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GB 15193.16-2014: National Food Safety Standard -- Toxicokinetic test
Status: Valid GB 15193.16: Evolution and historical versions
| Standard ID | Contents [version] | USD | STEP2 | [PDF] delivered in | Standard Title (Description) | Status | PDF |
| GB 15193.16-2014 | English | 189 |
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3 days [Need to translate]
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National Food Safety Standard -- Toxicokinetic test
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GB 15193.16-2014
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| GB 15193.16-2003 | English | 199 |
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Metabolic study
| Obsolete |
GB 15193.16-2003
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| GB 15193.16-1994 | English | 199 |
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Metabolic test
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GB 15193.16-1994
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PDF similar to GB 15193.16-2014
Basic data | Standard ID | GB 15193.16-2014 (GB15193.16-2014) | | Description (Translated English) | National Food Safety Standard -- Toxicokinetic test | | Sector / Industry | National Standard | | Classification of Chinese Standard | C53 | | Classification of International Standard | 07.100 | | Word Count Estimation | 8,848 | | Date of Issue | 12/24/2014 | | Date of Implementation | 5/1/2015 | | Older Standard (superseded by this standard) | GB 15193.16-2003 | | Regulation (derived from) | Health Planning Commission Bulletin 2014 No. 21 | | Issuing agency(ies) | National Health and Family Planning Commission of the People's Republic of China | | Summary | This Standard specifies toxicokinetics test basic test methods and technical requirements. This Standard is applicable to the subject matter of the toxicokinetic evaluation process. | GB 15193.16-2014: National Food Safety Standard -- Toxicokinetic test---This is a DRAFT version for illustration, not a final translation. Full copy of true-PDF in English version (including equations, symbols, images, flow-chart, tables, and figures etc.) will be manually/carefully translated upon your order.
National Food Safety Standard.Toxicokinetics test
National Standards of People's Republic of China
National Food Safety Standard
Toxicokinetics test
Issued on.2014-12-24
2015-05-01 implementation
People's Republic of China
National Health and Family Planning Commission released
Foreword
This standard replaces GB 15193.16-2003 "metabolic test."
This standard compared with GB 15193.16-2003, the main changes are as follows.
--- Standard name was changed to "national food safety standards toxicokinetics test";
--- Modify the scope;
--- Increasing the terms and definitions;
--- Modified test purposes and principles;
--- Modify the instruments and reagents;
--- Increased test methods;
--- Remove the biotransformation;
--- Remove the isotope experiment precautions;
--- Remove the test substances in biological samples analysis requirements;
--- Remove the result of the determination;
--- Increased data processing and evaluation of results;
--- Increasing the test report;
--- Expanded to explain the experiment.
National Food Safety Standard
Toxicokinetics test
1 Scope
This standard specifies the basic technical requirements and test methods for toxicokinetic tests.
This standard applies to the evaluation of the test substance toxicokinetics process.
2 Terms and definitions
2.1 test substance
Items for testing, refers specifically to meet the test requirements toxicokinetics the test.
2.2 Toxicokinetics
Test substance in the body absorption, distribution, biotransformation and excretion process time-varying dynamic characteristics.
2.3 Absorption
From the site of the test substance is usually administered biofilm transport outer or inner surface of the body's blood circulation to the process.
2.4 Distribution
After the test substance by absorption into the blood and body fluids in the body circulation and distribution process.
2.5 Metabolism
Test substance in the body through enzymatic or non-enzymatic reactions, the process of structural change occurs.
2.6 Excretion
The test substance and (or) its metabolites are cleared from the body process.
2.7 bioavailability
The extent of the test substance is absorbed by the body.
2.8 rate process
By the rate of change of the amount of poison dynamics of the test substance in unit time, usually with the amount of change per unit time through the process of representation
Rate process. Rate process toxicokinetics, including zero order, first order and nonlinear three types.
2.9 concentration - time curve
After administration of the test substance with time as the horizontal to the blood concentration of the test substance is made ordinate arithmetic graph reflects the test substance in the body
Disposal within the state, the rate of change over time and content of the test, the area under the curve reflects into the systemic circulation of the subject matter content.
2.10 apparent volume of distribution
When tested in vivo was partitioned Buda homeostasis hypothesis test substance concentration in the body fluid uniformly and plasma concentration of a test substance
Thus, this body was dissolved test substance required amount of fluid volume is apparent volume of distribution. It was tested in vivo test volume and plasma concentration
The ratio of representation.
2.11 total body clearance
Test substance by metabolism and (or) excretion from the body to clear the way of speed; within per unit time in vivo clearance of the test substance is apparent from points
Cloth volume fraction.
2.12 elimination half-life
Vivo blood test substance concentration required for half fall time, which is a parameter indicating the subject matter of the elimination rate.
2.13 peak concentration
After administering the test substance in the blood to reach the maximum concentration.
2.14 peak time
After the test is administered to achieve maximum blood concentration time.
3 test purposes and principles
For a group or several groups of experimental animals, respectively, through the appropriate channels at once or several times within a specified time administration of the test substance. Then measured body
Fluid, organ, tissue, fecal test substance and (or) change over time the amount or concentration of its metabolites. And then find the related poison power
Parameters to investigate the toxicological significance.
4 instruments and reagents
4.1 According to the test needs, with UV spectrophotometer, fluorescence spectrophotometer, thin layer chromatography, gas chromatography, high performance liquid chromatography
Instrument, temperament or LC-MS and other equipment.
4.2 radiometric instruments.
4.3 commonly used laboratory instruments and reagents.
5 Test methods
5.1 Basic information of the test substance
The test substance should provide the name, CAS number, batch number, source, purity, character, physical and chemical properties, storage conditions and preparation method, etc.
data.
5.2 Experimental Animals
5.2.1 animal species, the Department of choice
Experimental animals should be selected in line with the relevant provisions of GB GB 14922.2 and 14922.1 of. Possible selection and other toxicology testing phase
The same species, the Department, and to the typical toxicity of the test substance the animals. Rats generally preferred, usually six weeks weeks to 12 weeks, but if certificate
It proved its metabolic pathways to human proximity, should select the appropriate animal. General should use young, healthy adult animals. Selection of rodent
When objects, start of the test animal weight difference should not exceed ± 20% of average weight. Select other animals shall state the reasons.
5.2.2 Number and sex
Experimental animals sex without special provisions, such as toxicology studies have shown that there are significant gender differences in toxicity, should set up different gender
group. In general, female animals should be used in nulliparous and non-pregnant too young; each test group of animals should not be less than 5, in a non-rodent
Test substance, the discretion to reduce the number of animals.
5.2.3 Animal Feeding
Before the test, animals in the experimental animal room should be at least 3d ~ 5d acclimatization and quarantine observation. Animal rearing conditions, drinking
Water and feed should be in line with national standards and regulations (animal breeding conditions should be consistent with GB 14925, drinking water should be consistent with GB 5749, feeding
Material shall comply with the relevant provisions of GB 14924).
5.3 dose
Trials need to use at least two dose levels, so that each dose level should metabolite test or the test substance is sufficient to drain
It was measured out. Dose setting should take full account of existing toxicological data provided the information. If the lack of toxicological data, the
High dose levels should be less than the LD50, acute toxicity or below the dose range lower value. Low dose levels should be a high dose levels
section.
If the test set only one dose level, the dose should theoretically make the test substance or metabolite sufficient test substance in excrement
The measure does not produce significant toxicity, and should provide a reasonable justification is not provided reasons for two dose levels.
5.4 Test procedure and outcome measures
5.4.1 Prepare the test substance
Purity of the test substance should not be less than 98%. Test can be "unlabeled" or "flag" test substances. If the use of radioisotopes
Labeled test substance, the radiochemical purity of not less than 95% and should be marked on the radioisotope test molecule or a skeleton
Important functional groups on.
5.4.2 was tested routes of administration
When selecting a vehicle or other media, the test substance should be fully dissolved or uniformly suspended therein, the selected vehicle or medium for the test substance poison power
Science does not have any effect. Commonly used oral route, and in some cases may also be employed to swallow capsules, administered by the incorporated feed
Test substance.
Using intravenous administration of the test substance, should select the appropriate injection site and injection volume administration of the test substance, the selected vehicle or medium should not affect
The integrity of the blood or blood flow.
5.4.3 Establishment and validation of biological sample analysis methods
5.4.3.1 Since biological sample generally from whole blood, serum, plasma, urine, organ or tissue, with less sampling, low concentrations of the test substance,
Interfering substances and more individual differences and other characteristics, it is necessary according to the structure of the test substances, biological agents and the expected range of concentrations, the establishment of the Spirit
Sensitive, specific, accurate, and reliable quantitative biological sample analysis method, and the method for confirmation.
5.4.3.2 biological sample analysis methods are.
a) chromatography. Gas chromatography (GC), high performance liquid chromatography (HPLC), chromatography - mass spectrometry (LC-MS, LC-MS-MS,
GC-MS, GC-MS-MS), biological sample analysis is generally preferred chromatography;
b) Immunological methods. radioimmunoassay, enzyme immunoassay, fluorescence immunoassay method;
c) microbiological method;
d) isotope tracer method.
Confirmatory methods in general should investigate the following aspects.
a) Specificity. must prove analyte is expected analyte, endogenous substances and other metabolites can not interfere with the determination of the sample. Correct
Chromatography to analyze at least six different individuals in a biological sample chromatogram blank, blank samples plus biological control substance chromatogram
After administration of the test substance and a biological sample chromatogram.
b) a standard curve and quantitative range. According to the correlation with the analyte concentration in response, with the regression analysis (such as weighted least square
Multiplication) to obtain a standard curve. Low concentration range of the standard curve for the quantitative range in the concentration range of quantitative measurement results should be achieved
Test precision and accuracy requirements.
c) precision and accuracy. asked to choose three different concentrations of quality control samples at the same time to inspect the precision and accuracy of the method.
Choose low concentrations near the lower limit of quantification in less than three times the lower limit of quantification of the concentration; close to the upper limit of the standard curve of the high concentration;
Choose a middle concentration.
d) Quantitative limit. the limit of quantification is the lowest concentration point on the calibration curve, the determination to meet the requirements of at least three to five elimination half-life
Test substance concentration 1/10 to 1/20 when the test substance concentration in the sample, or peak concentration, its accuracy should be in a real concentration
80% to 120% range, and inter-assay relative standard deviation should be less than 20% within a batch.
e) Sample stability. depending on the circumstances of the biological sample containing the test substance at room temperature, frozen or freeze-thaw conditions and different storage
Time stability study to determine the biological sample storage conditions and time. Note also that the stability of the stock solution and the like
Stability of the post-disposal solution analysis.
f) extraction recovery. study should be high, medium and low concentrations of extraction recoveries, the results should be accurate and reproducible.
5.4.4 OUTCOME MEASURES
5.4.4.1 test blood concentration - time curve
5.4.4.1.1 Number of test animals
Select 9 to 11 different time points blood after administration of the test animals, animal per time point of not less than five. the best
Sampled repeatedly from the same individual animal. As indicated by the data of multiple animals together constitute a test substance in blood concentration - time curve up accordingly
The number of animals, in order to reflect the impact of individual differences in the test results.
5.4.4.1.2 sampling point
Before administration of the test substance needed for blood collection as a blank sample. To obtain a complete administration of the test substance in the blood after the test substance concentration - time
Curve, sampling time points should be designed to take into account the absorption of the test substance phase, the distribution phase (near the peak concentration) and the elimination phase. The entire sampling time shall be at least
Until three to five elimination half-life, or until the blood test substance concentration peak concentration of 1/10-1/20.
5.4.4.1.3 toxicokinetics parameters
According to blood tests measured the animals tested in each test concentration - time data obtained by the test substance is mainly toxicokinetics parameters.
Intravenous administration of the test substance should be provided elimination half-life, the apparent volume of distribution, the area under the curve parameters, total body clearance rate; extravascular
Administration of the test substance, in addition to providing the above parameters, there should provide peak concentration and peak time and other parameters, the test was taken in order to reflect the law.
5.4.4.1.4 a single administration of the test substance
After single administration of different doses of the test substance (or radioisotope labels), plasma or whole blood of the test substance at different times
Concentration (or the total radioactivity intensity), providing each test animal blood test substance concentration - time data and curves and mean, standard deviation
Its curve; poison each major subject animal pharmacokinetic parameters and mean, standard deviation.
5.4.4.1.5 repeated administration of the test substance
Repeated administration of the test substance, should be combined with a single test, select a general administration of the test dose was repeated at least three times to provide stability
State trough concentrations of the test substance, after reaching a steady state were the last administration of the test substance test. Plasma or whole blood concentration of the test substance at different times
Or the total radioactivity intensity, compared with the single administration of the test was to determine the toxicokinetics of repeated administration of the test substance when.
5.4.4.2 Absorption
Test substance absorption rate depends on the extent of the test substance and route of administration. It is generally believed that the test was administered intravenously precursor chemicals
Transient absorption rate calculated as 100%, the test substance shall be administered orally to determine the peak concentration, time to peak and area under the curve. Chemical analysis of the parent
Concentration versus time curve can be determined orally administered absorption coefficient of the test substance.
The ratio of the area under the curve and the area under the curve of intravenous bioavailability of orally administered the test substance.
5.4.4.3 Distribution
After selecting the appropriate doses of the test substance in experimental animals, measured in the blood, heart, liver toxicity based on physical and chemical properties and characteristics of the test substance,
The concentration of the spleen, lung, kidney, gastrointestinal tract, gonads, brain, body fat, skeletal muscle and other tissues in order to understand the distribution of the test substance in the main organs of the body.
Particular attention to high concentrations of the test substance, long storage time of tissues and organs, as well as distribution in the target organ toxicity. Reference blood test concentration -
Time trend curve, select at least three time points represent the relative absorption, distribution and elimination phase of the phase distribution of the test substance. If an organization
Higher concentrations of the test substance, should be added to the observation point, and further research in the organization of the test was eliminated. Each time point, there should be at least
5 animal data.
To organize the distribution of the test, it should pay attention to a representative sampling and consistency.
Tissue distribution of isotope markers test, the test substance should be provided labeled radiochemical purity, labeling efficiency (specific activity), marking position, to
They test substance dose and other parameters; detailed radiometric method employed to provide; provide biological tests using radioactive tracer too detailed
Cheng, and the correction equation when the biological sample measurement of radioactive decay were like. Under the experimental conditions permit, to the extent possible
Overall radiation after administration of the test substance at different phases of self-developed image.
5.4.4.4 Metabolism
We should adopt appropriate technical analysis of biological samples to determine metabolic pathways and extent of the test substance. It should clarify metabolite structure. body
Field test also helps to get tested metabolic pathways of information.
5.4.4.5 excretion
After excretion test, the administration of the test substance selected the appropriate dose, according to a certain time interval segment collect urine, feces, exhaled breath measured
Given the concentration of the test substance, the test substance is calculated by this route of excretion and rate of excretion. It should also be collected if necessary bile excretion detected by this route
Rate and excretion.
In the administration of the test dose was at least 90% has been eliminated, or in the above sample has been collected from the test substance is not detected, or the detection time
Up to 7d, to stop the collection of excreta. If exhaled test substance and (or) metabolite concentrations ≤1%, to stop the animals exhaled
Collection.
Record the test substance from feces, urine, exhaled air and other excretion rate and total excretion of the test substance in animals provide material balance data.
6 Data processing and evaluation of results
Depending on the type of test, will aggregate data. Reasonable choice of data processing and statistical methods of science, and an explanation of the name of the software
That version and sources.
7 Test report
7.1 Name of test, the test unit name and contact details, report number.
7.2 Test Requester name and contact information, sample acceptance date.
7.3 Test start and end dates, test project manager, technical director of the test unit, date of issue.
7.4 test summary.
7.5 test substance. name, lot number, dosage form, the state (including organoleptic, properties, package integrity, identification), the number of pre-treatment method, solvent.
7.6 Experimental animals. species, strain, level, quantity, weight, sex, origin (supplier name, animal production license number), animal inspection
Phytophthora, adaptation, breeding environment (temperature, relative humidity, using experimental animal facility license number), feed sources (supplier name, laboratory animals
Animal feed production license number).
7.7 Test method. the test group, the number of animals in each group, according to dose selection, route of administration and duration of the test substance, observed indicators, statistical methods.
7.8 Test results.
a) collection of experimental data in tabular form, should include different doses per animal number, sex, exposure dose, body weight, to
To the measured value (or intensity of radioactivity) and other test substance and its metabolites in biological material before and after the test substance raw data;
b) calculate the mean and standard each of the measured values of dose difference;
c) Draw the test substance concentration at different doses of - time curve;
d) Calculation of different doses and absorption, distribution, metabolism, excretion of the poisons kinetic parameters;
e) for metabolic studies, given the chemical structure of metabolites and metabolic pathways proposed;
f) test data, curve fitting the results with appropriate statistical manner.
Explanation 8 trial
According to the test results, the way the test substance into the body, the rate and extent of absorption, the test substance and its metabolites in organs, tissues and body
Distribution of fluid, the rate and extent of biotransformation, the major metabolite of biological conversion path, pathway excretion rate and capacity, by
Test was made and its metabolites accumulate in the evaluation of the possibility, the extent and duration. Combination of knowledge on a variety of relevant disciplines of poison
Kinetic parameters were evaluated toxicological significance.
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