T-4-118 - Guidelines to safety assessments of microorganisms in fertilizers and supplements regulated under the Fertilizers Act
The purpose of this document is to provide guidance on safety assessments of microorganisms contained in products that are regulated under the Fertilizers Act. These guidelines describe what is expected of applicants in terms of the information to be submitted for safety assessments. They also describe some of what the applicant may expect of the Canadian Food Inspection Agency (CFIA) during safety assessments and in decision-making.
Product Dafety Assessments
The Fertilizer Section of the CFIA conducts safety assessments of products regulated under the Fertilizers Act. These assessments are conducted on products proposed for research (e.g. field or greenhouse) or for registration. All safety assessments consider the health of users/bystanders that may be exposed to the product. Depending on the product's proposed pattern of use, the assessment may also address food safety and environmental safety.
The Fertilizer Section conducts all safety assessments. Health Canada and Environment Canada are consulted as needed (e.g., where residues in food crops are anticipated). Applicants are expected to participate in product safety assessments by providing the Fertilizer Section with sufficient technical information to demonstrate the safety of their products.
Product safety assessments include a screening stage and a follow-up stage. An inquiry often precedes an actual assessment. Revisions of safety assessments are conducted when an applicant intends to amend a pattern of use or formulation or when significant new information becomes available.
What is Expected of the Applicant
To obtain guidance on the product assessment process, most applicants approach the Fertilizer Section with an inquiry. This is most effective when the applicant can identify the microorganism(s) in the product, the product's other ingredients, whether the product is intended for research or sale, and how and by whom the product is intended to be used. Other information from Section 1 may also be useful.
A screening level safety assessment is the type of review most frequently conducted. It is generally sufficient for research permits and, when it is very comprehensive, it can also be sufficient for product registration.
Information to be submitted for the screening level safety assessment
When seeking product registration, an applicant is expected to submit a current summary of technical information pertaining to product safety, a rationale for product safety and copies of the reference material cited in the summary.
When seeking a research permit, an applicant is expected to submit the technical summary. The rationale and reference material will only have to be submitted if specifically requested by the Fertilizer Section.
Summary of technical information
The summary of technical information is a document which describes the product under review and provides a thorough identification and characterization of the constituent microorganism(s). We recommend that the applicant use Appendix 1 as a guide to the type of information that is often appropriate to include in the summary.
To locate the available technical information, we recommend that applicants consult several sources. Some which may be useful include: suppliers and manufacturers of the product and its ingredients; the public literature; databases such as those available through the National Library of Medicine (U.S.), the United States Environmental Protection Agency (USEPA), the Canadian Centre for Occupational Safety and Health (CCOSH), Medline, Biosis, Commonwealth Agricultural Bureau (CAB), Food Science and Technology Abstracts (FSTA), Agricola, and Aquatic Sciences and Fisheries Abstracts (ASFA), etc.
The information presented in this summary document should be properly referenced (including document name, date and page numbers, etc.) and should be presented in an orderly fashion (e.g. as in Appendix 1). The summary is expected to be 2 to 10 pages long, depending on the amount of information that is available.
NOTE: If a product consists of a mixture of microbial and chemical constituents, and the chemical constituents present safety concerns, the product safety assessment must be expanded to cover these chemical safety concerns. For guidance on the type of information that, from a chemical safety perspective, is appropriate to include in the summary of technical information, please consult Appendix 1 of Trade Memorandum T-4-113.
Rationale for product safety
The rationale for product safety is the applicant's statement of why the product should be considered safe for use when used as directed. It is helpful for the rationale to refer directly to data that is provided in the summary of technical information.
The rationale for product safety must consider the health of users/bystanders that may be exposed to the product. Depending on the product's proposed pattern of use, the rationale may also have to address food safety and environmental safety.
Reference material is the documentation (e.g., books, scientific articles, reports of studies) that the applicant used to obtain the data that is described in the summary of technical information.
The reference material is expected to be presented in an orderly fashion, preferably in indexed binders. For articles in foreign languages, English or French summaries should be included.
After reviewing the information that is submitted, the Fertilizer Section may determine that it is necessary for certain aspects of human or environmental safety to be more fully investigated or substantiated. If this is the case, the Fertilizer Section will identify a preliminary "data requirements" package.
This screening stage should be viewed as the main component of any safety assessment. As a general rule, the more comprehensive the screening stage submission, the less likely it is that additional data will be required.
When "data requirements" have been outlined by the Fertilizer Section, an applicant is expected to submit responses to the requirements. Once these have been received, the Fertilizer Section will conduct a follow-up assessment.
The applicant should note that responses may include surrogate data and requests for waivers.
To request waiver of any of the "data requirements" outlined by the Fertilizer Section, the data in question must not exist, and the request must be accompanied by a sound scientific rationale describing why the data should not be required for the safety assessment.
For surrogate data - data on similar organisms - to be considered by the Fertilizer Section, it must be accompanied by a sound scientific rationale for similarity between the organism in question and the organism described in the surrogate data.
Applicants must understand that based on the results of this follow-up assessment, it may be necessary for applicants to submit additional information.
Revision of a safety assessment is conducted when a product that has already gone through the safety assessment process is intended for new uses, new crops or new users, when the formulation changes, etc.
For this type of assessment, an applicant is expected to submit a description of the intended modification to the product or its use characteristics. Whether any additional information is needed depends on the specific circumstances surrounding the proposal and is determined on a case-by-case basis.
A revision may also be conducted when the Fertilizer Section becomes aware of new information that may reasonably be considered to affect the result of a previous safety assessment.
What the Applicant May Expect of the CFIA
Features of the Assessment Process
Rationale for product safety
It has been proposed that one should be able to predict the human and environmental effects and risks associated with the proposed use of a microorganism by an in depth knowledge of the organism in question. In fact, the Fertilizer Section prefers that the microorganisms contained in fertilizers and supplements be precisely identified and thoroughly characterized.
During the safety assessment, the Fertilizer Section will review the applicant's summary of technical information for crucial information such as the organism's growth requirements, its potential for survival and growth at different temperatures (e.g., at or above 35ºC), its potential for exerting toxicity, infectivity, pathogenicity, and sensitization, etc. Where information such as this is not included, the applicant can expect the Fertilizer Section to request further investigation and substantiation of the microorganism's essential characteristics.
If a product is intended for use in growing food or feed plants, and the safety assessment indicates the possible presence of a potential mammalian toxin (toxic through oral exposure), the applicant can expect the Fertilizer Section to require additional data that demonstrates the safety-in-use of the product. For guidance on submitting this additional data, please consult Trade Memorandum T-4-113.
Genetically modified microorganisms
The Fertilizer Section prefers that:
- the use of antibiotic resistance or other markers of clinical or veterinary importance be avoided;
- introduced or modified genetic material not be situated on a readily mobilizable genetic element, particularly one with a broad host range;
- recipient microorganisms be well characterized and not closely related to an organism known to present a significant clinical, agricultural or environmental risk; and,
- introduced or modified genetic material be limited to that required for the intended function.
If a genetically modified microorganism does not meet these features, the applicant can expect the Fertilizer Section to request a thorough investigation of the implications of using the microorganism(s) in question.
The potential for causing hypersensitivity reactions
Primarily because of their proteinaceous nature, microorganisms are considered a priori sensitizing i.e. able to induce sensitization or hypersensitivity reactions in susceptible individuals. However, microorganisms vary in the type and severity of reactions that they may cause. As part of Section II of Appendix I, the Fertilizer Section expects applicants to provide information on the sensitization potential of the microorganism in question. This includes reports of sensitization in animals and in humans, from controlled studies or other observations.
During the assessment process, the Fertilizer Section considers the safety of the product to users/bystanders. Consideration is given to the inherent effects that may be associated with the product or its constituent ingredients, and to the likelihood that these effects be observed. The likelihood is a function of exposure which, itself, is a function of many features such as: concentrations of the ingredient of concern in the product; levels of respirable particulates; how the product is handled; how often it is used; etc. Of particular interest in this respect are the precautionary measures that the users are advised of and expected to uphold.
It is generally considered that users in a workplace are aware of the hazards associated with the products they handle and obey precautionary measures which appear on the product label. Therefore, it is useful for applicants to describe, in the summary of technical information, the precautionary measures that are suggested to users. These will be taken into consideration when considering the potential exposure to the product and the likelihood that adverse effects would result from using the product as directed.
For products that are sold for home use, we do not assume that elaborate precautionary measures would be upheld. These measures are of lesser importance to this type of safety assessment.
If a product consists of a mixture of microbial and chemical constituents, and the chemical constituents present safety concerns, the applicant can expect the Fertilizer Section to require that the product safety assessment be expanded to cover these chemical safety concerns. (For guidance on information appropriate to include from a chemical safety perspective, please consult Appendix 1 of Trade Memorandum T-4-113.)
The Fertilizer Section will expect that the manufacturing process generates a microbial product with sufficient levels of the desired microorganism and insignificant levels of other microorganisms (e.g., that may present a safety concern). Where there is doubt about the manufacturing process, the applicant can expect the Fertilizer Section to request confirmation and substantiation in this area.
The Fertilizer Section will expect that adequate quality control procedures be in place to monitor the manufacturing process. Where there is doubt about the continued production of a consistent product, an identical microorganism at guaranteed levels, a safe product (with regard to potential contaminants, for example), the applicant can expect the Fertilizer Section to request confirmation and substantiation in this area.
Features of Risk Management
Note on mammalian toxins
If the safety assessment of a microbial product intended for growing food or feed plants indicates the possible presence of a potential mammalian toxin (toxic through oral exposure), and if additional safety data establishing the safety-in-use of the product is not submitted, the applicant can expect that the product will fail the safety assessment and will not be authorized for the intended use.
Managing the potential for hypersensitivity reactions
As discussed under "Features of the assessment process," microorganisms are considered a priori sensitizing. This characteristic alone does not mandate that microbial products carry precautionary labelling. However, where this generic characteristic is strengthened with actual evidence of hypersensitivity reactions from exposure to the microorganism in question or a closely related one, the Fertilizer Section generally recommends that the applicant add precautionary statements, such as protective measures and potential hazards, to the product label. Depending on the strength of the evidence, this recommendation may become a requirement. As well, it may be necessary to caution certain groups of individuals to the presence of a specific organism e.g. if the effect of that organism is particularly serious. And the applicant should also note that, although it is unlikely, it is possible that the sensitization reaction be sufficiently severe that certain uses for a microorganism in question be declined.
Non-sterile peat based products
Inoculant products that contain non-sterile peat or clay carriers may contain microorganisms capable of causing health problems in exposed individuals. Exposure to these microorganisms may be most likely during handling and inoculation activities, and may occur through inhalation or skin contact. Consequently, applicants can expect the Fertilizer Section to require that labels for non-sterile carrier inoculants and for pre-inoculated seeds carry precautionary statements warning users of the hazard and instructing them on how to avoid exposure.
Notes for General Guidance
To Simpplify the Process...
Companies are strongly encouraged to consult with officers in the Fertilizer Section very early in product development.
Companies are also encouraged to consult with the Fertilizer Section prior to conducting tests. The purpose of this consultation is to discuss protocols and help to ensure that these meet necessary criteria.
Anything that can be done to make a submission more clear and concise will facilitate and accelerate the assessment.
Companies have often found it very useful to seek the assistance of a consultant for compiling and reviewing the data and for preparing the submission.
Other Useful Information
These guidelines should be used in conjunction with other guidance documents, where appropriate, including:
- Trade Memorandum T-4-107 "Registration of Supplements Under the Fertilizers Act", and
- Trade Memorandum T-4-103 "Exemption of Supplement Products from Registration for Scientific Research"
All submissions are treated as confidential business information.
Technical Information for Safety Assessments of Microorganisms in Fertilizers and Supplements
Section 1: Description of Product and Its Intended Use(s)
1.1 Product Description
- general description
- list of all ingredients and contaminants
- concentration of each ingredient in the product
- Material Safety Data Sheets (MSDS) for product and/or ingredients
- brief description of purpose of ingredients
- brief outline of manufacturing process
1.2 For Products Intended for Research:
- test site information
- testing protocol
- monitoring procedures
- termination procedures
- precautionary measures that would be implemented with respect to food, worker and environmental safety
- contingency measures
1.3 For Products Intended for Registration:
- product name
- unit amount/package size
- use patterns
- information related to user exposure
- target market (consumer, commercial horticulture, large scale agriculture...)
- product label
- shelf life
Section 2: Identification / Characterization of Microorganisms(s)
2.1 Identification of Naturally Occurring or Parental Microorganism
- taxonomic name(s)
- criteria and data to substantiate taxonomic identity (at registration)
- common name(s), if any
- strain history
2.2 Characterization of Microorganism
2.2.1 For Naturally Occurring or Parental Microorganism
(A) Environmental fate:
- growth requirements and characteristics
- life cycle
- host range
- mode of action on host species
- mode of isolation
- geographic distribution and level of occurrence
- controlled environmental fate studies
- presence in association with food or feed plants (Please include information on any controlled residue studies that may have been conducted.)
(B) Human health and environmental effects:
- toxin production
- nature and degree of adverse effects associated with the microorganism(s) (e.g., toxicity, genotoxicity, infectivity, pathogenicity, irritation and sensitization/hypersensitivity potential)
- dermatophytic potential
- relationship to microorganism(s) which are associated with adverse health effects
- controlled health effects studies
- potential environmental effects
- controlled environmental effects studies (e.g. single species/ecosystem level effects, microcosm, field tests, etc.)
2.2.2 For Microorganisms Modified by Traditional Methods
- method of modification
- trait(s) selected
- mode of action of the trait (if known)
2.2.3 For Microorganisms Modified by Molecular Biological Techniques
(A) Source and function of introduced genetic material
- taxonomic name(s) of donor microorganism(s)
- gene transfer potential
- genetic material/gene(s) and gene product(s) in recipient microorganism, including copy numbers of inserted gene(s)
- promoter(s) including source(s)
- terminator sequence(s) including source(s)
- additional genetic sequences (e.g., marker genes, non-coding open reading frames, etc.)
- resistance to clinically or veterinarily important antibiotics, and potential impacts
(B) Strain Construction
- flow diagram detailing strain construction
- manipulations used to construct the modified microorganism
- summary diagram of final genetic construct
- legend for summary diagram of final genetic construct
2.2.4 For All Modified Microorganisms
- alteration(s) to characteristics of parental microorganism
- expression pattern(s) of introduced gene(s)
- unintended gene expression or gene suppression in the modified microorganism
- genetic stability
- fate of gene product(s) encoded by introduced gene(s)
2.3 Detection and Quantification of Naturally Occurring or Modified Microorganism
- tests to detect and quantify microorganism
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