Potential impurities in drug substances: Compound-specific toxicology limits for 20 synthetic reagents and by-products, and a class-specific toxicology limit for alkyl bromides

Albertini, 2013, Vinyl acetate monomer (VAM) genotoxicity profile: relevance for carcinogenicity, Crit. Rev. Toxicol., 43, 671, 10.3109/10408444.2013.827151 Antonucci, 2011, Toxicological assessment of 2-methyltetrahydrofuran and cyclopentyl methyl ether in support of their use in pharmaceutical chemical process development, Org. Process Res. Dev., 15, 939, 10.1021/op100303c Ashby, 1988, Chemical structure, Salmonella mutagenicity and extent of carcinogenicity as indicators of genotoxic carcinogenesis among 222 chemicals tested in rodents by the U.S. NCI/NTP, Mutat. Res., 204, 17, 10.1016/0165-1218(88)90114-0 Agency for Toxic Substances and Disease Registry (ATSDR), 1999 Baden, 1979, Carcinogenicity of halothane in Swiss/ICR mice, Anesthesiology, 51, 20, 10.1097/00000542-197907000-00005 Benigni, 2008, Structure alerts for carcinogenicity, and the Salmonella assay system: a novel insight through the chemical relational databases technology, Mutat. Res., 659, 248, 10.1016/j.mrrev.2008.05.003 Bercu, 2013, Advancing toxicology in RiskMAPP: setting ADEs based on the subsequent drug substance, Regul. Toxicol. Pharmacol., 65, 157, 10.1016/j.yrtph.2012.08.002 Bercu, 2016, Point of departure (PoD) selection for the derivation of acceptable daily exposures (ADEs) for active pharmaceutical ingredients (APIs), Regul. Toxicol. Pharmacol., 79, S48, 10.1016/j.yrtph.2016.05.028 Brigo, 2011, Development of the threshold of toxicological concern concept and its relationship to duration of exposure California Environmental Protection Agency (CALEPA), 1992 Canada, 2001 Chemicals Evaluation and Research Institute Japan (CERI), 2007 Conolly, 2003, Biologically motivated computational modeling of formaldehyde carcinogenicity in the F344 rat, Toxicol. Sci., 75, 432, 10.1093/toxsci/kfg182 Conolly, 2004, Human respiratory tract cancer risks of inhaled formaldehyde: dose-response predictions derived from biologically-motivated computational modeling of a combined rodent and human dataset, Toxicol. Sci., 82, 279, 10.1093/toxsci/kfh223 Cancer Potency Database (CPDB), 2011. https://toxnet.nlm.nih.gov/cpdb/ last updated September 1, 2011. Cruzan, 1998, Chronic toxicity/oncogenicity study of styrene in CD rats by inhalation exposure for 104 weeks, Toxicol. Sci., 46, 266, 10.1093/toxsci/46.2.266 Cruzan, 2001, Chronic toxicity/oncogenicity study of styrene in CD-1 mice by inhalation exposure for 104 weeks, J. Appl. Toxicol., 21, 185, 10.1002/jat.737 Custer, 2012, Impact of new mutagenicity data on marketed drugs: a case study Dhareshwar, 2008, Your prodrug releases formaldehyde: should you be concerned? No!, J. Pharm. Sci., 97, 4184, 10.1002/jps.21319 Dolan, 2005, Application of the threshold of toxicological concern concept to pharmaceutical manufacturing operations, Regul. Toxicol. Pharmacol., 43, 1, 10.1016/j.yrtph.2005.06.010 European Chemicals Agency (ECHA), 2008 European Chemicals Agency (ECHA), 2008 Eichenbaum, 2009, Assessment of the genotoxic and carcinogenic risks of p-nitrophenol when it is present as an impurity in a drug product, Regul. Toxicol. Pharmacol., 55, 33, 10.1016/j.yrtph.2009.05.018 Elder, 2015, Is avoidance of genotoxic intermediates/impurities tenable for complex, multistep syntheses?, Org. Process Res. Dev., 19, 1437, 10.1021/op500346q Ellis, 2013, Determination of compound-specific acceptable daily intakes for 11 mutagenic carcinogens used in pharmaceutical synthesis, Regul. Toxicol. Pharmacol., 65, 201, 10.1016/j.yrtph.2012.11.008 Faria, 2016, Using default methodologies to derive an acceptable daily exposure (ADE), Regul. Toxicol. Pharmacol., 79, S28, 10.1016/j.yrtph.2016.05.026 Felter, 2011, A proposed framework for assessing risk from less-than-lifetime exposures to carcinogens, Crit. Rev. Toxicol., 41, 507, 10.3109/10408444.2011.552063 Feron, 1982, Respiratory tract tumours in hamsters exposed to acetaldehyde vapour alone or simultaneously to benzo(a)pyrene or diethylnitrosamine, Eur. J. Cancer Clin. Oncol., 18, 13, 10.1016/0277-5379(82)90020-7 Fleischman, 1980, Carcinogenesis bioassay of acetamide, hexanamide, adipamide, urea and P-tolylurea in mice and rats, J. Environ. Pathol. Toxicol., 3, 149 Frank, 1996, vol. 1 Food Safety Commission (FSC), 2005 Fukunaga, 1993, Problems involved in the determination of endogenous acetaldehyde in human blood, Alcohol Alcohol, 28, 535 Galloway, 2013, Potentially mutagenic impurities: analysis of structural classes and carcinogenic potencies of chemical intermediates in pharmaceutical syntheses supports alternative methods to the default TTC for calculating safe levels of impurities, Regul. Toxicol. Pharmacol., 66, 326, 10.1016/j.yrtph.2013.05.005 Gaylor, 1995, Quick estimate of the regulatory virtually safe dose based on the maximum tolerated dose for rodent bioassays, Regul. Toxicol. Pharmacol., 22, 57, 10.1006/rtph.1995.1069 Gerber, 2009, What happened: the chemistry side of the incident with EMS contamination in Viracept tablets, Toxicol. Lett., 190, 248, 10.1016/j.toxlet.2009.02.020 Gocke, 2009, In vivo studies in the mouse to define a threshold for the genotoxicity of EMS and ENU, Mutat. Res., 678, 101, 10.1016/j.mrgentox.2009.04.005 Gocke, 2009, MNT and MutaMouse studies to define the in vivo dose response relations of the genotoxicity of EMS and ENU, Toxicol. Lett., 190, 286, 10.1016/j.toxlet.2009.03.021 Gocke, 2009, Literature review on the genotoxicity, reproductive toxicity, and carcinogenicity of ethyl methanesulfonate, Toxicol. Lett., 190, 254, 10.1016/j.toxlet.2009.03.016 Gocke, 2009, EMS in Viracept–initial ('traditional') assessment of risk to patients based on linear dose response relations, Toxicol. Lett., 190, 266, 10.1016/j.toxlet.2009.04.030 Gollapudi, 2013, Quantitative approaches for assessing dose-response relationships in genetic toxicology studies, Environ. Mol. Mutagen., 54, 8, 10.1002/em.21727 Gollapudi, 2015, The in vivo pig-a assay: a report of the international workshop on genotoxicity testing (IWGT) workgroup, Mutat. Res. Genet. Toxicol. Environ. Mutagen, 783, 23, 10.1016/j.mrgentox.2014.09.007 Harvey, 2017, Management of organic impurities in small molecule medicinal products: deriving safe limits for use in early development, Regul. Toxicol. Pharmacol., 84, 116, 10.1016/j.yrtph.2016.12.011 Hayes, 1998, Contact hypersensitivity to dicyclohexylcarbodiimide and diisopropylcarbodiimide in female B6C3F1 mice, Drug Chem. Toxicol., 21, 195, 10.3109/01480549809011647 Hill, 1998, Risk assessment of thyroid follicular cell tumors, Environ. Health Perspect., 106, 447, 10.1289/ehp.98106447 International Agency for Research on Cancer (IARC), 2001, vol 79 International Agency for Research on Cancer (IARC), 2002, vol 82 International Agency for Research on Cancer (IARC), 2006 International Agency for Research on Cancer (IARC), 2012, 100F International Conference on Harmonisation (ICH), 2006 International Conference on Harmonisation (ICH), 2006 International Conference on Harmonisation, 2011 International Conference on Harmonisation (ICH), 2014 International Conference on Harmonisation (ICH), 2016 International Conference on Harmonisation (ICH), 2017 International Programme on Chemical Safety (IPCS), 2002 Joint FAO/WHO Expert Committee on Food Additives (JECFA), 1999, Evaluation of certain food additives and contaminants Johnson, 2014, Derivation of point of departure (PoD) estimates in genetic toxicology studies and their potential applications in risk assessment, Environ. Mol. Mutagen., 55, 609, 10.1002/em.21870 Lachenmeier, 2009, Carcinogenicity of acetaldehyde in alcoholic beverages: risk assessment outside ethanol metabolism, Addiction, 104, 533, 10.1111/j.1360-0443.2009.02516.x MacGregor, 2015, IWGT report on quantitative approaches to genotoxicity risk assessment II. Use of point-of-departure (PoD) metrics in defining acceptable exposure limits and assessing human risk, Mutat. Res. Genet. Toxicol. Environ. Mutagen, 783, 66, 10.1016/j.mrgentox.2014.10.008 MacGregor, 2015, IWGT report on quantitative approaches to genotoxicity risk assessment I. Methods and metrics for defining exposure-response relationships and points of departure (PoDs), Mutat. Res. Genet. Toxicol. Environ. Mutagen, 783, 55, 10.1016/j.mrgentox.2014.09.011 Maronpot, 1986, Strain A mouse pulmonary tumor test results for chemicals previously tested in the National Cancer Institute carcinogenicity tests, J. Natl. Canc. Inst., 76, 1101 Moloney, 1962, The murine leukemias, Fed. Proc., 21, 19 Moloney, 1964, The rodent leukemias: virus-induced murine leukemias, Annu. Rev. Med., 15, 383, 10.1146/annurev.me.15.020164.002123 Müller, 2009, Considerations regarding a permitted daily exposure calculation for ethyl methanesulfonate, Toxicol. Lett., 190, 330, 10.1016/j.toxlet.2009.03.015 Müller, 2009, EMS in Viracept–the course of events in 2007 and 2008 from the non-clinical safety point of view, Toxicol. Lett., 190, 243, 10.1016/j.toxlet.2009.02.005 Müller, 2009, Ethyl methanesulfonate toxicity in Viracept–a comprehensive human risk assessment based on threshold data for genotoxicity, Toxicol. Lett., 190, 317, 10.1016/j.toxlet.2009.04.003 National Cancer Institute (NCI), 1976 Nicolette, 2016, Peptide bond-forming reagents HOAt and HATU are not mutagenic in the bacterial reverse mutation test, Environ. Mol. Mutagen., 57, 236, 10.1002/em.21997 Organization for Economic Co-operation and Development (OECD), 1997 Organization for Economic Co-operation and Development (OECD), 2002 Organization for Economic Co-operation and Development (OECD), 2011 Owen, 1990, Formaldehyde in drinking water: comparative hazard evaluation and an approach to regulation, Regul. Toxicol. Pharmacol., 11, 220, 10.1016/0273-2300(90)90023-5 Parris, 2017, Calculation of a permitted daily exposure value for the solvent 2-methyltetrahydrofuran, Regul. Toxicol. Pharmacol., 87, 54, 10.1016/j.yrtph.2017.04.012 Pattengale, 1982, Immunopathology of B-cell lymphomas induced in C57BL/6 mice by dualtropic murine leukemia virus (MuLV), Am. J. Pathol., 107, 362 Peto, 1984, The TD50: a proposed general convention for the numerical description of the carcinogenic potency of chemicals in chronic-exposure animal experiments, Environ. Health Perspect., 58, 1 Pfister, 2009, General 4-week toxicity study with EMS in the rat, Toxicol. Lett., 190, 271, 10.1016/j.toxlet.2009.04.031 Prescott, 2017, Evaluation of therapeutics for advanced-stage heart failure and other severely-debilitating or life-threatening diseases, Clin. Pharmacol. Ther., 102, 219, 10.1002/cpt.730 Proctor, 2007, Mode-of-action framework for evaluating the relevance of rodent forestomach tumors in cancer risk assessment, Toxicol. Sci., 98, 313, 10.1093/toxsci/kfm075 Robinson, 2002, Histochemical localisation of carboxylesterase activity in rat and mouse oral cavity mucosa, Toxicology, 180, 209, 10.1016/S0300-483X(02)00375-X Rosenkranz, 1977, Mutagenicity of halogenated alkanes and their derivatives, Environ. Health Perspect., 21, 79 Scheuplein, 1985, Formaldehyde: the food and drug Administrations's perspective, vol 210, 237 Schule, 2010, Monitoring and control of genotoxic impurity acetamide in the synthesis of zaurategrast sulfate, Org. Process Res. Dev., 14, 1008, 10.1021/op900330e Snodin, 2010, Genotoxic impurities: from structural alerts to qualification, Org. Process Res. Dev., 14, 960, 10.1021/op100118e Snodin, 2015, Regulatory risk assessments: is there a need to reduce uncertainty and enhance robustness?, Hum. Exp. Toxicol., 34, 1258, 10.1177/0960327115608326 Soffritti, 2002, Results of long-term experimental studies on the carcinogenicity of formaldehyde and acetaldehyde in rats, Ann. N. Y. Acad. Sci., 982, 87, 10.1111/j.1749-6632.2002.tb04926.x Starr, 2013, A novel bottom-up approach to bounding low-dose human cancer risks from chemical exposures, Regul. Toxicol. Pharmacol., 65, 311, 10.1016/j.yrtph.2013.01.004 Stoner, 1993, Lung tumors in strain A mice: application for studies in cancer chemoprevention, J. Cell. Biochem. Suppl., 17F, 95, 10.1002/jcb.240531014 Sussman, 2016, A harmonization effort for acceptable daily exposure derivation - considerations for application of adjustment factors, Regul. Toxicol. Pharmacol., 79, S57, 10.1016/j.yrtph.2016.05.023 Swenberg, 1993, Alpha 2u-globulin nephropathy: review of the cellular and molecular mechanisms involved and their implications for human risk assessment, Environ. Health Perspect., 101, 39, 10.1289/ehp.93101s639 Swenberg, 2013, Formaldehyde carcinogenicity research: 30 years and counting for mode of action, epidemiology, and cancer risk assessment, Toxicol. Pathol., 41, 181, 10.1177/0192623312466459 Teasdale, 2013, Risk assessment of genotoxic impurities in new chemical entities: strategies to demonstrate control, Org. Process Res. Dev., 17, 221, 10.1021/op300268u Travis, 2005, The role of the benchmark dose in a regulatory context, Regul. Toxicol. Pharmacol., 43, 280, 10.1016/j.yrtph.2005.07.003 Uebelacker, 2011, Quantitative determination of acetaldehyde in foods using automated digestion with simulated gastric fluid followed by headspace gas chromatography, J. Autom. Meth. Manag. Chem., 2011, 1, 10.1155/2011/907317 United States Environmental Protection Agency (USEPA), 1990 United States Environmental Protection Agency (USEPA), 2000 United States Environmental Protection Agency (USEPA), 2005 United States Environmental Protection Agency (USEPA), 2012 Weisburger, 1969, Prevention by arginine glutamate of the carcinogenicity of acetamide in rats, Toxicol. Appl. Pharmacol., 14, 163, 10.1016/0041-008X(69)90176-8 World Health Organization (WHO), 2005 World Health Organization (WHO), 2005 Williams, 1997, Chemicals with carcinogenic activity in the rodent liver; mechanistic evaluation of human risk, Canc. Lett., 117, 175, 10.1016/S0304-3835(97)00229-2 Wills, 2017, Comparing BMD-derived genotoxic potency estimations across variants of the transgenic rodent gene mutation assay, Environ. Mol. Mutagen., 58, 632, 10.1002/em.22137 Woutersen, 1986, Inhalation toxicity of acetaldehyde in rats. III. Carcinogenicity study, Toxicology, 41, 213, 10.1016/0300-483X(86)90201-5