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Table 3.7.1(a)
Hazard categories for reproductive toxicants
Categories |
Criteria |
CATEGORY 1 |
Known or presumed human reproductive toxicant Substances are classified in Category 1 for reproductive toxicity when they are known to have produced an adverse effect on sexual function and fertility, or on development in humans or when there is evidence from animal studies, possibly supplemented with other information, to provide a strong presumption that the substance has the capacity to interfere with reproduction in humans. The classification of a substance is further distinguished on the basis of whether the evidence for classification is primarily from human data (Category 1A) or from animal data (Category 1B). |
Category 1A |
Known human reproductive toxicant The classification of a substance in Category 1A is largely based on evidence from humans. |
Category 1B |
Presumed human reproductive toxicant The classification of a substance in Category 1B is largely based on data from animal studies. Such data shall provide clear evidence of an adverse effect on sexual function and fertility or on development in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of other toxic effects. However, when there is mechanistic information that raises doubt about the relevance of the effect for humans, classification in Category 2 may be more appropriate. |
CATEGORY 2 |
Suspected human reproductive toxicant Substances are classified in Category 2 for reproductive toxicity when there is some evidence from humans or experimental animals, possibly supplemented with other information, of an adverse effect on sexual function and fertility, or on development, and where the evidence is not sufficiently convincing to place the substance in Category 1. If deficiencies in the study make the quality of evidence less convincing, Category 2 could be the more appropriate classification. Such effects shall have been observed in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of the other toxic effects. |
Table 3.7.1(b)
Hazard category for lactation effects
EFFECTS ON OR VIA LACTATION |
Effects on or via lactation are allocated to a separate single category. It is recognised that for many substances there is no information on the potential to cause adverse effects on the offspring via lactation. However, substances which are absorbed by women and have been shown to interfere with lactation, or which may be present (including metabolites) in breast milk in amounts sufficient to cause concern for the health of a breastfed child, shall be classified and labelled to indicate this property hazardous to breastfed babies. This classification can be assigned on the: (a) human evidence indicating a hazard to babies during the lactation period; and/or (b) results of one or two generation studies in animals which provide clear evidence of adverse effect in the offspring due to transfer in the milk or adverse effect on the quality of the milk; and/or (c) absorption, metabolism, distribution and excretion studies that indicate the likelihood that the substance is present in potentially toxic levels in breast milk. |
The classification of a substance is derived from the hazard categories in the following order of precedence: Category 1A, Category 1B, Category 2 and the additional Category for effects on or via lactation. If a substance meets the criteria for classification into both of the main categories (for example Category 1B for effects on sexual function and fertility and also Category 2 for development) then both hazard differentiations shall be communicated by the respective hazard statements. Classification in the additional category for effects on or via lactation will be considered irrespective of a classification into Category 1A, Category 1B or Category 2.
Maternal mortality:
an increased incidence of mortality among the treated dams over the controls shall be considered evidence of maternal toxicity if the increase occurs in a dose-related manner and can be attributed to the systemic toxicity of the test material. Maternal mortality greater than 10 % is considered excessive and the data for that dose level shall not normally be considered for further evaluation.
Mating index
(no. animals with seminal plugs or sperm/no. mated × 100) ( 13 )
Fertility index
(no. animals with implants/no. of matings × 100)
Gestation length
(if allowed to deliver)
Body weight and body weight change:
Consideration of the maternal body weight change and/or adjusted (corrected) maternal body weight shall be included in the evaluation of maternal toxicity whenever such data are available. The calculation of an adjusted (corrected) mean maternal body weight change, which is the difference between the initial and terminal body weight minus the gravid uterine weight (or alternatively, the sum of the weights of the foetuses), may indicate whether the effect is maternal or intrauterine. In rabbits, the body weight gain may not be useful indicators of maternal toxicity because of normal fluctuations in body weight during pregnancy.
Food and water consumption (if relevant):
The observation of a significant decrease in the average food or water consumption in treated dams compared to the control group is useful in evaluating maternal toxicity, particularly when the test material is administered in the diet or drinking water. Changes in food or water consumption need to be evaluated in conjunction with maternal body weights when determining if the effects noted are reflective of maternal toxicity or more simply, unpalatability of the test material in feed or water.
Clinical evaluations (including clinical signs, markers, haematology and clinical chemistry studies):
The observation of increased incidence of significant clinical signs of toxicity in treated dams relative to the control group is useful in evaluating maternal toxicity. If this is to be used as the basis for the assessment of maternal toxicity, the types, incidence, degree and duration of clinical signs shall be reported in the study. Clinical signs of maternal intoxication include: coma, prostration, hyperactivity, loss of righting reflex, ataxia, or laboured breathing.
Post-mortem data:
Increased incidence and/or severity of post-mortem findings may be indicative of maternal toxicity. This can include gross or microscopic pathological findings or organ weight data, including absolute organ weight, organ-to-body weight ratio, or organ-to-brain weight ratio. When supported by findings of adverse histopathological effects in the affected organ(s), the observation of a significant change in the average weight of suspected target organ(s) of treated dams, compared to those in the control group, may be considered evidence of maternal toxicity.