Browse > Article
http://dx.doi.org/10.1007/s43188-020-00069-8

Filling data gap for nicotinic acid, nicotinate esters and nicotinamide for the determination of permitted daily exposure by a category approach  

Charehsaz, Mohammad (Department of Toxicology, Faculty of Pharmacy, Yeditepe University)
Tugcu, Gulcin (Department of Toxicology, Faculty of Pharmacy, Yeditepe University)
Aydin, Ahmet (Department of Toxicology, Faculty of Pharmacy, Yeditepe University)
Publication Information
Toxicological Research / v.37, no.3, 2021 , pp. 337-344 More about this Journal
Abstract
This study aimed to obtain necessary toxicological data using experimental and computational methods for the calculation of a common permitted daily exposure (PDE) which can be relevant for nicotinic acid and its esters and nicotinamide according to European Medicines Agency Guideline on setting health-based exposure limits. PDE calculation is mainly based on critical toxicological endpoints. During this procedure, critical toxicological endpoints data of an active pharmaceutical ingredient (API) may not be able to find satisfactorily. Hence, using toxicological data for another API that has a similar chemical structure can be a useful way. In this study, toxicological endpoints of nicotinic acid and its esters and nicotinamide were evaluated. Then, the data gaps in the toxicological endpoints were filledusing the read-across approach. Based on the current existing data, nicotinic acid and its esters and also nicotinamide are not genotoxic and do not have skin sensitization potential. These compounds do not present a concern for carcinogenicity and developmental/reproductive toxicity. Based on these critical endpoints and available experimental data, the final PDE of 10 mg/day was calculated for all category members. Our study showed the utility of the read-across for PDE calculation of APIs with experimental toxicological data gap.
Keywords
Read-across; Risk assessment; PDE; API;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Gini G, Franchi AM, Manganaro A, Golbamaki A, Benfenati E (2014) ToxRead: a tool to assist in read across and its use to assess mutagenicity of chemicals. SAR QSAR Environ Res 25:999-1011. https://doi.org/10.1080/1062936X.2014.976267   DOI
2 Gibney MJ, Lanham-New SA, sidy A, Vorster HH (2009) Introduction to human nutrition. Wiley, Chichester
3 Kristl J, Abramovie Z, Sentjure M (2003) Skin oxygenation after topical application of liposome-entrapped benzyl nicotinate as measured by EPR oximetry in vivo: influence of composition and size. AAPS Pharm Sci 5:19-27. https://doi.org/10.1208/ps050102   DOI
4 Koivukangas V, Oikarinen A, Salmela PI, Lahti A (2000) Microcirculatory response of skin to benzoic acid and methyl nicotinate in patients with diabetes. Diabet Med 17:130-133. https://doi.org/10.1046/j.1464-5491.2000.00248.x   DOI
5 Matthews P, Derry S, Moore RA, McQuay HJ (2009) Topical rubefacients for acute and chronic pain in adults. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD007403.pub2   DOI
6 Zaretzki J, Matlock M, Swamidass SJ (2013) XenoSite: accurately predicting CYP-mediated sites of metabolism with neural networks. J Chem Inf Model 53:3373-3383. https://doi.org/10.1021/ci400518g   DOI
7 US EPA (2012) Estimation Programs Interface SuiteTM (EPI Suite) for Microsoft VRWindows, v.4.1. United States Environmental Protection Agency, Washington
8 Naumann BD, Weideman PA (1995) Scientific basis for uncertainty factors used to establish occupational exposure limits for pharmaceutical active ingredients. Hum Ecol Risk Assess 1:590-613. https://doi.org/10.1080/10807039509380049   DOI
9 IdeaConsult (2015) Toxtree (v.3.1.0) Toxic Hazard Estimation by Decision Tree Approach
10 Varsou DD, Melagraki G, Sarimveis H, Afantitis A (2017) MouseTox: an online toxicity assessment tool for small molecules through Enalos Cloud platform. Food Chem Toxicol 110:83-93. https://doi.org/10.1016/j.fct.2017.09.058   DOI
11 World Health Organization (WHO) (2001) Guidance document for the use of data in development of chemical-specific adjustment factors (CSAFs) for interspecies differences and human variability in dose/concentration-response assessment. WHO/PCS/01.4. pp 1-77
12 International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). ICH harmonized tripartite guideline. Impurities: guideline for residual solvents Q3C(R5). https://www.pmda.go.jp/files/000156308.pdf. Accessed 15 July 2020
13 EMEA (1998) Methyl nicotinate-summary report. Committee for veterinary medicinal products. EMEA/MRL/465/98-Final. https://s3-us-west-2.amazonaws.com/drugbank/cite_this/attachments/files/000/000/063/original/WC500015074.pdf?1526077961. Accessed 15 July 2020
14 Petley AM, Wilkin TJ (1992) Oral nicotinamide impairs growth of rats. Diabetologia 35:A202
15 Patlewicz G, Ball N, Booth ED, Hulzebos E, Zvinavashe E, Hennes C (2013) Use of category approaches, read-across and (Q)SAR: general considerations. Regul Toxicol Pharmacol 67:1-12. https://doi.org/10.1016/j.yrtph.2013.06.002   DOI
16 International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). ICH harmonized tripartite guideline. Impurities: guideline for residual solvents Q3C (R6). https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3C/Q3C__R6___Step_4.pdf. Accessed 20 July 2020
17 Sussman RG, Naumann BD, Pfister T, Sehner C, Seaman C, Weideman PA (2016) A harmonization effort for acceptable daily exposure derivation-considerations for application of adjustment factors. Regul Toxicol Pharmacol 79:S57-S66. https://doi.org/10.1016/j.yrtph.2016.05.023   DOI
18 Pharmaceutical Inspection Convention, Co-Operation Scheme (PIC/S), Guide to good manufacturing practice for medicinal products, Annex 15. PS/INF 11/2015; 1 April 2015. https://picscheme.org/layout/document.php?id=118. Accessed 15 July 2020
19 Lovsin Barle E, Bizec JC, Glogovac M, Gromek K, Winkler GC (2018) Determination and application of the permitted daily exposure (PDE) for topical ocular drugs in multipurpose manufacturing facilities. Pharm Dev Technol 23:225-230. https://doi.org/10.1080/10837450.2017.1312442   DOI
20 Tugcu G, Charehsaz M, Aydin A (2019) Toxicological evaluation of ergocalciferol, cholecalciferol, and their metabolites by a category approach. Drug Chem Toxicol. https://doi.org/10.1080/01480545.2019.1650061   DOI
21 ECHA. Read-across Assessment Framework (RAAF). ECHA, Helsinki, Finland ECHA-17-R-01-EN. https://echa.europa.eu/documents/10162/13628/raaf_en.pdf. Accessed 18 July 2020
22 European Commission. Opinion of the scientific committee on food on the tolerable upper intake level of nicotinic acid and nicotinamide. https://ec.europa.eu/food/sites/food/files/safety/docs/sci-com_scf_out80j_en.pdf. Accessed 18 July 2020
23 Benigni R, Bossa C, Tcheremenskaia O, Battistelli CL, Crettaz P (2012) The new ISSMIC database on in vivo micronucleus and its role in assessing genotoxicity testing strategies. Mutagenesis 27:87-92. https://doi.org/10.1093/mutage/ger064   DOI
24 EPA. Inert reassessment of nicotinamide. https://www.epa.gov/sites/production/files/2015-04/documents/nicotinamide.pdf. Accessed 20 July 2020
25 US EPA (2016) Toxicity Estimation Software Tool (T.E.S.T.), v.4.2.1. United States Environmental Protection Agency, Washington
26 Ji C, Svensson F, Zoufir A, Bender A (2018) eMolTox: prediction of molecular toxicity with confidence. Bioinformatics 34:2508-2509. https://doi.org/10.1093/bioinformatics/bty135   DOI
27 Braga RC, Alves VM, Muratov EN et al (2017) Pred-Skin: a fast and reliable web application to assess skin sensitization effect of chemicals. J Chem Inf Model 57:1013-1017. https://doi.org/10.1021/acs.jcim.7b00194   DOI
28 Unna K (1939) Studies on the toxicity and pharmacology of nicotinic acid. J Pharmacol Exp Ther 65:95-103
29 Handler P, Dann WJ (1942) The inhibition of rat growth by nicotinamide. J Biol Chem 146:357-368   DOI
30 Horger LM, Gerheim EB (1958) Effects of excess dietary methionine and niacinamide in the rat. Proc Soc Exp Biol Med 97:444-446. https://doi.org/10.3181/00379727-97-23769   DOI
31 Schoental R (1977) The role of nicotinamide and of certain other modifying factors in diethylnitrosamine carcinogenesis: fusaria mycotoxins and "spontaneous" tumors in animals and man. Cancer 40:1833-1840. https://doi.org/10.1002/1097-0142(197710)40:4+<1833::aid-cncr2820400810>3.0.co;2-l   DOI
32 EMA (2014) Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. EMA/CHMP/CVMP/SWP/169430/2012. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-setting-health-based-exposure-limits-use-riskidentification-manufacturedifferent_en.pdf. Accessed 15 July 2020
33 Roe FJC (1964) Effect of massive doses of riboflavin, and other vitamins of the B group, on skin carcinogenesis in mice. Br J Cancer 16:252-257. https://doi.org/10.1038/bjc.1962.29   DOI
34 Rakieten N, Gordon BS, Beaty A, Cooney DA, Schein PS, Dixon RL (1976) Modification of renal tumorigenic effect of streptozotocin by nicotinamide: spontaneous reversibility of streptozotocin diabetes. Proc Soc Exp Biol Med 151:356-361. https://doi.org/10.3181/00379727-151-39209   DOI
35 Toth B (1983) Lack of carcinogenicity of nicotinamide and isonicotinamide following lifelong administration to mice. Oncology 40:72-75. https://doi.org/10.1159/000225695   DOI
36 Lahti A, Maibach HI (1984) An animal model for nonimmunologic contact urticaria. Toxicol Appl Pharmacol 76:219-224. https://doi.org/10.1016/0041-008X(84)90002-4   DOI