R.A. Jolly et al.

Regulatory Toxicology and Pharmacology 152 (2024) 105672

Nitrosamines in the Bacterial Reverse Mutation Test. Toxicol Rep 9, 250–255.
https://doi.org/10.1016/j.toxrep.2022.02.005. From NLM PubMed-not-MEDLINE.
Burns, M.J., Ponting, D.J., Foster, R.S., Thornton, B.P., Romero, N.E., Smith, G.F.,
Ashworth, I.W., Teasdale, A., Simon, S., Schlingemann, J., 2023. Revisiting the
Landscape of potential small and drug substance related nitrosamines in
pharmaceuticals. J. Pharmaceut. Sci. 112 (12), 3005–3011. https://doi.org/
10.1016/j.xphs.2023.10.001. Epub 2023 Oct 5. PMID: 37805074.
Cho, E., Allemang, A., Audebert, M., et al., 2022. AOP report: development of an adverse
outcome pathway for oxidative DNA damage leading to mutations and chromosomal
aberrations. Environ. Mol. Mutagen. 63 (3), 118–134. https://doi.org/10.1002/
em.22479.
Committee on Mutagenicity of Chemicals in Food, Consumer Products and the
Environment, 2018. Statement on quantitative assessment of genotoxicity data.
https://www.gov.uk/government/publications/quantitative-approaches-to-the-ass
essment-of-genotoxicity-data.
Cross, K.P., Ponting, D.J., 2021. Developing structure-activity relationships for Nnitrosamine activity. Comput Toxicol 20, 100186. https://doi.org/10.1016/j.
comtox.2021.100186.
De, S., Thapa, B., Sayyed, F.B., Frank, S.A., Cornwell, P.D., Jolly, R.A., 2024. Quantum
mechanical assessment of nitrosamine potency. Chem. Res. Toxicol. 37 (6),
1011–1022.
Dobo, K.L., Kenyon, M.O., Dirat, O., et al., 2022. Practical and science-based strategy for
establishing acceptable intakes for drug product N-nitrosamine impurities. Chem.
Res. Toxicol. 35 (3), 475–489. https://doi.org/10.1021/acs.chemrestox.1c00369.
EMA European Medicines Agency, 2023. EMA/409815/2020 Rev.20 Questions and
answers for marketing authorisation holders/applicants on the CHMP Opinion for
the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities
in human medicinal products.
EPA United States Environmental Protection Agency. Benchmark Dose Technical
Guidance. EPA/100/R-12/001 June 2012. Available at: https://www.epa.gov/sites/
default/files/2015-01/documents/benchmark_dose_guidance.pdf.
[EMA] European Medicines Agency, 2020. Nitrosamine impurities in human medicinal
products. EMA/369136/2020. Available at: https://www.ema.europa.eu/en/doc
uments/referral/nitrosamines-emea-h-a53-1490-assessment-report_en.pdf.
FDA, 2023. Control of Nitrosamine Impurities in Human Drugs. https://www.fda.go
v/regulatory-information/search-fda-guidance-documents/controlnitrosamine-impu
rities-human-drugs. (Accessed 24 March 2023).
FDA, 2022. Strattera USPI 021411s050lbl.
FDA, 2023a. Prozac USPI 018936 S112lbl. pdf.
FDA, 2023b. Cymbalta USPI 021427s055s057lbl.Pdf.
Fine, Jonathan, Allain, Leonardo, Schlingemann, Joerg, Ponting, David J.,
Thomas, Robert, Johnson, Georg E., 2023. Nitrosamine acceptable intakes should
consider variation in molecular weight: the implication of stoichiometric DNA
damage. Regul. Toxicol. Pharmacol. 145, 105505. ISSN 0273-2300.
Finkelshtein, E.I., 1999. The correlation of stretch vibrations frequencies with bond
dissociation energies. Application to carotenoids. In: Greve, J., Puppels, G.J., Otto, C.
(Eds.), Spectroscopy of Biological Molecules: New Directions. Springer, Dordrecht.
https://doi.org/10.1007/978-94-011-4479-7_77.
Frisch, M.J., et al., 2016. Gaussian 16, Revision B.0.1. Gaussian, Inc., Wallingford CT.
Gocke, E., Müller, L., 2009. In vivo studies in the mouse to define a threshold for the
genotoxicity of EMS and ENU. Mutat. Res. 678 (2), 101–107. https://doi.org/
10.1016/j.mrgentox.2009.04.005.
Gocke, E., Ballantyne, M., Whitwell, J., Müller, L., 2009. MNT and MutaMouse studies to
define the in vivo dose response relations of the genotoxicity of EMS and ENU.
Toxicol. Lett. 190 (3), 286–297. https://doi.org/10.1016/j.toxlet.2009.03.021.
EFSA Scientific Committee, Hardy, A., Benford, D., Halldorsson, T., et al., 2017. Update:
use of the benchmark dose approach in risk assessment. EFSA J. 15 (1), e04658
https://doi.org/10.2903/j.efsa.2017.4658.
Heflich, R.H., Johnson, G.E., Zeller, A., et al., 2020. Mutation as a toxicological endpoint
for regulatory decision-making. Environ. Mol. Mutagen. 61 (1), 34–41. https://doi.
org/10.1002/em.22338.
Hubrecht, R.C., Carter, E., 2019. The 3Rs and humane experimental technique:
implementing change. Animals 9 (10), 754. https://doi.org/10.3390/ani9100754.
PMID: 31575048; PMCID: PMC6826930.
ICH M7(R2), 2023. Assessment and Control of DNA Reactive (Mutagenic) Impurities in
Pharmaceuticals to Limit Potential Carcinogenic Risk. ICH. https://database.ich.
org/sites/default/files/M7_R1_Guideline.pdf.
Jacobson-Kram, D., Sistare, F.D., Jacobs, A.C., 2004. Use of transgenic mice in
carcinogenicity hazard assessment. Toxicol. Pathol. 32 (1_Suppl. l), 49–52. https://
doi.org/10.1080/01926230490424761.
Johnson, G.E., Soeteman-Hernández, L.G., Gollapudi, B.B., et al., 2014. Derivation of
point of departure (PoD) estimates in genetic toxicology studies and their potential
applications in risk assessment. Environ. Mol. Mutagen. 55 (8), 609–623. https://
doi.org/10.1002/em.21870.
Johnson, G.E., Dobo, K., Gollapudi, B., et al., 2021. Permitted daily exposure limits for
noteworthy N-nitrosamines. Environ. Mol. Mutagen. 62 (5), 293–305. https://doi.
org/10.1002/em.22446.
Kobets, T., Williams, G.M., 2019. Review of the evidence for thresholds for DNA-Reactive
and epigenetic experimental chemical carcinogens. Chem. Biol. Interact. 301,
88–111. https://doi.org/10.1016/j.cbi.2018.11.011.
Kostal, J., Voutchkova-Kostal, A., 2023. Quantum-mechanical approach to predicting the
carcinogenic potency of N-nitroso impurities in pharmaceuticals. Chem. Res.
Toxicol. 36 (2), 291–304. https://doi.org/10.1021/acs.chemrestox.2c00380.
Kruhlak, N.L., Schmidt, M., Froetschl, R., Graber, S., Haas, B., Horne, I., Horne, S.,
King, S.T., Koval, I.A., Kumaran, G., Langenkamp, A., McGovern, T.J., Peryea, T.,
Sanh, A., Ferreira, A.S., Van Aerts, L., Vespa, A., Whomsley, R., 2024. Determining

recommended acceptable intake limits for N-nitrosamine impurities in
pharmaceuticals: development and application of the carcinogenic potency
categorization approach (CPCA). Regulatory toxicology and pharmacology, volume
150, 2024, lester C, byrd E, shobair M, and yan G. Quantifying analogue suitability
for SAR-based read-across toxicological assessment. Chem. Res. Toxicol. 36 (2),
230–242.
Lantz, R.J., Gillespie, T.A., Rash, T.J., Kuo, F., Skinner, M., Kuan, H.Y., Knadler, M.P.,
2003. Metabolism, excretion, and pharmacokinetics of duloxetine in healthy human
subjects. Drug Metab. Dispos. 31 (9), 1142–1150. https://doi.org/10.1124/
dmd.31.9.1142. PMID: 12920170.
Lester, C., Byrd, E., Shobair, M., Yan, G., 2023 Feb 20. Quantifying analogue suitability
for SAR-based read-across toxicological assessment. Chem. Res. Toxicol. 36 (2),
230–242. https://doi.org/10.1021/acs.chemrestox.2c00311. Epub 2023 Jan 26.
PMID: 36701522; PMCID: PMC9945175.
Li, Y., Hecht, S.S., 2022a. Metabolic activation and DNA interactions of carcinogenic Nnitrosamines to which humans are commonly exposed. Int. J. Mol. Sci. 23 (9), 4559.
https://doi.org/10.3390/ijms23094559.
Li, Y., Hecht, S.S., 2022b. Metabolism and DNA adduct formation of tobacco-specific
NNitrosamines. Int. J. Mol. Sci. 23 (9), 5109. https://doi.org/10.3390/
ijms23095109.From.NLM.Medline.
López-López, J.A., Ayala, R., 2016. Assessment of the performance of commonly used
DFT functionals vs. MP2 in the study of IL-Water, IL-Ethanol and IL-(H2O)3 clusters.
J. Mol. Liq. 220, 970–982.
Lynch, A.M., Howe, J., Hildebrand, D., Harvey, J.S., Burman, M., Harte, D.S.G., Chen, L.,
Kmett, C., Shi, W., McHugh, C.F., Patel, K.K., Junnotula, V., Kenny, J., Haworth, R.,
Wills, J.W., 2024. N-Nitrosodimethylamine investigations in Muta™Mouse define
point-of-departure values and demonstrate less-than-additive somatic mutant
frequency accumulations. Mutagenesis 39 (2), 96–118. https://doi.org/10.1093/
mutage/geae001. PMID: 38183622; PMCID: PMC10928842.
Mandrioli, R., Forti, G.C., Raggi, M.A., 2006. Fluoxetine metabolism and
pharmacological interactions: the role of cytochrome p450. Curr. Drug Metabol. 7
(2), 127–133.
Mardirossian, N., Head-Gordon, M., 2016. How accurate are the Minnesota density
functionals for noncovalent interactions, isomerization energies, thermochemistry,
and barrier heights involving molecules composed of main-group elements? J. Chem.
Theor. Comput. 12, 4303–4325.
McCann, J., Gold, Lois Swirsky, Horn, Laura, McGill, R., Graedel, T.E., Kaldor, John,
1988. Statistical analysis of Salmonella test data and comparison to results of animal
cancer tests. Mutat. Res. Genet. Toxicol. 205 (Issues 1–4), 183–195. ISSN 0165-1218.
Meanwell, N.A., 2011. Improving drug candidates by design: a focus on physicochemical
properties as a means of improving compound disposition and safety. Chem. Res.
Toxicol. 24 (9), 1420–1456. https://doi.org/10.1021/tx200211v.From.NLM.
Medline.
Moser, I.W., Ashworth, Harris, L., Hillier, M.C., Nanda, K.K., Scrivens, G., 2023. Nnitrosamine formation in pharmaceutical solid drug products: experimental
observations. J. Pharmaceut. Sci. 112 (5), 1255–1267.
Nudelman, R., Kocks, Grace, Mouton, Bruno, Ponting, David J., Schlingemann, Joerg,
Simon, Stephanie, Smith, Graham F., Teasdale, Andrew, Werner, Anne-Laure, 2023.
The nitrosamine “saga”: lessons learned from five years of scrutiny. Organic Process
Research & Development Article ASAP. https://doi.org/10.1021/acs.oprd.3c00100.
OECD Organisation for Economic Co-operation and Development, 2022. OECD Guideline
for the Testing of Chemicals. Test Guideline 488: Transgenic Rodent Somatic and
Germ Cell Gene Mutation Assays. OECD, Paris, France. https://doi.org/10.1787/
9789264203907-en.
Oliveiria, A.A., Martins-Avila, C., Ponting, D.J., 2023. Collaborative analysis of complex
nitrosamines. The Toxicologist, a Supplement to Toxicological Sciences. Abstract
#5063.
Park, H.S., Kang, Y.K., 2019. Which DFT levels of theory are appropriate in predicting
the prolyl cis–trans isomerization in solution? New J. Chem. 43, 17159–17173.
Patlewicz, G., Ball, N., Becker, R.A., Booth, E.D., Cronin, M.T., Kroese, D., Steup, D., van
Ravenzwaay, B., Hartung, T., 2014. Read-across approaches–misconceptions,
promises and challenges ahead. ALTEX 31 (4), 387–396. https://doi.org/10.14573/
altex.1410071. PMID: 25368965.
Ponting, D.J., Foster, R.S., 2023. Drawing a line: where might the cohort of concern end?
Org. Process Res. Dev. 27 (10), 1703–1713. https://doi.org/10.1021/acs.
oprd.3c00008.
Ponting, D.J., Dobo, K.L., Kenyon, M.O., Kalgutkar, A.S., 2022. Strategies for assessing
acceptable intakes for novel N-nitrosamines derived from active pharmaceutical
ingredients. J. Med. Chem. 65 (23), 15584–15607. https://doi.org/10.1021/acs.
jmedchem.2c01498.
Purchase, I.F.H., 1985. A comparison of the potency of mutagenic effect of chemicals in
short-term tests with their carcinogenic effect in rodent carcinogenicity studies. In:
Vouk, Butler (Ed.), Methods for Estimating Risk of Chemical Injury, Hoel and Peakal.
Schlingemann, J., Burns, M.J., Ponting, D.J., Martins Avila, C., Romero, N.E.,
Jaywant, M.A., Smith, G.F., Ashworth, I.W., Simon, S., Saal, C., et al., 2022. The
landscape of PotentiaSmall and drug substance related nitrosamines in
pharmaceuticals. J. Pharmaceut. Sci. https://doi.org/10.1016/j.xphs.2022.11.013.
From.NLM.Publisher.
Schmezer, P., Eckert, C., Liegibel, U.M., Klein, R.G., Bartsch, H., 1998. Use of transgenic
mutational test systems in risk assessment of carcinogens. Arch. Toxicol Suppl. 20,
321–330. https://doi.org/10.1007/978-3-642-46856-8_29. PMID: 9442305.
Thresher, A., Foster, R., Ponting, D.J., Stalford, S.A., Tennant, R.E., Thomas, R., 2020.
Are all nitrosamines concerning? A review of mutagenicity and carcinogenicity data.
Regul. Toxicol. Pharmacol. 116, 104749 https://doi.org/10.1016/j.
yrtph.2020.104749.

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