Threshold Of Toxicological Concern Research Articles

Quantum Mechanical Assessment of Nitrosamine Potency.

Nitrosamines are in the cohort of concern (CoC) as determined by regulatory guidance. CoC compounds are considered highly potent carcinogens that need to be limited below the threshold of toxicological concern, 1.5 μg/day. Nitrosamines like NDMA and NDEA require strict control, while novel nitrosamine drug substance-related impurities (NDSRIs) may or may not be characterized as potent carcinogens. A risk assessment based on the structural features of NDSRIs is important in order to predict potency because they lack substance-specific carcinogenicity. Herein, we present a quantum mechanical (QM)-based analysis on structurally diverse sets of nitrosamines to better understand how structure influences the reactivity that could result in carcinogenicity. We describe the potency trend through activation energies corresponding to α-hydroxylation, aldehyde formation, diazonium intermediate formation, reaction with DNA base, and hydrolysis reactions, and other probable metabolic pathways associated with the carcinogenicity of nitrosamines. We evaluated activation energies for selected cases such as N-nitroso pyrrolidines, N-nitroso piperidines, N-nitroso piperazines, N-nitroso morpholines, N-nitroso thiomorpholine, N-methyl nitroso aromatic, fluorine-substituted nitrosamines, and substituted aliphatic nitrosamines. We compare these results to the recent framework of the carcinogenic potency characterization approach (CPCA) proposed by health authorities which is meant to give guidance on acceptable intakes (AI) for NDSRIs lacking substance-specific carcinogenicity data. We show examples where QM modeling and CPCA are aligned and examples where CPCA both underestimates and overestimates the AI. In cases where CPCA predicts high potency for NDSRIs, QM modeling can help better estimate an AI. Our results suggest that a combined mechanistic understanding of α-hydroxylation, aldehyde formation, hydrolysis, and reaction with DNA bases could help identify the structural features that underpin the potency of nitrosamines. We anticipate this work will be a valuable addition to the CPCA and provide a more analytical way to estimate AI for novel NDSRIs.

Safety assessment of Paeonia lactiflora root extract for a cosmetic ingredient employing the threshold of toxicological concern (TTC) approach

Botanical extracts, widely used in cosmetics, pose a challenge to safety assessment due to their complex compositions. The threshold of toxicological concern (TTC) approach, offering a safe exposure level for cosmetic ingredients, proves to be a promising solution for ensuring the safety of cosmetic ingredients with low exposure level. We assessed the safety of Paeonia lactiflora root extract (PLR), commonly used in skin conditioning products, with the TTC. We identified 50 constituents of PLR extract from the USDA database and literature exploration. Concentration of each constituent of PLR extract was determined with the information from USDA references, literature, and experimental analysis. The genotoxicity of PLR and its constituents was assessed in vitro and in silico respectively. Cramer class of the constituents of the PLR extract was determined with Toxtree 3.1 extended decision tree using ChemTunes®. Systemic exposure of each constituent from leave-on type cosmetic products containing PLR at a 1% concentration was estimated and compared with respective TTC threshold. Two constituents exceeding TTC threshold were further analyzed for dermal absorption using in silico tools, which confirmed the safety of PLR extract in cosmetics. Collectively, we demonstrated that the TTC is a useful tool for assessing botanical extract safety in cosmetics.

Computational framework for identifying and evaluating mutagenic and xenoestrogenic potential of food additives

Food additives are chemicals incorporated in food to enhance its flavor, color and prevent spoilage. Some of these are associated with substantial health hazards, including developmental disorders, increase cancer risk, and hormone disruption. Hence, this study aimed to comprehend the in-silico toxicology framework for evaluating mutagenic and xenoestrogenic potential of food additives and their association with breast cancer. A total of 2885 food additives were screened for toxicity based on Threshold of Toxicological Concern (TTC), mutagenicity endpoint prediction, and mutagenic structural alerts/toxicophores identification. Ten food additives were identified as having mutagenic potential based on toxicity screening. Furthermore, Protein-Protein Interaction (PPI) analysis identified ESR1, as a key hub gene in breast cancer. KEGG pathway analysis verified that ESR1 plays a significant role in breast cancer pathogenesis. Additionally, competitive interaction studies of the predicted potential mutagenic food additives with the estrogen receptor-α were evaluated at agonist and antagonist binding sites. Indole, Dichloromethane, Trichloroethylene, Quinoline, 6-methyl quinoline, Ethyl nitrite, and 4-methyl quinoline could act as agonists, and Paraldehyde, Azodicarbonamide, and 2-acetylfuranmay as antagonists. The systematic risk assessment framework reported in this study enables the exploration of mutagenic and xenoestrogenic potential associated with food additives for hazard identification and management.

Contamination of dairy products with tris(2,4-di-tert-butylphenyl) phosphite and implications for human exposure

Tris(2,4-di-tert-butylphenyl) phosphite (AO168), an organophosphite antioxidant, can be oxidized to tris(2,4-di-tert-butylphenyl) phosphate (AO168 = O) during the production, processing, and application of plastics. AO168 = O can be further transformed to bis(2,4-di-tert-butylphenyl) phosphate and 2,4-di-tert-butylphenol. Here, we discovered the contamination of AO168 and its transformation products in dairy products for the first time. More samples contained AO168 (mean concentration: 8.78 ng/g wet weight [ww]), bis(2,4-di-tert-butylphenyl) phosphate (mean:11.1 ng/g ww) and 2,4-di-tert-butylphenol (mean: 46.8 ng/g ww) than AO168 = O (mean: 40.2 ng/g ww). The concentrations of AO168 and its transformation products were significantly correlated, and differed with the packaging material and storage conditions of the product. Estimated daily intakes (EDIs) of AO168 and its transformation products were calculated. Although the overall dietary risks were below one, transformation products accounted for 96.7% of the total hazard quotients. The high-exposure EDIs of total AO168 were above the threshold of toxicological concern (300 ng/kg bw/day), and deserve continual monitoring.

Deep Eutectic Solvent Modified Surface Molecular Imprinting Polymers on Boron Nitride Sheets for Specific Recognition of the Genotoxic Impurity Benzo(a)Pyrene

As a typical genotoxic impurity (GTI), the concentration of benzo(a)pyrene (BaP) must be below the threshold of toxicological concern (TTC). However, achieving a trace BaP is a significant challenge by conventional separation media. Utilizing the unique recognition capabilities of surface molecular imprinting polymers (SMIPs), the versatility of N-vinyl-2-pyrrolidone deep eutectic solvents (NVP-DES), and the high surface area of two-dimensional nano-boron nitride (2D-nano-BN) sheets, a series of functionalized 2D-BN materials were prepared (NVP-DES-SMIP@2D-nano-BN) for the specific recognition and removal of BaP. Utilizing 2D-nano-BN sheets as the base, four NVP-DESs were employed as monomers, BaP as the template, EGDMA as the cross-linker, and BPO/DMA as the initiator to prepare NVP-DES-SMIP@2D-nano-BN. The free energy of DES was computed using Gaussian software, and characterization of NVP-DES-SMIP@2D-nano-BN was performed using Fourier transform infrared spectroscopy and transmission electron microscopy. Quantitative and qualitative determinations of BaP were conducted using high performance liquid chromatography and fluorescence. Using a recognition model, NVP-DES-SMIP@2D-nano-BN exhibited a Freundlich isotherm fit and second-order kinetics for BaP.

Lack of genotoxicity potential and safety assessment of 4-(2-hydroxyethyl) morpholine present as an impurity in pharmaceuticals and nutritional supplements

4-(2-Hydroxyethyl) morpholine (HEM) is widely used as a building block of macromolecules in the manufacture of pharmaceuticals and dietary supplements and could remain as an impurity in the finished products. An evaluation of HEM was conducted to identify endpoints that could be used to determine the point-of-departure (POD) for use in assessing the potential risk from exposure to HEM. No oral repeated dose toxicological studies of appropriate duration were found for HEM. Therefore, suitable analogue(s) were identified. Although oral repeated dose studies were available for the analogues, the studies were not of sufficient duration for use in the assignment of a POD for risk evaluation. Accordingly, the Threshold of Toxicological Concern (TTC) approach, which proposes that a de minimis value can be derived to qualitatively assess risk, was considered for HEM. To determine the appropriate TTC approach (genotoxic or non-genotoxic), the genotoxicity of HEM and its analogues were evaluated. The weight of the evidence indicated that HEM, and the appropriate analogues, are not genotoxic. Considering the chemical structure of HEM, the non-genotoxic Cramer class III TTC value of 1.5 μg/kg bw/day was determined to be appropriate for use in safety assessment of HEM as an impurity in products intended for human consumption.

RIFM fragrance ingredient safety assessment, 2,4,6-cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)-, CAS Registry Number 499-44-5

The existing information supports the use of this material as described in this safety assessment. This material has not been fully evaluated for photoallergenic potential.2,4,6-Cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, photoirritation/photoallergenicity, skin sensitization, and environmental safety. Data show that 2,4,6-cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- is not genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material, and the exposure to 2,4,6-cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). The skin sensitization endpoint was completed using the Dermal Sensitization Threshold (DST) for reactive materials (64 μg/cm2); exposure is below the DST. Based on data, 2,4,6-cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- is a photoirritant but is not a concern under the current declared use levels. 2,4,6-Cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- was not evaluated for photoallergenicity. The environmental endpoints were evaluated; for the hazard assessment based on the screening data, 2,4,6-cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use (VoU) in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

Update of the Cancer Potency Database (CPDB) to enable derivations of Thresholds of Toxicological Concern (TTC) for cancer potency

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.

Unraveling biomarkers of exposure for tenuazonic acid through urinary metabolomics

Mycotoxins are secondary metabolites produced by fungi such as Aspergillus, Alternaria, and Penicillium, affecting nearly 80% of global food crops. Tenuazonic acid (TeA) is the major mycotoxin produced by Alternaria alternata, a prevalent pathogen affecting plants, fruits, and vegetables. TeA is notably prevalent in European diets, however, TeA biomarkers of exposure and metabolites remain unknown. This research aims to bridge this knowledge-gap by gaining insights about human TeA exposure and metabolization. Nine subjects were divided into two groups. The first group received a single bolus of TeA at the Threshold of Toxicological Concern (TTC) to investigate the presence of TeA urinary biomarkers, while the second group served as a control. Sixty-nine urinary samples were prepared and analyzed using UPLC-Xevo TQ-XS for TeA quantification and UPLC-Orbitrap Exploris for polar metabolome acquisition. TeA was rapidly excreted during the first 13 h and the fraction extracted was 0.39 ± 0.22. The polar metabolome compounds effectively discriminating the two groups were filtered using Orthogonal Partial Least Squares-Discriminant Analysis and subsequently annotated (n = 122) at confidence level 4. Finally, the urinary metabolome was compared to in silico predicted TeA metabolites. Nine metabolites, including oxidized, N-alkylated, desaturated, glucuronidated, and sulfonated forms of TeA were detected.

Investigation of aclidinium bromide degradation by stability-indicating HPLC methods, characterization of impurities by NMR, and identification of degradation products by LC-MS

Aclidinium bromide (ACL) is a long-acting muscarinic receptor antagonist used for the long-term treatment of chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the degradation of aclidinium bromide under stress and stability testing conditions, for which we developed and validated the first stability-indicating, specific, precise, accurate, and robust assay and related substances HPLC methods. Nine of the compounds used as reference standards were synthesized and fully characterized by 1H and 13C NMR, MS, and FTIR techniques. Two of these molecules, namely ACL-dimer and ACL-desphenyl, are novel compounds and reported herein for the first time. Hydrolysis of aclidinium resulted in major degradation via the formation of ACL-desDTG and DTGA metabolites. ACL-desphenyl and phenol were observed only under oxidative conditions at very low levels (< 0.10%), while ACL-hydroxy, known as a metabolite of aclidinium and confirmed by LC/QDa and LC/Q-TOF m/z data, formed under oxidative stress-testing conditions, UV light, and daylight. The identification of two impurities formed only when aclidinium bromide was treated with hydrogen peroxide was done by LC/QDa and LC/Q-TOF studies and the novel structures were proposed as ACL-bromophenoxy and ACL-bromothiophenyl formed via bromination of the phenyl and thiophene ring on the aclidinium, respectively. The stress and photostability testing studies showed that the aclidinium bromide drug substance is not sensitive to elevated temperature (105 °C, 10 days), slightly sensitive to daylight and UV-radiation, and it showed significant degradation under all hydrolysis and oxidizing conditions. The related substances HPLC method reported herein is also capable to monitor the potential genotoxic impurity 3-bromopropoxybenzene (3-BPB), a class 2 impurity according to ICH M7, and ensures that the impurity remains below the threshold of toxicological concern (TTC) limit, making it safe for patients.

Scientific opinion on the renewal of the authorisation of Smoke Concentrate 809045 (SF-003) as a smoke flavouring Primary Product.

The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of the smoke flavouring Primary Product Smoke Concentrate 809045 (SF-003), for which a renewal application was submitted in accordance with Article 12(1) of Regulation (EC) No 2065/2003. This opinion refers to the assessment of data submitted on chemical characterisation, dietary exposure and genotoxicity of the Primary Product. Product Smoke Concentrate 809045 is obtained by pyrolysis of beech wood. The Panel concluded that the compositional data provided on the Primary Product are adequate. At the maximum proposed use levels, dietary exposure estimates calculated with DietEx ranged from 0.1 to 1.5 mg/kg body weight (bw) per day at the mean and from 0.2 to 5.2 mg/kg bw per day at the 95th percentile. The Panel concluded that eleven components in the Primary Product raise a potential concern for genotoxicity. In addition, a potential concern for genotoxicity was identified for the unidentified part of the mixture. The Primary Product contains furan-2(5H)-one and benzene-1,2-diol, for which a concern for genotoxicity was identified in vivo upon oral administration. Considering that the exposure estimates for these two components are above the threshold of toxicological concern (TTC) of 0.0025 μg/kg bw per day for DNA-reactive mutagens and/or carcinogens, the Panel concluded that the Primary Product raises concern with respect to genotoxicity.

Scientific opinion on the renewal of the authorisation of Zesti Smoke Code 10 (SF-002) as a smoke flavouring Primary Product.

The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of the smoke flavouring Primary Product Zesti Smoke Code 10 (SF-002), for which a renewal application was submitted in accordance with Article 12(1) of Regulation (EC) No 2065/2003. This opinion refers to the assessment of data submitted on chemical characterisation, dietary exposure and genotoxicity of thePrimary Product. Zesti Smoke Code 10 is obtained by pyrolysis of hickory and oak woods. Given the limitations of the quantification approach employed by the applicant, the Panel could not judge whether the applied methods meet the legal quality criterion that at least 80% of the volatile fraction shall be identified and quantified. At the maximum proposed use levels, dietary exposure estimates calculated with DietEx ranged from 0.02 to 4.6 mg/kg body weight (bw) per day at the mean and from no dietary exposure to 13.0 mg/kg bw per day at the 95th percentile. The Panel concluded that four components in the Primary Product raise a potential concern for genotoxicity. In addition, a potential concern for genotoxicity was identified for the unidentified part of the mixture. The Primary Product contains furan-2(5H)-one and benzene-1,2-diol, for which a concern for genotoxicity was identified in vivo upon oral administration. Considering that the exposure estimates for these two components are above the threshold of toxicological concern (TTC) of 0.0025 μg/kg bw per day for DNA-reactive mutagens and/or carcinogens, the Panel concluded that the Primary Product raises concern with respect to genotoxicity.

Scientific opinion on the renewal of the authorisation of SmokEz C-10 (SF-005) as a smoke flavouring Primary Product.

The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of the smoke flavouring Primary Product SmoKEz C-10 (SF-005), for which a renewal application was submitted in accordance with Article 12(1) of Regulation (EC) No 2065/2003. This opinion refers to the assessment of data submitted on chemical characterisation, dietary exposure and genotoxicity of the Primary Product. SmoKEz C-10 is obtained by pyrolysis of maple, oak, hickory, ash, birch, beech and cherry woods. Given the limitations of the quantification approach employed by the applicant, the Panel could not judge whether the applied methods meet the legal quality criterion that at least 80% of the volatile fraction shall be identified and quantified. At the maximum proposed use levels, dietary exposure estimates calculated with DietEx ranged from 0.01 to 5.1 mg/kg body weight (bw) per day at the mean and from no dietary exposure to 18.1 mg/kg bw per day at the 95th percentile. The Panel concluded that five components in the Primary Product raise a potential concern for genotoxicity. In addition, a potential concern for genotoxicity was identified for the unidentified part of the mixture. The Primary Product contains furan-2(5H)-one and benzene-1,2-diol, for which a concern for genotoxicity was identified in vivo upon oral administration. Considering that the exposure estimates for these two components are above the threshold of toxicological concern (TTC) of 0.0025 μg/kg bw per day for DNA-reactive mutagens and/or carcinogens, the Panel concluded that the Primary Product raises concern with respect to genotoxicity.

Scientific opinion on the renewal of the authorisation of SmokEz Enviro-23 (SF-006) as a smoke flavouring Primary Product.

The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of the smoke flavouring Primary Product SmokEz Enviro-23 (SF-006), for which a renewal application was submitted in accordance with Article 12(1) of Regulation (EC) No 2065/2003. This opinion refers to the assessment of data submitted on chemical characterisation, dietary exposure and genotoxicity of the Primary Product. SmokEz Enviro-23 is obtained by pyrolysis of oak, maple, hickory, ash, birch, beech and cherry woods. Given the limitations of the quantification approach employed by the applicant, the Panel could not judge whether the applied methods meet the legal quality criterion that at least 80% of the volatile fraction shall be identified and quantified. At the maximum proposed use levels, dietary exposure estimates calculated with DietEx ranged from 0.01 to 3.2 mg/kg body weight (bw) per day at the mean and from no dietary exposure to 9.5 mg/kg bw per day at the 95th percentile. The Panel concluded that four components in the Primary Product raise a potential concern for genotoxicity. In addition, a potential concern for genotoxicity was identified for the unidentified part of the mixture. The Primary Product contains furan-2(5H)-one and benzene-1,2-diol, for which a concern for genotoxicity was identified in vivo upon oral administration. Considering that the exposure estimates for these two components are above the threshold of toxicological concern (TTC) of 0.0025 μg/kg bw per day for DNA-reactive mutagens and/or carcinogens, the Panel concluded that the Primary Product raises concern with respect to genotoxicity.

Scientific opinion on the renewal of the authorisation of Scansmoke SEF7525 (SF-004) as a smoke flavouring Primary Product.

The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of the smoke flavouring Primary Product Scansmoke SEF7525 (SF-004), for which a renewal application was submitted in accordance with Article 12(1) of Regulation (EC) No 2065/2003. This opinion refers to the assessment of data submitted on chemical characterisation, dietary exposure and genotoxicity of the Primary Product. Scansmoke SEF7525 is obtained from a tar produced from a mixture of red oak, white oak, maple, beech and hickory. Based on the compositional data, the Panel noted that the identified and quantified proportion of the solvent-free fraction amounts to 32.6 weight (wt)%, thus the applied method does not meet the legal quality criterion that at least 50% of the solvent-free fraction shall be identified and quantified. At the maximum proposed use levels, dietary exposure estimates calculated with Food Additive Intake Model (FAIM) ranged from 0.6 to 3.8 mg/kg body weight (bw) per day at the mean and from 1.1 to 10.1 mg/kg bw per day at the 95th percentile. Based on the available information on genotoxicity on 44 identified components, the Panel concluded that two substances in the Primary Product, styrene and benzofuran, raise a potential concern for genotoxicity. In addition, a potential concern for genotoxicity was identified for the unidentified part of the mixture. Considering that the exposure estimates for styrene and benzofuran are above the threshold of toxicological concern (TTC) value of 0.0025 kg/kg bw per day for DNA-reactive mutagens and/or carcinogens and since further data are needed to clarify their potential genotoxicity, the Panel concluded that the potential safety concern for genotoxicity of the Primary Product cannot be ruled out.

Scientific opinion on the renewal of the authorisation of proFagus Smoke R714 (SF-001) as a smoke flavouring Primary Product.

The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of the smoke flavouring Primary Product proFagus Smoke R714 (SF-001), for which a renewal application was submitted in accordance with Article 12(1) of Regulation (EC) No 2065/2003. This opinion refers to the assessment of data submitted on chemical characterisation, dietary exposure and genotoxicity of the Primary Product. ProFagus Smoke R714 is obtained by pyrolysis of beech and oak woods as main source materials. Based on the compositional data, the Panel noted that the identified and quantified proportion of the solvent-free fraction amounts to 39 weight (wt)%, thus the applied method does not meet the legal quality criterion that at least 50% of the solvent-free fraction shall be identified and quantified. At the maximum proposed use levels, dietary exposure estimates calculated with DietEx ranged from 0.7 to 10.9 mg/kg body weight (bw) per day at the mean and from 2.2 to 42.5 mg/kg bw per day at the 95th percentile. The Panel concluded that three components in the Primary Product raise a potential concern for genotoxicity. In addition, a potential concern for genotoxicity was identified for the unidentified part of the mixture. The Primary Product contains furan-2(5H)-one, for which a concern for genotoxicity was identified in vivo upon oral administration. Considering that the exposure estimates for this component are above the threshold of toxicological concern (TTC) of 0.0025 μg/kg bw per day for DNA-reactive mutagens and/or carcinogens, the Panel concluded that the Primary Product raises concern with respect to genotoxicity.

Analysis of volatile organic compounds and potential odour compounds in food contact paperboard using headspace two-dimensional GC-QTOF-MS

The objective was to establish a robust and reliable approach for the characterisation of volatile organic compounds (VOCs) present in food contact paperboard. This was achieved through the utilisation of headspace solid-phase microextraction in tandem with comprehensive two-dimensional (2D) gas chromatography (GC) and quadrupole time-of-flight mass spectrometry (HS-SPME-GC × GC-QTOF-MS). The experimental parameters were optimised, involving the use of a DVB/C-WR/PDMS fibre at a temperature of 80 °C for a duration of 30 min. A total of 344 VOCs comprising aldehydes, ketones, alcohols, ethers, esters, alkanes and aromatic compounds, were tentatively identified in the samples. Twelve compounds believed to be from biogenic sources had a high odour impact making them major contributors to potential taint from the paperboard samples. Significant attention should be devoted to five compounds namely, 2-methylnaphthalene, 2-pentyl-furan, furfural, 1-octen-3-one and 1-octen-3-ol due to their potential adverse impact on the organoleptic qualities of packaged food items and their potential toxicity. Abbreviations: C-WR: carbon wide range; DVB: divinylbenzene; GC-MS: gas chromatography - mass spectrometry; GCxGC-QTOF-MS: comprehensive two-dimensional gas chromatography coupled to quadrupole-time-of-flight - mass spectrometry; HS-SPME: headspace - solid phase microextraction; LOD: limit of detection; LOQ: limit of quantification; OAV: odor activity values; PDMS: polydimethylsiloxane; RI: retention index; TTC: threshold of toxicological concern; VOC: volatile organic compound

The threshold of toxicological concern for insufficiently explored chemicals occurring in drinking water during transportation

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.

FEMA GRAS assessment of natural flavor complexes: Sage oil, Orris Root Extract and Tagetes Oil and related flavoring ingredients.

In recent years, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) has conducted a program to re-evaluate the safety of natural flavor complexes (NFCs) used as flavor ingredients. This publication, twelfth in the series, details the re-evaluation of NFCs whose constituent profiles are characterized by alicyclic or linear ketones. In its re-evaluation, the Expert Panel applies a scientific constituent-based procedure for the safety evaluation of NFCs in commerce using a congeneric group approach. Estimated intakes of each congeneric group of the NFC are evaluated using the well-established and conservative Threshold of Toxicological Concern (TTC) approach. In addition, studies on the toxicity and genotoxicity of members of the congeneric groups and the NFCs under evaluation are reviewed. The scope of the safety evaluation of the NFCs contained herein does not include added use in dietary supplements or any products other than food. Thirteen (13) NFCs derived from the Boronia, Cinnamomum, Thuja, Ruta, Salvia, Tagetes, Hyssopus, Iris, Perilla and Artemisia genera are affirmed as generally recognized as safe (GRAS) under conditions of their intended use as flavor ingredients based on an evaluation of each NFC and the constituents and congeneric groups therein.

Safety assessment of Cnidium officinale rhizome extract in cosmetics using the Threshold of Toxicological Concern (TTC) approach

Cosmetics often contain botanical extracts, which present a challenge for safety assessors due to their complex composition. The threshold of toxicological concern (TTC) approach is considered as a solution for the safety assessment of botanical extracts in cosmetics as part of next-generation risk assessment. In this study, we applied the TTC approach to evaluate the safety of Cnidium officinale rhizome extract (CORE), a widely used botanical extract in skin conditioning products. We identified 32 components of CORE through the USDA database and literature and determined the content of each component through literature or actual analysis where an authentic standard was available. Macro- and micronutrients were also analyzed to exclude them as safe components. The Toxtree® software was used to identify the Cramer class of remaining components. We estimated the systemic exposure of each component from leave-on type cosmetic products containing CORE at a 1% concentration and compared the results to TTC thresholds. All components of CORE had a systemic exposure below the TTC threshold. While batch variations and presence of unknown chemicals in individual CORE materials should be considered, this study demonstrated that the TTC approach can be a useful tool for the safety assessment of botanical extracts in cosmetics.