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There is increased interest in developing non-animal test systems for inhalation exposure safety assessments. However, defined methodologies are absent for predicting local respiratory effects from inhalation exposure to irritants. The current study introduces a concept for applying in vitro and in silico methods for inhalation exposure safety assessment. Three in vitro systems, representing the upper (MucilAir™—nasal epithelial tissue) and lower (A549 cells and human precision-cut lung slices) human respiratory regions, were exposed to six respiratory irritants. These irritant exposures were conducted as liquid droplets, aerosol, or vapors, and samples were collected over 24 h. Cytotoxicity, cytokine release, epithelial resistance, oxidative stress, and mitochondrial membrane potential were measured. To determine the human relevance of in vitro exposures, airway surface depositions were predicted by simulating airborne concentrations equivalent to the Cramer class III inhalation threshold of toxicological concern limit of 0.47 mg/person/day using an in silico model. A > 100-fold margin of exposure was calculated comparing lowest concentrations showing in vitro effects to in silico simulated values. While further studies are needed, this manuscript presents a basic requirement for employing non-animal methods to inform inhalation exposure safety assessments by combining in vitro and in silico assays. [ABSTRACT FROM AUTHOR]

ABSTRACT 3‐Phenylpropyl acetate, a small molecule with significant importance in the realm of flavours and fragrances, is consumed globally in quantities ranging from 1 to 10 tons per year. Given its widespread use, a thorough safety assessment is imperative. This review delves into the toxicological implications associated with 3‐phenylpropyl acetate, focusing on various aspects such as mutagenicity, genotoxicity, repeated dose toxicity, reproductive toxicity, skin sensitisation, phototoxicity/photoallergenicity, local respiratory toxicity, as well as biodegradation and ecotoxicity. By evaluating the available data on these parameters, a comprehensive risk assessment can be conducted to ensure the safe utilisation of this compound in various applications. [ABSTRACT FROM AUTHOR]

The Threshold of Toxicological Concern (TTC) is a very well-established concept in applied toxicology, and has become a key tool for the pragmatic human health risk assessment of data-poor chemicals. Within the pharmaceutical sector, regulatory guidance on genotoxins defaults to a TTC of 1.5 μg/day equating to a maximum lifetime cancer risk of 1 in 100,000. Higher doses for drug products where exposures are intermittent or otherwise "less-than-lifetime" (LTL) are also considered tolerable. This also allows substance-specific lifetime Acceptable Intakes (AIs) for known genotoxic carcinogens to be scaled up for shorter durations. The default TTCs for assessing LTL exposures build in conservatism such that there is deviation from strict linearity. However, close to the boundaries between LTL categories there can be such a difference in the default tolerable intakes that a health risk assessment can yield conflicting results. We have presented a theoretical case study based on our recent work that illustrates this apparent "cliff-edge." The total acceptable cumulative dose over a 56-day treatment is – in absolute terms – one third of that allowed over 28 days, despite the maximum cancer risk of the longer exposure being an order of magnitude higher. Our analysis suggests the need for careful consideration of what might represent tolerable exposures in the region of the category limits, rather than simply adopting the hardline default. Where a potential patient exposure is found to be above a default value, there is real value in refining the cancer risk estimates using the Lifetime Cumulative Dose approach. [ABSTRACT FROM AUTHOR]

There is increased interest in developing non-animal test systems for inhalation exposure safety assessments. However, defined methodologies are absent for predicting local respiratory effects from inhalation exposure to irritants. The current study introduces a concept for applying in vitro and in silico methods for inhalation exposure safety assessment. Three in vitro systems, representing the upper (MucilAir™—nasal epithelial tissue) and lower (A549 cells and human precision-cut lung slices) human respiratory regions, were exposed to six respiratory irritants. These irritant exposures were conducted as liquid droplets, aerosol, or vapors, and samples were collected over 24 h. Cytotoxicity, cytokine release, epithelial resistance, oxidative stress, and mitochondrial membrane potential were measured. To determine the human relevance of in vitro exposures, airway surface depositions were predicted by simulating airborne concentrations equivalent to the Cramer class III inhalation threshold of toxicological concern limit of 0.47 mg/person/day using an in silico model. A > 100-fold margin of exposure was calculated comparing lowest concentrations showing in vitro effects to in silico simulated values. While further studies are needed, this manuscript presents a basic requirement for employing non-animal methods to inform inhalation exposure safety assessments by combining in vitro and in silico assays.

Finding solutions to issues of drinking water safety is a significant component in activities aimed at public health protection. In accordance with sanitary-epidemiological requirements, drinking water, in particular, should be harmless as regards its chemical composition and have favorable organoleptic properties. It is especially vital to identify risk factors for public health associated with drinking water quality. Supplying high-quality drinking water to population is a relevant problem associated, among other things, with use of new materials and reagents. The major challenge posed by their hygienic assessment is a potential growth in human health risks caused by consuming tap drinking water contaminated with migrating organic compounds. Although each of them has been detected in low concentrations, they can cause adverse chronic health outcomes. The Threshold of Toxicological Concern (TTC) is a powerful tool of risk assessment. It is based on identifying a threshold value of effects produced on human health by chemicals for which no hygienic standards have been developed so far. Below such a threshold, there is very low (95 %) likelihood of a health risk being higher than its acceptable levels. An idea of some exposure levels unable to cause adverse health outcomes is embedded in establishing maximum permissible levels (MPLs) for chemicals with known toxicological profiles. The TTC enlarges this concept by assuming that the minimum value can be identified for many chemicals based on their composition even if there is no comprehensive database on their toxicity. The TTC can be used for evaluating up-to-date materials applied in drinking water supply in order to detect risks for human health caused by consumption of drinking water that had contacts with them. Such risk assessment relies on the results of examining water extracts and involves identifying priority chemicals for their further investigation and control.

Despite significant advances in cancer treatment with targeted therapies and immunotherapies, cytotoxic chemotherapies are still extensively used. Potential cytotoxic contamination in preparing and administrating cytotoxics is still a major source of concern. Besides advanced protections including biological safety cabinets, work surface contamination needs to be continuously controlled to ensure that handling procedures and cleaning were appropriate. Contamination monitoring needs to be standardized.The study searched Pubmed/Medline and Embase with"hazardous drug”, “cytotoxic drug”, “surface contamination”, “environmental contamination”, “wipe sample”, “pharmacy”, “care unit”, and selected studies reporting contamination results in work environment for pharmacy technicians and nurses, from 1 January 2017 to 31 December 2022.The 29 studies totalized 16,196 samples and 189,571 assays. Contamination results showed 39.8% sample positivity, and 8.2% assay positivity. Multicentric studies gathering at least 500 samples or up to 800 samples would limit heterogeneity in sample positivity. In addition, monitoring of an appropriate tracer selection including at least the 7 tracers with the highest contamination frequencies (cyclophosphamide, gemcitabine, fluorouracile, ifosfamide, platinum derivatives, paclitaxel and methotrexate) would facilitate contamination comparisons amongst studies and local results. Most recent studies reported thresholds for cyclophosphamide close to 0.1 ng/cm² at the 90th percentile.The overall risk of exposure for healthcare professionals is a major concern. Sample size in multicentric studies would require at least 500 samples; quantification of all tracers with the highest contamination frequencies need to be quantified. This approach would provide a basis to develop guidelines to appropriately monitor contamination in pharmacies and patient care area managers. [ABSTRACT FROM AUTHOR]

Abstract Background Several drugs for human use possess genotoxic properties as a necessary consequence of their intended therapeutic effect (e.g. antineoplastics). Health workers may be exposed to these chemicals in various occupational settings such as dose preparation and administration. To date, there are no quantitative risk assessment models to estimate the cancer risk of health workers due to the handling of genotoxic drugs. We therefore developed a quantitative risk assessment model to assess the cancer risk of occupational exposure to genotoxic drugs in healthcare settings based on the threshold of toxicological concern (TTC) concept. This model was used to evaluate the cancer risk of health workers due to the handling of genotoxic drugs in modern health care facilities. Methods We modified the threshold of toxicological concern (TTC) concept to fit the purpose of occupational cancer risk assessment. The risk model underlying ICH guideline M7 (R1): “assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk” was used as a starting point for our model. We conducted a short review of studies on the occupational exposure of health workers to genotoxic drugs. These occupational exposure data were compared to the acceptable exposure levels resulting from our TTC based risk model. Results Based on the threshold of toxicological concern (TTC) concept, we defined an acceptable daily intake (ADI) of 4 μg/day as threshold of no concern for the exposure of health workers to genotoxic drugs. Regarding the dermal exposure of health workers to genotoxic drugs, we derived a corresponding acceptable surface contamination level (ASCL) of 20 ng/cm2. Both ADI and ASCL are usually not exceeded in modern healthcare settings. Current safety precautions provide sufficient protection to health workers. Conclusions The application of our model indicates that workers in modern healthcare facilities are not at risk of developing work related cancer above widely accepted cancer risk levels due to the occupational exposure to genotoxic drugs. Hence, the present study may assist employers and public authorities to make informed decisions concerning the need for (further) protective measures and during risk communication to health workers.

Per ISO 10993-1:2018, a processing change to a medical device requires re-evaluation of biological risk. Here, we present the biological evaluation of a marketed cardiovascular implant following a detergent formulation change. This change was initially assessed through a qualitative toxicological risk assessment based on the fully disclosed detergent formulation and a limited panel of biological testing. The conclusion was that the new detergent did not impact the biological safety of the device. This assessment was rejected during regulatory review, and extractables and leachables under exhaustive extraction conditions were then evaluated for devices processed with new versus original detergent. New extractables were present at low levels (2–65 µg/device), and a toxicological risk assessment concluded no concern. The regulatory agency responded requesting additional biological testing to evaluate local effects, further characterization of compounds with a “tentative” identification, and leachable data to support clinically relevant exposure estimates. All additional data was collected per the agency request. Still, the conclusion, considering all data, was unchanged, suggesting the extensive chemical characterization and repeat biological testing unnecessary, especially considering animal use. This case study highlights the recent shift in regulatory expectations around chemical characterization and questions the value of additional biological testing when faced with low extractable levels of low toxicity concern. It also demonstrates the need to hold to key portions of the ISO 10993 risk management framework to avoid excessive burden on medical device development when there is little to no determined risk to patient safety.

Next generation risk assessment is defined as a knowledge-driven system that allows for cost-efficient assessment of human health risk related to chemical exposure, without animal experimentation. One of the key features of next generation risk assessment is to facilitate prioritization of chemical substances that need a more extensive toxicological evaluation, in order to address the need to assess an increasing number of substances. In this case study focusing on chemicals in food, we explored how exposure data combined with the Threshold of Toxicological Concern (TTC) concept could be used to prioritize chemicals, both for existing substances and new substances entering the market. Using a database of existing chemicals relevant for dietary exposure we calculated exposure estimates, followed by application of the TTC concept to identify substances of higher concern. Subsequently, a selected set of these priority substances was screened for toxicological potential using high-throughput screening (HTS) approaches. Remarkably, this approach resulted in alerts for a selection of substances that are already on the market and represent relevant exposure in consumers. Taken together, the case study provides proof-of-principle for the approach taken to identify substances of concern, and this approach can therefore be considered a supportive element to a next generation risk assessment strategy.

Background: Several drugs for human use possess genotoxic properties as a necessary consequence of their intended therapeutic effect (e.g. antineoplastics). Health workers may be exposed to these chemicals in various occupational settings such as dose preparation and administration. To date, there are no quantitative risk assessment models to estimate the cancer risk of health workers due to the handling of genotoxic drugs. We therefore developed a quantitative risk assessment model to assess the cancer risk of occupational exposure to genotoxic drugs in healthcare settings based on the threshold of toxicological concern (TTC) concept. This model was used to evaluate the cancer risk of health workers due to the handling of genotoxic drugs in modern health care facilities. Methods: We modified the threshold of toxicological concern (TTC) concept to fit the purpose of occupational cancer risk assessment. The risk model underlying ICH guideline M7 (R1): "assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk" was used as a starting point for our model. We conducted a short review of studies on the occupational exposure of health workers to genotoxic drugs. These occupational exposure data were compared to the acceptable exposure levels resulting from our TTC based risk model. Results: Based on the threshold of toxicological concern (TTC) concept, we defined an acceptable daily intake (ADI) of 4 μg/day as threshold of no concern for the exposure of health workers to genotoxic drugs. Regarding the dermal exposure of health workers to genotoxic drugs, we derived a corresponding acceptable surface contamination level (ASCL) of 20 ng/cm2. Both ADI and ASCL are usually not exceeded in modern healthcare settings. Current safety precautions provide sufficient protection to health workers. Conclusions: The application of our model indicates that workers in modern healthcare facilities are not at risk of developing work related cancer above widely accepted cancer risk levels due to the occupational exposure to genotoxic drugs. Hence, the present study may assist employers and public authorities to make informed decisions concerning the need for (further) protective measures and during risk communication to health workers. [ABSTRACT FROM AUTHOR]

Objective To analyze the risks of dietary exposure of diethylhexyl phthalate (DEHP), dibutyl phthalate (DBP), diisononyl phthalate (DINP), butylbenzyl phthalate (BBP), diisobutyl phthalate (DIBP), dimethyl phthalate (DMP) and diethyl phthalate (DEP) to 2-6 years children in China using RISK21, so as to provide risk management strategy for phthalic acid esters (PAEs). Methods RISK PLOT module was used to analyze and rank risks, with toxicity as Y-axis and exposure as X-axis and margin of exposure (MOE) and uncertainty factor as parameters. Matrix calculation was conducted, risks level and rank of 7 kinds of PAEs to 2-6 years children were illustrated by visualized graphs. TTC PLOT module was used to analyze risks of DMP, DEP and DIBP, which were lacking of toxicity data. Results RISK PLOT showed that the risks of 7 kinds of PAEs for general population located in the green area, which demonstrated that they had low risk to 2-6 years children, and the risks of high food consumption population ranked in descending order were DBP, DIBP, DEHP, DMP, DEP, DINP and BBP. TTC PLOT showed that the risks of DMP, DEP and DIBP were lower than the corresponding threshold of toxicological concern (TTC) that demonstrated low risks. Conclusion RISK21 framework and tools could be a very useful tool for risk assessment and further risk management, and low risks of dietary exposure of 7 kinds of PAEs to 2-6 years children in China by RISK21 analyzing.

Health risks resulting from dermal or inhalational exposures are frequently assessed based on rodent oral toxicity information due to a lack of species- or route-specific toxicity data. Default uncertainty factors (UFs; e.g., 10-fold) are also applied during risk assessments to account for variability such as inter-species, intra-species, exposure duration, dose–response, and route-to-route extrapolations. However, whether rodent oral data and a default UF approach can provide adequate protection for other mammalian species under dermal or inhalational exposure scenarios remains understudied, particularly for cleaning product ingredients. Therefore, we collated and examined publicly available median lethal dose (LD50), no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) values from different types of standard mammalian toxicity studies for rats (dermal and inhalational), mice, rabbits, guinea pigs, and dogs (oral, dermal and inhalational) using the Cleaning Product Ingredient Safety Initiative (CPISI) database. Probabilistic hazard assessments using chemical toxicity distributions (CTDs) were subsequently conducted, and threshold concentrations (TCs) and 95% confidence intervals (95% CIs) were derived to identify thresholds of toxicological concern (TTCs). Relative sensitivities among or between mammalian species, exposure routes, and chemical classes were also compared based on calculated TC5s and 95% CIs to support future toxicology studies and hazard and risk assessments. We then identified uncertainty factors (UFs) using both CTD comparisons and individual UF probability distributional approaches. Based on available rodent inhalational data, chemical category-specific UFs were derived for ethers. Additionally, we also determined whether default UFs of 10 or 100 would be protective for various distributions of cleaning product ingredients. Our novel observations among these routes of exposure and common mammalian model organisms appear particularly useful for read across and screening-level health hazard and risk assessments when limited data exists for specific chemicals.

Thousands of intentionally added substances can be used in printing inks and adhesives applied to plastic food packaging. Some of them can be transferred to foodstuffs through a phenomenon called migration, arising concerns on the potential adverse health effects derived from the exposure to chemicals that have not yet been assessed for their risks to humans. The large number of the substances concerned and the lack of prioritisation strategies hamper the work of control authorities, since it is not clear which substances should be monitored as first priority. In this study, a hazard prioritisation strategy is proposed. An inventory listing more than 6,000 substances used in inks and adhesives applied to plastic food packaging was compiled and filtered using several exclusion criteria aimed to set apart those substances for which there is no apparent need for further evaluation or because fall into one of the exclusion categories of the Threshold of Toxicological Concern (TTC) approach. Additionally, substances with a molecular weight >1,000 Da were removed. Approximately 2,300 substances were retained, for which a comprehensive hazard profiling was conducted based on the general scheme for the application of the TTC approach. First, structural alerts for genotoxic and non-genotoxic carcinogenicity were investigated. If a substance was neither genotoxic nor belonging to the chemical classes of organophosphates and carbamates, the Cramer classification was used. Furthermore, the substances were searched for their presence in three so-called 'Substances of Concern' lists and RASFF notifications. Groups of high, medium and low priority substances were established, resulting in 1,660 substances classified as high and medium priority. A panel of five experts evaluated these substances with respect to their relevance for further risk evaluations. By applying this hazard prioritisation strategy, 696 substances were identified as 'Very High Priority Substances' (VHPS) for which further assessments should be performed. [ABSTRACT FROM AUTHOR]

The activity of individual biotransformation products cannot be measured in multicomponent mixtures by the current status-quo assays. A prior separation and tedious isolation of compounds is required, and often in addition, a concentration step into a solvent suitable for the cell-/enzyme-based assay. Hence, the metabolizing S9 system, mimicking the complex biotransformation reactions in the liver, was aimed to be integrated into two orthogonal methods for analysis of the acetylcholinesterase (AChE) inhibition. For the microtiter plate assay method, the evaluation of the generated fluorescence signal was impaired by the incorporated S9 system. In contrast, the metabolic activator (S9 mixture) was successfully incorporated into the high-performance thin-layer chromatography (HPTLC) method. As proof of principle, four reference AChE inhibitors were studied in complex samples with and without metabolic activation. In addition to the neurotoxic carbamate eserine and the organophosphate insecticides chlorpyrifos, quinalphos and parathion, the tris(nonylphenyl) phosphite and nonylphenol, both originating from food contact materials, were tested in isolation but also in food packaging migrate and extract. A method comparison and benchmarking pointed to multifold advantages of using this newly developed bioanalytical tool for assessment of individual neurotoxins in complex samples. The sensitive HPTLC-S9-AChE assay allowed the detection of neurotoxic chemicals with and without metabolic activation, at levels consistent with the threshold of toxicological concern of organophosphates and carbamates. This new on surface metabolism system can be applied to other toxicities and samples. Image 1 • Metabolization of compounds by the S9 system was newly developed on the HPTLC plate. • Implementation of the S9 system in the HPTLC-AChE assay was successful. • Metabolization/separation/effect-directed detection of compounds was on the same surface. • HPTLC-S9-AChE assay is sensitive and efficient to detect AChE inhibitors at low levels. • Proof-of-principle in sample matrix was given for AChE inhibition of packaging materials. [ABSTRACT FROM AUTHOR]

Abstract 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.

Genotoxic impurities can be described as impurities that can induce genetic mutations and chromosomal breaks, or that damage the genetic information within a cell, which may lead to cancer. The European Medical Agency (EMA) and the United States Food and Drug Administration (US FDA) have set a threshold of toxicological concern (TTC) of genotoxic impurities 1.5 µg per day. In a continuous effort to develop an analytical method for the estimation of genotoxic impurities in quetiapine fumarate, a sensitive, simple, and precise high-performance thin-layer chromatography method has been developed and validated for the determination of 2-nitrophenyl (phenyl)sulfane as a genotoxic impurity at trace levels. The limits of detection (LOD) for quetiapine fumarate and 2-nitrophenyl (phenyl)sulfane were found to be 5.11 and 15.5 ng per band, whereas the limits of quantification (LOQ) were observed 0.09 and 0.3 ng per band, respectively. The calibration curve for 2-nitrophenyl (phenyl)sulfane was linear over the concentration range of 10 to 50 ng per band. The method was found to be specific, precise, linear, and accurate for the estimation of 2-nitrophenyl (phenyl)sulfane at trace levels in quetiapine fumarate. [ABSTRACT FROM AUTHOR]

• 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]

Botanical safety science continues to evolve as new tools for risk assessment become available alongside continual desire by consumers for "natural" botanical ingredients in consumer products. Focusing on botanical food/dietary supplements a recent international roundtable meeting brought together scientists to discuss the needs, available tools, and ongoing data gaps in the botanical safety risk assessment process. Participants discussed the key elements of botanical safety evaluations. They provided perspective on the use of a decision tree methodology to conduct a robust risk assessment and concluded with alignment on a series of consensus statements. This discussion highlighted the strengths and vulnerabilities in common assumptions, and the participants shared additional perspective to ensure that this end-to-end safety approach is sufficient, actionable and timely. Critical areas and data gaps were identified as opportunities for future focus. These include, better context on history of use, systematic assessment of weight of evidence, use of in silico approaches, inclusion of threshold of toxicological concern considerations, individual substances/matrix interactions of plant constituents, assessing botanical-drug interactions and adaptations needed to apply to in vitro and in vivo pharmacokinetic modelling of botanical constituents. [ABSTRACT FROM AUTHOR]

Genetic mutations, chromosomal breaks, and chromosomal rearrangements, which are induced due to organic impurities, are considered as potential genotoxic impurities. The European Medicines Agency (EMA) and the United States Food and Drug Administration (US FDA) have set a threshold of toxicological concern (TTC) of 1.5 µg per person per day for each impurity. A sensitive and simple high-performance thin-layer chromatography (HPTLC) method has been developed and validated for determination of the potential genotoxic impurity, namely, 2-chloroaniline, at trace levels in quetiapine fumarate. The method was found to be specific and selective for the application. The limit of detection (LOD) and limit of quantification (LOQ) for quetiapine fumarate were found to be 1.27 and 3.87 ng per band. The LOD and LOQ values for 2-chloroaniline were found 0.018 and 0.054 ng per band, respectively. The calibration curve for 2-chloroaniline was linear over a concentration range from 2.5 to 12.5 ng. The method was found to be specific, precise, linear, and accurate and can be employed for monitoring and estimation of levels of 2-chloroaniline in quetiapine fumarate. [ABSTRACT FROM AUTHOR]

Abstract Neonicotinoid insecticides have become one of the most widely used insecticides over the past two decades. Recent studies have shown considerable risk of neonicotinoids to beneficial insects, however, their health risks to mammals are still under debate. Limited empirical mammalian toxicity information for neonicotinoids inherently presents challenges to environmental health practitioners performing health hazard and risk assessment. Therefore, we first compiled and examined publicly available hazard data for neonicotinoids, and knowledge gaps on mammals were identified. Probabilistic hazard assessment using chemical toxicity distributions (CTDs) was subsequently conducted, and initial thresholds of toxicological concern were derived for rat, dog, mouse, and rabbit under comparative experimental scenarios. Using the rat model, for example, oral 5% threshold concentrations (TC5s) of 0.11 (0.02, 0.36) and 0.23 (0.001, 3.2) mg/kg bw/day were estimated using chronic developmental and reproductive no observed adverse effect levels (NOAELs), respectively, while acute TC5 of 0.71 (0.25, 1.6) mg/kg bw/day was identified using neurological NOAELs. Comparatively, dermal and inhalational TC5s were estimated as 1583 (1172, 1777) and 451 (294, 615) mg/kg bw/day (equivalent to 486 (322, 622) mg/m3), respectively, using acute median lethal doses. Uncertainty factors (UFs) were also estimated using both CTD comparisons and individual UF probability distribution approaches to test whether rodent oral toxicity information or default 10-fold UF approach can provide sufficient protection for mammals. These initially identified UFs were generally smaller than default values (e.g., 10) employed by regulatory stakeholders, yet larger UFs were occasionally noted. Our findings appear particularly useful for environmental health practitioners when conducting screening-level risk assessment for neonicotinoids, and provide an example for health hazard assessment of pesticides with limited toxicity information. Graphical abstract Unlabelled Image Highlights • Knowledge gaps of mammalian hazard data for neonicotinoids were identified. • Probabilistic hazard assessment for neonicotinoids was conducted. • TTCs for rat, dog, mouse and rabbit were identified for interim HLVs establishment. • Two probability data-driven approaches were used for UFs and ACRs derivations. • Our results can support read across, substitutions and health risk assessment. [ABSTRACT FROM AUTHOR]

Abstract Though numerous chemical ingredients are used in cleaning products, empirical mammalian toxicology information is often limited for many substances. Such limited data inherently presents challenges to environmental health practitioners performing hazard and risk assessments. Probabilistic hazard assessment using chemical toxicity distributions (CTDs) is an alternative approach for assessments of chemicals when toxicity information is lacking. The CTD concept allows for derivation of thresholds of toxicological concern (TTCs) to predict adverse effect thresholds for mammalian species. Unfortunately, comparative health hazard assessment of cleaning product ingredients in common use categories such as all-purpose cleaners (APC), dish care products (DCP) and laundry care products (LCP) has not been well studied. However, APC, DCP, and LCP are used routinely for household and industrial applications, resulting in residential and industrial occupational exposures. Therefore, we reviewed and then examined hazard information (median lethal dose (LD50), lowest-observed-adverse-effect level (LOAEL), and no-observed-adverse-effect level (NOAEL)) from different types of standard mammalian toxicity studies for oral toxicity in the rat model from the unique Cleaning Product Ingredient Safety Initiative mammalian toxicology database. Probabilistic distributions (CTDs) were subsequently constructed using LD50, NOAEL and LOAEL data from a specific toxicity study type for all available ingredients in these three use categories. Based on data availability, product type-specific and chemical category-specific CTDs were also generated and compared. For each CTD, threshold concentrations (TCs) and their 95% confidence intervals (95% CIs) at 1st, 5th, 10th, 50th, 90th, 95th and 99th percentiles were calculated using the log-normal model. To test whether the common default uncertainty factor (UF) approach (e.g., 3, 10) in mammalian health risk assessment provides sufficient protection, UFs were also derived for LOAEL-to-NOAEL and exposure duration (e.g., subchronic-to-chronic) extrapolations. Relationships between CTDs of acute LD50s and sublethal LOAELs/NOAELs were also examined for acute-to-chronic ratio calculations, which may be useful in extreme circumstances. Results from our critical review and meta-analysis appear particularly useful for hazard and risk practitioners when identifying TTCs for ingredients in product use categories, and other chemical classes. This approach can also support development of regulatory data dossiers through read across, chemical substitutions and screening-level health risk assessments when limited or no empirical toxicity information exists for industrial chemicals. Highlights • Chemical toxicity distributions were constructed for ingredients in APC, DCP and LCP. • Sub-distributions exist for different product types and chemical classes. • We identified use category-, product type- and class-specific TTCs. • Two probability data-driven approaches were used for UFs and ACRs derivations. • Our results can support read across, substitutions and health risk assessment. [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]

Several tons of chemicals are released every year into the environment and it is essential to assess the risk of adverse effects on human health and ecosystems. Risk assessment is expensive and time-consuming and only partial information is available for many compounds. A consolidated approach to overcome this limitation is the Threshold of Toxicological Concern (TTC) for assessment of the potential health impact and, more recently, eco-TTCs for the ecological aspect. The aim is to allow a safe assessment of substances with poor toxicological characterization. Only limited attempts have been made to integrate the human and ecological risk assessment procedures in a “One Health” perspective. We are proposing a strategy to define the Human-Biota TTCs (HB-TTCs) as concentrations of organic chemicals in freshwater preserving both humans and ecological receptors at the same time. Two sets of thresholds were derived: general HB-TTCs as preliminary screening levels for compounds with no eco- and toxicological information, and compound-specific HB-TTCs for chemicals with known hazard assessment, in terms of Predicted No effect Concentration (PNEC) values for freshwater ecosystems and acceptable doses for human health. The proposed strategy is based on freely available public data and tools to characterize and group chemicals according to their toxicological profiles. Five generic HB-TTCs were defined, based on the ecotoxicological profiles reflected by the Verhaar classes, and compound-specific thresholds for more than 400 organic chemicals with complete eco- and toxicological profiles. To complete the strategy, the use of in silico models is proposed to predict the required toxicological properties and suitable models already available on the VEGAHUB platform are listed.

The purpose of this study was to update the existing Cancer Potency Database (CPDB) in order to support the development of a dataset of compounds, with associated points of departure (PoDs), to enable a review and update of currently applied values for the Threshold of Toxicological Concern (TTC) for cancer endpoints. This update of the current CPDB, last reviewed in 2012, includes the addition of new data (44 compounds and 158 studies leading to additional 359 dose-response curves). Strict inclusion criteria were established and applied to select compounds and studies with relevant cancer potency data. PoDs were calculated from dose-response modeling, including the benchmark dose (BMD) and the lower 90% confidence limits (BMDL) at a specified benchmark response (BMR) of 10%. The updated full CPDB database resulted in a total of 421 chemicals which had dose-response data that could be used to calculate PoDs. This candidate dataset for cancer TTC is provided in a transparent and adaptable format for further analysis of TTC to derive cancer potency thresholds. • The Cancer Potency Database (CPDB) has been curated and updated. • A dataset to support cancer threshold of toxicological concern is proposed. • Points of departure are calculated i.e., BMDL10. • Transparency, robustness and adaptability of the TTC dataset is ensured. [ABSTRACT FROM AUTHOR]

Demands for increased analytical rigor have been growing within the botanical and dietary supplement industry due to concerns relative to safety, efficacy, and quality. Adulteration, ambiguous definitions, and insufficient perspective on safety are some of the major issues that arise when selecting a botanical extract. Herein, our comprehensive analytical approach is detailed for the selection of grape seed extracts. This approach provided characterization for the constituents above a threshold of toxicological concern by subjecting the extract to UHPLC-UV-CAD-HRMS and GC-FID & GC-HRMS. Thus, constituents within a wide range of volatility were evaluated. Furthermore, the extract was compared to authenticated botanical materials to confirm that no adulteration took place and was also compared to other grape seed extract sources to confirm that the material falls within the general profile. Finally, these data were cleared via an in silico safety assessment based on the list of constituents above the threshold of toxicological concern.

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]

An approach has been developed to characterize the individual chemical constituents of botanicals. The challenge was to identify and quantitate the significant analytes in these complex mixtures, largely in the absence of authentic standards. The data-rich information content generated by this three-detector configuration was specifically intended to be used to conduct safety and/or quality evaluations for complex botanical mixtures, on a chemical constituent basis. The approach utilized a broad gradient UHPLC chromatographic separation. Following the chromatographic separation and UV detection, the eluent was split and sent into a charged aerosol detector (CAD), for quantitation, and a quadrupole/time-of-flight high-resolution mass spectrometer for component identification. The known bias of the otherwise universal CAD response, for organic solvent composition of the mobile phase, was compensated by the addition of an inverse gradient make-up stream. This approach and the orthogonal information content from the chromatography and three different detectors was specifically designed to enable in-silico safety assessments. These guide, minimize, or even eliminate the need for in vivo and in vitro safety assessments. The methodology was developed and demonstrated using standardized extracts of Ginkgo biloba. Results from the development of this novel approach and the characterization example reported here demonstrate the suitability of this instrumental configuration for enabling in-silico safety assessments and proving general quality assessments of botanicals. [ABSTRACT FROM AUTHOR]

The Threshold of Toxicological Concern (TTC) concept defines a generic tolerable exposure for chemicals of unknown toxicity below which the risk of adverse health effects is considered very small. The original concept was refined and extended over the years, based either on differentiated structural classes or on additional information on certain toxicological endpoints. Initially, the focus of the TTC application was only on systemic toxic effects after repeated oral intake and consisted of one value. However, under well-defined boundary conditions, a long-term systemic inhalation TTC could also serve as a cut-off criterion for occupational exposure in those cases where workers are exposed to very low levels of chemicals by inhalation contact and could therefore reduce the need to perform animal tests. Within the scope of the European REACH legislation, several thousand systemic long-term inhalation Derived No Effect Levels (DNELs) for workers have been published. By statistical evaluation of the DNEL distribution of 1876 chemicals and the resulting 99th percentiles, we propose an inhalation workplace TTC for systemic effects in the region of 50 μg/m 3 (7 μg/kg body weight/day). Specific exclusion criteria apply for the discussed concept. [ABSTRACT FROM AUTHOR]

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An effective and thorough approach for the safety evaluation of natural flavor complexes (NFCs) was published in 2005 by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). An updated procedure is provided here, which maintains the essential concepts of the use of the congeneric group approach and the reliance on the threshold of toxicological concern (TTC) concept. The updated procedure emphasizes more rigorous considerations of unidentified constituents and the genotoxic potential of constituents. The update of the previously established procedure is the first step in a multi-year project to conduct safety re-evaluations for more than 250 NFCs that have uses that are currently considered Generally Recognized as Safe (GRAS) by the FEMA Expert Panel. In addition, this procedure can be more generally employed in the safety evaluation of NFCs. [ABSTRACT FROM AUTHOR]

A new dataset of cosmetics-related chemicals for the Threshold of Toxicological Concern (TTC) approach has been compiled, comprising 552 chemicals with 219, 40, and 293 chemicals in Cramer Classes I, II, and III, respectively. Data were integrated and curated to create a database of No-/Lowest-Observed-Adverse-Effect Level (NOAEL/LOAEL) values, from which the final COSMOS TTC dataset was developed. Criteria for study inclusion and NOAEL decisions were defined, and rigorous quality control was performed for study details and assignment of Cramer classes. From the final COSMOS TTC dataset, human exposure thresholds of 42 and 7.9 μg/kg-bw/day were derived for Cramer Classes I and III, respectively. The size of Cramer Class II was insufficient for derivation of a TTC value. The COSMOS TTC dataset was then federated with the dataset of Munro and colleagues, previously published in 1996, after updating the latter using the quality control processes for this project. This federated dataset expands the chemical space and provides more robust thresholds. The 966 substances in the federated database comprise 245, 49 and 672 chemicals in Cramer Classes I, II and III, respectively. The corresponding TTC values of 46, 6.2 and 2.3 μg/kg-bw/day are broadly similar to those of the original Munro dataset. [ABSTRACT FROM AUTHOR]

Botanicals used in dietary supplements industry can have toxicology concerns related to endpoint gaps that cannot be fully resolved by a history of use, or existence of conflicting safety data. However, traditional toxicological studies on botanicals are scientifically and pragmatically challenging due to testing of complex mixtures of constituents, cost, time, and animal usage. Alternatively, we developed an in silico decision-tree approach to address data gaps and inform need for further studies by toxicologically evaluating the chemical composition of botanicals. Following advanced multi-detector analytical characterization of a botanical, each chemical constituent is: (a.) quantitatively benchmarked against similar constituents in commonly consumed foods or botanicals with well-established safety profiles, (b.) systematically evaluated for toxicity data utilizing structure-activity relationships, and, (c.) compared to established thresholds of toxicological concern in absence of safety data or structural analogs. Finally, where safety endpoint gaps are identified which cannot be resolved without additional in vitro or in vivo studies, the botanical compositional data are critical to inform on study design. Results with three herbal preparations demonstrate the utility of this novel approach to identify potential hazards and establish safe human use levels for botanicals in a cost efficient and informative manner that minimizes animal use. [ABSTRACT FROM AUTHOR]

We performed a safety evaluation using the procedure devised by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) of the following four flavouring substances that belong to the class of ‘aliphatic primary alcohols, aldehydes, carboxylic acids, acetals, and esters containing additional oxygenated functional groups’ and are uniquely used in Japan: butyl butyrylacetate, ethyl 2-hydroxy-4-methylpentanoate, 3-hydroxyhexanoic acid and methyl hydroxyacetate. Although no genotoxicity study data were found in the published literature, none of the four substances had chemical structural alerts predicting genotoxicity. All four substances were categorised as class I by using Cramer’s classification. The estimated daily intake of each of the four substances was determined to be 0.007–2.9 μg/person/day by using the maximised survey-derived intake method and based on the annual production data in Japan in 2001, 2005 and 2010, and was determined to be 0.250–600.0 μg/person/day by using the single-portion exposure technique and based on average-use levels in standard portion sizes of flavoured foods. Both of these estimated daily intake ranges were below the threshold of toxicological concern for class I substances, which is 1800 μg/person/day. Although no information fromin vitroandin vivotoxicity studies for the four substances was available, these substances were judged to raise no safety concerns at the current levels of intake. [ABSTRACT FROM PUBLISHER]

The detection of perfluoroalkyl substances (PFAS) in surface and drinking water from various countries raised the attention to the presence of these chemicals in environmental probes and led to several regulatory actions to limit exposure in human beings. There was particular concern about perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), due to their former wide-spread use. Recently, several institutions published revisions of former regulatory or recommended maximum concentrations in drinking water and food, which are markedly lower than the former values. The present short overview describes the current regulations for PFAS and compares them with the outcome of several experimental studies in laboratory animals at low-level exposure to PFOA and PFOS. In addition, regulations for short-chain PFAS are presented which, due to lack of toxicological information, are evaluated according to the concepts of Threshold of Toxicological Concern (TTC) or the Health-related Indication Values (HRIV). [ABSTRACT FROM AUTHOR]

Epoxy fatty acids (EFAs) are secondary oxidation products formed from unsaturated fatty acid hydroperoxides. Seventeen food categories were analysed for C18 monoEFAs of food products available on the Belgian market. A quantitative exposure assessment was performed based on deterministic and probabilistic approaches combining these concentration data with consumption data obtained from the Belgian National Food Consumption Survey of 2004. A preliminary evaluation of any potential risk related to the intake of the studied EFAs through the studied foods was performed by applying the threshold of toxicological concern (TTC) concept. Three food categories out of 17 foods, mayonnaise, butter–margarine and ready-to-eat meals were found to contribute most to the intake of EFAs. According to probabilistic determination, these foods had P50 intakes of 0.4085, 0.3328 and 0.2997 mg kg–1 bw day–1 respectively. They had P99.5 intakes of 3.7183, 2.7921 and 38.6068 mg kg–1 bw day–1 respectively. The intake below the TTC was from the consumption of cooked meat, smoked salmon and raw cured ham, with P50 intakes of 0.0006, 0.0007 and 0.0011 mg kg–1 bw day–1 respectively, and the other foods were above the TTC. Based on the TTC concept, a risk to human health could be identified related to the consumption of cheese, snacks foods, plant oils, French fries, dry nuts, chips, cured minced raw meat, cookies, fresh and frozen salmon and bacon. [ABSTRACT FROM AUTHOR]

A non-targeted analytical method, using thermal desorption–gas chromatography–time of flight mass spectrometry, to detect, identify and semi-quantify volatile and semi-volatile organic constituents of e-cigarette aerosols is presented. A heart-cutting process with a Deans Switch has been applied to avoid saturation of the mass analyser by high-abundance bulk components. Between 30 and 90 compounds were detected in four aerosol samples generated by e-cigarettes, depending on the added flavourings. The method analyses in a single 80 mL, 3-second puff, GC-amenable compounds with volatilities ranging between those of propane (C3) and octacosane (C28) and abundance greater than approximately 5 ng. Method sensitivity is suitable for the application of thresholds of toxicological concern for product assessment at an exposure threshold of 1.5 μg per day. The method is compatible with the high-throughput screening of GC-amenable compounds in e-cigarette aerosols. [ABSTRACT FROM AUTHOR]

Environmental risk assessment is often affected by severe uncertainty. The frequently invoked precautionary principle helps to guide risk assessment and decision-making in the face of scientific uncertainty. In many contexts, however, uncertainties play a role not only in the application of scientific models but also in their development. Building on recent literature in the philosophy of science, this paper argues that precaution should be exercised at the stage when tools for risk assessment are developed as well as when they are used to inform decision-making. The relevance and consequences of this claim are discussed in the context of the threshold of the toxicological concern approach in food toxicology. I conclude that the approach does not meet the standards of an epistemic version of the precautionary principle. [ABSTRACT FROM AUTHOR]

A challenging step in human risk assessment of chemicals is the derivation of safe thresholds. The Threshold of Toxicological Concern (TTC) concept is one option which can be used for the safety evaluation of substances with a limited toxicity dataset, but for which exposure is sufficiently low. The application of the TTC is generally accepted for orally or dermally exposed cosmetic ingredients; however, these values cannot directly be applied to the inhalation route because of differences in exposure route versus oral and dermal. Various approaches of an inhalation TTC concept have been developed over recent years to address this. A virtual workshop organized by Cosmetics Europe, held in November 2020, shared the current state of the science regarding the applicability of existing inhalation TTC approaches to cosmetic ingredients. Key discussion points included the need for an inhalation TTC for local respiratory tract effects in addition to a systemic inhalation TTC, dose metrics, database building and quality of studies, definition of the chemical space and applicability domain, and classification of chemicals with different potencies. The progress made to date in deriving inhalation TTCs was highlighted, as well as the next steps envisaged to develop them further for regulatory acceptance and use. • Oral TTC values cannot directly be applied to the inhalation route. • Workshop: application of existing inhalation TTC approaches to cosmetic ingredients. • Comparison of inhalation TTC values derived from different databases. • Cramer Class classification appears not appropriate for inhalation TTC. • Suggested next steps for regulatory acceptance and use of inhalation TTCs. [ABSTRACT FROM AUTHOR]

Since the European Commission prohibited the use of bisphenol A in the production of polycarbonate (PC) baby bottles, many other materials have replaced PC for the manufacture of this type of food contact materials. In the present study, the potential migration risks associated with these alternative materials were investigated. First, all substances were evaluated for endocrine disruptive (ED) activity by using different existing lists of (suspected) ED chemicals. Next, the potential non-ED risks were assessed. A distinction was made between migrants listed in Annex I of European Regulation 10/2011 and the unlisted substances (e.g. non-intentionally added substances). For the listed substances, concentrations in the migration solutions were compared to their respective specific migration limits (SML) (when applicable). Migration of all substances was shown to be below their SML. The unlisted substances were evaluated using toxicological information from previous evaluations, or if not available, by applying the Threshold of Toxicological Concern (TTC) approach. In case the estimated exposure to the unlisted substance exceeded the human exposure TTC value, a more indepth risk assessment was performed. Based on the results of both parts of the study, four baby bottles were considered of high concern because of the potential toxicity of migrating compounds. [ABSTRACT FROM AUTHOR]

Since the first risk evaluation of Alternaria toxins by the European Food Safety Authority (EFSA) in 2011, new stable isotope dilution assays for tenuazonic acid (TA) broadened and deepened the data for exposure assessment. Moreover, recently unraveled high contents of TA in infant food based on sorghum/millet required an updated risk assessment. With the new data, the risk evaluation still revealed a low risk for adults as the maximum upper-bound data of the 95th percentile dietary exposure of TA can be estimated to be below the threshold of toxicological concern of 1500 ng/kg b.w. d. However, the evaluation of infant cereals based on sorghum/millet revealed a risk for the health of children consuming these foods, when two complementary approaches were applied. On the one hand, the maximum value of 1200 μg/kg TA in sorghum/millet-based infant food results in an intake of 3670 ng TA/kg b.w. d, which exceeds the threshold of toxicological concern by a factor of 2.4. On the other hand, this intake only leaves a margin of safety of 340 to the lowest dose showing subacute adverse effects in animals (1.25 mg/kg b.w. d), However, a safety factor of at least 1000 would be required. Therefore, infant cereals based on sorghum/millet with high content of TA cannot be regarded as safe. Based on toxicological considerations a limit of 500 μg TA per kg of sorghum/millet-based infant food is suggested. In these foods, other relevant Alternaria toxins such as alternariol or its methyl ether were not detected and obviously do not impose a risk for the consumers. [ABSTRACT FROM AUTHOR]

The present publication describes an integrative grouping concept to derive threshold values for inhalation exposure. The classification scheme starts with differences in toxicological potency and develops criteria to group compounds into two potency classes, namely toxic (T-group) or low toxic (L-group). The TTC concept for inhalation exposure is based on the TTC RepDose data set, consisting of 296 organic compounds with 608 repeated-dose inhalation studies. Initially, 21 structural features (SFs) were identified as being characteristic for compounds of either high or low NOEC values (Schüürmann et al., 2016). In subsequent analyses these SF groups were further refined by taking into account structural homogeneity, type of toxicological effect observed, differences in absorption, metabolism and mechanism of action (MoA), to better define their structural and toxicological boundaries. Differentiation of a local or systemic mode of action did not improve the classification scheme. Finally, 28 groups were discriminated: 19 T-groups and 9 L-groups. Clearly distinct thresholds were derived for the T- and L-toxicity groups, being 2 × 10 −5 ppm (2 μg/person/day) and 0.05 ppm (4260 μg/person/day), respectively. The derived thresholds and the classification are compared to the initial mainly structure driven grouping (Schüürmann et al., 2016) and to the Cramer classification. [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]

There are many substances in food and drinking water from different contamination sources for which only insufficient or no toxicity data exist. In order to prioritize and preliminarily assess the human health risks, the threshold of toxicological concern (TTC) approach was developed between 1996 and 2004. This concept has since been applied increasingly by regulatory food safety authorities. In parallel, the safety of this approach has been discussed by stakeholders, primarily on a conceptual basis. However, real examples showing the practical benefits of this approach have not been discussed. In this paper, the technical feasibility, applicability, safety, and further benefits of the TTC approach are illustrated and discussed based on four real cases: 1) halogenated contaminants of unknown origin in the drinking water (polychlorinated butadienes), 2) an unwanted by-product from epoxy resin coatings in canned fish (Cyclo-di-BADGE), 3) two cyclic compounds occurring in polyamide food packaging materials and kitchen utensils, and 4) mycotoxins (from Alternaria). These examples from different fields of application clearly demonstrate that the results of the TTC approach are an extremely useful starting point for adequate decisions and actions (if necessary) by risk assessment and risk management in food safety.

Non-relevant metabolites are defined in the EU regulation for plant protection product authorization and a detailed definition of non-relevant metabolites is given in an EU Commission DG Sanco (now DG SANTE – Health and Food Safety) guidance document. However, in water legislation at EU and member state level non-relevant metabolites of pesticides are either not specifically regulated or diverse threshold values are applied. Based on their inherent properties, non-relevant metabolites should be regulated based on substance-specific and toxicity-based limit values in drinking and groundwater like other anthropogenic chemicals. Yet, if a general limit value for non-relevant metabolites in drinking and groundwater is favored, an application of a Threshold of Toxicological Concern (TTC) concept for Cramer class III compounds leads to a threshold value of 4.5 μg L −1 . This general value is exemplarily shown to be protective for non-relevant metabolites, based on individual drinking water limit values derived for a set of 56 non-relevant metabolites. A consistent definition of non-relevant metabolites of plant protection products, as well as their uniform regulation in drinking and groundwater in the EU, is important to achieve legal clarity for all stakeholders and to establish planning security for development of plant protection products for the European market. [ABSTRACT FROM AUTHOR]