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Animals > Livestock Feeds > Trade Memoranda T-3-141 Supplement 2 - DATA REQUIREMENTS FOR PRODUCT SAFETY EVALUATIONS: EXPLANATORY NOTESApril, 1997 Introduction This guideline provides an explanation of the data requirements for safety evaluations of fertilizers, soil supplements and livestock feeds. It is to be used in conjunction with Trade Memorandum T-4-113 for fertilizer and soil supplements and with Trade Memorandum T-3-141 (Supplement 1) for livestock feeds. We have attempted to make these notes useful to those who are not necessarily trained in science or toxicology, but who wish to obtain a general understanding of the data requirements. A listing of standard protocols used to develop the technical information is also provided for your convenience. Questions regarding this memorandum may be directed to: Feed Section
Table of Contents (1 - 5) (6 - 11) Section Title (1-5) 1. Identification and Use of the Product a) Name and Synonyms 2. Chemical Components Including Impurities a) Name and Synonyms 3. Method(s) of Analysis, Recovery and Detection Limit Data for the Analyses a) Molecular Weight 5. Mammalian Toxicological Data a) Rate and Degree of Absorption 1. IDENTIFICATION AND USE OF THE PRODUCT a) Name and Synonyms: The name of the product as it appears on the product label or shipping bill. Commonly used alternates or acronyms, including names used in other countries, most common chemical name, a botanical or species identification, etc. b) Use Patterns: This describes the intended use of the product. The type of information required
includes: The Use Pattern should clearly specify whether the product will be used in food or feed production and whether it will be used indoors or outdoors, contained or uncontained, etc. c) Feed Additive Use Patterns: For feed additives, describe how the product is intended to be used in detail, including suggested rates and timing of feeding, intervals of feeding, and any "withdrawal times," (when product use should be reduced or discontinued). d) Species of Intended Use: Identify all animal or plant species and soil types for which the product is intended (if not described under Use patterns). e) Unit Amount: How and in what quantities is the product to be sold, transported and stored? (i.e., 50 L metal drum, 20 kg plastic-lined canvas sack, etc.) f) Product Label: A copy of the product label (if applicable) or bill of lading conforming to the appropriate Regulations must be provided. g) Material Safety Data Sheet (MSDS) for Product and Ingredients: An 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 points (such as possible contaminants) which may need to be examined in greater detail. An MSDS should also provide a detailed explanation of precautions and protective measures. The Workplace Hazardous Materials Information System (WHMIS) provides criteria for developing an MSDS. h) Outline of Manufacture: A general description of the production and formulation processes, identifying raw materials, chemical reactions, techniques and any other parameters which may influence the specifications, hence quality or safety of a product. This will serve as background information relating to product purity and any recycled materials (eg., by-products and wastes) used in manufacturing or formulating the end-product. A flow-chart diagram accompanying the description is preferred. 2 CHEMICAL COMPONENTS INCLUDING IMPURITIES a) Name and Synonyms: The exact chemical name and synonyms of all ingredients, including significant contaminants or impurities should be listed. For substances which need to be described by the reaction producing them (UVCBs), see Canadian Environmental Protection Act (CEPA) Guidelines, sec 4, and Appendix III. Blalock et al b) Chemical Abstract Service Number (CAS No.): 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. CEPA Guidelines, sec 4, Appendix IV c) 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 themselves been tested. Where isomeric mixtures exist, (closely related chemical variants), the ratio of isomers should be included, since this may affect toxicity. For polymers, (long chains of molecules), the structural formulae should show the repeating unit(s), along with an identification of links and cross-links. CEPA Guidelines, sec 4, Appendix VI. d) Concentrations in the Finished Product: The amount of all ingredients in the commercial product should be expressed as a percent by weight or by parts per million (ppm). e) Criteria for Chemical Identity and Purity: The exact formulation of a particular product may vary, depending upon the manufacturer. A precise description of ingredients including contaminants is needed to properly assess product safety (for example, a nuclear magnetic resonance (NMR) spectrum, or a gas chromatography (GC) profile). EPA PAG (Product chemistry) f) Estimated Shelf Life: This is the length of time the product can be stored without alterations to its chemical/biological integrity. This includes not only times under ideal conditions, but a description of the factors affecting shelf life, what happens when the product degrades or decays, how one can tell, whether this creates a particular hazard, and how the manufacturer has substantiated its estimation of shelf life. Charlambous, G The Shelf Life of Food and Beverages 3 METHOD(S) OF ANALYSIS, RECOVERY, AND DETECTION LIMIT DATA FOR THE ANALYSES An acceptable test method for the analysis of the proposed product must be provided. This method must establish statistically relevant recovery and detection limits and must allow third-party technicians to identify and quantify the active ingredients. For specific requirements of analytical methods, please see "Good Laboratory Practices Protocol for Fertilizer and Supplement Registration" or Trade Memorandum T-3-151 for feed ingredients. ASTM (For statistical standards) 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, other organisms or the environment. Please note the reference protocols associated with each data point. Unless otherwise specified, these data points apply to the technical grade formulation of the substance and not to an analytically purified sample. a) Molecular weight: Every chemical has a characteristic molecular "weight" determined by the elements or atoms that make it up. In the case of polymers, (molecules composed of atomic"chains" of varying length), an average is given to describe molecular weight and testing is performed on the lowest number-average composition. CEPA Guidelines, 4.2.2.1, (sec 4, Appendix VI, for polymers) b) Physical state: This indicates whether a substance or product is solid, liquid or gaseous at room temperature. c) Appearance: This describes the form of the product, such as a granular solid, gelatinous liquid, or a fine powder. d) Particle Size: If the substance is solid, what is its average particle size? What is the range of particle sizes, and their proportion of distribution? This property may be a significant factor determining the distribution and uptake of a substance, for example, whether it is taken up by organisms or inhaled into human lungs. OECD Test Guidelines, 110. e) Colour and Odour: Include this description for the chemical ingredients as well as for the formulated product, including any noted variations. f) Olfactory Detection Limit: This is the minimum concentration (eg., 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/Specific Gravity: For solids, this 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., 2.0 is twice as dense as water, 0.50 is half as dense). These measurements are used in several ways, such as when predicting the behaviour of a substance in the environment. OECD Test Guidelines, 109. h) Refractive Index: The speed of light changes as light passes from one medium to another, causing it to "bend," (as objects partially inserted into water look bent.) This property varies from one substance to another and is sometimes useful in identifying substances using a simple, accurate technique. ASTM D 1218, D 1747 i) Melting Point: The temperature, at a specified pressure, at which a solid becomes liquid. Some chemicals break down or undergo chemical reaction before reaching their melting point; details of this should be identified. OECD Test Guidelines, 102. j) Boiling Point: The temperature, at a specified pressure, at which a liquid becomes a gas. Some chemicals break down or undergo chemical reaction before reaching their boiling point; details of this should be identified. OECD Test Guidelines, 103. k) Flash Point: The minimum temperature at which a liquid gives off enough flammable vapours that these will ignite on contact with a flame or spark. This has obvious implications for worker safety during handling and storage. ASTM E 502-84 l) Auto-Ignition Point: The minimum temperature at which a flammable liquid will ignite spontaneously without an ignition source. Again, an important safety parameter. ASTM G 72-82, E 659-78 m) Vapour Pressure: 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, indicating, for example, whether it will tend to escape to the atmosphere or remain in soil. AOAC Methods of Analysis n) Vapour Density: A comparison between the mass of a gas and that of dry air which is assigned a value of 1, (i.e., 2.0 is twice as dense as air, 0.50 is half as dense). This is another important indicator of how a substance will behave. Less dense gases tend to rise and are quickly transported throughout the environment; heavier gases remain closer to the ground and dissipate less rapidly. ASTM E 12 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. p) pH: Indicates if a substance is acidic, alkaline or neutral and how strong an acid or base it is. Besides measuring potential corrosivity, pH can have a major effect on the interactions of a substance with living organisms, such as the degree to which it is absorbed or taken up. ASTM E 70 (general) q) Solubility: i) in Water: This measures the amount of a substance that will dissolve in water at a given temperature. Since water supports life and 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 of substances. OECDTest Guidelines, 105 ii) in Other Solvents: This measures the amount of a substance that will dissolve in solvents other than water. This provides a guide for choosing a solvent to extract a chemical from organic tissue or soil for further analysis, for instance. OECD Test Guidelines, 116 r) Octanol-Water Partition Coefficient: This measures the tendency of a substance to separate, either into organic solvents or into water. A fundamental toxicological data point, it is used in predicting whether a substance may build up in the fatty tissues of an organism and in predicting its tendency to adhere to soil particles. OECD Test Guidelines, 107, 117 s) Dissociation Constant: Dissociation is a specific type of chemical decomposition in which a molecule breaks up into charged particles called ions. Ions, in turn, are often involved in further chemical reactions and may be absorbed or distributed at a different rate. For given conditions, the rate of dissociation expressed as a value (the dissociation constant) is constant. OECD Test Guidelines, 112 t) Incompatibility: Some substances react violently or explosively with other substances. If the formulated product or any of its ingredients should not 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 give off 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 MAMMALIAN TOXICOLOGICAL DATA In order to assess the potentially harmful effects of substances on mammals, information from laboratory-scale tests is necessary. The type of toxicity data generally considered is outlined below. FDA Toxicological Principles [Core and current standards] a) Rate and Degree of Absorption: 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. b) Distribution, Metabolism and Elimination Data: These tests describe the fate of a chemical once it is absorbed into the body. Where does it go? Does it accumulate? How is it broken down or transformed? By what route and how quickly is it 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 useful information in designing toxicity tests, eg., in dose selection. It also aids in extrapolating animal data to human conditions. EPA Test Guidelines, and EPA PAG: Metabolism c) Acute Toxicity: Acute exposure tests examine the effects of short-term, single exposures to high concentrations of a substance. Exposures in these tests are typically 24 hours or less, with effects being monitored for two weeks. This is the first step in establishing the toxic potential of substances. This is especially useful for 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. OECD Test Guidelines, 401, 402, 403, 418, 420 i) Acute Median Lethality: The concentration of a substance which, 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 LC50, (lethal concentration, in parts per million). FDA Principles, acute oral LD50 ii) Skin/Eye Irritation: This determines if a substance has the potential to cause irritation or cell death (necrosis) when in contact with the skin or eyes. OECD Test Guidelines, 404, 405 iii) Skin Sensitization: Property of being able to "sensitize" organisms: Organisms may become more sensitive to a substance after an initial exposure and develop allergic reactions in subsequent exposures. OECD Test Guidelines, 406 d) Mutagenicity: A screening test in determining a substance's potential for causing genetic mutations which may lead to cancer or malformations in offspring. 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 "activation," that is, to determine if interaction with metabolic processes in the body makes a substance "mutagenic". OECD Test Guidelines, 471 - 485 e) Short-Term Toxicity: Short-term toxicity studies involve repeated exposure to substances over a longer (more typical) time frame. They are useful for detecting most longer-term adverse health effects, for establishing a threshold level at which no effects are observed (NOEL) for establishing possible cumulative effects of exposure, species and other types of variation and for suggesting appropriate conditions for chronic tests, if deemed necessary. A 90-day oral study is typical, but inhalation and dermal studies may be more appropriate, depending on typical human exposure conditions. OECD Test Guidelines, 407 - 413, 419 f) Teratogenicity: These types of tests explore the possibility of birth defects resulting from parental or placental exposure to chemicals. OECD Test Guidelines, 414 g) Developmental Toxicity: These tests examine adverse effects during the lifetime of an organism prior to conception, during pre-natal development or until puberty, resulting from exposure of either parent to a substance. US CFR 40: 798.4350, 798.4420, 798.4900 h) Reproductive Toxicity: Adverse effects of substances on male or female reproductive systems and capacity (from mating through lactation). OECD Test Guidelines, 415, 416 i) Carcinogenicity: Where 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. OECD Test Guidelines, 451, 452, 453 j) 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. k) Chemical Interaction: The toxic effect of a substance can sometimes be altered — either increased, decreased, or changed entirely — by interactions with other substances. A toxin may be rendered harmless by another, or its effect may be magnified many times. Data to identify and measure the significance of such interactions improves the hazard assessment for the substance. |
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