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Standard Operating Procedures - Product Properties
Date of Final Approval: January 8, 2003
General Guidance to Reviewers of Product Properties
Data, Labels, and Confidential Statements of Formula Submitted for Registration
and Reregistration of Pesticide Chemicals (Conventional)
Non-binding Nature of This Policy Guidance Document
Consistent Application of This Policy Guidance
Document
Comments regarding this document may be sent to Betsy Grimm (grim.betsy@epa.gov) or to the
public docket established for this document.
Registration and Reregistration of Pesticide Chemicals (Conventional)
Table of Contents
-
Purpose
-
Introduction
-
Why is Product Properties Needed?
-
Product Properties Data Requirements for Registration
and Reregistration of Pesticide Chemicals (Conventional)
-
Highlighting the Differences Between Technical Grade
of Active Ingredients (TGAIs), Pure Active Ingredients (PAIs), Manufacturing-Use
Product (MPs) and End-Use Products (EPs)
-
Regulatory References
-
Reviewer Needs
-
Product Properties Reviews
-
General Guidance
-
Organization of the Reviews
-
Review of an End-Use Product Formulated
from Registered Sources
-
Review of a Technical Grade of an Active
Ingredient (TGAI) and Products Produced by an Integrated Production
System
-
Joint Review of Certain Technical Grade
of Active Ingredients (TGAIs) with the Pest Management Regulatory
Agency in Canada (PMRA) [ Not Applicable to AD and SRRD]
-
Joint Review of Formulated Pesticide Products
with the Pest Management Regulatory Agency in Canada (PMRA)
[Not Applicable to AD and SRRD]
-
Other Reviews in Product Properties (Not
all are applicable to SRRD -except for Re-submissions, Re-packs,
and Alternate Formulations)
-
Confidential Business Information (CBI) and Non-CBI
Product Properties Requirements
-
Product Properties Studies Requiring Compliance
or Noncompliance with Good Laboratory Practices (GLP) Standards of
40CFR§160
-
Label Statements that Should be Reviewed by the
Product Chemist
-
Review of the Confidential Statements of Formula
(CSF)
-
How to Express Nominal Concentrations
-
Consistency between the Label and CSF
-
Verify the Following to Guard Against Common Errors
when Comparing the Label and CSF
-
Review Forms
-
Technical Grade of Active Ingredient
-
Form 8570-36, Compliance With PR Notice 98-1
on Self-Certification of Product Chemistry Data
-
Form 8570-37, Self-Certification Statement in
Compliance With PR Notice 98-1
-
Joint Review Form for a TGAI
-
Joint Review Form for MPs/EPs
Appendix A Example Reviews
-
Sample Review of an End-Use Product Formulated from
Registered Sources
-
Examples of "Me-Too" requests citing the Introduction,
Findings, and Recommendations
Appendix B Changes and Recommendations Under Consideration
|
-
Purpose
The purpose of this Standard Operating Procedure is to provide guidance
to reviewers of product properties in the following Divisions of the
Office of Pesticide Programs
(OPP):
- Registration Division (RD)
- Antimicrobials Division (AD)
- Special Review and Reregistration Division (SRRD)
- Health Effects Division (HED)
Reviews comprise product chemistry data, labels, and confidential
statements of formula (CSFs) submitted by pesticide registrants/applicants
seeking registration, reregistration and amendments, and re-submissions
of conventional chemical pesticides including antimicrobials. Biochemical
and microbial pesticides, as well as plant-incorporated protectants
(PIPs), have special data requirements, and their product property
submissions are reviewed by the Biopesticides and Pollution Prevention
Division (BPPD). However, many of the generic procedures here also
apply to BPPD reviews. The regulated pesticide industry and OPP's
regulators do adhere to certain laws, regulations, and guidelines,
listed in the Reference Section of this SOP.
This is a comprehensive document that covers all aspects of product
properties including Review Forms that may not be applicable to all
four of the OPP's Divisions listed above. Each of the four Divisions
(RD, AD, SRRD and HED) cited in this Part is encouraged to use the
proper Form based on the work assignment. Other than the Review Forms,
information in this SOP distills the expertise of OPP's scientists
and should provide adequate guidance to reviewers of product properties,
(except for biopesticides, which BPPD reviews under separate guidance).
-
Introduction
-
Product properties is the science that elucidates the chemistry,
identity, composition, analysis and properties of pesticide products.
Pesticides can be classified into two major categories:
-
conventional (including antimicrobials);
-
biopesticides, which includes biochemical pesticides, microbial
pesticides, and plant-incorporated protectants (PIPs).
-
Who Is Doing What in Product Chemistry?
Registration Division (RD)
The Technical Review Branch (TRB), Product Chemistry Team in
RD reviews registration of conventional chemical pesticides (including
antimicrobials and excluding biopesticides) of technical grade
of active ingredients (TGAI), pure active ingredients (PAI), manufacturing-use
products (MP), end-use products (EP), and amendments intended
for food and non-food uses. In addition, RD reviews experimental
use permits, "me-too" applications, alternate formulations, chemical
formula changes some of which are for compliance with the Food
Quality Protection Act (FQPA), applications/petitions requesting
clearances for inert ingredients for use in pesticide formulations
intended for food/non-food uses, analytical methods validations
by the Analytical Chemistry Branch of the Biological and Economic
Analysis Division (BEAD), product chemistry laboratory audits
by the Office of Enforcement
and Compliance Assurance (OECA), labels and Confidential Statements
of Formula (CSFs) of all products submitted to RD. In addition,
under the North
American Free Trade Agreement (NAFTA), RD and the
Pest
Management Regulatory Agency (PMRA) in Canada conduct joint
reviews of certain new active ingredients. Other assignments include
but are not limited to: review of electronic submissions of product
chemistry data, upgrades to the code of federal regulations, upgrades
to the Office
of Prevention, Pesticides and Toxic Substances (OPPTS) Test Guidelines
- Series 830-Product Properties, upgrades to the label review
manual/consumer labeling initiative, expansion and sharing of
the product chemistry data base with other divisions in OPP, harmonizing
RD's work output with that in other OPP Divisions, harmonizing
certain product chemistry guideline requirements with the Organization
for Economic Cooperation and Development (OECD), harmonizing
pesticide specifications with the
Food
and Agriculture Organization/World Health Organization (FAO/WHO), and monitoring the quality of all work output in conjunction with
the Office of Environmental
Information (OEI).
Antimicrobials Division (AD): Registration of
antimicrobial pesticides chemicals (conventional).
Biopesticides and Pollution Prevention Division (BPPD):
Registration and related activities of biopesticides.
Health Effects Division (HED): Reviews submissions
of product properties, CSFs, and labels for old chemical pesticides
(conventional) undergoing reregistration.
Special Review and Reregistration Division (SRRD): Reregistration
of pesticide chemicals (conventional) registered prior to 01/NOV/1984
and pesticides older than 15 years (after expiration of the exclusive
use period).
|
-
Why is Product Properties Needed?
The regulatory data requirements for product properties are outlined
in 40
Code of Federal Regulations (CFR) §158.150 to §158.190 for chemical
pesticides, §158.690 for biochemical pesticides, and §158.740 for
microbial pesticides. Detailed guidance on how to conduct these studies
are outlined in OPPTS
Test Guidelines Series 830, Product Properties; OPPTS
Test Guidelines, Series 880, Biochemical Test Guidelines; OPPTS
Test Guidelines, Series 885, Microbial Pesticides Test Guidelines,
Overview of Microbial Pest Control Agents, and OPPTS
Test Guidelines, Series 810, Product Efficacy. Listed below are
some of the regulatory requirements surrounding the need for product
chemistry:
-
Identification and characterization of each ingredient in pesticide
products.
-
Risk assessment.
-
Environmental Fate assessment.
-
Reentry determination and labeling precautions pertaining to
worker protection.
-
Labeling directions pertaining to tank mixes and spray applications.
-
Labeling ingredient statement, precautionary statements, the
physical or chemical hazards statement, and the storage and disposal
statement.
-
Expressing a product's composition and some properties on the
Confidential Statements of Formula (CSFs).
-
Developing the Reregistration Eligibility Decisions (REDs).
-
Public inquiry: chemical spills, injuries to the flora and fauna,
uses, contamination to various compartments of the environment,
still birth, drift, degradation, efficacy, fish kills, leaching,
runoff, marketing, storage, disposal, transportation, analytical
methods, flammability, corrosivity, explodability, etc.
-
Product Properties Data Requirements for
Registration and Reregistration of Pesticide Chemicals (Conventional):
Summary of Substances to be Tested in Each 830 Series Guideline
Group A: Product Identity, Composition, and
Analysis Test Guidelines
New guidelines (1996) |
1982 guidelines |
Title |
Test substance |
Technical grade and Pure active ingredient |
Manufacturing-use product |
End-use product |
830.1550 |
158.155 |
Product identity and composition |
Yes |
Yes |
Yes |
830.1600 |
158.160 |
Description of materials used to produce the product |
Yes |
Yes |
Yes |
830.1620 |
158.162 |
Description of production process |
Yes |
Yes |
Yes |
830.1650 |
158.165 |
Description of formulation process |
Yes |
Yes |
Yes |
830.1670 |
158.167 |
Discussion of formation of impurities |
Yes |
Yes |
Yes |
830.1700 |
158.170 |
Preliminary analysis |
Yes |
Yes |
Yes |
830.1750 |
158.175 |
Certified limits |
Yes |
Yes |
Yes |
830.1800 |
158.180 |
Enforcement analytical method |
Yes |
Yes |
Yes |
830.1900 |
64-1 |
Submittal of samples |
Yes |
Case-by-case |
Case-by-case |
Group B: Physical and Chemical Properties
(40 CFR§158.190)
New guidelines (1996) |
1982 guidelines |
Title |
Test substance |
Technical grade and Pure active ingredient |
Manufacturing-use product |
End-use product |
830.6302 |
63-2 |
Color |
Yes |
Yes |
No |
830.6303 |
63-3 |
Physical state |
Yes |
Yes |
Yes |
830.6304 |
63-4 |
Odor |
Yes |
Yes |
No |
830.6313 |
63-13 |
Stability to normal and elevated temperatures, metals, and metal
ions |
Yes |
No |
No |
830.6314 |
63-14 |
Oxidation / Reduction: Chemical Incompatibility |
No |
Yes |
Yes |
830.6315 |
63-15 |
Flammability |
No |
Yes |
Yes |
830.6316 |
63-16 |
Explodability |
No |
Yes |
Yes |
830.6317 |
63-17 |
Storage stability |
No |
Yes |
Yes |
830.6319 |
63-19 |
Miscibility |
No |
Yes |
Yes |
830.6320 |
63-20 |
Corrosion characteristics |
No |
Yes |
Yes |
830.6321 |
63-21 |
Dielectric breakdown voltage |
No |
No |
Yes |
830.7000 |
63-12 |
pH |
Yes |
Yes |
Yes |
830.7050 |
None |
UV/Visible absorption |
Yes (PAI) |
No |
No |
830.7100 |
63-18 |
Viscosity |
No |
Yes |
Yes |
830.7200 |
63-5 |
Melting point / melting range |
Yes (solids-PAI) |
No |
No |
830.7220 |
63-6 |
Boiling point / boiling range |
Yes (liquids-PAI) |
No |
No |
830.7300 |
63-7 |
Density / relative density / bulk density |
Yes |
Yes |
Yes |
830.7370 |
63-10 |
Dissociation constants in water |
Yes (case-by-case, PAI) |
No |
No |
830.7520 |
None |
Particle size, fiber length, and diameter distribution |
Yes (solids-PAI, water solubility <10-6g/l) |
No |
No |
830.7550 |
63-11 |
Partition coefficient (n-octanol / water), shake flask method |
Yes (for non-polar organics-PAI) |
No |
No |
830.7560 |
63-11 |
Partition coefficient (n-octanol / water), generator column
method |
Yes (for non-polar organics-PAI) |
No |
No |
830.7570 |
63-11 |
Partition coefficient (n-octanol / water), estimation by liquid
chromatography |
Yes (for non-polar organics-PAI) |
No |
No |
830.7840 |
63-8 |
Water solubility: Column elution method, shake flask method |
Yes (PAI) |
No |
No |
830.7860 |
63-8 |
Water solubility: generator column method [refer to f. under
Explanations]. |
Yes (PAI) |
No |
No |
830-xxxx |
63-8 |
Solubility in organic solvents [refer to g. under Explanations] |
Yes (PAI) |
No |
No |
830.7950 |
63-9 |
Vapor pressure |
Yes (PAI) |
No |
No |
Source: Table 2, page 18 of OPPTS Test Guidelines, Series-830, Product
Properties (1996).
- Yes = Required,
- No = Not required
- End-Use Product = EP,
- Guideline Reference No. = GRN,
- Manufacturing-Use Product = MP,
- Pure Active Ingredient = PAI,
- Technical Grade of Active Ingredient = TGAI
Explanations of Product Properties Data Requirements:
-
Column four lists the requirements for a technical grade and
pure active ingredients in which the test substance is the TGAI/PAI
for the technical grade of active ingredient and PAI for the pure
active ingredient. It should be noted that Guideline 830.1650
Description of formulation process is not required for products
produced by an integrated system except for products formulated
using non- registered sources or sources of an unknown composition
to the EPA.
-
Columns five and six list the requirements for non-integrated
MPs/EPs when either is formulated from registered sources with
no intended chemical reaction, subject of PR Notice 98-1, noting
that the storage stability (GRN 830.6317) is required for all
EPs and MPs.
-
All the requirements, where applicable, are needed for qualifying
products produced by an integrated production system, comprising
the following 14 classes (16 if TGAI and PAI are included):
Class Number |
Products |
1 and 2 |
MPs/EPs that are technicals. |
3 and 4 |
MPs/EPs manufactured from registered sources. |
5 and 6 |
MPs/EPs manufactured from unregistered sources. |
7 and 8 |
MPs/EPs manufactured from sources of an unknown composition
to the EPA. |
9 and 10 |
MPs/EPs formulated from unregistered sources. |
11 and 12 |
MPs/EPs formulated from sources of an unknown composition
to the EPA. |
13 and 14 |
MPs/EPs formulated from registered sources in which a chemical
reaction took place resulting in the formation of new ingredients. |
-
In the above 14 classes, applicants will need to do the same
studies as those for non-integrated products in b. above then
isolate the TGAI or PAI for the studies required for the TGAI
as in a. above, where applicable. If neither can be isolated,
a statement of composition of the practical equivalent of the
technical grade of active ingredient must be submitted.
-
Applicants are advised to consult the footnotes under the table
in 40CFR§ 158.190 for exemptions from the requirements if based
on scientific and/or regulatory reasons, e.g., N/A for dielectric
breakdown voltage if the product is solid or not recommended for
use around electrical equipment if it is liquid.
-
OPPTS 830.7840/830.7860, Water Solubility:
OPPTS Test Guidelines, Series 830, Product Properties, Guidelines
830.7840 and 830.7860, were originated from: the Environmental
Protection Agency's (EPA) Toxic Substances Control Act ( TSCA)
Chemical Fate Test Guidelines 796.1840, Water Solubility (Shake
Flask Method); 796.1860, Water Solubility (Generator Column Method);
EPA Pesticides Assessment Guidelines, Subdivision D, Product Chemistry,
Guideline 63-8, Solubility; and OECD Guidelines 105 Water Solubility.
However, the TSCA Chemical Fate Test Guidelines 796.1840 and 796.1860
for Water Solubility were deleted from the CFR 40 Part 796 in
the revision of 1995.
-
Solubility in Organic Solvents (830.xxxx):
This data requirement was cited in the preamble of OPPTS Test
Guidelines, Series 830, page 17 but was inadvertently omitted
from the table of requirements, page 18. It is included in the
table of requirements in this SOP under a temporary number (830.xxxx)
until it is given a specific guideline number when the Guidelines
are revised. The following references pertain to pesticide solubilities
in organic solvents:
-
William F. Linke (1963). Solubility Measurements, Chapter
20. In Standard Methods of Chemical Analysis (Sixth
Edition), Volume Two, Edited by Frank J. Welcher. D. Van Nostrand
Company, Inc., 24 West 40 Street, New York, New York. It describes
detailed test methods for determination of solubility of chemical
compounds in various organic solvents (1282 pages).
-
Lyman, W. J., W. F. Reehl, Rosenblatt, and Shinoda Kozo (1990).
Solubility in Various Solvents, Handbook of Chemical Property
Estimation Methods, Published by American Chemical Society,
Washington, D.C.
-
Becher, Paul and Marcel Dekker (1978). Principles of
Solution and Solubility. Translated in Collaboration
with New York and Basel (222 pages). The estimation of solubility
of compounds to various non-polar organic solvents is based
on the theoretical equations developed and calculated by the
authors as shown below:
- Estimation of solubility of gases in liquid solvents.
-ln x1 = ln (f1L/f1
V) + (V1 φ 2 2
(δ 1 - δ 2)2/RT
- Estimation of solubility of liquid solute in solvents.
RTc = [ 2 x 1c x 2c v12v
22 (δ1-δ2)
2/[x 1cv1 + x2cv2]
3
- Estimation of solubility of solids in liquid solvents.
If x1 , 0.01: ln x1 = ΔHf
/RT [T/Tm-1] - lnγ ∞
If x1, 0.1: ln x1 + (1-x1)2
ln γ 1∞ = ΔHf
/RT [T/Tm-1]
γ1∞ (activity coefficient): Refer
to Chapter 11, reference 2. above.
|
-
Highlighting the Differences Between Technical
Grade of Active Ingredients (TGAIs), Pure Active Ingredients (PAIs),
Manufacturing-Use Product (MPs) and End-Use Products (EPs)
Technical Grade of Active Ingredient (TGAI):
-
A material containing an active ingredient that prevents, destroys,
repels, or mitigates any pest or acts as a plant growth regulator,
a defoliant, a desiccant or a nitrogen stabilizer. TGAI can be
an MP or an EP composed solely of the TGAI.
-
The highest concentration of the active ingredient which is produced
on a commercial or pilot-plant production scale; and
-
Contains no inerts, except those used for purification.
Products involving chemical reaction can be represented by the
following equation:
reactants A + B → TGAI
TGAI can be composed of PAI (nominal concentration) + residuals
from the starting materials + impurities + contaminants + side
reactions + degradation products + residuals of solvents used
for purification (must be claimed on the CSF as residual solvents).
Pure Active Ingredient (PAI):
It is the purest form of a TGAI with a purity > 99%.
Manufacturing-Use Product (MP):
-
Any pesticide product other than an end-use product.
-
It has a label stating "for use in formulating other products";
and
-
May contain solvents and/or stabilizers.
End-Use Product (EP):
-
A pesticide product whose label includes directions for use;
and
-
The label does not state that it will be used in formulating
or manufacturing other products.
-
Regulatory References
-
OPPTS
Test Guidelines, Series 830-Product Properties (1996).
-
The
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA)
and Federal
Food, Drug, and Cosmetic Act (FFDCA) As Amended by the Food
Quality Protection Act (FQPA) of August 3, 1996:
FIFRA
Parts |
Subject |
2 |
Definitions. |
3 |
Registration. |
4 |
Reregistration of Registered Products. |
10 |
Protection of trade secrets. |
12 |
Unlawful acts. |
13 |
Stop sale, use, removal, and seizure. |
14 |
Penalties. |
19 |
Storage, disposal, transportation, and recall. |
-
40
CFR (Code of Federal Regulations)
Part |
Subject |
152 |
Pesticide Registration. |
153 |
Registration policies. |
156 |
Labeling requirements. |
158 |
Data requirements for registration/reregistration (emphasis
on Parts 158.150 to 158.190). |
160 |
Good Laboratory Practice (GLP) Standards, emphasis on Parts
160.135(a) and (b). |
180.1001 |
Tolerances and Exemptions from Tolerances. |
766 |
Dibenzo--Dioxins/Dibenzofurans. |
799 |
Chemical Fate Testing Guidelines, Subpart B: Physical and
Chemical Properties. |
-
21 CFR (Code of Federal Regulations)
21 CFR§175
21 CFR§182
-
Standard Evaluation Procedures (SEPs), 1992: End-Use Products
and Technicals. Helpful but need upgrading to conform with new
OPPTS Test Guidelines, Series 830-Product Properties, revisions
to 40 CFR, the self-certification program stipulated in PR Notice
98-1, revised CSF, and recent PR/FR Notices including a pending
DRAFT PR Notice on the definitions of "Identical and Substantially
Similar Products" by Sami Malak.
-
Hand Book for Reregistration of Pesticides, 1991.
-
The Blue Book: General Information on Applying for Registration
of Pesticides in the United States, 1999.
-
Rejection Rate Analysis of Product Chemistry, 1997.
-
Standard Operating Procedures (SOPs):
-
SOP#3068.2, 01/JUL/1981. Determination of Substantially Similar
Pesticides Under FIFRA Section 3(c)(7)(A).
-
SOP#3017.1, 28/JAN/1987. Product Chemistry Data and Pesticide
Sample Evaluation.
-
SOP#3096.1, 09/FEB/1987. Processing Inert Ingredient Clearances.
-
SOP#3095.5, 02/OCT/1992. Product Reregistration Procedures.
-
SOP#3095.6, 23/DEC/1993. Product Reregistration and Other
Post-RED Procedure.
-
Label
Review Manual/Consumer Labeling Initiative (1999).
-
Federal Register Notices
(FR). Most important:
-
New Inert Ingredients and New Food-Uses of Existing Inerts:
52(77) FR13308, 22/APR/1987.
-
List A chemicals: 54(34)FR7740, 22/FEB/1989.
-
List B chemicals: 54(100)FR22706, 25/MAY/1989.
-
List C chemicals: 54(140)FR30846, 24/JUL/1989.
-
List D chemicals: A list, no FR Notice.
-
Flammability Labeling Requirements for Total Release Fogger
Pesticides: 59(73)FR13058-13064, 15/APR/1994.
-
Inert Ingredients in Pesticide Products; Policy Statement:
52(77) FR13305-13309, 22/APR/1997.
-
Inert Ingredients no Longer Used in Pesticide Formulations:
63(121) FR34384-34391, 24/JUN/1998.
-
List of Active Ingredients Undergoing Reregistration:
- By Case Number.
- By Chemical Name.
- By Common Name.
-
Pesticide Regulation
Notices (PR) . Recent PR Notices can be retrieved from the
EPA's web site. Also, please refer to a list of pertinent Notices
in Appendix 3, SEP for End-Use Products (1992), with emphasis
on:
-
PR Notices 81-4, 83-3, 84-5 and 87-8 Label Improvement Programs
(84- 5, entitled: label improvement program for fumigants).
-
PR Notice 86-5 Standard format for data submissions (under
revisions).
-
PR Notice 87-6 Inert Ingredients in Pesticide Products.
-
PR Notice 87-7 Pesticide Contracting Manufacturing.
-
PR Notice 88-6 Changes in registration procedures.
-
PR Notice 90-1 Inert ingredients in pesticide formulations.
-
PR Notice 91-2 Accuracy of stated percentages for ingredients
statement.
-
PR Notice 94-8 Water Soluble Packaging.
-
PR Notice 96-8 Toxicologically Significant Levels of Pesticide
Active Ingredients.
-
PR Notice 97-1 Agency Action Under the Requirements of the
Food Quality Protection Act.
-
PR Notice 97-4 Consumer Access Numbers on Pesticide Labels.
-
PR Notice 97-5 Use of Common Names in the Label Inert Ingredients
Statement.
-
PR Notice 97-6 Use of term "Inert" in the Label Inert Ingredients
Statement.
-
PR Notice 98-1 Self-certification of product chemistry data.
-
PR Notice 98-6 Flammability Labeling Requirements for Total
Release Fogger Pesticides.
-
PR Notice 98-10 Notification, Non-Notification, and Minor
Formulation Amendment (superseded PR Notice 95-2).
-
PR Notice 99-1 Import of Unregistered Pesticides Intended
for Export.
-
PR Notice 2001-6 Disposal Instructions on Non-Antimicrobial
Residential/Household Use Pesticide Product Labels.
-
FIFRA Information Security Manual, 1984 (55 pages).
-
Computer Programs: WordPerfect®, OPPIN, Lotus Notes, Calendar,
Chemical Vocabulary (for clearance of ingredients), REFs, PRAT,
Adobe Acrobat Reader® and Adobe Acrobat 5® (for review
of electronic data submissions), ChemFinder, ChemDraw, Intranet
and Internet, OPP Applications, Agency LAN Services, etc.
-
Streamlining Registration of Antimicrobial Pesticides, a Progress
Report, 1997 (37 pages).
-
U.S. EPA Manual of Chemical Methods for Pesticides and Devices,
2nd Edition (1992).
-
Toxic Substances Control Act, Chemical Substances Inventory (several
volumes).
-
Library
holdings including, but not limited to: the Merck Index, Official
Methods of Analysis of AOAC International, Annual Book of ASTM
Standards, Part 46- Pesticides, CRC Handbook of Chemistry and
Physics, CRC Handbook of Pesticides, Handbook of Physical Properties
of Organic Chemicals, Chemical Property Estimation- Theory and
Application, Farm Chemicals, Organic Chemistry, Inorganic Chemistry,
Analytical Chemistry, Physical chemistry, Biochemistry, Chemistry
of Alkaloids, Toxicology, Secondary Plant Metabolites, etc.
-
Familiarizations with definitions in:
- OPP Glossary housed in OPP Applications.
- FIFRA.
- 40CFR Parts 152, 153, 156, 158 and 160; and
- OPPTS Test Guidelines, Series 830, Product Properties.
-
Malak, S. and D. McCall (2002). Proposed Revisions to Product
Chemistry Data Requirements for Registration of Pesticide Chemicals,
Chapter 23, ACS Symposium Series 824, Capturing and Reporting
Electronic Data, Willa Garner, Rodney M. Bennett, and Markus Jensen,
eds. (15 pages).
|
-
Reviewer Needs
-
References cited under "VI" above.
-
Clearances to use programs containing confidential information
such as OPPIN, the Chemical Vocabulary File (housed in RTP/NC),
PRATS and REFs: Branch Chiefs, please contact the OPP Help Desk
at 703-305-5435 for clearance.
-
Copies of Inert Ingredients Lists:
- Vol 1: Alphabetical Listings.
- Vol 2: Listing by Pesticide Products Code Numbers (abbreviated
as PC #).
- Vol 3: Listing by Chemical Abstract Service Number (CAS).
-
Registration Package: Contains FIFRA/FFDCA as Amended by the
FQPA,
40CFR§158, PR Notices, and Standard Forms (from RD's Front Office,
at 305-5447).
-
Sample labels, CSFs, reviews and a Reregistration Eligibility
Document [familiarity with all parts of the RED with emphasis
on the product chemistry chapter and the Data Call-In (DCI) Tables
at the end of each RED].
-
Product Properties Reviews
-
General Guidance
-
To assist the CRMs (Chemical Review Managers) and PMs (Product
Managers) in communicating the EPA's decisions in product
properties reviews to applicants/registrants, reviews can
be organized to project information on:
- Tracking
- Findings
- Recommendations
- Notes to the CRM
- "DETAILED CONSIDERATIONS"
- "CONFIDENTIAL APPENDIX A and B" if needed (refer to Part
IX under "What Product Chemistry Information is CBI?".
There is no need to use the EPA Letterhead in the reviews
because it is considered inefficient for internal use. Using
the EPA Letterhead consumes considerable disk space which
creates an excessively long electronic retrieval process.
However, when responding to applicants, the CRM can communicate
the Findings/Recommendations using EPA Letterhead.
-
Except for technical grades of active ingredients including
joint reviews of TGAIs with PMRA, all other reviews including
joint reviews with PMRA of manufacturing-use and end-use products
should be:
- signed by the reviewer
- logged out using PRAT
- delivered to the Branch Chief (BC) or Team Leader (TL)
for secondary review along with the data package, labels,
CSFs and an electronic copy of the review. The BC or TL
then delivers it to the Branch's Tracking Team.
After completing the necessary bookkeeping and closing PRAT,
the Branch's Tracking Team is responsible for storing an electronic
copy of each review in the Branch's computer hard drive and
delivering the review and data package to the respective Product
Management Team.
-
In addition to the directions in 2. above, the procedure
for a technical grade of active ingredient including joint
reviews of TGAIs with PMRA, requires additional hard and electronic
copies of the reviews to be delivered to the Branch Chief
for concurrence and to the Product Chemistry team in the Health
Effects Division (HED). Note that the original review, data
package and one electronic copy must be handled following
the procedure 2. above. This may not be a requirement by AD
and SRRD.
-
Methods Validation: The reviewer may request validation
of the following analytical methods:
-
new methods for the TGAIs and associated impurities.
-
modified methods.
-
methods for unregistered products.
-
on a case-by-case basis, methods for manufacturing-use
and end- use products if produced by an integrated system;
also, those produced by a non-integrated system if a chemical
reaction took place resulting in the formation of new
ingredients.
Requests for methods validation can be made part of the
review. However, it should be noted that there is a memorandum
of understanding between the pesticide industry and the EPA's
laboratory in Fort Meade, Maryland (Analytical Chemistry Branch/BEAD),
whereby pesticide registrants/applicants send the methods
and samples directly to the laboratory which then sends the
results of method validation to the CRM or TRB's Branch Chief.
Validation data must be reviewed by the reviewer of the corresponding
chemical. The reviewer will need to complete the review prior
to the Administrative due date so that both the review and
method validation are delivered to the CRM or branch chief
at about the same time. This may not be applicable to AD and
SRRD.
-
Organization of the Reviews
The organization of reviews depends upon the type of review.
The review structure should follow the standard formats as illustrated
or referenced in this section. This SOP addresses several review
types including:
-
Review of an End-Use Product Formulated from Registered Sources
(this is also sometimes referred to as the Review for non-integrated
products)
-
Review of a Technical Grade of an Active Ingredient and Products
Produced by an Integrated Production System
-
Joint Review of Certain Technical Grades of Active Ingredients
with the Pest Management Regulatory Agency in Canada (PMRA)
-
Joint Review of Formulated Pesticide Products with the Pest
Management Regulatory Agency in Canada (PMRA)
-
Other Reviews in Product Properties
|
-
Review of an End-Use Product
Formulated from Registered Sources:
The actual review used for the example is reproduced in its
entirety in Appendix A Example Reviews. The structure includes:
- Date Out
- Tracking information
- From reviewer
- To the product management
- Introduction
- Findings
- Recommendations
- Note to the CRM, if needed.
- Detailed Considerations on a new page
- Confidential Appendices A and B (if needed), each on a
new page.
Sample Review Structure of an End-Use Product Formulated
from Registered Sources:
NOTE: some applicants may comply with PR
Notice 98-1 on Self- Certification of Product Chemistry Data
and submit an abstract summary of the physical/chemical properties
on EPA Form 8570-36 (13 of 26 properties from Group "B"),
plus a signed and dated self-certification statement on EPA
Form 8570-37:
DATE OUT: DD/MMM/YYYY
PRODUCT CHEMISTRY REVIEW
OF MANUFACTURING- USE [ ] END-USE PRODUCT [X]
DP BARCODE No.: xxxxxx EPA
RECEIVED DATE: DD/MMM/YYYY REG./File
Symbol No.: xxx-xx
PRODUCT NAME:
, %AI
COMPANY NAME:
MRID NO:xxxxxx-01 ACTION CODE:
xxx
FROM: |
Reviewer's Name, Chemist /S/
Technical Review Branch /RD (7505 C)
OR
Product Reregistration Branch (7508C)
|
TO: |
# PM name/CRM names
Branch Name/RD(7505 C) |
INTRODUCTION:
FINDINGS:
CONCLUSIONS:
NOTE TO CRM:
DETAILED CONSIDERATIONS
REVIEW OF PRODUCT CHEMISTRY DATA:
DATA SUBMITTED
The reviewer's name and Central
File (Reg. No. xxxx-xxx).
7505C:RD/TRB:CM-2:Rm.xxx:initials of the typist: DD/MMM/YYYY:
703-xxx-xxxx: <xxxx-xxx>
CONFIDENTIAL APPENDIX A
NOTE TO REVIEWER: Confidential Appendix
A should be separated from the non-CBI part above. The codes
at the end are for identification and tracking if filed separately.
7505C:RD/TRB:CM-2:Rm.xxx:initials
of the typist: DD/MMM/YYYY: 703-xxx-xxxx:<xxxx-xxx>
-
Review
of a Technical Grade of an Active Ingredient (TGAI) and Products
Produced by an Integrated Production System
Please use the Technical Grade
of Active Ingredient Form included under, "REVIEW FORMS,"
in this SOP.
-
Joint
Review of Certain Technical Grade of Active Ingredients (TGAIs)
with the Pest Management Regulatory Agency in Canada (PMRA)
[ Not Applicable to AD and SRRD]
Please use the Joint Review
Form for a TGAI included under "REVIEW FORMS," in this SOP.
NOTE: Most of the
joint reviews are conducted on minimum risk chemicals. Either
the PMRA or the EPA conducts the full review and the second
conducts a peer review. It should be noted that PMRA relies
on the applicant/registrant validation of the analytical methods
because they do not have a laboratory and do not seek validation
by an independent laboratory. Nevertheless, the EPA reviewer
should ensure method validation by the EPA's ACB laboratory
in Fort Meade, Maryland whether the full review was conducted
by PMRA or EPA (please refer to Part VIII[A], General Guidance).
-
Joint
Review of Formulated Pesticide Products with the Pest Management
Regulatory Agency in Canada (PMRA) [Not Applicable to AD and
SRRD]
Formulated pesticide products
include formulated manufacturing-use products (MPs) and end-use
products (EPs). Please use the Joint Review form for MPs/EPs
(formulated products) included under "REVIEW FORMS" in this
SOP.
-
Other
Reviews in Product Properties (Not all are applicable to SRRD
-except for Re-submissions, Re-packs, and Alternate Formulations)
The majority of the reviews
in product properties are fast track, Amendments, chemical
formula changes, "Me-Too" requests, alternate formulations,
experimental- use permits, re-submissions, GLP laboratory
audits, etc. Such actions can be reviewed using the first
page of the Form for non-integrated products. The structure
of this form is illustrated in this section of the SOP under
the heading of Review of an End-Use Product Formulated from
Registered Sources. An actual example review is included in
Appendix A Example Reviews. In "Me-Too" registration, some
applicants choose the "cite-all method of support;" others
submit limited data choosing the "selective method of support"
while others submit the full data. In the latter situation,
if the pending product is an end-use product, the entire Form
for non-integrated products can be used. If it is a technical,
the procedure outlined for technical reviews in the TGAI Form
should be followed. Reference to this form is made in this
section of the SOP under the heading, Review of a Technical
Grade of an Active Ingredient and Products Produced by an
Integrated Production system. The form itself is in the section,
Review Forms, of this SOP. Some applicants seeking "me-too"
registration of a new TGAI, may submit the full data on their
pending TGAI plus data from the registered TGAI. This procedure
is carried out to support a "me-too" registration of the pending
product particularly if the registered product was older than
five years and the analysis, unlike state of the art instrumentation
used in the pending product, did not uncover ingredients at
the LOQ (level of quantitation) found in both products.
In the Introduction, the reviewer
should indicate the type of the action, what is requested,
date of a cover letter, application form or other forms, what
was submitted in support of the request, (e.g., data, label
by date received by EPA (punched), basic and/or alternate
formulations by number and dates), a certificate with respect
to citation of data, a formulator's exemption, the data matrix
and an authorization letter to permit the Agency access to
the files of the registered product. Two examples of "Me-Too"
requests citing the Introduction, Findings, and Recommendations
are presented in Appendix A Example Reviews.
|
-
Confidential
Business Information (CBI) and Non-CBI Product Properties Requirements
- Confidential Business Information
(CBI)
-
In Group A of OPPTS Test Guidelines,
Series 830, listed by GRN:
830.1550.....Product Identity
and composition
830.1600.....Description of
materials used to produce the product
830.1620.....Description of
production process
830.1650.....Description of
formulation process
830.1670.....Discussion of
formation of impurities
830.1700.....Preliminary analysis
830.1750.....Certified limits
830.1800.....Enforcement analytical
method (for impurities and ingredients of toxicological concern)
-
All CSFs.
-
Nitrosamine analysis data are
normally considered to be CBI.
-
Dioxin analysis data, even
if none are detected (i.e., below the LOQs), are usually considered
to be CBI.
-
Non-CBI
-
In Group A of the OPPTS Test
Guidelines, Series 830, listed by GRN:
830.1550.....Product Identity
and composition
830.1800.....Enforcement analytical
method (for the pure active ingredients and related compounds/isomers
that are pesticidally active [label claim nominal concentrations])
830.1900.....Submittal of samples
-
In Group B of the OPPTS Test
Guidelines, Series 830 (unless claimed CBI by the applicant/registrant):
All the Physical/Chemical Properties
(GRNs 830.6302 to 830.7950)
-
All Labels.
|
-
Product
Properties Studies Requiring Compliance or Noncompliance with Good
Laboratory Practices (GLP) Standards of 40CFR§160
-
Studies that must be conducted
in full compliance with GLP standards [40CFR§160.135(a)] (Also,
refer to page 16 in OPPTS Test Guidelines, Series 830):
830.1700.....Preliminary analysis
830.6313.....Stability to normal
and elevated temperatures, metals, and metal ions
830.6317.....Storage stability
830.7550.....Partition coefficient
(n-octanol/water), shake flask method
830.7560.....Partition coefficient
(n-octanol/water), generator column method
830.7570.....Partition coefficient
(n-octanol/water), estimation by liquid chromatography
830.7840.....Water solubility:
Column elution method, shake flask method
830.7860.....Water solubility,
generator column method
830.xxxx.....Solubility in organic
solvents
830.7950.....Vapor pressure
-
Studies requiring partial compliance
with GLP [40CFR§160.135(b)]
830.6302.....Color
830.6303.....Physical state
830.6304.....Odor
830.6314.....Oxidation/Reduction:
Chemical Incompatibility
830.6315.....Flammability
830.6316.....Explodability
830.6319.....Miscibility
830.6320.....Corrosion characteristics
830.6321.....Dielectric breakdown
voltage
830.7000.....pH
830.7050.....UV/Visible absorption
830.7100.....Viscosity
830.7200.....Melting point/melting
range
830.7220.....Boiling point/boiling
range
830.7300.....Density/relative density/bulk
density
830.7370.....Dissociation constants
in water
830.7520.....Particle size, fiber
length, and diameter distribution
-
The GLP requirements are not applicable
to descriptive requirements comprising:
830.1550.....Product Identity and
composition
830.1600.....Description of materials
used to produce the product
830.1620.....Description of production
process
830.1650.....Description of formulation
process
830.1670.....Discussion of formation
of impurities
830.1750.....Certified limits
830.1800.....Enforcement analytical
method (except for method validation)
830.1900.....Submittal of samples
|
-
Label Statements
that Should be Reviewed by the Product Chemist
It is recommended that a product chemistry
reviewer should first look at the label, then the CSF and finally
review the submitted data.
-
Label ingredient statement and
substatement as per the regulations of 40CFR§ 156(10)(g), PR Notices
81-4, 83-1, 83-2, 83-3, 84-1, 84-5, 87-8, 91-2, 97-5 and 97-6.
-
Physical or Chemical Hazards statement
as per the regulations of 40CFR§156(10)(h)(2)(iii).
-
Specified Directions concerning
the Storage and Disposal statement as per regulations of 40CFR§156(10)(i)(iv),
156.165, and PR Notice 2001-6.
Note: Reviewers are required
to indicate concurrence or no concurrence with the regulations,
or a need for upgrading pertinent product chemistry studies to
satisfy and/or upgrade each one of the above three statements.
In situations where no physical or chemical hazards exist, the
reviewer may write in their findings, "No physical or chemical
hazards are anticipated from subject product." It should be noted
that the product's composition and any submitted data pertaining
to GRNs 830.6315 Flammability and 830.6316 Explodability are indicative
of whether a product is potentially flammable and/or explosive.
Further, although the storage and disposal statement is part of
the product's uses, it still has to be reviewed by the product
chemistry reviewer because it distills product chemistry data
requirements on the product's stability (GRN 830.6313 Stability
to normal and elevated temperatures, metals, and metal ions),
flammability (GRN 830.6315 Flammability), explodability (830.6316
Explodability), storage stability (GRN 830.6317 Storage stability),
and corrosion characteristics (GRN 830.6320 Corrosion characteristics).
-
Consult the Label Review Manual
for other tips. Applicants have the option to use:
-
common names, if known, instead
of chemical names (PR Notice 97-5)
-
the term "Other Ingredients"
instead of "Inert Ingredients" (PR Notice 97-6), noting that
both common and chemical names are permissible
Note: Use of the term
"Other Ingredients" is highly recommended on the labels of
active ingredients because the balance of 98% to 100% is made
of impurities and associated ingredients that are not intentionally
added inert ingredients.
-
Products containing petroleum distillates,
xylene or xylene range aromatic solvents at > 10% should
be indicated on the label immediately below the ingredient statement
as a footnote below the term "Inert Ingredients" or "Other Ingredients"
as follows: "Contains petroleum distillates, xylene or xylene
range aromatic solvents."
-
Products containing ingredients
of toxicological concern should be indicated on the label immediately
below the ingredient statement as a footnote below the term "Inert
Ingredients" or "Other Ingredients" as follows: "This product
contains the toxic ingredient (name of the ingredient)."
-
Products containing arsenic in
any form must bear a statement of the percentages of total and
water soluble arsenic calculated as elemental arsenic.
-
-
Flammability statements on
labels: Please refer to 40CFR§156(10)(h) (2)(iii). The flash
point should be determined for all products containing combustible
liquids including those that will be packaged in pressurized
containers. In pressurized containers, the flash point can
be determined on the base product prior to packaging, or,
if unavailable, the base product can be obtained by degassing
the pressurized container. In addition, the flame extension
should also be determined in all pressurized containers and
reported in box 9 of the CSF along with any observed flash
back
-
Total Release Fogger: A pressurized
container designed to automatically release the total contents
in one operation (subject of PR Notice 98-6). If the product
has a flash point < 20°F [a flash back at any valve
opening or a flame extension < 18" (not in CFR or PR Notice
98-6)], then a label statement and a graphic symbol depicting
fire must be added under the "Physical and Chemical Hazards."
About 200 products fall under this category where labeling
changes can be amended by notification as per the regulations
of PR Notice 98-10. Please note that there are some "total
release foggers" that are not flammable or extremely flammable.
-
A labeling claim of a salt form
must indicate the acid equivalent in percentage as a footnote
below the term "Inert Ingredients" or "Other Ingredients." Similarly,
the metallic equivalent of elemental salts should be indicated
as a substatement to the ingredient statement. For example, a
claim of 86.7% cuprous oxide (Cu2O) should have a substatement
cited as follows: "equivalent to 77% metallic copper"
[(63.546 x 2) ÷ ((63.546 x 2)
+15.994)] x (86.7 ÷ 100) = .77 = 77% metallic copper
-
Some labels declare the salt form
of an active ingredient, whereas, the CSF declares the free acid.
Reason: the salt form is an unregistered integrated product while
the free acid is registered. The Reg. No. of the free acid would
be listed in Column 12 of the CSF and the same number is erroneously
cited for the salt form on the label, when in fact both are of
different composition. Ironically, the salt form would fall under
the definition of integrated products and it would not be feasible
to require applicants to change their label claim to conform with
that on the CSF. Ideally, however, both the label and CSF should
list the salt form and the acid equivalent as a substatement.
Occasionally, some applicants request and obtain a registration
number for the salt form that would appear on both the label and
CSF.
-
The nominal concentration of a
registered or unregistered salt form, produced by an integrated
production system, that should be declared on the label can be
calculated by multiplying the salt factor by the nominal concentration
of the free acid. The salt factor is calculated by dividing the
molecular weight of the salt form by the molecular weight of the
free acid. Similarly, when an unregistered metal salt or complex
is formed by an integrated production system, (e.g., when cupric
hydroxide reacts with naphthenic acid to form copper naphthenate),
the nominal concentration of the salt complex that should be declared
on the label can be calculated by multiplying the salt factor
by the nominal concentration of free acid. The salt factor is
calculated by dividing the molecular weight of copper naphthenate
by that of naphthenic acid. The metallic equivalent is calculated
by dividing the molecular weight of copper by the molecular weight
of copper naphthenate X 100. This percentage should be indicated
as a substatement to the ingredient statement.
This can be represented by the
following equations:
2C5H9COOH
+ Cu(OH)2 → CuC5H 9 (COOH)2
+ 2H2O
Naphthenic acid, MW = 113 + Cupric
hydroxide → Copper naphthenate, MW = 287.55
Salt Factor = MW of Cu Naphthenate
÷ (2) MW of naphthenic acid = 287.55 ÷ (113 x 2) = 1.27
% of the PAI on the label = the
nominal concentration of the free acid x 1.27 [the nominal concentration
of Naphthenic acid = % w/w X its purity (from REFs)].
% Cu in the formulation = MW of
Cu ÷ MW of complex x 100 = 63.55 ÷ 287.55 = 22.1%
Metallic Cu equivalent = % PAI
on label x 0.221
-
For significant changes in the
composition of pesticide formulations to a level below the lower
certified limits, the label of such products should bear an expiration
date in accordance with 40CFR§156.10(g)(6) as follows: "Not
for sale or use after (date)." Pesticide formulations
that fall into this category include hypochlorites, chlorinated
isocyanurates and bleaches.
-
Pesticidally active ingredients
and isomers, if pesticidally active ingredients, quantified at
> 0.1% by weight should be listed on the label as "Related
Compounds" otherwise they can be included with "Other Ingredients."
-
Over formulations and the use of
ranges for the active ingredients on the labels of end-use products
are not permitted. PR Notice 91-2 should be enforced for all products,
i.e., only one nominal concentration can be declared on the label
of such products.
-
Dielectric breakdown voltage must
be indicated for nonconductant liquid products that are to be
used on or around transformers and/or electrical outlets or equipment.
Otherwise, the following statement should be included under "Physical
or Chemical Hazards": "Do not use this product around electrical
equipment due to the possibility of a shock hazard."
|
-
Review
of the Confidential Statements of Formula (CSF)
It is recommended that a product chemistry
reviewer should first look at the label, then the CSF and finally
review the submitted data.
-
Applicants and reviewers should
follow the directions on the back of the CSF on how to complete
it.
-
-
The CSF for active ingredients
lists the label claim nominal concentration in column 13(b)
designated for percentages by weight in the current CSF (revised
4/94). The remaining ingredients are impurities plus other
ingredients associated with the production of the TGAI. The
certified upper and lower limits of the PAI and upper limits
of associated ingredients are based on the nominal concentration
to be listed in columns 14(a) and 14 (b), respectively. The
balance of 100% may not be achieved depending upon method
recovery, precision, accuracy, equipment used in the analysis,
and formation of complexes that, in some situations, cannot
be quantified. Recovery of > 98% is adequate [49(207)FR42863,
24/OCT/1984].
-
Some applicants list ingredients
of no toxicological concern, if each is quantified at <
0.1% as follows: "total other ingredients each quantified
at < 0.1.%."
-
Ingredients of toxicological
concern must be listed separately by chemical and/or common
name, CAS registry number, and percent nominal concentration
at the LOQ (level of quantitation) that can be in ppb.
-
The maximum nitrosamine contamination
allowed in pesticide products - NOT containing trifluralin
- is < 1 ppm, and the level found should be stated
as a footnote on the CSF. For trifluralin-containing products,
follow the guidance in the trifluralin Position Document 4
(PD4). The emergence of products containing multiple active
ingredients (MAIs) was not envisioned at the time of the issuance
of that PD4. Some broad spectrum herbicide EPs contain very
low percentages of trifluralin along with benefin and 2,4-D
analogues. Additionally, the last two trigger nitrosamine
analyses. Since the limit of quantitation [LOQ] required for
trifluralin analysis is a function of the percentage of that
Active Ingredient (AI) in those MAI EPs, extremely sensitive
analytical methodology is required. Nitrosamine
analysis data are normally considered to be CBI. The
registration number for the TGAI would be listed in box 4
of the CSF.
-
-
The CSF of a formulated manufacturing-use
(MP) product lists the percentage by weight of the active
ingredient in column 13(b) and the balance of 100% is either
solvents, stabilizers, or both. The label claim nominal concentration
can be calculated by multiplying the [(percentage by weight
X chemical purity of the active ingredient) ÷ 100]. Similarly,
the percentage by weight can be calculated by [(dividing label
claim nominal concentration by chemical purity of the TGAI)
X 100].
-
The nominal concentration can
be indicated between parentheses below the percentage by weight.
The value of the nominal concentration should fall between
the upper and lower certified limits and not be equal to either
one. The upper/lower certified limits should be based on nominal
concentrations to be listed on the same line with nominal
concentrations in columns 14(a) and 14(b), respectively. Because
of inadequate directions by the Agency on how to list nominal
concentrations and certified upper/lower limits on the CSF,
applicants have taken different approaches. Some, incorrectly,
base the upper/lower limits on percentages by weight; to guard
against rejection, some base it on both percentages by weight
and nominals. In either case, we should practice some leniency
with applicants and accept whatever method of calculation
is used. Reasons: Although certified limits for active ingredients
should be made available to the states for enforcement (non-CBI),
rarely do such values actually reach enforcement personnel.
Instead, they use the label claim nominal concentration and
calculate the lower limit as per the regulations of 40CFR§158.175(b)(2)
which is the enforcement level.
-
The registration number of
the source TGAI should be listed in column 12 and that for
the MP should be listed in box 4 of the CSF. If the technical
source is not registered, applicants should be advised to
list carryover impurities, if each is > 0.1% (e.g.,
a TGAI containing an impurity quantified at 0.4%, carryover
quantity to a 50% MP would be 0.2%). Similarly, carryover
nitrosamine should be indicated on the CSF as a footnote (e.g.,
a TGAI containing nitrosamine at 1 ppm, carryover quantity
to a 50% MP would be 0.5 ppm). Please note that end-use products
may contain ingredients of toxicological (TOX) concern as
a result of formulation. Some examples of these include N-nitroso
contaminants, dioxins, penta- and hexachlorbenzene. The 6/9/87
Dioxin Data Call-In (DCI) requires registrants of many chemical
TGAIs to provide information on the potential for formation
of tetrachlorodibenzo--dioxin or dibenzofuran contaminants
during certain manufacturing processes. Levels found above
the LOQ of 0.1 ppb are to be stated in a footnote on the CSF.
For penta- and hexachlorobenzene, levels found above an LOQ
of 100 ppb are also to be stated as a footnote on the CSF.
There is NO general allowable limit for dioxin in chemical
pesticides. Historically, on a case-by-case basis, some levels
were allowable, e.g., 25 ppb in 2,4-D products, before the
6/9/87 Dioxin DCI was issued. Dioxin analysis
data, even if none are detected (i.e., below the LOQs), are
usually considered to be CBI. The remaining
impurities would be included with the solvents and stabilizers.
-
Pesticidally active ingredients
and isomers, if pesticidally active, quantified at >
0.1% by weight should be listed separately on the CSF. Otherwise
they can be included with the solvents and stabilizers.
-
-
The CSF of a formulated end-use
product (EP) is completed in a manner similar to that explained
above for MPs except that the balance of 100% can be intentionally
added inert ingredients, solvents, stabilizers, emulsifiers,
fragrances, dyes, etc. Ingredients of no toxicological concern
and non- pesticidally active components can be included with
impurities if each is quantified at < 0.1%.
-
The current regulations of
40CFR§158.180 and OPPTS Test Guidelines, Series 830 do not
require enforcement analytical methods for inert ingredients
unless toxicologically significant. Accordingly, there are
no enforcement mechanisms for ingredients other than active
ingredients (PAI and impurities) and those of toxicological
concern. Further, the new OPPTS Test Guidelines, Series 830
are harmonized guidelines that serve as national and international
guidelines for product properties data requirements (international
means if a foreign country wishes to register a pesticide
in the United States, they need to follow OPPTS Test Guidelines,
Series 830- Product properties). At present most Organizations
for Economic Cooperation and Development (OECD) countries
do not require upper or lower limits for inert ingredients.
Therefore, we should be somewhat flexible in enforcing the
percentages by weight and upper/lower limits for inerts of
no toxicological concern. Wider limits than the standard certified
limits of 40CFR§158.175(b)(2) can be permitted if justified
by the applicant as per the regulations of 40CFR§158.175(d)(2).
The magnitude of wider limits was not defined in the regulations.
However, it is recognized by the product chemists that ±10%
over or below the standard certified limits would be acceptable.
Much wider limits may contribute to decreased product efficacy
because of interference and/or reaction between the ingredients.
Sample or batch analysis of end-use products is important:
- to quantify the label claim
nominal concentration and to ascertain reliability of the
enforcement analytical method in non-integrated products;
and
- to characterize the impurity
profile in integrated products.
-
There should be consistency between
the label and the CSF in citing the ingredient statement. They
should state the same chemical name, whether common name as per
PR Notice 97-5, or chemical name or both common and chemical names.
If the label claims the salt form, the same claim should be cited
on the CSF. The acid equivalent should be indicated on both the
label and the CSF.
-
Following the chemical name in
box 10 of the CSF, applicants should indicate the Chemical Abstract
Service Number, referred to as the CAS registry number, and purity
of the TGAI in percent. Chemical purity can also be obtained from
REFs and OPPIN by entering the Registration Number of the TGAI
(listed in box 4 or column 12 of the CSF), or chemical name from
the label or column 10 of the CSF. REFs and OPPIN indicate if
the product is active, canceled or transferred.
-
In an integrated production system,
the CSF must not be used to describe a manufacturing reaction
or formulation process. If an applicant has some valid reasons
to list a chemical reaction or describe a formulation process
in the CSF, the label ingredient statement can be indicated in
the CSF at the beginning of the CSF followed by the reactants,
then all associated output from the reaction including impurities,
contaminants, side reactions, residuals from the starting materials,
and residuals from solvents used to purify the production process,
plus any intentionally added inert ingredients in a formulated
product.
Example 1: In an acid/base
neutralization between dicamba acid and potassium salt to produce
potassium salt of dicamba, both the label and CSF must list the
potassium salt of dicamba at the same nominal concentration. The
nominal concentration can be indicated between parentheses in
Column 13(b) of the CSF and the upper/lower limits must correspond
to the nominal concentration to be indicated in Columns 14(a)
& 14(b). In the CSF, the reactants (dicamba acid & potassium
salt) can be listed following the ingredient statement (potassium
salt of dicamba) along with the amount of each reactant in Column
13(a) and percentage by weight of each in Column 13(b). The purity,
CAS registry number, and the salt factor (the salt factor is an
option that can be calculated by the chemist) of dicamba acid
must be listed in Column 10 following the common/chemical name
of the acid reactant. Again, all ingredients associated with the
production of dicamba salt must be indicated in the CSF.
Note: It should be noted
that a reaction between a salt and a free acid is not always 100%
complete even if the intention is to achieve that goal. Reasons:
- the reactants are not pure substances;
- it is difficult to quantify
the exact amounts used in the reaction; and
- in most reactions of this type,
the salt is used in excess of what is actually needed for the
purpose of depleting the free acid for economic and/or toxicological
reasons.
Example 2: Another example
of an integrated production system is the production of calcium
polysulfide in a reaction between Orthophenylphenol plus sodium
hydroxide. Yield in some of these reactions may vary considerably
and has been reported as low as 17% in one reaction. Ideally,
description of an integrated production or formulation system
can be included with the data under Guideline Reference No. 830.1620
Description of production process and 830.1650 Description of
formulation process. This should relieve the CSF from listing
the reactants.
-
Over formulations and the use of
ranges for the active ingredients on the CSFs of end-use products
are not permitted. PR Notice 91-2 will be enforced for all products,
i.e., only one nominal concentration can be declared on the CSF
of such products.
-
If a claim is made on the same
CSF for more than one alternate source of the technical grade
of active ingredient(s) with different purities, a footnote can
be cited on the CSF indicating the amount needed from each active
ingredient, depending on chemical purity, to achieve the claimed
nominal concentration. Examples: "1/ Use 11%"; "2/ Use 9%"; meaning
active ingredient 1 uses 11% to achieve the claimed 10% nominal
concentration and active ingredient 2 uses 9% to achieve the claimed
10% nominal concentration..
-
The certification statement appearing
in 40CFR§158.175(e) can be listed on the CSF. Preferably, it should
be included with product properties data requirements of Guideline
Reference Number 830.1750 Certified limits.
-
There is no need to list the titles
and source of the enforcement methods on the CSFs. Such information
can be referenced with the requirements pertaining to enforcement
analytical methods if previously submitted and found adequate
by the Agency. New or modified enforcement analytical methods
must be included with the data pertaining to Guideline Reference
Number 830.1800 Enforcement analytical method.
-
Unlike the directions on the back
of the present CSF under "# 10, Components in Formulation, directing
an applicant to list the ingredients as actually introduced into
the formulation," ingredients can be listed on the CSF in no particular
order. The amounts and order for introducing the ingredients in
manufacturing or formulation of a product can be listed in order
when describing the manufacturing or formulation process in the
submitted data.
-
Verify the clearance of inert ingredients
intended for food and/or non-food uses where applicable.
-
Verify tolerance exemptions for
inert ingredients intended for food uses (40CFR§180.10001 list
c, d, e).
-
Confirm the registration number
of the technical source using REFs or OPPIN to ensure the source
is registered. If product cancellation is indicated, check to
see if the product was transferred to other companies.
-
Confirm the nominal concentration
in the CSF for consistency with the label claim nominal concentration.
-
Confirm the claimed upper/lower
certified limits of the ingredients in the CSF by recalculating
values for accuracy using the standard certified limits of 40CFR§158.175(b)(2).
|
-
How to
Express Nominal Concentrations
Use the "Standard Certified Limits"
in 40CFR§158.175(b)(2), where N = Nominal concentration.
N < 1.0%.....± 10.0%
1.0% < N < 20.0%.....±
5.0%
20.0 % < N < 100.0%.....±
3.0%
-
Example
of labeling and CSF for a formulated end-use product
Label
Active ingredient.....24%
Other Ingredients.....76%
Total.....100%
CSF: Source technical
96% pure
Column
13 |
Column
14 |
(a) Amount in
lbs |
(b) % w/w |
(a) % Upper Limit |
(b) % Lower Limit |
250 Active |
25
(24) |
(24.72) |
(23.28) |
350 Inert |
35 |
36.05 |
33.95 |
400 Inert |
40 |
41.2 |
38.8 |
1000 |
100 |
|
|
Explanations to the Above
Table and the Nominal Concentration/Percentage by Weight Concept:
-
If the label claim of nominal
concentration is 24% and chemical purity of the TGAI is 96%,
then by calculation, a formulator will use 250 pounds in a
1000-pound batch = 25% w/w [(250 ÷ 1000) X 100]. Material
balance of 100% is achieved by adding two inerts totaling
750 pounds. To calculate the nominal concentration, multiply
percentage by weight by chemical purity then divide by 100:
[(25 X 96) ÷ 100] = 24%.
The general formula is: N =
[(P X w/w) ÷ 100], where
N = nominal concentration
P = chemical purity of the TGAI
w/w = percentage by weight.
On the other hand, the percentage
by weight can be calculated by dividing the label claim of
nominal concentration by chemical purity then multiplying
by 100: [(24 ÷ 96) X 100] = 25%.
-
Inert ingredients are composed
of a mixture of various components, sometimes more than 100,
each with a unique chemical name and CAS registry number.
Therefore, it is not practical to list nominal concentrations
for inerts since nominals are based on pure substances. If
an inert is 100% pure, then a % w/w would equal % N. However,
it would be confusing to list % w/w for some and % N for others.
Therefore, the percentages by weight of all inerts are listed
in Column 13(b) and their upper/lower limits can be calculated
based on % w/w since inerts have no nominals. Upper and lower
limits are listed in Columns 14(a) and 14(b), respectively.
-
Example
of labeling and CSF for a Technical Grade of Active Ingredient
(manufactured Product)
Label
Active ingredient.....96%
Other Ingredients.....4%
Total.....100%
CSF
Column
13 |
Column
14 |
(a) Amount, lbs |
(b) % w/w (nominal) |
(a) % Upper Limit |
(b) % Lower Limit |
960 (active) |
96.0 |
99 |
93 |
15 (impurity of TOX concern) |
1.5 |
2.0 |
|
20 (impurity) |
2.0 |
Upper limit is not required
by CFR, required by the guidelines |
|
995 (total method recovery)
[Yield: batch production was 1000 pounds]. |
99.5 |
|
|
Explanations to the Above
Table and the Nominal Concentrations Concept for A TGAI:
-
Based on sample analysis using
the enforcement analytical method, as shown in the table above,
the PAI (nominal concentration) of the TGAI is 96%
and the nominal concentration of two impurities are 1.5% and
2.0% for a total recovery of 99.5%. This % recovery is equivalent
to 995 pounds. Because batch production or the actual yield
was 1000 pounds, 5 pounds or 0.5% of the amount was not accounted
for by the method for various reasons associated with the
analytical method, purity of the reactants, laboratory conditions,
equipment, reagents, analytical chemists, and technicians.
-
If the amount is calculated
back from the determined nominal percentages, a second nominal
concentration for the TGAI can be calculated at 96.5%
based on the percentage recovery relative to the amount recovered
(960 ÷ 995). A third nominal for the TGAI can be calculated
at 95.0% (960 ÷ 1010) if considerations were
given to the expected production yield, meaning
the yield of 1000 pounds should have been 1010 based on the
molar ratios of the reactants, their purities, manufacturing
process/conditions and purification techniques. Production
yield can range from 17% to near 100%.
-
-
To simplify the situation,
the amount of a PAI and impurities in a TGAI are calculated
back from percentage recovery then recorded in the amount
column 13(a).
-
It is apparent from points
1 to 3(a) that the amount column adds to confusion when
entering TGAIs in a revised CSF (the present CSF is geared
toward formulated end-use products). For formulated products,
the amount reported on the CSF can range from as little
as 16 ounces (alkaloids) to a batch of 100 pounds, a 1000
or a million from which the CSF reviewer checks to see
if the percentages w/w are correct. This arithmetic is
irrelevant to the review of a CSF. Further any error by
the applicant in converting from amounts to percentage
by weight will be captured in the material balance of
100%. The actual amounts are reported to other science
disciplines for risk/benefit assessments.
-
The nominal concentration is
defined in 40CFR§158.153(h)(1) to mean "the amount
of an ingredient which is expected to be present in a typical
sample of a pesticide product at the time the product is produced,
expressed as a percentage by weight." It is apparent
from the above explanations, in points 1 to 3(b) above, that
the nominal concentration can be explained to mean: "The
percent of a pure ingredient within the minimum and maximum
guarantee that is most likely to be present in a typical sample
of a pesticide product as determined by validated analytical
techniques from production to use." Please note that
it is the percentage, not weight or amount, because weight
and amounts are calculated back based on percentages that
may or may not add up to the exact production volume. What
is reported on the CSF is one batch that does not reflect
the actual production volume.
-
Nominal concentrations and
upper/lower limits are required for all active ingredients
[(40CFR§158.155(a)]. Nominal concentrations are required for
all impurities quantified at > 0.1% and those of
toxicological concern quantified at any level. There is no
need for lower limits for impurities [(40CFR§158.155(d)].
Upper limits are required only if the impurity is of toxicological
concern [(40CFR§158.155(c)]. OPPTS Test Guidelines, Series
830 recommend nominal concentrations and upper limits for
all impurities.
|
-
Consistency
between the Label and CSF:
-
The label lists the name and address
of the registrant consistent with that in box 1 of the CSF.
-
-
The label cites the name of
the product consistent with that in box 3 of the CSF.
-
The common name and/or chemical
name of the product is cited on the label consistent with
that in box 10 of the CSF.
-
The registration number of a product
(TGAI, MP or EP) on the label is consistent with that in box 4
of the CSF.
-
The label claim nominal concentration
can be indicated between parentheses below the percentage by weight
in column 13(b) of the CSF.
-
Pesticidally active ingredients
are listed on the labels as "Related Compounds." They can be listed
as such on the CSF. Preferably, they should be listed separately.
Each is identified by chemical name, CAS registry number, nominal
concentration and the corresponding upper/lower limits.
-
Listing a chemical reaction on
the CSF: Please refer to the applicable entry in the section on
Review of the Confidential Statements of Formula.
-
Flammability statements on labels
should be consistent with values in box 9 of the CSF.
|
-
Verify
the Following to Guard Against Common Errors when Comparing the Label
and CSF:
-
Verify inconsistency between the
label and CSF in any of the points cited in the section of this
SOP regarding Consistency between the Label and CSF.
-
Be aware of an incomplete CSF:
All boxes and columns should be completed in accordance with the
directions on the back of the CSF.
-
-
The CSF corresponding to a
TGAI label should list the label claim nominal concentration
in column 13(b) and the balance of 98% to 100% is all impurities
and other production components. Some TGAIs can be MPs or
EPs. The labels of TGAIs and MPs should declare "For formulating
use only."
-
The label claim nominal concentration
of an MP can be indicated between parentheses below the percentage
by weight in column 13(b). The percentage by weight (not the
nominal) plus the percentages by weight of intentionally added
solvents and/or stabilizers should give a material balance
of 100%.
-
The label claim nominal concentration
of an EP can be indicated between parentheses below the percentage
by weight in column 13(b). The percentage by weight (not the
nominal) plus the percentages by weight of intentionally added
ingredients should give a material balance of 100%.
-
-
The upper and lower certified
limits in Columns 14(a) and 14(b) are required for each PAI
and intentionally added inert ingredient. Only the upper limit
is required for each impurity. Please note that the enforcement
limit is the lower limit for a PAI (label claim nominal concentration)
and the upper limit for ingredients of TOX concern.
-
The upper and lower limits
are normally proposed by the applicant based on sample/batch
analysis or by calculation when formulating a product. The
limits can be wider than the standard certified limits of
40CFR§158.175(b)(2) if explained by the applicant based on
scientific and/or regulatory reasons as per the regulations
of 40CFR§158.175(d)(2). There should be a value for lower
limits other than zero. A lower limit of zero should be rejected
and any missing limits can be calculated and completed by
the reviewer.
-
Verify if the CSF is basic or alternate.
If alternate, it should be identified as Alt A, Alt B, Alt C,
etc. Generally, only one basic formulation and unlimited alternate
formulations can be filed. An exception to this is that two or
more basic formulations can also be filed if each has a different
composition and nominal concentration of the same active ingredient
because of changes in manufacturing processes or site.
-
-
Verify that an alternate formulation,
submitted as per the regulations of 40CFR§152.43, has the
same registration number when submitted by the same registrant.
In rare occasions, a different applicant of a new product
can submit an alternate formulation to a registered product,
hence a different registration number. This latter situation
is indistinguishable from "me-too" registration as per the
regulations of FIFRA Section 3(c)(3)(B)(i)(I).
-
The labeling text of an alternate
formulation must be identical (40CFR§ 152.43) or substantially
similar [FIFRA Section 3(c)(3)(B)(i)(I)]. Discretion is advised
in reviewing the labels of alternate formulations because
applicants make substantial changes in the composition that
may lead to some changes in the physical/chemical properties
of the product (e.g., a change from flammable to nonflammable
when complying with the Clean Air Act or State Laws to reduce
the amount of Volatile Organic Compounds). Minor changes in
use patterns may fall under the definition of "Substantially
Similar Uses" as long as the new product does not pose risk
to man and the environment. For additional guidance, refer
to the Blue Book and PR Notice 98-10.
-
Use REFs and/or OPPIN to verify
chemical names, purities and CAS registry numbers.
-
For clearances of ingredients,
consult the chemical vocabulary file, 40CFR§ 180.1001, and the
inert ingredient list to verify clearances of all ingredients.
The Pesticide Product Clearance Code (PPCC) # should be indicated
on the CSF in the column under "EPA Use Only." The clearance code
for food chemicals should include the 40CFR§ 180.1001 code "c,"
"d," or "e."
-
The product's density for liquids
is reported on the label in lb/gal and for solids as lb/ft3.
The same value should be reported in box 7 of the CSF. In the
data it can be reported as g/ml (1 g/ml = 8.34 lb/gal).
-
For non-pressurized liquids, box
9 of the CSF should list the flash point (e.g., > 180F). For
pressurized containers, box 9 of the CSF should list the flame
extension in inches. In the latter situation, the flash point
should be listed first followed by the flame extension. Also include
reported flash back (e.g., 155°F / < 18" with no flash
back; or 18°F / > 18" with flash back).
|
-
Review
Forms:
-
Technical
Grade of Active Ingredient:
OFFICE OF PREVENTION, PESTICIDES AND
TOXIC SUBSTANCES
DATE: DD/MMM/YYYY
SUBJECT: |
PRODUCT CHEMISTRY
REVIEW OF A TECHNICAL GRADE OF ACTIVE INGREDIENT AND PRODUCTS
PRODUCED BY AN INTEGRATED PRODUCTION SYSTEM |
FROM: |
Reviewer's Name, Chemist
Product Chemistry Team
Technical Review Branch/RD (7505C) |
TO: |
PM # and Name/CRM Name
Branch Name/ RD (7505C) |
DP BARCODE: |
Dxxxxxx |
EPA REG. NO.: |
xxxxxx-xxx |
REGISTRANT: |
xxxxxxxxxxxxxxxxxxxxxxxxx |
CHEMICAL NAME:
|
Example: Chemical Name |
USE: |
Herbicide for use in further
preparation of herbicide products for use in agricultural
crops. |
DATE SUBMITTED: |
DD/MMM/YYYY |
ACTION CODE: |
xxx |
INTRODUCTION:
FINDINGS:
CONCLUSIONS:
NOTE TO CRM:
REVIEW OF PRODUCT CHEMISTRY,
OPPTS 830 SERIES
Chemical Name (IUPAC, ANSI,
etc.) |
Chemical Name 2-chloro-etc. |
Chemical Numbers (CAS; PC
Code): |
Reg. No. xxx-xxx
CAS No. 51218-45-2
PC Code 108801 |
Registration / Symbol No. |
xxxxx-xxx |
Type of Product (T, FI, MP,
EP) |
Technical Insecticide, 96%
pure |
DP Barcode |
DP # xxxxxx |
Reviewer |
Reviewer's Name, Chemist |
The applicant has submitted the
following MRID of product chemistry data: xxxxxx-xx
Table 1: Manufacturing
and Impurity Data for (Chemical Name): 2-chloro-etc.
GRN |
Requirement |
MRID |
Status1 |
Details and/or
Deficiency2 |
830.1550 |
Product Identity and composition |
|
|
|
830.1600 / 830.1620 |
Description of materials used
to produce the product / Description of production process |
|
|
|
830.1670 |
Discussion of formation of
impurities |
|
|
|
830.1700 |
Preliminary analysis |
|
|
|
830.1750 |
Certified limits |
|
|
|
830.1800 |
Enforcement analytical methods |
|
|
|
1A = Acceptable; N =
Unacceptable (see Deficiency); N/A = Not Applicable.
2 Refer to CBI Appendix A for details.
GRN 830.1550 Product Identity
and composition:
Chemical Name: 2-chloro-etc.
Common name: Chemical Name
Chemical Abstract Number: 51218-45-2
Empirical Formula: C15H22Cl
NO2
Molecular Weight: 283.8 g/mol
Molecular Structure:
GRN 830.1800 Enforcement
analytical method:
Method for the Active Ingredient
and Associated Impurities:
Analysis by on-line Gas Chromatography/Mass
Spectrometry (GC-MS):
APPARATUS:
GC Conditions:
Method for Certain Impurities:
Method for Water: The "Karl Fischer
Titration Method for Quantification of Water."
Table 2: Physical and Chemical
Properties for Chemical Name Technical: 2-chloro-etc.
GRN |
Requirement |
MRID |
Status1 |
Result2
or Deficiency |
830.6302 |
Color |
|
|
|
830.6303 |
Physical state |
|
|
|
830.6304 |
Odor |
|
|
|
830.6313 |
Stability to normal and elevated
temperatures, metals, and metal ions |
|
|
|
830.6314 |
Oxidation/Reduction: Chemical
Incompatibility |
|
|
|
830.6315 |
Flammability |
|
|
|
830.6316 |
Explodability |
|
|
|
830.6317 |
Storage stability |
|
|
|
830.6319 |
Miscibility |
|
|
|
830.6320 |
Corrosion characteristics |
|
|
|
830.6321 |
Dielectric breakdown voltage |
|
|
|
830.7000 |
pH |
|
|
|
830.7050 |
UV/Visible absorption |
|
|
|
830.7100 |
Viscosity |
|
|
|
830.7200 |
Melting point/ melting range |
|
|
|
830.7220 |
Boiling point / boiling range |
|
|
|
830.7300 |
Density/relative density/bulk
density |
|
|
|
830.7370 |
Dissociation constants in
water |
|
|
|
830.7520 |
Particle size, fiber length,
and diameter distribution |
|
|
|
830.7550 \ 830.7560 \ 830.7570 |
Partition coefficient (n-octanol/water),
shake flask method / Partition coefficient (n-octanol/water),
generator column method / Partition coefficient (n-octanol/water),
estimation by liquid chromatography |
|
|
|
830.7840 \ 830.7860 |
Water solubility: Column elution
method, shake flask method / Water solubility, generator column
method |
|
|
|
830.xxxx |
Solubility in organic solvents |
|
|
|
830.7950 |
Vapor pressure |
|
|
|
1 A = Acceptable; N
= Unacceptable (see Deficiency); N/A = Not applicable; G = Data
gap; U = Needs upgrading.
2 For example, "brown" for 830.6302; "155o
C" for 830.7200.
NOTE: No detailed information was
provided on the properties cited in the above table.
ATTACHMENTS:
Confidential Appendix A: Manufacturing
processes, composition, and discussion of formation of impurities
(pages xx to xx).
Confidential Appendix
A: Manufacturing, Composition, and Impurity Informantion
Chemical |
Chemical Name |
Registration Number |
xxxx-xxx |
DP Barcode |
D #xxxxx |
CAS Number |
#xxxxx-xx-x |
Product Type |
Herbicide, TGAI |
Test Substance |
TGAI |
Group A - GRNs 830.1550; 830.1600;
830.1620; 830.1670; 830.1700; and 830.1750 Product Identity and
composition (CSF), Description of materials used to produce the
product, Description of production process, Discussion of formation
of impurities, Preliminary analysis, and Certified limits:
GRN 830.1550 Product Identity
and composition:
Compound/Component1 |
Nominal
Concentration
(% w/w) |
Upper
Certified Concentration
(% w/w) |
Lower
Certified Concentration
(% w/w) |
Preliminary
Analysis (% w/w) 3 |
Mean
+ r.s.d.
(%) |
No. |
Name |
Type2 |
1 |
Chemical Name:
2-chloro-etc.
CAS #
xxxxx-xx-x |
A |
96 |
99.23 |
93.45 |
96.34 |
Not provided |
Process
Related Impurities1 |
Nominal
Concentration
(% w/w) |
Upper
Certified Concentration
(% w/w) |
Lower
Certified Concentration
(% w/w) |
Preliminary
Analysis (% w/w) 3 |
Mean
+ r.s.d.
(%) |
No. |
Name |
Type2 |
2 |
|
|
|
|
|
|
|
3 |
|
|
|
|
|
|
|
4 |
|
|
|
|
|
|
|
5 |
|
|
|
|
|
|
|
6 |
|
|
|
|
|
|
|
7 |
|
|
|
|
|
|
|
Impurities
identified in Preliminary Analysis but not included on the
CSF:1 |
Nominal
Concentration
(% w/w) |
Upper
Certified Concentration
(% w/w) |
Lower
Certified Concentration
(% w/w) |
Preliminary
Analysis (% w/w) 3 |
Mean
+ r.s.d.
(%) |
No. |
Name |
Type2 |
None |
|
|
|
|
|
|
1 Is there a significant
potential for formation of an impurity of special concern, such
as, chlorinated dioxins, nitrosamines, or hexachlorobenzene? Yes
/ No. If yes, which impurity(ies)? No.
2 A = active ingredient; O = additive, inert, solvent;
I = impurity.
3 Average of five batch analyses, calculated by this
reviewer. The mean and standard deviation were not provided.
4 n.d.= not detected; the limit of detection was <0.05%.
GRN 830.1600 Description
of materials used to produce the product:
Materials Used
in the Production |
CAS No. |
% Purity |
Supplier's Name
and Address |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
GRN 830.1620 Description
of production process:
GRN 830.1670 Discussion
of formation of impurities:
GRN 830.1700 Preliminary
analysis:
GRN 830.1750 Certified
limits:
The reviewer's name and Central
File (Reg. No. xxxx-xxx).
7505C:RD/TRB:CM-2:Rm.xxx:initials of the typist: DD/MMM/YYYY:
703-xxx-xxxx:<xxxx- xxx>
-
Form
8570-36, Compliance With PR Notice 98-1 on Self- Certification
of Product Chemistry Data:
Physical and Chemical
Properties of Non-Integrated Pesticide Products (PR Notice 98-1)
Form Approved OMB
No. 2070-0060
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
401 M Street, S.W.,
WASHINGTON, D.C. 20460 |
Paperwork
Reduction Act Notice: The public reporting burden
for this collection of information is estimated to average
1 hour per response for registration activities and 1 hour
per response for reregistration and special review activities,
including time for reading the instructions and completing
the necessary forms. Send comments regarding burden estimate
or any other aspect of this collection of information, including
suggestions for reducing the burden to: Director, OPPE Information
Management Division (2137), U.S. Environmental Protection
Agency, 401 M Street, S.W., Washington, DC 20460. Do not send
the completed form to this address. |
SUMMARY
OF THE PHYSICAL/CHEMICAL PROPERTIES (PR Notice 98-1) |
1. PRODUCT NAME: |
2. Reg.No. |
3. COMPANY NAME: |
4. SUBMISSION DATE: |
5. FIRST SUBMISSION[ ]
6. RESUBMISSION [ ] |
7. PESTICIDE TYPE: |
10. REGISTRATION [ ] |
8. FORMULATED
MANUFACTURING-USE PRODUCT [ ] or 9. END-USE PRODUCT [ ] |
11. REREGISTRATION [ ] |
13. PRODUCT MANAGER
OR CHEMICAL REVIEW MANAGER #/NAME( IF KNOWN): |
12. REREG. CASE # |
14.
GUIDELINE REFERENCE NO. (GRN 830-)/Title |
15.
VALUE or QUALITATIVE DESCRIPTION/METHOD(s) USED WHERE APPLICABLE
AND REFERENCES |
16. MRID or REPORT
NO. |
Group
B, series 830-Physical and Chemical Properties (40 CFR 158.190) |
-6302 Color |
|
|
-6303 Physical State |
|
|
-6304 Odor |
|
|
-6314 Oxidation/Reduction
Chemical Incompatibility |
|
|
-6315 Flammability/Flame Extension |
|
|
-6316 Explodability |
|
|
-6317 Storage Stability |
|
|
-6319 Miscibility |
|
|
-6320 Corrosion Characteristics |
|
|
-6321 Dielectric Breakdown
Voltage |
|
|
-7000 pH |
|
|
-7100 Viscosity |
|
|
-7300 Density/Relative Density/Bulk
Density |
|
|
EPA Form 8570-36 (07/JAN/1998)
-
Form
8570-37, Self-Certification Statement in Compliance With PR Notice
98-1:
Form Approved OMB
No. 2070-0060
![](https://webarchive.library.unt.edu/eot2008/20090510232735im_/http://www.epa.gov/oppfead1/trac/epalogo.gif) UNITED
STATES ENVIRONMENTAL PROTECTION AGENCY
401 M Street, S.W.
WASHINGTON, D.C. 20460 |
Paperwork
Reduction Act Notice: The public reporting burden
for this collection of information is estimated to average
0.25 hours per response for registration and 0.25 hours per
response for reregistration and special review activities,
including time for reading the instructions and completing
the necessary forms. Send comments regarding burden estimate
or any other aspect of this collection of information, including
suggestions for reducing the burden to: Director, OPPE Information
Management Division (2137), U.S. Environmental Protection
Agency, 401 M Street, S.W., Washington, DC 20460. Do not send
the completed form to this address. |
SELF-CERTIFICATION
STATEMENT FOR THE PHYSICAL/CHEMICAL PROPERTIES (PR NOTICE
98-1) |
Product Name: |
Reg. No./File
Symbol No.
(if known) or Company No. |
SELF-CERTIFICATION
STATEMENT:
I certify that the reported
information on the "Summary Form" represents a true and
accurate record of the test results of studies generated
or owned by (Company Name):
and that the values of the
properties reported are reliable. I further certify that
such data was generated in substantial conformity with OPPTS
Test Guidelines Series 830 Product Properties, applicable
to my product, and in effect at the time of submission.
As a condition of registration,
EPA may, by order, (1) withdraw a pending registration,
(2) suspend the registration of this product without opportunity
for hearing, or (3) assess civil penalties provided for
in section 14 of FIFRA for violations of section 12(a)(2)(N)
of FIFRA without opportunity for hearing, if I have not
submitted to EPA within thirty (30) days of receipt of a
request by the Agency, or within a specified time agreed
to by the Agency, test results of studies summarized in
the "Summary Form."
As a condition of registration,
EPA may, by order, (1) withdraw a pending registration,
(2) suspend the registration of this product without opportunity
for hearing, or (3) assess civil penalties provided for
in section 14 of FIFRA for violations of sections 12(a)(2)(N),
12(a)(2)(Q), or 12(a)(2)(R) of FIFRA without opportunity
for hearing, if I fail to provide to EPA within thirty (30)
days of receipt of a notification of error, or within a
specified time agreed to by the Agency, information that
EPA determines is required to correct the error. |
Type Applicant's
Name: |
Title: |
Telephone No. |
Applicant's Signature: |
Date: |
EPA Form 8570-37 (07/JAN/1998)
-
JOINT
REVIEW FORM FOR A TGAI:
Chemistry requirements
for the registration of a technical grade of active ingredient
(TGAI) or an integrated system product (ISP).
Example
Submission Number:
1999-2081
PCP Number:
Source Code:
Guarantee: |
Chemical Name..........99.5%
nominal on the label
99.5% (99.0-100%) on the CSF |
Data Submission and Review
History:
Table 1. Correspondence
Dates, LSS # and Content for Acetamiprid Technical
Date Received |
LSS # |
Content Summary |
Reviewer |
|
|
|
|
|
|
|
|
Product Identification
Table 2. Product Identification
DACO |
Title |
Data |
2.1 |
Applicant's Name and
Office Address |
xxxxx
xxxxx
xxxxx
|
2.2 |
Manufacturer's Name
and Office Address |
|
Manufacturing Plant's
Name and Address |
|
2.3 |
Trade Name |
|
2.3.1 |
Other Names |
|
2.4 |
Common Name: |
(ISO proposed) |
2.5 |
Chemical name: |
IUPAC: |
(E)-N1-etc. |
UICAP: |
(E)-N1-etc. |
CAS: |
(E)-N-etc. |
|
2.6 |
CAS Number |
xxxxxx-xx-x |
2.7 |
Structural Formula |
Structural Formula |
2.8 |
Molecular Formula |
C10H11ClN4 |
2.9 |
Molecular Weight |
222.68 |
2.11 Manufacturing Methods:
Reference:
2.11.1 Manufacturing Summary:
2.11.2 Description of Starting
Materials
2.11.3 Detailed Production
Process Description
2.11.4 Discussion of Formation
of Impurities
The chemical names, company codes,
origin and chemical structures of impurities are shown in Table
3.
Table 3. Chemical names,
company codes, possible origin and chemical structures of impurities.
Conclusion: A
description of the starting materials, the manufacturing process,
including chemical reactions as well as the origin of the impurities
has been satisfactorily provided and discussed.
2.12 Specifications:
Reference:
2.12.1 Establishing Certified
Limits
Chemical Name:
Nominal..........99.5%
Lower limit......99.0%
Upper limit......100%
The certified limits are within
the standard certified limits of N ± 3% for active in the concentration
range of 20 -100%.
2.12.2 Control Product
Specification Form
Table 4. Specifications
and batch analytical data of technical product.
Explanation to Table 4:
*HPLC-RT: HPLC retention time comparison with corresponding reference
standard.
Conclusion:
2.13 Preliminary Analysis:
Reference:
2.13.1 Methodology/Validation
Method(s): The contents of (xxxxx)and its related impurities are determined by reversed
phase high performance liquid chromatography with UV detection
using methyl-4-hydroxybenzoate as internal standard. The conditions
of the method are given in Table 5.
Table 5. Details of the
analytical methods used to determine active and impurities in
Acetamiprid Technical.
Sample preparation |
xxxxx was diluted with
internal standard in acetonitrile/water: 300/700 to desired
concentration. |
Analyte |
|
Instrument |
HPLC |
Detector |
UV detection at 254 nm |
Column |
Inertsil ODS-2 5m, 250 mm
length, 4.6 mm i.d., packed with |
Mobile phase |
acetonitrile/water/10% phosphoric
acid solution: 300/700/3.0 (v/v/v/) |
Oven temperature |
40°C |
Quantitation |
Internal standard using methyl-4-hydroxybenzoate |
Retention time (RT) |
Analyte |
RT (min) |
NI-25 |
7.06 |
|
Total run time |
10 minutes |
The validation data are shown in
Table 6.
Table 6. Validation data
method
Parameter |
Method |
Data |
Identity |
|
|
Accuracy |
|
|
Precision / reproducibility |
|
|
Linearity |
|
|
Specificity |
|
|
Stability |
|
|
Table 7. Method validation
data
Component |
Method Type |
Anal. Range w% |
Correlation Coefficient,
(R2) |
Recovery (%) |
RSD (%) |
MA*
(Y/N) |
xxxxx |
HPLC |
30-150 |
0.999986 |
99.8 |
0.09 |
Y |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Explanation to Table 7: * MA =
Method acceptability, Y = yes, N = no.
Conclusion:HPLC
with UV detection was used to determine the active ingredient
and the impurities of the TGAI. Validation data of accuracy, linearity
and precision were provided for each component specified. Chromatograms
of standard solutions of the active ingredient and impurities,
samples of the technical product and blank chromatograms showed
well-resolved peaks and absence of interferences at retention
times of interest. The method has been assessed as precise, accurate
and specific for the determinations.
2.13.2 Confirmation of
Identity
Reference:
Conclusion:
2.13.3 Batch Data
Reference:
Conclusion:
2.13.4 Impurities of Toxicological
Concern
Reference:
Conclusion:
2.14 Chemical and Physical
Properties:
Reference:
Table 8. Chemical and physical
properties.
DACO # |
Properties |
Test substance
purity |
Value |
a) Methods
b) Reference
c) Comments |
GLP
Y/N |
2.14.1 |
Color |
TGAI: 99.9%
PAI: 99.9% |
|
|
|
2.14.2 |
Physical state |
TGAI: 99.9%
PAI: 99.9% |
|
|
|
2.14.3 |
Odor |
TGAI: 99.9%
PAI: 99.9% |
|
|
|
2.14.4 |
Melting point/range |
TGAI: 99.7% |
|
|
|
2.14.5 |
Boiling point/range |
|
|
|
|
2.14.6 |
Specific gravity |
TGAI: 99.7% |
|
|
|
2.14.7 |
Water solubility (mg/L) at
25°C |
> 99% |
|
|
|
2.14.8 |
Solvent solubility at 25°C |
TGAI > 99% |
|
|
|
2.14.9 |
Vapor pressure at 25°C |
PAI > 99% |
|
|
|
2.14.10 |
Dissociation constant (pKa) |
PAI > 99% |
|
|
|
2.14.11 |
Octanol/water partition coefficient
(Kow) |
PAI > 99% |
|
|
|
2.14.12 |
UV/visible absorption spectrum |
99.9% |
|
|
|
2.14.13 |
Stability (temperature, metals) |
TGAI: 99.7 |
|
|
|
2.14.14 |
Storage stability |
|
|
|
|
Methodology for determination of
the environmentally relevant chemical and physical properties
Table 9 Details of water
solubility study.
2.14.7 Water solubility. |
Details |
Reference |
|
Test substance name |
|
Test substance purity and
type |
|
GLP compliance |
|
Study protocol used |
|
Conditions of study |
|
Deviations from study protocol |
|
Analytical method ID |
|
Validation data |
|
Comments/Conclusion |
|
Results |
|
Table10. Details of vapor
pressure study.
2.14.9 Vapor pressure. |
|
Reference |
|
Test substance name |
|
Test substance purity and
type |
|
GLP compliance |
|
Study protocol used |
|
Conditions of study |
|
Deviations from study protocol |
|
Analytical method used |
|
Validation data for analytical
method |
|
Comments/Conclusion |
|
Results |
|
Table 11. Details of dissociation
constant study.
2.14.10 Dissociation
constant. |
|
Reference |
|
Test substance name |
|
Test substance purity and
type |
|
GLP compliance |
|
Study protocol used |
|
Conditions of study |
|
Deviations from study protocol
|
|
Analytical method used |
|
Comments/Conclusion |
|
Results |
|
Table 12. Details of octanol/water
partition coefficient study.
2.14.11 Octanol/water
partition coefficient. |
|
Reference |
|
Test substance name |
|
Test substance purity and
type |
|
GLP compliance |
|
Study protocol used |
|
Conditions of study |
|
Deviations from study protocol |
|
Analytical method |
|
Validation data for analytical
method: linearity, precision, accuracy |
|
Comments/Conclusion |
|
Results |
|
Conclusion: Chemical
and physical properties relevant to the TGAI have been provided.
Methodology has been provided for determination of the environmentally
relevant chemical and physical properties.
2.15 Sample(s) of Chemical
Standard(s):
2.16 Other Studies/Data/Reports:
The following studies were submitted
but were not reviewed:
Overall
Summary of Data
Part 2. Chemistry data
for TGAI.
Technical product:
Review History
Summary written by:
Date written: March 21, 2000
Peer reviewed by:
Date peer reviewed: March 24, 2000
Last update date:
Review Retrievability:
The reviewer's name and Central
File (Reg. No. xxxx-xxx).
7505C:RD/TRB:CM-2:Rm.xxx:initials of the typist: DD/MMM/YYYY:
703-xxx-xxxx:<xxxx- xxx>
-
Joint
Review Form for MPs/EPs
Chemistry requirements
for the registration of a Manufacturing-use (MP) and an End-use
Product (EP).
Product Name:
xxxxx
Submission Number:
PCP Number:
Source Code(s):
Data Submission and Review
History:
Table 1. Correspondence
Dates, LSS # and Content for Adjust Brand 70 WP insecticide
Date Received |
LSS # |
Content Summary |
Reviewer |
|
|
|
|
|
|
|
|
3.1 Product Identification:
Reference:
3.1.1 Applicant's Name
and Office Address:
3.1.2 Formulating Plant's
Name and Address:
3.1.3 Trade Name:
3.1.4 Other Name:
xxxxx 70% WP, NI-25 Wettable Powder 70% (w/w).
3.2 Formulation Process
Reference:
3.2.1 Description of Starting
Materials
3.2.2 Description of the
Formulation Process
3.2.3 Discussion of the
Formation of Impurities of Toxicological Concern.
Conclusion:
3.3 Specifications:
Reference:
3.3.1 Establishing Certified
Limits/Guarantee:
xxxxx:
Nominal............70%
Lower Limit .....67%
Upper Limit..... 73%
The LCL and UCL exceed the standard
limits of ± 3%.
3.3.2 Control Product Specification
Form
Table 2. Specifications
of xxxxx (70 WSP insecticide)
Component
(Chemical Name) |
CAS No. |
Purpose |
Basic Formulation
% weight
(LCL -UCL) |
Alternate formulation
12462
% weight
(LCL -UCL) |
Alternate formulation
80667A
% weight
(LCL -UCL)
|
xxxxx,
99.5%. |
135410-20-7 |
Active Ingredient |
70.35 |
70.35 |
70.35 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Total |
|
|
|
|
|
Date of specifications:
Guarantee: xxxxx.....70%
nominal
Calculation of active
content:
% xxxxx:
70.35 × (0.995 purity) = 69.99%
Conclusion:
3.4 Product Analysis
Reference:
3.4.1 Enforcement Analytical
Method
Table 3. Details of the
analytical method used to determine xxxxx
Sample preparation |
|
Instrument |
|
Detector |
|
Column |
|
Mobile phase |
|
Quantitation |
|
Retention time (RT) |
|
Total run time |
|
The validation data are shown
in Table 4.
Table 4. Validation data
Parameter |
Method |
Data |
Identity |
|
|
Accuracy |
|
|
Precision |
|
|
Linearity |
|
|
Specificity |
|
|
Stability |
|
|
Conclusion:
3.4.2 Impurities of Toxicological
Concern.
Conclusion:
3.5 Chemical and Physical
Properties
Reference:
Table 5. Chemical and Physical
Properties
DACO # |
Property |
Value |
Comment |
GLP
(Y/N) |
3.5.1 |
Color |
|
|
|
3.5.2 |
Physical State |
|
|
|
3.5.3 |
Odor |
|
|
|
3.5.4 |
Formulation Type |
|
|
|
3.5.5 |
Container Material and Description |
|
|
|
3.5.6 |
Bulk density |
|
|
|
3.5.7 |
pH (1% aqueous solution) |
|
|
|
3.5.8 |
Oxidizing or Reducing Action |
|
|
|
3.5.9 |
Viscosity |
|
|
|
3.5.10 |
Storage Stability Data |
|
|
|
3.5.11 |
Flammability |
|
|
|
3.5.12 |
Explodability |
|
|
|
3.5.13 |
Miscibility |
|
|
|
3.5.14 |
Corrosion Characteristics |
|
|
|
3.5.15 |
Dielectric Breakdown Voltage |
|
|
|
Explanation to Table 5:
*BF: Basic formulation
AF: Alternate formulation
Conclusion:
3.6 Sample(s):
3.7 Other Studies/Data/Reports:
Overall
Summary of Data
Formulation:
Conclusion:
Review History:
Summary written by:
Date written:
Peer reviewed by:
Date peer reviewed:
Last update date:
Review Retrievability:
The reviewer's name and Central
File (Reg. No. xxxx-xxx).
7505C:RD/TRB:CM-2:Rm.xxx:initials of the typist: DD/MMM/YYYY:
703-xxx-xxxx:<xxxx- xxx>
|
Appendix A:
Example Reviews
-
Sample
Review of an End-Use Product Formulated from Registered Sources
NOTE: some applicants
may comply with PR Notice 98-1 on Self- Certification of Product Chemistry
Data and submit an abstract summary of the physical/chemical properties
on EPA Form 8570-36 (13 of 26 properties from Group "B"), plus a signed
and dated self-certification statement on EPA Form 8570-37.:
DATE OUT: DD/MMM/YYYY
PRODUCT CHEMISTRY REVIEW OF
MANUFACTURING- USE [ ] END-USE PRODUCT [X]
DP BARCODE No.: xxxxxx EPA RECEIVED DATE: DD/MMM/YYYY
REG./File Symbol No.: xxx-xx
PRODUCT NAME:
, %AI
COMPANY NAME:
MRID NO: xxxxxx-01 ACTION CODE:
xxx
FROM: |
Reviewer's Name, Chemist /S/
Technical Review Branch /RD (7505 C)
OR
Product Reregistration Branch (7508C) |
TO: |
# PM name/CRM names
Branch Name/RD(7505 C) |
INTRODUCTION:
In a letter dated 05/OCT/200-, the
applicant requested a FIFRA Section 3(c)(5) registration of a subject
product. In support of this action, the applicant included product
chemistry data, the product's CSF, a basic formulation dated 01/OCT/200-,
and label EPA received 10/OCT/200-.
FINDINGS:
-
A Reregistration Eligibility Document
(RED) for the technical grade of active ingredient in this product
was issued during September 2001. It was concluded that generic
data was determined to be substantially complete.
-
-
The subject product was produced
by a non-integrated formulation system, meaning that the technical
source in this formulated product is registered, Reg. No.
xxx-xx. The subject product contains xx% of: a common or chemical
name of AI, xx% pure, CAS registry #xxx-xx-x.
-
The subject product, a selective
liquid herbicide, is intended for broadleaf weed control in
field crops.
-
-
Product specific data gaps:
Corrosion characteristics (GRN 830.6320), and Viscosity (GRN
830.7100).
-
With the exception of the data
gaps cited in Finding 3(a) above, the remaining product chemistry
data included with this submission, satisfy the registration
requirements for this product.
-
Adequate analytical method is available
for enforcement. The method was previously submitted and reviewed
in connection with registration of the technical source, Reg.
No. xxx-xx. A method was included with this submission, MRID #xxxxxx-xx,
entitled "Determination of (a common or chemical name of the active
ingredient) in formulated products by the use of gas liquid chromatography
equipped with a flame ionization detector." The method. No. xxxx
was authored by xxxxx of Bayer Corporation, May 2001 (10 pages).
The method satisfies the requirements of 40 CFR 158.180. Sample
calculation and chromatograms were included with this submission.
-
-
Based on the submitted flammability
study showing that this product is extremely flammable, a
label statement is needed as per the regulations of 40CFR§156(10)(h)(2)(iii)
indicating that this product is: "Extremely Flammable, contents
(copy remainder of the sentence from CFR)..."
-
With the exception of 5(a)
above, the label ingredient statement, the physical/chemical
hazard statement, and the storage and disposal statement,
are in compliance with the regulations of 40 § 156.10.
-
-
The applicant will need to
revise the pH in box 7 of the CSF from 6 to 8, and complete
box 9 indicating the flash point of the product at 20°F.
-
The applicant should be advised
to list the nominal concentration between parentheses below
the percentage by weight in column 13(b) of the CSF. Further,
the upper and lower certified limits of the active ingredient
should be based on the nominal concentration not on percentage
by weight, not to exceed the standard certified limits of
40CFR§158.175(b)(2).
-
With the exception of the deficiencies
in 6(a) and 6(b) above, the submitted Confidential Statement
of Formula (CSF) was filled out correctly and completely in
compliance with the regulations. The nominal concentration
of the active ingredient agrees with the label claim nominal
concentration as per the regulations of PR Notice 91-2. Further,
the upper and lower limits are within the standard certified
limits of 40 CFR §158.175(b)(2).
-
All ingredients claimed on
the CSF are cleared for use in pesticide formulations.
CONCLUSIONS:
With the exception of the data gaps
cited in Findings 3(a), 5(a), 6(a) and 6(b), the applicant has satisfied
the remaining product chemistry data requirements for a FIFRA sec.
3(c)(5) registration of the subject product.
NOTE TO CRM:
After revising product's CSF, a basic
formulation dated 01/OCT/200-, it should supersede all previous basic
formulations.
DETAILED CONSIDERATIONS
REVIEW OF PRODUCT CHEMISTRY
DATA:
-
A statement of data confidentiality
dated DD/MMM/200- was included with this submission claiming confidentiality
of some of the data requirements on the basis of its falling within
the scope of FIFRA§10(d)(1) (A), (B), or (C). Review of CBI information
is to be found in Confidential Appendix A.
-
A GLP statement dated DD/MMM/200-
was included with this submission to the effect that some of the
submitted studies were conducted in full compliance with GLP requirements
of 40CFR§160.
DATA SUBMITTED
MRID #xxxxxx-xx. The submitted study
entitled " . . . ," was authored by . . . , performed by . . . , completed
on xxx/200- (xx pages).
Group A, Series 830-Product
Identity, Composition, and Analysis (40 CFR 155, 160, 162, 167, 175
and 180)
830.1550 Product Identity and composition
The subject product contains one registered
technical grade of active ingredient plus cleared inert ingredients.
The identities of all ingredients in this product are listed on the
product's CSFs, a basic formulation dated 01/OCT/200-.
830.1600 Description of materials used
to produce the product:
Refer to Confidential Appendix A.
830.1650 Description of formulation
process:
Refer to Confidential Appendix A.
830.1670 Discussion of formation of
impurities:
Refer to Confidential Appendix A.
830.1700 Preliminary analysis:
Refer to Confidential Appendix A.
830.1750 Certified limits:
Refer to Confidential Appendix A.
830.1800 Enforcement analytical method
MRID #xxxxxx-xx:
Adequate analytical method is available
for enforcement. The method was previously submitted and reviewed
in connection with registration of the technical source, Reg. No.
xxx-xx. A method was included with this submission, MRID #xxxxxx-
xx, entitled "Determination of (a common or chemical name of the active
ingredient) in formulated products by the use of gas liquid chromatography
equipped with a flame ionization detector." The method, No. xxxx was
authored by . . . of Bayer Corporation (10 pages). The method satisfies
the requirements of 40 CFR 158.180.
In this method: Give a brief description
of the principles on how extraction of the AI and determination, both
qualitative and quantitative, is achieved. Example: In this method,
the active ingredient is determined by making direct comparison between
the HPLC detector responses of the sample to that of a reference internal
standard containing a known amount of the standard (purchased or synthesized?).
Sample calculation and chromatograms are included with this submission.
Group B, Series 830-Physical
and Chemical Properties (40 CFR 158.190)
For applicants who comply with PR Notice
98-1, write the following paragraph:
"The applicant complied with PR Notice
98-1 and submitted the needed information on EPA Form 8570-36. A signed
and dated (DD/MMM/YYYY) self-certification statement, EPA Form 8570-37,
was also included. Summary of the physical/chemical properties on
EPA Form 8570-36 is adequate and is appended to this memorandum (one
page)."
Copies of EPA Forms 8570-36 and 8570-37
are appended at the end of this SOP under "REVIEW FORMS"
Applicants not complying with PR Notice
98-1, summarize the properties in the following table:
Group B, Series 830-Physical
and Chemical Properties (40 CFR 158.190)
GRN |
Requirement |
MRID |
Status1 |
Result2
or Deficiency |
830.6302 |
Color |
|
|
|
830.6303 |
Physical State |
|
|
|
830.6304 |
Odor |
|
|
|
830.6314 |
Oxidation/Reduction: Chemical
Incompatibility |
|
|
|
830.6315 |
Flammability |
|
|
|
830.6316 |
Explodability |
|
|
|
830.6317 |
Storage Stability |
|
|
|
830.6319 |
Miscibility |
|
|
|
830.6320 |
Corrosion characteristics |
|
|
|
830.6321 |
Dielectric breakdown voltage |
|
|
|
830.7000 |
pH |
|
|
|
830.7100 |
Viscosity |
|
|
|
830.7300 |
Density / relative density / bulk
density |
|
|
|
1 A = Acceptable; N = Unacceptable
(see Deficiency); N/A = Not applicable; G = Data gap; U = Needs upgrading.
2 For example, "brown" for 830.6302; "155 C" for 830.7200.
The reviewer's name and Central File
(Reg. No. xxxx-xxx).
7505C:RD/TRB:CM-2:Rm.xxx:initials of the typist: DD/MMM/YYYY: 703-xxx-xxxx:
<xxxx-xxx>
CONFIDENTIAL
APPENDIX A
NOTE TO REVIEWER:
Confidential Appendix A should be separated from the non-CBI part
above. The codes at the end are for identification and tracking if
filed separately.
830.1600 Description of materials used
to produce the product:
List materials from the submission.
If the applicant relied on the product's CSF, make the following statement:
"Materials used in formulating the subject product are listed on the
submitted CSF, a basic formulation dated 01/OCT/200-."
830.1650 Description of formulation
process:
Describe as provided in the submission.
830.1670 Discussion of formation of
impurities:
Describe as provided in the submission.
If no new ingredients were formed during the formulation process,
you may state "No new ingredients > 0.1% by weight were
known to be formed during formulation and storage of the product."
830.1700 Preliminary analysis:
Sample or batch analysis is important:
-
to quantify the label claim nominal
concentration of a non-integrated product and to ascertain reliability
of the enforcement analytical method in recovering the nominal
concentration of the TGAI to within the upper and lower standard
certified limits; and
-
to characterize the impurity profile
in integrated products.
830.1750 Certified limits:
The applicant reported the same ingredients
at percentages and lower/upper limits as those reported on the product's
CSF, a basic formulation dated 01/OCT/200-.
7505C:RD/TRB:CM-2:Rm.xxx:initials of
the typist: DD/MMM/YYYY: 703-xxx-xxxx: <xxxx-xxx>
-
Examples of "Me-Too"
requests citing the Introduction, Findings, and Recommendations
Example 1:
INTRODUCTION:
In a letter dated 08/SEP/200-, the
applicant requested a FIFRA Section 3(c)(3) (B)(i)(I) "me-too" registration
of subject product claiming its similarity to (product's name, Reg.
No. xxx-xx). In support of this action, the applicant included some
product chemistry data, the product's CSF, a basic formulation dated
DD/MMM/YYYY, a label EPA received DD/MMM/YYYY, Certification With
Respect to Citation of Data, and a Data Matrix choosing the selective
method of support.
FINDINGS:
-
This action is a first submission
to the Technical Review Branch. It was not indicated in the applicant's
letter if an authorization letter was submitted to permit the
Agency access to applicable data from the registered product.
-
The subject product is produced
by an integrated production system. This means that the technical
source is not registered (no registration number in Column 12
of the CSF). Further, the CSF included on page xx, MRID #xxxxxx-xx
was decreased in size to the point that it is difficult to read.
RECOMMENDATIONS
This action does not qualify for a
FIFRA Section 3(c)(3)(B)(i)(I) "me-too" registration because the technical
source is not registered. For future submissions, the applicant should
be advised to submit the full product chemistry data on the TGAI whether
or not a registration is sought. Further, applications must be accompanied
by a full size CSF, preferably an original copy, and an authorization
letter to permit the Agency access to data from the registered product.
The reviewer's name and Central File
(Reg. No. xxxx-xxx).
7505C:RD/TRB:CM-2:Rm.xxx:initials of the typist: DD/MMM/YYYY: 703-xxx-xxxx:
<xxxx-xxx>
Example 2:
INTRODUCTION:
In a letter dated DD/FEB/200-, the
applicant requested a FIFRA Section 3(c)(3) (B)(I) "me-too" registration
of subject product claiming its similarity to (product's name and
Reg. No.). In support of this action, the applicant cited product
chemistry data of Reg. No. xxx-xx and included a proposed basic formulation,
CSF dated 17/OCT/200-, and a label that EPA received 20/OCT/200-.
In addition, the CSF, a basic formulation dated DD/MMM/YYYY, and a
label accepted in 1998 of the registered product were also included
with this submission.
FINDINGS:
-
-
The subject product is not
similar to the registered product, because of the wide difference
in the label claim nominal concentration of the active ingredient.
The claims are 60% in the pending product as opposed to 95%
in the registered product. (Note: variations in the nominal
concentration of a pending product must be within the upper
and lower standard certified limits of the registered product).
-
The subject product is produced
by a non-integrated formulation system meaning that the technical
source in the product is registered. The product contains
10% permethrin, Reg. No. xxx-xx.
-
-
For the requirements of Group
"A," OPPTS Test Guidelines Series 830, the Agency can rely
on the currently approved analytical method for the active
ingredient in the product. There is no need for submittal
of samples. Further, product identity, composition, and certified
limits can be obtained from the proposed label and CSF.
-
Except for the requirements
in 2a above, the applicant will need to submit product chemistry
data requirements pertaining to Guideline Reference Numbers
(GRNs) 830.1650 Description of formulation process and 830.1670
Discussion of formation of impurities.
-
Concerning product chemistry
data requirements of Group "B," OPPTS Test Guidelines Series
830, pertaining to the physical/chemical properties, the applicant
has the option of following the regulations of PR Notice 98-1
and submitting a summary of pertinent physical/chemical properties
on EPA Form 8570-36. This form should be accompanied by a
signed and dated self-certification statement (EPA Form 8570-37).
Of the thirteen properties listed on EPA Form 8570-36, the
following six are applicable to your product and must be submitted:
GRNs 830.6314 Oxidation/Reduction: Chemical Incompatibility,
830.6316 Explodability, 830.6320 Corrosion characteristics,
830.6321 Dielectric breakdown voltage, 830.7000 pH and 830.7300
Density/relative density/bulk density.
CONCLUSIONS:
-
From the product chemistry view
point, the subject product does not qualify for a FIFRA Section
3(c)(3)(B)(I) "me-too" registration because of finding 1a above.
-
The applicant should be advised
to seek a FIFRA Section 3(c)(5) registration of the subject product
and comply with the requirements of Findings 2b and 2c above.
The reviewer's name and Central File
(Reg. No. xxxx-xxx).
7505C:RD/TRB:CM-2:Rm.xxx:initials of the typist: DD/MMM/YYYY: 703-xxx-xxxx:
<xxxx-xxx>
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Appendix
B: Changes and Recommendations Under Consideration
General
Comments
-
Regarding the Confidential Statement
of Formula (CSF), the amount column adds to confusion when entering
TGAIs in a revised CSF (the present CSF is geared toward formulated
end-use products). For formulated products, the amount reported on
the CSF can range from as little as 16 ounces (alkaloids) to a batch
of 100 pounds, a 1000 or a million from which the CSF reviewer checks
to see if the percentages w/w are correct. This arithmetic is irrelevant
to the review of a CSF. Further, any error by the applicant in converting
from amounts to percentage by weight will be captured in the material
balance of 100%. The actual amounts are reported to other science
disciplines for risk/benefit assessments. For these reasons, revisions
to the CSF have been recommended to delete the amount column and use
the present columns 13(a) and 13(b) for percentages by weight and
nominal concentrations, respectively. Deleting the amount column was
also echoed by the pesticide industry during their meeting with the
Agency on 06/AUG/1998.
-
The nominal concentration is defined
in 40CFR§158.153(h)(1) to mean "the amount of an ingredient
which is expected to be present in a typical sample of a pesticide
product at the time the product is produced, expressed as a percentage
by weight." The nominal concentration can be explained to
mean: "The percent of a pure ingredient within the minimum and
maximum guarantee that is most likely to be present in a typical sample
of a pesticide product as determined by validated analytical techniques
from production to use ." Please note that it is the percentage,
not weight or amount, because weight and amounts are calculated back
based on percentages that may or may not add up to the exact production
volume. What is reported on the CSF is one batch that does not reflect
the actual production volume. This distinction between percent nominal
and percentage by weight reinforces the recommendations to delete
the amount column.
-
A PR Notice is being drafted to define what is meant by "Substantially Similar Products."
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A
Proposed Form of a Cover Letter for Conducting Secondary Reviews of Contractor's
Reviews:
UNITED STATES ENVIRONMENTAL
PROTECTION AGENCY
WASHINGTON, D.C. 20460
![](https://webarchive.library.unt.edu/eot2008/20090510232735im_/http://www.epa.gov/oppfead1/trac/epalogo.gif)
OFFICE OF
PREVENTION, PESTICIDES AND
TOXIC SUBSTANCES
DATE OUT: DD/MMM/YYYY
MEMORANDUM
SUBJECT: |
PRODUCT CHEMISTRY SECONDARY REVIEW
OF:
A TECHNICAL GRADE OF ACTIVE INGREDIENT [ ]
MANUFACTURING-USE PRODUCT [ ]
END-USE PRODUCT [ ] |
DP BARCODE No.:
Action Code:
REG./File Symbol No.:
PRODUCT NAME:
COMPANY NAME:
REVIEWED BY:
CONTRACTOR'S NAME:
SECONDARY REVIEW BY: RD
(7505C) CRM #/Name:
FINDINGS:
The subject product has undergone secondary
review by RD. The review reflects EPA's regulations and the Findings/Conclusions
are scientifically sound.
Note to secondary reviewers: Please
indicate any Findings/Recommendations by the contractor with which you
disagree and make the necessary revisions on this page under Findings.
CONCLUSIONS:
The applicant has satisfied product chemistry
data requirements for a FIFRA Section 3(c)(5) registration of the subject
product. The product's label, EPA received DD/MMM/YYYY, and CSF, a basic
(and/or alternate) formulation(s) dated DD/MMM/YYYY are acceptable.
-OR-
At this time, we are unable to recommend
for registration of the subject product pending resolution of Findings
x and x cited above, as well as the contractor's findings #'s xx cited
on pages xx.
NOTE: If the full data
that was reviewed by the contractor should be reviewed again, the following
statement can be written as a "NOTE TO CRM" following Recommendations:
"A copy of (Contractor's name), dated DD/MMM/YYYY (xx pages) is appended
to our memorandum. Our review projects the Findings/ Conclusions up in
front to assist the CRM in communicating the Agency's decisions to the
applicant."
Attachment: Our memorandum (xx pages) and
the contractor's review of the subject product dated DD/MMM/YYYY (xx pages).
cc: The reviewer's name and Central File:
Rereg. No. (xxx-xx).
7508C:SRRD:CM-2:Rm.xxx: The typist's initials: 10/JAN/200- :703-308- :
< - >.
Non-binding Nature of This Policy
Guidance Document
This document describes a current policy
position of OPP, but it is not a legally binding regulation. It binds
no one-not the regulated community, not advocacy groups, not the public,
and not OPP. In any decision before OPP, any stakeholder may urge OPP
to:
- conclude that this policy guidance document
is inapplicable;
- consider factors other than those described
in this policy guidance document;
- make an exception to the policy guidance
document as written; or
- amend or abandon the policy in its entirety.
Even if no such arguments are made to OPP,
OPP may decide on its own initiative that the circumstances warrant the
Agency to act at variance from this policy guidance document. Thus affected
parties should not assume that carefully following this policy guidance
document will guarantee a specific decision or action by OPP. If OPP does
decide to vary from this policy guidance document, OPP would explicitly
state how it varies from the policy and provide a written explanation
for this variance in the context of that decision.
Consistent Application of This
Policy Guidance Document
Although OPP's policy guidance documents,
including this one, are non-binding, they reflect the current thinking
of OPP, and therefore OPP staff are expected to use them as guides for
decision-making unless there is a good reason for adopting an alternative
approach. Accordingly, this policy guidance documents should serve as
a reference and starting point for OPP staff for analyzing the issues
as they arise in individual pesticide matters. Importantly, it should
be remembered, however, that this policy guidance document does not provide
authority for reaching specific results–each individual decision must
be based on sound factual, scientific, and legal conclusions. Further,
if OPP staff believe, based upon their own analysis or upon comments of
any stakeholder, that an alternative decision-making approach to the one
outlined in this policy guidance document is warranted, that approach
would be presented to OPP decision-makers for their consideration. Any
decision by OPP to vary from this policy guidance document should be accompanied
by a written explanation provided in the context of that decision specifically
addressing the reason for the variance.
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