Some standard content:
ICS07.100
National Standard of the People's Republic of China
GB15193.1--2003
Replaces GB15193.1-1994
Procedures for toxicological assessment of food safety
Procedures for toxicological assessment of food2003-09-24Promulgated
Ministry of Health of the People's Republic of China
Standardization Administration of the People's Republic of China
Implementation on 2004-05-01
GB15193.1—2003
This standard is mandatory in its entirety.
This standard replaces GB15193.1—1994 "Procedures for toxicological assessment of food safety". Compared with GB15193.1-1994, the main revisions of this standard are as follows: In the "Scope", the specific content of the test substance is added: the safety of chemical, biological and physical factors that may cause harm to health during the production, processing, preservation, transportation and sales of food. The evaluation objects include food additives (including nutritional fortifiers), new food resources and their ingredients, new resource foods, irradiated foods, food containers and packaging materials, food tools, equipment, detergents, disinfectants, pesticide residues, veterinary drug residues, microorganisms used in the food industry, etc.; First, in the "Requirements for Test Substances", the following is added: "For formulated products, the formula of the test substance should be provided. If necessary, the physical and chemical properties (including chemical name, structure, purity, stability, solubility, etc.) and test reports of the components of the test substance should be provided; provide relevant information such as the source of raw materials, production process, possible human intake, etc."; In the "Four Phases and Contents of Toxicology Tests": "TK gene mutation test" is added to the genetic toxicity test in the second phase. The V79/HGPRT gene mutation test was changed from an alternative test to a mandatory item of gene mutation test in parallel with the Ames test. The original 4 alternative tests were changed to 3;
In the "Principles for selecting toxicity tests for non-test substances": "food containers and packaging materials, pesticide residues" were added. For the selection principles of spices, the "acute toxicity test" was deleted (1994 version 3.2.4.2.1.1, this version 6.4.1.1.1), one "mutagenicity test" in other food additives was changed to two "mutagenicity tests", and the Ames test or mouse bone marrow micronucleus test was changed to "the Ames test and the mouse bamboo pith micronucleus test were preferred" (1994 version 3.2.4.2.2.1, this version 6.4.1.2.1); the selection principles of toxicity tests for food containers and packaging materials were added; in the "judgment of the results of various toxicological tests": the results of the genetic toxicity test were all rewritten, and the original 4 items were changed to 3 items. "Principles for judging the results of tumorigenicity tests" were added. In the new resource food, the brackets are changed to "When the content exceeds 5%, protein should be supplemented to the same level as the control group. In principle, the added test substance should not exceed 10% of the feed" (1994 version 4.2.6, this version 7.2.6);
In "Factors to be considered in food safety evaluation": add "statistical significance and biological significance of test indicators", "physiological and toxic effects", "test substances with a large possible intake by humans" and "time-toxic effect relationship" factors; in comprehensive evaluation, add "In the final evaluation, the physical and chemical properties, toxicity, metabolic characteristics, accumulation, range of contact population, usage and convenience in food, possible human intake and other factors of the test substance must be comprehensively considered." Delete the content of "inspection unit".
From the implementation of this standard, GB15193.1-1994 will be abolished at the same time. This standard is proposed and managed by the Ministry of Health of the People's Republic of China. Drafting unit of this standard: Nutrition and Food Safety Institute of China Center for Disease Control and Prevention. The main drafters of this standard are: Cai Yin, Chen Junshi, Xu Jinkang, Li Youhui. This standard was first issued in 1994, and this is the first revision. 2
1 Scope
Procedure for toxicological evaluation of food safety
This standard specifies the procedure for toxicological evaluation of food safety. GB15193.1—2003
This standard is applicable to the safety evaluation of chemical, biological and physical factors that may cause harm to health during the production, processing, storage, transportation and sales of food. The evaluation objects include food additives (including nutritional fortifiers), new food resources and their ingredients, new resource foods, irradiated foods, food containers and packaging materials, food tools, equipment, detergents, disinfectants, pesticide residues, veterinary drug residues, microorganisms used in the food industry, etc.
2 Normative references
The clauses in the following documents become the clauses of this standard through reference in this standard. For any dated referenced document, all subsequent amendments (excluding errata) or revisions are not applicable to this standard. However, the parties to an agreement based on this standard are encouraged to study whether the latest versions of these documents can be used. For any undated referenced document, the latest version shall apply to this standard. GB15670-1995 Pesticide Registration Physics Test Methods Irradiated Food Hygiene Management Measures
Disinfection Management Measures
3 Terms and Definitions
The following terms and definitions apply to this standard. 3.1
Food additivefoodadditive
Chemical synthesis or natural substances added to food to improve food quality and color, aroma and taste and for the needs of preservation and processing technology. 3.2
Novel foodnovelfoods
Food or food raw materials that are newly discovered, newly developed (including new process and new technology production) or newly introduced in my country and have no eating habits or are only eaten in some areas.
4 Requirements for test substances
4.1 For single chemical substances, the physical and chemical properties (including chemical structure, purity, stability, etc.) of the test substance (including its impurities if necessary) should be provided. For formulated products, the formula of the test substance should be provided, and if necessary, the physical and chemical properties of each component of the test substance (including chemical name, structure, purity, stability, solubility, etc.) should be provided. 4.2 Provide relevant information such as the source of raw materials, production process, and possible human intake. 4.3 The test substance must be a standardized product that conforms to the established formula. Its composition, proportion and purity should be the same as those in actual application. When it is necessary to detect the toxicity of high-purity test substances and possible impurities or to conduct special tests, pure products can be selected, or pure products and impurities can be tested separately.
5 Four stages and contents of food safety toxicological evaluation tests 5.1 Stage I: Acute test.
Oral acute toxicity: LDso, combined acute toxicity, maximum tolerated dose method. 5.2 Phase II: Genetic toxicity test, traditional teratogenicity test, 30-day feeding test. GB15193.1—2003
The combination of genetic toxicity tests should consider the principle of combining prokaryotic cells with eukaryotic cells, in vivo tests with in vitro tests. Select one from the Ames test or V79/HGPRT gene mutation test, bone marrow cell micronucleus test or mammalian bone marrow cell chromosome aberration test, 5.2.3 or 5.2.4 test respectively.
5.2.1 Salmonella typhimurium/mammalian microsomal enzyme test (Ames test) or V79/HGPRT gene mutation test, Ames test is preferred, and other tests can be selected if necessary. 5.2.2 Bone marrow cell micronucleus test or mammalian bone marrow cell chromosome aberration test. 5.2.3 TK gene mutation test.
5.2.4 Mouse sperm teratogenesis analysis or testicular chromosome aberration analysis. 5.2.5 Other alternative genetic toxicity tests: dominant lethality test, fruit fly sex-linked recessive lethality test, non-programmed DNA synthesis test. 5.2.6 Traditional teratogenicity test.
5.2.7 30-day feeding test. If the test substance needs to undergo the third and fourth phase toxicity tests, this test can be omitted. 5.3 Phase III: Subchronic toxicity test - 90-day feeding test, reproduction test, metabolic test. 5.4 Phase IV: Chronic toxicity test (including tumorigenicity test). 6 Principles for selecting toxicity tests for different test substances 6.1 All innovative substances in my country are generally required to undergo four phases of testing, especially those whose chemical structure indicates the possibility of chronic toxicity, genotoxicity or carcinogenicity, or those with large production, wide range of use, and many opportunities for human intake. All four phases of toxicity testing must be carried out. 6.2 For derivatives or analogues with basically the same chemical structure as known substances (those that have undergone safety evaluation and are allowed to be used), whether the fourth phase of toxicity testing is required will be determined based on the results of the first, second, and third phases of toxicity testing. 6.3 For any known chemical substance for which the World Health Organization has published the acceptable daily intake (ADI, hereinafter referred to as the daily allowable intake), and the applicant has data to prove that the quality specifications of the Chinese product are consistent with those of foreign products, the first and second phase toxicity tests can be carried out first. If the test results are consistent with those of foreign products, further toxicity tests are generally not required, otherwise the third phase toxicity test should be carried out. 6.4 Selection of safety toxicological evaluation tests for food additives (including nutritional fortifiers), new food resources and new resource foods, food containers and packaging materials, irradiated foods, detergents and disinfectants for food and food tools and equipment, pesticide residues and veterinary drug residues. 6.4.1 Food additives
6.4.1.1 Spices
In view of the fact that there are many varieties of spices used in food, their chemical structures are very different, and the amount used is very small, the data and regulations of international organizations and foreign countries can be referred to in the evaluation to determine the tests that need to be carried out. 6.4.1.1.1 For those that the World Health Organization (WHO) has recommended for approval or has established a daily tolerance, and for those that two or more of the four international organizations, namely, the Fragrance Manufacturers Association (FEMA), the Council of Europe (COE) and the International Organization of the Fragrance Industry (IOFI), allow for use, an evaluation shall be conducted with reference to foreign data or regulations. 6.4.1.1.2 For those that have incomplete data or are approved by only one international organization, an acute toxicity test and one of the mutagenicity tests specified in this procedure shall be conducted first, and after a preliminary evaluation, a decision shall be made whether further tests are required. 6.4.1.1.3 For those that have no data available and are not allowed for use by international organizations, the first and second stage toxicity tests shall be conducted first, and after a preliminary evaluation, a decision shall be made whether further tests are required.
6.4.1.1.4 For single high-purity natural spices extracted from the edible parts of animals and plants, if their chemical structure and relevant data do not indicate that they are unsafe, toxicity tests are generally not required. 6.4.1.2 Other food additives
6.4.1.2.1 For those with relatively complete toxicological data and WHO has published daily tolerance or no daily tolerance is required, acute toxicity test and two mutagenicity tests are required, with Ames test and bone marrow cell micronucleus test as the first choice. However, for those with different production processes, purity of finished products and sources of impurities, after the first and second phase toxicity tests, consider whether to conduct the next phase of tests based on the test results. 6.4.1.2.2 For those approved for use by an international organization or country, but WHO has not published a daily tolerance, or the data is incomplete, a preliminary evaluation shall be conducted after the first and second phase tests to determine whether further group tests are needed. 4
GB 15193.1-—2003
6.4.1.2.3 For single-component, high-purity additives made from animals, plants or microorganisms, all new varieties must first undergo the first, second and third phase toxicity tests. For those that have been approved for use by an international organization or country abroad, the first and second phase toxicity tests shall be carried out. After preliminary evaluation, it will be decided whether further tests are needed. 6.4.1.3 Imported food additives
Importing units are required to provide toxicological information and information approved for use by the exporting country. The unit designated by the health administrative department of the State Council will review and decide whether toxicity tests are needed. 6.4.2 New food resources and new resource foods
In principle, new food resources and their foods should undergo the first, second and third phase toxicity tests, as well as necessary population epidemiological surveys. If necessary, the fourth phase test should be carried out. If, according to relevant literature and component analysis, no toxic substances or substances with very low toxicity that do not constitute health damage are found, and animals, plants and microorganisms (including crude extracts of animals, plants and microorganisms used as seasonings) that have been consumed for a long time by a large number of people without any harmful effects are found, the first and second stage toxicity tests can be carried out first, and after preliminary evaluation, it can be decided whether further toxicity tests are needed.
6.4.3 Food containers and packaging materials
In view of the fact that there are many varieties of food containers and packaging materials, the raw materials, production aids, monomers, residual reactants, solvents, plastic additives, side reactions and chemical degradation products used are different, the types and properties of food in contact, the processing, storage and preparation methods are different (such as heating, microwave cooking or irradiation, etc.), and the types, properties and quantities of contaminants that migrate into food are different, the evaluation can refer to the information and regulations of international organizations and foreign countries, respectively decide on the tests that need to be carried out, propose the test procedures and methods, and report to the units designated by the health administration and production management department of the State Council for approval before conducting the tests. 6.4.4 Irradiated food
Provide toxicology test data in accordance with the requirements of the "Irradiated Food Hygiene Management Measures". 6.4.5 Detergents and disinfectants for food and food tools and equipment shall be carried out in accordance with the "Disinfection Management Measures" issued by the Ministry of Health, with emphasis on residual properties. 6.4.6 Pesticide residues
Carry out in accordance with GB15670-1995.
6.4.7 Veterinary drug residues
Carry out with reference to GB15670-1995.
7 Purpose and result judgment of food safety toxicological evaluation test 7.1 Purpose of toxicological test
7.1. 1 Acute density testwww.bzxz.net
Determine LDs to understand the toxicity intensity, properties and possible target organs of the test substance, provide a basis for the selection of doses and toxicity observation indicators for further toxicity tests, and classify toxicity according to LDso. 7.1.2 Genetic toxicity test
Screen the genetic toxicity of the test substance and whether it has potential carcinogenicity. 7.1.3 Teratogenicity test
To understand whether the test substance has teratogenic effects. 7.1.4 30-day feeding test
For test substances that only need to undergo the first and second stage toxicity tests, on the basis of acute toxicity tests, a 30-day feeding test is conducted to further understand its toxic effects, observe the effects on growth and development, and preliminarily estimate the maximum no-observed-adverse-effect dose. 7.1.5 Subchronic toxicity test - 90-day feeding test, reproduction test observes the nature and target organs of the toxic effects of the test substance on animals after long-term feeding at different dose levels, understands the test substance's effects on animal reproduction and developmental toxicity on offspring, observes the effects on growth and development, and preliminarily determines the maximum no-observed-adverse-effect dose and the possibility of carcinogenicity; provides a basis for dose selection for chronic and carcinogenic tests. 5
GB 15193.1--2003
7.1.6 Metabolism test
Understand the absorption, distribution and excretion rate of the test substance in the body and its accumulation, and find possible target organs; provide a basis for selecting appropriate animal species and strains for chronic toxicity tests; understand the formation of metabolites. 7.1.7 Chronic toxicity test and carcinogenicity test
Understand the toxic effects and carcinogenicity after long-term contact with the test substance; finally determine the maximum no-observed-adverse-effect dose, and provide a basis for the final evaluation of whether the test substance can be used in food. 7.2 Determination of the results of various toxicological tests
7.2.1 Acute toxicity test
If the LDso is less than 10 times the possible intake of humans, the test substance will be abandoned for use in food and no other toxicological tests will be continued. If it is greater than 10 times, the next stage of toxicological testing can be entered. 7.2.2 Genotoxicity test
7.2.2.1 If one or more of the three tests (Ames test or V79/HGPRT gene mutation test, bone marrow cell micronucleus test or mammalian bone marrow cell chromosome aberration test, and any of 5.2.3 or 5.2.4) are positive in vivo and in vitro, it means that the test substance is likely to have genotoxic and carcinogenic effects, and the test substance should generally be abandoned for use in food. 7.2.2.2 If one of the three tests is negative in vivo or two in vitro tests are positive, then select two alternative tests (at least one of which is an in vivo test). If the selected tests are all negative, the next toxicity test can be carried out. If one of the tests is positive, then combined with the results of other tests, after discussion by experts, other alternative tests or the next toxicity test can be carried out. 7.2.2.3 If all three tests are negative, then the next toxicity test can be carried out. 7.2.3 30-day feeding test
For test substances that are only required to undergo the first and second phase toxicology tests, if no obvious toxic effects are found in the short-term feeding test, a preliminary evaluation can be made based on the results of other tests. If obvious effects are found in the test, especially when there is a dose-response relationship, further toxicity tests should be considered.
7.2.4 90-day feeding test, reproduction test, and traditional teratogenicity test are evaluated based on the maximum no observed adverse effect concentration obtained by the most sensitive indicators in these three tests. The principle is: 7.2.4.1 If the maximum no-observed-adverse-effect dose is less than or equal to 100 times the possible human intake, it indicates that the toxicity is relatively strong and the test substance should be abandoned for use in food.
7.2.4.2 If the maximum no-observed-adverse-effect dose is greater than 100 times but less than 300 times, a chronic toxicity test should be conducted. 7.2.4.3 If it is greater than or equal to 300 times, there is no need to conduct a chronic toxicity test and a safety evaluation can be conducted. 7.2.5 Chronic toxicity and carcinogenicity test
7.2.5.1 The principle of evaluating the maximum no-observed-adverse-effect dose obtained from the chronic toxicity test is as follows: 7.2.5.1.1 If the maximum no-observed-adverse-effect dose is less than or equal to 50 times the possible human intake, it indicates that the toxicity is relatively strong and the test substance should be abandoned for use in food.
7.2.5.1.2 If the maximum no-observed-adverse-effect dose is greater than 50 times but less than 100 times, after a safety evaluation, it is decided whether the test substance can be used in food.
7.2.5.1.3 If the maximum no-observed-adverse-effect dose is greater than or equal to 100 times, it can be considered for use in food. 7.2.5.2 The principle for defining the results of pathogenicity tests based on the incidence of swelling and pain, latent period and multiplicity obtained from carcinogenicity tests is: if one of the following conditions is met and there is a significant difference after statistical processing, the carcinogenicity test result can be considered positive. If there is a dose-response relationship, the judgment of positive is more reliable.
7.2.5.2.1 Tumors only occur in the experimental red animals, and no tumors occur in the control group. 7.2.5.2.2 Tumors occur in both the experimental and control group animals, but the incidence rate in the experimental group is higher. 7.2.5.2.3 Multiple tumors are obvious in the experimental animals, and there are no multiple tumors in the control group, or only a few animals have multiple tumors. 7.2.5.2.4 Although there is no significant difference in the incidence rate of tumors in the experimental and control group animals, the time of occurrence in the experimental group is earlier. 7.2.6 When testing new resource foods and other test substances, or when the maximum amount of test substance added to the feed (when it exceeds 5%, protein should be added to the content equivalent to that of the control group, and the added test substance should not exceed 10% of the feed in principle) or when the liquid test substance still does not reach the prescribed multiple of the maximum no-observed-adverse-effect dose of human possible intake after concentration, the safety evaluation shall be conducted by combining other toxicity test results and the actual consumption or drinking amount. 8 Factors to be considered in food safety evaluation 8.1 Statistical significance and biological significance of test indicators When analyzing the statistical significance of the difference between the test group and the control group, the biological significance of the difference in the indicators should be comprehensively considered based on the principle of whether there is a dose-response relationship, horizontal comparison of similar indicators, and comparison with the historical control value range of this laboratory. In addition, if the incidence of a certain tumor is found to be increased in the test group, even if there is no statistically significant difference compared with the control group, it should still be given attention. 8.2 Physiological and toxic effects
For abnormal changes in certain indicators in the experiment, it is important to distinguish whether it is a physiological manifestation or a toxic effect of the test substance when analyzing and evaluating the results.
8.3 For test substances with a large possible intake for humans, it should be considered that when the test substance is given in excessive amounts, it may affect the intake of nutrients and their bioavailability, thereby causing certain physiological manifestations in animals, which are not caused by the toxic effects of the test substance. 8.4 Time-toxicity effect relationship
When analyzing and evaluating the sexual effects caused by the test substance, it is necessary to consider the changes in the toxic effects over time at the same dose level.
8.5 Possible human intake
In addition to the intake of the general population, special and sensitive populations (such as children, pregnant women and high-intake populations) should also be considered. For foods consumed by pregnant women, nursing mothers or children, special attention should be paid to their embryotoxicity or reproductive developmental toxicity, neurotoxicity and immunological properties. 8.6 Human data
Due to the species differences between animals and humans, when evaluating the safety of food, the reaction data of the population after exposure to the test substance should be collected as much as possible, such as occupational exposure and accidental exposure. The in vivo metabolic data of volunteer subjects are of great significance for inferring the results of animal tests to humans. Under the condition of ensuring safety, human food trials can be considered in accordance with relevant regulations. 8.7 Animal toxicity test and in vitro test data Although the various animal tests and in vitro test systems listed in this procedure are still to be improved, they are the most important data obtained at the current level and the main basis for evaluation. When the test obtains a positive result and the judgment of the result involves whether the test substance can be used in food, the repeatability of the result and the dose-response relationship need to be considered. 8.8 Safety factor
When inferring the results of animal toxicity tests to humans, in view of the biological differences between species and individuals of animals and humans, the safety factor method is generally used to ensure safety for humans. The safety factor is usually 100 times, but it can be increased or decreased based on the physical and chemical properties of the test substance, toxicity, metabolic characteristics, the range of people exposed and the possible intake of people, the use of food and the scope of use.
8.9 Data of metabolic tests
Metabolism research is an important aspect of toxicological evaluation of chemical substances, because the differences in metabolism of different chemical substances and dosages often have a great impact on the funerary effects. In principle, in toxicity tests, animal strains with the same metabolic pathways and patterns as humans should be used as much as possible for testing. Studying the differences in absorption, distribution, excretion and biotransformation of test substances in experimental animals and humans is of great significance for accurately extrapolating the results of animal tests to humans. 8.10 Comprehensive evaluation
When making the final evaluation, the physical and chemical properties of the test substance, its size, metabolic characteristics, accumulation, range of people exposed, the amount used in food and the scope of use, the possible intake of people, and other factors must be comprehensively considered to weigh the possible harm to human health caused by the test substance and its possible beneficial effects. The basis for evaluation is not only the results of scientific experiments, but also related to the scientific level, technical conditions and social factors at that time. Therefore, as time goes by, it is likely that the conclusion will be different. With the continuous change of the situation, the progress of science and technology GB15193.1-2003
and the continuous progress of research work, it is necessary to re-evaluate the chemical substances that have passed the evaluation and make new conclusions. For substances that have been used in food for a long time, it is of great significance to conduct epidemiological surveys on the exposed population, but it is often difficult to obtain reliable data on the dose-response relationship; for new test substances, they can only rely on animal tests and other experimental research data. However, even with complete and detailed animal test data and some epidemiological research data on human contacts, it is difficult to make an evaluation that can guarantee the safety of everyone due to racial and individual differences in humans. Absolute safety does not actually exist. Based on the above materials, when making the final evaluation, the actual possibilities should be fully weighed and considered, and the conclusion should be made on the premise of ensuring the maximum benefit of the test substance and the minimum harm to human health and the environment.6 When testing new resource foods and other test substances, or when the maximum amount of test substance added to the feed (when it exceeds 5%, protein should be added to the content equivalent to that of the control group, and the added test substance should not exceed 10% of the feed in principle) or when the liquid test substance still does not reach the prescribed multiple of the maximum no-observed-adverse-effect dose that is the possible intake of humans after concentration, the safety evaluation shall be conducted by combining other toxicity test results and the actual consumption or drinking amount. 8 Factors to be considered in food safety evaluation 8.1 Statistical significance and biological significance of test indicators When analyzing the statistical significance of the difference between the test group and the control group, the biological significance of the difference in the indicators should be comprehensively considered based on the principle of whether there is a dose-response relationship, horizontal comparison of similar indicators, and comparison with the historical control value range of this laboratory. In addition, if the incidence of a certain tumor is found to be increased in the test group, even if there is no statistically significant difference compared with the control group, it should still be given attention. 8.2 Physiological and toxic effects
For abnormal changes in certain indicators in the experiment, it is important to distinguish whether it is a physiological manifestation or a toxic effect of the test substance when analyzing and evaluating the results.
8.3 For test substances with a large possible intake for humans, it should be considered that when the test substance is given in excessive amounts, it may affect the intake of nutrients and their bioavailability, thereby causing certain physiological manifestations in animals, which are not caused by the toxic effects of the test substance. 8.4 Time-toxicity effect relationship
When analyzing and evaluating the sexual effects caused by the test substance, it is necessary to consider the changes in the toxic effects over time at the same dose level.
8.5 Possible human intake
In addition to the intake of the general population, special and sensitive populations (such as children, pregnant women and high-intake populations) should also be considered. For foods consumed by pregnant women, nursing mothers or children, special attention should be paid to their embryotoxicity or reproductive developmental toxicity, neurotoxicity and immunological properties. 8.6 Human data
Due to the species differences between animals and humans, when evaluating the safety of food, the reaction data of the population after exposure to the test substance should be collected as much as possible, such as occupational exposure and accidental exposure. The in vivo metabolic data of volunteer subjects are of great significance for inferring the results of animal tests to humans. Under the condition of ensuring safety, human food trials can be considered in accordance with relevant regulations. 8.7 Animal toxicity test and in vitro test data Although the various animal tests and in vitro test systems listed in this procedure are still to be improved, they are the most important data obtained at the current level and the main basis for evaluation. When the test obtains a positive result and the judgment of the result involves whether the test substance can be used in food, the repeatability of the result and the dose-response relationship need to be considered. 8.8 Safety factor
When inferring the results of animal toxicity tests to humans, in view of the biological differences between species and individuals of animals and humans, the safety factor method is generally used to ensure safety for humans. The safety factor is usually 100 times, but it can be increased or decreased based on the physical and chemical properties of the test substance, toxicity, metabolic characteristics, the range of people exposed and the possible intake of people, the use of food and the scope of use.
8.9 Data of metabolic tests
Metabolism research is an important aspect of toxicological evaluation of chemical substances, because the differences in metabolism of different chemical substances and dosages often have a great impact on the funerary effects. In principle, in toxicity tests, animal strains with the same metabolic pathways and patterns as humans should be used as much as possible for testing. Studying the differences in absorption, distribution, excretion and biotransformation of test substances in experimental animals and humans is of great significance for accurately extrapolating the results of animal tests to humans. 8.10 Comprehensive evaluation
When making the final evaluation, the physical and chemical properties of the test substance, its size, metabolic characteristics, accumulation, range of people exposed, the amount used in food and the scope of use, the possible intake of people, and other factors must be comprehensively considered to weigh the possible harm to human health caused by the test substance and its possible beneficial effects. The basis for evaluation is not only the results of scientific experiments, but also related to the scientific level, technical conditions and social factors at that time. Therefore, as time goes by, it is likely that the conclusion will be different. With the continuous change of the situation, the progress of science and technology GB15193.1-2003
and the continuous progress of research work, it is necessary to re-evaluate the chemical substances that have passed the evaluation and make new conclusions. For substances that have been used in food for a long time, it is of great significance to conduct epidemiological surveys on the exposed population, but it is often difficult to obtain reliable data on the dose-response relationship; for new test substances, they can only rely on animal tests and other experimental research data. However, even with complete and detailed animal test data and some epidemiological research data on human contacts, it is difficult to make an evaluation that can guarantee the safety of everyone due to racial and individual differences in humans. Absolute safety does not actually exist. Based on the above materials, when making the final evaluation, the actual possibilities should be fully weighed and considered, and the conclusion should be made on the premise of ensuring the maximum benefit of the test substance and the minimum harm to human health and the environment.6 When testing new resource foods and other test substances, or when the maximum amount of test substance added to the feed (when it exceeds 5%, protein should be added to the content equivalent to that of the control group, and the added test substance should not exceed 10% of the feed in principle) or when the liquid test substance still does not reach the prescribed multiple of the maximum no-observed-adverse-effect dose that is the possible intake of humans after concentration, the safety evaluation shall be conducted by combining other toxicity test results and the actual consumption or drinking amount. 8 Factors to be considered in food safety evaluation 8.1 Statistical significance and biological significance of test indicators When analyzing the statistical significance of the difference between the test group and the control group, the biological significance of the difference in the indicators should be comprehensively considered based on the principle of whether there is a dose-response relationship, horizontal comparison of similar indicators, and comparison with the historical control value range of this laboratory. In addition, if the incidence of a certain tumor is found to be increased in the test group, even if there is no statistically significant difference compared with the control group, it should still be given attention. 8.2 Physiological and toxic effects
For abnormal changes in certain indicators in the experiment, it is important to distinguish whether it is a physiological manifestation or a toxic effect of the test substance when analyzing and evaluating the results.
8.3 For test substances with a large possible intake for humans, it should be considered that when the test substance is given in excessive amounts, it may affect the intake of nutrients and their bioavailability, thereby causing certain physiological manifestations in animals, which are not caused by the toxic effects of the test substance. 8.4 Time-toxicity effect relationship
When analyzing and evaluating the sexual effects caused by the test substance, it is necessary to consider the changes in the toxic effects over time at the same dose level.
8.5 Possible human intake
In addition to the intake of the general population, special and sensitive populations (such as children, pregnant women and high-intake populations) should also be considered. For foods consumed by pregnant women, nursing mothers or children, special attention should be paid to their embryotoxicity or reproductive developmental toxicity, neurotoxicity and immunological properties. 8.6 Human data
Due to the species differences between animals and humans, when evaluating the safety of food, the reaction data of the population after exposure to the test substance should be collected as much as possible, such as occupational exposure and accidental exposure. The in vivo metabolic data of volunteer subjects are of great significance for inferring the results of animal tests to humans. Under the condition of ensuring safety, human food trials can be considered in accordance with relevant regulations. 8.7 Animal toxicity test and in vitro test data Although the various animal tests and in vitro test systems listed in this procedure are still to be improved, they are the most important data obtained at the current level and the main basis for evaluation. When the test obtains a positive result and the judgment of the result involves whether the test substance can be used in food, the repeatability of the result and the dose-response relationship need to be considered. 8.8 Safety factor
When inferring the results of animal toxicity tests to humans, in view of the biological differences between species and individuals of animals and humans, the safety factor method is generally used to ensure safety for humans. The safety factor is usually 100 times, but it can be increased or decreased based on the physical and chemical properties of the test substance, toxicity, metabolic characteristics, the range of people exposed and the possible intake of people, the use of food and the scope of use.
8.9 Data of metabolic tests
Metabolism research is an important aspect of toxicological evaluation of chemical substances, because the differences in metabolism of different chemical substances and dosages often have a great impact on the funerary effects. In principle, in toxicity tests, animal strains with the same metabolic pathways and patterns as humans should be used as much as possible for testing. Studying the differences in absorption, distribution, excretion and biotransformation of test substances in experimental animals and humans is of great significance for accurately extrapolating the results of animal tests to humans. 8.10 Comprehensive evaluation
When making the final evaluation, the physical and chemical properties of the test substance, its size, metabolic characteristics, accumulation, range of people exposed, the amount used in food and the scope of use, the possible intake of people, and other factors must be comprehensively considered to weigh the possible harm to human health caused by the test substance and its possible beneficial effects. The basis for evaluation is not only the results of scientific experiments, but also related to the scientific level, technical conditions and social factors at that time. Therefore, as time goes by, it is likely that the conclusion will be different. With the continuous change of the situation, the progress of science and technology GB15193.1-2003
and the continuous progress of research work, it is necessary to re-evaluate the chemical substances that have passed the evaluation and make new conclusions. For substances that have been used in food for a long time, it is of great significance to conduct epidemiological surveys on the exposed population, but it is often difficult to obtain reliable data on the dose-response relationship; for new test substances, they can only rely on animal tests and other experimental research data. However, even with complete and detailed animal test data and some epidemiological research data on human contacts, it is difficult to make an evaluation that can guarantee the safety of everyone due to racial and individual differences in humans. Absolute safety does not actually exist. Based on the above materials, when making the final evaluation, the actual possibilities should be fully weighed and considered, and the conclusion should be made on the premise of ensuring the maximum benefit of the test substance and the minimum harm to human health and the environment.10 Comprehensive evaluation
When making the final evaluation, it is necessary to comprehensively consider the physical and chemical properties of the test substance, its size, metabolic characteristics, accumulation, range of people exposed, the amount used in food and the scope of use, the possible intake of people, and other factors, and weigh the possible harm to human health caused by the test substance and its possible beneficial effects. The basis for evaluation is not only the results of scientific experiments, but also related to the scientific level, technical conditions and social factors at that time. Therefore, as time goes by, it is likely that the conclusion will be different. With the continuous change of the situation, the progress of science and technology GB15193.1-2003
and the continuous progress of research work, it is necessary to re-evaluate the chemical substances that have passed the evaluation and make new conclusions. For substances that have been used in food for a long time, it is of great significance to conduct epidemiological surveys on the exposed population, but it is often difficult to obtain reliable data on the dose-response relationship; for new test substances, they can only rely on animal tests and other experimental research data. However, even with complete and detailed animal test data and some epidemiological research data on human contacts, it is difficult to make an evaluation that can guarantee the safety of everyone due to racial and individual differences in humans. Absolute safety does not actually exist. Based on the above materials, when making the final evaluation, the actual possibilities should be fully weighed and considered, and the conclusion should be made on the premise of ensuring the maximum benefit of the test substance and the minimum harm to human health and the environment.10 Comprehensive evaluation
When making the final evaluation, it is necessary to comprehensively consider the physical and chemical properties of the test substance, its size, metabolic characteristics, accumulation, range of people exposed, the amount used in food and the scope of use, the possible intake of people, and other factors, and weigh the possible harm to human health caused by the test substance and its possible beneficial effects. The basis for evaluation is not only the results of scientific experiments, but also related to the scientific level, technical conditions and social factors at that time. Therefore, as time goes by, it is likely that the conclusion will be different. With the continuous change of the situation, the progress of science and technology GB15193.1-2003
and the continuous progress of research work, it is necessary to re-evaluate the chemical substances that have passed the evaluation and make new conclusions. For substances that have been used in food for a long time, it is of great significance to conduct epidemiological surveys on the exposed population, but it is often difficult to obtain reliable data on the dose-response relationship; for new test substances, they can only rely on animal tests and other experimental research data. However, even with complete and detailed animal test data and some epidemiological research data on human contacts, it is difficult to make an evaluation that can guarantee the safety of everyone due to racial and individual differences in humans. Absolute safety does not actually exist. Based on the above materials, when making the final evaluation, the actual possibilities should be fully weighed and considered, and the conclusion should be made on the premise of ensuring the maximum benefit of the test substance and the minimum harm to human health and the environment.
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