浅析《毒理学关注阈值（TTC）方法应用技术指南》

doi:10.3969/j.issn.2097-2806.2025.08.011

摘要/Abstract

摘要：

毒理学关注阈值（TTC）是一种风险评估方法，用于确定化学物质的安全暴露阈值，当化学物质的暴露量小于该阈值时，认为其风险可忽略或可接受。2024年5月，中国食品药品检定研究院发布了《毒理学关注阈值（TTC）方法应用技术指南》，该指南首次明确规范了TTC方法用于化妆品安全评估的流程，详细介绍了具体步骤和使用要求。文章对指南的发布背景与意义、TTC方法在化妆品安全评估中的使用原则、TTC方法使用时的注意事项、使用TTC方法对植物提取物原料进行安全评估时的限制条件等进行解读，以期加强指南的指导作用，为更多的从业人员了解、掌握并应用该指南提供参考。

关键词: 毒理学关注阈值, 化妆品安全评估, 化妆品原料, 风险物质, 植物提取物

Abstract:

The threshold of toxicological concern （TTC） is a risk assessment methodology used to determine the safe exposure threshold for chemical substances. When the exposed quantity of a chemical substance is below this threshold, the risk is considered negligible or acceptable. The National Institutes for Food and Drug Control released the technical guidelines for the application of TTC method in May 2024, which for the first time explicitly standardizes the process of using the TTC method for cosmetic safety assessment, and details the specific steps and usage requirements. This paper interprets the background and significance of the release of the guide, the principles of its application in cosmetic safety assessment, the precautions when using the TTC method, and the restrictions when using the TTC method for safety assessment of plant extract raw materials. It aims to enhance the guiding role of the guideline and to provide a reference for more practitioners to understand, master, and apply the guideline.

Key words: the threshold of toxicological concern, cosmetic safety assessment, cosmetic raw materials, risk substances, plant extracts

中图分类号:

TQ658

周奕霏, 罗飞亚, 孙磊, 杨会英, 裴新荣, 吴先富, 路勇. 浅析《毒理学关注阈值（TTC）方法应用技术指南》[J]. 日用化学工业（中英文）, 2025, 55(8): 1042-1048.

Yifei Zhou, Feiya Luo, Lei Sun, Huiying Yang, Xinrong Pei, Xianfu Wu, Yong Lu. Analysis on the technical guidelines for the application of threshold of toxicological concern (TTC) method[J]. China Surfactant Detergent & Cosmetics, 2025, 55(8): 1042-1048.

参考文献 49

[1]	邢书霞. 欧盟和我国化妆品安全性评价体系的比较研究[J]. 中国卫生检验杂志, 2017, 27 (17) : 2581-2584.
[2]	Kim K B, Kwack S J, Lee J Y, et al. Current opinion on risk assessment of cosmetics[J]. Journal of Toxicology and Environmental Health, Part B, 2021, 24 (4) : 137-161.
[3]	Sigurnjak Bureš M, Cvetnić M, Miloloža M, et al. Modeling the toxicity of pollutants mixtures for risk assessment: a review[J]. Environmental Chemistry Letters, 2021, 19 (2) : 1629-1655.
[4]	Kar S, Leszczynski J. Exploration of computational approaches to predict the toxicity of chemical mixtures[J]. Toxics, 2019, 7 (1) : 15.
[5]	Munro I C, Renwick A G, Danielewska-Nikiel B. The threshold of toxicological concern (TTC) in risk assessment[J]. Toxicology Letters, 2008, 180 (2) : 151-156. doi: 10.1016/j.toxlet.2008.05.006 pmid: 18573621
[6]	Frawley J P. Scientific evidence and common sense as a basis for food-packaging regulations[J]. Food and Cosmetics Toxicology, 1967, 5: 293-308. pmid: 4861454
[7]	Gold L S, Sawyer C B, Magaw R, et al. A carcinogenic potency database of the standardized results of animal bioassays[J]. Environmental Health Perspectives, 1984, 58: 9-319. pmid: 6525996
[8]	刘成虎, 施燕平, 杜晓丹, 等. 毒理学关注阈值(TTC)在医疗器械生物学评价中的应用[J]. 中国医疗器械杂志, 2019, 43 (4) : 282-285.
[9]	郑明岚, 周少英, 刘学军, 等. 毒理学关注阈值(TTC)在化学物质风险评估中的应用[J]. 卫生研究, 2010, 39 (5) : 639-642.
[10]	Munro I C, Ford R A, Kennepohl E, et al. Correlation of structural class with no-observed-effect levels: A proposal for establishing a threshold of concern[J]. Food and Chemical Toxicology, 1996, 34 (9) : 829-867. pmid: 8972878
[11]	Brueschweiler B J. The TTC approach in practice and its impact on risk assessment and risk management in food safety. A regulatory toxicologist's perspective[J]. Chimia, 2014, 68 (10) : 710-715. doi: 10.2533/chimia.2014.710 pmid: 25437163
[12]	EFSA Scientific Committee, More S J, Bampidis V, et al. Guidance on the use of the threshold of toxicological concern approach in food safety assessment[J]. EFSA Journal, 2019, 17 (6) : e05708.
[13]	Kroes R, Renwick A G, Feron V, et al. Application of the threshold of toxicological concern (TTC) to the safety evaluation of cosmetic ingredients[J]. Food and Chemical Toxicology, 2007, 45 (12) : 2533-2562. pmid: 17664037
[14]	Belanger S E, Sanderson H, Embry M R, et al. It is time to develop ecological thresholds of toxicological concern to assist environmental hazard assessment[J]. Environmental Toxicology and Chemistry, 2015, 34 (12) : 2864-2869. doi: 10.1002/etc.3132 pmid: 26111584
[15]	Delaney E J. An impact analysis of the application of the threshold of toxicological concern concept to pharmaceuticals[J]. Regulatory Toxicology and Pharmacology, 2007, 49 (2) : 107-124. pmid: 17888551
[16]	朱洲海, 曾婉俐, 管莹. 毒理学关注阈值(TTC)方法的历史演化与发展[J]. 食品科学, 2013, 34 (7) : 340-344. doi: 10.7506/spkx1002-6630-201307072
[17]	Fischer K. Animal testing and marketing bans of the eu cosmetics legislation[J]. European Journal of Risk Regulation, 2017, 6 (4) : 613-621.
[18]	Pham L L, Borghoff S J, Thompson C M. Comparison of threshold of toxicological concern (TTC) values to oral reference dose (RfD) values[J]. Regulatory Toxicology and Pharmacology, 2020, 113: 104651.
[19]	Bernauer U, Bodin L, Chaudhry Q, et al. The SCCS notes of guidance for the testing of cosmetic ingredients and their safety evaluation-12th revision-SCCS/1647/22[R]. Luxembourg: European Commission, 2023.
[20]	Williams F M, Rothe H, Barrett G, et al. Assessing the safety of cosmetic chemicals: Consideration of a flux decision tree to predict dermally delivered systemic dose for comparison with oral TTC (Threshold of toxicological concern)[J]. Regulatory Toxicology and Pharmacology, 2016, 76: 174-186.
[21]	Bury D, Head J, Keller D, et al. The threshold of toxicological concern (TTC) is a pragmatic tool for the safety assessment: Case studies of cosmetic ingredients with low consumer exposure[J]. Regulatory Toxicology and Pharmacology, 2021, 123: 104964.
[22]	裴新荣, 孙磊, 邢书霞. 《化妆品安全评估技术导则(2021年版)》解读[J]. 环境卫生学杂志, 2021, 11 (5) : 442-446.
[23]	Tejs S. The Ames test: a methodological short review[J]. Environmental Biotechnology, 2008, 4 (1) : 7-14.
[24]	Cramer G M, Ford R A, Hall R L. Estimation of toxic hazard—a decision tree approach[J]. Food and Cosmetics Toxicology, 1976, 16 (3) : 255-276.
[25]	Mons M N, Heringa M B, Van Genderen J, et al. Use of the threshold of toxicological concern (TTC) approach for deriving target values for drinking water contaminants[J]. Water Research, 2013, 47 (4) : 1666-1678. doi: 10.1016/j.watres.2012.12.025 pmid: 23312671
[26]	Barle E L, Winkler G C, Glowienke S, et al. Setting occupational exposure limits for genotoxic substances in the pharmaceutical industry[J]. Toxicological Sciences, 2016, 151 (1) : 2-9. doi: 10.1093/toxsci/kfw028 pmid: 27207978
[27]	Etchepare R, Van Der Hoek J P. Health risk assessment of organic micropollutants in greywater for potable reuse[J]. Water Research, 2015, 72: 186-198. doi: 10.1016/j.watres.2014.10.048 pmid: 25472689
[28]	Kasper P. Assessment and acceptance of thresholds of genotoxic impurities in new drug substances[J]. International Journal of Pharmaceutical Medicine, 2004, 18: 209-214.
[29]	Feigenbaum A, Pinalli R, Giannetto M, et al. Reliability of the TTC approach: Learning from inclusion of pesticide active substances in the supporting database[J]. Food and Chemical Toxicology, 2015, 75: 24-38. doi: 10.1016/j.fct.2014.10.016 pmid: 25455897
[30]	Brüschweiler B J. TTC-based risk assessment of tetrachlorobutadienes and pentachlorobutadienes: The in vitro genotoxic contaminants in ground and drinking water[J]. Regulatory Toxicology and Pharmacology, 2010, 58 (2) : 341-344.
[31]	Plugge H, Das N, Kostal J. Toward a universal acute fish threshold of toxicological concern[J]. Environmental Toxicology and Chemistry, 2021, 40 (6) : 1740-1749. doi: 10.1002/etc.4991 pmid: 33492718
[32]	Escher S E, Tluczkiewicz I, Batke M, et al. Evaluation of inhalation TTC values with the database RepDose[J]. Regulatory Toxicology and Pharmacology, 2010, 58 (2) : 259-574.
[33]	Hoersch J, Hoffmann-Doerr S, Keller D. Derivation of an inhalation TTC for the workplace based on DNEL values reported under REACH[J]. Toxicology Letters, 2018, 290: 110-115. doi: S0378-4274(18)30117-6 pmid: 29596887
[34]	Ellison C A, Blackburn K L, Carmichael P L, et al. Challenges in working towards an internal threshold of toxicological concern (iTTC) for use in the safety assessment of cosmetics: Discussions from the Cosmetics Europe iTTC Working Group workshop[J]. Regulatory Toxicology and Pharmacology, 2019, 103: 63-72. doi: 10.1016/j.yrtph.2019.01.016
[35]	Ellison C A, Api A M, Becker R A, et al. Internal threshold of toxicological concern (iTTC): Where we are today and what is possible in the near future[J]. Frontiers in Toxicology, 2021, 2: 621541.
[36]	Kawamoto T, Fuchs A, Fautz R, et al. Threshold of toxicological concern (TTC) for botanical extracts (Botanical-TTC) derived from a meta-analysis of repeated-dose toxicity studies[J]. Toxicology Letters, 2019, 316: 1-9. doi: S0378-4274(19)30221-8 pmid: 31415786
[37]	Mahony C, Bowtell P, Huber M, et al. Threshold of toxicological concern (TTC) for botanicals: Concentration data analysis of potentially genotoxic constituents to substantiate and extend the TTC approach to botanicals[J]. Food and Chemical Toxicology, 2020, 138: 111182.
[38]	Safford R J. The dermal sensitisation threshold: A TTC approach for allergic contact dermatitis[J]. Regulatory Toxicology and Pharmacology, 2008, 51 (2) : 195-200. doi: 10.1016/j.yrtph.2008.02.010 pmid: 18406502
[39]	Bowden A M, Escher S E, Rose J, et al. Workshop report: Challenges faced in developing inhalation thresholds of toxicological concern (TTC): State of the science and next steps[J]. Regulatory Toxicology and Pharmacology, 2023, 142: 105434.
[40]	Blackburn K, Stickney J A, Carlson-Lynch H L, et al. Application of the threshold of toxicological concern approach to ingredients in personal and household care products[J]. Regulatory Toxicology and Pharmacology, 2005, 43 (3) : 249-259. pmid: 16213074
[41]	Re T A, Mooney D, Antignac E, et al. Application of the threshold of toxicological concern approach for the safety evaluation of calendula flower (Calendula officinalis) petals and extracts used in cosmetic and personal care products[J]. Food and Chemical Toxicology, 2009, 47 (6) : 1246-1254. doi: 10.1016/j.fct.2009.02.016 pmid: 19249334
[42]	Jeon S, Lee E Y, Nam S J, et al. Safety assessment of Paeonia lactiflora root extract for a cosmetic ingredient employing the threshold of toxicological concern (TTC) approach[J]. Regulatory Toxicology and Pharmacology, 2024, 149: 105620.
[43]	Jeon S, Lee E Y, Hillman P F, et al. Safety assessment of Cnidium officinale rhizome extract in cosmetics using the threshold of toxicological concern (TTC) approach[J]. Regulatory Toxicology and Pharmacology, 2023, 142: 105433.
[44]	Api A M, Belsito D, Botelho D, et al. RIFM fragrance ingredient safety assessment, S-isopropyl 3-methylthiobutyrate, CAS Registry Number 34322-06-0[J]. Food and Chemical Toxicology, 2020, 141.
[45]	Ma'or Z E, Halicz L, Portugal-Cohen M, et al. Safety evaluation of traces of nickel and chrome in cosmetics: The case of Dead Sea mud[J]. Regulatory Toxicology and Pharmacology, 2015, 73 (3) : 797-801.
[46]	Murat P, Ferre P J, Cosledan S, et al. Assessment of targeted non-intentionally added substances in cosmetics in contact with plastic packagings. Analytical and toxicological aspects[J]. Food and Chemical Toxicology, 2019, 128: 106-118. doi: S0278-6915(19)30158-9 pmid: 30905869
[47]	Leeman W R, Krul L, Houben G F. Reevaluation of the Munro dataset to derive more specific TTC thresholds[J]. Regulatory Toxicology and Pharmacology, 2014, 69 (2) : 273-278.
[48]	Wang Z, Scott W C, Williams E S, et al. Identification of novel uncertainty factors and thresholds of toxicological concern for health hazard and risk assessment: Application to cleaning product ingredients[J]. Environment International, 2018, 113: 357-376. doi: S0160-4120(17)31948-7 pmid: 29452931
[49]	Öberg M. Benchmark dose approaches in chemical health risk assessment in relation to number and distress of laboratory animals[J]. Regulatory Toxicology and Pharmacology, 2010, 58 (3) : 451-454.