User Guide to Thresholds and Classification - Environmental ...

241User Guide for Thresholds and ClassificationsClassification should not be automatically discounted for chemicals that produce developmental toxicity onlyin association with maternal toxicity, even if a specific maternally mediated mechanism has beendemonstrated. In such a case, a 6.8B classification may be considered more appropriate than a 6.8Aclassification. However, when a chemical is so toxic that maternal death or severe inanition results, or thedams in animal studies are prostrate and incapable of nursing, it may be reasonable to assume thatdevelopmental toxicity is produced solely as a secondary consequence of maternal toxicity and discount thedevelopmental effects. Classification may not necessarily be the outcome in the case of minordevelopmental changes, for example, a small reduction in foetal or pup bodyweight, or the retardation ofossification when seen in association with maternal toxicity.Some of the endpoints used to assess maternal toxicity are listed below. Data on these endpoints, ifavailable, needs to be evaluated in light of their statistical or biological significance and dose–responserelationship.Maternal mortalityAn increased incidence of mortality among treated dams over the controls should be consideredevidence of maternal toxicity, if the increase occurs in a dose-related manner and can be attributed tothe systemic toxicity of the test material. Maternal mortality greater than 10% is considered excessiveand the data for that dose level should not normally be considered for further evaluation.Mating index(number of animals with seminal plugs or sperm ÷ number of animals mated) × 100 5Fertility index(number of animals with implants ÷ number of matings) × 100 6Gestation length (if allowed to deliver)Bodyweight and bodyweight changeConsideration of the maternal bodyweight change and/or adjusted (corrected) maternal bodyweightshould be included in the evaluation of maternal toxicity whenever such data are available. Thecalculation of an adjusted (corrected) mean maternal bodyweight change, which is the differencebetween the initial and terminal bodyweight minus the gravid uterine weight (or the sum of the weights ofthe foetuses) may indicate whether the effect is maternal or intrauterine. In rabbits, the bodyweight gainmay not be a useful indicator of maternal toxicity, because of normal fluctuations in bodyweight duringpregnancy.Food and water consumption (if relevant)The observation of a significant decrease in the average food or water consumption in treated damscompared with the control group may be useful in evaluating maternal toxicity, particularly when the testmaterial is administered in the diet or drinking water. Changes in food or water consumption should be5 These indices can also be affected by the male.6 These indices can also be affected by the male.January 2012 EPA0109