GB 15193.1-2014National Food Safety Standard -- Procedures for toxicological assessment of food (English PDF)

2.1 It shall provide the test substance's name, batch number, content, storage

conditions, sources of raw materials, production processes, quality specifications,

character, human recommended (possible) intake, and other relevant information.

2.2 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 mixed substances (including formulated products), the

composition 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.

3.1 Acute oral toxicity test.

3.2 Genetic toxicity test.

3.2.1 Genetic toxicity test contents. Bacterial reverse mutation test, mammalian

erythrocyte micronucleus test, mammalian bone marrow chromosome aberration test,

mouse spermatogonia or spermatocytes chromosome aberration test, in-vitro mammalian

cell HGPRT gene mutation test, in-vitro mammalian cell TK gene mutation test, in-vitro

mammalian chromosome aberration test, rodent dominant lethal test, in-vitro mammalian

cell DNA damage repair (unscheduled DNA synthesis) test, Drosophila sex-linked

recessive lethal test.

3.3 28-day oral toxicity test.

3.4 90-day oral toxicity test.

3.5 Teratogenicity test.

3.6 Reproductive toxicity and reproductive-developmental toxicity test.

3.10 Chronic toxicity and carcinogenicity merge test.

4.1 For all substances that are firstly-innovated by our country, especially that the

chemical structure suggests that there are potential chronic toxicity, genetic toxicity or

carcinogenic properties;

4.2 For derivatives or analogs of which the chemical structure is basically same as that

of known substances (refer to those that have passed safety evaluation and are allowed

for use), or the substances that have safe-use history in some countries and regions, then

it may firstly conduct the acute oral toxicity studies, genetic toxicity test, 90-day oral

toxicity test, and teratogenicity test.

4.4 Selection of the safety toxicology assessment test for food additives, new

resources of food and ingredients, food related products, pesticide residue,

veterinary drug residue

4.4.1 Food additives

4.4.1.1 Flavoring

4.4.1.2 Enzyme preparations

4.4.1.2.1 For enzyme preparations that have long history of safe consumption and that

are produced from edible parts of animals or plants, if the World Health Organization has

announced the acceptable daily intake (ADI) or ADI is not required to be specified or

several countries have approved the use, on the basis of providing relevant proving

materials, generally it does not require to conduct toxicological test.

4.4.1.3 Other food additives

4.4.1.3.1 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,

or several countries have approved the use, if the quality specifications are consistent with

international quality specifications, then acute oral toxicity test and genetic toxicity tests

are required; if the quality specifications are not consistent with international quality

specifications, then it requires additional 28-day oral toxicity test; According to the test

results, determine whether it needs to further conduct other related toxicity test.

4.4.1.3.3 For the additives with single component and high-purity extracted from animal,

plant or microorganism, if it is a new variety, then it needs to conduct oral toxicity test,

genetic toxicity test, 28-day oral toxicity test, and teratogenicity test. After preliminary

assessment, determine whether it needs to conduct further test. If it has been approved

for use by a foreign country or an international organization, then it shall conduct oral

toxicity test, genetic toxicity test, and 28-day oral toxicity test. After preliminary

assessment, determine whether it needs to conduct further test.

4.4.2 New food raw materials

It shall be evaluated in accordance with "New food raw material declaration and

acceptance provisions" (State-Health-Food-Announcement [2013] 23).

4.4.3 Food related products

It shall be evaluated in accordance with "Food related product new varieties declaration

and acceptance provisions" (Health-Supervision-Announcement [2011] 49).

5.1 Objectives of toxicological test

5.1.1 Acute toxicity test

Understand the degree of toxicity, property and possible target organ of test substance;

provide basis for selection of dose and toxicity observation index for further toxicity test;

classify the acute toxicity dosage according to LD50.

5.1.5 Teratogenicity test

Understand whether the test substance has teratogenic effects and developmental toxicity;

and obtain the not-observed adverse effect doses of teratogenic effects and

developmental toxicity.

5.1.6 Reproductive toxicity test and reproductive-developmental toxicity test

Understand the test substance's reproductive-developmental toxicity to experimental

animals' reproduction and their offspring, such as gonadal function, estrous cycle, mating

behavior, gestation, childbirth, breast-feeding and weaning, and progeny growth and

development. Obtain the not-observed adverse effect dose-level; provide a scientific basis

for preliminarily formulating human-group safe contact limits.

5.2 Determination of various toxicology test results

5.2.1 Acute Toxicity Test

If LD50 is less than 100 times of recommended (possible) human-intake, then generally it

shall give up that the test substance can be used in food; no further additional toxicology

test shall be conducted.

5.2.2 Genetic Toxicity Test

5.2.2.1 If 2 or more items in genetic toxicity test combination are positive, then it

indicates that the test substance is likely to be genetic toxicity and carcinogenic effects;

generally it shall give up that the test substance can be used in food.

5.2.3 28-day oral toxicity test

For test substances that only require to conduct acute toxicity, genetic toxicity and 28-day

oral toxicity test, if the test is found without significant toxic effects, the preliminary

assessment may be made on considering other various test results. If the test is found to

have significant toxicity, especially when there is dose-response relationship, then it shall

consider to conduct further toxicity test.

5.2.4 90-day oral toxicity test

According to the not-observed adverse effect dose obtained by the test to conduct

assessment, the principle is.

5.2.5 Teratogenicity test

According to the test results, evaluate if the test substance is the teratogenic substance to

laboratory animals. If teratogenic test result is positive, then reproductive toxicity and

reproductive-developmental toxicity test shall not be continued. For other developmental

toxicities that are observed in teratogenicity test, it shall combine with 28-day and (or)

90-day oral toxicity test results to conduct the assessment.

5.2.7 Chronic toxicity and carcinogenicity test

5.2.7.1 According to the not-observed adverse effect dose obtained by the chronic

toxicity test to conduct assessment, the principle is.

5.2.7.2 According to the tumor incidence, latency and multiple that are obtained by

carcinogenicity test to conduct the judgment of carcinogenicity test results, the principle is

(for those that comply with one of the following conditions, it may be considered that the

carcinogenicity test result is positive. If dose-response relationship exists, then the

judgment is more reliable).

6.1 Test indicators' statistical significance, biological significance and

toxicological significance

6.2 Test substance of larger recommended (possible) human-intake

It shall consider that, when the given test substance is too high, it may affect nutrient

intake and bioavailability, so as to cause some toxicology performance, rather than that

the toxicity is caused by the test substance.

6.3 Time-toxic effect relationship

When conducting analysis and assessment to toxic effects of experimental animals that

are caused by the test substance, it shall consider that, at the same dose level, the toxic

effects change along the time.

6.6 Animal toxicity test and in-vitro test data

The various animal toxicity tests and in-vitro test systems listed in this Standard are the

most important data that can be obtained under the current management (regulations)

toxicological assessment level; it is also the main basis for safety assessment. When test

result is positive, and the result judgment is involved in whether the test substance could

be applied in food, the repeatability of result and dose-response relationship shall be

considered.

6.8 Data of toxicokinetics test

Toxicokinetic test is an important aspect for toxicological assessment to chemical

substances, because different chemical substances or dose amount often have significant

impact to the differences of toxicokinetic or metabolism. 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 and reducing

the uncertainty.

6.9 Comprehensive assessment

While conducting final assessment, the physiochemical property, structure, degree of

toxicity, metabolism characteristic, accumulation, contacted human being scope, usage

amount and usage scope in food, recommended (possible) intake for human being, and

other factors of test substance shall be comprehensively considered; 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.

......