Chapter 2 - Data Requirements for Single Ingredient Approval and Feed Registration
2.5 Data Requirements for Product Safety Evaluations: Explanatory Notes

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This section provides an explanation of the data requirements for safety evaluations of livestock feeds. It is to be used in conjunction with Section 2.3 "Single Ingredient Feed Evaluation Requirements" and Section 2.4 "Generic Data Requirements for Safety Evaluations of Single Ingredients" of the RG-1 Regulatory Guidance document.

We have attempted to make these notes useful to those who wish to obtain a general understanding of the data requirements, and to aid in the development of a complete data package. A listing of standard protocols used to develop the technical information is also provided for your convenience.

Questions should be forwarded to:

Animal Feed Division
Canadian Food Inspection Agency
59 Camelot Drive
Ottawa ON  K1A 0Y9
Fascimile: 613-773-7565 or 613-773-7566

1.0 Identification and Use of the Product

For each feed ingredient or product, please identify the following:

A) Name and Synonyms

The name of the product as it appears on the product label or bill of lading. Commonly used alternates or acronyms, including names used in other countries, most common chemical name, a botanical or species identification, etc.

B) Description of Use

Describe the intended use of the product in feed. The type of information required includes:

  • a detailed description of how the product is intended to be used
  • suggested and maximum use rates, timing, and frequency of feeding, and methods of application
  • mixing information if used in conjunction with other products
  • "withdrawal times" (i.e., when product use should be reduced or discontinued)
  • distribution, storage, and handling information including recommended emergency measures
  • strategies for reuse, resale, or disposal of unused product.

C) Species of Intended Use

Identify all livestock for which the product is intended.

D) Unit Amount

Identify what quantity is the product to be sold, transported and stored (e.g., 50 L metal drum, 20 kg plastic-lined canvas sack).

E) Product Label

Five (5) copies of the product label or bill of lading must be provided. Guidelines for labelling requirements of livestock feed can be found in Section 4.1 of the RG-1 Regulatory Guidance document.

F) Material Safety Data Sheet (MSDS) for Product and Ingredients

A MSDS is a comprehensive technical bulletin containing detailed information on a substance or product. It is a basic source of information for preliminary safety evaluations identifying items which may need to be examined in greater detail. The Workplace Hazardous Materials Information System (WHMIS) provides criteria for developing a MSDS. Please refer to Section 8.1 of the RG-1 Regulatory Guidance document "Responsibilities Regarding the Labelling of Feed Products under the Workplace Hazardous Material Information System (WHMIS)".

G) Outline of Manufacturing Process

Please provide a detailed description of the production and formulation processes, identifying all raw materials, processing times and temperatures, chemical and physical treatments including further processing steps, and other parameters which may influence the specifications, quality, or safety of a product.

A flow-chart diagram accompanying the description is recommended.

2.0 Chemical Components including Contaminants and Impurities

A) Name and Synonyms

The chemical name and synonyms of all ingredients should be listed.

Resources

B) Contaminants and Impurities

Contaminants and impurities that are inherent to this product or introduced through processing should be identified and characterized.

C) Chemical Abstracts Service Registry Number

An identification number is assigned by the Chemical Abstracts Service (CAS) to differentiate between known chemicals. This is a useful reference when searching for technical information and should be provided for each ingredient.

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D) Chemical Formula (Molecular and Structural)

The molecular formula identifies the basic elements (atoms) of molecules. A structural formula is a diagram of the bonds between atoms. Comparing these with the formulae of substances whose properties are known is useful in anticipating hazards of substances which have not been tested. If isomeric mixtures exist, the ratio of isomers should be included, since different isomers may have different toxicities. For polymers (long chains of molecules), the structural formulae should show the repeating units along with the identification of links and cross-links.

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E) Concentration of Components

The amount of all ingredients, contaminants and impurities should be expressed as a percent by weight of the final product or by parts per million (ppm).

F) Criteria for Identity and Purity

The exact formulation of a particular product may vary, depending upon the manufacturer. A precise description of ingredients, including physical/chemical properties and contaminants or impurities, is needed to properly assess product safety. The methods for measuring the ingredients and/or contaminants in the product must be stated. Examples of acceptable analytical methods for component detection include proximate analysis, nuclear magnetic resonance (NMR), mass spectrometry, chromatography, etc.

Please refer to Section 6.2 of the RG-1 Regulatory Guidance document for the information required about the analytical methods being applied by the applicant/registrant.

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G) Estimated Shelf Life

This is the length of time the product can be stored without significant alterations to its chemical or biological composition. This includes specified storage times under ideal conditions, a description of the factors affecting shelf life, what happens when the product undergoes degradation or transformation, how one can tell if degradation has occurred, hazards associated with exceeding shelf life, and how the manufacturer has substantiated its estimation of shelf life.

Shelf life can be determined based upon industry standards, quality assessment, and compositional assessment.

Resources

  • Manitoba Agriculture, Food and Rural Initiatives, Shelf-life Studies

3.0 Method(s) of Analysis, Recovery, and Detection Limit Data for the Analyses

Acceptable analytical methods are required both to establish the ingredient purity (including contaminants), and for the ability to detect the ingredient in feed at its intended use rate. Methods must establish statistically relevant recovery and detection limits, and must allow for third-party laboratories to identify and quantify the active ingredients. For specific requirements of analytical methods, please refer to Section 6.2 of the RG-1 Regulatory Guidance document.

Other Resources

4.0 Physicochemical Data

Physicochemical data is used to identify and differentiate between substances or products and to assist in predicting or determining the behaviour of substances in the human body, target and non-target organisms and the environment. Please note the reference protocols associated with each data point.

A) Molecular weight

Every chemical has a characteristic molecular "weight". In the case of polymers (long repeating chains of molecules), an average molecular weight is given.

Resources

OECD Guidelines for the Testing of Chemicals

B) Physical State

This indicates whether a substance or product is solid, liquid or gaseous at room temperature.

C) Appearance

This describes the physical form of the product. Examples include granular solid, gelatinous liquid or fine powder.

D) Particle Size

If the substance is solid, please describe the average particle size. Give the range of particle sizes and their proportion of distribution. This property may be a significant factor in determining the physical distribution and biological uptake of a substance.

Resources

OECD Guidelines for the Testing of Chemicals

ASTM International

E) Colour and Odour

Include this description for each ingredient as well as for the formulated product.

F) Olfactory Detection Limit

This is the minimum concentration (e.g., parts per million by volume in air), at which one can identify the substance by smell. This is important in determining whether or not smell can serve as an appropriate warning of the presence of the substance.

G) Density or Specific Gravity

Density of solids is measured as mass per volume (i.e., g/mL). For liquids, specific gravity compares density to that of water, which is assigned a value of 1 (i.e., a substance with a specific gravity of 2.0 is twice as dense as water). Specific gravity has no units and is measured at temperatures of 15.6, 20 and 25°C. These measurements are used in several ways, such as when predicting the behaviour of a substance in the environment and accounting for the inclusion concentrations in feed.

Resources

OECD Guidelines for the Testing of Chemicals

H) Refractive Index

As light passes from one medium to another the speed at which it moves changes. Changing the speed of light may cause it to "bend" or refract. This property varies from one substance to another and is sometimes useful in identifying substances through a simple accurate technique.

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I) Melting Point

This is the temperature (at a given pressure, 101.325 kPa: 1 atm) at which a solid becomes a liquid. In cases where the substance undergoes a chemical reaction (e.g., degradation, decomposition, rearrangement) other than melting, then the temperature at which the reaction occurs must be reported. As alternatives to the melting point, a pour point, softening point or sublimation point could be provided when appropriate.

Resources

OECD Guidelines for the Testing of Chemicals

J) Boiling Point

This is the temperature (at a given pressure, 101.325 kPa: 1 atm) at which a liquid becomes a gas. In cases where the substance undergoes a chemical reaction (e.g., degradation, decomposition, rearrangement) other than boiling, the temperature at which the reaction occurs must be reported.

Resources

OECD Guidelines for the Testing of Chemicals

K) Flash Point

Flash point is the minimum temperature at which a liquid can ignite upon contact with a flame or spark in the presence of oxygen. This has obvious implications for worker safety during handling and storage.

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L) Auto-ignition Point

The auto-ignition point is the minimum temperature at which a flammable liquid will ignite spontaneously without an ignition source.

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M) Vapour Pressure

This is a measurement of a liquid's ability to evaporate, or give off vapours at specific temperatures. It is usually expressed in millimetres of mercury (mmHg), and is a crucial indicator of the behaviour of a liquid product, indicating whether it will tend to escape to the atmosphere or remain in soil. The vapour pressure is not required if the chemical has a standard boiling point less than 0°C.

Resources

OECD Guidelines for the Testing of Chemicals

N) Vapour Density

The vapour density is a comparison between the mass of a gas and that of dry air which is assigned a value of 1, (for example, the substance with a vapour density of 2.0 is twice as dense as air). Less dense gases tend to rise and are quickly transported throughout the environment; heavier gases remain closer to the ground and dissipate less rapidly.

O) Henry's Law Constant

This is a measure of the solubility of a gas in liquid. It is indicative of a substance's tendency to move from water to air or vice-versa.

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P) Potential of hydrogen (pH)

This property indicates whether a substance is acidic, neutral or basic and quantifies the strength of acidity or alkalinity. The pH of a substance can have a major effect on its interactions with living organisms, such as the degree to which it is absorbed or taken up as well as contact exposure for workers.

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Q) Solubility

i) Water

Solubility describes the amount a substance will dissolve in water at a given temperature. Since many chemicals dissolve in water to a significant degree, it is often the route by which chemicals are taken up by organisms. It is also used in predictions of environmental fate.

Resources

OECD Guidelines for the Testing of Chemicals

ii) Other Solvents

Solubility describes the amount a substance will dissolve into solvents other than water. This provides a guide for choosing a solvent to extract a substance from complex matrices (i.e., tissue or soil).

Resources

OECD Guidelines for the Testing of Chemicals

R) Octanol-Water Partition Coefficient

This parameter measures the tendency of a substance to partition, either into organic solvents or water. It is used in predicting whether a substance may accumulate in the fatty tissues of an organism and predicts its tendency to adhere to soil particles.

Resources

OECD Guidelines for the Testing of Chemicals

S) Dissociation Constant

Dissociation is a specific type of chemical decomposition in which a molecule breaks up into charged particles called ions. Ions are often involved in further chemical reactions and may be absorbed or distributed at a different rate. For given conditions, the rate of dissociation (dissociation constant, or Kd) is constant.

Resources

OECD Guidelines for the Testing of Chemicals

T) Incompatibility

Dissociation is a specific type of chemical decomposition in which a molecule breaks up into charged particles called ions. Some substances react with other substances. If the formulated product or any of its ingredients come in contact with certain substances, this must be reported.

U) Polymerization

Some substances may spontaneously polymerize (form long molecular chains) under certain conditions. Many of these reactions can produce dangerous or explosive amounts of heat. Any such substances contained in the formulated product must be identified along with a description of conditions under which spontaneous polymerization is known to occur.

5.0 Mammalian Toxicological Data

In order to assess potential harmful effects of a substance to mammals, data from laboratory tests is necessary. Test animals must be dosed using the same route or routes of exposure that are anticipated to be the most significant route or routes for livestock and potential human exposure (e.g., oral, dermal or inhalation). Please note that the most significant route of exposure to a substance for the general human population may be different from exposures for workers in an occupational setting.

The type of toxicity data generally considered is outlined below.

A) Toxicokinetic Studies (Absorption, Distribution, Metabolism and Elimination)

For each route by which a substance can be taken into the body (oral, dermal, respiratory, etc.), absorption tests determine how extensively and how rapidly it can be absorbed.

Distribution, metabolism and elimination data describe the fate of a substance once it is absorbed into the body. Questions answered by this information include: What is the metabolic fate of the substance? Does it accumulate? How is it broken down or transformed? What metabolites are formed? By what route and how quickly are the substances eliminated? This information provides an indication of an organism's ability to tolerate short- or long-term exposure, either at high or low concentrations. It is also useful in designing toxicity tests (e.g., dose selection), and the extrapolation of data from animal models to human exposure.

Resources

OECD Guidelines for the Testing of Chemicals

B) Acute Toxicity Studies

Acute exposure tests examine the effects of single exposures to high concentrations of a substance. Exposures in these tests are typically 24 hours or less, with effects being monitored for up to two weeks. This is the first step in establishing the crucial relationship between the dose and the response, for ranking substances according to their relative acute toxicity, and for classification and precautionary label statements. Acute toxicity data is used to obtain preliminary information on specific toxic effects of substances and how these may be produced (mode of action). Some specialized acute tests are described below.

Resources

OECD Guidelines for the Testing of Chemicals

United States Code of Federal Regulations

i) Acute Median Lethality Studies

The concentration of a substance, when administered once to a group of animals for a short time, will cause death in half of the animals. This is expressed as an LD50 (lethal dose, in mg/kg of body weight) or the LC50 (lethal concentration, in parts per million).

Resources

OECD Guidelines for the Testing of Chemicals

ii) Skin/Eye Irritation Studies

This determines if a substance has the potential to cause irritation or cell death (necrosis) when in contact with the skin or eyes.

New methods must be assessed by the CFIA to determine whether they provide sufficient information, therefore, we advise that you contact the Animal Feed Division regarding the validity of methods that are alternatives to animal testing.

Resources

OECD Guidelines for the Testing of Chemicals

United States Code of Federal Regulations

iii) Skin Sensitization Studies

This evaluates the potential of a substance being able to "sensitize" organisms. Organisms may become more sensitive to a substance after an initial exposure and develop allergic reactions in subsequent exposures.

Properly conducted patch tests (positive or negative response) may be an acceptable alternative to animal testing. The concentration of a substance to exposed subjects will be a critical factor regarding the acceptability of the patch tests. In addition, information for the assessment of skin or ocular irritation may be obtained from Quantitative Structure-Activity Relationships (QSARs), with adequate scientific justification provided by the notifier regarding the validation and applicability domain of the model.

Resources

OECD Guidelines for the Testing of Chemicals

United States Code of Federal Regulations

C) Mutagenicity/Genotoxicity Studies

Mutations to DNA may lead to cancer or gene-based malformations in offspring. Screening tests are used in determining a substance's potential for causing genetic mutations. At least two types of tests are performed, conventionally one with bacteria and one with mammalian cell cultures. It is also necessary to perform tests with and without metabolic activation, that is, to determine if interactions with metabolic processes in the body results in a substance being mutagenic.

Resources

OECD Guidelines for the Testing of Chemicals

Health Canada

United States Code of Federal Regulations

D) Short-Term Toxicity Studies

Short-term toxicity studies involve repeated exposure to substances over a longer period of time (i.e. 14-90 days). They are useful for detecting long-term adverse health effects, for establishing a threshold level at which no effects are observed, for establishing possible cumulative effects of exposure, species variation, and suggesting appropriate conditions for chronic tests, if deemed necessary. A 90-day oral study is typical, and inhalation or dermal studies may be appropriate, depending on typical human exposure parameters.

Resources

OECD Guidelines for the Testing of Chemicals

E) Chronic Toxicity Studies

In some cases, chronic studies may be necessary to evaluate the safety of a substance over a longer period of time, such as the lifetime of the animal (e.g. 120 days to 1-2 years). These studies are practical for detecting subtle, adverse health effects, such as carcinogenesis and reproductive effects. Some of the chronic studies are outlined in the following sections.

Resources

OECD Guidelines for the Testing of Chemicals

F) Teratogenicity/Developmental Toxicity Studies

The teratogenicity studies investigate adverse effects induced during development from conception until birth.

The developmental toxicity tests examine adverse effects during the lifetime of an organism prior to conception, during pre-natal development or until sexual maturity, resulting from exposure of either parent to a substance.

Resources

OECD Guidelines for the Testing of Chemicals

United States Code of Federal Regulations

G) Reproductive Toxicity

These studies investigate the adverse effects of substances on male or female reproductive systems and thus their reproductive capacity from mating through to lactation. Typically, they are multi-generational studies.

Resources

OECD Guidelines for the Testing of Chemicals

United States Code of Federal Regulations

H) Neurotoxicity

These studies investigate the adverse effects of substances on the nervous system, (central nervous system and peripheral nervous system).

Resources

OECD Guidelines for the Testing of Chemicals

I) Carcinogenicity

When indicated by earlier tests or other data, a substance will be examined for its ability to induce cancer (tumours) in animals. Tests are typically conducted over a major portion of the animal's life span, often combined with chronic toxicity tests.

Resources

OECD Guidelines for the Testing of Chemicals

United States Code of Federal Regulations

J) Estrogenicity Studies

Resources

OECD Guidelines for the Testing of Chemicals

K) Epidemiological Studies

This type of study contains a compilation and analysis of information on humans who have been occupationally or accidentally exposed to a substance.

6.0 Suggested Maximum Residue Limit (MRL) or Tolerance

A Maximum Residue Limit (MRL) governs the concentration of a chemical that may accumulate in tissues of livestock without causing harm to the animal, or to humans that consume their products. This limit should be based upon an evaluation of information such as mammalian toxicity data, dietary intake estimates, and livestock metabolism data.

7.0 Human Exposure Data and Exposure Estimation

The following information is important in assessing the degree of exposure to workers and users of particular substances.

A) Major Routes of Exposure

Human exposure to a substance depends, in part, on how it can be taken up by the body, that is to say via the respiratory route, skin absorption, oral ingestion, etc. Based on the ingredients, its formulation, and its methods of use, please describe how users might be exposed.

B) Amount of Product Handled by Workers and Consumers

Give the total quantity of product that would typically be used by workers or those who have consumed the product on a daily basis (e.g. 50 litres/day).

C) Frequency and Duration of Exposure

State how often and with what frequency the product will normally be used. Indicate the duration of exposure for each use period.

D) Exposure Concentrations

State the concentration of the product when transported, stored and used. Please describe any intermediate preparation steps, such as mixing or dilution.

E) Exposure Studies

Include all data on human exposure, uptake into the body, and medical studies of workers who have been exposed to the product over long periods of time. In some cases exposure studies may have to be conducted to establish how much absorption and distribution takes place with intended conditions of use.

8.0 Livestock Metabolic Fate and Residue Studies

Mammalian toxicity data derived from tests on mice and rats offer limited information on the risk of a particular substance to livestock species. The following data requirements involve direct testing with livestock animals.

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A) Toxicokinetic Studies in Livestock Species

These tests describe what happens to a substance once it is ingested by livestock. The objectives are to establish the rate and mode(s) of absorption into systemic circulation, the distribution in the body, the rate of metabolism, possible metabolic pathways and all metabolites. Metabolic parameters to be evaluated include the rate and routes of elimination and the biological half life (t½). These data requirements should also include statistically significant analytical techniques for recovery and detection limits in all tissues evaluated.

Resources

OECD Guidelines for the Testing of Chemicals

B) Residue Studies for the Parent Compound and Metabolites

Residues in livestock tissue have the potential to enter the human food chain. Thus, it is important to determine how much of a substance actually remains in exposed animals and in which tissues it is found. This data requirement should also include statistically significant analytical techniques for recovery and detection limits in animal tissues.

Resources

OECD Guidelines for the Testing of Chemicals

9.0 Environmental Fate and Effects

The following data requirements, in combination with the physicochemical data, form the basis for predicting or determining which environmental compartments will be exposed to a substance following its release (or the release of its metabolites). It will also assist in the determination of how non-target organisms may be affected.

A) Vapour Pressure and Volatilization

This is a measure of a liquid's ability to evaporate or give off vapours at specific temperatures. Usually expressed in millimetres of mercury (mmHg), it is a crucial indicator of the behaviour of a liquid product, for example whether it will escape to the atmosphere or remain in soil.

Resources

OECD Guidelines for the Testing of Chemicals

United States Code of Federal Regulations

B) Hydrolysis

One of the main ways in which substances break down in the environment is by hydrolysis. The extent to which this reaction takes place under normal conditions, and the products of this type of reaction should be described. Please note that not all substances undergo hydrolysis reactions.

Resources

OECD Guidelines for the Testing of Chemicals

C) Photodegradation

Interaction with light is another important way in which substances are degraded in the environment. Photodegradation tests determine the potential for light-induced changes, as well as possible transformation products formed following this type of reaction.

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D) Adsorption-Desorption

The ability of a substance to adsorb ("attached") or to desorb (detach) from other particles or molecules affects how quickly it may move through a particular environmental compartment. Soil is a major adsorption medium for many substances.

Adsorption and desorption are often mediated by pH. Please account for the pH of the soil or other media.

Resources

OECD Guidelines for the Testing of Chemicals

United States Code of Federal Regulations

AOAC Methods of Analysis

E) Simple Biodegradation Tests

Resources

OECD Guidelines for the Testing of Chemicals

F) Biotransformation in Soil

Some substances undergo changes as a result of transformation by micro-organisms (i.e., microbial activities). These tests determine the potential for biodegradation, bioactivation or biotransformation taking place. Data for both aerobic and anaerobic conditions (in the presence or absence of oxygen) are useful because different micro-organisms are involved in biotransformation processes.

Resources

OECD Guidelines for the Testing of Chemicals

AOAC Methods of Analysis

G) Biotransformation in Aquatic Systems

In addition to soil biotransformation, substances may be transformed by the microbes in the aquatic environment. Data for both aerobic and anaerobic conditions are useful because different micro-organisms are involved in biotransformation processes.

Resources

OECD Guidelines for the Testing of Chemicals

AOAC Methods of Analysis

H) Biochemical Oxygen Demand

Oxygen demand is the quantity of oxygen required by micro-organisms to oxidize organic compounds in water. Results are measured as dissolved oxygen (DO) in mg of oxygen per litre (mg O2/L) or mg of oxygen per gram (mg O2/g) of compound. Organic contaminants can impair water quality by reducing oxygen levels which in turn can adversely affect aquatic organisms.

Resources

OECD Guidelines for the Testing of Chemicals

I) Toxicity to Aquatic Organisms

It is important to establish the adverse effects of substances on aquatic organisms. Often the mechanisms of these effects are unique to aquatic environments and toxicity cannot be predicted using laboratory mammals. Also, the repercussions of disturbing organisms at the bottom of the food chain can be of great concern to the entire ecosystem.

Resources

OECD Guidelines for the Testing of Chemicals

United States Code of Federal Regulations

J) Toxicity to Soil Organisms

The adverse effects of a substance on soil organisms are important because the long-term health of agricultural soils can be compromised by disturbing populations and communities.

Resources

OECD Guidelines for the Testing of Chemicals

ISO documents

K) Toxicity to Birds

The adverse effect of substances on birds can be important. Birds may be more susceptible to certain substances than laboratory animals, and therefore specific tests may be required. The difference in tolerance is partly due to differing environmental stresses and conditions as well as to metabolic and behavioural differences.

Resources

OECD Guidelines for the Testing of Chemicals

L) Toxicity to Wildlife

These toxicity tests are valuable for indicating the adverse effects a substance will have on animals in real environmental conditions. In the case of mammalian wildlife, livestock data may be suffucient.

Resources

OECD Guidelines for the Testing of Chemicals

ASTM International

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