United States Prevention, Pesticides EPA 738-R-00-017

Environmental Protection And Toxic Substances September 2000

Agency (7508C)

Report on FQPA

Tolerance Reassessment

Progress and Interim Risk

Management Decision

Phostebupirim
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

 WASHINGTON, D.C. 20460

OFFICE OF 

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

CERTIFIED MAIL

Dear Registrant:

This is to inform you that the Environmental Protection Agency (hereafter referred to as EPA or

the Agency) has completed its review of the available data and public comments received related to the

preliminary and revised human health risk assessment for the organophosphate pesticide phostebupirim

(also known as tebupirimphos). The enclosed “Report on FQPA Tolerance Reassessment and Interim

Risk Management Decision for Phostebupirim,” which was approved on September 29, 2000,

summarizes the Agency's assessment of the dietary and occupational risk from phostebupirim. Based

on its review, EPA has recommended risk mitigation measures to address the human health risks

associated with the current use of phostebupirim. These risk mitigation measures can be found in the

attached document. 

 The major means by which the Agency reassesses tolerances is through its reregistration

process. Each pesticide registered prior to 1984 is subject to a comprehensive evaluation of its effects

on human health and the environment. Such an evaluation includes a determination of whether the

tolerances are safe. Since phostebupirim was registered after 1984, it is not subject to reregistration. 

However, phostebupirim tolerances are subject to reassessment in accordance with the Federal Food,

Drug, and Cosmetic Act (FFDCA) as amended by the Food Quality Protection Act of 1996 (FQPA). 

The FQPA requires EPA to re-evaluate existing tolerances to ensure that children and other sensitive

subpopulations are protected from pesticide risk. 

When phostebupirim was registered in July 1995, it was granted a conditional registration

contingent on the submission of additional data. All of the data and information requested as conditions

of the registration have been received by the Agency. The Agency decided, in addition to reassessing

phostebupirim tolerances, to also reassess occupational risks under the Federal Insecticide, Fungicide,

and Rodenticide Act (FIFRA). The Agency has not conducted a new risk assessment for the effects of

phostebupirim on non-target species (e.g., fish and birds) since it believes that the conclusions reached

at the time of the initial decision to register phostebupirim in 1995 remain unchanged.

The "Report on FQPA Tolerance Reassessment Progress and Interim Risk Management

Decision for Phostebupirim" is based on the revised human health assessment, updated technical

information, and public comments received by the Agency, all of which are available in the

phostebupirim public docket. The docket includes both the preliminary and revised risk assessment for

phostebupirim as well as comments on the risk assessments submitted by the general public and
stakeholders. A Notice of Availability for this Report on FQPA Tolerance Reassessment Progress and

Interim Risk Management Decision for Phostebupirim is being published in the Federal Register. To

obtain a copy of this document, please contact the OPP Public Regulatory Docket (7502C), US EPA,

Ariel Rios Building, 1200 Pennsylvania Avenue, N.W., Washington D.C., 20460, telephone 

(703) 305 - 5805. Electronic copies of this report and the documents supporting it are available on the

internet and can be found on the Agency’s web page, www.epa.gov/pesticides/op. 

This document and the process used to develop it are the result of a pilot process to facilitate

greater public involvement and participation in the reregistration and/or tolerance reassessment

decisions for these pesticides. As part of the Agency’s effort to involve the public in the implementation

of the Food Quality Protection Act of 1996 (FQPA), the Agency is undertaking a special effort to

maintain open public dockets on the organophosphate pesticides and to engage the public in the

reregistration and tolerance reassessment processes for these chemicals. This open process follows the

guidance developed by the Tolerance Reassessment Advisory Committee (TRAC), a large multistakeholder advisory body which advised the Agency on implementing the new provisions of the

FQPA. The reregistration and tolerance reassessment reviews for the organophosphate pesticides are

following this new process. 

Please note that the phostebupirim risk assessment concerns only this particular

organophosphate. It does not address the cumulative effects of other organophosphates as a class. 

Because the FQPA directs the Agency to evaluate food tolerances on the basis of cumulative risk from

substances sharing a common mechanism of toxicity, such as the toxicity expressed by the

organophosphates through a common biochemical interaction with the cholinesterase enzyme, the

Agency will evaluate the cumulative risk posed by the entire organophosphate class of chemicals after

completing the risk assessments for individual organophosphates. The Agency is working towards

completion of a methodology to assess cumulative risk and the individual risk assessments for each

organophosphate are likely to be necessary elements of any cumulative assessment. The Agency has

decided to move forward with individual assessments and to identify mitigation measures necessary to

address those human health risks associated with the current uses of phostebupirim. The Agency will

issue the final tolerance reassessment decision for phostebupirim and finalize any other decisions once

the cumulative assessment for all organophosphates is complete.

 Based on the phostebupirim risk assessment, the Agency believes that current uses of

phostebupirim may pose unreasonable adverse effects to human health, and that such effects can be

mitigated with the risk mitigation measures identified in this document. Accordingly, the Agency

recommends that registrants implement these risk mitigation measures immediately. Section IV of this

document describes labeling amendments for end-use products and data requirements necessary to

implement these mitigation measures. Instructions for registrants on submitting revised labeling and the

time frame established to do so can be found in Section V of this document.

Should a registrant fail to implement any of the recommended occupational risk mitigation

measures, the Agency will continue to have concerns about the risks posed by phostebupirim. Where

the Agency has identified any unreasonable adverse effect to human health, the Agency may at any time
initiate appropriate regulatory action to address this concern. At that time, any affected person (s) may

challenge the Agency’s action.

If you have questions on this document or the label changes, please contact the Special Review

and Reregistration Division representative, Stacey Milan, at (703) 305-2505.

Sincerely yours,

Lois A. Rossi, Director

Special Review and 

Reregistration Division

Attachment

Report on FQPA Tolerance Reassessment Progress

and Interim Risk Management Decision

for

Phostebupirim 

Table of Contents

Phostebupirim Team ........................................................... i

Glossary of Terms and Abbreviations ............................................ iii

Executive Summary ........................................................... 1

I. Introduction ............................................................ 3

II. Chemical Overview ...................................................... 6

A. Regulatory History ................................................ 6

B. Chemical Identification ............................................. 6

C. Use Profile ....................................................... 7

D. Estimated Usage of Pesticide ........................................ 7

III. Summary of Phostebupirim Risk Assessments ................................ 8

A. Dietary Risk from Food ............................................ 8

1. Toxicity ................................................... 8

2. FQPA Safety Factor ......................................... 8

3. Population Adjusted Dose (PAD) ............................... 9

4. Exposure Assumptions ....................................... 9

5. Food Risk Characterization .................................. 10

B. Dietary Risk from Drinking Water .................................. 11

1. Surface water .............................................. 11

2. Ground water .............................................. 11

3. Drinking Water Levels of Comparison (DWLOCs) ............... 12

C. Aggregate Risk .................................................. 12

D. Occupational Risk ................................................ 12

1. Toxicity .................................................. 13

2. Exposure ............................................. 14

3. Risk Assessment ........................................... 15

a. Short-Term Risks .................................... 16

b. Intermediate-Term Risk ............................... 17

4. Post-Application Risk ....................................... 19
IV. FQPA Tolerance Reassessment Progress and Interim Risk 

Management Decision .................................................. 19

A. Determination of Tolerance Reassessment & Interim Risk 

Management Decision ............................................ 19

B. Summary of Phase 3 Comments and Revisions to Preliminary 

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

C. Summary of Phase 5 Comments and Responses ........................ 21

D. Regulatory Position ............................................... 22

1. FQPA and Occupational Risk Assessment ...................... 22

a. "Risk Cup" Determination ............................ 22

b. Tolerance Summary .................................. 23

2. Endocrine Disruptor Effects .................................. 24

3. Recommended Label Modifications ........................... 25

E. Regulatory Rationale ............................................. 26

1. Dietary Mitigation ......................................... 26

a. Dietary (Food) Risk Mitigation ......................... 26

b. Dietary (Water) Risk Mitigation ........................ 26

c. Aggregate (Food + Water) Risk Mitigation ............... 26

2. Occupational Risk Mitigation ................................ 26

3. Post Application Risk Mitigation .............................. 28

V. Recommended Mitigation Measures ...................................... 29

A. Manufacturing Use Products ....................................... 29

B. End-Use Products ................................................ 29

1. Labeling Changes for End-Use Products ........................ 29

2. Procedure and Timing for Label Amendment .................... 33

C. Existing Stocks .................................................. 33

VI. Related Documents and How to Access Them ............................... 33

VII. APPENDICES ........................................................ 35

A: Citations Supporting the FQPA Tolerance Reassessment and Interim 

Occupational Risk Management Decision (Bibliography) ................ 37

B: EPA’s Batching of Phostebupirim Products for Meeting Acute 

Toxicity Data Requirements for Reregistration ........................ 47

C: List of Available Related Documents ................................ 49
i

Phostebupirim Team

Office of Pesticide Programs:

Health Effects Risk Assessment

Robert Fricke

Christina Jarvis

Renee Sandvig

Environmental Fate (Drinking Water) Risk Assessment

Patricia Jennings

Use and Usage Analysis

David Brassard

David Widawsky

Registration Support

Marilyn Mautz

Risk Management

Jason Klug

Nancy Zahedi

Stacey Milan
ii
iii

Glossary of Terms and Abbreviations

AE Acid Equivalent

a.i. Active Ingredient

AGDCI Agricultural Data Call-In

ai Active Ingredient

aPAD Acute Population Adjusted Dose

AR Anticipated Residue

ARC Anticipated Residue Contribution 

BCF Bioconcentration Factor 

CAS Chemical Abstracts Service

CI Cation

CNS Central Nervous System

cPAD Chronic Population Adjusted Dose

CSF Confidential Statement of Formula

CFR Code of Federal Regulations

CSFII USDA Continuing Surveys for Food Intake by Individuals

DCI Data Call-In

DEEM Dietary Exposure Evaluation Model

DFR Dislodgeable Foliar Residue

DRES Dietary Risk Evaluation System

DWEL Drinking Water Equivalent Level (DWEL) The DWEL represents a medium specific

(i.e., drinking water) lifetime exposure at which adverse, noncarcinogenic health effects

are not anticipated to occur.

DWLOC Drinking Water Level of Comparison.

EC Emulsifiable Concentrate Formulation

EEC Estimated Environmental Concentration. The estimated pesticide concentration in an

environment, such as a terrestrial ecosystem.

EP End-Use Product

EPA U.S. Environmental Protection Agency

FAO Food and Agriculture Organization

FDA Food and Drug Administration

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act

FFDCA Federal Food, Drug, and Cosmetic Act

FQPA Food Quality Protection Act

FOB Functional Observation Battery

G Granular Formulation

GENEEC Tier I Surface Water Computer Model

GLC Gas Liquid Chromatography

GLN Guideline Number
iv

Glossary of Terms and Abbreviations

GM Geometric Mean

GRAS Generally Recognized as Safe as Designated by FDA

HA Health Advisory (HA). The HA values are used as informal guidance to municipalities

and other organizations when emergency spills or contamination situations occur.

HAFT Highest Average Field Trial

HDT Highest Dose Tested

IR Index Reservoir

LC50 Median Lethal Concentration. A statistically derived concentration of a substance that

can be expected to cause death in 50% of test animals. It is usually expressed as the

weight of substance per weight or volume of water, air or feed, e.g., mg/l, mg/kg or

ppm.

LD50 Median Lethal Dose. A statistically derived single dose that can be expected to cause

death in 50% of the test animals when administered by the route indicated (oral, dermal,

inhalation). It is expressed as a weight of substance per unit weight of animal, e.g.,

mg/kg.

LEL Lowest Effect Level

LOC Level of Concern

LOD Limit of Detection 

LOAEL Lowest Observed Adverse Effect Level

MATC Maximum Acceptable Toxicant Concentration

MCLG Maximum Contaminant Level Goal (MCLG) The MCLG is used by the Agency to

regulate contaminants in drinking water under the Safe Drinking Water Act.

mg/kg/day Milligram Per Kilogram Per Day

mg/L Milligrams Per Liter

MOE Margin of Exposure 

MP Manufacturing-Use Product

MPI Maximum Permissible Intake

MRID Master Record Identification (number). EPA's system of recording and tracking

studies submitted.

NA Not Applicable

N/A Not Applicable

NAWQA USGS National Water Quality Assessment

NOEC No Observable Effect Concentration

NOEL No Observed Effect Level

NOAEL No Observed Adverse Effect Level

NPDES National Pollutant Discharge Elimination System

NR Not Required

OP Organophosphate
v

Glossary of Terms and Abbreviations

OPP EPA Office of Pesticide Programs

OPPTS EPA Office of Prevention, Pesticides and Toxic Substances

Pa pascal, the pressure exerted by a force of one newton acting on an area of one square

meter.

PAD Population Adjusted Dose

PADI Provisional Acceptable Daily Intake

PAG Pesticide Assessment Guideline

PAM Pesticide Analytical Method

PCA Percent Crop Area

PDP USDA Pesticide Data Program

PHED Pesticide Handler's Exposure Data 

PHI Preharvest Interval

ppb Parts Per Billion

PPE Personal Protective Equipment

ppm Parts Per Million

PRN Pesticide Registration Notice

PRZM/

EXAMS Tier II Surface Water Computer Model 

Q1* The Carcinogenic Potential of a Compound, Quantified by the EPA's Cancer Risk

Model

RAC Raw Agriculture Commodity

RBC Red Blood Cell

RED Reregistration Eligibility Decision

REI Restricted Entry Interval

RfD Reference Dose

RQ Risk Quotient

RS Registration Standard

RUP Restricted Use Pesticide

SAP Science Advisory Panel

SCI-GROW Tier I Ground Water Computer Model

SF Safety Factor

SLC Single Layer Clothing

SLN Special Local Need (Registrations Under Section 24(c) of FIFRA)

TC Toxic Concentration. The concentration at which a substance produces a toxic effect. 

TD Toxic Dose. The dose at which a substance produces a toxic effect.

TEP Typical End-Use Product

TGAI Technical Grade Active Ingredient

TLC Thin Layer Chromatography

TMRC Theoretical Maximum Residue Contribution
vi

Glossary of Terms and Abbreviations

torr A unit of pressure needed to support a column of mercury 1 mm high under standard

conditions.

TRR Total Radioactive Residue

UF Uncertainty Factor

Fg/g Micrograms Per Gram

Fg/L Micrograms Per Liter

USDA United States Department of Agriculture

USGS United States Geological Survey

UV Ultraviolet 

WHO World Health Organization

WP Wettable Powder

WPS Worker Protection Standard
1

Executive Summary

EPA has completed its review of public comments on the revised risk assessment for

phostebupirim, and is, in this document, setting forth its interim decision on the risk mitigation for this

chemical. The revised dietary risk assessment includes the Agency’s review of additional studies and a

revision of the FQPA safety factor based on the study reviews. The Agency identified the risk

management measures set forth in this report after inviting stakeholders to provide proposals and

suggestions on appropriate mitigation measures. This report on FQPA Tolerance Reassessment

Progress and Interim Risk Management Decision will not be considered final until the cumulative risk

assessment of all organophosphate pesticides is complete. The cumulative assessment may result in

further risk mitigation measures for phostebupirim.

Phostebupirim is an organophosphate insecticide registered for use on field corn, seed corn,

sweet corn, and popcorn for the control of corn rootworms, wireworms, cutworms, seed corn

maggots, seedcorn beetle and white grubs. It was first registered in the United States in 1995 and is

registered as a 2.1% and 4.67% granular end-use product (Aztec® 2.1G and 4.67G), although only the

Aztec® 2.1G product is currently being marketed. The Aztec® 2.1G product has two formulations: a

new cellulose-based Biodac formulation along with a clay-based granular formulation. Phostebupirim

is used on average once a season at planting, at a maximum rate of 0.15 lbs ai/acre. Annual domestic

usage of phostebupirim is estimated to be approximately 270,000 pounds active ingredient. Between

3-6% of all corn acreage is treated.

Overall Risk Summary

EPA’s dietary (food) risk assessment for phostebupirim indicates that neither the acute nor

chronic risks exceed the Agency’s level of concern, i.e., less than 100% of the acute or chronic

Population Adjusted Dose (PAD) is utilized for the general U.S. population and all population

subgroups, including infants and children using a Tier 1 screening level assessment (100% crop treated

and tolerance levels).

Acute and chronic dietary risks from drinking water are also below the Agency's level of

concern. Surface water and ground water estimated environmental concentrations (EECs) do not

exceed the Agency's drinking water levels of comparison (DWLOC) for acute and chronic aggregate

dietary exposure. Aggregate risk, based on food and water exposure, does not exceed the Agency’s

level of concern; therefore, no risk mitigation based on dietary risk estimates is necessary at this time.

The Agency has determined that there is potential exposure to handlers for use-patterns

associated with phostebupirim. Occupational handler risk estimates are based on two separate studies

for estimating short-term and intermediate-term exposure risks and PHED exposure studies. With the

exception of intermediate-term risks for applicators, the risks in all exposure scenarios generally do not
2

exceed the Agency's level of concern when the appropriate PPE and engineering controls are utilized

during the loading and application processes.

EPA did not quantitatively assess the risks to post application workers. Minimal postapplication exposure is anticipated since phostebupirim is typically incorporated into the soil, is applied

at planting and is not systemic in the plant and degrades readily. 

Based on the phostebupirim risk assessment, the Agency believes that label changes requiring

use of dust/mist respirators (or comparable mitigation) by loaders of the Aztec® 2.1G clay-based

formulation would mitigate inhalation exposures. Loaders of the Aztec® 4.67G SmartBox® system

must have a dust/mist respirator immediately available for use in case of an emergency. The Agency is

not requiring the use of dust/mist respirators for handlers who use the cellulose-based formulation. 

EPA believes this formulation is sufficiently less dusty than the clay-based formulation that there will not

be a risk concern for loaders. 

The registrant will need to submit an exposure or dust comparison study to confirm that the

Biodac formulation is sufficiently less dusty than the clay-based formulation. This study should be

submitted to EPA by April 1, 2001. 

 

 Under current label restrictions, EPA does have risk concerns for the short and intermediateterm inhalation risk for applying granular phostebupirim with an open cab tractor drawn spreader

(MOE=79). However, the risk was calculated using low confidence PHED data (one study with a

small number of replicates using only a broadcast spreader). In actual use, phostebupirim will typically

be applied in-furrow or T-Band. These methods of application should make the granular formula less

available for exposure than in the broadcast spreader scenario. Therefore, the Agency believes the

MOE of 79 is an overestimate of the risk for this specific phostebupirim use scenario and inhalation

risks for applicators are likely to be acceptable. Therefore, no risk mitigation is required to address

applicator risk. 

Currently available data suggests that dermal occupational risk is also of concern. However,

EPA believes the current risk assessment overestimates this risk to workers as well. The registrant will

initiate a 21-day rat dermal toxicity study using the 4.67% granular formulation to better characterize

dermal risk from occupational exposure to phostebupirim products. The Agency believes that this

study will provide a more appropriate dermal endpoint for regulating both short and intermediate-term

worker exposures and that worker risk under current label conditions does not exceed the Agency’s

level of concern. This study should be submitted to EPA by April 1, 2001.

However, in the event that these studies do not adequately demonstrate that worker risk is not

a concern, the Agency will recommend that the registrant implement additional label amendments to

mitigate remaining worker risks that exceed the Agency's level of concern. The Agency will review the

phostebupirim data prior to July 5, 2001, the date the conditional registration expires. 
3

I. Introduction

This report on the progress toward tolerance reassessment for phostebupirim is the result of the

pilot process developed through the Tolerance Reassessment Advisory Committee (TRAC) to facilitate

greater public involvement in the ongoing FIFRA reregistration and/or FQPA tolerance reassessment

initiatives on pesticides. Since phostebupirim was first registered in 1995, it is currently not subject to

the reregistration process, only to the requirements of FQPA. However, some history and

background on reregistration and FIFRA is included here for informational purposes and to provide a

discussion of the existing laws requiring action on pesticides.

The Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) was amended in 1988 to

accelerate the reregistration of products with active ingredients registered prior to November 1, 1984. 

The amended Act calls for the development and submission of data to support the reregistration of an

active ingredient, as well as a review of all submitted data by the U.S. Environmental Protection Agency

(referred to as EPA or “the Agency”). Reregistration involves a thorough review of the scientific

database underlying a pesticide’s registration. The purpose of the Agency’s review is to reassess the

potential hazards arising from the currently registered uses of the pesticide; to determine the need for

additional data on health and environmental effects; and to determine whether the pesticide meets the

“no unreasonable adverse effects” criteria of FIFRA. 

On August 3, 1996, the Food Quality Protection Act of 1996 (FQPA) was signed into law.

This Act amends FIFRA to require tolerance reassessment of all existing tolerances. The Agency has

decided that, for those chemicals that have tolerances and are undergoing reregistration, the tolerance

reassessment will be initiated primarily through this reregistration process. It also requires that by

2006, EPA must review all tolerances in effect on the day before the date of the enactment of the

FQPA, which was August 3, 1996. FQPA also amends the FFDCA to require a safety finding in

tolerance reassessment based on factors including an assessment of cumulative effects of chemicals with

a common mechanism of toxicity. Phostebupirim belongs to a group of pesticides called

organophosphates, which share a common mechanism of toxicity - they all affect the nervous system by

inhibiting cholinesterase. Although FQPA significantly affects the Agency’s reregistration process, it

does not amend any of the existing reregistration deadlines. Therefore, the Agency is continuing its

reregistration program while it resolves the remaining issues associated with the implementation of 

FQPA. 

The Agency is also continuing its progress toward tolerance reassessment as required by

FQPA for all of the organophosphate chemicals, whether or not they are subject to the reregistration

process. While the methodology for completion of the cumulative assessment for all of the

organophosphates is being developed, individual risk assessments and risk mitigation measures, where

appropriate, are being conducted. Although not subject to the reregistration process, the individual

dietary assessment for the organophosphate phostebupirim has been completed, and will be used in the

cumulative assessment of all of the organophosphate chemicals to satisfy the requirements of FQPA. 
4

This document presents the Agency’s revised dietary risk assessment for phostebupirim, as part of the

tolerance reassessment process. The Agency has also revised occupational risk estimates for

phostebupirim. 

As part of the EPA's effort to involve the public in the implementation of FQPA, the Agency is

undertaking a special effort to maintain open public dockets on the organophosphate pesticides and to

engage the public in the reregistration and tolerance reassessment processes for these chemicals. The

public process was discussed by TRAC, a large multi-stakeholder advisory body which advised the

Agency on implementing the new provisions of the FQPA. The reregistration and tolerance

reassessment reviews for the organophosphates are following this new process. 

Phases 1 through 4 of the pilot process address the development and refinement of the risk

assessments. Phases 5 and 6 are concerned with the development and implementation of risk

management plans and provide opportunity for the registrants, user community, and general public to

propose risk mitigation based on the revised risk assessments. During phase 6 of the process, the

Agency prepares an Interim Reregistration Eligibility Decision (RED) Document or a Report on FQPA

Tolerance Reassessment and Interim Risk Management Decision Document, from which risk

management will be implemented. Prior to finalizing a risk management decision, the Agency typically

arranges a conference call with USDA, growers, registrants, and other interested parties to assess the

feasibility of proposed mitigation measures.

There is no comment period for this document. As part of the process developed by the

TRAC, which sought to open up the process to interested parties, the Agency’s risk assessment for

phosetebupirim has already been subject to numerous public comment periods and a further comment

period was deemed unnecessary. A Notice of Availability for this document, however, has been

published in the Federal Register.

 The implementation of FQPA has required the Agency to revisit some of its existing policies

relating to the determination and regulation of dietary risk, and has also raised a number of new issues

for which policies need to be created. These issues were refined and developed through collaboration

between the Agency and the Tolerance Reassessment Advisory Committee (TRAC), which was

composed of representatives from industry, environmental groups, and other interested parties. The

TRAC identified the following science policy issues it believed were key to the implementation of

FQPA and tolerance reassessment:

C Applying the FQPA 10-Fold Safety Factor

C Whether and How to Use "Monte Carlo" Analyses in Dietary Exposure Assessments 

C How to Interpret "No Detectable Residues" in Dietary Exposure Assessments

C Refining Dietary (Food) Exposure Estimates

C Refining Dietary (Drinking Water) Exposure Estimates

C Assessing Residential Exposure
5

C Aggregating Exposure from all Non-Occupational Sources

C How to Conduct a Cumulative Risk Assessment for Organophosphate or Other Pesticides with

a Common Mechanism of Toxicity

C Selection of Appropriate Toxicity Endpoints for Risk Assessments of Organophosphates

C Whether and How to Use Data Derived from Human Studies

The process developed by the TRAC calls for EPA to provide one or more documents for

public comment on each of the policy issues described above. Each of these issues is evolving and in a

different stage of refinement. Some issue papers have already been published for comment in the

Federal Register and others will be published shortly. 

In addition to the policy issues that resulted from the TRAC process, the Agency published in

the Federal Register on August 12, 1999, a draft Pesticide Registration Notice that presents EPA’s

proposed approach for managing risks from organophosphate pesticides to occupational users. This

notice describes the Agency’s baseline approach to managing risks to handlers and workers of

organophosphate pesticides. Generally, basic protective measures such as closed mixing and loading

systems, enclosed cab equipment, or protective clothing, as well as increased reentry intervals will be

required for most uses where current risk assessments indicate a risk and such protective measures are

feasible. The draft guidance policy also states that the Agency will assess each pesticide individually,

and based upon the risk assessment, determine the need for specific measures tailored to the potential

risks of the chemical. The measures included in this interim document are consistent with that draft

Pesticide Registration Notice.

This document consists of six sections. Section I contains the regulatory framework for

reregistration/tolerance reassessment as well as descriptions of the process developed by TRAC for

public comment on science policy issues for the organophosphate pesticides and the worker risk

management PR notice. Section II provides a profile of the use and usage of the chemical. Section III

gives an overview of the revised human health risk assessment resulting from public comments and

other information. Section IV presents the Agency's interim risk management decisions. Section V

summarizes required label changes based on the risk mitigation measures outlined in Section IV. 

Section VI provides information on how to access related documents. Finally, the Appendices list Data

Call-In (DCI) information. The revised risk assessments and related addenda are not included in this

document, but are available on the Agency's web page, www.epa.gov/pesticides/op, and in the Public

Docket.
6

II. Chemical Overview

A. Regulatory History

Phostebupirim was first registered in the United States in July 1995 for at-plant control of a

variety of soil-dwelling insect pests in or on corn. 

B. Chemical Identification

PHOSTEBUPIRIM

• Common Name: Phostebupirim

• Chemical Name: O-[2-(1,1-dimethylethyl)-5-pyrimidinyl] O-ethyl O-(1-

methylethyl) phosphorothioate

• Chemical Family: Organophosphate

• CAS Registry Number: 96182-53-5

• OPP Chemical Code: 129086

• Empirical Formula: C13H23N2O3PS

• Molecular Weight: 318.37 g/mol.

• Vapor Pressure: 3.75 x 10-4 mm Hg

• Trade and Other Names: Aztec 2.1% Granular Insecticide, Aztec 4.67%

Granular Insecticide

• Basic manufacturer: Bayer Corporation (technical registrant)
7

Technical phostebupirim is a colorless liquid. Phostebupirim is soluble in water at 5.5 mg/mL

and is completely miscible with all solvents tested at 20o C.

C. Use Profile

The following information is based on the currently registered uses of phostebupirim:

Type of pesticide: Insecticide.

Summary of Use Sites and Target Pests: Phostebupirim is only registered for use on

corn. Phostebupirim is used for the control of

corn rootworms, cutworms, and other soil

insect pests in corn commodities (forage and

fodder, pop, and sweet). 

Formulation Types Registered: In addition to the technical, there are three enduse formulations: two 2.1% granular

formulations (clay-based and cellulose-based)

and a 4.67% granular formulation for use only

with a SmartBox® applicator system.

Method and Rates of Application:

Equipment - Phostebupirim can be applied to corn only with tractor drawn spreader. 

Method and Rate - At-plant band and T-band application with soil incorporation, and infurrow application. Application rates vary from 0.11 to 0.15 pounds

active ingredient per acre.

Timing - At-plant.

Use Classification: Phostebupirim is a restricted use chemical, registered only for use on

corn.

D. Estimated Usage of Pesticide

This section summarizes the best estimates available for phostebupirim use, based on available

pesticide usage information for 1990 through 1997 as obtained by EPA and USDA - NASS. As

discussed in the February 8, 1999, "Quantitative Usage Analysis," approximately 270,000 pounds of

phostebupirim active ingredient are applied annually to corn. Approximately 3% of corn acreage

receive applications of phostebupirim, with up to 6% crop treated as a maximum estimate. The
8

majority of phostebupirim use (85%) occurs in the states of Iowa, Nebraska, Illinois, Indiana, Ohio,

and Minnesota. Phostebupirim use has been steadily increasing in the years for which data were

available. 

III. Summary of Phostebupirim Risk Assessments

Following is a summary of EPA’s human health risk findings and conclusions for the

organophosphate phostebupirim, as fully presented in the documents, “Phostebupirim: Dietary Risk

Assessment Update,” dated April 9, 1999, and "Occupational Exposure and Risk Assessment

Regarding the Use of Phostebupirim," dated May 5, 1999. The purpose of this summary is to assist the

reader by identifying the key features and findings of these risk assessments, and to better understand

the conclusions reached in the assessments. 

EPA's preliminary risk assessments for phostebupirim were made available for public comment

on May 26, 1999 (Phase 3 of the TRAC process). Comments submitted during the Phase 3 comment

period did not support any revisions to the Agency's risk assessments, as discussed in “Phostebupirim:

HED’s Response to Comments Submitted During Phase 3 (Public Comment Period),” dated

September 22, 1999. Thus, the preliminary and final risk assessments for phostebupirim are the same.

On March 27, 2000, the Agency requested public comment on risk management for phostebupirim. 

The risk assessments presented here form the basis of the Agency’s interim risk management

decision for phostebupirim only; the Agency must complete a cumulative assessment of the dietary risks

of all the organophosphate pesticides before any final tolerance decisions can be made for the

organophosphate pesticides, including phostebupirim.

A. Dietary Risk from Food

1. Toxicity

The Agency has reviewed all toxicity studies submitted and has determined that the toxicity

database is complete, and that it supports an interim human health risk determination for all currently

registered uses. Further details on the toxicity of phostebupirim can be found in the April 9, 1999,

“Phostebupirim: Dietary Risk Assessment Update.” A brief overview of the studies used for the

dietary risk assessment is outlined in Table 1 in this document.

2. FQPA Safety Factor

The FQPA safety factor is 1X. The toxicity database includes an acceptable two-generation

reproduction study in rats, acceptable developmental toxicity studies in rats and rabbits, and acceptable

acute and subchronic neurotoxicity studies in the rat. These studies show no increased susceptibility of

rat or rabbit fetuses to in utero exposure to phostebupirim. There was no indication of increased
9

susceptibility in the offspring as compared to parental animals in the two generation reproduction study. 

In these studies, effects in the fetuses/offspring were observed only at or above treatment levels which

resulted in evidence of parental toxicity. Therefore, the additional 10X factor for the protection of

infants and children as required by FQPA was reduced to 1X as discussed in the March 30, 1999,

“Phostebupirim - Report of the FQPA Safety Factor Committee.” As the dietary assessments were

based on water modeling, tolerance levels and a 100% crop treated assumption, the Agency also found

that the exposure assessments will not underestimate the potential dietary (food and water) exposures

for infants and children from the use of phostebupirim and no non-dietary (residential) exposures are

expected.

3. Population Adjusted Dose (PAD)

The Reference Dose (RfD) is derived from an exposure level at which there are no statistically

or biologically significant increases in the frequency or severity of adverse effects between the exposed

population and its appropriate control, along with the application of uncertainty factors. The PAD is a

relatively new term that characterizes the dietary risk of a chemical, and reflects the Reference Dose,

either acute or chronic, that has been adjusted to account for the FQPA safety factor (i.e., RfD/FQPA

safety factor). In the case of phostebupirim, the FQPA safety factor is 1; therefore, the acute or

chronic RfD = the acute or chronic PAD. A risk estimate that is less than 100% of the acute or chronic

PAD does not exceed the Agency’s level of risk concern.

4. Exposure Assumptions

Dietary risk analyses for phostebupirim were conducted with the Dietary Exposure Evaluation

Model (DEEMTM). DEEM incorporates consumption data generated in USDA’s Continuing Surveys

of Food Intakes by Individuals (CFSII), 1989-1992.

The Tier I acute dietary analysis used tolerance levels and assumed 100% of the registered

commodities were treated. The chronic dietary analysis for phostebupirim was also a Tier 1 estimate

with all residues at tolerance levels and 100% of the commodities assumed to be treated with

phostebupirim. Further refinements to the dietary risk assessment were not conducted, given the low

dietary risk estimates based on the tolerance-level residues and 100% crop treated screening

assumptions.
10

Table 1: Summary of Toxicological Endpoints and Other Factors Used in the Human Dietary

Risk Assessment of Phostebupirim

Assessment Dose Endpoint Study Uncertainty

Factor (UF)

FQPA Safety

Factor

PADc

Acute Dietary LOAEL = 0.5

mg/kg/daya

Plasma and

RBC ChEIb

Acute rat

neurotoxicity

(MRID

43473001)

UF = 300

100X interand

intraspecies

variation and

3X lack of

NOAEL

1X 0.002 mg/kg

(same as acute

RfD)

Chronic

Dietary

NOAEL =

0.02

mg/kg/day

Plasma, RBC

and brain ChEI

1-year dog

feeding study

(MRID

42005452 and

42119301)

UF = 100

100X interand

intraspecies

variation

1X 0.0002

mg/kg/day

(same as

chronic RfD)

a NOAEL not achieved in males

b ChEI = Cholinesterase Inhibition

c

 PAD = Population Adjusted Dose = Acute or Chronic RfD

 FQPA Safety Factor

5. Food Risk Characterization

Generally, a dietary risk estimate that is less than 100% of the acute or chronic Population

Adjusted Dose does not exceed the Agency’s risk concerns. The phostebupirim acute dietary risk

from food is well below the Agency’s level of concern – that is, less than 100% of the acute PAD is

utilized. For example, the percent of the acute PAD utilized for the most exposed subpopulation group,

children (1-6 years), is <5% at the 95th percentile. The 95th percentile is reported here because a Tier

1 deterministic assessment was conducted. A probabilistic assessment was not conducted at this time

because the results of the Tier I assessment were so low.

Similarly, the chronic dietary risk from food alone is well below the Agency’s level of concern. 

For the most exposed subpopulation group, children (1-6 years old), the percent of the chronic PAD

utilized is 17.6%. In summary, both acute and chronic dietary exposure and risk associated with

phostebupirim-treated foods are considered to be well below the Agency’s level of concern, even

when tolerance-level residue values are used along with a 100% crop treated assumption.

Refinements to the dietary analyses can be made using monitoring data and percent crop

treated data for the chronic dietary analysis, and a probabilistic assessment for acute dietary analysis;

however, given the low dietary risk estimates based on tolerance level residues and 100% crop treated

assumptions, the Agency determined that further refinements are not warranted at this time. 

Refinements will be considered when the cumulative assessment for all of the organophosphates is

conducted.
11

B. Dietary Risk from Drinking Water

Drinking water exposure to pesticides can occur through ground water and surface water

contamination. EPA considers both acute (one day) and chronic (lifetime) drinking water risks and

uses either modeling or actual monitoring data, if available, to estimate those risks. Modeling is

considered to be an unrefined assessment and provides a high-end estimate of risk. In the case of

phostebupirim, no monitoring data for either ground or surface water were available; therefore,

modeling was used to estimate drinking water risks from these sources.

The GENEEC model was used to estimate surface water concentrations, and SCI-GROW

was used to estimate groundwater concentrations of phostebupirim in drinking water. Both of these

models are considered to be screening models which provide high end estimates of water

concentrations. These drinking water assessments are described in greater detail in "Tier 1 Screen for

Drinking Water Assessment for Phostebupirim," dated December 8, 1997.

Based on available environmental fate data regarding half-lives under environmental conditions,

phostebupirim appears to be quite persistent in the environment. Based on relatively high Kad values,

phostebupirim also appears to be quite immobile in soil. Two phostebupirim metabolites have been

identified: TBHP (2-[1,1-dimethyllethyl]-5-hydroxypyrimidine) and OMAT (2-[1,1-dimethylethyl]-5-

pyrimidinyl ethyl 1-methylethyl phosphate). The OMAT metabolite is structurally very similar to

phostebupirim; however it appears to be quite mobile in soil.

1. Surface water

EPA used a Tier 1 GENEEC model to estimate the upper-bound phostebupirim concentrations

in drinking water derived from surface water based on phostebupirim use on corn. This model is the

least refined model, based on the most conservative assumptions, which is used as an initial screening

tool. The highest estimated concentrations of phostebupirim in surface water, based on this screening

model, were a peak acute concentration of 1.89 ppb and a chronic concentration of 0.86 ppb.

2. Ground water

Drinking water concentrations from ground water were estimated with SCI-GROW, also a

Tier 1 unrefined assessment tool. For ground water, the maximum acute and chronic estimated

concentration of phostebupirim is 0.3 ppb. This screening model does not provide different values for

acute and chronic estimated residue values. 
12

3. Drinking Water Levels of Comparison (DWLOCs)

To determine the maximum allowable contribution of water containing pesticide residues

permitted in the diet, EPA first looks at how much of the overall allowable risk is contributed by food

(and if appropriate, residential uses) then determines a “drinking water level of comparison” (DWLOC)

to determine whether modeled or monitored levels exceed this level. The Agency uses the DWLOC as

a surrogate to capture risk associated with exposure from pesticides in drinking water. The DWLOC

is the maximum concentration in drinking water which, when considered together with dietary exposure,

does not exceed a level of concern.

OPP has calculated DWLOCs for acute exposure to phostebupirim in surface and ground

water for the U.S. general population and children (ages 1-6). These DWLOCs are 68.36 ppb and

19.04 ppb, respectively. For chronic (non-cancer) exposure to phostebupirim in surface and ground

water, the DWLOCs are 6.48 ppb for the U.S. general population, and 1.65 ppb for children (ages 1-

6). 

Estimated maximum concentrations of phostebupirim in surface and ground water are 1.89 ppb

and 0.3 ppb, respectively. Estimated average concentrations of phostebupirim in surface and ground

water are 0.86 ppb and 0.3 ppb, respectively.

The maximum and average drinking water estimated concentrations in surface and ground

water are less than OPP’s levels of comparison for phostebupirim in drinking water. As residues of

phostebupirim in drinking water are less than calculated drinking water levels of comparison, the

Agency concludes that drinking water risk from phostebupirim use is not of concern. 

C. Aggregate Risk

Aggregate risk consists of the combined risk from exposure through food, drinking water, and

non-occupational uses of a pesticide. For phostebupirim, acute and chronic aggregate risk is limited to

food and water exposure because phostebupirim is not used in residential settings or other areas that

are frequented by the general public. Generally, the combined risks from these different exposures

must be less than 100% of the acute or chronic PAD, respectively. Since the ground and surface water

estimated concentrations are substantially below the DWLOCs based on screening models, acute and

chronic aggregate (food and water) exposure to phostebupirim is not of concern for any population

sub-group. There are no residential uses of phostebupirim, and no residential exposures resulting from

phostebupirim use on corn. 

D. Occupational Risk

Occupational workers can be exposed to a pesticide through mixing, loading, and/or applying a

pesticide, or re-entering treated sites. Risk to workers handling phostebupirim is measured by a
13

Margin of Exposure (MOE) which determines how close the occupational or residential exposure

comes to a No Observed Adverse Effect Level (NOAEL). Generally, MOEs greater than 100 do not

exceed the Agency’s level of concern.

1. Toxicity

Table 2 presents the acute toxicity categories for phostebupirim.

Table 2. Toxicity Categories

Study Type Toxicity Category

 (technical)

Toxicity

Category

(Aztec 4.67%)

Acute Oral Toxicity I II

Acute Dermal Toxicity I III

Acute Inhalation Toxicity I III

Primary Eye Irritation Not Available III

Primary Dermal Irritation Not Available IV

Dermal Sensitization Not Available slight

The phostebupirim endpoints were obtained from the Agency's "Risk Assessment for Use of

Aztec 2.1% Granular on Corn Commodities," dated February 16, 1995, and they indicate that there

are toxicological endpoints of concern for phostebupirim. Phostebupirim is not expected to be used on

a continuous long-term basis (greater than 6 months a year) resulting in chronic exposure. Therefore,

the risk assessments were conducted for short- (1-7 days) and intermediate- (one week- several

months) term occupational exposure scenarios. Dermal and inhalation endpoints of concern have been

identified for short-term and intermediate-term exposures.

Table 3 lists the toxicity endpoints selected for the phostebupirim risk assessment. These are

based primarily on plasma, red blood cell, and brain cholinesterase inhibition. While a 21-day rabbit

dermal toxicity study was submitted by the registrant, this could not be relied on for risk assessment

since phostebupirim is a sulfur-containing organophosphate and detoxification can occur in rabbits when

dermally exposed to sulfur-containing organophosphates. Phostebupirim is classified as a Group E

chemical, indicating that it is “Not Likely” to be carcinogenic in humans via relevant routes of exposure. 

This classification is supported by adequate carcinogenicity studies in rats and mice.
14

Table 3. Phostebupirim Hazard Endpoints and Uncertainty Factors

Route /

Duration

NOAEL

(mg/kg/day)

Effect Study Uncertainty Factors Absorption

Factor

 Dermal 

short term

0.1 Increased Number

of Fetal

Resorptions

developmental

toxicity in rabbits.

Interspecies: 10x

Intraspecies: 10x

100 percent

dermal 

assumed. 

Dermal

intermediate term

0.02 Red Blood Cell

Cholinesterase

Inhibition

1-year chronic dog

study

Interspecies: 10x

Intraspecies: 10x

100 percent

dermal 

assumed. 

Inhalation (short

and intermediate

term)

 0.043

(0.16 mg/m3)

a

 Red Blood Cell

Cholinesterase

Inhibition

28 day inhalation

study in rats.

Interspecies: 10x

Intraspecies: 10x

Wistar Rats, 6

hrs/day

exposure, 100

percent lung

absorption

assumed.

a 0.16 mg/m3

 was converted to 0.043 mg/kg/day by the following formula: NOAEL (mg/kg/day) = NOAEL (mg/m3) *

Conversion Factor (1m3 / 1000 L) * Wistar Rat Respiratory Volume for Males and Females (8.46 L/hr) * Body Weight of

Wistar Rats for Males and Females (1/0.187 kg) * Exposure Duration per day (6 hrs/day).4

2. Exposure

Chemical-specific exposure data were not available for phostebupirim; therefore, risks to

pesticide handlers were assessed using data from the Pesticide Handlers Exposure Database

(PHED), and standard assumptions about average body weight, work day, daily areas treated, volume

of pesticide used, etc. to calculate risk estimates. The quality of the data and exposure factors

represents the best sources of data currently available to the Agency for completing these kinds of

assessments; the application rates are derived directly from phostebupirim labels. The exposure factors

(e.g., body weight, amount treated per day, protection factors, etc.) are all standard values that have

been used by the Agency over several years, and the PHED unit exposure values are the best available

estimates of exposure. Some PHED unit exposure values are high quality while others represent low

quality, but are the best available data. The quality of the data used for each scenario assessed is

discussed in “Occupational Exposure and Risk Assessment Regarding the Use of Phostebupirim,”

dated May 5, 1999, which is available in the public docket.

The following general assumptions are made:

• Average body weight of an adult handler is 70 kg. An average body weight of 60 kg

was used for an adult female for short-term dermal exposure since the NOAEL is

based on a reproductive study. Since the dermal and inhalation NOAELs for the shortterm were not based on identical effects, the doses were not combined in this risk

assessment to identify a total MOE. However, the MOEs were combined for the

intermediate-term since the effect was the same. 
15

• Average work day interval represents an 8 hour workday (e.g., the acres treated or

volume of spray solution prepared in a typical day).

• Calculations of handler scenarios are completed using the application rates

recommended by the available phostebupirim labels. 

C PHED Version 1.1 data were used to estimate exposures for all scenarios.

• Due to a lack of scenario-specific data, the Agency calculated unit exposure values

using generic data from the Pesticide Handler Exposure Database (PHED) and, in lieu

of PHED data for a scenario, using protection factors that are applied to represent

various risk mitigation options (i.e., the use of PPE and engineering controls).

• Exposures were estimated for handlers using 213 acres per day maximum acreage (20

row planter) and 69 acres per day typical acreage (8 row planter) for a tractor drawn

spreader at the minimum and maximum application rates, since these data were

available from the "Corn Insecticide Cluster Risk Assessment for Occupational

Exposure," dated November, 1993.

3. Risk Assessment

Occupational exposure scenarios identified for phostebupirim were (1) loading phostebupirim

granulars and (2) applying phostebupirim granulars with a tractor drawn spreader. Within each of these

occupational categories, further analyses were conducted to determine the MOE at minimum and

maximum application rates, and at maximum and typical acreage. The Agency assessed the exposure

and risks for the two scenarios considering both inhalation and dermal exposure. Phostebupirim is not

expected to be used on a continuous long-term basis (greater than 6 months a year) resulting in chronic

exposure. Therefore, the risk assessments were conducted for short- (1-7 days) and intermediate-

(one week - several months) term occupational exposure scenarios. 

Based on the available toxicity data, it is not appropriate to combine short-term dermal and

inhalation MOEs because the effects observed at the LOAELs are different. However, it is necessary

to combine the intermediate-term dermal and inhalation MOEs, since the effects observed at the

LOAELs were identical. The short-term and intermediate-term MOE for dermal exposure were

calculated using a NOAEL of 0.1 mg/kg/day and a NOAEL of 0.02 mg/kg/day, respectively. Both the

short-term and intermediate-term MOE for inhalation exposure were calculated using a NOAEL of

0.16 mg/m3 which translates to 0.043 mg/kg/day. Since a developmental study was used to determine

the short-term dermal NOAEL, the body weight used to calculate short-term dermal dose was 60 kg,

the average weight of an adult female. No chronic scenarios were identified. All of the risk calculations

for handlers completed in this assessment are described in the document entitled, “Occupational

Exposure and Risk Assessment 
16

Regarding the Use of Phostebupirim,” dated May 5, 1999, available in the public docket. The results

are summarized in Tables 5-6 of this document. Table 4 summarizes the PPE requirements on current

phostebupirim labels.

Table 4: PPE on Current Phostebupirim Labels

Formulation Loaders Applicators

Aztec 2.1% Granular

Insecticide

Long pants, long sleeved shirt,

waterproof gloves and shoes

plus socks.

Long pants, long sleeved shirt,

waterproof gloves and shoes

plus socks.

Aztec 4.67% Granular

Insecticide

Long pants, long sleeved shirt,

waterproof gloves and shoes

plus socks. Smart Box®

required.

Long pants, long sleeved shirt,

waterproof gloves and shoes

plus socks.

a. Short-Term Risks

Table 5 presents the MOEs for short-term worker exposures. Under current phostebupirim

labels, short-term dermal MOEs exceed the Agency’s level of concern for all worker handler

scenarios, with the exception of loading granules with the Smart Box formulation and at the minimum

application rate and typical acreage for the 2.1G formulation. Additional personal protective equipment

(double layer of clothing for loaders and respirators for applicators) partially addresses these MOEs,

while engineering controls (closed loading systems and enclosed cabs) result in MOEs greater than 100

for all use scenarios with the exception of application at maximum rates and for the maximum acreage. 
17

Table 5: Short-Term Dermal and Inhalation Exposure to Phostebupirim*

Scenario Acres a Rateb

(pounds

ai/acre)

Short-Term Dermal MOEs Short-Term Inhalation MOEs

Current

Labelc

Current label

+ additional

PPEd

Engineering

controls e

Current

Labelc

Current

Label +

addn

PPEd

Engineering

Controls e

Loading

granules 

69 0.11 110 230 4700 230 1200 12000

0.15 84 170 3400 170 860 8600

Loading

granules

213 0.11 37 75 1500 76 380 3800

0.15 27 55 1100 55 280 2800

Applying

granules

with

tractor

drawn

spreader

69 0.11 110 190 380 330 1700 1800

0.15 81 140 280 240 1200 1300

Applying

granules

with

tractor

drawn

spreader

213 0.11 36 61 120 110 540 580

0.15 26 45 89 79 390 430

* Dermal and inhalation exposures were not combined due to the difference in effects observed at the LOAELs.

a Typical acreage = 69 acres; Maximum acreage = 213 acres.

b Minimum application rate = 0.11 lbs ai/Acre; Maximum application rate = 0.15 lbs ai/Acre.

c

 Current labels reflect risks for loaders, and applicators of the 2.1%G products, but only applicators for the 4.67%G product

(risks for loaders of the 4.67%G are reflected under engineering controls due to the Smart Box®). Current label specified PPE for

dermal unit exposure are long pants, long sleeved shirt, water-proof gloves, open mixing/loading, open cab tractor. Inhalation

exposure represents no respirator. 

d

 Additional PPE for all dermal scenarios includes double layer of clothing (50% Protection Factor for clothing). Additional PPE

for all inhalation scenarios includes a dust/mist respirator (80% Protection Factor).

e

 Engineering controls for dermal scenarios include closed mixing/loading (e.g., Lock and Load® or Smart Boxes® 98% protection

factor), single layer clothing, chemical resistant gloves. Engineering controls for inhalation scenarios include enclosed cab, single

layer clothing, no gloves (98% protection factor).

b. Intermediate-Term Risk

Table 6 presents MOEs for intermediate-term worker exposures. There are intermediate-term 

risks of concern for all use scenarios under current labels and with additional PPE, except for the Smart

Box formulation which has MOEs greater than 100 for loaders. Use of closed loading systems brings

all MOEs to greater than 100 for loaders, while use of enclosed cabs results in MOEs for applicators

ranging from 20 to 84, which exceed the Agency’s level of concern.
18

Table 6: Intermediate-Term Dermal and Inhalation Exposure to Phostebupirim*

Scenario Acres a Rateb

(pounds

ai/acre)

Intermediate-Term Dermal MOEs Intermediate-Term Inhalation MOEs Intermediate-Term Combined MOEs

Current

Labelc

Current

label +

additional

PPEd

Engineering

controls e

Current

Labelc

Current

label +

additional

PPEd

Engineering

controls e

Current

Labelc

Current

label +

additional

PPEd

Engineering

controls e

Loading

granules 

69 0.11 27 54 1100 230 1200 1200 24 52 990

0.15 20 40 800 170 860 8600 18 38 730

Loading

granules

213 0.11 9 18 350 76 380 3800 8 17 320

0.15 6 13 260 55 280 2800 6 12 240

Applying

granules

with tractor

drawn

spreader

69 0.11 26 44 88 330 1700 1800 24 43 84

0.15 18 32 64 240 1200 1300 17 31 61

Applying

granules

with tractor

drawn

spreader

213 0.11 8 14 28 110 540 580 8 14 27

0.15 6 10 21 79 390 430 6 10 20

* Dermal and inhalation exposures were combined since the effects observed at the LOAELs were identical. 

a Typical acreage = 69 acres; Maximum acreage = 213 acres.

b Minimum application rate = 0.11 lbs ai/Acre; Maximum application rate = 0.15 lbs ai/Acre.

c

 Current labels reflect risks for loaders, and applicators of the 2.1%G products, but only applicators for the 4.67%G product (risks for loaders of the 4.67%G are

reflected under engineering controls due to the Smart Box®). Current label specified PPE for dermal unit exposure are long pants, long sleeved shirt, water-proof

gloves, open mixing/loading, open cab tractor. Inhalation exposure represents no respirator. 

d

 Additional PPE for all dermal scenarios includes double layer of clothing (50% Protection Factor for clothing). Additional PPE for all inhalation scenarios

includes a dust/mist respirator (80% Protection Factor).

e

 Engineering controls for dermal scenarios include closed mixing/loading (e.g., Lock and Load® or Smart Boxes® 98% protection factor), single layer clothing,

chemical resistant gloves. Engineering controls for inhalation scenarios include enclosed cab, single layer clothing, no gloves (98% protection factor).
19

4. Post-Application Risk

The present labels for phostebupirim establish a re-entry interval (REI) of 0 hours. The

Agency’s decision to establish the REI at this level is reflected in the memorandum entitled "Requested

Waiver of WPS Label Statements for Aztec 2.1% Granular Insecticide," dated September 13, 1994.

This decision was based on the belief that soil incorporated insecticides, such as phostebupirim, would

not result in any dermal exposure after incorporation. 

Since the phostebupirim REI of zero hours was established in 1994, the Agency has clarified

implementation of the Worker Protection Standards and when an REI must be established. As part of

its reassessment of occupational risks for phostebupirim, EPA has reevaluated potential postapplication

exposures and risks following soil-incorporated applications during planting of corn. The Agency has

determined that the Worker Protection Standard and current Agency policy indicate that a restrictedentry interval must be established for this use pattern. The Agency notes that phostebupirim does not

qualify as a low risk pesticide, because of its high acute toxicity and because it is classified as an

organophosphate. Therefore, the restricted-entry interval will be established based on available data on

its dermal toxicity and its skin and eye irritation potential. 

Under the Worker Protection Standard (WPS), restricted entry intervals for all uses within the

scope of the WPS are based on the acute toxicity of the active ingredient. The toxicity categories of

the active ingredient for acute dermal toxicity, eye irritation, and skin irritation are used to determine the

WPS REI. If one or more of the three acute toxic affects are in toxicity category I, the WPS REI is

established at 48 hours (72 hours in areas that receive less than 25 inches of rainfall per year). Since

phostebupirim has a toxicity category of 1 for acute dermal, the REI should be 48 hours (72 hours in

areas that receive less than 25 inches of rainfall per year) to comply with the Worker Protection

Standard. 

IV. FQPA Tolerance Reassessment Progress and Interim Risk Management Decision

A. Determination of Tolerance Reassessment & Interim Risk Management

Decision

This interim evaluation presents the Agency's current position on products containing the active

ingredient phostebupirim. The Agency has sufficient information on the human health effects of

phostebupirim to make interim decisions as part of the tolerance reassessment process under FQPA

and to reassess occupational risks under FIFRA. Should a registrant fail to implement any of the

recommended risk mitigation measures outlined in this document, the Agency will continue to have

concerns about the risks posed by phostebupirim. Where the Agency has identified any unreasonable

adverse effect to human health, the Agency may at any time initiate appropriate regulatory action to

address this concern. At that time, any affected person(s) may challenge the Agency’s action. 
20

Based on its current evaluation of phostebupirim alone, the Agency has determined that

phostebupirim products, labeled and used as specified in this document, will not present unreasonable

dietary and occupational risks. Occupational risks can be brought above the Agency's level of concern

with additional personal protective equipment. In addition, data from both an exposure or dust

comparison study and a new dermal toxicity study will allow the Agency to refine its occupational risk

assessment.

The Agency will finalize the decision for phostebupirim after evaluating the cumulative risk of the

organophosphate class. Because the Agency has not yet completed the cumulative risk assessment for

the organophosphates, this interim decision does not fully address the reassessment of the existing

phostebupirim food residue tolerances as required by section 408(q) of the FQPA. When the Agency

has completed the cumulative assessment, phostebupirim tolerances will be reassessed along with the

other organophosphate pesticides and a final determination will be made. Such an incremental

approach to the tolerance reassessment process is consistent with the Agency's goal of improving the

transparency of the implementation of FQPA. By evaluating each organophosphate in turn and

identifying appropriate risk reduction measures, the Agency is addressing the risks from the

organophosphates in as timely a manner as possible.

This interim evaluation does not limit the Agency from making further FQPA determinations and

tolerance-related rulemakings that may be required on this pesticide or any other in the future. If the

Agency determines, as a result of this later implementation process, that any of the determinations

described in this Report on FQPA Tolerance Reassessment Progress and Interim Risk Management

document are no longer appropriate, the Agency will pursue appropriate action, including but not

limited to, reconsideration of any portion of this interim document.

B. Summary of Phase 3 Comments and Revisions to Preliminary Assessment

The Agency solicited comments on the preliminary human health assessment for phostebupirim. 

In response to the May 26, 1999, Federal Register Notice (64 FR 28469) announcing the availability

of the preliminary risk assessment and supporting documents, comments on the risk assessment were

submitted by the phostebupirim registrant, Bayer Corporation. The registrant disagreed with the

selection of a developmental toxicity study in rabbits for establishing the acute RfD and with the

selection of a developmental toxicity study for evaluating dermal exposure to workers. The Agency

acknowledged that it was more appropriate to use an acute neurotoxicity study for the acute dietary

endpoint and noted that the 3X FQPA safety factor had been reduced to 1X by the Hazard

Identification Assessment Review Committee as a result of its March 25, 1999, meeting based on the

Agency’s review of that data. However, the Agency noted that it was not appropriate to use the 21-

day dermal toxicity study in rabbits submitted by the registrant instead of the developmental toxicity

study to determine the endpoint for short-term dermal exposure. This is because the use of rabbits to

evaluate the dermal toxicity of sulfur-containing organophosphates is not appropriate because

detoxification can occur in rabbits when dermally exposed to sulfur-containing organophosphates. The
21

registrant also disagreed with the use of technical phostebupirim to measure inhalation exposure, rather

than use of a formulated product. The Agency determined that comments received during Phase 3 did

not warrant further revisions to the risk assessment. A fuller discussion of the registrant comments and

the Agency’s response can be found in “Phostebupirim: HED’s Response to Comments Submitted

During Phase 3 (Public Comment Period), dated September 22, 1999.

C. Summary of Phase 5 Comments and Responses

The availability of the revised risk assessment and supporting documents was announced on

March 27, 2000, in Federal Register Notice (65 FR 16197). Interested parties were provided a 60-

day period to submit comments, including risk mitigation proposals. Only two submissions were

received during this public comment period, one from the President of the Illinois Corn Growers

Association and the other from the phostebupirim registrant, Bayer Corporation. These comments are

available in their entirety in the docket. A brief summary of the comments and the Agency response is

noted here.

1) Comment. The President of the Illinois Corn Growers Association noted that Aztec plays an

important role in managing corn pests and objected to EPA's use of maximum rates and worst-case

scenarios in conducting risk assessments as unrealistic. He also expressed the opinion that EPA's use

of exposure data derived from a broadcast study was inappropriate because phostebupirim is applied

through in-furrow or banded application methods which are more targeted than broadcast application. 

Response. This comment provided no specific mitigation suggestions. However, the Agency's policy is

to use the maximum labeled application rates and maximum daily treated acreage for calculating short

and intermediate-term occupational risks. Since the endpoint of concern for phostebupirim results from

a short and intermediate-term exposure, it is appropriate to protect workers who use the maximum

recommended application rates and who are applying it to larger corn fields. The Agency has reviewed

acreage information for corn and believes that the 213 acres used is a realistic estimate of the maximum

number of acres of corn which may be treated with phostebupirim in a given day (based on the Corn

Cluster analysis and follow-up information). 

While the Agency does not agree that it was inappropriate to use exposure data derived from a

broadcast study in the risk assessment, EPA does agree that this has likely resulted in an overestimate

of exposure. This likely overestimate of exposure has been factored into the risk mitigation

recommended in this document.

2) Comment. Bayer Corporation did not provide any risk mitigation suggestions; instead Bayer

reiterated many of the same comments on the risk assessment raised in its Phase 3 comments. 

Specifically, (1) Bayer alleged that the Agency had chosen different toxicological endpoints in 1999

than in 1995 to assess occupational risk despite the submission of no new studies, (2) Bayer suggested

that the use of in-furrow and T-Band application data could reduce calculated exposure values, (3)
22

Bayer reiterated its objection to the Agency's rejection of the 21-day dermal toxicity study in rabbits for

regulating occupational dermal exposure, (4) Bayer objected to the Agency's assumption of 100%

dermal absorption, suggesting sufficient information was available to estimate a lower dermal absorption

value, (5) Bayer suggested that the Agency amortize intermediate-term exposure from the 1-year

chronic dog study to more accurately represent the shorter-term intermediate-term exposure, and (6)

Bayer proposed that 150 acres should be used for maximum daily acres treated rather than the 213

used by the Agency. 

Response. As discussed more fully in the Agency's June 23, 2000, Response to Bayer's Comments

found in the docket and on the internet, (1) the Agency used the exact same toxicological endpoints in

both its 1995 and 1999 occupational risk assessment, (2) the Agency's exposure data included the use

of in-furrow and T-Band application studies, (3) it is inappropriate to use dermal toxicity studies in

rabbits for sulfur-containing organophosphates such as phostebupirim, (4) the Agency does not have

sufficient information to estimate an appropriate dermal absorption value and therefore assumes 100%

dermal absorption in the absence of additional data, (5) the Agency agrees that a 1-year chronic dog

study is not the ideal study for estimating intermediate-term worker risk; however, the Agency does not

have sufficient information to amortize intermediate-term exposure from the 1-year chronic dog study

and in the absence of a more appropriate study, the 1-year chronic dog study is a more appropriate

duration study than the other available studies, and (6) the data available to the Agency indicates that

213 acres is an appropriate maximum daily acres treated value for corn and does not result in an overly

conservative estimate of risk. 

D. Regulatory Position

1. FQPA and Occupational Risk Assessment

a. "Risk Cup" Determination

As part of the FQPA tolerance reassessment process, EPA assessed the risks associated with

this individual organophosphate. FQPA also requires the Agency to consider available information on

cumulative risk from substances sharing a common mechanism of toxicity, such as the toxicity

expressed by the organophosphates through a common biochemical interaction with the cholinesterase

enzyme. The Agency will evaluate the cumulative risk posed by the entire class of organophosphates

once the methodology is developed and the policy concerning cumulative assessments is resolved. 

EPA has determined that risk from exposure to phostebupirim is within its own “risk cup.” In

other words, if phostebupirim did not share a common mechanism of toxicity with other chemicals,

EPA would be able to conclude today that the proposed tolerances for phostebupirim on corn meet the

FQPA safety standards. In reaching this determination, EPA has considered the available information

on the special sensitivity of infants and children, as well as chronic and acute food exposure. An

aggregate assessment was conducted for exposures through food and drinking water (there are no
23

residential uses). Results of this aggregate assessment indicate that the human health risks from these

combined exposures are considered to be within acceptable levels; that is, combined risks from all

exposures to phostebupirim "fit" within the individual risk cup. Therefore, unless phostebupirim can be

shown to meet the Agency's Threshold of Regulation policy such that no tolerances are required, the

Agency will consider establishing phostebupirim tolerances after EPA has completed a full assessment

of the cumulative risk from all organophosphates. 

b. Tolerance Summary

Time-limited tolerances of 0.01 parts per million (ppm) were established July 5, 1995, in 60

FR 34871 for phostebupirim residues in or on field corn, sweet corn, pop corn and corn forage and

fodder. The tolerances were set at the Limit of Detection (LOD). There have been no detected

residues of phostebupirim at the LOD in food monitoring programs or field trials where phostebupirim

was applied at the label rate. 

The time-limited tolerances for phostebupirim expired July 6, 1999, while the conditional

registration for phostebupirim was extended through July 5, 2001. The Agency was not able to

establish or extend tolerances for phostebupirim at the time the time-limited tolerance expired due to the

requirements under the FQPA to establish a reasonable certainty of no harm from the cumulative effects

of the residues of all organophosphates that show a common mechanism of toxicity, a level of

assessment which the Agency has not yet completed. However, the Agency believed it was

appropriate to allow for the continued conditional registration of phostebupirim for pre-plant

applications on corn since there is no reasonable expectation of finite residues of phostebupirim. This

determination was made before the Agency issued its Threshold of Regulation (TOR) policy for

deciding whether a pesticide food use pattern needs a tolerance. The Agency believes that

phostebupirim complies with the spirit of the policy because no phostebupirim residues in corn

commodities have been detected in either corn metabolism studies, crop field trials, or in sampling

programs. 

Under the TOR policy, a tolerance or an exemption from the tolerance requirement is not

necessary for a pesticide use that results in no detected residues in food and for which the degree of

potential risk posed by any theoretically possible residues is so minimal that tolerance setting serves no

purpose. While phostebupirim does not meet the TOR policy based on currently available data, Bayer

may be able to generate data which would support a finding under the policy that no tolerances are

required. In order to allow the EPA to make such a determination, it would be necessary to conduct

additional field trial studies using a more sensitive, validated, analytical method, along with exaggerated

application rates. For phostebupirim to be considered under the policy, the registrant should submit a

request in writing, along with any supplemental data to support its request, asking the Agency to

determine whether phostebupirim uses need a tolerance under the TOR policy.
24

The time-limited tolerances for residues of phostebupirim in/on plant commodities were

expressed in terms of residues of phostebupirim per se. Based upon the lack of phostebupirim residues

measured in field corn, popcorn, and sweet corn commodities (<0.01 ppm), there is no reasonable

expectation of finite residues of phostebupirim in meat, milk, poultry or eggs and no tolerances would

be needed for these commodities if the tolerances for the raw agricultural commodities were

established. If the Agency is able to establish phostebupirim tolerances after it completes its cumulative

dietary risk assessment from all organophosphates, Table 7 provides the appropriate tolerance levels

for phostebupirim [O-[2-(1,1-dimethylethyl)-5-pyrimidinyl] O-ethyl O-(1-methylethyl)

phosphorothioate], as supported by submitted residue data. Sufficient data are available to ascertain

the adequacy of these tolerances for the following commodities, as defined in 40 CFR § 180.486. 

Note that these tolerances cannot be established, or considered "reassessed" as required by FQPA,

until the cumulative risk assessment of all organophosphates is completed. 

Table 7: Tolerance Summary for Phostebupirim 

Commodity Parts per million

Corn, field, forage 0.01

Corn, field, stover 0.01

Corn, pop, forage 0.01

Corn, pop, stover 0.01

Corn, sweet, forage 0.01

Corn, sweet, stover 0.01

Corn, field, grain 0.01

Corn, pop, grain 0.01

Corn, sweet, kernel plus cob with husks

removed

0.01

2. Endocrine Disruptor Effects

EPA is required to develop a screening program to determine whether certain substances

(including all pesticides and inerts) "may have an effect in humans that is similar to an effect produced by

a naturally occurring estrogen, or such other endocrine effect...". The Agency is currently working with

interested stakeholders, including government agencies, public interest groups, industry and research

scientists in developing a screening and testing program and a priority setting scheme to implement this

program. The EPA may require further testing of phostebupirim for endocrine disruptor effects when

this program is in place.
25

3. Recommended Label Modifications

The Agency recommends the following measures, in addition to the existing label requirements,

to clarify and strengthen the existing label language to help minimize worker risks. These measures are

expected to result in minimal impact on grower costs and ability to effectively use phostebupirim

products. 

• Labels should state that for granular products packaged in the SmartBox® closed loading

system (or any other closed loading system that meets the requirements of the WPS), loaders,

applicators and other handlers must wear long-sleeved shirt, long pants, shoes plus socks, and

chemical resistant gloves such as or made out of any waterproof material. In addition, loaders

must be provided with and have immediately available for use in case of an emergency, a

NIOSH approved dust/mist respirator. 

• Labels should state that for clay-based products not packaged in the SmartBox® closed

loading system (or any other closed loading system that meets the requirements of the WPS),

loaders, applicators and other handlers must wear long-sleeved shirt, long pants, shoes plus

socks and chemical resistant gloves such as or made out of any waterproof material. In

addition, loaders must wear a dust/mist respirator. 

• Labels should state that for cellulose-based products not packaged in the SmartBox® closed

loading system (or any other closed loading system that meets the requirements of the WPS),

loaders, applicators and other handlers must wear long-sleeved shirt, long pants, shoes plus

socks and chemical resistant gloves such as or made out of any waterproof material. 

• The REI should be 48 hours or 72 hours where there is less than 25 inches of rainfall.

• Labels should state that PPE during early re-entry consists of coveralls, chemical resistant

gloves such as or made out of any waterproof material, socks plus shoes, and protective eye

wear.

• Labels should include a "double notification" statement. Double notification requires that

workers are advised about the application both orally and by posting warning signs at entrances

to treated areas during the REI.

The Agency is not recommending any further label modifications, beyond the above listed

measures, to mitigate occupational risks from phostebupirim use at this time. Bayer has agreed to

implement the above label modifications for the 2001 use season and the Agency believes that

remaining worker risk concerns will be adequately addressed as a result of confirmatory data, which

will be submitted by April 1, 2001, to refine the occupational risk assessment. The Agency will review

the phostebupirim data prior to July 5, 2000, the date the conditional registration expires.
26

E. Regulatory Rationale

The following is a summary of the rationale for managing risks associated with the use of

phostebupirim. Where labeling revisions are recommended, specific language is set forth in the

summary tables of Section V of this document.

1. Dietary Mitigation

a. Dietary (Food) Risk Mitigation

Acute and chronic dietary risk from food is well below the Agency's level of concern -- a Tier

1 DEEMTM analysis yielded percent acute and chronic PAD values that are only 4.79% and 17.6%

respectively at the 95th percentile of exposure for the most exposed population subgroup (children 1-6

years old). Therefore, no mitigation measures are recommended at this time to address acute or

chronic dietary risk from food.

b. Dietary (Water) Risk Mitigation

Acute and chronic dietary risk from water is not of concern based on the comparison of the

DWLOC against the estimated concentrations from surface and ground water modeling, based on Tier

1 screening models which provide an upper-bound unrefined estimate of drinking water concentrations. 

Therefore, no mitigation measures are recommended at this time to address acute or chronic drinking

water risks.

c. Aggregate (Food + Water) Risk Mitigation

For phostebupirim, the aggregate risk is limited to food and water. No risk mitigation for

aggregate risk is necessary at this time because food and drinking water estimates indicate that the

Agency's level of concern is not exceeded for any subgroup.

2. Occupational Risk Mitigation

Under the current label, the Agency's risk assessment shows a risk concern for short and

intermediate-term exposures for both granular loaders and applicators. Adding a dust/mist respirator

requirement to the 2.1G clay-based formulation product labels for loaders would address inhalation risk

concerns. The Agency believes the inhalation risks for applicators are overstated because the MOEs

were calculated with low confidence PHED data based on a broadcast spreader study. Phostebupirim

is applied in-furrow or T-Band, which will have lower exposures. Therefore, no risk mitigation is

necessary to address applicator inhalation risk.
27

 Although dermal risks are of concern, the registrant has agreed to initiate a 21-day rat dermal

toxicity study which the Agency believes will confirm that its current dermal risk assessment

overestimates the potential for worker exposure for the following reasons:

(1) In the absence of an acceptable dermal toxicity study, the Agency is regulating worker dermal

exposures based on an oral developmental study. The Agency's preference is to use routespecific studies when possible, and thus a dermal toxicity study would be preferred over an oral

study especially when coupled with the more conservative 100% dermal absorption

assumption. While it is not appropriate to use a rabbit dermal toxicity study for sulphurcontaining organophosphates like phostebupirim, it would be appropriate to use a rat dermal

toxicity study.

(2) The registrant is conducting its dermal toxicity study using the granular (4.67% a.i.) rather than

the technical (98% a.i.) formulation. The Agency believes this is appropriate since only a 2.1%

and 4.67% a.i. granular formulation are registered. This will provide a more realistic picture of

the impacts of the granular product, which has a much lower percent active ingredient than the

liquid technical product.

(3) Since short-term worker exposures are 1-7 days while intermediate-term exposures are 7 days

to several months, the Agency had to use two different studies to approximate these different

exposure durations. One, the oral rabbit developmental study, provided an acute (short-term)

exposure, while the other, the 1-year chronic dog study, provided a longer-term exposure

duration, although the Agency believes intermediate-term exposures to phostebupirim do not

exceed 30 days. By conducting a 21-day rat dermal toxicity study, the registrant will provide a

study which better represents both the short-term and intermediate-term worker exposure

durations. Thus, the Agency will be able to use a single, more appropriate, study to establish a

NOAEL for both short-term and intermediate-term exposure durations.

Thus, for the above-mentioned reasons, the Agency believes that a 21-day rat dermal toxicity

study will provide a more appropriate endpoint for regulating both short-term and intermediate-term

occupational dermal exposures and will provide a more refined occupational risk assessment. 

In conclusion, to mitigate inhalation risks to loaders, the Agency is recommending label

amendments to require the use of a dust/mist respirator when loading the Aztec® 2.1G granular claybased formulation. The Agency believes that handlers of Aztec® 2.1G cellulose-based products are

exposed to comparatively lower levels via inhalation. As a result, no mitigation is recommended at this

time for the Biodac cellulose-based formulation. However, to confirm the Agency’s belief that

cellulose-based formulations pose less inhalation risk than the clay-based formulation, the registrant has

agreed to submit an exposure or dust comparison study by April 1, 2001.
28

The Agency is not requiring further risk mitigation to address applicator inhalation risk. 

Although the risk assessment shows a risk concern for this exposure (MOE=79), the Agency believes

this risk is overstated. This is because the risk was calculated using low confidence PHED data (one

study with a small number of replicates using only a broadcast spreader). In actual use, phostebupirim

will typically be applied in-furrow or T-Band. These methods of application should make the granular

formula less available for exposure.

With regard to dermal risks, the Agency believes that the 21-day rat dermal toxicity study using

the 4.67G formulation, which the registrant will submit by April 1, 2001, will demonstrate that the

NOAEL is substantially higher and that worker dermal MOEs no longer exceed the Agency's level of

concern. As a result, the Agency is not recommending any additional measures at this time to address

worker risks from dermal exposure. However, in the event that there are risk concerns after results of

the new studies are reviewed, the Agency will recommend additional mitigation measures to the

registrant. 

3. Post Application Risk Mitigation

Since the phostebupirim REI of 0 hours was established in 1995, the Agency has clarified

implementation of the Worker Protection Standards and when an REI must be established. For

phostebupirim, EPA has reevaluated potential postapplication exposures and risks following

soil-incorporated applications during planting of corn. The Agency has determined that the Worker

Protection Standard and current Agency policy indicate that a restricted-entry interval should be

established for this use pattern. The Agency notes that phostebupirim does not qualify as a low risk

pesticide, because of its high acute toxicity and because it is classified as an organophosphate.

Therefore, the restricted-entry interval will be established based on available data on its dermal toxicity

and its skin and eye irritation potential. The restricted-entry interval (REI) is the time immediately after

a pesticide application when entry into the treated area is limited. The current REI on phostebupirim

end-use products of 0 hours must be replaced by 48 hours or 72 hours where average rainfall is less

than 25 inches per year in order to comply with the Worker Protection Standard (WPS). Early reentry PPE, as required by WPS, must also be specified on labels and include coveralls over longsleeved shirt, long pants, chemical resistant gloves such as or made out of any waterproof material,

chemical resistant footwear plus socks and protective eye wear. Protective eye wear is being required

because the active ingredient (a.i.) is assumed to be Toxicity Category I for Acute Eye Irritation in the

absence of available data. A double notification requirement for re-entry is required because the a.i. is

assumed to be Toxicity Category I for Dermal Irritation in the absence of available data.
29

V. Recommended Mitigation Measures

A. Manufacturing Use Products

The generic database supporting the registration of phostebupirim for use on corn has been

reviewed and determined to be substantially complete. However, the registrant is conducting a 21-day

rat dermal toxicity study and an exposure or dust comparison study which will provide further

refinement of the current risk assessment. Theses studies are to be submitted to the Agency by April 1,

2001.

B. End-Use Products

1. Labeling Changes for End-Use Products

The Agency recommends the following label language and modifications detailed in Table 8 to

mitigate occupational risks.
30

Table 8: Summary of Recommended Occupational Labeling for Phostebupirim

Description Recommended Labeling Placement on Label

End Use Products Intended for Use on Corn

PPE Requirements1 for 

granular products contained

in a SmartBox® system

“Personal Protective Equipment (PPE)”

“Some materials that are chemical-resistant to this product are any water proof materials. “If you want more

options, follow the instructions for category A on an EPA chemical-resistance category selection chart."

“Loaders, applicators and other handlers must wear:

-- Long-sleeved shirt and long pants,

-- Chemical resistant gloves such as or made out of any waterproof material,

-- Shoes plus socks

“See Engineering Controls for additional requirements.”

Precautionary Statements: 

Hazards to Humans and

Domestic Animals

PPE Requirements* for the

granular clay-based product 

(not in a SmartBox® system)

 

“Personal Protective Equipment (PPE)”

"Some materials that are chemical-resistant to this product are any water proof materials. If you want more

options, follow the instructions for category A on an EPA chemical-resistance category selection chart."

“Loaders, applicators and other handlers must wear:

-- Long-sleeved shirt and long pants

-- Chemical resistant gloves such as or made out of any waterproof material,

-- Shoes plus socks

In addition, loaders must wear:

-- A NIOSH-approved dust mist filtering respirator with MSHA/NIOSH approval number prefix TC-21C or a

NIOSH-approved respirator with any N2 R, P, or HE filter.”

Precautionary Statements: 

Hazards to Humans and

Domestic Animals 
Description Recommended Labeling Placement on Label

31

PPE Requirements1 for the

granular cellulose-based

product (not in a SmartBox®

system)

“Personal Protective Equipment (PPE)”

"Some materials that are chemical-resistant to this product are any water proof materials. “If you want more

options, follow the instructions for category A on an EPA chemical-resistance category selection chart."

“Loaders, applicators and other handlers must wear:

-- Long-sleeved shirt and long pants

-- Chemical resistant gloves such as or made out of any waterproof material

-- Shoes plus socks

Precautionary Statements: 

Hazards to Humans and

Domestic Animals

User Safety Requirements "Follow manufacturer's instructions for cleaning/maintaining PPE. If no such instructions for washables, use

detergent and hot water. Keep and wash PPE separately from other laundry."

Precautionary Statements: 

Hazards to Humans and

Domestic Animals 

(immediately following the

PPE requirements)

Engineering Controls for

Product packaged in the

SmartBox® system.

“Engineering Controls

This product is formulated into a “Smart Box” system that meets the definition of a closed loading system as

defined by the Worker Protection Standard for Agricultural Pesticides. IMPORTANT: In addition to wearing

the required PPE specified above, loaders must be provided and must have immediately available for use in

case of an accident or spill: A NIOSH-approved dust mist filtering respirator with MSHA/NIOSH approval

number prefix TC-21C or a NIOSH-approved respirator with any N* R, P, or HE filter.”

“When applicators use enclosed cabs, in a manner that meets the requirements listed in the Worker

Protection Standard (WPS) for agricultural pesticides (40 CFR 170.240(d)(4-6), the handler PPE requirements

may be reduced or modified as specified in the WPS.” 

Precautionary Statements: 

Hazards to Humans and

Domestic Animals 

(immediately following PPE

and User Safety

Requirements.) 

Engineering Controls

(not in SmartBox® system

or in any other closed

system)

“When applicators use enclosed cabs, in a manner that meets the requirements listed in the Worker

Protection Standard (WPS) for agricultural pesticides (40 CFR 170.240(d)(4-6), the handler PPE requirements

may be reduced or modified as specified in the WPS.” 
Description Recommended Labeling Placement on Label

32

User Safety

Recommendations

"User Safety Recommendations:

• Wash hands before eating, drinking, chewing gum, using tobacco, or using the toilet.

• Remove clothing/PPE immediately if pesticide gets inside. Then wash thoroughly and put on clean

clothing.

• Remove PPE immediately after handling this product. Wash the outside of the gloves before

removing. As soon as possible, wash thoroughly and change into clean clothing."

Precautionary Statements

under: Hazards to Humans

and Domestic Animals

immediately following

Engineering Controls

Restricted-Entry Interval "Do not enter or allow worker entry into treated areas during the restricted entry interval (REI) of 48 hours. 

The REI is 72 hours where average rainfall is less than 25 inches per year."

"Exception: if the product is soil-injected or soil-incorporated, the Worker Protection Standard, under certain

circumstances, allows workers to enter the treated area without restrictions if there will be no contact with

anything that has been treated."

Early Entry Personal

Protective Equipment

“PPE required for early entry to treated areas that is permitted under the Worker Protection Standard and that

involves contact with anything that has been treated, such as plants, soil, or water, is:

-- coveralls over long-sleeved shirt and long pants,

-- chemical resistant gloves such as or made out of any waterproof material,

-- chemical resistant footwear plus socks,

-- protective eye wear

Directions for Use,

Agricultural Use

Requirements Box

Double Notification

Statement

"Notify workers of the application by warning them orally and by posting warning signs at entrances to

treated areas."

Directions for Use,

Agricultural Use

Requirements Box

General Application

Restrictions

"Do not apply this product in a way that will contact workers or other persons, either directly or through

drift. Only protected handlers may be in the area during application."

Directions for Use directly

above the Agricultural Use

Box.

1

 PPE that is established on the basis of Acute Toxicity of the end-use product must be compared to the active ingredient PPE in this document. The more protective PPE must

be placed in the product labeling. For guidance on which PPE is considered more protective, see PR Notice 93-7.

2

 The registrant must drop the N type filter from the respirator statement if the pesticide product contains or is used with oil. 

Instructions in the Labeling Required section appearing in quotations represent the exact language that must appear on the label.

Instructions in the Labeling Required section not in quotes represent actions that the registrant must take to amend their labels or product registrations.
33

2. Procedure and Timing for Label Amendment

 Registrants should submit applications for amended registration. This application should

include the following items: EPA application form 8570-1 (filled in), five copies of each revised label,

and a description on the application, such as, "Responding to Interim Tolerance Reassessment

Evaluation and Risk Management Document." Registrants should send applications for amendment to

the appropriate following address within 90 days after receipt of this document. 

Document Processing Desk (APPL)

Office of Pesticide Programs

Room 266A, Crystal Mall 2

1921 Jefferson Davis Highway

Arlington, VA 22202

Attn: Marilyn Mautz

 Insecticide-Rodenticide Branch (7504C)

C. Existing Stocks

Registrants may generally distribute and sell products bearing old labels/labeling for 12 months

from the date of the issuance of this Report on FQPA Tolerance Reassessment and Interim Risk

Management Decision. Persons other than the registrant may generally distribute or sell such products

for 24 months from the date of the issuance of this Report on FQPA Tolerance Reassessment Progress

and risk management decision. However, existing stocks time frames will be established case-by-case,

depending on the number of products involved, the number of label changes, and other factors. Refer

to “Existing Stocks of Pesticide Products; Statement of Policy”; Federal Register, Volume 56, No.

123, June 26, 1991.

VI. Related Documents and How to Access Them

This report is supported by documents that are presently maintained in the OPP docket. The

OPP docket is located in Room 119, Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA. 

It is open Monday through Friday, excluding legal holidays from 8:30 AM to 4:00 PM.

The docket initially contained the preliminary risk assessment and related documents as of

January 15, 1999. On March 15, the first public comment period closed. EPA then considered

comments, revised the risk assessment, and placed the revised risk assessment in the docket on August

18, 1999. All documents, in hard copy form, may be viewed in the OPP docket room or viewed or

downloaded via the Internet (http://www.epa.gov/oppsrrd1/op/).
34
35

VII. APPENDICES
36
37

Appendix A: Citations Supporting the FQPA Tolerance Reassessment and Interim 

Occupational Risk Management Decision (Bibliography)

GUIDE TO APPENDIX A

1. CONTENTS OF BIBLIOGRAPHY. This bibliography contains citations of all studies

considered relevant by EPA in arriving at the positions and conclusions stated elsewhere in the

Reregistration Eligibility Document. Primary sources for studies in this bibliography have been

the body of data submitted to EPA and its predecessor agencies in support of past regulatory

decisions. Selections from other sources including the published literature, in those instances

where they have been considered, are included.

2. UNITS OF ENTRY. The unit of entry in this bibliography is called a "study." In the case of

published materials, this corresponds closely to an article. In the case of unpublished materials

submitted to the Agency, the Agency has sought to identify documents at a level parallel to the

published article from within the typically larger volumes in which they were submitted. The

resulting "studies" generally have a distinct title (or at least a single subject), can stand alone for

purposes of review and can be described with a conventional bibliographic citation. The

Agency has also attempted to unite basic documents and commentaries upon them, treating

them as a single study.

3. IDENTIFICATION OF ENTRIES. The entries in this bibliography are sorted numerically by

Master Record Identifier, or "MRID” number. This number is unique to the citation, and should

be used whenever a specific reference is required. It is not related to the six-digit "Accession

Number" which has been used to identify volumes of submitted studies (see paragraph 4(d)(4)

below for further explanation). In a few cases, entries added to the bibliography late in the

review may be preceded by a nine character temporary identifier. These entries are listed after

all MRID entries. This temporary identifying number is also to be used whenever specific

reference is needed.

4. FORM OF ENTRY. In addition to the Master Record Identifier (MRID), each entry consists

of a citation containing standard elements followed, in the case of material submitted to EPA, by

a description of the earliest known submission. Bibliographic conventions used reflect the

standard of the American National Standards Institute (ANSI), expanded to provide for certain

special needs.

a. Author. Whenever the author could confidently be identified, the Agency has chosen to

show a personal author. When no individual was identified, the Agency has shown an

identifiable laboratory or testing facility as the author. When no author or laboratory

could be identified, the Agency has shown the first submitter as the author.
38

b. Document date. The date of the study is taken directly from the document. When the

date is followed by a question mark, the bibliographer has deduced the date from the

evidence contained in the document. When the date appears as (1999), the Agency

was unable to determine or estimate the date of the document.

c. Title. In some cases, it has been necessary for the Agency bibliographers to create or

enhance a document title. Any such editorial insertions are contained between square

brackets.

d. Trailing parentheses. For studies submitted to the Agency in the past, the trailing

parentheses include (in addition to any self-explanatory text) the following elements

describing the earliest known submission:

(1) Submission date. The date of the earliest known submission appears

immediately following the word "received."

(2) Administrative number. The next element immediately following the word

"under" is the registration number, experimental use permit number, petition

number, or other administrative number associated with the earliest known

submission.

(3) Submitter. The third element is the submitter. When authorship is defaulted to

the submitter, this element is omitted.

(4) Volume Identification (Accession Numbers). The final element in the trailing

parentheses identifies the EPA accession number of the volume in which the

original submission of the study appears. The six-digit accession number

follows the symbol "CDL," which stands for "Company Data Library." This

accession number is in turn followed by an alphabetic suffix which shows the

relative position of the study within the volume.
BIBLIOGRAPHY

MRID CITATION

______________________________________________________________________________

39

 42408000 Miles, Inc. (1992). Submission of product chemistry data on a metabolite of MAT

7484 (phostebupirim). 

42408001 Sheets, L.; Phillips, S. (1992). Acute Oral Toxicity Study with

2-(1,1-Dimethyl-2-Hydroxethyl)-5-Hydroxypyrimidine (a Metabolite of MAT 7484) in

Rats: Lab Project Number: 92-012-MV. Unpublished study prepared by Miles Inc. 

18 p.

42457800 Miles, Inc. (1992). Submission of toxicity data in support of FIFRA 6(a)(2)

requirements for MAT 7484 Technical. 

42457801 Thornton, J. (1992). Letter Sent to Office of Pesticide Programs dated August 26,

1992 providing an addendum in German to a rabbit teratology study for MAT 7484. 

Prepared by Miles, Inc. 54 p.

42521100 Miles, Inc. (1992). Submission of leaching data for Aztec 2.1 Granular to support the

registration of MAT Technical and Aztec 2.1. 

42521101 Lin, J.; Toll, P. (1991). Field Measurement of Phostebupirim and Cyfluthrin Runoff

from a Corn Field in Jackson County, Illinois Treated with Aztec 2.1 G: Lab Project

Number: M4222402: 101309. Unpublished study prepared by Mobay Corp. 86 p.

42649900 Miles (1993). Submission of environmental data in support of the registration for MAT

7484 Technical and MAT 7484 2.1 Granular.

.

42649901 Lin, J. (1992). Supplement--Report Corrections: Field Measurement of

Phostebupirim and Cyfluthrin Runoff From a Corn Field in Jackson County, Illinois

Treated with Aztec 2.1 G: Lab Project Number: 101309-1: M4222402. Unpublished

study prepared by Miles Inc. 6 p.

42752600 Miles Inc. (1993) Submission of toxicity data in support of the EUP for AZTEC 2.1%

Granular. 

42754000 Miles (1993). Submission of residue analytical data in support of the petition and EUP

for MAT 7484. 
BIBLIOGRAPHY

MRID CITATION

______________________________________________________________________________

40

42754001 Gronberg, R.; Pfankuche, L. (1990). An Analytical Residue Method for the

Determination of MAT 7484 and MAT 7484 Oxygen Analog in Corn: Lab Project

Number: M4121601: 100202. Unpublished study prepared by Mobay Corp. 179 p.

42905300 Miles, Inc. (1993). Submission of Chronic Toxicity Data in Support of FIFRA 6(a)(2)

Requirements for MAT 7484 Technical.

 

42905301 Gagliano, G. (1993). Chronic Toxicity of (Carbon 14)-MAT 7484 to the Waterflea

(Daphnia magna) Under Static Renewal Conditions: Lab Project Number: 106217:

M4840702. Unpublished study prepared by Miles, Inc. 45 p.

42912600 Miles Inc. (1993). Submission of toxicity data in support of FIFRA 6(a)(2)

requirements for Aztec 2.1% G. 

42959000 Miles Inc. (1993). Submission of Product Chemistry Data in Response to EPA

Questions in Regard to Tolerance Petition for Bay MAT 7482, Aztec 2.1% G. 

42959001 Fontaine, L. (1993). Supplement to MRID: Product Chemistry (Manufacturing

Process) of BAY MAT 7484 Technical: Lab Project Number: BR 1841: ANR-00793. 

Unpublished study prepared by Miles Inc. 10 p.

42959002 Fontaine, L. (1993). Supplement to MRID: Product Chemistry (Physical and Chemical

Characteristics) of BAY MAT 7484 Technical: Lab Project Number: BR 1842:

106262. Unpublished study prepared by Miles Inc. 14 p.

42981900 Miles, Inc. (1993). Submission of Toxicology Data on Tebupirimphos in Support of

FIFRA 6(a)(2). 

42981901 Bartmann, K. (1993). Study of the Embryotoxic Effect (of Tebupirimphos) on Rabbits

After Oral Administration--Addenda B, C & D: Lab Project Number:

T4024648/T2030621: MAT 7484: 99812-1. Unpublished study prepared by Bayer

AG Fachbereich Toxikologie. 63 p.

43048200 Miles Agricultural Division (1993). Submission of toxicology and risk to endangered

species assessment data in support of registration for MAT 7484 Technical and

AZTEC 2.1%G and of tolerance petition. 
BIBLIOGRAPHY

MRID CITATION

______________________________________________________________________________

41

43092700 Miles Inc. (1994). Submission of Residue Chemistry Data for Phostebupirim in

Support of Registration for MAT Technical and AZTEC 2.1%G and of Tolerance

Petition. 

43092701 Yen, P.; Wendt, S. (1994). Leaching of Aged Residues of (carbon 

14)-Phostebupirim: Lab Project Number: M4092101: 105173. Unpublished study

prepared by Miles Inc., Environmental Research Dept. and Research & Development

Dept. 45 p.

43092702 Dehart, B.; Mattern, G. (1994). Field Dissipation of phostebupirim (sic) (MAT 7484)

on Illinois Soil: Lab Project Number: M4022104: 91-4811: 106240. Unpublished

study prepared by Agri-Growth Research, Inc.; Miles Inc., Research & Development

Dept. and Environmental Fate Analytical Dept. 105 p.

43092703 Valadez, S.; Dehart, B. (1994). Terrestrial Field Dissipation of Phostebupirim (MAT

7484) on Minnesota Soil: Lab Project Number: M4022103: 91-1820: 106241. 

Unpublished study prepared by Agri-Growth Research, Inc.; Miles Inc., Agriculture

Division and Miles Environmental Fate Analytical. 93 p.

43188300 Miles Inc. (1994). Submission of Product Chemistry Data for BAY MAT 7484

Technical in Support of Petition and Registration.

 

43188301 Fontaine, L. (1994). Product Chemistry of BAY MAT 7484 Technical: Lab Project

Number: BR 1870. Unpublished study prepared by Miles Inc. 68 p.

43456500 Miles, Inc. (1994). Submission of Pesticide Use Data in Support of Registration of and

Petitions for AZTEC 2.1% Granular and MAT Technical. 

43456501 Standart, V.; Fontaine, L.; Fischer, D.; et al. (1994). Potential Benefits Resulting From

the Registered Use of Aztec (Tebupirimphos plus Cyfluthrin) on Corn: Lab Project

Number:106522. Unpublished study prepared by Miles, Inc. 57 p.

43473000 Miles, Inc. (1994). Submission of Toxicity Data in Support of FIFRA 6(a)(2),

Registration, and Petitions for MAT 7484 Technical.

 
BIBLIOGRAPHY

MRID CITATION

______________________________________________________________________________

42

43473001 Sheets, L.; Hamilton, B. (1994) An Acute Oral Neurotoxicity Screening Study with

Technical Grade Phostebupirim (MAT 7484) in Fischer 344 Rats: Lab Project

Number: 106804: 93-412-UV. Unpublished study prepared by Miles, Inc. 404 p.

43582200 Miles, Inc. (1995). Submission of Product Use and Efficacy Data in Support of an

Experimental Use Permit for AZTEC 2.1% G.

43582201 Kroll, T.; Wollam, J. (1995). Aztec 2.1G: 1994 Experimental Use Program: Lab

Project Number: 106690. Unpublished study prepared by Miles, Inc. 66 p.

43597000 Miles, Inc. (1995). Submission of Environmental Fate Data in Support of Application

for Registration of MAT 7484 Technical and AZTEC 2.1% Granular and Petition for

Tolerances.

43597001 Dehart, B.; Lam, C.; Clay, V. (1995). Recalculation of the Field Dissipation Half-life

of Phostebupirim (MAT 7484) in Illinois Soil: Supplement: Lab Project Number:

106240-3: M4022103:106240. Unpublished study prepared by Miles, Inc. 21 p.

43597002 Dehart, B.; Lam, C.; Clay, V. (1995). Recalculation of the Field Dissipation Half-life

of Phostebupirim (MAT 7484) in Minnesota Soil: Supplement: Lab Project Number:

106241-3: M4022103:106241. Unpublished study prepared by Miles, Inc. 21 p.

43656300 Bayer Corp. (1995) Submission of Toxicology Data in Support of Tolerance Petitions

for and the Registrations of MAT 7484 Technical and AZTEC 2.1% Granular. 

43656301 Sheets, L. (1994). A Motor Activity Historical Control and Method Validation Study

Using Triadimefon and Chlorpromazine in Fischer 344 Rats: Lab Project Number:

93-992-WA: 106815. Unpublished study prepared by Miles, Inc. 53 p.

43656302 Sheets, L. (1995). A Subchronic Dietary Neurotoxicity Screening Study with

Technical Grade MAT 7484 (Phostebupirim) in Fischer 344 Rats: Lab Project

Number: 93-472-VM: 106866. Unpublished study prepared by Miles, Inc. 470 p.

44193600 Bayer Corp. (1996). Submission of Toxicity Data in Support of the FIFRA 6(a)(2)

Requirement for Mat 7484 Technical. 
BIBLIOGRAPHY

MRID CITATION

______________________________________________________________________________

43

44299800 Bayer Corp. (1997). Submission of Product Chemistry and Environmental Fate Data

in Support of the Registration of Tebupirimphos (MAT 7484 Technical) Insecticide. 

44299801 Fontaine, L. (1997). Product Chemistry of MAT 7484 Technical Insecticide: (Product

Identity and Composition): Lab Project Number: BR 1925: ANR-00397:

ANR-00497. Unpublished study prepared by Bayer Corp. 113 p.

44299802 Fontaine, L. (1997). Product Chemistry of MAT 7484 Technical Insecticide: (Analysis

and Certification of Ingredient Limits): Lab Project Number: BR 1926: 107564:

107565. Unpublished study prepared by Bayer Corp. 327 p.

44299803 Cink, J.; Davis, J.; Lin, H. (1997). Aerobic Soil Metabolism of (Pyrimidinyl-2-(carbon

14))Tebupirimphos in Three Soils and at Three Concentrations: (Final Report): Lab

Project Number:107345: M4042102. Unpublished study prepared by Bayer Corp.

141 p.

44409800 Bayer Corp. (1997). Submission of Product Chemistry and Toxicity Data in Support

of the Application for Registration of Aztec 4.67% Granular Insecticide. 

44409801 Fontaine, L. (1997). Product Chemistry of Aztec 4.67% Granular Insecticide: Lab

Project Number: TM C-45.11: 107568: 107289. Unpublished study prepared by

Bayer Corp. 74 p. {OPPTS 830.6302, 830.6303, 830.7000, 830.7300, 830.1800,

830.1750, 830.1670, 830.1600, 830.1550, 830.1620, 830.1650}

44409802 Warren, D.; Halliburton, A. (1997). Acute Oral Toxicity Study with Aztec 4.67 G in

Rats: Lab Project Number: 96-012-JW:107484: 8098. Unpublished study prepared

by Bayer Corp. 29 p.

44409803 Warren, D.; Gastner, M. (1997). Acute Dermal Toxicity Study with Aztec 4.67 G in

Rats: Lab Project Number: 96-022-JR:107475: 8075. Unpublished study prepared by

Bayer Corp. 29 p.

44409804 Warren, D.; Halliburton, A. (1997). Acute Four-Hour Inhalation Toxicity Study with

Aztec 4.67 G in Rats: Lab Project Number: 96-042-JT:107482: 8081. Unpublished

study prepared by Bayer Corp. 36 p.
BIBLIOGRAPHY

MRID CITATION

______________________________________________________________________________

44

44409805 Ivett, J. (1997). Primary Eye Irritation Study in Rabbits with Aztec 4.67G: Amended

Final Report: Lab Project Number: 17848-0-820: 8094: 107608. Unpublished study

prepared by Corning Hazleton, Inc. 26 p.

44409806 Wakefield, A. (1997). Acute Dermal Irritation/Corrosivity Study in Rabbits with Aztec

4.67G: Second Amended Final Report: Lab Project Number: 17848-0-802: 8171:

107752. Unpublished study prepared by Corning Hazleton, Inc. 24 p.

44409807 Warren, D.; Gastner, M. (1996). Dermal Sensitization Study with Aztec 4.67 G in

Guinea Pigs: Lab Project Number: 96-324-IL: 107454: 8020. Unpublished study

prepared by Bayer Corp. 27 p.

44815300 Bayer Corporation (1999). Submission of Toxicity, and Residue Chemistry Data in

Support of the Registration of Aztec 2.1 Granular Insecticide. 

44815305 Koch, D. (1998). AZTEC 2.1G--Magnitude of the Residue in Field Corn: Lab

Project Number: AZ19CO02: 107804: 43737. Unpublished study prepared by ABC

Laboratories, Inc. and Bayer Corporation. 762 p. {OPPTS 860.1500}

44870601 Polakoff, B.; Daniel, A.; Osborn, D. et al. (1999). Interim Report: Organophosphates

Market Basket Survey: Lab Project Number: OPMBS-01: 98-02:. Unpublished study

prepared by Novigen Sciences, Inc. 333 p.

44980000 Bayer Corporation (1999). Submission of Product Chemistry and Toxicity Data in

Support of the Registration of Aztec 2.1% G.

 

44980001 Fontaine, L. (1999). Product Chemistry of AZTEC 2.1 G: Lab Project Number: TM

C-45.11-07: BR 2009: 107293. Unpublished study prepared by Bayer Corporation. 

96 p.

44980002 Glaza, S. (1999). Primary Eye Irritation Study in Rabbits with AZTEC 2.1 G: Final

Report: Lab Project Number: 108978: 20001-0-820: 98-C335-UU. Unpublished

study prepared by Covance Laboratories, Inc. 20 p.

44980003 Glaza, S. (1999). Primary Dermal Irritation Study in Rabbits with AZTEC 2.1 G: Final

Report: Lab Project Number: 108980: 20001-0-830: 98-C325-UV. Unpublished

study prepared by Covance Laboratories, Inc. 20 p.
BIBLIOGRAPHY

MRID CITATION

______________________________________________________________________________

45

44980004 Glaza, S. (1999). Dermal Sensitization Study in Guinea Pigs--Closed Patch Technique

with AZTEC 2.1 G: Final Report: Lab Project Number: 108989: 98-C324-US:

81001067. Unpublished study prepared by Covance Laboratories, Inc. 60 p. 

{OPPTS 870.2600}

44980005 Pauluhn, J. (1999). Aztec 2.1 G: Study on Acute Inhalation Toxicity in Rats: Lab

Project Number: 109259: 28881: T0068060. Unpublished study prepared by Bayer

Ag. 140 p. {OPPTS 870.1300}

44980006 Sturdivant, W.; Halliburton, A. (1999). Acute Oral Toxicity Study with AZTEC 2.1 G

in Rats: Lab Project Number: 108962: 99-012-WR: 8850. Unpublished study

prepared by Bayer Corporation. 39 p. {OPPTS 870.1100}

44980007 Sturdivant, W.; Avila, V. (1999). Acute Dermal Toxicity Study with AZTEC 2.1 G in

Rats: Lab Project Number: 108959: 99-022-WK: 8848. Unpublished study prepared

by Bayer Corporation. 34 p. {OPPTS 870.1200}
46
47

Appendix B: EPA’s Batching of Phostebupirim Products for Meeting Acute Toxicity Data

Requirements for Reregistration

In an effort to reduce the time, resources and number of animals needed to fulfill the acute

toxicity data requirements for reregistration of products containing Phostebupirim as the primary

active ingredient, the Agency has batched products which can be considered similar for purposes of

acute toxicity. Factors considered in the sorting process include each product’s active and inert

ingredients (identity, percent composition and biological activity), type of formulation (e.g., emulsifiable

concentrate, aerosol, wettable powder, granular, etc.), and labeling (e.g., signal word, use classification,

precautionary labeling, etc.). Note the Agency is not describing batched products as “substantially

similar” since some products with in a batch may not be considered chemically similar or have identical

use patterns.

Using available information, batching has been accomplished by the process described in the

preceding paragraph. Notwithstanding the batching process, the Agency reserves the right to require,

at any time, acute toxicity data for an individual product should need arise.

Registrants of products within a batch may choose to cooperatively generate, submit or cite a

single battery of six acute toxicological studies to represent all the products within that batch. It is the

registrants’ option to participate in the process with all other registrants, only some of the other

registrants, or only their own products within in a batch, or to generate all the required acute

toxicological studies for each of their own products. If the registrant chooses to generate the data for a

batch, he/she must use one of the products within the batch as the test material. If the registrant

chooses to rely upon previously submitted acute toxicity data, he/she may do so provided that the data

base is complete and valid by to-days standards (see acceptance criteria attached), the formulation

tested is considered by EPA to be similar for acute toxicity, and the formulation has not been

significantly altered since submission and acceptance of the acute toxicity data. Regardless of whether

new data is generated or existing data is referenced, the registrants must clearly identify the test material

by EPA Registration Number. If more than one confidential statement of formula (CSF) exists for a

product, the registrant must indicate the formulation actually tested by identifying the corresponding

CSF.

In deciding how to meet the product specific data requirements, registrants must follow the

directions given in the Data Call-In Notice and its attachments appended to the RED. The DCI Notice

contains two response forms which are to be completed and submitted to the Agency within 90 days of

receipt. The first form, “Data Call-in Response, “ asks whether the registrant will meet the data

requirements for each product. The second form, “Requirements Status and Registrant’s Response,”

lists the product specific data required for each product, including the standard six acute toxicity tests. 

A registrant who wishes to participate in a batch must decide whether he/she will provide the data or

depend on someone else to do so. If the registrant supplies the data to support a batch of products,

he/she must select the one of the following options: Developing data (Option 1), Submitting an existing

Study (Option 4), Upgrading an existing Study (Option 5), or Citing an Existing Study (Option 6). If a
48

registrant depends on another’s data, he/she must choose among: Cost sharing (Option 2), Offers to

Cost Share (Option 3) or Citing an Existing Study (Option 6). If a registrant does not want to

participate in a batch, the choices are Options 1, 4, 5 or 6. However, a registrant should know that

choosing not to participate in a batch does not preclude other registrants in the batch from citing his/her

studies and offering to cost share (Option 3) those studies.

Four products were found which contain Phostebupirim as the active ingredient. These

products have been placed into one batch and a “No Batch” category in accordance with the active

and inert ingredients and type of formulation. 

Batch 1 EPA Reg. No. Percent active ingredient Formulation Type

3125-412 2.0 Solid

3125-539 2.0 Solid

No Batch EPA Reg. No. Percent active ingredient Formulation Type

3125-411 93.0 Liquid

3125-513 4.45 Solid
49

Appendix C: List of Available Related Documents

These documents are available from the Public Docket Office or at the following web site:

www.epa.gov/pesticides/op/phostebupirim.htm

1. Hazard Assessment of the Organophosphates

2. FQPA Safety Factor Recommendations for the Organophosphates

3. Frequently Asked Questions 

4. Federal Register Notice Vol. 65, Number 59, Pages 16197-16199 (Comment period ending

May 26, 2000)

5. Federal Register Notice Vol. 64, Number 101, Pages 28469-28471 (Comment period

ending July 26, 1999) 

6. Health Effects Preliminary Assessment 

7. Occupational Exposure and Risk Assessment Regarding the Use of Phostebupirim

8. Dietary Risk Assessment Update

9. HIARC Reevaluation of Acute Dietary RfD

10. Acute and Chronic Dietary Exposure and Risk Analysis

11. Reassessment of Acute and Chronic RfDs

12. Report of the FQPA Safety Factor Committee 

13. Tier 1 Screen for Drinking Water Assessment

14. Transmittal Letter to Bayer Corporation Regarding the Preliminary Risk Assessment

15. Phostebupirim Summary 

16. Overview of Phostebupirim Revised Risk Assessments 

17. Quantitative Usage Analysis

18. HED's Response to Comments on the Preliminary Risk Assessment

19. Letter to Bayer Regarding the Revised Risk Assessment

20. Registrant's Confidential Business Certification Statement

21. Bayer's Initial Response to "Risk Assessment Update for FQPA Requirements"