UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON

, D

. C

. 2 0460

OFF I CE OF
CHE M IC A L SAF E TY AND
PO LLUT ION PR EVE N TIO N



### MEMORANDUM

Date : November 9, 2015

SUBJECT: Pronamide. Human Health Ri s k Assessment for Registration Review and to

S upport New Sect ion 

### 3 Use on L ea f Lettuce 

### (Revised)

.

PC Code: 101701

Decision No

. : 0493477

Petition No

. : 4F8301 DP Barcode: 0422207, 0410291

Regi s tration No.: 62719-578 Regul a tory Action: Regi s tration Review / Section 3

Case No.: 0082 Ri sk A ssess ment Type : Single C hemi cal/Aggregate

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

MRID No.: see Refe r ences 40 CFR: 40 CFR § 180 .3 17



### FROM:

THROUGH :

TO: R ay K e nt

, Ph.D

., Se nior Scientisf 1

# ~**~** - Ideliz Negr6n-Encarnaci6n

,

### D fi"Ct# i st

. 

# .9Jt.&

.._I

--- Seyed Tadayon

, Chemist

-

### /'10:-~<J__-..**~;;** Risk Assessment Bran c h V and Yll

/ H ea lth Effects Division 

## (7509Pkft· / /}

Mik e M etzger

, Branch Chief 

# J ,..,P)

Risk Assessment Branch V an V I

Health Effects Division (7509P)

Office of Pesticide Programs 

## .-.£.JL 

## dO'"**~(tl ~**  Anna Lowit, RARC D etai l e d Reviewer

Char l es Smith

, RARC Detailed Reviewer

### , (\ 

### .n

1 -

### ~ William Irwin

, ToxSAC Detai l ed Reviewer 

# l u <J' 

# 11'-u-vri

Chris Schlosser

, ToxSAC Detai l ed Reviewer

Wil h e lm ena L i vi n gs ton

, Chemical Review Manager

Kevin Coste ll o
, Branch Chief

Ri sk Management and I mplementation Branch IV

Pesticide Re-evaluation Division (7508P)

Reuben Baris

, Risk Manager

Daniel Kenny

, Branch Ch i ef

H e rbicide Branch Registration Division (7505P)

Page 1 of72Pronamide Hum an Health Risk Assess m ent DP No. 04 22207

Tab le of Contents

1

. 0 Ex ecutive Summary

................................................................. .. ..... .. ... . ...... . ... .. ..... .. .......... 4

2.0 HED Recommendations

. . ................................................. . ...... .. .. . ...... .. .. . ... . .......... . ... . .. . .... 7

2.1 Data Deficiencies

............................................... . ........... . ................................................ 7

2

. 2 Tolerance Considerations

. ...... . ........... .. ... ..... .. .. ...... .. .. ... ..... .. ................................ . ..... .. . 7

2.2.1 E nforcem ent Analytical Method

........................ . ........... . ............... ... . ...... .. .. . ............ 8

2.2.2 Recommended Tolerances

.. .. ........... . ....... . ... .... ... . ........... . ...... . ... .. ...... . ...... . ................ 8

2.2.3 Revisions to P e titioned-For To ler a nces

.............................................................. l o+G

2.2.4 lnt ernationa l Harmonization

. ... .. ... ..... .. .. ..... .. ... . ....... .. .. . ...................................... 

### UH

2.3 Label Recommendations

............... .. ............................................................. . ...... . .... 

### UH

2.3.1 Recommendations from Residue Review s

....................... . .......... .. ...... . .. ..... . ... . .. . 

### 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 Id ent i ty

.. . .. . ... ... . . ....... . ... . ........................................................................... 

### JlH

3.2 Physical/Chemical Characteristics

.... .. ........... . ............................... . ................... .. .. 

### JlH

3.3 Pe s ticide Use Pattern

....................................... ..... .. .......... ......... ... ......... .. ..... ... ..... . ... 1 2H

3.4 Anticipated Exposure Pathways

........................... ... ...... . .. ... .... ... .. .... ...................... 

### 11-H

3

. 5 Consideration of Environmental Ju s tice

................................. . ...... . ....................... 1 4+4

4.0 Hazard Characterization and Dose-Response As s essment

...................................... 14+4

4

. 1 Toxicology Stu die s Available for Analysis

........................................................ . .... 14+4

4

. 2 Absorption, Distribution, Metabolism

, & E liminati on (ADME)

......................... 

### UH

4.2.1 Dermal Absorption

...... .. .. .. ... . .. .. .. ...... .. .. .. .. ...... . ...... .. .. ... . .. .. .. .. ...... . ... ..... .. . ...... . ..... 1 6+6

4.3 Toxicological Effects

... ..... .. .. ..... ... .. ... ........... . ..... .. ....... . .. ... .. ..................................... 11+6

4.4 Safety Factor for Infants and C hildren (FQPA Safety Factor)

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

.. .. .. ...... ... . ....... . .. .... .... .. ..... .. .. ..... .. . .....**~+8** 4.4

. 2 Evidence of Ne urotoxici ty

... . ........ . ........................................................... . ...........**~+9** 4

. 4.3 Evidence of Sensi tivi ty/S u sceptibility 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 Se l ections

................................... . ... . .. 1.2+9

4.5

. 1 Dose-Response Assessment

....... .. ... .......... .. ..... ... . ................... .. ...... . .. ... . ..... ... .. ..... 1.2+9

4.5.2 Recommendation for Combin ing Routes of Expos ur es for Risk Assessment

. 

### £1.U

4.5.3 Cancer C la ssification 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 Environmenta l Degradation

.............. .. .......................................... 282'8

5.1.3 Comparison of Metabolic Pathways

........................ . ... .. . ............................... . .... 282'8

5.1.4 Residues of Concern Summary and Rationa l e

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

.. . ........... .. ........... ... .......... . .......................................................**29~** 5.4 Dietary Risk Assessment

..................... . ... . ...... ... ..... .. ... .. .............................. .. .......... . 

### 11;.i.

Page 2 of 72Pronamide Human Health Risk Assessment DP No. D422207

Page 3 of 72 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 Aggregat e 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 followin g 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

................................ ................................ ... 68Pronamide Human Health Risk Assessment DP No. D422207

Page 4 of 72 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, recr eational 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 ( D RA) 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

reg istered 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), reside ntial/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 th e 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 lea f lettuce

. The liquid formulation (EPA REG #

62719

- 578) may be applied via aerial, chemigation

, and groundboom equipment. The proposed single maximum application rate s and PHIs range from 0.5 lbs ai/A (25 days) to 2.0 lbs ai/A (55 days) . Two broadcast ap plication s 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, thyroi d 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 f or carcinogenicity

.Pronamide Human Health Risk Assessment DP No. D422207

Page 5 of 7 2 Neurotoxic ity 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 n o effects observed in any of the pronamide toxicity studies below 4 mg/kg/day, t h is 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 sco ping 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 Sect ion

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 i ts 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 pea s , f ield trial data from two additional field trials for pea vines and hay an d four additional field trials for pea seed are required.

Dietary Exposure and Risk

Unrefined acute and chronic dietary assessments were p erformed

. T olerance level residues of pronamide were used for the registered uses and proposed new use on leaf le ttuce. 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 concentration s (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 ar e 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. H owever, the re is the potential for post

application exposure from currently registered turf use s (e.g., res idential turf, golf courses) and

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

All dermal and incidental oral risk estimates for post

- application exposure are no t of concern (i.e., dermal MOEs ≥ 10 0 and all incidental oral MOEs ≥ 100 0 )

.

Aggregate Exposure and RiskPronamide Human Health Risk Assessment DP No. D422207

Page 6 of 72 There was a single scenario assessing aggregate risk to children from post application exposure to pronamide from treat ed turf. Aggregate hand

- to

- mouth and chronic food and water exposure

is not of concer n 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 t he turf post

application MOEs are protective for any potential exposures related to spray drift

.

Occupational Exposure and Risk

O ccupational 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 protect ive 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 o f 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 interm ediate

- term scenarios h ave adequate

MOE s 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 registe red 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

. B ased on quantitative post

- application

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

.Pronamide Human Health Risk Assessment DP No. D422207

Page 7 of 72 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 Lo w

- 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 the ir use, can be found at the Agency website 1

.

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

. A dditional 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, D 383372 ).

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 registr ant 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 t he 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.htmlPronamide Human Health Risk Assessment DP No. D422207

Page 8 of 72 livestock commodities, and in drinking water, are pronamide and its metabolites containing the 3,5

- dichlorobe nzoyl 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

- dichlorobenzo ate ( MDCB). Method I was successfully radiovalidated using aged samples from the alfalfa and lettuce

metabolism studies.

Livestock: Modifications to the livestock enfo r cement method w ere 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 determinat ion of residues o f pronamide and metabolites containing the 3,5

- dichlorobenzoyl moiety converted to 3,5

- dichlorobenzoic acid (3,5

- DCBA) i n milk, bovine liver, kidney, muscle, and fat, and eggs and poultry muscle and fat is available for enforcement of

tolerances for livest ock 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. Ne grón

- Encarnación, D383372, 0 9 / 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 commodi ties 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 herbici de 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

-Pronamide Human Health Risk Assessment DP No. D422207

Page 9 of 72 dichlorobenzoic acid , expressed as the stoichiometric equivalent of propyzamide, 3,5

- dichloro

N

- (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

Toleranc e 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, l eaf 1.0 1

Pear 0.1 0.1

Radicchio 2.0 2.0

Raspberry 0.05 0.05

Toleranc e 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 0.02Pronamide Human Health Risk Assessment DP No. D422207

Page 10 of 72 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 0.10 1

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

Pea, field, hay

-- 3.0 1

Pea, field, vines

-- 1.5 1

1 To be re

- evaluated upon submission of adequate magnitude of residue studies.

2.2. 3 Revisions to Petitioned

- For Tolerances

The registrant ha d 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

patte rn. 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.Pronamide Human Health Risk Assessment DP No. D422207

Page 11 of 72 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 to lerances, and Canadian and Codex MRLs for pronamide is provided in Appendix G

. Currently, Mexican or Codex MRLs for

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

harmonized for measurement of pronamide, including meta bolites 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

Canadia n 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 Recommendati ons from Occupational Assessment

The current PPE for registered uses and the proposed use are c overalls 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 f rom Residential Assessment

None at this time

.

3.0 In troductionPronamide Human Health Risk Assessment DP No. D422207

Page 12 of 72 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

T able 3.1 Pronamide Nomenclature.

Compound

Empirical Formula C 12 H 11 Cl 2 NO

Molecular weight 256. 13

Common name p ronamide or p r opyzamide

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 , 11 th 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 8.5 x 10

- 5 torr. The log Kow for pronamide is 3.43. A table of physic o

- chemical properties for pronamide may be found in Appendi x 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

. T he 2002 r esidue c hemistry c hapter 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 f or cereal grains (Crop Group 15) and the forage, fodder, and straw o f 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 consideredPronamide Human Health Risk Assessment DP No. D422207

Page 13 of 72 adequate. However, restrictions for other crops such as legume vegetables and cotton (90 to

150

- day PBI), and brassica leafy vegetables, cucurbit vegetables, fruiting ve getables, 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.

Conclu sions : 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 Div ision and Pesticide Re

- evalu ation 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 Prelimin ary 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 closelyPronamide Human Health Risk Assessment DP No. D422207

Page 14 of 72 following application. The most likely activity is scouting for herbicide efficacy. Unlike scouting for insects or mites, there is little expected foli ar 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 co nsumer 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 assessm ents 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 perf ormed 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 postap plication 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 . Th e data from th e fo l low ing acceptable s tudies w e r e us e d to evaluate t he hazard p otential of pronamide :

 Oral subchronic toxicity stud y in the ratPronamide Human Health Risk Assessment DP No. D422207

Page 15 of 72  D ermal subchronic toxicity study in the rat

 P renatal developmental toxicity study in the rabbit

 M ulti

- generation reproduction study in the rat

 C hronic toxicity studies in the rat and dog

 Carcinogenicity studies in the rat and mouse

 M utagenicity battery

 A cute and subchronic neurotoxicity screening batteries in the rat

 M etabolism with pharmacokinetic stud ies in the rat

 D ermal abso rption studies in vivo and in vitro

 I mmunotoxicity 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 pat terns 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 d etermin e if there is a surge in LH (luteinizing hormone) levels in the

blood of rats af

ter administra tion 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 medi ated through alterations in liver enzyme s (TXR# 0057 211 ).

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

O rally administered p ronamide is quickly absorbed from the g.i. tract and rapidly eliminated

. In

a n ADME study with 14 C

- pronamide (MRIDs 41801801, 41929901 and 42858001) r adio label 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. T he half

- life of elimination of radioactivity f

rom 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 h ou rs in males and 45 hours in females ; and that of high dose (100 mg/kg) rats was monophasic with a half

- life of 24 hrs (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 unidentifiedPronamide Human Health Risk Assessment DP No. D422207

Page 16 of 72 metabolites and none exceeded 3.3% of the dose. Few metabolites were identified in the feces,

a nd 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 6 3 % 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

e xcretion 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 ( 14 C-Kerb 50W and 14 C-Kerb 3.3 F ) 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 /cm 2 ) or a high dose of 66 mg ai /kg (4.4 mg ai /cm 2 ). 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 14 C- pronamide administered by gavage in corn oil, or an i.v. dose of 1.3 mg/kg of 14 C- pronamide in DMSO. Quantitation of uptake was based primarily on radiolabel recovered from excreta.

A total of 19 % and 17 % of recovered 14 C-pronamide was eliminated in the excreta following the low and high dose of 14 C-Kerb 50 W, respectively. A total of 15% and 5 % of the recovered 14 C1 abe l was eliminated in the excreta following the low and high dose of 14 C- 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 d ermal absorption factor of 23%. Furthermore, thePronamide Human Health Risk Assessment DP No. D422207

Page 17 of 72 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 w as 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 ce ll division in the root systems of a select group of annual grasses and broadleaf weeds.

In mammals

, p ronamide is primarily a liver toxicant. L iver

- 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 effect s 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 t here

is no gender sensitivity in response to pronamide

.

Pronamide causes liver tumors in mice and th yroid 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 enzy mes associated with a second nuclear receptor, PPAR

- α. Induction of the nuclear receptors is followed by hepatocellular proliferation and eventually, liver tumors.

In rats t umor precursor effects such as decreases in T4 levels, increase s 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 blo od T4 levels at doses 2

- to 4

- fold

lower than doses resulting in thyroid tumors. B ased on mode of action studies, tumorigenesis for all three tumor types ha s been shown to be mediated by liver enzymes induced in response to

treatment with pronamide . In r ats

, pronamide induces C YP2B1 200 fold over background levels,

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

CYP 2 B 1 is a biological marker for the constitutive and rostane 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 i n 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 mult i

- generation reproduction study inPronamide Human Health Risk Assessment DP No. D422207

Page 18 of 72 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 e ffects 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 stu dies 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

acu te neurotoxicity ( ACN) study t he LOAEL wa s 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 a nd skin (Toxicity Category IV), and is not a dermal sensitizer.

4.4 Safety F actor 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 . T here was no evidence of quantitative or qualitative susceptibility in the developing organism and e vidence 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 o f the Toxicology Database

The toxicity database for pronamide is complete.

4.4.2 Eviden ce of N eurotoxicity

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 neurotox i city i n 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.Pronamide Human Health Risk Assessment DP No. D422207

Page 19 of 72 4.4.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r 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 Datab ase

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 f

ood and water has been provided.

4.5 Toxicity Endpoint and Point of D eparture 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 description s 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 a cute neurotoxicity study i n rat s (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 e ndpoint 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 in ter

- species extrapolation, 10X for intra

- species variation and a 10X for the use of a LOAEL (UF L ).

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 contain s subchronic andPronamide Human Health Risk Assessment DP No. D422207

Page 20 of 72 chronic toxicity, carcinogenicity and reproductive toxicity studies conducted in CD rat s and neurotoxicity studies (acute and subchronic) conducted in Fischer 344 rats.

In CD rat s, the target organs were liver, thyroid and the testes

. In the chronic toxicity/carcinogenicity study with CD rat s, pronamide caused in creased relative liver weight and histopathological lesions in the liver, thyroid, and ovaries at 4 3 mg/kg/day , the same dose

that induced thyroid and testicular tumors in rat s. The registrant has submitted mode of action studies for each of the tumor type s and the available MOA studies clearly identi fy 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 st udy 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 1 2 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 t erm 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 b e 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 ED SP program . The NOAEL f or the study is 2.5 mg/kg/day. Application of

a 10x UF L factor to the LOAEL of 40 mg/kg/day established in the ACN results in a n extrapolated NOAEL of 4.0 mg/kg/day. The lower NO AE L 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 UF L ). 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 bodyPronamide Human Health Risk Assessment DP No. D422207

Page 21 of 72 weight (10%) and food consumption (7

- 8% during the final two week of the study) were seen in

male s at 500 mg/kg/day. These effects were slightly enhanced at the next highest dose (1000 mg/kg/day); 12% decrease in body weigh t and 8

- 13% decrease in food consumption. The NOAEL of 100 mg/kg/day was selected as the POD for dermal risk asse ss ments.

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

concern. The occupational and resid ential LOC is a MOE of100 (includes UF A =10x and

UF H =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 r emains 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 exposur e scenarios,

these routes can be combined

. The dermal POD for pronamide is based on a study that measure s body weight decreases and decreased food consumption. No other effects were observed. Decreased body weight is also observed in most oral studies wi th pronamide , however the body weight effect s 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:

Prona mide 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 establis hed in the 2006 IPCS Human Relevance Framework. The MOAs were adequately supported by studies that clearlyPronamide Human Health Risk Assessment DP No. D422207

Page 22 of 72 identified the sequence of key events, dose

- response concordance and temporal relationship to the particular tumor type.

Quantification of carcinog enic 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.Pronamide Human Health Risk Assessment DP No. D422207

Page 23 of 72 4. 5

. 4 Summary of Points of Depa rture 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 Non

Occupational 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 UF A =10 X

UF H =10 X

UF L = 10 X

FQPA SF =1 X 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 year s 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 UF A =10 X

UF H =10 X

UF L = 10 X

FQPA SF =1X cRfD=cPAD=

0.04 mg/kg/day The POD of 4 0 mg/kg/day was selected based

on a weight of evidence approach using the

results from the 4 studies in rats listed below.

S ubchronic neuro to xicity (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.

A cute neurotoxicity ( A C N): NOAEL was not established. The LOAEL of 40 mg/kg/day with

a 10X LOAEL to NOAEL uncertainty factor (UF L ) 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 o varies at 42.59/55.09 mg/kg/day (LOAEL).

Male p ubertal study. NOAEL of 2.5 mg/kg/day. The LOAEL is 10 mg/kg/day

based on decreased serum T4.

Incidental

Oral Short

Term (1

- 30 days) LOAEL = 40

mg/kg/day UF A =10X

UF H =10X

UF L = 10 X

FQPA SF =1X Residential LOC

for MOE = 100 0 See Chronic RfDPronamide Human Health Risk Assessment DP No. D422207

Page 24 of 72 Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Pronamide for Use in Dietary and Non

Occupational 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 Short

Term (1

- 30 days) and

Intermediate

Term (1

- 6 months) NOAEL=

100 mg/kg/day UF A =10X

UF H =10X

FQPA SF=1 X 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

Intermediate

Term (1

- 6

mon ths) LOAEL = 40

mg/kg/day UF A =10X

UF H =10X

UF L = 10 X

FQPA SF =1X Residential LOC

for MOE = 1 00 0 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. UF A = extrapolation from animal to human (i nterspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a

NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = to account for the absence o f 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 Short

Term (1

- 30 days) and

Intermediate

Term (1

- 6 months) NOAEL=

100 mg/kg/day UF A =10X

UF H =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 dosingPronamide Human Health Risk Assessment DP No. D422207

Page 25 of 72 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

Intermediate

Term (1

- 6 months) LOAEL = 40

mg/kg/day UF A =10X

UF H =10X

UF L = 10 X Occupational

LOC for MOE =

100 0 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 le vel. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a

NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = 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, t hese 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 infl uence, 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 assess ment 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 cer tain 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 emp loys 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) hormonalPronamide Human Health Risk Assessment DP No. D422207

Page 26 of 72 s ystems. 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 mu st 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 identi fied for EDSP screening was published on June 14, 2013 2 and 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

- HQ

OPP

- 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

P rimary Crops : The qualitative nature of the residue in plants is adequately understood on alfalfa, lettuce and similar crops ( D275536, 02/28/2002 )

. Soil applied p ronamide is readily absorbed through the root system, translocated upward, and distributed into the entire plant. Conversely t ranslocation from lea f 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 lettu ce consist mainly of pronamide per

se , gluco se conjugates, and glucose

- malonyl conjugates

, all conta ining 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/Pronamide Human Health Risk Assessment DP No. D422207

Page 27 of 72 Pronamide

No evidence of fragmentation of the benzene ring or loss of the chlorine substituent s 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 co nfined rotational crop study (MRID 41462001 and 41913506). In this study, uniformly ring labeled [ 14 C]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 m onths, 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 r esidues 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 adequat ely understood ( D275536,

02/28/2002 )

. S tudies 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 m etabolic 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 andPronamide Human Health Risk Assessment DP No. D422207

Page 28 of 72 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 i n 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

- 2 6059

HED determined that all degradates of pro n amide 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 ( 8.5x 10

- 5 torr ) and is soluble in water up to 15 mg/L. The compound is stable to hydr olysis, relatively resistant to soil photolysis and moderately susceptible to aquatic photolysis. Pro namide degrade s relatively readily in aerobic soil

environments

, but is more persist ent in anaerobic environments and aquatic environments

. S orption to s oils is a function of organic carbon and also correlat es with cation exchange capacity.

Nonetheless t he compound is mobile in soil

, and thus presents a potential groundwater concern in

some area s, 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 pr onamide 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 identi fied

.Pronamide Human Health Risk Assessment DP No. D422207

Page 29 of 72 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 simila rity 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, f ield 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, vi nes 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

addre ssed

.

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 an d 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).Pronamide Human Health Risk Assessment DP No. D422207

Page 30 of 72 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.Pronamide Human Health Risk Assessment DP No. D422207

Page 31 of 72 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 Treate d 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

- FCI DTM model were less than

100% of the acute population adjusted dose (aPAD) at the 95 th percentile of exposure for the general U.S. population and all population subgroups. Pronamide acute dietary exposure (food + drinking water) was estimated at 0.00714 4 mg/kg/day for the general U.S. population (18% of the aPAD) and 0.01853 9 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 (fo od + 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 (C hildren 1

- 2 years old).Pronamide Human Health Risk Assessment DP No. D422207

Page 32 of 72 5.4.5 Cancer Dietary Risk Asses sment

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 as sessment 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 popu lation 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 ( 95 th Percentile) Chronic Dietary

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

General U.S. Population 0.00714 4 18 0.001706 4.3
All Infants (<1 year old) 0.01853 9 46 0.00385 4 9.6

Children 1

- 2 years old 0.01331 7 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 0.0065 70 16 0.001534 3.8

Adults 50

- 99 years old 0.00589 3 15 0.001526 3.8

Females 13

- 49 years old 0.00675 3 17 0.001558 3.9Pronamide Human Health Risk Assessment DP No. D422207

Page 33 of 72 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

- ap plication 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 Ha ndler 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 ind ividuals 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 tu rf: 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 SOPs 4 . 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 serv ed as the basis for completing the residential

post

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

SOPs 4

.

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 ant icipated that these applications will be intermittent in nature and dissipation due to rainfall/irrigation, grass growth, and grass

m owing is expected. There is the potential for intermediate

- term exposure to pronamide

,

4 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.htmlPronamide Human Health Risk Assessment DP No. D422207

Page 34 of 72 however, s ince the maximum yearly a pplication 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 analysi s 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 estimate s 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 o f 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 exposur e are

no t 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 MOEs 2 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 0.020 200 0 Object to Mouth 0.00062 6 5

, 0 00

Short

- and Intermediate

- term Incidental Soil

Ingestion 0.000051 790

, 00 0

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

2 MOE = POD (Dermal = 100 mg/kg/day and Incidental oral = 4 0 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

- A pplication 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 issuesPronamide Human Health Risk Assessment DP No. D422207

Page 35 of 72 related to volatilization of pesticides from its FIFRA Scientific Adviso ry Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010. 5 The A gency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis. 6 D uring Registration Rev iew, the Agency will utilize this analysis to determine if data (i.e., flux studies) or further analyses are required for pro namide

.

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 200 0

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 off

target 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 expo sures ( 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 pr oducts.

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 tur f application rate ( also 4 lb ai/A) 7 for

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/APronamide Human Health Risk Assessment DP No. D422207

Page 36 of 72 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 sou rces 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 w ere 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 f or children (1 to 2 years old from Table 4 )

Table 7.2 Short

- Term Aggregate Risk Calculations

Population Short

- Term Scenario

L OAEL mg/kg/day LOC 1 Max

Allowable Exposure 2 mg/kg/day Average

Food and

Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Tota l

Exposure mg/kg/day 4 Aggregate

MOE (food, water, and residential) 5

Child 4 0 100 0 0.04 0.004410 0.02 0.024 1 7 0 0

1 Based on a POD of 4 0 mg/kg from the LOAEL of an ACN study. The traditional inter

- and intraspecies factors are applied as well as a UF L of 10 for a total LOC of 100 0

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

3 Residential Exposure = Oral exposure (hand

- to

- mouth)

- Table 5.3.1

. 4 Total Exposure = Av era g e Food & Water Exposure + Residential Exposure

5 Aggregate MOE = NOAEL / (Av era g e 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 m ade 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 pro namide 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 re leased 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/.Pronamide Human Health Risk Assessment DP No. D422207

Page 37 of 72 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 lettu ce , 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 pattern s have

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

. U pdated

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

since the inhalation point of departure and LOC for pronamide ha ve 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 Age ncy 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 ap plications,

 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 Pa ckage (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, andPronamide Human Health Risk Assessment DP No. D422207

Page 38 of 7 2  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 assess ments. Each assumption and factor is deta iled 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 Ref erence Table 8 ”, 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 website 9

.

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 ca n be made 60 days apart; and (2) co mmercial 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 t he 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). Resul ts 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, res pirator, 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 ri sk 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.htmlPronamide Human Health Risk Assessment DP No. D422207

Page 39 of 72 The occupational handler exposure and risk estimates ind icate that the short

- and intermediate

term dermal and inhalation MOEs are not of concern to HED (i.e., MOEs > 100 for dermal and

> 1000 for inhalation) f

or 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 con cern 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 ass ess 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 re

entry exposure). The majority of pronamide usage occurs preemergen ce 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. E xposure 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

- appli cation Dermal Exposure/Risk Estimates

Most of the registered uses (with exception of lettuce), for pronamide are soil

- directed preplant

or pre

- e mergent 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

Page 40 of 72 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 p attern, short

- and intermediate

- term exposures are anticipated for the following reasons: (1) up to two applications ca n be made 60 days apart; and (2) commercial applicators may apply this product at various locations within a region over a period of week s. 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 Coeff

icients : 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 da ta 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 3 10 ” which, along with additional in formation about the ARTF data, can be found at the Agency website 11

.

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 (cm 2 /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.htmlPronamide Human Health Risk Assessment DP No. D422207

Page 41 of 72 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 Div ision’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 (F AR ). This default value is 25% and is based on an analysis of 19 DFR studies where the F AR 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 F AR 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 res idue 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, Exp osure 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 t han 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 gene ral 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

- applic ation

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

Page 42 of 72 Table 9

. 2 .2.2

. Occupational Post

- application Non

- Cancer Exposure and Risk Estimates for Pronamide

Crop/Site Activities Transfer

Coefficient (cm 2 /hr) Application

Rate (lb ai/A) DFR or

TTR 1 Dermal Dose (mg/kg/day) 2 MOE 3

(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/cm 2 ; 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/cm 2 ) × Transfer Coeffici ent × 0.001 mg/μg × 8 hrs/day ]  BW ( 80 kg).

3 MOE = POD (100 mg/kg/day ) / Daily Dermal Dose.

Restricted Entry Interval

. B ased 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

Pronamide (Propyzamide): Report of the Mechanism of Toxicity Assessment Review Committee (MTARC) Evaluation of the Available Mechanistic Information for the Active Ingredient, Pronamide ; TXR Number: 0050338; January 21, 2002

.

Pronamide. Tolerance Reassessment Eligibility Decision Document. Product and Residue Chemistry Chapter. PC Code: 101701. DP Barcode: D275536, February 28, 2002.

Pronamide (Propyzamide). Human Health Assessment Scoping Document in Support of Registration Review. D363904, June 17, 2009

P ronamide (Propyzamide): Report of the Cancer Assessment Review Committee : December 2,

201 4 ; TXR 0057037

.

Pronamide: Summary of Hazard and Science Policy Council (HASPOC) Meeting on April 24,

201 4 : Recommendations on Data Requirement for a Developmental Toxicity Rat Study: TXR

0056955.Pronamide Human Health Risk Assessment DP No. D422207

Page 43 of 72 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; D P 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; D P 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 ; D P 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

MRID 00062605. Sinkeldam, E.J. (1974) Sensitization Test with Kerb Technical in Guinea Pigs: Report No. R 4448. (Unpublished study received Feb 25, 1977 under 707

- 98; prepare d by Central Instituut voor Voedingsonderzoek TNO, Netherlands, submitted by Rohm & Haas Co., Philadelphia, Pa.; CDL:233726

- C)

MRID 00085505. Powers, M.B. (1966) Acute Oral Administration

-- Rats; Acute Eye Irritation

-- Rabbits; Acute Dermal Application

-- Rab bits; Acute Oral Administration

-- Dogs: Project No.

417

- 179 and No. 417

- 180. Final rept. (Unpublished study received Jun 15, 1969 under 9G0821; prepared by Hazleton Laboratories, Inc., submitted by Rohm & Haas Co., Philadelphia, Pa.;

CDL:091422

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Page 44 of 72 MRID 000 85506. 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 Jun 15, 1969 under 9G0821; prepared by Medical College of Virginia, Dept. of Pharmac ology, submitted by Rohm & Haas Co., Philadelphia, Pa.; CDL: 091422

- D)

MRID 00107968. Smith, J. (1974) Eighteen Month Study on the Carcinogenic Potential of Kerb (RH

- 315; Pronamide) in Mice. (Unpublished study re

- ceived Sep 16, 1974 under 3F1317;

prepare d in cooperation with Medical College of Virginia, submitted by Rohm & Haas Co., Philadelphia, PA; CDL:094304

- A)

MRID 00114114. Newberne, P.; McConnel, R.; Essigmann, E.; et al. (1982) Kerb: Chronic Toxicity Study in the Mouse: Project No. 77

- 1. (Unpub

- l ished study received Aug 31, 1982

under 707

- 98; prepared by Massachusetts Institute of Technology, Dept. of Nutrition and Food Science, Animal Pathology Laboratory, submitted by Rohm & Haas Co., Philadelphia, PA;

CDL:248233

- A)

MRID 00125789. Vogin, E. (19 71) Effects of RH315 on the Fetal Development in Rats: (Phase II): Laboratory No. 0512. (Unpublished study received Jan 28, 1983 under 707

- 98; prepared by Food and Drug Research Laboratories, Inc., submitted by Rohm & Haas Co., Philadelphia, PA;

CDL:249537

- A)

MRID 00133111. Larson, P.; Borzelleca, J. (1970) Toxicologic Study on the Effect of Adding

RH

- 315 to the Diet of Rats for a Period of Two Years. (Unpublished study received Feb 25,

1971 under 707

- 98; prepared by Medical College of Virginia, submitted by Rohm & Haas Co., Philadelphia, PA; CDL:004357

- A)

MRID 0014806 5. Costlow, R.; Kane, W. (1985) Teratology Study with Kerb Technical (No inert ingredient) in Rabbits: Report No. 83R

- 026. Unpublished study prepared by Rohm and Haas Co. 151 p.

MRID 40256701. DiDonato, L.; Hazelton, G. (1987) Kerb Herbicide: Dermal Absor ption Study

in Male Rats: Protocol No. 86P

- 467: Report No. 86R

- 225. Unpublished study prepared by Rohm and Haas Co. 136 p.

MRID 40334501. Solomon, H.; Holz, J. (1987) Kerb Herbicide: Oral (Gavage) Develop

- mental Toxicity Study in Rats: Protocol No. 86P

- 3 54B: Rept. No. 87R

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MRID 41117201. DiDonato, L.; Hazelton, G. (1989) Report Amendment 1 to Kerb Herbi

- cide: Dermal Absorption Study in Male Rats: Protocol No. 86P

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Page 45 of 72 MRID 41462001. Nelson, S.; NIcholls, R. (1990) Confined Rotation Crop Study for Carbon 14 Phenyl Labeled Pronamide: Lab Project Number: TR 34

- 90

- 11: EF

- 87

- 41. Unpublished study prepared by Rohm and Haas Co., in cooperation wit h Pan

- Agricultural Labs, Inc. 540 p.

MRID 41540301. Solomon, H.; Brown, W. (1990) Pronamide: Two

- generation Reproduction Study in Rats: Protocol No. 88P

- 309: Report No. 88R

- 257. Unpublished study prepared by Rohm and Haas Co., Toxicology Dept. 582 p.

MRID 41714001. Bailey, D. (1990) Kerb Herbicide(Technical, No Clay): 24

- Month Dietary Chronic Toxicity/Oncogenicity Study in Rats: Twelve Month Chronic Toxicity Phase: Lab Project Number: HLA 417

- 426S. Unpublished study prepared by Hazleton Laboratories

Am erica, Inc. 799 p.

MRID 41714002. Bailey, D. (1990) Kerb Herbicide (Technical, No Clay): 24

- Month Dietary Chronic Toxicity/Oncogenicity Study in Rats: 24

- Month Oncogenicity Study in Rats: Lab Project Number: HLA 417

- 426M: 87RC

- 62. Unpublished study prepar ed by Hazleton Laboratories America, Inc. 2218 p.

MRID 41801801. DiDonato, L.; Hazelton, G. (1991) C

- 14

- Pronamide (Kerb Herbicide): Pharmacokinetic Study in Rats: Lab Project Number: 89P

- 163: 89R

- 163. Unpublished study prepared by Rohm and Haas Co. 137 p

.

MRID 41807601. Briffaux, J. (1991) Pronamide (Kerb Technical Herbicide): 52 Week Oral (Dietary) Toxicity Study in the Beagle Dog: Final Report: Lab Project No. 616/503: 505069. Unpublished study prepared by Hazleton France. 827 p.

MRID 41913506. Nelson , S. (1991) Pronamide Confined Rotational Crop Study: Response to EPA Review (Shaughnessy No. 101701): Lab Project Number: 34

- 91

- 42. Unpublished study prepared by Rohm and Haas Company. 9 p.

MRID 41929901. Smith, S. (1991) Rat Metabolism of ?carbon 14| Pr onamide: Lab Project

Number: R&H 34

- 91

- 43. Unpublished study prepared by Rohm & Haas Co. 248 p.

MRID 42130301. Guichard, Y. (1991) Pronamide (Kerb Technical Herbicide): 52 Week Oral (Dietary) Toxicity Study in the Beagle Dog: Lab Project No: 616/503. Unpu blished study prepared by Hazleton France (HF). 44 p.

MRID 42669402. Goldman, P.; Bernacki, H. (1987) Pronamide: One

- month Dietary Toxicity Study in Rats: Lab Project Number: 86P

- 505: 86R

- 227. Unpublished study prepared by Rohm and Haas Co. 109 p.

MRID 42669403. Anderson, D.; Kulwich, B.; Hazelton, G. (1989) Pronamide Technical (no clay): Three

- month Dietary Toxicity Study in Rats: Lab Project Number: 87P

- 319: 88R

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Page 46 of 72 MRID 42858001. Smith, S. (1993) Metabolism of (carbon 14) Pronamide in Rats: Supplement A to: (carbon 14)

- pronamide (Kerb Herbicide): Pharmacokinetic Study in Rats: Lab Project

Number: 34

- 93

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- 163A. Unpublished study prepared by Rohm and Haas Company, Toxicology Department. 314 p.

MRID 43583901. Gingrich, S.; Parno, J. (1994) Kerb Technical: Acute Oral Toxicity Study in Male and Female Rats: Report Final: Lab Project Number: 94P

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MRID 43583902. Gingrich, S.; Parno, J. (1994) Kerb Technical: Acute Dermal Toxicity Study in Male and Female Rats: Report Final: Lab Project Number: 94P

- 178: 94R

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MRID 43583903. Gingrich, S.; Parno, J. (1994) Kerb Technical: Skin Irritation Study in Rabbits: Report Final: Lab Project Number: 94P

- 179: 94R

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MRID 43583904. Gingrich, S.; Parno, J. (1994) Kerb Technical: Eye Irritation Study in Rabbits: Report Final: Lab Pr oject Number: 94P

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MRID 44034201. Bernacki, H.; Ferguson, J. (1993) Kerb Technical: Acute Inhalation Toxicity Study in Rats: Lab Project Number: 93P/104: 93R/104. Unpublished study prepare d by Rohm and Haas Co. 49 p.

MRID 44952501. Martin, D. (1999) Determination of Transferable Turf Residues on Turf Treated with Pronamide (Kerb 50W Herbicide): Lab Project Number: TR34

- 99

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- 19:

002

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MRID 45919801. Stebbins, K.; Brooks, K.; Dryzga, M. (2002) Pronamide (Propyzamide): 28

- Day Dietary Toxicity Study in CD

- 1 Mice: Lab Project Number: 021076. Unpublished study prepared by The Dow Chemical Company. 333 p. {OPPTS 870. 3050}

MRID 46413407. Volkl, S. (2001) Degradation Rate of (Carbon 14)

- Propyzamide (Kerb) in Three Soils Incubated Under Aerobic Conditions. Project Number: 773897, 34/00/108. Unpublished study prepared by RCC Umweltchemie Ag. 134 p.

MRID 46424801. Stebbi ns, K.; Brooks, K. (2004) Pronamide (Propyzamide): 18

- Month Oncogenicity Study in CD

- 1 Mice. Project Number: 021118. Unpublished study prepared by The Dow Chemical Co. 1661 p.Pronamide Human Health Risk Assessment DP No. D422207

Page 47 of 72 MRID 46885701. Yano, B.; Dryzga, M. (2005) Pronamide Technical: 28

- Day Dermal T oxicity Study in F344/DuCrl Rats. Project Number: 051127. Unpublished study prepared by Dow Chemical Co. 308 p.

MRID 48599201. Crittenden, P. (2010) Pronamide

- A 28

- Day Dietary Immunotoxicity Study in

Male CD

- 1 Mice: Final Report. Project Number: WIL/410 031, 100086. Unpublished study prepared by WIL Research Laboratories, Inc. 362p.

MRID 48599202. Andrus, A.; Hukkanen, R. (2011) Pronamide: Acute Neurotoxicity Study in

F344/DuCrl Rats. Project Number: 101164. Unpublished study prepared by The Dow Chemical Co. 554p.

MRID 48599203. Marty, M.; Andrus, A.; Golden, R.; et al. (2011) Pronamide: 4

- Week Dietary Probe Study in F344/DuCrl Rats. Project Number: 101180. Unpublished study pre pared by The Dow Chemical Co. 106p.

MRID 48599204. Marty, M.; Andrus, A.; Stebbins, K. (2011) Pronamide: 90

- Day Dietary Subchronic Neurotoxicity Study in F344/DuCrl Rats. Project Number: 111003. Unpublished study prepared by The Dow Chemical Co. 577p.

MR ID 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 pr epared by The Dow Chemical Company. 314p.

MRID 49167410. Rasoulpour, R. ; Andrus, A. ; Thomas, J. (2013) Pronamide: 90

- Day Dietary Leydig Cell Tumor Mode of Action Study in Aged Crl:CD(SD) Rats. Project Number: 111057 WIL/410065, 368/010. Unpublished stud y prepared by Dow Chemical Co., The. 450p.Pronamide Human Health Risk Assessment DP No. D422207

Page 48 of 72 A ppendix 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 im

ply 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

yes d

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 12/10/2001Pronamide Human Health Risk Assessment DP No. D422207

Page 49 of 72 A.2 Toxicity Profile s

Table A.2.1 Acute Toxicity Profile

– Pronamide

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [Rat] 00085505 LD 50 > 5000 mg/kg IV

870.1100 Acute oral [Rat] 43583901 LD 50 > 5000 mg/kg IV

870.1200 Acute dermal [Rabbit] 43583902 LD 50 > 2000 mg/kg III

870.1300 Acute inhalation [Rat] 44034201 LC 50 > 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 c ould 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.Pronamide Human Health Risk Assessment DP No. D422207

Page 50 of 72 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 d ermal absorption value is available

870.3465 90

- Day inhalation

toxicity (species) Not submitted Waiver granted in 2003. ( TXR# 0051730)Pronamide Human Health Risk Assessment DP No. D422207

Page 51 of 72 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

individ ual 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 dose

selection rationale was not provided.

870.3700 Prenatal

developmental (rabbit) 00148065 (1985)

Acceptable

- guideline 0, 5, 20, 80 mg/kg/day Materna l 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 t hat a hunched appearance was more commonly observed in

the treated animals.

Developmenta l NOAEL = 20 mg/kg/day LOAEL = 80 mg/kg/day based on abortionsPronamide Human Health Risk Assessment DP No. D422207

Page 52 of 72 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/day

females 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) Acceptable

guideline 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).Pronamide Human Health Risk Assessment DP No. D422207

Page 53 of 72 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 hype rtrophy; 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 h epatocyte 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 m ales; 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.Pronamide Human Health Risk Assessment DP No. D422207

Page 54 of 72 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 (i ncreased 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 hepatocellula r adenomas at 75 and 375 mg/kg/day.

870.4200 Carcinogenicity

(C57BL/6 x

C3H/anf F 1 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 non

GLP 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 R everse 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.Pronamide Human Health Risk Assessment DP No. D422207

Page 55 of 72 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 12/10/2001Pronamide Human Health Risk Assessment DP No. D422207

Page 56 of 72 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)

14 C

- 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 pro namide 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.

14 C

- 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 m g/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

neuro tox 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)Pronamide Human Health Risk Assessment DP No. D422207

Page 57 of 72 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 CYP2B1Pronamide Human Health Risk Assessment DP No. D422207

Page 58 of 72 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 afte r 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 6 00 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 perfor med 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 60 0 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 treatment

related 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, u ncoordinated 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 resolv ed by Day 4, and 1 or 2 males and/or females with red periocular soiling on Days 3 or 4.

On Day 1 i n 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 inPronamide Human Health Risk Assessment DP No. D422207

Page 59 of 72 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 decrea ses 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 f

indings 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 incoordin ation 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

n eurotoxicity study in rats (870.6200; OECD 424). Dose and Endpoint for Risk Assessment: POD = 4 0 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 a cute neurotoxicity study in rat s 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 10 00 X uncertainty factor (UF), consisting of the usual 10x interspecies uncertainty factor for extrapolation from animal to human (UF A ); the usual 10x intraspecies factor forPronamide Human Health Risk Assessment DP No. D422207

Page 60 of 72 variation in human response (UF H ); and a 10x factor for LOAEL to NOAEL extrapolation (UF L ) . The acute r eference d ose (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= aPa D = 4 0 mg/kg/day = 0.04 mg/kg/day

10 0 0 (UF)

Where 1000 (UF) = 10 (UF A ) x 10 (UF H ) x 10 (UF L )

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 (UF L ) is

considered appropriate to assess longer term assessments. The derived POD of 4 mg/kg/ was selected for the chronic dietary, in cidental o ral (short

- term), and i nhalation (short

- and

intermediate

- term) e ndpoint s based on a weight of evidence a pproach 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) S ubchronic neurotoxicity (SC N) 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

4 0 mg/kg/day with a 10X LOAEL to NOAEL uncertainty factor (UF L ) 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 les ions 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. HEDPronamide Human Health Risk Assessment DP No. D422207

Page 61 of 72 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 LOAEL s of 11. 2 8 mg/kg/ day (SCN) and 42. 6 mg/kg/day (c hronic /carcinogenicity rat) and also 40 mg/kg/day (ACN)

. This POD is appropriate for use across all exposure durations.

Application of a 100

- fold uncertai nty 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 (UF L )

cRfd= cPa D = 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.: 4 6885701 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.

T erminal body weight was d ecreased (p≤0.05) by 10% and 12% at 500 and 1000 mg/kg/day, respectively. Overall (Days 1

- 28) body weight gain s of 5 00 and 1000 mg/kg/day male rats were decreased by 40% and 45%, respectively, while food consumption was decrease d (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 increase d 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 effect s were noted in females.Pronamide Human Health Risk Assessment DP No. D422207

Page 62 of 72 This 28

- day dermal toxicity study in the Fischer 344 rat is a cceptable , g uideline 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 mal es 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 follo wing 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 res idential levels of concern for the margin of exposure is 100 (includes

UF A =10x and UF H =10x)

.Pronamide Human Health Risk Assessment DP No. D422207

Page 63 of 72 Appendix B. Metabolites and Metabolic Pathways for Pronamide

The following are rat metabolites found in the urine and feces.Pronamide Human Health Risk Assessment DP No. D422207

Page 64 of 72Pronamide Human Health Risk Assessment DP No. D422207

Page 65 of 72 The following is the proposed metabolic pathway in the rat supplied by the registrant.Pronamide Human Health Risk Assessment DP No. D422207

Page 66 of 72 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

Pestici de Manual

- World Compendium. 11 th ed. Surrey,

UK: The Briti sh 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

- 7 torr )

Dissociation constant, pKa Not applicable
Octanol/water partition coefficient, log K OW (25°C) 3.43

Aerobic Soil Metabolism Half

- life (days) 165 MRID 46413407 cited in Milians, D414467 (2015)Pronamide Human Health Risk Assessment DP No. D422207

Page 67 of 72 Appendix D. Summary of Registered and Proposed Uses for Pronamide

Crop/Use Site Application Timing and Type of Application Registered

Formulations Maximum

Applicatio n 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 d ays 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 2 24 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/ o r 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 PHIPronamide Human Health Risk Assessment DP No. D422207

Page 68 of 72 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 = 100 0 )

Mitigation Level = baseline

unless indicated otherwise Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7

Mixer/Loader Aerial application of Wettable powder in Water Soluble Package (WSP) Nursery (ornamentals, vegetables, trees, container stock) 8.6 (E ngineering

Control ) 0.083

(E ngineering

Control ) 1.5 60 0.011 9,100 0.00027 15 0 ,000

Sod 1.5 350 0.0644 1,600 0.00158 25,000 Field crop, typical acreage 8 and Orchard 10 4 0.171 580 0.0042 9

, 50 0 Field crop, high

- acreage 9 2 1200 0.294 340 0.0072 5

, 60 0 Chemigation application of Wettable powder in Water Soluble Package (WSP) Sod 1.5

350 0.0644 1,600 0.00158 25

, 00 0 Field crop, typical acreage 8

and Orchard 10 4 0.171 580 0.0042 9

, 50 0

Field crop, high

- acreage 9 2 0.0585 1,200 0.0021 19

, 00 0
Nursery (ornamentals, vegetables, trees, container stock) 1.5 60 0.011 9,100 0.00027 15 0 ,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 22 0 ,000 Field

- grown ornamental crops Nursery (ornamentals, vegetables, trees, container stock) 1.5 60 0.011 9,100 0.00027 15 0 ,000

Sod 1.5 80 0.0148 8,800 0.00036 11 0 ,000 Field crop, typical acreage 8 and Orchard 10 4 0.0393 2,500 0.00096 42

, 00 0 Field crop, high

- acreage 9 2 200 0.049 2,000 0.0012 33

, 00 0 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 12 0 ,000

Sod 1.44

350 0.238 420 0.00138 29

, 00 0 Field crop, typical acreage 8 and Orchard 10 4 0.658 150 0.00384 1 0 ,000

Field crop, high

- acreage 9 29.1 ( DL/G ) 0.219 2 1200 0.873 110 0.00658 6

, 10 0 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 12 0 ,000

Sod 1.44

350 0.238 420 0.00138 29

, 00 0 Field crop, typical acreage 8 and Orchard 10 4 0.658 150 0.00384 1 0 ,000 Field crop, high

- acreage 9 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 12 0 ,000

Sod 1.44 80 0.0541 1,800 0.000315 13 0 ,000 Golf course (fairways, tees, greens) 40 0.0271 3,700 0.000158 25 0 ,000 Field crop, typical acreage 8 4 80 0.15 670 0.000876 46

, 00 0 Field crop, high

- acreage 9 2 200 0.188 530 0.0011 36

, 00 0Pronamide Human Health Risk Assessment DP No. D422207

Page 69 of 72 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 = 100 0 )

Mitigation Level = baseline

unless indicated otherwise Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7

Applicator

Aerial spray application Nursery (ornamentals, vegetables, trees, container stock) 2.08 (E ngineering

Control ) 0.0049

(E ngineering

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 acreage 8 and Orchard 10 4 0.0364 2,700 0.0000858 470,000 Field crop, high

- acreage 9 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 acreage 8 and Orchard 10 4 0.315 320 0.00136 29,000
Field crop, high

- acreage 9 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 acreage 8 and Orchard 10 4 0.193 520 0.00613 6,500
Field crop, typical and high

- acreage 9 2 0.0963 1,000 0.00306 13,000Pronamide Human Health Risk Assessment DP No. D422207

Page 70 of 72 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 = 100 0 )

Mitigation Level = baseline

unless indicated otherwise Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7

Mixer/Loader/Applicator Wettable powder in Water Soluble Package (WSP) via Backpack Orchard 10 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 Manually

Pressurized 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 Mechanically

pressurized 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 Orchard 10 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 Manually

pressurized Handwand Landscaping, turf (lawns, athletic fields, parks, etc.) 430 ( Single layer / Glove ) 30 0.0155 6,500 0.00108 37,000

Liquids via Mechanically

pressurized 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.)

Orchard 10 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) × Con version 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, Br assica, 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 farm s, 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 c rops, apples, apricot, artichoke, cherry, peach, pear, peach, pear, plum, nectarine, citrus fruits, tree nuts, grapes, Christ mas tree plantations @4 lb ai/APronamide Human Health Risk Assessment DP No. D422207

Page 71 of 72 Appendix F . International Residue Limits Table

Pronamide (aka Propyzamide; PC C ode 101701)

Summary of US and International Tolerances and Maximum Residue Limits
Residue Definition :
US Canada Mexico 1 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 Mexico 1 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 0.02Pronamide Human Health Risk Assessment DP No. D422207

Page 72 of 72 Summary of US and International Tolerances and Maximum Residue Limits
Residue Definition :
US Canada Mexico 1 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 degr adates, 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 paragra ph 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