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Threshold of toxicological concern values for non-genotoxic effects in industrial chemicals: re-evaluation of the Cramer classification

  • Regulatory Toxicology
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Abstract

The TTC concept employs available data from animal testing to derive a distribution of NOAELs. Taking a probabilistic view, the 5th percentile of the distribution is taken as a threshold value for toxicity. In this paper, we use 824 NOAELs from repeated dose toxicity studies of industrial chemicals to re-evaluate the currently employed TTC values, which have been derived for substances grouped according to the Cramer scheme (Cramer et al. in Food Cosm Toxicol 16:255–276, 1978) by Munro et al. (Food Chem Toxicol 34:829–867, 1996) and refined by Kroes and Kozianowski (Toxicol Lett 127:43–46, 2002), Kroes et al. 2000. In our data set, consisting of 756 NOAELs from 28-day repeated dose testing and 57 NOAELs from 90-days repeated dose testing, the experimental NOAEL had to be extrapolated to chronic TTC using regulatory accepted extrapolation factors. The TTC values derived from our data set were higher than the currently used TTC values confirming the safety of the latter. We analysed the prediction of the Cramer classification by comparing the classification by this tool with the guidance values for classification according to the Globally Harmonised System of classification and labelling of the United Nations (GHS). Nearly 90% of the chemicals were in Cramer class 3 and assumed as highly toxic compared to 22% according to the GHS. The Cramer classification does underestimate the toxicity of chemicals only in 4.6% of the cases. Hence, from a regulatory perspective, the Cramer classification scheme might be applied as it overestimates hazard of a chemical.

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References

  • Australian Guidelines (2008) Australian Guidelines for water recycling: augmentation of drinking water supplies 2008. Environment Protection and Heritage Council, National Health and Medical Research Council, Natural Resource Management Ministerial Council, Australia

    Google Scholar 

  • Barlow S (2005) Threshold of toxicological concern: a tool for assessing substances of unknown toxicity present at low levels in the diet. ILSI Concise monograph series, ISBN 1-57881-188-0. ILSI Press, Washington DC

  • Bernauer U, Heinemeyer G, Heinrich-Hirsch B, Ulbrich B, Gundert-Remy U (2008) Exposure-triggered reproductive toxicity testing under the REACH legislation: a proposal to define significant/relevant exposure. Toxicol Lett 176:68–76

    Article  PubMed  CAS  Google Scholar 

  • BioChemfinder version 12.0 (2009) CambridgeSoft Coroparte, Cambridge, MA 02149, USA

  • Blackburn K, Stickney JA, Carlson-Lynch HL, McGinnis PM, Chappell L, Felter SP (2005) Application of the threshold of toxicological concern approach to ingredients in personal and household care products. Regul Toxicol Pharmacol 43:249–259

    Article  PubMed  CAS  Google Scholar 

  • Carthew P, Clapp C, Gutsell S (2009) Exposure-based waiving: The application of the toxicological threshold of concern (TTC) to inhalation exposure for aerosol ingredients in consumer products. Food Chem Toxicol 47:1287–1295

    Article  PubMed  CAS  Google Scholar 

  • Cramer GM, Ford RA, Hall RL (1978) Estimation of toxic hazard—a decision tree approach. Food Cosm Toxicol 16:255–276

    Article  CAS  Google Scholar 

  • Crane M, Gross MY, Daginnus K, Deviller G, de Wolf W, Dungey S, Galli C, Gourmelon A, Jacobs M, Matthiessen P, Micheletti C, Nestmann E, Pavan M, Paya-Perez A, Ratte T, Safford B, Sokull-Kluttgen B, Stock F, Stolzenberg HC, Wheeler JR, Willuhn M, Worth AP, Zaldivar Comenges JM (2009) Thresholds of toxicological concern for endocrine active substances in the aquatic environment. Integr Environ Assess Manag 6:2–11

    Google Scholar 

  • Dahl SG, Aarons L, Gundert-Remy U, Karlsson MO, Schneider YJ, Steimer JL, Trocóniz IF (2010) Incorporating physiological and biochemical mechanisms into pharmacokinetic-pharmacodynamic models: a conceptual framework. Basic Clin Pharmacol Toxicol 106:2–12

    PubMed  CAS  Google Scholar 

  • Dekant W, Melching-Kollmuß S, Kalberlah F (2010) Toxicity assessment strategies, data requirements, and risk assessment approaches to derive health based guidance values for non-relevant metabolites of plant protection products. Regul Toxicol Pharmacol 56:135–142

    Article  PubMed  CAS  Google Scholar 

  • EC (2008) Regulation No. 1272/2008 Official Journal of the European Union L 353/1-1355. Chapter 3.9.2, Section 3.9.2.95, and 3.9.2.96, Table 3.9.2

  • ECETOC (1995) Assessment factors in human health risk assessment. In: Technical reports European Chemical Industry Ecology and Toxicology Centre. Technical Report 68, ECETOC, Brussels

  • ECHA (2010a) Guidance on information requirements and chemical safety assessment. Part B: Hazard Assessment. Chapter R.5: Adaptation of information requirements. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm?time=1303993238. Accessed 26 May 2011

  • ECHA (2010b) Guidance on information requirements and chemical safety assessment. Part B: Hazard Assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version2 p 29, Table R.8-5. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm?time=1303993238. Accessed: 26 May 2011

  • EMEA (2006) Guideline on the Limits of Genotoxic Impurities. Committee for Medicinal Products for Human Use (CPMP). European Medicines Agency. London, 28 June 2006, CPMP/SWP/5199/02. EMEA/CHMP/QWP/251344/2006. Accessed 20 April 2011

  • EMEA (2007) Draft Guideline on the Assessment of Genotoxic Constituents in Herbal Substances/Preparations. Committee on herbal Medicinal Products (HMPC), European Medicines Agency. London, 31 October 2007, EMEA/HMPC/107079/2007. Accessed 29 April 2011

  • Escher SE, Tluczkiewicz I, Batke M, Bitsch A, Melber C, Kroese ED, Buist HE, Mangelsdorf I (2010) Evaluation of inhalation TTC values with the database RepDose. Reg Toxicol Pharmacol 58:259–274

    Article  CAS  Google Scholar 

  • Fawell J (2008) Health risks of micropollutants–the need for a new approach. Water Sci Technol 57:183–187

    Article  PubMed  CAS  Google Scholar 

  • FDA (2008) Guidance for industry. genotoxic and carcinogenic impurities in drug substances and products: recommended approaches. Draft Guidance. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), December 2008

  • Felter S, Lane RW, Latulippe ME, Llewellyn GC, Olin SS, Scimeca JA, Trautman TD (2009) Refining the threshold of toxicological concern (TTC) for risk prioritization of trace chemicals in food. Food Chem Toxicol 47:2236–2245

    Article  PubMed  CAS  Google Scholar 

  • Gold LS, Zeiger E (eds) (1997) Handbook of carcinogenic potency and genotoxicity databases. CRC Press, Boca Raton

    Google Scholar 

  • Gold LS, Slone TH, Bernstein L (1989) Summary of carcinogenic potency and positivity for 492 rodent carcinogens in the carcinogenic potency database. Environ Health Perspect 79:259–272

    Article  PubMed  CAS  Google Scholar 

  • Guha R, Howard MT, Hutchison GR, Murray-Rust P, Rzepa H, Steinbeck C, Wegner JK, Willighagen Egon (2006) The blue obelisk-interoperability in chemical informatics. J Chem Inf Model 46(3):991–998

    Article  PubMed  CAS  Google Scholar 

  • Humfrey CDN (2007) Recent developments in the risk assessment of potentially genotoxic impurities in pharmaceutical drug substances. Toxicol Sci 100:24–28

    Article  PubMed  CAS  Google Scholar 

  • Kalberlah F, Schneider K (1998) Examination of the data as the basis for the quantification of extrapolation factors. Final report of the research project No. 116 06 113 of the Federal Environmental Agency 797

  • Knudsen TB, Martin MT, Kavlock RJ, Judson RS, Dix DJ, Singh AV (2009) Profiling the activity of environmental chemicals in prenatal developmental toxicity studies using the U.S. EPA’s ToxRefDB. Reprod Toxicol 28:209–219

    Article  PubMed  CAS  Google Scholar 

  • Kroes R, Kozianowski G (2002) Threshold of toxicological concern (TTC) in food safety assessment. Toxicol Lett 127:43–46

    Article  PubMed  CAS  Google Scholar 

  • Kroes R, Galli C, Munro I, Schilter B, Tran L-A, Walker R, Wurtzen G (2000) Threshold of toxicological Concern for chemical substances present in the diet: a practical tool for assessing the need for toxicity testing. Food Chem Toxicol 38:255–312

    Article  PubMed  CAS  Google Scholar 

  • Kroes R, Renwick AG, Cheeseman MA, Kleiner J, Mangelsdorf I, Piersma A, Schilter B, Schlatter J, van Schothorst F, Vos JG, Wurtzen G (2004) Structure-based thresholds of toxicological concern (TTC): guidance for application to substances present at low levels in the diet. Food Chem Toxicol 42:65–83

    Article  PubMed  CAS  Google Scholar 

  • Kroes R, Renwick AG, Feron V, Galli CL, Gibney M, Greim H, Guy RH, Lhuguenot JC, van de Sandt JJ (2007) Application of the threshold of toxicological concern (TTC) to the safety evaluation of cosmetic ingredients. Food Chem Toxicol 45:2533–2562

    Article  PubMed  CAS  Google Scholar 

  • Mazzatorta P, Estevez MD, Coulet M, Schilter B (2008) Modeling oral rat chronic toxicity. J Chem Inf Model 10:1949–1954

    Article  Google Scholar 

  • Melching-Kollmuß S, Dekant W, Kalberlah F (2010) Application of the “threshold of toxicological concern” to derive tolerable concentrations of “non-relevant metabolites” formed from plant protection products in ground and drinking water. Reg Toxicol Pharmacol 56:126–134

    Article  Google Scholar 

  • Müller L, Mauthe RJ, Riley CM, Andino MM, De Antonis D, Beels C, DeGeorge J, De Knaep AGM, Ellison D, Fagerland JA, Frank R, Fritschel B, Galloway S, Harpur E, Humfrey CDN, Jacks AS, Jagota N, Mackinnon J, Mohan G, Ness DK, O’Donovan MR, Smith MD, Vudathala G, Yotti L (2006) A rationale for determining, testing and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity. Reg Toxicol Pharmacol 44:198–211

    Article  Google Scholar 

  • Munro IC, Ford RA, Kennepohl E, Sprenger JG (1996) Correlation of structural class with no-observed effect levels: a proposal for establishing a threshold of concern. Food Chem Toxicol 34:829–867

    Article  PubMed  CAS  Google Scholar 

  • OECD (Organisation for Economic Co-operation and Development) (1998a) Guideline for the testing of chemicals. Section 4: Health effects. Repeated dose 28-day oral toxicity study in rodents. ISBN: 9789264070707

  • OECD (Organisation for Economic Co-operation and Development) (1998b) Guideline for the testing of Chemicals. Section 4: Health effects. Repeated dose 90-day oral toxicity study in rodents. ISBN: 9789264070707

  • Patlewicz G, Jeliazkova N, Safford RJ, Worth AP, Aleksiev B (2008) An evaluation of the implementation of the Cramer classification scheme in the Toxtree software. SAR QSAR Environ Res 19:495–524

    Article  PubMed  CAS  Google Scholar 

  • Renwick AG (2004) Toxicology databases and the concept of thresholds of toxicological concern as used by the JECFA for the safety evaluation of flavouring agents. Toxicol Lett 149:223–234

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez C, Cook A, Van Buynder P, Devine B, Weinstein P (2007a) Screening health risk assessment of micropollutants for indirect potable reuse schemes: a three-tiered approach. Water Sci Technol 56:35–42

    PubMed  CAS  Google Scholar 

  • Rodriguez C, Weinstein P, Cook A, Devine B, Van Buynder P (2007b) A proposed approach for the assessment of chemicals in indirect potable reuse schemes. J Toxicol Environ Health Part A 70:1654–1663

    Article  PubMed  CAS  Google Scholar 

  • Safford RJ (2008) The dermal sensitisation threshold—a TTC approach for allergic contact dermatitis. Regul Toxicol Pharmacol 51:195–200

    Article  PubMed  CAS  Google Scholar 

  • SCP (2000). Opinion of the scientific committee on plants regarding the draft guidance document on relevant metabolites (Document SANCO/221/2000-Rev.2 of October 1999) (opinion adopted by the Scientific Committee on Plants on 30 November 2000). http://ec.europa.eu/food/fs/sc/scp/out82_ppp_en.html

  • R Development Core Team (2011) R: a language and environment for statistical computing, R foundation for statistical computing,Vienna, Austria, ISBN: 3-900051-07-0. http://www.R-project.org

  • UNECE (2009) GHS (Globally Harmonized System of Classification and Labelling of Chemicals) 3rd revised Edition. Geneva, Switzerland. http://live.unece.org/fileadmin/DAM/trans/danger/publi/ghs/ghs_rev03/English/03e_part3.pdf

  • van Ravenzwaay B, Dammann M, Buesen R, Schneider S (2011) The threshold of toxicological concern for prenatal developmental toxicity. Regul Toxicol Pharmacol 59:81–90

    Article  PubMed  Google Scholar 

  • Weininger D (1988) SMILES, a chemical language and information system. 1. Introduction to methodology and encoding rules. J Chem Inf Comput Sci 28:31–36

    Article  CAS  Google Scholar 

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Acknowledgments

This work was supported by a grant from German Federal Ministry of Environment, Radiation Protection and Nature Conservation, Germany; Project No. UBA/Z 6, Kap. 1602/Tit.685 04, 90381-547. We thank Dr. Ulrike Bernauer, BfR, for her comments on an earlier version of this paper. Data presented in this publication are part of the Master Thesis of Dr. Hoger Kalkhof prepared during the Master educational program at Charité–Universitätsmedizin Berlin.

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The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Institute for Clinical Pharmacology and Toxicology, Charité–Universitätsmedizin Berlin, Luisenstr. 7, 10117, Berlin, Germany

    H. Kalkhof, R. Stahlmann & U. Gundert-Remy

  2. Federal Institute for Risk Assessment, BfR, Bundesinstitut fuer Risikobewertung, Thielallee, 88-92, 14195, Berlin, Germany

    M. Herzler & U. Gundert-Remy

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  1. H. Kalkhof
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Correspondence to U. Gundert-Remy.

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Kalkhof, H., Herzler, M., Stahlmann, R. et al. Threshold of toxicological concern values for non-genotoxic effects in industrial chemicals: re-evaluation of the Cramer classification. Arch Toxicol 86, 17–25 (2012). https://doi.org/10.1007/s00204-011-0732-z

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