RG-1 Regulatory guidance:
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 7.1 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
- CEPA "Guidelines for the Notification and Testing of New Substances: Chemicals and Polymers" (Appendix 5)
- Chemical Abstracts Services (CAS) Registry
- International Union of Pure and Applied Chemistry (IUPAC)
- Combined Chemical Dictionary
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.
Resources
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.
Resources
- ChemBioFinder.com
- CEPA "Guidelines for the Notification and Testing of New Substances: Chemicals and Polymers" (Appendix 5)
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.
Resources
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.
Resources
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.
Resources
- ISO 2592 :2000 – Determination of flash and fire points – Cleveland open cup method
- ISO 1523 :2002 – Determination of flash point – Closed cup equilibrium method
L) Auto-ignition Point
The auto-ignition point is the minimum temperature at which a flammable liquid will ignite spontaneously without an ignition source.
Resources
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.
Resources
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.
Resources
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
- Test No. 107: Partition Coefficient (n-octanol/water): Shake Flask Method
- Test No. 117: Partition Coefficient (n-octanol/water), High Performance Liquid Chromatography (HPLC) Method
- Test No. 123: Partition Coefficient (1-octanol/water): Slow-Stirring Method
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
- Test No. 402: Acute Dermal Toxicity
- Test No. 403: Acute Inhalation Toxicity
- Test No. 420: Acute Oral Toxicity – Fixed Dose Procedure
- Test No. 423: Acute Oral Toxicity – Acute Toxic Class Method
- Test No. 425: Acute Oral Toxicity – Up and Down Procedure (UDP)
- Test No. 436: Acute Inhalation Toxicity – Acute Toxic Class Method
United States Code of Federal Regulations
- United States Code of Federal Regulations
Dermal Toxicity (40CFR798.2250)
Inhalation Toxicity (40CFR798.2450)
Oral Toxicity (40CFR798.2650)
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
- Test No. 404: Acute Dermal Irritation/Corrosion
- Test No. 405: Acute Eye Irritation/Corrosion
- Test No. 427: Skin Absorption in vivo Method
- Test No. 428: Skin Absorption in vitro Method
- Test No. 430: In vitro Skin Corrosion: Transcutaneous Electrical Resistance Test (TER)
- Test No. 431: In vitro Skin Corrosion: Human Skin Mode Test
- Test No. 435: In Vitro Membrane Barrier Test Method for Skin Corrosion
- Test No. 437: Bovine Corneal Opacity and Permeability Test Method for Identifying Ocular Corrosives and Severe Irritants
- Test No. 438: Isolated Chicken Eye Test Method for Identifying Ocular Corrosives and Severe Irritants
- Test No. 439: In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method
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
- Test No. 406: Skin Sensitization
- Test No. 442A: Skin Sensitization: Local Lymph Node Assay: DA
- Test No. 442B: Skin Sensitization: Local Lymph Node Assay: BrdU -ELISA
- Test No. 429: Skin Sensitization: Local Lymph Node Assay
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
- Test No. 471: Bacterial Reverse Mutation Test
- Test No. 473: In Vitro Mammalian Chromosome Aberration Test
- Test No. 474: Mammalian Erythrocyte Micronucleus Test
- Test No. 475: Mammalian Bone Marrow Chromosome Aberration Test
- Test No. 476: In vitro Mammalian Cell Gene Mutation Test
- Test No. 477: Genetic Toxicology: Sex-linked Recessive Lethal Test in Drosophilia melanogaster
- Test No. 478: Genetic Toxicology: Rodent Dominant Lethal Test (Adopted: April 4 1984)
- Test No. 479: Genetic Toxicology: In vitro Sister Chromatid Exchange Assay in Mammalian Cells
- Test No. 480: Genetic Toxicology: Saccharomyces cerevisae, Gene Mutation Assay
- Test No. 481: Genetic Toxicology: Saccharomyces cerevisae, Miotic Recombination Assay
- Test No. 482: Genetic Toxicology: DNA Damage and Repair/Unscheduled DNA Synthesis in Mammalian Cells in vitro
- Test No. 483: Mammalian Spermatogonial Chromosome Aberration Test
- Test No. 484: Genetic Toxicology: Mouse Spot Test
- Test No. 485: Genetic Toxicology: Mouse Heritable Translocation Assay
- Test No. 486: Unscheduled DNA Synthesis (UDS) Test with Mammalian Liver Cells In vivo
- Test No. 487: In vitro Mammalian Cell Micronucleus Test
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
- Test No. 407: Repeated Dose 28-Day Oral Toxicity Study in Rodents
- Test No. 408: Repeated Dose 90-Day Oral Toxicity Study in Rodents
- Test No. 409: Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents
- Test No. 410: Repeated Dose Dermal Toxicity: 21/28-day Study
- Test No. 411: Subchronic Dermal Toxicity: 90-Day Study
- Test No. 412: Subacute Inhalation Toxicity: 28-Day Study
- Test No. 413: Subacute Inhalation Toxicity: 90-Day Study
- Test No. 419: Delayed Neurotoxicity of Organophosphorus Substances: 28-Day Repeated Dose Study
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
- Test No. 452: Chronic Toxicity Studies
- Test No. 453: Combined Chronic Toxicity/Carcinogenicity Studies
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
- Test No. 414: Prenatal Development Toxicity Study
- Test No. 421: Reproduction/Developmental Toxicity Study
- Test No. 422: Combined Reproduction Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test
United States Code of Federal Regulations
- United States Code of Federal Regulations
Inhalation Developmental Toxicity Study (40CFR798.4350)
Developmental Toxicity Study (40CFR798.4900)
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
- Test No. 414: Prenatal Development Toxicity Study
- Test No. 415: One-generational Reproduction Toxicity Study
- Test No. 416: Two-generational Reproduction Toxicity Study
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
- Test No. 418: Delayed Neurotoxicity of Organophosphorus Substances Following Acute Exposure
- Test No. 419: Delayed Neurotoxicity of Organophosphorus Substances: 28-Day Repeated Dose Study
- Test No. 424: Neurotoxicity Study in Rodents
- Test No. 426: Developmental Neurotoxicity Study
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
- Test No. 451: Carcinogenicity Studies
- Test No. 453: Combined Chronic Toxicity/Carcinogenicity Studies
United States Code of Federal Regulations
- United States Code of Federal Regulations
Oncogenicity (40CFR798.3300)
Combined Chronic Toxicity/Oncogenicity (40CFR798.3320)
J) Estrogenicity Studies
Resources
OECD Guidelines for the Testing of Chemicals
- Test No. 440:Uterotrophic Bioassay in Rodents: a short-term screening test for oestrogenic properties
- Test No. 441: Hershberger Bioassay in Rats: a short-term screening assay for (anti)androgenic properties
- Test No. 455: The stably transfected human estrogen receptor-alpha transcriptional activation assay for detection of estrogenic agonist-activity 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.
Resources
- World Health Organization
Guidelines for the Study of Dietary Intakes of Chemical Contaminants
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.
Resources
- AOAC Methods of Analysis
- ASTM E896-92(2005)e1 – Standard Test Method for Conducting Aqueous Direct Photolysis Tests
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
- Test No. 106: Adsorption-Desorption Using a Batch Equilibrium Method
- Test No. 121: Estimation of the Adsorption Coefficient (Koc) on Soil and Sewage Sludge using High Performance Liquid Chromatography (HPLC)
United States Code of Federal Regulations
AOAC Methods of Analysis
E) Simple Biodegradation Tests
Resources
OECD Guidelines for the Testing of Chemicals
- Test No. 301: Ready Biodegradability
- Test No. 310: Ready Biodegradability – CO2 in sealed vessels (Headspace Test)
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
- ISO 11266:1994 – Soil quality – Guidance on laboratory testing for biodegradation of organic chemicals in soil under aerobic conditions
- ISO 15473:2002 – Soil quality – Guidance on laboratory testing for biodegradation of organic chemicals in soil under anaerobic conditions
OECD Guidelines for the Testing of Chemicals
- Test No. 304A: Inherent Biodegradability in Soil
- Test No. 307: Aerobic and Anaerobic Transformation in Soil
- Test No. 308: Aerobic and Anaerobic Transformation in Aquatic Sediment Systems
- Test No. 312: Leaching in Soil Columns
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
- ISO 14592-1:2002 – Water quality – Evaluation of the aerobic biodegradability of organic compounds at low concentrations – Part 1: Shake-flask batch test with surface water or surface water/sediment suspensions
- ISO 14592-2:2002 – Water quality – Evaluation of the aerobic biodegradability of organic compounds at low concentrations – Part 2: Continuous flow river model with attached biomass
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
- ISO 5815-1:2003 – Water quality – Determination of biochemical oxygen demand after n days (BODn) – Part 1: Dilution and seeding method with allylthiourea addition
- ISO 5815-2:2003 – Water quality – Determination of biochemical oxygen demand after n days (BODn) – Part 2: Method for undiluted samples
- ISO 6060:1989 – Water quality – Determination of the chemical oxygen demand
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
- Test No. 201: Freshwater Alga and Cyanobacteria, Growth Inhibition
- Test No. 202: Daphnia spp. Acute Immobilisation Test
- Test No. 203: Fish, Acute Toxicity Test
- Test No. 204: Fish, Prolonged Toxicity Test: 14-Day Study
- Test No. 210: Fish, Early-Life Stage Toxicity Test
- Test No. 211: Daphina magna Reproduction Test
- Test No. 212: Fish, Short-term Toxicity Test on Embryo and Sac-Fry Stages
- Test No. 215: Fish, Juvenile Growth Test
- Test No. 218: Sediment-Water Chironomid Toxicity using Spiked Sediment
- Test No. 219: Sediment-Water Chironomid Toxicity using Spiked Water
- Test No. 221: Lemna sp. Growth Inhibition Test
- Test No. 225: Sediment-Water Lumbriculus Toxicity Test Using Spiked Sediment
- Test No. 229: Fish Short Term Reproduction Assay
- Test No. 230: 21-Day Fish Assay: A Short Term Screening for Oestrogenic and Androgenic Activity, and Aromatase Inhibition
- Test No. 231: Amphibian Metamorphosis Assay
- Test No. 233: Sediment-Water Chironomid Life-Cycle Toxicity Test Using Spiked Water or Spiked Sediment
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
- Test No. 207: Earthworm, Acute Toxicity Tests
- Test No. 216: Soil Microorganisms: Nitrogen Transformation Test
- Test No. 217: Soil Microorganisms: Carbon Transformation Test
- Test No. 222: Earthworm Reproduction Test (Eisenia fetida/Eisenia andrei)
- Test No. 226: Predatory Mite (Hypoaspis (Geolaelaps) Aculeifer) Reproduction Test in Soil
- Test No. 232: Collembolan Reproduction Test in Soil
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
- Test No. 205: Avian Dietary Toxicity Test
- Test No. 206: Avian Reproduction Test
- Test No. 223: Avian Acute Oral Toxicity Test
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
- Test No. 213: Honeybees, Acute Oral Toxicity Test
- Test No. 214: Honeybees, Acute Contact Toxicity Test
- Test No. 228: Determination of Developmental Toxicity of a Test Chemical to Cipteran Dung Flies (Scathophaga Stercoraria L. (Scathophagidae), Musca automnalis De Geer (Muscidae))
ASTM International
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