Skip to main content

Advertisement

SpringerLink
Log in

Feasibility study to support a threshold of sensitization concern concept in risk assessment based on human data

  • Regulatory Toxicology
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

In analogy to the Threshold of Toxicological Concern concept, a Threshold of Sensitization Concern (TSC) concept is proposed for chemicals with respect to their ability to induce an allergic contact dermatitis. Recently, the derivation of a dermal sensitization threshold was suggested based on an evaluation of animal data. In order to establish the concept with human data, we conducted a meta-analysis taking into account No Expected Sensitization Induction Levels for fragrance ingredients from the IFRA/RIFM dataset. Based on a statistical analysis by applying Sensitization Assessment Factors that account for interindividual variability and different exposure conditions, TSC values of 0.91 or 0.30 μg/cm2 can be derived in terms of amount per skin area. TSC values are compared with typical exposure levels of cosmetic products. A substance can be considered to be virtually safe if the quotient of exposure level and TSC is <1. The findings derived from human data include several conservative assumptions and largely support the dermal sensitization thresholds previously derived from animal data. The TSC concept might in principle be used for any untested chemical and therefore help in some cases to waive animal testing.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

AEL:

Acceptable Exposure Level

Deo/AP:

Deodorants/antiperspirants

EC3:

Effective concentration inducing a threefold increase of lymph node responses compared to controls

ECETOC:

European Centre for Ecotoxicology and Toxicology of Chemicals

ELINCS:

European list of notified substances

HRIPT:

Human repeated insult patch test

IFRA:

International Fragrance Association

LLNA:

Local lymph node assay

NESIL:

No Expected Sensitization Induction Level

NO(A)EL:

No Observed (Adverse) Effect Level

QRA:

Quantitative risk assessment

(Q)SAR:

(Quantitative) Structure Activity Relationship

REACH:

Registration, Evaluation and Authorisation of Chemicals

RIFM:

Research Institute for Fragrance Materials, Inc.

SAF:

Sensitization Assessment Factor

TSC:

Threshold of Sensitization Concern

TTC:

Threshold of Toxicological Concern

References

  • Api AM (2002) Sensitization methodology and primary prevention of the research institute for fragrance materials. Dermatology (Basel, Switzerland) 205:84–87

    Google Scholar 

  • Api AM, Basketter DA, Cadby A, Cano M-F, Ellis G, Gerberick GF, Griem P, McNamee PM, Ryan CA, Safford B (2006) Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients. Toxicologist 90:465

    Google Scholar 

  • Api AM, Basketter DA, Cadby PA, Cano MF, Ellis G, Gerberick GF, Griem P, McNamee PM, Ryan CA, Safford R (2008) Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients. Regul Toxicol Pharmacol 52:3–23

    Article  CAS  PubMed  Google Scholar 

  • Azzalini A (1985) A class of distributions which includes the normal ones. Scand J Statis 12:171–178

    Google Scholar 

  • Azzalini A (2008) R package ‘sn’: the skew-normal and skew-t distributions (version 0.4-10). http://azzalini.stat.unipd.it/SN

  • Bailey NTJ (1995) Statistical methods in biology. Cambridge University Press, Cambridge

    Google Scholar 

  • Barratt MD, Langowski JJ (1999) Validation and subsequent development of the DEREK skin sensitization rulebase by analysis of the BgVV list of contact allergens. J Chem Inf Comput Sci 39:294–298

    CAS  PubMed  Google Scholar 

  • Basketter DA, Andersen KE, Liden C, Van Loveren H, Boman A, Kimber I, Alanko K, Berggren E (2005a) Evaluation of the skin sensitizing potency of chemicals by using the existing methods and considerations of relevance for elicitation. Contact Derm 52:39–43

    Article  CAS  PubMed  Google Scholar 

  • Basketter DA, Clapp C, Jefferies D, Safford B, Ryan CA, Gerberick F, Dearman RJ, Kimber I (2005b) Predictive identification of human skin sensitization thresholds. Contact Derm 53:260–267

    Article  PubMed  Google Scholar 

  • 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  CAS  PubMed  Google Scholar 

  • EFFA (2008) EFFA code of practice 2008 version 2 for the hazard classification and labelling and for transport of flavour and fragrance substances and preparations according to the EU-regulations (Attachment 1-3). http://www.effa.be/cop_2008.htm

  • Frawley JP (1967) Scientific evidence and common sense as a basis for food-packaging regulations. Food Cosmet Toxicol 5:293–308

    Article  CAS  PubMed  Google Scholar 

  • Gerberick GF, Robinson MK, Felter SP, White IR, Basketter DA (2001) Understanding fragrance allergy using an exposure-based risk assessment approach. Contact Derm 45:333–340

    Article  CAS  PubMed  Google Scholar 

  • Gerberick GF, Ryan CA, Kern PS, Schlatter H, Dearman RJ, Kimber I, Patlewicz GY, Basketter DA (2005) Compilation of historical local lymph node data for evaluation of skin sensitization alternative methods. Dermatitis 16:157–202

    PubMed  Google Scholar 

  • Healy MJ (1979) Outliers in clinical chemistry quality-control schemes. Clin Chem 25:675–677

    CAS  PubMed  Google Scholar 

  • International Fragrance Association (2003) IFRA Standard—linalool—38th Amendment

  • International Fragrance Association (2006a) IFRA Standard—citral—40th Amendment

  • International Fragrance Association (2006b) IFRA Standard—farnesol—40th Amendment

  • International Fragrance Association (2006c) IFRA Standard—phenylacetaldehyde—40th Amendment

  • International Fragrance Association (2007a) IFRA Standard—alpha-amyl cinnamic alcohol—42nd Amendment

  • International Fragrance Association (2007b) IFRA Standard—alpha- amyl cinnamic aldehyde—42nd Amendment

  • International Fragrance Association (2007c) IFRA Standard—alpha-hexyl cinnamic aldehyde—42nd Amendment

  • International Fragrance Association (2007d) IFRA Standard—alpha-methyl cinnamic aldehyde—42nd Amendment

  • International Fragrance Association (2007e) IFRA Standard—anisyl alcohol—42nd Amendment

  • International Fragrance Association (2007f) IFRA Standard—benzyl alcohol—42nd Amendment

  • International Fragrance Association (2007g) IFRA Standard—benzyl benzoate—42nd Amendment

  • International Fragrance Association (2007h) IFRA Standard—benzyl cinnamate—42nd Amendment

  • International Fragrance Association (2007i) IFRA Standard—benzyl salicylate—42nd Amendment

  • International Fragrance Association (2007j) IFRA Standard—citronellol—42nd Amendment

  • International Fragrance Association (2007k) IFRA Standard—geraniol—42nd Amendment

  • International Fragrance Association (2007l) IFRA Standard—hexyl salicylate—42nd Amendment

  • International Fragrance Association (2007m) IFRA Standard—isocyclocitral—42nd Amendment

  • International Fragrance Association (2008a) IFRA Standard—1-(1,2,3,4,5,6,7,8-octahydro-2,3,8,8-tetramethyl-2-naphthalenyl) ethanone (OTNE)—43rd Amendment

  • International Fragrance Association (2008b) IFRA Standard—1-octen-3-yl acetate—43rd Amendment

  • International Fragrance Association (2008c) IFRA Standard—2-ethoxy-4-methylphenol—43rd Amendment

  • International Fragrance Association (2008d) IFRA Standard—2-methoxy-4-methylphenol—43rd Amendment

  • International Fragrance Association (2008e) IFRA Standard—2,2-dimethyl-3-(3-tolyl)propan-1-ol—43rd Amendment

  • International Fragrance Association (2008f) IFRA Standard—3-propylidenephthalide—43rd Amendment

  • International Fragrance Association (2008g) IFRA Standard—3 and 4-(4-hydroxy-4-methylpentyl)-3-cyclohexene-1-carboxaldehyde (HMPCC)—43rd Amendment

  • International Fragrance Association (2008h) IFRA Standard—alpha-43A hexylidene cyclopentanone—43rd Amendment

  • International Fragrance Association (2008i) IFRA Standard—carvone—43rd Amendment

  • International Fragrance Association (2008j) IFRA Standard—cinnamic alcohol—43rd Amendment

  • International Fragrance Association (2008k) IFRA Standard—cinnamic aldehyde—43rd Amendment

  • International Fragrance Association (2008l) IFRA Standard—cinnamyl nitrile—43rd Amendment

  • International Fragrance Association (2008m) IFRA Standard—coumarin—43rd Amendment

  • International Fragrance Association (2008n) IFRA Standard—eugenol—43rd Amendment

  • International Fragrance Association (2008o) IFRA Standard—hydroxycitronellal—43rd Amendment

  • International Fragrance Association (2008p) IFRA Standard—isocyclogeraniol—43rd Amendment

  • International Fragrance Association (2008q) IFRA Standard—isoeugenol—43rd Amendment

  • International Fragrance Association (2008r) IFRA Standard—jasmine absolute (grandiflorum)—43rd Amendment

  • International Fragrance Association (2008s) IFRA Standard—jasmine absolute (sambac)—43rd Amendment

  • International Fragrance Association (2008t) IFRA Standard—menthadiene-7-methyl formate—43rd Amendment

  • International Fragrance Association (2008u) IFRA Standard—methoxy dicyclopentadiene carboxaldehyde (scentenal)—43rd Amendment

  • International Fragrance Association (2008v) IFRA Standard—methyl heptine carbonate—43rd Amendment

  • International Fragrance Association (2008w) IFRA Standard—methyl ionone, mixed isomers—43rd Amendment

  • International Fragrance Association (2008x) IFRA Standard—methyl octine carbonate—43rd Amendment

  • International Fragrance Association (2008y) IFRA Standard—Oakmoss Extracts—43rd Amendment

  • International Fragrance Association (2008β) IFRA Standard—p-tert-butyldihydrocinnamaldehyde (bourgeonal)—43rd Amendment

  • International Fragrance Association (2008α) IFRA Standard—p-tert-butyl-alpha-methylhydrocinnamic aldehyde (BMHCA)—43rd Amendment

  • International Fragrance Association (2008γ) IFRA Standard—peru balsam extracts and distillates—43rd Amendment

  • International Fragrance Association (2008δ) IFRA Standard—rose ketones—43rd Amendment

  • International Fragrance Association (2008ζ) IFRA Standard—treemoss extracts—43rd Amendment

  • International Fragrance Association (2008ε) IFRA Standard—trans-2-hexenal—43rd Amendment

  • International Fragrance Association (2008η) IFRA Standard—ylang ylang extracts—43rd Amendment

  • International Fragrance Association (2008z) IFRA Standard—p-mentha-1,8-dien-7-al (perilla aldehyde)—43rd Amendment

  • Kimber I, Basketter DA, Butler M, Gamer A, Garrigue JL, Gerberick GF, Newsome C, Steiling W, Vohr HW (2003) Classification of contact allergens according to potency: proposals. Food Chem Toxicol 41:1799–1809

    Article  CAS  PubMed  Google Scholar 

  • Kroes R, Galli C, Munro I, Schilter B, Tran L, 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  CAS  PubMed  Google Scholar 

  • Kroes R, Renwick AG, Cheeseman M, 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  CAS  PubMed  Google Scholar 

  • Kroes R, Kleiner J, Renwick A (2005) The threshold of toxicological concern concept in risk assessment. Toxicol Sci 86:226–230

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Langton K, Patlewicz GY, Long A, Marchant CA, Basketter DA (2006) Structure-activity relationships for skin sensitization: recent improvements to derek for windows. Contact Derm 55:342–347

    Article  CAS  PubMed  Google Scholar 

  • McNamee PM, Api AM, Basketter DA, Frank Gerberick G, Gilpin DA, Hall BM, Jowsey I, Robinson MK (2008) A review of critical factors in the conduct and interpretation of the human repeat insult patch test. Regul Toxicol Pharmacol. 52(1):24–34

    Article  PubMed  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  CAS  PubMed  Google Scholar 

  • Oppel T, Schnuch A (2006) Häufigste Auslöser allergischer Kontaktekzeme (The most frequent allergens in allergic contact dermatitis). Dtsch Med Wochenschr 131:1584–1589

    Article  CAS  PubMed  Google Scholar 

  • Politano VT, Api AM (2008) The research institute for fragrance materials’ human repeated insult patch test protocol. Regul Toxicol Pharmacol. 52(1):35–38

    Article  CAS  PubMed  Google Scholar 

  • R-Development-Core-Team (2008) R: a language and environment for statistical computing. Vienna, Austria

    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  CAS  PubMed  Google Scholar 

  • Rulis AM (1986) De minimis and the threshold of regulation. In: Felix CW (ed) Food protection technology. Lewis Publishers, Chelsea, pp 29–37

    Google Scholar 

  • Safford RJ (2008) The dermal sensitisation threshold-A TTC approach for allergic contact dermatitis. Regul Toxicol Pharmacol 51(2):195–200

    Article  CAS  PubMed  Google Scholar 

  • Schnuch A, Geier J, Uter W, Frosch PJ, Lehmacher W, Aberer W, Agathos M, Arnold R, Fuchs T, Laubstein B, Lischka G, Pietrzyk PM, Rakoski J, Richter G, Rueff F (1997) National rates and regional differences in sensitization to allergens of the standard series. Population-adjusted frequencies of sensitization (PAFS) in 40, 000 patients from a multicenter study (IVDK). Contact Derm 37:200–209

    Article  CAS  PubMed  Google Scholar 

  • Schnuch A, Uter W, Geier J, Lessmann H, Frosch PJ (2007) Sensitization to 26 fragrances to be labelled according to current European regulation. Results of the IVDK and review of the literature. Contact Derm 57:1–10

    Article  CAS  PubMed  Google Scholar 

  • Varmuza K (1998) Chemometrics: multivariate view on chemical problems. In: Schleyer PVR, Allinger NL, Clark T, Gasteiger J, Kollman PA, Schaefer HFIII, Schreiner PR (eds) Encyclopedia of computational chemistry. Wiley, Chichester, pp 346–366

    Google Scholar 

Download references

Acknowledgments

The authors would like to thank Elke Mertens for editorial assistance and Winfried Steiling for reviewing the manuscript.

Author information

Authors and Affiliations

  1. Corporate Product Safety, Department of Human Safety Assessment, Henkel AG & Co. KGaA, Düsseldorf, Germany

    Detlef Keller & Julia Scheel

  2. Adhesive Technologies, Scientific Computing, Henkel AG & Co. KGaA, Düsseldorf, Germany

    Matthias Krauledat

Authors
  1. Detlef Keller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthias Krauledat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Julia Scheel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Julia Scheel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Keller, D., Krauledat, M. & Scheel, J. Feasibility study to support a threshold of sensitization concern concept in risk assessment based on human data. Arch Toxicol 83, 1049–1060 (2009). https://doi.org/10.1007/s00204-009-0460-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-009-0460-9

Keywords

Search

Navigation