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1 Translated English of Chinese Standard: GB NATIONAL STANDARD OF THE GB PEOPLE S REPUBLIC OF CHINA ICS C 53 Replacing GB Procedures for toxicological assessment of food Issued on: September 24, 2003 Implemented on: May 01, 2004 Issued by: Ministry of Health of the People s Republic of China; Standardization Administration of the People s Republic of China. Page 1 of 14

2 Table of Contents Foreword Scope Normative reference Terms and definitions Requirements for test substances stages and contents of toxicological assessment for food safety Principle of selecting toxicity test for different test substances Objective of toxicological assessment of food and result judgment Factors that need to be considered during food safety assessment Page 2 of 14

3 Foreword Full text of this Standard is compulsory. This Standard replaces GB Procedures for toxicological assessment of food. Compared with GB , the main changes in this Standard are as follows: - Specific contents of test substance have been added in Scope : the safety of chemical, biological and physical factors that may cause harm to health concerned during food production, processing, storing, transport and selling process; assessment objects including food additives (including food enrichment), new resources of food and ingredients, novel foods, irradiated food, food container and packing materials, food tools, equipment, detergent, disinfectant, pesticide residue, veterinary drug residue, industrial microorganisms for food, etc.; - In Requirements for test substance : add For formulated products, the formula of test substance shall be provided; when necessary, physical property, chemical property (including chemical name, structure, purity, stability, solubility, etc.) of all compositions of test substances, test report and relevant data shall be provided; source of raw materials, production technology, possible intake for human being and other relevant data shall be provided ; - In Four stages and toxicological test : TK gene mutation test has been added in Genetic toxicity test of second-stage. For V79/HGPRT gene mutation test, it has been changed FROM optional test TO must-test item of gene mutation test in parallel with Ames test. The previous optional tests have changed to 3 items from 4 items; - In Principle of selecting toxicity test for different test substances : add Food container and packing material, pesticide residue. For the selection principle to flavoring, Acute toxicity test (Article in 1994 edition, Article in this edition) has been deleted; for additives for other food, the one-item mutagenicity test has been changed to 2-items mutagenicity tests ; Ames test or mouse bone marrow micronucleus test (MNT) preferred has been changed to Ames test and mouse bone marrow micronucleus test (MNT) preferred (Article in 1994 edition, Article in this edition); selection principle of toxicity test for food container and packing material has been added; - In Result judgment of all toxicological tests : result judgments of genetic toxicity have been re-drafted; and the article-number has been changed from previous 4 to 3. Result judgment principle for carcinogenicity test has been added. The content in the bracket of novel food has been changed to if it exceeds 5%, protein shall be supplemented to the content equivalent to control-group, and the added test substances shall not exceed 10% of feed at most in principle (Article in Page 3 of 14

4 Procedures for toxicological assessment of food 1. Scope This Standard specifies the procedure for toxicological assessment of food. This Standard is applicable to the assessment of the safety of chemical, biological and physical factors that may cause harm to health concerned during food production, processing, storing, transport and selling process. Assessment objects include food additives (including food enrichment), new resources of food and ingredients, novel foods, irradiated food, food container and packing materials, food tools, equipment, detergent, disinfectant, pesticide residue, veterinary drug residue, industrial microorganisms for food, etc. 2. Normative reference The articles contained in the following documents have become part of this Standard when they are quoted herein. For the dated documents so quoted, all the modifications or revisions made thereafter shall not be applicable to this Standard. For the undated documents so quoted, the latest editions shall be applicable to this Standard. GB The Toxicological Testing Method for Pesticides Hygiene control measures for irradiated food Disinfection Management Measures 3. Terms and definitions For the purpose of this Standard, the following terms and definitions apply. 3.1 Food additive It refers to the synthetic chemicals or natural materials that are added in food to improve the food quality and color, aroma and taste, and for the needs of preservation and processing. 3.2 Novel foods It refers to food or raw materials of food that are newly discovered, developed (including new process and new technology) or introduced that have not been eaten yet or merely eaten in individual-limited regions. Page 5 of 14

5 4. Requirements for test substances 4.1 For single-ingredient chemical substance, the physical, chemical property (including chemical structure, purity, stability, etc.) of test substance (including impurities when necessary) shall be provided. For formulated product, the formula of test substance shall be provided; when necessary, physical property, chemical property (including chemical name, structure, purity, stability, solubility, etc.) of all compositions of test substances and relevant data shall be provided. 4.2 Source of raw materials, production technology, possible intake for human being and other relevant data shall be provided. 4.3 The test substance must be standardized product that conforms to given formula; its composition, proportion and purity shall be the same as the practical application; when testing the toxicity of test substance with high purity, and when testing the toxicity of possible-existed impurity or conducting special test, pure substance may be selected; or conduct toxicity test with pure substance or impurity respectively stages and contents of toxicological assessment for food safety 5.1 First-stage: acute toxicity test Acute oral toxicity: LD50, Acute combination toxicity, maximum tolerated dose method. 5.2 Second-stage: genetic toxicity test, traditional teratogenicity test, thirty-day feeding test. For the combination of genetic toxicity test, it shall consider the principle of the combination of prokaryotic cell and eukaryotic cell, in-vivo test and in-vitro test. Select one-test from Ames test or V79/HGPRT gene mutation test, bone marrow micronucleus test or mammalian bone marrow chromosome aberration test, or respectively Salmonella typhimurium/mammal microsomal enzyme test (Ames test) or V79/HGPRT gene mutation test. Ames test is preferred, and other tests are selected when necessary Micronucleus test of bone marrow cells or test of bone marrow micronucleus test (PCE) TK gene mutation test Analysis of sperm abnormality in mice or chromosome mutagenic analysis. Page 6 of 14

6 referring to international organizations and foreign data, and regulations for assessment All the flavorings that have been approved for use or have been formulated for daily acceptable intake by World Health Organization (WHO), and allowed by two or more organizations of WHO, FEMA, COE and IOFI, then it may be assessed by referring to foreign data or regulations If the data is incomplete or is only approved by one of the international organizations, then acute toxicity test and one of mutagenicity tests specified by this procedure shall be conducted first; decide whether further test is needed after preliminary assessment If no data can be referred to and it is not yet allowed to use by international organization, then conduct the first-stage and second-stage toxicity test first; decide whether further test is needed after preliminary assessment For single natural flavoring with high purity that is extracted from animal or plant, if the chemical structure and relevant data do not show unsafety, then toxicity test is generally not required Other food additives For the additives with comparatively complete toxicological data and the World Health Organization has announced the ADI or that the ADI is not required to be specified, then acute toxicity test and two mutagenicity tests are required; Ames test and micronucleus test of bone marrow cells shall be preferred. However, the additives with different production process, purity of finished products and source of impurities, it shall consider whether the next stage test is needed according to the test results after the first-stage and second-stage toxicity tests For the additives that have been approved to use by one or more international organization, but the World Health Organization has not announced the ADI; or the data is incomplete, then it shall decide whether next stage toxicity test is needed after preliminary assessment of the first-stage and second-stage toxicity tests For the additives with single component and high purity extracted from animal, plant or microorganism, it shall conduct the first-stage, second-stage and third-stage toxicity tests for new varieties; for the additives that have been approved for use by an international organization or a foreign country, it shall conduct the first-stage and second-stage tests; then decide whether next stage test is needed after preliminary assessment Imported food additives Importing organization shall provide toxicological information and data approved for use by exporting country. Whether toxicity test is required shall be decided after the review of designated organization by administrative agency for health of the State Council. Page 8 of 14

7 If the maximum unobserved harm effect dose is less than or equal to 50 times of possible ADI for human being, then it shows strong toxicity; test substance shall be abandoned to be used in food If the maximum unobserved harm effect dose is larger than 50 times and less than 100 times, then this test substance shall be decided whether it can be used for food after safety assessment If the maximum unobserved harm effect dose is larger than or equal to 100 times, then this test substance can be considered to be used in food The principle of carcinogenic test result judgment according to the incidence, incubation period and multiple of tumor from carcinogenic test is: if it conforms to one of the conditions listed below, and has significant difference after statistical treatment, then it can be considered that the carcinogenic test result is positive. If dose-response relationship exists, then the judgment is more reliable Tumor occurs in animals of experimental-group only and not in control-group Tumor occurs in both experimental-group and control-group, but the rate is higher in experimental-group Multiple tumor is obvious in animals of experimental-group, no multiple tumor occurs in control-group or only a few animals have multiple tumor The difference of incidence of tumor in experimental-group and control-group is not obvious, but the occurrence time is earlier in experimental-group When test substance like novel foods is under test, if the maximum addition of feed mixed in test substance (add protein till it is equivalent to the content of control-group; and the added test substance shall not be higher than 10% of feed in principle) or if the liquid test substance could not REACH the specified multiple of possible ADI that the maximum unobserved harm effect dose is human being, then combine other toxicity test results and practical intakes for safety assessment. 8. Factors that need to be considered during food safety assessment 8.1 Statistical significance and biological significance When analyzing the significance of indicator difference in experimental-group and control-group statistically, it shall take the principle of whether there are dose-response relationship, horizontal comparison of similar indicators, and historical reference value scope, so as to comprehensively consider whether indicator difference has biological significance. In addition, if some tumor incidence rate is increased in experimental-group, Page 12 of 14

8 biological differences among animal, human being, and human individual, safety coefficient is generally adopted to ensure the human being s safety. Safety coefficient is usually 100 times; however, it could be amplified or reduced by comprehensively considering the physiochemical property, degree of toxicity, metabolism characteristic, contacted human being scope and possible ADI for human being, usage amount, application scope of food, and other factors of test substances. 8.9 Data on metabolism test Metabolism study is an important aspect for toxicological assessment to chemical substances, because different chemical substances, dose amount and difference on metabolism usually have significant impact on toxic effect. In toxicity test, the animal species with the same metabolism method and mode as human being shall be, in principle, applied as much as possible for test. Studying the difference of test substance s absorption, distribution, excretion and biotransformation on animal and human being has important significance on deducting the animal test results to human being more-correctly Comprehensive assessment While conducting final assessment, the physiochemical property, degree of toxicity, metabolism characteristic, accumulation, contacted human being scope, usage amount and usage scope, possible ADI for human being, and other factors of test substance shall be comprehensively considered; and balance the harm that test substance may cause to human health and the possible benefit effect. The basis for assessment is not only the result of scientific test, but is related to the scientific level, technological condition and social factors at that time. Therefore, with the time passing by, the conclusion is likely to be different. With the constant change of condition, advance of scientific technology and development of study, it s necessary to reassess the evaluated chemical substances and make new conclusions. For the substances that have been applied in food for a relative long-time, they are of great significance to the epidemiology investigation for contact people; however, it is usually difficult to obtain the reliable data on dose-response relationship. For new test substances, only animal test and other test study data can be relied on. However, even if there are complete and detailed animal test data and some human being contact epidemiology study data, it is still hard to make assessment that it could guarantee every person s safety due to the different species of human being and individuals. The so-called absolute safety actually does not exist. On the basis of the above data, while making final assessment, it shall comprehensively balance and consider the practical possibility, so as to make conclusions under the premise of ensuring the maximum benefit of test substance and minimum harm to human health and environment. END Page 14 of 14