyl 3,5-dichlorobenzoate, expressed as 

the stoichiometric equivalent of propyzamide, 3,5-dichloro-N-(1,1-dimethyl-2-propynyl)benzamide, in or on the 

commodity.

Commodity Parts per million

Pea, field, seed 0.05

Rhubarb 0.1

(d) Indirect or inadvertent residues. Tolerances are established for indirect or inadvertent residues of the herbicide 

propyzamide, including its metabolites and degradates, in or on the commodities in the table in this paragraph. 

Compliance with the tolerance levels specified in this paragraph is to be determined by measuring only those 

propyzamide residues convertible to methyl 3,5-dichlorobenzoate, expressed as the stoichiometric equivalent of 

propyzamide, 3,5-dichloro-N-(1,1-dimethyl-2-propynyl)benzamide, in or on the commodity.

Commodity Parts per million

Grain, cereal, forage, group 16 0.6

Grain, cereal, hay, group 16 0.2

Grain, cereal, straw, group 16 0.3