A Practical Approach, Second Edition=Ronald D. Ho.pdf

PERSPECTIVES ON THE DEVELOPMENTAL AND REPRODUCTIVE TOXICITY GUIDELINES 747Table 19.5Comparison of current guidelines for the assessment of fertility and early embryonicdevelopmentGuideline ICH 4.1.3 a EPA OPPTS b FDA Red Book c OECD dSpecies (No.)MatingRoute of testcompoundadministrationExposure to testcompoundProcedures ontest animalsAt least one species, preferablyrats (16 to 20 litters)1:1 advisable; mating period of2–3 weeks or until observationof plugSimilar to the route used byhumansPremating treatment interval of 2weeks for females and 2, 4, or10 weeks for males; treatmentshould continue throughoutmating to termination of malesand at least through implantationfor femalesSacrifice females aftermidgestation and males anytime after matingDams: clinical signs; body weight;feed; gross necropsy; vaginalsmears; preserve ovaries, uteriand organs with macroscopicfindings; count corpora lutea andimplantation sites (live and deadconceptuses)Males: gross necropsy; preservetestes, epididymides, andorgans with macroscopicfindings; assess sperm countand viability— — —— — —— — —— — —— — —aFDA, Fed. Regist., 59(183), 1994; FDA, Fed. Regist., 61(67), April 5, 1996.bReproduction and fertility assessments are covered in the EPA OPPTS 870.3800 multigenerationalguideline.cReproduction and fertility assessments are covered in the FDA “Redbook” two generation guideline.dReproduction and fertility assessments are covered in the OECD 415 and 416 multigenerationguidelines.The current ICH guideline 2 allows any combination of intervals A through F, provided all theintervals are evaluated. This procedure eliminates differences in durations of the various segmentsand allows evaluation of the conceptuses at any time in gestation. Additional flexibility was addedto the fertility assessments by allowing the duration of the premating treatment period in maleanimals to be reduced from 60 to 28 days (4 weeks) 3 and later to 14 days 4 when the results of a4-week subchronic study in the same strain and species do not identify adverse effects on malereproductive organs. Most studies continue to be performed using the 28-day exposure period.Should adverse effects be present in the subchronic (multidose) study, the 60-day prematingtreatment period may be used, or other studies may be performed to characterize the effects. Incontrast, the FDA Red Book 21 and the OECD 28,29 and EPA 23 approaches are to provide more fixedprotocol designs to evaluate the same endpoints as those in studies performed for evaluation ofpharmaceuticals. A full comparison of the ICH endpoints and the multiple protocols that evaluatethese endpoints is provided in Table 19.5, Table 19.6, Table 19.7, and Table 19.8.F. Reproductive PerformanceMating and fertility are essential endpoints of reproductive studies; the techniques used in theseevaluations are the same as those used for impregnating animals to be used in developmental© 2006 by Taylor & Francis Group, LLC