Oral Toxicity Data Research Articles

Screening of repeated dose toxicity data in safety evaluation reports of cosmetic ingredients issued by the Scientific Committee on Consumer Safety between 2009 and 2019

A focal point in the safety evaluation of cosmetic ingredients includes oral repeated dose toxicity testing, which is intended to address the most complex human endpoints. Seven years after the full implementation of the animal testing ban for cosmetic ingredients in the EU, there are still no alternative methods available capable of fully replacing oral repeated dose toxicity testing. Until this issue is resolved, the development of new cosmetic ingredients remains seriously hampered. The present paper describes a thorough screening of the oral repeated dose toxicity data included in safety evaluation reports of cosmetic ingredients addressed in the Annexes of the Cosmetics Regulation (EC) No 1223/2009, issued by the Scientific Committee on Consumer Safety between 2009 and 2019. The liver and the haematological system were identified as the potentially most frequently affected organs upon oral administration of cosmetic ingredients to animals. Evaluation of altered biochemical, morphological, and histopathological parameters related to hepatotoxicity indicated that the most recurrent events are liver weight changes, elevated liver enzymes, and alterations in serum cholesterol and bilirubin levels. Combined listing of affected parameters associated with steatosis and cholestasis indicated the possible occurrence of cholestasis, provoked by a limited number of cosmetic ingredients. The most frequently affected parameters related to the haematological system were indicative of anaemia. An in-depth analysis allowed characterisation of both regenerative and non-regenerative anaemia, pointing to direct and indirect haematotoxicity, respectively. The results presented in this study call for prioritisation of research targeted towards the development of new approach methodologies fit for animal-free repeated dose toxicity evaluation of cosmetic ingredients.

Toxicity Assessment of SiO2 and TiO2 in Normal Colon Cells, In Vivo and in Human Colon Organoids.

We conducted systemic assessments on the toxicity of silicon dioxide (SiO2) and titanium dioxide (TiO2) nanoparticles using different forms of normal colon cells (CCD-18Co), in vivo and in human colon organoids. The in vivo acute oral toxicity data showed that the LD50 values are greater than 2000 mg/kg for both the SiO2 and TiO2 nanoparticles; however, the SiO2 and TiO2 nanoparticles induced cytotoxicity in two-dimensional CCD-18Co cells and three-dimensional CCD-18Co spheroids and human colon organoids, with IC50 values of 0.6, 0.8 and 0.3 mM for SiO2 and 2.5, 1.1 and 12.5 mM for TiO2 nanoparticles, respectively. The data suggest that, when SiO2 and TiO2 are in nanoparticle form, cytotoxicity is induced; thus, care should be taken with these materials.

Acute Oral Toxicity and Anti-inflammatory and Analgesic Effects of Aqueous and Methanolic Stem Bark Extracts of Piliostigma thonningii (Schumach.).

Inflammation and pain are devastating conditions characterizing many diseases. Their manifestation ranges from mild body discomfort, to a debilitating experience, which may culminate in organ failure or death. In conventional medicine, corticosteroids, nonsteroidal anti-inflammatory drugs, opioids, and adjuvants are utilized to manage symptoms related to pain and inflammation. Despite their reported successes, these agents are only palliative, debatably inaccessible, unaffordable, and cause many undesirable side effects. As a result, the search for alternative and complementary therapies is warranted. Medicinal plants have been intensively utilized by humans for a long time to treat various ailments. In spite of their reported efficacies, empirical scientific data supporting their healing claims is scanty. P. thonningii (Schumach.) has been used in African traditional medicine, especially by traditional herbalists in Nigeria and Kenya, to treat conditions associated with inflammation. Even though analgesic, anti-inflammatory, and toxicity studies have been performed on leaf extracts, and some of their isolated compounds in Nigeria, there is scanty data supporting the use of stem bark extracts, which are commonly utilized in Kenya for pain, and inflammation management. Moreover, scientific data regarding safety and toxicity of the stem bark extracts of P. thonningii utilized in Kenya by traditional herbalists are inadequate. Based on this background, acute oral toxicity evaluation of the aqueous and methanolic stem bark extracts of P. thonningii, in Swiss albino mice, was performed according to the OECD/OCDE (2008) guidelines. Anti-inflammatory activities were investigated using the xylene-induced ear oedema in mice, whereas analgesic activities were examined following the acetic acid-induced writhing technique. The acute oral toxicity data was analyzed, and interpreted according to the OECDE (2008) guidelines. Anti-inflammatory and analgesic activities data were tabulated on MS Excel, and exported to GraphPad Prism (v8.3). Descriptive statistics were computed, and expressed as mean ± SEM. Thereafter, One-Way ANOVA followed by Tukey's test was performed. p < 0.05 was considered statistically significant. All the studied plant extracts had LD50 values > 2000 mg/kg bw, and were hence deemed to be nontoxic according to OECD/OCDE document no. 425. The results showed that the acetic acid-induced writhing frequency in mice administered the aqueous stem bark extract of P. thonningii, at a dose of 500 mg/kg bw, was not significantly different from that recorded for mice which received the reference drug (acetylsalicylic acid 75 mg) (p > 0.05). Additionally, at all the studied extract doses, significantly lower acetic acid-induced writhing frequencies were recorded in mice that received the aqueous stem bark extract of P. thonningii, compared with the writhing frequencies in mice that received the methanolic extract of the same plant (p < 0.05). On the other hand, the aqueous stem bark extract of P. thonningii, at doses of 100 mg/kg bw and 500 mg/kg bw, and the methanolic stem bark extract of the same plant, at a dose level of 500 mg/kg bw, exhibited significantly higher percentage inhibitions of xylene-induced oedema than the percentage inhibitions shown by the reference drug (dexamethasone 1 mg/kg bw) (p < 0.05). Generally, the aqueous stem bark extract of P. thonningii, at all the studied dose levels, caused significantly higher inhibitions of xylene-induced ear oedema in mice, compared with the percentage inhibitions shown by methanolic stem bark (p < 0.05). Therefore, the aqueous, and methanolic stem bark extracts of P. thonningii, grown in Kenya, possess peripheral analgesic and anti-inflammatory activities in Swiss albino mice. Hence, they have a potential of offering safe analgesic, and anti-inflammatory compounds. Further studies aimed at isolating, elucidating, and characterizing bioactive components from the studied extracts are recommended. Moreover, specific mode(s) through which these extracts exert the reported bioactivities should be established. Further toxicological investigations involving the studied plant extracts are encouraged to fully establish their safety.

SAR and QSAR modeling of a large collection of LD50 rat acute oral toxicity data

The median lethal dose for rodent oral acute toxicity (LD50) is a standard piece of information required to categorize chemicals in terms of the potential hazard posed to human health after acute exposure. The exclusive use of in vivo testing is limited by the time and costs required for performing experiments and by the need to sacrifice a number of animals. (Quantitative) structure–activity relationships [(Q)SAR] proved a valid alternative to reduce and assist in vivo assays for assessing acute toxicological hazard. In the framework of a new international collaborative project, the NTP Interagency Center for the Evaluation of Alternative Toxicological Methods and the U.S. Environmental Protection Agency’s National Center for Computational Toxicology compiled a large database of rat acute oral LD50 data, with the aim of supporting the development of new computational models for predicting five regulatory relevant acute toxicity endpoints. In this article, a series of regression and classification computational models were developed by employing different statistical and knowledge-based methodologies. External validation was performed to demonstrate the real-life predictability of models. Integrated modeling was then applied to improve performance of single models. Statistical results confirmed the relevance of developed models in regulatory frameworks, and confirmed the effectiveness of integrated modeling. The best integrated strategies reached RMSEs lower than 0.50 and the best classification models reached balanced accuracies over 0.70 for multi-class and over 0.80 for binary endpoints. Computed predictions will be hosted on the EPA’s Chemistry Dashboard and made freely available to the scientific community.

Transitioning the generalised read-across approach (GenRA) to quantitative predictions: A case study using acute oral toxicity data

Read-across approaches continue to evolve as does their utility in the field of risk assessment. Previously we presented our generalised read-across (GenRA) approach (Shah et al., 2016), which utilises chemical descriptor and/or in vitro bioactivity data to make read-across predictions on the basis of the similarity weighted average of nearest neighbours. The current public version of GenRA predicts 574 apical outcomes as a binary call from repeat dose toxicity studies available in ToxRefDB (Helman et al., 2019). Here we investigated the application of GenRA to quantitative values, specifically using a large dataset of rat oral acute LD50 toxicity data (LD50 values for 7011 discrete chemicals) that had been collected under the auspices of the ICCVAM acute toxicity workgroup (ATWG). GenRA LD50 predictions were made based on the following criteria – chemicals were characterised by Morgan chemical fingerprints with a minimum similarity threshold of 0.5 and a maximum of 10 nearest neighbours over the entire dataset. An R2 value of 0.61 and RMSE of 0.58 was achieved based on these parameters. Monte Carlo cross validation was then used to estimate confidence in the R2. Cross validated R2 values were found to fall in the range of 0.47–0.62. However, when evaluating GenRA locally to clusters of mechanistically or structurally-similar chemicals, average R2 values improved up to 0.91. GenRA can be extended to make reasonable quantitative predictions of acute oral rodent toxicity with improved performance exhibited for specific local domains.

Using a hybrid read-across method to evaluate chemical toxicity based on chemical structure and biological data

Read-across has become a primary approach to fill data gaps for chemical safety assessments. Chemical similarity based on structure, reactivity, and physic-chemical property information is a traditional approach applied for read-across toxicity studies. However, toxicity mechanisms are usually complicated in a biological system, so only using chemical similarity to perform the read-across for new compounds was not satisfactory for most toxicity endpoints, especially when the chemically similar compounds show dissimilar toxicities.This study aims to develop an enhanced read-across method for chemical toxicity predictions. To this end, we used two large toxicity datasets for read-across purposes. One consists of 3979 compounds with Ames mutagenicity data, and the other contains 7332 compounds with rat acute oral toxicity data. First, biological data for all compounds in these two datasets were obtained by querying thousands of PubChem bioassays. The PubChem bioassays with at least five compounds from either of these two datasets showing active responses were selected to generate comprehensive bioprofiles. The read-across studies were performed by using chemical similarity search only and also by using a hybrid similarity search based on both chemical descriptors and bioprofiles. Compared to traditional read-across based on chemical similarity, the hybrid read-across approach showed improved accuracy of predictions for both Ames mutagenicity and acute oral toxicity. Furthermore, we could illustrate potential toxicity mechanisms by analyzing the bioprofiles used for this hybrid read-across study. The results of this study indicate that the new hybrid read-across approach could be an applicable computational tool for chemical toxicity predictions. In this way, the bottleneck of traditional read-across studies can be overcome by introducing public biological data into the traditional process. The incorporation of bioprofiles generated from the additional biological data for compounds can partially solve the “activity cliff” issue and reveal their potential toxicity mechanisms. This study leads to a promising direction to utilize data-driven approaches for computational toxicology studies in the big data era.

Nonanimal Models for Acute Toxicity Evaluations: Applying Data-Driven Profiling and Read-Across.

Background:Low-cost, high-throughput in vitro bioassays have potential as alternatives to animal models for toxicity testing. However, incorporating in vitro bioassays into chemical toxicity evaluations such as read-across requires significant data curation and analysis based on knowledge of relevant toxicity mechanisms, lowering the enthusiasm of using the massive amount of unstructured public data.Objective:We aimed to develop a computational method to automatically extract useful bioassay data from a public repository (i.e., PubChem) and assess its ability to predict animal toxicity using a novel bioprofile-based read-across approach.Methods:A training database containing 7,385 compounds with diverse rat acute oral toxicity data was searched against PubChem to establish in vitro bioprofiles. Using a novel subspace clustering algorithm, bioassay groups that may inform on relevant toxicity mechanisms underlying acute oral toxicity were identified. These bioassays groups were used to predict animal acute oral toxicity using read-across through a cross-validation process. Finally, an external test set of over 600 new compounds was used to validate the resulting model predictivity.Results:Several bioassay clusters showed high predictivity for acute oral toxicity (positive prediction rates range from 62–100%) through cross-validation. After incorporating individual clusters into an ensemble model, chemical toxicants in the external test set were evaluated for putative acute toxicity (positive prediction rate equal to 76%). Additionally, chemical fragment–in vitro–in vivo relationships were identified to illustrate new animal toxicity mechanisms.Conclusions:The in vitro bioassay data-driven profiling strategy developed in this study meets the urgent needs of computational toxicology in the current big data era and can be extended to develop predictive models for other complex toxicity end points. https://doi.org/10.1289/EHP3614

A case study on the application of an expert-driven read-across approach in support of quantitative risk assessment of p,p’-dichlorodiphenyldichloroethane

Deriving human health risk estimates for environmental chemicals has traditionally relied on in vivo toxicity databases to characterize potential adverse health effects and associated dose-response relationships. In the absence of in vivo toxicity information, new approach methods (NAMs) such as read-across have the potential to fill the required data gaps. This case study applied an expert-driven read-across approach to identify and evaluate analogues to fill non-cancer oral toxicity data gaps for p,p’-dichlorodiphenyldichloroethane (p,p’-DDD), an organochlorine contaminant known to occur at contaminated sites in the U.S. The source analogue p,p’-dichlorodiphenyltrichloroethane (DDT) and its no-observed-adverse-effect level of 0.05 mg/kg-day were proposed for the derivation of screening-level health reference values for the target chemical, p,p’-DDD. Among the primary similarity contexts (structure, toxicokinetics, and toxicodynamics), toxicokinetic considerations were instrumental in separating p,p’-DDT as the best source analogue from other potential candidates (p,p’-DDE and methoxychlor). In vitro high-throughput screening (HTS) assays from ToxCast were used to evaluate similarity in bioactivity profiles and make inferences toward plausible mechanisms of toxicity to build confidence in the read-across approach. This work demonstrated the value of NAMs such as read-across and in vitro HTS in human health risk assessment of environmental contaminants with the potential to inform regulatory decision-making.

QSAR and Classification Study on Prediction of Acute Oral Toxicity of N-Nitroso Compounds.

To better understand the mechanism of in vivo toxicity of N-nitroso compounds (NNCs), the toxicity data of 80 NNCs related to their rat acute oral toxicity data (50% lethal dose concentration, LD50) were used to establish quantitative structure-activity relationship (QSAR) and classification models. Quantum chemistry methods calculated descriptors and Dragon descriptors were combined to describe the molecular information of all compounds. Genetic algorithm (GA) and multiple linear regression (MLR) analyses were combined to develop QSAR models. Fingerprints and machine learning methods were used to establish classification models. The quality and predictive performance of all established models were evaluated by internal and external validation techniques. The best GA-MLR-based QSAR model containing eight molecular descriptors was obtained with Q2loo = 0.7533, R2 = 0.8071, Q2ext = 0.7041 and R2ext = 0.7195. The results derived from QSAR studies showed that the acute oral toxicity of NNCs mainly depends on three factors, namely, the polarizability, the ionization potential (IP) and the presence/absence and frequency of C–O bond. For classification studies, the best model was obtained using the MACCS keys fingerprint combined with artificial neural network (ANN) algorithm. The classification models suggested that several representative substructures, including nitrile, hetero N nonbasic, alkylchloride and amine-containing fragments are main contributors for the high toxicity of NNCs. Overall, the developed QSAR and classification models of the rat acute oral toxicity of NNCs showed satisfying predictive abilities. The results provide an insight into the understanding of the toxicity mechanism of NNCs in vivo, which might be used for a preliminary assessment of NNCs toxicity to mammals.

Profiling Acute Oral and Inhalation Toxicity Data Using a Computational Workflow to Screen for Facile Chemical Reactivity

Abstract We are developing computational approaches for mechanisms of acute toxicity. Facile chemical reactivity involves formation of covalent adducts between electrophiles and nucleophiles and can be molecular initiating events for adverse outcome pathways. Using an open-source Konstanz Information Miner workflow, we developed a profiler to identify reactive moieties that covers five chemically facile-reactive classes: (1) Michael acceptors, (2) Schiff base formation, (3) acylation, (4) nucleophilic aromatic substitution, and (5) bimolecular nucleophilic substitution. We hypothesized that nonspecific chemical reactivity may be a more prominent molecular initiating event for high acute toxicity for inhalation compared to oral exposure routes because of ensuing respiratory irritation with pulmonary edema resulting in lethality. We tested this hypothesis by stratifying rodent acute oral and 4-hour inhalation toxicity databases (DBs) according to the globally harmonized system (GHS) classification and our p...

3-Nitro-1,2,4-triazol-5-one (2014).

3-Nitro-1,2,4-triazol-5-one (NTO) is a potential replacement for energetics in military munitions. It is a component of IMX-101, a munition designed to prevent unintentional detonation. This report summarizes the dermal, oral, and inhalation animal toxicity data, including the results of genotoxicity and limited reproductive and developmental studies. NTO has an acute LD50 in rats and mice of >5000 mg/kg, is a potential eye and skin irritant, but does not induce skin sensitization. Acute inhalation toxicity studies in rats were negative, but testicular hypoplasia was observed in a 14-day oral study in rats administered NTO at >500 mg/kg/day. Similar findings were noted in an oral 90-day study at dosages >315 mg/kg/day and in reproductive toxicity studies at >125 mg/kg/day. NTO did not cause any developmental defects. All genotoxicity studies were negative. ADME and pharmacokinetics data showed rapid uptake and elimination of NTO from both inhalation and oral intakes. Biotransformation by liver microsomes demonstrated two separate pathways, one aerobic and the other anaerobic. NTO is not considered an endocrine disruptor. There is very little human data regarding NTO or the IMX-101 mixtures. Using testicular changes in rats as the point of departure for deriving a Workplace Environmental Exposure Level (WEEL) for NTO, the resulting BMDL10 was 40 mg/kg/day, and the 8-hour time-weighted average was 2 mg/m2.

Toxic equivalency factors (TEFs) after acute oral exposure of azaspiracid 1, −2 and −3 in mice

Azaspiracids (AZAs) are marine algal toxins that can be accumulated by edible shellfish to cause a foodborne gastrointestinal poisoning in humans. In the European Union, only AZA1, −2 and −3 are currently regulated and their concentration in shellfish is determined through their toxic equivalency factors (TEFs) derived from the intraperitoneal lethal potency in mice. Nevertheless, considering the potential human exposure by oral route, AZAs TEFs should be calculated by comparative oral toxicity data. Thus, the acute oral toxicity of AZA1, −2 and −3 was investigated in female CD-1 mice treated with different doses (AZA1: 135–1100μg/kg; AZA2 and AZA3: 300–1100μg/kg) and sacrificed after 24h or 14days. TEFs derived from the median lethal doses (LD50) were 1.0, 0.7 and 0.5, respectively for AZA1, −2 and −3. In fact, after 24h from gavage administration, LD50s were 443μg/kg (AZA1; 95% CL: 350−561μg/kg), 626μg/kg (AZA2; 95% CL: 430−911μg/kg) and 875μg/kg (AZA3; 95% CL: 757−1010μg/kg). Mice dead more than 5h after the treatment or those sacrificed after 24h (doses: ≥175μg AZA1/kg, ≥500μg AZA2/kg and ≥600μg AZA3/kg) showed enlarged pale liver, while increased serum markers of liver alteration were recorded even at the lowest doses. Blood chemistry revealed significantly increased serum levels of K+ ions (≥500mg/kg), whereas light microscopy showed tissue changes in the gastrointestinal tract, liver and spleen. No lethality, macroscopic, tissue or haematological changes were recorded two weeks post exposure, indicating reversible toxic effects. LC–MS/MS analysis of the main organs showed a dose-dependency in gastrointestinal absorption of these toxins: at 24h, the highest levels were detected in the stomach and, in descending order, in the intestinal content, liver, small intestine, kidneys, lungs, large intestine, heart as well as detectable traces in the brain. After 14days, AZA1 and AZA2 were still detectable in almost all the organs and intestinal content.

Read-across for rat oral gavage repeated-dose toxicity for short-chain mono-alkylphenols: A case study

Short-chain mono-alkylphenols provide an example of where a category-approach to read-across may be used to estimate the repeated-dose endpoint for a number of derivatives. Specifically, the NOAELs of 50mg/kgbw/d for mono-methylphenols based on a LOAEL of very low systemic toxicity can be read across with confidence to untested mono-alkylphenols in the category. These simple alkylphenols are non-reactive and exhibit an unspecific, reversible polar narcosis mode of toxic action. Briefly, polar narcotics act via unspecific, reversible interactions with biological membranes in a manner similar to cataleptic anaesthetics. The read-across premise includes rapid and complete absorption via the gastrointestinal tract, distribution in the circulatory system, first-pass phase II metabolism in the liver and elimination of sulphates and glucuronides in the urine. Thus, toxicokinetic parameters are considered to be similar and have the same toxicological significance. Six analogues have high quality experimental oral repeated-dose toxicity data (i.e., OECD TG 408 or OECD TG 422). These repeated-dose toxicity test results exhibit qualitative consistency in symptoms. Typical findings include decreased body weight and slightly increased liver and kidney weights which are generally without concurrent histopathological effects. The sub-chronic findings are quantitatively consistent with the No Observed Adverse Effect Level (NOAEL) of ≥50mg/kgbw/d.Chemical similarity between the analogues is readily defined and data uncertainty associated with the similarities in toxicokinetic properties, as well as toxicodynamic properties, are low. Uncertainty associated with mechanistic relevance and completeness of the read-across is low-to-moderate, largely because there is no adverse outcome pathway or intermediate event data. Uncertainty associated with mechanistic relevance and completeness of the read-across is reduced by the concordance of in vivo, in vitro, US EPA toxicity forecaster (ToxCast) results, as well as in silico data. The rat oral repeated-dose NOAEL values for the source substances can be read across to fill the data gaps of the untested analogues in this category with uncertainty deemed equivalent to results from a TG 408 assessment.

Derivation of an oral toxicity reference value for nickel

Nickel (Ni) is in the earth's crust and can be found in environmental compartments such as water, soil, and air, as well as food. This paper presents an assessment of the oral nickel toxicity data in support of non-cancer health-based oral exposure limits or toxicity reference values (TRVs). This paper derives TRVs for three populations of interest: adults, toddlers, and people who have been dermally sensitized to nickel. The adult/lifetime TRV of 20 μg Ni/kg-day is based on post-implantation loss/perinatal mortality in a 2-generation reproductive study in rats. Several recent assessments by regulatory agencies have used the same study and endpoint, but the dose-response modeling conducted here was more appropriate for the study design. Toxicokinetic data from rats and humans indicate that the applied uncertainty factors are very conservative. Because the endpoint relates to fetal exposure and is not relevant to toddlers, a toddler TRV was derived based on decreased body weight in young rats; this TRV was also 20 μg Ni/kg-day. A separate TRV of 4 μg Ni/kg in addition to Ni in food was derived for protection of nickel-sensitized populations from flare-up of dermatitis, based on studies of single exposures in humans under conditions that maximize oral absorption.

The margin of internal exposure (MOIE) concept for dermal risk assessment based on oral toxicity data – A case study with caffeine

Route-to-route extrapolation is a common part of human risk assessment. Data from oral animal toxicity studies are commonly used to assess the safety of various but specific human dermal exposure scenarios. Using theoretical examples of various user scenarios, it was concluded that delineation of a generally applicable human dermal limit value is not a practicable approach, due to the wide variety of possible human exposure scenarios, including its consequences for internal exposure. This paper uses physiologically based kinetic (PBK) modelling approaches to predict animal as well as human internal exposure dose metrics and for the first time, introduces the concept of Margin of Internal Exposure (MOIE) based on these internal dose metrics. Caffeine was chosen to illustrate this approach. It is a substance that is often found in cosmetics and for which oral repeated dose toxicity data were available. A rat PBK model was constructed in order to convert the oral NOAEL to rat internal exposure dose metrics, i.e. the area under the curve (AUC) and the maximum concentration (Cmax), both in plasma. A human oral PBK model was constructed and calibrated using human volunteer data and adapted to accommodate dermal absorption following human dermal exposure. Use of the MOIE approach based on internal dose metrics predictions provides excellent opportunities to investigate the consequences of variations in human dermal exposure scenarios. It can accommodate within-day variation in plasma concentrations and is scientifically more robust than assuming just an exposure in mg/kg bw/day.

Read-across of 90-day rat oral repeated-dose toxicity: A case study for selected n-alkanols

n-Alkanols provide an excellent example where a category-approach to read-across may be used to estimate the repeated-dose endpoint for a number of untested derivatives (target chemicals) using experimental data for tested derivatives (source chemicals). n-Alkanols are non-reactive and exhibit the unspecific, reversible simple anaesthesia or non-polar narcosis mode of toxic action in that the metabolic products of the parent alcohols do not contribute to the toxic endpoint evaluated. In this case study, the chemical category is limited to the readily bioavailable (C5–C13) analogues. The toxicokinetic premise includes rapid absorption via the gastrointestinal tract, distribution in the circulatory system, and first-pass metabolism in the liver resulting in metabolism via oxidation to CO2 and with minor elimination of oxidative intermediate as glucuronides. Two analogues have experimental 90-day oral repeated-dose toxicity data which exhibit qualitative and quantitative consistency. Typical findings include decreased body weight, slightly increased liver weight which, in some cases, is accompanied by clinical chemical and haematological changes but generally without concurrent histopathological effects at the Lowest Observed Effect Level (LOEL). Chemical similarity between the analogues is readily defined by a variety of structure-related properties; data uncertainty associated with toxicokinetic and toxicodynamic similarities is low. Uncertainty associated with mechanistic relevance and completeness of the read-across is reduced by the concordance of in vivo and in vitro results, as well as high throughput and in silico methods data. As shown in detail, the 90-day oral repeated-dose toxicity No Observed Effect Level (NOEL) value of 1000mg/kgbw/d for 1-pentanol and 1-hexanol based on a LOEL of very low systemic toxicity can be read across to fill the data gaps of the untested analogues in this category with acceptable uncertainty.

Acute Oral Toxicity of Tetrodotoxin in Mice: Determination of Lethal Dose 50 (LD50) and No Observed Adverse Effect Level (NOAEL)

Tetrodotoxin (TTX) is starting to appear in molluscs from the European waters and is a hazard to seafood consumers. This toxin blocks sodium channels resulting in neuromuscular paralysis and even death. As a part of the risk assessment process leading to a safe seafood level for TTX, oral toxicity data are required. In this study, a 4-level Up and Down Procedure was designed in order to determine for the first time the oral lethal dose 50 (LD50) and the No Observed Adverse Effect Level (NOAEL) in mice by using an accurate well-characterized TTX standard.

Salting the Earth: The Environmental Impact of Oil and Gas Wastewater Spills.

Salting the Earth: The Environmental Impact of Oil and Gas Wastewater Spills.

Acute oral toxicity of chemicals in terrestrial life stages of amphibians: Comparisons to birds and mammals

Amphibians are currently the most threatened and rapidly declining group of vertebrates and this has raised concerns about their potential sensitivity and exposure to plant protection products and other chemicals. Current environmental risk assessment procedures rely on surrogate species (e.g. fish and birds) to cover the risk to aquatic and terrestrial life stages of amphibians, respectively. Whilst a recent meta-analysis has shown that in most cases amphibian aquatic life stages are less sensitive to chemicals than fish, little research has been conducted on the comparative sensitivity of terrestrial amphibian life stages. Therefore, in this paper we address the questions “What is the relative sensitivity of terrestrial amphibian life stages to acute chemical oral exposure when compared with mammals and birds?” and “Are there correlations between oral toxicity data for amphibians and data for mammals or birds?” Identifying a relationship between these data may help to avoid additional vertebrate testing. Acute oral amphibian toxicity data collected from the scientific literature and ecotoxicological databases were compared with toxicity data for mammals and birds. Toxicity data for terrestrial amphibian life stages are generally sparse, as noted in previous reviews. Single-dose oral toxicity data for terrestrial amphibian life stages were available for 26 chemicals and these were positively correlated with LD50 values for mammals, while no correlation was found for birds. Further, the data suggest that oral toxicity to terrestrial amphibian life stages is similar to or lower than that for mammals and birds, with a few exceptions. Thus, mammals or birds are considered adequate toxicity surrogates for use in the assessment of the oral exposure route in amphibians. However, there is a need for further data on a wider range of chemicals to explore the wider applicability of the current analyses and recommendations.

Analysis of public oral toxicity data from REACH registrations 2008-2014.

SummaryThe European Chemicals Agency, ECHA, made available a total of 13,832 oral toxicity studies for 8,568 substances up to December 2014. 75% of studies were from the retired OECD Test Guideline 401 (11% TG 420, 11% TG 423 and 1.5% TG 425). Concordance across guidelines, evaluated by comparing LD50 values ≥ 2,000 or < 2,000 mg/ kg bodyweight from chemicals tested multiple times between different guidelines, was at least 75% and for their own repetition more than 90%.In 2009, Bulgheroni et al. created a simple model for predicting acute oral toxicity using no observed adverse effect levels (NOAEL) from 28-day repeated dose toxicity studies in rats. This was reproduced here for 1,625 substances. In 2014, Taylor et al. suggested no added value of the 90-day repeated dose oral toxicity test given the availability of a low 28-day study with some constraints. We confirm that the 28-day NOAEL is predictive (albeit imperfectly) of 90-day NOAELs, however, the suggested constraints did not affect predictivity.1,059 substances with acute oral toxicity data (268 positives, 791 negatives, all Klimisch score 1) were used for modeling: The Chemical Development Kit was used to generate 27 molecular descriptors and a similarity-informed multilayer perceptron showing 71% sensitivity and 72% specificity. Additionally, the k-nearest neighbors (KNN) algorithm indicated that similarity-based approaches alone may be poor predictors of acute oral toxicity, but can be used to inform the multilayer perceptron model, where this was the feature with the highest information value.