http://fragrancematerialsafetyresource.elsevier.com/sites/default/files/Criteria_Document_Final.pdf

Criteria for the Research Institute for Fragrance Materials, Inc. (RIFM) safety evaluation process for fragrance ingredients

The threshold of toxicological concern (TTC) is a pragmatic risk assessment tool that is based on the principle of establishing a human exposure threshold value for all chemicals, below which there is a very low probability of an appreciable risk to human health. The concept that there are levels of exposure that do not cause adverse effects is inherent in setting acceptable daily intakes (ADIs) for chemicals with known toxicological profiles. The TTC principle extends this concept by proposing that a de minimis value can be identified for many chemicals, in the absence of a full toxicity database, based on their chemical structures and the known toxicity of chemicals which share similar structural characteristics. The establishment and application of widely accepted TTC values would benefit consumers, industry and regulators. By avoiding unnecessary toxicity testing and safety evaluations when human intakes are below such a threshold, application of the TTC approach would focus limited resources of time, cost, animal use and expertise on the testing and evaluation of substances with the greatest potential to pose risks to human health and thereby contribute to a reduction in the use of animals. An Expert Group of the European branch of the International Life Sciences Institute-ILSI Europe-has examined the TTC principle for its wider applicability in food safety evaluation. The Expert Group examined metabolism and accumulation, structural alerts, endocrine disrupting chemicals and specific endpoints, such as neurotoxicity, teratogenicity, developmental toxicity, allergenicity and immunotoxicity, and determined whether such properties or endpoints had to be taken into consideration specifically in a step-wise approach. The Expert Group concluded that the TTC principle can be applied for low concentrations in food of chemicals that lack toxicity data, provided that there is a sound intake estimate. The use of a decision tree to apply the TTC principle is proposed, and this paper describes the step-wise process in detail. Proteins, heavy metals and polyhalogenated-dibenzodioxins and related compounds were excluded from this approach. When assessing a chemical, a review of prior knowledge and context of use should always precede the use of the TTC decision tree. The initial step is the identification and evaluation of possible genotoxic and/or high potency carcinogens. Following this step, non-genotoxic substances are evaluated in a sequence of steps related to the concerns that would be associated with increasing intakes. For organophosphates a TTC of 18microg per person per day (0.3 microg/kg bw/day) is proposed, and when the compound is not an OP, the TTC values for the Cramer structural classes III, II and I, with their respective TTC levels (e.g. 1800, 540 and 90 microg per person per day; or 30, 9 and 1.5 microg/kg bw /day), would be applied sequentially. All other endpoints or properties were shown to have a distribution of no observed effect levels (NOELs) similar to the distribution of NOELs for general toxicity endpoints in Cramer classes I, II and III. The document was discussed with a wider audience during a workshop held in March 2003 (see list of workshop participants).

Structure-Based Thresholds of Toxicological Concern (TTC): Guidance for Application to Substances Present at Low Levels in the Diet

The Scientific Committee confirms that the Threshold of Toxicological Concern (TTC) is a pragmatic screening and prioritisation tool for use in food safety assessment. This Guidance provides clear step-by-step instructions for use of the TTC approach. The inclusion and exclusion criteria are defined and the use of the TTC decision tree is explained. The approach can be used when the chemical structure of the substance is known, there are limited chemical-specific toxicity data and the exposure can be estimated. The TTC approach should not be used for substances for which EU food/feed legislation requires the submission of toxicity data or when sufficient data are available for a risk assessment or if the substance under consideration falls into one of the exclusion categories. For substances that have the potential to be DNA-reactive mutagens and/or carcinogens based on the weight of evidence, the relevant TTC value is 0.0025 μg/kg body weight (bw) per day. For organophosphates or carbamates, the relevant TTC value is 0.3 μg/kg bw per day. All other substances are grouped according to the Cramer classification. The TTC values for Cramer Classes I, II and III are 30 μg/kg bw per day, 9 μg/kg bw per day and 1.5 μg/kg bw per day, respectively. For substances with exposures below the TTC values, the probability that they would cause adverse health effects is low. If the estimated exposure to a substance is higher than the relevant TTC value, a non-TTC approach is required to reach a conclusion on potential adverse health effects.

/pdf/guidance-on-the-use-of-the-threshold-of-toxicological-fv4royb4yl.pdf

Guidance on the use of the Threshold of Toxicological Concern approach in food safety assessment.

Developmental and reproductive toxicity (DART) end points are important hazard end points that need to be addressed in the risk assessment of chemicals to determine whether or not they are the critical effects in the overall risk assessment. These hazard end points are difficult to predict using current in silico tools because of the diversity of mechanisms of action that elicit DART effects and the potential for narrow windows of vulnerability. DART end points have been projected to consume the majority of animals used for compliance with REACH; thus, additional nonanimal predictive tools are urgently needed. This article presents an empirically based decision tree for determining whether or not a chemical has receptor-binding properties and structural features that are consistent with chemical structures known to have toxicity for DART end points. The decision tree is based on a detailed review of 716 chemicals (664 positive, 16 negative, and 36 with insufficient data) that have DART end-point data and ...

Framework for Identifying Chemicals with Structural Features Associated with the Potential to Act as Developmental or Reproductive Toxicants

Toxicological risk assessment and prioritization of drinking water relevant contaminants of emerging concern.

https://www.scialliconsulting.com/publications/08%20Laufersweiler%20TTC.pdf

Correlation of chemical structure with reproductive and developmental toxicity as it relates to the use of the threshold of toxicological concern

The approach to assessing the risks of noncancer toxicity has differed historically from that used to assess the potential risks of carcinogenicity. Assessment of risks of carcinogenicity has historically assumed that a small number of molecular events can evoke mutagenic changes in a single cell, ultimately leading to self-replicating damage and carcinogenicity. Generally, this is considered a nonthreshold effect because presumably all levels of exposure may pose a small, but finite, probability of generating a response. In contrast, it is most often assumed that noncarcinogenic changes have a threshold, a dose level below which a response is unlikely, because homeostatic, compensating, and adaptive mechanisms in the cell protect against toxic effects.



Modern understanding of mode of action (MOA), loosely defined as how a chemical causes the observed effect, has led to refinements in this dichotomy. Rather than considering cancer versus noncancer effects, the focus is on whether or not the chemical causes its effects by a mutagenic MOA, specifically DNA interaction. Nonthreshold approaches are generally used for effects resulting from interaction with DNA, while effects resulting from a nonmutagenic MOA (including both cancer and noncancer endpoints) are generally evaluated using threshold approaches. A recent NRC publication [1], however, recommended linear extrapolation under certain conditions for noncancer endpoints that do not involved interaction with DNA. The issues raised by that publication are addressed later in this chapter.



Recognizing both the historical approach and the importance of evaluation of MOA, this chapter will continue to use the term “noncancer risk,” but the methods described here should be understood to apply to both noncancer endpoints and cancer endpoints for which MOA information indicates that a threshold applies. This chapter describes the general framework for noncancer risk assessment and some salient principles for evaluating the quality of data and formulating judgments about the nature and magnitude of the hazard. Highlights of noncancer risk assessment methods used by a variety of agencies and organizations, and examples of how occupational risk assessment is moving toward a more systematic use of risk assessment principles are presented.



This chapter also has several specific aims. The first is to provide scientifically supportable quantitative risk assessment procedures to meet the risk assessment goals listed in the following paragraph. A second aim is to provide a scientific rationale that may be used to determine whether new quantitative risk assessment procedures not specifically examined in this chapter are scientifically supportable. The final aim of this chapter is to provide a basis for developing new or improved quantitative risk assessment procedures.



The quantitative risk assessment procedures described in this chapter have been developed to meet a variety of risk assessment goals. Although the protection of the public and occupational health are common themes that run through these separate risk assessment goals, the goals are sufficiently different to warrant separate and distinct procedures. Examples of such goals are as follows: 



to rank chemicals as to possible hazard;




to prioritize chemicals for further evaluation, in combination with exposure information;




to screen chemicals (e.g., new chemicals or ones under development), for purposes such as identifying which ones are appropriate for further development;




to determine and/or estimate a level of daily exposure that is likely to be without an appreciable risk of deleterious effects during a lifetime;




to determine and/or estimate the likely human response to exposure to various levels of a particular chemical or mixture.






Moreover, differing amounts of toxicity data are needed for various quantitative procedures. Thus, both the problem being addressed and the amount of data available affect the choice of procedure.


Keywords:

benchmark dose;
categorical regression;
dose–response;
dosimetry;
hazard characterization;
mode of action;
physiologically based pharmacokinetic modeling;
probabilistic RfD;
problem formulation;
risk characterization;
uncertainty factor;
weight of evidence

Noncancer Risk Assessment: Principles and Practice in Environmental and Occupational Settings

Introduction to Human Health Risk Assessment

Non-clinical in vitro studies were conducted to investigate the characteristics of extracts from tobacco free nicotine pouches alongside a reference snus product and/or 1R6F reference cigarette. In vitro investigations were conducted in the Neutral Red Uptake (NRU) cytotoxicity assay, Bacterial Reverse Mutation (Ames) assay, and in vitro Mammalian Cell Micronucleus (ivMN) assay. These products were also investigated for their oral irritation potential in the EpiGingival™ 3D tissue model. Results from the Ames, in vitro Micronucleus and NRU assays indicated that the tested products were non-mutagenic, non-genotoxic and non-cytotoxic in contrast to results obtained for the 1R6F reference cigarette. Results from Complete Artificial Saliva (CAS) extracts from these products also failed to be classified as irritants (as measured using the MTT assay), in the EpiGingival™ 3D tissue model. 

https://doi.org/10.1016/j.toxrep.2022.06.008

Irene M. Baskerville-Abraham

Papers

Correlation of chemical structure with reproductive and developmental toxicity as it relates to the use of the threshold of toxicological concern

Noncancer Risk Assessment: Principles and Practice in Environmental and Occupational Settings

Introduction to Human Health Risk Assessment

In vitro evaluation of mutagenic, cytotoxic, genotoxic and oral irritation potential of nicotine pouch products

Evaluation of chemical grouping workflows for flavor inhalation risk assessment: selected furan moiety-containing chemicals as a case study