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Animals > Livestock Feeds > Trade Memoranda T-3-141 - Supplement 2 - DATA REQUIREMENTS FOR PRODUCT SAFETY EVALUATIONS: EXPLANATORY NOTESApril, 1997 Table of Contents (1 - 5) (6 - 11) Section Title (6-11) 6 Suggested Maximum Residue Limit (MRL) or Tolerance 7 Human Exposure Data and Exposure Estimation a) Major Routes of Exposure 8 Specifics for Food Plant Usage a) Crop Identification 9 Livestock Metabolic Fate and Residue Studies a) Metabolic Fate Studies 10 Environmental Fate and Effects a) Vapour Pressure and Volatilization 11 Bibliography of Protocols, Test Guidelines, Reference Materials and Services 6 SUGGESTED MAXIMUM RESIDUE LIMIT (MRL)) OR TOLERANCE An MRL is to be suggested, based on an evaluation of information, such as mammalian toxicity data, dietary intake estimates and livestock metabolism data. This criteria governs the concentration of a chemical that may build up in the tissues of plants or livestock without causing harm to the plant or animal, or to the humans that consume their products. 7 HUMAN EXPOSURE DATA AND EXPOSURE ESTIMATION The following information is important in assessing the degree of exposure of workers and users to 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, whether via the respiratory route, skin absorption, oral ingestion, etc. Based on the properties of a product's ingredients, its formulation and methods of use, how might users be exposed? b) Amount of Product Handled by Workers and Consumers: What is the total quantity of product that would typically be used in a given application cycle (eg., 50 litres/day)? c) Frequency and Duration of Exposure: How often and how many times will the product normally be used? How long is the product used each time? d) Exposure Concentrations: How concentrated is the product when transported, stored and actually used? Is it diluted before use? Include references to intermediate preparation steps, such as mixing. 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 into and distribution through the body takes place with intended conditions of use. EPA PAG, Subdivision U; "Application Exposure Monitoring" 8 SPECIFICS FOR FOOD PLANT USAGE The following information is required to assess the safety of substances to be used in conjunction with food or feed crops. EPA Test Guidelines: Chemical Fate a) Crop Identification: This indicates the specific agricultural crop(s) on which the product is intended to be used. b) Rates, Timing, Intervals to Harvest: This section is to specify exactly how a product will be used and applied, including the rates of application, times at which the product is to be used and the intervals between application and harvest. These are important in determining whether it or its break-down products will remain in a crop at the time of harvest or when consumed by animals or humans. This information is required for each crop. c) Plant Metabolism Data: This information describes the fate of a substance in the plant; how it is broken down; what is the break-down product; to what extent does it break down; and at what rate. This study should include the levels and identities of the resulting breakdown products. WHO/FAO Guidelines to CODEX d) Product, Metabolite and/or Contaminant Residue Studies: These tests determine the amount of parent substances, contaminants or their break-down products which remain as residues in a particular crop at harvest or when consumed. This is a most important step in establishing the potential exposure of livestock or humans through the food chain. Residue studies are performed using recommended crops and rates, timing, and intervals of harvest. WHO/FAO Guidelines to CODEX e) Phytotoxicity: It is possible that one characteristic, such as germination, be improved at the expense of another, such as yield. Plant toxicity or phytotoxicity tests investigate these possibilities. EPA PAG, (Non-target plants) f) Analytical Methods for Metabolism and Residue Studies: The submitted data must be accompanied by a description of the analytical methods upon which it is based. This will enable us to evaluate the accuracy and usefulness of the data. Recovery and detection limits should be included. AOAC Methods of Analysis 9 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 several livestock species. The following data requirements involve direct testing with livestock and apply to products the livestock are likely to be exposed to via their feed. FDA, Animal Drug Analytical Manual a) Metabolic Fate Studies: These tests describe exactly what happens to a substance once it is ingested by livestock. How is it absorbed, and how quickly? How is it distributed throughout the body and how quickly? How is it broken down, and what are the resultant metabolites (by-products)? By what route is the substance and its metabolites eliminated from the body, and at what rate? What is their "half-life?". Appropriate methods for the recovery and analysis of the substance and its metabolites in animal tissues should be included. Detection limits of such methods must be stated. AOAC Methods of Analysis b) Residue Studies for the Parent Compound and its Possible 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 occurs. This data requirement should also include statistically significant analytical techniques for recovery and detection limits in animal tissues. AOAC Methods of Analysis. c) Elimination Data: The ability of an organism to break down and eliminate a substance is a major consideration in evaluating the hazards of a substance. Elimination data provides a quantitative determination of this ability and indicates how effectively livestock can deplete a chemical. AOAC Methods of Analysis 10 ENVIRONMENTAL FATE AND EFFECTS The following data requirements, in combination with the physicochemical data, form the basis for predicting or determining which parts of the environment will be "exposed" to a substance following its release (or the release of its break-down products) and how the organisms therein may be affected. EPA Test Guidelines: Environmental Effects 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. AOAC Methods of Analysis b) 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. This can indicate how reactive the chemical may be. OECD Test Guidelines, 112 c) Hydrolysis: One of the main ways in which substances break down in the environment is by splitting through combination with water molecules. The extent to which this reaction may take place under normal conditions and the by-products of this type of reaction should be described. OECD Test Guidelines, 111 d) Photodegradation: Another important way in which substances are broken down is by interaction with light. Tests are used to determine the potential for such degradation as well as the substance's break-down products following this type of reaction. US CFR 40: 796.3700, 796.3780, 796.3800, 796.1050 e) Solubility 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. OECD Test Guidelines, 105. f) 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. g) 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, 117 305 (bioaccumulation) h) Adsorption-Desorption: The ability of a substance to adsorb or become "attached" to and then desorb or detach from other particles or molecules — such as soil — affects how quickly it may move through, or how long it may remain in a particular environment. OECD Test Guidelines, 106 i) Leaching: This type of study establishes the potential for substances to move through different types of soil, usually under the influence of water movement. This helps to predict whether land-applied substances will reach ground water. US CFR 40: 796.2700 j) Biotransformation in Soil: Some substances undergo changes as a result of transformation by microorganisms, i.e., "biodegradation". These tests determine the potential for biodegradation and the break-down products which result from biodegradation. Data for both aerobic and anaerobic conditions (in the presence or absence of oxygen) are useful because different microorganisms are involved in each case and both conditions are found in the environment. OECD Test Guidelines, 304. k) Biotransformation in Aquatic Systems: As with soil biotransformation, substances may be transformed by the microbial reactions in an aquatic environment. Data for aerobic and anaerobic conditions should again be supplied. OECD Test Guidelines, 301, 302, 306 l) Biochemical Oxygen Demand: The quantity of oxygen required by microorganisms to oxidize organic compounds in a water sample. Results are measured in mg of oxygen per litre or per gram of compound. Organic contaminants can impair water quality by reducing oxygen levels which in turn adversely affects aquatic organisms. ASTM D 4478-85, D 888 m) 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 toward the bottom of the food chain can be very serious to the entire ecosystem. OECD Test Guidelines, 201, 202, 203, 204, 210 n) Toxicity to Soil Organisms: The adverse effects of substances on soil organisms is important because the long-term
health of agricultural soils can be compromised by disturbing their populations. OECD Test Guidelines, 207 (earthworm) o) Toxicity to Birds: The adverse effect of substances on birds can be important. Birds may be more susceptible to the adverse effects of chemicals than laboratory animals. This difference in tolerance is partly due to differing environmental stresses and conditions as well as to metabolic and behavioral differences between organisms. OECD Test Guidelines, 205, 206 p) Toxicity to Wildlife: These toxicity tests are valuable for indicating the adverse effects a chemical will have on animals under actual environmental conditions. EPA PAG, (Wildlife aquatic organisms, Wild mammal toxicity)
11 BIBLIOGRAPHY OF PROTOCOLS, TEST GUIDELINES, REFERENCE MATERIALS AND SERVICES Amdur, MO et al (editors) American Association of Cereal Chemists American College of Veterinary Toxicologists Association of Official Analytical Chemists American Society for Testing and Materials Blalock, CR et al (editors) Canadian Environmental Protection Act Canadian Food Inspection Agency Chemical Evaluation Search and Retrieval System (CESARS) Charlambous, George Chemical Abstracts Service Clesceri, Lenore S, et al (editors) Environment Canada "Enviroguide" : Série de la Protection de l'environnement, Méthods de référence SPE 1/RM/1 - SPE 1/RM/22 (1992) Food and Agriculture Organization (FAO) - see World Health Organization/Food and Agriculture Ogranization (WHO/FAO) Fazio, T (editor) Freed, VH, et al Health Canada Health Canada The Use of Genotoxicity Tests in Regulation (1989) Genotoxicity Assays Recommended in the Health Protection Branch Genotoxicity Committee Report: Conduct and Reporting for Effective Evaluation (1989) Compendium of Analytical Methods, Volume 1: Official Methods of Microbiological Analysis of Food; Polyscience Publications and Supply & Services Canada; Ottawa: 1989 Guidelines on the Use of Mutagenicity Tests in the Toxicological Evaluation of Chemicals, Health Canada, 1986 Heitzman, RJ Helrich, Kenneth, (editor) Keith, LH (editor) Lawrence, James F Lude, David R (editor) Nair, GE (editor) National Academy of Sciences National Institute of Standards and Technology (NIST) National Institute for Occupational Safety and Health (NIOSH) Official Journal of the European Communities (OJEC) Ontario Ministry of the Environment Organization for Economic Co-operation and Development Paget and Thomson, (editors) Stahr, HM (editor) United States Code of Federal Regulations United States Department of Health and Human Services United States Environmental Protection Agency Health Effects Test Guidelines Short-term Tests for Health and Ecological Effects Test Guidelines: Chemical Fate Test Guidelines: Environmental Effects New and Revised Chemical Fate Test Guidelines New Environmental Effects Test Guidelines New and Revised Health Effects Test Guidelines Selected Analytical Methods Approved and Cited by the US Environmental Protection Agency, American Public Health Association, 15th edition, 1981; supplement to Standard Methods for the Examination of Water and Wastewater, 15th edition. EPA Toxicology Handbook United States Food and Drug Administration General Principles for Evaluating the Safety of Compounds Used in Food-Producing Animals, US Department of Health and Human Services, 1986 Macroanalytical Procedures Manual, FDA Technical Bulletin #5, 1984 Animal Drug Analytical Manual, US Department of Health and Human Services, Centre for Veterinary Medicine; AOAC Arlington, Virginia: 1985 Pesticide Analytical Manual, Volume 1: Foods and Feeds; US Food and Drug Administration, Washington, DC: 1987 Wernimont, Grant T World Health Organization/Food and Agriculture Organization (WHO/FAO) Guide to Short-term Tests for Detecting Mutagenic and Carcinogenic Chemicals, International Program on Chemical Safety, Environmental Health Criteria 51, NEP, ILO, WHO; World Health Organization, Geneva: 1985 Principles for the Toxicological Assessment of Pesticide Residues in Food, International Program on Chemical Safety, Environmental Health Criteria 104, World Health Organization, Geneva: 1990 Guidelines to CODEX: Recommendations Concerning Pesticide Residues, Part 5; "Recommended Method of Sampling for the Determination of Pesticide Residues"; World Health Organization, Food and Agriculture Organization of the United Nations, Rome: Doc # CAC/PR 5-1984, updated at 20th CCPR, 1988 Guide to specifications for general notices, general analytical techniques, identification tests, test solutions, and other reference materials, Food and Agriculture Organization of the United Nations/World Health Organization, Rome: 1991 |
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