United States Prevention, Pesticides EPA738-R-94-018
Environmental Protection And Toxic Substances September 1994
Agency (7508W)
&EPA Reregistration
Eligibility Decision (RED)
Difenzoquat
-------
\
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
\*W+>/
WASHINGTON, D.C. 20460
OFFICE OF
PREVENTION, PESTICIDES
AND TOXIC SUBSTANCES
CERTIFIED MAIL
Dear Registrant:
I am pleased to announce that the Environmental Protection Agency has completed its
reregistration eligibility review and decisions on the pesticide active ingredient difenzoquat.
The enclosed Reregistration Eligibility Decision (RED) contains the Agency's evaluation of
the data base of this chemical, its conclusions of the potential human health and environmental
risks of the current product uses, and its decisions and conditions under which these uses and
products will be eligible for reregistration. The RED includes the data and labeling
requirements for products for reregistration. It may also include requirements for additional
data (generic) on the active ingredient to confirm the risk assessments.
To assist you with a proper response, read the enclosed document entitled "Summary
of Instructions for Responding to the RED". This summary also refers to other enclosed
documents which include further instructions. You must follow all instructions and submit
complete and timely responses. The first set of required responses are due 90 days from
the date of this letter. The second set of required responses are due 8 months from the
date of this letter. Complete and timely responses will avoid the Agency taking the
enforcement action of suspension against your products.
If you have questions on the product specific data requirements or wish to meet with
the Agency, please contact the Special Review and Reregistration Division representative
Franklin Gee at (703) 308-8008. Address any questions on required generic data to the
Special Review and Reregistration Division representative Andrew Ertman at (703) 308-8063.
Sincerely yours,
Louis P. True, Jr., Acting Director
Special Review and
Reregistration Division
Enclosures:
-------
SUMMARY OF INSTRUCTIONS FOR RESPONDING TO
THE REREGISTRATION ELIGIBILITY DECISION (RED)
1. DATA CALL-IN (PCI) OR "90-DAY RESPONSE" If generic data are required for
reregistration, a DCI letter will be enclosed describing such data. If product specific data
are required, another DCI letter will be enclosed listing such requirements. If both generic
and product specific data are required, a combined Generic and Product Specific letter will
be enclosed describing such data. Complete the two response forms provided with each DCI
letter (or four forms for the combined) by following the instructions provided. You must
submit the response forms for each product and for each DCI within 90 days of the date
of this letter (RED issuance date); otherwise, your product may be suspended.
2. TIME EXTENSIONS AND DATA WAIVER REQUESTS No time extension requests
will be granted for the 90-day response. Time extension requests may be submitted only with
respect to actual data submissions. Requests for data waivers must be submitted as part of the
90-day response. Requests for time extensions should be submitted in the 90-day response,
but certainly no later than the 8-month response date. All data waiver and time extension
requests must be accompanied by a full justification. All waivers and time extensions must be
granted by EPA in order to go into effect.
3. APPLICATION FOR REREGISTRATION OR "8-MONTH RESPONSE" You must
submit the following items for each product within eight months of the date of this letter
(RED issuance date).
a. Application for Reregistration (EPA Form 8570-1). Use only an original
application form. Mark it "Application for Reregistration." Send your Application for
Reregistration (along with the other forms listed in b-e below) to the address listed in item 5.
b. Five copies of draft labeling which complies with the RED and current regulations
and requirements. Only make labeling changes which are required by the RED and current
regulations (40 CFR 156.10) and policies. Submit any other amendments (such as formulation
changes, or labeling changes not related to reregistration) separately. You may delete uses
which the RED says are ineligible for reregistration. For further labeling guidance, refer to
the labeling section of the EPA publication " General Information on Applying for Registration
in the U.S., Second Edition, August 1992" (available from the National Technical Information
Service, publication #PB92-221811; telephone number 703-487-4650).
c. Generic or Product Specific Data. Submit all data in a format which complies
with PR Notice 86-5, and/or submit citations of data already submitted and give the EPA
identifier (MRID) numbers. Before citing these studies, you must make sure that they meet
the Agency's acceptance criteria (attached to the DCI).
d. Two copies of the Confidential Statement of Formula (CSF) for each basic and
each alternate formulation. The labeling and CSF which you submit for each product must
comply with P.R. Notice 91-2 by declaring the active ingredient as the nominal
concentration. You have two options for submitting a CSF: (1) accept the standard certified
limits (see 40 CFR §158.175) or (2) provide certified limits that are supported by the analysis
of five batches. If you choose the second option, you must submit or cite the data for the five
batches along with a certification statement as described in 40 CFR §158.175(e). A copy of
the CSF is enclosed; follow the instructions on its back.
-------
e. Certification With Respect to Data Compensation Requirements. Complete and
sign EPA form 8570-31 for each product.
4. COMMENTS IN RESPONSE TO FEDERAL REGISTER NOTICE Comments
pertaining to the content of the RED may be submitted to the address shown in the Federal
Register Notice which announces the availability of this RED.
5. WHERE TO SEND PRODUCT SPECIFIC PCI RESPONSES (90-DAY) AND
APPLICATIONS FOR REREGISTRATION (8-MONTH RESPONSES)
By U.S. Mail:
Document Processing Desk (RED-SRRD-PRB)
Office of Pesticide Programs (7504C)
EPA, 401 M St. S.W.
Washington, D.C. 20460-0001
By express:
Document Processing Desk (RED-SRRD-PRB)
Office of Pesticide Programs (7504C)
Room 266A, Crystal Mall 2
1921 Jefferson Davis Hwy.
Arlington, VA 22202
6. EPA'S REVIEWS—EPA will screen all submissions for completeness; those which are not
complete will be returned with a request for corrections. EPA will try to respond to data
waiver and time extension requests within 60 days. EPA will also try to respond to all 8-
month submissions with a final reregistration determination within 14 months after the RED
has been issued.
-------
REREGISTRATION ELIGIBILITY DECISION
DIFENZOQUAT
LIST A
CASE 0223
ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF PESTICIDE PROGRAMS
SPECIAL REVIEW AND REREGISTRATION DIVISION
-------
TABLE OF CONTENTS
DIFENZOQUAT REREGISTRATION ELIGIBILITY DECISION TEAM i
EXECUTIVE SUMMARY vi
I. INTRODUCTION 1
II. CASE OVERVIEW 2
A. Chemical Overview 2
B. Use Profile 2
C. Estimated Usage of Pesticide 3
D. Data Requirements 3
E. Regulatory History 3
III. SCIENCE ASSESSMENT 4
A. Physical Chemistry Assessment 4
B. Human Health Assessment 5
1. Toxicology Assessment 5
a. Acute Toxicity 5
b. Subchronic Toxicity 7
c. Chronic toxicity 7
d. Carcinogenicity 9
e. Developmental Toxicity 11
f. Reproductive Toxicity 12
g. Mutagenicity 12
h. Metabolism 13
i. Neurotoxicity 14
j. Other Toxic Endpoints 15
k. Peer Review 15
1. Reference Dose 15
2. Exposure Assessment 15
a. Dietary Exposure 15
b. Occupational and Residential Exposure 18
3. Risk Assessment 20
a. Dietary 20
b. Occupational and Residential 21
4. Data Requirements 21
C. Environmental Assessment 22
1. Environmental Fate 22
a. Environmental Chemistry, Fate and Transport 22
b. Environmental Fate Assessment 24
2. Ecological Effects 25
a. Ecological Effects Data 25
(1) Terrestrial Data 25
(2) Aquatic Data 25
(3) Insect Data 26
(4) Non-Target Plants Data 26
-------
b. Ecological Effects Risk Assessment 26
(1) Terrestrial Organisms 26
(2) Aquatic Organisms 27
(3) Nontarget Insects 28
(4) Nontarget Plants 29
(5) Spray-Drift Label Advisory 29
c. Endangered and Threatened Species 29
d. Risk Mitigation 30
3. Data Requirements 30
IV. RISK MANAGEMENT AND REREGISTRATION DECISION 30
A. Determination of Eligibility 30
1. Eligibility Decision 31
2. Eligible and Ineligible Uses 31
B. Regulatory Position 31
1. Tolerance Reassessment 31
2. Restricted Use Classification 33
3. Reference Dose (RfD) 33
4. Spray Drift Label Advisory 34
5. Endangered Species Statement 34
6. Labeling Rationale 34
V. ACTIONS REQUIRED BY REGISTRANTS 37
A. Manufacturing-Use Products 37
1. Additional Generic Data Requirements 37
2. Labeling Requirements for Manufacturing-Use Products 37
B. End-Use Products 38
1. Additional Product-Specific Data Requirements 38
2. Labeling Requirements for End-Use Products 38
3. Worker Protection Standard (WPS) 38
C. Existing Stocks 38
VI. APPENDICES 39
APPENDIX A. Table of Use Patterns Subject to Reregistration 41
APPENDIX B. Table of the Generic Data Requirements and Studies Used to
Make the Reregistration Decision 45
APPENDIX C. Citations Considered to be Part of the Data Base Supporting the
Reregistration of Difenzoquat 55
APPENDIX D. List of Available Related Documents 73
APPENDIX E 77
PR Notice 86-5 79
PR Notice 91-2 97
APPENDIX F. Combined Generic and Product Specific Data Call-In 103
Attachment 1. Chemical Status Sheets 123
Attachment 2. Combined Generic and Product Specific Data Call-in
-------
Response Forms (Form A inserts) Plus Instructions 127
Attachment 3. Generic and Product Specific Requirement Status and
Registrant's Response Forms (Form B inserts) and Instructions
133
Attachment 4. EPA Batching of End-Use Products for Meeting Data
Requirements for Reregistration 139
Attachment 5. EPA Acceptance Criteria 143
Attachment 6. List of All Registrants Sent This Data Call-in (insert) Notice
157
Attachment 7. Cost Share Data Compensation Forms, Confidential
Statement of Formula Form and Instructions 159
APPENDIX G. FACT SHEET 169
-------
DIFENZOQUAT REREGISTRATION ELIGIBILITY DECISION TEAM
Office of Pesticide Programs:
Biological and Economic Analysis Division
George W. Keitt, Jr.
Arthur Grube
Ghulam Ali
Margaret Cogdell
Environmental Fate and Effects Division
Sharlene Matten
Mike Rexrode
Richard Mahler
Health Effects Division
Charles Frick
Krystyna Locke
Susan Hummel
Jeff Evans
Steven Schaible
Registration Division
Dan Kenny
Mark J. Perry
Special Review and Reregistration Division
Andrew Ertman
Walt Waldrop
Carol Stangel
Biological Analysis Branch
Economic Analysis Branch
Economic Analysis Branch
LUIS Staff
Science Analysis and Coordination Staff
Ecological Effects Branch
Environmental Fate and Groundwater Branch
Chemical Coordination Branch
Toxicology Branch I
Reregistration Support Chemistry Branch
Occupational and Residential Exposure Branch
Science Analysis Branch
Fungicide-Herbicide Branch
Registration Support Branch
Reregistration Branch
Reregistration Branch
Policy, Planning and Operations Branch
-------
11
-------
GLOSSARY OF TERMS AND ABBREVIATIONS
AE Acid equivalent
a.i. Active Ingredient
CAS Chemical Abstracts Service
CSF Confidential Statement of Formula
DWEL Drinking Water Equivalent Level (DWEL) The DWEL represents a medium
specific (i.e. drinking water) lifetime exposure at which adverse, non
carcinogenic health effects are not anticipated to occur.
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
FDA Food and Drug Administration
FIFRA Federal Insecticide, Fungicide, and Rodenticide Act
FFDCA Federal Food, Drug, and Cosmetic Act
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.
HOT Highest Dose Tested
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/1, mg/kg or ppm.
in
-------
GLOSSARY OF TERMS AND ABBREVIATIONS
LD
50
LDlo
LEL
LOG
LOEL
MCLG
MP
MPI
MOE
MRID
N/A
NPDES
NOEL
OPP
PADI
ppm
RED
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.
Lethal Dose-low. Lowest Dose at which lethality occurs
Lowest Effect Level
Level of Concern
Lowest Observed Effect Level
Maximum Contaminant Level Goal (MCLG) The MCLG is used by the
Agency to regulate contaminants in drinking water under the Safe Drinking
Water Act.
Manufacturing-Use Product
Maximum Permissible Intake
Margin Of Exposure
Master Record Identification (number). EPA's system of recording and
tracking studies submitted.
Not Applicable
National Pollutant Discharge Elimination System
No Observed Effect Level
Office of Pesticide Programs
Provisional Acceptable Daily Intake
Parts Per Million
The Carcinogenic Potential of a Compound, Quantified by the EPA's Cancer
Risk Model
Reregistration Eligibility Decision
IV
-------
GLOSSARY OF TERMS AND ABBREVIATIONS
RfD Reference Dose
RS Registration Standard
TD Toxic Dose. The dose at which a substance produces a toxic effect.
TC Toxic Concentration. The concentration at which a substance produces a toxic
effect.
TGAI Technical Grade Active Ingredient
TMRC Theoretical Maximum Residue Contribution
-------
EXECUTIVE SUMMARY
This Reregistration Eligibility Decision document (RED) addresses the reregistration
eligibility of the pesticide difenzoquat, l,2-dimethyl-3,5-diphenyl-lH-pyrazolium.
Difenzoquat is a postemergent herbicide that is produced by American Cyanamid
Company and marketed under the trade name Avenge®. Difenzoquat is used to control wild
oats (Avena fatua) in barley and wheat. Wild oats is an annual grassy weed with growth habits
that out-compete wheat and barley and create serious yield losses. There is one manufacturing
use product and one end-use formulation of difenzoquat; a soluble concentrate/liquid (SC/L).
This formulation is applied postemergence as a ground or aerial broadcast treatment.
Difenzoquat was first registered as a pesticide in July, 1975. A Registration Standard
was issued in December, 1988 (NTIS# PB89-162127). This Registration Standard
summarized available data supporting the registration of products containing difenzoquat used
as a herbicide for control of wild oats in alfalfa (seed crop in CA), barley and wheat. The use
on alfalfa is no longer registered. The Registration Standard also required additional product
chemistry, residue chemistry, toxicology, and environmental fate data.
The Agency has now completed its review of the difenzoquat target data base including
data submitted in response to the 1988 Registration Standard and has determined that the uses
of difenzoquat as currently registered will not cause unreasonable adverse effects to humans or
the environment. All currently registered uses of difenzoquat are eligible for reregistration.
The Agency is requiring additional studies in the residue chemistry, toxicology, environmental
fate and ecological effects disciplines that will be called in on a confirmatory basis. The
following data are required: an acute neurotoxicity screening battery in the rat, a 90-day
neurotoxicity screening battery in the rat, additional data to upgrade a previously submitted
confined rotational crop study, a non-guideline bridging study in lieu of additional terrestrial
field dissipation studies, spray drift studies and phytotoxicity data.
Difenzoquat was classified "Group E" as to its carcinogenic potential (Evidence of
non-carcinogenicity for humans) by the Office of Pesticide Programs (OPP) Reference Dose
RfD/Peer Review Committee on 2/24/94. The Committee recommended that the RfD for
difenzoquat be established at 0.2 mg/kg/day. This value was based on the systemic NOEL of
20 mg/kg/day from the one-year dog feeding study and an uncertainty factor (UF) of 100.
The Theoretical Maximum Residue Contribution (TMRC) for the over all U.S. population
from existing and proposed tolerances is 0.1% of the RfD. The subgroup most highly
exposed, children aged one through six has an Anticipated Residue Contribution (ARC) of
0.2% of the RfD. All existing difenzoquat tolerances have been reassessed and no changes are
required. New tolerances must be established for wheat bran wheat shorts, barley hulls, and
barley bran.
There are no toxicological endpoints of concern for workers with the exception of
acute eye irritation (Toxicity Category I). Because difenzoquat does not meet the Agency's
VI
-------
toxicity criteria, neither handler (mixer/loader/applicator) nor postapplication/reentry data are
required to support the reregistration of difenzoquat. Because difenzoquat is in toxicity
category I for primary eye irritation, the 48 hour restricted entry interval (REI) imposed by
the Worker Protection Standard (WPS) will be maintained.
Based on the existing data base, it is the Agency's conclusion that the use of
difenzoquat as a herbicide will not pose a serious acute or chronic environmental threat.
Difenzoquat only poses minimum acute and chronic risks to avian, mammalian and aquatic
species, and non-target insects. Since difenzoquat is an herbicide, it is anticipated that the risk
to non-target aquatic and terrestrial plants will be high. Additional data on phytotoxicity to
non-target plants are being required.
Difenzoquat has been shown to be persistent and relatively immobile. However, the
environmental fate assessment is not comprehensive because the route of dissipation has not
been determined. The field dissipation studies contrast with laboratory data and indicate that
difenzoquat residues decline with time. It appears from the laboratory data that difenzoquat is
immobile in soil and the potential for ground water contamination is minimal. Additional data
are required on a confirmatory basis comparing the recovery of difenzoquat between the
methods used in laboratory and field studies.
Confirmatory data are required on confined rotational crops, terrestrial field
dissipation, and spray drift. Data that are not part of the target data base are also required
on neurotoxicity and phyto toxicity. The neurotoxicity data are required based on the results of
the one-year dog feeding study and the developmental toxicity study in rats. Additional data
are required to upgrade an existing confined rotational crop study. The dissipation data are
required to determine the actual route of dissipation of difenzoquat in the field. The
phytotoxicity data are required to refine the Agency's assessment that difenzoquat, as an
herbicide, will be harmful to non-target aquatic and terrestrial plants. The spray drift data are
required because difenzoquat is applied aerially.
Before reregistering the products containing difenzoquat, the Agency is requiring that
product specific data, revised Confidential Statements of Formula (CSF) and revised labeling
be submitted within eight months of the issuance of this document. These data include product
chemistry for each registration and acute toxicity testing. After reviewing these data and any
revised labels and finding them acceptable in accordance with Section 3(c)(5) of FIFRA, the
Agency will reregister a product. Those products which contain other active ingredients will
be eligible for reregistration only when the other active ingredients are determined to be
eligible for reregistration.
vn
-------
I. INTRODUCTION
In 1988, the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) was
amended to accelerate the reregistration of products with active ingredients registered prior to
November 1, 1984. The amended Act provides a schedule for the reregistration process to be
completed in nine years. There are five phases to the reregistration process. The first four
phases of the process focus on identification of data requirements to support the reregistration
of an active ingredient and the generation and submission of data to fulfill the requirements.
The fifth phase is a review by the U.S. Environmental Protection Agency (referred to as "the
Agency") of all data submitted to support reregistration.
FIFRA Section 4(g)(2)(A) states that in Phase 5 "the Administrator shall determine
whether pesticides containing such active ingredient are eligible for registration" before calling
in data on products and either reregistering products or taking "other appropriate regulatory
action." Thus, reregistration involves a thorough review of the scientific data base 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" criterion of FIFRA.
This document presents the Agency's decision regarding the reregistration eligibility of
the registered uses of difenzoquat. The document consists of six sections. Section I is the
introduction. Section II describes difenzoquat, its uses, data requirements and regulatory
history. Section III discusses the human health and environmental assessment based on the
data available to the Agency. Section IV presents the reregistration decision for difenzoquat.
Section V discusses the reregistration requirements for difenzoquat. Finally, Section VI is the
Appendices which support this Reregistration Eligibility Decision. Additional details
concerning the Agency's review of applicable data are available on request.
-------
II. CASE OVERVIEW
A. Chemical Overview
The following active ingredient is covered by this Reregistration Eligibility
Document:
• Common Name: Difenzoquat
• Chemical Name: l,2-dimethyl-3,5-diphenyl-lH-pyrazolium
• Chemical Family: Pyrazolium
• CAS Registry Number: 43222-48-6 (salt)
• OPP Chemical Code: 106401 (salt)
• Empirical Formula: C18H20N204S (salt)
• Trade and Other Names: Avenge®
• Basic Manufacturer: American Cyanamid Company
B. Use Profile
The following is information on the current registered uses with an overview of
use sites and application methods. A detailed table of the uses of difenzoquat can be
found in Appendix A.
For Difenzoquat:
Type of Pesticide: Herbicide
Use Sites: Barley and Wheat
Target Pests: Wild Oats
Formulation Types Registered: Soluble Concentrate/Liquid (SC/L)
Method and Rates of Application:
Equipment Aerial and ground equipment
Method and Rate Broadcast 0.6 - 1.0 Ib cation/acre
Timing Postemergence treatment
-------
C. Estimated Usage of Pesticide
This section summarizes the best estimates available for the pesticide uses of
difenzoquat. These estimates are derived from a variety of published and proprietary
sources available to the Agency. The data, reported on an aggregate and site (crop)
basis, reflect annual fluctuations in use patterns as well as the variability in using data
from various information sources.
The table below summarizes the pesticide use by site.
Name of Site
BARLEY
WHEAT3
TOTAL
Acres Planted1
(000)
8,321
73,141
81,462
Acres Treated
(000)
< 416
200 - 300
200-716
Percentage
of Acres2
< 5
< 0.5
Active
Ingredient2
Ibs a.i. (000)
30-85
100- 150
130 - 235
Percentage of
Total Difenzoquat
Use
23-36
64-77
1 Three years 1990 - 1992 average is reported.
2 Sources: EPA Proprietary Sources
USDA
Agricultural Chemical Usage, 1992 Field Crops Summary, March, 1993
3 For wheat 1992 usage data is reported.
D. Data Requirements
Data requested in the December, 1988 Registration Standard for difenzoquat
included studies on product chemistry, residue chemistry, toxicology, ecological
effects, and environmental fate. These data were required to support the uses listed in
the Registration Standard. Appendix B includes all data requirements identified by the
Agency for currently registered uses needed to support reregistration.
E. Regulatory History
Difenzoquat is the accepted common name for l,2-dimethyl-3,5-diphenyl-lH-
pyrazolium. It is manufactured by American Cyanamid Company and is marketed
under the trade name Avenge® . Avenge ® contains the methyl sulfate salt of
difenzoquat.
Difenzoquat was first registered in July, 1975 for use on wheat and barley to
control wild oats (Avena fatua). Currently wheat and barley are the only crops upon
which difenzoquat is used. Difenzoquat is a postemergent herbicide that is readily
absorbed by plants and is not significantly metabolized or further degraded.
-------
In December, 1988, EPA issued a Registration Standard for products containing
difenzoquat methyl sulfate as an active ingredient (NTISf PB89-162127). A Pesticide
Fact Sheet for difenzoquat was also issued in December, 1988 (NTIS# PB89-162119).
These documents provide a summary and the rationale of the regulatory position for
difenzoquat at that time.
Currently, there are two active products containing difenzoquat methyl sulfate
which are registered under Section 3 of the Federal Insecticide, Fungicide, and
Rodenticide Act. They consist of a 96% technical (manufacturing use) product and a
31.2% soluble concentrate end-use product.
III. SCIENCE ASSESSMENT
A. Physical Chemistry Assessment
DESCRIPTION OF CHEMICAL
Difenzoquat (l,2-dimethyl-3,5-diphenyl-l//-pyrazolium ion) is formulated as a
methyl sulfate salt for use as a selective herbicide for the postemergence control of
wild oats in barley and wheat.
CH3so;
N—N
H,C
CH,
Empirical Formula: C17H17N2(ion)
Molecular Weight:
CAS Registry No.:
Shaughnessy No.:
C18H20N204S (salt)
249.3 (ion)
360.4 (salt)
49866-87-7 (ion)
43222-48-6 (salt)
106402 (ion)
106401 (salt)
IDENTIFICATION OF ACTIVE INGREDIENT
Technical difenzoquat methyl sulfate is an odorless, colorless to pale yellow
crystalline solid with a melting point of 156-158° C and bulk density of 0.796 g/mL.
-------
Difenzoquat methyl sulfate is soluble in water and methanol, slightly soluble in acetone
and ethylene dichloride, and nearly insoluble in most organic solvents.
MANUFACTURING-USE PRODUCTS
There is one manufacturing-use product (MP) registered for difenzoquat methyl
sulfate, which is the American Cyanamid 96% technical (T; EPA Reg. No. 241-239).
There are no registered MPs for the difenzoquat ion (Shaughnessy No. 106402). The
American Cyanamid 96% T is the only MP subject to a reregistration eligibility
decision.
B. Human Health Assessment
1. Toxicology Assessment
The toxicological data base in support of the food uses for difenzoquat
methyl sulfate is adequate and will support reregistration eligibility.
a. Acute Toxicity
Test
Acute Oral LD50 Rat
Acute Dermal LD,n Rabbit
Acute Inhalation LC50 Rat
Eye Irritation Rabbit*
Dermal Irritation Rabbit*
Skin Sensitization Guinea Pig*
Citation
MRID 41325406
Duplicate: 41300502
MRID 41325407
MRID 41325408
MRID 41300501
MRID 00041883
MRID 41325409
Results
617 mg/kg male
373 mg/kg female
484 mg/kg male and female
> 2000 mg/kg
0.62 mg/L male
0.36 mg/L female
0.50 mg/L male and female
Severe irritation
No irritation
(intact skin)
Severe irritation
(abraded skin)
Negative
Toxicity
Category
III
II
II
III
III
II
II
I
IV
II
N/A1
1 N/A = Not Applicable
* Note: Data pertaining to acute eye irritation, dermal irritation, and dermal sensitization are not required to
support the reregistration of the TGAI. These data are presented for informational purposes.
-------
The following toxic signs were observed in the above studies:
Acute Oral LD50 Rat: Salivation, decreased activity, prostration and
diuresis. Salivation was observed in all groups (200, 400 and 800
mg/kg); decreased activity and prostration, in the mid-dose and high-
dose groups; and diuresis, only in the high-dose group. Signs of toxicity
generally occurred during the first 24 hours following dosing and
disappeared completely, in the surviving animals, within 1-2 days.
Necropsy was unremarkable in the survivors. Most of the non-survivors
had congested livers and kidneys and enlarged, fluid-filled, pale
intestines (MRID 41325406).
Acute Dermal LD50 Rabbit: Severe skin irritation (erythema, edema,
small sores, subdural hematoma, fissuring, dark red welts and necrosis)
at the application site, anorexia, diarrhea, emaciation and nasal
discharge; weight loss in males (99 g in 14 days) and little weight gain
in females (16 g in 14 days); and pale kidneys and congested lungs in the
non-surviving females (MRID 41325407).
Acute Inhalation LC50 Rat: Inactivity, eye irritation (treated animals
closed their eyes and controls did not) and nasal discharge at all
concentrations tested (0.255, 0.438, 0.579, 1.14 and 1.72 mg/L) during
exposure; deaths (all animals) in the last two groups during the first 3
hours of exposure and in the 0.579 mg/L group (4/10 males and 9/10
females) during the first hour after exposure; ruffled appearance, brown
discharge (ocular, oral, nasal), unsteady gait and tremors, in most
animals, for 4 to 6 days after exposure; and dark red lungs with free
flowing dark red liquid on the cut surface of the lungs, noted at
necropsy, in the 1.72 mg/L group (MRID 41325408).
Primary Eye Irritation Rabbit: Corneal opacity persisted in 1/6 male
rabbits (females were not tested) until the termination of the study (day
21 after exposure). Other toxic signs (conjunctival redness, chemosis
and discharge) were present in 1-2 rabbits on day 7, but not on day 14
(MRID 41300501).
Primary Dermal Irritation Rabbit: The intact test sites completely
recovered from slight erythema and edema by 72 hours, whereas the
abraded test sites did not show recovery from severe erythema and
edema by 72 hours (last observation time) (MRID 00041883).
-------
b. Subchronic Toxicity
90-Day Feeding Non-Rodent: In a subchronic (non-rodent) feeding
study, young purebred beagle dogs (4-6/sex/group) were dosed with
technical AC 84,777 (difenzoquat) orally for 90 days at doses of 0, 100,
500 or 2500 ppm, which were equivalent to 0, 2.5, 12.5 or 62.5
mg/kg/day, respectively (1 ppm = 0.025 mg/kg). The diets containing
AC 84, 777 were offered to each dog for 1 hour daily, 6 days a week.
Parameters examined included clinical signs of toxicity, mortality,
ophthalmology, body weights, food consumption, hematology, clinical
chemistry, urinalysis, necropsy, organ weights (kidney, adrenals, heart,
testes and ovaries), organ/body weight ratios and histopathological
examination of organs/tissues. Compound related effects were not
observed. Systemic NOEL for both sexes is, therefore, 2500 ppm (25
mg/kg/day; HDT) (MRID 00037922; duplicate MRID 00069540,
00075774).
21-Day Dermal Toxicity Rabbit: In a repeated dose dermal toxicity
study, New Zealand rabbits, 5-7/sex/group, were exposed dermally to
technical AC 84,777 (difenzoquat) for 3 weeks (5 days/week, 6
hours/day). The exposure of females was delayed by 21 days to allow
for replacement of the animals due to the poor health of the initial
shipment of females. The dose levels of AC 84,777 used were 0, 250,
500 or 1000 (limit dose) mg/kg/day. Parameters examined included
clinical signs of toxicity, mortality, body weights, food consumption,
hematology, clinical chemistry, necropsy, organ weights (liver, kidneys,
adrenals and gonads), organ/body weight ratios and histopathological
examination of selected organs/tissues from the control and high-dose
groups. Tissues with gross lesions and skin (treated areas) were also
examined histopathologically from all rabbits in the low-dose and mid-
dose groups. Treatment-related skin reactions/effects included very
slight erythema in 1/6 mid-dose females; very slight edema in 5/7 high-
dose males; eschar in 1/7 mid-dose males, 7/7 high-dose males, 2/6
mid-dose females and 4/5 high-dose females; epithelial hyperplasia at the
application sites in 5/7 high-dose males, 2/5 high-dose females and 1/6
mid-dose females; and necrosis at the application site in 4/7 high-dose
males. Therefore, the NOEL and LOEL for dermal toxicity are 250
mg/kg/day and 500 mg/kg/day, respectively. The NOEL and LOEL
for systemic toxicity are both > 1000 mg/kg/day (MRID 41325410).
c. Chronic toxicity
Chronic Toxicity/Oncogenicity Rodent: A chronic feeding/
carcinogenicity study was conducted using Wistar-derived rats which
7
-------
were fed diets containing 0, 100, 500 or 2500/5000 ppm of technical AC
84,777 (difenzoquat) for 104 weeks. These dose levels were equivalent
to 0, 5, 25 or 125/250 mg/kg/day (1 ppm = 0.05 mg/kg). The
2500/5000 ppm group was dosed with 2500 ppm of difenzoquat for 30
weeks and 5000 ppm until the termination of the study. No reason was
given for the dose increase, especially since decreased body weight gains
were already observed at the 2500 ppm level. There were 100 rats/sex
in the control group and 60/sex in each of the treated groups. Interim
sacrifice (10 rats/sex/group) took place at 90 days. Parameters
examined included clinical signs of toxicity, mortality, ophthalmology,
hematology, clinical chemistry, urinalysis, necropsy, organ weights,
organ/body weight ratios and histopathological examination of
organs/tissues. With the exception of decreased body weight gains,
difenzoquat had no effect on any of the parameters examined.
Compared with the concurrent controls, body weight gains were slightly
but consistently decreased in the high-dose males (4-9%) and females (8-
16%). For male rats, the decreased weight gains were statistically
significant (p = 0.05) during weeks 4,13 and 26; and for female rats,
only at week 26. Based on the above findings, systemic NOEL for both
sexes is 500 ppm (25 mg/kg/day) and systemic LOEL is 2500 ppm (125
mg/kg/day) (MRID 00036710).
Chronic Toxicity Non-Rodent: Groups of purebred beagle dogs (4-
6/sex/dose) were administered technical AC 84,777 (difenzoquat) in
capsules for 52 weeks. Group I (controls) received empty gelatin
capsules and Group II, 12.5 mg/kg/day of difenzoquat. The remaining
groups were dosed with difenzoquat as follows: Group III - 37.5
mg/kg/day for the first 28 days and 20 mg/kg/day from day 29 through
week 52; Group IV - 75 mg/kg/day for the first 6 days, 50 mg/kg/day
during days 7 and 8, 44 mg/kg/day during days 9-28 and 30 mg/kg/day
from day 29 through week 52; and Group V - 125 mg/kg/day for the
first 4 days, 100 mg/kg/day during days 5 and 6, and 75 mg/kg/day
until day 9 when all dogs died or were sacrificed moribund. It was not
reported how the initial doses were selected. However, due to
mortality, poor health and lack of food consumption observed in Groups
IV and V, doses for these groups were decreased until the dogs could
tolerate them. Due to continued poor food consumption in Group III,
difenzoquat level was also decreased in that group. Therefore, the final
dose levels of difenzoquat administered to dogs in Groups I through IV,
from day 29 (week 5) until the termination of the study (week 52) were
0, 12.5, 20 and 30 mg/kg/day, respectively. Parameters examined
included clinical signs of toxicity, mortality, ophthalmoscopy, body
weights, food consumption, hematology, clinical chemistry, urinalysis,
necropsy, organ weights, organ/body weight and organ/brain weight
8
-------
ratios and histopathological examination of organs/tissues. Toxic signs
were not observed in male and female dogs which were dosed with
difenzoquat at levels of 12.5 and 20 mg/kg/day, and in male dogs
treated with 30 mg/kg/day of difenzoquat. However, female dogs dosed
with 30 mg/kg/day of difenzoquat gained significantly less weight than
did the controls throughout the study (40-60% of the control values; p =
0.05 or 0.01). No other toxic signs were observed. Toxic signs were
observed mostly at difenzoquat levels of 44-125 (HDT) m/kg/day, which
were administered to dogs during the first 28 days of the study, and
included:
1. High mortality - 4 dogs (1/6 males and 3/6 females) died in
Group IV and all dogs (4/4 males and 4/4 females) died in Group
V.
2. Watery stools, emesis, salivation, tremors, lethargy, irregular
gait, lateral recumbency, dilated pupils, and partially or
completely closed eyes.
3. Weight loss during weeks 1-2 and decreased weight gain (by
38% for males and 89% for females) during weeks 3-4, relative
to the control values.
4. Decreased food consumption for Group IV males (25-36%) and
females (35-50%), and for Group V males (54-99.55) and
females (50-99.5%), relative to the control values.
5. Macroscopic findings in the non-surviving dogs: discoloration
and/or abnormal contents of the esophagus, stomach, and small
and large intestines.
6. Microscopic findings in the non-surviving dogs: myocardial
degeneration (6 dogs), myocardial necrosis (1 dog), and lesions
in the gastrointestinal tract (necrotic ulcer and acute inflammation
of the esophagus; luminal or mucoid exudate, necrotic ulcer and
congestion of the stomach; and congestion, exudate and necrotic
ulcer in the large and small intestines).
Based on the decreases in body weight gain during weeks 5 through 52,
the systemic NOEL is 20 mg/kg/day for the female dogs and 30
mg/kg/day for the male dogs (MRID 42800401).
d. Carcinogenicity
Chronic Toxicity/Oncogenicity Rodent: A chronic feeding/
carcinogenicity study was conducted using Wistar-derived rats which
were fed diets containing 0, 100, 500 or 2500/5000 ppm of technical AC
84,777 (difenzoquat) for 104 weeks. These dose levels were equivalent
to 0, 5, 25 or 125/250 mg/kg/day (1 ppm = 0.05 mg/kg). The
9
-------
2500/5000 ppm group was dosed with 2500 ppm of difenzoquat for 30
weeks and 5000 ppm until the termination of the study. No reason was
given for the dose increase, especially since decreased body weight gains
were already observed at the 2500 ppm level. There were 100 rats/sex
in the control group and 60/sex in each of the treated groups. Interim
sacrifice took place at 90 days. Predominant neoplastic lesions were
observed in the adrenals (cortical adenoma), lungs (reticulum cell
sarcoma), pituitary (adenoma), thyroid (follicular adenoma and
adenocarcinoma), mammary glands (adenocarcinoma and
fibroadenoma), ovaries (adenoma) and uterus (polyps). With the
exception of thyroid follicular adenocarcinoma in the mid-dose and high-
dose male rats, none of the other neoplasms were treatment-related. The
percent incidence of thyroid follicular adenocarcinoma in the control,
low-dose, mid-dose and high-dose male rats was 4.1, 2.9, 6.3 and 10.2,
respectively. According to Dr. Lynnard Slaughter, Consulting
Pathologist, Toxicology Branch, Health Effects Division, the historical
incidence of thyroid follicular adenocarcinoma in the male Wistar-
derived rats is about 19%. The incidence of thyroid follicular
adenocarcinoma observed in this study was, therefore, within normal
limits and difenzoquat was not considered to be carcinogenic under the
conditions of this study. Based on decreased body weight gains in the
high-dose males and females, it appeared that the Maximum Tolerated
Dose (MTD) was reached (MRID 00036710).
Oncogenicity Mouse: Groups of CD-I mice (55/sex/dose) were
administered technical AC 84,777 (difenzoquat) at dietary levels of 0,
200, 500 or 1000 ppm for 79/80 weeks. These levels were equivalent to
0, 26.9, 69.4 and 150.1 mg/kg/day for males and 0, 39.7, 97.9 and
202.4 mg/kg/day for females. In addition, 10 mice/sex/dose, receiving
the same diets, were sacrificed during weeks 53-54. Parameters
examined included clinical signs of toxicity, mortality, body weights,
food consumption, hematology, necropsy, organ weights, organ/body
weight and organ/brain weight ratios, and histopathological examination
of organs/tissues. The only treatment-related and statistically significant
(p = 0.05) toxic sign observed was a decrease in body weight gain in
the high-dose males (62% maximum) and females (54% maximum), and
in the mid-dose males (34% maximum). The systemic NOEL was,
therefore, 200 ppm (26.9 mg/kg/day) for males and 500 ppm (97.9
mg/kg/day) for females. The systemic LOEL was 500 ppm (69.4
mg/kg/day) for males and 1000 ppm (202.4 mg/kg/day) for females.
The number of tumor-bearing male and female mice was lower in the
treated groups than in the controls, and pulmonary adenoma was the
most common neoplasm. Difenzoquat was, therefore, not carcinogenic
under the conditions of this study. Based on decreased body weight
10
-------
gains in the high-dose and mid-dose groups, it appeared that the MTD
was reached (MRID 42800402).
e. Developmental Toxicity
Teratogenicity Rat: A developmental study was conducted with
pregnant Charles River rats (25/group) which were given daily doses of
technical AC 84,777 (difenzoquat) by gavage on gestation days 6
through 15. The dose levels used were 0, 30, 60, 120 or 240
mg/kg/day. The dams were sacrificed on day 20 and the fetuses
examined. Maternal toxicity was observed in the last two groups and
included long-lasting, recurrent and statistically significant (p < 0.01)
excessive salivation in 72-76% of the animals; decreased body weight
gain during the dosing period (82.6% and 84.1%, respectively, of the
control group value; p < 0.05); and decreased food consumption during
the dosing period (93.8% and 89.7%, respectively, of the control group
value; p < 0.05 and p < 0.01, respectively). One rat in the 240 mg/kg
group had decreased motor activity, head-tilt and tremors, and another
rat from the same group had red urine. A slight, statistically
insignificant, decrease in the mean fetal weights (96.9% of the control
value, males and females), in the 240 mg/kg group, was the only
developmental toxicity observed in this study. Therefore, the NOEL
and LOEL for maternal toxicity are 60 mg/kg/day and 120 mg/kg/day,
respectively. The NOEL and LOEL for developmental toxicity are 120
mg/kg/day and 240 mg/kg/day, respectively (MRID 41521203).
Teratogenicity Rabbit: Artificially inseminated New Zealand rabbits
(18/group) were treated with technical AC 84,777 (difenzoquat) on
gestation days 7 through 17. The test material was administered by
gavage at dose levels of 0, 50, 100 or 250 mg/kg. The does were
sacrificed on day 29 and the fetuses examined for external, visceral and
skeletal abnormalities. Maternal toxicity was observed only in the 250
mg/kg group and included high mortality (61%) and high percentage of
does with resorptions only (33%, compared with 6% in the control
group). Developmental toxicity (malformation of the vertebrae) was
observed mostly in the high-dose group. Relative to the concurrent
control incidence, there was a small and possibly treatment-related
increase in the number of fetuses with vertebrae centra abnormalities in
the 250 mg/kg group. The fetal percent incidence of this skeletal
malformation in the control, low-dose, mid-dose and high-dose groups
was 0, 0, 1 and 12, respectively. However, maternal mortality of 61%
in the 250 mg/kg group resulted in an insufficient number of fetuses
(only 17) to permit a meaningful evaluation of the developmental effects
in that group. Considering the above findings, the NOEL and LOEL
11
-------
for maternal toxicity are 100 mg/kg/day and 250 mg/kg/day,
respectively. The NOEL and LOEL for developmental toxicity are also
100 mg/kg/day and 250 mg/kg/day, respectively (MRID 00142521).
f. Reproductive Toxicity
3-Generation Reproduction Rat: Charles River rats (10 males and 20
females/group) were fed diets containing 0, 500 or 2500 ppm of
technical AC 84,777 (difenzoquat) for three successive generations.
These dose levels were equivalent to 0, 25 and 125 mg/kg/day of
difenzoquat (1 ppm = 0.05 mg/kg). The feeding of the test material
was started 14 weeks (P1 parents) or 9 weeks (P2 and P3 parents) before
mating and was continued through the mating, gestation and lactation
periods. One litter was produced per generation. The only parental
effect observed in all three generations was a decreased body weight
gain in the high-dose females during the pre-mating period (the only
time when body weights were recorded in this study). Although,
compared with the controls, these weight decreases were statistically
significant (p < 0.05), they were either small (5 or 6%) and probably
biologically insignificant or occurred in animals which were smaller
(20%) than controls at the start of the treatment. Male and female pups
in the high-dose group weighed less at birth in the second (F2A) and third
(F3A) generations, and at weaning in all generations, than did those in the
control group. The mean weight decreases at birth were statistically
significant (p < 0.05) and ranged from 6.2 to 7.0% (males) and 6.0 to
8.2% (females). The mean weight decreases at weaning were also
statistically significant (p < 0.05) and ranged from 14.0 to 15.2%
(males) and 13.9 to 15.5% (females). In the low-dose group, a
statistically significant (p < 0.05) mean body weight decrease (8.7%)
was observed only at weaning in the F3A female pups. The mean body
weight decrease (6.7%), observed at weaning in the low-dose F3A male
pups, was statistically insignificant. The mean body weight decreases,
observed in the low-dose F1A and F2A male and female pups, were small
(2.1-4.3%) and also statistically insignificant. Based on these findings,
the parental NOEL is > 2500 ppm (125 mg/kg/day). The
reproductive/developmental NOEL and LOEL are 500 ppm (25
mg/kg/day) and 2500 ppm (125 mg/kg/day), respectively (MRID
00037924; duplicate MRID 00030578).
g. Mutagenicity
Gene Mutation: Under the conditions of the Chinese hamster ovary
(CHO) cell HGPRT forward gene mutation assay, doses of non-activated
difenzoquat (500 - 1600 ug/mL), and doses of S9-activated difenzoquat
12
-------
(500 - 1250 ug/mL) did not induce a mutagenic response. Higher levels
(2000 ug/mL without S9 and 1600-2000 ug/mL with S9) were severely
cytotoxic. Based on these findings, it was concluded that difenzoquat
was tested over an appropriate range of concentrations with no evidence
of a mutagenic effect (MRID 41325411).
Structural Chromosomal Aberration: Difenzoquat was assessed for its
potential to induce structural chromosome aberrations in late, middle and
early stages of the Chinese hamster ovary (CHO) cell cycle at five non-
activated nominal doses of 100 to 10,000 ug/mL (actual concentrations:
> 65 to 5700 ug/mL) and five 59-activated nominal doses of 33 to 3330
ug/mL (actual concentrations: > 24 to 1900 ug/mL). Nominal doses >
3330 ug/mL +/- S9 (analytically, > 1900 ug/mL) were cytotoxic. A
significant increase in the percentage of cells with aberrations was seen
at 3330 ug/mL - S9 (1900 mg/mL) 3 hours posttreatment. However,
the significant effect was confined to one dose, was not reproduced in a
repeat 3 hour treatment, and was not observed in cultures 8 or 12 hours
following treatment. There were no significantly increased aberration
frequencies in cells recovered 3, 8 or 12 hours post-exposure to the S9-
activated test material. It was, therefore, concluded that AC 84,777 was
adequately tested and found to be non-clastogenic in this series of
experiments (MRID 41415303).
Other Genotoxic Effects: At concentrations ranging from 0.8 to 80
ug/well, difenzoquat did not induce unscheduled DNA synthesis (UDS)
in primary rat hepatocytes. Higher levels (> 266 ug/well) were
cytotoxic. Positive response was obtained with 2-acetamidofluorene (2-
AAF), a positive control. Based on these findings, it was concluded that
difenzoquat was tested over an appropriate range of concentrations with
appropriate controls and showed no evidence of USD (MRID
41415304).
h. Metabolism
General Metabolism: The absorption, distribution, metabolism and
excretion of difenzoquat were studied in groups of male and female
Sprague Dawley rats administered a single oral gavage dose of 5 or 125
mg/kg [14C]-difenzoquat, or a 14-day repeated oral dosing of 5 mg/kg
unlabeled difenzoquat followed by a single dose of 5 mg/kg [14C]-labeled
difenzoquat on day 15. An additional group of rats received an
intravenous injection of 5 mg/kg [14C]-difenzoquat. [14C]-Difenzoquat
was poorly absorbed, distributed, and metabolized in rats for all dosing
regimens. Most of the radioactivity (63-80% of the administered dose)
was rapidly eliminated in the feces within 24 hours while recoveries
13
-------
were low in the urine (1.3-6.9% of the administered dose) of all oral
dose groups. Rats dosed intravenously with 5 mg/kg [14C]-difenzoquat
excreted 23.6-25.3% of the administered dose in the urine and 30.1-
32.2% in the feces after 24 hours. The results from the pilot study
conducted on 4 rats exposed orally to radiolabeled 5 mg/kg difenzoquat
indicated that there was no detectable amount of radioactivity in the
expired air as [14C]-C02. The study indicates that difenzoquat and/or its
metabolites do not bioaccumulate to an appreciable extent following oral
and intravenous exposure. The distribution of difenzoquat after oral
dosing was minimal; the tissues contained negligible levels of
radioactivity. Tissue levels were usually less than 0.01 ppm in the
single and repeated 5 mg/kg [14C]-difenzoquat-dosed groups and usually
less than 0.1 ppm in the 125 mg/kg group. Following intravenous
dosing, most radioactivity in the tissues was also less than 0.01 ppm; the
highest levels were in the heart (0.22 - 0.26 ppm) and muscle (0.35-0.37
ppm). The metabolism of difenzoquat is minimal because most of the
radioactivity was detected in the feces as unmetabolized parent
compound. There were 6 minor bands quantitated on HPLC following
oral and/or intravenous dosing; however, no attempt was made to
identify any of these metabolites. Based on these results, there were no
remarkable sex, dose or treatment related differences in the absorption,
distribution, metabolism, and elimination of [14C]-difenzoquat in rats.
The study also showed that oral administration of 5 and 125 mg/kg
difenzoquat, as well as intravenous dosing with 5 mg/kg, did not induce
any apparent treatment-related clinical effects (MRID 41844501).
i. Neurotoxicity
Based on the clinical findings observed in the one-year dog
feeding study with difenzoquat (MRID 42800401; emesis, salivation,
tremors, lethargy, irregular gait, lateral recumbency, dilated pupils, and
partially or completely closed eyes) and the developmental toxicity study
in rats (MRID 41521203; recurrent extensive salivation at two highest
doses tested; one rat at the highest dose tested had decreased motor
activity, head-tilt and tremors), the Agency concluded that the following
studies are required for difenzoquat: Acute Neurotoxicity Screening
Battery in the Rat (81-8) and 90-Day Neurotoxicity Screening Battery in
the Rat (82-7). Should these studies be positive, a Developmental
Neurotoxicity Study (83-6) would also be required.
14
-------
j. Other Toxic Endpoints
A Dermal Penetration/Absorption Study (85-2) with technical
difenzoquat is not needed because there are no toxicological endpoints to
indicate that this study should be required.
Domestic Animal Safety Studies (86-1) are not required due to
the use pattern of difenzoquat (a selective postemergence herbicide for
control of wild oats in barley and wheat).
k. Peer Review
The carcinogenic potential of difenzoquat was evaluated by the
OPP Reference Dose RfD/Peer Review Committee on February 24,
1994. The Committee classified difenzoquat into "Group E" (evidence
of non-carcinogenicity for humans), based on a lack of evidence of
carcinogenicity in adequate studies with two animal species, rat and
mouse.
1. Reference Dose
On February 24, 1994, the OPP Reference Dose RfD/Peer
Review Committee recommended that the RfD for difenzoquat be
established at 0.2 mg/kg/day. This value was based on the systemic
NOEL of 20 mg/kg/day from the one-year dog feeding study (83-lb;
MRID 42800401) and an uncertainty factor (UF) of 100. There are no
Codex MRLs established or proposed for residues of difenzoquat.
2. Exposure Assessment
a. Dietary Exposure
Plant Metabolism: The qualitative nature of the residue in plants is
adequately understood based on acceptable cereal grain (barley and
wheat) metabolism studies. These studies indicated that difenzoquat was
absorbed from the foliage and translocated throughout the plant but was
not extensively metabolized. The terminal residue of concern in plants
is difenzoquat (MRIDs 00037957, 00037958, 00042200).
Animal Metabolism: The qualitative nature of the residue in animals is
adequately understood based on acceptable poultry and ruminant
metabolism studies. The residue of concern in both poultry and
ruminant is difenzoquat. In the poultry metabolism study, laying hens
were dosed with [14C]difenzoquat at levels equivalent to 1, 10, or 12
15
-------
ppm in the diet (4x, 35x, or 42x the maximum theoretical dietary
burden, respectively). Residues were non-detectable in eggs, muscle,
and fat; difenzoquat was the only residue detected in liver and kidney
accounting for > 90% of the total radioactive residue in each tissue. In
the ruminant metabolism study, goats were administered with
[14C]difenzoquat at 23 or 98 ppm in the diet (lOx or 41x the maximum
theoretical dietary burden, respectively). Residues were non-detectable
in the milk, fat, and muscle of goats. Difenzoquat was the predominant
residue in liver and kidney; the 0-4-glucuronide of parent difenzoquat
was present as a minor metabolite (MRIDs 00110347, 41634802,
41634803, 42141601, and 42141602).
Residue Analytical Methods - Plants and Animals: Adequate residue
analytical methods are available for purposes of reregistration. For
tolerance enforcement, two GLC/FID methods (Methods I for plant and
II for animal commodities) are listed in the Pesticide Analytical Manual
(PAM, Vol. II). For residue data collection, methods based on the
enforcement methods and with acceptable method validation data, were
used for plant (American Cyanamid methods M-411 and M-1417) and
animal matrices (American Cyanamid methods M-457 and M-504). The
registrant has submitted adequate validation data for analytical methods
M-457 (ruminant) and M-504 (poultry), using liver and kidney samples
from metabolism studies. In addition, the registrant has satisfied the
requirements for data on the recovery of difenzoquat using FDA Multi-
residue protocols, and these data have been forwarded to FDA for
review (MRIDs 00004614, 00004630, 00037959, 00038488, 00052480,
00052481, PP#6F1703, 41521201, 41521202, 41634802, 41634803,
41921101, and 41921102).
Storage Stability: Adequate storage stability data on difenzoquat are
available to support the storage conditions and intervals of samples from
metabolism and magnitude of the residue studies in plants and animals.
Residues of difenzoquat per se are stable under frozen (-10 C) storage
conditions for up to 24 months in/on wheat grain and wheat straw. No
storage stability data are needed for livestock tissues since the samples
were analyzed within one month of collection (MRIDs 41634801 and
42323201).
Magnitude of the Residue in Plants: All data requirements for
magnitude of difenzoquat residue in plants have been evaluated and
deemed adequate. The registered uses of difenzoquat on barley and
wheat along with the established tolerances on these commodities are
supported by acceptable field residue data from trials reflecting the
maximum registered use patterns (MRIDs 00004610, 00004611,
16
-------
00004612, 00004613, 00004637, 00004641, 00004647, 00004648,
00004652, 00004653, 00004654, 00004655, 00004656, 00004657,
00004658, 00004659, 00004660, 00005567, 00052478, 00060111,
00060117, 00060118, 00108772, 00110331, 00110347, 00110349, and
00110355).
Magnitude of the Residue in Processed Food/Feed: The data
requirements for magnitude of the residue in processed food/feed have
been evaluated and deemed adequate. Acceptable wheat grain
processing and grain dust data have been submitted; the wheat
processing data will be translated to barley. The wheat grain processing
data indicated that residues of difenzoquat concentrated 4x and 4.6x in
wheat bran and shorts, respectively, and minimal concentration occurred
in middlings. Residues did not concentrate in flour or grain dust. The
registrant has submitted a petition for the establishment of food/feed
additive tolerances as a result of the wheat processing study. The
Agency has reviewed these tolerance proposals and recommended the
establishment of: (i) food additive tolerance in wheat bran at 0.25 ppm;
and (ii) feed additive tolerances in wheat shorts at 0.25 ppm, barley
hulls at 1 ppm, and barley bran at 1 ppm (MRIDs 41895301 and
42243500, FAP#2H5638).
Magnitude of the Residue in Meat, Milk, Poultry and Eggs: Acceptable
animal feeding studies have been conducted. The results of these studies
indicate that the established tolerances of 0.05 ppm (based on the limit of
detection of the analytical method) for difenzoquat residues in the fat,
meat, and meat byproducts of cattle, goats, hogs, sheep, and poultry are
adequate. The cattle feeding study showed no detectable residues of
difenzoquat in the muscle, fat, and kidney of beef cattle fed up to 10
ppm (4x the estimated dietary burden calculated from feed commodities
with established and proposed tolerances). The poultry feeding study
showed no detectable residues of difenzoquat in the eggs, muscle, liver,
kidney, fat, and skin of laying hens administered with up to 0.5 ppm (2x
the estimated dietary burden). Finite residues were detected only in the
cattle liver; this observation is consistent with the ruminant metabolism
study where finite residues were detected only in the liver and kidney of
animals dosed at 4Ix the estimated dietary burden. No tolerances are
needed for residues of difenzoquat in milk and eggs; the presently
registered uses of difenzoquat are classified as Category 3 of 40 CFR
§180.6(a) with respect to the need for tolerances in milk and eggs.
Category 3 of 40 CFR §180.6(a) states "that it is not possible to
establish with certainty whether finite residues will be incurred, but
there is no reasonable expectation of finite residues" (MRIDs 00037959
and 00052481, FAP#2H5638).
17
-------
Confined/Field Rotational Crops: A confined rotational crop study has
been reviewed and requires additional data to upgrade the study to an
acceptable status. The registrant is required to perform additional
characterization/identification of 14C-residues in/on selected fractions and
submit supporting storage stability data. The requirements for limited
field trials and for establishment of plantback intervals, if needed,
remain, but may be waived, pending resolution of the deficiencies from
the confined rotational crop study. (MRID 42811001).
b. Occupational and Residential Exposure
Handler (Mixer/Loader/Applicator) Exposure
The need for handler data is determined by both the toxicity and
exposure potential of a chemical. Handler exposure monitoring data
were not required in the Difenzoquat Registration Standard. The
Agency has determined that additional exposure data for handlers are not
required to support the reregistration of difenzoquat due to its low acute
toxicity and lack of other adverse effects with the exception of primary
eye irritation.
Postapplication/Reentry Exposure (Workers) and REI
The need for postapplication/reentry data is determined by both
the toxicity and exposure potential of a chemical. Difenzoquat does not
meet the Agency's toxicity or exposure criteria for requiring reentry
data. However, because difenzoquat is in toxicity category I for
primary eye irritation, the 48 hour restricted entry interval (REI)
imposed by the Worker Protection Standard (WPS) will be
maintained.
Personal Protective Equipment (PPE) Requirements
Handler PPE For each end-use product, PPE requirements for pesticide
handlers will be set during reregistration in one of two ways:
1. If the Agency has no special concerns regarding other adverse
effects of an active ingredient, the PPE for pesticide handlers will be
established based on the acute toxicity of the end-use product. For
occupational-use products, PPE will be established using the process
described in PR Notice 93-7 or more recent EPA guidelines.
2. If the Agency has special concerns about an active ingredient due
to very high acute toxicity or the certain adverse effects, such as allergic
18
-------
effects or other effects (cancer, developmental toxicity, reproductive
effects, etc):
• the Agency may establish in the RED minimum or "baseline"
handler PPE requirements for that active ingredient that pertain
to all or most occupational end-use products containing that
active ingredient.
• these minimum PPE requirements must be compared with the
PPE that would be designated on the basis of the acute toxicity of
each end-use product, and
• the more stringent choice for each type of PPE (i.e., bodywear,
hand protection, footwear, eyewear, etc.) must be placed on the
label of the end-use product.
There are no special toxicological concerns about difenzoquat
that warrant the establishment of active-ingredient-based PPE
requirements for pesticide handlers.
Early Entry PPE Personal protective equipment requirements for
persons who must enter areas that remain under a restricted-entry
interval are based on the toxicity concerns about the active ingredient.
The requirements are set in one of two ways:
1. If the Agency has no additional concerns about an active
ingredient, it establishes the early-entry PPE requirements RED based
on the acute dermal toxicity, skin irritation potential, and eye irritation
potential of the active ingredient.
2. If the Agency has special concerns about an active ingredient due
to very high acute toxicity or to other adverse effects, such as allergic
effects or cancer, developmental toxicity, reproductive effects, etc., it
may establish early-entry PPE requirements that are more stringent than
would be established on the basis of acute toxicity concerns.
For all products containing difenzoquat, the PPE required for
entry permitted during a restricted entry interval when there will be
contact with pesticide residues is: coveralls, chemical-resistant gloves,
shoes plus socks, and protective eyewear.
19
-------
3. Risk Assessment
a. Dietary
Toxicological Endpoints: Exposure calculated in the DRES chronic
analysis was compared to a Reference Dose (RfD) of 0.20 mg/kilograms
body weight/day, based on a No Observed Effect Level (NOEL) of 20
mg/kg bwt/day and an uncertainty factor of 100. The NOEL was taken
from a 1 year feeding study in dogs in which there was decreased body
weight gain in females at the LOEL. There are no data gaps in the
studies supporting the RfD. An acute dietary risk assessment was
performed for difenzoquat in which exposure was compared to a NOEL
of 37.5 mg/kg/day for difenzoquat methyl sulfate. The NOEL was
taken from a chronic dietary study in dogs, with mortality being the
effect upon which the endpoint was based.
Residue Information: Food uses evaluated in this analysis were the
published tolerances listed in 40 CFR 180.369 and in the Tolerance
Index System (TIS) for residues of difenzoquat derived from application
of its methyl sulfate salt, and the proposed food additive tolerance of
0.25 ppm for difenzoquat on wheat bran (FAP#2H5638).
Chronic Exposure: The DRES chronic exposure analysis assumed
tolerance level residues and 100 percent crop treated to estimate the
Theoretical Maximum Residue Contribution (TMRC) for the overall
U.S. population and 22 population subgroups. These exposure estimates
were then compared to the RfD to estimate chronic dietary risk. The
TMRC for the overall U.S. population from uses supported through
reregistration is 0.000219 mg/kg bwt/day, which represents 0.1% of the
RfD. The proposed food additive tolerance for "wheat, bran"
contributes an additional 0.000003 mg/kg bwt/day, which does not raise
the TMRC as a percentage of the RfD. The subgroup most highly
exposed, children aged one through six, has a TMRC from supported
uses of 0.000416 mg/kg bwt/day, or 0.2% of the RfD. The proposed
tolerance contributes an additional exposure of 0.000005 mg/kg
bwt/day, which does not cause any increase in the TMRC as a
percentage of the RfD.
Acute exposure The DRES detailed acute exposure analysis evaluates
individual food consumption as reported by respondents in the USDA
1977-78 Nationwide Food Consumption Survey (NFCS) and estimates
the distribution of single day exposures through the diet for the U.S.
population and certain subgroups. The analysis reflects consumers only
and assumes a uniform distribution of difenzoquat in the commodity
20
-------
supply. Since the toxicological effect to which high end exposure is
being compared in this analysis is mortality, and no particular age or sex
category was specified, Margins of Exposure (MOEs) were calculated
for the overall population and all subgroups offered in the analysis
(Infants < 1 yr, Children 1 through 6 years, Males 13 yrs and older,
Females 13 years and older).
The MOE is a measure of how closely the high end exposure
approaches the NOEL (the highest dose at which no effects were
observed in the laboratory test), and is calculated as the ratio of the
NOEL to the exposure (NOEL/Exposure = MOE).
In this analysis, the calculated exposure for the highest exposed
individual for each of the subgroups was compared to the NOEL of 37.5
mg/kg bwt/day. The lowest MOE of all of the subgroups was 16,667,
for the subgroup infants less than one year old. This means that for that
subgroup, those infants most highly exposed to difenzoquat in their diet
would receive 1/16,667 the dose that represents the NOEL in animals
for acute toxicity. MOEs ranged from 16,677 to 50,000.
Acute risk is probably overestimated by this analysis, since it is
very unlikely that tolerance level residues would exist on all of the food
items considered in this analysis and eaten in one day by an individual.
b. Occupational and Residential
Workers are potentially at risk for eye irritation (Toxicity
Category I). The Agency concluded that there were no additional
toxicological endpoints of concern for workers.
4. Data Requirements
The following data required for the reregistration of difenzoquat are
considered confirmatory:
Toxicology: An Acute Neurotoxicity Screening Battery in the rat (81-8) and
90-Day Neurotoxicity Screening Battery in the rat (82-7). Should these studies
be positive, a Developmental Neurotoxicity study (83-6) would also be
required.
Residue Chemistry: Additional data are required to update the rotational crop
study (MRID 42811001). The field rotational crop study is reserved.
21
-------
C. Environmental Assessment
1. Environmental Fate
a. Environmental Chemistry, Fate and Transport
The following environmental fate studies submitted in support of
reregistration have been reviewed and are included in the RED:
Hydrolysis: A study showed that difenzoquat did not hydrolyze in
sterile aqueous buffered solutions (pH 5,7, and 9) that were incubated
in the dark at 25 °C for 28 days. Using three different thin-layer
chromatography systems, [14C]difenzoquat was the only compound
detected in the treated solutions at 28 days posttreatment. During the
study, material balances ranged from 98.2 to 101.1% of the applied with
no discernable pattern of decline (MRID 41325403).
Photolysis in Water: Difenzoquat did not degrade in sterile aqueous
buffered (pH 7) solutions that were continuously irradiated with a xenon
arc lamp at 25 °C for 28 days. Using three different TLC systems,
[14C] difenzoquat was the only compound detected in the irradiated and
dark control solutions at 28 days posttreatment. During the study,
material balances ranged from 98.6 to 101.6% of the applied with no
discernable pattern of decline (MRID 41325404).
Photolysis on Soil: Difenzoquat did not degrade on sandy loam soil that
was continuously irradiated with a xenon arc lamp for 28 days at 25 °C.
Based on data from three different TLC systems, [14C]difenzoquat
comprised 98.0-99.8% of the applied radioactivity in the irradiated and
dark control solutions at 28 days posttreatment. Two unidentified
[14C] compounds were each <_\A% of the applied in the irradiated and
dark control solutions; unidentified "1" was detected at all sampling
intervals, and unidentified "2" was detected only at 3 and 4 weeks
posttreatment. During the study, the material balances ranged from
99.07 to 106.23% of the applied with no discernable pattern of decline
(MRID 41325405).
Aerobic Soil Metabolism: Difenzoquat did not degrade in aerobic sandy
loam soil that was incubated for 1 year in the dark at 20 °C and 75% of
0.33 bar moisture. During the study, extractable [14C]residues totaled
96.9-98.9% of the applied; [14C]difenzoquat was the only compound
detected in the soil extracts at 12 months posttreatment. Unextracted
[14C]residues in the soil were 1.1-3.1% of the applied at all sampling
intervals, and [14C]volatiles (organic and 14C02) totaled < 1% at 12
22
-------
months posttreatment. During the study, the material balances ranged
from 97.10 to 107.68% of the applied with no discernable pattern of
decline (MRID 41903701).
Anaerobic Soil Metabolism: Difenzoquat did not degrade in anaerobic
(flooded plus oxygen-free atmosphere) sandy loam soil that was
incubated in the dark at 20 °C for 2 months. During the study,
extractable [14C]residues associated with the soil totaled 96.5-102.2% of
the applied; during anaerobic incubation, only 0.14-0.21% was
associated with the floodwater. [14C] Difenzoquat was the only
compound detected in the soil extracts. Unextracted [14C]residues in the
soil were 1.18-2.48% of the applied at all sampling intervals.
[14C]Volatiles (organic and 14C02) were not detected during the aerobic
portion of the experiment, and were not measured during the anaerobic
portion of the experiment. During the study, the material balances
ranged from 99.06 to 104.23% of the applied with no discernable
pattern of decline (MRID 41903702).
Leaching and Adsorption/Desorption: Based on batch equilibrium
experiments, difenzoquat was immobile in sandy loam, sandy clay loam,
silt loam, and clay loam soils, with Freundlich Kadsorptlon values of 124-
685 in calcium chloride solutions and 181-2680 in water (MRID
41703401).
Terrestrial Field Dissipation: Freezer storage stability data were
submitted to support six previously submitted and reviewed field
dissipation studies. The Difenzoquat Registration Standard required
freezer storage stability data to support these data and fulfill the
guideline data requirement. The freezer storage stability data are
adequate to support the existing data. However, under present day
review criteria these six studies are no longer acceptable primarily
because differences in extraction technique do not allow determination of
the extent of mobility. In addition, many details needed to judge the
validity of the studies were lacking. In these field studies, half-lives
varied from 49-75 days in California to 254-354 days in Oregon.
Furthermore, the registrant must determine a route of dissipation of
difenzoquat and its residues, and whether difenzoquat binds to soil or
not. The Agency is requiring a non-guideline laboratory study
comparing the recovery of 14C-difenzoquat between the methods used in
laboratory and field studies. This added bridging information is needed
to assist the Agency in determining if the major route of difenzoquat
dissipation is soil binding (00045626, 00045627, 00045628, 00045629,
00045631, 00045632, 41903703, 42327501).
23
-------
b. Environmental Fate Assessment
Except for field dissipation studies (164-1), all of the required
environmental fate data requirements are fulfilled at this time.
Difenzoquat is persistent (the chemical did not degrade in any of
the laboratory studies performed: hydrolysis, aqueous and soil
photolysis, and aerobic and anaerobic soil metabolism). This chemical
is relatively immobile (Kds ranged from 124 to 685, Kocs ranged from
23,071 to 36,231). In aged and unaged soil column leaching studies
with sand, sandy loam and silt loam soils, 90.88 and 96.7% of the
applied radioactivity remained in the top 3.5 inches of the columns after
20 inches of water was applied, respectively, and 0.47-2.59 % was
recovered in the leachates.
A preliminary assessment of the environmental fate of
difenzoquat indicates that soil binding appears to be the principal route
of dissipation. This assessment is supported by laboratory data which
shows a high degree of adsorption to soil but no degradation of the
parent material.
However, the field dissipation studies contrast sharply with
laboratory data and indicate that difenzoquat residues decline with time.
Because different methods were used in the laboratory and field studies
to extract difenzoquat from soil, it is not possible to conclude at this
time that difenzoquat is bound in the field soils. The submitted
laboratory and field studies do not provide a coherent description of the
environmental fate of difenzoquat nor explain the discrepancies between
laboratory data, which indicate persistence, and field data, which
indicate slow to moderate dissipation. It appears from the laboratory
data that difenzoquat is immobile in the soil and the potential for ground
water contamination is minimal.
Typically, results from the field dissipation studies along with
data from the other environmental fate studies would be used to
determine the leaching potential of difenzoquat and whether groundwater
monitoring studies are needed. However, it cannot be determined based
solely on laboratory data how far through field soil difenzoquat or its
degradates will move by leaching. Therefore, without acceptable
terrestrial field studies, the potential for contamination of groundwater
cannot be assessed. The information gained from further field terrestrial
dissipation studies may enable the Agency to determine the persistence,
potential mobility and route of dissipation of difenzoquat under actual
use conditions.
24
-------
A non-guideline laboratory study is required comparing the
recovery of 14C-difenzoquat between the methods used in laboratory and
field studies. This added bridging information is needed to assist the
Agency in determining if the major route of difenzoquat dissipation is
soil binding. The soils in these new studies should be the same as used
in the field studies.
Upon review of data bridging laboratory and field extraction
methodologies, the Agency will reevaluate the need for further
terrestrial field dissipation studies.
2. Ecological Effects
a. Ecological Effects Data
(1) Terrestrial Data
Effects to Birds All avian dietary studies show that the
compound is practically non-toxic to birds, while the oral toxicity
study shows that the compound is slightly toxic to birds. Avian
toxicity requirements have been fulfilled with two dietary studies,
71-2(a) Bobwhite quail LC50 = 4,640 ppm (MRID 00052458),
71-2(b) Mallard LC50 = 10,388 ppm (MRID 00037928), and one
oral study, 71-1 (a) Bobwhite quail LD50 = 1,577 mg/kg (MRID
00058830).
(2) Aquatic Data
Effects on Freshwater Fish Aquatic testing on freshwater fish
show that difenzoquat is slightly to practically non-toxic to fish.
The guideline requirements for freshwater fish, 72-1 (a) and 72-
l(c), are fulfilled for this compound. Test results for freshwater
fish include 72-1 (c) Acute Fish (rainbow trout) LC50 = 694
mg/L (MRID 00037926) and 72-1 (a) Acute Fish (bluegill) LC50
= 46.5 -696 mg/L (MRID 00037926; MRID DIF0601).
Effects on Freshwater Invertebrates Aquatic testing on
freshwater invertebrates indicated that difenzoquat is moderately
toxic to invertebrates. Guideline requirement 72-2(a) is fulfilled
for this compound. Acute studies on freshwater invertebrates
include 72-2(b) Daphnia magna EC50 = 2.63 ppm (MRID
00057909).
25
-------
(3) Insect Data
Difenzoquat is non-toxic to honey bees (no deaths when a dose
equivalent of 36 Ib/A was administered).
(4) Non-Target Plants Data
Non-target plant data are required. These studies are required
because difenzoquat i) is used on terrestrial food and feed sites,
ii) is applied by ground rigs, iii) has a water solubility greater
than 10 ppm (difenzoquat solubility is 7.65 X 105 ppm) or a
vapor pressure greater than 1.0 X 105 mg Hg at 25°C, and iv) the
Typical End-Use Product (TEP) is not thoroughly incorporated
immediately after application (aerial application and
chemigation).
The Agency is requiring Tier II Plant Testing:
123-la Seed Germination/Seedling Emergence
123-lb Vegetative Vigor
123-2 Aquatic Plant Growth (The study should be conducted on
each of the following species: Selenastrum capricornutum,
Lemna gibba, Skeletonema costatum, Anabaena flos-aquae, and a
freshwater diatom.)
b. Ecological Effects Risk Assessment
Difenzoquat is applied to crops once per growing season at rates
of 0.6 to 1.0 Ibs ai/A. Difenzoquat is readily absorbed but not
metabolized or degraded by plants. The only pest claim for this
compound is for the control of wild oats (Avena fatua).
(1) Terrestrial Organisms
Difenzoquat acute toxicity values to birds suggest that
difenzoquat presents a slight to moderate potential for toxicity to
wildlife. These acute values are as follows: mallard ducks (LC50
= 10,388 ppm) and bobwhite quail (LC50 = 4,640 ppm).
The available data show that difenzoquat is slightly to
practical non-toxic to birds. In order to predict plant residues,
the maximum application rate of 1 Ib ai/A at one application per
season was used as follows:
26
-------
short grass 240 ppm
long grass 110 ppm
leafy crops 125 ppm
small insects 58 ppm
large insects 12 ppm
grain 10 ppm
fruit 7 ppm
The expected residues do not trigger adverse effects to
avian or mammalian species from the present registered uses of
difenzoquat. Adverse chronic effects to birds are not expected
from exposure to this compound because of its low acute avian
toxicity values, the low mammalian toxicity and the use
restriction of one application per season.
Chronic toxicity to wildlife has not been evaluated
directly, but appears to be slight as noted by mammalian chronic
testing. No further testing on wildlife will be required at this
time. Difenzoquat chronic toxicity to wildlife appears to be
slight. Testing conducted on mammalian species (rats) showed
that through the major routes of exposure (dermal and
inhalation), the following toxicological characteristics were
noted:
Subchronic toxicity: Systemic NOEL was 2,500 ppm. No
compound related effects were observed in 90-day feeding study
(MRID 00037922 duplicate MRID 00069540, 00075774).
Oncogenicity: Negative at the 5,000 ppm level in rats (MRID
00036710).
Teratogenicity: Negative for teratogenicity, fetotoxicity and
maternal toxicity in rats at 2,500 ppm (MRID 41521203).
Reproduction: A 3-generation rat reproduction study found the
parental NOEL was equal to or greater than 2,500 ppm and
reproductive/developmental NOEL was 500 ppm (MRID
00037924; duplicate MRID 00030578).
(2) Aquatic Organisms
Difenzoquat acute toxicity values to aquatic species
suggest that difenzoquat presents a slight to moderate potential
for toxicity. These acute values are as follows: rainbow trout
27
-------
(LC50 = 694 mg/L), acute bluegill (LC50 =46.5-696 mg/L) and
Daphnia (LC50 = 2.6 ppm).
The aquatic risk from difenzoquat exposure was evaluated
by comparing the preliminary estimated environmental
concentrations (EEC) with the level of concern for acute aquatic
risk (i.e. runoff or drift EEC > 0.5 LC50 Daphnia; 3.05 - 12.2
ppb < 1.3 ppm) as well as difenzoquat toxicity and use pattern
information. Difenzoquat appears to pose minimal acute risk to
aquatic organisms because the EEC is < 0.5 LC50 value.
The preliminary EEC's for this herbicide were calculated
by using a water body scenario at a maximum rate of 1.0 Ib ai/A
for simulated ground and aerial application to 6 feet of water.
These values are summarized as follows:
1) Ground Application = runoff 12.2 ug/L (0.012 ppm)
2) Aerial Application = runoff 7.3 ug/L (0.007 ppm)
drift 3.05 ug/L (0.003 ppm)
Chronic risk to fish is unlikely because expected exposure
is < 0.01 the lowest LC50 values and only one application per
season is permitted. No additional data are required.
The current uses of difenzoquat on wheat and barley
appear to result in low toxic impact on aquatic organisms. This
conclusion is based upon the following information:
1) moderate to slight toxicity of difenzoquat to fish
and aquatic invertebrates;
2) Preliminary EEC values that suggest no risk (these
values are at least 2 orders of magnitude below the
acute risk criteria);
3) Restriction of one application per season;
4) Mammalian data do not indicate chronic effects.
(3) Nontarget Insects
Difenzoquat is non-toxic to honey bees (no deaths when a
dose equivalent of 36 Ib/A was administered).
28
-------
(4) Nontarget Plants
Difenzoquat is an herbicide that is applied aerially. There
is a potential for direct exposure of the toxicant to terrestrial and
aquatic plants. In order to evaluate toxicity of this compound to
plants, Tier II Plant Testing is required (see section III(C)(3)).
Although there are no data available on effects to non-
target plants, it is anticipated that, since difenzoquat is an
herbicide, risk to non-target aquatic and terrestrial plants will be
high. The required plant data are necessary in order to assess
risks to non-target plants. Phytotoxicity data are not part of the
target data base for reregistration.
(5) Spray-Drift Label Advisory
In order to inform the user of best management practices
that would minimize spray drift from the target site, the Agency
is currently preparing spray drift labeling statements. This future
labeling may be required for all difenzoquat products that may be
applied aerially to agricultural crops.
c. Endangered and Threatened Species
EPA has been working with the U.S. Fish and Wildlife Service
and other federal and state agencies to develop a program to avoid
jeopardizing the continued existence of listed species from the use of
pesticides. The Endangered Species Protection Program is expected to
become final in 1994. Limitations on the use of difenzoquat may be
required to protect endangered and threatened species, but these
limitations have not yet been defined, and they may be formulation
specific. OPP anticipates that consultation with the Fish and Wildlife
Service will be conducted in accordance with the species-based priority
approach described in the Program. After completion of the
consultation, registrants will be informed if any required label
modifications are necessary. Such modifications would most likely
consist of the generic label statement referring pesticide users to use
limitations contained in county Bulletins.
Although the Endangered Species Protection Program has not
been finalized, it can be assumed that endangered plant species occurring
in counties where wheat and barley are grown may be affected from
exposure to this herbicide.
29
-------
d. Risk Mitigation
The Agency has determined that the current uses of difenzoquat
do not pose any unreasonable threat to the environment, and based on
available data, no levels of concern (LOCs) have been exceeded.
However, it can be anticipated that difenzoquat, as an herbicide, will
pose some risk to non-target plants. The Agency remains concerned and
is exploring risk mitigation for all herbicides.
3. Data Requirements
Environmental Fate:
164-1 Non-guideline laboratory study comparing the recovery of 14C-
difenzoquat between the methods used in laboratory and field dissipation
studies
165-1 Confined Rotational Crop (supplemental data)
201-1 Droplet Size Spectrum
202-1 Drift Field Evaluation
Ecological Effects:
123-la Seed Germination/Seedling Emergence
123-2b Vegetative Vigor
123-2 Aquatic Plant Growth (Selenastrum capricornutum, Lemna gibba,
Skeletonema costatum, Anabaena flos-aquae, and a freshwater diatom)
IV. RISK MANAGEMENT AND REREGISTRATION DECISION
A. Determination of Eligibility
Section 4(g)(2)(A) of FIFRA calls for the Agency to determine, after
submission of relevant data concerning an active ingredient, whether products
containing the active ingredients are eligible for reregistration. The Agency has
previously identified and required the submission of the generic (i.e. active ingredient
specific) data required to support reregistration of products containing difenzoquat as
the active ingredient. The Agency has completed its review of these generic data, and
has determined that the data are sufficient to support reregistration of all products
containing difenzoquat. Appendix B identifies the generic data requirements that the
Agency reviewed as part of its determination of reregistration eligibility of difenzoquat,
and lists the submitted studies that the Agency found acceptable.
The Agency made its reregistration eligibility determination based upon the
target data base required for reregistration, the current guidelines for conducting
30
-------
acceptable studies to generate such data and the data identified in Appendix B.
Although the Agency has found that all uses of difenzoquat are eligible for
reregistration, it should be understood that the Agency may take appropriate regulatory
action, and/or require the submission of additional data to support the registration of
products containing difenzoquat, if new information comes to the Agency's attention or
if the data requirements for registration (or the guidelines for generating such data)
change.
1. Eligibility Decision
The Agency has determined that difenzoquat products, labeled and used
as specified in this Reregistration Eligibility Decision, will not pose
unreasonable risks or adverse effects to humans or the environment.
Based on the reviews of the generic data for the active ingredient
difenzoquat, the Agency has sufficient information on its health effects and on
its potential for causing adverse effects in fish and wildlife and the environment.
The Agency concludes that products containing difenzoquat for all uses are
eligible for reregistration.
2. Eligible and Ineligible Uses
The Agency has determined that all uses of difenzoquat are eligible for
reregistration.
B. Regulatory Position
The following is a summary of the regulatory positions and rationales for
difenzoquat. Where labeling revisions are imposed, specific language is set forth in
Section V of this document.
1. Tolerance Reassessment
Tolerances Listed Under 40 CFR §180.369
Sufficient data are available to ascertain the adequacy of the established
tolerances listed in 40 CFR §180.369 for the following commodities: barley
grain; barley straw; wheat grain; wheat straw; fat, meat, and meat byproducts
of cattle, goats, hogs, horses, and sheep; and fat, meat and meat byproducts of
poultry. No tolerances are needed for residues of difenzoquat in milk and eggs;
the presently registered uses of difenzoquat are classified as Category 3 of 40
CFR §180.6(a) with respect to the need for tolerances in milk and eggs.
31
-------
Category 3 of 40 CFR §180.6(a) states "that it is not possible to establish with
certainty whether finite residues will be incurred, but there is no reasonable
expectation of finite residues."
Proposed Food (40 CFR §185.xxx) and Feed (40 CFR §186.xxx) Tolerances
No food/feed additive tolerances have been established for difenzoquat
derived from application of the methyl sulfate salt and calculated as the cation.
The registrant has submitted a petition (FAP#2H5638) proposing the
establishment of food/feed additive tolerances as a result of an adequate wheat
processing study. The Agency has reviewed these tolerance proposals and
recommended for the establishment of: (i) food additive tolerance in wheat
bran at 0.25 ppm; and (ii) feed additive tolerances in wheat shorts at 0.25 ppm,
barley hulls at 1 ppm, and barley bran at 1 ppm.
A summary of the difenzoquat tolerance reassessment is presented in the
table below. There are no changes required in existing tolerances.
Dietary Exposure Estimates
The dietary exposure assessment for difenzoquat will be based on
tolerance level residues and proposed tolerance levels for processed
commodities. Tolerance level residues will greatly overestimate the dietary
exposure to residues of difenzoquat.
Codex Harmonization
There are no Codex MRLs established or proposed for residues of
difenzoquat. Therefore, there are no questions with respect to compatibility of
U.S. tolerances with Codex MRLs.
Tolerance Reassessment Summary for Difenzoquat
Commodity
Current Tolerance
Tolerance
Reassessment (nnnV)
Comment
Tolerances listed under 40 CFR §180.369
Barley, grain
Barley, straw
Cattle, fat
Cattle, mbyp
Cattle, meat
Goats, fat
0.2
20
0.05
0.05
0.05
0.05
All established tolerances
are supported by adequate
residue chemistry data.
32
-------
Commodity
Goats, mbyp
Goats, meat
Hogs, fat
Hogs, mbyp
Hogs, meat
Horses, fat
Horses, mbyp
Horses, meat
Poultry, fat
Poultry, mbyp
Poultry, meat
Sheep, fat
Sheep, mbyp
Sheep, meat
Wheat, grain
Wheat, straw
Current Tolerance
fppm^
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
20
Tolerance
Reassessment fppnYl
Comment
Proposed Food Additive Tolerances (40 CFR §185. xxx)
Wheat, bran
None
0.25
Tolerance pending
(FAP#2H5638)
Proposed Feed Additive Tolerances (40 CFR §186. xxx)
Barley, hulls
Barley, bran
Wheat, shorts
None
None
None
1
1
0.25
Tolerance pending
(FAP#2H5638)
2.
Restricted Use Classification
Difenzoquat is not currently classified for restricted use. The Agency
has determined that difenzoquat products should not be classified for restricted
use at this time. After an analysis of additional data submitted, the Agency will
reassess whether any difenzoquat uses warrant a restricted use classification.
3. Reference Dose (RfD)
Difenzoquat is not a RfD exceeder. The reference dose for difenzoquat
was determined to be 0.2 mg/kg/day. This value was based on the systemic
NOEL of 20 mg/kg/day from the one-year dog feeding study (MRID
42800401) and an uncertainty factor (UF) of 100. The TMRC for the overall
U.S. population from uses supported through reregistration is 0.000219 mg/kg
33
-------
bwt/day, which represents 0.1% of the RfD. The proposed food additive
tolerance for "wheat, bran" contributes an additional 0.000003 mg/kg bwt/day,
which does not raise the TMRC as a percentage of the RfD. The subgroup
most highly exposed, children aged one through six, has a TMRC from
supported uses of 0.000416 mg/kg bwt/day, or 0.2% of the RfD. The
proposed tolerance contributes an additional exposure of 0.000005 mg/kg
bwt/day, which does not cause any increase in the TMRC as a percentage of the
RfD.
4. Spray Drift Label Advisory
In order to inform the user of best management practices that would
minimize spray drift from the target site, the Agency is currently preparing
spray drift labeling statements. This future labeling may be required for all
difenzoquat products that may be applied aerially to agricultural crops.
5. Endangered Species Statement
Currently, the Agency is developing a program ("The Endangered
Species Protection Program") to identify all pesticides whose use may cause
adverse impacts on endangered and threatened species and to implement
mitigation measures that will eliminate the adverse impacts. The program
would require use modifications or a generic product label statement, requiring
users to consult county-specific bulletins. These bulletins would provide
information about specific use restrictions to protect endangered and threatened
species in the county. Consultations with the Fish and Wildlife Service will be
necessary to assess risks to newly listed species or from proposed new uses.
The Agency plans to publish a description of the Endangered Species
Program in the Federal Register in 1994 and by 1995 have enforceable county-
specific bulletins available. Because the Agency is taking this approach for
protecting endangered and threatened species, it is not imposing label
modifications at this time through the RED. Rather, any requirements for
product use modifications will occur in the future under the Endangered Species
Protection Program.
6. Labeling Rationale
a. Compliance with Worker Protection Standard
Any product whose labeling reasonably permits use in the
production of an agricultural plant on any farm, forest, nursery, or
greenhouse must comply with the labeling requirements of PR Notice
93-7, "Labeling Revisions Required by the Worker Protection Standard
(WPS), and PR Notice 93-11, "Supplemental Guidance for PR Notice
34
-------
93-7, which reflect the requirements of EPA's labeling regulations for
worker protection statements (40 CFR part 156, subpart K). These
labeling revisions are necessary to implement the Worker Protection
Standard for Agricultural Pesticides (40 CFR part 170) and must be
completed in accordance with, and within the deadlines specified in, PR
Notices 93-7 and 93-11. Unless otherwise specifically directed in this
RED, all statements required by PR Notices 93-7 and 93-11 are to be on
the product label exactly as instructed in those notices.
After April 21, 1994, except as otherwise provided in PR
Notices 93-7 and 93-11, all products within the scope of those notices
must bear WPS PR Notice complying labeling when they are distributed
or sold by the primary registrant or any supplementally registered
distributor.
After October 23, 1995, except as otherwise provided in PR
Notices 93-7 and 93-11, all products within the scope of those notices
must bear WPS PR Notice complying labeling when they are distributed
or sold by any person.
Post-application Reentry
Under the Worker Protection Standard (WPS), interim restricted
entry intervals (REI) for all uses within the scope of the WPS are
established on the basis of the acute toxicity of the active ingredient. The
toxicity categories of the active ingredient for acute dermal toxicity, eye
irritation potential, and skin irritation potential are used to determine the
interim WPS REI. If one or more of the three acute toxicity effects are
in toxicity category I, the interim WPS REI is established at 48 hours.
If none of the acute toxicity effects are in category I, but one or more of
the three is classified as category II, the interim WPS REI is established
at 24 hours. If none of the three acute toxicity effects are in category I
or II, the interim WPS REI is established at 12 hours. A 48-hour REI is
increased to 72 hours when an organophosphate pesticide is applied
outdoors in arid areas. In addition, the WPS specifically retains two
types of REI's established by the Agency prior to the promulgation of
the WPS: product-specific REI's established on the basis of adequate
data and interim REI's that are longer than those that would be
established under the WPS.
The technical grade of difenzoquat is in toxicity category I for
acute eye irritation, and the REI imposed by the WPS was 48 hours.
The RED evaluation of the REI established by the WPS concluded that
no changes were warranted and the REI should remain at 48 hours. The
35
-------
48 hour REI established by the WPS applies to all registered uses of
difenzoquat since all the registered uses fall under the scope of the WPS.
Personal Protective Equipment (PPE) Requirements
Handler PPE For each end-use product, PPE requirements for pesticide
handlers will be set during reregistration in one of two ways:
1. If the Agency has no special concerns regarding other adverse
effects of an active ingredient, the PPE for pesticide handlers will be
established based on the acute toxicity of the end-use product. For
occupational-use products, PPE will be established using the process
described in PR Notice 93-7 or more recent EPA guidelines.
2. If the Agency has special concerns about an active ingredient due
to very high acute toxicity or certain adverse effects, such as allergic
effects or other effects (cancer, developmental toxicity, reproductive
effects, etc):
• the Agency may establish in the RED minimum or "baseline"
handler PPE requirements for that active ingredient that pertain
to all or most occupational end-use products containing that
active ingredient.
• these minimum PPE requirements must be compared with the
PPE that would be designated on the basis of the acute toxicity of
each end-use product, and
• the more stringent choice for each type of PPE (i.e., bodywear,
hand protection, footwear, eyewear, etc.) must be placed on the
label of the end-use product.
There are no special toxicological concerns about difenzoquat
that warrant the establishment of active-ingredient-based PPE
requirements for pesticide handlers.
Early Entry PPE Personal protective equipment requirements for
persons who must enter areas that remain under a restricted-entry
interval are based on the toxicity concerns about the active ingredient.
The requirements are set in one of two ways:
1. If the Agency has no additional concerns about an active
ingredient, it establishes the early-entry PPE requirements RED based
on the acute dermal toxicity, skin irritation potential, and eye irritation
potential of the active ingredient.
36
-------
2. If the Agency has special concerns about an active ingredient due
to very high acute toxicity or to other adverse effects, such as allergic
effects or cancer, developmental toxicity, reproductive effects, etc., it
may establish early-entry PPE requirements that are more stringent than
would be established on the basis of acute toxicity concerns.
For all products containing difenzoquat, the PPE required for
entry during a restricted entry interval is: coveralls, chemical-resistant
gloves, shoes plus socks, and protective eyewear.
V. ACTIONS REQUIRED BY REGISTRANTS
This section specifies the data requirements and responses necessary for the
reregistration of both manufacturing-use and end-use products.
A. Manufacturing-Use Products
1. Additional Generic Data Requirements
The generic data base supporting the reregistration of difenzoquat for the
above eligible uses has been reviewed and determined to be substantially
complete. Data are required for the following guidelines:
81-8 Acute Neurotoxicity Screening Battery Rat
82-7 90-Day Neurotoxicity Screening Battery Rat
123-la Seed Germination/Seedling Emergence
123-lb Vegetative Vigor
123-2 Aquatic Plant Growth (Selenastrum capricornutum,
Lemna gibba, Skeletonema costatum, Anabaena flos-
aquae, and a freshwater diatom)
• 164-1 Non-guideline laboratory study comparing the recovery of
14C-difenzoquat between the methods used in laboratory
and field dissipation studies
• 165-1 Confined Rotational Crop (supplemental data)
• 201-1 Droplet Size Spectrum
• 202-1 Drift Field Evaluation
2. Labeling Requirements for Manufacturing-Use Products
No additional labeling requirements are being required for
manufacturing use products at this time.
37
-------
B. End-Use Products
1. Additional Product-Specific Data Requirements
Section 4(g)(2)(B) of FIFRA calls for the Agency to obtain any needed
product-specific data regarding the pesticide after a determination of eligibility
has been made. The product specific data requirements are listed in Appendix
G, the Product Specific Data Call-in Notice.
Registrants must review previous data submissions to ensure that they
meet current EPA acceptance criteria (Appendix F; Attachment E) and if not,
commit to conduct new studies. If a registrant believes that previously
submitted data meet current testing standards, then study MRID numbers should
be cited according to the instructions in the Requirement Status and Registrants
Response Form provided for each product.
2. Labeling Requirements for End-Use Products
No additional labeling requirements are being required for end-use
products at this time.
3. Worker Protection Standard (WPS)
The RED evaluation of the REI established by the WPS concluded that
no changes were warranted and the REI should remain at 48 hours. This REI
must be inserted into the standardized REI statement required by PR Notice 93-
7. The PPE for early entry for difenzoquat includes coveralls, chemical
resistant gloves, shoes plus socks, and protective eyewear. These PPE must be
inserted into the early entry PPE statement required by PR Notice 93-7.
C. Existing Stocks
Registrants may generally distribute and sell products bearing old
labels/labeling for 26 months from the date of the issuance of this Reregistration
Eligibility Decision (RED). Persons other than the registrant may generally distribute
or sell such products for 50 months from the date of the issuance of this RED.
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.
The Agency has determined that registrants may distribute and sell difenzoquat
products bearing old labels/labeling for 26 months from the date of issuance of this
RED. Persons other than the registrant may distribute or sell such products for 50
months from the date of the issuance of this RED.
38
-------
VI. APPENDICES
39
-------
40
-------
APPENDIX A. Table of Use Patterns
Subject to Reregistration
41
-------
42
-------
APPENDIX A
CASE 0223, [Difenzoquat] Chemical 106401 [Difenzoquat methyl sulfate]
SITE Application Type, Application
Timing, Application Equipment )
Form(s) Min. Appl.
Rate (AI un-
Surface Type (Antimicrobial only) & Effica-
cy Influencing Factor (Antimicrobial only)
less noted
otherwise)
Max. Appl. Soil Max. tt Apps Max. Dose [(AI Min. Restr. Geographic Limitations Use
Rate (AI Tex. @ Max. Rate unless noted Interv Entry Allowed Disallowed Limitations
unless noted Max. /crop /year otherwise)/A] (days) Interv Codes
otherwise) Dose cycle /crop /year [day(s)]
cycle
USES ELIGIBLE FOR REREGISTRATION
FOOD/FEED USES
BARLEY
Spray., Postemergence., Aircraft.
Spray., Postemergence., Ground.
WHEAT
Spray., Postemergence., Aircraft.
Spray., Postemergence., Ground.
SC/L NA
SC/L NA
SC/L NA
SC/L NA
Use Group: TERRESTRIAL FOOD+FEED CROP
1 Ib (CI) A * 1 NS NS NS NS NS
1 Ib (CI) A * 1 NS NS NS NS NS
Use Group: TERRESTRIAL FOOD+FEED CROP
1 Ib (CI) A * 1 NS NS NS NS NS
1 Ib (CI) A * 1 NS NS NS NS NS
C46
C46
C46
C46
43
-------
APPENDIX A - CASE 0223, [Difenzoquat] Chemical 106401 [Difenzoquat methyl sulfate]
HEADER ABBREVIATIONS
Min. Appl. Rate (AI unless : Minimum dose for a single application to a single site. System calculated. Microbial claims only.
noted otherwise)
Max. Appl. Rate (AI unless : Maximum dose for a single application to a single site. System calculated.
noted otherwise)
Soil Tex. Max. Dose : Maximum dose for a single application to a single site as related to soil texture (Herbicide claims only).
Maximum number of Applications at Maximum Dosage Rate. Example: "4 applications per year" is expressed as "4/1 yr"; "4 applications per 3
years" is expressed as "4/3 yr"
Maximum dose applied to a site over a single crop cycle or year. System calculated.
Max. # Apps ® Max. Rate
Max. Dose [(AI unless
noted otherwise)/A]
Min. Interv (days)
Restr. Entry Interv (days)
Minimum Interval between Applications (days)
Restricted Entry Interval (days)
SOIL TEXTURE FOR MAX APP. RATE
* : Non-specific
C : Coarse
M : Medium
F : Fine
O : Others
FORMULATION CODES
SC/L : SOLUBLE CONCENTRATE/LIQUID
ABBREVIATIONS
AN : As Needed
NA : Not Applicable
NS : Not Specified (on label)
UC : Unconverted due to lack of data (on label), or with one of following units: bag, bait, bait block, bait pack, bait station, bait station(s), block, briquet,
briquets, bursts, cake, can, canister, capsule, cartridges, coil, collar, container, dispenser, drop, eartag, grains, lure, pack, packet, packets, pad, part,
parts, pellets, piece, pieces, pill, pumps, sec, sec burst, sheet, spike, stake, stick, strip, tab, tablet, tablets, tag, tape, towelette, tray, unit, --
APPLICATION RATE
DCNC
No Calc
W
V
cwt
nnE-xx : nn times (10 power -xx); for instance, "1.234E-04" is equivalent to ".0001234"
Dosage Can Not be Calculated
No Calculation can be made
PPM calculated by weight
PPM Calculated by volume
Hundred Weight
nn times (10 power -xx); for instance, "1.234E-04" is equivalent to
USE LIMITATIONS CODES
C46 : Do not apply through any type of irrigation system.
* NUMBER IN PARENTHESES REPRESENTS THE NUMBER OF TIME UNITS (HOURS,DAYS, ETC.) DESCRIBED IN THE LIMITATION.
44
-------
APPENDIX B. Table of the Generic
Data Requirements and Studies Used to
Make the Reregistration Decision
45
-------
46
-------
GUIDE TO APPENDIX B
Appendix B contains listings of data requirements which support the reregistration for active
ingredients within the case Difenzoquat covered by this Reregistration Eligibility Decision
Document. It contains generic data requirements that apply to Difenzoquat in all products,
including data requirements for which a "typical formulation" is the test substance.
The data table is organized in the following format:
1. Data Requirement (Column 1). The data requirements are listed in the order in
which they appear in 40 CFR Part 158. the reference numbers accompanying each test refer to
the test protocols set in the Pesticide Assessment Guidelines, which are available from the
National Technical Information Service, 5285 Port Royal Road, Springfield, VA 22161 (703)
487-4650.
2. Use Pattern (Column 2). This column indicates the use patterns for which the data
requirements apply. The following letter designations are used for the given use patterns:
A Terrestrial food
B Terrestrial feed
C Terrestrial non-food
D Aquatic food
E Aquatic non-food outdoor
F Aquatic non-food industrial
G Aquatic non-food residential
H Greenhouse food
I Greenhouse non-food
J Forestry
K Residential
L Indoor food
M Indoor non-food
N Indoor medical
0 Indoor residential
3. Bibliographic citation (Column 3). If the Agency has acceptable data in its files, this
column lists the identifying number of each study. This normally is the Master Record
Identification (MRID) number, but may be a "GS" number if no MRID number has been
assigned. Refer to the Bibliography appendix for a complete citation of the study.
47
-------
48
-------
APPENDIX B
Data Supporting Guideline Requirements for the Reregistration of Difenzoquat
REQUIREMENT
USE
PATTERN
CITATION(S)
PRODUCT CHEMISTRY
61-1
61-2A
61-2B
62-1
62-2
62-3
63-2
63-3
63-4
63-5
63-6
63-7
63-8
63-9
63-10
63-11
63-12
63-13
Chemical Identity
Starting Materials & Manufacturing Process
Formation of Impurities
Preliminary Analysis
Certification of limits
Analytical Method
Color
Physical State
Odor
Melting Point
Boiling Point
Density
Solubility
Vapor Pressure
Dissociation Constant
Octanol/Water Partition
PH
Stability
All
All
All
All
All
All
All
All
All
All
N/A
All
All
All
All
All
All
All
41325401
41325401
41325401
41415301
41415301
41415301
41325402
41325402
41325402
41325402
41325402
41325402
41325402
41325402, 42243501
41325402
41325402
41325402
49
-------
Data Supporting Guideline Requirements for the Reregistration of Difenzoquat
REQUIREMENT
63-14
63-15
63-16
63-17
63-18
63-19
63-20
Oxidizing/Reducing Action
Flammability
Explodability
Storage stability
Viscosity
Miscibility
Corrosion characteristics
USE
PATTERN
All
N/A
All
All
N/A
N/A
All
CITATION(S)
41325402
41325402
41593501
41593501
ECOLOGICAL EFFECTS
71-1A
71-2A
71-2B
72-1A
72-1C
72-2A
123-1A
123-1B
123-2
Acute Avian Oral - Quail/Duck
Avian Dietary - Quail
Avian Dietary - Duck
Fish Toxicity Bluegill
Fish Toxicity Rainbow Trout
Invertebrate Toxicity
Seed Germination/Seedling Emergence
Vegetative Vigor
Aquatic Plant Growth
AB
AB
AB
AB
AB
AB
AB
AB
AB
00058830
00052458
00037928
00037926
00037926
00057909
DATA GAP
DATA GAP
DATA GAP
TOXICOLOGY
81-1
81-2
Acute Oral Toxicity - Rat
Acute Dermal Toxicity - Rabbit/Rat
AB
AB
41325406, 41300502 (duplicate)
41325407
50
-------
Data Supporting Guideline Requirements for the Reregistration of Difenzoquat
REQUIREMENT
81-3
81-4
81-5
81-6
81-8
82-1B
Acute Inhalation Toxicity - Rat
Primary Eye Irritation - Rabbit
Primary Dermal Irritation - Rabbit
Dermal Sensitization - Guinea Pig
Acute Neurotoxicity - Rat
90-Day Feeding - Non-Rodent
USE
PATTERN
AB
AB
AB
AB
AB
AB
CITATION(S)
41325408
41300501
00041883
41325409
DATA GAP
00037922 (00069540, 00075774;
82-2 21-Day Dermal - Rabbit/Rat
82-7 90-Day Neurotoxicity - Rat
83-1A Chronic Feeding Toxicity - Rodent
83-IB Chronic Feeding Toxicity - Non-Rodent
83-2A Oncogenicity - Rat
83-2B Oncogenicity - Mouse
83-3A Developmental Toxicity - Rat
83-3B Developmental Toxicity - Rabbit
83-4 2-Generation Reproduction - Rat
84-2A Gene Mutation (Ames Test)
84-2B Structural Chromosomal Aberration
84-4 Other Genotoxic Effects
85-1 General Metabolism
AB
AB
AB
AB
AB
AB
AB
AB
AB
AB
AB
AB
AB
duplicates)
41325410
DATA GAP
00036710
42800401
00036710
42800402
41521203
00144521
00037924 (00030578; duplicate)
41325411
41415303
41415304
41844501
51
-------
Data Supporting Guideline Requirements for the Reregistration of Difenzoquat
REQUIREMENT
USE
PATTERN
CITATION(S)
ENVIRONMENTAL FATE
161-1
161-2
161-3
162-1
162-2
163-1
164-1
165-1
201-1
202-1
RESIDUE
171-4A
171-4B
Hydrolysis
Photodegradation - Water
Photodegradation - Soil
Aerobic Soil Metabolism
Anaerobic Soil Metabolism
Leaching/Adsorption/Desorption
Terrestrial Field Dissipation
Confined Rotational Crop
Droplet Size Spectrum
Drift Field Evaluation
CHEMISTRY
Nature of Residue - Plants
Nature of Residue - Livestock
AB
AB
AB
AB
AB
AB
AB
AB
AB
AB
41325403
41325404
41325405
41903701
41903702
41703401
00045626, 00045627, 00045628
00045629, 00045631, 00045632
41903703, 42327501, (DATA GAP)
42811001 (DATA GAP)
DATA GAP
DATA GAP
00037957, 00037958, 00042200
00110347, 41634802, 41634803
171-4C Residue Analytical Method - Plants
171-4D Residue Analytical Method - Animal
42141601, 42141602
00004614, 00004630, 41521202
41921101, 41921102
00037959,
00052481,
00038488, 00052480
41521201, 41521202
41634802, 41634803
52
-------
Data Supporting Guideline Requirements for the Reregistration of Difenzoquat
REQUIREMENT
USE
PATTERN
CITATION(S)
171-4E
171-4J
171-4K
171-4L
Storage Stability
Magnitude of Residues - Meat/Milk/Poultry/Egg
Crop Field Trials
- Barley
- Wheat
Processed Food
- Barley
- Wheat
41634801, 42323201
00037959, 00052481
00004610, 00004611, 00004612
00004613, 00005567, 00052478
00060117, 00060118, 00108772
00110331, 00110349, 00110355
00004637,
00004648,
00004654,
00004657,
00004660,
00004641,
00004652,
00004655,
00004658,
00060111,
00004647
00004653
00004656
00004659
00110347
00110349
41895301, 42243500
41895301, 42243500
53
-------
54
-------
APPENDIX C. Citations Considered to
be Part of the Data Base Supporting the
Reregistration of Difenzoquat
55
-------
56
-------
GUIDE TO APPENDIX C
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.
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
(19??), the Agency was unable to determine or estimate the date of the document.
57
-------
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.
58
-------
BIBLIOGRAPHY
MRID
CITATION
00004610 Feeny, R.W.; Higham, J.W.; Snyder, E.H.; Colbert, D.R.; Agamalian, H.
(1975) Avenge (CL 84,777): Determination of CL 84,777 (1,2-Dimethyl
pyrazolium methyl sulfate) and Bromoxynil (3,5Dibromo-4-
hydroxylbenzonitrile) Residues in Barley Straw and Grain Following Ground
Application (California): Report No. C592. (Unpublished study received Jan 8,
1975 under 241-EX-64; prepared in cooperation with Lake Ontario
Environmental Laboratory, submitted by American Cyanamid Co., Princeton,
N.J.; CDL: 224170-R)
00004611 Higham, J.W.; Feeny, R.W.; Snyder, E.H; Kushnak, G.; O'Hare, T.R. (1975)
Avenge (CL 84,777): Determination of CL 84,777 (1, 2-Dimethyl-3,5-diphenyl
pyrazolium methyl sulfate), Bromoxynil (3,5-Dibromo-4-hydroxylbenzonitrile)
and MCPA (2-Methyl-4 chlorophenoxyacetic acid) Residues in Barley Grain and
Straw Following Ground Application of Avenge Alone and in Combination with
MCPA, Bromoxynil, 2,4-D and Bromoxynil plus MCPA: Montana: Report No.
C-593. (Unpublished study received Jan 8, 1975 under 241-EX-64; prepared in
cooperation with Montana State Univ. and Lake Ontario Environmental
Laboratory, submitted by American Cyanamid Co., Princeton, N.J.;
CDL:224170-S)
00004612 Higham, J.W.; Feeny, R.W.; Poeppel, M.O.; O'Hare, T.R. (1975) Avenge (CL
84,777): Determination of CL 84,777 (l,2-Dimethyl-3,5-diphenyl pyrazolium
methyl sulfate) and Bromoxynil (3,5-Dibromo-4- hydroxybenzonitrile) Residues
in Barley Straw and Grain Following Ground Application (North Dakota):
Report No. C-595. (Unpublished study received Jan 8, 1975 under 241-EX-64;
prepared in cooperation with Lake Ontario Environmental Laboratory, submitted
by American Cyanamid Co., Princeton, N.J; CDL:224170-U)
00004613 Higham, J.W.; Feeny, R.W; Cheston, K.G.; Snyder, E.H.; Nowatski, R.;
O'Hare, T.R. (1975) Avenge (CL 84,777): Determination of CL 84,777
(l,2-Dimethyl-3,5-diphenyl pyrazolium methyl sulfate), Bromoxynil
(3,5-Dibromo-4-hydroxylbenzonitrile) and MCPA (2-Methyl-4-
chlorophenoxyacetic acid) Residues in Barley Grain and Straw Following Ground
Application of Avenge Alone and in Combination with MCPA, Bromoxynil or
2,4-D (North Dakota): Report No. C-596. (Unpublished study received Jan 8,
1975 under 241-EX-64; prepared in cooperation with Lake Ontario
Environmental Laboratory, submitted by American Cyanamid Co., Princeton,
N.J.; CDL:224170-V)
59
-------
BIBLIOGRAPHY
MRID
CITATION
00004614 Higham, J.W.; Steller, W.A. (1974) Avenge (CL 84,777): The Gas
Chromatographic Determination of (l,2-Dimethyl-3,5-diphenyl pyrazolium
methyl sulfate) in Fortified Barley Foliage, Grain and Straw: Report No. C-519.
Includes method M-411 dated Apr 26, 1973. (Unpublished study received Jan 8,
1975 under 241-EX-64; submitted by American Cyanamid Co., Princeton, N.J.;
CDL: 224170-W)
00004630 Higham, J.W.; Manuel, A.J.; Snyder, E.H. (1974) Avenge (CL 84,777): The
Gas Chromatographic Determination of (l,2-Dimethyl-3,5-diphenyl pyrazolium
methyl sulfate) in Fortified Wheat Foliage, Grain, and Straw: Report No.
C-537. Includes method M-411 dated Apr 26, 1973. (Unpublished study
received Nov 14, 1975 under 6F1703; submitted by American Cyanamid Co.,
Princeton, N.J.; CDL:094738-B)
00004637 Elenewski, C.A.; Wang, T. (1975) Avenge (CL 84,777): Determination of CL
84,777 (l,2-Dimethyl-3,3,5-diphenyl-lH-pyrazolium methyl sulfate) Residues in
Wheat Grain and Straw Following Ground Application (California, 1975):
Report No. C-842. (Unpublished study received Nov 14, 1975 under 6F1703;
submitted by American Cyanamid Co., Princeton, N.J.; CDL:094738-K)
00004641 Elenewski, C.A.; Wang, T. (1975) Avenge (CL 84,777): Determination of CL
84,777 (l,2-Dimethyl-3,5-diphenyl-lH-pyrazolium methyl sulfate) Residues in
Wheat Grain and Straw Following Ground Application (Oklahoma, 1975):
Report No. C-794. (Unpublished study received Nov 14, 1975 under 6F1703;
submitted by American Cyanamid Co., Princeton, N.J.; CDL:094738-0)
00004647 Elenewski, C.A.; Wang, T. (1975) Avenge (CL 84,777): Determination of CL
84,777 (l,2-Dimethyl-3,5-diphenyl-lH-pyrazolium methyl sulfate) Residues in
Wheat Grain and Straw Following Ground Application (Texas, 1975): Report
No. C-840. (Unpublished study received Nov 14, 1975 under 6F1703; submitted
by American Cyanamid Co., Princeton, N.J.; CDL:094738-U)
00004648 Elenewski, C.A.; Wang, T. (1975) Avenge (CL 84,777): Determination of CL
84,777 (l,2-Dimethyl-3,5-diphenyl-lH-pyrazolium methyl sulfate) Residues in
Wheat Grain and Straw Following Ground Application (Texas, 1975): Report
No. C-841. (Unpublished study received Nov 14, 1975 under 6F1703; submitted
by American Cyanamid Co., Princeton, N.J.; CDL:094738-V)
60
-------
BIBLIOGRAPHY
MRID
CITATION
00004652 Elenewski, C.A.; Wang, T. (1975) Avenge (CL 84,777): Determination of CL
84-777 (l,2-Dimethyl-3,5-diphenyl-lH-pyrazolium methyl sulfate) and
Bromoxynil (3,5-Dibromo-4-hydroxylbenzonitrile) Residues in Wheat Grain and
Straw Following Aerial Application of Avenge Alone and in Combination with
Bromoxynil, (Arizona): Report No. C-808. (Unpublished study received Nov
14, 1975 under 6F1703; prepared in cooperation with Biodynamics, Inc.,
submitted by American Cyanamid Co., Princeton, N.J.; CDL: 094738-AA)
00004653 Elenewski, C.A.; Wang, T. (1975) Avenge (CL 84,777): Determination of CL
84,777 (l,2-Dimethyl-3,5-diphenyl-lH-pyrazolium methyl sulfate) and
Bromoxynil (3,5-Dibromo-4-hydroxylbenzonitrile) Residues in Wheat Grain and
Straw Following Ground Application of Avenge Alone and in Combination with
Bromoxynil, (California): Report No. C-807. (Unpublished study received Nov
14, 1975 under 6F1703; prepared in cooperation with Biodynamics, Inc.,
submitted by American Cyanamid Co., Princeton, N.J.; CDL:094738-AB)
00004654 Elenewski, C.A.; Wang, T. (1975) Avenge (CL 84,777): Determination of CL
84,777 (l,2-Dimethyl-3,5-diphenyl-lH-pyrazolium methyl sulfate) and
Bromoxynil (3,5-Dibromo-4-hydroxylbenzonitrile) Residues in Wheat Grain and
Straw Following Aerial Application of Avenge Alone and in Combination with
Bromoxynil, (California): Report No. C-814. (Unpublished study received Nov
14, 1975 under 6F1703; prepared in cooperation with Biodynamics, Inc.,
submitted by American Cyanamid Co., Princeton, N.J.; CDL:094738-AC)
00004655 Elenewski, C.A.; Wang, T. (1975) Avenge (CL 84,777): Determination of CL
84,777 (l,2-Dimethyl-3,5-diphenyl-lH-pyrazolium methyl sulfate), Bromoxynil
(3,5-Dibromo-4-hydroxylbenzonitrile) and MCPA (2-Methyl-4-
chlorophenoxyacetic acid) Residues in Durum Wheat Grain and Straw Following
Aerial Application of Avenge Alone and in Combination with MCPA or
Bromoxynil, (Minnesota): Report No. C-823. (Unpublished study received Nov
14, 1975 under 6F1703; prepared in cooperation with Biodynamics, Inc.,
submitted by American Cyanamid Co., Princeton, N.J.; CDL:094738-AD)
61
-------
BIBLIOGRAPHY
MRID
CITATION
00004656 Elenewski, C.A.; Wang, T. (1975) Avenge (CL 84,777): Determination of CL
84,777 (l,2-Dimethyl-3,5-diphenyl-lH-pyrazolium methyl sulfate) and
Bromoxynil (3,5-Dibromo-4-hydroxylbenzonitrile) Residues in Wheat Grain and
Straw Following Ground Application of Avenge Alone and in Combination with
Bromoxynil, (Montana): Report No. C-812. (Unpublished study received Nov
14, 1975 under 6F1703; prepared in cooperation with Biodynamics, Inc.,
submitted by American Cyanamid Co., Princeton, N.J.; CDL: 094738-AE)
00004657 Elenewski, C.A.; Wang, T. (1975) Avenge (CL 84,777): Determination of CL
84,777 (l,2-Dimethyl-3,5-diphenyl-lH-pyrazolium methyl sulfate) and
Bromoxynil (3,5-Dibromo-4-hydroxylbenzonitrile) Residues in Wheat Grain and
Straw Following Aerial Applications of Avenge Alone and in Combination with
Bromoxynil, (Montana): Report No. C-813. (Unpublished study received Nov
14, 1975 under 6F1703; prepared in cooperation with Biodynamics, Inc.,
submitted by American Cyanamid Co., Princeton, N.J.; CDL:094738-AF)
00004658 Elenewski, C.A.; Wang, T. (1975) Avenge (CL 84,777): Determination of CL
84,777 (l,2-Dimethyl-3,5-diphenyl-lH-pyrazolium methyl sulfate) and
Bromoxynil (3,5-Dibromo-4-hydroxylbenzonitrile) Residues in Wheat Grain and
Straw Following Ground Application of Avenge Alone and in Combination with
Bromoxynil, (Oregon): Report No. C-806. (Unpublished study received Nov 14,
1975 under 6F1703; prepared in cooperation with Biodynamics, Inc., submitted
by American Cyanamid Co., Princeton, N.J.; CDL: 094738-AG)
00004659 Elenewski, C.A.; Wang, T. (1975) Avenge (CL 84,777): Determination of CL
84,777 (l,2-Dimethyl-3,5-diphenyl-lH-pyrazolium methyl sulfate), Bromoxynil
(3,5-Dibromo-4-hydroxylbenzonitrile) and MCPA (2-Methyl-4-
chlorophenoxyacetic acid) Residues in Wheat Grain and Straw Following Ground
Application of Avenge Alone and in combination with MCPA or Bromoxynil,
(Oregon): Report No. C820. (Unpublished study received Nov 14, 1975 under
6F1703; prepared in cooperation with Biodynamics, Inc., submitted by American
Cyanamid Co., Princeton, N.J.; CDL:094738-AH)
00004660 Feeny, R.W.; Poeppel, M.O. (1974) Avenge (CL 84,777): Determination of CL
84,777 (l,2-Dimethyl-3,5-diphenyl-lH-pyrazolium methyl sulfate) Residues in
Wheat Grain and Straw Following Ground Application, (Washington): Report
No. C-780. (Unpublished study received Nov 14, 1975 under 6F1703; submitted
by American Cyanamid Co., Princeton, N.J.; CDL:094738-AI)
62
-------
BIBLIOGRAPHY
MRID
CITATION
00005567 Higham, J.W.; Feeny, R.W.; Cheston, K.G.; Snyder, E.H.; Wingfield, C.B.
(1975) Avenge (AC 84,777): Determination of CL 84, 777
(l,2-Dimethyl-3,5-diphenyl pyrazolium methyl sulfate), Bromoxynil
(3,5-Dibromo-4-hydroxylbenzonitrile) and MCPA (2-Methyl-4-
chlorophenoxyacetic acid) Residues in Barley Grain and Straw Following Ground
Application (Colorado): Report No. C-594. (Unpublished study received Jan 8,
1975 under 241-EX-64; prepared in cooperation with Lake Ontario
Environmental Laboratory, submitted by American Cyanamid Co., Princeton,
N.J.; CDL:224170-T)
00030578 Reno, F.E. (1974) Three-Generation Reproduction Study in Rats: AC 84,777.
Final rept. (Unpublished study received on unknown date under 4G1453;
prepared by Hazleton Laboratories, Inc., submitted by American Cyanamid Co.,
Princeton, N.J.; CDL:094933-F)
00036710 Bailey, D.E.; Gallo, M.A.; Cox, G.E. (1975) Final Report: Chronic Oral
Toxicity Study in Rats with AC 84,777: Laboratory No. 1626. (Unpublished
study received Nov 14, 1975 under 6F1703; prepared by Food and Drug
Research Laboratories, Inc., submitted by American Cyanamid Co., Princeton,
N.J.; CDL:094731-A)
00037922 Cox, G.E.; Bailey, D.E.; Morgareidge, K.; et al. (1973) Report: 90Day Feeding
Study in Dogs with AC 84777: Laboratory No. 1680. (Unpublished study
received Nov 14, 1975 under 6F1703; prepared by Food and Drug Research
Laboratories, Inc. and Consultants in Ophthalmology, submitted by American
Cyanamid Co., Princeton, N.J.; CDL:094732-A)
00037924 Reno, F.E. (1974) Final Report: Three-Generation Reproduction Study in Rats:
Project No. 362-147. (Unpublished study received Nov 14, 1975 under 6F1703;
prepared by Hazleton Laboratories, Inc., submitted by American Cyanamid Co.,
Princeton, N.J.; CDL: 094732-C)
00037926 Sleight, B.H., III. (1973) Acute Toxicity of AC-84777 to Bluegill (Lepomis
macrochirus) and Rainbow Trout (Salmo gairdneri). (Unpublished study
received Nov 14, 1975 under 6F1703; prepared by Bionomics, Inc., submitted
by American Cyanamid Co., Princeton, N.J.; CDL:094732-F)
63
-------
BIBLIOGRAPHY
MRID
CITATION
00037928 Fink, R. (1973) Final Report: Eight-Day Dietary LC50-Mallard Ducks: Project
No. 362-142. (Unpublished study received Nov 14, 1975 under 6F1703;
prepared by Environmental Sciences Corp., submitted by American Cyanamid
Co., Princeton, N.J.; CDL: 094732-1)
00037957 Cox, G.; Gatterdam, P.; Miller, P.; et al. (1973) Avenge Wild Oat Herbicide:
Persistence and Metabolism of CL-84,777 l,2-Dimethyl-3,5-diphenyl pyrazolium
methyl sulfate in Barley and Wheat: PD-M 10. Final rept. (Unpublished study
received Nov 14, 1975 under 6F1703; submitted by American Cyanamid Co.,
Princeton, N.J.; CDL:094733-Q)
00037958 Gatterdam, P.; Jenney, K.; Patterson, M. (1975) Avenge Difenzoquat: Fate on
Barley under Field Conditions (Fort Collins, Colorado): PD-M 10.
(Unpublished study received Nov 14, 1975 under 6F1703; submitted by
American Cyanamid Co., Princeton, N.J.; CDL:094733-R)
00037959 Berger, H.; Colavita, J.H.; Kim, O.K.; et al. (1974) Plant Industry Toxicology:
Egg and Tissue Residue Study in Chickens Treated with Avenge Herbicide: FD
22. Includes method M-504 dated Apr 10, 1974. (Unpublished study including
report no. C-447, received Nov 14, 1975 under 6F1703; submitted by American
Cyanamid Co., Princeton, N.J.; CDL:094733-S)
00038488 Steller, W.A.; Snyder, E.H. (1973) Avenge: GLC Determination of Avenge (CL
84,777) Residues in Cattle Tissues (Kidney, Liver, Muscle and Fat): Report No.
C-388. Includes method M-457 dated Sep 24, 1973. (Unpublished study
received Nov 14, 1975 under 6F1703; submitted by American Cyanamid Co.,
Princeton, N.J.; CDL:094733-N)
00041883 American Cyanamid Company (1973) Toxicity Data: Avenge Herbicide,
Technical: Report A-73-38. (Unpublished study received Nov 25, 1974 under
5G1576; CDL:094325-B)
00042200 Barren, F.R. (1976) Letter sent to Richard F. Mountfort dated Jun 3, 1976:
Avenge wild oat herbicide. (Unpublished study received Nov 14, 1975 under
6F1703; submitted by American Cyanamid Co., Princeton, N.J.;
CDL:094752-A)
64
-------
BIBLIOGRAPHY
MRID
CITATION
00045626 Kim, D.K.; Wang, T.; Higham, J.; et al. (1975) Avenge: Determination of CL
84,777 (l,2-Dimethyl-3,5-Diphenyl-lH-pyrazolium methyl sulfate) Residues in
Soil: California: Report No. C-838. (Unpublished study received Nov 14, 1975
under 6F1703; submitted by American Cyanamid Co., Princeton, N.J.;
CDL:094739-C)
00045627 Kim, D.K.; Weis, M.E.; Van Scoik, W.S. (1974) Avenge: The Gas
Chromatograph Determination of (l,2-Dimethyl-3,5-diphenyl pyrazolium methyl
sulfate) Residues in Soil (Undisturbed Soil Plot—Minnesota): Report No. C-560.
(Unpublished study received Nov 14, 1975 under 6F1703; prepared in
cooperation with Univ. of Minnesota, Agronomy Dept., Northwest Experiment
Station, submitted by American Cyanamid Co., Princeton, N.J.;
CDL:094739-D)
00045628 Kim, O.K.; Feeny, R.W.; Weis, M.E.; et al. (1974) Avenge: Determination of
CL 84,777 (l,2-Dimethyl-3,5-diphenyl pyrazolium methyl sulfate) Residues in
Soil: (Minnesota): Report No. C-561. (Unpublished study received Nov 14, 1975
under 6F1703; prepared in cooperation with Univ. of Minnesota, Agronomy
Dept., Northwest Experiment Station, submitted by American Cyanamid Co.,
Princeton, N.J.; CDL:094739-E)
00045629 Kim, O.K.; O'Hare, T.R.; Van Scoik, W.S. (1974) Avenge: Determination of
CL 84,777 (l,2-Dimethyl-3,5-diphenyl pyrazolium methyl sulfate) Residues in
Soil (Montana): Report No. C-558. (Unpublished study received Nov 14, 1975
under 6F1703; prepared in cooperation with Montana State Univ., Experiment
Station, submitted by American Cyanamid Co., Princeton, N.J.; CDL:
094739-F)
00045631 Kim, O.K.; Amen, C.R.; Jensen, A.O.; et al. (1974) Avenge: Determination of
CL 84,777 (l,2-Dimethyl-3,5-diphenyl pyrazolium methyl sulfate) Residues in
Soil: Oregon: Report No. C-557. (Unpublished study received Nov 14, 1975
under 6F1703; prepared in cooperation with Oregon State Univ., Crop Science
Dept., submitted by American Cyanamid Co., Princeton, N.J.; CDL:
(094739-H)
65
-------
BIBLIOGRAPHY
MRID
CITATION
00045632 Kim, D.K.; O'Hare, T.R.; Van Scoik, W.S.; et al. (1974) Avenge:
Determination of CL 84,777 (l,2-Dimethyl-3,5-diphenyl pyrazolium methyl
sulfate): Residues in Soil: (South Dakota): Report No. C-559. (Unpublished
study received Nov 14, 1975 under 6F1703; prepared in cooperation with South
Dakota State Univ., submitted by American Cyanamid Co., Princeton, N.J.;
CDL:094739-I)
00052458 Fink, R. (1973) Final Report: Eight-Day Dietary LC50-Bobwhite Quail: Project
No. 362-141. (Unpublished study received Nov 14, 1975 under 6F1703;
prepared by Environmental Sciences Corp., submitted by American Cyanamid
Co., Princeton, N.J.; CDL: 094732-J)
00052478 Poeppel, M.O.; Wang, T.; O'Hare, T.R.; et al. (1975) Residues of Various
Chemicals in Barley Grain and Straw: Report No. C-722. (Unpublished study
including report nos. C-783, C-784, C-839..., received Nov 14, 1975 under
6F1703; prepared in cooperation with Lake Ontario Environmental Laboratory
and others, submitted by American Cyanamid Co., Princeton, N.J.;
CDL:094737-A)
00052480 Kim, ?; Steller, ? (1974) GLC Determination of CL 84,777 Residues in Chicken
Tissues (Kidney, Liver, Muscle, Skin and Eggs). Method M-504 dated Apr 10,
1974. (Unpublished study received Nov 14, 1975 under 6F1703; submitted by
American Cyanamid Co., Princeton, N.J.; CDL:094737-C)
00052481 Kim, D.; Cheston, K. (1975) Avenge Wild Oat Herbicide: Residues in Cattle
Tissues (Muscle, Liver, Kidney and Fat): Report No. C-777. (Unpublished
study received Nov 14, 1975 under 6F1703; submitted by American Cyanamid
Co., Princeton, N.J.; CDL:094737-D)
00057909 LeBlanc, G.A. (1976) Acute Toxicity of Avenge to Daphnia magna.
(Unpublished study received Jun 29, 1976 under 241-250; prepared by EG&G,
Bionomics, submitted by American Cyanamid Co., Princeton, N.J.;
CDL:224778-B)
00058830 Fink, R. (1976) Final Report: Acute Oral LD50-Mallard Duck: Project No.
130-111. (Unpublished study received Jun 29, 1976 under 241-250; prepared by
Truslow Farms, Inc., submitted by American Cyanamid Co., Princeton, N.J.;
CDL:224778-C)
66
-------
BIBLIOGRAPHY
MRID
CITATION
00060111 American Cyanamid Company (1977) General Summary: Avenge in Wheat
Grain and Straw*. (Compilation; unpublished study received Apr 26, 1977
under 241-250; CDL:229617-A)
00060117 American Cyanamid Company (1975) General Summary: Studies to Determine
Avenge and 2,4-D Residues in Barley Grain and Straw. (Compilation;
unpublished study received Apr 26, 1977 under 241250; CDL:229616-A)
00060118 American Cyanamid Company (1975) Avenge Residue—Barley. (Unpublished
study received Apr 26, 1977 under 241-250; CDL: 229616-B)
00069540 Cox, G.E.; Bailey, D.E.; Morgareidge, K. (1973) Report: 90-day Feeding Study
in Dogs with AC 84777: Laboratory No. 1680. (Unpublished study received on
unknown date under 241-EX-70; prepared by Food and Drug Research
Laboratories, Inc., submitted by American Cyanamid Co., Princeton, N.J.;
CDL:223486-A)
00075774 Cox, G.E.; Bailey, D.E.; Morgareidge, K. (1973) 90-day Feeding Study in Dogs
with AC 84777: Laboratory No. 1680. (Unpublished study received on unknown
date under unknown admin, no.; prepared by Food and Drug Research
Laboratories, Inc., submitted by American Cyanamid Co., Princeton, N.J.;
CDL:122845-A)
00108772 American Cyanamid Co. (1975) Analyses for Residues of Avenge in Soil, Crops
and Animals. (Compilation; unpublished study received Nov 14, 1975 under
6F1703; CDL:094735-A)
00110331 American Cyanamid Co. (1974) The Results of Tests on the Amount of Residue
Remaining in Barley Plant, Straw, Grain, Milk, Tissues and Soil Including a
Description of Analytical Methods Used. (Compilation; unpublished study
received on unknown date under 4G1453; CDL:093871-A)
00110347 American Cyanamid Co. (1974) Residues of Avenge in Wheat, Soil, and Various
Crops. (Compilation; unpublished study received Nov 25, 1974 under 5G1576;
CDL:094322-A; 094321)
00110349 American Cyanamid Co. (1974) Environmental Study: Avenge Herbicide.
(Compilation; unpublished study received Nov 25, 1974 under 5G1576;
CDL:094326-B)
67
-------
BIBLIOGRAPHY
MRID
CITATION
00110355 American Cyanamid Co. (1975) Avenge Residue—Barley. (Compilation;
unpublished study received Nov 14, 1975 under 6F1703; CDL: 094736-A)
00144521 Mackenzie, K. (1984) A Teratology Study with AC 84,777 in Rabbits: Final
Report: Study No. 6123-114. Unpublished study prepared by Hazleton
Laboratories America, Inc. 61 p.
41300501 Fischer, J. (1989) Eye Irritation Study in Albino Rabbits with AC 84,777
(Avenge): Toxicology Report No. A88-128; Study T-0118. Unpublished study
prepared by American Cyanamid Co., Toxicology Dept. 12 p.
41300502 Fischer, J. (1989) Oral LD50 Study in Albino Rats with AC 84,777: Toxicology
Report Number A89-195; Study T-0180. Unpublished study prepared by
American Cyanamid Co., Toxicology Dept. 14 p.
41325401 Luckhowec, J.; Long, D. (1989) Product Identity and Composition of Avenge
Herbicide Technical. Unpublished study prepared by American Cyanamid Co.
158 p.
41325402 Teeter, D. (1989) Physical and Chemical Characteristics of Avenge Herbicide
Technical. Unpublished study prepared by American Cyanamid Co. 253 p.
41325403 Mangels, G. (1989) Difenzoquat (AC 84,777): Hydrolysis: Lab Project
Number: E/89/3. Unpublished study prepared by American Cyanamid Co. 253
P-
41325404 Mangels, G. (1989) Difenzoquat (AC 84,777): Photodegradation in Water: Lab
Project Number: E/89/6. Unpublished study prepared by American Cyanamid
Co. 19 p.
41325405 Mangels, G. (1989) Difenzoquat (CL 84,777): Photolysis on Soil: Lab Project
Number: E/89/24. Unpublished study prepared by American Cyanamid Co. 34
P-
41325406 Fischer, J. (1989) Oral LD50 Study in Albino Rats with AC 84,777: Lab Project
Number: A89/195: T/0180. Unpublished study prepared by American Cyanamid
Co. 14 p.
68
-------
BIBLIOGRAPHY
MRID
CITATION
41325407 Fischer, J. (1989) Dermal LD50 Study in the Albino Rabbit with AC 84,777:
Lab Project Number: T/0178. Unpublished study prepared by American
Cyanamid Co. 12 p.
41325408 Hershman, R. (1989) AC 84,777 Lot Number: AC 6027-188: Acute Inhalation
Toxicity, LD50, 4 Hour Exposure-Rats: Lab Project Number: 89/6760A.
Unpublished study prepared by Biosearch, Inc. 128 p.
41325409 Bielucke, J. (1989) Dermal Sensitization Study with AC 84,777 Lot Number: AC
6027-118 in Guinea Pigs: Lab Project Number: 89/6761A. Unpublished study
prepared by Biosearch, Inc. 30 p.
41325410 Moore, G. (1989) AC 84,777 Lot # AC 6027-118: Twenty-one Day Dermal
Toxicity Study—Rabbits: Lab Project Number: 89/6762A. Unpublished study
prepared by Biosearch, Inc. 170 p.
41325411 Johnson, E. (1989) Mutagenicity Testing of AC 84,777 in the in vitro
CHO/HGPRT Mutation Assay: Lab Project Number: 0488. Unpublished study
prepared by American Cyanamid Co. 42 p.
41521201 Chukwudebe, A. (1990) Difenzoquat Methyl Sulfate (CL 84,777): validation of
GC Method SOP M-504, at the 0.05 PPM Level, for the determination of CL
84,777 Residues in Chicken Tissue (Muscle, Kidney, Liver, Fat, and Skin): Lab
Report No.: C.3331. Unpublished study prepared by American Cyanamid Co.,
Agricultural Research Div. 41 p.
41521202 Gross, J. (1990) Difenzoquat (CL 84,777): Characteristics of Difenzoquat (CL
84,777) through FDA Multi-residue Methods: Lab Report No.: C-3399.
Unpublished study prepared by American Cyanamid Co., Agricultural Research
Div. 24 p.
41521203 Lochry, E. (1990) An Oral Developmental Toxicity (Embryo-fetal
Toxicity/Teratogenicity) Study with AC 84,777 in Rats: Argus Reseach
Laboratories Protocol: 101-008. Unpublished study prepared by Argus Research
Laboratories, Inc. 279 p.
41593501 Luckhowec, J. (1990) Storage Stability and Corrosion Characteristics:
Difenzoquat: Lab Project Number: P-34. Unpublished study prepared by
American Cyanamid Co. 21 p.
69
-------
BIBLIOGRAPHY
MRID
CITATION
41634801 Chukwudebe, A. (1990) Difenzoquat Methyl Sulfate CL 84,777: Storage
Stability of Residue of CL 84,777 in Wheat Grain and Straw at the 6-Month
Interval: Lab Project Number: C/3453. Unpublished study prepared by
American Cyanamid Company. 50 p.
41634802 Mallipudi, N.; Robinson, R.; Chukwudebe, A. (1990) Difenzoquat Methyl
Sulfate CL 84,777: Metabolic Fate of Carbon-14 CL 84,777 in Tissues and Eggs
of the Laying Hen: Lab Project Number: RPT/0039. Unpublished study
prepared by Xenobiotic Laboratories, Inc. 205 p.
41634803 Mallipudi, N.; Robinson, R.; Chukwudebe, A. (1990) Difenzoquat Methyl
Sulfate CL 84,777: Metabolic Fate of Carbon-14 CL 84,777 Blood, Milk, and
Edible Tissue of Lactating Goats: Lab Project Number: RPT/0040. Unpublished
study prepared by Xenobiotic Laboratories, Inc. 166 p.
41703401 Mangels, G. (1987) Difenzoquat (AC 84,777): Adsorption/Desorption on Soil:
Lab Project Number: PD-M 24-1. Unpublished study prepared by American
Cyanamid Co. 76 p.
41895301 Kleiner, A. (1991) CL 84,777 (Difenzoquat/2ASU): Residues of Total CL
84,777 in Processed Wheat (Post;ND; 1990): Lab Project Number: C-3617:
C-3588. Unpublished study prepared by American Cyanamid Co. 118 p.
41903701 Mangels, G. (1988) Difenzoquat (AC 84,777): Aerobic Soil Metabolism : Lab
Project Number: PD-M 25-58. Unpublished study prepared by American
Cyanamid Co. 41 p.
41903702 Mangels, G. (1988) Difenzoquat (AC 84,777): Anaerobic Soil Metabolism: Lab
Project Number: PD-M 25-50. Unpublished study prepared by American
Cyanamid Co. 23 p.
41903703 Chukwudebe, A. (1991) Difenzoquat Methyl Sulfate (CL 84,777): Freezer
Stability of Residues of CL 84,777 in Soil at the 12-month Interval: Lab Project
Number: C-3528. Unpublished study prepared by American Cyanamid Co. 26
P-
70
-------
BIBLIOGRAPHY
MRID
CITATION
41921101 Gross, J. (1991) Avenge: Validation of GC Method M-1417 for the
Determination of CL 84,777 Residues in Wheat Grain and Processed Wheat
Fractions (Bran, Flour, Middlings, Shorts and Germ and Grain Dust): Lab
Project Number: C-3618. Unpublished study prepared by American Cyanamid
Company. 37 p.
41921102 Peterson, R. (1984) Avenge Difenzoquat Methyl Sulfate: Validation of GC
Method M-1417 for the Determination of CL 84,777 Residues in Wheat and
Barley Grain: Lab Project Number: C-2395. Unpublished study prepared by
American Cyanamid Company. 15 p.
42141601 Mallipudi, N.; Zdybak, J. (1991) Carbon 14-Difenzoquat (CL 84,777): Isolation
and Identification of Metabolites of Goat Liver and Kidney: Lab Project Number:
RPT 0071. Unpublished study prepared by XenoBiotic Labs., Inc. 69 p.
42243500 American Cyanamid Co. (1992) Submission of Proposed Food/Feed Additive
Tolerances for Difenzoquat: Product Chemistry Study. Transmittal of 1 study.
42243501 Banick, W. (1988) Avenge Technical (CL 84,777) Dissociation Constant: Lab
Project Number: APBR 135. Unpublished study prepared by American
Cyanamid Co. 7 p.
42323201 Gross, J. (1992) Difenzoquat Methyl Sulfate (CL 84,777): Freezer Stability of
Residues of CL 84,777 in Wheat Grain and Straw after Twenty-Four (24)
Months: Lab Project Number: C-3783: C-3782. Unpublished study prepared by
American Cyanamid Co. 41 p.
42800401 Kelly, C. (1993) One-Year Oral Toxicity Study in Purebred Beagle Dogs with
AC 84,777 via Capsule Administration: Avenge Technical Herbicide: Lab
Project Number: 90-3640: 971-90-180. Unpublished study prepared by
Bio/dynamics, Inc. 850 p.
42800402 MacKenzie, K. (1989) Chronic Dietary Toxicity and Oncogenicity Study with
AC 84,777 in Mice: Final Report: Lab Project Number: 6123-145: C-3121:
C-3240. Unpublished study prepared by Hazleton Labs. America, Inc. 1366 p.
71
-------
BIBLIOGRAPHY
MRID CITATION
42811001 Zdybak, J.; Robinson, R. (1993) Confined Rotational Crop Study with (carbon
14)-Difenzoquat (CL 84,777): Analysis of Soil and Plant Samples: Lab Project
Number: 90071: RPT0091: EF-90-327. Unpublished study prepared by
XenBiotic Labs, Inc. 379 p.
72
-------
APPENDIX D. List of Available
Related Documents
73
-------
74
-------
The following is a list of available documents related to Difenzoquat. It's purpose is to
provide a path to more detailed information if it is needed. These accompanying documents are
part of the Administrative Record for Difenzoquat and are included in the EPA's Office of
Pesticide Programs Public Docket.
1. Health and Environmental Effects Science Chapters
2. Detailed Label Usage Information System (LUIS) Report
3. Difenzoquat RED Fact Sheet
4. PR Notice 86-5 (included in this appendix)
5. PR Notice 91-2 (included in this appendix) pertains to the Label Ingredient
Statement
75
-------
76
-------
APPENDIX E. PR Notices 86-5 and 91-2
77
-------
78
-------
PR Notice 86-5
79
-------
80
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
pno WASHINGTON, D.C. 20460
July 29, 1986
OFFICE OF
PR NOTICE 86-5 PREVENTION, PESTICIDES
AND TOXIC SUBSTANCES
NOTICE TO PRODUCERS, FORMULATORS, DISTRIBUTORS
AND REGISTRANTS
Attention: Pers9ns responsible for Federal registration of
pesticides.
Subject: Standard format for data submitted under the
Federal Insecticide, Fungicide, and Rodenticide Act
(FIFRA) and certain provisions of the Federal Food,
Drug, and Cosmetic Act (FFDCA).
I. Purpose
To require data to be submitted to the Environmental
Protection Agency (EPA) in a standard format. This Notice also
provides additional guidance about, and illustrations of, the
required formats.
II. Applicability
This PR Notice applies to all data that are submitted to EPA
to satisfy data requirements for granting or maintaining pesticide
registrations, experimental use permits, tolerances, and related
approvals under certain provisions of FIFRA and FFDCA. These data
are defined in FIFRA §10(d)(1). This Notice d9es not apply to
commercial, financial, or production information, which are, and
must continue to be, submitted differently under separate cover.
Ill. Effective Date
This notice is effective on November 1, 1986. Data formatted
according to this notice may be submitted prior to the effective
date. As of the effective date, submitted data packages that do
not conform to these requirements may be returned to the submitter
for necessary revision.
IV. Background
On September 26, 1984, EPA published proposed regulations in
the Federal Register (49 FR 37956) which include Requirements for
Data Submission (40 CFR §158.32), and Procedures for Claims of
Confidentiality of Data (40 CFR §158.33). These regulations
specify the format for data submitted to EPA under Section 3 of
FIFRA and Sections 408 and 409 of FFDCA, and procedures which must
be followed to make and substantiate claims of confidentiality.
No entitlements to data confidentiality are changed, either by the
proposed regulation or by this notice.
OPP is making these requirements mandatory through this
Notice to gain resource-saving benefits from their use before the
entire proposed regulation becomes final. Adequate lead time is
being provided for submitters to comply with the new requirements.
81
-------
V. Relationship of this Notice to Other OPP Policy and Guidance
While this Notice contains requirements for organizing and
formatting submittals of supporting data, it does not address the
substance of test reports themselves. "Data reporting" guidance
is now under development in OPP, and will specify how the study
objectives, protocol, observations, findings, and conclusions are
organized and presented within the study report. The data
reporting guidance will be C9mpatible with submittal format
requirements described in this Notice.
OPP has also promulgated a policy (PR Notice 86-4 dated April
15, 1986) that provides for early screening of certain
applications for registration under FIFRA §3. The objective of
the screen is to avoid the additional C9sts and prolonged delays
associated with handling significantly incomplete application
packages. As of the effective date of this Notice, the screen
will include in its criteria for acceptance of applicati9n
packages the data formatting requirements described herein.
OPP has also established a public docket which imposes
deadlines for inserting int9 the docket documents submitted in
connection with Special Reviews and Registrati9n Standards (see 40
CFR §154.15 and §155.32). To meet these deadlines, OPP is
requiring an additional copy of any data submitted to the docket.
Please refer to Page 10 for more information about this
requirement.
For several years, OPP has required that each application for
registration or other action include a list of all applicable data
requirements and an indication of how each is satisfied--the
statement of the method of support f9r the application.
Typically, many requirements are satisfied by reference to data
previously submitted--either by the applicant or by another party.
That requirement is not altered by this notice, which applies only
to data submitted with an application.
VI. Format Requirements
A more detailed discussion of these format requirements
foll9ws the index on the next page, and samples of some of the
requirements are attached. Except for the language 9f the two
alternative forms of the Statement of Data Confidentiality Claims
(shown in Attachment 3) which cam^t be altered, these samples are
illustrative. As long as the required information is included and
clearly identifiable, the form of the samples may be altered to
reflect the submitter's preference.
- INDEX-
Text Example
Page Page
A. Organization of the Submittal Package 3 17
B. Transmittal Document 4 11
C. Individual Studies 4
C. 1 Special Considerations for Identifying Studies . . 5
D. Organization of each Study Volume 6 17
D. 1 Study Title Page 7 12
D. 2 Statement of Data Confidentiality Claims
(based on FIFRA §10 (d) (1)1 8 13
D. 3 Confidential Attachment 8 15
D. 4 Supplemental Statement of Data Confidentiality
82
-------
Claims (other than those based on FIFRA §10(d)(1)) 8 14
D. 5 Good Laboratory Practice Compliance Statement . . 9 16
E. Reference to Previously Submitted Data 9
F. Physical Format Requirements & Number of Copies .... 9
G. Special Requirements for Submitting Data to the Docket . 10
A. Organization of Submittal Package
A "submittal package" consists of all studies submitted at
the same time for review in support of a single regulat9ry acti9n,
along with a transmittal document and other related administrative
material (e.g. the method of supp9rt statement, EPA Forms 8570-1,
8570-4, 8570-20, etc.) as appropriate.
Data submitters must organize each submittal package as
described in this Notice. The transmittal and any other admin-
istrative material must be grouped together in the first physical
volume. Each study included in the submittal package must then be
bound separately.
Submitters sometimes provide additional materials that are
intended to clarify, emphasize, or otherwise comment to help
Product Managers and reviewers better understand the submittal.
If such materials relate to one study, they should be
included as an appendix to that study.
- If such materials relate to more than one study (as for
example a summary of all studies in a discipline) or to the
submittal in general, they must be included in the submittal
package as a separate study (with title page and statement of
confidentiality claims).
B. Transmittal Document
The first item in each submittal package must be a trans-
mittal document. This document identifies the submitter or all
joint submitters; the regulatory action in support of which the
package is being submitted--i.e., a registration application,
Petition, experimental use permit (EUP), §3 (c) (2) (B)_ data call-in,
6(a)(2) submittal, or a special review; the transmittal date; and
a list of all individual studies included in the package in the
order of their appearance, showing (usually by Guideline reference
number) the data requirement(s) addressed by each one. The
EPA-assigned number for the regulat9ry action (e.g. the
registration, EUP, or tolerance petition number) should be
included in the transmittal document as well, if it is known to
the submitter. See Attachment 1 for an example of an acceptable
transmittal document.
The list of included studies in the transmittal of a data
submittal package supporting a registration application should be
subdivided by discipline, reflecting the order in which data
requirements appear in 40 CFR 158.
The list of included studies in the transmittal of a data
submittal package supporting a petiti9n for tolerance or an
application for an EUP should be subdivided into sections A, B,
C,.... of the petition or application, as defined in 40 CFR 180.7
and 158.125, (petitions) or Pesticide Assessment Guidelines,
Subdivision I (EUPs) as appropriate.
When a submittal package supports a tolerance petition and an
applicati9n for a registration or an EUP, list the petition
studies first, then the balance of the studies. Within these two
groups of studies follow the instructions above.
83
-------
C. Individual Studies
A study is the report of a single scientific investigation,
including all supporting analyses required for logical complete-
ness. A study should be identifiable and distinguishable by a
C9nventional bibliographic citation including author, date, and
title. Studies generally correspond in scope to a single Guide-
line requirement for supporting data, with 39016 exceptions dis-
cussed in section C.I. Each study included in a submittal package
must be bound as a separate entity. (See comments on binding
studies on page 9.)
Each study must be consecutively paginated, beginning from
the title page as page 1. The total number of pages in the com-
plete study must be shown on the study title page. In addition
(to ensure that inadvertently separated pages can be reassociated
with the proper study during handling or review) use either of the
following:
- Include the total number of pages in the complete study on
each page (i.e., 1 of 250, 2 of 250, ...250 of 250).
- Include a company name or mark and study number on each
page of the study, e g , Company Name-1986-23. Never reuse
a study number for marking the pages of subsequent studies.
When a single study is extremely long, binding it in mul-
tiple volumes is permissible so long as the entire study is pag-
inated in a single series, and each volume is plainly identified
by the study title and its position in the multi-volume sequence.
C.1 Special Considerations for Identifying Studies
Some studies raise special problems in study identification,
because they address Guidelines of broader than normal scope or
for other reasons.
a. Safety Studies. Several Guidelines require testing for
safety in more than one species. In these cases each species
tested should be reported as a separate study, and bound
separately.
Extensive supplemental reports of pathology reviews, feed
analyses, historical C9ntrol data, and the like are often assoc-
iated with safety studies. Whenever possible these should be
submitted with primary reports of the study, and bound with the
primary study as appendices. When such supplemental reports are
submitted independently of the primary report, take care to fully
identify the primary report to which they pertain.
Batteries of acute toxicity tests, performed on the same end
use product and covered by a single title page, may be bound
together and reported as a single study.
b. Product Chemistry Studies. All product chemistry data
within a submittal package submitted in support of an end-use
Eroduct produced from registered manufacturing-use products should
e bound as a single study under a single title page.
Product chemistry data submitted in support of a technical
product, other manufacturing-use product, an experimental use
permit, an import t9lerance petiti9n, or an end-use product
produced from unregistered source ingredients, should be bound as
a single study for each Guideline series (61, 62, and 63) for
C9nventional pesticides, or for the equivalent subject range for
biorational pesticides. The first of the three studies in a
complete product chemistry submittal for a biochemical pesticide
would cover Guidelines 151-10, 151-11, and 151-12; the second
would cover Guidelines 151-13, 151-15, and 151-16; the third W9uld
cover Guideline 151-17. The first study for a microbial pesticide
would cover Guidelines 151-20, 151-21, and 151-22; the second
would cover Guidelines 151-23 and 151-25; the third would cover
84
-------
Guideline 151-26.
Note particularly that product chemistry studies are likely
to contain Confidential Business Information as defined in FIFRA
§10(d)(1)(A), (B) , or (C), and if so must be handled as described
in section D.3. of this notice.
c. Residue Chemistry Studies. Guidelines 171-4, 153-3, and
153-4 are extremely broad in scope; studies addressing residue
chemistry requirements must thus be defined at a level below that
of the Guideline code. The general principle, however, of
limiting a study to the report of a single investigation still
applies fully. Data shoula be treated as a single study and bound
separately for each analytical method, each report of the nature
of the residue in a single crop or animal species, and for each
report of the magnitude of residues resulting from treatment of a
single crop or from processing a single crop. When more than one
commodity is derived from a single crop (such as beet tops and
beet roots) residue data on all such C9mmodities should be
reported as a single study. When multiple field trials are
associated with a single crop, all such trials should be reported
as a single study.
D.
Organization of Each Study Volume
Each complete study must include all applicable elements in
the list below, in the order indicated. (Also see Page 17.)
Several of these elements are further explained in the following
paragraphs. Entries in the column headed "example" cite the page
number of this notice where the element is illustrated.
Element
Study Title Page
Statement of Data
Confidentiality
Claims
Certification of Good
Laboratory Practice
Flagging statements
Body of Study
Study Appendices
Cover Sheet to Confi-
dential Attachment
When Required Example
Always Page 12
One of the two alternative Page 13
forms of this statement
is always required
If study reports Iaborat9ry Page 16
work subject to GLP require-
ments
For certain t9xicology studies (When
flagging requirements are finalized.)
Always - with an English language
translation if required.
At submitter's option
If CBI is claimed under FIFRA
§10 (d) (1) (A) , (B) , or (C)
CBI Attachment
Supplemental Statement
of Data Confidentiality
Claims
If CBI is claimed under FIFRA
§10 (d) (1) (A) , (B) , or (C) Page 15
Only if confidentiality is Page 14
claimed on a basis other than
FIFRA §10(d)(1)(A), (B), or (C)
D.I. Title Page
A title page is always required for each submitted study,
published or unpublished. The title page must always be freely
85
-------
releasable to requestors; DO NOT INCLUDE CBI ON THE TITLE PAGE.
An example of an acceptable title page is on page 12 of this
notice. The following information must appear on the title page:
a. Study title. The study title should be as descriptive as
possible It must clearly identify the substance(s) tested and
correspond to the name of the data requirement as it appears in
the Guidelines.
b. Data requirement addressed. Include on the title page the
Guideline number(s) of the specific requirement(s) addressed by
the study.
c. Author(s). Cite only individuals with primary intellectual
responsibility for the C9ntent of the study. Identify them
plainly as authors, to distinguish them from the performing
laboratory, study sponsor, or other names that may also appear on
the title page.
d. Study Date. The title page must include a single date for
the study. If parts of the study were performed at different
times, use only the date of the latest element in the study.
e. Performing Laboratory IdentificatJ9n. If the study reports
work done by one or more laboratories,Include on the title page
the name and address 9f the performing laboratory or laboratories,
and the laboratory's internal project number(s) for the work.
Clearly distinguish the laboratory's project identifier from any
other reference numbers provided by the study sponsor or
submitter.
f. Supplemental SubmissJ9ns. If the study is a commentary on or
supplement to another previously submitted study, or if it
responds to EPA questions raised with respect to an earlier study,
include on the title page elements a. through d. for the
previ9usly submitted study, along with the EPA Master Record
Identifier (MRID) or Accession number of the earlier study if you
know these numbers. (Supplements submitted in the same submittal
package as the primary study should be appended to and bound with
the primary study. Do not include supplements to more than one
study under a single title page).
g. Facts of Publication. If the study is a reprint of a pub-
lished d9cument, identity on the title page all relevant facts of
publication, such as the J9urnal title, volume, issue, inclusive
page numbers, and publication date.
D.2. Statements of Data Confidentiality Claims Under FIFRA
§10(d) (1) .
Each submitted study must be accompanied by one of the two
alternative forms of the statement of Data Confidentiality Claims
specified in the proposed regulation in §158.33 (b) and (c) (See
Attachment 3). These statements apply only to claims of data
confidentiality based on FIFRA §10(d)(1)(A), (B), or (C). Use the
appropriate alternative form of the statement either to assert a
claim of §10(d)(1) data confidentiality (§158.33(b)) or to waive
such a claim (§158.33(c)). In either case, the statement must be
signed and dated, and must include the typed name and title of the
official who signs it. Do not make CBI claims with respect to
analytical methods associated with pet-itions for tolerances or
emergency exemptions (see NOTE Pg 13).
86
-------
D.3. Confidential Attachment
If the claim is made that a study includes confidential busi-
ness information as defined by the criteria of FIFRA §10(D)(1)(A),
(B), or (C) (as described in D.2. above) all such information must
be excised from the body of the study and confined to a separate
study-specific Confidential Attachment. Each passage of CBI so
isolated must be identified by a reference number cited within the
body of the study at the point from which the passage was excised
(See Attachment 5).
The Confidential Attachment to a study must be identified by
a cover sheet fully identifying the parent study, and must be
clearly marked "Confidential Attachment." An appropriately
annotated photocopy of the parent study title page may be used as
this cover sheet. Paginate the Confidential Attachment separately
from the body of the study, beginning with page 1 of X on the
title page. Each passage confined to the Confidential Attachment
must be associated with a specific cross reference to the page(s)
in the main body of the study on which it is cited, and with a
reference to the applicable passage(s) of FIFRA §10(d)(1) on which
the confidentiality claim is based.
D.4. Supplemental Statement of Data Confidentiality Claims (See
Attachment 4)
If you wish to make a claim of confidentiality for any
portion of a submitted study other than described by FIFRA §10(d)
(1)(A), (B), or (C), the following provisions apply:
- The specific information to which the claim applies must be
clearly marked in the body of the study as subject to a claim
of confidentiality.
- A Supplemental Statement 9f Data Confidentiality Claims
must be submitted, identifying each passage claimed confi-
dential and describing in detail the basis for the claim. A
list of the points to address in such a statement is included
in Attachment 4 on Pg 14.
- The Supplemental Statement of Data Confidentiality Claims
must be signed and dated and must include the typed name and
title of the official who signed it.
D.5. Good Laboratory Practice Compliance Statement
This statement is required if the study contains laboratory
work subject to GLP requirements specified in 40 CFR 160. Samples
of these statements are shown in Attachment 6.
E. Reference to Previously Submitted Data
DO NOT RESUBMIT A STUDY THAT HAS PREVIOUSLY BEEN SUBMITTED
FOR ANOTHER PURPOSE unless EPA specifically requests it. A copy
of the title page plus the MRID number (if known) is sufficient to
allow us to retrieve the study immediately for review. This
prevents duplicate entries in the Agency files, and saves you
the cost of sending more copies of the study. References to pre-
viously submitted studies should not be included in the transmit-
tal document, but should be incorp9rated into the statement of the
method of support for the application.
F. Physical Format Requirements
All elements in the data submittal package must be on uniform
8 1/2 by 11 inch white paper, printed on one side 9nly in black
ink, with high contrast and good resolution. Bindings for indi-
vidual studies must be secure, but easily removable to permit
disassembly for microfilming. Check with EPA for special
instructions bef9re submitting data in any medium other than
paper, such as film or magnetic media.
87
-------
Please be particularly attentive to the following points:
• Do not include frayed or torn pages.
• Do not include carbon copies, or copies in other than
black ink.
• Make sure that photocopies are clear, complete, and
fully readable.
• Do not include oversize computer printouts or fold-out
pages.
• Do not bind any documents with glue or binding tapes.
• Make sure that all pages of each study, including any
attachments or appendices, are present and in correct
sequence.
Number of Copies Required - All submittal packages except
those associated with a Registration Standard or Special Review
(See Part G below) must be provided In three complete, identical
copies. (The proposed regulations specified two copies; three are
now being required to expedite and reduce the cost of processing
data into the OPP Pesticide Document Management System and getting
it into review.)
G. Special Requirements for Submitting Data to the Docket
Data submittal packages associated with a Registration Stan-
dard 9r Special Review must be provided in four C9pies, from one
of which all material claimed as CBI has been excised. This
fourth copy will become part of the public docket for the RS or SR
case. If no claims of confidentiality are made for the study, the
fourth copy should be identical to the other three. When portions
of a study submitted in supp9rt of an RS or SR are claimed as CBI,
the first three copies will include the CBI material as provided
in section D of this notice. The following special preparation is
required for the fourth copy.
• Remove the "Supplemental Statement of Data
Confidentiality Claims".
• Remove the "Confidential Attachment".
• Excise from the body of the study any information you
claim as confidential, even if it does not fall within
the scope of FIFRA §10(d) (1) (A), (B) , or (C) . Do not
close up or paraphrase text remaining after this
excision.
• Mark the fourth copy plainly on both its cover and its
title page with the phrase "Public Docket Material -
contains no information claimed as confidential".
V. For Further Information
For further information contact John Carley, Chief,
Information Services Branch, Program Management and Support
Division, (703) 305-5240.
/B/
James W. Akerman
Acting Director,
Registration Division
-------
Attachment 1. Sample Transmittal Document
Attachment 2. Sample Title Page for a Newly Submitted Study
Attachment 3. Statements of Data Confidentiality Claims
Attachment 4. Supplemental Statement of Data Confidentiality
Claims
Attachment 5. Samples of Confidential Attachments
Attachment 6. Sample G9od Laboratory Practice Statements
Attachment 7. Format Diagrams for Submittal Packages and Studies
89
-------
ATTACHMENT 1
ELEMENTS TO BE INCLUDED IN THE TRANSMITTAL DOCUMENT*
1. Name and address of submitter (or all joint submitters**)
"Smith Chemical Corporation Jones Chemical Company
1234 West Smith Street -and- 5678 Wilson Blvd
Cincinnati, OH 98765 Covington, KY 56789
"Smith Chemical Corp will act as sole agent for all submitters.
2. Regulatory action in support of which this package is
submitted
Use the EPA identification number (e.g. 359-EUP-67) if you know
it. Otherwise describe the type of request (e.g. experimental use
permit, data call-in - of xx-xx-xx date).
3. Transmittal date
4. List of submitted studies
Vol 1. Administrative materials - forms, previous corres-
pondence with Project Managers, and so forth.
Vol 2. Title of first study in the submittal (Guideline
No.)
Vol n Title of nth study in the submittal (Guideline
No.)
* Applicants commonly provide this information in a tran-
smittal letter. This remains an acceptable practice so
long as all four elements are included.
* Indicate which of the J9int submitters is empowered to
act 9n behalf of all J9int submitters in any matter con-
cerning data compensation or subsequent use or release
of the data.
Company Official:
Name Signature
Company Name
Company Contact:
Name Phone
90
-------
ATTACHMENT 2
SAMPLE STUDY TITLE PAGE FOR A NEWLY SUBMITTED STUDY
Study Title
(Chemical name) - Magnitude of Residue on Corn
Data Requirement
Guideline 171-4
Author
John C. Davis
Study Completed On
January 5, 1979
Performing Laboratory
ABC Agricultural Laboratories
940 West Bay Drive
Wilmington, CA 39897
Laboratory Project ID
ABC 47-79
Page 1 of X
(X is the total number of pages in the study)
91
-------
ATTACHMENT 3
STATEMENTS OF DATA CONFIDENTIALITY CLAIMS
1. No claim of confidentiality under FIFRA §10(d)(1)(A),(B), or (C).
STATEMENT OF NO DATA CONFIDENTIALITY CLAIMS
No claim of confidentiality is made for any information contained in this
study on the basis of its falling within the scope of FIFRA
6§10(d)(1)(A), (B), or (C).
Company
Company Agent: Typed Name Date:
Title Signature
2. Claim of confidentiality under FIFRA §10(d)(1)(A), (B), or (C).
Information claimed confidential on the basis of its falling within the
scope of FIFRA §10(d)(1)(A), (B), or (C) has been removed to a
confidential appendix, and is cited by cross-reference number in the body
of the study.
Company:
Company Agent: Typed Name Date:
Title Signature
STATEMENT OF DATA CONFIDENTIALITY CLAIMS
NOTE: Applicants f9r permanent or temporary tolerances should note
that it is OPP policy that no permanent tolerance, temporary
tolerance, or request for an emergency exemption incorporating an
analytical method, can be approved unless the applicant waives all
claims of confidentiality f9r the analytical method. These
analytical methods are published in the FDA Pesticide Analytical
Methods Manual, and therefore cannot be claimed as confidential.
OPP implements this policy by returning submitted analytical
methods, for which confidentiality claims have been made, to the
submitter, to obtain the confidentiality waiver before they can be
processed.
92
-------
ATTACHMENT 4
SUPPLEMENTAL STATEMENT OF DATA CONFIDENTIALITY CLAIMS
For any portion of a submitted study that is not described by
FIFRA §10(d)(1)(A), (B), or (C), but for which you claim
confidential treatment on another basis, the following information
must be included within a Supplemental Statement of Data
Confidentiality Claims:
• Identify specifically by page and line number(s) each
portion of the study for which you claim
confidentiality.
• Cite the reasons why the cited passage qualifies for
confidential treatment.
• Indicate the length of time--until a specific date or
event, or permanently--for which the information should
be treated as confidential.
• Identify the measures taken to guard against undesired
disclosure of this information.
• Describe the extent to which the information has been
disclosed, and what precautions have been taken in con-
nection with those disclosures.
• Encl9se copies of any pertinent determinati9ns of confi-
dentiality made by EPA, other Federal agencies, of
courts concerning this information.
• If y9u assert that disclosure of this information would
be likely to result in substantial harmful effects to
you, describe those harmful effects and explain why they
should be viewed as substantial.
• If you assert that the informati9n in voluntarily sub-
mitted, indicate whether you believe disclosure of this
information might tend to lessen the availability to EPA
of similar information in the future, and if so, how.
93
-------
ATTACHMENT 5
EXAMPLES OF SEVERAL CONFIDENTIAL ATTACHMENTS
Example 1. (Confidential word or phrase that has been deleted from
the study)
CROSS REFERENCE NUMBER 1 This cross reference number is used in the study in place of the
following paragraph (s) at the indicated volume and page
references.
DELETED WORDS OR PHRASE: Ethylene Glycol
PAGE LINES REASON FOR THE DELETION FIFRA
REFERENCE
6 14 Identity of Inert Ingredient §10(d)(C)
28 25
100 19
Example 2. (Confidential paragraph(s) that have been deleted from
the study)
CROSS REFERENCE NUMBER 5 This cross reference number is used in the study in place of the
following paragraph (s) at the indicated volume and page
references.
DELETED PARAGRAPH(S) :
( )
( Reproduce the deleted paragraph (s) here )
PAGE LINES REASON FOR THE DELETION FIFRA REFERENCE
20. 2-17 Description of the quality control process § 1 0 (d) ( 1) (C)
Example 3. (Confidential pages that have been deleted from the
study)
CROSS REFERENCE NUMBER 7 This cross reference number is used in the study in place of the
following paragraph (s) at the indicated volume and page
references.
DELETED PAGES(S): are attached immediately behind this page
PAGES LINES REASON FOR THE DELETION FIFRA REFERENCE
35-41. Description of product manufacturing process § 10 (d) (1) (A)
94
-------
ATTACHMENT 6 .
SAMPLE GOOD LABORATORY PRACTICE STATEMENTS
Example 1.
This study meets the requirements for 40 CFR Part 160
Submitter
Sponsor
Study Director
Example 2.
This study does not meet the requirements of 40 CFR Part 160, and
differs in the following ways:
1.
2.
3.
Submitter
Sponsor
Study Director_
Example 3.
The submitter of this study was neither the sponsor of this study nor
conducted it, and does not know whether it has been conducted in
accordance with 40 CFR Part 160.
Submitter
95
-------
ATTACHMENT 7.
FORMAT OF THE SUBMITTAL PACKAGE
Transmittal Document
Related Administrative Materials
(e.g. Method of Support Statement, etc.)
Other materials about the submittal
(e.g., summaries of groups of studies
to aid in their review).
Studies submitted as unique
to the format below.
FORMAT OF SUBMITTED STUDIES
• Study title page.
Statement of Confidentiality Claims.
GLP and flagging* statements - as appropriate.
Body of the study, with English
language translation if required.
Appendices to the study.
Title Page of the Confidential
Attachment.
Confidential Attachment.
Supplemental Statement
of Confidentiality Claims
" * When flagging requirements
are finalised.
Documents which must be submitted as
appropriate to meet established requirements.
Documents submitted at submitter's option.
LEGEND
96
-------
PR Notice 91-2
97
-------
98
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
PARNEDVTO%PII&J8I
PR NOTICE 91-2
NOTICE TO MANUFACTURERS, PRODUCERS, FORMULATORS,
AND REGISTRANTS OF PESTICIDES
ATTENTION: Persons Responsible for Federal Registration of
Pesticide Products.
SUBJECT: Accuracy of Stated Percentages for Ingredients
Statement
I. PURPOSE:
The purpose of this notice is to clarify the Office of
Pesticide P^gram's P9licy with respect to the statement of
percentages in a pesticide's label's ingredient statement.
Specifically, the amount (percent by weight) of ingredient(s)
specified in the ingredient statement on the label must be stated
as the nominal concentration of such ingredient(s), as that term
is defined in 40 CFR 158.153(1). Accordingly, the Agency has
established the nominal concentration as the only acceptable
label claim for the amount of active ingredient in the product.
II. BACKGROUND
For some time the Agency has accepted two different methods
9f identifying on the label what percentage is claimed for the
ingredient(s) contained in a pesticide. Some applicants claimed a
percentage which represented a level between the upper and the
lower certified limits. This was referred to as the nominal
concentration. Other applicants claimed the lower limit as the
percentage of the ingredient(s) that would be expected to be
present in their product at the end of the product's shelf-life.
Unfortunately, this led to a great deal of confusion among the
regulated industry, the regulators, and the consumers as to
exactly how much of a given ingredient was in a given product.
The Agency has established the nominal concentration as the only
acceptable label claim for the amount of active ingredient in the
product.
Current regulations require that the percentage listed in
the active ingredient statement be as precise as possible
reflecting go9d manufacturing practices 40 CFR 156.10(g)(5). The
certified limits required for each active ingredient are intended
to encompass any such "good manufacturing practice" variations 40
CFR 158.175 (c) (3) .
The upper and lower certified limits, which must be proposed
in connection with a product's registration, represent the
amounts of an ingredient that may legally be present 40 CFR
99
-------
158.175. The lower certified limit is used as the enforceable
lower limit for the product composition according to FIFRA
section 12(a)(1)(C), while the nominal concentration appearing on
the label would be the routinely achieved concentration used for
calculation of dosages and dilutions.
The nominal concentration would in fact state the greatest
degree of accuracy that is warranted with respect to actual
product compositi9n because the nominal concentration would be
the amount of active ingredient typically found in the product.
It is imp9rtant for registrants to note that certified
limits for active ingredients are not considered to be trade
secret information under FIFRA section 10(b). In this respect the
certified limits will be routinely provided by EPA to States for
enforcement purposes, since the nominal concentration appearing
on the label may not represent the enforceable composition for
purposes of section 12(a)(1)(C).
III. REQUIREMENTS
As described below under Unit V. " COMPLIANCE SCHEDULE," all
currently registered products as well as all applications for new
registration must comply with this Notice by specifying the
nominal C9ncentrati9n expressed as a percentage by weight as the
label claim in the ingredient(s) statement and equivalence
statements if applicable (e.g., elemental arsenic, metallic zinc,
salt of an acid). In addition, the requirement for performing
sample analyses of five or more representative samples must be
fulfilled. C9pies of the raw analytical data must be submitted
with the nominal ingredient label claim. Further information
about the analysis requirement may be found in the 40 CFR
158.170. All products are required to pr9vide certified limits
for each active, inert ingredient, impurities of toxicological
significance(i.e., upper limit(s) 9nly) and on a case by case
basis as specified by EPA. These limits are to be set based on
representative sampling and chemical analysis(i.e., quality
control) of the product.
The format of the ingredient statement must conform to 40
CFR 156-Labeling Requirements For Pesticides and Devices.
After July 1, 1997, all pesticide ingredient Statements must
be changed to nominal concentration.
IV. PRODUCTS THAT REQUIRE EFFICACY DATA
All pesticides are required to be efficacious. Therefore,
the certified lower limits may not be lower then the minimum
level to achieve efficacy. This is extremely important for
products which are intended to C9ntrol pests which threaten the
public health, e.g., certain antimicrobial and rodenticide
products. Refer to 40 CFR 153.640.
In those cases where efficacy limits have been established,
the Agency will not accept certified lower limits which are below
that level for the shelf life of the product.
V. COMPLIANCE SCHEDULE
As described earlier, the purpose of this Notice is to make
the registration process more uniform and more manageable for
100
-------
both the agency and the regulated community. It is the Agency's
intention to implement the requirements of this notice as
smoothly as possible so as not to disrupt or delay the Agency's
high priority programs, i.e., reregistration, new chemical, or
fast track (FIFRA section 3(c)(3)(B). Therefore,
applicants/registrants are expected to comply with the
requirements of this Notice as follows:
(1) Beginning July 1, 1991, all new product registrations
submitted to the Agency are to comply with the
requirements of this Notice.
(2) Registrants having products subject to reregistration
under FIFRA section 4(a) are to comply with the
requirements of this Notice when specific products are
called in by the Agency under Phase V of the
Reregistration Program.
(3) All other products/applications that are not subject to
(1) and (2) ab9ve will have until July 1, 1997, to
comply with this Notice. Such applications should note
"Conversion to Nominal Concentrations on the
application form. These types Or amendments will not be
handled as "Fast Track" applications but will be
handled as routine requests.
VI. FOR FURTHER INFORMATION
Contact Tyrone Aiken for information or questions concerning
this notice on (703) 308-7031.
Ann* E. tiridaay, Director
Registration Division (H-7505
101
-------
102
-------
APPENDIX F. Combined Generic and Product Specific
Data Call-In
103
-------
104
-------
\ UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
^
" WASHINGTON, D.C. 20460
GENERIC AND PRODUCT SPECIFIC
DATA CALL-IN NOTICE
CERTIFIED MAIL
Dear Sir or Madam:
This Notice requires you and other registrants of pesticide products containing the
active ingredient identified in Attachment A of this Notice, the Data Call-In Chemical Status
Sheet, to submit certain data as noted herein to the U.S. Environmental Protection Agency
(EPA, the Agency). These data are necessary to maintain the continued registration of your
product(s) containing this active ingredient. Within 90 days after you receive this Notice you
must respond as set forth in Section III below. Your response must state:
1. How you will comply with the requirements set forth in this Notice and its
Attachments 1 through 7; or
2. Why you believe you are exempt from the requirements listed in this Notice and
in Attachment 3 (for both generic and product specific data), the Requirements
Status and Registrant's Response Form, (see section III-B); or
3. Why you believe EPA should not require your submission of data in the manner
specified by this Notice (see section III-D).
If you do not respond to this Notice, or if you do not satisfy EPA that you will comply
with its requirements or should be exempt or excused from doing so, then the registration of
your product(s) subject to this Notice will be subject to suspension. We have provided a list of
all of your products subject to this Notice in Attachment 2. All products are listed on both the
generic and product specific Data Call-in Response Forms. Also included is a list of all
registrants who were sent this Notice (Attachment 6).
The authority for this Notice is section 3(c)(2)(B) of the Federal Insecticide, Fungicide
and Rodenticide Act as amended (FIFRA), 7 U.S.C. section 136a(c)(2)(B). Collection of this
information is authorized under the Paperwork Reduction Act by OMB Approval No.
2070-0107 and 2070-0057 (expiration date 3-31-96).
105
-------
This Notice is divided into six sections and seven Attachments. The Notice itself
contains information and instructions applicable to all Data Call-in Notices. The Attachments
contain specific chemical information and instructions. The six sections of the Notice are:
Section I - Why You are Receiving this Notice
Section II - Data Required by this Notice
Section III - Compliance with Requirements of this Notice
Section IV - Consequences of Failure to Comply with this Notice
Section V - Registrants' Obligation to Report Possible Unreasonable Adverse Effects
Section VI - Inquiries and Responses to this Notice
The Attachments to this Notice are:
1 - Data Call-In Chemical Status Sheet
2 - Generic Data Call-In and Product Specific Data Call-In Response Forms with
Instructions
3 - Generic Data Call-In and Product Specific Data Call-In Requirements Status
and Registrant's Response Forms with Instructions
4 - EPA Grouping of End-Use Products for Meeting Acute Toxicology Data
Requirements for Reregistration
5 - EPA Acceptance Criteria
6 - List of Registrants Receiving This Notice
7 - Cost Share and Data Compensation Forms
SECTION I. WHY YOU ARE RECEIVING THIS NOTICE
The Agency has reviewed existing data for this active ingredient (s) and reevaluated the
data needed to support continued registration of the subject active ingredient(s). This
reevaluation identified additional data necessary to assess the health and safety of the continued
use of products containing this active ingredient(s). You have been sent this Notice because
you have product (s) containing the subject active ingredients.
SECTION II. DATA REQUIRED BY THIS NOTICE
II-A. DATA REQUIRED
The data required by this Notice are specified in the Requirements Status and
Registrant's Response Forms: Attachment 3 (for both generic and product specific data
requirements). Depending on the results of the studies required in this Notice, additional
studies/testing may be required.
II-B. SCHEDULE FOR SUBMISSION OF DATA
You are required to submit the data or otherwise satisfy the data requirements specified
in the Requirements Status and Registrant's Response Forms (Attachment 3) within the
timeframes provided.
II-C. TESTING PROTOCOL
All studies required under this Notice must be conducted in accordance with test
standards outlined in the Pesticide Assessment Guidelines for those studies for which
guidelines have been established.
106
-------
These EPA Guidelines are available from the National Technical Information Service
(NTIS), Attn: Order Desk, 5285 Port Royal Road, Springfield, Va 22161 (Telephone number:
703-487-4650).
Protocols approved by the Organization for Economic Cooperation and Development
(OECD) are also acceptable if the OECD recommended test standards conform to those
specified in the Pesticide Data Requirements regulation (40 CFR § 158.70). When using the
OECD protocols, they should be modified as appropriate so that the data generated by the
study will satisfy the requirements of 40 CFR § 158. Normally, the Agency will not extend
deadlines for complying with data requirements when the studies were not conducted in
accordance with acceptable standards. The OECD protocols are available from OECD, 2001 L
Street, N.W., Washington, D.C. 20036 (Telephone number 202-785-6323; Fax telephone
number 202-785-0350).
All new studies and proposed protocols submitted in response to this Data Call-In
Notice must be in accordance with Good Laboratory Practices [40 CFR Part 160].
II-D. REGISTRANTS RECEIVING PREVIOUS SECTION 3(c)(2)(B) NOTICES ISSUED
BY THE AGENCY
Unless otherwise noted herein, this Data Call-in does not in any way supersede or
change the requirements of any previous Data Call-ln(s), or any other agreements entered into
with the Agency pertaining to such prior Notice. Registrants must comply with the
requirements of all Notices to avoid issuance of a Notice of Intent to Suspend their affected
products.
SECTION III. COMPLIANCE WITH REQUIREMENTS OF THIS NOTICE
You must use the correct forms and instructions when completing your response to this
Notice. The type of Data Call-In you must comply with (Generic or Product Specific) is
specified in item number 3 on the four Data Call-in forms (Attachments 2 and 3).
III-A. SCHEDULE FOR RESPONDING TO THE AGENCY
The appropriate responses initially required by this Notice for generic and product
specific data must be submitted to the Agency within 90 days after your receipt of this Notice.
Failure to adequately respond to this Notice within 90 days of your receipt will be a basis for
issuing a Notice of Intent to Suspend (NOIS) affecting your products. This and other bases for
issuance of NOIS due to failure to comply with this Notice are presented in Section IV-A and
IV-B.
III-B. OPTIONS FOR RESPONDING TO THE AGENCY
1. Generic Data Requirements
The options for responding to this Notice for generic data requirements are: (a)
voluntary cancellation, (b) delete use(s), (c) claim generic data exemption, (d) agree to satisfy
the generic data requirements imposed by this Notice or (e) request a data waiver (s).
A discussion of how to respond if you choose the Voluntary Cancellation option, the
Delete Use(s) option or the Generic Data Exemption option is presented below. A discussion
of the various options available for satisfying the generic data requirements of this Notice is
contained in Section III-C. A discussion of options relating to requests for data waivers is
contained in Section III-D.
107
-------
Two forms apply to generic data requirements, one or both of which must be used in
responding to the Agency, depending upon your response. These two forms are the
Data-Call-in Response Form, and the Requirements Status and Registrant's Response Form,
(contained in Attachments 2 and 3, respectively).
The Data Call-In Response Forms must be submitted as part of every response to this
Notice. The Requirements Status and Registrant's Response Forms also must be submitted if
you do not qualify for a Generic Data Exemption or are not requesting voluntary cancellation
of your registration^). Please note that the company's authorized representative is required to
sign the first page of both Data Call-In Response Forms and the Requirements Status and
Registrant's Response Forms (if this form is required) and initial any subsequent pages. The
forms contain separate detailed instructions on the response options. Do not alter the printed
material. If you have questions or need assistance in preparing your response, call or write the
contact person (s) identified in Attachment 1.
a. Voluntary Cancellation -
You may avoid the requirements of this Notice by requesting voluntary cancellation of
your product (s) containing the active ingredient that is the subject of this Notice. If you wish
to voluntarily cancel your product, you must submit completed Generic and Product Specific
Data Call-in Response Forms (Attachment 2), indicating your election of this option.
Voluntary cancellation is item number 5 on both Data Call-In Response Form(s). If you
choose this option, these are the only forms that you are required to complete.
If you chose to voluntarily cancel your product, further sale and distribution of your
product after the effective date of cancellation must be in accordance with the Existing Stocks
provisions of this Notice, which are contained in Section IV-C.
b. Use Deletion -
You may avoid the requirements of this Notice by eliminating the uses of your product
to which the requirements apply. If you wish to amend your registration to delete uses, you
must submit the Requirements Status and Registrant's Response Form (Attachment 3), a
completed application for amendment, a copy of your proposed amended labeling, and all
other information required for processing the application. Use deletion is option number 7
under item 9 in the instructions for the Requirements Status and Registrant's Response Forms.
You must also complete a Data Call-In Response Eorm by signing the certification, item
number 8. Application forms for amending registrations may be obtained from the
Registration Support Branch, Registration Division, Office of Pesticide Programs, EPA, by
calling (703) ~~-~
If you choose to delete the use(s) subject to this Notice or uses subject to specific data
requirements, further sale, distribution, or use of your product after one year from the due
date of your 90 day response, is allowed only if the product bears an amended label.
c. Generic Data Exemption -
Under section 3(c)(2)(D) of FIFRA, an applicant for registration of a product is
exempt from the requirement to submit or cite generic data concerning an active ingredient if
the active ingredient in the product is derived exclusively from purchased, registered pesticide
products containing the active ingredient. EPA has concluded, as an exercise of its discretion,
that it normally will not suspend the registration of a product which would qualify and
continue to qualify for the generic data exemption in section 3(c)(2)(D) of FIFRA. To qualify,
all of the following requirements must be met:
108
-------
(i). The active ingredient in your registered product must be present solely because of
incorporation of another registered product which contains the subject active ingredient
and is purchased from a source not connected with you;
(ii). Every registrant who is the ultimate source of the active ingredient in your
product subject to this DCI must be in compliance with the requirements of this Notice
and must remain in compliance; and
(iii). You must have provided to EPA an accurate and current " Confidential Statement
of Formula" for each of your products to which this Notice applies.
To apply for the Generic Data Exemption you must submit a completed Data Call-in
Response Form, Attachment 2 and all supporting documentation. The Generic Data Exemption
is item number 6a on the Data Call-in Response Form. If you claim a generic data exemption
you are not required to compiete the Requirements Status and Registrant's Response Form.
Generic Data Exemption cannot be selected as an option for responding to product specific
data requirements.
If you are granted a Generic Data Exemption, you rely on the efforts of other persons
to provide the Agency with the required data. If the registrant^) who have committed to
generate and submit the required data fail to take appropriate steps to meet requirements or are
no longer in compliance with this Data Call-In Notice, the Agency will consider that both they
and you are not compliance and will normally initiate proceedings to suspend the registrations
of both your and their product(s), unless you commit to submit and do submit the required
data within the specified time. In such cases the Agency generally will not grant a time
extension for submitting the data.
d. Satisfying the Generic Data Requirements of this Notice
There are various options available to satisfy the generic data requirements of this
Notice. These options are discussed in Section III-C.l. of this Notice and comprise options 1
through 6 of item 9 in the instructions for the Requirements Status and Registrant's Response
Form and item 6b on the Data Call-In Response Form, if you choose item 6b (agree to satisfy
the generic data requirements), you must submit the Data Call-In Response Form and the
Requirements Status and Registrant's Response Form as weii as any other information/data
pertaining to the option chosen to address the data requirement. Your response must be on the
forms marked "GENERIC" in item number 3.
e. Request for Generic Data Waivers.
Waivers for generic data are discussed in Section III-D.l. of this Notice and are
covered by options 8 and 9 of item 9 in the instructions for the Requirements Status and
Registrant's Response Form. If you choose one of these options, you must submit both forms
as well as any other information/data pertaining to the option chosen to address the data
requirement.
2. Product Specific Data Requirements
The options for responding to this Notice for product specific data are: (a) voluntary
cancellation, (b) agree to satisfy the product specific data requirements imposed by this Notice
or (c) request a data waiver (s).
A discussion of how to respond if you choose the Voluntary Cancellation option is
presented below. A discussion of the various options available for satisfying the product
specific data requirements of this Notice is contained in Section III-C.2. A discussion of
109
-------
options relating to requests for data waivers is contained in Section III-D.2.
Two forms apply to the product specific data requirements one or both of which must
be used in responding to the Agency, depending upon your response. These forms are the
Data-Call-in Response Form, and the Requirements Status and Registrant's Response Form,
for product specific data (contained in Attachments 2 and 3, respectively). 1 he Data CallTn
Response Form must be submitted as part of every response to this Notice. In addition, one
copy of the Requirements Status and Registrant's Response Form also must be submitted for
each product listed on the Data Caii-ln Response Form uniess the voluntary cancellation option
is selected. Please note that the company's authorized representative is required to sign the
first page of the Data Call-in Response Form and Requirements Status and Registrant s
Response Form (if this form is required) and initial any subsequent pages. The forms contain
separate detailed instructions on the response options. Do not alter the printed material. If you
have questions or need assistance in preparing your response, call or write the contact
person(s) identified in Attachment 1.
a. Voluntary Cancellation
You may avoid the requirements of this Notice by requesting voluntary cancellation of
your product (s) containing the active ingredient that is the subject of this Notice. If you wish
to voluntarily cancel your product, you must submit a completed Data Call-in Response Form,
indicating your election of this option. Voluntary cancellation is item number b on both the
Generic and Product Specific Data Call-in Response Forms. If you choose this
option, you must complete both Data Call-In response forms. These are the only forms that
you are required to complete.
If you choose to voluntarily cancel your product, further sale and distribution of your
product after the effective date of cancellation must be in accordance with the Existing Stocks
provisions of this Notice which are contained in Section IV-C.
b. Satisfying the Product Specific Data Requirements of this Notice.
There are various options available to satisfy the product specific data requirements of
this Notice. These options are discussed in Section III-C.2. of this Notice and comprise
options 1 through 6 of item 9 in the instructions for the product specific Requirements Status
and Registrant's Response Form and item numbers 7a and 7b (agree to satisfy the product
specific data requirements for an MUP or EUP as applicable) on the product specific Data
Call-in Response Form. Note that the options available for addressing product specific data
requirements differ slightly from those options for fulfilling generic data requirements.
Deletion of a use(s) and the low volume/minor use option are not valid options for fulfilling
product specific data requirements. It is important to ensure that you are using the correct
forms and instructions when completing your response to the Reregistration Eligibility
Decision document.
c. Request for Product Specific Data Waivers.
Waivers for product specific data are discussed in Section III-D.2. of this Notice and
are covered by option 7 of item 9 in the instructions for the Requirements Status and
Registrant's Response Form. If you choose this option, you must submit the Data Call-In
Response Form and the Requirements Status and Registrant's Response Form as well as any
other information/data pertaining to the option chosen to address the data requirement. Your
response must be on the forms marked "PRODUCT SPECIFIC" in item number 3.
110
-------
III-C SATISFYING THE DATA REQUIREMENTS OF THIS NOTICE
1. Generic Data
If you acknowledge on the Generic Data Call-In Response Form that you agree to
satisfy the generic data requirements (i.e. you select item number 6b), then you must select
one of the six options on the Generic Requirements Status and Registrant's Response Form
related to data production for each data requirement. Your option selection should be entered
under item number 9, "Registrant Response." The six options related to data production are
the first six options discussed under item 9 in the instructions for completing the Requirements
Status and Registrant's Response Form. These six options are listed
immediately below with information in parentheses to guide you to additional instructions
provided in this Section. The options are:
(1) I will generate and submit data within the specified timeframe (Developing
Data)
(2) I have entered into an agreement with one or more registrants to develop data
jointly (Cost Sharing)
I have made offers to cost-share (Offers to Cost Share)
I am submitting an existing study that has not been submitted previously to the
Agency by anyone (Submitting an Existing Study)
(5) I am submitting or citing data to upgrade a study classified by EPA as partially
acceptable and upgradeable (Upgrading a Study)
(6) I am citing an existing study that EPA has classified as acceptable or an existing
study that has been submitted but not reviewed by the Agency (Citing an
-i-i.-i. Oj_1\ OJVO
Existing Study)
Option 1. Developing Data
If you choose to develop the required data it must be in conformance with Agency
deadlines and with other Agency requirements as referenced herein and in the attachments. All
data generated and submitted must comply with the Good Laboratory Practice (GLP) rule (40
CFR Part 160), be conducted according to the Pesticide Assessment Guidelines (PAG) and be
in conformance with the requirements of PR Notice 86-5. In addition, certain studies require
Agency approval of test protocols in advance of study initiation. Those studies for which a
protocol must be submitted have been identified in the Requirements Status and Registrant's
Response Form and/or footnotes to the form. If you wish to use a protocol which differs from
the options discussed in Section II-C of this Notice, you must submit a detailed description of
the proposed protocol and your reason for wishing to use it. The Agency may choose to reject
a protocol not specified in Section II-C. If the Agency rejects your protocol you will be
notified in writing, however, you should be aware that rejection of a proposed protocol will
not be a basis for extending the deadline for submission of data.
A progress report must be submitted for each study within 90 days from the date you
are required to commit to generate or undertake some other means to address that study
requirement, such as making an offer to cost share or agreeing to share in the cost of
developing that study. This 90-day progress report must include the date the study was or will
be initiated and, for studies to be started within 12 months of commitment, the name and
address of the laboratory(ies) or individuals who are or will be conducting the study.
In addition, if the time frame for submission of a final report is more than 1 year,
interim reports must be submitted at 12 month intervals from the date you are required to
commit to generate or otherwise address the requirement for the study. In addition to the other
information specified in the preceding paragraph, at a minimum, a brief description of current
activity on and the status of the study must be included as well as a full description of any
problems encountered since the last progress report.
Ill
-------
The time frames in the Requirements Status and Registrant's Response Form are the
time frames that the Agency is allowing tor the submission of completed study reports or
protocols. The noted deadlines run from the date of the receipt of this Notice by the registrant.
If the data are not submitted by the deadline, each registrant is subject to receipt of a Notice of
Intent to Suspend the affected registration(s).
If you cannot submit the data/reports to the Agency in the time required by this Notice
and intend to seek additional time to meet the requirements(s), you must submit a request to
the Agency which includes: (1) a detailed description of the expected difficulty and (2) a
proposed schedule including alternative dates for meeting such requirements on a step-by-step
basis. You must explain any technical or laboratory difficulties and provide documentation
from the laboratory performing the testing. While EPA is considering your request, the
original deadline remains. The Agency will respond to your request in writing. If EPA does
not grant your request, the original deadline remains. Normally, extensions can be requested
only in cases of extraordinary testing problems beyond the expectation or control of the
registrant. Extensions will not be given in submitting the 90-day responses. Extensions will
not be considered if the request for extension is not made in a timely fashion; in no event shall
an extension request be considered if it is submitted at or after the lapse of the subject
deadline.
Option 2. Agreement to Share in Cost to Develop Data
If you choose to enter into an agreement to share in the cost of producing the required
data but will not be submitting the data yourself, you must provide the name of the registrant
who will be submitting the data. You must also provide EPA with documentary evidence that
an agreement has been formed. Such evidence may be your letter offering to join in an
agreement and the other registrant's acceptance of your offer, or a written statement by the
parties that an agreement exists. The agreement to produce the data need not specify all of the
terms of the final arrangement between the parties or the mechanism to resolve the terms.
Section 3(c)(2)(B) provides that if the parties cannot resolve the terms of the agreement they
may resolve their differences through binding arbitration.
Option 3. Offer to Share in the Cost of Data Development
If you have made an offer to pay in an attempt to enter into an agreement or amend an
existing agreement to meet the requirements of this Notice and have been unsuccessful, you
may request EPA (by selecting this option) to exercise its discretion not to suspend your
registration (s), although you do not comply with the data submission requirements of this
Notice. EPA has determined that as a general policy, absent other relevant considerations, it
will not suspend the registration of a product of a registrant who has in good faith sought and
continues to seek to enter into a joint data development/cost sharing program, but the other
registrant^) developing the data has refused to accept the offer. To qualify for this option, you
must submit documentation to the Agency proving that you have made an offer to another
registrant (who has an obligation to submit data) to share in the burden of developing that
data. You must also submit to the Agency a completed EPA Form 8570-32, Certification of
Offer to Cost Share in the Development of Data, Attachment 7. In addition, you must
demonstrate that the other registrant to whom the offer was made has not accepted your offer
to enter into a cost-sharing agreement by including a copy of your offer and proof of the other
registrant's receipt of that offer (such as a certified mail receipt). Your offer must, in addition
to anything else, offer to share in the burden of producing the data upon terms to be agreed to
or, failing agreement, to be bound by binding arbitration as provided by FIFRA section
3(c)(2)(Bj(iii) and must not qualify this offer. The other registrant must also inform EPA of its
election of an option to develop and submit the data required by this Notice by submitting a
Data Call-In Response Form and a Requirements Status and Registrant's Response Form
committing to develop and submit the data required by this Notice.
112
-------
In order for you to avoid suspension under this option, you may not withdraw your
offer to share in the burden of developing the data. In addition, the other registrant must fulfill
its commitment to develop and submit the data as required by this Notice. If the other
registrant fails to develop the data or for some other reason is subject to suspension, your
registration as well as that of the other registrant normally will be subject to initiation of
suspension proceedings, unless you commit to submit, and do submit, the required data in the
specified time frame. In such cases, the Agency generally will not grant a time extension for
submitting the data.
Option 4. Submitting an Existing Study
If you choose to submit an existing study in response to this Notice, you must
determine that the study satisfies the requirements imposed by this Notice. You may only
submit a study that has not been previously submitted to the Agency or previously cited by
anyone. Existing studies are studies which predate issuance of this Notice. Do not use this
option if you are submitting data to upgrade a study. (See Option 5).
You should be aware that if the Agency determines that the study is not acceptable, the
Agency will require you to comply with this Notice, normally without an extension of the
required date of submission. The Agency may determine at any time that a study is not valid
and needs to be repeated.
To meet the requirements of the DCI Notice for submitting an existing study, all of the
following three criteria must be clearly Met:
a. You must certify at the time that the existing study is submitted that the raw
data and specimens from the study are available for audit and review and you
must identify where they are available. This must be done in accordance with
the requirements of the Good Laboratory Practice (GLP) regulation, 40 CFR
Part 160. As stated in 40 CFR 160.3 'Raw data' means any laboratory
worksheets, records, memoranda, notes, or exact copies thereof, that are the
result of original observations and activities of a study and are necessary for the
reconstruction and evaluation of the report of that study. In the event that exact
transcripts of raw data have been prepared (e.g., tapes which have been
transcribed verbatim, dated, and verified accurate by signature), the exact copy
or exact transcript may be substituted for the original source as raw data. 'Raw
data' may include photographs, microfilm or microfiche copies, computer
printouts, magnetic media, including dictated observations, and recorded data
from automated instruments." The term "specimens", according to 40 CFR
160.3, means "any material derived from a test system for examination or
analysis."
b. Health and safety studies completed after May 1984 also must also contain all
GLP-required quality assurance and quality control information, pursuant to the
requirements or 40 CFR Part 160. Registrants also must certify at the time of
submitting the existing study that such GLP information is available for post
May 1984 studies by including an appropriate statement on or attached to the
study signed by an authorized official or representative of the registrant.
c. You must certify that each study fulfills the acceptance criteria for the Guideline
relevant to the study provided in the FIFRA Accelerated Reregistration Phase 3
Technical Guidance and that the study has been conducted according to the
Pesticide Assessment Guidelines (PAG) or meets the purpose of the PAG (both
available from NTIS). A study not conducted according to the PAG may be
submitted to the Agency for consideration if the registrant believes that the
study clearly meets the purpose of the PAG. The registrant is referred to 40
113
-------
CFR 158.70 which states the Agency's policy regarding acceptable protocols. If
you wish to submit the study, you must, in addition to certifying that the
purposes of the PAG are met by the study, clearly articulate the rationale why
you believe the study meets the purpose of the PAG, including copies of any
supporting information or data. It has been the Agency's experience that studies
completed prior to January 1970 rarely satisfied the purpose of the PAG and
that necessary raw data usually are not available for such studies.
If you submit an existing study, you must certify that the study meets all requirements
of the criteria outlined above.
If EPA has previously reviewed a protocol for a study you are submitting, you must
identify any action taken by the Agency on the protocol and must indicate, as part of your
certification, the manner in which all Agency comments, concerns, or issues were addressed
in the final protocol and study.
If you know of a study pertaining to any requirement in this Notice which does not
meet the criteria outlined above but does contain factual information regarding unreasonable
adverse effects, you must notify the Agency of such a study. If such study is in the Agency's
files, you need only cite it along with the notification. If not in the Agency's files, you must
submit a summary and copies as required by PR Notice 86-5.
Option 5. Upgrading a Study
If a study has been classified as partially acceptable and upgradeable, you may submit
data to upgrade that study. The Agency will review the data submitted and determine if the
requirement is satisfied. If the Agency decides the requirement is not satisfied, you may still
be required to submit new data normally without any time extension. Deficient, but
upgradeable studies will normally be classified as supplemental. However, it is important to
note that not all studies classified! as supplemental are upgradeable. If you have questions
regarding the classification of a study or whether a study may be upgraded, call or write the
contact person listed in Attachment 1. If you submit data to upgrade an existing study you
must satisfy or supply information to correct all deficiencies in the study identified by EPA.
You must provide a clearly articulated rationale" of how the deficiencies have been remedied or
corrected and why the study should be rated as acceptable to EPA. Your submission must also
specify the MRID number (s) of the study which you are attempting to upgrade and must be in
conformance with PR Notice 86-5.
Do not submit additional data for the purpose of upgrading a study classified as
unacceptable and determined by the Agency as not capable of being upgraded.
This option also should be used to cite data that has been previously submitted to
upgrade a study, but has not yet been reviewed by the Agency. You must provide the MRID
number of the data submission as well as the MRID nurriber of the study being upgraded.
The criteria for submitting an existing study, as specified in Option 4 above, apply to
all data submissions intended to upgrade studies. Additionally, your submission of data
intended to upgrade studies must be accompanied by a certification that you comply with each
of those criteria, as well as a certification regarding protocol compliance with Agency
requirements.
Option 6. Citing Existing Studies
If you choose to cite a study that has been previously submitted to EPA, that study
must have been previously classified by EPA as acceptable, or it must be a study which has
not yet been reviewed by the Agency. Acceptable toxicology studies generally will have been
114
-------
classified as "core-guideline" or "core-minimum." For ecological effects studies, the
classification generally would be a rating of "core." For all other disciplines the classification
would be "acceptable." With respect to any studies for which you wish to select this option,
you must provide the MRID number of the study you are citing and, if the study has been
reviewed by the Agency, you must provide the Agency's classification of the study.
If you are citing a study of which you are not the original data submitter, you must
submit a completed copy of EPA Form 8570-31, Certification with Respect to Data
Compensation Requirements.
2. Product Specific Data
If you acknowledge on the product specific Data Call-in Response Form that you agree
to satisfy the product specific data requirements (i.e. you select option Ya or Yb), then you
must select one of the six options on the Requirements Status and Registrant's Response Form
related to data production for each data requirement. Your option selection should be entered
under item number 9, "Registrant Response." The six options related to data production are
the first six options discussed under item 9 in the instructions for completing the Requirements
Status and Registrant's Response Form. These six options are listed immediately below with
information in parentheses to guide registrants to additional instructions provided in this
Section. The options are:
(1) I will generate and submit data within the specified time-frame (Developing
Data)
(2) I have entered into an agreement with one or more registrants to develop data
jointly (Cost Sharing)
I have made offers to cost-share (Offers to Cost Share)
I am submitting an existing study that has not been submitted previously to the
Agency by anyone (Submitting an Existing Study)
(5) I am submitting or citing data to upgrade a study classified by EPA as partially
acceptable and upgradeable (Upgrading a Study)
(6) I am citing an existing study that EPA has classified as acceptable or an existing
study that has been
submitted but not reviewed by the Agency (Citing an Existing Study)
Option 1. Developing Data — The requirements for developing product specific data are the
same as those described for generic data (see Section III.C.I, Option 1) except that normally
no protocols or progress reports are required.
Option 2. Agree to Share in Cost to Develop Data — If you enter into an agreement to cost
share, the same requirements apply to product specific data as to generic data (see Section
III.C.I, Option 2). However, registrants may only choose this option for acute toxicity data
and certain efficacy data and only if EPA has indicated in the attached data tables that your
product and at least one other product are similar for purposes of depending on
the same data. If this is the case, data may be generated for just one of the products in the
group. The registration number of the product for which data will be submitted must be noted
in the agreement to cost share by the registrant selecting this option.
Option 3. Offer to Share in the Cost of Data Development —The same requirements for
generic data (Section lll.C.l., Option 3) apply to this option. This option only applies to acute
toxicity and certain efficacy data as described in option 2 above.
Option 4. Submitting an Existing Study — The same requirements described for generic data
(see Section lll.C.l" Option 4) apply to this option for product specific data.
115
-------
Option 5. Upgrading a Study — The same requirements described for generic data (see Section
llI.C.l., Option b) apply to this option for product specific data.
Option 6. Citing Existing Studies — The same requirements described for generic data (see
Section 111.0.17, Option 6) apply to this option for product specific data.
Registrants who select one of the above 6 options must meet all of the requirements
described in the instructions for completing the Data Call-in Response Form and the
Requirements Status and Registrant's Response Form, and in the generic data requirements
section (lll.C.l.j, as appropriate.
III-D REQUESTS FOR DATA WAIVERS
1. Generic Data
There are two types of data waiver responses to this Notice. The first is a request for a
low volume/minor use waiver and the second is a waiver request based on your belief that the
data requirement(s) are not appropriate for your product.
a. Low Volume/Minor Use Waiver
Option 8 under item 9 on the Requirements Status and Registrant's Response
Form. Section 3(c)(2)(A) of FIFRA requires EPA to consider the appropriateness of
requiring data for low volume, minor use pesticides. In implementing this provision,
EPA considers low volume pesticides to be only those active ingredients whose total
production volume for all pesticide registrants is small. In determining whether to grant
a low volume, minor use waiver, the Agency will consider the extent, pattern and
volume of use, the economic incentive to conduct the testing, the importance of the
pesticide, and the exposure and risk from use of the pesticide. If an active ingredient is
used for both high volume and low volume uses, a low volume exemption will not be
approved. If all uses of an active ingredient are low volume and the combined volumes
for all uses are also low, then an exemption may be granted, depending on review of
other information outlined below. An exemption will not be granted if any registrant of
the active ingredient elects to conduct the testing. Any registrant receiving a low
volume minor use waiver must remain within the sales figures in their forecast
supporting the waiver request in order to remain qualified for such waiver. If granted a
waiver, a registrant will be required, as a condition of the waiver, to submit annual
sales reports. The Agency will respond to requests for waivers in writing.
To apply for a low volume, minor use waiver, you must submit the following
information, as applicable to your product(s), as part of your 90-day response to this
Notice:
(i). Total company sales (pounds and dollars) of all registered product(s)
containing the active ingredient. If applicable to the active ingredient, include foreign
sales for those products that are not registered in this country but are applied to sugar
(cane or beet), coffee, bananas, cocoa, and other such crops. Present the above
information by year for each of the past five years.
(ii) Provide an estimate of the sales (pounds and dollars) of the active
ingredient for each major use site. Present the above information by year for each of
the past five years.
116
-------
(iii) Total direct production cost of product (s) containing the active ingredient
by year for the past five years. Include information on raw material cost, direct labor
cost, advertising, sales and marketing, and any other significant costs listed separately.
(iv) Total indirect production cost (e.g. plant overhead, amortized plant and
equipment) charged to product (s) containing the active ingredient by year for the past
five years. Exclude all non-recurring costs that were directly related to the active
ingredient, such as costs of initial registration and any data development.
(v) A list of each data requirement for which you seek a waiver. Indicate the
type of waiver sought and the estimated cost to you (listed separately for each data
requirement and associated test) of conducting the testing needed to fulfill each of these
data requirements.
(vi) A list of each data requirement for which you are not seeking any waiver
and the estimated cost to you (listed separately for each data requirement and associated
test) of conducting the testing needed to fulfill each of these data requirements.
(vii) For each of the next ten years, a year-by-year forecast of company sales
(pounds and dollars) of the active ingredient, direct production costs of product (s)
containing the active ingredient (following the parameters in item 2 above), indirect
production costs of product(s) containing the active ingredient (following the
parameters in item 3 above), and costs of data development pertaining to the active
ingredient.
(viii) A description of the importance and unique benefits of the active
ingredient to users. Discuss the use patterns and the effectiveness of the active
ingredient relative to registered alternative chemicals and non-chemical control
strategies. Focus on benefits unique to the active ingredient, providing information that
is as quantitative as possible. If you do not have quantitative data upon which to base
your estimates, then present the reasoning used to derive your estimates. To assist the
Agency in determining the degree of importance of the active ingredient in terms of its
benefits, you should provide information on any of the following factors, as applicable
to your product(s): (a) documentation of the usefulness of the active ingredient in
Integrated Pest Management, (b) description of the beneficial impacts on the
environment of use of the active ingredient, as opposed to its registered alternatives,
(c) information on the breakdown of the active ingredient after use and on its
persistence in the environment, and (d) description of its usefulness against a pest(s) of
public health significance.
Failure to submit sufficient information for the Agency to make a determination
regarding a request for a low volume/minor use waiver will result in denial of the
request for a waiver.
b. Request for Waiver of Data
Option 9, under Item 9, on the Requirements Status and Registrant's Response
Form. This option may be used if you believe that a particular data requirement should
not apply because the requirement is inappropriate. You must submit a rationale
explaining why you believe the data requirements should not apply. You also must
submit the current label(s) of your product(s) and, if a current copy of your
Confidential Statement of Formula is not already on file you must submit a current
copy.
You will be informed of the Agency's decision in writing. If the Agency
determines that the data requirements of this Notice are not appropriate to your
117
-------
product(s), you will not be required to supply the data pursuant to section 3(c)(2)(B). If
EPA determines that the data are required Tor your product(s) you must choose a ~~
method or meeting the requirements of this Notice within the time frame provided by
this Notice. Within 30 days or your receipt or the Agency's written decision, you must
submit a revised Requirements Status and Registrant s Response Form indicating the
option chosen.
2. Product Specific Data
If you request a waiver for product specific data because you believe it is
inappropriate, you must attach a complete justification for the request including
technical reasons, data and references to relevant EPA regulations, guidelines or
policies. (Note: any supplemental data must be submitted in the format required by PR
Notice 86-5). This will be the only opportunity to state the reasons or provide
information in support of your request. If the Agency approves your waiver request,
you will not be required to supply the data pursuant to section 3(c)(2)(B) of FIFRA. If
the Agency denies your waiver request, you must choose an option for meeting the data
requirements of this Notice within 30 days of the receipt of the Agency's decision.
You must indicate and submit the option chosen on the product specific Requirements
Status and Registrant's Response Form. Product specific data requirements for product
chemistry, acute toxicity and efficacy (where appropriate) are required for all products
and the Agency would grant a waiver only under extraordinary circumstances. You
should also be aware that submitting a waiver request will not automatically extend the
due date for the study in question. Waiver requests submitted~without adequate
supporting rationale will be denied and the original due date will remain in force.
SECTION IV. CONSEQUENCES OF FAILURE TO COMPLY WITH THIS
JMUTICE
IV-A NOTICE OF INTENT TO SUSPEND
The Agency may issue a Notice of Intent to Suspend products subject to this Notice due
to failure by a registrant to comply with the requirements of this Data Call-In Notice, pursuant
to FIFRA section 3 (c) (2) (B). Events which may be the basis for issuance of a Notice of Intent
to Suspend include, but are not limited to, the following:
1. Failure to respond as required by this Notice within 90 days of your receipt of
this Notice.
2. Failure to submit on the required schedule an acceptable proposed or final
protocol when such is required to be submitted to the Agency for review.
3. Failure to submit on the required schedule an adequate progress report on a
study as required by this Notice.
4. Failure to submit on the required schedule acceptable data as required by this
Notice.
5. Failure to take a required action or submit adequate information pertaining to
any option chosen to address the data requirements (e.g., any required action or
information pertaining to submission or citation of existing studies or offers,
arrangements, or arbitration on the sharing of costs or the formation of Task
Forces, failure to comply with the terms of an agreement or arbitration
concerning joint data development or failure to comply with any terms of a data
waiver).
118
-------
6. Failure to submit supportable certifications as to the conditions of submitted
studies, as required by Section III-C of this Notice.
7. Withdrawal of an offer to share in the cost of developing required data.
8. Failure of the registrant to whom you have tendered an offer to share in the cost
of developing data and provided proof of the registrant's receipt of such offer
or failure of a registrant on whom you rely for a generic data exemption either
to:
i. Inform EPA of intent to develop and submit the data required by this Notice
on a Data Call-in Response Form and a Requirements Status and Registrant's
Response Form.
ii. Fulfill the commitment to develop and submit the data as required by this
Notice; or
iii. Otherwise take appropriate steps to meet the requirements stated in this
Notice,
unless you commit to submit and do submit the required data in the specified
time frame.
9. Failure to take any required or appropriate steps, not mentioned above, at any
time following the issuance of this Notice.
IV-B. BASIS FOR DETERMINATION THAT SUBMITTED STUDY IS
UNACCEPTABLE
The Agency may determine that a study (even if submitted within the required time) is
unacceptable and constitutes a basis for issuance of a Notice of Intent to Suspend. The grounds
for suspension include, but are not limited to, failure to meet any of the following:
1) EPA requirements specified in the Data Call-In Notice or other documents
incorporated by reference (including, as applicable, EPA Pesticide Assessment
Guidelines, Data Reporting Guidelines, and GeneTox Health Effects Test Guidelines)
regarding the design, conduct, and reporting of required studies. Such requirements
include, but are not limited to, those relating to test material, test procedures, selection
of species, number of animals, sex and distribution of animals, dose and effect levels to
be tested or attained, duration of test, and, as applicable, Good Laboratory Practices.
2) EPA requirements regarding the submission of protocols, including the
incorporation of any changes required by the Agency following review.
3) EPA requirements regarding the reporting of data, including the manner of
reporting, the completeness of results, and the adequacy of any required supporting (or
raw) data, including, but not limited to, requirements referenced or included in this
Notice or contained in PR 86-5. All studies must be submitted in the form of a final
report; a preliminary report will not be considered to fulfill the submission
requirement.
IV-C EXISTING STOCKS OF SUSPENDED OR CANCELLED PRODUCTS
EPA has statutory authority to permit continued sale, distribution and use of existing
stocks of a pesticide product which has been suspended or cancelled if doing so would be
consistent with the purposes of the Act.
119
-------
The Agency has determined that such disposition by registrants of existing stocks for a
suspended registration when a section 3 (c) (2) (B) data request is outstanding generally would
not be consistent with the Act's purposes. Accordingly, the Agency anticipates granting
registrants permission to sell, distribute, or use existing stocks of suspended product(s) only in
exceptional circumstances. If you believe such disposition of existing stocks of your product (s)
which may be suspended for failure to comply with this Notice should be permitted, you have
the burden of clearly demonstrating to EPA that granting such permission would be consistent
with the Act. You also must explain why an "existing stocks" provision is necessary, including
a statement of the quantity of existing stocks and your estimate of the time required for their
sale, distribution, and use. Unless you meet this burden, the Agency will not consider any
request pertaining to the continued sale, distribution, or use of your existing stocks after
suspension.
If you request a voluntary cancellation of your product(s) as a response to this Notice
and your product is in full compliance with all Agency requirements, you will have, under
most circumstances, one year from the date your 90 day response to this Notice is due, to sell,
distribute, or use existing stocks. Normally, the Agency will allow persons other than the
registrant such as independent distributors, retailers and end users to sell, distribute or use
such existing stocks until the stocks are exhausted. Any sale, distribution or use of stocks of
voluntarily cancelled products containing an active ingredient for which the Agency has
particular risk concerns will be determined on a case-by-case basis.
Requests for voluntary cancellation received after the 90 day response period required
by this Notice will not result in the agency granting any additional time to sell, distribute, or
use existing stocks beyond a year from the date the 90 day response was due, unless you
demonstrate to the Agency that you are in full compliance with all Agency requirements,
including the requirements of this Notice. For example, if you decide to voluntarily cancel
your registration six months before a 3-year study is scheduled to be submitted, all progress
reports and other information necessary to establish that you have been conducting the study in
an acceptable and good faith manner must have been submitted to the Agency, before EPA
will consider granting an existing stocks provision.
SECTION V. REGISTRANTS' OBLIGATION TO REPORT POSSIBLE
LJJMREASONABLE ADVERSE EFFECTS
Registrants are reminded that FIFRA section 6 (a) (2) states that if at any time after a
pesticide is registered a registrant has additional factual information regarding unreasonable
adverse effects on the environment by the pesticide, the registrant shall submit the information
to the Agency. Registrants must notify the Agency of any factual information they have, from
whatever source, including but not limited to interim or preliminary results of studies,
regarding unreasonable adverse effects on man or the environment. This requirement
continues as long as the products are registered by the Agency.
SECTION VI. INQUIRIES AND RESPONSES TO THIS NOTICE
If you have any questions regarding the requirements and procedures established by
this Notice, call the contact person(sj listed in Attachment 1, the Data Call-in Chemical Status
Sheet.
All responses to this Notice must include completed Data Call-in Response Forms
(Attachment 2|and completed Requirements Status and Registrant's Response Forms
(Attachment 3), for both (generic and product specific data) and any other documents required
by this Notice, and should be submitted to the contact person(s) identified in Attachment 1. If
120
-------
the voluntary cancellation or generic data exemption option is chosen, only the Generic and
Product Specific Data Call-in Response Forms need be submitted.
The Office of Compliance (OC) of the Office of Enforcement and Compliance
Assurance (OECA), EPA, will be monitoring the data being generated in response to this
Notice.
Sincerely yours,
Louis P. True, Jr., Acting Director
Special Review and
Reregistration Division
Attachments
The Attachments to this Notice are:
1 - Data Call-In Chemical Status Sheet
2 - Generic Data Caii-ln and Product Specific Data Call-In Response Forms with
Instructions
3 - Generic Data Call-In and Product Specific Data Call-In Requirements Status
and Registrant's Response Forms with Instructions
4 - EPA Grouping of End-Use Products for Meeting Acute Toxicology Data
Requirements for Reregistration
5 - EPA Acceptance Criteria
6 - List of Registrants Receiving This Notice
7 - Confidential Statement of Formula, Cost Share and Data Compensation Forms
121
-------
122
-------
Attachment 1. Chemical Status Sheets
123
-------
124
-------
Difenzoquat DATA CALL-IN CHEMICAL STATUS SHEET
INTRODUCTION
You have been sent this Generic Data Call-In Notice because you have product(s)
containing Difenzoquat.
This Generic Data Call-In Chemical Status Sheet, contains an overview of data
required by this notice, and point of contact tor inquiries pertaining to the reregistration of
Difenzoquat. This attachment is to be used in conjunction with (1) the Generic Data Call-In
Notice, (2) the Generic Data Call-In Response Form (Attachment 2), (3) the Requirements
Status and Registrant's Form (Attachment 2), (4) a list of registrants receiving this DCI
(Attachment 4), (5) the EPA Acceptance Criteria (Attachment 5), and (6) the Cost Share and
Data Compensation Forms in replying to this Difenzoquat Generic Data Call In (Attachment
F). Instructions and guidance accompany each form.
DATA REQUIRED BY THIS NOTICE
The additional data requirements needed to complete the generic database for
Difenzoquat are contained in the Requirements Status and Registrant's Response, Attachment
C. The Agency has concluded that additional product chemistry data on Difenzoquat are
needed. These data are needed to fully complete the reregistration of all eligible Difenzoquat
products.
INQUIRIES AND RESPONSES TO THIS NOTICE
If you have any questions regarding the generic data requirements and procedures
established by this Notice, please contact Andrew Ertman at (703) 308-8063.
All responses to this Notice for the generic data requirements should be submitted to:
Andrew Ertman, Chemical Review Manager
Reregistration Branch
Special Review and Registration Division (H7508W)
Office of Pesticide Programs
U.S. Environmental Protection Agency
Washington, D.C. 20460
RE: Difenzoquat
125
-------
DIFENZOQUAT DATA CALL-IN CHEMICAL STATUS SHEET
INTRODUCTION
You have been sent this Product Specific Data Call-In Notice because you have
product(s) containing Difenzoquat.
This Product Specific Data Call-In Chemical Status Sheet contains an overview of data
required by this notice, and point of contact tor inquiries pertaining to the reregistration of
Difenzoquat. This attachment is to be used in conjunction with (1) the Product Specific Data
Call-In Notice, (2) the Product Specific Data Call-In Response Form (Attachment 2), (3) the
Requirements Status and Registrant's Form (Attachment 3), (4) EPA's Grouping of End-Use
Products for Meeting Acute Toxicology Data Requirement (Attachment 4), (5) the EPA
Acceptance Criteria (Attachment 5), (6) a list of registrants receiving this DCI (Attachment 6)
and (7) the Cost Share and Data Compensation Forms in replying to this Difenzoquat Product
Specific Data Call-In (Attachment 7). Instructions and guidance accompany each form.
DATA REQUIRED BY THIS NOTICE
The additional data requirements needed to complete the database for Difenzoquat are
contained in the Requirements Status and Registrant's Response, Attachment 3. The Agency
has concluded that additional data on Difenzoquat are needed tor specific products. These data
are required to be submitted to the Agency within the time frame listed. These data are
needed to fully complete the reregistration of all eligible Difenzoquat products.
INQUIRIES AND RESPONSES TO THIS NOTICE
If you have any questions regarding the generic database of Difenzoquat, please contact
Andrew Ertman at (703) 308-8063.
If you have any questions regarding the product specific data requirements and
procedures established by this Notice, please contact Franklin Gee at (703) 308-8008.
All responses to this Notice for the Product Specific data requirements should be
submitted to:
Veronica Dutch
Chemical Review Manager Team 81
Product Reregistration Branch
Special Review and Reregistration Branch 7508W
Office of Pesticide Programs
U.S. Environmental Protection Agency
Washington, D.C. 20460
RE: Difenzoquat
126
-------
Attachment 2. Combined Generic and Product Specific
Data Call-In Response Forms (Form A inserts) Plus
Instructions
127
-------
128
-------
Instructions For Completing The "Data Call-in Response Forms" For The Generic And
Product Specific Data Call-In
INTRODUCTION
These instructions apply to the Generic and Product Specific "Data Call-In Response Forms"
and are to be used by registrants to respond to generic and product specific Data Call-Ins as
part of EPA's Reregistration Program under the Federal Insecticide, Fungicide, and
Rodenticide Act. The type of data call-in (generic or product specific) is indicated in item
number 3 ("Date and Type of DCI") on each form. BOTH "Data Call-In Response" forms
must be completed.
Although the form is the same for both generic and product specific data, instructions for
completing these forms are different. Please read these instructions carefully before filling out
the forms.
EPA has developed these forms individually for each registrant, and has reprinted these forms
with a number of items. DO NOT use these forms for any other active ingredient.
Items 1 through 4 have been reprinted on the form. Items 5 through 7 must be completed by
the registrant as appropriate. Items 8 through 11 must be completed by the registrant before
submitting a response to the Agency.
The public reporting burden for this collection of information is estimated to average 15
minutes per response, including time for reviewing instructions, searching existing data
sources, gathering and maintaining the data needed, and completing and reviewing the
collection of information. Send comments regarding the burden estimate or any other aspect of
this collection of information, including suggestions for reducing this burden, to Chief,
Information Policy Branch, Mail Code 213o, U.S. Environmental Protection Agency, 401 M
St., S.W., Washington, D.C. 20460; and to the Office of Management and Budget,
Paperwork Reduction Project 2070-0107, Washington, D.C. 20503.
129
-------
INSTRUCTIONS FOR COMPLETING THE DATA CALL-IN RESPONSE FORMS
Generic and Product Specific Data Call-in
Item l.ON BOTH FORMS: This item identifies your company name, number and address.
Item 2.ON BOTH FORMS: This item identifies the case number, case name, EPA chemical
number and chemical name.
Item 3.ON BOTH FORMS: This item identifies the type of Data Call-in. The date of
issuance is date stamped.
Item 4.ON BOTH FORMS: This item identifies the EPA product registrations relevant to
the data call-in. Please note that you are also responsible for informing the Agency of your
response regarding any product that you believe may be covered by this Data Call-In but that
is not listed by the Agency in Item 4. You must bring any such apparent omission to the
Agency's attention within the period required for submission of this response form.
Item 5.ON BOTH FORMS: Check this item for each product registration you wish to cancel
voluntarily. If a registration number is listed for a product for which you previously requested
voluntary cancellation, indicate in Item 5 the date of that request. Since this Data Call-in
requires both generic and product specific data, you must complete item 5 on both Data Call-
in response forms. You do not need to complete any item on the Requirements Status and
Registrant's Response Forms.
Item 6a.ON THE GENERIC DATA FORM: Check this Item if the Data Call-in is for
generic data as indicated in Item 3 and you are eligible for a Generic Data Exemption for the
chemical listed in Item 2 and used in the subject product. By electing this exemption, you
agree to the terms and conditions of a Generic Data Exemption as explained in the Data
Call-in Notice.
If you are eligible for or claim a Generic Data Exemption, enter the EPA registration Number
of each registered source of that active ingredient that you use in your product.
Typically, if you purchase an EPA-registered product from one or more other producers
(who, with respect to the incorporated product, are in compliance with this and any other
outstanding Data Call-In Notice), and
INSTRUCTIONS FOR COMPLETING THE DATA CALL-IN RESPONSE FORMS
Generic and Product Specific Data Caii-in
incorporate that product into all your products, you may complete this item for all products
listed on this form. If, however, you produce the active ingredient yourself, or use any
unregistered product (regardless of the fact that some of your sources are registered), you may
not claim a Generic Data Exemption and you may not select this item.
Item 6b.ON THE GENERIC DATA FORM: Check this Item if the Data Call-in is for
generic data as indicated in Item 3 and if you are agreeing to satisfy the generic data
requirements of this Data Call-In. Attach the Requirements Status and Registrant's Response
Form that indicates how you will satisfy those requirements.
NOTE: Item 6a and 6b are not applicable for Product Specific Data.
130
-------
Item 7a.ON THE PRODUCT SPECIFIC DATA FORM: For each manufacturing use
product (MUP) for which you wish to maintain registration, you must agree to satisfy the data
requirements by responding "yes."
Item Tb.For each end use product (EUP) for which you wish to maintain registration, you
must agree to satisfy the data requirements by responding "yes."
FOR BOTH MUP and EUP products
You should also respond "yes" to this item (7a for MUP's and 7b for EUP's) if your product
is identical to another product and you qualify for a data exemption. You must provide the
EPA registration numbers of your source (s); do not complete the Requirements Status and
Registrant's Response form. Examples of such products include repackaged products and
Special Local Needs (Section 24c) products which are identical to federally registered
products.
If you are requesting a data waiver, answer "yes" here; in addition, on the "Requirements
Status and Registrant's Response" form under Item 9, you must respond with option 7 (Waiver
Request) for each study for which you are requesting a waiver.
NOTE: Item 7 a and 7b are not applicable for Generic Data.
INSTRUCTIONS FOR COMPLETING THE DATA CALL-IN RESPONSE FORMS
Generic and Product Specific Data Caii-ln
Item 8.ON BOTH FORMS: This certification statement must be signed by an authorized
representative of your company and the person signing must include his/her title. Additional
pages used in your response must be initialled and dated in the space provided for the
certification.
Item 9.ON BOTH FORMS: Enter the date of signature.
Item 10.ON BOTH FORMS: Enter the name of the person EPA should contact with
questions regarding your response.
Item 11.ON BOTH FORMS: Enter the phone number of your company contact.
Note: You may provide additional information that does not fit on this form in a signed letter that accompanies your response. For example, you
may wish to report that your product has already been transferred to another company or that you have already voluntarily cancelled this
product. For these cases, please supply all relevant details so that EPA can ensure that its records are correct.
131
-------
132
-------
Attachment 3. Generic and Product Specific Requirement
Status and Registrant's Response Forms (Form B inserts)
and Instructions
133
-------
134
-------
Instructions For Completing The "Data Call-in Response Forms" For The Generic And
Product Specific Data Call-In
INTRODUCTION
These instructions apply to the Generic and Product Specific "Data Call-In Response Forms"
and are to be used by registrants to respond to generic and product specific Data Call-Ins as
part of EPA's Reregistration Program under the Federal Insecticide, Fungicide, and
Rodenticide Act. The type of data call-in (generic or product specific) is indicated in item
number 3 ("Date and Type of DCI") on each form. BOTH "Data Call-In Response" forms
must be completed.
Although the form is the same for both generic and product specific data, instructions for
completing these forms are different. Please read these instructions carefully before filling out
the forms.
EPA has developed these forms individually for each registrant, and has reprinted these forms
with a number of items. DO NOT use these forms for any other active ingredient.
Items 1 through 4 have been reprinted on the form. Items 5 through 7 must be completed by
the registrant as appropriate. Items 8 through 11 must be completed by the registrant before
submitting a response to the Agency.
The public reporting burden for this collection of information is estimated to average 15
minutes per response, including time for reviewing instructions, searching existing data
sources, gathering and maintaining the data needed, and completing and reviewing the
collection of information. Send comments regarding the burden estimate or any other aspect of
this collection of information, including suggestions for reducing this burden, to Chief,
Information Policy Branch, Mail Code 213o, U.S. Environmental Protection Agency, 401 M
St., S.W., Washington, D.C. 20460; and to the Office of Management and Budget,
Paperwork Reduction Project 2070-0107, Washington, D.C. 20503.
135
-------
INSTRUCTIONS FOR COMPLETING THE DATA CALL-IN RESPONSE FORMS
Generic and Product Specific Data Call-in
Item l.ON BOTH FORMS: This item identifies your company name, number and address.
Item 2.ON BOTH FORMS: This item identifies the case number, case name, EPA chemical
number and chemical name.
Item 3.ON BOTH FORMS: This item identifies the type of Data Call-in. The date of
issuance is date stamped.
Item 4.ON BOTH FORMS: This item identifies the EPA product registrations relevant to
the data call-in. Please note that you are also responsible for informing the Agency of your
response regarding any product that you believe may be covered by this Data Call-In but that
is not listed by the Agency in Item 4. You must bring any such apparent omission to the
Agency's attention within the period required for submission of this response form.
Item 5.ON BOTH FORMS: Check this item for each product registration you wish to cancel
voluntarily. If a registration number is listed for a product for which you previously requested
voluntary cancellation, indicate in Item 5 the date of that request. Since this Data Call-in
requires both generic and product specific data, you must complete item 5 on both Data Call-
in response forms. You do not need to complete any item on the Requirements Status and
Registrant's Response Forms.
Item 6a.ON THE GENERIC DATA FORM: Check this Item if the Data Call-in is for
generic data as indicated in Item 3 and you are eligible for a Generic Data Exemption for the
chemical listed in Item 2 and used in the subject product. By electing this exemption, you
agree to the terms and conditions of a Generic Data Exemption as explained in the Data
Call-in Notice.
If you are eligible for or claim a Generic Data Exemption, enter the EPA registration Number
of each registered source of that active ingredient that you use in your product.
Typically, if you purchase an EPA-registered product from one or more other producers
(who, with respect to the incorporated product, are in compliance with this and any other
outstanding Data Call-In Notice), and
INSTRUCTIONS FOR COMPLETING THE DATA CALL-IN RESPONSE FORMS
Generic and Product Specific Data Caii-in
incorporate that product into all your products, you may complete this item for all products
listed on this form. If, however, you produce the active ingredient yourself, or use any
unregistered product (regardless of the fact that some of your sources are registered), you may
not claim a Generic Data Exemption and you may not select this item.
Item 6b.ON THE GENERIC DATA FORM: Check this Item if the Data Call-in is for
generic data as indicated in Item 3 and if you are agreeing to satisfy the generic data
requirements of this Data Call-In. Attach the Requirements Status and Registrant's Response
Form that indicates how you will satisfy those requirements.
NOTE: Item 6a and 6b are not applicable for Product Specific Data.
136
-------
Item 7a.ON THE PRODUCT SPECIFIC DATA FORM: For each manufacturing use
product (MUP) for which you wish to maintain registration, you must agree to satisfy the data
requirements by responding "yes."
Item Tb.For each end use product (EUP) for which you wish to maintain registration, you
must agree to satisfy the data requirements by responding "yes."
FOR BOTH MUP and EUP products
You should also respond "yes" to this item (7a for MUP's and 7b for EUP's) if your product
is identical to another product and you qualify for a data exemption. You must provide the
EPA registration numbers of your source (s); do not complete the Requirements Status and
Registrant's Response form. Examples of such products include repackaged products and
Special Local Needs (Section 24c) products which are identical to federally registered
products.
If you are requesting a data waiver, answer "yes" here; in addition, on the "Requirements
Status and Registrant's Response" form under Item 9, you must respond with option 7 (Waiver
Request) for each study for which you are requesting a waiver.
NOTE: Item 7 a and 7b are not applicable for Generic Data.
INSTRUCTIONS FOR COMPLETING THE DATA CALL-IN RESPONSE FORMS
Generic and Product Specific Data Caii-ln
Item 8.ON BOTH FORMS: This certification statement must be signed by an authorized
representative of your company and the person signing must include his/her title. Additional
pages used in your response must be initialled and dated in the space provided for the
certification.
Item 9.ON BOTH FORMS: Enter the date of signature.
Item 10.ON BOTH FORMS: Enter the name of the person EPA should contact with
questions regarding your response.
Item 11.ON BOTH FORMS: Enter the phone number of your company contact.
Note: You may provide additional information that does not fit on this form in a signed letter that accompanies your response. For example, you
may wish to report that your product has already been transferred to another company or that you have already voluntarily cancelled this
product. For these cases, please supply all relevant details so that EPA can ensure that its records are correct.
137
-------
138
-------
Attachment 4. EPA Batching of End-Use Products for
Meeting Data Requirements for Reregistration
139
-------
140
-------
EPA'S DECISION NOT TO BATCH PRODUCTS CONTAINING DIFENZOQUAT FOR
PURPOSES OF 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 end-use products containing the active
ingredient difenzoquat, the Agency considered batching end-use products. This process
involves grouping similar products 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, etcj.
However, batching of products containing difenzoquat was not possible after
considering the available information described above. Table I lists the end-use products (2)
containing difenzoquat. These products were either considered not to be similar for purposes
of acute toxicity or the Agency lacked sufficient information for decision making purposes.
The registrant is responsible for meeting the acute toxicity data requirements for each product.
Registrants must generate all the required acute toxicological studies for each of their
products. If a 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 today's standards (see
acceptance criteria attached).
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," lists the product
specific data required for each product, including the standard six acute toxicity tests. A
registrant must select 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). Since the products containing difenzoquat could not be batched, registrants
cannot choose from the remaining options: Cost Sharing (Option 2) or Offers to Cost Share
(Option 3).
Table T fNo Batch)
EPA Reg. No.
241-239
241-266
% Active Ingredients
96.5% difenzoquat
31.2% difenzoquat
Formulation Type
Solid
Liquid
141
-------
142
-------
Attachment 5. EPA Acceptance Criteria
143
-------
144
-------
SUBDIVISION D
Guideline Study Title
Series 61 Product Identity and Composition
Series 62 Analysis and Certification of Product Ingredients
Series 63 Physical and Chemical Characteristics
145
-------
61 Product Identity and Composition
ACCEPTANCE CRITERIA
Does your study meet the following acceptance criteria?
1. Name of technical material tested (include product name and trade name, if appropriate).
2. Name, nominal concentration, and certified limits (upper and lower) for each active ingredient and each intentionally-
added inert ingredient.
3. Name and upper certified limit for each impurity or each group of impurities present at > 0.1% by weight and for
certain lexicologically significant impurities (e.g., dioxins, nitrosamines) present at < 0.1%.
4. Purpose of each active ingredient and each intentionally-added inert.
5. Chemical name from Chemical Abstracts index of Nomenclature and Chemical Abstracts Service (CAS) Registry
Number for each active ingredient and, if available, for each intentionally-added inert.
6. Molecular, structural, and empirical formulas, molecular weight or weight range, and any company assigned
experimental or internal code numbers for each active ingredient.
7. Description of each beginning material in the manufacturing process.
EPA Registration Number if registered;
for other beginning materials, the following:
Name and address of manufacturer or supplier.
Brand name, trade name or commercial designation.
Technical specifications or data sheets by which manufacturer or supplier describes composition, properties or
toxicity.
8. Description of manufacturing process.
Statement of whether batch or continuous process.
Relative amounts of beginning materials and order in which they are added.
Description of equipment.
Description of physical conditions (temperature, pressure, humidity) controlled in each step and the parameters
that are maintained.
Statement of whether process involves intended chemical reactions.
Flow chart with chemical equations for each intended chemical reaction.
Duration of each step of process.
Description of purification procedures.
Description of measures taken to assure quality of final product.
9. Discussion of formation of impurities based on established chemical theory addressing (1) each impurity which may
be present at _>_ 0.1% or was found at _>_ 0.1% by product analyses and (2) certain lexicologically significant impurities
(see #3).
146
-------
62 Analysis and Certification of Product Ingredients
ACCEPTANCE CRITERIA
The following criteria apply to the technical grade of the active ingredient being reregistered. Use a table to present the
information in items 6, I, and 8.
Does your study meet the following acceptance criteria?
1. Five or more representative samples (batches in case of batch process) analyzed for each active ingredient and all
impurities present at > 0.1%.
2. Degree of accountability or closure > ca 98%.
3. Analyses conducted for certain traceTdxTc impurities at lower than 0.1% (examples, nitrosamines in the case of
products containing dinitroanilines or containing secondary or tertiary amines/alkanolamines plus nitrites;
polyhalogenated dibenzodioxins and dibenzofurans). [Note that in the case of nitrosamines both fresh and stored
samples must be analyzed.].
4. Complete and detailed description of each step in analytical method used to analyze above samples.
5. Statement of precision and accuracy of analytical method used to analyze above samples.
6. Identities and quantities (including mean and standard deviation) provided for each analyzed ingredient.
7. Upper and lower certified limits proposed for each active ingredient and intentionally added inert along with
explanation of how the limits were determined.
8. Upper certified limit proposed for each impurity present at > 0.1% and for certain lexicologically significant
impurities at < 0.1% along with explanation of how limit determined.
9. Analytical methods to verify certified limits of each active ingredient and impurities (latter not required if exempt
from requirement of tolerance or if generally recognized as safe by FDA) are fully described.
10. Analytical methods (as discussed in 19) to verify certified limits validated as to their precision and accuracy.
147
-------
63 Physical and Chemical Characteristics
ACCEPTANCE CRITERIA
The following criteria apply to the technical grade of the active ingredient being reregistered.
Does your study meet the following acceptance criteria?
63-2 Color
Verbal description of coloration (or lack of it)
Any intentional coloration also reported in terms of Munsell color system
63-3 Physical State
Verbal description of physical state provided using terms such as "solid, granular, volatile liquid"
Based on visual inspection at about 20-25° C
63-4 Odor
Verbal description of odor (or lack of it) using terms such as "garlic-like, characteristic of aromatic compounds"
Observed at room temperature
63-5 MeltingPoint
Reported in °C
Any observed decomposition reported
63-6 Boiling Point
Reported in °C
Pressure under which B.P. measured reported
Any observed decomposition reported
63-7 Density, Bulk Density, Specific Gravity
Measured at about 20-25° C
Density of technical grade active ingredient reported in g/ml or the specific gravity of liquids reported with
reference to water at zO° C. [Note: culk density of registered~products may oe reported m lbs/ft3 or Ibs/gallon.]
63-8 Solubility
Determined in distilled water and representative polar and non-polar solvents, including those used in formulations
and analytical methods for the pesticide
Measured at about 20-25° C
Reported in g/100 ml (other units like ppm acceptable if sparingly soluble)
63-9 Vapor Pressure
Measured at 25° C (or calculated by extrapolation from measurements made at higher temperature if pressure too
low to measure at 25° C)
Experimental procedure described
Reported in mm Hg (torr) or other conventional units
63-10 Dissociation Constant
Experimental method described
Temperature of measurement specified (preferably about
on OT: o r*\
20-25 C)
63-11 Octanol/water Partition Coefficient
Measured at about 20-25° C
Experimentally determined and description of procedure provided (preferred method-45 Fed. Register 77350)
Data supporting reported value provided
63-12 pH
Measured at about 20-25° C
Measured following dilution or dispersion in distilled water
63-13 Stability
Sensitivity to metal ions and metal determined
Stability at normal and elevated temperatures
Sensitivity to sunlight determined
148
-------
SUBDIVISION F
Guideline Study Title
81-1 Acute Oral Toxicity in the Rat
81-2 Acute Dermal Toxicity in the Rat, Rabbit or Guinea Pig
81-3 Acute Inhalation Toxicity in the Rat
81-4 Primary Eye Irritation in the Rabbit
81-5 Primary Dermal Irritation Study
81-6 Dermal Sensitization in the Guinea Pig
149
-------
81-1 Acute Oral Toxicity in the Rat
ACCEPTANCE CRITERIA
Does your study meet the following acceptance criteria?
1. Identify material tested (technical, end-use product, etc).
2. At least 5 young adult rats/sex/group.
3.^ Dosing, single oral may be administered over 24 hrs.
4.*! Vehicle control if other than water.
5. Doses tested, sufficient to determine a toxicity category or a limit dose (5000 mg/kg).
6. Individual observations at least once a day.
7. Observation period to last at least 14 days, or until all test animals appear normal whichever is longer.
8. Individual daily observations.
9. Individual body weights.
10. Gross necropsy on all animals.
Criteria marked with an * are supplemental and may not be required for every study.
ntal an
150
-------
81-2 Acute Dermal toxicity in the Rat, Rabbit or Guinea Pig
ACCEPTANCE CRITERIA
Does your study meet the following acceptance criteria?
1. Identify material tested (technical, end-use product, etc).
2. At least 5 animals/sex/group.
3.^ Rats 200-300 gm, rabbits 2.0-3.0 kg or guinea pigs 350-450 gm.
4. Dosing, single dermal.
5. Dosing duration at least 24 hours.
6.^ Vehicle control, only if toxicity of vehicle is unknown.
7.1 Doses tested, sufficient to determine a toxicity category or a limit dose (2000 mg/kg).
8. Application site clipped or shaved at least 24 hours oefore dosing.
9. Application site at least 10% of body surface area.
10. Application site covered with a porous nonirritating cover to retain test material and to prevent
ingestion.
11. Individual observations at least once a day.
12. Observation period to last at least 14 days.
13. Individual body weights.
14. Gross necropsy on all animals.
Criteria marked with an * are supplemental and may not be required for every study.
101
-------
81-3 Acute Inhalation Toxicity in the Rat
ACCEPTANCE CRITERIA
Does your study meet the following acceptance criteria?
1. Identify material tested (technical, end-use product, etc).
2. Product is a gas, a solid which may produce a significant vapor hazard based on toxicity and expected use or contains
particles of inhalable size for man (aerodynamic diameter 15 pm or less).
3. At least 5 young adult rats/sex/group.
4. Dosing, at least 4 hours by inhalation.
5. Chamber air flow dynamic, at least 10 air changes/hour, at least 19% oxygen content.
6. Chamber temperature, 22° C (+_2°), relative humidity 40-60%.
7. Monitor rate of air flow.
8. Monitor actual concentrations of test material in breathing zone.
9. Monitor aerodynamic particle size for aerosols.
10. Doses tested, sufficient to determine a toxicity category or a limit dose (5 mg/L actual concentration of respirable
substance).
11. Individual observations at least once a day.
12. Observation period to last at least 14 days.
13. Individual body weights.
14. Gross necropsy on all animals.
152
-------
81-4 Primary Eye Irritation in the Rabbit
ACCEPTANCE CRITERIA
Does your study meet the following acceptance criteria?
1. Identify material tested (technical, end-use product, etc).
2. Study not required if material is corrosive, causes severe
dermal irritation or has a pH of < 2 or > 11.5.
3. 6 adult rabbits.
4. Dosing, instillation into the conjunctival sac of one eye
per animal.
5. Dose, 0.1 ml if a liquid; 0.1 ml or not more than 100 mg if a solid, paste or particulate substance.
6. Solid or granular test material ground to a fine dust.
7. Eyes not washed for at least 24nours.
8. Eyes examined and graded for irritation before dosing and
at 1, 24, 48 and 72 hr, then daily until eyes are normal
or 21 days (whichever is shorter).
9.^ Individual daily observations.
Criteria marked with an * are supplemental and may not be required for every study.
10 O
-------
81-5 Primary Dermal Irritation Study
ACCEPTANCE CRITERIA
Does your study meet the following acceptance criteria?
1. Identify material tested (technical, end-use product, etc).
2. Study not required if material is corrosive or has a pH of <7. or > 11.5.
3. 6 adult animals.
4. Dosing, single dermal.
5. Dosing duration 4 hours.
6. Application site shaved or clipped at least 24 hours prior to dosing.
7. Application site approximately 6 cm2.
8. Application site covered with a gauze patch held in place with nonirritating tape.
9. Material removed, washed with water, without trauma to application site.
10. Application site examined and graded for irritation at 1, 24, 48 and 72 hr, then daily until normal or 14 days (whichever
is snorter).
11.^ Individual daily observations.
Criteria marked with an * are supplemental and may not be required for every study.
ntal an
154
-------
81-6 Dermal Sensitization in the Guinea Pig
ACCEPTANCE CRITERIA
Does your study meet the following acceptance criteria?
1. Identify material tested (technical, end-use product, etc).
2. Study not required if material is corrosive or has a
pHof <2of >11.5.
3. une oflhe following methods is utilized:
Freund's complete adjuvant test
Guinea pig maximization test
Split adjuvant technique
Buehler test
Open epicutaneous test
Mauer optimization test
Footpad technique in guinea pig.
4. Complete description of test.
5.^ Reference for test.
6C Test followed essentially as described in reference document.
7. Positive control included (may provide historical data conducted within the last 6 months).
Criteria marked with an * are supplemental and may not be required for every study.
155
-------
156
-------
Attachment 6. List of All Registrants Sent This Data Call-In (insert) Notice
157
-------
158
-------
Attachment 7. Cost Share Data Compensation Forms, Confidential Statement of
Formula Form and Instructions
159
-------
160
-------
~s>
s
CN
I
UJ
5
2
£
S
9
a
6
CQ
O
•
5
i
Q.
O
11
.^^^
*o
«N
0
uj
|
(Q
>.
•S
'c
3
CO
"S
c
•s
-
fc £
lit "s
tes Environmental Protec
of Pesticide Programs (T
Washington, DC 2046O
ial Statement
S3 *
United S
Offi
nfiden
o
U
^
LJJ
jif^
^J^f
^
1
o
g.
•§
,3
o
:§.
o
o
3
1
O
0
CO
CO
®
•a
|
c
(0
0)
E
<0
Cvi
(Include ZIP Code)
~
w
I
1
'o
0)
TJ
C
CO
CD
Z
^
£
1
E
o
u.
V
.c
>•
c
0
u
CO
b
Z
g
n
CD
k-
f
|
£
2
LU
X)
1
CO
LU
6
z
c
o
S
1
*
c
o
U)
0)
LU
0)
to
U.
~ii
C
I
ID
LL.
CD
X
a.
CO
s
c
ffl
Q
3
03
O
"3
\
j
s
I
a
1
2
a.
cr>
- c
1-2
3 p
^0
*~
|
| -I
TJ S ~*
? > -°
^ a
^
1
5 1
(D 3F
00°
E J5
O 3
0,03
"=1
*~ (D
6
z
0?
(C
2
LU
U)
2?
1
oB
CD
Z
1
3
U)
•~
11
n (List as actually intrude
mmonly accepted chert,
imber.l
°3c
n Formulat
•ion. Give
\. and CAS
ill
N
£<»§
5«g-
• o t
2.ES
z
0
UJ
co
<
0.
UJ
se
8
^
ro
1
^
'5
I—
•-
is
'u
D
a
c
)f Approvil
Name<
T3
,
9-
8
c
(D
o
^5.
Q.
5
5
"5
c
D)
•c
•£.
S:
o
o
^
LL
a.
LU
,
o
'"P
%
.
o
•=
(U
1
c
(D
±J
£3
in
-------
162
-------
Instructions for Completing the Confidential Statement of Formula
The Confidential Statement of Formula (CSF) Form 8570-4 must be used. Two legible, signed
copies of the form are required. Following are basic instructions:
a. All the blocks on the form must be filled in and answered completely.
b. If any block is not applicable, mark it N/A.
c. The CSF must be signed, dated and the telephone number of the responsible
party must be provided.
d. All applicable information which is on the product specific data submission
must also be reported on the CSF.
e. All weights reported under item 7 must be in pounds per gallon for liquids and
pounds per cubic feet for solids.
f. Flashpoint must be in degrees Fahrenheit and flame extension in inches.
g. For all active ingredients, the EPA Registration Numbers for the currently
registered source products must be reported under column 12.
h. The Chemical Abstracts Service (CAS) Numbers for all actives and inerts and
all common names for the trade names must be reported.
i. For the active ingredients, the percent purity of the source products must be
reported under column 10 and must be exactly the same as on the source
product's label.
j. All the weights in columns 13.a. and 13.b. must be in pounds, kilograms, or
grams. In no case will volumes be accepted. Do not mix English and metric
system units (i.e., pounds and kilograms).
k. All the items under column 13.b. must total 100 percent.
1. All items under columns 14.a. and 14.b. for the active ingredients must
represent pure active form.
m. The upper and lower certified limits for ail active and inert ingredients must
follow the 40 CFR 158.175 instructions. An explanation must be provided if the
proposed limits are different than standard certified limits.
n. When new CSFs are submitted and approved, all previously submitted CSFs
become obsolete for that specific formulation.
163
-------
164
-------
r/EPA
United States Environmental Protection Agency
Washington, DC 20460
CERTIFICATION OF OFFER TO COST
SHARE IN THE DEVELOPMENT OF DATA
Form Approved
OMB No. 2070-0106
2070-0057
Approval Expires 3-31-96
Public reporting burden for this collection of information is estimated to average 15 minutes per response, including
time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and
completing and reviewing the collection of information. Send comments regarding the burden estimate or any other
aspect of this collection of information, including suggestions for reducing this burden, to Chief, Information Policy
Branch, PM-223, U.S. Environmental Protection Agency, 401 M St., S.W., Washington, DC 20460; and to the Office
of Management and Budget, Paperwork Reduction Project (2070-0106), Washington, DC 20503.
Please fill in blanks below.
Company Name
Product Name
Company Number
EPA Reg. No.
I Certify that:
My company is willing to develop and submit the data required by EPA under the authority of the Federal
Insecticide, Fungicide and Rodenticide Act (FIFRA), if necessary. However, my company would prefer to
enter into an agreement with one or more registrants to develop jointly or share in the cost of developing
data.
My firm has offered in writing to enter into such an agreement. That offer was irrevocable and included an
offer to be bound by arbitration decision under section 3(c)(2)(B)(iii) of FIFRA if final agreement on all
terms could not be reached otherwise. This offer was made to the following firm(s) on the following
date(s):
Name of Firm(s)
Date of Offer
Certification:
I certify that I am duly authorized to represent the company named above, and that the statements that I have made on
this form and all attachments therein are true, accurate, and complete. I acknowledge that any knowingly false or
misleading statement may be punishable by fine or imprisonment or both under applicable law.
Signature
Name and
of Company's Authorized Representative
Date
Title (Please Type or Print)
EPA Form 8570-32 (5/91) Replaces EPA Form 8580, which is obsolete
165
-------
166
-------
&EPA
United States Environmental
Washington, DC
CERTIFICATION WITH
DATA COMPENSATION
Protection
20460
Agency
RESPECT TO
REQUIREMENTS
OUf M*. 3070-0107
2070-0057
Approval Expire* 3-31-96
Public reporting burden for this collection of information is estimated to average 15 minutes per response, including
time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and
completing and reviewing the collection of information. Send comments regarding the burden estimate or any other
aspect of this collection of information, including suggestions for reducing this burden, to Chief, Information Policy
Branch, PM-223, U.S. Environmental Protection Agency, 401 M St., S.W., Washington, DC 20460; and to the Office
of Management and Budget. Paperwork Reduction Project (2070-0106), Washington. DC 20503.
Please fill In blanks below.
Company Nam*
Product N«M
Company Numbar
SPA *•?. HO.
I Certify that:
1. For each study cited in support of registration or ^registration under the Federal Insecticide, Fungicide and
Rodenticide Act (FIFRA) that is an exclusive use study, I am the original data submitter, or I have obtained the
written permission of the original data submitter to cite that study.
2. That for each study cited in support of registration or ^registration under FIFRA that is NOT an exclusive use
study, I am the original data submitter, or I have obtained the written permission of the original data submitter, or I
have notified in writing the company(ies) that submitted data I have cited and have offered to: (a) Pay
compensation for those data in accordance with sections 3(C)(1)(D) and 3(c)(2)(D) of FIFRA; and (b) Commence
negotiation to determine which data are subject to the compensation requirement of FIFRA and the amount of
compensation due. if any. The companies I have notified are: (check one)
[ ] The companies who have submitted the studies listed on the back of this form or attached
sheets, or indicated on the attached -Requirements Status and Registrants' Response Form.'
3. That I have previously complied wfth section 3(c)(i )(D) of FIFRA for the studies I have cited in support of
registration or reregistratton under FIFRA.
Signature
Date
Name and Till* (Pl«aa« Typ* or Print)
GENERAL OFFER TO PAY: I hereby offer and agree to pay compensation to other persons, with regard to me
registration or reregistratton of my products, to the extent required by FIFRA sections 3(C)(1)(D) and 3(c)(2)(D).
Signature
Date
Name and Title
-------
168
-------
APPENDIX G. FACT SHEET
169
-------
170
-------
United States
Environmental Protection
Anpnrw
Preventi on Pesti ci des
And Toxic Substances
EPA-738-F-94-014
September 1994
&ERA R.E.D. FACTS
Pesticide
Reregistration
Use Profile
Regulatory
History
Human Health
Assessment
Difenzoquat
All pesticides sold or distributed in the United States must be registered
by EPA, based on scientific studies showing that they can be used without
posing unreasonable risks to people or the environment. Because of advances
in scientific knowledge, the law requires that pesticides which were first
registered years ago be reregistered to ensure that they meet today's more
stringent standards.
In evaluating pesticides for reregistration, EPA obtains and reviews a
complete set of studies from pesticide producers, describing the human health
and environmental effects of each pesticide. The Agency imposes any
regulatory controls that are needed to effectively manage each pesticide's risks.
EPA then reregisters pesticides that can be used without posing unreasonable
risks to human health or the environment.
When a pesticide is eligible for reregistration, EPA announces this and
explains why in a Reregistration Eligibility Decision (RED) document. This
fact sheet summarizes the information in the RED for reregistration Case 0223,
difenzoquat.
Difenzoquat is a selective, post-emergent herbicide used to control wild
oats in barley and wheat. Wild oats is an annual grassy weed that out-competes
barley and wheat, causing serious yield losses. Marketed under the trade name
Avenge, difenzoquat is a soluble concentrate/liquid applied once per growing
season as a ground or aerial broadcast treatment. Most of the product used in
the U.S. is applied to wheat crops (64-77%).
Difenzoquat was first registered as a pesticide in the U.S. in July 1975,
for its current uses. EPA issued a Registration Standard for difenzoquat in
December 1988 (NTIS #PB89-162127). Currently, two difenzoquat pesticide
products are registered. One is a technical grade, manufacturing use product
containing 96% of the active ingredient; the other is the end-use product
Avenge, a soluble concentrate containing 31.2% active ingredient.
Toxicity
In acute toxicity studies, difenzoquat has caused severe irritation to the
eyes of rabbits. It has been placed in Toxicity Category I, indicating the
greatest degree of acute toxicity, for eye irritation effects. Difenzoquat causes
a moderate degree of acute toxicity administered orally, to the skin and by
171
-------
inhalation, and has been placed in Toxicity Categories II and III for these
effects.
In a subchronic feeding study using beagle dogs, difenzoquat caused no
treatment-related effects. However, treatment-related skin reactions and effects
were noted in a dermal toxicity study using rabbits.
A chronic toxicity study using rats resulted only in decreased body
weight gains. A study using beagle dogs resulted in numerous toxic signs
including high mortality, decreased food consumption, weight loss, tremors,
lethargy and irregular gait. Difenzoquat is not carcinogenic in studies using
rats and mice, and has been classified as a Group E carcinogen (a compound
showing evidence of non-carcinogenicity for humans).
Developmental toxicity studies using rats and rabbits resulted in maternal
toxicity in the higher dose groups, a decrease in fetal weights in rats, and
vertebrae abnormalities in rabbit offspring. In a reproductive toxicity study
using rats, difenzoquat caused maternal decreased body weight gain and weight
decreases in pups at birth and weaning. Difenzoquat is not mutagenic.
Neurotoxicity studies still are required.
Dietary Exposure
People may be exposed to low level residues of difenzoquat in the diet
when consuming wheat, barley or the meat of poultry, cattle, hogs and sheep.
Tolerances or maximum residue limits are established, and have been
reassessed, for residues of difenzoquat in barley and wheat grain and straw, in
the meat, fat and byproducts of cattle, goats, hogs, horses and sheep, and in
poultry meat and meat byproducts (please see 40 CFR 180.369). Tolerances
are not established or needed for milk or eggs, but food and feed additive
tolerances must be established for wheat bran and shorts, and barley bran and
hulls.
EPA estimates that the overall U.S. population is exposed to about 0.1%
of the difenzoquat Reference Dose (RfD), or amount believed not to cause
adverse effects if consumed daily over a 70-year lifetime. Children aged one
through six, the most highly exposed population subgroup, are exposed to
about 0.2% of the RfD. The new food additive tolerance for wheat bran will
not cause a measurable increase in these extremely low exposure levels.
Occupational and Residential Exposure
Pesticide handlers (mixers, loaders and applicators) may be exposed to
difenzoquat during application. However, difenzoquat generally is of low
acute toxicity and causes no toxicity concerns for workers, with the exception
of primary eye irritation. Since difenzoquat is extremely acutely toxic to the
eyes and is placed in Toxicity Category I for eye irritation, a 48 hour restricted
entry interval (REI) imposed by the Worker Protection Standard (WPS) will
be maintained. During this time period, workers who must enter treated areas
will be required to wear personal protective equipment (PPE) including
coveralls, chemical-resistant gloves, shoes plus socks, and protective eyewear.
Human Risk Assessment
Although difenzoquat is used on barley and wheat crops, consumers are
exposed to extremely low level residues in their diets posing no known risks.
Difenzoquat generally is of low acute toxicity but poses a risk of acute eye
172
-------
Environmental
Assessment
Additional Data
RedUJred
irritation to workers. To mitigate this risk, a 48 hour restricted entry interval
will be maintained. People who must enter treated areas during this time are
required to wear designated protective clothing and equipment including
protective eyewear.
Environmental Fate
Difenzoquat is persistent and relatively immobile. However, the
environmental fate assessment is not complete because the route of dissipation
has not been established. Laboratory data indicate that difenzoquat binds
with/is immobile in soil and has little potential for ground water contamination.
However, field dissipation studies contrast sharply and indicate that residues
decline with time. Additional, confirmatory data are required to compare the
recovery methods used in laboratory and field studies.
Ecological Effects
Difenzoquat is slightly toxic to practically non-toxic to birds and
freshwater fish, but is moderately toxic to freshwater invertebrates. It is non-
toxic to honey bees.
Ecological Effects Risk Assessment
Current uses of difenzoquat do not pose any unreasonable threat to the
environment. Difenzoquat is believed to present a slight to moderate potential
for acute toxicity to wildlife and aquatic species. Actual acute risks, however,
appear to be minimal. Chronic toxicity to wildlife appears to be slight, and
chronic risk to fish is unlikely.
Since difenzoquat is a herbicide that is applied aerially, risk to non-target
aquatic and terrestrial plants, including endangered plant species, is expected
to be high. Additional, confirmatory data are required to assess these risks.
In addition, EPA is exploring risk mitigation for all herbicides.
EPA is requiring the following generic data for difenzoquat to confirm
its regulatory assessments and conclusions:
Acute and 90-Day Neurotoxicity Screening Studies;
Seed Germination/Seedling Emergence;
Vegetative Vigor;
Aquatic Plant Growth;
Confined Rotational Crop;
Droplet Size Spectrum;
Drift Field Evaluation;
Non-guideline laboratory study comparing recovery methods used in
previous laboratory and field dissipation studies.
The Agency also is requiring product-specific data including product
chemistry and acute toxicity studies, revised Confidential Statements of
Formula (CSF) and revised labeling for reregistration.
173
-------
Product Labeling
Changes Required
The labels of all registered pesticide products containing difenzoquat
must comply with EPA's current pesticide labeling requirements. No
additional labeling requirements are required for the end-use product at this
time. However:
° The Restricted Entry Interval (REI) established by the Worker Protection
Standard must remain at 48 hours. This REI must be inserted into the
standardized REI statement required by PR Notice 93-7.
° Personal protective equipment (PPE) for early entry includes coveralls,
chemical resistant gloves, shoes plus socks, and protective eyewear. These
items must be inserted into the early entry PPE statement required by PR
Notice 93-7.
Regulatory
Conclusion
For More
Information
The use of currently registered pesticide products containing difenzoquat
in accordance with approved labeling will not pose unreasonable risks or
adverse effects to humans or the environment. Therefore, all uses of these
products are eligible for reregistration.
These difenzoquat products will be reregistered once the confirmatory
generic data, product specific data, revised Confidential Statements of Formula
and revised labeling are received and accepted by EPA.
EPA is requesting public comments on the Reregistration Eligibility
Decision (RED) document for difenzoquat during a 60-day time period, as
announced in a Notice of Availability published in the Federal Register. To
obtain a copy of the RED document or to submit written comments, please
contact the Pesticide Docket, Public Response and Program Resources Branch,
Field Operations Division (7506C), Office of Pesticide Programs (OPP), US
EPA, Washington, DC 20460, telephone 703-305-5805.
Following the comment period, the difenzoquat RED document will be
available from the National Technical Information Service (NTIS), 5285 Port
Royal Road, Springfield, VA 22161, telephone 703-487-4650.
For more information about EPA's pesticide reregistration program, the
difenzoquat RED, or reregistration of individual products containing
difenzoquat, please contact the Special Review and Reregistration Division
(7508W), OPP, US EPA, Washington, DC 20460, telephone 703-308-8000.
For information about the health effects of pesticides, or for assistance
in recognizing and managing pesticide poisoning symptoms, please contact the
National Pesticides Telecommunications Network (NPTN). Call toll-free 1-
800-858-7378, between 8:00 am and 6:00 pm Central Time, Monday through
Friday.
174
------- |