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Analytical Methods & Procedures

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
1. General Guidance
2. Organization of the Reviews
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
- Example of labeling and CSF for a formulated end-use product
- Example of labeling and CSF for a Technical Grade of Active Ingredient (manufactured Product)
Consistency between the Label and CSF
Verify the Following to Guard Against Common Errors when Comparing the Label and CSF
Review Forms

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

General Comments
A Proposed Form of a Cover Letter for Conducting Secondary Reviews of Contractor's Reviews

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
1. 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:
  1. conventional (including antimicrobials);
  2. biopesticides, which includes biochemical pesticides, microbial pesticides, and plant-incorporated protectants (PIPs).
2. 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:
1. Identification and characterization of each ingredient in pesticide products.
2. Risk assessment.
3. Environmental Fate assessment.
4. Reentry determination and labeling precautions pertaining to worker protection.
5. Labeling directions pertaining to tank mixes and spray applications.
6. Labeling ingredient statement, precautionary statements, the physical or chemical hazards statement, and the storage and disposal statement.
7. Expressing a product's composition and some properties on the Confidential Statements of Formula (CSFs).
8. Developing the Reregistration Eligibility Decisions (REDs).
9. 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
New guidelines (1996)	1982 guidelines	Title	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
New guidelines (1996)	1982 guidelines	Title	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:
1. 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).
2. 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.
3. 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:
  1. Estimation of solubility of gases in liquid solvents.
    -ln x₁ = ln (f₁^L/f₁^V) + (V₁ φ ₂ ² (δ₁ - δ ₂)²/RT
  2. Estimation of solubility of liquid solute in solvents.
    RTc = [ 2 x _1c x _2c v₁²v ₂² (δ¹-δ²)²/[x _1cv₁ + x_2cv₂] ³
  3. Estimation of solubility of solids in liquid solvents.
    If x₁ , 0.01: ln x₁ = ΔH_f /RT [T/Tm-1] - lnγ ∞
    
    If x1, 0.1: ln x₁ + (1-x₁)² ln γ ₁∞ = ΔH_f /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):
1. 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.
2. The highest concentration of the active ingredient which is produced on a commercial or pilot-plant production scale; and
3. 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):
1. Any pesticide product other than an end-use product.
2. It has a label stating "for use in formulating other products"; and
3. May contain solvents and/or stabilizers.
End-Use Product (EP):
1. A pesticide product whose label includes directions for use; and
2. 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.

FQPA	All parts

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):
1. SOP#3068.2, 01/JUL/1981. Determination of Substantially Similar Pesticides Under FIFRA Section 3(c)(7)(A).
2. SOP#3017.1, 28/JAN/1987. Product Chemistry Data and Pesticide Sample Evaluation.
3. SOP#3096.1, 09/FEB/1987. Processing Inert Ingredient Clearances.
4. SOP#3095.5, 02/OCT/1992. Product Reregistration Procedures.
5. 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:
1. New Inert Ingredients and New Food-Uses of Existing Inerts: 52(77) FR13308, 22/APR/1987.
2. List A chemicals: 54(34)FR7740, 22/FEB/1989.
3. List B chemicals: 54(100)FR22706, 25/MAY/1989.
4. List C chemicals: 54(140)FR30846, 24/JUL/1989.
5. List D chemicals: A list, no FR Notice.
6. Flammability Labeling Requirements for Total Release Fogger Pesticides: 59(73)FR13058-13064, 15/APR/1994.
7. Inert Ingredients in Pesticide Products; Policy Statement: 52(77) FR13305-13309, 22/APR/1997.
8. Inert Ingredients no Longer Used in Pesticide Formulations: 63(121) FR34384-34391, 24/JUN/1998.
List of Active Ingredients Undergoing Reregistration:
1. By Case Number.
2. By Chemical Name.
3. 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:
1. PR Notices 81-4, 83-3, 84-5 and 87-8 Label Improvement Programs (84- 5, entitled: label improvement program for fumigants).
2. PR Notice 86-5 Standard format for data submissions (under revisions).
3. PR Notice 87-6 Inert Ingredients in Pesticide Products.
4. PR Notice 87-7 Pesticide Contracting Manufacturing.
5. PR Notice 88-6 Changes in registration procedures.
6. PR Notice 90-1 Inert ingredients in pesticide formulations.
7. PR Notice 91-2 Accuracy of stated percentages for ingredients statement.
8. PR Notice 94-8 Water Soluble Packaging.
9. PR Notice 96-8 Toxicologically Significant Levels of Pesticide Active Ingredients.
10. PR Notice 97-1 Agency Action Under the Requirements of the Food Quality Protection Act.
11. PR Notice 97-4 Consumer Access Numbers on Pesticide Labels.
12. PR Notice 97-5 Use of Common Names in the Label Inert Ingredients Statement.
13. PR Notice 97-6 Use of term "Inert" in the Label Inert Ingredients Statement.
14. PR Notice 98-1 Self-certification of product chemistry data.
15. PR Notice 98-6 Flammability Labeling Requirements for Total Release Fogger Pesticides.
16. PR Notice 98-10 Notification, Non-Notification, and Minor Formulation Amendment (superseded PR Notice 95-2).
17. PR Notice 99-1 Import of Unregistered Pesticides Intended for Export.
18. 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, 2^nd 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:
1. OPP Glossary housed in OPP Applications.
2. FIFRA.
3. 40CFR Parts 152, 153, 156, 158 and 160; and
4. 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
1. References cited under "VI" above.
2. 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.
3. Copies of Inert Ingredients Lists:
  1. Vol 1: Alphabetical Listings.
  2. Vol 2: Listing by Pesticide Products Code Numbers (abbreviated as PC #).
  3. Vol 3: Listing by Chemical Abstract Service Number (CAS).
4. 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).
5. 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
1. 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:
  1. Tracking
  2. Findings
  3. Recommendations
  4. Notes to the CRM
  5. "DETAILED CONSIDERATIONS"
  6. "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.
2. 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:
  1. signed by the reviewer
  2. logged out using PRAT
  3. 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.
3. 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.
4. Methods Validation: The reviewer may request validation of the following analytical methods:
  1. new methods for the TGAIs and associated impurities.
  2. modified methods.
  3. methods for unregistered products.
  4. 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
1. Confidential Business Information (CBI)
  1. 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)
  2. All CSFs.
  3. Nitrosamine analysis data are normally considered to be CBI.
  4. Dioxin analysis data, even if none are detected (i.e., below the LOQs), are usually considered to be CBI.
2. Non-CBI
  1. 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
  2. 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)
  3. All Labels.
Product Properties Studies Requiring Compliance or Noncompliance with Good Laboratory Practices (GLP) Standards of 40CFR§160
1. 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
2. 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
3. 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.
1. 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.
2. Physical or Chemical Hazards statement as per the regulations of 40CFR§156(10)(h)(2)(iii).
3. 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).
4. Consult the Label Review Manual for other tips. Applicants have the option to use:
  1. common names, if known, instead of chemical names (PR Notice 97-5)
  2. 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.
5. 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."
6. 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)."
7. Products containing arsenic in any form must bear a statement of the percentages of total and water soluble arsenic calculated as elemental arsenic.
8. 1. 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
  2. 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.
9. 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
10. 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.
11. 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
12. 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.
13. 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."
14. 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.
15. 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.
1. Applicants and reviewers should follow the directions on the back of the CSF on how to complete it.
2. 1. 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].
  2. 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.%."
  3. 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.
  4. 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.
3. 1. 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].
  2. 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.
  3. 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.
  4. 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.
4. 1. 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%.
  2. 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:
    1. to quantify the label claim nominal concentration and to ascertain reliability of the enforcement analytical method in non-integrated products; and
    2. to characterize the impurity profile in integrated products.
5. 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.
6. 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.
7. 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 parenth