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• 213 Point-of-Departures on botanical extracts were collected. • Cramer III TTC can be considered as conservative enough for botanical extracts. • A novel TTC value of 663 μg/day for botanical extracts is proposed. Threshold of Toxicological Concern (TTC) is a promising approach for evaluating the human health risk for systemic toxicity when there is a lack of toxicological information. The threshold for systemic toxicity is reportedly 1800, 540, and 90 μg/day for Cramer I–III chemical structures, according to Munro's structural decision tree, and 0.15 μg/day for genotoxic compounds. However, the concept of TTC has been developed for single substances; therefore, the applicability of TTC for mixtures remains unclear. To expand application of probability approach for mixtures, a validation study using the point of departures (PoDs) derived from mixtures is required. In the present study, we investigated novel TTC of botanical extracts (Botanical-TTC) for cosmetics from a meta-analysis based on the PoDs derived from repeated dose toxicity testing in botanical extracts. Accordingly, 213 PoDs were determined by repeated-dose toxicity studies and divided using a default uncertainty factor of 100 combined with the extrapolation factor of study duration to calculate the derived-no-effect-level (DNEL) and derived-minimal-effect-level (DMEL). The minimum DNEL/DMEL was 1.6-fold higher than the Cramer III TTC. In addition, because human health risk below the 1 st percentile value (663 μg/day) was considered as extremely limited, the exposure level can be proposed as Botanical-TTC. [ABSTRACT FROM AUTHOR]

• The TTC concept was tested on substances relevant to food safety. • The threshold values for Cramer Classes I and III substances were comparable to the original Munro threshold values. • Comparison with the GHS classification confirmed Cramer classification is conservative for substances relevant to food safety. • This confirms the applicability of the TTC values to substances relevant to food safety. The Threshold of Toxicological Concern (TTC) concept integrates data on exposure, chemical structure, toxicity and metabolism to identify a safe exposure threshold value for chemicals with insufficient toxicity data for risk assessment. The TTC values were originally derived from a non-cancer dataset of 613 compounds with a potentially small domain of applicability. There is interest to test whether the TTC values are applicable to a broader range of substances, particularly relevant to food safety using EFSA's new OpenFoodTox database. After exclusion of genotoxic compounds, organophosphates or carbamates or those belonging to the TTC exclusion categories, the remaining 329 substances in the EFSA OpenFoodTox database were categorized under the Cramer decision tree, into low (Class I), moderate (II), or high (III) toxicity profile. For Cramer Classes I and III the threshold values were 1000 μg/person per day (90% confidence interval: 187–2190) and 87 μg/person per day (90% confidence interval: 60–153), respectively, compared to the corresponding original threshold values of 1800 and 90 μg/person per day. This confirms the applicability of the TTC values to substances relevant to food safety. Cramer Class II was excluded from our analysis because of containing too few compounds. Comparison with the Globally Harmonized System of classification confirmed that the Cramer classification scheme in the TTC approach is conservative for substances relevant to food safety. [ABSTRACT FROM AUTHOR]

This study aimed at deriving occupational thresholds of toxicological concern for inhalation exposure to systemically-acting organic chemicals using predicted internal doses. The latter were also used to evaluate the quantitative relationship between occupational exposure limit and internal dose. Three internal dose measures were identified for investigation: (i) the daily area under the venous blood concentration vs. time curve, (ii) the daily rate of the amount of parent chemical metabolized, and (iii) the maximum venous blood concentration at the end of an 8-hr work shift. A dataset of 276 organic chemicals with 8-hr threshold limit values-time-weighted average was compiled along with their molecular structure and Cramer classes (Class I: low toxicity, Class II: intermediate toxicity, Class III: suggestive of significant toxicity). Using a human physiologically-based pharmacokinetic model, the three identified dose metrics were predicted for an 8-hr occupational inhalation exposure to the threshold limit value for each chemical. Distributional analyses of the predicted dose metrics were performed to identify the percentile values corresponding to the occupational thresholds of toxicological concern. Also, simple linear regression analyses were performed to evaluate the relationship between the 8-hr threshold limit value and each of the predicted dose metrics, respectively. No threshold of toxicological concern could be derived for class II due to few chemicals. Based on the daily rate of the amount of parent chemical metabolized, the proposed internal dose-based occupational thresholds of toxicological concern were 5.61 × 10−2 and 9 × 10−4 mmol/d at the 10th percentile level for classes I and III, respectively, while they were 4.55 × 10−1 and 8.5 × 10−3 mmol/d at the 25th percentile level. Even though high and significant correlations were observed between the 8-hr threshold limit values and the predicted dose metrics, the one with the rate of the amount of chemical metabolized was remarkable regardless of the Cramer class (r2 = 0.81; n = 276). The proposed internal dose-based occupational thresholds of toxicological concern are potentially useful for screening-level assessments as well as prioritization within an integrated occupational risk assessment framework. [ABSTRACT FROM AUTHOR]

Toxicological risk assessment of contaminants of emerging concern (CEC) in (sources of) drinking water is required to identify potential health risks and prioritize chemicals for abatement or monitoring. In such assessments, concentrations of chemicals in drinking water or sources are compared to either (i) health-based (statutory) drinking water guideline values, (ii) provisional guideline values based on recent toxicity data in absence of drinking water guidelines, or (iii) generic drinking water target values in absence of toxicity data. Here, we performed a toxicological risk assessment for 163 CEC that were selected as relevant for drinking water. This relevance was based on their presence in drinking water and/or groundwater and surface water sources in downstream parts of the Rhine and Meuse, in combination with concentration levels and physicochemical properties. Statutory and provisional drinking water guideline values could be derived from publically available toxicological information for 142 of the CEC. Based on measured concentrations it was concluded that the majority of substances do not occur in concentrations which individually pose an appreciable human health risk. A health concern could however not be excluded for vinylchloride, trichloroethene, bromodichloromethane, aniline, phenol, 2-chlorobenzenamine, mevinphos, 1,4-dioxane, and nitrolotriacetic acid. For part of the selected substances, toxicological risk assessment for drinking water could not be performed since either toxicity data (hazard) or drinking water concentrations (exposure) were lacking. In absence of toxicity data, the Threshold of Toxicological Concern (TTC) approach can be applied for screening level risk assessment. The toxicological information on the selected substances was used to evaluate whether drinking water target values based on existing TTC levels are sufficiently protective for drinking water relevant CEC. Generic drinking water target levels of 37 μg/L for Cramer class I substances and 4 μg/L for Cramer class III substances in drinking water were derived based on these CEC. These levels are in line with previously reported generic drinking water target levels based on original TTC values and are shown to be protective for health effects of the majority of contaminants of emerging concern evaluated in the present study. Since the human health impact of many chemicals appearing in the water cycle has been studied insufficiently, generic drinking water target levels are useful for early warning and prioritization of CEC with unknown toxicity in drinking water and its sources for future monitoring. [ABSTRACT FROM AUTHOR]

The threshold of toxicological concern (TTC) of a compound represents an exposure value below which the associated human health risk is considered negligible. As such, this approach offers assessing the risk of potential toxicants when little or no toxicological information is available. For the inhalation repeated-dose TTC, the goal was to derive structural alerts that discriminate between high- and low-toxic compounds. A further aim was to identify physicochemical parameters related to the inhalation-specific bioavailability of the compounds, and to explore their use as predictors of high vs low toxicity. 296 compounds with subacute, subchronic and chronic inhalation toxicity NOEC (no-observed effect concentration) values were subdivided into three almost equal-sized high-, medium- and low-toxic (HTox, MTox, LTox) potency classes. Whereas the derived 14 HTox and 7 LTox structural alerts yield an only moderate discrimination between these three groups, the high-toxic vs low-toxic mis-classification is very low: LTox-predicted compounds are not HTox to 97.5%, and HTox-predicted compounds not LTox to 88.6%. The probability of a compound being HTox vs LTox is triggered further by physicochemical properties encoding the tendency to evaporate from blood. The new structural alerts may aid in the predictive inhalation toxicity assessment of compounds as well as in designing low-toxicity chemicals, and provide a rationale for the chemistry underlying the toxicological outcome that can also be used for scoping targeted experimental studies. [ABSTRACT FROM AUTHOR]

Raspberry ketone (4-(4-hydroxyphenyl)-2-butanone) is marketed on the Internet as a food supplement. The recommended intake is between 100 and 1400 mg per day. The substance is naturally occurring in raspberries (up to 4.3 mg/kg) and is used as a flavouring substance. Toxicological studies on raspberry ketone are limited to acute and subchronic studies in rats. When the lowest recommended daily dose of raspberry ketone (100 mg) as a food supplement is consumed, it is 56 times the established threshold of toxicological concern (TTC) of 1800 μg/day for Class 1 substances. The margin of safety (MOS) based on a NOAEL of 280 mg/kg bw/day for lower weight gain in rats is 165 at 100 mg and 12 at 1400 mg. The recommended doses are a concern taking into account the TTC and MOS. Investigations of raspberry ketone in quantitative structure-activity relationship (QSAR) models indicated potential cardiotoxic effects and potential effects on reproduction/development. Taking into account the high intake via supplements, the compound's toxic potential should be clarified with further experimental studies. In UK the pure compound is regarded as novel food requiring authorisation prior to marketing but raspberry ketone is not withdrawn from Internet sites from this country. [ABSTRACT FROM AUTHOR]

A main challenge in food safety research is to demonstrate that processing of foodstuffs does not lead to the formation of substances for which the safety upon consumption might be questioned. This is especially so since food is a complex matrix in which the analytical detection of substances, and consequent risk assessment thereof, is difficult to determine. Here, a pragmatic novel safety assessment strategy is applied to the production of non-selective extracts (NSEs), used for different purposes in food such as for colouring purposes, which are complex food mixtures prepared from reference juices. The Complex Mixture Safety Assessment Strategy (CoMSAS) is an exposure driven approach enabling to efficiently assess the safety of the NSE by focussing on newly formed substances or substances that may increase in exposure during the processing of the NSE. CoMSAS enables to distinguish toxicologically relevant from toxicologically less relevant substances, when related to their respective levels of exposure. This will reduce the amount of work needed for identification, characterisation and safety assessment of unknown substances detected at low concentration, without the need for toxicity testing using animal studies. In this paper, the CoMSAS approach has been applied for elderberry and pumpkin NSEs used for food colouring purposes. [ABSTRACT FROM AUTHOR]

Abstract: In the absence of toxicological data on a chemical, the threshold of toxicological concern (TTC) approach provides a system to estimate a conservative exposure below which there is a low probability of risk for adverse health effects. The original toxicology dataset underlying the TTC was based on NOELs from repeat dose studies. Subsequently there have been several efforts to assess whether or not these limits are also protective for reproductive/developmental effects. This work expands the database of chemicals with reproductive and developmental data, presents these data in a comprehensive and transparent format and groups the chemicals according to the TTC “Cramer Class” rules. Distributions of NOAELs from each of these classes were used to assess whether the previously proposed TTC values based on repeat dose data are protective for reproductive/developmental toxicity endpoints as well. The present analysis indicates that, for each Cramer Class, the reproductive and developmental endpoints would be protected at the corresponding general TTC tiers derived by . [Copyright &y& Elsevier]

Abstract: The REACH Regulation 1907/2006/EC aims to improve knowledge of the potential risks to humans and the environment of the large number of chemicals produced and used in the EU. The testing requirements are likely to trigger numerous toxicological studies, potentially involving millions of experimental animals, despite the professed goal of REACH to reduce vertebrate testing. It may be necessary therefore to shift emphasis away from animal studies towards more pragmatic strategies, reserving animal tests for the substances of greatest concern. One approach is to waive certain tests based on levels of exposure to the substance. This review explores application of ‘Exposure-Based Waiving’ (EBW) of toxicity studies, with a particular focus on inhalation where possible, considering the potential qualitative and quantitative supporting arguments that might be made, including the use of thresholds of toxicological concern. Incorporating EBW into intelligent testing strategies for substance registration could advance the goals of REACH and the 3Rs (reduction, replacement and refinement of animals in research) by reducing the usage of animals in toxicity tests, whilst maintaining appropriate protection of human health and the environment. However greater regulatory evaluation, acceptance and guidance are required for EBW to achieve its full impact. [Copyright &y& Elsevier]

Abstract: Limits for tolerable concentrations of ground water metabolites (“non-relevant metabolites” without targeted toxicities and specific classification and labeling) derived from active ingredients (AI) of plant protection products (PPPs) are discussed in the European Union. Risk assessments for “non-relevant metabolites” need to be performed when concentrations are above 0.75μg/L. Since oral uptake is the only relevant exposure pathway for “non-relevant metabolites”, risk assessment approaches as used for other chemicals with predominantly oral exposure in humans are applicable. The concept of “thresholds of toxicological concern” (TTC) defines tolerable dietary intakes for chemicals without toxicity data and is widely applied to chemicals present in food in low concentrations such as flavorings. Based on a statistical evaluation of the results of many toxicity studies and considerations of chemical structures, the TTC concept derives a maximum daily oral intake without concern of 90μg/person/day for non-genotoxic chemicals, even for those with appreciable toxicity. When using the typical exposure assessment for drinking water contaminants (consumption of 2L of drinking water/person/day, allocation of 10% of the tolerable daily intake to drinking water), a TTC-based upper concentration limit of 4.5μg/L for “non-relevant metabolites” in ground/drinking water is delineated. In the present publication it has been evaluated, whether this value would cover all relevant toxicities (repeated dose, reproductive and developmental, and immune effects). Taking into account, that after evaluation of specific reproduction toxicity data from chemicals and pharmaceuticals, a value of 1μg/kgbw/day has been assessed as to cover developmental and reproduction toxicity, a TTC value of 60μg/person/day was assessed as to represent a safe value. Based on these reasonable worst case assumptions, a TTC-derived threshold of 3μg/L in drinking water is derived. When a non-relevant metabolite is present in concentration below 3μg/L, animal testing for toxicity is not considered necessary for a compound-specific risk assessment since the application of the TTC covers all relevant toxicities to be considered in such assessment and any health risk resulting from these exposures is very low. [Copyright &y& Elsevier]

Abstract: The Threshold of Toxicological Concern (TTC) is a useful concept that is becoming of increasing interest as an addition to the arsenal of tools used for characterising the toxicological risk of human exposure to chemicals. Traditionally used for low level indirect additives, flavours and contaminants in foods, the TTC obviates the need for toxicological testing of chemicals where human exposure is low. Proposals have recently been made for the use of the TTC for low level ingredients in cosmetic and personal care products. However, use of the TTC is only protective for systemic toxicity endpoints, and cannot be used for local endpoints such as contact sensitisation. In this paper a probabilistic analysis of available sensitisation data, similar to that used in the development of the TTC, is presented. The incidence of sensitisers in the world of chemicals was estimated using the ELINCS (European List of Notified Chemical Substances) data set, and a distribution for sensitisation potency was established using a recently published compilation of Local Lymph Node Assay data. From the analysis of these data sets it is concluded that a Dermal Sensitisation Threshold (DST) can be established below which there is no appreciable risk of sensitisation, even for an untested ingredient. Use of a DST would preclude the need for sensitisation testing of ingredients where dermal exposure is sufficiently low. [Copyright &y& Elsevier]

Micropollutants in water provide a challenge to both science and society. The final consideration is to understand whether they are harmful to human health or to aquatic life and to determine what actions should be taken. The numbers of substances that are being identified requires a new approach to risk assessment and to solving the problem based on proper prioritisation of the needs for more targeted and multidisciplinary research delivering high quality data. The concept of threshold of toxicological concern has been applied to food and could usefully be applied to water. However, this approach also needs to be combined with practical and pragmatic assessments of the behaviour of substances in water and their removal by drinking water treatment. Such an approach provides a bridge from problem identification to problem solving. [ABSTRACT FROM AUTHOR]

Abstract: A scientific rationale is provided for estimating acceptable daily intake values (ADIs) for compounds with limited or no toxicity information to support pharmaceutical manufacturing operations. These ADIs are based on application of the “thresholds of toxicological concern” (TTC) principle, in which levels of human exposure are estimated that pose no appreciable risk to human health. The same concept has been used by the US Food and Drug Administration (FDA) to establish “thresholds of regulation” for indirect food additives and adopted by the Joint FAO/WHO Expert Committee on Food Additives for flavoring substances. In practice, these values are used as a statement of safety and indicate when no actions need to be taken in a given exposure situation. Pharmaceutical manufacturing relies on ADIs for cleaning validation of process equipment and atypical extraneous matter investigations. To provide practical guidance for handling situations where relatively unstudied compounds with limited or no toxicity data are encountered, recommendations are provided on ADI values that correspond to three categories of compounds: (1) compounds that are likely to be carcinogenic, (2) compounds that are likely to be potent or highly toxic, and (3) compounds that are not likely to be potent, highly toxic or carcinogenic. Corresponding ADIs for these categories of materials are 1, 10, and 100μg/day, respectively. [Copyright &y& Elsevier]

The concept that “safe levels of exposure” for humans can be identified for individual chemicals is central to the risk assessment of compounds with known toxicological profiles. The Threshold of Toxicological Concern (TTC) is a concept that refers to the establishment of a level of exposure for all chemicals, whether or not there are chemical-specific toxicity data, below which there would be no appreciable risk to human health. The concept proposes that a low level of exposure with a negligible risk can be identified for many chemicals, including those of unknown toxicity, based on knowledge of their chemical structures. The present paper aims to describe the history of the TTC principle, its use to date, its potential future applications and the incorporation of the TTC principle in the Risk Assessment paradigm. [ABSTRACT FROM AUTHOR]