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GB 15193.17-2015: National food safety standard -- Chronic toxicity and carcinogenicity combination test
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National food safety standard -- Chronic toxicity and carcinogenicity combination test
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Basic data | Standard ID | GB 15193.17-2015 (GB15193.17-2015) | | Description (Translated English) | National food safety standard -- Chronic toxicity and carcinogenicity combination test | | Sector / Industry | National Standard | | Classification of Chinese Standard | C53 | | Classification of International Standard | 7.1 | | Word Count Estimation | 9,978 | | Date of Issue | 2015-08-07 | | Date of Implementation | 2015-10-07 | | Older Standard (superseded by this standard) | GB 15193.17-2003 | | Regulation (derived from) | National Food Safety Standard Announcement 2015 No.6 | | Issuing agency(ies) | National Health and Family Planning Commission of the People's Republic of China | | Summary | This standard specifies the basic test methods and technical requirements for the chronic toxicity and carcinogenicity test. This standard applies to the evaluation of the chronic toxicity and carcinogenicity of the test substance. | GB 15193.17-2015: National food safety standard -- Chronic toxicity and carcinogenicity combination test
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(National food safety standards chronic toxicity and carcinogenicity tests merger)
National Standards of People's Republic of China
National Food Safety Standard
Combined chronic toxicity and carcinogenicity tests
Issued on.2015-08-07
2015-10-07 implementation
People's Republic of China
National Health and Family Planning Commission released
Foreword
This standard replaces GB 15193.17-2003 "chronic toxicity and carcinogenicity studies."
This standard compared with GB 15193.17-2003, the main changes are as follows.
--- Standard name was changed to "national food safety standards combined chronic toxicity and carcinogenicity tests";
--- Modify and adjust the overall style structure;
--- Modify the scope of the standard;
--- Increase the "minimum observed adverse effect level", "maximum tolerated dose" and "satellite group" of terms and definitions, modify the "Maximum
No observed adverse effect level "," chronic toxicity "," cancer "and" target organ "of terms and definitions;
--- Modified for experimental purposes and principles of representation;
--- Added "instruments and reagents" content;
--- Changed to "experimental animals" requirements, increase the "animal preparation" and "animal husbandry" content;
--- Modify the "dose group and" requirements;
--- Increasing the test substance by gavage, the incorporation of the specific requirements of a given feed or water;
--- Modified "test period" content;
--- Modify the test outcome measures (general observation, hematology, blood biochemistry, pathology) requirements, weight gain,
Food intake and water intake, eye examination, urinalysis and other indicators of content;
--- Deleted "data collection" content;
--- Modify the "data processing" content added "results of the evaluation" content;
--- Modifications and additions for the test reporting requirements;
--- Added "explained test" content.
National Food Safety Standard
Combined chronic toxicity and carcinogenicity tests
1 Scope
This standard specifies the basic technical requirements and test methods for chronic toxicity and carcinogenicity tests combined.
This standard applies to the evaluation of the test substance chronic toxicity and carcinogenic effects.
2 Terms and definitions
2.1 Chronic toxicity
Experimental animals after long-term toxic effects of repeated administration of the test substance caused.
2.2 carcinogenicity
Experimental animals after long-term repeated administration of the test substance caused tumors (benign and malignant) lesions.
2.3 No observed adverse effect level
Through animal experiments, the existing technical means and detection index was not observed any of the test substance-related toxic effects maximum dose.
2.4 Minimum observed adverse effect level
Under specified conditions, the test substance causing a minimal effect dose animal tissue morphology, function, growth and development, and other harmful effects.
2.5 target organ
Organ by the test substance caused significant toxic effects of experimental animals.
2.6 The maximum tolerated dose
From 90 days oral toxicity test to determine the dose, this dose should be less than 10% weight loss in the animals in the control group, and are not generated by
Non-tumor factors caused death and lead to shortened life or pathological signs of poisoning injuries.
2.7 Satellite Group
Toxicity of the design and implementation of the additional group of animals, animal handling and feeding conditions and its main research similar to the test medium or
Test convalescence observation and testing can also be used to observe and testing does not include other indicators and parameters in the main study.
3 test purposes and principles
OK during most of the life of experimental animals, orally administered repeated chronic toxicity and carcinogenic effects caused by the test substance, the test substance Learn
Chronic toxicity dose - response relationship between tumor incidence, the target organ, the nature of the tumor, the tumor occurrence time and the number of tumors per animal, determined slow
Toxicity was not observed adverse effect level (NOAEL) and the minimum observed adverse effect level (LOAEL), for predicting the human exposure
Chronic toxicity and carcinogenicity test substance and the final assessment of whether the test was to provide the basis for the food.
4 instruments and reagents
4.1 Instruments and equipment
Anatomy of commonly used laboratory equipment, animal scales, electronic scales, biological microscope, biochemical analyzer, hematology analyzer, blood coagulation analyzer
Instrument, urine analyzers, centrifuges, slicing machines.
4.2 Reagents
Formaldehyde, xylene, ethanol, hematoxylin-eosin, paraffin, blood dilution, chemical and biological reagents, analytical reagents coagulation, urinalysis reagent.
5 Test methods
5.1 test substance
The test substance should be used in the original sample, if it can not use the original sample, the test should be treated in accordance with the principles of the test substance for proper disposal. will
Test was incorporated into feed, drinking water or gavage administration.
5.2 Experimental Animals
5.2.1 animal selection
Experimental animals should be selected in line with national standards and regulations (GB 14923, GB 14922.1, GB 14922.2). Should be selected from tumor
Low fat animal species and strains of rats preferred, generally weeks 6 weeks to 8 weeks. Start of the test animals of each sex should not exceed the weight difference
± 20% over the average weight. At least 120 the number of animals in each group (including chronic toxicity tests 20, carcinogenicity test 100), male and female,
It should be non-parous female rats, non-pregnant rats. If you plan to test interim necropsy or chronic toxicity testing end of the observation made convalescence (for satellite), should be increased
Plus the number of animals (n = interim necropsy at least 20, male and female, chronic toxicity test period is usually 12 months, the data can be used as carcinogenic test
Interim necropsy data transcendent; satellite group is usually only increased in the control group and high-dose groups of at least 20, male and female). Animals of the control group
Do the test substance and the number should be the same group.
5.2.2 Animal Preparation
Before the test, animals in the experimental animal room should be at least 3d ~ 5d acclimatization and quarantine observation.
5.2.3 Animal Feeding
Animal feeding conditions, drinking water, feed should be in line with national standards and regulations (GB 14925, GB 5749, GB 14924.1,
GB 14924.2, GB 14924.3). During the test animals free access to water and food, according to the component group sex feeding cage, cage number of animals (per general
No more than three) shall meet the minimum space required for experimental animals in order not to affect the free movement of animals and the animals were observed for signs appropriate. Trial period
Between each non-animal test should be less than 10% of mortality, dying animal blood biochemical tests should be carried out as far as possible, as well as gross anatomy
Histopathological examination of biological specimens each loss rate should be less than 10%.
Dose group and 5.3
5.3.1 Test subjects were set up at least three groups, a negative (vehicle) control group, the control group except that no administration of the test substance, the rest were treated by the same
Trial was set. If necessary, additional untreated control group.
5.3.2 The high dose should choose the maximum tolerated dose, in principle, should make the animals appear more obvious toxicity, but does not cause excess mortality;
Low dose does not cause any toxic effects; the dose should be between high-dose and low-dose, can cause mild toxic effects. General dose
Group 2 spacing is appropriate to four times, no more than 10-fold.
5.4 test period
Any change of reversible toxicity chronic toxicity test 5.4.1 Test period of at least 12 months, the group monitored by satellite test substance caused sustained
Or delayed effects after the test was stopped to observe the period of not less than 28d, more than 1/3 of the test period. Carcinogenicity studies test period
24 months, longer lifetime and lower individual rates of spontaneous tumors of animals may be extended.
5.4.2 During the test, when the number of animals the lowest dose or control group survival was only 25% at the beginning of time (male and female animals were calculated),
May terminate the test. High dose group of animals was due to significant toxicity test with early death, not the trial was terminated.
5.5 Test procedure and outcome measures
5.5.1 The test is administered
5.5.1.1 according to the characteristics of the test substance and test purposes, select the test was incorporated into feed, water or orally administered. If the test was its driving
Was palatability, should be given orally.
5.5.1.2 test was orally administered to the test substance is dissolved or suspended in a suitable vehicle, the preferred solvent is water, water-insoluble test substance
You can use vegetable oils (such as olive oil, corn oil, etc.), do not dissolve in water or oil test substance may be used as carboxymethyl cellulose, starch, etc. dubbed suspension
Or paste like. The test substance should now use the existing, data show that except for its storage solution or suspension stabilizer. Taking into account the use of solvent
Media may test substance by the body absorption, distribution, metabolism and accumulation; on the test of physical and chemical properties and toxicity resulting therefrom
Impact characteristics; impact on animal food intake or water intake or nutritional status. To ensure that the test substance concentration in vivo stability, daily
Same period gavage once (weekly gavage 6d), during the test, the first four weeks weighed twice a week for 5 weeks to week 13 weighed weekly
1, then every 4 weeks weighed 1, weight-adjusted volume of gavage. Gavage volume generally not more than 10mL/kg body weight; as an oily liquid
Body, stomach volume should not exceed 4mL/kg body weight. Each group was given the volume of the same.
5.5.1.3 incorporated into feed or drinking water test substance administered to the test substance and feed (or water) and mixed well to ensure the stability of the test substance formulation
Qualitative and uniformity, without affecting the animal feeding, nutrition and water balance amount of principle. When a small amount of the test substance added to the feed, will be advised
After the test was added a small amount of feed mix well, then add a certain amount of feed mix, so repeated 3 times to 4 times. It was incorporated into the feed ratio test
EXAMPLE generally less than 5% by mass of, if more than 5% (maximum not more than 10%), to adjust the feed nutrient levels in the control group (if that is
When the test was no calories or nutrients, and the addition ratio of more than 5% in the control group diet should be filled methyl cellulose, incorporated in an amount equivalent to high dose
Volume), it was tested with each dose group feed nutrient levels remain the same, while additional untreated control group; the heat was also a visual test or operation
Develop sub-group dose adjustment of status feed nutrient levels, making it consistent with the control group diet nutrient levels. Test substance dosage unit
Per kilogram of body weight is ingested test substance mg (or g) number, namely mg/kg body weight (or g/kg body weight), the dose of test substance incorporated into a single feed
Bits can also be expressed as mg/kg (or g/kg) of feed, the incorporation of water is expressed as mg/mL of water. When the test was incorporated into the feed, the need to test substance
Dose (mg/kg body weight) by animal food intake per 100g of body weight of the test substance converted into feed concentration (mg/kg feed).
5.5.2 General observations
Observed at least daily during the test 1 5.5.2.1 General clinical manifestations of animals, and animals recorded signs of poisoning, the extent and duration
Room and death. Observation includes hair, skin, eyes, mucous membranes, secretions, excretions, respiratory system, nervous system, autonomic activity (eg.
Tears, vertical hair response, pupil size, unusual respiratory) and behavior (such as gait, posture, response to treatment, with or without tonic or clonic live
Moving, rigid reactions, abnormal behavior, etc.).
5.5.2.2 Special attention should tumorigenesis, tumor record time, location, size, shape, and so developments.
5.5.2.3 for the dying and dead animals should be dissected and recorded as accurately as possible the time of death.
5.5.3 body weight, food intake and water intake
During the 13 weeks before the test animals were recorded weekly body weight, food consumption or water intake (when the test substance when administered by drinking water), then every 4 weeks.
At the end of the test, calculated animal weight gain, total food intake, food efficiency (first 3 months), the total intake of the test substance.
5.5.4 eye examination
Before the test, the animals eye examination (cornea, conjunctiva, iris), the end of the test, the high-dose group and control group animals eye
Ministry inspection, if found that high-dose group were ocular changes, to deal with the other group of animals to be checked.
5.5.5 Hematology
5.5.5.1 Test 3 months, 6 months and 12 months, blood tests and, if necessary, test the end of the first 18 months and time trials
Also available for groups of at least check each of 10 male and female animals, each inspection should be possible to use the same animal. If 90 days oral toxicity test
Dose levels not seen any considerable and hematological changes, the test may not be the first three-month inspection.
5.5.5.2 Check the indicators, including white blood cell count and classification (at least three categories), red blood cell count, platelet count, hemoglobin concentration, red blood
Cell hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC),
Prothrombin time (PT), activated partial thromboplastin time (APTT) and the like. If the impact on the hematopoietic system, should be added to the measured reticulocyte
Count and bone marrow smear cytology.
5.5.6 blood biochemical examination
5.5.6.1 5.5.5.1 by time and the number of animals will be specified. If 90 days after oral toxicity test dosage levels considerably and did not show any blood
Biochemical indicators of change, the test may not be the first three-month inspection. Blood should be before the animals were fasted overnight.
5.5.6.2 Check indicators include electrolyte balance, carbohydrate, fat and protein metabolism, liver (cells, bile duct) and other aspects of renal function. Comprising at least alanine
Aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), glutamyl peptidase (GGT), urea
(Urea), creatinine (Cr), blood glucose (Glu), total protein (TP), albumin (Alb), total cholesterol (TC), triglyceride (TG), calcium, chlorine, potassium,
Sodium, total bilirubin, etc., can be detected phosphorus, uric acid (UA), if necessary, total bile acid (TBA), globulin, cholinesterase, sorbitol dehydrogenase, high-speed rail
Hemoglobin, specific hormones and other indicators.
5.5.7 Urine
5.5.7.1 Test 3 months, 6 months and 12 months urine tests, if necessary, test at the end of 18 months, and also test
Can be carried out, at least check each of the 10 male and female animals. If the dose level of 90 days after oral toxicity tests did not show any considerable and urine seizure
Check abnormal results, the test may not be the first three-month inspection.
5.5.7.2 inspection items including appearance, urine protein, relative density, pH, glucose and occult blood, etc., if the expected toxic reaction indications, should be increased in urine
Fluid examination about the project, such as urinary sediment microscopy, cell analysis.
5.5.8 pathology
5.5.8.1 Gross anatomy
All test animals, including death or dying during the test and sacrificed animals were sacrificed and the expiration of the test animals were dissected and should
Visually comprehensive system, including surface, cranial, thoracic and abdominal cavity and its organs, and weighing the brain, heart, liver, kidney, spleen, uterus, ovary, testis
Absolute weight pills, epididymis, thymus, adrenal glands, and calculate the relative weight of the [Dirty/body ratio and (or) Dirty/brain ratio], if necessary, should choose another
Organs, such as thyroid (including parathyroid), prostate.
5.5.8.2 Histopathological examination
Principles 5.5.8.2.1 histopathological examination (focus on examination tumors and precancerous lesions).
a) prior to high-dose group and the control group were all preserved organs and tissues fixed for histopathological examination;
b) found that high-dose group after lesions of the lower dose group corresponding organ and tissue for histopathological examination;
c) to check the gross anatomy visible diseased organs and tissue for histopathological examination;
d) death or dying during the test and sacrificed animals to deal with all the tissues and organs preserved for histopathological examination;
e) a pair of organs such as kidney, adrenal gland, etc., should be carried out on both sides of organ histopathology.
5.5.8.2.2 saved should be fixed for histopathological examination of organs and tissues including the salivary glands, esophagus, stomach, duodenum, jejunum, ileum,
Cecum, colon, rectum, liver, pancreas, brain (including brain, cerebellum and brain stem), pituitary gland, sciatic nerve, spinal cord (cervical, thoracic and lumbar), adrenal gland,
Parathyroid, thyroid, thymus, trachea, lung, aorta, heart, bone marrow, lymph nodes, spleen, kidney, bladder, prostate, testis, epididymis, child
Palace, ovarian, breast and so on. Necessary, to add measured seminal vesicles and coagulating gland, lacrimal glands, Ringer gland, turbinate, cervix, fallopian tubes, vagina, bone, muscle
Meat, skin and eyes and other tissues and organs. Histopathological examination should be reported histopathological lesions given photo.
5.5.9 Other indicators
If necessary, depending on the nature of the test substance and toxicity observed, add other indicators (such as neurotoxicity, immunotoxicity, endocrine toxicity
Indicators).
6 Data processing and evaluation of results
6.1 Data Processing
6.1.1 store all data and results are summarized in tabular form, listing the number of animals in each group before the start of the test, the animals die during the test
Number of death and time of death, the number of animals tumors and other toxic reactions, tumor location description, quantity, nature, precancerous lesions and tumors
The incubation period described see other toxicities, including the time of occurrence of toxic effects, duration and extent.
6.1.2 tumor incidence is the number of animals suffering from cancer in the effective percentage of the total number of animals at the end of the entire trial. Total number of valid animal
Refers to the total number of cancer survivors found the earliest animals.
Tumor incidence calculation see formula (1).
Tumor incidence =
Number of animals suffering from cancer at the end of the test
Total animals × 100% effective
(1)
6.1.3 Tumor incubation period from ingestion of the test substance found in the tumor play time. Because visceral tumor imperceptible, usually caused by the tumor
Time of death of the animal as tumors of the time.
6.1.4 animal body weight, food intake, water intake (the test was administered via drinking water), food utilization, hematological, blood biochemistry, urine
Check the index, organ weight, dirty/body ratio and (or) Dirty/brain ratio, gross and histopathological examination, the number of animals suffering from tumors, each animal
Tumor number, the number of various tumors (benign and malignant), the tumor incidence and tumor latency and other results were statistically analyzed. General situation
Conditions, measurement data using analysis of variance test was performed between each dose group and control group were compared, classified data using Fisher exact points
Cloth test, chi-square test, rank sum test, ranked data using Ridit analysis, rank sum test and so on.
6.2 Evaluation Results
6.2.1 Chronic toxicity test results of the evaluation shall include the performance of the test substance chronic toxicity, the dose - response relationship, the target organ, reversibility, slow draw
Corresponding NOAEL toxicity and (or) LOAEL.
6.2.2 carcinogenicity studies provided negative results when rats are established in a trial period of 18 months, the survival rate of animals in each group is not less than 50%; Rats
During the test period of 24 months, the survival rate of animals in each group not less than 25%.
Analyzing 6.2.3 carcinogenicity studies positive results using the standard World Health Organization (WHO) raised [WHO (1969), Principlesfor
thetestingandevaluationofdrugforcarcinogenicity.WHOTechnicalReportSeries426], any of the following
It one, the test substance can be determined for the rat carcinogens.
a) tumor occurs only in experimental animals, the control group no tumor;
b) the test group and control group animals were tumors, but the experimental group was higher;
c) multiple tumors in experimental animals significantly, no multiple tumors in the control group, only a small number of animals or multiple tumors;
d) test and control groups of animals tumor incidence was not significantly different, but the experimental group occurred earlier time.
7 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, weeks of age, gender, origin (supplier name, animal production license number),
Animal quarantine, adaptation, breeding environment (temperature, relative humidity, using experimental animal facility license number), feed sources (supplier name,
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. The animal growth activity, toxicity characteristics (including the presence of time and outcome), weight gain, food intake, water intake
(The test was administered via drinking water), food utilization, clinical observation (signs of toxicity, extent, duration, survival), eye examination, blood
Fluid examination, blood biochemical examination, urinalysis, gross anatomy, organ weight, dirty/body ratio and (or) dirty/brain ratio, histopathological examination,
Tumor location, number of tumors, nature of tumors, precancerous lesions, tumor incidence, tumor latency, neurotoxicity or immunotoxicity check junction
fruit. As the test was incorporated into feed or by incorporation of water give, the reports of the actual dose administered dose.
7.9 Test Conclusions. Long-term oral toxicity test substances and carcinogenic effects, the dose - response relationship, the target organ and reversibility determine chronic toxicity
NOAEL and (or) LOAEL conclusions drawn carcinogenic conclusions.
Explanation 8 trial
Due to the presence of human and animal species differences, results extrapolated to humans or used for risk assessment has some limitations. Chronic toxicity
NOAEL and LOAEL can provide valuable information to determine the health-based guidance values crowd.
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