GB/T 15670.3-2017 PDF English
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Toxicological test methods for pesticides registration - Part 3: Acute oral toxicity test - Up-and-down-procedure
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GB/T 15670.3-2017: Toxicological test methods for pesticides registration - Part 3: Acute oral toxicity test - Up-and-down-procedure
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GB
NATIONAL STANDARD OF THE
PEOPLE'S REPUBLIC OF CHINA
ICS 65.100
B 17
Toxicological test methods for pesticides registration - Part
3.Acute oral toxicity test - Up-and-down-procedure
Issued on: JULY 12, 2017
Implemented on: FEBRUARY 1, 2018
Issued by. General Administration of Quality Supervision, Inspection and
Quarantine of PRC;
Standardization Administration of PRC.
Table of Contents
Foreword... 3
1 Scope... 5
2 Normative references... 5
3 Terms and definitions... 5
4 Purpose of the test... 6
5 Experimental overview... 6
6 Test methods... 6
7 Test results and evaluation... 10
8 Test report... 11
Appendix A (Normative) Table of dose levels (mg/kg body weight) with a starting dose
of 175 mg/kg body weight and a slope of 1~8... 12
Appendix B (Normative) Calculation of LD50 in formal tests... 13
Toxicological test methods for pesticides registration - Part
3.Acute oral toxicity test - Up-and-down-procedure
1 Scope
This part of GB/T 15670 specifies the basic principles, methods and requirements for
the up-and-down-procedure of acute oral toxicity testing.
This part applies to acute oral toxicity tests conducted for pesticide registration.
2 Normative references
The following documents are essential for the application of this document. For any
dated referenced document, only the dated version applies to this document. For any
undated referenced document, the latest version (including all amendments) applies to
this document.
GB 14925 Laboratory animal - Environment and housing facilities
Regulations on Pesticide Registration Information (Order No. 10 of the Ministry
of Agriculture of the People's Republic of China [2007])
3 Terms and definitions
The following terms and definitions apply to this document.
3.1 acute oral toxicity
The health-damaging effects that occur in animals in the short term after the test
substance is orally administered to experimental animals once or multiple times within
24 hours.
3.2 dose
The amount of the test substance administered, which is expressed as the mass of the
test substance received per unit body weight of the experimental animal (mg/kg body
weight).
3.3 median lethal dose
LD50
The statistical dose of a toxicant that causes half of the total number of animals to die
after the test substance is given to the experimental animals once or multiple times
within 24 hours. It is expressed as the mass of the test substance received by the
experimental animals per unit body weight (mg/kg body weight).
3.4 dose-response relationship
The relationship between the dose and the incidence of a specific effect.
4 Purpose of the test
Acute oral toxicity test is the first step to evaluate the toxicity of the test substance.
Through short-term administration of toxicant by oral, the toxicity characteristics and
dose-response relationship of the test substance are preliminarily understood, which
provides a basis for acute toxicity classification, label management and other
toxicology test dose selection.
5 Experimental overview
The up-and-down procedure (UDP) is a step-by-step administration procedure. Animals
of the same sex are tested, and one animal is administered at a time. The first animal is
administered a dose that is preferably lower than the estimated LD50.The increase or
decrease in the subsequent dose of administration depends on the administration result
(survival or death) of the previous animal. When the preliminary estimate of the LD50
of the test substance and the slope of the dose-response curve are not available, the
computer simulation result suggests that the starting dose can be 175 mg/kg body
weight, and the dose interval is calculated using the antilogarithm of 0.5 (corresponding
to a default dose progression factor of 3.2). The point estimate value and 95%
confidence interval of LD50 are calculated by the maximum likelihood method.
NOTE. The dose progression factor is determined by the antilogarithm of the reciprocal of the slope of
the dose-response curve (3.2 is the progression factor for a slope of 2).
The number of animals used in the formal test is about 6~9.The number of animals
used in the limit test is no more than 5.This method is only applicable to test substances
that cause death within 1~2 days after administration, and is not applicable to test
substances that are expected to cause death to happen more than 5 days (including 5
days) after administration.
6 Test methods
6.1 Test substances
6.4.1.2 If 3 of the 5 administered animals die within 48 hours or their death is within
the 14-day observation period, the administration is terminated and the formal test
begins.
6.4.2 Formal test
6.4.2.1 Before the experiment, the rats were fasted overnight but had unlimited access
to water.
6.4.2.2 Selection of starting dose and dose progression factor. When an estimate of the
lethal dose of the test substance is not available, the default starting dose is 175 mg/kg
body weight. The dose sequence set corresponding to the progression factor 3.2 of a
dose-response slope of 2 is 1.75 mg/kg body weight, 5.5 mg/kg body weight, 17.5
mg/kg body weight, 55 mg/kg body weight, 175 mg/kg body weight, 555 mg/kg body
weight and 2000 mg/kg body weight; or 1.75 mg/kg body weight, 5.5 mg/kg body
weight, 17.5 mg/kg body weight, 55 mg/kg body weight, 175 mg/kg body weight, 555
mg/kg body weight, 1750 mg/kg body weight and 5000 mg/kg body weight. If the slope
of the dose-response curve of the test substance is known to be relatively steep or
relatively flat, the dose progression factor can be reduced or increased. Appendix A lists
the dose levels available with a starting dose of 175 mg/kg body weight and a slope of
1~8.
6.4.2.3 At the beginning of the test, weigh the fasted animals and administer the test
substance orally using a gavage needle, one animal at a time, with an interval of 48
hours between each animal. The administration dose for the second animal depends on
the result of the first animal's administration. If the animal dies or is in a dying state,
the dose is adjusted down by one level according to the progression factor; if the animal
survives, the dose is adjusted up by one level. When the subsequent doses show the
opposite result to the starting dose, add 4 more animals to be administered the test
substance sequentially and then terminate the test, or when any of the termination
requirements (see 6.4.2.6) are reached, the test can be terminated. After administration,
the rats shall continue to fast for 3 h~4 h. The observation period for each animal is 14
d.
6.4.2.4 If animals survive within 48 hours after administration but die later in the
subsequent observation period, it indicates that the dose selection is inappropriate and
consideration may be given to giving 2 more animals a dose lower than the dose that
causes death, restarting the test and extending the observation period.
6.4.2.5 The test results are used to calculate the LD50 and 95% confidence interval of
the test substance using the maximum likelihood method (see Appendix B).
6.4.2.6 The test can be terminated if any of the following conditions are met.
a) When three animals survive the sequential administration at the upper dose
range;
b) When 5 opposite results occur among 6 animals randomly selected and
sequentially administered;
c) At least 4 animals are sequentially administered after the first adverse result
and the likelihood ratio for each dose calculated starting from the first adverse
result exceeds the critical value.
If the LD50 and slope vary widely, the study can be terminated after 4~6 animals are
administered sequentially after the opposite result has appeared. In some cases, the
slope of the dose-response curve of the test substance is flat, and it may be necessary to
add 15 animals.
6.5 Test observation and inspection
6.5.1 Clinical observation
During the 24 hours after administration (especially within 30 minutes and the first 4
hours after administration) and the 14-day observation period, observe and record the
poisoning reactions of each animal regularly every day. Clinical observations shall at
least include.
a) Central nervous system and neuromuscular system. abnormal posture,
abnormal voice, restlessness, dullness, tremor, convulsion, paralysis,
movement disorder, hypersensitivity or slowness in external response,
abnormal behavior such as excessive and repeated scratching around the
mouth, combing, circling, even self-mutilation, walking backward, etc.;
b) Autonomic nervous system. pupil dilation or constriction, salivation and
tearing;
c) Respiratory system. nasal discharge, epistaxis, flaring of the nostrils, deep and
slow breathing, tachypnea, wasp waist;
d) Urogenital system. dirty perineum, discharge, vaginal or breast swelling;
e) Skin and coat. skin congestion, cyanosis; fluffy or wet coat, dirty;
f) Eyes. proptosis, conjunctival congestion, hemorrhagic discharge, corneal
opacity;
g) Digestive system. diarrhea, anorexia.
The time and severity of tremors, convulsions, salivation, diarrhea, lethargy and coma,
the death time or the recovery time shall be recorded. Animals on the verge of death or
severe pain, as well as animals that survive the end of the experiment, shall be humanely
8 Test report
The test report shall at least include the following contents.
a) Test name, test unit name and contact information, and report number;
b) Test entrusting unit and contact information, sample acceptance date and
sample sealing status;
c) The start and end dates of the test, the person in charge of the test project, the
technical person in charge of the test unit, and the date of issuance;
d) Test summary;
e) Name of the test substance, Chemical Abstracts Service Number (CAS
Number) of the active ingredient (if known), code (if any), purity (or content),
dosage form, production date (batch number), physical and chemical
properties, solvents used for preparation and method;
f) The species, strain, grade, number, weight, sex, source (supplier name,
laboratory animal quality certificate number, laboratory animal production
license number), quarantine and adaptation of the experimental animals, the
feeding environment of the experimental animals, including temperature,
relative humidity, feed, single cage or group feeding, and the license number
of the experimental animal facility;
g) Dose and group. including the principle or basis for selecting the dose, the
method of animal grouping, sex and number of animals;
h) Test conditions and methods. including main instruments and equipment,
routes of administration, administration scheme, test period, observation
indicators and method for calculating LD50, etc.;
i) Test results. summarize item by item in the form of text description and table,
including clinical manifestations of poisoning, onset, duration and recovery
time of poisoning manifestations, time of death after administration, weight
changes, correlation with dose, and gross anatomical and histopathological
changes, etc., and indicate the statistical processing method of the results;
j) Test conclusion. give clear conclusions, such as LD50, 95% confidence interval
and toxicity classification, and discuss relevant issues when necessary;
k) Description of the original record preservation status.
termination regulations or terminate the test at a higher dose, so that the LD50
of the test substance is reported to exceed the upper limit and the hazard
classification is made;
b) The dose that causes animal death is higher than the dose that causes animal
survival, and the LD50 is somewhere in between. This test will not give an
accurate LD50 value (if the σ value is provided, the maximum likelihood ratio
LD50 estimate can also be calculated);
c) If the death and survival of the administered animals only occur at the same
dose, all the animals die at a dose higher than this dose, and all the animals
survive at a dose lower than this dose, then the LD50 is equivalent to this dose.
B.1.4 Except for the above cases, the acute oral toxicity test application software
package (AOT425StatPgm) can be used to perform the maximum likelihood function
calculation. SAS (i.e. PROC NLIN), BMDP (i.e. program AR) or other computer
program packages can also be used to complete the maximum likelihood function
calculation. In the BASIC program, σ needs to be programmed as a parameter, and the
output result is the estimated value of the logarithm (LD50) and its standard error.
B.2 Confidence Interval (CI) calculation
B.2.1 Only after the LD50 estimate of the formal test is obtained by using the
AOT425StatPgm software package can the confidence interval be calculated and
meaningful information be provided for the reliability and effectiveness of the formal
test. A wide range of the LD50 confidence interval indicates that there is a lot of
uncertainty in the reliability and effectiveness of the estimated LD50; when the
confidence interval is narrow, the uncertainty of the LD50 is negligible, and the
reliability and effectiveness are relatively high. When the formal test is repeated, the
LD50 estimate obtained is closer to the original estimate, and both are closer to the true
LD50 value.
B.2.2 Two methods for estimating the interval estimate of the true LD50.
a) At least three different doses of toxicity tests are carried out, and at least one
animal survived and one animal died at the intermediate dose. The true LD50
and 95% confidence interval can be calculated using the maximum likelihood
method. Due to the reduction in the number of experimental animals used, the
confidence interval value is not very accurate. The provisions of random
termination of the test have improved this to a certain extent, but there are still
some differences from the true confidence interval.
b) If all animals administered with a certain dose or a dose one level lower
survive, and all animals administered with the next higher dose die, the
confidence interval is between the two. It shall be considered an approximate
......
Source: Above contents are excerpted from the full-copy PDF -- translated/reviewed by: www.ChineseStandard.net / Wayne Zheng et al.
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