Tips for Avoiding Confidential Statement of Formula or Product Chemistry Issues with Biopesticides
Current as of March 5, 2007
Below are recommendations that may assist registrants in reducing common mistakes when preparing and submitting biopesticide product chemistry data and the Confidential Statement of Formula (CSF).
On This Page
- General Recommendations for registering a biopesticide
- Confidential Statement of Formula (CSF) Tips
- Product Chemistry Tips
- Biochemical Pesticides Tips
- Microbial Pest Control Agents (MCPA) Tips
- Plant Incorporated Protectants (PIPs) Tips
- Determine whether the pesticide is a biopesticide, an antimicrobial, or a conventional pesticide.
The Biochemical Classification Committee (BCC) performs this function. Contact Russell Jones (firstname.lastname@example.org), the BCC representative for the Office of Pesticide Programs (OPP), Biopesticides and Polllution Prevention Divison for more information on this process.
In general, the BCC requires the following information to support a “Biochemical Classification Determination.”
- Evidence of the pesticide’s natural occurrence, or evidence that the pesticide is structurally similar and functionally identical to naturally-occurring compounds
- Evidence for a non-toxic mode of action against the target pest. A non-toxic mode of action may include such pest control methods as attraction, repellency, growth regulation, induction of systemic acquired resistance, desiccation, smothering, etc.
- Product chemistry information (structure(s), CAS #, source(s), physical/chemical properties, etc) for each proposed active and other ingredients in the formulated product.
- Rate and timing of application.
- Any available information regarding toxicity of the product (acute, subchronic, chronic, developmental, carcinogenicity, mutagenicity, etc).
- Efficacy data, if products are to be used specifically against a public health pest (e.g., mosquitos, flies, cockroaches, fireants, termites, rodents). (See List of Pests of Significant Public Health Importance PDF (32 pp, 347 kb About PDF)
- Schedule a pre-registration meeting with BPPD
Contact either the Biochemical or Microbial Pesticides BPPD Branch Chief to schedule a meeting. Your meeting needs to be far in advance of performing studies or submitting a registration package. Submit an agenda with the proposed product. Identify needs for a Section 3 registration, tolerance exemption, or EUP. Be prepared to discuss potential data waiver justifications. Many of the “case-by-case” requirements associated with product chemistry and toxicology can be discussed at these meetings.
- Submit the entire registration package at one time.
If a package or application is incomplete, under 40CFR §152.105, EPA sends a letter to the applicant stating that the applicant has 75 days from the letter date to correct the problem or the application will be withdrawn. Applicants may request additional time to correct the deficiencies. For registration actions under the Pesticide Registration Improvement Act (PRIA), this lost time In either case, EPA will renegotiate the PRIA due date.
- Follow the recommendations provided.
Complex biopesticide applications should also consider hiring a regulatory consultant to facilitate registration, see Biopesticide Regulatory Consultants List.
Once information is submitted, registrants will be contacted with the decision within 30 days.
A CSF preparation guide for plant-incorporated protectants (PIPs) is not available. Registrants for PIPs may also contact the BPPD Microbial Pesticides Branch Chief for details on PIP CSF preparation.
The CSF preparation guide addresses most CSF issues but additional problems can be avoided by checking the items below:
- Match the Brand name on the label to the name on the CSF
- Match the active ingredient name and percentage on the label to that on the CSF
- Provide CAS numbers for all ingredients (except perhaps for PIPs and microbials)
- Provide inert ingredients that are cleared for the products potential uses
- If an inert component is an attractant for the target pest, re-consider it as an active ingredient
- List active and inert components by their chemical name (not brand name)
- Provide nominal concentration and upper and lower certified limits for the active ingredient(s)
- If the active ingredient(s) are not 100% pure, provide the concentration and upper and lower certified limits for the pure active ingredient
- The upper certified limit of 100% for the technical grade active ingredients, pure active ingredients, or manufacturing products
- The upper certified limit for end-use product ingredients can exceed 100%
- Provide justification when certified limits are beyond that recommended in 40 CFR §158.175
- Provide an original signature and date on the CSF
- List ingredient sources with complete addresses (not the phrase “commodity”)
- Provide a separate CSF for each alternate formulation
- When water is used as an inert, provide a complete address for the source
- Insert physical characteristics from the product chemistry into blocks 7, 8, and 9 of the CSF form.
- Leave block 4 blank if an EPA registration number is unavailable or insert the company number (EPA will then assign a product number)
- Provide a “Purpose in Formulation” (block 15) for each ingredient (e.g. diluent, preservative, surfactant, impurity)
- Ensure that the nominal percentages in column 13b total up to 100%
Product chemistry guidance is available at Biopesticides Data Tables and Guidelines.
Even with the available guidance, many submitted packages contain a variety of problematic issues. Avoid delays in registration due to product chemistry. Be sure to:
- Present the ingredients at a single concentration (ie, not 30-70% pure)
- Address each product chemistry data requirement with a rationale or statement, even if the requirement does not apply (ie cite the 40CFR footnote)
- Provide summaries AND copies of literature when waiver rationales cite published or unpublished literature
- The FDA determination of Generally Regarded as Safe (GRAS) should not be cited as a sole waiver rationale
- In the pre-registration meeting, discuss whether the certified limits recommended in 40 CFR §158.175 apply to the product
- The Material Safety Data Sheets should not be used as a sole support for product chemistry requirements
- When MSDS’s are used as support, ensure that the supplier, % purity, and impurities of toxicological concern are identified appropriately
- Manufacturing processes can best be followed when presented in conjunction with a flow chart
- Provide data for the end-use product, even if the manufacturing product comes from a registered source
- Biochemical Pesticides Tips
- Pheromones and Allelochemicals
In general, guideline requirements for biochemical pesticides are similar to those of conventional pesticides.
Product chemistry is the primary data requirement for pheromones and allelochemicals. The Organization for Economic Co-operation and Development (OECD) Guidance for Registration Requirements for Pheromones and Other Semiochemicals Used for Arthropod Pest Control PDF (25 pp, 78 kb About PDF) provides a good overview of what factors should be considered.
- data demonstrating allomonal, kairomonal, synomonal, or pheromonal activity
- straight chain lepidopteran pheromone products should demonste similarity to unbranched aliphatic compounds having 9-18 carbons, up to 3 double bonds, and a terminal alcohol, acetate, or aldehyde functional group
- information on the size of the carrier bead for formulated products using microencapsulation
Registration of inorganic pesticides should consider both solid matrices and potentially soluble components when being described via product chemistry. Matrix product chemistry should include the the percent carbon, the percent crystalline silica and particle size analysis.
- asbestos fiber quantification is also encouraged for products having vermiculite as a component
- soluble components such as metals and metalloids shouldt also be described in order to capture the potential for soluble leachates
- mined or waste ash products are compositionally heterogeneous, so a discussion of mining or production methods that ensure product consistency should be provided
Plant extracts are oily heterogeneous mixtures of terpinoid molecules that have been pressed or processed from plants. Submissions should identify the species and variety of the plant. The active components (and/or surrogate analytical markers) in the extract should also be identified, quantified, and have certified limits.
If the identity of any ingredient or impurity can not be specified as a discrete chemical substance, sufficient information must be provided for EPA review (40 CFR 158.155 (f)). Blending, batch deletion, enrichment with purified components may be used to maintain product consistency. Nominal concentrations will be used for enforcement purposes and must be listed on the product label and CSF. Impurities >0.1% composition should also be identified, quantified, and listed on the CSF (40 CFR 158.155 (d)(1), (2), (3)).
Peroxide products are characterized by having strong chemical reactivity. Submissions with multiple components should identify secondary byproducts from the reaction and identify the relative component equilibriums in storage over time and at relevant temperatures.
Animal byproducts include such pesticides as urine, blood, and egg solids. Animal byproduct pesticides have the unique potential to transfer viruses, bacteria, fungi, and parasites to humans or other animals. Because of this potential, registrants should submit information regarding the lack of such contaminants.
Detailed information on the manufacturing process, analytical methods, and quality assurance/quality control (QA/QC) should be provided to demonstrate that the product is free of all potential mammalian pathogens. Justifications for acceptable levels of microbial contaminants and control methods when such levels are exceeded must be included in the QA/QC discussion. These protocols should be submitted to EPA prior to use in a study.
Products with volatile components should provide adequate characterization of the volatile components, including the rate of production in different environmental scenarios, and growth media or chemicals used to produce the volatiles. A discussion of the predicted variability of volatile production is also important to include in product submissions.
Products to be dispensed within a trap or dispenser should include a detailed description of the dispensing/trapping device, including anticipated propellents or additional conventional pesticides. Biopesticide submissions conjoined with conventional pesticides should contact the Ombudsman for conventional pesticide products for additional registration information.
Products that are plant or insect regulators should include a discussion of the mechanism of action. The discussion can be supported by data and/or published literature. Activity related to a particular chemical isomer should also be described.
In general, MCPAs should be expressed as viable organisms per unit weight or volume (e.g. cfu/g) or international units of potency per unit weight. Methods might need to be combined to verify certified limits and impurities. Consult the specific microbial testing guidelines.
- Bacteria, Fungi, Protozoans, Phages and Viruses
Adequate identification of microbes, microbial contaminants, and/or impurities is important for these pesticides. Each microbe should be identified by taxonomic position, serotype, and/or strain utilizing the best methods currently available and have an assigned or nationally recognized collection number (ie Bacillus thuringensis subsp kustaki AA1234; Beauveria bassiana strain 123).
Alternate names are also important to provide a link to the older literature on the microbe. Identification information should include:
- the phenotype coded for, and its stability (and rate or exchange with other organisms), and
- method used to alter the genetics
- information on the natural occurrence of the microbe, its relationship to other species, and its life cycle and mode of action with respect to target species and known host range.
A detailed description of the manufacturing process and QA/QC methods should also be submitted. This description must include methods taken to prevent contamination, ensure a uniform product, and identify the MCPA.
Impurities to describe are:
- metabolic byproducts,
- mutant strains
- microbial contaminants (especially mammalian pathogens or antagonistic microbes),
- chemical contaminants
If hazardous contaminants are detected during production or purification, mitigation measures may be proposed in order to ensure that these are present in the final product in non-hazardous quantities. Storage stability should also be submitted to establish expiration dates for the claimed label rates of live microbial active ingredient.
Microbial products which produce volatile fumigants should fulfill standard microbial guideline requirements for product chemistry. Registrants for these products should also provide adequate characterization of the volatile components, including the rate of production in different environmental scenarios, and growth media (nutrient sources/solid carriers) used to produce the volatiles. A discussion of the predicted variability of volatile production is also important to include in product characterization submissions.
Microbial consortia and composted material pesticides are inherently difficult to describe using standard product chemistry guidance because of the complexity of components. Contact the Biological and Pollution Prevention Division (BPPD) Microbial Pesticides Branch Chief for further information regarding these types of pesticide products.
In general, PIP’s and their associated marker proteins require much of the same CSF information as biochemicals and microbials. For PIPs, however, bulk density, pH, and flash point, (CSF form blocks 7, 8, 9) are typically not applicable (n/a).
On PIP CSFs, the “Components in Formulation” (block 10) should identify the protein, the genetic material necessary for its production, and the plant into which it was incorporated, since PIPs do not have CAS numbers. Neil Crickmore’s work at the University of Sussex, (UK) provides useful examples of PIP nomenclature
Registrants should express “Each Component in Formulation” (block 13) in terms of plant parts (Whole plant, leaf, root, pollen, seed), in order to provide satisfactory information for Insect Resistance Management and human and ecological risk assessments. Quantitative determinations of the amount of pesticidal protein produced by each plant part should also be presented on a % dry weight basis.
- Single Protein PIPs
Product characterization for single protein PIPs has been described in detail at the Science Advisory Panel (SAP) meetings on December 8-9, 1999 and the June 2004
In general, single protein PIPs should include details of:
- the inserted DNA
- transgenic protein production and RNA expression
- the transformation system
- the inheritance and stability of functionally induced traits.
USDA and the Canadian Food Inspection Agency have provided a useful example of molecular and genetic points to consider when characterizing transgenic plants.
Product characterization for multiple or “stacked” protein PIPs should include relevant information on the registered single protein PIP components as well as discussion of any potential antagonistic, synergistic, or potentiating toxicological interactions. Contact the Biological and Pollution Prevention Division (BPPD) Microbial Pesticides Branch Chief more details.
These products include PIPs whose inserted genetic material is derived from a plant virus sequence encoding a coat protein. Informational requirements for PVCP registration are currently being determined. Contact the Biological and Pollution Prevention Division (BPPD) Microbial Pesticides Branch Chief for more details.