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TG 488 recommends 28 consecutive days of exposure with sampling of germ cells from seminiferous tubules 28\u00a0days post-exposure (i.e., 28\u2009+\u200928d). We analyzed mutant frequencies (MF) in male germ cells up to 70\u00a0days post-exposure to determine whether designs other than 28\u2009+\u200928d are necessary for assessing germ cell mutagenicity. Adult MutaMouse males received various doses of benzo(a)pyrene (BaP), <jats:italic>N<\/jats:italic>-ethyl-<jats:italic>N<\/jats:italic>-nitrosourea (ENU), isopropyl methanesulfonate (iPMS), or procarbazine (PRC) alongside vehicle controls for 28\u00a0days orally. Germ cells were collected from seminiferous tubules at\u2009+\u20093d,\u2009+\u200928d,\u2009+\u200942d, or\u2009+\u200970d post-exposure and MF quantified using the <jats:italic>lacZ<\/jats:italic> assay. Significant increases in <jats:italic>lacZ<\/jats:italic> MF were observed for all four chemicals at 28\u2009+\u200928d. No further increases occurred at later sampling times. There was no significant effect with BaP at 28\u2009+\u20093d, and a significantly stronger response with ENU and BaP at 28\u2009+\u200928d compared to 28\u2009+\u20093d. PRC produced the strongest response at 28\u2009+\u20093d, while there was no impact of different sampling times for iPMS. Both these chemicals significantly reduced testis weight at 28\u2009+\u20093d and 28\u2009+\u200928d. Finally, benchmark dose modeling generated overlapping confidence intervals among the four sampling times for ENU, iPMS, and PRC. However, for BaP, the confidence interval was significantly greater at 28\u2009+\u20093d than at the other sampling times. These results support the use of the 28\u2009+\u200928d design as the recommended experimental design for germ cells in TG 488 and that later sampling times are not necessary.<\/jats:p>","DOI":"10.1007\/s00204-025-04085-1","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T15:06:26Z","timestamp":1747839986000},"page":"3611-3624","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Temporal analyses of germ cell mutations using the MutaMouse model support the recommended design in OECD test guideline 488"],"prefix":"10.1007","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3590-6092","authenticated-orcid":false,"given":"Gu","family":"Zhou","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7637-7686","authenticated-orcid":false,"given":"Andrew","family":"Williams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3847-8371","authenticated-orcid":false,"given":"Danielle P. 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