Threshold Of Toxicological Concern Research Articles

RIFM fragrance ingredient safety assessment, cis-3-hexenyl tiglate, CAS Registry Number 67883-79-8

The existing information supports the use of this material as described in this safety assessment. cis-3-Hexenyl tiglate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analogs 2-methyl-trans-2-butenoic acid (CAS # 80-59-1) and cis-3-hexenol (CAS # 928-96-1) show that cis-3-hexenyl tiglate is not expected to be genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the Threshold for Toxicological Concern (TTC) for a Cramer Class I material; exposure to cis-3-hexenyl tiglate is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day and 1.4 mg/day, respectively). Data from analog 2-hexenoic acid, 2-methyl-, methyl ester, (2E)- (CAS # 16493-96-2) provided cis-3-hexenyl tiglate a No Expected Sensitization Induction Level (NESIL) of 1100 μg/cm2 for the skin sensitization endpoint. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/Vis) spectra; cis-3-hexenyl tiglate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; cis-3-hexenyl tiglate 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 in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

RIFM fragrance ingredient safety assessment, 4,8-decadienal, (4Z,8Z)-, CAS Registry Number 1958027-35-4

Summary: The existing information supports the use of this material as described in this safety assessment.4,8-Decadienal, (4Z,8Z)- was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analogs 4,7-decadienal (CAS # 934534-30-2) and nona-2-trans-6-cis-dienal (CAS # 557-48-2) show that 4,8-decadienal, (4Z,8Z)- is not expected to be genotoxic. Data on analog 10-undecenal (CAS # 112-45-8) provide a calculated Margin of Exposure (MOE) > 100 for the repeated dose toxicity and fertility endpoints and a No Expected Sensitization Induction Level (NESIL) of 1700 μg/cm2 for the skin sensitization endpoint. The developmental toxicity and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for Cramer Class I materials; exposure is below the TTC (0.03 mg/kg/day and 1.4 mg/day, respectively). The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/Vis) spectra; 4,8-decadienal, (4Z,8Z)- is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 4,8-decadienal, (4Z,8Z)- was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards. Its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

Hazard prioritisation of substances in printing inks and adhesives applied to plastic food packaging

ABSTRACT 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.

FEMA GRAS assessment of natural flavor complexes: Eucalyptus oil and other cyclic ether-containing flavoring ingredients

In 2015, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) initiated a program for the re-evaluation of the safety of over 250 natural flavor complexes (NFCs) used as flavor ingredients. This publication, the sixth in the series, will summarize the re-evaluation of eight NFCs whose constituent profiles are characterized by significant amounts of eucalyptol and/or other cyclic ethers. This re-evaluation was based on a procedure first published in 2005 and subsequently updated in 2018 that evaluates the safety of naturally occurring mixtures for their intended use as flavoring ingredients. The procedure relies on a complete chemical characterization of the NFC intended for commerce and the organization of its chemical constituents into well-defined congeneric groups. The safety of the NFC is evaluated using the well-established and conservative threshold of toxicological concern (TTC) concept in addition to data on absorption, metabolism and toxicology of the constituents of the congeneric groups and the NFC under evaluation. Eight NFCs derived from the Eucalyptus, Melaleuca, Origanum, Laurus, Rosmarinus and Salvia genera were affirmed as generally recognized as safe (GRAS) under their conditions of intended use as flavor ingredients based on an evaluation of each NFC and the constituents and congeneric groups therein.

FEMA GRAS assessment of natural flavor complexes: Origanum oil, thyme oil and related phenol derivative-containing flavoring ingredients

In 2015, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) initiated a re-evaluation of the safety of over 250 natural flavor complexes (NFCs) used as flavor ingredients, mostly consisting of a variety of essential oils and botanical extracts. This publication, seventh in the series, re-evaluates NFCs with constituent profiles dominated by phenolic derivatives including carvacrol, thymol and related compounds using a constituent-based procedure first published in 2005 and updated in 2018. The procedure is based on the chemical characterization of each NFC as intended for commerce and the estimated intake of the constituent congeneric groups. The procedure applies the threshold of toxicological concern (TTC) concept and evaluates relevant data on absorption, metabolism, genotoxic potential and toxicology of the constituent congeneric groups and the NFC under evaluation. Herein, the FEMA Expert Panel affirmed the generally recognized as safe (GRAS) status of seven phenolic derivative-based NFCs, Origanum Oil (Extractive) (FEMA 2828), Savory Summer Oil (FEMA 3013), Savory Summer Oleoresin (FEMA 3014), Savory Winter Oil (FEMA 3016), Savory Winter Oleoresin (FEMA 3017), Thyme Oil (FEMA 3064) and Thyme White Oil (FEMA 3065) under their conditions of intended use as flavor ingredients.

Threshold of Toxicological Concern-An Update for Non-Genotoxic Carcinogens.

The Threshold of Toxicological Concern (TTC) concept can be applied to organic compounds with the known chemical structure to derive a threshold for exposure, below which a toxic effect on human health by the compound is not expected. The TTC concept distinguishes between carcinogens that may act as genotoxic and non-genotoxic compounds. A positive prediction of a genotoxic mode of action, either by structural alerts or experimental data, leads to the application of the threshold value for genotoxic compounds. Non-genotoxic substances are assigned to the TTC value of their respective Cramer class, even though it is recognized that they could test positive in a rodent cancer bioassay. This study investigated the applicability of the Cramer classes specifically to provide adequate protection for non-genotoxic carcinogens. For this purpose, benchmark dose levels based on tumor incidence were compared with no observed effect levels (NOELs) derived from non-, pre- or neoplastic lesions. One key aspect was the categorization of compounds as non-genotoxic carcinogens. The recently finished CEFIC LRI project B18 classified the carcinogens of the Carcinogenicity Potency DataBase (CPDB) as either non-genotoxic or genotoxic compounds based on experimental or in silico data. A detailed consistency check resulted in a dataset of 137 non-genotoxic organic compounds. For these 137 compounds, NOEL values were derived from high quality animal studies with oral exposure and chronic duration using well-known repositories, such as RepDose, ToxRef, and COSMOS DB. Further, an effective tumor dose (ETD10) was calculated and compared with the lower confidence limit on benchmark dose levels (BMDL10) derived by model averaging. Comparative analysis of NOEL/EDT10/BMDL10 values showed that potentially bioaccumulative compounds in humans, as well as steroids, which both belong to the exclusion categories, occur predominantly in the region of the fifth percentiles of the distributions. Excluding these 25 compounds resulted in significantly higher but comparable fifth percentile chronic NOEL and BMDL10 values, while the fifth percentile EDT10 value was slightly higher but not statistically significant. The comparison of the obtained distributions of NOELs with the existing Cramer classes and their derived TTC values supports the application of Cramer class thresholds to all non-genotoxic compounds, such as non-genotoxic carcinogens.

Safety of Plastic Food Packaging: The Challenges about Non-Intentionally Added Substances (NIAS) Discovery, Identification and Risk Assessment.

Several food contact materials (FCMs) contain non-intentionally added substances (NIAS), and most of the substances that migrate from plastic food packaging are unknown. This review aimed to situate the main challenges involving unknown NIAS in plastic food packaging in terms of identification, migration tests, prediction, sample preparation, determination methods and risk assessment trials. Most studies have identified NIAS in plastic materials as polyurethane adhesives (PU), polyethylene terephthalate (PET), polyester coatings, polypropylene materials (PP), multilayers materials, plastic films, polyvinyl chloride (PVC), recycled materials, high-density polyethylene (HDPE) and low-density polyethylene (LDPE). Degradation products are almost the primary source of NIAS in plastic FCMs, most from antioxidants as Irganox 1010 and Irgafos 168, following by oligomers and side reaction products. The NIAS assessment in plastics FCMs is usually made by migration tests under worst-case conditions using food simulants. For predicted NIAS, targeted analytical methods are applied using GC-MS based methods for volatile NIAS and GC-MS and LC-MS based methods for semi- and non-volatile NIAS; non-targeted methods to analyze unknown NIAS in plastic FCMs are applied using GC and LC techniques combined with QTOF mass spectrometry (HRMS). In terms of NIAS risk assessment and prioritization, the threshold of toxicological concern (TTC) concept is the most applied tool for risk assessment. Bioassays with sensitive analytical techniques seem to be an efficient method to identify NIAS and their hazard to human exposure; the combination of genotoxicity testing with analytical chemistry could allow the Cramer class III TTC application to prioritize unknown NIAS. The scientific justification for implementing a molecular weight-based cut-off (<1000 Da) in the risk assessment of FCMs should be reevaluated. Although official guides and opinions are being issued on the subject, the whole chain’s alignment is needed, and more specific legislation on the steps to follow to get along with NIAS.

The Threshold of Toxicological Concern (TTC) is a pragmatic tool for the safety assessment: Case studies of cosmetic ingredients with low consumer exposure

The Threshold of Toxicological Concern (TTC) is an internationally accepted pragmatic and conservative tool for the safety assessment of substances, which is used in a wide range of regulatory contexts. The TTC approach produces human exposure threshold values (TTC values) originally derived by Munro from oral toxicity data on cancer and non-cancer toxicity endpoints. This database has been recently substantially enlarged by the COSMOS database, an enhanced oral non-cancer TTC dataset on a larger chemical domain, thereby resulting in a new, transparent and public TTC database also including 552 cosmetics-related chemicals. The 5th percentile point of departure value for each Cramer Class was determined, from which human exposure TTC values have been derived. The combined COSMOS/Munro dataset provided TTC values of 46, 6.2 and 2.3 μg/kg bw/day for Cramer Classes I, II or III, respectively. In order to demonstrate the diverse scope and successful application of the TTC concept to cosmetic ingredients including hair dyes, fragrances and plant-derived ingredients, Cosmetics Europe has prepared several case studies. Overall, the TTC concept is not only useful to replace animal testing but can also successfully be applied to the safety evaluation of cosmetic ingredients in the marketed formulas with low human exposure.

Evaluation, Method Development, and Validation for Content Determination of Potential Genotoxic Impurities (PGIs) at the TTC Level in Telmisartan API

Telmisartan is an angiotensin II receptor antagonist used in the cure of hypertension and other heart diseases. In the current research work, the synthetic route of Telmisartan, including those of starting materials, was evaluated to identify nine potential genotoxic impurities (PGIs) (impurities I–IX) by making use of the literature-, statistical-, and rule-based methods. To date, no suitable methods have been developed for the separation and quantification of these nine impurities in Telmisartan at the threshold of toxicological concern (TTC) level. Based on the identified impurities, four chromatographic methods were developed and validated as per the International Council on Harmonisation (ICH) guidelines. The developed methods are practical and efficient in the detection as well as quantification of PGIs and may be adopted to guarantee the safe use of Telmisartan.

Active pharmaceutical contaminants in dietary supplements: A tier-based risk assessment approach

The presence of active pharmaceutical ingredients (APIs) in adulterated or contaminated dietary supplements is a current product safety concern. Since there are limited guidelines, and no published consensus methods, we developed a tier-based framework incorporating typical lines of evidence for determining the human health risk associated with APIs in dietary supplements. Specifically, the tiered approach outlines hazard identification and decision to test for APIs in products based on criteria for likelihood of contamination or adulteration, and evaluation of manufacturer production standards. For products with detectable levels of APIs, a variety of default approaches, including the use of fraction of the therapeutic dose and the threshold of toxicological concern (TTC), as well as health-based exposure limits (HBELs) are applied. In order to demonstrate its practical use, as well as any limitations and/or special considerations, this framework was applied to five dietary supplements (currently available to the public). We found that the detected levels of APIs in some dietary supplements were above the recommended dose of the drugs, and thus, pose a significant health risk to consumers and potentially workers involved in manufacturing of these supplements. The results support the value of increased product quality surveillance and perhaps regulatory activity.

Fractions of Concern: Challenges and Strategies for the Safety Assessment of Biological Matter in Cosmetics

Cosmetic ingredients based on more or less refined biological matter (plants, fungi, bacteria, etc.) are gaining popularity. Advances in green chemistry and biotechnology are supporting this general trend further. Following numerous bans on the use of newly generated animal testing data in cosmetic safety assessments, and the worldwide demand for “cruelty-free” products, many alternative methods have been developed to assess the toxicity of ingredients. Whilst great strides have been, and continue to be, made, the area of systemic toxicity is one where international harmonisation and regulatory acceptance is still evolving. A strategy for the fractional assessment of biological matter is suggested to make approaches, such as threshold of toxicological concern (TTC) methodology, fit for purpose. Within this strategy, analytical data are used to generate compound classes which are quantified and assessed separately. Whilst this strategy opens new windows for assessing the safety of complex mixtures with a lack of toxicological data, it also raises awareness of the increasing complexity of cosmetic formulations and the general problem of additivity/synergy being rarely addressed. Extremely complex mixtures are and will be a growing challenge for safety assessors.

Toward a Universal Acute Fish Threshold of Toxicological Concern.

Threshold of toxicological concern (TTC) is a concept that has been around for decades in human health sciences. Ecotoxicology recently adopted a variant of this concept as eco-TTC. Adoption of the concept of TTC considerably reduces the amount of animal testing required for regulatory purposes. We provide an application of a universal TTC for the entirety of acute fish toxicity data (i.e., establishment of an exposure level below which there would be minimal probability of acute fish toxicity for any chemical, without consideration of mechanism of action). We calculated TTC values for a number of subgroups using various approaches. These approaches were evaluated using data from a cohort of 69 999 acute fish toxicological assays. This database was normalized/curated for units, exposure duration, quality assurance/control, and duplicates, which reduced it to 47 694 assays. Data were not normally but log-normally distributed, making geometric means the most appropriate statistical parameter. Thus, we developed descriptive statistics using geometric means with 95, 99, and 99.9% confidence intervals. Various assessment factors (akin to predicted-no-effect concentration derivation) were applied to the geometric means to derive TTCs. Other approaches employed were the calculation of y = 0 intercepts as well as development of 95 and 99.75% cutoffs of cumulative data as well as modular uncertainty scoring tool (MUST) analysis. All of the methodologies derived highly congruent TTCs ranging from to 2 to 8 μg/L except for the 99.75th percentile cutoff of 0.3 μg/L. The data would be most useful in making a binary testing/no testing required decision. For acute fish toxicity, a TTC value of 2 μg/L was most appropriate, based on the 95th percentile of data distribution without any assessment factor. Environ Toxicol Chem 2021;40:1740-1749. © 2021 SETAC.

RIFM fragrance ingredient safety assessment, 6-nonenenitrile, (Z)- (9CI), CAS Registry Number 80639-54-9

The existing information supports the use of this material as described in this safety assessment. 6-Nonenenitrile, (Z)- (9CI) was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog 3-(cis-3-hexenyloxy)propanenitrile (CAS # 142653-61-0) show that 6-nonenenitrile, (Z)- (9CI) is not expected to be genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class III material, and the exposure to 6-nonenenitrile, (Z)- (9CI) is below the TTC (0.0015 mg/kg/day, 0.0015 mg/kg/day, and 0.47 mg/day, respectively). Data from read-across analog 3-(cis-3-hexenyloxy)propanenitrile (CAS # 142653-61-0) show that there are no safety concerns for 6-nonenenitrile, (Z)- (9CI) for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; 6-nonenenitrile, (Z)- (9CI) is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 6-nonenenitrile, (Z)- (9CI) 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 in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

RIFM fragrance ingredient safety assessment, hexadeca-1,5-lactone, CAS Registry Number 7370-44-7

The existing information supports the use of this material as described in this safety assessment.Hexadeca-1,5-lactone was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from the target material and read-across analog hydroxynonanoic acid, δ-lactone (CAS # 3301-94-8) show that hexadeca-1,5-lactone is not expected to be genotoxic. Data from analog δ-decalactone (CAS # 705-86-2) provide a calculated Margin of Exposure (MOE) > 100 for the repeated dose and reproductive toxicity endpoints. Data from analog δ-octalactone (CAS # 698-76-0) show that there are no safety concerns for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; hexadeca-1,5-lactone is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material; exposure is below the TTC (1.4 mg/day). For the hazard assessment based on the screening data, hexadeca-1,5-lactone is not Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards. Hexadeca-1,5-lactone could not be risk screened as there were no reported volumes of use for either North America or Europe in the 2015 IFRA Survey.

RIFM fragrance ingredient safety assessment, ethyl 2-methyl-4-pentenoate, CAS Registry Number 53399-81-8

The existing information supports the use of this material as described in this safety assessment.Ethyl 2-methyl-4-pentenoate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog methyl undec-10-enoate (CAS # 111-81-9) show that ethyl 2-methyl-4-pentenoate is not expected to be 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 ethyl 2-methyl-4-pentenoate 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 non-reactive materials (900 μg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/Vis) spectra; ethyl 2-methyl-4-pentenoate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; ethyl 2-methyl-4-pentenoate 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 in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

RIFM fragrance ingredient safety assessment, 5- and 6-decenoic acid, CAS Registry Number 72881-27-7

Summary: The existing information supports the use of this material as described in this safety assessment.5- and 6-Decenoic acid was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog oleic acid (CAS # 112-80-1) show that 5- and 6-decenoic acid is not expected to be 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 5- and 6-decenoic acid 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 non-reactive materials (900 μg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/Vis) spectra; 5- and 6-decenoic acid is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 5- and 6-decenoic acid 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 in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

Defining the Human-Biota Thresholds of Toxicological Concern for Organic Chemicals in Freshwater: The Proposed Strategy of the LIFE VERMEER Project Using VEGA Tools.

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.

Development of a New Threshold of Toxicological Concern Database of Non-cancer Toxicity Endpoints for Industrial Chemicals.

In cases where chemical-specific toxicity data are absent or limited, the threshold of toxicological concern (TTC) offers an alternative to assess human exposure below which “there would be no appreciable risk to human health.” The application of TTC to non-cancer systemic endpoints has been pursued for decades using a chemical classification and Point of Departure (POD). This study presents a new POD dataset of oral subacute/subchronic toxicity studies in rats for 656 industrial chemicals retrieved from the Hazard Evaluation Support System (HESS) Integrated Platform, which contains hundreds of reliable repeated-dose toxicity test data of industrial chemicals under the Chemical Substances of Control Law in Japan. The HESS TTC dataset was found to have less duplication with substances in other reported TTC datasets. Each chemical was classified into a Cramer Class, with 68, 3, and 29% of these 656 chemicals distributed in Classes III, II, and I, respectively. For each Cramer Class, a provisional Tolerable Daily Intake (TDI) was derived from the 5th percentile of the lognormal distribution of PODs. The TDIs were 1.9 and 30 μg/kg bw/day for Classes III and I, respectively. The TDI for Cramer Class II could not be determined due to insufficient sample size. This work complements previous studies of the TTC approach and increases the confidence of the thresholds for non-cancer endpoints by including unique chemical structures. This new TTC dataset is publicly available and can be merged with existing databases to improve the TTC approach.

Application of the Threshold of Toxicological Concern (TTC) in Food Safety: Challenges and Opportunities.

The safety assessment of chemicals added or found in food has traditionally made use of data from in vivo studies performed on experimental animals. The nature and amount of data required to carry out a risk assessment is generally stipulated either in the different food legislations or in sectoral guidance documents. However, there are still cases where no or only limited experimental data are available or not specified by law, for example for contaminants or for some minor metabolites from active substances in plant protection products. For such cases, the Threshold of Toxicological Concern (TTC) can be applied. This review explores the use of the TTC approach in food safety in the European Union, in relation to the different food sectors, legal requirements and future opportunities.

Clustering and prioritization to design a risk-based monitoring program in groundwater sources for drinking water

BackgroundThe number of chemical parameters included in monitoring programs of water utilities increased in the last decade. In accordance with the European Drinking Water Directive, utilities aim at a tailored risk-based monitoring (RBM) program. Here, such a RBM program was developed for the largest Dutch water utility, mostly using groundwater as a source. Data from target analyses and high-resolution mass spectrometry-based suspect screening was used to cluster the different source waters. Targets were prioritized based on (preliminary) drinking water guideline values or the threshold of toxicological concern. Suspects were prioritized for further identity confirmation based on semi-quantitative occurrence concentrations combined with in vitro toxicity information. Finally, a RBM program was suggested for each cluster of source waters.ResultsOut of 731 target chemicals, 153 were detected at least once over a 5-year period. Roughly 10% of the detected non-target screening features matched to suspects. 108 source waters were clustered into 7 clusters. Source waters with low numbers and concentrations of organic chemicals were located in areas with all land-use types, while clusters of source waters with higher numbers of chemicals were related to infiltrated surface water. For perfluorinated chemicals, 25 suspects matched features detected in source waters and 7 features detected in drinking water. For the target chemicals, simple treatment showed the lowest and sorption-based techniques relatively high removal efficiencies. The chemical composition of all drinking waters related to non-contaminated source waters. (Preliminary) guideline values were available for 45 of the retrieved target chemicals, and used for prioritization for monitoring frequencies. These chemicals individually posed no appreciable concern to human health. Suspects were prioritized for further identity confirmation based on semi-quantitative occurrence in produced water, detection frequencies and information on toxic potency. Once confirmed and assessed as relevant, the suspects could be added to target monitoring.ConclusionThis approach provided a feasible workflow for RBM of target chemicals for clusters of groundwater sources, connected to a feed of new relevant chemicals based on suspect screening.