TABLE I.
Chemicals and a priori Classifications
| Chemical, abbreviation | CAS No., source if not Sigma-Aldrich | Chemical set | A priori mammalian cell genotoxicity and MoA classifications | Notes; References |
|---|---|---|---|---|
| 17β-Estradiol (est) | 50–28–2 | Training | Genotoxic; Aneugen | Steroid hormone; Hernández et al. (2013) |
| AMG-900 (amg) | 945595–80–2 | Training | Genotoxic; Aneugen | Pan-Aurora kinase inhibitor (A/B/C); Payton et al. (2010) |
| Carbendazim (car) | 10605–21–7 | Training | Genotoxic; Aneugen | Mitotic spindle poison; Van Hummelen et al. (1995) |
| Colchicine (col) | 64–86–8 | Training | Genotoxic; Aneugen | Mitotic spindle poison; Kirkland et al. (2016) |
| Crizotinib | 877399–52–5 | Training | Genotoxic; Aneugen | Tyrosine kinase inhibitor, potent activity against c-Met and ALK, with evidence of off-target Aurora kinase inhibition; Kong et al. (2018) |
| Diethylstilbestrol (des) | 56–53–1 | Training | Genotoxic; Aneugen | Synthetic estrogen; Parry et al. (2002) |
| Flubendazole (flu) | 3143015–6 | Training | Genotoxic; Aneugen | Mitotic spindle poison; Tweats et al. (2016) |
| Griseofulvin (gli) | 126–07–8 | Training | Genotoxic; Aneugen | Mitotic spindle poison; Oliver et al. (2006) |
| Mebendazole (meb) | 31431–39–7 | Training | Genotoxic; Aneugen | Mitotic spindle poison; Van Hummelen et al. (1995) |
| Nocodazole (noc) | 31430–18–9 | Training | Genotoxic; Aneugen | Mitotic spindle poison; Verdoodt et al. (1999) |
| Noscapine (nos) | 128–62–1 | Training | Genotoxic; Aneugen | Mitotic spindle poison; Schuler et al. (1999) |
| Paclitaxel (pac) | 33069–62–4 | Training | Genotoxic; Aneugen | Mitotic spindle poison; Kirkland et al. (2016) |
| Vinblastine sulfate (vin) | 143–67–9 | Training | Genotoxic; Aneugen | Mitotic spindle poison; Kirkland et al. (2016) |
| Vincristine sulfate (vis) | 2068–78–2 | Training | Genotoxic; Aneugen | Mitotic spindle poison; Kondo et al. (1992) |
| 1,3-Propane sultone (psu) | 1120–71–4 | Training | Genotoxic; Clastogen | Alkylator; Dertinger et al. (2011) |
| 4-Nitroquinoline 1-oxide (nqo) | 56–57–5 | Training | Genotoxic; Clastogen | Likely several modes of clastogenic action that may include ROS; Kirkland et al. (2016) |
| 5-Fluorouracil | 51–21–8 | Training | Genotoxic; Clastogen | Anti-metabolite, thymidylate synthase inhibitor; Kirkland et al. (2016) |
| Aphidicolin | 38966–21–1 | Training | Genotoxic; Clastogen | DNA polymerase inhibitor; Glover et al. (1984) |
| Azathioprine | 446–86–6 | Training | Genotoxic; Clastogen | Prodrug of mercaptopurine, purine analog; Henderson et al. (1993) |
| Azidothymidine (azt) | 30516–87–1 | Training | Genotoxic; Clastogen | Nucleoside analog; Kirkland et al. (2016) |
| Bleomycin sulfate (bls) | 9041–93–4 | Training | Genotoxic; Clastogen | Radiomimetic; Rosefort et al. (2004) |
| Camptothecin (cam) | 7689–03–4 | Training | Genotoxic; Clastogen | Topoisomerase I inhibitor; Attia et al. (2009) |
| Chlorambucil (chl) | 305–03–3 | Training | Genotoxic; Clastogen | Nitrogen mustard-type alkylator; Dertinger et al. (2012) |
| Cisplatin (cis) | 15663–27–1 | Training | Genotoxic; Clastogen | Atypical alkylator; Kirkland et al. (2016) |
| Cytosine arabinoside (cya) | 147–94–4 | Training | Genotoxic; Clastogen | Anti-metabolite; Kirkland et al. (2016) |
| Doxorubicin | 23214–92–8 | Training | Genotoxic; Clastogen | Anthracycline, likely several modes of action that includes inhibition of topoisomerase II; Gewirtz (1999) |
| Emodin | 518–82–1 | Training | Genotoxic; Clastogen | Anthraquinone, topoisomerase II inhibitor; Li et al. (2010) |
| Ethyl methanesulfonate (ems) | 62–50–0 | Training | Genotoxic; Clastogen | Alkylator; Gocke et al. (2009) |
| Etoposide (etp) | 33419–42–0 | Training | Genotoxic; Clastogen | Topoisomerase II inhibitor; Kirkland et al. (2016) |
| Glycidamide (gly) | 5694–00–8 | Training | Genotoxic; Clastogen | Major in vivo metabolite of acrylamide; Paulsson et al. (2003) |
| Hydralazine HCl | 304–20–1 | Training | Genotoxic; Clastogen | Prepared in RPMI medium; Martelli et al. (1995) |
| Hydrogen peroxide (hyp) | 7722–84–1 | Training | Genotoxic; Clastogen | ROS, prepared in RPMI medium; Kimura et al. (2013) |
| Hydroxyurea (hyu) | 127–07–1 | Training | Genotoxic; Clastogen | Anti-metabolite, ribonucleotide reductase inhibitor; Dertinger et al. (2012) |
| Melphalan | 142–82–3 | Training | Genotoxic; Clastogen | Nitrogen mustard-type alkylator; Dertinger et al. (2012) |
| Menadione (men) | 58–27–5 | Training | Genotoxic; Clastogen | ROS implicated; Cojocel et al. (2006) |
| Methotrexate | 59–05–2 | Training | Genotoxic; Clastogen | Anti-metabolite; Keshava et al. (1998) |
| Methyl methanesulfonate | 66–27–3 | Training | Genotoxic; Clastogen | Alkylator; Kirkland et al. (2016) |
| N-Methyl-N′-nitro-N-nitrosoguanidine (MNNG) | 70–25–7 | Training | Genotoxic; Clastogen | Alkylator; Nikolova et al. (2014) |
| Mitomycin C (mmc) | 50–07–7 | Training | Genotoxic; Clastogen | DNA cross-linker; Kirkland et al. (2016) |
| N-Ethyl-N-nitrosourea | 759–73–9 | Training | Genotoxic; Clastogen | Alkylator; Kirkland et al. (2016) |
| Olaparib (ola) | 763113–22–0 | Training | Genotoxic; Clastogen | PARP inhibitor; FDA approved label (Lynparza™ 2014) |
| Propyl gallate | 121–79–9 | Training | Genotoxic; Clastogen | ROS likely; Tayama and Nakagawa (2001) |
| Resorcinol diglycidyl ether | 101–90–6 | Training | Genotoxic; Clastogen | Gulati et al. (1989) |
| Stavudine | 3056–17–5 | Training | Genotoxic; Clastogen | Nucleoside analog; FDA approved label (Zerit® 2002) |
| Temozolomide (tmz) | 85622–93–1 | Training | Genotoxic; Clastogen | Alkylator; Chinnasamy et al. (1997) |
| Thiotepa (thi) | 52–24–4 | Training | Genotoxic; Clastogen | Alkylator; Dertinger et al. (2012) |
| Topotecan (top) | 123948–87–8 | Training | Genotoxic; Clastogen | Topoisomerase I inhibitor; Aydemir and Bilaloğlu (2003) |
| Alosetron HCl | 122852–42–0 | Training | Non-genotoxic | 5-HT3 antagonist; Kirkland et al. (2016) |
| Amitrole | 61–82–5 | Training | Non-genotoxic | Kirkland et al. (2016) |
| Anthranilic acid | 118–92–3 | Training | Non-genotoxic | Kirkland et al. (2016) |
| Brefeldin A | 20350–15–6 | Training | Non-genotoxic | ER-golgi transporter inhibitor, ER stress-induced apoptosis; Moon et al. (2012) |
| Caffeine | 58–08–2 | Training | Non-genotoxic | Mitochondria-dependent apoptosis, ROS involvement likely; Lu et al. (2008) |
| Carbonyl cyanide m-chlorophenyl hydrazone (CCCP) | 555–60–2 | Training | Non-genotoxic | Uncoupler of oxidative phosphorylation; de Graaf et al. (2004) |
| Clofibrate | 637–07–0 | Training | Non-genotoxic | Antilipidemic agent; IARC Monograph (2018) |
| Cyclohexanone | 108–94–1 | Training | Non-genotoxic | Industrial chemical; Kirkland et al. (2008) |
| Cycloheximide | 66–81–9 | Training | Non-genotoxic | Protein synthesis inhibitor; Youngblom et al. (1989) |
| D-Limonene | 5989–27–5 | Training | Non-genotoxic | Male rat kidney tumors due to α2μ-globulin nephropathy; Kirkland et al. (2016) |
| D-Mannitol | 69–65–8 | Training | Non-genotoxic | Polyol; Kirkland et al. (2016) |
| Dexamethasone | 50–02–2 | Training | Non-genotoxic | Glucocorticoid receptor agonist; Krishna et al. (1995) |
| Dextrose | 50–99–7 | Training | Non-genotoxic | Sugar; Lotz et al. (2009) |
| Di-(2-ethylhexyl) phthalate (DEHP) | 117–81–7 | Training | Non-genotoxic | Organic plasticizer; Kirkland et al. (2016) |
| Diethanolamine | 111–42–2 | Training | Non-genotoxic | Secondary amine; Kirkland et al. (2016) |
| Erythromycin | 114–07–8 | Training | Non-genotoxic | Antibiotic; Kirkland et al. (2016) |
| Famotidine | 76824–35–6 | Training | Non-genotoxic | Histamine H2 receptor antagonist; FDA approved label (Pepcid® 2011) |
| Imatinib mesylate | 152459–95–5 | Training | Non-genotoxic | Protein-tyrosine kinase inhibitor; FDA approved label (Gleevec® 2001) |
| Hexachloroethane | 67–72–1 | Training | Non-genotoxic | Industrial chemical; Kirkland et al. (2016) |
| Lidocaine | 137–58–6 | Training | Non-genotoxic | Amide, local anesthetic; FDA approved label (Lidoderm® 2004) |
| Lovastatin | 75330–75–5 | Training | Non-genotoxic | HMG-CoA reductase inhibitor; FDA approved label (Mevacor® 2012) |
| Melamine | 108–78–1 | Training | Non-genotoxic | Industrial organic base; Kirkland et al. (2016) |
| Methyl carbamate | 598–55–0 | Training | Non-genotoxic | Industrial intermediate; Kirkland et al. (2016) |
| N-Butyl chloride | 109–69–3 | Training | Non-genotoxic | Fumigant; Kirkland et al. (2016) |
| Ofloxacin | 82419–36–1 | Training | Non-genotoxic | Fluoroquinoline antibiotic; FDA approved label (Floxin® 2008) |
| Paroxetine | 61869–08–7 | Training | Non-genotoxic | SSRI antidepressant; FDA approved label (Paxil® 2011) |
| Phenanthrene | 85–01–8 | Training | Non-genotoxic | Polycyclic aromatic hydrocarbon; Kirkland et al. (2008) |
| Phenformin HCl | 834–28–6 | Training | Non-genotoxic | Biguanide antidiabetic; Kirkland et al. (2016) |
| Progesterone | 57–83–0 | Training | Non-genotoxic | Steroid hormone; Kirkland et al. (2008) |
| Pyridine | 110–86–1 | Training | Non-genotoxic | Heterocyclic organic compound; Kirkland et al. (2016) |
| Sodium chloride | 7647–14–5 | Training | Non-genotoxic | Prepared in RPMI medium; Matsushima et al. (1999) |
| Sodium dodecyl sulfate | 151–21–3 | Training | Non-genotoxic | Ionic detergent; National Toxicology Program Report (2018b) |
| Sucrose | 57–50–1 | Training | Non-genotoxic | Diaz et al. (2007) |
| Tert-butyl alcohol | 75–65–0 | Training | Non-genotoxic | Kirkland et al. (2016) |
| Thapsigargin | 6726–95–8 | Training | Non-genotoxic | ER stress-induced apoptosis; Futami et al. (2005) |
| Tolterodine L-tartrate | 124937–52–6 | Training | Non-genotoxic | Muscarinic receptor antagonist; Kirkland et al. (2016) |
| Tunicamycin | 11089–65–9 | Training | Non-genotoxic | Glycosylation inhibitor, ER stress-mediated apoptosis; Han et al. (2008) |
| Zonisamide | 68291–97–4 | Training | Non-genotoxic | Sulfonamide anticonvulsant; Kirkland et al. (2016) |
| 10j | MSD | Test | Genotoxic; Aneugen | Tyrosine kinase inhibitor; Ames neg., CHO MN pos., CHO ChromAb neg. but polyploidy evident; MSD in-house results |
| 13 m | MSD | Test | Genotoxic; assumed Aneugen | Tyrosine kinase inhibitor; CHO and TK6 MN pos.; MSD in-house results |
| 14n | MSD | Test | Genotoxic; Aneugen | Serine/threonine kinase inhibitor; Ames neg., CHO MN pos., CHO ChromAb neg. but polyploidy and endoreduplication evident; TK6 MN neg.; MSD in-house results |
| 16p | MSD | Test | Genotoxic; Mixed | Azobenzimidazole structure; Likely >1 MoA; Ames neg., CHO MN and ChromAb pos. with premature centromere separation at metaphase in addition to structural aberrations, Rat MN neg.; MSD in-house results |
| 17q | MSD | Test | Genotoxic; assumed Aneugen | Benzimidazole structure; Ames neg., CHO MN pos.; MSD in-house results |
| Phenolphthalein, supplied coded as 3c | 77–09–8; MSD | Test | Genotoxic; Mixed | Likely >1 MoA; Spindle poison, centromere amplification (Heard et al. 2013); CHO ChromAb pos.; MSD in-house results |
| 6f | MSD | Test | Genotoxic; Aneugen | Kinase inhibitor, leucine-rich repeat; Ames neg., CHO MN pos., CHO ChromAb neg., rat MN pos.; MSD in-house results |
| Hesperadin | 422513–13–1; Selleckchem | Test | Genotoxic; Aneugen | Aurora kinase inhibitor (B); in vitro MN pos., aberrant metaphases; Hauf et al. (2003), Kurihara et al. (2006) |
| Tozasertib | 639089–54–6; Selleckchem | Test | Genotoxic; Aneugen | Pan-Aurora kinase inhibitor (A/B/C); Gollapudi et al. (2014) |
| ZM-447439 | 331771–20–1; Selleckchem | Test | Genotoxic; Aneugen | Aurora kinase inhibitor (A/B); Gollapudi et al. (2014) |
| 7 g | MSD | Test | Genotoxic, MoA uncertain | Possibly >1 MoA; Ames pos., CHO MN pos., CHO ChromAb neg., TK6 MN pos., HPBL MN neg.; mechanism affects tubulin so suspected aneugen, but Ames pos. suggests primary DNA damage; MSD in-house results |
| 9i | MSD | Test | Genotoxic; Clastogen | Non-nucleoside antiviral; Ames neg., CHO MN pos., CHO ChromAb pos.; MSD in-house results |
| AZD2858 | 486424–20–8; Selleckchem | Test | Genotoxic; Clastogen | Glycogen synthase-3 inhibitor; in vitro MN and ChromAb pos., Ann Doherty, personal communication |
| Beta-Lapachone | 4707–32–8; Selleckchem | Test | Genotoxic; Clastogen | Topoisomerase I inhibitor; in vitro ChromAb and comet pos.; Degrassi et al. (1993) |
| Ciprofloxacin | 85721–33–1; Selleckchem | Test | Genotoxic; Clastogen | Topoisomerase II inhibitor; in vitro MN pos.; Curry et al. (1996) |
| Dasatinib | 302962–49–8; Selleckchem | Test | Genotoxic; Clastogen | Tyrosine kinase inhibitor, especially Ber-Abl, Scr, c-Kit; Ames neg., clastogenic in CHO, in vivo MN neg.; Sprycel® (dasatinib) (2010) |
| Genistein | 446–72–0 | Test | Genotoxic; Clastogen | Topoisomerase II inhibitor; in vitro MN pos.; Klein and King (2007) |
| Irinotecan | 57852–57–0; Selleckchem | Test | Genotoxic; Clastogen | Topoisomerase I inhibitor; Ames neg., in vitro ChromAb pos., in vivo MN pos.; Camptosar (2014) |
| Mitoxantrone 2HCl | 70476–82–3; Selleckchem | Test | Genotoxic; Clastogen | Topoisomerase II inhibitor; in vitro MN pos., γH2AX pos.; Smart et al. (2008) |
| Teniposide | 29767–20–2; Selleckchem | Test | Genotoxic; Clastogen | Topoisomerase II inhibitor; in vitro ChromAb pos., in vitro MLA pos.; DeMarini et al. (1987) |
| Entecavir, supplied coded as 19 s | MSD | Test | Genotoxic; Clastogen | Guanine nucleoside analog; CHO MN pos., CHO ChromAb pos.; MSD in-house data |
| Hydroquinone, supplied coded as 1a | 123–31–9; MSD | Test | Genotoxic; Mixed | Likely >1 MoA; Kirkland et al. (2016) |
| 20 t | MSD | Test | Genotoxic; Clastogen | Adenosine nucleoside analog; Ames neg., CHO MN pos., CHO ChromAb pos.; MSD in-house results |
| Tetrahydroxydiboron, supplied coded as 4d | MSD | Test | Genotoxic; Clastogen | Ames pos., CHO MN pos., CHO ChromAb pos.; MSD in-house results |
| 6-Thioguanine | 154–42–7 | Test | Genotoxic; Clastogen | Antimetabolite, purine analog; Ames pos., in vitro ChromAb pos., in vivo MN pos.; National Toxicology Program Report (2018a) |
| 11 k | MSD | Test | Non-genotoxic | Tryrosine kinase inhibitor; Ames neg., CHO MN neg., Rat MN neg.; MSD in-house data |
| 12 L | MSD | Test | Non-genotoxic | Drug candidate; Ames neg., CHO MN neg.; MSD in-house results |
| 15o | MSD | Test | Non-genotoxic (in TK6 cells) | Tryrosine kinase inhibitor; CHO MN weak pos. only at 24 hr; CHO ChromAb neg., TK6 MN neg., Rat MN neg.; MSD in-house results |
| 18r | MSD | Test | Non-genotoxic | Benzimidazole structure; Ames neg., CHO MN neg.; MSD in-house results |
| 2b | 20624–25–3; MSD | Test | Non-genotoxic | Sodium diethyldicarbamate trihydrate; CHO MN pos., TK6 MN pos., but cited authors attribute results to cytotoxicity; Hilliard et al. (1998), Galloway et al. (1998), Greenwood et al. (2004); Cu and Zn chelator, superoxide dismutase inhibitor; Heikkila et al. (1976), Nicotera et al. (1989) |
| 5e | MSD | Test | Non-genotoxic (in mammalian cells) | Aryl boronic acid; Ames pos., CHO MN neg.; MSD in-house results |
| 8 h | MSD | Test | Non-genotoxic | HDAC inhibitor; Ames neg., CHO MN neg.; CHO ChromAb neg.; MSD in-house results |
| Ampicillin trihydrate | 7177–48–2 | Test | Non-genotoxic | Ames neg., in vitro ChromAb neg., in vivo MN neg.; Kirkland et al. (2016) |
| Anisomycin | 22862–76–6 | Test | Non-genotoxic | Protein biosynthesis inhibitor; in vitro MN neg. with high levels of apoptosis; personal communication, Maik Schuler |
| Chlorocholine chloride | 999–81–5 | Test | Non-genotoxic | Ames neg., in vitro and in vivo ChromAb neg.; Kirkland et al. (2016) |
| Menthol | 89–78–1 | Test | Non-genotoxic | Ames neg., in vitro MN neg. in p53 competent cell lines, in vivo MN and comet neg.; Kirkland et al. (2016) |
| Osimertinib | 1421373–65–0 | Test | Non-genotoxic | EGFR kinase inhibitor; in vitro and in vivo genetox neg.; Tagrisso™ (Osimertinib) (2012) |
| Topiramate | 97240–79–4 | Test | Non-genotoxic | Ames, in vitro ChromAb and MLA neg., in vivo ChromAb Neg.; Kirkland et al. (2016) |
| Tris (2-ethylhexyl) phosphate | 78–42–2 | Test | Non-genotoxic | Ames neg., in vitro ChromAb neg., in vivo ChromAb and MN neg.; Kirkland et al. (2016) |
| Zafirlukast | 107753–78–6 | Test | Non-genotoxic | Ames, in vitro ChromAb, MLA, and Hprt neg.; Kirkland et al. (2016) |
Abbreviations: CHO, Chinese hamster ovary cells; ChromAb, chromosome aberration; EGFR, epithelial growth factor receptor; ER, endoplasmic reticulum; FDA, US Food and Drug Administration; Hprt, hypoxanthine guanine phosphoribosyltransferase; MDS, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.; MLA, mouse lymphoma assay; MN, micronuclei; MoA, mode of action; NTP, National Toxicology Program; PARP, poly ADP ribose polymerase; ROS, reactive oxygen species.