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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 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:
  1. the reactants are not pure substances;
  2. it is difficult to quantify the exact amounts used in the reaction; and
  3. 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.
8. 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.
9. 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..
10. 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.
11. 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.
12. 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.
13. Verify the clearance of inert ingredients intended for food and/or non-food uses where applicable.
14. Verify tolerance exemptions for inert ingredients intended for food uses (40CFR§180.10001 list c, d, e).
15. 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.
16. Confirm the nominal concentration in the CSF for consistency with the label claim nominal concentration.
17. 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%.
1. 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).
2. 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:
1. The label lists the name and address of the registrant consistent with that in box 1 of the CSF.
2. 1. The label cites the name of the product consistent with that in box 3 of the CSF.
  2. The common name and/or chemical name of the product is cited on the label consistent with that in box 10 of the CSF.
3. The registration number of a product (TGAI, MP or EP) on the label is consistent with that in box 4 of the CSF.
4. The label claim nominal concentration can be indicated between parentheses below the percentage by weight in column 13(b) of the CSF.
5. 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.
6. Listing a chemical reaction on the CSF: Please refer to the applicable entry in the section on Review of the Confidential Statements of Formula.
7. 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:
1. 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.
2. Be aware of an incomplete CSF: All boxes and columns should be completed in accordance with the directions on the back of the CSF.
3. 1. 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."
  2. 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%.
  3. 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%.
4. 1. 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.
  2. 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.
5. 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.
6. 1. 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).
  2. 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.
7. Use REFs and/or OPPIN to verify chemical names, purities and CAS registry numbers.
8. 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."
9. 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).
10. 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:

EPA logo/seal

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; "155^o 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	Nominal Concentration (% w/w)	Upper Certified Concentration (% w/w)	Lower Certified Concentration (% w/w)	Preliminary Analysis (% w/w) ³	Mean + r.s.d. (%)
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	Nominal Concentration (% w/w)	Upper Certified Concentration (% w/w)	Lower Certified Concentration (% w/w)	Preliminary Analysis (% w/w) ³	Mean + r.s.d. (%)
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	Nominal Concentration (% w/w)	Upper Certified Concentration (% w/w)	Lower Certified Concentration (% w/w)	Preliminary Analysis (% w/w) ³	Mean + r.s.d. (%)
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

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

Reference:

xxxx

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
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 (pK_a)	PAI > 99%
2.14.11	Octanol/water partition coefficient (K_ow)	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):

TGAI(s):

xxxxx

Guarantee:

xxxxx

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

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.
1. 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.
2. The subject product, a selective liquid herbicide, is intended for broadleaf weed control in field crops.
1. Product specific data gaps: Corrosion characteristics (GRN 830.6320), and Viscosity (GRN 830.7100).
2. 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.
1. 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)..."
2. 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.
1. 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.
2. 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).
3. 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).
4. 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: