GB 30000.24-2013Rules for classification and labelling of chemicals - Part 24: Reproductive toxicity (English PDF)

4.2.2 The basis of classification

4.2.2.1 classification should be based on the standards and the overall weight of evidence assessment. Having a detrimental effect on the internal reproductive The specific nature of the chemicals should be classified as reproductive toxicants, however, if such effect is non-specific consequence of other toxic effects produced , The chemicals should not be classified as such.

4.2.2.2 In the evaluation of toxic effects on the developing offspring, should be adopted that may affect maternal toxicity.

4.2.2.3 If human evidence Category 1A classification as the main basis, should be reliable evidence of the harmful substances on reproduction in humans influences. Evidence used for classification should be from well conducted epidemiological studies which include the use of appropriate controls, balanced assessment, and appropriate When combined with bias or confounding factors. If the data from human studies is not very accurate, you should use the proper data from animal studies as a supplement, and should Classified as category 1B.

4.2.3 The weight of evidence

4.2.3.1 classified as reproductive toxicants to the overall weight of evidence assessment. This means that the need to determine the combined reproductive toxicity All existing information about the impact. This information includes human studies, human case reports and studies of specific reproductive epidemiology, as well as animals Asia Chronic, chronic and specificity of the findings, these results should provide information related to reproductive and endocrine organ toxicity. and also May include assessing the relevance of chemical substances on the substance of the research, particularly in the information on the substance is scarce time. Available evidence Weights can be affected by various factors, such as the nature and severity of the quality of the studies, consistency of results, the effect of differences between groups is statistically significant Level, the number of affected endpoints, routes of exposure associated with human bias and freedom. Positive and negative results should be combined to Assess the strength of the evidence. However a single study, conducted according to scientific principles and is statistically significant or biologically significant positive results Analyzing classification can be used (see 4.2.2.3).

4.2.3.2 animal and human toxicokinetics research findings site of action and mechanism or mode of action may provide relevant information, This information can be reduced or increased attention to human health hazards. If it can really prove and clearly identify the mechanism or mode Nothing to do with humans, or there are very significant differences in toxicokinetics, that may determine this risk will not effect on humans, then the experimental animals Matter produces reproductive harmful effects should not be classified.

4.2.3.3 In some reproductive toxicity studies in experimental animals, observed only small or very small effect on the toxicological significance, and therefore may not necessarily As a basis for classification. For example, small changes in semen parameters or fetal malformation spontaneous ossification retardation, fetal weight or postnatal development of micro Small differences.

4.2.3.4 Data from animal studies should preferably be able to provide clear evidence that the system in the absence of other toxic effects of the situation, there are specific Reproductive toxicity. However, if the offspring developmental toxicity and other harmful effects associated with maternal appear together, as far as possible these should be combined with the universalization have The potential impact of harmful effects assessed. The preferable method is to first combine the deleterious effects on the embryo/fetus, and then evaluate maternal toxicity , As well as other factors that may affect them as a part of the weight of evidence. In general, affect the development of maternal toxicity was observed from the dose does not It shall be automatically deducted. Only causal relationship is determined or negative, can not bind at maternally toxic doses observed in a case by case basis Developmental effects.

4.2.3.5 If you acquire the appropriate information, it is necessary to determine whether developmental toxicity is due to a specific parent indirect mechanism or to a non-specific relay Onset mechanism caused, for example, maternal stress and the disruption of homeostasis. In general, the presence of maternal toxicity should not be used to deny the discovery of embryonic / Fetus, unless it can be clearly demonstrated that this effect is minor and non-specific, particularly harmful effect in the offspring is obvious, for example, Irreversible effects malformations like. In some cases, reason to believe that reproductive toxicity is due to a secondary consequence of maternal toxicity and reduce The impact of, for example, if the highly toxic chemical may cause the mother can not reproduce, the offspring can not breast-feeding or severe weakness or dying parent.

4.2.4 Maternal toxicity

4.2.4.1 offspring may be affected by maternal toxicity effects throughout pregnancy and birth in the early stages of development, either through tight And maternal homeostasis destroy non-specific mechanisms, or by specific maternally indirect mechanism. Therefore, the analysis of the developmental outcome to Determine classification for developmental effects it is necessary to fully integrate maternal toxicity may affect. This is a complex issue, because maternal toxicity and There is uncertainty among offspring developmental outcome. When analyzing the standard classification for developmental effects, should make use of all existing studies, the use of expert Judgment and weight of evidence to determine the extent caused by the influence of maternal toxicity. We should first binding harmful effects on the embryo/fetus terms, then Maternal toxicity, as well as any other factors that may affect these results, use them as weight of evidence, to help a conclusion about classification.

4.2.4.2 based on actual observations, convinced maternal toxicity depends on its severity, may affect the development via non-specific secondary mechanisms, producing Health and various effects, such as decreased fetal weight, delayed ossification, and suck back some of the effects of certain malformations in some species of the family may occur. however, A limited number, the relationship between developmental effects and maternal toxicity usual research, between species could not confirm the existence of a consistent reproducible energy relationship. Even developmental effects occurring in the presence of maternal toxicity, and is also considered to be evidence of developmental toxicity, unless the by-case analysis Clearly demonstrated that the developmental effects are secondary to maternal toxicity effects. In addition, the classification should be combined with significant toxic effects on the offspring of, for example, Structural malformations, embryo/fetal deaths, birth defects and other significant features of irreversible effects.

4.2.4.3 produced only with respect to maternal toxicity and developmental toxicity of chemicals, even if a parent has proved to be specific indirect mechanisms, nor should Automatic classification does not consider. In this case, the classification to category 2 to category 1 is more appropriate. However, when a chemical is toxic as well as very large In maternal death or severe weakness, or breast-feeding mother has been unable to weak offspring, the offspring developmental toxicity can be reasonably certain that only the parent drug Of secondary results without binding offspring developmental toxicity. If minor developmental changes (such as a slight decrease in fetal/Aberdeen weight, ossification Delay) with maternal toxicity appear together, it may not necessarily be classified.

4.2.4.4 Evaluation of some maternal toxicity endpoints as follows: Data on these end points, if available, the need for statistical data Or biological significance and dose response relationship shall be assessed.

--- Maternal mortality. maternal mortality and if the test substance dose-related and can be attributed to the systemic toxicity of the test substance, It should be tested maternal mortality rate higher than the control group viewed as evidence of maternal toxicity. Maternal mortality greater than 10% is considered To be very large, and this dose level data is not necessary for further evaluation.

--- Mating index (visible sperm or vaginal plugs animals number/total number of animals used for mating × 100).

--- Fertility index (number of animals have fertilized egg implantation/total number of animals mated × 100).

--- Time to pregnancy (if childbirth).

--- Body weight and body weight change. if the maternal weight data maternal body weight change and/or corrected available, as should be combined with its mother Evaluating the evidence of toxicity. Maternal body weight change corrected mean calculated that the initial and final weight minus the pregnant uterus quality Amount (or the total mass of the fetus), indicating that the change is possible within the uterus or the mother. In rabbit trials, weight gain can be Not used as indicators of maternal toxicity, this is because the rabbit weight normally fluctuate during pregnancy.

--- Food and water consumption (if relevant). test parent observed compared with the control group, the average consumption of food or water significantly reduced, Assessment of maternal toxicity may be useful, especially when the test substance is added to food or drinking water when. Food or water consumption Changes should be combined and used to assess the maternal body weight up, should pay attention to whether the influence of maternal toxicity, or simply because the food or Water test substance affect appetite.

--- Clinical assessment (including clinical signs, markers, hematology and clinical chemistry disease). measured by the parent with respect to the control group, Ming The significant increase in the incidence of clinical signs of toxicity may be useful for the assessment of maternal toxicity. If this information is used to assess maternal toxicity Based on the type should be reported in the study of clinical symptoms, incidence, degree and duration. The obvious clinical signs of maternal intoxication Conditions include. coma, exhaustion, hyperactivity, loss of righting reflex, ataxia, or difficulty breathing. Data

--- check body. increased incidence and/or severity of the autopsy results may be indicative of maternal toxicity. This may include Pathological findings or organ quality data as a whole or microscopic, such as organ absolute quality, and quality of organs or organ weight ratio Quality and the ratio of brain mass. When receiving organs affected deleterious histopathological findings support the observed test parent Suspicious target organs compared with the control group had an average quality significantly changed, it can be seen as evidence of maternal toxicity. NOTE. Mating index and the Fertility index may be affected by the impact of male

4.2.5 Animal and experimental data

4.2.5.1 can be a series of test methods, including. developmental toxicity test methods, prenatal and postnatal toxicity tests and toxicity generation or second-generation experiment method.

4.2.5.2 screening test results are also used as the basis of the classification, although recognized that the reliability of the evidence is not as comprehensive study res...